WO2019085978A1 - 杂芳基酰胺类化合物、其制备方法、药用组合物及其应用 - Google Patents
杂芳基酰胺类化合物、其制备方法、药用组合物及其应用 Download PDFInfo
- Publication number
- WO2019085978A1 WO2019085978A1 PCT/CN2018/113549 CN2018113549W WO2019085978A1 WO 2019085978 A1 WO2019085978 A1 WO 2019085978A1 CN 2018113549 W CN2018113549 W CN 2018113549W WO 2019085978 A1 WO2019085978 A1 WO 2019085978A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- group
- piperidinyl
- piperazinyl
- substituted
- Prior art date
Links
- -1 Heteroaryl amide compounds Chemical class 0.000 title claims abstract description 618
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 257
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 110
- 229910052739 hydrogen Inorganic materials 0.000 claims description 42
- 125000004193 piperazinyl group Chemical group 0.000 claims description 42
- 150000003839 salts Chemical class 0.000 claims description 37
- 125000003386 piperidinyl group Chemical group 0.000 claims description 36
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 28
- 239000011737 fluorine Substances 0.000 claims description 28
- 229910052731 fluorine Inorganic materials 0.000 claims description 28
- 125000001424 substituent group Chemical group 0.000 claims description 27
- 125000000623 heterocyclic group Chemical group 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 20
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 18
- 239000000651 prodrug Substances 0.000 claims description 17
- 229940002612 prodrug Drugs 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 15
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- 239000012453 solvate Substances 0.000 claims description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- 125000005429 oxyalkyl group Chemical group 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000002541 furyl group Chemical group 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000002883 imidazolyl group Chemical group 0.000 claims description 9
- 125000004076 pyridyl group Chemical group 0.000 claims description 9
- 125000001544 thienyl group Chemical group 0.000 claims description 9
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 8
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 8
- 125000006823 (C1-C6) acyl group Chemical group 0.000 claims description 7
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 7
- 125000003277 amino group Chemical group 0.000 claims description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 7
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 7
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 6
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 6
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 6
- 125000006163 5-membered heteroaryl group Chemical class 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- MFNYBOWJWGPXFM-UHFFFAOYSA-N cyclobutanecarboxamide Chemical compound NC(=O)C1CCC1 MFNYBOWJWGPXFM-UHFFFAOYSA-N 0.000 claims description 6
- PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- XRLDSWLMHUQECH-UHFFFAOYSA-N cyclopentanecarboxamide Chemical compound NC(=O)C1CCCC1 XRLDSWLMHUQECH-UHFFFAOYSA-N 0.000 claims description 6
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 claims description 6
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 6
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims description 6
- 125000006126 n-butyl sulfonyl group Chemical group 0.000 claims description 6
- 125000006124 n-propyl sulfonyl group Chemical group 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000004428 fluoroalkoxy group Chemical group 0.000 claims description 5
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- FWEBZXSOLOXPEH-UHFFFAOYSA-N N-[3-[(ethylsulfonylamino)sulfamoyl]propyl]methanesulfonamide Chemical compound CCS(=O)(=O)NNS(=O)(=O)CCCNS(=O)(=O)C FWEBZXSOLOXPEH-UHFFFAOYSA-N 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 4
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 4
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 201000008968 osteosarcoma Diseases 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- DVOVBGJJSFSOPZ-UHFFFAOYSA-N 2-acetamidopropanamide Chemical compound NC(=O)C(C)NC(C)=O DVOVBGJJSFSOPZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 150000003857 carboxamides Chemical class 0.000 claims description 2
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims 12
- 206010027476 Metastases Diseases 0.000 claims 1
- 230000009401 metastasis Effects 0.000 claims 1
- 230000004614 tumor growth Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 62
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000000543 intermediate Substances 0.000 description 34
- 239000007858 starting material Substances 0.000 description 33
- 235000019439 ethyl acetate Nutrition 0.000 description 26
- 210000004027 cell Anatomy 0.000 description 21
- 239000000203 mixture Substances 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 13
- 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 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- LUMJVOCXIGRWEH-UHFFFAOYSA-N 4h-pyrrolo[2,3-d][1,3]thiazole-5-carboxylic acid Chemical compound S1C=NC2=C1C=C(C(=O)O)N2 LUMJVOCXIGRWEH-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 201000010099 disease Diseases 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 238000001308 synthesis method Methods 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 150000008052 alkyl sulfonates Chemical class 0.000 description 8
- 125000005228 aryl sulfonate group Chemical group 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 239000007821 HATU Substances 0.000 description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000010189 synthetic method Methods 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 description 6
- 239000011707 mineral Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 125000001153 fluoro group Chemical group F* 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 239000003643 water by type Substances 0.000 description 5
- KPGXRSRHYNQIFN-UHFFFAOYSA-L 2-oxoglutarate(2-) Chemical compound [O-]C(=O)CCC(=O)C([O-])=O KPGXRSRHYNQIFN-UHFFFAOYSA-L 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 229910002651 NO3 Inorganic materials 0.000 description 4
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 4
- 229940072107 ascorbate Drugs 0.000 description 4
- 235000010323 ascorbic acid Nutrition 0.000 description 4
- 239000011668 ascorbic acid Substances 0.000 description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 125000002837 carbocyclic group Chemical group 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000002502 liposome Substances 0.000 description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 3
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 3
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 3
- LDFOPBTWMRPREB-UHFFFAOYSA-N 4h-pyrrolo[3,2-d][1,3]thiazole-5-carboxylic acid Chemical compound N1=CSC2=C1C=C(C(=O)O)N2 LDFOPBTWMRPREB-UHFFFAOYSA-N 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 0 CC(C)C=CC[Mn]c(c(N)c(c(N*)c1O)N)c1NC=C Chemical compound CC(C)C=CC[Mn]c(c(N)c(c(N*)c1O)N)c1NC=C 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 125000004663 dialkyl amino group Chemical group 0.000 description 3
- 125000006001 difluoroethyl group Chemical group 0.000 description 3
- 239000002270 dispersing agent Substances 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 150000007522 mineralic acids Chemical group 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000002953 preparative HPLC Methods 0.000 description 3
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 3
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 3
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 3
- 239000011593 sulfur Chemical group 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- YTHHMLBZZWWLCK-UHFFFAOYSA-N (3-nitrophenyl)methyl methanesulfonate Chemical compound CS(=O)(=O)OCC1=CC(=CC=C1)[N+](=O)[O-] YTHHMLBZZWWLCK-UHFFFAOYSA-N 0.000 description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 2
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 2
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-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
- IRTCAMYFJKXIEV-UHFFFAOYSA-N 1-[(4-methylsulfanylphenoxy)methyl]-3-nitrobenzene Chemical compound CSC1=CC=C(C=C1)OCC1=CC(=CC=C1)[N+](=O)[O-] IRTCAMYFJKXIEV-UHFFFAOYSA-N 0.000 description 2
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-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
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- XUJFOSLZQITUOI-UHFFFAOYSA-N 4-(trifluoromethoxy)aniline Chemical compound NC1=CC=C(OC(F)(F)F)C=C1 XUJFOSLZQITUOI-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- IMPPGHMHELILKG-UHFFFAOYSA-N 4-ethoxyaniline Chemical compound CCOC1=CC=C(N)C=C1 IMPPGHMHELILKG-UHFFFAOYSA-N 0.000 description 2
- IPDCVNLRSZTOHO-UHFFFAOYSA-N 4-methylpyrrolo[2,3-d][1,3]thiazole-5-carboxylic acid Chemical compound Cn1c(cc2scnc12)C(O)=O IPDCVNLRSZTOHO-UHFFFAOYSA-N 0.000 description 2
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- 241000167854 Bourreria succulenta Species 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- 101000573199 Homo sapiens Protein PML Proteins 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 125000001769 aryl amino group Chemical group 0.000 description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 235000019693 cherries Nutrition 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 description 2
- 125000005170 cycloalkyloxycarbonyl group Chemical group 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 125000006517 heterocyclyl carbonyl group Chemical group 0.000 description 2
- 102000054896 human PML Human genes 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 210000005265 lung cell Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- YEPWCJHMSVABPQ-UHFFFAOYSA-N methyl 3-amino-4-methylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(N)=C1 YEPWCJHMSVABPQ-UHFFFAOYSA-N 0.000 description 2
- VZDNXXPBYLGWOS-UHFFFAOYSA-N methyl 3-aminobenzoate Chemical compound COC(=O)C1=CC=CC(N)=C1 VZDNXXPBYLGWOS-UHFFFAOYSA-N 0.000 description 2
- LZXXNPOYQCLXRS-UHFFFAOYSA-N methyl 4-aminobenzoate Chemical compound COC(=O)C1=CC=C(N)C=C1 LZXXNPOYQCLXRS-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 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 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- TXEYQDLBPFQVAA-UHFFFAOYSA-N tetrafluoromethane Chemical compound FC(F)(F)F TXEYQDLBPFQVAA-UHFFFAOYSA-N 0.000 description 2
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 description 1
- FSMDIXFTJVXPHR-UHFFFAOYSA-N (4-propan-2-yloxyphenyl)carbamic acid Chemical compound CC(C)OC1=CC=C(NC(O)=O)C=C1 FSMDIXFTJVXPHR-UHFFFAOYSA-N 0.000 description 1
- 125000002733 (C1-C6) fluoroalkyl group Chemical group 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- CSEWAUGPAQPMDC-UHFFFAOYSA-N 2-(4-aminophenyl)acetic acid Chemical compound NC1=CC=C(CC(O)=O)C=C1 CSEWAUGPAQPMDC-UHFFFAOYSA-N 0.000 description 1
