TW202400598A - 嘧啶醯胺化合物及其用途 - Google Patents
嘧啶醯胺化合物及其用途 Download PDFInfo
- Publication number
- TW202400598A TW202400598A TW112120054A TW112120054A TW202400598A TW 202400598 A TW202400598 A TW 202400598A TW 112120054 A TW112120054 A TW 112120054A TW 112120054 A TW112120054 A TW 112120054A TW 202400598 A TW202400598 A TW 202400598A
- Authority
- TW
- Taiwan
- Prior art keywords
- group
- compound
- pyrazolo
- cancer
- alkoxy
- Prior art date
Links
- FUXJMHXHGDAHPD-UHFFFAOYSA-N pyrimidine-2-carboxamide Chemical class NC(=O)C1=NC=CC=N1 FUXJMHXHGDAHPD-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 191
- 150000003839 salts Chemical class 0.000 claims abstract description 39
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 26
- 201000011510 cancer Diseases 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- -1 cyano, hydroxyl Chemical group 0.000 claims description 115
- 125000003545 alkoxy group Chemical group 0.000 claims description 68
- 125000000217 alkyl group Chemical group 0.000 claims description 55
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 31
- 125000001072 heteroaryl group Chemical group 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical group 0.000 claims description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 206010009944 Colon cancer Diseases 0.000 claims description 7
- 201000007270 liver cancer Diseases 0.000 claims description 7
- 208000014018 liver neoplasm Diseases 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 206010005003 Bladder cancer Diseases 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 206010014733 Endometrial cancer Diseases 0.000 claims description 3
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 3
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 3
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 201000004101 esophageal cancer Diseases 0.000 claims description 3
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 3
- 206010046766 uterine cancer Diseases 0.000 claims description 3
- 206010005949 Bone cancer Diseases 0.000 claims description 2
- 208000018084 Bone neoplasm Diseases 0.000 claims description 2
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 206010038389 Renal cancer Diseases 0.000 claims description 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000000728 Thymus Neoplasms Diseases 0.000 claims description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 201000010536 head and neck cancer Diseases 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 201000010982 kidney cancer Diseases 0.000 claims description 2
- 201000011682 nervous system cancer Diseases 0.000 claims description 2
- 201000008968 osteosarcoma Diseases 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 201000000849 skin cancer Diseases 0.000 claims description 2
- 201000002314 small intestine cancer Diseases 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 201000009377 thymus cancer Diseases 0.000 claims description 2
- 201000002510 thyroid cancer Diseases 0.000 claims description 2
- HPARLNRMYDSBNO-UHFFFAOYSA-N 1,4-benzodioxine Chemical compound C1=CC=C2OC=COC2=C1 HPARLNRMYDSBNO-UHFFFAOYSA-N 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims 1
- 239000007787 solid Substances 0.000 description 104
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 62
- 239000000243 solution Substances 0.000 description 34
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 24
- 235000019439 ethyl acetate Nutrition 0.000 description 22
- 239000000843 powder Substances 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000003814 drug Substances 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 239000000377 silicon dioxide Substances 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000007112 amidation reaction Methods 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 230000009435 amidation Effects 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 239000002246 antineoplastic agent Substances 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 239000011521 glass Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- LJOTUUWIRODVMV-UHFFFAOYSA-N ClC1=NC(=C2C(=N1)N(N=C2)C1CCN(CC1)C(=O)OC(C)(C)C)NCC1=CC=C(C=C1)OC Chemical compound ClC1=NC(=C2C(=N1)N(N=C2)C1CCN(CC1)C(=O)OC(C)(C)C)NCC1=CC=C(C=C1)OC LJOTUUWIRODVMV-UHFFFAOYSA-N 0.000 description 5
- 229940041181 antineoplastic drug Drugs 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 230000004614 tumor growth Effects 0.000 description 5
- BYEANWQDRDXPPA-UHFFFAOYSA-N 5-nitrothiophene-2-carbonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)S1 BYEANWQDRDXPPA-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- KVJIRFGNHAAUNQ-UHFFFAOYSA-N 2,4,6-trichloropyrimidine-5-carbaldehyde Chemical compound ClC1=NC(Cl)=C(C=O)C(Cl)=N1 KVJIRFGNHAAUNQ-UHFFFAOYSA-N 0.000 description 3
- TYMWHTJGWKSXRY-UHFFFAOYSA-N 4,6-dichloro-1-methylpyrazolo[3,4-d]pyrimidine Chemical compound N1=C(Cl)N=C2N(C)N=CC2=C1Cl TYMWHTJGWKSXRY-UHFFFAOYSA-N 0.000 description 3
- TVNFAHSWOCLZGO-UHFFFAOYSA-N 4,6-dichloro-1-phenylpyrazolo[3,4-d]pyrimidine Chemical compound C12=NC(Cl)=NC(Cl)=C2C=NN1C1=CC=CC=C1 TVNFAHSWOCLZGO-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- SRPFKNCYOTZXDC-UHFFFAOYSA-N C(C)(C)(C)C1=CC=C(C=C1)C1=NC(=C2C(=N1)N(N=C2)C)NC(=O)C=1SC(=CC=1)[N+](=O)[O-] Chemical compound C(C)(C)(C)C1=CC=C(C=C1)C1=NC(=C2C(=N1)N(N=C2)C)NC(=O)C=1SC(=CC=1)[N+](=O)[O-] SRPFKNCYOTZXDC-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 238000000719 MTS assay Methods 0.000 description 3
- 231100000070 MTS assay Toxicity 0.000 description 3
- 238000006751 Mitsunobu reaction Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000006069 Suzuki reaction reaction Methods 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 238000005576 amination reaction Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000010926 purge Methods 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- FSVJFNAIGNNGKK-KRWDZBQOSA-N (11br)-2-(cyclohexanecarbonyl)-3,6,7,11b-tetrahydro-1h-pyrazino[2,1-a]isoquinolin-4-one Chemical compound N1([C@H](C2=CC=CC=C2CC1)C1)C(=O)CN1C(=O)C1CCCCC1 FSVJFNAIGNNGKK-KRWDZBQOSA-N 0.000 description 2
- MNJYZNVROSZZQC-UHFFFAOYSA-N (4-tert-butylphenyl)boronic acid Chemical compound CC(C)(C)C1=CC=C(B(O)O)C=C1 MNJYZNVROSZZQC-UHFFFAOYSA-N 0.000 description 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- FZTLLUYFWAOGGB-UHFFFAOYSA-N 1,4-dioxane dioxane Chemical compound C1COCCO1.C1COCCO1 FZTLLUYFWAOGGB-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- IXLBKCICUWBZOQ-UHFFFAOYSA-N 6-chloro-1-methylpyrazolo[3,4-d]pyrimidin-4-amine Chemical compound N1=C(Cl)N=C2N(C)N=CC2=C1N IXLBKCICUWBZOQ-UHFFFAOYSA-N 0.000 description 2
- LMQXTXZITKPCOV-UHFFFAOYSA-N 6-chloro-1-phenylpyrazolo[3,4-d]pyrimidin-4-amine Chemical compound N1=CC=2C(N)=NC(Cl)=NC=2N1C1=CC=CC=C1 LMQXTXZITKPCOV-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- ICLJAUIYDZZAHO-UHFFFAOYSA-N C(C)(C)(C)C1=CC=C(C=C1)C1=C2C(=NC(=N1)N)N(N=C2)C Chemical compound C(C)(C)(C)C1=CC=C(C=C1)C1=C2C(=NC(=N1)N)N(N=C2)C ICLJAUIYDZZAHO-UHFFFAOYSA-N 0.000 description 2
- KBHLXEXLBSWWIP-UHFFFAOYSA-N C(C)(C)(C)C1=CC=C(C=C1)C1=NC(=C2C(=N1)N(N=C2)C)N Chemical compound C(C)(C)(C)C1=CC=C(C=C1)C1=NC(=C2C(=N1)N(N=C2)C)N KBHLXEXLBSWWIP-UHFFFAOYSA-N 0.000 description 2
- OEVDZAAYGGFIII-UHFFFAOYSA-N COC1=CC=C(C=C1)CNC2=C3C=NN(C3=NC(=N2)C4=CC=C(C=C4)Cl)C5CCN(CC5)C(=O)O Chemical compound COC1=CC=C(C=C1)CNC2=C3C=NN(C3=NC(=N2)C4=CC=C(C=C4)Cl)C5CCN(CC5)C(=O)O OEVDZAAYGGFIII-UHFFFAOYSA-N 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- WVKFTSCQNPOCDW-UHFFFAOYSA-N ClC1=CC=C(C=C1)C1=NC(=C2C(=N1)N(N=C2)C1CCN(CC1)C(=O)OC(C)(C)C)NCC1=CC=C(C=C1)OC Chemical compound ClC1=CC=C(C=C1)C1=NC(=C2C(=N1)N(N=C2)C1CCN(CC1)C(=O)OC(C)(C)C)NCC1=CC=C(C=C1)OC WVKFTSCQNPOCDW-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 2
- 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 2
- BPZYAPHVUPUHLL-NSHDSACASA-N NC1=C2C(=NC(=N1)C=1C=NC(=CC=1)F)N(N=C2)[C@@H]1CN(CC1)C(C=C)=O Chemical compound NC1=C2C(=NC(=N1)C=1C=NC(=CC=1)F)N(N=C2)[C@@H]1CN(CC1)C(C=C)=O BPZYAPHVUPUHLL-NSHDSACASA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 2
- 150000001345 alkine derivatives Chemical group 0.000 description 2
- 125000005277 alkyl imino group Chemical group 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 125000004467 aryl imino group Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 238000000099 in vitro assay Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 2
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- VJLYHTOSFSGXGH-CQSZACIVSA-N (2R)-1-[3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxybenzoyl]pyrrolidine-2-carboxylic acid Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)N2[C@H](CCC2)C(=O)O)C=CC=1 VJLYHTOSFSGXGH-CQSZACIVSA-N 0.000 description 1
- CAYQIZIAYYNFCS-UHFFFAOYSA-N (4-chlorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Cl)C=C1 CAYQIZIAYYNFCS-UHFFFAOYSA-N 0.000 description 1
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 1
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 description 1
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- 229940005561 1,4-benzoquinone Drugs 0.000 description 1
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 1
- JBMTUXVKTGBMLE-UHFFFAOYSA-N 1-methylpyrazolo[3,4-d]pyrimidin-4-amine Chemical compound N1=CN=C2N(C)N=CC2=C1N JBMTUXVKTGBMLE-UHFFFAOYSA-N 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- YYVPZQADFREIFR-UHFFFAOYSA-N 3,3-difluoropyrrolidine;hydrochloride Chemical compound [Cl-].FC1(F)CC[NH2+]C1 YYVPZQADFREIFR-UHFFFAOYSA-N 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- MROVZCRMXJZHCN-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(2-hydroxyethyl)benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCCO)C=CC=1 MROVZCRMXJZHCN-UHFFFAOYSA-N 0.000 description 1
- VTNULXUEOJMRKZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(2H-tetrazol-5-ylmethyl)benzamide Chemical compound N=1NN=NC=1CNC(C1=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)=O VTNULXUEOJMRKZ-UHFFFAOYSA-N 0.000 description 1
- GDSLUYKCPYECNN-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[(4-fluorophenyl)methyl]benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCC2=CC=C(C=C2)F)C=CC=1 GDSLUYKCPYECNN-UHFFFAOYSA-N 0.000 description 1
