JP2021512873A - Tnikを阻害するための化合物及びその医学的使用 - Google Patents
Tnikを阻害するための化合物及びその医学的使用 Download PDFInfo
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- JP2021512873A JP2021512873A JP2020542093A JP2020542093A JP2021512873A JP 2021512873 A JP2021512873 A JP 2021512873A JP 2020542093 A JP2020542093 A JP 2020542093A JP 2020542093 A JP2020542093 A JP 2020542093A JP 2021512873 A JP2021512873 A JP 2021512873A
- Authority
- JP
- Japan
- Prior art keywords
- pyrazole
- amino
- phenyl
- methylphenyl
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 276
- 230000002401 inhibitory effect Effects 0.000 title abstract description 25
- 101000662997 Homo sapiens TRAF2 and NCK-interacting protein kinase Proteins 0.000 title abstract 2
- 102100037671 TRAF2 and NCK-interacting protein kinase Human genes 0.000 title abstract 2
- 239000000203 mixture Substances 0.000 claims abstract description 87
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 66
- 150000003839 salts Chemical class 0.000 claims abstract description 51
- 201000011510 cancer Diseases 0.000 claims abstract description 39
- 238000000034 method Methods 0.000 claims abstract description 31
- 239000000126 substance Substances 0.000 claims abstract description 29
- 238000011282 treatment Methods 0.000 claims abstract description 28
- 230000002265 prevention Effects 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 144
- -1 -CO 2 H Chemical group 0.000 claims description 92
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
- 229910052736 halogen Inorganic materials 0.000 claims description 27
- 150000002367 halogens Chemical class 0.000 claims description 27
- 206010009944 Colon cancer Diseases 0.000 claims description 21
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 229910052731 fluorine Inorganic materials 0.000 claims description 18
- GTCAXTIRRLKXRU-UHFFFAOYSA-N carbamic acid methyl ester Natural products COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 claims description 17
- 229960004768 irinotecan Drugs 0.000 claims description 17
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 12
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 9
- 206010017758 gastric cancer Diseases 0.000 claims description 9
- 201000011549 stomach cancer Diseases 0.000 claims description 9
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 8
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 8
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 8
- HBOJMBLYBBBTHG-UHFFFAOYSA-N 3-ethyl-4-[[5-(4-hydroxyphenyl)-1H-pyrazol-3-yl]amino]phenol Chemical compound C(C)C=1C=C(C=CC=1NC1=NNC(=C1)C1=CC=C(C=C1)O)O HBOJMBLYBBBTHG-UHFFFAOYSA-N 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 7
- 206010033128 Ovarian cancer Diseases 0.000 claims description 7
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 201000007270 liver cancer Diseases 0.000 claims description 7
- 208000014018 liver neoplasm Diseases 0.000 claims description 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 7
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 6
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 208000032839 leukemia Diseases 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 201000001441 melanoma Diseases 0.000 claims description 6
- 150000004885 piperazines Chemical class 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- VIOKFHLEBVZNKI-UHFFFAOYSA-N N-[4-[[5-(4-hydroxyphenyl)-1H-pyrazol-3-yl]amino]-3-methylphenyl]acetamide Chemical compound OC1=CC=C(C=C1)C1=CC(=NN1)NC1=C(C=C(C=C1)NC(C)=O)C VIOKFHLEBVZNKI-UHFFFAOYSA-N 0.000 claims description 4
- RHRRYPDCZNSYCF-UHFFFAOYSA-N N-[4-[[5-(4-hydroxyphenyl)-1H-pyrazol-3-yl]amino]-3-methylphenyl]methanesulfonamide Chemical compound OC1=CC=C(C=C1)C1=CC(=NN1)NC1=C(C=C(C=C1)NS(=O)(=O)C)C RHRRYPDCZNSYCF-UHFFFAOYSA-N 0.000 claims description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 4
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 4
- 229930192474 thiophene Natural products 0.000 claims description 4
- IVSXLVWZXJGYMX-UHFFFAOYSA-N 4-[[5-[3-(2-fluoro-5-methoxyphenyl)phenyl]-1H-pyrazol-3-yl]amino]-3-methylphenol Chemical compound FC1=C(C=C(C=C1)OC)C1=CC(=CC=C1)C1=CC(=NN1)NC1=C(C=C(C=C1)O)C IVSXLVWZXJGYMX-UHFFFAOYSA-N 0.000 claims description 3
- KYFYQNXANZLSIA-UHFFFAOYSA-N 4-[[5-[4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl]-1H-pyrazol-3-yl]amino]-3-methylphenol Chemical compound CC1=NNC(=C1C1=CC=C(C=C1)C1=CC(=NN1)NC1=C(C=C(C=C1)O)C)C KYFYQNXANZLSIA-UHFFFAOYSA-N 0.000 claims description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 3
- VFCVLFYRPLYRJR-UHFFFAOYSA-N N-[4-[[5-(4-fluorophenyl)-1H-pyrazol-3-yl]amino]-3-methylphenyl]methanesulfonamide Chemical compound FC1=CC=C(C=C1)C1=CC(=NN1)NC1=C(C=C(C=C1)NS(=O)(=O)C)C VFCVLFYRPLYRJR-UHFFFAOYSA-N 0.000 claims description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 3