- IJGNOXRNUJCZJK-UHFFFAOYSA-N 3-[(4-methylsulfanylphenoxy)methyl]aniline Chemical compound C1=CC(SC)=CC=C1OCC1=CC=CC(N)=C1 IJGNOXRNUJCZJK-UHFFFAOYSA-N 0.000 description 1
- CJYDQTAWSHWBIT-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(2-hydroxy-2-methylpropyl)benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCC(C)(C)O)C=CC=1 CJYDQTAWSHWBIT-UHFFFAOYSA-N 0.000 description 1
- CWNPOQFCIIFQDM-UHFFFAOYSA-N 3-nitrobenzyl alcohol Chemical compound OCC1=CC=CC([N+]([O-])=O)=C1 CWNPOQFCIIFQDM-UHFFFAOYSA-N 0.000 description 1
- QASBCTGZKABPKX-UHFFFAOYSA-N 4-(methylsulfanyl)phenol Chemical compound CSC1=CC=C(O)C=C1 QASBCTGZKABPKX-UHFFFAOYSA-N 0.000 description 1
- APRZHQXAAWPYHS-UHFFFAOYSA-N 4-[5-[3-(carboxymethoxy)phenyl]-3-(4,5-dimethyl-1,3-thiazol-2-yl)tetrazol-3-ium-2-yl]benzenesulfonate Chemical compound S1C(C)=C(C)N=C1[N+]1=NC(C=2C=C(OCC(O)=O)C=CC=2)=NN1C1=CC=C(S([O-])(=O)=O)C=C1 APRZHQXAAWPYHS-UHFFFAOYSA-N 0.000 description 1
- AQEFYZWJSZQKRN-UHFFFAOYSA-N 4-methylpyrrolo[3,2-d][1,3]thiazole-5-carboxylic acid Chemical compound Cn1c(cc2ncsc12)C(O)=O AQEFYZWJSZQKRN-UHFFFAOYSA-N 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- RXGJTUSBYWCRBK-UHFFFAOYSA-M 5-methylphenazinium methyl sulfate Chemical compound COS([O-])(=O)=O.C1=CC=C2[N+](C)=C(C=CC=C3)C3=NC2=C1 RXGJTUSBYWCRBK-UHFFFAOYSA-M 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 125000005330 8 membered heterocyclic group Chemical group 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- BHNISTGQBAPFFE-UHFFFAOYSA-N CN1C(=CC2=C1N=CS2)C(=O)O.CN2C(=CC1=C2N=CS1)C(=O)O Chemical compound CN1C(=CC2=C1N=CS2)C(=O)O.CN2C(=CC1=C2N=CS1)C(=O)O BHNISTGQBAPFFE-UHFFFAOYSA-N 0.000 description 1
- HSGJHWJAPOQBHH-UHFFFAOYSA-N CN1C(=CC=2N=CSC21)C(=O)O.CN2C(=CC=1N=CSC12)C(=O)O Chemical compound CN1C(=CC=2N=CSC21)C(=O)O.CN2C(=CC=1N=CSC12)C(=O)O HSGJHWJAPOQBHH-UHFFFAOYSA-N 0.000 description 1
- NNTGZEGNGUUTRL-UHFFFAOYSA-N COC(c1cc(NC(c([nH]2)cc3c2nc[s]3)=O)ccc1)=O Chemical compound COC(c1cc(NC(c([nH]2)cc3c2nc[s]3)=O)ccc1)=O NNTGZEGNGUUTRL-UHFFFAOYSA-N 0.000 description 1
- ZONLFBBCSULPOG-UHFFFAOYSA-N COc(cc1)ccc1OCc1cc(NC(c([nH]2)cc3c2nc[s]3)=O)ccc1 Chemical compound COc(cc1)ccc1OCc1cc(NC(c([nH]2)cc3c2nc[s]3)=O)ccc1 ZONLFBBCSULPOG-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 240000001238 Gaultheria procumbens Species 0.000 description 1
- 235000007297 Gaultheria procumbens Nutrition 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000006679 Mentha X verticillata Nutrition 0.000 description 1
- 235000002899 Mentha suaveolens Nutrition 0.000 description 1
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000238367 Mya arenaria Species 0.000 description 1
- JITKUDZBHHDTDV-UHFFFAOYSA-N NCc1ccccc1-c1cc(cccc2)c2[o]1 Chemical compound NCc1ccccc1-c1cc(cccc2)c2[o]1 JITKUDZBHHDTDV-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- PUZGHZYSPUJIIZ-UHFFFAOYSA-N [O-][N+](c(cc1)ccc1NC(c([nH]1)cc2c1nc[s]2)=O)=O Chemical compound [O-][N+](c(cc1)ccc1NC(c([nH]1)cc2c1nc[s]2)=O)=O PUZGHZYSPUJIIZ-UHFFFAOYSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000676 alkoxyimino group Chemical group 0.000 description 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 description 1
- 125000004948 alkyl aryl alkyl group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 1
- 125000005120 alkyl cycloalkyl alkyl group Chemical group 0.000 description 1
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 description 1
- 125000005213 alkyl heteroaryl group Chemical group 0.000 description 1
- 125000005600 alkyl phosphonate group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 125000005122 aminoalkylamino group Chemical group 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000001691 aryl alkyl amino group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005100 aryl amino carbonyl group Chemical group 0.000 description 1
- 125000004658 aryl carbonyl amino group Chemical group 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 125000005199 aryl carbonyloxy group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000007958 cherry flavor Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000004465 cycloalkenyloxy group Chemical group 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 description 1
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 description 1
- 125000004472 dialkylaminosulfonyl group Chemical group 0.000 description 1
- 125000004986 diarylamino group Chemical group 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- GJYVZUKSNFSLCL-UHFFFAOYSA-N dichloromethanol Chemical compound OC(Cl)Cl GJYVZUKSNFSLCL-UHFFFAOYSA-N 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- XWFJPGZVQINIEB-UHFFFAOYSA-N ethyl 4-methylpyrrolo[2,3-d][1,3]thiazole-5-carboxylate Chemical compound CCOC(=O)c1cc2scnc2n1C XWFJPGZVQINIEB-UHFFFAOYSA-N 0.000 description 1
- QTXMGEFQNFKHPS-UHFFFAOYSA-N ethyl 4-methylpyrrolo[3,2-d][1,3]thiazole-5-carboxylate Chemical compound CCOC(=O)c1cc2ncsc2n1C QTXMGEFQNFKHPS-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000007614 genetic variation Effects 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 235000015220 hamburgers Nutrition 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 125000005241 heteroarylamino group Chemical group 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 1
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000005191 hydroxyalkylamino group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000005040 ion trap Methods 0.000 description 1
- 238000000534 ion trap mass spectrometry Methods 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
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000003041 laboratory chemical Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000012177 large-scale sequencing Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 238000002156 mixing Methods 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
- HLKXEQAYKCBPNT-UHFFFAOYSA-N n-methyl-4-propan-2-yloxyaniline Chemical compound CNC1=CC=C(OC(C)C)C=C1 HLKXEQAYKCBPNT-UHFFFAOYSA-N 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
- 239000007908 nanoemulsion Substances 0.000 description 1
- 239000002077 nanosphere Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000002353 niosome Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000005173 quadrupole mass spectroscopy Methods 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007892 solid unit dosage form Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 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
- MCDZFKYXODNTBB-UHFFFAOYSA-N tert-butyl n-(4-propan-2-yloxyphenyl)carbamate Chemical compound CC(C)OC1=CC=C(NC(=O)OC(C)(C)C)C=C1 MCDZFKYXODNTBB-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Definitions
- the present invention relates to the field of medicinal chemistry, and in particular to a class of compounds having broad spectrum antitumor activity, a process for the preparation thereof, a pharmaceutical composition comprising the same, and the use of these compounds in the manufacture of a medicament for treating a tumor.
- Tumors are malignant diseases that seriously threaten the health of human life, and their overall incidence is still on the rise in the world.
- the large-scale sequencing of tumor genomes in recent years has revealed the high complexity of tumor genetic variation. Many tumor cells have multiple tumor-driven mutant genes, tumor heterogeneity and tumor evolution, and most tumor-driven mutant genes are difficult to become therapeutic. Challenges such as targets.
- the present invention aims to obtain a compound having a broad spectrum of antitumor activity.
- the inventors of the present invention have designed and synthesized a series of heteroaryl amide derivatives with novel structure, high safety and high activity, and studied this kind of research.
- the inhibitory activity of the novel derivatives on tumors are designed and synthesized.
- the present invention provides a compound of the formula:
- Another object of the present invention is to provide a process for the preparation of the above compounds.
- Another object of the present invention is to provide a pharmaceutical composition comprising the above compound.
- Another object of the present invention is to provide a use of the above compound and a pharmaceutical composition comprising the same for the preparation of an antitumor drug.
- the present invention has been achieved by the following technical solutions.
- the invention provides a compound of the formula:
- X 1 is selected from N, S;
- X 2 is selected from N, S; and
- X 1 is different from X 2 ;
- R 1 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl;
- R 2 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl;
- R 3 is selected from;
- Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently selected from:
- heterocyclic ring containing one or more heteroatoms selected from N, O and S, optionally a C1-C6 alkyl group, a C1-C6 alkane Oxyl, hydroxy, amino, C1-C6 alkoxycarbonyl, C1-C6 acyl, cyano, optionally substituted heterocyclic,
- piperidinyl 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidine 4-hydroxypiperidinyl, 4-(4-methylpiperazinyl)piperidinyl, 4-(4-ethylpiperazinyl)piperidinyl, 4-(4-isopropylpiperazinyl Piperidinyl, 4-(4-acetylpiperazinyl)piperidinyl, 4-(4-tert-butoxycarbonylpiperazinyl)piperidinyl, 4-(4-methanesulfonylpiperazinyl) Piperidinyl, 4-(4-(2-hydroxyethyl)piperazinyl)piperidinyl, 4-(4-(2-cyanoethyl)piperazinyl)piperidinyl, 4-(4- (3-hydroxypropyl)
- a heteroaryl group such as, but not limited to, a pyridyl group, a furyl group, a thienyl group, a benzofuranyl group;
- Z 2 and Z 3 may form an oxygen-containing substituted or unsubstituted five-membered or six-membered ring; the substituent may be selected from the same substituents as Z 1 ;
- Z 4 and Z 5 may form a nitrogen-containing substituted or unsubstituted five-membered or six-membered ring; the substituent may be selected from the same substituents as Z 1 ;
- R 1 is selected from the group consisting of H, C1-C3 alkyl.
- R 1 is selected from the group consisting of H, methyl, and ethyl.
- R 2 is selected from the group consisting of H, C1-C3 alkyl.
- R 2 is selected from the group consisting of H, methyl, and ethyl.
- the pharmaceutically acceptable salt is a mineral or organic acid salt, wherein the mineral acid salt is a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, a hydrogencarbonate. a salt and a carbonate, a sulfate or a phosphate, the organic acid salt being a formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartaric acid a salt, a citrate, an ascorbate, an alpha-ketoglutarate, an alpha-glycerophosphate, an alkylsulfonate or an arylsulfonate; preferably, the alkylsulfonate is methanesulfonic acid a salt or ethyl sulfonate; the aryl sulfonate being a besylate or p-toluenesulfonate.
