NZ620610B2 - Heterocyclic derivative and pharmaceutical drug - Google Patents
Heterocyclic derivative and pharmaceutical drug Download PDFInfo
- Publication number
- NZ620610B2 NZ620610B2 NZ620610A NZ62061012A NZ620610B2 NZ 620610 B2 NZ620610 B2 NZ 620610B2 NZ 620610 A NZ620610 A NZ 620610A NZ 62061012 A NZ62061012 A NZ 62061012A NZ 620610 B2 NZ620610 B2 NZ 620610B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- amino
- carbonyl
- phenyl
- chloromethylphenyl
- trifluoromethyl
- Prior art date
Links
- 125000000623 heterocyclic group Chemical group 0.000 title claims description 27
- 229940079593 drug Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 497
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 101710096361 Prostaglandin E synthase Proteins 0.000 claims abstract description 31
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 21
- 201000011510 cancer Diseases 0.000 claims abstract description 12
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 12
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 7
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 7
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 7
- 208000008035 Back Pain Diseases 0.000 claims abstract description 6
- 208000005171 Dysmenorrhea Diseases 0.000 claims abstract description 6
- 206010013935 Dysmenorrhoea Diseases 0.000 claims abstract description 6
- 201000009273 Endometriosis Diseases 0.000 claims abstract description 6
- 206010020853 Hypertonic bladder Diseases 0.000 claims abstract description 6
- 208000008930 Low Back Pain Diseases 0.000 claims abstract description 6
- 208000009722 Overactive Urinary Bladder Diseases 0.000 claims abstract description 6
- 208000028911 Temporomandibular Joint disease Diseases 0.000 claims abstract description 6
- 201000008482 osteoarthritis Diseases 0.000 claims abstract description 6
- 208000020629 overactive bladder Diseases 0.000 claims abstract description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 6
- -1 monoalkylamino Chemical group 0.000 claims description 382
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 208
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 138
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 78
- 125000000217 alkyl group Chemical group 0.000 claims description 60
- 229910052736 halogen Inorganic materials 0.000 claims description 53
- 150000002367 halogens Chemical class 0.000 claims description 53
- 125000003545 alkoxy group Chemical group 0.000 claims description 49
- ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 claims description 45
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 38
- 241001024304 Mino Species 0.000 claims description 36
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 34
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 32
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 26
- 125000004076 pyridyl group Chemical group 0.000 claims description 19
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
- QPIQCBVKRJVCGC-UHFFFAOYSA-N COCC1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O QPIQCBVKRJVCGC-UHFFFAOYSA-N 0.000 claims description 15
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 13
- 208000002193 Pain Diseases 0.000 claims description 12
- 125000004414 alkyl thio group Chemical group 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 206010061218 Inflammation Diseases 0.000 claims description 11
- KKQREKXTNHJTIS-UHFFFAOYSA-N O=C(C1=NC(C=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NCC1CCCCC1 Chemical compound O=C(C1=NC(C=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NCC1CCCCC1 KKQREKXTNHJTIS-UHFFFAOYSA-N 0.000 claims description 11
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 11
- 230000004054 inflammatory process Effects 0.000 claims description 11
- DYYFDGYTZMRDDE-UHFFFAOYSA-N CCC1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CCC1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O DYYFDGYTZMRDDE-UHFFFAOYSA-N 0.000 claims description 10
- VYYLNVKQYMWPPH-UHFFFAOYSA-N O=C(C1=NC(C=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NCCC1CCCCC1 Chemical compound O=C(C1=NC(C=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NCCC1CCCCC1 VYYLNVKQYMWPPH-UHFFFAOYSA-N 0.000 claims description 10
- BAVIFUJYBGWGLT-UHFFFAOYSA-N CC1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CC1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O BAVIFUJYBGWGLT-UHFFFAOYSA-N 0.000 claims description 8
- KQEZRLNTQSKLOO-UHFFFAOYSA-N COCC1=CC=CC2=C1N=C(C(NC1=C(CCl)C=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC1=CC=CC2=C1N=C(C(NC1=C(CCl)C=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O KQEZRLNTQSKLOO-UHFFFAOYSA-N 0.000 claims description 8
- PCQSEVWAKRMSOT-UHFFFAOYSA-N COCC1=CC=CC2=C1N=C(C(NCC(C=CC=C1)=C1Cl)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC1=CC=CC2=C1N=C(C(NCC(C=CC=C1)=C1Cl)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O PCQSEVWAKRMSOT-UHFFFAOYSA-N 0.000 claims description 8
- 201000004624 Dermatitis Diseases 0.000 claims description 8
- 208000027418 Wounds and injury Diseases 0.000 claims description 8
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 8
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 8
- 125000001041 indolyl group Chemical group 0.000 claims description 8
- YXNNKPYIOKMZGF-UHFFFAOYSA-N CC(C)(C)C(C(NC1=CC(CCl)=CC=C1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CC(C)(C)C(C(NC1=CC(CCl)=CC=C1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O YXNNKPYIOKMZGF-UHFFFAOYSA-N 0.000 claims description 7
- PYIOEKIJVRPUKE-UHFFFAOYSA-N CN(C)C1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CN(C)C1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O PYIOEKIJVRPUKE-UHFFFAOYSA-N 0.000 claims description 7
- ZHCCEPUGRXWUBB-UHFFFAOYSA-N CN(C)N1C(C(NC2=CC(CCl)=CC=C2)=O)=NC2=C1C=CC=C2NC(C(C=C(C=C1)Cl)=C1Cl)=O Chemical compound CN(C)N1C(C(NC2=CC(CCl)=CC=C2)=O)=NC2=C1C=CC=C2NC(C(C=C(C=C1)Cl)=C1Cl)=O ZHCCEPUGRXWUBB-UHFFFAOYSA-N 0.000 claims description 7
- WUHNAEPWPPKSRJ-UHFFFAOYSA-N COCC1=CC=CC2=C1N=C(C(NC1CCCCC1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC1=CC=CC2=C1N=C(C(NC1CCCCC1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O WUHNAEPWPPKSRJ-UHFFFAOYSA-N 0.000 claims description 7
- NCJVOUJBYCFMTP-UHFFFAOYSA-N O=C(C(NC1=C2C=CC=C1)(N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)Cl)NC1=CC(CCl)=CC=C1 Chemical compound O=C(C(NC1=C2C=CC=C1)(N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)Cl)NC1=CC(CCl)=CC=C1 NCJVOUJBYCFMTP-UHFFFAOYSA-N 0.000 claims description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
- 125000004981 cycloalkylmethyl group Chemical group 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- HGABJVMWXHUDAE-UHFFFAOYSA-N CC(C(NCC1=C(C(F)(F)F)C=CC=C1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CC(C(NCC1=C(C(F)(F)F)C=CC=C1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O HGABJVMWXHUDAE-UHFFFAOYSA-N 0.000 claims description 6
- NSLMIPVTZPIEFH-UHFFFAOYSA-N CC(C)(C)C(C(NC1=CC(CCl)=CC=C1)=O)(NC1=C2C=CC=C1)N2NC(C(C=C(C=C1)Cl)=C1Cl)=O Chemical compound CC(C)(C)C(C(NC1=CC(CCl)=CC=C1)=O)(NC1=C2C=CC=C1)N2NC(C(C=C(C=C1)Cl)=C1Cl)=O NSLMIPVTZPIEFH-UHFFFAOYSA-N 0.000 claims description 6
- QBRXJFVYSNGOPL-UHFFFAOYSA-N CC(C)(C)OC(CNN1C(NC(C2=C(C(F)(F)F)C=CC=C2)=O)=NC2=C1C=CC=C2C(NC1=CC(CCl)=CC=C1)=O)=O Chemical compound CC(C)(C)OC(CNN1C(NC(C2=C(C(F)(F)F)C=CC=C2)=O)=NC2=C1C=CC=C2C(NC1=CC(CCl)=CC=C1)=O)=O QBRXJFVYSNGOPL-UHFFFAOYSA-N 0.000 claims description 6
- BATZNGVVXZHLFA-UHFFFAOYSA-N CC(C=C1)=C(C)C=C1NC(C1=NC(C(COC)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O Chemical compound CC(C=C1)=C(C)C=C1NC(C1=NC(C(COC)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O BATZNGVVXZHLFA-UHFFFAOYSA-N 0.000 claims description 6
- GOALYNQSQSDXJH-UHFFFAOYSA-N CC(C=C1)=CC(C)=C1NC(C1=NC(C(COC)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O Chemical compound CC(C=C1)=CC(C)=C1NC(C1=NC(C(COC)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O GOALYNQSQSDXJH-UHFFFAOYSA-N 0.000 claims description 6
- VBQJGBBICCQSHR-UHFFFAOYSA-N CN(C)N1C(C(NC2=CC(CCl)=CC=C2)=O)=NC2=C1C=CC=C2NC(C(C(Cl)=CC=C1)=C1Cl)=O Chemical compound CN(C)N1C(C(NC2=CC(CCl)=CC=C2)=O)=NC2=C1C=CC=C2NC(C(C(Cl)=CC=C1)=C1Cl)=O VBQJGBBICCQSHR-UHFFFAOYSA-N 0.000 claims description 6
- DLWPDPBDCVHCGS-UHFFFAOYSA-N COCC(C(NCC1=C(C(F)(F)F)C=CC=C1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC(C(NCC1=C(C(F)(F)F)C=CC=C1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O DLWPDPBDCVHCGS-UHFFFAOYSA-N 0.000 claims description 6
- BDKOYJGLVMSSMK-UHFFFAOYSA-N O=C(C1=NC(C(C2CC2)=CC=C2)=C2N1NC(C(C=C(C=C1)Cl)=C1Cl)=O)NC1=CC(CCl)=CC=C1 Chemical compound O=C(C1=NC(C(C2CC2)=CC=C2)=C2N1NC(C(C=C(C=C1)Cl)=C1Cl)=O)NC1=CC(CCl)=CC=C1 BDKOYJGLVMSSMK-UHFFFAOYSA-N 0.000 claims description 6
- MARBYPZUFCWOLS-UHFFFAOYSA-N O=C(C1=NC(C(C2CCCC2)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NC1=CC(CCl)=CC=C1 Chemical compound O=C(C1=NC(C(C2CCCC2)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NC1=CC(CCl)=CC=C1 MARBYPZUFCWOLS-UHFFFAOYSA-N 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 206010003246 arthritis Diseases 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 6
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- QJSCOQXFRWQHHA-UHFFFAOYSA-N CC(OCN1C(NC(C2=C(C(F)(F)F)C=CC=C2)=O)=NC2=C1C=CC=C2C(NC1=CC(CCl)=CC=C1)=O)=O Chemical compound CC(OCN1C(NC(C2=C(C(F)(F)F)C=CC=C2)=O)=NC2=C1C=CC=C2C(NC1=CC(CCl)=CC=C1)=O)=O QJSCOQXFRWQHHA-UHFFFAOYSA-N 0.000 claims description 5
- QFJKBRWSGXSVIE-UHFFFAOYSA-N CC1=C(COC)C=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CC1=C(COC)C=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O QFJKBRWSGXSVIE-UHFFFAOYSA-N 0.000 claims description 5
- IIBQESDLFKDOAV-UHFFFAOYSA-N CC1=CC=C(CNC(C(COC)(NC2=C3C=CC=C2)N3NC(C2=C(C(F)(F)F)C=CC=C2)=O)=O)C=C1 Chemical compound CC1=CC=C(CNC(C(COC)(NC2=C3C=CC=C2)N3NC(C2=C(C(F)(F)F)C=CC=C2)=O)=O)C=C1 IIBQESDLFKDOAV-UHFFFAOYSA-N 0.000 claims description 5
- WLPLYWCMDRDWEQ-UHFFFAOYSA-N CCC(C(NCC1=C(C(F)(F)F)C=CC=C1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CCC(C(NCC1=C(C(F)(F)F)C=CC=C1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O WLPLYWCMDRDWEQ-UHFFFAOYSA-N 0.000 claims description 5
- DFRQXPNODHTIRO-UHFFFAOYSA-N CCOC1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CCOC1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O DFRQXPNODHTIRO-UHFFFAOYSA-N 0.000 claims description 5
- RURZNRWVQSWMBA-UHFFFAOYSA-N COCC(C(NC1=CC=CS1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC(C(NC1=CC=CS1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O RURZNRWVQSWMBA-UHFFFAOYSA-N 0.000 claims description 5
- UVRWSIZMHGGEAT-UHFFFAOYSA-N COCC1=CC=CC2=C1N=C(C(NC(C(F)=CC=C1)=C1F)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC1=CC=CC2=C1N=C(C(NC(C(F)=CC=C1)=C1F)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O UVRWSIZMHGGEAT-UHFFFAOYSA-N 0.000 claims description 5
- VKJPQKUCZGFWSR-UHFFFAOYSA-N COCC1=CC=CC2=C1N=C(C(NC1=NC(C=CC=C3)=C3O1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC1=CC=CC2=C1N=C(C(NC1=NC(C=CC=C3)=C3O1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O VKJPQKUCZGFWSR-UHFFFAOYSA-N 0.000 claims description 5
- MPWLFBPELIGZEP-UHFFFAOYSA-N O=C(C(NC1=C2C=CC=C1)(N1CCC1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)NC1=CC(CCl)=CC=C1 Chemical compound O=C(C(NC1=C2C=CC=C1)(N1CCC1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)NC1=CC(CCl)=CC=C1 MPWLFBPELIGZEP-UHFFFAOYSA-N 0.000 claims description 5
- VTZVXEYMDMDZPL-UHFFFAOYSA-N O=C(C1=NC(C(C2CC2)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NC1=CC(CCl)=CC=C1 Chemical compound O=C(C1=NC(C(C2CC2)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NC1=CC(CCl)=CC=C1 VTZVXEYMDMDZPL-UHFFFAOYSA-N 0.000 claims description 5
- LVOOMBLOCOSTAW-UHFFFAOYSA-N O=C(C1=NC(C=CC(NC(C(C=CC=C2F)=C2Cl)=O)=C2)=C2N1)NCOCC1=CC(CCl)=CC=C1 Chemical compound O=C(C1=NC(C=CC(NC(C(C=CC=C2F)=C2Cl)=O)=C2)=C2N1)NCOCC1=CC(CCl)=CC=C1 LVOOMBLOCOSTAW-UHFFFAOYSA-N 0.000 claims description 5
- OHTLIXRBYYMPMY-UHFFFAOYSA-N O=C(C1=NC(C=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NCC1CCCC1 Chemical compound O=C(C1=NC(C=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NCC1CCCC1 OHTLIXRBYYMPMY-UHFFFAOYSA-N 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 5
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 208000005641 Adenomyosis Diseases 0.000 claims description 4
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 208000035143 Bacterial infection Diseases 0.000 claims description 4
- 206010006811 Bursitis Diseases 0.000 claims description 4
- CNAXDXDFGXPINH-UHFFFAOYSA-N CC(C)(C)CNC(C1=NC(C(COC)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O Chemical compound CC(C)(C)CNC(C1=NC(C(COC)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O CNAXDXDFGXPINH-UHFFFAOYSA-N 0.000 claims description 4
- LRCDMAAPJQQMFP-RUZDIDTESA-N CC(C)(C)OC(N(CCC1)[C@@H]1N1C(NC(C2=C(C(F)(F)F)C=CC=C2)=O)=NC2=C1C=CC=C2C(NC1=CC(CCl)=CC=C1)=O)=O Chemical compound CC(C)(C)OC(N(CCC1)[C@@H]1N1C(NC(C2=C(C(F)(F)F)C=CC=C2)=O)=NC2=C1C=CC=C2C(NC1=CC(CCl)=CC=C1)=O)=O LRCDMAAPJQQMFP-RUZDIDTESA-N 0.000 claims description 4
- LRCDMAAPJQQMFP-VWLOTQADSA-N CC(C)(C)OC(N(CCC1)[C@H]1N1C(NC(C2=C(C(F)(F)F)C=CC=C2)=O)=NC2=C1C=CC=C2C(NC1=CC(CCl)=CC=C1)=O)=O Chemical compound CC(C)(C)OC(N(CCC1)[C@H]1N1C(NC(C2=C(C(F)(F)F)C=CC=C2)=O)=NC2=C1C=CC=C2C(NC1=CC(CCl)=CC=C1)=O)=O LRCDMAAPJQQMFP-VWLOTQADSA-N 0.000 claims description 4
- HRNCWNHQTCCSDM-UHFFFAOYSA-N CC(C=C1)=CC=C1NC(C(COC)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O Chemical compound CC(C=C1)=CC=C1NC(C(COC)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O HRNCWNHQTCCSDM-UHFFFAOYSA-N 0.000 claims description 4
- PACLIPMVUVESMG-UHFFFAOYSA-N CC(C=CC=C1)=C1NC(C(COC)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O Chemical compound CC(C=CC=C1)=C1NC(C(COC)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O PACLIPMVUVESMG-UHFFFAOYSA-N 0.000 claims description 4
- ONQMLSMYTNFCAB-UHFFFAOYSA-N CC(N(CC1)C1C1=NC(C(C(NC2=CC(CCl)=CC=C2)=O)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O Chemical compound CC(N(CC1)C1C1=NC(C(C(NC2=CC(CCl)=CC=C2)=O)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O ONQMLSMYTNFCAB-UHFFFAOYSA-N 0.000 claims description 4
- SFFKSHOKUXBUGT-UHFFFAOYSA-N CC1(CC1)C1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CC1(CC1)C1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O SFFKSHOKUXBUGT-UHFFFAOYSA-N 0.000 claims description 4
- CFYGJWGWMRBQTB-UHFFFAOYSA-N CC1=C(COC)C=CC2=C1N=C(C(NCC(C=CC=C1)=C1Cl)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CC1=C(COC)C=CC2=C1N=C(C(NCC(C=CC=C1)=C1Cl)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O CFYGJWGWMRBQTB-UHFFFAOYSA-N 0.000 claims description 4
- XVJOGHPEKNQCKX-UHFFFAOYSA-N CCN1C(C(NCC2=C(C(F)(F)F)C=CC=C2)=O)=NC2=C1C=CC=C2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CCN1C(C(NCC2=C(C(F)(F)F)C=CC=C2)=O)=NC2=C1C=CC=C2NC(C1=C(C(F)(F)F)C=CC=C1)=O XVJOGHPEKNQCKX-UHFFFAOYSA-N 0.000 claims description 4
- KCCKOSRLMYVWIV-UHFFFAOYSA-N CCOC(C(NCC1=C(C(F)(F)F)C=CC=C1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CCOC(C(NCC1=C(C(F)(F)F)C=CC=C1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O KCCKOSRLMYVWIV-UHFFFAOYSA-N 0.000 claims description 4
- HCVYIEBROAHWFM-UHFFFAOYSA-N CCOCC1=CC=CC(C(NC(C=C2)=CC3=C2N=C(C(NC2=CC(CCl)=CC=C2)=O)N3COC)=O)=C1Cl Chemical compound CCOCC1=CC=CC(C(NC(C=C2)=CC3=C2N=C(C(NC2=CC(CCl)=CC=C2)=O)N3COC)=O)=C1Cl HCVYIEBROAHWFM-UHFFFAOYSA-N 0.000 claims description 4
- GOEMOSSLPZFDHZ-UHFFFAOYSA-N CN1C(C(NCC2=C(C(F)(F)F)C=CC=C2)=O)=NC2=C1C=CC=C2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CN1C(C(NCC2=C(C(F)(F)F)C=CC=C2)=O)=NC2=C1C=CC=C2NC(C1=C(C(F)(F)F)C=CC=C1)=O GOEMOSSLPZFDHZ-UHFFFAOYSA-N 0.000 claims description 4
- MQZFSIDORMAJCZ-UHFFFAOYSA-N CNCC1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CNCC1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O MQZFSIDORMAJCZ-UHFFFAOYSA-N 0.000 claims description 4
- UXTBFTOZEVGWJO-UHFFFAOYSA-N COCC(C(NC1=CC=C(C(F)(F)F)C=C1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC(C(NC1=CC=C(C(F)(F)F)C=C1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O UXTBFTOZEVGWJO-UHFFFAOYSA-N 0.000 claims description 4
- XBNITRVLSLQXKP-UHFFFAOYSA-N COCC(C(NCC1=CC=CS1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC(C(NCC1=CC=CS1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O XBNITRVLSLQXKP-UHFFFAOYSA-N 0.000 claims description 4
- YSPSRGLCMKCDJA-UHFFFAOYSA-N COCC1=CC=CC2=C1N=C(C(NC(C=CC=C1)=C1F)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC1=CC=CC2=C1N=C(C(NC(C=CC=C1)=C1F)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O YSPSRGLCMKCDJA-UHFFFAOYSA-N 0.000 claims description 4
- KVAGXLOKYPGZAV-UHFFFAOYSA-N COCC1=CC=CC2=C1N=C(C(NN1C3=CC=CC=C3C=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC1=CC=CC2=C1N=C(C(NN1C3=CC=CC=C3C=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O KVAGXLOKYPGZAV-UHFFFAOYSA-N 0.000 claims description 4
- KKEHTSDMUPKTKX-UHFFFAOYSA-N COCN1C(C(NC2=CC(CCl)=CC=C2)=O)=NC2=C1C=CC=C2NC(C1=CC=CN=C1Cl)=O Chemical compound COCN1C(C(NC2=CC(CCl)=CC=C2)=O)=NC2=C1C=CC=C2NC(C1=CC=CN=C1Cl)=O KKEHTSDMUPKTKX-UHFFFAOYSA-N 0.000 claims description 4
- JIKZFXFDILTJNP-UHFFFAOYSA-N COCN1C(C(NC2=CC(CCl)=CC=C2)=O)=NC2=C1C=CC=C2NC(C1=NC=CC=C1Cl)=O Chemical compound COCN1C(C(NC2=CC(CCl)=CC=C2)=O)=NC2=C1C=CC=C2NC(C1=NC=CC=C1Cl)=O JIKZFXFDILTJNP-UHFFFAOYSA-N 0.000 claims description 4
- 206010008334 Cervicobrachial syndrome Diseases 0.000 claims description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
- 208000023890 Complex Regional Pain Syndromes Diseases 0.000 claims description 4
- 206010010741 Conjunctivitis Diseases 0.000 claims description 4
- 201000006107 Familial adenomatous polyposis Diseases 0.000 claims description 4
- 208000001640 Fibromyalgia Diseases 0.000 claims description 4
- 206010017533 Fungal infection Diseases 0.000 claims description 4
- 201000005569 Gout Diseases 0.000 claims description 4
- 206010019233 Headaches Diseases 0.000 claims description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 4
- 208000005615 Interstitial Cystitis Diseases 0.000 claims description 4
- 208000003618 Intervertebral Disc Displacement Diseases 0.000 claims description 4
- 208000003456 Juvenile Arthritis Diseases 0.000 claims description 4
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 claims description 4
- 208000019695 Migraine disease Diseases 0.000 claims description 4
- QZMQMMFPGRRESX-UHFFFAOYSA-N NC(C(NC1=CC(CCl)=CC=C1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound NC(C(NC1=CC(CCl)=CC=C1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O QZMQMMFPGRRESX-UHFFFAOYSA-N 0.000 claims description 4
- CFTHSSFKZDIVIE-UHFFFAOYSA-N O=C(C1=NC(C=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NCC1=C(C(F)(F)F)C=CC=C1 Chemical compound O=C(C1=NC(C=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NCC1=C(C(F)(F)F)C=CC=C1 CFTHSSFKZDIVIE-UHFFFAOYSA-N 0.000 claims description 4
- YIDNAKWYOIGMRO-UHFFFAOYSA-N O=C(C1=NC(C=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NCC1CCC1 Chemical compound O=C(C1=NC(C=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NCC1CCC1 YIDNAKWYOIGMRO-UHFFFAOYSA-N 0.000 claims description 4
- WSLQBZIXNAREHA-UHFFFAOYSA-N OC(CNN1C(NC(C2=C(C(F)(F)F)C=CC=C2)=O)=NC2=C1C=CC=C2C(NC1=CC(CCl)=CC=C1)=O)=O Chemical compound OC(CNN1C(NC(C2=C(C(F)(F)F)C=CC=C2)=O)=NC2=C1C=CC=C2C(NC1=CC(CCl)=CC=C1)=O)=O WSLQBZIXNAREHA-UHFFFAOYSA-N 0.000 claims description 4
- 208000001132 Osteoporosis Diseases 0.000 claims description 4
- 206010033645 Pancreatitis Diseases 0.000 claims description 4
- 206010036595 Premature delivery Diseases 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- 206010039705 Scleritis Diseases 0.000 claims description 4
- 206010039710 Scleroderma Diseases 0.000 claims description 4
- 206010041591 Spinal osteoarthritis Diseases 0.000 claims description 4
- 206010043220 Temporomandibular joint syndrome Diseases 0.000 claims description 4
- 208000004760 Tenosynovitis Diseases 0.000 claims description 4
- 206010046851 Uveitis Diseases 0.000 claims description 4
- 206010047115 Vasculitis Diseases 0.000 claims description 4
- 208000036142 Viral infection Diseases 0.000 claims description 4
- 206010052428 Wound Diseases 0.000 claims description 4
- 208000026935 allergic disease Diseases 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- 208000010668 atopic eczema Diseases 0.000 claims description 4
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 4
- 208000036319 cervical spondylosis Diseases 0.000 claims description 4
- 208000029664 classic familial adenomatous polyposis Diseases 0.000 claims description 4
- 230000006378 damage Effects 0.000 claims description 4
- 230000004064 dysfunction Effects 0.000 claims description 4
- 201000009274 endometriosis of uterus Diseases 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 208000024386 fungal infectious disease Diseases 0.000 claims description 4
- 231100000869 headache Toxicity 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 4
- 208000014674 injury Diseases 0.000 claims description 4
- 201000004614 iritis Diseases 0.000 claims description 4
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 201000010260 leiomyoma Diseases 0.000 claims description 4
- 210000003041 ligament Anatomy 0.000 claims description 4
- 206010027599 migraine Diseases 0.000 claims description 4
- 201000008383 nephritis Diseases 0.000 claims description 4
- 208000004296 neuralgia Diseases 0.000 claims description 4
- 206010029446 nocturia Diseases 0.000 claims description 4
- 230000011164 ossification Effects 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 4
- 201000003068 rheumatic fever Diseases 0.000 claims description 4
- 208000005198 spinal stenosis Diseases 0.000 claims description 4
- 208000005801 spondylosis Diseases 0.000 claims description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 210000004291 uterus Anatomy 0.000 claims description 4
- 230000009385 viral infection Effects 0.000 claims description 4
- 125000000134 2-(methylsulfanyl)ethyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])[*] 0.000 claims description 3
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 3
- RIYKKNGCHCZPGG-UHFFFAOYSA-N CC(C)(C)N(C1)CC1N1C(NC(C2=C(C(F)(F)F)C=CC=C2)=O)=NC2=C1C=CC=C2C(NC1=CC(CCl)=CC=C1)=O Chemical compound CC(C)(C)N(C1)CC1N1C(NC(C2=C(C(F)(F)F)C=CC=C2)=O)=NC2=C1C=CC=C2C(NC1=CC(CCl)=CC=C1)=O RIYKKNGCHCZPGG-UHFFFAOYSA-N 0.000 claims description 3
- GSHBWSKYSARVJU-UHFFFAOYSA-N CC(C)(C)OCCNC1=NC(C(NC(C(C=CC=C2F)=C2Cl)=O)=CC=C2)=C2N1C1=CC(CCl)=CC=C1 Chemical compound CC(C)(C)OCCNC1=NC(C(NC(C(C=CC=C2F)=C2Cl)=O)=CC=C2)=C2N1C1=CC(CCl)=CC=C1 GSHBWSKYSARVJU-UHFFFAOYSA-N 0.000 claims description 3
- ZVNFXWMHANVYKC-UHFFFAOYSA-N CC(C)(CNC1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)CO Chemical compound CC(C)(CNC1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)CO ZVNFXWMHANVYKC-UHFFFAOYSA-N 0.000 claims description 3
- MQJCXZTYAQFAIH-UHFFFAOYSA-N CC1=CC(C(NN2C(C(NC3=CC(CCl)=CC=C3)=O)=NC3=C2C=CC=C3COC)=O)=C(C(F)(F)F)C=C1 Chemical compound CC1=CC(C(NN2C(C(NC3=CC(CCl)=CC=C3)=O)=NC3=C2C=CC=C3COC)=O)=C(C(F)(F)F)C=C1 MQJCXZTYAQFAIH-UHFFFAOYSA-N 0.000 claims description 3
- SJJZTZBEQGKNKT-UHFFFAOYSA-N CCC(OCCNC1=NC(C(NC(C(C=C(C=C2)Cl)=C2Cl)=O)=CC=C2)=C2N1C1=CC(CCl)=CC=C1)=O Chemical compound CCC(OCCNC1=NC(C(NC(C(C=C(C=C2)Cl)=C2Cl)=O)=CC=C2)=C2N1C1=CC(CCl)=CC=C1)=O SJJZTZBEQGKNKT-UHFFFAOYSA-N 0.000 claims description 3
- CMXDCXPHBWMOMB-UHFFFAOYSA-N CCC(OCCOC1=CC=CC(C(NC2=CC=CC3=C2N=C(C(NC2=CC(CCl)=CC=C2)=O)N3COC)=O)=C1Cl)=O Chemical compound CCC(OCCOC1=CC=CC(C(NC2=CC=CC3=C2N=C(C(NC2=CC(CCl)=CC=C2)=O)N3COC)=O)=C1Cl)=O CMXDCXPHBWMOMB-UHFFFAOYSA-N 0.000 claims description 3
- AFFUAOZOWMREQF-UHFFFAOYSA-N CCCC(C)CC1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CCCC(C)CC1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O AFFUAOZOWMREQF-UHFFFAOYSA-N 0.000 claims description 3
- LFHOZFBDCMWJSM-UHFFFAOYSA-N CCCNC(C(COC)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O Chemical compound CCCNC(C(COC)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O LFHOZFBDCMWJSM-UHFFFAOYSA-N 0.000 claims description 3
- UVVSETCQXABWQJ-UHFFFAOYSA-N CCOCCC1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CCOCCC1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O UVVSETCQXABWQJ-UHFFFAOYSA-N 0.000 claims description 3
- VVKPWLYLHRAYRB-UHFFFAOYSA-N CCOCCOC1=CC=CC(C(NC(C=C2C(NC3=CC(CCl)=CC=C3)=O)=CC3=C2N=CN3COC)=O)=C1Cl Chemical compound CCOCCOC1=CC=CC(C(NC(C=C2C(NC3=CC(CCl)=CC=C3)=O)=CC3=C2N=CN3COC)=O)=C1Cl VVKPWLYLHRAYRB-UHFFFAOYSA-N 0.000 claims description 3
- FIIYZTPDLWAQTN-UHFFFAOYSA-N CN(C)C1=CC=CC2=C1N=C(C(NC1C3=CC=CC=C3CC1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CN(C)C1=CC=CC2=C1N=C(C(NC1C3=CC=CC=C3CC1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O FIIYZTPDLWAQTN-UHFFFAOYSA-N 0.000 claims description 3
- GEEYPTQKIRHIQG-UHFFFAOYSA-N CN(C)CC1=NC(C(C(NC2=CC(CCl)=CC=C2)=O)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CN(C)CC1=NC(C(C(NC2=CC(CCl)=CC=C2)=O)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O GEEYPTQKIRHIQG-UHFFFAOYSA-N 0.000 claims description 3
- USYUWSSFLVKDPM-UHFFFAOYSA-N COCC(C(NC1=CC=CC2=CC=CC=C12)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC(C(NC1=CC=CC2=CC=CC=C12)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O USYUWSSFLVKDPM-UHFFFAOYSA-N 0.000 claims description 3
- WNNDTFTXCIPNDJ-UHFFFAOYSA-N COCC(C(NC1=CC=CC=C1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC(C(NC1=CC=CC=C1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O WNNDTFTXCIPNDJ-UHFFFAOYSA-N 0.000 claims description 3
- UVXWLLNRVCXSAB-UHFFFAOYSA-N COCC(C(NC1=NC=CC=C1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC(C(NC1=NC=CC=C1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O UVXWLLNRVCXSAB-UHFFFAOYSA-N 0.000 claims description 3
- LJEPBLJSICGEJG-UHFFFAOYSA-N COCC1=CC=CC2=C1N=C(C(NC1=C(CC3=CC=CC=C3)C=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC1=CC=CC2=C1N=C(C(NC1=C(CC3=CC=CC=C3)C=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O LJEPBLJSICGEJG-UHFFFAOYSA-N 0.000 claims description 3
- QGTAJDPZJFELRP-UHFFFAOYSA-N COCC1=CC=CC2=C1N=C(C(NC1=C(CO)C(Cl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC1=CC=CC2=C1N=C(C(NC1=C(CO)C(Cl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O QGTAJDPZJFELRP-UHFFFAOYSA-N 0.000 claims description 3
- HQQLMXBMYSBMKY-UHFFFAOYSA-N COCC1=CC=CC2=C1N=C(C(NC1C3=CC=CC=C3CC1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC1=CC=CC2=C1N=C(C(NC1C3=CC=CC=C3CC1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O HQQLMXBMYSBMKY-UHFFFAOYSA-N 0.000 claims description 3
- VWVHGSOTJZBRKQ-UHFFFAOYSA-N COCC1=CC=CC2=C1N=C(C(NCC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC1=CC=CC2=C1N=C(C(NCC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O VWVHGSOTJZBRKQ-UHFFFAOYSA-N 0.000 claims description 3
- BBLQLOUMZXMCHB-UHFFFAOYSA-N COCC1=CC=CC2=C1N=C(C(NCC1=CC=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC1=CC=CC2=C1N=C(C(NCC1=CC=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O BBLQLOUMZXMCHB-UHFFFAOYSA-N 0.000 claims description 3
- SGJRHSOPKMZJTK-UHFFFAOYSA-N COCC1=CC=CC2=C1N=C(C(NCC1CCCCC1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC1=CC=CC2=C1N=C(C(NCC1CCCCC1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O SGJRHSOPKMZJTK-UHFFFAOYSA-N 0.000 claims description 3
- XLMUEIFUTJFYBB-UHFFFAOYSA-N COCC1=CC=CC2=C1N=C(C(NCC1CCCCCC1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC1=CC=CC2=C1N=C(C(NCC1CCCCCC1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O XLMUEIFUTJFYBB-UHFFFAOYSA-N 0.000 claims description 3
- IORKLTKPWMSTCD-UHFFFAOYSA-N COCC1=NC(C(NC(C2=C(C(F)(F)F)C=CC=C2)=O)=CC=C2)=C2N1C1=CC=CC2=C1CCCC2 Chemical compound COCC1=NC(C(NC(C2=C(C(F)(F)F)C=CC=C2)=O)=CC=C2)=C2N1C1=CC=CC2=C1CCCC2 IORKLTKPWMSTCD-UHFFFAOYSA-N 0.000 claims description 3
- LBHBTTCZDBDBCK-UHFFFAOYSA-N COCCCNC1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCCCNC1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O LBHBTTCZDBDBCK-UHFFFAOYSA-N 0.000 claims description 3
- NMAHXOMNCDIIJI-UHFFFAOYSA-N COCCN1C(C(NC2=CC(CCl)=CC=C2)=O)=NC2=C1C=CC=C2NC(C(C=C(C=C1)Cl)=C1Cl)=O Chemical compound COCCN1C(C(NC2=CC(CCl)=CC=C2)=O)=NC2=C1C=CC=C2NC(C(C=C(C=C1)Cl)=C1Cl)=O NMAHXOMNCDIIJI-UHFFFAOYSA-N 0.000 claims description 3
- OQXZRXUSSQEZRN-UHFFFAOYSA-N COCCNC1=NC(C(C(NC2=CC(CCl)=CC=C2)=O)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCCNC1=NC(C(C(NC2=CC(CCl)=CC=C2)=O)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O OQXZRXUSSQEZRN-UHFFFAOYSA-N 0.000 claims description 3
- GMAWFKGNGJGWNK-UHFFFAOYSA-N COCCOCC1=CC=CC2=C1N=C(NC(C1=C(C(F)(F)F)C=CC=C1)=O)N2C1=CC(CCl)=CC=C1 Chemical compound COCCOCC1=CC=CC2=C1N=C(NC(C1=C(C(F)(F)F)C=CC=C1)=O)N2C1=CC(CCl)=CC=C1 GMAWFKGNGJGWNK-UHFFFAOYSA-N 0.000 claims description 3
- GKFWGSWMYGGONT-UHFFFAOYSA-N COCN1C(C(NC2=CC(CCl)=CC=C2)=O)=NC2=C1C=CC=C2NC(C(C(Cl)=CC=C1)=C1Cl)=O Chemical compound COCN1C(C(NC2=CC(CCl)=CC=C2)=O)=NC2=C1C=CC=C2NC(C(C(Cl)=CC=C1)=C1Cl)=O GKFWGSWMYGGONT-UHFFFAOYSA-N 0.000 claims description 3
- OPNBYMSSFGPVJH-UHFFFAOYSA-N COCN1C(C(NC2=CC(CCl)=CC=C2)=O)=NC2=C1C=CC=C2NC(C(C=C(C=C1)Cl)=C1Cl)=O Chemical compound COCN1C(C(NC2=CC(CCl)=CC=C2)=O)=NC2=C1C=CC=C2NC(C(C=C(C=C1)Cl)=C1Cl)=O OPNBYMSSFGPVJH-UHFFFAOYSA-N 0.000 claims description 3
- DTQAPLMJWCUJFA-UHFFFAOYSA-N COCN1C(C(NC2=CC(CCl)=CC=C2)=O)=NC2=C1C=CC=C2NC(C(C=CC=C1C(F)(F)F)=C1Cl)=O Chemical compound COCN1C(C(NC2=CC(CCl)=CC=C2)=O)=NC2=C1C=CC=C2NC(C(C=CC=C1C(F)(F)F)=C1Cl)=O DTQAPLMJWCUJFA-UHFFFAOYSA-N 0.000 claims description 3
- HLXRJXIDBFZWLZ-UHFFFAOYSA-N COCN1C(C(NC2=CC(CCl)=CC=C2)=O)=NC2=C1C=CC=C2NC(C1=NC=CC=C1F)=O Chemical compound COCN1C(C(NC2=CC(CCl)=CC=C2)=O)=NC2=C1C=CC=C2NC(C1=NC=CC=C1F)=O HLXRJXIDBFZWLZ-UHFFFAOYSA-N 0.000 claims description 3
- SLFACWKGQAFDJI-UHFFFAOYSA-N COCN1C(NC(C(C=CC=C2CCC3=CC=CC=C3)=C2Cl)=O)=NC2=C1C=CC=C2C(NC1=CC(CCl)=CC=C1)=O Chemical compound COCN1C(NC(C(C=CC=C2CCC3=CC=CC=C3)=C2Cl)=O)=NC2=C1C=CC=C2C(NC1=CC(CCl)=CC=C1)=O SLFACWKGQAFDJI-UHFFFAOYSA-N 0.000 claims description 3
- COQBJCWAGBRQDH-UHFFFAOYSA-N NC(CC1=NC(C(C(NCC2=C(C(F)(F)F)C=CC=C2)=O)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O Chemical compound NC(CC1=NC(C(C(NCC2=C(C(F)(F)F)C=CC=C2)=O)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O COQBJCWAGBRQDH-UHFFFAOYSA-N 0.000 claims description 3
- LWELAXLQCUHGQA-UHFFFAOYSA-N O=C(C1=NC(C(C2C3=CC=CN3C=C2)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NC1=CC(CCl)=CC=C1 Chemical compound O=C(C1=NC(C(C2C3=CC=CN3C=C2)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NC1=CC(CCl)=CC=C1 LWELAXLQCUHGQA-UHFFFAOYSA-N 0.000 claims description 3
- GCPWMLMPVXMNDH-UHFFFAOYSA-N O=C(C1=NC(C(C2CCCC2)=CC=C2)=C2N1NC(C(C=C(C=C1)Cl)=C1Cl)=O)NC1=CC(CCl)=CC=C1 Chemical compound O=C(C1=NC(C(C2CCCC2)=CC=C2)=C2N1NC(C(C=C(C=C1)Cl)=C1Cl)=O)NC1=CC(CCl)=CC=C1 GCPWMLMPVXMNDH-UHFFFAOYSA-N 0.000 claims description 3
- BFKGPERGDITCRQ-LJQANCHMSA-N O=C(C1=NC(C(NC[C@@H]2OCCC2)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NC1=CC(CCl)=CC=C1 Chemical compound O=C(C1=NC(C(NC[C@@H]2OCCC2)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NC1=CC(CCl)=CC=C1 BFKGPERGDITCRQ-LJQANCHMSA-N 0.000 claims description 3
- BFKGPERGDITCRQ-IBGZPJMESA-N O=C(C1=NC(C(NC[C@H]2OCCC2)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NC1=CC(CCl)=CC=C1 Chemical compound O=C(C1=NC(C(NC[C@H]2OCCC2)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NC1=CC(CCl)=CC=C1 BFKGPERGDITCRQ-IBGZPJMESA-N 0.000 claims description 3
- VSCCHPKJPNAZQQ-UHFFFAOYSA-N O=C(C1=NC(C=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NC1=CC(CCl)=CC=C1 Chemical compound O=C(C1=NC(C=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NC1=CC(CCl)=CC=C1 VSCCHPKJPNAZQQ-UHFFFAOYSA-N 0.000 claims description 3
- KZMLGIPXVKSVIQ-UHFFFAOYSA-N O=C(C1=NC(C=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NC1CCCCC1 Chemical compound O=C(C1=NC(C=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NC1CCCCC1 KZMLGIPXVKSVIQ-UHFFFAOYSA-N 0.000 claims description 3
- ZYIOMWVRXZOIRM-UHFFFAOYSA-N OC(C1)CN1C1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound OC(C1)CN1C1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O ZYIOMWVRXZOIRM-UHFFFAOYSA-N 0.000 claims description 3
- VSNMFPLDAKDMDZ-UHFFFAOYSA-N OC1(CNC(C2=NC(C=CC=C3)=C3N2NC(C2=C(C(F)(F)F)C=CC=C2)=O)=O)CCCCC1 Chemical compound OC1(CNC(C2=NC(C=CC=C3)=C3N2NC(C2=C(C(F)(F)F)C=CC=C2)=O)=O)CCCCC1 VSNMFPLDAKDMDZ-UHFFFAOYSA-N 0.000 claims description 3
- YLTRDOJJGNUPQO-UHFFFAOYSA-N OCCNC1=NC(C(C(NC2=CC(CCl)=CC=C2)=O)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound OCCNC1=NC(C(C(NC2=CC(CCl)=CC=C2)=O)=CC=C2)=C2N1NC(C1=C(C(F)(F)F)C=CC=C1)=O YLTRDOJJGNUPQO-UHFFFAOYSA-N 0.000 claims description 3
- 208000006011 Stroke Diseases 0.000 claims description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 3
- 125000005874 benzothiadiazolyl group Chemical group 0.000 claims description 3
- 125000006312 cyclopentyl amino group Chemical group [H]N(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 3
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 3
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 3
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 claims description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 208000030507 AIDS Diseases 0.000 claims description 2
- 208000024827 Alzheimer disease Diseases 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- ORQWGZMYHDHQJM-UHFFFAOYSA-N CC(C)(CNC1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)COC Chemical compound CC(C)(CNC1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)COC ORQWGZMYHDHQJM-UHFFFAOYSA-N 0.000 claims description 2
- BXLOPNCDGRLRSU-UHFFFAOYSA-N CN(C)N1C(C(NC2=CC(CCl)=CC=C2)=O)=NC2=C1C=CC=C2NC(C(C=CC(Cl)=C1)=C1Cl)=O Chemical compound CN(C)N1C(C(NC2=CC(CCl)=CC=C2)=O)=NC2=C1C=CC=C2NC(C(C=CC(Cl)=C1)=C1Cl)=O BXLOPNCDGRLRSU-UHFFFAOYSA-N 0.000 claims description 2
- OVTOGCOVTNYZNJ-UHFFFAOYSA-N CN(CC1)CCN1C1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CN(CC1)CCN1C1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O OVTOGCOVTNYZNJ-UHFFFAOYSA-N 0.000 claims description 2
- KCDSSZPFSKNBTL-UHFFFAOYSA-N COC(C1)CN1C1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COC(C1)CN1C1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O KCDSSZPFSKNBTL-UHFFFAOYSA-N 0.000 claims description 2
- YWQATGGEHXWGPA-UHFFFAOYSA-N COCC(C(NC1=NC2=CC=CC=C2C=C1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound COCC(C(NC1=NC2=CC=CC=C2C=C1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O YWQATGGEHXWGPA-UHFFFAOYSA-N 0.000 claims description 2
- NXPCOCSHLAXREQ-UHFFFAOYSA-N COCCCC1=CC=CC(C(NC(C=C2)=CC3=C2N=C(C(NC2=CC(CCl)=CC=C2)=O)N3COC)=O)=C1Cl Chemical compound COCCCC1=CC=CC(C(NC(C=C2)=CC3=C2N=C(C(NC2=CC(CCl)=CC=C2)=O)N3COC)=O)=C1Cl NXPCOCSHLAXREQ-UHFFFAOYSA-N 0.000 claims description 2
- DCXKTTJNOUJWJO-UHFFFAOYSA-N COCN1C(C(NC2=CC(CCl)=CC=C2)=O)=NC2=C1C=CC=C2NC(C1=C(C(F)(F)F)C=CC(F)=C1)=O Chemical compound COCN1C(C(NC2=CC(CCl)=CC=C2)=O)=NC2=C1C=CC=C2NC(C1=C(C(F)(F)F)C=CC(F)=C1)=O DCXKTTJNOUJWJO-UHFFFAOYSA-N 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000007514 Herpes zoster Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- NMWCDEHMMWIURI-UHFFFAOYSA-N O=C(C1=NC(C=CC(NC(C(C=CC=C2F)=C2Cl)=O)=C2)=C2N1C1CCCC1)NC1=CC(CCl)=CC=C1 Chemical compound O=C(C1=NC(C=CC(NC(C(C=CC=C2F)=C2Cl)=O)=C2)=C2N1C1CCCC1)NC1=CC(CCl)=CC=C1 NMWCDEHMMWIURI-UHFFFAOYSA-N 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 125000005084 alkoxyalkylaminoalkyl group Chemical group 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 206010022000 influenza Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 201000009240 nasopharyngitis Diseases 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 2
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 208000035473 Communicable disease Diseases 0.000 claims 1
- 208000015181 infectious disease Diseases 0.000 claims 1
- 230000003612 virological effect Effects 0.000 claims 1
- 201000010099 disease Diseases 0.000 abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 2
- 125000001424 substituent group Chemical group 0.000 abstract description 2
- 230000036210 malignancy Effects 0.000 abstract 2
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 abstract 1
- 230000000069 prophylactic effect Effects 0.000 abstract 1
- 229940124597 therapeutic agent Drugs 0.000 abstract 1
- 238000000034 method Methods 0.000 description 575
- 239000000843 powder Substances 0.000 description 332
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 302
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 175
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 168
- 239000000243 solution Substances 0.000 description 132
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 110
- 235000019439 ethyl acetate Nutrition 0.000 description 101
- BWDPPMPQZZILAG-UHFFFAOYSA-N 3-(chloromethyl)aniline Chemical compound NC1=CC=CC(CCl)=C1 BWDPPMPQZZILAG-UHFFFAOYSA-N 0.000 description 83
- 239000000203 mixture Substances 0.000 description 77
- 238000006243 chemical reaction Methods 0.000 description 74
- 239000011541 reaction mixture Substances 0.000 description 70
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 69
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 69
- 239000002904 solvent Substances 0.000 description 63
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 58
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 58
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 55
- 239000012267 brine Substances 0.000 description 54
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 44
- JJKWHOSQTYYFAE-UHFFFAOYSA-N 2-methoxyacetyl chloride Chemical compound COCC(Cl)=O JJKWHOSQTYYFAE-UHFFFAOYSA-N 0.000 description 41
- MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 description 40
- 238000001816 cooling Methods 0.000 description 40
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 39
- 238000004440 column chromatography Methods 0.000 description 36
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 34
- 229960002986 dinoprostone Drugs 0.000 description 33
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 33
- 238000012360 testing method Methods 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 31
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 31
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 238000001914 filtration Methods 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 29
- DIUKLCJZYOPHGW-UHFFFAOYSA-N 2-chloro-3-fluorobenzoyl chloride Chemical compound FC1=CC=CC(C(Cl)=O)=C1Cl DIUKLCJZYOPHGW-UHFFFAOYSA-N 0.000 description 28
- 238000004519 manufacturing process Methods 0.000 description 28
- 102100033076 Prostaglandin E synthase Human genes 0.000 description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- KQRCBMPPEPNNDS-UHFFFAOYSA-N 2-bromo-3-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC(F)=C1Br KQRCBMPPEPNNDS-UHFFFAOYSA-N 0.000 description 26
- 230000008569 process Effects 0.000 description 25
- 239000010410 layer Substances 0.000 description 24
- 229920006395 saturated elastomer Polymers 0.000 description 24
- 239000002244 precipitate Substances 0.000 description 23
- 238000000921 elemental analysis Methods 0.000 description 22
- 239000012044 organic layer Substances 0.000 description 22
- 239000002253 acid Substances 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 20
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 20
- 230000005764 inhibitory process Effects 0.000 description 19
- 239000007788 liquid Substances 0.000 description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 19
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 17
- ZSKQIFWUTUZAGF-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=CC=C1C(F)(F)F ZSKQIFWUTUZAGF-UHFFFAOYSA-N 0.000 description 17
- 239000007858 starting material Substances 0.000 description 16
- 239000000725 suspension Substances 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- KPLHXWFXDADDMP-UHFFFAOYSA-N methyl 6-amino-1h-benzimidazole-2-carboxylate Chemical compound C1=C(N)C=C2NC(C(=O)OC)=NC2=C1 KPLHXWFXDADDMP-UHFFFAOYSA-N 0.000 description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
- 235000017557 sodium bicarbonate Nutrition 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 239000005457 ice water Substances 0.000 description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 11
- RSINFFVFOTUDEC-UHFFFAOYSA-N 2,5-dichlorobenzoyl chloride Chemical compound ClC(=O)C1=CC(Cl)=CC=C1Cl RSINFFVFOTUDEC-UHFFFAOYSA-N 0.000 description 11
- 239000007924 injection Substances 0.000 description 11
- 238000002347 injection Methods 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- USECIYVEPXUVHT-UHFFFAOYSA-N 2-propan-2-yloxyethanamine Chemical compound CC(C)OCCN USECIYVEPXUVHT-UHFFFAOYSA-N 0.000 description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 10
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 10
- 239000012346 acetyl chloride Substances 0.000 description 10
- 229920000609 methyl cellulose Polymers 0.000 description 10
- 239000001923 methylcellulose Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- 150000001408 amides Chemical class 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 238000006722 reduction reaction Methods 0.000 description 9
- MXIUWSYTQJLIKE-UHFFFAOYSA-N 2-(trifluoromethyl)benzoyl chloride Chemical compound FC(F)(F)C1=CC=CC=C1C(Cl)=O MXIUWSYTQJLIKE-UHFFFAOYSA-N 0.000 description 8
- FNVOFDGAASRDQY-UHFFFAOYSA-N 3-amino-2,2-dimethylpropan-1-ol Chemical compound NCC(C)(C)CO FNVOFDGAASRDQY-UHFFFAOYSA-N 0.000 description 8
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 238000006482 condensation reaction Methods 0.000 description 8
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 8
- 229940098779 methanesulfonic acid Drugs 0.000 description 8
- 239000012046 mixed solvent Substances 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 8
- 230000035484 reaction time Effects 0.000 description 8
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- AUUAQLYMPGNQRW-UHFFFAOYSA-N CCOCC1=CC=CC(C(O)=O)=C1Cl Chemical compound CCOCC1=CC=CC(C(O)=O)=C1Cl AUUAQLYMPGNQRW-UHFFFAOYSA-N 0.000 description 7
- 239000007821 HATU Substances 0.000 description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 7
- GGRLWLOZCZZFML-UHFFFAOYSA-N OC(C(C=CC=C1CCC2=CC=CC=C2)=C1Cl)=O Chemical compound OC(C(C=CC=C1CCC2=CC=CC=C2)=C1Cl)=O GGRLWLOZCZZFML-UHFFFAOYSA-N 0.000 description 7
- 239000012298 atmosphere Substances 0.000 description 7
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 150000002170 ethers Chemical class 0.000 description 7
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- YXDYHFYQRLFAFN-UHFFFAOYSA-N methyl 6-nitro-1h-benzimidazole-2-carboxylate Chemical compound [O-][N+](=O)C1=CC=C2NC(C(=O)OC)=NC2=C1 YXDYHFYQRLFAFN-UHFFFAOYSA-N 0.000 description 7
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 description 6
- JOMMESUNTRWXSL-UHFFFAOYSA-N 3-methoxy-n,2,2-trimethylpropan-1-amine Chemical compound CNCC(C)(C)COC JOMMESUNTRWXSL-UHFFFAOYSA-N 0.000 description 6
- FBPOCUYOKZNARE-UHFFFAOYSA-N COCC(C(OC)=O)(NC1=C2C=CC=C1)N2[N+]([O-])=O Chemical compound COCC(C(OC)=O)(NC1=C2C=CC=C1)N2[N+]([O-])=O FBPOCUYOKZNARE-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- GISRWBROCYNDME-PELMWDNLSA-N F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C Chemical compound F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C GISRWBROCYNDME-PELMWDNLSA-N 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- SLGMMDLJXMHXJD-UHFFFAOYSA-N O=C(C(C1=CC=CC=C11)=NN1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NCC1=C(C(F)(F)F)C=CC=C1 Chemical compound O=C(C(C1=CC=CC=C11)=NN1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NCC1=C(C(F)(F)F)C=CC=C1 SLGMMDLJXMHXJD-UHFFFAOYSA-N 0.000 description 6
- AXHIDDISVNJPNP-UHFFFAOYSA-N OC(C(C=CC=C1C#CC2CC2)=C1Cl)=O Chemical compound OC(C(C=CC=C1C#CC2CC2)=C1Cl)=O AXHIDDISVNJPNP-UHFFFAOYSA-N 0.000 description 6
- 230000000202 analgesic effect Effects 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000012456 homogeneous solution Substances 0.000 description 6
- 229930195733 hydrocarbon Natural products 0.000 description 6
- 150000002430 hydrocarbons Chemical class 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000013642 negative control Substances 0.000 description 6
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 239000013641 positive control Substances 0.000 description 6
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- OUGRUBQYUABKOI-UHFFFAOYSA-N OC(C(NC1=C2C=CC=C1)(N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)Cl)=O Chemical compound OC(C(NC1=C2C=CC=C1)(N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)Cl)=O OUGRUBQYUABKOI-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 239000000654 additive Substances 0.000 description 5
- 230000003110 anti-inflammatory effect Effects 0.000 description 5
- 150000004982 aromatic amines Chemical class 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- 239000012452 mother liquor Substances 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 150000003180 prostaglandins Chemical class 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 4
- JBLIDPPHFGWTKU-UHFFFAOYSA-N 2,6-dichlorobenzoyl chloride Chemical compound ClC(=O)C1=C(Cl)C=CC=C1Cl JBLIDPPHFGWTKU-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- NIAQQWWHPMXRCY-UHFFFAOYSA-N CC(C=CC1=C2N=C(C(NC3=CC(CCl)=CC=C3)=O)O1)=C2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CC(C=CC1=C2N=C(C(NC3=CC(CCl)=CC=C3)=O)O1)=C2NC(C1=C(C(F)(F)F)C=CC=C1)=O NIAQQWWHPMXRCY-UHFFFAOYSA-N 0.000 description 4
- LWPCQBUSWYDUGX-UHFFFAOYSA-N CC1(C(NCC2=C(C(F)(F)F)C=CC=C2)=O)OC(C=CC=C2NC(C3=C(C(F)(F)F)C=CC=C3)=O)=C2N1 Chemical compound CC1(C(NCC2=C(C(F)(F)F)C=CC=C2)=O)OC(C=CC=C2NC(C3=C(C(F)(F)F)C=CC=C3)=O)=C2N1 LWPCQBUSWYDUGX-UHFFFAOYSA-N 0.000 description 4
- OZGPXGURGMKVKI-UHFFFAOYSA-N CCC(C=CC1=C2N=C(C(NC3=CC(CCl)=CC=C3)=O)O1)=C2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CCC(C=CC1=C2N=C(C(NC3=CC(CCl)=CC=C3)=O)O1)=C2NC(C1=C(C(F)(F)F)C=CC=C1)=O OZGPXGURGMKVKI-UHFFFAOYSA-N 0.000 description 4
- VBCFAVDPKYAORV-UHFFFAOYSA-N CCC1C(C=CC=C2)=C2OC1(C(O)=O)Br Chemical compound CCC1C(C=CC=C2)=C2OC1(C(O)=O)Br VBCFAVDPKYAORV-UHFFFAOYSA-N 0.000 description 4
- MGCIWOZTBRPMCN-UHFFFAOYSA-N COC(C(CCl)(NC1=C2C=CC=C1)N2[N+]([O-])=O)=O Chemical compound COC(C(CCl)(NC1=C2C=CC=C1)N2[N+]([O-])=O)=O MGCIWOZTBRPMCN-UHFFFAOYSA-N 0.000 description 4
- VXSPVZSHFKVOHC-UHFFFAOYSA-N COC(C1=NC(C=CC(N)=C2)=C2N1Cl)=O Chemical compound COC(C1=NC(C=CC(N)=C2)=C2N1Cl)=O VXSPVZSHFKVOHC-UHFFFAOYSA-N 0.000 description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- RGJVAPXRZNDTFR-UHFFFAOYSA-N OC(C(CC(N1CCCC1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O Chemical compound OC(C(CC(N1CCCC1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O RGJVAPXRZNDTFR-UHFFFAOYSA-N 0.000 description 4
- 102000004226 Prostaglandin-E Synthases Human genes 0.000 description 4
- 108090000748 Prostaglandin-E Synthases Proteins 0.000 description 4
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 4
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
- 230000000996 additive effect Effects 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 4
- 239000012300 argon atmosphere Substances 0.000 description 4
- 239000000679 carrageenan Substances 0.000 description 4
