TWI657079B - 苯并咪唑及咪唑并吡啶甲脒化合物 - Google Patents
苯并咪唑及咪唑并吡啶甲脒化合物 Download PDFInfo
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- TWI657079B TWI657079B TW105115008A TW105115008A TWI657079B TW I657079 B TWI657079 B TW I657079B TW 105115008 A TW105115008 A TW 105115008A TW 105115008 A TW105115008 A TW 105115008A TW I657079 B TWI657079 B TW I657079B
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- Prior art keywords
- hydroxy
- formamidine
- fluorophenyl
- chloro
- amino
- Prior art date
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- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 title description 3
- ZMZFZXPTSNKLSW-UHFFFAOYSA-N 1H-imidazo[4,5-b]pyridine-2-carboximidamide Chemical class C1=CC=C2NC(C(=N)N)=NC2=N1 ZMZFZXPTSNKLSW-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 277
- 239000003112 inhibitor Substances 0.000 claims abstract description 183
- 150000003839 salts Chemical class 0.000 claims abstract description 119
- 238000000034 method Methods 0.000 claims abstract description 48
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
- 230000001404 mediated effect Effects 0.000 claims abstract description 6
- -1 haloalkane Radical Chemical class 0.000 claims description 352
- 239000003814 drug Substances 0.000 claims description 107
- 239000000203 mixture Substances 0.000 claims description 84
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 80
- 125000000217 alkyl group Chemical group 0.000 claims description 80
- 125000000623 heterocyclic group Chemical group 0.000 claims description 78
- 125000001072 heteroaryl group Chemical group 0.000 claims description 64
- 125000003118 aryl group Chemical group 0.000 claims description 59
- 125000003545 alkoxy group Chemical group 0.000 claims description 58
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 58
- 125000001424 substituent group Chemical group 0.000 claims description 57
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 51
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 51
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 45
- 239000003795 chemical substances by application Substances 0.000 claims description 44
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 42
- 238000011282 treatment Methods 0.000 claims description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 37
- 201000010099 disease Diseases 0.000 claims description 35
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 34
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 33
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 31
- 108090000623 proteins and genes Proteins 0.000 claims description 31
- 230000000694 effects Effects 0.000 claims description 26
- 206010028980 Neoplasm Diseases 0.000 claims description 23
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 23
- 150000001412 amines Chemical class 0.000 claims description 19
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 239000002246 antineoplastic agent Substances 0.000 claims description 14
- 102000004169 proteins and genes Human genes 0.000 claims description 14
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 12
- 201000011510 cancer Diseases 0.000 claims description 11
- 230000002401 inhibitory effect Effects 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 229960005486 vaccine Drugs 0.000 claims description 11
- 125000006647 (C3-C15) cycloalkyl group Chemical group 0.000 claims description 10
- 229940127089 cytotoxic agent Drugs 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 8
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 8
- 238000002560 therapeutic procedure Methods 0.000 claims description 8
- 102000004127 Cytokines Human genes 0.000 claims description 7
- 108090000695 Cytokines Proteins 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 125000002950 monocyclic group Chemical group 0.000 claims description 7
- ZVKMPCIYSWINQG-UHFFFAOYSA-N N'-(3-chloro-4-fluorophenyl)-6,7-difluoro-N-hydroxy-3H-benzimidazole-4-carboximidamide Chemical compound ClC=1C=C(C=CC=1F)NC(=NO)C1=CC(=C(C=2N=CNC=21)F)F ZVKMPCIYSWINQG-UHFFFAOYSA-N 0.000 claims description 6
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 6
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 5
- 230000001506 immunosuppresive effect Effects 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- PHDWADHAFGADGX-UHFFFAOYSA-N 6-chloro-N'-(3-chloro-4-fluorophenyl)-N-hydroxy-1H-benzimidazole-4-carboximidamide Chemical compound ClC=1C=C(C2=C(N=CN2)C=1)C(NC1=CC(=C(C=C1)F)Cl)=NO PHDWADHAFGADGX-UHFFFAOYSA-N 0.000 claims description 4
- DTWHYGIVYKPWEM-UHFFFAOYSA-N 7-bromo-N'-(3-chloro-4-fluorophenyl)-N-hydroxy-3H-benzimidazole-4-carboximidamide Chemical compound BrC1=CC=C(C2=C1N=CN2)C(NC1=CC(=C(C=C1)F)Cl)=NO DTWHYGIVYKPWEM-UHFFFAOYSA-N 0.000 claims description 4
- VPWDYMGEKQBIOX-UHFFFAOYSA-N N'-(3-chloro-4-fluorophenyl)-7-fluoro-N-hydroxy-3H-benzimidazole-4-carboximidamide Chemical compound ClC=1C=C(C=CC=1F)NC(=NO)C1=CC=C(C=2N=CNC=21)F VPWDYMGEKQBIOX-UHFFFAOYSA-N 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- SZEDBAHUAYBZQR-UHFFFAOYSA-N 2-amino-N'-(3-bromo-4-fluorophenyl)-7-fluoro-N-hydroxy-3H-benzimidazole-4-carboximidamide Chemical compound NC=1NC2=C(N=1)C(=CC=C2C(NC1=CC(=C(C=C1)F)Br)=NO)F SZEDBAHUAYBZQR-UHFFFAOYSA-N 0.000 claims description 3
- WZJSSFPEIFJITD-UHFFFAOYSA-N 2-amino-N'-(3-bromophenyl)-7-fluoro-N-hydroxy-3H-benzimidazole-4-carboximidamide Chemical compound NC=1NC2=C(N=1)C(=CC=C2C(NC1=CC(=CC=C1)Br)=NO)F WZJSSFPEIFJITD-UHFFFAOYSA-N 0.000 claims description 3
- DBIHNTUXQRFBBC-UHFFFAOYSA-N 2-amino-N'-(3-chloro-4-fluorophenyl)-6,7-difluoro-N-hydroxy-3H-benzimidazole-4-carboximidamide Chemical compound NC=1NC2=C(N=1)C(=C(C=C2C(NC1=CC(=C(C=C1)F)Cl)=NO)F)F DBIHNTUXQRFBBC-UHFFFAOYSA-N 0.000 claims description 3
- UGSTXFFWSGQALS-UHFFFAOYSA-N 2-amino-N'-(3-chlorophenyl)-7-fluoro-N-hydroxy-3H-benzimidazole-4-carboximidamide Chemical compound NC=1NC2=C(N=1)C(=CC=C2C(NC1=CC(=CC=C1)Cl)=NO)F UGSTXFFWSGQALS-UHFFFAOYSA-N 0.000 claims description 3
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 3
- OQLZINXFSUDMHM-UHFFFAOYSA-N Acetamidine Chemical compound CC(N)=N OQLZINXFSUDMHM-UHFFFAOYSA-N 0.000 claims description 3
- 206010062016 Immunosuppression Diseases 0.000 claims description 3
- 208000036142 Viral infection Diseases 0.000 claims description 3
- 230000012010 growth Effects 0.000 claims description 3
- 230000035755 proliferation Effects 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 230000009385 viral infection Effects 0.000 claims description 3
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 2
- DRZGZRZPQNZOPQ-UHFFFAOYSA-N 2-amino-6,7-difluoro-N'-[4-fluoro-3-(trifluoromethyl)phenyl]-N-hydroxy-3H-benzimidazole-4-carboximidamide Chemical compound NC=1NC2=C(N=1)C(=C(C=C2C(NC1=CC(=C(C=C1)F)C(F)(F)F)=NO)F)F DRZGZRZPQNZOPQ-UHFFFAOYSA-N 0.000 claims description 2
- OOQPOTADUXQCCR-UHFFFAOYSA-N 2-amino-7-fluoro-N'-[4-fluoro-3-(trifluoromethyl)phenyl]-N-hydroxy-3H-benzimidazole-4-carboximidamide Chemical compound NC=1NC2=C(N=1)C(=CC=C2C(NC1=CC(=C(C=C1)F)C(F)(F)F)=NO)F OOQPOTADUXQCCR-UHFFFAOYSA-N 0.000 claims description 2
- TXWZQIMDNKUEQF-UHFFFAOYSA-N 2-amino-N'-(3-bromo-4-fluorophenyl)-6,7-difluoro-N-hydroxy-3H-benzimidazole-4-carboximidamide Chemical compound NC=1NC2=C(N=1)C(=C(C=C2C(NC1=CC(=C(C=C1)F)Br)=NO)F)F TXWZQIMDNKUEQF-UHFFFAOYSA-N 0.000 claims description 2
- HZKKBFRSFIBMMO-UHFFFAOYSA-N 2-amino-N'-(3-bromophenyl)-6,7-difluoro-N-hydroxy-3H-benzimidazole-4-carboximidamide Chemical compound NC=1NC2=C(N=1)C(=C(C=C2C(NC1=CC(=CC=C1)Br)=NO)F)F HZKKBFRSFIBMMO-UHFFFAOYSA-N 0.000 claims description 2
- LTEZAKDOAUZMHP-UHFFFAOYSA-N 2-amino-N'-(3-chloro-4-fluorophenyl)-7-fluoro-N-hydroxy-3H-benzimidazole-4-carboximidamide Chemical compound NC=1NC2=C(N=1)C(=CC=C2C(NC1=CC(=C(C=C1)F)Cl)=NO)F LTEZAKDOAUZMHP-UHFFFAOYSA-N 0.000 claims description 2
- DIZPLHZORLKMOQ-UHFFFAOYSA-N 2-amino-N'-(3-chlorophenyl)-6,7-difluoro-N-hydroxy-3H-benzimidazole-4-carboximidamide Chemical compound NC=1NC2=C(N=1)C(=C(C=C2C(NC1=CC(=CC=C1)Cl)=NO)F)F DIZPLHZORLKMOQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- ZOJKONNIMMYXNL-UHFFFAOYSA-N N'-(3-chloro-4-fluorophenyl)-6,7-difluoro-N-hydroxy-2-(hydroxymethyl)-3H-benzimidazole-4-carboximidamide Chemical compound ClC=1C=C(C=CC=1F)NC(=NO)C1=CC(=C(C=2N=C(NC=21)CO)F)F ZOJKONNIMMYXNL-UHFFFAOYSA-N 0.000 claims description 2
- LHCVVTPTUFLRLC-UHFFFAOYSA-N N'-(3-chloro-4-fluorophenyl)-N-hydroxy-2-(methoxymethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide Chemical compound ClC=1C=C(C=CC=1F)NC(=NO)C1=C2C(=NC=C1)N=C(N2)COC LHCVVTPTUFLRLC-UHFFFAOYSA-N 0.000 claims description 2
- QYSPOJDBIHMAMH-UHFFFAOYSA-N N'-(3-chloro-4-fluorophenyl)-N-hydroxy-2-(methylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide Chemical compound ClC=1C=C(C=CC=1F)NC(=NO)C1=C2C(=NC=C1)N=C(N2)NC QYSPOJDBIHMAMH-UHFFFAOYSA-N 0.000 claims description 2
- WZBUGDROWLOZQJ-UHFFFAOYSA-N N'-(3-chloro-4-fluorophenyl)-N-hydroxy-2-(methylaminomethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide Chemical compound ClC=1C=C(C=CC=1F)NC(=NO)C1=C2C(=NC=C1)N=C(N2)CNC WZBUGDROWLOZQJ-UHFFFAOYSA-N 0.000 claims description 2
- PXFXHIFJSHNNAN-UHFFFAOYSA-N N'-(3-chloro-4-fluorophenyl)-N-hydroxy-2-[2-(methylamino)ethyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide Chemical compound ClC=1C=C(C=CC=1F)NC(=NO)C1=C2C(=NC=C1)NC(=N2)CCNC PXFXHIFJSHNNAN-UHFFFAOYSA-N 0.000 claims description 2
- NDWORAUPSZDAKB-UHFFFAOYSA-N N'-(3-chlorophenyl)-2-[(dimethylamino)methyl]-6,7-difluoro-N-hydroxy-3H-benzimidazole-4-carboximidamide Chemical compound ClC=1C=C(C=CC=1)NC(=NO)C1=CC(=C(C2=C1NC(=N2)CN(C)C)F)F NDWORAUPSZDAKB-UHFFFAOYSA-N 0.000 claims description 2
- DSAKIHQFMCDCET-UHFFFAOYSA-N N'-(3-chlorophenyl)-6,7-difluoro-N-hydroxy-2-(methylaminomethyl)-3H-benzimidazole-4-carboximidamide Chemical compound ClC=1C=C(C=CC=1)NC(=NO)C1=CC(=C(C2=C1NC(=N2)CNC)F)F DSAKIHQFMCDCET-UHFFFAOYSA-N 0.000 claims description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 2
- 125000006317 cyclopropyl amino group Chemical group 0.000 claims description 2
- 239000003018 immunosuppressive agent Substances 0.000 claims description 2
- 229960004854 viral vaccine Drugs 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 12
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 claims 5
- DPMKCLMUYWVMNW-UHFFFAOYSA-N N'-(3-chloro-4-fluorophenyl)-N-hydroxy-3-methylimidazo[4,5-b]pyridine-7-carboximidamide Chemical compound ClC=1C=C(C=CC=1F)NC(=NO)C1=C2C(=NC=C1)N(C=N2)C DPMKCLMUYWVMNW-UHFFFAOYSA-N 0.000 claims 3
- VFQWPYTWIAGEHU-UHFFFAOYSA-N 2-[2-(azetidin-1-yl)ethyl]-N'-(3-chloro-4-fluorophenyl)-N-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide Chemical compound N1(CCC1)CCC=1NC=2C(=NC=CC=2C(NC2=CC(=C(C=C2)F)Cl)=NO)N=1 VFQWPYTWIAGEHU-UHFFFAOYSA-N 0.000 claims 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 2
- 101001037256 Homo sapiens Indoleamine 2,3-dioxygenase 1 Proteins 0.000 claims 2
- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 claims 2
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims 2
- GHXUMWVZYRFZEB-UHFFFAOYSA-N 2-[(1-aminocyclopropyl)methylamino]-N'-(3-chloro-4-fluorophenyl)-N-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide Chemical compound NC1(CC1)CNC=1NC=2C(=NC=CC=2C(NC2=CC(=C(C=C2)F)Cl)=NO)N=1 GHXUMWVZYRFZEB-UHFFFAOYSA-N 0.000 claims 1
- OPCOXUMJTKYQJZ-UHFFFAOYSA-N 2-[2-(1-aminocyclopropyl)ethylamino]-N'-(3-chloro-4-fluorophenyl)-N-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide Chemical compound NC1(CC1)CCNC=1NC=2C(=NC=CC=2C(NC2=CC(=C(C=C2)F)Cl)=NO)N=1 OPCOXUMJTKYQJZ-UHFFFAOYSA-N 0.000 claims 1
- VSDPBRXXOYZWOZ-UHFFFAOYSA-N 2-[2-(2-azabicyclo[4.1.0]heptan-2-yl)ethylamino]-N'-(3-chloro-4-fluorophenyl)-N-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide Chemical compound C12N(CCCC2C1)CCNC=1NC=2C(=NC=CC=2C(NC2=CC(=C(C=C2)F)Cl)=NO)N=1 VSDPBRXXOYZWOZ-UHFFFAOYSA-N 0.000 claims 1
- KVVOKCZMKLLPAH-UHFFFAOYSA-N 2-[2-(3-azabicyclo[3.3.1]nonan-3-yl)ethyl]-N'-(3-chloro-4-fluorophenyl)-N-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide Chemical compound C12CN(CC(CCC1)C2)CCC=1NC=2C(=NC=CC=2C(NC2=CC(=C(C=C2)F)Cl)=NO)N=1 KVVOKCZMKLLPAH-UHFFFAOYSA-N 0.000 claims 1
- LNBYNCDNINZRQQ-UHFFFAOYSA-N 2-[2-(4-benzylpiperidin-1-yl)ethyl]-N'-(3-chloro-4-fluorophenyl)-N-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide Chemical compound C(C1=CC=CC=C1)C1CCN(CC1)CCC=1NC=2C(=NC=CC=2C(NC2=CC(=C(C=C2)F)Cl)=NO)N=1 LNBYNCDNINZRQQ-UHFFFAOYSA-N 0.000 claims 1
- OVIFLRSLJGCCCY-UHFFFAOYSA-N 2-[2-(benzenesulfonamido)ethylamino]-N'-(3-chloro-4-fluorophenyl)-N-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide Chemical compound ClC=1C=C(C=CC=1F)NC(=NO)C1=C2C(=NC=C1)N=C(N2)NCCNS(=O)(=O)C1=CC=CC=C1 OVIFLRSLJGCCCY-UHFFFAOYSA-N 0.000 claims 1
- BFEPNJKANROCEJ-UHFFFAOYSA-N 2-amino-N'-(3-bromophenyl)-6-fluoro-N-hydroxy-1H-benzimidazole-4-carboximidamide Chemical compound NC1=NC2=C(N1)C(=CC(=C2)F)C(NC1=CC(=CC=C1)Br)=NO BFEPNJKANROCEJ-UHFFFAOYSA-N 0.000 claims 1
- ABRWCYCOKDNAMV-UHFFFAOYSA-N 2-amino-N'-(3-chloro-4-fluorophenyl)-6-fluoro-N-hydroxy-1H-benzimidazole-4-carboximidamide Chemical compound NC1=NC2=C(N1)C(=CC(=C2)F)C(NC1=CC(=C(C=C1)F)Cl)=NO ABRWCYCOKDNAMV-UHFFFAOYSA-N 0.000 claims 1
- AJBCBJWXEQHXRW-UHFFFAOYSA-N 2-amino-N'-(3-chlorophenyl)-6-fluoro-N-hydroxy-1H-benzimidazole-4-carboximidamide Chemical compound NC1=NC2=C(N1)C(=CC(=C2)F)C(NC1=CC(=CC=C1)Cl)=NO AJBCBJWXEQHXRW-UHFFFAOYSA-N 0.000 claims 1
- ZZIQIFKRUIIZEX-UHFFFAOYSA-N 2-chloro-N'-(3-chloro-4-fluorophenyl)-6,7-difluoro-N-hydroxy-3H-benzimidazole-4-carboximidamide Chemical compound ClC1=NC2=C(N1)C(=CC(=C2F)F)C(NC1=CC(=C(C=C1)F)Cl)=NO ZZIQIFKRUIIZEX-UHFFFAOYSA-N 0.000 claims 1
- PCBZRNYXXCIELG-WYFCWLEVSA-N COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 Chemical compound COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 PCBZRNYXXCIELG-WYFCWLEVSA-N 0.000 claims 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims 1
- MEOBAGWQVLEBAN-UHFFFAOYSA-N ClC=1C=C(C=CC=1F)N(C(=NO)C1=C2C(=NC=C1)N=CN2)C Chemical compound ClC=1C=C(C=CC=1F)N(C(=NO)C1=C2C(=NC=C1)N=CN2)C MEOBAGWQVLEBAN-UHFFFAOYSA-N 0.000 claims 1
- VFBUKYKJZVGASA-UHFFFAOYSA-N N'-(3-bromo-4-fluorophenyl)-6,7-difluoro-N-hydroxy-2-(2-pyrrolidin-1-ylethylamino)-3H-benzimidazole-4-carboximidamide Chemical compound BrC=1C=C(C=CC=1F)NC(=NO)C1=CC(=C(C2=C1NC(=N2)NCCN1CCCC1)F)F VFBUKYKJZVGASA-UHFFFAOYSA-N 0.000 claims 1
- NIVNSIQWRQDIFV-UHFFFAOYSA-N N'-(3-bromo-4-fluorophenyl)-N-hydroxy-2-(methylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide Chemical compound BrC=1C=C(C=CC=1F)NC(=NO)C1=C2C(=NC=C1)N=C(N2)NC NIVNSIQWRQDIFV-UHFFFAOYSA-N 0.000 claims 1
- KISKTBBEJBDKKO-CQSZACIVSA-N N'-(3-bromophenyl)-6,7-difluoro-N-hydroxy-2-[[(3R)-1-(2-methoxyethyl)pyrrolidin-3-yl]amino]-3H-benzimidazole-4-carboximidamide Chemical compound BrC=1C=C(C=CC=1)NC(=NO)C1=CC(=C(C2=C1NC(=N2)N[C@H]1CN(CC1)CCOC)F)F KISKTBBEJBDKKO-CQSZACIVSA-N 0.000 claims 1
- DKXQAXUBFUNCOO-UHFFFAOYSA-N N'-(3-bromophenyl)-N-hydroxy-2-(2-piperidin-1-ylethyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide Chemical compound BrC=1C=C(C=CC=1)NC(=NO)C1=C2C(=NC=C1)N=C(N2)CCN1CCCCC1 DKXQAXUBFUNCOO-UHFFFAOYSA-N 0.000 claims 1
- OMABCNBBSPSENF-UHFFFAOYSA-N N'-(3-bromophenyl)-N-hydroxy-2-(methylamino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide Chemical compound BrC=1C=C(C=CC=1)NC(=NO)C1=C2C(=NC=C1)N=C(N2)NC OMABCNBBSPSENF-UHFFFAOYSA-N 0.000 claims 1
- GHCXWTXFOJZKIF-UHFFFAOYSA-N N'-(3-chloro-4-fluorophenyl)-2-(ethylaminomethyl)-N-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide Chemical compound ClC=1C=C(C=CC=1F)NC(=NO)C1=C2C(=NC=C1)NC(=N2)CNCC GHCXWTXFOJZKIF-UHFFFAOYSA-N 0.000 claims 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
本發明提供式I之吲哚胺2,3-二氧酶1(IDO1)抑制劑:
或其醫藥上可接受之鹽,其中X、L、n、m、R1、R2a、R2b、Rn、Rm及Rt係如本文中所定義;以及包括式I化合物或其醫藥上可接受之鹽之醫藥組合物,及使用其治療由IDO1介導之病況的方法。
Description
本發明概言之係關於吲哚胺2,3-二氧酶1(IDO1)活性之抑制劑及其使用及製造方法。
由可誘導型含血紅素之酶吲哚胺2,3-二氧酶1(IDO1)分解代謝必需胺基酸色胺酸係維持許多癌症中之免疫抑制微環境的重要路徑。IDO1催化色胺酸降解成犬尿胺酸,且其對免疫抑制之效應係由於降低之色胺酸可用性及色胺酸代謝物之產生,從而對細胞毒性T淋巴球產生多方面負面效應、以及免疫抑制調節性T細胞之擴增。IDO1在多種癌症中升高,係藉由化學療法、靶向療法或免疫療法誘導。腫瘤微環境中之IDO1表現與多種癌症中之較差預後相關。IDO1抑制劑經放置以增強多種腫瘤學治療(包括免疫療法、靶向藥劑及化學療法)之效能。實際上,依帕卡司他(epacadostat)(INCB24360)(一種有效力之選擇性IDO1抑制劑)進入臨床試驗且與伊匹單抗(ipilimumab)(抗CTLA4)組合在黑色素瘤中展示活性。
除上述外,已顯示IDO1在慢性感染、HIV及AIDS、自體免疫疾病或病症(例如,類風濕性關節炎)、及免疫耐受、防止子宮中胎兒排斥中起作用。IDO1之抑制亦可為用於患有神經或神經精神疾病或病症(例如抑鬱症)之患者之重要治療策略。
業內仍需要可用於治療由IDO1介導之增殖病症或疾病的另外治療劑。
本發明提供用作IDO1之抑制劑之化合物。本揭示內容亦提供組合物(包括醫藥組合物)、包括該等化合物之套組及使用該等化合物之方法。本文提供之化合物可用於治療由IDO1介導之疾病、病症或病況。本揭示內容亦提供用於療法中之化合物。本揭示內容進一步提供用於治療由IDO1介導之疾病、病症或病況之方法中的化合物。此外,本揭示內容提供化合物之用途,其用於製造用於治療由IDO1介導之疾病、病症或病況的藥劑。
在一個態樣中,提供具有式I之結構之化合物:
其中R1係單環或二環芳基或雜芳基,其中每一單環或二環芳基或雜芳基視情況經1個、2個或3個獨立地選自以下之取代基取代:羥基、鹵基、-CN、C1-6鹵烷基、C1-6鹵烷氧基、C1-6烷氧基、C1-6烷基、C2-6烯基、C2-6炔基及C3-6環烷基,其中可選取代基中之二者可接合形成另外部分飽和雜環;且其中每一C1-6烷氧基、C1-6烷基、C2-6烯基、C2-6炔基及C3-6環烷基視情況經1個、2個或3個獨立地選自以下之取代基取代:羥基、鹵基、-CN、-N(R20)(R22)及C3-6環烷基;X係N或CR2c;
R2a、R2b及R2c獨立地係氫、羥基、鹵基、CN、C1-6鹵烷基、C1-6鹵烷氧基、C1-6烷氧基或C1-6烷基;R2d及R2e獨立地係氫、C1-6鹵烷基、C1-6鹵烷氧基或C1-6烷基;n及m獨立地係0、1、2或3;每一Rn及Rm獨立地係氫、羥基、鹵基、C1-6烷氧基、C1-6烷基、C3-6環烷基、芳基、雜環基或雜芳基;或兩個Rn或Rm接合形成C3-6環烷基;且其中每一C1-6烷氧基、C1-6烷基、C3-6環烷基、芳基、雜環基或雜芳基視情況經1個、2個或3個獨立地選自以下之取代基取代:羥基、鹵基、-CN、-N(R20)(R22)、C2-6烯基、C2-6炔基、C1-6鹵烷基、C1-6鹵烷氧基、C1-6烷氧基、C1-6烷基及C3-6環烷基;L係鍵、-NR3-、-C(O)-NR3-、-NR3-C(O)-、-NR3SO2-、-NR3SO2-NR3-、-SO2NR3-、-O-、-S-或-S(O)t-,其中t係0、1或2;每一R3獨立地係氫、C1-6烷基、C3-6環烷基、芳基、雜環基或雜芳基;且Rt係氫、C1-6烷基、C1-6烷氧基、-C(O)R20、-C(O)OR20、-NC(O)OR20、-N(R20)(R22)、-C(O)N(R20)(R22)、-SO2R20、-N(R20)SO2(R21)、-N(R20)SO2-N(R21)(R22)、-SO2N(R20)(R22)、C3-15環烷基、芳基、雜芳基或雜環基,限制條件係在Rt係C1-6烷氧基、-NC(O)OR20、-N(R20)(R22)、-N(R20)SO2(R21)、-N(R20)SO2-N(R21)(R22)或-SO2N(R20)(R22)且m係0時,則L係鍵;其中該C1-6烷基、C1-6烷氧基、C3-15環烷基、芳基、雜環基或雜芳基視情況經1個、2個或3個獨立地選自以下之取代基取代:羥基、鹵基、-NO2、C1-6鹵烷基、C1-6鹵烷氧基、-C(O)R20、-N(R20)(R22)、-SO2R20、-N(R20)SO2(R21)、-N(R20)SO2-N(R21)(R22)、-SO2N(R20)(R22)、C3-6環烷基、-CN、C1-6烷氧基、C1-6烷基及雜環基;
且其中該雜環基視情況經一個或兩個側氧基取代;其中該C3-6環烷基、C1-6烷基或C1-6烷氧基視情況經1個、2個或3個獨立地選自以下之取代基取代:羥基、鹵基、-NO2、C1-6鹵烷基、C1-6鹵烷氧基、C1-6烷氧基、-N(R20)(R22)、-SO2R20、-N(R20)SO2(R22)、-N(R20)SO2-N(R21)(R22)-及-SO2N(R20)(R22);且該C1-6烷基視情況經芳基取代;R20、R21及R22獨立地選自氫、C1-6烷基、C1-6鹵烷基、C3-6環烷基、芳基、雜環基及雜芳基;其中該芳基、雜環基或雜芳基視情況經1個、2個或3個鹵素取代;或其醫藥上可接受之鹽、異構物或混合物。
一些實施例提供使用通篇所述式I或其他式之化合物的方法,其用於治療哺乳動物(具體而言人類)之適於由IDO1抑制劑治療的疾病或病況。
在某些實施例中,本揭示內容提供醫藥組合物,其包含治療有效量之本揭示內容之化合物(例如通篇所述式I或其他式之化合物)及至少一種醫藥上可接受之賦形劑。
通篇闡述本揭示內容之本發明。另外,本發明之具體實施例係如本文中所揭示。
以下說明闡釋實例性方法、參數及諸如此類。然而,應認識到,該說明並不意欲限制本發明之範疇,而是提供作為實例性實施例之說明。
如本發明說明書中所用,除非在使用其之上下文中另外說明,否則以下詞語、片語及符號通常意欲具有如下文所述含義。
並不介於兩個字母或符號之間之破折號(「-」)用於指示取代基之附接點。舉例而言,-CONH2經由碳原子附接。在化學基團前面或後面之破折號係為方便起見;化學基團可經或不經一或多個破折號繪示而不失去其普通含義。穿過結構中之線繪製之波形線指示基團之附接點。除非化學上或結構上要求,否則書寫或命名化學基團之順序並不指示或暗示方向性。
前綴「Cu-v」指示以下基團具有u至v個碳原子。舉例而言,「C1-6烷基」指示烷基具有1至6個碳原子。
在提及「約」時,本文之值或參數包括(及闡述)關於該值或參數本身之實施例。在某些實施例中,術語「約」包括指示量±10%。在其他實施例中,術語「約」包括指示量±5%。在某些其他實施例中,術語「約」包括指示量±1%。同樣,關於術語「約X」包括「X」之說明。同樣,除非上下文另外明確規定,否則單數形式「一」及「該」包括複數個指示物。因此,例如,在提及「化合物」時包括複數種該等化合物且在提及「分析」時包括提及一或多種分析及熟習此項技術者已知之其等效形式。
「烷基」係指無支鏈或具支鏈飽和烴鏈。如本文所用烷基具有1至20個碳原子(即,C1-20烷基)、1至8個碳原子(即,C1-8烷基)、1至6個碳原子(即,C1-6烷基)或1至4個碳原子(即,C1-4烷基)。烷基之實例包括甲基、乙基、丙基、異丙基、正丁基、第二丁基、異丁基、第三丁基、戊基、2-戊基、異戊基、新戊基、己基、2-己基、3-己基及3-甲基戊基。在具有特定碳數之烷基殘基由化學名稱命名或由分子式鑑別時,可涵蓋所有具有該碳數之位置異構物;因此,例如,「丁基」包括正丁基(即-(CH2)3CH3)、第二丁基(即-CH(CH3)CH2CH3)、異丁基(即
-CH2CH(CH3)2)及第三丁基(即-C(CH3)3);且「丙基」包括正丙基(即-(CH2)2CH3)及異丙基(即-CH(CH3)2)。
「烯基」係指含有至少一個碳-碳雙鍵且具有2至20個碳原子(即,C2-20烯基)、2至8個碳原子(即,C2-8烯基)、2至6個碳原子(即,C2-6烯基)或2至4個碳原子(即,C2-4烯基)之脂肪族基團。烯基之實例包括乙烯基、丙烯基、丁二烯基(包括1,2-丁二烯基及1,3-丁二烯基)。
「炔基」係指含有至少一個碳-碳三鍵且具有2至20個碳原子(即,C2-20炔基)、2至8個碳原子(即,C2-8炔基)、2至6個碳原子(即,C2-6炔基)或2至4個碳原子(即,C2-4炔基)之脂肪族基團。術語「炔基」亦包括具有一個三鍵及一個雙鍵之彼等基團。
「烷氧基」係指基團「烷基-O-」。烷氧基之實例包括甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、第三丁氧基、第二丁氧基、正戊氧基、正己氧基及1,2-二甲基丁氧基。「鹵烷氧基」係指如上文所定義烷氧基,其中一或多個氫原子由鹵素置換。
「醯基」係指基團-C(=O)R,其中R係氫、烷基、環烷基、雜環基、芳基、雜烷基或雜芳基;其各自可視情況經取代,如本文中所定義。醯基之實例包括甲醯基、乙醯基、環己基羰基、環己基甲基-羰基及苯甲醯基。
「醯胺基」係指「C-醯胺基」(其係指基團-C(=O)NRyRz)及「N-醯胺基」(其係指基團-NRyC(=O)Rz)二者,其中Ry及Rz獨立地選自由氫、烷基、芳基、鹵烷基或雜芳基組成之群;其各自可視情況經取代。
「胺基」係指基團-NRyRz,其中Ry及Rz獨立地選自由氫、烷基、鹵烷基、芳基或雜芳基組成之群;其各自可視情況經取代。
「芳基」係指具有單一環(例如單環)或多個環(例如二環或三環)(包括稠合系統)之芳香族碳環基團。如本文所用芳基具有6至20個環
碳原子(即,C6-20芳基)、6至12個碳環原子(即,C6-12芳基)或6至10個碳環原子(即,C6-10芳基)。芳基之實例包括苯基、萘基、茀基及蒽基。然而,芳基並不涵蓋下文所定義雜芳基或以任何方式與其重疊。若一或多個芳基與雜芳基環稠合,則所得環系統係雜芳基。
「氰基」或「甲腈」係指基團-CN。
「環烷基」係指具有單一環或多個環(包括稠合、橋接及螺環系統)之飽和或部分飽和環狀烷基。術語「環烷基」包括環烯基(即具有至少一個雙鍵之環狀基團)。如本文所用環烷基具有3至20個環碳原子(即,C3-20環烷基)、3至12個環碳原子(即,C3-12環烷基)、3至10個環碳原子(即,C3-10環烷基)、3至8個環碳原子(即,C3-8環烷基)或3至6個環碳原子(即,C3-6環烷基)。環烷基之實例包括環丙基、環丁基、環戊基及環己基。
「鹵素」或「鹵基」包括氟、氯、溴及碘。「鹵烷基」係指如上文所定義無支鏈或具支鏈烷基,其中一或多個氫原子由鹵素置換。舉例而言,若殘基經一個以上鹵素取代,則其可藉由使用對應於所附接鹵素部分之數目之前綴提及。二鹵烷基基三鹵烷基係指經兩個(「二」)或三個(「三」)鹵基取代之烷基,該等鹵基可為(但不必係)相同鹵素。鹵烷基之實例包括二氟甲基(-CHF2)及三氟甲基(-CF3)。
「雜烷基」係指一或多個碳原子(及任何相關氫原子)各自獨立地經相同或不同雜原子基團置換的烷基。術語「雜烷基」包括具有碳及雜原子之無支鏈或具支鏈飽和鏈。舉例而言,1、2或3個碳原子可獨立地經相同不同雜原子基團置換。雜原子基團包括(但不限於)-NR-、-O-、-S-、-S(O)-、-S(O)2-及諸如此類,其中R係H、烷基、芳基、環烷基、雜烷基、雜芳基或雜環基,其各自可視情況經取代。雜烷基之實例包括-OCH3、-CH2OCH3、-SCH3、-CH2SCH3、-NRCH3及-CH2NRCH3,其中R係氫、烷基、芳基、芳基烷基、雜烷基或雜芳
基,其各自可視情況經取代。如本文所用雜烷基包括1至10個碳原子、1至8個碳原子或1至4個碳原子;及1至3個雜原子、1至2個雜原子或1個雜原子。
「雜芳基」係指具有單一環、多個環或多個稠合環且具有一或多個獨立地選自氮、氧及硫之環雜原子之芳香族基團。如本文所用雜芳基包括1至20個環碳原子(即,C1-20雜芳基)、3至12個環碳原子(即,C3-12雜芳基)或3至8個碳環原子(即,C3-8雜芳基);及1至5個雜原子、1至4個雜原子、1至3個環雜原子、1至2個環雜原子或1個環雜原子,該等雜原子獨立地選自氮、氧及硫。雜芳基之實例包括嘧啶基、嘌呤基、吡啶、嗒嗪基、苯并噻唑基及吡唑基。雜芳基不涵蓋如上文所定義芳基或與其重疊。
「雜環基」或「雜環」係指具有一或多個獨立地選自氮、氧及硫之環雜原子之不飽和非芳香族環狀烷基。如本文所用之「雜環基」或「雜環」係指飽和或部分飽和之環,除非另外指示,否則例如在一些實施例中,若指定,「雜環基」或「雜環」係指部分飽和之環。術語「雜環基」或「雜環」包括雜環烯基(即,具有至少一個雙鍵之雜環基)。雜環基可為單一環或多個環,其中多個環可稠合、橋接或螺接。如本文所用雜環基具有2至20個環碳原子(即,C2-20雜環基)、2至12個環碳原子(即,C2-12雜環基)、2至10個環碳原子(即,C2-10雜環基)、2至8個環碳原子(即,C2-8雜環基)、3至12個環碳原子(即,C3-12雜環基)、3至8個環碳原子(即,C3-8雜環基)或3至6個環碳原子(即,C3-6雜環基);具有1至5個環雜原子、1至4個環雜原子、1至3個環雜原子、1至2個環雜原子或1個環雜原子,該等環雜原子獨立地選自氮、硫或氧。雜環基之實例包括吡咯啶基、六氫吡啶基、六氫吡嗪基、氧雜環丁基、二氧戊環基、氮雜環丁基及嗎啉基。如本文所用術語「橋接-雜環基」係指在雜環基之兩個非毗鄰原子處與一或多個(例如,1
或2個)具有至少一個雜原子之四員至十員環狀部分連接的四員至十員環狀部分,其中每一雜原子獨立地選自氮、氧及硫。如本文所用之「橋接-雜環基」包括二環及三環系統。同樣,如本文所用術語「螺-雜環基」係指三員至十員雜環基具有一或多個另外環之環系統,其中該一或多個另外環係三員至十員環烷基或三員至十員雜環基,其中該一或多個另外環之單一原子亦係三員至十員雜環基之原子。螺-雜環基之實例包括二環及三環系統,例如2-氧雜-7-氮雜螺[3.5]壬基、2-氧雜-6-氮雜螺[3.4]辛基及6-氧雜-1-氮雜螺[3.3]庚基。
「羥基」(「Hydroxy」或「hydroxyl」)係指基團-OH。
「側氧基」係指基團(=O)或(O)。
「磺醯基」係指基團-S(O)2R,其中R係烷基、鹵烷基、雜環基、環烷基、雜芳基或芳基。磺醯基之實例係甲基磺醯基、乙基磺醯基、苯基磺醯基及甲苯磺醯基。
可使用某些常用替代化學名稱。舉例而言,諸如二價「烷基」、二價「芳基」等二價基團亦可分別稱作「伸烷基」(「alkylene」或「alkylenyl」)、「伸芳基」(「arylene」或「arylenyl」)。同樣,除非另外明確指明基團之組合在本文中係指一個部分(例如芳基烷基),否則最後提及之基團含有該部分附接至分子之其餘部分所藉由之原子。
術語「可選」或「視情況」意指隨後闡述之事件或情況可能發生或可能不發生,且該說明包括該事件或情況發生之情形及該事件或情況不發生之情形。同樣,術語「視情況經取代」係指所命名原子或基團上之任一或多個氫原子可由除氫外之部分置換或可不經置換。
術語「經取代」意指所命名原子或基團上之任一或多個氫原子經一或多個除氫外之取代基置換,限制條件係不超過所命名原子之正常價。一或多個取代基包括(但不限於)烷基、烯基、炔基、烷氧基、
醯基、胺基、醯胺基、甲脒基、芳基、疊氮基、胺甲醯基、羧基、羧基酯、氰基、胍基、鹵基、鹵烷基、雜烷基、雜芳基、雜環基、羥基、肼基、亞胺基、側氧基、硝基、烷基亞磺醯基、磺酸、烷基磺醯基、硫氰酸酯、硫醇、硫酮或其組合。藉由用無窮地附加之其他取代基(例如,具有經取代烷基之經取代芳基,該經取代烷基自身由經取代芳基取代,該經取代芳基進一步由經取代雜烷基取代等等)定義取代基所獲得之聚合物或類似的無限結構並不意欲包括於本文中。除非另有說明,否則本文所述化合物中之系列取代之最大數目係3。舉例而言,具有兩個其他經取代芳基之經取代芳基的系列取代限於((經取代芳基)經取代芳基)經取代芳基。類似地,上述定義並不意欲包括不允許之取代型式(例如,經5個氟取代之甲基或具有兩個毗鄰氧環原子之雜芳基)。該等不允許取代型式已為熟習此項技術者所熟知。在用於修飾化學基團時,術語「經取代」可闡述本文中定義之其他化學基團。舉例而言,術語「經取代芳基」包括(但不限於)「烷基芳基」。除非另外指明,否則若基團闡述為視情況經取代,則基團之任何取代基自身未經取代。
在一些實施例中,術語「經取代烷基」係指具有一或多個取代基(包括羥基、鹵基、烷氧基、環烷基、雜環基、芳基及雜芳基)之烷基。在其他實施例中,「經取代環烷基」係指具有一或多個取代基(包括烷基、鹵烷基、環烷基、雜環基、芳基、雜芳基、烷氧基、鹵基、側氧基及羥基)之環烷基;「經取代雜環基」係指具有一或多個取代基(包括烷基、鹵烷基、雜環基、環烷基、芳基、雜芳基、烷氧基、鹵基、側氧基及羥基)之雜環基;「經取代芳基」係指具有一或多個取代基(包括鹵基、烷基、鹵烷基、環烷基、雜環基、雜芳基、烷氧基及氰基)之芳基;「經取代雜芳基」係指具有一或多個取代基(包括鹵基、烷基、鹵烷基、雜環基、雜芳基、烷氧基及氰基)之雜芳
基,且「經取代磺醯基」係指基團-S(O)2R,其中R經一或多個取代基(包括烷基、環烷基、雜環基、芳基及雜芳基)取代。在其他實施例中,一或多個取代基可進一步經各自經取代之鹵基、烷基、鹵烷基、羥基、烷氧基、環烷基、雜環基、芳基或雜芳基取代。在其他實施例中,取代基可進一步經各自未經取代之鹵基、烷基、鹵烷基、烷氧基、羥基、環烷基、雜環基、芳基或雜芳基取代。
一些化合物以互變異構物形式存在。互變異構物彼此平衡。舉例而言,含有醯胺之化合物可與亞胺基酸互變異構物平衡存在。不管顯示何種互變異構物且不管互變異構物間之平衡性質,化合物應由熟習此項技術者理解為包含醯胺及亞胺基酸互變異構物二者。因此,含有醯胺之化合物應理解為包括其亞胺基酸互變異構物。同樣,含有亞胺基酸之化合物應理解為包括其醯胺互變異構物。
本文中給出之任何式或結構亦意欲表示化合物之未經標記形式以及經同位素標記形式。經同位素標記之化合物具有由本文中給出之式繪示之結構,只是一或多個原子由具有選擇原子質量或質量數之原子置換。可納入本揭示內容之化合物中之同位素之實例包括氫、碳、氮、氧、磷、氟及氯之同位素、例如但不限於2H(氘、D)、3H(氚)、11C、13C、14C、15N、18F、31P、32P、35S、36Cl及125I。各種經同位素標記之本發明化合物係例如其中納入放射性同位素(例如3H、13C及14C)之化合物。該等經同位素標記之化合物可用於代謝研究、反應動力學研究、檢測或成像技術(例如正電子發射斷層掃描術(PET)或單光子發射電腦斷層掃描術(SPECT),包括藥物或受質組織分佈分析)或患者之放射性治療。
本揭示內容亦包括式I化合物,其中附接至碳原子之1至n個氫由氘置換,其中n係分子中氫之數目。該等化合物展現增加之代謝抗性且因此在投與哺乳動物(具體而言人類)時可用於增加任何式I化合物之
半衰期。參見(例如)Foster,「Deuterium Isotope Effects in Studies of Drug Metabolism,」Trends Pharmacol.Sci.5(12):524-527(1984)。該等化合物係藉由業內熟知之方式、例如藉由採用一或多個氫由氘置換之起始材料來合成。
本揭示內容之氘標記或取代之治療化合物可具有關於分佈、代謝及排泄(ADME)之改良之DMPK(藥物代謝及藥物動力學)性質。用較重同位素(例如氘)取代可得到某些治療優點,該等優點係自較大代謝穩定性(例如增加之活體內半衰期)、降低之劑量需求及/或治療指數改良產生。18F標記之化合物可用於PET或SPECT研究。經同位素標記之本揭示內容之化合物及其前藥通常係藉由實施下文所述方案或實例及製備中所揭示之程序藉由用容易獲得之經同位素標記之試劑取代未經同位素標記之試劑來製備。應理解,氘在此上下文中應視為式I化合物中之取代基。
該較重同位素(特定而言氘)之濃度可藉由同位素富集因子定義。在本揭示內容之化合物中,未明確命名為特定同位素之任何原子意指代表該原子之任何穩定同位素。除非另外陳述,否則在位置明確命名為「H」或「氫」時,該位置應理解為在其天然豐度同位素組合物處具有氫。因此,在本揭示內容之化合物中,明確命名為氘(D)之任何原子意指代表氘。
在許多情形下,本揭示內容之化合物藉助存在胺基及/或羧基或其相似基團能夠形成酸性及/或鹼性鹽。
術語給定化合物之「醫藥上可接受之鹽」係指保留給定化合物之生物有效性及性質且並不在生物上或以其他方式不合意之鹽。可自無機鹼及有機鹼製備醫藥上可接受之鹼加成鹽。衍生自無機鹼之鹽包括(僅舉例而言)鈉、鉀、鋰、銨、鈣及鎂鹽。衍生自有機鹼之鹽包括(但不限於)一級、二級及三級胺之鹽,例如烷基胺、二烷基胺、三烷
基胺、經取代烷基胺、二(經取代烷基)胺、三(經取代烷基)胺、烯基胺、二烯基胺、三烯基胺、經取代烯基胺、二(經取代烯基)胺、三(經取代烯基)胺、單、二或三環烷基胺、單、二或三芳基胺或混合胺等。適宜胺之具體實例包括(僅舉例而言)異丙胺、三甲基胺、二乙基胺、三(異丙基)胺、三(正丙基)胺、乙醇胺、2-二甲基胺基乙醇、六氫吡嗪、六氫吡啶、嗎啉、N-乙基六氫吡啶及諸如此類。
醫藥上可接受之酸加成鹽可自無機酸及有機酸製備。衍生自無機酸之鹽包括鹽酸、氫溴酸、硫酸、硝酸、磷酸及諸如此類。衍生自有機酸之鹽包括乙酸、丙酸、羥乙酸、丙酮酸、草酸、蘋果酸、丙二酸、琥珀酸、馬來酸、富馬酸、酒石酸、檸檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、對-甲苯磺酸、柳酸及諸如此類。
如本文所用之「醫藥上可接受載劑」或「醫藥上可接受之賦形劑」包括任何及所有溶劑、分散介質、塗覆劑、抗細菌劑及抗真菌劑、等滲劑及吸收延遲劑及諸如此類。用於醫藥活性物質之該等介質及試劑之使用為業內所熟知。除任何與活性成份不相容之習用介質或試劑以外,本發明涵蓋其於治療組合物中之用途。亦可將補充活性成份納入組合物中。
「治療」(「treatment」或「treating」)係獲得有益或期望結果(包括臨床結果)之方法。有益或期望結果可包括以下中之一或多者:a)抑制疾病或病況(例如,減少自疾病或病況產生之一或多種症狀,及/或減輕疾病或病況之程度);b)減緩或阻止與疾病或病況相關之一或多種臨床症狀之發展(例如,穩定疾病或病況、預防或延遲疾病或病況之惡化或進展、及/或預防或延遲疾病或病況傳播(例如,轉移));及/或c)減輕疾病,亦即引起臨床症狀消退(例如,改善疾病狀態、提供疾病或病況之部分或完全緩解、增強另一用藥之效應、延遲疾病進展、增加生活品質及/或延長存活。
「預防」(「prevention」或「preventing」)意指使得疾病或病況之臨床症狀不發展之疾病或病況之任何治療。在一些實施例中,化合物可投與處於疾病或病況之風險或具有疾病或病況之家族史的個體(包括人類)。
「個體」係指已經為或將為治療、觀察或實驗之目標之動物,例如哺乳動物(包括人類)。本文所述方法可用於人類療法及/或獸醫應用。在一些實施例中,個體係哺乳動物。在一個實施例中,個體係人類。
術語本文所述化合物或其醫藥上可接受之鹽、異構物或混合物之「治療有效量」或「有效量」意指在投與個體時足以實現治療以提供治療益處(例如改善症狀或減緩疾病進展)的量。舉例而言,治療有效量可為足以減少對IDO1活性之抑制有反應之疾病或病況之症狀的量。治療有效量可根據個體、及所治療疾病或病況、個體之重量及年齡、疾病或病況之嚴重程度及投與方式而變,其可由熟習此項技術者輕易地測定。
術語「抑制」指示生物活性或過程之基線活性減少。「IDO1活性之抑制」或其變化形式係指相對於在不存在本申請案化合物下IDO1之活性,IDO1活性直接或間接因應本申請案化合物之存在而降低。「IDO1之抑制」係指相對於在不存在本文所述化合物下IDO1之活性,IDO1活性直接或間接因應本文所述化合物之存在而降低。在一些實施例中,可在同一個體中在治療之前或在未接受治療之其他個體中比較IDO1活性之抑制。
本文提供用作IDO1之抑制劑之化合物。在一個態樣中,提供具有式I之結構之化合物:
其中R1係單環或二環芳基或雜芳基,其中每一單環或二環芳基或雜芳基視情況經1個、2個或3個獨立地選自以下之取代基取代:羥基、鹵基、-CN、C1-6鹵烷基、C1-6鹵烷氧基、C1-6烷氧基、C1-6烷基、C2-6烯基、C2-6炔基及C3-6環烷基,其中可選取代基中之二者可接合形成另外部分飽和雜環;且其中每一C1-6烷氧基、C1-6烷基、C2-6烯基、C2-6炔基及C3-6環烷基視情況經1個、2個或3個獨立地選自以下之取代基取代:羥基、鹵基、-CN、-N(R20)(R22)及C3-6環烷基;X係N或CR2c;R2a、R2b及R2c獨立地係氫、羥基、鹵基、CN、C1-6鹵烷基、C1-6鹵烷氧基、C1-6烷氧基或C1-6烷基;R2d及R2e獨立地係氫、C1-6鹵烷基、C1-6鹵烷氧基或C1-6烷基;n及m獨立地係0、1、2或3;每一Rn及Rm獨立地係氫、羥基、鹵基、C1-6烷氧基、C1-6烷基、C3-6環烷基、芳基、雜環基或雜芳基;或兩個Rn或Rm接合形成C3-6環烷基;且其中每一C1-6烷氧基、C1-6烷基、C3-6環烷基、芳基、雜環基或雜芳基視情況經1個、2個或3個獨立地選自以下之取代基取代:羥基、鹵基、-CN、-N(R20)(R22)、C2-6烯基、C2-6炔基、C1-6鹵烷基、C1-6鹵烷氧基、C1-6烷氧基、C1-6烷基及C3-6環烷基;
L係鍵、-NR3-、-C(O)-NR3-、-NR3-C(O)-、-NR3SO2-、-NR3SO2-NR3-、-SO2NR3-、-O-、-S-或-S(O)t-,其中t係0、1或2;每一R3獨立地係氫、C1-6烷基、C3-6環烷基、芳基、雜環基或雜芳基;且Rt係氫、C1-6烷基、C1-6烷氧基、-C(O)R20、-C(O)OR20、-NC(O)OR20、-N(R20)(R22)、-C(O)N(R20)(R22)、-SO2R20、-N(R20)SO2(R21)、-N(R20)SO2-N(R21)(R22)、-SO2N(R20)(R22)、C3-15環烷基、芳基、雜芳基或雜環基,限制條件係在Rt係C1-6烷氧基、-NC(O)OR20、-N(R20)(R22)、-N(R20)SO2(R21)、-N(R20)SO2-N(R21)(R22)或-SO2N(R20)(R22)且m係0時,則L係鍵;其中該C1-6烷基、C1-6烷氧基、C3-15環烷基、芳基、雜環基或雜芳基視情況經1個、2個或3個獨立地選自以下之取代基取代:羥基、鹵基、-NO2、C1-6鹵烷基、C1-6鹵烷氧基、-C(O)R20、-N(R20)(R22)、-SO2R20、-N(R20)SO2(R21)、-N(R20)SO2-N(R21)(R22)、-SO2N(R20)(R22)、C3-6環烷基、-CN、C1-6烷氧基、C1-6烷基及雜環基;且其中該雜環基視情況經一個或兩個側氧基取代;其中該C3-6環烷基、C1-6烷基或C1-6烷氧基視情況經1個、2個或3個獨立地選自以下之取代基取代:羥基、鹵基、-NO2、C1-6鹵烷基、C1-6鹵烷氧基、C1-6烷氧基、-N(R20)(R22)、-SO2R20、-N(R20)SO2(R22)、-N(R20)SO2-N(R21)(R22)-及-SO2N(R20)(R22);且該C1-6烷基視情況經芳基取代;R20、R21及R22獨立地選自氫、C1-6烷基、C1-6鹵烷基、C3-6環烷基、芳基、雜環基及雜芳基;其中該芳基、雜環基或雜芳基視情況經1個、2個或3個鹵素取代;或其醫藥上可接受之鹽、異構物或混合物。
在一些實施例中,R1係視情況經1個、2個或3個獨立地選自以下之取代基取代之二環芳基或雜芳基:羥基、鹵基、-CN、C1-6鹵烷基、C1-6鹵烷氧基、C1-6烷氧基、C1-6烷基、C2-6烯基、C2-6炔基及C3-6環烷基,其中可選取代基中之二者可接合形成另外部分飽和雜環;且其中每一C1-6烷氧基、C1-6烷基、C2-6烯基、C2-6炔基及C3-6環烷基視情況經1個、2個或3個獨立地選自以下之取代基取代:羥基、鹵基、-CN、-N(R20)(R22)及C3-6環烷基。
在一些實施例中,R1係視情況經1個、2個或3個獨立地選自以下之取代基取代之二環芳基或雜芳基:羥基、鹵基、-CN、C1-6鹵烷基、C1-6鹵烷氧基、C1-6烷氧基、C1-6烷基、C2-6烯基、C2-6炔基及C3-6環烷基。
在一些實施例中,化合物係選自由以下組成之群:N'-羥基-N-萘-2-基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N'-羥基-N-萘-1-基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(4-氯萘-1-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯萘-2-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(1-苯并呋喃-4-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(1-苯并呋喃-6-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(1-苯并呋喃-7-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;及N-(1-苯并呋喃-5-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒。
在一些實施例中,R1係視情況經1個、2個或3個獨立地選自以下之取代基取代之苯基:羥基、鹵基、-CN、C1-6鹵烷基、C1-6鹵烷氧基、C1-6烷氧基、C1-6烷基、C2-6烯基、C2-6炔基及C3-6環烷基,其中可選取代基中之二者可接合形成另外部分飽和雜環;且其中每一C1-6烷氧基、C1-6烷基、C2-6烯基、C2-6炔基及C3-6環烷基視情況經1個、2個或3個獨立地選自以下之取代基取代:羥基、鹵基、-CN、-
N(R20)(R22)及C3-6環烷基。
在一些實施例中,R1係視情況經1個、2個或3個獨立地選自以下之取代基取代之苯基:羥基、鹵基、-CN、-CHF2、-O-CHF2、-CF3、-O-CF3、C1-4烷氧基、C1-4烷基、C2-4烯基、C2-4炔基及C3-6環烷基,且其中可選取代基中之二者可接合形成另外部分飽和雜環。
在一些實施例中,R2a、R2b及(若存在)R2c中之至少一者不為氫。在一些實施例中,R2a不為氫。在一些實施例中,R2b不為氫。在一些實施例中,R2c不為氫。
在一些實施例中,化合物係選自由以下組成之群:N-(3-氯-4-氟苯基)-6-氟-N'-羥基-1H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-7-氟-N'-羥基-3H-苯并咪唑-4-甲脒;7-氯-N-(3-氯-4-氟苯基)-N'-羥基-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-7-(三氟甲基)-1H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-2-(2-嗎啉-4-基乙基胺基)-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-2-(甲基胺基甲基)-1H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-6-氟-N'-羥基-7-甲基-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-7-甲基-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-7-(三氟甲氧基)-3H-苯并咪唑-4-甲脒;及N-(3-氯-4-氟苯基)-5-氟-N'-羥基-3H-苯并咪唑-4-甲脒。
在一些實施例中,L係鍵。
在一些實施例中,Rt係視情況經1個、2個或3個獨立地選自以下之取代基取代之C1-6烷基:羥基、鹵基、-NO2、C1-6鹵烷基、C1-6鹵烷
氧基、C3-6環烷基、-CN及C1-6烷氧基。
在一些實施例中,化合物係選自由以下組成之群:N-(3-氯-4-氟苯基)-N'-羥基-2-(甲氧基甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒;2-(氯甲基)-N-[4-氟-3-(三氟甲基)苯基]-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-[4-氟-3-(三氟甲基)苯基]-N'-羥基-2-(羥基甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-(羥基甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-(1-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-(2,2,2-三氟-1-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-2-[環丙基(羥基)甲基]-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-(2-羥基丙-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒;及2-(胺基甲基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒。
在一些實施例中,Rt係C3-15環烷基、芳基、雜芳基或雜環基,其中該環烷基、芳基、雜環基或雜芳基視情況經1個、2個或3個獨立地選自以下之取代基取代:羥基、鹵基、-NO2、C1-6鹵烷基、C1-6鹵烷氧基、C3-6環烷基、-CN、C1-6烷氧基及C1-6烷基。
在一些實施例中,化合物係選自由以下組成之群:N-(3-氯-4-氟苯基)-N'-羥基-2-(2-嗎啉-4-基乙基)-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-(吡咯啶-1-基甲基)-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-(六氫吡啶-1-基甲基)-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-吡啶-3-基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-(1H-吡咯-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[(2S)-吡咯啶-2-基]-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-(1H-吡唑-5-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-(1H-咪唑-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-2-環丙基-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-噻吩-2-基-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-(嗎啉-4-基甲基)-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[羥基(苯基)甲基]-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-甲基-1H-咪唑并[4,5-b]吡啶-7-甲
脒;N-(3-氯-4-氟苯基)-2-乙基-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-(2-六氫吡啶-1-基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-(2-吡咯啶-1-基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒;及N-(3-氯-4-氟苯基)-N'-羥基-2-(5-甲基-1H-咪唑-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒。
在一些實施例中,Rt係氫。
在一些實施例中,化合物係選自由以下組成之群:N-(3-乙炔基苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-乙炔基-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-[3-(二氟甲基)苯基]-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N'-羥基-N-[3-(三氟甲氧基)苯基]-1H-咪唑并[4,5-b]吡啶-7-甲脒;N'-羥基-N-苯基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-乙基苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-[4-氟-3-(三氟甲氧基)苯基]-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(4-氟-3-甲氧基苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(5-溴-2-氟苯基)-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-溴-5-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N'-羥基-N-[3-(三氟甲基)苯基]-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-[3-氟-5-(三氟甲基)苯基]-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-溴苯基)-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒;
N-(3-溴-4-氟苯基)-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯苯基)-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-[4-氟-3-(三氟甲基)苯基]-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(4-氟-3-丙-1-炔基苯基)-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-溴-4-氯苯基)-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3,4-二氯苯基)-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(4-氯苯基)-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(4-溴苯基)-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(4-氟苯基)-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氰基-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N'-羥基-N-[4-(三氟甲基)苯基]-3H-咪唑并[4,5-b]吡啶-7-甲脒;N'-羥基-N-(3-甲氧基苯基)-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(4-氟-3-丙-2-基苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N'-羥基-N-(4-甲基苯基)-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(5-氯-2-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(5-溴-2,4-二氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(5-氯-2,4-二氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(2,5-二氯苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3,5-二氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯2,4-二氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-環丙基-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(4-氟-3-苯基苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-丁-1-炔基-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲
脒;N-[3-(2-環丙基乙炔基)-4-氟苯基]-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;及N'-羥基-N-[4-(三氟甲氧基)苯基]-1H-咪唑并[4,5-b]吡啶-7-甲脒。
在一些實施例中,L係-NR3。
在一些實施例中,Rt係視情況經1個、2個或3個獨立地選自以下之取代基取代之C1-6:羥基、鹵基、-NO2、C1-6鹵烷基、C1-6鹵烷氧基、-N(R20)(R22)、-SO2R20、C3-6環烷基、-CN及C1-6烷氧基。
在一些實施例中,化合物係選自由以下組成之群:N-(3-氯-4-氟苯基)-2-[2-(二甲基胺基)乙基]-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[2-(甲基胺基)乙基]-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-(2-((2-甲氧基乙基)胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒N-(3-氯-4-氟苯基)-2-[(2,2-二甲基丙基胺基)甲基]-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[2-(2-甲氧基乙基胺基)乙基]-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-[7-[(Z)-N-(3-氯-4-氟苯基)-N'-羥基甲脒基]-1H-咪唑并[4,5-b]吡啶-2-基]胺基甲酸乙基酯;N-(3-氯-4-氟苯基)-N'-羥基-2-(甲基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-(2,2,2-三氟乙基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-2-(二甲基胺基)-N'-羥基-1H-咪唑并[4,5-b]吡
啶-7-甲脒;N-(3-氯-4-氟苯基)-2-[2-(二乙基胺基)乙基]-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-2-[2-(二甲基胺基)-1-羥基乙基]-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[(2-甲基丙基胺基)甲基]-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-(甲基胺基甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-2-[2-[2,2-二氟乙基(甲基)胺基]乙基]-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-(丙-2-基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-2-[(2,2-二氟乙基胺基)甲基]-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[[(3-羥基-2,2-二甲基丙基)胺基]甲基]-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[(丙-2-基胺基)甲基]-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-2-(乙基胺基甲基)-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-2-(乙基胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[(3-甲氧基丙基胺基)甲基]-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-2-[(二甲基胺基)甲基]-N'-羥基-3H-咪唑并[4,5-
b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[[3-甲氧基丙基(甲基)胺基]甲基]-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[(2-甲氧基乙基胺基)甲基]-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[(2,2,2-三氟乙基胺基)甲基]-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-2-[[2-(二甲基胺基)乙基胺基]甲基]-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[(3-羥基丙基胺基)甲基]-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-[[7-[(Z)-N-(3-氯-4-氟苯基)-N'-羥基甲脒基]-3H-咪唑并[4,5-b]吡啶-2-基]甲基]乙醯胺;N-(3-氯苯基)-N'-羥基-2-(甲基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[2-[2-甲氧基乙基(甲基)胺基]乙基]-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-2-[2-(二乙基胺基)乙基胺基]-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;及N-(3-氯苯基)-2-((二甲基胺基)甲基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒。
在一些實施例中,L係-NR3且Rt係C3-15環烷基、芳基、雜芳基或雜環基,其中該環烷基、芳基、雜環基或雜芳基視情況經1個、2個或3個獨立地選自以下之取代基取代:羥基、鹵基、-NO2、C1-6鹵烷基、C1-6鹵烷氧基、C3-6環烷基、-CN及C1-6烷氧基。
在一些實施例中,化合物係選自由以下組成之群:
N-(3-氯-4-氟苯基)-2-(環丙基胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-2-(環丙基甲基胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-(2-苯基乙基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒;2-苯胺基-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-2-[(3,3-二氟環丁基)胺基]-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[(嘧啶-2-基胺基)甲基]-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-2-(環丁基胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[(1,3-噻唑-2-基甲基胺基)甲基]-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-2-[(環丙基甲基胺基)甲基]-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[(吡啶-2-基甲基胺基)甲基]-3H-咪唑并[4,5-b]吡啶-7-甲脒;2-[(苄基胺基)甲基]-N-(3-氯-4-氟苯基)-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[[(2-甲氧基苯基)甲基胺基]甲基]-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[(2-吡啶-2-基乙基胺基)甲基]-3H-咪唑并[4,5-b]吡啶-7-甲脒;
N-(3-氯-4-氟苯基)-2-[(環丙基胺基)甲基]-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[(吡啶-3-基甲基胺基)甲基]-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[(噁烷-2-基甲基胺基)甲基]-1H-咪唑并[4,5-b]吡啶-7-甲脒;2-(苯胺基甲基)-N-(3-氯-4-氟苯基)-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[(噁烷-3-基甲基胺基)甲基]-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[(嘧啶-2-基甲基胺基)甲基]-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[(3-嗎啉-4-基丙基胺基)甲基]-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[(噁烷-4-基胺基)甲基]-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[(吡啶-4-基甲基胺基)甲基]-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[(吡嗪-2-基甲基胺基)甲基]-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[(氧雜環戊-3-基甲基胺基)甲基]-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[(2-嘧啶-2-基乙基胺基)甲基]-3H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-2-[2-[環丙基甲基(甲基)胺基]乙基]-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒;
N-(3-氯-4-氟苯基)-N'-羥基-2-(2-嗎啉-4-基乙基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-2-[(1-甲基六氫吡啶-2-基)甲基胺基]-1H-咪唑并[4,5-b]吡啶-7-甲脒;及N-(3-氯-4-氟苯基)-N'-羥基-2-[(1-甲基吡咯啶-3-基)胺基]-1H-咪唑并[4,5-b]吡啶-7-甲脒。
在一些實施例中,L係-NR3且Rt係氫。
在一些實施例中,化合物係選自由以下組成之群:2-(2-胺基乙基)-N-(3-氯-4-氟苯基)-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒;及2-胺基-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒。
在一些實施例中,L係-SO2NR3-。
在一些實施例中,化合物係選自由以下組成之群:2-(苯磺醯胺基甲基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,及N-(3-氯-4-氟苯基)-N'-羥基-2-(甲烷磺醯胺基甲基)-3H-咪唑并[4,5-b]吡啶-7-甲脒。
在一些實施例中,X係-N-。
在一些實施例中,X係-CR2c-。
在一些實施例中,化合物係選自由以下組成之群:N-(3-氯-4-氟苯基)-6-氟-N'-羥基-1H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-7-氟-N'-羥基-3H-苯并咪唑-4-甲脒;7-氯-N-(3-氯-4-氟苯基)-N'-羥基-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-7-(三氟甲基)-1H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-2-(2-嗎啉-4-基乙基胺基)-
3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-2-(甲基胺基甲基)-1H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-6-氟-N'-羥基-7-甲基-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-7-甲基-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-7-(三氟甲氧基)-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-5-氟-N'-羥基-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-2-(羥基甲基)-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-2-嗎啉-4-基-3H-苯并咪唑-4-甲脒;N-(3-氯苯基)-6,7-二氟-N'-羥基-2-(1-甲基六氫吡啶-3-基)-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-N'-羥基-3H-苯并咪唑-4-甲脒;6-氯-N-(3-氯-4-氟苯基)-N'-羥基-3H-苯并咪唑-4-甲脒;7-溴-N-(3-氯-4-氟苯基)-N'-羥基-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-2-[(3-甲氧基丙基胺基)甲基]-1H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-2-[3-(二甲基胺基)丙基]-6,7-二氟-N'-羥基-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-2-[2-(二甲基胺基)乙基]-6,7-二氟-N'-羥基-1H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-2-(甲基胺基)-3H-苯并咪唑-4-甲脒;
N-(3-溴-4-氟苯基)-2-[2-(二甲基胺基)乙基]-6,7-二氟-N'-羥基-1H-苯并咪唑-4-甲脒;N-(3-溴苯基)-2-[2-(二甲基胺基)乙基]-6,7-二氟-N'-羥基-1H-苯并咪唑-4-甲脒;N-(3-氯苯基)-2-[2-(二甲基胺基)乙基]-6,7-二氟-N'-羥基-1H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-2-[3-(二甲基胺基)丙基胺基]-6,7-二氟-N'-羥基-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-2-(2-甲氧基乙基胺基)-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-2-[2-(二甲基胺基)乙基胺基]-6,7-二氟-N'-羥基-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-2-[2-(二乙基胺基)乙基胺基]-6,7-二氟-N'-羥基-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-2-[(丙-2-基胺基)甲基]-1H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-2-[(二甲基胺基)甲基]-6,7-二氟-N'-羥基-1H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-2-(乙基胺基甲基)-6,7-二氟-N'-羥基-1H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-2-[2-(二甲基胺基)乙基胺基]-7-氟-N'-羥基-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-2-[2-(甲基胺基)乙基]-1H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-2-[2-(二乙基胺基)乙基]-6,7-二氟-N'-羥基-1H-苯并咪唑-4-甲脒;
N-(3-氯-4-氟苯基)-7-氟-N'-羥基-2-(2-甲基磺醯基乙基胺基)-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-2-(2-甲基磺醯基乙基胺基)-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-2-[(環丙基甲基胺基)甲基]-6,7-二氟-N'-羥基-1H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-7-氟-N'-羥基-2-(3-嗎啉-4-基丙基胺基)-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-2-(2-吡咯啶-1-基乙基胺基)-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-2-[2-(4,4-二氟六氫吡啶-1-基)乙基胺基]-6,7-二氟-N'-羥基-3H-苯并咪唑-4-甲脒;N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-2-(1-嗎啉-4-基丙-2-基胺基)-3H-苯并咪唑-4-甲脒;2-(胺基甲基)-N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-1H-苯并咪唑-4-甲脒;2-胺基-N-(3-氯-4-氟苯基)-7-氟-N'-羥基-3H-苯并咪唑-4-甲脒;2-胺基-N-(3-溴-4-氟苯基)-6,7-二氟-N'-羥基-3H-苯并咪唑-4-甲脒;2-胺基-N-(3-溴苯基)-6,7-二氟-N'-羥基-3H-苯并咪唑-4-甲脒;2-胺基-N-(3-氯苯基)-6,7-二氟-N'-羥基-3H-苯并咪唑-4-甲脒;2-胺基-N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-3H-苯并咪唑-4-甲脒;2-胺基-N-(3-溴苯基)-7-氟-N'-羥基-3H-苯并咪唑-4-甲脒;2-胺基-N-(3-溴-4-氟苯基)-7-氟-N'-羥基-3H-苯并咪唑-4-甲脒;2-胺基-N-(3-氯苯基)-7-氟-N'-羥基-3H-苯并咪唑-4-甲脒;