- ZMCQQCBOZIGNRV-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[2-(1,2,4-triazol-1-yl)ethyl]benzamide Chemical compound NCC1=CC(OC2=CC=CC(=C2)C(=O)NCCN2C=NC=N2)=NC(=C1)C(F)(F)F ZMCQQCBOZIGNRV-UHFFFAOYSA-N 0.000 description 1
- AJZDHLHTTJRNQJ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[2-(tetrazol-1-yl)ethyl]benzamide Chemical compound N1(N=NN=C1)CCNC(C1=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)=O AJZDHLHTTJRNQJ-UHFFFAOYSA-N 0.000 description 1
- MZSAMHOCTRNOIZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylaniline Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(NC2=CC=CC=C2)C=CC=1 MZSAMHOCTRNOIZ-UHFFFAOYSA-N 0.000 description 1
- HAEQAUJYNHQVHV-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylbenzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NC2=CC=CC=C2)C=CC=1 HAEQAUJYNHQVHV-UHFFFAOYSA-N 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- RHMPLDJJXGPMEX-UHFFFAOYSA-N 4-fluorophenol Chemical compound OC1=CC=C(F)C=C1 RHMPLDJJXGPMEX-UHFFFAOYSA-N 0.000 description 1
- DVWJFIKPUBURHV-UHFFFAOYSA-N 6-chloro-1-methylpyrazolo[3,4-d]pyrimidine Chemical compound N1=C(Cl)N=C2N(C)N=CC2=C1 DVWJFIKPUBURHV-UHFFFAOYSA-N 0.000 description 1
- LHCPRYRLDOSKHK-UHFFFAOYSA-N 7-deaza-8-aza-adenine Chemical compound NC1=NC=NC2=C1C=NN2 LHCPRYRLDOSKHK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- FKBYEYJUEZQVPA-UHFFFAOYSA-N C(C)(C)(C)C1=CC=C(C=C1)C1=C2C(=NC(=N1)Cl)N(N=C2)C Chemical compound C(C)(C)(C)C1=CC=C(C=C1)C1=C2C(=NC(=N1)Cl)N(N=C2)C FKBYEYJUEZQVPA-UHFFFAOYSA-N 0.000 description 1
- MPKAHVWKYJTPOI-UHFFFAOYSA-N C(C)(C)(C)C1=CC=C(C=C1)C1=C2C(=NC(=N1)NC(=O)C=1SC(=CC=1)[N+](=O)[O-])N(N=C2)C Chemical compound C(C)(C)(C)C1=CC=C(C=C1)C1=C2C(=NC(=N1)NC(=O)C=1SC(=CC=1)[N+](=O)[O-])N(N=C2)C MPKAHVWKYJTPOI-UHFFFAOYSA-N 0.000 description 1
- FXSAXCAZTFHESC-UHFFFAOYSA-N C1CNCC1N2C3=NC(=NC(=C3C=N2)N)C4=CN=C(C=C4)F Chemical compound C1CNCC1N2C3=NC(=NC(=C3C=N2)N)C4=CN=C(C=C4)F FXSAXCAZTFHESC-UHFFFAOYSA-N 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 1
- ZAPDOMIZHUSHMW-UHFFFAOYSA-N FC1(CN(CC1)C1=NC(=C2C(=N1)N(N=C2)C1=CC=CC=C1)N)F Chemical compound FC1(CN(CC1)C1=NC(=C2C(=N1)N(N=C2)C1=CC=CC=C1)N)F ZAPDOMIZHUSHMW-UHFFFAOYSA-N 0.000 description 1
- AHXMBZDAEOACHK-UHFFFAOYSA-N FC1(CN(CC1)C1=NC(=C2C(=N1)N(N=C2)C1=CC=CC=C1)NC(=O)C=1SC(=CC=1)[N+](=O)[O-])F Chemical compound FC1(CN(CC1)C1=NC(=C2C(=N1)N(N=C2)C1=CC=CC=C1)NC(=O)C=1SC(=CC=1)[N+](=O)[O-])F AHXMBZDAEOACHK-UHFFFAOYSA-N 0.000 description 1
- FXSAXCAZTFHESC-VIFPVBQESA-N FC1=CC=C(C=N1)C1=NC(=C2C(=N1)N(N=C2)[C@@H]1CNCC1)N Chemical compound FC1=CC=C(C=N1)C1=NC(=C2C(=N1)N(N=C2)[C@@H]1CNCC1)N FXSAXCAZTFHESC-VIFPVBQESA-N 0.000 description 1
- HDBXEQFXQVITHG-UHFFFAOYSA-N FC1=CC=C(OC2=NC(=C3C(=N2)N(N=C3)C2=CC=CC=C2)NC(=O)C=2SC(=CC=2)[N+](=O)[O-])C=C1 Chemical compound FC1=CC=C(OC2=NC(=C3C(=N2)N(N=C3)C2=CC=CC=C2)NC(=O)C=2SC(=CC=2)[N+](=O)[O-])C=C1 HDBXEQFXQVITHG-UHFFFAOYSA-N 0.000 description 1
- 102000007317 Farnesyltranstransferase Human genes 0.000 description 1
- 108010007508 Farnesyltranstransferase Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- OMKOVCXCKULXJK-UHFFFAOYSA-N NC1=C2C(=NC(=N1)C1=CC=C(C=C1)Cl)N(N=C2)C1CCN(CC1)C(=O)OC(C)(C)C Chemical compound NC1=C2C(=NC(=N1)C1=CC=C(C=C1)Cl)N(N=C2)C1CCN(CC1)C(=O)OC(C)(C)C OMKOVCXCKULXJK-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241001122767 Theaceae Species 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-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
- REAYFGLASQTHKB-UHFFFAOYSA-N [2-[3-(1H-pyrazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound N1N=CC(=C1)C=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 REAYFGLASQTHKB-UHFFFAOYSA-N 0.000 description 1
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 description 1
- 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 1
- YQYBUJYBXOVWQW-UHFFFAOYSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-(3,4-dihydro-1H-isoquinolin-2-yl)methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C=CC=1)C(=O)N1CC2=CC=CC=C2CC1 YQYBUJYBXOVWQW-UHFFFAOYSA-N 0.000 description 1
- BYWBCSRCPLBDFU-CYBMUJFWSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-[(3R)-3-aminopyrrolidin-1-yl]methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C=CC=1)C(=O)N1C[C@@H](CC1)N BYWBCSRCPLBDFU-CYBMUJFWSA-N 0.000 description 1
- LJHFUFVRZNYVMK-CYBMUJFWSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-[(3R)-3-hydroxypyrrolidin-1-yl]methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C=CC=1)C(=O)N1C[C@@H](CC1)O LJHFUFVRZNYVMK-CYBMUJFWSA-N 0.000 description 1
- LJHFUFVRZNYVMK-ZDUSSCGKSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-[(3S)-3-hydroxypyrrolidin-1-yl]methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C=CC=1)C(=O)N1C[C@H](CC1)O LJHFUFVRZNYVMK-ZDUSSCGKSA-N 0.000 description 1
- JWSIZPAOIFLWKM-UHFFFAOYSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-[3-(dimethylamino)-4-hydroxypyrrolidin-1-yl]methanone Chemical compound CN(C)C1CN(CC1O)C(=O)c1cccc(Oc2cc(CN)cc(n2)C(F)(F)F)c1 JWSIZPAOIFLWKM-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000012042 active reagent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 1
- 125000005365 aminothiol group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000005264 aryl amine group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl 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
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 125000005604 azodicarboxylate group Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 230000006369 cell cycle progression Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction 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
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000006392 deoxygenation reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 125000005266 diarylamine group Chemical group 0.000 description 1
- 125000005056 dihydrothiazolyl group Chemical group S1C(NC=C1)* 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- BQIVJVAZDJHDJF-LURJTMIESA-N ethyl (2s)-2-amino-3-methylbutanoate Chemical compound CCOC(=O)[C@@H](N)C(C)C BQIVJVAZDJHDJF-LURJTMIESA-N 0.000 description 1
- ZJXZSIYSNXKHEA-UHFFFAOYSA-N ethyl dihydrogen phosphate Chemical compound CCOP(O)(O)=O ZJXZSIYSNXKHEA-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000007614 genetic variation Effects 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 1
- 238000009474 hot melt extrusion Methods 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration 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
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 239000008184 oral solid dosage form Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 229940127084 other anti-cancer agent Drugs 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- JOVOSQBPPZZESK-UHFFFAOYSA-N phenylhydrazine hydrochloride Chemical compound Cl.NNC1=CC=CC=C1 JOVOSQBPPZZESK-UHFFFAOYSA-N 0.000 description 1
- 229940038531 phenylhydrazine hydrochloride Drugs 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- IVDHYUQIDRJSTI-UHFFFAOYSA-N sorafenib tosylate Chemical compound [H+].CC1=CC=C(S([O-])(=O)=O)C=C1.C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 IVDHYUQIDRJSTI-UHFFFAOYSA-N 0.000 description 1
- 229960000487 sorafenib tosylate Drugs 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea group Chemical group NC(=S)N UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本發明揭示一種如下式(I)之化合物或其立體異構物、互變異構物、或其藥學上可接受之鹽類：
Description
本揭露係關於可抑制腫瘤細胞生長之化合物、包括該化合物之醫藥組成物、以及該化合物或醫藥組成物之用途。
近年來，發現食品或食品添加劑以及環境汙染可能是近年來引起癌症的原因或催化劑。並非偶然地，於已開發國家及全世界內也發生了同樣的事件，癌症的高發生率為令人震驚的跡象。根據美國癌症協會發布的數據，癌症已被證實是對公共健康的最大威脅。
一般用於治療癌症的方法包含手術、放射療法、化學療法及免疫療法。近年來，已經開發了幾種透過新的抗癌機制用於癌症治療的治療劑，並且已經證實透過使用這些治療劑治療可以提高患者的存活率。已知治療劑可透過例如抑制細胞週期進程、血管生成、法尼基轉移酶(farnesyl transferase)及酪胺酸激酶(tyrosine kinases)來治療癌症。
儘管已知某些藥劑對癌症展現出治療功效，但是這些藥劑仍有其限制。例如，有的抗癌藥僅對特定癌症具有治療功效，例如用於治療肺癌的抗癌藥不一定對乳癌有治療功效。此外，抗癌藥的治療功效還取決於腫瘤細胞的位置、患者的遺傳變異、以及藥物的副作用。另外，癌細胞可透過淋巴系統或血液循環系統從其原始部位擴散至患者的另一器官，從而引起轉移性癌症。
由於罹患癌症的風險通常隨著年齡增加，故隨著壽命的延長和大眾生活方式的改變，癌症的發生率也會增加。因此，長期以來未滿足提供用於癌症治療及預防的新藥物的需求。
本揭露係關於某些可以抑制腫瘤細胞生長之化合物。
本揭露的一態樣涉及下式(I)之化合物或其立體異構物(stereoisomer)、互變異構物(tautomer)、或其藥學上可接受之鹽類：
於此式中，R1為芳基或雜芳基，其中芳基和雜芳基各自選擇性地被一至三個選自由鹵素、氰基、烷基和選擇性地被烷氧基取代之烷氧基所組成之群組之基團取代；R2為芳基、雜芳基、與雜環烷基稠合之芳基、與雜芳基稠合之芳基或與雜芳基稠合之雜芳基，其中芳基、雜芳基、與雜環烷基稠合之芳基、與雜芳基稠合之芳基或與雜芳基稠合之雜芳基各自選擇性地被一至三個選自由鹵素、烷基、烷氧基、氰基、羥基、-NRaRb、-C(=O)NRaRb、-C(=O)ORc、-C(=O)Rd和氧基(oxy group)所組成之群組之基團取代，其中烷氧基選擇性地被烷氧基、羥基、磷酸基團或-OC(=O)Re取代，且烷基選擇性地被羥基或烷氧基中之至少一種取代；Ra和Rb各自獨立為H、烷基或烷氧基；Rc為H或選擇性地被羥基或烷氧基中之至少一種取代之烷基；Rd為烷基；以及Re為選擇性地被胺基或羧基中之至少一種取代之烷基。
本文中的術語「烷基」是指含有1-12個碳原子(例如，C1-C10、C1-C8及C1-C6)的直鏈或支鏈烴基。實例包含甲基、乙基、正丙基、異丙基、正丁基、異丁基及叔丁基。
術語「雜環烷基」是指具有一或多個雜原子(例如：O、N、P及S)的非芳香族5-8元單環、8-12元雙環、或11-14元三環系統。實例包含哌嗪基(piperazinyl)、咪唑啶基(imidazolidinyl)、氮雜環庚烷(azepanyl)、吡咯烷基(pyrrolidinyl)、二氫噻二唑基、二噁烷基、嗎啉基、四氫吡喃基(tetrahydropyranyl)及四氫呋喃基。
術語「烷氧基(alkoxy)」或「烷氧基(alkyloxy)」是指-O-烷基。實例包含甲氧基、乙氧基、丙氧基及異丙氧基。
術語「鹵素」是指氟、氯、溴、或碘基。
術語「胺基」是指衍生自胺的基團，其為未被取代或被烷基、芳基、環烷基、雜環烷基、或雜芳基單/雙取代。
術語「芳基」是指6個碳的單環、10個碳的雙環、14個碳的三環芳香族環系統。芳基的實例包含苯基、萘基及蒽基。
術語「雜芳基」是指具有一或多個雜原子(例如：O、N、P及S)的芳香族5-8元單環、8-12元雙環、或11-14元三環系統。實例包含噻吩基(thiophenyl)、三唑基、噁唑基(oxazolyl)、噻二唑基、四唑基、吡唑基、吡啶基、呋喃基、咪唑基、苯並咪唑基、嘧啶基、噻吩基(thienyl)、喹啉基、吲哚基、噻唑基及苯並噻唑基。
本文提及的烷基、雜環烷基、烷氧基、芳基及雜芳基包含取代及未取代之基團兩者。雜環烷基、烷氧基、芳基及雜芳基上可能的取代基包含但
不限於C1-6烷基、C2-6烯基、C2-6炔基、C3-12環烷基、C3-12環烯基、C1-12雜環烷基、C1-12雜環烯基、C1-6烷氧基、芳基、芳氧基、雜芳基、雜芳氧基、胺基、C1-6烷基胺基、C1-20二烷基胺基、芳基胺基、二芳基胺基、C1-6烷基磺胺基(alkylsulfonamino)、芳基磺胺基(arylsulfonamino)、C1-6烷基亞胺基(alkylimino)、芳基亞胺基(arylimino)、C1-6烷基亞磺胺基(alkylsulfonimino)、芳基亞磺胺基(arylsulfonimino)、羥基、鹵素、硫基、C1-6烷硫基、芳硫基、C1-6烷基磺醯基、芳基磺醯基、醯基胺基(acylamino)、胺基醯基(aminoacyl)、胺基硫醯基、醯胺基(amido)、甲脒基(amidino)、胍基、脲基、硫脲基、氰基、硝基、亞硝基、疊氮基、醯基、硫醯基、醯氧基、羧基及羧酸酯。另一方面，烷基上可能的取代基包含除了C1-6烷基以外的所有上述取代基。雜環烷基、芳基及雜芳基也可以彼此稠合。
除了上述式(I)的化合物，如果可適用它們的藥學上可接受之鹽類及溶劑化物也被本揭露所涵蓋。可以在陰離子與化合物上帶正電荷的基團(例如胺基)之間形成鹽類。適合的陰離子的實例包含氯離子、溴離子、碘離子、硫酸根、硝酸根、磷酸根、檸檬酸根、甲磺酸根、三氟乙酸根、乙酸根、蘋果酸根(malate)、甲苯磺酸根(tosylate)、酒石酸根、富馬酸根(fumurate)、谷胺酸根、葡醣醛酸根(glucuronate)、乳酸根、戊二酸根及順丁烯二酸根(maleate)。也可以在陽離子與帶負電荷的基團之間形成鹽類。適合的陽離子的實例包含鈉離子、鉀離子、鎂離子、鈣離子及銨陽離子(諸如四甲銨離子(tetramethylammonium ion))。鹽類更包含含有季氮原子的鹽類。溶劑化物是指在活性化合物與藥學上可接受之溶劑之間形成的複合物。藥學上可接受之溶劑的實例包含水、乙醇、異丙醇、乙酸乙酯、乙酸及乙醇胺。
本揭露的另一態樣是用於治療癌症之醫藥組成物。
