CN112262141A - 可用作线粒体解偶联剂的咪唑吡啶 - Google Patents
可用作线粒体解偶联剂的咪唑吡啶 Download PDFInfo
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- CN112262141A CN112262141A CN201980038722.7A CN201980038722A CN112262141A CN 112262141 A CN112262141 A CN 112262141A CN 201980038722 A CN201980038722 A CN 201980038722A CN 112262141 A CN112262141 A CN 112262141A
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- Prior art keywords
- trifluoromethyl
- pyrazin
- phenyl
- amine
- imidazo
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- 230000002438 mitochondrial effect Effects 0.000 title claims abstract description 57
- 150000005232 imidazopyridines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 331
- 150000003839 salts Chemical class 0.000 claims abstract description 63
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 23
- 206010022489 Insulin Resistance Diseases 0.000 claims abstract description 20
- 201000011510 cancer Diseases 0.000 claims abstract description 20
- 208000008589 Obesity Diseases 0.000 claims abstract description 18
- 235000020824 obesity Nutrition 0.000 claims abstract description 18
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 18
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims abstract description 16
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims abstract description 14
- 206010063837 Reperfusion injury Diseases 0.000 claims abstract description 9
- 208000012947 ischemia reperfusion injury Diseases 0.000 claims abstract description 9
- 230000009471 action Effects 0.000 claims abstract description 8
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims abstract description 8
- 102000004877 Insulin Human genes 0.000 claims abstract description 7
- 108090001061 Insulin Proteins 0.000 claims abstract description 7
- 229940125396 insulin Drugs 0.000 claims abstract description 7
- 206010019280 Heart failures Diseases 0.000 claims abstract description 6
- 208000018737 Parkinson disease Diseases 0.000 claims abstract description 6
- 208000010706 fatty liver disease Diseases 0.000 claims abstract description 6
- 230000014101 glucose homeostasis Effects 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 186
- -1 hydroxy, amino Chemical group 0.000 claims description 127
- 125000001424 substituent group Chemical group 0.000 claims description 75
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
- 238000006467 substitution reaction Methods 0.000 claims description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 125000004432 carbon atom Chemical group C* 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 31
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 29
- 125000003118 aryl group Chemical group 0.000 claims description 28
- 229910052760 oxygen Inorganic materials 0.000 claims description 27
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- XFTQRUTUGRCSGO-UHFFFAOYSA-N pyrazin-2-amine Chemical compound NC1=CN=CC=N1 XFTQRUTUGRCSGO-UHFFFAOYSA-N 0.000 claims description 21
- 150000003254 radicals Chemical class 0.000 claims description 21
- 238000011282 treatment Methods 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 19
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 125000000304 alkynyl group Chemical group 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 125000004043 oxo group Chemical group O=* 0.000 claims description 14
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 13
- 230000000694 effects Effects 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 239000008103 glucose Substances 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 8
- 206010012601 diabetes mellitus Diseases 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- 125000002950 monocyclic group Chemical group 0.000 claims description 7
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- LZEMWQPCKJNOBE-UHFFFAOYSA-N 2-(trifluoromethyl)-5-[4-(trifluoromethyl)phenoxy]-N-[4-(trifluoromethyl)phenyl]-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound FC(C1=NC=2C(=NC(=C(N=2)OC2=CC=C(C=C2)C(F)(F)F)NC2=CC=C(C=C2)C(F)(F)F)N1)(F)F LZEMWQPCKJNOBE-UHFFFAOYSA-N 0.000 claims description 5
- BFJVNJDXUCBPAL-UHFFFAOYSA-N 3-[3,5-bis(trifluoromethyl)phenyl]-5-methoxy-2-(trifluoromethyl)imidazo[4,5-b]pyrazin-6-amine Chemical compound COC1=C(N=C2C(=N1)N(C(=N2)C(F)(F)F)C2=CC(=CC(=C2)C(F)(F)F)C(F)(F)F)N BFJVNJDXUCBPAL-UHFFFAOYSA-N 0.000 claims description 5
- VFFSCIYWXOUYDA-UHFFFAOYSA-N 3-methyl-2-(trifluoromethyl)-5-[4-(trifluoromethyl)anilino]-7H-imidazo[4,5-b]pyrazin-6-one Chemical compound CN1C2=NC(NC3=CC=C(C=C3)C(F)(F)F)=C(O)N=C2N=C1C(F)(F)F VFFSCIYWXOUYDA-UHFFFAOYSA-N 0.000 claims description 5
- UUBIPPLMSYTRKG-UHFFFAOYSA-N 5-(2,2,2-trifluoroethoxy)-N-[4-(trifluoromethoxy)phenyl]-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound C(OC1=NC=2NC(=NC=2N=C1NC1=CC=C(C=C1)OC(F)(F)F)C(F)(F)F)C(F)(F)F UUBIPPLMSYTRKG-UHFFFAOYSA-N 0.000 claims description 5
- XCHHLWGUZALRQY-UHFFFAOYSA-N 5-[2-fluoro-3-(trifluoromethyl)anilino]-2-(trifluoromethyl)-3,7-dihydroimidazo[4,5-b]pyrazin-6-one Chemical compound FC1=C(C=CC=C1C(F)(F)F)NC=1N=C2C(=NC=1O)NC(=N2)C(F)(F)F XCHHLWGUZALRQY-UHFFFAOYSA-N 0.000 claims description 5
- WTLSKVKGVJFPRG-UHFFFAOYSA-N 5-[2-fluoro-4-(trifluoromethoxy)anilino]-2-(trifluoromethyl)-3,7-dihydroimidazo[4,5-b]pyrazin-6-one Chemical compound FC1=C(C=CC(=C1)OC(F)(F)F)NC=1N=C2C(=NC=1O)NC(=N2)C(F)(F)F WTLSKVKGVJFPRG-UHFFFAOYSA-N 0.000 claims description 5
- KUAYBCDDOIHASK-UHFFFAOYSA-N 5-ethoxy-N-[4-(trifluoromethoxy)phenyl]-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound O(CC)C1=NC=2NC(=NC=2N=C1NC1=CC=C(C=C1)OC(F)(F)F)C(F)(F)F KUAYBCDDOIHASK-UHFFFAOYSA-N 0.000 claims description 5
- MZLKGBVTGIBHLF-UHFFFAOYSA-N 5-methoxy-1-methyl-2-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]imidazo[4,5-b]pyrazin-6-amine Chemical compound COC=1N=C2C(=NC=1NC1=CC=C(C=C1)C(F)(F)F)N(C(=N2)C(F)(F)F)C MZLKGBVTGIBHLF-UHFFFAOYSA-N 0.000 claims description 5
- KECDIARABDMLEB-UHFFFAOYSA-N 5-methoxy-2-methyl-N-[4-(trifluoromethyl)phenyl]-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound COC=1N=C2C(=NC=1NC1=CC=C(C=C1)C(F)(F)F)NC(=N2)C KECDIARABDMLEB-UHFFFAOYSA-N 0.000 claims description 5
- CPUZWLPSUQPMKA-UHFFFAOYSA-N 5-methoxy-2-phenyl-N-[4-(trifluoromethoxy)phenyl]-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound COC1=C(N=C2C(=N1)NC(=N2)C1=CC=CC=C1)NC1=CC=C(C=C1)OC(F)(F)F CPUZWLPSUQPMKA-UHFFFAOYSA-N 0.000 claims description 5
- HMZRYSFNLOGKFA-UHFFFAOYSA-N 5-methoxy-3-methyl-2-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]imidazo[4,5-b]pyrazin-6-amine Chemical compound COC1=C(N=C2C(=N1)N(C(=N2)C(F)(F)F)C)NC1=CC=C(C=C1)C(F)(F)F HMZRYSFNLOGKFA-UHFFFAOYSA-N 0.000 claims description 5
- VQLIVXQEPPWTPA-UHFFFAOYSA-N 5-methoxy-N-[2-methyl-5-(trifluoromethyl)phenyl]-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound O(C)C1=NC=2NC(=NC=2N=C1NC1=CC(=CC=C1C)C(F)(F)F)C(F)(F)F VQLIVXQEPPWTPA-UHFFFAOYSA-N 0.000 claims description 5
- NCUKXFKLJCARBT-UHFFFAOYSA-N 5-methoxy-N-[3-(trifluoromethoxy)phenyl]-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound O(C)C1=NC=2NC(=NC=2N=C1NC1=CC=CC(=C1)OC(F)(F)F)C(F)(F)F NCUKXFKLJCARBT-UHFFFAOYSA-N 0.000 claims description 5
- JWACRZLKDCMANU-UHFFFAOYSA-N 5-methoxy-N-[4-(trifluoromethoxy)phenyl]-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound O(C)C1=NC=2NC(=NC=2N=C1NC1=CC=C(OC(F)(F)F)C=C1)C(F)(F)F JWACRZLKDCMANU-UHFFFAOYSA-N 0.000 claims description 5
- IVMOUTRERRSIPH-UHFFFAOYSA-N 5-methoxy-N-methyl-2-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound COC=1N=C2C(=NC=1N(C1=CC=C(C=C1)C(F)(F)F)C)NC(=N2)C(F)(F)F IVMOUTRERRSIPH-UHFFFAOYSA-N 0.000 claims description 5
- ARHOMIAGTNBUJJ-UHFFFAOYSA-N 5-methoxy-N-phenyl-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound COC=1N=C2C(=NC=1NC1=CC=CC=C1)NC(=N2)C(F)(F)F ARHOMIAGTNBUJJ-UHFFFAOYSA-N 0.000 claims description 5
- RBKGAMLQBHMTJS-UHFFFAOYSA-N 5-propan-2-yloxy-2-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound C(C)(C)OC=1N=C2C(=NC=1NC1=CC=C(C=C1)C(F)(F)F)NC(=N2)C(F)(F)F RBKGAMLQBHMTJS-UHFFFAOYSA-N 0.000 claims description 5
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 5
- RCXJJMWDEGKFPG-UHFFFAOYSA-N N-(3-iodophenyl)-5-methoxy-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound O(C)C1=NC=2NC(=NC=2N=C1NC1=CC=CC(=C1)I)C(F)(F)F RCXJJMWDEGKFPG-UHFFFAOYSA-N 0.000 claims description 5
- CKHPPWXXDBMEOJ-UHFFFAOYSA-N N-(4-tert-butylphenyl)-5-methoxy-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound C1(C(C)(C)C)=CC=C(NC2=C(OC)N=C3NC(=NC3=N2)C(F)(F)F)C=C1 CKHPPWXXDBMEOJ-UHFFFAOYSA-N 0.000 claims description 5
- GPMAFUBTTRPUOI-UHFFFAOYSA-N N-[2-fluoro-3-(trifluoromethyl)phenyl]-5-methoxy-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound O(C)C1=NC=2NC(=NC=2N=C1NC1=CC=CC(=C1F)C(F)(F)F)C(F)(F)F GPMAFUBTTRPUOI-UHFFFAOYSA-N 0.000 claims description 5
- JGTYXOHHAWYUHX-UHFFFAOYSA-N N-[2-fluoro-4-(trifluoromethoxy)phenyl]-5-methoxy-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound O(C)C1=NC=2NC(=NC=2N=C1NC1=C(F)C=C(OC(F)(F)F)C=C1)C(F)(F)F JGTYXOHHAWYUHX-UHFFFAOYSA-N 0.000 claims description 5
- AVWYSBJXCHVNHD-UHFFFAOYSA-N N-[2-fluoro-4-(trifluoromethoxy)phenyl]-5-propoxy-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound C(COC1=NC=2NC(=NC=2N=C1NC1=C(F)C=C(OC(F)(F)F)C=C1)C(F)(F)F)C AVWYSBJXCHVNHD-UHFFFAOYSA-N 0.000 claims description 5
- AJJCXZCIIQBDAW-UHFFFAOYSA-N N-[2-fluoro-4-(trifluoromethyl)phenyl]-5-methoxy-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound O(C)C1=NC=2NC(=NC=2N=C1NC1=CC=C(C=C1F)C(F)(F)F)C(F)(F)F AJJCXZCIIQBDAW-UHFFFAOYSA-N 0.000 claims description 5
- OLHVGPNRNLAVSB-UHFFFAOYSA-N N-[2-fluoro-5-(trifluoromethyl)phenyl]-5-methoxy-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound O(C)C1=C(NC2=CC(=CC=C2F)C(F)(F)F)N=C2C(=N1)NC(=N2)C(F)(F)F OLHVGPNRNLAVSB-UHFFFAOYSA-N 0.000 claims description 5
- ABWJZVVAXQDPNY-UHFFFAOYSA-N N-[2-iodo-4-(trifluoromethoxy)phenyl]-5-methoxy-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound IC1=C(C=CC(=C1)OC(F)(F)F)NC=1N=C2C(=NC=1OC)NC(=N2)C(F)(F)F ABWJZVVAXQDPNY-UHFFFAOYSA-N 0.000 claims description 5
- RLLGIWHDQUOMPZ-UHFFFAOYSA-N N-[3-fluoro-4-(trifluoromethoxy)phenyl]-5-methoxy-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound O(C)C1=C(NC2=CC=C(C(=C2)F)OC(F)(F)F)N=C2C(=N1)NC(=N2)C(F)(F)F RLLGIWHDQUOMPZ-UHFFFAOYSA-N 0.000 claims description 5
- KZUROQMQOHMHNE-UHFFFAOYSA-N N-[3-fluoro-4-(trifluoromethyl)phenyl]-5-methoxy-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound O(C)C1=NC=2NC(=NC=2N=C1NC1=CC=C(C(=C1)F)C(F)(F)F)C(F)(F)F KZUROQMQOHMHNE-UHFFFAOYSA-N 0.000 claims description 5
- 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 claims description 4
- IRWOOUKFFNRSPT-UHFFFAOYSA-N 5-(2-fluorophenoxy)-2-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound FC1=C(OC=2N=C3C(=NC=2NC2=CC=C(C=C2)C(F)(F)F)NC(=N3)C(F)(F)F)C=CC=C1 IRWOOUKFFNRSPT-UHFFFAOYSA-N 0.000 claims description 4
- ZBZNPGYEEVNEJZ-UHFFFAOYSA-N 5-butoxy-N-[4-(trifluoromethoxy)phenyl]-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound C(OC1=NC=2NC(=NC=2N=C1NC1=CC=C(OC(F)(F)F)C=C1)C(F)(F)F)CCC ZBZNPGYEEVNEJZ-UHFFFAOYSA-N 0.000 claims description 4
- ONWNYFRIRZAYQQ-UHFFFAOYSA-N 5-ethoxy-N-[2-fluoro-4-(trifluoromethoxy)phenyl]-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound C(OC1=NC=2NC(=NC=2N=C1NC1=C(F)C=C(OC(F)(F)F)C=C1)C(F)(F)F)C ONWNYFRIRZAYQQ-UHFFFAOYSA-N 0.000 claims description 4
- YRXSTNMPMQYZLG-UHFFFAOYSA-N 5-methoxy-2-(1,1,2,2,2-pentafluoroethyl)-N-[4-(trifluoromethoxy)phenyl]-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound COC1=C(N=C2C(=N1)NC(=N2)C(C(F)(F)F)(F)F)NC1=CC=C(C=C1)OC(F)(F)F YRXSTNMPMQYZLG-UHFFFAOYSA-N 0.000 claims description 4
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- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- XCZSTMLJLYCVNL-UHFFFAOYSA-N N-(2,3-difluorophenyl)-5-methoxy-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound O(C)C1=NC=2NC(=NC=2N=C1NC1=C(F)C(F)=CC=C1)C(F)(F)F XCZSTMLJLYCVNL-UHFFFAOYSA-N 0.000 claims description 4
- RYOYVLCURMECKB-UHFFFAOYSA-N N-(3,5-difluorophenyl)-5-methoxy-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyrazin-6-amine Chemical compound O(C)C1=NC=2NC(=NC=2N=C1NC1=CC(F)=CC(=C1)F)C(F)(F)F RYOYVLCURMECKB-UHFFFAOYSA-N 0.000 claims description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/18—Oxygen or sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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Abstract
本公开提供了式(I‑A)和(I‑B)的化合物及其药学上可接受的盐。本文定义了变量R、R2、R3、X1、X2、X3、Y1、Y和Z。某些式(I‑A)和(I‑B)的化合物用作不影响质膜电位的选择性线粒体质子载体解偶联剂。这些化合物可用于治疗对线粒体解偶联有反应的病状或降低其风险,所述病状例如癌症、肥胖症、II型糖尿病、脂肪肝疾病、胰岛素抵抗、帕金森氏病、缺血再灌注损伤、心力衰竭、非酒精性脂肪肝疾病(NALFD)或非酒精性脂肪性肝炎(NASH)。由于线粒体解偶联剂减少了活性氧(ROS)的产生,而活性氧已知会导致年龄相关性细胞损伤,因此所述化合物可用于延长寿命。式(I‑A)和(I‑B)的化合物和盐也可用于调节患者中的葡萄糖稳态或胰岛素作用。
Description
相关申请的交叉引用
本申请要求2018年4月20日提交的美国临时申请第62/660,880号的优先权,其由此通过引用整体并入。
背景技术
细胞呼吸是基本目标为以ATP的形式产生能量的生理过程。在细胞呼吸期间,源于营养物质的化学能转化为ATP。具体地,线粒体基质中的营养物质的氧化生成了高能电子载体烟酰胺腺嘌呤二核苷酸(NADH)和黄素腺嘌呤二核苷酸(FADH2),它们被位于线粒体内膜(MIM)中的线粒体电子传递链(ETC)氧化。通过ETC的电子流动是一个放能过程,其驱动一系列的质子泵,以使质子逆着其浓度梯度从基质流出到膜间空间(IMS)。所得的质子浓度(ΔpH)和电(ΔΨ)梯度被称为质子动力(pmf)。经由ATP合酶重新进入线粒体基质的质子驱动ATP的吸能产生。因此,线粒体ATP产生涉及经由跨MIM的质子梯度将电子传递与磷酸化反应偶联。
线粒体解偶联描述了将营养物质氧化与ATP产生解偶联的过程。线粒体解偶联是一个正常的生理过程,其随着基础或可诱导质子从膜间空间泄漏而发生。基础质子泄漏占哺乳动物的基础代谢率的~20–25%。这种代谢效率低下的原因尚不完全清楚;但是,膜脂质组成和腺嘌呤核苷酸转位酶(ANT)的丰度是导致基础质子泄漏速率的因素。诱导的质子泄漏是由反应性物种和激活解偶联蛋白(UCP)的脂肪酸驱动的。UCP位于MIM中,并且促进了将质子转移到与ATP合酶无关的基质中。
哺乳动物中有五种已知的UCP(UCP1-5),它们具有不同的组织定位。表征最充分的UCP是UCP1和UCP2。UCP1在褐色和米色的脂肪组织中表达,并且在非颤抖性产热中起作用。UCP1不太可能作为简单的质子通道运作,而是经由需要长链脂肪酸的机制转移质子。相反,UCP2具有广泛的组织分布,并且在产热中不起作用。UCP2使线粒体解偶联,以防止超极化并减少线粒体超氧化物的产生。
小分子线粒体解偶联剂通过独立于蛋白质复合物将质子传递到基质中而直接充当质子载体,或者可替代地,经由蛋白质(例如,ANT)介导解偶联。质子解偶联剂的亲脂性足以使其通过MIM,而弱酸性则足以实现部分和可逆的pH依赖性电离。线粒体解偶联具有治疗相关的两个主要表型,包含增加营养物质氧化以补偿ATP产生效率的不足和减少来自ETC的超氧化物产生。ETC是大多数组织中活性氧(ROS)的主要来源。当氧化还原中心的辅酶或辅基上的单个电子与分子氧相互作用时,ETC源超氧化物的形成经由非酶过程而发生。ETC中的单个电子仅短暂存在于氧化还原中心中,并且处于不稳定状态的单个电子的停留时间会增加超氧化物产生的可能性。线粒体解偶联剂通过刺激更快的电子转移(这缩短了ETC中的单个电子的停留时间)来减少线粒体超氧化物的产生。
线粒体解偶联剂的治疗潜力与其增加营养物质氧化和减少来自ETC的超氧化物产生的双重作用有关。一方面,营养物质氧化的增加促进了瘦身,并且是治疗肥胖症和相关代谢疾病的治疗策略。另一方面,线粒体ROS与多种病理学有关,包含缺血再灌注损伤、炎症、胰岛素抵抗、神经变性和许多其它病理学。重要的是,线粒体解偶联剂防止ROS的产生,这与清除已产生的ROS的抗氧化剂相比是有利的。因此,减少线粒体ROS的产生具有显著的治疗潜力,并且具有优于抗氧化剂清除剂的优点。