2-胺基-6,7-二氟-N-[4-氟-3-(三氟甲基)苯基]-N'-羥基-3H-苯并咪唑-4-甲脒;2-胺基-7-氟-N-[4-氟-3-(三氟甲基)苯基]-N'-羥基-3H-苯并咪唑-4-甲脒;N-(3-氯苯基)-4,5-二氟-N'-羥基-2-(((3-甲氧基丙基)胺基)甲基)-1H-苯并[d]咪唑-7-甲脒;N-(3-氯苯基)-2-(((環丙基甲基)胺基)甲基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒;N-(3-氯苯基)-2-((二甲基胺基)甲基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒;N-(3-氯苯基)-4,5-二氟-N'-羥基-2-((異丙基胺基)甲基)-1H-苯并[d]咪唑-7-甲脒;N-(3-氯苯基)-2-((乙基胺基)甲基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒;N-(3-氯苯基)-4,5-二氟-N'-羥基-2-(羥基甲基)-1H-苯并[d]咪唑-7-甲脒;N-(3-氯苯基)-4,5-二氟-N'-羥基-2-((甲基胺基)甲基)-1H-苯并[d]咪唑-7-甲脒;2-(胺基甲基)-N-(3-氯苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒;及N-(3-氯-4-氟苯基)-4-氟-N'-羥基-2-((2-嗎啉基乙基)胺基)-1H-苯并[d]咪唑-7-甲脒。
在一些實施例中,L係-C(O)-NR3-。
在一些實施例中,化合物係選自由以下組成之群:N-[7-[(Z)-N-(3-氯-4-氟苯基)-N'-羥基甲脒基]-1H-咪唑并[4,5-b]吡啶-2-基]胺基甲酸乙基酯;
N-[[7-[(Z)-N-(3-氯-4-氟苯基)-N'-羥基甲脒基]-3H-咪唑并[4,5-b]吡啶-2-基]甲基]乙醯胺;及N-[7-[(Z)-N-(3-氯-4-氟苯基)-N'-羥基甲脒基]-1H-咪唑并[4,5-b]吡啶-2-基]胺基甲酸丙-2-基酯。
在一些實施例中,L係N,m係1,且n係0。
在一些實施例中,L係N,m係2,且n係0。
在一些實施例中,L係N,m係3,且n係0。
在一個實施例中,式I化合物係由式IA或IB代表:
在一個實施例中,R1係選自由以下組成之群:
在一個實施例中,R1係。
在一個實施例中,式I化合物由式II代表:
在一個實施例中,式I化合物由式IIA或IIB代表:
在一個實施例中,式I化合物由式III代表:
在一個實施例中,式I化合物由式IV代表:
在一個實施例中,本文所述任何式之基團係選
自由以下組成之群:氫、(1-甲基六氫吡啶-2-基)甲基胺基、(1-甲基吡咯啶-3-基)胺基、(2-嘧啶-2-基乙基胺基)甲基、(2S)-吡咯啶-2-基、(異丙基氧基羰基)胺基、(1,3-噻唑-2-基甲基胺基)甲基、1H-咪唑-2-基、1H-吡唑-5-基、1H-吡咯-2-基、1-羥基乙基、2-(2-甲氧基乙基胺基)乙基、2-(二乙基胺基)乙基、2-(二乙基胺基)乙基胺基、2-(二甲基胺基)-
1-羥基乙基、2-(二甲基胺基)乙基、2-(二甲基胺基)乙基胺基、[2-(二甲基胺基)乙基胺基]甲基、2-(甲基胺基)乙基、2,2,2-三氟-1-羥基乙基、2,2,2-三氟乙基胺基、(2,2,2-三氟乙基胺基)甲基、2-[2,2-二氟乙基(甲基)胺基]乙基、(2,2-二氟乙基胺基)甲基、(2,2-二甲基丙基胺基)甲基、2-[2-甲氧基乙基(甲基)胺基]乙基、2-[環丙基甲基(甲基)胺基]乙基、2-胺基乙基、2-羥基乙基、2-羥基丙-2-基、(2-甲氧基乙基胺基)甲基、[(2-甲氧基苯基)甲基胺基]甲基、2-嗎啉-4-基乙基、2-嗎啉-4-基乙基胺基、2-苯基乙基胺基、2-六氫吡啶-1-基乙基、(2-吡啶-2-基乙基胺基)甲基、2-吡咯啶-1-基乙基、3-(二甲基胺基)丙基、(3,3-二氟環丁基)胺基、[(3-羥基-2,2-二甲基丙基)胺基]甲基、(3-羥基丙基胺基)甲基、[3-甲氧基丙基(甲基)胺基]甲基、(3-甲氧基丙基胺基)甲基、3-嗎啉-4-基丙基胺基、(3-嗎啉-4-基丙基胺基)甲基、5-甲基-1H-咪唑-2-基、2-甲基磺醯基乙基胺基、2-(4,4-二氟六氫吡啶-1-基)乙基胺基、1-嗎啉-4-基丙-2-基胺基、3-(二甲基胺基)丙基胺基、2-甲氧基乙基胺基、2-吡咯啶-1-基乙基胺基、1-甲基六氫吡啶-3-基、胺基甲基、(二甲基胺基)甲基,乙醯胺基甲基、胺基、胺基甲基、苯胺基、苯胺基甲基、苯磺醯胺基甲基、(苄基胺基)甲基、氯甲基、環丁基胺基、環丙基、環丙基(羥基)甲基、環丙基胺基、(環丙基胺基)甲基、環丙基甲基胺基、(環丙基甲基胺基)甲基、二甲基胺基、乙氧基羰基胺基、乙基、乙基胺基、乙基胺基甲基、羥基(苯基)甲基、羥基甲基、甲烷磺醯胺基甲基、甲氧基甲基、甲基、甲基胺基、甲基胺基甲基、(甲基丙基胺基)甲基、嗎啉-4-基、嗎啉-4-基甲基、(噁烷-2-基甲基胺基)甲基、(噁烷-3-基甲基胺基)甲基、(噁烷-4-基胺基)甲基、(氧雜環戊-3-基甲基胺基)甲基、六氫吡啶-1-基甲基、丙-2-基胺基、(丙-2-基胺基)甲基、(吡嗪-2-基甲基胺基)甲基、吡啶-3-基、(吡啶-3-基甲基胺基)甲基、(吡啶-4-基甲基胺基)甲基、(嘧啶-2-基胺基)甲基、(嘧
啶-2-基甲基胺基)甲基、吡咯啶-1-基甲基及噻吩-2-基。
在一個實施例中,本文所述任何式之基團係選
自由以下組成之群:
在一個實施例中,本文所述任何式之基團係選
自由以下組成之群:
在一個實施例中,本文所述任何式之基團係選
自由以下組成之群:
在一個實施例中,式I化合物由式IIA或IIB代表:
其中R2a、R2b、X、Rm、Rn、m、n及Rt係如本文中所定義且每一R1a獨立地係羥基、鹵基、-CN、C1-6鹵烷氧基、C1-6鹵烷基、C1-6烷氧基、C1-6烷基、C2-6烯基、C2-6炔基及C3-6環烷基,或可選取代基中之二者可接合形成另外部分飽和雜環,且
s係0、1、2或3。
在一些實施例中,每一R1a獨立地係羥基、鹵基、-CN、C1-6鹵烷氧基或C1-6鹵烷基。在一些實施例中,每一R1a獨立地係鹵基或-CF3。在一些實施例中,每一R1a獨立地係鹵基。在一些實施例中,s係0。在一些實施例中,s係1。在一些實施例中,s係2。在一些實施例中,s係3。
一般而言,使用ChemBioDraw Ultra命名本文中例示之具體化合物。然而,應瞭解,可使用其他名稱以鑑別相同結構之化合物。具體而言,亦可使用化學技術中通常認識之其他術語系統及符號(包括例如化學文摘服務社(Chemical Abstract Service)(CAS)及國際純化學與應用化學聯合會(International Union of Pure and Applied Chemistry)(IUPAC))命名化合物。可利用常見名稱或系統性或非系統性名稱命名其他化合物或基團。
舉例而言,實例10之化合物(下文顯示)可稱作N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒或N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-3H-苯并咪唑-4-甲脒,其中兩個名稱提供以下結構。
亦提供本文所述任何式之化合物的所有互變異構物形式。互變異構物彼此平衡。不管顯示何種互變異構物且不管互變異構物間之平衡性質,化合物應由熟習此項技術者理解為包含二者。下文顯示苯并咪唑及咪唑并[4,5-b]吡啶互變異構物之非限制性實例:
亦提供本文所述化合物或其醫藥上可接受之鹽、異構物或混合物,其中附接至碳原子之1至n個氫原子可由氘原子或D置換,其中n係分子中之氫原子之數目。如業內所知,氘原子係氫原子之非放射性同位素。該等化合物可增加代謝抗性,且因此在投與哺乳動物時可用於增加本文所述化合物或其醫藥上可接受之鹽、異構物或混合物之半衰期。參見(例如),Foster,「Deuterium Isotope Effects in Studies of Drug Metabolism」,Trends Pharmacol.Sci.,5(12):524-527(1984)。該等化合物係藉由業內已知之方式、例如藉由採用一或多個氫原子由氘置換之起始材料來合成。
亦提供本文所述化合物之醫藥上可接受之鹽、水合物、溶劑合物、互變異構物形式、多形體及前藥。「醫藥上可接受」或「生理上可接受」係指可用於製備適於獸醫或人類醫藥使用之醫藥組合物的化合物、鹽、組合物、劑型及其他材料。「醫藥上可接受之鹽」或「生理上可接受之鹽」包括(例如)與無機酸之鹽及與有機酸之鹽。另外,若本文所述化合物係以酸加成鹽形式獲得,則可藉由鹼化酸性鹽之溶液獲得游離鹼。相反,若產物係游離鹼,則加成鹽(具體而言醫藥上可接受之加成鹽)可根據自鹼性化合物製備酸加成鹽之習用程序藉由將游離鹼溶解於適宜有機溶劑中並用酸處理溶液來產生。熟習此項技術者應識別可用於製備無毒性醫藥上可接受之加成鹽之各種合成方法。
「溶劑合物」係藉由溶劑與化合物之相互作用來形成。亦提供本文所述化合物之鹽之溶劑合物。亦提供本文所述化合物之水合物。
「前藥」係在投與人體時根據相同化學或酶路徑轉化成生物活性母體藥物之藥物的無生物活性之衍生物。
在某些實施例中,提供本文所述化合物或其醫藥上可接受之鹽或混合物之其光學異構物、外消旋物或其他混合物。在彼等情況下,單一鏡像異構物或非鏡像異構物(即光學活性形式)可藉由不對稱合成或藉由拆分外消旋物來獲得。外消旋物之拆分可藉由(例如)習用方法、例如在拆分試劑存在下結晶或使用(例如)手性高壓液相層析(HPLC)管柱之層析來完成。另外,亦提供本文所述羥基脒化合物之Z-及E-形式(或順式-及反式-形式)。特定而言,即使若對於碳-碳雙鍵以及羥基脒鍵二者命名僅一個名稱,但包括Z-及E-形式。
本文提供之包括本文所述化合物或其醫藥上可接受之鹽、異構物或混合物的組合物可包括外消旋混合物或含有鏡像異構物過量之一種鏡像異構物或單一非鏡像異構物或非鏡像異構物混合物的混合物。該等化合物之所有該等異構形式明確包括於本文中,如同每一及每個異構形式皆明確且個別地列示。
在某些實施例中,本文亦提供本文所述化合物或其醫藥上可接受之鹽、異構物或混合物之結晶及非晶形形式。
在某些實施例中,亦提供本文所述化合物或其醫藥上可接受之鹽、異構物或混合物之螯合物、非共價複合物及其混合物。「螯合物」係藉由使化合物在兩個(或更多個)點處與金屬離子配位來形成。「非共價複合物」係藉由化合物與另一分子之相互作用來形成,其中化合物與分子之間不形成共價鍵。舉例而言,複合可經由凡得瓦(van der Waals)相互作用、氫鍵結及靜電相互作用(亦稱作離子鍵結)來發生。
本文所述方法可適於活體內或離體細胞群體。「活體內」意指
在活的個體內,如同在動物或人類內。在此上下文中,本文所述方法可在個體中治療使用。「離體」意指在活的個體外。離體細胞群體之實例包括活體外細胞培養物及包括自個體獲得之流體或組織試樣之生物試樣。該等試樣可藉由業內熟知之方法獲得。實例性生物流體試樣包括血液、腦脊髓液、尿液及唾液。實例性組織試樣包括腫瘤及其生檢。在此上下文中,本發明可用於多種目的,包括治療及實驗目的。舉例而言,本發明可離體用於確定對於給定適應症、細胞類型、個體及其他參數之IDO1抑制劑之投與時間表及/或劑量。自該使用搜集之資訊可用於實驗目的或用於診療所中以設定活體內治療之方案。本發明可適宜之其他離體用途闡述於下文中或將為熟習此項技術者所明瞭。可進一步表徵所選化合物以檢查人類或非人類個體中之安全或耐受劑量。可使用熟習此項技術者通常已知之方法檢查該等性質。
在一些實施例中,本文所述化合物可用於治療患有或懷疑患有對IDO1活性之抑制有反應或相信有反應之疾病狀態、病症及病況(亦統稱為「適應症」)的個體。在一些實施例中,本文所述化合物可用於抑制IDO1多肽之活性。在一些實施例中,本文所述化合物可用於抑制過度或破壞性免疫反應或細胞(例如癌細胞)之生長或增殖,或抑制免疫抑制。
適於經本文所述化合物治療之實例性適應症包括(但不限於)癌症、病毒感染(例如HIV感染、HBV感染、HCV感染)、其他感染(例如,皮膚感染、GI感染、尿路感染、泌尿生殖感染及全身性感染)、抑鬱症、神經退化病症(例如阿茲海默氏病(Alzheimer's disease)及亨庭頓氏病(Huntington's disease))、創傷、年齡相關性白內障、器官移植(例如,器官移植排斥)及自體免疫疾病。
自體免疫疾病之實例包括(但不限於)氣喘、膠原疾病(例如類風濕性關節炎)、全身性紅斑狼瘡、夏普氏症候群(Sharp's syndrome)、
CREST症候群(鈣質沉著、雷諾症候群(Raynaud's syndrome)、食管活動不良、指端硬化、毛細管擴張)、皮肌炎、血管炎(韋格納氏病(Morbus Wegener's))及薛格連氏症候群(Sjögren's syndrome)、腎病(例如古巴士德氏症候群(Goodpasture's syndrome)、快速進行性腎小球性腎炎及膜增殖性腎小球性腎炎II型)、內分泌疾病(例如I型糖尿病)、自體免疫多內分泌腺病-念珠菌病-外胚層營養不良(APECED)、自體免疫甲狀旁腺病、惡性貧血、性腺不足、特發性艾迪森氏病(Morbus Addison's)、甲狀腺機能亢進、橋本氏甲狀腺炎(Hashimoto's thyroiditis)及原發性黏液水腫、皮膚疾病(例如尋常天皰瘡、大皰性類天皰瘡、妊娠期皰疹、大皰性表皮松解及重型多形性紅斑)、肝病(例如原發性膽汁性肝硬化、自體免疫膽管炎、1型自體免疫肝炎、2型自體免疫肝炎、原發性硬化性膽管炎)、神經元疾病(例如多發性硬化、重症肌無力、肌無力蘭伯特-伊格爾斯症候群(myasthenic Lambert-Eaton syndrome)、獲得性肌神經切斷、格林-巴利症候群(Guillain-Barre syndrome)(馬勒-費雪症候群(Muller-Fischer syndrome))、僵硬人症候群、小腦變性、共濟失調、斜視性眼陣攣、感覺神經病變及失弛緩症)、血液疾病(例如自體免疫溶血性貧血、特發性血小板減少紫斑症(韋爾霍夫病(Morbus Werlhof)))、與自體免疫反應相關之傳染病(例如AIDS、過敏性發炎、發炎性腸病、牛皮癬及全身性紅斑狼瘡)或瘧疾及查加斯氏病(Chagas disease)。
在一些實施例中,本文所述化合物可用於治療癌症、病毒感染、抑鬱症、神經退化病症、創傷、年齡相關性白內障、器官移植排斥或自體免疫疾病。
在其他實施例中,欲治療之疾病係實體腫瘤。在特定實施例中,實體腫瘤係來自胰臟癌、膀胱癌、結腸直腸癌、乳癌、前列腺癌、腎癌、肝細胞癌、肺癌、卵巢癌、子宮頸癌、胃癌、食管癌、頭
頸癌、黑色素瘤、神經內分泌癌、CNS癌、腦瘤(例如,神經膠質瘤、退行發育性少突神經膠質瘤、成人多形性神經膠母細胞瘤及成人退行發育性星細胞瘤)、骨癌或軟組織肉瘤。在一些實施例中,實體腫瘤係來自非小細胞肺癌、小細胞肺癌、結腸癌、CNS癌、黑色素瘤、卵巢癌、腎癌、前列腺癌或乳癌。
在一些實施例中,疾病係自體免疫疾病。在特定實施例中,自體免疫疾病係全身性紅斑狼瘡(SLE)、重症肌無力、類風濕性關節炎(RA)、急性彌漫性腦脊髓炎、特發性血小板減少紫斑症、多發性硬化(MS)、牛皮癬、薛格連氏症候群、牛皮癬、自體免疫溶血性貧血、氣喘或慢性阻塞性肺病(COPD)。在其他實施例中,疾病係發炎。在其他實施例中,疾病係過度或破壞性免疫反應,例如氣喘、類風濕性關節炎、多發性硬化、慢性阻塞性肺病(COPD)及狼瘡。
提供治療患有或懷疑患有對IDO1活性之抑制有反應或相信有反應之疾病或病況的個體之方法,其係藉由向該個體投與本文所述化合物或其醫藥上可接受之鹽、異構物或混合物來完成。亦提供抑制IDO1多肽之激酶活性之方法,其係藉由使多肽與本文所述化合物或其醫藥上可接受之鹽、異構物或混合物接觸來完成。亦提供抑制造血來源之癌細胞生長或增殖之方法,其包含使癌細胞與有效量之本文所述化合物或其醫藥上可接受之鹽、異構物或混合物接觸。
在一個實施例中,本申請案之化合物可與一或多種正使用及/或經研發以治療癌症或發炎病症之另外治療劑組合使用。一或多種另外治療劑可為化學治療劑、免疫治療劑、放射性治療劑、抗贅瘤劑、抗癌劑、抗增殖劑、抗纖維變性劑、抗血管生成劑、治療性抗體或其任一組合。
一或多種另外治療劑可為針對以下之抑制劑:PI3K(例如PI3Kγ、PI3Kβ、PI3Kδ及/或PI3Kα)、傑那斯(Janus)激酶(JAK)(例如
JAK1、JAK2及/或JAK3)、脾酪胺酸激酶(SYK)、布魯頓氏(Bruton’s)酪胺酸激酶(BTK)、含有溴結構域之蛋白質抑制劑(BRD)(例如BRD4)、賴胺醯氧化酶蛋白質(LOX)、賴胺醯氧化酶樣蛋白質(LOXL)(例如LOXL1-5)、基質金屬蛋白酶(MMP)(例如MMP 1-10)、腺苷A2B受體(A2B)、異檸檬酸去氫酶(IDH)(例如IDH1)、細胞凋亡信號調節激酶(ASK)(例如ASK1)、絲胺酸/蘇胺酸激酶TPL2、盤狀結構域受體(DDR)(例如DDR1及DDR2)、組織蛋白去乙醯酶(HDAC)、蛋白激酶C(PKC)或其任一組合。
磷酸肌醇3-激酶抑制劑(PI3K抑制劑)藉由抑制磷酸肌醇3-激酶(包括(但不限於)PI3Kγ、PI3Kβ、PI3Kδ及PI3Kα)中之一或多者起作用。PI3K抑制劑之非限制性實例包括渥曼青黴素(wortmannin)、去甲氧綠膠黴(demethoxyviridin)、LY294002、艾代拉裡斯(idelalisib)、哌立福辛(perifosine)、PX-866、IPI-145、BAY 80-6946、BEZ235、RP6530、TGR 1202、INK1117、GDC-0941、BKM120、XL147(亦稱作SAR245408)、XL765(亦稱作SAR245409)、Palomid 529、GSK1059615、ZSTK474、PWT33597、IC87114、CAL263、RP6503、PI-103、GNE-477、CUDC-907及AEZS-136。在一些實施例中,PI3抑制劑係PI3Kδ抑制劑,例如艾代拉裡斯、IPI-145、RP6530及RP6503、以及揭示於美國專利第8,569,296號及PCT公開案WO 2014/006572及WO 2015/001491中之彼等。
在一些實施例中,一或多種另外治療劑可為MMP9抑制劑或抑制MMP9之表現及/或活性之藥劑。MMP9之代表性蛋白質序列係GenBank登錄號NP_004985。該抑制劑可為小分子或生物。舉例而言,Gu等人,The Journal of Neuroscience,25(27):6401-6408(2005)揭示特定MMP9抑制劑SB-3CT(CAS 292605-14-2)。此外,亦已證實siRNA、反義RNA及抗體抑制MMP9之表現或活性且在本發明之範疇
內。在一個實施例中,MMP9抑制劑係單株抗MMP9抗體。在一些實施例中,一或多種另外治療劑包括MMP9抑制劑及核苷類似物(例如吉西他濱(gemcitabine)。
一種、兩種、三種或更多種治療劑(例如PI3K抑制劑、JAK抑制劑、SYK抑制劑、BTK抑制劑、BRD4抑制劑、LOXL2抑制劑、MMP9抑制劑、A2B抑制劑、IDH抑制劑、ASK抑制劑、TPL2抑制劑、DDR1抑制劑、TBK抑制劑、HDAC抑制劑、PKC抑制劑)可進一步與化學治療劑、免疫治療劑、放射性治療劑、抗贅瘤劑、抗癌劑、抗纖維變性劑、抗血管生成劑、治療性抗體或其任一組合一起使用或組合。
化學治療劑可藉由其作用成(例如)以下基團之機制來分類:抗代謝物/抗癌劑,例如嘧啶類似物(氟尿苷(floxuridine)、卡培他濱(capecitabine)及阿糖胞苷(cytarabine));嘌呤類似物、葉酸拮抗劑及相關抑制劑,抗增殖/抗有絲分裂劑,包括天然產品,例如長春花生物鹼(vinca alkaloid)(長春鹼(vinblastine)、長春新鹼(vincristine))及微管(例如紫杉烷(taxane)(太平洋紫杉醇(paclitaxel)、歐洲紫杉醇(docetaxel))、長春鹼(vinblastin)、諾考達唑(nocodazole)、埃博黴素(epothilone)及溫諾平(navelbine))、表鬼臼毒素(epidipodophyllotoxin)(依託泊苷(etoposide)、替尼泊苷(teniposide));DNA損傷劑(放線菌素(actinomycin)、安吖啶(amsacrine)、白消安(busulfan)、卡鉑(carboplatin)、氮芥苯丁酸(chlorambucil)、順鉑(cisplatin)、環磷醯胺(cyclophosphamide)、癌得星(Cytoxan)、放線菌素(dactinomycin)、道諾黴素(daunorubicin)、多柔比星(doxorubicin)、泛艾黴素(epirubicin)、異環磷醯胺(iphosphamide)、美法侖(melphalan)、甲氯乙胺(merchlorehtamine)、絲裂黴素(mitomycin)、米托蒽醌(mitoxantrone)、亞硝基脲(nitrosourea)、丙卡巴肼(procarbazine)、紫
杉醇(taxol)、剋癌易(taxotere)、替尼泊苷、依託泊苷、三伸乙基硫代磷醯胺);抗生素,例如放線菌素(放線菌素D)、道諾黴素、多柔比星(阿德力黴素(adriamycin))、伊達比星(idarubicin)、蒽環、米托蒽醌、博來黴素(bleomycin)、普卡黴素(plicamycin)(光輝黴素(mithramycin))及絲裂黴素;酶(L-天冬醯胺酶,其系統性代謝L-天冬醯胺剝奪不具有合成其自身天冬醯胺之能力之細胞);抗血小板劑;抗增殖/抗有絲分裂烷基化劑,例如氮芥環磷醯胺及類似物、美法侖、氮芥苯丁酸)、及(六甲基三聚氰胺及噻替派(thiotepa))、烷基亞硝基脲(BCNU)及類似物、鏈脲黴素(streptozocin))、三氮烯-達卡巴嗪(trazenes-dacarbazinine)(DTIC);抗增殖/抗有絲分裂抗代謝物,例如葉酸類似物(胺甲喋呤(methotrexate));鉑配位錯合物(順鉑、奧鉑(oxiloplatinim)、卡鉑)、丙卡巴肼、羥基脲、米托坦(mitotane)、胺魯米特(aminoglutethimide);激素、激素類似物(雌激素、他莫昔芬(tamoxifen)、戈舍瑞林(goserelin)、比卡魯胺(bicalutamide)、尼魯米特(nilutamide))及芳香酶抑制劑(來曲唑(letrozole)、阿那曲唑(anastrozole));抗凝劑(肝素、合成肝素鹽及凝血酶之其他抑制劑);纖維蛋白溶解劑(例如組織血纖維蛋白溶酶原活化劑、鏈球菌激酶及尿激酶)、阿斯匹林(aspirin)、雙嘧達莫(dipyridamole)、噻氯匹定(ticlopidine)、氯吡格雷(clopidogrel);抗遷移劑;抗分泌劑(佈雷菲德菌素(breveldin));免疫抑制劑,他克莫司(tacrolimus)西羅莫司(sirolimus)硫唑嘌呤(azathioprine)、麥考酚酯(mycophenolate);化合物(TNP-470、染料木黃酮(genistein))及生長因子抑制劑(血管內皮生長因子抑制劑、纖維母細胞生長因子抑制劑);血管收縮肽受體阻斷劑、一氧化氮供體;反義寡核苷酸;抗體(曲妥珠單抗(trastuzumab)、利妥昔單抗(rituximab));細胞週期抑制劑及分化誘導物(維甲酸(tretinoin));抑制劑、拓撲異構酶抑制劑(多柔比星(阿德力黴素)、道
諾黴素、放線菌素、恩尼泊苷(eniposide)、泛艾黴素、依託泊苷、伊達比星、伊立替康(irinotecan)及米托蒽醌、托泊替康(topotecan)、伊立替康、喜樹鹼(camptothesin))、皮質類固醇(可的松(cortisone)、地塞米松(dexamethasone)、氫化可體松(hydrocortisone)、甲基潑尼松龍(methylpednisolone)、普賴松(prednisone)及潑尼松龍(prenisolone));生長因子信號轉導激酶抑制劑;功能障礙誘導物、毒素,例如霍亂毒素、蓖麻毒蛋白、假單胞菌屬外毒素、百日咳博德特菌(Bordetella pertussis)腺苷酸環化酶毒素或白喉毒素及半胱天冬酶活化劑;及染色質。
如本文所用術語「化學治療劑」或「化學治療」(或「化學療法」,在用化學治療劑治療之情形下)意指涵蓋可用於治療癌症之任何非蛋白質性(即,非肽性)化學化合物。化學治療藥劑之實例包括烷基化劑,例如噻替派及環磷醯胺(CYTOXAN);磺酸烷基酯,例如白消安、英丙舒凡(improsulfan)及哌泊舒凡(piposulfan);氮丙啶,例如苯并多巴(benzodopa)、卡波醌(carboquone)、米得哌(meturedopa)及烏得哌(uredopa);伸乙基亞胺及甲基蜜胺,包括六甲蜜胺(alfretamine)、三伸乙基蜜胺、三伸乙基磷醯胺、三伸乙基硫代磷醯胺及三羥甲基蜜胺;番荔枝內酯(acetogenin)(尤其係布拉他辛(bullatacin)及布拉他辛酮(bullatacinone));喜樹鹼(包括合成類似物托泊替康);苔蘚抑制素(bryostatin);卡利抑制素(callystatin);CC-1065(包括其合成類似物阿多來新(adozelesin)、卡折來新(carzelesin)及比折來新(bizelesin));念珠藻素(cryptophycin)(尤其係念珠藻素1及念珠藻素8);多拉斯他汀(dolastatin);多卡米星(duocarmycin)(包括類似物單甲基-奧瑞斯他汀E及單甲基-奧瑞斯他汀F);多卡米星(多卡米星)(包括合成類似物KW-2189及CBI-TMI);艾榴素(eleutherobin);水鬼蕉鹼(pancratistatin);匍枝珊瑚醇(sarcodictyin);海綿素
(spongistatin);氮芥,例如氮芥苯丁酸、萘氮芥(chlornaphazine)、氯磷醯胺(cholophosphamide)、雌氮芥(estramustine)、異環磷醯胺(ifosfamide)、甲基二氯乙基胺(mechlorethamine)、鹽酸甲基二氯乙基胺氧化物(甲mechlorethamine oxide hydrochloride)、美法侖、新氮芥(novembichin)、苯乙酸氮芥膽甾醇酯(phenesterine)、潑尼莫司汀(prednimustine);曲磷胺(trofosfamide)、尿嘧啶氮芥;硝基脲,例如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(foremustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)及雷莫司汀(ranimnustine);抗生素,例如烯二炔抗生素(例如,卡奇黴素(calicheamicin),尤其係卡奇黴素γII及卡奇黴素φI1(例如,參見Agnew,Chem.Intl.Ed.Engl,33:183-186(1994));達內黴素(dynemicin),包括達內黴素A;雙膦酸鹽,例如氯屈膦酸鹽(clodronate);埃斯培拉黴素(esperamicin);以及新製癌菌素髮色團(neocarzinostatin chromophore)及相關色蛋白烯二炔抗生素發色團)、阿克拉黴素(aclacinomysin)、放線菌素、安麯黴素(authramycin)、偶氮絲胺酸、博萊黴素、放線菌素C(cactinomycin)、卡拉黴素(carabicin)、洋紅黴素(carminomycin)、嗜癌黴素(carzinophilin)、色黴素(chromomycin)、放線菌素、道諾黴素、地托比星(detorubicin)、6-重氮基-5-側氧基-L-正白胺酸、多柔比星(包括嗎啉基-多柔比星、氰基嗎啉基-多柔比星、2-吡咯啉基-多柔比星及去氧多柔比星)、泛艾黴素、依索比星(esorubicin)、伊達比星、麻西羅黴素(marcellomycin)、絲裂黴素(例如絲裂黴素C)、黴酚酸(mycophenolic acid)、諾拉黴素(nogalamycin)、橄欖黴素(olivomycin)、培洛黴素(peplomycin)、泊非黴素(porfiromycin)、嘌呤黴素(puromycin)、三鐵阿黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑黴素(streptonigrin)、鏈脲黴素、殺結核菌素(tubercidin)、烏苯美司(ubenimex)、淨司他汀
(zinostatin)、佐柔比星(zorubicin);抗代謝物,例如胺甲喋呤及5-氟尿嘧啶(5-FU);葉酸類似物,例如二甲葉酸(denopterin)、胺甲喋呤、蝶羅呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤類似物,例如氟達拉濱(fludarabine)、6-巰基嘌呤、硫咪嘌呤(thiamiprine)、硫鳥嘌呤;嘧啶類似物,例如安西他濱(ancitabine)、阿紮胞苷(azacitidine)、6-阿紮尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷、二去氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依諾他濱(enocitabine)、氟尿苷(floxuridine);雄激素,例如卡普睪酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睪內酯(testolactone);抗腎上腺素,例如胺魯米特、米托坦、曲洛司坦(trilostane);葉酸補充劑,例如亞葉酸;乙醯葡醛酸內酯(aceglatone);醛磷醯胺糖苷(aldophosphamide glycoside);胺基乙醯丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶;黑思布希(hestrabucil);比生群(bisantrene);依達曲沙(edatraxate);地磷醯胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);依氟鳥胺酸(elformthine);依利乙銨(elliptinium acetate);埃博黴素;依託格魯(etoglucid);硝酸鎵;羥基脲;香菇多糖(lentinan);甲醯四氫葉酸;氯尼達明(lonidainine);類美登素(maytansinoid),例如美登素(maytansine)及安絲菌素(ansamitocin);米托胍腙(mitoguazone);米托蒽醌;莫哌達醇(mopidamol);尼群克林(nitraerine);噴司他汀(pentostatin);蛋胺氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);氟嘧啶;亞葉酸;鬼臼酸;2-乙基醯肼;丙卡巴肼;PSK(r);雷佐生(razoxane);根黴素(rhizoxin);西佐喃(sizofiran);鍺螺胺(spirogermanium);細格孢氮雜酸(tenuazonic acid);三亞胺醌(triaziquone);2,2’,2”-三氯三乙胺;單端孢黴烯(trichothecene)(尤其
係T-2毒素、疣皰菌素A(verrucarin A)、桿孢菌素(roridin A)及蛇形菌素(anguidine));烏拉坦(urethane);長春地辛(vindesine);達卡巴嗪(dacarbazine);甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴衛矛醇(mitolactol);哌泊溴烷(pipobroman);噶薩托辛(gacytosine);阿拉伯糖苷(arabinoside)(「Ara-C」);環磷醯胺;噻替派;類紫杉醇,例如太平洋紫杉醇(TAXOL(r)及多西紫杉醇(doxetaxel)(TAXOTERE(r));氮芥苯丁酸;吉西他濱(Gemzar(r));6-硫鳥嘌呤;巰基嘌呤;胺甲喋呤;鉑類似物,例如順鉑及卡鉑;長春鹼;鉑;依託泊苷(VP-16);異環磷醯胺;米托蒽醌;長春新鹼;長春瑞濱(vinorelbine)(Navelbine(r));能滅瘤(novantrone);替尼泊苷;依達曲沙(edatrexate);道諾黴素;胺喋呤(aminopterin);截瘤達(xeoloda);伊班膦酸鹽(ibandronate);CPT-11;拓撲異構酶抑制劑RFS 2000;二氟甲基鳥胺酸(DMFO);類視色素,例如視黃酸;卡培他濱;FOLFIRI(氟尿嘧啶、甲醯四氫葉酸及伊立替康)及上述藥劑中任一者之醫藥上可接受之鹽、酸或衍生物。本申請案中使用或包括一或多種化學治療劑。舉例而言,吉西他濱、nab-太平洋紫杉醇及吉西他濱/nab-太平洋紫杉醇與JAK抑制劑及/或PI3Kδ抑制劑一起用於治療過度增殖病症。
「化學治療劑」之定義中亦包括用於調節或抑制激素對腫瘤之作用之抗激素劑,例如抗雌激素及選擇性雌激素受體調節劑(SERM),包括(例如)他莫昔芬(包括NolvadexTM)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)、4-羥基他莫昔芬、曲沃昔芬(trioxifene)、可莫昔芬(keoxifene)、LY117018、奧那司酮(onapristone)及托瑞米芬(toremifene)(Fareston(r));酶芳香酶之抑制劑,其調節腎上腺中之雌激素產生,例如4(5)-咪唑、胺魯米特、乙酸甲地孕酮(megestrol acetate)(Megace(r))、依西美坦(exemestane)、福
美坦(formestane)、法曲唑(fadrozole)、伏氯唑(vorozole)(Rivisor(r))、來曲唑(Femara(r))及阿那曲唑(anastrozole)(Arimidex(r).);及抗雄激素,例如氟他胺(flutamide)、尼魯米特(nilutamide)、比卡魯胺(bicalutamide)、柳培林(leuprohde)及戈舍瑞林(goserelin);及上述藥劑中任一者之醫藥上可接受之鹽、酸或衍生物。
抗血管生成劑包括(但不限於)視黃酸及其衍生物、2-甲氧基雌二醇、血管抑素(r)、內皮抑素(r)、舒拉明(suramin)、角鯊胺(squalamine)、金屬蛋白酶-1之組織抑制劑、金屬蛋白酶-2之組織抑制劑、血纖維蛋白溶酶原活化劑抑制劑-1、血纖維蛋白溶酶原活化劑抑制劑-2、軟骨衍生之抑制劑、太平洋紫杉醇(nab-太平洋紫杉醇)、血小板因子4、硫酸魚精蛋白(鯡精蛋白)、硫酸幾丁質衍生物(自雪花蟹殼製備)、硫酸多醣肽多醣複合物(sp-pg)、星狀孢菌素、基質代謝之調節劑,包括(例如)脯胺酸類似物((1-氮雜環丁烷-2-甲酸(LACA)、順式羥基脯胺酸、D,L-3,4-脫氫脯胺酸、硫脯胺酸、.α.-二吡啶、β-胺基丙腈富馬酸鹽、4-丙基-5-(4-吡啶基)-2(3H)-噁唑酮;胺甲喋呤、米托蒽醌、肝素、干擾素、2巨球蛋白-血清、chimp-3、糜蛋白酶抑制素、β-環糊精十四硫酸鹽、依匹黴素(eponemycin);煙麯黴素(fumagillin)、硫羥蘋果酸金鈉、d-青黴胺(CDPT)、β-1-抗膠原酶-血清、α-2-抗胞漿素、比生群、氯苯紮利(lobenzarit)二鈉、n-2-羧基苯基-4-氯鄰胺基苯甲酸二鈉或「CCA」、沙利竇邁(thalidomide);血管生成抑制類固醇、羧基胺基咪唑(cargboxynaminolmidazole);金屬蛋白酶抑制劑,例如BB94。其他抗血管生成劑包括抗體,較佳針對該等血管生成生長因子之單株抗體:β-FGF、α-FGF、FGF-5、VEGF同種型、VEGF-C、HGF/SF及Ang-1/Ang-2。參見Ferrara N.及Alitalo,K.「Clinical application of angiogenic growth factors and their
inhibitors」(1999)Nature Medicine 5:1359-1364。
抗纖維變性劑包括(但不限於)諸如β-胺基丙腈(BAPN)等化合物以及揭示於以下中之化合物:於1990年10月23日頒予Palfreyman等人之標題為「Inhibitors of lysyl oxidase」之關於賴胺醯氧化酶之抑制劑及其用於治療與膠原異常沈積相關之疾病及病況的用途之美國專利第4,965,288號;於1991年3月5日頒予Kagan等人之標題為「Anti-fibrotic agents and methods for inhibiting the activity of lysyl oxidase in situ using adjacently positioned diamine analogue substrate」關於抑制LOX用於治療各種病理纖維變性狀態之化合物之美國專利第4,997,854號,其以引用方式併入本文中。其他實例性抑制劑闡述於以下中:於1990年7月24日頒予Palfreyman等人之標題為「Inhibitors of lysyl oxidase」之關於諸如2-異丁基-3-氟-、氯-或溴-烯丙基胺等化合物的美國專利第4,943,593號;以及例如美國專利第5,021,456號;美國專利第5,5059,714號;美國專利第5,120,764號;美國專利第5,182,297號;美國專利第5,252,608號(關於2-(1-萘基氧基甲基)-3-氟烯丙基胺);及美國專利申請案第2004/0248871號,該等案件以引用方式併入本文中。實例性抗纖維變性劑亦包括與賴胺醯氧化酶之活性位點之羰基反應的一級胺,且更具體而言在與羰基結合後產生藉由共振穩定之產物之彼等,例如以下一級胺:乙二胺、肼、苯基肼及其衍生物、胺基脲、及尿素衍生物、胺基腈(例如β-胺基丙腈(BAPN))或2-硝基乙胺、不飽和或飽和鹵基胺(例如2-溴-乙胺、2-氯乙胺、2-三氟乙胺、3-溴丙胺、對-鹵基苄基胺)、硒高半胱胺酸內酯。同樣,抗纖維變性劑係穿透或不穿透細胞之銅螯合劑。實例性化合物包括間接抑制劑,該等化合物阻斷源自賴胺醯基及羥基賴胺醯基殘基由賴胺醯氧化酶氧化脫胺之醛衍生物,例如硫醇胺,具體而言D-青黴胺或其類似物,例如2-胺基-5-巰基-5-甲基己酸、D-2-胺基-3-甲基-3-((2-乙醯胺基乙基)二硫基)丁
酸、對-2-胺基-3-甲基-3-((2-胺基乙基)二硫基)丁酸、4-((對-1-二甲基-2-胺基-2-羧基乙基)二硫基)丁烷亞磺酸鈉、2-乙醯胺基乙基-2-乙醯胺基乙烷硫醇亞磺酸鹽、4-巰基丁烷亞磺酸鈉三水合物。
免疫治療劑包括且不限於適於治療患者之治療性抗體;例如阿巴伏單抗(abagovomab)、阿德木單抗(adecatumumab)、阿福圖珠單抗(afutuzumab)、阿倫單抗(alemtuzumab)、阿托珠單抗(altumomab)、阿麥妥昔(amatuximab)、麻安莫單抗(anatumomab)、阿西莫單抗(arcitumomab)、巴維昔單抗(bavituximab)、貝妥莫單抗(bectumomab)、貝伐珠單抗(bevacizumab)、比伐單抗(bivatuzumab)、蘭妥莫單抗(blinatumomab)、貝倫妥單抗(brentuximab)、坎妥珠單抗(cantuzumab)、卡妥索單抗(catumaxomab)、西妥昔單抗(cetuximab)、西他珠單抗(citatuzumab)、西妥木單抗(cixutumumab)、伏妥珠單抗(clivatuzumab)、可那木單抗(conatumumab)、達雷木單抗(daratumumab)、卓齊妥單抗(drozitumab)、力戈圖單抗(duligotumab)、斯吉妥單抗(dusigitumab)、地莫單抗(detumomab)、達西珠單抗(dacetuzumab)、達洛珠單抗(dalotuzumab)、依美昔單抗(ecromeximab)、埃羅妥珠單抗(elotuzumab)、恩司昔單抗(ensituximab)、厄馬索單抗(ertumaxomab)、埃達珠單抗(etaracizumab)、法勒珠單抗(farietuzumab)、芬克拉妥珠單抗(ficlatuzumab)、芬妥木單抗(figitumumab)、弗蘭托單抗(flanvotumab)、弗妥昔單抗(futuximab)、蓋尼塔單抗(ganitumab)、吉妥珠單抗(gemtuzumab)、吉瑞妥昔單抗(girentuximab)、格萊木單抗(glembatumumab)、替伊莫單抗(ibritumomab)、伊戈伏單抗(igovomab)、英加妥珠單抗(imgatuzumab)、英達妥昔單抗(indatuximab)、伊珠單抗(inotuzumab)、英妥木單抗(intetumumab)、伊匹單抗(ipilimumab)、伊妥木單抗(iratumumab)、拉貝珠單抗
(labetuzumab)、來沙木單抗(lexatumumab)、林妥珠單抗(lintuzumab)、洛伏珠單抗(lorvotuzumab)、魯卡木單抗(lucatumumab)、馬帕木單抗(mapatumumab)、馬妥珠單抗(matuzumab)、米拉珠單抗(milatuzumab)、明瑞莫單抗(minretumomab)、米妥莫單抗(mitumomab)、莫妥莫單抗(moxetumomab)、納那妥單抗(narnatumab)、那莫單抗(naptumomab)、奈昔木單抗(necitumumab)、尼妥珠單抗(nimotuzumab)、若莫單抗(nofetumomabn)、卡妥珠單抗(ocaratuzumab)、奧法木單抗(ofatumumab)、奧拉妥單抗(olaratumab)、昂妥珠單抗(onartuzumab)、奧妥珠單抗(oportuzumab)、瑞戈伏單抗(oregovomab)、帕尼單抗(panitumumab)、帕圖珠單抗(parsatuzumab)、帕圖單抗(patritumab)、帕圖莫單抗(pemtumomab)、帕妥珠單抗(pertuzumab)、平妥單抗(pintumomab)、普托木單抗(pritumumab)、拉妥木單抗(racotumomab)、拉圖單抗(radretumab)、利妥木單抗(rilotumumab)、利妥昔單抗(rituximab)、羅妥木單抗(robatumumab)、沙妥莫單抗(satumomab)、昔洛珠單抗(sibrotuzumab)、司妥昔單抗(siltuximab)、司妥佐單抗(simtuzumab)、索利圖單抗(solitomab)、他妥珠單抗(tacatuzumab)、他妥莫單抗(taplitumomab)、替妥莫單抗(tenatumomab)、替普莫單抗(teprotumumab)、加珠單抗(tigatuzumab)、托西莫單抗(tositumomab)、曲妥珠單抗(trastuzumab)、托卡珠單抗(tucotuzumab)、烏妥昔單抗(ublituximab)、維妥珠單抗(veltuzumab)、沃妥珠單抗(vorsetuzumab)、沃圖莫單抗(votumumab)、紮魯木單抗(zalutumumab)、CC49及3F8。所列示治療性抗體可進一步經放射性同位素粒子(例如銦In 111、釔Y 90、碘I-131)標記或與其組合。
本申請案亦提供治療經歷一或多種標準療法(例如化學療法、放
射療法、免疫療法、手術或其組合)之個體的方法。因此,可在投與化學療法、放射療法、免疫療法、手術或其組合之前、期間或之後投與一或多種治療劑或抑制劑。
在某些實施例中,個體可為如下人類:(i)對於至少一種化學療法治療實質上難治或(ii)在用化學療法治療後復發或(i)及(ii)二者。在一些實施例中,個體對於至少兩種、至少三種、或至少四種化學療法治療(包括標準或實驗化學療法)難治。
在某些實施例中,個體對於至少一種、至少兩種、至少三種、或至少四種選自以下之化學療法治療(包括標準或實驗化學療法)難治:氟達拉濱、利妥昔單抗、奧妥珠單抗、烷基化劑、阿倫單抗及其他化學療法治療,例如CHOP(環磷醯胺、多柔比星、長春新鹼、普賴松);R-CHOP(利妥昔單抗-CHOP);hyperCVAD(多分次環磷醯胺、長春新鹼、多柔比星、地塞米松、胺甲喋呤、阿糖胞苷);R-hyperCVAD(利妥昔單抗-hyperCVAD);FCM(氟達拉濱、環磷醯胺、米托蒽醌);R-FCM(利妥昔單抗、氟達拉濱、環磷醯胺、米托蒽醌);硼替佐米(bortezomib)及利妥昔單抗;替西羅莫司及利妥昔單抗;替西羅莫司及Velcade®;碘-131托西莫單抗(Bexxar®)及CHOP;CVP(環磷醯胺、長春新鹼、普賴松);R-CVP(利妥昔單抗-CVP);ICE(異環磷醯胺、卡鉑、依託泊苷);R-ICE(利妥昔單抗-ICE);FCR(氟達拉濱、環磷醯胺、利妥昔單抗);FR(氟達拉濱、利妥昔單抗);及D.T.PACE(地塞米松、沙利竇邁、順鉑、阿德力黴素®、環磷醯胺、依託泊苷)。
下文闡述化學療法治療(包括標準或實驗化學療法)之其他實例。另外,某些淋巴瘤之治療參閱Cheson,B.D.,Leonard,J.P.,「Monoclonal Antibody Therapy for B-Cell Non-Hodgkin’s Lymphoma」The New England Journal of Medicine 2008,359(6),第
613-626頁;及Wierda,W.G.,「Current and Investigational Therapies for Patients with CLL」Hematology 2006,第285-294頁。美國之淋巴瘤發病率型式概述於Morton,L.M.等人「Lymphoma Incidence Patterns by WHO Subtype in the United States,1992-2001」Blood 2006,107(1),第265-276頁。
治療淋巴瘤或白血病之免疫治療劑之實例包括(但不限於)利妥昔單抗(例如Rituxan)、阿倫單抗(例如Campath、MabCampath)、抗CD19抗體、抗CD20抗體、抗MN-14抗體、抗TRAIL、抗TRAIL DR4及DR5抗體、抗CD74抗體、阿泊珠單抗(apolizumab)、貝伐珠單抗、CHIR-12.12、依帕珠單抗(hLL2-抗CD22人類化抗體)、加利昔單抗(galiximab)、ha20、替伊莫單抗、魯昔單抗(lumiliximab)、米拉珠單抗、奧法木單抗、PRO131921、SGN-40、WT-1類似物肽疫苗、WT1 126-134肽疫苗、托西莫單抗、自體人類腫瘤衍生之HSPPC-96及維妥珠單抗(veltuzumab)。另外免疫療法藥劑包括使用個體患者之腫瘤之遺傳組成的癌症疫苗,例如淋巴瘤疫苗實例係GTOP-99(MyVax®)。
用於治療淋巴瘤或白血病之化學療法藥劑之實例包括阿地介白素(aldesleukin)、阿伏昔地(alvocidib)、抗瘤酮AS2-1(antineoplaston AS2-1)、抗瘤酮A10、抗胸腺細胞球蛋白、阿米福汀三水合物(amifostine trihydrate)、胺基喜樹鹼、三氧化砷、β阿裡辛(beta alethine)、Bcl-2家族蛋白質抑制劑ABT-263、BMS-345541、硼替佐米(Velcade®)、苔蘚抑制素1、白消安、卡鉑、campath-1H、CC-5103、卡莫司汀、乙酸卡泊芬淨(caspofungin acetate)、氯法拉濱(clofarabine)、順鉑、克拉屈濱(Cladribine)(Leustarin)、氮芥苯丁酸(瘤克寧)、薑黃素(Curcumin)、環孢素、環磷醯胺(Cyloxan、Endoxan、Endoxana、Cyclostin)、阿糖胞苷、地尼白介素2(denileukin diftitox)、地塞米松、DT PACE、歐洲紫杉醇、多拉斯他
汀10、多柔比星(阿德力黴素®、阿黴素(Adriblastine))、鹽酸多柔比星、恩紮妥林(enzastaurin)、阿法依伯汀(epoetin alfa)、依託泊苷、依維莫司(Everolimus)(RAD001)、芬維A銨(fenretinide)、非格司亭(filgrastim)、美法侖、美司鈉(mesna)、夫拉平度(Flavopiridol)、氟達拉濱(福達樂(Fludara))、格爾德黴素(Geldanamycin)(17-AAG)、異環磷醯胺、伊立替康鹽酸鹽、伊沙匹隆(ixabepilone)、雷利竇邁(Lenalidomide)(Revlimid®、CC-5013)、淋巴因子活化殺傷細胞、美法侖、胺甲喋呤、米托蒽醌鹽酸鹽、莫特沙芬釓(motexafin gadolinium)、麥考酚酸嗎乙酯、奈拉濱(nelarabine)、奧利默森(oblimersen)(Genasense)奧巴克拉(Obatoclax)(GX15-070)、奧利默森、乙酸奧曲肽(octreotide acetate)、ω-3脂肪酸、奧沙利鉑(oxaliplatin)、太平洋紫杉醇、PD0332991、聚乙二醇化脂質體鹽酸多柔比星、聚乙二醇非格司亭、噴司他丁(Pentstatin)(Nipent)、哌立福辛、普賴蘇濃(Prednisolone)、普賴松、R-羅可韋汀(R-roscovitine)(Selicilib、CYC202)、重組干擾素α、重組介白素-12、重組介白素-11、重組flt3配體、重組人類促血小板生成素、利妥昔單抗、沙格司亭(sargramostim)、檸檬酸西地那非(sildenafil citrate)、斯伐他汀(simvastatin)、西羅莫司、苯乙烯基碸、他克莫司、坦螺旋黴素(tanespimycin)、替西羅莫司(CCl-779)、沙利竇邁、治療性同種巴球、噻替派、替吡法尼(tipifarnib)、Velcade®(硼替佐米或PS-341)、長春新鹼(Oncovin)、硫酸長春新鹼、二酒石酸長春瑞濱、伏立諾他(Vorinostat)(SAHA)、伏立諾他、及FR(氟達拉濱、利妥昔單抗)、CHOP(環磷醯胺、多柔比星、長春新鹼、普賴松)、CVP(環磷醯胺、長春新鹼及普賴松)、FCM(氟達拉濱、環磷醯胺、米托蒽醌)、FCR(氟達拉濱、環磷醯胺、利妥昔單抗)、hyperCVAD(多分次環磷醯胺、長春新鹼、多柔比星、地塞米松、胺甲喋呤、阿糖胞苷)、ICE
(異環磷醯胺、卡鉑及依託泊苷)、MCP(米托蒽醌、氮芥苯丁酸及普賴蘇濃)、R-CHOP(利妥昔單抗加上CHOP)、R-CVP(利妥昔單抗加上CVP)、R-FCM(利妥昔單抗加上FCM)、R-ICE(利妥昔單抗-ICE)及R-MCP(利妥昔單抗-MCP)。
在一些實施例中,癌症係黑色素瘤。與本文所述化合物組合使用之適宜藥劑包括(但不限於)達卡巴嗪(DTIC)、視情況以及其他化學療法藥物(例如卡莫司汀(BCNU)及順鉑);「達特茅斯(Dartmouth)方案」,其由DTIC、BCNU、順鉑及他莫昔芬組成;順鉑、長春鹼及DTIC之組合、替莫唑胺或YERVOYTM。本發明化合物亦可與免疫療法藥物(包括細胞介素,例如干擾素α、介白素2及腫瘤壞死因子(TNF))組合用於治療黑色素瘤。
本文所述化合物亦可與疫苗療法組合用於治療黑色素瘤。抗黑色素瘤疫苗在一些方式中類似於用於預防由病毒引起之疾病(例如脊髓灰質炎、麻疹及腮腺炎)的抗病毒疫苗。可向患者注射稱作抗原之弱化黑色素瘤細胞或黑色素瘤細胞之部分以刺激身體之免疫系統以破壞黑色素瘤細胞。
亦可使用高溫分離肢體灌注技術用藥劑之組合(包括一或多種本文所述化合物)治療限於臂或腿之黑色素瘤。此治療方案將所涉及肢體之循環與身體之其餘部分暫時分離並向進給肢體之動脈中注射高劑量化學療法,由此向腫瘤區域提供高劑量,而不將內部器官暴露於該等劑量,其原本可能引起嚴重副作用。通常將流體升溫至102℉至104℉。美法侖係此化學療法程序中之最常用藥物。此可與稱作腫瘤壞死因子(TNF)之另一藥劑一起給予。
治療性治療可補充有上文所提及療法中之任一者與幹細胞移植或治療或與其組合。經改良方法之一個實例係放射免疫療法,其中單株抗體與放射性同位素粒子(例如銦In 111、釔Y 90、碘I-131)組合。
組合療法之實例包括(但不限於)碘-131托西莫單抗(Bexxar®)、釔-90替伊莫單抗(Zevalin®)、Bexxar®與CHOP。
其他治療程序包括末梢血幹細胞移植、自體造血幹細胞移植、自體骨髓移植、抗體療法、生物療法、酶抑制劑療法、全身輻照、輸注幹細胞、具有幹細胞支持之骨髓消融、活體外處理之末梢血幹細胞移植、臍帶血移植、免疫酶技術、藥理學研究、低-LET鈷-60γ射線療法、博來黴素、習用手術、輻射療法及非骨髓根除之同種造血幹細胞移植。
在某些實施例中,提供治療或預防患有或處於患有HBV感染之風險之人類之該感染的方法,其包含向該人類投與治療有效量之本文所揭示之化合物或其醫藥上可接受之鹽與治療有效量之一或多種(例如,一種、兩種、三種、四種、一種或兩種或一至三種或一至四種)另外治療劑的組合。在一個實施例中,提供治療患有或處於患有HBV感染之風險之人類之該感染的方法,其包含向該人類投與治療有效量之本文所揭示之化合物或其醫藥上可接受之鹽與治療有效量之一或多種(例如,一種、兩種、三種、四種、一種或兩種或一至三種或一至四種)另外治療劑的組合。
在某些實施例中,本發明提供治療HBV感染之方法,其包含向有需要之患者投與治療有效量之本文所揭示之化合物或其醫藥上可接受之鹽與治療有效量之一或多種適於治療HBV感染之另外治療劑的組合。
在一個實施例中,提供包含本文所揭示之化合物或其醫藥上可接受之鹽與一或多種(例如,一種、兩種、三種、四種、一種或兩種或一至三種或一至四種)另外治療劑的組合及醫藥上可接受之載劑、稀釋劑或賦形劑的醫藥組合物。
在一個實施例中,提供包含本文所揭示之化合物或其醫藥上可接受之鹽與一或多種(例如,一種、兩種、三種、四種、一種或兩種或一至三種或一至四種)另外治療劑之組合的套組。
在上述實施例中,另外治療劑可為抗HBV藥劑。舉例而言,在一些實施例中,另外治療劑選自由以下組成之群:HBV組合藥物、HBV DNA聚合酶抑制劑、免疫調節劑、類鐸(toll-like)受體調節劑(tlr1、tlr2、tlr3、tlr4、tlr5、tlr6、tlr7、tlr8、tlr9、tlr10、tlr11、tlr12及tlr13之調節劑)、干擾素α受體配體、玻尿酸酶抑制劑、重組IL-7、B型肝炎表面抗原(HBsAg)抑制劑、靶向肝炎B核心抗原(HbcAg)之化合物、親環素抑制劑、HBV治療性疫苗、HBV預防性疫苗、HBV病毒進入抑制劑、NTCP(Na+-牛磺膽酸鹽共轉運多肽)抑制劑、靶向病毒mRNA之反義寡核苷酸、短干擾RNA(siRNA)、miRNA基因療法藥劑、內核酸酶調節劑、核糖核苷酸還原酶之抑制劑、B型肝炎病毒E抗原抑制劑、重組清除劑受體A(SRA)蛋白質、Src激酶抑制劑、HBx抑制劑、cccDNA抑制劑、短合成髮夾RNA(sshRNA)、HBV抗體(包括靶向B型肝炎病毒之表面抗原之HBV抗體)及雙特異性抗體及「抗體樣」治療性蛋白(例如DARTs®、Duobodies®、Bites®、XmAbs®、TandAbs ®、Fab衍生物)、CCR2趨化介素拮抗劑、胸腺素激動劑、細胞介素、核蛋白抑制劑(HBV核心或衣殼蛋白抑制劑)、視黃酸可誘導基因1之刺激劑、NOD2之刺激劑、NOD1之刺激劑、精胺酸酶-1抑制劑、STING激動劑、PI3K抑制劑、淋巴毒素β受體活化劑、天然殺傷細胞受體2B4抑制劑、淋巴球-活化基因3抑制劑、CD160抑制劑、細胞毒性T-淋巴球相關蛋白4抑制劑、CD137抑制劑、殺傷細胞凝集素樣受體亞家族G成員1抑制劑、TIM-3抑制劑、B-及T-淋巴球衰減因子抑制劑、CD305抑制劑、PD-1抑制劑、PD-L1抑制劑、PEG-干擾素λ、重組胸腺素α-1、BTK抑制劑、TIGIT之調節劑、CD47之調節劑、
SIRPα之調節劑、ICOS之調節劑、CD27之調節劑、CD70之調節劑、OX40之調節劑、NKG2D之調節劑、Tim-4之調節劑、B7-H4之調節劑、B7-H3之調節劑、NKG2A之調節劑、GITR之調節劑、CD160之調節劑、HEVEM之調節劑、CD161之調節劑、Axl之調節劑、Mer之調節劑、Tyro之調節劑、基因調節劑或編輯劑(例如CRISPR(包括CRISPR Cas9))、鋅指核酸酶或合成核酸酶(TALEN)、B型肝炎病毒複製抑制劑化合物,例如以下中揭示之彼等:US20100143301(Gilead Sciences)、US20110098248(Gilead Sciences)、US20090047249(Gilead Sciences)、US8722054(Gilead Sciences)、US20140045849(Janssen)、US20140073642(Janssen)、WO2014/056953(Janssen)、WO2014/076221(Janssen)、WO2014/128189(Janssen)、US20140350031(Janssen)、WO2014/023813(Janssen)、US20080234251(Array Biopharma)、US20080306050(Array Biopharma)、US20100029585(Ventirx Pharma)、US20110092485(Ventirx Pharma)、US20110118235(Ventirx Pharma)、US20120082658(Ventirx Pharma)、US20120219615(Ventirx Pharma)、US20140066432(Ventirx Pharma)、US20140088085(VentirxPharma)、US20140275167(Novira therapeutics)、US20130251673(Novira therapeutics)、US8513184(Gilead Sciences)、US20140030221(Gilead Sciences)、US20130344030(Gilead Sciences)、US20130344029(Gilead Sciences)、US20140343032(Roche)、WO2014037480(Roche)、US20130267517(Roche)、WO2014131847(Janssen)、WO2014033176(Janssen)、WO2014033170(Janssen)、WO2014033167(Janssen)、US20140330015(Ono pharmaceutical)、US20130079327(Ono pharmaceutical)、US20130217880(Ono pharmaceutical)、及其他用於治療HBV之藥劑及其組合。
在某些實施例中,另外治療劑選自由以下組成之群:HBV組合藥物、HBV DNA聚合酶抑制劑、類鐸受體7調節劑、類鐸受體8調節劑、類鐸受體7及8調節劑、類鐸受體3調節劑、干擾素α受體配體、HBsAg抑制劑、靶向HbcAg之化合物、親環素抑制劑、HBV治療性疫苗、HBV預防性疫苗、HBV病毒進入抑制劑、NTCP抑制劑、靶向病毒mRNA之反義寡核苷酸、短干擾RNA(siRNA)、B型肝炎病毒E抗原抑制劑、HBx抑制劑、cccDNA抑制劑、HBV抗體(包括靶向B型肝炎病毒之表面抗原之HBV抗體)、胸腺素激動劑、細胞介素、核蛋白抑制劑(HBV核心或衣殼蛋白抑制劑)、視黃酸可誘導基因1之刺激劑、NOD2之刺激劑、NOD1之刺激劑、重組胸腺素α-1、BTK抑制劑及B型肝炎病毒複製抑制劑及其組合。
在某些實施例中,本文所揭示之化合物調配為錠劑,其可視情況含有一或多種用於治療HBV之其他化合物。在某些實施例中,錠劑可含有用於治療HBV之另一活性成份,例如HBV DNA聚合酶抑制劑、免疫調節劑、類鐸受體調節劑(tlr1、tlr2、tlr3、tlr4、tlr5、tlr6、tlr7、tlr8、tlr9、tlr10、tlr11、tlr12及tlr13之調節劑)、tlr7之調節劑、tlr8之調節劑、tlr7及tlr8之調節劑、干擾素α受體配體、玻尿酸酶抑制劑、B型肝炎表面抗原(HBsAg)抑制劑、靶向肝炎B核心抗原(HbcAg)之化合物、親環素抑制劑、HBV病毒進入抑制劑、NTCP(Na+-牛磺膽酸鹽共轉運多肽)抑制劑、內核酸酶調節劑、核糖核苷酸還原酶之抑制劑、B型肝炎病毒E抗原抑制劑、Src激酶抑制劑、HBx抑制劑、cccDNA抑制劑、CCR2趨化介素拮抗劑、胸腺素激動劑、核蛋白抑制劑(HBV核心或衣殼蛋白抑制劑)、視黃酸可誘導基因1之刺激劑、NOD2之刺激劑、NOD1之刺激劑、精胺酸酶-1抑制劑、STING激動劑、PI3K抑制劑、淋巴毒素β受體活化劑、天然殺傷細胞受體2B4抑制劑、淋巴球-活化基因3抑制劑、CD160抑制劑、細胞毒性T-
淋巴球相關蛋白4抑制劑、CD137抑制劑、殺傷細胞凝集素樣受體亞家族G成員1抑制劑、TIM-3抑制劑、B-及T-淋巴球衰減因子抑制劑、CD305抑制劑、PD-1抑制劑、PD-L1抑制劑、BTK抑制劑、TIGIT之調節劑、CD47之調節劑、SIRP α之調節劑、ICOS之調節劑、CD27之調節劑、CD70之調節劑、OX40之調節劑、NKG2D之調節劑、Tim-4之調節劑、B7-H4之調節劑、B7-H3之調節劑、NKG2A之調節劑、GITR之調節劑、CD160之調節劑、HEVEM之調節劑、CD161之調節劑、Axl之調節劑、Mer之調節劑、Tyro之調節劑及B型肝炎病毒複製抑制劑及其組合。
在某些實施例中,該等錠劑適於每日一次投用。
在某些實施例中,另外治療劑選自以下中之一或多者:(1)選自由以下組成之群之組合藥物:泰諾福韋雙索酯富馬酸鹽(tenofovir disoproxil fumarate)+恩曲他濱(emtricitabine)(TRUVADA®);阿德福韋(adefovir)+克來夫定(clevudine)、ABX-203+拉米夫定(lamivudine)+PEG-IFNα、ABX-203+阿德福韋+PEG-IFNα及GBV-015;(2)選自由以下組成之群之HBV DNA聚合酶抑制劑:倍斯福韋(besifovir)、恩替卡韋(entecavir)(Baraclude®)、阿德福韋(Hepsera®)、泰諾福韋雙索酯富馬酸鹽(Viread®)、泰諾福韋亞拉芬醯胺、泰諾福韋、泰諾福韋雙索酯、泰諾福韋亞拉芬醯胺富馬酸鹽、泰諾福韋亞拉芬醯胺半富馬酸鹽、泰諾福韋二吡呋酯(tenofovir dipivoxil)、泰諾福韋二吡呋酯富馬酸鹽、泰諾福韋十八烷基氧基乙基酯、替比夫定(telbivudine)(Tyzeka®)、帕拉德福韋(pradefovir)、克來夫定、恩曲他濱(Emtriva®)、利巴韋林、拉米夫定(Epivir-HBV®)、疊氮膦、泛昔洛韋(famciclovir)、SNC-019754、FMCA、福色林(fusolin)、AGX-1009及美他卡韋(metacavir);
(3)選自由以下組成之群之免疫調節劑:林他莫德(rintatolimod)、鹽酸艾米朵爾(imidol hydrochloride)、英加侖(ingaron)、德馬韋(dermaVir)、氯奎寧(plaquenil)(羥基氯喹)、普留淨、羥基脲、麥考酚酸嗎乙酯(MPA)及其酯衍生物麥考酚酸嗎乙酯(MMF)、WF-10、利巴韋林、IL-12、聚合物聚次乙亞胺(PEI)、Gepon、VGV-1、MOR-22、BMS-936559及IR-103;(4)選自由以下組成之群之類鐸受體7調節劑:GS-9620、GSK-2245035、咪喹莫特(imiquimod)、雷西莫特(resiquimod)、DSR-6434、DSP-3025、IMO-4200、MCT-465、3M-051、SB-9922、3M-052、Limtop、TMX-30X、TMX-202 RG-7863及RG-7795;(5)選自由以下組成之群之類鐸受體8調節劑:莫特莫德(motolimod)、雷西莫特、3M-051、3M-052、MCT-465、IMO-4200、VTX-763、VTX-1463;(6)選自由以下組成之群之類鐸受體3調節劑:林他莫德、聚-ICLC、MCT-465、MCT-475、Riboxxon、Riboxxim及ND-1.1;(7)選自由以下組成之群之干擾素α受體配體:干擾素α-2b(Intron A®)、聚乙二醇化干擾素α-2a(Pegasys®)、干擾素α 1b(Hapgen®)、韋德納(Veldona)、因法杜(Infradure)、羅擾素-A(Roferon-A)、YPEG-干擾素α-2a(YPEG-rhIFNα-2a)、P-1101、阿格隆(Algeron)、阿法羅納(Alfarona)、英加侖(干擾素γ)、rSIFN-co(重組超化合物干擾素)、Y聚乙二醇干擾素α-2b(YPEG-rhIFNα-2b)、MOR-22、聚乙二醇干擾素α-2b(PEG-Intron®)、拜複能(Bioferon)、樂複能(Novaferon)、因木他(Inmutag)(Inferon)、Multiferon®、干擾素α-n1(Humoferon®)、干擾素β-1a(Avonex®)、沙複能(Shaferon)、干擾素α-2b(AXXO)、阿法複能(Alfaferone)、干擾素α-2b(BioGeneric Pharma)、干擾素-α 2(CJ)、拉複南(Laferonum)、VIPEG、
BLAUFERON-B、BLAUFERON-A、Intermax α、瑞地能(Realdiron)、蘭斯伸(Lanstion)、派加複能(Pegaferon)、PDferon-B PDferon-B、干擾素α-2b(IFN,Laboratorios Bioprofarma)、α干擾素a 2b、卡複能(Kalferon)、派格納(Pegnano)、法能舒(Feronsure)、PegiHep、干擾素α 2b(Zydus-Cadila)、Optipeg A、Realfa 2B、樂力複能(Reliferon)、干擾素α-2b(Amega)、干擾素α-2b(Virchow)、聚乙二醇干擾素α-2b(Amega)、Reaferon-EC、比奎複能(Proquiferon)、尤尼複能(Uniferon)、烏力複能(Urifron)、干擾素α-2b(Changchun Institute of Biological Products)、安特複能(Anterferon)、山複能(Shanferon)、類複能(Layfferon)、上生雷泰(Shang Sheng Lei Tai)、因特芬(INTEFEN)、賽諾金(SINOGEN)、扶康肽(Fukangtai)、派格司他(Pegstat)、rHSA-IFN α-2b及因特拉泊(Interapo)(Interapa);(8)選自由以下組成之群之玻尿酸酶抑制劑:阿特聚姆(astodrimer);(9)IL-10之調節劑;(10)選自由以下組成之群之HBsAg抑制劑:HBF-0259、PBHBV-001、PBHBV-2-15、PBHBV-2-1、REP 9AC、REP-9C及REP 9AC’;(11)選自CYT003之類鐸受體9調節劑;(12)選自由以下組成之群之親環素抑制劑:OCB-030、SCY-635及NVP-018;(13)選自由以下組成之群之HBV預防性疫苗:海克西姆(Hexaxim)、海裡薩(Heplisav)、莫斯基裡克斯(Mosquirix)、DTwP-HBV疫苗、Bio-Hep-B、D/T/P/HBV/M(LBVP-0101;LBVW-0101)、DTwP-Hepb-Hib-IPV疫苗、Heberpenta L、DTwP-HepB-Hib、V-419、CVI-HBV-001、泰曲海(Tetrabhay)、B型肝炎預防性疫苗(Advax Super
D)、Hepatrol-07、GSK-223192A、Engerix B®、重組B型肝炎疫苗(肌內,Kangtai Biological Products)、重組B型肝炎疫苗(多形漢森酵母(Hansenual polymorpha yeast),肌內,Hualan Biological Engineering)、比姆珍(Bimmugen)、優複瓦(Euforavac)、優曲瓦(Eutravac)、anrix-DTaP-IPV-Hep B、Infanrix-DTaP-IPV-Hep B-Hib、Pentabio Vaksin DTP-HB-Hib、Comvac 4、Twinrix、Euvax-B、Tritanrix HB、Infanrix Hep B、Comvax、DTP-Hib-HBV疫苗、DTP-HBV疫苗、Yi Tai、Heberbiovac HB、Trivac HB、GerVax、DTwP-Hep B-Hib疫苗、Bilive、Hepavax-Gene、SUPERVAX、Comvac5、Shanvac-B、Hebsulin、Recombivax HB、Revac B mcf、Revac B+、Fendrix、DTwP-HepB-Hib、DNA-001、Shan6、rhHBsAG疫苗及DTaP-rHB-Hib疫苗;(14)選自由以下組成之群之HBV治療性疫苗:HBsAG-HBIG複合物、Bio-Hep-B、NASVAC、abi-HB(靜脈內)、ABX-203、泰曲海、GX-110E、GS-4774、肽疫苗(εPA-44)、Hepatrol-07、NASVAC(NASTERAP)、IMP-321、BEVAC、Revac B mcf、Revac B+、MGN-1333、KW-2、CVI-HBV-002、AltraHepB、VGX-6200、FP-02、TG-1050、NU-500、HBVax、im/TriGrid/抗原疫苗、Mega-CD40L輔助性疫苗、HepB-v、NO-1800、重組VLP基治療性疫苗(HBV感染,VLP Biotech)、AdTG-17909、AdTG-17910 AdTG-18202、ChronVac-B及Lm HBV;(15)選自由以下組成之群之HBV病毒進入抑制劑:Myrcludex B;(16)選自由以下組成之群之靶向病毒mRNA之反義寡核苷酸:ISIS-HBVRx;(17)選自由以下組成之群之短干擾RNA(siRNA):TKM-HBV
(TKM-HepB)、ALN-HBV、SR-008、ddRNAi及ARC-520;(18)選自由以下組成之群之內核酸酶調節劑:PGN-514;(19)選自由以下組成之群之核糖核苷酸還原酶之抑制劑:曲咪道克斯(Trimidox);(20)選自由以下組成之群之B型肝炎病毒E抗原抑制劑:沃貢寧(wogonin);(21)選自由以下組成之群之靶向B型肝炎病毒之表面抗原之HBV抗體:GC-1102、XTL-17、XTL-19、XTL-001、KN-003及完全人類單株抗體療法(B型肝炎病毒感染,Humabs BioMed);(22)包括單株抗體及多株抗體之選自由以下組成之群之HBV抗體:祖泰曲(Zutectra)、上生甘迪(Shang Sheng Gan Di)、Uman Big(Hepatitis B Hyperimmune)、Omri-Hep-B、Nabi-HB、Hepatect CP、HepaGam B、艾加泰博(igantibe)、Niuliva、CT-P24、B型肝炎免疫球蛋白(靜脈內,pH4,HBV感染,Shanghai RAAS Blood Products)及Fovepta(BT-088);(23)選自由以下組成之群之CCR2趨化介素拮抗劑:丙帕鍺(propagermanium);(24)選自由以下組成之群之胸腺素激動劑:胸腺法新(Thymalfasin);(25)選自由以下組成之群之細胞介素:重組IL-7、CYT-107、介白素-2(IL-2,Immunex);重組人類介白素-2(Shenzhen Neptunus)及西莫白介素(celmoleukin);(26)選自由以下組成之群之核蛋白抑制劑(HBV核心或衣殼蛋白抑制劑):NVR-1221、NVR-3778、BAY 41-4109、甲磺酸莫非賽定(morphothiadine mesilate)及DVR-23;(27)選自由以下組成之群之視黃酸可誘導基因1之刺激劑:SB-
9200、SB-40、SB-44、ORI-7246、ORI-9350、ORI-7537、ORI-9020、ORI-9198及ORI-7170;(28)選自由以下組成之群之NOD2之刺激劑:SB-9200;(29)選自由以下組成之群之重組胸腺素α-1:NL-004及聚乙二醇化胸腺素α 1;(30)選自由以下組成之群之B型肝炎病毒複製抑制劑:異噻氟定(isothiafludine)、IQP-HBV、RM-5038及新加泰(Xingantie);(31)選自由以下組成之群之PI3K抑制劑:艾代拉裡斯、AZD-8186、布帕裡斯(buparlisib)、CLR-457、皮克裡斯(pictilisib)、來那替尼(neratinib)、氯構色替(rigosertib)、氯構色替鈉、EN-3342、TGR-1202、艾派裡斯(alpelisib)、杜維裡斯、UCB-5857、泰塞裡斯(taselisib)、XL-765、戈達特裡斯(gedatolisib)、VS-5584、克盤裡斯(copanlisib)、CAI奧拉米特(CAI orotate)、哌立福辛、RG-7666、GSK-2636771、DS-7423、帕紐裡斯(panulisib)、GSK-2269557、GSK-2126458、CUDC-907、PQR-309、INCB-040093、匹拉裡斯(pilaralisib)、BAY-1082439、甲磺酸普喹替尼(puquitinib mesylate)、SAR-245409、AMG-319、RP-6530、ZSTK-474、MLN-1117、SF-1126、RV-1729、索那裡斯(sonolisib)、LY-3023414、SAR-260301及CLR-1401;(32)選自由以下組成之群之cccDNA抑制劑:BSBI-25;(33)選自由以下組成之群之PD-L1抑制劑:MEDI-0680、RG-7446、德瓦魯單抗(durvalumab)、KY-1003、KD-033、MSB-0010718C、TSR-042、ALN-PDL、STI-A1014及BMS-936559;(34)選自由以下組成之群之PD-1抑制劑:尼沃魯單抗(nivolumab)、派姆單抗(pembrolizumab)、匹利珠單抗(pidilizumab)、BGB-108及mDX-400;
(35)選自由以下組成之群之BTK抑制劑:ACP-196、達沙替尼(dasatinib)、依魯替尼(ibrutinib)、PRN-1008、SNS-062、ONO-4059、BGB-3111、MSC-2364447、X-022、斯派魯替尼(spebrutinib)、TP-4207、HM-71224、KBP-7536及AC-0025;(36)選自由以下組成之群之用於治療HBV之其他藥物:龍膽苦苷(gentiopicrin,gentiopicroside)、硝唑尼特(nitazoxanide)、比利納盤(birinapant)、NOV-205(Molixan;BAM-205)、奧利戈泰(Oligotide)、米伏替酯(Mivotilate)、複能(Feron)、左旋咪唑、Ka Shu Ning、奧樂複能(Alloferon)、WS-007、Y-101(Ti Fen Tai)、rSIFN-co、PEG-IIFNm、KW-3、BP-Inter-014、齊墩果酸、HepB-nRNA、cTP-5(rTP-5)、HSK-II-2、HEISCO-106-1、HEISCO-106、海巴納(Hepbarna)、IBPB-006IA、海普因芬(Hepuyinfen)、DasKloster 0014-01、Jiangantai(Ganxikang)、胡黃連苦苷(picroside)、GA5 NM-HBV、DasKloster-0039、海普蘭泰(hepulantai)、IMB-2613、TCM-800B、經還原麩胱甘肽及ZH-2N;及(37)揭示於以下中之化合物:US20100143301(Gilead Sciences)、US20110098248(Gilead Sciences)、US20090047249(Gilead Sciences)、US8722054(Gilead Sciences)、US20140045849(Janssen)、US20140073642(Janssen)、WO2014/056953(Janssen)、WO2014/076221(Janssen)、WO2014/128189(Janssen)、US20140350031(Janssen)、WO2014/023813(Janssen)、US20080234251(Array Biopharma)、US20080306050(Array Biopharma)、US20100029585(Ventirx Pharma)、US20110092485(Ventirx Pharma)、US20110118235(Ventirx Pharma)、US20120082658(Ventirx Pharma)、US20120219615(Ventirx Pharma)、US20140066432(Ventirx Pharma)、US20140088085(VentirxPharma)、US20140275167
(Novira therapeutics)、US20130251673(Novira therapeutics)、US8513184(Gilead Sciences)、US20140030221(Gilead Sciences)、US20130344030(Gilead Sciences)、US20130344029(Gilead Sciences)、US20140343032(Roche)、WO2014037480(Roche)、US20130267517(Roche)、WO2014131847(Janssen)、WO2014033176(Janssen)、WO2014033170(Janssen)、WO2014033167(Janssen)、US20140330015(Ono pharmaceutical)、US20130079327(Ono pharmaceutical)及US20130217880(Ono pharmaceutical)。
在某些實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與一種、兩種、三種、四種或更多種另外治療劑。在某些實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與兩種另外治療劑。在其他實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與三種另外治療劑。在其他實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與四種另外治療劑。一種、兩種、三種、四種或更多種另外治療劑可為選自相同種類之治療劑之不同治療劑,及/或其可選自不同種類之治療劑。
在具體實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與HBV DNA聚合酶抑制劑。在另一具體實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與HBV DNA聚合酶抑制劑及至少一種選自由以下組成之群之另外治療劑:免疫調節劑、類鐸受體調節劑(tlr1、tlr2、tlr3、tlr4、tlr5、tlr6、tlr7、tlr8、tlr9、tlr10、tlr11、tlr12及tlr13之調節劑)、干擾素α受體配體、玻尿酸酶抑制劑、重組IL-7、HBsAg抑制劑、靶向HbcAg之化合物、親環素抑制劑、HBV治療性疫苗、HBV預防性疫苗HBV病毒進入抑制劑、NTCP抑制劑、靶向病毒mRNA之反義寡核苷酸、短干擾RNA(siRNA)、miRNA基因療法藥劑、內核酸酶調節劑、核糖核苷酸還原酶之抑制劑、B型
肝炎病毒E抗原抑制劑、重組清除劑受體A(SRA)蛋白質、src激酶抑制劑、HBx抑制劑、cccDNA抑制劑、短合成髮夾RNA(sshRNA)、HBV抗體(包括靶向B型肝炎病毒之表面抗原之HBV抗體)及雙特異性抗及「抗體樣」治療性蛋白(例如DARTs®、Duobodies®、Bites®、XmAbs®、TandAbs ®、Fab衍生物)、CCR2趨化介素拮抗劑、胸腺素激動劑、細胞介素、核蛋白抑制劑(HBV核心或衣殼蛋白抑制劑)、視黃酸可誘導基因1之刺激劑、NOD2之刺激劑、NOD1之刺激劑、精胺酸酶-1抑制劑、STING激動劑、PI3K抑制劑、淋巴毒素β受體活化劑、天然殺傷細胞受體2B4抑制劑、淋巴球-活化基因3抑制劑、CD160抑制劑、細胞毒性T-淋巴球相關蛋白4抑制劑、CD137抑制劑、殺傷細胞凝集素樣受體亞家族G成員1抑制劑、TIM-3抑制劑、B-及T-淋巴球衰減因子抑制劑、CD305抑制劑、PD-1抑制劑、PD-L1抑制劑、PEG-干擾素λ、重組胸腺素α-1、BTK抑制劑、TIGIT之調節劑、CD47之調節劑、SIRPα之調節劑、ICOS之調節劑、CD27之調節劑、CD70之調節劑、OX40之調節劑、NKG2D之調節劑、Tim-4之調節劑、B7-H4之調節劑、B7-H3之調節劑、NKG2A之調節劑、GITR之調節劑、CD160之調節劑、HEVEM之調節劑、CD161之調節劑、Axl之調節劑、Mer之調節劑、Tyro之調節劑、基因調節劑或編輯劑(例如CRISPR(包括CRISPR Cas9))、鋅指核酸酶或合成核酸酶(TALEN)及B型肝炎病毒複製抑制劑。
在另一具體實施例中,將本文所揭示之化合物或其醫藥上可接受之鹽與HBV DNA聚合酶抑制劑及選自由以下組成之群之至少第二另外治療劑:免疫調節劑、類鐸受體調節劑(tlr1、tlr2、tlr3、tlr4、tlr5、tlr6、tlr7、tlr8、tlr9、tlr10、tlr11、tlr12及tlr13之調節劑)、HBsAg抑制劑、HBV治療性疫苗、HBV抗體(包括靶向B型肝炎病毒之表面抗原之HBV抗體)及雙特異性抗體及「抗體樣」治療性蛋白(例如
DARTs®、Duobodies®、Bites®、XmAbs®、TandAbs ®、Fab衍生物)、親環素抑制劑、視黃酸可誘導基因1之刺激劑、PD-1抑制劑、PD-L1抑制劑、精胺酸酶-1抑制劑、PI3K抑制劑及NOD2之刺激劑。
在另一具體實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與HBV DNA聚合酶抑制劑及選自由以下組成之群之至少第二另外治療劑:HBV病毒進入抑制劑、NTCP抑制劑、HBx抑制劑、cccDNA抑制劑、靶向B型肝炎病毒之表面抗原之HBV抗體、短干擾RNA(siRNA)、miRNA基因療法藥劑、短合成髮夾RNA(sshRNA)及核蛋白抑制劑(HBV核心或衣殼蛋白抑制劑)。
在另一具體實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與HBV DNA聚合酶抑制劑、一種或兩種選自由以下組成之群之另外治療劑:免疫調節劑、類鐸受體調節劑(tlr1、tlr2、tlr3、tlr4、tlr5、tlr6、tlr7、tlr8、tlr9、tlr10、tlr11、tlr12及tlr13之調節劑)、HBsAg抑制劑、HBV治療性疫苗、HBV抗體(包括靶向B型肝炎病毒之表面抗原之HBV抗體)及雙特異性抗體及「抗體樣」治療性蛋白(例如DARTs®、Duobodies®、Bites®、XmAbs®、TandAbs ®、Fab衍生物)、親環素抑制劑、視黃酸可誘導基因1之刺激劑、PD-1抑制劑、PD-L1抑制劑、精胺酸酶-1抑制劑、PI3K抑制劑及NOD2之刺激劑,以及一種或兩種選自由以下組成之群之另外治療劑:HBV病毒進入抑制劑、NTCP抑制劑、HBx抑制劑、cccDNA抑制劑、靶向B型肝炎病毒之表面抗原之HBV抗體、短干擾RNA(siRNA)、miRNA基因療法藥劑、短合成髮夾RNA(sshRNA)及核蛋白抑制劑(HBV核心或衣殼蛋白抑制劑)。
在特定實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與一種、兩種、三種、四種或更多種選自以下之另外治療劑:阿德福韋(Hepsera®)、泰諾福韋雙索酯富馬酸鹽+恩曲他濱
(TRUVADA®)、泰諾福韋雙索酯富馬酸鹽(Viread®)、恩替卡韋(Baraclude®)、拉米夫定(Epivir-HBV®)、泰諾福韋亞拉芬醯胺、泰諾福韋、泰諾福韋雙索酯、泰諾福韋亞拉芬醯胺富馬酸鹽、泰諾福韋亞拉芬醯胺半富馬酸鹽、替比夫定(Tyzeka®)、克來夫定®、恩曲他濱(Emtriva®)、聚乙二醇干擾素α-2b(PEG-Intron®)、Multiferon®、干擾素α 1b(Hapgen®)、干擾素α-2b(Intron A®)、聚乙二醇化干擾素α-2a(Pegasys®)、干擾素α-n1(Humoferon®)、利巴韋林、干擾素β-1a(Avonex®)、拜複能、英加侖、因木他(Inferon)、阿格隆、羅擾素-A、奧利戈泰、祖泰曲、沙複能、干擾素α-2b(AXXO)、阿法複能、干擾素α-2b(BioGeneric Pharma)、複能、干擾素-α 2(CJ)、BEVAC、拉複南、VIPEG、BLAUFERON-B、BLAUFERON-A、Intermax A、瑞地能、蘭斯伸、派加複能、PDferon-B、干擾素α-2b(IFN,Laboratorios Bioprofarma)、α干擾素a 2b、卡複能、派格納、法能舒、PegiHep、干擾α 2b(Zydus-Cadila)、Optipeg A、Realfa 2B、樂力複能、干擾素α-2b(Amega)、干擾素α-2b(Virchow)、聚乙二醇干擾素α-2b(Amega)、Reaferon-EC、比奎複能、尤尼複能、烏力複能、干擾素α-2b(Changchun Institute of Biological Products)、安特複能、山複能、MOR-22、介白素-2(IL-2,Immunex)、重組人類介白素-2(Shenzhen Neptunus)、類複能、卡舒寧、上生雷泰、因特芬、賽諾金、扶康肽、奧樂複能及西莫白介素;在特定實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與恩替卡韋(Baraclude®)、阿德福韋(Hepsera®)、泰諾福韋雙索酯富馬酸鹽(Viread®)、泰諾福韋亞拉芬醯胺、泰諾福韋、泰諾福韋雙索酯、泰諾福韋亞拉芬醯胺富馬酸鹽、泰諾福韋亞拉芬醯胺半富馬酸鹽、替比夫定(Tyzeka®)或拉米夫定(Epivir-HBV®)。
在特定實施例中,組合本文所揭示之化合物或其醫藥上可接受
之鹽與恩替卡韋(Baraclude®)、阿德福韋(Hepsera®)、泰諾福韋雙索酯富馬酸鹽(Viread®)、泰諾福韋亞拉芬醯胺半富馬酸鹽、替比夫定(Tyzeka®)或拉米夫定(Epivir-HBV®)。
在特定實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與選自由以下組成之群之第一另外治療劑:恩替卡韋(Baraclude®)、阿德福韋(Hepsera®)、泰諾福韋雙索酯富馬酸鹽(Viread®)、泰諾福韋亞拉芬醯胺、泰諾福韋、泰諾福韋雙索酯、泰諾福韋亞拉芬醯胺富馬酸鹽、泰諾福韋亞拉芬醯胺半富馬酸鹽、替比夫定(Tyzeka®)或拉米夫定(Epivir-HBV®),以及選自由以下組成之群之至少第二另外治療劑:免疫調節劑、類鐸受體調節劑(tlr1、tlr2、tlr3、tlr4、tlr5、tlr6、tlr7、tlr8、tlr9、tlr10、tlr11、tlr12及tlr13之調節劑)、干擾素α受體配體、玻尿酸酶抑制劑、重組IL-7、HBsAg抑制劑、靶向HbcAg之化合物、親環素抑制劑、HBV治療性疫苗、HBV預防性疫苗、HBV病毒進入抑制劑、NTCP抑制劑、靶向病毒mRNA之反義寡核苷酸、短干擾RNA(siRNA)、miRNA基因療法藥劑、內核酸酶調節劑、核糖核苷酸還原酶之抑制劑、B型肝炎病毒E抗原抑制劑、重組清除劑受體A(SRA)蛋白質、src激酶抑制劑、HBx抑制劑、cccDNA抑制劑、短合成髮夾RNA(sshRNA)、HBV抗體(包括靶向B型肝炎病毒之表面抗原之HBV抗體)及雙特異性抗體及「抗體樣」治療性蛋白(例如DARTs®、Duobodies®、Bites®、XmAbs®、TandAbs ®、Fab衍生物)、CCR2趨化介素拮抗劑、胸腺素激動劑、細胞介素、核蛋白抑制劑(HBV核心或衣殼蛋白抑制劑)、視黃酸可誘導基因1之刺激劑、NOD2之刺激劑、NOD1之刺激劑、重組胸腺素α-1、精胺酸酶-1抑制劑、STING激動劑、PI3K抑制劑、淋巴毒素β受體活化劑、天然殺傷細胞受體2B4抑制劑、淋巴球-活化基因3抑制劑、CD160抑制劑、細胞毒性T-淋巴球相關蛋白4抑制劑、CD137抑制劑、殺傷細
胞凝集素樣受體亞家族G成員1抑制劑、TIM-3抑制劑、B-及T-淋巴球衰減因子抑制劑、CD305抑制劑、PD-1抑制劑、PD-L1抑制劑、PEG-干擾素λ、BTK抑制劑、TIGIT之調節劑、CD47之調節劑、SIRPα之調節劑、ICOS之調節劑、CD27之調節劑、CD70之調節劑、OX40之調節劑、NKG2D之調節劑、Tim-4之調節劑、B7-H4之調節劑、B7-H3之調節劑、NKG2A之調節劑、GITR之調節劑、CD160之調節劑、HEVEM之調節劑、CD161之調節劑、Axl之調節劑、Mer之調節劑、Tyro之調節劑、基因調節器或編輯器(例如CRISPR(包括CRISPR Cas9))、鋅指核酸酶或合成核酸酶(TALEN)及B型肝炎病毒複製抑制劑。
在特定實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與選自由以下組成之群之第一另外治療劑:恩替卡韋(Baraclude®)、阿德福韋(Hepsera®)、泰諾福韋雙索酯富馬酸鹽(Viread®)、泰諾福韋亞拉芬醯胺、泰諾福韋、泰諾福韋雙索酯、泰諾福韋亞拉芬醯胺富馬酸鹽、泰諾福韋亞拉芬醯胺半富馬酸鹽、替比夫定(Tyzeka®)或拉米夫定(Epivir-HBV®),以及選自由以下組成之群之至少第二另外治療劑:聚乙二醇干擾素α-2b(PEG-Intron®)、Multiferon®、干擾素α 1b(Hapgen®)、干擾素α-2b(Intron A®)、聚乙二醇化干擾素α-2a(Pegasys®)、干擾素α-n1(Humoferon®)、利巴韋林、干擾素β-1a(Avonex®)、拜複能、英加侖、因木他(Inferon)、阿格隆、羅擾素-A、奧利戈泰、祖泰曲、沙複能、干擾素α-2b(AXXO)、阿法複能、干擾素α-2b(BioGeneric Pharma)、複能、干擾素-α 2(CJ)、BEVAC、拉複南、VIPEG、BLAUFERON-B、BLAUFERON-A、Intermax A、瑞地能、蘭斯伸、派加複能、PDferon-B、干擾素α-2b(IFN,Laboratorios Bioprofarma)、α干擾素a 2b、卡複能、派格納、法能舒、PegiHep、干擾素α 2b(Zydus-
Cadila)、Optipeg A、Realfa 2B、樂力複能、干擾素α-2b(Amega)、干擾素α-2b(Virchow)、聚乙二醇干擾素α-2b(Amega)、Reaferon-EC、比奎複能、尤尼複能、烏力複能、干擾素α-2b(Changchun Institute of Biological Products)、安特複能、山複能、MOR-22、介白素-2(IL-2,Immunex)、重組人類介白素-2(Shenzhen Neptunus)、類複能、卡舒寧、上生雷泰、因特芬、賽諾金、扶康肽、奧樂複能及西莫白介素;在特定實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與選自由以下組成之群之第一另外治療劑:恩替卡韋(Baraclude®)、阿德福韋(Hepsera®)、泰諾福韋雙索酯富馬酸鹽(Viread®)、泰諾福韋亞拉芬醯胺、泰諾福韋、泰諾福韋雙索酯、泰諾福韋亞拉芬醯胺富馬酸鹽、泰諾福韋亞拉芬醯胺半富馬酸鹽、替比夫定(Tyzeka®)或拉米夫定(Epivir-HBV®),以及選自由以下組成之群之至少第二另外治療劑:免疫調節劑、類鐸受體調節劑(tlr1、tlr2、tlr3、tlr4、tlr5、tlr6、tlr7、tlr8、tlr9、tlr10、tlr11、tlr12及tlr13之調節劑)、HBsAg抑制劑、HBV治療性疫苗、HBV抗體(包括靶向B型肝炎病毒之表面抗原之HBV抗體)及雙特異性抗體及「抗體樣」治療性蛋白(例如DARTs®、Duobodies®、Bites®、XmAbs®、TandAbs ®、Fab衍生物)、親環素抑制劑、視黃酸可誘導基因1之刺激劑、精胺酸酶-1抑制劑、PI3K抑制劑、PD-1抑制劑、PD-L1抑制劑及NOD2之刺激劑。
在特定實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與選自由以下組成之群之第一另外治療劑:恩替卡韋(Baraclude®)、阿德福韋(Hepsera®)、泰諾福韋雙索酯富馬酸鹽(Viread®)、泰諾福韋亞拉芬醯胺、泰諾福韋、泰諾福韋雙索酯、泰諾福韋亞拉芬醯胺富馬酸鹽、泰諾福韋亞拉芬醯胺半富馬酸鹽、替比
夫定(Tyzeka®)或拉米夫定(Epivir-HBV®),以及選自由以下組成之群之至少第二另外治療劑:HBV病毒進入抑制劑、NTCP抑制劑、HBx抑制劑、cccDNA抑制劑、靶向B型肝炎病毒之表面抗原之HBV抗體、短干擾RNA(siRNA)、miRNA基因療法藥劑、短合成髮夾RNA(sshRNA)及核蛋白抑制劑(HBV核心或衣殼蛋白抑制劑)。
在特定實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與選自由以下組成之群之第一另外治療劑:恩替卡韋(Baraclude®)、阿德福韋(Hepsera®)、泰諾福韋雙索酯富馬酸鹽(Viread®)、泰諾福韋亞拉芬醯胺、泰諾福韋、泰諾福韋雙索酯、泰諾福韋亞拉芬醯胺富馬酸鹽、泰諾福韋亞拉芬醯胺半富馬酸鹽、替比夫定(Tyzeka®)或拉米夫定(Epivir-HBV®),一種或兩種選自由以下組成之群之另外治療劑:免疫調節劑、類鐸受體調節劑(tlr1、tlr2、tlr3、tlr4、tlr5、tlr6、tlr7、tlr8、tlr9、tlr10、tlr11、tlr12及tlr13之調節劑)、HBsAg抑制劑、HBV治療性疫苗、HBV抗體(包括靶向B型肝炎病毒之表面抗原之HBV抗體)及雙特異性抗體及「抗體樣」治療性蛋白(例如DARTs®、Duobodies®、Bites®、XmAbs®、TandAbs ®、Fab衍生物)、親環素抑制劑、視黃酸可誘導基因1之刺激劑、PD-1抑制劑、PD-L1抑制劑、精胺酸酶-1抑制劑、PI3K抑制劑及NOD2之刺激劑,以及一種或兩種選自由以下組成之群之另外治療劑:HBV病毒進入抑制劑、NTCP抑制劑、HBx抑制劑、cccDNA抑制劑、靶向B型肝炎病毒之表面抗原之HBV抗體、短干擾RNA(siRNA)、miRNA基因療法藥劑、短合成髮夾RNA(sshRNA)及核蛋白抑制劑(HBV核心或衣殼蛋白抑制劑)。
在某些實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與5-30mg泰諾福韋亞拉芬醯胺富馬酸鹽、泰諾福韋亞拉芬醯胺半富馬酸鹽或泰諾福韋亞拉芬醯胺。在某些實施例中,組合本文所揭
示之化合物或其醫藥上可接受之鹽與5-10mg、5-15mg、5-20mg、5-25mg、25-30mg、20-30mg、15-30mg或10-30mg泰諾福韋亞拉芬醯胺富馬酸鹽、泰諾福韋亞拉芬醯胺半富馬酸鹽或泰諾福韋亞拉芬醯胺。在某些實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與10mg泰諾福韋亞拉芬醯胺富馬酸鹽、泰諾福韋亞拉芬醯胺半富馬酸鹽或泰諾福韋亞拉芬醯胺。在某些實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與25mg泰諾福韋亞拉芬醯胺富馬酸鹽、泰諾福韋亞拉芬醯胺半富馬酸鹽或泰諾福韋亞拉芬醯胺。可將如本文所揭示之化合物(例如,式(I)化合物)與本文提供之藥劑以化合物之任何劑量量(例如,50mg至500mg化合物)組合,如同明確地及單獨地列舉之劑量之每一組合一般。
在某些實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與100-400mg泰諾福韋雙索酯富馬酸鹽、泰諾福韋雙索酯半富馬酸鹽或泰諾福韋雙索酯。在某些實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與100-150mg、100-200,100-250mg、100-300mg、100-350mg、150-200mg、150-250mg、150-300mg、150-350mg、150-400mg、200-250mg、200-300mg、200-350mg、200-400mg、250-350mg、250-400mg、350-400mg或300-400mg泰諾福韋雙索酯富馬酸鹽、泰諾福韋雙索酯半富馬酸鹽或泰諾福韋雙索酯。在某些實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與300mg泰諾福韋雙索酯富馬酸鹽、泰諾福韋雙索酯半富馬酸鹽或泰諾福韋雙索酯。在某些實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與250mg泰諾福韋雙索酯富馬酸鹽、泰諾福韋雙索酯半富馬酸鹽或泰諾福韋雙索酯。在某些實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與150mg泰諾福韋雙索酯富馬酸鹽、泰諾福韋雙索酯半富馬酸鹽或泰諾福韋雙索酯。可將如本文所揭示之化合物
(例如,式(I)化合物)與本文提供之藥劑以化合物之任何劑量量(例如,50mg至500mg化合物)組合,如同明確地及單獨地列舉之劑量之每一組合一般。