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 2
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 2
- HMTSIHRHPDQRQZ-UHFFFAOYSA-N 3-chloro-N-[3-methyl-4-[[5-(4-pyrazol-1-ylphenyl)-1H-pyrazol-3-yl]amino]phenyl]propanamide Chemical compound N1(N=CC=C1)C1=CC=C(C=C1)C1=CC(=NN1)NC1=C(C=C(C=C1)NC(CCCl)=O)C HMTSIHRHPDQRQZ-UHFFFAOYSA-N 0.000 claims description 2
- GKIGZRIOOQHENJ-UHFFFAOYSA-N 4-[[5-(4-aminophenyl)-1H-pyrazol-3-yl]amino]-3-methoxyphenol Chemical compound NC1=CC=C(C=C1)C1=CC(=NN1)NC1=C(C=C(C=C1)O)OC GKIGZRIOOQHENJ-UHFFFAOYSA-N 0.000 claims description 2
- ZEMYEFRBTZCOLM-UHFFFAOYSA-N 4-[[5-(4-aminophenyl)-1H-pyrazol-3-yl]amino]-3-methylphenol Chemical compound NC1=CC=C(C=C1)C1=CC(=NN1)NC1=C(C=C(C=C1)O)C ZEMYEFRBTZCOLM-UHFFFAOYSA-N 0.000 claims description 2
- RUPDTKJWAFMAFM-UHFFFAOYSA-N N-[3-methyl-4-[[5-(4-pyrazol-1-ylphenyl)-1H-pyrazol-3-yl]amino]phenyl]-3-morpholin-4-ylpropanamide Chemical compound N1(N=CC=C1)C1=CC=C(C=C1)C1=CC(=NN1)NC1=C(C=C(C=C1)NC(CCN1CCOCC1)=O)C RUPDTKJWAFMAFM-UHFFFAOYSA-N 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims 6
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims 4
- SMDWEXKVAMWHGK-UHFFFAOYSA-N 1-[4-[[5-(4-bromophenyl)-1H-pyrazol-3-yl]amino]-3-methylphenyl]-3-methylurea Chemical compound BrC1=CC=C(C=C1)C1=CC(=NN1)NC1=C(C=C(C=C1)NC(=O)NC)C SMDWEXKVAMWHGK-UHFFFAOYSA-N 0.000 claims 2
- SMHLYTWREGNCEV-UHFFFAOYSA-N 1-[4-[[5-(4-methoxyphenyl)-1H-pyrazol-3-yl]amino]-3-methylphenyl]-3-methylurea Chemical compound COC1=CC=C(C=C1)C1=CC(=NN1)NC1=C(C=C(C=C1)NC(=O)NC)C SMHLYTWREGNCEV-UHFFFAOYSA-N 0.000 claims 2
- AKWKXDHRODVHCB-UHFFFAOYSA-N 2-fluoro-4-[[5-(4-hydroxyphenyl)-1H-pyrazol-3-yl]amino]-5-methylphenol Chemical compound FC1=C(C=C(C(=C1)NC1=NNC(=C1)C1=CC=C(C=C1)O)C)O AKWKXDHRODVHCB-UHFFFAOYSA-N 0.000 claims 2
- KJSXXPMGIXTGFK-UHFFFAOYSA-N 3-ethyl-4-[[5-(4-pyrazol-1-ylphenyl)-1H-pyrazol-3-yl]amino]phenol Chemical compound N1(N=CC=C1)C1=CC=C(C=C1)C1=CC(=NN1)NC1=C(C=C(C=C1)O)CC KJSXXPMGIXTGFK-UHFFFAOYSA-N 0.000 claims 2
- CNBFYEGCAWCKGK-UHFFFAOYSA-N N-[3-ethyl-4-[[5-(4-hydroxyphenyl)-1H-pyrazol-3-yl]amino]phenyl]acetamide Chemical compound C(C)C=1C=C(C=CC=1NC1=NNC(=C1)C1=CC=C(C=C1)O)NC(C)=O CNBFYEGCAWCKGK-UHFFFAOYSA-N 0.000 claims 2
- AANLZTUOVQAZMA-UHFFFAOYSA-N N-[4-[[5-(3-fluoro-4-hydroxyphenyl)-1H-pyrazol-3-yl]amino]-3-methylphenyl]methanesulfonamide Chemical compound FC=1C=C(C=CC=1O)C1=CC(=NN1)NC1=C(C=C(C=C1)NS(=O)(=O)C)C AANLZTUOVQAZMA-UHFFFAOYSA-N 0.000 claims 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 2
- LVJHRBXHOMDQHN-UHFFFAOYSA-N 1-[4-[3-(4-hydroxy-2-methylanilino)-1H-pyrazol-5-yl]phenyl]azetidin-2-one Chemical compound OC1=CC(=C(C=C1)NC1=NNC(=C1)C1=CC=C(C=C1)N1C(CC1)=O)C LVJHRBXHOMDQHN-UHFFFAOYSA-N 0.000 claims 1
- DWOMBLRWBUKFBN-UHFFFAOYSA-N 1-[4-[3-(4-hydroxy-2-methylanilino)-1H-pyrazol-5-yl]phenyl]piperidin-2-one Chemical compound OC1=CC(=C(C=C1)NC1=NNC(=C1)C1=CC=C(C=C1)N1C(CCCC1)=O)C DWOMBLRWBUKFBN-UHFFFAOYSA-N 0.000 claims 1
- ONRTWSBJIHROKJ-UHFFFAOYSA-N 1-[4-[3-(4-hydroxy-2-methylanilino)-1H-pyrazol-5-yl]phenyl]pyrrolidin-2-one Chemical compound OC1=CC(=C(C=C1)NC1=NNC(=C1)C1=CC=C(C=C1)N1C(CCC1)=O)C ONRTWSBJIHROKJ-UHFFFAOYSA-N 0.000 claims 1
- CAKDEILUYMOJDC-UHFFFAOYSA-N 1-[4-[4-fluoro-3-(4-hydroxy-2-methylanilino)-1H-pyrazol-5-yl]phenyl]pyrrolidin-2-one Chemical compound FC=1C(=NNC=1C1=CC=C(C=C1)N1C(CCC1)=O)NC1=C(C=C(C=C1)O)C CAKDEILUYMOJDC-UHFFFAOYSA-N 0.000 claims 1
- NAFRYUQVIPZCDY-UHFFFAOYSA-N 1-[4-[[4-fluoro-5-(4-pyrazol-1-ylphenyl)-1H-pyrazol-3-yl]amino]-3-methylphenyl]-3-methylurea Chemical compound N1(N=CC=C1)C1=CC=C(C=C1)C1=C(C(=NN1)NC1=C(C=C(C=C1)NC(=O)NC)C)F NAFRYUQVIPZCDY-UHFFFAOYSA-N 0.000 claims 1
- QKUFOZACPGELEU-UHFFFAOYSA-N 1-[4-[[5-(1-benzothiophen-2-yl)-1H-pyrazol-3-yl]amino]-3-methylphenyl]-3-methylurea Chemical compound S1C2=C(C=C1C1=CC(=NN1)NC1=C(C=C(C=C1)NC(=O)NC)C)C=CC=C2 QKUFOZACPGELEU-UHFFFAOYSA-N 0.000 claims 1
- SGIUFPYFDDTQEX-UHFFFAOYSA-N 1-[4-[[5-(3-fluoro-4-hydroxyphenyl)-1H-pyrazol-3-yl]amino]-3-methylphenyl]-3-methylurea Chemical compound FC=1C=C(C=CC=1O)C1=CC(=NN1)NC1=C(C=C(C=C1)NC(=O)NC)C SGIUFPYFDDTQEX-UHFFFAOYSA-N 0.000 claims 1
- NOUVMQJGEJZDNY-UHFFFAOYSA-N 1-[4-[[5-[4-(2-fluoro-5-methoxyphenyl)phenyl]-1H-pyrazol-3-yl]amino]-3-methylphenyl]-3-methylurea Chemical compound FC1=C(C=C(C=C1)OC)C1=CC=C(C=C1)C1=CC(=NN1)NC1=C(C=C(C=C1)NC(=O)NC)C NOUVMQJGEJZDNY-UHFFFAOYSA-N 0.000 claims 1
- XFFDHFAXOONDCS-UHFFFAOYSA-N 1-methyl-3-[3-methyl-4-[[5-(4-methylsulfonylphenyl)-1H-pyrazol-3-yl]amino]phenyl]urea Chemical compound CNC(=O)NC1=CC(=C(C=C1)NC1=NNC(=C1)C1=CC=C(C=C1)S(=O)(=O)C)C XFFDHFAXOONDCS-UHFFFAOYSA-N 0.000 claims 1
- SKXZVTNMCQLZMD-UHFFFAOYSA-N 1-methyl-3-[3-methyl-4-[[5-(4-pyrazol-1-ylphenyl)-1H-pyrazol-3-yl]amino]phenyl]urea Chemical compound N1(N=CC=C1)C1=CC=C(C=C1)C1=CC(=NN1)NC1=C(C=C(C=C1)NC(=O)NC)C SKXZVTNMCQLZMD-UHFFFAOYSA-N 0.000 claims 1
