CN111848600B - 2,4,4-三取代二氢噁唑衍生物及其用途 - Google Patents
2,4,4-三取代二氢噁唑衍生物及其用途 Download PDFInfo
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- CN111848600B CN111848600B CN202010749278.4A CN202010749278A CN111848600B CN 111848600 B CN111848600 B CN 111848600B CN 202010749278 A CN202010749278 A CN 202010749278A CN 111848600 B CN111848600 B CN 111848600B
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- methyl
- dihydrooxazole
- triazol
- phenyl
- biphenyl
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- -1 2,4, 4-trisubstituted dihydrooxazole Chemical class 0.000 title claims abstract description 26
- 239000003814 drug Substances 0.000 claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 206010017533 Fungal infection Diseases 0.000 claims abstract description 12
- 208000031888 Mycoses Diseases 0.000 claims abstract description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 65
- 241001480037 Microsporum Species 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 241000222122 Candida albicans Species 0.000 claims description 12
- 229940095731 candida albicans Drugs 0.000 claims description 10
- 238000006467 substitution reaction Methods 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- 241001225321 Aspergillus fumigatus Species 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- FCMUIKBWXRDRMN-UHFFFAOYSA-N 4-(2,4-difluorophenyl)-2-[4-(3-fluorophenyl)phenyl]-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC=C(C=C1)C1=CC(=CC=C1)F)C1=C(C=C(C=C1)F)F FCMUIKBWXRDRMN-UHFFFAOYSA-N 0.000 claims description 4
- 241000221204 Cryptococcus neoformans Species 0.000 claims description 4
- 241000223238 Trichophyton Species 0.000 claims description 4
- 229940091771 aspergillus fumigatus Drugs 0.000 claims description 4
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- GERWUIDIGDBAGO-UHFFFAOYSA-N 1-[4-[4-[4-phenyl-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazol-2-yl]phenyl]piperazin-1-yl]ethanone Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC=C(C=C1)N1CCN(CC1)C(C)=O)C1=CC=CC=C1 GERWUIDIGDBAGO-UHFFFAOYSA-N 0.000 claims description 3
- CSAMVZSMGPDVPI-UHFFFAOYSA-N 2-(6-bromo-1-benzothiophen-2-yl)-4-(2,4-dichlorophenyl)-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC2=C(S1)C=C(C=C2)Br)C2=C(C=C(C=C2)Cl)Cl CSAMVZSMGPDVPI-UHFFFAOYSA-N 0.000 claims description 3
- NSHUZONZAYANBP-UHFFFAOYSA-N 2-(6-bromo-1-benzothiophen-2-yl)-4-(2,4-difluorophenyl)-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC2=C(S1)C=C(C=C2)Br)C2=C(C=C(C=C2)F)F NSHUZONZAYANBP-UHFFFAOYSA-N 0.000 claims description 3
- OQJHOAOJXPNANZ-UHFFFAOYSA-N 2-(6-bromo-1-benzothiophen-2-yl)-4-(3,5-difluorophenyl)-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC2=C(S1)C=C(C=C2)Br)C2=CC(=CC(=C2)F)F OQJHOAOJXPNANZ-UHFFFAOYSA-N 0.000 claims description 3
- RDYVQGAFJVBGSH-UHFFFAOYSA-N 2-(6-bromo-1-benzothiophen-2-yl)-4-(4-chlorophenyl)-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC2=C(S1)C=C(C=C2)Br)C2=CC=C(C=C2)Cl RDYVQGAFJVBGSH-UHFFFAOYSA-N 0.000 claims description 3
- XQGUANABEGFDSR-UHFFFAOYSA-N 2-(6-bromo-1-benzothiophen-2-yl)-4-(4-fluorophenyl)-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC2=C(S1)C=C(C=C2)Br)C2=CC=C(C=C2)F XQGUANABEGFDSR-UHFFFAOYSA-N 0.000 claims description 3
- KYZKMSXMEHOMGN-UHFFFAOYSA-N 2-(6-chloro-1-benzothiophen-2-yl)-4-(2,4-dichlorophenyl)-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC2=C(S1)C=C(C=C2)Cl)C2=C(C=C(C=C2)Cl)Cl KYZKMSXMEHOMGN-UHFFFAOYSA-N 0.000 claims description 3
- DYKQCQVMNLYFGC-UHFFFAOYSA-N 2-(6-chloro-1-benzothiophen-2-yl)-4-(2,4-difluorophenyl)-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC2=C(S1)C=C(C=C2)Cl)C2=C(C=C(C=C2)F)F DYKQCQVMNLYFGC-UHFFFAOYSA-N 0.000 claims description 3
- KQFPZMUJFKULRN-UHFFFAOYSA-N 2-(6-chloro-1-benzothiophen-2-yl)-4-(3,5-difluorophenyl)-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC2=C(S1)C=C(C=C2)Cl)C2=CC(=CC(=C2)F)F KQFPZMUJFKULRN-UHFFFAOYSA-N 0.000 claims description 3
- HDRXGGWSEWGELG-UHFFFAOYSA-N 2-(6-chloro-1-benzothiophen-2-yl)-4-(4-chlorophenyl)-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC2=C(S1)C=C(C=C2)Cl)C2=CC=C(C=C2)Cl HDRXGGWSEWGELG-UHFFFAOYSA-N 0.000 claims description 3
- KTOAMCQQWXLGKV-UHFFFAOYSA-N 2-(6-chloro-1-benzothiophen-2-yl)-4-(4-fluorophenyl)-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC2=C(S1)C=C(C=C2)Cl)C2=CC=C(C=C2)F KTOAMCQQWXLGKV-UHFFFAOYSA-N 0.000 claims description 3
- SRKWWDJZMJKUBV-UHFFFAOYSA-N 2-(6-chloro-1-benzothiophen-2-yl)-4-(4-fluorophenyl)-4-(tetrazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=NN=C1)CC1(N=C(OC1)C1=CC2=C(S1)C=C(C=C2)Cl)C2=CC=C(C=C2)F SRKWWDJZMJKUBV-UHFFFAOYSA-N 0.000 claims description 3
- JIBRROSJWTWYEC-UHFFFAOYSA-N 2-(6-fluoro-1-benzothiophen-2-yl)-4-(4-fluorophenyl)-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC2=C(S1)C=C(C=C2)F)C2=CC=C(C=C2)F JIBRROSJWTWYEC-UHFFFAOYSA-N 0.000 claims description 3
- KDGLBQTTXTVHQZ-UHFFFAOYSA-N 2-phenyl-5-[4-[4-phenyl-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazol-2-yl]phenyl]-1,3,4-oxadiazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC=C(C=C1)C=1OC(=NN1)C1=CC=CC=C1)C1=CC=CC=C1 KDGLBQTTXTVHQZ-UHFFFAOYSA-N 0.000 claims description 3
- NMGKXVFWEOQFJT-UHFFFAOYSA-N 4-(2,4-dichlorophenyl)-2-(6-fluoro-1-benzothiophen-2-yl)-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC2=C(S1)C=C(C=C2)F)C2=C(C=C(C=C2)Cl)Cl NMGKXVFWEOQFJT-UHFFFAOYSA-N 0.000 claims description 3
- PXGSQTSUZKLFDR-UHFFFAOYSA-N 4-(2,4-dichlorophenyl)-2-[4-(2-fluorophenyl)phenyl]-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC=C(C=C1)C1=C(C=CC=C1)F)C1=C(C=C(C=C1)Cl)Cl PXGSQTSUZKLFDR-UHFFFAOYSA-N 0.000 claims description 3