在某些實施例中,在組合本文所揭示之化合物與一或多種如上文所述另外治療劑時,組合物之組份作為同時或依序方案投與。在依序投與時,該組合可以兩次或更多次投與來投與。
在某些實施例中,將本文所揭示之化合物與一或多種另外治療劑以單式劑型組合用於同時投與患者,例如以固體劑型用於經口投與。
在某些實施例中,本文所揭示之化合物與一或多種另外治療劑一起投與。本文所揭示之化合物與一或多種另外治療劑之共投與通常係指本文所揭示之化合物及一或多種另外治療劑之同時或依序投與,使得患者體內存在治療有效量之本文所揭示之化合物及一或多種另外治療劑二者。
共投與包括在投與單位劑量之一或多種另外治療劑之前或之後投與單位劑量之本文所揭示之化合物,例如在投與一或多種另外治療劑數秒、數分鐘或數小時內投與本文所揭示之化合物。舉例而言,在一些實施例中,首先投與單位劑量之本文所揭示之化合物,在數秒或數分鐘之後投與單位劑量之一或多種另外治療劑。或者,在其他實施例中,首先投與單位劑量之一或多種另外治療劑,在數秒或數分鐘之後投與單位劑量之本文所揭示之化合物。在一些實施例中,首先投與單位劑量之本文所揭示之化合物,在數小時(例如,1-12小時)時段後投與單位劑量之一或多種另外治療劑。在其他實施例中,首先投與單位劑量之一或多種另外治療劑,在數小時(例如,1-12小時)時段後投與單位劑量之本文所揭示之化合物。
在某些實施例中,提供治療或預防患有或處於患有HIV感染之風險之人類之該感染的方法,其包含向該人類投與治療有效量之本文所揭示之化合物或其醫藥上可接受之鹽與治療有效量之一或多種(例如,一種、兩種、三種、四種、一種或兩種或一至三種或一至四種)另外治療劑的組合。在一個實施例中,提供治療患有或處於患有HIV感染之風險之人類之該感染的方法,其包含向該人類投與治療有效量之本文所揭示之化合物或其醫藥上可接受之鹽與治療有效量之一或多種(例如,一種、兩種、三種、四種、一種或兩種或一至三種或一至四種)另外治療劑的組合。
在某些實施例中,本發明提供治療HIV感染之方法,其包含向有需要之患者投與治療有效量之本文所揭示之化合物或其醫藥上可接受之鹽與治療有效量之一或多種適於治療HIV感染之另外治療劑的組合。
在一個實施例中,提供包含本文所揭示之化合物或其醫藥上可接受之鹽與一或多種(例如,一種、兩種、三種、四種、一種或兩種或一至三種或一至四種)另外治療劑之組合及醫藥上可接受之載劑、稀釋劑或賦形劑的醫藥組合物。
在一個實施例中,提供包含本文所揭示之化合物或其醫藥上可接受之鹽與一或多種(例如,一種、兩種、三種、四種、一種或兩種或一至三種或一至四種)另外治療劑之組合的套組。
在上述實施例中,另外治療劑可為抗HBV藥劑。舉例而言,在一些實施例中,另外治療劑選自由以下組成之群:HIV蛋白酶抑制劑、反轉錄酶之HIV非核苷抑制劑、反轉錄酶之HIV核苷或核苷酸抑制劑、HIV整合酶抑制劑、HIV非催化性位點(或別位)整合酶抑制劑、進入抑制劑(例如,CCR5抑制劑、gp41抑制劑(即,融合抑制劑)及CD4附接抑制劑)、CXCR4抑制劑、gpl20抑制劑、G6PD及NADH-
氧化酶抑制劑、靶向HIV衣殼之化合物(「衣殼抑制劑」;例如,衣殼聚合抑制劑或衣殼破壞化合物,例如揭示於以下中之彼等:WO 2013/006738(Gilead Sciences)、US 2013/0165489(University of Pennsylvania)及WO 2013/006792(Pharma Resources)、藥物動力學增強子及用於治療HIV之其他藥物及其組合。
在其他實施例中,另外治療劑選自以下中之一或多者:(1)選自由以下組成之群之HIV蛋白酶抑制劑:胺普那韋(amprenavir)、阿紮那韋(atazanavir)、呋山那韋(fosamprenavir)、英地那韋(indinavir)、洛匹那韋(lopinavir)、利托那韋(ritonavir)、奈費那韋(nelfmavir)、沙奎那韋(saquinavir)、替拉那韋(tipranavir)、貝卡那韋(brecanavir)、達如那韋(darunavir)、TMC-126、TMC-114、莫折那韋(mozenavir)(DMP-450)、JE-2147(AG1776)、L-756423、RO0334649、KNI-272、DPC-681、DPC-684、GW640385X、DG17、PPL-100、DG35及AG 1859;(2)選自由以下組成之群之反轉錄酶之HIV非核苷或非核苷酸抑制劑:卡普韋林(capravirine)、乙米韋林(emivirine)、地拉韋啶(delaviridine)、依法韋侖(efavirenz)、奈韋拉平(nevirapine)、(+)卡拉諾萊得(calanolide)A、依曲韋林(etravirine)、GW5634、DPC-083、DPC-961、DPC-963、MIV-150、TMC-120、利匹韋林(rilpivirene)、BILR 355 BS、VRX 840773、來司韋林(lersivirine)(UK-453061)、RDEA806、KM023及MK-1439;(3)選自由以下組成之群之反轉錄酶之HIV核苷或核苷酸抑制劑:齊多夫定(zidovudine)、恩曲他濱、去羥肌苷(didanosine)、司他夫定(stavudine)、紮昔他賓(zalcitabine)、拉米夫定、阿巴卡韋(abacavir)、硫酸阿巴卡韋、胺多索韋(amdoxovir)、艾夫他濱(elvucitabine)、阿洛夫定(alovudine)、MIV-210、±- FTC、D-d4FC、
恩曲他濱、疊氮膦、福齊夫定替酯(fosalvudine tidoxil)、阿立他濱(apricitibine)(AVX754)、KP-1461、GS-9131(Gilead Sciences)及福齊夫定替酯(先前稱作HDP 99.0003)、泰諾福韋、泰諾福韋雙索酯富馬酸鹽、泰諾福韋亞拉芬醯胺(Gilead Sciences)、泰諾福韋亞拉芬醯胺半富馬酸鹽(Gilead Sciences)、GS-9148(Gilead Sciences)、阿德福韋、阿德福韋二吡呋酯、CMX-001(Chimerix)或CMX-157(Chimerix);(4)選自由以下組成之群之HIV整合酶抑制劑:薑黃素、薑黃素之衍生物、菊苣酸、菊苣酸之衍生物、3,5-二綠原酸、3,5-二綠原酸之衍生物、金精三羧酸、金精三羧酸之衍生物、咖啡酸苯乙基酯、咖啡酸苯乙基酯之衍生物、酪胺酸磷酸化抑制劑、酪胺酸磷酸化抑制劑之衍生物、槲皮素、槲皮素之衍生物、S-1360、AR-177、L-870812及L-870810、雷特格韋(raltegravir)、BMS-538158、GSK364735C、BMS-707035、MK-2048、BA 011、埃替格韋(elvitegravir)、德羅格韋(dolutegravir)及GSK-744;(5)HIV非催化性位點或別位整合酶抑制劑(NCINI),包括但不限於BI-224436、CX0516、CX05045、CX14442、揭示於以下中之化合物:WO 2009/062285(Boehringer Ingelheim)、WO 2010/130034(Boehringer Ingelheim)、WO 2013/159064(Gilead Sciences)、WO 2012/145728(Gilead Sciences)、WO 2012/003497(Gilead Sciences)、WO 2012/003498(Gilead Sciences),其各自之全部內容亦引用方式併入;(6)選自由以下組成之群之gp41抑制劑:恩夫韋肽(enfuvirtide)、西夫韋肽(sifuvirtide)、艾博韋肽(albuvirtide)、FB006M及TRI-1144;(7)CXCR4抑制劑AMD-070;
(8)進入抑制劑SP01A;(9)gpl20抑制劑BMS-488043;(10)G6PD及NADH-氧化酶抑制劑免疫素(immunitin);(11)選自由以下組成之群之CCR5抑制劑:阿普拉維洛(aplaviroc)、維克力維洛(vicriviroc)、馬拉維洛(maraviroc)、塞尼利維洛(cenicriviroc)、PRO-140、INCB15050、PF-232798(Pfizer)及CCR5mAb004;(12)選自由以下組成之群之CD4附接抑制劑:艾巴利單抗(ibalizumab)(TMB-355)及BMS-068(BMS-663068);(13)選自由以下組成之群之藥物動力學增強子:可比司他(cobicistat)及SPI-452;及(14)選自由以下組成之群之用於治療HIV之其他藥物:BAS-100、SPI-452、REP 9、SP-01A、TNX-355、DES6、ODN-93、ODN-112、VGV-1、PA-457(貝韋利馬(bevirimat))、HRG214、VGX-410、KD-247、AMZ 0026、CYT 99007A-221 HIV、DEBIO-025、BAY 50-4798、MDX010(伊匹單抗)、PBS 119、ALG 889及PA-1050040(PA-040)及其組合。
在某些實施例中,另外治療劑係選自由以下組成之群之類鐸受體8調節劑:莫特莫德、雷西莫特、3M-051、3M-052、MCT-465、IMO-4200、VTX-763、VTX-1463及揭示於以下中之彼等:US20140045849(Janssen)、US20140073642(Janssen)、WO2014/056953(Janssen)、WO2014/076221(Janssen)、WO2014/128189(Janssen)、US20140350031(Janssen)、WO2014/023813(Janssen)、US20080234251(Array Biopharma)、US20080306050(Array Biopharma)、US20100029585(Ventirx Pharma)、US20110092485(Ventirx Pharma)、US20110118235(Ventirx
Pharma)、US20120082658(Ventirx Pharma)、US20120219615(Ventirx Pharma)、US20140066432(Ventirx Pharma)、US20140088085(VentirxPharma)、US20140275167(Novira therapeutics)、US20130251673(Novira therapeutics)。
在某些實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與一種、兩種、三種、四種或更多種另外治療劑。在某些實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與兩種另外治療劑。在其他實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與三種另外治療劑。在其他實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與四種另外治療劑。兩種、三種、四種或更多種另外治療劑可為選自相同種類之治療劑之不同治療劑,及/或其可選自不同種類之治療劑。在具體實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與反轉錄酶之HIV核苷或核苷酸抑制劑及反轉錄酶之HIV非核苷抑制劑。在另一具體實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與反轉錄酶之HIV核苷或核苷酸抑制劑及HIV蛋白酶抑制化合物。在又一實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與反轉錄酶之HIV核苷或核苷酸抑制劑、反轉錄酶之HIV非核苷抑制劑及HIV蛋白酶抑制化合物。在另一實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與反轉錄酶之HIV核苷或核苷酸抑制劑、反轉錄酶之HIV非核苷抑制劑及藥物動力學增強子。在另一實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與兩種反轉錄酶之HIV核苷或核苷酸抑制劑。
在特定實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與硫酸阿巴卡韋、泰諾福韋、泰諾福韋雙索酯富馬酸鹽、泰諾福韋亞拉芬醯胺或泰諾福韋亞拉芬醯胺半富馬酸鹽。
在特定實施例中,組合本文所揭示之化合物或其醫藥上可接受
之鹽與泰諾福韋、泰諾福韋雙索酯富馬酸鹽、泰諾福韋亞拉芬醯胺或泰諾福韋亞拉芬醯胺半富馬酸鹽。
在特定實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與選自由以下組成之群之第一另外治療劑:硫酸阿巴卡韋、泰諾福韋、泰諾福韋雙索酯富馬酸鹽、泰諾福韋亞拉芬醯胺及泰諾福韋亞拉芬醯胺半富馬酸鹽,以及選自由以下組成之群之第二另外治療劑:恩曲他濱及拉米夫定。在特定實施例中,組合本文所揭示之化合物或其醫藥上可接受之鹽與選自由以下組成之群之第一另外治療劑:泰諾福韋、泰諾福韋雙索酯富馬酸鹽、泰諾福韋亞拉芬醯胺及泰諾福韋亞拉芬醯胺半富馬酸鹽,以及第二另外治療劑,其中第二另外治療劑係恩曲他濱。
在某些實施例中,在組合本文所揭示之化合物與一或多種如上文所述另外治療劑時,組合物之組份作為同時或依序方案投與。在依序投與時,該組合可以兩次或更多次投與來投與。
在某些實施例中,將本文所揭示之化合物與一或多種另外治療劑以單式劑型組合用於同時投與患者,例如以固體劑型用於經口投與。
在某些實施例中,本文所揭示之化合物與一或多種另外治療劑一起投與。本文所揭示之化合物與一或多種另外治療劑之共投與通常係指本文所揭示之化合物及一或多種另外治療劑之同時或依序投與,使得患者體內存在治療有效量之本文所揭示之化合物及一或多種另外治療劑二者。
共投與包括在投與單位劑量之一或多種另外治療劑之前或之後投與單位劑量之本文所揭示之化合物,例如在投與一或多種另外治療劑數秒、數分鐘或數小時內投與本文所揭示之化合物。舉例而言,在一些實施例中,首先投與單位劑量之本文所揭示之化合物,在數秒或
數分鐘之後投與單位劑量之一或多種另外治療劑。或者,在其他實施例中,首先投與單位劑量之一或多種另外治療劑,在數秒或數分鐘之後投與單位劑量之本文所揭示之化合物。在一些實施例中,首先投與單位劑量之本文所揭示之化合物,在數小時(例如,1-12小時)時段後投與單位劑量之一或多種另外治療劑。在其他實施例中,首先投與單位劑量之一或多種另外治療劑,在數小時(例如,1-12小時)時段後投與單位劑量之本文所揭示之化合物。
本文亦提供包括式I化合物或其醫藥上可接受之鹽、立體異構物、前藥或溶劑合物及適宜包裝的套組。在一個實施例中,套組進一步包括使用說明書。在一個態樣中,套組包括式I化合物或其醫藥上可接受之鹽、立體異構物、前藥或溶劑合物及化合物在治療適應症(包括本文所述疾病或病況)中之使用之標記及/或說明書。
本文亦提供包括適宜容器中之本文所述化合物或其醫藥上可接受之鹽、異構物或混合物之製品。容器可為小瓶、罐、安瓿、預裝載注射器及靜脈內袋。
本文提供之化合物通常係以醫藥組合物形式投與。因此,本文亦提供含有一或多種本文所述化合物或其醫藥上可接受之鹽、異構物或混合物及一或多種選自載劑、佐劑及賦形劑之醫藥上可接受之媒劑的醫藥組合物。適宜醫藥上可接受之媒劑可包括(例如)惰性固體稀釋劑及填充劑、稀釋劑,包括無菌水溶液及各種有機溶劑、滲透增強子、增溶劑及佐劑。該等組合物係以醫藥技術中熟知之方式製備。參見(例如)Remington’s Pharmaceutical Sciences,Mace Publishing Co.,Philadelphia,Pa.第17版(1985);及Modern Pharmaceutics,Marcel Dekker,Inc.第3版(G.S.Banker及C.T.Rhodes編輯)。
醫藥組合物可以單一或多個劑量投與。醫藥組合物可藉由各種方法(包括例如直腸、經頰、鼻內及經皮途徑)投與。在某些實施例中,醫藥組合物可藉由動脈內注射、靜脈內、腹膜內、非經腸、肌內、皮下、經口、局部或以吸入劑形式投與。
一種投與模式係非經腸,例如藉由注射。可納入本文所述醫藥組合物用於藉由注射投與之形式包括(例如)水性或油性懸浮液、或含有芝麻油、玉米油、棉籽油或花生油之乳液、以及酏劑、甘露醇、右旋糖、或無菌水溶液及類似醫藥媒劑。
經口投與可為投與本文所述化合物之另一途徑。投與可經由(例如)膠囊或腸包衣錠劑。在製備包括至少一種本文所述化合物或其醫藥上可接受之鹽、異構物或混合物之醫藥組合物中,通常藉由賦形劑稀釋活性成份及/或將其包封於可呈膠囊、小藥囊、紙或其他容器形式之載劑中。當賦形劑用做稀釋劑時,其可呈固體、半固體或液體材料形式,其對活性成份起媒劑、載劑或介質作用。因此,該等組合物可呈錠劑、丸劑、粉劑、菱形錠劑、藥囊、藥丸、酏劑、懸浮液、乳液、溶液、糖漿、氣溶膠(作為固體或存於液體介質中)、軟膏(含有例如高達10重量%活性化合物)、軟及硬明膠膠囊、無菌可注射溶液及無菌包裝的粉劑之形式。
適宜賦形劑之一些實例包括乳糖、右旋糖、蔗糖、山梨糖醇、甘露醇、澱粉、阿拉伯膠(gum acacia)、磷酸鈣、藻酸鹽、黃蓍膠、明膠、矽酸鈣、微晶纖維素、聚乙烯基吡咯啶酮、纖維素、無菌水、糖漿及甲基纖維素。該等調配物可另外包括:潤滑劑,例如滑石粉、硬脂酸鎂及礦物油;潤濕劑;乳化及懸浮劑;防腐劑,例如羥基苯甲酸甲酯及羥基苯甲酸丙酯;增甜劑;及矯味劑。
可藉由採用業內已知之程序調配包括至少一種本文所述化合物或其醫藥上可接受之鹽、異構物或混合物之組合物以便在投與個體後
提供活性成份之快速、持續或延遲釋放。經口投與之控制釋放藥物遞送系統包括滲透幫浦系統及含有聚合物塗佈之儲存器或藥物-聚合物基質調配物之溶解系統。控制釋放系統之實例係於美國專利第3,845,770號、第4,326,525號、第4,902,514號及第5,616,345號中給出。用於本發明方法中之另一調配物採用經皮遞送裝置(「貼片」)。此等經皮貼片可用於以控制量提供本文所述化合物之連續或不連續輸注。用於遞送醫藥劑之經皮貼劑之構築及使用為業內熟知。參見(例如)美國專利第5,023,252號、第4,992,445號及第5,001,139號。該等貼片可經構築以供醫藥劑之連續、脈衝式或隨選即用地(on demand)遞送。
對於製備組合物(例如錠劑)而言,可將主要活性成份與醫藥賦形劑混合以形成含有本文所述化合物或其醫藥上可接受之鹽、異構物或混合物之均質混合物的固體預調配組合物。當提及該等預調配組合物呈均相時,活性成份可均勻分散於整個組合物中,以便可容易地將組合物再分成相等地有效單位劑型,例如錠劑、丸劑及膠囊。
本文所述錠劑或丸劑可經塗佈或以其他方式複合以提供具有持久作用優點之劑型,或以保護免於經受胃之酸性條件。舉例而言,錠劑或丸劑可包括內部劑量組份及外部劑量組份,後者為前者之包膜形式。該兩種組份可藉由腸溶性層分開,該腸溶性層用以抵抗胃內的分解作用並允許內部組份完整地進入十二指腸或延遲釋放。該等腸溶性層或包衣可使用多種材料,該等材料包括大量聚合酸及聚合酸與諸如蟲膠、十六烷醇及乙酸纖維素等材料之混合物。
供吸入或吹入用之組合物可包括醫藥上可接受之水性或有機溶劑、或其混合物中之溶液及懸浮液以及粉末。該等液體或固體組合物可含有上文所述醫藥上可接受之適宜賦形劑。在一些實施例中,該等組合物係藉由口或鼻呼吸途徑投與以供局部或全身效應。在其他實施
例中,醫藥上可接受之溶劑中之組合物可藉由使用惰性氣體霧化。經霧化溶液可直接自霧化裝置吸入或可將該霧化裝置附接至面罩帷罩或間歇式正壓呼吸機。溶液、懸浮液或粉末組合物可較佳經口或經鼻自以適當方式遞送調配物之裝置投與。
用於任何特定個體之本申請案之化合物之具體劑量量將取決於多種因素,包括經歷療法之個體中之所採用具體化合物之活性、年齡、體重、一般健康狀況、性別、飲食、投與時間、投與途徑及排泄速率、藥物組合及特定疾病之嚴重程度。舉例而言,劑量可表示為本文所述化合物之毫克數/公斤個體體重(mg/kg)。介於約0.1mg/kg與150mg/kg之間之劑量可為適當的。在一些實施例中,約0.1mg/kg與100mg/kg可為適當的。在其他實施例中,介於0.5mg/kg與60mg/kg之間之劑量可為適當的。在調節廣泛不同大小之個體之間之劑量時,根據個體之體重之正規化尤其有用,例如在兒童及成人中使用藥物時或在將非人類個體(例如狗)中之有效劑量轉化成適於人類個體之劑量時發生。
日劑量亦可闡述為每個劑量或每天投與之本文所述化合物之總量。式I化合物之日劑量可介於約1mg與4,000mg之間、介於約2,000mg/天至4,000mg/天之間、介於約1mg/天至2,000mg/天之間、介於約1mg/天至1,000mg/天之間、介於約10mg/天至500mg/天之間、介於約20mg/天至500mg/天之間、介於約50mg/天至300mg/天之間、介於約75mg/天至200mg/天之間或介於約15mg/天至150mg/天之間。
在經口投與時,人類個體之總日劑量可介於1mg與1,000mg之間、介於約10-500mg/天、介於約50-300mg/天、介於約75-200mg/天或介於約100-150mg/天。
本申請案之化合物或其組合物可使用上述任一適宜模式每日投
與一次、兩次、三次或四次。同樣,化合物之投與或利用其之治療可持續數天;例如對於一個治療週期,治療通常將持續至少7天、14天或28天。治療週期已為癌症化學療法熟知,且在週期之間通常與約1至28天、通常約7天或約14天之休息期交替。在其他實施例中,治療週期亦可係連續的。
在特定實施例中,該方法包含向個體投與約1mg至500mg本文所述化合物之初始日劑量及以增量增加劑量直至獲得臨床效能為止。可使用約5mg、10mg、25mg、50mg或100mg之增量以增加劑量。可每日、每隔一天、每週兩次或每週一次增加劑量。
該等化合物可使用本文所揭示之方法及其常規修改形式(根據本文揭示內容將明瞭)及業內熟知之方法來製備。除本文教示外,可使用習用及熟知合成方法。本文所述典型化合物之合成可如以下實例中所述完成。若可用,試劑可購自(例如)Sigma Aldrich或其他化學供應商。
本文所述化合物之典型實施例可使用下述一般反應方案來合成。應明瞭,假定如下本文說明:可藉由用具有類似結構之其他材料取代起始材料來改變一般方案以產生相應地不同之產物。遵循合成之說明以提供起始材料可如何變化以提供相應產物之各個實例。假定取代基經定義之期望產物,通常可藉由檢查測定必需起始材料。起始材料通常係自商業來源獲得或使用已公開方法合成。對於合成作為闡述於本發明中之實施例之化合物,欲合成化合物之結構之檢查將提供每一取代基之身份。假定本文中之實例,最終產物之身份通常藉由簡單檢查過程將使得可明瞭必需起始材料之身份。一般而言,本文所述化合物通常於室溫及壓力下穩定且可分離。
本揭示內容之化合物可自容易獲得之起始材料使用(例如)以下一般方法及程序來製備。應瞭解,儘管給出了典型或較佳製程條件(即反應溫度、時間、反應物之莫耳比、溶劑、壓力等),但除非另有說明,否則亦可使用其他製程條件。最佳反應條件可隨所用特定反應物或溶劑而變化,但此等條件可由熟習此項技術者藉由常規最優化程序來確定。
此外,如彼等熟習此項技術者所明瞭,可能需要習用保護基團以防止某些官能基發生不期望反應。用於各種官能基之適宜保護基團以及用於保護及去保護特定官能基之適宜條件為業內所熟知。舉例而言,諸多保護基團闡述於T.W.Greene及G.M.Wuts(1999)Protecting Groups in Organic Synthesis,第3版,Wiley,New York及其中所引用之參考文獻中。
此外,本揭示內容之化合物可含有一或多個對掌性中心。因此,若期望,此等化合物可以純淨立體異構物形式(即,以個別鏡像異構物或非鏡像異構物形式)或以富含立體異構物之混合物形式製備或分離。除非另有說明,否則所有該等立體異構體(及富含其之混合物)皆包括在本揭示內容之範疇內。純淨立體異構體(或富含其之混合物)可使用(例如)此項技術熟知之光學活性起始材料或立體選擇性試劑來製備。另一選擇為,可使用(例如)對掌性管柱層析、對掌性拆分劑及諸如此類來分離該等化合物之外消旋混合物。
用於以下反應之起始材料係眾所周知之化合物或可藉由已知程序或其明顯修改形式製備。舉例而言,許多起始材料購自商業供應商,例如Aldrich Chemical Co.(Milwaukee,Wisconsin,USA)、Bachem(Torrance,California,USA)、Emka-Chemce或Sigma(St.Louis,Missouri,USA)。其他材料可藉由闡述於諸如下列標準參考文獻中之
程序或其明顯修改形式製得:Fieser and Fieser's Reagents for Organic Synthesis,第1-15卷(John Wiley,and Sons,1991)、Rodd's Chemistry of Carbon Compounds,第1-5卷及增刊(Elsevier Science Publishers,1989)organic Reactions,第1-40卷(John Wiley,and Sons,1991)、March's Advanced Organic Chemistry,(John Wiley,and Sons,第5版,2001)及Larock's Comprehensive Organic Transformations(VCH Publishers Inc.,1989)。
術語「溶劑」、「惰性有機溶劑」或「惰性溶劑」係指在所述相關反應條件下為惰性之溶劑(包括例如苯、甲苯、乙腈、四氫呋喃(「THF」)、二甲基甲醯胺(「DMF」)、氯仿、二氯甲烷(methylene chloride或dichloromethane)、二乙醚、甲醇及諸如此類)。除非指定相反含義,否則本發明反應中所使用之溶劑係惰性有機溶劑,且反應係在惰性氣體、較佳氮下實施。
術語「補足量」意指添加足以達成所述功能(例如,使溶液達到期望體積(即,100%))之量。
式I化合物可藉由首先提供經取代之咪唑并[4,5-b]吡啶或苯并咪唑核心及視情況進一步視需要修飾該核心以提供本文所揭示之取代基來製得。
方案1顯示式I化合物之製備,其中m、n、L、R1、R2a、R2b及X
係如本文中所定義,且R4係如本文中所定義之,或
使用標準反應條件及保護/去保護步驟(視需要)轉化成其之官能基。
方案1
在方案1中,於升高溫度(通常約80℃至100℃)下在適宜溶劑(例如,甲酸、乙醇等)中使適宜地經取代之1-a及1-b偶合並環化以提供咪唑并[4,5-b]吡啶或苯并咪唑核心1-c。隨後在標準條件下使用Lawesson試劑(即,2,4-雙(4-甲氧基苯基)-1,3,2,4-二硫二磷雜環丁烷-2,4-二硫化物)使1-c轉化成相應硫醯胺1-d。藉由使用羥基胺環化硫醯胺1-d獲得1-e。藉由與適宜鹼(例如,NaOH)反應使1-e水解以獲得化合物1-f。或者,使用五氯化磷將1-c轉變成化合物1-f,之後用水性羥基胺處理。
方案2顯示式I化合物之合成,其中Rt係氫,且R1、R2a、R2b及X係如本文中所定義。
在方案2中,使用發煙硝酸硝化2-a以提供2-b,隨後在還原條件
(例如,鋅、鐵等)下將其環化以提供C-2未經取代之咪唑并[4,5-b]吡啶或苯并咪唑2-c。藉由使相應酯2-c與適宜胺2-d在標準醯胺鍵形成反應條件下反應提供醯胺2-e,且隨後使用方案1中上文所示方法將其轉化成式I化合物。
方案3顯示式I化合物之合成,其中Rt係-NH2,且R1、R2a、R2b及X係如本文中所定義。
在方案3中,藉由3-a與溴化氰反應獲得3-b。藉由使相應酯3-b與適宜胺3-c在標準醯胺鍵形成反應條件下反應提供醯胺3-d,且隨後使用方案1中上文所示方法將其轉化成式I化合物。
在某些實施例中,製程可包含R4之保護及去保護/進一步修飾(方
案1)以提供式I化合物中之期望基團。方案4顯示實例
性保護/去保護或進一步修飾以提供式I化合物,其中Rt、Rm、m、L、R1、R2a、R2b及X係如本文中所定義。
方案4
在方案4中,可使用適宜保護基團PG(例如矽基醚)保護適宜地經取代之4-a以提供4-b(參見例如T.W.Greene及G.M.Wuts(1999)Protecting Groups in Organic Synthesis,第3版,Wiley,New York及其中所引用之參考文獻)。隨後將4-b轉化成相應硫醯胺4-c並使用羥基胺如方案1中上文所示環化以提供4-d。隨後可藉由去保護及可選進一步修飾將4-d轉化成化合物4-e。舉例而言,可使4-d去保護並轉化成適宜脫離基(例如,TMS-O-基團)且隨後與適宜胺反應以提供式4-e化合物,其中L係-NR3-。隨後使用方案1中上文所示方法將4-e轉化成式I化合物。
上述方案中每一中間體可在後續步驟之前分離及/或純化或未經純化及/或分離即用於下一步驟。亦應瞭解,添加任何取代基可產生多種異構產物,其中之任一者或全部可使用習用技術分離並純化。
本發明包括以下實例以展示本揭示內容之具體實施例。彼等熟習此項技術者應瞭解,在以下實例中揭示之技術代表本發明者所發現可良好實踐本揭示內容之技術,且因此可認為構成本發明實踐之具體模式。然而,根據本發明揭示內容,彼等熟習此項技術者應瞭解,可
對所揭示具體實施例作出多種改變且仍獲得相似或類似結果,而不背離本發明之精神及範疇。
3-甲醯胺基-4-甲基苯甲酸甲基酯.將-3-胺基-4-甲基苯甲酸甲基酯(5.1g,31mmol)於甲酸(42mL)中之溶液於110℃下攪拌4hr。使反應混合物冷卻至室溫。添加水並將水層用乙酸乙酯洗滌三次。將合併之有機層經硫酸鈉乾燥,過濾並濃縮,以產生期望產物。C10H11NO3.194.0(M+1)。
3-甲醯胺基-4-甲基-2-硝基苯甲酸甲基酯.於0℃下經45min向發煙硝酸中逐份添加3-甲醯胺基-4-甲基苯甲酸甲基酯(5.3g,27mmol)。反應混合物於0℃下再攪拌1h,且隨後添加冰並將混合物於室溫下攪拌1.5h。過濾沈澱固體,並用水洗滌。藉由矽膠純化固體,以產生期望產物。C10H10N2O5.239.0(M+1)。
4-甲基-1H-苯并[d]咪唑-7-甲酸甲基酯.將3-甲醯胺基-4-甲基-2-硝基苯甲酸甲基酯(1.0g,4.2mmol)及鐵(1.2g,21mmol)於甲醇(10mL)及乙酸(5mL)中之混合物於70℃下攪拌3hr。向冷卻之反應混合物中添加乙酸乙酯及水並過濾混合物且用乙酸乙酯洗滌固體。用乙酸乙酯將水性層洗滌兩次。將合併之有機層經硫酸鈉乾燥,過濾並濃縮以產生期望產物。C10H10N2O2.191.1(M+1)。
N-(3-氯-4-氟苯基)-4-甲基-1H-苯并[d]咪唑-7-甲醯胺.於0℃下在氮下經5min向3-氯-4-氟苯胺(253mg,1.74mmol)於二氯乙烷中之溶液中逐滴添加三甲基鋁(2M於庚烷中,1.74mL,3.47mmol)。使溶液升溫至室溫並攪拌30min。將溶液冷卻至0℃並向此溶液中添加4-甲基-1H-苯并[d]咪唑-7-甲酸甲基酯(220mg,1.16mmol)。將溶液於85℃下攪拌6hr且隨後冷卻至室溫。向混合物中添加乙酸乙酯及10%檸檬酸並將所得沈澱過濾並在高真空上乾燥,以產生期望產物。C15H11ClFN3O.304.4(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-4-甲基-1H-苯并[d]咪唑-7-甲脒.將N-(3-氯-4-氟苯基)-4-甲基-1H-苯并[d]咪唑-7-甲醯胺(154mg,0.507mmol)、五氯化磷(158mg,0.761mmol)於磷醯氯(1.5mL)及1,2-二氯乙烷(1.5mL)中之混合物於80℃下攪拌2.5hr。將反應混合物濃縮並懸浮於乙醇(1.5mL)並向此混合物中添加水中之50%羥基胺(0.311mL,5.07mmol)。將反應混合物攪拌1hr並濃縮。藉由製備型HPLC純化殘餘物,以產生期望化合物。C15H12ClFN4O.319.1(M+1)。
將硝酸(18mL)在乾冰/丙酮浴中冷卻至-10℃並添加2-甲醯胺基-4-(三氟甲氧基)苯甲酸甲基酯(1.97g,7.0mol)並將反應物於-10℃下攪拌4小時。將反應物緩慢用水(20mL)驟冷並用EtOAc(3×10mL)萃取。將合併之有機層用鹽水(1×30mL)洗滌且在真空中濃縮,以產生呈異構物之混合物之2-甲醯胺基-3-硝基-4-(三氟甲氧基)苯甲酸甲基酯。
將2-甲醯胺基-3-硝基-4-(三氟甲氧基)苯甲酸甲基酯(2.2g,7.0mmol)溶解於乙醇(15mL)及水(5mL)中。一次性添加氯化銨(0.108mol)並將反應物於室溫下攪拌。經5分鐘逐份添加鋅粉(0.108mol)並在添加完成後將反應物攪拌5分鐘。隨後藉由真空過濾移除鋅並在真空中濃縮濾液。將粗製物溶解於水(20mL)中且用EtOAc(4×10mL)萃取。將合併之有機層用鹽水(1×50mL)洗滌,經硫酸鈉乾燥,且在真空中濃縮,以產生3-胺基-2-甲醯胺基-4-(三氟甲氧基)苯甲酸甲基酯。
將3-胺基-2-甲醯胺基-4-(三氟甲氧基)苯甲酸甲基酯(1.32g,5.0mmol)溶解於甲酸(15mL)中並加熱至80℃並持續1小時。將反應物冷卻至rt,在真空中濃縮,並用飽和碳酸氫鈉溶液(10mL)驟冷。將混合物用EtOAc(4×5mL)萃取並將合併之有機層用鹽水(1×15mL)洗滌且在真空中濃縮。藉由管柱層析純化粗物質,以產生4-(三氟甲氧基)-1H-苯并[d]咪唑-7-甲酸甲基酯。
N-(3-氯-4-氟苯基)-N'-羥基-4-(三氟甲氧基)-1H-苯并[d]咪唑-7-甲脒.實例2係類似於實例10使用4-(三氟甲氧基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替4,5-二氟-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。C15H9ClF4N4O2.389.0/391.1(M+1)。
實例3 (N-(3-氯-4-氟苯基)-6-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒)係類似於實例59使用6-氟-1H-苯并[d]咪唑-7-甲酸代替1H-咪唑并[4,5-b]吡啶-7-甲酸來製得。C14H9ClF2N4O.323.1/325.0(M+1)。
實例4係類似於實例59使用5-氟-1H-苯并[d]咪唑-7-甲酸代替1H-咪唑并[4,5-b]吡啶-7-甲酸來製得。C14H9ClF2N4O.323.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.01(s,1H),8.87(d,J=15.9Hz,2H),7.60(dd,J=8.7,2.4Hz,1H),7.20(dd,J=10.2,2.4Hz,1H),7.02(t,J=9.1Hz,1H),6.95(dd,J=6.6,2.7Hz,1H),6.52(ddd,J=9.0,4.1,2.7Hz,1H)。
實例5係類似於實例59使用4-氟-1H-苯并[d]咪唑-7-甲酸代替1H-咪唑并[4,5-b]吡啶-7-甲酸來製得。C14H9ClF2N4O.323.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 10.75(s,1H),8.75(s,1H),8.27(s,1H),7.16(dd,J=8.4,4.6Hz,1H),7.09-6.94(m,2H),6.90(dd,J=6.6,2.7Hz,1H),6.47(ddd,J=9.0,4.0,2.7Hz,1H)。
實例6係類似於實例59使用4-氯-1H-苯并[d]咪唑-7-甲酸代替1H-咪唑并[4,5-b]吡啶-7-甲酸來製得。C14H9Cl2FN4O.339.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 10.85(s,1H),8.81(s,1H),8.39(s,1H),7.29(d,J=8.1Hz,1H),7.18(d,J=8.1Hz,1H),7.01(t,J=9.1Hz,1H),6.93(dd,J=6.6,2.7Hz,1H),6.47(ddd,J=9.0,4.0,2.7Hz,1H)。
實例7係類似於實例59使用4-(三氟甲基)-1H-苯并[d]咪唑-7-甲酸代替1H-咪唑并[4,5-b]吡啶-7-甲酸來製得。C15H9ClF4N4O.373.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 10.97(d,J=5.0Hz,1H),8.83(s,1H),8.35(s,1H),7.52(d,J=7.9Hz,1H),7.30(d,J=7.8Hz,1H),7.01(t,J=9.1Hz,1H),6.93(dd,J=6.6,2.7Hz,1H),6.46(ddd,J=9.0,4.1,2.8Hz,1H)。
實例8係類似於實例59使用1H-苯并[d]咪唑-7-甲酸代替1H-咪唑并[4,5-b]吡啶-7-甲酸來製得。C14H10ClFN4O.305.1(M+1)。
3,5-二氟-4-甲基-2-硝基苯甲酸.於0℃下經1hr向濃硝酸(65%於水中,7.5mL)及硫酸(15mL)中之溶液中逐份添加3,5-二氟-4-甲基苯甲酸(5.0g,29mmol)。使溶液升溫至室溫並攪拌18hr。將反應混合物傾倒至冰上並將所得沈澱過濾並在高真空上乾燥,以產生期望產物(6.3g)。C8H5F2NO4.217.9(M+1)。
N-(3-氯-4-氟苯基)-3,5-二氟-4-甲基-2-硝基苯甲醯胺.於0℃下向3-氯-4-氟苯胺(670mg,4.6mmol)、3,5-二氟-4-甲基-2-硝基苯甲酸(1.0
g,4.6mmol)及三乙胺(1.9mL,14mmol)於二氯甲烷(40mL)中之溶液中添加磷醯氯(0.64mL,6.9mmol)。使反應混合物升溫至室溫並攪拌1hr。向反應混合物中添加飽和碳酸氫鈉並將水層用二氯甲烷洗滌三次。將合併之有機層經硫酸鈉乾燥,過濾,吸附至二氧化矽上並藉由矽膠層析純化,以產生期望產物(1.6g)。C14H8ClF3N2O3.345.0(M+1)。
3-胺基-N-(3-氯-4-氟苯基)-5-氟-4-甲基-2-硝基苯甲醯胺.將N-(3-氯-4-氟苯基)-3,5-二氟-4-甲基-2-硝基苯甲醯胺(674mg,1.96mmol)及於乙醇(2mL)中之28%氫氧化銨水溶液之溶液於80℃下攪拌18hr。向此溶液中添加水並將所得沈澱過濾並在高真空上乾燥,以產生期望產物(583mg)。C14H10ClF2N3O3.364.0(M+23)。
N-(3-氯-4-氟苯基)-5-氟-3-甲醯胺基-4-甲基-2-硝基苯甲醯胺.將乙酸酐(0.4mL,4.3mmol)於甲酸(4mL)中之混合物攪拌5min。向此溶液中添加3-胺基-N-(3-氯-4-氟苯基)-5-氟-4-甲基-2-硝基苯甲醯胺(583mg,1.7mmol)。將反應混合物攪拌2hr並傾倒至冷水上並將所得沈澱過濾並在高真空上乾燥,以產生期望產物(562mg)。C15H10ClF2N3O4.370.0(M+1)。
N-(3-氯-4-氟苯基)-5-氟-4-甲基-1H-苯并[d]咪唑-7-甲醯胺係類似於實例1使用N-(3-氯-4-氟苯基)-5-氟-3-甲醯胺基-4-甲基-2-硝基苯甲醯胺代替3-甲醯胺基-4-甲基-2-硝基苯甲酸甲基酯來製得。C15H10ClF2N3O.322.2(M+1)。
N-(3-氯-4-氟苯基)-6-氟-N'-羥基-7-甲基-3H-苯并咪唑-4-甲脒係類似於實例1使用N-(3-氯-4-氟苯基)-5-氟-4-甲基-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-4-甲基-1H-苯并[d]咪唑-7-甲醯胺來製得。C15H11ClF2N4O.337.0(M+1)。1H NMR(400MHz,DMSO-d 6 )δ 10.97(s,1H),8.96(s,1H),8.86(s,1H),7.20-7.11(m,1H),7.01(t,J=9.2Hz,1H),6.97(dd,J=6.5,2.6Hz,1H),2.44(d,J=1.6Hz,3H)。
將3-胺基-4,5-二氟-2-硝基苯甲酸(15g,68.8mmol)溶解於甲醇(200mL)中並經5分鐘向溶液中逐滴添加硫酸(20mL)。附接回流冷凝器並將反應物加熱至71℃過夜。隨後將反應物冷卻至室溫且在真空中濃縮至約50mL溶劑。將反應物用飽和碳酸鉀中和至pH=7且隨後用EtOAc(5×40mL)萃取。將合併之有機層用鹽水(1×60mL)洗滌且在真空中濃縮,以產生黃色固體狀3-胺基-4,5-二氟-2-硝基苯甲酸甲基酯,其未經進一步純化即使用。
將3-胺基-4,5-二氟-2-硝基苯甲酸酯(14.5g,62mmol)溶解於乙醇
(150mL)及水(50mL)中。一次性添加氯化銨(0.934mol)並將反應物於室溫下攪拌。經5分鐘逐份添加鋅粉(0.934mol)並在添加完成後將反應物攪拌5分鐘。隨後藉由真空過濾移除鋅並在真空中濃縮濾液。將粗製物溶解於水(60mL)中且用EtOAc(4×40mL)萃取。將合併之有機層用鹽水(1×50mL)洗滌,經硫酸鈉乾燥,且在真空中濃縮,以產生褐色粉末狀2,3-二胺基-4,5-二氟苯甲酸甲基酯。
將2,3-二胺基-4,5-二氟苯甲酸甲基酯(60mg,0.30mmol)溶解於甲酸(2mL)中並在密封管中加熱至100℃並保持10分鐘。將反應物冷卻至室溫並在真空中濃縮。將殘餘物溶解於飽和碳酸氫鈉(2mL)中且用EtOAc(3×3mL)萃取。將合併之有機層用水(1×5mL)洗滌且在真空中濃縮,以產生褐色固體狀4,5-二氟-1H-苯并[d]咪唑-7-甲酸甲基酯,其未經進一步純化即使用。
在惰性氣氛下將4,5-二氟-1H-苯并[d]咪唑-7-甲酸甲基酯(12mg,0.056mmol)溶解於DCE(1mL)中。向反應物中逐滴添加三甲基鋁(0.085mL,2.0M於甲苯中),之後添加3-氯-4-氟苯胺(0.085mmol)。將反應物於rt下在惰性氣氛下攪拌過夜。將反應物用飽和碳酸氫鈉(3mL)驟冷並用EtOAc(3×2mL)萃取。將合併之有機層用水(1×4mL)洗滌且在真空中濃縮,以產生N-(3-氯-4-氟苯基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺,其直接用於下一反應。將粗物質溶解於POCl3(2mL)中並添加PCl5(0.083mmol)。將反應物在密封管中加熱至85℃並保持12小時。將反應物冷卻至室溫並在真空中濃縮。將殘餘物溶解於乙醇(2mL)與羥基胺(0.55mmol,50%於水中)之預混合溶液中並將反應物
於室溫下攪拌5分鐘。將反應物在真空中濃縮並藉由反相HPLC純化,以得到白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒。C14H8ClF3N4O.341.1/343.2(M+1)。1H NMR(400MHz,DMSO-d 6 )δ 10.87(s,1H),8.77(s,1H),8.28(s,1H),7.25(d,J=5.5Hz,1H),7.03(t,J=9.0Hz,1H),6.96(dd,J=6.5,2.8Hz,1H),6.48(d,J=9.1Hz,1H)。
5-氯-3-甲醯胺基-2-硝基苯甲酸甲基酯係類似於實例1使用3-胺基-5-氯-2-硝基苯甲酸甲基酯代替3-胺基-4-甲基苯甲酸甲基酯來製得。C9H7ClN2O5.281.1(M+23).
6-氯-1H-苯并[d]咪唑-4-甲酸甲基酯係類似於實例1使用5-氯-3-甲醯胺基-2-硝基苯甲酸甲基酯代替3-甲醯胺基-4-甲基-2-硝基苯甲酸甲基酯來製得。C9H7ClN2O2.211.2(M+1)。
6-氯-N-(3-氯-4-氟苯基)-1H-苯并[d]咪唑-4-甲醯胺係類似於實例1使用6-氯-1H-苯并[d]咪唑-4-甲酸甲基酯代替4-甲基-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。C14H8Cl2FN3O.324.2(M+1)。
6-氯-N-(3-氯-4-氟苯基)-N'-羥基-1H-苯并[d]咪唑-4-甲脒係類似於實例1使用6-氯-N-(3-氯-4-氟苯基)-1H-苯并[d]咪唑-4-甲醯胺代替N-(3-氯-4-氟苯基)-4-甲基-1H-苯并[d]咪唑-7-甲醯胺來製得。C14H9Cl2FN4O.339.0(M+1)。
4-溴-3-甲醯胺基苯甲酸甲基酯係類似於實例9使用3-胺基-4-溴苯甲酸甲基酯代替3-胺基-N-(3-氯-4-氟苯基)-5-氟-4-甲基-2-硝基苯甲醯胺來製得。C9H8BrNO3.279.9/281.9[M+23]+.
4-溴-3-甲醯胺基-2-硝基苯甲酸甲基酯.於-10℃下經90min向發煙硝酸(14mL)中逐份添加4-溴-3-甲醯胺基苯甲酸甲基酯(5.1g,20mmol)。將混合物於0℃下攪拌1h且隨後傾倒於冰上並進行攪拌並經1.5h升溫至rt。經由過濾分離固體並將濾墊用水洗滌。將固體吸收於EtOAc中,用鹽水洗滌,濃縮至矽膠上,並經由矽膠上管柱層析純化,以產生期望產物及其區域異構物之混合物(3.5g)。C9H7BrN2O5.324.9/326.9[M+23]+。
4-溴-1H-苯并[d]咪唑-7-甲酸甲基酯係類似於實例1使用4-溴-3-甲醯胺基-2-硝基苯甲酸甲基酯代替3-甲醯胺基-4-甲基-2-硝基苯甲酸甲
基酯來製得。C9H7BrN2O2.254.9/256.9[M+1]+。
4-溴-N-(3-氯-4-氟苯基)-1H-苯并[d]咪唑-7-甲醯胺係類似於實例1使用4-溴-1H-苯并[d]咪唑-7-甲酸甲基酯代替4-甲基-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。C14H8BrClFN3O.368.0/369.9[M+1]+。
4-溴-N-(3-氯-4-氟苯基)-N'-羥基-1H-苯并[d]咪唑-7-甲脒係類似於實例1使用4-溴-N-(3-氯-4-氟苯基)-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-4-甲基-1H-苯并[d]咪唑-7-甲醯胺來製得。C14H9BrClFN4O.382.9/384.9[M+1]+。
將2,3-二胺基-4,5-二氟苯甲酸甲基酯(0.5g,2.0mmol)溶解於甲醇(7.0mL)及水(2.50mL)中。添加溴化氰(3.0mmol)並使反應物在密封管中回流45min。使反應物冷卻至rt並用水(4mL)及EtOAc(4mL)稀釋。分離水層並用飽和碳酸鈉中和至pH=8。將中和之水層用EtOAc(3×4mL)萃取並將合併之有機層用鹽水(1×5mL)洗滌,經硫酸鈉乾燥,且在真空中濃縮,以產生褐色固體狀2-胺基-4,5-二氟-1H-苯并[d]咪唑-7-甲酸甲基酯。
在惰性氣氛下將2-胺基-4,5-二氟-1H-苯并[d]咪唑-7-甲酸甲基酯(75mg,0.33mmol)溶解於DCE(4mL)中並冷卻至0℃。逐滴添加三甲基鋁(1.2mL,2M己烷),之後添加3-氯-4-氟苯胺(1.0mmol),且隨後將反應物加熱至70℃並保持2天。將反應物冷卻至rt並用飽和碳酸氫鹽溶液驟冷。將反應物用EtOAc(3×3mL)萃取並將合併之有機層用鹽水(1×6mL)洗滌且在真空中濃縮。將粗物質乾燥裝載至矽膠上並藉由管柱層析(EtOAc/hex)純化,以產生白色粉末狀2-胺基-N-(3-氯-4-氟苯基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺。
將2-胺基-N-(3-氯-4-氟苯基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺(20mg,0.0587mmol)及Lawesson試劑(0.176mmol)溶解於甲苯(2mL)中並加熱至90℃過夜。使反應物冷卻至rt並藉由真空過濾移除沈澱並濃縮濾液。藉由管柱層析(EtOAc/hex)純化粗物質,以產生黃色油狀2-胺基-N-(3-氯-4-氟苯基)-4,5-二氟-1H-苯并[d]咪唑-7-硫代甲醯胺。
將2-胺基-N-(3-氯-4-氟苯基)-4,5-二氟-1H-苯并[d]咪唑-7-硫代甲醯胺(20mg,0.0561mmol)溶解於乙醇(2mL)中並添加羥基胺(50%於水溶液中,0.561mmol)並將反應物於rt下攪拌過夜。將反應物在真空中濃縮並藉由反相HPLC純化,以產生白色固體狀2-胺基-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒。C14H9ClF3N5O.356.0/357.9(M+1)。1H NMR(400MHz,甲醇-d 4)δ 7.27(dd,J=5.8,2.7Hz,1H),7.15(t,J=8.6Hz,1H),7.03-6.98(m,2H),6.94(s,1H),
6.67(d,J=3.8Hz,1H)。
實例14係類似於實例13使用3-溴-4-氟苯胺代替3-氯-4-氟苯胺來製得。C14H9BrF3N5O.400.0/402.0(M+1)。1H NMR(400MHz,DMSO-d 6 )δ 10.94(s,1H),8.76(s,1H),7.12(dd,J=6.1,2.6Hz,1H),7.06(t,J=8.8Hz,2H),6.61-6.51(m,1H)。
實例15係類似於實例13使用3-溴苯胺代替3-氯-4-氟苯胺來製得。C12H10BrF2N5O.382.0/384.1(M+1)。1H NMR(400MHz,甲醇-d 4 )δ 7.11-6.96(m,4H),6.69-6.63(m,1H)。
實例16係類似於實例13使用3-氯苯胺代替3-氯-4-氟苯胺來製得。C14H10ClF2N5O.338.0/340.1(M+1)。1H NMR(400MHz,甲醇-d 4 )δ
8.69-8.59(m,2H),8.51-8.45(m,1H),8.39(t,J=2.1Hz,1H),8.21-8.15(m,1H)。
實例17係類似於實例13使用4-氟-3-(三氟甲基)苯胺代替3-氯-4-氟苯胺來製得。C15H9F6N5O.390.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.04(s,1H),8.93(s,1H),8.16(s,2H),7.24-7.10(m,3H),6.83(dt,J=7.9,3.5Hz,1H)。
實例18係類似於實例15使用2-胺基-4-氟-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-胺基-4,5-二氟-1H-苯并[d]咪唑-7-甲酸酯來製得。C14H11BrFN5O.364.0/366.0(M+1)。1H NMR(400MHz,甲醇-d 4)δ 7.16(dd,J=8.8,4.5Hz,1H),7.09-6.92(m,4H),6.65(d,J=8.1Hz,1H)。
實例19係類似於實例14使用2-胺基-4-氟-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-胺基-4,5-二氟-1H-苯并[d]咪唑-7-甲酸酯來製得。C14H10BrF2N5O.382.0/384.0(M+1)。1H NMR(400MHz,甲醇-d 4)δ 7.15(dd,J=8.8,4.6Hz,1H),7.10-6.99(m,2H),6.95(t,J=8.6Hz,1H),6.69(dt,J=8.8,3.5Hz,1H)。
實例20係類似於實例16使用2-胺基-4-氟-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-胺基-4,5-二氟-1H-苯并[d]咪唑-7-甲酸酯來製得。C14H11ClFN5O.320.1/322.1(M+1)。1H NMR(400MHz,甲醇-d 4)δ 7.16(dd,J=8.8,4.6Hz,1H),7.10-6.99(m,2H),6.89(ddd,J=8.0,2.0,0.9Hz,1H),6.79(t,J=2.0Hz,1H),6.64-6.58(m,1H)。
實例21係類似於實例17使用2-胺基-4-氟-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-胺基-4,5-二氟-1H-苯并[d]咪唑-7-甲酸酯來製得。C15H10F5N5O.372.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 10.95(s,1H),8.93(s,1H),8.32(s,2H),7.24-7.05(m,4H),6.83(dd,J=8.5,4.2Hz,1H)。
將3-胺基-4-氟-2-硝基苯甲酸(5g,25mmol)溶解於甲醇(120mL)中並經5分鐘向溶液中逐滴添加硫酸(2.5mL)。附接回流冷凝器並將反應物加熱至71℃過夜。隨後將反應物冷卻至室溫且在真空中濃縮至約50mL溶劑。將反應物用飽和碳酸鉀中和至pH=7且隨後用EtOAc(5×40mL)萃取。將合併之有機層用鹽水(1×60mL)洗滌且在真空中濃縮,以產生黃色固體狀3-胺基-4-氟-2-硝基苯甲酸甲基酯,其未經進一步純化即使用。
將3-胺基-4-氟-2-硝基苯甲酸酯(2.32g,11.0mmol)溶解於乙醇(100mL)及水(35mL)中。一次性添加氯化銨(0.163mol)並將反應物於室溫下攪拌。經5分鐘逐份添加鋅粉(0.163mol)並在添加完成後將反應物攪拌5分鐘。隨後藉由真空過濾移除鋅並在真空中濃縮濾液。將粗製物溶解於水(20mL)中且用EtOAc(4×10mL)萃取。將合併之有機層用鹽水(1×50mL)洗滌,經硫酸鈉乾燥,且在真空中濃縮,以產生褐色粉末狀2,3-二胺基-4-氟苯甲酸甲基酯。
將2,3-二胺基-4-氟苯甲酸甲基酯(0.1g,0.54mmol)溶解於甲醇(2.0mL)及水(1.0mL)中。添加溴化氰(0.54mmol)並使反應物在密封管中回流45min。使反應物冷卻至rt並用水(4mL)及EtOAc(4mL)稀釋。分離水層並用飽和碳酸鈉中和至pH=8。將中和之水層用EtOAc(3×4mL)萃取並將合併之有機層用鹽水(1×5mL)洗滌,經硫酸鈉乾燥,且
在真空中濃縮,以產生褐色固體狀2-胺基-4-氟-1H-苯并[d]咪唑-7-甲酸甲基酯。
實例22係類似於實例13使用2-胺基-4-氟-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-胺基-4,5-二氟-1H-苯并[d]咪唑-7-甲酸酯來製得。C14H10ClF2N5O.338.1/339.2(M+1)。1H NMR(400MHz,甲醇-d 4 )δ 7.14(dd,J=8.8,4.6Hz,1H),7.00(dt,J=23.9,9.2Hz,2H),6.91(dd,J=6.4,2.7Hz,1H),6.64(dt,J=8.8,3.4Hz,1H)。
4,5-二氟-2-((2-嗎啉基乙基)胺基)-1H-苯并[d]咪唑-7-甲酸甲基酯.向溶解之2,3-二胺基-4,5-二氟苯甲酸甲基酯(50mg,0.25mmol)於THF(3ml)中之溶液中添加4-(2-異氰硫基乙基)嗎啉(0.43g,0.002mmol)及三乙胺(0.36g,0.003mol)。將反應混合物於80℃下加熱過夜,隨後向反應混合物中添加1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(0.47g,0.002mol),於80℃下加熱1h。將反應混合物用EtOAc稀釋,並用NaHCO3飽和溶液洗滌,蒸發有機層並利用Combi-急速管柱層析純化殘餘物,以得到84mg期望產物。C15H18F2N4O3.341.2(M+1)。
N-(3-氯-4-氟苯基)-4,5-二氟-2-((2-嗎啉基乙基)胺基)-1H-苯并[d]咪唑-7-甲醯胺.向溶解之3-氯-4-氟苯胺(12.8mg,0.088mmol)於二氯乙烷(2ml)中之溶液中添加三甲胺(0.088ml,2M於甲苯中)及三乙胺(0.36g,0.003mol)。隨後向反應混合物中添加4,5-二氟-2-((2-嗎啉基乙基)胺基)-1H-苯并[d]咪唑-7-甲酸甲基酯(20mg,0.06mmol)。將反應混合物於室溫下攪拌2h,隨後將反應混合物用EtOAc稀釋,並用NaHCO3飽和溶液洗滌,蒸發有機層並利用Combi-急速管柱層析純化殘餘物,以得到27mg期望產物。C20H19ClF3N5O2.454.4(M+1)。
N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-嗎啉基乙基)胺基)-1H-苯并[d]咪唑-7-甲脒.實例23係類似於實例107使用羥基脒形成之一般程序來製得。C20H20ClF3N6O2.469.1(M+1)。1H NMR(400MHz,甲醇-d4)δ 7.01-6.85(m,3H),6.67(ddd,J=8.9,4.0,2.8Hz,1H),4.00(t,J=4.8Hz,4H),3.81-3.73(m,2H),3.49-3.36(m,6H)。
N-(3-氯苯基)-4,5-二氟-2-(甲氧基甲基)-1H-苯并[d]咪唑-7-甲醯胺係類似於實例45使用3-氯苯胺代替3-氯-4-氟苯胺來製得。C16H12ClF2N3O2.352.1[M+1]+。
4-(3-氯苯基)-3-(4,5-二氟-2-(甲氧基甲基)-1H-苯并[d]咪唑-7-基)-1,2,4-噁二唑-5(4H)-酮係類似於實例45使用N-(3-氯苯基)-4,5-二氟-2-(甲氧基甲基)-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-4,5-二氟-2-(甲氧基甲基)-1H-苯并[d]咪唑-7-甲醯胺來製得。C17H11ClF2N4O3.393.0[M+1]+。
3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯苯基)-1,2,4-噁二唑-5(4H)-酮及4-(3-氯苯基)-3-(4,5-二氟-2-(羥基甲基)-1H-苯并[d]咪唑-7-基)-1,2,4-噁二唑-5(4H)-酮係類似於實例45使用4-(3-氯苯基)-3-(4,5-二氟-2-(甲氧基甲基)-1H-苯并[d]咪唑-7-基)-1,2,4-噁二唑-5(4H)-酮代替4-(3-氯-4-氟苯基)-3-(4,5-二氟-2-(甲氧基甲基)-1H-苯并[d]咪唑-7-基)-1,2,4-噁二唑-5(4H)-酮來製得。C16H8BrClF2N4O2.440.9/442.9
[M+1]+。C16H9ClF2N4O3.379.0[M+1]+。
N-(3-氯苯基)-4,5-二氟-N'-羥基-2-(((3-甲氧基丙基)胺基)甲基)-1H-苯并[d]咪唑-7-甲脒.實例24係類似於實例45使用3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯苯基)-1,2,4-噁二唑-5(4H)-酮代替3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮來製得。C19H20ClF2N5O2.424.1[M+1]+。
實例25係類似於實例45分別使用3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯苯基)-1,2,4-噁二唑-5(4H)-酮及環丙基甲胺代替3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-甲氧基丙胺來製得。C19H18ClF2N5O.406.1[M+1]+。
實例26係類似於實例45分別使用3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯苯基)-1,2,4-噁二唑-5(4H)-酮及二甲胺代替3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-甲氧基丙胺來製得。C17H16ClF2N5O.380.1[M+1]+。1H NMR(400MHz,DMSO-d 6 )δ 12.93(br s,1H),11.00(br s,1H),10.27(br s,1H),8.86(s,1H),7.38-7.23(m,1H),7.06-6.96(m,1H),6.85(t,J=2.1Hz,1H),6.81(d,J=7.8Hz,1H),6.47(dd,J=8.2,1.8Hz,1H),4.58(s,2H),2.85(s,6H)。
實例27係類似於實例45分別使用3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯苯基)-1,2,4-噁二唑-5(4H)-酮及異丙胺代替3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-甲氧基丙胺來製得。C18H18ClF2N5O.394.1[M+1]+。1H NMR(400MHz,DMSO-d 6 )δ 12.88(br s,1H),11.03(br s,1H),9.27(br s,3H),8.85(s,1H),7.31-7.20(m,1H),7.04(t,J=8.1Hz,1H),6.83(d,J=8.1Hz,1H),6.80(t,J=2.1Hz,1H),6.49(dd,J=8.3,1.8Hz,1H),4.51-4.43(m,2H),3.54-3.35(m,1H),1.28(d,J=
6.3Hz,6H)。
實例28係類似於實例45分別使用3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯苯基)-1,2,4-噁二唑-5(4H)-酮及乙胺代替3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-甲氧基丙胺來製得。C17H16ClF2N5O.380.1[M+1]+。1H NMR(400MHz,DMSO-d 6 )δ 12.87(br s,1H),11.01(br s,1H),9.27(br s,2H),8.85(s,1H),7.30-7.21(m,1H),7.03(t,J=8.0Hz,1H),6.87-6.78(m,2H),6.52-6.45(m,1H),4.54-4.38(m,2H),3.17-2.98(m,2H),1.23(t,J=7.2Hz,3H)。
實例29係類似於實例46使用4-(3-氯苯基)-3-(4,5-二氟-2-(羥基甲基)-1H-苯并[d]咪唑-7-基)-1,2,4-噁二唑-5(4H)-酮代替4-(3-氯-4-氟苯基)-3-(4,5-二氟-2-(羥基甲基)-1H-苯并[d]咪唑-7-基)-1,2,4-噁二唑-5(4H)-酮來製得。C15H11ClF2N4O2.353.0[M+1]+。1H NMR(400MHz,DMSO-d 6 )δ 11.00(br s,1H),8.79(s,1H),7.16(dd,J=12.0,7.0Hz,1H),7.07-7.00(m,1H),6.85-6.79(m,2H),6.53-6.47(m,1H),
4.67(s,2H)。
實例30係類似於實例45分別使用3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯苯基)-1,2,4-噁二唑-5(4H)-酮及甲胺代替3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-甲氧基丙胺來製得。C16H14ClF2N5O.366.0[M+1]+。1H NMR(400MHz,DMSO-d 6 )δ 12.86(br s,1H),11.00(br s,1H),9.24(br s,2H),8.84(s,1H),7.30-7.19(m,1H),7.03(t,J=8.0Hz,1H),6.88-6.75(m,2H),6.53-6.45(m,1H),4.45(t,J=5.6Hz,2H),2.74-2.64(m,3H)。
實例31係類似於實例45分別使用3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯苯基)-1,2,4-噁二唑-5(4H)-酮及氨(0.5M溶液於二噁烷中)代替3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-甲氧基丙胺來製得。C15H12ClF2N5O.352.0[M+1]+。1H NMR(400MHz,DMSO-d 6 )δ 12.77(br s,1H),11.00(br s,1H),8.83(s,1H),8.52(br s,3H),7.21(dd,
J=12.0,6.9Hz,1H),7.04(t,J=8.1Hz,1H),6.83(dd,J=7.8,2.0Hz,1H),6.80(t,J=2.1Hz,1H),6.49(dd,J=8.2,2.1Hz,1H),4.34(q,J=5.4Hz,2H)。
將2,3-二胺基-4,5-二氟苯甲酸甲基酯(5.0g,25mmol,1當量)溶解於甲酸(120mL)中並於80℃下攪拌3小時。隨後在真空中移除甲酸且獲得褐色固體狀4,5-二氟-1H-苯并[d]咪唑-7-甲酸甲基酯。C9H6F2N2O2,213.0(M+1)。1H NMR(400MHz,DMSO-d 6)δ 8.43(s,1H),7.83(dd,J=11.5,7.2Hz,1H),3.95(s,3H)。19F NMR(377MHz,DMSO-d 6)δ -146.16(dd,J=21.8,7.2Hz,1F),-149.09(dd,J=21.8,11.6Hz,1F)。
向4,5-二氟-1H-苯并[d]咪唑-7-甲酸甲基酯(6.0g,28mmol,1當量)於THF(60mL)中之懸浮液中分三份添加NaH之60wt%分散液(1.7g,42mmol,1.5當量)。一旦氣體逸出停止,將反應混合物冷卻至0℃並添加SEM-Cl(6.0mL,34mmol,1.2當量)。隨後移除冰浴並將反應物於室溫下攪拌3小時,之後用飽和NH4Cl水溶液驟冷。將反應混合物用水稀釋並用EtOAc萃取三次。將合併之有機層經MgSO4乾燥,過濾並在真空中濃縮。藉由矽膠層析(0-5% MeOH/CH2Cl2,經20分鐘)純化粗產物。分離出黃色固體狀4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯。C15H20F2N2O3Si,342.9(M+1)。1H NMR(400MHz,氯仿-d)δ 8.17(s,1H),7.91(dd,J=11.5,7.5Hz,1H),5.68(s,2H),4.06(s,3H),3.64-3.45(m,2H),0.98-0.85(m,2H),
-0.04(d,J=0.6Hz,9H)。19F NMR(377MHz,氯仿-d)δ -144.34(m,1F),-150.20(m,1F)。
向4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯(2.2g,6mmol,1當量)於乙腈(46.2mL)中之溶液中添加NCS(1.29g,10mmol,1.5當量)。於100℃下將反應混合物在密封容器中攪拌12小時。隨後在真空中移除乙腈並藉由矽膠層析(0-5% MeOH/CH2Cl2,經20分鐘)純化粗產物。獲得結晶黃色固體狀2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯。C15H19ClF2N2O3Si,376.9/378.9(M+1)。
向2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯(0.29g,0.46mmol,1當量)於DMSO(2mL)中之溶液中添加嗎啉(0.14mL,1.6mmol,3.5當量)。將反應物於60℃下攪拌3小時,之後用DMF/H2O稀釋並藉由反相HPLC(10-90% CH3CN/H2O,經20min)純化。獲得白色固體狀4,5-二氟-2-嗎啉基-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯之TFA鹽。C19H27F2N3O4Si,428.1(M+1)。
N-(3-氯-4-氟苯基)-4,5-二氟-2-嗎啉基-1H-苯并[d]咪唑-7-甲醯胺係類似於實例13使用4,5-二氟-2-嗎啉基-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯及3-氯-4-氟苯胺代替2-胺基-4,5-二氟-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。C18H14ClF3N4O2,411.1/413.0(M+1)。
實例32係類似於實例59使用N-(3-氯-4-氟苯基)-4,5-二氟-2-嗎啉基-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C18H15ClF3N5O2.426.1/428.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 10.78(br.s,1H),8.82(s,1H),7.04(t,J=9.1Hz,1H),7.00(dd,J=6.6,2.7Hz,1H),6.93(dd,J=12.1,6.9Hz,1H),6.51(ddd,J=9.0,4.1,2.7Hz,1H),3.69-3.62(m,4H),3.53-3.44(m,4H)。
將2,3-二胺基-4-氟苯甲酸甲基酯(150mg,0.814mmol)及1-異氰硫基-2-(甲基磺醯基)乙烷(5.0mmol)溶解於THF(4.5mL)中並添加三乙
胺(7.0mmol)並將反應物加熱回流過夜。添加1-乙基-3-(3-二甲基胺基丙基)碳二亞胺(5.0mmol)並將反應物於回流溫度下再加熱1小時。使反應物冷卻至室溫,用水驟冷,並用EtOAc(3×3mL)萃取。將合併之有機層用鹽水(1×4mL)洗滌,濃縮,並藉由矽膠管柱層析純化,以產生4-氟-2-((2-(甲基磺醯基)乙基)胺基)-1H-苯并[d]咪唑-7-甲酸甲基酯。
實例33係類似於實例22使用4-氟-2-((2-(甲基磺醯基)乙基)胺基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-胺基-4-氟-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。C17H16ClF2N5O3S.444.1/446/1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.89(s,1H),8.85(s,1H),7.12-6.98(m,3H),6.95(dd,J=6.5,2.7Hz,1H),6.55(ddd,J=9.0,4.1,2.7Hz,1H),3.89(d,J=6.3Hz,2H),3.51(t,J=6.1Hz,2H),3.08(s,3H)。
實例34係類似於實例33使用4-(2-異氰硫基乙基)嗎啉代替1-異氰硫基-2-(甲基磺醯基)乙烷來製得。
實例35係類似於實例39使用2-(甲基磺醯基)乙胺代替N1,N1-二甲基丙烷-1,3-二胺且在環化反應中添加三乙胺(1.2eq)來製得。C17H15ClF3N5O3S.462.1/464.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.94(s,1H),8.82(d,J=4.0Hz,1H),7.65(s,1H),7.10(t,J=9.1Hz,1H),7.03-6.91(m,2H),6.55(dt,J=9.0,3.5Hz,1H),3.84(d,J=5.9Hz,2H),3.48(t,J=6.4Hz,2H),3.06(s,3H)。
實例36係類似於實例39使用2-(4,4-二氟六氫吡啶-1-基)乙胺代替N1,N1-二甲基丙烷-1,3-二胺來製得。C21H20ClF5N6O.503.2/505/2(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.81(s,1H),8.71(s,1H),6.94(dd,J=6.5,2.8Hz,1H),6.87(dd,J=12.2,6.9Hz,1H),6.76(s,1H),6.59(s,1H),6.53(ddd,J=9.0,4.1,2.8Hz,1H),3.78-3.67(m,2H),3.50(s,4H),3.41(t,J=5.7Hz,2H),2.34(dt,J=13.6,7.8Hz,4H)。
實例37係類似於實例39使用1-嗎啉基丙-2-胺代替N1,N1-二甲基丙烷-1,3-二胺來製得。C21H22ClF3N6O2.483.1/485.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.82(s,1H),8.69(s,1H),7.14-6.97(m,2H),6.93(dd,J=6.6,2.8Hz,1H),6.87(dd,J=12.3,7.1Hz,1H),6.58-6.49(m,1H),4.41-4.26(m,1H),3.85(s,4H),3.49(s,2H),3.32(d,J=6.3Hz,4H),1.26(d,J=6.7Hz,3H)。
向2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯(0.16g,0.43mmol,1當量)於DMSO(1mL)中之溶液中添加甲胺於甲醇中之2M溶液(0.76mL,1.51mmol,3.5當量)及三乙胺(0.06mL,0.43mmol,1當量)。將反應物於60℃下攪拌2小時,之後用水稀釋並用EtOAc萃取。將合併之有機物經MgSO4乾燥,過濾並在真空中濃縮。藉由矽膠層析(0-3% MeOH/CH2Cl2)純化粗產物。獲得黃色油狀4,5-二氟-2-(甲基胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯。C16H23F2N3O3Si.372.05(M+1)。
N-(3-氯-4-氟苯基)-4,5-二氟-2-(甲基胺基)-1H-苯并[d]咪唑-7-甲醯胺係類似於實例13使用4,5-二氟-2-(甲基胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯及3-氯-4-氟苯胺代替2-胺基-4,5-二氟-1H-苯并[d]咪唑-7-甲酸甲基酯並於室溫下攪拌過夜來製得。藉由反相HPLC(10-90% CH3CN/H2O,經20min)純化粗產物並分離出白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-2-(甲基胺基)-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽。C15H10ClF3N4O.355.06/356.98(M+1)。
實例38係類似於實例59使用N-(3-氯-4-氟苯基)-4,5-二氟-2-(甲基胺基)-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(甲基胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C15H11ClF3N5O.370.05/371.98(M+1)。1H NMR(400MHz,DMSO-d 6)δ 10.94(s,1H),8.79(s,1H),7.08(t,J=9.0Hz,1H),7.06-7.01(m,1H),6.99(dd,J=6.6,2.7Hz,1H),6.53(ddd,J=8.9,4.0,2.7Hz,1H),2.98(d,J=3.7Hz,3H)。19F NMR(377MHz,DMSO-d 6)δ -73.7,-126.8,-147.4,-155.1(TFA鹽)。
向2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯(0.25g,0.66mmol,1當量)於DMSO(1.25mL)中之溶液中添加N,N-二甲基丙烷-1,3-二胺(0.10mL,0.81mmol,1.2當量)。將反應物於60℃下攪拌6小時,之後用DMF/水稀釋並藉由反相HPLC(10-90% CH3CN/H2O,經15min)純化。獲得黃色油狀2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯之TFA鹽。C20H32F2N4O3Si.443.18(M+1)。
於室溫下向2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯(TFA鹽,159mg,0.36mmol,1當量)及3-氯-4-氟苯胺(209mg,1mmol,4當量)於DCE(7.5mL)中之溶液中添加AlMe3於甲苯中之2M溶液(1.26mL,3mmol,7當量)。將反應物攪拌過夜,之後用2M NaOH水溶液驟冷並用乙酸乙酯萃取。將合併之有機物經MgSO4乾燥,過濾並在真空中濃縮。將粗產物溶解於CH2Cl2(2mL)中並添加TFA(2mL)。將SEM-去保護攪拌過夜,之後在真空中濃縮。藉由反相HPLC(10-90% CH3CN/H2O,經15min)純化粗產物。獲得灰白色固體狀N-(3-氯-4-氟苯基)-2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1H-苯并[d]-咪唑-7-甲醯胺之TFA鹽。C19H19ClF3N5O.426.18/428.13(M+1)。
實例39係類似於實例59使用N-(3-氯-4-氟苯基)-2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C19H20ClF3N6O.441.12/443.09(M+1)。1H NMR(400MHz,DMSO-d 6)δ 10.85(s,1H),9.72(s,1H),8.74(s,1H),7.09(t,J=9.1Hz,1H),7.00-6.85(m,2H),6.55(ddd,J=9.0,4.1,2.7Hz,1H),3.42(m,2H),3.10(m,2H),2.80(s,6H),1.93(m,2H)。19F NMR(377MHz,DMSO-d 6)δ -73.7,-127.1,-149.4,-156.5。
4,5-二氟-2-((2-甲氧基乙基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯係類似於實例39使用2-甲氧基乙胺及三乙胺(1當量)代替N,N-二甲基丙烷-1,3-二胺來製得。分離出黃色油狀4,5-二氟-2-((2-甲氧基乙基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯之TFA鹽。C18H27F2N3O4Si.416.09/417.07(M+1)。
N-(3-氯-4-氟苯基)-4,5-二氟-2-((2-甲氧基乙基)胺基)-1H-苯并[d]咪唑-7-甲醯胺係類似於實例39使用4,5-二氟-2-((2-甲氧基乙基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-2-((2-甲氧基乙基)胺基)-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽。C17H14ClF3N4O2.399.09/401.02(M+1)。
實例40係類似於實例59使用N-(3-氯-4-氟苯基)-4,5-二氟-2-((2-甲氧基乙基)胺基)-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-甲氧基乙基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C17H15ClF3N5O2.414.09/416.01(M+1)。1H NMR(400MHz,DMSO-d 6)δ 10.98(s,1H),8.79(s,1H),8.11(s,1H),7.09(t,J=9.1Hz,1H),7.04(dd,J=12.1,7.0Hz,1H),6.99(dd,J=6.6,2.7Hz,1H),6.55(ddd,J=8.9,4.0,2.7Hz,1H),3.56(t,J=5.1Hz,2H),3.51(t,J=4.7Hz,2H),3.29(s,3H)。19F NMR(377MHz,DMSO-d 6)δ -75.18(6F),-126.96(1F),-147.44(1F),-155.18(1F)。
4,5-二氟-2-((2-(吡咯啶-1-基)乙基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯係類似於實例39使用2-(吡咯啶-1-基)乙胺代替N,N-二甲基丙烷-1,3-二胺來製得。分離出黃色油狀4,5-二氟-2-((2-(吡咯啶-1-基)乙基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯之TFA鹽。C21H32F2N4O3Si.455.21(M+1)。
N-(3-氯-4-氟苯基)-4,5-二氟-2-((2-(吡咯啶-1-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲醯胺係類似於實例39使用4,5-二氟-2-((2-(吡咯啶-1-基)乙基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-2-((2-(吡咯啶-1-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽。C20H19ClF3N5O.438.21/440.12(M+1)。
實例41係類似於實例59使用N-(3-氯-4-氟苯基)-4,5-二氟-2-((2-(吡咯啶-1-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(吡咯啶-1-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C20H20ClF3N6O.453.14/455.11(M+1)。1H NMR(400MHz,DMSO-d 6)δ 10.78(s,1H),9.84(s,1H),8.70(s,1H),7.09(t,J=9.1Hz,1H),7.02(s,1H),6.93(dd,J=6.6,2.7Hz,1H),6.84(dd,J=12.3,6.9Hz,1H),6.53(ddd,J=9.0,4.0,2.7Hz,1H),4.00(dq,J=8.3,7.1Hz,1H),3.75-3.60(m,3H),3.45-3.35(m,3H),2.05-1.80(m,4H),1.24(td,J=7.0,0.9Hz,1H)。19F NMR(377MHz,DMSO-d 6)δ -74.94(9F),-127.34(1F),-150.32(1F),-157.02(1F)。
2-((2-(二乙基胺基)乙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯係類似於實例39使用N,N-二乙基乙烷-1,2-二胺代替N,N-二甲基丙烷-1,3-二胺來製得。分離出黃色油狀2-((2-(二乙基胺基)乙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯之TFA鹽。C21H34F2N4O3Si.457.22(M+1)。
N-(3-氯-4-氟苯基)-2-((2-(二乙基胺基)乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺係類似於實例39使用2-((2-(二乙基胺基)乙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-2-((2-(二乙基胺基)乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽。C20H21ClF3N5O.440.21/442/11(M+1)。
實例42係類似於實例59使用N-(3-氯-4-氟苯基)-2-((2-(二乙基胺基)乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-2-((2-(二乙基胺基)乙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C20H22ClF3N6O.455.18/457.11(M+1)。1H NMR(400MHz,DMSO-d 6)δ 10.77(s,1H),9.73(s,1H),8.70(s,1H),7.08(t,J=9.1Hz,1H),6.97(s,1H),6.92(dd,J=6.5,2.7Hz,1H),6.85(dd,J=12.2,6.9Hz,1H),6.53(ddd,J=9.0,4.0,2.7Hz,1H),3.68(m,2H),3.31(m,2H),3.26-3.13(m,4H),1.20(t,J=7.2Hz,6H)。19F NMR(376MHz,DMSO-d 6)δ -74.9,-127.3,-150.3,-157.1。
2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯係類似於實例39使用N,N-二甲基乙烷-1,2-二胺代替N,N-二甲基丙烷-1,3-二胺來製得。分離出黃色油狀2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯之TFA鹽。C19H30F2N4O3Si.429.17(M+1)。
N-(3-氯-4-氟苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺係類似於實例39使用2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽。C18H17ClF3N5O.412.19/414.09(M+1)。
實例43係類似於實例59使用N-(3-氯-4-氟苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C18H18ClF3N6O.427.14/429.09(M+1)。1H NMR(400MHz,DMSO-d 6)δ 10.78(s,1H),9.74(s,1H),8.71(s,1H),7.09(t,J=10.7Hz,1H),7.04(br s,1H),6.93(dd,J=6.5,2.7Hz,1H),6.84(dd,J=12.2,7.0Hz,1H),6.53(ddd,J=9.0,4.0,2.7Hz,1H),3.69(q,J=5.9Hz,2H),3.31(t,J=5.8Hz,2H),2.86(s,6H)。19F NMR(376MHz,DMSO-d 6)δ -74.99(9F),-127.32(1F),-150.28(1F),-156.83(1F)。
實例44係類似於實例53使用1-甲基六氫吡啶-3-甲酸代替3-(二甲基胺基)丙酸來製得。分離出無色油狀4,5-二氟-2-(1-甲基六氫吡啶-3-基)-1H-苯并[d]咪唑-7-甲酸之TFA鹽。C14H15F2N3O2.296.14/297.12(M+1)。
向4,5-二氟-2-(1-甲基六氫吡啶-3-基)-1H-苯并[d]咪唑-7-甲酸(TFA鹽,63mg,0.19mmol,1當量)、3-氯苯胺(0.05mL,0.48mmol,2.5當量)及DIPEA(0.16mL,0.95mmol,5當量)於DMF(1mL)中之溶液中添加HATU(87mg,0.23mmol,1.2當量)並將反應物於室溫下攪拌過夜。藉由反相HPLC(10-90% CH3CN/H2O)純化粗產物並獲得白色固體狀N-(3-氯苯基)-4,5-二氟-2-(1-甲基六氫吡啶-3-基)-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽。C20H19ClF2N4O.405.19/407.12(M+1)。
實例44係類似於實例59使用N-(3-氯-4-氟苯基)-4,5-二氟-2-(1-甲基六氫吡啶-3-基)-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。分離出白色固體狀N-(3-氯苯基)-4,5-二氟-N'-羥基-2-(1-甲基六氫吡啶-3-基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C20H20ClF2N5O.420.22/422.17(M+1)。
4,5-二氟-2-(甲氧基甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯.將2,3-二胺基-4,5-二氟苯甲酸甲基酯(2.0g,9.9mmol)於甲氧基乙酸(23mL)
中之混合物於120℃下攪拌3hr。向混合物中添加飽和碳酸氫鈉並將水層用乙酸乙酯洗滌三次。將合併之有機層經硫酸鈉乾燥,過濾,吸收至二氧化矽上並藉由矽膠層析純化,以產生期望產物。C11H10F2N2O3.257.3(M+1)。
N-(3-氯-4-氟苯基)-4,5-二氟-2-(甲氧基甲基)-1H-苯并[d]咪唑-7-甲醯胺.於0℃下在氮下經5min向3-氯-4-氟苯胺(1.30g,8.90mmol)於二氯乙烷(60mL)中之溶液中逐滴添加三甲基鋁(2M於庚烷中,8.90mL,17.8mmol)。使溶液升溫至室溫並攪拌30min。將溶液冷卻至0℃並向此溶液中添加4,5-二氟-2-(甲氧基甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯(1.52g,5.93mmol)。將溶液於85℃下攪拌3hr且隨後冷卻至室溫。添加水及10%檸檬酸並將所得沈澱過濾並在高真空上乾燥,以產生期望產物。C16H11ClF3N3O2.370.1(M+1)。
4-(3-氯-4-氟苯基)-3-(4,5-二氟-2-(甲氧基甲基)-1H-苯并[d]咪唑-7-基)-1,2,4-噁二唑-5(4H)-酮.將N-(3-氯-4-氟苯基)-4,5-二氟-2-(甲氧基甲基)-1H-苯并[d]咪唑-7-甲醯胺(1.80g,4.86mmol)、五氯化磷(1.52g,7.29mmol)於磷醯氯(14mL)及1,2-二氯乙烷(14mL)中之混合物於80℃下攪拌2.5hr。將反應混合物濃縮並懸浮於乙醇(14mL)中並向此混合物中添加水中之50%羥基胺(3.0mL,49mmol)。將反應混合物攪拌1.5hr。向反應混合物中添加水並藉由過濾收集所得沈澱並在高真空
上乾燥。將乾燥固體及羰基二咪唑(1.6g,9.7mmol)懸浮於乙酸乙酯(50mL)中並將反應混合物攪拌18hr。將所得溶液吸收至矽膠上並藉由矽膠層析純化,以產生期望產物。C17H10ClF3N4O3.411.0(M+1)。
3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及4-(3-氯-4-氟苯基)-3-(4,5-二氟-2-(羥基甲基)-1H-苯并[d]咪唑-7-基)-1,2,4-噁二唑-5(4H)-酮.於0℃下向4-(3-氯-4-氟苯基)-3-(4,5-二氟-2-(甲氧基甲基)-1H-苯并[d]咪唑-7-基)-1,2,4-噁二唑-5(4H)-酮(937mg,2.28mmol)於二氯甲烷(16mL)中之混合物中添加1M三溴化硼於二氯甲烷中之溶液(3.42mL,3.42mmol)。使反應物升溫至室溫並攪拌18hr。將反應混合物用二氯甲烷及飽和碳酸氫鈉稀釋並將水層用二氯甲烷洗滌三次。合併之有機層含有過濾出之沈澱,以產生白色固體狀4-(3-氯-4-氟苯基)-3-(4,5-二氟-2-(羥基甲基)-1H-苯并[d]咪唑-7-基)-1,2,4-噁二唑-5(4H)-酮(203mg)。將濾液經硫酸鈉乾燥,過濾,裝載至矽膠管柱上並藉由矽膠層析純化,以產生3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮。C16H7BrClF3N4O2.459.0(M+1)。C16H8ClF3N4O3.397.1(M+1)。
N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-2-(((3-甲氧基丙基)胺基)甲基)-1H-苯并[d]咪唑-4-甲脒.將3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪
唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(12mg,0.026mmol)及3-甲氧基丙胺(0.027mL,0.26mmol)於乙腈(1mL)中之溶液於65℃下攪拌10min。將反應物濃縮。將殘餘物吸收於四氫呋喃(0.3mL)及水(0.3mL)中。向此溶液中添加2N氫氧化鈉(0.19mL,0.34mmol)並將反應混合物攪拌10min。向混合物中添加乙酸(0.05mL)並將溶液直接裝載至製備型HPLC上用於純化,以產生期望產物。C19H19ClF3N5O2.442.1(M+1)。
向4-(3-氯-4-氟苯基)-3-(4,5-二氟-2-(羥基甲基)-1H-苯并[d]咪唑-7-基)-1,2,4-噁二唑-5(4H)-酮(20mg,0.050mmol)於四氫呋喃(0.4mL)及水(0.4mL)中之溶液中添加2N氫氧化鈉(0.38mL,0.76mmol)並將反應混合物攪拌10min。向混合物中添加乙酸(0.06mL)並將溶液直接裝載至製備型HPLC上用於純化,以產生期望產物。C15H10ClF3N4O2.371.0(M+1)。1H NMR(400MHz,DMSO-d 6 )δ 10.93(s,1H),8.80(s,1H),7.16(dd,J=12.0,7.0Hz,1H),7.04(t,J=9.1Hz,1H),6.93(dd,J=6.5,2.7Hz,1H),6.49(ddd,J=9.0,4.1,2.7Hz,1H),4.63(s,2H)。
實例47係類似於實例45使用二噁烷中之0.5M氨代替3-甲氧基丙胺來製得。C15H11ClF3N5O.370.1(M+1)。
實例48係類似於實例45使用四氫呋喃中之2M甲胺代替3-甲氧基丙胺來製得。C16H13ClF3N5O.384.0(M+1)。1H NMR(400MHz,DMSO-d 6 )δ 12.84(s,1H),10.92(s,1H),9.21(s,2H),8.82(s,1H),7.34-7.17(m,1H),7.04(t,J=9.1Hz,1H),6.90(dd,J=6.6,2.7Hz,1H),6.48(dt,J=9.0,3.5Hz,1H),4.40(t,J=5.8Hz,2H),2.65(s,3H)。
實例49係類似於實例45使用環丙基甲胺代替3-甲氧基丙胺來製得。C19H17ClF3N5O.424.0(M+1)。
實例50係類似於實例45使用四氫呋喃中之2M乙胺代替3-甲氧基丙胺來製得。C17H15ClF3N5O.398.0(M+1)。1H NMR(400MHz,DMSO-d 6 )δ 12.85(s,1H),10.92(s,1H),9.25(s,2H),8.82(s,1H),7.33-7.20(m,1H),7.05(t,J=9.0Hz,1H),6.91(dd,J=6.5,2.7Hz,1H),6.50(dt,J=9.0,3.6Hz,1H),4.43(t,J=5.9Hz,2H),3.11-2.95(m,2H),1.21(t,J=7.2Hz,3H)。
實例51係類似於實例使用異丙胺代替3-甲氧基丙胺來製得。C18H17ClF3N5O.412.1(M+1)。1H NMR(400MHz,DMSO-d 6 )δ 12.85(s,1H),10.94(s,1H),9.25(s,2H),8.82(s,1H),7.33-7.20(m,1H),7.06(t,J=9.0Hz,1H),6.90(dd,J=6.5,2.7Hz,1H),6.50(dt,J=9.1,3.5Hz,1H),4.49-4.37(m,2H),3.48-3.33(m,1H),1.26(d,J=6.5Hz,6H)。
實例52係類似於實例45使用二甲胺代替3-甲氧基丙胺來製得。C17H15ClF3N5O.398.1(M+1)。1H NMR(400MHz,DMSO-d 6 )δ12.93(s,1H),10.93(s,1H),10.28(s,1H),8.83(s,1H),7.40-7.23(m,1H),
7.03(t,J=9.1Hz,1H),6.95(dd,J=6.6,2.7Hz,1H),6.49(dt,J=9.0,3.5Hz,1H),4.56(s,2H),2.83(s,6H)。
2-(2-(二甲基胺基)乙基)-6,7-二氟-1H-苯并[d]咪唑-4-甲酸.於120℃下將2,3-二胺基-4,5-二氟苯甲酸甲基酯(2.0g,9.89mmol)及3-(二甲基胺基)丙酸(6.08g,39.6mmol)於濃鹽酸中之混合物在密封帶螺旋蓋燒瓶中攪拌過夜。在減壓下濃縮反應物。粗產物未經純化即原樣用於下一步驟。C12H13F2N3O2.270.10(M+1)。
N-(3-氯-4-氟苯基)-2-(2-(二甲基胺基)乙基)-6,7-二氟-1H-苯并[d]咪唑-4-甲醯胺.將2-(2-(二甲基胺基)乙基)-6,7-二氟-1H-苯并[d]咪唑-4-甲酸(300mg,1.114mmol)、3-氯-4-氟苯胺(300mg,1.114mmol)、雙(2-側氧基-3-噁唑啶基)次膦醯氯(567mg,2.23mmol)及二異丙基乙胺(1.94mL,11.1mmol)於二氯甲烷(8mL)中之混合物攪拌2hr。將反應混合物過濾並吸收至矽膠上並藉由矽膠層析純化,以產生期望產物。C18H16ClF3N4O.