- 229920001525 carrageenan Polymers 0.000 description 4
- 235000010418 carrageenan Nutrition 0.000 description 4
- 229940113118 carrageenan Drugs 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- 229940111134 coxibs Drugs 0.000 description 4
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 description 4
- 229960001123 epoprostenol Drugs 0.000 description 4
- NPTDXPDGUHAFKC-UHFFFAOYSA-N ethynylcyclopropane Chemical group C#CC1CC1 NPTDXPDGUHAFKC-UHFFFAOYSA-N 0.000 description 4
- 150000008282 halocarbons Chemical class 0.000 description 4
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 239000003999 initiator Substances 0.000 description 4
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 4
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 4
- 229910052697 platinum Inorganic materials 0.000 description 4
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 4
- YIBNHAJFJUQSRA-YNNPMVKQSA-N prostaglandin H2 Chemical compound C1[C@@H]2OO[C@H]1[C@H](/C=C/[C@@H](O)CCCCC)[C@H]2C\C=C/CCCC(O)=O YIBNHAJFJUQSRA-YNNPMVKQSA-N 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 4
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 3
- DVCFNCQPOANJGU-SCSAIBSYSA-N (2r)-oxolane-2-carbonyl chloride Chemical compound ClC(=O)[C@H]1CCCO1 DVCFNCQPOANJGU-SCSAIBSYSA-N 0.000 description 3
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 3
- YTEUDCIEJDRJTM-UHFFFAOYSA-N 2-(chloromethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCl YTEUDCIEJDRJTM-UHFFFAOYSA-N 0.000 description 3
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 description 3
- PQUOEPYRTBAJTK-UHFFFAOYSA-N 3-methoxy-2,2-dimethylpropan-1-amine Chemical compound COCC(C)(C)CN PQUOEPYRTBAJTK-UHFFFAOYSA-N 0.000 description 3
- QKCOKEIMHOFEHO-UHFFFAOYSA-N 3-methoxy-2-methylpropan-1-amine Chemical compound COCC(C)CN QKCOKEIMHOFEHO-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- XYWIPYBIIRTJMM-IBGZPJMESA-N 4-[[(2S)-2-[4-[5-chloro-2-[4-(trifluoromethyl)triazol-1-yl]phenyl]-5-methoxy-2-oxopyridin-1-yl]butanoyl]amino]-2-fluorobenzamide Chemical compound CC[C@H](N1C=C(OC)C(=CC1=O)C1=C(C=CC(Cl)=C1)N1C=C(N=N1)C(F)(F)F)C(=O)NC1=CC(F)=C(C=C1)C(N)=O XYWIPYBIIRTJMM-IBGZPJMESA-N 0.000 description 3
- HZQBLHMRCALFDM-UHFFFAOYSA-N 6-(bromomethyl)-1,3-benzoxazole-2-carboxylic acid Chemical compound OC(=O)c1nc2ccc(CBr)cc2o1 HZQBLHMRCALFDM-UHFFFAOYSA-N 0.000 description 3
- DXGJJRGXCRCGNL-UHFFFAOYSA-N CC(CCC1=CC=CC(C(O)=O)=C1Cl)CO Chemical compound CC(CCC1=CC=CC(C(O)=O)=C1Cl)CO DXGJJRGXCRCGNL-UHFFFAOYSA-N 0.000 description 3
- OGNFKOPLGWTPRI-UHFFFAOYSA-N CC1=CC=CC2=C1NC(COC)(C(O)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CC1=CC=CC2=C1NC(COC)(C(O)=O)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O OGNFKOPLGWTPRI-UHFFFAOYSA-N 0.000 description 3
- COMMBERVPVZVCY-UHFFFAOYSA-N COC(C(CC(N1CCCC1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O Chemical compound COC(C(CC(N1CCCC1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O COMMBERVPVZVCY-UHFFFAOYSA-N 0.000 description 3
- JBRZJSNCRXUNJN-UHFFFAOYSA-N COC(C(NC1=C2C=CC=C1)(N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)Cl)=O Chemical compound COC(C(NC1=C2C=CC=C1)(N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)Cl)=O JBRZJSNCRXUNJN-UHFFFAOYSA-N 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- ZWUVAOZQHHWNDV-UHFFFAOYSA-N NC(CC(C(O)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O Chemical compound NC(CC(C(O)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O ZWUVAOZQHHWNDV-UHFFFAOYSA-N 0.000 description 3
- FSYGCMSLCYPIMX-UHFFFAOYSA-N O=C(C(C1)(NC(C2=C(C(F)(F)F)C=CC=C2)=O)OC2=C1C=CC=C2)NCC1=C(C(F)(F)F)C=CC=C1 Chemical compound O=C(C(C1)(NC(C2=C(C(F)(F)F)C=CC=C2)=O)OC2=C1C=CC=C2)NCC1=C(C(F)(F)F)C=CC=C1 FSYGCMSLCYPIMX-UHFFFAOYSA-N 0.000 description 3
- PSDCBULFVSLFTG-UHFFFAOYSA-N O=C(C(C1=CC=CC=C11)=NN1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NC1CCCCC1 Chemical compound O=C(C(C1=CC=CC=C11)=NN1NC(C1=C(C(F)(F)F)C=CC=C1)=O)NC1CCCCC1 PSDCBULFVSLFTG-UHFFFAOYSA-N 0.000 description 3
- VLMYIDVKSRCBEK-UHFFFAOYSA-N OC(C(C=CC=C1C#CC2=CC=CC=C2)=C1Cl)=O Chemical compound OC(C(C=CC=C1C#CC2=CC=CC=C2)=C1Cl)=O VLMYIDVKSRCBEK-UHFFFAOYSA-N 0.000 description 3
- ANIHUUKXFHAXGI-UHFFFAOYSA-N OC(C(C=CC=C1OCC(F)F)=C1Cl)=O Chemical compound OC(C(C=CC=C1OCC(F)F)=C1Cl)=O ANIHUUKXFHAXGI-UHFFFAOYSA-N 0.000 description 3
- BTJZQHMGTZCLTB-UHFFFAOYSA-N OC(C(C=CC=C1OCCCC(F)(F)F)=C1Cl)=O Chemical compound OC(C(C=CC=C1OCCCC(F)(F)F)=C1Cl)=O BTJZQHMGTZCLTB-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- WJKDJSRGLDAXHI-UHFFFAOYSA-N [3-(trifluoromethyl)pyridin-2-yl]methanamine Chemical compound NCC1=NC=CC=C1C(F)(F)F WJKDJSRGLDAXHI-UHFFFAOYSA-N 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000005658 halogenation reaction Methods 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 3
- GRWIABMEEKERFV-UHFFFAOYSA-N methanol;oxolane Chemical compound OC.C1CCOC1 GRWIABMEEKERFV-UHFFFAOYSA-N 0.000 description 3
- BLJHLOLVEXWHFS-UHFFFAOYSA-N methyl 2,3-diaminobenzoate Chemical compound COC(=O)C1=CC=CC(N)=C1N BLJHLOLVEXWHFS-UHFFFAOYSA-N 0.000 description 3
- 210000001589 microsome Anatomy 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 239000004323 potassium nitrate Substances 0.000 description 3
- 235000010333 potassium nitrate Nutrition 0.000 description 3
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 3
- 201000007094 prostatitis Diseases 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 229910001220 stainless steel Inorganic materials 0.000 description 3
- 239000010935 stainless steel Substances 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 230000008961 swelling Effects 0.000 description 3
- KDDNKZCVYQDGKE-UHFFFAOYSA-N (2-chlorophenyl)methanamine Chemical compound NCC1=CC=CC=C1Cl KDDNKZCVYQDGKE-UHFFFAOYSA-N 0.000 description 2
- ZRUPXAZUXDFLTG-YFKPBYRVSA-N (2s)-1-aminopentan-2-ol Chemical compound CCC[C@H](O)CN ZRUPXAZUXDFLTG-YFKPBYRVSA-N 0.000 description 2
- DVCFNCQPOANJGU-BYPYZUCNSA-N (2s)-oxolane-2-carbonyl chloride Chemical compound ClC(=O)[C@@H]1CCCO1 DVCFNCQPOANJGU-BYPYZUCNSA-N 0.000 description 2
- SSUJUUNLZQVZMO-UHFFFAOYSA-N 1,2,3,4,8,9,10,10a-octahydropyrimido[1,2-a]azepine Chemical compound C1CCC=CN2CCCNC21 SSUJUUNLZQVZMO-UHFFFAOYSA-N 0.000 description 2
- ONRNRVLJHFFBJG-UHFFFAOYSA-N 1,2-di(imidazol-1-yl)ethane-1,2-dione Chemical compound C1=CN=CN1C(=O)C(=O)N1C=CN=C1 ONRNRVLJHFFBJG-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- BSXPDVKSFWQFRT-UHFFFAOYSA-N 1-hydroxytriazolo[4,5-b]pyridine Chemical compound C1=CC=C2N(O)N=NC2=N1 BSXPDVKSFWQFRT-UHFFFAOYSA-N 0.000 description 2
- GTDXPJJHRWOFDI-UHFFFAOYSA-N 1-methylcyclopropane-1-carbonyl chloride Chemical compound ClC(=O)C1(C)CC1 GTDXPJJHRWOFDI-UHFFFAOYSA-N 0.000 description 2
- RUFPHBVGCFYCNW-UHFFFAOYSA-N 1-naphthylamine Chemical compound C1=CC=C2C(N)=CC=CC2=C1 RUFPHBVGCFYCNW-UHFFFAOYSA-N 0.000 description 2
- XDIAMRVROCPPBK-UHFFFAOYSA-N 2,2-dimethylpropan-1-amine Chemical compound CC(C)(C)CN XDIAMRVROCPPBK-UHFFFAOYSA-N 0.000 description 2
- CZZZABOKJQXEBO-UHFFFAOYSA-N 2,4-dimethylaniline Chemical compound CC1=CC=C(N)C(C)=C1 CZZZABOKJQXEBO-UHFFFAOYSA-N 0.000 description 2
- JFJQMUQRTCGSFC-UHFFFAOYSA-N 2-(chloromethyl)aniline Chemical compound NC1=CC=CC=C1CCl JFJQMUQRTCGSFC-UHFFFAOYSA-N 0.000 description 2
- QBAYIBZITZBSFO-UHFFFAOYSA-N 2-(trifluoromethyl)benzamide Chemical compound NC(=O)C1=CC=CC=C1C(F)(F)F QBAYIBZITZBSFO-UHFFFAOYSA-N 0.000 description 2
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- WJYAYXKXZNITAZ-UHFFFAOYSA-N 2-chloro-3-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC(F)=C1Cl WJYAYXKXZNITAZ-UHFFFAOYSA-N 0.000 description 2
- ZPMWWAIBJJFPPQ-UHFFFAOYSA-N 2-ethoxyacetyl chloride Chemical compound CCOCC(Cl)=O ZPMWWAIBJJFPPQ-UHFFFAOYSA-N 0.000 description 2
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 2
- 229940093475 2-ethoxyethanol Drugs 0.000 description 2
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 2
- HCGFUIQPSOCUHI-UHFFFAOYSA-N 2-propan-2-yloxyethanol Chemical compound CC(C)OCCO HCGFUIQPSOCUHI-UHFFFAOYSA-N 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- DOLQYFPDPKPQSS-UHFFFAOYSA-N 3,4-dimethylaniline Chemical compound CC1=CC=C(N)C=C1C DOLQYFPDPKPQSS-UHFFFAOYSA-N 0.000 description 2
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- JSMDUOFOPDSKIQ-UHFFFAOYSA-N 3-methoxypropanoyl chloride Chemical compound COCCC(Cl)=O JSMDUOFOPDSKIQ-UHFFFAOYSA-N 0.000 description 2
- ISULZYQDGYXDFW-UHFFFAOYSA-N 3-methylbutanoyl chloride Chemical compound CC(C)CC(Cl)=O ISULZYQDGYXDFW-UHFFFAOYSA-N 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- LMTOFAYSICBYRU-UHFFFAOYSA-N 4-chloro-1,3-benzoxazol-2-amine Chemical compound C1=CC=C2OC(N)=NC2=C1Cl LMTOFAYSICBYRU-UHFFFAOYSA-N 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- WRDWWAVNELMWAM-UHFFFAOYSA-N 4-tert-butylaniline Chemical compound CC(C)(C)C1=CC=C(N)C=C1 WRDWWAVNELMWAM-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- QLMWQMKUVJXLBL-UHFFFAOYSA-N CC(C)(C)N1C(C(OC)=O)=NC(C=C2)=C1C=C2N Chemical compound CC(C)(C)N1C(C(OC)=O)=NC(C=C2)=C1C=C2N QLMWQMKUVJXLBL-UHFFFAOYSA-N 0.000 description 2
- WQWKZQZFTMBWIP-UHFFFAOYSA-N CC(CO)C#CC1=CC=CC(C(O)=O)=C1Cl Chemical compound CC(CO)C#CC1=CC=CC(C(O)=O)=C1Cl WQWKZQZFTMBWIP-UHFFFAOYSA-N 0.000 description 2
- MGTJVEHUPYMLML-UHFFFAOYSA-N CC(OCC(C(OC)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O Chemical compound CC(OCC(C(OC)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O MGTJVEHUPYMLML-UHFFFAOYSA-N 0.000 description 2
- JHCWPSGRKADTQJ-UHFFFAOYSA-N CC(OCC(C(OC)=O)(NC1=C2C=CC=C1)N2[N+]([O-])=O)=O Chemical compound CC(OCC(C(OC)=O)(NC1=C2C=CC=C1)N2[N+]([O-])=O)=O JHCWPSGRKADTQJ-UHFFFAOYSA-N 0.000 description 2
- PRWTWJNFTGLGFQ-UHFFFAOYSA-N CC(OCNC1(C(OC)=O)NC(C=CC=C2)=C2N1)=O Chemical compound CC(OCNC1(C(OC)=O)NC(C=CC=C2)=C2N1)=O PRWTWJNFTGLGFQ-UHFFFAOYSA-N 0.000 description 2
- RNANAUQYJVCFJP-UHFFFAOYSA-N CC1=CC=C2N(COCC[Si](C)(C)C)N=C(C(O)=O)C2=C1Br Chemical compound CC1=CC=C2N(COCC[Si](C)(C)C)N=C(C(O)=O)C2=C1Br RNANAUQYJVCFJP-UHFFFAOYSA-N 0.000 description 2
- GHAMVHOOXRTFCE-UHFFFAOYSA-N CC1=CC=C2N(COCC[Si](C)(C)C)N=C(C(O)=O)C2=C1N Chemical compound CC1=CC=C2N(COCC[Si](C)(C)C)N=C(C(O)=O)C2=C1N GHAMVHOOXRTFCE-UHFFFAOYSA-N 0.000 description 2
- KOIIQHBJONVJDH-UHFFFAOYSA-N CC1=CC=C2N(COCC[Si](C)(C)C)N=C(C(O)=O)C2=C1NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CC1=CC=C2N(COCC[Si](C)(C)C)N=C(C(O)=O)C2=C1NC(C1=C(C(F)(F)F)C=CC=C1)=O KOIIQHBJONVJDH-UHFFFAOYSA-N 0.000 description 2
- UFUNRGACHQVVLF-UHFFFAOYSA-N CC1=CC=C2N(COCC[Si](C)(C)C)N=C(C(O)=O)C2=C1NC(OCC1=CC=CC=C1)=O Chemical compound CC1=CC=C2N(COCC[Si](C)(C)C)N=C(C(O)=O)C2=C1NC(OCC1=CC=CC=C1)=O UFUNRGACHQVVLF-UHFFFAOYSA-N 0.000 description 2
- DJXAAAWNFPTIGX-UHFFFAOYSA-N CCOC(C(O)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CCOC(C(O)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O DJXAAAWNFPTIGX-UHFFFAOYSA-N 0.000 description 2
- WTJJMNOFLMOQKY-UHFFFAOYSA-N CCOC(C(OC)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CCOC(C(OC)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O WTJJMNOFLMOQKY-UHFFFAOYSA-N 0.000 description 2
- HRDKXMGISTVXAX-UHFFFAOYSA-N CCOC(C(OC)=O)(NC1=C2C=CC=C1)N2[N+]([O-])=O Chemical compound CCOC(C(OC)=O)(NC1=C2C=CC=C1)N2[N+]([O-])=O HRDKXMGISTVXAX-UHFFFAOYSA-N 0.000 description 2
- DKEWUJJUMLWQSD-UHFFFAOYSA-N CCOC(CC(C(OC)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O Chemical compound CCOC(CC(C(OC)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O DKEWUJJUMLWQSD-UHFFFAOYSA-N 0.000 description 2
- AJKOUHKGVOPTDI-UHFFFAOYSA-N CCOC(CC1(C(OC)=O)NC(C=CC=C2)=C2N1)=O Chemical compound CCOC(CC1(C(OC)=O)NC(C=CC=C2)=C2N1)=O AJKOUHKGVOPTDI-UHFFFAOYSA-N 0.000 description 2
- IHQGQUJPCGERCV-UHFFFAOYSA-N CCOCCOCC1=CC=CC(C(O)=O)=C1Cl Chemical compound CCOCCOCC1=CC=CC(C(O)=O)=C1Cl IHQGQUJPCGERCV-UHFFFAOYSA-N 0.000 description 2
- WDLUFLUTAJUBJF-UHFFFAOYSA-N CN(C)C(C(O)=O)(NC1=C2C=CC=C1)N2[N+]([O-])=O Chemical compound CN(C)C(C(O)=O)(NC1=C2C=CC=C1)N2[N+]([O-])=O WDLUFLUTAJUBJF-UHFFFAOYSA-N 0.000 description 2
- LOBMNLFJCABHNG-UHFFFAOYSA-N CN(C)C(C(OC)=O)(NC1=C2C=CC=C1)N2[N+]([O-])=O Chemical compound CN(C)C(C(OC)=O)(NC1=C2C=CC=C1)N2[N+]([O-])=O LOBMNLFJCABHNG-UHFFFAOYSA-N 0.000 description 2
- ZBGGQIOKICTUHW-UHFFFAOYSA-N CN(C)C(CC(C(O)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O Chemical compound CN(C)C(CC(C(O)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O ZBGGQIOKICTUHW-UHFFFAOYSA-N 0.000 description 2
- HIUDDMRRPHHBHF-UHFFFAOYSA-N CN(C)C(CC(C(OC)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O Chemical compound CN(C)C(CC(C(OC)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O HIUDDMRRPHHBHF-UHFFFAOYSA-N 0.000 description 2
- ARLTWILWSZZTFJ-UHFFFAOYSA-N CN(C)C1(C(OC)=O)NC(C=CC=C2)=C2N1 Chemical compound CN(C)C1(C(OC)=O)NC(C=CC=C2)=C2N1 ARLTWILWSZZTFJ-UHFFFAOYSA-N 0.000 description 2
- XINXPIMRHQIPAR-UHFFFAOYSA-N CN(C)CC(C(O)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CN(C)CC(C(O)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O XINXPIMRHQIPAR-UHFFFAOYSA-N 0.000 description 2
- RECXVCOYIYFRHP-UHFFFAOYSA-N CN(C)CC(C(OC)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CN(C)CC(C(OC)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O RECXVCOYIYFRHP-UHFFFAOYSA-N 0.000 description 2
- UZDAMBUWWAIENR-UHFFFAOYSA-N CN1C(C(O)=O)=NC2=C1C=CC=C2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CN1C(C(O)=O)=NC2=C1C=CC=C2NC(C1=C(C(F)(F)F)C=CC=C1)=O UZDAMBUWWAIENR-UHFFFAOYSA-N 0.000 description 2
- OZAYUDIWDAELPH-UHFFFAOYSA-N CN1C(C(OC)=O)=NC2=C1C=CC=C2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CN1C(C(OC)=O)=NC2=C1C=CC=C2NC(C1=C(C(F)(F)F)C=CC=C1)=O OZAYUDIWDAELPH-UHFFFAOYSA-N 0.000 description 2
- QIMIQIUIILKQPC-UHFFFAOYSA-N CNC(CC(C(O)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O Chemical compound CNC(CC(C(O)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O QIMIQIUIILKQPC-UHFFFAOYSA-N 0.000 description 2
- BNLDLVPGUUHNMG-UHFFFAOYSA-N CNC(CC(C(OC)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O Chemical compound CNC(CC(C(OC)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O BNLDLVPGUUHNMG-UHFFFAOYSA-N 0.000 description 2
- MTNUCBFEKBUHBQ-UHFFFAOYSA-N COC(C(C1CCCC1)(NC1=C2C=CC=C1)N2[N+]([O-])=O)=O Chemical compound COC(C(C1CCCC1)(NC1=C2C=CC=C1)N2[N+]([O-])=O)=O MTNUCBFEKBUHBQ-UHFFFAOYSA-N 0.000 description 2
- PXSBOHKWLXEKPG-UHFFFAOYSA-N COC(C(C=CC=C1OCC(F)F)=C1Cl)=O Chemical compound COC(C(C=CC=C1OCC(F)F)=C1Cl)=O PXSBOHKWLXEKPG-UHFFFAOYSA-N 0.000 description 2
- APSNZYLYPXYCIN-UHFFFAOYSA-N COC(C(C=CC=C1OCCCC(F)(F)F)=C1Cl)=O Chemical compound COC(C(C=CC=C1OCCCC(F)(F)F)=C1Cl)=O APSNZYLYPXYCIN-UHFFFAOYSA-N 0.000 description 2
- PWBOXDYEUZDBNL-UHFFFAOYSA-N COC(C(CC(N)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O Chemical compound COC(C(CC(N)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O PWBOXDYEUZDBNL-UHFFFAOYSA-N 0.000 description 2
- KQDKZVRKQYLVIV-UHFFFAOYSA-N COC(C(NC1=C2C=CC=C1)(N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)SC)=O Chemical compound COC(C(NC1=C2C=CC=C1)(N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)SC)=O KQDKZVRKQYLVIV-UHFFFAOYSA-N 0.000 description 2
- NCYNMFGTMREIQA-UHFFFAOYSA-N COC(C(NC1=C2C=CC=C1)(N2[N+]([O-])=O)Cl)=O Chemical compound COC(C(NC1=C2C=CC=C1)(N2[N+]([O-])=O)Cl)=O NCYNMFGTMREIQA-UHFFFAOYSA-N 0.000 description 2
- YWIDWMPIHPLBFX-UHFFFAOYSA-N COC(C(NC1=C2C=CC=C1)(N2[N+]([O-])=O)SC)=O Chemical compound COC(C(NC1=C2C=CC=C1)(N2[N+]([O-])=O)SC)=O YWIDWMPIHPLBFX-UHFFFAOYSA-N 0.000 description 2
- ULTCEYHEBIRCSS-UHFFFAOYSA-N COC(C1(NC(C=CC=C2)=C2N1)Cl)=O Chemical compound COC(C1(NC(C=CC=C2)=C2N1)Cl)=O ULTCEYHEBIRCSS-UHFFFAOYSA-N 0.000 description 2
- VQGGDGRYOVHKQY-UHFFFAOYSA-N COC(C1(NC(C=CC=C2)=C2N1)SC)=O Chemical compound COC(C1(NC(C=CC=C2)=C2N1)SC)=O VQGGDGRYOVHKQY-UHFFFAOYSA-N 0.000 description 2
- DDKPHXRJGKMTLG-UHFFFAOYSA-N COC(C1=NC(C=CC(N)=C2)=C2N1C1CC1)=O Chemical compound COC(C1=NC(C=CC(N)=C2)=C2N1C1CC1)=O DDKPHXRJGKMTLG-UHFFFAOYSA-N 0.000 description 2
- GKEHSHYIMLVIPU-UHFFFAOYSA-N COC(C1=NC(C=CC(N)=C2)=C2N1SC)=O Chemical compound COC(C1=NC(C=CC(N)=C2)=C2N1SC)=O GKEHSHYIMLVIPU-UHFFFAOYSA-N 0.000 description 2
- MBBPZCQQNQYPLX-UHFFFAOYSA-N COC(C1=NC(C=CC(OCCN)=C2)=C2N1)=O Chemical compound COC(C1=NC(C=CC(OCCN)=C2)=C2N1)=O MBBPZCQQNQYPLX-UHFFFAOYSA-N 0.000 description 2
- YDBQQQOOSXSMMV-UHFFFAOYSA-N COCC(C(O)=O)(NC1=C2C=CC=C1)N2[N+]([O-])=O Chemical compound COCC(C(O)=O)(NC1=C2C=CC=C1)N2[N+]([O-])=O YDBQQQOOSXSMMV-UHFFFAOYSA-N 0.000 description 2
- KBAXXUBUKUPSRK-UHFFFAOYSA-N COCCN1C(C(OC)=O)=NC(C=C2)=C1C=C2N Chemical compound COCCN1C(C(OC)=O)=NC(C=C2)=C1C=C2N KBAXXUBUKUPSRK-UHFFFAOYSA-N 0.000 description 2
- SAUSLPDMAMUFMN-UHFFFAOYSA-N COCN1C(C(OC)=O)=NC(C=C2)=C1C=C2N Chemical compound COCN1C(C(OC)=O)=NC(C=C2)=C1C=C2N SAUSLPDMAMUFMN-UHFFFAOYSA-N 0.000 description 2
- ZJIMWHCIHBASNX-UHFFFAOYSA-N CSC(C(O)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O Chemical compound CSC(C(O)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O ZJIMWHCIHBASNX-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- YYJYOFBMDABCRV-UHFFFAOYSA-N ClCC1=CC=CC(CN2C(C=CC(Br)=C3)=C3OC2)=C1 Chemical compound ClCC1=CC=CC(CN2C(C=CC(Br)=C3)=C3OC2)=C1 YYJYOFBMDABCRV-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- MXGDOLKDZSEAFS-UHFFFAOYSA-N O=C(C(C1)(NC(C2=C(C(F)(F)F)C=CC=C2)=O)OC2=C1C=CC=C2)NC1=CC(CCl)=CC=C1 Chemical compound O=C(C(C1)(NC(C2=C(C(F)(F)F)C=CC=C2)=O)OC2=C1C=CC=C2)NC1=CC(CCl)=CC=C1 MXGDOLKDZSEAFS-UHFFFAOYSA-N 0.000 description 2
- ABBNTWMQPALYIE-UHFFFAOYSA-N O=C(C(C1)(NC(C2=C(C(F)(F)F)C=CC=C2)=O)OC2=C1C=CC=C2)NC1CCCCC1 Chemical compound O=C(C(C1)(NC(C2=C(C(F)(F)F)C=CC=C2)=O)OC2=C1C=CC=C2)NC1CCCCC1 ABBNTWMQPALYIE-UHFFFAOYSA-N 0.000 description 2
- MRACFBHNFNDVQB-JOCHJYFZSA-N O=C(C(C=CC=C1F)=C1Cl)NC(C=C1)=CC2=C1N=C([C@@H]1OCCC1)N2C1=CC(CCl)=CC=C1 Chemical compound O=C(C(C=CC=C1F)=C1Cl)NC(C=C1)=CC2=C1N=C([C@@H]1OCCC1)N2C1=CC(CCl)=CC=C1 MRACFBHNFNDVQB-JOCHJYFZSA-N 0.000 description 2
- AJEKICXEFJVCDJ-UHFFFAOYSA-N O=C(C(NC1=C2C=CC=C1)(N2NC(C(C=C(C=C1)Cl)=C1Cl)=O)Cl)NC1=CC(CCl)=CC=C1 Chemical compound O=C(C(NC1=C2C=CC=C1)(N2NC(C(C=C(C=C1)Cl)=C1Cl)=O)Cl)NC1=CC(CCl)=CC=C1 AJEKICXEFJVCDJ-UHFFFAOYSA-N 0.000 description 2
- MRXCKLOUNGBIAP-UHFFFAOYSA-N O=C(C(NC1=C2C=CC=C1)(N2NC(C(C=CC=C1F)=C1Cl)=O)Cl)NC1=CC(CCl)=CC=C1 Chemical compound O=C(C(NC1=C2C=CC=C1)(N2NC(C(C=CC=C1F)=C1Cl)=O)Cl)NC1=CC(CCl)=CC=C1 MRXCKLOUNGBIAP-UHFFFAOYSA-N 0.000 description 2
- LGNXRECZLXHUCI-UHFFFAOYSA-N O=C(C1=NC(C=CC(Br)=C2)=C2O1)NCCC1=CC(CCl)=CC=C1 Chemical compound O=C(C1=NC(C=CC(Br)=C2)=C2O1)NCCC1=CC(CCl)=CC=C1 LGNXRECZLXHUCI-UHFFFAOYSA-N 0.000 description 2
- FUSZCSPRFAFBBN-UHFFFAOYSA-N OC(C(C=CC=C1CCC2CC2)=C1Cl)=O Chemical compound OC(C(C=CC=C1CCC2CC2)=C1Cl)=O FUSZCSPRFAFBBN-UHFFFAOYSA-N 0.000 description 2
- NGOAAOWTRUQBBM-UHFFFAOYSA-N OC(C1=NC(C=CC(CCBr)=C2)=C2O1)=O Chemical compound OC(C1=NC(C=CC(CCBr)=C2)=C2O1)=O NGOAAOWTRUQBBM-UHFFFAOYSA-N 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 102100030484 Prostaglandin E synthase 2 Human genes 0.000 description 2
- 108050003514 Prostaglandin E synthase 2 Proteins 0.000 description 2
- 102100028642 Prostaglandin E synthase 3 Human genes 0.000 description 2
- 101710103638 Prostaglandin E synthase 3 Proteins 0.000 description 2
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 2
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 description 2
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 2
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 229920000392 Zymosan Polymers 0.000 description 2
- YNOGYQAEJGADFJ-RXMQYKEDSA-N [(2r)-oxolan-2-yl]methanamine Chemical compound NC[C@H]1CCCO1 YNOGYQAEJGADFJ-RXMQYKEDSA-N 0.000 description 2
- YNOGYQAEJGADFJ-YFKPBYRVSA-N [(2s)-oxolan-2-yl]methanamine Chemical compound NC[C@@H]1CCCO1 YNOGYQAEJGADFJ-YFKPBYRVSA-N 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 229940114079 arachidonic acid Drugs 0.000 description 2
- 235000021342 arachidonic acid Nutrition 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 230000007211 cardiovascular event Effects 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 2
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 2
- 238000007872 degassing Methods 0.000 description 2
- ZWWWLCMDTZFSOO-UHFFFAOYSA-N diethoxyphosphorylformonitrile Chemical compound CCOP(=O)(C#N)OCC ZWWWLCMDTZFSOO-UHFFFAOYSA-N 0.000 description 2
- ZWWCURLKEXEFQT-UHFFFAOYSA-N dinitrogen pentaoxide Chemical compound [O-][N+](=O)O[N+]([O-])=O ZWWCURLKEXEFQT-UHFFFAOYSA-N 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 210000002683 foot Anatomy 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 210000000548 hind-foot Anatomy 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 150000007928 imidazolide derivatives Chemical class 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 2
- 210000005265 lung cell Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- LKUBWDNDGBVKFK-UHFFFAOYSA-N methyl 1h-benzimidazole-2-carboxylate Chemical compound C1=CC=C2NC(C(=O)OC)=NC2=C1 LKUBWDNDGBVKFK-UHFFFAOYSA-N 0.000 description 2
- PGIBXNLSUXQITJ-UHFFFAOYSA-N n'-[3-(dimethylamino)propyl]propanimidamide;hydrochloride Chemical compound Cl.CCC(N)=NCCCN(C)C PGIBXNLSUXQITJ-UHFFFAOYSA-N 0.000 description 2
- 238000006396 nitration reaction Methods 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 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 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- BHMBVRSPMRCCGG-OUTUXVNYSA-N prostaglandin D2 Chemical compound CCCCC[C@H](O)\C=C\[C@@H]1[C@@H](C\C=C/CCCC(O)=O)[C@@H](O)CC1=O BHMBVRSPMRCCGG-OUTUXVNYSA-N 0.000 description 2
- BHMBVRSPMRCCGG-UHFFFAOYSA-N prostaglandine D2 Natural products CCCCCC(O)C=CC1C(CC=CCCCC(O)=O)C(O)CC1=O BHMBVRSPMRCCGG-UHFFFAOYSA-N 0.000 description 2
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 2
- JWEQRJSCTFBRSI-PCLIKHOPSA-N rboxylate Chemical compound COC(=O)C1C(N2C3=O)C4=CC=CC=C4OC1(C)N=C2S\C3=C\C(C=1)=CC=C(OC)C=1COC1=CC=CC=C1C JWEQRJSCTFBRSI-PCLIKHOPSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- BHIGZYWRVWZUHG-UHFFFAOYSA-N tert-butyl n-(3-hydroxy-2,2-dimethylpropyl)carbamate Chemical compound CC(C)(C)OC(=O)NCC(C)(C)CO BHIGZYWRVWZUHG-UHFFFAOYSA-N 0.000 description 2
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 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
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 1
- XIHOYQMBAUMKCY-UHFFFAOYSA-N (2-amino-3-chlorophenyl)methanol Chemical compound NC1=C(Cl)C=CC=C1CO XIHOYQMBAUMKCY-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- ZRUPXAZUXDFLTG-RXMQYKEDSA-N (2r)-1-aminopentan-2-ol Chemical compound CCC[C@@H](O)CN ZRUPXAZUXDFLTG-RXMQYKEDSA-N 0.000 description 1
- JBULSURVMXPBNA-RXMQYKEDSA-N (2s)-2-amino-3,3-dimethylbutan-1-ol Chemical compound CC(C)(C)[C@H](N)CO JBULSURVMXPBNA-RXMQYKEDSA-N 0.000 description 1
- RNAWBUIUUZSPIT-UHFFFAOYSA-N (3-methyloxetan-2-yl)methanamine Chemical compound NCC1OCC1C RNAWBUIUUZSPIT-UHFFFAOYSA-N 0.000 description 1
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 1
- HMTSWYPNXFHGEP-UHFFFAOYSA-N (4-methylphenyl)methanamine Chemical compound CC1=CC=C(CN)C=C1 HMTSWYPNXFHGEP-UHFFFAOYSA-N 0.000 description 1
- UKGJZDSUJSPAJL-YPUOHESYSA-N (e)-n-[(1r)-1-[3,5-difluoro-4-(methanesulfonamido)phenyl]ethyl]-3-[2-propyl-6-(trifluoromethyl)pyridin-3-yl]prop-2-enamide Chemical compound CCCC1=NC(C(F)(F)F)=CC=C1\C=C\C(=O)N[C@H](C)C1=CC(F)=C(NS(C)(=O)=O)C(F)=C1 UKGJZDSUJSPAJL-YPUOHESYSA-N 0.000 description 1
- ZGYIXVSQHOKQRZ-COIATFDQSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-[(3s)-oxolan-3-yl]oxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N#CC1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZGYIXVSQHOKQRZ-COIATFDQSA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- VMFCTZUYOILUMY-UHFFFAOYSA-N 1,1-difluoro-2-iodoethane Chemical compound FC(F)CI VMFCTZUYOILUMY-UHFFFAOYSA-N 0.000 description 1
- KRUCRVZSHWOMHC-UHFFFAOYSA-N 1,1-dioxo-1-benzothiophen-6-amine Chemical compound NC1=CC=C2C=CS(=O)(=O)C2=C1 KRUCRVZSHWOMHC-UHFFFAOYSA-N 0.000 description 1
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 description 1
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 1
- JPBLHOJFMBOCAF-UHFFFAOYSA-N 1,3-benzoxazol-2-amine Chemical compound C1=CC=C2OC(N)=NC2=C1 JPBLHOJFMBOCAF-UHFFFAOYSA-N 0.000 description 1
- 125000000355 1,3-benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- APWRZPQBPCAXFP-UHFFFAOYSA-N 1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide Chemical compound O=C1NC=CC2=C(C=CC=C12)N1N=CC(=C1C(F)(F)F)C(=O)NC1=CC(=NC=C1)C(F)(F)F APWRZPQBPCAXFP-UHFFFAOYSA-N 0.000 description 1
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 1
- XUSXTHMTOSFZII-UHFFFAOYSA-N 1-(aminomethyl)cyclohexan-1-ol Chemical compound NCC1(O)CCCCC1 XUSXTHMTOSFZII-UHFFFAOYSA-N 0.000 description 1
- UDPCIPDJGNJPBG-UHFFFAOYSA-N 1-(trifluoromethyl)cyclopropane-1-carbonyl chloride Chemical compound FC(F)(F)C1(C(Cl)=O)CC1 UDPCIPDJGNJPBG-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 1
- KODLUXHSIZOKTG-UHFFFAOYSA-N 1-aminobutan-2-ol Chemical compound CCC(O)CN KODLUXHSIZOKTG-UHFFFAOYSA-N 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- CWLUFVAFWWNXJZ-UHFFFAOYSA-N 1-hydroxypyrrolidine Chemical compound ON1CCCC1 CWLUFVAFWWNXJZ-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 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
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
- RHXSYTACTOMVLJ-UHFFFAOYSA-N 1H-benzimidazole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=NC2=C1 RHXSYTACTOMVLJ-UHFFFAOYSA-N 0.000 description 1
- DRLGIZIAMHIQHL-UHFFFAOYSA-N 2,1,3-benzothiadiazol-4-amine Chemical compound NC1=CC=CC2=NSN=C12 DRLGIZIAMHIQHL-UHFFFAOYSA-N 0.000 description 1
- NUBKYCCXDNYHLQ-UHFFFAOYSA-N 2,2-dimethylpentanoyl chloride Chemical compound CCCC(C)(C)C(Cl)=O NUBKYCCXDNYHLQ-UHFFFAOYSA-N 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- RXWFVKGUUGWOTP-UHFFFAOYSA-N 2,3-dihydro-1h-benzimidazole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)NC2=C1 RXWFVKGUUGWOTP-UHFFFAOYSA-N 0.000 description 1
- LEWZOBYWGWKNCK-UHFFFAOYSA-N 2,3-dihydro-1h-inden-5-amine Chemical compound NC1=CC=C2CCCC2=C1 LEWZOBYWGWKNCK-UHFFFAOYSA-N 0.000 description 1
- JTOIZLCQNWWDCN-UHFFFAOYSA-N 2,4-bis(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(C(F)(F)F)C=C1C(F)(F)F JTOIZLCQNWWDCN-UHFFFAOYSA-N 0.000 description 1
- CEOCVKWBUWKBKA-UHFFFAOYSA-N 2,4-dichlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1Cl CEOCVKWBUWKBKA-UHFFFAOYSA-N 0.000 description 1
- PINBPLCVZSKLTF-UHFFFAOYSA-N 2,5-bis(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC(C(F)(F)F)=CC=C1C(F)(F)F PINBPLCVZSKLTF-UHFFFAOYSA-N 0.000 description 1
- ODUZJBKKYBQIBX-UHFFFAOYSA-N 2,6-difluoroaniline Chemical compound NC1=C(F)C=CC=C1F ODUZJBKKYBQIBX-UHFFFAOYSA-N 0.000 description 1
- OZJZCCMIOZPPIT-UHFFFAOYSA-N 2-(2-methoxyethoxy)acetyl chloride Chemical compound COCCOCC(Cl)=O OZJZCCMIOZPPIT-UHFFFAOYSA-N 0.000 description 1
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 1
- VBLXCTYLWZJBKA-UHFFFAOYSA-N 2-(trifluoromethyl)aniline Chemical compound NC1=CC=CC=C1C(F)(F)F VBLXCTYLWZJBKA-UHFFFAOYSA-N 0.000 description 1
- BLMLZYILSIZQTL-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxy]ethanamine Chemical compound CC(C)(C)OCCN BLMLZYILSIZQTL-UHFFFAOYSA-N 0.000 description 1
- UHGULLIUJBCTEF-UHFFFAOYSA-N 2-aminobenzothiazole Chemical compound C1=CC=C2SC(N)=NC2=C1 UHGULLIUJBCTEF-UHFFFAOYSA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- DWOBGCPUQNFAFB-UHFFFAOYSA-N 2-benzylaniline Chemical compound NC1=CC=CC=C1CC1=CC=CC=C1 DWOBGCPUQNFAFB-UHFFFAOYSA-N 0.000 description 1
- SITHNMNGOHVILG-UHFFFAOYSA-N 2-bromo-3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1Br SITHNMNGOHVILG-UHFFFAOYSA-N 0.000 description 1
- XWQZHBMGOSCGBQ-UHFFFAOYSA-N 2-bromo-3-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC(Cl)=C1Br XWQZHBMGOSCGBQ-UHFFFAOYSA-N 0.000 description 1
- BIDXHLMXMWMYJC-UHFFFAOYSA-N 2-bromo-3-fluorobenzoyl chloride Chemical compound FC1=CC=CC(C(Cl)=O)=C1Br BIDXHLMXMWMYJC-UHFFFAOYSA-N 0.000 description 1
- NZCKTGCKFJDGFD-UHFFFAOYSA-N 2-bromobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Br NZCKTGCKFJDGFD-UHFFFAOYSA-N 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- CBFPZKKUVNEIFF-UHFFFAOYSA-N 2-chloro-3,6-difluorobenzoyl chloride Chemical compound FC1=CC=C(F)C(C(Cl)=O)=C1Cl CBFPZKKUVNEIFF-UHFFFAOYSA-N 0.000 description 1
- AXOAWWUSRZCGKS-UHFFFAOYSA-N 2-chloro-3-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC(C(F)(F)F)=C1Cl AXOAWWUSRZCGKS-UHFFFAOYSA-N 0.000 description 1
- MUFPMNCISYCXFY-UHFFFAOYSA-N 2-chloro-5-[3-[(2-methylpropan-2-yl)oxy]prop-1-ynyl]benzoic acid Chemical compound CC(C)(C)OCC#CC1=CC=C(Cl)C(C(O)=O)=C1 MUFPMNCISYCXFY-UHFFFAOYSA-N 0.000 description 1
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 description 1
- RXTRRIFWCJEMEL-UHFFFAOYSA-N 2-chloropyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1Cl RXTRRIFWCJEMEL-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- QIGSPXPODKLGRK-UHFFFAOYSA-N 2-methyl-2-prop-2-ynoxypropane Chemical compound CC(C)(C)OCC#C QIGSPXPODKLGRK-UHFFFAOYSA-N 0.000 description 1
- QDLPJHIEFRSZJK-UHFFFAOYSA-N 2-methylbut-3-yn-1-ol Chemical compound OCC(C)C#C QDLPJHIEFRSZJK-UHFFFAOYSA-N 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- CYWGSFFHHMQKET-UHFFFAOYSA-N 2-methylsulfanylethanamine Chemical compound CSCCN CYWGSFFHHMQKET-UHFFFAOYSA-N 0.000 description 1
- BZSXEZOLBIJVQK-UHFFFAOYSA-N 2-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=CC=C1C(O)=O BZSXEZOLBIJVQK-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- WRXNJTBODVGDRY-UHFFFAOYSA-N 2-pyrrolidin-1-ylethanamine Chemical compound NCCN1CCCC1 WRXNJTBODVGDRY-UHFFFAOYSA-N 0.000 description 1
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- BUTKIHRNYUEGKB-UHFFFAOYSA-N 3,3-dimethylbutanoyl chloride Chemical compound CC(C)(C)CC(Cl)=O BUTKIHRNYUEGKB-UHFFFAOYSA-N 0.000 description 1
- BUQPTOSHKHYHHB-UHFFFAOYSA-N 3,5-dichloropyridine-4-carboxylic acid Chemical compound OC(=O)C1=C(Cl)C=NC=C1Cl BUQPTOSHKHYHHB-UHFFFAOYSA-N 0.000 description 1
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 1
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 1
- RRLCUHSIABCHRW-UHFFFAOYSA-N 3-(bromomethyl)aniline Chemical compound NC1=CC=CC(CBr)=C1 RRLCUHSIABCHRW-UHFFFAOYSA-N 0.000 description 1
- YGYGASJNJTYNOL-CQSZACIVSA-N 3-[(4r)-2,2-dimethyl-1,1-dioxothian-4-yl]-5-(4-fluorophenyl)-1h-indole-7-carboxamide Chemical compound C1CS(=O)(=O)C(C)(C)C[C@@H]1C1=CNC2=C(C(N)=O)C=C(C=3C=CC(F)=CC=3)C=C12 YGYGASJNJTYNOL-CQSZACIVSA-N 0.000 description 1
- WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 1
- SRVXSISGYBMIHR-UHFFFAOYSA-N 3-[3-[3-(2-amino-2-oxoethyl)phenyl]-5-chlorophenyl]-3-(5-methyl-1,3-thiazol-2-yl)propanoic acid Chemical compound S1C(C)=CN=C1C(CC(O)=O)C1=CC(Cl)=CC(C=2C=C(CC(N)=O)C=CC=2)=C1 SRVXSISGYBMIHR-UHFFFAOYSA-N 0.000 description 1
- FVXBTPGZQMNAEZ-UHFFFAOYSA-N 3-amino-2-methylpropan-1-ol Chemical compound NCC(C)CO FVXBTPGZQMNAEZ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- HBYCYCNDBPBPKH-UHFFFAOYSA-N 3-bromo-2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC(Br)=C1Cl HBYCYCNDBPBPKH-UHFFFAOYSA-N 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- MQZNDDUMJVSIMH-UHFFFAOYSA-N 3-chloro-2,2-dimethylpropanoyl chloride Chemical compound ClCC(C)(C)C(Cl)=O MQZNDDUMJVSIMH-UHFFFAOYSA-N 0.000 description 1
- XTMUXJBJCMRWPG-UHFFFAOYSA-N 3-chloropyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC=C1Cl XTMUXJBJCMRWPG-UHFFFAOYSA-N 0.000 description 1
- GFXIPEXVMCDDBA-UHFFFAOYSA-N 3-ethoxypropanoyl chloride Chemical compound CCOCCC(Cl)=O GFXIPEXVMCDDBA-UHFFFAOYSA-N 0.000 description 1
- IRERRSXDWUCFIY-UHFFFAOYSA-N 3-fluoropyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC=C1F IRERRSXDWUCFIY-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- DRHXPCBQKKTJHA-UHFFFAOYSA-N 3-methoxy-2,2-dimethylpropanoyl chloride Chemical compound COCC(C)(C)C(Cl)=O DRHXPCBQKKTJHA-UHFFFAOYSA-N 0.000 description 1
- KSXGQRBTBLQJEF-UHFFFAOYSA-N 3-methoxyazetidine;hydrochloride Chemical compound Cl.COC1CNC1 KSXGQRBTBLQJEF-UHFFFAOYSA-N 0.000 description 1
- FAXDZWQIWUSWJH-UHFFFAOYSA-N 3-methoxypropan-1-amine Chemical compound COCCCN FAXDZWQIWUSWJH-UHFFFAOYSA-N 0.000 description 1
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- MQOFXVWAFFJFJH-UHFFFAOYSA-N 4,4-difluorocyclohexan-1-amine Chemical compound NC1CCC(F)(F)CC1 MQOFXVWAFFJFJH-UHFFFAOYSA-N 0.000 description 1
- VJPPLCNBDLZIFG-ZDUSSCGKSA-N 4-[(3S)-3-(but-2-ynoylamino)piperidin-1-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide Chemical compound C(C#CC)(=O)N[C@@H]1CN(CCC1)C1=C2C(=C(NC2=C(C=C1F)C(=O)N)C)C VJPPLCNBDLZIFG-ZDUSSCGKSA-N 0.000 description 1
- YFCIFWOJYYFDQP-PTWZRHHISA-N 4-[3-amino-6-[(1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl]pyrazin-2-yl]-N-[(1S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl]-2-fluorobenzamide Chemical compound CNC[C@@H](NC(=O)c1ccc(cc1F)-c1nc(cnc1N)[C@H]1CC[C@H](O)[C@@H](F)C1)c1cc(F)cc(Br)c1 YFCIFWOJYYFDQP-PTWZRHHISA-N 0.000 description 1
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 1
- DBCAQXHNJOFNGC-UHFFFAOYSA-N 4-bromo-1,1,1-trifluorobutane Chemical compound FC(F)(F)CCCBr DBCAQXHNJOFNGC-UHFFFAOYSA-N 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- IRPVABHDSJVBNZ-RTHVDDQRSA-N 5-[1-(cyclopropylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=NN(CC2CC2)C(C2[C@@H]3CN(C[C@@H]32)C2COC2)=C1 IRPVABHDSJVBNZ-RTHVDDQRSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- KCBWAFJCKVKYHO-UHFFFAOYSA-N 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-propan-2-yl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrazolo[3,4-d]pyrimidine Chemical compound C1(CC1)C1=NC=NC(=C1C1=NC=C2C(=N1)N(N=C2)CC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C(C)C)OC KCBWAFJCKVKYHO-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 1
- WREVVZMUNPAPOV-UHFFFAOYSA-N 8-aminoquinoline Chemical compound C1=CN=C2C(N)=CC=CC2=C1 WREVVZMUNPAPOV-UHFFFAOYSA-N 0.000 description 1
- ZRPZPNYZFSJUPA-UHFFFAOYSA-N ARS-1620 Chemical compound Oc1cccc(F)c1-c1c(Cl)cc2c(ncnc2c1F)N1CCN(CC1)C(=O)C=C ZRPZPNYZFSJUPA-UHFFFAOYSA-N 0.000 description 1
- ZHGNHOOVYPHPNJ-UHFFFAOYSA-N Amigdalin Chemical compound FC(F)(F)C(=O)OCC1OC(OCC2OC(OC(C#N)C3=CC=CC=C3)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C2OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C1OC(=O)C(F)(F)F ZHGNHOOVYPHPNJ-UHFFFAOYSA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- JLCRRGUUZISQIS-UHFFFAOYSA-N C1=CC(=C(C=C1Br)C(=O)O)NO Chemical compound C1=CC(=C(C=C1Br)C(=O)O)NO JLCRRGUUZISQIS-UHFFFAOYSA-N 0.000 description 1
- IYCDIBKUPJWQMY-UHFFFAOYSA-N CC(C)(C)OC(N(C)CC(C(NC1=CC(CCl)=CC=C1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O Chemical compound CC(C)(C)OC(N(C)CC(C(NC1=CC(CCl)=CC=C1)=O)(NC1=C2C=CC=C1)N2NC(C1=C(C(F)(F)F)C=CC=C1)=O)=O IYCDIBKUPJWQMY-UHFFFAOYSA-N 0.000 description 1
- OZUXTNOAVAMQNR-UHFFFAOYSA-N CC(C)(C)OCC#CC1=CC=CC(Cl)=C1C(O)=O Chemical compound CC(C)(C)OCC#CC1=CC=CC(Cl)=C1C(O)=O OZUXTNOAVAMQNR-UHFFFAOYSA-N 0.000 description 1
- DFHYQLNFHYFQRS-UHFFFAOYSA-N CC(C=CC=C12)=C1C(C(O)=O)=NN2Br Chemical compound CC(C=CC=C12)=C1C(C(O)=O)=NN2Br DFHYQLNFHYFQRS-UHFFFAOYSA-N 0.000 description 1
- DUYCIFAQBHCHOW-UHFFFAOYSA-N CCC(OCCOC1=CC=CC(C(O)=O)=C1Cl)=O Chemical compound CCC(OCCOC1=CC=CC(C(O)=O)=C1Cl)=O DUYCIFAQBHCHOW-UHFFFAOYSA-N 0.000 description 1
- GUPMYKOYLWXOAT-UHFFFAOYSA-N CCOC(C(C=CC=C1C#CC2CC2)=C1Cl)=O Chemical compound CCOC(C(C=CC=C1C#CC2CC2)=C1Cl)=O GUPMYKOYLWXOAT-UHFFFAOYSA-N 0.000 description 1
- LFKNYJVWAPZQAF-UHFFFAOYSA-N CCOC1(C(OC)=O)NC(C=CC=C2)=C2N1 Chemical compound CCOC1(C(OC)=O)NC(C=CC=C2)=C2N1 LFKNYJVWAPZQAF-UHFFFAOYSA-N 0.000 description 1
- CXMWSFUVCGGQRA-UHFFFAOYSA-N CCOCC1=CC=CC(C(OCC)=O)=C1Cl Chemical compound CCOCC1=CC=CC(C(OCC)=O)=C1Cl CXMWSFUVCGGQRA-UHFFFAOYSA-N 0.000 description 1
- BFLJNJOTPSBGQH-UHFFFAOYSA-N CN(C)C1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2[N+]([O-])=O Chemical compound CN(C)C1=CC=CC2=C1N=C(C(NC1=CC(CCl)=CC=C1)=O)N2[N+]([O-])=O BFLJNJOTPSBGQH-UHFFFAOYSA-N 0.000 description 1
- KBCSTOPDHZMONL-UHFFFAOYSA-N COC(C1(CC#N)NC(C=CC=C2)=C2N1)=O Chemical compound COC(C1(CC#N)NC(C=CC=C2)=C2N1)=O KBCSTOPDHZMONL-UHFFFAOYSA-N 0.000 description 1
- GRJYFYGIHYXCST-UHFFFAOYSA-N COC(C1(CCl)NC(C=CC=C2)=C2N1)=O Chemical compound COC(C1(CCl)NC(C=CC=C2)=C2N1)=O GRJYFYGIHYXCST-UHFFFAOYSA-N 0.000 description 1
- PIGDMDLEFDDDIU-UHFFFAOYSA-N COC(C1(NC(C=CC=C2)=C2N1)S)=O Chemical compound COC(C1(NC(C=CC=C2)=C2N1)S)=O PIGDMDLEFDDDIU-UHFFFAOYSA-N 0.000 description 1
- KDCWKDROIVVPNN-UHFFFAOYSA-N COC1=CC=C(CNC2=CC=CC3=C2N=C(C(NC2=CC(CCl)=CC=C2)=O)N3NC(C2=C(C(F)(F)F)C=CC=C2)=O)C=C1 Chemical compound COC1=CC=C(CNC2=CC=CC3=C2N=C(C(NC2=CC(CCl)=CC=C2)=O)N3NC(C2=C(C(F)(F)F)C=CC=C2)=O)C=C1 KDCWKDROIVVPNN-UHFFFAOYSA-N 0.000 description 1
- BFPPTJRAWGLPOS-UHFFFAOYSA-N COCC1(C(OC)=O)NC(C=CC=C2)=C2N1 Chemical compound COCC1(C(OC)=O)NC(C=CC=C2)=C2N1 BFPPTJRAWGLPOS-UHFFFAOYSA-N 0.000 description 1
- FQKZNNOTCHJLHM-UHFFFAOYSA-N COCCCC1=CC=CC(C(O)=O)=C1Cl Chemical compound COCCCC1=CC=CC(C(O)=O)=C1Cl FQKZNNOTCHJLHM-UHFFFAOYSA-N 0.000 description 1
- PVLHRJABBOCONY-UHFFFAOYSA-N C[Si](C)(C)CCOCC1=C2C(C(NN(C3CCCCC3)C(C3=C(C(F)(F)F)C=CC=C3)=O)=O)=NNC2=CC=C1 Chemical compound C[Si](C)(C)CCOCC1=C2C(C(NN(C3CCCCC3)C(C3=C(C(F)(F)F)C=CC=C3)=O)=O)=NNC2=CC=C1 PVLHRJABBOCONY-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
- 229920002261 Corn starch Polymers 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 238000011891 EIA kit Methods 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 206010065952 Hyperpathia Diseases 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 102100037611 Lysophospholipase Human genes 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- FCDCUDRWYHLCGH-VKHMYHEASA-N O=C([C@H](C=CN1)C1=O)Cl Chemical compound O=C([C@H](C=CN1)C1=O)Cl FCDCUDRWYHLCGH-VKHMYHEASA-N 0.000 description 1
- IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 1
- 108010058864 Phospholipases A2 Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 1
- RYXZOQOZERSHHQ-UHFFFAOYSA-N [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenylphosphane Chemical compound C=1C=CC=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1OC1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RYXZOQOZERSHHQ-UHFFFAOYSA-N 0.000 description 1
- CDPJFYDPGGIGPV-UHFFFAOYSA-N [3-(chloromethyl)phenyl]methanamine Chemical compound NCC1=CC=CC(CCl)=C1 CDPJFYDPGGIGPV-UHFFFAOYSA-N 0.000 description 1
- HMQAGZNMDDEKPR-UHFFFAOYSA-N [N+](=O)([O-])C1=CC2=C(NC(=N2)C(=O)OC)C=C1.NC1=CC2=C(NC(=N2)C(=O)OC)C=C1 Chemical compound [N+](=O)([O-])C1=CC2=C(NC(=N2)C(=O)OC)C=C1.NC1=CC2=C(NC(=N2)C(=O)OC)C=C1 HMQAGZNMDDEKPR-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- UQUPQEUNHVVNKW-UHFFFAOYSA-N azetidin-1-ium-3-ol;chloride Chemical compound Cl.OC1CNC1 UQUPQEUNHVVNKW-UHFFFAOYSA-N 0.000 description 1
- HGQULGDOROIPJN-UHFFFAOYSA-N azetidin-1-ium;chloride Chemical compound Cl.C1CNC1 HGQULGDOROIPJN-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].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 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- QHXLIQMGIGEHJP-UHFFFAOYSA-N boron;2-methylpyridine Chemical compound [B].CC1=CC=CC=N1 QHXLIQMGIGEHJP-UHFFFAOYSA-N 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- GTCAXTIRRLKXRU-UHFFFAOYSA-N carbamic acid methyl ester Natural products COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- DGLFSNZWRYADFC-UHFFFAOYSA-N chembl2334586 Chemical compound C1CCC2=CN=C(N)N=C2C2=C1NC1=CC=C(C#CC(C)(O)C)C=C12 DGLFSNZWRYADFC-UHFFFAOYSA-N 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- KZZKOVLJUKWSKX-UHFFFAOYSA-N cyclobutanamine Chemical compound NC1CCC1 KZZKOVLJUKWSKX-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- AVKNGPAMCBSNSO-UHFFFAOYSA-N cyclohexylmethanamine Chemical compound NCC1CCCCC1 AVKNGPAMCBSNSO-UHFFFAOYSA-N 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- WEPUZBYKXNKSDH-UHFFFAOYSA-N cyclopentanecarbonyl chloride Chemical compound ClC(=O)C1CCCC1 WEPUZBYKXNKSDH-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000003544 deproteinization Effects 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- SYZWSSNHPZXGML-UHFFFAOYSA-N dichloromethane;oxolane Chemical compound ClCCl.C1CCOC1 SYZWSSNHPZXGML-UHFFFAOYSA-N 0.000 description 1
- WILYSFGDCDXQIC-UHFFFAOYSA-N dichloromethylidene(dimethyl)azanium Chemical compound C[N+](C)=C(Cl)Cl WILYSFGDCDXQIC-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 125000004982 dihaloalkyl group Chemical group 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- IUNMPGNGSSIWFP-UHFFFAOYSA-N dimethylaminopropylamine Chemical compound CN(C)CCCN IUNMPGNGSSIWFP-UHFFFAOYSA-N 0.000 description 1
- OMBRFUXPXNIUCZ-UHFFFAOYSA-N dioxidonitrogen(1+) Chemical class O=[N+]=O OMBRFUXPXNIUCZ-UHFFFAOYSA-N 0.000 description 1
- CNXMDTWQWLGCPE-UHFFFAOYSA-N ditert-butyl-(2-phenylphenyl)phosphane Chemical group CC(C)(C)P(C(C)(C)C)C1=CC=CC=C1C1=CC=CC=C1 CNXMDTWQWLGCPE-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- IJMOJOIZKMFVSI-UHFFFAOYSA-N ethyl 3-(2-aminoethoxy)prop-2-enoate hydrochloride Chemical compound Cl.CCOC(=O)C=COCCN IJMOJOIZKMFVSI-UHFFFAOYSA-N 0.000 description 1
- FRWJLWVJGAUGGM-UHFFFAOYSA-N ethyl 5-bromo-2,3-dihydro-1-benzofuran-2-carboxylate Chemical compound BrC1=CC=C2OC(C(=O)OCC)CC2=C1 FRWJLWVJGAUGGM-UHFFFAOYSA-N 0.000 description 1
- WHQLQYRFIHPMNA-UHFFFAOYSA-N ethyl acetate;oxolane Chemical compound C1CCOC1.CCOC(C)=O WHQLQYRFIHPMNA-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000027950 fever generation Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
- 150000002327 glycerophospholipids Chemical class 0.000 description 1
- 229960001269 glycine hydrochloride Drugs 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000000954 inflammatory inducer Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([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
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 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
- 239000011976 maleic acid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- 229910001960 metal nitrate Inorganic materials 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- OJYMXUTVJGSQML-UHFFFAOYSA-N methyl 2-amino-3-[(2-methoxyacetyl)amino]benzoate Chemical compound COCC(=O)NC1=CC=CC(C(=O)OC)=C1N OJYMXUTVJGSQML-UHFFFAOYSA-N 0.000 description 1
- HDCLJQZLTMJECA-UHFFFAOYSA-N methyl 2-amino-3-nitrobenzoate Chemical compound COC(=O)C1=CC=CC([N+]([O-])=O)=C1N HDCLJQZLTMJECA-UHFFFAOYSA-N 0.000 description 1
- GREOJHHAAXRYGY-UHFFFAOYSA-N methyl 2-chloro-3-hydroxybenzoate Chemical compound COC(=O)C1=CC=CC(O)=C1Cl GREOJHHAAXRYGY-UHFFFAOYSA-N 0.000 description 1
- CATAJHNFXWLJRA-UHFFFAOYSA-N methyl 5-(bromomethyl)-2-chlorobenzoate Chemical compound COC(=O)C1=CC(CBr)=CC=C1Cl CATAJHNFXWLJRA-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000006682 monohaloalkyl group Chemical group 0.000 description 1
- ULDIVZQLPBUHAG-UHFFFAOYSA-N n',n',2,2-tetramethylpropane-1,3-diamine Chemical compound CN(C)CC(C)(C)CN ULDIVZQLPBUHAG-UHFFFAOYSA-N 0.000 description 1
- CURJNMSGPBXOGK-UHFFFAOYSA-N n',n'-di(propan-2-yl)ethane-1,2-diamine Chemical compound CC(C)N(C(C)C)CCN CURJNMSGPBXOGK-UHFFFAOYSA-N 0.000 description 1
- UDGSVBYJWHOHNN-UHFFFAOYSA-N n',n'-diethylethane-1,2-diamine Chemical compound CCN(CC)CCN UDGSVBYJWHOHNN-UHFFFAOYSA-N 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- AVAWMINJNRAQFS-UHFFFAOYSA-N n,n-dimethylpyrrolidin-3-amine Chemical compound CN(C)C1CCNC1 AVAWMINJNRAQFS-UHFFFAOYSA-N 0.000 description 1
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YPOVDCYMBVIROJ-UHFFFAOYSA-N n-ethoxy-2-methylpropan-2-amine Chemical compound CCONC(C)(C)C YPOVDCYMBVIROJ-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000000802 nitrating effect Effects 0.000 description 1
- JCZMXVGQBBATMY-UHFFFAOYSA-N nitro acetate Chemical compound CC(=O)O[N+]([O-])=O JCZMXVGQBBATMY-UHFFFAOYSA-N 0.000 description 1
- ONTGMLYFJLDCPR-UHFFFAOYSA-M nitronium;trifluoromethanesulfonate Chemical compound O=[N+]=O.[O-]S(=O)(=O)C(F)(F)F ONTGMLYFJLDCPR-UHFFFAOYSA-M 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-O nitrosooxidanium Chemical compound [OH2+]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-O 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 description 1
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 238000002732 pharmacokinetic assay Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- LZMJNVRJMFMYQS-UHFFFAOYSA-N poseltinib Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC(OC=2C=C(NC(=O)C=C)C=CC=2)=C(OC=C2)C2=N1 LZMJNVRJMFMYQS-UHFFFAOYSA-N 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- PXGPLTODNUVGFL-UHFFFAOYSA-N prostaglandin F2alpha Natural products CCCCCC(O)C=CC1C(O)CC(O)C1CC=CCCCC(O)=O PXGPLTODNUVGFL-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- MNPNBAKLSZRZBM-SSDOTTSWSA-N tert-butyl (2R)-2-carbonochloridoylpyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@@H]1C(Cl)=O MNPNBAKLSZRZBM-SSDOTTSWSA-N 0.000 description 1
- MNPNBAKLSZRZBM-ZETCQYMHSA-N tert-butyl (2s)-2-carbonochloridoylpyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(Cl)=O MNPNBAKLSZRZBM-ZETCQYMHSA-N 0.000 description 1
- SJMDMGHPMLKLHQ-UHFFFAOYSA-N tert-butyl 2-aminoacetate Chemical compound CC(C)(C)OC(=O)CN SJMDMGHPMLKLHQ-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-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
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- GLQWRXYOTXRDNH-UHFFFAOYSA-N thiophen-2-amine Chemical compound NC1=CC=CS1 GLQWRXYOTXRDNH-UHFFFAOYSA-N 0.000 description 1
- FKKJJPMGAWGYPN-UHFFFAOYSA-N thiophen-2-ylmethanamine Chemical compound NCC1=CC=CS1 FKKJJPMGAWGYPN-UHFFFAOYSA-N 0.000 description 1
- DKGYESBFCGKOJC-UHFFFAOYSA-N thiophen-3-amine Chemical compound NC=1C=CSC=1 DKGYESBFCGKOJC-UHFFFAOYSA-N 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 238000013389 whole blood assay Methods 0.000 description 1
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- 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
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
-
- 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
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- 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
- A61K31/42—Oxazoles
- A61K31/423—Oxazoles condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- 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
- A61K31/433—Thidiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/06—Antiabortive agents; Labour repressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/10—Radicals substituted by halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/14—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/26—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Disclosed herein are benzimidazole compounds of formula I where the substituents are as defined herein. The compounds of the invention or pharmaceutically acceptable salt thereof have high mPGES-1 inhibitory activity and can be used as a prophylactic agent or therapeutic agent for a variety of diseases involving mPGES-1, such as, rheumatoid arthritis, osteoarthritis, temporomandibular joint disease, low back pain, endometriosis, dysmenorrhea, overactive bladder, malignancy, or neurodegenerative disease. ses involving mPGES-1, such as, rheumatoid arthritis, osteoarthritis, temporomandibular joint disease, low back pain, endometriosis, dysmenorrhea, overactive bladder, malignancy, or neurodegenerative disease.