- the mineral acid salt is a hydrochloride,
- the present invention provides a compound represented by the following formula I, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof,
- R 1 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl;
- R 2 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl;
- R 3 is selected from;
- Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently selected from:
- heterocyclic ring containing one or more heteroatoms selected from N, O and S, optionally a C1-C6 alkyl group, a C1-C6 alkane Oxyl, hydroxy, amino, C1-C6 alkoxycarbonyl, C1-C6 acyl, cyano, optionally substituted heterocyclic,
- piperidinyl 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidine 4-hydroxypiperidinyl, 4-(4-methylpiperazinyl)piperidinyl, 4-(4-ethylpiperazinyl)piperidinyl, 4-(4-isopropylpiperazinyl Piperidinyl, 4-(4-acetylpiperazinyl)piperidinyl, 4-(4-tert-butoxycarbonylpiperazinyl)piperidinyl, 4-(4-methanesulfonylpiperazinyl) Piperidinyl, 4-(4-(2-hydroxyethyl)piperazinyl)piperidinyl, 4-(4-(2-cyanoethyl)piperazinyl)piperidinyl, 4-(4- (3-hydroxypropyl)
- a heteroaryl group such as, but not limited to, a pyridyl group, a furyl group, a thienyl group, a benzofuranyl group;
- Z 2 and Z 3 may form an oxygen-containing substituted or unsubstituted five-membered or six-membered ring; the substituent may be selected from the same substituents as Z 1 ;
- Z 4 and Z 5 may form a nitrogen-containing substituted or unsubstituted five-membered or six-membered ring; the substituent may be selected from the same substituents as Z 1 ;
- R 1 is selected from the group consisting of H, C1-C3 alkyl.
- R 1 is selected from the group consisting of H, methyl, and ethyl.
- R 2 is selected from the group consisting of H, C1-C3 alkyl.
- R 2 is selected from the group consisting of H, methyl, and ethyl.
- R 3 is selected from:
- n 0, 1 or 2
- one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 is selected from the group consisting of -H: hydroxy, -O-C1-C6 alkyl, -O-C1-C6 Fluoroalkyl, -C1-C6 fluoroalkyl, -C1-C6 alkoxycarbonyl, amino, optionally -C1-C6 alkyl, -C1-C6 alkylsulfonyl or -C1-C6 alkylcarbonyl Substituted amino, aminosulfonyl, nitro, substituted phenyl-C1-C6 alkyl-aminocarbonyl-C1-C6 alkyl (more preferably phenyl-C1-C6 alkyl-aminocarbonyl-C1 substituted by halogen) -C6 alkyl), phenyl-O-C1-C6 alkyl substituted by C1-C
- two of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are independently selected from the following, and the rest are -H (more preferably Z 2 , Z 3 each or Z 1 , Z 4 each or Z 2 , Z 4 is each independently selected from the group consisting of -H): -C1-C6 fluoroalkyl group, 6-membered heterocyclic group -C1-C6 alkyl group substituted by -C1-C6 alkyl group (more preferably -C1) -C6 alkyl-substituted piperazinyl-C1-C6 alkyl), -C1-C6 alkyl, substituted phenylcarbonyl-amino, -C1-C6 alkyl-O-carbonyl, -C1-C6 alkyl 5-membered heteroaryl (more preferably -C1-C6 alkyl substituted imidazolyl);
- one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 is selected from the group consisting of -H: pyridyl, furyl, thienyl, benzofuranyl;
- one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 is selected from the group consisting of the following -H:aminosulfonyl group.
- R 3 is selected from:
- n 0 or 1
- Z 1 , Z 2 , Z 4 , Z 5 are each -H
- Z 3 is selected from the group consisting of hydroxyl group, -O-C1-C6 alkyl group, -O-C1-C6 fluorine-containing alkyl group, a -C1-C6 fluoroalkyl group, a -C1-C6 alkoxycarbonyl group, an amino group, an amino group optionally substituted by a -C1-C6 alkyl group, a -C1-C6 alkylsulfonyl group or a -C1-C6 alkylcarbonyl group, Aminosulfonyl, nitro;
- Z 2 or Z 4 is selected from the group consisting of -H:-C1-C6 alkoxycarbonyl, substituted phenyl-C1-C6 alkyl-aminocarbonyl-C1-C6 alkyl (more preferably substituted by halogen) Phenyl-C1-C6 alkyl-aminocarbonyl-C1-C6 alkyl) substituted by C1-C6 alkyl-O-, halogen, C1-C6 alkyl-S- or C1-C6 alkylsulfonyl phenyl-O-C1-C6 alkyl,
- Z 2 and Z 3 are each independently selected from the group consisting of -H:-C1-C6 fluorine-containing alkyl group, 6-membered heterocyclic group-C1-C6 alkyl group substituted by -C1-C6 alkyl group (more Preferred is piperazinyl-C1-C6 alkyl substituted by -C1-C6 alkyl);
- Z 1 , Z 4 are each independently selected from the group consisting of -H:-C1-C6 alkyl, substituted phenylcarbonyl-amino, -C1-C6 alkyl-O-carbonyl;
- Z 2 and Z 4 are each independently selected from the group consisting of -H:-C1-C6 fluorine-containing alkyl group, -C1-C6 alkyl-substituted 5-membered heteroaryl group (more preferably -C1-C6 alkyl group). Substituted imidazolyl);
- Z 1 or Z 5 is selected from the group consisting of -H: pyridin-4-yl, pyridin-3-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, Thiophen-3-yl, benzofuranyl;
- Z 1 , Z 2 , Z 4 , Z 5 are each -H, and Z 3 is an aminosulfonyl group.
- R 3 is selected from:
- the pharmaceutically acceptable salt is a mineral or organic acid salt, wherein the mineral acid salt is a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, a hydrogencarbonate. a salt and a carbonate, a sulfate or a phosphate, the organic acid salt being a formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartaric acid a salt, a citrate, an ascorbate, an alpha-ketoglutarate, an alpha-glycerophosphate, an alkylsulfonate or an arylsulfonate; preferably, the alkylsulfonate is methanesulfonic acid a salt or ethyl sulfonate; the aryl sulfonate being a besylate or p-toluenesulfonate.
- the mineral acid salt is a hydrochloride,
- the present invention provides a compound of the following formula II, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof:
- R 1 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl;
- R 2 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl;
- R 3 is selected from:
- Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently selected from:
- heterocyclic ring containing one or more heteroatoms selected from N, O and S, optionally a C1-C6 alkyl group, a C1-C6 alkane Oxyl, hydroxy, amino, C1-C6 alkoxycarbonyl, C1-C6 acyl, cyano, optionally substituted heterocyclic,
- piperidinyl 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidine 4-hydroxypiperidinyl, 4-(4-methylpiperazinyl)piperidinyl, 4-(4-ethylpiperazinyl)piperidinyl, 4-(4-isopropylpiperazinyl Piperidinyl, 4-(4-acetylpiperazinyl)piperidinyl, 4-(4-tert-butoxycarbonylpiperazinyl)piperidinyl, 4-(4-methanesulfonylpiperazinyl) Piperidinyl, 4-(4-(2-hydroxyethyl)piperazinyl)piperidinyl, 4-(4-(2-cyanoethyl)piperazinyl)piperidinyl, 4-(4- (3-hydroxypropyl)
- a heteroaryl group such as, but not limited to, a pyridyl group, a furyl group, a thienyl group, a benzofuranyl group;
- Z 2 and Z 3 may form an oxygen-containing substituted or unsubstituted five-membered or six-membered ring; the substituent may be selected from the same substituents as Z 1 ;
- Z 4 and Z 5 may form a nitrogen-containing substituted or unsubstituted five-membered or six-membered ring; the substituent may be selected from the same substituents as Z 1 ;
- R 1 is selected from the group consisting of H, C1-C3 alkyl.
- R 1 is selected from the group consisting of H, methyl, and ethyl.
- R 2 is selected from the group consisting of H, C1-C3 alkyl.
- R 2 is selected from the group consisting of H, methyl, and ethyl.
- R 3 is selected from:
- n 0 or 1
- one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 is selected from the group consisting of -H: hydroxy, -O-C1-C6 alkyl, -O-C1-C6 Fluoroalkyl, -C1-C6 fluoroalkyl;
- two of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are independently selected from the group consisting of -H (more preferably Z 2 , Z 4 or Z 2 , and Z 3 are each independently selected from Hereinafter, the remainder is -H): -C1-C6 fluorine-containing alkyl group, -C1-C6 alkyl-substituted 5-membered heteroaryl group (more preferably -C1-C6 alkyl-substituted imidazolyl group), -C1-C6 An alkyl-substituted 6-membered heterocyclic-C1-C6 alkyl group (more preferably a piperazinyl-C1-C6 alkyl group substituted by a -C1-C6 alkyl group);
- n 1
- Z 1 , Z 2 , Z 3 , Z 4 , Z 5 is a benzofuranyl group, and the rest is -H.
- R 3 is selected from:
- n 0 or 1
- Z 1 , Z 2 , Z 4 , Z 5 are each -H, and Z 3 is selected from the group consisting of hydroxyl group, -O-C1-C6 alkyl group, -O-C1-C6 fluorine-containing alkyl group, -C1-C6 fluorine-containing alkyl group;
- Z 2 and Z 4 are each independently selected from the group consisting of -H:-C1-C6 fluorine-containing alkyl group, -C1-C6 alkyl-substituted 5-membered heteroaryl group (more preferably -C1-C6 alkyl group). Substituted imidazolyl);
- Z 2 , Z 3 or Z 3 , Z 4 are each independently selected from the group consisting of -H:-C1-C6 fluorine-containing alkyl group, 6-membered heterocyclic group substituted by -C1-C6 alkyl group- a C1-C6 alkyl group (more preferably a piperazinyl-C1-C6 alkyl group substituted by a -C1-C6 alkyl group);
- Z 1 , Z 3 , Z 4 , Z 5 are each -H, and Z 2 is a benzofuranyl group.
- R 3 is selected from:
- the pharmaceutically acceptable salt is a mineral or organic acid salt, wherein the mineral acid salt is a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, a hydrogencarbonate. a salt and a carbonate, a sulfate or a phosphate, the organic acid salt being a formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartaric acid a salt, a citrate, an ascorbate, an alpha-ketoglutarate, an alpha-glycerophosphate, an alkylsulfonate or an arylsulfonate; preferably, the alkylsulfonate is methanesulfonic acid a salt or ethyl sulfonate; the aryl sulfonate being a besylate or p-toluenesulfonate.
- the mineral acid salt is a hydrochloride,
- C 1 -C 6 alkyl refers to any straight or branched chain group containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-amyl, n-hexyl and the like.
- C 1 -C 3 alkyl refers to any straight or branched chain group containing from 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, and the like.
- oxyalkyl group means a group in which an alkyl skeleton is substituted by one or more alkoxy groups, for example, a methoxyethyl group, a methoxyethoxymethyl group, or the like. .
- a C1-C6 oxyalkyl group means a group formed by substituting a C1-C6 alkyl skeleton with one or more C1-C6 alkoxy groups, for example, methoxyethyl, methoxyethoxy Methyl group and the like.
- a C1-C3 oxyalkyl group means a group formed by substituting a C1-C3 alkyl skeleton with one or more C1-C6 alkoxy groups.
- fluorinated alkyl group means a group in which an alkyl skeleton is substituted by one or more fluorine groups, for example, a monofluoromethyl group, a difluoroethyl group, a trifluoromethyl group or the like.
