CN117567457A - 噻唑酮亚砜和砜类化合物及其制备方法和应用 - Google Patents
噻唑酮亚砜和砜类化合物及其制备方法和应用 Download PDFInfo
- Publication number
- CN117567457A CN117567457A CN202311503289.4A CN202311503289A CN117567457A CN 117567457 A CN117567457 A CN 117567457A CN 202311503289 A CN202311503289 A CN 202311503289A CN 117567457 A CN117567457 A CN 117567457A
- Authority
- CN
- China
- Prior art keywords
- compound
- alkyl
- nmr
- cdcl
- compounds
- 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.)
- Pending
Links
- -1 Thiazolone sulfoxide Chemical class 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 104
- 201000008968 osteosarcoma Diseases 0.000 claims abstract description 26
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 10
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 10
- 201000005202 lung cancer Diseases 0.000 claims abstract description 10
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 10
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims abstract description 5
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 4
- 210000004027 cell Anatomy 0.000 claims description 44
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 150000003462 sulfoxides Chemical class 0.000 claims description 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- 210000004881 tumor cell Anatomy 0.000 claims description 6
- VZUNGTLZRAYYDE-UHFFFAOYSA-N N-methyl-N'-nitro-N-nitrosoguanidine Chemical compound O=NN(C)C(=N)N[N+]([O-])=O VZUNGTLZRAYYDE-UHFFFAOYSA-N 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 208000029742 colonic neoplasm Diseases 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 238000003786 synthesis reaction Methods 0.000 claims description 5
- 125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- 238000005580 one pot reaction Methods 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 230000035755 proliferation Effects 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 3
- 206010027476 Metastases Diseases 0.000 claims description 3
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000009401 metastasis Effects 0.000 claims description 3
- 238000013508 migration Methods 0.000 claims description 3
- 230000005012 migration Effects 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- MZSAMHOCTRNOIZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylaniline Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(NC2=CC=CC=C2)C=CC=1 MZSAMHOCTRNOIZ-UHFFFAOYSA-N 0.000 claims description 2
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 claims description 2
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 claims description 2
- 239000000443 aerosol Substances 0.000 claims description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 2
- 230000006907 apoptotic process Effects 0.000 claims description 2
- 125000005605 benzo group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000006071 cream Substances 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 2
- 239000012530 fluid Substances 0.000 claims description 2
- 239000000499 gel Substances 0.000 claims description 2
- 230000012010 growth Effects 0.000 claims description 2
- 230000008595 infiltration Effects 0.000 claims description 2
- 238000001764 infiltration Methods 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 150000004702 methyl esters Chemical class 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 230000001737 promoting effect Effects 0.000 claims description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 4
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 10
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 238000001727 in vivo Methods 0.000 abstract description 2
- 230000004783 oxidative metabolism Effects 0.000 abstract description 2
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- 229940041181 antineoplastic drug Drugs 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 18
- 230000000694 effects Effects 0.000 description 15
- 125000004432 carbon atom Chemical group C* 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- 239000002609 medium Substances 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 238000004809 thin layer chromatography Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 229930182555 Penicillin Natural products 0.000 description 9
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000004113 cell culture Methods 0.000 description 9
- 239000006285 cell suspension Substances 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- 229940049954 penicillin Drugs 0.000 description 9
- 229960005322 streptomycin Drugs 0.000 description 9
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 229940125782 compound 2 Drugs 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 229940125904 compound 1 Drugs 0.000 description 7
- 239000012091 fetal bovine serum Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 229940126214 compound 3 Drugs 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- IHDKBHLTKNUCCW-UHFFFAOYSA-N 1,3-thiazole 1-oxide Chemical compound O=S1C=CN=C1 IHDKBHLTKNUCCW-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 238000011068 loading method Methods 0.000 description 5
- 230000002503 metabolic effect Effects 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- 230000000171 quenching effect Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 150000003457 sulfones Chemical class 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- AGNFWIZBEATIAK-UHFFFAOYSA-N 4-phenylbutylamine Chemical compound NCCCCC1=CC=CC=C1 AGNFWIZBEATIAK-UHFFFAOYSA-N 0.000 description 2
- VWIOMFMPIVMLIR-UHFFFAOYSA-N 6-methoxycarbonylpyridine-2-carboxylic acid Chemical compound COC(=O)C1=CC=CC(C(O)=O)=N1 VWIOMFMPIVMLIR-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- SNQQJEJPJMXYTR-UHFFFAOYSA-N dimethyl pyridine-2,6-dicarboxylate Chemical compound COC(=O)C1=CC=CC(C(=O)OC)=N1 SNQQJEJPJMXYTR-UHFFFAOYSA-N 0.000 description 2
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000001415 gene therapy Methods 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- QQVIHTHCMHWDBS-UHFFFAOYSA-N isophthalic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000011859 microparticle Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 2
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 2
- 238000007738 vacuum evaporation Methods 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 1
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 1
- KEIFWROAQVVDBN-UHFFFAOYSA-N 1,2-dihydronaphthalene Chemical compound C1=CC=C2C=CCCC2=C1 KEIFWROAQVVDBN-UHFFFAOYSA-N 0.000 description 1
- UXFWTIGUWHJKDD-UHFFFAOYSA-N 2-(4-bromobutyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCCCBr)C(=O)C2=C1 UXFWTIGUWHJKDD-UHFFFAOYSA-N 0.000 description 1
- UHDNUPHSDMOGCR-UHFFFAOYSA-N 3-Formylbenzoic acid Chemical compound OC(=O)C1=CC=CC(C=O)=C1 UHDNUPHSDMOGCR-UHFFFAOYSA-N 0.000 description 1
- MTJGVAJYTOXFJH-UHFFFAOYSA-N 3-aminonaphthalene-1,5-disulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C2=CC(N)=CC(S(O)(=O)=O)=C21 MTJGVAJYTOXFJH-UHFFFAOYSA-N 0.000 description 1
- HNAYRVKSWGSQTP-UHFFFAOYSA-N 3-methoxypyridin-2-amine Chemical compound COC1=CC=CN=C1N HNAYRVKSWGSQTP-UHFFFAOYSA-N 0.000 description 1