Description
HETEROCYCLIC DERIVATIVE AND PHARMACEUTICAL
[Field of the Invention]
The present invention relates to novel heterocyclic
derivatives.
[Background Art]
Prostaglandins (PG) are produced abundantly in the site
of inflammation and involved in progress of inflammation.
Prostaglandin production is initiated with the release of
arachidonic acid from membrane glycerophospholipid by
phospholipase A2, and the arachidonic acid is then converted
into prostaglandin H2 (PGH2) by cyclooxygenase (COX). PGH2 is
converted into prostaglandins including prostaglandin E2
(PGE2), prostaglandin F2α (PGF2α), prostaglandin D2 (PGD2),
prostaglandin I2 (PGI2), and thromboxane A2 (TXA2). These
prostaglandins are known to have various physiological or
pathophysiological activities, including inflammation
inducing effect. Especially, PGE2 is known as an inflammatory
inducer in acute and chronic inflammations and further known
to induce pyrexia and hyperpathia. Non-steroidal
anti-inflammatory drugs (NSAIDs) and selective COX-2
inhibitors have anti-inflammatory effect via reduced
production of PGE2 based on their COX-1 and/or COX-2 inhibitory
effect. PGE2 synthase (PGES) catalyzes the final step of the
synthetic pathway of PGE2, which is an inflammatory mediator.
To date, three subtypes of PGES, microsomal prostaglandin E
synthase-1 (mPGES-1) [for example, Non-Patent Document 1],
mPGES-2 [for example, Non-Patent Document 2] and cytosolic
prostaglandin synthase (cPGES) [for example, Non-Patent
Document 3] are known. Among these, mPGES-1, in the same manner
as COX-2, is primarily induced during inflammation and plays
a major part in PGE2 production in inflammatory lesion. On the
other hand, cPGES is constitutively expressed PGES and coupled
to COX-1 to play a part in basal PGE2 production [for example,
Non-Patent Document 4]. As to mPGES-2, it is a subject of
controversy as there is a report that it can be coupled to both
COX isoforms. The studies in mPGES-1 deficient mouse suggest
that mPGES-1 contributes to pathological progress in various
inflammation models, such as acetic acid writhing model (e.g.,
Non-Patent Document 5), arthritis model (e.g., Non-Patent
Documents 5 and 6), multiple sclerosis model (e.g., Non-Patent
Document 7), fever model (e.g., Non-Patent Document 8). Also,
mPGES-1 inhibitors specifically inhibit COXdependent PGE2
production, and therefore, they are expected to reduce various
side effects, compared with NSAIDs or COX-2 inhibitors. It is
believed that elevated risk of cardiovascular events by COX-2
inhibitors is attributed to enhanced coagulation system and
vasoconstriction via inhibited COXdependent PGI2
production (e.g., Non-Patent Document 9). In contrast,
mPGES-1 inhibitors are believed not to increase the risk of
cardiovascular events, which is a problem with COX-2 inhibitors,
since they do not inhibit PGI2 production (e.g., Non-Patent
Document 10). mPGES-1 inhibitors are expected to serve as a
safe anti-inflammatory agent by inhibiting only PGE2 production,
which participates in inflammation. Thus, a pharmaceutical
agent which is able to inhibit mPGES-1, and reduce PGE2
production is useful in the treatment or prevention of a disease,
such as an inflammatory disease in which mPGES-1 participates.
mPGES-1 inhibitors have been disclosed in the patent
applications by NovaSAID AB (Patent Documents 1 and 2) and
Boehringer Ingelheim International GmbH (Patent Document 3).
[Prior Art Documents]
[Patent Documents]
[Patent Document 1] WO2009/103778
[Patent Document 2] US2010/0324086
[Patent Document 3] WO2011/048004
[Non-Patent Documents]
[Non-Patent Document 1] Jakobsson et al., Proc. Natl. Acad.
Sci. USA, 1999, 96, 7220-7225
[Non-Patent Document 2] Tanikawa et al., Biochem. Biophys.
Res. Commun., 2002, 291, 884-889
[Non-Patent Document 3] Tanioka et al., J. Biol. Chem., 2000,
275, 32775-32782
[Non-Patent Document 4] Murakami et al., J. Biol. Chem., 2000,
275, 32783-32792
[Non-Patent Document 5] Kamei et al., J. Biol. Chem., 2004,
279, 33684-33695
[Non-Patent Document 6] Kojima et al., J. Immunol., 2008,
108, 3861-3868
[Non-Patent Document 7] Kimura et al., Proc. Natl. Acad. Sci.
USA, 2000, 106, 21807-21812
[Non-Patent Document 8] Engblom et al., Nat. Neurosci., 2003,
6, 1137-1138
[Non-Patent Document 9] Foudi et al., Cardiovasc. Res., 2009,
81, 269-277
[Non-Patent Document 10] Cheng et al., J. Clin. Invest., 2006,
116, 1391-1399
[Non-Patent Document 11] J. Biol. Chem., 2004, 279(13),
12647-12658
[Non-Patent Document 12] Biomed. Pharmacother., 2011, 65(1),
77-84
[Non-Patent Document 13] Acta. Med. Okayama, 2008, 62(6),
373-378
[Non-Patent Document 14] Proc. Natl. Acad. Sci. USA, 2009,
106, 21807-21812
[Non-Patent Document 15] J. Biol. Chem., 279(32),
33684-33695
[Non-Patent Document 16] J. Immunol., 2008, 180, 8361-8368
[Non-Patent Document 17] Glia, 2011, 59, 208-218
[Non-Patent Document 18] J. Burn. Care. Res., 2011, 32(1),
79-90
[Non-Patent Document 19] J. Biol. Chem., 2003, 278(21),
19396-19405
[Non-Patent Document 20] Oncogene, 2012, 31(24), 2943-2952
[Non-Patent Document 21] Cancer Res., 2008, 68(9), 3251-3259
[Non-Patent Document 22] Proc. Natl. Acad. Sci. USA, 2006,
103, 14507-14512
[Non-Patent Document 23] Proc. Natl. Acad. Sci. USA, 2006,
103(31), 11790-11795
[Non-Patent Document 24] J. Rheumatol., 2005, 32(5), 887-895
[Non-Patent Document 25] J. Pharmacol. Exp. Ther., 2008, 326,
754-763
[Non-Patent Document 26] Kidney Int., 2011, 79(1), 77-88
[Non-Patent Document 27] J. Immunol., 2012, 188, 4093-4102
[Non-Patent Document 28] Am. J. Physiol. Lung Cell Mol.
Physiol., 2004, 287, L981-L991
[Non-Patent Document 29] Am. J. Physiol. Lung Cell Mol.
Physiol., 2005, 288, L1010-L1016
[Non-Patent Document 30] J. Immunol., 2012, 188, 4093-4102
[Non-Patent Document 31] Oncogene, 2012, 31(24), 2943-2952
[Non-Patent Document 32] Arthritis Res. Ther., 2011, 13, R6
[Summary of the Invention]
[Problem to be solved by the invention]
The present invention provides a novel heterocycle
derivative or a pharmaceutically acceptable salt thereof.
Also, the invention provides with a pharmaceutical composition
containing such heterocycle derivative or a pharmaceutically
acceptable salt thereof as an active ingredient.
[Means for solving the problem]
The present invention is based on the inventors'
discovery that the novel heterocycle derivative or a
pharmaceutically acceptable salt thereof, as described below,
has an excellent mPGES-1 inhibiting activity.
The present invention provides a heterocycle derivative
represented by the general formula [1] or its tautomer
(hereinafter referred to as "compound of the invention"), or
a pharmaceutically acceptable salt thereof.
[Chemical Formula 1]
O NH
wherein
ring A is a group represented by the general formulae [2], [3]
or [4]:
[Chemical Formula 2]
wherein
X is NH, N-alkyl, or O;
A is hydrogen or alkyl;
A is
i) hydrogen;
ii) halogen;
iii) alkyl optionally substituted with one to three
groups selected from the group consisting of halogen,
amino, monoalkylamino, dialkylamino, carbamoyl,
monoalkylaminocarbonyl, dialkylaminocarbonyl, a
saturated cyclic aminocarbonyl, alkoxy, alkoxyalkoxy
and alkylcarbonyloxy;
iv) cycloalkyl optionally substituted with alkyl
optionally substituted with one to three halogens;
v) alkoxy;
vi) a saturated heterocycle group optionally
substituted with alkyl, alkyloxycarbonyl,
alkylcarbonyl or oxo;
vii) alkylthio;
viii) alkylsulfonyl;
ix) alkylsulfinyl;
x) a group represented by the general formula [5]:
[Chemical Formula 3]
wherein R and R are the same or different group
selected from
a) hydrogen,
b) alkyl optionally substituted with a group
selected from the group consisting of
monoalkylamino, dialkylamino, a saturated
cyclic amino optionally substituted with alkyl,
a saturated heterocycle group optionally
substituted with alkyl, alkoxy, hydroxycarbonyl,
hydroxyl, alkyloxycarbonyl and alkylthio, or
c) cycloalkyl; or
xi) a saturated cyclic amino optionally substituted
with alkyl, amino, monoalkylamino, dialkylamino,
alkoxy or hydroxyl;
R is phenyl, benzyl, naphthyl, cycloalkyl, cycloalkylmethyl,
heteroaryl, heteroarylmethyl,
1,2,3,4-tetrahydronaphthalenyl,
1,2,3,4-tetrahydronaphthalenyl,
2,3-dihydro-1H-indenyl, 2,3-dihydro-1H-indenyl,
1,2-dihydrocyclobutabenzenyl,
1,2-dihydrocyclobutabenzenyl or alkyl,
wherein said phenyl, benzyl, cycloalkyl, cycloalkylmethyl,
heteroaryl and heteroarylmethyl is optionally substituted
with one to three groups selected from the group consisting
i) halogen,
ii) alkyl optionally substituted with one to three groups
selected from the group consisting of halogen, hydroxy and
phenyl,
iii) alkoxy,
iv) hydroxy, and
v) cyano;
R is phenyl or pyridyl,
wherein said phenyl and pyridyl is optionally substituted
with one to three groups selected from the group consisting
i) halogen,
ii) alkylsulfonyl,
iii) alkoxy optionally substituted with one to three
halogens or alkoxy;
iv) alkynyl optionally substituted with alkoxyalkyl or
cycloalkyl, and
v) alkyl optionally substituted with one to three groups
selected from the group consisting of alkoxy, alkoxyalkoxy,
cycloalkyl, phenyl and halogen.
A preferred embodiment of the invention is any one of the
following (A) to (C), or a pharmaceutically acceptable salt
thereof:
(A) a compound of the invention or a pharmaceutically
acceptable salt thereof, wherein the ring A is a group of
formula [4] and X is NH;
(B) a compound of the invention or a pharmaceutically
acceptable salt thereof, wherein R is phenyl,
1,2,3,4-tetrahydronaphthalenyl,
1,2,3,4-tetrahydronaphthalenyl,
2,3-dihydro-1H-indenyl,
2,3-dihydro-1H-indenyl,
1,2-dihydrocyclobutabenzenyl, or
1,2-dihydrocyclobutabenzenyl, and said phenyl is
optionally substituted with one to three groups selected
from the group consisting of
i) halogen,
ii) alkyl optionally substituted with one to three
halogens,
iii) alkoxy, and
iv) cyano
; or
(C) a compound of the invention a pharmaceutically
acceptable salt thereof, wherein R is phenyl and said
phenyl is optionally substituted with one to three groups
selected from the group consisting of
i) halogen
ii) alkylsulfonyl,
iii) alkoxy optionally substituted with alkoxy,
iv) alkynyl optionally substituted with alkoxyalkyl or
cycloalkyl, and
v) alkyl optionally substituted with one to three groups
selected from the group consisting of halogen, alkoxy,
alkoxyalkoxy, cycloalkyl and phenyl
A more preferred embodiment of the invention is a compound
of the invention or a pharmaceutically acceptable salt thereof,
wherein
the ring A is a group of formula [4],
X is NH,
A is
i) hydrogen,
ii) alkyl optionally substituted with a group selected from
the group consisting of halogen, monoalkylamino,
dialkylamino, monoalkylaminocarbonyl,
dialkylaminocarbonyl, a saturated cyclic aminocarbonyl,
alkoxy, alkoxyalkoxy and alkylcarbonyloxy,
iii) cycloalkyl optionally substituted with alkyl
optionally substituted with one to three halogens,
iv) alkoxy,
v) a saturated heterocyclic group optionally substituted
with alkyl or alkyloxycarbonyl,
vi) alkylthio,
vii) alkylsulfonyl,
viii) alkylsulfinyl,
ix) amino substituted with alkyl wherein said alkyl is
optionally substituted with a group selected from the group
consisting of monoalkylamino, dialkylamino, a saturated
cyclic amino optionally substituted with alkyl,
tetrahydrofuryl, morpholino, alkoxy, hydroxycarbonyl,
hydroxyl and alkylthio,
x) amino substituted with cycloalkyl or
xi) a saturated cyclic amino optionally substituted with
alkyl, dialkylamino, alkoxy or hydroxyl, and
R is
i) phenyl optionally substituted with one to three groups
selected from the group consisting of halogen, alkyl
optionally substituted with one to three halogens, alkoxy
and cyano,
ii) 1,2,3,4-tetrahydronaphthalenyl,
iii) 2,3-dihydro-1H-indenyl,
iv) benzyl optionally substituted with halogen or alkyl
optionally substituted with one to three halogens,
v) cycloalkyl,
vi) cycloalkylmethyl,
vii) naphthyl,
viii) pyridylmethyl optionally substituted with alkyl
optionally substituted one to three halogens,
ix) thienyl,
x) thienylmethyl,
xi) benzothiazolyl,
xii) benzothiadiazolyl,
xiii) indolyl or
xiv) alkyl, and
R is phenyl or pyridyl
wherein said phenyl is optionally substituted with one to three
groups selected from the group consisting of
i) halogen,
ii) alkylsulfonyl,
iii) alkoxy optionally substituted with alkoxy,
iv) alkynyl optionally substituted with alkoxyalkyl or
cycloalkyl, and
v) alkyl optionally substituted with one to three groups
selected from the group consisting of halogen, alkoxy,
alkoxyalkoxy, cycloalkyl and phenyl, and
said pyridyl is optionally substituted with halogen
A further more preferred embodiment of the invention is
a compound of the invention or a pharmaceutically acceptable
salt thereof, wherein
the ring A is a group of formula [4],
X is NH,
A is alkyl substituted with alkoxy, dialkylamino,
tetrahydrofuryl, tetrahydrofurylmethyl, alkoxyalkylamino, or
cycloalkyl optionally substituted with alkyl optionally
substituted with one to three halogens,
R is phenyl substituted with one halogen and one methyl, and
R is phenyl optionally substituted with one trifluoromethyl
or two halogens
A particularly preferred embodiment of the invention is
any one of the following (1)-(239), or its tautomer or a
pharmaceutically acceptable salt thereof:
N-[2-(trifluoromethyl)benzyl]({[2-(trifluoromethyl)pheny
l]carbonyl}amino)-1H-benzimidazolecarboxamide,
N-cyclohexyl({[2-(trifluoromethyl)phenyl]carbonyl}amino)
-1H-benzimidazolecarboxamide,
N-(3-chloromethylphenyl)({[2-(trifluoromethyl)phenyl]
carbonyl}amino)-1H-benzimidazolecarboxamide,
N-[(1-hydroxycyclohexyl)methyl]({[2-(trifluoromethyl)phe
nyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
N-[2-(trifluoromethyl)benzyl]({[2-(trifluoromethyl)pheny
l]carbonyl}amino}-2,3-dihydrobenzofurancarboxamide),
N-cyclohexyl({[2-(trifluoromethyl)phenyl]carbonyl}amino)
-2,3-dihydrobenzofurancarboxamide,
N-(3-chloromethylphenyl)({[2-(trifluoromethyl)phenyl]
carbonyl}amino)-2,3-dihydrobenzofurancarboxamide,
N-cyclohexyl({[2-(trifluoromethyl)phenyl]carbonyl}amino)
-1H-indazolecarboxamide,
N-[2-(trifluoromethyl)benzyl]({[2-(trifluoromethyl)pheny
l]carbonyl}amino)-1H-indazolecarboxamide,
(10)
N-(3-chloromethylphenyl)(methoxymethyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide,
(11)
2-methyl-N-[2-(trifluoromethyl)benzyl]({[2-(trifluoromet
hyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(12)
N-cyclohexylmethyl({[2-(trifluoromethyl)phenyl]carbon
yl}amino)-1H-benzimidazolecarboxamide,
(13)
N-(3-chloromethylphenyl)methyl({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(14)
N-cyclopentylmethyl({[2-(trifluoromethyl)phenyl]carbo
nyl}amino)-1H-benzimidazolecarboxamide,
(15)
N-cyclobutylmethyl({[2-(trifluoromethyl)phenyl]carbon
yl}amino)-1H-benzimidazolecarboxamide,
(16)
N-(3-chloromethylphenyl)ethyl({[2-(trifluoromethyl
)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(17)
N-cyclohexylethyl({[2-(trifluoromethyl)phenyl]carbony
l}amino)-1H-benzimidazolecarboxamide,
(18)
2-ethyl-N-[2-(trifluoromethyl)benzyl]({[2-(trifluorometh
yl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(19)
N-cyclohexyl(methoxymethyl)({[2-(trifluoromethyl)phen
yl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(20)
2-(methoxymethyl)-N-[2-(trifluoromethyl)benzyl]({[2-(tri
fluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarb
oxamide,
(21)
2-(methoxymethyl)-N-(2-methylphenyl)({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(22)
2-(methoxymethyl)-N-(4-methylphenyl)({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(23)
N-(2-chlorobenzyl)(methoxymethyl)({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(24)
2-(methoxymethyl)-N-(4-methylbenzyl)({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(25)
N-(4,4-difluorocyclohexyl)(methoxymethyl)({[2-(triflu
oromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxa
mide,
(26)
N-(4-tert-buthylphenyl)(methoxymethyl)({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamid
(27)
2-(methoxymethyl)-N-[4-(trifluoromethyl)phenyl]({[2-(tri
fluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarb
oxamide,
(28)
N-(2,4-dimethylphenyl)(methoxymethyl)({[2-(trifluorom
ethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
(29)
N-(2-chloromethylphenyl)(methoxymethyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide,
(30)
N-(3,4-dimethylphenyl)(methoxymethyl)({[2-(trifluorom
ethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
(31)
N-(3-chloromethylphenyl)(methoxymethyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide,
(32)
N-(2,3-dihydro-1H-indenyl)(methoxymethyl)({[2-(tri
fluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarb
oxamide,
(33)
2-(methoxymethyl)-N-(5,6,7,8-tetrahydronaphthalenyl)(
{[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol
ecarboxamide,
(34)
N-(2-fluorophenyl)(methoxymethyl)({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(35)
2-(methoxymethyl)-N-(2-methoxypheny)({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(36)
2-(methoxymethyl)-N-(4-methoxypheny)({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(37)
N-(3-bromomethylphenyl)(methoxymethyl)({[2-(triflu
oromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxa
mide,
(38)
N-(3-chloromethylbenzyl)(methoxymethyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide,
(39)
N-(2,6-difluorophenyl)(methoxymethyl)({[2-(trifluorom
ethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
(40)
N-(3-cyanomethylphenyl)(methoxymethyl)({[2-(triflu
oromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxa
mide,
(41)
2-(methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-N-{[3-(trifluoromethyl)pyridinyl]methyl}-1H-benzim
idazolecarboxamide,
(42)
N-(2-chloromethylphenyl)(methoxymethyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide,
(43)
2-(2-aminooxoethyl)-N-(3-chloromethylphenyl)({[2-(
trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolec
arboxamide,
(44)
2-(2-aminooxoethyl)-N-[2-(trifluoromethyl)benzyl]({[2
-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4
-carboxamide,
(45)
N-(3-chloromethylphenyl)methyl({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(46)
N-cyclohexylmethyl({[2-(trifluoromethyl)phenyl]carbon
yl}amino)-1H-benzimidazolecarboxamide,
(47)
1-methyl-N-[2-(trifluoromethyl)benzyl]({[2-(trifluoromet
hyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(48)
N-(3-chloromethylphenyl)ethyl({[2-(trifluoromethyl
)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(49)
N-cyclohexylethyl({[2-(trifluoromethyl)phenyl]carbony
l}amino)-1H-benzimidazolecarboxamide,
(50)
1-ethyl-N-[2-(trifluoromethyl)benzyl]({[2-(trifluorometh
yl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(51)
N-(3-chloromethylphenyl)methyl({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1,3-benzoxazolecarboxamide,
(52)
2-methyl-N-[2-(trifluoromethyl)benzyl]({[2-(trifluoromet
hyl)phenyl]carbonyl}amino)-1,3-benzoxazolecarboxamide,
(53)
N-(3-chloromethylphenyl)ethyl({[2-(trifluoromethyl
)phenyl]carbonyl}amino)-1,3-benzoxazolecarboxamide,
(54)
N-(3-chloromethylphenyl)ethoxy({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(55)
2-ethoxy-N-[2-(trifluoromethyl)benzyl]({[2-(trifluoromet
hyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(56)
N-(3-chloromethylphenyl)(1-chloromethylpropanyl
)({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimi
dazolecarboxamide,
(57)
N-(3-chloromethylphenyl)[(dimethylamino)methyl]({[
2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-
4-carboxamide,
(58)
N-(3-chloromethylphenyl)(2-methylpropyl)({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo
xamide,
(59)
2-(2-methylpropyl)-N-[2-(trifluoromethyl)benzyl]({[2-(tr
ifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecar
boxamide,
(60) tert-butyl
3-{4-[(3-chloromethylphenyl)carbamoyl]({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazolyl}azetidin
ecarboxylate,
(61)
N-(3-chloromethylphenyl)[(methylamino)methyl]({[2-
(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide,
(62)
{4-[(3-chloromethylphenyl)carbamoyl]({[2-(trifluorome
thyl)phenyl]carbonyl}amino)-1H-benzimidazolyl}methyl
acetate,
(63)
N-(3-chloromethylphenyl)[(2R)-tetrahydrofuranyl]-6
-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidaz
olecarboxamide,
(64)
2-[[(2R)-tetrahydrofuranyl]-N-[2-(trifluoromethyl)benzyl
]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimi
dazolecarboxamide,
(65)
N-(3-chloromethylphenyl)[(2S)-tetrahydrofuranyl]-6
-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidaz
olecarboxamide,
(66)
2-[[(2S)-tetrahydrofuranyl]-N-[2-(trifluoromethyl)benzyl
]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimi
dazolecarboxamide,
(67)
2-(1-acetylazetidinyl)-N-(3-chloromethylphenyl)({[
2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-
4-carboxamide,
(68) tert-butyl
(2S){4-[(3-chloromethylphenyl)carbamoyl]({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolyl}pyr
rolidinecarboxylate,
(69) tert-butyl
(2R){4-[(3-chloromethylphenyl)carbamoyl]({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolyl}pyr
rolidinecarboxylate,
(70)
N-(3-chloromethylphenyl)[(2S)-pyrrolidinyl]({[2
-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4
-carboxamide,
(71)
N-(3-chloromethylphenyl)[(2S)methylpyrrolidinyl
]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimi
dazolecarboxamide,
(72)
2-[(2S)acetylpyrrolidinyl]-N-(3-chloromethylphenyl
)({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimi
dazolecarboxamide,
(73)
N-(3-chloromethylphenyl)[(2-methoxyethoxy)methyl](
{[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol
ecarboxamide,
(74)
N-(3-chloromethylphenyl)(1-methoxymethylpropany
l)({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzim
idazolecarboxamide,
(75)
2-tert-butyl-N-(3-chloromethylphenyl)({[2-(trifluorom
ethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
(76)
2-tert-butyl({[2-(trifluoromethyl)phenyl]carbonyl}amino)
-N-{[3-(trifluoromethyl)pyridinyl]methyl}-1H-benzimidazo
lecarboxamide,
(77)
N-(3-chloromethylphenyl)(2-ethoxyethyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide,
(78)
N-(3-chloromethylphenyl)(ethoxymethyl)({[2-(triflu
oromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxa
mide,
(79)
2-(ethoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}am
ino)-N-{[3-(trifluoromethyl)pyridinyl]methyl}-1H-benzimi
dazolecarboxamide,
(80)
N-(3-chloromethylphenyl)(2-methoxyethyl)({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo
xamide,
(81)
N-(3-chloromethylphenyl)(2,2-dimethylpropyl)({[2-(
trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolec
arboxamide,
(82)
N-(3-chloromethylphenyl)cyclopropyl({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamid
(83)
N-(3-chloromethylphenyl)(2-methylpentanyl)({[2-
(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide,
(84)
N-(3-chloromethylphenyl)(1-methylcyclopropyl)({[2-
(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide,
(85)
2-tert-butyl-N-(3-chloromethylphenyl)({[2-(trifluorom
ethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
(86)
2-tert-butyl-N-(3-chloromethylphenyl){[(2,5-dichlorop
henyl)carbonyl]amino}-1H-benzimidazolecarboxamide,
(87)
2-tert-butyl-N-(3-chloromethylphenyl){[(2,5-dichlorop
henyl)carbonyl]amino}-1H-benzimidazolecarboxamide,
(88)
N-(3-chloromethylphenyl)[1-(trifluoromethyl)cycloprop
yl]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzi
midazolecarboxamide,
(89)
N-(3-chloromethylphenyl)(methoxymethyl)methyl({
[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide,
(90)
N-(2-chlorobenzyl)(methoxymethyl)methyl({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide,
(91)
6-{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)(methoxymethyl)-1H-benzimidazolecarboxam
ide,
(92)
6-{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)methoxymethyl-1H-benzimidazolecarboxamid
(93)
6-{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)(methoxymethyl)-1H-benzimidazolecarboxam
ide,
(94)
N-(3-chloromethylphenyl){[(2-chlorophenyl)carbonyl]am
ino}(methoxymethyl)-1H-benzimidazolecarboxamide,
(95)
N-(3-chloromethylphenyl){[(2-chloropyridinyl)carbo
nyl]amino}(methoxymethyl)-1H-benzimidazolecarboxamide
(96)
6-{[(2-bromophenyl)carbonyl]amino}-N-(3-chloromethylphen
yl)(methoxymethyl)-1H-benzimidazolecarboxamide,
(97)
N-(3-chloromethylphenyl){[(2,6-dichlorophenyl)carbony
l]amino}(methoxymethyl)-1H-benzimidazolecarboxamide,
(98)
N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}(methoxymethyl)-1H-benzimidazolecarboxamide,
(99)
6-{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)(methoxymethyl)-1H-benzimidazolecarboxam
ide,
(100)
6-{[(2-chloro-3,6-difluorophenyl)carbonyl]amino}-N-(3-chlor
omethylphenyl)(methoxymethyl)-1H-benzimidazolecarb
oxamide,
(101)
6-{[(2-bromochlorophenyl)carbonyl]amino}-N-(3-chlorom
ethylphenyl)(methoxymethyl)-1H-benzimidazolecarboxami
(102)
6-{[(2-bromofluorophenyl)carbonyl]amino}-N-(3-chlorom
ethylphenyl)(methoxymethyl)-1H-benzimidazolecarboxami
(103)
N-(3-chloromethylphenyl){[(2-chloromethylphenyl)ca
rbonyl]amino}(methoxymethyl)-1H-benzimidazolecarboxam
ide,
(104)
N-(3-chloromethylphenyl){[(2-chloromethylphenyl)ca
rbonyl]amino}(methoxymethyl)-1H-benzimidazolecarboxam
ide,
(105)
6-{[(5-bromochlorophenyl)carbonyl]amino}-N-(3-chlorom
ethylphenyl)(methoxymethyl)-1H-benzimidazolecarboxami
(106)
6-{[(2-bromochlorophenyl)carbonyl]amino}-N-(3-chlorom
ethylphenyl)(methoxymethyl)-1H-benzimidazolecarboxami
(107)
N-(3-chloromethylphenyl){[(2-chloromethylphenyl)ca
rbonyl]amino}(methoxymethyl)-1H-benzimidazolecarboxam
ide,
(108)
N-(3-chloromethylphenyl)(methoxymethyl)({[5-methyl
(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide,
(109)
6-({[2,5-bis(trifluoromethyl)phenyl]carbonyl}amino)-N-(3-ch
loromethylphenyl)(methoxymethyl)-1H-benzimidazolec
arboxamide,
(110)
6-({[2,4-bis(trifluoromethyl)phenyl]carbonyl}amino)-N-(3-ch
loromethylphenyl)(methoxymethyl)-1H-benzimidazolec
arboxamide,
(111)
N-(3-chloromethylphenyl)({[5-fluoro(trifluoromethy
l)phenyl]carbonyl}amino)(methoxymethyl)-1H-benzimidazole
carboxamide,
(112)
N-(3-chloromethylphenyl)({[2-chloro(trifluoromethy
l)phenyl]carbonyl}amino)(methoxymethyl)-1H-benzimidazole
carboxamide,
(113)
N-(3-chloromethylphenyl)[({2-chloro[2-(propanyl
oxy)ethoxy]phenyl}carbonyl)amino](methoxymethyl)-1H-benz
imidazolecarboxamide,
(114)
6-({[2-chloro(2-ethoxyethoxy)phenyl]carbonyl}amino)-N-(3
-chloromethylphenyl)(methoxymethyl)-1H-benzimidazole-
4-carboxamide,
(115)
6-({[2-chloro(3-methoxypropyl)phenyl]carbonyl}amino)-N-(
3-chloromethylphenyl)(methoxymethyl)-1H-benzimidazole
carboxamide,
(116)
6-({[5-(3-tert-butoxypropynyl)chlorophenyl]carbony
l}amino)-N-(3-chloromethylphenyl)(methoxymethyl)-1H-b
enzimidazolecarboxamide,
(117)
6-({[5-(3-tert-butoxypropyl)chlorophenyl]carbonyl}amino)
-N-(3-chloromethylphenyl)(methoxymethyl)-1H-benzimida
zolecarboxamide,
(118)
6-({[2-chloro(3-hydroxymethylbutyl)phenyl]carbonyl}am
ino)-N-(3-chloromethylphenyl)(methoxymethyl)-1H-benzi
midazolecarboxamide,
(119)
6-({[2-chloro(ethoxymethyl)phenyl]carbonyl}amino)-N-(3-c
hloromethylphenyl)(methoxymethyl)-1H-benzimidazole
carboxamide,
(120)
6-[({2-chloro[(2-ethoxyethoxy)methyl]phenyl}carbonyl)ami
no]-N-(3-chloromethylphenyl)(methoxymethyl)-1H-benzim
idazolecarboxamide,
(121)
6-({[2-chloro(2-cyclopropylethyl)phenyl]carbonyl}amino)-
N-(3-chloromethylphenyl)(methoxymethyl)-1H-benzimidaz
olecarboxamide,
(122)
N-(3-chloromethylphenyl)({[2-chloro(2-phenylethyl)
phenyl]carbonyl}amino)(methoxymethyl)-1H-benzimidazole-4
-carboxamide,
(123)
N-(3-chloromethylphenyl)cyclopentyl({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamid
(124)
N-(3-chloromethylphenyl)cyclopentyl{[(2,5-dichloro
phenyl)carbonyl]amino}-1H-benzimidazolecarboxamide,
(125)
6-{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)cyclopentyl-1H-benzimidazolecarboxamide,
(126)
6-[{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro-2
-methylphenyl)[(2R)-tetrahydrofuranyl]-1H-benzimidazo
lecarboxamide,
(127)
N-(3-chloromethylphenyl){[(2,6-dichlorophenyl)carbony
l]amino}[(2R)-tetrahydrofuranyl]-1H-benzimidazolec
arboxamide,
(128)
N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}[(2R)-tetrahydrofuranyl]-1H-benzimidazolec
arboxamide,
(129)
N-(3-chloromethylphenyl)[(2S)oxopyrrolidinyl]-6
-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidaz
olecarboxamide,
(130)
N-(3-chloromethylphenyl)[(2R)oxopyrrolidinyl]-6
-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidaz
olecarboxamide,
(131)
N-(3-chloromethylphenyl)[2-oxo(pyrrolizinyl)eth
yl]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzi
midazolecarboxamide,
(132)
N-(3-chloromethylphenyl)[2-(dimethylamino)oxoethyl
]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimi
dazolecarboxamide,
(133)
N-(3-chloromethylphenyl)[2-(methylamino)oxoethyl]-
6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimida
zolecarboxamide,
(134)
2-chloro-N-(3-chloromethylphenyl)({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(135)
N-(3-chloromethylphenyl)[(2-methoxyethyl)amino]({[
2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-
4-carboxamide,
(136)
N-(3-chloromethylphenyl)[(2-hydroxyethyl)amino]({[
2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-
4-carboxamide,
(137)
N-(3-chloromethylphenyl)(methylamino)({[2-(trifluo
romethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxam
ide,
(138)
N-(3-chloromethylphenyl)(ethylamino)({[2-(trifluor
omethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxami
(139)
N-(3-chloromethylphenyl)[(2,2-dimethylpropyl)amino]-6
-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidaz
olecarboxamide,
(140)
N-(3-chloromethylphenyl)(cyclopentylamino)({[2-(tr
ifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecar
boxamide,
(141)
N-(3-chloromethylphenyl)(piperidinyl)({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo
xamide,
(142)
N-(3-chloromethylphenyl)(4-methylpiperazinyl)({
[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide,
(143)
2-[bis(2-hydroxyethyl)amino]-N-(3-chloromethylphenyl)
({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazo
lecarboxamide,
(144)
N-(3-chloromethylphenyl)(dimethylamino)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide,
(145)
N-(3-chloromethylphenyl){[2-(morpholinyl)ethyl]ami
no}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzi
midazolecarboxamide,
(146)
N-(3-chloromethylphenyl){[2-(dimethylamino)ethyl]amin
o}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzim
idazolecarboxamide,
(147)
N-(3-chloromethylphenyl)(3-hydroxyazetidinyl)({
[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide,
(148)
N-(3-chloromethylphenyl)[(3S)(dimethylamino)pyrrol
izinyl]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1
H-benzimidazolecarboxamide,
(149)
N-(3-chloromethylphenyl)[(3S)hydroxypyrroliziny
l]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzim
idazolecarboxamide,
(150)
N-(3-chloromethylphenyl){[2-(diethylamino)ethyl]amino
}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimi
dazolecarboxamide,
(151)
N-(3-chloromethylphenyl){[2-(pyrrolizinyl)ethyl]am
ino}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benz
imidazolecarboxamide,
(152)
N-(3-chloromethylphenyl){[3-(dimethylamino)propyl]ami
no}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzi
midazolecarboxamide,
(153)
N-(3-chloromethylphenyl){[3-(dimethylamino)-2,2-dimet
hylpropyl]amino}({[2-(trifluoromethyl)phenyl]carbonyl}am
ino)-1H-benzimidazolecarboxamide,
(154)
N-(3-chloromethylphenyl){[2-(dipropanylamino)ethyl
]amino}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-b
enzimidazolecarboxamide,
(155)
N-(3-chloromethylphenyl)(morpholinyl)({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo
xamide,
(156)
2-amino-N-(3-chloromethylphenyl)({[2-(trifluoromethyl
)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(157)
N-(3-chloromethylphenyl)[(3-hydroxy-2,2-dimethylpropy
l)amino]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-
benzimidazolecarboxamide,
(158)
N-(3-chloromethylphenyl){[(3-methyloxetanyl)methyl
]amino}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-b
enzimidazolecarboxamide,
(159) tert-butyl
N-{4-[(3-chloromethylphenyl)carbamoyl]({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazolyl}glycinat
(160)
N-{4-[(3-chloromethylphenyl)carbamoyl]({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazolyl}glycine,
(161)
N-(3-chloromethylphenyl)[(3-hydroxy-2,2-dimethylpropy
l)amino]methyl({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxamide,
(162)
N-(3-chloromethylphenyl)[(3-methoxy-2,2-dimethylpropy
l)amino]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-
benzimidazolecarboxamide,
(163)
N-(3-chloromethylphenyl)(pyrrolizinyl)({[2-(tri
fluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarb
oxamide,
(164)
2-(azetidinyl)-N-(3-chloromethylphenyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide,
(165)
N-(3-chloromethylphenyl)(3-methoxyazetidinyl)({
[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide,
(166)
N-(3-chloromethylphenyl)[(2-hydroxymethylpropyl)am
ino]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benz
imidazolecarboxamide,
(167)
N-(3-chloromethylphenyl){[(2S)-tetrahydrofuranylme
thyl]amino}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-
1H-benzimidazolecarboxamide,
(168)
N-(3-chloromethylphenyl){[(2R)-tetrahydrofuranylme
thyl]amino}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-
1H-benzimidazolecarboxamide,
(169)
N-(3-chloromethylphenyl){[(2S)hydroxymethylbuta
nyl]amino}({[2-(trifluoromethyl)phenyl]carbonyl}amino
)-1H-benzimidazolecarboxamide,
(170)
N-(3-chloromethylphenyl){[(2R)hydroxymethylbuta
nyl]amino}({[2-(trifluoromethyl)phenyl]carbonyl}amino
)-1H-benzimidazolecarboxamide,
(171)
N-(3-chloromethylphenyl){[(2S)hydroxy-3,3-dimethyl
butanyl]amino}({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxamide,
(172)
N-(3-chloromethylphenyl)[(3-methoxy-2,2-dimethylpropy
l)(methyl)amino]({[2-(trifluoromethyl)phenyl]carbonyl}am
ino)-1H-benzimidazolecarboxamide,
(173)
N-(3-chloromethylphenyl)[(3-methoxypropyl)amino]({
[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide,
(174)
N-(3-chloromethylphenyl){[2-(propanyloxy)ethyl]ami
no}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzi
midazolecarboxamide,
(175)
2-[(2-tert-butoxyethyl)amino]-N-(3-chloromethylphenyl)-6
-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidaz
olecarboxamide,
(176)
N-(3-chloromethylphenyl)[(2-methoxymethylpropyl)am
ino]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benz
imidazolecarboxamide,
(177)
N-(3-chloromethylphenyl){[2-(methylsulfanyl)ethyl]ami
no}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzi
midazolecarboxamide,
(178)
N-(3-chloromethylphenyl)(methylsulfanyl)({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo
xamide,
(179)
N-(3-chloromethylphenyl)(methylsulfonyl)({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo
xamide,
(180)
N-(3-chloromethylphenyl)(methylsulfinyl)({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo
xamide,
(181)
6-{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)(dimethylamino)-1H-benzimidazolecarboxam
ide,
(182)
N-(3-chloromethylphenyl){[(2,6-dichlorophenyl)carbony
l]amino}(dimethylamino)-1H-benzimidazolecarboxamide,
(183)
N-(3-chloromethylphenyl){[(2,4-dichlorophenyl)carbony
l]amino}(dimethylamino)-1H-benzimidazolecarboxamide,
(184)
N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}(dimethylamino)-1H-benzimidazolecarboxamide,
(185)
6-{[(2-bromofluorophenyl)carbonyl]amino}-N-(3-chlorom
ethylphenyl)(dimethylamino)-1H-benzimidazolecarboxami
(186)
6-{[(2-bromochlorophenyl)carbonyl]amino}-N-(3-chlorom
ethylphenyl)(dimethylamino)-1H-benzimidazolecarboxami
(187)
6-({[2-chloro(cyclopropylethynyl)phenyl]carbonyl}amino)-
N-(3-chloromethylphenyl)(dimethylamino)-1H-benzimidaz
olecarboxamide,
(188)
N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}[(3-hydroxy-2,2-dimethylpropyl)amino]-1H-benzimi
dazolecarboxamide,
(189)
N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}[(3-methoxy-2,2-dimethylpropyl)amino]-1H-benzimi
dazolecarboxamide,
(190)
N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}[(2-hydroxymethylpropyl)amino]-1H-benzimidazo
lecarboxamide,
(191)
N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}[(2-methoxymethylpropyl)amino]-1H-benzimidazo
lecarboxamide,
(192)
N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}{[2-(propanyloxy)ethyl]amino}-1H-benzimidazol
ecarboxamide,
(193)
6-[{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro-2
-methylphenyl){[2-(propanyloxy)ethyl]amino}-1H-benzim
idazolecarboxamide,
(194)
2-[(2-tert-butoxyethyl)amino]{[(2-chlorofluorophenyl)
carbonyl]amino}-N-(3-chloromethylphenyl)-1H-benzimidazol
ecarboxamide,
(195)
6-[{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro-2
-methylphenyl)[(3-methoxy-2,2-dimethylpropyl)amino]-1H-b
enzimidazolecarboxamide,
(196)
6-[{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro-2
-methylphenyl)[(2-methoxymethylpropyl)amino]-1H-benzi
midazolecarboxamide,
(197)
6-[{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro-2
-methylphenyl){[(2S)-tetrahydrofuranylmethyl]amino}-1
H-benzimidazolecarboxamide,
(198)
6-[{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro-2
-methylphenyl){[(2R)-tetrahydrofuranylmethyl]amino}-1
H-benzimidazolecarboxamide,
(199)
6-[{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro-2
-methylphenyl)[(3-hydroxy-2,2-dimethylpropyl)amino]-1H-b
enzimidazolecarboxamide,
(200)
6-[{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro-2
-methylphenyl){[(2S)hydroxymethylbutanyl]amino}
-1H-benzimidazolecarboxamide,
(201)
N-(3-chloromethylphenyl)(dimethylamino)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide,
(202)
N-(4-tert-buthylphenyl)(dimethylamino)({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamid
(203)
N-(2,3-dihydro-1H-indenyl)(dimethylamino)({[2-(tri
fluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarb
oxamide,
(204)
6-{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)(dimethylamino)-1H-benzimidazolecarboxam
ide,
(205)
N-(3-chloromethylphenyl){[(2,6-dichlorophenyl)carbony
l]amino}(dimethylamino)-1H-benzimidazolecarboxamide,
(206)
N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}(dimethylamino)-1H-benzimidazolecarboxamide,
(207)
N-(3-chloromethylphenyl)cyclopropyl{[(2,5-dichloro
phenyl)carbonyl]amino}-1H-benzimidazolecarboxamide,
(208)
N-(3-chloromethylphenyl)cyclopropyl{[(2,5-dichloro
phenyl)carbonyl]amino}-1H-benzimidazolecarboxamide,
(209)
N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}(1-methylcyclopropyl)-1H-benzimidazolecarboxa
mide,
(210)
N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}(1-methylcyclopropyl)-1H-benzimidazolecarboxa
mide,
(211)
N-(3-chloromethylphenyl)(methoxymethyl)({[2-(methy
lsulfonyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxa
mide,
(212)
N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}(2-methoxyethyl)-1H-benzimidazolecarboxamide,
(213)
2-(methoxymethyl)-N-phenyl({[2-(trifluoromethyl)phenyl]c
arbonyl}amino)-1H-benzimidazolecarboxamide,
(214)
2-(methoxymethyl)-N-propyl({[2-(trifluoromethyl)phenyl]c
arbonyl}amino)-1H-benzimidazolecarboxamide,
(215)
2-(methoxymethyl)-N-(pyridinyl)({[2-(trifluoromethyl)
phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(216)
N-benzyl(methoxymethyl)({[2-(trifluoromethyl)phenyl]c
arbonyl}amino)-1H-benzimidazolecarboxamide,
(217)
N-(cyclohexylmethyl)(methoxymethyl)({[2-(trifluoromet
hyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(218)
2-(methoxymethyl)-N-(naphthalenyl)({[2-(trifluorometh
yl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(219)
2-(methoxymethyl)-N-(thiophenyl)({[2-(trifluoromethyl
)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(220)
N-(2,1,3-benzothiadiazolyl)(methoxymethyl)({[2-(tr
ifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecar
boxamide,
(221)
N-(1,1-dioxidebenzothiophenyl)(methoxymethyl)({
[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide,
(222)
2-(methoxymethyl)-N-(thiophenylmethyl)({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamid
(223)
N-(1H-indolyl)(methoxymethyl)({[2-(trifluoromethyl
)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(224)
N-(1,3-benzothiazolyl)(methoxymethyl)({[2-(trifluo
romethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxam
ide,
(225)
N-(2,2-dimethylpropyl)(methoxymethyl)({[2-(trifluorom
ethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
(226)
2-(methoxymethyl)-N-(thiophenyl)({[2-(trifluoromethyl
)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(227)
N-(5-chloro-1,3-benzoxazolyl)(methoxymethyl)({[2-(
trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolec
arboxamide,
(228)
N-(2-benzylphenyl)(methoxymethyl)({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(229)
2-(methoxymethyl)-N-(quinolinyl)({[2-(trifluoromethyl
)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(230)
N-(cycloheptylmethyl)(methoxymethyl)({[2-(trifluorome
thyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide,
(231)
N-(1,3-benzoxazolyl)(methoxymethyl)({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamid
(232)
N-(6-chloro-1,3-benzoxazolyl)(methoxymethyl)({[2-(
trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolec
arboxamide,
(233)
N-[3-chloro(hydroxymethyl)phenyl](methoxymethyl)({
[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide,
(234)
N-(3-chloromethylphenyl){[(3-fluoropyridinyl)carbo
nyl]amino}(methoxymethyl)-1H-benzimidazolecarboxamide
(235)
N-(3-chloromethylphenyl){[(3-chloropyridinyl)carbo
nyl]amino}(methoxymethyl)-1H-benzimidazolecarboxamide
(236)
N-(3-chloromethylphenyl){[(3,5-dichloropyridinyl)c
arbonyl]amino}(methoxymethyl)-1H-benzimidazolecarboxa
mide,
(237)
6-{[(5-butoxychlorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)(methoxymethyl)-1H-benzimidazolecarboxam
ide,
(238)
6-({[2-chloro(2,2-difluoroethoxy)phenyl]carbonyl}amino)-
N-(3-chloromethylphenyl)(methoxymethyl)-1H-benzimidaz
olecarboxamide,
(239)
N-(3-chloromethylphenyl)({[2-chloro(4,4,4-trifluor
obutoxy)phenyl]carbonyl}amino)(methoxymethyl)-1H-benzimi
dazolecarboxamide.