N-(3-氯-4-氟苯基)-2-(2-(二甲基胺基)乙基)-6,7-二氟-N'-羥基-1H-
苯并[d]咪唑-4-甲脒.實例53係類似於實例95來製得。C18H17ClF3N5O.411.11(M+1)。1H NMR(400MHz,DMSO-d 6 )δ 10.92(s,1H),8.78(s,1H),7.17(dd,J=12.0,7.0Hz,1H),7.04(t,J=9.1Hz,1H),6.93(dd,J=6.6,2.7Hz,1H),6.50(ddd,J=9.0,4.1,2.7Hz,1H),3.53(t,J=7.5Hz,2H),3.26(t,J=7.6Hz,2H),2.83(s,6H)
N-(3-溴-4-氟苯基)-2-(2-(二甲基胺基)乙基)-6,7-二氟-1H-苯并[d]咪唑-4-甲醯胺係類似於實例53使用3-溴-4-氟苯胺代替3-氯-4-氟苯胺來製得。C18H16BrF3N4O.441.1(M+1)。
N-(3-溴-4-氟苯基)-2-(2-(二甲基胺基)乙基)-6,7-二氟-N'-羥基-1H-苯并[d]咪唑-4-甲脒.實例54係類似於實例95來製得。C18H17BrF3N5O.456.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 10.89(s,1H),8.76(s,1H),7.17(dd,J=11.9,7.0Hz,1H),7.07(dd,J=6.1,2.7Hz,1H),7.00(t,J=8.8Hz,1H),6.53(ddd,J=8.9,4.1,2.7Hz,1H),3.53(t,J=7.5Hz,2H),3.26(t,J=7.5Hz,2H),2.83(s,6H)。
N-(3-溴苯基)-2-(2-(二甲基胺基)乙基)-6,7-二氟-1H-苯并[d]咪唑-4-甲醯胺係類似於實例53使用3-溴苯胺代替3-氯-4-氟苯胺來製得。C18H16BrF3N4O.423.1(M+1)。
N-(3-溴苯基)-2-(2-(二甲基胺基)乙基)-6,7-二氟-N'-羥基-1H-苯并[d]咪唑-4-甲脒.實例55係類似於實例95來製得。C18H18BrF2N5O.438.10。1H NMR(400MHz,DMSO-d 6)δ 10.98(s,1H),8.78(s,1H),7.22-7.07(m,1H),7.00-6.85(m,3H),6.55-6.40(m,1H),3.54(t,J=7.5Hz,2H),3.35-3.20(m,2H),2.84(s,6H)。
N-(3-氯苯基)-2-(2-(二甲基胺基)乙基)-6,7-二氟-1H-苯并[d]咪唑-4-甲醯胺係類似於實例53使用3-氯苯胺代替3-氯-4-氟苯胺來製得。C18H17ClF2N4O.379.11(M+1)。
N-(3-氯苯基)-2-(2-(二甲基胺基)乙基)-6,7-二氟-N'-羥基-1H-苯并[d]咪唑-4-甲脒.實例56係類似於實例95來製得。C18H18ClF2N5O.394.12(M+1)。1H NMR(400MHz,DMSO-d 6)δ 10.94(s,1H),8.78(s,1H),7.14(dd,J=12.0,7.0Hz,1H),7.00(t,J=8.0Hz,1H),6.86-6.74(m,2H),6.51-6.38(m,1H),3.54(t,J=7.5Hz,2H),3.27(t,J=7.5Hz,2H),2.83(s,6H)。
2-(7-((3-氯-4-氟苯基)胺甲醯基)-4,5-二氟-1H-苯并[d]咪唑-2-基)乙酸乙基酯係類似於實例53使用2,3-二胺基-N-(3-氯-4-氟苯基)-4,5-二氟苯甲醯胺來製得。C18H13ClF3N3O3.412.10(M+1)。
N-(3-氯-4-氟苯基)-4,5-二氟-2-(2-羥基乙基)-1H-苯并[d]咪唑-7-甲醯胺係類似於實例183使用2-(7-((3-氯-4-氟苯基)胺甲醯基)-4,5-二氟-1H-苯并[d]咪唑-2-基)乙酸乙基酯來製得。C16H11ClF3N3O2.370.10(M+1)。
N-(3-氯-4-氟苯基)-4,5-二氟-2-(2-((三異丙基矽基)氧基)乙基)-1H-苯并[d]咪唑-7-甲醯胺係類似於實例183使用N-(3-氯-4-氟苯基)-4,5-二氟-2-(2-羥基乙基)-1H-苯并[d]咪唑-7-甲醯胺來製得。C25H31ClF3N3O2Si.526.18(M+1)。
N-(3-氯-4-氟苯基)-4,5-二氟-2-(2-((三異丙基矽基)氧基)乙基)-1H-苯并[d]咪唑-7-硫代甲醯胺係類似於實例183使用N-(3-氯-4-氟苯基)-4,5-二氟-2-(2-((三異丙基矽基)氧基)乙基)-1H-苯并[d]咪唑-7-甲醯胺來製得。C25H31ClF3N3OSSi.542.16(M+1)。
4-(3-氯-4-氟苯基)-3-(4,5-二氟-2-(2-((三異丙基矽基)氧基)乙基)-1H-苯并[d]咪唑-7-基)-1,2,4-噁二唑-5(4H)-酮係類似於實例183使用N-(3-氯-4-氟苯基)-4,5-二氟-2-(2-((三異丙基矽基)氧基)乙基)-1H-苯并[d]咪唑-7-硫代甲醯胺來製得。C26H30ClF3N4O3Si.567.17(M+1)。
甲烷磺酸2-(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-4,5-二氟-1-(甲基磺醯基)-1H-苯并[d]咪唑-2-基)乙基酯係類似於實例112使用4-(3-氯-4-氟苯基)-3-(4,5-二氟-2-(2-((三異丙基矽基)氧基)乙基)-1H-苯并[d]咪唑-7-基)-1,2,4-噁二唑-5(4H)-酮來製得。C19H14ClF3N4O7S2.567.00(M+1)。
N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-2-(2-(甲基胺基)乙基)-1H-苯并[d]咪唑-4-甲脒.實例57係類似於實例112使用甲烷磺酸2-(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-4,5-二氟-1-(甲基磺醯基)-1H-苯并[d]咪唑-2-基)乙基酯代替甲烷磺酸2-(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-3-(甲基磺醯基)-3H-咪唑并[4,5-b]吡啶-2-基)乙基酯製得。C16H16ClFN6O.363.11(M+1)。
實例58係類似於實例57使用甲烷磺酸2-(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-4,5-二氟-1-(甲基磺醯基)-1H-苯
并[d]咪唑-2-基)乙基酯及二乙胺代替甲烷磺酸2-(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-3-(甲基磺醯基)-3H-咪唑并[4,5-b]吡啶-2-基)乙基酯及甲胺製得。C20H21ClF3N5O.440.14。1H NMR(400MHz,DMSO-d 6)δ 10.85(s,1H),8.78(s,1H),7.18(dd,J=11.9,6.9Hz,1H),7.03(t,J=9.0Hz,1H),6.94(dd,J=6.6,2.7Hz,1H),6.48(ddd,J=9.0,4.0,2.7Hz,1H),3.50(t,J=7.6Hz,2H),3.24(t,J=7.7Hz,2H),3.19(q,J=8.3,7.3Hz,4H),1.20(t,J=7.3Hz,6H)。
將1H-咪唑并[4,5-b]吡啶-7-甲酸(300mg,2.0mmol)、3-氯-4-氟苯胺(2.0mmol)及HATU(2.4mmol)溶解於DMF(5mL)中並添加DIPEA(6mmol)。將反應物於rt下攪拌過夜。將反應物用飽和碳酸氫鈉溶液(5mL)驟冷並將反應物用EtOAc(3×5mL)萃取。將合併之有機層用鹽水(1×8mL)洗滌且在真空中濃縮。藉由管柱層析(EtOAc/hex)純化粗物質,以產生N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺。
將N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(122mg,0.42mmol)及PCl5(0.63mmol)溶解於POCl3(2mL)中並加熱至85℃並保持12小時。將反應物冷卻至rt並在真空中濃縮。將殘餘物溶解於羥基胺(50%水溶液,4.0mmol)及乙醇(2mL)之預混合溶液中並將反應物於rt下攪拌10分鐘。將反應物在真空中濃縮並藉由反相HPLC純化,以產生白色固體狀N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒。C13H9ClFN5O.306.0/308.0(M+1)。1H NMR(400MHz,
DMSO-d 6)δ 11.14(s,1H),8.92(d,J=1.9Hz,1H),8.64(s,1H),8.43-8.39(m,1H),7.28-7.23(m,1H),7.03(t,J=9.1Hz,1H),6.98-6.92(m,1H),6.51(dt,J=8.9,3.4Hz,1H)。
實例60係類似於實例59使用5-氯-2-氟苯胺代替3-氯-4-氟苯胺來製得。C13H9ClFN5O.306.1/308.2(M+1)。1H NMR(400MHz,甲醇-d 4)δ 8.88(s,1H),8.46(d,J=5.3Hz,1H),7.35(d,J=5.3Hz,1H),7.01-6.95(m,2H),6.92-6.85(m,1H)。
實例61係類似於實例59使用5-溴-2,4-二氟苯胺代替3-氯-4-氟苯胺來製得。C13H8BrF2N5O.368.0/370.0(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.03(s,1H),8.71(s,1H),8.59(s,1H),8.36(d,J=4.8Hz,1H),7.34-7.21(m,3H)。
實例62係類似於實例59使用5-氯-2,4-二氟苯胺代替3-氯-4-氟苯胺
來製得。C13H8ClF2N5O.324.0/326.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.08(s,1H),8.71(d,J=17.2Hz,2H),8.42-8.34(m,1H),7.34(dd,J=10.7,9.3Hz,1H),7.28(d,J=5.0Hz,1H),7.15(t,J=8.2Hz,1H)。
實例63係類似於實例59使用3,5-二氯-4-氟苯胺代替3-氯-4-氟苯胺來製得。C13H8Cl2FN5O.340.1/342.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.26(s,1H),10.10(s,1H),9.07(d,J=1.1Hz,1H),8.53(s,1H),8.45-8.37(m,1H),7.31(d,J=5.2Hz,1H),6.81-6.73(m,2H)。
實例64係類似於實例59使用3-氯-2,4-二氟苯胺代替3-氯-4-氟苯胺來製得。C13H8ClF2N5O.324.1/326.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 10.99(s,0H),8.67(s,1H),8.51(s,1H),8.34(dd,J=5.0,2.3Hz,1H),7.22(s,1H),7.04(t,J=9.0Hz,1H),6.84(s,1H)。
實例65係類似於實例59使用3-環丙基-4-氟苯胺代替3-氯-4-氟苯胺來製得。C16H14FN5O.312.1(M+1)。
實例66係類似於實例59使用4-(三氟甲氧基)苯胺代替3-氯-4-氟苯胺來製得。C14H10F3N5O2.338.1(M+1)。
實例67係類似於實例59使用苯并呋喃-4-胺代替3-氯-4-氟苯胺來製得。C15H11N5O2.294.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.32(s,1H),8.92(s,1H),8.86(s,1H),8.34(dd,J=5.2,2.7Hz,1H),7.83(d,J=2.2Hz,1H),7.16-7.09(m,2H),7.06(dd,J=2.3,1.0Hz,1H),6.95(t,J=8.0Hz,1H),6.36(d,J=7.8Hz,1H)。
實例68係類似於實例59使用苯并呋喃-6-胺代替3-氯-4-氟苯胺來製得。C15H11N5O2.294.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ
11.17(s,1H),8.89(d,J=33.4Hz,2H),8.40(d,J=6.1Hz,1H),7.79-7.74(m,1H),7.30(dd,J=8.6,2.0Hz,1H),7.24(t,J=5.9Hz,1H),6.90(t,J=2.5Hz,1H),6.76(dd,J=2.2,1.1Hz,1H),6.69(dt,J=8.4,1.9Hz,1H)。
實例69係類似於實例59使用苯并呋喃-7-胺代替3-氯-4-氟苯胺來製得。C15H11N5O2.294.1(M+1)。
實例70係類似於實例59使用苯并呋喃-5-胺代替3-氯-4-氟苯胺來製得。C15H11N5O2.294.1(M+1)。
實例71係類似於實例59使用酸及5-溴-2-氟苯胺代替3-氯-4-氟苯胺來製得。C13H9BrFN5O.350.1/352.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.16(s,1H),10.06(s,1H),8.74(s,1H),8.57(s,1H),8.35(d,J=5.1H,1H),7.25(s,1H),7.14-6.92(m,3H)。
實例72係類似於實例59使用5-溴-3-氟苯胺代替3-氯-4-氟苯胺來製得。C13H9BrFN5O.350.1/352.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.32(s,1H),9.08(s,1H),8.55(s,1H),8.37(d,J=5.1Hz,1H),7.23(d,J=5.1Hz,1H),6.84-6.75(m,1H),6.66(t,J=1.9Hz,1H),6.30(dt,J=11.3,2.1Hz,1H)。
實例73係類似於實例59使用3-(三氟甲基)苯胺代替3-氯-4-氟苯胺來製得。C14H10F3N5O.322.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.34(s,1H),9.13(s,1H),8.77(s,1H),8.43(d,J=5.1Hz,1H),7.29(d,J=5.1Hz,1H),7.27-7.13(m,1H),7.13-7.02(m,2H),6.90-6.71(m,1H)。
實例74係類似於實例59使用2,2-二氟苯并[d][1,3]二氧雜環戊烯-5-胺代替3-氯-4-氟苯胺來製得。
N-(2,2-二氟苯并[d][1,3]二氧雜環戊烯-5-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.C14H9F2N5O3.334.1(M+1)。1H NMR(400MHz,
DMSO-d 6)δ 11.00(d,J=13.0Hz,1H),8.86(s,1H),8.46(s,1H),8.34(d,J=5.0Hz,1H),7.22(d,J=31.8Hz,1H),7.00(d,J=8.7Hz,1H),6.78(d,J=2.2Hz,1H),6.34(dd,J=8.7,2.3Hz,1H)。
實例75係類似於實例59使用3-氟-5-(三氟甲基)苯胺代替3-氯-4-氟苯胺來製得。C14H9F4N5O.340.1(M+1)。
將1H-咪唑并[4,5-b]吡啶-7-甲酸(200mg,1.0mmol)及2,5-二氯苯胺(2.0mmol)溶解於DCM(3mL)中並冷卻至0℃。逐滴添加三乙胺(4.0mmol),之後添加POCl3(2.0mmol),並使反應物緩慢到達rt並攪拌15min。將反應物用飽和碳酸氫鈉溶液驟冷並用EtOAc(3×5mL)萃取。將合併之有機層用鹽水(1×7mL)洗滌且在真空中濃縮。藉由管柱層析(EtOAc/hex)純化粗物質,以產生N-(2,5-二氯苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺。
將N-(2,5-二氯苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(40mg,0.13mmol)溶解於POCl3(2mL)中並添加PCl5(0.195mmol)。將反應物加熱至80℃過夜,使其冷卻至rt且在真空中濃縮。將粗製物溶解於羥基胺
(50%於水中,1.0mmol)及乙醇(2mL)之預混合溶液中並將其於rt下攪拌10min,隨後在真空中濃縮。藉由反相HPLC純化粗製物,以產生N-(2,5-二氯苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒。C13H9Cl2N5O.322.0/324.0(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.50(s,1H),8.80(s,1H),8.71(s,1H),8.48-8.39(m,1H),7.43-7.34(m,2H),6.98(dd,J=8.6,2.4Hz,1H),6.69(d,J=3.2Hz,1H)。
將1H-咪唑并[4,5-b]吡啶-7-甲酸(1.5g,9.0mmol)、3-溴-4-氟苯胺(11.0mmol)及HATU(12.0mmol)溶解於DMF(15.0mL)中並添加DIPEA(28.0mmol)並將反應物於rt下攪拌過夜。將反應物用飽和碳酸氫鈉溶液驟冷並藉由真空過濾分離出沈澱。將沈澱用水、之後二乙醚洗滌,以產生黃色粉末狀N-(3-溴-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺。
將N-(3-溴-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(150mg,0.448mmol)及苯基酉朋酸(2.0mmol)溶解於脫氣THF(2.0mL)及水(0.50mL)中。添加PdCl2(dppf)(0.090mmol)及K2CO3(2.0mmol)並將反應物加熱至65℃過夜。使反應物冷卻至rt並用飽和碳酸氫鹽溶液驟冷。將溶液用EtOAc(3×4mL)萃取並將合併之有機層用鹽水(1×5
((EtOAc/hex)洗,產生N-(6-氟-[1,1'-聯苯]-3-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺。
將N-(6-氟-[1,1'-聯苯]-3-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(100mg,0.301mmol)溶解於POCl3中,添加PCl5(2.0mmol),並將反應物加熱至80℃過夜。將反應物冷卻至rt並在真空中濃縮。將粗製物溶解於羥基胺(50%於水中,3.0mmol)及乙醇(2mL)之預混合溶液中並將其於rt下攪拌10min。藉由反相HPLC純化反應物,以產生N-(6-氟-[1,1'-聯苯]-3-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒。C19H14FN5O.348.2(M+1)。
將N-(3-溴-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(100mg,0.298mmol)、PdCl2(PPh3)2(0.015mmol)及CuI(0.0298mmol)溶解於脫氣DMF(0.75mL)中並添加DIPEA(3.0mmol)。使丁-1-炔鼓泡通過反應5min且隨後移除。將反應物在丁-1-炔氣氛下攪拌過夜。將反應物用水驟冷並用EtOAc(3×3mL)萃取。將合併之有機層用鹽水(1×5mL)洗滌並在真空中濃縮。藉由管柱層析(EtOAc/hex)純化粗製物,以產生N-(3-(丁-1-炔-1-基)-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(57mg,62%)。
將N-(3-(丁-1-炔-1-基)-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(56mg,0.182mmol)溶解於POCl3(2mL)中並添加PCl5(0.272mmol)並將反應物加熱至80℃並保持45min。將反應物冷卻至rt並在真空中濃縮。將材料溶解於羥基胺(50%於水中,2.0mmol)及乙醇(2mL)之預
混合溶液中並將其於rt下攪拌10min。藉由反相HPLC純化反應物,以產生N-(3-(丁-1-炔-1-基)-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒。C17H14FN5O.324.2(M+1)。
實例79係類似於實例78使用乙炔基環丙烷(5eq)代替丁-1-炔來製得。C18H14FN5O.336.1(M+1)。
N-(3-溴苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺.向1H-咪唑并[4,5-b]吡啶-7-甲酸(0.102g,0.625mmol)、3-溴苯胺(0.07mL,0.625mmol)、HOBt(0.101g,0.750mmol)及DIEA(0.27mL,1.56mmol)於DMF(3mL)中之溶液中添加EDC(0.16mL,0.75mmol)。將混合物於室溫下攪拌16h。將混合物用飽和碳酸氫鹽溶液稀釋並經由過濾分離出固體。將固體懸浮於10%檸檬酸溶液中且隨後經由過濾分離。將濾餅用水沖洗並在真空下乾燥,以產生期望產物。C13H9BrN4O.317.0/319.0[M+1]+。
N-(3-溴苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.向N-(3-溴苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(0.062g,0.195mmol)及磷醯氯
(0.18mL,1.95mmol)於DCE(2mL)中之混合物中添加五氯化磷(0.061g,0.293mmol)。將混合物於80℃下攪拌2h。將混合物冷卻至rt並在減壓下濃縮。將殘餘物吸收於EtOH(3mL)中並添加羥基胺(0.12mL 50w/w%水溶液,1.96mmol)。將混合物於rt下攪拌2h。濃縮混合物並將殘餘物溶解於DMSO/水中並經由製備型HPLC純化,以產生期望產物。C13H10BrN5O.332.0/334.0[M+1]+。1H NMR(400MHz,DMSO-d 6 )δ 11.25(br s,1H),8.94(br s,1H),8.71(br s,1H),8.42(dd,J=5.0,2.5Hz,1H),7.26(dd,J=5.2,2.2Hz,1H),7.01-6.98(m,1H),6.96-6.91(m,2H),6.51(ddd,J=4.9,3.8,2.2Hz,1H)。
N-(3-溴-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺.向1H-咪唑并[4,5-b]吡啶-7-甲酸(0.097g,0.595mmol)、3-溴-4-氟苯胺(0.114g,0.597mmol)、HOBt(0.099g,0.729mmol)及DIEA(0.26mL,1.49mmol)於DMF(3mL)中之溶液中添加EDC(0.15mL,0.71mmol)。將混合物於室溫下攪拌16h。將混合物用飽和碳酸氫鹽溶液稀釋並經由過濾分離出固體。將固體吸收於DCM/MeCN中,濃縮至矽膠上,並經由矽膠上急速層析純化,以產生期望產物。C13H8BrFN4O.335.0/337.0[M+1]+。
N-(3-溴-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例81係類似於實例80使用N-(3-溴-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-溴苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來合成。
(C13H9BrFN5O.350.0/352.0[M+1]+。1H NMR(400MHz,DMSO-d 6 )δ 11.18(br s,1H),8.94(br s,1H),8.69(br s,1H),8.42(d,J=5.1Hz,1H),7.26(d,J=5.1Hz,1H),7.09(dd,J=6.1,2.7Hz,1H),7.00(t,J=8.8Hz,1H),6.54(ddd,J=8.9,4.1,2.7Hz,1H)。
N-(3-氯苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例80使用3-氯苯胺代替3-溴苯胺來合成。C13H9ClN4O.273.0[M+1]+。
N-(3-氯苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例82係類似於實例80使用N-(3-氯苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-溴苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來合成。C13H10ClN5O.288.0[M+1]+。1H NMR(400MHz,DMSO-d 6 )δ 11.28(br s,1H),8.98(s,1H),8.75(br s,1H),8.43(dd,J=4.9,1.5Hz,1H),7.26(dd,J=5.1,1.5Hz,1H),6.99(t,J=8.1Hz,1H),6.87-6.78(m,2H),6.47(ddd,J=8.3,2.2,0.9Hz,1H)。
N-(4-氟-3-(三氟甲基)苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例80使用4-氟-3-(三氟甲基)苯胺代替3-溴苯胺來合成。C14H8F4N4O.325.0[M+1]+。
N-(4-氟-3-(三氟甲基)苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例83係類似於實例80使用N-(4-氟-3-(三氟甲基)苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-溴苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來合成。C14H9F4N5O.340.1[M+1]+。1H NMR(400MHz,DMSO-d 6 )δ 11.18(br s,1H),9.09(s,1H),8.55(br s,1H),8.40(dd,J=5.0,1.8Hz,1H),7.29(d,J=5.0Hz,1H),7.16-7.07(m,2H),6.85-6.79(m,1H)。
4-氟-3-(丙-1-炔-1-基)苯胺.藉由鼓泡N2約5min使3-溴-4-氟苯胺(0.254g,1.337mmol)及三甲基(丙-1-炔-1-基)矽烷(0.59mL,4.010mmol)於DMF(1.5mL)中之溶液脫氣。添加CuI(0.025g,0.134mmol)、Pd(PPh3)2Cl2(0.094g,0.134mmol)及TBAF(4.68mL THF中之1M溶液,4.68mmol)並將混合物於65℃下加熱16h。將混合物用水稀釋並用DCM萃取3×。將合併之有機層用飽和碳酸氫鹽溶液及鹽水洗滌,乾燥(Na2SO4),過濾並濃縮。經由矽膠上急速層析純化殘餘物,以產生期望產物。C9H8FN.150.0[M+1]+。
N-(4-氟-3-(丙-1-炔-1-基)苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺.向1H-咪唑并[4,5-b]吡啶-7-甲酸(0.030g,0.184mmol)、4-氟-3-(丙-1-
炔-1-基)苯胺(0.028g,0.134mmol)、HOBt(0.030g,0.221mmol)及DIEA(0.08mL,0.46mmol)於DMF(2mL)中之溶液中添加EDC(0.05mL,0.22mmol)。將混合物於室溫下攪拌16h。將混合物用飽和碳酸氫鹽溶液稀釋並用EtOAc萃取3×。將將合併之有機層用10%檸檬酸溶液及鹽水洗滌,乾燥(Na2SO4),過濾,濃縮至矽膠上,並經由矽膠上急速層析純化,以產生期望產物。C16H11FN4O.295.1[M+1]+。
N-(4-氟-3-(丙-1-炔-1-基)苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例84係類似於實例80使用N-(4-氟-3-(丙-1-炔-1-基)苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-溴苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來合成。C16H12FN5O.310.1[M+1]+。1H NMR(400MHz,DMSO-d 6 )δ 11.02(br s,1H),8.75(s,1H),8.60(br s,1H),8.36(d,J=4.9Hz,1H),7.18(d,J=5.0Hz,1H),6.85(t,J=9.1Hz,1H),6.78(dd,J=6.3,2.8Hz,1H),6.52(ddd,J=8.8,4.4,2.9Hz,1H),1.98(s,3H)。
N-(3-溴-4-氯苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例80使用3-溴-4-氯苯胺代替4-氟-3-(丙-1-炔-1-基)苯胺來合成。C13H8BrClN4O.350.9/352.9[M+1]+。
N-(3-溴-4-氯苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例
85係類似於實例80使用N-(3-溴-4-氯苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-溴苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來合成。C13H9BrClN5O.366.0/368.0[M+1]+。1H NMR(400MHz,DMSO-d 6 )δ 11.27(br s,1H),9.01(s,1H),8.65(br s,1H),8.40(dd,J=5.1,1.7Hz,1H),7.25(dd,J=5.0,1.5Hz,1H),7.17(d,J=8.7Hz,1H),7.11(dd,J=2.7,0.8Hz,1H),6.49(dd,J=8.7,2.6Hz,1H)。
N-(3,4-二氯苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺.實例86係類似於實例80使用3,4-二氯苯胺代替3-溴苯胺來合成。C13H8Cl2N4O.307.0[M+1]+。
N-(3,4-二氯苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例86係類似於實例80使用N-(3,4-二氯苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-溴苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來合成。C13H9Cl2N5O.322.0[M+1]+。1H NMR(400MHz,DMSO-d 6 )δ 11.33(br s,1H),9.09(s,1H),8.71(br s,1H),8.44(dd,J=5.2,1.8Hz,1H),7.29(dd,J=5.0,1.6Hz,1H),7.21(d,J=8.7Hz,1H),7.00(d,J=2.7Hz,1H),6.49(dd,J=8.8,2.6Hz,1H)。
N-(4-氯苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺.向1H-咪唑并[4,5-
b]吡啶-7-甲酸(0.110g,0.674mmol)、4-氯苯胺(0.088g,0.689mmol)、HOBt(0.109g,0.807mmol)及DIEA(0.30mL,1.72mmol)於DMF(3mL)中之溶液中添加EDC(0.18mL,0.809mmol)。將混合物於室溫下攪拌16h。將混合物用飽和碳酸氫鹽溶液稀釋並經由過濾分離出固體。將固體懸浮於約3mL THF中。經由過濾移除固體,且用THF洗滌濾餅。將濾液乾燥(Na2SO4),過濾並在減壓下濃縮,以產生期望產物。C13H9ClN4O.273.0[M+1]+。
N-(4-氯苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例87係類似於實例80使用N-(4-氯苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-溴苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來合成。C13H10ClN5O.288.0[M+1]+。1H NMR(400MHz,DMSO-d 6 )δ 11.19(br s,1H),8.92(s,1H),8.75(br s,1H),8.41(d,J=5.1Hz,1H),7.21(d,J=5.1Hz,1H),7.07(d,J=8.8Hz,2H),6.68(d,J=8.8Hz,2H)。
N-(4-溴苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例80使用4-溴苯胺代替3-溴苯胺來合成。C13H9BrN4O.339.0/341.0[M+23]+.
N-(4-溴苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例88係類似於實例80使用N-(4-溴苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替
N-(3-溴苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來合成。C13H10BrN5O.332.0/334.0[M+1]+。1H NMR(400MHz,DMSO-d 6 )δ 11.19(br s,1H),8.89(s,1H),8.72(br s,1H),8.41(d,J=5.0Hz,1H),7.21(d,J=5.3Hz,1H),7.19(d,J=8.7Hz,2H),6.62(d,J=8.8Hz,2H)。
N-(4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例80使用5-氟苯胺代替3-溴苯胺來合成。C13H9FN4O.257.0[M+1]+。
N-(4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例89係類似於實例80使用N-(4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-溴苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來合成。C13H10FN5O.272.1[M+1]+。1H NMR(400MHz,DMSO-d 6 )δ 11.05(br s,1H),8.80(s,1H),8.72(br s,1H),8.39(dd,J=5.1,1.3Hz,1H),7.18(d,J=5.1Hz,1H),6.88(t,J=8.8Hz,2H),6.71(dd,J=9.0,4.8Hz,2H)。
N-(3-氰基-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例80使用3-氰基-4-氟苯胺代替3-溴苯胺來合成。C14H8FN5O.282.0[M+1]+。
N-(3-氰基-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例90係類似於實例80使用N-(3-氰基-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-溴苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來合成。C14H9FN6O.297.1[M+1]+。
N-(4-(三氟甲基)苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例84使用4-(三氟甲基)苯胺代替4-氟-3-(丙-1-炔-1-基)苯胺來合成。C14H9F3N4O.307.0[M+1]+。
N'-羥基-N-(4-(三氟甲基)苯基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例91係類似於實例80使用N-(4-(三氟甲基)苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-溴苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來合成。C14H10F3N5O.322.1[M+1]+。
N-(3-甲氧基苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例80使用3-甲氧基苯胺代替3-溴苯胺來合成。C14H12N4O2.269.1[M+1]+。
N'-羥基-N-(3-甲氧基苯基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例
92係類似於實例80使用N-(3-甲氧基苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-溴苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來合成。C14H13N5O2.284.1[M+1]+。
N-(4-氟-3-異丙基苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例80使用4-氟-3-異丙基苯胺代替3-溴苯胺來合成。C16H15FN4O.299.0[M+1]+。
N-(4-氟-3-異丙基苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例93係類似於實例80使用N-(4-氟-3-異丙基苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-溴苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來合成。C16H16FN5O.314.1[M+1]+。
N-(對甲苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例84使用對甲苯胺代替4-氟-3-(丙-1-炔-1-基)苯胺來合成。C14H12N4O.253.1[M+1]+。
N'-羥基-N-(對甲苯基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例94係
類似於實例80使用N-(對甲苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-溴苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來合成。C14H13N5O.268.1[M+1]+。
N-(3-乙炔基苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺.將1H-咪唑并[4,5-b]吡啶-7-甲酸(100mg,0.613mmol)、雙(2-側氧基-3-噁唑啶基)次膦醯氯(312mg,1.23mmol)及二異丙基乙胺(0.534mL,3.06mmol)於二氯甲烷(10mL)中之溶液攪拌16hr。將反應混合物過濾並吸收至矽膠上並藉由矽膠層析純化,以產生期望產物(140mg)。C15H10N4O.263.1(M+1)。
N-(3-乙炔基苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.將N-(3-乙炔基苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(41mg,0.155mmol)、五氯化磷(48mg,0.233mmol)於磷醯氯(0.3mL)及1,2-二氯乙烷(0.3mL)中之混合物於80℃下攪拌2hr。將反應混合物濃縮並懸浮於乙醇(2mL)中並向此混合物中添加50%水中之羥基胺(0.265mL,4.33mmol)。將反應混合物攪拌1hr並濃縮。藉由製備HPLC純化殘餘物,以產生兩種產物(實例95及實例96)。N-(3-乙炔基苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.C15H11N5O.278.07(M+1)1H NMR(400MHz,DMSO-d 6)δ 11.23(s,1H),8.90(s,1H),8.78(s,1H),8.43(d,J=5.1Hz,1H),7.24(d,J=5.1Hz,1H),7.00(t,J=8.1Hz,1H),6.93-
6.85(m,2H),6.59(ddd,J=8.2,2.3,1.1Hz,1H),4.07(s,1H)。
N-(3-乙基苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒係如實例95中所述製得。C15H15N5O.281.10(M+1)1H NMR(400MHz,DMSO-d 6)δ 11.09(s,1H),8.74(d,J=15.8Hz,2H),8.39(d,J=5.1Hz,1H),7.19(d,J=5.1Hz,1H),6.98-6.87(m,1H),6.64(ddd,J=7.5,1.6,0.9Hz,1H),6.55-6.43(m,2H),2.34(q,J=7.6Hz,2H),0.89(t,J=7.6Hz,3H)。
N-(3-乙炔基-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例95使用3-乙炔基-4-氟苯胺代替3-乙炔基苯胺來製得。C15H9FN4O.281.00(M+1)。
N-(3-乙炔基-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例97係類似於實例95來製得。C15H10FN5O.295.09(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.17(s,1H),8.90(s,1H),8.78(s,1H),8.43(d,J=5.1Hz,1H),7.26(d,J=5.1Hz,1H),6.98-6.89(m,2H),6.62
(ddd,J=9.0,4.4,2.9Hz,1H),4.39(d,J=0.6Hz,1H)。
N-(3-(二氟甲基)苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例95使用3-(二氟甲基)苯胺代替3-乙炔基苯胺來製得。C14H10F2N4O.289.10(M+1)。
N-(3-(二氟甲基)苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例98係類似於實例95使用N-(3-(二氟甲基)苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C14H11F2N5O.304.10(M+1)1H NMR(400MHz,DMSO-d 6)δ,12.51(s,1H),11.17(s,1H),8.92(d,J=25.4Hz,1H),8.41(s,1H),8.33(d,J=5.0Hz,1H),7.41-7.23(m,1H),7.19-7.02(m,1H),7.02-6.80(m,2H),6.73(d,J=8.2Hz,1H)。
N-(3-(三氟甲氧基)苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例95使用3-(三氟甲氧基)苯胺代替3-乙炔基苯胺來製得。C14H9F3N4O2.323.07(M+1)
N-羥基-N-(3-(三氟甲氧基)苯基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例99係類似於實例95使用N-(3-(三氟甲氧基)苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C14H10F3N5O2.338.10(M+1)。1H NMR(400MHz,DMSO-d 6)δ 9.54(s,1H),9.22(s,1H),8.58(d,J=5.3Hz,1H),7.40(d,J=5.3Hz,1H),7.12(td,J=8.1,0.5Hz,1H),6.74(ddt,J=8.2,2.1,1.0Hz,1H),6.69-6.61(m,3H)。
N-苯基-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例95使用苯胺代替3-乙炔基苯胺來製得。C13H10N4O.239.10(M+1)。
N-羥基-N-苯基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例100係類似於實例95使用N-苯基-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C13H11N5O.254.101H NMR(400MHz,DMSO-d 6)δ 12.51(s,1H),11.01(s,1H),8.63(s,1H),8.40(d,J=1.1Hz,1H),8.34-8.26(m,1H),7.08-6.99(m,2H),6.95(dd,J=8.5,7.3Hz,1H),6.82-6.76(m,1H),6.73-6.58(m,2H)。
N-(4-氟-3-(三氟甲氧基)苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例95使用4-氟-3-(三氟甲氧基)苯胺代替3-乙炔基苯胺來製得。C14H8F4N4O2.341.06(M+1)。
N-(4-氟-3-(三氟甲氧基)苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例101係類似於實例95使用N-(4-氟-3-(三氟甲氧基)苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C14H9F4N5O2.355.07(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.26(s,1H),9.10(s,1H),8.77(s,1H),8.45(d,J=5.1Hz,1H),7.30(d,J=5.1Hz,1H),7.24-7.10(m,1H),6.76-6.70(m,2H)。
N-(萘-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例95使用萘-2-胺代替3-乙炔基苯胺來製得。C17H12N4O.289.10(M+1)。
N-羥基-N-(萘-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒(實例102)及N-(3-氯萘-2-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒(實例103)係類似於實例95使用N-(萘-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得,產
生兩種產物(N-羥基-N-(萘-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒及N-(3-氯萘-2-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒)。C17H13N5O.304.11(M+1)及C17H12C1N5O.338.11(M+1)。
N-(3-氯萘-2-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒係根據實例102來製得。C17H12ClN5O.338.11(M+1)。
N-(萘-1-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例95使用萘-1-胺代替3-乙炔基苯胺來製得。C17H12N4O.289.10(M+1)。
N'-羥基-N-(萘-1-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒(實例104)及N-(4-氯萘-1-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒(實例105)係類似於實例95使用N-(萘-1-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得,以產生兩種產物(N'-羥基-N-(萘-1-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒及N-(4-氯萘-1-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒)。C17H13N5O.304.11(M+1)
N-(4-氯萘-1-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例105係類似於實例104來製得。C17H12ClN5O.338.11(M+1)。
N-(4-氟-3-甲氧基苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例95使用4-氟-3-甲氧基苯胺代替3-乙炔基苯胺來製得。C14H11FN4O2.286.09(M+1)。
N-(4-氟-3-甲氧基苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例106係類似於實例95使用4-氟-3-甲氧基苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C14H12FN5O2.302.10(M+1)。
2-氯-3-硝基異菸鹼酸經20min向2-氯-4-甲基-3-硝基吡啶(5.0g,29mmol)於硫酸(40mL)中之溶液中逐份添加二鉻酸鉀(11.3g,38.5mmol)。將反應物於60℃下攪拌過夜並傾倒至冰上。將水用乙酸乙酯
洗滌三次並將合併之有機層經硫酸鈉乾燥,過濾並濃縮,以產生期望產物。C6H3ClN2O4.203.1(M+1)。
2-氯-N-(3-氯-4-氟苯基)-3-硝基異菸鹼醯胺.在冰浴中向3-氯-4-氟苯胺(3.84g,26.4mmol)、2-氯-3-硝基異菸鹼酸(5.34g,26.4mmol)及三乙胺(11mL,79mmol)於二氯甲烷(100mL)中之溶液中添加磷醯氯(3.69mL,39.6mmol)。移除冰浴並將反應物攪拌1hr。添加飽和碳酸氫鈉並將水層用二氯甲烷洗滌三次。將合併之有機層經硫酸鈉乾燥,過濾並濃縮至矽膠上並藉由矽膠層析(二氯甲烷中之0->100%乙酸乙酯)純化,以產生期望產物。C12H6C12FN3O3.330.0(M+1)。
2-胺基-N-(3-氯-4-氟苯基)-3-硝基異菸鹼醯胺.於90℃下將2-氯-N-(3-氯-4-氟苯基)-3-硝基異菸鹼醯胺(4.78g,14.5mmol)於乙醇(15mL)及水中之28%氫氧化銨(14.1mL,101.4mmol)中之混合物在密閉容器中攪拌1.5hr。在冰浴中冷卻反應混合物並將所得沈澱過濾並用冷乙醇洗滌。在高真空上乾燥固體,以產生期望產物。Cl2H8ClFN4O3.311.1(M+1)。
2,3-二胺基-N-(3-氯-4-氟苯基)異菸鹼醯胺.於40psi氫下將2-胺基-N-(3-氯-4-氟苯基)-3-硝基異菸鹼醯胺(3.43g,11.0mmol)及10%碳載鈀(250mg)於甲醇(100mL)中之混合物在帕爾振盪器中混合2hr。
將反應物過濾並濃縮,以產生期望產物。C12H10ClFN4O.281.1(M+1)。
N-(3-氯-4-氟苯基)-2-甲基-1H-咪唑并[4,5-b]吡啶-7-甲醯胺.將2,3-二胺基-N-(3-氯-4-氟苯基)異菸鹼醯胺(1.06g,3.77mmol)於乙酸(11 mL)中之混合物於180℃下在微波中攪拌1hr。添加水並將所得沈澱過濾並在高真空上乾燥,以產生期望產物。C14H10ClFN4O.305.1(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-2-甲基-1H-咪唑并[4,5-b]吡啶-7-甲脒.將N-(3-氯-4-氟苯基)-2-甲基-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(132mg,0.433mmol)、五氯化磷(135mg,0.650mmol)於磷醯氯(2mL)及1,2-二氯乙烷(2mL)中之混合物於80℃下攪拌2.5hr。將反應混合物濃縮並懸浮於乙醇(2mL)中並向此混合物中添加50%水中之羥基胺(0.265mL,4.33mmol)。將反應混合物攪拌1hr並濃縮。藉由製備型HPLC純化殘餘物,以產生期望化合物。C14H11ClFN5O.320.0(M+1)。
N-(3-氯-4-氟苯基)-2-乙基-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例107使用丙酸代替乙酸來製得。C15H12ClFN4O.319.1(M+1)。
N-(3-氯-4-氟苯基)-2-乙基-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例108係類似於實例107使用N-(3-氯-4-氟苯基)-2-乙基-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-甲基-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C15H13ClFN5O.334.1(M+1)。
N-(3-氯-4-氟苯基)-2-環丙基-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例107使用環丙烷羧酸代替乙酸來製得。C16H12ClFN4O.331.1(M+1)。
N-(3-氯-4-氟苯基)-2-環丙基-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例109係類似於實例107使用N-(3-氯-4-氟苯基)-2-環丙基-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-甲基-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C16H13ClFN5O.346.1(M+1)。
N-(3-氯-4-氟苯基)-2-(甲氧基甲基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例107使用甲氧基乙酸代替乙酸來製得。C15H12ClFN4O2.334.9(M+1)。
4-(3-氯-4-氟苯基)-3-(2-(甲氧基甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮.將N-(3-氯-4-氟苯基)-2-(甲氧基甲基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(2.62g,7.82mmol)、五氯化磷(2.44g,11.7mmol)於磷醯氯(22mL)及1,2-二氯乙烷(22mL)中之混合物於80℃下攪拌2.5hr。將反應混合物濃縮並懸浮於乙醇(20mL)中並向此混合物中添加水中之50%羥基胺(4.8mL,78mmol)。將反應混合物攪拌1hr並濃縮。添加水及水性飽和碳酸氫鈉並將固體過濾並在高真空上乾燥。將固體懸浮於乙酸乙酯(100mL)中並向此混合物中添加羰基二咪唑(1.90g,11.7mmol)。將混合物攪拌18hr並濃縮。藉由矽膠層析純化殘餘物,以產生期望產物(871mg)。C16H11ClFN5O3.376.3(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-2-(甲氧基甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例110係類似於實例95使用N-(3-氯-4-氟苯基)-2-(甲氧基甲基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C15H13ClFN5O2.350.1(M+1)。
於0℃下向4-(3-氯-4-氟苯基)-3-(2-(甲氧基甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮(400mg,1.07mmol)於二氯甲烷(8mL)中之混合物添加1M三溴化硼於二氯甲烷(1.60mL,1.60mmol)中之溶液。使反應物升溫至室溫並攪拌18hr。將反應混合物用二氯甲烷及飽和碳酸氫鈉稀釋並將水層用二氯甲烷洗滌三次。將合併之有機層經硫酸鈉乾燥,過濾,裝載至矽膠管柱上並藉由矽膠層析純化,以產生兩種產物:4-(3-氯-4-氟苯基)-3-(2-(羥基甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮(385mg)及3-(2-(溴甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮。C15H9ClFN5O3.362.0(M+1)。
3-(2-(溴甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮.C15H8BrClFN5O2.425.9(M+1)。
甲烷磺酸(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-
3-基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-2-基)甲基酯.於-78℃下經10min向4-(3-氯-4-氟苯基)-3-(2-(羥基甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮(510mg,1.41mmol)及三乙胺(1.97mL,14.1mmol)於二氯甲烷(20mL)中之溶液中逐滴添加甲磺醯氯(0.548mL,7.05mmol)。使反應混合物升溫至0℃並攪拌10min。添加水並將水層用乙酸乙酯洗滌三次。將合併之有機層經硫酸鈉乾燥,過濾並濃縮。藉由矽膠層析純化殘餘物,以產生兩種產物:甲烷磺酸(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-2-基)甲基酯(440mg)及4-(3-氯-4-氟苯基)-3-(2-(氯甲基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮。C17H13ClFN5O7S2.518.2(M+1)。
4-(3-氯-4-氟苯基)-3-(2-(氯甲基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮係自上述反應製得。C16H10Cl2FN5O4S.458.0(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-2-(嗎啉基甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.將甲烷磺酸(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-2-基)甲基酯(27mg,0.052mmol)及嗎啉(0.10mL,1.1mmol)於乙腈(1mL)中之溶液於65℃下攪拌10min。濃縮反應物。將殘餘物吸收於四氫呋喃(0.5
mL)及水(0.5mL)中。向此溶液中添加2N氫氧化鈉(0.39mL,0.78mmol)並將反應混合物攪拌10min。向混合物中添加乙酸(0.05mL)並將溶液直接裝載至製備型HPLC上用於純化,以產生期望產物。C18H18ClFN6O2.405.1(M+1)。
N-(3-氯-4-氟苯基)-2-((二甲基胺基)甲基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.將4-(3-氯-4-氟苯基)-3-(2-(氯甲基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮(30mg,0.065mmol)及二甲胺(2M於THF中,0.655mL,1.3mmol)於乙腈(1mL)中之溶液於65℃下攪拌3hr min。濃縮反應物。將殘餘物吸收於四氫呋喃(0.5mL)及水(0.5mL)中。向此溶液中添加2N氫氧化鈉(0.39mL,0.78mmol)並將反應混合物攪拌10min。向混合物中添加乙酸(0.05mL)並將溶液直接裝載至製備型HPLC上用於純化,以產生期望產物(12mg)。C16H16ClFN6O.363.1(M+1)。
N-(3-氯-4-氟苯基)-2-((乙基胺基)甲基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例114係類似於實例112使用THF中之2M乙胺代替嗎啉來製得。C16H16ClFN6O.363.1(M+1)。1H NMR(400MHz,DMSO-
d 6)δ 12.76(s,1H),11.16(s,1H),9.29(s,2H),8.96(s,1H),8.38(d,J=5.0Hz,1H),7.41-6.99(m,2H),6.92(dd,J=6.5,2.7Hz,1H),6.51(d,J=8.7Hz,1H),4.47(s,2H),3.08(s,2H),1.23(t,J=7.3Hz,3H)。
2-((苄基胺基)甲基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例115係類似於實例112使用苄基胺代替嗎啉來製得。C21H18ClFN6O.425.1(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-2-((異丙基胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例116係類似於實例112使用異丙胺代替嗎啉來製得。C17H18ClFN6O.377.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.18(s,1H),9.28(s,2H),8.96(s,1H),8.38(d,J=5.0Hz,1H),7.24-6.96(m,2H),6.91(dd,J=6.5,2.7Hz,1H),6.51(s,1H),4.48(s,2H),3.56-3.28(m,1H),1.37-1.15(m,6H)。
N-(3-氯-4-氟苯基)-2-(((環丙基甲基)胺基)甲基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例117係類似於實例112使用環丙基甲胺代替嗎啉來製得。C18H18ClFN6O.388.9(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.14(s,1H),9.41(s,2H),8.95(s,1H),8.38(d,J=5.0Hz,1H),7.28-6.98(m,2H),6.91(dd,J=6.5,2.7Hz,1H),6.52(ddd,J=9.0,4.0,2.8Hz,1H),4.50(s,2H),2.96(s,2H),1.17-0.92(m,1H),0.68-0.48(m,2H),0.42-0.24(m,2H)。
N-(3-氯-4-氟苯基)-2-(((環丙基甲基)胺基)甲基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例118係類似於實例112使用2,2,2-三氟乙胺代替嗎啉來製得。C16H13ClF4N6O.416.7(M+1)。
N-(3-氯-4-氟苯基)-2-((環丙基胺基)甲基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例119係類似於實例112使用環丙胺代替嗎啉來製得。C17H16ClFN6O.374.9(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-2-(((3-甲氧基丙基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例120係類似於實例112使用3-甲氧基丙胺代替嗎啉來製得。C18H20ClFN6O2.407.1(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-2-(((吡啶-2-基甲基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例121係類似於實例112使用吡啶-2-基甲胺代替嗎啉來製得。C20H17ClFN7O.426.1(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-2-(((3-甲氧基丙基)(甲基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例122係類似於實例112使用3-(2-(溴甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及甲烷磺酸3-甲氧基-N-甲基丙-1-胺代替(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-1H-咪唑并
[4,5-b]吡啶-2-基)甲基酯及嗎啉來製得。C19H22ClFN6O2.421.2(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-2-(((2-甲氧基苄基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例123係類似於實例112使用4-(3-氯-4-氟苯基)-3-(2-(氯甲基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮及2-甲氧基苄基胺代替甲烷磺酸(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-2-基)甲基酯及嗎啉來製得。C22H20ClFN6O2.455.1(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-2-(((2-甲氧基乙基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例124係類似於實例112使用2-甲氧基乙胺代替嗎啉來製得。C17H18ClFN6O2.393.1(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-2-(((2-(吡啶-2-基)乙基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例125係類似於實例112使用2-(吡啶-2-基)乙胺代替嗎啉來製得。C21H19ClFN7O.440.1(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-2-(((吡啶-3-基甲基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例126係類似於實例112使用3-甲基吡啶胺代替嗎啉來製得。C20H17ClFN7O.426.1(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-2-((((四氫-2H-吡喃-2-基)甲基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例127係類似於實例112使用4-(3-氯-4-氟苯基)-3-(2-(氯甲基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮及甲烷磺酸(四氫-2H-吡喃-2-基)甲胺代替(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-2-基)甲基酯及嗎啉來製得。C20H22ClFN6O2.433.1(M+1)。
將甲烷磺酸(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-2-基)甲基酯(14mg,0.027mmol)及苯胺(0.025mL,0.27mmol)於乙腈(1mL)中之溶液於65℃下攪拌18hr。向該溶液中添加異丙胺(0.1mL)並將反應物於65℃下攪拌5min。濃縮反應物。將殘餘物吸收於四氫呋喃(0.3mL)及水(0.3mL)中。向此溶液中添加2N氫氧化鈉(0.2mL,0.41mmol)並將反應混合物攪拌10min。向混合物中添加乙酸(0.05mL)並將溶液直接裝載至製備型HPLC上用於純化,以產生期望產物。C20H16ClFN6O.411.1(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-2-((((四氫-2H-吡喃-3-基)甲基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例129係類似於實例112使用(四氫-2H-吡喃-3-基)甲胺代替嗎啉來製得。C20H22ClFN6O2.433.1(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-2-(((嘧啶-2-基甲基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例130係類似於實例112使用嘧啶-2-基甲胺代替嗎啉來製得。C19H16ClFN8O.427.1(M+1)。
實例131係類似於實例112使用3-嗎啉基丙-1-胺代替嗎啉來製得。C21H25ClFN7O2.462.2(M+1)。
實例132係類似於實例112使用4-(3-氯-4-氟苯基)-3-(2-(氯甲基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮及四氫-2H-吡喃-4-胺代替甲烷磺酸(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-2-基)甲基酯及嗎啉來製得。C19H20ClFN6O2.419.1(M+1)。
實例133係類似於實例112使用4-甲基吡啶胺代替嗎啉來製得。
C20H17ClFN7O.426.1(M+1)。
實例134係類似於實例112使用吡嗪-2-基甲胺代替嗎啉來製得。C19H16ClFN8O.427.1(M+1)。
實例135係類似於實例112使用4-(3-氯-4-氟苯基)-3-(2-(氯甲基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮及(四氫呋喃-3-基)甲胺代替甲烷磺酸(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-2-基)甲基酯及嗎啉來製得。C19H20ClFN6O2.419.1(M+1)。
實例136係類似於實例112使用N,N-二甲基乙烷-1,2-二胺代替嗎啉來製得。C18H21ClFN7O.406.1(M+1)。
實例137係類似於實例112使用2-(嘧啶-2-基)乙胺代替嗎啉來製得。C20H18ClFN8O.441.1(M+1)。
實例138係類似於實例112使用3-胺基丙醇代替嗎啉來製得。C17H18ClFN6O2.393.1(M+1)。
實例139係類似於實例112使用吡咯啶代替嗎啉來合成。C18H18ClFN6O.389.1[M+1]+。
實例140係類似於實例112使用六氫吡啶代替嗎啉來合成。C19H20ClFN6O.403.1[M+1]+。
實例141係類似於實例112分別使用3-(2-(溴甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及2,2-二甲基丙-1-胺代替甲烷磺酸(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-2-基)甲基酯及嗎啉來合成。C19H22ClFN6O.405.2[M+1]+。
實例142係類似於實例112分別使用3-(2-(溴甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及2,2-二氟乙胺代替甲烷磺酸(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-2-基)甲基酯及嗎啉來合成。C16H14ClF3N6O.399.1[M+1]+。
實例143係類似於實例112分別使用3-(2-(溴甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基-2,2-二甲基丙-1-醇代替甲烷磺酸(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-2-基)甲基
酯及嗎啉來合成。C19H22ClFN6O2.421.2[M+1]+。
實例144係類似於實例112分別使用3-(2-(溴甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及噻唑-2-基甲胺代替甲烷磺酸(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-2-基)甲基酯及嗎啉來合成。C18H15ClFN7OS.432.1[M+1]+。
將甲烷磺酸(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-2-基)甲基酯(17mg,0.033mmol)及二噁烷中之0.5M氨(1.44mL,0.722mmol)於乙腈(1mL)中之溶液於65℃下攪拌30min。濃縮反應物。將殘餘物吸收於四氫呋喃(0.5mL)中並向此溶液中添加三乙胺(0.021mL,0.15mmol)及乙醯氯(0.003mL,0.045mmol)。將反應物攪拌3hr,且隨後再添加乙醯氯(0.003mL,0.045mmol)。將反應物攪拌2hr並濃縮。將殘餘物吸收於四氫呋喃(0.3mL)及水(0.3mL)中。向此溶液中添加2N氫氧化鈉(0.22mL,0.44mmol)並將反應混合物攪拌10min。向混合物中添加乙酸(0.05mL)並將溶液直接裝載至製備型HPLC上用於純化,以產生期望
產物。C16H14ClFN6O2.377.1(M+1)。
甲基-2-(噻吩-2-基)-1H-咪唑并[4,5-b]吡啶.將4-甲基-3-硝基吡啶-2-胺(400mg,2.61mmol)、噻吩-2-甲醛(449mg,3.92mmol)及亞硫酸氫鈉(1.61g,7.84mmol)於二甲基亞碸(5mL)及乙醇(5mL)中之溶液於90℃下攪拌18hr。使混合物冷卻至室溫並向此混合物中添加水並將水層用乙酸乙酯洗滌三次。將合併之有機層經硫酸鈉乾燥,過濾,吸收至矽膠上並藉由矽膠層析純化,以產生期望產物。C11H9N3S.216.1(M+1)。
2-(噻吩-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲酸甲基酯.將7-甲基-2-(噻吩-2-基)-1H-咪唑并[4,5-b]吡啶(234mg,1.09mmol)及二氧化硒(482,4.35mmol)於吡啶(2.5mL)中之溶液於120℃下攪拌24小時。經由矽藻土墊過濾反應混合物並用熱水及甲醇洗滌矽藻土墊。濃縮濾液並在高真空上乾燥所得殘餘物。將殘餘物吸收於甲醇(10mL)中並向此溶液中添加亞硫醯氯(0.55mL,7.6mmol)。將溶液於70℃下攪拌4小時。濃縮所得混合物,以產生期望產物。C12H9N3O2S.260.1(M+1)。
N-(3-氯-4-氟苯基)-2-(噻吩-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺.於0℃下在氮下經5min向3-氯-4-氟苯胺(239mg,1.64mmol)於二
氯乙烷中之溶液中逐滴添加三甲基鋁(2M於庚烷中,1.57,3.15mmol)。使溶液升溫至室溫並攪拌30min。將溶液冷卻至0℃並向此溶液中添加2-(噻吩-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲酸甲基酯(272mg,1.05mmol)。將溶液於85℃下攪拌18hr,且隨後冷卻至室溫。向溶液中小心地添加飽和碳酸氫鈉並將水層用二氯甲烷洗滌三次。用10%檸檬酸酸化水層並將所得沈澱過濾並在高真空上乾燥,以產生期望產物。C17H10ClFN4OS.373.1(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-2-(噻吩-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例146係類似於實例107使用N-(3-氯-4-氟苯基)-2-(噻吩-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-甲基-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C17H11ClFN5OS.388.1(M+1)。
N-(3-氯-4-氟苯基)-2-(吡啶-3-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺.於100℃下在空氣氣氛下將2,3-二胺基-N-(3-氯-4-氟苯基)異菸鹼醯胺(0.150g,0.534mmol)及菸鹼醛(0.50mL,5.34mmol)於DMSO中之混合物攪拌16h。將混合物冷卻至rt並用水稀釋。將水層用EtOAc萃取3×並將合併之有機層用鹽水洗滌,乾燥(Na2SO4),過濾,濃縮至矽膠上,並經由矽膠上管柱層析純化,以產生最終產物。
C18H11ClFN5O.368.1[M+1]+。
實例147係類似於實例80使用N-(3-氯-4-氟苯基)-2-(吡啶-3-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-溴苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯來合成胺。C18H12ClFN6O.383.1[M+1]+。
N-(3-氯-4-氟苯基)-2-(1H-吡咯-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例147使用1H-吡咯-2-甲醛代替菸鹼醛來合成。C17H11ClFN5O.356.1[M+1]+。
實例148係類似於實例80使用N-(3-氯-4-氟苯基)-2-(1H-吡咯-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-溴苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來合成。C17H12ClFN6O.371.1[M+1]+。
2,3-二胺基異菸酸甲基酯.將2,3-二胺基異菸鹼酸(2.0g,13mmol)於硫酸(2.5mL)及甲醇(25mL)中之混合物於120℃下在微波中攪拌1hr。向反應混合物中添加飽和碳酸氫鈉水溶液直至鹼性且將水層用乙酸乙酯洗滌三次。將合併之有機層經硫酸鈉乾燥,過濾並濃縮,以產生期望產物。C7H9N3O2.168.1(M+1)。
2-(1H-咪唑-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲酸甲基酯係類似於實例147使用2,3-二胺基異菸酸甲基酯及1H-咪唑-2-甲醛來製得。C11H9N5O2.244.0(M+1)。
N-(3-氯-4-氟苯基)-2-(1H-咪唑-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例146使用2-(1H-咪唑-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲酸甲基酯代替2-(噻吩-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲酸甲基酯來製得。C16H10ClFN6O.357.2(M+1)。
實例149係類似於實例107使用N-(3-氯-4-氟苯基)-2-(1H-咪唑-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-甲基-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C16H11ClFN7O.372.1(M+1)。1H NMR(400MHz,DMSO-d 6 )δ 11.07(s,1H),8.92(s,1H),8.33(d,J=5.1Hz,1H),7.44(s,2H),7.18(d,J=5.1Hz,1H),7.02(t,J=9.1Hz,1H),6.96(dd,J=6.5,2.7Hz,1H),6.56(ddd,J=9.0,4.1,2.7
Hz,1H)。
N-(3-氯-4-氟苯基)-2-(1H-吡唑-5-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例147使用1H-吡唑-5-甲醛代替菸鹼醛來合成。C16H10ClFN6O.357.1[M+1]+。
N-(3-氯-4-氟苯基)-N'-羥基-2-(1H-吡唑-5-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例150係類似於實例80使用N-(3-氯-4-氟苯基)-2-(1H-吡唑-5-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-溴苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來合成。C16H11ClFN7O.372.1[M+1]+。
2-(4-甲基-1H-咪唑-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲酸甲基酯.將2,3-二胺基異菸酸甲基酯(0.102g,0.610mmol)及4-甲基-1H-咪唑-2-甲醛(0.319g,2.90mmol)於DMSO(5mL)中之混合物於100℃下在空氣氣氛下攪拌16h。將混合物用水稀釋並經由過濾分離出固體。將濾餅用水洗滌且隨後在乾冰上冷卻並在凍乾器上乾燥,以產生期望產物,
其未經純化即使用。C12H11N5O2.258.1[M+1]+。
N-(3-氯-4-氟苯基)-2-(4-甲基-1H-咪唑-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺.向THF(2mL)中之DABAL-Me3(0.128g,0.499mmol)中添加3-氯-4-氟苯胺(0.073g,0.499mmol)。將混合物於40℃下攪拌1h。添加2-(4-甲基-1H-咪唑-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲酸甲基酯(0.080g,0.311mmol)於THF(2.5mL)中之漿液並將混合物於65℃下攪拌16h。將混合物藉由添加1N HCl(1mL)驟冷且隨後用水/EtOAc稀釋。將水層用EtOAc萃取3×。將合併之有機層用鹽水洗滌,乾燥(Na2SO4),過濾,濃縮至矽膠上,並經由矽膠上管柱層析純化,以產生期望產物。C17H12ClFN6O.371.1[M+1]+。
N-(3-氯-4-氟苯基)-N'-羥基-2-(4-甲基-1H-咪唑-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.向N-(3-氯-4-氟苯基)-2-(4-甲基-1H-咪唑-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(0.009g,0.024mmol)於DCE(0.5mL)及磷醯氯(0.5mL)中之混合物中添加五氯化磷(0.008g,0.036mmol)。將混合物於90℃下攪拌4h。添加另外五氯化磷(0.008g,0.036mmol)並將混合物於90℃下攪拌72h。將混合物冷卻至rt並濃縮。將殘餘物用EtOH(3mL)稀釋並添加羥基胺(0.05mL 50w/w%水溶液,0.82mmol)。濃縮混合物並將殘餘物用DMSO/水稀釋並經由製備型HPLC純化,以產生期望產物。C17H13ClFN7O.386.0[M+1]+。
(S)-2-((2-胺基-4-((3-氯-4-氟苯基)胺甲醯基)吡啶-3-基)胺甲醯基)吡咯啶-1-甲酸第三丁基酯.於0℃下向DCM(20mL)中之N-Boc-L-脯胺酸(0.429g,1.991mmol)中逐滴添加氯甲酸異丁基酯(0.57mL,4.38mmol),之後添加TEA(0.69mL,4.98mmol)。添加2,3-二胺基-N-(3-氯-4-氟苯基)異菸鹼醯胺(0.559g,1.991mmol)並使混合物升溫至rt並攪拌16h。將混合物用水稀釋並將水相用EtOAc萃取3×。將合併之有機層用鹽水洗滌,乾燥(Na2SO4),過濾,濃縮至矽膠上,並經由矽膠上管柱層析純化,以產生期望產物。C22H25ClFN5O4.478.2[M+1]+。
2-(7-((3-氯-4-氟苯基)胺甲醯基)-1H-咪唑并[4,5-b]吡啶-2-基)吡咯啶-1-甲酸第三丁基酯.將(S)-2-((2-胺基-4-((3-氯-4-氟苯基)胺甲醯基)吡啶-3-基)胺甲醯基)吡咯啶-1-甲酸第三丁基酯(0.094g,0.197mmol)於AcOH(4mL)中之溶液加熱至65℃保持4h並加熱至80℃保持2h。將混合物冷卻至rt並濃縮。將殘餘物分配在飽和碳酸氫鹽溶液與EtOAc之間並將水層用EtOAc萃取3×。將合併之有機層濃縮至矽膠上並經由矽膠上管柱層析純化,以產生期望產物。C22H23ClFN5O3.460.1[M+1]+。
2-(7-((3-氯-4-氟苯基)胺基甲醯硫基)-1H-咪唑并[4,5-b]吡啶-2-基)吡咯啶-1-甲酸第三丁基酯.將2-(7-((3-氯-4-氟苯基)胺甲醯基)-1H-咪唑并[4,5-b]吡啶-2-基)吡咯啶-1-甲酸第三丁基酯(0.043g,0.093mmol)及Lawesson試劑(0.076g,0.187mmol)於甲苯(2mL)中之混合物於95℃下攪拌16h。將混合物冷卻至rt,濃縮至矽膠上,並經由矽膠上管柱層析純化,以產生期望產物。C22H23ClFN5O2S.476.1[M+1]+。
2-(7-(N-(3-氯-4-氟苯基)-N'-羥基甲脒基)-1H-咪唑并[4,5-b]吡啶-2-基)吡咯啶-1-甲酸第三丁基酯.向2-(7-((3-氯-4-氟苯基)胺基甲醯硫基)-1H-咪唑并[4,5-b]吡啶-2-基)吡咯啶-1-甲酸第三丁基酯(0.019g,0.040mmol)於MeOH(2mL)中之混合物中添加羥基胺(0.12mL 50w/w%水溶液,2.00mmol)。將混合物於70℃下攪拌45min。將混合物冷卻至rt並用鹽水及EtOAc稀釋。將水層用EtOAc萃取4×。將合併之有機層用鹽水洗滌,乾燥(Na2SO4),過濾並濃縮,以產生期望產物。C22H24ClFN6O3.475.2[M+1]+。
N-(3-氯-4-氟苯基)-N'-羥基-2-(吡咯啶-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.向2-(7-(N-(3-氯-4-氟苯基)-N'-羥基甲脒基)-1H-咪唑并[4,5-b]吡啶-2-基)吡咯啶-1-甲酸第三丁基酯(0.018g,0.038mmol)於
DCM(1mL)中之溶液中添加TFA(1mL)。將混合物於rt下攪拌10min且隨後濃縮。將殘餘物溶解於DMSO/水中並經由製備型HPLC純化,以產生期望產物。C17H16ClFN6O.375.1[M+1]+。
N-(3-氯-4-氟苯基)-2-氰醯胺基(cyanamido)-3-硝基異菸鹼醯胺.將2-氯-N-(3-氯-4-氟苯基)-3-硝基異菸鹼醯胺(1.02g,3.09mmol)、氰胺(260mg,6.18mmol)及碳酸鉀(1.28g,9.27mmol)於二甲基甲醯胺(10mL)中之混合物於80℃下攪拌2hr。將反應混合物吸收至矽膠上並藉由矽膠層析純化,以產生期望產物(1.03g)。C13H7ClFN5O3.336.0(M+1)。
2-胺基-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺.將N-(3-氯-4-氟苯基)-2-氰醯胺基-3-硝基異菸鹼醯胺(1.07g,3.20mmol)及亞硫酸氫鈉(1.96g,9.59mmol)於乙醇(10mL)及二甲基亞碸(10mL)中之混合物於70℃下攪拌24hr。添加水並將水層用乙酸乙酯洗滌三次。將合併之有機層經硫酸鈉乾燥,過濾並吸收至矽膠上並藉由矽膠層析純化,以產生期望產物。C13H9ClFN5O.306.1(M+1)。
2-胺基-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例153係類似於實例107使用2-胺基-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-甲基-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C13H10ClFN6O.321.0(M+1)。1H NMR(400MHz,DMSO-d 6 )δ 8.84(s,1H),8.15-8.10(m,1H),7.94-7.89(m,1H),7.10(t,J=9.0Hz,1H),7.00-6.92(m,1H),6.91-6.79(m,1H),6.63-6.54(m,1H)。
N-(3-氯-4-氟苯基)-2-(環丙基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺.向2,3-二胺基-N-(3-氯-4-氟苯基)異菸鹼醯胺(0.54g,0.002mol)溶解於THF(5ml)中之溶液中添加異硫氰酸環丙基酯(0.23g,0.002mmol)及三乙胺(1.95g,0.02mol)。將反應混合物於80℃下加熱過夜,隨後向反應混合物中添加1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(0.44g,0.002mol),於80℃下加熱1h。用EtOAc稀釋反應混合物且隨後添加水。產物沖出,以得到2oomg期望產物.C16H13ClFN5O.346.1(M+1)。
N-(3-氯-4-氟苯基)-2-(環丙基胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例154係類似於實例107使用羥基脒形成之一般程序來製得。C16H14ClFN6O.361.1(M+1)。1H NMR(400MHz,DMSO-d6)δ
11.36(s,1H),8.93(s,1H),8.80(s,1H),8.01(d,J=6.1Hz,1H),7.13-7.00(m,2H),6.97(d,J=6.1Hz,1H),6.55(ddd,J=9.0,4.0,2.7Hz,1H),2.81(dq,J=6.9,3.4Hz,1H),0.83(td,J=7.1,5.0Hz,2H),0.59(p,J=4.7Hz,2H)。
實例155係類似於實例154使用異硫氰酸苯基酯來製得。C19H14ClFN6O.397.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.37(s,1H),10.09(s,1H),8.92(s,1H),8.05(d,J=6.1Hz,1H),7.66(d,J=8.1Hz,2H),7.39(t,J=7.7Hz,2H),7.14-7.04(m,2H),7.02(dt,J=5.6,2.6Hz,2H),6.60(ddd,J=9.0,4.0,2.8Hz,1H)。