- C 3 -C 6 cycloalkyl refers to a hydrocarbon of a 3-6 membered monocyclic ring system having a saturated ring, and the C 3 -C 6 cycloalkyl group may be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a ring. Heji and so on.
- cyano refers to the -CN residue.
- nitro refers to a -NO 2 group.
- alkoxy refers to any of the above alkyl groups (eg, C 1 -C 6 alkyl, C 1 -C 3 alkyl, etc.), cycloalkyl (eg, C). 3 -C 6 cycloalkyl), which is connected to the rest of the molecule through an oxygen atom (-O-).
- heteroaryl refers to an aromatic heterocyclic ring, usually a 5-, 6-, 7-, 8-membered heterocyclic ring having 1 to 3 heteroatoms selected from N, O or S;
- the base ring can optionally be further fused or attached to both aromatic and non-aromatic carbocyclic and heterocyclic rings.
- Non-limiting examples of such heteroaryl groups are, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, fluorenyl, imidazolyl, thiazolyl, isothiazolyl, thiazolyl, pyrrolyl, benzene Base-pyrrolyl, furyl, phenyl-furanyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzofuranyl, benzothienyl, benzo1,3-dioxolane (benzodioxan), isoindoline, benzimidazolyl, oxazolyl, quinolyl, isoquinolyl, 1,2,3-triazolyl, 1-phenyl-1, 2,3-Triazolyl, 2,3-dihydroindenyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo
- heterocyclyl (also referred to as “heterocycloalkyl”) refers to 3-, 4-, 5-, 6- and 7-membered saturated or partially unsaturated carbocyclic rings wherein one or more carbon atoms Substituted by heteroatoms such as nitrogen, oxygen and sulfur.
- heterocyclic groups are, for example, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, dihydrofuran, tetrahydrofuran, 1,3- Dioxolane, piperidine, piperazine, morpholine, morphinolyl, tetrahydropyrrolyl, thiomorpholinyl and the like.
- 6-membered heterocyclyl refers to a 6-membered saturated or partially unsaturated carbocyclic ring in which one or more carbon atoms are replaced by a hetero atom such as nitrogen, oxygen, and sulfur.
- hetero atom such as nitrogen, oxygen, and sulfur.
- 6-membered heterocyclic groups are, for example, pyran, piperidine, piperazine, morpholine, morphinolyl, thiomorpholinyl and the like.
- 5-membered heterocyclyl refers to a 5-membered saturated or partially unsaturated carbocyclic ring in which one or more carbon atoms are replaced by a hetero atom such as nitrogen, oxygen and sulfur.
- Non-limiting examples of 5-membered heterocyclic groups are, for example, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, 1,3-dioxolane, and the like.
- heterocyclic group is one or more of "C1-C6 alkyl group", “C1-C3 alkyl group”, “C3-C6 cycloalkyl group”, etc. Replace.
- C1-C6 fluoroalkyl refers to a group wherein a C1-C6 alkyl skeleton is substituted by one or more fluoro groups, for example, carbon tetrafluoride, monofluoromethyl, difluoroethyl, tri Fluoromethyl and the like.
- C1-C3 fluoroalkyl refers to a group in which a C1-C3 alkyl skeleton is substituted with one or more fluoro groups, for example, carbon tetrafluoride, monofluoromethyl, difluoroethyl. Base, trifluoromethyl and the like.
- alkoxy refers to any of the above alkyl groups (eg, C 1 -C 6 alkyl, C 1 -C 3 alkyl, etc.), cycloalkyl (eg, C). 3 -C 6 cycloalkyl), which is connected to the rest of the molecule through an oxygen atom (-O-).
- any group whose name is a compound name such as "fluorine-containing oxyalkyl group” shall mean a moiety conventionally derived therefrom, for example, from a fluorine group.
- a substituted oxyalkyl group is constructed wherein the alkyl group is as defined above.
- fluoroalkoxy group there is also a "fluoroalkoxy group”.
- arylamino shall mean a moiety that is conventionally derived therefrom, for example, from an amino group substituted with an aryl group, wherein the aryl group is as defined above.
- heteroarylamino can be understood.
- the meanings of "hydroxysulfonyl", “aminosulfonyl” and the like can be understood.
- any term such as alkylamino, dialkylamino, alkoxycarbonyl, alkoxycarbonylamino, heterocyclylcarbonyl, heterocyclylcarbonylamino, cycloalkyloxycarbonyl, alkoxycarbonyl, etc.
- a group wherein the alkyl group, the alkoxy group, the aryl group, the C 3 -C 7 cycloalkyl group and the heterocyclic group are as defined above.
- each of the above substituents may be further substituted with one or more of the above-exemplified groups, if appropriate.
- a substituted oxyalkyl group is constructed wherein the alkyl group is as defined above.
- oxygen-substituted or unsubstituted five- or six-membered ring or "nitrogen-substituted or unsubstituted five- or six-membered ring” means 5- or 6-membered saturated or partially unsaturated A carbocyclic ring in which one or more carbon atoms are replaced by oxygen or nitrogen.
- Non-limiting examples are, for example, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, dihydrofuran, tetrahydrofuran, 1,3-dioxolan, piperidine, piperazine , morpholine, tetrahydropyrrolyl and the like.
- prodrug refers to a derivative that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the invention. Prodrugs undergo this reaction to become active compounds only under biological conditions, or they are active in their unreacted form. Prodrugs can generally be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, ed., 5th Edition).
- the term "pharmaceutically acceptable salt of a compound of formula (I)" is an organic acid addition salt formed from an organic acid forming a pharmaceutically acceptable anion, including but not limited to formate, Acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, ascorbate, alpha-ketoglutarate, alpha-glycerophosphate Or an alkyl sulfonate or an aryl sulfonate; preferably, the alkyl sulfonate is a methanesulfonate or ethyl sulfonate; the aryl sulfonate is a besylate or a Tosylate.
- Suitable inorganic salts can also be formed including, but not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, bicarbonate and carbonate, sulfate or phosphate, and the like.
- compositions can be obtained using standard procedures well known in the art, for example, by reacting a sufficient amount of a basic compound with a suitable acid that provides a pharmaceutically acceptable anion.
- treating generally refers to obtaining the desired pharmacological and/or physiological effects.
- the effect may be prophylactic according to the prevention of the disease or its symptoms in whole or in part; and/or may be therapeutic according to the partial or complete stabilization or cure of the disease and/or side effects due to the disease.
- treatment encompasses any treatment for a patient's condition, including: (a) prevention of a disease or condition in a patient who is susceptible to an infectious disease or condition but has not yet diagnosed the disease; (b) inhibition of the symptoms of the disease, That is, to prevent its development; or (c) to alleviate the symptoms of the disease, that is, to cause the disease or symptoms to degenerate.
- the compound, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof wherein the compound is the following example One of the compounds described.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound according to any one of the above aspects, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvent And a pharmaceutically acceptable carrier, diluent or excipient.
- a method of preparing the pharmaceutical composition comprises incorporating a suitable pharmaceutical excipient, carrier, diluent, and the like.
- the pharmaceutical preparations of the invention are prepared in a known manner, including conventional methods of mixing, dissolving or lyophilizing.
- the compounds of the present invention can be formulated into pharmaceutical compositions and administered to a patient in a variety of ways suitable for the chosen mode of administration, for example, orally or parenterally (by intravenous, intramuscular, topical or subcutaneous routes).
- the compounds of the invention may be administered systemically, for example, orally, in association with a pharmaceutically acceptable carrier such as an inert diluent or an assimilable edible carrier. They can be enclosed in hard or soft shell gelatin capsules and can be compressed into tablets.
- a pharmaceutically acceptable carrier such as an inert diluent or an assimilable edible carrier. They can be enclosed in hard or soft shell gelatin capsules and can be compressed into tablets.
- the active compound may be combined with one or more excipients and in the form of swallowable tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. use.
- Such compositions and preparations should contain at least 0.1% of active compound.
- the ratio of such compositions and formulations may of course vary and may range from about 1% to about 99% by weight of a given unit dosage form.
- the amount of active compound is such that an effective dosage level can be obtained.
- Tablets, lozenges, pills, capsules and the like may also contain: a binder such as tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, Potato starch, alginic acid, etc.; a lubricant such as magnesium stearate; and a sweetener such as sucrose, fructose, lactose or aspartame; or a flavoring agent such as mint, wintergreen or cherry.
- a binder such as tragacanth, acacia, corn starch or gelatin
- an excipient such as dicalcium phosphate
- a disintegrating agent such as corn starch, Potato starch, alginic acid, etc.
- a lubricant such as magnesium stearate
- a sweetener such as sucrose, fructose, lactose or aspartame
- a flavoring agent such as mint, wintergreen or cherry
- any material used to prepare any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
- the active compound can be incorporated into sustained release formulations and sustained release devices.
- the active compound can also be administered intravenously or intraperitoneally by infusion or injection.
- An aqueous solution of the active compound or a salt thereof can be prepared, optionally mixed with a non-toxic surfactant.
- Dispersing agents in glycerol, liquid polyethylene glycols, triacetin and mixtures thereof, and oils can also be prepared. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
- Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersions of the active ingredient (optionally encapsulated in liposomes) containing the immediate formulation of a suitable injectable or injectable solution or dispersing agent. Or sterile powder. In all cases, the final dosage form must be sterile, liquid, and stable under the conditions of manufacture and storage.
- the liquid carrier can be a solvent or liquid dispersion medium including, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oils, non-toxic glycerides, and suitable mixtures thereof.
- Proper fluidity can be maintained, for example, by liposome formation, by maintaining the desired particle size in the case of a dispersing agent, or by the use of a surfactant.
- the action of preventing microorganisms can be produced by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
- isotonic agents such as sugars, buffers or sodium chloride.
- Prolonged absorption of the injectable compositions can be brought about by the use of compositions that delay the absorbent (for example, aluminum monostearate and gelatin).
- Sterile injectable solutions are prepared by combining the required active compound in a suitable solvent with the various other ingredients enumerated above, and then sterilized by filtration.
- the preferred preparation methods are vacuum drying and lyophilization techniques which result in a powder of the active ingredient plus any additional ingredients present in the previously sterile filtration solution. .
- Useful solid carriers include comminuted solids (e.g., talc, clay, microcrystalline cellulose, silica, alumina, etc.).
- Useful liquid carriers include water, ethanol or ethylene glycol or a water-ethanol/ethylene glycol mixture, and the compounds of the present invention may be dissolved or dispersed in an effective amount, optionally with the aid of a non-toxic surfactant.
- Adjuvants such as fragrances
- additional antimicrobial agents can be added to optimize the properties for a given use.
- Thickeners can also be used with liquid carriers to form coatable pastes, gels, ointments , soap, etc., used directly on the user's skin.