- ORLGLBZRQYOWNA-UHFFFAOYSA-N 4-methylpyridin-2-amine Chemical compound CC1=CC=NC(N)=C1 ORLGLBZRQYOWNA-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000011226 adjuvant chemotherapy Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- SXGBREZGMJVYRL-UHFFFAOYSA-N butan-1-amine;hydrobromide Chemical compound [Br-].CCCC[NH3+] SXGBREZGMJVYRL-UHFFFAOYSA-N 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 208000011654 childhood malignant neoplasm Diseases 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 238000009096 combination chemotherapy Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- VNGOYPQMJFJDLV-UHFFFAOYSA-N dimethyl benzene-1,3-dicarboxylate Chemical compound COC(=O)C1=CC=CC(C(=O)OC)=C1 VNGOYPQMJFJDLV-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 230000009982 effect on human Effects 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000000622 irritating effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000001853 liver microsome Anatomy 0.000 description 1
- NIXOIRLDFIPNLJ-UHFFFAOYSA-M magnesium;benzene;bromide Chemical compound [Mg+2].[Br-].C1=CC=[C-]C=C1 NIXOIRLDFIPNLJ-UHFFFAOYSA-M 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- PHVXTQIROLEEDB-UHFFFAOYSA-N n-[2-(2-chlorophenyl)ethyl]-4-[[3-(2-methylphenyl)piperidin-1-yl]methyl]-n-pyrrolidin-3-ylbenzamide Chemical compound CC1=CC=CC=C1C1CN(CC=2C=CC(=CC=2)C(=O)N(CCC=2C(=CC=CC=2)Cl)C2CNCC2)CCC1 PHVXTQIROLEEDB-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 description 1
- 229960000572 olaparib Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D277/34—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
本发明属于药物化学领域，具体涉及噻唑酮亚砜和砜类化合物及其制备方法和应用，该类化合物或者组合物可用于治疗骨肉瘤，结直肠癌，肺癌以及乳腺癌等相关疾病。本发明制备得到的化合物在体内减少氧化代谢，有发展成为更好抗肿瘤药物的潜力。
Description
技术领域
本发明属于药物化学领域，具体涉及噻唑酮亚砜和砜类化合物及其制备方法和应用。
背景技术
骨肉瘤是来源于间充质细胞的最常见和最严重的原发性恶性骨肿瘤，在青少年中发病率很高。骨肉瘤是第三大最常见的儿童癌症，全球每年发病率为每百万儿童2-4例。其癌症死亡率在儿童和青少年中排名第二。20世纪70年代之前，随着医学和药学的发展，已有多种方法，包括放疗、化疗、基因治疗、种免疫治疗、或结合手术治疗等，但这些方法并没有显著改善患者的预后和生存率。目前，骨肉瘤的标准治疗方法包括手术切除和联合化疗，化疗主要包括阿霉素、顺铂、甲氨蝶呤和环磷酰胺。尽管通过应用高剂量化疗药物或化疗药物的组合和用药顺序，骨肉瘤患者的5年生存率已提高到60-70％，但在过去40年中，这一比例没有进一步提高，在肺转移患者中约为20％-30％的五年内生存率，由于缺乏关键驱动基因的鉴定，基因治疗药物，如奥拉帕尼、吉西他滨、多西他赛；免疫治疗药物，如米伐他汀、阿维珠单抗和帕博利珠单抗，效果并不比辅助化疗好。因此，开发小分子靶向抑制剂迫在眉睫。
现有技术报道了4种噻唑啉酮骨架类化合物，具有多种药理学活性，如化合物1具有抗菌和抗真菌活性，化合物2抗炎症活性具有抗癌活性，化合物3具有抗病毒/抗HIV活性化合物4具有抗癌活性等。
本申请人之前报道了噻唑酮的相关骨架对多种骨肉瘤细胞具有良好的抑制作用，但是没有报道噻唑酮的氧化产物，亚砜和砜具有相似的抑制活性。本发明人研究了噻唑酮亚砜和砜的产物，并合成得到了该类化合物，可能在体内减少氧化代谢，从而发展成为更好的骨肉瘤抑制剂。
发明内容
针对现有技术的不足，本发明提供一种噻唑酮亚砜和砜类化合物及其制备方法和应用。
本发明的技术方案如下：一方面，本发明提供如式I所示的化合物或其药学上可接受的盐：
其中Y选自Z选自N或CR6；X选自CH2、O、NH；n为0～5的整数；
R1选自6-10元芳基、9-10元苯并杂环基、C3-C6环烷基、Ph(CH2)m-或5-10元杂芳基；所述6-10元芳基、9-10元苯并杂环基、C3-C6环烷基、Ph(CH2)m-或5-10元杂芳基任选地被一个或多个R7取代；其中m为1-3的整数；
R2、R6和R7独立地选自H、氰基、卤素、NO2、羟基、-NR8R9、C1-C6烷基、(C1-C6烷基)-O-、(C1-C6烷基)-S-、(C1-C6烷基)-C(O)-、PhC(O)-、(C1-C6烷基)-OC(O)-、R8R9NC(O)-、C2-C6烯基、C2-C6炔基、C3-C6环烷基、C3-C6环烯基、6-10元芳基、3-10元杂环烷基或5-10元杂芳基；其中所述C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、C3-C6环烯基、6-10元芳基、3-10元杂环烷基或5-10元杂芳基任选地被H、卤素、氰基、羟基、-NR8R9、NO2、C1-C3烷基、C1-C3烷氧基或卤代C1-C3烷基取代；
R3选自H、羟基、6-10元芳基、5-10元杂芳基、(C1-C6烷基)-O-、(C1-C6烷基)-OC(O)-、R8R9NC(O)-、PhC(O)-、Ph(CH2)qO-，其中q为1-3的整数；
R4和R5独立地选自H，C1-C6烷基；
R8和R9各自独立地选自H、苯基或C1-C6烷基。
在一些典型的实施方案中，Z选自N或CH。
在一些典型的实施方案中，n为0～2的整数。
在一些实施方案中，R1选自苯基、萘基、吡啶基、苯并[d][1,3]二恶唑基、环丙基、环己烷基、苄基、苯乙烷基、喹啉基、异恶唑基，上述基团任选地被一个或多个R7取代。
在一些典型的实施方案中，R1选自苯基、萘基、 上述基团任选地被一个或多个R7取代。
在一些实施方案中，所述R7选自H、C1-C6烷基、卤素、羟基、(C1-C6烷基)-O-或6-10元芳基。
在一些典型的实施方案中，所述R7选自H、CH3、F、OH、CH3O-、Cl或苯基。
在一些实施方案中，R2选自H、C2-C6炔基、(C1-C6烷基)-OC(O)-或6-10元芳基。
在一些典型的实施方案中，R2选自H、乙炔基、CH3OC(O)-或苯基。
在一些典型的实施方案中，R3选自H、羟基、苯基、CH3O-、(CH3)3CO-、
在一些典型的实施方案中，R4和R5选自H。
另一方面，本发明提供下列化合物或其药学上可接受的盐：
另一方面，本发明提供一种制备式I化合物的方法，包括但不限于以下合成方案：
合成方案1：
其中R1、R2、R3、R4、R5、X、Y、Z、n同式I化合物所定义。
化合物1-1在酸性条件下合成二甲酸甲酯类化合物，随后，在碱性条件下，单一水解一个酯基，得到化合物1-2；化合物1-2和化合物发生缩合，得到化合物1-3；化合物1-3经过还原甲酯得到相应的醇类化合物1-4，随后氧化得到醛类化合物1-5；化合物1-5、化合物R1NH2和化合物/>发生3组分一锅法的反应得到化合物1-6，化合物1-6在间氯过氧苯甲酸的作用下按条件氧化得到亚砜和砜类化合物1-7。
合成方案2：
其中R1、R2、R3、R4、R5、X、Y、Z、n同式I化合物所定义。
化合物1-1在酸性条件下合成二甲酸甲酯类化合物2-2，化合物2-2与硼氢化钠发生单一酯还原得到醇类化合物2-3；化合物2-3被IBX氧化得到化合物2-4，化合物2-4在经过在碱性条件下的水解得到化合物2-5，化合物2-5和化合物发生缩合，得到化合物2-6，化合物2-6、化合物R1NH2和化合物/>发生3组分一锅法的反应得到化合物2-7，化合物2-7在间氯过氧苯甲酸的作用下按条件氧化得到亚砜和砜类化合物2-8。
在一些实施方案中，本发明提供了一种药物组合物，其包含治疗有效量的式I化合物或其药学上可接受的盐和药学上可接受的载体。其中，所述药物组合物被配制成丸剂、胶囊剂、乳膏、凝胶剂、赋形剂、可注射流体、气雾剂、糖浆剂或透皮贴剂等。
本发明还提出了所述式I化合物或药学上可接受的盐，或药物组合物在制备预防和/或治疗肿瘤的药物中的应用。
其中，所述式I化合物用于抑制肿瘤细胞的增殖、生长、迁移、浸润、转移和复发，或促进肿瘤细胞的凋亡。
其中，所述肿瘤细胞为骨肉瘤细胞、人结肠癌细胞、肺癌细胞、乳腺癌等。所述骨肉瘤细胞包括SJSA-1、U2OS、HOS、MNNG/HOS、MG63、143b和SW1353；所述肺癌细胞包括A549；所述结直肠癌细胞包括HCT116。
相关定义
除非有特定说明，下列用在说明书和权利要求书中的术语具有下述含义：
本发明“化合物”可以是不对称的，例如，具有一个或多个手性中心。除非另有说明，本发明的“化合物”指的是任意一种立体异构体或两种以上的立体异构体的混合物。立体异构体包括但不限于对映异构体和非对映异构体。本发明的含有不对称碳原子的化合物可以以光学活性纯的形式或两种以上的立体异体的混合物的形式被分离得到。光学活性纯的形式可以从两种以上的立体异构体的混合物中进行拆分，或通过使用手性原料或手性试剂合成。
本发明“化合物”还包括互变异构体形式。互变异构体形式来源于一个单键与相邻的双键交换并一起伴随一个质子的迁移。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。
本文中的数字范围，是指给定范围中的各个整数。例如，“C1-C6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子；“C3-C6”是指该基团可具有3个碳原子、4个碳原子、5个碳原子或6个碳原子。
术语“元”是指组成环的骨架原子或原子团的数目。例如，“5-7元”是指组成环的骨架原子或原子团的数目为5个、6个或7个。因此，举例而言，吡啶、哌啶、哌嗪和苯为六元环，而噻吩、吡咯为五元环。
术语“被取代”是指特定基团上的任意一个或多个氢原子被取代基取代，只要特定基团的价态是正常的并且取代后的化合物是稳定的。例如，“被卤素取代”是指特定基团上的任意一个或多个氢原子被卤素取代，只要特定基团的价态是正常的并且取代后的化合物是稳定的。
术语“烷基”指饱和的脂族烃基团，包括直链的或支链的饱和烃基，所述烃基具有所示出的碳原子数。如术语“C1-C6烷基”包括C1烷基、C2烷基、C3烷基、C4烷基、C5烷基、C6烷基，实例包括，但不限于，甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、2-戊基、3-戊基、正己基、2-己基、3-己基等。
术语“烷氧基”指具有烷基-O-结构的基团，烷基为包括直链的或支链的饱和一价烃基。如“C1-C3烷氧基”包括甲氧基、乙氧基、正丙氧基、异丙氧基。
术语“环烷基”指单环饱和烃体系，无杂原子，无双键。术语“3-6元环烷基”的实例包括，但不限于，环丙基、环丁基、环戊基、环己基。
术语“卤素”指氟、氯、溴和碘。
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合双环的芳香环基团，其通过从母体芳香环体系的单一碳原子上除去一个氢原子而得到。包括与饱和环、部分不饱和环或芳香碳环稠合的双环基团；实例包括，但不限于，苯基、萘基、蒽基、茚、茚满、1,2-二氢萘、1,2,3,4-四氢萘。
术语“杂芳基”指包含至少一个独立地选自氮、氧和硫杂原子的一价芳基。例如“5-7元杂芳基”实例包括，但不限于，吡啶基、噻吩基、咪唑基、嘧啶基、吡啶基、呋喃基、吡嗪基、噻唑基。
术语“9-10元苯并杂环基”是指苯环与杂环稠和形成的具有9-10个环原子或环原子团的环体系，苯环与杂环共享一对相邻环原子，且与母核结构的连接位点位于苯环部分。其中杂环部分为具有环碳原子和1至4个环杂原子或杂原子团的5-6元饱和、部分不饱和或完全不饱和的环体系，杂原子或杂原子团独立地选自氮、硫、氧、亚砜、砜等。
术语“卤代C1-C3烷基”是指C1-C3烷基上的氢原子被任意个数的氟、氯、溴和碘取代后形成的基团。
中的/>是指化学键连接处。
指该环上的氢原子任意被一个或多个R2取代。
术语“药学上可接受的盐”是指保留了特定化合物的游离酸和碱的生物学效力而没有生物学不良作用的盐。例如酸(包括有机酸和无机酸)加成盐或碱加成盐(包括有机碱和无机碱)。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。
术语“药学上可接受的载体”是指对机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些载体。包括但不限于国家食品药品监督管理局许可的可用于人或动物的任何稀释剂、崩解剂、粘合剂、助流剂、润湿剂。
本发明的有益效果：本发明公开了噻唑酮的亚砜和砜类化合物或药学上可接受的盐及其制备方法，该类化合物或者组合物可用于治疗骨肉瘤，人结肠癌，乳腺癌以及肺癌等相关疾病，在肿瘤疾病的研究上具有重要意义。
具体实施方式
下面的实施例可以使本专业的本领域技术人员更全面地理解本发明，但并不因此将本发明限制在所述的实施例范围之中。
长链胺化合物的合成方法，不限于以下制备方法。
方法一：
反应式(I)中R3的定义同式(I)。
在干燥的三口烧瓶中加入化合物A、氢化钠，进行氮气保护，随后加入干燥的DMSO或者DMF，于110℃下搅拌10min，然后将N-(4-溴丁基)邻苯二甲酰亚胺和催化量的KI溶于干燥的DMSO或DMF溶液中加入到反应液中，于110℃下继续搅拌，薄层色谱法监测反应。反应完全后加入饱和氯化钠，用二氯甲烷萃取三次，收集有机相，无水硫酸钠干燥，浓缩后通过柱层析分离纯化(石油醚/乙酸乙酯＝9:1)。
向上述分离纯化得到的产物加入乙醇、水和肼，65℃下反应15h，薄层色谱法监测反应，反应完全后加入1M氢氧化钠溶液，用二氯甲烷萃取三次，收集有机相，无水硫酸钠干燥，浓缩后无需纯化直接用于反应。
方法二：
反应式(2)的具体操作步骤如下：
在干燥的三口烧瓶中，四氢呋喃作为溶剂，加入化合物1和三乙胺，在0℃的温度下，滴加二碳酸二叔丁基酯，反应过夜，后处理，加水淬灭，加入乙酸乙酯萃取，收集有机相，在用1M盐酸洗有机相(3次)，无水硫酸钠干燥，旋干得到化合物2，随后，将化合物2，4-正丁基溴化胺和氢氧化钠(50％w)加入到甲苯中，移至零度条件下，反应30分钟，加入碘甲烷，反应过夜，后处理，加入乙醚萃取，旋干，湿法上样，柱层析分离得到化合物3，最后在4M盐酸乙酸乙酯中反应去掉Boc保护基，得到长链氨基的化合物4。
方法三：
反应式(3)的具体操作如下：
将化合物1上Boc保护基团，得到化合物2，随后，将化合物2和苯基格氏试剂(PhMgBr)反应，后处理得到开环的化合物3,得到化合物3在硼氢化钠的条件下还原得到化合物4，最后，在三氟乙酸的条件下去Boc保护基得到最终的长链烷基胺化合物5.
方法四：
反应式(4)合成长链烷基胺的路线：
将化合物1在酸性条件下发生酯化得到长链烷基酯类化合物2，也可以将化合物1在碱性条件下，先上氨基保护基(Boc)得到化合物3，随后和氨基类化合物缩合得到酰胺类化合物4，最后，在酸性条件下水解得到长链烷基化合物5.
实施例1
化合物1为例，具体的操作步骤如下：
步骤ab:向吡啶-2,6-二羧酸(10g)在甲醇(100mL)中的搅拌溶液中，加入浓硫酸(0.5毫升)。将反应混合物在80℃回流16小时。反应完成后，通过真空蒸发除去溶剂，加入水，过滤形成的固体并干燥，得到吡啶-2,6-二羧酸二甲酯，随后将吡啶-2,6-二羧酸二甲酯(2g)溶解到甲醇(20mL)中，加入KOH(1.2eq.)，在室温的条件下反应过夜。后处理，减压蒸馏除去甲醇，加水和乙酸乙酯萃取，水层被收集，随后加入1M盐酸调节pH到7，随后，再用乙酸乙酯萃取，有机相收集，干燥，浓缩得到白色固体6-(甲氧羰基)吡啶甲酸(1.2g)。
步骤c:在50mL的圆底烧瓶中添加6-(甲氧羰基)吡啶甲酸(1eq.)，HOBt(2eq.)和DIPEA(4eq.),随后，在氮气，0℃的条件下反应10分钟后，加入EDCI(2eq.),继续搅拌10分钟后，加入4苯基丁胺(1.1eq.)，随后将反应移至室温，反应16小时后，TLC检测反应，新点生成，加水淬灭，二氯甲烷萃取，有机相收集，干燥，浓缩，湿法上样，柱色谱分离纯化得到酰胺缩合的产物3a。
步骤d:将化合物3a(1eq.)溶解到甲醇中，随后加入甲醇钠(cat.)和硼氢化钠(2eq.),在室温的条件下，反应16小时，TLC检测，原料完全反应，新点生成，加水淬灭，减压蒸馏除去甲醇，随后，剩余物用乙酸乙酯萃取，有机相收集，干燥，浓缩，柱色谱分离纯化得到酯还原的产物4a.
步骤e:将化合物4a(1eq.)溶解到乙酸乙酯中，加入IBX(1.1eq.)，随后升高温度至85℃，反应过夜，TLC检测，原料完全反应，新点生成，反应中有白色固体，过滤得到滤液，减压蒸馏除去溶剂，随后柱色谱分离纯化得到羟基氧化成醛的化合物5a.