實例156係類似於實例154使用(2-異氰硫基乙基)苯來製得。C21H18ClFN6O.425.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.36(s,1H),8.92(s,1H),7.95(d,J=6.3Hz,1H),7.37-7.16(m,6H),7.13-7.05(m,1H),7.02(dd,J=6.5,2.8Hz,1H),6.96-6.85(m,1H),6.57(ddd,J=8.9,4.0,2.8Hz,1H),3.73-3.62(m,2H),2.89(t,J=7.3Hz,
2H)。
實例157係類似於實例154使用1,1,1-三氟-2-異氰硫基乙烷來製得。C15H11ClF4N6O.403.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.42(s,1H),8.95(s,1H),8.00(d,J=6.2Hz,1H),7.05(ddd,J=19.0,8.5,4.0Hz,3H),6.95(d,J=6.5Hz,1H),6.57(dt,J=9.0,3.3Hz,1H),4.30(s,3H)。
實例158係類似於實例154使用異硫氰酸甲基酯來製得。C14H12ClFN6O.335.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 12.08(s,1H),11.37(s,1H),8.96(s,1H),7.96(d,J=6.2Hz,1H),7.08(t,J=9.1Hz,1H),7.03-6.97(m,1H),6.91(d,J=6.2Hz,1H),6.56(ddd,J=9.0,4.0,2.8Hz,1H),3.00(d,J=4.8Hz,3H)。
(7-((3-氯-4-氟苯基)胺甲醯基)-1H-咪唑并[4,5-b]吡啶-2-基)胺基甲酸異丙基酯.於0℃下向2-胺基-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(30mg,0.098mmol)及三乙胺(0.041mL,0.29mmol)於二氯甲烷中之混合物中添加氯甲酸異丙基酯溶液(1M於甲苯中,0.118mL,0.118mmol)。使反應物升溫至室溫並攪拌1hr。添加飽和碳酸氫鈉並將水層用二氯甲烷洗滌三次。將合併之有機層經硫酸鈉乾燥,過濾並濃縮。將殘餘物裝載至矽膠管柱上並藉由矽膠層析純化,以產生與7-((3-氯-4-氟苯基)胺甲醯基)-2-((異丙氧基羰基)胺基)-1H-咪唑并[4,5-b]吡啶-1-甲酸異丙基酯混合之期望產物。C17H15ClFN5O3.392.2(M+1)。
(7-(N-(3-氯-4-氟苯基)-N'-羥基甲脒基)-1H-咪唑并[4,5-b]吡啶-2-基)胺基甲酸異丙基酯.實例159係類似於實例107使用(7-((3-氯-4-氟苯基)胺甲醯基)-1H-咪唑并[4,5-b]吡啶-2-基)胺基甲酸異丙基酯代替N-(3-氯-4-氟苯基)-2-甲基-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C17H16ClFN6O3.407.0(M+1)。1H NMR(400MHz,DMSO-d 6 )δ 8.83(s,1H),8.18(d,J=5.4Hz,1H),7.13(t,J=9.1Hz,1H),7.02-6.91(m,2H),6.67-6.57(m,1H),5.00(dq,J=6.3,6.3Hz,1H),1.31(d,J=6.2Hz,6H)。
實例160係類似於實例154使用O-異硫氰醯甲酸乙基酯來製得。C16H14ClFN6O3.393.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.54(s,1H),8.83(s,1H),8.20(d,J=5.6Hz,1H),7.11(t,J=9.1Hz,1H),7.03(d,J=5.6Hz,1H),6.95(dd,J=6.5,2.7Hz,1H),6.62(ddd,J=8.9,4.0,2.7Hz,1H),4.26(q,J=7.1Hz,2H),1.28(t,J=7.1Hz,3H)。
實例161係類似於實例154使用異硫氰酸環丙基甲基酯來製得。C17H16ClFN6O.375.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.37(s,1H),8.93(s,1H),7.94(t,J=5.3Hz,1H),7.50-7.25(m,1H),7.14-6.97(m,2H),6.91(d,J=6.3Hz,1H),6.58(ddd,J=9.0,4.0,2.7Hz,1H),3.31(t,J=6.5Hz,2H),1.11(d,J=13.1Hz,1H),0.57-0.40(m,2H),0.33-0.19(m,2H)。
實例162係類似於實例154使用1,1-二氟-3-異氰硫基環丁烷來製得。C17H14ClF3N6O.411.0(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.41(d,J=18.8Hz,1H),8.97(s,1H),8.69(s,1H),7.99(dd,J=7.9,6.6Hz,1H),7.09-6.97(m,2H),6.94(d,J=6.2Hz,1H),6.54(ddd,J=
9.0,4.0,2.8Hz,1H),4.28(s,1H),3.03(tt,J=14.3,7.9Hz,2H),2.77(d,J=10.6Hz,2H)。
N-(3-氯-4-氟苯基)-2-(乙基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例154使用異硫氰酸乙基酯來製得。C15H13ClFN5O.333.9(M+1)。
N-(3-氯-4-氟苯基)-2-(乙基胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例163係類似於實例107使用N-(3-氯-4-氟苯基)-2-(乙基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-甲基-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C15H14ClFN6O.349.1(M+1)。
N-(3-氯-4-氟苯基)-2-(環丁基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺.實例164係類似於實例154使用異硫氰酸環丁基酯來製得。C17H15ClFN5O.360.2(M+1)。
N-(3-氯-4-氟苯基)-2-(環丁基胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例164係類似於實例107使用N-(3-氯-4-氟苯基)-2-(環丁基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-甲基-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C17H16ClFN6O.375.1(M+1)。1H NMR(400MHz,DMSO-d 6 )δ 11.40(s,1H),8.98(s,1H),7.96(d,J=6.2Hz,1H),7.09(t,J=9.1Hz,1H),7.05(dd,J=6.1,2.5Hz,1H),6.92(d,J=6.2Hz,1H),6.62-6.50(m,1H),4.34(q,J=7.2Hz,1H),2.39-2.24(m,2H),2.15-1.98(m,2H),1.82-1.58(m,2H)。
N-(3-氯-4-氟苯基)-2-(異丙基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例154使用異硫氰酸異丙基酯來製得。C16H15ClFN5O.348.2(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-2-(異丙基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例165係類似於實例107使用N-(3-氯-4-氟苯基)-2-(異丙基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-甲基-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C16H16ClFN6O.363.1
(M+1)。1H NMR(400MHz,DMSO-d 6 )δ 11.42(s,1H),8.97(s,1H),7.96(d,J=6.3Hz,1H),7.11(t,J=9.0Hz,1H),7.05(dd,J=6.6,2.7Hz,1H),6.92(d,J=6.3Hz,1H),6.62-6.56(m,1H),4.06(sex,J=6.5Hz,1H),1.25(d,J=6.3Hz,6H)。
實例166係類似於實例158使用N-(3-氯-4-氟苯基)-2-(甲基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C14H13ClN6O,316.3/318.6(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.42(br.s,1H),8.97(s,1H),7.97(d,J=6.3Hz,1H),7.06(t,J=8.1Hz,1H),6.99-6.79(m,2H),6.62-6.43(m,1H),3.01(d,J=4.8Hz,3H)。
將1H-咪唑并[4,5-b]吡啶-7-甲酸(10g,61mmol,1當量)溶解於甲醇(160mL)中,添加H2SO4(10mL,189mmol,3.08當量),並將反應物於80℃下攪拌過夜。於0℃下藉由添加NaOMe於甲醇中之溶液(80mL,13wt%溶液,189mmol,3.08當量)將反應物小心地驟冷。隨後在真空中移除甲醇,將所得固體在水中製成漿液並過濾。將固體在真空烘箱(65℃)中乾燥過夜。獲得褐色固體狀1H-咪唑并[4,5-b]吡啶-7-甲酸甲基酯。C8H7N3O2,178.06(M+1)。
向1H-咪唑并[4,5-b]吡啶-7-甲酸甲基酯(7.8g,44mmol,1當量)於THF/DMF混合物(70mL,6:1比率)中之懸浮液中分三份添加NaH之60wt%分散液(2.1g,53mmol,1.2當量)。一旦氣體逸出停止,將反應混合物冷卻至0℃並添加SEM-Cl(9.3mL,53mmol,1.2當量)。隨後移除冰浴並將反應物於室溫下攪拌3小時,之後用飽和NH4Cl水溶液驟冷。將反應混合物用水稀釋並用EtOAc萃取三次。將合併之有機層經MgSO4乾燥,過濾並在真空中濃縮。藉由矽膠層析(0-5% MeOH/CH2Cl2,經20分鐘)純化粗產物。分離出黃色固體狀1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲酸甲基酯。C14H21N3O3Si.308.01(M+1)。
向1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲酸甲基酯(1.1g,4mmol,1當量)於乙腈(23.1mL)中之溶液中添加NCS(0.72g,5mmol,1.5當量)。將反應混合物於100℃下在密封容器中攪拌12小時。隨後在真空中移除乙腈並藉由矽膠層析(0-5% MeOH/CH2Cl2,經20分鐘)純化粗產物。獲得黃色固體狀2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲酸甲基酯。C14H20ClN3O3Si.341.94/343.93(M+1)。
上述化合物係類似於實例39使用N,N-二乙基乙烷-1,2-二胺代替N,N-二甲基丙烷-1,3-二胺及2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲酸甲基酯代替2-氯-4,5-二氟-1-((2-(三甲基矽
基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。獲得黃色油狀2-((2-(二乙基胺基)乙基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲酸甲基酯之TFA鹽。C20H35N5O3Si.422.23(M+1)。
上述化合物係類似於實例39使用2-((2-(二乙基胺基)乙基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-2-((2-(二乙基胺基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺之TFA鹽。C19H22ClFN6O.405.21/407.14(M+1)。
N-(3-氯-4-氟苯基)-2-((2-(二乙基胺基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒係類似於實例59使用N-(3-氯-4-氟苯基)-2-((2-(二乙基胺基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-2-((2-(二乙基胺基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C19H23ClFN7O.420.16/422.13(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.30(s,1H),8.93(s,1H),7.97(d,J=6.2Hz,1H),7.09(t,J=9.0Hz,1H),6.99(dd,J=6.5,2.7Hz,1H),6.94(d,J=6.0Hz,1H),6.56(ddd,J=9.0,4.0,2.7Hz,1H),3.75(m,2H),3.32(t,J=6.1Hz,2H),3.23(q,J=7.2Hz,4H),1.21(t,J
=7.2Hz,6H)。19F NMR(376MHz,DMSO-d 6)δ -74.40(9F),-126.69(1F)。
上述化合物係類似於實例39使用2-嗎啉基乙胺代替N,N-二甲基丙烷-1,3-二胺及2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲酸甲基酯代替2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。分離出黃色油狀2-((2-嗎啉基乙基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲酸甲基酯之TFA鹽。C20H33N5O4Si.436.21(M+1)。
上述化合物係類似於實例39使用2-((2-嗎啉基乙基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-2-((2-嗎啉基乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺之TFA鹽。C19H20ClFN6O2.419.22/421.14(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-2-((2-嗎啉基乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒係類似於實例59使用N-(3-氯-4-氟苯基)-2-((2-嗎啉基乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-N'-羥基-2-((2-嗎啉基乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C19H21ClFN7O2.434.16/436.14(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.31(br s,1H),10.11(br s,1H),8.94(s,1H),7.98(d,J=6.2Hz,1H),7.10(t,J=9.1Hz,1H),7.00(dd,J=6.6,2.7Hz,1H),6.94(d,J=6.1Hz,1H),6.57(ddd,J=9.0,4.0,2.8Hz,1H),3.87-3.71(m,8H),3.44-3.20(m,4H)。19F NMR(376MHz,DMSO-d 6)δ -74.51(9F),-126.65(1F)。
2-(二甲基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲酸甲基酯.向2,3-二胺基異菸酸甲基酯(0.2g,1mmol)溶解於DCM(5mL)中之溶液中添加二氯亞甲基二甲基氯化銨(phosgeniminium chloride)(0.39g,2mmol)及三乙胺(0.6g,6mmol)。將反應混合物於40℃下攪拌3h。隨後將反應物用NaHCO3溶液驟冷,用EtOAc稀釋,蒸發有機溶劑,用Combi-Flash管柱純化殘餘物,以得到期望產物。C10H12N4O2.221.1(M+1)。
N-(3-氯-4-氟苯基)-2-(二甲基胺基)-1H-苯并[d]咪唑-7-甲醯胺係類似於實例23使用2-(二甲基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲酸甲基
酯來製得。C16H14ClFN4O.334.2(M+1)。
N-(3-氯-4-氟苯基)-2-(二甲基胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例169係類似於實例107使用羥基脒形成之一般程序來製得。C15H14ClFN6O.349.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.36(d,J=9.1Hz,1H),10.09(s,1H),9.00(s,1H),7.94(d,J=6.3Hz,1H),7.12-6.98(m,2H),6.90(d,J=6.3Hz,1H),6.54(ddd,J=9.0,4.0,2.7Hz,1H),3.87(s,6H)。
2,3-二胺基-N-(4-氟-3-(三氟甲基)苯基)異菸鹼醯胺.向3-氟-4-三氟甲基-苯胺(0.1g,0.65mmol)、2,3-二胺基異菸鹼酸(0.234g,1mmol)及三乙胺(0.18mL,1mmol)於DMF(2mL)中之溶液中添加HATU(0.186g,0.78mmol)。將反應物於RT下攪拌16hr。添加飽和碳酸氫鈉並將水層用AcOEt洗滌三次。將合併之有機層經硫酸鈉乾燥,過濾並濃縮至矽膠上並藉由矽膠層析(己烷中之0->100%乙酸乙酯)純化,以產生黃色晶體狀期望產物。C13H10F4N4O.315.1(M+1)。
N-(4-氟-3-(三氟甲基)苯基)-2-(羥基甲基)-3H-咪唑并[4,5-b]吡啶-7-甲醯胺將2,3-二胺基-N-(4-氟-3-(三氟甲基)苯基)異菸鹼醯胺(0.078
g,0.25mmol)及2-羥基乙酸(0.378g,5mmol)在微波反應器中淨加熱至170℃並保持20min。添加二噁烷/水(0.6/2mL)中之LiOH(0.15g,6mmol)並攪拌30min。添加飽和碳酸氫鈉並將水層用AcOEt洗滌三次。將合併之有機層經硫酸鈉乾燥,過濾,以產生期望產物。C15H10F4N4O2.355.1(M+1)。
2-(氯甲基)-N-(4-氟-3-(三氟甲基)苯基)-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒.於RT下將N-(4-氟-3-(三氟甲基)苯基)-2-(羥基甲基)-3H-咪唑并[4,5-b]吡啶-7-甲醯胺(0.22g,0.62mmol)、POCl3(0.6ml,6mM)及PCL5(0.26g,0.1mM)在二噁烷(0.6ml)中攪拌30min。移除揮發物並添加過量乙腈中之NH2OH(2ml,1/10 50% NH2OH於水/乙腈中),於RT下攪拌10min。移除揮發物。藉由製備型HPLC(水中之5-100% MeCN,0.1% TFA)進行純化,以得到期望產物。C15H10ClF4N5O.386.1.08(M-1)。
於RT下將2-(氯甲基)-N-(4-氟-3-(三氟甲基)苯基)-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒(0.006g,0.17mM)、NaI(0.010g,0.67mM)及NaOAc(0.010g,1.7mM)在丙酮(3ml)中攪拌30min。在過濾後,移除揮發物。藉由製備型HPLC(水中之5-100% MeCN,0.1% TFA)進行純化,以得到期望產物。C15H11F4N5O2.準確質量:370.1(M+1)。
向2,3-二胺基-N-(3-氯-4-氟苯基)異菸鹼醯胺(200mg,0.713mmol)及2-羥基丙酸(1.0mL,13mmol)之懸浮液中充氬1min,隨後密封並於180℃下在微波反應器中攪拌1h。將所得混合物冷卻至室溫並用1M氫氧化鋰(20mL,20mmol)處理,隨後攪拌30min。過濾出所得沈澱並用水沖洗,以得到N-(3-氯-4-氟苯基)-2-(1-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺。C15H12ClFN4O2.335.1(M+1)。
N-(3-氯-4-氟苯基)-2-(1-((三異丙基矽基)氧基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例183使用N-(3-氯-4-氟苯基)-2-(1-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C24H32ClFN4O2Si.491.2(M+1)。
N-(3-氯-4-氟苯基)-2-(1-((三異丙基矽基)氧基)乙基)-1H-咪唑并[4,5-b]吡啶-7-硫代甲醯胺係類似於實例183使用N-(3-氯-4-氟苯基)-2-(1-((三異丙基矽基)氧基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-
(3-氯-4-氟苯基)-2-(2-((三異丙基矽基)氧基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C24H32ClFN4OSSi.507.2(M+1)。
將N-(3-氯-4-氟苯基)-2-(1-((三異丙基矽基)氧基)乙基)-1H-咪唑并[4,5-b]吡啶-7-硫代甲醯胺(30mg,0.059mmol)於甲醇(3mL)中之懸浮液用氯化氫(二噁烷中之4.0M溶液,0.12mL,0.46mmol)處理。將所得溶液於70℃下攪拌過夜,隨後冷卻至室溫,用另外量之氯化氫(二噁烷中之4.0M溶液,0.12mL,0.46mmol)處理,並於70℃下再攪拌7h。隨後將反應混合物冷卻至室溫並在減壓下濃縮。將所得殘餘物吸收於甲醇(2.4mL)中,用羥基胺(50%水溶液,0.370mL,6.0mmol)處理,並於70℃下在密封小瓶中攪拌2h。隨後將混合物冷卻至室溫,用二甲基亞碸稀釋,並藉由反相製備型HPLC純化,以提供N-(3-氯-4-氟苯基)-N'-羥基-2-(1-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒。C15H13ClFN5O2.350.1(M+1)。
向2,3-二胺基-N-(3-氯-4-氟苯基)異菸鹼醯胺(400mg,1.43mmol)及2-羥基-2-苯基乙酸(1.74g,11.4mmol)於二噁烷(3.5mL)中之懸浮液充氬1min,隨後密封並於180℃下在微波反應器中攪拌1h。將所得混合物冷卻至室溫並用1M氫氧化鋰(14.3mL,14.3mmol)處理,隨後攪拌30min。過濾出所得沈澱並用水沖洗,以得到N-(3-氯-4-氟苯基)-2-
(羥基(苯基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺。C20H14ClFN4O2.397.1(M+1)。
2-(((第三丁基二甲基矽基)氧基)(苯基)甲基)-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例183使用N-(3-氯-4-氟苯基)-2-(羥基(苯基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺及三氟甲烷磺酸第三丁基二甲基矽基酯代替N-(3-氯-4-氟苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺及三氟甲烷磺酸三異丙基矽基酯來製得。C26H28ClFN4O2Si.511.2(M+1)。
2-(((第三丁基二甲基矽基)氧基)(苯基)甲基)-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-硫代甲醯胺係類似於實例183使用2-(((第三丁基二甲基矽基)氧基)(苯基)甲基)-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(2-((三異丙基矽基)氧基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C26H28ClFN4OSSi.527.1(M+1)。
實例173係類似於實例172使用2-(((第三丁基二甲基矽基)氧基)(苯
基)甲基)-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-硫代甲醯胺代替N-(3-氯-4-氟苯基)-2-(1-((三異丙基矽基)氧基)乙基)-1H-咪唑并[4,5-b]吡啶-7-硫代甲醯胺來製得。C20H15ClFN5O2.413.0(M+1)。
N-(3-氯-4-氟苯基)-2-(環丙基(羥基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例173使用2-環丙基-2-羥基乙酸代替2-羥基-2-苯基乙酸來製得。C17H14ClFN4O2.361.1(M+1)。
2-(((第三丁基二甲基矽基)氧基)(環丙基)甲基)-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例183使用N-(3-氯-4-氟苯基)-2-(環丙基(羥基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺及三氟甲烷磺酸第三丁基二甲基矽基酯代替N-(3-氯-4-氟苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺及三氟甲烷磺酸三異丙基矽基酯來製得。C23H28ClFN4O2Si.475.2(M+1)。
2-(((第三丁基二甲基矽基)氧基)(環丙基)甲基)-N-(3-氯-4-氟苯
基)-1H-咪唑并[4,5-b]吡啶-7-硫代甲醯胺係類似於實例183使用2-(((第三丁基二甲基矽基)氧基)(環丙基)甲基)-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(2-((三異丙基矽基)氧基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C23H28ClFN4OSSi.491.2(M+1)。
實例175係類似於實例172使用2-(((第三丁基二甲基矽基)氧基)(環丙基)甲基)-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-硫代甲醯胺代替N-(3-氯-4-氟苯基)-2-(1-((三異丙基矽基)氧基)乙基)-1H-咪唑并[4,5-b]吡啶-7-硫代甲醯胺來製得。C17H15ClFN5O2.376.1(M+1)。
向2,3-二胺基-N-(3-氯-4-氟苯基)異菸鹼醯胺(400mg,1.43mmol)及2-羥基-2-甲基丙酸(1.19g,11.4mmol)於二噁烷(2mL)中之懸浮液充氬1min,隨後密封並於180℃下在微波反應器中攪拌1h。將所得混合物冷卻至室溫並用1M氫氧化鋰(14.3mL,14.3mmol)處理,隨後攪拌30min。隨後過濾混合物,並將所得濾液用2M鹽酸酸化,以產生沈澱。過濾出固體並用水洗滌,以提供N-(3-氯-4-氟苯基)-2-(2-羥基丙-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺。C16H14ClFN4O2.349.1(M+1)。
2-(2-((第三丁基二甲基矽基)氧基)丙-2-基)-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例183使用N-(3-氯-4-氟苯基)-2-(2-羥基丙-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺及三氟甲烷磺酸第三丁基二甲基矽基酯代替N-(3-氯-4-氟苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺及三氟甲烷磺酸三異丙基矽基酯來製得。C22H28ClFN4O2Si.463.2(M+1)。
2-(2-((第三丁基二甲基矽基)氧基)丙-2-基)-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-硫代甲醯胺係類似於實例183使用2-(2-((第三丁基二甲基矽基)氧基)丙-2-基)-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(2-((三異丙基矽基)氧基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C22H28ClFN4OSSi.479.1(M+1)。
實例175係類似於實例172使用2-(2-((第三丁基二甲基矽基)氧基)丙-2-基)-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-硫代甲醯胺代替N-(3-氯-4-氟苯基)-2-(1-((三異丙基矽基)氧基)乙基)-1H-咪唑并[4,5-b]
吡啶-7-硫代甲醯胺來製得。C16H15ClFN5O2.364.1(M+1)。
N-(3-氯-4-氟苯基)-2-(2,2,2-三氟-1-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例175使用3,3,3-三氟-2-羥基丙酸代替2-羥基-2-甲基丙酸來製得。C15H9ClF4N4O2.389.0(M+1)。
2-(1-((第三丁基二甲基矽基)氧基)-2,2,2-三氟乙基)-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例183使用N-(3-氯-4-氟苯基)-2-(2,2,2-三氟-1-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺及三氟甲烷磺酸第三丁基二甲基矽基酯代替N-(3-氯-4-氟苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺及三氟甲烷磺酸三異丙基矽基酯來製得。C21H23ClF4N4O2Si.503.1(M+1)。
2-(1-((第三丁基二甲基矽基)氧基)-2,2,2-三氟乙基)-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-硫代甲醯胺係類似於實例183使用2-(1-((第三丁基二甲基矽基)氧基)-2,2,2-三氟乙基)-N-(3-氯-4-氟苯基)-1H-
咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(2-((三異丙基矽基)氧基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C21H23ClF4N4OSSi.519.1(M+1)。
實例176係類似於實例172使用2-(1-((第三丁基二甲基矽基)氧基)-2,2,2-三氟乙基)-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-硫代甲醯胺代替N-(3-氯-4-氟苯基)-2-(1-((三異丙基矽基)氧基)乙基)-1H-咪唑并[4,5-b]吡啶-7-硫代甲醯胺來製得。C15H10ClF4N5O2.404.1(M+1)。
將4-(3-氯-4-氟苯基)-3-(2-(羥基甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮(20mg,0.055mmol)於四氫呋喃(0.75mL)中之溶液用水(0.75mL)、之後2M氫氧化鈉(0.75mL,1.5mmol)處理。將混合物攪拌20min,隨後用乙酸酸化並藉由反相製備型HPLC純化,以提供期望產物。C14H11ClFN5O2.336.1(M+1)。
實例178係類似於實例112使用甲胺(THF中之2.0M溶液)代替嗎啉
來製得。C15H14ClFN6O.349.1(M+1)。
將甲烷磺酸(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-2-基)甲基酯(10mg,0.019mmol)於乙腈(0.5mL)中之溶液用氨(二噁烷中之0.5M溶液,0.50mL,0.25mmol)處理並於室溫下攪拌過夜。隨後在減壓下濃縮混合物。將所得殘餘物吸收於四氫呋喃(0.50mL)中並用水(0.50mL)、之後2M氫氧化鈉(0.20mL,0.40mmol)處理。將所得混合物於室溫下攪拌5min,隨後用乙酸酸化並藉由反相製備型HPLC純化,以提供期望產物。C14H12ClFN6O.335.1(M+1)。
將甲烷磺酸(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-2-基)甲基酯(36mg,0.069mmol)於乙腈(2mL)中之溶液用氨(二噁烷中之0.5M溶液,1.9mL,0.97mmol)處理並於室溫下攪拌過夜。隨後在減壓下濃縮混合物。將所得殘餘物溶解於二氯甲烷(2mL)中並用吡啶(0.054mL,0.67mmol)處理並分成相等體積之兩批。隨後將該等批之一冷卻至0℃並
在攪拌下逐滴添加苯磺醯氯(二氯甲烷中之0.78M溶液,0.130mL,0.100mmol)。隨後使反應混合物升溫至室溫並攪拌10min,隨後冷卻至0℃並用水處理。隨後在減壓下部分濃縮混合物,隨後用四氫呋喃(1mL)、之後2M氫氧化鈉(1mL)處理並攪拌15min。隨後將混合物用乙酸酸化,在減壓下部分濃縮,用二甲基亞碸(1mL)稀釋,並藉由反相製備型HPLC純化,以提供期望產物。C20H16ClFN6O3S.475.1(M+1)。
實例181係類似於實例180使用甲磺醯氯代替苯磺醯氯來製得。C15H14ClFN6O3S.413.0(M+1)。
將甲烷磺酸(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-2-基)甲基酯(59mg,0.114mmol)於乙腈(3mL)中之溶液用氨(二噁烷中之0.5M溶液,1.9mL,0.97mmol)處理並於室溫下攪拌過夜。隨後將溶液分成相等體積之兩批。在減壓下濃縮該等批之一並將所得殘餘物吸收於DMSO(1mL)中。將溶液用N,N-二異丙基乙胺(0.061mL,0.35mmol)、之後2-氟嘧啶(23mg,0.23mmol)處理並於室溫下攪拌48h。隨後將混合物用水
(1mL)及2M氫氧化鈉(0.5mL)處理並攪拌15min,隨後用乙酸酸化,用二甲基亞碸稀釋,並藉由反相製備型HPLC純化,以提供期望產物。C18H14ClFN8O.413.1(M+1)。
2-(7-((3-氯-4-氟苯基)胺甲醯基)-1H-咪唑并[4,5-b]吡啶-2-基)乙酸乙基酯.將2,3-二胺基-N-(3-氯-4-氟苯基)異菸鹼醯胺(10.9g,38.8mmol)及3-乙氧基-3-亞胺基丙酸乙基酯鹽酸鹽(30.4g,155mmol)於乙醇(100mL)中之懸浮液於80℃下攪拌24h。隨後將混合物冷卻至室溫並添加另外一份3-乙氧基-3-亞胺基丙酸乙基酯鹽酸鹽(30.4g,155mmol)。將懸浮液於80℃下再攪拌24h。隨後將混合物冷卻至室溫並過濾出所得固體,用水沖洗,並在空氣流下乾燥,以得到期望產物。C17H14ClFN4O3.377.1(M+1)。
N-(3-氯-4-氟苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺.在氮之正壓下向2-(7-((3-氯-4-氟苯基)胺甲醯基)-1H-咪唑并[4,5-b]吡啶-2-基)乙酸乙基酯(5.55g,14.7mmol)於THF(210mL)中之攪拌懸浮液中分五個相等份添加硼氫化鋰(3.21g,147mmol)。隨後將所得混合物於40℃下攪拌1h。隨後將混合物冷卻至0℃並緩慢添加水(83mL),使得內部溫度保持低於15℃。攪拌30min後,緩慢添加1M鹽酸
(660mL),使得內部溫度保持低於20℃。隨後將混合物加熱至40℃並攪拌2h。將所得溶液冷卻至室溫並用乙酸乙酯(3×500mL)萃取。將合併之有機層經硫酸鈉乾燥,過濾,並在減壓下濃縮,以得到期望產物(2.46g)。水層含有黃色沈澱,將其過濾出,用水沖洗,並在空氣流下乾燥,以得到另外量之期望產物。C15H12ClFN4O2.335.1(M+1)。
N-(3-氯-4-氟苯基)-2-(2-((三異丙基矽基)氧基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺.在氮氣氛下向N-(3-氯-4-氟苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(2.46g,7.35mmol)於二氯甲烷(75mL)中之攪拌懸浮液中添加2,6-二甲基吡啶(10.2mL,88.2mmol)。隨後將混合物冷卻至0℃並在攪拌下逐滴添加三氟甲烷磺酸三異丙基矽基酯(11.9mL,44.1mmol)。隨後使混合物升溫至室溫並再攪拌90min。在劇烈攪拌下添加水,隨後分開有機層及水層並將有機層用水再洗滌四次。隨後將有機層吸附至矽膠上並藉由急速層析(0-100% EtOAc/己烷)純化。合併含有產物之部分並在減壓下濃縮,隨後與乙腈一起研磨,以得到期望產物。C24H32ClFN4O2Si.491.4(M+1)。
N-(3-氯-4-氟苯基)-2-(2-((三異丙基矽基)氧基)乙基)-1H-咪唑并[4,5-b]吡啶-7-硫代甲醯胺.將N-(3-氯-4-氟苯基)-2-(2-((三異丙基矽基)氧基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(2.27g,4.62mmol)及
2,4-雙(4-甲氧基苯基)-1,3,2,4-二硫二磷雜環丁烷2,4-二硫化物(3.74g,9.24mmol)於甲苯(92mL)中之懸浮液於95℃下攪拌4h。隨後將混合物冷卻至室溫並過濾,用二氯甲烷沖洗。將合併之濾液吸附至矽膠上並藉由急速層析(0-75% EtOAc/己烷)純化,以提供期望產物。C24H32ClFN4OSSi.507.2(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.將4-(3-氯-4-氟苯基)-3-(2-(2-((三異丙基矽基)氧基)乙基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮(40mg,0.079mmol)及氯化氫(二噁烷中之4.0M溶液,0.158mL,0.631mmol)於甲醇(4mL)中之溶液於70℃下在密封帶螺旋蓋燒瓶中攪拌過夜。隨後將混合物冷卻至室溫並在減壓下濃縮。將所得殘餘物吸收於甲醇(1.6mL)中之羥基胺(50%水溶液,0.259mL,3.991mmol)中,於70℃下在密封帶螺旋蓋燒瓶中攪拌1h。隨後將混合物冷卻至室溫。將混合物用乙酸(0.300mL,5.24mmol)酸化,用二甲基亞碸(4mL)稀釋,並藉由反相製備型HPLC純化,以提供期望產物。C15H13ClFN5O2.350.10(M+1)。
4-(3-氯-4-氟苯基)-3-(2-(2-((三異丙基矽基)氧基)乙基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮.將N-(3-氯-4-氟苯基)-2-(2-
((三異丙基矽基)氧基)乙基)-1H-咪唑并[4,5-b]吡啶-7-硫代甲醯胺(1.70g,3.33mmol)及羥基胺(50%水溶液,20.4mL,333mmol)於甲醇(135mL)中之懸浮液於70℃下在密封帶螺旋蓋燒瓶中攪拌1h。隨後將混合物冷卻至室溫並在減壓下部分濃縮,以得到白色水性懸浮液。過濾出固體並在減壓下乾燥,隨後吸收於乙酸乙酯(135mL)中並用1,1’-羰基二咪唑(702mg,4.33mmol)處理。將混合物於30℃下攪拌1h,隨後吸附至矽膠上並藉由急速層析(0-100% EtOAc/己烷)純化,以提供期望產物。C25H31ClFN5O3Si.532.2(M+1)。
甲烷磺酸2-(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-2-基)乙基酯.將4-(3-氯-4-氟苯基)-3-(2-(2-((三異丙基矽基)氧基)乙基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮(1.95g,3.67mmol)及氯化氫(二噁烷中之4.0M溶液,7.3mL,29mmol)於甲醇(180mL)中之溶液於70℃下在密封帶螺旋蓋燒瓶中攪拌過夜。隨後將混合物冷卻至室溫並在減壓下濃縮。將所得殘餘物吸收於二氯甲烷(75mL)中,用N,N-二異丙基乙胺(6.4mL,37mmol)處理,並在氮氣氛下冷卻至0℃。在攪拌下經5min逐滴添加甲磺醯氯(2.0mL,26mmol)。30min後,將混合物用水處理,分離各層,並將有機層用水再洗滌兩次。隨後在減壓下濃縮有機相並藉由急速層析(0-65% EtOAc/己烷)純化以提供期望產物(注意:假定咪唑環上之甲烷磺醯基之連接性係於如所指示之N(1)處,但並不嚴格排除於N(3)處之連接性)。C18H15ClFN5O7S2.532.1(M+1)。
將甲烷磺酸2-(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-3H-咪唑并[4,5-b]吡啶-2-基)乙基酯(20mg,0.038mmol)於乙腈(0.2mL)中之溶液用二甲胺(四氫呋喃中之2.0M溶液,0.38mL,0.75mmol)處理,並將所得溶液於室溫下攪拌1h。隨後在減壓下濃縮混合物。將所得殘餘物吸收於四氫呋喃(0.5mL)中,用水(0.5mL)、之後2M氫氧化鈉(0.23mL,0.46mmol)處理,並於室溫下攪拌15min。將混合物用乙酸(0.064mL,1.1mmol)酸化,用二甲基亞碸(3mL)稀釋,並藉由反相製備型HPLC純化,以提供期望產物。C17H18ClFN6O.377.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.11(s,1H),8.91(s,1H),8.31(d,J=5.1Hz,1H),7.15(d,J=5.1Hz,1H),7.05(t,J=9.1Hz,1H),6.93(dd,J=6.5,2.7Hz,1H),6.51(ddd,J=9.0,4.1,2.7Hz,1H),3.54(t,J=7.3Hz,2H),3.30(t,J=7.3Hz,2H),2.86(s,6H)。
實例185係類似於實例184使用二乙胺代替二甲胺來製得。C19H22ClFN6O.405.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.08(s,1H),8.91(s,1H),8.30(d,J=5.1Hz,1H),7.16(d,J=5.2Hz,1H),7.04(t,J=9.1Hz,1H),6.93(dd,J=6.5,2.7Hz,1H),6.50(ddd,J=9.0,4.1,2.7Hz,1H),3.52(t,J=7.5Hz,2H),3.28(t,J=7.5Hz,2H),
3.21(q,J=7.2Hz,4H),1.22(t,J=7.2Hz,6H)。
實例186係類似於實例184使用1-環丙基-N-甲基甲胺代替二甲胺來製得。C20H22ClFN6O.417.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.08(s,1H),8.90(s,1H),8.31(d,J=5.1Hz,1H),7.17(d,J=5.1Hz,1H),7.04(t,J=9.1Hz,1H),6.93(dd,J=6.5,2.7Hz,1H),6.51(ddd,J=9.0,4.1,2.7Hz,1H),3.59(br s,2H),3.33(t,J=7.4Hz,2H),3.10(d,J=7.3Hz,2H),2.88(s,3H),1.18-1.06(m,1H),0.70-0.62(m,2H),0.44-0.38(m,2H)。
將甲烷磺酸2-(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-3H-咪唑并[4,5-b]吡啶-2-基)乙基酯(30mg,0.056mmol)於乙腈(0.9mL)中之溶液用N,N-二異丙基乙胺(0.20mL,1.1mmol)、之後2,2-二氟-N-甲基乙胺鹽酸鹽(148mg,1.13mmol)處理。將所得溶液攪拌2h,隨後用二甲胺(四氫呋喃中之2.0M溶液,0.5mL,1.0mmol)處理。再攪拌1h後,將混合物用異丙胺(0.2mL,2.3mmol)處理並攪拌20min(以清除其餘咪唑基甲烷磺醯基)。隨後在
減壓下濃縮溶液並將所得殘餘物吸收於四氫呋喃(0.75mL)中。將溶液用水(0.75mL)、之後2M氫氧化鈉(0.38mL,0.76mmol)處理,並於室溫下攪拌20min。添加另外量之2M氫氧化鈉(0.75mL,1.5mmol),並重新開始攪拌15min。最後,將混合物用乙酸酸化,在減壓下部分蒸發,用二甲基亞碸稀釋,並藉由反相製備型HPLC純化,以提供期望產物。C18H18ClF3N6O.427.1(M+1)。
將甲烷磺酸2-(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-2-基)乙基酯(20mg,0.038mmol)及甲胺(四氫呋喃中之2.0M溶液,0.376mL,0.752mmol)於乙腈(1mL)中之溶液攪拌2hr。濃縮反應物。將殘餘物吸收於四氫呋喃(0.5mL)及水(0.5mL)中。向此溶液中添加2N氫氧化鈉(0.22mL,0.43mmol)並將反應混合物攪拌10min。向混合物中添加乙酸(0.035mL)並將溶液直接裝載至製備型HPLC上用於純化,以產生期望產物。C16H16ClFN6O.363.11(M+1)。
實例189係類似於實例188使用氨(二噁烷中之0.5M溶液)代替二甲胺(四氫呋喃中之2.0M溶液)來製得。C15H14ClFN6O.349.1(M+1)。
實例190係類似於實例188使用2-甲氧基乙胺代替二甲胺(四氫呋喃中之2.0M溶液)來製得。C18H20ClFN6O2.407.1(M+1)。
實例191係類似於實例188使用嗎啉代替二甲胺(四氫呋喃中之2.0M溶液)來製得。C19H20ClFN6O2.419.13(M+1)
實例192係類似於實例184使用六氫吡啶代替二甲胺來製得。C20H22ClFN6O.417.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.10(s,1H),8.90(s,1H),8.30(d,J=5.1Hz,1H),7.16(d,J=5.1Hz,1H),7.04(t,J=9.1Hz,1H),6.93(dd,J=6.5,2.7Hz,1H),6.52(ddd,J=9.0,4.1,2.8Hz,1H),3.69-2.76(m,8H),1.99-1.28(m,6H)。
實例193係類似於實例184使用吡咯啶代替二甲胺來製得。C19H2OClFN6O.403.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.10(s,1H),8.89(s,1H),8.31(d,J=5.1Hz,1H),7.16(d,J=5.1Hz,1H),7.04(t,J=9.1Hz,1H),6.94(dd,J=6.6,2.7Hz,1H),6.51(ddd,J=9.0,4.1,2.7Hz,1H),3.61(t,J=7.4Hz,2H),3.57-2.99(m,6H),1.96(br s,4H)。
實例194係類似於實例187使用2-甲氧基-N-甲基乙胺代替2,2-二氟-N-甲基乙胺鹽酸鹽及N,N-二異丙基乙胺來製得。C19H22ClFN6O2.421.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.09(s,1H),8.89(s,1H),8.30(d,J=5.1Hz,1H),7.15(d,J=5.1Hz,1H),7.04(t,J=9.1Hz,1H),6.93(dd,J=6.5,2.7Hz,1H),6.52(ddd,J=9.0,4.1,2.8Hz,1H),3.70(t,J=5.0Hz,2H),3.60(t,J=7.4Hz,2H),3.40(t,J=5.1Hz,2H),3.36-3.29(m,5H),2.86(s,3H)。
N-(3-氯-4-氟苯基)-2-(2,2-二甲基-1,3-二氧戊環-4-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺.將2,3-二胺基-N-(3-氯-4-氟苯基)異菸鹼醯胺(3.00g,10.7mmol)及2,2-二甲基-1,3-二氧戊環-4-甲醛(50重量%於二氯甲烷中,13.9g,53.4mmol)於二甲基亞碸(110mL)中之溶液在空氣氣氛下於100℃下劇烈攪拌過夜。將混合物冷卻至室溫,用水及鹽水溶液稀釋,並用二氯甲烷(700mL)萃取。隨後將有機層用水(500mL)洗滌三次,在減壓下濃縮,並吸附至矽膠上用於藉由急速層析(0-70% EtOAc/己烷)純化,以提供期望產物。C18H16ClFN4O3.391.1(M+1)。
N-(3-氯-4-氟苯基)-2-(1,2-二羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺.將N-(3-氯-4-氟苯基)-2-(2,2-二甲基-1,3-二氧戊環-4-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(300mg,0.768mmol)於甲醇(38mL)中之懸浮液用氯化氫(4.0M於二噁烷中,1.5mL,6.0mmol)處理並於70℃下攪拌過夜。在減壓下濃縮混合物,以提供期望產物。C15H12ClFN4O3.351.1(M+1)。
N-(3-氯-4-氟苯基)-2-(2,2,3,3,8,8,9,9-八甲基-4,7-二氧雜-3,8-二矽雜癸-5-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺.在攪拌下在氮氣氛下將N-(3-氯-4-氟苯基)-2-(1,2-二羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(727mg,2.07mmol)及2,6-二甲基吡啶(3.9mL,33mmol)於二氯甲烷(41mL)中之懸浮液冷卻至0℃。隨後將混合物逐滴並在攪拌下用三氟
甲烷磺酸第三丁基二甲基矽基酯(3.8mL,17mmol)處理。隨後使混合物升溫至室溫並攪拌20min,隨後吸附至矽膠上用於藉由急速層析(0-40% EtOAc/己烷)純化,以提供期望產物。C27H40ClFN4O3Si2.579.3(M+1)。
2-(1-((第三丁基二甲基矽基)氧基)-2-羥基乙基)-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺.將N-(3-氯-4-氟苯基)-2-(2,2,3,3,8,8,9,9-八甲基-4,7-二氧雜-3,8-二矽雜癸-5-基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(200mg,0.345mmol)於乙醇(7mL)中之懸浮液用對甲苯磺酸吡啶鎓鹽(781mg,3.11mmol)處理並於80℃下攪拌90min。隨後將混合物冷卻至室溫,用飽和碳酸氫鈉水溶液稀釋,並用乙酸乙酯萃取三次。將合併之有機層吸附至矽膠上用於藉由急速層析(20-55% EtOAc/己烷)純化,以提供期望產物。C21H26ClFN4O3Si.365.3(M+1)。
甲烷磺酸2-((第三丁基二甲基矽基)氧基)-2-(7-((3-氯-4-氟苯基)胺甲醯基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-2-基)乙基酯.在攪拌下在氮氣氛下將2-(1-((第三丁基二甲基矽基)氧基)-2-羥基乙基)-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(90mg,0.19mmol)及N,N-二異丙基乙胺(0.74mL,1.9mmol)於二氯甲烷(3.9mL)中之溶液冷卻至0℃。將混合物逐滴並在攪拌下用甲磺醯氯(0.075mL,0.97mmol)處理。5min後,將混合物用水稀釋,隨後用二氯甲烷萃取三
次。將合併之有機層裝載至矽膠柱上用於藉由急速層析(0-100% EtOAc/己烷)純化,以提供期望產物。C23H30ClFN4O7S2Si.621.2(M+1)。
2-(1-((第三丁基二甲基矽基)氧基)-2-(二甲基胺基)乙基)-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺.將甲烷磺酸2-((第三丁基二甲基矽基)氧基)-2-(7-((3-氯-4-氟苯基)胺甲醯基)-1-(甲基磺醯基)-3H-咪唑并[4,5-b]吡啶-2-基)乙基酯(90mg,0.145mmol)於乙腈(2.9mL)中之溶液用二甲胺(2.0M於四氫呋喃中,2.90mL,5.80mmol)處理並於60℃下攪拌3h。隨後添加另外二甲胺(2.0M於四氫呋喃中,1.0mL,2.0mmol)並於60℃下重新開始攪拌2h。隨後將混合物冷卻至室溫並在減壓下濃縮。藉由急速層析(0-30% MeOH/DCM)純化所得殘餘物,從而提供期望產物。C23H31ClFN5O2Si.492.3(M+1)。
2-(1-((第三丁基二甲基矽基)氧基)-2-(二甲基胺基)乙基)-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-硫代甲醯胺係類似於實例183使用2-(1-((第三丁基二甲基矽基)氧基)-2-(二甲基胺基)乙基)-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(2-((三異丙基矽基)氧基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C23H31ClFN5OSSi.508.2(M+1)。
N-(3-氯-4-氟苯基)-2-(2-(二甲基胺基)-1-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-硫代甲醯胺.於80℃下將2-(1-((第三丁基二甲基矽基)氧基)-2-(二甲基胺基)乙基)-N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-硫代甲醯胺(59mg,0.12mmol)及氯化氫(二噁烷中之4.0M溶液,0.226mL,0.906mmol)於甲醇(5.8mL)中之溶液攪拌24h。隨後將混合物冷卻至室溫,用二甲基亞碸稀釋,並藉由反相製備型HPLC純化,以提供期望產物。C17H17ClFN5OS.594.2(M+1)。
N-(3-氯-4-氟苯基)-2-(2-(二甲基胺基)-1-羥基乙基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.將N-(3-氯-4-氟苯基)-2-(2-(二甲基胺基)-1-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-硫代甲醯胺(5mg,0.013mmol)及羥基胺(50%水溶液,0.156mL,2.54mmol)於甲醇(1mL)中之溶液於70℃下攪拌10min。隨後將混合物用二甲基亞碸稀釋並藉由反相製備型HPLC純化,以提供期望產物。C17H18ClFN6O2.393.1(M+1)。
實例196係類似於實例112分別使用3-(2-(溴甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及2-甲基丙-1-胺代替甲烷磺酸(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二
唑-3-基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-2-基)甲基酯及嗎啉來合成。C18H20ClFN6O.391.1[M+1]+。
N,4-二甲基-3-硝基吡啶-2-胺.將4-甲基-3-硝基-2-氯吡啶(2.07g,12.0mmol)及甲胺(40%於水中,7.2mL,84mmol)於乙醇(14mL)中之溶液於80℃下攪拌1.5hr。濃縮反應物,以產生期望產物。C7H9N3O2.168.0(M+1)。
2-甲基胺基-3-胺基-4-甲基吡啶.於40psi氫下將N,4-二甲基-3-硝基吡啶-2-胺(2.01g,12.0mmol)及10%碳載鈀(128mg,0.12mmol)之混合物在帕爾振盪器中混合2hr。將反應混合物過濾並濃縮,以產生期望產物。C7H11N3.138.1(M+1)。
3,7-二甲基-3H-咪唑并[4,5-b]吡啶.將2-甲基胺基-3-胺基-4-甲基吡啶(830mg,6.05mmol)於原甲酸三甲基酯(20mL)中之溶液於100℃下攪拌3hr並濃縮。藉由矽膠層析純化殘餘物,以產生期望產物。C8H9N3.148.0(M+1)。
3-甲基-3H-咪唑并[4,5-b]吡啶-7-甲酸.於100℃下經兩天向3,7-二
甲基-3H-咪唑并[4,5-b]吡啶(726mg,4.93mmol)、碳酸鈉(523mg,4.93mmol)於水(30mL)中之溶液中逐份添加過錳酸鉀(7.8g,49.2mmol)。向起始材料中添加Na2CO3及水。加熱反應混合物直至沸騰,此產生均質溶液。分小份向沸騰溶液中添加KMnO4。將反應物再攪拌1小時。LCMS顯示低轉化率。於100℃下以小批料再添加KMnO4並保持接下來兩天。熱過濾反應混合物並將濾液用1N HCl酸化,濃縮並藉由prep HPLC純化,以產生期望產物。C8H7N3O2.178.0(M+1)。
N-(3-氯-4-氟苯基)-3-甲基-3H-咪唑并[4,5-b]吡啶-7-甲醯胺.將3-甲基-3H-咪唑并[4,5-b]吡啶-7-甲酸(100mg,0.564mmol)、羥基苯并三唑(173mg,1.13mmol)、1-乙基-3-(3-二甲基胺基丙基)碳二亞胺鹽酸鹽(216mg,1.13mmol)及二異丙基乙胺(0.690mL,3.95mmol)於二甲基甲醯胺(2mL)中之溶液攪拌18hr。向反應混合物中添加飽和碳酸氫鈉。所有一起攪拌過夜。添加飽和碳酸氫鈉水溶液並將所得固體過濾,與10%檸檬酸一起研磨,過濾,並在高真空上乾燥。C14H10ClFN4O.305.1(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-3-甲基-3H-咪唑并[4,5-b]吡啶-7-甲脒.實例197係類似於實例107使用N-(3-氯-4-氟苯基)-3-甲基-3H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-甲基-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C14H11ClFN5O.320.0(M+1)。
以下化合物係根據所述程序使用適當起始材料來製備。
實例204係類似於實例188使用乙胺(四氫呋喃中之2.0M溶液)代替二甲胺來製得。C17H18ClFN6O.377.1(M+1)。
實例205係類似於實例188使用異丙胺代替二甲胺來製得。C18H20ClFN6O.391.1(M+1)。
實例206係類似於實例188使用異丁基胺代替二甲胺來製得。C19H22ClFN6O.405.1(M+1)。
實例207係類似於實例188使用環丙胺代替二甲胺來製得。C18H18ClFN6O.389.1(M+1)。
實例208係類似於實例188使用環丙基甲胺代替二甲胺來製得。C19H20ClFN6O.403.1(M+1)。
實例209係類似於實例188使用4,5-二氫-1H-咪唑-2-胺代替二甲胺來製得。C18H18ClFN8O.417.1(M+1)。
實例210係類似於實例112使用2-(2-胺基乙基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒代替4-(3-氯-4-氟苯基)-3-(2-(羥基甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮來製得。C17H15ClF3N5O3S.462.3(M+1)。
2-(2-胺基乙基)-4,5-二氟-1H-苯并[d]咪唑-7-甲酸係類似於實例53使用3-胺基丙酸代替3-(二甲基胺基)丙酸來製得。C10H9F2N3O2.241.1(M+1)。
向2-(2-胺基乙基)-4,5-二氟-1H-苯并[d]咪唑-7-甲酸(2g,8.29mmol)於THF(30mL)及飽和碳酸氫鈉溶液30mL中之混合物中添加二碳酸二-第三丁基酯(7.24g,33mmol)。攪拌72h。用4N HCl酸化並使pH達到約1。將反應混合物用乙酸乙酯(50mL×3)萃取。將合併之有機層經硫酸鈉乾燥,過濾並濃縮。藉由矽膠層析純化殘餘物,以產生2-(2-((第三丁氧基羰基)胺基)乙基)-4,5-二氟-1H-苯并[d]咪唑-7-甲酸。C15H17F2N3O4.342.1(M+1)。
(2-(7-((3-氯-4-氟苯基)胺甲醯基)-4,5-二氟-1H-苯并[d]咪唑-2-基)乙基)胺基甲酸第三丁基酯係類似於實例53使用2-(2-((第三丁氧基羰基)胺基)乙基)-4,5-二氟-1H-苯并[d]咪唑-7-甲酸代替2-(2-(二甲基胺基)乙基)-6,7-二氟-1H苯并[d]咪唑-4-甲酸來製得。469.12(M+1)。C21H20ClF3N4O3.469.12(M+1)。
2-(2-胺基乙基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒係類似於實例53使用(2-(7-((3-氯-4-氟苯基)胺甲醯基)-4,5-二氟-1H-苯并[d]咪唑-2-基)乙基)胺基甲酸第三丁基酯代替N-(3-氯-4-氟苯基)-2-(2-(二甲基胺基)乙基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺來製得。C16H13ClF3N5O.384.2(M+1)。
向配備有攪拌棒之500mL圓底燒瓶中裝入2,3-二胺基-N-(3-氯-4-氟苯基)異菸鹼醯胺(34g,121.1mmol)及1,1’-羰基二咪唑(CDI)(29.5g,181.7mmol),之後裝入THF(300mL)。將反應混合物在室溫下攪拌16hr。在減壓下移除THF 150mL。隨後向反應混合物中緩慢添加水250mL。隨後將反應混合物攪拌1小時,且經由真空過濾分離出沈澱
並用水(100mL×3)洗滌。於40℃下將固體在真空烘箱中乾燥過夜,以得到淺紅色固體(34g,110.8mmol),且其未經進一步純化即用於下一步驟。C13H8ClFN4O2.307.2(M+1)。
將N-(3-氯-4-氟苯基)-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(5.0g,16.3mmol)溶解於POCl3(33eq.,538mmol,82.5mL)中並添加PCl5(3eq.,48.9mmol,10.19g)。將反應物在玻璃容器中密封並加熱至100℃並保持16小時。使反應物冷卻至室溫且隨後轉移至圓底燒瓶。在減壓下移除POCl3並殘餘物吸收於100mL對-二噁烷中。在單獨圓底燒瓶中,向200mL對-二噁烷中添加NH2OH(50%於水中,92.8eq,1.52mol,100mL)並在連續攪拌下在冰浴中冷卻至約3℃。向羥基胺混合物中極緩慢添加(經約45min,逐滴)粗製亞胺醯氯於對-二噁烷中之混合物,同時維持羥基胺/二噁烷溶液約3℃。一旦添加完成,使反應物緩慢到達室溫並攪拌20min。隨後將反應物用EtOAc(500mL)、飽和碳酸氫鈉溶液(300mL)及鹽水(150mL)稀釋並將其再攪拌20min。萃取反應物並將有機層用鹽水(200mL)洗滌一次,經Na2SO4乾燥,過濾,並濃縮至乾燥,以產生粗製2-氯-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,其未經進一步純化即用於下一步驟。C13H8Cl2FN5O.340.1(M+1)。
將前述步驟之粗製2-氯-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒(5.5g,16.31mmol,假定自N-(3-氯-4-氟苯基)-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-甲醯胺開始100%產率)溶解於乙酸乙酯(80mL,C=0.2M)中並添加1,1’-羰基二咪唑(CDI)(2eq,5.3g,32.6mmol)。將反應物於室溫下攪拌(加蓋但在空氣下)1小時直至
藉由LCMS觀察不到SM為止。隨後將反應物小心地用水(80mL,觀察到一些氣體逸出)稀釋並將反應物攪拌10min,之後傾倒至分液漏斗中(添加約15mL鹽水以幫助乳液破裂)並萃取有機層。將有機層再用水(約50mL與約10mL鹽水)萃取一次且隨後濃縮有機層。將粗製物熱裝載至矽膠上並藉由管柱層析(Rf 0.75,於100% EtOAc中,管柱運行40-100% EtOAc/hex)純化,以產生淺黃色固體狀3-(2-氯-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮。C14H6Cl2FN5O2.365.9(M+1)。
將3-(2-氯-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(804mg,2.2mmol)稱重至圓底燒瓶中,隨後將其排空並用氬吹掃兩次。經由注射器添加CH2Cl2(30.0mL,C=0.075M)並將反應物在冰浴中冷卻至0℃。添加休尼格鹼(2.5eq,5.49mmol,0.956mL),之後添加SEM-Cl(2.3eq,5.051mmol,0.894mL)(逐滴添加)。將反應物於0℃下攪拌20min直至藉由LCMS觀察不到起始材料為止。隨後在分液漏斗中將反應物傾倒至DI水(40mL)中且隨後振盪。移除有機層並在減壓下濃縮。將粗製物熱裝載至矽膠上並藉由管柱層析(20-80% EtOAc/hex,Rf=0.42,於40% EtOAc/hex中)純化,以產生淺黃色油狀3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮,其在靜置時固化。
將3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(0.015g,0.03mmol)溶解於DMSO(0.5ml)中,並向溶液中添加2-甲氧基乙胺(4.54mg,0.060mmol)。將反應混合物於60℃下加熱2h。將混合物冷卻至rt並分配在飽和碳酸氫鹽溶液(1mL)與EtOAc(2mL)之間並將水層用EtOAc(1mL)萃取1×。將合併之有機層用飽和碳酸氫鹽溶液(1mL)洗滌。隨後濃縮有機層並吸收於DCM(1.6mL)及三氟乙酸(0.4mL)中。將反應混合物攪拌1h並濃縮。將殘餘物吸收於四氫呋喃(0.5mL)中。向此溶液中添加2N氫氧化鈉溶液(0.22mL,0.44mmol)並將反應混合物攪拌30min。向混合物中添加乙酸(0.10mL)、DMSO(2mL)及水(2mL),將溶液直接裝載至製備型HPLC上用於純化,以產生期望產物。C16H16ClFN6O2.379.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.72(s,1H),11.43(s,1H),8.95(s,1H),7.97(d,J=6.3Hz,1H),7.11(t,J=9.0Hz,1H),7.04(dd,J=6.5,2.7Hz,1H),6.93(d,J=6.3Hz,1H),6.60(ddd,J=9.0,4.0,2.8Hz,1H),3.61(t,J=5.3Hz,2H),3.53(t,J=5.1Hz,2H),3.30(s,3H)。
實例213係類似於實例211使用2-(2-胺基乙基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒代替2-(2-胺基乙基)-4,5-二氟-1H-苯并[d]咪唑-7-甲酸來製得。C21H21ClF3N5O3.484.4(M+1)。
實例214係類似於實例212使用2-(4,4-二氟六氫吡啶-1-基)乙胺代替2-甲氧基乙胺來製得。C20H21ClF3N7O.468.88(M+1)。1H NMR(400MHz,DMSO-d6)δ 8.94(s,1H),7.96(d,J=5.8Hz,1H),7.09(t,J=9.0Hz,1H),6.98(s,1H),6.91(d,J=6.0Hz,1H),6.55(dt,J=8.9,3.5Hz,1H),3.33(m,8H),2.33-2.18(m,4H)。
實例215係類似於實例212使用N1,N1-二甲基乙烷-1,2-二胺代替2-甲氧基乙胺來製得。C17H19ClFN7O.392.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 8.93(s,1H),7.94(s,1H),7.08(t,J=9.1Hz,1H),6.96(s,1H),6.89(d,J=5.9Hz,1H),6.54(d,J=8.6Hz,1H),3.73(s,2H),3.31(s,2H),2.85(s,6H)。
實例216係類似於實例212使用(2-胺基乙基)(甲基)胺基甲酸第三丁基酯代替2-甲氧基乙胺來製得。C16H17ClFN7O.378.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 8.94(s,1H),8.57(s,2H),7.95(d,J=6.0
Hz,1H),7.09(t,J=9.0Hz,1H),6.97(s,1H),6.90(d,J=6.2Hz,1H),6.59-6.47(m,1H),3.67(s,2H),3.16(s,2H),2.61(s,3H)。
實例217係類似於實例212使用1-甲基氮雜環庚烷-3-胺代替2-甲氧基乙胺來製得。C20H23ClFN7O.432.2(M+1)。1H NMR(400MHz,DMSO-d 6)δ 8.92(s,1H),7.96(s,1H),7.09(t,J=9.0Hz,1H),6.97(s,1H),6.90(d,J=6.1Hz,1H),6.55(s,1H),4.25(s,1H),3.6-3.3(m,3H),3.18(s,2H),2.87(s,3H),2.13-1.41(m,6H)。
實例218係類似於實例212使用4-(2-胺基乙基)硫嗎啉1,1-二氧化物代替2-甲氧基乙胺來製得。C19H21ClFN7O3S.482.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.40(s,1H),8.97(s,1H),7.96(d,J=6.4Hz,1H),7.09(t,J=9.0Hz,1H),7.02(dd,J=6.5,2.7Hz,1H),6.91(d,J=6.2Hz,1H),6.61-6.52(m,1H),3.55(d,J=5.9Hz,2H),3.12(s,5H),3.06(s,5H),2.81(s,2H)。
實例219係類似於實例212使用N1-(2-甲氧基乙基)-N1-甲基乙烷-1,2-二胺代替2-甲氧基乙胺來製得。C19H23ClFN7O2.427.03(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.36(s,1H),8.96(s,1H),7.97(d,J=6.2Hz,1H),7.09(t,J=9.0Hz,1H),6.98(d,J=6.4Hz,1H),6.93(d,J=6.2Hz,1H),6.55(ddd,J=9.0,4.0,2.8Hz,1H),3.78(s,2H),3.64(t,J=5.0Hz,2H),3.37(s,4H),3.24(s,3H),2.86(s,3H)。
實例220係類似於實例212使用N 1-(2,2-二氟乙基)-N 1-甲基乙烷-1,2-二胺代替2-甲氧基乙胺來製得。C18H19ClF3N7O.442.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.40(s,1H),8.96(s,1H),7.96(d,J=6.3Hz,1H),7.09(t,J=9.0Hz,1H),7.01(dd,J=6.5,2.8Hz,1H),6.92(d,J=6.2Hz,1H),6.56(ddd,J=8.9,3.9,2.7Hz,1H),6.25(t,J=55.0Hz,1H),3.62(d,J=6.5Hz,2H),3.18(s,2H),2.97(s,2H),2.57(s,2H)。
實例221係類似於實例212使用3-嗎啉基丙-1-胺代替2-甲氧基乙胺
來製得。C20H23ClFN7O2.448.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.38(s,1H),8.96(s,1H),7.97(d,J=6.2Hz,1H),7.09(t,J=9.0Hz,1H),7.01(dd,J=6.5,2.7Hz,1H),6.92(d,J=6.2Hz,1H),6.60-6.52(m,1H),4.2-3.55(m,8H),3.49(d,J=6.5Hz,2H),3.15(t,J=8.0Hz,2H),1.98(d,J=8.0Hz,2H)。
實例222係類似於實例212使用2-(六氫吡啶-1-基)乙胺代替2-甲氧基乙胺來製得。C20H23ClFN7O.432.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 8.94(s,1H),7.96(d,J=6.2Hz,1H),7.09(t,J=9.1Hz,1H),6.98(d,J=6.3Hz,1H),6.91(d,J=6.0Hz,1H),6.60-6.51(m,1H),3.74(M,4H),3.28(d,J=7.0Hz,2H),1.73(s,5H),1.54(s,3H)。
實例223係類似於實例212使用2-(3-氟六氫吡啶-1-基)乙胺代替2-甲氧基乙胺來製得。C21H24ClFN6O.431.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.37(s,1H),8.94(s,1H),7.93(s,1H),7.08(t,J=9.0Hz,1H),7.02(m,1H),6.90(s,1H),6.56(d,J=9.0Hz,1H),1.68(m,6H),1.46(d,J=7.7Hz,2H),1.30(s,1H),1.16(m,3H),0.90m,3H)。
實例224係類似於實例212使用2-(四氫-2H-吡喃-4-基)乙胺代替2-甲氧基乙胺來製得。C20H22ClFN6O2.433.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.36(s,1H),8.95(s,1H),7.94(d,J=6.2Hz,1H),7.08(t,J=9.1Hz,1H),7.04-6.99(m,1H),6.90(d,J=6.1Hz,1H),6.60-6.51(m,1H),3.82(dd,J=11.0,4.2Hz,2H),3.26(d,J=12.0Hz,2H),1.62-1.43(m,7H),1.17(d,J=12.6Hz,2H)。
實例225係類似於實例212使用2,2-二氟乙胺代替2-甲氧基乙胺來製得。C15H12ClF3N6O.385.1(M+H)+。1H NMR(400MHz,DMSO-d6)δ 11.46(s,1H),8.98(s,1H),7.08(t,J=9.0Hz,1H),7.03(dd,J=6.5,2.7Hz,1H),6.93(d,J=6.3Hz,1H),6.62-6.52(m,1H),6.22(t,J=55.3Hz,1H),3.87(d,J=16.8Hz,2H)。
實例226係類似於實例212使用氧雜環丁-3-胺代替2-甲氧基乙胺來製得。C16H14ClFN6O2.377.1(M+1)。1H NMR(400MHz,DMSO-
d6)δ 8.88(s,1H),7.96(s,1H),7.06(t,J=9.1Hz,1H),7.01(d,J=5.4Hz,1H),6.96(d,J=6.5Hz,1H),6.54(ddd,J=9.0,4.1,2.8Hz,1H),4.57(s,1H),4.32(t,J=9.8Hz,1H),4.05(s,1H),3.58(s,2H)。
實例227係類似於實例212使用四氫呋喃-3-胺代替2-甲氧基乙胺來製得。C17H16ClFN6O2.391.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.40(s,1H),8.94(s,1H),8.50(s,1H),7.96(d,J=6.3Hz,1H),7.09(t,J=9.0Hz,1H),7.02(dd,J=6.5,2.7Hz,1H),6.92(d,J=6.3Hz,1H),6.57(ddd,J=8.9,4.0,2.8Hz,1H),4.44(q,J=5.8,3.7Hz,1H),3.93-3.78(m,2H),3.74(td,J=8.4,5.3Hz,1H),3.69(d,1H),2.30-2.18(m,1H),1.90(dd,J=14.8,7.7Hz,1H)。
實例228係類似於實例212使用四氫-2H-吡喃-4-胺代替2-甲氧基乙胺來製得。C18H18ClFN6O2.405.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.43(s,1H),8.97(s,1H),7.97(d,J=6.3Hz,1H),7.10(t,J=9.1Hz,1H),7.06(dd,J=6.7,2.9Hz,1H),6.94(d,J=6.3Hz,1H),6.58(dt,J=8.9,3.4Hz,1H),4.04-3.86(m,3H),3.41(td,J=11.7,2.1Hz,2H),1.87(d,J=12.5Hz,2H),1.70-1.48(m,2H)。
將3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(0.025g,0.047mmol)、3-胺基丙醯胺鹽酸鹽(0.023g,0.188mmol)及DIPEA(0.05mL,0.282mmol)於DMSO(0.5mL)中之混合物於60℃下攪拌16h。將混合物冷卻至rt,用水稀釋,並用EtOAc萃取3×。將合併之有機層用鹽水洗滌,乾燥(Na2SO4),過濾並濃縮。將所得殘餘物吸收於DCM(0.5mL)及TFA(0.5mL)中並攪拌16h。濃縮反應溶液。將所得殘餘物吸收於THF(0.5mL)及水(0.5mL)及氫氧化鈉(0.76mL 2N溶液,1.5mmol)中。將所得溶液攪拌10min,用AcOH(0.10mL,1.8mmol)酸化,並藉由製備型HPLC純化,以產生期望產物(0.009g)。C17H14ClF3N6O2.427.0(M+1)。
實例230係類似於實例229使用N1-(2,2-二氟乙基)乙烷-1,2-二胺鹽酸鹽代替3-胺基丙醯胺鹽酸鹽來製得。C17H17ClF3N7O.428.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.28(s,1H),8.91(s,1H),7.95(d,J=6.1Hz,1H),7.09(t,J=9.0Hz,1H),6.97(dd,J=6.6,2.7Hz,1H),6.90(d,J=6.1Hz,1H),6.56(ddd,J=9.0,4.0,2.7Hz,1H),
6.53-6.21(m,1H),3.8-3.3(m,5H)3.26(t,J=5.9Hz,2H)。
實例231係類似於實例212使用N 1-環丙基-N 1-甲基乙烷-1,2-二胺代替2-甲氧基乙胺來製得。C19H21ClFN7O.418.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.27(s,1H),8.92(s,1H),7.95(d,J=6.0Hz,1H),7.83(s,1H),7.08(t,J=9.1Hz,1H),6.97(d,J=6.4Hz,1H),6.91(d,J=6.0Hz,1H),6.55(ddd,J=9.0,4.0,2.8Hz,1H),3.76(s,3H),2.90(s,3H),1.02-0.66(m,5H)。
實例232係類似於實例212使用N 1-環丙基-N 1-(2-甲氧基乙基)乙烷-1,2-二胺代替2-甲氧基乙胺來製得。C21H25ClFN7O2.462.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.32(s,1H),8.93(s,1H),7.96(d,J=6.1Hz,1H),7.08(t,J=9.0Hz,1H),7.02-6.89(m,2H),6.56(ddd,J=8.9,4.0,2.7Hz,1H),3.76(s,4H),3.65(d,J=5.1Hz,1H),3.37(s,4H),3.26(s,3H),0.79(s,4H)。
實例233係類似於實例212使用22-(氮雜環丁-1-基)乙胺代替2-甲氧基乙胺來製得。C18H19ClFN7O.404.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.31(s,1H),9.92(s,1H),8.92(s,1H),7.96(d,J=6.1Hz,1H),7.08(t,J=9.0Hz,1H),6.98(dd,J=6.6,2.7Hz,1H),6.93(d,J=6.1Hz,1H),6.55(ddd,J=9.0,4.0,2.7Hz,1H),4.10(d,J=8.9Hz,4H),3.38(s,4H),2.32(d,J=6.7Hz,2H)。
實例234係類似於實例212使用3-甲氧基丙-1-胺代替2-甲氧基乙胺來製得。C17H18ClFN6O2.427.03(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.89(s,1H),11.39(s,1H),8.95(s,1H),7.96(d,J=6.2Hz,1H),7.10(t,J=9.0Hz,1H),7.04(dd,J=6.5,2.7Hz,1H),6.92(d,J=6.2Hz,1H),6.59(ddd,J=9.0,4.0,2.8Hz,1H),3.49(q,J=6.6Hz,2H),3.41(t,J=6.0Hz,2H),3.25(s,3H),1.83(p,J=6.5Hz,2H)。
實例235係類似於實例212使用1-(2-胺基乙基)吡咯啶-2-酮代替2-甲氧基乙胺來製得。C19H19ClFN7O2.432.2(M+1)。1H NMR(400
MHz,DMSO-d6)δ 11.99(s,1H),11.43(s,1H),8.97(s,1H),7.98(d,J=6.3Hz,1H),7.10(t,J=9.0Hz,1H),7.04(dd,J=6.5,2.8Hz,1H),6.96(d,J=6.3Hz,1H),6.58(ddd,J=8.9,4.0,2.8Hz,1H),3.59(q,J=6.0Hz,2H),3.41(dt,J=14.1,6.5Hz,4H),2.17(dd,J=8.7,7.5Hz,2H),2.01-1.73(m,2H)。
實例236係類似於實例212使用2-(嗎啉基磺醯基)乙胺代替2-甲氧基乙胺來製得。C19H21ClFN7O4S.498.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.45(s,1H),8.96(s,1H),7.97(d,J=6.4Hz,1H),7.09(t,J=9.0Hz,1H),7.02(dd,J=6.5,2.7Hz,1H),6.93(d,J=6.4Hz,1H),6.57(ddd,J=9.0,4.0,2.8Hz,1H),3.86(q,J=6.5Hz,2H),3.68-3.58(m,4H),3.43(t,J=6.7Hz,2H),3.21-3.09(m,4H)。
實例237係類似於實例212使用2-(3-氟六氫吡啶-1-基)乙胺TFA鹽代替2-甲氧基乙胺來製得。C20H22ClF2N7O.450.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.33(s,1H),8.95(s,1H),7.99(d,J=6.1Hz,1H),7.11(t,J=9.1Hz,1H),7.01(dd,J=6.5,2.8Hz,1H),6.94(d,J=
6.1Hz,1H),6.58(ddd,J=8.9,4.0,2.7Hz,1H),5.09(d,J=44.9Hz,1H),3.88-3.73(m,2H),3.43(s,2H),3.35(s,2H),3.11(s,2H),2.03-1.66(m,4H)。
實例238係類似於實例212分別使用4-(3-溴-4-氟苯基)-3-(2-氯-3-((2-(三甲基矽基)乙氧基)甲基)-3H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮及2-嗎啉基乙胺代替3-(2-氯-3-((2-(三甲基矽基)乙氧基)甲基)-3H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及2-甲氧基乙胺來製得。C19H21BrFN7O2.478.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.30(s,1H),8.92(s,1H),7.97(d,J=6.1Hz,1H),7.12(dd,J=6.1,2.7Hz,1H),7.05(t,J=8.7Hz,1H),6.92(d,J=6.1Hz,1H),6.58(ddd,J=8.9,4.1,2.7Hz,1H),3.80(m,6H),3.33(s,6H)。
實例239係類似於實例212使用N1-甲基-N1-(四氫-2H-吡喃-4-基)乙烷-1,2-二胺代替2-甲氧基乙胺來製得。C21H25ClFN7O2.462.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 8.91(s,1H),7.08(t,J=9.1Hz,1H),6.95(s,1H),6.90(d,J=6.0Hz,1H),6.54(dt,J=9.0,3.4Hz,
1H),3.94(d,J=11.8Hz,2H),3.31(d,J=12.1Hz,3H),2.82(s,3H),1.87(d,J=13.4Hz,2H),1.65(dd,J=12.0,4.6Hz,2H)。
實例240係類似於實例212使用N1-異丙基-N1-甲基乙烷-1,2-二胺代替2-甲氧基乙胺來製得。C19H23ClFN7O.420.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.28(s,1H),8.91(s,1H),7.95(d,J=5.9Hz,1H),7.84(s,1H),7.08(t,J=9.0Hz,1H),6.96(s,1H),6.90(d,J=6.0Hz,1H),6.54(dt,J=8.8,3.5Hz,1H),3.74(s,2H),3.69-3.59(m,1H),3.27(s,2H),2.76(s,3H),1.20(d,J=6.6Hz,6H)。
實例241係類似於實例212使用(1-(胺基甲基)環丙基)胺基甲酸第三丁基酯代替2-甲氧基乙胺來製得。C17H17ClFN7O.390.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.34(s,1H),8.92(s,1H),8.34(s,3H),7.95(d,J=6.1Hz,1H),7.09(t,J=9.0Hz,1H),6.98(dd,J=6.5,2.7Hz,1H),6.91(d,J=6.2Hz,1H),6.56(ddd,J=9.0,4.0,2.8Hz,1H),3.68(s,2H),0.92(d,J=5.5Hz,4H)。
實例242係類似於實例212使用(1-(2-胺基乙基)環丙基)胺基甲酸第三丁基酯代替2-甲氧基乙胺來製得。C18H19ClFN7O.404.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.33(s,1H),8.93(s,1H),8.20(s,3H),7.95(d,J=6.2Hz,1H),7.08(t,J=9.0Hz,1H),6.99(dd,J=6.5,2.7Hz,1H),6.93(d,J=6.1Hz,1H),6.61-6.50(m,1H),3.57(t,2H),1.89(t,J=7.0Hz,2H),0.81(d,J=6.9Hz,2H),0.69(d,J=5.9Hz,2H)。
(2-(2-氧雜-5-氮雜二環[4.1.0]庚-5-基)乙基)胺基甲酸第三丁基酯.將(2-溴乙基)胺基甲酸第三丁基酯(0.500g,3.688mmol)、2-氧雜-5-氮雜二環[4.1.0]庚烷鹽酸鹽(0.826g,3.688mmol)及DIPEA(1.285mL,7.375mmol)於DMSO(4mL)中之混合物於40℃下攪拌16h。將混合物用飽和NaHCO3溶液稀釋。將水層用EtOAc萃取3×。將合併之有機層用鹽水洗滌,乾燥(Na2SO4),過濾並濃縮。藉由矽膠層析純化殘餘物,以產生期望產物(0.440g)。C12H22N2O3.243.1(M+1)。
2-(2-氧雜-5-氮雜二環[4.1.0]庚-5-基)乙胺鹽酸鹽.向(2-(2-氧雜-5-氮雜二環[4.1.0]庚-5-基)乙基)胺基甲酸第三丁基酯(0.08g,0.33mmol)於THF中之溶液中添加HCl(2.0mL二噁烷中之4M溶液,8
mmol)。將混合物於rt下攪拌16h。濃縮混合物,以產生呈HCl鹽形式之期望產物(0.071g)。C7H16N2O.143.1(M+1)。
實例243係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及2-(2-氧雜-5-氮雜二環[4.1.0]庚-5-基)乙胺鹽酸鹽代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。C20H21ClFN7O2.446.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.35(s,1H),8.96(s,1H),7.96(d,J=6.2Hz,1H),7.09(t,J=9.0Hz,1H),7.00(dd,J=6.5,2.7Hz,1H),6.92(d,J=6.2Hz,1H),6.56(dt,J=9.0,3.4Hz,1H),3.80-3.63(m,4H),3.53(t,J=11.5Hz,2H),3.18(s,2H),2.96-2.60(m,2H),0.90(d,J=149.8Hz,2H)。
(2-(7-氧雜-4-氮雜螺[2.5]辛-4-基)乙基)胺基甲酸第三丁基酯係類似於實例243使用7-氧雜-4-氮雜螺[2.5]辛烷鹽酸鹽代替2-氧雜-5-氮雜二環[4.1.0]庚烷鹽酸鹽來製得。C14H16N2O2.245.1(M+1)。
2-(7-氧雜-4-氮雜螺[2.5]辛-4-基)乙胺鹽酸鹽係類似於實例243使
用(2-(7-氧雜-4-氮雜螺[2.5]辛-4-基)乙基)胺基甲酸第三丁基酯代替(2-(2-氧雜-5-氮雜二環[4.1.0]庚-5-基)乙基)胺基甲酸第三丁基酯來製得。C8H16N2O.157.1(M+1)。
實例244係類似於實例229使用2-(7-氧雜-4-氮雜螺[2.5]辛-4-基)乙胺代替3-胺基丙醯胺鹽酸鹽來製得。C21H23ClFN7O2.460.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.34(s,1H),8.96(s,1H),7.97(d,J=6.1Hz,1H),7.09(t,J=9.0Hz,1H),6.98(d,J=6.0Hz,1H),6.93(d,J=6.1Hz,1H),6.56(dt,J=8.8,3.7Hz,1H),4.2-3.00(m,10H),1.20-0.34(m,4H)。
(R)-(2-(3-氟吡咯啶-1-基)乙基)胺基甲酸第三丁基酯係類似於實例242使用(R)-3-氟吡咯啶鹽酸鹽代替2-氧雜-5-氮雜二環[4.1.0]庚烷鹽酸鹽來製得。C11H21FN2O2.233.2(M+1)。
(R)-2-(3-氟吡咯啶-1-基)乙胺鹽酸鹽係類似於實例242使用(R)-(2-(3-氟吡咯啶-1-基)乙基)胺基甲酸第三丁基酯代替(2-(2-氧雜-5-氮雜二環[4.1.0]庚-5-基)乙基)胺基甲酸第三丁基酯來製得。C6H13FN2.