DETAILED DESCRIPTION OF THE INVENTION
Detail description of the terms used in the present
specification is provided as follows.
Examples of "halogen" include fluorine, chlorine,
bromine and iodine.
Examples of "alkyl" include straight or branched alkyl
having 1 to 8 carbon atoms, such as, for example, methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,
n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl,
n-octyl. Among which alkyl having 1 to 6 carbon atoms is
preferred, and alkyl having 1 to 3 carbon atoms is more
preferred.
The alkyl moiety of "monoalkylamino", "dialkylamino",
"monoalkyl aminocarbonyl", "dialkylaminocarbonyl",
"alkylcarbonyloxy", "alkyloxycarbonyl", "alkylcarbonyl",
"alkylthio", "alkylsulfonyl", "alkylsulfinyl", "alkoxyalkyl",
"monohaloalkyl", "dihaloalkyl", "trihaloalkyl" and
"alkoxyalkylamino" is as defined above for "alkyl".
Examples of "alkoxy" include straight or branched alkoxy
having 1 to 8 carbon atoms, such as, for example, methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,
t-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy.
The alkoxy moiety of "alkoxyalkoxy", "alkoxyalkyl" and
"alkoxyalkylamino" is as defined above for "alkoxy".
Examples of "heteroaryl" include monocyclic or bicyclic
aromatic rings having 1 to 3 hetero atoms selected from the group
consisting of nitrogen atom, oxygen atom and sulfur atom.
Specific examples include furyl (e.g., 2-furyl, 3-furyl),
thienyl (e.g., 2-thienyl, 3-thienyl), pyrrolyl (e.g.,
1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g.,
1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g.,
1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazoryl (e.g.,
1,2,4-triazolyl, 1,2,4-triazolyl, 1,2,4-triazolyl),
tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl),
oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl),
isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl),
oxadiazolyl (e.g., 1,3,4-oxadiazolyl), thiazolyl (e.g.,
2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl (e.g.,
1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl),
isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl,
-isothiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl,
4-pyridyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl),
pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl,
-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl),
benzothiadiazolyl (e.g., 1,2,3-benzothiadiazolyl,
1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl,
2,1,3-benzothiadiazolyl), benzothiazolyl (e.g.,
benzothiazolyl, benzothiazolyl, benzothiazolyl,
benzothiazolyl, benzothiazolyl), indolyl (e.g.,
indolyl and indolyl, indolyl, indolyl,
indolyl), benzothiophenyl (e.g., 1-benzothiophenyl,
1-benzothiophenyl, 1-benzothiophenyl,
1-benzothiophenyl, 1-benzothiophenyl,
1-benzothiophenyl), 1,1-dioxobenzothiophenyl (e.g.,
1,1-dioxobenzothiophenyl,
1,1-dioxobenzothiophenyl,
1,1-dioxobenzothiophenyl,
1,1-dioxobenzothiophenyl,
1,1-dioxobenzothiophenyl,
1,1-dioxobenzothiophenyl), quinolyl (quinolinyl,
quinolinyl, quinolinyl, quinolinyl, quinolinyl,
quinolinyl, quinolinyl) and 1,3-benzoxazolyl.
The heteroaryl moiety of "heteroarylmethyl" is as defined
above for "heteroaryl".
Examples of "a saturated cyclic amino" include 4- to
7-membered saturated cyclic amino groups having one or two
nitrogen atoms, said ring optionally having one oxygen or sulfur
atom and optionally substituted with oxo. Specific examples
include 1-azetidinyl, 1-pyrrolidinyl, 1-imidazolidinyl,
piperidino, 1-piperazinyl, 1-tetrahydropyrimidinyl,
4-morpholino, 4-thiomorpholino, 1-homopiperazinyl, and
2-oxo-oxazolidinyl.
The saturated cyclic amino moiety of "a saturated cyclic
aminocarbonyl" is as defined above for "a saturated cyclic
amino".
Examples of "a saturated heterocycle group" include 4-
to 6-membered saturated heterocycle group having one nitrogen
or oxygen atom in the ring. Specific examples include
2-pyrrolidinyl, 3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl,
4-piperidinyl, 2-oxetanyl, 3-oxetanyl, 2-tetrahydrofuranyl,
and 3-tetrahydrofuranyl.
Examples of "cycloalkyl" include cycloalkyl having 3 to
8 carbon atoms. Specific examples include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and
cyclooctyl.
The cycloalkyl moiety of "cycloalkyl methyl" is as
defined above for "cycloalkyl".
Examples of "naphthyl" include 1-naphthyl and
2-naphthyl.
Examples of "pyridyl" include 2-pyridyl, 3-pyridyl and
4-pyridyl.
Examples of "alkynyl" include straight or branched
alkynyl having 2 to 6 carbon atoms. Specific examples include
ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl, 2-propynyl,
2-butynyl, 3-butynyl, 1-methylpropynyl, 2-pentynyl,
3-pentynyl and 4-pentynyl,.
[Mode for Carrying Out the Invention]
The compound of the invention can be prepared according
to the following procedures, working examples or procedures
known in the art. If the starting material has a substituent
group that may interfere with a reaction during the process,
it may be protected with an appropriate protecting group
according to known method before subjecting to the reaction.
The following abbreviations can be used herein to
simplify the description.
p-: para-,
t-: tert-,
s-: sec-,
m-: meta-,
THF: tetrahydrofuran,
DMF: N,N-dimethylformamide,
DMA: N,N-dimethylacetamide,
HBTU: O-(benzotriazolyl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate,
HATU:
O-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate,
TFA: trifluoroacetic acid,
DME: ethylene glycol dimethyl ether,
NMP: N-methylpyrrolidone,
DMSO: dimethyl sulfoxide,
MeOH: methanol,
EtOH: ethanol.
Process 1
[Formula 4]
CO H
R NH
O NH
wherein ring A, R and R are as defined above.
This reaction is the condensation of Compound [6] with
Compound [7] and can be performed according to a method for
condensation reaction known per se. A compound of the invention
can be synthesized by the reaction of a carboxylic acid Compound
or its reactive derivative with an amine derivative [7].
Examples of such reactive derivative of Compound [6] include
those commonly used in an amide condensation formation, such
as, for example, acid halides (e.g., acid chloride, acid
bromide), mixed anhydrides, imidazolides, active amides. When
using Compound [6], the reaction can be performed using a
condensing agent at a temperature in the range from -20°C to
100°C in the presence or absence of a base. Examples of the
condensing agent which may be used for this reaction include
1,1'-oxalyldiimidazole,
1-ethyl(3-dimethylaminopropyl)carbodiimide,
dicyclohexylcarbodiimide, diethyl cyanophosphonate, HBTU,
HATU, 1H-benzotriazolyl-oxy-tris-pyrrolidino-phosphonium
hexafluorophosphate. Examples of the base which can be used
for this reaction include organic bases such as triethylamine,
N,N-diisopropylethylamine, N,N-dimethylaniline, pyridine,
1,8-diazabicyclo[5,4,0]undecene. Any solvent may be used
so long as it does not interfere with the reaction, and examples
of such solvent include ethers such as THF, 1,4-dioxane and
diethyl ether, amides such as DMF and DMA, nitriles such as
acetonitrile and propionitrile, hydrocarbons such as benzene
and toluene, halogenated hydrocarbons such as chloroform and
methylene chloride, and mixed solvents thereof. Also, an
additive agent can be used if necessary. Examples of such
additive agent which can be used include 1-hydroxybenzotriazol
and 1-hydroxyaza-benzotriazol. Preferred reaction time is
generally within the range from 10 minutes to 24 hours, but it
should vary depending on the starting material, the reaction
temperature, etc. Preferred amounts of Compound [7] and the
condensing agent to be used are within the range from 1 to 3
moles for one mole of Compound [6]. Preferred amount of the
base to be used is within the range from 1 Eq to 10 Eq, preferably
from 1 Eq to 4 Eq, to Compound [6].
For example, Compound [6] can be prepared according to
the process as described below.
[Formula 5]
O OH
A A A
CO R CO R
CO H
[9A]
[Step 1-A]
[Step 2]
NH O NH
O NH
[8A]
CO R
[9B]
[Step 1-B]
[8B]
wherein ring A and R are as defined above, X represents halogen
and R represents alkyl.
Step 1-A
This reaction is a condensation reaction of Compound [8A]
with Compound [9A] to synthesize Compound [10] according to
Process 1 as described above.
Step 1-B
The reaction is a coupling reaction of Compound [8B] with
Compound [9B] using palladium catalyst, and the reaction is
performed according to a method known per se. The solvent which
can be used is not limited so long as it does not interfere with
a reaction, and examples of such solvent include hydrocarbons
such as toluene and xylene, ethers such as 1,4-dioxane and THF,
amides such as DMF, DMA and NMP, and a mixed solvent thereof.
The reaction is performed in the presence of a base at a
temperature in the range from 20°C to 200°C, optionally using
microwave. Examples of the palladium catalyst which can be used
include tris(dibenzylideneacetone)(chloroform)dipalladium
(0), tris(dibenzylideneacetone)dipalladium (0) and palladium
acetate (II). Suitable amount of such palladium catalyst is
within the range from 0.001 mol to 0.3 mol, to 1 mol of aryl
halide. Examples of the ligand for the palladium catalyst which
can be used include 1,1'-bis(diphenylphosphino)ferrocene,
4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene,
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl,
(±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl,
2-(di-t-butylphosphino)biphenyl,
bis[2-(diphenylphosphino)phenyl] ether, tri-t-butylphosphine,
etc. Examples of the base which can be used include sodium
t-butoxide, tripotassium phosphate and cesium carbonate. The
amount of the base to be used is within the range from 1 Eq to
Eq, preferably within the range from 1 Eq to 4 Eq, to Compound
[8B]. Appropriate reaction time is generally within the range
from 10 minutes to 24 hours, but it should vary depending on
the starting material, the reaction temperature, etc.
Step 2
Compound [6] can be prepared by hydrolyzing Compound [10]
according to a known method. The reaction is usually performed
in the presence of acid or base in a suitable solvent. Examples
of the acid used in the hydrolysis include inorganic acids such
as hydrochloric acid and sulfuric acid, and examples of the base
include inorganic bases such as sodium hydroxide and potassium
hydroxide. Examples of reaction solvent include alcohols such
as MeOH and EtOH, ethers such as THF and dioxane, water, and
mixed solvents thereof. The reaction is performed at a
temperature within the range from 0°C to 100°C, and the reaction
time is usually within the range from 30 minutes to 24 hours.
For example, Compound [8A] can be prepared by the
following process.
[Formula 6]
A 5 A 5
CO R CO R
NO NH
[8A]
wherein ring A and R are as defined above.
This reaction is a reduction reaction of Compound [11]
to aromatic amine, and the reaction can be carried out with a
conventional method. For example, the reaction is achieved by
catalytic hydrogen reduction of Compound [11] using a catalyst
such as Raney nickel, palladium, rhodium, platinum, etc., in
a suitable solvent under hydrogen gas atmosphere, hydride
reduction using lithium aluminum hydride, etc., iron reduction
using reduced iron reagent and ammonium chloride etc., or zinc
reduction using zinc dust and acetic acid, etc. In addition,
there are also a method using sulfides such as hydrosulfite
sodium and a reducing method by ammonium formate, hydrazine,
etc. with a metal catalyst such as palladium on carbon.
Selection of the solvent depends on the kind of compound or
reagent to be used, and the solvent may be used alone or as a
mixture thereof. Examples of such solvent include toluene, THF,
1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, acetone,
acetonitrile, DMF, or alcohols such as MeOH, EtOH and
tert-butanol, and water. Although the reaction temperature
depends on the kind of compound and reagent to be used, it is
usually within the range from 0°C to 300°C, preferably within
the range from 20°C to 150°C.
When the ring A of Compound [8A] is a group represented
by the general formula [2] or [3], the compound can be prepared
according to the method described in WO2008/65508. When the
ring A of Compound [8A] is a group represented by the general
formula [4], the compound can be prepared according to a method
described in literature (e.g., EP2226315, J. Org. Chem., 1960,
,942, etc.). Also, the compound may be prepared according
to the following process.
[Formula 7]
CO R
CO R
2 [13]
[Step 1]
[14]
X 5 5
CO R
2 CO R CO R
[Step 2] [Step 3]
[Step 4]
NO NH
[16]
[8A']
1 5 2 2
wherein X , R and A are as defined above, and X represents
NH or OH.
Step 1
This reaction is an acylation reaction of Compound [12]
with Compound [13] or its reactive derivative and can be
performed according to method known per se as acylation reaction.
Examples of the reactive derivative of Compound [13] include
those generally used for acylation reaction and include acid
halides (e.g., acid chloride, acid bromide), mixed acid
anhydrides, imidazolides, active amides, etc. When using
Compound [13], the reaction can be conducted using a condensing
agent in the presence or absence of a base at temperature within
a range from -20°C to 100°C. Examples of the condensing agent
which can be used for this reaction include
1,1'-oxalyldiimidazole,
1-ethyl(3-dimethylaminopropyl)carbodiimide,
dicyclohexylcarbodiimide, diethyl cyanophosphonate, HBTU,
HATU and 1H-benzotriazolyloxytripyrrolidinophosphonium
hexafluorophosphate. Examples of the base which can be used
for this reaction include organic bases such as triethylamine,
N,N-diisopropylethylamine, N,N-dimethylaniline, pyridine,
1,8-diazabicyclo[5,4,0]undecene. The solvent to be used is
not limited so long as it does not interfere with a reaction,
and examples of such solvent include ethers such as THF,
1,4-dioxane and diethyl ether, amides such as DMF and DMA,
nitriles such as acetonitrile and propionitrile, hydrocarbons
such as benzene and toluene, halogenated hydrocarbons such as
chloroform and methylene chloride, and a mixed solvent thereof.
Also, an additive agent can be used if necessary. Examples of
such additive agent which can be used include
1-hydroxybenzotriazol and 1-hydroxyaza-benzotriazol.
Preferred amount of the base to be used is within the range from
1 Eq to 10 Eq, preferably 1 Eq to 4 Eq, to Compound [13].
Preferred reaction time is generally within the range from 10
minutes to 24 hours, but it should vary depending on the starting
material, the reaction temperature, etc. Preferred amounts of
Compound [13] and the condensing agent to be used are within
the range from 1 to 3 moles for one mole of Compound [12].
Step 2
This reaction is intramolecular cyclization of Compound
using an acid catalyst and can be performed according to
a method known per se. The reaction is performed in a suitable
solvent or in the absence of a solvent, and examples of the acid
which can be used include hydrochloric acid, p-toluenesulfonic
acid, acetic acid, pyridinium p-toluenesulfonate,
polyphosphoric acid, phosphoryl chloride, etc. The reaction
can be carried out usually at a temperature within the range
from 0°C to 200°C.
The solvent which can be used is not limited so long as it does
not interfere with a reaction, and examples of such solvent
includes hydrocarbons such as toluene and xylene, alcohols such
as MeOH and EtOH, ethers such as 1,4-dioxane and THF, amides
such as DMF and DMA, halogenated hydrocarbon such as chloroform
and dichloromethane, acetonitrile, or a mixed solvent thereof.
The reaction time is generally within the range from 30 minutes
to 48 hours although it should vary depending on the starting
material and the reaction temperature.
Step 3
This reaction is a nitration reaction of Compound [15]
and can be performed according to a known method. Generally,
a nitrating agent, such as nitric acid, mixed acid, metal
nitrate, acetyl nitrate, dinitrogen pentaoxide, nitronium salt
(e.g., nitronium tetrafluoro borate, nitronium
trifluoromethanesulfonate), etc., is used. The reaction
solvent is not limited so long as it does not interfere with
a reaction, and example of such solvent include halogenated
solvents such as dichloromethane and chloroform, pentane, TFA,
sulfolane, acetonitrile, etc.
The reaction is carried out under neutral or acidic condition.
When the reaction is carried out under acidic condition,
examples of the acid to be used include sulfuric acid, nitric
acid, acetic acid, and acetic anhydride. Also, only such acid
may be used as a reaction solvent without using of the reaction
solvent as mentioned above. The reaction temperature is
generally within the range from -20°C to room temperature
although it should vary depending on the compound and reagent
to be used. Preferred reaction time is generally within the
range from 30 minutes to 24 hours although it should vary
depending on the starting material and the reaction
temperature.
Step 4
This reaction is a reduction reaction of Compound [16]
to an aromatic amine and can be carried out to prepare Compound
[8A'] according to the similar process of the preparation of
Compound [8A].
Compound [8B] can be prepared according to the method
described in literature (e.g., J. Med. Chem., 1999, 42, 5020,
WO2008/65508). When the ring A of Compound [8B] is a group
represented by the general formula [4], the compound also can
be prepared by the following process.
[Formula 8]
2 1 2 5
wherein A , X, X , X and R are as defined above.
Step 1
This reaction is a condensation reaction of Compound [17]
with Compound [13] or its reactive derivative and can be carried
out to prepare Compound [18] according to the similar procedure
of Step 1 in the process for Compound [8A'].
Step 2
This reaction is an intramolecular cyclization reaction
of acyl group and amino group using an acid catalyst and can
be carried out to prepare Compound [8B’] according to the
procedure of Step 2 in the above-mentioned process of the
preparation of Compound [8A'].
For example, Compound [17] can be prepared according to
the following process.
[Formula 9]
wherein X and R are as defined above.
Step 1-1
This reaction is a halogenation reaction of Compound [19]
and can be carried out according to a method known per se as
halogenation reaction. Examples of halogenating agent which
can be used include N-bromosuccinimide, N-iodosuccinimide,
bromine, iodine, etc., and generally, the reaction can be
carried out at a temperature within the range from 0°C to 200°C.
The solvent which can be used is not limited so long as it does
not interfere with a reaction, and examples of such solvent
include hydrocarbons, such as toluene and xylene, ethers such
as 1,4-dioxane and THF, amides such as DMF and DMA, halogenated
hydrocarbons such as chloroform and dichloromethane,
acetonitrile, and a mixed solvent thereof. Also a suitable base
may be added if necessary, and examples of such base which can
be used include pyridine, N,N-diisopropylethylamine, etc. The
amount of the base to be used, for example, is within the range
from 1 Eq to 10 Eq, preferably within the range from 1 Eq - 4
Eq, to Compound [19]. Preferred reaction time is generally
within the range from 30 minutes to 24 hours although it should
vary depending on the starting material and the reaction
temperature.
Step 1-2
This reaction is a reduction reaction of Compound [20]
to an aromatic amine, and can be performed to prepare Compound
[17A] according to the similar process of the above-mentioned
Compound [8A].
Step 2-1
This reaction is a halogenation reaction of Compound [21]
and can be performed to prepare Compound [17B] according to the
similar procedure of Step 1-1 in the process of the preparation
of Compound [17].
Process 2
[Formula 10]
wherein ring A, R and R are as defined above.
This reaction is a condensation reaction of Compound
[22A] with Compound [9A] and can be performed according to
Process 1 to prepare a compound of the invention.
Also, a compound of the invention may be prepared by the
following procedures.
[Formula 11]
wherein ring A, R , R and X are as defined above.
This reaction is a coupling reaction of Compound [22B]
with Compound [9B], and can be performed to prepare a compound
of the invention according to the similar procedure of Step 1-B
in the process of Compound [6].
Compound [22A] can be prepared according to the following
process, for example.
[Formula 12]
wherein ring A and R are as defined above.
Step 1
This reaction is a hydrolysis reaction of Compound [11]
as starting material and can be performed to prepare Compound
according to the similar procedure of Step 2 in the process
of the preparation of Compound [6].
Step 2
This reaction is a condensation reaction of Compound [23]
with Compound [7] and can be performed to prepare Compound [24]
according to Process 1.
Step 3
This reaction is a reduction reaction of Compound [24]
to an aromatic amine and can be performed to prepare Compound
[22A] according to the process of the preparation of Compound
[8A].
For example, Compound [22B] can also be prepared by the
following process.
[Formula 13]
wherein ring A, R and X are as defined above.
This reaction is a condensation reaction of Compound [25]
with Compound [7], and can be performed to prepare Compound
[22B] according to Process 1. Compound [25] can be prepared
according to a method described in literature (e.g.,
EP234872B1; US6387938B1; Bioorg. Med. Chem., 1999, 7, 2271; J.
Med. Chem., 1999, 42, 5020), and can also be prepared by
hydrolyzing Compound [8B] according to the similar procedure
of Step 2 in the process of the preparation of Compound [6].
Process 3
When the ring A is a group represented by the general
formula [4] and A is alkylthio, alkoxy or a group represented
by the general formula [5], the compound can be prepared
according to the following process.
[Formula 14]
1 2 1 0
wherein R , R and X are as defined above, and A represents
halogen, mesylate, tosylate, etc., and A represents alkylthio,
alkoxy or a group represented by the general formula [5].
This reaction is a nucleophilic substitution reaction of
Compound [26] by amines, metal alkoxy or substituted thiol and
can be carried out according to known method. The reaction is
carried out in a suitable solvent or in the absence of a solvent,
using an excessive amount of reagents, or in the presence of
a base. Examples of suitable base to be used include pyridine,
triethylamine, N,N-diisopropylethylamine, potassium
carbonate, sodium hydrogencarbonate, etc. The solvent to be
used is not limited so long as it does not interfere with a
reaction, and examples of such solvent include ethers such as
THF and diethyl ether, amides such as DMF and DMA, nitriles such
as acetonitrile and propionitrile, hydrocarbons such as benzene
and toluene, alcohols such as MeOH and EtOH, water, or a mixed
solvent thereof. Also, an excessive amount of the amine may
be used in the reaction instead of the solvent. The reaction
is generally carried out at a temperature within the range from
0°C to 200°C although it should depend on the compound and
reagents to be used. The amount of the base is, for example,
within the range from 1 Eq to 10 Eq, preferably within the range
from 1 Eq to 4 Eq, to Compound [26]. Preferred reaction time
is generally within the range from 30 minutes to 24 hours
although it should vary depending on the starting material and
the reaction temperature.
Compound [26] can be prepared, for example, according to
the following process.
[Formula 15]
1 1 2 5 0
wherein X , R , R , R and A are as defined above.
Step 1
This reaction is a nitration reaction of Compound [27]
as a starting material and can be performed according to the
similar procedure of Step 3 in the process for the preparation
of Compound [8A']. Compound [27] can be prepared according to
a method described in literature (e.g., WO2006/116412; J. Med.
Chem., 1993, 36, 2182).
Step 2
This reaction is a reduction reaction of Compound [28]
to an aromatic amine and can be performed to prepare Compound
according to the similar procedure of the process for the
preparation of Compound [8A].
Step 3
This reaction is a condensation reaction of Compound [29]
with Compound [9A] and can be performed to prepare Compound [30]
according to the similar procedure in Process 1.
Step 4
This reaction is a hydrolysis reaction of Compound [30]
and can be performed to prepare Compound [31] according to
similar procedure in Step 2 in the preparation of Compound [6].
Step 5
This reaction is a condensation reaction of Compound [31]
with Compound [7] and can be performed to prepare Compound [26]
according to similar procedure in Process 1.
Process 4
The compound also can be prepared by the following process
in case where the ring A is a group represented by the general
formula [4] and A is alkylsulfinyl, alkylsulfonyl.
[Formula 16]
1 2 1 4
wherein R , R , and X are as defined above, A represents
alkylthio and A represents alkylsulfinyl, alkylsulfonyl.
This reaction is an oxidation reaction of Compound [32]
as a starting material and can be carried out according to a
conventional method. For example, the reaction is achieved in
a suitable solvent using a peroxide such as potassium
permanganate, metachloro perbenzoic acid and oxone
permonosulfate. The solvent should be selected according to
the kind of starting material and not limited so long as it does
not interfere with a reaction, and examples of such solvent
include dichloromethane, chloroform, dichloroethane, THF,
1,4-dioxane, DME, toluene, MeOH, etc., and such solvent may be
used alone or as a mixed solvent. The amount of the oxidizing
agent is within the range from 0.5 Eq to 10 Eq, preferably within
the range from 0.9 Eq to 3 Eq, to the starting material. The
reaction temperature is usually within the range from -20°C to
80°C, preferably within the range from 0°C to 50°C although it
should depend on the kinds of the compound and reagent to be
used. Preferred reaction temperature is usually within the
range from 30 minutes to 24 hours although it depends on the
kind of starting material to be used and the reaction
temperature.
The compound of the invention may be used as a
pharmaceutical as it is, and also a pharmaceutically acceptable
salt thereof formed according to known method may be used.
Examples of such salt include inorganic salt of acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid and
phosphoric acid, and organic salt of acids such as acetic acid,
citric acid, tartaric acid, maleic acid, succinic acid, fumaric
acid, p-toluenesulfonic acid, benzenesulfonic acid, and
methanesulfonic acid.
For example, a hydrochloride of a compound of the
invention can be formed by dissolving the compound of the
invention in a solution of hydrogen chloride in alcohol, ethyl
acetate or diethyl ether.
The compound of the invention may have an asymmetrical
carbon, and each of such optical isomers and a mixture thereof
are within the scope of the present invention. Such optical
isomer can be prepared by optical resolution from a racemic
mixture as obtained in the following working examples,
according to known method using an optically active acid such
as tartaric acid, dibenzoyltartaric acid, mandelic acid,
-camphor sulfonic acid, etc., or by the use of an optically
active compound previously prepared as a starting material.
Alternatively, such compound may be prepared by optical
resolution using a chiral column or asymmetric synthesis.
Some of the compounds of the invention may exist as
tautomers, and each of such tautomers and a mixture thereof are
within the scope of the invention.
For example, the heterocycle derivative represented by
the general formula [1] (i.e., heterocycle derivative
represented by the following genera formula [1X]), wherein the
ring A is a group represented by the general formula [4] and
X is NH, may form a heterocycle derivative represented by the
following general formula [1XA].
[Formula 17]
1 2 2
wherein R , R , and A are as defined above.
As shown in the test examples as described below, the
compound of the invention or a pharmaceutically acceptable salt
thereof has mPGES-1 inhibiting activity. Also, since the
compound of the invention or a pharmaceutically acceptable salt
thereof has mPGES-1 inhibiting activity, it has PGE2 inhibitory
effect, analgesic action and anti-inflammatory effect.
Therefore, the compound of the invention or a
pharmaceutically acceptable salt thereof can be used as a
preventing or treating agent for diseases that involve mPGES-1,
diseases associated with PGE2, and diseases on which
effectiveness is expected based on analgesic or
anti-inflammatory action.
Examples of disease which can apply a compound of the
invention or a pharmaceutically acceptable salt thereof include
inflammatory bowel disease (e.g., see Non-Patent Document 11),
irritable bowel syndrome, migraine, headache, low back pain,
spinal stenosis, herniated disk, temporomandibular joint
disorders, cervical syndrome, cervical spondylosis,
endometriosis (e.g., see Non-Patent Document 12), adenomyosis,
preterm labour and delivery, threatened premature delivery,
dysmenorrhea, overactive bladder, nocturia (e.g., see
Non-Patent Document 13), interstitial cystitis,
neurodegenerative disease such as Alzheimer's disease,
multiple sclerosis (e.g., see Non-Patent Document 14),
psoriasis, rheumatoid arthritis (e.g., see Non-Patent Document
and Non-Patent Document 16), rheumatic fever, fibromyalgia,
neuralgia (e.g., see Non-Patent Document 17), complex regional
pain syndrome, fascial dysfunction, viral infections such as
influenza, common cold, zoster and AIDS, bacterial infection,
mycosis, burn (e.g., see Non-Patent Document 18), inflammation
and pain after operation, injury and dental extraction,
malignant tumors such as colon cancer, breast cancer, lung
cancer, prostatic cancer, etc. (e.g., see Non-Patent Document
19, Non-Patent Document 20, and Non-Patent Document 21),
atherosclerosis (e.g., see Non-Patent Document 22), stroke
(e.g., see Non-Patent Document 23), gout, arthritis,
osteoarthritis (e.g., see Non-Patent Document 24 and Non-Patent
Document 25), juvenile arthritis, ankylosing spondylitis,
tenosynovitis, ligament ossification, systemic lupus
erythematosus, vasculitis, pancreatitis, nephritis (e.g., see
Non-Patent Document 26), conjunctivitis, iritis, scleritis,
uveitis, wound therapy, dermatitis, eczema, osteoporosis,
asthma (e.g., see Non-Patent Document 27), chronic obstructive
pulmonary disease (e.g., see Non-Patent Document 28), pulmonary
fibrosis (e.g., see Non-Patent Document 29), allergic disease
(e.g., see Non-Patent Document 30), familial adenomatous
polyposis (e.g., see Non-Patent Document 31), scleroderma (e.g.,
see Non-Patent Document 32), bursitis, leiomyoma of uterus,
prostatitis, and a pain from cancer.
When administered as a pharmaceutical, a compound of the
invention or a pharmaceutically acceptable salt thereof is
administered as it is or as a pharmaceutical composition
containing, for example, 0.001% to 99.5%, preferably 0.1% to
90%, in a pharmaceutically acceptable non-toxic and inactive
carrier to a mammal including human.
In the pharmaceutical composition, a diluent in the form
of a solid, a semi-solid or a liquid, a bulking agent, and one
or more of other formulation additives can be used as a carrier.
Preferably, the pharmaceutical composition of the invention is
administered in a unit dosage from. The pharmaceutical
composition may be administered by intra-tissue administration,
oral administration, intravenous administration, local
administration such as dermal administration, ocular
instillation, intraperitoneal administration, intrathoracic
administration, etc., or transrectal administration. Of
course, the composition should be administered in a dosage form
suitable for these administration routes.
The dosage as a medicament should be adjusted preferably
in consideration of conditions of the patient such as age, body
weight, nature and severity of the disease, route of
administration, the compound of the invention to be
administered, whether such compound is a salt or not, and the
kind of such salt. For oral administration, a daily dosage
of the compound of the invention or a pharmaceutically
acceptable salt thereof as an active ingredient for adult is
generally within the range from 0.01 mg to 5 g, preferably 1
mg to 500 mg for adult human. However, a lower dosage under
said range may be sufficient in some cases, or a higher dosage
over the said range may be needed in other cases. Generally,
a daily dosage is administered once in a day or may be
administered in several divisions in a day. Alternatively, a
daily dosage can be administered intravenously by prompt
administration or continuous infusion over 24 hours.
[Example]
Although the present invention is further described in
detail in the following Reference Examples, Examples, Test
Examples and Formulation Examples, present invention is not
limited thereto.
The measurement conditions for high-performance liquid
chromatography mass spectrometer; LCMS are as follows.
Analytical instrument: ACUITY UPLC MS/PDA System (Waters)
Mass spectrometer: Waters 3100 MS detector
Photodiode array detector: ACUITY PDA detector (210-400 nm)
Column: Acuity BEH C , 1.7 μm, 2.1x50mm
Flow rate: 0.5 mL/min
Column temperature:40°C
Solvent:
A liquid: 0.1% formic acid/H O (v/v)
B liquid: 0.1% formic acid / acetonitrile (v/v)
Gradient condition:
Method A:
0.0-2.5min; %A liquid / %B liquid = 90/10 → 10/90
2.5-3.0min; %A liquid / %B liquid = 10/90
3.0-3.5min; %A liquid / %B liquid = 0/100
Method B:
0.0-2.5min; %A liquid / %B liquid = 50/50 → 10/90
2.5-3.0min; %A liquid / %B liquid = 10/90
3.0-3.5min; %A liquid / %B liquid = 0/100
The values [MS(m/z)] (MS: mass spectrometry) observed in
the mass spectrometry are expressed in m/z, and the retention
times are expressed in Rt (minute).
Reference Example 1
2-Chloro(ethoxymethyl)benzoic acid
The mixture of methyl 5-(bromomethyl)chlorobenzoate
(prepared as described in WO2010/132999) (0.2g), potassium
carbonate (0.21g), EtOH (3 mL) and THF (3 mL) was stirred at
80°C for 4 hours. The reaction mixture was cooled to room
temperature, water was then added, and the mixture was extracted
with ethyl acetate. The organic layer was separated and washed
with brine, and dried over magnesium sulfate and concentrated
in vacuo. The residue was purified on column chromatography
to obatin ethyl 2-chloro(ethoxymethyl)benzoate (0.15g).
This was dissolved in THF-MeOH-H O (3:3:2, 8 mL), and lithium
hydroxide hydrate (0.15g) was added, and the mixture was stirred
at room temperature for 14 hours. The reaction mixture was
acidified with 1N hydrochloric acid and extracted with ethyl
acetate. The organic layer was washed with brine, dried over
magnesium sulfate, and concentrated in vacuo to obtain the
titled compound (0.12g) as pale yellow oil.
Reference Example 2
2-Chloro[(2-ethoxyethoxy)methyl]benzoic acid
The titled compound was obtained according to the
procedure as described in Reference Example 1, using
2-ethoxyethanol instead of EtOH.
Reference Example 3
2-Chloro(cyclopropylethynyl)benzoic acid
To a solution of ethyl 5-bromochlorobenzoate(1.9g) in
DMF (12 mL), toluene (0.3 mL), cyclopropylacetylene (714 mg),
copper iodide (275 mg), dichloro
bis(triphenylphosphine)palladium (1.01g) and triethylamine
(20.1 mL) were added, and the mixture was degassed, stirred at
100°C under argon atmosphere for 8 hours later, and then the
reaction mixture was cooled to room temperature and diluted with
ethyl acetate. The insoluble material was filtered off on
celite. The mother liquor was washed with brine, dried over
magnesium sulfate and concentrated. By purification on column
chromatography, ethyl
2-chloro(cyclopropylethynyl)benzoate (1.86g) was obtained
as brown oil.
This was dissolved in MeOH-THF (1:1, 60 mL), 10% aqueous
sodium hydroxide solution (20 mL) was added, and the solution
was stirred at room temperature for 2 hours. The solvent was
removed under reduced pressure, water was added to the residue,
and the mixture was separated with diethyl ether.
The aqueous layer was separated, acidified with 1N
hydrochloric acid and extracted with ethyl acetate. The
organic layer was dried over magnesium sulfate and concentrated
in vacuo. The residual solid was washed with n-hexane, and the
titled compound (1.02g) was obtained as beige powder.
Reference Example 4
2-Chloro(2-cyclopropylethyl)benzoic acid
To a solution of 2-chloro(cyclopropylethynyl)benzoic
acid (200 mg) in ethyl acetate (20 mL) was added 10% palladium
on carbon (40 mg), and the mixture was stirred under hydrogen
atmosphere (0.2MPa)), for 14 hours later, then was filtered off
on celite, and the mother liquor was concentrated in vacuo.
The residue was purified on silica gel column chromatography
to obtain the titled compound (190 mg) as yellow oil.
Reference Example 5
2-Chloro(2-phenylethyl)benzoic acid
[Step 1]
2-chloro(phenylethynyl)benzoic acid
According to the procedure as described in Reference
Example 3 using phenylacetylene instead of
cyclopropylacetylene, 2-chloro(phenylethynyl)benzoic acid
was obtained as yellow powder.
[Step 2]
2-Chloro(2-phenylethyl)benzoic acid
The titled compound was obtained as pale yellow powder,
according to the procedure as described in Reference Example
4, using 2-chloro(phenylethynyl)benzoic acid instead of
2-chloro(cyclopropylethynyl)benzoic acid.
Reference Example 6
-(3-tert-Butoxypropynyl)chlorobenzoic acid
The titled compound was obtained as white powder
according to the procedure as described in Reference Example
3, using tert-butylpropargyl ether was used instead of
cyclopropylacetylene.
Reference Example 7
-(3-tert-Butoxypropyl)chlorobenzoic acid
The titled compound was obtained as a pale yellow oil
according to the procedure as described in Reference Example
4, using 5-(3-tert-butoxypropynyl)chlorobenzoic acid
instead of 2-chloro(cyclopropylethynyl)benzoic acid.
Reference Example 8
2-Chloro(3-hydroxymethylbutyl)benzoic acid
[Step 1]
2-Chloro(3-hydroxymethylbutynyl)benzoic acid
The titled compound was obtained as white powder
according to the procedure as described in Reference Example
3, using 2-methylbutynol instead of
cyclopropylacetylene.
[Step 2]
2-Chloro(3-hydroxymethylbutyl)benzoic acid
The titled compound was obtained as a pale yellow oil
according to the procedure as described in Reference Example
4, using 2-chloro(3-hydroxymethylbutynyl)benzoic
acid instead of 2-chloro(cyclopropylethynyl)benzoic acid.
Reference Example 9
3-Methoxy-N,2,2-trimethylpropanamine
[Step 1]
tert-Butyl (3-hydroxy-2,2-dimethylpropyl) carbamate
A solution of 3-amino-2,2-dimethylpropanol (6.98g)
and sodium carbonate (7.18g) in 1,4-dioxane-H O (1:1, 240 mL)
was stirred under ice-cooling, and di-tert-butyl dicarbonate
(14.77g) was added, and the mixture was stirred for 5 hours.
Ethyl acetate was added, and the organic layer was separated,
washed sequentially with water and brine, dried over magnesium
sulfate and concentrated in vacuo to obtain the titled compound
(12.7g) as a colorless solid.
[Step 2]
3-Methoxy-N,2,2-trimethylpropanamine
A solution of 60% sodium hydride (1.89g) in DMF (60 mL)
was stirred under ice-cooling, a solution of tert-butyl
(3-hydroxy-2,2-dimethylpropyl) carbamate (3.84g) in DMF (45
mL) was dropped slowly over 5 minutes. Methyl iodide (10.73g)
was added and the mixture was stirred at room temperature for
3 hours. Diethyl ether was added to the reaction mixture. The
organic layer was separated, washed sequentially with water and
brine, dried over magnesium sulfate and concentrated in vacuo.
The residue was purified on column chromatography to obtain
tert-butyl (3-methoxy-2,2-dimethylpropyl)methyl carbamate
(3.1g) as a colorless oil. This was stirred under ice-cooling,
TFA (8 mL) was added, and the mixture was stirred at room
temperature for 1 hour later. The mixture was stirred under
ice-cooling, and raised the pH to about pH 9 with 1N aqueous
sodium hydroxide solution, and extracted with diethyl ether.
The diethyl ether layer was dried and concentrated in vacuo with
magnesium sulfate to obtain the titled compound (2.6g) as pale
yellow oil.
Reference Example 10
-Butoxychlorobenzoic acid
To a solution of 2-chlorofluorobenzoic acid (50 mg)
and 1-butanol (263 μL) in THF (0.5 mL) and DMF (3 mL) was added
potassium t-butoxide (329 mg) and the solution was reacted at
120°C for 10 minutes in a microwave synthesizer (Biotage,
Initiator). The reaction mixture was cooled and acidified by
addition of water and 2M hydrochloric acid, extracted with
diethyl ether, dried over anhydrous sodium sulfate. The
solvent was removed in vacuo, and the residue was purified on
column chromatography to obtain the titled compound (17 mg) as
white powder.
Reference Example 11
2-Chloro(2,2-difluoroethoxy)benzoic acid
[Step 1]
Methyl 2-chloro(2,2-difluoroethoxy)benzoate
To a suspension of methyl 2-chlorohydroxybenzoate (50
mg) and potassium carbonate (111 mg) in acetone (1 mL) was added
2-iodo-1,1-difluoroethane (35 μL), and the suspension was
reacted at 120°C for 10 minutes in a microwave synthesizer
(Biotage, Initiator). After reaction at 130°C for additional
minutes, the reaction mixture was directly purified on silica
gel column chromatography to obtain the titled compound (55 mg)
as yellow oil.
[Step 2]
2-Chloro(2,2-difluoroethoxy)benzoic acid
To a solution of methyl
2-chloro(2,2-difluoroethoxy)benzoate (55 mg) in MeOH (1 mL)
was added 1M aqueous lithium hydroxide (0.88 mL), and the
solution was stirred at room temperature for 12 hours. The
reaction mixture was stirred under ice-cooling, 2M hydrochloric
acid was added slowly to acidify to pH 2-3, and the precipitation
solid was filtered. The solid was washed sequentially with a
small amount of water and diethyl ether, dried under reduced
pressure to obtain the titled compound (28 mg) as white powder.
Reference Example 12
2-Chloro(4,4,4-trifluorobutoxy)benzoic acid
[Step 1]
Methyl 2-chloro(4,4,4-trifluorobutoxy)benzoate
To a suspension of methyl 2-chlorohydroxy benzoate (50
mg) and potassium carbonate (111 mg) in acetone (1 mL) was added
1-bromo-4,4,4-trifluorobutane (50 μL) and the suspension was
reacted at 120°C for 10 minutes in a microwave synthesizer
(Biotage, Initiator). The reaction mixture was directly
purified on silica gel column chromatography to obtain the
titled compound (74 mg) as colorless oil.
[Step 2]
2-Chloro(4,4,4-trifluorobutoxy)benzoic acid
To a solution of methyl
2-chloro(4,4,4-trifluorobutoxy)benzoate (74 mg) in MeOH (1
mL) was added 1M aqueous lithium hydroxide solution (0.99 mL)
and the reaction mixture was stirred at room temperature for
12 hours. The reaction mixture was stirred under ice-cooling,
and 2M hydrochloric acid was added slowly to acidify to pH 2-3.
The precipitated solid was filtered, washed with water, and
dried under reduced pressure to obtain the titled compound (49
mg) as a colorless powder.
Example 1
N-[2-(Trifluoromethyl)benzyl]({[2-(trifluoromethyl)pheny
l]carbonyl}amino)-1H-benzimidazolcarboxamide
[Step 1]
Methyl 1H-benzimidazolecarboxylate
To a suspension of methyl 2-aminonitrobenzoate (1.0
g) in formic acid (> 87%) was added 5% palladium on carbon (100
mg) and the suspension was heated with stirring at 100°C for
23 hours. After the reaction mixture was cooled to room
temperature, the catalyst was filtered off on celite, and the
mother liquor was concentrated in vacuo. The residual solid
was washed with diethyl ether under stirring, the solid was
collected by filtration to obtain the titled compound (872 mg)
as a colorless powder.
[Step 2]
Methyl 6-nitro-1H-benzimidazolecarboxylate
Methyl 1H-benzimidazolecarboxylate (315 mg) was
dissolved in conc. sulfuric acid (3 mL), and the solution was
stirred on ice bath. A small amount of potassium nitrate (199
mg) was added portion-wise, the solution was stirred at room
temperature for 4 hours. The reaction mixture was poured into
ice, alkalified with 3N aqueous sodium hydroxide solution under
stirring on ice bath, and extracted with ethyl acetate. The
ethyl acetate layer was washed sequentially with water and brine,
dried over anhydrous magnesium sulfate. The titled compound
(334 mg) was obtained as colorless powder after distilling off
a solvent under reduced pressure.
[Step 3]
Methyl 6-amino-1H-benzimidazolecarboxylate
Methyl 6-nitro-1H-benzimidazolecarboxylate (304 mg)
was suspended in MeOH (10 mL), the suspension was added with
% palladium on carbon (30 mg), and stirred under hydrogen (1
atm) atmosphere. The catalyst was filtered off on celite and
washed with MeOH, and the mother liquor was concentrated in
vacuo to obtain the titled compound (269 mg) as pale yellow
powder.
MS(ESI+) m/z 192(M+H)
[Step 4]
methyl
6-({[2-(Trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimida
zolecarboxylate
To a solution of methyl
6-amino-1H-benzimidazolecarboxylate (266 mg) in dehydrated
THF (12 mL), N,N-diisopropylethylamine (284 μL) was added, and
the solution was stirred under ice-cooling. To this solution,
2-(trifluoromethyl)benzoyl chloride (284 μL) in dehydrated THF
(5 mL) was added slowly dropwise, and stirred at the same
temperature for 3 hours. After ice water was added, THF was
removed under reduced pressure, and aqueous saturated sodium
bicarbonate was added, and the mixture was extracted with ethyl
acetate. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate, and the solvent was removed under
reduced pressure. The residue was purified on NH silica gel
column chromatography (ethyl acetate -> ethyl acetate/MeOH) to
obtain the titled compound (309 mg) as pale yellow powder.
[Step 5]
6-({[2-(Trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimida
zolecarboxylic acid
Methyl
6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimida
zolecarboxylate (356 mg) was dissolved in MeOH (10 mL), and
1N aqueous sodium hydroxide solution (2 mL) was added, and the
reaction mixture was stirred at room temperature overnight.
After MeOH was removed under reduced pressure, water was added
to the residue, and the solution was acidified with 1N
hydrochloric acid to pH 5 under ice-cooling. The precipitate
was collected by filtration to obtain the titled compound (276
mg) as slightly brown powder.
[Step 6]
N-[2-(Trifluoromethyl)benzyl]({[2-(trifluoromethyl)pheny
l]carbonyl}amino)-1H-benzimidazolecarboxamide
To a solution of
6-({[2-(Trifluoromethyl)phenyl]carbonyl}amino-1H-benzimidaz
olecarboxylic acid (50 mg) in DMF (2 mL) were added
N'-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine
hydrochloride (33 mg), 1-hydroxybenzotriazol (23 mg) and
triethylamine (24 μL), and 2-(trifluoromethyl)benzylamine (24
μL) was added under ice-cooling, and the solution was stirred
at room temperature overnight. The mixture was poured into ice
water and extracted with ethyl acetate. The ethyl acetate layer
was washed sequentially with water and brine, dried over
anhydrous magnesium sulfate, and removed the solvent under
reduced pressure. The residue was washed with n-hexane/ethyl
acetate (1:1), and collected by filtration to obtain the titled
compound (61 mg) as colorless powder. MS(ESI+)m/z 507(M+H)
Example 2
N-Cyclohexyl({[2-(trifluoromethyl)phenyl]carbonyl}amino)
-1H-benzimidazolecarboxamide
The titled compound was obtained as colorless powder
according to the procedure as described in Step 6 of Example
1 using cyclohexylamine instead of
2-(trifluoromethyl)benzylamine. MS(ESI+)m/z 431(M+H)
Example 3
N-(3-Chloromethylphenyl)({[2-(trifluoromethyl)phenyl]
carbonyl}amino)-1H-benzimidazolecarboxamide
To a solution of
6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimida
zolecarboxylic acid (example 1, Step 5) (40 mg) in DMF (2
mL), HBTU (53 mg), triethylamine (20 μL) were added. Under
ice-cooling, 3-chloromethylaniline (17 μL) was added and the
solution was stirred at room temperature for 24 hours.
The reaction mixture was poured into ice water, extracted with
ethyl acetate. The ethyl acetate layer was washed sequentially
with water and brine, dried over anhydrous magnesium sulfate
and removed the solvent under reduced pressure.
The residue was washed with n-hexane/ethyl acetate (1:1) and
collected by filtration to obtain the titled compound (33 mg)
as colorless powder. MS(ESI+)m/z 473(M+H)
Example 5
N-[(1-Hydroxycyclohexyl)methyl]({[2-(trifluoromethyl)phe
nyl]carbonyl}amino)-1H-benzimidazolecarboxamide
The titled compound was obtained as colorless powder
according to the procedure as described in Step 6 of Example
1, using 1-aminomethylcyclohexanol instead of
2-(trifluoromethyl)benzylamine. MS(ESI+)m/z 461(M+H)
Example 6
N-[2-(Trifluoromethyl)benzyl]({[2-(trifluoromethyl)pheny
l]carbonyl}amino)-2,3-dihydrobenzofurancarboxamide)
[Step 1]
Ethyl 5-bromo-2,3-dihydrobenzofurancarboxylate
To a solution of
-bromo-2,3-dihydrobenzofurancarboxylic acid (1.0g) in
EtOH (15 mL), sulfuric acid (0.5 mL) was added, and the solution
was heated at reflux for 30 hours. The reaction mixture was
cooled to room temperature, and EtOH was removed. The residue
was added with water, and the solution was extracted with ethyl
acetate. The ethyl acetate layer was washed sequentially with
saturated aqueous sodium bicarbonate and brine, dried over
anhydrous magnesium sulfate. The solvent was removed under
reduced pressure to obtain the titled compound (1.07g) as pale
yellow powder.