醫藥組成物含有上述式(I)之化合物中之一者或其藥學上可接受之鹽類及藥學上可接受之載體、賦形劑或稀釋劑。
本揭露還涵蓋了這種組成物在製備用於治療癌症的藥物中之用途。
用於口服給藥的組成物可以是任何口服可接受的劑型，包含膠囊、錠劑、乳劑及水懸浮液、分散液及溶液。對於錠劑而言，常用的載體包含乳糖及玉米澱粉，通常還添加諸如硬脂酸鎂的潤滑劑。對於以膠囊形式的口服給藥，有用的稀釋劑包含乳糖及乾燥的玉米澱粉。當口服給藥水懸浮液或乳劑時，可以將活性成分懸浮或溶解在與乳化劑或懸浮劑結合的油相中，如果需要，可以添加某些甜味劑、調味劑或著色劑。口服固體劑型可透過噴霧乾燥技術來製備；熱熔擠出策略、微粉化及奈米研磨技術。
可以根據藥物製劑領域中眾所周知的技術來製備鼻用氣霧劑或吸入組成物。例如，可以使用本領域已知的苯甲醇或其他適合的防腐劑、吸收促進劑、碳氟化合物及/或其他增溶劑或分散劑，將這種組成物製備為在鹽水中的溶液。具有活性化合物之組成物也可以以栓劑的形式用於直腸給藥。
醫藥組成物中的載體、賦形劑及稀釋劑在與組成物的活性成分之相容性上須為「可接受的」(且較佳能夠穩定活性成分)，並且對要被治療的主體無害。可以將一或多種增溶劑用作藥物賦形劑以傳遞活性化合物。其他載體的實例包含膠體氧化矽、硬脂酸鎂、纖維素、硫酸月桂酯鈉(sodium lauryl sulfate)以及D&C Yellow #10。
治療癌症之方法仍在本揭露的範圍內。
該方法包含給予需求主體有效量式(I)之化合物或其藥學上可接受之鹽類。
上述化合物或含有一或多種上述化合物的醫藥組成物可以以口服、胃腸外、透過吸入噴霧、局部、直腸、鼻、頰、或經由植入儲藏器的方式給予主體。本文中的術語「腸胃外」包含皮下、皮內、靜脈內、肌肉內、關節內、動脈內、滑膜內(intrasynovial)、胸骨內、脊椎內(intrathecal)、病灶內、及顱內注射或輸注技術。
術語「治療(treating、treat或treatment)」是指將化合物施用於或給予主體，以治癒、緩解、減輕、改變、矯正(remedy)、改善、或影響疾病、症狀、或其傾向(predisposition)。「有效量」是指賦予主體期望的效果所需的化合物之量。如本領域技術人員所知，有效量取決於給藥途徑、賦形劑用法以及與其他治療方法(諸如其他活性劑的使用)共同使用的可能性而變化。
下文描述中闡述了本揭露的一或多個實施例的細節。根據描述及申請權利範圍，本揭露的其他特徵、目的、以及優點將是顯而易見的。
本揭露的一實施例為式(I)之化合物或其立體異構物、互變異構物、或其藥學上可接受之鹽類：
其中每個變數R1及R2的定義如「發明內容」段落所述。
R1可以透過將各種肼(hydrazine)衍生物縮合成稠合的芳香族雜環5元環來產生。此外，也可以透過光延(Mitsunobu)反應或透過簡單取代反應來建構。Mitsunobu反應使用三苯磷(triphenylphosphine)及偶氮二甲酸酯(azodicarboxylate)(諸如偶氮二甲酸二乙酯(diethyl azodicarboxylate,DEAD)或偶氮二甲酸二異丙酯(diisopropyl azodicarboxylate,DIAD)以將醇轉化為各種官能團(諸如酯的有機反應))，醇與磷反應形成良好的離去基，然後以經典的SN2親核試劑取代的方式進行立體化學轉化，形成碳-碳鍵衍生物。
R2可以透過Suzuki合成，而Sonogashira反應是一種在有機合成中用於形成碳-碳鍵的交叉偶合反應(cross-coupling reaction)，其使用鈀催化劑作為催化劑以在末端炔烴(terminal alkyne)與芳基雜芳基或乙烯基鹵化物之間形成碳-碳鍵，並在雜芳族取代中被NR、OR、SR親核試劑取代。
本發明的另一實施例為上述實施例的化合物或其立體異構體、互變異構體或藥學上可接受之鹽類，其中R1可為苯基或噻吩基(thiophenyl)，且苯基或噻吩基可各自選擇性地被一至三個選自由鹵素、氰基、烷基和選擇性地被烷氧基取代之烷氧基所組成之群組之基團取代。
本發明的另一實施例為上述實施例的化合物或其立體異構體、互變異構體或藥學上可接受之鹽類，其中R1可為選擇性地被一或兩個選自由鹵素、氰基、烷基和選擇性地被烷氧基取代之烷氧基所組成之群組之基團取代之苯基。
本發明的另一實施例為上述實施例的化合物或其立體異構體、互變異構體或藥學上可接受之鹽類，其中R1可為選擇性地被烷基或氰基取代之噻吩基(thiophenyl)。
本發明的另一實施例為上述實施例的化合物或其立體異構體、互
變異構體或藥學上可接受之鹽類，其中R2可為
，X1可為N或C，X2為N
或C，且R3和R4可各自獨立地選自由氫、鹵素、烷基、烷氧基、氰基、羥基、-NRaRb、-C(=O)NRaRb、-C(=O)ORc、-C(=O)Rd和氧基所組成之群組，其中烷氧基選擇性地被烷氧基、羥基、磷酸基團或-OC(=O)Re取代，且烷基選擇性地被羥基或烷氧基取代；或R3和R4可與其間的原子一起形成雜環，其選擇性地被一或兩個選自由鹵素、氧基或選擇性地被羥基或烷氧基取代之烷基所組成之群組之基團取代；或R3和R4可與其間的原子一起形成雜芳環，其選擇性地被烷氧基或烷基取代，其中烷氧基選擇性地被烷氧基取代，烷基選擇性地被羥基或烷氧基取代。Ra、Rb、Rc、Rd和Re的定義同上，故不再贅述。
本發明的另一實施例為上述實施例的化合物或其立體異構體、互
變異構體或藥學上可接受之鹽類，其中R2可為
，X1可為N或C。R3和R4
的定義同上，故不再贅述。
本發明的另一實施例為上述實施例的化合物或其立體異構體、互
變異構體或藥學上可接受之鹽類，其中R2可為
。R3和R4的定義同上，
故不再贅述。
本發明的另一實施例為上述實施例的化合物或其立體異構體、互
變異構體或藥學上可接受之鹽類，其中R2可為
，且R3和R4可各自獨立
為烷氧基(例如甲氧基)或氰基。在本發明的一實施例中，R1可為被鹵素取代之苯基。
本發明的另一實施例為上述實施例的化合物或其立體異構體、互變異構體或藥學上可接受之鹽類，其中R2可為選擇性地被一或兩個選自由鹵素和選擇性地被羥基取代之烷基所組成之群組之基團取代之苯並二氧雜環戊烯基(benzodioxolyl)；選擇性地被氧基取代之四氫喹啉基(tetrahydroquinolinyl)；選擇性地被烷基取代之苯並噁唑基(benzoxazolyl)，其中烷基選擇性地被烷氧基取代；苯並噻吩基(benzothiophenyl)；選擇性地被烷基或烷氧基取代之苯並噻唑基(benzothiazolyl)，其中烷氧基選擇性地被烷氧基取代；或咪唑並吡啶基(imidazopyridinyl)。
本發明的另一實施例為上述實施例的化合物或其立體異構體、互
變異構體或藥學上可接受之鹽類，其中R2可為
、
、
或
，R5可各自為氫、鹵素、烷基、烷氧基、氰基、羥基、-NRaRb、-C(=O)NRaRb、
-C(=O)ORc或-C(=O)Rd，其中烷氧基選擇性地被烷氧基、羥基、磷酸基團或-OC(=O)Re取代，且烷基選擇性地被羥基或烷氧基取代。
本發明的另一實施例為上述實施例的化合物或其立體異構體、互
變異構體或藥學上可接受之鹽類，其中R2可為
、
、
、
或
。R5的定義同上，故不再贅述。
本發明的另一實施例為上述實施例的化合物或其立體異構體、互
變異構體或藥學上可接受之鹽類，其中R2可為
、
或
。R5的定義同上，故不再贅述。
本發明的另一實施例為上述實施例的化合物或其立體異構體、互變異構體或藥學上可接受之鹽類，其中R2可為
、
或
，且R5可各自為氰基、-C(=O)ORc或選擇性地被羥基取代之烷氧基，其中Rc為烷基。
本發明的另一實施例為上述實施例的化合物或其立體異構體、互變異構體或藥學上可接受之鹽類，其中R2可為
，R5可為-C(=O)ORc，且Rc可為烷基(例如甲基)。在本發明的一實施例中，R1可為被氰基取代之苯基。
本發明的另一實施例為上述實施例的化合物或其立體異構體、互變異構體或藥學上可接受之鹽類，其中R2可為
，且R5可為氰基。在本發明的一實施例中，R1可為被F取代之苯基。
本發明的另一實施例為上述實施例的化合物或其立體異構體、互變異構體或藥學上可接受之鹽類，其中R2可為
，且R5可為選擇性地被羥基取代之烷氧基(例如羥基乙氧基)。在本發明的一實施例中，R1可為被F取代之苯基。
本發明的另一實施例可為選自由列出於下表1至6中的化合物1-1至1-25、化合物2-1至2-3、化合物3-1至3-9、化合物4-1至4-19、化合物5-1至5-36以及化合物6-1至6-3所組成之群組中之化合物或其立體異構物(stereoisomer)、互變異構物(tautomer)或其藥學上可接受之鹽類。
本發明的再另一實施例可為化合物1-8、化合物5-6、化合物5-8或化合物5-16或其立體異構體、互變異構體或藥學上可接受之鹽類。
本發明之化合物可含有不對稱或對掌性(chiral)中心，並且以不同立體異構(stereoisomeric)的形式存在。除非另有說明，否則本發明之化合物之所有立體異構的形式及其混合物、包含外消旋(racemic)混合物是在本發明的範圍內。此外，本發明之化合物也可以以不同的幾何(geometric)及位置(positional)異構物存在。例如，順式(cis-forms)及反式(trans-forms)以及具有雙鍵或稠合環(fused ring)之化合物的混合物也在本發明的範圍內。
非鏡像異構物(Diastereomeric)混合物可以透過任何方法(諸如透過層析法(chromatography)及/或分級結晶(fractional crystallization))分離成他們個別的非鏡像異構物。鏡像異構物(Enantiomers)可透過使用對掌性HPLC管柱分離，或透過與適合的具旋光性的化合物(optically active compound)反應將鏡像異構混合物轉化為非鏡像異構混合物來分離非鏡像異構物，並將個別的非鏡像異構物轉化為純鏡像異構物。可透過不對稱轉變(asymmetric transformation)、透過使用具旋光性的起始材料或透過使用旋光性試劑、催化劑、基質或溶劑的不對稱合成，將立體異構物轉化為另一種立體異構物來合成特定的立體異構物。
本發明還包括一種醫藥組成物，包括(1)本發明之化合物或其立體異構物、互變異構物、或其藥學上可接受之鹽類；以及(2)藥學上可接受之載體、賦形劑或稀釋劑。該組成物還可包括至少一種額外的藥物，例如抗癌藥物。本發明之化合物或其藥學上可接受之鹽類或組成物可用於製備抑制腫瘤細胞生長或治療癌症的藥物。
本發明還包括用於治療癌症之方法，包括給予需求主體有效量的本發明之化合物或其立體異構物、互變異構物、或其藥學上可接受之鹽類的步驟。
本發明還涵蓋了抑制腫瘤細胞生長之方法，包括給予需求主體有效量的本發明的化合物或其立體異構物、互變異構物、或其藥學上可接受之鹽類的步驟。
於本發明中，前述主體可為哺乳類動物，例如人類。
於本發明中，本發明的化合物或其立體異構物、互變異構物、或其藥學上可接受之鹽類可以抑制腫瘤細胞的生長，從而達到治療癌症的目的。癌症的實例包括但不限於胃癌(gastric cancer)、結腸癌(colon cancer)、大腸直腸癌(colorectal cancer)、乳癌(breast cancer)、肺癌(lung cancer)、前列腺癌(prostate cancer)、膀胱癌(bladder cancer)、胰腺癌(pancreatic cancer)、肝癌(liver cancer)、子宮癌(uterine cancer)、子宮頸癌(cervical cancer)、子宮內膜癌(endometrial cancer)、食道癌(esophageal cancer)、白血病(leukemia)、淋巴瘤(lymphoma)、腎臟癌(kidney cancer)、骨肉瘤(osteosarcoma)、卵巢癌(ovarian cancer)、皮膚癌(skin cancer)、小腸癌(small intestine cancer)、胸腺癌(thymus cancer)、甲狀腺癌(thyroid cancer)、神經系統癌(nervous system cancers)、骨癌(bone cancer)、腦癌(brain cancer)或頭頸癌(head and neck cancer)。在本發明的一實施例中，癌症可為肝癌、結腸癌或肺癌。
本發明的化合物或其立體異構物、互變異構物、或其藥學上可接受之鹽類可與至少一種額外的藥物(諸如抗癌藥物)合併施用。給藥製劑可以是例如(a)一種單一製劑，包括本發明之化合物或其立體異構物、互變異構物、或其藥學上可接受之鹽類，藥學上可接受之載體、賦形劑或稀釋劑以及至少一種額外的藥物；或是(b)兩種製劑以任何順序同時或依序給藥，其中一種製劑包括本
發明之化合物或其立體異構物、互變異構物、或其藥學上可接受之鹽類，藥學上可接受載體、賦形劑或稀釋劑，另一種製劑包括至少一種額外的藥物。
適合的抗癌劑可包含賀癌平(Herceptin)、利妥昔(Rituximab)、多烯紫杉醇(Docetaxel)、凱希得平(Capecitabine)、西妥昔單抗(Cetuximab)、吉非替尼(Gefitinib)、PD-1、索拉非尼甲苯磺酸(Sorafenib tosylate)或伊馬替尼(Imatinib)，但本發明不限於此。本領域已知的任何其他抗癌劑也可以用於本發明中。
合成式(I)之化合物的方法為本領域眾所周知的。例如參見R.Larock,Comprehensive Organic Transformations(2nd Ed.,VCH Publishers 1999)；P.G.M.Wuts以及T.W.Greene,Greene’s Protective Groups in Organic Synthesis(4th Ed.,John Wiley and Sons 2007)、L.Fieser and M.Fieser,Fieser and Fieser’s Reagents for Organic Synthesis(John Wiley and Sons 1994)、L.Paquette,ed.,Encyclopedia of Reagents for Organic Synthesis(2nd ed.,John Wiley and Sons 2009)、P.Roszkowski,J.K.Maurin,Z.、Czarnocki“Enantioselective synthesis of(R)-(-)-praziquantel(PZQ)”Tetrahedron：Asymmetry 17(2006)1415-1419、以及L.Hu,S.Magesh,L.Chen,T.Lewis,B.Munoz,L.Wang“Direct inhibitors of keapl-nrf2 interaction as antioxidant inflammation modulators,”WO2013/067036。
由此製備的式(I)之化合物可以使用體外測定法(例如NCI-60篩選平台或MTS方法)來初步篩選。隨後可以使用本領域已知的體內測定法對其進行評估。可以進一步測試選定化合物，以驗證其在疾病相關功效及不良反應模型中的功效。可以根據結果決定適當的劑量範圍及給藥途徑。
下列實施例清楚地展現本發明的前述及其他技術內容、特徵及/或效果。透過具體實施例的闡述，人們將進一步理解本發明為達到上述目的而採用的技術手段及效果。此外，由於本文所揭露的內容應由本領域技術人員容
易理解且可實施，因此，不脫離本發明的概念的所有相等改變或修改應由所附申請專利範圍所涵蓋。
無須進一步闡述，相信本領域的技術人員可基於以上描述最大程度地利用本發明。因此，以下具體實施例被解釋為僅是說明性的，而不以任何方式限制本揭露的其餘部分。本文所引用的所有出版物透過全文併入做為參考。
以下描述用於合成本發明的示例性化合物的方法。
除非另有說明，否則所有使用的起始材料都是可商購並按供應原樣使用。在經火焰乾燥的玻璃器皿中進行需要無水條件的反應，並在氬氣或氮氣氣氛下冷卻。除非另有說明，否則反應在氬氣或氮氣下進行，並透過分析薄層(analytical thin-layer)層析法進行監測，該分析薄層層析法在預塗有由默克公司提供的矽膠60 F254的玻璃背板(5cm_10cm)上進行。產生的層析圖的可視化是透過在紫外燈(λ=254nm)下觀察，然後浸入含有乙酸(3%體積百分濃度)的茚三酮(Ninhydrin)(0.3%體積百分濃度)的nBuOH溶液或磷鉬酸(2.5%體積百分濃度)的乙醇溶液，並用熱風槍焦化(charring)。在如下使用之前，將反應的溶劑在氬氣或氮氣氣氛下乾燥：藉由乾燥分子篩5A(LC technology solution Inc)的管柱乾燥THF、甲苯、及DCM。DMF透過氫化鈣乾燥或可商購無水的DMF。常規使用快速層析法純化及分離產物混合物，以由RediSep提供的RediSep Rf矽膠一次性快速層析管柱Gold®20-40/40-60微米矽膠及可重複使用的RediSep Rf Gold® C18反相層析管柱20-40微米。沖提液(Eluent)系統以體積百分濃度表示。於Bruker AVIII(400MHz)上記錄13C及1H NMR光譜。使用氯仿-d或二甲基亞碸-d6及CD3OD作為溶劑，且使用TMS(δ0.00ppm)作為內標準品(internal standard)。化學位移數值(Chemical shift values)以相對於TMS的ppm(δ)單位表示。多重態(Multiplicities)紀錄為s(單重態)、br s(寬單重態)、d(雙重態)、t(三重態)、q(四重
態)、dd(雙重雙重態)、dt(雙重三重態)、m(多重態)。耦合常數(Coupling constants)(J)以Hz表示。使用Thermo LTQ XL質譜儀紀錄電噴物質譜(Electrospray mass spectra,ESMS)。光譜數據紀錄為m/z值。
在製備本發明之化合物時，可能需要保護中間物的遠端官能基(例如伯胺或仲胺)。根據遠端官能基的性質及製備方法的條件，對此類保護的需求可能有所不同。適合的胺基保護基團(NHPg)包括例如乙醯基、三氟乙醯基、叔丁氧羰基(tbutoxycarbonyl,BOC)、9-芴基亞甲基氧羰基(9-fluorenylmethyleneoxycarbonyl,Fmoc)以及苄氧羰基(CBz)。相似地，「羥基保護基」是指阻斷或保護羥基官能基的羥基的取代基。適合的羥基保護基(OPg)包括例如烯丙基(allyl)、乙醯基、甲矽烷基、芐基、對甲氧基芐基(paramethoxy benzyl)及三苯甲基(trityl)等。本領域技術人員可以容易地確定是否需要這種保護。
實驗步驟
步驟1：環化(Cyclization)
將反應燒瓶冷卻至-78℃的EtOH(50ml)的2,4,6-三氯嘧啶-5-甲醛(2,4,6-trichloropyrimidine-5-carbaldehyde)(3.71g，17.5mmol)的溶液中加入甲基肼(methyl hydrazine)(0.93ml，17.5mmol)及TEA(8ml)。將混合物在-78℃下攪拌30分鐘，然後在0℃下攪拌2小時。將溶液在不加熱的情況下真空濃縮。向減小體積的溶液中加入乙酸乙酯(EtOAc)，且溶液以飽和碳酸氫鈉(NaHCO3)溶液洗滌，並在不加熱的情況下真空濃縮。用小的矽膠塞過濾(2：1=EtOAc：Hex)，並濃縮，得到所需為黃色固體的產物4,6-二氯-1-甲基-1H-吡唑並[3,4-d]嘧啶(4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine)(2.84g，80%)。
步驟2：胺化(Amination)
向反應燒瓶加入4,6-二氯-1-甲基-1H-吡唑並[3,4-d]嘧啶(4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine)(2.84g，14mmol)懸浮液中加入THF(56ml)，等待固體完全溶解。然後加入20g 30%氨水溶液，並在室溫(25℃)下反應24小時，然後將60ml水倒入溶液中，抽氣過濾得到為黃色固體粉末的6-氯-1-甲基-1H-吡唑並[3,4-d]嘧啶-4-胺(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine)(2.17g，85%)。
步驟3：Suzuki耦合反應
使用6個交替的真空/氮氣沖洗循環向100ml玻璃燒瓶中的6-氯-1-甲基-1H-吡唑並[3,4-d]嘧啶-4-胺(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine)(1.84g，10mmol)、4-(叔丁基)苯基硼酸(4-(tert-butyl)phenyl boronic acid)(2.67g，15mmol)、四(三苯基膦)鈀(Tetrakis(triphenylphosphine)palladium)(0)(1.16g，1mmol)、1,4-二噁烷(40ml)、水(2ml)及碳酸銫水溶液(2.0M，20ml，40mmol)的懸浮液進行脫氧。將反應混合物加熱至100℃持續16小時。冷卻至室溫後，將矽藻土(Celite)粉末倒入燒瓶中，並在室溫下攪拌10分鐘，然後抽氣過濾，將濾液分配在乙酸乙酯(80ml)
與飽和碳酸氫鈉水溶液(30ml)之間。分離各層，並用鹽水(30ml)洗滌有機層，經硫酸鈉乾燥、過濾，並減壓濃縮。殘餘物透過矽膠層析法純化(0-25%正己烷/乙酸乙酯，線性梯度)，得到為黃色粉末的6-(4-(叔丁基)苯基)-1-甲基-1H-吡唑並[3,4-d]嘧啶-4-胺(6-(4-(tert-butyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine)(2.25g，80%)。
步驟4：醯胺化(Amidation)反應
由羰基酸的醯胺化形成的N-(6-(4-(叔丁基)苯基)-1-甲基-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(4-(tert-butyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
6-(4-(叔丁基)苯基)-1-甲基-1H-吡唑並[3,4-d]嘧啶-4-胺(6-(4-(tert-butyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine)(843mg，3.00mmol)的吡啶(6ml)溶液中，加入5-硝基噻吩-2-羰基氯(5-nitrothiophene-2-carbonyl chloride)(900mg，4.68mmol)。將反應混合物在環境溫度攪拌15小時。加入水，且產物用乙酸乙酯萃取。分離有機層，乾燥(無水硫酸鈉)並真空蒸發。產物透過矽膠管柱層析法純化(正己烷-乙酸乙酯梯度沖提液)，並用正己烷及丙酮再結晶(recrystallization)，得到標題化合物。產量980mg(75%)。為黃色粉末的N-(6-(4-(叔丁基)苯基)-1-甲基-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(4-(tert-butyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)。
實驗步驟
透過縮合及閉環反應進行環化
向反應燒瓶加入50ml乙醇並透過冰浴冷卻至0℃的2,4,6-三氯嘧啶-5-甲醛(2,4,6-trichloropyrimidine-5-carbaldehyde)(3.7g，17.5mmol)溶液中加入苯肼鹽酸鹽(phenylhydrazine hydrochloride)(2.53g，17.5mmol)及8ml TEA。將混合物在0℃下攪拌30分鐘，並自發地達到環境溫度。將溶液在不加熱的情況下真空濃縮。向減小體積的溶液中加入乙酸乙酯，且溶液用飽和碳酸氫鈉溶液洗滌，並在不加熱的情況下真空濃縮。用小的矽膠塞過濾(EtOAc：Hex=2：1)並濃縮，得到黃色固體的所需產物4,6-二氯-1-苯基-1H-吡唑並[3,4-d]嘧啶(4,6-dichloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine)(3.94g，85%)。