步骤f:将醛类化合物5a(1eq.)和4-甲基吡啶-2-胺(1eq.)加入到甲苯，在140℃的条件下，搅拌30分钟，冷却后，加入巯基乙酸(3eq.)，随后在140℃条件下反应过夜，TLC和LCMS检测，原料完全反应，新点生成，减压除去溶解，随后湿法上样，柱层析分离提纯得到噻唑酮类化合物6a.
步骤g:在50mL的圆底烧瓶中加入噻唑酮类化合物6a(1eq.)和无水二氯甲烷，随后将混合物移至0℃的条件下，加入间氯过氧苯甲酸(3eq.)，随后移至室温反应过夜，LCMS检测，原料完全反应，目标分子量生成，后处理，往反应中添加饱和的硫代硫酸那钠，随后用二氯甲烷萃取，有机相收集，无水硫酸钠干燥，旋干，柱色谱分离纯化得到最终的噻唑酮砜类目标化合物1.1H NMR(400MHz,CDCl3)δ8.21(d,J＝7.8Hz,1H),8.17(s,1H),8.01–7.96(m,2H),7.69(d,J＝7.8Hz,1H),7.51(t,J＝6.0Hz,1H),7.28(t,J＝7.2Hz,2H),7.18(d,J＝7.6Hz,3H),6.88(d,J＝5.2Hz,1H),6.81(s,1H),4.19–4.03(m,2H),3.50-3.37(m,2H),2.65(t,J＝7.2Hz,2H),2.34(s,3H),1.69-1.60(m,4H)；13C NMR(100MHz,CDCl3)δ163.33,163.25,150.2,150.1,149.9,149.6,147.3,142.1,139.3,128.52,128.46,126.7,125.9,123.3,122.6,117.0,80.3,53.1,39.4,35.6,29.1,28.8,21.5.
实施例2
1H NMR(400MHz,CDCl3)δ8.23(d,J＝7.8Hz,1H),8.11(d,J＝4.4Hz,1H),7.95(t,J＝7.8Hz,1H),7.76(s,1H),7.60(d,J＝7.8Hz,1H),7.37(t,J＝8.8Hz,1H),7.30-7.18(m,2H),7.20(t,J＝8.2Hz,4H),6.56(s,1H),4.13-4.04(m,2H),3.55-3.39(m,2H),2.67(t,J＝6.6Hz,2H),1.70–1.65(m,4H)；13C NMR(100MHz,CDCl3)δ163.2,161.1,153.6(J＝270Hz),150.7,148.0,144.3(J＝5Hz),142.3,139.3,137.6(J＝13Hz),128.6,128.5,126.2,126.0,125.7(J＝18Hz),125.0(J＝4Hz),123.6,81.8,51.8,39.6,35.7,29.2,28.9；19F NMR(375MHz,CDCl3)δ-118.97.
实施例3
1H NMR(400MHz,CDCl3)δ8.35(dd,J＝9.2,4.0Hz,1H),8.22(dd,J＝7.8,1.0Hz,1H),8.01–7.97(m,2H),7.70(dd,J＝7.6Hz,0.4Hz,1H),7.45(t,J＝6.0Hz,1H),7.39-7.34(m,1H),7.29(t,J＝7.2Hz,2H),7.22-7.18(m,3H),6.73(d,J＝0.8Hz,1H),4.18–4.03(m,2H),3.42(q,J＝6.2Hz,2H),2.65(t,J＝7.2Hz,2H),1.66–1.61(m,4H)；13C NMR(100MHz,CDCl3)δ163.3,163.1,158.4-155.8(J＝253.5Hz),150.3,149.4,145.5(J＝2.4Hz),142.1,139.5,135.5-135.3(J＝25.8Hz),128.54,128.49,126.7,126.0,125.8-125.6(J＝16.9Hz),123.4,117.7-117.6(J＝4.6Hz),80.3,52.8,39.5,35.6,29.1,28.8；19F NMR(376MHz,CDCl3)δ-129.4.
实施例4
1H NMR(400MHz,CDCl3)δ8.20(d,J＝7.6Hz,1H),7.99–7.88(m,4H),7.62(d,J＝7.6Hz,1H),7.31-7.27(m,3H),7.22–7.17(m,3H),7.13(dd,J＝8.0,4.6Hz,1H),7.04(s,1H),4.23–4.11(m,2H),3.55–3.36(m,2H),2.67(t,J＝6.4Hz,2H),1.72–1.66(m,4H)；13CNMR(100MHz,CDCl3)δ164.8,163.3,150.7,147.3,146.1,142.4,140.8,139.4,139.2,130.0,128.6,128.5,126.6,126.0,125.0,123.7,82.4,53.1,39.6,35.7,29.1,29.0.
实施例5
1H NMR(400MHz,CDCl3)δ8.18(d,J＝7.8Hz,1H),8.05–7.80(m,3H),7.64(d,J＝7.8Hz,1H),7.30-7.25(m,4H),7.18(t,J＝7.2Hz,4H),6.49(s,1H),4.12–4.02(m,2H),3.90(s,3H),3.51-3.40(m,2H),2.66(t,J＝7.2Hz,2H),1.73-1.63(m,4H)；13C NMR(100MHz,CDCl3)δ163.5,161.3,150.6,150.5,148.4,142.2,140.4,138.9,138.8,128.6,128.5,125.9,125.7,124.8,123.2,121.2,82.5,56.5,51.8,39.6,35.6,29.4,28.9.
实施例6
1H NMR(400MHz,CDCl3)δ8.24(d,J＝7.8Hz,1H),7.91(t,J＝7.8Hz,1H),7.81(t,J＝6.2Hz,1H),7.53(d,J＝7.8Hz,1H),7.28(t,J＝7.2Hz,3H),7.20–7.14(m,4H),6.94(d,J＝8.4Hz,1H),6.84(t,J＝7.8Hz,1H),6.17(s,1H),4.10–3.98(m,2H),3.85(s,3H),3.53–3.48(m,2H),2.68(t,J＝7.0Hz,2H),1.75–1.67(m,4H)；13C NMR(100MHz,CDCl3)δ163.3,163.2,154.6,150.7,148.5,142.2,139.1,130.6,129.4,128.6,128.5,126.6,126.0,123.62,123.55,121.1,112.6,82.9,56.1,50.8,39.6,35.6,29.4,28.9.
实施例7
以化合物7为例，具体的操作步骤如下：
步骤a：向间苯二羧酸(10g)在甲醇(100mL)中的搅拌溶液中，加入浓硫酸(0.5毫升)。将反应混合物在80℃回流16小时。反应完成后，通过真空蒸发除去溶剂，加入水，过滤形成的固体并干燥，得到间苯二羧酸二甲酯(2b,9g)。
步骤b：将化合物2b(1eq.)溶解到四氢呋喃中，随后加入硼氢化钠(1.2eq.)，在50℃的条件下，滴加甲醇，反应5小时，TLC检测，原料反应，新点生成，加水淬灭，减压蒸馏除去甲醇和四氢呋喃，随后，剩余物用乙酸乙酯萃取，有机相收集，干燥，浓缩，柱色谱分离纯化得到酯还原的产物3b.
步骤c:将化合物3b(1eq.)溶解到乙酸乙酯中，加入IBX(1.1eq.)，随后升高温度至85℃，反应过夜，TLC检测，原料完全反应，新点生成，反应中有白色固体，过滤得到滤液，减压蒸馏除去溶剂，随后柱色谱分离纯化得到羟基氧化成醛的化合物4b.
步骤d:将酯类化合物4b(1eq.)溶解到甲醇中，加入氢氧化钾(2eq.)反应过夜，TLC检测，原料完全反应。随后，加水稀释，减压蒸馏除掉甲醇，乙酸乙酯萃取，水相用1M盐酸来调节pH到6。白色固体析出，过滤得到白色固体5b.
步骤e:在50mL的圆底烧瓶中添加3-甲酰基苯甲酸(5b,1eq.)，HOBt(2eq.)和DIPEA(4eq.),随后，在氮气，0℃的条件下反应10分钟后，加入EDCI(2eq.),继续搅拌10分钟后，加入4-苯基丁胺(1.1eq.)，随后将反应移至室温，反应16小时后，TLC检测反应，新点生成，加水淬灭，二氯甲烷萃取，有机相收集，干燥，浓缩，湿法上样，柱色谱分离纯化得到酰胺缩合的产物6b。
步骤f:将醛类化合物6b(1eq.)和3-甲氧基吡啶-2-胺(1eq.)加入到甲苯，在140℃的条件下，搅拌30分钟，冷却后，加入巯基乙酸(3eq.)，随后在140℃条件下反应过夜，TLC和LCMS检测，原料完全反应，新点生成，减压除去溶解，随后湿法上样，柱层析分离提纯得到噻唑酮类化合物7b.
步骤g:在50mL的圆底烧瓶中加入噻唑酮类化合物7b(1eq.)和无水二氯甲烷，随后将混合物移至0℃的条件下，加入间氯过氧苯甲酸(3eq.),随后移至室温反应过夜，LCMS检测，原料完全反应，目标分子量生成，后处理，往反应中添加饱和的硫代硫酸那钠，随后用二氯甲烷萃取，有机相收集，无水硫酸钠干燥，旋干，柱色谱分离纯化得到最终的噻唑酮砜类目标化合物7。1H NMR(400MHz,CDCl3)δ7.94(d,J＝4.4Hz,1H),7.83(s,1H),7.74(d,J＝7.8Hz,1H),7.57(d,J＝7.8Hz,1H),7.40(t,J＝7.8Hz,1H),7.30–7.26(m,2H),7.25(d,J＝7.8Hz,1H),7.21(d,J＝5.6Hz,1H),7.17(t,J＝6.6Hz,3H),6.50(s,1H),6.15(t,J＝5.8Hz,1H),4.17–4.06(m,2H),3.91(s,3H),3.49–3.38(m,2H),2.66(t,J＝7.2Hz,2H),1.74–1.58(m,4H)；13C NMR(100MHz,CDCl3)δ166.6,161.2,151.3,142.1,140.5,138.3,135.7,131.8,129.3,129.2,128.5,128.5,128.1,127.2,126.0,125.2,120.9,82.2,56.4,51.7,40.1,35.6,29.3,28.8.
实施例8
1H NMR(400MHz,CDCl3)δ7.79(d,J＝9.8Hz,2H),7.57(s,1H),7.32(t,J＝7.8Hz,2H),7.28–7.22(m,5H),7.18(t,J＝7.4Hz,3H),6.15(s,1H),5.99(s,1H),4.12–4.03(m,2H),3.42(q,J＝6.6Hz,2H),3.18(s,1H),2.65(t,J＝7.2Hz,2H),1.73–1.57(m,4H)；13C NMR(100MHz,CDCl3)δ165.5,162.1,142.1,136.5,135.7,133.7,132.2,130.3,129.8,128.56,128.55,128.4,127.5,126.1,125.2,124.2,83.2,81.5,80.2,50.9,40.3,35.6,29.2,28.8.
实施例9
1H NMR(400MHz,CDCl3)δ8.21(d,J＝7.6Hz,1H),7.98–7.94(m,3H),7.70(d,J＝7.6Hz,1H),7.52(t,J＝5.8Hz,1H),7.29–7.25(m,2H),7.19–7.17(m,3H),6.85(s,1H),6.60(dd,J＝5.8,2.4Hz,1H),4.21–4.03(m,2H),3.82(s,3H),3.49–3.36(m,2H),2.65(t,J＝7.2Hz,2H),1.71–1.58(m,4H)；13C NMR(100MHz,CDCl3)δ167.4,163.4,163.2,151.0,150.2,149.8,148.4,142.1,139.3,128.5,128.4,126.7,125.9,123.2,108.7,101.8,80.2,55.6,53.1,39.4,35.5,29.1,28.7.
实施例10
1H NMR(400MHz,CDCl3)δ8.21(d,J＝8.0Hz,2H),7.98(t,J＝8.0Hz,2H),7.69(d,J＝7.8Hz,1H),7.51–7.45(m,2H),7.28(t,J＝7.4Hz,2H),7.19(t,J＝6.8Hz,3H),6.80(s,1H),4.17–4.02(m,2H),3.46–3.39(m,2H),2.65(t,J＝7.2Hz,2H),2.23(s,3H),1.68–1.59(m,4H)；13C NMR(100MHz,CDCl3)δ163.22,163.17,150.2,149.8,147.7,147.4,142.2,139.3,139.1,131.1,128.6,128.5,126.7,126.0,123.3,116.0,80.3,53.0,39.5,35.6,29.2,28.8,17.9.