线粒体调节细胞代谢,并且在一些最普遍的人类疾病(包含肥胖症、癌症、糖尿病、神经变性和心脏病)的发病机理中发挥重要作用。这些疾病中的多种疾病都可以通过使用减轻线粒体氧化损伤并且增加能量消耗的药理剂(例如,线粒体解偶联剂)来改善。遗传和药理学上的解偶联对与线粒体氧化应激有关的病症(例如,缺血再灌注损伤、帕金森氏病、胰岛素抵抗、衰老和心力衰竭)以及可受益于能量消耗增加的病症(例如,肥胖症)具有有益作用。
线粒体解偶联剂是已知的,并且已被示出可有效治疗肥胖症。例如,2,4-二硝基苯酚(DNP)是一种熟知的导致人类体重减轻的小分子线粒体质子载体。服用~300mg/d的患者在数月中平均每周稳定下降1.5磅,而食物摄入量没有变化。类似地,用DNP治疗的小鼠表现出血清葡萄糖、甘油三酯和胰岛素水平的改善以及氧化损伤减少、体重降低和寿命延长。然而,DNP对其它细胞膜具有脱靶作用,从而导致治疗指数狭窄。随后,DNP在1938年被美国食品和药物管理局从北美市场撤出。目前,还没有足够安全用于人类的解偶联剂药物。
不影响质膜电位的选择性线粒体质子载体解偶联剂的开发将拓宽线粒体解偶联剂的安全界限,并提供了可以将线粒体解偶联用于治疗肥胖症、II型糖尿病和其它与线粒体功能有关的疾病、病症和病状的全新希望。在本领域中长期切身需要可用于使用线粒体解偶联剂来预防和治疗肥胖症、糖尿病,调节葡萄糖稳态,减少脂肪过多、防止缺血再灌注损伤和调节胰岛素作用的组合物和方法,以及可用作线粒体解偶联剂的化合物。本公开满足了这些需要。
发明内容
本公开提供了式I-A和I-B的化合物
或其药学上可接受的盐。在式I-A和I-B中,变量,例如X1、X2、X3、Y、Y1、R2和R3具有以下定义。
X1和X2为C或N,其中X1和X2中的至少一个为N。
X3为H、C1-C4烷基、C1-C2卤代烷基、苯基或卤素取代苯基。
Y为O或NR。
Y1为O或NR1。
Z为O或S。
R为H或甲基。
R1为氢或C1-C8烷基、C2-C8烯基或C2-C8炔基。
R2为C1-C8烷基、C2-C8烯基或C2-C8炔基;或
R2为-C0-C4烷基(C3-C7环烷基)、-C0-C4烷基(桥联C7-C12环烷基)、-C0-C4烷基(芳基)、-C0-C4烷基(单环或双环杂芳基)或-C0-C4烷基(4到7元杂环烷基),其中的每一个任选地被一个或多个独立地选自以下的取代基取代:R11和0或1个取代基R12;或
R1和R2连结以形成3到7元环,其中一个碳任选地由N、S或O置换。
R3为H或C1-C8烷基、C2-C8烯基或C2-C8炔基,或
R3为-C0-C4烷基(C3-C7环烷基)、-C0-C4烷基(芳基)或-C0-C4烷基(杂芳基),其中的每一个任选地被一个或多个独立地选择的R11取代基取代。
其中在R1、R2和R3的定义中的每个C0-C4烷基、C1-C8烷基、C2-C8烯基或C2-C8炔基中,一个或多个碳原子任选地由O、NR10、-C(O)-、-C(O)O-、-OC(O)、-S(O)n-、-S(O)nNR10、-NR10S(O)n-、-NR10C(O)NR10、-C(O)NR10-或-NR10C(O)-置换,其中n为0、1或2,并且其中所述C0-C4烷基、C1-C8烷基、C2-C8烯基或C2-C8炔基任选地被一个或多个取代基R13取代。
在每次出现时,R10独立地选自氢、C1-C6烷基和-C0-C2烷基(C3-C7环烷基)。
在每次出现时,R11独立地选自卤素、羟基、氨基、硝基、氰基、-CHO、-COOH、氧代、卤代巯基以及C1-C8烷基、C2-C8烯基和C2-C8炔基,其中在R11的定义中的每个C1-C8烷基、C2-C8烯基和C2-C8炔基中,一个或多个碳原子任选地由O、NR10、-C(O)-、-C(O)O-、-OC(O)、-S(O)n-、-C(O)NR10-或-NR10C(O)-置换,其中n为0、1或2,并且其中每个C0-C4烷基、C1-C8烷基、C2-C8烯基或C2-C8炔基任选地被一个或多个取代基R13取代。
R12选自-C0-C4烷基(C3-C7环烷基)、-O-C0-C4烷基(C3-C7环烷基)、-C0-C4烷基(芳基)、-O-C0-C4烷基(芳基)、-C0-C4烷基(5到6元杂芳基)、-O-C0-C4烷基(5到6元杂芳基)、-C0-C4烷基(5到6元杂环烷基)和-O-C0-C4烷基(5到6元杂环烷基),其中的每一个任选地被一个或多个独立地选自以下的取代基取代:卤素、羟基、氨基、硝基、氰基、-CHO、-COOH、氧代、C1-C2卤代烷基、C1-C2卤代烷氧基、C1-C6烷基、C1-C6烷氧基、C1-C6烷基酯、-C0-C4烷基(单或二C1-C6烷基氨基)、C2-C6烷酰基、C2-C6烯基和C2-C6炔基。
在每次出现时,R13独立地选自卤素、羟基、氨基、硝基、氰基、-CHO、-COOH、氧代、C3-C7环烷基和苯基。
本公开包含一种药物组合物,其包括式I-A或I-B的化合物或盐以及药学上可接受的赋形剂。
本公开包含一种治疗或预防对线粒体解偶联有反应的病状的方法,其包括向需要这种治疗的患者施用治疗有效量的式I-A或I-B的化合物或盐。对线粒体解偶联有反应的病状包含肥胖症、II型糖尿病、脂肪肝疾病、胰岛素抵抗、帕金森氏病、缺血再灌注损伤、心力衰竭、非酒精性脂肪肝疾病(NALFD)或非酒精性脂肪性肝炎(NASH)。
本公开包含一种调节患者中的葡萄糖稳态或胰岛素作用的方法,其包括向需要其的患者施用治疗有效量的式I-A或I-B的化合物或盐。
本公开还包含一种治疗患者中的高脂血症、糖血症、葡萄糖耐量、胰岛素敏感性、脂肪过多、胰岛素抵抗、肥胖症或糖尿病的方法,其包括向所述患者施用治疗有效量的根据权利要求1到30中任一项所述的化合物。
附图说明
图1。被给予正常饮食、西式饮食或西式饮食加上化合物2-21的小鼠的饮食诱导的肥胖症逆转数据。图1A,体重与时间的关系;图1B,脂肪量(通过EchoMRI测量)与时间的关系;图1C,食物摄入(最后14天)与时间的关系。
具体实施方式
在说明书和权利要求书中,除非另有说明或与上下文相反,否则术语将具有本部分中所述的定义。除非另有定义,否则本文使用的所有技术和科学术语已被本公开所属领域的普通技术人员通常理解。尽管类似于或等同于本文描述的那些的任何方法和材料可以用于本公开的实施例的实践或测试;但优选方法和材料描述如下。
术语“一个/一种(a/an)”不表示数量限制,而是表示存在至少一个所引用的项目。术语“或”是指“和/或”。如本文使用,术语“约”是指大约、左右、大致或大概。当术语“约”与数值范围结合使用时,其通过延伸边界将所述范围修饰为高于和低于所述数值。通常,术语“约”在本文中用于以10%的变化将数值修饰为高于和低于所述值。因此,约50%是指在45%-55%的范围内。
在本文中由端点叙述的数值范围包含所述范围内的所有数字和分数(例如,1到5包含1、1.5、2、2.75、3、3.90、4和5)。
术语“另外的治疗活性化合物”或“另外的治疗剂”是指用于针对所治疗的特定损伤、疾病或病症的另外的治疗用途的化合物的使用或施用。例如,这种化合物可以包含用于治疗不相关的疾病或病症或可能对所治疗的损伤、疾病或病症的主要治疗没有反应的疾病或病症的化合物。
如本文使用,术语“施用(administration of/administering)”化合物应被理解为是指向需要治疗的受试者提供本公开的化合物。
“激动剂”是物质的组合物,当将其施用于哺乳动物(例如,人类)时,其增强或扩展归因于受试者中的目标化合物或目标分子的水平或存在的生物活性。
“减轻疾病或病症症状”是指降低症状的严重程度或受试者经历这种症状的频率或两者。
“拮抗剂”是物质的组合物,当将其施用于哺乳动物(例如,人类)时,其抑制归因于受试者中的目标化合物或分子的水平或存在的生物活性。
如本文使用,“式I-A或I-B的化合物”是指式I-A或I-B的范围内的任何化合物,并且除非上下文另有指示,否则包含式I-A和I-B的药学上可接受的盐。
术语“包括(comprises/comprising)”和替代过渡短语“包含(includes/including)”、“含有(contain/containing)”是开放式过渡短语,其具有美国专利法赋予它们的含义。“包括”和其它开放式术语涵盖中间术语“基本上由……组成”和封闭式术语“由……组成(consisting of/consists of)”。叙述了开放式过渡短语之一的权利要求可以用任何其它过渡短语写出,除非上下文或技术明确禁止,否则其可以更具限制性。
术语“递送媒剂”是指可以用于在体内递送化合物或可以加入包括施用于植物或动物的化合物的组合物的任何种类的装置或材料。这包含但不限于可植入装置、细胞聚集体、基质材料、凝胶等。
“疾病”是动物的一种健康状态,在这种状态下,动物无法维持稳态,并且在这种状态下,如果所述疾病没有得到改善,则动物的健康继续恶化。相反,动物中的“病症”是一种健康状态,在这种状态下,动物能够维持稳态,但是在这种状态下,动物的健康状态相较于没有所述病症的情况较为不利。如果未治疗,病症不一定会导致动物的健康状况的进一步下降。
如本文使用,“有效量”或“治疗有效量”是指足以产生所选择的效果(例如,减轻疾病或病症的症状)的量。在以组合的形式施用化合物(例如,多种化合物)的背景中,当与另外一种或多种化合物组合施用时,每种化合物的量可能与单独施用所述化合物时不同。因此,尽管化合物的组合的有效量总体上将所述组合当作一个整体,但是每种化合物的实际量可以有所不同。
如在说明书和所附权利要求书中使用,术语“例如(for example/forinstance)”、“诸如”、“包含”等旨在引入进一步阐明更一般主题的实例。除非另有说明,否则提供这些实例仅是为了帮助理解本公开,并非旨在以任何方式进行限制。
术语“式”和“结构”在本文中可互换使用。
如本文使用,术语“抑制”是指本公开的化合物减少或阻碍所描述的功能(例如,具有抑制性钠通道活性)的能力。优选地,抑制是指功能被抑制至少10%,更优选被抑制至少25%,甚至更优选被抑制至少50%,最优选被抑制至少75%。术语“抑制”、“减少”和“阻断”在本文可互换使用。
如本文使用,“注射或应用”包含通过多种途径和手段施用本公开的化合物,所述途径和手段包含但不限于局部、口服、颊、静脉内、肌肉内、动脉内、髓内、鞘内、心室内、经皮、皮下、腹膜内、鼻内、肠内、局部、舌下、阴道、眼内、肺部或直肠手段。
如本文使用,“说明材料”包含出版物、记录、图表或任何其它表达介质,其可以用于传达试剂盒中的本公开的化合物用于减轻本文叙述的各种疾病或病症的有效性。任选地或可替代地,说明材料可以描述一种或多种减轻哺乳动物细胞或组织中的疾病或病症的方法。例如,本公开的试剂盒的说明材料可以被固定到含有所标识的公开化合物的容器上,或者与含有所标识的化合物的容器一起装运。
可替代地,说明材料可以与容器分开装运,其目的是使说明材料和化合物由接收者协同使用。
术语“线粒体解偶联”,也被称为“解偶联”,是指质子经由独立于ATP合酶的途径进入线粒体基质,从而使营养物质氧化与ATP产生解偶联的过程。本过程在药理学上可以由小分子线粒体质子载体诱导,所述质子载体直接将质子穿过线粒体内膜进入基质。需氧细胞中的能量产生的主要途径涉及线粒体中的营养物质(包含脂肪、碳水化合物和氨基酸)的氧化,这促进了质子从线粒体基质流出。本过程在整个线粒体内膜上产生了pH和电化学梯度。质子通常经由ATP合酶重新进入线粒体基质,这导致了ATP产生。质子还可以经由独立于ATP合酶的途径重新进入线粒体基质,这使营养物质氧化和质子流出与ATP产生“解偶联”。
术语“调节”是指更改活性、功能或过程的水平。术语“调节”涵盖抑制和刺激活性、功能或过程。
如本文使用,药物组合物的“肠胃外施用”包含特征在于对受试者的组织进行物理破坏以及通过组织中的缺口施用药物组合物的任何施用途径。因此,肠胃外施用包含但不限于注射组合物、通过手术切口施用组合物、通过穿透组织的非手术伤口施用组合物等方式施用药物组合物。特别地,肠胃外施用被认为包含但不限于皮下、腹膜内、肌肉内、胸骨内注射以及肾脏透析输注技术。
如本文使用,术语“每次应用”是指将组合物、药物或化合物施用于受试者。
术语“药物组合物”应是指包括至少一种活性成分和药学上可接受的载剂(例如,药学上可接受的赋形剂)的组合物。
“药学上可接受的赋形剂”是指可用于制备通常是安全、无毒且生物学上或其它方面都非不合乎需要的药物组合物/组合的赋形剂,并且包含兽医学用途以及人类药学用途上可接受的赋形剂。所述术语还涵盖由美国联邦政府的监管机构批准用于药物组合物或在《美国药典》中列出的用于动物(包含人类)的任何非活性剂。
术语“药学上可接受的载剂”包含任何标准药物载剂,例如磷酸盐缓冲盐溶液、水、乳液(例如,油/水或水/油乳液)以及各种类型的润湿剂。所述术语还涵盖由美国联邦政府的监管机构批准或在《美国药典》中列出的用于动物(包含人类)的任何试剂。
“药学上可接受的”是指对于人类或兽医学应用是生理上可耐受的。如本文使用,“药物组合物”包含用于人类和兽医学用途的调配物。
“多个”是指至少两个。
如本文使用,术语“预防”是指阻止某事发生或显著降低某事发生的可能性,例如通过针对可能的某事或可能的结果采取预先措施。在医学背景中,“预防”包含为减少罹患疾病或病状的可能性而采取的行动。
“预防性(preventive/prophylactic)”治疗是施用于未表现出疾病或病症的病征或仅表现出早期病征的受试者的治疗。施用预防性治疗是为了降低与所述疾病或病症发展相关联的病理发展的风险。
“前药”是指在体内转化为母药的试剂。前药通常是有用的,因为在一些情况下,它们可能比母药更容易施用。例如,通过口服施用,它们可以具有生物利用度,而母药则不是。与母药相比,前药在药物组合物中的溶解度也可以得到改善,或者可以表现出适口性增加或更易于调配。
分析、诊断或治疗的“受试者”是动物。这种动物包含哺乳动物,优选人类。如本文使用,“需要其的受试者”是将受益于本公开的方法的患者、动物、哺乳动物或人类。
如本文使用,术语“症状”是指患者经历并指示疾病的任何病态现象或在结构、功能或感觉上与正常的偏离。相反,“病征”是疾病的客观证据。例如,流鼻血是一个病征。这对患者、医生、护士和其它观察者是显而易见的。
“治疗性”治疗是为了减少或消除那些病征而向表现出病理病征的受试者施用的治疗。
“治疗有效量”的化合物是足以对施用所述化合物的受试者提供有益作用的量的化合物。
如本文使用,“治疗(treat/treating/treatment)”包含治疗、改善或抑制损伤或疾病相关病状或损伤或疾病相关病状的症状。在一个实施例中,预防了疾病、损伤或疾病相关病状或损伤或疾病相关病状的症状;而另一个实施例提供了损伤或疾病相关病状或损伤或疾病相关病状的症状的预防性治疗。
化学定义
“烷基”是具有指定数量的碳原子(通常为1到约8个碳原子)的支链或直链饱和脂族烃基团。如本文使用,术语C1-C6烷基指示具有1、2、3、4、5或6个碳原子的烷基基团。其它实施例包含具有1到6个碳原子、1到4个碳原子或1或2个碳原子的烷基基团,例如C1-C8烷基、C1-C4烷基和C1-C2烷基。烷基的实例包含但不限于甲基、乙基、正丙基、异丙基、正丁基、3-甲基丁基、叔丁基、正戊基、仲戊基、庚基和辛基。“C0-Cn烷基”与另一基团一起使用(例如,C0-C4烷基(C3-C7环烷基)),以指示所述另一基团(在这种情况下为C3-C7环烷基)与它所取代的基团通过单个共价键(C0)结合或通过具有指示数量的碳原子的亚烷基连接基团附接。
“烯基”是具有一个或多个可以在沿着链的任何稳定点处存在的碳-碳双键的支链或直链脂族烃基团,其具有指定数量的碳原子。烯基的实例包含但不限于乙烯基、丙烯基、1,3-丁二烯基、1-丁烯基、己烯基和戊烯基。
“炔基”是具有一个或多个可以在沿着链的任何稳定点处存在的碳-碳三键的支链或直链脂族烃基团,其具有指定数量的碳原子。炔基的实例包含但不限于乙炔基、丙炔基、1-丁炔基、2-丁炔基和1-戊炔基。
“烷酰基”是如上定义的烷基基团,其通过羰基桥(-C(=O)-)与其所取代的基团共价结合。羰基氧包含在取代基团的碳的计数中。C2烷酰基为-C(=O)CH3。
“烷氧基”是如上定义的烷基基团,其指示数量的碳原子通过氧桥(-O-)与其所取代的基团共价结合。烷氧基的实例包含但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、2-丁氧基、叔丁氧基、正戊氧基、2-戊氧基、3-戊氧基、异戊氧基、新戊氧基、正己氧基、2-己氧基、3-己氧基和3-甲基戊氧基。
“烷基氨基”是如本文定义的烷基基团,其通过氨基键与其所取代的基团共价结合。烷基氨基基团可以是其中氨基是仲氨基(烷基NH-)的单烷基基团或其中氨基是叔氨基(烷基1)(烷基2)N-的二烷基基团。二烷基氨基的烷基基团相同或不同。
“烷基酯”是如本文定义的烷基基团,其通过酯键与其所取代的基团共价结合。酯键可以处于任一取向,例如,式-OC(O)-烷基的基团或式-C(O)O-烷基的基团。
“芳基”指示具有至少一个芳族环的单环、双环或三环环系。芳基基团在一个或多个芳族环中仅含有碳。芳基基团可以稠合到含有N、O或S杂原子的非芳族环。典型的芳基基团含有1到3个独立的、稠合的或侧链的环和6到约18个环原子,而没有杂原子作为环成员。当指示时,这种芳基就按可以进一步被碳或非碳原子或基团取代。实例包含苯基、萘基、联苯基、四氢萘基、茚满基和茚基基团。
“环烷基”是具有指定数量的碳原子的饱和烃环基团。单环环烷基基团通常具有3到约8个碳环原子,3到7个环原子或3到6个(3、4、5或6个)碳环原子。环烷基取代基可以是取代的氮、氧或碳原子的侧基,或者可以具有两个取代基的取代碳原子可以具有作为螺环基团附接的环烷基基团。环烷基基团的实例包含环丙基、环丁基、环戊基和环己基。
“桥联环烷基”是具有两个或两个以上仅含碳环原子的环的环烷基基团,并且碳环中的一个含有与碳环中的两个“桥头”原子连接的1个碳原子或2-3个非支链碳原子的“桥”。桥头原子通常是不相邻的碳环原子。桥环烷基基团的实例包含但不限于双环[2.2.2]辛基、双环[3.3.1]壬基、金刚烷基和双环[3.3.3]十一碳烷基。
“卤素”或“卤代”包含溴代、氯代、氟代和碘代。
“卤代烷基”指示具有指定数量的碳原子的支链和直链烷基基团,其被1个或多个卤素原子(多达最大允许数量的卤素原子)取代。卤代烷基的实例包含但不限于三氟甲基、二氟甲基、2-氟乙基、2,2,2-三氟乙基和五氟乙基。
“卤代烷氧基”指示如本文定义的卤代烷基基团,其通过氧桥(醇自由基的氧)附接。
“卤代巯基”是被一个或多个卤素原子(多达最大允许数量的卤素原子)取代的硫。
“杂芳基”是具有至少一个芳族环的环或环系,所述芳族环含有独立地选自N、O和S的杂原子,其余的环原子为碳。稠环可以含有或不含有杂原子,并且不需要是芳族的。优选的是,杂芳基环系中的杂原子的总数不超过4,并且杂芳基环系中的S和O原子的总数不超过2。单环杂芳基基团通常具有5到7个环原子。在一些实施例中,双环杂芳基基团为9到10元杂芳基基团,即含有9或10个环原子的基团,其中一个5到7元芳族环稠合到第二芳族或非芳族环。当杂芳基基团的芳族环中的S和O原子的总数超过1时,这些杂原子彼此不相邻。杂芳基基团的实例包含但不限于噁唑基、吡喃基、吡嗪基、吡唑并嘧啶基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹啉基、四唑基、噻唑基、噻吩吡唑基、硫苯基、三唑基、苯并[d]噁唑基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并噁二唑基、二氢苯并二氧基、呋喃基、咪唑基、吲哚基和异噁唑基。
“杂环烷基”是饱和环状基团,其含有1个或多个独立地选自N、O和S的环原子,并且其余的环原子为碳。杂环烷基的实例包含四氢吡喃基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、硫吗啉基、噁唑烷基、四氢噻吩基、四氢硫吡喃基、噻唑烷基和吡咯烷基。
“药学上可接受的盐”包含所公开的化合物的衍生物,其中母体化合物通过制备其无机和有机无毒酸或碱加成盐而被修饰。本化合物的盐可以通过常规化学方法由含有碱性或酸性部分的母体化合物合成。通常,可以通过使这些化合物的游离酸形式与化学计算量的适当的碱(例如,Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应,或通过使这些化合物的游离碱形式与化学计算量的适当的酸反应来制备这种盐。也可以制备有机酸(例如,羧酸)的碱金属(例如,钠、钾或锂)或碱土金属(例如,钙)盐。
这种反应通常在水或有机溶剂或两者的混合物中进行。
药学上可接受的盐的实例包含但不限于碱性残基(例如,胺或含氮杂芳基环(例如,吡啶、喹啉、异喹啉))的矿物或有机酸盐;酸性残基(例如,羧酸)的碱或有机盐;等等。药学上可接受的盐包含例如由无毒的无机或有机酸形成的母体化合物的常规无毒盐和季铵盐。例如,常规的无毒酸盐包含衍生自无机酸(例如,盐酸、氢溴酸、硫酸、磷酸、硝酸等)的盐;由有机酸(例如,乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、丙二酸、酒石酸、柠檬酸、抗坏血酸、帕莫酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、甲磺酸、乙磺酸、苯磺酸、磺胺酸、2-乙酰氧基苯甲酸、富马酸、琥珀酸、甲苯磺酸、甲烷磺酸、乙烷二磺酸,草酸、α-酮戊二酸酯、α-甘油磷酸酯、羟基乙磺酸、HO2C-(CH2)n-CO2H(其中n为0-4)等)制备的盐。
仅作为实例,衍生自无机碱的盐包含钠、钾、锂、铵、钙和镁盐。衍生自有机碱的盐包含但不限于伯胺、仲胺和叔胺(例如,烷基胺、二烷基胺、三烷基胺、取代烷基胺、二(取代烷基)胺、三(取代烷基)胺、烯基胺、二烯基胺、三烯基胺、取代烯基胺、二(取代烯基)胺、三(取代烯基)胺、环烷基胺、二(环烷基)胺、三(环烷基)胺、取代环烷基胺、二取代环烷基胺、三取代环烷基胺、环烯基胺、二(环烯基)胺、三(环烯基)胺、取代环烯基胺、二取代环烯基胺、三取代环烯基胺、芳基胺、二芳基胺、三芳基胺、杂芳基胺、二杂芳基胺、三杂芳基胺、杂环胺、二杂环胺、三杂环胺、混合的二胺和三胺(其中胺上的至少两个取代基是不同的并且选自由以下组成的群组:烷基、取代烷基、烯基、取代烯基、环烷基、取代环烷基、环烯基、取代环烯基、芳基、杂芳基、杂环)等)的盐。还包含其中两个或三个取代基与氨基氮一起形成杂环或杂芳基基团的胺。仅作为示例,合适的胺的实例包含异丙胺、三甲胺、二乙胺、三(异丙基)胺、三(正丙基)胺、乙醇胺、2-二甲基氨基乙醇、三甲胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴明、胆碱、甜菜碱、乙二胺、葡糖胺、N-烷基葡糖胺、可可碱、嘌呤、哌嗪、哌啶、吗啉、N-乙基哌啶等。还应理解,其它羧酸衍生物将可用于本公开的实践中,例如羧酸酰胺,包含羧酰胺、低级烷基羧酰胺、二烷基羧酰胺等。
可以在例如G.Steffen Paulekuhn等人,《药物化学杂志(Journal of MedicinalChemistry)》,2007,50,6665和《药用盐手册:性质、选择和使用(Handbook ofPharmaceutical Salts:Properties,Selection and Use)》,P.Heinrich Stahl和Camille G.Wermuth编辑,Wiley-VCH,2002中找到另外的合适的盐的列表。
术语“取代”是指指定原子或基团上的任何一个或多个氢被指示基团的选择置换,条件是不超过指定原子的正常价。除非另有说明,否则每个取代基独立于其它取代基选择。“任选地取代”是指存在0到最大允许数量的取代基。当取代基是氧代(即=O)时,原子上的2个氢被置换。当氧代基团取代杂芳族部分时,所得的分子有时可以采用互变异构形式。例如,在2位或4位由氧代取代的吡啶基基团有时可以被写为吡啶或羟基吡啶。仅当取代基和/或变量的组合产生稳定的化合物或有用的合成中间体时,这种组合才是允许的。稳定的化合物或稳定的结构是指足以抵抗从反应混合物中分离并随后调配成有效治疗剂的化合物。除非另有说明,否则将取代基命名为核心结构。例如,应理解,氨基烷基是指本取代基与核心结构的附接点在烷基部分中,而烷基氨基是指附接点是连接到氨基基团的氮的键。然而,短线(“-”)指示取代基的附接点。-C1-C4烷基(环烷基)附接在1-4个碳亚烷基连接基团处。
本公开包含其中任何氢由氘置换的式I-A和I-B的氘代化合物。“氘代”是指在指定位置的氢由氘置换。在某一位置被氘代的式I-A或I-B的化合物的任何样品中,式I-A或I-B的化合物的一些离散分子将可能在指定位置具有氢而不是氘。然而,在指定位置具有氘的样品中的式I-A或I-B的化合物的分子的百分比将比天然存在的百分比大得多。氘代位置的氘富集。如本文使用,术语“富集”是指氘相对于所述位置处的其它氢物种的百分比。作为一个实例,如果说式I的化合物中的某一位置含有50%的氘富集,其是指指定位置处的氘含量为50%(而不是氢)。为了清楚起见,证实了本文使用的术语“富集”不表示相对于天然丰度的富集百分比。在一个实施例中,式I-A或I-B的氘代化合物将在任何氘代位置具有至少10%的氘富集。在其它实施例中,在指定的一个或多个氘代位置处将存在至少50%、至少90%或至少95%的氘富集。“氘代取代基”是其中至少一个氢以指定的富集百分比由氘置换的取代基。“任选地氘代”是指所述位置可以在任一氢处,并且所述位置处的氘量仅是天然存在的氘水平或所述位置富集了高于天然存在的氘水平的氘。
本公开的某些化合物可以含有一个或多个不对称元素(例如,立体异构中心、立体异构轴等),例如不对称碳原子,使得化合物可以以不同的立体异构形式存在。例如,这些化合物可以是消旋体或光学活性形式。对于具有两个或两个以上不对称元素的化合物,这些化合物还可以是非对映体的混合物。对于具有不对称中心的化合物,应理解为涵盖了所有的光学异构体及其混合物。在这些情况下,可以通过不对称合成,由光学纯的前体合成或通过消旋体的拆分来获得单一对映体,即光学活性形式。消旋体的拆分也可以例如通过常规方法来完成,例如在拆分剂存在下进行结晶,或使用例如手性HPLC柱进行层析。另外,具有碳-碳双键的化合物可以以Z和E形式出现,并且所述化合物的所有异构形式都包含在本公开中。
化学描述
本公开提供了式I-A和I-B的化合物及其药学上可接受的盐:
变量,例如式I-A和I-B中的R、R2、R2、X1、X2、X3、Y、Y1或Z可以具有发明内容部分中所述的任何定义,或者可以具有以下所述的任何值。
式I还包含子式,其中变量具有任何以下定义。可以组合以下任何变量定义,只要得到稳定的化合物即可。
Y可以为N-R。
Y可以为O。
X1和X2可以均为氮。
Z可以为O;并且X1和X2可以均为氮。
X1和X2中的一个可以为氮,而另一个可以为碳。
Z可以为O,并且X1和X2中的一个可以为氮,而另一个可以为碳。
X3变量
X3可以具有以下定义。
(i)X3为氢。
(ii)X3为甲基、三氟甲基、五氟乙基、苯基或氟取代苯基。
(ii)X3为三氟甲基。
R和R1变量
R和R1可以具有以下定义。
(i)R为氢。
(ii)Y为NR1,并且R1为氢或未取代的C1-C6烷基。
(iii)Y为NR1,并且R1为氢。
R2变量
R2可以具有以下定义
(i)R2为-C0-C4烷基(C3-C7环烷基)、-C0-C4烷基(桥联C7-C12环烷基)、-C0-C4烷基(芳基)、-C0-C4烷基(单环或双环杂芳基)或-C0-C4烷基(4到7元杂环烷基),其中的每一个任选地被一个或多个独立地选自以下的取代基取代:R11和0或1个取代基R12;
在每个C0-C4烷基中,一个或多个碳原子任选地由O、NR10、-C(O)-、-C(O)O-、-OC(O)、-S(O)n-、-C(O)NR10-或-NR10C(O)-置换,其中n为0、1或2,并且其中所述C0-C4烷基、C1-C8烷基、C2-C8烯基或C2-C8炔基任选地被一个或多个取代基R13取代。
(ii)R2为C1-C8烷基,其任选地被一个或多个独立地选自以下的取代基取代:卤素、羟基、氨基、硝基、氰基和氧代。
(iii)R2为-C0-C4烷基(桥联C7-C12环烷基)或-C0-C4烷基(芳基),其中的每一个任选地被一个或多个独立地选自以下的取代基取代:R11和0或1个取代基R12;在C0-C4烷基中,一个或多个碳原子任选地由O、NR10、-C(O)-、-C(O)O-、-OC(O)、-S(O)n-、-C(O)NR10-或-NR10C(O)-置换,其中n为0、1或2,并且其中所述C0-C4烷基任选地由R13取代。
(iv)R2为-C0-C4烷基(桥联C7-C12环烷基)或-C0-C4烷基(芳基),其中的每一个任选地被一个或多个独立地选自以下的取代基取代:R11和0或1个取代基R12;在C0-C4烷基中,一个或多个碳原子任选地由O、NR10、-C(O)-、-C(O)O-、-OC(O)、-S(O)n-、-C(O)NR10-或-NR10C(O)-置换,其中n为0、1或2,并且其中所述C0-C4烷基任选地由R13取代。
(v)R2为C0-C2烷基(桥联C7-C12环烷基),其任选地被一个或多个独立地选自R11的取代基取代。
(vi)R2为金刚烷-1-基或-CH2(金刚烷-1-基),其中的每一个未被取代或被卤素、羟基、氨基、硝基、氰基、C1-C4烷基、C1-C4烷氧基、-C0-C2烷基(单或双C1-C4烷基氨基)、C1-C2卤代烷基和C1-C2卤代烷氧基取代。
(vii)R2为-C0-C4烷基(苯基)、萘基或芴基,其中的每一个任选地被一个或多个独立地选自以下的取代基取代:R11和0或1个取代基R12;在C0-C4烷基中,一个或多个碳原子任选地由O、NR10、-C(O)-、-C(O)O-、-OC(O)、-S(O)n-、-C(O)NR10-或-NR10C(O)-置换,其中n为0、1或2,并且其中所述C0-C4烷基任选地由R13取代。
(viii)R2为苯基,其任选地由一个或多个独立地选自R11的取代基取代。
(ix)R2为苯基,其任选地由一个或多个独立地选自以下的取代基取代:卤素、羟基、氨基、硝基、氰基、氧代、卤代巯基以及C1-C8烷基、C2-C8烯基和C2-C8炔基,其中在R11的定义中的每个C1-C8烷基、C2-C8烯基和C2-C8炔基中,一个或多个碳原子任选地由O、NR10、-C(O)O-、-OC(O)或-S(O)n-置换,其中n为0、1或2,并且其中每个C1-C8烷基、C2-C8烯基或C2-C8炔基任选地被一个或多个取代基R13取代。
(x)R2为-C0-C4烷基(苯基),其任选地被一个或多个独立地选自以下的取代基取代:R11和0或1个取代基R12;在C0-C4烷基中,一个或多个碳原子任选地由O、NR10、-C(O)-、-C(O)O-、-OC(O)、-S(O)n-、-C(O)NR10-或-NR10C(O)-,其中n为0、1或2,并且其中所述C0-C4烷基任选地由R13取代;
R12选自-C0-C4烷基(C3-C7环烷基)、-O-C0-C4烷基(C3-C7环烷基)、-C0-C4烷基(苯基)、-O-C0-C4烷基(苯基)、-C0-C4烷基(5到6元杂芳基)、-O-C0-C4烷基(5到6元杂芳基),其中的每一个任选地被一个或多个独立地选自以下的取代基取代:卤素、羟基、氨基、硝基、氰基、-CHO、-COOH、氧代、C1-C2卤代烷基、C1-C2卤代烷氧基、C1-C6烷基、C1-C6烷氧基、C1-C6烷基酯、-C0-C4烷基(单或二C1-C6烷基氨基)、C2-C6烷酰基、C2-C6烯基和C2-C6炔基。
(xi)R2为萘基,或
R2为苯基,其被1、2或3个独立地选自以下的取代基取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C2卤代烷基和C1-C2卤代烷氧基,或
R2为苯基,其任选地被1或2个独立地选自以下的取代基取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C2卤代烷基和C1-C2卤代烷氧基,并且其被一个苯基取代基取代,所述苯基取代基任选地被1、2或3个独立地选自以下的取代基取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C2卤代烷基和C1-C2卤代烷氧基。
R3变量
R3可以具有任何以下定义。
(i)R3为氢。
(ii)R3为C1-C8烷基、C2-C8烯基或C2-C8炔基,在C1-C8烷基、C2-C8烯基或C2-C8炔基中,一个或多个碳原子任选地由O、NR10、C(O)O-、-OC(O)或-S(O)n-置换,其中n为0、1或2,并且其中所述C1-C8烷基、C2-C8烯基或C2-C8炔基任选地被一个或多个取代基R13取代。
(iii)R3为C1-C6烷基,其任选地被羟基、卤素、三氟甲基或三氟甲氧基取代。
(iv)R3为-C0-C4烷基(C3-C7环烷基)或-C0-C4烷基(芳基),其任选地被一个或多个独立地选择的R11取代基取代。
在一个实施例中,本公开包含式I-A和I-B的化合物及其盐,其中所述变量具有以下定义。
Y1为NR1,并且R1为氢或甲基;并且
R2为萘基,或