- GCYKPNFVRKLBMD-UHFFFAOYSA-N 4-(2,4-difluorophenyl)-2-[4-(2-fluorophenyl)phenyl]-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC=C(C=C1)C1=C(C=CC=C1)F)C1=C(C=C(C=C1)F)F GCYKPNFVRKLBMD-UHFFFAOYSA-N 0.000 claims description 3
- DYJCMBOEWYSYCV-UHFFFAOYSA-N 4-(3,5-difluorophenyl)-2-(6-fluoro-1-benzothiophen-2-yl)-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC2=C(S1)C=C(C=C2)F)C2=CC(=CC(=C2)F)F DYJCMBOEWYSYCV-UHFFFAOYSA-N 0.000 claims description 3
- RFBQORKKYIOIDP-UHFFFAOYSA-N 4-(3,5-difluorophenyl)-2-[4-(2-fluorophenyl)phenyl]-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC=C(C=C1)C1=C(C=CC=C1)F)C1=CC(=CC(=C1)F)F RFBQORKKYIOIDP-UHFFFAOYSA-N 0.000 claims description 3
- JREZIFIQNLDOJK-UHFFFAOYSA-N 4-(3,5-difluorophenyl)-2-[4-(3-fluorophenyl)phenyl]-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC=C(C=C1)C1=CC(=CC=C1)F)C1=CC(=CC(=C1)F)F JREZIFIQNLDOJK-UHFFFAOYSA-N 0.000 claims description 3
- LFLUGLJGCZWYDE-UHFFFAOYSA-N 4-(4-chlorophenyl)-2-(4-thiophen-3-ylphenyl)-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC=C(C=C1)C1=CSC=C1)C1=CC=C(C=C1)Cl LFLUGLJGCZWYDE-UHFFFAOYSA-N 0.000 claims description 3
- HMNORGYSISZKOU-UHFFFAOYSA-N 4-(4-chlorophenyl)-2-[4-(2-fluorophenyl)phenyl]-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC=C(C=C1)C1=C(C=CC=C1)F)C1=CC=C(C=C1)Cl HMNORGYSISZKOU-UHFFFAOYSA-N 0.000 claims description 3
- NQTIQHNZMXZUFX-UHFFFAOYSA-N 4-(4-chlorophenyl)-2-[4-(3-fluorophenyl)phenyl]-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC=C(C=C1)C1=CC(=CC=C1)F)C1=CC=C(C=C1)Cl NQTIQHNZMXZUFX-UHFFFAOYSA-N 0.000 claims description 3
- LIVLINYHTKMLRN-UHFFFAOYSA-N 4-(4-chlorophenyl)-2-[4-(furan-3-yl)phenyl]-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC=C(C=C1)C1=COC=C1)C1=CC=C(C=C1)Cl LIVLINYHTKMLRN-UHFFFAOYSA-N 0.000 claims description 3
- VLNHLPDQPVIMBC-UHFFFAOYSA-N 4-(4-fluorophenyl)-2-(4-thiophen-3-ylphenyl)-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC=C(C=C1)C1=CSC=C1)C1=CC=C(C=C1)F VLNHLPDQPVIMBC-UHFFFAOYSA-N 0.000 claims description 3
- WTXFRMCKLJLVDP-UHFFFAOYSA-N 4-(4-fluorophenyl)-2-[4-(2-fluorophenyl)phenyl]-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC=C(C=C1)C1=C(C=CC=C1)F)C1=CC=C(C=C1)F WTXFRMCKLJLVDP-UHFFFAOYSA-N 0.000 claims description 3
- GRRCEUHIAGYRDK-UHFFFAOYSA-N 4-(4-fluorophenyl)-2-[4-(3-fluorophenyl)phenyl]-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC=C(C=C1)C1=CC(=CC=C1)F)C1=CC=C(C=C1)F GRRCEUHIAGYRDK-UHFFFAOYSA-N 0.000 claims description 3
- MXLNMGLQUWCDGY-UHFFFAOYSA-N 4-(4-fluorophenyl)-2-[4-(furan-3-yl)phenyl]-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC=C(C=C1)C1=COC=C1)C1=CC=C(C=C1)F MXLNMGLQUWCDGY-UHFFFAOYSA-N 0.000 claims description 3
- YZECXNPQWNHMHU-UHFFFAOYSA-N N-[4-[4-phenyl-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazol-2-yl]phenyl]benzamide Chemical compound C(C1=CC=CC=C1)(=O)NC1=CC=C(C=C1)C=1OCC(N1)(C1=CC=CC=C1)CN1N=CN=C1 YZECXNPQWNHMHU-UHFFFAOYSA-N 0.000 claims description 3
- 241000223229 Trichophyton rubrum Species 0.000 claims description 3
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000005257 alkyl acyl group Chemical group 0.000 claims description 3
- 125000005605 benzo group Chemical group 0.000 claims description 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- LUMBSCWASVCSFB-UHFFFAOYSA-N 4-(2,4-dichlorophenyl)-2-(4-thiophen-3-ylphenyl)-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC=C(C=C1)C1=CSC=C1)C1=C(C=C(C=C1)Cl)Cl LUMBSCWASVCSFB-UHFFFAOYSA-N 0.000 claims description 2
- PCGOFYSHHFSECI-UHFFFAOYSA-N 4-(2,4-dichlorophenyl)-2-[4-(3-fluorophenyl)phenyl]-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC=C(C=C1)C1=CC(=CC=C1)F)C1=C(C=C(C=C1)Cl)Cl PCGOFYSHHFSECI-UHFFFAOYSA-N 0.000 claims description 2
- CGTVOUSDNWQTPD-UHFFFAOYSA-N 4-(2,4-dichlorophenyl)-2-[4-(furan-3-yl)phenyl]-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC=C(C=C1)C1=COC=C1)C1=C(C=C(C=C1)Cl)Cl CGTVOUSDNWQTPD-UHFFFAOYSA-N 0.000 claims description 2
- CJXRFXYYMYXHLL-UHFFFAOYSA-N 4-(2,4-difluorophenyl)-2-(4-thiophen-3-ylphenyl)-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC=C(C=C1)C1=CSC=C1)C1=C(C=C(C=C1)F)F CJXRFXYYMYXHLL-UHFFFAOYSA-N 0.000 claims description 2
- IMXXINRINZRAFV-UHFFFAOYSA-N 4-(2,4-difluorophenyl)-2-[4-(furan-3-yl)phenyl]-4-(1,2,4-triazol-1-ylmethyl)-5H-1,3-oxazole Chemical compound N1(N=CN=C1)CC1(N=C(OC1)C1=CC=C(C=C1)C1=COC=C1)C1=C(C=C(C=C1)F)F IMXXINRINZRAFV-UHFFFAOYSA-N 0.000 claims description 2
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- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 9
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- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims 2
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- 125000004244 benzofuran-2-yl group Chemical group [H]C1=C(*)OC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
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- 229960004022 clotrimazole Drugs 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- Organic Chemistry (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明属于药物合成技术领域，涉及一类2,4,4‑三取代二氢噁唑衍生物及其药学上可接受的盐、水合物、溶剂化物或其前药，它们的制备方法以及其作为治疗由真菌感染引起的各类疾病的药物中的用途。本发明所述的2,4,4‑三取代二氢噁唑衍生物及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药的通式如(I)所示：其中，MBG、X、Y、M、R1如权利要求和说明书所述。
Description
技术领域
本发明属于药物合成技术领域，涉及一类2,4,4-三取代二氢噁唑衍生物及其药学上可接受的盐、水合物、溶剂化物或其前药，它们的制备方法以及其作为治疗由真菌感染引起的各类疾病的药物中的用途。
背景技术
真菌感染可分为浅表真菌感染和深部真菌感染，其中浅表真菌感染主要由癣菌引起，如皮肤，毛发和指(趾)甲等真菌感染；深部真菌感染主要由白色念珠菌、新生隐球菌和烟曲霉菌引起，如皮下组织、内膜等深部组织的感染。近三十年，随着免疫缺陷的患者越来越多，真菌感染率急剧飙升，严重威胁人类健康，寻找新结构类型的抗真菌药物迫在眉睫。