- GOUIKNZHVPQEHY-UHFFFAOYSA-N 1-methyl-3-[3-methyl-4-[[5-[4-(1H-pyrazol-4-yl)phenyl]-1H-pyrazol-3-yl]amino]phenyl]urea Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)C1=CC(=NN1)NC1=C(C=C(C=C1)NC(=O)NC)C GOUIKNZHVPQEHY-UHFFFAOYSA-N 0.000 claims 1
- YJNGMHWWMKCRKN-UHFFFAOYSA-N 1-methyl-3-[3-methyl-4-[[5-[4-[5-(trifluoromethyl)-1H-pyrazol-4-yl]phenyl]-1H-pyrazol-3-yl]amino]phenyl]urea Chemical compound CNC(=O)NC1=CC(=C(C=C1)NC1=NNC(=C1)C1=CC=C(C=C1)C=1C(=NNC=1)C(F)(F)F)C YJNGMHWWMKCRKN-UHFFFAOYSA-N 0.000 claims 1
- FSLHLZSZPJSMLF-UHFFFAOYSA-N 2,5-difluoro-4-[[5-(4-pyrazol-1-ylphenyl)-1H-pyrazol-3-yl]amino]phenol Chemical compound N1(N=CC=C1)C1=CC=C(C=C1)C1=CC(=NN1)NC1=CC(=C(C=C1F)O)F FSLHLZSZPJSMLF-UHFFFAOYSA-N 0.000 claims 1
- FPSFYSNUUPYYPE-UHFFFAOYSA-N 2-fluoro-4-[3-(2-fluoro-4-hydroxyanilino)-1H-pyrazol-5-yl]phenol Chemical compound FC1=C(C=CC(=C1)C1=CC(=NN1)NC1=C(C=C(C=C1)O)F)O FPSFYSNUUPYYPE-UHFFFAOYSA-N 0.000 claims 1
- NBRNMIVJHZJYNB-UHFFFAOYSA-N 2-fluoro-4-[3-(4-hydroxy-2-methylanilino)-1H-pyrazol-5-yl]phenol Chemical compound FC1=C(C=CC(=C1)C1=CC(=NN1)NC1=C(C=C(C=C1)O)C)O NBRNMIVJHZJYNB-UHFFFAOYSA-N 0.000 claims 1
- VBQGGXTUOSTGDV-UHFFFAOYSA-N 2-fluoro-4-[[5-(4-hydroxyphenyl)-1H-pyrazol-3-yl]amino]phenol Chemical compound FC1=C(C=CC(=C1)NC1=NNC(=C1)C1=CC=C(C=C1)O)O VBQGGXTUOSTGDV-UHFFFAOYSA-N 0.000 claims 1
- ZCPKBUKBYOOEPX-UHFFFAOYSA-N 2-fluoro-4-[[5-(4-imidazol-1-ylphenyl)-1H-pyrazol-3-yl]amino]phenol Chemical compound N1(C=NC=C1)C1=CC=C(C=C1)C1=CC(=NN1)NC1=CC(=C(C=C1)O)F ZCPKBUKBYOOEPX-UHFFFAOYSA-N 0.000 claims 1
- AEBZOJJOTUABMO-UHFFFAOYSA-N 2-fluoro-4-[[5-(4-pyrazol-1-ylphenyl)-1H-pyrazol-3-yl]amino]phenol Chemical compound N1(N=CC=C1)C1=CC=C(C=C1)C1=CC(=NN1)NC1=CC(=C(C=C1)O)F AEBZOJJOTUABMO-UHFFFAOYSA-N 0.000 claims 1
- ZIBSIJMARIUUMN-UHFFFAOYSA-N 2-fluoro-5-methyl-4-[[5-(4-pyrazol-1-ylphenyl)-1H-pyrazol-3-yl]amino]phenol Chemical compound N1(N=CC=C1)C1=CC=C(C=C1)C1=CC(=NN1)NC1=CC(=C(C=C1C)O)F ZIBSIJMARIUUMN-UHFFFAOYSA-N 0.000 claims 1
- RHYCDTQSYJRLMC-UHFFFAOYSA-N 2-fluoro-5-methyl-4-[[5-[4-(1H-pyrazol-4-yl)phenyl]-1H-pyrazol-3-yl]amino]phenol Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)C1=CC(=NN1)NC1=CC(=C(C=C1C)O)F RHYCDTQSYJRLMC-UHFFFAOYSA-N 0.000 claims 1
- SQFOEDDCYKXRCG-UHFFFAOYSA-N 2-methyl-N-[3-methyl-4-[[5-(4-pyrazol-1-ylphenyl)-1H-pyrazol-3-yl]amino]phenyl]propanamide Chemical compound N1(N=CC=C1)C1=CC=C(C=C1)C1=CC(=NN1)NC1=C(C=C(C=C1)NC(C(C)C)=O)C SQFOEDDCYKXRCG-UHFFFAOYSA-N 0.000 claims 1
- FJUCABFYQPQOTG-UHFFFAOYSA-N 3-chloro-4-[[5-(4-hydroxyphenyl)-1H-pyrazol-3-yl]amino]phenol Chemical compound ClC=1C=C(C=CC=1NC1=NNC(=C1)C1=CC=C(C=C1)O)O FJUCABFYQPQOTG-UHFFFAOYSA-N 0.000 claims 1
- TUIUBDGEGGHKJK-UHFFFAOYSA-N 3-chloro-4-[[5-(4-imidazol-1-ylphenyl)-1H-pyrazol-3-yl]amino]phenol Chemical compound N1(C=NC=C1)C1=CC=C(C=C1)C1=CC(=NN1)NC1=C(C=C(C=C1)O)Cl TUIUBDGEGGHKJK-UHFFFAOYSA-N 0.000 claims 1
- OVJPGIGNWARLNQ-UHFFFAOYSA-N 3-chloro-4-[[5-(4-pyrazol-1-ylphenyl)-1H-pyrazol-3-yl]amino]phenol Chemical compound N1(N=CC=C1)C1=CC=C(C=C1)C1=CC(=NN1)NC1=C(C=C(C=C1)O)Cl OVJPGIGNWARLNQ-UHFFFAOYSA-N 0.000 claims 1
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- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
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Abstract
【選択図】 図1
Description
発明が解決しようとする課題
従って、本開示の一目的は、TNIK(Traf2及びNck相互作用キナーゼ)の阻害活性を有する化合物、その化合物を有効剤として含む医薬組成物、及び癌を治療又は予防するためのその医学的使用を提供することである。
発明の概要
上述の目的を達成するため、一実施形態では、下記化学式1で表される化合物、又はその薬学的に許容される塩が提供される。
YはN又はCHであり、
ZはN又はC−Vであり、
AはH、ハロゲン、−OH、−CO2−C1−6アルキル、−CO2H、−CN、−C1−6アルキル、−C1−6ハロアルキル、−OR1、−NH2、−NHR2、置換又は非置換ピペラジン、−NHSO2R3、−NHCO2−C1−6アルキル、−NHCON−C1−6アルキル又は−NHCOR4であり、
BはH、−C1−6ハロアルキル、C1−6アルキル、ハロゲン又はC1−6アルコキシであり、
VはH、−CH2OH、ハロゲン、−CO2H、−CO2−C1−6アルキル、−OH、−NH2、フェノキシ又は−NHCO−C1−6アルキルであり、
XはH又はFであり、
Wは置換又は非置換の芳香環、ヘテロアリール又は縮合ヘテロアリールであって、
R1はC1−6アルキル、ベンジル、C1−6ハロアルキル又はフェニルであり、
R2はC1−6アルキル、C1−6ハロアルキル、−CH2CH2−モルホリン又はフェニルであり、
R3はC1−6アルキル、C1−6ハロアルキル、又は置換又は非置換フェニルであり、
R4はC1−6アルキル、C1−6ハロアルキル、−CH2CH2Cl、−CH2CH2NMe2、−CH2NMe2又は−CH2CH2−モルホリンである。)
以下の説明は本質的に単なる例示であり、本開示、用途又は使用を限定することを意図していない。
本開示で使用される一般用語を本明細書で定義して明確にする。
下記化学式1で表される化合物、又はその薬学的に許容される塩が提供される。
YはN又はCHであり、
ZはN又はC−Vであり、
AはH、ハロゲン、−OH、−CO2−C1−6アルキル、−CO2H、−CN、−C1−6アルキル、−C1−6ハロアルキル、−OR1、−NH2、−NHR2、置換又は非置換ピペラジン、−NHSO2R3、−NHCO2−C1−6アルキル、−NHCON−C1−6アルキル又は−NHCOR4であり、
BはH、−C1−6ハロアルキル、C1−6アルキル、ハロゲン又はC1−6アルコキシであり、
VはH、−CH2OH、ハロゲン、−CO2H、−CO2−C1−6アルキル、−OH、−NH2、フェノキシ又は−NHCO−C1−6アルキルであり、
XはH又はFであり、
Wは置換又は非置換の芳香環、ヘテロアリール又は縮合ヘテロアリールであって、
R1はC1−6アルキル、ベンジル、C1−6ハロアルキル又はフェニルであり、
R2はC1−6アルキル、C1−6ハロアルキル、−CH2CH2−モルホリン又はフェニルであり、
R3はC1−6アルキル、C1−6ハロアルキル、又は置換又は非置換フェニルであり、
R4はC1−6アルキル、C1−6ハロアルキル、−CH2CH2Cl、−CH2CH2NMe2、−CH2NMe2又は−CH2CH2−モルホリンである。)
YはN又はCHであり、
ZはN又はC−Vであり、
AはH、ハロゲン、−OH、−CO2−C1−3アルキル、−CO2H、−CN、−C1−3アルキル、−OR1、−NH2、−NHR2、置換又は非置換ピペラジン、−NHSO2R3、−NHCO2−C1−6アルキル、−NHCON−C1−6アルキル又は−NHCOR4であり、
BはH、−C1−3ハロアルキル、C1−3アルキル、ハロゲン又はC1−3アルコキシであり、