透過Mitsunobu反應形成N-C鍵
4-(6-氯-4-((4-甲氧基芐基)胺基)-1H-吡唑並[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(tert-butyl 4-(6-chloro-4-((4-methoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate)的形成。
在N2下向火焰乾燥的圓底瓶中加入在無水四氫呋喃(anhydrous tetrahydrofuran)(175ml)中的6-氯-N-(4-甲氧基芐基)-1H-吡唑並[3,4-d]嘧啶-4-胺(6-chloro-N-(4-methoxy benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine)(4.35g，15mmol)、4-羥基-1-哌啶甲酸叔丁酯(t-butyl
4-hydroxy-1-piperidinecarboxylate)(3.96g，20mmol)、以及PPh3(5.24g，20mmol)。將混合物冷卻至0℃，並逐滴加入在四氫呋喃(tetrahydrofuran)(30ml)中的偶氮二甲酸二異丙基酯(diisoproyl azodicarboxylate,DIAD)(4.0ml，20mmol)。使混合物回溫至室溫，並攪拌過夜。然後將反應物過濾，並溶解於DCM。濾出不溶物。將濾液濃縮，溶解於DCM，並置於冰箱5小時。濾出形成的晶體，並透過矽膠層析法(5-12%甲醇/DCM)純化濾液，得到純的4-(6-氯-4-((4-甲氧基芐基)胺基)-1H-吡唑並[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(tert-butyl 4-(6-chloro-4-((4-methoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate)(4.78g，70%)。
Suzuki耦合反應
4-(6-(4-氯苯基)-4-((4-甲氧基芐基)胺基)-1H-吡唑並[3,4-d]嘧啶-1-基)哌啶-1-羧酸酯(4-(6-(4-chlorophenyl)-4-((4-methoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate)的形成。
使用6個交替的真空/氮氣沖洗循環向100ml玻璃燒瓶中的4-(6-氯-4-((4-甲氧基芐基)胺基)-1H-吡唑並[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(tert-butyl 4-(6-chloro-4-((4-methoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate)(4.73g,10mmol)、4-氯苯基硼酸(4-chlorophenyl boronic acid)(1.87g，12mmol)、四(三苯基膦)鈀(Tetrakis(triphenylphosphine)palladium)(0)(1.16g，1mmol)、1,4-二噁烷(1,4-dioxane)(100ml)、水(40ml)、及碳酸銫水溶液(1.0M，40ml，40mmol)的懸浮液進行脫氧。將反應混合物加熱至90℃持續16小時。冷卻至室溫後，將矽藻土(Celite)粉末倒入燒瓶中，並在室溫下攪拌10分鐘，然後抽氣過濾，將濾液分配在乙酸乙酯(160ml)與飽和碳酸氫鈉水溶液(80ml)之間。分離各層，並用鹽水
(80ml)洗滌有機層，經硫酸鈉乾燥、過濾，並減壓濃縮。殘餘物透過矽膠層析法純化(0-35%正己烷/乙酸乙酯，線性梯度)，得到為黃色粉末的4-(6-(4-氯苯基)-4-((4-甲氧基芐基)胺基)-1H-吡唑並[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(tert-butyl 4-(6-(4-chloro phenyl)-4-((4-methoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate)(4.23g，77%)。
透過DDQ去保護(Deprotection)
4-(4-胺基-6-(4-氯苯基)-1H-吡唑並[3,4-d]嘧哌-1-基)哌啶-1-甲酸叔丁酯(tert-butyl 4-(4-amino-6-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate)的形成
向在反應燒瓶中的4-(6-(4-(氯苯基)-4-((4-甲氧基芐基)胺基)-1H-吡唑並[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(tert-butyl 4-(6-(4-chlorophenyl)-4-((4-methoxybenzyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate)(4.12g，7.5mmol)及DDQ：2,3-二氯-5,6-二氰對苯醌(2,3-Diohloro-5,6-dicyano-1,4-benzoquinone)(2.04g，9.0mmol)的混合物中倒入125ml DCM、25ml水(H2O)，並在室溫下攪拌過夜。反應結束後，加入DCM及碳酸氫鈉水溶液進行萃取，使用DCM(150ml x3)萃取水層，使用無水硫酸鎂去除水，並用矽藻土(Celite)過濾並濃縮，然後使用矽膠管柱層析法(10% EA/DCM)，得到為白色固體的4-(4-胺基-6-(4-氯苯基)-1H-吡唑並[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(tert-butyl 4-(4-amino-6-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate)2.54g(產率79%)。
透過TFA去保護(Deprotection)
(S)-6-(6-氟吡啶-3-基)-1-(吡咯烷-3-基)-1H-吡唑並[3,4-d]嘧啶-4-胺((S)-6-(6-fluoropyridin-3-yl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine)的形成
於室溫下，向20ml DCM中的(S)-3-(4-胺基-6-(6-氟吡啶-3-基)-1H-吡唑並[3,4-d]嘧啶-1-基)吡咯烷-1-甲酸叔丁酯(tert-butyl(S)-3-(4-amino-6-(6-fluoropyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate)(2.00g，5mmol)溶液逐滴加入5ml TFA持續1小時。用LCMS判斷反應後，濃縮以去除溶劑，加入EA，並透過加入10%氫氧化鈉調整至pH=11，使用EA(100ml x3)萃取水層，使用無水硫酸鎂去除收集的有機層中的水，過濾並濃縮，得到為黃色固體的(S)-6-(6-氟吡啶-3-基)-1-(吡咯烷-3-基)-1H-吡唑並[3,4-d]嘧啶-4-胺((S)-6-(6-fluoropyridin-3-yl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine)1.28g(86%)。
以丙烯醯氯(acryloyl chloride)醯胺化(Amidation)
(S)-1-(3-(4-胺基-6-(6-氟吡啶-3-基)-1H-吡唑並[3,4-d]嘧啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮((S)-1-(3-(4-amino-6-(6-fluoropyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one)的形成
透過冰浴降溫至0℃的情況下將TEA(2.02g，20mmol)及丙烯醯氯(acryloyl chloride)加入至在50ml TFA中的(S)-6-(6-氟吡啶-3-基)-1-(吡咯烷-3-基)-1H-吡唑並[3,4-d]嘧啶-4-胺((S)-6-(6-fluoropyridin-3-yl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine)(1.20g，4mmol)的溶液中。將所得混合物攪拌50分鐘，然後用8ml甲醇使混合物結束反應，然後萃取並濃縮混合物，並透過矽膠管柱層析法(0-10%甲醇的DCM溶液)純化，得到為淡黃色固體的(S)-1-(3-(4-胺基-6-(6-氟吡啶-3-基)-1H-吡唑並[3,4-d]嘧啶-1-基)吡咯烷-1-基)丙-2-烯-1-酮
((S)-1-(3-(4-amino-6-(6-fluoropyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one)1.06g(75%)
胺化(Amination)
向反應燒瓶中的4,6-二氯-1-苯基-1H-吡唑並[3,4-d]嘧啶(3.71g，14mmol)的懸浮液中加入60ml THF，等待固體完全溶解。然後加入20g、30%的銨溶液，並在室溫(25℃)下反應24小時。將60ml水倒入溶液中、抽氣過濾，得到為黃色固體粉末的6-氯-1-甲基-1H-吡唑並[3,4-d]嘧啶-4-胺(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine)(2.93g，85%)。
N-烷基化(N-Alhylation)
6-(3,3-二氟吡咯烷-1-基)-1-苯基-1H-吡唑並[3,4-d]嘧啶-4-胺(6-(3,3-difluoropyrrolidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine)的形成
在100ml玻璃燒瓶中的6-氯-1-苯基-1H-吡唑並[3,4-d]嘧啶-4-胺(6-chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine)(2.46g，10mmol)、3,3-二氟吡咯烷鹽酸鹽(3,3-Difluoropyrrolidine hydrochloride)(2.15g，15mmol)、1,4-二噁烷(1,4-dioxane)(50ml)、碳酸銫(Cesium carbonate)(13.03g，40mmol)的懸浮液。將反應混合物加熱至100℃持續16小時，然後冷卻至環境溫度，並透過抽氣過濾，除去濾液，並用乙酸乙酯(60ml)萃取三次。分離各層，用鹽水(30ml)洗滌有機層，經硫酸鈉乾燥、過濾，並減壓濃縮。殘餘物透過矽膠層析法純化(正己烷/0-30%乙酸乙酯，線性梯度改變極性)，得到為淡黃色粉末的6-(3,3-二氟吡咯烷-1-基)-1-苯基-1H-吡唑並[3,4-d]嘧啶-4-胺(6-(3,3-difluoropyrrolidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine)(2.66g，83%)。
醯胺化(Amidation)
透過羰基酸的醯胺化形成N-(6-(3,3-二氟吡咯烷-1-基)-1-苯基-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(3,3-difluoropyrrolidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
向在30ml THF中的6-(3,3-二氟吡咯烷-1-基)-1-苯基-1H-吡唑並[3,4-d]嘧啶-4-胺(6-(3,3-difluoropyrrolidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine)(948mg，3.00mmol)及三乙胺(triethyamine)(2.06ml)的溶液中加入5-硝基噻吩-2-羰基氯(5-nitrothiophene-2-carbonyl chloride)(900mg，4.68mmol)。將反應混合物在環境溫度攪拌15小時。加入水，並將產物用乙酸乙酯萃取。分離有機層，以無水硫酸鈉乾燥並真空蒸發。產物透過矽膠管柱層析法純化(正己烷-乙酸乙酯，梯度改變極性)，並再結晶(DCM及甲醇)，得到標題化合物。產量為1060mg(75%)，為黃色粉末的N-(6-(4-(叔丁基)苯基)-1-甲基-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(4-(tert-butyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)。
烷氧基化(Alkoxylation)
形成6-(4-氟苯氧基)-1-苯基-1H-吡唑並[3,4-d]嘧啶-4-胺(6-(4-fluorophenoxy)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine)
在100ml玻璃燒瓶中的6-氯-1-苯基-1H-吡唑並[3,4-d]嘧啶-4-胺(6-chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine)(2.46g，10mmol)、4-氟苯酚(4-fluorophenol)(1.68g，15mmol)、1,4-二噁烷(1,4-dioxane)(50ml)、碳酸銫(Cesium carbonate)(13.03g，40mmol)的懸浮液。將反應混合物加熱至100℃持續16小時。冷卻至室溫後，抽氣過濾、除去濾液，並用乙酸乙酯(60ml x3)萃取。分離各層，用鹽水(30ml)洗滌有機層，經硫酸鈉乾燥、過濾，並減壓濃縮。殘
餘物透過矽膠層析法純化(正己烷/0-25%乙酸乙酯，線性梯度改變極性)，得到為淡黃色粉末的6-(4-氟苯氧基)-1-苯基-1H-吡唑並[3,4-d]嘧啶-4-胺(6-(4-fluorophenoxy)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine)(2.60g，81%)。
醯胺化(Amidation)
透過羰基酸的醯胺化形成N-(6-(4-氟苯氧基)-1-苯基-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(4-fluorophenoxy)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
向在30ml THF中的6-(3,3-二氟吡咯烷-1-基)-1-苯基-1H-吡唑並[3,4-d]嘧啶-4-胺(6-(3,3-difluoropyrrolidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine)(948mg，3.00mmol)及三乙胺(triethyamine)(2.06ml)的溶液中加入5-硝基噻吩-2-羰基氯(5-nitrothiophene-2-carbonyl chloride)(900mg，4.68mmol)。將反應混合物在環境溫度攪拌15小時。加入水，且產物用乙酸乙酯萃取。分離有機層，乾燥(無水硫酸鈉)並真空蒸發。產物透過矽膠管柱層析法純化(正己烷-乙酸乙酯梯度沖提液)，並用DCM及甲醇再結晶，得到標題化合物。產量為1100mg(77%)形成為黃色粉末的N-(6-(4-氟苯氧基)-1-苯基-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(4-fluorophenoxy)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)。
實驗步驟
將溶解在乙醇(50ml)中的2,4,6-三氯嘧啶-5-甲醛(2,4,6-trichloropyrimidine-5-carbaldehyde)(3.7g，17.5mmol)的溶液冷卻至-78℃，加入甲基肼(methyl hydrazine)(0.93ml，17.5mmol)及TEA(8ml)。將混合物在-78℃下攪拌30分鐘，然後在0℃下放置2小時。將溶液在不加熱的情況下真空濃縮。向減小體積的溶液中加入乙酸乙酯，且溶液用飽和碳酸氫鈉溶液洗滌，並在不加熱的情況下真空濃縮。以小的矽膠塞(2：1=EtOAc：Hex)過濾並濃縮，得到所需為黃色固體的產物4,6-二氯-1-甲基-1H-吡唑並[3,4-d]嘧啶(4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine)(2.84g，80%)。
4-(4-(叔丁基)苯基)-6-氯-1-甲基-1H-吡唑並[3,4-d]嘧啶(4-(4-(tert-butyl)phenyl)-6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine)的形成
Suzuki耦合反應
使用5個交替的真空/氮氣沖洗循環向在100mL玻璃燒瓶中的4,6-二氯-1-甲基-1H-吡唑並[3,4-d]嘧啶(4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine)(2.03g，10mmol)、4-(叔丁基)苯基硼酸(4-(tert-butyl)phenyl boronic
acid)(2.67g，15mmol)、四(三苯基膦)鈀(Tetrakis(triphenylphosphine)palladium)(0)(1.16g，1mmol)、1,4-二噁烷(1,4-dioxane)(40ml)、水(2ml)、及碳酸銫水溶液(aqueous Cesium carbonate solution)(2.0M，20ml，40mmol)的懸浮液進行脫氧。將反應混合物加熱至90℃持續15小時。冷卻至室溫後，將矽藻土(Celite)粉末倒入燒瓶中，並在室溫攪拌10分鐘，然後抽氣過濾，並將濾液分配在乙酸乙酯(80ml)與飽和碳酸氫鈉水溶液(30ml)之間。分離各層，用鹽水(30ml)洗滌有機層，經硫酸鈉乾燥、過濾，並減縮濃縮。殘餘物透過矽膠層析法純化(0-25%正己烷/乙酸乙酯，線性梯度改變極性)，得到為黃色粉末的4-(4-(叔丁基)苯基)-6-氯-1-甲基-1H-吡唑並[3,4-d]嘧啶(4-(4-(tert-butyl)phenyl)-6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine)(2.55g，85%)。
4-(4-(叔丁基)苯基)-1-甲基-1H-吡唑並[3,4-d]嘧啶-6-胺(4-(4-(tert-butyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine)
胺化(Amination)
向反應燒瓶中的4,6-二氯-1-甲基-1H-吡唑並[3,4-d]嘧啶(4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine)(2.11g，7mmol)的懸浮液中加入32ml THF，等待固體完全溶解，然後加入10g、30%的銨溶液，並在室溫(25℃)下反應24小時。將60ml水倒入溶液中，抽氣過濾得到為黃色固體粉末的4-(4-(叔丁基)苯基)-1-甲基-1H-吡唑並[3,4-d]嘧啶-6-胺(4-(4-(tert-butyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine)(1.58g，80%)。
醯胺化(Amidation)
透過羰基酸的醯胺化形成N-(4-(4-(叔丁基)苯基)-1-甲基-1H-吡唑並[3,4-d]嘧啶-6-基)-5-硝基噻吩-2-甲醯胺
向在吡啶(6ml)中的4-(4-(叔丁基)苯基)-1-甲基-1H-吡唑並[3,4-d]嘧啶-6-胺(4-(4-(tert-butyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine)(843mg，3.00mmol)的溶液中加入5-硝基噻吩-2-羰基氯(5-nitrothiophene-2-carbonyl chloride)(900mg，4.68mmol)。將反應混合物在環境溫度攪拌15小時，加入水，產物用乙酸乙酯萃取。分離有機層，以無水硫酸鈉乾燥，並真空蒸發。產物透過矽膠管柱層析法純化(正己烷-乙酸乙酯，梯度改變極性)，並再結晶(正己烷及丙酮)，得到標題化合物。產量為1021mg(78%)，為黃色粉末的N-(4-(4-(叔丁基)苯基)-1-甲基-1H-吡唑並[3,4-d]嘧啶-6-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-5-nitrothiophene-2-carboxamide)。
於體外MTS測定法中評估式(I)之化合物
細胞存活率的測量是基於NCI-60篩選方法(Nat.Rev.Cancer 6,813-823,2006)。簡而言之，將細胞以最佳接種密度接種至96孔盤中。24小時後，透過MTS測定法(Promega)處理接種Hep3B細胞株的兩個孔盤中之一者以確定初始時間的細胞存活率(Tz)。將化合物以2倍連續稀釋液添加，以提供總共6種藥物濃度和DMSO對照。將孔盤再培養2天，然後透過MTS測定法[在6個濃度量(Ti)的藥物存在下的對照成長量(C)及測試成長量]來測量細胞存活率。由[(Ti-Tz)/Tz]x100=-50計算得出LC50，這是在藥物治療結束時與開始時相比減少50%的藥物濃度。
表1至表6中製備的化合物以三種體外測定法進行測試，表7顯示了Hep3B、SW480及NCI-H460的結果，如下所示。於本文中，Hep3B是指肝癌細胞株，SW480是指結腸直腸癌細胞株，而NCI-H460是指人類肺癌細胞株。
於表1至表6所示的化合物中，如果某些化合物的合成步驟與前述化合物的合成步驟相似，則不再重複詳細的合成步驟。
下表1至表6中顯示了式(I)之示例性化合物的結構與體外活性。發現多數揭露的化合物抑制Hep3B細胞(肝癌細胞株)的生長。
表1
化合物1-1
N-(1-(4-甲氧基苯基)-6-(5-甲氧基吡啶-3-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(1-(4-methoxyphenyl)-6-(5-methoxypyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.01(br.s.,1H),9.25(d,J=1.5Hz,1H),8.61(s,1H),8.47(d,J=2.4Hz,1H),8.37(d,J=4.4Hz,1H),8.21-8.29(m,2H),8.07-8.17(m,2H),7.13-7.24(m,2H),3.96(s,3H),3.85(s,3H).MS(M+1)：504.黃色固體。
化合物1-2