目前临床上抗真菌药物根据作用机制的不同，可以分为抑制麦角甾醇合成的唑类药物；破坏细胞壁的棘白霉素类抗真菌药物、造成细胞膜泄漏的多烯类药物和作用于核酸的抗代谢类抗真菌药物。其中，唑类药物通过抑制羊毛甾醇14α-去甲基化酶(CYP51)的活性，阻断麦角甾醇的合成，是抗真菌药物领域研究最活跃，最成熟的靶点。目前临床上的唑类抗真菌药物主要分为两类：咪唑类药物如咪康唑(Miconazole)、克霉唑(Clotrimazole)、酮康唑(Ketoconazole)；三氮唑类药物如氟康唑(Fluconazole)、伊曲康唑(Itraconazole、伏立康唑(Voriconazole)和泊沙康唑(Posaconazole)。尽管唑类药物在临床上发挥着不可替代的作用，但是该类药物严重的毒副作用和耐药菌株的产生，督促着药物化学家开发更多结构类型、高效低毒、给药方式多样的抗真菌药物。
发明内容
本发明的目的是针对现有技术的不足，提供一类2,4,4-三取代二氢噁唑衍生物，以及所述衍生物的药学可接受的盐、水合物、溶剂化合物或前药，并提供所述衍生物的制备方法以及所述衍生物的用途；同时提供含有所述2,4,4-三取代二氢噁唑衍生物的药物组合物。本发明在参考文献的基础上，设计并合成了一系列2,4,4-三取代二氢噁唑衍生物，该类化合物经体外抗真菌活性测试表明，该类化合物具有较强的抗真菌活性，在治疗真菌感染疾病中具有较大研究价值。
为实现上述目的，本发明提供通式I所示的2,4,4-三取代二氢噁唑衍生物及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药：
其中：
MBG是取代或未取代的四唑基、取代或未取代的三唑基、取代或未取代的咪唑基、或取代或未取代的吡啶基；所述的取代基为：氢、C1-C4烷基、C1-C4烷氧基。
Y为O或S；
X为CH、CH2、N、NH、或O；
R1为(C1-C5)烷基、(C3-C6)环烷基、(C1-C4)烷氧基、羧基、-COOR2、-CON(R2)2、5-10元芳基或者5-10元杂芳基，且所述芳基或杂芳基任选0-3个相同或不同的R2取代；
Ar环为C3-C6环烷基、5-10元杂环基、C6-C10芳基或C5-C10杂芳基，其中，所述杂环基、杂芳基含有1-3个选自N、O或S的杂原子，并且Ar任选0-3个相同或不同的M取代；
M为氢、羟基、卤素、硝基、氨基、氰基、(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C1-C6)烷氧基、(C1-C6)烷基硫基、任选被羟基、氨基或卤代的(C1-C6)烷基或(C1-C6)烷氧基或(C1-C6)烷基硫基、被单或二(C1-C6烷基)取代的氨基、(C1-C6)烷基酰氨基、游离的、成盐的、酯化的和酰胺化的羧基、(C1-C6)烷基亚磺酰基、磺酰基、(C1-C6)烷氧基、(C1-C6)烷基、(C1-C6)烷基酰基、氨基甲酰基、被单或二(C1-C6烷基)取代的氨基甲酰基、(C1-C3)亚烷基二氧基的取代基；除了M为所连接的供电、吸电基团外，M也可以为5-10元杂环基、C6-C12芳基或C5-C12杂芳基，所述杂环基和杂芳基含有1-3个选自O、N和S的杂原子，且所述的杂环基、芳基或杂芳基任选0-3个相同或不同的R2取代；
R2为氢、羟基、卤素、硝基、氨基、氰基、(C1-C6)烷基、(C1-C6)烯基、(C1-C6)炔基、(C1-C6)烷氧基、任选被羟基、氨基或卤代的(C1-C6)烷基或(C1-C6)烷氧基、被单或二(C1-C6烷基)取代的氨基、(C1-C6)烷基酰氨基、游离的、成盐的、酯化的和酰胺化的羧基、(C1-C6)烷基亚磺酰基、磺酰基、(C1-C6)烷氧基、(C1-C6)烷基、(C1-C6)烷基酰基、氨基甲酰基、被单或二(C1-C6烷基)取代的氨基甲酰基、(C1-C3)亚烷基二氧基。
本发明优选通式I所示的化合物，及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药，
其中，
MBG选自以下结构：
本发明优选通式I所示的化合物，及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药，
其中，
Y为O；
本发明优选通式I所示的化合物，及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药，
其中，
Y为O；
MBG选自以下结构：
本发明优选通式I所示的化合物，及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药，
其中，
R1为(C1-C5)烷基、(C3-C6)环烷基、苄基、-(CHF)Ph、-(CF2)Ph或苯基，且苄基、-(CHF)Ph、-(CF2)Ph和苯基的苯环上任选0-3个R2取代。
本发明优选通式I所示的化合物，及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或前药，
其中，
Y为O；
R1为(C1-C5)烷基、(C3-C6)环烷基、苄基、-(CHF)Ph、-(CF2)Ph或苯基，且苄基、-(CHF)Ph、-(CF2)Ph和苯基的苯环上任选0-3个R2取代；
MBG为以下结构之一：
Ar环为呋喃基、噻吩基、噁唑基、异噁唑基、吡咯基、吡唑基、苯基、萘基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并吡唑基或吲哚基，且Ar任选1-3个相同或不同的M取代。
本发明优选如下化合物及其药学上可接受的盐、水合物、溶剂化物或前药，但这些化合物并不意味着对本发明的任何限制：
4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-甲基-4,5-二氢噁唑
4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-异丙基-4,5-二氢噁唑
4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-环丙基-4,5-二氢噁唑
4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-苄基-4,5-二氢噁唑
4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-5-(氟(苯基)甲基)-4,5-二氢噁唑
4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-5-(二氟(苯基)甲基)-4,5-二氢噁唑
4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-苯基-4,5-二氢噁唑
4-((1H-四氮唑-2-基)甲基)-2-([1,1'-联苯]-4-基)-4-苯基-4,5-二氢噁唑
3-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)-5-苯基异噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-2-(5-苯基噻吩-2-基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(4-(呋喃-3-基)苯基)-4-苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(4-(噻吩-3-基)苯基)-4-苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(萘-2-基)-4-苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(苯并呋喃-2-基)-4-苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(苯并[b]噻吩-2-基)-4-苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(苯并[d]噻唑-2-基)-4-苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2,4-二苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(4-(苄氧基)苯基)-4-苯基-4,5-二氢噁唑
N-(4-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)苯基)苯甲酰胺
1-(4-(4-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)苯基)哌嗪-1-基)乙酮
2-(4-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)苯基)-5-苯基-1,3,4-噁二唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氟苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氯苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氟苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氯苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氟苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氯苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氟苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氯苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氟苯基)-2-(5-(三氟甲氧基)苯并[b]噻吩-2-基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(4-氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(4-氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(4-氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(4-氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(4-氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(4-氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(4-氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
4-((1H-四氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑
而且，按照本发明所属领域的一些通常方法，本发明中通式I的部分化合物具有碱性基团，可以与酸生成药学上可接受的盐。可药用加成盐包括无机酸和有机酸加成盐，与下列酸加成的盐是特别优选的：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。
此外，本发明还包括本发明衍生物的前药。本发明衍生物的前药是通式I的衍生物，它们自身可能具有较弱的活性甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
通式I所示的化合物可以以非溶剂化形式和含有药学上可接受的溶剂(如水、乙醇等)的溶剂化形式。通式I所示的化合物可以含有不对称或手性中心，因此可以以不同立体异构形式存在。本发明的所有立体异构形式，包括但不限于非对映异构体、对映异构体和阻转异构体以及它们的混合物(如外消旋混合物)，均包括在本发明的范围内。
通式I所示的化合物可以以不同的互变异构体形式存在，所有这些形式均包括在本发明的范围内。术语“互变异构体”或“互变异构形式”是指经由低能垒互相转化的不同能量的结构异构体。
本发明中“卤素”是指氟、氯、溴或碘代；“烷基”是指直链或支链的烷基；“亚烷基”是指直链或支链的亚烷基；“芳基”是指除去芳烃中的一个或不同位置的两个氢原子而得到的有机基团，如苯基、萘基；“杂芳基”是指含有一个或多个选自N、O、S杂原子的单环或多环的环状体系，该环状体系是指具有芳香性的，并且除去环状体系中的一个或不同位置的两个氢原子而得到的有机基团，如噻唑基，咪唑基、吡啶基、吡唑基、(1,2,3)-和(1,2,4)-三唑基、呋喃基、噻吩基、吡咯基，吲哚基，苯并噻唑基，噁唑基，异噁唑基，萘基，喹啉基，异喹啉基，苯并咪唑基，苯并噁唑基等。
本发明可以含有通式I的衍生物，及其药学上可接受的盐、水合物、溶剂化物或前药作为活性成份，与药学上可接受的载体或赋形剂混合制备成组合物，并制备成临床上可接受的剂型，上述药学上可接受的赋形剂是指任何可用于药学领域的稀释剂、辅助剂和/或载体。本发明的衍生物可以与其他活性成份组合使用，只要它们不产生其他不利的作用，例如过敏反应。