R2为苯基,其被1、2或3个独立地选自以下的取代基取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C2卤代烷基和C1-C2卤代烷氧基,或
R2为苯基,其任选地被1或2个独立地选自以下的取代基取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C2卤代烷基和C1-C2卤代烷氧基,并且其被一个苯基取代基取代,所述苯基取代基任选地被1、2或3个独立地选自以下的取代基取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C2卤代烷基和C1-C2卤代烷氧基。
在另一个实施例中,本公开包含式I-A或I-B的化合物,其中所述变量具有以下定义。
X1和X2均为N;
X3为氢、甲基、三氟甲基、五氟乙基、苯基或3-氟苯基;
Y为NR1,并且R1为氢或甲基;
Z为O;
R为氢或甲基;
R1为氢或C1-C2烷基;
R2为萘基,或
R2为苯基,其被1、2或3个独立地选自以下的取代基取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C2卤代烷基和C1-C2卤代烷氧基,或
R2为苯基,其任选地被1或2个独立地选自以下的取代基取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C2卤代烷基和C1-C2卤代烷氧基,并且其被一个苯基取代基取代,所述苯基取代基任选地被1,2或3个独立地选自以下的取代基取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C2卤代烷基和C1-C2卤代烷氧基;并且
R3为H或任选地被羟基或三氟甲基取代的C1-C6烷基。
作为另外的实施例,提供了用于制备本公开的式(例如,本公开的通式)的化合物或用于制备可用于制备本公开的式I-A或I-B或其它式的化合物的中间体的工艺。作为本公开的另外的实施例,还提供了可用于制备式I-A或I-B或其它式的化合物的中间体。
药物组合物
本公开包含一种药物组合物,其包括本公开的化合物或其盐以及药学上可接受的赋形剂。
本公开提供了包括式I-A或I-B的化合物的药物组合物。所述药物组合物可以包括一种或多种本公开的化合物及其药学上可接受的盐以及药学上可接受的载剂。在一个实施例中,所述化合物作为药物组合物施用。
施用途径可以取决于所施用的化合物的类型而有所不同。一方面,通过各种途径(例如,口服、局部、直肠、肌肉内、粘膜内、鼻内、吸入、眼内和静脉内)施用化合物。
本公开进一步提供了作为速释或控释调配物的式I-A或I-B的化合物的施用。
所施用的一种或多种活性化合物的剂量将取决于所治疗的病状、特定化合物以及其它临床因素,例如所治疗的受试者的年龄、性别、体重和健康、所述一种或多种化合物的施用途径以及所施用的组合物的类型(片剂、凝胶帽、胶囊、溶液、混悬液、吸入剂、气雾剂、酏剂、锭剂、注射剂、贴剂、软膏、霜剂等)。应当理解,本公开可应用于人类和兽医学用途。
作为另外的实施例,提供了用于制备本公开的任何式的化合物或用于制备可用于制备本公开的任何式的化合物的中间体的工艺。作为本公开的另外的实施例,还提供了可用于制备式I-A和I-B的化合物的中间体。
作为本公开的另外的实施例,提供了用于制备本公开的任何式的化合物的工艺,并且通过以下程序对其进行了说明,其中除非另有限定,否则通用自由基的含义如上文所给出。
在一个实施例中,本公开的化合物可以与药学上可接受的载剂(例如,惰性稀释剂或可同化的可食用载剂)组合全身施用(例如,口服)。它们可以装入硬壳或软壳明胶胶囊中,可以压制成片剂,或可以直接与患者饮食中的食物掺混。对于口服治疗性施用,活性化合物可以与一种或多种赋形剂组合,并以可吸收片剂、口腔片剂、含片、胶囊,酏剂、混悬液、糖浆、糯米纸等形式使用。这种组合物和制剂应含有至少0.1%的活性化合物。组合物和制剂的百分比当然可以变化,并且可以方便地在给定单位剂型的重量的约2%到约60%之间。这种在治疗上有用的组合物中的活性化合物的量应使得将获得有效剂量水平。
片剂、含片、丸剂、胶囊等还可以含有以下:可以加入粘合剂,例如黄蓍胶、阿拉伯树胶、玉米淀粉或明胶;赋形剂,例如磷酸二钙;崩解剂,例如玉米淀粉、马铃薯淀粉、海藻酸等;润滑剂,例如硬脂酸镁;和甜味剂,例如蔗糖、果糖、乳糖或阿斯巴甜,或调味剂,例如薄荷、冬青油或樱桃调味剂。当单位剂型是胶囊时,除上述类型的材料外,它还可以含有液体载剂,例如植物油或聚乙二醇。各种其它材料可以作为包衣存在或以其它方式改变固体单位剂型的物理形式。例如,片剂、丸剂或胶囊可以用明胶、蜡、虫胶或糖等包衣。糖浆或酏剂可以含有活性化合物、蔗糖或果糖(作为甜味剂)、对羟基苯甲酸甲酯和对羟基苯甲酸丙酯(作为防腐剂)、染料和调味剂(例如,樱桃或橘子调味剂)。当然,用于制备任何单位剂型的任何材料应是药学上可接受的,并且在使用量上基本上是无毒的。另外,可以将活性化合物掺入缓释制剂和装置中。
活性化合物也可以通过输注或注射静脉内或腹膜内施用。活性化合物或其盐的溶液可以在水中制备,任选地与无毒的表面活性剂混合。分散液也可以在甘油、液体聚乙二醇、三醋精及其混合物中以及在油中制备。在普通的储存和使用条件下,这些制剂含有防腐剂以防止微生物的生长。
适合用于注射或输注的药物剂型可以包含无菌水溶液或分散液或包括活性成分的无菌粉末,所述无菌粉末适于临时制备无菌可注射或可输注溶液或分散液,其任选地包封在脂质体中。在所有情况下,最终剂型在制造和储存条件下均应无菌、流动且稳定。液体载剂或媒剂可以是溶剂或液体分散介质,其包括例如水、乙醇、多元醇(例如,甘油、丙二醇、液体聚乙二醇等)、植物油、无毒甘油酯和其合适的混合物。适当的流动性可以例如通过形成脂质体,通过维持所需的颗粒尺寸(在分散液的情况下)或通过使用表面活性剂来维持。可以通过各种抗细菌剂和抗真菌剂(例如,对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等)来防止微生物的作用。在许多情况下,优选包含等渗剂,例如糖、缓冲液或氯化钠。通过在组合物中使用延迟吸收的试剂(例如,单硬脂酸铝和明胶),可以使可注射组合物的吸收延长。
通过将所需量的活性化合物与所需的上述各种其它成分掺入适当的溶剂中,然后过滤灭菌,来制备无菌可注射溶液。在用于制备无菌可注射溶液的无菌粉末的情况下,优选的制备方法是真空干燥和冷冻干燥技术,其产生活性成分加上先前无菌过滤的溶液中存在的任何另外的所需成分的粉末。
对于局部施用,本化合物可以以纯的形式应用,即当它们是液体时。然而,通常期望以组合物或调配物的形式将它们与皮肤病学上可接受的载剂(其可以是固体或液体)一起施用于皮肤。
有用的固体载剂包含细粒固体,例如滑石、粘土、微晶纤维素、二氧化硅、氧化铝等。有用的液体载剂包含水、醇或二醇或水-醇/二醇共混物,其中本化合物可以任选地借助于无毒表面活性剂以有效水平溶解或分散。可以加入佐剂(例如,芳香剂和另外的抗微生物剂),以优化用于给定用途的性质。所得的液体组合物可以从吸收垫上应用,用于浸渍绷带和其它敷料,或使用泵式或气雾剂喷雾器喷到患处。增稠剂(例如,合成聚合物、脂肪酸、脂肪酸盐和酯、脂肪醇、改性纤维素或改性矿物材料)也可以与液体载剂一起使用,以形成可涂抹的糊剂、凝胶、软膏、肥皂等,从而直接用于使用者的皮肤。
可以用于将式I-A和I-B的化合物递送到皮肤的有用的皮肤病学组合物的实例是本领域已知的;例如,参见Jacquet等人(美国专利第4,608,392号)、Geria(美国专利第4,992,478号)、Smith等人(美国专利第4,559,157号)和Wortzman(美国专利第4,820,508号)。可以通过在动物模型中比较它们的体外活性和体内活性来确定本公开的化合物的有用剂量。在小鼠和其它动物中推断用于人类的有效剂量的方法是本领域已知的;例如,参见美国专利第4,938,949号。
通常,本公开的一种或多种化合物在液体组合物(例如,洗剂)中的浓度为约0.1-25wt-%,优选约0.5-10wt-%。在半固体或固体组合物(例如,凝胶或粉末)中的浓度将为约0.1-5wt-%,优选约0.5-2.5wt-%。用于治疗所需的化合物或其活性盐或衍生物的量不仅会因所选择的特定盐而有所不同,而且还会随施用途径、所治疗病状的性质以及患者的年龄和状况而有所不同,并且最终将由主治医师或临床医生决定。
例如,在与向人类口服施用有关的一个实施例中,大约0.1至300mg/kg/天或大约0.5至50mg/kg/天或大约1至10mg/kg/天的剂量通常是足够的,但是将取决于诸如所治疗的病症、治疗的长度、受试者的年龄、性别、体重和/或健康等因素而有所不同。一方面,使用单位剂量。一方面,单位剂量在注射器中提供。药物的组合可以在含有所有所使用的药物的调配物中施用,或者药物可以分开施用。在一些情况下,预期多个施用剂量/多次施用将是必需的或有用的。另外,对于一些治疗方案,将使用至少两种化合物。一方面,将施用至少三种化合物。本公开进一步提供了改变治疗时间的长度。
然而,一般而言,合适的剂量将在约0.5到约100mg/kg的范围内,例如每天约10到约75mg/kg体重,例如每天接受者的每千克体重3到约50mg,优选在6-90mg/kg/天的范围内,最优选在15-60mg/kg/天的范围内。
所述化合物方便地以单位剂型施用;例如,每单位剂型含有5-1000mg、方便地10-750mg、最方便地50-500mg活性成分。
理想地,当活性成分需要进入循环并经由血液递送时,在一个实施例中,应施用活性成分以达到活性化合物的峰值血浆浓度约0.5到约75μM,优选约1到50μM,最优选约2到约30μM。这可以例如通过静脉内注射0.05-5%的活性成分的溶液(任选地在盐水中)或以含有约1-100mg活性成分的大丸剂口服施用来实现。可以通过连续输注以提供约0.01-5.0mg/kg/小时或通过含有约0.4-15mg/kg活性成分的间歇输注来维持期望的血液水平。
所需剂量可以方便地以单剂量或以适当间隔(例如,每天两个、三个、四个或更多个亚剂量)施用的分剂量存在。所述亚剂量本身可以进一步分为例如多个离散的松散间隔施用;例如从吹入器多次吸入或通过将多滴药液滴入眼中。
本公开的药物组合物可以进一步包括单独或组合(例如,2、3或4种另外的添加剂)的另外的治疗性添加剂。另外的添加剂的实例包含但不限于:(a)抗微生物剂,(b)类固醇(例如,氢化可的松、曲安西龙);(c)止痛药(例如,阿司匹林、NSAID和局部麻醉药);(d)抗炎剂;和(e)其组合。在体内酶消化的非合成基质蛋白(例如,胶原蛋白、糖胺聚糖和透明质酸)可用于递送(参见美国专利第4,394,320号;第4,472,840号;第5,366,509号;第5,606,019号;第5,645,591号;和第5,683,459号),并且适合与本公开一起使用。可以使用其它可植入介质和装置来在体内递送本公开的化合物。这些包含但不限于海绵(例如,购自Integra的那些)、纤维蛋白凝胶、由聚乳酸乙醇酸共聚物(PLAGA)的烧结微球形成的支架和由天然胶原蛋白以及其它蛋白质形成的纳米纤维。本公开的化合物可以进一步与生长因子、营养因子、药物、含钙化合物、抗炎剂、抗微生物剂或能够加快或促进骨或组织生长、稳定性和重塑的任何其它物质组合。
本公开的组合物还可以与无机填料或颗粒组合。例如,用于可植入移植物中的无机填料或颗粒可以选自羟基磷灰石、磷酸三钙、陶瓷玻璃、无定形磷酸钙、多孔陶瓷颗粒或粉末、网状钛或钛合金或颗粒状钛或钛合金。
可以在本公开中使用的其它抗微生物剂的实例包含但不限于异烟肼、乙胺丁醇、吡嗪酰胺、链霉素、氯法齐明、利福布汀、氟喹诺酮、氧氟沙星、司帕沙星、利福平、阿奇霉素、克拉霉素、氨苯砜、四环素、红霉素、环丙沙星、强力霉素、氨苄青霉素、两性霉素B、酮康唑、氟康唑、乙胺嘧啶、磺胺嘧啶、克林霉素、林可霉素、喷他眯、阿托伐醌、巴龙霉素、地卡扎里尔(diclarazaril)、阿昔洛韦、三氟尿苷、膦甲酸、青霉素、庆大霉素、更昔洛韦、伊曲康唑、咪康唑、吡啶硫酮Zn和银盐(例如,氯化物、溴化物、碘化物和高碘酸盐)。
在一个实施例中,本公开的化合物可以首先被包封到微胶囊、微球、微粒、微纤维、增强纤维等中,以促进混合并实现受控、延长、延迟和/或持续释放以及与其它药剂或药物组合。包封生物活性剂还可以保护试剂免于在本公开的复合物的形成期间降解。
在本公开的另一个实施例中,由于由细胞重塑引起的依赖于时间尺度的生物吸收,当将本公开的组合物植入受试者时,化合物可控地释放到受试者中。一方面,可以使用所述组合物来置换组织中的不连续区域。所述不连续区域可以是创伤、疾病、病症或病状、手术、损伤等的结果。
如本文使用,“说明材料”包含出版物、记录、图表或任何其它表达介质,其可以用于传达本公开的组合物对其指定用途的有效性。本公开的试剂盒的说明材料可以例如被固定到含有组合物的容器上,或者与含有组合物的容器一起装运。可替代地,说明材料可以与容器分开装运,其目的是使说明材料和化合物由接收者协同使用。
本公开的方法包含试剂盒,所述试剂盒包括本公开中标识的化合物和描述了将所述化合物或包括所述化合物的组合物施用于受试者的说明材料。这应被解释为包含本领域技术人员已知的试剂盒的其它实施例,例如包括适合于在将化合物施用于受试者之前溶解或混悬本公开的组合物的溶剂(优选无菌)的试剂盒。优选地,受试者是人类。
根据本公开,如上所述或如以下实例所讨论,可以使用本领域技术人员已知的常规化学、细胞、组织化学、生物化学、分子生物学、微生物学和体内技术。文献中对这种技术进行了充分解释。
无需另外的描述,相信本领域的普通技术人员可以使用前面的描述和以下说明性实例来制备和利用本公开的化合物。
治疗方法
线粒体调节细胞代谢,并且在一些最普遍的人类疾病(包含肥胖症、癌症、糖尿病、神经变性和心脏病)的发病机理中发挥重要作用。本公开的化合物包含可用于治疗和预防这些疾病和病症及本文所述的其它疾病和病症以及线粒体解偶联剂可使用的其它疾病和病症。
许多抗糖尿病药物(例如,胰岛素增敏剂)通过将葡萄糖有效地“推送”到营养物质过载的组织中来促进从血液清除葡萄糖;但是,与这种方法相反,我们的策略旨在减少细胞营养物质的储存,使得组织从循环“拉动”葡萄糖。本方法是在运动和卡路里限制干预之后建模的,这也减少了细胞营养物质的储存,以改善糖血症和胰岛素敏感性。在用线粒体解偶联剂2,4-二硝基苯酚(DNP)治疗的人类中验证了原理论证。DNP减少脂肪过多并改善人类中的代谢;但是,它的治疗窗口也非常狭窄,并且已于1938年被撤销FDA批准。其它抗糖尿病药物(包含甲状腺激素激动剂和11-β羟基类固醇脱氢酶1型抑制剂)具有增加能量消耗的脱靶作用,这可以介导这些化合物的一些保护作用。然而,还没有专门针对增加能量消耗的药物。
在一个实施例中,本公开的化合物可用于治疗与线粒体功能缺陷相关联或可以用用作解偶联剂的药物或试剂治疗的疾病、病症和病状。所述方法可以包括向需要其的受试者施用药物组合物,所述药物组合物包括有效量的式I-A或I-B的化合物或其盐(作为第一治疗剂)以及药学上可接受的载剂和任选地的至少一种另外的治疗剂。
在一个实施例中,本公开提供了用于在不使用线粒体解偶联剂向电子传递链提供电子的情况下增加氧消耗,减少细胞活性氧,使线粒体内膜去极化并增加氧消耗速率的组合物和方法,所述方法包括使细胞或线粒体与包括至少一种本公开的化合物和任选的另外的治疗剂的组合物接触。
例如,本文公开了本公开的线粒体解偶联剂既防止又逆转了饲喂高脂肪和高糖西式饮食的小鼠中的体脂肪量的增加。除体脂肪外,线粒体解偶联剂还降低了胰岛素水平,这很重要,因为它可以纠正高胰岛素血症,改善葡萄糖耐量并防止饮食诱导的葡萄糖耐量。本文还公开了线粒体解偶联剂的施用逆转了胰岛素抵抗(包含饮食诱导的胰岛素抵抗),并且恢复了胰岛素敏感性指数。因此,本公开的化合物可用于预防和治疗糖尿病。还公开了本公开的化合物减少肝脂肪,从而提供了对脂肪肝疾病的治疗。本文公开了本公开的化合物可以在不改变食物摄入的情况下防止体重增加,并且可以防止饮食诱导的脂肪积聚。本公开的化合物还可用于逆转饮食诱导的体重或脂肪增加,并且可以逆转饮食诱导的脂肪增加和脂肪肝。
呼吸期间生成的活性氧随时间而引起生物损伤,从而导致突变和其它生物变化,这导致癌症、衰老和寿命缩短。线粒体解偶联减少了活性氧的产生,从而潜在地降低了患癌症的风险,降低了衰老的影响,并延长了寿命。线粒体解偶联剂逆转或干扰癌症代谢的许多方面,因此可在多种癌症类型中有效。例如,线粒体解偶联剂可有效治疗p53表达或活性受损的癌症(https://www.nature.com/articles/s41467-018-05805-1)(例如,某些乳腺癌和卵巢癌)、Ras突变型癌症(https://www.cell.com/molecular-cell/pdf/S1097-2765(15)00004-0.pdf)和/或β-连环蛋白突变型癌症(https://www.ncbi.nlm.nih.gov/pubmed/28107588)。线粒体解偶联剂被证明可治疗肾上腺皮质癌(http://clincancerres.aacrjournals.org/content/clincanres/early/2016/02/12/1078-0432.CCR-15-2256.full.pdf)、黑素瘤(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833689/)、原发性结肠癌(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056247/)和远隔器官(包含肝)转移(https://www.nature.com/articles/s41419-017-0092-6)。
本公开的化合物可以表现出以下性质或活性中的至少一种:能量消耗激动剂,线粒体解偶联剂,抗氧化剂,增加氧消耗,使线粒体内膜去极化,刺激分离的线粒体中的呼吸,增加或刺激氧消耗而向电子传递链提供电子,在质膜处没有质子载体活性,减少再灌注诱导的线粒体氧化应激,减少细胞活性氧,改善葡萄糖耐量,提供免受高脂肪诱导的葡萄糖耐量的保护,激活AMPK而不消耗ATP,预防、逆转或治疗胰岛素抵抗,预防、逆转或治疗高胰岛素血症,预防、逆转或治疗高脂血症,改善血脂谱,改善瘦身,改善胰岛素敏感性,防止缺血再灌注损伤,并且毒性比其它线粒体抑制剂更低。在一个实施例中,本公开的化合物具有这些性质中的两种或两种以上。在一个实施例中,本公开的化合物具有这些性质中的三种或三种以上。在一个实施例中,本公开的化合物具有这些性质中的四种、五种、六种、七种、八种、九种、十种、十一种、十二种或十二种以上。在一个实施例中,本公开的化合物具有这些性质的中的一种、两种、三种、四种、五种、六种、七种、八种、九种、十种。
可以例如取决于受试者的年龄、性别、健康和体重以及待治疗的特定疾病、病症或病状,以不同的时间、剂量并不止一次地向受试者施用本公开的化合物。一方面,化合物以约0.1mg/kg到约500mg/kg体重的剂量施用。另一方面,化合物以约0.5mg/kg到约100mg/kg体重或约0.5mg/kg到约25mg/kg体重的剂量施用。又一方面,化合物以约1.0mg/kg到约50mg/kg体重的剂量施用。一方面,施用约3.0mg/kg。另一方面,施用约5.0mg/kg。一方面,所述剂量选自0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1.0、2.0、3.0、4.0、5.0、6.0、7.0、8.0、9.0、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、34、35、36、37、38、39、40、41、42、43、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、110、120、130、140、150、160、170、180、190、200、300、400和500mg/kg体重以及所列数字范围内的所有分数、小数和整数。另一方面,化合物以约10mg到约500mg/单位剂量的单位剂量施用。
一方面,向受试者施用化合物不止一次。一方面,所述化合物是在质膜处没有质子载体活性的线粒体质子载体解偶联剂。
一方面,本公开提供了一种治疗或预防对线粒体解偶联有反应的病状的方法,其包括向需要这种治疗的患者施用治疗有效量的式I-A或I-B的化合物或其盐。
一方面,与线粒体功能缺陷相关联的疾病、病症或病状选自由以下组成的群组:肥胖症、缺血再灌注损伤、高胰岛素血症、高脂血症、糖血症、葡萄糖耐量、胰岛素敏感性、脂肪过多、胰岛素抵抗、肥胖症、糖尿病、癌症、神经变性、心脏病、肾病、心力衰竭、帕金森氏病、创伤性脑损伤、中风、衰老和可受益于能量消耗增加的病症。一方面,所述化合物是线粒体解偶联剂。
一方面,对线粒体解偶联有反应的病状是肥胖症、II型糖尿病、脂肪肝疾病、胰岛素抵抗、癌症、多发性硬化、亨廷顿舞蹈病、阿尔茨海默氏痴呆症、帕金森氏病、缺血再灌注损伤、心力衰竭、非酒精性脂肪肝疾病(NALFD)或非酒精性脂肪性肝炎(NASH)。
本公开还包含一种延长寿命的方法,其包括向人类或非人类动物施用有效量的式I的化合物或其盐。延长寿命可以经由通过延迟年龄相关性疾病的发作或与年龄相关性变化(包含神经退行性疾病、年龄相关性认知能力下降或年龄相关性运动神经元反应下降)来延迟衰老。本公开包含一种通过延迟与衰老有关的疾病的发作来延长寿命的方法,其包括向人类或非人类动物施用有效量的式I的化合物或其盐。
本公开包含一种调节患者中的葡萄糖稳态或胰岛素作用的方法,其包括向所述患者施用治疗有效量的式I-A或I-B的任何一个的化合物或盐。
本公开包含一种治疗患者中的高脂血症、糖血症、葡萄糖耐量、胰岛素敏感性、脂肪过多、胰岛素抵抗、肥胖症或糖尿病的方法,其包括向所述患者施用治疗有效量的式I-A或I-B的化合物。
本领域普通技术人员将认识到,基于本文公开的教导,并非所有构型都需要是有效的或与所述属的其它化合物一样有效。
现在参考以下实例和实施例描述本公开。无需另外的描述,相信本领域的普通技术人员可以使用前面的描述和下面的说明性实例来制备和利用本公开并实践所要求保护的方法。因此,仅出于说明的目的而提供了以下工作实例,并且所述工作实例具体地指出了本公开的优选实施例,并且不应被解释为以任何方式限制本公开的其余部分。因此,实例应被解释为涵盖由于本文提供的教导而变得显而易见的任何和所有变型。
实例
一般方法
在以下合成实例中使用了以下起始材料和一般程序。
在所有合成实例中,室温(rt)为约21℃。
NMR溶剂参考:(CD3)2CO(2.05/29.84ppm);(CD3)2SO(2.50/39.52ppm)。
NMR缩写:aq.=水性,app=表观,br=宽,s=单峰,d=双峰,t=三重峰,q=四重峰,p=五重峰。*是指旋转异构体。
咪唑-吡嗪系列
一般程序A.用于制备5-甲氧基化合物
在六打兰(dram)小瓶中,将所需的噁二唑-吡嗪1(0.2mmol)、铁(1mmol)、三氟甲磺酸镱(III)(0.02mmol)溶于冰乙酸(0.45mL)和所需的氟化酯(三氟乙酸乙酯或五氟丙酸甲酯)(2mL);将混合物在95℃下剧烈搅拌4小时。在冷却至室温之后,将5mL H2O和5mL EtOAc加入反应混合物中,并将其通过硅藻土垫过滤。分离有机层,并将水层用EtOAc萃取三次。合并有机层,用饱和NaHCO3水溶液洗涤,通过Na2SO4干燥,并减压浓缩。将残余物通过硅胶柱层析(0-20%EtOAc/己烷)纯化,得到所需的5-甲氧基-2-三氟甲基-N-苯基-1H-咪唑并[4,5-b]吡嗪-6-胺,其为浅黄色固体。
一般程序2B.用于制备5-羟基取代化合物
在密封管中,将所需的甲氧基取代咪唑-吡嗪(0.05mmol)和碘化钠(0.15mmol)溶于冰乙酸(0.2mL)和48%氢溴酸溶液(1mL)。将混合物在90℃下剧烈搅拌2小时。在冷却至室温之后,将反应混合物用饱和NaHCO3水溶液淬灭,并用EtOAc萃取三次。合并有机层,用饱和NaHCO3水溶液洗涤,通过Na2SO4干燥,并减压浓缩。将残余物通过硅胶柱层析(10%-30%EtOAc/己烷)纯化,得到所需的5-羟基-2-三氟甲基-N-苯基-1H-咪唑并[4,5-b]吡嗪-6-胺,其为黄色固体。
一般程序2C.用于制备N-甲基化合物
在一个小瓶中,将所需的咪唑-吡嗪(1当量)溶于2mL二氯甲烷,然后逐滴加入甲基碘(20当量)和三甲胺(1.5当量)。将所得的混合物在室温下在黑暗中搅拌。16小时后,减压蒸发溶剂,并通过硅胶柱层析(0%-20%EtOAc/己烷)纯化,得到所需的5-甲氧基-1-甲基-N-苯基-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-6-胺,其为黄色固体。
一般程序2D.5-甲氧基-2-取代-N-苯基-1H-咪唑并[4,5-B]吡嗪-6-胺的制备
在六打兰小瓶中,将所需的噁二唑-吡嗪1(1mmol)、铁(10mmol)和三氟甲磺酸镱(III)(0.1mmol)溶于冰乙酸(5.0mL),然后加入所需的原酸酯(10mmol)。将混合物在95℃下剧烈搅拌3小时。在冷却至室温之后,将20mL H2O和20mL EtOAc加入反应混合物中,并通过硅藻土垫过滤。分离有机层,并将水层用EtOAc萃取三次。合并有机层,用饱和NaHCO3水溶液洗涤,通过Na2SO4干燥,并减压浓缩。将残余物通过硅胶柱层析纯化,得到5-甲氧基-2-取代-N-苯基-1H-咪唑并[4,5-b]吡嗪-6-胺,其为浅黄色固体。
下面的方案1示出了一般程序2A、2B、2C和2D之间的关系。
以下实例1-60公开了式I-A和I-B的化合物。实例1-60的一些化合物是使用非商购起始材料制备的。用于制备这些起始材料的程序在实例61中给出。
实例1. 6-甲氧基-N-(4-(三氟甲氧基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-1)的合成
通过程序2A,用6-甲氧基-N-(4-(三氟甲氧基)苯基)-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-156)合成化合物2-1,得到2-1(70%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ13.06(brs,1H),8.65(brs,1H),8.11(d,2H,J=9.1Hz),7.33(d,2H,J=8.6Hz),4.11(s,3H);13C NMR(125MHz,丙酮-d6)δ148.1,143.6,140.8,139.2,135.2(d,J=40.7Hz),121.5,120.7(q,J=254.6Hz),120.6,119.3(q,J=268.4Hz),53.9;19F NMR(376MHz,丙酮-d6)δ-58.88(s,3F),-64.41(s,3F);HRMS(ESI):C14H10F6N5O2 +[M+H]+计算值:394.0733,观测值:394.0714。
实例2. 6-甲氧基-N-(4-(N-丁基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-2)的合成
通过程序2A,用N-(4-丁基苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-157)合成化合物2-2,得到2-2(63%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.35(brs,1H),7.86(d,2H,J=8.5Hz),7.20(d,2H,J=8.5Hz),4.10(s,3H),2.61(t,2H,J=7.7Hz),1.62(m,2H),1.38(h,2H,J=7.4Hz),0.94(t,3H,J=7.4Hz);13C NMR(125MHz,丙酮-d6)δ148.0,141.3,137.6,137.0,134.6(d,J=41.0Hz),128.4,119.3(q,J=268.2Hz),119.6,53.8,34.7,33.8,22.1,13.3;19F NMR(376MHz,丙酮-d6)δ-64.30(s,3F);HRMS(ESI):C17H19F3N5O+[M+H]+计算值:366.1536,观测值:366.1531。
实例3. 6-甲氧基-N-(2-氟-5-(三氟甲基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-3)的合成
通过程序2A,用N-(-氟-5-(三氟甲基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-158)合成化合物2-3,得到2-3(62%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ9.05(d,1H,J=7.0Hz),8.08(brs,1H),7.51(t,1H,J=7.6Hz),7.49(s,1H)4.19(s,3H);13C NMR(125MHz,丙酮-d6)δ154.9(d,J=248.4Hz),148.2,140.0,136.1(q,J=41.1Hz),128.8(d,J=10.9Hz),126.3(qd,J=32.6,3.6Hz),124.2(q,J=271.3Hz),120.1(dd,J=8.4,3.9Hz),119.2(q,J=268.7Hz),117.7,115.7(d,J=21.1Hz),54.3;19F NMR(376MHz,丙酮-d6)δ-62.49(d,3F,J=1.6Hz),-64.56(s,3F),-125.47(m,1F);HRMS(ESI):C14H9F7N5O+[M+H]+计算值:396.0690,观测值:396.0705。
实例4. 6-甲氧基-N-(3-(三氟甲氧基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-4)的合成
通过程序2A,用6-甲氧基-N-(3-(三氟甲氧基)苯基)-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-141)合成化合物2-4,得到2-4(58%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ13.06(brs,1H),8.72(brs,1H),8.22(brs,1H),7.89(d,1H,J=8.2Hz),7.45(t,1H,J=8.2Hz),6.99(d,1H,J=8.2Hz),4.10(s,3H);13C NMR(125MHz,丙酮-d6)δ150.2(q,J=1.7Hz),149.1,142.7,141.5,136.3(q,J=41.1Hz),130.8,121.5(q,J=255.4Hz),120.2(q,J=268.6Hz),118.8,114.9,112.4,54.9;19F NMR(376MHz,丙酮-d6)δ-57.87(s,3F),-64.00(s,3F);HRMS(ESI):C14H9F6N5NaO2 +[M+Na]+计算值:416.0553,观测值:416.0537。
实例5. 6-甲氧基-N-(2-甲基-5-(三氟甲基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-5)的合成
通过程序2A,用6-甲氧基-N-(2-甲基-5-(三氟甲基)苯基)-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-142)合成化合物2-5,得到2-5(58%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ12.97(brs,1H),8.61(brs,1H),7.91(brs,1H),7.50(d,1H,J=7.9Hz),7.37(d,1H,J=7.9Hz),4.17(s,3H),2.45(s,3H);13C NMR(125MHz,丙酮-d6)δ149.1,142.1,139.3,136.2(q,J=41.0Hz),134.6,131.9,129.1(q,J=31.8Hz),125.4(q,J=271.2Hz),120.7,120.2(q,J=268.5Hz),118.7,55.1,18.0;19F NMR(376MHz,丙酮-d6)δ-62.71(s,3F),-64.45(s,3F);HRMS(ESI):C15H12F6N5O+[M+H]+计算值:392.0941,观测值:392.0953。
实例6. 6-甲氧基-N-(2-氟-3-(三氟甲基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-6)的合成