N-(6-(6-氰基吡啶-3-基)-1-(4-甲氧基苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(6-cyanopyridin-3-yl)-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.02(br.s.,1H),9.68(d,J=1.5Hz,1H),8.88(dd,J=8.1,2.2Hz,1H),8.59(s,1H),8.32(d,J=4.4Hz,1H),8.15-8.27(m,2H),7.98-8.14(m,2H),7.03-7.25(m,2H),3.85(s,3H).MS(M+1)：499.黃色固體。
化合物1-3
N-(1-(2,4-二氟苯基)-6-(6-(2-甲氧基乙氧基)吡啶-3-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(1-(2,4-difluorophenyl)-6-(6-(2-methoxyethoxy)pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.04(s,1H),9.16(d,J=2.4Hz,1H),8.64(s,1H),8.56(dd,J=8.8,2.4Hz,1H),8.38(d,J=4.4Hz,1H),8.26(d,J=4.4Hz,1H),7.88(td,J=8.8,5.9Hz,1H),7.67(ddd,J=10.5,9.0,2.9Hz,1H),7.30-7.45(m,1H),6.99(d,J=9.3Hz,1H),4.38-4.53(m,2H),3.68(dd,J=5.4,3.9Hz,2H),3.30(s,3H).MS(M+1)：554.黃色固體。
化合物1-4
N-(6-(4-氟-3-甲氧基苯基)-1-(4-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(4-fluoro-3-methoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.04(br.s.,1H),8.60(s,1H),8.28-8.36(m,3H),8.23-8.28(m,2H),8.14(ddd,J=8.7,4.5,2.0Hz,1H),7.36-7.54(m,3H),4.00(s,3H).MS(M+1)：509.白色固體。
化合物1-5
N-(6-(5-甲氧基-6-(2-甲氧基乙氧基)吡啶-3-基)-1-(4-甲氧基苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(5-methoxy-6-(2-methoxyethoxy)pyridin-3-yl)-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.00(br.s.,1H),8.84(d,J=1.5Hz,1H),8.57(s,1H),8.35(d,J=4.4Hz,1H),8.26(d,J=4.4Hz,1H),8.19(d,J=2.0Hz,1H),8.13-8.18(m,2H),7.14-7.26(m,2H),4.50(dd,J=5.4,3.9Hz,2H),3.94(s,3H),3.85(s,3H),3.71(dd,J=5.4,3.9Hz,2H).MS(M+1)：578.棕色固體。
化合物1-6
N-(1-(3-氯苯基)-6-(4-氟-3-甲氧基苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(1-(3-chlorophenyl)-6-(4-fluoro-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.04(br.s.,1H),8.65(s,1H),8.55(t,J=2.0Hz,1H),8.36(d,J=4.4Hz,1H),8.24-8.32(m,3H),8.14(ddd,J=8.3,4.4,2.0Hz,1H),7.67(t,J=8.1Hz,1H),7.39-7.52(m,2H),4.01(s,3H).MS(M+1)：525.黃色固體。
化合物1-7
N-(6-(6-氰基-5-氟吡啶-3-基)-1-(4-甲氧基苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(6-cyano-5-fluoropyridin-3-yl)-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.08(br.s.,1H),9.58(s,1H),8.78(dd,J=9.5,1.7Hz,1H),8.66(s,1H),8.34(d,J=4.4Hz,1H),8.27(d,J=4.4Hz,1H),8.10-8.16(m,2H),7.18-7.23(m,2H),3.87(s,4H).MS(M+1)：517.黃色固體。
化合物1-8
N-(6-(3-氰基-4-甲氧基苯基)-1-(3-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(3-cyano-4-methoxyphenyl)-1-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.02(br.s.,1H),8.74-8.79(m,2H),8.67(s,1H),8.34(d,J=4.4Hz,1H),8.27(d,J=4.4Hz,1H),8.23(dd,J=8.1,1.2Hz,1H),8.16-8.21(m,1H),7.70(td,J=8.2,6.6Hz,1H),7.50-7.55(m,1H),7.28(td,J=8.3,2.4Hz,1H),4.05(s,3H).MS(M+1)：516.黃色固體。
化合物1-9
N-(6-(6-氰基-5-乙氧基吡啶-3-基)-1-(3-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(6-cyano-5-ethoxypyridin-3-yl)-1-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.10(br.s.,1H),9.27(d,J=1.0Hz,1H),8.68(s,1H),8.50(s,1H),8.36(d,J=4.4Hz,1H),8.26(d,J=4.4Hz,1H),8.06-8.22(m,2H),7.63-7.72(m,1H),7.27(td,J=8.3,2.4Hz,1H),4.42(q,J=6.8Hz,2H),1.49(t,J=6.8Hz,3H).MS(M+1)：531.卡其色固體。
化合物1-10
N-(6-(4-氟-3-(2-羥基乙氧基)苯基)-1-(4-甲氧基苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(4-fluoro-3-(2-hydroxyethoxy)phenyl)-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 11.96(br.s.,1H),8.57(s,1H),8.36(d,J=4.4Hz,1H),8.22-8.31(m,2H),8.08-8.18(m,3H),7.41(dd,J=11.2,8.8Hz,1H),7.18(d,J=9.3Hz,2H),4.98(t,J=5.6Hz,1H),4.21(t,J=4.9Hz,2H),3.85(s,3H),3.82(q,J=5.4Hz,2H).MS(M+1)：551.橙色固體。
化合物1-11
N-(6-(4-氟-3-(3-羥基丙氧基)苯基)-1-(4-甲氧基苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(4-fluoro-3-(3-hydroxypropoxy)phenyl)-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.02(br.s.,1H),8.57(s,1H),8.34(d,J=4.4Hz,1H),8.20-8.32(m,2H),8.09-8.18(m,3H),7.41(dd,J=11.2,8.8Hz,1H),7.15-7.23(m,2H),4.63(t,J=5.1Hz,1H),4.27(t,J=6.4Hz,2H),3.85(s,3H),3.63(q,J=5.9Hz,2H),1.97(t,J=6.1Hz,2H).MS(M+1)：565.黃色固體。
化合物1-12
N-(1-(3-氰基苯基)-6-(4-氟-3-(2-羥基乙氧基)苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(1-(3-cyanophenyl)-6-(4-fluoro-3-(2-hydroxyethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.00(br.s.,1H),8.81(t,J=1.7Hz,1H),8.61-8.66(m,1H),8.59(dt,J=8.1,1.6Hz,1H),8.35(d,J=4.9Hz,1H),8.19-8.27(m,2H),8.10(ddd,J=8.7,4.5,2.0Hz,1H),7.78-7.87(m,2H),7.41(dd,J=11.2,8.8Hz,
1H),4.93-5.00(m,1H),4.23(t,J=4.9Hz,2H),3.81-3.88(m,2H).MS(M+1)：546.黃色固體。
化合物1-13
N-(6-(4-氟-3-(2-羥基乙氧基)苯基)-1-(4-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(4-fluoro-3-(2-hydroxyethoxy)phenyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 11.99(br.s.,1H),8.60(s,1H),8.35(d,J=4.4Hz,1H),8.23-8.32(m,4H),8.12(ddd,J=8.4,4.5,2.2Hz,1H),7.43-7.50(m,2H),7.41(dd,J=11.0,8.6Hz,1H),4.98(t,J=5.4Hz,1H),4.22(t,J=4.9Hz,2H),3.83(q,J=5.1Hz,2H).MS(M+1)：539.黃色固體。
化合物1-14
N-(1-(4-氰基苯基)-6-(4-氟-3-(2-羥基乙氧基)苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(1-(4-cyanophenyl)-6-(4-fluoro-3-(2-hydroxyethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.08(br.s.,1H),8.67(s,1H),8.58-8.64(m,2H),8.26-8.33(m,2H),8.21-8.26(m,1H),8.16(ddd,J=8.6,4.6,2.0Hz,1H),8.04-8.12(m,2H),7.42(dd,J=11.0,8.6Hz,1H),4.99(t,J=5.6Hz,1H),4.24(t,J=4.9Hz,2H),3.84(q,J=5.2Hz,2H).MS(M+1)：546.黃色固體。
化合物1-15
N-(6-(4-氟-3-(2-羥基乙氧基)苯基)-1-(3-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(4-fluoro-3-(2-hydroxyethoxy)phenyl)-1-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.08(br.s.,1H),8.65(s,1H),8.37(d,J=4.4Hz,1H),8.10-8.32(m,6H),7.63-7.74(m,1H),7.39-7.50(m,1H),7.22-7.32(m,1H),4.99(t,J=5.4Hz,1H),4.23(t,J=4.9Hz,2H),3.83(q,J=5.1Hz,2H).MS(M+1)：539.黃色固體。
化合物1-16
N-(6-(4-氰基-3-(甲基胺基)苯基)-1-(3-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(4-cyano-3-(methylamino)phenyl)-1-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.12(s,1H),8.70(s,1H),8.40(d,J=4.4Hz,1H),8.25-8.30(m,2H),8.18-8.25(m,2H),7.88(d,J=1.0Hz,1H),7.77-7.86(m,1H),7.66-7.76(m,2H),7.29(td,J=8.6,2.4Hz,1H),2.94(s,4H).MS(M+1)：515.黃色固體。
化合物1-17
N-(6-(4-氟-3-甲氧基苯基)-1-(3-氟-4-甲氧基苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.00(br.s.,1H),8.58(s,1H),8.35(d,J=4.4Hz,1H),8.22-8.27(m,2H),8.09-8.18(m,2H),8.04-8.09(m,1H),7.38-7.47(m,2H),4.00(s,3H),3.93(s,3H).MS(M+1)：539.淡黃色固體。
化合物1-18
N-(6-(4-氯-3-氰基苯基)-1-(3-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(4-chloro-3-cyanophenyl)-1-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.00(br.s.,1H),8.86(d,J=2.0Hz,1H),8.70(dd,J=8.6,2.2Hz,1H),8.65(s,1H),8.32(d,J=4.4Hz,1H),8.25(d,J=4.4Hz,1H),8.18(dd,J=8.3,1.5Hz,1H),8.08(dt,J=10.8,2.4Hz,1H),7.98(d,J=8.3Hz,1H),7.67(td,J=8.3,6.8Hz,1H),7.26(td,J=8.6,2.4Hz,1H).MS(M+1)：520.灰色粉末。
化合物1-19
N-(6-(3-氰基-4-氟苯基)-1-(3-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(3-cyano-4-fluorophenyl)-1-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiopheno-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.03(br.s.,1H),8.89(dd,J=6.4,2.0Hz,1H),8.83(ddd,J=8.9,5.5,2.2Hz,1H),8.69(s,1H),8.34(d,J=4.4Hz,1H),8.26(d,J=3.9Hz,1H),8.22(dd,J=7.8,1.5Hz,1H),8.13(dt,J=10.8,2.2Hz,1H),7.79(t,J=8.8Hz,1H),7.70(td,J=8.3,6.8Hz,1H),7.28(td,J=8.7,2.2Hz,1H).MS(M+1)：504.黃色固體。
化合物1-20
N-(6-(3-氰基-4-(2-羥基乙氧基)苯基)-1-(4-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(3-cyano-4-(2-hydroxyethoxy)phenyl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 11.97(br.s.,1H),8.76(d,J=2.0Hz,1H),8.73(dd,J=9.0,2.2Hz,1H),8.63(s,1H),8.35(d,J=4.4Hz,1H),8.25-8.31(m,3H),7.44-7.53(m,3H),5.00(t,J=5.1Hz,1H),4.30(t,J=4.9Hz,2H),3.81(q,J=4.9Hz,2H).MS(M+1)：546.黃色固體。
化合物1-21
N-(6-(3-氰基-4-乙氧基苯基)-1-(3-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(3-cyano-4-ethoxyphenyl)-1-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 11.85(s,1H),8.60-8.68(m,2H),8.58(s,1H),8.34(d,J=4.4Hz,1H),8.24(d,J=4.4Hz,1H),8.15(dd,J=8.1,1.2Hz,1H),8.09(dt,J=11.0,2.3Hz,1H),7.64(td,J=8.3,6.4Hz,1H),7.42(d,J=9.3Hz,1H),7.23(td,J=8.4,2.7Hz,1H),4.29(q,J=7.2Hz,2H),1.42(t,J=6.8Hz,3H).MS(M+1)：530.黃色固體。
化合物1-22
N-(6-(4-氰基-3-氟苯基)-1-(3-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(4-cyano-3-fluorophenyl)-1-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.07(br.s.,1H),8.70(s,1H),8.47(dd,J=7.8,1.5Hz,1H),8.44(dd,J=10.5,1.2Hz,1H),8.34(d,J=4.4Hz,1H),8.27(d,J=4.4Hz,1H),8.15-8.24(m,2H),8.07-8.15(m,1H),7.70(td,J=8.3,6.4Hz,1H),7.28(td,J=8.1,2.4Hz,1H).MS(M+1)：504.黃色固體。
化合物1-23
N-(6-(4-胺基甲醯基-3-(甲基胺基)苯基)-1-(3-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(4-carbamoyl-3-(methylamino)phenyl)-1-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.02(br.s.,1H),8.64(s,1H),8.34-8.41(m,1H),8.28-8.34(m,1H),8.22-8.28(m,1H),8.15-8.22(m,1H),8.09-8.15(m,1H),7.93(br.s.,1H),7.77-7.86(m,2H),7.62-7.72(m,2H),7.25(td,J=8.7,2.2Hz,2H),2.96(d,J=4.9Hz,3H).MS(M+1)：533.黃色固體。
化合物1-24
N-(6-(4-氟-3-羥基苯基)-1-(3-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(4-fluoro-3-hydroxyphenyl)-1-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.05(br.s.,1H),10.21(s,1H),8.64(s,1H),8.36(d,J=4.4Hz,1H),8.26(d,J=4.9Hz,1H),8.22(ddd,J=8.3,2.0,1.0Hz,1H),8.13-8.19(m,2H),7.98-8.06(m,1H),7.69(td,J=8.2,6.6Hz,1H),7.33-7.40(m,1H),7.22-7.33(m,1H).MS(M+1)：495.黃色固體。
化合物1-25
N-(6-(3-氰基-4-甲基苯基)-1-(3-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(3-cyano-4-methylphenyl)-1-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.01(br.s.,1H),8.77(d,J=1.5Hz,1H),8.60-8.70(m,2H),8.35(d,J=4.4Hz,1H),8.26(d,J=4.4Hz,1H),8.21(dd,J=8.3,1.5Hz,1H),8.14(dt,J=10.8,2.2Hz,1H),7.65-7.76(m,2H),7.27(td,J=8.7,2.2Hz,1H),2.59(s,3H).MS(M+1)：500.黃色固體。
表2
化合物2-1
N-(6-(2,2-二氟苯並[d][1,3]二氧雜環戊烯-5-基)-1-(4-甲氧基苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 11.74(s,1H),8.47(s,1H),8.27-8.35(m,2H),8.18-8.26(m,2H),8.01-8.08(m,2H),7.53(d,J=8.3Hz,1H),7.06-7.17(m,2H),3.83(s,3H).MS(M+1)：553.黃色固體。
化合物2-2
N-(6-(苯並[d][1,3]二氧雜環戊烯-5-基)-1-(3-氰基苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[d][1,3]dioxol-5-yl)-1-(3-cyanophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 11.94(br.s.,1H),8.69-8.75(m,2H),8.64(s,1H),8.36(d,J=4.4Hz,1H),8.21(d,J=4.9Hz,1H),8.16(dd,J=8.3,2.0Hz,1H),8.00(d,J=1.5Hz,1H),7.77-7.88(m,2H),7.08(d,J=8.3Hz,1H),6.14(s,2H).MS(M+1)：512.黃色固體。
化合物2-3
N-(1-(3-氰基苯基)-6-(2-(2-羥基乙基)苯並[d][1,3]二氧雜環戊烯-5-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(1-(3-cyanophenyl)-6-(2-(2-hydroxyethyl)benzo[d][1,3]dioxol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 11.99(br.s.,1H),8.58-8.66(m,1H),8.54-8.58(m,1H),8.52(s,1H),8.44(d,J=4.4Hz,1H),8.21(d,J=4.4Hz,1H),8.03(dd,J=8.1,1.7Hz,1H),7.82-7.90(m,1H),7.76-7.82(m,2H),6.99(d,J=8.3Hz,1H),6.41(t,J=5.1Hz,1H),4.87(t,J=4.9Hz,1H),3.61-3.71(m,2H),2.04-2.18(m,2H).MS(M+1)：556.黃色固體。
表3
化合物3-1