133.1(M+1)。
實例245係類似於實例229使用(R)-2-(3-氟吡咯啶-1-基)乙胺鹽酸鹽代替3-胺基丙醯胺鹽酸鹽來製得。C19H20ClF2N7O.436.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.34(s,1H),8.95(s,1H),7.96(d,J=6.2Hz,1H),7.09(t,J=9.0Hz,1H),6.98(dd,J=6.3,2.7Hz,1H),6.92(d,J=6.1Hz,1H),6.55(ddd,J=8.9,4.0,2.7Hz,1H),5.48(d,J=53.2Hz,1H),3.90-3.35(m,8H),2.43-2.09(m,2H)。
(S)-(2-(3-氟吡咯啶-1-基)乙基)胺基甲酸第三丁基酯係類似於實例243使用(S)-3-氟吡咯啶鹽酸鹽代替2-氧雜-5-氮雜二環[4.1.0]庚烷鹽酸鹽來製得。C11H21FN2O2.233.2(M+1)。
(S)-2-(3-氟吡咯啶-1-基)乙胺鹽酸鹽係類似於實例242使用(S)-(2-(3-氟吡咯啶-1-基)乙基)胺基甲酸第三丁基酯代替(2-(2-氧雜-5-氮雜二環[4.1.0]庚-5-基)乙基)胺基甲酸第三丁基酯來製得。C6H13FN2.133.1(M+1)。
實例246係類似於實例229使用(S)-2-(3-氟吡咯啶-1-基)乙胺鹽酸鹽代替3-胺基丙醯胺鹽酸鹽來製得。C19H20ClF2N7O.436.2(M+1)1H NMR(400MHz,DMSO-d6)δ 11.35(s,1H),8.95(s,1H),7.97(d,J=6.2Hz,1H),7.09(t,J=9.0Hz,1H),6.99(dd,J=6.5,2.7Hz,1H),6.92(d,J=6.2Hz,1H),6.55(ddd,J=9.0,4.0,2.8Hz,1H),5.48(d,J=53.1Hz,1H),3.90-3.35(m,8H),2.44-2.11(m,2H)。
(2-(2-氮雜二環[4.1.0]庚-2-基)乙基)胺基甲酸第三丁基酯係類似於實例243使用(2-氮雜二環[4.1.0]庚烷代替2-氧雜-5-氮雜二環[4.1.0]庚烷鹽酸鹽來製得。C13H24N2O2.241.3(M+1)。
2-(2-氮雜二環[4.1.0]庚-2-基)乙胺鹽酸鹽係類似於實例243使用(2-(2-氮雜二環[4.1.0]庚-2-基)乙基)胺基甲酸第三丁基酯代替(2-(2-氧雜-5-氮雜二環[4.1.0]庚-5-基)乙基)胺基甲酸第三丁基酯來製得。C8H16N2.141.3(M+1)。
實例247係類似於實例229使用2-(2-氮雜二環[4.1.0]庚-2-基)乙胺鹽酸鹽代替3-胺基丙醯胺鹽酸鹽來製得。C21H23ClFN7O.444.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.36(s,1H),8.96(s,1H),8.08(s,1H),7.97(d,J=6.2Hz,1H),7.09(t,J=9.0Hz,1H),6.99(dd,J=6.5,2.7Hz,1H),6.93(d,J=6.2Hz,1H),6.55(ddd,J=9.0,4.1,2.8Hz,1H),3.90-3.30(m,5H),3.12(s,1H),3.01(s,1H),2.90(d,J=19.4Hz,1H),1.98(d,J=10.9Hz,1H),1.54(s,2H),1.43-1.28(m,1H),1.00-0.91(m,1H),0.91-0.81(m,1H)。
實例248係類似於實例243使用4-氮雜螺[2.5]辛烷鹽酸鹽代替2-氧雜-5-氮雜二環[4.1.0]庚烷鹽酸鹽來製得。C14H26N2O2.255.3(M+1)。
2-(4-氮雜螺[2.5]辛-4-基)乙胺鹽酸鹽係類似於實例243使用(2-(4-氮雜螺[2.5]辛-4-基)乙基)胺基甲酸第三丁基酯代替(2-(2-氧雜-5-氮雜二環[4.1.0]庚-5-基)乙基)胺基甲酸第三丁基酯來製得。C9H18N2.155.3(M+1)。
實例248係類似於實例229使用2-(4-氮雜螺[2.5]辛-4-基)乙胺鹽酸
鹽代替3-胺基丙醯胺鹽酸鹽來製得。C22H25ClFN7O.458.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.31(s,1H),8.95(s,1H),7.97(d,J=6.0Hz,1H),7.78(s,1H),7.08(t,J=9.0Hz,1H),6.96(s,1H),6.92(d,J=6.0Hz,1H),6.54(dt,J=9.0,3.5Hz,1H),3.8-3.3(m,8H),1.80(s,2H),1.65(s,2H),1.04(s,2H),0.76(s,2H)。
(2-(3-氟氮雜環丁-1-基)乙基)胺基甲酸第三丁基酯係類似於實例243使用3-氟氮雜環丁烷鹽酸鹽代替2-氧雜-5-氮雜二環[4.1.0]庚烷鹽酸鹽來製得。C10H26FN2O2.218.2(M+1)。
2-(3-氟氮雜環丁-1-基)乙胺鹽酸鹽係類似於實例243使用(2-(3-氟氮雜環丁-1-基)乙基)胺基甲酸第三丁基酯代替(2-(2-氧雜-5-氮雜二環[4.1.0]庚-5-基)乙基)胺基甲酸第三丁基酯來製得。C9H18N2.119.1(M+1)。
實例249係類似於實例229使用2-(3-氟氮雜環丁-1-基)乙胺鹽酸鹽代替3-胺基丙醯胺鹽酸鹽來製得。C18H18ClF2N7O.422.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.95(s,1H),11.34(s,1H),8.94(s,1H),
7.97(d,J=6.2Hz,1H),7.08(t,J=9.0Hz,1H),6.98(dd,J=6.4,2.7Hz,1H),6.92(d,J=6.2Hz,1H),6.55(ddd,J=9.0,4.1,2.7Hz,1H),5.45-5.30(m,1H),4.52(dd,J=20.6,12.4,5.9Hz,2H),4.33(dd,J=22.1,12.2Hz,2H),3.63(s,2H),3.48(s,2H)。
(2-(3,3-二氟氮雜環丁-1-基)乙基)胺基甲酸第三丁基酯係類似於實例243使用3,3-二氟氮雜環丁烷鹽酸鹽代替2-氧雜-5-氮雜二環[4.1.0]庚烷鹽酸鹽來製得。C10H18F2N2O2.237.2(M+1)。
2-(3,3-二氟氮雜環丁-1-基)乙胺鹽酸鹽係類似於實例243使用(2-(3,3-二氟氮雜環丁-1-基)乙基)胺基甲酸第三丁基酯代替(2-(2-氧雜-5-氮雜二環[4.1.0]庚-5-基)乙基)胺基甲酸第三丁基酯來製得。C5H10F2N2.137.1(M+1)。
實例250係類似於實例229使用2-(3,3-二氟氮雜環丁-1-基)乙胺鹽酸鹽代替3-胺基丙醯胺鹽酸鹽來製得。C18H17ClF3N7O.440.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.41(s,1H),8.96(s,1H),7.97(d,J=6.3Hz,1H),7.09(t,J=9.0Hz,1H),7.01(dd,J=6.5,2.7
Hz,1H),6.93(d,J=6.3Hz,1H),6.56(ddd,J=9.0,4.0,2.8Hz,1H),4.09(s,4H),3.54(s,2H),3.07(s,2H)。
(2-(4-氮雜螺[2.4]庚-4-基)乙基)胺基甲酸第三丁基酯係類似於實例244使用4-氮雜螺[2.4]庚烷鹽酸鹽代替2-氧雜-5-氮雜二環[4.1.0]庚烷鹽酸鹽來製得。C13H24N2O2.241.2(M+1)。
2-(4-氮雜螺[2.4]庚-4-基)乙胺鹽酸鹽係類似於實例243使用(2-(4-氮雜螺[2.4]庚-4-基)乙基)胺基甲酸第三丁基酯代替(2-(2-氧雜-5-氮雜二環[4.1.0]庚-5-基)乙基)胺基甲酸第三丁基酯來製得。C8H16N2.141.1(M+1)。
實例251係類似於實例229使用2-(4-氮雜螺[2.4]庚-4-基)乙胺鹽酸鹽代替3-胺基丙醯胺鹽酸鹽來製得。C21H23ClFN7O.444.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.33(s,1H),8.95(s,1H),7.97(d,J=6.1Hz,1H),7.08(t,J=9.0Hz,1H),6.98(d,J=6.4Hz,1H),6.93(d,J=6.1Hz,1H),6.55(ddd,J=8.9,4.0,2.7Hz,1H),3.65-3.75(m,4H),3.17(t,J=6.0Hz,2H),2.17-1.92(m,4H),1.22(t,2H),0.84(t,2H)。
(3-(3-氟六氫吡啶-1-基)丙基)胺基甲酸第三丁基酯係類似於實例243使用3-氟六氫吡啶鹽酸鹽代替2-氧雜-5-氮雜二環[4.1.0]庚烷鹽酸鹽來製得。C13H25FN2O2.261.2(M+1)。
3-(3-氟六氫吡啶-1-基)丙-1-胺鹽酸鹽係類似於實例243使用(3-(3-氟六氫吡啶-1-基)丙基)胺基甲酸第三丁基酯代替(2-(2-氧雜-5-氮雜二環[4.1.0]庚-5-基)乙基)胺基甲酸第三丁基酯來製得。C8H17FN2.161.1(M+1)。
實例252係類似於實例229使用3-(3-氟六氫吡啶-1-基)丙-1-胺鹽酸鹽代替3-胺基丙醯胺鹽酸鹽來製得。C21H24ClF2N7O.464.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 12.07(s,1H),11.38(s,1H),8.96(s,1H),8.22(d,J=58.7Hz,1H),7.97(d,J=6.2Hz,1H),7.09(t,J=9.0Hz,1H),7.01(dd,J=6.5,2.7Hz,1H),6.93(d,J=6.2Hz,1H),6.56(ddd,J=9.0,4.0,2.8Hz,1H),5.08(d,J=45.5Hz,1H),3.47(d,J=6.4Hz,1H),3.35(s,3H),3.12(q,J=7.4Hz,2H),3.02(s,2H),2.08-1.84(m,4H),1.75(d,J=14.5Hz,2H)。
實例253係類似於實例212使用N 1-苯基乙烷-1,2-二胺代替2-甲氧基乙胺來製得。C21H19ClFN7O.440.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.42(s,1H),8.96(s,1H),7.95(d,J=6.3Hz,1H),7.14-7.04(m,4H),7.02(dd,J=6.5,2.8Hz,1H),6.90(d,J=6.3Hz,1H),6.65-6.50(m,4H),3.62(d,J=6.0Hz,2H),3.28(t,J=6.3Hz,2H)。
實例254係類似於實例212使用N 1-甲基-N 1-苯基乙烷-1,2-二胺代替2-甲氧基乙胺來製得。C22H21ClFN7O.454.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.95(s,1H),11.42(s,1H),8.97(s,1H),7.95(d,J=6.4Hz,1H),7.19-7.12(m,2H),7.09(t,J=9.0Hz,1H),7.03(dd,J=6.5,2.7Hz,1H),6.92(d,J=6.3Hz,1H),6.75(d,J=8.1Hz,2H),6.61(tt,J=7.3,1.0Hz,1H),6.56(ddd,J=9.0,4.0,2.8Hz,1H),3.64(M,4H),2.89(s,3H)。
實例255係類似於實例212使用3-(胺基甲基)四氫-2H-噻喃1,1-二
氧化物代替2-甲氧基乙胺來製得。C19H20ClFN6O3S.467.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.41(s,1H),8.96(s,1H),7.95(d,J=6.3Hz,1H),7.09(t,J=9.0Hz,1H),7.03(dd,J=6.5,2.7Hz,1H),6.92(d,J=6.3Hz,1H),6.57(ddd,J=9.0,4.0,2.8Hz,1H),3.06(m,2H),3.00-2.87(m,1H),2.31(m,2H),2.06(dd,J=10.3,3.9Hz,2H),1.76(d,J=13.6Hz,2H),1.24(q,J=12.4Hz,2H)。
實例256係類似於實例212使用2-甲氧基環丙胺代替2-甲氧基乙胺來製得。C18H18ClFN6O2.405.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.34(s,1H),8.95(s,1H),7.98(d,J=6.3Hz,1H),7.07(t,J=9.1Hz,1H),7.02(d,J=5.5Hz,1H),6.94(d,J=6.2Hz,1H),6.55(ddd,J=8.9,4.0,2.8Hz,1H),3.67-3.51(m,2H),2.88(s,1H),1.13(t,J=7.0Hz,3H),1.11-1.04(m,2H),0.83(s,1H)。
實例257係類似於實例212分別使用4-(3-溴-4-氟苯基)-3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮及甲胺(四氫呋喃中之2.0M溶液)代替3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-
1,2,4-噁二唑-5(4H)-酮及2-甲氧基乙胺來製得。C14H12BrFN6O.379.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 12.12(s,1H),11.38(s,1H),8.95(s,1H),7.97(d,J=6.2Hz,1H),7.16(dd,J=6.1,2.7Hz,1H),7.04(t,J=8.8Hz,1H),6.92(d,J=6.2Hz,1H),6.58(ddd,J=8.9,4.1,2.7Hz,1H),3.00(d,J=4.7Hz,3H)。
實例258係類似於實例184使用六亞甲基亞胺代替二甲胺來製得。C21H24ClFN6O.431.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.09(s,1H),8.90(s,1H),8.30(d,J=5.1Hz,1H),7.16(d,J=5.1Hz,1H),7.04(t,J=9.1Hz,1H),6.93(dd,J=6.5,2.7Hz,1H),6.51(ddd,J=9.0,4.1,2.8Hz,1H),3.58(t,J=7.5Hz,2H),3.45-3.22(m,6H),1.90-1.74(m,4H),1.69-1.57(m,4H)。
實例259係類似於實例184使用氮雜環丁烷鹽酸鹽及N,N-二異丙基乙胺代替二甲胺來製得。C18H18ClFN6O.389.1(M+1)。
實例260係類似於實例184使用(R)-吡咯啶-3-醇代替二甲胺來製得。C19H20ClFN6O2.419.1(M+1)。
實例261係類似於實例184使用(S)-吡咯啶-3-醇鹽酸鹽及N,N-二異丙基乙胺代替二甲胺來製得。C19H20ClFN6O2.419.1(M+1)。
實例262係類似於實例184使用4-羥基六氫吡啶代替二甲胺來製得。C20H22ClFN6O2.433.1(M+1)。
2-(7-((3-溴-4-氟苯基)胺甲醯基)-1H-咪唑并[4,5-b]吡啶-2-基)乙酸
乙基酯係類似於實例183使用2,3-二胺基-N-(3-溴-4-氟苯基)異菸鹼醯胺代替2,3-二胺基-N-(3-氯-4-氟苯基)異菸鹼醯胺來製得。C17H14BrFN4O3.421.2,423.1(M+1)。
N-(3-溴-4-氟苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例184使用2-(7-((3-溴-4-氟苯基)胺甲醯基)-1H-咪唑并[4,5-b]吡啶-2-基)乙酸乙基酯代替2-(7-((3-氯-4-氟苯基)胺甲醯基)-1H-咪唑并[4,5-b]吡啶-2-基)乙酸乙基酯來製得。C15H12BrFN4O2.379.0,381.0(M+1)。
N-(3-溴-4-氟苯基)-2-(2-(二甲基胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例184使用N-(3-溴-4-氟苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C17H17BrFN5O.406.1,408.1(M+1)。
N-(3-溴-4-氟苯基)-2-(2-(二甲基胺基)乙基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例XX係類似於實例184使用N-(3-溴-4-氟苯基)-2-(2-(二甲基胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(2-(二甲基胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來
製得。C17H18BrFN6O.421.0,423.0(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.99(s,1H),8.86(s,1H),8.27(dd,J=5.0,0.5Hz,1H),7.13(d,J=5.1Hz,1H),7.07(dd,J=6.1,2.7Hz,1H),6.99(t,J=8.8Hz,1H),6.53(ddd,J=9.0,4.1,2.8Hz,1H),3.38-3.18(m,4H),2.69(s,6H)。
2-(7-((3-氯苯基)胺甲醯基)-1H-咪唑并[4,5-b]吡啶-2-基)乙酸乙基酯係類似於實例183使用2,3-二胺基-N-(3-氯苯基)異菸鹼醯胺代替2,3-二胺基-N-(3-氯-4-氟苯基)異菸鹼醯胺來製得。C17H15ClN4O3.359.3(M+1)。
N-(3-氯苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例184使用2-(7-((3-氯苯基)胺甲醯基)-1H-咪唑并[4,5-b]吡啶-2-基)乙酸乙基酯代替2-(7-((3-氯-4-氟苯基)胺甲醯基)-1H-咪唑并[4,5-b]吡啶-2-基)乙酸乙基酯來製得。C15H13ClN4O2.317.1(M+1)。
N-(3-氯苯基)-2-(2-(二甲基胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例184使用N-(3-氯苯基)-2-(2-羥基乙基)-1H-咪唑并
[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C17H18ClN5O.344.3(M+1)。
N-(3-氯苯基)-2-(2-(二甲基胺基)乙基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒係類似於實例184使用N-(3-氯苯基)-2-(2-(二甲基胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(2-(二甲基胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C17H19ClN6O.359.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 12.49(s,1H),11.10(s,1H),8.86(s,1H),8.22(d,J=5.2Hz,1H),7.08(d,J=5.0Hz,1H),6.97(t,J=8.0Hz,1H),6.83(t,J=2.1Hz,1H),6.77(dd,J=7.8,1.9Hz,1H),6.44(dd,J=8.1,2.1Hz,1H),2.93(t,J=7.3Hz,2H),2.61(t,J=7.3Hz,2H),2.16(s,6H)。
2-(7-((3-溴苯基)胺甲醯基)-1H-咪唑并[4,5-b]吡啶-2-基)乙酸乙基酯係類似於實例使用2,3-二胺基-N-(3-溴苯基)異菸鹼醯胺代替2,3-二胺基-N-(3-氯-4-氟苯基)異菸鹼醯胺製得。C17H15BrN4O3.403.3,405.2(M+1)。
N-(3-溴苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例184使用2-(7-((3-溴苯基)胺甲醯基)-1H-咪唑并[4,5-b]吡啶-2-基)乙酸乙基酯代替2-(7-((3-氯-4-氟苯基)胺甲醯基)-1H-咪唑并[4,5-b]吡啶-2-基)乙酸乙基酯來製得。C15H13BrN4O2.361.0,363.0(M+1)。
N-(3-溴苯基)-2-(2-(二甲基胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例184使用N-(3-溴苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C17H18BrN5O.388.2,390.2(M+1)。
N-(3-溴苯基)-2-(2-(二甲基胺基)乙基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.實例266係類似於實例184使用N-(3-溴苯基)-2-(2-(二甲基胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(2-(二甲基胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C17H19BrN6O.403.0,405.0(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.05(s,1H),8.85(s,1H),8.23(dd,J=5.1,0.5Hz,1H),7.09(d,J=5.1Hz,1H),7.00-6.97(m,1H),6.93-6.87(m,2H),6.50-6.45(m,1H),2.95(t,J=7.3Hz,2H),2.69-2.62(m,2H),2.19(s,6H)。
N-(2-(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-2-基)乙基)-N-(2,4-二甲氧基苄基)甲烷磺醯胺.在攪拌下將4-(3-氯-4-氟苯基)-3-(2-(2-((2,4-二甲氧基苄基)胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮(15mg,0.029mmol)及吡啶(0.046mL,0.57mmol)於二氯甲烷(1.0mL)中之溶液在冰浴中冷卻並用甲磺醯氯(0.022mL,0.29mmol)處理。隨後使反應混合物升溫至室溫。35min後,添加另一份甲磺醯氯(0.022mL,0.29mmol),15min後用吡啶(0.023mL,0.29mmol)進一步處理。另一15min後,反應似乎已停止(基於LCMS分析),其中添加試劑無效應,因此添加N,N-二異丙基乙胺(0.10mL,0.57mmol),從而在15min內完全轉化。將反應混合物在減壓下濃縮,並直接裝載至矽膠柱上用於藉由急速層析(0-20%甲醇/二氯甲烷)純化,以得到期望產物(20mg)。C27H26ClFN6O8S2.681.0(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-2-(2-(甲基磺醯胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.將N-(2-(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-1H-咪唑并[4,5-b]吡啶-2-基)乙基)-
N-(2,4-二甲氧基苄基)甲烷磺醯胺(20mg,0.029mmol)及三乙基矽烷(0.023mL,0.15mmol)於二氯甲烷(1mL)中之溶液用三氟乙酸(1mL)處理,並將反應混合物於室溫下攪拌過夜。隨後在減壓下濃縮混合物並吸收於四氫呋喃(0.75mL)及水(0.75mL)中,並用2M氫氧化鈉水溶液(0.75mL,1.5mmol)處理。於室溫下攪拌15min後,將反應混合物用乙酸酸化,用二甲基亞碸稀釋,並藉由反相製備型HPLC純化,以提供期望產物(7mg)。C16H16ClFN6O3S.427.0(M+1)。
將4-(3-氯-4-氟苯基)-3-(2-(2-((2,4-二甲氧基苄基)胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮(15mg,0.029mmol)及磺醯胺(27mg,0.29mmol)於吡啶(1mL)中之懸浮液於120℃下攪拌20min。隨後將混合物冷卻至室溫並在減壓下濃縮。將所得殘餘物懸浮於二氯甲烷(0.5mL)中並用三乙基矽烷(0.022mL,0.14mmol)、之後三氟乙酸(0.5mL)處理。於室溫下攪拌1h後,將反應混合物在減壓下濃縮並吸收於四氫呋喃(0.75mL)及水(0.75mL)中,並用2M氫氧化鈉水溶液(0.75mL,1.5mmol)處理。15min後,添加另一份2M氫氧化鈉(1mL,2mmol),且將反應物再攪拌15min。隨後將混合物用乙酸酸化,用二甲基亞碸稀釋,並藉由反相製備型HPLC純化,以提供期望產物(7mg)。C15H15ClFN7O3S.428.0(M+1)。
N-(3-氯苯基)-2-(2-(吡咯啶-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例184使用N-(3-氯苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺及吡咯啶代替二甲胺來製得。C19H20ClN5O.370.1(M+1)。
N-(3-氯苯基)-N'-羥基-2-(2-(吡咯啶-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒係類似於實例使用N-(3-氯苯基)-2-(2-(吡咯啶-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(2-(二甲基胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C19H21ClN6O.385.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.08(s,1H),8.90(s,1H),8.26(dd,J=5.1,0.6Hz,1H),7.11(d,J=5.0Hz,1H),6.98(t,J=8.0Hz,1H),6.84-6.76(m,2H),6.46(dd,J=8.1,2.1Hz,1H),3.50-2.84(m,8H),1.87(s,4H)。
N-(3-溴苯基)-2-(2-(吡咯啶-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例184使用N-(3-溴苯基)-2-(2-羥基乙基)-1H-咪唑并
[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺及使用吡咯啶代替二甲胺來製得。C19H20BrN5O.414.1,416.1(M+1)。
N-(3-溴苯基)-N’-羥基-2-(2-(吡咯啶-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.向N-(3-溴苯基)-2-(2-(吡咯啶-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(54mg,0.13mmol)於1,2-二氯乙烷(1.0mL)及磷醯氯(1.0mL)中之懸浮液中添加五氯化磷(33mg,0.16mmol)。將混合物於90℃下攪拌1h。隨後添加另一份五氯化磷(33mg,0.16mmol),並於90℃下重新開始再攪拌45min。隨後添加第三份五氯化磷(33mg,0.16mmol),並於90℃下重新開始再攪拌1h。隨後將反應混合物冷卻至室溫並在減壓下濃縮。在劇烈攪拌下將所得殘餘物用乙醇(1.0mL)中之羥基胺(50wt.%於水中,1.0mL,16mmol)處理。將混合物攪拌15min,隨後用飽和氯化鈉水溶液及二氯甲烷/異丙醇(2:1)稀釋。隨後分離各層且在減壓下濃縮有機相。將所得粗製殘餘物懸浮於二氯甲烷中之30%甲醇中,過濾以移除鹽,並直接裝載至矽膠柱上用於藉由急速層析(0-50%甲醇/二氯甲烷)純化。彙集含有產物之部分並在減壓下濃縮,隨後吸收於二氯甲烷中之5%甲醇中並經由矽藻土過濾以移除矽膠,其可自具有材料之管柱溶析。在減壓下濃縮濾液,與甲醇(3×)共蒸發以移除殘餘二氯甲烷,溶解於甲醇/水中,冷凍並凍乾,以得到灰白色固體狀產物(30mg)。C19H21BrN6O.429.1,431.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.07(s,1H),8.90(s,1H),8.27(d,J=5.1Hz,1H),7.15-7.09(m,1H),7.01-6.96(m,1H),6.95-6.88(m,2H),6.51-6.47(m,1H),3.71-2.85(m,8H),1.89(s,4H)。
將4-(3-氯-4-氟苯基)-3-(2-(2-((2,4-二甲氧基苄基)胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮(15mg,0.029mmol)及4-(二甲基胺基)吡啶(1片)於二氯甲烷(1mL)中之溶液用乙酸酐(0.027mL,0.29mmol)處理並於室溫下攪拌10min。隨後在減壓下濃縮反應混合物。將所得殘餘物溶解於二氯甲烷(0.5mL)中並用三乙基矽烷(0.022mL,0.14mmol)、之後三氟乙酸(0.5mL)處理。將反應溶液於室溫下攪拌過夜,隨後在減壓下濃縮,吸收於四氫呋喃(1mL)及水(1mL)中,並用2M氫氧化鈉水溶液(1mL,2mmol)處理。攪拌15min後,將混合物用乙酸酸化,用二甲基亞碸稀釋,並藉由反相製備型HPLC純化,以提供期望產物(9mg)。C17H16ClFN6O2.391.1(M+1)。
N-(3-氯苯基)-2-(2-(六氫吡啶-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例184使用N-(3-氯苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺及使用六氫吡啶代替二甲胺來製得。C20H22ClN5O.384.3(M+1)。
N-(3-氯苯基)-N'-羥基-2-(2-(六氫吡啶-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒係類似於實例184使用N-(3-氯苯基)-2-(2-(六氫吡啶-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(2-(二甲基胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C20H23ClN6O.399.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.08(s,1H),8.91(s,1H),8.27(dd,J=5.0,0.7Hz,1H),7.11(d,J=5.0Hz,1H),6.98(t,J=8.0Hz,1H),6.84-6.76(m,2H),6.46(dd,J=8.2,2.1Hz,1H),3.67-2.70(m,8H),1.73(s,4H),1.53(s,2H)。
N-(3-溴苯基)-2-(2-(六氫吡啶-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺係類似於實例184使用N-(3-溴苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺及使用六氫吡啶代替二甲胺來製得。C20H22BrN5O.428.3,430.3(M+1)。
N-(3-溴苯基)-N'-羥基-2-(2-(六氫吡啶-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒係類似於實例184使用N-(3-溴苯基)-2-(2-(六氫吡啶-1-
基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(2-(二甲基胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C20H23BrN6O.443.1,445.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.07(s,1H),8.90(s,1H),8.27(dd,J=5.1,0.8Hz,1H),7.12(d,J=4.5Hz,1H),6.98-6.96(m,1H),6.95-6.89(m,2H),6.52-6.47(m,1H),3.63-2.72(m,8H),1.88-1.35(m,6H)。
將4-(3-氯-4-氟苯基)-3-(2-(2-((2,4-二甲氧基苄基)胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮(30mg,0.057mmol)及N,N-二異丙基乙胺(0.20mL,1.2mmol)於二氯甲烷(1mL)中之溶液逐滴並在攪拌下用氯甲酸甲酯(0.044mL,0.57mmol)處理。1h後,添加另一份氯甲酸甲酯(0.044mL,0.57mmol),並將反應混合物再攪拌5min。在減壓下濃縮混合物。將所得殘餘物溶解於二氯甲烷(0.5mL)中並用三乙基矽烷(0.046mL,0.29mmol)、之後三氟乙酸(0.5mL)處理。將反應溶液於室溫下攪拌過夜,隨後在減壓下濃縮,吸收於四氫呋喃(0.75mL)及水(0.75mL)中,並用2M氫氧化鈉水溶液(1.5mL,3mmol)處理。攪拌5min後,將混合物用乙酸酸化,用二甲基亞碸稀釋,並藉由反相製備型HPLC純化,以提供期望產物。C17H16ClFN6O3.407.1(M+1)。
4-(3-氯-4-氟苯基)-3-(2-(2-((2,4-二甲氧基苄基)胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮.將甲烷磺酸2-(7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-1-(甲基磺醯基)-3H-咪唑并[4,5-b]吡啶-2-基)乙基酯(60mg,0.11mmol)於乙腈(2.2mL)中之溶液用2,4-二甲氧基苄基胺(0.34mL,2.2mmol)處理。將所得溶液於室溫下攪拌2.5h。隨後在減壓下濃縮反應混合物,並將所得殘餘物吸收於二氯甲烷(1mL)中並用三氟乙酸(1mL)處理。將溶液於室溫下攪拌過夜,隨後在減壓下濃縮。將粗物質溶解於二氯甲烷中並用飽和碳酸鉀水溶液洗滌。將水層用二氯甲烷萃取兩次,並將合併之有機層裝載至矽膠柱上用於藉由急速層析(0-20%甲醇/二氯甲烷)純化,以提供期望產物。C25H22ClFN6O4.525.2(M+1)。
N-(3-氯-4-氟苯基)-2-(2-((2,4-二甲氧基苄基)胺基)乙基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒係類似於實例177使用4-(3-氯-4-氟苯基)-3-(2-(2-((2,4-二甲氧基苄基)胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮代替4-(3-氯-4-氟苯基)-3-(2-(羥基甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮來製得。C24H24ClFN6O3.499.2(M+1)。
實例275係類似於實例184使用4-苄基六氫吡啶代替二甲胺來製得。C27H28ClFN6O.507.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.08(s,1H),8.91(s,1H),8.29(d,J=5.1Hz,1H),7.34-7.25(m,2H),7.24-7.12(m,4H),7.03(t,J=9.1Hz,1H),6.92(dd,J=6.4,2.7Hz,1H),6.55-6.46(m,1H),3.51(s,4H),3.29(t,J=7.4Hz,2H),2.96(s,2H),2.62-2.48(m,2H),1.78(d,J=14.5Hz,3H),1.41(s,2H)。
實例276係類似於實例184使用3-氮雜二環[3.3.1]壬烷鹽酸鹽及N,N-二異丙基乙胺代替二甲胺來製得。C23H26ClFN6O.457.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.07(s,1H),8.93(s,1H),8.32(dd,J=5.0,3.2Hz,1H),7.14(dd,J=5.0,3.0Hz,1H),7.05(td,J=9.1,3.0Hz,1H),6.93-6.88(m,1H),6.50(ddd,J=8.7,6.2,2.6Hz,1H),3.69(d,J=12.4Hz,2H),3.54-3.47(m,2H),3.41-3.34(m,2H),3.25(d,J=12.3Hz,2H),2.14(s,3H),1.89-1.57(m,7H)。
實例277係類似於實例184使用3-氮雜二環[3.2.1]辛烷鹽酸鹽及N,N-二異丙基乙胺代替二甲胺來製得。C22H24ClFN6O.443.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.07(s,1H),8.92(s,1H),8.31(d,J=5.1Hz,1H),7.15(d,J=5.1Hz,1H),7.05(t,J=9.0Hz,1H),6.92(dd,J=6.5,2.6Hz,1H),6.53-6.46(m,1H),3.50(t,J=6.9Hz,2H),3.42(d,J=11.7Hz,2H),3.30(t,J=7.2Hz,2H),3.08(d,J=11.6Hz,2H),2.40(s,2H),1.80(s,4H),1.70(d,J=11.2Hz,1H),1.49(d,J=10.0Hz,1H)。
實例278係類似於實例212使用1-甲基六氫吡啶-3-胺代替2-甲氧基乙胺來製得。C19H21ClFN7O.418.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.36(s,1H),9.79(s,1H),8.95(s,1H),7.98(d,J=5.1Hz,1H),7.10(t,J=9.1Hz,1H),7.05-6.90(m,2H),6.61-6.55(m,1H),4.18-4.01(m,1H),2.97-2.72(m,6H),2.11-1.62(m,4H),1.57-1.41(m,1H)。
將3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(25mg,0.050mmol)於DMSO(0.5mL)中之溶液用(S)-1-(2-胺基乙基)吡咯啶-3-醇(13mg,0.10mmol)處理。將溶液於60℃下攪拌過夜,隨後冷卻至室溫,用乙酸乙酯稀釋,並用飽和氯化鈉水溶液(3×)洗滌。將有機層經硫酸鈉乾燥,過濾並在減壓下濃縮。將所得殘餘物溶解於二氯甲烷(0.5mL)中並用三氟乙酸(0.5mL)處理。將溶液於室溫下攪拌1h,隨後在減壓下濃縮,吸收於四氫呋喃(0.5mL)及水(0.5mL)中並用2M氫氧化鈉水溶液(0.99mL,2.0mmol)處理。在攪拌10min後,將混合物用乙酸酸化,用二甲基亞碸稀釋,並藉由反相製備型HPLC純化,以提供(S)-N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(3-羥基吡咯啶-1-基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒(10mg)及(S)-N-(3-氯-4-氟苯基)-N'-羥基-2-(3-羥基吡咯啶-1-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒(4mg)。
(S)-N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(3-羥基吡咯啶-1-基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.C19H21ClFN7O2.434.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.40(s,1H),8.99(s,1H),7.99(d,J=6.2Hz,1H),7.15-7.07(m,1H),7.04-6.98(m,1H),6.98-6.93(m,1H),6.61-6.54(m,1H),4.45(s,1H),4.16-2.91(m,8H),2.14(s,1H),
1.94-1.82(m,1H)。
(S)-N-(3-氯-4-氟苯基)-N'-羥基-2-(3-羥基吡咯啶-1-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.C17H16ClFN6O2.391.1(M+1)。1H NMR(400MHz,DMSO-d 6)δ 11.38(s,1H),9.03(s,1H),8.02-7.94(m,1H),7.11-7.03(m,2H),6.91(d,J=6.0Hz,1H),6.60-6.53(m,1H),4.46(s,1H),3.79-3.50(m,4H),2.14-2.02(m,1H),1.98(s,1H)。
實例281係類似於實例212使用1-(2-甲氧基乙基)吡咯啶-3-胺代替2-甲氧基乙胺來製得。C20H23ClFN7O2.448.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.32(s,1H),9.98(s,1H),8.95(s,1H),7.99(d,J=4.3Hz,1H),7.09(t,J=9.1Hz,1H),7.04-6.92(d,J=17.3Hz,3H),6.57(ddd,J=8.3,5.8,2.4Hz,1H),4.70-4.49(m,2H),4.00-3.09(m,10H),2.08(s,1H),1.97(s,1H)。
實例282係類似於實例212使用(4-甲基嗎啉-3-基)甲胺代替2-甲氧基乙胺來製得。C19H21ClFN7O2.434.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.40(s,1H),8.97(s,1H),7.99(d,J=6.3Hz,1H),7.10(t,J=9.0Hz,1H),7.01(dd,J=6.6,2.6Hz,1H),6.96(d,J=6.2Hz,1H),6.57(ddd,J=9.0,4.0,2.7Hz,1H),4.12-3.75(m,6H),3.28-3.14(m,3H),3.01(s,3H)。
實例283係類似於實例212使用2-(吡咯啶-1-基)乙-1-胺代替2-甲氧基乙胺來製得。C19H21ClFN7O.418.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.35(s,1H),8.97(s,1H),7.98(d,J=6.2Hz,1H),7.10(t,J=9.0Hz,1H),7.03-6.98(m,1H),6.94(d,J=6.1Hz,1H),6.57(ddd,J=9.1,4.1,2.8Hz,1H),3.82-3.35(m,8H),1.94(s,4H)。
實例284係類似於實例333使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮、2H-吡喃-4-甲胺、四氫-4-[(甲基磺醯基)甲基]-鹽酸鹽及
N,N-二異丙基乙胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(2-胺基乙基)胺基甲酸第三丁基酯來製得(雙-TFA鹽,白色固體)。C21H24ClFN6O4S.511.4(M+1)。1H NMR(400MHz,DMSO-d 6 )δ 11.45(s,1H),8.96(s,1H),7.95(d,J=6.4Hz,1H),7.12(t,J=9.0Hz,1H),7.04(dd,J=6.5,2.7Hz,1H),6.92(d,J=6.4Hz,1H),6.60(ddd,J=8.9,4.0,2.8Hz,1H),3.85(d,J=6.6Hz,4H),3.81-3.45(m,4H),3.10(s,3H),1.77-1.65(m,2H),1.61(dd,J=8.5,4.6Hz,2H)。19F NMR(377MHz,DMSO-d 6 )δ -74.67(6F),-126.62(1F)。
實例285係類似於實例333使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮、(2-甲基磺醯基苯基)甲胺鹽酸鹽及N,N-二異丙基乙胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(2-胺基乙基)胺基甲酸第三丁基酯來製得(雙-TFA鹽,白色固體)。C21H18ClFN6O3S.489.4(M+1)。1H NMR(400MHz,DMSO-d 6 )δ 11.88(br s,1H),11.43(s,1H),8.95(s,1H),8.31(br s,1H),8.03-7.91(m,2H),7.75-7.67(m,1H),7.66-7.56(m,2H),7.09(t,J=9.0Hz,1H),7.03(d,J=6.3Hz,1H),6.93(d,J=6.3Hz,1H),6.59(dt,J=8.9,3.5Hz,1H),5.06(d,J=6.2Hz,2H),3.39(s,3H)。19F NMR(376MHz,DMSO-d 6 )δ -74.4(6F),
-126.6(1F)。
實例286係類似於實例333分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及1-(3-胺基六氫吡啶-1-基)乙酮代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(2-胺基乙基)胺基甲酸第三丁基酯來製得(雙-TFA鹽,灰白色固體)。C20H21ClFN7O2.446.4(M+1)。1H NMR(400MHz,DMSO-d 6 )δ 11.46(s,1H),8.98(s,1H),8.17(br s,1H),7.98(t,J=6.6Hz,1H),7.11(td,J=9.0,4.1Hz,1H),7.04(td,J=6.7,2.6Hz,1H),6.92(dd,J=8.6,6.3Hz,1H),6.66-6.51(m,1H),4.06-3.70(m,3H),3.30-3.20(m,3H),2.01(d,J=27.2Hz,3H),1.98-1.95(m,1H)1.80-1.60(m,2H),1.59-1.41(m,1H)。19F NMR(376MHz,DMSO-d 6 )δ -74.53(6F),-126.59(1F)。
4-氟-2-(甲氧基甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯係類似於實例45使用2,3-二胺基-4-氟苯甲酸甲基酯代替2,3-二胺基-4,5-二氟苯甲
酸甲基酯來製得。C11H11FN2O3.239.0(M+1)。
N-(3-氯-4-氟苯基)-4-氟-2-(甲氧基甲基)-1H-苯并[d]咪唑-7-甲醯胺係類似於實例45使用4-氟-2-(甲氧基甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替4,5-二氟-2-(甲氧基甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。C16H12ClF2N3O2.352.0(M+1)。
4-(3-氯-4-氟苯基)-3-(4-氟-2-(甲氧基甲基)-1H-苯并[d]咪唑-7-基)-1,2,4-噁二唑-5(4H)-酮係類似於實例45使用N-(3-氯-4-氟苯基)-4-氟-2-(甲氧基甲基)-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-4,5-二氟-2-(甲氧基甲基)-1H-苯并[d]咪唑-7-甲醯胺來製得。C17H11ClF2N4O3.393.0(M+1)。
3-(2-(溴甲基)-4-氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮係類似於實例45使用4-(3-氯-4-氟苯基)-3-(4-氟-2-(甲氧基甲基)-1H-苯并[d]咪唑-7-基)-1,2,4-噁二唑-5(4H)-酮代替4-(3-氯-4-氟苯基)-3-(4,5-二氟-2-(甲氧基甲基)-1H-苯并[d]咪唑-7-基)-1,2,4-噁二唑-5(4H)-酮來製得。C16H8BrClF2N4O2.440.9/442.9
(M+1)。
N-(3-氯-4-氟苯基)-2-((乙基胺基)甲基)-4-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒.實例287係類似於實例45分別使用3-(2-(溴甲基)-4-氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及乙胺(2M於THF中)代替3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-甲氧基丙胺來製得。C17H16ClF2N5O.360.1(M+1)。
實例288係類似於實例45分別使用3-(2-(溴甲基)-4-氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及二甲胺(2M於THF中)代替3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-甲氧基丙胺來製得。C17H16ClF2N5O.380.0(M+1)。
實例289係類似於實例45分別使用3-(2-(溴甲基)-4-氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及異丙胺代替3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-甲氧基丙胺來製得。C18H18ClF2N5O.394.1(M+1)。
實例290係類似於實例45分別使用3-(2-(溴甲基)-4-氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及甲胺(2M於THF中)代替3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-啶二唑-5(4H)-酮及3-甲氧基丙胺來製得。C16H14ClF2N5O.366.0(M+1)。
實例291係類似於實例45分別使用3-(2-(溴甲基)-4-氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及氨(0.5M於二噁烷中)代替3-(2-(溴甲基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-甲氧基丙胺來製得。C15H12ClF7N5O.352.0(M+1)。
實例292係類似於實例333使用1-胺基-2-甲基丙-2-醇代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C18H17ClF3N5O2.428.1(M+1)。
實例293係類似於實例333使用1-胺基丙-2-醇代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C17H15ClF3N5O2.414.1(M+1)。
實例294係類似於實例333使用2-胺基乙醯胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C16H12ClF3N6O2.413.3(M+1)。
實例295係類似於實例333使用2-胺基乙-1-醇代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C16H13ClF3N5O2.400.1(M+1)。
實例296係類似於實例333使用3-胺基環丁醇代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C18H15ClF3N5O2.426.3(M+1)。
實例297係類似於實例333使用N-(3-胺基丙基)吡啶-2-胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C22H19ClF3N7O.490.3(M+1)。
實例298係類似於實例333使用2-胺基乙烷磺醯胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C16H14ClF3N6O3S.463.1(M+1)。
實例299係類似於實例333使用(1-甲基-1H-吡唑-5-基)甲胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C19H15ClF3N7O.450.1(M+1)。
實例300係類似於實例333使用2-(1H-吡唑-1-基)乙-1-胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C19H15ClF3N7O.450.1(M+1)。
實例301係類似於實例333使用甘胺酸二甲基醯胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C18H16ClF3N6O2.441.1(M+1)。
4,5-二氟-2-(2-羥基-2-甲基丙基)-1H-苯并[d]咪唑-7-甲酸.將3-羥基-3-甲基丁酸(1.6mL,15.1mmol)及2,3-二胺基-4,5-二氟苯甲酸甲基酯(1.529g,7.56mmol)於HCl(7.5mL 6M水溶液)中之混合物於120℃下在密封管中攪拌16h。將混合物冷卻至rt並濃縮以移除HCl。將其餘溶液冷凍並凍乾,以產生粗製期望產物。C12H12F2N2O3.271.1(M+1)。
N-(3-氯-4-氟苯基)-4,5-二氟-2-(2-羥基-2-甲基丙基)-1H-苯并[d]咪唑-7-甲醯胺係類似於實例80分別使用4,5-二氟-2-(2-羥基-2-甲基丙基)-1H-苯并[d]咪唑-7-甲酸及3-氯-4-氟苯胺代替1H咪唑并[4,5-b]吡啶-7-甲酸及3-溴苯胺來製得。C18H15ClF3N3O2.420.1(M+23)。
2-(2-((第三丁基二甲基矽基)氧基)-2-甲基丙基)-N-(3-氯-4-氟苯基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺.於0℃下向N-(3-氯-4-氟苯基)-4,5-二氟-2-(2-羥基-2-甲基丙基)-1H-苯并[d]咪唑-7-甲醯胺(0.145g,0.365mmol)及2,6-二甲基吡啶(0.34mL,2.9mmol)於DCM(7mL)中之溶液中添加三氟甲烷磺酸第三丁基二甲基矽基酯(0.17mL,0.740mmol)。使混合物升溫至rt並攪拌48h。添加2,6-二甲基吡啶(0.34mL,2.9mmol)及三氟甲烷磺酸第三丁基二甲基矽基酯(0.34mL,1.48mmol)。4h後,添加2,6-二甲基吡啶(0.34mL,2.9mmol)及三氟甲烷磺酸第三丁基二甲基矽基酯(0.34mL,1.48mmol)並將混合物攪拌4h。將混合物濃縮至矽膠上並經由矽膠層析純化,以產生期望產物。C24H29ClF3N3O2Si.512.2(M+1)。
2-(2-((第三丁基二甲基矽基)氧基)-2-甲基丙基)-N-(3-氯-4-氟苯基)-4,5-二氟-1H-苯并[d]咪唑-7-硫代甲醯胺係類似於實例13使用2-(2-((第三丁基二甲基矽基)氧基)-2-甲基丙基)-N-(3-氯-4-氟苯基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺代替2-胺基-N-(3-氯-4-氟苯基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺來製得。C24H29ClF3N3OSSi.528.3(M+1)。
2-(2-((第三丁基二甲基矽基)氧基)-2-甲基丙基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒係類似於實例13使用2-(2-((第三丁基二甲基矽基)氧基)-2-甲基丙基)-N-(3-氯-4-氟苯基)-4,5-二氟-1H-苯并[d]咪唑-7-硫代甲醯胺代替2-胺基-N-(3-氯-4-氟苯基)-4,5-二氟-1H-苯并[d]咪唑-7-硫代甲醯胺來製得。C24H30ClF3N4O2Si.527.3(M+1)。
N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(2-羥基-2-甲基丙基)-1H-苯并[d]咪唑-7-甲脒.於0℃下向2-(2-((第三丁基二甲基矽基)氧基)-2-甲基丙基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒(0.007g,0.013mmol)於THF(1mL)中之溶液中添加HF.吡啶(0.02mL,0.664mmol)。使混合物升溫至rt並攪拌16h。添加HF.吡啶(0.04mL,1.32mmol)並將混合物再攪拌24h。將混合物用EtOAc稀釋並用飽和NaHCO3溶液洗滌。用EtOAc萃取水層。將合併之有機層用鹽水洗滌並濃縮。藉由矽膠層析純化殘餘物,以產生期望產物(0.001g)。C18H16ClF3N4O2.413.1(M+H)。
實例303係類似於實例333使用4-二甲基胺基丁-1-胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C20H22ClF3N6O.455.2(M+H)。
實例304係類似於實例333使用1-Boc-3-(胺基甲基)六氫吡啶代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C20H20ClF3N6O.453.2(M+H)。
2-((1-甲基六氫吡啶-2-基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲酸.將2,3-二胺基異菸鹼酸鹽酸鹽(200mg,0.106mmol)及2-(1-甲基六氫吡啶-2-基)乙酸(498mg,0.317mmol)於硫酸(1.5mL)中之懸浮液於室溫下攪拌5min,且隨後密封於小瓶中並於160℃下攪拌3小時。一旦混合物冷卻,添加水(2mL)並藉由製備型HPLC純化溶液,以產生期望產物。C14H18N4O2.275.1(M+1)。
N-(3-氯-4-氟苯基)-2-((1-甲基六氫吡啶-2-基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺.將2-((1-甲基六氫吡啶-2-基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲酸(75mg,0.273mmol)、4-氟-3-氯苯胺(60mg,0.410mmol)、雙(2-側氧基-3-噁唑啶基)次膦醯氯(139mg,0.547mmol)及N,N-二異丙基乙胺(0.240ml,1.37mmol)於二氯甲烷(1.5mL)中之溶液攪拌3小時。濃縮反應混合物並藉由製備型HPLC純化。將所得凍乾物質與飽和碳酸氫鈉水溶液(5mL)混合,過濾,用水洗並在高真空上乾燥,產生期望產物。C20H21ClFN5O.402.1(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-2-((1-甲基六氫吡啶-2-基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.向N-(3-氯-4-氟苯基)-2-((1-甲基六氫吡啶-2-基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(11mg,0.027mmol)及碳酸鉀(26mg,0.192mmol)於二氯甲烷(0.5ml)中之混合物中添加五氯化磷(11mg,0.055mmol)。將反應混合物攪拌2小時並濃縮。將殘餘物吸收於乙醇(0.5ml)及羥基胺(0.07mL,50%於水中,1.08mmol)中並攪拌1小時。濃縮反應混合物並藉由製備型HPLC純化,產生期望產物。C20H22ClFN6O.417.1(M+1)。
實例306係類似於實例333分別使用4-(3-溴苯基)-3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮及2-嗎啉基乙-1-胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(2-胺基乙基)胺基甲酸第三丁基酯來製得。C19H22BrN7O2.460.2/462.1(M+H)。1H NMR(400MHz,DMSO-d6)δ 11.35(s,1H),8.94(s,1H),7.98(d,J=6.1Hz,1H),7.09-6.95(m,3H),6.93(d,J=5.9Hz,1H),6.61-6.50(m,1H),3.95-3.20(m,12H)。
N-(3-氯-4-氟苯基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲醯胺.向N-(3-氯-4-氟苯基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺(1.92g,5.89mmol)及TEA(3.3mL,23.6mmol)於DCM(60mL)中之溶液中添加SEMCl(2.6mL,14.7mmol)。45min後,添加TEA(1.1mL,7.9mmol)及SEMC1(0.9mL,4.9mmol)。20min後,將混合物用EtOAc稀釋,濃縮至矽膠上,並經由矽膠層析純化,以產生期望產物。C20H21ClF3N3O2Si.456.2(M+1)。
N-(3-氯-4-氟苯基)-5-氟-4-甲氧基-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲醯胺.將N-(3-氯-4-氟苯基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲醯胺(0.250g,0.548mmol)及甲醇鈉(0.50mL 25% MeOH溶液,2.19mmol)於MeOH(1mL)中之混合物於65℃下攪拌8h。將混合物冷卻至rt並用飽和NH4Cl溶液稀釋。將水層用EtOAc萃取3×。將合併之有機層用鹽水洗滌,乾燥(Na2SO4),過濾並濃縮,以產生期望產物。C21H24ClF2N3O3Si.468.3(M+1)。
N-(3-氯-4-氟苯基)-5-氟-N'-羥基-4-甲氧基-1H-苯并[d]咪唑-7-甲脒係類似於實例305使用N-(3-氯-4-氟苯基)-5-氟-4-甲氧基-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-((1-甲基六氫吡啶-2-基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。C15H11ClF2N4O2.353.1(M+H)。
實例308係類似於實例333分別使用3-(2-氯-1-((2-(三甲基矽基)乙
氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及2-甲基吡啶胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(2-胺基乙基)胺基甲酸第三丁基酯來製得。C19H15ClFN7O.412.2(M+H)。1H NMR(400MHz,DMSO-d6)δ 11.48(s,1H),8.99(s,1H),8.59(ddd,J=4.9,1.8,0.9Hz,1H),7.98(d,J=6.4Hz,1H),7.84(td,J=7.7,1.8Hz,1H),7.42(d,J=7.9Hz,1H),7.36(ddd,J=7.4,5.0,1.1Hz,1H),7.11(t,J=9.0Hz,1H),7.05(dd,J=6.5,2.7Hz,1H),6.95(d,J=6.3Hz,1H),6.60(ddd,J=9.0,3.9,3.0Hz,1H),4.80(d,J=5.7Hz,2H)。
實例309係類似於實例333分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及2-(1H-吡唑-1-基)乙-1-胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(2-胺基乙基)胺基甲酸第三丁基酯來製得。C18H16ClFN8O.415.2(M+H)。
實例310係類似於實例333分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(1-甲基-1H-吡唑-3-基)甲胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(2-胺基乙基)胺基甲酸第三丁基酯來製得。C18H16ClFN8O.415.2(M+H)。
實例311係類似於實例333分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及4,4,4-三氟丁基胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(2-胺基乙基)胺基甲酸第三丁基酯來製得。C17H15ClF4N6O.431.1(M+H)。
實例312係類似於實例333分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3,3,3-三氟丙胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(2-胺基乙基)胺基甲酸第三丁基酯來製得。C16H13ClF4N6O.417.1(M+H)。1H NMR(400MHz,DMSO-d6)δ 11.42(s,1H),8.98(s,1H),7.97(d,J=6.2Hz,1H),7.10(t,J=9.0Hz,1H),7.03(dd,J=6.3,2.4Hz,1H),6.94(d,J=6.3Hz,1H),6.58(ddd,J=9.0,4.0,3.0Hz,1H),3.78-3.63(m,2H),2.76-2.56(m,2H)。
實例313係類似於實例333分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及2-(2-甲氧基乙氧基)乙胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(2-胺基乙基)胺基甲酸第三丁基酯來製得。C18H20ClFN6O3.423.2(M+H)。
2-(3-(環丙基(甲基)胺基)丙基)異吲哚啉-1,3-二酮.將2-(3-溴丙
基)異吲哚啉-1,3-二酮(1.89g,7.03mmol)、環丙基甲胺(0.59mL,7.03mmol)及碳酸鉀(1.94g,14mmol)於二甲基甲醯胺(7mL)中之溶液於40℃下攪拌6hr。添加水並將水層用二乙醚洗滌三次。將合併之有機層用鹽水洗滌並經硫酸鎂乾燥,過濾並濃縮。藉由矽膠層析純化殘餘物以產生期望產物(1.8g)。C15H18N2O2.259.2(M+1)。
N-(3-氯-4-氟苯基)-2-((3-(環丙基(甲基)胺基)丙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒.將2-(3-(環丙基(甲基)胺基)丙基)異吲哚啉-1,3-二酮(63mg,0.24mmol)及肼(0.006mL,0.2mmol)於乙醇(1mL)中之溶液於80℃下攪拌1小時。將反應物冷卻至室溫,過濾並濃縮。向所得殘餘物中添加3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(24mg,0.024mmol)及二甲亞碸(0.25mL)。將所得溶液於65℃下攪拌1小時。將反應混合物冷卻並用乙酸乙酯稀釋並用飽和氯化鈉水溶液洗滌三次。將有機層經硫酸鈉乾燥,過濾並濃縮。將所得殘餘物吸收於二氯甲烷(0.5mL)及三氟乙酸(0.5mL)中並攪拌3小時。濃縮反應溶液。將所得殘餘物吸收於四氫呋喃(0.2mL)及甲醇(0.2mL)中並向此溶液中添加2N氫氧化鈉(0.24mL,0.48mmol)。將所得溶液攪拌30min並濃縮並藉由製備型HPLC純化,以產生期望產物(9mg)。C20H23ClFN7O.432.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.34(s,1H),8.95(s,1H),7.96(d,J=6.2Hz,1H),7.09(t,J=9.0Hz,1H),7.00(d,J=5.6Hz,1H),6.92(d,J=6.1Hz,1H),6.61-6.53(m,1H),3.54-3.42(m,2H),3.30-3.19(m,3H),2.92-2.77(m,5H),2.05-1.92
(m,3H),0.96-0.78(m,6H)。
2-(3-(環丙基胺基)丙基)異吲哚啉-1,3-二酮係類似於實例314使用環丙胺代替環丙基甲胺來製得。C14H16N2O2.245.1(M+1)。
N-(3-氯-4-氟苯基)-2-((3-(環丙基胺基)丙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒係類似於實例314使用2-(3-(環丙基胺基)丙基)異吲哚啉-1,3-二酮代替2-(3-(環丙基(甲基)胺基)丙基)異吲哚啉-1,3-二酮來製得。C19H21ClFN7O.418.2(M+H)。
2-(3-(環丙基(乙基)胺基)丙基)異吲哚啉-1,3-二酮係類似於實例314使用N-乙基環丙胺代替環丙基甲胺來製得。C16H20N2O2.273.2(M+1)。
N-(3-氯-4-氟苯基)-2-((3-(環丙基(乙基)胺基)丙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒係類似於實例314使用2-(3-(環丙基(乙基)胺基)丙基)異吲哚啉-1,3-二酮代替2-(3-(環丙基(甲基)胺基)丙基)異吲哚啉-1,3-二酮來製得。C21H25ClFN7O.446.2(M+H)。1H NMR(400MHz,DMSO-d6)δ 11.33(s,1H),8.96(s,1H),7.97(d,J=6.1Hz,1H),7.10(t,J=9.0Hz,1H),7.05-6.98(m,1H),6.97-6.89(m,1H),6.58(dt,J=8.9,3.5Hz,1H),3.51(s,2H),3.35-3.18(m,4H),2.94-2.73(m,1H),2.15-1.92(m,2H),1.26(t,J=7.3Hz,3H),1.02-0.78(m,4H)。
實例317係類似於實例333分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及2-(4-氟六氫吡啶-1-基)乙-1-胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(2-胺基乙基)胺基甲酸第三丁基酯來製得。C20H22ClF2N7O.450.2(M+H)。1H NMR(400MHz,DMSO-d6)δ 11.30(s,1H),8.94(s,1H),7.98(d,J=5.6Hz,1H),7.10(t,J=9.1Hz,1H),6.99(d,J=5.7Hz,1H),6.96-6.85(m,1H),6.64-6.45(m,1H),5.10-4.80(m,1H),3.86-3.70(m,2H),3.50-3.20(m,6H),2.23-1.93(m,4H)。
實例318係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及2-(2,2,2-三氟乙氧基)乙-1-胺鹽酸鹽代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。C17H15ClF4N6O2.447.1(M+H)。
實例319係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-(2,2,2-三氟乙氧基)丙-1-胺鹽酸鹽代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。C18H17ClF4N6O2.461.2(M+H)。1H NMR(400MHz,DMSO-d6)δ 11.36(s,1H),8.94(s,1H),7.94(d,J=6.2Hz,1H),7.08(t,J=9.0Hz,1H),7.01(dd,J=6.5,2.3Hz,1H),6.89(d,J=6.3Hz,1H),6.56(ddd,J
=8.9,3.9,2.8Hz,2H),4.04(q,J=9.5Hz,2H),3.65(t,J=6.1Hz,2H),3.52-3.42(m,2H),1.85(p,J=6.9Hz,2H)。
(2-(3-甲氧基六氫吡啶-1-基)乙基)胺基甲酸第三丁基酯.將(2-溴乙基)胺基甲酸第三丁基酯(0.147g,0.656mmol)、3-甲氧基六氫吡啶鹽酸鹽(0.099g,0.656mmol)及DIPEA(0.25mL,1.44mmol)於DMSO(1.5mL)中之混合物於40℃下攪拌16h。將混合物用飽和NaHCO3溶液稀釋。將水層用EtOAc萃取3×。將合併之有機層用鹽水洗滌,乾燥(Na2SO4),過濾並濃縮。藉由矽膠層析純化殘餘物,以產生期望產物(0.047g)。C13H26N2O3.259.2(M+1)。
2-(3-甲氧基六氫吡啶-1-基)乙-1-胺.向(2-(3-甲氧基六氫吡啶-1-基)乙基)胺基甲酸第三丁基酯(0.047g,0.182mmol)於THF中之溶液中添加HCl(2.3mL 4M二噁烷中之溶液,9.1mmol)。將混合物於rt下攪拌16h。濃縮混合物,以產生呈HCl鹽形式之期望產物(0.042g)。C8H18N2O.159.2(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(3-甲氧基六氫吡啶-1-基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒係類似於實例229分別使用3-(2-氯
-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及2-(3-甲氧基六氫吡啶-1-基)乙-1-胺鹽酸鹽代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。C21H25ClFN7O2.462.2(M+H)。1H NMR(400MHz,DMSO-d 6)δ 11.30(s,1H),8.93(s,1H),7.97(d,J=5.6Hz,0H),7.09(t,J=9.1Hz,1H),7.03-6.75(m,2H),6.55(ddd,J=9.0,3.9,2.7Hz,1H),3.88-3.02(m,14H),2.00-1.54(m,2H)。
實例321係類似於實例333分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-(二氟甲氧基)丙-1-胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(2-胺基乙基)胺基甲酸第三丁基酯來製得。C17H16ClF3N6O2.429.1(M+H)。1H NMR(400MHz,DMSO-d 6)δ 11.38(s,1H),8.94(s,1H),7.94(d,J=6.2Hz,1H),7.08(t,J=9.0Hz,1H),7.05-6.96(m,1H),6.93-6.80(m,1H),6.66(t,J=76.1Hz,1H),6.56(ddd,J=8.8,4.2,2.8Hz,1H),3.90(t,J=6.2Hz,2H),3.55-3.45(m,2H),1.96-1.83(m,2H)。
實例322係類似於實例333分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(R)-(-)-四氫糠基胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(2-胺基乙基)胺基甲酸第三丁基酯來製得。C18H18ClFN6O2.405.2(M+1)。
實例323係類似於實例333分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(S)-(+)-四氫糠基胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(2-胺基乙基)胺基甲酸第三丁基酯來製得。C18H18ClFN6O2.405.2(M+H)。1H NMR(400MHz,DMSO-d 6)δ 11.45(s,1H),8.97(s,1H),7.98(d,J=6.3Hz,1H),7.11(t,J=9.0Hz,1H),7.04(dd,J=6.5,2.8Hz,1H),6.93(d,J=6.3Hz,1H),6.60(ddd,J=8.9,4.0,3.0Hz,1H),4.09-3.98(m,1H),3.80(dt,J=8.2,6.7Hz,1H),3.68(dt,J=8.1,6.8Hz,1H),3.63-3.52(m,1H),3.51-3.38(m,1H),2.03-1.76(m,3H),1.66-1.49(m,1H)。
實例324係類似於實例333分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及2-(氧雜環戊-2-基)乙-1-胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(2-胺基乙基)胺基甲酸第三丁基酯來製得。C19H20ClFN6O2.419.2(M+H)。1H NMR(400MHz,DMSO-d 6)δ 11.38(s,1H),8.96(s,1H),7.95(d,J=6.1Hz,1H),7.10(t,J=9.0Hz,1H),7.03(dd,J=6.5,2.7Hz,1H),6.91(d,J=6.2Hz,1H),6.58(ddd,J=9.0,4.1,3.0Hz,1H),3.89-3.75(m,2H),3.62(td,J=7.9,6.4Hz,1H),3.54-3.47(m,2H),2.03-1.67(m,5H),1.52-1.37(m,1H)。
2-(六氫吡啶-2-基甲基)-1H-咪唑并[4,5-b]吡啶-7-甲酸.將2,3-二胺基異菸鹼酸鹽酸鹽(200mg,0.106mmol)及2-(六氫吡啶-2-基)乙酸(453mg,0.317mmol)於硫酸(1.5mL)中之懸浮液於室溫下攪拌5min,且隨後密封於小瓶中並於160℃下攪拌3小時。一旦混合物冷卻,添加水(2mL)並藉由製備型HPLC純化溶液,以產生期望產物。C13H16N4O2.261.1(M+1)。
2-((1-(第三丁氧基羰基)六氫吡啶-2-基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲酸.將2-(六氫吡啶-2-基甲基)-1H-咪唑并[4,5-b]吡啶-7-甲酸(205mg,0.788mmol)、二碳酸二-第三丁基酯(189mg,0.866mmol)及三乙胺(0.440ml,3.15mmol)於二氯甲烷(8mL)中之溶液攪拌3hr並濃縮,以產生期望產物。C18H24N4O4.361.1(M+1)。
2-((7-((3-氯-4-氟苯基)胺甲醯基)-1H-咪唑并[4,5-b]吡啶-2-基)甲基)六氫吡啶-1-甲酸第三丁基酯.將2-((1-(第三丁氧基羰基)六氫吡啶-2-基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲酸(283mg,0.785mmol)、4-氟-3-氯苯胺(171mg,1.18mmol)、六氟磷酸1-[雙(二甲基胺基)亞甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物(388mg,1.02mmol)及N,N-二異丙基乙胺(0.684ml,3.93mmol)於二甲基甲醯胺(1.5mL)中之溶液攪拌3小時。濃縮反應混合物並藉由製備型HPLC純化。將所得凍乾物質與飽和碳酸氫鈉水溶液(5mL)混合,過濾,用水洗滌並在高真空上乾燥,以產生期望產物。C24H27ClFN5O3.488.1(M+1)。
N-(3-氯-4-氟苯基)-N'-羥基-2-(六氫吡啶-2-基甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒.向2-((7-((3-氯-4-氟苯基)胺甲醯基)-1H-咪唑并
[4,5-b]吡啶-2-基)甲基)六氫吡啶-1-甲酸第三丁基酯(100mg,0.205mmol)及碳酸鉀(198mg,1.43mmol)於二氯甲烷(2ml)中之混合物中添加五氯化磷(85mg,0.409mmol)。將反應混合物攪拌2小時並濃縮。將殘餘物吸收於乙醇(2ml)及羥基胺(0.50mL,50%於水中,8mmol)中並攪拌1小時。濃縮反應混合物並藉由製備型HPLC純化,以產生期望產物。C19H20ClFN6O.403.1(M+1)。
實例326係類似於實例305使用3-(二甲基胺基)-2-甲基丙酸代替2-(1-甲基六氫吡啶-2-基)乙酸來製得。C18H20ClFN6O.391.1(M+1)。
實例327係類似於實例325使用3-(甲基胺基)丁酸代替2-(六氫吡啶-2-基)乙酸來製得。C17H18ClFN6O.377.1(M+1)。
實例328係類似於實例305使用3-(二甲基胺基)丁酸代替2-(1-甲基六氫吡啶-2-基)乙酸來製得。C18H20ClFN6O.391.1(M+1)。
實例329係類似於實例325使用2-(吡咯啶-2-基)乙酸代替2-(六氫吡啶-2-基)乙酸來製得。C18H18ClFN6O.389.1(M+1)。
實例330係類似於實例39使用2-(吡咯啶-1-基)乙胺代替N,N-二甲基丙烷-1,3-二胺及使用3-氯苯胺代替3-氯-4-氟苯胺來製得。C20H21ClF2N6O.435.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.02-10.85(m,1H),10.79(s,1H),9.83-9.63(m,1H),8.68(s,1H),7.03(t,J=8.0Hz,1H),6.89-6.73(m,2H),6.55-6.44(m,1H),3.74-3.60(m,2H),3.44-3.32(m,2H),2.05-1.83(m,4H)。
實例331係類似於實例39使用2-(吡咯啶-1-基)乙胺代替N,N-二甲基丙烷-1,3-二胺及使用3-溴苯胺代替3-氯-4-氟苯胺來製得。C20H21BrF2N6O.479.1(M+1)。NMR(400MHz,DMSO-d6)δ 10.80(s,1H),9.83-9.67(m,1H),8.67(s,1H),7.01-6.73(m,6H),6.52(dt,J=7.7,1.8Hz,1H),3.71-3.59(m,2H),3.42-3.32(m,2H),1.93(s,4H)。
實例332係類似於實例39使用2-(吡咯啶-1-基)乙胺代替N,N-二甲基丙烷-1,3-二胺及使用3-溴-4-氟苯胺代替N,N-二甲基丙烷-1,3-二胺來製得。C20H20BrF3N6O.497.1(M+1)。
6,7-二氟-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-4-甲酸甲基酯.將
2,3-二胺基-4,5-二氟苯甲酸甲基酯(10g,50mmol)及羰基二咪唑(12g,75mmol)於THF(100mL)中之溶液攪拌過夜。向反應混合物中添加二乙醚並過濾沈澱並在高真空上乾燥,以產生期望產物。C9H6F2N2O3.229.5(M+1)。
2-氯-4,5-二氟-1H-苯并[d]咪唑-7-甲酸甲基酯.將6,7-二氟-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-4-甲酸甲基酯(9.98g,43.7mmol)於磷醯氯(80mL)中之混合物於120℃下攪拌過夜。將溶液冷卻並濃縮。向於冰浴中冷卻之固體殘餘物中小心添加飽和碳酸氫鈉水溶液。過濾漿液並將濾液用水洗滌並在高真空上乾燥,以產生期望產物。C9H5ClF2N2O2.247.2(M+1)。
2-氯-N-(3-氯-4-氟苯基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺.於0℃下經5min向3-氯-4-氟苯胺(4.43g,30mmol)於二氯乙烷(50mL)中之溶液中逐滴添加三甲基鋁溶液(30.4mL,2M於庚烷中,61mmol)。移除冰浴並將混合物攪拌30分鐘。利用冰浴使溶液冷卻並向此溶液中添加固體狀2-氯-4,5-二氟-1H-苯并[d]咪唑-7-甲酸甲基酯(5g,20mmol)。將反應物於60℃下攪拌6小時。將反應物在冰浴中冷卻並向此冷卻之混合物中添加10%檸檬酸(30mL)。向此溶液中添加2N氫氧化鈉並將水層用乙酸乙酯洗滌三次。將合併之有機層經硫酸鈉乾燥,過濾並濃縮,以產生期望產物。C14H6Cl2F3N3O.360.5(M+1)。
3-(2-氯-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮.將2-氯-N-(3-氯-4-氟苯基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺(6.56g,18.2mmol)及碳酸鉀(17.6g,127mmol)於二氯甲烷(100mL)中之混合物一起攪拌5min。向此混合物中添加五氯化磷(7.58g,36mmol)並將混合物攪拌2小時。再添加五氯化磷(7.58g,36mmol)並將混合物再攪拌3小時。將反應混合物濃縮並放置於冰浴中。經20min向冷卻之殘餘物中添加羥基胺溶液(44.5mL,50%於水中,728mmol)及乙醇(100mL)。移除冰浴並將反應物攪拌30min。將反應混合物濃縮並吸收於水中並用乙酸乙酯洗滌三次。將合併之有機層經硫酸鈉乾燥,過濾並濃縮至約50ml。向此溶液中添加羰基二咪唑(5.9g,36mmol)。將反應溶液攪拌30min並用乙酸乙酯稀釋並用1N鹽酸洗滌兩次並用飽和氯化鈉水溶液洗滌一次。將有機層經硫酸鈉乾燥,過濾,並濃縮,以產生期望產物。C15H5Cl2F3N4O2.401.0(M+1)。
3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮.向3-(2-氯-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(7.3g,18mmol)及三乙胺(15mL,109mmol)於二氯甲烷(200mL)中之溶液中添加(2-(氯甲氧基)乙基)三甲基矽烷(8mL,46mmol)。將反應
物攪拌2hr,並吸附至矽膠上並藉由矽膠層析純化,以產生期望產物。C21H19C12F3N4O3Si.554.9(M+23)。
3-(2-((2-胺基乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮.將3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(390mg,0.734mmol)及(2-胺基乙基)胺基甲酸第三丁基酯(141mg,0.881mmol)於二甲亞碸(3.5mL)中之溶液於65℃下攪拌過夜。將反應混合物冷卻並用乙酸乙酯稀釋並用飽和氯化鈉水溶液洗滌三次。將有機層經硫酸鈉乾燥,過濾並濃縮。將所得殘餘物吸收於二氯甲烷(3mL)及三氟乙酸(3mL)中並攪拌3小時。將反應溶液濃縮並吸收於飽和碳酸氫鈉水溶液中並用乙酸乙酯洗滌三次。將合併之有機層經硫酸鈉乾燥,過濾並濃縮,以產生期望產物(312mg)。C17H12ClF3N6O2.425.2(M+1)。
2-((2-胺基乙基)胺基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒.將3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(29mg,0.056mmol)及(2-胺基乙基)胺基甲酸第三丁基酯(44mg,0.27mmol)於二甲亞碸(0.2mL)中之溶液於65℃下攪拌過夜。將反應混合
物冷卻並用乙酸乙酯稀釋並用飽和氯化鈉水溶液洗滌三次。將有機層經硫酸鈉乾燥,過濾並濃縮。將所得殘餘物吸收於二氯甲烷(0.5mL)及三氟乙酸(0.5mL)中並攪拌3小時。濃縮反應溶液。將所得殘餘物吸收於四氫呋喃(0.2mL)及甲醇(0.2mL)中並向此溶液中添加2N氫氧化鈉(0.27mL,0.54mmol)。將所得溶液攪拌30min並濃縮並藉由製備型HPLC純化,以產生期望產物。C16H14ClF3N6O.399.1(M+1)。
向3-(2-((2-胺基乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(29mg,0.068mmol)及三乙胺(0.048mL,0.34mmol)於四氫呋喃(0.5mL)中之溶液中添加乙醯氯(0.007mL,0.10mmol)。將所得溶液攪拌1小時並濃縮。將所得殘餘物吸收於四氫呋喃(0.4mL)及甲醇(0.4mL)中並向此溶液中添加2N氫氧化鈉(0.34mL,0.68mmol)。將所得溶液攪拌1小時,濃縮並藉由製備型HPLC純化,以產生期望產物(11mg).C18H16ClF3N6O2.441.1(M+1)。
實例335係類似於實例334使用甲磺醯氯代替乙醯氯來製得。C17H16ClF3N6O3S.477.1(M+1)。
實例336係類似於實例334使用環丙基磺醯氯代替乙醯氯來製得。C19H18ClF3N6O3S.503.1(M+1)。
實例337係類似於實例334使用氯甲酸甲酯代替乙醯氯來製得。C18H16ClF3N6O3.457.1(M+1)。
將3-(2-((2-胺基乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(33mg,0.078mmol)及磺醯胺(75mg,0.78mmol)之溶液於110℃下攪拌20min並濃縮。將所得殘餘物吸
收於四氫呋喃(0.4mL)及甲醇(0.4mL)中並向此溶液中添加2N氫氧化鈉(0.38mL,0.76mmol)。將所得溶液攪拌1小時,濃縮,並藉由製備型HPLC純化,以產生期望產物。C16H15ClF3N7O3S.478.1(M+1)。
實例339係類似於實例334使用苯磺醯氯代替乙醯氯來製得。C22H18ClF3N6O3S.539.1(M+1)。
實例340係類似於實例333使用3-胺基丙腈代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C17H12ClF3N6O.409.4(M+1)。
實例341係類似於實例334使用異氰酸乙基酯代替乙醯氯來製得。C19H19ClF3N7O2.470.0(M+1)。
實例342係類似於實例333使用2-甲基吡啶胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C20H14ClF3N6O.447.2(M+1)。
實例343係類似於實例333使用2-甲基吡啶胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C20H14ClF3N6O.447.3(M+1)。
N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((吡啶-3-基甲基)胺基)-1H-苯并[d]咪唑-7-甲脒.實例344係類似於實例333使用2-(1-甲基-1H-咪唑-2-基)乙胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。
C20H17ClF3N7O.464.3(M+1)。
實例345係類似於實例333使用(1H-咪唑-2-基)甲胺二鹽酸鹽及二異丙基乙胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C18H13ClF3N7O.436.3(M+1)。經由此順序之未反應之2-((2-胺基乙基)胺基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒產生實例346(2-氯-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒)。C14H7Cl2F3N4O.375.1(M+1)。
實例347係類似於實例333使用2-(胺基甲基)苯胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C21H16ClF3N6O.461.1(M+1)。
實例348係類似於實例333使用2-(胺基甲基)-N,N-二甲基苯胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C23H20ClF3N6O.489.2(M+1)。
實例349係類似於實例333使用(1-甲基-1H-咪唑-2-基)甲胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C19H15ClF3N7O.450.1(M+1)。
實例350係類似於實例333使用嘧啶-2-基甲胺鹽酸鹽及二異丙基乙胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C19H13ClF3N7O.448.1(M+1)。
實例351係類似於實例333使用N1,N1,2,2-四甲基丙烷-1,3-二胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C21H24ClF3N6O.469.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.80(s,1H),8.71(s,1H),7.08(t,J=9.1Hz,1H),6.91(dd,J=6.5,2.7Hz,1H),6.89-6.80(m,1H),6.52(ddd,J=9.0,4.0,2.7Hz,1H),3.33(s,2H),2.98(s,2H),2.85(s,6H),1.03(s,6H)。
實例352係類似於實例333使用N1,N1,2-三甲基丙烷-1,3-二胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C20H22ClF3N6O.455.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.80(s,1H),8.74(s,1H),7.07(t,J=9.1Hz,1H),6.97-6.80(m,2H),6.52(dt,J=8.2,3.5Hz,1H),3.38-3.25(m,2H),3.02-2.61(m,8H),2.31-2.16(m,1H),1.01-0.89(m,3H)。
實例353係類似於實例333使用N3,N3-二甲基丁烷-1,3-二胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C20H22ClF3N6O.455.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.78(s,1H),8.71(s,1H),7.07(t,J=9.1Hz,1H),6.91(dd,J=6.6,2.7Hz,1H),6.89-6.79(m,1H),6.52(dt,J=9.0,3.4Hz,1H),3.49-3.28(m,3H),2.69(d,J=4.4Hz,6H),2.01(d,J=11.7Hz,1H),1.71(dt,J=14.1,7.5Hz,1H),1.22(d,J=6.5Hz,3H)。
實例354係類似於實例333使用2-(1-甲基吡咯啶-2-基)乙胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C21H22ClF3N6O.467.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.79(s,1H),9.55(s,1H),8.70(s,1H),7.07(t,J=9.1Hz,1H),6.92(dd,J=6.5,2.7Hz,1H),6.89-6.81(m,1H),6.51(ddd,J=9.0,4.1,2.8Hz,1H),3.62-3.47(m,1H),3.47-3.32(m,2H),3.32-3.18(m,1H),3.11-2.98(m,1H),2.81(d,J=4.6Hz,3H),2.34-2.09(m,2H),2.05-1.69(m,3H),1.68-1.57(m,1H)。
實例355係類似於實例333使用2-(1-甲基六氫吡啶-2-基)乙胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C22H24ClF3N6O.481.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.75(s,1H),9.13(s,1h),8.67(s,1H),7.07(t,J=8.9Hz,1H),6.93-6.88(m,1H),6.80-6.74(m,1H),6.55-6.49(m,1H),2.85-2.81(m,2H),2.80-2.75,(m,2H),2.56-2.6(m,1H),2.52(s,3H),1.83-1.35(m,8H)。
實例356係類似於實例333使用(4-甲基嗎啉-2-基)甲胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C20H20ClF3N6O2.469.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.79(s,1H),9.89(s,1H),8.67(s,1H),7.09(t,J=9.1Hz,1H),6.91(dd,J=6.5,2.8Hz,1H),6.81(dd,J=12.3,6.9Hz,1H),6.53(ddd,J=8.9,4.1,2.7Hz,1H),4.07(d,J=12.7Hz,1H),3.96-3.83(m,1H),3.66(t,J=12.4Hz,1H),3.59-3.32(m,4H),3.10-2.95(m,1H),2.90-2.80(m,4H)。
實例357係類似於實例333使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及使用(4-甲基嗎啉-2-基)甲胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C19H21ClFN7O2.434.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.38(s,1H),10.18(s,1H),8.93(s,1H),7.96(d,J=6.2Hz,1H),7.10(t,J=9.0Hz,1H),6.99(dd,J=6.5,2.8Hz,1H),6.91(d,J=6.2Hz,1H),6.58(ddd,J=9.0,4.1,2.8Hz,1H),4.07(d,J=12.8Hz,1H),3.90(s,1H),3.73-3.34(m,5H),3.08-2.94(m,1H),2.92-2.77(m,4H)。
實例358係類似於實例333使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及使用(1-甲
基-1H-吡唑-5-基)甲胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C18H16ClFN8O.415.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.45(s,1H),8.98(s,1H),7.97(d,J=6.3Hz,1H),7.32(d,J=1.9Hz,1H),7.08(t,J=9.0Hz,1H),7.04(dd,J=6.5,2.7Hz,1H),6.93(d,J=6.4Hz,1H),6.61-6.53(m,1H),6.18(d,J=1.9Hz,1H),4.71(d,J=5.9Hz,2H),3.83(s,3H)。
實例359係類似於實例333使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及使用(4-甲基嗎啉-2-基)甲胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C17H17ClFN7O2.406.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.43(s,1H),8.95(s,1H),7.98(d,J=6.2Hz,1H),7.10(t,J=9.0Hz,1H),7.02(dd,J=6.5,2.7Hz,1H),6.92(d,J=6.2Hz,1H),6.58(ddd,J=8.9,3.9,2.7Hz,1H),4.30(d,J=4.9Hz,2H),2.98(s,3H),2.89(s,3H)。
實例360及361係類似於實例333使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及使用氧雜環丁-3-基甲胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C17H16ClFN6O2.391.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 12.73(s,1H),11.22(s,1H),8.92(s,1H),8.09(s,1H),7.08(t,J=9.0Hz,1H),7.03(d,J=5.4Hz,1H),6.99(dd,J=6.4,2.7Hz,1H),6.53(ddd,J=9.0,4.1,2.8Hz,1H),4.98(s,1H),4.23(dd,J=12.4,4.9Hz,1H),3.78(dd,J=12.3,8.6Hz,1H),3.35-3.23(m,1H)。C17H16ClFN6O2.391.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.16(s,1H),9.44-9.28(m,1H),9.09(s,1H),7.97-7.85(m,1H),7.09(dd,J=6.5,2.7Hz,1H),7.04(t,J=9.0Hz,1H),6.83(s,1H),6.59(dt,J=8.9,3.6Hz,1H),4.26(dd,J=12.3,4.8Hz,1H),3.91-3.81(m,1H),3.25(t,J=10.9Hz,1H)。
實例362係類似於實例333使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-
5(4H)-酮代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及使用2-(1-甲基-1H-咪唑-2-基)乙胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C19H18ClFN8O.429.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.36(s,1H),8.96(s,1H),7.97(d,J=6.2Hz,1H),7.58(d,J=2.0Hz,1H),7.54(d,J=2.0Hz,1H),7.08(t,J=9.0Hz,1H),6.99(dd,J=6.5,2.7Hz,1H),6.94(d,J=6.2Hz,1H),6.60-6.50(m,1H),3.83-3.68(m,5H),3.31-3.21(m,2H)。
實例363係類似於實例333使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及使用N1-(吡啶-2-基)丙烷-1,3-二胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C21H20ClFN8O.455.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.34(s,1H),8.95(s,1H),7.95(d,J=6.2Hz,1H),7.92(d,J=6.2Hz,1H),7.85-7.74(m,1H),7.08(t,J=9.0Hz,1H),7.01(dd,J=6.5,2.7Hz,1H),6.91(d,J=6.2Hz,1H),6.84-6.72(m,1H),6.56(dt,J=9.0,4.0,3.0Hz,1H),3.56-3.44(m,2H),3.42-3.31(m,2H),1.96-1.83(m,2H)。
實例364係類似於實例333使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及使用異戊基胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C18H20ClFN6O.391.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.41(s,1H),8.95(s,1H),7.95(d,J=6.3Hz,1H),7.09(t,J=8.9Hz,1H),7.03(dd,J=6.6,2.7Hz,1H),6.91(d,J=6.2Hz,1H),6.62-6.53(m,1H),3.27(d,J=6.3Hz,2H),0.92(s,9H)。
實例365係類似於實例333使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及使用異丁基胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C17H18ClFN6O.377.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.38(s,1H),8.95(s,1H),7.95(d,J=6.2Hz,1H),7.08(t,J=9.0Hz,1H),7.03(dd,J=6.6,
2.7Hz,1H),6.91(d,J=6.2Hz,1H),6.61-6.51(m,1H),3.29-3.18(m,2H),1.95-1.78(m,1H),0.90(d,J=6.7Hz,6H)。
實例366係類似於實例333使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及使用(四氫-2H-吡喃-2-基)甲胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C19H20ClFN6O2.419.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.43(s,1H),8.95(s,1H),7.95(d,J=6.4Hz,1H),7.10(t,J=9.0Hz,1H),7.02(dd,J=6.5,2.7Hz,1H),6.90(d,J=6.3Hz,1H),6.62-6.54(m,1H),3.91(d,J=11.2Hz,1H),3.57-3.43(m,2H),3.44-3.30(m,2H),1.84-1.71(m,1H),1.58(d,J=12.7Hz,1H),1.54-1.38(m,3H),1.30-1.14(m,1H)。
實例367係類似於實例333使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-
5(4H)-酮代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及使用(四氫呋喃-3-基)甲胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。C18H18ClFN6O2.405.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.38(s,1H),8.96(s,1H),7.95(d,J=6.3Hz,1H),7.08(t,J=9.0Hz,1H),7.03(dd,J=6.5,2.7Hz,1H),6.91(d,J=6.2Hz,1H),6.59-6.53(m,1H),3.75(td,J=8.1,5.6Hz,1H),3.68(dd,J=8.6,7.0Hz,1H),3.62(td,J=8.0,6.7Hz,1H),3.47(dd,J=8.7,5.1Hz,1H),3.43-3.36(m,2H),2.00-1.90(m,1H),1.58(dq,J=12.8,6.4,6.3Hz,1H)。
將2,3-二胺基-4-氟苯甲酸甲基酯(0.150g,0.814mmol)溶解於THF(4.0mL)中並添加4-(2-異氰硫基乙基)嗎啉(5.0mmol)及三乙胺(7.0mmol)。將反應物密封於小瓶中並加熱至66℃並保持12小時。一次性添加1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(5.0mmol)並將反應物於66℃下再加熱1小時。將反應物冷卻至rt並用飽和碳酸氫鈉溶液(4mL)驟冷。將反應混合物用EtOAc(3×3mL)萃取並將合併之有機層用水洗滌一次,濃縮,並藉由矽膠管柱層析(0-15% MeOH/CH2Cl2,Rf=0.33,於10% MeOH/CH2Cl2中)純化,以產生4-氟
-2-((2-嗎啉基乙基)胺基)-1H-苯并[d]咪唑-7-甲酸甲基酯。
在惰性條件下將4-氟-2-((2-嗎啉基乙基)胺基)-1H-苯并[d]咪唑-7-甲酸甲基酯(0.208g,0.645mmol)及3-氯-4-氟苯胺(3.0mmol)溶解於DCE(6.0mL)中。於0℃下添加三甲基鋁(5.0mmol,2.26mL)並隨後將反應物加熱至60℃過夜。使反應物冷卻至rt,用水(3mL)驟冷並用EtOAc(4×3mL)萃取。將合併之有機層用水洗滌一次,濃縮,並藉由矽膠層析(Rf=0.37 10% MeOH/DCM)純化,以產生期望產物。
N-(3-氯-4-氟苯基)-4-氟-N'-羥基-2-((2-嗎啉基乙基)胺基)-1H-苯并[d]咪唑-7-甲脒係類似於實例10使用羥基脒形成之程序來製得。C20H21ClF2N6O2.451.8(M+1)。
將1H-咪唑并[4,5-b]吡啶-7-甲酸(0.20g,1.22mmol)及3-氯-4-氟-N-甲基苯胺鹽酸鹽(1.02mmol)溶解於DMF(3.0mL)中並添加HATU(1.2mmol)及DIPEA(2.78mmol)並將反應物於rt下攪拌過夜。將反應物用飽和/碳酸氫鈉溶液(3.0mL)驟冷並將反應物用EtOAc(32mL)萃取。將合併之有機層用水(1×4mL)洗滌並藉由矽膠層析(Rf=0.25 50%
EtOAc/hex)純化粗製物,以產生N-(3-氯-4-氟苯基)-N-甲基-1H-咪唑并[4,5-b]吡啶-7-甲醯胺。
將N-(3-氯-4-氟苯基)-N-甲基-1H-咪唑并[4,5-b]吡啶-7-甲醯胺(0.05g,0.164mmol)溶解於甲苯(3.0mL)中並添加Lawesson試劑(0.656mmol)。將反應物密封於小瓶中並於100℃下加熱過夜。隨後將反應物冷卻至rt並藉由真空過濾移除固體。濃縮濾液並藉由矽膠層析純化,以產生N-(3-氯-4-氟苯基)-N-甲基-1H-咪唑并[4,5-b]吡啶-7-硫代甲醯胺。
將N-(3-氯-4-氟苯基)-N-甲基-1H-咪唑并[4,5-b]吡啶-7-硫代甲醯胺(0.014g,0.0455mmol)溶解於乙醇(3.0mL)中並添加羥基胺(50%水溶液)(0.455mmol)並將反應物於rt下攪拌過夜。將反應物濃縮至乾燥,隨後藉由RP HPLC純化,以產生N-(3-氯-4-氟苯基)-N'-羥基-N-甲基-1H-咪唑并[4,5-b]吡啶-7-甲脒(3.1mg,21%)。C14H11ClFN5O.320.7(M+1)。
將2,3-二胺基-5-氟苯甲酸(5.0g,29mmol)溶解於硫酸(5.0mL)及MeOH(40.0mL)中並加熱至71℃過夜。使反應物冷卻至rt,隨後濃縮
至約一半體積。將反應物用飽和碳酸鈉溶液中和至pH=7,隨後用EtOAc(5×20mL)萃取。將合併之有機層用水洗滌一次並濃縮至乾燥,以產生2,3-二胺基-5-氟苯甲酸甲基酯。
將2,3-二胺基-5-氟苯甲酸甲基酯(2.0g,11.0mmol)及溴化氰(11.0mmol)溶解於甲醇(45mL)及水(20mL)中並加熱至70℃並保持30min。將反應物冷卻至rt並用水(5mL)及EtOAc(20mL)稀釋。分離水層並用飽和碳酸鈉溶液中和至pH=7,隨後用EtOAc(4×10mL)萃取。將合併之有機層用水洗滌一次,隨後濃縮,以產生2-胺基-5-氟-1H-苯并[d]咪唑-7-甲酸甲基酯。
將2-胺基-5-氟-1H-苯并[d]咪唑-7-甲酸甲基酯(0.2g,0.956mmol)及3-氯-4-氟苯胺(4.0mmol)溶解於DCE(3.0mL)中並在惰性氣氛下冷卻至0℃。添加三甲基鋁(7.0mmol,3.34mL)並將反應物緩慢加熱至65℃過夜。將反應物冷卻至rt,用水(3mL)驟冷並用EtOAc(3×5mL)萃取。將合併之有機層用水洗滌一次並藉由矽膠層析(Rf 100% EtOAc=0.32)純化,以產生2-胺基-N-(3-氯-4-氟苯基)-5-氟-1H-苯并[d]咪唑-7-甲醯胺。
將2-胺基-N-(3-氯-4-氟苯基)-5-氟-1H-苯并[d]咪唑-7-甲醯胺及Lawesson試劑(3.0mmol)溶解於甲苯中並於100℃下加熱過夜。使反應物冷卻至rt並藉由過濾移除固體。濃縮濾液且其未經進一步純化即直接用於下一反應。
將2-胺基-N-(3-氯-4-氟苯基)-5-氟-1H-苯并[d]咪唑-7-硫代甲醯胺(0.267g,0.788mmol)溶解於乙醇(3mL)中並添加羥基胺(50%水溶液)(0.5mL)並將反應物於rt下攪拌過夜。將反應物濃縮並藉由RP HPLC純化,以產生2-胺基-N-(3-氯-4-氟苯基)-5-氟-N'-羥基-1H-苯并[d]咪唑
-7-甲脒。C14H10ClF2N5O.338.1(M+1)。
實例371係類似於實例370使用3-氯苯胺代替3-氯-4-氟苯胺來製得。C14H11ClFN5O.320.7(M+1)。1H NMR(400MHz,DMSO-d6)δ 12.05(s,1H),11.10(s,1H),8.83(s,1H),8.26(s,2H),7.26(dd,J=8.3,2.4Hz,1H),7.06(t,J=8.3Hz,1H),6.91(dd,J=10.5,2.4Hz,1H),6.88-6.83(m,2H),6.57-6.48(m,1H)。
實例372係類似於實例370使用3-溴苯胺代替3-氯-4-氟苯胺來製得。C14H11BrFN5O.365.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 12.05(s,1H),11.10(s,1H),8.82(s,1H),8.27(s,2H),7.26(dd,J=8.3,2.4Hz,1H),7.04-6.95(m,3H),6.91(dd,J=10.5,2.4Hz,1H),6.60-6.51(m,1H)。
實例373係類似於實例370使用3-溴-4-氟苯胺代替3-氯-4-氟苯胺來製得。C14H10BrF2N5O.383.2(M+1)。1H NMR(400MHz,DMSO-
d6)δ 12.11(s,1H),11.03(s,1H),8.79(s,1H),8.36-8.23(m,2H),7.26(dd,J=8.3,2.4Hz,1H),7.13-7.04(m,2H),6.92(dd,J=10.5,2.4Hz,1H),6.60(ddd,J=8.9,4.2,2.8Hz,1H)。
實例374係類似於實例32使用4-(2-胺基乙基)硫嗎啉1,1-二氧化物來製得。C20H20ClF3N6O3S.517.9(M+1)。
在氬下將N1,N1-二乙基乙烷-1,2-二胺(0.50g,4.0mmol)及碳酸氫鈉(86mmol)溶解於DCM(12.0mL)中。逐滴添加硫光氣(17.0mmol)並將反應物於rt下攪拌2小時。添加DCM(10mL)及水(10mL)並將水層用DCM(2×8mL)萃取。將合併之有機層用水(1×20mL)洗滌並濃縮至5mL之體積,以產生N,N-二乙基-2-異氰硫基乙-1-胺,其未經進一步純化即使用。
N-(3-氯-4-氟苯基)-2-((2-(二乙基胺基)乙基)胺基)-4-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒係類似於實例23使用N,N-二乙基-2-異氰硫基乙-1-胺、2,3-二胺基-4-氟苯甲酸甲基酯及3-氯-4-氟苯胺來製得。C20H22ClF3N6O.437.9(M+1)。
實例376係類似於實例375使用2-(吡咯啶-1-基)乙-1-胺代替N1,N1-二乙基乙烷-1,2-二胺來製得。C20H21ClF2N6O.435.8(M+1)。
實例377係類似於實例32使用2-嗎啉基丙-1-胺來製得。C21H22ClF3N6O2.483.9(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.82(s,1H),8.71(s,1H),7.17(s,1H),7.09(td,J=9.1,2.4Hz,2H),6.94(dd,J=6.5,2.7Hz,1H),6.88(dd,J=12.2,6.9Hz,1H),6.78(d,J=6.4Hz,1H),6.60(d,J=9.1Hz,1H),6.54(ddd,J=9.0,4.1,2.7Hz,1H),3.89(s,4H),3.72(s,1H),3.69-3.55(m,2H),3.37(s,4H),1.29(d,J=6.6Hz,3H)。
實例378係類似於實例23使用N1,N1-二甲基丙烷-1,2-二胺來製得。C19H20ClF3N6O.441.8(M+1)。
實例379係類似於實例23使用2,3-二胺基-5-氟苯甲酸甲基酯及2-異氰硫基-N,N-二甲基乙-1-胺來製得。C18H19ClF2N6O.409.8(M+1)。1H NMR(400MHz,甲醇-d4)δ 7.19(dd,J=8.1,2.4Hz,1H),6.97(t,J=8.9Hz,1H),6.94-6.89(m,2H),6.69(dt,J=8.8,3.4Hz,1H),3.85(d,J=5.8Hz,3H),3.46(dd,J=12.2,6.4Hz,3H),2.99(s,6H)。
實例380係類似於實例375使用1-(2-異氰硫基乙基)吡咯啶來製得。C20H21ClF2N6O.435.8(M+1)。
實例381係類似於實例23使用2,3-二胺基-4-氟苯甲酸甲基酯及3-異氰硫基-N,N,2,2-四甲基丙-1-胺(自N1,N1,2,2-四甲基丙烷-1,3-二胺製得)來製得。C21H25ClF2N6O.451.9(M+1)。