实施例11
1H NMR(400MHz,CDCl3)δ8.33(d,J＝8.4Hz,1H),8.21(d,J＝7.8Hz,1H),8.14(d,J＝4.0Hz,1H),7.98(t,J＝7.8Hz,1H),7.71(d,J＝7.6Hz,1H),7.65(td,J＝8.8,1.8Hz,1H),7.50(t,J＝6.0Hz,1H),7.29(t,J＝8.0Hz,2H),7.19(t,J＝6.8Hz,3H),7.06–7.03(m,1H),6.83(s,1H),4.20–4.04(m,2H),3.42(q,J＝6.4Hz,2H),2.65(t,J＝7.2Hz,2H),1.68–1.58(m,4H)；13C NMR(100MHz,CDCl3)δ163.4,163.1,150.1,149.6,149.4,147.7,142.1,139.3,138.4,128.5,128.4,126.7,125.9,123.2,121.3,116.5,80.1,52.9,39.4,35.5,29.0,28.7.
实施例12
1H NMR(400MHz,CDCl3)δ8.22(d,J＝7.8Hz,1H),8.10(dd,J＝4.6,1.6Hz,1H),7.93(t,J＝7.8Hz,1H),7.65(t,J＝6.0Hz,1H),7.57–7.54(m,2H),7.28(t,J＝8.0Hz,2H),7.18(t,J＝7.4Hz,3H),7.12(dd,J＝7.6,4.6Hz,1H),6.45(s,1H),4.17–4.04(m,2H),3.45(q,J＝6.4Hz,2H),2.65(t,J＝7.2Hz,2H),2.35(s,3H),1.71–1.60(m,4H)；13C NMR(100MHz,CDCl3)δ163.3,162.1,150.7,148.6,148.1,146.5,142.2,140.4,139.1,130.5,128.6,128.5,126.2,126.0,123.7,123.4,82.6,52.1,39.5,35.6,29.3,28.9,18.3
实施例13
1H NMR(400MHz,CDCl3)δ8.37(d,J＝8.4Hz,1H),8.21(d,J＝7.8Hz,1H),8.16(d,J＝4.8Hz,1H),7.99(t,J＝7.6Hz,1H),7.77–7.70(m,2H),7.46(t,J＝6.0Hz,1H),7.08(t,J＝6.0Hz,1H),6.83(s,1H),4.24–4.09(m,2H),3.41–3.36(m,2H),1.57–1.50(m,2H),1.38–1.29(m,2H),0.93(t,J＝7.4Hz,3H)；13C NMR(100MHz,CDCl3)δ163.4,163.1,150.3,149.7,149.6,147.8,139.4,138.5,126.7,123.3,121.4,116.6,80.2,53.1,39.3,31.5,20.2,13.8.
实施例14
1H NMR(400MHz,CDCl3)δ8.33(d,J＝8.4Hz,1H),8.20(d,J＝7.8Hz,1H),8.15(d,J＝4.8Hz,1H),7.99(t,J＝7.8Hz,1H),7.71(d,J＝7.8Hz,2H),7.53–7.49(m,2H),7.39(s,1H),7.07(t,J＝6.2Hz,1H),6.81(s,1H),6.23(s,1H),4.31–4.08(m,4H),3.42–3.30(m,2H),1.93–1.86(m,2H),1.59–1.52(m,2H)；13C NMR(100MHz,CDCl3)δ163.5,163.3,150.1,149.8,149.51,147.8,139.41,139.37,138.6,129.2,126.8,123.3,121.4,116.6,105.5,80.2,53.1,51.6,38.9,27.7,26.7.
实施例15
1H NMR(400MHz,CDCl3)δ8.33(d,J＝8.6Hz,1H),8.20(d,J＝7.8Hz,1H),8.15(d,J＝5.0Hz,1H),7.97(t,J＝7.8Hz,1H),7.90(t,J＝5.8Hz,1H),7.72(d,J＝7.8Hz,1H),7.49(td,J1＝8.0Hz,J2＝2.0Hz,1H),7.35–7.28(m,5H),7.04(t,J＝6.2Hz,1H),6.79(s,1H),4.61–4.54(m,2H),4.18(d,J＝16.6Hz,1H),3.75(d,J＝16.6Hz,1H),3.71–3.67(m,1H),3.65–3.61(m,2H),3.59–3.52(m,1H)；13C NMR(100MHz,CDCl3)δ163.2,163.0,150.23,150.18,149.6,147.6,139.2,138.5,138.0,128.6,128.0,127.9,127.2,123.3,121.3,116.7,80.1,73.3,68.6,53.0,39.4.
实施例16
1H NMR(400MHz,CDCl3)δ8.34(d,J＝8.4Hz,1H),8.15–8.10(m,3H),7.91(t,J＝7.8Hz,1H),7.71–7.65(m,2H),7.00(dd,J＝7.2,4.8Hz,1H),6.78(s,1H),5.31(d,J＝16.8Hz,1H),4.07(d,J＝16.8Hz,1H),3.61–3.52(m,1H),3.37–3.27(m,4H),3.13–3.07(m,1H),2.31(t,J＝6.4Hz,2H),2.09–2.01(m,1H),1.89–1.79(m,3H),1.77–1.62(m,2H)；13CNMR(100MHz,CDCl3)δ171.2,163.6,163.4,150.5,150.3,149.6,147.4,138.7,138.3,127.3,123.1,121.1,116.6,80.3,53.4,46.7,45.8,39.9,32.7,26.0,24.3,23.6.
实施例17
1H NMR(400MHz,CDCl3)δ8.35(d,J＝8.4Hz,1H),8.20(d,J＝7.6Hz,1H),8.15(d,J＝4.8Hz,1H),7.97(t,J＝7.8Hz,1H),7.75–7.69(m,2H),7.56(t,J＝5.4Hz,1H),7.06(t,J＝6.2Hz,1H),6.82(s,1H),4.29(d,J＝16.4Hz,1H),4.10(d,J＝16.8Hz,1H),3.45–3.38(m,4H),3.32(s,3H),1.64–1.58(m,4H)；13C NMR(100MHz,CDCl3)δ163.4,163.3,150.3,149.8,149.5,147.7,139.3,138.5,126.8,123.3,121.4,116.7,80.2,72.3,58.7,53.1,39.2,26.8,26.4.
实施例18
1H NMR(400MHz,CDCl3)δ8.18(d,J＝7.8Hz,1H),8.01(t,J＝5.6Hz,1H),7.95(d,J＝4.6Hz,1H),7.90(t,J＝7.8Hz,1H),7.64(d,J＝7.8Hz,1H),7.32(d,J＝8.4Hz,1H),7.22(dd,J＝8.4,4.6Hz,1H),6.48(s,1H),4.18–4.05(m,2H),3.95(s,3H),3.56–3.47(m,1H),3.45–3.40(m,3H),3.33(s,3H),1.71–1.62(m,4H)；13C NMR(100MHz,CDCl3)δ163.5,161.3,150.7,150.6,148.4,140.4,138.9,138.8,125.7,124.9,123.3,121.2,82.6,72.3,58.7,56.5,51.8,39.5,27.1,26.6.
实施例19
1H NMR(400MHz,CDCl3)δ8.35(d,J＝8.4Hz,1H),8.18(d,J＝7.8Hz,1H),8.13(d,J＝4.4Hz,1H),7.96(t,J＝7.8Hz,1H),7.71(d,J＝7.6Hz,2H),7.65(d,J＝6.4Hz,1H),7.05(t,J＝6.0Hz,1H),6.82(s,1H),4.52(dd,J＝16.6,2.0Hz,1H),4.12(d,J＝16.6Hz,1H),3.57(s,3H),3.53–3.46(m,1H),3.41–3.33(m,1H),2.35(t,J＝7.2Hz,2H),1.95–1.85(m,2H)；13C NMR(100MHz,CDCl3)δ173.9,163.44,163.38,150.1,150.0,149.5,147.7,139.2,138.5,127.1,123.3,121.3,116.6,80.3,53.2,51.8,39.0,31.6,24.5.
实施例20
1H NMR(400MHz,CDCl3)δ8.07(s,1H),8.02(d,J＝4.8Hz,1H),7.81(d,J＝10.0Hz,2H),7.49(s,1H),7.43(d,J＝6.4Hz,2H),7.38(s,1H),7.10(s,1H),6.88(d,J＝5.2Hz,1H),6.87(s,1H),6.24(s,1H),4.20–4.00(m,4H),3.41–3.37(m,2H),2.36(s,3H),1.96–1.89(m,2H),1.60–1.53(m,2H)；13C NMR(100MHz,CDCl3)δ166.7,162.1,150.0,149.2,147.4,139.2,135.7,131.2,129.9,129.4,129.3,128.6,125.9,122.9,118.3,105.6,80.7,52.1,51.2,39.6,28.0,25.9,21.4.
实施例21
1H NMR(400MHz,CDCl3)δ8.30(s,1H),8.02(d,J＝5.0Hz,1H),7.79(s,1H),7.69(d,J＝7.2Hz,1H),7.44–7.38(m,2H),7.26(t,J＝7.4Hz,2H),7.16(t,J＝8.6Hz,3H),6.88(d,J＝5.8Hz,2H),6.42(t,J＝5.8Hz,1H),3.91(d,J＝17.2Hz,1H),3.59(dd,J＝17.0,1.6Hz,1H),3.41(q,J＝6.4Hz,2H),2.63(t,J＝7.2Hz,2H),2.38(s,3H),1.71–1.57(m,4H)；13C NMR(100MHz,CDCl3)δ168.3,166.5,151.0,149.9,147.4,142.1,136.2,132.2,129.8,128.8,128.49,128.46,127.8,126.0,125.2,122.4,115.8,83.6,53.6,40.2,35.5,29.2,28.7,21.5.
实施例22
1H NMR(400MHz,CDCl3)δ8.30(s,1H),8.03(s,1H),7.84(s,1H),7.77(d,J＝6.8Hz,1H),7.49(s,1H),7.47–7.39(m,3H),6.99(s,1H),6.88(s,2H),6.25(s,1H),4.19(t,J＝7.0Hz,2H),3.95(d,J＝17.2Hz,1H),3.62(d,J＝16.8Hz,1H),3.44–3.40(m,2H),2.39(d,J＝3.0Hz,3H),1.98–1.92(m,2H),1.63–1.57(m,2H)；13C NMR(100MHz,CDCl3)δ168.3,166.7,151.1,149.9,147.5,139.3,136.1,132.2,129.8,129.5,128.9,128.0,125.3,122.4,115.9,105.8,83.7,53.6,51.3,39.8,28.2,26.0,21.6.
实施例23
1H NMR(400MHz,CDCl3)δ7.80(s,1H),7.74(s,1H),7.48(s,2H),7.32–7.23(m,7H),7.19(t,J＝7.2Hz,3H),6.13(s,1H),6.03(s,1H),4.07(t,,J＝18.8Hz,2H),3.50–3.39(m,2H),2.66(t,J＝7.0Hz,2H),1.75–1.63(m,4H)；13C NMR(100MHz,CDCl3)δ166.4,162.2,142.1,136.3,135.9,130.7,129.8,129.7,129.6,128.8,128.6,128.5,128.2,127.3,126.0,125.2,83.5,50.9,40.2,35.6,29.3,28.8.
实施例24
1H NMR(400MHz,CDCl3)δ7.69(s,1H),7.50(d,J＝8.4Hz,1H),7.37(d,J＝8.0Hz,1H),7.34–7.24(m,8H),7.18(t,J＝6.6Hz,3H),7.08(d,J＝7.6Hz,1H),5.91(s,1H),4.08–3.98(m,2H),2.65(t,J＝7.0Hz,2H),2.32(t,J＝6.8Hz,2H),1.78–1.67(m,4H)；13C NMR(100MHz,CDCl3)δ171.5,162.4,142.1,139.3,136.2,130.23,130.15,129.6,128.6,128.5,128.1,126.0,125.2,123.2,118.9,83.9,50.7,37.7,35.8,31.1,25.1.