- the therapeutic requirements of a compound or an active salt or derivative thereof depend not only on the particular salt selected, but also on the mode of administration, the nature of the disease to be treated, and the age and condition of the patient, ultimately depending on the attending physician or clinician decision.
- unit dosage form is a unit dispersion unit containing a unit dosage unit suitable for administration to humans and other mammalian bodies.
- the unit dosage form can be a capsule or tablet, or a plurality of capsules or tablets.
- the amount of unit dose of the active ingredient may vary or be adjusted between about 0.1 and about 1000 mg or more, depending on the particular treatment involved.
- milk liposomes such as milk liposomes, microspheres and nanospheres
- microparticle dispersion systems including polymeric micelles, nanoemulsions, submicroemuls Agents prepared from microcapsules, microspheres, liposomes, and niosomes (also known as nonionic surfactant vesicles).
- the present invention provides a method for preparing the compound according to any one of the above technical solutions, comprising the steps of:
- Reaction conditions (a) an amide condensation reaction under basic conditions (triethylamine, diisopropylethylamine, etc.).
- the present invention provides a compound according to any one of the above aspects, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, and a compound comprising the same
- a combination of drugs for treating a tumor wherein the tumor includes, but is not limited to, gastric cancer, liver cancer, hematological tumor, osteosarcoma, prostate cancer, breast cancer, lung cancer.
- the compounds of the invention are synthesized using the methods described herein or other methods well known in the art.
- Thin layer chromatography was carried out on a silica gel GF254 precoated plate (Qingdao Marine Chemical Plant). Column chromatography was carried out by silica gel (300-400 mesh, Yantai Zhihuang Silica Gel Development Reagent Factory) under medium pressure or by column chromatography using a pre-packed silica gel cartridge (ISCO or Welch) using an ISCO Combiflash Rf200 rapid purification system. The ingredients were developed by UV light ( ⁇ : 254 nm) and by iodine vapor.
- the compounds were prepared by preparative HPLC on a Waters Symmetry C18 (19 x 50 mm, 5 ⁇ m) column or via a Waters X Terra RP 18 (30 x 150 mm, 5 ⁇ m) column using a Waters preparation equipped with a 996 Waters PDA detector.
- Method 1 Phase A: 0.1% TFA / MeOH 95/5 ; phase B: MeOH / H 2 O 95/5 . Gradient: 10 to 90% B for 8 min, 90% B 2 min; flow rate 20 mL/min.
- Method 2 Phase A: 0.05% NH 4 OH / MeOH 95/5; phase B: MeOH / H 2 O 95/5 . Gradient: 10 to 100% B for 8 min, maintaining 100% B 2 min. The flow rate was 20 mL/min.
- Electrospray (ESI) mass spectra were obtained on a Finnigan LCQ ion trap.
- HPLC-UV-MS analysis for evaluating compound purity was performed by combining an ion trap MS apparatus with an HPLC system SSP4000 (Thermo Separation Products) equipped with an autosampler LC Pal (CTC Analytics) and a UV6000LP diode array Detector (UV detection 215-400 nm). Device control, data acquisition and processing with Xcalibur 1.2 software (Finnigan). HPLC chromatography was carried out at room temperature and a flow rate of 1 mL/min using a Waters X Terra RP 18 column (4.6 x 50 mm; 3.5 [mu]m).
- Mobile phase A is ammonium acetate 5 mM buffer (pH 5.5 using acetic acid): acetonitrile 90:10
- mobile phase B ammonium acetate 5 mM buffer (pH 5.5 using acetic acid): acetonitrile 10:90; gradient 0 to 100 %B was run for 7 minutes and then held at 100% B for 2 minutes before rebalancing.
- HATU O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
- UV UV: UV
- Ethyl 4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylate (3 mmol, 630.75 mg) was dissolved in 12 mL of tetrahydrofuran, then 4 mL of 1N lithium hydroxide solution was added and reacted at 52 ° C 7h. After removing most of the solvent by concentration under reduced pressure, ice water was added, and pH was adjusted to weakly acidic with 1N diluted hydrochloric acid to precipitate a solid.
- the raw materials used in the above synthesis are all commercially available reagents.
- DMEM Dulbecco's modified eagle medium
- RPMI 1640 containing 10% fetal bovine serum, 100 ⁇ g/mL ampicillin, 100 ⁇ g/mL streptomycin
- MTS reaction solution (containing 2 mg/mL of MTS[3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4- (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt ); 100 ⁇ g/mL of PES (phenazine methosulfate)).
- the cell plate of the mixed compound was placed in a cell culture incubator (37 ° C; 5% CO 2 ) for 48 h, and then 20 ⁇ L of MTS reaction solution was added, mixed and placed in a cell culture incubator (37 ° C; 5% CO 2 ) Incubation for 1-4 hr; OD values at 490 nm wavelength were measured using a microplate reader (VARIOSKAN FLASH, Thermo).
- Three parallels were set for each set of experiments, with a final concentration of 0.1% DMSO as a negative control, and a medium without cells and compounds as a blank control.
- the cell growth inhibition rate is calculated by the following formula:
- IC 50 value calculation The semi-inhibitory concentration of the compound acting on the cells was calculated using GradPad Prism 5 software according to the measured cell inhibition rate.
- compounds I-27 and I-28 have good growth inhibitory activity against human promyelocytic leukemia cell line HL-60, human osteosarcoma cell U20S, and human prostate cancer cell line LNCAP.