本发明的药用组合物可配制成若干种剂型，其中含有药物领域中一些常用的赋形剂。如上所述的若干种剂型可以采用注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂、软膏剂等剂型药物。
用于本发明药物组合物的载体是药物领域中可得到的常见类型，包括：粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂、防腐剂、加溶剂和基质等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药，如果某些药物在胃部条件下不稳定的，可将其配制成肠衣片剂。
本发明通式I的化合物可以通过包括化学领域众所周知的方法来合成，尤其根据本发明的说明来制备；本发明中的室温指环境温度，为10℃至30℃。
应当理解的是，本文所述的实施例和反应方案仅为例举说明目的，本领域技术人员可以据此进行各种修改和改变，并且这些修饰和改变均包括在本发明的主旨和范围内以及所附权利要求的范围内。
化合物制备的一般反应方案
本发明的化合物及其药学上可接受的盐可由如下物质制备：(a)原料一般可以从商业来源获取的或者使用本领域技术人员所熟知的方法来制备，或根据本发明所述的方法制备，(b)可由文献记载的方法制备的已知起始物质，(c)本文的方案和实验过程中所描述的新中间体。本发明中的化合物可以通过以下反应方案及描述合成。
方案I
上述方案I展示出了制备化合物I的一般合成路线，其中Ar、M、R1和MBG如权利要求书所述。
将D-丝氨酸甲酯盐酸盐A1与原料A2发生酰胺反应得到中间体A3，-80℃条件下，中间体A3与SOCl2发生反应得到中间体A4，中间体A4在碱性条件下与R1-X(X为卤素)发生取代反应得到中间体A5，四氢铝锂还原中间体A5的酯基得到中间体A6，A6与SOCl2发生取代反应得到中间体A7，A7与MBG发生取代反应得到目标化合物I。
方案II
上述方案II展示出了制备化合物R1为
时，化合物的一般合成路线，其中Ar、M、R1、R2和MBG如权利要求书所述。
原料B1与AgNO2发生取代反应得到中间体B2，中间体B2与甲醛发生双羟甲基化反应得到中间体B3，中间体B3与2,2-二甲氧基丙烷发生反应得到中间体B4，中间体B4与Pd/C发生还原反应得到中间体B5，中间体B5与原料B6发生酰胺反应得到中间体B7，中间体B7在酸性条件下脱去保护基得到中间体B8，中间体B8与SOCl2发生取代反应，得到中间体B9，中间体B9与MBG发生取代反应，得到目标化合物B10。
本发明的积极进步效果在于：本发明提供了2,4,4-三取代二氢噁唑衍生物，其制备方法、药物组合物和应用。本发明的2,4,4-三取代二氢噁唑衍生物对各种浅表和深部真菌具有良好的抗真菌活性，与现有临床应用的抗真菌药物相比，具有高效、低毒、抗真菌谱广等优点，可用于制备抗真菌药物。
本发明提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解，下属实例和制备例的范围并不以任何方式限制本发明的范围。本发明的通式I的化合物，可按照方案I和方案II的合成方法制备得来，这些路线中应用的全部可变因数如权利要求中的定义。
具体实施方式
不需要进一步详细说明，认为本领域熟练技术人员借助于前面的描述，可以最大程度的利用本发明。因此下面提供的实施例旨在阐述而不是限制本发明的范围。
原料一般可以从商业来源获取的或者使用本领域技术人员所熟知的方法来制备，或根据本发明所述的方法制备。未经特殊说明，所用试剂均为分析纯或化学纯。
化合物结构确证所用的质谱用Agilent 1100LC/MS测定。柱层析纯化产物使用的是青岛海洋化工厂生产的100-200目或者200-300目硅胶。
实施例1：4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-甲基-4,5-二氢噁唑
步骤a中：将原料1-1(1.1mmol)、联苯甲酸1-2(1.1mmol)和PyBOP(1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐)(1.2mmol)加入到DMF中，室温搅拌反应8h，TLC检测反应完毕，加水，乙酸乙酯萃取，饱和食盐水洗涤有机层，无水硫酸钠干燥过夜。滤除干燥剂，减压浓缩得中间体1-3。
步骤b中：将中间体1-3(5mmol)、SOCl2(12.5mmol)和三乙胺(12.5mmol)加入二氯甲烷中，室温搅拌反应，TLC检测反应完全，蒸除有机溶剂，乙酸乙酯溶解，水洗3次，饱和NaCl洗涤有机层，无水Na2SO4干燥过夜。滤除干燥剂，减压浓缩、柱层析得中间体1-4。
步骤c中：将中间体1-4(5mmol)溶于无水THF中，缓慢滴加LiN(Pr-i)2(10mmol)的THF溶液，反应约1h，加入CH3I(10mmol)，TLC检测反应完全，升至室温，加饱和NH4Cl溶液淬灭，减压蒸除有机溶剂，乙酸乙酯萃取，饱和NaCl洗涤有机层，无水Na2SO4干燥过夜。滤除干燥剂，减压浓缩得中间体1-5。
步骤d中：冰浴条件下，将中间体1-5(5mmol)溶于THF中，分批加入四氢铝锂(10mmol)，TLC检测反应完全，加饱和NH4Cl溶液淬灭反应，减压蒸除有机溶剂，乙酸乙酯萃取，饱和NaCl洗涤有机层，无水Na2SO4干燥过夜。滤除干燥剂，减压浓缩得中间体1-6。
在步骤e中：将中间体1-6(5mmol)、SOCl2(20mmol)和三乙胺(20mmol)加入二氯甲烷中，室温搅拌反应，TLC检测反应完全，蒸除有机溶剂，乙酸乙酯溶解，水洗3次，饱和NaCl洗涤有机层，无水Na2SO4干燥过夜。滤除干燥剂，减压浓缩、柱层析得中间体1-7。
在步骤f中：冰浴条件下，将咪唑(15mmol)加入DMF中，加入NaH(20mmol)，搅拌30min后加入中间体1-7(5mmol)，继续反应，TLC检测反应完毕，将反应液倾入水中，乙酸乙酯萃取，饱和NaCl洗涤有机层，无水Na2SO4干燥过夜。滤除干燥剂，减压浓缩、柱层析得目标化合物1。1H-NMR(400MHz,DMSO-d6)δ7.90(d,J＝8.4Hz,2H),7.77(d,J＝8.4Hz,2H),7.74–7.70(m,2H),7.59(s,1H),7.50(t,J＝7.5Hz,2H),7.41(t,J＝7.3Hz,1H),7.14(s,1H),6.81(s,1H),4.31(d,J＝8.9Hz,1H),4.22–4.14(m,2H),4.12(d,J＝8.9Hz,1H),1.31(s,3H).HRMS(ESI,m/z)calcdforC20H19N3O,[M+H]+,318.1601；found 318.1632.
按照实施例1的方法，分别使用相应的卤代烷，制备得到实施例2-6。
实施例2：4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-异丙基-4,5-二氢噁唑
ESI-MS[M+H]+(m/z):346.1。
实施例3：4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-环丙基-4,5-二氢噁唑
ESI-MS[M+H]+(m/z):344.1。
实施例4：4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-苄基-4,5-二氢噁唑
1H-NMR(400MHz,DMSO-d6)δ7.81(d,J＝8.5Hz,2H),7.75–7.68(m,4H),7.61(s,1H),7.49(t,J＝7.5Hz,2H),7.41(t,J＝7.3Hz,1H),7.28–7.14(m,6H),6.81(s,1H),4.31(s,2H),4.23(d,J＝9.2Hz,1H),4.16(d,J＝9.2Hz,1H),3.04(d,J＝13.5Hz,1H),2.91(d,J＝13.5Hz,1H).HRMS(ESI,m/z)calcd for C26H23N3O,[M+H]+,394.1914；found 394.1949.
实施例5：4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-5-(氟(苯基)甲基)-4,5-二氢噁唑
HRMS(ESI,m/z)calcd for C26H22FN3O,[M+H]+,412.1820；found 412.1857.
实施例6：4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-5-(二氟(苯基)甲基)-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ7.84(d,J＝8.4Hz,2H),7.76(d,J＝8.3Hz,2H),7.71(d,J＝7.4Hz,2H),7.69–7.62(m,3H),7.55–7.48(m,5H),7.42(t,J＝7.4Hz,1H),7.14(s,1H),6.76(s,1H),4.69(d,J＝10.1Hz,1H),4.59(d,J＝14.2Hz,1H),4.36–4.29(m,2H).HRMS(ESI,m/z)calcd for C26H21F2N3O,[M+H]+,430.1725；found 430.1727.
实施例7：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-苯基-4,5-二氢噁唑
步骤a中：将AgNO2(10mmol)加入乙醚(30mL)中，室温搅拌，滴加溴苄(5mmol)，避光搅拌反应5h，将反应液倾入水中，用乙醚萃取3次，减压蒸除乙醚得淡黄色油状液体，柱层析得中间体5-2。
步骤b中：将中间体5-2(4mmol)溶于乙醇中，加入甲醛溶液(24mmol)、NaOH(4mmol)，室温搅拌反应，TLC检测反应完毕，减压蒸除有机溶剂，加水，乙酸乙酯萃取3次，合并有机层，饱和NaCl洗涤有机层，无水Na2SO4干燥过夜。滤除干燥剂，减压浓缩、柱层析得中间体5-3。
步骤c中：将2,2-二甲氧基丙烷(4.5mmol)加入中间体5-3(3mmol)的丙酮溶液中，加入对甲基苯磺酸(0.6mmol)，室温反应，TLC检测反应完全，减压蒸除溶剂，柱层析得中间体5-4。
在步骤d中：将中间体5-4(2mmol)溶于甲醇(10mL)溶液中，加入Pd/C，通入H2，室温反应，TLC检测反应完全，过滤，减压蒸除溶剂得中间体5-5。
步骤e中：将原料联苯甲酸5-6(1.1mmol)、中间体5-5(1.1mmol)和PyBOP(1.2mmol)加入DMF(10mL)中，室温搅拌反应8h，TLC检测反应完毕，加水，乙酸乙酯萃取，饱和食盐水洗涤有机层，无水硫酸钠干燥过夜。滤除干燥剂，减压浓缩得中间体5-7。
步骤f中：将中间体5-7(5mmol)加入到冰乙酸/水(V:V＝3:1)中，40℃反应，TLC检测反应完全，倾入水中，乙酸乙酯萃取，饱和NaCl洗涤有机层，无水Na2SO4干燥过夜。滤除干燥剂，减压浓缩、柱层析得中间体5-8。
步骤g中：将中间体5-8(5mmol)、SOCl2(25mmol)和三乙胺(25mmol)加入二氯甲烷中，室温搅拌反应，TLC检测反应完全，蒸除有机溶剂，乙酸乙酯溶解，水洗3次，饱和NaCl洗涤有机层，无水Na2SO4干燥过夜。滤除干燥剂，减压浓缩、柱层析得中间体5-9。
步骤h中：冰浴条件下，将唑(15mmol)加入DMF(10mL)中，加入NaH(20mmol)，搅拌30min后加入中间体5-9(5mmol)，继续反应，TLC检测反应完毕，将反应液倾入水中，乙酸乙酯萃取，饱和NaCl洗涤有机层，无水Na2SO4干燥过夜。滤除干燥剂，减压浓缩、柱层析得目标化合物7。1H-NMR(600MHz,DMSO-d6)δ8.32(s,1H),7.96(d,J＝8.4Hz,2H),7.90(s,1H),7.79(d,J＝8.3Hz,2H),7.73(d,J＝7.5Hz,2H),7.53–7.49(m,4H),7.44–7.39(m,3H),7.32(t,J＝7.3Hz,1H),5.13(d,J＝8.9Hz,1H),4.74(d,J＝14.2Hz,1H),4.61(d,J＝14.1Hz,1H),4.46(d,J＝8.9Hz,1H).HRMS(ESI,m/z)calcd for C24H20N4O,[M+Na]+,403.1529；found403.1563.
按照实施例7的方法，分别使用相应的原料制备得到实施例8-56。
实施例8：4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-苯基-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ7.99(d,J＝8.4Hz,2H),7.81(d,J＝8.4Hz,2H),7.74(d,J＝7.2Hz,2H),7.55–7.49(m,5H),7.44–7.39(m,3H),7.32(t,J＝7.3Hz,1H),7.09(s,1H),6.75(s,1H),4.82(d,J＝9.1Hz,1H),4.52(d,J＝14.2Hz,1H),4.43(d,J＝9.1Hz,1H),4.35(d,J＝14.2Hz,1H).HRMS(ESI,m/z)calcd for C25H21N3O,[M+H]+,380.1757；found380.1796.