[Step 2]
Ethyl
-({[2-(Trifluoromethyl)phenyl]carbonyl}amino)-2,3-dihydro-
1-benzofurancarboxylate
1,4-dioxane (20 ml) was added to ethyl
-bromo-2,3-dihydrobenzofurancarboxylate (600 mg),
2-(trifluoromethyl)benzamide (501 mg),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos)
(96 mg), cesium carbonate (1.01g) and
tris(dibenzylideneacetone)dipalladium (114 mg). After
degassing, the mixture was stirred at 100°C under argon
atmosphere for 24 hours. The reaction mixture was filtered off
on celite, the solvent was removed under reduced pressure. The
resultant residue was purified on silica gel column
chromatography to obtain the titled compound (220 mg) as
slightly yellow powder.
[Step 3]
-({[2-(Trifluoromethyl)phenyl]carbonyl}amino)-2,3-dihydro-
1-benzofurancarboxylic acid
To a suspension of ethyl
-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-2,3-dihydro-
1-benzofurancarboxylate (220 mg) obtained in Step 2 in EtOH
(5 mL), 1N aqueous sodium hydroxide solution (1 mL) was added
and the mixture was stirred at 80°C for 4 hours. The reaction
mixture was cooled to room temperature, and EtOH was removed
under reduced pressure. The residue was added with water, and
acidified to pH 3 with 1N hydrochloric acid under ice-cooling
and extracted with ethyl acetate. The organic layer was washed
sequentially with water and brine, dried over anhydrous
magnesium sulfate, and removed the solvent under reduced
pressure to obtain the titled compound (195 mg) as slightly
yellow powder.
[Step 4]
N-[2-(Trifluoromethyl)benzyl]({[2-(trifluoromethyl)pheny
l]carbonyl}amino)-2,3-dihydrobenzofurancarboxamide
To a solution of
-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-2,3-dihydro-
1-benzofurancarboxylic acid (35 mg) in DMF (2 mL),
N'-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine
hydrochloride (23 mg), 1-hydroxybenzotriazol (23 mg) and
triethylamine (17 μL) were added. Under ice-cooling, The
mixture was added 2-(trifluoromethyl)benzylamine (15 μL), and
stirred at room temperature overnight. The reaction mixture
was poured into ice water, and extracted with ethyl acetate.
The ethyl acetate layer was washed sequentially with water and
brine, dried over anhydrous magnesium sulfate and removed the
solvent under reduced pressure. The residue was washed with
n-hexane/ethyl acetate (1:1) and collected by filtration to
obtain the titled compound (43 mg) as colorless powder.
MS(ESI+) m/z 509 (M+H) , Rt = 2.31 minutes (method A)
Example 7
N-Cyclohexyl({[2-(trifluoromethyl)phenyl]carbonyl}amino)
-2,3-dihydrobenzofurancarboxamide
The titled compound was obtained as colorless powder
according to the procedure as described in Step 4 of Example
6 using cyclohexylamine instead of
2-(trifluoromethyl)benzylamine.
MS(ESI+) m/z 433 (M+H) , Rt= 2.25 minutes (method A)
Example 8
N-(3-Chloromethylphenyl)({[2-(trifluoromethyl)phenyl]
carbonyl}amino)-2,3-dihydrobenzofurancarboxamide
The titled compound was obtained as colorless powder
according to the procedure as described in Example 3, using
-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-2,3-dihydro-
1-benzofurancarboxylic acid instead of
6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimida
zolecarboxylic acid. MS(ESI+) m/z 475 (M+H) , Rt= 2.47
minutes (method A)
Example 9
N-Cyclohexyl({[2-(trifluoromethyl)phenyl]carbonyl}amino)
-1H-indazolecarboxamide
[Step 1]
Methyl
-bromo{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole
carboxylate
Under argon atmosphere, a solution of methyl
-bromo-1H-indazolecarboxylate (as prepared according to
WO2008/65508) (658 mg) in DMF (20 mL) was stirred under
ice-cooling. 60% Sodium hydride (124 mg) was added slowly, and
the mixture was stirred for 30 minutes at same temperature.
2-(Trimethylsilyl)ethoxymethyl chloride (544 μL) was added
dropwise slowly using a syringe, and the mixture was stirred
at room temperature for 4 hours. The mixture was poured into
ice water and extracted with ethyl acetate. The ethyl acetate
layer was washed sequentially with water and brine, dried over
anhydrous magnesium sulfate, and removed the solvent under
reduced pressure. The residue was purified on silica gel column
chromatography to obtain the titled compound (696 mg) as
slightly yellow oil.
[Step 2]
Methyl
-{[(benzyloxy)carbonyl]amino}{[2-(trimethylsilyl)ethoxy
]methyl}-1H-indazolecarboxylate
The titled compound was obtained as slightly yellow oil
from methyl
-bromo{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole
carboxylate prepared in Step 1, according to the procedure as
described in Step 2 of Example 6, using benzyl carbamate instead
of 2-(trifluoromethyl)benzamide.
[Step 3]
Methyl
-amino{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole
carboxylate
To a solution of methyl
-{[(benzyloxy)carbonyl]amino}{[2-(trimethylsilyl)ethoxy
]methyl}-1H-indazolecarboxylate (364 mg) in MeOH (10 mL) was
added 5% palladium on carbon (55 mg), and the reaction mixture
was stirred overnight under hydrogen atmosphere at an ordinary
pressure. The reaction mixture was filtered off on celite and
washed with MeOH. The mother liquor was concentrated under
reduced pressure to obtain the titled compound (234 mg) as green
powder.
[Step 4]
Methyl
-({[2-(trifluoromethyl)phenyl]carbonyl}amino){[2-(trime
thylsilyl)ethoxy]methyl}-1H-indazolecarboxylate
The titled compound (323 mg) was obtained as colorless
powder according to the procedure as described in Step 4 of
Example 1, using methyl
-amino{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole
carboxylate (231 mg).
[Step 5]
-({[2-(Trifluoromethyl)phenyl]carbonyl}amino){[2-(trime
thylsilyl)ethoxy]methyl}-1H-indazolecarboxylic acid
The titled compound (291 mg) was obtained as colorless
powder according to the procedure as described in Step 5 of
Example 1, using methyl
-({[2-(trifluoromethyl)phenyl]carbonyl}amino){[2-(trime
thylsilyl)ethoxy]methyl}-1H-indazolecarboxylate (321 mg).
[Step 6]
N-Cyclohexyl({[2-(trifluoromethyl)phenyl]carbonyl}amino)
-1H-indazolecarboxamide
To a solution of
-({[2-(trifluoromethyl)phenyl]carbonyl}amino){[2-(trime
thylsilyl)ethoxy]methyl}-1H-indazolecarboxylic acid
(obtained in Step 5) (48 mg) in DMF (2 mL) were added HBTU (46
mg) and triethylamine (17 μL), and the mixture was stirred at
room temperature, and added with cyclohexylamine (12.5 μL) and
stirred at same temperature overnight. The reaction mixture
was poured into ice water, extracted with ethyl acetate. The
ethyl acetate layer was washed sequentially with saturated
aqueous sodium bicarbonate and brine, dried over anhydrous
magnesium sulfate, and removed the solvent under reduced
pressure. The residue is triturated in n-hexane/ethyl acetate
(10:1), and collected by filtration to obtain 59 mg of
N-cyclohexyl({[2-(trifluoromethyl)phenyl]carbonyl}amino)
[2-(trimethylsilyl)ethoxymethyl]-indazolecarboxamide
as colorless powder. This was dissolved in MeOH (2 mL), 6N
hydrochloric acid (2 mL) was added, and the solution was stirred
on oil bath at 60-80°C for 10 hours. The solvent was removed,
and ice water was added to the residue. The precipitate was
collected by filtration and dried to obtain the titled compound
(33 mg) as colorless powder.
MS(ESI+) m/z 431 (M+H) , Rt= 1.91 minutes (method A)
Elemental Analysis for C H F N O +0.1H O
22 21 3 4 2 2
Calcd.(%) C:61.13 H:4.94 N:12.96
Found.(%) C:60.93 H:4.91 N:12.71
Example 10
N-[2-(Trifluoromethyl)benzyl]({[2-(trifluoromethyl)pheny
l]carbonyl}amino)-1H-indazolecarboxamide
The titled compound was obtained as colorless powder
according to the procedure as described in Step 6 of Example
9, using 2-(trifluoromethyl)benzylamine instead of
cyclohexylamine.
MS(ESI+) m/z 507 (M+H) , Rt= 2.05 minutes (method A)
Example 11
N-(3-Chloromethylphenyl)(methoxymethyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide hydrochloride
[Step 1]
Methyl 2-amino[(methoxyacetyl)amino]benzoate
To a solution of methyl 2,3-diaminobenzoate (3.0g) in THF
(50 mL) was added N,N-diisopropylethylamine (4.0 mL). The
solution was stirred under ice-cooling, and added with
methoxyacetyl chloride (1.81 mL) in THF (10 mL) dropwise slowly
and stirred for 3 hours at same temperature. The reaction
mixture was added with saturated aqueous sodium bicarbonate,
and removed THF under reduced pressure. The residue was added
with saturated aqueous sodium bicarbonate, and extracted with
ethyl acetate, dried over anhydrous magnesium sulfate, and
removed the solvent under reduced pressure. The residue was
purified on silica gel column chromatography to obtain the
titled compound (3.60g) as pale yellow powder.
[Step 2]
Methyl 2-(methoxymethyl)-1H-benzimidazolecarboxylate
Methyl 2-amino[(methoxyacetyl)amino]benzoate (280
mg) was dissolved in acetic acid (6 mL), and the solution was
heated at 100°C for 0.5 hour with stirring. After cooling the
reaction mixture to room temperature, acetic acid was removed.
The residue was added with saturated aqueous sodium bicarbonate
under ice-cooling, and extracted with ethyl acetate. The
organic layer was washed sequentially with water and brine,
dried over anhydrous magnesium sulfate and removed the solvent
under reduced pressure to obtain the titled compound (241 mg)
as pale yellow powder.
[Step 3]
Methyl
2-(methoxymethyl)nitro-1H-benzimidazolecarboxylate
The titled compound (274 mg) was obtained as colorless
powder according to the procedure as described in Step 2 of
Example 1, using methyl
2-(methoxymethyl)-1H-benzimidazolecarboxylate (240 mg)
instead of methyl 1H-benzimidazolecarboxylate.
[Step 4]
Methyl
6-amino(methoxymethyl)-1H-benzimidazolecarboxylate
The titled compound (202 mg) was obtained as yellow powder
according to the procedure as described in Step 3 of Example
1, using methyl
2-(methoxymethyl)nitro-1H-benzimidazolecarboxylate
(271 mg) instead of methyl
6-nitro-1H-benzimidazolecarboxylate.
[Step 5]
Methyl
2-(methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylate
The titled compound (281 mg) was obtained as colorless
powder according to the procedure as described in Step 4 of
Example 1, using methyl
6-amino(methoxymethyl)-1H-benzimidazolecarboxylate
(200 mg) instead of methyl
6-amino-1H-benzimidazolecarboxylate.
[Step 6]
2-(Methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylic acid
The titled compound (263 mg) was obtained as colorless
powder according to the procedure as described in Step 5 of
Example 1, using methyl
2-(methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylate (278 mg) instead of
methyl
6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimida
zolecarboxylate.
[Step 7]
N-(3-Chloromethylphenyl)(methoxymethyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide
To a solution of
2-(methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylic acid (153 mg) in DMF (5 mL),
were added HBTU (178 mg) and triethylamine (65 μL). The mixture
was added with 3-chloromethylaniline (56 μL) under stirring
at room temperature, and the mixture was stirred overnight. The
reaction mixture was poured into saturated aqueous sodium
bicarbonate, extracted with ethyl acetate. The ethyl acetate
layer was washed sequentially with water and brine, dried over
anhydrous magnesium sulfate, and removed the solvent under
reduced pressure. The residue was purified on silica gel column
chromatography to obtain
N-(3-chloromethylphenyl)(methoxymethyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide (165 mg) as colorless powder.
[Step 8]
N-(3-Chloromethylphenyl)(methoxymethyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide hydrochloride
N-(3-chloromethylphenyl)(methoxymethyl)({[2-
(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide (165 mg) obtained in Step 7 was suspended in EtOH
(3 mL). The suspension was added with 1M hydrochloric acid
(0.32 mL) and stirred to obtain a homogeneous solution, and
removed the solvent under reduced pressure. The residue was
triturated in ethyl acetate, collected by filtration, and dried
to obtain the titled compound (167 mg) as colorless powder.
MS(ESI+) m/z 517 (M+H) , Rt= 2.41 minutes (method A)
Elemental Analysis for C H ClF N O •HCl+1.0H O
20 3 4 3 2
Calcd. (%) C:52.55 H:4.06 N:9.81
Found. (%) C:52.35 H:3.96 N:9.89
Example 12
2-Methyl-N-[2-(trifluoromethyl)benzyl]({[2-(trifluoromet
hyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 11, using
acetyl chloride instead of methoxyacetyl chloride, and
2-(trifluoromethyl)benzylamine instead of
3-chloromethyl-aniline.
MS(ESI+) m/z 521 (M+H) ,
Rt= 1.74 minutes (method A)
Elemental Analysis for C H F N O •HCl+1.5H O
18 6 4 2 2
Calcd.(%) C:51.42 H:3.80 N:9.60
Found.(%) C:51.68 H:3.81 N:9.45
Example 13
N-Cyclohexylmethyl({[2-(trifluoromethyl)phenyl]carbon
yl}amino)-1H-benzimidazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 11, using
acetyl chloride instead of methoxyacetyl chloride,
cyclohexylamine instead of 3-chloromethylaniline.
MS(ESI+) m/z 445 (M+H) , Rt= 1.52 minutes (method A)
Example 14
N-(3-Chloromethylphenyl)methyl({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 11, using
acetyl chloride instead of methoxyacetyl chloride.
MS(ESI+) m/z 487 (M+H) , Rt= 2.10 minutes (method A)
Example 15
N-Cyclopentylmethyl({[2-(trifluoromethyl)phenyl]carbo
nyl}amino)-1H-benzimidazolecarboxamide
The titled compound was obtained as colorless powder
according to the procedure as described in Step 1 to Step 7 of
Example 11, using acetyl chloride instead of methoxyacetyl
chloride, and cyclopentylamine instead of
3-chloromethylaniline.
MS(ESI+) m/z 431 (M+H) , Rt= 1.39 minutes (method A)
Example 16
N-Cyclobutylmethyl({[2-(trifluoromethyl)phenyl]carbon
yl}amino)-1H-benzimidazolecarboxamide
The titled compound was obtained as colorless powder
according to the procedure as described in Step 1 to Step 7 of
Example 11, using acetyl chloride instead of methoxyacetyl
chloride, and cyclobutylamine instead of
3-chloromethylaniline.
MS(ESI+) m/z 417 (M+H) , Rt= 1.29 minutes (method A)
Example 17
N-(3-Chloromethylphenyl)ethyl({[2-(trifluoromethyl
)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
The titled compound was obtained as white powder
according to the procedure as described in Step 1 to Step 7 of
Example 11, using propionyl chloride instead of methoxyacetyl
chloride.
MS(ESI+) m/z 501 (M+H) , Rt= 2.39 minutes (method A)
Example 18
N-Cyclohexylethyl({[2-(trifluoromethyl)phenyl]carbony
l}amino)-1H-benzimidazolecarboxamide
The titled compound was obtained as colorless powder
according to the procedure as described in Step 1 to Step 7 of
Example 11, using propionyl chloride instead of methoxyacetyl
chloride, and cyclohexylamine instead of
3-chloromethylaniline.
MS(ESI+) m/z 459 (M+H) , Rt= 1.75 minutes (method A)
Example 19
2-Ethyl-N-[2-(trifluoromethyl)benzyl]({[2-(trifluorometh
yl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
The titled compound was obtained as colorless powder
according to the procedure as described in Step 1 to Step 7 of
Example 11, using propionyl chloride instead of methoxyacetyl
chloride, and 2-(trifluoromethyl)benzylamine instead of
3-chloromethylaniline.
MS(ESI+) m/z 535 (M+H) , Rt= 1.96 minutes (method A)
Example 20
N-Cyclohexyl(methoxymethyl)({[2-(trifluoromethyl)phen
yl]carbonyl}amino)-1H-benzimidazolecarboxamide
The titled compound was obtained as colorless powder
according to the procedure as described in Step 1 to Step 7 of
Example 11, using cyclohexylamine instead of
3-chloromethylaniline.
MS(ESI+) m/z 475 (M+H) , Rt= 1.97 minutes (method A)
Example 21
2-(Methoxymethyl)-N-[2-(trifluoromethyl)benzyl]({[2-(tri
fluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarb
oxamide
The titled compound was obtained as colorless powder
according to the procedure as described in Step 1 to Step 7 of
Example 11, using 2-(trifluoromethyl)benzylamine instead of
3-chloromethylaniline.
MS(ESI+) m/z 551 (M+H) , Rt= 2.12 minutes (method A)
Example 22
2-(Methoxymethyl)-N-(2-methylphenyl)({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
ortho-toluidine instead of 3-chloromethylaniline.
MS(ESI+) m/z 483 (M+H) , Rt= 1.06 minutes (method B)
Example 23
2-(Methoxymethyl)-N-(4-methylphenyl)({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
para-toluidine instead of 3-chloromethylaniline.
MS(ESI+) m/z 483 (M+H) , Rt= 1.06 minutes (method B)
Example 24
N-(2-Chlorobenzyl)(methoxymethyl)({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 11, using
2-chlorobenzylamine instead of 3-chloromethylaniline.
MS(ESI+) m/z 517 (M+H) , Rt= 2.04 minutes (method A)
Example 25
2-(Methoxymethyl)-N-(4-methylbenzyl)({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
4-methylbenzylamine instead of 3-chloromethylaniline.
MS(ESI+) m/z 497 (M+H) , Rt= 1.99 minutes (method A)
Example 26
N-(4,4-Difluorocyclohexyl)(methoxymethyl)({[2-(triflu
oromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxa
mide hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
4,4-difluorocyclohexylamine instead of
3-chloromethylaniline.
MS(ESI+) m/z 511 (M+H) , Rt= 1.88 minutes (method A)
Example 27
N-(4-tert-Buthylphenyl)(methoxymethyl)({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamid
e hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
4-tert-butylaniline instead of 3-chloromethylaniline.
MS(ESI+) m/z 525 (M+H) , Rt= 1.63 minutes (method B)
Example 28
2-(Methoxymethyl)-N-[4-(trifluoromethyl)phenyl]({[2-(tri
fluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarb
oxamide hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
1-amino(trifluoromethyl)benzene instead of
3-chloromethylaniline.
MS(ESI+) m/z 537 (M+H) , Rt= 1.39 minutes (method B)
Example 29
N-(2,4-Dimethylphenyl)(methoxymethyl)({[2-(trifluorom
ethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
2,4-dimethylaniline instead of 3-chloromethylaniline.
MS(ESI+) m/z497 (M+H) , Rt= 1.24 minutes (method B)
Example 30
N-(2-Chloromethylphenyl)(methoxymethyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
2-chloromethylaniline instead of
3-chloromethylaniline.
MS(ESI+) m/z 517 (M+H) , Rt= 1.42 minutes (method B)
Example 31
N-(3,4-Dimethylphenyl)(methoxymethyl)({[2-(trifluorom
ethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
3,4-dimethylaniline instead of 3-chloromethylaniline.
MS(ESI+) m/z 497 (M+H) , Rt= 1.22 minutes (method B)
Example 32
N-(3-Chloromethylphenyl)(methoxymethyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
3-chloromethylaniline instead of
3-chloromethylaniline.
MS(ESI+) m/z 517 (M+H) , Rt= 1.46 minutes (method B)
Example 33
N-(2,3-Dihydro-1H-indenyl)(methoxymethyl)({[2-(tri
fluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarb
oxamide hydrochloride
The titled compound was obtained as gray powder according
to the procedure as described in Example 11, using 5-aminoindan
instead of 3-chloromethylaniline.
MS(ESI+) m/z 509 (M+H) , Rt= 2.36 minutes (method A)
Example 34
2-(Methoxymethyl)-N-(5,6,7,8-tetrahydronaphthalenyl)(
{[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol
ecarboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
,6,7,8-tetrahydronaphthylamine instead of
3-chloromethylaniline.
MS(ESI+) m/z 523 (M+H) , Rt= 2.44 minutes (method A)
Example 35
N-(2-Fluorophenyl)(methoxymethyl)({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
A stirring solution of
2-(methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylic acid in THF (2 mL) was
stirred under ice-cooling, addedwith catalytic amount of DMF,
and then oxalyl chloride (7.7 μL) was added. One hour later,
the reaction mixture was added with additional oxalyl chloride
(7.7 μL) and stirred for additional one hour, and removed
volatile elements under reduced pressure. The residue was
dissolved in THF (2 mL), and 2-fluoroaniline (8.8 μL) and
triethylamine (11 μL) were added sequentially, and the mixture
was stirred at room temperature for 1 hour and added with
saturated aqueous sodium bicarbonate, and extracted with ethyl
acetate.
The ethyl acetate layer was washed with brine, dried over
anhydrous magnesium sulfate, and concentrated. The residue
was triturated in n-hexane/diethyl ether to obtain the titled
compound (21 mg) as colorless powder.
MS(ESI+) m/z 487 (M+H) , Rt= 2.14 minutes (method A)
Example 36
2-(Methoxymethyl)-N-(2-methoxypheny)({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
The titled compound was obtained as colorless powder
according to the procedure as described in Step 1 to Step 7 of
Example 11, using ortho-anisidine instead of
3-chloromethylaniline.
MS(ESI+) m/z 499 (M+H) , Rt= 2.07 minutes (method A)
Example 37
2-(Methoxymethyl)-N-(4-methoxypheny)({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
The titled compound was obtained as colorless powder
according to the procedure as described in Step 1 to Step 7 of
Example 11, using para-anisidine instead of
3-chloromethylaniline.
MS(ESI+) m/z 499 (M+H) , Rt= 1.96 minutes (method A)
Example 38
N-(3-Bromomethylphenyl)(methoxymethyl)({[2-(triflu
oromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxa
mide
The titled compound was obtained as colorless powder
according to the procedure as described in Step 1 to Step 7 of
Example 11, using 3-bromomethylaniline instead of
3-chloromethylaniline.
MS(ESI+) m/z 563 (M+H) , Rt= 2.45 minutes (method A)
Example 39
N-(3-Chloromethylbenzyl)(methoxymethyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Step 1 to Step 7 of
Example 11, using 3-chloromethylbenzylamine instead of
3-chloromethylaniline.
MS(ESI+) m/z 531 (M+H) , Rt= 2.19 minutes (method A)
Example 40
N-(2,6-Difluorophenyl)(methoxymethyl)({[2-(trifluorom
ethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
The titled compound was obtained as colorless powder
according to the procedure as described in Example 35, using
2,6-difluoroaniline instead of 2-fluoroaniline.
MS(ESI+) m/z 505 (M+H) , Rt= 1.94 minutes (method A)
Example 41
N-(3-Cyanomethylphenyl)(methoxymethyl)({[2-(triflu
oromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxa
mide
To a solution of
N-(3-bromomethylphenyl)(methoxymethyl)({[2-(triflu
oromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxa
mide (Example 38) (85 mg) in DMF (0.5 mL), was added zinc cyanide
(60% content, 60 mg). After degassing, the mixture was added
with tetrakis(triphenylphosphine)palladium (88 mg), and
stirred at 100°C for 24 hours. The reaction mixture was added
with ice water, and extracted with ethyl acetate. The ethyl
acetate layer was washed sequentially with water and brine,
dried over anhydrous magnesium sulfate, and removed the solvent
under reduced pressure. The residue was purified on
preparative thin-layer chromatography to obtain the titled
compound (14 mg) as colorless powder.
MS(ESI+) m/z 508 (M+H) , Rt= 1.02 minutes (method B)
Example 42
2-(Methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-N-{[3-(trifluoromethyl)pyridinyl]methyl}-1H-benzim
idazolecarboxamide dihydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
2-(aminomethyl)(trifluoromethyl)pyridine instead of
3-chloromethylaniline.
MS(ESI+) m/z 552 (M+H) , Rt= 1.86 minutes (method A)
Example 43
N-(2-Chloromethylphenyl)(methoxymethyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
2-chloromethylaniline instead of
3-chloromethylaniline.
MS(ESI+) m/z 517 (M+H) , Rt= 2.35 minutes (method A)
Example 44
2-(2-Aminooxoethyl)-N-(3-chloromethylphenyl)({[2-(
trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolec
arboxamide hydrochloride
[Step 1]
Methyl
2-(2-aminooxoethyl)nitro-1H-benzimidazolecarboxyla
Under ice-cooling, potassium nitrate (117 mg) was added
slowly portion wise to a stirring solution of methyl
2-(cyanomethyl)-1H-benzimidazolecarboxylate (prepared as
described in EP1479681) (226 mg) in conc. sulfuric acid (5 mL),
and the mixture was stirred at room temperature for 5 hours.
The reaction mixturewas poured into ice, and alkalified with
3N aqueous sodium hydroxide solution, and extracted with ethyl
acetate. The ethyl acetate layer was washed with sequentially
with water and brine, dried over anhydrous magnesium sulfate
and removed the solvent under reduced pressure. The residue
was washed with MeOH, filtered and dried to obtain the titled
compound (243 mg).
[Step 2]
Methyl
6-amino(2-aminooxoethyl)-1H-benzimidazolecarboxyla
The titled compound was obtained as yellow powder
according to the procedure as described in Step 4 of Example
11, using methyl
2-(2-aminooxoethyl)nitro-1H-benzimidazolecarboxyla
te instead of methyl
2-(methoxymethyl)nitro-1H-benzimidazolecarboxylate.
[Step 3]
Methyl
2-(2-aminooxoethyl)({[2-(trifluoromethyl)phenyl]carbo
nyl}amino)-1H-benzimidazolecarboxylate
The titled compound was obtained as orange powder
according to the procedure as described in Step 4 of Example
1, using methyl
6-amino(2-aminooxoethyl)-1H-benzimidazolecarboxyla
te instead of methyl 6-amino-1H-benzimidazolecarboxylate.
[Step 4]
2-(2-Aminooxoethyl)({[2-(trifluoromethyl)phenyl]carbo
nyl}amino)-1H-benzimidazolecarboxylic acid
The titled compound was obtained as brown powder
according to the procedure as described in Step 5 of Example
1, using methyl
2-(2-aminooxoethyl)({[2-(trifluoromethyl)phenyl]carbo
nyl}amino)-1H-benzimidazolecarboxylate instead of methyl
6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimida
zolecarboxylate.
[Step 5]
2-(2-Aminooxoethyl)-N-(3-chloromethylphenyl)({[2-(
trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolec
arboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Step 7 of Example
11, using
2-(2-aminooxoethyl)({[2-(trifluoromethyl)phenyl]carbo
nyl}amino)-1H-benzimidazolecarboxylic acid instead of
2-(methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylic acid.
MS(ESI+) m/z 530 (M+H) , Rt= 1.86 minutes (method A)
Example 45
2-(2-Aminooxoethyl)-N-[2-(trifluoromethyl)benzyl]({[2
-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4
-carboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Step 7 of Example
11, using
2-(2-aminooxoethyl)({[2-(trifluoromethyl)phenyl]carbo
nyl}amino)-1H-benzimidazolecarboxylic acid instead of
2-(methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylic acid, and
2-(trifluoromethyl)benzylamine instead of
3-chloromethylaniline.
MS(ESI+) m/z 564 (M+H) , Rt= 1.72 minutes (method A)
Example 46
N-(3-Chloromethylphenyl)methyl({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
[Step 1]
Methyl
1-methyl({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-
benzimidazolecarboxylate
To a solution of methyl
6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimida
zolecarboxylate (Example 1, Step 4) (189 mg) in THF (5 mL),
NaH (60%, 25 mg) was added slowly under ice-cooling, and the
mixture was stirred at same temperature for 30 minutes and
additionally at room temperature for 1 hour. The reaction
mixture was further stirred under ice-cooling, and was added
with methyl iodide (81 μL) slowly, and stirred at room
temperature overnight. The reaction mixture was added with
saturated aqueous ammonium chloride, and extracted with ethyl
acetate. The organic layer was washed sequentially with water
and brine, dried over anhydrous magnesium sulfate, and removed
the solvent under reduced pressure. The residue was purified
on column chromatography to obtain the titled compound (78 mg)
as colorless powder.
[Step 2]
1-Methyl({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-
benzimidazolecarboxylic acid
The titled compound was obtained as colorless powder
according to the procedure as described in Step 5 of Example
1, using methyl
1-methyl({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-
benzimidazolecarboxylate instead of methyl
6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimida
zolecarboxylate.
[Step 3]
N-(3-Chloromethylphenyl)methyl({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
The titled compound was obtained as colorless powder
according to the procedure as described in Step 7 of Example
11, using
1-methyl({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-
benzimidazolecarboxylic acid instead of
2-(methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylic acid.
MS(ESI+) m/z 487 (M+H) , Rt= 1.44 minutes (method B)
Example 47
N-Cyclohexylmethyl({[2-(trifluoromethyl)phenyl]carbon
yl}amino)-1H-benzimidazolecarboxamide
The titled compound was obtained as colorless powder
according to the procedure as described in Example 46, using
cyclohexylamine instead of 3-chloromethylaniline.
MS(ESI+)m/z 445(M+H)
Example 48
1-Methyl-N-[2-(trifluoromethyl)benzyl]({[2-(trifluoromet
hyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
The titled compound was obtained as colorless powder
according to the procedure as described in Example 46, using
2-(trifluoromethyl)benzylamine instead of
3-chloromethylaniline.
MS(ESI+) m/z 521 (M+H) , Rt= 1.06 minutes (method B)
Example 49
N-(3-Chloromethylphenyl)ethyl({[2-(trifluoromethyl
)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
The titled compound was obtained as white powder
according to the procedure as described in Example 46, using
ethyl iodide instead of methyl iodide.
MS(ESI+) m/z 501 (M+H) , Rt= 2.53 minutes (method A)
Example 50
N-Cyclohexylethyl({[2-(trifluoromethyl)phenyl]carbony
l}amino)-1H-benzimidazolecarboxamide
The titled compound was obtained as colorless powder
according to the procedure as described in Example 46, using
ethyl iodide instead of methyl iodide, and cyclohexylamine
instead of 3-chloromethylaniline.
MS(ESI+) m/z 459 (M+H) , Rt= 2.14 minutes (method A)
Example 51
1-Ethyl-N-[2-(trifluoromethyl)benzyl]({[2-(trifluorometh
yl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
The titled compound was obtained as colorless powder
according to the procedure as described in Example 46, using
ethyl iodide instead of methyl iodide, and
2-(trifluoromethyl)benzylamine instead of
3-chloromethylaniline.
MS(ESI+) m/z 535 (M+H) , Rt= 2.28 minutes (method A)
Example 52
N-(3-Chloromethylphenyl)methyl({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1,3-benzoxazolecarboxamide
[Step 1]
6-Bromomethyl-1,3-benzoxazolecarboxylic acid
To a solution of 5-bromohydroxyanthranilic acid
(prepared as described in Eur. J. Med. Chem., 1999, 34,729) (400
mg) in xylene (30 mL), were added acetyl chloride (135 μL),
triethylamine (265 μL) and pyridinium p-toluenesulfonate (130
mg), and the mixture was heated at reflux for 8 hours. The
reaction mixture was cooled to room temperature, diluted with
ethyl acetate, washed sequentially with water and brine, and
dried over anhydrous magnesium sulfate, and removed the solvent
under reduced pressure. The residue was purified on silica gel
column chromatography to obtain the titled compound (471 mg).
[Step 2]
6-Bromo-N-(3-chloromethylphenyl)methyl-1,3-benzoxazol
ecarboxamide
To a solution of
6-bromomethyl-1,3-benzoxazolecarboxylic acid (136 mg)
in DMF (2 mL), were added HBTU (242 mg) and triethylamine (110
μL). The mixture was added with 3-chloromethylaniline (76
μL)and stirred at room temperature over night. The reaction
mixture was poured into ice water and extracted with ethyl
acetate. The ethyl acetate layer was washed sequentially with
water and brine, dried over anhydrous magnesium sulfate, and
removed the solvent under reduced pressure. The residue was
purified on silica gel column chromatography to obtain the
titled compound (53 mg) as white powder.
[Step 3]
N-(3-Chloromethylphenyl)methyl({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1,3-benzoxazolecarboxamide
The titled compound was obtained as white powder
according to the procedure as described in Step 2 of Example
6, using
6-bromo-N-(3-chloromethylphenyl)methyl-1,3-benzoxazol
ecarboxamide instead of ethyl
-bromo-2,3-dihydrobenzofurancarboxylate.
MS(ESI) m/z 488 (M+H) , Rt= 1.96 minutes (method B)
Example 53
2-Methyl-N-[2-(trifluoromethyl)benzyl]({[2-(trifluoromet
hyl)phenyl]carbonyl}amino)-1,3-benzoxazolecarboxamide
[Step 1]
6-Bromomethyl-N-[2-(trifluoromethyl)benzyl]-1,3-benzoxaz
olecarboxamide
The titled compound was obtained as white powder
according to the procedure as described in Step 2 of Example
52, using 2-(trifluoromethyl)benzylamine instead of
3-chloromethylaniline.
[Step 2]
2-Methyl-N-[2-(trifluoromethyl)benzyl]({[2-(trifluoromet
hyl)phenyl]carbonyl}amino)-1,3-benzoxazolecarboxamide
The titled compound was obtained as white powder
according to the procedure as described in Step 2 of Example
6, using
6-bromomethyl-N-[2-(trifluoromethyl)benzyl]-1,3-benzoxaz
olecarboxamide instead of ethyl
-bromo-2,3-dihydrobenzofurancarboxylate.
MS(ESI) m/z 522 (M+H) , Rt= 2.49 minutes (method A)
Example 54
N-(3-Chloromethylphenyl)ethyl({[2-(trifluoromethyl
)phenyl]carbonyl}amino)-1,3-benzoxazolecarboxamide
[Step 1]
6-Bromoethyl-1,3-benzoxazolecarboxylic acid
The titled compound was obtained according to the
procedure as described in Step 1 of Example 52, using propionyl
chloride instead of acetyl chloride.
[Step 2]
6-Bromo-N-(3-chloromethylphenyl)ethyl-1,3-benzoxazole
carboxamide
The titled compound was obtained according to the
procedure as described in Step 2 of Example 52, using
6-bromoethyl-1,3-benzoxazolecarboxylic acid instead of
6-bromomethyl-1,3-benzoxazolecarboxylic acid.
[Step 3]
N-(3-Chloromethylphenyl)ethyl({[2-(trifluoromethyl
)phenyl]carbonyl}amino)-1,3-benzoxazolecarboxamide
The titled compound was obtained as powder according to
the procedure as described in Step 2 of Example 6, using
6-bromo-N-(3-chloromethylphenyl)ethyl-1,3-benzoxazole
carboxamide instead of ethyl
-bromo-2,3-dihydrobenzofurancarboxylate.
MS(ESI) m/z 502 (M+H) , Rt= 2.29 minutes (method B)
Example 55
N-(3-Chloromethylphenyl)ethoxy({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
[Step 1]
Methyl 2-ethoxynitro-1H-benzimidazolecarboxylate
To a stirring solution of methyl
2-ethoxy-1H-benzimidazolecarboxylate (prepared as
described in J. Med. Chem., 1993, 36, 2182) (500 mg) in conc.
sulfuric acid (5 mL), potassium nitrate (275 mg) was added
portion-wise under ice-cooling, and the mixture was stirred at
room temperature for 2.5 hours. The reaction mixture was poured
into ice, alkalified with aqueous sodium hydroxide solution,
and extracted with ethyl acetate. The ethyl acetate layer was
washed sequentially with water and brine, dried over anhydrous
magnesium sulfate, and removed the solvent under reduced
pressure to obtain the titled compound (595 mg) as white powder.
[Step 2]
Methyl 6-aminoethoxy-1H-benzimidazolecarboxylate
The titled compound was obtained as pale yellow powder
according to the procedure as described in Step 3 of Example
1, using methyl
2-ethoxynitro-1H-benzimidazolecarboxylate instead of
methyl 6-nitro-1H-benzimidazolecarboxylate.
[Step 3]
Methyl
2-ethoxy({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-
benzimidazolecarboxylate
The titled compound was obtained as colorless powder
according to the procedure as described in Step 4 of Example
1, using methyl
6-aminoethoxy-1H-benzimidazolecarboxylate instead of
methyl 6-amino-1H-benzimidazolecarboxylate.
[Step 4]
2-Ethoxy({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-
benzimidazolecarboxylic acid
The titled compound was obtained as colorless powder
according to the procedure as described in Step 5 of Example
1, using methyl
2-ethoxy({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-
benzimidazolecarboxylate instead of methyl
6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimida
zolecarboxylate.
[Step 5]
N-(3-Chloromethylphenyl)ethoxy({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
The titled compound was obtained as white powder
according to the procedure as described in Step 7 of Example
11, using
2-ethoxy({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-
benzimidazolecarboxylic acid instead of
2-(methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylic acid.
MS(ESI+) m/z 517 (M+H) , Rt= 1.72 minutes (method B)
Example 56
2-Ethoxy-N-[2-(trifluoromethyl)benzyl]({[2-(trifluoromet
hyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
The titled compound was obtained as white powder
according to the procedure as described in Example 55, using
2-(trifluoromethyl)benzylamine instead of
3-chloromethylaniline.
MS(ESI+) m/z 551 (M+H) , Rt= 1.32 minutes (method B)
Example 57
N-(3-Chloromethylphenyl)(1-chloromethylpropanyl
)({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimi
dazolecarboxamide
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
3-chloro-2,2-dimethylpropionyl chloride instead of
methoxyacetyl chloride.
MS(ESI+) m/z 563 (M+H) , Rt= 2.75 minutes (method A)
Example 58
N-(3-Chloromethylphenyl)[(dimethylamino)methyl]({[
2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-
4-carboxamide hydrochloride
[Step 1]
Methyl
2-(chloromethyl)nitro-1H-benzimidazolecarboxylate
The titled compound was obtained as slightly yellow
powder according to the procedure as described in Step 2 of
Example 1, using methyl
2-(chloromethyl)-1H-benzimidazolecarboxylate (prepared as
described in WO2003/106430) instead of methyl
1H-benzimidazolecarboxylate.
[Step 2]
Methyl
2-[(dimethylamino)methyl]nitro-1H-benzimidazolecarbox
ylate
To a solution of methyl
2-(chloromethyl)nitro-1H-benzimidazolecarboxylate (72
mg) in acetonitrile (3 mL), was added 2M dimethylamine/MeOH
solution (1.3 mL), and the mixture was stirred at 80°C
overnight.
The solvent was removed under reduced pressure, and the residue
was purified on silica gel chromatography to obtain the titled
compound (68 mg) as slightly yellow solid.
[Step 3]
Methyl
6-amino[(dimethylamino)methyl]-1H-benzimidazolecarbox
ylate
The titled compound was obtained as yellow amorphous
according to the procedure as described in Step 3 of Example
1, using methyl
2-[(dimethylamino)methyl]nitro-1H-benzimidazolecarbox
ylate instead of methyl
6-nitro-1H-benzimidazolecarboxylate.
[Step 4]
Methyl
2-[(dimethylamino)methyl]({[2-(trifluoromethyl)phenyl]ca
rbonyl}amino)-1H-benzimidazolecarboxylate
The titled compound was obtained as colorless powder
according to the procedure as described in Step 4 of Example
1, using methyl
6-amino[(dimethylamino)methyl]-1H-benzimidazolecarbox
ylate instead of methyl
6-amino-1H-benzimidazolecarboxylate.
[Step 5]
2-[(Dimethylamino)methyl]({[2-(trifluoromethyl)phenyl]ca
rbonyl}amino)-1H-benzimidazolecarboxylic acid
The titled compound was obtained as yellow amorphous
according to the procedure as described in Step 5 of Example
1, using methyl
2-[(dimethylamino)methyl]({[2-(trifluoromethyl)phenyl]ca
rbonyl}amino)-1H-benzimidazolecarboxylate instead of
methyl
6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimida
zolecarboxylate.
[Step 6]
N-(3-Chloromethylphenyl)[(dimethylamino)methyl]({[
2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-
4-carboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Step 7 of Example
11, using
2-[(dimethylamino)methyl]({[2-(trifluoromethyl)phenyl]ca
rbonyl}amino)-1H-benzimidazolecarboxylic acid instead of
2-(methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylic acid.
MS(ESI+) m/z 530 (M+H) , Rt= 1.54 minutes (method A)
Example 59
N-(3-Chloromethylphenyl)(2-methylpropyl)({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo
xamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
isovaleryl chloride instead of methoxyacetyl chloride.
MS(ESI+) m/z 529 (M+H) , Rt= 1.95 minutes (method B)
Example 60
2-(2-Methylpropyl)-N-[2-(trifluoromethyl)benzyl]({[2-(tr
ifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecar
boxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
isovaleryl chloride instead of methoxyacetyl chloride, and
2-(trifluoromethyl)benzylamine instead of
3-chloromethylaniline.
MS(ESI+) m/z 563 (M+H) , Rt= 1.20 minutes (method B)
Example 61
tert-Butyl
3-{4-[(3-chloromethylphenyl)carbamoyl]({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazolyl}azetidin
ecarboxylate
The titled compound was obtained as pale yellow powder
according to the procedures as described in Steps 1 to 7 of
Example 11, using
1-(tert-butoxycarbonyl)azetidinecarbonyl chloride
(prepared as described in US6020368) instead of methoxyacetyl
chloride.
MS(ESI+) m/z 628 (M+H) , Rt= 1.87 minutes (method B)
Example 62
N-(3-Chloromethylphenyl)[(methylamino)methyl]({[2-
(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide dihydrochloride
[Step 1]
Methyl
2-{[(tert-butoxycarbonyl)(methyl)amino]methyl}nitro-1H-b
enzimidazolecarboxylate
To a solution of methyl
2-(chloromethyl)nitro-1H-benzimidazolecarboxylate
(Example 58, Step 1) (72 mg) in acetonitrile (2 mL), was added
40% methylamine/MeOH solution (0.27 mL), and the mixture was
stirred at 80°C for 1 hour. The solvent was removed under
reduced pressure. The residue was added with water, and
extracted with ethyl acetate. The ethyl acetate layer was
washed with brine, dried over anhydrous magnesium sulfate, and
concentrated. The obtained residue (68 mg) was dissolved in
anhydrous THF (2 mL), triethylamine (93 μL) was added to the
solution. Di-tert-butyl dicaronate (141 μL) was added to the
solution with stirring under ice-cooling for 3 hours. The
reaction mixture was added with water , and extracted with ethyl
acetate. The ethyl acetate layer was washed with brine, dried
over anhydrous magnesium and concentrated under reduced
pressure. The residue was purified on column chromatography
to obtain the titled compound (54 mg) as slightly yellow
amorphous.
[Step 2]
Methyl
6-amino{[(tert-butoxycarbonyl)(methyl)amino]methyl}-1H-b
enzimidazolecarboxylate
The titled compound was obtained as yellow amorphous
according to the procedure as described in Step 3 of Example
1, using methyl
2-{[(tert-butoxycarbonyl)(methyl)amino]methyl}nitro-1H-b
enzimidazolecarboxylate instead of methyl
6-nitro-1H-benzimidazolecarboxylate.
[Step 3]
Methyl
2-{[(tert-butoxycarbonyl)(methyl)amino]methyl}({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo
xylate
The titled compound was obtained as slightly yellow
amorphous according to the procedure as described in Step 4 of
Example 1, using methyl
6-amino{[(tert-butoxycarbonyl)(methyl)amino]methyl}-1H-b
enzimidazolecarboxylate instead of methyl
6-amino-1H-benzimidazolecarboxylate.
[Step 4]
2-{[(tert-Butoxycarbonyl)(methyl)amino]methyl}({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo
xylic acid
The titled compound was obtained as yellow amorphous
according to the procedure as described in Step 5 of Example
1, using methyl
2-{[(tert-butoxycarbonyl)(methyl)amino]methyl}({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo
xylate instead of methyl
6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimida
zolecarboxylate.
[Step 5]
N-(3-Chloromethylphenyl)[(methylamino)methyl]({[2-
(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide dihydrochloride
2-{[(tert-Butoxycarbonyl)(methyl)amino]methyl}-N-(3-c
hloromethylphenyl)({[2-(trifluoromethyl)phenyl]carbon
yl}amino)-1H-benzimidazolecarboxamide (9 mg) was obtained
according to the procedure as described in Step 7 of Example
11, using
2-{[(tert-butoxycarbonyl)(methyl)amino]methyl}({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo
xylic acid instead of
2-(methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylic acid. This was dissolved
in methylene chloride (1 mL). The residue was added with TFA
(0.5 mL) under ice-cooling, and stirred for 0.5 hour. The
reaction miature was added with ice and then saturated aqueous
sodium bicarbonate, and extracted with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure.
The residue was purified on column chromatography to obtain
N-(3-chloromethylphenyl)[(methylamino)methyl]({[2-
(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide (5 mg) as slightly yellow powder. This was
dissolved in MeOH (0.5 mL), and treated with 1M hydrochloric
acid (2 Eq), and concentrated to obtain the titled compound (5
mg) as slightly yellow powder.
MS(ESI+) m/z 516 (M+H) , Rt= 1.55 minutes (method A)
Example 63
{4-[(3-Chloromethylphenyl)carbamoyl]({[2-(trifluorome
thyl)phenyl]carbonyl}amino)-1H-benzimidazolyl}methyl
acetate
[Step 1]
Methyl
2-[(acetyloxy)methyl]nitro-1H-benzimidazolecarboxylat
To a solution of methyl
2-(chloromethyl)nitro-1H-benzimidazolecarboxylate
(Example 58, Step 1) (99 mg) in DMF (1 mL), was added sodium
acetate (17 mg), and the mixture was stirred at 50°C for 6 hours.
The reaction mixture was added with ice water, and extracted
with ethyl acetate. The ethyl acetate layer was washed with
brine, dried over anhydrous magnesium sulfate and concentrated.
The residue was purified on column chromatography to obtain the
titled compound (65 mg) as colorless powder.
[Step 2]
Methyl
2-[(acetyloxy)methyl]amino-1H-benzimidazolecarboxylat
The titled compound was obtained as pale yellow powder
according to the procedure as described in Step 3 of Example
1, using methyl
2-[(acetyloxy)methyl]nitro-1H-benzimidazolecarboxylat
e instead of methyl 6-nitro-1H-benzimidazolecarboxylate.
[Step 3]
Methyl
2-[(acetyloxy)methyl]({[2-(trifluoromethyl)phenyl]carbon
yl}amino)-1H-benzimidazolecarboxylate
The titled compound was obtained as pale yellow amorphous
according to the procedure as described in Step 4 of Example
1, using methyl
2-[(acetyloxy)methyl]amino-1H-benzimidazolecarboxylat
e instead of methyl 6-amino-1H-benzimidazolecarboxylate.
[Step 4]
2-(Hydroxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylic acid
The titled compound was obtained as colorless powder
according to the procedure as described in Step 5 of Example
1, using methyl
2-[(acetyloxy)methyl]({[2-(trifluoromethyl)phenyl]carbon
yl}amino)-1H-benzimidazolecarboxylate instead of methyl
6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimida
zolecarboxylate.
[Step 5]
{4-[(3-Chloromethylphenyl)carbamoyl]({[2-(trifluorome
thyl)phenyl]carbonyl}amino)-1H-benzimidazolyl}methyl
acetate
A mixture of
2-(hydroxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylic acid (50 mg) and
N,N-diisopropylethylamine (49 μL) in methylene chloride-THF
(1:1)(2 mL) was stirred under ice-cooling, added with acetyl
chloride (19 μL), and stirred at room temperature overnight.
The reaction mixture was poured into a cold 10% aqueous citric
acid solution, and extracted with ethyl acetate. The organic
layer was separated, and washed with brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure.
The residue was dissolved in DMF (3 mL), and added with HBTU
(65 mg) and triethylamine (24 μL), and stirred at room
temperature. The mixture was added with
3-chloromethylaniline (16 μL) and stirred overnight. The
reaction mixture was poured into ice water, and extracted with
ethyl acetate. The organic layer was washed sequentially with
water and brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure.
The obtained residue was purified on column chromatography to
obtain the titled compound (6 mg) as colorless powder.
MS(ESI+) m/z 545 (M+H) , Rt= 2.41 minutes (method A)
Example 64
N-(3-Chloromethylphenyl)[(2R)-tetrahydrofuranyl]-6
-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidaz
olecarboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
(2R)-tetrahydrofurancarbonyl chloride (prepared as
described in WO2006/79642) instead of methoxyacetyl chloride.
MS(ESI+) m/z 543 (M+H) , Rt= 2.56 minutes (method A)
Elemental Analysis for C H ClF N O •HCl+1.5H O
27 22 3 4 3 2
Calcd.(%) C:53.48 H:4.32 N:9.24
Found.(%) C:53.26 H:4.17 N:9.19
Example 65
2-[(2R)-Tetrahydrofuranyl]-N-[2-(trifluoromethyl)benzyl]
({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimid
azolecarboxamide
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
(2R)-tetrahydrofurancarbonyl chloride (prepared as
described in WO2006/79642) instead of methoxyacetyl chloride,
and 2-(trifluoromethyl)benzylamine instead of
3-chloromethylaniline.
MS(ESI+) m/z 577 (M+H) , Rt= 2.25 minutes (method A)
Example 66
N-(3-Chloromethylphenyl)[(2S)-tetrahydrofuranyl]-6
-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidaz
olecarboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
(2S)-tetrahydrofurancarbonyl chloride (prepared as
described in WO2006/79642) instead of methoxyacetyl chloride.
MS(ESI+) m/z 543 (M+H) , Rt= 2.56 minutes (method A)
Example 67
2-[(2S)-Tetrahydrofuranyl]-N-[2-(trifluoromethyl)benzyl]
({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimid
azolecarboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
(2S)-tetrahydrofurancarbonyl chloride (prepared as
described in WO2006/79642) instead of methoxyacetyl chloride,
and 2-(trifluoromethyl)benzylamine instead of
3-chloromethylaniline.
MS(ESI+) m/z 577 (M+H) , Rt= 2.25 minutes (method A)
Example 68
2-(1-Acetylazetidinyl)-N-(3-chloromethylphenyl)({[
2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-
4-carboxamide hydrochloride
To a solution of tert-butyl
3-{4-[(3-chloromethylphenyl)carbamoyl]({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazoleanyl}azeti
dinecarboxylate (Example 61) (50 mg) in methylene chloride
(2 mL), was added thioanisole (50 μL). The mixture was added
with TFA (1 mL) under ice-cooling, and the mixture was stirred
at room temperature for 2 hours. The reaction mixture was
poured into saturated aqueous sodium bicarbonate and extracted
with ethyl acetate. The organic layer was washed with brine,
dried over anhydrous magnesium sulfate, and removed the solvent
under reduced pressure. The residue was triturated in
n-hexane/ethyl acetate, and the precipitate was collected by
filtration and dried to obtain
2-(azetidinyl)-N-(3-chloromethylphenyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide (38 mg). This was dissolved in THF (1 mL), and added with
pyridine (23 μL), and the mixture was stirred under ice-cooling.
The mixture was added dropwise with acetyl chloride (7.7 μL),
and stirred at room temperature for 2 hours. The reaction
mixture was poured into ice water, and extracted with ethyl
acetate. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate, and removed the solvent under
reduced pressure. The residue was purified on column
chromatography to obtain
2-(1-acetylazetidinyl)-N-(3-chloromethylphenyl)({[
2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-
4-carboxamide (7.5 mg). This was dissolved in MeOH (0.5 mL),
treated with 1M hydrogen chloride/MeOH, and concentrated to
obtain the titled compound (5.5 mg) as slightly gray powder.
MS(ESI+) m/z 570 (M+H) , Rt= 1.98 minutes (method A)
Example 69
tert-Butyl
(2S){4-[(3-chloromethylphenyl)carbamoyl]({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolyl}pyr
rolidine 1-carboxylate
The titled compound was obtained as white powder
according to the procedures as described in Steps 1 to 7 of
Example 11, using tert-butyl
(2S)(chlorocarbonyl)pyrrolidinecarboxylate (prepared
as described in Tetrahedron Asymmetry, 2007, 18, 2011) instead
of methoxyacetyl chloride.
MS(ESI+) m/z 642 (M+H) , Rt= 2.77 minutes (method A)
Example 70
tert-Butyl
(2R){4-[(3-chloromethylphenyl)carbamoyl]({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolyl}pyr
rolidinecarboxylate
The titled compound was obtained as white powder
according to the procedures as described in Steps 1 to 7 of
Example 11, using tert-butyl
(2R)(chlorocarbonyl)pyrrolidinecarboxylate (prepared
as described in Tetrahedron Asymmetry, 2007, 18, 2011) instead
of methoxyacetyl chloride.
MS(ESI+) m/z 642 (M+H) , Rt= 2.77 minutes (method A)
Example 71
N-(3-Chloromethylphenyl)[(2S)-pyrrolidinyl]({[2
-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4
-carboxamide dihydrochloride
To a solution of tert-butyl
(2S){4-[(3-chloromethylphenyl)carbamoyl]({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazoleyl}py
rrolidinecarboxylate (26 mg) (Example 69) in ethyl acetate
(2 mL), was added 4N hydrogen chloride/ethyl acetate solution
(2 mL), and the mixture was stirred at room temperature for 2
hours. N-hexane was added to the reaction mixture, the
precipitates was collected, and dried to obtain the titled
compound (20 mg) as pale yellow powder.
MS(ESI+) m/z 542 (M+H) , Rt= 1.65 minutes (method A)
Example 72
N-(3-Chloromethylphenyl)[(2S)methylpyrrolidinyl
]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimi
dazolecarboxamide
To a solution of
N-(3-chloromethylphenyl)[(2S)-pyrrolidinyl]({[2
-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4
-carboxamide (Example 71) (25 mg) in MeOH (0.4 mL), was added
38% aqueous formaldehyde solution (7.2 μL), and the mixture was
stirred at room temperature overnight. The mixture was added
with 2-picoline borane (10 mg), and stirred for 3 hours, removed
the solvent under reduced pressure. The residue was purified
on column chromatography to obtain the titled compound (11 mg)
as white powder.
