JP6860559B2 - Ｅｐ４アンタゴニスト - Google Patents
Ｅｐ４アンタゴニスト Download PDFInfo
- Publication number
- JP6860559B2 JP6860559B2 JP2018519749A JP2018519749A JP6860559B2 JP 6860559 B2 JP6860559 B2 JP 6860559B2 JP 2018519749 A JP2018519749 A JP 2018519749A JP 2018519749 A JP2018519749 A JP 2018519749A JP 6860559 B2 JP6860559 B2 JP 6860559B2
- Authority
- JP
- Japan
- Prior art keywords
- trifluoromethyl
- pyrazole
- dihydro
- ethyl
- imidazole
- 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.)
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- 239000005557 antagonist Substances 0.000 title description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 1014
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 569
- -1 -CH 3 Chemical group 0.000 claims description 360
- 239000005711 Benzoic acid Substances 0.000 claims description 307
- 235000010233 benzoic acid Nutrition 0.000 claims description 307
- 150000001875 compounds Chemical class 0.000 claims description 211
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 208
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 190
- 206010028980 Neoplasm Diseases 0.000 claims description 149
- 201000011510 cancer Diseases 0.000 claims description 71
- 238000011282 treatment Methods 0.000 claims description 57
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 54
- ZXLOZYMBPKHFKM-UHFFFAOYSA-N 3-[[2,5-bis(trifluoromethyl)phenyl]methyl]-1,2-dihydroimidazole Chemical compound FC(C1=CC=C(C=C1CN1CNC=C1)C(F)(F)F)(F)F ZXLOZYMBPKHFKM-UHFFFAOYSA-N 0.000 claims description 50
- 150000003839 salts Chemical class 0.000 claims description 50
- 239000002253 acid Substances 0.000 claims description 40
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 37
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 33
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims description 22
- 125000006482 3-iodobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(I)=C1[H])C([H])([H])* 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 16
- KGOMUMXJNKZCDA-UHFFFAOYSA-N C1NC=CN1CC2=C(C=C(C=C2)C(F)(F)F)C(F)(F)F Chemical compound C1NC=CN1CC2=C(C=C(C=C2)C(F)(F)F)C(F)(F)F KGOMUMXJNKZCDA-UHFFFAOYSA-N 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 13
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 13
- 150000003857 carboxamides Chemical class 0.000 claims description 11
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 claims description 10
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 10
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 10
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 10
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 claims description 10
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 claims description 7
- 125000006512 3,4-dichlorobenzyl group Chemical group [H]C1=C(Cl)C(Cl)=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 7
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 7
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 7
- 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000006180 3-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])[H])C([H])([H])* 0.000 claims description 7
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 7
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 7
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 claims description 7
- 206010005003 Bladder cancer Diseases 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 7
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 7
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 7
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 7
- 201000010881 cervical cancer Diseases 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 7
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 7
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 7
- CKDONALRQYMQNJ-UHFFFAOYSA-N CC1=CC(=CC=C1CN1CNC=C1)C(F)(F)F Chemical compound CC1=CC(=CC=C1CN1CNC=C1)C(F)(F)F CKDONALRQYMQNJ-UHFFFAOYSA-N 0.000 claims description 6
- RSQWFGBLKPLJQP-UHFFFAOYSA-N CCC1=CC=C(C(F)(F)F)C=C1CN1C=CNC1 Chemical compound CCC1=CC=C(C(F)(F)F)C=C1CN1C=CNC1 RSQWFGBLKPLJQP-UHFFFAOYSA-N 0.000 claims description 6
- QMVDXRGZLCWHBY-UHFFFAOYSA-N FC(C(C=C1C(F)(F)F)=CC=C1N1C=CNC1)(F)F Chemical compound FC(C(C=C1C(F)(F)F)=CC=C1N1C=CNC1)(F)F QMVDXRGZLCWHBY-UHFFFAOYSA-N 0.000 claims description 6