VはH、−CH2OH、ハロゲン、−CO2H、−CO2−C1−3アルキル、−OH、−NH2、フェノキシ又は−NHCO−C1−3アルキルであり、
XはH又はFであり、
Wは置換又は非置換のフェニル、ピリジル、チオフェン、チアゾール、ピロール、ベンゾチオフェン、インドール、オキサゾール、ピラゾール、イミダゾール、ピリミジン、ベンゾピラゾール、ベンゾチアゾール、ベンゾオキサゾール、ベンゾイミダゾール又はベンゾチオフェンであって、
R1はベンジル、C1−3ハロアルキル又はフェニルであり、
R2はCF3、C1−3アルキル、−CH2CH2−モルホリン又はフェニルであり、
R3はC1−3アルキル、又は置換又は非置換フェニルであり、
R4はC1−3アルキル、CF3、−CH2CH2Cl、−CH2CH2NMe2、−CH2NMe2又は−CH2CH2−モルホリンである。
YはN又はCHであり、
ZはC−Vであり、
Aは−OH、−CO2−C1−2アルキル、−メチル、−OR1、−NH2、−NHR2、置換又は非置換ピペラジン、−NHSO2R3、−NHCO2−C1−6アルキル、−NHCON−C1−6アルキル又は−NHCOR4であり、
BはH、−C1−3ハロアルキル、C1−3アルキル、ハロゲン又はC1−3アルコキシであり、
VはH、−CH2OH、F、−CO2H、−CO2−C1−2アルキル、−OH、−NH2、フェノキシ又は−NHCOCH3であり、
XはH又はFであり、
Wは置換又は非置換のフェニル、ピリジル、チオフェン、チアゾール、ピロール、ベンゾチオフェン又はインドールであって、
R1はベンジル、CF3又はフェニルであり、
R2はCF3、C1−3アルキル、−CH2CH2−モルホリン又はフェニルであり、
R3はC1−3アルキル、又は置換又は非置換フェニルであり、
R4はC1−3アルキル、CF3、−CH2CH2Cl、−CH2CH2NMe2、−CH2NMe2又は−CH2CH2−モルホリンである。
YはCHであり、
ZはC−Vであり、
Aは−OH、−NHR2、−NHSO2R3、−NHCO2−C1−6アルキル、−NHCON−C1−6アルキル又は−NHCOR4であり、
BはH、−C1−3ハロアルキル、C1−3アルキル、ハロゲン又はC1−3アルコキシであり、
VはH、−CH2OH、F、−OH又は−NHCOCH3であり、
XはH又はFであり、
Wは、下記式:
R2はCF3、C1−3アルキル、−CH2CH2−モルホリン又はフェニルであり、
R3はC1−3アルキル、又は置換又は非置換フェニルであり、
R4はC1−3アルキル、CF3、−CH2CH2Cl、−CH2CH2NMe2、−CH2NMe2又は−CH2CH2−モルホリンである。
YはCHであり、
ZはC−Vであり、
Aは−OH、−NHR2、−NHSO2R3、−NHCO2−C1−6アルキル、−NHCON−C1−6アルキル又は−NHCOR4であり、
BはH、−C1−3ハロアルキル、C1−3アルキル、ハロゲン又はC1−3アルコキシであり、
VはH、F、−OH又は−NHCOCH3であり、
XはH又はFであり、
Wは下記式:
R2はCF3又はC1−3アルキルであり、
R3はC1−3アルキルであり、
R4はC1−3アルキル、CF3、−CH2CH2Cl、−CH2CH2NMe2、−CH2NMe2又は−CH2CH2−モルホリンである。
YはCHであり、
ZはC−Vであり、
Aは−OH、−NHCF3、−NHSO2R3、−NHCO2−C1−6アルキル、−NHCON−C1−6アルキル又は−NHCOR4であり、
BはC1−3アルキル又はハロゲンであり、
VはH又はFであり、
XはH又はFであり、
Wは下記式:
R3はC1−3アルキルであり、
R4はC1−3アルキル、CF3、−CH2CH2Cl、−CH2CH2NMe2、−CH2NMe2又は−CH2CH2−モルホリンである。
本開示は更に、上述の1種以上の化合物の治療有効量を対象に投与することによって、疾患又は病態を有するか又は罹患し易い対象においてその疾患又は病態を治療するための方法を提供する。一実施形態では、治療は予防的治療である。他の実施形態では、治療は緩和治療である。他の実施形態では、治療は回復治療である。
TNIK活性を阻害するための本開示の化合物は、様々な病態の治療又は予防(例えば、抗腫瘍)に有用である。この化合物を使用して、TNIK活性を阻害又は妨害、腫瘍又は癌を治療、又はそのような疾患の悪化を予防することができる。従って、本開示は、細胞におけるTNIK活性を阻害又は妨害するための方法であって、この細胞を本開示の化合物の有効量と接触させる方法を提供する。一実施形態では、このような細胞は対象(例えば、癌患者)に存在する。他の実施形態では、対象において癌を治療するか又は腫瘍の増殖を防止するための本開示による化合物の医学的使用が提供される。本開示の方法は、治療有効量又は予防的有効量のTNIK阻害剤を含む医薬組成物を治療又は予防を必要とする対象に投与することを含む。
本開示に従って治療される適切な対象としては哺乳動物対象が挙げられる。本開示に係る哺乳動物としては、ヒト、イヌ、ネコ、ウシ、ヤギ、ウマ、ヒツジ、ブタ、齧歯類、ウサギ、霊長類等が挙げられるが、これらに限定されず、子宮内の哺乳動物も包含する。対象はいずれの性別でもよく、どの発育段階でもよい。
本開示の化合物は一般に治療有効量にて投与する。
上述の疾患又は病態の治療のために、本明細書に記載の化合物又はその薬学的に許容される塩は以下のように投与することができる。
本開示の化合物は、経口投与(例えば、嚥下による投与)を行って、化合物が胃腸管に入るように、又は口から直接血流に吸収されるようにすることができる(例えば、頬側投与又は舌下投与)。
本開示の化合物は、血流、筋肉又は内臓に直接投与することができる。非経口投与に適した手段としては、静脈内、筋肉内、皮下動脈内、腹腔内、くも膜下腔内、頭蓋内等が挙げられる。非経口投与に適した装置としては、注射器(例えば、有針注射器や無針注射器)及び輸注方法が挙げられる。
本開示の化合物は、皮膚に対する局所的な投与又は経皮的な投与を行うことができる。この局所投与のための製剤としては、ローション、溶液、クリーム、ゲル、ヒドロゲル、軟膏、フォーム、インプラント、パッチ等を挙げることができる。局所投与製剤用の薬学的に許容される担体としては、水、アルコール、鉱油、グリセリン、ポリエチレングリコール等を挙げることができる。局所投与は、電気穿孔、イオン泳動、フォノフォレシス等によって行うこともできる。
疾患又は病態を治療又は予防するための医薬組成物を調製する方法は、本開示が関連する技術分野で周知である。例えば、Handbook of Pharmaceutical Excipients (7th ed.), Remington: The Science and Practice of Pharmacy (20th ed.)、Encyclopedia of Pharmaceutical Technology (3rd ed.)、又はSustained and Controlled Release Drug Delivery Systems (1978)に基づき、薬学的に許容される賦形剤、担体、添加剤等を選択した後、本開示の化合物と混合して、医薬組成物を調製することができる。
本開示の化合物は単独で使用するか、又は他の薬学的活性化合物と併用して上述のよう病態を治療することができる。本発明の化合物と他の薬学的活性化合物は(同一剤形又は別々の剤形で)同時に投与するか又は逐次的に投与することができる。従って、一実施形態では、本開示は、本開示の1種以上の化合物と1種以上の更なる薬学的活性化合物の治療有効量を対象に投与して病態を治療するための方法を包含する。
本開示は、TNIK活性を阻害することによって様々な薬理学的効果を有する化合物、この化合物を有効な剤として含む医薬組成物、この化合物の(特に癌を治療するための)医学的使用、及び治療又は予防を必要とする対象にこの化合物を投与することを含む治療又は予防方法を提供する。本開示の化合物及びその薬学的に許容される塩は、TNIKに対して良好な安全性と高い選択性を有し、従って、薬物として優れた特性を示す。
以下使用する試薬と溶媒は、Aldrich Chemical Co.(米国、ウィスコンシン州ミルウォーキー)から購入した。1H−NMRスペクトルは、Bruker Avance 300MHz、Bruker Avance III HD 300MHz、Bruker Avance 500MHz NMR分光計等で評価した。
段階1.(4−ニトロフェニル)(フェニル)カルバミン酸tert−ブチル
段階1.4−フルオロ−N−(4−ニトロフェニル)ベンゼンスルホンアミド
段階1.N−(3−メチル−4−ニトロフェニル)メタンスルホンアミド
段階1.N−(3−メチル−4−ニトロフェニル)アセトアミド
段階1.2,2,2−トリフルオロ−N−(3−メチル−4−ニトロフェニル)アセトアミド
段階1.1−(4−アミノ−3−メチルフェニル)−3−メチル尿素
段階1.3−メチル−N1−(2−モルホリノエチル)ベンゼン−1,4−ジアミン
段階1.1−(4−(4−アミノ−3−メチルフェニル)ピペラジン−1−イル)エタン−1−オン
段階1.5−(4−(ベンジルオキシ)フェニル)−N−(2−メチル−4−(ピペラジン−1−イル)フェニル)−1H−ピラゾール−3−アミン
段階1.3,3−ビス(メチルチオ)−1−(4−ニトロフェニル)プロパ−2−エン−1−オン
段階1.アセチル(3−アセチルフェニル)カルバミン酸tert−ブチル
段階1.4−(3,3−ビス(メチルチオ)アクリロイル)安息香酸メチル
段階1.(4−メチル−3−((5−(4−ニトロフェニル)−1H−ピラゾール−3−イル)アミノ)フェニル)メタノール
段階1.1−(4−(1H−ピラゾール−1−イル)フェニル)エタン−1−オン
段階1.(5−(4−(1H−ピラゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)(2−メチル−4−(3−モルホリノプロパンアミド)フェニル)カルバミン酸tert−ブチル
段階1.1−(2’−フルオロ−5’−メトキシ−[1,1’−ビフェニル]−3−イル)−3,3−ビス(メチルチオ)プロパ−2−エン−1−オン
段階1.2−フルオロ−5−メチル−4−ニトロフェノール
段階1.3−((tert−ブトキシカルボニル)(4−ヒドロキシ−2−メチルフェニル)アミノ)−5−(4−(3,5−ジメチル−1H−ピラゾール−4−イル)フェニル)−1H−ピラゾール−1−カルボン酸tert−ブチル
段階1.(3−メチル−4−ニトロフェニル)カルバミン酸メチル
1.TNIK活性阻害の有効性、qPCRを使用したインビトロTNIKキナーゼアッセイ