MS(ESI+) m/z 556 (M+H) , Rt= 1.67 minutes (method A)
Example 73
2-[(2S)Acetylpyrrolidinyl]-N-(3-chloromethylphenyl
)({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimi
dazolecarboxamide
To a solution of
N-(3-chloromethylphenyl)[(2S)-pyrrolidinyl]({[2
-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4
-carboxamide (Example 71) (26 mg) in THF solution (0.5 mL), was
added pyridine (12 μL), and the mixture was stirred under
ice-cooling. The mixture was deed with acetyl chloride (5.1
μL), and stirred at room temperature for 1 hour. The reaction
mixture was added with ice water, and the mixture was extracted
with ethyl acetate. The organic layer was washed with brine,
dried over anhydrous magnesium sulfate, and removed the solvent
under reduced pressure. The residue was purified on column
chromatography to obtain the titled compound (15 mg) as white
powder.
MS(ESI+) m/z 584 (M+H) , Rt= 2.26 minutes (method A)
Example 74
N-(3-Chloromethylphenyl)[(2-methoxyethoxy)methyl](
{[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol
ecarboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
2-(methoxyethoxy)acetyl chloride instead of methoxyacetyl
chloride.
MS(ESI+) m/z 561 (M+H) , Rt= 2.43 minutes (method A)
Example 75
N-(3-Chloromethylphenyl)(1-methoxymethylpropany
l)({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzim
idazolecarboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
3-methoxy-2,2-dimethylpropanoyl chloride (prepared as
described in Bull. Chem. Soc. Jpn., 2001, 74, 1695) instead of
methoxyacetyl chloride.
MS(ESI+) m/z 559 (M+H) , Rt= 2.82 minutes (method A)
Example 76
2-tert-Butyl-N-(3-chloromethylphenyl)({[2-(trifluorom
ethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
pivaloyl chloride instead of methoxyacetyl chloride.
MS(ESI+) m/z 529 (M+H) , Rt= 3.03 minutes (method A)
Example 77
2-tert-Butyl({[2-(trifluoromethyl)phenyl]carbonyl}amino)
-N-{[3-(trifluoromethyl)pyridinyl]methyl}-1H-benzimidazo
lecarboxamide dihydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
pivaloyl chloride instead of methoxyacetyl chloride, and
2-(aminomethyl)(trifluoromethyl)pyridine instead of
3-chloromethylaniline.
MS(ESI+) m/z 564 (M+H) , Rt= 2.39 minutes (method A)
Example 78
N-(3-Chloromethylphenyl)(2-ethoxyethyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
3-ethoxy-propionylchloride (prepared as described in
EP1803350) instead of methoxyacetyl chloride.
MS(ESI+) m/z 545 (M+H) , Rt= 2.69 minutes (method A)
Example 79
N-(3-Chloromethylphenyl)(ethoxymethyl)({[2-(triflu
oromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxa
mide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
ethoxyacetyl chloride (prepared as described in US2004/39038)
instead of methoxyacetyl chloride.
MS(ESI+) m/z 531 (M+H) , Rt= 2.77 minutes (method A)
Example 80
2-(Ethoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}am
ino)-N-{[3-(trifluoromethyl)pyridinyl]methyl}-1H-benzimi
dazolecarboxamide dihydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
ethoxyacetyl chloride (prepared as described in US2004/39038)
instead of methoxyacetyl chloride, and
2-(aminomethyl)(trifluoromethyl)pyridine instead of
3-chloromethylaniline.
MS(ESI+) m/z 566 (M+H) , Rt= 2.18 minutes (method A)
Example 81
N-(3-Chloromethylphenyl)(2-methoxyethyl)({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo
xamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
methoxypropionyl chloride instead of methoxyacetyl chloride.
MS(ESI+) m/z 531 (M+H) , Rt= 2.58 minutes (method A)
Example 82
N-(3-Chloromethylphenyl)(2,2-dimethylpropyl)({[2-(
trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolec
arboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
tert-butylacetyl chloride instead of methoxyacetyl chloride.
MS(ESI+) m/z 543 (M+H) , Rt= 3.25 minutes (method A)
Example 83
N-(3-Chloromethylphenyl)cyclopropyl({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamid
e hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
cyclopropanecarbonyl chloride instead of methoxyacetyl
chloride.
MS(ESI+) m/z 513 (M+H) , Rt= 2.91 minutes (method A)
Example 84
N-(3-chloromethylphenyl)(2-methylpentanyl)({[2-
(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
2,2-dimethylpentanoyl chloride (prepared as described in J. Am.
Chem. Soc., 1974, 96, 1518) instead of methoxyacetyl chloride.
MS(ESI+) m/z 557 (M+H) , Rt= 3.16 minutes (method B)
Example 85
N-(3-Chloromethylphenyl)(1-methylcyclopropyl)({[2-
(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
1-methyl-cyclopropanecarbonyl chloride (prepared as described
in WO2009/68512) instead of methoxyacetyl chloride.
MS(ESI+) m/z 527 (M+H) , Rt= 3.16 minutes (method A)
Elemental Analysis for C H ClF N O •HCl+1.0H O
27 22 3 4 2 2
Calcd.(%) C:55.78 H:4.33 N:9.64
Found.(%) C:55.48 H:3.94 N:9.63
Example 86
2-tert-Butyl-N-(3-chloromethylphenyl)({[2-(trifluorom
ethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
pivaloyl chloride instead of methoxyacetyl chloride, and
3-chloromethylaniline instead of
3-chloromethylaniline.
MS(ESI+) m/z 529 (M+H) , Rt= 2.83 minutes (method B)
Example 87
2-tert-Butyl-N-(3-chloromethylphenyl){[(2,5-dichlorop
henyl)carbonyl]amino}-1H-benzimidazolecarboxamide
hydrochloride
[Step 1]
Methyl 6-aminotert-butyl-1H-benzimidazolecarboxylate
The title compound was obtained as white powder according
to the procedures as described in step 1 to step 4 of Example
11, using pivaloyl chloride instead of methoxyacetyl chloride
in Step 1.
[Step 2]
2-tert-Butyl{[2,5-dichlorophenyl]carbonyl]amino}-1H-benz
imidazolecarboxylic acid
The title compound was obtained according to the
procedures as described in step 4 and step 5 of Example 1, using
methyl 6-aminotert-butyl-1H-benzimidazolecarboxylate
instead of methyl 6-amino-1H-benzimidazolecarboxylate, and
2,5-dichlorobenzoyl chloride instead of
2-(trifluoromethyl)benzoyl chloride.
[Step 3]
2-tert-Butyl-N-(3-chloromethylphenyl){[(2,5-dichlorop
henyl)carbonyl]amino}-1H-benzimidazolecarboxamide
hydrochloride
The title compound was obtained according to the
procedures as described in step 7 and step 8 of Example 11, using
2-tert-Butyl{[2,5-dichlorophenyl]carbonyl]amino}-1H-benz
imidazolecarboxylic acid instead of
2-(methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylic acid.
MS(ESI+) m/z 529 (M+H) , Rt= 2.97 minutes (method B)
Example 88
2-tert-Butyl-N-(3-chloromethylphenyl){[(2,5-dichlorop
henyl)carbonyl]amino}-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as white powder
according to the procedures as described in step 7 and step 8
of Example 11, using
2-tert-Butyl{[2,5-dichlorophenyl]carbonyl]amino}-1H-benz
imidazolecarboxylic acid instead of
2-(methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylic acid, and
3-chloromethylaniline instead of
3-chloromethylaniline.
MS(ESI+) m/z 529 (M+H) , Rt= 3.05 minutes (method B)
Example 89
N-(3-Chloromethylphenyl)[1-(trifluoromethyl)cycloprop
yl]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzi
midazolecarboxamide
The titled compound was obtained as white powder
according to the procedures as described in Steps 1 to 7 of
Example 11, using 1-(trifluoromethyl)cyclopropanecarbonyl
chloride (prepared as described in WO2005/23773) instead of
methoxyacetyl chloride.
MS(ESI+) m/z 581 (M+H) , Rt= 3.15 minutes (method A)
Example 90
N-(3-Chloromethylphenyl)(methoxymethyl)methyl({
[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide
[Step 1]
2-(Methoxymethyl)methyl({[2-(trifluoromethyl)phenyl]c
arbonyl}amino)-1H-benzimidazolecarboxylic acid
The titled compound was obtained according to the
procedure as described in Example 46, using methyl
2-(methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylate instead of methyl
6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimida
zolecarboxylate.
[Step 2]
N-(3-Chloromethylphenyl)(methoxymethyl)methyl({
[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide
The titled compound was obtained as colorless powder
according to the procedure as described in Step 7 of Example
11, using
2-(methoxymethyl)methyl({[2-(trifluoromethyl)phenyl]c
arbonyl}amino)-1H-benzimidazolecarboxylic acid instead of
2-(methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylic acid.
MS(ESI+) m/z 531 (M+H) , Rt= 2.58 minutes (method A)
Example 91
N-(2-Chlorobenzyl)(methoxymethyl)methyl({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide
The titled compound was obtained as colorless powder
according to the procedure as described in Step 7 of Example
11, using
2-(methoxymethyl)methyl({[2-(trifluoromethyl)phenyl]c
arbonyl}amino)-1H-benzimidazolecarboxylic acid instead of
2-(methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylic acid, and 2-chloro
benzylamine instead of 3-chloromethylaniline.
MS(ESI+) m/z 531 (M+H) , Rt= 2.25 minutes (method A)
Example 92
6-{[(2-Chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)(methoxymethyl)-1H-benzimidazolecarboxam
ide hydrochloride
[Step 1]
6-Amino-N-(3-chloromethylphenyl)(methoxymethyl)-1H-be
nzimidazolecarboxamide
To a suspension of methyl
2-(methoxymethyl)nitro-1H-benzimidazolecarboxylate
(Example 11, Step 3) (4.8g) in MeOH (120 mL), were added lithium
hydroxide hydrate (4.56g) and water (54 mL). The mixture was
stirred at room temperature for 16 hours. Under ice-cooling,
1N hydrochloric acid was added slowly to the reaction mixture
to adjust the pH to about 2. The precipitate was collected by
filtration and dried to obtain
2-(methoxymethyl)nitro-1H-benzimidazolecarboxylic
acid (4.6g). To the solution of
2-(methoxymethyl)nitro-1H-benzimidazolecarboxylic
acid (4.6g) in DMF (90 mL), HBTU (8.23g), triethylamine (2.19g)
and 3-chloromethylaniline (3.07g) were added sequentially,
and the solution was stirred for 18 hours. The reaction mixture
was poured into saturated aqueous sodium bicarbonate and
stirred for 1 hour. The precipitate was collected by filtration
and washed sequentially with water and ethyl acetate to obtain
N-(3-chloromethylphenyl)(methoxymethyl)nitro-1H-be
nzimidazolecarboxamide (7.2g) as pale yellow powder. To
the solution of
N-(3-chloromethylphenyl)(methoxymethyl)nitro-1H-be
nzimidazolecarboxamide (7.2g) in MeOH-THF (1:1, 120 mL),
were added 1% platinum + 0.1% copper-activated carbon (Degussa
type CF105 R/W) (1.4g). The mixture was stirred under hydrogen
atmosphere (3 atm) for 4 hours. The catalyst was filtered off,
and the mother liquid was concentrated. The residual solid was
washed with ethyl acetate to obtain
6-amino-N-(3-chloromethylphenyl)(methoxymethyl)-1H-be
nzimidazolecarboxamide (5.1g) as pale yellow powder.
[Step 2]
6-{[(2-Chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)(methoxymethyl)-1H-benzimidazolecarboxam
ide hydrochloride
To a solution of
6-amino-N-(3-chloromethylphenyl)(methoxymethyl)-1H-be
nzimidazolecarboxamide (40 mg) in THF (1 mL), was added
N,N-diisopropylethylamine (24 μL), and the mixture was stirred
under ice-cooling. The mixture was added with
2-chlorofluorobenzoyl chloride (24 mg), and stirred for 3
hours. The reaction mixture was added with saturated aqueous
sodium bicarbonate, and extracted with ethyl acetate. The
ethyl acetate layer was washed with brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure.
The residue was purified on column chromatography to obtain
6-{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)(methoxymethyl)-1H-benzimidazolecarboxam
ide (50 mg). This was dissolved in ethyl acetate (2 mL), and
treated with 4N hydrogen chloride/ethyl acetate (1.2 Eq). The
precipitate was collected by filtration, and dried to obtain
the titled compound (40 mg) as white powder.
MS(ESI+) m/z 501 (M+H) , Rt= 2.39 minutes (method A)
Example 93
6-{[(2-Chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)methoxymethyl-1H-benzimidazolecarboxamid
e hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Step 2 of Example
92, using 2-chlorofluorobenzoyl chloride instead of
2-chlorofluorobenzoyl chloride.
MS(ESI+) m/z 501 (M+H) , Rt= 2.40 minutes (method A)
Example 94
6-{[(2-Chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)(methoxymethyl)-1H-benzimidazolecarboxam
ide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Step 2 of Example
92, using 2-chlorofluorobenzoyl chloride instead of
2-chlorofluorobenzoyl chloride.
MS(ESI+) m/z 501 (M+H) , Rt= 2.41 minutes (method A)
Example 95
N-(3-Chloromethylphenyl){[(2-chlorophenyl)carbonyl]am
ino}(methoxymethyl)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Step 2 of Example
92, using 2-chlorobenzoyl chloride instead of
2-chlorofluorobenzoyl chloride.
MS(ESI+) m/z 483 (M+H) , Rt= 2.36 minutes (method A)
Example 96
N-(3-Chloromethylphenyl){[(2-chloropyridinyl)carbo
nyl]amino}(methoxymethyl)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Step 2 of Example
92, using 2-chloronicotinoyl chloride instead of
2-chlorofluorobenzoyl chloride.
MS(ESI+) m/z 484 (M+H) , Rt= 2.16 minutes (method A)
Example 97
6-{[(2-Bromophenyl)carbonyl]amino}-N-(3-chloromethylphen
yl)(methoxymethyl)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Step 2 of Example
92, using 2-bromobenzoyl chloride instead of
2-chlorofluorobenzoyl chloride.
MS(ESI+) m/z 527 (M+H) , Rt= 2.39 minutes (method A)
Example 98
N-(3-Chloromethylphenyl){[(2,6-dichlorophenyl)carbony
l]amino}(methoxymethyl)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Step 2 of Example
92, using 2,6-dichlorobenzoyl chloride instead of
2-chlorofluorobenzoyl chloride.
MS(ESI+) m/z 517 (M+H) , Rt= 2.46 minutes (method A)
Example 99
N-(3-Chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}(methoxymethyl)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Step 2 of Example
92, using 2,5-dichlorobenzoyl chloride instead of
2-chlorofluorobenzoyl chloride.
MS(ESI+) m/z 517 (M+H) , Rt= 2.54 minutes (method A)
Example 100
6-{[(2-Chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)(methoxymethyl)-1H-benzimidazolecarboxam
ide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Step 2 of Example
92, using 2-chlorofluorobenzoyl chloride instead of
2-chlorofluorobenzoyl chloride.
MS(ESI+) m/z 501 (M+H) , Rt= 2.43 minutes (method A)
Example 101
6-{[(2-Chloro-3,6-difluorophenyl)carbonyl]amino}-N-(3-chlor
omethylphenyl)(methoxymethyl)-1H-benzimidazolecarb
oxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Step 2 of Example
92, using 2-chloro-3,6-difluorobenzoyl chloride instead of
2-chlorofluorobenzoyl chloride.
MS(ESI+) m/z 519 (M+H) , Rt= 2.46 minutes (method A)
Example 102
6-{[(2-Bromochlorophenyl)carbonyl]amino}-N-(3-chlorom
ethylphenyl)(methoxymethyl)-1H-benzimidazolecarboxami
de hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Step 2 of Example
92, using 2-chlorobromobenzoyl chloride (prepared as
described in WO2008/124575) instead of
2-chlorofluorobenzoyl chloride.
MS(ESI+) m/z 561 (M+H) , Rt= 2.50 minutes (method A)
Example 103
6-{[(2-Bromofluorophenyl)carbonyl]amino}-N-(3-chlorom
ethylphenyl)(methoxymethyl)-1H-benzimidazolecarboxami
de hydrochloride
To a solution of
6-amino-N-(3-chloromethylphenyl)(methoxymethyl)-1H-be
nzimidazolecarboxamide (50 mg) in DMF (1.5 mL), were added
HBTU (66 mg), N,N-diisopropylethylamine (30 μL) and
2-bromofluorobenzoic acid (38 mg) in turn, and the mixture
was stirred at room temperature for 24 hours. The reaction
mixture was poured into saturated aqueous sodium bicarbonate,
and extracted with ethyl acetate. The organic layer was
separated, washed sequentially with water and brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified on column chromatography
to obtain
6-{[(2-bromofluorophenyl)carbonyl]amino}-N-(3-chlorom
ethylphenyl)(methoxymethyl)-1H-benzimidazolecarboxami
de (46 mg). This was dissolved in ethyl acetate (2 mL), and
treated with 4N hydrogen chloride/ethyl acetate (1.2 Eq). The
precipitate was collected by filtration, and dried to obtain
the titled compound (24 mg) as white powder.
MS(ESI+) m/z 545 (M+H) , Rt= 2.44 minutes (method A)
Example 104
N-(3-Chloromethylphenyl){[(2-chloromethylphenyl)ca
rbonyl]amino}(methoxymethyl)-1H-benzimidazolecarboxam
ide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 103, using
2-chloromethylbenzoic acid instead of
2-bromofluorobenzoic acid.
MS(ESI+) m/z 497 (M+H) , Rt= 2.44 minutes (method A)
Example 105
N-(3-Chloromethylphenyl){[(2-chloromethylphenyl)ca
rbonyl]amino}(methoxymethyl)-1H-benzimidazolecarboxam
ide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 103, using
2-chloromethylbenzoic acid instead of
2-bromofluorobenzoic acid.
MS(ESI+) m/z 497 (M+H) , Rt= 2.47 minutes (method A)
Example 106
6-{[(5-Bromochlorophenyl)carbonyl]amino}-N-(3-chlorom
ethylphenyl)(methoxymethyl)-1H-benzimidazolecarboxami
de hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 103, using
-bromochlorobenzoic acid instead of
2-bromofluorobenzoic acid.
MS(ESI+) m/z 561 (M+H) , Rt= 2.62 minutes (method A)
Example 107
6-{[(2-Bromochlorophenyl)carbonyl]amino}-N-(3-chlorom
ethylphenyl)(methoxymethyl)-1H-benzimidazolecarboxami
de hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 103, using
2-bromochlorobenzoic acid instead of
2-bromofluorobenzoic acid.
MS(ESI+) m/z 561 (M+H) , Rt= 2.63 minutes (method A)
Example 108
N-(3-Chloromethylphenyl){[(2-chloromethylphenyl)ca
rbonyl]amino}(methoxymethyl)-1H-benzimidazolecarboxam
ide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 103, using
2-chloromethylbenzoic acid instead of
2-bromofluorobenzoic acid.
MS(ESI+) m/z 497 (M+H) , Rt= 2.54 minutes (method A)
Example 109
N-(3-Chloromethylphenyl)(methoxymethyl)({[5-methyl
(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 103, using
-methyl(trifluoromethyl)benzoic acid instead of
2-bromofluorobenzoic acid.
MS(ESI+) m/z 531 (M+H) , Rt= 2.59 minutes (method A)
Example 110
6-({[2,5-Bis(trifluoromethyl)phenyl]carbonyl}amino)-N-(3-ch
loromethylphenyl)(methoxymethyl)-1H-benzimidazolec
arboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 103, using
2,5-bis(trifluoromethyl)benzoic acid instead of
2-bromofluorobenzoic acid.
MS(ESI+) m/z 585 (M+H) , Rt= 2.76 minutes (method A)
Example 111
6-({[2,4-Bis(trifluoromethyl)phenyl]carbonyl}amino)-N-(3-ch
loromethylphenyl)(methoxymethyl)-1H-benzimidazolec
arboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 103, using
2,4-bis(trifluoromethyl)benzoic acid instead of
2-bromofluorobenzoic acid.
MS(ESI+) m/z 585 (M+H) , Rt= 2.80 minutes (method A)
Example 112
N-(3-Chloromethylphenyl)({[5-fluoro(trifluoromethy
l)phenyl]carbonyl}amino)(methoxymethyl)-1H-benzimidazole
carboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 103, using
-fluoro(trifluoromethyl)benzoic acid instead of
2-bromofluorobenzoic acid.
MS(ESI+) m/z 535 (M+H) , Rt= 2.68 minutes (method A)
Example 113
N-(3-Chloromethylphenyl)({[2-chloro(trifluoromethy
l)phenyl]carbonyl}amino)(methoxymethyl)-1H-benzimidazole
carboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 103, using
2-chloro(trifluoromethyl)benzoic acid instead of
2-bromofluorobenzoic acid.
MS(ESI+) m/z 551 (M+H) , Rt= 2.76 minutes (method A)
Example 114
N-(3-Chloromethylphenyl)[({2-chloro[2-(propanyl
oxy)ethoxy]phenyl}carbonyl)amino](methoxymethyl)-1H-benz
imidazolecarboxamide hydrochloride
Under argon atmosphere, potassium tert-butoxide (168 mg)
was added to a solution of 2-isopropoxyethanol (172 μL) in NMP
(1.5 mL). The mixture was stirred at room temperature for 10
minutes, added with 2-chlorofluorobenzoic acid (87 mg), and
then stirred at 130°C for 4 hours. The reaction mixture was
cooled on ice bath, and added with water, and then acidified
with 1N hydrochloric acid and extracted with ethyl acetate.
The organic layer was separated, washed with brine, and dried
over anhydrous magnesium sulfate, and concentrated under
reduced pressure to obtain crude
2-chloro[2-(propanyloxy)ethoxy]benzoic acid. This was
dissolved in DMF (2 mL), added with HATU (61 mg),
N,N-diisopropylethylamine (29 μL) and
6-amino-N-(3-chloromethylphenyl)(methoxymethyl)-1H-be
nzimidazolecarboxamide (50 mg) in this order, and stirred
at room temperature for 12 hours. The reaction mixture was
poured into saturated aqueous sodium bicarbonate, and extracted
with ethyl acetate. The organic layer was separated, washed
sequentially with water and brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure.
The residue was purified on column chromatography to obtain
N-(3-chloromethylphenyl)[({2-chloro[2-(propanyl
oxy)ethoxy]phenyl}carbonyl)amino](methoxymethyl)-1H-benz
imidazolecarboxamide (41 mg) as white powder. This was
dissolved in ethyl acetate (2 mL), and treated with 4N hydrogen
chloride/ethyl acetate (1.2 Eq). The precipitate was
collected by filtration, and dried to obtain the titled compound
(28 mg) as white powder.
MS(ESI+) m/z 585 (M+H) , Rt= 3.14 minutes (method A)
Example 115
6-({[2-Chloro(2-ethoxyethoxy)phenyl]carbonyl}amino)-N-(3
-chloromethylphenyl)(methoxymethyl)-1H-benzimidazole-
4-carboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 114, using
2-ethoxyethanol instead of 2-isopropoxy ethanol.
MS(ESI+) m/z 571 (M+H) , Rt= 2.71 minutes (method A)
Example 116
6-({[2-Chloro(3-methoxypropyl)phenyl]carbonyl}amino)-N-(
3-chloromethylphenyl)(methoxymethyl)-1H-benzimidazole
carboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 103, using
2-chloro(3-methoxypropyl)benzoic acid (prepared as
described in Bioorg. Med. Chem. Lett., 2010, 20, 2204) instead
of 2-bromofluorobenzoic acid.
MS(ESI+) m/z 555 (M+H) , Rt= 2.73 minutes (method A)
Example 117
6-({[5-(3-tert-Butoxypropynyl)chlorophenyl]carbonyl}a
mino)-N-(3-chloromethylphenyl)(methoxymethyl)-1H-benz
imidazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 103, using
-(3-tert-butoxypropynyl)chlorobenzoic acid (Reference
Example 6) instead of 2-bromofluorobenzoic acid.
MS(ESI+) m/z 593 (M+H) , Rt= 3.17 minutes (method A)
Example 118
6-({[5-(3-tert-Butoxypropyl)chlorophenyl]carbonyl}amino)
-N-(3-chloromethylphenyl)(methoxymethyl)-1H-benzimida
zolecarboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 103, using
-(3-tert-butoxypropyl)chlorobenzoic acid (Reference
Example 7) instead of 2-bromofluorobenzoic acid.
MS(ESI+) m/z 597 (M+H) , Rt= 3.28 minutes (method A)
Example 119
6-({[2-Chloro(3-hydroxymethylbutyl)phenyl]carbonyl}am
ino)-N-(3-chloromethylphenyl)(methoxymethyl)-1H-benzi
midazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 103, using
2-chloro(3-hydroxymethylbutyl)benzoic acid (Reference
Example 8) instead of 2-bromofluorobenzoic acid.
MS(ESI+) m/z 569 (M+H) , Rt= 2.64 minutes (method A)
Example 120
6-({[2-Chloro(ethoxymethyl)phenyl]carbonyl}amino)-N-(3-c
hloromethylphenyl)(methoxymethyl)-1H-benzimidazole
carboxamide
The titled compound was obtained as white powder
according to the procedure as described in Example 103, using
2-chloro(ethoxymethyl)benzoic acid (Reference Example 1)
instead of 2-bromofluorobenzoic acid.
MS(ESI+) m/z 541 (M+H) , Rt= 2.52 minutes (method A)
Example 121
6-[({2-Chloro[(2-ethoxyethoxy)methyl]phenyl}carbonyl)ami
no]-N-(3-chloromethylphenyl)(methoxymethyl)-1H-benzim
idazolecarboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 103, using
2-chloro[(2-ethoxyethoxy)methyl]benzoic acid (Reference
Example 2) instead of 2-bromofluorobenzoic acid.
MS(ESI+) m/z 585 (M+H) , Rt= 2.51 minutes (method A)
Example 122
6-({[2-Chloro(2-cyclopropylethyl)phenyl]carbonyl}amino)-
N-(3-chloromethylphenyl)(methoxymethyl)-1H-benzimidaz
olecarboxamide
The titled compound was obtained as white powder
according to the procedure as described in Example 103, using
2-chloro(2-cyclopropylethyl)benzoic acid (Reference
Example 4) instead of 2-bromofluorobenzoic acid.
MS(ESI+) m/z 551 (M+H) , Rt= 2.92 minutes (method A)
Example 123
N-(3-Chloromethylphenyl)({[2-chloro(2-phenylethyl)
phenyl]carbonyl}amino)(methoxymethyl)-1H-benzimidazole-4
-carboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 103, using
2-chloro(2-phenylethyl)benzoic acid (Reference Example 5)
instead of 2-bromofluorobenzoic acid.
MS(ESI+) m/z 587 (M+H) , Rt= 2.98 minutes (method A)
Example 124
N-(3-Chloromethylphenyl)cyclopentyl({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamid
e hydrochloride
[Step 1]
Methyl 2-cyclopentylnitro-1H-benzimidazolecarboxylate
The titled compound was obtained as pale yellow powder
according to the procedure as described in Steps 1 to 3 of Example
11, using cyclopentanecarbonyl chloride instead of
methoxyacetyl chloride.
[Step 2]
6-Amino-N-(3-chloromethylphenyl)cyclopentyl-1H-benzim
idazolecarboxamide
The titled compound was obtained as yellow powder
according to the procedure as described in Step 1 of Example
92, using methyl
2-cyclopentylnitro-1H-benzimidazolecarboxylate
instead of methyl
2-(methoxymethyl)nitro-1H-benzimidazolecarboxylate.
[Step 3]
N-(3-Chloromethylphenyl)cyclopentyl({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamid
e hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Step 2 of Example
92, using
6-amino-N-(3-chloromethylphenyl)cyclopentyl-1H-benzim
idazolecarboxamide instead of
6-amino-N-(3-chloromethylphenyl)(methoxymethyl)-1H-be
nzimidazolecarboxamide, and 2-(trifluoromethyl)benzoyl
chloride instead of 2-chlorofluorobenzoyl chloride.
MS(ESI+) m/z 541 (M+H) , Rt= 3.21 minutes (method A)
Example 125
N-(3-Chloromethylphenyl)cyclopentyl{[(2,5-dichloro
phenyl)carbonyl]amino}-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Step 2 of Example
92, using
6-amino-N-(3-chloromethylphenyl)cyclopentyl-1H-benzim
idazolecarboxamide instead of
6-amino-N-(3-chloromethylphenyl)(methoxymethyl)-1H-be
nzimidazolecarboxamide, and 2,5-dichlorobenzoyl chloride
instead of 2-chlorofluorobenzoyl chloride.
MS(ESI+) m/z 543 (M+H) , Rt= 3.32 minutes (method A)
Example 126
6-{[(2-Chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)cyclopentyl-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Step 2 of Example
92, using
6-amino-N-(3-chloromethylphenyl)cyclopentyl-1H-benzim
idazolecarboxamide instead of
6-amino-N-(3-chloromethylphenyl)(methoxymethyl)-1H-be
nzimidazolecarboxamide.
MS(ESI+) m/z 525 (M+H) , Rt= 3.24 minutes (method A)
Example 127
6-{[(2-Chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)[(2R)-tetrahydrofuranyl]-1H-benzimidazol
ecarboxamide hydrochloride
[Step 1]
Methyl
6-nitro[(2R)-tetrahydrofuranyl]-1H-benzimidazoleca
rboxylate
The titled compound was obtained as pale yellow powder
according to the procedure as described in Steps 1 to 3 of Example
11, using (2R)-tetrahydrofurancarbonyl chloride (prepared
as described in WO2006/79642) instead of methoxyacetyl
chloride.
[Step 2]
6-Amino-N-(3-chloromethylphenyl)[(2R)-tetrahydrofuran
yl]-1H-benzimidazolecarboxamide
The titled compound was obtained as yellow powder
according to the procedure as described in Step 1 of Example
92, using methyl
6-nitro[(2R)-tetrahydrofuranyl]-1H-benzimidazoleca
rboxylate instead of methyl
2-(methoxymethyl)nitro-1H-benzimidazolecarboxylate.
[Step 3]
6-{[(2-Chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)[(2R)-tetrahydrofuranyl]-1H-benzimidazol
ecarboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Step 2 of Example
92, using
6-amino-N-(3-chloromethylphenyl)[(2R)-tetrahydrofuran
yl]-1H-benzimidazolecarboxamide instead of
6-amino-N-(3-chloromethylphenyl)(methoxymethyl)-1H-be
nzimidazolecarboxamide.
MS(ESI+) m/z 527 (M+H) , Rt= 2.75 minutes (method A)
Example 128
N-(3-Chloromethylphenyl){[(2,6-dichlorophenyl)carbony
l]amino}[(2R)-tetrahydrofuranyl]-1H-benzimidazolec
arboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Step 2 of Example
92, using
6-amino-N-(3-chloromethylphenyl)[(2R)-tetrahydrofuran
yl]-1H-benzimidazolecarboxamide instead of
6-amino-N-(3-chloromethylphenyl)(methoxymethyl)-1H-be
nzimidazolecarboxamide, and 2,6-dichlorobenzoyl chloride
instead of 2-chlorofluorobenzoyl chloride.
MS(ESI+) m/z 543 (M+H) , Rt= 2.80 minutes (method A)
Example 129
N-(3-Chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}[(2R)-tetrahydrofuranyl]-1H-benzimidazolec
arboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Step 2 of Example
92, using
6-amino-N-(3-chloromethylphenyl)[(2R)-tetrahydrofuran
yl]-1H-benzimidazolecarboxamide instead of
6-amino-N-(3-chloromethylphenyl)(methoxymethyl)-1H-be
nzimidazolecarboxamide, and 2,5-dichlorobenzoyl chloride
instead of 2-chlorofluorobenzoyl chloride.
MS(ESI+) m/z 543 (M+H) , Rt= 2.86 minutes (method A)
Example 130
N-(3-Chloromethylphenyl)[(2S)oxopyrrolidinyl]-6
-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidaz
olecarboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
(S)-(-)pyrrolidone 5-carbonyl chloride (prepared as
described in Tetrahedron Lett., 1997, 38, 2259) instead of
methoxyacetyl chloride.
MS(ESI+) m/z 556 (M+H) , Rt= 2.03 minutes (method A)
Example 131
N-(3-Chloromethylphenyl)[(2R)oxopyrrolidinyl]-6
-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidaz
olecarboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 11, using
(R)-(+)pyrrolidonecarbonyl chloride (prepared as
described in Tetrahedron Lett., 1997, 38, 2259) instead of
methoxyacetyl chloride.
MS(ESI+) m/z 556 (M+H) , Rt= 2.03 minutes (method A)
Example 132
N-(3-Chloromethylphenyl)[2-oxo(pyrrolidinyl)eth
yl]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzi
midazolecarboxamide hydrochloride
[Step 1]
Methyl
2-(2-ethoxyoxoethyl)-1H-benzimidazolecarboxylate
A solution of methyl 2,3-diaminobenzoate(680 mg) and
ethyl 3-aminoethoxyacrylate hydrochloride (880 mg) in EtOH
(12 mL) was stirred at 60°C for 2 hours. EtOH was removed under
reduced pressure, and the residue was purified on column
chromatography to obtain the titled compound (1.14g) as a pale
yellow solid.
[Step 2]
Methyl
2-(2-ethoxyoxoethyl)({[2-(trifluoromethyl)phenyl]carb
onyl}amino)-1H-benzimidazolecarboxylate
The titled compound was obtained as pale yellow powder
according to the procedures as described in Steps 3 to 5 of
Example 11, using methyl
2-(2-ethoxyoxoethyl)-1H-benzimidazolecarboxylate
instead of methyl 1H-benzimidazolecarboxylate as a starting
material.
[Step 3]
Methyl
2-[2-oxo(pyrrolidinyl)ethyl]({[2-(trifluoromethyl)
phenyl]carbonyl}amino)-1H-benzimidazolecarboxylate
Pyrrolidine (1 mL) was added to methyl
2-(2-ethoxyoxoethyl)({[2-(trifluoromethyl)phenyl]carb
onyl}amino)-1H-benzimidazolecarboxylate (80 mg), and the
solution was stirred at 70°C for 30 minutes. The reaction
mixture was diluted with ethyl acetate, and washed with brine.
The ethyl acetate layer was concentrated under reduced pressure.
The residue was purified on column chromatography to obtain the
titled compound (74 mg) as white powder.
[Step 4]
2-[2-Oxo(pyrrolidinyl)ethyl]({[2-(trifluoromethyl)
phenyl]carbonyl}amino)-1H-benzimidazolecarboxylic acid
A solution of methyl
2-[2-oxo(pyrrolidinyl)ethyl]({[2-(trifluoromethyl)
phenyl]carbonyl}amino)-1H-benzimidazolecarboxylate (74
mg), lithium hydroxide hydrate (66 mg) in MeOH-water (1:1, 2
mL) was stirred at 50°C for 30 minutes. The reaction mixture
was removed the solvent under reduced pressure, added with water,
and to neutralize by 1N hydrochloric acid under ice-cooling.
The precipitate was collected by filtration, washed with
diethyl ether, and dried under reduced pressure to obtain the
titled compound (60 mg) as pale yellow powder.
[Step 5]
N-(3-Chloromethylphenyl)[2-oxo(pyrrolidinyl)eth
yl]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzi
midazolecarboxamide hydrochloride
To a solution of
2-[2-oxo(pyrrolidinyl)ethyl]({[2-(trifluoromethyl)
phenyl]carbonyl}amino)-1H-benzimidazolecarboxylic acid
(30 mg) and HATU (30 mg) in DMF (0.5 mL), were added
N,N-diisopropylethylamine (28 μL) and
3-chloromethylaniline (10 μL), and the mixture was stirred
at room temperature for 15 minutes. The reaction mixture was
diluted with ethyl acetate, washed with brine, and the organic
layer was concentrated under reduced pressure. The residue was
purified on column chromatography to obtain pale yellow powder
(28 mg). This was suspended in MeOH (1 mL), and 2N hydrogen
chloride/EtOH solution (1 Eq) was added to obtain a homogeneous
solution, which was then concentrated under reduced pressure.
The residue was triturated in diethyl ether and washed. The
precipitate was collected by filtration and dried under reduced
pressure to obtain the titled compound (20 mg) as white powder.
MS(ESI+) m/z 584 (M+H) , Rt= 2.24 minutes (method A)
Example 133
N-(3-Chloromethylphenyl)[2-(dimethylamino)oxoethyl
]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimi
dazolecarboxamide hydrochloride
[Step 1]
Methyl
2-[2-(dimethylamino)oxoethyl]({[2-(trifluoromethyl)ph
enyl]carbonyl}amino)-1H-benzimidazolecarboxylate
The titled compound was obtained as pale yellow powder
according to the procedure as described in Step 3 of Example
132, using 40% aqueous dimethylamine solution and THF instead
of pyrrolidine.
[Step 2]
2-[2-(Dimethylamino)oxoethyl]({[2-(trifluoromethyl)ph
enyl]carbonyl}amino)-1H-benzimidazolecarboxylic acid
The titled compound was obtained as gray powder according
to the procedure as described in Step 4 of Example 132, using
methyl
2-[2-(dimethylamino)oxoethyl]({[2-(trifluoromethyl)ph
enyl]carbonyl}amino)-1H-benzimidazolecarboxylate instead
of methyl
2-[2-oxo(pyrrolidinyl)ethyl]({[2-(trifluoromethyl)
phenyl]carbonyl}amino)-1H-benzimidazolecarboxylate.
[Step 3]
N-(3-Chloromethylphenyl)[2-(dimethylamino)oxoethyl
]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimi
dazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Step 5 of Example
132, using
2-[2-(dimethylamino)oxoethyl]({[2-(trifluoromethyl)ph
enyl]carbonyl}amino)-1H-benzimidazolecarboxylic acid
instead of
2-[2-oxo(pyrrolidinyl)ethyl]({[2-(trifluoromethyl)
phenyl]carbonyl}amino)-1H-benzimidazolecarboxylic acid.
MS(ESI+) m/z 558 (M+H) , Rt= 2.12 minutes (method A)
Example 134
N-(3-Chloromethylphenyl)[2-(methylamino)oxoethyl]-
6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimida
zolecarboxamide hydrochloride
[Step 1]
Methyl
2-[2-(methylamino)oxoethyl]({[2-(trifluoromethyl)phen
yl]carbonyl}amino)-1H-benzimidazolecarboxylate
The titled compound was obtained as white powder
according to the procedure as described in Step 3 of Example
132, using 40% aqueous methylamine solution and THF instead of
pyrrolidine.
[Step 2]
2-[2-(Methylamino)oxoethyl]({[2-(trifluoromethyl)phen
yl]carbonyl}amino)-1H-benzimidazolecarboxylic acid
The titled compound was obtained as brown powder
according to the procedure as described in Step 4 of Example
132, using methyl
2-[2-(methylamino)oxoethyl]({[2-(trifluoromethyl)phen
yl]carbonyl}amino)-1H-benzimidazolecarboxylate instead of
methyl
2-[2-oxo(pyrrolidinyl)ethyl]({[2-(trifluoromethyl)
phenyl]carbonyl}amino)-1H-benzimidazolecarboxylate.
[Step 3]
N-(3-Chloromethylphenyl)[2-(methylamino)oxoethyl]-
6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimida
zolecarboxamide hydrochloride
The titled compound was obtained as pale red powder
according to the procedure as described in Step 5 of Example
132, using
2-[2-(methylamino)oxoethyl]({[2-(trifluoromethyl)phen
yl]carbonyl}amino)-1H-benzimidazolecarboxylic acid
instead of
2-[2-oxo(pyrrolidinyl)ethyl]({[2-(trifluoromethyl)
phenyl]carbonyl}amino)-1H-benzimidazolecarboxylic acid.
MS(ESI+) m/z 544 (M+H) , Rt= 1.98 minutes (method A)
Example 135
2-Chloro-N-(3-chloromethylphenyl)({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
[Step 1]
Methyl 2-chloro-1H-benzimidazolecarboxylate
A solution of methyl 2-oxo
2,3-dihydro-1H-benzimidazolecarboxylate (prepared as
described in US2009/186879) (2.0g) in phosphoryl chloride (18
mL) was stirred at 120°C for 2.5 hours. Excessive phosphoryl
chloride was removed under reduced pressure. The residue was
added with saturated aqueous sodium bicarbonate under
ice-cooling, and extracted with ethyl acetate. The ethyl
acetate layer was dried over anhydrous magnesium sulfate and
concentrated. The residue was purified on column
chromatography to obtain the titled compound (1.5g) as white
powder.
[Step 2]
Methyl 2-chloronitro-1H-benzimidazolecarboxylate
The titled compound (0.98g) was obtained as pale yellow
powder according to the procedure as described in Step 2 of
Example 1, using methyl
2-chloro-1H-benzimidazolecarboxylate (1.46g) instead of
methyl-1H-benzimidazolecarboxylate.
[Step 3]
Methyl 6-aminochloro-1H-benzimidazolecarboxylate
To a solution of methyl
2-chloronitro-1H-benzimidazolecarboxylate (0.87g) in
MeOH (100 mL), was added 1% platinum + 0.1% copper-activated
carbon (Degussa type CF105 R/W) (0.19g), and the mixture was
stirred under hydrogen atmosphere (0.2 MPa) for 4 hours. The
reaction mixture was filtered off through celite and washed with
MeOH. The mother liquid was concentrated to obtain the titled
compound (0.78g) as yellow powder.
[Step 4]
Methyl
2-chloro({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-
benzimidazolecarboxylate
The titled compound (0.69g) was obtained as colorless
powder according to the procedure as described in Step 4 of
Example 1, using methyl
6-aminochloro-1H-benzimidazolecarboxylate (0.78g)
instead of methyl 6-amino-1H-benzimidazolecarboxylate.
[Step 5]
2-Chloro({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-
benzimidazolecarboxylic acid
The titled compound (620 mg) was obtained as white powder
according to the procedure as described in Step 5 of Example
1, using methyl
2-chloro({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-
benzimidazolecarboxylate (688 mg) instead of methyl
6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimida
zolecarboxylate.
[Step 6]
2-Chloro-N-(3-chloromethylphenyl)({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
Oxalyl chloride (1.42 mL) was added dropwise to a stirring
solution of
2-chloro({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-
benzimidazolecarboxylic acid (1.27g) in THF (13 mL) under
ice-cooling. The mixture was added with DMF (five drops), and
stirred at room temperature for 2 hours. From the reaction
mixture was removed the solvent and excessive oxalyl chloride
under reduced pressure. The residue was added with toluene,
and concentrated under reduced pressure, dried, and then
dissolved in THF (10 mL). The solution was dropped slowly to
a solution of 3-chloromethylaniline (0.42 mL) and
N,N-diisopropylethylamine (2.3 mL) in THF (10 mL) under
ice-cooling for 1 hour. The reaction mixture was diluted with
ethyl acetate, washed with brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure.
The residue was purified on column chromatography to obtain the
titled compound (0.58g) as white powder.
MS(ESI+) m/z 507 (M+H) , Rt= 2.56 minutes (method A)
Example 136
N-(3-Chloromethylphenyl)[(2-methoxyethyl)amino]({[
2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-
4-carboxamide hydrochloride
2-Methoxyethylamine (2 mL) was added to
2-chloro-N-(3-chloromethylphenyl)({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide (40
mg, Example 135). The mixture was stirred at 150°C in a sealed
pressure-proof stainless steel container for 17 hours. The
reaction mixture was washed with brine and concentrated under
reduced pressure. The residue was purified on column
chromatography to obtain
N-(3-chloromethylphenyl)[(2-methoxyethyl)amino]({[
2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-
4-carboxamide (35 mg) as white powder. This was dissolved in
MeOH (1 mL), was added with 2N hydrogen chloride/EtOH solution
(1 Eq), stirred and concentrated. The residue was triturated
in diethyl ether, and the precipitate was collected by
filtration and dried to obtain the titled compound (28 mg) as
white powder.
MS(ESI+) m/z 546 (M+H) , Rt= 1.80 minutes (method A)
Example 137
N-(3-Chloromethylphenyl)[(2-hydroxyethyl)amino]({[
2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-
4-carboxamide hydrochloride
The titled compound was obtained as brown powder
according to the procedure as described in Example 136, using
2-aminoethanol instead of 2-methoxyethylamine.
MS(ESI+) m/z 532 (M+H) , Rt= 1.58 minutes (method A)
Example 138
N-(3-Chloromethylphenyl)(methylamino)({[2-(trifluo
romethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxam
ide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 136, using
40% aqueous methylamine solution instead of
2-methoxyethylamine.
MS(ESI+) m/z 502 (M+H) , Rt= 1.69 minutes (method A)
Example 139
N-(3-Chloromethylphenyl)(ethylamino)({[2-(trifluor
omethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxami
de hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 136, using
70% aqueous ethylamine solution instead of
2-methoxyethylamine.
MS(ESI+) m/z 516 (M+H) , Rt= 1.80 minutes (method A)
Example 140
N-(3-Chloromethylphenyl)[(2,2-dimethylpropyl)amino]-6
-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidaz
olecarboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 136, using
neopentylamine instead of 2-methoxyethylamine.
MS(ESI+) m/z 558 (M+H) , Rt= 2.22 minutes (method A)
Elemental Analysis for C H Cl N O •HCl+0.5H O
28 27 3 5 2 2
Calcd.(%) C:55.73 H:4.84 N:11.61
Found.(%) C:55.99 H:4.75 N:11.69
Example 141
N-(3-Chloromethylphenyl)(cyclopentylamino)({[2-(tr
ifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecar
boxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 136, using
cyclopentylamine instead of 2-methoxyethylamine.
MS(ESI+) m/z 556 (M+H) , Rt= 2.10 minutes (method A)
Example 142
N-(3-Chloromethylphenyl)(piperidinyl)({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo
xamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 136, using
piperidine instead of 2-methoxyethylamine.
MS(ESI+) m/z 556 (M+H) , Rt= 2.54 minutes (method A)
Example 143
N-(3-Chloromethylphenyl)(4-methylpiperazinyl)({
[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide dihydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 136, using
1-methylpiperazine instead of 2-methoxyethylamine.
MS(ESI+) m/z 571 (M+H) , Rt= 1.63 minutes (method A)
Example 144
2-[Bis(2-hydroxyethyl)amino]-N-(3-chloromethylphenyl)
({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazo
lecarboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 136, using
diethanolamine instead of 2-methoxyethylamine.
MS(ESI+) m/z 576 (M+H) , Rt= 1.66 minutes (method A)
Example 145
N-(3-Chloromethylphenyl)(dimethylamino)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
50% aqueous dimethylamine solution instead of
2-methoxyethylamine.
MS(ESI+) m/z 516 (M+H) , Rt= 2.13 minutes (method A)
Elemental Analysis for C H ClF N O •HCl+0.5H O
21 3 5 2 2
Calcd.(%) C:53.49 H:4.13 N:12.48
Found.(%) C:53.44 H:4.17 N:12.39
Example 146
N-(3-Chloromethylphenyl){[2-(morpholinyl)ethyl]ami
no}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzi
midazolecarboxamide hydrochloride
The titled compound was obtained as pink powder according
to the procedure as described in Example 136, using
4-(2-aminoethyl)morpholine instead of 2-methoxyethylamine.
MS(ESI+) m/z 601 (M+H) , Rt= 1.53 minutes (method A)
Example 147
N-(3-Chloromethylphenyl){[2-(dimethylamino)ethyl]amin
o}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzim
idazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
N,N-dimethylethylenediamine instead of 2-methoxyethylamine.
MS(ESI+) m/z 559 (M+H) , Rt= 1.51 minutes (method A)
Example 148
N-(3-Chloromethylphenyl)(3-hydroxyazetidinyl)({
[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 136, using
3-hydroxyazetidine hydrochloride, N,N-diisopropylethylamine
and EtOH instead of 2-methoxyethylamine.
MS(ESI+) m/z 544 (M+H) , Rt= 1.77 minutes (method A)
Example 149
N-(3-Chloromethylphenyl)[(3S)(dimethylamino)pyrrol
idinyl]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1
H-benzimidazolecarboxamide dihydrochloride
The titled compound was obtained as brown powder
according to the procedure as described in Example 136, using
(S)-(-)dimethylaminopyrrolidine,
N,N-diisopropylethylamine and EtOH instead of
2-methoxyethylamine.
MS(ESI+) m/z 585 (M+H) , Rt= 1.53 minutes (method A)
Example 150
N-(3-Chloromethylphenyl)[(3S)hydroxypyrrolidiny
l]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzim
idazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
(S)hydroxypyrrolidine, N,N-diisopropylethylamine and EtOH
instead of 2-methoxyethylamine.
MS(ESI+) m/z 558 (M+H) , Rt= 1.75 minutes (method A)
Example 151
N-(3-Chloromethylphenyl){[2-(diethylamino)ethyl]amino
}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimi
dazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
N,N-diethylethylenediamine instead of 2-methoxyethylamine.
MS(ESI+) m/z 587 (M+H) , Rt= 1.57 minutes (method A)
Example 152
N-(3-Chloromethylphenyl){[2-(pyrrolidinyl)ethyl]am
ino}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benz
imidazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
1-(2-aminoethyl)pyrrolidine instead of 2-methoxyethylamine.
MS(ESI+) m/z 585 (M+H) , Rt= 1.59 minutes (method A)
Example 153
N-(3-Chloromethylphenyl){[3-(dimethylamino)propyl]ami
no}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzi
midazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
N,N-dimethyl-1,3-propanediamine instead of
2-methoxyethylamine.
MS(ESI+) m/z 573 (M+H) , Rt= 1.43 minutes (method A)
Example 154
N-(3-Chloromethylphenyl){[3-(dimethylamino)-2,2-dimet
hylpropyl]amino}({[2-(trifluoromethyl)phenyl]carbonyl}am
ino)-1H-benzimidazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
N,N,2,2-tetramethyl-1,3-propanediamine instead of
2-methoxyethylamine.
MS(ESI+) m/z 601 (M+H) , Rt= 1.56 minutes (method A)
Example 155
N-(3-Chloromethylphenyl){[2-(dipropanylamino)ethyl
]amino}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-b
enzimidazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
N,N-diisopropylethylenediamine instead of
2-methoxyethylamine.
MS(ESI+) m/z 615 (M+H) , Rt= 1.69 minutes (method A)
Example 156
N-(3-Chloromethylphenyl)(morpholinyl)({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo
xamide
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136 using
morpholine instead of 2-methoxyethylamine.
MS(ESI+) m/z 558 (M+H) , Rt= 2.25 minutes (method A)
Example 157
2-Amino-N-(3-chloromethylphenyl)({[2-(trifluoromethyl
)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
hydrochloride
According to the procedure as described in Example 136,
N-(3-chloromethylphenyl)[(4-methoxybenzyl)amino]({
[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide (97 mg) was obtained as yellow powder, using
4-methoxybenzylamine instead of 2-methoxyethylamine. This
was dissolved in TFA (2 mL), and the solution was stirred at
70°C for 2 hours, and removed TFA under reduced pressure. The
residue was added with saturated aqueous sodium bicarbonate,
and extracted with ethyl acetate. The ethyl acetate layer was
washed with brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was purified
on column chromatography to obtain
2-amino-N-(3-chloromethylphenyl)({[2-(trifluoromethyl
)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide (35
mg). This was suspended in MeOH (3 mL), added with 2N hydrogen
chloride/MeOH solution (0.3 mL), and removed MeOH under reduced
pressure. The residue was triturated in 2-propanol/diethyl
ether, and the precipitate was collected by filtration and dried
to obtain the titled compound (21 mg) as yellow powder.
MS(ESI+) m/z 488 (M+H) , Rt= 1.62 minutes (method A)
Example 158
N-(3-Chloromethylphenyl)[(3-hydroxy-2,2-dimethylpropy
l)amino]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-
benzimidazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
3-amino-2,2-dimethylpropanol instead of
2-methoxyethylamine.
MS(ESI+) m/z 574 (M+H) , Rt= 1.81 minutes (method A)
Example 159
N-(3-Chloromethylphenyl){[(3-methyloxetanyl)methyl
]amino}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-b
enzimidazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
1-(3-methyloxetanyl)methanamine (prepared as described in
US2009/76062) instead of 2-methoxyethylamine.
MS(ESI+) m/z 572 (M+H) , Rt= 1.66 minutes (method A)
Example 160
tert-Butyl
N-{4-[(3-chloromethylphenyl)carbamoyl]({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazolyl}glycinat
e hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
glycine tert-butyl ester instead of 2-methoxyethylamine.
MS(ESI+) m/z 602 (M+H) , Rt= 2.42 minutes (method A)
Example 161
N-{4-[(3-Chloromethylphenyl)carbamoyl]({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazolyl} glycine
hydrochloride
TFA (1 mL) was added to a solution of tert-butyl
N-{4-[(3-chloromethylphenyl)carbamoyl]({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazolyl}glycinat
e (95 mg) in methylene chloride (2 mL), and the mixture was
stirred for 1 hour at room temperature, and concentrated. The
residue was neutralized with 1N aqueous NaOH under ice-cooling
and extracted with EtOAc. The ethyl acetate layer was dried
over anhydrous magnesium sulfate and concentrated. The
residue was purified on column chromatography to obtain
N-{4-[(3-chloromethylphenyl)carbamoyl]({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazolyl}glycine
(50 mg) as white powder.
N-{4-[(3-chloromethylphenyl)carbamoyl]({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazolyl}glycine
(16 mg) was suspended in MeOH. The suspension was added with
2N hydrogen chloride/EtOH solution (1 Eq) to obtain a
homogeneous solution. The reaction mixture was removed the
solvent under reduced pressure. The residue was triturated in
diethyl ether, and the precipitate was collected by filtration
and dried to obtain the titled compound (12 mg) as white powder.
MS(ESI+) m/z 546 (M+H) , Rt= 1.74 minutes (method A)
Example 162
N-(3-Chloromethylphenyl)[(3-hydroxy-2,2-dimethylpropy
l)amino]methyl({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxamide hydrochloride
Sodium hydroxide powder (6.2 mg) was added to a solution
N-(3-chloromethylphenyl)[(3-hydroxy-2,2-dimethylpropy
l)amino]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-
benzimidazolecarboxamide (80 mg) in DMF (2 mL), and the
solution was stirred at room temperature for 30 minutes, added
with methyl iodide (8.7 μL), and stirred for 17 hours. The
reaction mixture was diluted with ethyl acetate, washed with
brine, and concentrated under reduced pressure. The residue
was purified on column chromatography to obtain
N-(3-chloromethylphenyl)[(3-hydroxy-2,2-dimethylpropy
l)amino]methyl({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxamide (20 mg) as white powder.
This was suspended in MeOH, and added with 2N hydrogen
chloride/EtOH (1 Eq) and stirred to obtain the solution and
removed the solvent under reduced pressure. The residue was
washed with diethyl ether, and the precipitate was collected
by filtration and dried to obtain the titled compound (15 mg)
as white powder.