- ZYTVUAXKDWNTNW-UHFFFAOYSA-N FC(C(C=C1CN2C=CNC2)=CC=C1C1=CC=CC=C1)(F)F Chemical compound FC(C(C=C1CN2C=CNC2)=CC=C1C1=CC=CC=C1)(F)F ZYTVUAXKDWNTNW-UHFFFAOYSA-N 0.000 claims description 6
- HUCTVUPALHMDMU-UHFFFAOYSA-N FC(C1=CC=C(C(F)(F)F)C(N2C=CNC2)=C1)(F)F Chemical compound FC(C1=CC=C(C(F)(F)F)C(N2C=CNC2)=C1)(F)F HUCTVUPALHMDMU-UHFFFAOYSA-N 0.000 claims description 6
- WXGKQRCUUWPJSW-UHFFFAOYSA-N FC(C1=CC=CC(C(F)(F)F)=C1CN1C=CNC1)(F)F Chemical compound FC(C1=CC=CC(C(F)(F)F)=C1CN1C=CNC1)(F)F WXGKQRCUUWPJSW-UHFFFAOYSA-N 0.000 claims description 6
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 206010038038 rectal cancer Diseases 0.000 claims description 6
- 201000001275 rectum cancer Diseases 0.000 claims description 6
- 125000003143 4-hydroxybenzyl group Chemical group [H]C([*])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 235000001968 nicotinic acid Nutrition 0.000 claims description 5
- 239000011664 nicotinic acid Substances 0.000 claims description 5
- 229940081066 picolinic acid Drugs 0.000 claims description 5
- JEXOSIVOIFWCSU-UHFFFAOYSA-N CC(C1=CC=C(C(F)(F)F)C=C1C)N1C=CNC1 Chemical compound CC(C1=CC=C(C(F)(F)F)C=C1C)N1C=CNC1 JEXOSIVOIFWCSU-UHFFFAOYSA-N 0.000 claims description 4
- KZUCYBAYBWNPEB-UHFFFAOYSA-N FC(C1=CC=C(C=C1CN1CNC=C1)C(F)(F)F)F Chemical compound FC(C1=CC=C(C=C1CN1CNC=C1)C(F)(F)F)F KZUCYBAYBWNPEB-UHFFFAOYSA-N 0.000 claims description 4
- DUYTUUFUZIJQED-UHFFFAOYSA-N FCC1=CC=C(C=C1CN1CNC=C1)C(F)(F)F Chemical compound FCC1=CC=C(C=C1CN1CNC=C1)C(F)(F)F DUYTUUFUZIJQED-UHFFFAOYSA-N 0.000 claims description 4
- DKRFNIRCESYVBB-AWEZNQCLSA-N N-[(1S)-1-[4-(cyanocarbamoyl)phenyl]ethyl]-6-(trifluoromethyl)-1-[[3-(trifluoromethyl)phenyl]methyl]-2,3-dihydroimidazo[1,2-b]pyrazole-7-carboxamide Chemical compound C(#N)NC(=O)C1=CC=C(C=C1)[C@H](C)NC(=O)C1=C2N(N=C1C(F)(F)F)CCN2CC1=CC(=CC=C1)C(F)(F)F DKRFNIRCESYVBB-AWEZNQCLSA-N 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- VXNCSZWNPZTPID-UHFFFAOYSA-N [2-(1,2-dihydroimidazol-3-ylmethyl)-4-(trifluoromethyl)phenyl]methanol Chemical compound OCC1=CC=C(C=C1CN1CNC=C1)C(F)(F)F VXNCSZWNPZTPID-UHFFFAOYSA-N 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
- 229960003512 nicotinic acid Drugs 0.000 claims description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- 208000015347 renal cell adenocarcinoma Diseases 0.000 claims description 4
- YCWRFIYBUQBHJI-UHFFFAOYSA-N 2-(4-aminophenyl)acetonitrile Chemical group NC1=CC=C(CC#N)C=C1 YCWRFIYBUQBHJI-UHFFFAOYSA-N 0.000 claims description 3
- UJHFCEIGEJFCBX-UHFFFAOYSA-N 2-(trifluoromethyl)-4-[[3-(trifluoromethyl)phenyl]methyl]-6,7-dihydro-5H-pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound FC(C1=NN2C(N(CCC2)CC2=CC(=CC=C2)C(F)(F)F)=C1C(=O)N)(F)F UJHFCEIGEJFCBX-UHFFFAOYSA-N 0.000 claims description 3
- KSEWMEXHJLSVPT-UHFFFAOYSA-N 2-(trifluoromethyl)-4-[[4-(trifluoromethyl)phenyl]methyl]-6,7-dihydro-5H-pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound FC(C1=NN2C(N(CCC2)CC2=CC=C(C=C2)C(F)(F)F)=C1C(=O)N)(F)F KSEWMEXHJLSVPT-UHFFFAOYSA-N 0.000 claims description 3
- ZGFKPECFBHRPGJ-UHFFFAOYSA-N CN1CN(C=C1)CC1=CC(=CC=C1C(F)(F)F)C(F)(F)F Chemical compound CN1CN(C=C1)CC1=CC(=CC=C1C(F)(F)F)C(F)(F)F ZGFKPECFBHRPGJ-UHFFFAOYSA-N 0.000 claims description 3
- 201000009030 Carcinoma Diseases 0.000 claims description 3
- JCCWSGDPKMLGTD-UHFFFAOYSA-N FC(C1=NN2C(N(CCC2)C2=CC=C(C=C2)C(F)(F)F)=C1C(=O)N)(F)F Chemical compound FC(C1=NN2C(N(CCC2)C2=CC=C(C=C2)C(F)(F)F)=C1C(=O)N)(F)F JCCWSGDPKMLGTD-UHFFFAOYSA-N 0.000 claims description 3
- YKJDETHKFXRFSK-UHFFFAOYSA-N FC(C1=NN2C(N(CCC2)CC2=C(C=CC=C2)C(F)(F)F)=C1C(=O)N)(F)F Chemical compound FC(C1=NN2C(N(CCC2)CC2=C(C=CC=C2)C(F)(F)F)=C1C(=O)N)(F)F YKJDETHKFXRFSK-UHFFFAOYSA-N 0.000 claims description 3
- 230000000112 colonic effect Effects 0.000 claims description 3
- 125000001736 nosyl group Chemical group S(=O)(=O)(C1=CC=C([N+](=O)[O-])C=C1)* 0.000 claims description 3
- IDNXVUDDZDHJGX-UHFFFAOYSA-N 4-[(2-chlorophenyl)methyl]-2-(trifluoromethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound ClC1=C(CN2C=3N(CCC2)N=C(C3C(=O)N)C(F)(F)F)C=CC=C1 IDNXVUDDZDHJGX-UHFFFAOYSA-N 0.000 claims description 2