- compound I-2 as an example, as shown in Table 5, we selected 3 lung cancer cells (NCI-1975, HCC827, A549) and 3 leukemia cells (SHI-1, THP-1, NB-4) and Two human embryo lung cells (WI-38 and HFL-1) were tested.
- Compound exhibited selectivity for tumor cell growth inhibition (IC 50 of 0.008 ⁇ 0.280 ⁇ M), and a smaller effect on normal human embryonic lung cell growth (IC 50> 5 ⁇ M), have a good therapeutic window.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims (7)
- 以下通式的化合物:其中,X 1选自N,S;X 2选自N,S;且X 1与X 2不相同;R 1选自H,C1-C6烷基,C3-C6环烷基;优选R 1选自H,C1-C3烷基;更优选R 1选自H,甲基、乙基;R 2选自H,C1-C6烷基,C3-C6环烷基;优选R 2选自H,C1-C3烷基;更优选R 2选自H,甲基、乙基;R 3选自;(1)氢,氟,氯,溴,碘,硝基,氰基,氨基,任选被-C1-C6烷基、C1-C3烷基、-C1-C6烷基磺酰基或-C1-C6烷基羰基取代的氨基,羟基,羟基甲酰基,甲氧基甲酰基,乙氧基甲酰基,正丙氧基甲酰基,异丙氧基甲酰基,氨基甲酰基,N-甲基氨基甲酰基,N-乙基氨基甲酰基,N-正丙基氨基甲酰基,N-异丙基氨基甲酰基,N-环丙基氨基甲酰基,N-正丁基氨基甲酰基,N-异丁基氨基甲酰基,N-叔丁基氨基甲酰基,N-环丁基氨基甲酰基,N-正戊基氨基甲酰基,N-异戊基氨基甲酰基,N-环戊基氨基甲酰基,N-正己基氨基甲酰基,N-异己基氨基甲酰基,N-环己基氨基甲酰基,N,N-二甲基氨基甲酰基,N,N-二乙基氨基甲酰基,N,N-二正丙基氨基甲酰基,N,N-二异丙基氨基甲酰基,环丙胺基甲酰基,环丁胺基甲酰基,环戊胺基甲酰基,环己胺基甲酰基,4-羟基哌啶基甲酰基,哌嗪基甲酰基,4-甲基哌嗪基甲酰基,4-乙基哌嗪基甲酰基,4-正丙基哌嗪基甲酰基,4-异丙基哌嗪基甲酰基,甲磺酰基,乙磺酰基,正丙基磺酰基,异丙基磺酰基,正丁基磺酰基,异丁基磺酰基,羟基磺酰基,氨基磺酰基,N-甲基氨基磺酰基,N-乙基氨基磺酰基,N-正丙基氨基磺酰基,N-异丙基氨基磺酰基,N-环丙基氨基磺酰基,N-正丁基氨基磺酰基,N-异丁基氨基磺酰基,N-叔丁基氨基磺酰基,N-环丁基氨基磺酰基,N-正戊基氨基磺酰基,N-异戊基氨基磺酰基,N-环戊基氨基磺酰基,N-正己基氨基磺酰基,N-异己基氨基磺酰基,N-环己基氨基磺酰基,N,N-二甲基氨基磺酰基,N,N-二乙基氨基磺酰基,N,N-二正丙基氨基磺酰基,N,N-二异丙基氨基磺酰基,环丙胺基磺酰基,环丁胺基磺酰基,环戊胺基磺酰基,环己胺基磺酰基,4-羟基哌啶基磺酰基,哌嗪基磺酰基,4-甲基哌嗪基磺酰基,4-乙基哌嗪基磺酰基,4-正丙基哌嗪基磺酰基,4-异丙基哌嗪基磺酰基,甲酰胺基,乙酰胺基,丙酰胺基,正丁酰胺基,异丁酰胺基,环丙基甲酰胺基,环丁基甲酰胺基,环戊基甲酰胺基,环己基甲酰胺基,甲磺酰胺基,乙磺酰胺基,正丙磺酰胺基,异丙磺酰胺基,正丁磺酰胺基,异丁磺酰胺基,取代的苯基-C1-C6烷基-氨基羰基-C1-C6烷基,经C1-C6烷基-O-、卤素、C1-C6烷基-S-或C1-C6烷基磺酰基取代的苯基-O-C1-C6烷基,被-C1-C6烷基取代的6元杂环基-C1-C6烷基;(2)-O-C1-C6烷基,-O-C1-C6含氟烷基,-C1-C6含氟烷基,-C1-C6烷氧基羰基,C1-C3烷基,C1-C3烷氧基,C1-C3含氧烷基,C1-C3含氟烷基,C1-C3含氟烷氧基;(3)包含选自N、O和S的一个或多个杂原子的五元或六元杂环,所述五元或六元杂环任选地被C1-C6烷基、C1-C6烷氧基、羟基、氨基、C1-C6烷氧羰基、C1-C6酰基、氰基、任选被取代的杂环基取代,包括但不限于:哌啶基,4-N,N-二甲基氨基哌啶基,4-N,N-二乙基氨基哌啶基,4-N,N-二异丙基氨基哌啶基,4-羟基哌啶基,4-(4-甲基哌嗪基)哌啶基,4-(4-乙基哌嗪基)哌啶基,4-(4-异丙基哌嗪基)哌啶基,4-(4-乙酰基哌嗪基)哌啶基,4-(4-叔丁氧甲酰基哌嗪基)哌啶基,4-(4-甲磺酰基哌嗪基)哌啶基,4-(4-(2-羟基乙基)哌嗪基)哌啶基,4-(4-(2-氰基乙基)哌嗪基)哌啶基,4-(4-(3-羟基丙基)哌嗪基)哌啶基,4-(4-(2-N,N-二甲基氨基乙基)哌嗪基)哌啶基,4-(4-(2-N,N-二乙基氨基乙基)哌嗪基)哌啶基,4-(4-(3-N,N-二甲基氨基丙基)哌嗪基)哌啶基,4-(4-(3-N,N-二乙基氨基丙基)哌嗪基)哌啶基,4-(四氢吡咯基)哌啶基,4-(3-N,N-二甲基氨基四氢吡咯基)哌啶基;4-甲基哌嗪基,4-乙基哌嗪基,4-异丙基哌嗪基,4-乙酰基哌嗪基,4-叔丁氧甲酰基哌嗪基,4-甲 磺酰基哌嗪基,4-(2-羟基乙基)哌嗪基,4-(2-氰基乙基)哌嗪基,4-(3-羟基丙基)哌嗪基,4-(2-N,N-二甲基氨基乙基)哌嗪基,4-(2-N,N-二乙基氨基乙基)哌嗪基,4-(3-N,N-二甲基氨基丙基)哌嗪基,4-(3-N,N-二乙基氨基丙基)哌嗪基,2-氧代-哌嗪-4-基,4-(N-甲基-4-哌啶基)哌嗪基,4-(N-乙基-4-哌啶基)哌嗪基,4-(N-乙酰基-4-哌啶基)哌嗪基;吗啡啉基,3,5-二甲基吗啡啉基,硫代吗啉基,四氢吡咯基,3-N,N-二甲基四氢吡咯基,3-N,N-二乙基四氢吡咯基;(4)杂芳基,例如但不限于吡啶基、呋喃基、噻吩基、苯并呋喃基;(5)Z 2与Z 3可以形成含氧的取代或未取代的五元环或六元环;取代基可以选自与Z 1相同的取代基;(6)Z 4与Z 5可以形成含氮的取代或未取代的五元环或六元环;取代基可以选自与Z 1相同的取代基;2)氢,C1-C6烷基,环丙基,环丁基,环戊基,环己基,N,N-二甲基氨基,N,N-二乙基氨基,N,N-二异丙基氨基,2-N,N-二甲基氨基乙基,2-羟基乙基,2-吗啡啉基乙基,2-硫代吗啉基乙基,2-(4-甲基哌嗪基)乙基,3-N,N-二甲基氨基丙基,3-N,N-二乙基氨基丙基,3-N,N-二异丙基氨基丙基,3-羟基丙基,3-吗啡啉基丙基,3-硫代吗啉基丙基,3-(4-甲基哌嗪基)丙基,N-甲基-4-哌啶基,N-乙基-4-哌啶基,N-异丙基-4-哌啶基,N-乙酰基-4-哌啶基;或上述化合物的立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物。
- 根据权利要求1的化合物,其为以下:其中:R 1选自H,C1-C6烷基,C3-C6环烷基;优选R 1选自H,C1-C3烷基;更优选R 1选自H,甲基、乙基;R 2选自H,C1-C6烷基,C3-C6环烷基;优选R 2选自H,C1-C3烷基;更优选R 2选自H,甲基、乙基;R 3选自;(1)氢,氟,氯,溴,碘,硝基,氰基,氨基,任选被-C1-C6烷基、C1-C3烷基、-C1-C6烷基磺酰基或-C1-C6烷基羰基取代的氨基,羟基,羟基甲酰基,甲氧基甲酰基,乙氧基甲酰基,正丙氧基甲酰基,异丙氧基甲酰基,氨基甲酰基,N-甲基氨基甲酰基,N-乙基氨基甲酰基,N-正丙基氨基甲酰基,N-异丙基氨基甲酰基,N-环丙基氨基甲酰基,N-正丁基氨基甲酰基,N-异丁基氨基甲酰基,N-叔丁基氨基甲酰基,N-环丁基氨基甲酰基,N-正戊基氨基甲酰基,N-异戊基氨基甲酰基,N-环戊基氨基甲酰基,N-正己基氨基甲酰基,N-异己基氨基甲酰基,N-环己基氨基甲酰基,N,N-二甲基氨基甲酰基,N,N-二乙基氨基甲酰基,N,N-二正丙基氨基甲酰基,N,N-二异丙基氨基甲酰基,环丙胺基甲酰基,环丁胺基甲酰基,环戊胺基甲酰基,环己胺基甲酰基,4-羟基哌啶基甲酰基,哌嗪基甲酰基,4-甲基哌嗪基甲酰基,4-乙基哌嗪基甲酰基,4-正丙基哌嗪基甲酰基,4-异丙基哌嗪基甲酰基,甲磺酰基,乙磺酰基,正丙基磺酰基,异丙基磺酰基,正丁基磺酰基,异丁基磺酰基,羟基磺酰基,氨基磺酰基,N-甲基氨基磺酰基,N-乙基氨基磺酰基,N-正丙基氨基磺酰基,N-异丙基氨基磺酰基,N-环丙基氨基磺酰基,N-正丁基氨基磺酰基,N-异丁基氨基磺酰基,N-叔丁基氨基磺酰基,N-环丁基氨基磺酰基,N-正戊基氨基磺酰基,N-异戊基氨基磺酰基,N-环戊基氨基磺酰基,N-正己基氨基磺酰基,N-异己基氨基磺酰基,N-环己基氨基磺酰基,N,N-二甲基氨基磺酰基,N,N-二乙基氨基磺酰基,N,N-二正丙基氨基磺酰基,N,N-二异丙基氨基磺酰基,环丙胺基磺酰基,环丁胺基磺酰基,环戊胺基磺酰基,环己胺基磺酰基,4-羟基哌啶基磺酰基,哌嗪基磺酰基,4-甲基哌嗪基磺酰基,4-乙基哌嗪基磺酰基,4-正丙基哌嗪基磺酰基,4-异丙基哌嗪基磺酰基,甲酰胺基,乙酰胺基,丙酰胺基,正丁酰胺基,异丁酰胺基,环丙基甲酰胺基,环丁基甲酰胺基,环戊基甲酰胺基,环己基甲酰胺基,甲磺酰胺基,乙磺 酰胺基,正丙磺酰胺基,异丙磺酰胺基,正丁磺酰胺基,异丁磺酰胺基,取代的苯基-C1-C6烷基-氨基羰基-C1-C6烷基,经C1-C6烷基-O-、卤素、C1-C6烷基-S-或C1-C6烷基磺酰基取代的苯基-O-C1-C6烷基,被-C1-C6烷基取代的6元杂环基-C1-C6烷基;(2)-O-C1-C6烷基,-O-C1-C6含氟烷基,-C1-C6含氟烷基,-C1-C6烷氧基羰基,C1-C3烷基,C1-C3烷氧基,C1-C3含氧烷基,C1-C3含氟烷基,C1-C3含氟烷氧基;(3)包含选自N、O和S的一个或多个杂原子的五元或六元杂环,所述五元或六元杂环任选地被C1-C6烷基、C1-C6烷氧基、羟基、氨基、C1-C6烷氧羰基、C1-C6酰基、氰基、任选被取代的杂环基取代,包括但不限于:哌啶基,4-N,N-二甲基氨基哌啶基,4-N,N-二乙基氨基哌啶基,4-N,N-二异丙基氨基哌啶基,4-羟基哌啶基,4-(4-甲基哌嗪基)哌啶基,4-(4-乙基哌嗪基)哌啶基,4-(4-异丙基哌嗪基)哌啶基,4-(4-乙酰基哌嗪基)哌啶基,4-(4-叔丁氧甲酰基哌嗪基)哌啶基,4-(4-甲磺酰基哌嗪基)哌啶基,4-(4-(2-羟基乙基)哌嗪基)哌啶基,4-(4-(2-氰基乙基)哌嗪基)哌啶基,4-(4-(3-羟基丙基)哌嗪基)哌啶基,4-(4-(2-N,N-二甲基氨基乙基)哌嗪基)哌啶基,4-(4-(2-N,N-二乙基氨基乙基)哌嗪基)哌啶基,4-(4-(3-N,N-二甲基氨基丙基)哌嗪基)哌啶基,4-(4-(3-N,N-二乙基氨基丙基)哌嗪基)哌啶基,4-(四氢吡咯基)哌啶基,4-(3-N,N-二甲基氨基四氢吡咯基)哌啶基;4-甲基哌嗪基,4-乙基哌嗪基,4-异丙基哌嗪基,4-乙酰基哌嗪基,4-叔丁氧甲酰基哌嗪基,4-甲磺酰基哌嗪基,4-(2-羟基乙基)哌嗪基,4-(2-氰基乙基)哌嗪基,4-(3-羟基丙基)哌嗪基,4-(2-N,N-二甲基氨基乙基)哌嗪基,4-(2-N,N-二乙基氨基乙基)哌嗪基,4-(3-N,N-二甲基氨基丙基)哌嗪基,4-(3-N,N-二乙基氨基丙基)哌嗪基,2-氧代-哌嗪-4-基,4-(N-甲基-4-哌啶基)哌嗪基,4-(N-乙基-4-哌啶基)哌嗪基,4-(N-乙酰基-4-哌啶基)哌嗪基;吗啡啉基,3,5-二甲基吗啡啉基,硫代吗啉基,四氢吡咯基,3-N,N-二甲基氨基四氢吡咯基,3-N,N-二乙基氨基四氢吡咯基;(4)杂芳基,例如但不限于吡啶基、呋喃基、噻吩基、苯并呋喃基;(5)Z 2与Z 3可以形成含氧的取代或未取代的五元环或六元环;取代基可以选自与Z 1相同的取代基;(6)Z 4与Z 5可以形成含氮的取代或未取代的五元环或六元环;取代基可以选自与Z 1相同的取代基;2)氢,C1-C6烷基,环丙基,环丁基,环戊基,环己基,N,N-二甲基氨基,N,N-二乙基氨基,N,N-二异丙基氨基,2-N,N-二甲基氨基乙基,2-羟基乙基,2-吗啡啉基乙基,2-硫代吗啉基乙基,2-(4-甲基哌嗪基)乙基,3-N,N-二甲基氨基丙基,3-N,N-二乙基氨基丙基,3-N,N-二异丙基氨基丙基,3-羟基丙基,3-吗啡啉基丙基,3-硫代吗啉基丙基,3-(4-甲基哌嗪基)丙基,N-甲基-4-哌啶基,N-乙基-4-哌啶基,N-异丙基-4-哌啶基,N-乙酰基-4-哌啶基;R 3优选选自:当n=0时,Z 1,Z 2,Z 3,Z 4,Z 