MS(ESI+) m/z 588 (M+H) , Rt= 2.06 minutes (method A)
Example 163
N-(3-Chloromethylphenyl)[(3-methoxy-2,2-dimethylpropy
l)amino]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-
benzimidazolecarboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 136, using
3-methoxy-2,2-dimethyl propylamine (prepared as described in
WO2007/28051) instead of 2-methoxyethylamine.
MS(ESI+) m/z 588 (M+H) , Rt= 2.11 minutes (method A)
Elemental Analysis for C H ClF N O •HCl+0.5H O
29 29 3 5 3 2
Calcd.(%) C:54.98 H:4.93 N:11.06
Found.(%) C:54.94 H:4.63 N:11.09
Example 164
N-(3-Chloromethylphenyl)(pyrrolidinyl)({[2-(tri
fluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarb
oxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
pyrrolidine instead of 2-methoxyethylamine.
MS(ESI+) m/z 542 (M+H) , Rt= 2.15 minutes (method A)
Elemental Analysis for C H ClF N O •HCl+1.0H O
27 23 3 5 2 2
Calcd.(%) C:54.37 H:4.39 N:11.74
Found.(%) C:54.34 H:4.66 N:12.26
Example 165
2-(Azetidinyl)-N-(3-chloromethylphenyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide hydrochloride
A solution of
2-chloro-N-(3-chloromethylphenyl)({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide (80
mg, Example 135), azetidine hydrochloride (60 mg) and
N,N-diisopropylethylamine (208μL) in EtOH (1.8 mL) was reacted
at 120°C for 20 minutes in a microwaves reactor (Biotage,
Initiator). The reaction mixture was concentrated under
reduced pressure, and the residue was purified on column
chromatography to obtain
2-(azetidinyl)-N-(3-chloromethylphenyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide (27 mg). This was dissolved in MeOH (1 mL), and added
with 2N hydrogen chloride/MeOH solution (1 Eq), and stirred and
concentrated. The residue was triturated in diethyl ether, and
the precipitate was collected by filtration and dried to obtain
the titled compound (21 mg) as white powder.
MS(ESI+) m/z 528 (M+H) , Rt= 2.09 minutes (method A)
Example 166
N-(3-Chloromethylphenyl)(3-methoxyazetidinyl)({
[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 136, using
3-methoxy azetidine hydrochloride, N,N-diisopropylethylamine
and EtOH instead of 2-methoxyethylamine.
MS(ESI+) m/z 558 (M+H) , Rt= 2.20 minutes (method A)
Example 167
N-(3-Chloromethylphenyl)[(2-hydroxymethylpropyl)am
ino]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benz
imidazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
1-aminomethylpropanol (prepared as described in
WO2009/57827) and THF instead of 2-methoxyethylamine.
MS(ESI+) m/z 560 (M+H) , Rt= 1.87 minutes (method A)
Example 168
N-(3-Chloromethylphenyl){[(2S)-tetrahydrofuranylme
thyl]amino}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-
1H-benzimidazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
(S)-(+)-tetrahydrofurfurylamine and THF instead of
2-methoxyethylamine.
MS(ESI+) m/z 572 (M+H) , Rt= 2.04 minutes (method A)
Example 169
N-(3-Chloromethylphenyl){[(2R)-tetrahydrofuranylme
thyl]amino}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-
1H-benzimidazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
(R)-(-)-tetrahydrofurfurylamine and THF instead of
2-methoxyethylamine.
MS(ESI+) m/z 572 (M+H) , Rt= 2.04 minutes (method A)
Elemental Analysis for C H Cl N O •HCl+0.7H O.
28 25 3 5 3 2
Calcd.(%) C:54.15 H:4.45 N:11.28
Found.(%) C:54.16 H:4.57 N:11.19
Example 170
N-(3-Chloromethylphenyl){[(2S)hydroxymethylbuta
nyl]amino}({[2-(trifluoromethyl)phenyl]carbonyl}amino
)-1H-benzimidazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
(S)-(+)aminomethylbutanol and THF instead of
2-methoxyethylamine.
MS(ESI+) m/z 574 (M+H) , Rt= 1.98 minutes (method A)
Example 171
N-(3-Chloromethylphenyl){[(2R)hydroxymethylbuta
nyl]amino}({[2-(trifluoromethyl)phenyl]carbonyl}amino
)-1H-benzimidazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
(R)-(-)aminomethylbutanol and THF instead of
2-methoxyethylamine.
MS(ESI+) m/z 574 (M+H) , Rt= 1.98 minutes (method A)
Example 172
N-(3-Chloromethylphenyl){[(2S)hydroxy-3,3-dimethyl
butanyl]amino}({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
(S)-tert-leucinol and THF instead of 2-methoxyethylamine.
MS(ESI+) m/z 588 (M+H) , Rt= 2.20 minutes (method A)
Example 173
N-(3-Chloromethylphenyl)[(3-methoxy-2,2-dimethylpropy
l)(methyl)amino]({[2-(trifluoromethyl)phenyl]carbonyl}am
ino)-1H-benzimidazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
3-methoxy-N,2,2-trimethylpropanamine (Reference Example
9) and THF instead of 2-methoxyethylamine.
MS(ESI+) m/z 602 (M+H) , Rt= 2.71 minutes (method A)
Example 174
N-(3-Chloromethylphenyl)[(3-methoxypropyl)amino]({
[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
3-methoxypropylamine and THF instead of 2-methoxyethylamine.
MS(ESI+) m/z 560 (M+H) , Rt= 2.10 minutes (method A)
Example 175
N-(3-Chloromethylphenyl){[2-(propanyloxy)ethyl]ami
no}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzi
midazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
2-aminoethyl isopropyl ether and THF instead of
2-methoxyethylamine.
MS(ESI+) m/z 574 (M+H) , Rt= 2.29 minutes (method A)
Example 176
2-[(2-tert-Butoxyethyl)amino]-N-(3-chloromethylphenyl)-6
-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidaz
olecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
O-tert-butylaminoethanol and THF instead of
2-methoxyethylamine.
MS(ESI+) m/z 588 (M+H) , Rt= 2.42 minutes (method A)
Example 177
N-(3-Chloromethylphenyl)[(2-methoxymethylpropyl)am
ino]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benz
imidazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
2-methoxymethylpropylamine and THF instead of
2-methoxyethylamine.
MS(ESI+) m/z 574 (M+H) , Rt= 2.30 minutes (method A)
Example 178
N-(3-Chloromethylphenyl){[2-(methylsulfanyl)ethyl]ami
no}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzi
midazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 136, using
2-(methylthio)ethylamine and THF instead of
2-methoxyethylamine.
MS(ESI+) m/z 562 (M+H) , Rt= 2.51 minutes (method A)
Example 179
N-(3-Chloromethylphenyl)(methylsulfanyl)({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo
xamide
[Step 1]
Methyl 2-(methylsulfanyl)-1H-benzimidazolecarboxylate
To a solution of methyl
2-sulfanyl-1H-benzimidazolecarboxylate (prepared as
described in WO2003/106430) (1.0g) in DMF (15 mL), were added
potassium carbonate (700 mg) and methyl iodide (0.32 mL), and
the mixture was stirred at room temperature for 3 days. The
reaction mixture was diluted with ethyl acetate, washed with
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified on column
chromatography to obtain the titled compound (860 mg) as white
powder.
[Step 2]
Methyl
2-(methylsulfanyl)nitro-1H-benzimidazolecarboxylate
The titled compound (840 mg) was obtained as pale yellow
powder according to the procedure as described in Step 2 of
Example 1, using methyl
2-(methylsulfanyl)-1H-benzimidazolecarboxylate (860 mg)
instead of methyl-1H-benzimidazolecarboxylate.
[Step 3]
Methyl
6-amino(methylsulfanyl)-1H-benzimidazolecarboxylate
The titled compound (380 mg) was obtained as pale yellow
powder according to the procedure as described in Step 3 of
Example 1, using methyl
2-(methylsulfanyl)nitro-1H-benzimidazolecarboxylate
(840 mg) instead of methyl
6-nitro-1H-benzimidazolecarboxylate.
[Step 4]
Methyl
2-(methylsulfanyl)({[2-(trifluoromethyl)phenyl]carbonyl}
amino)-1H-benzimidazolecarboxylate
The titled compound (250 mg) was obtained as white powder
according to the procedure as described in Step 4 of Example
1, using methyl
6-amino(methylsulfanyl)-1H-benzimidazolecarboxylate
(150 mg) instead of methyl
6-amino-1H-benzimidazolecarboxylate.
[Step 5]
2-(Methylsulfanyl)({[2-(trifluoromethyl)phenyl]carbonyl}
amino)-1H-benzimidazolecarboxylic acid
The titled compound (240 mg) was obtained as pale yellow
powder according to the procedure as described in Step 5 of
Example 1,, using methyl
2-(methylsulfanyl)({[2-(trifluoromethyl)phenyl]carbonyl}
amino)-1H-benzimidazolecarboxylate (250 mg) instead of
methyl
6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimida
zolecarboxylate.
[Step 6]
N-(3-Chloromethylphenyl)(methylsulfanyl)({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo
xamide
The titled compound (35 mg) was obtained as white powder
according to the procedure as described in Step 6 of Example
135, using
2-(methylsulfanyl)({[2-(trifluoromethyl)phenyl]carbonyl}
amino)-1H-benzimidazolecarboxylic acid (45 mg) instead of
2-chloro({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-
benzimidazolecarboxylic acid.
MS(ESI+) m/z 519 (M+H) , Rt= 2.79 minutes (method A)
Example 180
N-(3-Chloromethylphenyl)(methylsulfonyl)({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo
xamide
To a solution of
N-(3-chloromethylphenyl)(methylsulfanyl)({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo
xamide (33 mg) in MeOH (5 mL), was added an aqueous solution
(0.5 mL) of Oxone monpoersulfate compound (75 mg), and the
mixture was stirred at room temperature for 17 hours.
Additionally the mixture was added with an aqueous solution (0.5
mL) of Oxone monopersulfate compound (50 mg), and stirred for
3 hours. The reaction mixture was diluted with ethyl acetate
and washed with saturated aqueous sodium bicarbonate. The
organic layer was separated, and concentrated under reduced
pressure. The residue was purified on column chromatography
to obtain titled compound (11 mg) as white powder.
MS(ESI+) m/z 551 (M+H) , Rt= 2.54 minutes (method A)
Example 181
N-(3-Chloromethylphenyl)(methylsulfinyl)({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo
xamide
To a solution of
N-(3-chloromethylphenyl)(methylsulfanyl)({[2-(trif
luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo
xamide (26 mg) in THF (3 mL), was added an aqueous solution of
m-chloroperbenzoic acid (75%, 12 mg) (1 mL), and the mixture
was stirred at room temperature for 3 hours. The reaction
mixture was diluted with ethyl acetate, washed sequentially
with saturated aqueous sodium bicarbonate and brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified on column chromatography
to yield the titled compound (10 mg) as pale yellow powder.
MS(ESI+) m/z 535 (M+H) , Rt= 2.42 minutes (method A)
Example 182
6-{[(2-Chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)(dimethylamino)-1H-benzimidazolecarboxam
ide hydrochloride
[Step 1]
Methyl 2-(dimethylamino)-1H-benzimidazolecarboxylate
(Dichloromethylene)dimethyliminium chloride (4.93g)
was added to a solution of methyl 2,3-diaminobenzoate(4.2g) in
methylene chloride (75 mL), and the solution was stirred on oil
bath at 50°C for 1 hour. The reaction mixture was added with
saturated aqueous sodium bicarbonate was added, and extracted
with ethyl acetate. The organic layer was separated, washed
with brine and concentrated under reduced pressure. The
residue was purified on column chromatography to obtain the
titled compound (4.7g) as a pale yellow solid.
[Step 2]
Methyl
2-(dimethylamino)nitro-1H-benzimidazolecarboxylate
The titled compound (1.8g) was obtained as orange powder
according to the procedure as described in Step 2 of Example
1, using methyl
2-(dimethylamino)-1H-benzimidazolecarboxylate (4.57g)
instead of methyl 1H-benzimidazolecarboxylate.
[Step 3]
2-(Dimethylamino)nitro-1H-benzimidazolecarboxylic
acid
A solution of methyl
2-(dimethylamino)nitro-1H-benzimidazolecarboxylate
(1.5g) and lithium hydroxide hydrate (2.4g) in THF-H O (1:1,
100 mL) was stirred at 50°C for 2 hours. THF was removed under
reduced pressure, and 1N hydrochloric acid was added to the
residue with stirring under ice-cooling to adjust the pH to 5.
The precipitate was collected by filtration and dried under
reduced pressure to obtain the titled compound (1.38g) as yellow
solid.
[Step 4]
N-(3-Chloromethylphenyl)(dimethylamino)nitro-1H-be
nzimidazolecarboxamide
To a solution of
2-(dimethylamino)nitro-1H-benzimidazolecarboxylic
acid (520 mg) and HBTU (1.03g) in DMF (6 mL), were added
N,N-diisopropylethylamine (942 μL) and
3-chloromethylaniline (323 μL), and the mixture was stirred
at room temperature for 15 hours. The reaction mixture was
diluted with the ethyl acetate-THF (1:1), washed with brine,
and the organic layer was dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was
washed with MeOH to obtain the titled compound (650 mg) as a
yellow solid.
[Step 5]
6-Amino-N-(3-chloromethylphenyl)(dimethylamino)-1H-be
nzimidazolecarboxamide
To a suspension of
N-(3-chloromethylphenyl)(dimethylamino)nitro-1H-be
nzimidazolecarboxamide (580 mg) in MeOH-THF (1:1, 60 mL),
was added 2N hydrogen chloride/EtOH (1 mL). The mixture was
added with 1% platinum + 0.1% copper-activated carbon (Degussa
type CF105 R/W) (150 mg) and stirred vigorously under hydrogen
atmosphere (0.2MPa) for 3 hours. The reaction mixture was
filtered off through celite, and the mother mixture was
concentrated. The residue was added with saturated aqueous
sodium bicarbonate, and extracted with ethyl acetate. The
ethyl acetate layer was washed with brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure.
The residue was purified on column chromatography to obtain the
titled compound (265 mg) as brown powder.
[Step 6]
6-{[(2-Chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)(dimethylamino)-1H-benzimidazolecarboxam
ide hydrochloride
To a solution of
6-amino-N-(3-chloromethylphenyl)(dimethylamino)-1H-be
nzimidazolecarboxamide (30 mg) in THF (1 mL), was added
N,N-diisopropylethylamine (22 μL). The mixture was stirred
under ice-cooling, and added slowly with
2-chlorofluorobenzoyl chloride (13 μL), and stirred for 2
hours. The reaction mixture was diluted with ethyl acetate,
washed sequentially with saturated aqueous sodium bicarbonate
and brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified
on column chromatography to obtain
6-{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)(dimethylamino)-1H-benzimidazolecarboxam
ide (30 mg) as pale yellow powder. This was suspended in MeOH
(1 mL), and was added with 1N hydrogen chloride/MeOH (1 Eq)
to obtain a homogeneous solution, and removed MeOH under reduced
pressure. The residue was triturated in n-hexane/ethyl
acetate (1:1), and the precipitate was collected by filtration
and dried under reduced pressure to obtain the titled compound
(23 mg) as pale yellow powder.
MS(ESI+) m/z 500 (M+H) , Rt= 2.13 minutes (method A)
Example 183
N-(3-Chloromethylphenyl){[(2,6-dichlorophenyl)carbony
l]amino}(dimethylamino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Step 6 of Example
182, using 2,6-dichlorobenzoyl chloride instead of
2-chlorofluorobenzoyl chloride.
MS(ESI+) m/z 516 (M+H) , Rt= 2.19 minutes (method A)
Example 184
N-(3-Chloromethylphenyl){[(2,4-dichlorophenyl)carbony
l]amino}(dimethylamino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Step 6 of Example
182, using 2,4-dichlorobenzoyl chloride instead of
2-chlorofluorobenzoyl chloride.
MS(ESI+) m/z 516 (M+H) , Rt= 2.31 minutes (method A)
Example 185
N-(3-Chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}(dimethylamino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Step 6 of Example
182, using 2,5-dichlorobenzoyl chloride instead of
2-chlorofluorobenzoyl chloride.
MS(ESI+) m/z 516 (M+H) , Rt= 2.31 minutes (method A)
Elemental Analysis for C H Cl N O •HCl+0.5H O
24 20 3 5 2 2
Calcd.(%) C:51.27 H:3.94 N:12.46
Found.(%) C:51.10 H:4.02 N:12.45
Example 186
6-{[(2-Bromofluorophenyl)carbonyl]amino}-N-(3-chlorom
ethylphenyl)(dimethylamino)-1H-benzimidazolecarboxami
de hydrochloride
The titled compound was obtained as gray powder according
to the procedure as described in Step 6 of Example 182, using
2-bromofluorobenzoyl chloride (prepared as described in
WO2007/144327) instead of 2-chlorofluorobenzoyl chloride.
MS(ESI+) m/z 544 (M+H) , Rt= 2.23 minutes (method A)
Example 187
6-{[(2-Bromochlorophenyl)carbonyl]amino}-N-(3-chlorom
ethylphenyl)(dimethylamino)-1H-benzimidazolecarboxami
de hydrochloride
The titled compound was obtained as light brown powder
according to the procedure as described in Step 6 of Example
182, using 2-bromochlorobenzoyl chloride instead of
2-chlorofluorobenzoyl chloride.
MS(ESI+) m/z 560 (M+H) , Rt= 2.29 minutes (method A)
Example 188
6-({[2-Chloro(cyclopropylethynyl)phenyl]carbonyl}amino)-
N-(3-chloromethylphenyl)(dimethylamino)-1H-benzimidaz
olecarboxamide hydrochloride
To a solution of 2-chloro(cyclopropylethynyl)benzoic
acid (33 mg, Reference Example 3),
6-amino-N-(3-chloromethylphenyl)(dimethylamino)-1H-be
nzimidazolecarboxamide (50 mg) and HATU (72 mg) in DMF (1
mL), was added N,N-diisopropylethylamine (66 μL), and the
mixture was stirred at room temperature for 17 hours. The
reaction mixture was diluted with ethyl acetate, and washed
sequentially with saturated aqueous sodium bicarbonate and
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified on column
chromatography to obtain
6-({[2-chloro(cyclopropylethynyl)phenyl]carbonyl}amino)-
N-(3-chloromethylphenyl)(dimethylamino)-1H-benzimidaz
olecarboxamide (74 mg). This was suspended in MeOH (1 mL),
and was added with 2N hydrogen chloride/EtOH solution (1 Eq)
to obtain a homogeneous solution, and removed the solvent under
reduced pressure. The residue was triturated in ethyl acetate,
and the precipitated was collected by filtration and dried under
reduced pressure to obtain the titled compound (58 mg) as pale
yellow powder.
MS(ESI+) m/z 546 (M+H) , Rt= 2.60 minutes (method A)
Example 189
N-(3-Chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}[(3-hydroxy-2,2-dimethylpropyl)amino]-1H-benzimi
dazolecarboxamide hydrochloride
[Step 1]
Methyl
2-chloro{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimi
dazolecarboxylate
The titled compound (1.68g) was obtained as colorless
amorphous according to the procedure as described in Step 4 of
Example 1, using methyl
6-aminochloro-1H-benzimidazolecarboxylate instead of
methyl 6-amino-1H-benzimidazolecarboxylate, and
2,5-dichlorobenzoyl chloride instead of
2-(trifluoromethyl)benzoyl chloride.
[Step 2]
2-Chloro{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimi
dazolecarboxylic acid
The titled compound (1.41g) was obtained as white powder
according to the procedure as described in Step 5 of Example
1, using methyl
2-chloro{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimi
dazolecarboxylate (1.68g) instead of methyl
6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimida
zolecarboxylate.
[Step 3]
2-Chloro-N-(3-chloromethylphenyl){[(2,5-dichloropheny
l)carbonyl]amino}-1H-benzimidazolecarboxamide
The titled compound was obtained as a white solid
according to the procedure as described in Step 6 of Example
135, using
2-chloro{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimi
dazolecarboxylic acid instead of
2-chloro({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-
benzimidazolecarboxylic acid.
[Step 4]
N-(3-Chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}[(3-hydroxy-2,2-dimethylpropyl)amino]-1H-benzimi
dazolecarboxamide hydrochloride
THF (1 mL) was added to
2-chloro-N-(3-chloromethylphenyl){[(2,5-dichloropheny
l)carbonyl]amino}-1H-benzimidazolecarboxamide (50 mg) and
3-amino-2,2-dimethylpropanol (400 mg). The mixture was
stirred at 150°C in a sealed pressure-proof stainless steel
container for 8 hours. The reaction mixture was diluted with
ethyl acetate, washed with brine and concentrated under reduced
pressure. The residue was purified on column chromatography
to obtain
N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}[(3-hydroxy-2,2-dimethylpropyl)amino]-1H-benzimi
dazolecarboxamide (50 mg) as pale yellow powder. This was
dissolved in MeOH (1 mL), and added with 2N Hydrogen
chloride/EtOH solution (1 Eq), and stirred and concentrated.
The residue was triturated in diethyl ether, and the precipitate
was collected by filtration and dried to obtain the titled
compound (40 mg) as white powder.
MS(ESI+) m/z 574 (M+H) , Rt= 2.06 minutes (method A)
Example 190
N-(3-Chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}[(3-methoxy-2,2-dimethylpropyl)amino]-1H-benzimi
dazolecarboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 189, using
3-methoxy-2,2-dimethylpropylamine instead of
3-amino-2,2-dimethylpropanol.
MS(ESI+) m/z 588 (M+H) , Rt= 2.41 minutes (method A)
Example 191
N-(3-Chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}[(2-hydroxymethylpropyl)amino]-1H-benzimidazo
lecarboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 189, using
2-hydroxymethylpropylamine instead of
3-amino-2,2-dimethylpropanol.
MS(ESI+) m/z 560 (M+H) , Rt= 2.12 minutes (method A)
Example 192
N-(3-Chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}[(2-methoxymethylpropyl)amino]-1H-benzimidazo
lecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 189, using
2-methoxymethylpropylamine instead of
3-amino-2,2-dimethylpropanol.
MS(ESI+) m/z 574 (M+H) , Rt= 2.48 minutes (method A)
Example 193
N-(3-Chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}{[2-(propanyloxy)ethyl]amino}-1H-benzimidazol
ecarboxamide hydrochloride
The titled compound was obtained as milky white powder
according to the procedure as described in Example 189, using
2-aminoethyl isopropyl ether instead of
3-amino-2,2-dimethylpropanol.
MS(ESI+) m/z 574 (M+H) , Rt= 2.60 minutes (method A)
Elemental Analysis for C H Cl N O •HCl+0.1H O
27 26 3 5 3 2
Calcd.(%) C:52.89 H:4.47 N:11.42
Found.(%) C:52.55 H:4.10 N:11.36
Example 194
6-{[(2-Chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl){[2-(propanyloxy)ethyl]amino}-1H-benzimi
dazolecarboxamide hydrochloride
[Step 1]
2-Chloro{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-
chloromethylphenyl)-1H-benzimidazolecarboxamide
The titled compound was obtained as a white solid
according to the procedures as described in Steps 1 to 3 of
Example 189, using 2-chlorofluorobenzoyl chloride instead
of 2,5-dichlorobenzoyl chloride in Step 1.
[Step 2]
6-{[(2-Chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl){[2-(propanyloxy)-ethyl]amino}-1H-benzim
idazolecarboxamide hydrochloride
THF (1 mL) was added to
2-chloro{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-
chloromethylphenyl)-1H-benzimidazolecarboxamide (50
mg) and 2-aminoethyl isopropyl ether (32 mg). The mixture was
stirred at 150°C in a sealed pressure-proof stainless steel
container for 17 hours. The reaction mixture was diluted with
ethyl acetate and washed with brine and concentrated under
reduced pressure. The residue was purified on column
chromatography to obtain
6-[{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro-2
-methylphenyl){[2-(propanyloxy)ethyl]amino}-1H-benzim
idazolecarboxamide (41 mg) as pale yellow powder. This was
dissolved in MeOH (1 mL), and added with 2N hydrogen
chloride/EtOH solution (1 Eq), and stirred and concentrated.
The residue was triturated in diethyl ether, and the precipitate
was collected by filtration and dried to obtain the titled
compound (35 mg) as white powder.
MS(ESI+) m/z 558 (M+H) , Rt= 2.41 minutes (method A)
Example 195
2-[(2-tert-Butoxyethyl)amino]{[(2-chlorofluorophenyl)
carbonyl]amino}-N-(3-chloromethylphenyl)-1H-benzimidazol
ecarboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Step 2 of Example
194, using O-tert-butyl 2-aminoethanol instead of 2-aminoethyl
isopropyl ether.
MS(ESI+) m/z 572 (M+H) , Rt= 2.49 minutes (method A)
Example 196
6-[{[(2-Chlorofluorophenyl)carbonyl]amino}-N-(3-chloro-2
-methylphenyl)[(3-methoxy-2,2-dimethylpropyl)amino]-1H-b
enzimidazolecarboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Step 2 of Example
194, using 3-methoxy-2,2-dimethylpropylamine instead of
2-aminoethyl isopropyl ether.
MS(ESI+) m/z 572 (M+H) , Rt= 2.51 minutes (method A)
Example 197
6-[{[(2-Chlorofluorophenyl)carbonyl]amino}-N-(3-chloro-2
-methylphenyl)[(2-methoxymethylpropyl)amino]-1H-benzi
midazolecarboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Step 2 of Example
194, using 2-methoxymethylpropylamine instead of
2-aminoethyl isopropyl ether.
MS(ESI+) m/z 558 (M+H) , Rt= 2.34 minutes (method A)
Example 198
6-{[(2-Chlorofluorophenyl)-carbonyl]amino}-N-(3-chloro-2
-methylphenyl){[(2S)-tetrahydrofuranylmethyl]amino}-1
H-benzimidazolecarboxamide hydrochloride
The titled compound was obtained as pale pink powder
according to the procedure as described in Step 2 of Example
194, using (S)-(+)-tetrahydrofurfurylamine instead of
2-aminoethyl isopropyl ether.
MS(ESI+) m/z 556 (M+H) , Rt= 2.28 minutes (method A)
Example 199
6-{[(2-Chlorofluorophenyl)-carbonyl]amino}-N-(3-chloro-2
-methylphenyl){[(2R)-tetrahydrofuranylmethyl]amino}-1
H-benzimidazolecarboxamide hydrochloride
The titled compound was obtained as pale pink powder
according to the procedure as described in Step 2 of Example
194, using (R)-(-)-tetrahydrofurfurylamine instead of
2-aminoethyl isopropyl ether.
MS(ESI+) m/z 556 (M+H) , Rt= 2.28 minutes (method A)
Example 200
6-[{[(2-Chlorofluorophenyl)carbonyl]amino}-N-(3-chloro-2
-methylphenyl)[(3-hydroxy-2,2-dimethylpropyl)amino]-1H-b
enzimidazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Step 2 of Example
194, using 3-amino-2,2-dimethylpropanol instead of
2-aminoethyl isopropyl ether.
MS(ESI+) m/z 558 (M+H) , Rt= 2.22 minutes (method A)
Example 201
6-{[(2-Chlorofluorophenyl)-carbonyl]amino}-N-(3-chloro-2
-methylphenyl){[(2S)hydroxymethylbutanyl]amino}
-1H-benzimidazolecarboxamide hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Step 2 of Example
194, using (S)-(+)aminomethylbutanol instead of
2-aminoethyl isopropyl ether.
MS(ESI+) m/z 558 (M+H) , Rt= 2.31 minutes (method A)
Example 202
N-(3-Chloromethylphenyl)(dimethylamino)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide hydrochloride
[Step 1]
2-(dimethylamino)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylic acid
To a stirring solution of methyl
6-aminochloro-1H-benzimidazolecarboxylate (400 mg,
Example 135, Step 3) and triethylamine (209 μL) in THF (18 mL),
2-(trifluoromethyl)benzoyl chloride (316 μL) was dropped
slowly under ice-cooling. After 1 hour, the reaction mixture
was diluted with ethyl acetate, washed sequentially with water
and brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure to obtain crude methyl
2-chloro({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-
benzimidazolecarboxylate. This was dissolved in THF (15
mL) and MeOH (7 mL), and added with 1N aqueous lithium hydroxide
solution (9 mL), and stirred at room temperature overnight. The
reaction mixture was removing THF and MeOH under reduced
pressure. The residue was added with water, and neutralized with
1N hydrochloric acid under ice-cooling. The precipitation was
collected by filtration to obtain crude
2-chloro({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-
benzimidazolecarboxylic acid. This was dissolved in THF
(10 mL), and added with 40% aqueous dimethylamine solution (7
mL), and stirred at 120°C for 14 hours. The reaction mixture
was cooled to room temperature, removed THF under reduced
pressure. The residue was added with water, and adjusted to
PH 3-4 with 1N hydrochloric acid under ice-cooling. The
precipitate was collected by filtration, washed with diethyl
ether, and dried under reduced pressure to obtain the titled
compound (589 mg) as slightly yellow solid.
[Step 2]
N-(3-Chloromethylphenyl)(dimethylamino)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide hydrochloride
To a solution of
2-(dimethylamino)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylic acid (50 mg) and HATU (82
mg) in DMF (1 mL), were added N,N-diisopropylethylamine (88 μL)
and 3-chloromethylaniline (26 μL), and the mixture was
stirred at room temperature for 1 hour. The reaction mixture
was diluted with ethyl acetate, washed sequentially with
saturated aqueous sodium bicarbonate and brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified on column chromatography
to obtain
N-(3-chloromethylphenyl)(dimethylamino)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide (65 mg) as white powder. This was suspended in MeOH (1.5
mL), and added with 2N hydrogen chloride/MeOH (1 Eq), stirred
and concentrated. The residue was triturated in diethyl ether,
and the precipitate was collected by filtration and dried to
obtain the titled compound (40 mg) as white powder.
MS(ESI+) m/z 516 (M+H) , Rt= 2.20 minutes (method A)
Example 203
N-(4-tert-Buthylphenyl)(dimethylamino)({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamid
e hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Step 2 of Example
202, using 4-tert-butylaniline instead of
3-chloromethylaniline.
MS(ESI+) m/z 524 (M+H) , Rt= 2.30 minutes (method A)
Example 204
N-(2,3-Dihydro-1H-indenyl)(dimethylamino)({[2-(tri
fluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarb
oxamide hydrochloride
The titled compound was obtained as gray powder according
to the procedure as described in Step 2 of Example 202, using
-aminoindan instead of 3-chloromethylaniline.
MS(ESI+) m/z 508 (M+H) , Rt= 2.11 minutes (method A)
Example 205
6-{[(2-Chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)(dimethylamino)-1H-benzimidazolecarboxam
ide hydrochloride
[Step 1]
6-Amino-N-(3-chloromethylphenyl)(dimethylamino)-1H-be
nzimidazolecarboxamide
N-(3-chloromethylphenyl)(dimethylamino)nitro
-1H-benzimidazolecarboxamide (520 mg) was obtained as
yellow powder according to the procedure as described in Step
4 of Example 182, using 3-chloromethylaniline instead of
3-chloromethylaniline. This was then reacted according to
the procedure as described in Step 5 of Example 182, to obtain
the titled compound (358 mg) as yellow powder.
[Step 2]
6-{[(2-Chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)(dimethylamino)-1H-benzimidazolecarboxam
ide hydrochloride
To a solution of
6-amino-N-(3-chloromethylphenyl)(dimethylamino)-1H-be
nzimidazolecarboxamide (50 mg) in THF (1.5 mL), was added
N,N-diisopropylethylamine (37 μL) and the mixture was stirred
under ice-cooling. The mixture was added slowly with
2-chlorofluorobenzoyl chloride (24 μL), and stirred for 2
hours. The reaction mixture was diluted with ethyl acetate,
washed sequentially with saturated aqueous sodium bicarbonate
and brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was purified
on column chromatography to obtain
6-{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)(dimethylamino)-1H-benzimidazolecarboxam
ide (30 mg) as pale yellow powder. This was then suspended in
MeOH (1 mL), and added with 2N hydrogen chloride/MeOH (1 Eq)
to obtain a homogeneous solution, and MeOH was removed under
reduced pressure. The residue was triturated in
n-hexane/ethyl acetate (1:1), and the precipitate was collected
by filtration and dried to obtain the titled compound (24 mg)
as pale purple powder.
MS(ESI+) m/z 500 (M+H) , Rt= 2.20 minutes (method A)
Example 206
N-(3-Chloromethylphenyl){[(2,6-dichlorophenyl)carbony
l]amino}(dimethylamino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as pale purple powder
according to the procedure as described in Step 2 of Example
205, using 2,6-dichlorobenzoyl chloride instead of
2-chlorofluorobenzoyl chloride.
MS(ESI+) m/z 516 (M+H) , Rt= 2.26 minutes (method A)
Example 207
N-(3-Chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}(dimethylamino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Step 2 of Example
205, using 2,5-dichlorobenzoyl chloride instead of
2-chlorofluorobenzoyl chloride.
MS(ESI+) m/z 516 (M+H) , Rt= 2.39 minutes (method A)
Elemental Analysis for C H Cl N O •HCl
24 20 3 5 2
Calcd.(%) C:52.10 H:3.83 N:12.66
Found.(%) C:51.96 H:3.61 N:12.76
Example 208
N-(3-Chloromethylphenyl)cyclopropyl{[(2,5-dichloro
phenyl)carbonyl]amino}-1H-benzimidazolecarboxamide
hydrochloride
[Step 1]
Methyl 6-aminocyclopropyl-1H-benzimidazolecarboxylate
The title compound was obtained as white powder according
to the procedures as described in step 1 to step 4 of Example
11, using cyclopropanecarbonyl chloride instead of
methoxyacetyl chloride in Step 1.
[Step 2]
2-Cyclopropyl{[2,5-dichlorophenyl]carbonyl]amino}-1H-ben
zimidazolecarboxylic acid
The title compound was obtained according to the
procedures as described in step 4 and step 5 of Example 1, using
methyl 6-aminocyclopropyl-1H-benzimidazolecarboxylate
instead of methyl 6-amino-1H-benzimidazolecarboxylate, and
2,5-dichlorobenzoyl chloride instead of
2-(trifluoromethyl)benzoyl chloride.
[Step 3]
N-(3-Chloromethylphenyl)cyclopropyl{[(2,5-dichloro
phenyl)carbonyl]amino}-1H-benzimidazolecarboxamide
hydrochloride
The title compound was obtained according to the
procedures as described in step 7 and step 8 of Example 11, using
2-cyclopropyl{[2,5-dichlorophenyl]carbonyl]amino}-1H-ben
zimidazolecarboxylic acid instead of
2-(methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylic acid.
MS(ESI+) m/z 513 (M+H) , Rt= 1.88 minutes (method A)
Example 209
N-(3-Chloromethylphenyl)cyclopropyl{[(2,5-dichloro
phenyl)carbonyl]amino}-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as white powder
according to the procedures as described in step 7 and step 8
of Example 11, using
2-cyclopropyl{[2,5-dichlorophenyl]carbonyl]amino}-1H-ben
zimidazolecarboxylic acid instead of
2-(methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylic acid, and
3-chloromethylaniline instead of
3-chloromethylaniline.
MS(ESI+) m/z 513 (M+H) , Rt= 1.85 minutes (method A)
Example 210
N-(3-Chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}(1-methylcyclopropyl)-1H-benzimidazolecarboxa
mide hydrochloride
[Step 1]
Methyl
6-amino(1-methylcyclopropyl)-1H-benzimidazolecarboxyl
The title compound was obtained as white powder according
to the procedures as described in step 1 to step 4 of Example
11, using 1-methyl-cyclopropanecarbonyl chloride (prepared as
described in WO2009/68512) instead of methoxyacetyl chloride
in Step 1.
[Step 2]
2-(1-Methylcyclopropyl){[2,5-dichlorophenyl]carbonyl]ami
no}-1H-benzimidazolecarboxylic acid
The title compound was obtained according to the
procedures as described in step 4 and step 5 of Example 1, using
methyl
6-amino(1-methylcyclopropyl)-1H-benzimidazolecarboxyl
ate instead of methyl 6-amino-1H-benzimidazolecarboxylate,
and 2,5-dichlorobenzoyl chloride instead of
2-(trifluoromethyl)benzoyl chloride.
[Step 3]
N-(3-Chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}(1-methylcyclopropyl)-1H-benzimidazolecarboxa
mide hydrochloride
The title compound was obtained according to the
procedures as described in step 7 and step 8 of Example 11, using
2-(1-methylcyclopropyl){[2,5-dichlorophenyl]carbonyl]ami
no}-1H-benzimidazolecarboxylic acid instead of
2-(methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylic acid.
MS(ESI+) m/z 527 (M+H) , Rt= 2.12 minutes (method A)
Example 211
N-(3-Chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}(1-methylcyclopropyl)-1H-benzimidazolecarboxa
mide hydrochloride
The titled compound was obtained as white powder
according to the procedures as described in step 7 and step 8
of Example 11, using
2-(1-methylcyclopropyl){[2,5-dichlorophenyl]carbonyl]ami
no}-1H-benzimidazolecarboxylic acid instead of
2-(methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylic acid, and
3-chloromethylaniline instead of
3-chloromethylaniline.
MS(ESI+) m/z 527 (M+H) , Rt= 2.18 minutes (method A)
Example 212
N-(3-Chloromethylphenyl)(methoxymethyl)({[2-(methy
lsulfonyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxa
mide
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 103, using
2-(methylsulfonyl)benzoic acid instead of
2-bromofluorobenzoic acid.
MS(ESI+) m/z 527 (M+H) , Rt= 2.08 minutes (method A)
Example 213
N-(3-Chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}(2-methoxyethyl)-1H-benzimidazolecarboxamide
hydrochloride
[Step 1]
Methyl
6-amino(2-methoxyethyl)-1H-benzimidazolecarboxylate
The title compound was obtained as white powder according
to the procedures as described in step 1 to step 4 of Example
11, using methoxypropionyl chloride instead of methoxyacetyl
chloride in Step 1.
[Step 2]
2-(2-Methoxyethyl){[2,5-dichlorophenyl]carbonyl]amino}-1
H-benzimidazolecarboxylic acid
The title compound was obtained according to the
procedures as described in step 4 and step 5 of Example 1, using
methyl
6-amino(2-methoxyethyl)-1H-benzimidazolecarboxylate
instead of methyl 6-amino-1H-benzimidazolecarboxylate, and
2,5-dichlorobenzoyl chloride instead of
2-(trifluoromethyl)benzoyl chloride.
[Step 3]
N-(3-Chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}(2-methoxyethyl)-1H-benzimidazolecarboxamide
hydrochloride
The title compound was obtained according to the
procedures as described in step 7 and step 8 of Example 11, using
2-(2-methoxyethyl){[2,5-dichlorophenyl]carbonyl]amino}-1
H-benzimidazolecarboxylic acid instead of
2-(methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a
mino)-1H-benzimidazolecarboxylic acid.
MS(ESI+) m/z 531 (M+H) , Rt= 2.43 minutes (method A)
Example 214
2-(Methoxymethyl)-N-phenyl({[2-(trifluoromethyl)phenyl]c
arbonyl}amino)-1H-benzimidazolecarboxamide hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
aniline instead of 3-chloromethylaniline.
MS(ESI+) m/z 469 (M+H) , Rt= 2.01 minutes (method A)
Example 215
2-(Methoxymethyl)-N-propyl({[2-(trifluoromethyl)phenyl]c
arbonyl}amino)-1H-benzimidazolecarboxamide hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
n-propylamine instead of 3-chloromethylaniline.
MS(ESI+) m/z 435 (M+H) , Rt= 1.61 minutes (method A)
Example 216
2-(Methoxymethyl)-N-(pyridinyl)({[2-(trifluoromethyl)
phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
3-aminopyridine instead of 3-chloromethylaniline.
MS(ESI+) m/z 470 (M+H) , Rt= 1.25 minutes (method A)
Example 217
N-Benzyl(methoxymethyl)({[2-(trifluoromethyl)phenyl]c
arbonyl}amino)-1H-benzimidazolecarboxamide hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
benzylamine instead of 3-chloromethylaniline.
MS(ESI+) m/z 483 (M+H) , Rt= 1.83 minutes (method A)
Example 218
N-(Cyclohexylmethyl)(methoxymethyl)({[2-(trifluoromet
hyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
cyclohexanemethylamine instead of 3-chloromethylaniline.
MS(ESI+) m/z 489 (M+H) , Rt= 2.11 minutes (method A)
Example 219
2-(Methoxymethyl)-N-(naphthalenyl)({[2-(trifluorometh
yl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
1-naphthylamine instead of 3-chloromethylaniline.
MS(ESI+) m/z 519 (M+H) , Rt= 2.29 minutes (method A)
Example 220
2-(Methoxymethyl)-N-(thiophenyl)({[2-(trifluoromethyl
)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
3-aminothiophene instead of 3-chloromethylaniline.
MS(ESI+) m/z 475 (M+H) , Rt= 1.92 minutes (method A)
Example 221
N-(2,1,3-Benzothiadiazolyl)(methoxymethyl)({[2-(tr
ifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecar
boxamide hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
4-amino-2,1,3-benzothiadiazole instead of
3-chloromethylaniline.
MS(ESI+) m/z 527 (M+H) , Rt= 2.16 minutes (method A)
Example 222
N-(1,1-Dioxidebenzothiophenyl)(methoxymethyl)({
[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
6-aminobenzo[b]thiophene 1,1-dioxide instead of
3-chloromethylaniline.
MS(ESI+) m/z 557 (M+H) , Rt= 1.82 minutes (method A)
Example 223
2-(Methoxymethyl)-N-(thiophenylmethyl)({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamid
e hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
2-thiophene methylamine instead of 3-chloromethylaniline.
MS(ESI+) m/z 489 (M+H) , Rt= 1.77 minutes (method A)
Example 224
N-(1H-Indolyl)(methoxymethyl)({[2-(trifluoromethyl
)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
-aminoindole instead of 3-chloromethylaniline.
MS(ESI+) m/z 508 (M+H) , Rt= 1.75 minutes (method A)
Example 225
N-(1,3-Benzothiazolyl)(methoxymethyl)({[2-(trifluo
romethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxam
ide hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
2-aminobenzothiazole instead of 3-chloromethylaniline.
MS(ESI+) m/z 526 (M+H) , Rt= 2.20 minutes (method A)
Example 226
N-(2,2-Dimethylpropyl)(methoxymethyl)({[2-(trifluorom
ethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
neopentyl amine instead of 3-chloromethylaniline.
MS(ESI+) m/z 463 (M+H) , Rt= 1.95 minutes (method A)
Example 227
2-(Methoxymethyl)-N-(thiophenyl)({[2-(trifluoromethyl
)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained was obtained as
colorless powder according to the procedure as described in
Example 11, using 2-aminothiophene instead of
3-chloromethylaniline.
MS(ESI+) m/z 475 (M+H) , Rt= 1.94 minutes (method A)
Example 228
N-(5-Chloro-1,3-benzoxazolyl)(methoxymethyl)({[2-(
trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolec
arboxamide hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
2-aminochlorobenzoxazole instead of
3-chloromethylaniline.
MS(ESI+) m/z 544 (M+H) , Rt= 2.09 minutes (method A)
Example 229
N-(2-Benzylphenyl)(methoxymethyl)({[2-(trifluoromethy
l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
2-benzylaniline instead of 3-chloromethylaniline.
MS(ESI+) m/z 559 (M+H) , Rt= 2.34 minutes (method A)
Example 230
2-(Methoxymethyl)-N-(quinolinyl)({[2-(trifluoromethyl
)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 11, using
8-aminoquinoline instead of 3-chloromethylaniline.
MS(ESI+) m/z 520 (M+H) , Rt= 2.03 minutes (method A)
Example 231
N-(Cycloheptylmethyl)(methoxymethyl)({[2-(trifluorome
thyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 11, using
cycloheptanemethyleneamine instead of
3-chloromethylaniline.
MS(ESI+) m/z 503 (M+H) , Rt= 2.23 minutes (method A)
Example 232
N-(1,3-Benzoxazolyl)(methoxymethyl)({[2-(trifluoro
methyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamid
e hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
2-aminobenzoxazole instead of 3-chloromethylaniline.
MS(ESI+) m/z 510 (M+H) , Rt= 1.80 minutes (method A)
Example 233
N-(6-Chloro-1,3-benzoxazolyl)(methoxymethyl)({[2-(
trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolec
arboxamide hydrochloride
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
2-aminochlorobenzoxazole instead of
3-chloromethylaniline.
MS(ESI+) m/z 544 (M+H) , Rt= 2.09 minutes (method A)
Example 234
NChloro(hydroxymethyl)phenyl](methoxymethyl)({[
2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-
4-carboxamide
The titled compound was obtained as colorless powder
according to the procedure as described in Example 11, using
(2-aminochlorophenyl)methanol (prepared as described in J.
Med. Chem., 2005, 48, 2080) instead of
3-chloromethylaniline.
MS(ESI+) m/z 533 (M+H) , Rt= 2.08 minutes (method A)
Example 235
N-(3-Chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}(dimethylamino)-1H-benzimidazolecarboxamide
methanesulfonate
To a suspension of N-(3-chloromethylphenyl)
{[(2,5-dichlorophenyl)carbonyl]amino}(dimethylamino)-
1H-benzimidazolecarboxamide (200 mg)(obtained in Example
207) in MeOH (2 ml), was added methanesulfonic acid (1 Eq). The
mixture was stirred at room temperature for 30 minutes, and
filtered off through glass filter to collect crystals, which
were dried under reduced pressure to obtain the titled compound
(180 mg) as white powder.
Elemental Analysis for C H Cl N O •CH SO H+1.5H O
24 20 3 5 2 3 3 2
Calcd.(%) C:46.92 H:4.25 N:10.94
Found.(%) C:46.85 H:4.04 N:10.89
Example 236
N-(3-Chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}(dimethylamino)-1H-benzimidazolecarboxamide
4-methylbenzenesulfonate
The titled compound was obtained as white powder
according to the procedure as described in Example 235, using
p-toluenesulfonic acid monohydrate (1 Eq) instead of
methanesulfonic acid.
Elemental Analysis for C H Cl N O •C H O S+1.2H O
24 20 3 5 2 7 8 3 2
Calcd.(%) C:52.40 H:4.31 N:9.86
Found.(%) C:52.24 H:4.28 N:9.95
Example 237
N-(3-Chloromethylphenyl){[(2,5-dichlorophenyl)carbony
l]amino}(dimethylamino)-1H-benzimidazolecarboxamide
sulfate
The titled compound was obtained as white powder
according to the procedure as described in Example 235, using
sulfuric acid (1 Eq) instead of methanesulfonic acid.
Elemental Analysis for C H Cl N O •H SO +1.5H O
24 20 3 5 2 2 4 2
Calcd.(%) C:44.91 H:3.93 N:10.91
Found.(%) C:44.71 H:3.81 N:10.85
Example 238
N-(3-Chloromethylphenyl)(methoxymethyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide methanesulfonate
Methanesulfonic acid (1 Eq) was added to a suspension of
N-(3-chloromethylphenyl)(methoxymethyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide (250 mg)(obtained in Example 11) in MeOH (2 ml). After
stirring for 30 minutes at room temperature, MeOH was removed
under reduced pressure to obtain the titled compound as white
powder.
Elemental Analysis for C H ClF N O •CH SO H+1.0H O
20 3 4 3 3 3 2
Calcd.(%) C:49.49 H:4.15 N:8.88
Found.(%) C:49.20 H:4.14 N:8.78
Example 239
N-(3-Chloromethylphenyl)(methoxymethyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide 4-methylbenzenesulfonate
The titled compound was obtained as white powder
according to the procedure as described in Example 238, using
p-toluenesulfonic acid monohydrate (1 Eq) instead of
methanesulfonic acid.
Elemental Analysis for C H ClF N O •C H O S
20 3 4 3 7 8 3
Calcd.(%) C:55.78 H:4.10 N:8.13
Found.(%) C:55.62 H:4.12 N:8.16
Example 240
N-(3-Chloromethylphenyl)(methoxymethyl)({[2-(trifl
uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox
amide sulfate
The titled compound was obtained as white powder
according to the procedure as described in Example 238, using
sulfuric acid (1 Eq) instead of methanesulfonic acid.
Elemental Analysis for C H ClF N O •H SO +0.5H O
20 3 4 3 2 4 2
Calcd.(%) C:48.12 H:3.72 N:8.98
Found.(%) C:48.34 H:3.57 N:8.99
Example 241
N-(3-Chloromethylphenyl)(1-methylcyclopropyl)({[2-
(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide methanesulfonate
Methanesulfonic acid (1 Eq) was added to a suspension of
N-(3-chloromethylphenyl)(1-methylcyclopropyl)({[2-
(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide (250 mg)(obtained in Example 85) in MeOH (2 ml).
After stirring at room temperature for 30 minutes, MeOH was
removed under reduced pressure to obtain the titled compound
as white powder.
Elemental Analysis for C H ClF N O •CH SO H+0.5H O
27 22 3 4 2 3 3 2
Calcd.(%) C:53.21 H:4.31 N:8.86
Found.(%) C:52.97 H:4.14 N:8.90
Example 242
N-(3-Chloromethylphenyl)(1-methylcyclopropyl)({[2-
(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide 4-methylbenzenesulfonate
The titled compound was obtained as white powder
according to the procedure as described in Example 241, using
p-toluenesulfonic acid monohydrate (1 Eq) instead of
methanesulfonic acid.
Elemental Analysis for C H ClF N O •C H O S
27 22 3 4 2 7 8 3
Calcd.(%) C:58.41 H:4.32 N:8.01
Found.(%) C:58.13 H:4.50 N:8.00
Example 243
N-(3-Chloromethylphenyl)(1-methylcyclopropyl)({[2-
(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole
carboxamide sulfate
The titled compound was obtained as white powder
according to the procedure as described in Example 241, using
sulfuric acid (1 Eq) instead of methanesulfonic acid.
Elemental Analysis for C H ClF N O •H SO +0.6H O
27 22 3 4 2 2 4 2
Calcd.(%) C:51.00 H:3.99 N:8.81
Found.(%) C:51.35 H:4.39 N:8.85
Example 244
N-(3-Chloromethylphenyl){[(3-fluoropyridinyl)carbo
nyl]amino}(methoxymethyl)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 103, using
3-fluoropyridinecarboxylic acid instead of
2-bromofluorobenzoic acid.
MS(ESI+) m/z 468 (M+H) , Rt= 2.17 minutes (method A)
Example 245
N-(3-Chloromethylphenyl){[(3-chloropyridinyl)carbo
nyl]amino}(methoxymethyl)-1H-benzimidazolecarboxamide
hydrochloride
The titled compound was obtained as pale yellow powder
according to the procedure as described in Example 103, using
3-chloropicolinic acid instead of 2-bromofluorobenzoic
acid.
MS(ESI+) m/z 484 (M+H) , Rt= 2.08 minutes (method A)
Example 246
N-(3-Chloromethylphenyl){[(3,5-dichloropyridinyl)c
arbonyl]amino}(methoxymethyl)-1H-benzimidazolecarboxa
mide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 103, using
3,5-dichloroisonicotinic acid instead of
2-bromofluorobenzoic acid.
MS(ESI+) m/z 518 (M+H) , Rt= 2.24 minutes (method A)
Example 247
6-{[(5-Butoxychlorophenyl)carbonyl]amino}-N-(3-chloro
methylphenyl)(methoxymethyl)-1H-benzimidazolecarboxam
ide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 103, using
-butoxychlorobenzoic acid (prepared in Reference Example
) instead of 2-bromofluorobenzoic acid.
MS(ESI+) m/z 555 (M+H) , Rt= 2.67 minutes (method A)
Example 248
6-({[2-Chloro(2,2-difluoroethoxy)phenyl]carbonyl}amino)-
N-(3-chloromethylphenyl)(methoxymethyl)-1H-benzimidaz
olecarboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 103, using
2-chloro(2,2-difluoroethoxy)benzoic acid (prepared in
Reference Example 11) instead of 2-bromofluorobenzoic acid.
MS(ESI+) m/z 563 (M+H) , Rt= 1.66 minutes (method A)
Example 249
N-(3-Chloromethylphenyl)({[2-chloro(4,4,4-trifluor
obutoxy)phenyl]carbonyl}amino)(methoxymethyl)-1H-benzimi
dazolecarboxamide hydrochloride
The titled compound was obtained as white powder
according to the procedure as described in Example 103, using
2-chloro(4,4,4-trifluorobutoxy)benzoic acid (prepared in
Reference Example 12) instead of 2-bromofluorobenzoic acid.
MS(ESI+) m/z 609 (M+H) , Rt= 1.99 minutes (method A)
The chemical structures of the compounds of Examples 1
to 249 are shown in the following Tables 1 to 14.
[Table 1]
Example Structure Example Structure Example Structure
1 7 13
2 8 14
3 9 15
16
11 17
6 12 18
[Table 2]
Example Structure Example Structure Example Structure
19 25 31
26 32
21 27 33
22 28 34
23 29 35
24 30 36
[Table 3]
Example Structure Example Structure Example Structure
37 43 49
38 44 50
39 45 51
40 46 52
41 47 53
42 48 54
[Table 4]
Example Structure Example Structure Example Structure
55 61 67
56 62 68
57 63 69
58 64 70
59 65 71
60 66 72
[Table 5]
Example Structure Example Structure Example Structure
73 79 85
74 80 86
75 81 87
76 82 88
77 83 89
78 84 90
[Table 6]
Example Structure Example Structure Example Structure
91 97 103
92 98 104
93 99 105
94 100 106
95 101 107
96 102 108
[Table 7]
Example Structure Example Structure Example Structure
109 115 121
110 116 122
111 117 123
112 118 124
113 119 125
114 120 126
[Table 8]
Example Structure Example Structure Example Structure
127 133 139
128 134 140
129 135 141
130 136 142
131 137 143
132 138 144
[Table 9]
Examp Exam Exam
Structure Structure Structure
le ple ple
145 151 157
146 152 158
147 153 159
148 154 160
149 155 161
150 156 162
[Table 10]
Example Structure Example Structure Example Structure
163 169 175
164 170 176
165 171 177
166 172 178
167 173 179
168 174 180
[Table 11]
Example Structure Example Structure Example Structure
181 187 193
182 188 194
183 189 195
184 190 196
185 191 197
186 192 198
[Table 12]
Example Structure Example Structure Example Structure
199 205 211
200 206 212
201 207 213
202 208 214
203 209 215
204 210 216
[Table 13]
Example Structure Example Structure Example Structure
217 223 229
218 224 230
219 225 231
220 226 232
221 227 233
222 228 234
[Table 14]
Example Structure Example Structure Example Structure
235 241 247
236 242 248
237 243 249
238 244
239 245
240 246
Test Example 1: mPGES-1 inhibiting activity
mPGES-1 microsome fractions were prepared from CHO-K1
cells transiently transfected with plasmid encoding the human
mPGES-1cDNA. Microsomes were diluted with potassium phosphate
buffer containing reduced glutathione (pH7.4), and DMSO
containing test compound or DMSO alone, which was each 1% of
DMSO final concentration, was added and incubated at 4°C for
minutes. Then, the enzymatic reactions were initiated by
the addition of PGH2 substrate (final concentration 1 μM) and
incubated at 4°C for 60 seconds. The reaction was terminated
by addition of the citrate solution (final citrate
concentration 50mM) containing ferric chloride (final
concentration 1 mg/mL). PGE2 production in the enzyme reaction
aliquot was measured using HTRF kit (Cisbio International,
catalogue #62P2APEC). The solution free of test compound was
used as positive control, and the solution free of test compound
and microsome sample was used as negative control. 100%
activity was defined as PGE2 production in the positive control
minus PGE2 production in negative control. IC50 value was
calculated by standard method.