实施例25
1H NMR(400MHz,CDCl3)δ7.80(s,1H),7.75(t,J＝3.4Hz 1H),7.48(d,J＝4.4Hz,2H),7.28(d,J＝7.4Hz,2H),7.20–7.16(m,4H),7.12(s,1H),7.05–7.00(m,2H),6.20(t,J＝5.8Hz,1H),6.01(s,1H),4.10–4.00(m,2H),3.45–3.40(m,2H),2.65(t,J＝7.2Hz,2H),2.28(s,3H),1.74–1.58(m,4H)；13C NMR(100MHz,CDCl3)δ166.4,162.3,142.1,139.8,136.2,135.7,130.7,129.7,129.6,129.4,129.2,128.9,128.6,128.55,128.52,127.3,126.02,125.97,122.4,83.7,50.9,40.2,35.6,29.2,28.8,21.5.
实施例26
1H NMR(400MHz,CDCl3)δ7.79(s,1H),7.75(d,J＝6.2Hz,1H),7.47(s,2H),7.29(t,J＝7.2Hz,2H),7.18(d,J＝7.4Hz,3H),6.77(s,1H),6.66(q,J＝8.4Hz,2H),6.27(s,1H),5.93(s,3H),4.09–3.99(m,2H),3.42(q,J＝6.4Hz,2H),2.65(t,J＝7.4Hz,2H),1.75–1.60(m,4H)；13C NMR(100MHz,CDCl3)δ166.4,162.5,148.4,147.6,142.1,136.2,130.9,129.7,129.3,129.2,128.9,128.55,128.51,127.5,126.0,119.4,108.6,107.2,102.1,84.0,50.9,40.2,35.6,29.2,28.8.
实施例27
1H NMR(400MHz,CDCl3)δ7.80(s,1H),7.76–7.73(m,1H),7.49-7.47(m,2H),7.28(t,J＝7.8Hz,2H),7.22-7.17(m,4H),6.87(t,J＝2.2Hz,1H),6.81-6.75(m,2H),6.17(t,J＝5.4Hz,1H),6.01(s,1H),4.10-4.01(m,2H),3.72(s,3H),3.43(q,J＝6.8Hz,2H),2.66(t,J＝7.2Hz,2H),1.74–1.59(m,4H)；13C NMR(100MHz,CDCl3)δ166.4,162.2,160.3,142.1,136.8,136.2,130.7,130.3,129.7,129.5,128.9,128.6,128.5,127.2,126.0,117.3,113.6,111.6,83.5,55.6,51.0,40.2,35.6,29.2,28.8.
实施例28
1H NMR(400MHz,CDCl3)δ7.82(s,1H),7.75(d,J＝7.0Hz,1H),7.50–7.44(m,2H),7.30–7.22(m,3H),7.18(t,J＝8.0Hz,3H),7.10(d,J＝9.6Hz,1H),7.02(d,J＝8.0Hz,1H),6.93(t,J＝8.2Hz,1H),6.30(t,J＝5.8Hz,1H),6.04(s,1H),4.11–4.02(m,2H),3.42–3.39(m,2H),2.65(t,J＝7.2Hz,2H),1.73–1.58(m,4H)；13C NMR(100MHz,CDCl3)δ166.3,162.7(J＝247.1Hz),162.2,142.1,137.2(J＝9.8Hz),136.3,130.8(J＝8.9Hz),130.6,129.8,129.1,129.0,128.54,128.51,127.3,126.0,120.4(J＝3.3Hz),115.1(J＝20.9Hz),112.7(J＝24.7Hz),80.3,52.9,40.2,35.6,29.2,28.8；19F NMR(376MHz,CDCl3)δ-109.7.
实施例29
1H NMR(400MHz,CDCl3)δ7.81(s,1H),7.75(d,J＝7.6Hz,1H),7.53–7.45(m,2H),7.36(s,1H),7.28(t,J＝7.2Hz,2H),7.22–7.12(m,6H),6.15(s,1H),6.01(s,1H),4.07(t,J＝17.8Hz,2H),3.47–3.43(m,2H),2.66(t,J＝7.0Hz,2H),1.72–1.61(m,4H)；13C NMR(100MHz,CDCl3)δ166.3,162.2,142.1,136.9,136.3,135.2,130.6,129.9,129.2,129.0,128.6,128.5,128.4,127.3,126.0,125.4,123.1,83.2,50.8,40.3,35.6,29.2,28.8.
实施例30
1H NMR(400MHz,CDCl3)δ7.78(s,1H),7.69(d,J＝7.6Hz,1H),7.52(d,J＝7.6Hz,1H),7.43(t,J＝7.8Hz,1H),7.28(t,J＝7.8Hz,3H),7.23–7.17(m,4H),6.89–6.84(m,2H),6.22(s,1H),6.03(s,1H),4.09(t,J＝17.4Hz,2H),3.84(s,3H),3.46–3.42(m,2H),2.67(t,J＝7.2Hz,2H),1.75–1.61(m,4H)；13C NMR(100MHz,CDCl3)δ166.6,162.6,154.5,142.1,135.7,132.0,130.5,129.8,129.2,128.8,128.6,128.5,128.3,128.1,126.0,123.3,121.1,112.5,82.6,56.0,51.2,40.2,35.6,29.3,28.8.
实施例31
1H NMR(400MHz,CDCl3)δ7.86(s,1H),7.76–7.74(m,1H),7.53–7.47(m,6H),7.41(t,J＝7.4Hz,2H),7.39–7.32(m,3H),7.29–7.26(m,2H),7.18(t,J＝6.8Hz,3H),6.22(s,1H),6.08(s,1H),4.14–4.05(m,2H),3.47–3.41(m,2H),2.65(t,J＝7.2Hz,2H),1.74–1.59(m,4H)；13C NMR(100MHz,CDCl3)δ166.4,162.3,142.1,141.1,139.7,136.3,134.9,130.7,129.8,129.5,129.0,128.9,128.55,128.52,128.2,128.0,127.3,127.2,126.0,125.4,83.5,51.0,40.2,35.6,29.2,28.8.
实施例32
1H NMR(400MHz,CDCl3)δ9.81(s,1H),8.16(d,J＝8.0Hz,1H),8.05(d,J＝8.0Hz,1H),8.02(s,1H),7.86(d,J＝7.6Hz,2H),7.77(d,J＝8.8Hz,1H),7.65–7.58(m,2H),7.50(t,J＝7.8Hz,1H),7.40(d,J＝8.8Hz,1H),7.19(t,J＝7.4Hz,,2H),7.10(t,J＝7.0Hz,3H),6.67(s,1H),6.05(s,1H),4.03–3.89(m,2H),3.44–3.30(m,2H),2.57(t,J＝7.0Hz,2H),1.66–1.55(m,4H)；13C NMR(100MHz,CDCl3)δ167.0,163.1,142.2,136.0,134.1,133.7,132.5,130.2,129.4,129.1,128.74,128.71,128.6,128.5,128.4,128.3,128.2,125.9,125.4,125.2,122.7,69.3,58.9,40.1,35.5,29.2,28.8.
实施例33
1H NMR(400MHz,CDCl3)δ7.80(d,J＝7.8Hz,1H),7.75(s,1H),7.56(t,J＝7.8Hz,1H),7.43(d,J＝7.8Hz,1H),7.31–7.26(m,2H),7.20–7.17(m,3H),6.23(s,1H),5.46(s,1H),3.85(s,2H),3.49–3.44(m,2H),2.69–2.60(m,3H),1.75–1.63(m,4H),1.04–0.94(m,2H),0.69–0.59(m,2H)；13C NMR(100MHz,CDCl3)δ166.5,163.7,142.1,136.5,130.6,130.1,129.9,128.8,128.6,128.5,126.8,126.0,82.9,51.2,40.3,35.6,29.3,28.8,26.7,8.4,6.3.
实施例34
1H NMR(400MHz,CDCl3)δ7.77(d,J＝7.6Hz,2H),7.53(t,J＝7.6Hz,1H),7.43(d,J＝7.6Hz,1H),7.28(t,J＝7.4Hz,2H),7.18(d,J＝7.2Hz,3H),6.23(s,1H),5.55(s,1H),4.32(t,J＝11.8Hz,1H),3.87–3.74(m,2H),3.50–3.45(m,2H),2.67(t,J＝7.0Hz,2H),1.90–1.81(m,2H),1.73–1.54(m,6H),1.51(t,J＝12.0Hz,1H),1.41–1.22(m,3H),1.03–0.87(m,2H)；13CNMR(100MHz,CDCl3)δ166.5,162.8,142.1,136.3,133.0,129.7,129.6,128.6,128.5,126.4,126.0,79.6,54.5,50.2,40.3,35.6,31.8,29.9,29.3,28.8,25.7,25.4,25.1.
实施例35
1H NMR(400MHz,CDCl3)δ7.81(d,J＝7.6Hz,1H),7.62(s,1H),7.46(t,J＝7.6Hz,1H),7.30–7.23(m,6H),7.14(d,J＝6.8Hz,3H),7.04(s,2H),6.51(t,J＝5.2Hz,1H),5.38(d,J＝14.8Hz,1H),5.34(s,1H),3.90–3.80(m,2H),3.69(d,J＝14.8Hz,1H),3.40–3.35(m,2H),2.61(t,J＝6.8Hz,2H),1.67–1.56(m,4H)；13C NMR(100MHz,CDCl3)δ166.4,162.7,142.1,136.2,133.6,131.1,129.7,129.3,129.2,128.7,128.6,128.5,128.4,126.9,125.9,80.7,50.3,45.8,40.1,35.5,29.1,28.7,14.2.
实施例36
1H NMR(400MHz,CDCl3)δ7.81(d,J＝7.6Hz,1H),7.54(s,1H),7.51(t,J＝7.8Hz,1H),7.32–7.24(m,6H),7.21–7.18(m,3H),7.10(d,J＝7.2Hz,2H),6.19(t,J＝5.2Hz,1H),5.15(s,1H),4.33–4.28(m,1H),3.84(t,J＝17.2Hz,2H),3.48–3.43(m,2H),2.97–2.89(m,2H),2.86–2.79(m,1H),2.67(t,J＝7.2Hz,2H),1.76–1.61(m,4H)；13C NMR(100MHz,CDCl3)δ166.4,162.6,142.1,137.6,136.3,131.1,129.8,129.2,129.1,128.8,128.6,128.5,127.5,127.3,126.0,82.2,50.5,44.4,40.2,35.6,33.6,29.3,28.8.
实施例37
1H NMR(400MHz,CDCl3)δ7.74(d,J＝12.0Hz,2H),7.51(t,J＝7.6Hz,1H),7.45(d,J＝7.8Hz,1H),7.28(t,J＝7.8Hz,2H),7.18(t,J＝6.6Hz,3H),6.83(s,1H),6.31(s,1H),6.15(s,1H),4.06–3.95(m,2H),3.47–3.42(m,2H),2.66(t,J＝7.2Hz,2H),2.39(s,3H),1.75–1.63(m,4H)；13C NMR(100MHz,CDCl3)δ171.5,166.4,160.8,156.4,142.1,136.2,130.4,130.0,129.8,128.6,128.5,126.0,125.5,97.2,80.9,50.0,40.2,35.6,29.3,28.8,12.8.
实施例38
1H NMR(400MHz,CDCl3)δ8.29(d,J＝8.4Hz,1H),8.19(d,J＝4.4Hz,1H),7.77–7.71(m,3H),7.46(d,J＝4.0Hz,2H),7.28(t,J＝7.8Hz,2H),7.18(d,J＝7.2Hz,3H),7.10–7.07(t,J＝6.2Hz,1H),6.88(s,1H),6.15(s,1H),4.17–4.04(m,2H),3.46–3.41(m,2H),2.65(t,J＝7.2Hz,2H),1.74–1.59(m,4H)；13C NMR(100MHz,CDCl3)δ166.7,162.2,149.2,148.0,142.1,138.6,136.0,131.4,129.9,129.5,128.6,128.5,128.3,126.03,126.00,121.8,117.9,80.7,52.2,40.2,35.6,29.3,28.8.