N-(6-(苯並[d]噁唑-5-基)-1-(4-甲氧基苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[d]oxazol-5-yl)-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(DMSO-d6)：δ 11.94(br.s.,1H),8.91(d,J=1.5Hz,1H),8.86(s,1H),8.62-8.68(m,1H),8.59(s,1H),8.39(d,J=4.4Hz,1H),8.26(d,J=4.4Hz,1H),8.12-8.18(m,2H),7.94(d,J=8.8Hz,1H),7.18-7.26(m,2H),3.87(s,3H).MS(M+1)：514.黃色固體。
化合物3-2
N-(6-(苯並[d]噁唑-5-基)-1-(4-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[d]oxazol-5-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide
1H NMR(400MHz,DMSO-d6)：δ 11.99(br.s.,1H),8.92(d,J=1.5Hz,1H),8.86(s,1H),8.62-8.67(m,2H),8.39(d,J=4.4Hz,1H),8.28-8.35(m,2H),8.27(d,J=4.4Hz,1H),7.95(d,J=8.8Hz,1H),7.47-7.55(m,2H).MS(M+1)：502.黃色固體。
化合物3-3
N-(6-(苯並[d]噁唑-5-基)-1-(2,4-二氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[d]oxazol-5-yl)-1-(2,4-difluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.05(br.s.,1H),8.81-8.86(m,2H),8.66(s,1H),8.53(dd,J=8.8,1.5Hz,1H),8.38(d,J=4.4Hz,1H),8.27(d,J=4.4Hz,1H),7.87-7.95(m,2H),7.66-7.74(m,1H),7.37-7.44(m,1H).MS(M+1)：520.橙色固體。
化合物3-4
N-(6-(苯並[d]噁唑-5-基)-1-(4-氰基苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[d]oxazol-5-yl)-1-(4-cyanophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(DMSO-d6)：δ 11.87(br.s.,1H),8.89(d,J=1.5Hz,1H),8.64(s,1H),8.67(s,1H),8.56-8.63(m,3H),8.37(d,J=4.4Hz,1H),8.12(s,1H),7.93-7.99(m,2H),7.78(d,J=8.8Hz,1H).MS(M+1)：509.棕色固體。
化合物3-5
N-(1-(4-氰基苯基)-6-(2-(2-甲氧基乙基)苯並[d]噁唑-5-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(1-(4-cyanophenyl)-6-(2-(2-methoxyethyl)benzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(DMSO-d6)：δ 11.69(br.s.,1H),8.55(s,1H),8.47(s,1H),8.31-8.43(m,3H),8.28(d,J=4.4Hz,1H),8.18(d,J=4.4Hz,1H),7.93(d,J=8.8Hz,2H),7.66(d,J=8.3Hz,1H),3.84(t,J=6.4Hz,2H),3.20(t,J=6.1Hz,2H).MS(M+1)：567.棕色固體。
化合物3-6
N-(1-(3-氰基苯基)-6-(2-(甲氧基甲基)苯並[d]噁唑-5-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(1-(3-cyanophenyl)-6-(2-(methoxymethyl)benzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 11.97(br.s.,1H),8.81(d,J=1.0Hz,1H),8.68(dt,J=5.9,2.9Hz,1H),8.61-8.66(m,2H),8.58(dd,J=8.6,1.7Hz,1H),8.37(d,J=4.4Hz,1H),8.26(d,J=4.9Hz,1H),7.90(d,J=8.8Hz,1H),7.79-7.88(m,2H),4.77(s,2H),3.46(s,3H).MS(M+1)：553.卡其色固體。
化合物3-7
N-(6-(苯並[d]噁唑-5-基)-1-(3-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[d]oxazol-5-yl)-1-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 11.99(br.s.,1H),8.84-8.93(m,2H),8.61-8.68(m,2H),8.37(d,J=4.4Hz,1H),8.26(d,J=4.4Hz,1H),8.15-8.25(m,2H),7.97(d,J=8.8Hz,1H),7.70(td,J=8.3,6.8Hz,1H),7.26(td,J=8.6,2.0Hz,1H).MS(M+1)：502.卡其色固體。
化合物3-8
N-(6-(苯並[d]噁唑-6-基)-1-(3-甲氧基苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[d]oxazol-6-yl)-1-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 11.98(br.s.,1H),8.89(s,1H),8.79(d,J=1.5Hz,1H),8.57-8.66(m,2H),8.37(d,J=4.4Hz,1H),8.26(d,J=4.4Hz,1H),7.98(d,
J=8.3Hz,1H),7.89-7.96(m,2H),7.51-7.59(m,1H),6.96-7.04(m,1H),3.91(s,3H).MS(M+1)：514.黃色固體。
化合物3-9
N-(1-(3-氟苯基)-6-(2-(甲氧基甲基)苯並[d]噁唑-5-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(1-(3-fluorophenyl)-6-(2-(methoxymethyl)benzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 11.97(br.s.,1H),8.83(d,J=1.5Hz,1H),8.62(s,1H),8.59(dd,J=8.6,1.7Hz,1H),8.36(d,J=4.4Hz,1H),8.13-8.27(m,3H),7.91(d,J=8.3Hz,1H),7.68(td,J=8.2,6.6Hz,1H),7.21-7.30(m,1H),4.76(s,2H),3.41-3.49(m,3H).MS(M+1)：546.黃色固體。
表4
化合物4-1
N-(6-(苯並[b]噻吩-5-基)-1-(4-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[b]thiophen-5-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.05(br.s.,1H),9.05(s,1H),8.62(s,1H),8.48-8.56(m,1H),8.39(d,J=4.4Hz,1H),8.33(dd,J=9.0,4.6Hz,2H),8.26(d,J=4.4Hz,1H),8.19(d,J=8.8Hz,1H),7.88(d,J=5.4Hz,1H),7.64(d,J=5.4Hz,1H),7.46-7.54(m,2H).MS(M+1)：517.淡橙色固體。
化合物4-2
N-(6-(苯並[d]噻唑-5-基)-1-(3-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺
(N-(6-(benzo[d]thiazol-5-yl)-1-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.03(br.s.,1H),9.50(s,1H),9.20(d,J=1.5Hz,1H),8.65(s,1H),8.62(dd,J=8.6,1.7Hz,1H),8.34-8.41(m,2H),8.22-8.28(m,2H),8.19(dt,J=10.9,2.4Hz,1H),7.70(td,J=8.3,6.8Hz,1H),7.27(td,J=8.6,2.0Hz,1H).MS(M+1)：518.黃色固體。
化合物4-3
N-(1-(3-氟苯基)-6-(2-甲基苯並[d]噻唑-5-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(1-(3-fluorophenyl)-6-(2-methylbenzo[d]thiazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 11.94(br.s.,1H),8.97(d,J=1.5Hz,1H),8.60(s,1H),8.50(dd,J=8.3,1.5Hz,1H),8.33(d,J=4.4Hz,1H),8.20-8.27(m,2H),8.12-8.20(m,2H),7.68(td,J=8.2,6.6Hz,1H),7.24(td,J=8.7,2.2Hz,1H),2.84(s,3H).MS(M+1)：532.棕色固體。
化合物4-4
N-(6-(苯並[d]噻唑-5-基)-1-(4-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[d]thiazol-5-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.01(br.s.,1H),9.50(s,1H),9.21(d,J=1.5Hz,1H),8.51-8.70(m,2H),8.22-8.43(m,5H),7.44-7.55(m,2H).MS(M+1)：518.黃色固體。
化合物4-5
N-(6-(苯並[d]噻唑-5-基)-1-(噻吩-3-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[d]thiazol-5-yl)-1-(thiophen-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.05(br.s.,1H),9.51(s,1H),9.28(d,J=1.5Hz,1H),8.70-8.75(m,1H),8.61(s,1H),8.30-8.39(m,3H),8.26(d,J=4.4Hz,1H),7.97-8.03(m,1H),7.82(dd,J=5.1,3.2Hz,1H).MS(M+1)：505.6.黃色固體。
化合物4-6
N-(1-(3-氯苯基)-6-(2-甲基苯並[d]噻唑-5-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(1-(3-chlorophenyl)-6-(2-methylbenzo[d]thiazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.04(br.s.,1H),9.02(s,1H),8.66(s,1H),8.55(dd,J=8.3,1.5Hz,1H),8.41-8.45(m,1H),8.34-8.41(m,2H),8.20-8.29(m,2H),7.70(t,J=8.1Hz,1H),7.49(dd,J=7.6,1.7Hz,1H),2.86(s,3H).MS(M+1)：548.黑色固體。
化合物4-7
N-(6-(苯並[d]噻唑-5-基)-1-(4-甲氧基苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[d]thiazol-5-yl)-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 11.93(br.s.,1H),9.49(s,1H),9.19(d,J=0.98Hz,1H),8.60(dd,J=1.47,8.31Hz,1H),8.57(s,1H),8.38(d,J=4.40Hz,1H),
8.32(d,J=8.31Hz,1H),8.24(d,J=4.40Hz,1H),8.10-8.16(m,2H),7.16-7.23(m,2H),3.86(s,3H).MS(M+1)：530.橙色固體。
化合物4-8
N-(6-(苯並[d]噻唑-5-基)-1-(噻吩-2-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[d]thiazol-5-yl)-1-(thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.09(br.s.,1H),9.52(s,1H),9.28(d,J=1.5Hz,1H),8.71(dd,J=8.3,1.5Hz,1H),8.65(s,1H),8.35-8.42(m,2H),8.27(d,J=4.4Hz,1H),7.88(dd,J=3.4,1.5Hz,1H),7.47(dd,J=5.4,1.5Hz,1H),7.21(dd,J=5.6,3.7Hz,1H).MS(M+1)：506.橙色固體。
化合物4-9
N-(6-(苯並[d]噻唑-5-基)-1-(5-甲基噻吩-3-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[d]thiazol-5-yl)-1-(5-methylthiophen-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.03(br.s.,1H),9.51(s,1H),9.28(d,J=1.0Hz,1H),8.72(dd,J=8.6,1.2Hz,1H),8.60(s,1H),8.32-8.45(m,2H),8.27(d,J=4.4Hz,1H),8.09(d,J=1.5Hz,1H),7.67(s,1H),2.58(s,3H).MS(M+1)：520.棕色固體。
化合物4-10
N-(6-(苯並[d]噻唑-5-基)-1-苯基-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[d]thiazol-5-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.04(s,1H),9.51(s,1H),9.24(d,J=1.5Hz,1H),8.63-8.72(m,2H),8.42(d,J=4.4Hz,1H),8.37(d,J=8.8Hz,1H),8.32(dd,J=8.8,1.0Hz,2H),8.28(d,J=4.9Hz,1H),7.65-7.71(m,2H),7.43-7.48(m,1H).MS(M+1)：500.棕色固體。
化合物4-11
N-(6-(苯並[d]噻唑-5-基)-1-(對甲苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[d]thiazol-5-yl)-1-(p-tolyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.02(br.s.,1H),9.50(s,1H),9.22(d,J=1.5Hz,1H),8.62-8.67(m,2H),8.33-8.41(m,2H),8.27(d,J=4.4Hz,1H),8.13-8.19(m,2H),7.43-7.52(m,J=8.3Hz,2H),2.42(s,3H).MS(M+1)：514.黃色固體。
化合物4-12
N-(6-(苯並[d]噻唑-5-基)-1-(間甲苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[d]thiazol-5-yl)-1-(m-tolyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 11.99(br.s.,1H),9.50(s,1H),9.21(d,J=1.5Hz,1H),8.60-8.66(m,2H),8.32-8.41(m,2H),8.25(d,J=4.4Hz,1H),8.16(d,J=7.8Hz,1H),8.08(s,1H),7.54(t,J=8.1Hz,1H),7.25(d,J=7.3Hz,1H),2.48(s,3H).MS(M+1)：514.黃色固體。
化合物4-13
N-(6-(苯並[d]噻唑-5-基)-1-(3,5-二氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[d]thiazol-5-yl)-1-(3,5-difluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 11.90(br.s.,1H),9.46(s,1H),9.08(d,J=1.0Hz,1H),8.57(s,1H),8.48(dd,J=8.3,1.5Hz,1H),8.33(d,J=4.4Hz,1H),8.28(d,J=8.8Hz,1H),8.21(d,J=4.4Hz,1H),8.03(dd,J=8.8,2.0Hz,2H),7.17-7.27(m,1H).MS(M+1)：536.棕色固體。
化合物4-14
N-(6-(苯並[d]噻唑-5-基)-1-(4-(2-甲氧基乙氧基)苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[d]thiazol-5-yl)-1-(4-(2-methoxyethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.04(br.s.,1H),9.51(s,1H),9.23(d,J=1.5Hz,1H),8.65(dd,J=8.6,1.7Hz,1H),8.62(s,1H),8.36(d,J=8.3Hz,2H),8.27(d,J
=4.4Hz,1H),8.13-8.20(m,2H),7.21-7.28(m,2H),4.18-4.26(m,2H),3.68-3.77(m,2H),3.35(s,3H).MS(M+1)：574.橙色固體。
化合物4-15
N-(6-(苯並[d]噻唑-5-基)-1-(3-氟-4-甲氧基苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[d]thiazol-5-yl)-1-(3-fluoro-4-methoxy phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.01(br.s.,1H),9.50(s,1H),9.21(d,J=1.0Hz,1H),8.57-8.67(m,2H),8.32-8.42(m,2H),8.26(d,J=4.4Hz,1H),8.08-8.17(m,2H),7.41-7.51(m,1H),3.95(s,3H).MS(M+1)：548.棕色固體。
化合物4-16
N-(6-(苯並[d]噻唑-5-基)-1-(4-氟-3-甲氧基苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[d]thiazol-5-yl)-1-(4-fluoro-3-methoxy phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 11.96(br.s.,1H),9.48(s,1H),9.18(d,J=1.5Hz,1H),8.57-8.62(m,2H),8.37(d,J=4.4Hz,1H),8.31(d,J=8.3Hz,1H),8.24(d,J=4.4Hz,1H),8.15(dd,J=7.8,2.4Hz,1H),7.86(ddd,J=8.9,3.8,2.4Hz,1H),7.46(dd,J=11.2,8.8Hz,1H),4.02(s,3H).MS(M+1)：548.棕色固體。
化合物4-17
N-(6-(苯並[d]噻唑-5-基)-1-(3-氟-4-(2-甲氧基乙氧基)苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[d]thiazol-5-yl)-1-(3-fluoro-4-(2-methoxyethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 9.51(s,1H),9.21(d,J=1.5Hz,1H),8.55-8.69(m,2H),8.37(d,J=8.3Hz,1H),8.11-8.27(m,5H),7.44-7.55(m,1H),4.25-4.33(m,2H),3.74(dd,J=5.1,3.7Hz,2H),3.36(s,3H).MS(M+1)：592.橙色固體。
化合物4-18
N-(6-(苯並[d]噻唑-5-基)-1-(3-甲氧基苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[d]thiazol-5-yl)-1-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 11.99(br.s.,1H),9.50(s,1H),9.21(d,J=1.5Hz,1H),8.63(s,1H),8.39(d,J=4.4Hz,1H),8.35(d,J=8.8Hz,1H),8.25(d,J=4.4Hz,1H),7.98(t,J=2.2Hz,1H),7.92(dd,J=8.1,1.2Hz,1H),7.55-7.63(m,2H),7.00(ddd,J=8.3,2.4,1.0Hz,1H),3.92(s,3H).MS(M+1)：530.棕色固體。
化合物4-19
N-(1-(4-氟苯基)-6-(2-(2-甲氧基乙氧基)苯並[d]噻唑-5-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(1-(4-fluorophenyl)-6-(2-(2-methoxyethoxy)benzo[d]thiazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 11.95(br.s.,1H),8.80(d,J=1.5Hz,1H),8.64(s,1H),8.45(dd,J=8.6,1.7Hz,1H),8.37(d,J=4.4Hz,1H),8.22-8.34(m,3H),8.07(d,J=8.3Hz,1H),7.44-7.58(m,2H),4.71(dt,J=4.2,2.3Hz,2H),3.77(dt,J=4.2,2.3Hz,2H),3.34(s,3H).MS(M+1)：592.淡黃色固體。
表5
化合物5-1