通过程序2A,用N-(2-氟-3-(三氟甲基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-140)合成化合物2-6,得到2-6(65%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ13.06(brs,1H),8.78(brs,1H),8.09(brs,1H),7.45(m,2H),4.17(s,3H);13C NMR(125MHz,丙酮-d6)δ151.5(d,J=254.5Hz),149.1,141.2,136.9(q,J=40.9Hz),130.0(d,J=9.4Hz),126.8,125.5(d,J=4.6Hz),123.8(q,J=271.5Hz),120.8,120.1(q,J=268.8Hz),118.5(dd,J=32.8,10.7Hz),55.2;19F NMR(376MHz,丙酮-d6)δ-61.72(d,3F,J=12.9Hz),-64.59(s,3F),-132.21(s,1F);HRMS(ESI):C14H8F7N5NaO+[M+Na]+计算值:418.0509,观测值:418.0516。
实例7. 6-甲氧基-N-(3-氟苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-7)的合成
通过程序2A,用1-143合成化合物2-7,得到2-7(55%产率),其为浅黄色固体。1HNMR(500MHz,丙酮-d6)δ13.00(brs,1H),8.62(brs,1H),8.08(dt,1H,J=12.2,2.3Hz),7.63(d,1H,J=8.2Hz),7.35(td,1H,J=8.2,6.8Hz),6.79(td,1H,J=8.2,2.6Hz),4.09(s,3H);13C NMR(125MHz,丙酮-d6)δ163.9(d,J=240.8Hz),149.0,142.7(d,J=11.4Hz),141.6,136.2(q,J=41.1Hz),130.8(d,J=9.8Hz),120.2(q,J=268.5Hz),116.0,109.4(d,J=21.6Hz),106.9(d,J=27.2Hz),54.8;19F NMR(376MHz,丙酮-d6)δ-64.46(s,3F),-113.8(m,1F);HRMS(ESI):C13H10F4N5O+[M+H]+计算值:328.0816,观测值:328.0838。
实例8. 6-甲氧基-(3,5-双(三氟甲基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-8)的合成
通过程序2A,用N-(3,5-双(三氟甲基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-139)合成化合物2-8,得到2-8(50%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ9.10(brs,1H),8.74(s,2H),7.64(s,1H),4.13(s,3H);13C NMR(125MHz,丙酮-d6)δ149.2,143.0,141.0,137.1(q,J=40.9Hz),132.4(q,J=32.8Hz),124.6(q,J=271.9Hz),120.1(q,J=268.7Hz),119.6,115.4(dt,J=7.4,3.8Hz),55.0;19F NMR(376MHz,丙酮-d6)δ-63.51(s,6F),-64.54(s,3F);HRMS(ESI):C15H9F9N5O+[M+H]+计算值:446.0658,观测值:446.0680。
实例9. 6-甲氧基-(2-氟苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-9)的合成
通过程序2A,用N-(2-氟苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-159)合成化合物2-9,得到2-9(53%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.52(t,1H,J=8.2Hz),7.89(brs,1H),7.24(m,2H),7.11(m,1H),4.16(s,3H);13C NMR(125MHz,丙酮-d6)δ153.5(d,J=242.9Hz),148.1,140.6,135.4(q,J=41.0Hz),127.7(d,J=10.2Hz),127.7(d,J=10.2Hz),124.7(d,J=3.5Hz),124.4(d,J=3.7Hz),123.4(d,J=7.8Hz),121.5,119.2(q,J=268.5Hz),114.8(d,J=19.5Hz),54.2;19F NMR(376MHz,丙酮-d6)δ-64.47(s,3F),-130.86(m,1F);HRMS(ESI):C13H10F4N5O+[M+H]+计算值:328.0816,观测值:328.0824
实例10. 6-甲氧基-N-(对甲苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-10)的合成
通过程序2A,用6-甲氧基-N-(对甲苯基)-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-144)合成化合物2-10,得到2-10(49%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.31(brs,1H),7.83(d,2H,J=8.1Hz),7.16(d,2H,J=8.1Hz),4.08(s,3H),2.30(s,3H);13CNMR(125MHz,丙酮-d6)δ148.9,142.2,138.3,135.5(d,J=40.7Hz),132.7,129.9,120.5,120.2(q,J=268.3Hz),54.7,20.8;19F NMR(376MHz,丙酮-d6)δ-64.30(s,3F);HRMS(ESI):C14H13F3N5O+[M+H]+计算值:324.1067,观测值:324.1079。
实例11. 6-甲氧基-N-苯基-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-11)的合成
通过程序2A,用6-甲氧基-N-苯基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-146)合成化合物2-11,得到2-11(56%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.39(brs,1H),7.96(d,2H,J=7.9Hz),7.34(t,2H,J=7.9Hz),7.04(t,1H,J=7.4Hz),4.09(s,3H);13C NMR(125MHz,丙酮-d6)δ149.0,142.0,140.8,135.7(d,J=41.1Hz),129.4,123.3,120.4,120.2(q,J=268.4Hz),54.8;19F NMR(376MHz,丙酮-d6)δ-64.36(s,3F);HRMS(ESI):C13H11F3N6O+[M+H]+计算值:310.0910,观测值:310.0918。
实例12. 6-甲氧基-N-(4-甲氧基苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-12)的合成
通过程序2A,用6-甲氧基-N-(4-甲氧基苯基)-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-145)合成化合物2-12,得到2-12(45%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ7.84(brs,1H),7.83(d,2H,J=9.1Hz),6.93(d,2H,J=9.1Hz),4.08(s,3H);3.80(s,3H);13C NMR(125MHz,丙酮-d6)δ155.6,148.0,141.5,134.2(d,J=41.3Hz),132.8,121.5,119.4(q,J=268.2Hz),113.7,54.8,53.8;19F NMR(376MHz,丙酮-d6)δ-64.26(s,3F);HRMS(ESI):C14H12F3N5O2 +[M+H]+计算值:340.1016,观测值:340.1032。
实例13. 6-甲氧基-N-(3-氟-4-(三氟甲氧基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-13)的合成
通过程序2A,用N-(3-氟-4-(三氟甲氧基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-151)合成化合物2-13,得到2-13(63%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.81(brs,1H),8.33(dd,1H,J=13.5,2.6Hz),7.74(ddd,1H,J=9.0,2.6,1.5Hz),7.44(td,1H,J=9.0,1.5Hz),4.10(s,3H);13C NMR(125MHz,丙酮-d6)δ155.1(d,J=246.8Hz),149.1,141.7(d,J=10.4Hz),141.2,136.7(q,J=40.7Hz),130.8(d,J=12.6Hz),124.9,121.6(q,J=256.3Hz),120.2(q,J=268.6Hz),116.3(d,J=3.3Hz),108.3(d,J=24.3Hz),54.9;19F NMR(376MHz,丙酮-d6)δ-60.04(dd,3F,J=14.2,5.1Hz),-64.51(s,3F),-129.63(m,1F);HRMS(ESI):C14H9F7N5O2 +[M+H]+计算值:412.0639,观测值:412.0652。
实例14. 6-甲氧基-N-(2-氟-4-(三氟甲基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-14)的合成
通过程序2A,用N-(2-氟-4-(三氟甲基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-202)合成化合物2-14,得到2-14(53%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.87(t,1H,J=8.4Hz),8.06(brs,1H),7.60(m,2H),4.17(s,3H);13CNMR(125MHz,丙酮-d6)δ153.1(d,J=244.9Hz),149.2,140.5,137.3(q,J=41.0Hz),132.5(d,J=9.6Hz),131.0(d,J=10.8Hz),124.8(qd,J=270.6,2.6Hz),124.5(qd,J=33.2,7.3Hz),122.7(p,J=4.0Hz),121.2,120.1(q,J=268.8Hz),113.2(dq,J=23.0,3.8Hz),55.2;19F NMR(376MHz,丙酮-d6)δ-62.35(s,3F),-64.62(s,3F),-129.81(m,1F);HRMS(ESI):C14H19F7N5O+[M+H]+计算值:396.0690,观测值:396.0704。
实例15. 6-甲氧基-N-(3,5-二氟苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-15)的合成
通过程序2A,用N-(2,3-二氟苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-147)合成化合物2-15,得到2-15(60%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.80(brs,1H),7.76(dd,2H,J=10.3,2.3Hz),6.65(tt,1H,J=10.3,2.3Hz),4.09(s,3H);13C NMR(125MHz,丙酮-d6)δ164.1(d,J=242.3Hz),164.0(d,J=242.3Hz),149.0,143.6(t,J=14.0Hz),141.4,136.8(q,J=41.3Hz),120.1(q,J=268.7Hz),102.7(dd,J=30.3,15.0Hz),97.6(d,J=26.3Hz),54.9;19F NMR(376MHz,丙酮-d6)δ-64.53(s,3F),-111.35(t,2F,J=9.6Hz);HRMS(ESI):C13H9F5N5O+[M+H]+计算值:346.0722,观测值:346.0723。
实例16. 6-甲氧基-N-(2,3-二氟苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-16)的合成
通过程序2A,用N-(3,5-二氟苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-148)合成化合物2-16,得到2-16(62%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.24(ddt,1H,J=8.5,6.9,1.6Hz),8.01(brs,1H),7.21(tdd,1H,J=8.3,5.8,2.1Hz),7.05(dddd,1H,J=10.1,8.7,7.5,1.5Hz),4.15(s,3H);13C NMR(125MHz,丙酮-d6)δ151.4(d,J=244.2Hz),151.3(d,J=244.2Hz),149.0,143.2(d,J=244.9Hz),143.1(d,J=244.9Hz),141.3,136.8(q,J=41.0Hz),130.5(dd,J=7.6,2.1Hz),125.0(d,J=8.2,4.9Hz),120.1(q,J=268.5Hz),118.1,111.8(d,J=17.2Hz),55.1;19F NMR(376MHz,丙酮-d6)δ-64.35(s,3F),-140.58(m,1F),-154.27(m,1F);HRMS(ESI):C13H9F5N5O+[M+H]+计算值:346.0722,观测值:346.0717。
实例17. 6-甲氧基-N-(2-氟苯甲基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-17)的合成
通过程序2A,用6-甲氧基-N-(2-(三氟甲基)苯基)-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-160)合成化合物2-17,得到2-17(40%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.60(d,2H,J=8.3Hz),7.97(brs,1H),7.75(d,2H,J=7.9Hz),7.71(t,2H,J=7.9Hz),7.32(t,1H,J=7.6Hz),4.18(s,3H);13C NMR(125MHz,丙酮-d6)δ149.0,141.5,138.1(d,J=1.6Hz),136.8(q,J=40.9Hz),133.9.127.2(q,J=5.5Hz),125.5(q,J=272.2Hz),124.3,120.7(q,J=29.3Hz),120.1(q,J=268.6Hz),55.3;19F NMR(376MHz,丙酮-d6)δ-61.55(s,3F),-64.56(s,3F);HRMS(ESI):C14H9F6N5O+[M+H]+计算值:378.0784,观测值:378.0791。
实例18.N-([1,1'-联苯]-4-基)-6-甲氧基-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-18)的合成
通过程序2A,用N-([1,1'-联苯]-4-基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-161)合成化合物2-18,得到2-18(50%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.53(brs,1H),8.08(d,2H,J=8.7Hz),7.66(m,4H),7.45(t,2H,J=7.7Hz),7.32(t,1H,J=7.6Hz),4.11(s,3H);13C NMR(125MHz,丙酮-d6)δ149.1,141.9,141.5,140.3,135.9(d,J=40.9Hz),135.8,129.7,127.9,127.7,127.3,120.7,120.2(q,J=268.4Hz),54.8;19F NMR(376MHz,丙酮-d6)δ-64.33(s,3F);HRMS(ESI):C19H15F3N5O+[M+H]+计算值:386.1223,观测值:386.1222。
实例19. 6-甲氧基-N-(4-(叔丁基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-19)的合成
通过程序2A,用N-(4-(叔丁基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-162)合成化合物2-19,得到2-19(45%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.34(brs,1H),7.86(d,2H,J=8.8Hz),7.39(d,2H,J=8.8Hz),4.09(s,3H),1.32(s,9H);13C NMR(125MHz,丙酮-d6)δ148.9,146.1,142.2,138.2,135.6(d,J=40.4Hz),126.2,120.4,120.3(q,J=268.3Hz),54.7,34.8,31.7;19F NMR(376MHz,丙酮-d6)δ-64.29(s,3F);HRMS(ESI):C17H19F3N5O+[M+H]+计算值:366.1536,观测值:366.1541。
实例20. 6-甲氧基-N-(萘-2-基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-20)的合成
通过程序2A,用6-甲氧基-N-(萘-2-基)-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-152)合成化合物2-20,得到2-20(40%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.74(brs,1H),8.59(brs,1H),7.87(m,2H),7.82(dd,2H,J=12.7,8.2Hz),7.47(ddd,1H,J=8.1,6.8,1.3Hz),7.38(ddd,1H,J=8.1,6.8,1.3Hz),4.12(s,3H);13C NMR(125MHz,丙酮-d6)δ149.1,141.9,138.4,136.0(d,J=41.1Hz),135.1,130.9,129.1,128.4,128.1,127.2,125.1,121.7,120.3(q,J=268.5Hz),115.7,54.8;19F NMR(376MHz,丙酮-d6)δ-64.30(s,3F);HRMS(ESI):C17H13F3N5O+[M+H]+计算值:360.1067,观测值:360.1074。
实例21. 6-甲氧基-N-(2-氟-4-(三氟甲氧基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-21)的合成
通过程序2A,用N-(2-氟-4-(三氟甲氧基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-163)合成化合物2-21,得到2-21(62%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.59(t,1H,J=9.1Hz),7.98(brs,1H),7.34(dd,1H,J=11.3,2.7Hz),7.26(d,1H,J=9.1Hz),4.16(s,3H);13C NMR(125MHz,丙酮-d6)δ154.2(d,J=246.9Hz),149.0,144.5(d,J=10.7Hz),141.3,136.8(q,J=40.9Hz),128.1(d,J=10.4Hz),123.3,121.4(q,J=255.8Hz),120.1(q,J=268.7Hz),118.1(q,J=3.6Hz),110.2(d,J=23.6Hz),55.1;19F NMR(376MHz,丙酮-d6)δ-59.10(s,3F),-64.55(s,3F),-125.5(m,1F);HRMS(ESI):C14H9F7N5O2 +[M+H]+计算值:412.0639,观测值:412.0646。
实例22. 6-甲氧基-N-(4-(三氟甲基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-22)的合成
通过程序2A,用6-甲氧基-N-(4-(三氟甲基)苯基)-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-165)合成化合物2-22,得到2-22(70%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.77(brs,1H),8.21(d,2H,J=8.7Hz),7.67(d,2H,J=8.7Hz),4.10(s,3H);13CNMR(125MHz,丙酮-d6)δ149.2,144.5,141.2,136.7(q,J=40.9Hz),126.7(q,J=3.7Hz),125.3(q,J=271.8Hz),123.9(q,J=32.4Hz),120.2(q,J=268.6Hz),119.8,54.9;19F NMR(376MHz,丙酮-d6)δ-62.17(s,3F),-64.50(s,3F);HRMS(ESI):C14H10F6N5O+[M+H]+计算值:378.0784,观测值:378.0789
实例23. 6-甲氧基-N-(3-氟-4-(三氟甲基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-23)的合成
通过程序2A,用N-(3-氟-4-(三氟甲基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-178)合成化合物2-23,得到2-23(63%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.99(brs,1H),8.34(dd,1H,J=14.2,2.0Hz),7.82(d,1H,J=8.6Hz),7.66(t,1H,J=8.6Hz),4.10(s,3H);13C NMR(125MHz,丙酮-d6)δ160.9(d,J=250.4Hz),149.2,146.7(d,J=11.7Hz),140.7,137.3(q,J=40.9Hz),128.1,124.2(q,J=270.9Hz),120.1(q,J=268.7Hz),115.3,110.9(d,J=32.9,12.8Hz),107.1(d,J=26.4Hz),55.0;19FNMR(376MHz,丙酮-d6)δ-60.78(d,3F,J=12.2Hz),-64.58(s,3F),-115.26(m,1F);HRMS(ESI):C28H17F14N10O2 +[2M+H]+计算值:791.1307,观测值:791.1286。
实例24. 6-甲氧基-N-(4-乙基苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-24)的合成
通过程序2A,用N-(4-乙基苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-153)合成化合物2-24,得到2-24(58%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.33(brs,1H),7.85(d,2H,J=8.5Hz),7.19(d,2H,J=8.5Hz),4.09(s,3H),2.62(q,2H,J=7.6Hz),1.21(t,3H,J=7.6Hz);13C NMR(125MHz,丙酮-d6)δ148.9,142.2,139.3,138.5,135.6(d,J=40.7Hz),133.0,128.7,120.5,120.3(q,J=268.3Hz),54.7,28.9,16.3;19FNMR(376MHz,丙酮-d6)δ-64.31(s,3F);HRMS(ESI):C15H15F3N5O+[M+H]+计算值:338.1223,观测值:338.1225。
实例25. 6-甲氧基-N-(4-异丙基苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-25)的合成
通过程序2A,用N-(4-异丙基苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-164)合成化合物2-25,得到2-25(60%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.40(brs,1H),7.87(d,2H,J=8.5Hz),7.23(d,2H,J=8.5Hz),4.08(s,3H),2.90(h,1H,J=7.0Hz),1.24(t,6H,J=7.0Hz);13C NMR(125MHz,丙酮-d6)δ148.9,143.9,142.2,138.5,135.4(d,J=41.3Hz),127.2,123.4,120.6,120.2(q,J=268.3Hz),54.7,34.2,24.4;19F NMR(376MHz,丙酮-d6)δ-64.31(s,3F);HRMS(ESI):C16H17F3N5O+[M+H]+计算值:352.1380,观测值:352.1380。
实例26. 6-甲氧基-N-(4-氯苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-26)的合成
通过程序2A,用N-(4-氯苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-149)合成化合物2-26,得到2-26(53%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.55(brs,1H),8.01(d,2H,J=9.0Hz),7.35(d,2H,J=9.0Hz),4.09(s,3H);13C NMR(125MHz,丙酮-d6)δ149.0,141.7,139.8,136.1(q,J=41.0Hz),129.3,127.4,123.4,121.7,120.2(q,J=268.4Hz),54.8;19F NMR(376MHz,丙酮-d6)δ-64.37(s,3F);HRMS(ESI):C13H10ClF3N5O+[M+H]+计算值:352.0520,观测值:344.0519。
实例27. 6-甲氧基-N-(2-氟-4-戊基苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-27)的合成
通过程序2A,用N-(2-氟-4-戊基苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-155)合成化合物2-27,得到2-27(56%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.34(t,1H,J=8.4Hz),7.82(brs,1H),7.07(m,2H),4.16(s,3H),2.62(t,2H,J=7.7Hz),1.64(m,2H),1.34(m,4H),0.90(t,3H,J=7.0Hz);13C NMR(125MHz,丙酮-d6)δ154.5(d,J=242.9Hz),148.9,141.8,140.0(d,J=6.6Hz),136.1(q,J=41.0Hz),126.0(d,J=10.6Hz),124.9(d,J=3.1Hz),122.7,120.2(q,J=268.5Hz),115.6(d,J=19.1Hz),55.0,35.7,32.1,31.9,23.2,14.3;19F NMR(376MHz,丙酮-d6)δ-64.44(s,3F),-130.75(m,1F);HRMS(ESI):C36H39F8N10O2 +[2M+H]+计算值:795.3124,观测值:795.3098。
实例28. 6-甲氧基-N-(3-氟-4-戊基苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-28)的合成
通过程序2A,用N-(3-氟-4-戊基苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-154)合成化合物2-28,得到2-28(58%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.53(brs,1H),8.01(dd,1H,J=13.0,2.2Hz),7.54(dd,1H,J=8.3,2.2Hz),7.21(t,1H,J=8.3Hz),4.09(s,3H),2.62(t,2H,J=7.7Hz),1.62(m,2H),1.35(m,4H),0.90(t,3H,J=7.0Hz);13C NMR(125MHz,丙酮-d6)δ161.7(d,J=240.3Hz),148.9,141.7,140.3(d,J=11.5Hz),136.1(q,J=41.0Hz),131.3(d,J=6.8Hz),123.7(d,J=16.8Hz),120.2(q,J=268.4Hz),116.0,107.0(d,J=28.5Hz),54.8,32.1,30.9,23.1,14.3;19F NMR(376MHz,丙酮-d6)δ-64.39(s,3F),-119.31(m,1F);HRMS(ESI):C18H20F4N5O+[M+H]+计算值:398.1598,观测值:398.1594。
实例29. 6-甲氧基-N-(4-戊基苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-29)的合成
通过程序2A,用6-甲氧基-N-(4-戊基苯基)-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-167)合成化合物2-29,得到2-29(51%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.32(brs,1H),7.85(d,1H,J=8.5Hz),7.18(d,1H,J=8.5Hz),4.09(s,3H),2.59(t,2H,J=7.7Hz),1.62(m,2H),1.34(m,4H),0.89(t,3H,J=7.0Hz);13C NMR(125MHz,丙酮-d6)δ148.9,142.2,138.4,137.9,135.5(q,J=41.1Hz),129.3,120.5,120.3(q,J=268.3Hz),54.7,35.9,32.2,23.2,14.3;19F NMR(376MHz,丙酮-d6)δ-64.29(s,3F);HRMS(ESI):C36H41F6N10O2 +[2M+H]+计算值:759.3313,观测值:759.3290。
实例30. 6-甲氧基-N-(4-碘苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-30)的合成
通过程序2A,用N-(4-碘苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-169)合成化合物2-30,得到2-30(54%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.58(brs,1H),7.86(d,2H,J=8.9Hz),7.67(d,2H,J=8.9Hz),4.08(s,3H);13C NMR(125MHz,丙酮-d6)δ149.0,141.5,140.9,138.3,136.2(q,J=40.5Hz),122.3,120.2(q,J=268.4Hz),85.1,54.8;19F NMR(376MHz,丙酮-d6)δ-64.41(s,3F);HRMS(ESI):C26H19F6I2N12O2 +[2M+H]+计算值:870.9681,观测值:870.9661。
实例31. 6-甲氧基-N-(3-碘苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-31)的合成