实施例9：4-((1H-四氮唑-2-基)甲基)-2-([1,1'-联苯]-4-基)-4-苯基-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ9.26(s,1H),7.98(d,J＝8.5Hz,2H),7.81(d,J＝8.5Hz,2H),7.75–7.73(m,2H),7.54–7.50(m,4H),7.44–7.39(m,3H),7.33(t,J＝7.3Hz,1H),5.08(d,J＝14.2Hz,1H),5.03(d,J＝9.2Hz,1H),4.96(d,J＝14.2Hz,1H),4.49(d,J＝9.2Hz,1H).HRMS(ESI,m/z)calcd for C23H19N5O,[M+Na]+,404.1482；found 404.1514.
实施例10：3-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)-5-苯基异噁唑
1H-NMR(600MHz,DMSO-d6)δ8.34(s,1H),8.00–7.98(m,2H),7.92(s,1H),7.59–7.56(m,4H),7.49(dd,J＝8.2,1.0Hz,2H),7.41(t,J＝7.6Hz,2H),7.34(t,J＝7.3Hz,1H),5.19(d,J＝9.1Hz,1H),4.78(d,J＝14.2Hz,1H),4.67(d,J＝14.2Hz,1H),4.55(d,J＝9.1Hz,1H).HRMS(ESI,m/z)calcd for C21H17N5O2,[M+Na]+,394.1274；found 394.1315.
实施例11：4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-2-(5-苯基噻吩-2-基)-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.28(s,1H),7.92(s,1H),7.77–7.74(m,2H),7.57(d,J＝0.8Hz,2H),7.49–7.46(m,4H),7.40(t,J＝7.7Hz,3H),7.33(t,J＝7.3Hz,1H),5.12(d,J＝8.8Hz,1H),4.73(d,J＝14.2Hz,1H),4.60(d,J＝14.2Hz,1H),4.46(d,J＝8.8Hz,1H).HRMS(ESI,m/z)calcd for C22H18N4OS,[M+Na]+,409.1094；found 409.1134.
实施例12：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(4-(呋喃-3-基)苯基)-4-苯基-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.31(d,J＝12.2Hz,2H),7.88(d,J＝5.0Hz,2H),7.86(s,1H),7.79(t,J＝1.7Hz,1H),7.74(d,J＝8.4Hz,2H),7.53–7.49(m,2H),7.39(t,J＝7.7Hz,2H),7.32(t,J＝7.3Hz,1H),7.06–7.02(m,1H),5.11(d,J＝8.9Hz,1H),4.72(d,J＝14.2Hz,1H),4.59(d,J＝14.1Hz,1H),4.44(d,J＝8.9Hz,1H).HRMS(ESI,m/z)calcd forC22H18N4O2,[M+Na]+,393.1322；found 393.1356.
实施例13：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(4-(噻吩-3-基)苯基)-4-苯基-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.31(s,1H),8.04(dd,J＝2.9,1.3Hz,1H),7.92–7.87(m,3H),7.84(d,J＝8.5Hz,2H),7.69(dd,J＝5.0,2.9Hz,1H),7.63(dd,J＝5.0,1.3Hz,1H),7.53–7.50(m,2H),7.39(t,J＝7.7Hz,2H),7.32(t,J＝7.3Hz,1H),5.11(d,J＝8.9Hz,1H),4.73(d,J＝14.2Hz,1H),4.60(d,J＝14.1Hz,1H),4.44(d,J＝8.9Hz,1H).HRMS(ESI,m/z)calcd for C22H18N4OS,[M+Na]+,409.1094；found 409.1140.
实施例14：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(萘-2-基)-4-苯基-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.43(s,1H),8.33(s,1H),8.08(d,J＝7.9Hz,1H),8.03(d,J＝0.9Hz,2H),8.00(d,J＝8.1Hz,1H),7.88(s,1H),7.66–7.63(m,1H),7.62–7.59(m,1H),7.55(dd,J＝8.2,1.1Hz,2H),7.41(t,J＝7.7Hz,2H),7.33(t,J＝7.3Hz,1H),5.18(d,J＝8.8Hz,1H),4.76(d,J＝14.2Hz,1H),4.63(d,J＝14.2Hz,1H),4.50(d,J＝8.8Hz,1H).HRMS(ESI,m/z)calcd for C22H18N4O,[M+Na]+,377.1373；found 377.1403.
实施例15：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(苯并呋喃-2-基)-4-苯基-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.91(s,1H),7.78–7.72(m,2H),7.53–7.48(m,4H),7.40(t,J＝7.6Hz,2H),7.37–7.32(m,2H),5.17(d,J＝8.9Hz,1H),4.74(d,J＝14.2Hz,1H),4.63(d,J＝14.2Hz,1H),4.50(d,J＝8.9Hz,1H).HRMS(ESI,m/z)calcd forC20H16N4O2,[M+Na]+,367.1165；found 367.1203.
实施例16：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(苯并[d]噻唑-2-基)-4-苯基-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.33(s,1H),8.26–8.22(m,1H),8.15(dd,J＝7.3,1.7Hz,1H),7.91(s,1H),7.63(pd,J＝7.1,1.3Hz,2H),7.53–7.48(m,2H),7.43(t,J＝7.7Hz,2H),7.35(t,J＝7.3Hz,1H),5.29(d,J＝9.0Hz,1H),4.81(d,J＝14.2Hz,1H),4.69(d,J＝14.2Hz,1H),4.62(d,J＝9.0Hz,1H).HRMS(ESI,m/z)calcd for C19H15N5OS,[M+Na]+,384.0890；found 384.0923.
实施例17：4-((1H-1,2,4-三氮唑-1-基)甲基)-2,4-二苯基-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.30(s,1H),7.90–7.85(m,3H),7.58(t,J＝7.4Hz,1H),7.51–7.48(m,4H),7.39(t,J＝7.6Hz,2H),7.31(t,J＝7.3Hz,1H),5.11(d,J＝9.0Hz,1H),4.72(d,J＝14.1Hz,1H),4.60(d,J＝14.1Hz,1H),4.44(d,J＝9.0Hz,1H).HRMS(ESI,m/z)calcd for C18H16N4O,[M+Na]+,327.1216；found 327.1248.
实施例18：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(4-(苄氧基)苯基)-4-苯基-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.27(s,1H),7.88(s,1H),7.82(d,J＝8.9Hz,2H),7.49(d,J＝7.2Hz,2H),7.46(d,J＝7.2Hz,2H),7.42–7.33(m,5H),7.30(t,J＝7.3Hz,1H),7.10(d,J＝8.9Hz,2H),5.18(s,2H),5.06(d,J＝8.9Hz,1H),4.69(d,J＝14.1Hz,1H),4.56(d,J＝14.1Hz,1H),4.39(d,J＝8.9Hz,1H).HRMS(ESI,m/z)calcd for C25H22N4O2,[M+H]+,411.1816；found 411.1856.
实施例19：N-(4-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)苯基)苯甲酰胺
1H-NMR(600MHz,DMSO-d6)δ10.52(s,1H),8.30(s,1H),7.98(d,J＝7.9Hz,2H),7.92(d,J＝8.8Hz,2H),7.90–7.86(m,3H),7.62(t,J＝7.3Hz,1H),7.56(t,J＝7.5Hz,2H),7.51(d,J＝7.2Hz,2H),7.39(t,J＝7.7Hz,2H),7.32(t,J＝7.3Hz,1H),5.09(d,J＝8.9Hz,1H),4.71(d,J＝14.1Hz,1H),4.59(d,J＝14.1Hz,1H),4.43(d,J＝8.9Hz,1H).HRMS(ESI,m/z)calcd for C25H21N5O2,[M+Na]+,446.1587；found 446.1640.
实施例20：1-(4-(4-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)苯基)哌嗪-1-基)乙酮
1H-NMR(600MHz,DMSO-d6)δ8.25(s,1H),7.87(s,1H),7.71(d,J＝9.0Hz,2H),7.50–7.47(m,2H),7.37(t,J＝7.7Hz,2H),7.30(t,J＝7.3Hz,1H),6.98(d,J＝9.0Hz,2H),5.02(d,J＝8.9Hz,1H),4.67(d,J＝14.1Hz,1H),4.54(d,J＝14.1Hz,1H),4.35(d,J＝8.9Hz,1H),3.59–3.57(m,4H),3.35–3.31(m,4H),2.04(s,3H).HRMS(ESI,m/z)calcd forC24H26N6O2,[M+Na]+,453.2009；found 453.2050.
实施例21：2-(4-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)苯基)-5-苯基-1,3,4-噁二唑
1H-NMR(600MHz,DMSO-d6)δ8.33(s,1H),8.26(d,J＝8.5Hz,2H),8.17(dd,J＝8.0,1.5Hz,2H),8.11(d,J＝8.5Hz,2H),7.89(s,1H),7.69–7.64(m,3H),7.54–7.51(m,2H),7.41(t,J＝7.7Hz,2H),7.33(t,J＝7.3Hz,1H),5.18(d,J＝8.9Hz,1H),4.76(d,J＝14.2Hz,1H),4.63(d,J＝14.2Hz,1H),4.51(d,J＝8.9Hz,1H).HRMS(ESI,m/z)calcd for C26H20N6O2,[M+Na]+,471.1540；found 471.1577.