N-(1-(4-氟苯基)-6-(1H-吡咯-1-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(1-(4-fluorophenyl)-6-(1H-pyrrol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitro thiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.02(s,1H),8.59(s,1H),8.34(d,J=4.4Hz,1H),8.20-8.30(m,3H),7.86(t,J=2.4Hz,2H),7.43-7.51(m,2H),6.36-6.42(m,2H).MS(M+1)：450.黃色固體。
化合物5-2
N-(1-(4-氟苯基)-6-(噻唑-4-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(1-(4-fluorophenyl)-6-(thiazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.28(br.s.,1H),9.30(br.s.,1H),8.69(br.s.,1H),8.62(br.s.,1H),8.34(br.s.,3H),8.24(d,J=3.9Hz,1H),7.44-7.51(m,2H).MS(M+1)：468.淡黃色固體。
化合物5-3
1-(1-(4-氟苯基)-4-(5-硝基噻吩-2-甲醯胺基)-1H-吡唑並[3,4-d]嘧啶-6-基)-1H-吡咯-3-甲酸甲酯(Methyl 1-(1-(4-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxylate)
1H NMR(400MHz,DMSO-d6)：δ 12.01(br.s.,1H),8.61(s,1H),8.37(t,J=2.0Hz,1H),8.31(d,J=4.4Hz,1H),8.24(d,J=4.4Hz,1H),8.13-8.23(m,2H),7.85(dd,J=3.2,2.2Hz,1H),7.45(t,J=8.8Hz,2H),6.70(dd,J=3.4,2.0Hz,1H),3.78(s,3H).MS(M+1)：508.棕色固體。
化合物5-4
N-(6-(4-氯-1H-吡唑-1-基)-1-(3-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(4-chloro-1H-pyrazol-1-yl)-1-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.24(br.s.,1H),8.84(s,1H),8.61(s,1H),8.33(d,J=4.4Hz,1H),8.22(d,J=4.4Hz,1H),8.16(dd,J=8.3,2.0Hz,1H),8.00-8.10(m,2H),7.61-7.72(m,1H),7.24(td,J=8.4,2.7Hz,1H).MS(M+1)：485.黃色固體。
化合物5-5
N-(6-(4-氯-1H-吡唑-1-基)-1-(3-氯苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(4-chloro-1H-pyrazol-1-yl)-1-(3-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.31(br.s.,1H),8.85(s,1H),8.63(s,1H),8.33(dd,J=8.3,1.5Hz,1H),8.29(t,J=2.2Hz,1H),8.24-8.28(m,1H),8.20-8.24(m,1H),8.05(s,1H),7.65(t,J=8.3Hz,1H),7.42-7.51(m,1H).MS(M+1)：501.黃色固體。
化合物5-6
1-(1-(4-氰基苯基)-4-(5-硝基噻吩-2-甲醯胺基)-1H-吡唑並[3,4-d]嘧啶-6-基)-1H-吡咯-3-甲酸甲酯(Methyl 1-(1-(4-cyanophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxylate)
1H NMR(400MHz,DMSO-d6)：δ 12.09(br.s.,1H),8.68(s,1H),8.49-8.56(m,J=8.8Hz,2H),8.45(t,J=2.0Hz,1H),8.26(br.s.,1H),8.14(d,J=4.4Hz,1H),7.98-8.03(m,J=9.3Hz,2H),7.90-7.93(m,1H),6.69(dd,J=3.2,1.7Hz,1H),3.79(s,3H).MS(M+1)：515.黃色固體。
化合物5-7
N-(6-(4-氰基-1H-吡唑-1-基)-1-(3-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(4-cyano-1H-pyrazol-1-yl)-1-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.37(br.s.,1H),9.47(s,1H),8.65(s,1H),8.46(s,1H),8.32(d,J=3.9Hz,1H),8.14-8.25(m,2H),8.05(dt,J=10.8,2.2Hz,1H),7.65(td,J=8.3,6.8Hz,1H),7.19-7.31(m,1H).MS(M+1)：476.黃色固體。
化合物5-8
N-(6-(4-氰基-1H-吡唑-1-基)-1-(4-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(4-cyano-1H-pyrazol-1-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.44(br.s.,1H),9.50(s,1H),8.62(s,1H),8.38-8.49(m,1H),8.25-8.29(m,2H),8.19-8.24(m,2H),7.42-7.47(m,2H).MS(M+1)：476.黃棕色固體。
化合物5-9
1-(4-(5-硝基噻吩-2-甲醯胺基)-1-(噻吩-3-基)-1H-吡唑並[3,4-d]嘧啶-6-基)-1H-吡咯-3-甲酸甲酯(Methyl 1-(4-(5-nitrothiophene-2-carboxamido)-1-(thiophen-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxylate)
1H NMR(400MHz,DMSO-d6)：δ 12.06(br.s.,1H),8.64(s,1H),8.49(t,J=2.0Hz,1H),8.34(d,J=4.4Hz,1H),8.22-8.31(m,2H),8.01(dd,J=3.2,2.2Hz,1H),7.88(dd,J=5.1,1.2Hz,1H),7.79(dd,J=5.4,3.4Hz,1H),6.74(dd,J=3.2,1.7Hz,1H),3.74-3.85(m,3H).MS(M+1)：496.黃色固體。
化合物5-10
N-(1-(4-氟苯基)-6-(3-(2-甲氧基乙氧基)-1H-吡唑-1-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(1-(4-fluorophenyl)-6-(3-(2-methoxyethoxy)-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(DMSO-d6,400MHz)：δ 12.19(br.s.,1H),8.60(d,J=2.9Hz,1H),8.56(s,1H),8.36(d,J=4.4Hz,1H),8.21-8.29(m,3H),7.41-7.51(m,2H),6.24(d,J=2.9Hz,1H),4.25-4.44(m,2H),359-3.76(m,2H),3.32(s,4H).MS(M+1)：525.黃色固體。
化合物5-11
N-(6-(4-氟-1H-咪唑-1-基)-1-(4-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(4-fluoro-1H-imidazol-1-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.17(br.s.,1H),8.65(s,1H),8.42-8.53(m,1H),8.20-8.39(m,4H),7.73(dd,J=8.3,1.5Hz,1H),7.44(t,J=9.3Hz,2H).MS(M+1)：469.黃棕色固體。
化合物5-12
1-(1-(5-氰基噻吩-2-基)-4-(5-硝基噻吩-2-甲醯胺基)-1H-吡唑並[3,4-d]嘧啶-6-基)-1H-吡咯-3-甲酸甲酯(Methyl 1-(1-(5-cyanothiophen-2-yl)-4-(5-nitrothiophene-2-carboxamido)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxylate)
1H NMR(400MHz,DMSO-d6)：δ 12.18(br.s.,1H),8.71(s,1H),8.46(t,J=2.0Hz,1H),8.22-8.31(m,2H),8.00-8.07(m,2H),7.90(d,J=3.9Hz,1H),6.75(dd,J=3.2,1.7Hz,1H),3.81(s,3H).MS(M+1)：521.黃棕色固體。
化合物5-13
N-(1-(3-氟苯基)-6-(3-(2-羥基乙氧基)-1H-吡唑-1-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(1-(3-fluorophenyl)-6-(3-(2-hydroxyethoxy)-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.18(br.s.,1H),8.52-8.64(m,2H),8.36(d,J=4.4Hz,1H),8.23(d,J=4.4Hz,1H),8.08-8.20(m,2H),7.58-7.68(m,1H),7.23(td,J=8.4,2.2Hz,1H),6.24(d,J=2.4Hz,1H),4.91(t,J=5.4Hz,1H),4.28(t,J=5.1Hz,2H),3.76(q,J=5.2Hz,2H).MS(M+1)：511.黃綠色固體。
化合物5-14
1-(1-(3-氰基苯基)-4-(5-硝基噻吩-2-甲醯胺基)-1H-吡唑並[3,4-d]嘧啶-6-基)-1H-吡咯-3-甲酸甲酯(Methyl 1-(1-(3-cyanophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxylate)
1H NMR(DMSO-d6,400MHz)：δ 12.10(br.s.,1H),8.70(s,1H),8.52-8.65(m,2H),8.43(t,J=1.7Hz,1H),8.33(d,J=3.9Hz,1H),8.27(d,J=4.4Hz,1H),7.80-7.93(m,3H),6.74(dd,J=3.2,1.7Hz,1H),3.79(s,3H).MS(M+NH3)：531.奶茶色固體。
化合物5-15
1-(1-(4-氟苯基)-4-(5-硝基噻吩-2-甲醯胺基)-1H-吡唑並[3,4-d]嘧啶-6-基)-1H-吡咯-3-甲酸乙酯(Ethyl 1-(1-(4-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxylate)
1H NMR(400MHz,DMSO-d6)：δ 12.03(s,1H),8.62(s,1H),8.37(t,J=2.0Hz,1H),8.33(d,J=4.4Hz,1H),8.25(d,J=4.4Hz,1H),8.15-8.23(m,2H),7.86(dd,J=3.2,2.2Hz,1H),7.41-7.50(m,2H),6.70(dd,J=3.2,1.7Hz,1H),4.25(q,J=6.8Hz,2H),1.30(t,J=7.1Hz,3H).MS(M+1)：522.黃綠色固體。
化合物5-16
N-(1-(4-氟苯基)-6-(3-(2-羥基乙氧基)-1H-吡唑-1-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(1-(4-fluorophenyl)-6-(3-(2-hydroxyethoxy)-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.22(br.s.,1H),8.61(d,J=2.9Hz,1H),8.55(s,1H),8.34(d,J=4.4Hz,1H),8.21-8.29(m,3H),7.41-7.49(m,2H),6.23(d,J=2.9Hz,1H),4.90(t,J=5.4Hz,1H),4.27(t,J=4.9Hz,2H),3.75(q,J=5.4Hz,2H).MS(M+1)：511.黃色固體。
化合物5-17
1-(1-(3-氟苯基)-4-(5-硝基噻吩-2-甲醯胺基)-1H-吡唑並[3,4-d]嘧啶-6-基)-1H-吡咯-3-甲酸2-羥乙基酯(2-hydroxyethyl 1-(1-(3-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxylate)
1H NMR(400MHz,DMSO-d6)：δ 12.14(br.s.,1H),8.66(s,1H),8.44(t,J=2.0Hz,1H),8.34(d,J=4.4Hz,1H),8.26(d,J=4.4Hz,1H),8.15(dd,J=8.1,1.2Hz,1H),8.03(dt,J=10.8,2.2Hz,1H),7.87(dd,J=3.2,2.2Hz,1H),7.68(td,J=8.3,6.8Hz,1H),7.27(td,J=8.4,2.2Hz,1H),6.72-6.78(m,1H),4.89(t,J=5.4Hz,1H),4.18-4.28(m,2H),3.69(q,J=5.4Hz,2H).MS(M+1)：538.淡黃色固體。
化合物5-18
2-((1-(1-(4-氟苯基)-4-(5-硝基噻吩-2-甲醯胺基)-1H-吡唑並[3,4-d]嘧啶-6-基)-1H-吡唑-3-基)氧基)乙基磷酸二氫酯(2-((1-(1-(4-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrazol-3-yl)oxy)ethyl dihydrogen phosphate)
1H NMR(400MHz,DMSO-d6)：δ 12.23(br.s.,1H),8.62(d,J=2.9Hz,1H),8.56(s,1H),8.39(d,J=4.4Hz,1H),8.22-8.30(m,3H),7.42-7.49(m,2H),6.26(d,J=2.9Hz,1H),4.40-4.47(m,2H),4.14-4.21(m,2H).MS(M+1)：591.淡黃色固體。
化合物5-19
1-(1-(5-氰基噻吩-3-基)-4-(5-硝基噻吩-2-甲醯胺基)-1H-吡唑並[3,4-d]嘧啶-6-基)-1H-吡咯-3-甲酸甲酯(Methyl 1-(1-(5-cyanothiophen-3-yl)-4-(5-nitrothiophene-2-carboxamido)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxylate)
1H NMR(400MHz,DMSO-d6)：δ 12.10(br.s.,1H),8.75(s,1H),8.61-8.67(m,2H),8.51(d,J=2.0Hz,1H),8.30(br.s.,1H),8.24-8.28(m,1H),8.08(d,J=2.0Hz,1H),6.73(d,J=2.0Hz,1H),3.80(s,3H).MS(M+1)：521.棕色固體。
化合物5-20
N-(1-(3-氟苯基)-6-(3-(4-羥基丁氧基)-1H-吡唑-1-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(1-(3-fluorophenyl)-6-(3-(4-hydroxybutoxy)-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.21(br.s.,1H),8.54-8.62(m,2H),8.32(d,J=4.4Hz,1H),8.23(d,J=4.4Hz,1H),8.14-8.21(m,2H),7.65(td,J=8.3,6.4Hz,1H),7.19-7.29(m,1H),6.23(d,J=2.9Hz,1H),4.46(t,J=5.1Hz,1H),4.27(t,J=6.6Hz,2H),3.42-3.52(m,2H),1.74-1.87(m,2H),1.52-1.65(m,2H).MS(M+1)：539.淡黃色固體。
化合物5-21
N-(6-(3-(3-羥基丙氧基)-1H-吡唑-1-基)-1-(噻吩-3-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(3-(3-hydroxypropoxy)-1H-pyrazol-1-yl)-1-(thiophen-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.26(br.s.,1H),8.71(d,J=2.9Hz,1H),8.53(s,1H),8.35(br.s.,1H),8.18-8.28(m,2H),7.92(dd,J=5.4,1.5Hz,1H),7.71-7.88(m,1H),6.24(d,J=2.9Hz,1H),4.51-4.66(m,1H),4.34(t,J=6.4Hz,2H),3.49-3.66(m,2H),1.91(t,J=6.4Hz,2H).MS(M+1)：513.淡黃色固體。
化合物5-22
N-(1-(4-氟苯基)-6-(3-(4-羥基丁氧基)-1H-吡唑-1-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(1-(4-fluorophenyl)-6-(3-(4-hydroxybutoxy)-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.22(br.s.,1H),8.60(d,J=2.9Hz,1H),8.56(s,1H),8.33(d,J=4.4Hz,1H),8.19-8.31(m,3H),7.38-7.51(m,2H),6.22(d,J=2.9Hz,1H),4.45(t,J=5.1Hz,1H),4.26(t,J=6.6Hz,2H),3.43-3.51(m,2H),1.73-1.84(m,2H),1.52-1.63(m,2H).MS(M+1)：539.淡黃色固體。
化合物5-23
1-(1-(4-氰基苯基)-4-(5-硝基噻吩-2-甲醯胺基)-1H-吡唑並[3,4-d]嘧啶-6-基)-1H-吡咯-3-甲酸2-羥乙基酯(2-hydroxyethyl 1-(1-(4-cyanophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxylate)
1H NMR(400MHz,DMSO-d6)：δ 12.13(br.s.,1H),8.67(s,1H),8.44-8.51(m,2H),8.42(t,J=2.0Hz,1H),8.32(d,J=4.4Hz,1H),8.25(d,J=4.4Hz,1H),8.04-8.09(m,2H),7.92(dd,J=3.2,2.2Hz,1H),6.74(dd,J=3.2,1.7Hz,1H),4.88(t,J=5.6Hz,1H),4.18-4.27(m,2H),3.69(q,J=5.1Hz,2H).MS(M+1)：545.棕褐色固體。
化合物5-24
1-(1-(3-氟苯基)-4-(5-硝基噻吩-2-甲醯胺基)-1H-吡唑並[3,4-d]嘧啶-6-基)-1H-吡咯-3-甲酸甲酯(methyl 1-(1-(3-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxylate)
1H NMR(400MHz,DMSO-d6)：δ 11.95(br.s.,1H),8.58(s,1H),8.28-8.35(m,2H),8.23(d,J=4.4Hz,1H),8.08(dd,J=8.1,1.2Hz,1H),7.96(dt,J=10.8,2.2Hz,1H),7.75-7.81(m,1H),7.63(td,J=8.3,6.4Hz,1H),7.23(td,J=8.4,2.7Hz,1H),6.68(dd,J=3.4,2.0Hz,1H),3.77(s,3H).MS(M+1)：508.亮黃色固體。
化合物5-25
1-(1-(5-甲基噻吩-3-基)-4-(5-硝基噻吩-2-甲醯胺基)-1H-吡唑並[3,4-d]嘧啶-6-基)-1H-吡咯-3-甲酸甲酯(methyl 1-(1-(5-methylthiophen-3-yl)-4-(5-nitrothiophene-2-carboxamido)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxylate)
1H NMR(400MHz,DMSO-d6)：δ 12.05(br.s.,1H),8.59(s,1H),8.48(t,J=2.0Hz,1H),8.22-8.32(m,2H),7.96-8.03(m,2H),7.59(t,J=1.5Hz,1H),6.73(dd,J=3.2,1.7Hz,1H),3.80(s,3H),2.56(s,3H).MS(M+1)：510.淡黃色固體。
化合物5-26
1-(1-(4-氰基苯基)-4-(5-硝基噻吩-2-甲醯胺基)-1H-吡唑並[3,4-d]嘧啶-6-基)-N-甲氧基-N-甲基-1H-吡咯-3-甲醯胺(1-(1-(4-cyanophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-methoxy-N-methyl-1H-pyrrole-3-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.12(br.s.,1H),8.66-8.70(m,1H),8.46-8.51(m,2H),8.42(t,J=2.0Hz,1H),8.34(d,J=4.4Hz,1H),8.26(d,J=4.4Hz,1H),
8.07-8.11(m,2H),7.88-7.92(m,1H),6.78(dd,J=3.2,1.7Hz,1H),3.79(s,3H),3.28(s,3H).MS(M+1)：544.棕色固體。
化合物5-27
N-甲氧基-N-甲基-1-(1-(5-甲基噻吩-3-基)-4-(5-硝基噻吩-2-甲醯胺基)-1H-吡唑並[3,4-d]嘧啶-6-基)-1H-吡咯-3-甲醯胺(N-methoxy-N-methyl-1-(1-(5-methylthiophen-3-yl)-4-(5-nitrothiophene-2-carboxamido)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrrole-3-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.07(br.s.,1H),8.59(s,1H),8.46(t,J=2.0Hz,1H),8.34(d,J=4.4Hz,1H),8.26(d,J=4.4Hz,1H),7.96(dd,J=3.2,2.2Hz,1H),7.93(d,J=1.5Hz,1H),7.61(t,J=1.2Hz,1H),6.78(dd,J=3.2,1.7Hz,1H),3.79(s,3H),3.28(s,3H),2.54-2.59(m,3H).MS(M+1)：539.淡棕色固體。