通过程序2A,用N-(3-碘苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-170)合成化合物2-31,得到2-31(52%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.53(d,1H,J=1.9Hz),8.51(brs,1H),7.93(ddd,H,J=8.2,2.2,0.9Hz),7.41(ddd,H,J=8.2,2.2,0.9Hz),7.13(t,2H,J=8.2Hz),4.09(s,3H);13C NMR(125MHz,丙酮-d6)δ148.1,141.4,140.6,135.4(q,J=40.8Hz),131.1,130.4,127.6,119.3(q,J=268.5Hz),118.7,93.6,53.9;19F NMR(376MHz,丙酮-d6)δ-64.42(s,3F);HRMS(ESI):C26H19F6I2N12O2 +[2M+H]+计算值:870.9681,观测值:870.9663。
实例32. 6-甲氧基-N-(3-(三氟甲基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-32)的合成
通过程序2A,用6-甲氧基-N-(3-(三氟甲基)苯基)-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-166)合成化合物2-32,得到2-32(65%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.75(brs,1H),8.49(brs,1H),8.21(d,1H,J=8.2Hz),7.57(t,1H,J=8.2Hz),7.36(d,1H,J=8.2Hz),4.11(s,3H);13C NMR(125MHz,丙酮-d6)δ150.2(q,J=1.7Hz),148.2,140.9,140.6,135.7(q,J=40.8Hz),130.4(q,J=31.7Hz),130.0,124.5(q,J=271.5Hz),122.7,119.3(q,J=268.5Hz),118.4(q,J=3.8Hz),115.5(q,J=4.0Hz),54.0;19F NMR(376MHz,丙酮-d6)δ-63.15(s,3F),-64.43(s,3F);HRMS(ESI):C14H10F6N5O+[M+H]+计算值:378.0784,观测值:378.0794。
实例33. 6-甲氧基-N-(2-氟-4-(叔丁基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-33)的合成
通过程序2A,用N-(4-(叔丁基)-2-氟苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-168)合成化合物2-33,得到2-33(57%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.63(d,1H,J=8.1Hz),7.91(brs,1H),7.14(dd,2H,J=8.7,1.1Hz),4.16(s,3H),1.34(s,9H);13C NMR(125MHz,丙酮-d6)δ152.5(d,J=241.5Hz),151.6,148.9,148.2(d,J=3.5Hz),141.7,136.1(q,J=41.0Hz),127.7(d,J=10.3Hz),121.7(d,J=3.1Hz),121.1(d,J=8.5Hz),120.2(q,J=268.4Hz),120.0,114.3(d,J=19.0Hz),55.0,35.2,31.8;19F NMR(376MHz,丙酮-d6)δ-64.37(s,3F),-135.04(s,1F);HRMS(ESI):C17H18F4N5O+[M+H]+计算值:384.1442,观测值:384.1443。
实例34. 6-甲氧基-2-(全氟乙基)-N-(4-(三氟甲氧基)苯基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-34)的合成
通过程序2A,用N-(2-氟-3-(三氟甲基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-140)合成化合物2-34,得到2-34(65%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.78(brs,1H),8.11(brs,1H),7.44(m,2H),4.17(s,3H);13C NMR(125MHz,丙酮-d6)δ151.5(d,J=254.1Hz),150.5,149.2,141.2,135.8(t,J=29.9Hz),130.0(d,J=9.3Hz),126.9,125.5(d,J=4.6Hz),123.8(q,J=271.6Hz),120.9(q,J=4.6Hz),120.1(q,J=268.8Hz),118.5(dd,J=32.8,10.7Hz),55.2;19F NMR(376MHz,丙酮-d6)δ-61.71(d,3F,J=13.0Hz),-84.23(d,3F,J=3.0Hz),-114.17(d,3F,J=3.1Hz)-132.12(s,1F);HRMS(ESI):C15H9F9N5O+[M+H]+计算值:446.0658,观测值:446.0661。
实例35. 6-丁氧基-N-(4-(三氟甲氧基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-35)的合成
通过程序2A,用6-丁氧基-N-(4-(三氟甲氧基)苯基)-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-181)合成化合物2-35,得到2-35(53%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.59(brs,1H),8.05(d,2H,J=9.1Hz),7.32(d,2H,J=8.5Hz),4.51(t,2H,J=6.7Hz),1.86(m,2H),1.53(m,2H),0.99(t,3H,J=7.4Hz);13C NMR(125MHz,丙酮-d6)δ148.6,144.4(d,J=1.7Hz),141.6,140.0,136.1(q,J=40.9Hz),122.4,121.7,121.5(q,J=254.5Hz),120.2(q,J=268.5Hz),68.0,31.4,19.8,14.1;19F NMR(376MHz,丙酮-d6)δ-58.91(s,3F),-64.42(s,3F);HRMS(ESI):C17H16F6N5O2 +[M+H]+计算值:436.1203,观测值:436.1180。
实例36. 6-(2,2,2-三氟乙氧基)-N-(4-(三氟甲氧基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-36)的合成
通过程序2A,用N-(2-氟苯基)-6-(2,2,2-三氟乙氧基)-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-187)合成化合物2-36,得到2-36(59%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.77(brs,1H),8.02(d,2H,J=9.1Hz),7.32(d,2H,J=8.6Hz),5.15(q,2H,J=8.7Hz);13C NMR(125MHz,丙酮-d6)δ146.4,144.9(d,J=1.9Hz),141.4,139.7,137.4(q,J=41.1Hz),124.7(q,J=277.0Hz),122.3,121.6(q,J=254.7Hz),120.1(q,J=268.7Hz),63.5(q,J=36.3Hz);19F NMR(376MHz,丙酮-d6)δ-58.88(s,3F),-64.62(s,3F),-73.82(t,3F,J=8.8Hz);HRMS(ESI):C15H9F9N5O2 +[M+H]+计算值:462.0607,观测值:462.0586。
实例37. 6-乙氧基-N-(4-(三氟甲氧基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-37)的合成
通过程序2A,用6-乙氧基-N-(4-(三氟甲氧基)苯基)-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-203)合成化合物2-37,得到2-37(68%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.58(brs,1H),8.06(d,2H,J=9.1Hz),7.31(d,2H,J=8.7Hz),4.56(q,2H,J=7.1Hz),1.46(t,3H,J=7.1Hz);13C NMR(125MHz,丙酮-d6)δ148.5,144.5(q,J=1.7Hz),141.7,140.1,136.3(q,J=41.0Hz),122.3,121.60,121.57(q,J=254.5Hz),120.2(q,J=268.5Hz),64.1,14.6;19F NMR(376MHz,丙酮-d6)δ-58.89(s,3F),-64.40(s,3F);HRMS(ESI):C15H11F6N5NaO2 +[M+Na]+计算值:430.0709,观测值:430.0701。
实例38. 6-乙氧基-N-(2-氟-4-(三氟甲氧基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-38)的合成
通过程序2A,用6-乙氧基-N-(2-氟-4-(三氟甲氧基)苯基)-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-200)合成化合物2-38,得到2-38(65%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.57(t,1H,J=9.0Hz),8.03(brs,1H),7.36(dd,1H,J=11.3,2.3Hz),7.26(d,1H,J=9.0Hz),4.59(q,2H,J=7.1Hz),1.50(t,3H,J=7.1Hz);13C NMR(125MHz,丙酮-d6)δ154.2(d,J=247.0Hz),148.5,144.4(d,J=11.0Hz),141.2,136.5(q,J=40.7Hz),128.1(d,J=10.3Hz),123.3,121.4(q,J=255.8Hz),120.1(q,J=268.6Hz),118.2(q,J=3.8Hz),110.2(d,J=23.6Hz),64.4,14.5;19F NMR(376MHz,丙酮-d6)δ-59.13(s,3F),-64.53(s,3F),-125.60(s,1F);HRMS(ESI):C15H11F7N5O2 +[M+H]+计算值:426.0795,观测值:426.0799。
实例39. 6-丙氧基-N-(2-氟-4-(三氟甲氧基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-39)的合成
通过程序2A,用N-(2-氟-4-(三氟甲氧基)苯基)-6-丙氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-201)合成化合物2-39,得到2-39(59%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ8.58(t,1H,J=9.0Hz),8.02(brs,1H),7.36(dd,1H,J=11.4,2.7Hz),7.27(d,1H,J=9.0Hz),4.50(t,2H,J=6.6Hz),1.93(h,2H,J=7.3Hz),1.10(t,3H,J=7.4Hz);13C NMR(125MHz,丙酮-d6)δ154.1(d,J=246.8Hz),148.6,144.3(d,J=10.0Hz),141.2,136.5(q,J=40.9Hz),128.1(d,J=10.1Hz),123.3,121.4(q,J=255.9Hz),120.1(q,J=268.7Hz),118.2(q,J=3.8Hz),110.2(d,J=23.5Hz),69.9,22.6,10.7;19F NMR(376MHz,丙酮-d6)δ-59.14(s,3F),-64.54(s,3F),-126.01(s,1F);HRMS(ESI):C16H13F7N5O2 +[M+H]+计算值:440.0952,观测值:440.0956。
实例40. 6-甲氧基-2-(三氟甲基)-5-(4-(三氟甲基)苯氧基)-1H-咪唑并[4,5-B]吡嗪(2-40)的合成
通过程序2A,用5-甲氧基-6-(4-(三氟甲基)苯氧基)-[1,2,5]噁二唑并[3,4-b]吡嗪(1-199)合成化合物2-40,得到2-40(70%产率),其为浅黄色固体。1H NMR(500MHz,丙酮-d6)δ7.84(d,2H,J=8.4Hz),7.51(d,2H,J=8.4Hz),4.12(s,3H);13C NMR(125MHz,丙酮-d6)δ157.6,151.0,148.3,139.1(q,J=41.1Hz),127.9(q,J=3.9Hz),127.4(q,J=32.6Hz),125.2(q,J=271.1Hz),122.6,119.8(q,J=269.2Hz),55.0;19F NMR(376MHz,丙酮-d6)δ-62.52(s,3F),-65.03(s,3F);HRMS(ESI):C14H9F6N4O+[M+H]+计算值:379.0624,观测值:379.0623
实例41.N-(2-碘-4-(三氟甲氧基)苯基)-6-甲氧基-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-41)的合成
通过程序2A,用N-(2-碘-4-(三氟甲氧基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-171)合成化合物2-41,得到2-41(46%产率),其为浅黄色固体。1H NMR((CD3)2CO,400MHz)δ12.91(bs,1H),8.67(d,1H,J=9.1Hz),7.98(s,1H),7.80(s,1H),7.37(d,1H,J=9.1Hz),4.15(s,3H);13C NMR((CD3)2CO,100MHz)δ148.84,144.22(q,J=1.9Hz),140.77,140.14,136.83(q,J=41.3Hz),134.80,134.53,132.46,122.61,121.37(q,J=256.1Hz),120.75,120.03(q,J=268.2Hz),89.99,55.36;19F NMR((CD3)2CO,376MHz)δ-58.99(s,3F),-64.48(s,3F);HRMS(ESI):C14H9F6IN5O2 +[M+H]+计算值:519.9705,观测值:519.9714。
实例42.N-(2-氯-4-(三氟甲氧基)苯基)-6-甲氧基-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-42)的合成
通过程序2A,用N-(2-氯-4-(三氟甲氧基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-172)合成化合物2-42,得到2-42(72%产率),其为浅黄色固体。1H NMR((CD3)2CO,400MHz)δ12.84(bs,1H),8.70(d,1H,J=9.1Hz),7.82(s,1H),7.34(s,1H),7.16(d,1H,J=9.1Hz),4.05(s,3H);13C NMR((CD3)2CO,100MHz)δ148.38,143.30(q,J=1.9Hz),139.76,136.75(q,J=41.2Hz),135.70,134.29,122.82,122.60,121.13(q,J=256.7Hz),120.99,120.13,119.76(q,J=269.4Hz),55.03;19F NMR((CD3)2CO,376MHz)δ-59.12(s,3F),-64.50(s,3F);HRMS(ESI):C14H9F6ClN5O2 +[M+H]+计算值:428.0349,观测值:428.0357。
实例43.N-(3-氯-4-(三氟甲氧基)苯基)-6-甲氧基-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-43)的合成
通过程序2A,用N-(3-氯-4-(三氟甲氧基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-173)合成化合物2-43,得到2-43(42%产率),其为浅黄色固体。1H NMR((CD3)2CO,400MHz)δ12.84(bs,1H),8.64(s,1H),8.40(s,1H),7.86(d,1H,J=9.1Hz),7.37(d,1H,J=9.1Hz),4.04(s,3H);13C NMR((CD3)2CO,100MHz)δ148.79,140.87,140.85,139.67(q,J=2.0Hz),136.41(q,J=41.2Hz),134.71,134.12,127.44,123.79,121.42(q,J=257.4Hz),120.98,119.96(q,J=267.3Hz),119.53,54.68;19F NMR((CD3)2CO,376MHz)δ-58.98(s,3F),-64.41(s,3F);HRMS(ESI):C14H9F6ClN5O2 +[M+H]+计算值:428.0349,观测值:428.0350。
实例44.N-(3-溴-4-(三氟甲氧基)苯基)-6-甲氧基-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-44)的合成
通过程序2A,用1-174合成化合物2-44,得到2-44(51%产率),其为浅黄色固体。1HNMR((CD3)2CO,400MHz)δ13.03(bs,1H),8.61(s,1H),8.52(d,1H,J=2.7Hz),7.91(dd,1H,J=9.1Hz),7.35(dq,1H,J=9.1Hz),4.03(s,3H);13C NMR((CD3)2CO,100MHz)δ148.57,140.85(q,J=1.9Hz),140.69,140.64,136.22(q,J=41.0Hz),134.46,134.01,123.79,123.13,121.21(q,J=257.4Hz),119.93,119.80(q,J=268.5Hz),116.05,54.51;19F NMR((CD3)2CO,376MHz)δ-58.61(s,3F),-64.38(s,3F);HRMS(ESI):C14H9F6BrN5O2 +[M+H]+计算值:471.9844,观测值:471.9845。
实例45. 5-异丙氧基-2-(三氟甲基)-N-(4-(三氟甲基)苯基)-1H-咪唑并[4,5-B]吡嗪-6-胺(2-45)的合成
通过程序2A,用6-异丙氧基-N-(4-(三氟甲基)苯基)-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺1-183合成化合物2-45,得到2-45(67%产率),其为浅黄色固体。1H NMR((CD3)2CO,400MHz)δ13.04(bs,1H),8.70(brs,1H),8.16(d,2H,J=8.4Hz),7.66(d,2H,J=8.4Hz),5.49(h,1H,J=6.2Hz),1.45(h,6H,J=6.2Hz);19F NMR((CD3)2CO,376MHz)δ-62.16(s,3H),-64.49(s,3H);HRMS(ESI):C16H13F6N5O+[M+H]+计算值:405.1019,观测值:405.0999。
实例46. 5-(2-氟苯氧基)-2-(三氟甲基)-N-(4-(三氟甲基)苯基)-1H-咪唑并[4,5-B]吡嗪-6-胺(2-46)的合成
通过程序2A,用6-(2-氟苯氧基)-N-(4-(三氟甲基)苯基)-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-184)合成化合物2-46,得到2-46(21%产率),其为浅黄色固体。1H NMR((CD3)2CO,400MHz)δ13.11(brs,1H),9.19(brs,1H),8.28(d,2H,J=8.6Hz),7.71(d,2H,J=8.6Hz),7.47(td,1H,J=8.0,1.3Hz),7.44–7.31(m,3H);19F NMR((CD3)2CO,376MHz)δ-62.18(s,3F),-64.82(s,3F),-129.73–-129.82(m,1F);HRMS(ESI):C19H11F7N5O+[M+H]+计算值:458.0846,观测值:458.0846。
实例47. 2-(三氟甲基)-5-(4-(三氟甲基)苯氧基)-N-(4-(三氟甲基)苯基)-1H-咪唑并[4,5-B]吡嗪-6-胺(2-47)的合成
通过程序2A,用6-(4-(三氟甲基)苯氧基)-N-(4-(三氟甲基)苯基)-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-185)合成化合物2-47,得到2-47(17%产率),其为浅黄色固体。1H NMR((CD3)2CO,400MHz)δ13.19(bs,1H),9.20(brs,1H),8.25(d,2H,J=8.5Hz),7.88(d,2H,J=8.5Hz),7.71(d,2H,J=8.5Hz),7.62(d,2H,J=8.5Hz);19F NMR(376MHz,丙酮-d6)δ-62.19(s,3F),-62.53(s,3F),-64.84(s,3F);HRMS(ESI):C20H11F9N5O+[M+H]+计算值:508.0814,观测值:508.0816。
实例49. 5-甲氧基-N-甲基-2-(三氟甲基)-N-(4-(三氟甲基)苯基)-1H-咪唑并[4,5-B]吡嗪-6-胺(2-49)的合成
通过程序2A,用6-甲氧基-N-甲基-N-(4-(三氟甲基)苯基)-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-177)合成化合物2-49,得到2-49(32%产率),其为浅黄色固体。1H NMR(400MHz,丙酮-d6)δ13.17(brs,1H),7.57(d,2H,J=8.4Hz),7.13(d,2H,J=8.4Hz),3.85(s,3H),3.53(s,3H);13C NMR(100MHz,丙酮-d6)δ153.68,151.85,143.75,139.38(q,J=41.2Hz),137.84,136.65,126.67(q,J=3.9Hz),125.80(q,J=271.3Hz),123.51(q,J=32.5Hz),120.00(q,J=269.1Hz),119.93,54.48,39.87;19F NMR(376MHz,丙酮-d6)δ-62.06(s,3F),-64.95(s,3F);HRMS(ESI):C15H12F6N5O+[M+H]+计算值:392.0941,观测值:392.0930。
实例50. 5-甲氧基-N-(4-(三氟甲基)苯基)-1H-咪唑并[4,5-B]吡嗪-6-胺(2-50)的合成
通过程序2D,用6-甲氧基-N-(4-(三氟甲基)苯基)-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-165)合成化合物2-50,得到2-50(58%产率),其为浅黄色固体。1H NMR(400MHz,丙酮-d6)δ11.97(brs,1H),8.50(brs,1H),8.19(d,2H,J=8.3Hz),8.14(s,1H),7.63(d,2H,J=8.6Hz),4.06(s,3H);19F NMR(376MHz,丙酮-d6)δ-61.99(s,3F);HRMS(ESI):C13H11F3N5O+[M+H]+计算值:310.0910,观测值:310.0900。
实例51. 5-甲氧基-2-甲基-N-(4-(三氟甲基)苯基)-1H-咪唑并[4,5-B]吡嗪-6-胺(2-51)的合成
通过程序2D,用6-甲氧基-N-(4-(三氟甲基)苯基)-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-165)合成化合物2-51,得到2-51(39%产率),其为浅黄色固体。1H NMR(400MHz,丙酮-d6)δ11.76(brs,1H),8.34(brs,1H),8.14(d,2H,J=8.5Hz),7.60(d,2H,J=8.5Hz),4.02(s,3H),2.60(s,3H);13C NMR(100MHz,丙酮-d6)δ149.88,146.80,145.47(q,J=1.2Hz),144.75,137.76,126.67(q,J=3.8Hz),125.89(q,J=269.9Hz),122.67(q,J=32.4Hz),119.33,118.72,54.41,15.61 19F NMR(376MHz,丙酮-d6)δ-61.93(s,3F)
实例52. 5-((4-(三氟甲氧基)苯基)氨基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-6-醇(2-52)的合成
通过程序2B,用2-1合成化合物2-52,得到2-52(60%产率),其为浅黄色固体。1HNMR(500MHz,丙酮-d6)δ9.01(brs,1H),8.17(d,2H,J=9.1Hz),7.33(d,2H,J=8.9Hz);13CNMR(125MHz,丙酮-d6)δ152.9,147.8,144.8(d,J=2.3Hz),139.5,130.7(q,J=41.8Hz),127.5,126.1,122.4,121.54(q,J=254.7Hz),121.50,120.6,120.2(q,J=267.3Hz);19FNMR(376MHz,丙酮-d6)δ-58.88(s,3F),-63.49(s,3F);HRMS(ESI):C13H8F6N5O2 +[M+H]+计算值:380.0582,观测值:380.0593。
实例53. 5-((2-氟-4-(三氟甲氧基)苯基)氨基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-6-醇(2-53)的合成
通过程序2B,用2-21合成化合物2-53,得到2-53(55%产率),其为浅黄色固体。1HNMR(500MHz,丙酮-d6)δ8.72(t,1H,J=9.1Hz),7.37(dd,1H,J=11.5,2.7Hz),7.25(d,1H,J=9.1Hz);13C NMR(125MHz,丙酮-d6)δ153.5(d,J=247.0Hz),152.9,147.3,144.3(dd,J=10.7,2.3Hz),131.3(q,J=41.5Hz),128.0,127.8(d,J=10.0Hz),126.1,121.8(d,J=2.1Hz),121.4(q,J=255.9Hz),120.1(q,J=267.5Hz),118.2(d,J=3.5Hz),110.2(d,J=23.2Hz);19F NMR(376MHz,丙酮-d6)δ-59.14(s,3F),-63.61(s,3F),-127.66(t,1F,J=10.1Hz);HRMS(ESI):C13H7F7N5O2 +[M+H]+计算值:398.0488,观测值:398.0502。
实例54. 5-((2-氟-3-(三氟甲基)苯基)氨基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-6-醇(2-54)的合成
通过程序2B,用2-6合成化合物2-54,得到2-54(51%产率),其为浅黄色固体。1HNMR(500MHz,丙酮-d6)δ8.90(brs,1H),8.82(brs,1H),7.42(m,1H);13C NMR(125MHz,丙酮-d6)δ152.9,150.9(d,J=253.3Hz),147.3,131.5(q,J=41.6Hz),129.6(d,J=9.0Hz),128.2,125.6(d,J=4.6Hz),125.4,123.7(q,J=271.5Hz),120.7(q,J=4.8Hz),120.1(q,J=267.8Hz),118.4(dd,J=32.8,10.4Hz);19F NMR(376MHz,丙酮-d6)δ-61.69(s,3F),-61.71(d,3F,J=13.0Hz),-134.24(m,1F);HRMS(ESI):C13H7F7N5O+[M+H]+计算值:382.0539,观测值:382.0532。
实例55. 5-((4-(三氟甲基)苯基)氨基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-6-醇(2-55)的合成
通过程序2B,用2-22合成化合物2-55,得到2-55(62%产率),其为浅黄色固体。1HNMR(500MHz,丙酮-d6)δ13.10(brs,1H),12.02(brs,1H),9.16(brs,1H),8.27(d,2H,J=8.5Hz),7.69(d,2H,J=8.5Hz);13C NMR(125MHz,丙酮-d6)δ152.9,147.6,143.7,131.0(q,J=41.6Hz),126.7(q,J=3.8Hz),125.5(q,J=270.4Hz),124.5(q,J=32.3Hz),120.1(q,J=267.4Hz),120.0;19F NMR(376MHz,丙酮-d6)δ-62.25(s,3F),-63.59(s,3F);HRMS(ESI):C13H7F6N5O+[M+H]+计算值:363.0549,观测值:363.0547。
实例56. 5-((4-(叔丁基)苯基)氨基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡嗪-6-醇(2-56)的合成
通过程序2B,用2-19合成化合物2-56,得到2-56(61%产率),其为浅黄色固体。1HNMR(500MHz,丙酮-d6)δ8.79(brs,1H),7.94(d,2H,J=8.7Hz),7.41(d,2H,J=8.7Hz),1.32(s,9H);13C NMR(125MHz,丙酮-d6)δ153.0,147.9,146.5,137.6,130.0(q,J=41.4Hz),126.9,126.5,126.3,125.8,122.8,118.6,120.2(q,J=267.1Hz),120.1,34.8,31.7;19FNMR(376MHz,丙酮-d6)δ-63.38(s,3F);HRMS(ESI):C16H17F3N5O+[M+H]+计算值:352.1380,观测值:352.1396。
实例57. 6-甲氧基-1-甲基-2-(三氟甲基)-N-(4-(三氟甲基)苯基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-57)的合成
通过程序2C,用2-22合成化合物2-57,得到2-57(34%产率),其为浅黄色固体。1HNMR(500MHz,丙酮-d6)δ8.73(brs,1H),8.24(d,2H,J=8.5Hz),7.67(d,2H,J=8.5Hz),4.17(s,3H),3.99(s,3H);HRMS(ESI):C14H10F6N5O+[M+H]+计算值:392.0941,观测值:392.0932。
实例58. 5-甲氧基-1-甲基-2-(三氟甲基)-N-(4-(三氟甲基)苯基)-1H-咪唑并[4,5-B]吡嗪-6-胺(2-58)的合成
通过程序2C,用2-22合成化合物2-58,得到2-58(34%产率),其为浅黄色固体。1HNMR(500MHz,丙酮-d6)δ8.84(brs,1H),8.25(d,2H,J=8.5Hz),7.69(d,2H,J=8.5Hz),4.06(s,3H),4.00(s,3H);HRMS(ESI):C15H12F6N5O+[M+H]+计算值:392.0941,观测值:392.0934。
实例59. 1-甲基-2-(三氟甲基)-6-((4-(三氟甲基)苯基)氨基)-1H-咪唑并[4,5-B]吡嗪-5-醇(2-59)的合成