实施例39
1H NMR(400MHz,CDCl3)δ8.11(s,1H),8.04(d,J＝4.4Hz,1H),7.75(s,1H),7.71(s,1H),7.46(d,J＝4.0Hz,2H),7.28(t,J＝8.2Hz,2H),7.19(t,J＝6.8Hz,3H),6.90(d,J＝4.8Hz,1H),6.88(s,1H),6.09(s,1H),4.15–4.03(m,2H),3.47–3.43(m,2H),2.66(t,J＝7.0Hz,2H),2.39(s,3H),1.75–1.62(m,4H)；13C NMR(100MHz,CDCl3)δ166.7,162.1,150.2,149.3,147.6,142.1,136.0,131.5,129.9,129.5,128.6,128.5,128.2,126.04,126.00,123.1,118.4,80.8,52.2,40.2,35.6,29.3,28.8,21.5.
实施例40
1H NMR(400MHz,CDCl3)δ8.92(d,J＝3.2Hz,1H),8.10(d,J＝8.4Hz,1H),7.78(s,1H),7.73(t,J＝7.2Hz,2H),7.64(d,J＝7.2Hz,1H),7.55(d,J＝8.0Hz,1H),7.45–7.40(m,2H),7.34–7.28(m,3H),7.18(t,J＝9.4Hz,3H),7.06(s,1H),6.13(s,1H),4.35–4.22(m,2H),3.39–3.31(m,2H),2.63(t,J＝7.0Hz,2H),1.70–1.56(m,4H)；13C NMR(100MHz,CDCl3)δ166.6,163.8,150.8,143.5,142.1,136.7,135.5,132.6,132.0,131.0,129.5,129.1,128.6,128.5,128.4,127.4,126.2,126.0,122.2,83.1,51.6,40.1,35.6,29.2,28.8.
实施例41
1H NMR(400MHz,CDCl3)δ8.30(s,1H),8.12(s,1H),8.08(s,1H),7.31–7.15(m,10H),6.37(s,1H),6.11(s,1H),4.18–4.06(m,2H),3.91(s,3H),3.41(q,J＝6.4Hz,2H),2.64(t,J＝7.2Hz,2H),1.72–1.57(m,4H)；13C NMR(100MHz,CDCl3)δ165.4,165.2,162.2,142.1,136.4,135.5,132.0,131.7,131.6,130.3,129.7,129.3,128.54,128.51,128.4,126.0,125.4,83.2,52.9,51.0,40.3,35.5,29.1,28.8.
实施例42
1H NMR(400MHz,CDCl3)δ8.29(d,J＝8.4Hz,1H),8.18(dd,J＝5.2,1.8Hz,1H),7.79–7.72(m,3H),7.53(s,1H),7.28(t,J＝7.2Hz,3H),7.18(t,J＝8.2Hz,3H),7.09(dd,J＝7.4,4.8Hz,1H),6.83(s,1H),6.27(t,J＝5.8Hz,1H),4.18–4.04(m,2H),3.41(q,J＝6.6Hz,2H),3.15(s,1H),2.64(t,J＝7.2Hz,2H),1.72–1.57(m,4H)；13C NMR(100MHz,CDCl3)δ165.7,162.0,149.0,148.0,142.1,138.6,136.2,132.8,132.1,131.7,128.54,128.51,126.5,126.0,123.8,121.9,117.7,81.8,80.3,79.8,52.2,40.3,35.5,29.2,28.8.
实施例43
1H NMR(400MHz,CDCl3)δ7.95(d,J＝1.2Hz,1H),7.75(s,1H),7.64(s,1H),7.51–7.40(m,5H),7.34–7.23(m,7H),7.18(t,J＝6.4Hz,3H),6.31(s,1H),6.10(s,1H),4.12–4.01(m,2H),3.46–3.40(m,2H),2.65(t,J＝7.2Hz,2H),1.73–1.58(m,4H)；13C NMR(101MHz,CDCl3)δ166.4,162.3(J＝8.2Hz)143.1(J＝2.7Hz),142.1,139.0,136.8,135.8,129.9(J＝3.5Hz),129.7,129.4,129.2,128.60,128.55,128.51,128.2,127.9(J＝2.2Hz),127.4,126.0,125.7,125.3,83.5,51.0,40.3,35.6,29.2,28.8.
实施例44
1H NMR(400MHz,CDCl3)δ8.31(d,J＝7.6Hz,1H),7.99(t,J＝7.8Hz,1H),7.66(s,1H),7.55(d,J＝7.6Hz,1H),7.34–7.16(m,10H),5.97(s,1H),4.03(t,J＝18.6Hz,2H),3.52–3.46(m,2H),2.66(t,J＝6.2Hz,2H),1.70–1.66(m,4H)；13C NMR(100MHz,CDCl3)δ163.2,163.0,151.0,148.7,142.2,139.7,136.2,129.8,128.6,128.5,128.4,126.4,126.0,125.0,124.0,83.7,51.1,39.6,35.6,29.3,28.9.
实施例45
1H NMR(400MHz,CDCl3)δ8.24(s,1H),8.13(d,J＝7.6Hz,1H),8.00(d,J＝5.2Hz,1H),7.91(t,J＝7.8Hz,1H),7.68(t,J＝5.8Hz,1H),7.61(d,J＝7.6Hz,1H),7.48(s,1H),7.39(d,J＝2.0Hz,1H),6.87(d,J＝5.2Hz,1H),6.82(s,1H),6.22(s,1H),4.16(t,J＝7.0Hz,2H),4.10(d,J＝17.2Hz,1H),3.72(d,J＝17.2Hz,1H),3.48–3.32(m,2H),2.37(s,3H),1.94–1.87(m,2H),1.61–1.54(m,2H)；13C NMR(100MHz,CDCl3)δ168.4,163.4,151.0,150.6,150.2,149.8,147.2,139.3,139.2,129.2,125.0,122.7,122.2,115.5,105.4,83.9,54.6,51.5,38.8,27.7,26.6,21.4.
实施例46
1H NMR(400MHz,CDCl3)δ8.32(d,J＝7.8Hz,1H),8.02(t,J＝7.8Hz,1H),7.58(d,J＝7.8Hz,2H),7.26(s,3H),7.17(d,J＝7.6Hz,3H),7.07(d,J＝9.6Hz,1H),6.97(d,J＝5.6Hz,2H),5.97(s,1H),4.02(s,2H),3.47(p,J＝7.8Hz,2H),2.66(t,J＝7.0Hz,2H),1.76–1.62(m,4H)；13C NMR(100MHz,CDCl3)δ163.1,162.9,162.8(J＝247.3Hz),151.1,148.3,142.1,139.9,137.6(J＝9.9Hz),130.9(J＝9.1Hz),128.6,128.5,126.4,126.0,124.1,119.9(J＝3.3Hz),115.2(J＝20.9Hz),112.4(J＝24.7Hz),83.2,51.1,39.6,35.6,29.2,28.9；19F NMR(375MHz,CDCl3)δ-109.5.
实施例47
1H NMR(400MHz,CDCl3)δ8.31(d,J＝7.8Hz,1H),8.01(t,J＝7.8Hz,1H),7.63–7.58(m,2H),7.32(s,1H),7.29–7.22(m,4H),7.20–7.17(m,3H),7.09–7.06(m,1H),6.00–5.98(m,1H),4.07–3.98(m,2H),3.50–3.46(m,2H),2.66(t,J＝7.0Hz,2H),1.72–1.64(m,4H)；13CNMR(100MHz,CDCl3)δ163.2,162.9,151.0,148.2,142.1,139.8,137.2,135.3,130.7,128.55,128.48,128.4,126.5,126.0,125.2,124.1,122.7,83.1,51.0,39.6,35.6,29.2,28.9.
实施例48
/>
1H NMR(400MHz,CDCl3)δ8.20(d,J＝7.6Hz,1H),8.12(d,J＝8.2Hz,1H),7.98(t,J＝7.8Hz,1H),7.71(d,J＝7.6Hz,1H),7.55–7.47(m,2H),7.28(t,J＝8.2Hz,2H),7.19(t,J＝6.2Hz,3H),6.88(d,J＝7.6Hz,1H),6.87(s,1H),4.21-4.04(m,2H),3.42(q,J＝6.0Hz,2H),2.65(t,J＝7.2Hz,2H),2.26(s,3H),1.68-1.59(m,4H)；13C NMR(100MHz,CDCl3)δ162.9,156.6,149.9,149.8,148.3,141.8,138.9,138.4,128.2,128.1,126.4,125.6,122.9,120.4,113.0,79.9,52.9,39.1,35.3,28.8,28.5,23.7.
实施例49
1H NMR(400MHz,CDCl3)δ8.47(d,J＝1.6Hz,1H),8.23(d,J＝7.8Hz,1H),8.06(d,J＝5.2Hz,1H),8.00(t,J＝7.8Hz,1H),7.71(d,J＝7.8Hz,1H),7.43(t,J＝5.8Hz,1H),7.28(t,J＝7.6Hz,2H),7.20–7.17(m,3H),7.09(dd,J＝5.4,1.8Hz,1H),6.77(s,1H),4.19–4.04(m,2H),3.49–3.36(m,2H),2.66(t,J＝7.2Hz,2H),1.70–1.58(m,4H)；13C NMR(100MHz,CDCl3)δ163.6,163.1,150.32,150.31,149.4,148.3,146.2,142.1,139.5,128.6,128.5,126.8,126.0,123.5,121.9,116.7,80.1,52.9,39.5,35.6,29.1,28.8.
实施例50
1H NMR(400MHz,CDCl3)δ8.35(d,J＝8.4Hz,1H),8.14(t,J＝5.6Hz,2H),7.96–7.89(m,3H),7.74-764(m,3H),7.53(t,J＝7.2Hz,1H),7.41(t,J＝7.6Hz,2H),7.02(t,J＝6.0Hz,1H),6.83(s,1H),4.60(d,J＝16.6Hz,1H),4.13(d,J＝16.6Hz,1H),3.59–3.43(m,2H),3.11–2.97(m,2H),2.12–1.97(m,2H)；13C NMR(100MHz,CDCl3)δ200.0,163.5,163.4,150.1,150.0,149.5,147.6,139.1,138.5,136.7,133.3,128.7,128.2 127.0,123.3,121.3,116.7,80.2,53.2,39.3,36.1,23.8.
实施例51
1H NMR(400MHz,CDCl3)δ8.50(s,1H),8.35(d,J＝8.4Hz,1H),8.17(t,J＝5.8Hz,2H),7.97(t,J＝7.8Hz,1H),7.75–7.71(m,2H),7.56(d,J＝8.0Hz,2H),7.29(t,J＝7.8Hz,2H),7.10–7.06(m,2H),6.81(s,1H),4.45(d,J＝16.6Hz,1H),4.11(d,J＝16.6Hz,1H),3.62-3.44(m,2H),2.44–2.31(m,2H),2.03-1.95(m,2H)；13C NMR(100MHz,CDCl3)δ170.8,164.2,163.9,149.91,149.87,149.4,147.9,139.4,138.6,138.3,129.1,127.1,124.2,123.4,121.6,119.8,116.7,80.2,53.2,38.7,35.0,26.1.
实施例52
1H NMR(400MHz,CDCl3)δ8.37(d,J＝8.4Hz,1H),8.17–8.12(m,2H),8.06(t,J＝5.8Hz,1H),7.93(t,J＝7.6Hz,1H),7.72–7.68(m,2H),7.03(t,J＝6.2Hz,1H),6.79(s,1H),5.10(d,J＝16.8Hz,1H),4.07(d,J＝16.8Hz,1H),3.57–3.49(m,1H),3.41–3.34(m,1H),3.29–3.15(m,4H),2.38(t,J＝6.6Hz,2H),2.07–2.02(m,1H),1.91–1.81(m,1H),1.11(t,J＝7.0Hz,3H),0.97(t,J＝7.0Hz,3H)；13C NMR(100MHz,CDCl3)δ171.6,163.6,163.5,150.6,150.3,149.7,147.5,138.9,138.4,127.2,123.3,121.2,116.7,80.3,53.4,42.1,40.4,39.9,31.1,24.2,14.3,13.0.