- AMMRJINDLHDRIJ-UHFFFAOYSA-N 4-[(3-chlorophenyl)methyl]-2-(trifluoromethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound ClC=1C=C(CN2C=3N(CCC2)N=C(C3C(=O)N)C(F)(F)F)C=CC1 AMMRJINDLHDRIJ-UHFFFAOYSA-N 0.000 claims description 2
- RXLTVXRSZUCFCL-UHFFFAOYSA-N ClC1=CC=C(CN2C=3N(CCC2)N=C(C3C(=O)N)C(F)(F)F)C=C1 Chemical compound ClC1=CC=C(CN2C=3N(CCC2)N=C(C3C(=O)N)C(F)(F)F)C=C1 RXLTVXRSZUCFCL-UHFFFAOYSA-N 0.000 claims description 2
- OMUHVUSRKIFYBS-UHFFFAOYSA-N FC(CO)(F)C1=CC=C(C=C1CN1CNC=C1)C(F)(F)F Chemical compound FC(CO)(F)C1=CC=C(C=C1CN1CNC=C1)C(F)(F)F OMUHVUSRKIFYBS-UHFFFAOYSA-N 0.000 claims description 2
- AYCDVHZVHJJZOS-HNNXBMFYSA-N N-[(1S)-1-(4-cyclopropylphenyl)ethyl]-6-(trifluoromethyl)-1-[[4-(trifluoromethyl)phenyl]methyl]-2,3-dihydroimidazo[1,2-b]pyrazole-7-carboxamide Chemical compound C[C@H](NC(=O)C1=C2N(CC3=CC=C(C=C3)C(F)(F)F)CCN2N=C1C(F)(F)F)C1=CC=C(C=C1)C1CC1 AYCDVHZVHJJZOS-HNNXBMFYSA-N 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 1
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 285
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 230
- 239000000203 mixture Substances 0.000 description 142
- 239000000243 solution Substances 0.000 description 125
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 108
- 238000006243 chemical reaction Methods 0.000 description 107
- 235000019439 ethyl acetate Nutrition 0.000 description 107
- 238000000034 method Methods 0.000 description 75
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 67
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 67
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 62
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 59
- 239000012044 organic layer Substances 0.000 description 59
- 239000007787 solid Substances 0.000 description 56
- 239000011541 reaction mixture Substances 0.000 description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 46
- 239000000047 product Substances 0.000 description 46
- 230000009467 reduction Effects 0.000 description 41
- 239000011734 sodium Substances 0.000 description 40
- 239000012267 brine Substances 0.000 description 34
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- 229940125904 compound 1 Drugs 0.000 description 30
- 238000010898 silica gel chromatography Methods 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 29
- 229920006395 saturated elastomer Polymers 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 26
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 26
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 25
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 24
- 238000003818 flash chromatography Methods 0.000 description 24
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- 125000003118 aryl group Chemical group 0.000 description 22
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
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- 125000000217 alkyl group Chemical group 0.000 description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 17
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
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- 125000001424 substituent group Chemical group 0.000 description 14
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 13
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 13
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- 125000001072 heteroaryl group Chemical group 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 11
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Classifications
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- C07—ORGANIC CHEMISTRY
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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| AU2016338679A1 (en) | 2018-06-07 |
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| BR112018007664A2 (pt) | 2018-11-06 |
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| EP3362454A1 (en) | 2018-08-22 |
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| JP7090770B2 (ja) | 2022-06-24 |
| CA3002144A1 (en) | 2017-04-20 |
| BR112018007664B1 (pt) | 2023-12-19 |
| CA3002144C (en) | 2024-01-23 |
| US11434246B2 (en) | 2022-09-06 |
| EP3362454B1 (en) | 2021-12-08 |
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| JP2021100969A (ja) | 2021-07-08 |
| MX390051B (es) | 2025-03-20 |
| US10941148B2 (en) | 2021-03-09 |
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