通过程序2B,用2-58合成化合物2-59,得到2-59(78%产率),其为浅黄色固体。1HNMR(500MHz,丙酮-d6)δ11.75(brs,1H),8.19(brs,1H),8.37(d,2H,J=8.5Hz),7.73(d,2H,J=8.5Hz),4.01(s,3H);13C NMR(125MHz,丙酮-d6)δ153.0,147.5,143.6,130.8(q,J=39.7Hz),126.9(q,J=3.9Hz),125.6(q,J=269.9Hz),124.6(q,J=32.3Hz),120.4(q,J=267.9Hz),120.2;19F NMR(376MHz,丙酮-d6)δ-62.16(s,3F),-62.31(s,3F);HRMS(ESI):C14H10F6N5O+[M+H]+计算值:378.0784,观测值:378.0786。
实例60. 6-甲氧基-2-苯基-N-(4-(三氟甲氧基)苯基)-1H-咪唑并[4,5-B]吡嗪-5-胺(2-60)的合成
通过程序2D,用1-156合成化合物2-60,得到2-60;19F NMR(376MHz,丙酮-d6)δ-58.83(s,3F);HRMS(ESI):C19H15F3N5O2 +[M+H]+计算值:402.1172,观测值:402.1174。
实例61. 5-甲氧基-N-(4-(三氟甲氧基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡啶-6-胺(2-61)的合成
步骤1.5,6-二氯-3-硝基吡啶-2-胺2-61-a的合成
向6-氯-3-硝基吡啶-2-胺(20g,115mmol)的乙酸(100mL)混悬液中,加入N-氯琥珀酰亚胺(16.157g,121mmol),并将得到的反应混合物在100℃下搅拌一小时。使反应混合物冷却至室温,并向其中加入N-氯琥珀酰亚胺(2.0g)。将得到的反应混合物在100℃下搅拌1小时。使得到的反应混合物冷却至室温。并经由蒸馏去除乙酸。将残余物混悬在水中,加入饱和碳酸氢钠水溶液直到pH=8,并将固体残余物过滤。然后,将固体用水洗涤两次。收集固体,将其溶于丙酮并用水沉淀,并过滤,得到2-61-a,其为纯黄色固体(11g,46%)。1H NMR(400MHz,DMSO-d6)δ8.59(s,1H),8.34(s,2H)。
步骤2. 5,6-二氯-[1,2,5]噁二唑并[3,4-b]吡啶1-氧化物2-61-b的合成
将2-61-a(4.50g,21.64mmol)和二乙酸碘苯(17.421g,54.087mmol)加入密封管中,并在80℃下于丙酮(100mL)中搅拌16小时。然后,将反应物减压浓缩以去除溶剂,然后在110℃下经由减压蒸馏去除乙酸。所得的粗产物通过硅胶层析(0-100%乙酸乙酯/己烷)纯化,得到2-61-b,其为黄色固体(2.00g,45%)。1H NMR(400MHz,丙酮-d6)δ8.52(s,1H)。
步骤3. 5,6-二氯-[1,2,5]噁二唑并[3,4-b]吡啶(2-61-c)的合成
在干燥烧瓶中,将2-61-b(1.000g,14.56mmol)溶于干燥DCM(50mL),并在0℃下在氩气下缓慢加入三苯基膦(3.82g,14.56mmol)。将混合物在35℃下搅拌24小时。将反应物减压浓缩,并用饱和碳酸氢钠和乙酸乙酯萃取3次。合并所有有机馏分,通过无水硫酸钠干燥,浓缩并经由硅胶层析(己烷:乙酸乙酯0-5%)纯化,得到2-61-c,其为灰白色固体(1.00g,54%)。1H NMR(500MHz,丙酮-d6)δ8.90(s,1H)。13C NMR(126MHz,丙酮-d6)δ158.79,157.25,144.06,134.70,127.03。
步骤4. 6-氯-5-甲氧基-[1,2,5]噁二唑并[3,4-b]吡啶(2-61-d)的合成
在火焰干燥的烧瓶中,将NaH(0.13g,3.16mmol,60%w/w分散液)加入干燥THF(10mL)中,并在氩气下搅拌1分钟。在一分钟内逐滴加入甲醇(141μL,3.47mmol)的干燥THF(5mL)溶液,并将混合物搅拌10分钟。然后,在1分钟内逐滴加入5-3(600mg,3.16mmol)的干燥THF(5mL)溶液,并将混合物在室温下搅拌30分钟。然后,使混合物减压还原,并经由硅胶层析(己烷:乙酸乙酯0-5%)纯化,得到2-26-d,其为白色结晶固体(538mg,92%)。1H NMR(500MHz,丙酮-d6)δ8.57(s,1H),4.21(s,3H)。
步骤5.N-(2-氟苯基)-5-甲氧基-2-(三氟甲基)-1H-咪唑并[4,5-b]吡啶-6-胺(2-61)的合成
使用程序2-D,得到2-61,其为白色固体(22mg,46%)。1H NMR(400MHz,丙酮-d6)δ12.62(s,1H),7.57(d,J=1.4Hz,1H),7.41(td,J=8.3,1.7Hz,1H),7.27–7.12(m,2H),7.09–6.98(m,1H),6.77(s,1H),4.06(s,3H)。19F NMR(376MHz,丙酮-d6)δ-64.49,-128.65。13C NMR(126MHz,丙酮-d6)δ154.39(d,J=243.2Hz),153.62,137.51(q,J=40.5Hz),130.32(d,J=12.5Hz),126.72,124.77(d,J=3.7Hz),122.78(d,J=8.5Hz),120.60,119.29(d,J=268.8Hz),115.76(d,J=19.6Hz),53.63。HRMS(ESI+)m/z C14H11F4N4O+(M+H)+计算值:327.0864,实测值:327.0868。
实例62. 5-甲氧基-N-(4-(三氟甲氧基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡啶-6-胺(2-62)
使用程序2-D,得到2-62,其为米色固体(53mg,45%)。1H NMR(500MHz,丙酮-d6)δ7.83(s,1H),7.38–7.17(m,5H),4.03(s,3H)。(NH不可见)13C NMR(126MHz,氯仿-d)δ154.98,143.47(d,J=2.3Hz),143.22,138.58(q,J=40.4Hz),127.29,123.15,121.60(q,J=253.8Hz),120.19(q,J=268.3Hz),119.73,54.42。HRMS(ESI+)m/z C15H11F6N4O2(M+H)+计算值:393.0781,实测值:393.0784。
实例63. 5-甲氧基-N-(3-(三氟甲氧基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-B]吡啶-6-胺(2-63)
使用程序2-D,得到2-63,其为褐色固体(21mg,17%)。1H NMR(500MHz,丙酮-d6)δ7.91(s,1H),7.43–7.35(m,2H),7.25–7.18(m,1H),7.16–7.11(m,1H),6.86–6.79(m,1H),4.02(s,3H).13C NMR(126MHz,丙酮-d6)δ155.44,150.91(d,J=2.1Hz),146.26,138.94(q,J=40.6Hz),131.51,126.21,122.48(q,J=255.2Hz),120.17(d,J=266.4Hz),116.38,113.09,110.24,54.43。HRMS(ESI+)m/z C15H11F6N4O2(M+H)+计算值:393.0781,实测值:393.0783。
实例64. 5-甲氧基-2-(三氟甲基)-N-(4-(三氟甲基)苯基)-1H-咪唑并[4,5-B]吡啶-6-胺(2-64)
使用程序2-D,得到2-64,其为米色固体(21mg,35%)。1H NMR(400MHz,丙酮-d6)δ12.81(s,1H),8.00(s,1H),7.61–7.50(m,3H),7.30(d,J=8.4Hz,2H),4.01(s,3H)。HRMS(ESI+)m/z C15H11F6N4O+(M+H)+计算值:377.0832,实测值:377.0829。
实例65. 5-甲氧基-2-(三氟甲基)-N-(3-(三氟甲基)苯基)-1H-咪唑并[4,5-B]吡啶-6-胺(2-65)
使用程序2-D,得到2-65,其为米色固体(24mg,49%)。1H NMR(500MHz,丙酮-d6)δ12.72(s,1H),7.92(s,1H),7.57–7.34(m,4H),7.20(dt,J=6.2,1.7Hz,1H),4.02(s,3H)。HRMS(ESI+)m/z C15H11F6N4O+(M+H)+计算值:377.0832,实测值:377.0828。
实例66.N-(2-氟-4-(三氟甲氧基)苯基)-5-甲氧基-2-(三氟甲基)-1H-咪唑并[4,5-B]吡啶-6-胺(2-66)
使用程序2-D,得到2-66,其为白色固体(23mg,39%)。1H NMR(400MHz,丙酮-d6)δ12.67(s,1H),7.40(t,J=9.1Hz,1H),7.28(ddq,J=11.4,2.7,0.9Hz,1H),7.17–7.11(m,1H),6.92(s,1H),4.03(s,3H)。HRMS(ESI+)m/z C15H10F7N4O2+(M+H)+计算值:411.0686,实测值:411.0688。
实例67.N-(3-氟苯基)-5-甲氧基-2-(三氟甲基)-3H-咪唑并[4,5-B]吡啶-6-胺(2-67)
使用程序2-D,得到2-67,其为米色固体(41mg,65%)。1H NMR(400MHz,丙酮-d6)δ12.96(s,1H),7.88(d,J=53.6Hz,1H),7.47–7.13(m,1H),7.00(ddd,J=44.4,27.7,9.9Hz,2H),6.63(dt,J=30.6,8.7Hz,1H),4.00(s,3H);13C NMR(126MHz,丙酮-d6)δ164.67,155.35,145.97,137.80(q,J=41.0Hz),130.65,129.25,126.75,124.88,121.74,116.72,113.91,112.37,105.55,53.56(d,J=37.2Hz);19F NMR(376MHz,丙酮-d6)δ-64.50(d,J=50.4Hz),-113.82(dd,J=105.3,9.4Hz)。HRMS(ESI+)=C14H11F4N4O+[M+H]+计算值:327.0791;实测值:327.0865。
实例68.N-(2,3-二氟苯基)-5-甲氧基-2-(三氟甲基)-3H-咪唑并[4,5-B]吡啶-6-胺(2-68)
使用程序2-D,得到2-68,其为米色固体(43mg,70%)。1H NMR(400MHz,丙酮-d6)δ12.77(s,1H),7.69(s,1H),7.15–7.04(m,2H),6.95(s,1H),6.88(qd,J=6.4,5.9,2.9Hz,1H),4.02(s,3H);13C NMR(101MHz,丙酮-d6)δ152.34(d,J=10.8Hz),149.91(d,J=11.0Hz),137.95(q,J=40.4Hz),124.37,124.32,124.28,124.23,123.22,120.55,117.87,115.20,114.57,109.09,53.62;19F NMR(376MHz,丙酮-d6)δ-64.56,-140.27。HRMS(ESI+)=C14H10F5N4O+[M+H]+计算值:345.0697;实测值:344.0772。
实例69. 5-甲氧基-N-(4-甲氧基苯基)-2-(三氟甲基)-3H-咪唑并[4,5-B]吡啶-6-胺(2-69)
使用程序2-D,得到2-69,其为深粉色固体(13mg,21%)。1H NMR(400MHz,丙酮-d6)δ12.50(s,1H),7.54(s,1H),7.34(s,1H),7.25(d,J=8.3Hz,2H),6.94(d,J=8.8Hz,2H),4.03(s,3H),3.78(s,3H);13C NMR(126MHz,丙酮-d6)δ156.05,152.00,143.11,136.54(q),134.32,130.53,129.64,128.95,123.46,122.29,122.20,114.61,109.29,99.98,54.84;19FNMR(376MHz,丙酮-d6)δ-64.32(d,J=62.6Hz)。HRMS(ESI+)=C15H14F3N4O2+[M+H]+计算值:339.0991;实测值:339.1060。
实例70.N-(3-(叔丁基)苯基)-5-甲氧基-2-(三氟甲基)-3H-咪唑并[4,5-B]吡啶-6-胺(2-70)
使用程序2-D,得到2-70,其为橙色固体(32mg,52%)。1H NMR(400MHz,丙酮-d6)δ12.40(s,1H),7.72(s,1H),7.34(s,1H),7.24(t,J=7.9Hz,1H),7.11(d,J=7.8Hz,1H),7.03(d,J=6.5Hz,1H),4.03(s,3H),1.30(s,9H);13C NMR(126MHz,丙酮-d6)δ152.34,137.19,128.92,120.46,118.90,118.32,116.32,101.92,53.48,34.39,30.72;19F NMR(376MHz,丙酮-d6)δ-64.35。HRMS(ESI+)=C18H20F3N4O+[M+H]+计算值:365.1545;实测值:365.1587。
实例71.N-(2-氟-3-(三氟甲基)苯基)-5-甲氧基-2-(三氟甲基)-3H-咪唑并[4,5-B]吡啶-6-胺(2-71)
使用程序2-D,得到2-71,其为黄色固体(21mg,35%)。1H NMR(400MHz,丙酮-d6)δ12.83(s,1H),7.78(s,1H),7.48(s,1H),7.35–7.16(m,2H),7.09(s,1H),4.02(s,3H);19FNMR(376MHz,丙酮-d6)δ-61.70,-61.74,-64.66。HRMS(ESI+)=C15H10F7N4O+[M+H]+计算值:395.0698;实测值:395.0738。
实例72.N-(3,5-双(三氟甲基)苯基)-5-甲氧基-2-(三氟甲基)-3H-咪唑并[4,5-B]吡啶-6-胺(2-72)
使用程序2-D,得到2-72,其为白色固体(32mg,54%)。1H NMR(400MHz,丙酮-d6)δ12.94(s,2H),8.06(s,1H),7.85(s,1H),7.60(s,3H),7.38(s,1H),4.00(s,3H);19F NMR(376MHz,丙酮-d6)δ-63.74,-64.75。HRMS(ESI+)=C16H10F9N4O+[M+H]+计算值:445.0666;实测值:445.0707。
实例73. 5-甲氧基-N-(对甲苯基)-2-(三氟甲基)-3H-咪唑并[4,5-B]吡啶-6-胺(2-73)
使用程序2-D,得到2-73,其为类金色固体(30mg,48%)。1H NMR(400MHz,丙酮-d6)δ12.83(s,1H),7.74(s,1H),7.20(d,J=9.6Hz,2H),7.14(d,J=8.2Hz,2H),7.04(s,1H),4.02(s,3H),2.27(s,3H);13C NMR(101MHz,丙酮-d6)δ152.34,139.12,137.92–135.67(m),131.66,130.62,129.75(d,J=4.2Hz),129.10,127.39,122.00,120.31,118.98,111.30,101.36,53.30,19.84(d,J=4.2Hz);19F NMR(376MHz,丙酮-d6)δ-64.37(d,J=61.5Hz)。HRMS(ESI+)=C15H14F3N4O+[M+H]+计算值:323.1075;实测值:323.1116。
实例74. 5-甲氧基-N-(2-甲基-4-(三氟甲氧基)苯基)-2-(三氟甲基)-3H-咪唑并[4,5-B]吡啶-6-胺(2-74)
使用程序2-D,得到2-74,其为米色固体(8mg,20%)。1H NMR(400MHz,丙酮-d6)δ12.88(s,1H),7.48–7.35(m,1H),7.31–7.08(m,3H),4.05(s,3H),2.31(s,3H);13C NMR(101MHz,丙酮-d6)δ154.50,152.41,144.84,140.42,139.19,133.99,131.55,129.30,127.01,120.57,119.44(d,J=5.1Hz),114.00,102.62,53.57,17.06;19F NMR(376MHz,丙酮-d6)δ-58.77(d,J=13.8Hz),-64.47(d,J=62.0Hz)。HRMS(ESI+)=C16H13F6N4O2+[M+H]+计算值:407.0898;实测值:407.0936。
实例75. 5-甲氧基-2-(三氟甲基)-N-(4-(6-(三氟甲基)吡啶-3-基)苯基)-1H-咪唑并[4,5-B]吡啶-6-胺(2-75)
使用程序2-D,得到2-75,其为白色固体(36mg,62%)。1H NMR(500MHz,丙酮-d6)δ12.77(s,1H),9.03(d,J=2.2Hz,1H),8.28(dd,J=8.2,2.3Hz,1H),7.96(s,1H),7.88(d,J=8.2Hz,1H),7.80–7.72(m,2H),7.50–7.19(m,3H),4.05(s,3H)。
13C NMR(126MHz,丙酮-d6)δ155.18,148.50,145.95(q,J=34.4Hz),145.08,139.93,138.66(q,J=40.5Hz),135.43,129.12,128.86,126.69,123.03(q,J=273.0Hz),121.40(q,J=3.1Hz),120.78,120.17(q,J=271.4Hz),118.71,54.46。HRMS(ESI+)m/zC20H14F6N5O+(M+H)+计算值:454.1097,实测值:454.1099。噁唑类似物
一般程序4-A。
将6-溴吡嗪-2-胺(5.00g 1.0当量)在0℃下溶于干燥THF(15mL),加入NBS(20g2.2当量)并搅拌5分钟。使反应物升温至室温,并搅拌12小时。减压蒸发溶剂,并将残余物用乙酸乙酯和硫代硫酸钠萃取。然后,将有机层用水和盐水洗涤。合并的有机层通过硫酸钠干燥,过滤并浓缩。产物经由硅胶层析(乙酸乙酯:己烷)纯化。
一般程序4-B。
在3,5,6-三溴吡嗪-2-胺(146mg,0.5mmol)、三乙胺(202mg,2mmol)和催化量的DMAP(5mol%)的干燥CH2Cl2(5mL)溶液的混合物中,在室温下加入3-氟苯甲酰氯(176mg,1mmol)。将混合物在室温下搅拌过夜,并减压浓缩。然后,将残余物溶于MeOH(5mL),并加入K2CO3(100mg)。将混合物在60℃下搅拌1小时。然后,将混合物向下还原,并将产物经由硅胶层析(乙酸乙酯:己烷)纯化。
一般程序4-C。
经由分子内O-芳基化合成吡嗪-噁唑的一般程序:向10mL密封管中加入CuI(0.05mmol)、菲咯啉(0.1mmol)、特定的苯甲酰胺(0.5mmol)、K3PO4(1.0mmol)和无水DMF(1mL)。然后,在无惰性气氛下密封所述管并在85℃下加热5小时。将反应混合物冷却至室温,用10mL水稀释并用乙酸乙酯(3x20 mL)萃取。合并的有机相用水和盐水洗涤,通过无水Na2SO4干燥,并减压浓缩。将残余物通过硅胶层析(乙酸乙酯:己烷)纯化。
一般程序4-D。
单/双Buchwald胺化的一般程序:在压力小瓶中装入5,6-二溴-2-(3-氟苯基)噁唑并[4,5-b]吡嗪(1当量)、Pd2dba3(10mol%)、Xantphos(10mol%)、2-氟苯胺(2.5当量)和K2CO3(2.5当量)。然后,将烧瓶排空并用氩气回填3次。通过隔膜加入干燥的脱气的1,4-二噁烷(4mL),并将混合物在110℃下搅拌16小时。将反应物冷却至室温,并将混合物用乙酸乙酯稀释,通过硅藻土过滤,然后减压浓缩。将残余物通过硅胶层析(乙酸乙酯:己烷)纯化。
实例76.N5,N6-双(2-氟苯基)-2-(3-氟苯基)噁唑并[4,5-B]吡嗪-5,6-二胺的合成(4-1)
步骤1. 3,5,6-三溴吡嗪-2-胺的合成
通过一般程序4-A合成,得到4-1-a,其为黄色固体。(87%产率)。1H NMR(400MHz,氯仿-d)δ5.24(s,2H)。13C NMR(101MHz,氯仿-d)δ151.18,138.87,125.23,121.60。
步骤2. 3-氟-N-(3,5,6-三溴吡嗪-2-基)苯甲酰胺的合成
通过一般程序4-B合成,得到4-1-b,其为白色固体。(57%产率)。1H NMR(400MHz,丙酮-d6)δ10.18(s,1H),7.99–7.88(m,1H),7.84–7.77(m,1H),7.70–7.58(m,1H),7.52–7.39(m,1H)。19F NMR(376MHz,丙酮-d6)δ-113.45(td,J=9.1,5.7Hz)。13C NMR(101MHz,DMSO-d6)δ165.58(d,J=3.8Hz),162.35(dd,J=1266.3,246.0Hz),150.91,147.92,137.17,134.65,132.15(d,J=8.4Hz),127.02(d,J=8.8Hz),124.65(d,J=3.4Hz),121.21(d,J=21.5Hz),114.82(d,J=24.4Hz)。
步骤3. 5,6-二溴-2-(3-氟苯基)噁唑并[4,5-b]吡嗪的合成
通过一般程序4-C合成,得到4-1-c,其为黄色固体。(55%产率)。1H NMR(400MHz,DMSO-d6)δ8.19–8.11(m,1H),8.10–8.04(m,1H),7.81–7.72(m,1H),7.70–7.62(m,1H)。19FNMR(376MHz,DMSO-d6)δ-110.77–-110.97(m,1F)。13C NMR(101MHz,DMSO-d6)δ170.33,165.58(d,J=3.8Hz),163.57,161.12,150.91,147.92,135.91(d,J=252.6,239.2Hz),132.15(d,J=8.4Hz),127.02(d,J=8.8Hz),124.65(d,J=3.4Hz),121.21(d,J=21.5Hz),114.82(d,J=24.4Hz)。
步骤5.N5,N6-双(2-氟苯基)-2-(3-氟苯基)噁唑并[4,5-b]吡嗪-5,6-二胺(4-1)的合成
通过一般程序4-D合成,得到4-1,其为灰黄色固体。(49%产率)。1H NMR(500MHz,DMSO-d6)δ8.93(d,J=5.5Hz,1H),8.57(d,J=5.9Hz,1H),7.92(d,J=7.8Hz,1H),7.86–7.79(m,1H),7.76–7.66(m,2H),7.65–7.56(m,1H),7.42(td,J=8.6,2.6Hz,1H),7.38–7.14(m,7H)。19F NMR(376MHz,DMSO-d6)δ-111.51–-111.92(m,1F),-120.99,-121.82。13C NMR(126MHz,DMSO-d6)δ162.36(d,J=244.7Hz),157.57(d,J=3.5Hz),155.39(d,J=246.4Hz),154.96(d,J=245.1Hz),145.01,140.41,139.51,135.81,131.63,131.57,127.16,127.07,125.67,125.61,125.40(d,J=1.9Hz),124.83–124.53(m),124.47(d,J=3.3Hz),122.49(d,J=2.7Hz),118.30,118.13,115.94(d,J=22.8Hz),115.79(d,J=22.7Hz),112.86(dt,J=27.6,24.3,21.9Hz)。HRMS(ESI-):C23H13F3N5O-[M-H]-计算值:432.1078,实测值:432.1073
羟基噁唑
一般程序4-E。
向无水DMF中加入氢化钠(1.2当量,60%分散液),并搅拌1分钟。向本搅拌的混合物中分批加入苄醇(1.2当量)的无水DMF(0.1M)溶液。将混合物在室温下搅拌30分钟,然后加入6-氯吡嗪-2-胺的无水DMF(0.1M)溶液。将反应物在100℃下搅拌16小时,并在完成后用异丙醇缓慢淬灭。然后,使反应物在乙酸乙酯和水之间分配。有机层用水洗涤3次,用盐水洗涤3次,然后通过硫酸钠干燥。将合并的有机层减压浓缩,并将产物经由硅胶层析纯化。
一般程序4-F。
向随后的苯胺/苄基醚吡嗪噁唑(1.0当量)中加入HPLC甲醇(4mL)。吹扫圆底并用氮气鼓泡5分钟。5分钟后,在正氮气压力下加入Pd/C 10%。然后,将混合物在氢气球下于室温下搅拌1.5小时。然后,将反应物通过硅藻土塞(plug)过滤,用乙酸乙酯洗涤,减压浓缩,并经由硅胶层析(甲醇/DCM)纯化,得到产物,其为光敏性高度不稳定的固体。
实例77.合成6-(苄氧基)-N-(2-氟苯甲酰基)-2-(3-氟苯甲酰基)噁唑并[4,5-B]吡嗪-5-胺(4-2)_
步骤1. 5-(苄氧基)-N-(3,5-双(三氟甲基)苯基)-2-(3-氟苯基)噁唑并[4,5-b]吡嗪-6-胺(4-2-a)的合成
通过一般程序4-E合成,得到4-2-a,其为黄色固体。(19%产率)。1H NMR(400MHz,丙酮-d6)δ7.54(s,1H),7.48–7.44(m,2H),7.42(t,J=0.4Hz,1H),7.40–7.28(m,3H),5.76(s,2H),5.29(s,2H)。13C NMR(101MHz,丙酮-d6)δ158.87,154.08,137.45,128.28,128.01,127.70,122.65,120.40,66.64。
步骤2. 6-(苄氧基)-3,5-二溴吡嗪-2-胺(4-2-b)的合成
通过一般程序4-A合成,得到4-2-b,其为黄色固体。(47%产率)。1H NMR(400MHz,丙酮-d6)δ7.53–7.46(m,2H),7.43–7.31(m,3H),6.29(s,2H),5.37(s,2H)。13C NMR(101MHz,丙酮-d6)δ156.13,152.15,137.32,129.30,128.93,128.87,111.11,108.84,69.65。
步骤3.N-(6-(苄氧基)-3,5-二溴吡嗪-2-基)-3-氟苯甲酰胺(4-2-c)
通过一般程序4-B合成,得到4-2-c,其为黄色固体。(66%产率)。1H NMR(400MHz,氯仿-d)δ8.34(s,1H),7.72–7.62(m,2H),7.57–7.49(m,3H),7.43–7.29(m,4H),5.47(s,2H)。19F NMR(376MHz,氯仿-d)δ-110.39–-110.50(m,1F)。
步骤4. 5-(苄氧基)-6-溴-2-(3-氟苯基)噁唑并[4,5-b]吡嗪(4-2-d)的合成
通过一般程序4-C合成,得到4-2-d,其为黄色固体。(9%产率)。1H NMR(400MHz,丙酮-d6)δ8.15–8.10(m,1H),8.03–7.95(m,1H),7.77–7.68(m,1H),7.62–7.56(m,2H),7.53–7.47(m,1H),7.46–7.40(m,2H),7.40–7.34(m,1H),5.60(s,2H)。19F NMR(376MHz,丙酮-d6)δ-112.76(s,1F)。13C NMR(101MHz,丙酮-d6)δ164.17,162.90(d,J=246.0Hz),156.02,146.69,144.44,136.18,131.64(d,J=8.4Hz),128.48,128.30(d,J=8.7Hz),128.12,127.87,123.83(d,J=3.3Hz),122.08,119.91(d,J=21.6Hz),114.25(d,J=24.5Hz),69.73。
步骤5. 6-(苄氧基)-N-(2-氟苯基)-2-(3-氟苯基)噁唑并[4,5-b]吡嗪-5-胺(4-2)的合成
通过一般程序4-D合成,得到4-9,其为黄色固体。(53%产率)。1H NMR(400MHz,氯仿-d)δ8.63(td,J=8.3,1.6Hz,1H),8.05–7.97(m,1H),7.95–7.87(m,1H),7.70(d,J=3.8Hz,1H),7.60–7.34(m,6H),7.26–7.11(m,3H),7.08–7.00(m,1H),5.65(s,2H)。19F NMR(376MHz,氯仿-d)δ-108.22–-116.82(m,1F),-131.72(ddd,J=12.6,8.1,4.4Hz,1F)。13CNMR(101MHz,氯仿-d)δ164.36,163.11(d,J=246.8Hz),159.11(d,J=3.5Hz),152.84(d,J=243.5Hz),147.50,145.98,138.83,135.83,134.87,130.83(d,J=8.4Hz),129.30(d,J=8.8Hz),128.87,128.69,128.53,127.49(d,J=10.0Hz),124.79(d,J=3.9Hz),123.22(d,J=7.7Hz),122.70(d,J=3.4Hz),120.26,118.37(d,J=21.5Hz),114.95(d,J=19.1Hz),113.90(d,J=24.5Hz),69.72。HRMS(ESI+):C24H17F2N4O2+[M+H]+计算值:431.1314,实测值:431.1316
实例78. 2-(3-氟苯基)-6-((2-氟苯基)氨基)噁唑并[4,5-B]吡嗪-5-醇(4-3)
通过一般程序4-F合成,得到4-10,其为灰黄色固体。(70%产率)。1H NMR(500MHz,DMSO-d6)δ13.35(s,1H),9.00(s,1H),8.17(t,J=8.0Hz,1H),7.84(d,J=7.8Hz,1H),7.73(d,J=9.7Hz,1H),7.60(q,J=7.4Hz,1H),7.33(ddd,J=37.0,15.6,8.1Hz,3H),7.19(q,J=7.1Hz,1H)。19F NMR(376MHz,DMSO-d6)δ-111.72(td,J=9.4,6.1Hz,1F)。13C NMR(126MHz,DMSO-d6)δ162.40(d,J=244.5Hz),153.86(d,J=244.8Hz),131.64,131.57(d,J=10.3Hz),128.73(d,J=8.9Hz),126.44(d,J=10.9Hz),125.08–124.80(m),124.71(d,J=4.2Hz),122.88–122.58(m),121.75(d,J=3.5Hz),117.50(dq,J=29.7,21.6,21.2,20.9Hz),115.50,115.34(tdd,J=21.8,19.1,11.6Hz),112.08(d,J=24.8Hz)。HRMS(ESI-):C17H9F2N4O2-[M-H]-计算值:339.0699,实测值:339.0695
实例79. 5-(苄氧基)-N-(3,5-双(三氟甲基)苯基)-2-(3-氟苯基)噁唑并[4,5-B]吡嗪-6-胺(4-4)
通过一般程序4-D合成,得到4-3,其为灰黄色固体。(32%产率)。1H NMR(400MHz,氯仿-d)δ8.26(s,2H),8.04(d,J=7.8Hz,1H),7.94(dt,J=9.3,2.1Hz,1H),7.62–7.36(m,7H),7.32–7.06(m,4H),5.63(s,2H)。19F NMR(376MHz,氯仿-d)δ-62.94。
实例80. 6-((3,5-双(三氟甲基)苯基)氨基)-2-(3-氟苯基)噁唑并[4,5-B]吡嗪-5-醇(4-5)的合成
通过一般程序4-F合成,得到4-12,其为灰黄色固体。(32%产率)。1H NMR(400MHz,丙酮-d6)δ9.50(s,1H),8.82(dq,J=1.4,0.7Hz,2H),7.93(ddd,J=7.8,1.5,0.9Hz,1H),7.81–7.74(m,1H),7.73–7.70(m,1H),7.67–7.56(m,1H),7.40–7.25(m,1H)。19F NMR(376MHz,丙酮-d6)δ-63.50(s,6F),-113.31–-113.39(m,1F)。
起始材料
实例81.实例1-60的起始材料的制备
通过亲核芳族取代制备起始材料化合物的一般程序
一般程序1-C。取5-氯-6-烷氧基-[1,2,5]噁二唑并[3,4-b]吡嗪,将其溶于无水THF(0.1M–0.2M),并在氩气气氛下加入密封管中。加入相对应的苯胺(2.2当量),并将反应物在65℃下搅拌16小时。然后,减压去除溶剂,并通过在SiO2上用EtOAc/己烷的溶剂系统层析纯化,得到所需产物,即5-氨基-6-烷氧基-[1,2,5]噁二唑并[3,4-b]吡嗪。方案3示出了一般程序1-C。
方案3.