实施例53
1H NMR(400MHz,CDCl3)δ8.36(d,J＝8.4Hz,1H),8.21(d,J＝8.0Hz,1H),8.16(d,J＝4.8Hz,1H),7.99(t,J＝7.6Hz,1H),7.77–7.71(m,2H),7.56(t,J＝6.0Hz,1H),7.08(dd,J1＝7.2Hz,J2＝5.2Hz,1H),6.82(s,1H),4.32(d,J＝16.4Hz,1H),4.11(d,J＝16.8Hz,1H),3.67(s,3H),3.48 -3.32(m,2H),2.36(t,J＝7.0Hz,2H),1.70–1.58(m,4H)；13C NMR(100MHz,CDCl3)δ174.0,163.5,163.3,150.3,149.8,149.6,147.8,139.3,138.6,126.9,123.4,121.4,116.6,80.2,53.2,51.8,39.0,33.5,29.0,22.0；
实施例54
1H NMR(400MHz,CDCl3)8.40(d,J＝8.4Hz,1H),8.21–8.16(m,3H),7.97(t,J＝7.6Hz,1H),7.73(t,J＝8.0Hz,2H),7.06(t,J＝6.0Hz,1H),6.81(s,1H),4.59(d,J＝16.4Hz,1H),4.12(d,J＝16.4Hz,1H),3.80–3.70(m,4H),3.65–3.54(m,1H),2.67–2.54(m,2H)；13C NMR(100MHz,CDCl3)δ173.1,163.2,163.0,150.4,150.3,149.7,147.6,139.1,138.5,127.6,123.3,121.3,116.8,80.3,53.5,52.1,34.8,33.6.
实施例55
1H NMR(400MHz,CDCl3)δ8.34(d,J＝8.4Hz,1H),8.22(d,J＝7.6Hz,1H),8.16(d,J＝4.4Hz,1H),7.99(t,J＝7.6Hz,1H),7.77–7.71(m,3H),7.09(t,J＝6.2Hz,1H),6.81(s,1H),4.34(d,J＝16.4Hz,1H),4.11(d,J＝16.4Hz,1H),3.69(t,J＝5.8Hz,2H),3.53–3.38(m,2H),1.87(s,1H),1.87–1.57(m,4H)；13C NMR(100MHz,CDCl3)δ163.9,163.3,150.5,149.8,149.5,147.8,139.3,138.6,127.0,123.5,121.5,116.6,80.3,62.5,53.3,39.2,29.9,26.2.
实施例56
1H NMR(400MHz,CDCl3)δ8.38(d,J＝8.4Hz,1H),8.22(d,J＝7.6Hz,1H),8.17(d,J＝4.0Hz,1H),7.99(t,J＝7.8Hz,1H),7.76(t,J＝7.8Hz,1H),7.71(d,J＝7.6Hz,1H),7.51(t,J＝5.2Hz,1H),7.10–7.07(m,1H),6.84(s,1H),4.28–4.09(m,2H),3.44–3.36(m,4H),1.66–1.53(m,4H),1.19(s,9H)；13C NMR(100MHz,CDCl3)δ163.2,163.1,150.3,149.6,149.5,147.7,139.2,138.5,126.6,123.2,121.3,116.6,80.1,72.6,60.9,53.0,39.3,27.8,27.6,26.5.
实施例57
1H NMR(400MHz,CDCl3)δ8.22(dd,J＝13.6,8.2Hz,2H),7.97(t,J＝7.6Hz,2H),7.69(d,J＝7.6Hz,1H),7.58–7.53(m,2H),6.81(s,1H),4.26(d,J＝16.4Hz,1H),4.09(d,J＝16.4Hz,1H),3.45–3.39(m,4H),3.33(s,3H),2.25(s,3H),1.65–1.59(m,4H)；13C NMR(100MHz,CDCl3)δ163.3,163.1,150.3,149.9,147.7,147.4,139.2,139.1,131.1,126.8,123.3,116.1,80.4,72.3,58.7,53.1,39.2,26.9,26.4,17.9.
实施例58
1H NMR(400MHz,CDCl3)δ8.23(d,J＝7.8Hz,1H),8.13(d,J＝4.4Hz,1H),7.93(t,J＝7.8Hz,1H),7.74(t,J＝5.2Hz,1H),7.59(d,J＝7.6Hz,1H),7.55(d,J＝7.8Hz,1H),7.15(dd,J＝7.6,4.8Hz,1H),6.46(s,1H),4.25(d,J＝16.4Hz,1H),4.09(d,J＝16.4Hz,1H),3.52–3.40(m,4H),3.33(s,3H),2.36(s,3H),1.69–1.63(m,4H)；13C NMR(100MHz,CDCl3)δ163.4,162.0,150.8,148.8,140.5,139.1,130.6,126.3,123.8,123.5,82.8,72.4,58.7,52.1,39.3,26.9,26.6,18.2.
实施例59
1H NMR(400MHz,CDCl3)δ7.94(d,J＝4.4Hz,1H),7.86(s,1H),7.74(d,J＝7.6Hz,1H),7.55(d,J＝7.8Hz,1H),7.37(t,J＝7.6Hz,1H),7.25(t,J＝8.4Hz,1H),7.17(dd,J1＝8.4Hz,J2＝4.8Hz,1H),6.75(t,J＝4.8Hz,1H),6.50(s,1H),4.18–4.06(m,2H),3.93(s,3H),3.41–3.37(m,4H),3.32(s,3H),1.68–1.61(m,4H)；13C NMR(100MHz,CDCl3)δ166.6,161.3,151.2,140.4,138.3,135.7,131.6,129.1,128.1,127.4,125.2,120.8,82.2,72.5,58.7,56.3,51.6,40.0,27.2,26.4.
实施例60
1H NMR(400MHz,CDCl3)δ7.85(s,1H),7.73(d,J＝7.2Hz,1H),7.55-7.48(m,2H),7.41-7.33(m,4H),7.30-7.23(m,4H),7.19(t,J＝7.4Hz,2H),6.12(s,1H),5.96(s,1H),3.92(d,J＝17.0Hz,1H),3.61(d,J＝17.0Hz,1H),3.47(q,J＝6.4Hz,2H),2.67(t,J＝7.2Hz,2H),1,76-1.63(m,4H)；13C NMR(100MHz,CDCl3)δ168.3,166.2,142.1,137.9,136.76,131.9,130.3,129.6,128.9,128.6,128.2,127.4,126.1,125.5,123.8,86.6,52.5,40.3,35.6,29.3,28.8.
实施例61
1H NMR(400MHz,CDCl3)δ7.87(s,1H),7.76(d,J＝7.6Hz,1H),7.55–7.48(m,2H),7.28(t,J＝7.0Hz,4H),7.23–7.16(m,4H),7.11(t,J＝7.0Hz,1H),7.06(d,J＝7.6Hz,1H),6.26(s,1H),5.95(s,1H),3.91(d,J＝16.8Hz,1H),3.57(d,J＝17.2Hz,1H),3.49–3.43(m,2H),2.66(t,J＝7.2Hz,2H),2.31(s,3H),1.73–1.62(m,4H)；13C NMR(100MHz,CDCl3)δ168.4,166.2,142.1,139.8,137.7,136.6,131.8,130.3,129.4,128.9,128.54,128.52,128.4,128.3,126.0,125.5,124.7,121.0,86.7,52.4,40.3,35.6,29.3,28.8,21.6.
实施例62
1H NMR(400MHz,CDCl3)δ7.89(s,1H),7.78(d,J＝7.6Hz,1H),7.52(t,J＝7.6Hz,1H),7.46(d,J＝7.6Hz,1H),7.26(t,J＝7.0Hz,3H),7.18–7.10(m,4H),6.92(t,J＝8.0Hz,1H),6.51(s,1H),5.98(s,1H),3.90(d,J＝17.2Hz,1H),3.55(d,J＝16.8Hz,1H),3.46–3.41(m,2H),2.64(t,J＝6.8Hz,2H),1.70–1.60(m,4H)；13C NMR(100MHz,CDCl3)δ168.4,166.1,162.8(J＝245.8Hz),142.1,139.3(J＝10.0Hz),136.7,131.2,130.7(J＝9.1Hz),130.33,128.8,128.50,128.46,126.0,125.4,118.4(J＝3.1Hz),114.0(J＝21.0Hz),110.7(J＝25.4Hz),86.0,52.3,40.2,35.5,29.2,28.8；19F NMR(375MHz,CDCl3)δ-109.9.
实施例63
1H NMR(400MHz,CDCl3)δ7.74(d,J＝7.6Hz,1H),7.56(s,1H),7.49(t,J＝7.6Hz,1H),7.31–7.26(m,7H),7.22–7.17(m,4H),6.19(s,1H),5.37(s,1H),5.30(d,J＝15.2Hz,1H),3.97(d,J＝14.8Hz,2H),3.82(d,J＝17.2Hz,1H),3.52(d,J＝17.2Hz,1H),3.45–3.43(m,2H),2.67(t,J＝7.2Hz,2H),1.75–1.61(m,4H)；13C NMR(100MHz,CDCl3)δ168.8,166.2,142.0,136.5,134.1,131.0,130.1,129.2,129.1,128.44,128.42,128.35,128.26,128.2,125.9,125.1,83.8,52.2,47.0,40.1,35.5,29.2,28.7.
实施例64
1H NMR(400MHz,CDCl3)δ7.72(s,1H),7.68(d,J＝7.6Hz,1H),7.49(t,J＝7.6Hz,1H),7.41(d,J＝8.0Hz,1H),7.28(t,J＝8.4Hz,2H),7.19(t,J＝7.2Hz,3H),6.96(s,1H),6.32(s,1H),6.11(s,1H),3.86(d,J＝17.2Hz,1H),3.59(d,J＝17.2Hz,1H),3.48–3.43(m,2H),2.67(t,J＝7.2Hz,2H),2.41(s,3H),1.74–1.62(m,4H)；13C NMR(100MHz,CDCl3)δ171.2,167.9,166.5,157.8,142.1,136.5,130.6,130.1,128.8,128.54,128.51,128.1,126.0,125.0,95.7,83.1,52.1,40.2,35.6,29.2,28.8,12.8.
实施例65
1H NMR(400MHz,CDCl3)δ8.25(d,J＝7.6Hz,1H),7.98(t,J＝7.8Hz,1H),7.68(s,1H),7.55(d,J＝7.8Hz,1H),7.37–7.26(m,8H),7.18(d,J＝6.4Hz,3H),6.01(s,1H),3.95(d,J＝16.8Hz,1H),3.66(d,J＝17.2Hz,1H),3.52–3.46(m,2H),2.67(t,J＝6.4Hz,2H),1.71–1.67(m,4H)；13C NMR(100MHz,CDCl3)δ168.5,163.0,151.3,149.8,142.2,139.9,137.7,129.7,128.6,128.5,127.7,126.0,124.5,124.3,123.4,86.8,53.2,39.6,35.6,29.3,28.9.
实施例66
1H NMR(400MHz,CDCl3)δ8.14(d,J＝7.6Hz,1H),8.01–7.98(m,2H),7.89(t,J＝7.8Hz,1H),7.70(d,J＝7.6Hz,1H),7.33(d,J＝8.0Hz,1H),7.25-7.22(m,1H),6.36(s,1H),3.99(d,J＝16.8Hz,1H),3.93(s,3H),3.66(d,J＝16.8Hz,1H),3.55–3.40(m,4H),3.33(s,3H),1.72–1.62(m,4H)；13C NMR(100MHz,CDCl3)δ167.5,163.4,150.8,150.7,150.6,140.5,139.9,139.2,124.6,124.3,122.7,121.2,85.2,72.3,58.7,56.5,53.3,39.4,27.1,26.6.