5中的一个选自以下,其余为-H:羟基,-O-C1-C6烷基,-O-C1-C6含氟烷基,-C1-C6含氟烷基,-C1-C6烷氧基羰基,氨基,任选被-C1-C6烷基、-C1-C6烷基磺酰基或-C1-C6烷基羰基取代的氨基,氨基磺酰基,硝基,取代的苯基-C1-C6烷基-氨基羰基-C1-C6烷基(更优选被卤素取代的苯基-C1-C6烷基-氨基羰基-C1-C6烷基),经C1-C6烷基-O-、卤素、C1-C6烷基-S-或C1-C6烷基磺酰基取代的苯基-O-C1-C6烷基;或者,Z 1,Z 2,Z 3,Z 4,Z 5中的2个独立地选自以下,其余为-H(更优选Z 2,Z 3各自或者Z 1,Z 4各自或者Z 2,Z 4各自独立地选自以下,其余为-H):-C1-C6含氟烷基,被-C1-C6烷基取代的6元杂环基-C1-C6烷基(更优选被-C1-C6烷基取代的哌嗪基-C1-C6烷基),-C1-C6烷基,取代的苯基羰基-氨基,-C1-C6烷基-O-羰基,-C1-C6烷基取代的5元杂芳基(更优选-C1-C6烷基取代的咪唑基);当n=1时,Z 1,Z 2,Z 3,Z 4,Z 5中的一个选自以下,其余为-H:吡啶基、呋喃基、噻吩基、苯并呋喃基;当n=2时,Z 1,Z 2,Z 3,Z 4,Z 5中的一个选自以下,其余为-H:氨基磺酰基;R 3更优选选自:当n=0时,Z 1,Z 2,Z 4,Z 5各自为-H,Z 3选自以下:羟基,-O-C1-C6烷基,-O-C1-C6含氟烷基,-C1-C6含氟烷基,-C1-C6烷氧基羰基,氨基,任选被-C1-C6烷基、-C1-C6烷基磺酰基或-C1-C6烷基羰基取代的氨基,氨基磺酰基,硝基;或者,Z 2或Z 4选自以下,其余为-H:-C1-C6烷氧基羰基,取代的苯基-C1-C6烷基-氨基羰基-C1-C6烷基(更优选被卤素取代的苯基-C1-C6烷基-氨基羰基-C1-C6烷基),经C1-C6烷基-O-、卤素、C1-C6烷基-S-或C1-C6烷基磺酰基取代的苯基-O-C1-C6烷基,或者,Z 2,Z 3各自独立地选自以下,其余为-H:-C1-C6含氟烷基,被-C1-C6烷基取代的6元杂环基-C1-C6烷基(更优选被-C1-C6烷基取代的哌嗪基-C1-C6烷基);或者,Z 1,Z 4各自独立地选自以下,其余为-H:-C1-C6烷基,取代的苯基羰基-氨基,-C1-C6烷基-O-羰基;或者,Z 2,Z 4各自独立地选自以下,其余为-H:-C1-C6含氟烷基,-C1-C6烷基取代的5元杂芳基(更优选-C1-C6烷基取代的咪唑基);当n=1时,Z 1或Z 5选自以下,其余为-H:吡啶-4-基、吡啶-3-基、呋喃-2-基、呋喃-3-基、噻吩-2-基、噻吩-3-基、苯并呋喃基;当n=2时,Z 1,Z 2,Z 4,Z 5各自为-H,Z 3为氨基磺酰基;R 3最优选选自:或上述化合物的立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物。
- 根据权利要求1的化合物,其为以下:其中:R 1选自H,C1-C6烷基,C3-C6环烷基;优选R 1选自H,C1-C3烷基;更优选R 1选自H,甲基、乙基;R 2选自H,C1-C6烷基,C3-C6环烷基;优选R 2选自H,C1-C3烷基;更优选R 2选自H,甲基、乙基;R 3选自:(1)氢,氟,氯,溴,碘,硝基,氰基,氨基,羟基,羟基甲酰基,甲氧基甲酰基,乙氧基甲酰基,正丙氧基甲酰基,异丙氧基甲酰基,氨基甲酰基,N-甲基氨基甲酰基,N-乙基氨基甲酰基,N-正丙基氨基甲酰基,N-异丙基氨基甲酰基,N-环丙基氨基甲酰基,N-正丁基氨基甲酰基,N-异丁基氨基甲酰基,N-叔丁基氨基甲酰基,N-环丁基氨基甲酰基,N-正戊基氨基甲酰基,N-异戊基氨基甲酰基,N-环戊基氨基甲酰基,N-正己基氨基甲酰基,N-异己基氨基甲酰基,N-环己基氨基甲酰基,N,N-二甲基氨基甲酰基,N,N-二乙基氨基甲酰基,N,N-二正丙基氨基甲酰基,N,N-二异丙基氨基甲酰基,环丙胺基甲酰基,环丁胺基甲酰基,环戊胺基甲酰基,环己胺基甲酰基,4-羟基哌啶基甲酰基,哌嗪基甲酰基,4-甲基哌嗪基甲酰基,4-乙基哌嗪基甲酰基,4-正丙基哌嗪基甲酰基,4-异丙基哌嗪基甲酰基,甲磺酰基,乙磺酰基,正丙基磺酰基,异丙基磺酰基,正丁基磺酰基,异丁基磺酰基,羟基磺酰基,氨基磺酰基,N-甲基氨基磺酰基,N-乙基氨基磺酰基,N-正丙基氨基磺酰基,N-异丙基氨基磺酰基,N-环丙基氨基磺酰基,N-正丁基氨基磺酰基,N-异丁基氨基磺酰基,N-叔丁基氨基磺酰基,N-环丁基氨基磺酰基,N-正戊基氨基磺酰基,N-异戊基氨基磺酰基,N-环戊基氨基磺酰基,N-正己基氨基磺酰基,N-异己基氨基磺酰基,N-环己基氨基磺酰基,N,N-二甲基氨基磺酰基,N,N-二乙基氨基磺酰基,N,N-二正丙基氨基磺酰基,N,N-二异丙基氨基磺酰基,环丙胺基磺酰基,环丁胺基磺酰基,环戊胺基磺酰基,环己胺基磺酰基,4-羟基哌啶基磺酰基,哌嗪基磺酰基,4-甲基哌嗪基磺酰基,4-乙基哌嗪基磺酰基,4-正丙基哌嗪基磺酰基,4-异丙基哌嗪基磺酰基,甲酰胺基,乙酰胺基,丙酰胺基,正丁酰胺基,异丁酰胺基,环丙基甲酰胺基,环丁基甲酰胺基,环戊基甲酰胺基,环己基甲酰胺基,甲磺酰胺基,乙磺酰胺基,正丙磺酰胺基,异丙磺酰胺基,正丁磺酰胺基,异丁磺酰胺基;(2)-O-C1-C6烷基,-O-C1-C6含氟烷基,-C1-C6含氟烷基,C1-C3烷基,C1-C3烷氧基,C1-C3含氧烷基,C1-C3含氟烷基,C1-C3含氟烷氧基,被-C1-C6烷基取代的6元杂环基-C1-C6烷基;(3)包含选自N、O和S的一个或多个杂原子的五元或六元杂环,所述五元或六元杂环任选地被C1-C6烷基、C1-C6烷氧基、羟基、氨基、C1-C6烷氧羰基、C1-C6酰基、氰基、任选被取代的杂环基取代,包括但不限于:哌啶基,4-N,N-二甲基氨基哌啶基,4-N,N-二乙基氨基哌啶基,4-N,N-二异丙基氨基哌啶基,4-羟基哌啶基,4-(4-甲基哌嗪基)哌啶基,4-(4-乙基哌嗪基)哌啶基,4-(4-异丙基哌嗪基)哌啶基,4-(4-乙酰基哌嗪基)哌啶基,4-(4-叔丁氧甲酰基哌嗪基)哌啶基,4-(4-甲磺酰基哌嗪基)哌啶基,4-(4-(2-羟基乙基)哌嗪基)哌啶基,4-(4-(2-氰基乙基)哌嗪基)哌啶基,4-(4-(3-羟基丙基)哌嗪基)哌啶基,4-(4-(2-N,N-二甲基氨基乙基)哌嗪基)哌啶基,4-(4-(2-N,N-二乙基氨基乙基)哌嗪基)哌啶基,4-(4-(3-N,N-二甲基氨基丙基)哌嗪基)哌啶基,4-(4-(3-N,N-二乙基氨基丙基)哌嗪基)哌啶基,4-(四氢吡咯基)哌啶基,4-(3-N,N-二甲基氨基四氢吡咯基)哌啶基;4-甲基哌嗪基,4-乙基哌嗪基,4-异丙基哌嗪基,4-乙酰基哌嗪基,4-叔丁氧甲酰基哌嗪基,4-甲磺酰基哌嗪基,4-(2-羟基乙基)哌嗪基,4-(2-氰基乙基)哌嗪基,4-(3-羟基丙基)哌嗪基,4-(2-N,N-二甲基氨基乙基)哌嗪基,4-(2-N,N-二乙基氨基乙基)哌嗪基,4-(3-N,N-二甲基氨基丙基)哌嗪基,4-(3-N,N-二乙基氨基丙基)哌嗪基,2-氧代-哌嗪-4-基,4-(N-甲基-4-哌啶基)哌嗪基,4-(N-乙基-4-哌啶基)哌嗪基,4-(N-乙酰基-4-哌啶基)哌嗪基;吗啡啉基,3,5-二甲基吗啡啉基,硫代吗啉基,四氢吡咯基,3-N,N-二甲基氨基四氢吡咯基,3-N,N-二乙基氨基四氢吡咯基;(4)杂芳基,例如但不限于吡啶基、呋喃基、噻吩基、苯并呋喃基;(5)Z 2与Z 3可以形成含氧的取代或未取代的五元环或六元环;取代基可以选自与Z 1相同的取代基;(6)Z 4与Z 5可以形成含氮的取代或未取代的五元环或六元环;取代基可以选自与Z 1相同的取代基;2)氢,C1-C6烷基,环丙基,环丁基,环戊基,环己基,N,N-二甲基氨基,N,N-二乙基氨基,N,N-二异丙基氨基,2-N,N-二甲基氨基乙基,2-羟基乙基,2-吗啡啉基乙基,2-硫代吗啉基乙基,2-(4-甲基哌嗪基)乙基,3-N,N-二甲基氨基丙基,3-N,N-二乙基氨基丙基,3-N,N-二异丙基氨基丙基,3-羟基丙基,3-吗啡啉基丙基,3-硫代吗啉基丙基,3-(4-甲基哌嗪基)丙基,N-甲基-4-哌啶基,N-乙基-4-哌啶基,N-异丙基-4-哌啶基,N-乙酰基-4-哌啶基;R 3优选选自:当n=0时,Z 1,Z 2,Z 3,Z 4,Z 5中的一个选自以下,其余为-H:羟基,-O-C1-C6烷基,-O-C1-C6含氟烷基,-C1-C6含氟烷基;或者,Z 1,Z 2,Z 3,Z 4,Z 5中的2个独立地选自以下,其余为-H(更优选Z 2,Z 4各自或者Z 2,Z 3各自独立地选自以下,其余为-H):-C1-C6含氟烷基,-C1-C6烷基取代的5元杂芳基(更优选-C1-C6烷基取代的咪唑基),被-C1-C6烷基取代的6元杂环基-C1-C6烷基(更优选被-C1-C6烷基取代的哌嗪基-C1-C6烷基);当n=1时,Z 1,Z 2,Z 3,Z 4,Z 5中的一个为苯并呋喃基,其余为-H;R 3更优选选自:当n=0时,Z 1,Z 2,Z 4,Z 5各自为-H,Z 3选自以下:羟基,-O-C1-C6烷基,-O-C1-C6含氟烷基,-C1-C6含氟烷基;或者,Z 2,Z 4各自独立地选自以下,其余为-H:-C1-C6含氟烷基,-C1-C6烷基取代的5元杂芳基(更优选-C1-C6烷基取代的咪唑基);或者,Z 2,Z 3各自或Z 3,Z 4各自独立地选自以下,其余为-H:-C1-C6含氟烷基,被-C1-C6烷基取代的6元杂环基-C1-C6烷基(更优选被-C1-C6烷基取代的哌嗪基-C1-C6烷基);当n=1时,Z 1,Z 3,Z 4,Z 5各自为-H,Z 2为苯并呋喃基;R 3最优选选自:或上述化合物的立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物。
- 药物组合物,其包含权利要求1-4中任一项的化合物或其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物以及任选的药学上可以接受的赋形剂。
- 权利要求1-4中任一项的化合物或其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物或者权利要求6所述的药物组合物在制备用于治疗肿瘤生长与转移的药物中的用途,其中所述肿瘤包括但不限于:胃癌、肝癌、血液肿瘤、骨肉瘤、前列腺癌、乳腺癌、肺癌。
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020207015837A KR20200112810A (ko) | 2017-11-03 | 2018-11-02 | 헤테로아릴 아미드 화합물, 이에 대한 제조 방법, 이의 약학적 조성물 및 이의 적용 |
CA3084846A CA3084846A1 (en) | 2017-11-03 | 2018-11-02 | Heteroaryl amide compounds, preparation method therefor, pharmaceutical compositions thereof, and applications thereof |
EP18872080.9A EP3705481A4 (en) | 2017-11-03 | 2018-11-02 | HETEROARYL AMIDE COMPOUNDS, METHODS FOR THEIR PRODUCTION, PHARMACEUTICAL COMPOSITIONS AND APPLICATIONS THEREOF |
RU2020118133A RU2020118133A (ru) | 2017-11-03 | 2018-11-02 | Гетероариламидные соединения, способ их получения, их фармацевтические композиции и применение |
AU2018359934A AU2018359934A1 (en) | 2017-11-03 | 2018-11-02 | Heteroaryl amide compounds, preparation method therefor, pharmaceutical compositions thereof, and applications thereof |
US16/760,779 US20200325156A1 (en) | 2017-11-03 | 2018-11-02 | Heteroaryl amide compounds, preparation method therefor, pharmaceutical compositions thereof, and applications thereof |
CN201880071456.3A CN111295387B (zh) | 2017-11-03 | 2018-11-02 | 杂芳基酰胺类化合物、其制备方法、药用组合物及其应用 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201711069948.2 | 2017-11-03 | ||