化合物1-138. 5-氯-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪(1-138)的合成
将5,6-二氯-[1,2,5]噁二唑并[3,4-b]吡嗪(1-2)(2.00g)溶于无水THF(25mL)并加入Et3N(1.46mL,1当量)。混合溶液,并在几分钟内逐滴加入MeOH(0.9当量)。溶液进化成浆液,并在室温下搅拌30分钟。然后,减压去除溶剂,并通过在SiO2上层析(梯度:5-15%EtOAc/己烷)纯化,得到1-138(68%),其为无色固体。
化合物1-139.N-(3,5-双(三氟甲基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-139)的合成
通过程序1-C,使用1-138合成化合物1-139,得到1-139(89%产率),其为灰白色固体:1H NMR(500MHz,丙酮-d6)δ10.02(s,1H),8.76(d,J=1.5Hz,2H),7.93–7.75(m,1H),4.27(s,3H);19F NMR(376MHz,丙酮-d6)δ-63.57(s 6F);13C NMR(126MHz,丙酮-d6)δ156.22,151.28,150.61,147.92,140.78,132.63(q,J=33.3Hz),124.30(d,J=272.7Hz),122.30(q,J=4.7Hz),118.56(h,J=4.2Hz),56.75;HRMS(ESI+)m/z C13H8F6N5O2[M+H]+计算值:380.0577,实测值:380.0578
化合物1-140.N-(2-氟-3-(三氟甲基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-140)的合成
通过程序1-C,使用1-138合成化合物1-140,得到1-140(80%产率),其为米色固体:1H NMR(400MHz,丙酮-d6)δ9.38–9.25(m,1H),8.54–8.42(m,1H),7.66(dddd,J=8.2,6.6,1.7,0.8Hz,1H),7.53(tt,J=8.0,1.1Hz,1H),4.30(s,3H);19F NMR(376MHz,丙酮-d6)δ-61.75(d,J=13.0Hz 3F),-126.91–-127.08(m 1F);13C NMR(101MHz,丙酮-d6)δ156.23,152.35(dq,J=256Hz,2.4,Hz),151.59,150.82,148.32,130.95(d,J=1.8Hz),127.41(d,J=10.6Hz),125.69(d,J=5.0Hz),124.68(q,J=4.8,1.3Hz),123.58(q,J=272.9Hz),56.81;HRMS(ESI+)m/z C12H8F4N5O2[M+H]+计算值:330.0609,实测值:330.0655。
化合物1-141. 6-甲氧基-N-(3-(三氟甲氧基)苯基)-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-141)的合成
通过程序1-C,使用1-138合成化合物1-141,得到1-141(95%产率),其为黄色固体:1H NMR(500MHz,丙酮-d6)δ9.73(s,1H),8.17(td,J=2.2,1.1Hz,1H),8.08–7.95(m,1H),7.56(t,J=8.2Hz,1H),7.17(ddt,J=8.3,2.3,1.1Hz,1H),4.23(s,3H);19F NMR(376MHz,丙酮-d6)δ-58.50(s 3F);13C NMR(126MHz,丙酮-d6)δ156.30,151.57,150.54,149.99(q,J=2.2Hz),147.70,140.38,131.22,121.44(q,J=257.9Hz),120.99,117.84,114.87,56.56;HRMS(ESI+)m/z C12H9F3N5O3[M+H]+计算值:328.0652,实测值:328.0666。
化合物1-142. 6-甲氧基-N-(2-甲基-5-(三氟甲基)苯基)-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-142)的合成
通过程序1-C,使用1-138合成化合物1-142,得到1-142(93%产率),其为灰白色固体:1H NMR(500MHz,丙酮-d6)δ9.28(s,1H),8.09(s,1H),7.58(d,J=1.2Hz,2H),4.28(s,3H),2.45(d,J=1.1Hz,3H);19F NMR(376MHz,丙酮-d6)δ-62.80(s 3F);13C NMR(126MHz,丙酮-d6)δ156.55,151.95,150.83,148.91,139.26(d,JCF=1.6Hz),137.13,132.43,129.07(d,JCF=32.4Hz),125.50(d,JCF=272.0Hz),124.08(q,JCF=4.0Hz),123.60(q,JCF=4.3Hz),56.65,18.17;HRMS(ESI+)m/z C13H11F3N5O2[M+H]+计算值:326.0859,实测值:326.0906。
化合物1-143.N-(3-氟苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-143)的合成
通过程序1-C,使用1-138合成化合物1-143,得到1-143(74%产率),其为黄色固体:1H NMR(500MHz,丙酮-d6)δ9.64(s,1H),8.03(dt,J=11.5,2.3Hz,1H),7.79–7.70(m,1H),7.44(td,J=8.3,6.7Hz,1H),6.97(tt,J=8.5,1.6Hz,1H),4.21(s,3H);19F NMR(376MHz,丙酮-d6)δ-113.03–-113.17(m,1F);13C NMR(126MHz,丙酮-d6)δ163.47(d,JCF=242.0Hz),156.24,151.58,150.46,147.54,140.37(d,JCF=11.3Hz),131.14(d,JCF=9.6Hz),118.07(d,JCF=3.5Hz),112.23(d,JCF=21.5Hz),109.28(d,JCF=27.1Hz),56.52;HRMS(ESI+)m/z C11H9FN5O2[M+H]+计算值:262.0735,实测值:262.0774。
6-甲氧基-N-(对甲苯基)-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-144)的合成
通过程序1-C,使用1-138合成化合物1-144,得到1-144(89%产率),其为黄色固体:1H NMR(500MHz,丙酮-d6)δ8.85(s,1H),7.87–7.78(m,2H),7.42–7.29(m,2H),4.31(s,3H),2.45(s,3H);13C NMR(126MHz,丙酮-d6)δ185.23,180.64,179.30,176.38,164.91,164.16,158.88,151.37,146.81,85.25,49.52;HRMS(ESI+)m/z C12H12N5O2[M+H]+计算值:258.0986,实测值:258.0990。
化合物1-145. 6-甲氧基-N-(4-甲氧基苯基)-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-145)的合成
通过程序1-C,使用1-138合成化合物1-145,得到1-145(90%产率),其为黄色固体:1H NMR(500MHz,丙酮-d6)δ8.83(s,1H),7.88–7.81(m,2H),7.13–7.06(m,2H),4.31(s,3H),3.92(s,3H);13C NMR(126MHz,丙酮-d6)δ186.85,185.32,180.74,179.36,176.41,159.58,153.17,146.82,143.53,85.23,84.64;HRMS(ESI+)m/z C12H12N5O3[M+H]+计算值:274.0935,实测值:274.0940。
化合物1-146. 6-甲氧基-N-苯基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-146)的合成
通过程序1-C,使用1-138合成化合物1-146,得到1-146(94%产率),其为米色固体:1H NMR(500MHz,丙酮-d6)δ8.90(s,1H),8.00–7.94(m,2H),7.59–7.51(m,2H),7.38–7.32(m,1H),4.32(s,3H);碳;HRMS(ESI+)m/z C11H10N5O2[M+H]+计算值:244.0829,实测值:244.0834。
化合物1-147.N-(2,3-二氟苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-147)的合成
通过程序1-C,使用1-138合成化合物1-147,得到1-147(90%产率),其为灰白色固体:1H NMR(500MHz,丙酮-d6)δ9.78(s,1H),7.90–7.76(m,2H),6.87(tt,J=9.1,2.3Hz,1H),4.23(s,3H);19F NMR(376MHz,丙酮-d6)δ-110.31–-110.43(m 2F);13C NMR(126MHz,丙酮-d6)δ163.85(dd,J=244.2,14.9Hz),156.20,151.42,150.52,147.71,141.32(t,J=13.8Hz),105.62–104.84(m),100.62(t,J=26.2Hz),56.62;HRMS(ESI+)m/z C11H8F2N5O2[M+H]+计算值:280.0641,实测值:280.0645。
化合物1-148.N-(3,5-二氟苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-148)的合成
通过程序1-C,使用1-138合成化合物1-148,得到1-148(98%产率),其为灰白色固体:1H NMR(500MHz,丙酮-d6)δ9.09(s,1H),7.93–7.85(m,1H),7.34–7.19(m,2H),4.27(s,3H);19F NMR(376MHz,丙酮-d6)δ-139.41–-139.55(m,1F),-148.52–-148.79(m,1F);13C NMR(126MHz,丙酮-d6)δ156.24,151.66,151.41(dd,J=245.7,11.2Hz),150.80,148.32,144.85(dd,J=249.2,14.4Hz),127.59(dd,J=8.7,1.9Hz),125.11(dd,J=7.9,5.0Hz),121.81(d,J=3.5Hz),117.78,115.38(d,J=17.1Hz),56.75;HRMS(ESI+)m/z C11H8F2N5O2[M+H]+计算值:280.0641,实测值:280.0654。
化合物1-149.N-(4-氯苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-149)的合成
通过程序1-C,使用1-138合成化合物1-149,得到1-149(96%产率),其为米色固体:1H NMR(500MHz,丙酮-d6)δ9.62(s,1H),8.11–8.00(m,2H),7.53–7.40(m,2H),4.22(s,3H);13C NMR(126MHz,丙酮-d6)δ156.37,151.72,150.56,147.58,137.61,130.37,129.62,124.03,56.50;HRMS(ESI+)m/z C11H9ClN5O2[M+H]+计算值:278.0439,实测值:278.0455。
化合物1-151.N-(3-氟-4-(三氟甲氧基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-151)的合成
通过程序1-C,使用1-138合成化合物1-151,得到1-151(97%产率),其为米色固体:1H NMR(500MHz,丙酮-d6)δ9.83(s,1H),8.42–8.11(m,1H),8.05–7.69(m,1H),7.67–7.32(m,1H),4.23(s,3H);19F NMR(376MHz,丙酮-d6)δ-59.87(d,J=5.2Hz,3F),-128.91(s,1F);13C NMR(126MHz,丙酮-d6)δ156.28(d,JCF=4.7Hz),154.88(d,JCF=248.8Hz),151.48(d,JCF=3.6Hz),150.58(d,JCF=3.7Hz),147.70(d,JCF=5.4Hz),139.50–139.12(m),133.31–132.85(m),125.10(d,JCF=2.4Hz),121.48(d,JCF=256.8Hz),118.81,111.56–110.66(m),56.61;HRMS(ESI+)m/z C12H8F4N5O3[M+H]+计算值:346.0558,实测值:346.0568。
化合物1-152. 6-甲氧基-N-(萘-2-基)-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-152)的合成
通过程序1-C,使用1-138合成化合物1-152,得到1-152(97%产率),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ9.69(s,1H),8.81–8.77(m,1H),8.00–7.86(m,4H),7.58–7.44(m,2H),4.26(app d,J=0.5Hz,3H);13C NMR(101MHz,丙酮-d6)δ156.51,151.91,150.62,147.68,136.27,134.59,131.98,129.40,128.70,128.47,127.54,126.42,122.24,119.47,56.50;HRMS(ESI+)m/z C15H12N5O2[M+H]+计算值:294.0986,实测值:294.0992。
化合物1-153.N-(4-乙基苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-153)的合成
通过程序1-C,使用1-138合成化合物1-153,得到1-153(57%产率),其为黄色固体:1H NMR(500MHz,丙酮-d6)δ9.46(s,1H),7.96–7.85(m,2H),7.36–7.20(m,2H),4.23(s,3H),2.66(q,J=7.6Hz,2H),1.24(t,J=7.6Hz,3H);13C NMR(126MHz,丙酮-d6)δ156.43,151.94,150.52,147.46,142.04,136.31,128.93,122.60,56.41,28.90,16.01;HRMS(ESI+)m/z C13H14N5O2[M+H]+计算值:272.1142,实测值:272.1158。
化合物1-154.N-(3-氟-4-戊基苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-154)
通过程序1-C,使用1-138合成化合物1-154,得到1-154(68%产率),其为黄色固体:1H NMR(500MHz,丙酮-d6)δ9.61(s,1H),7.99(dd,J=12.4,2.2Hz,1H),7.71(dd,J=8.3,2.2Hz,1H),7.33(t,J=8.5Hz,1H),4.24(s,3H),2.66(t,J=7.7Hz,2H),1.72–1.53(m,2H),1.43–1.31(m,4H),1.00–0.88(m,3H);19F NMR(376MHz,丙酮-d6)δ-118.57–-118.67(m,1F).;13C NMR(126MHz,丙酮-d6)δ161.43(d,JCF=241.7Hz),156.34,151.73,150.52,147.50,138.02(d,JCF=11.3Hz),131.57(d,JCF=6.6Hz),126.77(d,JCF=16.7Hz),118.06(d,JCF=3.6Hz),109.32(d,JCF=28.3Hz),56.49,32.17,29.53,29.10,23.10,14.27;HRMS(ESI+)m/z C16H19FN5O2[M+H]+计算值:332.1517,实测值:332.1533。
化合物1-155.N-(2-氟-4-戊基苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-155)的合成
通过程序1-C,使用1-138合成化合物1-155,得到1-155(90%产率),其为黄色固体:1H NMR(500MHz,丙酮-d6)δ9.08(s,1H),8.08(t,J=8.3Hz,1H),7.25–7.03(m,2H),4.28(s,3H),2.74–2.59(m,2H),1.74–1.51(m,2H),1.46–1.19(m,4H),0.91(t,J=6.8Hz,3H);19FNMR(376MHz,丙酮-d6)δ-126.34(dd,J=11.6,8.2Hz);13C NMR(126MHz,丙酮-d6)δ156.25,155.81(d,JCF=246.6Hz),151.82,150.68,148.02,143.68(d,JCF=7.3Hz),125.90(d,JCF=1.4Hz),125.16(d,JCF=3.6Hz),123.28(d,JCF=11.7Hz),116.08(d,JCF=19.2Hz),56.68,35.80(d,JCF=1.8Hz),32.08,31.65,23.11,14.29;HRMS(ESI+)m/z C16H19FN5O2[M+H]+计算值:332.1517,实测值:332.1527。
化合物1-156. 6-甲氧基-N-(4-(三氟甲氧基)苯基)-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-156)的合成
通过程序1-C,使用1-138合成化合物1-156,得到1-156(66%产率),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ9.70(brs,1H),8.18–8.13(m,2H),7.44–7.39(m,2H),4.23(s,3H);13C NMR(100MHz,丙酮-d6)δ156.48,151.79,150.68,147.77,146.48(q,J=1.9Hz),137.88,124.16,122.51(q,J=255.13Hz),56.61;19F NMR(376MHz,丙酮-d6)δ-58.78(s,3F);HRMS(ESI):C12H9F3N5O3 +[M+H]+计算值:328.0652,观测值:328.0667。
化合物1-157.N-(4-丁基苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-157)的合成
通过程序1-C,使用1-138合成化合物1-157,得到1-157(66%产率),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ9.47(brs,1H),7.94–7.90(m,2H),7.30–7.25(m,2H),4.22(s,3H),2.63(t,2H,J=7.6Hz),1.61(q,2H,J=7.8Hz),1.37(h,2H,J=7.8),0.93(t,3H,J=7.3Hz);13C NMR(100MHz,丙酮-d6)δ155.59,151.08,149.66,146.61,139.77,135.44,128.61,121.65,55.52,34.78,33.58,22.05,13.29;HRMS(ESI):C15H18N5O2 +[M+H]+计算值:300.1455,观测值:300.1443。
化合物1-158.N-(-氟-5-(三氟甲基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-158)的合成
通过程序1-C,使用1-138合成化合物1-158,得到1-158(83%产率),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ9.26(brs,1H),8.64(d,1H,J=7.0Hz),7.74–7.68(m,1H),7.61–7.53(m,1H),4.30(s,3H);13C NMR(100MHz,丙酮-d6)δ157.93(d,J=254Hz),156.26,151.58,150.85,148.27,127.34(q,J=34Hz),127.08(d,J=12Hz),125.17(h,J=5Hz),124.76(q,J=272Hz),123.37(m,J=2Hz),117.70(d,J=21Hz),56.91;19F NMR(376MHz,丙酮-d6)δ-62.62(s,3F),-119.21--119.31(m,1F);HRMS(ESI):C12H8F4N5O2 +[M+H]+计算值:330.0609,观测值:330.0611。
化合物1-159.N-(2-氟苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-159)的合成
通过程序1-C,使用1-138合成化合物1-159,得到1-159(95%产率),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ9.14(brs,1H),8.26–8.18(m,1H),7.38–7.26(m,3H),4.29(s,3H);13C NMR(100MHz,丙酮-d6)δ156.44(d,J=246Hz),156.11,151.93,150.88,148.28,128.10(d,J=8Hz),126.31,126.12(d,J=11Hz),125.55(d,J=4Hz),116.53(d,J=20Hz),56.85;19F NMR(376MHz,丙酮-d6)δ-125.90--126.04(m,1F);HRMS(ESI):C11H9FN5O2 +[M+H]+计算值:262.0735,观测值:262.0741。
化合物1-160. 6-甲氧基-N-(2-(三氟甲基)苯基)-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-160)的合成
通过程序1-C,使用1-138合成化合物1-160,得到1-160(90%产率),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ9.15(brs,1H),8.14(d,1H,J=8.2Hz),7.89–7.78(m,1H),7.60–7.53(m,1H),4.31(s,3H);13C NMR(100MHz,丙酮-d6)δ156.34,151.83,150.85,149.32,135.75(q,J=2Hz),134.27(q,J=1Hz),129.33,128.12,127.60(q,J=5Hz),125.39(q,J=30Hz),124.86(q,J=274Hz),56.97;19F NMR(376MHz,丙酮-d6)δ-61.16(s,1F);HRMS(ESI):C12H9F3N5O2 +[M+H]+计算值:312.0703,观测值:312.0700。
化合物1-161.N-([1,1'-联苯]-4-基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-161)的合成
通过程序1-C,使用1-138合成化合物1-161,得到1-161(70%产率),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ9.63(brs,1H),8.15(d,2H,J=8.6Hz),7.76(d,2H,J=8.6Hz),7.71(d,2H,J=7.6Hz),7.48(t,2H,J=7.5Hz),7.36(t,1H,J=7.3Hz),4.25(s,3H);13C NMR(100MHz,丙酮-d6)δHRMS(ESI):C17H14N5O2 +[M+H]+计算值:320.1142,观测值:320.1127。
化合物1-162.N-(4-(叔丁基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-162)的合成
通过程序1-C,使用1-138合成化合物1-162,得到1-162(98%产率),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ9.49(brs,1H),7.95–7.90(m,2H),7.50–7.45(m,2H),4.21(s,3H),1.33(m,9H);13C NMR(100MHz,丙酮-d6)δ156.57,152.06,150.65,148.91,147.61,136.18,126.53,122.40,56.52,35.14,31.72。HRMS(ESI):C15H18N5O2 +[M+H]+计算值:300.1455,观测值:300.1464。
化合物1-163.N-(2-氟-4-(三氟甲氧基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-163)的合成
通过程序1-C,使用1-138合成化合物1-163,得到1-163(96%产率),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ9.23(brs,1H),8.30(t,1H J=8.8Hz),7.41(dd,1H,J=10.9Hz),7.35(d,1H,J=9.1Hz),4.29(s,3H);13C NMR(100MHz,丙酮-d6)δ156.36,156.16(d,J=250Hz),151.77,150.91,148.36,147.39(dq,J=11Hz),127.61(d,J=2Hz),125.43(d,J=12Hz),121.41(q,J=257Hz),118.21(d,J=4Hz),110.64(d,J=24Hz),56.86;19FNMR(376MHz,丙酮-d6)δ-58.97(s,3F),-120.20(t,1F,J=9.8Hz);HRMS(ESI):C12H8F4N5O3 +[M+H]+计算值:346.0558,观测值:346.0538。
化合物1-164.N-(4-异丙基苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-164)的合成
通过程序1-C,使用1-138合成化合物1-164,得到1-164(95%产率),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ9.48(brs,1H),7.95–7.90(m,2H),7.35–7.30(m,2H),4.22(s,3H),2.94(h,1H,J=6.9Hz),1.25(d,6H,J=6.9Hz);13C NMR(100MHz,丙酮-d6)δ156.61,152.09,150.67,147.65,146.77,136.51,127.60,122.78,56.52,34.50,24.40;HRMS(ESI):C14H16N5O2 +[M+H]+计算值:286.1299,观测值:286.1299。
化合物1-165. 6-甲氧基-N-(4-(三氟甲基)苯基)-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-165)的合成
通过程序1-C,使用1-138合成化合物1-165,得到1-165(79%产率),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ9.82(brs,1H),8.29(d,2H,J=8.8Hz),7.80(d,2H,J=8.8Hz),4.24(s,3H);19F NMR(376MHz,丙酮-d6)δ-62.62(s,3F);13C NMR(100MHz,丙酮-d6)δHRMS(ESI):C12H9F3N5O2 +[M+H]+计算值:312.0703,观测值:312.0710。
化合物1-166. 6-甲氧基-N-(3-(三氟甲基)苯基)-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-166)的合成
通过程序1-C,使用1-138合成化合物1-166,得到1-166(79%产率),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ9.76(brs,1H),8.43(brs,1H),8.31(d,1H,J=8.4Hz),7.66(t,1H,J=8.1Hz),7.53(d,1H,J=8.1Hz),4.23(s,3H);13C NMR(100MHz,丙酮-d6)δ156.24,151.51,150.50,147.69,139.48,131.35(q,J=32Hz),130.72,125.86(q,J=1Hz),125.04(q,J=272Hz),122.10(q,J=4Hz),118.85(q,J=4Hz),56.56;19F NMR(376MHz,丙酮-d6)δ-63.19(s,3F);HRMS(ESI):C12H9F3N5O2 +[M+H]+计算值:312.0703,观测值:312.0696。
化合物1-167. 6-甲氧基-N-(4-戊基苯基)-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-167)的合成
通过程序1-C,使用1-138合成化合物1-167,得到1-167(45%产率),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ9.40(brs,1H),7.90(d,2H,J=8.6Hz),7.24(d,2H,J=8.6Hz),4.20(s,3H),2.60(t,2H,J=7.8Hz),1.62(q,2H,J=7.7Hz),1.40–1.27(m,4H),0.89(t,3H,J=6.9Hz);13C NMR(100MHz,丙酮-d6)δ156.44,151.97,150.55,147.42,140.71,136.34,129.52,122.51,56.49,36.00,32.25,32.02,23.24,14.40;HRMS(ESI):C16H20N5O2 +[M+H]+计算值:314.1611,观测值:314.1619。
化合物1-168.N-(4-(叔丁基)-2-氟苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-168)的合成
通过程序1-C,使用1-138合成化合物1-168,得到1-168(88%产率),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ9.10(brs,1H),8.20(dd,1H,J=7.5Hz),7.39–7.33(m,1H),7.24–7.17(m,1H),4.29(s,3H),1.35(s,9H);13C NMR(100MHz,丙酮-d6)δ156.45,154.31(d,J=244Hz),151.99,150.87,148.58(d,J=4Hz),148.31,125.03(d,J=7Hz),123.56,115.89(d,J=20Hz),113.64(d,J=20Hz),56.89,35.39,31.83;19F NMR(376MHz,丙酮-d6)δ-129.41--129.53(m,1F);HRMS(ESI):C15H17FN5O2 +[M+H]+计算值:318.1361,观测值:318.1353。
化合物1-169.N-(4-碘苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-169)的合成
通过程序1-C,使用1-138合成化合物1-169,得到1-169(95%产率),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ9.61(brs,1H),7.91–7.87(m,2H),7.82–7.78(m,2H),4.22(s,3H);13C NMR(100MHz,丙酮-d6)δ156.53,151.84,150.68,147.72,138.82,124.63,124.53,89.12,56.62;HRMS(ESI):C11H9IN5O2 +[M+H]+计算值:369.9795,观测值:369.9810。
化合物1-170.N-(3-碘苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-170)的合成
通过程序1-C,使用1-138合成化合物1-170,得到1-170(94%产率),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ9.57(brs,1H),8.50(s,1H),8.06(d,1H,J=8.3Hz),7.59(d,1H,J=7.9Hz),7.25(t,1H,J=8.1Hz),4.23(s,3H);13C NMR(100MHz,丙酮-d6)δ156.47,151.78,150.69,147.74,140.18,134.83,131.61,131.08,121.95,94.28,56.65;HRMS(ESI):C11H9IN5O2 +[M+H]+计算值:369.9795,观测值:369.9782。
化合物1-171.N-(2-碘-4-(三氟甲氧基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-171)的合成
通过程序1-C,使用1-138合成化合物1-171,得到1-171(67%产率),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ9.09(brs,1H),8.39(d,1H,J=9.0Hz),7.96–7.93(m,1H),7.58–7.53(m,1H),4.33(s,3H);13C NMR(100MHz,丙酮-d6)δ156.19,151.53,150.66,148.01,146.95(q,J=2Hz),138.65,132.66,126.22,122.78,121.28(q,J=256Hz),94.34,57.09;19F NMR(376MHz,丙酮-d6)δ-58.78(s,3F);HRMS(ESI):C12H8IF3N5O3 +[M+H]+计算值:453.9624,观测值:453.9636。
化合物1-172.N-(2-氯-4-(三氟甲氧基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-172)的合成
通过程序1-C,使用1-138合成化合物1-172,得到1-172(98%产率),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ9.07(brs,1H),8.59(d,1H,J=9.1Hz),7.61–7.59(m,1H),7.48(d,1H,J=9.1Hz),4.32(s,3H);13C NMR(100MHz,丙酮-d6)δ156.00,151.33,150.53,147.53,146.60(q,J=2Hz),134.08,127.66,125.96,123.32,121.49,121.24(q,J=256Hz),57.10;19F NMR(376MHz,丙酮-d6)δ-58.87(s,3F);HRMS(ESI):C12H8F3ClN5O3 +[M+H]+计算值:362.0268,观测值:362.0265。
化合物1-173.N-(3-氯-4-(三氟甲氧基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-173)的合成
通过程序1-C,使用1-138合成化合物1-173,得到1-173(85%产率),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ9.68(brs,1H),8.37(d,1H,J=2.6Hz),8.02(dd,1H,J=9.0Hz),7.50(dq,1H,J=9.0Hz),4.20(s,3H);13C NMR(100MHz,丙酮-d6)δ155.81,151.08,150.18,147.14,141.74(q,J=2Hz),138.42,127.50,123.84,123.69,121.84,121.21(q,J=256Hz),56.43;19F NMR(376MHz,丙酮-d6)δ-58.79(s,3F);HRMS(ESI):C12H8F3ClN5O3 +[M+H]+计算值:362.0268,观测值:362.0265。
化合物1-174.N-(3-溴-4-(三氟甲氧基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-174)的合成
通过程序1-C,使用1-138合成化合物1-174,得到1-174(97%产率),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ9.67(brs,1H),8.50(d,1H,J=2.6Hz),8.08(dd,1H,J=9.0Hz),7.49(dq,1H,J=9.0Hz),4.20(s,3H);13C NMR(100MHz,丙酮-d6)δ155.85,151.13,150.22,147.17,143.16(q,J=2Hz),138.51,126.79,123.45,122.56,121.22(q,J=257Hz),116.21,56.47;19F NMR(376MHz,丙酮-d6)δ-58.43(s,3F);HRMS(ESI):C12H8F3BrN5O3 +[M+H]+计算值:405.9763,观测值:405.9763。
化合物1-177. 6-甲氧基-N-甲基-N-(4-(三氟甲基)苯基)-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-177)的合成
通过程序1-C,使用1-138合成化合物1-177,得到1-177(72%产率),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ7.81(d,2H,J=8.3Hz),7.62(d,2H,J=8.3Hz),3.72(s,3H),3.63(s,3H);19F NMR(376MHz,丙酮-d6)δ-62.74(s,3F);HRMS(ESI):C13H11F3N5O2 +[M+H]+计算值:326.0859,观测值:326.0845。
化合物1-178.N-(3-氟-4-(三氟甲基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-178)的合成