實例382係類似於實例23使用2,3-二胺基-4-氟苯甲酸甲基酯、2-異氰硫基-N,N-二甲基乙-1-胺及3-溴-4-氟苯胺來製得。C18H19BrF2N6O.454.3(M+1)。1H NMR(400MHz,甲醇-d4)δ 7.41(dd,J=6.0,2.4Hz,1H),7.36(dd,J=8.7,4.4Hz,1H),7.16(dd,J=9.9,8.7Hz,1H),7.09-7.01(m,2H),3.94(t,J=5.9Hz,2H),3.52(t,J=6.0Hz,2H),3.01(s,6H)。
實例383係類似於實例23使用2,3-二胺基-4-氟苯甲酸甲基酯、2-異氰硫基-N,N-二甲基乙-1-胺及3-溴苯胺來製得。C18H20BrFN6O.436.3(M+1)。1H NMR(400MHz,甲醇-d4)δ 7.33(dd,J=8.8,4.5Hz,1H),7.26(d,J=8.4Hz,2H),7.19-7.06(m,2H),6.93(d,J=8.6Hz,1H),3.92(t,J=6.0Hz,2H),3.51(t,J=6.0Hz,2H),3.01(s,6H)。
實例384係類似於實例23使用2,3-二胺基-4-氟苯甲酸甲基酯、2-異氰硫基-N,N-二甲基乙-1-胺及3-氯苯胺來製得。C18H20ClFN6O.391.8(M+1)。1H NMR(400MHz,甲醇-d4)δ 7.39(dd,J=8.7,4.4Hz,1H),7.22-7.01(m,5H),6.94(dq,J=7.1,2.3Hz,1H),3.94(t,J=6.0Hz,2H),3.52(t,J=6.1Hz,3H),3.00(s,6H)。
實例385係類似於實例32使用2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯、N1,N1-二甲基丙烷-1,3-二胺及3-氯苯胺來製得。C19H21ClF2N6O.423.9(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.88(s,1H),9.69(s,1H),8.74(s,1H),7.05(t,J=
8.3Hz,1H),6.95-6.78(m,3H),6.52(dt,J=8.3,1.6Hz,1H),3.42(d,J=6.4Hz,2H),3.09(d,J=10.5Hz,2H),2.80(d,J=4.4Hz,6H),1.94(p,J=6.8Hz,2H)。
實例386係類似於實例32使用2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯、N1,N1-二甲基丙烷-1,3-二胺及3-溴苯胺來製得。C19H21BrF2N6O.468.3(M+1)。1H NMR(400MHz,甲醇-d4)δ 7.37-7.27(m,1H),7.10-6.99(m,3H),6.69(ddd,J=8.0,2.2,1.1Hz,1H),3.57(t,J=6.6Hz,2H),3.28-3.21(m,2H),2.93(s,6H),2.18-2.08(m,2H)。
實例387係類似於實例32使用2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯、N1,N1-二甲基丙烷-1,3-二胺及3-溴-4-氟苯胺來製得。C19H20BrF3N6O.486.3(M+1)。1H NMR(400MHz,甲醇-d4)δ 7.14-7.04(m,2H),6.96(t,J=8.6Hz,1H),6.74(ddd,J=8.9,4.0,2.7Hz,1H),3,56(t,J=6.6Hz,2H),3.28-3.21(m,2H),2.93(s,6H),2.17-2.09(m,2H)。
實例388係類似於實例23使用2,3-二胺基-4-氟苯甲酸甲基酯及3-異氰硫基-N,N-二甲基丙-1-胺來製得。C19H21ClF2N6O.423.8(M+1)1H NMR(400MHz,甲醇-d4)δ 7.44(dd,J=8.8,4.3Hz,1H),7.39(dd,J=6.4,2.3Hz,1H),7.23(dd,J=9.8,8.8Hz,1H),7.15-7.05(m,2H),3.62(t,J=6.8Hz,2H),3.34-3.30(m,2H),2.17(t,J=8.0Hz,2H)。
實例389係類似於實例23使用2,3-二胺基-5-氟苯甲酸甲基酯、3-異氰硫基-N,N-二甲基丙-1-胺及3-氯-4-氟苯胺來製得。C19H21ClF2N6O.423.8(M+1)。
實例390係類似於實例32使用N1-苄基-N1-甲基乙烷-1,2-二胺來製得。C24H22ClF3N6O.503.9(M+1)。
實例391係類似於實例184使用N-(3-氯-4-氟苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺及1-環己基-N-甲基甲胺來製得。C23H28ClFN6O.459.9(M+1)。
實例392係類似於實例184使用N,2,2-三甲基丙-1-胺鹽酸鹽來製得。C21H26ClFN6O.434.1(M+1)。
實例393係類似於實例184使用N-甲基環己胺來製得。C22H26ClFN6O.445.9(M+1)。
將2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯(1.39g,4.0mmol)及(2-胺基乙基)(甲基)胺基甲酸第三丁基酯(6.0mmol)溶解於DMSO(5.0mL)中並於60℃下加熱過夜。使反應物冷卻至rt並用水(3mL)驟冷。將反應物用EtOAc(5×3mL)萃取並將合併之有機層用水洗滌一次並藉由矽膠管柱層析純化,以產生2-((2-((第三丁氧基羰基)(甲基)胺基)乙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯。
在惰性氣氛下將2-((2-((第三丁氧基羰基)(甲基)胺基)乙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯(1.14g,2.0mmol)及3-氯-4-氟苯胺(9.0mmol)溶解於DCE(15.0mL)中。於0℃下添加三甲基鋁(9.0mmol,4.430mL)並使反應物達到rt並攪拌過夜。將反應物用水(5mL)驟冷並用DCM(3×6mL)萃取。將合併之有機層用水(1×8mL)洗滌並濃縮至乾燥。將粗製物溶解於DCM(8mL)中並添加TFA(4mL)並將反應物於rt下攪拌1小時。將反應物濃縮並藉由矽膠層析純化,以產生N-(3-氯-4-氟苯基)-4,5-二氟-2-((2-(甲基胺基)乙基)胺基)-1H-苯并[d]咪唑-7-甲醯胺。
在惰性條件下將N-(3-氯-4-氟苯基)-4,5-二氟-2-((2-(甲基胺基)乙基)胺基)-1H-苯并[d]咪唑-7-甲醯胺(0.053g,0.132mmol)及四氫-2H-吡喃-4-甲醛(0.126mmol)溶解於DCE(2.0mL)中。添加三乙醯氧基硼氫化鈉(STAB)(0.176mmol)並將反應物於rt下攪拌2小時。將反應物用水(3mL)驟冷且隨後用DCM(3×4mL)萃取。將合併之有機層用水洗滌一次,經Mg2SO4乾燥,過濾並濃縮,以產生N-(3-氯-4-氟苯基)-4,5-二氟-2-((2-(甲基((四氫-2H-吡喃-4-基)甲基)胺基)乙基)胺基)-1H-苯并[d]咪唑-7-甲醯胺,隨後使用本文所述羥基脒形成條件將其轉化成N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(甲基((四氫-2H-吡喃-4-基)甲基)胺基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒。C23H26ClF3N6O2.512.0(M+1)。1H NMR(400MHz,甲醇-d4)δ 7.45(s,1H),6.95(t,J=8.9Hz,1H),6.86(td,J=7.4,4.9Hz,2H),6.66-6.60(m,1H),3.90-3.81(m,2H),3.75(t,J=5.1Hz,2H),3.43(d,J=5.9Hz,2H),3.41-3.35(m,2H),3.14(d,J=7.1Hz,2H),3.00(s,3H),1.71(d,J=13.0Hz,2H),1.43-1.26(m,3H)。
將3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(0.03g,0.0565mmol)及(2-胺基乙基)(甲基)胺基甲酸第三丁基酯(0.0847mmol)溶解於DMS(0.6mL)中並於60℃下加熱過夜。將反應物冷卻至rt,用水稀釋,並用DCM(3×1mL)萃取。將合併之有機層用水洗滌一次並濃縮,以產生(2-((7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-2-基)胺基)乙基)(甲基)胺基甲酸第三丁基酯,其未經進一步純化即使用。
將(2-((7-(4-(3-氯-4-氟苯基)-5-側氧基-4,5-二氫-1,2,4-噁二唑-3-基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-2-基)胺基)乙基)(甲基)胺基甲酸第三丁基酯(0.057mmol)溶解於DCM(2mL)中並添加TFA(1.0mL)並將反應物於rt下攪拌2小時,之後濃縮至乾燥。隨後將殘餘物溶解於MeOH(2.0mL)中並添加1M NaOH(0.5mL)並將反應物於rt下攪拌30min。隨後將反應物濃縮並藉由RP HPLC純化成N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(甲基胺基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒。C17H16ClF3N6O.413.8(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.72(s,1H),8.65(s,1H),8.50(s,2H),6.98(t,J=9.1Hz,1H),6.85-6.80(m,1H),6.76(s,1H),6.42(dt,J=8.9,3.4Hz,1H),3.52(d,J=5.8Hz,2H),3.04(t,J=5.9Hz,2H),2.50(t,J=5.3Hz,3H)。
實例396係類似於實例184使用N-(3-氯-4-氟苯基)-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺及N-甲基-1-苯基甲胺來製得。C23H22ClFN6O.454.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.07(s,1H),8.90(s,1H),8.30(d,J=5.0Hz,1H),7.56(dd,J=6.4,3.3Hz,2H),7.50(dt,J=4.5,2.9Hz,3H),7.15(d,J=5.1Hz,1H),7.03(t,J=9.1Hz,1H),6.91(dd,J=6.5,2.7Hz,1H),6.51(ddd,J=8.9,4.0,2.7Hz,1H),4.44(s,2H),3.57(t,J=7.5Hz,2H),3.36(t,J=7.4Hz,2H),2.76(s,3H)。
實例397係類似於實例395使用2-乙基丁醛以供還原胺化來製得。C23H28ClF3N6O.498.1(M+1)。
實例398係類似於實例394使用環丙烷甲醛以供還原胺化來製得。C21H22ClF3N6O.468.1(M+1)。1H NMR(400MHz,甲醇-d4)δ 6.95(t,J=8.9Hz,1H),6.92-6.86(m,2H),6.66(ddd,J=8.9,3.9,2.8Hz,1H),3.77(t,J=5.3Hz,2H),3.46(d,J=8.4Hz,2H),3.14(d,J=7.2Hz,2H),3.02(s,3H),1.16(ddd,J=7.7,4.7,2.9Hz,1H),0.71(dd,J=8.1,1.5Hz,2H),0.40(dd,J=4.7,1.3Hz,2H)。
實例399係類似於實例184使用N-甲基-1-(四氫-2H-吡喃-4-基)甲胺來製得。C22H26ClFN6O2.461.9(M+1)。
實例400係類似於實例184使用1-(1,4-二噁烷-2-基)-N-甲基甲胺鹽酸鹽來製得。C21H24ClFN6O3.463.9(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.09(s,1H),8.89(s,1H),8.31(d,J=5.1Hz,1H),7.16(d,J=5.1Hz,1H),7.05(t,J=9.1Hz,1H),6.93(dd,J=6.5,2.7Hz,1H),6.52(ddd,J=9.0,4.0,2.7Hz,1H),4.10-4.01(m,1H),3.83-3.20(m,13H),2.89(s,3H)。
實例401係類似於實例184使用N-甲基-2-(四氫-2H-吡喃-4-基)乙-1-胺來製得。C23H28ClFN6O2.476.0(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.07(s,1H),8.91(s,1H),8.30(d,J=5.1Hz,1H),7,16(d,J=5.1Hz,1H),7.04(t,J=9.1Hz,1H),6.93(dd,J=6.5,2.7Hz,1H),6.55-6.48(m,1H),3.83(dd,J=11.2,4.3Hz,2H),3.55(s,1H),3.35-3.23(m,4H),3.23-3.15(m,2H),2.84(s,3H),1.59(dd,J=15.6,10.5Hz,6H),1.20(d,J=11.8Hz,2H)。
實例402係類似於實例395使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(2-胺基乙基)(環丙基)胺基甲酸第三丁基酯來製得。C18H19ClFN7O.404.8(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.39(s,1H),8.97(s,3H),7.99(d,J=6.3Hz,1H),7.11(t,J=9.1Hz,1H),7.01(dd,J=6.5,2.7Hz,1H),6.95(d,J=6.3Hz,1H),6.58(ddd,J=9.0,4.1,2.8Hz,1H),3.75(s,2H),3.31(s,2H),2.80(s,1H),0.87-0.75(m,4H)。
實例403係類似於實例402使用N1-環丙基-N1-乙基乙烷-1,2-二胺來製得。C20H23ClFN7O.432.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 8.95(s,1H),7.97(d,J=6.1Hz,1H),7.10(t,J=9.1Hz,1H),6.99(s,1H),6.93(d,J=6.0Hz,1H),6.61-6.53(m,1H),3.80(s,2H),3.45(s,2H),3.33(s,2H),2.86(s,1H),1.27(t,J=7.2Hz,3H),1.00-0.78(m,4H)。
實例404係類似於實例402使用N-(2-胺基乙基)乙醯胺來製得。C17H17ClFN7O2.406.3(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.42(s,1H),8.97(s,1H),8.03(s,1H),7.97(d,J=6.3Hz,1H),7.11(t,J=9.0Hz,1H),7.04(dd,J=6.5,2.7Hz,1H),6.92(d,J=6.3Hz,1H),6.63-6.55(m,1H),3.50(d,J=6.0Hz,2H),3.30(d,J=6.0Hz,2H),1.82(s,3H)。
實例405係類似於實例402使用N-(2-胺基乙基)甲烷磺醯胺來製得。C16H17ClFN7O3S.442.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.44(s,1H),8.97(s,1H),7.97(d,J=6.3Hz,1H),7.25(d,J=5.8Hz,1H),7.11(t,J=9.0Hz,1H),7.03(s,1H),6.92(d,J=6.4Hz,1H),6.59(dt,J=8.9,3.4Hz,1H),3.57(d,J=6.2Hz,2H),3.21(d,J=6.1Hz,2H),2.94(s,3H)。
實例406係類似於實例402使用N1-環丙基-N1-異丙基乙烷-1,2-二胺來製得。C21H25ClFN7O.446.4(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.30(s,1H),8.94(s,1H),7.97(s,1H),7.10(t,J=9.0Hz,1H),7.03-6.94(m,1H),6.92(d,J=6.0Hz,1H),6.56(d,J=8.4Hz,1H),3.80(s,3H),3.42(s,2H),2.86(s,1H),1.30(d,J=6.7Hz,6H),1.01(s,2H),0.89(s,2H)。
實例407係類似於實例402使用2-((2-胺基乙基)(環丙基)胺基)乙-1-醇二鹽酸鹽及休尼格鹼來製得。C20H23ClFN7O2.448.2(M+1)。1H NMR(400MHz,甲醇-d4)δ 7.89(d,J=6.5Hz,1H),7.05(d,J=6.5Hz,1H),7.03-6.95(m,2H),6.67(ddd,J=8.9,4.0,2.8Hz,1H),4.06(t,J=6.3Hz,2H),4.01-3.95(m,2H),3.71(t,J=6.3Hz,2H),3.59-3.52(m,2H),2.98(dt,J=7.3,3.5Hz,1H),1.19-1.12(m,2H),1.07-1.01(m,2H)。
實例408係類似於實例402使用(2-胺基乙基)胺基甲酸第三丁基酯來製得。C15H15ClFN7O.364.9(M+1)。
實例409係類似於實例402使用4-(胺基甲基)吡咯啶-2-酮來製得。C18H17ClFN7O2.418.4(M+1)。
實例410係類似於實例402使用(1H-吡唑-5-基)甲胺來製得。C17H14ClFN8O.401.1(M+1)。
將3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(0.06g,0.121mmol)及(3-胺基丙基)胺基甲酸第三丁基酯(0.181mmol)溶解於DMSO(2.80mL)中並於60℃下加熱過夜。將反應物冷卻至rt,用水(3mL)稀釋並用EtOAc(3×2mL)萃取。將合併之有機層用水(1×5mL)洗滌並濃縮。將粗製物溶解於DCM(2mL)中並添加TFA(1.0mL)並將反應物於rt下攪拌2小時,之後濃縮至乾燥,以產生3-(2-((3-胺基丙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮。
將3-(2-((3-胺基丙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(0.015g,0.0317mmol)溶解於THF(1.0mL)中並添加三乙胺(0.186mmol)。緩慢添加乙醯氯(0.0557mmol)並將反應物於rt下攪拌1小時,之後濃縮至乾燥。將殘餘物溶解於THF(0.4mL)、MeOH(0.4mL)及1M NaOH(0.6mL)中並於rt下攪拌1小時。將反應物濃縮並藉由RP HPLC純化,以產生兩種產物:N-(3-((7-(N-(3-氯-4-氟苯基)-N'-羥基甲脒基)-1H-咪唑并[4,5-b]吡啶-2-基)胺
基)丙基)乙醯胺(2.8mg,18%)及2-((3-胺基丙基)胺基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒。
N-(3-((7-(N-(3-氯-4-氟苯基)-N'-羥基甲脒基)-1H-咪唑并[4,5-b]吡啶-2-基)胺基)丙基)乙醯胺:C18H19ClFN7O2.420.2(M+1)。1H NMR(400MHz,甲醇-d4)δ 7.84(d,J=6.5Hz,1H),7.04-6.96(m,3H),6.67(ddd,J=8.9,4.0,2.8Hz,1H),3.58(t,J=6.7Hz,2H),3.28(d,J=6.7Hz,2H),1.96(s,3H),1.87(t,J=6.7Hz,2H)。
2-((3-胺基丙基)胺基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒:C16H17ClFN7O.378.3(M+1)。1H NMR(400MHz,甲醇-d4)δ 7.85(d,J=6.6Hz,1H),7.04-6.95(m,3H),6.68(ddd,J=8.9,3.9,2.8Hz,1H),3.68(t,J=6.6Hz,2H),3.11-3.03(m,2H),2.12-2.02(m,2H)。
實例413係類似於實例411使用3-(2-((2-胺基乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮、磺醯胺及吡啶來製得。C15H16ClFN8O3S.443.1(M+1)。1H NMR(400MHz,甲醇-d4)δ 7.84(d,J=6.5Hz,1H),7.04-6.95(m,3H),6.67(ddd,J=8.8,4.0,2.7Hz,1H),3.73(td,J=6.1,5.6,0.9Hz,3H),1.87(ddt,J=6.6,4.6,2.4Hz,1H)。
實例414係類似於實例411使用3-(2-((2-胺基乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮、苯磺醯氯及三乙胺來製得。C21H19ClFN7O3S.504.1(M+1)。
實例415係類似於實例411使用3-(2-((2-胺基乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮、氯甲酸甲酯及三乙胺來製得。C17H17ClFN7O3.422.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.43(s,1H),8.96(s,1H),7.97(d,J=6.4Hz,1H),7.28(s,1H),7.11(t,J=9.0Hz,1H),7.04(dd,J=6.5,2.8Hz,1H),6.93(d,J=6.3Hz,1H),6.59(ddd,J=9.0,4.0,2.7Hz,1H),3.53(d,J=3.9Hz,5H),3.25(d,J=6.0Hz,2H)。
實例416係類似於實例411使用3-(2-((2-胺基乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮、環丙烷磺醯氯及三乙胺來製得。C18H19ClFN7O3S.468.9(M+1)。1H NMR(400MHz,甲醇-d4)δ 7.84(d,J=6.5Hz,1H),7.04-6.96(m,3H),6.67(ddd,J=8.9,3.9,2.8Hz,1H),3.70(dd,J=6.5,5.3Hz,2H),3.42(dd,J=6.6,5.3Hz,2H),2.56(ddd,J=7.9,5.5,2.9Hz,1H),1.10-0.97(m,4H)。
實例417係類似於實例411使用3-(2-((2-胺基乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮、三氟甲磺醯氯及三乙胺來製得。C16H14ClF4N7O3S.496.3(M+1)。
實例418係類似於實例402使用(1H-咪唑-2-基)甲胺二鹽酸鹽及休
尼格鹼來製得。C17H14ClFN8O.401.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 8.90(s,1H),7.97(d,J=5.9Hz,1H),7.60(s,2H),7.10(t,J=9.0Hz,1H),6.94(d,J=15.7Hz,2H),6.60-6.53(m,1H),4.92(s,2H)。
實例419係類似於實例402使用(1H-咪唑-5-基)甲胺二鹽酸鹽及休尼格鹼來製得。C17H14ClFN8O.401.2(M+1)。
實例420係類似於實例402使用(3-甲基-1,2,4-噁二唑-5-基)甲胺來製得。C17H14ClFN8O2.417.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 8.97(s,1H),8.50(d,J=12.2Hz,1H),7.99(d,J=6.4Hz,1H),7.11(d,J=9.1Hz,1H),7.08-7.03(m,1H),6.96(d,J=6.4Hz,1H),6.60(ddd,J=9.0,4.0,2.7Hz,1H),4.97(d,J=6.0Hz,2H),2.32(s,3H)。
實例421係類似於實例402使用4-(3-溴苯基)-3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮及甲胺(2.0M於MeOH中)來製得。C14H13BrN6O.361.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 8.97(s,1H),7.97(d,J=6.2Hz,1H),7.07(d,J=2.0Hz,1H),7.02-6.92(m,3H),6.57(dt,J=7.0,2.1Hz,1H),3.02(d,J=4.7Hz,3H)。
實例422係類似於實例411使用3-(2-((3-胺基丙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮、氯甲酸甲酯及三乙胺來製得。C18H19ClFN7O3.436.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 8.94(s,1H),7.96(d,J=6.2Hz,1H),7.19(d,J=5.6Hz,1H),7.10(t,J=9.0Hz,1H),7.04(dd,J=6.6,2.7Hz,1H),6.91(d,J=6.2Hz,1H),6.59(ddd,J=8.9,4.0,2.8Hz,1H),3.53(s,3H),3.44(d,J=6.5Hz,2H),3.07(d,J=6.3Hz,2H),1.79-1.64(m,2H)。
實例423係類似於實例402使用4-(3-溴苯基)-3-(2-氯-1-((2-(三甲基
矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮及氫化鈉於MeOH中以原位生成甲醇鈉來製得。C14H12BrN5O2.362.0(M+1)。
實例424係類似於實例402使用4-(3-溴苯基)-3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮、2-(甲基磺醯基)乙-1-胺鹽酸鹽及休尼格鹼來製得。C16H17BrN6O3S.453.2(M+1)。
實例425係類似於實例424使用N-(2-胺基乙基)甲烷磺醯胺來製得。C16H18BrN7O3S.468.2(M+1)。
實例426係類似於實例424使用4-(3-溴苯基)-3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮及2-胺基乙烷-1-磺醯胺來製得。C15H16BrN7O3S.454.2(M+1)。
實例427係類似於實例402使用(5-甲基-1,3,4-噁二唑-2-基)甲胺草酸鹽及休尼格鹼來製得。C17H14ClFN8O2.417.2(M+1)。
4,5-二氟-2-(((1-甲基六氫吡啶-2-基)甲基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯係類似於實例39使用(1-甲基六氫吡啶-2-基)甲胺代替N,N-二甲基丙烷-1,3-二胺來製得。分離出黃色油狀4,5-二氟-2-(((1-甲基六氫吡啶-2-基)甲基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯之TFA鹽。C22H34F2N4O3Si.469.2(M+1)。
N-(3-氯-4-氟苯基)-4,5-二氟-2-(((1-甲基六氫吡啶-2-基)甲基)胺基)-1H-苯并[d]咪唑-7-甲醯胺係類似於實例39使用4,5-二氟-2-(((1-甲基六氫吡啶-2-基)甲基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯
并[d]咪唑-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-2-(((1-甲基六氫吡啶-2-基)甲基)胺基)-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽。C21H21ClF3N5O.452.2/454.1(M+1)。
實例428係類似於實例59使用N-(3-氯-4-氟苯基)-4,5-二氟-2-(((1-甲基六氫吡啶-2-基)甲基)胺基)-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(((1-甲基六氫吡啶-2-基)甲基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C21H22ClF3N6O.467.2/469.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.78(s,1H),9.25(s,1H),8.69(s,1H),7.10(t,J=9.1Hz,1H),7.00(s,1H),6.92(dd,J=6.5,2.7Hz,1H),6.83(dd,J=12.2,6.8Hz,1H),6.53(ddd,J=9.0,4.1,2.7Hz,1H),3.79(m,1H),3.68(m,1H),3.41(m,1H),3.24(m,1H),3.04(m,1H),2.97(s,3H),2.83(m,1H),1.94(m,1H),1.85-1.70(m,2H),1.65-1.40(m,2H)。19F NMR(377MHz,DMSO)δ -75.02(9F),-127.46(1F),-150.44(1F),-157.01(1F)。
實例429係類似於實例39使用(4-甲基嗎啉-3-基)甲胺代替N,N-二
甲基丙烷-1,3-二胺來製得。分離出黃色油狀4,5-二氟-2-(((4-甲基嗎啉-3-基)甲基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯之TFA鹽。C21H32F2N4O4Si.471.2(M+1)。
N-(3-氯-4-氟苯基)-4,5-二氟-2-(((4-甲基嗎啉-3-基)甲基)胺基)-1H-苯并[d]咪唑-7-甲醯胺係類似於實例39使用4,5-二氟-2-(((4-甲基嗎啉-3-基)甲基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-2-(((4-甲基嗎啉-3-基)甲基)胺基)-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽。C20H19ClF3N5O2.454.2/456.1(M+1)。
實例429係類似於實例59使用N-(3-氯-4-氟苯基)-4,5-二氟-2-(((4-甲基嗎啉-3-基)甲基)胺基)-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(((4-甲基嗎啉-3-基)甲基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C20H20ClF3N6O2.469.1/471.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.76(s,1H),8.68(s,1H),7.09(t,J=9.1Hz,1H),6.92(dd,J=6.5,2.8Hz,2H),6.83(dd,J=12.2,6.8Hz,1H),6.53(ddd,J=8.9,4.0,2.7Hz,1H),4.10-3.84(m,4H),3.80-3.65(m,2H),3.58-3.34(m,2H),3.26(m,1H),3.03(s,
3H)。19F NMR(377MHz,DMSO-d6)δ -74.98(9F),-127.43(1F),-150.47(dd,J=21.1,12.8Hz,1F),-157.02(1F)。
N-(3-溴苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺係類似於實例39使用2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。分離出白色固體狀N-(3-溴苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽。C18H18BrF2N5O.438.1/440.1(M+1)。
實例430係類似於實例59使用N-(3-溴苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。分離出灰白色固體狀N-(3-溴苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C18H19BrF2N6O.455.1/456.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.80(s,1H),8.68(s,1H),7.04-6.93(m,3H),6.89(s,1H),6.81(dd,J=12.2,6.9Hz,1H),6.54(dt,J=7.7,1.7Hz,1H),3.70(m,2H),3.32(m,2H),2.86(s,6H)。19F NMR(377MHz,DMSO)δ -74.85(9F),-150.52(1F),-157.05(1F)。
N-(3-氯苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺係類似於實例39使用2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。分離出白色固體狀N-(3-氯苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽。C18H18ClF2N5O.394.1/396.2(M+1)。
實例431係類似於實例59使用N-(3-氯苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。分離出灰白色固體狀N-(3-氯苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C18H19ClF2N6O.409.1/411.1(M+1)).1H NMR(400MHz,DMSO-d6)δ 10.79(s,1H),8.68(s,1H),7.05(t,J=8.0Hz,1H),6.86-6.72(m,3H),6.54-6.46(m,1H),3.69(s,3H),3.32(s,4H),2.86(s,6H)。19F NMR(376MHz,DMSO-d6)δ -74.52,-150.61,-157.17。
N-(3-溴-4-氟苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺係類似於實例39使用2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯及使用3-溴-4-氟苯胺代替3-氯-4-氟苯胺來製得。分離出白色固體狀N-(3-溴-4-氟苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽。C18H17BrF3N5O.456.1/458.1(M+1)。
實例432係類似於實例59使用N-(3-溴-4-氟苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-1H-咪唑并[4,5-b]吡啶-7-甲醯胺來製得。分離出灰白色固體狀N-(3-溴-4-氟苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C18H18BrF3N6O.471.2/474.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.71(s,1H),8.64(s,1H),7.08-7.01(m,2H),6.79(s,2H),6.54(ddd,J=9.0,4.2,2.7Hz,1H),3.66(s,2H),3.30(s,2H),2.84(s,6H)。
4,5-二氟-2-((3-嗎啉基丙基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯係類似於實例39使用3-嗎啉基丙-1-胺代替N,N-二甲基丙烷-1,3-二胺來製得。分離出黃色油狀4,5-二氟-2-((3-嗎啉基丙基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯之TFA鹽。C22H34F2N4O4Si.485.1(M+1)。
N-(3-氯-4-氟苯基)-4,5-二氟-2-((3-嗎啉基丙基)胺基)-1H-苯并[d]咪唑-7-甲醯胺係類似於實例39使用4,5-二氟-2-((3-嗎啉基丙基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-2-((3-嗎啉基丙基)胺基)-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽。C21H21ClF3N5O2.468.2/470.1(M+1)。
實例433係類似於實例432使用N-(3-氯-4-氟苯基)-4,5-二氟-2-((3-嗎啉基丙基)胺基)-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-溴-4-氟苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((3-嗎啉基丙基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C21H22ClF3N6O2.483.1/485.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.75(s,1H),8.66(s,1H),7.09(t,J=9.1Hz,1H),6.92(dd,J=6.5,2.7Hz,1H),6.82(s,2H),6.54(dq,J=9.0,3.1Hz,1H),3.82(m,2H),3.42(m,2H),3.27(m,2H),3.17(t,J=7.9Hz,2H),1.97(t,J=7.8Hz,
2H)。
4,5-二氟-2-((3-(吡咯啶-1-基)丙基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯係類似於實例39使用3-(吡咯啶-1-基)丙-1-胺代替N,N-二甲基丙烷-1,3-二胺來製得。分離出黃色油狀4,5-二氟-2-((3-(吡咯啶-1-基)丙基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯之TFA鹽。C22H34F2N4O3Si.469.2(M+1)。
N-(3-氯-4-氟苯基)-4,5-二氟-2-((3-(吡咯啶-1-基)丙基)胺基)-1H-苯并[d]咪唑-7-甲醯胺係類似於實例39使用4,5-二氟-2-((3-(吡咯啶-1-基)丙基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-2-((3-(吡咯啶-1-基)丙基)胺基)-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽。C21H21ClF3N5O.452.0/454.1(M+1)。
實例434係類似於實例432使用N-(3-氯-4-氟苯基)-4,5-二氟-2-((3-(吡咯啶-1-基)丙基)胺基)-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-溴-4-氟
苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((3-(吡咯啶-1-基)丙基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C21H22ClF3N6O.467.2/469.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.75(s,1H),9.68(s,1H),8.66(s,1H),7.09(t,J=9.1Hz,1H),6.92(dd,J=6.5,2.7Hz,1H),6.90-6.75(m,2H),6.54(ddd,J=9.0,4.1,2.8Hz,1H),3.55-3.34(m,8H),3.17(m,2H),1.93(m,6H)。19F NMR(377MHz,DMSO)δ -74.57,-127.43,-150.48,-157.56。
(S)-4,5-二氟-2-((1-甲基吡咯啶-3-基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯係類似於實例39使用(S)-1-甲基吡咯啶-3-胺代替N,N-二甲基丙烷-1,3-二胺來製得。分離出黃色油狀(S)-4,5-二氟-2-((1-甲基吡咯啶-3-基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯之TFA鹽。C21H32F2N4O3Si.441.0(M+1)。
(S)-N-(3-氯-4-氟苯基)-4,5-二氟-2-((1-甲基吡咯啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲醯胺係類似於實例39使用(S)-4,5-二氟-2-((1-甲基吡咯啶-3-基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基
矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。分離出白色固體狀(S)-N-(3-氯-4-氟苯基)-4,5-二氟-2-((1-甲基吡咯啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽。C19H17ClF3N5O.424.1/426.1(M+1)。
實例435係類似於實例432使用(S)-N-(3-氯-4-氟苯基)-4,5-二氟-2-((1-甲基吡咯啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-溴-4-氟苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺來製得。分離出灰白色固體狀2-(((3R)-4-胺基-1-甲基吡咯啶-3-基)胺基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽(15.8mg,67%)。C19H19ClF3N7O.454.1/456.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.80(s,1H),8.67(s,1H),7.10(t,J=9.2Hz,1H),7.08(br s,1H),6.92(dd,J=6.5,2.7Hz,1H),6.83(dd,J=12.2,7.0Hz,1H),6.54(ddd,J=8.9,4.0,2.7Hz,1H),6.10(s,2H),4.77(s,1H),4.00(dq,J=8.3,7.0Hz,1H),3.90(dd,J=12.5,8.1Hz,1H),3.82(t,J=9.9Hz,1H),3.67(d,J=12.7Hz,1H),3.58(td,J=11.2,8.1Hz,1H),3.38(s,3H),2.76-2.64(m,1H),2.25-2.12(m,1H)。19F NMR(376MHz,DMSO)δ -74.87,-127.5,-150.4,-156.9.
2-((2-(二甲基胺基)-2-苯基乙基)胺基)-4,5-二氟-1-((2-(三甲基矽
基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯係類似於實例39使用N 1,N 1-二甲基-1-苯基乙烷-1,2-二胺代替N,N-二甲基丙烷-1,3-二胺來製得。分離出黃色油狀2-((2-(二甲基胺基)-2-苯基乙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯之TFA鹽。C25H34F2N4O3Si,505.1(M+1)。
N-(3-氯-4-氟苯基)-2-((2-(二甲基胺基)-2-苯基乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺係類似於實例39使用2-((2-(二甲基胺基)-2-苯基乙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-2-((2-(二甲基胺基)-2-苯基乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽。C24H21ClF3N5O.488.1/490.1(M+1)。
實例436係類似於實例432使用N-(3-氯-4-氟苯基)-2-((2-(二甲基胺基)-2-苯基乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-溴-4-氟苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-((2-(二甲基胺基)-2-苯基乙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C24H22ClF3N6O.503.1/505.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.75(s,1H),10.68(s,1H),8.66(s,1H),7.62-7.55(m,
1H),7.53(d,J=3.3Hz,3H),7.09(t,J=8.9Hz,1H),6.89(dd,J=6.5,2.7Hz,1H),6.85-6.74(m,1H),6.67-6.58(m,1H),6.54-6.46(m,1H),4.69(m,1H),4.26(m,1H),3.97(m,1H),2.75(s,6H)。19F NMR(377MHz,DMSO-d6)δ -74.37(9F),-127.54(1F),-150.55(1F),-156.90(1F)。
2-(((1R,2R)-2-(二甲基胺基)環己基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯係類似於實例39使用(1R,2R)-N 1,N 1-二甲基環己烷-1,2-二胺代替N,N-二甲基丙烷-1,3-二胺來製得。分離出黃色油狀2-(((1R,2R)-2-(二甲基胺基)環己基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯之TFA鹽。C23H36F2N4O3Si.483.2(M+1)。
N-(3-氯-4-氟苯基)-2-(((1R,2R)-2-(二甲基胺基)環己基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺係類似於實例39使用2-(((1R,2R)-2-(二甲基胺基)環己基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-2-(((1R,2R)-2-(二甲基胺基)環己基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽。
C22H23ClF3N5O.466.2/468.1(M+1)。
實例437係類似於實例402使用N-(3-氯-4-氟苯基)-2-(((1R,2R)-2-(二甲基胺基)環己基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(((1-(二甲基胺基)環己基)甲基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-(((1R,2R)-2-(二甲基胺基)環己基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C22H24ClF3N6O.481.2/483.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.78(s,1H),8.91(s,1H),8.67(s,1H),7.11(t,J=9.1Hz,1H),6.91(dd,J=6.5,2.7Hz,1H),6.84(dd,J=12.3,7.0Hz,1H),6.79(d,J=9.7Hz,1H),6.53(ddd,J=9.0,4.0,2.7Hz,1H),4.02(m,1H),3.33(m,1H),2.77(s,3H),2.78(s,3H),2.07(m,1H),1.93(app.d,J=9.9Hz,1H),1.83(app.d,J=11.8Hz,1H),1.70(app.d,J=9.5Hz,1H),1.63-1.48(m,1H),1.36(dq,J=27.4,13.2,12.3Hz,3H)。19F NMR(377MHz,DMSO-d6)δ -75.02(9F),-127.56(1F),-150.41(1F),-156.89(1F)。
2-(((1-(二甲基胺基)環戊基)甲基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯係類似於實例39使用1-(胺基甲基)-N,N-二甲基環戊-1-胺代替N,N-二甲基丙烷-1,3-二胺來製
得。分離出黃色油狀2-(((1-(二甲基胺基)環戊基)甲基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸酯甲基之TFA鹽。C23H36F2N4O3Si.483.2(M+1)。
N-(3-氯-4-氟苯基)-2-(((1-(二甲基胺基)環戊基)甲基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺係類似於實例39使用2-(((1-(二甲基胺基)環戊基)甲基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-2-(((1-(二甲基胺基)環戊基)甲基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽。C22H23ClF3N5O.466.2/468.1(M+1)。
實例438係類似於實例402使用N-(3-氯-4-氟苯基)-2-(((1-(二甲基胺基)環戊基)甲基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(((1-(二甲基胺基)環己基)甲基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-(((1-(二甲基胺基)環戊基)甲基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C22H24ClF3N6O.481.2/483.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.79(s,1H),9.68(s,1H),8.70(s,1H),7.15-7.01(m,2H),6.93(dd,J=6.5,2.7Hz,1H),6.85(dd,J=12.2,6.9Hz,1H),6.52(ddd,J=9.0,4.1,2.8Hz,1H),3.74(d,J=6.6Hz,2H),2.84
(s,3H),2.83(s,3H),1.96-1.79(m,4H),1.71(t,J=5.6Hz,4H)。19F NMR(377MHz,DMSO)δ -74.89(9F),-127.51(1F),-150.42(1F),-157.09(1F)。
2-((3-(二甲基胺基)環己基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯係類似於實例39使用N 1,N 1-二甲基環己烷-1,3-二胺代替N,N-二甲基丙烷-1,3-二胺來製得。分離出黃色油狀2-((3-(二甲基胺基)環己基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯之TFA鹽。C23H36F2N4O3Si.483.1(M+1)。
N-(3-氯-4-氟苯基)-2-((3-(二甲基胺基)環己基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺係類似於實例39使用2-((3-(二甲基胺基)環己基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-2-((3-(二甲基胺基)環己基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽。C22H23ClF3N5O.466.2(M+1)。
實例439係類似於實例402使用N-(3-氯-4-氟苯基)-2-((3-(二甲基胺基)環己基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(((1-(二甲基胺基)環己基)甲基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺來製得。藉由反相HPLC分離兩種非鏡像異構物且分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-(((1S,3S)-3-(二甲基胺基)環己基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。(C22H24ClF3N6O.481.1/483.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.81(s,1H),9.45(s,1H),8.69(s,1H),7.10(t,J=9.1Hz,1H),6.92(dd,J=6.5,2.7Hz,1H),6.81(t,J=9.8Hz,1H),6.54(ddd,J=9.0,4.0,2.7Hz,1H),3.33(m,1H),2.76(d,J=5.0Hz,3H),2.74(d,J=4.9Hz,3H),2.39(d,J=11.9Hz,1H),1.93(dd,J=27.6,11.7Hz,4H),1.48-1.30(m,4H),1.21(d,J=13.5Hz,1H)。19F NMR(377MHz,DMSO-d6)δ -74.82,-127.48,-149.43,-156.88。
自實例439中所述之順序分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-(((1S,3R)-3-(二甲基胺基)環己基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C22H24ClF3N6O.481.1/483.0(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.77(s,1H),9.27(s,1H),8.65(s,1H),7.11(t,J=9.1Hz,1H),7.00(s,1H),6.91(dd,J=6.5,2.7Hz,1H),6.79(dd,J=12.0,7.5Hz,1H),6.54(dt,J=9.1,3.5Hz,1H),5.06(q,J=9.0Hz,1H),4.21(m,1H),3.29(m,1H),2.77(d,J=4.6Hz,3H),2.72(d,J=
4.7Hz,3H),2.29(d,J=14.9Hz,1H),1.98(m,1H),1.77(m,3H),1.56(m,3H)。
2-(((1-(二甲基胺基)環丁基)甲基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯係類似於實例39使用1-(胺基甲基)-N,N-二甲基環丁-1-胺代替N,N-二甲基丙烷-1,3-二胺來製得。分離出黃色油狀2-(((1-(二甲基胺基)環丁基)甲基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯之TFA鹽。C22H34F2N4O3Si.469.2(M+1)。
N-(3-氯-4-氟苯基)-2-(((1-(二甲基胺基)環丁基)甲基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺係類似於實例39使用2-(((1-(二甲基胺基)環了基)甲基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-2-(((1-(二甲基胺基)環丁基)甲基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽。C21H21ClF3N5O.452.2/545.1(M+1)。
實例441係類似於實例402使用N-(3-氯-4-氟苯基)-2-(((1-(二甲基胺基)環丁基)甲基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(((1-(二甲基胺基)環己基)甲基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-(((1-(二甲基胺基)環丁基)甲基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C21H22ClF3N6O.467.2/469.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.79(s,1H),8.70(s,1H),7.17(t,J=6.6Hz,1H),7.08(t,J=9.1Hz,1H),6.94(dd,J=6.5,2.7Hz,1H),6.87(dd,J=12.2,6.9Hz,1H),6.54(ddd,J=9.0,4.0,2.7Hz,1H),6.06(s,1H),4.06(d,J=6.6Hz,2H),3.20(s,6H),2.74(dt,J=14.1,10.0Hz,2H),2.12-1.99(m,2H),1.85-1.70(m,2H)。19F NMR(376MHz,DMSO-d6)δ -75.09,-127.43,-150.31,-156.83。
4,5-二氟-2-((1-甲基六氫吡啶-4-基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯係類似於實例39使用1-甲基六氫吡啶-4-胺代替N,N-二甲基丙烷-1,3-二胺來製得。分離出黃色油狀4,5-二氟-2-((1-甲基六氫吡啶-4-基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯之TFA鹽。C21H32F2N4O3Si.455.1(M+1)。
N-(3-氯-4-氟苯基)-4,5-二氟-2-((1-甲基六氫吡啶-4-基)胺基)-1H-苯并[d]咪唑-7-甲醯胺係類似於實例39使用4,5-二氟-2-((1-甲基六氫吡啶-4-基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-2-((1-甲基六氫吡啶-4-基)胺基)-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽。C20H19ClF3N5O.438.2/440.3(M+1)。
實例442係類似於實例402使用N-(3-氯-4-氟苯基)-4,5-二氟-2-((1-甲基六氫吡啶-4-基)胺基)-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(((1-(二甲基胺基)環己基)甲基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((1-甲基六氫吡啶-4-基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C20H20ClF3N6O.453.1/455.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.78(s,1H),9.26(s,1H),8.68(s,1H),7.09(t,J=9.1Hz,1H),6.92(m,1H),6.82(m,1H),6.53(ddd,J=8.9,4.1,2.7Hz,1H),4.31-4.17(m,1H),3.09(q,J=11.6Hz,4H),2.80(d,J=4.7Hz,3H),2.17(d,J=13.6Hz,2H),1.64(q,J=13.0,11.7Hz,2H)。
4,5-二氟-2-((1-甲基六氫吡啶-3-基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯係類似於實例39使用1-甲基六氫吡啶-3-胺代替N,N-二甲基丙烷-1,3-二胺來製得。分離出黃色油狀4,5-二氟-2-((1-甲基六氫吡啶-3-基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯之TFA鹽。C21H32F2N4O3Si.455.2(M+1)。
N-(3-氯-4-氟苯基)-4,5-二氟-2-((1-甲基六氫吡啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲醯胺係類似於實例39使用4,5-二氟-2-((1-甲基六氫吡啶-3-基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-2-((1-甲基六氫吡啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽。C20H19ClF3N5O.438.2/440.1(M+1)。
實例443係類似於實例402使用N-(3-氯-4-氟苯基)-4,5-二氟-2-((1-甲基六氫吡啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(((1-(二甲基胺基)環己基)甲基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((1-甲基六氫吡啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C20H20ClF3N6O.453.2/455.1(M+1)。1H NMR(400MHz,
DMSO-d6)δ 10.80(s,1H),9.63(s,1H),8.68(s,1H),7.10(t,J=9.1Hz,1H),6.92(dd,J=6.5,2.8Hz,1H),6.82(dd,J=12.3,6.9Hz,1H),6.54(ddd,J=9.0,4.1,2.7Hz,1H),4.03(m,1H),3.65(m,1H),3.42(m,1H),2.88(d,J=4.7Hz,1H),2.83(d,J=4.6Hz,3H),2.78(d,J=8.7Hz,1H),2.06-1.65(m,3H),1.53-1.38(m,1H)。19F NMR(377MHz,DMSO-d6)δ -74.95(9F),-127.50(1F),-150.55(1F),-156.90(1F)。
2-(((1S,2S)-2-(二甲基胺基)環己基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯係類似於實例39使用(1S,2S)-N1,N1-二甲基環己烷-1,2-二胺代替N,N-二甲基丙烷-1,3-二胺來製得。分離出黃色油狀2-(((1S,2S)-2-(二甲基胺基)環己基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯之TFA鹽。C23H36F2N4O3Si.483.2/484.1(M+1)。
N-(3-氯-4-氟苯基)-2-(((1S,2S)-2-(二甲基胺基)環己基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺係類似於實例39使用2-(((1S,2S)-2-(二甲基胺基)環己基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯
來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-2-(((1S,2S)-2-(二甲基胺基)環己基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽。C22H23ClF3N5O.466.2/468.1(M+1)。
實例444係類似於實例402使用N-(3-氯-4-氟苯基)-2-(((1S,2S)-2-(二甲基胺基)環己基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺代替N-(3-氯-4-氟苯基)-2-(((1-(二甲基胺基)環己基)甲基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-(((1S,2S)-2-(二甲基胺基)環己基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C22H24ClF3N6O.481.2/483.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.92-10.67(m,1H),8.92(s,1H),8.67(s,1H),7.11(t,J=9.1Hz,1H),6.91(dd,J=6.5,2.7Hz,1H),6.88-6.75(m,2H),6.53(ddd,J=9.0,4.0,2.7Hz,1H),4.04(m,1H),3.33(td,J=11.6,3.5Hz,1H),2.77(d,J=4.3Hz,6H),2.13-2.03(m,1H),1.94(app.d,J=10.7Hz,1H),1.83(app.d,J=11.9Hz,1H),1.70(app.d,J=9.4Hz,1H),1.53(app.dd,J=13.6,10.1Hz,1H),1.37(m,3H)。19F NMR(376MHz,DMSO-d6)δ -75.01(9F),-127.56(1F),-150.41(1F),-156.9(d,J=22.3Hz,1F)。
實例445係類似於實例333使用(S)-3-胺基六氫吡啶-1-甲酸第三丁
基酯代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀(S)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(六氫吡啶-3-基胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C19H18ClF3N6O.439.2/441.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.78(s,1H),8.69-8.50(m,3H),7.10(t,J=9.1Hz,1H),6.91(dd,J=6.5,2.7Hz,1H),6.86(m,1H),6.79(m,1H),6.55(ddd,J=9.0,4.1,2.8Hz,1H),4.00(m,1H),3.47(app.d,J=11.9Hz,1H),3.21(app.d,J=12.3Hz,1H),2.93-2.79(m,2H),2.00(m,1H),1.89(m,1H),1.80-1.63(m,1H),1.57(m,1H)。19F NMR(376MHz,DMSO)δ -74.92,-127.48,-150.57,-156.96。
實例446係類似於實例333使用(R)-3-胺基六氫吡啶-1-甲酸第三丁基酯代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀(R)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(六氫吡啶-3-基胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C19H18ClF3N6O.439.2/441.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.79(s,1H),8.78-8.51(m,3H),7.10(t,J=9.1Hz,1H),6.91(dd,J=6.5,2.7Hz,1H),6.86(d,J=6.6Hz,1H),6.81(dd,J=12.1,6.8Hz,1H),6.54(ddd,J=9.0,4.0,2.8Hz,1H),4.02(m,1H),3.47(app.d,J=12.2Hz,1H),3.21(app.d,J=12.4Hz,1H),2.93-2.80(m,2H),2.00(app.d,J=12.2Hz,1H),1.89(m,1H),1.71(m,1H),1.56(m,1H)。19F NMR(377MHz,DMSO-d6)δ -74.88(9F),-127.50(1F),-150.58(1F),-156.99(1F)。
實例447係類似於實例333使用(S)-1-甲基吡咯啶-3-胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀(S)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((1-甲基吡咯啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C19H18ClF3N6O.439.2/441.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.76(br.s,1H),9.75(br.s,1H),8.67(d,J=3.5Hz,1H),7.09(td,J=9.1,3.4Hz,1H),6.98(m,1H),6.92(dt,J=6.5,2.4Hz,1H),6.85(m,1H),6.53(dt,J=8.9,3.5Hz,1H),4.49(m,1H),3.94(m,1H),3.36(m,1H),3.23(m,1H),3.06(m,1H),2.89(app.dd,J=9.0,4.8Hz,3H),2.06(m,1H),1.90(m,1H)。19F NMR(376MHz,DMSO-d6)δ -74.77,-127.47,-150.47,-156.78。
實例448係類似於實例333使用1-胺基-3-(二甲基胺基)丙-2-醇代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-((3-(二甲基胺基)-2-羥基丙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C19H20ClF3N6O2.457.2/459.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.86(br.s,1H),9.38(br.s,1H),8.73(s,1H),7.30(m,1H),7.10(t,J=9.1Hz,1H),6.94(dd,J=6.5,2.7Hz,1H),6.88(dd,J=12.2,6.9Hz,1H),6.54(ddd,J=9.0,4.0,
2.7Hz,1H),4.11(dq,J=9.7,5.0Hz,1H),3.47(dt,J=13.9,5.5Hz,1H),3.39(m,1H),3.16(app.d,J=12.8Hz,1H),3.06(dd,J=12.9,10.1Hz,1H),2.81(s,6H)。19F NMR(377MHz,DMSO-d6)δ -75.02,-127.32,-149.66,-156.59。
實例449係類似於實例333使用4-(2-胺基乙基)-1-甲基六氫吡嗪-2-酮代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(4-甲基-3-側氧基六氫吡嗪-1-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C21H21ClF3N7O2.496.2/498.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.81(br.s,1H),8.71(s,1H),7.14(br.s,1H),7.10(t,J=9.1Hz,1H),6.94(dd,J=6.5,2.7Hz,1H),6.87(dd,J=12.2,6.9Hz,1H),6.53(ddd,J=8.9,4.0,2.7Hz,1H),3.90(s,2H),3.71(m,2H),3.65-3.50(m,4H),3.35(m,2H),2.89(s,3H)。19F NMR(376MHz,DMSO-d6)δ -75.14,-127.23,-149.86,-156.94。
4,5-二氟-2-((1-甲基六氫吡啶-3-基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯係類似於實例39使用1-(胺基
甲基)-N,N-二甲基環己-1-胺代替N,N-二甲基丙烷-1,3-二胺來製得。分離出黃色油狀2-(((1-(二甲基胺基)環己基)甲基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯之TFA鹽。C21H32F2N4O3Si.497.3(M+1)。
N-(3-氯-4-氟苯基)-2-(((1-(二甲基胺基)環己基)甲基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺係類似於實例39使用4,5-二氟-2-((1-甲基六氫吡啶-3-基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯來製得。分離出白色固體狀N-(3-氯-4-氟苯基)-2-(((1-(二甲基胺基)環己基)甲基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺。C23H25ClF3N5O.480.2/482.1(M+1)。
將N-(3-氯-4-氟苯基)-2-(((1-(二甲基胺基)環己基)甲基)胺基)-4,5-二氟-1H-苯并[d]咪唑-7-甲醯胺之TFA鹽(103mg,0.15mmol,1當量)溶解於EtOAc中,添加飽和NaHCO3水溶液並將混合物用EtOAc萃取兩次。將合併之有機物經MgSO4乾燥,過濾並在真空中濃縮。將所得殘餘物溶解於CH2Cl2(1mL)中並添加碳酸鉀(148mg,01.05mmol,7當量)及PCl5(95mg,0.46mmol,3當量)。將反應物於室溫下攪拌3小時,之後在真空中濃縮。於0℃下添加TMSONH2(0.185mL,1.5mmol,10當量)於三氟乙醇(1.5mL)中之溶液。將反應物緩慢升溫至室
溫並攪拌1小時,之後在真空中濃縮。添加2N HCl溶液並將所得混合物攪拌30分鐘,之後用DMF/H2O稀釋並藉由反相HPLC純化。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-(((1-(二甲基胺基)環己基)甲基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C23H26ClF3N6O.495.2/497.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.80(s,1H),9.49(br.s,1H),8.68(s,1H),7.10(t,J=9.1Hz,1H),7.03(br.s,1H),6.92(dd,J=6.5,2.7Hz,1H),6.85(dd,J=12.2,6.9Hz,1H),6.53(dt,J=8.9,3.5Hz,1H),4.31(m,1H),3.86(d,J=6.5Hz,1H),2.81(s,3H),2.80(s,3H),1.83-1.93(m,2H),1.74-1.43(m,7H),1.20(m,1H)。19F NMR(376MHz,DMSO)δ -75.00,-127.52,-150.3,-156.97。
實例451係類似於實例333使用1-甲基氮雜環庚烷-3-胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((1-甲基氮雜環庚烷-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C21H22ClF3N6O.467.2/469.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.77(s,1H),9.68(br.s,1H),8.66(s,1H),7.10(t,J=9.1Hz,1H),6.91(dd,J=6.5,2.7Hz,1H),6.83(m,1H),6.54(m,1H),4.19(m,1H),3.37(m,2H),3.20(m,2H),2.87(s,3H),2.03(m,1H),1.97-1.54(m,5H)。19F NMR(376MHz,DMSO-d6)δ -74.83,-127.52,-150.54,-156.65。
實例452係類似於實例333使用(S)-1-(2-胺基乙基)吡咯啶-3-醇代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀(S)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(3-羥基吡咯啶-1-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C20H20ClF3N6O2.469.2/471.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.76(s,1H),10.04(br.s,1H),8.68(s,1H),7.09(t,J=9.1Hz,1H),6.97-6.90(m,2H),6.83(dd,J=12.2,6.9Hz,1H),6.53(ddd,J=9.0,4.1,2.8Hz,1H),4.43(m,1H),3.68(m,6H),3.41(m,2H),2.15(m,1H),1.88(m,1H)。19F NMR(376MHz,DMSO)δ -74.97,-127.34,-150.40,-156.84。
實例453係類似於實例333使用1-(2-甲氧基乙基)六氫吡啶-3-胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((1-(2-甲氧基乙基)六氫吡啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C22H24ClF3N6O2.497.2/499.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.81(s,1H),9.63(br.s,1H),8.68(s,1H),7.10(t,J=9.1Hz,1H),6.96-6.88(m,2H),6.81(dd,J=12.2,6.9Hz,1H),6.55(ddd,J=9.0,
4.0,2.8Hz,1H),3.72(m,1H),3.67(app.t,J=4.9Hz,2H),3.50(m,1H),3.35(m,2H),3.32(s,3H),3.25(m,1H),2.95-2.70(m,2H),2.05-1.75(m,3H),1.48(m,1H)。19F NMR(377MHz,DMSO-d6)δ -75.0(9F),-127.5(1F),-150.6(1F),-157.0(1F)。
實例454係類似於實例333使用1-(2-甲氧基乙基)吡咯啶-3-胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((1-(2-甲氧基乙基)吡咯啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C21H22ClF3N6O2.483.3/485.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.80(s,1H),10.19(br.s,1H),8.72(s,1H),7.26(d,J=10.0Hz,1H),7.13-7.05(m,2H),6.93(dd,J=6.5,2.6Hz,1H),6.87(dt,J=12.0,4.8Hz,1H),6.53(ddd,J=9.0,4.0,2.8Hz,1H),4.65-4.45(m,1H),3.98-3.70(m,1H),3.67-3.56(m,3H),3.50-3.37(m,3H),3.32(d,J=7.0Hz,3H),3.11(m,1H),2.37-2.25(m,1H),2.07-1.84(m,1H)。19F NMR(377MHz,DMSO-d6)δ -75.04(9F),-127.36(1F),-150.26(1F),-156.63(1F)。
實例455係類似於實例333使用1-異丙基六氫吡啶-3-胺代替(2-胺
基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((1-異丙基六氫吡啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C22H24ClF3N6O.481.3/483.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.79(s,1H),9.26(s,1H),8.67(s,1H),7.10(t,J=9.1Hz,1H),6.92(dd,J=6.5,2.7Hz,1H),6.85-6.75(m,2H),6.54(m,1H),4.16(m,1H),3.59-3.51(m,2H),3.36(m,1H),2.94-2.77(m,2H),2.00(m,2H),1.77(m,1H),1.54(m,1H),1.26(t,J=6.2Hz,6H)。19F NMR(377MHz,DMSO-d6)δ -74.90(9F),-127.52(1F),-150.59(1F),-157.02(1F)。
實例456係類似於實例333使用2-(3-甲氧基氮雜環丁-1-基)乙-1-胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(3-甲氧基氮雜環丁-1-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C20H20ClF3N6O2.469.2/471.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.79(s,1H),9.94(br.s,1H),8.72(s,1H),7.09(t,J=9.1Hz,1H),6.97-6.90(m,2H),6.85(dd,J=12.2,6.9Hz,1H),6.53(ddd,J=8.9,4.0,2.8Hz,1H),4.30-4.15(m,3H),4.03(m,2H),3.55(m,2H),3.41(m,2H),3.25(s,3H)。19F NMR(377MHz,DMSO-d6)δ -75.03(9F),-127.30(1F),-150.32(1F),-157.00(1F)。
實例457係類似於實例333使用(R)-1-甲基吡咯啶-3-胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀(R)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((1-甲基吡咯啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C19H18ClF3N6O.439.2/441.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.80(s,1H),10.11(br.s,0.5H),9.85(br.s,0.5H),8.71(s,1H),7.28(d,J=9.3Hz,0.5H),7.15-7.01(m,1.5H),6.93(dt,J=6.3,2.8Hz,1H),6.87(dd,J=12.2,6.9Hz,1H),6.53(m,1H),4.53(m,0.5H),4.45(m,0.5H),3.71(m,0.5H),3.62(m,0.5H),3.35(m,1H),3.23(m,0.5H),3.16-2.97(m,1.5H),2.90(d,J=5.0Hz,1.5H),2.88(d,J=4.6Hz,1.5H),2.56(m,0.5H),2.31(m,0.5H),2.06(m,0.5H),1.91(m,0.5H)。19F NMR(377MHz,DMSO-d6)δ -75.00,-127.38,-150.33,-156.70。
實例458係類似於實例333使用(3R,4R)-4-甲氧基-1-甲基吡咯啶-3-胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(((3R,4R)-4-甲氧基-1-甲基吡咯啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C20H20ClF3N6O2.469.2/471.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.76(s,1H),10.13(br.s,1H),8.70(s,1H),7.20(m,1H),7.09(td,J=
9.1,3.0Hz,1H),6.92(dd,J=6.5,2.7Hz,1H),6.86(m,1H),6.53(dt,J=8.9,3.4Hz,1H),4.41(m,1H),4.09(m,1H),3.95(m,1H),3.71(m,1H),3.37(m,3H),3.21(m,1H),3.10(m,1H),2.90(m,3H)。19F NMR(377MHz,DMSO-d6)δ -74.80,-127.49,-150.49,-157.01。
實例459係類似於實例460使用(S)-N-(3-氯苯基)-4,5-二氟-2-((1-甲基六氫吡啶-3-基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸酯來製得。分離出灰白色固體狀(S*)-N-(3-氯苯基)-4,5-二氟-N'-羥基-2-((1-甲基六氫吡啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C20H21ClF2N6O.435.2/437.1(M+1);435.2/437.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.90(s,1H),9.66(br.s,1H),8.67(s,1H),7.06(t,J=8.1Hz,1H),6.95(m,1H),6.82(dd,J=8.0,2.2Hz,1H),6.79(t,J=2.2Hz,1H),6.53(dd,J=8.2,2.1Hz,1H),4.06(m,1H),3.67(m,1H),3.42(m,1H),2.83(d,J=4.4Hz,3H),2.82-2.73(m,2H),2.00(m,2H),1.75(m,1H),1.45(m,1H);1H NMR(400MHz,DMSO-d6)δ 10.88(s,1H),9.63(br.s,1H),8.69(s,1H),7.06(t,J=8.0Hz,1H),6.92(m,1H),6.83(m,2H),6.79(t,J=2.2Hz,1H),6.52(dd,J=8.1,2.2Hz,1H),4.06(m,1H),3.65(m,1H),3.42(m,1H),2.83(d,J=4.6Hz,3H),2.81-2.75(m,2H),1.99(m,2H),1.72(m,1H),1.45(m,1H)。19F NMR(376MHz,DMSO-d6)δ -74.95,-150.50,-156.86。
4,5-二氟-2-((1-甲基六氫吡啶-3-基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯係類似於實例39使用1-甲基六氫吡啶-3-胺代替N,N-二甲基丙烷-1,3-二胺來製得。分離出非晶形黃色油狀4,5-二氟-2-((1-甲基六氫吡啶-3-基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯之TFA鹽。C21H32F2N4O3Si.455.2(M+1)。
N-(3-氯苯基)-4,5-二氟-2-((1-甲基六氫吡啶-3-基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲醯胺係類似於實例39使用4,5-二氟-2-((1-甲基六氫吡啶-3-基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯代替2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲酸甲基酯及3-氯苯胺代替3-氯-4-氟苯胺來製得。藉由矽膠層析(0-16% MeOH/CH2Cl2 w/0.5% NEt3)純化N-(3-氯苯基)-4,5-二氟-2-((1-甲基六氫吡啶-3-基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲醯胺,分離出白色固體狀。C21H32F2N4O3Si.455.2(M+1)。使用手性SFC(AD-H,15% iPrOH,60mL/min,100巴)分離每一鏡像異構物。C26H34ClF2N5O2Si.550.3/552.1(M+1)。
將(R)-N-(3-氯苯基)-4,5-二氟-2-((1-甲基六氫吡啶-3-基)胺基)-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-甲醯胺(60mg,0.11mmol,1當量)溶解於CH2Cl2(2mL)中並添加TFA(2mL)。將SEM-去保護攪拌過夜,之後在真空中濃縮。將粗產物溶解於EtOAc中,添加飽和NaHCO3水溶液並將混合物用EtOAc萃取兩次。將合併之有機物經MgSO4乾燥,過濾並在真空中濃縮。將所得殘餘物溶解於CH2Cl2(1mL)中並添加碳酸鉀(106mg,0.76mmol,7當量)及PCl5(68mg,0.33mmol,3當量)。將反應物於室溫下攪拌3小時,之後在真空中濃縮。於0℃下添加TMSONH2(0.132mL,1.1mmol,10當量)於三氟乙醇(1.5mL)中之溶液。將反應物緩慢升溫至室溫並攪拌1小時,之後在真空中濃縮。添加2N HCl溶液並將所得混合物攪拌30分鐘,之後用DMF/H2O稀釋並藉由反相HPLC純化。分離出灰白色固體狀(R)-N-(3-氯苯基)-4,5-二氟-N'-羥基-2-((1-甲基六氫吡啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C20H21ClF2N6O.435.2/437.1(M+1);435.2/437.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.90(s,1H),9.66(br.s,1H),8.67(s,1H),7.06(t,J=8.1Hz,1H),6.95(m,1H),6.82(dd,J=8.0,2.2Hz,1H),6.79(t,J=2.2Hz,1H),6.53(dd,J=8.2,2.1Hz,1H),4.06(m,1H),3.67(m,1H),3.42(m,1H),2.83(d,J=4.4Hz,3H),2.82-2.73(m,2H),2.00(m,2H),1.75(m,1H),1.45(m,1H);1H NMR(400MHz,DMSO-d6)δ 10.88(s,1H),9.63(br.s,1H),8.69(s,1H),7.06(t,J=8.0Hz,1H),6.92(m,1H),6.83(m,2H),6.79(t,J=2.2Hz,1H),6.52(dd,J=8.1,2.2Hz,1H),4.06(m,1H),3.65(m,1H),3.42(m,1H),2.83(d,J=4.6Hz,3H),2.81-2.75(m,2H),
1.99(m,2H),1.72(m,1H),1.45(m,1H)。19F NMR(376MHz,DMSO-d6)δ -74.95,-150.50,-156.86。
實例461係類似於實例333使用N 1,N 1-二甲基環戊烷-1,2-二胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-((2-(二甲基胺基)環戊基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C21H22ClF3N6O.467.3/469.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.74(s,1H),8.69(s,1H),7.09(t,J=9.0Hz,1H),6.91(dd,J=6.5,2.7Hz,1H),6.83(m,1H),6.52(m,1H),4.34(m,1H),3.63(m,1H),2.85(s,6H),2.15-2.00(m,2H),1.87(m,1H),1.79-1.63(m,3H)。
實例462係類似於實例333使用(S)-3-胺基氮雜環庚烷-1-甲酸第三丁基酯代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀(S)-2-(氮雜環庚烷-3-基胺基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C20H20ClF3N6O.453.3(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.79(s,1H),8.77(br.s,2H),8.66(s,1H),7.10(t,J=9.1Hz,1H),6.91(dd,J=6.5,2.7Hz,1H),6.86(d,J=
6.9Hz,1H),6.82(dd,J=12.3,6.9Hz,1H),6.58-6.51(m,1H),4.15(m,1H),3.42(m,1H),3.26(m,1H),3.21-3.11(m,2H),2.04(m,1H),1.92-1.54(m,5H)。19F NMR(376MHz,DMSO-d6)δ -74.9,-127.5,-150.5,-156.8。
實例463係類似於實例333使用(R)-3-胺基氮雜環庚烷-1-甲酸第三丁基酯代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀(R)-2-(氮雜環庚烷-3-基胺基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C20H20ClF3N6O.453.2/455.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.78(s,1H),8.76(br.s,2H),8.66(s,1H),7.10(t,J=9.1Hz,1H),6.91(dd,J=6.5,2.7Hz,1H),6.83(d,J=6.8Hz,1H),6.80(d,J=6.7Hz,1H),6.54(ddd,J=9.0,4.1,2.8Hz,1H),4.15(m,1H),3.42(m,1H),3.26(m,1H),3.20-3.07(m,2H),2.05(m,1H),1.91-1.54(m,5H)。19F NMR(376MHz,DMSO-d6)δ -74.8,-127.5,-150.5,-156.8。
實例464係類似於實例333使用3-胺基吡咯啶-1-甲酸第三丁基酯
代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(吡咯啶-3-基胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C18H16ClF3N6O.425.2/427.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.78(s,1H),8.89(br.s,1H),8.79(br.s,1H),8.70(s,1H),7.12-7.05(m,2H),6.92(dd,J=6.5,2.7Hz,1H),6.85(dd,J=12.3,6.9Hz,1H),6.53(ddd,J=8.9,4.0,2.7Hz,1H),4.44(m,1H),3.47(m,1H),3.27(m,2H),2.27(m,1H),1.94(m,1H)。19F NMR(377MHz,DMSO-d6)δ -74.9(9F),-127.4(1F),-150.44(1F),-156.81(1F)。
實例465係類似於實例333使用(R)-1-(氧雜環丁-3-基)六氫吡啶-3-胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀(R)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((1-(氧雜環丁-3-基)六氫吡啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C22H22ClF3N6O2.495.3/497.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.82(s,1H),10.61br.(s,1H),8.70(s,1H),7.10(t,J=9.1Hz,1H),7.04(m,1H),6.92(dd,J=6.6,2.7Hz,1H),6.84(dd,J=12.3,6.9Hz,1H),6.54(dt,J=8.9,3.4Hz,1H),4.80-4.65(m,4H),4.40(m,1H),4.14(m,1H),3.53(m,1H),3.38(m,1H),2.84-2.65(m,2H),2.1-1.90(m,2H),1.77(m,1H),1.53(m,1H)。19F NMR(377MHz,DMSO-d6)δ -74.8(9F),-127.3(1F),-150.3(1F),-156.7(1F)。
實例466係類似於實例333使用(1,4-二甲基六氫吡啶-2-基)甲胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-(((1,4-二甲基六氫吡啶-2-基)甲基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C22H24ClF3N6O.481.3/483.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.79(s,1H),9.20(br.s,1H),8.69(s,1H),7.10(t,J=9.1Hz,1H),7.02(m,1H),6.92(dd,J=6.5,2.7Hz,1H),6.84(dd,J=12.2,6.9Hz,1H),6.54(ddd,J=9.0,4.1,2.7Hz,1H),3.81(m,1H),3.66(m,1H),3.40(m,1H),3.27(m,1H),3.08(m,1H),2.99(s,3H),1.93(m,1H),1.84-1.60(m,2H),1.25(m,1H),0.93(d,J=6.4Hz,3H)。19F NMR(376MHz,DMSO-d6)δ -75.1,-127.4,-150.4,-157.0。
實例467係類似於實例333使用3-(胺基甲基)嗎啉-4-甲酸第三丁基酯代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((嗎啉-3-基甲基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C19H18ClF3N6O2.455.2/457.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.80(s,1H),9.06(br.s,2H),8.71(s,
1H),7.10(t,J=9.1Hz,1H),7.02(m,1H),6.92(dd,J=6.6,2.7Hz,1H),6.83(dd,J=12.3,6.9Hz,1H),6.53(dt,J=9.0,3.4Hz,1H),3.95(m,1H),3.88(m,1H),3.67(m,1H),3.62-3.50(m,4H),3.30(m,1H),3.09(m,1H)。19F NMR(377MHz,DMSO-d6)δ -74.9(9F),-127.2(1F),-150.2(1F),-156.4(1F)。
實例468係類似於實例333使用(3R,4S)-3-胺基-4-羥基吡咯啶-1-甲酸第三丁基酯代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(((3R,4S)-4-羥基吡咯啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C18H16ClF3N6O2.441.2/443.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.83(s,1H),9.18(br.s,1H),8.81(br.s,1H),8.69(s,1H),7.11(t,J=9.1Hz,1H),6.95-6.90(m,2H),6.82(dd,J=12.3,6.8Hz,1H),6.53(dt,J=8.8,3.4Hz,1H),6.13(br.s,1H),4.49(m,1H),4.36(m,1H),3.56(m,1H),3.42(m,1H),3.17(m,1H),3.01(m,1H)。19F NMR(377MHz,DMSO-d6)δ -74.7(9F),-127.4(1F),-150.3(1F),-156.8(1F)。
實例469係類似於實例333使用(1R,5R)-8-甲基-8-氮雜二環[3.2.1]辛-2-胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(((1R,5R)-8-甲基-8-氮雜二環[3.2.1]辛-2-基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C22H22ClF3N6O.479.3/481.1(M+1)。1H NMR(400MHz,DMSO-d6,非鏡像異構物之2:1混合物)δ 10.82(br.s,1H),9.72(s,1H),8.69(d,J=7.8Hz,1H),7.17-7.03(m,2H),6.90(td,J=6.5,2.8Hz,1H),6.81(dd,J=12.3,7.0Hz,1H),6.55(ddd,J=8.9,4.6,3.1Hz,1H),4.29(m,1H),4.05-3.70(m,2H),2.75(d,J=4.9Hz,'2H'),2.63(d,J=4.8Hz,'1H'),2.23(m,1H),2.14-1.80(m,5H),1.73(m,1H),1.54(m,1H)。19F NMR(377MHz,DMSO)δ -75.02,主要:-127.83,-150.68,-156.90,次要:-127.66,-150.46,-156.51
實例470係類似於實例333使用(S)-2-(2-(三氟甲基)吡咯啶-1-基)乙-1-胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀(S)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(2-(三氟甲基)吡咯啶-1-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C21H19ClF6N6O.521.3/523.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.99(br.s,1H),8.82(s,1H),7.95(br.s,1H),7.13-7.03(m,2H),6.97(dd,J=6.5,2.7Hz,1H),6.54(ddd,J=9.0,4.1,2.8Hz,1H),3.59-3.40(m,3H),3.19(m,1H),3.03(dt,J=13.6,7.1Hz,1H),2.82(dt,J=12.7,5.2Hz,1H),2.46(m,1H),2.04(m,1H),1.87-1.64(m,3H)。19F NMR(377MHz,
DMSO-d6)δ -75.31(9F),-75.43(d,J=8.2Hz,3F),-126.82(1F),-147.12(1F),-155.04(1F)。
實例471係類似於實例333使用(四氫-1H-吡咯嗪-7a(5H)-基)甲胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-2-(((六氫-1H-吡咯嗪-7a-基)甲基)胺基)-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C22H22ClF3N6O.479.4/481.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.75(br.s,1H),8.74(s,1H),7.08(t,J=9.1Hz,1H),6.93(dd,J=6.5,2.7Hz,1H),6.87(dd,J=12.2,7.1Hz,1H),6.50(dq,J=9.0,3.0Hz,1H),3.69(app.d,J=5.9Hz,2H),3.46(dq,J=12.0,6.1Hz,2H),3.20(m,2H),2.14-1.96(m,4H),1.95-1.80(m,4H)。19F NMR(377MHz,DMSO-d6)δ -75.1(9F),-127.3(1F),-149.9(dd,J=22.6,12.3Hz,1F),-156.8(1F)。
實例472係類似於實例333使用2-(胺基甲基)-3,3-二甲基氮雜環丁烷-1-甲酸第三丁基酯代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-(((3,3-二甲基氮雜環丁-2-基)甲基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。
C20H20ClF3N6O.453.2/455.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.80(s,1H),8.97(br.s,1H),8.75-8.65(m,2H),7.09(t,J=9.1Hz,1H),6.97-6.78(m,3H),6.53(ddd,J=9.0,4.1,2.8Hz,1H),4.24(m,1H),3.80-3.59(m,3H),3.49(m,1H),1.27(s,3H),1.22(s,3H)。19F NMR(377MHz,DMSO-d6)δ -75.0(9F),-127.3(1F),-150.3(1F),-156.7(d,J=23.0Hz,1F)。
實例473係類似於實例333使用4-(吡咯啶-1-基)四氫-2H-吡喃-3-胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((4-(吡咯啶-1-基)四氫-2H-吡喃-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C23H24ClF3N6O2.509.3/511.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.79(s,1H),9.65(br.s,1H),8.68(s,1H),7.20(d,J=8.0Hz,1H),7.11(t,J=9.1Hz,1H),6.91(dd,J=6.5,2.7Hz,1H),6.84(dd,J=12.3,6.8Hz,1H),6.54(ddd,J=9.0,4.0,2.8Hz,1H),4.35(s,1H),4.04(dd,J=12.5,3.2Hz,1H),3.83-3.73(m,2H),3.66(m,1H),3.55-3.40(m,5H),2.13(m,1H),2.00-1.85(m,4H),1.71(m,1H)。19F NMR(377MHz,DMSO-d6)δ -74.93(9F),-127.54(1F),-150.41(1F),-156.80(1F)。
實例474係類似於實例333來製得。分離出灰白色固體狀2-(((1S,2R)-2-胺基環己基)胺基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C20H20ClF3N6O.453.2/455.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.79(s,1H),8.64(s,1H),7.78(br.s,3H),7.12(t,J=9.1Hz,1H),6.95(d,J=8.5Hz,1H),6.88(dd,J=6.5,2.7Hz,1H),6.76(dd,J=12.3,6.8Hz,1H),6.53(ddd,J=9.0,3.9,2.6Hz,1H),4.27(m,1H),3.45(m,1H),1.81-1.60(m,4H),1.58-1.31(m,4H)。19F NMR(376MHz,DMSO-d6)δ -74.8,-127.66,-150.5,-156.8。
實例475係類似於實例333使用2-甲基-1,2,3,4-四氫異喹啉-4-胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-甲基-1,2,3,4-四氫異喹啉-4-基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C24H20ClF3N6O.501.3/503.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.78(s,1H),10.32(br.s,1H),8.69(s,1H),7.49(m,1H),7.45-7.34(m,2H),7.30-7.20(m,2H),7.07(m,1H),6.95-6.80(m,2H),6.51(m,1H),5.62(m,1H),5.16(m,1H),4.61(m,1H),4.37(m,1H),3.40(m,1H),3.03(s,
3H)。19F NMR(376MHz,DMSO-d6)δ -74.8,-127.4,-150.0-156.9。
實例476係類似於實例333使用(3S,4S)-N 3,N 3-二乙基四氫呋喃-3,4-二胺來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-(((3S*,4S*)-4-(二乙基胺基)四氫呋喃-3-基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C22H24ClF3N6O2.497.3/499.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.77(s,1H),10.18(br.s,1H),8.69(s,1H),7.38(s,1H),7.08(t,J=9.1Hz,1H),6.97-6.81(m,2H),6.53(dt,J=9.0,3.4Hz,1H),4.63(m,1H),4.21(m,1H),4.15-4.03(m,2H),3.59(m,2H),3.40-3.20(m,4H),1.23(t,J=7.2Hz,6H)。19F NMR(376MHz,DMSO-d6)δ -74.9,-127.4,-150.1,-157.2。
實例477係類似於實例333使用6-胺基-1,4-氧氮雜環庚烷-4-甲酸第三丁基酯代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀2-((1,4-氧氮雜環庚烷-6-基)胺基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C19H18ClF3N6O2.455.2/457.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.81(s,1H),
9.01(br.s,2H),8.69(s,1H),7.11(t,J=9.1Hz,1H),6.97(d,J=7.3Hz,1H),6.91(dd,J=6.5,2.7Hz,1H),6.82(dd,J=12.3,6.9Hz,1H),6.53(ddd,J=9.0,4.1,2.8Hz,1H),4.33(m,1H),3.99-3.74(m,4H),3.54(m,1H),3.46(m,1H),3.32(m,1H)。19F NMR(377MHz,DMSO-d6)δ -74.9(9F),-127.5(1F),-150.5(1F),-156.8(1F)。
實例478係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及2-((2S,6R)-2,6-二甲基嗎啉基)乙-1-胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-((2-((2S,6R)-2,6-二甲基嗎啉基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C21H25ClFN7O2.462.3/464.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.40(br.s,1H),8.98(s,1H),8.20(br.s,1H),8.00(d,J=6.2Hz,1H),7.10(t,J=9.0Hz,1H),7.02(dd,J=6.5,2.7Hz,1H),6.95(d,J=6.2Hz,1H),6.57(ddd,J=8.9,4.0,2.7Hz,1H),3.88-3.78(m,4H),3.63-3.53(m,2H),3.40-3.31(m,2H),2.77-2.61(m,2H),1.15(d,J=6.3Hz,6H)。19F NMR(377MHz,DMSO-d6)δ -74.60(9F),-126.59(1F)。
實例479係類似於實例333分別使用(3R,4R)-4-甲氧基-1-甲基吡咯啶-3-胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-N'-羥基-2-(((3R,4R)-4-甲氧基-1-甲基吡咯啶-3-基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C19H21ClFN7O2.434.2/436.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.25(br.s,1H),10.23(br.s,1H),8.92(s,1H),7.98(s,1H),7.09(t,J=9.0Hz,1H),7.03-6.90(m,2H),6.67(m,1H),4.49(m,1H),4.11(m,1H),3.97(m,1H),3.72(m,1H),3.36(s,3H),3.30-3.04(m,2H),2.90(s,3H)。19F NMR(377MHz,DMSO-d6)δ -74.4,-126.7。
實例480係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(3R,4R)-N3,N3-二乙基四氫呋喃-3,4-二胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-(((3R,4R)-4-(二乙基胺基)四
氫呋喃-3-基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C21H25ClFN7O2.462.2/464.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.20(br.s,1H),8.86(s,1H),7.96(s,2H),7.07(s,1H),7.00-6.85(m,1H),6.53(s,1H),4.65(m,1H),4.21(m,1H),4.16-4.05(m,2H),3.36-3.22(m,4H),1.24(t,J=7.2Hz,6H)。
實例481係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(S)-2-(2-(三氟甲基)吡咯啶-1-基)乙-1-胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白色固體狀(S)-N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(2-(三氟甲基)吡咯啶-1-基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C20H20ClF4N7O.486.3/488.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.41(br.s,1H),8.95(s,1H),7.97(d,J=6.4Hz,1H),7.10(t,J=9.0Hz,1H),7.02(dd,J=6.5,2.7Hz,1H),6.94(d,J=6.3Hz,1H),6.59(dt,J=9.0,3.5Hz,1H),3.60-3.50(m,2H),3.18(m,1H),3.06(m,1H),2.81(dt,J=11.6,5.4Hz,1H),2.45(m,1H),2.02(m,1H),1.87-1.64(m,4H)。19F NMR(376MHz,DMSO-d6)δ -74.5,-75.5,-126.5。
實例482係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(R)-(4-甲基嗎啉-3-基)甲胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白色固體狀(R)-N-(3-氯-4-氟苯基)-N'-羥基-2-(((4-甲基嗎啉-3-基)甲基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C19H21ClFN7O2.434.2/436.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 8.87(br.s,1H),7.95(s,1H),7.09(t,J=8.9Hz,1H),7.05-6.8(m,2H),6.57(dt,J=9.0,3.4Hz,1H),4.09-3.88(m,2H),3.69-3.40(m,7H),2.98(s,3H)。
實例483係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及2-(2,6-二甲基嗎啉基)丙-1-胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-((2-(2,6-二甲基嗎啉基)丙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C22H27ClFN7O2.