複数のキナーゼ標識T7ファージ株をBL21株由来大腸菌宿主中で並行して増殖させた。大腸菌を対数期まで増殖させ、凍結ストック由来のT7ファージに感染させ(感染多重度=0.4)、32℃で振盪させながらインキュベートし、これを細胞が溶解するまで行った(90〜150分)。溶菌液を遠心分離(6000×g)し、濾過(0.2μm)して細胞片を除去した。残りのキナーゼをHEK−293細胞で生成させた後、qPCR検出用DNAで標識した。ストレプトアビジン被覆磁気ビーズをビオチン化小分子リガンドで室温にて30分間処理し、キナーゼアッセイ用アフィニティー樹脂を得た。リガンドが結合したビーズを過剰なビオチンでブロックし、ブロッキング緩衝液(SeaBlock(Pierce社)、1%BSA、0.05%Tween20、1mM DTT)で洗浄して、未結合のリガンドを除去し、非特異的なファージ結合を減らした。結合反応は、1×結合緩衝液(20%SeaBlock、0.17×PBS、0.05%Tween20、6mM DTT)中でキナーゼ、リガンド結合アフィニティービーズ及び試験化合物を組み合わせて行った。試験化合物は100%DMSOで40×ストックとして調製し、アッセイに向けて直接希釈した。全ての反応はポリプロピレン384ウェルプレート(最終体積:0.04mL)で行った。
化合物の阻害特性は、TNIKキナーゼ酵素システムと発光ADP−Glo(商標)キナーゼアッセイ(Promega Corporation)を用い、製造元のプロトコルに従って評価した。試験化合物をTNIKキナーゼと共にインキュベートした。反応は、2μLのATP、2μLのMBPタンパク質及び2μLのTNIKを含む反応混合物を補充した10μLのキナーゼ緩衝液中で37℃にて30分間行った。反応条件を表5に示す。キナーゼ反応後、5μLの反応混合物を384ウェルアッセイプレート(Greiner社、固体白色低結合プレート)に移した。次に、5μLのADP−Glo試薬を各ウェルに添加し、37℃で30分間インキュベートした。45分後、10μLのキナーゼ検出試薬を各ウェルに添加し、37℃で30分間インキュベートした後、SpectraMax M5eマイクロプレートリーダー(Molecular Devices社、カリフォルニア州メンロパーク)で発光シグナルを検出した。GraphPad Prismソフトウェア(GraphPad Software Inc.、米国カリフォルニア州ラホーヤ)を使用してIC50値を計算し、キットの性能を確認した。カットオフアッセイでは、TNIKキナーゼに対する化合物の阻害活性を、阻害剤の指示濃度に対するキナーゼ阻害活性の割合で表した。TNIKキナーゼ値に対する化合物のIC50は、4パラメータロジスティック方程式を当てはめた対数濃度反応曲線で計算し、化合物濃度の対数に対する阻害活性の割合(%)の用量反応曲線で表した。
1)細胞培養
ヒト大腸癌細胞株SW480(カタログ番号CCL−228)とSW620(カタログ番号CCL−227)をAmerican Type Culture Collection(ATCC)から入手し、10%ウシ胎児血清(FBS)(Thermo Fisher Scientific Inc.、マサチューセッツ州ウォルサム)、100U/mLペニシリン及び100μg/mLストレプトマイシン(Gibco社、メリーランド州ゲイサーズバーグ)を補充したDMEM(Thermo Fisher Scientific Inc.、米国マサチューセッツ州ウォルサム)中で保持した。細胞がコンフルエントになるまで、37℃、5%CO2で増殖させた。
細胞生存率はCell Counting Kit−8(Dojindo Molecular Technologies社)を用いて測定した。SW480細胞とSW620細胞(2.5×104個/ウェル)を96ウェルプレートに播種し、24時間インキュベートした。インキュベーション後、100μLのフェノールを含まない0.1%FBS含有DMEM培地中で段階希釈した化合物(0.1、0.3、1、3、10及び30μM)に細胞を曝露した。48時間後、CCK−8試薬を添加し(10μL/ウェル)、37℃で1時間インキュベートした。マイクロプレートリーダー(Bio−Rad Laboratories社、カリフォルニア州ハーキュリーズ)を使用して450nmで光学密度を測定した。GraphPad Prismソフトウェア(GraphPad Software Inc.、米国カリフォルニア州ラホーヤ)を使用してIC50値を計算し、キットの性能を確認した。実験は3回行った。
1)細胞培養
CHO−K1(KCLB no.10061)細胞を、T75フラスコの10%FBS(Gibco社)と1%ペニシリン/ストレプトマイシン(Gibco社)を含むRPMI培地(Gibco社)で培養(37℃、5%CO2)した。培養物をDPBS(ダルベッコリン酸緩衝食塩水、Gibco社)で洗浄し、2mLの0.05%トリプシン−EDTA(トリプシン−EDTA、Gibco社)を添加し、1分間培養した。次に、細胞懸濁液を1500rpmで2分間遠心分離し、細胞ペレットを得て次の段階に備えた。
培養したCHO−K1細胞を細胞培養液で希釈して4×104個(細胞)/cm2とし、培養プレートに播種した。プレートを5%CO2の条件で37℃にて一晩培養した。翌日、レポーター遺伝子のトランスフェクションを以下のように行った。1.35μgのレポーターDNA(M50 Super 8XTOPFlash、no.12456、Addgene社)とリポフェクタミン2000(Lipofectamine 2000試薬、no.11668、Invitrogen社)をOpti−MEM培地(Gibco社)で希釈し、これらの試薬のプロトコルに従ってトランスフェクション用の溶液を調製した。一晩の培養により付着したCHO−K1細胞の細胞培地を、FBSとペニシリン/ストレプトマイシンを含まないRPMI培地と交換した。次に、溶液を用いて細胞をトランスフェクトし、5時間培養した(37℃、5%CO2)。その後、トランスフェクトした細胞を1%FBSと1%ペニシリン/ストレプトマイシンを含むRPMI培地で一晩培養し、トランスフェクトした細胞を安定化させた。安定化したCHO−K1細胞を1%FBSを含むRPMI培地で希釈し、96ウェルプレートに2.5×104個(細胞)となるように播種した。プレートを一晩培養して細胞を付着させた。翌日、付着した細胞を使用してレポーター活性と細胞毒性を評価した。
試験化合物のDMSO溶液を1%FBSを含む培地で希釈して、試験濃度の10倍濃度の溶液を調製した。これらの溶液の0.1容量をトランスフェクトしたCHO−K1細胞に添加し、37℃、5%CO2で一晩培養した。翌日、40μg/mLの組換えWnt3aタンパク質(マウス組換えWnt3a、no.1324−WN、R&Dsystems社)を、1%FBSを含むRPMI培地で200ng/mLに希釈した。0.1容量の希釈Wnt3aタンパク質溶液を、試験化合物を含むCHO−K1細胞に添加した。次に、CHO−K1細胞を更に7時間培養した(37℃、5%CO2)。
ルシフェラーゼアッセイシステム(no.E1960、Promega社)を使用した。細胞内のルシフェラーゼ活性は、マイクロプレートリーダー(SpectraMax M5e Multi−Mod Microplate Reader、Molecular Devices社)によって測定した。発光値を細胞生存率に対して規格化し、試験化合物なしでWnt3aによって刺激された細胞の発光強度(100%)と試験化合物もWnt3a刺激もない場合の細胞の発光強度(0%)の両方に基づいて試験化合物のIC50値を計算した。
試験化合物のDMSO溶液を1%FBS含有培地で希釈して、試験濃度の10倍濃度の溶液を調製した。これらの溶液の0.1容量をトランスフェクトしたCHO−K1細胞に添加し、37℃、5%CO2で一晩培養した。翌日、40μg/mLの組換えWnt3aタンパク質(マウス組換えWnt3a、no.1324−WN、R&Dsystems社)を、1%FBSを含むRPMI培地で200ng/mLに希釈した。0.1容量の希釈Wnt3aタンパク質溶液を、試験化合物を含むCHO−K1細胞に添加した。次に、CHO−K1細胞を更に7時間培養した(37℃、5%CO2)。その後、10μLのCCK−8溶液(Cell Counting Kit−8、Dojindo Molecular Technologies社)を添加し、1時間培養した(37℃、5%CO2)。次に、ウェル内の細胞生存率をマイクロプレートリーダー(SpectraMax M5e Multi−Mod Microplate Reader、Molecular Devices社)によって450nmで測定した。決定した細胞生存率を使用してルシフェラーゼ活性を規格化した。
試験5−1
ヒト由来の結腸直腸癌細胞であるSW620細胞を移植した雄性ヌードマウスを使用した。試験化合物を数回投与し、試験化合物による腫瘍の阻害効果を評価した。
本発明の化合物を投与した後の腫瘍の増殖を阻害する効果を評価した。ヒト由来の結腸直腸癌細胞SW620を移植した雄性ヌードマウスに試験化合物を繰り返し投与した。
Claims (17)
- 下記化学式1で表される化合物、又はその薬学的に許容される塩。
YはN又はCHであり、
ZはN又はC−Vであり、
AはH、ハロゲン、−OH、−CO2−C1−6アルキル、−CO2H、−CN、−C1−6アルキル、−C1−6ハロアルキル、−OR1、−NH2、−NHR2、置換又は非置換ピペラジン、−NHSO2R3、−NHCO2−C1−6アルキル、−NHCON−C1−6アルキル又は−NHCOであり、
BはH、−C1−6ハロアルキル、C1−6アルキル、ハロゲン又はC1−6アルコキシであり、
VはH、−CH2OH、ハロゲン、−CO2H、−CO2−C1−6アルキル、−OH、−NH2、フェノキシ又は−NHCO−C1−6アルキルであり、
XはH又はFであり、
Wは置換又は非置換の芳香環、ヘテロアリール又は縮合ヘテロアリールであって、
R1はC1−6アルキル、ベンジル、C1−6ハロアルキル又はフェニルであり、
R2はC1−6アルキル、C1−6ハロアルキル、−CH2CH2−モルホリン又はフェニルであり、
R3はC1−6アルキル、C1−6ハロアルキル、又は置換又は非置換フェニルであり、
R4はC1−6アルキル、C1−6ハロアルキル、−CH2CH2Cl、−CH2CH2NMe2、−CH2NMe2又は−CH2CH2−モルホリンである。) - 前記化学式1中、
YはN又はCHであり、
ZはN又はC−Vであり、
AはH、ハロゲン、−OH、−CO2−C1−3アルキル、−CO2H、−CN、−C1−3アルキル、−OR1、−NH2、−NHR2、置換又は非置換ピペラジン、−NHSO2R3、−NHCO2−C1−6アルキル、−NHCON−C1−6アルキル又は−NHCOR4であり、
BはH、−C1−3ハロアルキル、C1−3アルキル、ハロゲン又はC1−3アルコキシであり、
VはH、−CH2OH、ハロゲン、−CO2H、−CO2−C1−3アルキル、−OH、−NH2、フェノキシ又は−NHCO−C1−3アルキルであり、
XはH又はFであり、
Wは置換又は非置換のフェニル、ピリジル、チオフェン、チアゾール、ピロール、ベンゾチオフェン、インドール、オキサゾール、ピラゾール、イミダゾール、ピリミジン、ベンゾピラゾール、ベンゾチアゾール、ベンゾオキサゾール、ベンゾイミダゾール又はベンゾチオフェンであって、
R1はベンジル、C1−3ハロアルキル又はフェニルであり、