实施例22：4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氟苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.32(d,J＝8.0Hz,2H),7.90–7.84(m,3H),7.79(t,J＝1.7Hz,1H),7.74(d,J＝8.5Hz,2H),7.55–7.52(m,2H),7.21(t,J＝8.9Hz,2H),7.04(dd,J＝1.8,0.8Hz,1H),5.09(d,J＝9.0Hz,1H),4.72(d,J＝14.1Hz,1H),4.59(d,J＝14.1Hz,1H),4.43(d,J＝9.0Hz,1H).HRMS(ESI,m/z)calcd for C22H17FN4O2,[M+Na]+,411.1228；found411.1264.
实施例23：4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氯苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
ESI-MS[M+H]+(m/z):405.1。
实施例24：4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氟苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
ESI-MS[M+H]+(m/z):407.1。
实施例25：4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氯苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
ESI-MS[M+H]+(m/z):439.1。
实施例26：4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氟苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
ESI-MS[M+H]+(m/z):405.1。
实施例27：4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氯苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
ESI-MS[M+H]+(m/z):421.1。
实施例28：4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氟苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
ESI-MS[M+H]+(m/z):423.1。
实施例29：4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氯苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
ESI-MS[M+H]+(m/z):455.1。
实施例30：4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氟苯基)-2-(5-(三氟甲氧基)苯并[b]噻吩-2-基)-4,5-二氢噁唑
ESI-MS[M+H]+(m/z):481.1。
实施例31：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.29(s,1H),8.02–7.96(m,2H),7.91(d,J＝16.4Hz,2H),7.55–7.50(m,2H),7.35(td,J＝9.0,2.5Hz,1H),7.23(t,J＝8.9Hz,2H),5.17(d,J＝8.9Hz,1H),4.75(d,J＝14.2Hz,1H),4.62(d,J＝14.2Hz,1H),4.50(d,J＝8.9Hz,1H).HRMS(ESI,m/z)calcd for C20H14F2N4OS,[M+Na]+,419.0749；found 419.0778.
实施例32：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(4-氯苯基)-4,5-二氢噁唑
ESI-MS[M+H]+(m/z):413.1。
实施例33：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.34(s,1H),8.04–7.99(m,2H),7.97(s,1H),7.87(s,1H),7.67–7.61(m,1H),7.40–7.34(m,2H),7.13(td,J＝8.5,2.5Hz,1H),5.18(dd,J＝9.1,2.6Hz,1H),4.65(d,J＝14.3Hz,1H),4.59(d,J＝14.3Hz,1H),4.52(dd,J＝9.0,1.5Hz,1H).HRMS(ESI,m/z)calcd for C20H13F3N4OS,[M+Na]+,437.0654；found 437.0688.
实施例34：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
ESI-MS[M+H]+(m/z):415.1。
实施例35：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
ESI-MS[M+H]+(m/z):447.1。
实施例36：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.29(s,1H),8.24(d,J＝1.3Hz,1H),7.97(d,J＝8.6Hz,1H),7.94(s,1H),7.90(s,1H),7.54–7.49(m,3H),7.25–7.21(m,2H),5.17(d,J＝8.9Hz,1H),4.75(d,J＝14.2Hz,1H),4.62(d,J＝14.2Hz,1H),4.51(d,J＝8.9Hz,1H).HRMS(ESI,m/z)calcd for C20H14ClFN4OS,[M+Na]+,435.0453；found 435.0480.
实施例37：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(4-氯苯基)-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.30(s,1H),8.24(d,J＝1.9Hz,1H),7.97(d,J＝8.5Hz,1H),7.95(d,J＝0.4Hz,1H),7.89(s,1H),7.51–7.45(m,5H),5.17(d,J＝8.9Hz,1H),4.76(d,J＝14.2Hz,1H),4.63(d,J＝14.2Hz,1H),4.51(d,J＝9.0Hz,1H).HRMS(ESI,m/z)calcdfor C20H14Cl2N4OS,[M+Na]+,451.0158；found 451.0195.
实施例38：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.34(s,1H),8.26(d,J＝1.8Hz,1H),7.99(d,J＝7.4Hz,2H),7.86(s,1H),7.66–7.60(m,1H),7.51(dd,J＝8.6,1.9Hz,1H),7.40–7.34(m,1H),7.12(td,J＝8.5,2.4Hz,1H),5.18(dd,J＝9.1,2.5Hz,1H),4.65(d,J＝14.3Hz,1H),4.59(d,J＝14.3Hz,1H),4.53(dd,J＝8.9,1.3Hz,1H).HRMS(ESI,m/z)calcd for C20H13ClF2N4OS,[M+Na]+,453.0359；found 453.0383.
实施例39：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.32(s,1H),8.25(d,J＝1.8Hz,1H),7.98(d,J＝8.0Hz,2H),7.90(s,1H),7.50(dd,J＝8.6,2.0Hz,1H),7.24–7.18(m,3H),5.15(d,J＝9.1Hz,1H),4.80(d,J＝14.2Hz,1H),4.67(d,J＝14.1Hz,1H),4.55(d,J＝9.1Hz,1H).HRMS(ESI,m/z)calcd for C20H13ClF2N4OS,[M+Na]+,453.0359；found 453.0383.
实施例40：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
ESI-MS[M+H]+(m/z):463.1。
实施例41：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.39(d,J＝1.7Hz,1H),8.28(s,1H),7.93(s,1H),7.92–7.88(m,2H),7.62(dd,J＝8.5,1.8Hz,1H),7.53–7.50(m,2H),7.23(t,J＝8.9Hz,2H),5.17(d,J＝8.9Hz,1H),4.75(d,J＝14.2Hz,1H),4.62(d,J＝14.2Hz,1H),4.51(d,J＝8.9Hz,1H).HRMS(ESI,m/z)calcd for C20H14BrFN4OS,[M+Na]+,478.9948；found 480.9957.
实施例42：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(4-氯苯基)-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.40–8.37(m,1H),8.30(s,1H),7.94(s,1H),7.92–7.89(m,2H),7.62(dd,J＝8.5,1.8Hz,1H),7.50(d,J＝8.7Hz,2H),7.46(d,J＝8.7Hz,2H),5.17(d,J＝8.9Hz,1H),4.76(d,J＝14.2Hz,1H),4.63(d,J＝14.2Hz,1H),4.51(d,J＝8.9Hz,1H).ESI-MS[M+H]+(m/z):473.1。
实施例43：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.40(d,J＝1.7Hz,1H),8.34(s,1H),7.97(s,1H),7.92(d,J＝8.5Hz,1H),7.86(s,1H),7.65–7.61(m,2H),7.39–7.35(m,1H),7.12(td,J＝8.5,2.5Hz,1H),5.18(dd,J＝9.1,2.6Hz,1H),4.65(d,J＝14.3Hz,1H),4.59(d,J＝14.3Hz,1H),4.53(dd,J＝9.0,1.5Hz,1H).HRMS(ESI,m/z)calcd for C20H13BrF2N4OS,[M+Na]+,496.9854；found 498.9869.
实施例44：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.39(s,1H),8.32(s,1H),7.97(s,1H),7.93–7.88(m,2H),7.64–7.59(m,1H),7.25–7.18(m,3H),5.15(d,J＝9.1Hz,1H),4.80(d,J＝14.2Hz,1H),4.67(d,J＝14.1Hz,1H),4.55(d,J＝9.1Hz,1H).HRMS(ESI,m/z)calcd for C20H13BrF2N4OS,[M+Na]+,496.9854；found 498.9869.
实施例45：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
ESI-MS[M+H]+(m/z):507.1。
实施例46：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(4-氟苯基)-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.34(s,1H),7.99–7.96(m,2H),7.90(s,1H),7.68(dd,J＝8.3,1.4Hz,2H),7.59(td,J＝7.9,1.6Hz,1H),7.57–7.54(m,2H),7.50–7.46(m,1H),7.37–7.33(m,2H),7.23(t,J＝8.9Hz,2H),5.13(d,J＝9.0Hz,1H),4.74(d,J＝14.2Hz,1H),4.61(d,J＝14.1Hz,1H),4.46(d,J＝9.0Hz,1H).HRMS(ESI,m/z)calcd for C24H18F2N4O,[M+Na]+,439.1341；found 439.1382.
实施例47：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(4-氯苯基)-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.35(s,1H),7.98(d,J＝8.4Hz,2H),7.90(s,1H),7.68(dd,J＝8.3,1.4Hz,2H),7.61–7.58(m,1H),7.54(d,J＝8.6Hz,2H),7.50–7.47(m,1H),7.46(d,J＝8.6Hz,2H),7.34(dd,J＝10.7,4.4Hz,2H),5.12(d,J＝9.0Hz,1H),4.75(d,J＝14.2Hz,1H),4.62(d,J＝14.1Hz,1H),4.45(d,J＝9.0Hz,1H).HRMS(ESI,m/z)calcd forC24H18ClFN4O,[M+Na]+,455.1045；found 455.1093.
实施例48：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.39(s,1H),8.00(d,J＝8.5Hz,2H),7.87(s,1H),7.72–7.68(m,3H),7.60(td,J＝7.9,1.6Hz,1H),7.50–7.46(m,1H),7.39–7.33(m,3H),7.11(td,J＝8.5,2.5Hz,1H),5.15(dd,J＝9.2,2.5Hz,1H),4.64(d,J＝14.3Hz,1H),4.58(d,J＝14.3Hz,1H),4.48(dd,J＝9.1,1.6Hz,1H).HRMS(ESI,m/z)calcd for C24H17F3N4O,[M+Na]+,457.1247；found 457.1282.