CN201711069948.2A CN109748927A (zh) | 2017-11-03 | 2017-11-03 | 杂芳基酰胺类化合物、其制备方法、药用组合物及其应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2019085978A1 true WO2019085978A1 (zh) | 2019-05-09 |
Family
ID=66332837
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2018/113549 WO2019085978A1 (zh) | 2017-11-03 | 2018-11-02 | 杂芳基酰胺类化合物、其制备方法、药用组合物及其应用 |
Country Status (8)
Country | Link |
---|---|
US (1) | US20200325156A1 (zh) |
EP (1) | EP3705481A4 (zh) |
KR (1) | KR20200112810A (zh) |
CN (2) | CN109748927A (zh) |
AU (1) | AU2018359934A1 (zh) |
CA (1) | CA3084846A1 (zh) |
RU (1) | RU2020118133A (zh) |
WO (1) | WO2019085978A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021062318A1 (en) * | 2019-09-26 | 2021-04-01 | The Global Alliance For Tb Drug Development, Inc. | Thiazole carboxamide compounds and use thereof for the treatment of mycobacterial infections |
CN114746088A (zh) * | 2019-09-26 | 2022-07-12 | 结核病药物开发全球联盟公司 | 吲哚甲酰胺化合物和其用于治疗分枝杆菌感染的用途 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101790313A (zh) * | 2007-06-06 | 2010-07-28 | 葛兰素史密丝克莱恩有限责任公司 | 化合物 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JO2629B1 (en) * | 2004-08-19 | 2012-06-24 | افينتيس فارما سوتيكالز انك | Branched carboxylic acid amides containing thienobirol, carboxylic acid amides containing pyrolithiazole, and the like as kinase inhibitors casein epsilon |
-
2017
- 2017-11-03 CN CN201711069948.2A patent/CN109748927A/zh active Pending
-
2018
- 2018-11-02 RU RU2020118133A patent/RU2020118133A/ru unknown
- 2018-11-02 WO PCT/CN2018/113549 patent/WO2019085978A1/zh unknown
- 2018-11-02 US US16/760,779 patent/US20200325156A1/en not_active Abandoned
- 2018-11-02 EP EP18872080.9A patent/EP3705481A4/en not_active Withdrawn
- 2018-11-02 CN CN201880071456.3A patent/CN111295387B/zh active Active
- 2018-11-02 KR KR1020207015837A patent/KR20200112810A/ko unknown
- 2018-11-02 AU AU2018359934A patent/AU2018359934A1/en not_active Abandoned
- 2018-11-02 CA CA3084846A patent/CA3084846A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101790313A (zh) * | 2007-06-06 | 2010-07-28 | 葛兰素史密丝克莱恩有限责任公司 | 化合物 |
Non-Patent Citations (5)
Title |
---|
"Burger's Medicinal Chemistry and Drug Discovery", 1995, MACK PUBLISHING COMPANY, pages: 172 - 178,949-982 |
"Purification of Laboratory Chemicals", 1980, D. R.; PERGAMON PRESS |
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 87, 2014, pages 529 - 539 |
SARTORI, LUCA ET AL.: "Thieno[3, 2-b]pyrrole-5-carboxamides as New Rever- sible Inhibitors of Histone Lysine Demethylase KDMIA/LSDI.Part 1.High-Throu- ghput Screening and reliminary Exploration", JOURNAL OF MEDICINAL CHEMISTRY, vol. 60, no. 5, 10 February 2017 (2017-02-10), pages 1673 - 1692, XP055507204 * |
See also references of EP3705481A4 |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021062318A1 (en) * | 2019-09-26 | 2021-04-01 | The Global Alliance For Tb Drug Development, Inc. | Thiazole carboxamide compounds and use thereof for the treatment of mycobacterial infections |
CN114746088A (zh) * | 2019-09-26 | 2022-07-12 | 结核病药物开发全球联盟公司 | 吲哚甲酰胺化合物和其用于治疗分枝杆菌感染的用途 |
EP4034106A4 (en) * | 2019-09-26 | 2023-10-25 | The Global Alliance for TB Drug Development, Inc. | THIAZOLE CARBOXAMIDE COMPOUNDS AND THEIR USE FOR THE TREATMENT OF MYCOBACTERIAL INFECTIONS |
Also Published As
Publication number | Publication date |
---|---|
KR20200112810A (ko) | 2020-10-05 |
RU2020118133A (ru) | 2021-12-03 |
CN111295387B (zh) | 2022-12-06 |
CA3084846A1 (en) | 2019-05-09 |
EP3705481A1 (en) | 2020-09-09 |
CN111295387A (zh) | 2020-06-16 |
US20200325156A1 (en) | 2020-10-15 |
CN109748927A (zh) | 2019-05-14 |
AU2018359934A1 (en) | 2020-06-18 |
EP3705481A4 (en) | 2021-09-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7050093B2 (ja) | 置換5員および6員複素環式化合物、その調製方法、薬剤の組み合わせおよびその使用 | |
TWI748996B (zh) | 嘧啶類七元環化合物、其製備方法、藥用組合物及其應用 | |
IL126558A (en) | Benzofuran carboxamides and pharmaceutical compositions containing them | |
WO2021147879A1 (zh) | Shp2抑制剂及其应用 | |
EP3626718A1 (en) | Five- and six-membered aza-aromatic compound, preparation method therefor, pharmaceutical composition, and application | |
JP7439018B2 (ja) | 置換アリールエーテル系化合物、その調製方法、医薬組成物およびその応用 | |
WO2021218755A1 (zh) | Shp2抑制剂及其组合物和应用 | |
BR112015030399B1 (pt) | Derivados heterocíclicos, uso dos referidos derivados e composição farmacêutica para a prevenção ou tratamento de doenças associadas com a ativação da proteína stat3 | |
JP2024505732A (ja) | ピリドピリミジノン系誘導体及びその製造方法と使用 | |
WO2021238827A1 (zh) | Egfr抑制剂、其制备方法及用途 | |
CN111295378A (zh) | 灰黄霉素化合物及其药物用途 | |
WO2020238785A1 (zh) | 包括甲基和三氟甲基的双取代磺酰胺类选择性bcl-2抑制剂 | |
WO2019085978A1 (zh) | 杂芳基酰胺类化合物、其制备方法、药用组合物及其应用 | |
CN109641909A (zh) | 雷帕霉素信号通路抑制剂的机理靶标及其治疗应用 | |
TWI729810B (zh) | 噻唑衍生物的製造方法 | |
WO2021249324A1 (zh) | 烯基嘧啶类化合物、其制备方法与应用 | |
CN110407839B (zh) | 含杂芳基酰胺结构的三唑并杂环类化合物的制备及应用 | |
EP4083031A1 (en) | Quinoline compound and application thereof | |
WO2021254464A1 (zh) | 取代喹唑啉类化合物、其制备方法、药物组合及应用 | |
NZ744393B2 (en) | Pyrimidine seven-membered-ring compounds, preparation method therefor, pharmaceutical composition thereof, and uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 18872080 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 3084846 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2018872080 Country of ref document: EP Effective date: 20200603 |
|
ENP | Entry into the national phase |
Ref document number: 2018359934 Country of ref document: AU Date of ref document: 20181102 Kind code of ref document: A |