476.3/478.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.80(br.s,1H),11.31(br.s,1H),8.95(s,1H),7.99(d,J=6.0Hz,1H),7.10(t,J=9.0Hz,1H),7.00(dd,J=6.6,2.7Hz,1H),6.93(d,J=6.0Hz,1H),6.57(ddd,J=9.0,4.0,2.7Hz,1H),3.98-3.66(m,7H),2.83-2.65(m,2H),1.28(d,J=6.6Hz,3H),1.17(d,J=4.3Hz,3H),1.15(d,J=4.2Hz,3H)。19F NMR(377MHz,DMSO-d6)δ -74.5(9H),-126.8(1H)。
實例484係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及2-(2,6-二甲基嗎啉基)-2-甲基丙-1-胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-((2-(2,6-二甲基嗎啉基)-2-甲基丙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C23H29ClFN7O2.490.2/492.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.60(br.s,1H),11.27(br.s,1H),8.89(s,1H),7.99(d,J=6.0Hz,1H),7.10(t,J=9.0Hz,1H),7.00(dd,J=6.5,2.7Hz,1H),6.92(d,J=6.0Hz,1H),6.57(ddd,J=8.9,3.9,2.7Hz,1H),4.00-3.85(m,2H),3.78-3.50(m,4H),2.70(m,2H),1.32(s,6H),1.19(s,3H),1.17(s,3H)。19F NMR(376MHz,DMSO-d6)δ -74,51(9F),-126.81(1F)。
實例485係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及2-(2,5-二甲基嗎啉基)乙-1-胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-((2-(2,5-二甲基嗎啉基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C21H25ClFN7O2.462.3/464.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.28(br.s,1H),8.92(m,1H),7.99(d,J=6.0Hz,1H),7.10(t,J=9.0Hz,1H),6.99(d,J=6.3Hz,1H),6.93(t,J=6.8Hz,1H),6.58(ddd,J=9.3,4.4,2.9Hz,1H),4.00-3.75(m,6H),3.37-3.17(m,2H),2.93(m,2H),1.33(d,J=6.8Hz,2H),1.16(d,J=6.2Hz,4H)。19F NMR(376MHz,DMSO-d6)δ -74.5,-126.6。
實例486係類似於實例333使用(1R,2R)-N1,N1-二甲基環戊烷-1,2-二胺代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-(((1R,2R)-2-(二甲基胺基)環戊基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C21H22ClF3N6O.467.3/469.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.74(br.s,1H),
8.69(s,1H),7.09(t,J=9.0Hz,1H),6.91(dd,J=6.5,2.7Hz,1H),6.84(m,1H),6.52(m,1H),4.34(m,1H),3.61(m,1H),2.85(s,6H),2.17-1.96(m,2H),1.89(m,1H),1.80-1.59(m,3H)。19F NMR(376MHz,DMSO-d6)δ -74.8,-127.4,-150.3,-157.2。
於-78℃下向2-(二甲基胺基)乙烷-1-硫醇(0.01mL,0.096mmol,1.9當量)於0.5mL THF中之溶液中添加0.04mL n-BuLi(0.06mmol,1.6當量)。將混合物攪拌10分鐘,之後添加0.5mL THF中之3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮(25mg,0.05mmol,1當量)。將反應物緩慢升溫至室溫並攪拌3小時,之後用飽和NH4Cl水溶液驟冷。將反應混合物用EtOAc萃取兩次,將合併之有機層經MgSO4乾燥,過濾且在真空中濃縮。將粗產物溶解於0.75mL CH2Cl2中並添加0.75mL TFA。將反應物於室溫下攪拌3小時,之後在真空中濃縮。隨後將粗產物溶解於0.4mL THF中,添加0.4mL MeOH及0.9mL 2N NaOH水溶液。將反應物於室溫下攪拌30分鐘,之後用0.9mL 2N HCl水溶液中和,用DMF稀釋並藉由反相HPLC純化。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-((2-(二甲基胺基)乙基)硫基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C17H18ClFN6OS.409.3/411.0(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.99(br.s,1H),8.87(s,1H),8.21(d,J=5.2Hz,1H),7.15-7.00(m,2H),6.93(dd,J=6.6,2.7Hz,1H),6.50(ddd,J=8.9,4.0,2.7Hz,1H),3.70-3.55(m,2H),3.55-3.45(m,2H),2.89(s,
6H)。19F NMR(376MHz,DMSO-d6)δ -74.69(9F),-127.08(1F)。
實例488係類似於實例212使用3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-((2-(二甲基胺基)乙基)硫基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C18H17ClF3N5OS.444.3/446.0(M+1)。1H NMR(400MHz,DMSO-d6)δ 12.91(br.s,1H),10.83(br.s,1H),9.65(s,1H),8.76(s,1H),7.18-7.00(m,2H),6.96(dd,J=6.6,2.7Hz,1H),6.49(ddd,J=9.0,4.1,2.7Hz,1H),3.61-3.44(m,4H),2.87(d,J=3.0Hz,6H)。19F NMR(377MHz,DMSO-d6)δ -74.5(6F),-127.0(1F),-149.5(1F),-154.15(1F)。
實例489係類似於實例333使用(1-(2-胺基乙基)六氫吡啶-2-基)甲醇代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(2-(羥基甲基)六氫吡啶-1-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C22H24ClF3N6O2.497.3/499.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.80(s,1H),9.56(br.s,1H),8.72(s,1H),7.09(t,J=9.1Hz,1H),6.98(s,1H),6.94
(dd,J=6.5,2.7Hz,1H),6.85(dd,J=12.2,6.9Hz,1H),6.52(ddd,J=9.0,4.1,2.7Hz,1H),3.88(m,1H),3.80-3.65(m,2H),3.60-3.40(m,3H),3.35-3.20(m,2H),3.13(m,1H),1.90-1.65(m,5H),1.50(m,1H)。19F NMR(377MHz,DMSO-d6)δ -75.1(9F),-127.3(1F),-150.2(1F),-156.9(1F)。
實例490係類似於實例333使用(1-(2-胺基乙基)吡咯啶-2-基)甲醇代替(2-胺基乙基)胺基甲酸第三丁基酯來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(2-(羥基甲基)吡咯啶-1-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C21H22ClF3N6O2.483.3/485.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.79(br.s,1H),9.82(br.s,1H),8.70(s,1H),7.09(t,J=9.1Hz,1H),7.02(s,1H),6.94(dd,J=6.6,2.7Hz,1H),6.85(dd,J=12.2,6.9Hz,1H),6.53(ddd,J=9.0,4.1,2.7Hz,1H),3.78-3.64(m,4H),3.63-3.50(m,3H),3.35(m,1H),3.19(m,1H),2.14-1.95(m,2H),1.90(m,1H),1.75(m,1H)。19F NMR(376MHz,DMSO-d6)δ -75.1,-127.3,-150.2,-156.9.
實例491係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙
氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及2-(3,3-二氟吡咯啶-1-基)乙-1-胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-((2-(3,3-二氟吡咯啶-1-基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C19H19ClF3N7O.454.3/456.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.40(br.s,1H),8.97(s,1H),7.98(d,J=6.2Hz,1H),7.11(t,J=9.0Hz,1H),7.03(dd,J=6.5,2.7Hz,1H),6.94(d,J=6.2Hz,1H),6.59(ddd,J=8.9,4.0,2.7Hz,1H),3.62(m,2H),3.34(m,2H),3.18-2.89(m,4H),2.45-2.28(m,2H)。19F NMR(377MHz,DMSO-d6)δ -74.7(9F),-92.1(2F),-126.6(1F)。
實例492係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及2-胺基乙烷-1-磺醯胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-N'-羥基-2-((2-胺磺醯基乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C15H15ClFN7O3S.428.1/430.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 12.00(br.s,1H),11.47(br.s,1H),8.99(s,1H),7.97(d,J=6.4Hz,1H),7.11(t,J=9.0Hz,1H),7.06(s,2H),
7.04(dd,J=6.8,3.0Hz,1H),6.92(d,J=6.4Hz,1H),6.59(ddd,J=8.9,4.0,2.8Hz,1H),3.87(q,J=6.5Hz,2H),3.35(t,J=6.6Hz,2H)。19F NMR(377MHz,DMSO-d6)δ -74.6(6F),-126.5(1F)。
實例493係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及2-(甲基磺醯基)乙-1-胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(甲基磺醯基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C16H16ClFN6O3S.427.1/429.0(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.46(br.s,1H),8.97(s,1H),7.99(d,J=6.3Hz,1H),7.11(t,J=9.0Hz,1H),7.04(dd,J=6.5,2.7Hz,1H),6.95(d,J=6.3Hz,1H),6.59(dq,J=8.8,3.0Hz,1H),3.91(q,J=6.4Hz,2H),3.51(d,J=6.4Hz,2H),3.07(s,3H)。19F NMR(376MHz,DMSO-d6)δ -74.6(6F),-126.5(1F)。
實例494係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙
氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及嘧啶-2-基甲胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-N'-羥基-2-((嘧啶-2-基甲基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C18H14ClFN8O.413.2/415.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.49(br.s,1H),9.00(s,1H),8.83(d,J=4.9Hz,2H),7.99(d,J=6.3Hz,1H),7.48(t,J=4.9Hz,1H),7.11(t,J=9.0Hz,1H),7.05(dd,J=6.5,2.7Hz,1H),6.95(d,J=6.3Hz,1H),6.60(dt,J=8.9,3.3Hz,1H),4.91(d,J=5.9Hz,2H)。19F NMR(377MHz,DMSO-d6)δ -74.7(6F),-126.6(1F)。
實例495係類似於實例333使用(R)-1-(2-甲氧基乙基)吡咯啶-3-胺二鹽酸鹽及N-乙基-N-異丙基丙-2-胺代替(2-胺基乙基)胺基甲酸第三丁基酯及使用3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯苯基)-1,2,4-噁二唑-5(4H)-酮代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮來製得。分離出灰白色固體狀(R)-N-(3-氯苯基)-4,5-二氟-N'-羥基-2-((1-(2-甲氧基乙基)吡咯啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C21H23ClF2N6O2.465.2/467.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.87(s,1H),10.20(br.s,1H),8.74(s,1H),7.26(m,1H),7.04(m,1H),6.82(m,2H),6.50(m,
1H),4.65-4.40(m,1H),3.98-3.70(m,1H),3.68-3.55(m,3H),3.51-3.36(m,2H),3.33(m,3H),3.13(m,2H),2.10-1.85(m,2H)。19F NMR(377MHz,DMSO-d6)δ -75.0(9F),-150.3(1F),-156.7(1F)。
實例496係類似於實例333使用(R)-1-(2-甲氧基乙基)吡咯啶-3-胺二鹽酸鹽及N-乙基-N-異丙基丙-2-胺代替(2-胺基乙基)胺基甲酸第三丁基酯及使用4-(3-溴苯基)-3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-1,2,4-噁二唑-5(4H)-酮代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮來製得。分離出灰白色固體狀(R)-N-(3-溴苯基)-4,5-二氟-N'-羥基-2-((1-(2-甲氧基乙基)吡咯啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒之TFA鹽。C21H23BrF2N6O2.509.2/511.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 10.84(s,1H),10.18(br.s,1H),8.69(d,J=2.6Hz,1H),7.17(m,1H),7.05(m,1H),7.00-6.91(m,3H),6.84(dd,J=12.3,6.9Hz,1H),6.55(dt,J=7.7,1.7Hz,1H),4.65-4.35(m,1H),4.00-3.70(m,1H),3.65-3.55(m,3H),3.51-3.36(m,2H),3.32(m,3H),3.12(m,2H),2.11-1.85(m,2H)。19F NMR(376MHz,DMSO-d6)δ -75.0(9F),-150.4(9F),-156.7(9F)。
實例497係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(S)-1-(氧雜環丁-3-基)六氫吡啶-3-胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白色固體狀(S)-N-(3-氯-4-氟苯基)-N'-羥基-2-((1-(氧雜環丁-3-基)六氫吡啶-3-基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C21H23ClFN7O2.460.2/462.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.39(br.s,1H),8.95(s,1H),8.16(br.s,1H),7.98(d,J=6.2Hz,1H),7.11(t,J=9.0Hz,1H),7.02(dd,J=6.5,2.7Hz,1H),6.94(d,J=6.2Hz,1H),6.59(dt,J=8.9,3.5Hz,1H),4.75-4.65(m,4H),4.20-4.05(m,2H),3.80-3.55(m,2H),2.85-2.60(m,2H),2.05-1.85(m,2H),1.81-1.45(m,2H)。19F NMR(376MHz,DMSO-d6)δ -74.6,-126.7。
實例498係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及1-(2-甲氧基乙基)六氫吡啶-3-胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白
色固體狀N-(3-氯-4-氟苯基)-N'-羥基-2-((1-(2-甲氧基乙基)六氫吡啶-3-基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C21H25ClFN7O2.462.1/464.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 9.70(br.s,1H),8.89(br.s,1H),7.96(s,1H),7.10(t,J=9.0Hz,1H),6.98(m,1H),6.90(m,1H),6.58(dt,J=8.9,3.5Hz,1H),4.20(m,1H),3.75-3.60(m,2H),3.50-3.25(m,4H),3.32(s,3H),2.95-2.80(m,2H),2.09-1.73(m,3H),1.51(m,1H)。19F NMR(376MHz,DMSO-d6)δ -74.31,-126.85。
實例499係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及1-環丙基吡咯啶-3-胺三氟乙酸鹽(1:2)及N-乙基-N-異丙基丙-2-胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-((1-環丙基吡咯啶-3-基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C20H21ClFN7O.430.1/432.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.21(br.s,1H),8.89(s,1H),7.96(m,1H),7.08(t,J=9.1Hz,1H),7.05-6.80(m,2H),6.57(dt,J=8.9,3.5Hz,1H),4.60-4.45(m,2H),3.95-3.45(m,4H),3.05-2.90(m,2H),1.00-0.75(m,4H)。
實例500係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(R)-1-(氧雜環丁-3-基)六氫吡啶-3-胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白色固體狀(R)-N-(3-氯-4-氟苯基)-N'-羥基-2-((1-(氧雜環丁-3-基)六氫吡啶-3-基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C21H23ClFN7O2.460.2/462.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.39(br.s,1H),8.95(s,1H),8.17(br.s,1H),7.98(d,J=6.2Hz,1H),7.11(t,J=9.0Hz,1H),7.02(dd,J=6.5,2.7Hz,1H),6.93(d,J=6.2Hz,1H),6.59(dt,J=8.9,3.5Hz,1H),4.75-4.55(m,4H),4.20-4.05(m,2H),3.80-3.60(m,2H),2.84-2.59(m,2H),2.10-1.80(m,2H),1.80-1.51(m,2H)。19F NMR(377MHz,DMSO-d6)δ -74.6(9F),-126.8(1F)。
實例501係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二
唑-5(4H)-酮及4-(2-胺基乙基)-1-甲基六氫吡嗪-2-酮代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(4-甲基-3-側氧基六氫吡嗪-1-基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C20H22ClFN8O2.461.2/463.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.36(br.s,1H),8.95(s,1H),7.97(d,J=6.2Hz,1H),7.11(t,J=9.0Hz,1H),7.02(dd,J=6.5,2.7Hz,1H),6.92(d,J=6.2Hz,1H),6.59(m,1H),3.80-3.60(m,3H),3.45-3.35(m,3H),3.25-3.05(m,2H),3.05-2.90(m,2H),2.85(s,3H)。19F NMR(377MHz,DMSO-d6)δ -74.7(9F),-126.7(1F)。
實例502係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及2-(3,3-二氟六氫吡啶-1-基)乙-1-胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-((2-(3,3-二氟六氫吡啶-1-基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C20H21ClF3N7O.468.3/470.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.38(s,1H),8.95(s,1H),7.98(d,J=6.2Hz,1H),7.11(t,J=9.0Hz,1H),7.02(dd,J=6.5,2.7Hz,1H),6.93(d,J=6.2Hz,1H),6.59(ddd,J=9.0,4.1,2.8
Hz,1H),3.66(m,2H),3.10(m,2H),2.90(m,2H),2.75(m,2H),1.97(m,2H),1.77(m,2H)。19F NMR(377MHz,DMSO-d6)δ -84.9(9F),-108.4(2F),-136.8(1F)。
實例503係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及1-(3-胺基吡咯啶-1-基)乙-1-酮代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白色固體狀2-((1-乙醯基吡咯啶-3-基)胺基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C19H19ClFN7O2.432.4/434.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.40(s,1H),8.96(s,1H),7.98(dd,J=6.3,4.2Hz,1H),7.11(t,J=9.0Hz,1H),7.04(dd,J=6.3,2.6Hz,1H),6.94(dd,J=7.9,6.3Hz,1H),6.60(dt,J=9.3,3.3Hz,1H),4.54-4.36(m,2H),3.77(m,1H),3.59(m,1H),2.34-2.11(m,2H),2.07(m,1H),1.96(d,J=11.3Hz,3H)。19F NMR(376MHz,DMSO-d6)δ -74.5,-126.5。
實例504係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及1-(甲基磺醯基)吡咯啶-3-胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-N'-羥基-2-((1-(甲基磺醯基)吡咯啶-3-基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C18H19ClFN7O3S.468.4/470.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.41(s,1H),8.96(s,1H),7.99(d,J=6.3Hz,1H),7.10(t,J=9.0Hz,1H),7.03(dd,J=6.5,2.7Hz,1H),6.95(d,J=6.3Hz,1H),6.60(ddd,J=9.0,4.1,2.8Hz,1H),4.55-4.42(m,2H),3.59(m,1H),3.27(m,1H),2.95(s,3H),2.37-2.21(m,2H),2.05(m,1H)。19F NMR(376MHz,DMSO-d6)δ -74.5,-126.5。
實例505係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-(甲基磺醯基)丙-1-胺鹽酸鹽及N-乙基-N-異丙基丙-2-胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺
鹽酸鹽來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-N'-羥基-2-((3-(甲基磺醯基)丙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C17H18ClFN6O3S.441.3/443.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.39(br.s,1H),8.95(s,1H),7.97(d,J=6.3Hz,1H),7.10(t,J=9.0Hz,1H),7.04(dd,J=6.5,2.7Hz,1H),6.92(d,J=6.2Hz,1H),6.59(ddd,J=9.0,4.0,2.7Hz,1H),3.56(m,2H),3.20(m,2H),3.00(s,3H),2.04(p,J=7.1Hz,2H)。19F NMR(377MHz,DMSO-d6)δ -74.2(6F),-126.3(1F)。
實例506係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-(胺基甲基)四氫噻吩1,1-二氧化物鹽酸鹽及N-乙基-N-異丙基丙-2-胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-(((1,1-二側氧基四氫噻吩-3-基)甲基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C18H18ClFN6O3S.453.3/455.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 8.95(br.s,1H),7.97(d,J=6.3Hz,1H),7.10(t,J=9.0Hz,1H),7.03(dd,J=6.4,2.7Hz,1H),6.93(d,J=6.2Hz,1H),6.59(m,1H),3.56(m,2H),3.24(m,2H),3.08(m,1H),2.91(dd,J=13.2,9.5Hz,1H),2.74(d,J=11.6Hz,1H),2.25(m,1H),1.86(dq,J=13.1,9.3Hz,1H)。19F NMR(376MHz,DMSO-d6)δ -74.4,-126.5。
實例507係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-((4-氟苯基)磺醯基)丙-1-胺代替3-(2-氯-4,5-二氟-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白色固體狀N-(3-氯-4-氟苯基)-2-((3-((4-氟苯基)磺醯基)丙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C22H19ClF2N6O3S.521.4/523.1(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.38(br.s,1H),8.94(s,1H),7.97(m,3H),7.51(m,2H),7.10(t,J=9.0Hz,1H),7.03(dd,J=6.5,2.7Hz,1H),6.92(d,J=6.3Hz,1H),6.59(dt,J=9.0,3.5Hz,1H),3.50(m,2H),3.43(m,2H),1.89(p,J=7.1Hz,2H)。19F NMR(376MHz,DMSO-d6)δ -74.4,-105.2,-126.5。
實例508係類似於實例229分別使用3-(2-氯-1-((2-(三甲基矽基)乙氧基)甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及(R)-1-(氧雜環丁-3-基)吡咯啶-3-胺代替3-(2-氯-4,5-二氟
-1-((2-(三甲基矽基)乙氧基)甲基)-1H-苯并[d]咪唑-7-基)-4-(3-氯-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮及3-胺基丙醯胺鹽酸鹽來製得。分離出灰白色固體狀(R)-N-(3-氯-4-氟苯基)-N'-羥基-2-((1-(氧雜環丁-3-基)吡咯啶-3-基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒之TFA鹽。C20H21ClFN7O2.446.4/448.2(M+1)。1H NMR(400MHz,DMSO-d6)δ 11.30(br.s,1H),8.93(s,1H),7.99(d,J=6.1Hz,1H),7.09(t,J=9.0Hz,1H),7.03-6.92(m,2H),6.58(ddd,J=8.9,4.0,2.7Hz,1H),4.78(t,J=7.4Hz,2H),4.69-4.55(m,3H),4.47(m,1H),3.8-3.3(m,5H),2.09(d,J=11.6Hz,1H)。19F NMR(376MHz,DMSO-d6)δ -74.6,-126.7。
在下文實例中使用使用本文所述方法及業內熟知之彼等實施活性測試。
為量測組織培養物種之IDO1抑制,在IFNγ(其誘導IDO1表現)存在下用測試化合物處理HeLa細胞。在培育後,分析細胞上清液之犬尿胺酸含量,其係IDO1活性之指示。
在補充有10% FBS(Corning編號35-011-CV)及1% P/S/G(Corning編號30-009-CL)之DMEM(Corning編號15-018-CM)中以1,250個細胞/孔之密度將H1-HeLa細胞(ATCC編號CRL-1958)以50μL/孔之體積接種於在384孔板(Greiner編號82051-282)中並於37℃、5% CO2/100%濕度下培育過夜。次日,將測試化合物添加於各個濃度之DMSO(0.5%最終)中,並藉由在細胞平鋪培養基中添加50uL/孔之50ng/mL INFγ(Peprotech編號300-02)可誘導地表現IDO1。作為陽性對照,向若干孔中添加無IFNγ之50uL細胞平鋪培養基。48小時培育後,於10℃下使板以1,200RPM旋轉沈澱5min。隨後將65μL/孔之上清液轉移至含有
10uL/孔之30% TCA(Sigma編號TO699)之新384孔板(Thermo編號262160),且將板密封並於60℃下培育30min。隨後於10℃下將板以2,000RPM離心15min。將40μL/孔之上清液轉移至新384孔板(Thermo編號262160)並與40μL/孔之2%(w/v)對-二甲基胺基苯甲醛(Sigma編號156417)在冰乙酸(Sigma編號A6283)中反應。將反應物於室溫下培育10min且使用PerkinElmer Envision板讀數器讀取480nm處之吸光度。
基於陽性(- IFNγ)及陰性(+ IFNγ)對照正規化表1中之數據,並自劑量-反應曲線與四參數方程之擬合計算EC50值。所有EC50值皆代表四次測定之最小值之幾何平均值。該等分析通常產生在所報告平均值之2倍內之結果。
Claims (23)
- 一種式I化合物,其中R1係單環或二環芳基或雜芳基,其中各單環或二環芳基或雜芳基視情況經1個、2個或3個獨立地選自以下之取代基取代:羥基、鹵基、-CN、C1-6鹵烷基、C1-6鹵烷氧基、C1-6烷氧基、C1-6烷基、C2-6烯基、C2-6炔基及C3-6環烷基,其中可選取代基中之二者可接合形成另外部分飽和雜環;且其中各C1-6烷氧基、C1-6烷基、C2-6烯基、C2-6炔基及C3-6環烷基視情況經1個、2個或3個獨立地選自以下之取代基取代:羥基、鹵基、-CN、-N(R20)(R22)及C3-6環烷基;X係N或CR2c;R2a、R2b及R2c獨立地係氫、羥基、鹵基、CN、C1-6鹵烷基、C1-6鹵烷氧基、C1-6烷氧基或C1-6烷基;R2d及R2e獨立地係氫、C1-6鹵烷基、C1-6鹵烷氧基或C1-6烷基;n及m獨立地係0、1、2或3;各Rn及Rm獨立地係氫、羥基、鹵基、C1-6烷氧基、C1-6烷基、C3-6環烷基、芳基、雜環基或雜芳基;或兩個Rn或Rm接合形成C3-6環烷基;且其中各C1-6烷氧基、C1-6烷基、C3-6環烷基、芳基、雜環基或雜芳基視情況經1個、2個或3個獨立地選自以下之取代基取代:羥基、鹵基、-CN、-N(R20)(R22)、C2-6烯基、C2-6炔基、C1-6鹵烷基、C1-6鹵烷氧基、C1-6烷氧基、C1-6烷基及C3-6環烷基;L係鍵、-NR3-、-C(O)-NR3-、-NR3-C(O)-、-NR3SO2-、-NR3SO2-NR3-、-SO2NR3-、-O-、-S-或-S(O)t-,其中t係0、1或2;各R3獨立地係氫、C1-6烷基、C3-6環烷基、芳基、雜環基或雜芳基;且Rt係氫、C1-6烷基、C1-6烷氧基、-C(O)R20、-C(O)OR20、-NC(O)OR20、-N(R20)(R22)、-C(O)N(R20)(R22)、-SO2R20、-N(R20)SO2(R21)、-N(R20)SO2-N(R21)(R22)、-SO2N(R20)(R22)、C3-15環烷基、芳基、雜芳基或雜環基,限制條件係當Rt係C1-6烷氧基、-NC(O)OR20、-N(R20)(R22)、-N(R20)SO2(R21)、-N(R20)SO2-N(R21)(R22)或-SO2N(R20)(R22)且m係0時,則L係鍵;其中該C1-6烷基、C1-6烷氧基、C3-15環烷基、芳基、雜環基或雜芳基視情況經1個、2個或3個獨立地選自以下之取代基取代:羥基、鹵基、-NO2、C1-6鹵烷基、C1-6鹵烷氧基、-C(O)R20、-N(R20)(R22)、-SO2R20、-N(R20)SO2(R21)、-N(R20)SO2-N(R21)(R22)、-SO2N(R20)(R22)、C3-6環烷基、-CN、C1-6烷氧基、C1-6烷基及雜環基;且其中該雜環基視情況經一個或兩個側氧基(oxo)取代;其中該C3-6環烷基、C1-6烷基或C1-6烷氧基視情況經1個、2個或3個獨立地選自以下之取代基取代:羥基、鹵基、-NO2、C1-6鹵烷基、C1-6鹵烷氧基、C1-6烷氧基、-N(R22)(R22)、-SO2R20、-N(R20)SO2(R22)、-N(R20)SO2-N(R21)(R22)-及-SO2N(R20)(R22);且該C1-6烷基視情況經芳基取代;R20、R21及R22獨立地選自氫、C1-6烷基、C1-6鹵烷基、C3-6環烷基、芳基、雜環基及雜芳基;其中該芳基、雜環基或雜芳基視情況經1個、2個或3個鹵素取代;或其醫藥上可接受之鹽、立體異構物、互變異構物或混合物。
- 如請求項1或2之化合物,其中R1係視情況經1個、2個或3個獨立地選自以下之取代基取代之二環芳基或雜芳基:羥基、鹵基、-CN、C1-6鹵烷基、C1-6鹵烷氧基、C1-6烷氧基、C1-6烷基、C2-6烯基、C2-6炔基及C3-6環烷基;或其醫藥上可接受之鹽、立體異構物、互變異構物或混合物。
- 如請求項1或2之化合物,其中R1係視情況經1個、2個或3個獨立地選自以下之取代基取代之苯基:羥基、鹵基、-CN、C1-6鹵烷基、C1-6鹵烷氧基、C1-6烷氧基、C1-6烷基、C2-6烯基、C2-6炔基及C3-6環烷基,且其中該等可選取代基中之二者可接合形成另外部分飽和雜環;或其醫藥上可接受之鹽、立體異構物、互變異構物或混合物。
- 如請求項1或2之化合物,其中X係N;或其醫藥上可接受之鹽、立體異構物、互變異構物或混合物。
- 如請求項1或2之化合物,其中X係CR2c;或其醫藥上可接受之鹽、立體異構物、互變異構物或混合物。
- 如請求項1或2之化合物,其中L係鍵;或其醫藥上可接受之鹽、立體異構物、互變異構物或混合物。
- 如請求項1或2之化合物,其中L係-NR3;或其醫藥上可接受之鹽、立體異構物、互變異構物或混合物。
- 如請求項1或2之化合物,其中Rt係氫;或其醫藥上可接受之鹽、立體異構物、互變異構物或混合物。
- 如請求項1或2之化合物,其中Rt係視情況經1個、2個或3個獨立地選自以下之取代基取代之C1-6烷基:羥基、鹵基、-NO2、C1-6鹵烷基、C1-6鹵烷氧基、C3-6環烷基、-CN及C1-6烷氧基;或其醫藥上可接受之鹽、立體異構物、互變異構物或混合物。
- 如請求項1或2之化合物,其中Rt係C3-15環烷基、芳基、雜芳基或雜環基,其中該環烷基、芳基、雜環基或雜芳基視情況經1個、2個或3個獨立地選自以下之取代基取代:羥基、鹵基、-NO2、C1-6鹵烷基、C1-6鹵烷氧基、C3-6環烷基、-CN、C1-6烷氧基及C1-6烷基;或其醫藥上可接受之鹽、立體異構物、互變異構物或混合物。
- 如請求項1或2之化合物,其中L係-NR3且Rt係C3-15環烷基、芳基、雜芳基或雜環基,其中該環烷基、芳基、雜環基或雜芳基視情況經1個、2個或3個獨立地選自以下之取代基取代:羥基、鹵基、-NO2、C1-6鹵烷基、C1-6鹵烷氧基、C3-6環烷基、-CN及C1-6烷氧基;或其醫藥上可接受之鹽、立體異構物、互變異構物或混合物。
- 一種化合物,其係選自由以下組成之群:N-(3-氯-4-氟苯基)-N'-羥基-4-甲基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-4-(三氟甲氧基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-6-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-5-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,4-氯-N-(3-氯-4-氟苯基)-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-4-(三氟甲基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-6-氟-N'-羥基-7-甲基-3H-苯并咪唑-4-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,6-氯-N-(3-氯-4-氟苯基)-N'-羥基-1H-苯并[d]咪唑-4-甲脒,4-溴-N-(3-氯-4-氟苯基)-N'-羥基-1H-苯并[d]咪唑-7-甲脒,2-胺基-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,2-胺基-N-(3-溴-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,2-胺基-N-(3-溴苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,2-胺基-N-(3-氯苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,2-胺基-4,5-二氟-N-(4-氟-3-(三氟甲基)苯基)-N'-羥基-1H-苯并[d]咪唑-7-甲脒,2-胺基-N-(3-溴苯基)-4-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,2-胺基-N-(3-溴-4-氟苯基)-4-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,2-胺基-N-(3-氯苯基)-4-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,2-胺基-4-氟-N-(4-氟-3-(三氟甲基)苯基)-N'-羥基-1H-苯并[d]咪唑-7-甲脒,2-胺基-N-(3-氯-4-氟苯基)-4-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,2-胺基-N-(3-氯-4-氟苯基)-4-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-嗎啉基乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯苯基)-4,5-二氟-N'-羥基-2-(((3-甲氧基丙基)胺基)甲基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯苯基)-2-(((環丙基甲基)胺基)甲基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯苯基)-2-((二甲基胺基)甲基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒N-(3-氯苯基)-4,5-二氟-N'-羥基-2-((異丙基胺基)甲基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯苯基)-2-((乙基胺基)甲基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯苯基)-4,5-二氟-N'-羥基-2-(羥基甲基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯苯基)-4,5-二氟-N'-羥基-2-((甲基胺基)甲基)-1H-苯并[d]咪唑-7-甲脒,2-(胺基甲基)-N-(3-氯苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-嗎啉基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4-氟-N'-羥基-2-((2-(甲基磺醯基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4-氟-N'-羥基-2-((2-嗎啉基乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(甲基磺醯基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(4,4-二氟六氫吡啶-1-基)乙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((1-嗎啉基丙-2-基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(甲基胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-甲氧基乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(吡咯啶-1-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(二乙基胺基)乙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯苯基)-4,5-二氟-N'-羥基-2-(1-甲基六氫吡啶-3-基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-2-(((3-甲氧基丙基)胺基)甲基)-1H-苯并[d]咪唑-4-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(羥基甲基)-1H-苯并[d]咪唑-7-甲脒,2-(胺基甲基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((甲基胺基)甲基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-(((環丙基甲基)胺基)甲基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((乙基胺基)甲基)-6,7-二氟-N'-羥基-1H-苯并[d]咪唑-4-甲脒,N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-2-((異丙基胺基)甲基)-1H-苯并[d]咪唑-4-甲脒,N-(3-氯-4-氟苯基)-2-((二甲基胺基)甲基)-6,7-二氟-N'-羥基-1H-苯并[d]咪唑-4-甲脒,N-(3-氯-4-氟苯基)-2-(2-(二甲基胺基)乙基)-6,7-二氟-N'-羥基-1H-苯并[d]咪唑-4-甲脒,N-(3-溴-4-氟苯基)-2-(2-(二甲基胺基)乙基)-6,7-二氟-N'-羥基-1H-苯并[d]咪唑-4-甲脒,N-(3-溴苯基)-2-(2-(二甲基胺基)乙基)-6,7-二氟-N'-羥基-1H-苯并[d]咪唑-4-甲脒,N-(3-氯苯基)-2-(2-(二甲基胺基)乙基)-6,7-二氟-N'-羥基-1H-苯并[d]咪唑-4-甲脒,N-(3-氯-4-氟苯基)-6,7-二氟-N'-羥基-2-(2-(甲基胺基)乙基)-1H-苯并[d]咪唑-4-甲脒,N-(3-氯-4-氟苯基)-2-(2-(二乙基胺基)乙基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(5-氯-2-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(5-溴-2,4-二氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(5-氯-2,4-二氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3,5-二氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-2,4-二氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-環丙基-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N'-羥基-N-(4-(三氟甲氧基)苯基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(苯并呋喃-4-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(苯并呋喃-6-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(苯并呋喃-7-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(苯并呋喃-5-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(5-溴-2-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-溴-5-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N'-羥基-N-(3-(三氟甲基)苯基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(2,2-二氟苯并[d][1,3]二氧雜環戊烯(dioxol)-5-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氟-5-(三氟甲基)苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(2,5-二氯苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(6-氟-[1,1'-聯苯]-3-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-(丁-1-炔-1-基)-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-(環丙基乙炔基)-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-溴苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-溴-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(4-氟-3-(三氟甲基)苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(4-氟-3-(丙-1-炔-1-基)苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-溴-4-氯苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3,4-二氯苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(4-氯苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(4-溴苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氰基-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N'-羥基-N-(4-(三氟甲基)苯基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N'-羥基-N-(3-甲氧基苯基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(4-氟-3-異丙基苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N'-羥基-N-(對甲苯基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-乙炔基苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-乙基苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-乙炔基-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-(二氟甲基)苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-羥基-N-(3-(三氟甲氧基)苯基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-羥基-N-苯基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(4-氟-3-(三氟甲氧基)苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-羥基-N-(萘-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯萘-2-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N'-羥基-N-(萘-1-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(4-氯萘-1-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(4-氟-3-甲氧基苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-甲基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-乙基-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-環丙基-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(甲氧基甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,4-(3-氯-4-氟苯基)-3-(2-(羥基甲基)-1H-咪唑并[4,5-b]吡啶-7-基)-1,2,4-噁二唑-5(4H)-酮,N-(3-氯-4-氟苯基)-N'-羥基-2-(嗎啉基甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((二甲基胺基)甲基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((乙基胺基)甲基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-((苄基胺基)甲基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((異丙基胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(((環丙基甲基)胺基)甲基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((2,2,2-三氟乙基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((環丙基胺基)甲基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((3-甲氧基丙基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((吡啶-2-基甲基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((3-甲氧基丙基)(甲基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((2-甲氧基苄基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((2-甲氧基乙基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((2-(吡啶-2-基)乙基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((吡啶-3-基甲基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((((四氫-2H-吡喃-2-基)甲基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((苯基胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((((四氫-2H-吡喃-3-基)甲基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((嘧啶-2-基甲基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((3-嗎啉基丙基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((四氫-2H-吡喃-4-基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((吡啶-4-基甲基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((吡嗪-2-基甲基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((((四氫呋喃-3-基)甲基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(((2-(二甲基胺基)乙基)胺基)甲基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((2-(嘧啶-2-基)乙基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((3-羥基丙基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(吡咯啶-1-基甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(六氫吡啶-1-基甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((新戊基胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(((2,2-二氟乙基)胺基)甲基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((3-羥基-2,2-二甲基丙基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((噻唑-2-基甲基)胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-((7-(N-(3-氯-4-氟苯基)-N'-羥基甲脒基)-1H-咪唑并[4,5-b]吡啶-2-基)甲基)乙醯胺,N-(3-氯-4-氟苯基)-N'-羥基-2-(噻吩-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(吡啶-3-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(1H-吡咯-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(1H-咪唑-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(1H-吡唑-5-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(4-甲基-1H-咪唑-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(吡咯啶-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-胺基-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(環丙基胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(苯基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(苯乙基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2,2,2-三氟乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(甲基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,(7-(N-(3-氯-4-氟苯基)-N'-羥基甲脒基)-1H-咪唑并[4,5-b]吡啶-2-基)胺基甲酸異丙基酯,(7-(N-(3-氯-4-氟苯基)-N'-羥基甲脒基)-1H-咪唑并[4,5-b]吡啶-2-基)胺基甲酸乙基酯,N-(3-氯-4-氟苯基)-2-((環丙基甲基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((3,3-二氟環丁基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(乙基胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(環丁基胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(異丙基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯苯基)-N'-羥基-2-(甲基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(二乙基胺基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-嗎啉基乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(二甲基胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-(氯甲基)-N-(4-氟-3-(三氟甲基)苯基)-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒,N-(4-氟-3-(三氟甲基)苯基)-N'-羥基-2-(羥基甲基)-3H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(1-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(羥基(苯基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(環丙基(羥基)甲基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(2-羥基丙-2-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(2,2,2-三氟-1-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(羥基甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((甲基胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-(胺基甲基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(苯基磺醯胺基甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(甲基磺醯胺基甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((嘧啶-2-基胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(2-羥基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(2-(二甲基胺基)乙基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(2-(二乙基胺基)乙基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(2-((環丙基甲基)(甲基)胺基)乙基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(2-((2,2-二氟乙基)(甲基)胺基)乙基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(2-(甲基胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-(2-胺基乙基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(2-((2-甲氧基乙基)胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(2-嗎啉基乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(2-(六氫吡啶-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(2-(吡咯啶-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(2-((2-甲氧基乙基)(甲基)胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(2-(二甲基胺基)-1-羥基乙基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((異丁基胺基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-3-甲基-3H-咪唑并[4,5-b]吡啶-7-甲脒, N -(3-氯-4-氟苯基)- N '-羥基-2-[2-(2-甲氧基乙基胺基)乙基]-3 H -咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-[3-(二甲基胺基)丙基]-6,7-二氟-N'-羥基-3H-苯并咪唑-4-甲脒,N-(3-氯-4-氟苯基)-7-氟-N'-羥基-2-(3-嗎啉-4-基丙基胺基)-3H-苯并咪唑-4-甲脒,N-(3-氯-4-氟苯基)-2-[2-(二甲基胺基)乙基胺基]-7-氟-N'-羥基-3H-苯并咪唑-4-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-[(1-甲基六氫吡啶-2-基)甲基胺基]-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-[(1-甲基吡咯啶-3-基)胺基]-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(2-(乙基胺基)乙基)-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(2-(異丙基胺基)乙基)-3H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(2-(異丁基胺基)乙基)-3H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(2-(環丙基胺基)乙基)-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(2-((環丙基甲基)胺基)乙基)-N'-羥基-3H-咪唑并[4,5-b]吡啶-7-甲脒,2-(2-(2-胺基-4,5-二氫-1H-咪唑-1-基)乙基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(2-(甲基磺醯胺基)乙基)-1H-苯并[d]咪唑-7-甲脒,2-(2-胺基乙基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-甲氧基乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,(2-(7-(N-(3-氯-4-氟苯基)-N'-羥基甲脒基)-4,5-二氟-1H-苯并[d]咪唑-2-基)乙基)胺基甲酸第三丁基酯,N-(3-氯-4-氟苯基)-2-((2-(4,4-二氟六氫吡啶-1-基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(二甲基胺基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(甲基胺基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((1-甲基氮雜環庚烷-3-基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(1,1-二側氧基(dioxido)硫嗎啉基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-((2-甲氧基乙基)(甲基)胺基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-((2,2-二氟乙基)(甲基)胺基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((3-嗎啉基丙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(六氫吡啶-1-基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-環己基乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(四氫-2H-吡喃-4-基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2,2-二氟乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(氧雜環丁-3-基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((四氫呋喃-3-基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((四氫-2H-吡喃-4-基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,3-((7-(N-(3-氯-4-氟苯基)-N'-羥基甲脒基)-4,5-二氟-1H-苯并[d]咪唑-2-基)胺基)丙醯胺),N-(3-氯-4-氟苯基)-2-((2-((2,2-二氟乙基)胺基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(環丙基(甲基)胺基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(環丙基(2-甲氧基乙基)胺基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-((2-(氮雜環丁-1-基)乙基)胺基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((3-甲氧基丙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(2-側氧基吡咯啶-1-基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(嗎啉基磺醯基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(3-氟六氫吡啶-1-基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-溴-4-氟苯基)-N'-羥基-2-((2-嗎啉基乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(甲基(四氫-2H-吡喃-4-基)胺基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(異丙基(甲基)胺基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-(((1-胺基環丙基)甲基)胺基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-((2-(1-胺基環丙基)乙基)胺基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-((2-(2-氧雜-5-氮雜二環[4.1.0]庚-5-基)乙基)胺基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-((2-(7-氧雜-4-氮雜螺[2.5]辛-4-基)乙基)胺基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,(R)-(3-氯-4-氟苯基)-2-((2-(3-氟吡咯啶-1-基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,(S)-(3-氯-4-氟苯基)-2-((2-(3-氟吡咯啶-1-基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-((2-(2-氮雜二環[4.1.0]庚-2-基)乙基)胺基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-((2-(4-氮雜螺[2.5]辛-4-基)乙基)胺基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(3-氟氮雜環丁-1-基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(3,3-二氟氮雜環丁-1-基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-((2-(4-氮雜螺[2.4]庚-4-基)乙基)胺基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((3-(3-氟六氫吡啶-1-基)丙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(苯基胺基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(甲基(苯基)胺基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(((1,1-二側氧基四氫-2H-噻喃-3-基)甲基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-乙氧基環丙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-溴-4-氟苯基)-N'-羥基-2-(甲基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-(2-(氮雜環庚烷-1-基)乙基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-(2-(氮雜環丁-1-基)乙基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,(R)-N-(3-氯-4-氟苯基)-N'-羥基-2-(2-(3-羥基吡咯啶-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,(S)-N-(3-氯-4-氟苯基)-N'-羥基-2-(2-(3-羥基吡咯啶-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(2-(4-羥基六氫吡啶-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-溴-4-氟苯基)-2-(2-(二甲基胺基)乙基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯苯基)-2-(2-(二甲基胺基)乙基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-溴苯基)-2-(2-(二甲基胺基)乙基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(2-(甲基磺醯胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(2-(胺磺醯基胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯苯基)-N'-羥基-2-(2-(吡咯啶-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-溴苯基)-N'-羥基-2-(2-(吡咯啶-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(2-(7-(N-(3-氯-4-氟苯基)-N'-羥基甲脒基)-1H-咪唑并[4,5-b]吡啶-2-基)乙基)乙醯胺,N-(3-氯苯基)-N'-羥基-2-(2-(六氫吡啶-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-溴苯基)-N'-羥基-2-(2-(六氫吡啶-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,(2-(7-(N-(3-氯-4-氟苯基)-N'-羥基甲脒基)-1H-咪唑并[4,5-b]吡啶-2-基)乙基)胺基甲酸甲基酯,N-(3-氯-4-氟苯基)-2-(2-((2,4-二甲氧基苄基)胺基)乙基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-(2-(4-苄基六氫吡啶-1-基)乙基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-(2-(3-氮雜二環[3.3.1]壬-3-基)乙基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-(2-(3-氮雜二環[3.2.1]辛-3-基)乙基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((1-甲基六氫吡啶-3-基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,(S)-N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(3-羥基吡咯啶-1-基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,(S)-N-(3-氯-4-氟苯基)-N'-羥基-2-(3-羥基吡咯啶-1-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((1-(2-甲氧基乙基)吡咯啶-3-基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((4-甲基嗎啉-3-基)甲基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(吡咯啶-1-基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((4-((甲基磺醯基)甲基)四氫-2H-吡喃-4-基)甲基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(甲基磺醯基)苄基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-((1-乙醯基六氫吡啶-3-基)胺基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((乙基胺基)甲基)-4-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((二甲基胺基)甲基)-4-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4-氟-N'-羥基-2-((異丙基胺基)甲基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4-氟-N'-羥基-2-((甲基胺基)甲基)-1H-苯并[d]咪唑-7-甲脒,2-(胺基甲基)-N-(3-氯-4-氟苯基)-4-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-羥基-2-甲基丙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-羥基丙基)胺基)-1H-苯并[d]咪唑-7-甲脒,2-((7-(N-(3-氯-4-氟苯基)-N'-羥基甲脒基)-4,5-二氟-1H-苯并[d]咪唑-2-基)胺基)乙醯胺,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-羥基乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((3-羥基環丁基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((3-(吡啶-2-基胺基)丙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-胺磺醯基乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(((1-甲基-1H-吡唑-5-基)甲基)胺基)-1H-苯并[d]咪唑-7-甲脒,2-((2-(1H-吡唑-1-基)乙基)胺基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,2-((7-(N-(3-氯-4-氟苯基)-N'-羥基甲脒基)-4,5-二氟-1H-苯并[d]咪唑-2-基)胺基)-N,N-二甲基乙醯胺,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(2-羥基-2-甲基丙基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((4-(二甲基胺基)丁基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((六氫吡啶-3-基甲基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((1-甲基六氫吡啶-2-基)甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-溴苯基)-N'-羥基-2-((2-嗎啉基乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-5-氟-N'-羥基-4-甲氧基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((吡啶-2-基甲基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-((2-(1H-吡唑-1-基)乙基)胺基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((1-甲基-1H-吡唑-3-基)甲基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((4,4,4-三氟丁基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((3,3,3-三氟丙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(2-甲氧基乙氧基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((3-(環丙基(甲基)胺基)丙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((3-(環丙基胺基)丙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((3-(環丙基(乙基)胺基)丙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(4-氟六氫吡啶-1-基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(2,2,2-三氟乙氧基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((3-(2,2,2-三氟乙氧基)丙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(3-甲氧基六氫吡啶-1-基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((3-(二氟甲氧基)丙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,(R)-N-(3-氯-4-氟苯基)-N'-羥基-2-(((四氫呋喃-2-基)甲基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,(S)-N-(3-氯-4-氟苯基)-N'-羥基-2-(((四氫呋喃-2-基)甲基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(四氫呋喃-2-基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(六氫吡啶-2-基甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(1-(二甲基胺基)丙-2-基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(2-(甲基胺基)丙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(2-(二甲基胺基)丙基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(吡咯啶-2-基甲基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯苯基)-4,5-二氟-N'-羥基-2-((2-(吡咯啶-1-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-溴苯基)-4,5-二氟-N'-羥基-2-((2-(吡咯啶-1-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-溴-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(吡咯啶-1-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,2-((2-胺基乙基)胺基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(2-((7-(N-(3-氯-4-氟苯基)-N'-羥基甲脒基)-4,5-二氟-1H-苯并[d]咪唑-2-基)胺基)乙基)乙醯胺,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(甲基磺醯胺基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(環丙烷磺醯胺基)乙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,(2-((7-(N-(3-氯-4-氟苯基)-N'-羥基甲脒基)-4,5-二氟-1H-苯并[d]咪唑-2-基)胺基)乙基)胺基甲酸甲基酯,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(胺磺醯基胺基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(苯基磺醯胺基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-氰基乙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(3-乙基脲基)乙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((吡啶-2-基甲基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((吡啶-3-基甲基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((吡啶-3-基甲基)胺基)-1H-苯并[d]咪唑-7-甲脒,2-(((1H-咪唑-2-基)甲基)胺基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,2-氯-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,2-((2-胺基苄基)胺基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(二甲基胺基)苄基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(((1-甲基-1H-咪唑-2-基)甲基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((嘧啶-2-基甲基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((3-(二甲基胺基)-2,2-二甲基丙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((3-(二甲基胺基)-2-甲基丙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((3-(二甲基胺基)丁基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(1-甲基吡咯啶-2-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(1-甲基六氫吡啶-2-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(((4-甲基嗎啉-2-基)甲基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((4-甲基嗎啉-2-基)甲基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((1-甲基-1H-吡唑-5-基)甲基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-((7-(N-(3-氯-4-氟苯基)-N'-羥基甲脒基)-1H-咪唑并[4,5-b]吡啶-2-基)胺基)-N,N-二甲基乙醯胺,N-(3-氯-4-氟苯基)-N'-羥基-2-(3-(羥基甲基)氮雜環丁-1-基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((氧雜環丁-3-基甲基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(1-甲基-1H-咪唑-2-基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((3-(吡啶-2-基胺基)丙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(新戊基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(異丁基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((四氫-2H-吡喃-2-基)甲基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((四氫呋喃-3-基)甲基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-4-氟-N'-羥基-2-((2-嗎啉基乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-N-甲基-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-胺基-N-(3-氯-4-氟苯基)-5-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,2-胺基-N-(3-氯苯基)-5-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,2-胺基-N-(3-溴苯基)-5-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,2-胺基-N-(3-溴-4-氟苯基)-5-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(1,1-二側氧基硫嗎啉基)乙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(二乙基胺基)乙基)胺基)-4-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4-氟-N'-羥基-2-((2-(吡咯啶-1-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-嗎啉基丙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((1-(二甲基胺基)丙-2-基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(二甲基胺基)乙基)胺基)-5-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-5-氟-N'-羥基-2-((2-(吡咯啶-1-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((3-(二甲基胺基)-2,2-二甲基丙基)胺基)-4-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-溴-4-氟苯基)-2-((2-(二甲基胺基)乙基)胺基)-4-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-溴苯基)-2-((2-(二甲基胺基)乙基)胺基)-4-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯苯基)-2-((2-(二甲基胺基)乙基)胺基)-4-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯苯基)-2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-溴苯基)-2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-溴-4-氟苯基)-2-((3-(二甲基胺基)丙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((3-(二甲基胺基)丙基)胺基)-4-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((3-(二甲基胺基)丙基)胺基)-5-氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,2-((2-(苄基(甲基)胺基)乙基)胺基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-(2-((環己基甲基)(甲基)胺基)乙基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(2-(甲基(新戊基)胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(2-(環己基(甲基)胺基)乙基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(甲基((四氫-2H-吡喃-4-基)甲基)胺基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(甲基胺基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,2-(2-(苄基(甲基)胺基)乙基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-((2-乙基丁基)(甲基)胺基)乙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-((環丙基甲基)(甲基)胺基)乙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(2-(甲基((四氫-2H-吡喃-4-基)甲基)胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-(2-(((1,4-二噁烷-2-基)甲基)(甲基)胺基)乙基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(2-(甲基(2-(四氫-2H-吡喃-4-基)乙基)胺基)乙基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(環丙基胺基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(環丙基(乙基)胺基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(2-((7-(N-(3-氯-4-氟苯基)-N'-羥基甲脒基)-1H-咪唑并[4,5-b]吡啶-2-基)胺基)乙基)乙醯胺,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(甲基磺醯胺基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(環丙基(異丙基)胺基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(環丙基(2-羥基乙基)胺基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-((2-胺基乙基)胺基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((5-側氧基吡咯啶-3-基)甲基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-(((1H-吡唑-5-基)甲基)胺基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-((7-(N-(3-氯-4-氟苯基)-N'-羥基甲脒基)-1H-咪唑并[4,5-b]吡啶-2-基)胺基)丙基)乙醯胺,2-((3-胺基丙基)胺基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(胺磺醯基胺基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(苯基磺醯胺基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,(2-((7-(N-(3-氯-4-氟苯基)-N'-羥基甲脒基)-1H-咪唑并[4,5-b]吡啶-2-基)胺基)乙基)胺基甲酸甲基酯,N-(3-氯-4-氟苯基)-2-((2-(環丙烷磺醯胺基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-((三氟甲基)磺醯胺基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-(((1H-咪唑-2-基)甲基)胺基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-(((1H-咪唑-5-基)甲基)胺基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((3-甲基-1,2,4-噁二唑-5-基)甲基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-溴苯基)-N'-羥基-2-(甲基胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,(3-((7-(N-(3-氯-4-氟苯基)-N'-羥基甲脒基)-1H-咪唑并[4,5-b]吡啶-2-基)胺基)丙基)胺基甲酸甲基酯,N-(3-溴苯基)-N'-羥基-2-甲氧基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-溴苯基)-N'-羥基-2-((2-(甲基磺醯基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-溴苯基)-N'-羥基-2-((2-(甲基磺醯胺基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-溴苯基)-N'-羥基-2-((2-胺磺醯基乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((5-甲基-1,3,4-噁二唑-2-基)甲基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(((1-甲基六氫吡啶-2-基)甲基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(((4-甲基嗎啉-3-基)甲基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-溴苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-溴-4-氟苯基)-2-((2-(二甲基胺基)乙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-2-((3-嗎啉基丙基)胺基)-1H-苯并[d]咪唑-7-甲醯胺,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((3-(吡咯啶-1-基)丙基)胺基)-1H-苯并[d]咪唑-7-甲脒,2-(((3R)-4-胺基-1-甲基吡咯啶-3-基)胺基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(二甲基胺基)-2-苯基乙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-(((1R,2R)-2-(二甲基胺基)環己基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-(((1-(二甲基胺基)環戊基)甲基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-(((1S,3S)-3-(二甲基胺基)環己基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-(((1S,3R)-3-(二甲基胺基)環己基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-(((1-(二甲基胺基)環丁基)甲基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((1-甲基六氫吡啶-4-基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((1-甲基六氫吡啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-(((1S,2S)-2-(二甲基胺基)環己基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,(S)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(六氫吡啶-3-基胺基)-1H-苯并[d]咪唑-7-甲脒,(R)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(六氫吡啶-3-基胺基)-1H-苯并[d]咪唑-7-甲脒,(S)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((1-甲基吡咯啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((3-(二甲基胺基)-2-羥基丙基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(4-甲基-3-側氧基六氫吡嗪-1-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-(((1-(二甲基胺基)環己基)甲基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((1-甲基氮雜環庚烷-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒,(S)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(3-羥基吡咯啶-1-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((1-(2-甲氧基乙基)六氫吡啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((1-(2-甲氧基乙基)吡咯啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((1-異丙基六氫吡啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(3-甲氧基氮雜環丁-1-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,(R)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((1-甲基吡咯啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(((3R,4R)-4-甲氧基-1-甲基吡咯啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒,(S)-N-(3-氯苯基)-4,5-二氟-N'-羥基-2-((1-甲基六氫吡啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒,(R)-N-(3-氯苯基)-4,5-二氟-N'-羥基-2-((1-甲基六氫吡啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(二甲基胺基)環戊基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,(S)-2-(氮雜環庚烷-3-基胺基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,(R)-2-(氮雜環庚烷-3-基胺基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(吡咯啶-3-基胺基)-1H-苯并[d]咪唑-7-甲脒,(R)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((1-(氧雜環丁-3-基)六氫吡啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-(((1,4-二甲基六氫吡啶-2-基)甲基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((嗎啉-3-基甲基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(((3R,4S)-4-羥基吡咯啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-(((1R,5R)-8-甲基-8-氮雜二環[3.2.1]辛-2-基)胺基)-1H-苯并[d]咪唑-7-甲脒,(S)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(2-(三氟甲基)吡咯啶-1-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-2-(((六氫-1H-吡咯嗪-7a-基)甲基)胺基)-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-(((3,3-二甲基氮雜環丁-2-基)甲基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((4-(吡咯啶-1-基)四氫-2H-吡喃-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒,2-(((1S,2R)-2-胺基環己基)胺基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-甲基-1,2,3,4-四氫異喹啉-4-基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-(((3S,4S)-4-(二乙基胺基)四氫呋喃-3-基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,2-((1,4-氧氮雜環庚烷(oxazepan)-6-基)胺基)-N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-((2S,6R)-2,6-二甲基嗎啉基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-(((3R,4R)-4-甲氧基-1-甲基吡咯啶-3-基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(((3R,4R)-4-(二乙基胺基)四氫呋喃-3-基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,(S)-N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(2-(三氟甲基)吡咯啶-1-基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,(R)-N-(3-氯-4-氟苯基)-N'-羥基-2-(((4-甲基嗎啉-3-基)甲基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(2,6-二甲基嗎啉基)丙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(2,6-二甲基嗎啉基)-2-甲基丙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(2,5-二甲基嗎啉基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(((1R,2R)-2-(二甲基胺基)環戊基)胺基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(二甲基胺基)乙基)硫基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(二甲基胺基)乙基)硫基)-4,5-二氟-N'-羥基-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(2-(羥基甲基)六氫吡啶-1-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-4,5-二氟-N'-羥基-2-((2-(2-(羥基甲基)吡咯啶-1-基)乙基)胺基)-1H-苯并[d]咪唑-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(3,3-二氟吡咯啶-1-基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-胺磺醯基乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(甲基磺醯基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((嘧啶-2-基甲基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,(R)-N-(3-氯苯基)-4,5-二氟-N'-羥基-2-((1-(2-甲氧基乙基)吡咯啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒,(R)-N-(3-溴苯基)-4,5-二氟-N'-羥基-2-((1-(2-甲氧基乙基)吡咯啶-3-基)胺基)-1H-苯并[d]咪唑-7-甲脒,(S)-N-(3-氯-4-氟苯基)-N'-羥基-2-((1-(氧雜環丁-3-基)六氫吡啶-3-基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((1-(2-甲氧基乙基)六氫吡啶-3-基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((1-環丙基吡咯啶-3-基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,(R)-N-(3-氯-4-氟苯基)-N'-羥基-2-((1-(氧雜環丁-3-基)六氫吡啶-3-基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((2-(4-甲基-3-側氧基六氫吡嗪-1-基)乙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((2-(3,3-二氟六氫吡啶-1-基)乙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,2-((1-乙醯基吡咯啶-3-基)胺基)-N-(3-氯-4-氟苯基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((1-(甲基磺醯基)吡咯啶-3-基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-N'-羥基-2-((3-(甲基磺醯基)丙基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-(((1,1-二側氧基四氫噻吩-3-基)甲基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,N-(3-氯-4-氟苯基)-2-((3-((4-氟苯基)磺醯基)丙基)胺基)-N'-羥基-1H-咪唑并[4,5-b]吡啶-7-甲脒,及(R)-N-(3-氯-4-氟苯基)-N'-羥基-2-((1-(氧雜環丁-3-基)吡咯啶-3-基)胺基)-1H-咪唑并[4,5-b]吡啶-7-甲脒;或其醫藥上可接受之鹽、立體異構物、互變異構物或混合物。
- 一種醫藥組合物,其包含如請求項1至15中任一項之化合物或其醫藥上可接受之鹽、立體異構物、互變異構物或混合物及至少一種醫藥上可接受之媒劑。
- 一種如請求項1至15中任一項之化合物或其醫藥上可接受之鹽、立體異構物、互變異構物或混合物之用途,其用於製造用以治療由IDO1介導之疾病或病況之藥劑。
- 一種抑制IDO1蛋白之活性之離體(ex vivo)方法,其係藉由使該蛋白質與如請求項1至15中任一項之化合物或其醫藥上可接受之鹽、立體異構物、互變異構物或混合物接觸。
- 一種如請求項1至15中任一項之化合物或其醫藥上可接受之鹽、立體異構物、互變異構物或混合物之用途,其用於製造用以抑制癌細胞生長或增殖之藥劑。
- 一種如請求項1至15中任一項之化合物或其醫藥上可接受之鹽、立體異構物、互變異構物或混合物之用途,其用於製造用以抑制患者之免疫抑制的藥劑。
- 一種如請求項1至15中任一項之化合物、其醫藥上可接受之鹽、立體異構物、互變異構物或混合物之用途,其用於製造用以治療患者之癌症或病毒感染的藥劑。
- 如請求項21之用途,其中該藥劑係與抗病毒劑、化學治療劑、免疫抑制劑、輻射、抗腫瘤疫苗、抗病毒疫苗、細胞介素療法或酪胺酸激酶抑制劑組合投與。
- 如請求項21之用途,其中該藥劑係與HBV抑制劑或HIV抑制劑組合投與。
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HRP20211456T1 (hr) | 2014-12-26 | 2021-12-24 | Emory University | Protuvirusni derivati n4-hidroksicitidina |
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WO2019027855A1 (en) * | 2017-08-02 | 2019-02-07 | Merck Sharp & Dohme Corp. | NOVEL SUBSTITUTED PHENYL COMPOUNDS AS INHIBITORS OF INDOLEAMINE 2,3-DIOXYGENASE (IDO) |
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EP3294732B1 (en) | 2019-09-25 |
KR20180004811A (ko) | 2018-01-12 |
AR104642A1 (es) | 2017-08-02 |
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HK1248235A1 (zh) | 2018-10-12 |
CN107849024A (zh) | 2018-03-27 |
ES2761824T3 (es) | 2020-05-21 |
AU2016263083B2 (en) | 2019-04-04 |
TW201706251A (zh) | 2017-02-16 |
JP2019070042A (ja) | 2019-05-09 |
EA201792259A1 (ru) | 2018-06-29 |
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