实施例49：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.37(s,1H),7.99(d,J＝8.5Hz,2H),7.90(s,1H),7.69(dd,J＝8.3,1.4Hz,2H),7.59(td,J＝7.9,1.6Hz,1H),7.50–7.46(m,1H),7.38–7.33(m,2H),7.26(dd,J＝8.6,2.2Hz,2H),7.21(tt,J＝9.1,2.3Hz,1H),5.11(d,J＝9.2Hz,1H),4.79(d,J＝14.2Hz,1H),4.66(d,J＝14.1Hz,1H),4.50(d,J＝9.2Hz,1H).HRMS(ESI,m/z)calcd for C24H17F3N4O,[M+Na]+,457.1247；found 457.1281.
实施例50：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
ESI-MS[M+H]+(m/z):467.1。
实施例51：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(4-氟苯基)-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.33(s,1H),7.96(d,J＝8.5Hz,2H),7.89(s,1H),7.84(d,J＝8.5Hz,2H),7.62–7.59(m,2H),7.57–7.53(m,3H),7.28–7.20(m,3H),5.13(d,J＝9.0Hz,1H),4.74(d,J＝14.2Hz,1H),4.61(d,J＝14.1Hz,1H),4.45(d,J＝9.0Hz,1H).HRMS(ESI,m/z)calcd for C24H18F2N4O,[M+Na]+,439.1341；found 439.1390.
实施例52：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(4-氯苯基)-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.34(s,1H),7.96(d,J＝8.4Hz,2H),7.89(s,1H),7.84(d,J＝8.4Hz,2H),7.61–7.59(m,2H),7.55–7.52(m,3H),7.46(d,J＝8.6Hz,2H),7.26(td,J＝8.1,1.5Hz,1H),5.12(d,J＝9.0Hz,1H),4.74(d,J＝14.2Hz,1H),4.62(d,J＝14.1Hz,1H),4.45(d,J＝9.0Hz,1H).HRMS(ESI,m/z)calcd for C24H18ClFN4O,[M+Na]+,455.1045；found 455.1083.
实施例53：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.38(s,1H),7.98(d,J＝8.5Hz,2H),7.88–7.84(m,3H),7.71(td,J＝8.7,6.8Hz,1H),7.63–7.60(m,2H),7.55(td,J＝8.1,6.2Hz,1H),7.40–7.35(m,1H),7.29–7.25(m,1H),7.11(td,J＝8.5,2.5Hz,1H),5.14(dd,J＝9.1,2.5Hz,1H),4.64(d,J＝14.3Hz,1H),4.58(d,J＝14.3Hz,1H),4.47(dd,J＝9.1,1.6Hz,1H).HRMS(ESI,m/z)calcd for C24H17F3N4O,[M+Na]+,457.1247；found 457.1286.
实施例54：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
1H-NMR(600MHz,DMSO-d6)δ8.37(s,1H),7.97(d,J＝8.5Hz,2H),7.90(s,1H),7.84(d,J＝8.5Hz,2H),7.62–7.59(m,2H),7.57–7.53(m,1H),7.29–7.24(m,3H),7.23–7.19(m,1H),5.11(d,J＝9.2Hz,1H),4.79(d,J＝14.2Hz,1H),4.65(d,J＝14.1Hz,1H),4.50(d,J＝9.2Hz,1H).HRMS(ESI,m/z)calcd for C24H17F3N4O,[M+Na]+,457.1247；found 457.1279.
实施例55：4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
ESI-MS[M+H]+(m/z):467.1。
实施例56：4-((1H-四氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑
1H NMR(600MHz,DMSO)δ9.19(s,1H),8.26(d,J＝1.9Hz,1H),7.99(t,J＝4.3Hz,2H),7.56–7.47(m,3H),7.24(t,J＝8.9Hz,2H),5.12–5.06(m,2H),4.97(d,J＝14.2Hz,1H),4.54(d,J＝9.2Hz,1H).ESI-MS[M+H]+(m/z):414.1。
本发明部分产物的药理研究。
实验方法:参考常规的体外抑菌试验方法(Reference method for brothdilution antifungal susceptibility testing of yeasts and filamentous fungi；Approved Standard M27-A3 and M38-A2)。
实验材料和方法:
(1)实验菌株：
本实验选用了以下5种常见的人体致病标准真菌菌株作为筛选对象，真菌菌株由沈阳药科大学提供。
表1实验所用菌种及其编号
| 菌种名称 | Species | 菌株选择 |
| 白色念珠菌 | Candida albicans | SC5314 |
| 白色念珠菌 | Candida albicans | CPCC400523 |
| 新生隐球菌 | Cryptococcus neofrmans | GIM 2.209 |
| 热带假丝酵母菌 | Candida tropicalis | cgmcc 2.3739 |
| 烟曲霉菌 | Aspergillus fumigatus | cgmcc 3.7795 |
(2)试验方法：
RPMI-1640培养基的配制：RPMI-1640 10g,NaHCO3 2.0g，三氮吗啡琳丙磺酸(sigma)34.5g，加800mL无菌蒸馏水溶解，lmol/L NaOH调整pH至7.0后，定容至1000mL，0.22μm微孔滤膜过滤除菌后放置4℃保存备用。
丝状真菌菌悬液的制备：丝状真菌(红色毛癣菌、疵状毛癣菌、石膏样小抱子菌和烟曲霉菌)等连续两次传代接种于沙氏培养基平板，在35℃培养箱中培养48h，菌落上加入0.85％生理盐水5mL，制备菌液。用分光光度计调整菌液浓度，A值调整至0.3-0.5；再用培养基稀释50倍作为接种菌悬液。
球状真菌菌悬液的制备：球状菌(白色念珠菌、热带假丝酵母菌、光滑假丝酵母菌和新生隐球菌)。将活化后的菌株用分区划线法接种于沙氏固体培养基平板上，于32℃恒温培养2-3天，取适量单菌落接入含l0 mL 0.85％无菌生理盐水的三角瓶中，震荡15分钟，用灭菌枪头取少量菌液于血细胞计数板上，显微镜下计数。加RPMI-1640培养基稀释，使最终菌悬液的浓度为1x106个/mL。
药液制备：称取上述化学合成药各6.40mg，依次加入l.0mL二甲基亚砜(DMSO),l.0mL吐温-20和8.0mL灭菌蒸馏水，混匀。配成药液浓度为0.64mg/mL。以相同方法配制阳性对照药氟康唑、伏立康唑。
接种：第一步，加RPMI-1640培养基：每行的第1孔加入180μL RPMI-1640培养基，2-11孔加入100μL RPMI-1640培养基，12孔加入200μL RPMI-1640培养基。第二步，加药样：向第1孔中加入20μL待测药液，用移液枪混匀后吸取100μL至2孔，依次进行2倍稀释至第10孔后混匀弃去100μL。第三步，加菌悬液：向1-11孔中各加100μL接种菌悬液。第11孔为生长对照，第12孔为空白培养基对照。阳性对照药物不设空白药物对照，即从第1孔开始做倍比梯度稀释直至第10孔，测试浓度(μg/mL)范围32、16、8、4、2、1、0、5、0.25、0.125、0.0625。
培养和检测：以空白对照无菌生长，阳性对照生长良好作为判断试验操作是否合格的标准。每板测试8个样品，每个菌均设置阳性药物对照。待测药物稀释法同上。
表2实例化合物最低抑菌浓度((MIC,μg/ml)
从上述试验结果可以清楚地看出，本发明所要保护的通式I的化合物及其盐类具有良好的抗真菌活性，多个化合物的抗真菌活性强于对照药，与现有的抗真菌药物相比，具有结构新颖、低毒、高效、广谱等优点，因此本发明的化合物具有很好的工业应用前景。
本发明中通式I的化合物可单独施用，但通常是和药用载体混合物给予，所述药用载体的选择要根据所需用药途径和标准药物实践，下面分别用该类化合物的各种药物剂型，例如片剂、胶囊剂、注射剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂和软膏剂的制备方法，说明其在制药领域中的新应用。
实施例17：片剂。
用含有权利要求1中化合物的化合物(以实施例31化合物为例)10g，按照药剂学一般压片法加辅料20g混匀后，压制成100片，每片重300mg。
实施例18：胶囊剂。
用含有权利要求1中化合物的化合物(以实施例31化合物为例)10g，按照药剂学胶囊剂的要求将辅料20g混匀后，装入空心胶囊，每个胶囊重300mg。
实施例19：注射剂。
用含有权利要求1中化合物的化合物(以实施例31化合物为例)10g，按照药剂学常规方法，进行活性炭吸附，经0.65μm微孔滤膜过滤后，填入氮气罐制成水针制剂，每只装2mL，共灌装100瓶。
实施例20：气雾剂。
用含有权利要求1中化合物的化合物(以实施例31化合物为例)10g，用适量丙二醇溶解后，加入蒸馏水及其他辐料后，制成500mL的澄清溶液即得。
实施例21：栓剂。
用含有权利要求1中化合物的化合物(以实施例31化合物为例)10g，将之研细加入甘油适量，研匀后加入已熔化的甘油明胶，研磨均匀，倾入已涂润滑剂的模型中，制得栓剂50颗。
实施例22：膜剂。
用含有权利要求1中化合物的化合物(以实施例31化合物为例)10g，将聚乙烯醇、药用甘油、水等搅拌膨胀后加热溶解，80目筛网过滤，再将实施例18化合物加入到滤液中搅拌溶解，涂膜机制膜100片。
实施例23：滴丸剂。
用含有权利要求1中化合物的化合物(以实施例31化合物为例)10g，与明胶等基质50g加热熔化混匀后，滴入低温液体石蜡中，共制得滴丸1000丸。
实施例24：外用搽剂。
用含有权利要求1中化合物的化合物(以实施例31化合物为例)10g，按照常规药剂学方法与乳化剂等辅料2.5g混合研磨，再加蒸馏水至200mL制得。
实施例25：软膏剂。
用含有权利要求1中化合物的化合物(以实施例31化合物为例)10g，研细后与凡士林等油性基质500g研匀制得。
尽管已经通过特定实施方案描述了本发明，但修改和等价变化对于精通此领域的技术人员而言是显见的，且它们都包含在本发明范围。
Claims (7)
1.通式（I）所示的化合物或其药学上可接受的盐：
其中：
MBG是
、
；
Y 为O；
X为N；
“
”为双建;
R1为 C3-C6环烷基、苄基、-(CHF)Ph、-(CF2)Ph或苯基，且苄基、-(CHF)Ph、-(CF2)Ph和苯基的苯环上任选0-3个R2取代；
Ar环为呋喃基、噻吩基、噁唑基、异噁唑基、吡咯基、吡唑基、苯基、萘基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并吡唑基或吲哚基，且Ar任选1-3个相同或不同的M取代；
M为羟基、卤素、硝基、氨基、氰基、C1-C6烷基、5-10元杂环基、C6-C12芳基或C5-C12杂芳基，所述杂环基和杂芳基含有1-3个选自O、N和S的杂原子，且所述的杂环基、芳基或杂芳基任选0-3个相同或不同的R2取代；
R2为羟基、卤素、硝基、氨基、氰基、C1-C6烷基、C1-C6烷基酰基。
2.如权利要求1所述的化合物或其药学上可接受的盐：其中：