Test Example 2: Inhibition of PGE2 and PGF2α production in A549
cell
Human A549 cells were seeded on to a 96-well plate at 2x10
cells/100 μL per well and allowed to incubate overnight. After
removing the culture medium and washed with phosphate buffered
saline, the culture medium was replaced by RPMI culture medium
with 3%FBS containing a DMSO solution containing test compound
or DMSO alone, which was each 0.1% of DMSO final concentration.
After incubation for 60 minutes, IL-1β (5 ng/well) was added
and incubated at 37°C for 24 hours. Then, PGE2 in the culture
medium was measured using HTRF kit (Cisbio International,
catalogue #62P2APEC), and PGF2α in the culture medium was
measured using EIA kit (Cayman Chemical Company, catalogue
#516011). The solution free of test compound was used as
positive control, and the solution free of test compound and
IL-1β was used as negative control. 100% activity was defined
as PGE2 and PGF2α production in the positive control minus PGE2
and PGF2α production in the negative control. IC50 value was
calculated by standard method.
The results of Test Example 1 and Test Example 2 are shown in
Tables 15-18 ("-" means unadministered test).
[Table 15]
A549 Cell A549 Cell
mPGES-1 PGE2 mPGES-1 PGE2
Example Inhibition Production Example Inhibition Production
IC50 (nM) Inhibition IC50 (nM) Inhibition
IC50 (nM) IC50 (nM)
1 12.7 88.9 39 10.4 236.9
2 7.6 240.5 40 194.5 300.2
3 1.5 24.6 41 52.5 145.0
42 28.5 1857.9
453.4 - 43 70.7 438.3
6 27.4 - 44 4.1 1101.2
7 105.1 341.6 45 4.9 2084.5
8 160.3 105.8 46 26.0 230.8
9 452.2 - 47 269.6 -
332.8 - 48 49.9 146.3
11 6.6 12.9 49 100.3 375.3
12 7.1 41 50 140.3 810.2
13 35.1 75.6 51 120.2 330.4
14 3.8 15.2 52 40.2 280.7
37.4 465.0 53 179.3 279.9
16 63.9 1303.5 54 23.2 225.3
17 9.8 21.6 55 2.7 64.3
18 21.6 110.1 56 7.5 85.0
19 9.4 47.8 57 0.5 16.8
5.6 98 58 5.4 157.0
21 8.3 69.4 59 2.1 12.9
22 4.8 104.2 60 19.8 8.0
23 7.2 115.7 61 3.2 66.7
24 10.5 750.6 62 11.0 51.6
89.0 849.6 63 5.6 54.8
26 171.5 871.5 64 2.3 20.1
27 2.4 16.0 65 9.6 72.2
28 3.3 114.4 66 9.9 57.3
29 3.5 85.5 67 11.0 56.4
1.8 210.1 68 63.4 10000<
31 4.1 69.0 69 10.0 21.6
32 5.2 71.7 70 4.6 146.9
33 3.0 33.6 71 33.1 227.2
34 4.9 27.6 72 9.8 60.0
20.3 204.6 73 18.6 76.4
36 147.2 234.2 74 71.3 10.4
37 23.3 265.1 75 31.7 19.7
38 6.6 17.4 76 0.2 5.5
[Table 16]
A549 Cell A549 Cell
mPGES-1 PGE2 mPGES-1 PGE2
Example Inhibition Production Example Inhibition Production
IC50 (nM) Inhibition IC50 (nM) Inhibition
IC50 (nM) IC50 (nM)
77 1.7 32.9 115 11.5 37.0
78 96.8 176.8 116 9.7 251.5
79 15.0 284.6 117 583.8 -
80 29.4 1251.4 118 7.3 5.3
81 5.0 404.5 119 207.6 -
82 0.4 6.3 120 57.5 513.2
83 9.8 16.5 121 6.3 432.4
84 0.8 6.5 122 9.7 1000<
85 0.5 3.7 123 8.7 99.8
86 1.0 5.1 124 2.2 3.2
87 5.7 6.9 125 25.6 56.9
88 15.1 9.2 126 5.6 13.1
89 1.2 2.1 127 6.3 144.1
90 117.7 348.4 128 1 253.3
91 327.3 - 129 59.4 177.6
92 6.7 32.2 130 3.9 10000<
93 4.2 153.5 131 32.8 10000<
94 9.1 182.1 132 2.2 590.4
95 5.1 105.3 133 7.0 487.5
96 34.0 125.7 134 10.3 921.3
97 6.1 43.1 135 0.3 87.3
98 6.0 11.9 136 2.4 61.9
99 3.7 18.9 137 3.3 1106.7
100 33.3 122.2 138 2.2 87.4
101 77.8 117.9 139 1.9 72.8
102 1.6 49.1 140 0.2 33.0
103 2.8 59.6 141 0.4 36.5
104 2.9 71.1 142 0.4 82.7
105 8.9 324.6 143 5.3 87.5
106 4.5 63.8 144 9.7 2992.1
107 1.5 42.0 145 1.6 13.0
108 11.5 87.9 146 3.1 128.9
109 7.8 8.7 147 15.8 185.9
110 2.6 35.5 148 1.9 324.4
111 764.8 - 149 1.0 43.3
112 2.6 186.7 150 2.1 375.8
113 約 0.1 1.2 151 11.6 327.5
114 3.5 8.8 152 31.6 854.4
[Table 17]
A549 Cell A549 Cell
mPGES-1 PGE2 mPGES-1 PGE2
Example Inhibition Production Example Inhibition Production
IC50 (nM) Inhibition IC50 (nM) Inhibition
IC50 (nM) IC50 (nM)
153 22.3 617.8 191 3.9 49.5
154 20.0 64.4 192 9.9 18.1
155 100.6 208.7 193 0.4 18.9
156 1.6 24.6 194 0.4 33.8
157 3.9 10856.6 195 2.3 17.2
158 8.5 82.2 196 6.5 35.9
159 403.3 - 197 5.2 34.4
160 7.6 71.6 198 6.0 34.1
161 3.8 10000< 199 9.7 43.2
162 23.8 52.2 200 4.6 107.6
163 5.9 23.2 201 0.5 253.0
164 0.3 13.3 202 4.9 5.9
165 1.3 7.4 203 1.4 5.2
166 3.2 29.0 204 1.0 12.2
167 1.0 217.3 205 3.7 25.6
168 3.2 23.9 206 3.2 74.5
169 2.4 88.6 207 3.6 6.2
170 3.2 17.8 208 0.7 13.0
171 4.7 97.8 209 1.0 10.3
172 4.5 134.4 210 4.7 13.8
173 1.1 60.8 211 2.5 8.5
174 2.0 117.2 212 42.3 305.4
175 3.6 143.9 213 0.9 141.6
176 0.3 138.4 214 5.2 60.7
177 8.3 45.2 215 140.4 772.5
178 1.2 12.8 216 203.6 -
179 3.6 20.2 217 26.9 316.7
180 1.1 773.6 218 5.3 42.8
181 1.1 705.0 219 2.0 26.0
182 1.6 38.4 220 8.6 -
183 1.9 6.1 221 2.2 -
184 1.0 138.2 222 661.1 -
185 4.5 5.6 223 68.2 -
186 6.1 13.9 224 26.5 -
187 3.6 12.7 225 15.6 -
188 456.9 1019.5 226 26.9 -
189 1.4 24.5 227 0.1 -
190 0.1 7.0 228 1.7 -
[Table 18]
A549 Cell A549 Cell
mPGES-1 PGE2 mPGES-1 PGE2
Example Inhibition Production Example Inhibition Production
IC50 (nM) Inhibition IC50 (nM) Inhibition
IC50 (nM) IC50 (nM)
229 2.3 39 244 56.2 104
230 1.9 100 245 25.7 166
231 1.9 150 246 35.9 132
232 7.7 125 247 68.4 55
233 2.5 195 248 201 -
234 97.4 198 249 404 -
Test Example 3: Inhibition of PGE2 production in human whole
blood
Human whole blood assay was carried out according to
Brideau et al. (Inflamm. Res., vol.45, p.68, 1996). Venous
bloods from volunteers were collected into each tube
(containing heparin). These volunteers did not have clinical
appearance of inflammation and not take NSAID at least seven
days before the blood collection. DMSO solution containing
test compound or DMSO alone, which was each 0.25% of DMSO final
concentration, was added to the blood, and incubated at 37°C
for 20 minutes. LPS from E. coli (E. coli serotype 0111:B4
diluted with phosphate-buffered saline) was added at the final
concentration of 100μg/mL and incubated at 37°C for 24 hours.
After the incubation, the blood was centrifuged at 2000 rpm for
minutes at 4°C, and PGE2 in the supernatant was measured using
HTRF kit (Cisbio International, catalogue #62P2APEC). The
solution free of test compound was used as positive control,
and the solution free of test compound and LPS was used as
negative control. 100% activity was defined as PGE2 production
in the positive control minus PGE2 production in the negative
control. IC50 value was calculated by standard method.
Test Example 4: Inhibition of PGE2 production in mouse air pouch
model
Air pouch was established in BALB/c mose by the
subcutaneous injection (twice at intervals of 3 days) of
sterilized air into the back. 3 days after the second air
injection, 0.5% zymosan was injected into the air pouch. 5
hours later, 1 mL of phosphate-buffered saline containing 10μM
indomethacin was injected into the air pouch to wash the
interior thereof, and the white blood cells and PGE2 in the pouch
fluid were measured. PGE2 was quantified using HTRF kit (Cisbio
International, catalogue #62P2APEC). The test compound was
suspended in 0.5% methylcellulose solution and administered
orally 1 hour before the zymosan injection. The group which was
administered only methylcellulose solution was used as control
for comparison.
Test Example 5: Pharmacokinetic assay in rat
A 10mg/5mL liquid of a test compound was prepared by
suspending the compound in 0.5% methylcellulose solution. The
liquid was administered orally to female SD rats at fasting
state at a dose of 10 mg/kg, and bloods were collected from the
jugular vein 1, 2, 4 and 6 hours after the administration. The
Blood samples were centrifuged to separate plasma. After
deproteinization of the plasma, the concentration of the test
compound in plasma was measured by HPLC.
Test Example 6: Evaluation of analgesic effect using mouse
writhing test
Analgesic effect was evaluated from pain-related
behavior induced by the intraperitoneal injection of 0.6%
acetic acid solution (10mL/kg) into ddY mouse. The number of
times of writhing in 20 minutes after the acetic acid injection
was counted as pain-related behavior. The test compound was
suspended in 0.5% methylcellulose solution and administered
orally 1 hour before the acetic acid injection. The group which
was administered only methylcellulose solution was used as
control for comparison.
Test Example 7: Evaluation of analgesic effect using mouse
formalin test
Analgesic effect was evaluated from pain-related
behavior induced by the injection of 5% formalin solution (0.02
mL/mouse) into the right hind-foot pad of ICR mouse. The sum
of the duration of licking in 30 minutes after the formalin
injection was measured as pain-related behavior. The test
compound was suspended in 0.5% methylcellulose solution and
administered orally 1 hour before the formalin injection. The
group which was administered only methylcellulose solution was
used as control for comparison.
Test Example 8: Evaluation of antiinflamatory effect in rat
carrageenan edema model
Antiinflamatory effect was evaluated from paw edema
induced by the injection of 0.5% carrageenan solution (0.1
mL/rat) into the right hind-foot pad of SD rat. The volume of
the paw was measured before and 3 hours later the carrageenan
injection using a plethysmometer (Unicom Inc., catalogue
#TK-105). Swelling volume was determined from the increase in
the volume from the volume before the injection. The inhibiting
rate was determined as the ratio of the average swelling volume
in the group given the test compound to the average swelling
in the controll group. The test compound was suspended in 0.5%
methylcellulose solution and administered orally 1 hour before
the carrageenan injection. The group which was administered
only methylcellulose solution was used as control for
comparison.
The compound of the invention or a pharmaceutically
acceptable salt thereof showed potent mPGES-1 inhibiting
activity and inhibited PGE2 production, as shown in Test Example
1 and Test Example 2. Thus, it is particularly useful as an
agent for the treatment or prevention of inflammatory bowel
disease, irritable bowel syndrome, migraine, headache, low back
pain, spinal stenosis, herniated disk, temporomandibular joint
disorder, cervical syndrome, cervical spondylosis,
endometriosis, adenomyosis, preterm labour and delivery,
threatened premature delivery, dysmenorrhea, overactive
bladder, nocturia, interstitial cystitis, neurodegenerative
disease, psoriasis, rheumatoid arthritis, rheumatic fever,
fibromyalgia, neuralgia, complex regional pain syndrome,
fascial dysfunction, viral infections, bacterial infection,
mycosis, burn, inflammation and pain after operation, injury
and dental extraction, malignant tumors, atherosclerosis,
stroke, gout, arthritis, osteoarthritis, juvenile arthritis,
ankylosing spondylitis, tenosynovitis, ligament ossification,
systemic lupus erythematosus, vasculitis, pancreatitis,
nephritis, conjunctivitis, iritis, scleritis, uveitis, wound
therapy, dermatitis, eczema, osteoporosis, asthma, chronic
obstructive pulmonary disease, pulmonary fibrosis, allergic
disease, familial adenomatous polyposis, scleroderma,
bursitis, leiomyoma of uterus, prostatitis, and a pain from
cancer.
Formulation 1: 80 mg Tablets for oral administration
Ingredient Quantity (mg/teblet)
Compound of Example 1 5.0
Corn starch 46.6
Cellulose, crystalline 24.0
Methylcellulose 4.0
Magnesium stearate 0.4
The components are blended and compressed to form
tablets.
[Industrial applicability]
The compound of the invention or a pharmaceutically
acceptable salt thereof has mPGES-1 inhibiting activity and is
particularly useful as an agent for the treatment or prevention
of inflammatory bowel disease, irritable bowel syndrome,
migraine, headache, low back pain, spinal stenosis, herniated
disk, temporomandibular joint disorder, cervical syndrome,
cervical spondylosis, endometriosis, adenomyosis, preterm
labour and delivery, threatened premature delivery,
dysmenorrhea, overactive bladder, nocturia, interstitial
cystitis, neurodegenerative disease, psoriasis, rheumatoid
arthritis, rheumatic fever, fibromyalgia, neuralgia, complex
regional pain syndrome, fascial dysfunction, viral infections,
bacterial infection, mycosis, burn, inflammation and pain after
operation, injury and dental extraction, malignant tumors,
atherosclerosis, stroke, gout, arthritis, osteoarthritis,
juvenile arthritis, ankylosing spondylitis, tenosynovitis,
ligament ossification, systemic lupus erythematosus,
vasculitis, pancreatitis, nephritis, conjunctivitis, iritis,
scleritis, uveitis, wound therapy, dermatitis, eczema,
osteoporosis, asthma, chronic obstructive pulmonary disease,
pulmonary fibrosis, allergic disease, familial adenomatous
polyposis, scleroderma, bursitis, leiomyoma of uterus,
prostatitis, and a pain from cancer.
Claims (13)
1. A heterocyclic derivative represented by the general formula [1]: or its tautomer or a pharmaceutically acceptable salt thereof, wherein ring A is a group represented by the general formulae [4]: wherein X is NH or N-alkyl; A is i) hydrogen; ii) halogen; iii) alkyl optionally substituted with one to three groups selected from the group consisting of halogen, amino, monoalkylamino, dialkylamino, carbamoyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, a saturated cyclic aminocarbonyl, alkoxy, alkoxyalkoxy and alkylcarbonyloxy; iv) cycloalkyl optionally substituted with alkyl optionally substituted with one to three halogens; v) alkoxy; vi) a saturated heterocycle group optionally substituted with alkyl, alkyloxycarbonyl, alkylcarbonyl or oxo; vii) alkylthio; viii) alkylsulfonyl; ix) alkylsulfinyl; x) a group of the general formula [5]: wherein R and R are the same or different group selected from a) hydrogen, b) alkyl optionally substituted with a group selected from the group consisting of monoalkylamino, dialkylamino, a saturated cyclic amino optionally substituted with alkyl, a saturated heterocycle group optionally substituted with alkyl, alkoxy, hydroxycarbonyl, hydroxyl, alkyloxycarbonyl and alkylthio, or c) cycloalkyl; or xi) a saturated cyclic amino optionally substituted with alkyl, amino, monoalkylamino, dialkylamino, alkoxy or hydroxyl; R is phenyl, benzyl, naphthyl, cycloalkyl, cycloalkylmethyl, heteroaryl, heteroarylmethyl, 1,2,3,4-tetrahydronaphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, 2,3-dihydro-1H-indenyl, 2,3-dihydro-1H-indenyl, 1,2-dihydrocyclobutabenzenyl, 1,2-dihydrocyclobutabenzenyl or alkyl, wherein said phenyl, benzyl, cycloalkyl, cycloalkylmethyl, heteroaryl and heteroarylmethyl is optionally substituted with one to three groups selected from the group consisting of i) halogen, ii) alkyl optionally substituted with one to three groups selected from the group consisting of halogen, hydroxy and phenyl, iii) alkoxy, iv) hydroxy, and v) cyano; R is phenyl or pyridyl, wherein said phenyl and pyridyl is optionally substituted with one to three groups selected from the group consisting of i) halogen, ii) alkylsulfonyl, iii) alkoxy optionally substituted with one to three halogens or alkoxy; iv) alkynyl optionally substituted with alkoxyalkyl or cycloalkyl, and v) alkyl optionally substituted with one to three groups selected from the group consisting of alkoxy, alkoxyalkoxy, cycloalkyl, phenyl and halogen.
2. The heterocyclic derivative according to claim 1, wherein X is NH, or its tautomer or a pharmaceutically acceptable salt thereof.
3. The heterocyclic derivative according to claim 1, wherein R is phenyl, 1,2,3,4-tetrahydronaphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, 2,3-dihydro-1H-indenyl, 2,3-dihydro-1H-indenyl, 1,2-dihydrocyclobutabenzenyl, or 1,2-dihydrocyclobutabenzenyl, and said phenyl is optionally substituted with one to three groups selected from the group consisting of i) halogen, ii) alkyl optionally substituted with one to three halogens, iii) alkoxy, and iv) cyano, or its tautomer or a pharmaceutically acceptable salt thereof.
4. The heterocyclic derivative according to claim 1, wherein R is phenyl and said phenyl is optionally substituted with one to three groups selected from the group consisting of i) halogen ii) alkylsulfonyl, iii) alkoxy optionally substituted with alkoxy, iv) alkynyl optionally substituted with alkoxyalkyl or cycloalkyl, and v) alkyl optionally substituted with one to three groups selected from the group consisting of halogen, alkoxy, alkoxyalkoxy, cycloalkyl and phenyl, or its tautomer or a pharmaceutically acceptable salt thereof.
5. The heterocyclic derivative according to claim 1, wherein X is NH, A is i) hydrogen, ii) alkyl optionally substituted with a group selected from the group consisting of halogen, monoalkylamino, dialkylamino, monoalkylaminocarbonyl, dialkylaminocarbonyl, a saturated cyclic aminocarbonyl, alkoxy, alkoxyalkoxy and alkylcarbonyloxy, iii) cycloalkyl optionally substituted with alkyl optionally substituted with one to three halogens, iv) alkoxy, v) a saturated heterocyclic group optionally substituted with alkyl or alkyloxycarbonyl, vi) alkylthio, vii) alkylsulfonyl, viii) alkylsulfinyl, ix) amino substituted with alkyl wherein said alkyl is optionally substituted with a group selected from the group consisting of monoalkylamino, dialkylamino, a saturated cyclic amino optionally substituted with alkyl, tetrahydrofuryl, morpholino, alkoxy, hydroxycarbonyl, hydroxyl and alkylthio, x) amino substituted with cycloalkyl or xi) a saturated cyclic amino optionally substituted with alkyl, dialkylamino, alkoxy or hydroxyl, and R is i) phenyl optionally substituted with one to three groups selected from the group consisting of halogen, alkyl optionally substituted with one to three halogens, alkoxy and cyano, ii) 1,2,3,4-tetrahydronaphthalenyl, iii) 2,3-dihydro-1H-indenyl, iv) benzyl optionally substituted with halogen or alkyl optionally substituted with one to three halogens, v) cycloalkyl, vi) cycloalkylmethyl, vii) naphthyl, viii) pyridylmethyl optionally substituted with alkyl optionally substituted one to three halogens, ix) thienyl, x) thienylmethyl, xi) benzothiazolyl, xii) benzothiadiazolyl, xiii) indolyl or xiv) alkyl, and R is phenyl or pyridyl wherein said phenyl is optionally substituted with one to three groups selected from the group consisting of i) halogen, ii) alkylsulfonyl, iii) alkoxy optionally substituted with alkoxy, iv) alkynyl optionally substituted with alkoxyalkyl or cycloalkyl, and v) alkyl optionally substituted with one to three groups selected from the group consisting of halogen, alkoxy, alkoxyalkoxy, cycloalkyl and phenyl, and said pyridyl is optionally substituted with halogen, or its tautomer or a pharmaceutically acceptable salt thereof.
6. The heterocyclic derivative according to claim 1, wherein X is NH, A is alkyl substituted with alkoxy, dialkylamino, tetrahydrofuryl, tetrahydrofurylmethyl, alkoxyalkylamino, or cycloalkyl optionally substituted with alkyl optionally substituted with one to three halogens, R is phenyl substituted with one halogen and one methyl, and R is phenyl optionally substituted with one trifluoromethyl or two halogens, or its tautomer or a pharmaceutically acceptable salt thereof.
7. The heterocyclic derivative according to claim 1 selected from: N-[2-(trifluoromethyl)benzyl]({[2-(trifluoromethyl)pheny l]carbonyl}amino)-1H-benzimidazolecarboxamide, N-cyclohexyl({[2-(trifluoromethyl)phenyl]carbonyl}amino) -1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl)({[2-(trifluoromethyl)phenyl] carbonyl}amino)-1H-benzimidazolecarboxamide, N-[(1-hydroxycyclohexyl)methyl]({[2-(trifluoromethyl)phe nyl]carbonyl}amino)-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl)(methoxymethyl)({[2-(trifl uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox amide, 2-methyl-N-[2-(trifluoromethyl)benzyl]({[2-(trifluoromet hyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, N-cyclohexylmethyl({[2-(trifluoromethyl)phenyl]carbon yl}amino)-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl)methyl({[2-(trifluoromethy l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, N-cyclopentylmethyl({[2-(trifluoromethyl)phenyl]carbo nyl}amino)-1H-benzimidazolecarboxamide, N-cyclobutylmethyl({[2-(trifluoromethyl)phenyl]carbon yl}amino)-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl)ethyl({[2-(trifluoromethyl )phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, N-cyclohexylethyl({[2-(trifluoromethyl)phenyl]carbony l}amino)-1H-benzimidazolecarboxamide, 2-ethyl-N-[2-(trifluoromethyl)benzyl]({[2-(trifluorometh yl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, N-cyclohexyl(methoxymethyl)({[2-(trifluoromethyl)phen yl]carbonyl}amino)-1H-benzimidazolecarboxamide, 2-(methoxymethyl)-N-[2-(trifluoromethyl)benzyl]({[2-(tri fluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarb oxamide, 2-(methoxymethyl)-N-(2-methylphenyl)({[2-(trifluoromethy l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, 2-(methoxymethyl)-N-(4-methylphenyl)({[2-(trifluoromethy l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, N-(2-chlorobenzyl)(methoxymethyl)({[2-(trifluoromethy l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, 2-(methoxymethyl)-N-(4-methylbenzyl)({[2-(trifluoromethy l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, N-(4,4-difluorocyclohexyl)(methoxymethyl)({[2-(triflu oromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxa mide, N-(4-tert-buthylphenyl)(methoxymethyl)({[2-(trifluoro methyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamid 2-(methoxymethyl)-N-[4-(trifluoromethyl)phenyl]({[2-(tri fluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarb oxamide, N-(2,4-dimethylphenyl)(methoxymethyl)({[2-(trifluorom ethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide N-(2-chloromethylphenyl)(methoxymethyl)({[2-(trifl uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox amide, N-(3,4-dimethylphenyl)(methoxymethyl)({[2-(trifluorom ethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide N-(3-chloromethylphenyl)(methoxymethyl)({[2-(trifl uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox amide, N-(2,3-dihydro-1H-indenyl)(methoxymethyl)({[2-(tri fluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarb oxamide, 2-(methoxymethyl)-N-(5,6,7,8-tetrahydronaphthalenyl)( {[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol ecarboxamide, N-(2-fluorophenyl)(methoxymethyl)({[2-(trifluoromethy l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, 2-(methoxymethyl)-N-(2-methoxypheny)({[2-(trifluoromethy l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, 2-(methoxymethyl)-N-(4-methoxypheny)({[2-(trifluoromethy l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, N-(3-bromomethylphenyl)(methoxymethyl)({[2-(triflu oromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxa mide, N-(3-chloromethylbenzyl)(methoxymethyl)({[2-(trifl uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox amide, N-(2,6-difluorophenyl)(methoxymethyl)({[2-(trifluorom ethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide N-(3-cyanomethylphenyl)(methoxymethyl)({[2-(triflu oromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxa mide, 2-(methoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}a mino)-N-{[3-(trifluoromethyl)pyridinyl]methyl}-1H-benzim idazolecarboxamide, N-(2-chloromethylphenyl)(methoxymethyl)({[2-(trifl uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox amide, 2-(2-aminooxoethyl)-N-(3-chloromethylphenyl)({[2-( trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolec arboxamide, 2-(2-aminooxoethyl)-N-[2-(trifluoromethyl)benzyl]({[2 -(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4 -carboxamide, N-(3-chloromethylphenyl)methyl({[2-(trifluoromethy l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, N-cyclohexylmethyl({[2-(trifluoromethyl)phenyl]carbon yl}amino)-1H-benzimidazolecarboxamide, 1-methyl-N-[2-(trifluoromethyl)benzyl]({[2-(trifluoromet hyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl)ethyl({[2-(trifluoromethyl )phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, N-cyclohexylethyl({[2-(trifluoromethyl)phenyl]carbony l}amino)-1H-benzimidazolecarboxamide, 1-ethyl-N-[2-(trifluoromethyl)benzyl]({[2-(trifluorometh yl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl)ethoxy({[2-(trifluoromethy l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, 2-ethoxy-N-[2-(trifluoromethyl)benzyl]({[2-(trifluoromet hyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl)(1-chloromethylpropanyl )({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimi dazolecarboxamide, N-(3-chloromethylphenyl)[(dimethylamino)methyl]({[ 2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole- 4-carboxamide, N-(3-chloromethylphenyl)(2-methylpropyl)({[2-(trif luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo xamide, 2-(2-methylpropyl)-N-[2-(trifluoromethyl)benzyl]({[2-(tr ifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecar boxamide, tert-butyl 3-{4-[(3-chloromethylphenyl)carbamoyl]({[2-(trifluoro methyl)phenyl]carbonyl}amino)-1H-benzimidazolyl}azetidin ecarboxylate, N-(3-chloromethylphenyl)[(methylamino)methyl]({[2- (trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole carboxamide, {4-[(3-chloromethylphenyl)carbamoyl]({[2-(trifluorome thyl)phenyl]carbonyl}amino)-1H-benzimidazolyl}methyl acetate, N-(3-chloromethylphenyl)[(2R)-tetrahydrofuranyl]-6 -({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidaz olecarboxamide, 2-[[(2R)-tetrahydrofuranyl]-N-[2-(trifluoromethyl)benzyl ]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimi dazolecarboxamide, N-(3-chloromethylphenyl)[(2S)-tetrahydrofuranyl]-6 -({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidaz olecarboxamide, 2-[[(2S)-tetrahydrofuranyl]-N-[2-(trifluoromethyl)benzyl ]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimi dazolecarboxamide, 2-(1-acetylazetidinyl)-N-(3-chloromethylphenyl)({[ 2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole- 4-carboxamide, tert-butyl (2S){4-[(3-chloromethylphenyl)carbamoyl]({[2-(trif luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolyl}pyr rolidinecarboxylate, tert-butyl (2R){4-[(3-chloromethylphenyl)carbamoyl]({[2-(trif luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolyl}pyr rolidinecarboxylate, N-(3-chloromethylphenyl)[(2S)-pyrrolidinyl]({[2 -(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4 -carboxamide, N-(3-chloromethylphenyl)[(2S)methylpyrrolidinyl ]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimi dazolecarboxamide, 2-[(2S)acetylpyrrolidinyl]-N-(3-chloromethylphenyl )({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimi dazolecarboxamide, N-(3-chloromethylphenyl)[(2-methoxyethoxy)methyl]( {[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol ecarboxamide, N-(3-chloromethylphenyl)(1-methoxymethylpropany l)({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzim idazolecarboxamide, 2-tert-butyl-N-(3-chloromethylphenyl)({[2-(trifluorom ethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide 2-tert-butyl({[2-(trifluoromethyl)phenyl]carbonyl}amino) -N-{[3-(trifluoromethyl)pyridinyl]methyl}-1H-benzimidazo lecarboxamide, N-(3-chloromethylphenyl)(2-ethoxyethyl)({[2-(trifl uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox amide, N-(3-chloromethylphenyl)(ethoxymethyl)({[2-(triflu oromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxa mide, 2-(ethoxymethyl)({[2-(trifluoromethyl)phenyl]carbonyl}am ino)-N-{[3-(trifluoromethyl)pyridinyl]methyl}-1H-benzimi dazolecarboxamide, N-(3-chloromethylphenyl)(2-methoxyethyl)({[2-(trif luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo xamide, N-(3-chloromethylphenyl)(2,2-dimethylpropyl)({[2-( trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolec arboxamide, N-(3-chloromethylphenyl)cyclopropyl({[2-(trifluoro methyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamid N-(3-chloromethylphenyl)(2-methylpentanyl)({[2- (trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole carboxamide, N-(3-chloromethylphenyl)(1-methylcyclopropyl)({[2- (trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole carboxamide, 2-tert-butyl-N-(3-chloromethylphenyl)({[2-(trifluorom ethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide 2-tert-butyl-N-(3-chloromethylphenyl){[(2,5-dichlorop henyl)carbonyl]amino}-1H-benzimidazolecarboxamide, 2-tert-butyl-N-(3-chloromethylphenyl){[(2,5-dichlorop henyl)carbonyl]amino}-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl)[1-(trifluoromethyl)cycloprop yl]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzi midazolecarboxamide, N-(3-chloromethylphenyl)(methoxymethyl)methyl({ [2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole carboxamide, N-(2-chlorobenzyl)(methoxymethyl)methyl({[2-(trifl uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox amide, 6-{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro methylphenyl)(methoxymethyl)-1H-benzimidazolecarboxam ide, 6-{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro methylphenyl)methoxymethyl-1H-benzimidazolecarboxamid 6-{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro methylphenyl)(methoxymethyl)-1H-benzimidazolecarboxam ide, N-(3-chloromethylphenyl){[(2-chlorophenyl)carbonyl]am ino}(methoxymethyl)-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl){[(2-chloropyridinyl)carbo nyl]amino}(methoxymethyl)-1H-benzimidazolecarboxamide 6-{[(2-bromophenyl)carbonyl]amino}-N-(3-chloromethylphen yl)(methoxymethyl)-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl){[(2,6-dichlorophenyl)carbony l]amino}(methoxymethyl)-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony l]amino}(methoxymethyl)-1H-benzimidazolecarboxamide, 6-{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro methylphenyl)(methoxymethyl)-1H-benzimidazolecarboxam ide, 6-{[(2-chloro-3,6-difluorophenyl)carbonyl]amino}-N-(3-chlor omethylphenyl)(methoxymethyl)-1H-benzimidazolecarb oxamide, 6-{[(2-bromochlorophenyl)carbonyl]amino}-N-(3-chlorom ethylphenyl)(methoxymethyl)-1H-benzimidazolecarboxami 6-{[(2-bromofluorophenyl)carbonyl]amino}-N-(3-chlorom ethylphenyl)(methoxymethyl)-1H-benzimidazolecarboxami N-(3-chloromethylphenyl){[(2-chloromethylphenyl)ca rbonyl]amino}(methoxymethyl)-1H-benzimidazolecarboxam ide, N-(3-chloromethylphenyl){[(2-chloromethylphenyl)ca rbonyl]amino}(methoxymethyl)-1H-benzimidazolecarboxam ide, 6-{[(5-bromochlorophenyl)carbonyl]amino}-N-(3-chlorom ethylphenyl)(methoxymethyl)-1H-benzimidazolecarboxami 6-{[(2-bromochlorophenyl)carbonyl]amino}-N-(3-chlorom ethylphenyl)(methoxymethyl)-1H-benzimidazolecarboxami N-(3-chloromethylphenyl){[(2-chloromethylphenyl)ca rbonyl]amino}(methoxymethyl)-1H-benzimidazolecarboxam ide, N-(3-chloromethylphenyl)(methoxymethyl)({[5-methyl (trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole carboxamide, 6-({[2,5-bis(trifluoromethyl)phenyl]carbonyl}amino)-N-(3-ch loromethylphenyl)(methoxymethyl)-1H-benzimidazolec arboxamide, 6-({[2,4-bis(trifluoromethyl)phenyl]carbonyl}amino)-N-(3-ch loromethylphenyl)(methoxymethyl)-1H-benzimidazolec arboxamide, N-(3-chloromethylphenyl)({[5-fluoro(trifluoromethy l)phenyl]carbonyl}amino)(methoxymethyl)-1H-benzimidazole carboxamide, N-(3-chloromethylphenyl)({[2-chloro(trifluoromethy l)phenyl]carbonyl}amino)(methoxymethyl)-1H-benzimidazole carboxamide, N-(3-chloromethylphenyl)[({2-chloro[2-(propanyl oxy)ethoxy]phenyl}carbonyl)amino](methoxymethyl)-1H-benz imidazolecarboxamide, 6-({[2-chloro(2-ethoxyethoxy)phenyl]carbonyl}amino)-N-(3 -chloromethylphenyl)(methoxymethyl)-1H-benzimidazole- 4-carboxamide, 6-({[2-chloro(3-methoxypropyl)phenyl]carbonyl}amino)-N-( 3-chloromethylphenyl)(methoxymethyl)-1H-benzimidazole carboxamide, 6-({[5-(3-tert-butoxypropynyl)chlorophenyl]carbony l}amino)-N-(3-chloromethylphenyl)(methoxymethyl)-1H-b enzimidazolecarboxamide, 6-({[5-(3-tert-butoxypropyl)chlorophenyl]carbonyl}amino) -N-(3-chloromethylphenyl)(methoxymethyl)-1H-benzimida zolecarboxamide, 6-({[2-chloro(3-hydroxymethylbutyl)phenyl]carbonyl}am ino)-N-(3-chloromethylphenyl)(methoxymethyl)-1H-benzi midazolecarboxamide, 6-({[2-chloro(ethoxymethyl)phenyl]carbonyl}amino)-N-(3-c hloromethylphenyl)(methoxymethyl)-1H-benzimidazole carboxamide, 6-[({2-chloro[(2-ethoxyethoxy)methyl]phenyl}carbonyl)ami no]-N-(3-chloromethylphenyl)(methoxymethyl)-1H-benzim idazolecarboxamide, 6-({[2-chloro(2-cyclopropylethyl)phenyl]carbonyl}amino)- N-(3-chloromethylphenyl)(methoxymethyl)-1H-benzimidaz olecarboxamide, N-(3-chloromethylphenyl)({[2-chloro(2-phenylethyl) phenyl]carbonyl}amino)(methoxymethyl)-1H-benzimidazole-4 -carboxamide, N-(3-chloromethylphenyl)cyclopentyl({[2-(trifluoro methyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamid N-(3-chloromethylphenyl)cyclopentyl{[(2,5-dichloro phenyl)carbonyl]amino}-1H-benzimidazolecarboxamide, 6-{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro methylphenyl)cyclopentyl-1H-benzimidazolecarboxamide, 6-[{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro-2 -methylphenyl)[(2R)-tetrahydrofuranyl]-1H-benzimidazo lecarboxamide, N-(3-chloromethylphenyl){[(2,6-dichlorophenyl)carbony l]amino}[(2R)-tetrahydrofuranyl]-1H-benzimidazolec arboxamide, N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony l]amino}[(2R)-tetrahydrofuranyl]-1H-benzimidazolec arboxamide, N-(3-chloromethylphenyl)[(2S)oxopyrrolidinyl]-6 -({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidaz olecarboxamide, N-(3-chloromethylphenyl)[(2R)oxopyrrolidinyl]-6 -({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidaz olecarboxamide, N-(3-chloromethylphenyl)[2-oxo(pyrrolizinyl)eth yl]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzi midazolecarboxamide, N-(3-chloromethylphenyl)[2-(dimethylamino)oxoethyl ]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimi dazolecarboxamide, N-(3-chloromethylphenyl)[2-(methylamino)oxoethyl]- 6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimida zolecarboxamide, 2-chloro-N-(3-chloromethylphenyl)({[2-(trifluoromethy l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl)[(2-methoxyethyl)amino]({[ 2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole- 4-carboxamide, N-(3-chloromethylphenyl)[(2-hydroxyethyl)amino]({[ 2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole- 4-carboxamide, N-(3-chloromethylphenyl)(methylamino)({[2-(trifluo romethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxam ide, N-(3-chloromethylphenyl)(ethylamino)({[2-(trifluor omethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxami N-(3-chloromethylphenyl)[(2,2-dimethylpropyl)amino]-6 -({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidaz olecarboxamide, N-(3-chloromethylphenyl)(cyclopentylamino)({[2-(tr ifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecar boxamide, N-(3-chloromethylphenyl)(piperidinyl)({[2-(trif luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo xamide, N-(3-chloromethylphenyl)(4-methylpiperazinyl)({ [2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole carboxamide, 2-[bis(2-hydroxyethyl)amino]-N-(3-chloromethylphenyl) ({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazo lecarboxamide, N-(3-chloromethylphenyl)(dimethylamino)({[2-(trifl uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox amide, N-(3-chloromethylphenyl){[2-(morpholinyl)ethyl]ami no}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzi midazolecarboxamide, N-(3-chloromethylphenyl){[2-(dimethylamino)ethyl]amin o}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzim idazolecarboxamide, N-(3-chloromethylphenyl)(3-hydroxyazetidinyl)({ [2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole carboxamide, N-(3-chloromethylphenyl)[(3S)(dimethylamino)pyrrol izinyl]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1 H-benzimidazolecarboxamide, N-(3-chloromethylphenyl)[(3S)hydroxypyrroliziny l]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzim idazolecarboxamide, N-(3-chloromethylphenyl){[2-(diethylamino)ethyl]amino }({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimi dazolecarboxamide, N-(3-chloromethylphenyl){[2-(pyrrolizinyl)ethyl]am ino}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benz imidazolecarboxamide, N-(3-chloromethylphenyl){[3-(dimethylamino)propyl]ami no}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzi midazolecarboxamide, N-(3-chloromethylphenyl){[3-(dimethylamino)-2,2-dimet hylpropyl]amino}({[2-(trifluoromethyl)phenyl]carbonyl}am ino)-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl){[2-(dipropanylamino)ethyl ]amino}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-b enzimidazolecarboxamide, N-(3-chloromethylphenyl)(morpholinyl)({[2-(trif luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo xamide, 2-amino-N-(3-chloromethylphenyl)({[2-(trifluoromethyl )phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl)[(3-hydroxy-2,2-dimethylpropy l)amino]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H- benzimidazolecarboxamide, N-(3-chloromethylphenyl){[(3-methyloxetanyl)methyl ]amino}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-b enzimidazolecarboxamide, tert-butyl N-{4-[(3-chloromethylphenyl)carbamoyl]({[2-(trifluoro methyl)phenyl]carbonyl}amino)-1H-benzimidazolyl}glycinat N-{4-[(3-chloromethylphenyl)carbamoyl]({[2-(trifluoro methyl)phenyl]carbonyl}amino)-1H-benzimidazolyl}glycine, N-(3-chloromethylphenyl)[(3-hydroxy-2,2-dimethylpropy l)amino]methyl({[2-(trifluoromethyl)phenyl]carbonyl}a mino)-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl)[(3-methoxy-2,2-dimethylpropy l)amino]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H- benzimidazolecarboxamide, N-(3-chloromethylphenyl)(pyrrolizinyl)({[2-(tri fluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarb oxamide, 2-(azetidinyl)-N-(3-chloromethylphenyl)({[2-(trifl uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox amide, N-(3-chloromethylphenyl)(3-methoxyazetidinyl)({ [2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole carboxamide, N-(3-chloromethylphenyl)[(2-hydroxymethylpropyl)am ino]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benz imidazolecarboxamide, N-(3-chloromethylphenyl){[(2S)-tetrahydrofuranylme thyl]amino}({[2-(trifluoromethyl)phenyl]carbonyl}amino)- 1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl){[(2R)-tetrahydrofuranylme thyl]amino}({[2-(trifluoromethyl)phenyl]carbonyl}amino)- 1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl){[(2S)hydroxymethylbuta nyl]amino}({[2-(trifluoromethyl)phenyl]carbonyl}amino )-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl){[(2R)hydroxymethylbuta nyl]amino}({[2-(trifluoromethyl)phenyl]carbonyl}amino )-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl){[(2S)hydroxy-3,3-dimethyl butanyl]amino}({[2-(trifluoromethyl)phenyl]carbonyl}a mino)-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl)[(3-methoxy-2,2-dimethylpropy l)(methyl)amino]({[2-(trifluoromethyl)phenyl]carbonyl}am ino)-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl)[(3-methoxypropyl)amino]({ [2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole carboxamide, N-(3-chloromethylphenyl){[2-(propanyloxy)ethyl]ami no}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzi midazolecarboxamide, 2-[(2-tert-butoxyethyl)amino]-N-(3-chloromethylphenyl)-6 -({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidaz olecarboxamide, N-(3-chloromethylphenyl)[(2-methoxymethylpropyl)am ino]({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benz imidazolecarboxamide, N-(3-chloromethylphenyl){[2-(methylsulfanyl)ethyl]ami no}({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzi midazolecarboxamide, N-(3-chloromethylphenyl)(methylsulfanyl)({[2-(trif luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo xamide, N-(3-chloromethylphenyl)(methylsulfonyl)({[2-(trif luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo xamide, N-(3-chloromethylphenyl)(methylsulfinyl)({[2-(trif luoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbo xamide, 6-{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro methylphenyl)(dimethylamino)-1H-benzimidazolecarboxam ide, N-(3-chloromethylphenyl){[(2,6-dichlorophenyl)carbony l]amino}(dimethylamino)-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl){[(2,4-dichlorophenyl)carbony l]amino}(dimethylamino)-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony l]amino}(dimethylamino)-1H-benzimidazolecarboxamide, 6-{[(2-bromofluorophenyl)carbonyl]amino}-N-(3-chlorom ethylphenyl)(dimethylamino)-1H-benzimidazolecarboxami 6-{[(2-bromochlorophenyl)carbonyl]amino}-N-(3-chlorom ethylphenyl)(dimethylamino)-1H-benzimidazolecarboxami 6-({[2-chloro(cyclopropylethynyl)phenyl]carbonyl}amino)- N-(3-chloromethylphenyl)(dimethylamino)-1H-benzimidaz olecarboxamide, N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony l]amino}[(3-hydroxy-2,2-dimethylpropyl)amino]-1H-benzimi dazolecarboxamide, N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony l]amino}[(3-methoxy-2,2-dimethylpropyl)amino]-1H-benzimi dazolecarboxamide, N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony l]amino}[(2-hydroxymethylpropyl)amino]-1H-benzimidazo lecarboxamide, N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony l]amino}[(2-methoxymethylpropyl)amino]-1H-benzimidazo lecarboxamide, N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony l]amino}{[2-(propanyloxy)ethyl]amino}-1H-benzimidazol ecarboxamide, 6-[{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro-2 -methylphenyl){[2-(propanyloxy)ethyl]amino}-1H-benzim idazolecarboxamide, 2-[(2-tert-butoxyethyl)amino]{[(2-chlorofluorophenyl) carbonyl]amino}-N-(3-chloromethylphenyl)-1H-benzimidazol ecarboxamide, 6-[{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro-2 -methylphenyl)[(3-methoxy-2,2-dimethylpropyl)amino]-1H-b enzimidazolecarboxamide, 6-[{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro-2 -methylphenyl)[(2-methoxymethylpropyl)amino]-1H-benzi midazolecarboxamide, 6-[{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro-2 -methylphenyl){[(2S)-tetrahydrofuranylmethyl]amino}-1 H-benzimidazolecarboxamide, 6-[{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro-2 -methylphenyl){[(2R)-tetrahydrofuranylmethyl]amino}-1 H-benzimidazolecarboxamide, 6-[{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro-2 -methylphenyl)[(3-hydroxy-2,2-dimethylpropyl)amino]-1H-b enzimidazolecarboxamide, 6-[{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro-2 -methylphenyl){[(2S)hydroxymethylbutanyl]amino} -1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl)(dimethylamino)({[2-(trifl uoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarbox amide, N-(4-tert-buthylphenyl)(dimethylamino)({[2-(trifluoro methyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamid N-(2,3-dihydro-1H-indenyl)(dimethylamino)({[2-(tri fluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarb oxamide, 6-{[(2-chlorofluorophenyl)carbonyl]amino}-N-(3-chloro methylphenyl)(dimethylamino)-1H-benzimidazolecarboxam ide, N-(3-chloromethylphenyl){[(2,6-dichlorophenyl)carbony l]amino}(dimethylamino)-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony l]amino}(dimethylamino)-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl)cyclopropyl{[(2,5-dichloro phenyl)carbonyl]amino}-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl)cyclopropyl{[(2,5-dichloro phenyl)carbonyl]amino}-1H-benzimidazolecarboxamide, N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony l]amino}(1-methylcyclopropyl)-1H-benzimidazolecarboxa mide, N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony l]amino}(1-methylcyclopropyl)-1H-benzimidazolecarboxa mide, N-(3-chloromethylphenyl)(methoxymethyl)({[2-(methy lsulfonyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxa mide, N-(3-chloromethylphenyl){[(2,5-dichlorophenyl)carbony l]amino}(2-methoxyethyl)-1H-benzimidazolecarboxamide, 2-(methoxymethyl)-N-phenyl({[2-(trifluoromethyl)phenyl]c arbonyl}amino)-1H-benzimidazolecarboxamide, 2-(methoxymethyl)-N-propyl({[2-(trifluoromethyl)phenyl]c arbonyl}amino)-1H-benzimidazolecarboxamide, 2-(methoxymethyl)-N-(pyridinyl)({[2-(trifluoromethyl) phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, N-benzyl(methoxymethyl)({[2-(trifluoromethyl)phenyl]c arbonyl}amino)-1H-benzimidazolecarboxamide, N-(cyclohexylmethyl)(methoxymethyl)({[2-(trifluoromet hyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, 2-(methoxymethyl)-N-(naphthalenyl)({[2-(trifluorometh yl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, 2-(methoxymethyl)-N-(thiophenyl)({[2-(trifluoromethyl )phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, N-(2,1,3-benzothiadiazolyl)(methoxymethyl)({[2-(tr ifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolecar boxamide, N-(1,1-dioxidebenzothiophenyl)(methoxymethyl)({ [2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole carboxamide, 2-(methoxymethyl)-N-(thiophenylmethyl)({[2-(trifluoro methyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamid N-(1H-indolyl)(methoxymethyl)({[2-(trifluoromethyl )phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, N-(1,3-benzothiazolyl)(methoxymethyl)({[2-(trifluo romethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxam ide, N-(2,2-dimethylpropyl)(methoxymethyl)({[2-(trifluorom ethyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide 2-(methoxymethyl)-N-(thiophenyl)({[2-(trifluoromethyl )phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, N-(5-chloro-1,3-benzoxazolyl)(methoxymethyl)({[2-( trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolec arboxamide, N-(2-benzylphenyl)(methoxymethyl)({[2-(trifluoromethy l)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, 2-(methoxymethyl)-N-(quinolinyl)({[2-(trifluoromethyl )phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, N-(cycloheptylmethyl)(methoxymethyl)({[2-(trifluorome thyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamide, N-(1,3-benzoxazolyl)(methoxymethyl)({[2-(trifluoro methyl)phenyl]carbonyl}amino)-1H-benzimidazolecarboxamid N-(6-chloro-1,3-benzoxazolyl)(methoxymethyl)({[2-( trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazolec arboxamide, N-[3-chloro(hydroxymethyl)phenyl](methoxymethyl)({ [2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole carboxamide, N-(3-chloromethylphenyl){[(3-fluoropyridinyl)carbo nyl]amino}(methoxymethyl)-1H-benzimidazolecarboxamide N-(3-chloromethylphenyl){[(3-chloropyridinyl)carbo nyl]amino}(methoxymethyl)-1H-benzimidazolecarboxamide N-(3-chloromethylphenyl){[(3,5-dichloropyridinyl)c arbonyl]amino}(methoxymethyl)-1H-benzimidazolecarboxa mide, 6-{[(5-butoxychlorophenyl)carbonyl]amino}-N-(3-chloro methylphenyl)(methoxymethyl)-1H-benzimidazolecarboxam ide, 6-({[2-chloro(2,2-difluoroethoxy)phenyl]carbonyl}amino)- N-(3-chloromethylphenyl)(methoxymethyl)-1H-benzimidaz olecarboxamide, and N-(3-chloromethylphenyl)({[2-chloro(4,4,4-trifluor obutoxy)phenyl]carbonyl}amino)(methoxymethyl)-1H-benzimi dazolecarboxamide, or a tautomer or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition containing a compound selected from the group consisting of the heterocyclic derivative according to any one of claims 1 to 7, its tautomerand a pharmaceutically acceptable salt thereof as an active ingredient.
9. An mPGES-1 inhibiting agent containing a compound selected from the group consisting of the heterocyclic derivative according to any one of claims 1 to 7, its tautomer and a pharmaceutically acceptable salt thereof as an active ingredient.
10. An agent containing a compound selected from the group consisting of the heterocyclic derivative according to any one of claims 1 to 7, its tautomer and a pharmaceutically acceptable salt thereof as an active ingredient, for the prevention or treatment of inflammatory bowel disease, irritable bowel syndrome, migraine, headache, low back pain, spinal stenosis, herniated disk, temporomandibular joint disorders, cervical syndrome, cervical spondylosis, endometriosis, adenomyosis, preterm labour and delivery, threatened premature delivery, dysmenorrhea, overactive bladder, nocturia, interstitial cystitis, neurodegenerative disease, psoriasis, rheumatoid arthritis, rheumatic fever, fibromyalgia, neuralgia, complex regional pain syndrome, fascial dysfunction, viral infections, bacterial infection, mycosis, burn, inflammation and pain after operation, injury and dental extraction, malignant tumors, atherosclerosis, stroke, gout, arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tenosynovitis, ligament ossification, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, conjunctivitis, iritis, scleritis, uveitis, wound therapy, dermatitis, eczema, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic disease, familial adenomatous polyposis, scleroderma, bursitis, leiomyoma of uterus, or a pain from cancer.
11. The agent according to claim 10, wherein the neurodegenerative disease is Alzheimer's disease or multiple sclerosis.
12. The agent according to claim 10, wherein the viral infectious disease is influenza, common cold, zoster or AIDS.
13. The agent according to claim 10, wherein the malignant tumor is colon cancer, breast cancer, lung cancer or prostatic cancer.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2011-179134 | 2011-08-18 | ||
JP2011179134 | 2011-08-18 | ||
PCT/JP2012/070902 WO2013024898A1 (en) | 2011-08-18 | 2012-08-17 | Heterocyclic derivative and pharmaceutical drug |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ620610A NZ620610A (en) | 2016-04-29 |
NZ620610B2 true NZ620610B2 (en) | 2016-08-02 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2012295805B2 (en) | Heterocyclic derivative and pharmaceutical drug | |
ES2588752T3 (en) | Sulfonamide compounds that have antagonistic TRPM8 activity | |
CA2777565A1 (en) | Hematopoietic growth factor mimetic diphenylamine small molecule compounds and their uses | |
JP2010504342A (en) | Rho kinase inhibitor | |
JP2009531445A (en) | p38 inhibitors and methods of use thereof | |
JP2012502986A (en) | Modulator of P2X3 receptor activity | |
TW200417546A (en) | New compounds | |
AU2017239625B2 (en) | Novel heterocyclic carboxamides as modulators of kinase activity | |
WO2007136668A9 (en) | N-benzoyl-and n-benzylpyrrolidin-3-ylamines as histamine-3 antagonists | |
CN110845490B (en) | 2-acylaminothiazole derivative or salt thereof | |
KR20160073413A (en) | Quinazolinone and isoquinolinone derivative | |
AU2017385292A1 (en) | Antitumor agent and bromodomain inhibitor | |
JP2006169138A (en) | Pyrazolopyridinepyrazolone derivative, its acid addition salt and pde inhibitor | |
NZ620610B2 (en) | Heterocyclic derivative and pharmaceutical drug | |
WO2019119481A1 (en) | Carbazole derivative kinase inhibitor | |
CN114573567B (en) | Indazole cyclotriazole compound and preparation method and application thereof | |
WO2023127883A1 (en) | Indazole compound and pharmaceutical |