化合物5-28
1-(1-(3-氟苯基)-4-(5-硝基噻吩-2-甲醯胺基)-1H-吡唑並[3,4-d]嘧啶-6-基)-N-甲氧基-N-甲基-1H-吡咯-3-甲醯胺(1-(1-(3-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-methoxy-N-methyl-1H-pyrrole-3-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.08(br.s.,1H),8.63(s,1H),8.41(t,J=2.0Hz,1H),8.32(d,J=4.4Hz,1H),8.24(d,J=4.9Hz,1H),8.05-8.13(m,2H),7.80-7.87(m,1H),7.66(td,J=8.2,6.6Hz,1H),7.22-7.29(m,1H),6.77(dd,J=3.2,1.7Hz,1H),3.79(s,3H),3.27(s,3H).MS(M+1)：537.黃色固體。
化合物5-29
1-(1-(4-氟苯基)-4-(5-硝基噻吩-2-甲醯胺基)-1H-吡唑並[3,4-d]嘧啶-6-基)-N-甲氧基-N-甲基-1H-吡咯-3-甲醯胺(1-(1-(4-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-methoxy-N-methyl-1H-pyrrole-3-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.07(s,1H),8.63(s,1H),8.41(t,J=1.7Hz,1H),8.34(d,J=4.4Hz,1H),8.26(d,J=4.4Hz,1H),8.17-8.24(m,2H),7.83-7.89(m,1H),7.43-7.52(m,2H),6.77(dd,J=3.2,1.7Hz,1H),3.78(s,3H),3.27(s,3H).MS(M+1)：537.黃色固體。
化合物5-30
2-((1-(1-(4-氟苯基)-4-(5-硝基噻吩-2-甲醯胺基)-1H-吡唑並[3,4-d]嘧啶-6-基)-1H-吡唑-3-基)氧基)乙酸乙酯(2-((1-(1-(4-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrazol-3-yl)oxy)ethyl acetate)
1H NMR(400MHz,DMSO-d6)：δ 12.23(br.s.,1H),8.62(d,J=2.4Hz,1H),8.55(s,1H),8.09-8.38(m,4H),7.45(t,J=9.0Hz,2H),6.25(d,J=2.9Hz,1H),4.42-4.66(m,2H),4.25-4.42(m,2H),2.05(s,3H).MS(M+1)：553.黃色固體粉末。
化合物5-31
N-(6-(3-乙醯基-1H-吡咯-1-基)-1-(4-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(3-acetyl-1H-pyrrol-1-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.13(br.s.,1H),8.64(s,1H),8.49(t,J=2.0Hz,1H),8.30(d,J=4.4Hz,1H),8.20-8.28(m,3H),7.91(dd,J=3.4,2.0Hz,1H),7.43-7.52(m,2H),6.72-6.78(m,1H),2.46(s,3H).MS(M+1)：492.黃色固體粉末。
化合物5-32
2-((1-(1-(4-氟苯基)-4-(5-硝基噻吩-2-甲醯胺基)-1H-吡唑並[3,4-d]嘧啶-6-基)-1H-吡唑-3-基)氧基)丙酸乙酯(2-((1-(1-(4-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrazol-3-yl)oxy)ethyl propionate)
1H NMR(400MHz,DMSO-d6)：δ 12.23(br.s.,1H),8.63(d,J=2.9Hz,1H),8.55-8.60(m,1H),8.36(d,J=4.4Hz,1H),8.22-8.31(m,3H),7.41-7.51(m,2H),6.27(d,J=2.9Hz,1H),4.44-4.50(m,2H),4.37-4.43(m,2H),2.36(q,J=7.3Hz,2H),1.03(t,J=7.6Hz,3H).MS(M+1)：567.淡黃色固體粉末。
化合物5-33
N-(1-(4-氟苯基)-6-(3-丙醯基-1H-吡咯-1-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(1-(4-fluorophenyl)-6-(3-propionyl-1H-pyrrol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.09(br.s.,1H),8.64(s,1H),8.47(t,J=2.0Hz,1H),8.33(d,J=4.4Hz,1H),8.20-8.27(m,3H),7.89(dd,J=3.2,2.2Hz,1H),7.42-7.51(m,2H),6.76(dd,J=3.2,1.7Hz,1H),2.88(q,J=7.3Hz,2H),1.09(t,J=7.3Hz,3H).MS(M+1)：506.棕色固體。
化合物5-34
2-((1-(1-(4-氟苯基)-4-(5-硝基噻吩-2-甲醯胺基)-1H-吡唑並[3,4-d]嘧啶-6-基)-1H-吡唑-3-基)氧基)L-纈胺酸乙酯2,2,2-三氟乙酸酯(2-((1-(1-(4-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrazol-3-yl)oxy)ethyl L-valinate 2,2,2-trifluoroacetate)
1H NMR(400MHz,DMSO-d6)：δ 8.64(d,J=2.9Hz,1H),8.59(s,1H),8.38(d,J=4.4Hz,1H),8.18-8.32(m,3H),7.36-7.55(m,2H),6.24(d,J=2.9Hz,1H),4.62-4.79(m,1H),4.45-4.60(m,3H),4.01(d,J=4.4Hz,1H),2.16(dq,J=11.5,6.9Hz,1H),0.99(d,J=6.8Hz,3H),0.95(d,J=6.8Hz,3H).MS(M+1)：610.黃色固體粉末。
化合物5-35
(S)-2-胺基-4-(2-((1-(1-(4-氟苯基)-4-(5-硝基噻吩-2-甲醯胺基))-1H-吡唑並[3,4-d]嘧啶-6-基)-1H-吡唑-3-基)氧基)乙氧基)-4-氧代丁酸((S)-2-amino-4-(2-((1-(1-(4-fluorophenyl)-4-(5-nitrothiophene-2-carboxamido)-1H-p
yrazolo[3,4-d]pyrimidin-6-yl)-1H-pyrazol-3-yl)oxy)ethoxy)-4-oxobutanoic acid)與2,2,2-三氟乙酸(2,2,2-trifluoroacetic acid)之化合物(1：1)
1H NMR(400MHz,DMSO-d6)：δ 8.63(d,J=2.9Hz,1H),8.58(s,1H),8.39(d,J=4.4Hz,1H),8.21-8.31(m,3H),7.46(t,J=9.0Hz,2H),6.27(d,J=2.9Hz,1H),4.41-4.54(m,4H),3.94(t,J=5.4Hz,1H),2.93(dd,J=17.1,4.9Hz,1H),2.81(dd,J=17.1,6.8Hz,1H).MS(M+1)：626.黃色固體粉末。
化合物5-36
N-(6-(3-乙醯基-1H-吡咯-1-基)-1-(3-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(3-acetyl-1H-pyrrol-1-yl)-1-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.13(br.s.,1H),8.65(s,1H),8.48(t,J=2.0Hz,1H),8.34(d,J=4.4Hz,1H),8.26(d,J=4.4Hz,1H),8.17(dd,J=8.3,1.5Hz,1H),8.04(dt,J=10.8,2.2Hz,1H),7.88(dd,J=3.2,2.2Hz,1H),7.69(td,J=8.3,6.8Hz,1H),7.27(td,J=8.4,2.2Hz,1H),6.76(dd,J=3.2,1.7Hz,1H),2.46(s,3H).MS(M+1)：492.亮棕色粉末。
表6
化合物6-1
N-(1-(3-氟苯基)-6-(2-氧代-1,2,3,4-四氫喹啉-7-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(1-(3-fluorophenyl)-6-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.07(br.s.,1H),10.41(s,1H),8.62(s,1H),8.37(d,J=4.4Hz,1H),8.31(dd,J=8.1,1.2Hz,1H),8.25(d,J=4.4Hz,1H),8.08-8.19(m,2H),8.04(d,J=1.5Hz,1H),7.69(td,J=8.3,6.4Hz,1H),7.38(d,J=8.3Hz,1H),7.28(td,J=8.3,2.4Hz,1H),2.98(t,J=7.6Hz,2H),2.52(t,J=7.6Hz,2H).MS(M+1)：530.黃色固體。
化合物6-2
N-(1-(4-氟苯基)-6-(咪唑並[1,2-a]吡啶-6-基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺
(N-(1-(4-fluorophenyl)-6-(imidazo[1,2-a]pyridin-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.07(br.s.,1H),9.59(s,1H),8.61(s,1H),8.36(d,J=4.4Hz,1H),8.23-8.33(m,4H),8.17(s,1H),7.72(d,J=9.3Hz,1H),7.68(d,J=1.5Hz,1H),7.43-7.52(m,2H).MS(M+1)：501.黃色固體。
化合物6-3
N-(6-(苯並[d]噁唑-6-基)-1-(4-氟苯基)-1H-吡唑並[3,4-d]嘧啶-4-基)-5-硝基噻吩-2-甲醯胺(N-(6-(benzo[d]oxazol-6-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6)：δ 12.00(br.s.,1H),8.90(s,1H),8.81(d,J=1.0Hz,1H),8.57-8.68(m,2H),8.23-8.42(m,4H),7.97(d,J=8.3Hz,1H),7.39-7.58(m,2H).MS(M+1)：502.黃色固體。
表7中顯示式(I)的示例性化合物的體外活性。結果表明本發明之化合物確實具有抑制各種腫瘤細胞生長的功效。
表7
本說明書中揭露的所有特徵可以以任何組合結合。本說明書中揭露的每個特徵可以由具有相同、等同或相似目的的替代特徵取代。因此，除非另有明確說明，否則所揭露的每個特徵僅是一通用系列等同或相似特徵的示例。
此外，根據上文描述，本領域技術人員可以輕易地確定本發明的基本特徵，並且在不脫離本發明的精神及範圍的情況下，可以對本揭露進行各種變化和修改以使其適應各種用途和條件。因此，其他實施例也在本申請專利範圍之內。
Claims (26)
- 一種式(I)化合物：
或其立體異構物、互變異構物或其藥學上可接受之鹽類，其中，R1為芳基或雜芳基，其中芳基和雜芳基各自選擇性地被一至三個選自由鹵素、氰基、烷基和選擇性地被烷氧基取代之烷氧基所組成之群組之基團取代；R2為芳基、雜芳基、與雜環烷基稠合之芳基、與雜芳基稠合之芳基或與雜芳基稠合之雜芳基，其中芳基、雜芳基、與雜環烷基稠合之芳基、與雜芳基稠合之芳基或與雜芳基稠合之雜芳基各自選擇性地被一至三個選自由鹵素、烷基、烷氧基、氰基、羥基、-NRaRb、-C(=O)NRaRb、-C(=O)ORc、-C(=O)Rd和氧基所組成之群組之基團取代，其中烷氧基選擇性地被烷氧基、羥基、磷酸基團或-OC(=O)Re取代，且烷基選擇性地被羥基或烷氧基中之至少一種取代；Ra和Rb各自獨立為H、烷基或烷氧基；Rc為H或選擇性地被羥基或烷氧基中之至少一種取代之烷基；Rd為烷基；以及Re為選擇性地被胺基或羧基中之至少一種取代之烷基。 - 如請求項1所述之化合物，其中，R1為苯基或噻吩基，且苯基或噻吩基各自選擇性地被一至三個選自由鹵素、氰基、烷基和選擇性地被烷氧基取代之烷氧基所組成之群組之基團取代。
- 如請求項2所述之化合物，其中，R1為選擇性地被一或兩個選自由鹵素、氰基、烷基和選擇性地被烷氧基取代之烷氧基所組成之群組之基團取代之苯基。
- 如請求項2所述之化合物，其中，R1為選擇性地被烷基或氰基取代之噻吩基。
- 如請求項1所述之化合物，其中，R2為，X1為N或C，X2為N或C，且R3和R4各自獨立地選自由氫、鹵素、烷基、烷氧基、氰基、羥基、-NRaRb、-C(=O)NRaRb、-C(=O)ORc、-C(=O)Rd和氧基所組成之群組，其中烷氧基選擇性地被烷氧基、羥基、磷酸基團或-OC(=O)Re取代，且烷基選擇性地被羥基或烷氧基取代；或R3和R4與其間的原子一起形成雜環，其選擇性地被一或兩個選自由鹵素、氧基或選擇性地被羥基或烷氧基取代之烷基所組成之群組之基團取代；或R3和R4與其間的原子一起形成雜芳環，其選擇性地被烷氧基或烷基取代，其中烷氧基選擇性地被烷氧基取代，烷基選擇性地被羥基或烷氧基取代。
- 如請求項5所述之化合物，其中，R2為，X1為N或C。
- 如請求項6所述之化合物，其中，R2為。
- 如請求項7所述之化合物，其中，R3和R4各自獨立為烷氧基或氰基。
- 如請求項8所述之化合物，其中，R1為被鹵素取代之苯基。
- 如請求項5所述之化合物，其中，R2為選擇性地被一或兩個選自由鹵素和選擇性地被羥基取代之烷基所組成之群組之基團取代之苯並二氧 雜環戊烯基；選擇性地被氧基取代之四氫喹啉基；選擇性地被烷基取代之苯並噁唑基，其中烷基選擇性地被烷氧基取代；苯並噻吩基；選擇性地被烷基或烷氧基取代之苯並噻唑基，其中烷氧基選擇性地被烷氧基取代；或咪唑並吡啶基。
- 如請求項1所述之化合物，其中，R2為、
、
或
，R5各自為氫、鹵素、烷基、烷氧基、氰基、羥基、-NRaRb、-C(=O)NRaRb、-C(=O)ORc或-C(=O)Rd，其中烷氧基選擇性地被烷氧基、羥基、磷酸基團或-OC(=O)Re取代，且烷基選擇性地被羥基或烷氧基取代。
- 如請求項11所述之化合物，其中，R2為、
、
- 如請求項12所述之化合物，其中，R2為、
- 如請求項13所述之化合物，其中，R5各自為氰基、-C(=O)ORc或選擇性地被羥基取代之烷氧基，其中Rc為烷基。
- 如請求項1所述之化合物，其中，R2為，R5為-C(=O)ORc，且Rc為烷基。
- 如請求項15所述之化合物，其中，R1為被氰基取代之苯基。
- 如請求項1所述之化合物，其中，R2為，且R5為氰基。
- 如請求項17所述之化合物，其中，R1為被F取代之苯基。
- 如請求項1所述之化合物，其中，R2為，且R5為選擇性地被羥基取代之烷氧基。
- 如請求項19所述之化合物，其中，R1為被F取代之苯基。
- 如請求項1所述之化合物，其中該化合物為選自由化合物1-1至1-25、化合物2-1至2-3、化合物3-1至3-9、化合物4-1至4-19、化合物5-1至5-36以及化合物6-1至6-3所組成之群組中之任一者。
- 如請求項1所述之化合物，其中該化合物為化合物1-8、化合物5-6、化合物5-8或化合物5-16。
- 一種醫藥組成物，包括：一如請求項1所述之化合物或其立體異構物、互變異構物或其藥學上可接受之鹽類；以及一藥學上可接受之載體。
- 一種治療癌症之方法，包括：給予一需求主體施用一有效量之如請求項1所述之化合物或其立體異構物、互變異構物或其藥學上可接受之鹽類。
- 如請求項24所述之方法，其中該癌症是選自由胃癌、結腸癌、大腸直腸癌、乳癌、肺癌、前列腺癌、膀胱癌、胰腺癌、肝癌、子宮癌、子宮頸癌、子宮內膜癌、食道癌、白血病、淋巴瘤、腎臟癌、骨肉瘤、卵巢癌、皮膚癌、小腸癌、胸腺癌、甲狀腺癌、神經系統癌、骨癌、腦癌和頭頸癌所組成之群組。
- 如請求項24所述之方法，其中該癌症為肝癌、結腸癌或肺癌。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US202263351892P | 2022-06-14 | 2022-06-14 | |
| US63/351,892 | 2022-06-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TW202400598A true TW202400598A (zh) | 2024-01-01 |
Family
ID=89191762
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW112120054A TW202400598A (zh) | 2022-06-14 | 2023-05-30 | 嘧啶醯胺化合物及其用途 |
Country Status (2)
| Country | Link |
|---|---|
| TW (1) | TW202400598A (zh) |
| WO (1) | WO2023244430A1 (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4048656A4 (en) * | 2019-10-22 | 2023-11-29 | Alphala Co., Ltd. | PYRROLAMIDE COMPOUNDS AND USE THEREOF |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006073610A2 (en) * | 2004-11-23 | 2006-07-13 | Reddy Us Therapeutics, Inc. | Novel bicyclic heterocyclic compounds, process for their preparation and compositions containing them |
| EP2250155B1 (en) * | 2008-01-09 | 2013-07-03 | Array Biopharma, Inc. | 5h-cyclopenta[d]pyrimidines as akt protein kinase inhibitors |
| EP4048656A4 (en) * | 2019-10-22 | 2023-11-29 | Alphala Co., Ltd. | PYRROLAMIDE COMPOUNDS AND USE THEREOF |
-
2023
- 2023-05-30 TW TW112120054A patent/TW202400598A/zh unknown
- 2023-05-30 WO PCT/US2023/023800 patent/WO2023244430A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2023244430A1 (en) | 2023-12-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR102589982B1 (ko) | Ｅｇｆｒ 억제제, 및 이의 제조 및 적용 | |
| ES2671354T3 (es) | Inhibidores de ADN-PK | |
| AU2015280138B2 (en) | Phosphatidylinositol 3-kinase inhibitors | |
| TWI588141B (zh) | 經取代之苄基吲唑 | |
| JP7337951B2 (ja) | 癌を治療するための窒素含有芳香族ヘテロ環アミド誘導体 | |
| ES2753386T3 (es) | Derivados de 2-hidroxi-1-{4-[(4-fenil)fenil]carbonil}piperazin-1-il}etano-1-ona y compuestos relacionados como inhibidores de sintasa de ácido graso (FASN) para el tratamiento del cáncer | |
| TWI694078B (zh) | 吡咯並三嗪類衍生物、其製備方法及其用途 | |
| CN113121575A (zh) | 一种(取代的苯基)(取代的嘧啶)胺基衍生物及其制备方法和药物用途 | |
| KR20170098865A (ko) | Egfr 조정제로서의 치환된 2-아닐리노피리미딘 유도체 | |
| CN105503827B (zh) | Egfr抑制剂及其制备方法和用途 | |
| TWI555742B (zh) | 2,3,4,6-tetra-substituted benzene-1,5-diamine derivatives, The use of medicine | |
| CN104470934B (zh) | 蛋白激酶抑制剂 | |
| WO2016011979A1 (zh) | 2，4-二取代7H-吡咯并[2，3-d]嘧啶衍生物、其制法与医药上的用途 | |
| CA3107365A1 (en) | Pyrazine compounds and uses thereof | |
| CN101119996A (zh) | 化学化合物 | |
| WO2014180182A1 (zh) | [1,2,4]三唑并[4,3-a]吡啶类衍生物，其制备方法或其在医药上的应用 | |
| CN114907341A (zh) | 吡啶并嘧啶酮类衍生物及其制备方法和用途 | |
| WO2020233669A1 (zh) | 含吲哚类衍生物抑制剂、其制备方法和应用 | |
| TW202400598A (zh) | 嘧啶醯胺化合物及其用途 | |
| TW202400601A (zh) | 作為ｐａｒｐ抑製劑的取代的三環類化合物及其用途 | |
| WO2019196720A1 (zh) | 一类精氨酸甲基转移酶抑制剂及其药物组合物和用途 | |
| TWI750855B (zh) | 嘧啶醯胺化合物及其用途 | |
| CN117957219A (zh) | 一种吡啶类衍生物及其用途 | |
| CN105541792B (zh) | 多环类pi3k抑制剂 | |
| CN113004252B (zh) | 一种芳基并咪唑类衍生物及其用途 |