R2はCF3、C1−3アルキル、−CH2CH2−モルホリン又はフェニルであり、
R3はC1−3アルキル、又は置換又は非置換フェニルであり、
R4はC1−3アルキル、CF3、−CH2CH2Cl、−CH2CH2NMe2、−CH2NMe2又は−CH2CH2−モルホリンである、請求項1に記載の化合物。 - 前記化学式1中、
YはN又はCHであり、
ZはC−Vであり、
Aは−OH、−CO2−C1−2アルキル、−メチル、−OR1、−NH2、−NHR2、置換又は非置換ピペラジン、−NHSO2R3、−NHCO2−C1−6アルキル、−NHCON−C1−6アルキル又は−NHCOR4であり、
BはH、−C1−3ハロアルキル、C1−3アルキル、ハロゲン又はC1−3アルコキシであり、
VはH、−CH2OH、F、−CO2H、−CO2−C1−2アルキル、−OH、−NH2、フェノキシ又は−NHCOCH3であり、
XはH又はFであり、
Wは置換又は非置換のフェニル、ピリジル、チオフェン、チアゾール、ピロール、ベンゾチオフェン又はインドールであって、
R1はベンジル、CF3又はフェニルであり、
R2はCF3、C1−3アルキル、−CH2CH2−モルホリン又はフェニルであり、
R3はC1−3アルキル、又は置換又は非置換フェニルであり、
R4はC1−3アルキル、CF3、−CH2CH2Cl、−CH2CH2NMe2、−CH2NMe2又は−CH2CH2−モルホリンである、請求項1に記載の化合物。 - 前記化学式1中、
YはCHであり、
ZはC−Vであり、
Aは−OH、−NHR2、−NHSO2R3、−NHCO2−C1−6アルキル、−NHCON−C1−6アルキル又は−NHCOR4であり、
BはH、−C1−3ハロアルキル、C1−3アルキル、ハロゲン又はC1−3アルコキシであり、
VはH、−CH2OH、F、−OH又は−NHCOCH3であり、
XはH又はFであり、
Wは下記式:
R2はCF3、C1−3アルキル、−CH2CH2−モルホリン又はフェニルであり、
R3はC1−3アルキル、又は置換又は非置換フェニルであり、
R4はC1−3アルキル、CF3、−CH2CH2Cl、−CH2CH2NMe2、−CH2NMe2又は−CH2CH2−モルホリンである、請求項3に記載の化合物。 - 前記化学式1中、
YはCHであり、
ZはC−Vであり、
Aは−OH、−NHR2、−NHSO2R3、−NHCO2−C1−6アルキル、−NHCON−C1−6アルキル又は−NHCOR4であり、
BはH、−C1−3ハロアルキル、C1−3アルキル、ハロゲン又はC1−3アルコキシであり、
VはH、F、−OH又は−NHCOCH3であり、
XはH又はFであり、
Wは下記式:
R2はCF3又はC1−3アルキルであり、
R3はC1−3アルキルであり、
R4はC1−3アルキル、CF3、−CH2CH2Cl、−CH2CH2NMe2、−CH2NMe2又は−CH2CH2−モルホリンである、請求項4に記載の化合物。 - 前記化合物は、
4−((5−(4−メトキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェノール、
4−((5−(4−アミノフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェノール、
N1−(5−(4−クロロフェニル)−1H−ピラゾール−3−イル)−N4−プロピルベンゼン−1,4−ジアミン、
4−(3−((4−ヒドロキシ−2−メチルフェニル)アミノ)−1H−ピラゾール−5−イル)ベンゾニトリル、
4−((5−(4−アミノフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メトキシフェノール、
4−((5−(4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェノール、
4−((5−(4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)フェノール、
3−フルオロ−4−((5−(4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)フェノール、
N−(4−((5−(4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)メタンスルホンアミド、
N−(4−((5−(4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)アセトアミド、
4−((4−フルオロ−5−(4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェノール、
4−((5−(4−(1H−イミダゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェノール、
4−((5−(4−(1H−イミダゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)フェノール、
N−(4−((5−(4−(ジメチルアミノ)フェニル)−1H−ピラゾール−3−イル)アミノ)フェニル)アセトアミド、
4−((5−(4−(ジメチルアミノ)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェノール、
3−エチル−4−((5−(4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)フェノール、
4−(3−((4−ヒドロキシ−2−メチルフェニル)アミノ)−1H−ピラゾール−5−イル)−2−メチルフェノール、
N−(4−((5−(4−ヒドロキシ−3−メチルフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)アセトアミド、
2−フルオロ−4−(3−((4−ヒドロキシ−2−メチルフェニル)アミノ)−1H−ピラゾール−5−イル)フェノール、
4−((5−(4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−(トリフルオロメチル)フェノール、
2−フルオロ−4−((5−(4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)フェノール、
N−(4−((5−(4−(1H−イミダゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)メタンスルホンアミド、
N−(4−((5−(4−(1H−イミダゾール−1−イル)フェニル)−4−フルオロ−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)メタンスルホンアミド、
4−((5−(4−(1H−イミダゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−エチルフェノール、
4−((5−(ベンゾ[b]チオフェン−2−イル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェノール、
4−((5−(ベンゾ[b]チオフェン−2−イル)−1H−ピラゾール−3−イル)アミノ)−3−エチルフェノール、
4−((5−(ベンゾ[b]チオフェン−3−イル)−1H−ピラゾール−3−イル)アミノ)−3−エチルフェノール、
4−((5−(5−クロロチオフェン−2−イル)−1H−ピラゾール−3−イル)アミノ)−3−エチルフェノール、
3−クロロ−4−((5−(4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)フェノール、
4−((5−(5−ブロモピリジン−3−イル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェノール、
4−((5−(4−(1H−ピラゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−エチルフェノール、
N−(4−((5−(4−(1H−ピラゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)アセトアミド、
4−((5−(1H−インドール−3−イル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェノール、
4−((5−(1H−インドール−3−イル)−1H−ピラゾール−3−イル)アミノ)−3−エチルフェノール、
N−(3−クロロ−4−((5−(4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)フェニル)アセトアミド、
N−(3−クロロ−4−((5−(4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)フェニル)メタンスルホンアミド、
3−エチル−4−((5−(4−ヨードフェニル)−1H−ピラゾール−3−イル)アミノ)フェノール、
N−(4−((5−(4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)ブチルアミド、
2,2,2−トリフルオロ−N−(4−((5−(4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)アセトアミド、
4−(3−((4−アミノ−2−メチルフェニル)アミノ)−1H−ピラゾール−5−イル)フェノール、
N−(3−エチル−4−((5−(4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)フェニル)アセトアミド、
N−(2−フルオロ−4−((5−(4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)−5−メチルフェニル)メタンスルホンアミド、
4−((5−(6−クロロピリジン−3−イル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェノール、
(4−((5−(4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)カルバミン酸エチル、
N−(4−((5−(3−フルオロ−4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)メタンスルホンアミド、
4−(3−((2−エチル−4−ヒドロキシフェニル)アミノ)−1H−ピラゾール−5−イル)−2−フルオロフェノール、
1−(4−((5−(3−フルオロ−4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)−3−メチル尿素、
2−フルオロ−4−(3−((2−フルオロ−4−ヒドロキシフェニル)アミノ)−1H−ピラゾール−5−イル)フェノール、
N−(4−((5−(4−(1H−イミダゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)フェニル)アセトアミド、