测试例1抗肿瘤活性测试实验
本发明采用CCK-8法测定了本发明制备的化合物对6种骨肉瘤细胞(SJSA-1、U2OS、HOS、MNNG/HOS、MG63、143b和SW1353)，1种胰腺癌细胞(PANC-1)，1种肺癌细胞(A549)和结肠癌细胞(HCT116)的增殖抑制效果。
1.接种细胞：
1)用含10％胎牛血清、1％青霉素和链霉素的1640培养液配成单个细胞悬液，以每孔2500个SJSA-1型骨肉瘤细胞接种到96孔细胞培养板，每孔体积100μl。
2)用含10％胎牛血清、1％青霉素和链霉素的DMEM培养液配成单个细胞悬液，以每孔2500个MNNG/HOS型骨肉瘤细胞接种到96孔细胞培养板，每孔体积100μl。
3)用含10％胎牛血清、1％青霉素和链霉素的McCoy'5A培养液配成单个细胞悬液，以每孔2500个U-2-OS型骨肉瘤细胞接种到96孔细胞培养板，每孔体积100μl。
4)用含10％胎牛血清、1％青霉素和链霉素的DMEM培养液配成单个细胞悬液，以每孔2500个MG63型骨肉瘤细胞接种到96孔细胞培养板，每孔体积100μl。
5)用含10％胎牛血清、1％青霉素和链霉素的1640培养液配成单个细胞悬液，以每孔2500个HOS型骨肉瘤细胞接种到96孔细胞培养板，每孔体积100μl。
6)用含10％胎牛血清、1％青霉素和链霉素的1640培养液配成单个细胞悬液，以每孔2500个143B型骨肉瘤细胞接种到96孔细胞培养板，每孔体积100μl。
7)用含10％胎牛血清、1％青霉素和链霉素的1640培养液配成单个细胞悬液，以每孔2500个A549型肺癌细胞接种到96孔细胞培养板，每孔体积100μl。
8)用含10％胎牛血清、1％青霉素和链霉素的1640培养液配成单个细胞悬液，以每孔2500个HCT116结直肠癌细胞接种到96孔细胞培养板，每孔体积100μl。
9)用含10％胎牛血清、1％青霉素和链霉素的1640培养液配成单个细胞悬液，以每孔2500个SW1353型骨肉瘤细胞接种到96孔细胞培养板，每孔体积100μl。
2.然后将本发明制备的21个化合物，用DMSO溶解，分别用对应的细胞培养基配制成终浓度为1μM的药物溶液，分别加入到十种不同细胞(100μL/孔)中，对照组加入1‰DMSO，CO2培养箱中培养72小时；
3.培养72h后倾去培养液，加入100μL 1:10稀释的CCK-8溶液，37℃孵育2小时后，使用LabServK3型酶标仪测450nm处吸光度A，参考波长620nm，计算细胞的存活率(见表1)。
4.细胞增殖活力(％)＝[A(加药)-A(空白)]/[A(0加药)-A(空白)]×100。
表1
表1展示了本发明的部分化合物的活性数据。由表1的数据可以看出，化合物2-7、11、13、15、17-21等14个化合物作用下，骨肉瘤细胞SJSA-1存活率低于10％，说明这14个化合物对骨肉瘤细胞SJSA-1有非常好的抑制作用；化合物2-7等13个化合物对骨肉瘤细胞U2OS具有一定的抑制作用；化合物4-6等7个化合物作用下，骨肉瘤细胞HOS存活率低于10％，说明这7个化合物对HOS细胞具有较好的抑制作用；化合物2等14个化合物对MNNG/HOS细胞具有很好的抑制作用；化合物1等14个化合物对MG63细胞具有很好的抑制作用；化合物5和6两个化合物对143b细胞具有很好的抑制作用；化合物11等2个化合物对人结肠癌细胞HCT116具有较好的抑制作用；化合物4等3个化合物对肺癌细胞A549具有很好的抑制作用；化合物2等14个化合物对骨肉瘤SW1353细胞具有一定的抑制作用。未展示的化合物对上述细胞也具有一定抑制增殖活性。
测试例2代谢稳定性
在上述的化合物中，从结构和活性角度，选择了化合物17和18进行肝微粒测试，发现相对于发明人之前研究的化合物R-8i，化合物17和18，在MNNG-HOS细胞中的抑制活性有200nM，但是，在人和鼠的体外肝微粒代谢实验中，半衰期都得到提高，最好的能够到达156分钟，提高了75倍。代谢生物利用度由差转为中等偏良好。
表2化合物的肝微粒体稳定性a
a微球体的稳定性由中国科学院上海药物研究所进行。
b肝微粒体固有清除率(mL/min/g蛋白质)。
c代谢稳定性标准：代谢稳定性>70，稳定性好；70>代谢稳定性>30，中度稳定性；代谢稳定性<30，稳定性差。
R-8i：/>
Claims (10)
1.式I所示的化合物或其药学上可接受的盐：
其中Y选自Z选自N或CR6；X选自CH2、O、NH；n为0～5的整数；
R1选自6-10元芳基、9-10元苯并杂环基、C3-C6环烷基、Ph(CH2)m-或5-10元杂芳基；所述6-10元芳基、9-10元苯并杂环基、C3-C6环烷基、Ph(CH2)m-或5-10元杂芳基任选地被一个或多个R7取代；其中m为1-3的整数；
R2、R6和R7独立地选自H、氰基、卤素、NO2、羟基、-NR8R9、C1-C6烷基、(C1-C6烷基)-O-、(C1-C6烷基)-S-、(C1-C6烷基)-C(O)-、PhC(O)-、(C1-C6烷基)-OC(O)-、R8R9NC(O)-、C2-C6烯基、C2-C6炔基、C3-C6环烷基、C3-C6环烯基、6-10元芳基、3-10元杂环烷基或5-10元杂芳基；其中所述C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、C3-C6环烯基、6-10元芳基、3-10元杂环烷基或5-10元杂芳基任选地被H、卤素、氰基、羟基、-NR8R9、NO2、C1-C3烷基、C1-C3烷氧基或卤代C1-C3烷基取代；
R3选自H、羟基、6-10元芳基、5-10元杂芳基、(C1-C6烷基)-O-、(C1-C6烷基)-OC(O)-、R8R9NC(O)-、PhC(O)-、Ph(CH2)qO-，其中q为1-3的整数；
R4和R5独立地选自H，C1-C6烷基；
R8和R9各自独立地选自H、苯基或C1-C6烷基。
2.根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，Z选自N或CH；n为0～2的整数；优选地，R4和R5选自H。
3.根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，R1选自苯基、萘基、吡啶基、苯并[d][1,3]二恶唑基、环丙基、环己烷基、苄基、苯乙烷基、喹啉基、异恶唑基，上述基团任选地被一个或多个R7取代；优选地，R1选自苯基、萘基、 上述基团任选地被一个或多个R7取代；优选地，所述R7选自H、C1-C6烷基、卤素、羟基、(C1-C6烷基)-O-或6-10元芳基；更优选地，所述R7选自H、CH3、F、OH、CH3O-、Cl或苯基。
4.根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，R2选自H、C2-C6炔基、(C1-C6烷基)-OC(O)-或6-10元芳基；优选地，R2选自H、乙炔基、CH3OC(O)-或苯基。
5.根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，R3选自H、羟基、苯基、CH3O-、(CH3)3CO-、/>
6.下列化合物或其药学上可接受的盐，
7.一种药物组合物，其包含治疗有效量的权利要求1所述的式I化合物或其药学上可接受的盐和药学上可接受的载体，其中，所述药物组合物被配制成丸剂、胶囊剂、乳膏、凝胶剂、赋形剂、可注射流体、气雾剂、糖浆剂或透皮贴剂。
8.权利要求1所述式I化合物或药学上可接受的盐，或权利要求7所述的药物组合物在制备预防和/或治疗肿瘤的药物中的应用，其中，所述式I化合物用于抑制肿瘤细胞的增殖、生长、迁移、浸润、转移和复发，或促进肿瘤细胞的凋亡。
9.根据权利要求8的应用，其特征在于，所述肿瘤为骨肉瘤、人结肠癌、肺癌或乳腺癌；所述肿瘤细胞包括骨肉瘤细胞、肺癌细胞和结直肠癌细胞，骨肉瘤细胞包括SJSA-1、U2OS、HOS、MNNG/HOS、MG63、143b和SW1353；所述肺癌细胞包括A549；所述结直肠癌细胞包括HCT116。
10.一种制备权利要求1所述式I化合物的方法，包括合成方案1或2：
合成方案1：
其中R1、R2、R3、R4、R5、X、Y、Z、n同式I化合物所定义；
化合物1-1在酸性条件下合成二甲酸甲酯类化合物，随后，在碱性条件下，单一水解一个酯基，得到化合物1-2；化合物1-2和化合物发生缩合，得到化合物1-3；化合物1-3经过还原甲酯得到相应的醇类化合物1-4，随后氧化得到醛类化合物1-5；化合物1-5、化合物R1NH2和化合物/>发生3组分一锅法的反应得到化合物1-6，化合物1-6在间氯过氧苯甲酸的作用下按条件氧化得到亚砜和砜类化合物1-7；
合成方案2：
其中R1、R2、R3、R4、R5、X、Y、Z、n同式I化合物所定义；
化合物1-1在酸性条件下合成二甲酸甲酯类化合物2-2，化合物2-2与硼氢化钠发生单一酯还原得到醇类化合物2-3；化合物2-3被IBX氧化得到化合物2-4，化合物2-4在经过在碱性条件下的水解得到化合物2-5，化合物2-5和化合物发生缩合，得到化合物2-6，化合物2-6、化合物R1NH2和化合物/>发生3组分一锅法的反应得到化合物2-7，化合物2-7在间氯过氧苯甲酸的作用下按条件氧化得到亚砜和砜类化合物2-8。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311503289.4A CN117567457A (zh) | 2023-11-13 | 2023-11-13 | 噻唑酮亚砜和砜类化合物及其制备方法和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311503289.4A CN117567457A (zh) | 2023-11-13 | 2023-11-13 | 噻唑酮亚砜和砜类化合物及其制备方法和应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117567457A true CN117567457A (zh) | 2024-02-20 |
Family
ID=89890935
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311503289.4A Pending CN117567457A (zh) | 2023-11-13 | 2023-11-13 | 噻唑酮亚砜和砜类化合物及其制备方法和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117567457A (zh) |
-
2023
- 2023-11-13 CN CN202311503289.4A patent/CN117567457A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2020203882A1 (en) | Compounds and uses thereof for the modulation of hemoglobin | |
| EP3495354A1 (en) | Ido1 inhibitor and preparation method and application thereof | |
| CN113087712B (zh) | L-氨基酸-6-胶霉毒素酯三氟乙酸盐及其制备方法 | |
| CN110627801A (zh) | 一类hdac抑制剂及其用途 | |
| CN114751891B (zh) | 一种(2-(1h-吲哚-3-基)-1h-咪唑-4-基)苯基甲酮类化合物及其应用 | |
| JP7050054B2 (ja) | Ｐｄｅ４阻害剤としての縮合環系化合物 | |
| CN110590796A (zh) | 喜树碱衍生物及其制备方法和应用 | |
| CN111704646A (zh) | 甾体类化合物及其制备方法和用途 | |
| CN113416189B (zh) | 一类β-卡波林氮芥衍生物、制备方法和抗肿瘤用途 | |
| CN110156817B (zh) | 双吴茱萸碱分子抗肿瘤衍生物及其制备与应用 | |
| CN115043826B (zh) | 一类青藤碱呋咱衍生物及其制备方法和应用 | |
| CN117567457A (zh) | 噻唑酮亚砜和砜类化合物及其制备方法和应用 | |
| CN112500412B (zh) | 一种Peganumine A生物碱结构简化物及应用 | |
| CN105985349B (zh) | 七元环小檗碱类似物及其药物组合物、制备方法和用途 | |
| CN110256405B (zh) | 5-烃基-n-取代芳基吡啶酮衍生物及其制备方法和用途 | |
| CN110759961B (zh) | 一类熊果酸吲哚醌酰胺衍生物及其制备方法和应用 | |
| CN109748914B (zh) | 吡啶并嘧啶类化合物及其应用 | |
| WO2022134262A1 (zh) | 二吡咯甲烯-1-酮类化合物及其制备方法 | |
| JP6059734B2 (ja) | ２−アルキル−又は２−アリール−置換タンシノン誘導体、その調製方法及び適用 | |
| CN111808121A (zh) | 一类含杂原子的新型高b环小檗碱类似物及其c-h活化合成方法 | |
| CZ2000711A3 (cs) | Opticky čisté analogy kamptothecinu, meziprodukty syntézy a způsob přípravy | |
| CN109776411B (zh) | 氮芥喹诺酮衍生物及其制备方法和应用 | |
| CN114437102B (zh) | 一种新型的冬凌草甲素去6位羟基衍生物、其制备方法及医药用途 | |
| CN114560845B (zh) | 喹啉化合物的晶型ɑ及其制备方法和应用 | |
| CN113563330B (zh) | 一类β-卡波林的3位衍生物及其制备方法和用途 |
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 |