通过程序1-C,使用1-138合成化合物1-178,得到1-178(84%产率),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ9.91(s,1H),8.36–8.13(m,1H),8.05–7.89(m,1H),7.84–7.70(m,1H),4.23(s,3H)。19F NMR(376MHz,丙酮-d6)δ-61.28(d,J=12.3Hz),-114.52(td,J=12.7,8.2Hz)。13C NMR(101MHz,丙酮-d6)δ160.48(dq,J=252.0,2.4Hz),156.12,151.25,150.48,147.65,144.43–144.20(m),128.63–128.38(m),123.75(dd,J=269.7,1.1Hz),117.61(d,J=3.5Hz),114.45–113.26(m),109.89(d,J=26.4Hz),56.67;HRMS(ESI+):(C12H8F4N5O2+)+[M+H]-计算值:330.0609,实测值:330.0624
化合物1-181. 6-丁氧基-N-(4-(三氟甲氧基)苯基)-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-181)的合成
通过程序1-C,使用1-179合成化合物1-181,得到1-181(63%产率),其为灰白色固体:1H NMR(400MHz,丙酮-d6)δ9.70–9.52(m,1H),8.19–8.02(m,2H),7.56–7.35(m,2H),4.67(t,J=6.7Hz,2H),1.97–1.84(m,2H),1.61–1.48(m,2H),0.99(t,J=7.4Hz,3H);19F NMR(376MHz,丙酮-d6)δ-58.78(s,3F);13C NMR(101MHz,丙酮-d6)δ155.93,151.58,150.64,147.80,146.45(q,JCF=1.9Hz),137.63,124.41,122.37,121.44f(q,JCF=255.4Hz),70.40,30.88,19.68,14.02;HRMS(ESI+)m/z C15H15F3N5O3[M+H]+计算值:370.1122,实测值:370.1129。
化合物1-183. 6-异丙氧基-N-(4-(三氟甲基)苯基)-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-183)的合成
步骤1. 5-氯-6-异丙氧基-[1,2,5]噁二唑并[3,4-b]吡嗪(1-183-int))的合成
在25ml圆底烧瓶中,将5,6-二氯-[1,2,5]噁二唑并[3,4-b]吡嗪(1-2)(0.403g,2.11mmol)和Et3N(0.214g,2.11mmol)溶于10mL无水THF。加入异丙醇(0.127g,2.11mmol)。将混合物加热至45℃并搅拌16小时。将混合物浓缩并在SiO2上层析纯化,得到1-183-int(19%),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ5.58(h,J=6.2Hz,1H),1.53(d,J=6.2Hz,6H);13C NMR(100MHz,丙酮-d6)δ157.58,153.76,152.27,151.35,76.09,21.66。
步骤2. 6-异丙氧基-N-(4-(三氟甲基)苯基)-[1,2,5]噁二唑并[3,4-b]吡嗪-5-胺(1-183)的合成
在螺旋帽小瓶中,将1-183-int(0.088g,0.410mmol)溶于3mL无水THF,并加入4-(三氟甲基)苯胺(0.145g,0.902mmol)。将混合物加热至回流并搅拌16小时。第二天,将混合物浓缩并通过在SiO2上层析纯化,得到1-183(83%),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ9.65(brs,1H),8.21(d,2H,J=8.5Hz),7.78(d,2H,J=8.5Hz),5.68(h,1H,J=6.2Hz),1.52(d,6H,J=6.2Hz);13C NMR(100MHz,丙酮-d6)δ155.34,151.48,150.82,148.17,142.30,126.98(q,J=3.9Hz),126.88(q,J=32.4Hz),125.45(q,J=272.6Hz),122.82,75.30,21.76;19F NMR(376MHz,丙酮-d6)δ-62.61(s,3F);HRMS(ESI):C14H9F6IN5O2 +[M+H]+计算值:519.9705,观测值:519.9714。
化合物1-184. 6-(2-氟苯氧基)-N-(4-(三氟甲基)苯基)-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-184)的合成
在螺旋帽小瓶中,将1-2(0.300g,1.57mmol)在0℃下溶于8mL无水THF。在另一个小瓶中,将2-氟苯酚(0.166g,1.73mmol)和叔丁醇钠(0.194g,1.73mmol)在0℃下混合在2mL无水THF中。将本混合物在搅拌的同时逐滴加入初始小瓶中。随后加入4-(三氟甲基)苯胺(0.506g,3.14mmol)。将混合物回流并搅拌16小时。第二天,将混合物浓缩并在SiO2上层析纯化,得到1-184(18%),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ10.21(brs,1H),8.38(d,2H,J=8.4Hz),7.84(d,2H,J=8.4Hz),7.56(td,1H,J=7.8,1.6Hz),7.53–7.36(m,3H);19FNMR(376MHz,丙酮-d6)δ-62.57(s,3F),-129.41--129.49(m,1F);HRMS(ESI):C14H9F6IN5O2 +[M+H]+计算值:519.9705,观测值:519.9714。
化合物1-185. 6-(4-(三氟甲基)苯氧基)-N-(4-(三氟甲基)苯基)-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-185)的合成
在螺旋帽小瓶中,将1-2(0.150g,0.785mmol)在0℃下溶于3mL无水THF。在另一个小瓶中,将4-(三氟甲基)苯酚(0.127g,0.785mmol)和叔丁醇钠(0.076g,0.785mmol)在0℃下混合在2mL无水THF中。将本混合物在搅拌的同时逐滴加入初始小瓶中。随后加入4-(三氟甲基)苯胺(0.506g,3.14mmol)。将混合物回流并搅拌16小时。第二天,将混合物浓缩并通过在SiO2上层析纯化,得到1-185(45%),其为黄色固体:1H NMR(400MHz,丙酮-d6)δ10.20(brs,1H),8.36(d,2H,J=8.4Hz),7.97(d,2H,J=8.4Hz),7.84(d,2H,J=8.5Hz),7.73(d,2H,J=8.5Hz);19F NMR(376MHz,丙酮-d6)δ-62.62(s,3F),-62.72(s,3F);HRMS(ESI):C18H10F6N5O2 +[M+H]+计算值:442.0733,观测值:442.0726。
化合物1-187.N-(2-氟苯基)-6-(2,2,2-三氟乙氧基)-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-187)的合成
将含有1-2(0.21g,1.1mmol)的圆底烧瓶排空并用N2冲洗(3次)。然后,在N2气氛下,将固体在冰浴中冷却,并依次用干燥THF(3mL)、2-氟苯胺(0.10mL,1.0mmol)和Et3N(0.15mL,1.1mmol)稀释。将所得的红色溶液在冰浴中冷却,搅拌2.5小时,过滤以去除盐,用EtOAc冲洗,浓缩以去除溶剂,通过SiO2塞(CH2Cl2),浓缩为粗黄色/橙色固体(0.179g)。将圆底烧瓶中的粗固体(0.179g)排空,并用N2重填充(3次)。然后,将固体依次用无水THF(3mL)、2,2,2-三氟乙醇(0.15mL,2.1mmol)和Et3N(0.15mL,1.1mmol)稀释。将所得的混合物在室温下在N2气氛下搅拌17小时,过滤以去除盐,用EtOAc冲洗,并浓缩为红色固体。固体通过在SiO2上层析(梯度:10-15%EtOAc/己烷)纯化,得到1-187(34%),其为浅黄色固体:1H NMR((CD3)2CO,500MHz)δ9.31(s,1H),8.08(t,J=7.8Hz,1H),7.38-7.30(m,3H),5.32(q,J=8.5Hz,2H);13C NMR((CD3)2CO,125MHz)δ156.5(d,JCF=247Hz),154.5,152.1,150.2,147.8,128.6(d,JCF=8.0Hz),126.85,125.8(d,JCF=11.4Hz),125.5(d,JCF=3.8Hz),124.1(q,JCF=277Hz),116.6(d,JCF=19.6Hz),65.12(q,JCF=37.1Hz).19F NMR((CD3)2CO,376MHz)δ-73.7(t,J=8.5Hz,3F),-124.6to-124.7(m,1F);HRMS(ESI-)m/z C12H6F4N5O2(M-H)-计算值:328.0463,实测值:328.0492。
化合物1-199. 5-甲氧基-6-(4-(三氟甲基)苯氧基)-[1,2,5]噁二唑并[3,4-B]吡嗪(1-199)的合成
在6打兰小瓶中,将1-138(0.295g,1.57mmol)在0℃溶于5mL干燥THF。在另一个小瓶中,将4-(三氟甲基)苯酚(0.140g,1.49mmol)和叔丁醇钠(0.143g,1.49mmol)在0℃下混合在3mL干燥THF中。将本混合物在搅拌的同时逐滴加入初始6打兰小瓶中。将最终混合物回流并搅拌0.5小时,然后浓缩和并经由快速层析纯化,得到1-199(21%),其为灰白色固体。1H NMR((CD3)2CO,400MHz)δ7.93(d,2H,J=8.4Hz),7.64(d,2H,J=8.4Hz),4.29(s,3H);13CNMR(100MHz,丙酮-d6)δ157.43,156.64,155.53(q,J=1.5Hz),151.70,150.93,129.26(q,J=32.6Hz),128.31(q,J=3.8Hz),125.07(q,J=271.1Hz),123.65,56.92;19F NMR(376MHz,丙酮-d6)δ-62.76(s,3F);HRMS(ESI):C12H11F3N5O3 +[M+NH4]+计算值:330.0808,观测值:330.0805。
化合物1-200. 6-乙氧基-N-(2-氟-4-(三氟甲氧基)苯基)-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-200)的合成
在6打兰小瓶中,将1-163(0.1200g,0.348mmol)溶于1.70mL 3:1乙醇/二噁烷。加入碳酸钠(0.1105g,1.043mmol),并将混合物加热至90℃并搅拌16小时。将所得的混合物减压浓缩,并经由快速层析(0-15%EtOAc的己烷溶液)纯化,得到1-200(82%产率),其为黄色固体。1H NMR((CD3)2CO,400MHz)δ9.16(s,1H),8.31(t,1H,J=8.8Hz),7.41–7.36(m,1H),7.35–7.30(m,1H),4.73(q,2H,J=7.1Hz),1.54(t,3H,J=7.1Hz);13C NMR(100MHz,丙酮-d6)δ155.91(d,J=250.6Hz),155.55,151.44,150.74,148.11,147.19(dq,J=10.6,1.9Hz),127.24,125.29(d,J=11.3Hz),121.27(q,J=257.0Hz),118.04(d,J=3.8Hz),110.42(dq,J=23.7,1.2Hz),66.84,14.08;19F NMR(376MHz,丙酮-d6)δ-58.94(s,3F),-120.46--120.55(m,1F);HRMS(ESI):C13H10F4N5O3 +[M+H]+计算值:360.0720,观测值:360.0727。
化合物1-201.N-(2-氟-4-(三氟甲氧基)苯基)-6-丙氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-201)的合成
在6打兰小瓶中,将1-163(0.1000g,0.290mmol)溶于1.33mL 3:1丙醇/二噁烷。加入碳酸钠(0.0921g,0.869mmol),并将混合物加热至90℃并搅拌16小时。将所得的混合物减压浓缩,并经由快速层析(0-15%EtOAc的己烷溶液)纯化,得到1-201(93%产率),其为黄色固体。1H NMR((CD3)2CO,400MHz)δ9.14(s,1H),8.32(t,1H,J=8.8Hz),7.43–7.37(m,1H),7.37–7.30(m,1H),4.65(t,2H,J=6.6Hz),1.97(h,2H,J=7.4Hz),1.11(t,3H,J=7.4Hz);13C NMR(100MHz,丙酮-d6)δ155.76,151.52,150.81,148.19,147.22(dq,J=10.7,2.3Hz),127.26(d,J=1.6Hz),125.40(d,J=11.1Hz),121.33(q,J=256.7Hz),118.13(dd,J=3.9,1.0Hz),110.48(dd,J=23.7,1.0Hz),72.29,22.28,10.64;19F NMR(376MHz,丙酮-d6)δ-58.98(s,3F),-120.8--120.90(m,1F);HRMS(ESI):C14H12F4N5O3 +[M+H]+计算值:374.0871,观测值:374.0870。
化合物1-202.N-(2-氟-4-(三氟甲基)苯基)-6-甲氧基-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-202)的合成
通过程序1-C,使用1-138合成化合物1-202,得到1-202(87%产率),其为黄色固体。1H NMR((CD3)2CO,400MHz)δ9.23(s,1H),8.63–8.57(m,1H),7.75–7.67(m,2H),4.31(s,3H);19F NMR(376MHz,丙酮-d6)δ-62.86(s,3F),-123.84(t,1F,J=9.7Hz);HRMS(ESI):C13H10F4N5O3 +[M+H]+计算值:
化合物1-203. 6-乙氧基-N-(4-(三氟甲氧基)苯基)-[1,2,5]噁二唑并[3,4-B]吡嗪-5-胺(1-203)的合成
在6打兰小瓶中,将1-156(0.1000g,0.499mmol)溶于1.70mL 3:1乙醇/二噁烷。加入碳酸钠(0.1600g,1.500mmol),并将混合物加热至90℃并搅拌16小时。将所得的混合物减压浓缩,并经由快速层析(0-15%EtOAc的己烷溶液)纯化,得到1-203(82%产率),其为黄色固体。1H NMR(400MHz,丙酮-d6)δ9.65(s,1H),8.16–8.04(m,2H),7.45–7.38(m,2H),4.71(qd,J=7.0,1.1Hz,2H),1.51(qt,J=7.1,1.0Hz,3H).19F NMR(376MHz,丙酮-d6)δ-58.76(s3F)。13C NMR(101MHz,丙酮-d6)δ155.80,151.57,150.62,147.77,146.42(q,J=2.0Hz),137.68,124.28,122.37,121.44(q,J=255.3Hz),66.61,14.13。
实例82.化合物的生物活性
通过确定氧消耗速率(OCR)的增加来确定所合成的化合物的生物活性。
通常根据Kenwood BM等人(《分子计量学(Mol.Met.)》,(2014)3:114-123)的方法测量整个细胞中的氧消耗速率(OCR)。
使用Seahorse XF-24通量分析仪(海马生物科学公司(Seahorse Biosciences),北比尔里卡,马萨诸塞州)测量OCR。将NMuLi、C2C12和L6细胞以3.5x104个细胞/孔的密度接种在Seahorse 24孔组织培养板中,将分离的心肌细胞以4x104个细胞/孔的密度接种,并将人原代成纤维细胞以1.1x104个细胞/孔的密度接种。然后,使细胞粘附24小时。在测定之前,将培养基换成含有丙酮酸盐和谷氨酰胺的无缓冲DMEM(Gibco#12800-017,在37℃下pH=7.4),并在37℃下将细胞平衡30分钟。在测定期间注射化合物,并使用2分钟的测量时间段测量OCR。
每种条件使用2-3个孔,并对三个板求平均(n=6-9)。统计显著性通过双因素ANOVA以及邦弗朗尼事后检验确定。
活性(OCR的增加)在表1中列出。活性以归入统计堆的EC50值报告:A=5μM或更小;B=>5到20μM;C=超过20μM;NA=无作用。
实例83.饮食诱发的肥胖症小鼠研究
将3月龄雄性C57BL/6J小鼠分配到正常饮食(Chow,n=5)或西式饮食(WD,n=10)28天。28天后,将WD组的一半换成含有化合物2-21(其浓度导致消耗~40mg/kg/天1-112(2-21 40mpk))的WD。如所指示,记录体重(A)、脂肪量(通过EchoMRI(B)测量)和食物摄入(C,最后14天)。接受含有2-21的WD的小鼠体重和脂肪量减少,而食物摄入没有显著变化。
实例83.ROS产生测定
本公开的某些化合物还降低了ROS产生,这可以在本测定中测量。将L6成肌细胞接种到L6生长培养基中的黑壁透明底部96孔微孔板中,并使其生长至汇合。然后,将细胞用PBS洗涤两次,并在5%CO2/95%空气中于37℃下与7.5μM CM-H2DCFDA和补充有25mM D-葡萄糖的0.5ng/μL每种命中化合物或媒剂对照(DMSO)的KRP缓冲液(136mM NaCl、4.7mM KCl、10mM NaPO4、0.9mM MgSO4、0.9mM CaCl2,pH 7.4)的溶液共同温育1小时。使用100nM H2O2作为ROS产生的阳性对照。在温育之后,将细胞用PBS洗涤三次以去除过量的探针。然后,将细胞用100μL/孔PBS覆盖,并通过TecanM200酶标仪(帝肯集团公司(Tecan GroupLtd.),瑞士)使用顶部读数配置并将激发和发射滤光片分别设置为495±9nm和530±20nm来测量荧光强度。荧光数据记录在Magellan(版本6.4)软件上,并导出到Microsoft Excel以进行后续分析。从每个孔减去背景荧光(从不接收CM-H2DCFDA探针的孔发出的荧光)后,以每种条件的媒剂对照的荧光百分比表示ROS产生。消除了将ROS水平提高20%以上的化合物。
Claims (32)
1.一种式I-A或I-B的化合物
或其药学上可接受的盐,其中
X1和X2为C或N,其中X1和X2中至少一个为N;
X3为H、C1-C4烷基、C1-C2卤代烷基、苯基或卤素取代苯基;
Y为O或NR;
Y1为O或NR1;
Z为O或S;
R为H或甲基;
R1为氢或C1-C8烷基、C2-C8烯基或C2-C8炔基;
R2为C1-C8烷基、C2-C8烯基或C2-C8炔基;或
R2为-C0-C4烷基(C3-C7环烷基)、-C0-C4烷基(桥联C7-C12环烷基)、-C0-C4烷基(芳基)、-C0-C4烷基(单环或双环杂芳基)或-C0-C4烷基(4到7元杂环烷基),其中的每一个任选地被一个或多个独立地选自以下的取代基取代:R11和0或1个取代基R12;或
R1和R2连结以形成3到7元环,其中一个碳任选地由N、S或O置换;
R3为H或C1-C8烷基、C2-C8烯基或C2-C8炔基,或
R3为-C0-C4烷基(C3-C7环烷基)、-C0-C4烷基(芳基)或-C0-C4烷基(杂芳基),其中的每一个任选地被一个或多个独立地选择的R11取代基取代;
其中在R1、R2和R3的定义中的每个C0-C4烷基、C1-C8烷基、C2-C8烯基或C2-C8炔基中,一个或多个碳原子任选地由O、NR10、-C(O)-、-C(O)O-、-OC(O)、-S(O)n-、-S(O)nNR10、-NR10S(O)n-、-NR10C(O)NR10、-C(O)NR10-或-NR10C(O)-置换,其中n为0、1或2,并且其中所述C0-C4烷基、C1-C8烷基、C2-C8烯基或C2-C8炔基任选地被一个或多个取代基R13取代;
在每次出现时,R10独立地选自氢、C1-C6烷基和-C0-C2烷基(C3-C7环烷基);
在每次出现时,R11独立地选自卤素、羟基、氨基、硝基、氰基、-CHO、-COOH、氧代、卤代巯基以及C1-C8烷基、C2-C8烯基和C2-C8炔基,其中在R11的定义中的每个C1-C8烷基、C2-C8烯基和C2-C8炔基中,一个或多个碳原子任选地由O、NR10、-C(O)-、-C(O)O-、-OC(O)、-S(O)n-、-C(O)NR10-或-NR10C(O)-置换,其中n为0、1或2,并且其中每个C0-C4烷基、C1-C8烷基、C2-C8烯基或C2-C8炔基任选地被一个或多个取代基R13取代;
R12选自-C0-C4烷基(C3-C7环烷基)、-O-C0-C4烷基(C3-C7环烷基)、-C0-C4烷基(芳基)、-O-C0-C4烷基(芳基)、-C0-C4烷基(5到6元杂芳基)、-O-C0-C4烷基(5到6元杂芳基)、-C0-C4烷基(5到6元杂环烷基)和-O-C0-C4烷基(5到6元杂环烷基),其中的每一个任选地被一个或多个独立地选自以下的取代基取代:卤素、羟基、氨基、硝基、氰基、-CHO、-COOH、氧代、C1-C2卤代烷基、C1-C2卤代烷氧基、C1-C6烷基、C1-C6烷氧基、C1-C6烷基酯、-C0-C4烷基(单或二C1-C6烷基氨基)、C2-C6烷酰基、C2-C6烯基和C2-C6炔基;并且
在每次出现时,R13独立地选自卤素、羟基、氨基、硝基、氰基、-CHO、-COOH、氧代、C3-C7环烷基和苯基。
4.根据权利要求1到3中任一项所述的化合物或其盐,其中Y为N-R。
5.根据权利要求1到4中任一项所述的化合物或其盐,其中Z为O,并且X1和X2均为氮。
6.根据权利要求1到4中任一项所述的化合物或其盐,其中Z为O,并且X1和X2中的一个为氮,而另一个为碳。
7.根据权利要求1到6中任一项所述的化合物或其盐,其中X3为氢、甲基、三氟甲基、五氟乙基、苯基或氟取代苯基。
8.根据权利要求7所述的化合物或其盐,其中X3为三氟甲基。
9.根据权利要求1到8中任一项所述的化合物或其盐,其中R为氢。
10.根据权利要求1到9中任一项所述的化合物或其盐,其中Y1是NR1,并且R1为氢或未取代的C1-C6烷基。
11.根据权利要求10所述的化合物或其盐,其中R1为氢。
12.根据权利要求1到11中任一项所述的化合物或其盐,其中R2为-C0-C4烷基(C3-C7环烷基)、-C0-C4烷基(桥联C7-C12环烷基)、-C0-C4烷基(芳基)、-C0-C4烷基(单环或双环杂芳基)或-C0-C4烷基(4到7元杂环烷基),其中的每一个任选地被一个或多个独立地选自以下的取代基取代:R11和0或1个取代基R12;
在每个C0-C4烷基中,一个或多个碳原子任选地由O、NR10、-C(O)-、-C(O)O-、-OC(O)、-S(O)n-、-C(O)NR10-或-NR10C(O)-置换,其中n为0、1或2,并且其中所述C0-C4烷基、C1-C8烷基、C2-C8烯基或C2-C8炔基任选地被一个或多个取代基R13取代。
13.根据权利要求12所述的化合物或其盐,其中
R2为-C0-C4烷基(桥联C7-C12环烷基)或-C0-C4烷基(芳基),其中的每一个任选地被一个或多个独立地选自以下的取代基取代:R11和0或1个取代基R12;
在C0-C4烷基中,一个或多个碳原子任选地由O、NR10、-C(O)-、-C(O)O-,-OC(O)、-S(O)n-、-C(O)NR10-或-NR10C(O)-置换,其中n为0、1或2,并且其中所述C0-C4烷基任选地被R13取代。
14.根据权利要求13所述的化合物或其盐,其中
R2为-C0-C4烷基(苯基)、萘基或芴基,其中的每一个任选地被一个或多个独立地选自以下的取代基取代:R11和0或1个取代基R12;
在C0-C4烷基中,一个或多个碳原子任选地由O、NR10、-C(O)-、-C(O)O-、-OC(O)、-S(O)n-、-C(O)NR10-或-NR10C(O)-置换,其中n为0、1或2,并且其中所述C0-C4烷基任选地被R13取代。
15.根据权利要求13所述的化合物或其盐,其中
R2为苯基,其任选地由一个或多个独立地选自R11的取代基取代。
16.根据权利要求12所述的化合物或其盐,其中
R2为苯基,其任选地由一个或多个独立地选自以下的取代基取代:卤素、羟基、氨基、硝基、氰基、氧代、卤代巯基以及C1-C8烷基、C2-C8烯基和C2-C8炔基,其中在每个C1-C8烷基、C2-C8烯基和C2-C8炔基中,一个或多个碳原子任选地由O、NR10、-C(O)O-、-OC(O)或-S(O)n-置换,其中n为0、1或2,并且其中每个C1-C8烷基、C2-C8烯基或C2-C8炔基任选地被一个或多个取代基R13取代。
17.根据权利要求12所述的化合物或其盐,其中:
R2为-C0-C4烷基(苯基),其任选地被一个或多个独立地选自以下的取代基取代:R11和0或1个取代基R12;
在C0-C4烷基中,一个或多个碳原子任选地由O、NR10、-C(O)-、-C(O)O-、-OC(O)、-S(O)n-、-C(O)NR10-或-NR10C(O)-置换,其中n为0、1或2,并且其中所述C0-C4烷基任选地由R13取代;
R12选自-C0-C4烷基(C3-C7环烷基)、-O-C0-C4烷基(C3-C7环烷基)、-C0-C4烷基(苯基)、-O-C0-C4烷基(苯基)、-C0-C4烷基(5到6元杂芳基)、-O-C0-C4烷基(5到6元杂芳基),其中的每一个任选地被一个或多个独立地选自以下的取代基取代:卤素、羟基、氨基、硝基、氰基、-CHO、-COOH、氧代、C1-C2卤代烷基、C1-C2卤代烷氧基、C1-C6烷基、C1-C6烷氧基、C1-C6烷基酯、-C0-C4烷基(单或二C1-C6烷基氨基)、C2-C6烷酰基、C2-C6烯基和C2-C6炔基。
18.根据权利要求1所述的化合物或其盐,其中
Y1为NR1,并且R1为氢或甲基;并且
R2为萘基,或
R2为苯基,其被1、2或3个独立地选自以下的取代基取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C2卤代烷基和C1-C2卤代烷氧基,或
R2为苯基,其任选地被1或2个独立地选自以下的取代基取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C2卤代烷基和C1-C2卤代烷氧基,并且其被一个苯基取代基取代,所述苯基取代基任选地被1、2或3个独立地选自以下的取代基取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C2卤代烷基和C1-C2卤代烷氧基。
19.一种化合物或其盐,其中Y为NR1。
20.根据权利要求1到19中任一项所述的化合物或其盐,其中
R3为氢。
21.根据权利要求1到19中任一项所述的化合物或其盐,其中
R3为C1-C8烷基、C2-C8烯基或C2-C8炔基,
在R3的C1-C8烷基、C2-C8烯基或C2-C8炔基中,一个或多个碳原子任选地由O、NR10、C(O)O-、-OC(O)或-S(O)n-置换,其中n为0、1或2,并且其中所述C1-C8烷基、C2-C8烯基或C2-C8炔基任选地被一个或多个取代基R13取代。
22.根据权利要求20所述的化合物或其盐,其中
R3为C1-C6烷基,其任选地被羟基、卤素、三氟甲基或三氟甲氧基取代。
23.根据权利要求1到19中任一项所述的化合物或其盐,其中
R3为-C0-C4烷基(C3-C7环烷基)或-C0-C4烷基(芳基),其任选地被一个或多个独立地选择的R11取代基取代。
24.根据权利要求1所述的化合物或其盐,其中
X1和X2均为N;
X3为甲基、三氟甲基、苯基或3-氟苯基;
Y为NR1,并且R1为氢或甲基;
Z为O;
R为氢或甲基;
R1为氢或C1-C2烷基;
R2为萘基,或
R2为苯基,其被1、2或3个独立地选自以下的取代基取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C2卤代烷基和C1-C2卤代烷氧基,或
R2为苯基,其任选地被1或2个独立地选自以下的取代基取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C2卤代烷基和C1-C2卤代烷氧基,并且其被一个苯基取代基取代,所述苯基取代基任选地被1,2或3个独立地选自以下的取代基取代:卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C2卤代烷基和C1-C2卤代烷氧基;并且
R3为H或任选地被羟基或三氟甲基取代的C1-C6烷基。
25.根据权利要求1所述的化合物或其盐,其中所述化合物为:
6-甲氧基-N-(4-(三氟甲氧基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(4-(正丁基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(2-氟-5-(三氟甲基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(3-(三氟甲氧基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(2-甲基-5-(三氟甲基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(2-氟-3-(三氟甲基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(3-氟苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-(3,5-双(三氟甲基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-(2-氟苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺
6-甲氧基-N-(对甲苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-苯基-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
N-(4-甲氧基苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(3-氟-4-(三氟甲氧基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(2-氟-4-(三氟甲基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(3,5-二氟苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(2,3-二氟苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(2-氟苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
N-([1,1'-联苯]-4-基)-6-甲氧基-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(4-(叔丁基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(萘-2-基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(2-氟-4-(三氟甲氧基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(4-(三氟甲基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(3-氟-4-(三氟甲基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(4-乙基苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(4-异丙基苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(4-氯苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺
6-甲氧基-N-(2-氟-4-戊基苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(3-氟-4-戊基苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(4-戊基苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;~
6-甲氧基-N-(4-碘苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;2-30
6-甲氧基-N-(3-碘苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(3-(三氟甲基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-N-(2-氟-4-(叔丁基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-2-(全氟乙基)-N-(4-(三氟甲氧基)苯基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-丁氧基-N-(4-(三氟甲氧基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-(2,2,2-三氟乙氧基)-N-(4-(三氟甲氧基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-乙氧基-N-(4-(三氟甲氧基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;2-37
6-乙氧基-N-(2-氟-4-(三氟甲氧基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-丙氧基-N-(2-氟-4-(三氟甲氧基)苯基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
6-甲氧基-2-(三氟甲基)-5-(4-(三氟甲基)苯氧基)-1H-咪唑并[4,5-b]吡嗪;2-40
N-(2-碘-4-(三氟甲氧基)苯基)-6-甲氧基-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
N-(2-氯-4-(三氟甲氧基)苯基)-6-甲氧基-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
N-(3-氯-4-(三氟甲氧基)苯基)-6-甲氧基-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
N-(3-溴-4-(三氟甲氧基)苯基)-6-甲氧基-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
5-异丙氧基-2-(三氟甲基)-N-(4-(三氟甲基)苯基)-1H-咪唑并[4,5-b]吡嗪-6-胺;
5-(2-氟苯氧基)-2-(三氟甲基)-N-(4-(三氟甲基)苯基)-1H-咪唑并[4,5-b]吡嗪-6-胺;
2-(三氟甲基)-5-(4-(三氟甲基)苯氧基)-N-(4-(三氟甲基)苯基)-1H-咪唑并[4,5-b]吡嗪-6-胺;
2-(三氟甲基)-5,6-双(4-(三氟甲基)苯氧基)-1H-咪唑并[4,5-b]吡嗪;
5-甲氧基-N-甲基-2-(三氟甲基)-N-(4-(三氟甲基)苯基)-1H-咪唑并[4,5-b]吡嗪-6-胺;
5-甲氧基-N-(4-(三氟甲基)苯基)-1H-咪唑并[4,5-b]吡嗪-6-胺;
5-甲氧基-2-甲基-N-(4-(三氟甲基)苯基)-1H-咪唑并[4,5-b]吡嗪-6-胺;
5-((4-(三氟甲氧基)苯基)氨基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-6-醇;
5-((2-氟-4-(三氟甲氧基)苯基)氨基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-6-醇;
5-((2-氟-3-(三氟甲基)苯基)氨基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-6-醇;
5-((4-(三氟甲基)苯基)氨基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-6-醇;2-55
5-((4-(叔丁基)苯基)氨基)-2-(三氟甲基)-1H-咪唑并[4,5-b]吡嗪-6-醇;
6-甲氧基-1-甲基-2-(三氟甲基)-N-(4-(三氟甲基)苯基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
5-甲氧基-1-甲基-2-(三氟甲基)-N-(4-(三氟甲基)苯基)-1H-咪唑并[4,5-b]吡嗪-6-胺;
1-甲基-2-(三氟甲基)-6-((4-(三氟甲基)苯基)氨基)-1H-咪唑并[4,5-b]吡嗪-5-醇;
6-甲氧基-2-苯基-N-(4-(三氟甲氧基)苯基)-1H-咪唑并[4,5-b]吡嗪-5-胺;
2-(3-氟苯基)-6-((2-氟苯基)氨基)噁唑并[4,5-b]吡嗪-5-醇;或
6-((3,5-双(三氟甲基)苯基)氨基)-2-(3-氟苯基)噁唑并[4,5-b]吡嗪-5-醇。
26.一种药物组合物,其包括根据权利要求1到25中任一项所述的化合物或其盐以及药学上可接受的载剂。
27.一种治疗对线粒体解偶联有反应的病状或降低患上所述病状的风险的方法,其包括向需要这种治疗的患者施用治疗有效量的根据权利要求1到25中任一项所述的化合物或盐。
28.根据权利要求27所述的方法,其中所述对线粒体解偶联有反应的病状是肥胖症、II型糖尿病、脂肪肝疾病、胰岛素抵抗、癌症、多发性硬化、亨廷顿舞蹈病、阿尔茨海默氏痴呆症、帕金森氏病、缺血再灌注损伤、心力衰竭、非酒精性脂肪肝疾病(NALFD)或非酒精性脂肪性肝炎(NASH)。
29.一种调节患者中的葡萄糖稳态或胰岛素作用的方法,其包括向所述患者施用治疗有效量的根据权利要求1到25中任一项所述的化合物或盐。
30.一种治疗患者中的高脂血症、糖血症、葡萄糖耐量、胰岛素敏感性、脂肪过多、胰岛素抵抗、肥胖症或糖尿病的方法,其包括向所述患者施用治疗有效量的根据权利要求1到25中任一项所述的化合物。
31.一种用于降低有患癌症风险的患者中的癌症风险的方法,其包括向所述患者施用治疗有效量的根据权利要求1到25中任一项所述的化合物。
32.根据权利要求27所述的方法,其中所述对线粒体解偶联有反应的病状是癌症,并且所述癌症是癌细胞p53表达或活性受损的癌症、癌细胞具有Ras突变的癌症、癌细胞具有β-连环蛋白突变的癌症、肾上腺皮质癌、黑素瘤、原发性结肠癌或肝转移癌。
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CN201980038852.0A Pending CN112261941A (zh) | 2018-04-20 | 2019-04-22 | 可用作线粒体解偶联剂的氨基吡嗪及相关化合物 |
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