N−(4−((5−(4−(1H−イミダゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)フェニル)メタンスルホンアミド、
4−((5−(4−(1H−イミダゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−フルオロフェノール、
4−((5−(4−(1H−イミダゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−(トリフルオロメチル)フェノール、
N−(4−((5−(4−(1H−イミダゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−クロロフェニル)アセトアミド、
4−((5−(4−(1H−イミダゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−2−フルオロフェノール、
4−((5−(4−(1H−イミダゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−クロロフェノール、
N−(4−((5−(4−(1H−イミダゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−2−フルオロ−5−メチルフェニル)アセトアミド、
N−(4−((5−(4−(1H−ピラゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)−3−クロロプロパンアミド、
N−(4−((5−(4−(1H−ピラゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)−3−モルホリノプロパンアミド、
2−(ジメチルアミノ)−N−(4−((5−(3−フルオロ−4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)アセトアミド、
N−(4−((5−(3−フルオロ−4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)−3−モルホリノプロパンアミド、
3−(ジメチルアミノ)−N−(4−((5−(3−フルオロ−4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)プロパンアミド、
N−(4−((5−(4−(1H−ピラゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)メタンスルホンアミド、
4−((5−(4−(1H−ピラゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−(トリフルオロメチル)フェノール、
4−((5−(4−(1H−ピラゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−フルオロフェノール、
N−(4−((5−(4−ヨードフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)メタンスルホンアミド、
N−(4−((5−(1H−インドール−3−イル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)メタンスルホンアミド、
4−((5−(4−(1H−ピラゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−2−フルオロフェノール、
4−((5−(4−(1H−ピラゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−クロロフェノール、
3−メチル−4−((5−フェニル−1H−ピラゾール−3−イル)アミノ)フェノール、
N−(3−メチル−4−((5−フェニル−1H−ピラゾール−3−イル)アミノ)フェニル)アセトアミド、
N−(3−メチル−4−((5−フェニル−1H−ピラゾール−3−イル)アミノ)フェニル)メタンスルホンアミド、
N−(4−((5−(4−メトキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)メタンスルホンアミド、
N−(4−((5−(4−シアノフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)メタンスルホンアミド、
N−(4−((5−(4−ブロモフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)メタンスルホンアミド、
N−(4−((5−(3−フルオロ−4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)メタンスルホンアミド、
N−(3−メチル−4−((5−(4−モルホリノフェニル)−1H−ピラゾール−3−イル)アミノ)フェニル)アセトアミド、
3−メチル−4−((5−(4−モルホリノフェニル)−1H−ピラゾール−3−イル)アミノ)フェノール、
N−(3−メチル−4−((5−(4−モルホリノフェニル)−1H−ピラゾール−3−イル)アミノ)フェニル)メタンスルホンアミド、
N−(4−((5−(4−フルオロフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)メタンスルホンアミド、
1−(4−(3−((4−ヒドロキシ−2−メチルフェニル)アミノ)−1H−ピラゾール−5−イル)フェニル)ピロリジン−2−オン、
1−(4−(3−((4−ヒドロキシ−2−メチルフェニル)アミノ)−1H−ピラゾール−5−イル)フェニル)ピペリジン−2−オン、
1−(4−((5−(4−(1H−ピラゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)−3−メチル尿素、
(4−((5−(4−(1H−ピラゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)カルバミン酸メチル、
(4−((5−(4−(1H−ピラゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)カルバミン酸エチル、
N−(3−メチル−4−((5−(4−(2−オキソピロリジン−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)フェニル)アセトアミド、
N−(3−メチル−4−((5−(4−(2−オキソピペリジン−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)フェニル)アセトアミド、
4−((5−(6−メトキシピリジン−3−イル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェノール、
N−(4−((5−(6−メトキシピリジン−3−イル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)メタンスルホンアミド、
N−(4−((5−(6−メトキシピリジン−3−イル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)アセトアミド、
1−(4−(3−((4−ヒドロキシ−2−メチルフェニル)アミノ)−1H−ピラゾール−5−イル)フェニル)アゼチジン−2−オン、
4−((5−(6−(1H−ピラゾール−1−イル)ピリジン−3−イル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェノール、
N−(4−((5−(6−(1H−ピラゾール−1−イル)ピリジン−3−イル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)アセトアミド、
N−(4−((5−(6−(1H−ピラゾール−1−イル)ピリジン−3−イル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)メタンスルホンアミド、
N−(3−クロロ−4−((5−(4−(2−オキソピロリジン−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)フェニル)アセトアミド、
4−((5−(4−(ジメチルアミノ)フェニル)−4−フルオロ−1H−ピラゾール−3−イル)アミノ)−3−メチルフェノール、
N−(4−((5−(ベンゾ[b]チオフェン−2−イル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)メタンスルホンアミド、
1−(4−((5−(ベンゾ[b]チオフェン−2−イル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)−3−メチル尿素、
(4−((5−(ベンゾ[b]チオフェン−2−イル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)カルバミン酸エチル、
(4−((5−(ベンゾ[b]チオフェン−2−イル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)カルバミン酸メチル、
N−(4−((5−(4−(1H−ピラゾール−1−イル)フェニル)−4−フルオロ−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)メタンスルホンアミド、
N−(3−クロロ−4−((5−(4−メトキシフェニル)−1H−ピラゾール−3−イル)アミノ)フェニル)アセトアミド、
4−((5−(3−(1H−ピラゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェノール、
N−(4−((5−(3−(1H−ピラゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)メタンスルホンアミド、
N−(4−((5−(4−(1H−ピラゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)イソブチルアミド、
1−(4−(4−フルオロ−3−((4−ヒドロキシ−2−メチルフェニル)アミノ)−1H−ピラゾール−5−イル)フェニル)ピロリジン−2−オン、
N−(4−((5−(4−(1H−ピラゾール−1−イル)フェニル)−4−フルオロ−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)アセトアミド、
(4−((5−(4−(1H−ピラゾール−1−イル)フェニル)−4−フルオロ−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)カルバミン酸メチル、
(4−((5−(4−(1H−ピラゾール−1−イル)フェニル)−4−フルオロ−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)カルバミン酸エチル、
4−((4−フルオロ−5−(4−メトキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェノール、
1−(4−((5−(4−(1H−ピラゾール−1−イル)フェニル)−4−フルオロ−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)−3−メチル尿素、
3−エチル−4−((4−フルオロ−5−(4−ヨードフェニル)−1H−ピラゾール−3−イル)アミノ)フェノール、
3−メチル−4−((5−(3−(ピリジン−3−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)フェノール、
3−メチル−4−((5−(4−(ピリジン−3−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)フェノール、
4−((5−(4−(4−フルオロ−1H−ピラゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェノール、
N−(4−((5−(4−(4−フルオロ−1H−ピラゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)メタンスルホンアミド、
4−((4−フルオロ−5−(1H−インドール−3−イル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェノール、
3−エチル−4−((5−(3−ヨードフェニル)−1H−ピラゾール−3−イル)アミノ)フェノール、
4−((5−(2’−フルオロ−5’−メトキシ−[1,1’−ビフェニル]−3−イル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェノール、
4−((5−(4−(1H−ピラゾール−4−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェノール、
3−メチル−4−((5−(3−(1−メチル−1H−ピラゾール−4−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)フェノール、
4−((5−(2’−フルオロ−5’−メトキシ−[1,1’−ビフェニル]−4−イル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェノール、
4−((5−(4−(1H−ピラゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−2−フルオロ−5−メチルフェノール、
2−フルオロ−4−((5−(4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)−5−メチルフェノール、
3−メチル−4−((5−(4−(1−メチル−1H−ピラゾール−4−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)フェノール、
4−((5−(4−(3,5−ジメチル−1H−ピラゾール−4−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェノール、
3−メチル−4−((5−(4−(3−(トリフルオロメチル)−1H−ピラゾール−4−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)フェノール、
4−((5−(4−(1H−ピラゾール−4−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−エチルフェノール、
1−(4−((5−(4−(1H−ピラゾール−4−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)−3−メチル尿素、
(4−((5−(4−(1H−ピラゾール−4−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)カルバミン酸メチル、
4−((5−(4−(1H−ピラゾール−4−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−2−フルオロ−5−メチルフェノール、
1−(4−((5−(2’−フルオロ−5’−メトキシ−[1,1’−ビフェニル]−4−イル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)−3−メチル尿素、
(4−((5−(2’−フルオロ−5’−メトキシ−[1,1’−ビフェニル]−4−イル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)カルバミン酸メチル、
1−(4−((5−(4−メトキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)−3−メチル尿素、
(4−((5−(4−メトキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)カルバメート、
4−((5−(4−(1H−ピラゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−2,5−ジフルオロフェノール、
1−メチル−3−(3−メチル−4−((5−(4−(メチルスルホニル)フェニル)−1H−ピラゾール−3−イル)アミノ)フェニル)尿素、
(3−メチル−4−((5−(4−(メチルスルホニル)フェニル)−1H−ピラゾール−3−イル)アミノ)フェニル)カルバミン酸メチル、
1−メチル−3−(3−メチル−4−((5−(4−(3−(トリフルオロメチル)−1H−ピラゾール−4−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)フェニル)尿素、
(3−メチル−4−((5−(4−(3−(トリフルオロメチル)−1H−ピラゾール−4−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)フェニル)カルバミン酸メチル、
1−(4−((5−(4−ブロモフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)−3−メチル尿素、
(4−((5−(4−ブロモフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)カルバミン酸メチル、
(3−メチル−4−((5−(4−(1−メチル−1H−ピラゾール−4−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)フェニル)カルバミン酸メチル、
3−メチル−4−((5−(4−(トリフルオロメチル)フェニル)−1H−ピラゾール−3−イル)アミノ)フェノール、
(3−メチル−4−((5−(4−(トリフルオロメチル)フェニル)−1H−ピラゾール−3−イル)アミノ)フェニル)カルバミン酸メチル、
(4−((5−(3−フルオロ−4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)カルバミン酸メチル、
(4−((5−(4−クロロフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)カルバミン酸メチル、又は
(4−((5−(4−アミノフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)カルバミン酸メチルである、請求項1に記載の化合物。 - 前記化合物は、
3−エチル−4−((5−(4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)フェノール
4−((5−(4−(ジメチルアミノ)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェノール
N−(4−((5−(4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)メタンスルホンアミド
N−(4−((5−(4−(1H−イミダゾール−1−イル)フェニル)−4−フルオロ−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)メタンスルホンアミド、
4−((5−(4−(1H−ピラゾール−1−イル)フェニル)−1H−ピラゾール−3−イル)アミノ)−3−エチルフェノール、
N−(3−エチル−4−((5−(4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)フェニル)アセトアミド、
2−フルオロ−4−((5−(4−ヒドロキシフェニル)−1H−ピラゾール−3−イル)アミノ)−5−メチルフェノール、
1−(4−((5−(4−メトキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)−3−メチル尿素、
(4−((5−(4−メトキシフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)カルバメート、
1−(4−((5−(4−ブロモフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)−3−メチル尿素、又は
(4−((5−(4−アミノフェニル)−1H−ピラゾール−3−イル)アミノ)−3−メチルフェニル)カルバミン酸メチルである、請求項1に記載の化合物。 - 請求項1〜8のいずれか一項に記載の化合物又はその薬学的に許容される塩と、薬学的に許容される担体とを含む組成物。
- 請求項1〜8のいずれか一項に記載の化合物又はその薬学的に許容される塩を有効成分として含む、癌を治療又は予防するための組成物。
- 他の薬学的に活性な化合物として、イリノテカン又はその薬学的に許容される塩を更に含む、請求項11に記載の組成物。
- 前記癌は結腸直腸癌、乳癌、脳腫瘍、胃癌、肝臓癌、卵巣癌、肺癌、胃腸癌、白血病又は黒色腫である、請求項10又は11に記載の組成物。
- 前記癌は結腸直腸癌である、請求項12に記載の組成物。
- 癌を治療又は予防するための方法であって、癌の治療又は予防を必要とする対象に、請求項1〜8のいずれか一項に記載の化合物又はその薬学的に許容される塩の治療有効量を投与することを含む方法。
- 癌の治療又は予防を必要とする対象に、イリノテカン又はその薬学的に許容される塩の治療有効量を投与することを更に含む、請求項14に記載の方法。
- 前記癌は結腸直腸癌、乳癌、脳腫瘍、胃癌、肝臓癌、卵巣癌、肺癌、胃腸癌、白血病又は黒色腫である、請求項14又は15に記載の方法。
- 前記癌は結腸直腸癌である、請求項16に記載の方法。
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