Ar环为呋喃基、噻吩基、噁唑基、异噁唑基、吡咯基、吡唑基、苯基、萘基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并吡唑基或吲哚基，且Ar任选1-3个相同或不同的M取代。
3.如下的化合物或其药学上可接受的盐，选自：
4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-甲基-4,5-二氢噁唑
4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-异丙基-4,5-二氢噁唑
4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-环丙基-4,5-二氢噁唑
4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-苄基-4,5-二氢噁唑
4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-5-(氟(苯基)甲基)-4,5-二氢噁唑
4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-5-(二氟(苯基)甲基)-4,5-二氢噁唑
4-((1H-咪唑-1-基)甲基)-2-([1,1'-联苯]-4-基)-4-苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑 -1-基)甲基)-2-([1,1'-联苯]-4-基)-4-苯基-4,5-二氢噁唑
4-((1H-四氮唑-2-基)甲基)-2-([1,1'-联苯]-4-基)-4-苯基-4,5-二氢噁唑
3-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)-5-苯基异噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-2-(5-苯基噻吩-2-基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(4-(呋喃-3-基)苯基)-4-苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(4-(噻吩-3-基)苯基)-4-苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(萘-2-基)-4-苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(苯并呋喃-2-基)-4-苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(苯并[b]噻吩-2-基)-4-苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(苯并[d]噻唑-2-基)-4-苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2,4-二苯基-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(4-(苄氧基)苯基)-4-苯基-4,5-二氢噁唑
N-(4-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)苯基)苯甲酰胺
1-(4-(4-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)苯基)哌嗪-1-基)乙酮
2-(4-(4-((1H-1,2,4-三氮唑-1-基)甲基)-4-苯基-4,5-二氢噁唑-2-基)苯基)-5-苯基-1,3,4-噁二唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氟苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氯苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氟苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氯苯基)-2-(4-(呋喃-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氟苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(4-氯苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氟苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氯苯基)-2-(4-(噻吩-3-基)苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-4-(2,4-二氟苯基)-2-(5-(三氟甲氧基)苯并[b]噻吩-2-基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(4-氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氟苯并[b]噻吩-2-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(4-氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(4-氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(6-溴苯并[b]噻吩-2-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(4-氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(4-氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(2'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(4-氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(4-氯苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(3,5-二氟苯基)-4,5-二氢噁唑
4-((1H-1,2,4-三氮唑-1-基)甲基)-2-(3'-氟-[1,1'-联苯]-4-基)-4-(2,4-二氯苯基)-4,5-二氢噁唑
4-((1H-四氮唑-1-基)甲基)-2-(6-氯苯并[b]噻吩-2-基)-4-(4-氟苯基)-4,5-二氢噁唑。
4.一种药用组合物，包含权利要求1-3任何一项的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的赋形剂。
5.如权利要求1所述的化合物，及其药学上可接受的盐的制备方法：
路线 I
路线 II
其中，Ar、M、R1、R2和MBG如权利要求1所述。
6.权利要求1-3中任何一项的化合物或其药学上可接受的盐或权利要求4所述的药用组合物在制备治疗真菌感染疾病药物中的应用。
7.如权利要求6所述的应用，其中所述的真菌感染疾病与一种或多种以下致病真菌有关：伞状犁头霉(Absidia corymbifera)、荚膜阿耶罗菌(Ajellomyces capsulatus)、皮炎阿耶罗菌((Ajellomyces dermatitidis)、苯黑末节皮真菌(Arthroderma benhamiae)、粉节皮菌(Arthroderma fulvum)、石膏样节皮菌(Arthroderma gypseum)、内弯节皮菌(Arthroderma incurvatum)、太田节皮菌(Arthroderma otae)、万博节皮菌(Arthrodermavanbreuseghemii)、黄曲霉(Aspergillus flavus)、烟曲霉(Aspergillus fumigatus)、黑曲霉(Aspergillus niger)、皮炎芽生菌(Blastomyces dermatitidis)、白色念珠菌(Candida albicans)、光滑念珠菌(Candida glabrata)、季也蒙念珠菌(Candidaguilliermondii)、克鲁斯念珠菌(Candida krusei)、近平滑念珠菌(Candidaparapsilosis)、热带假丝念珠菌(Candida tropicalis)、菌膜假丝酵母(Candidapelliculosa)、卡氏枝抱瓶霉(Cladophialophora carrionii)、粗球孢子菌(Coccidioidesimmitis)、新生隐球菌(Cryptococcus neoformans)、小克银汉霉菌属(Cunninghamellasp.)、絮状表皮癣菌(Epidermophyton floccosum)、皮炎外瓶霉(Exophialadermatitidis)、新型线黑粉菌(Filobasidiella neoformans)、佩德罗索氏着色芽生菌(Fonsecaea pedrosoi)、腐皮镰刀菌(Fusarium solani)、白地霉(Geotrichum candidum)、荚膜组织胞浆菌(Histoplasma capsulatum)、威尼克外瓶霉(Hortaea werneckii)、东方伊萨酵母(工ssatschenkia orientalis)、灰马杜拉分枝菌(Madurella grisae)、糠批马拉色菌(Malassezia fur fur)、球形马拉色菌(Malassezia globosa)、钝形马拉色菌(Malassezia obtusa)、厚皮马拉色菌(Malassezia pachydermatis)、限制性马拉色菌(Malassezia restricta)、斯洛非马拉色菌(Malassezia slooffiae)、合轴马拉色菌(Malassezia sympodialis)、犬小孢子菌(Microsporum cams)、黄褐色小孢子菌(Microsporum fulvum)、石膏样小孢子菌(Microsporum gypseum)、卷枝毛霉菌(Mucorcircinelloides)、红球丛赤壳(Nectria haematococca)、宛氏拟青霉(Paecilomycesvariotii)、巴西副球孢子菌(Paracoccidioides brasiliensis)、马尔尼菲青霉菌(Peniciliium marneffei)、异常毕赤酵母(Pichia anomala)、季也蒙毕赤酵母(Pichiaguilliermondii)、卡氏肺孢子虫(Pneumocystis carinii)、波氏假阿利什菌(Pseudallescheria boydii)、稻根霉菌(Rhizopus oryzae)、深红酵母(Rhodotorularubra)、尖端赛多孢子菌(Scedosporium apiospernium)、裂褶菌(Schizophyllumcommune)、申克孢子丝菌(Sporothrix schenckii)、须发癣菌(Trichophytonmentagrophytes)、红色毛癣菌(Trichophyton rubrum)、疵状癣菌(Trichophytonverrucosum)、紫色毛癣菌(Trichophyton violaceum)、阿萨希毛孢子菌(Trichosporonasahii)、皮肤毛孢子菌(Trichosporon cutaneum)、墨毛孢子菌(Trichosporon inkin)、粘状毛孢子菌(Trichosporon mucoides)、耳念珠菌(Candida auris)。
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| CN114605283B (zh) * | 2022-03-22 | 2024-11-19 | 江苏阿尔法集团盛基药业(宿迁)有限公司 | 一种高效制备孟鲁司特钠侧链中间体的方法 |
| CN114605282B (zh) * | 2022-03-22 | 2024-10-08 | 江苏阿尔法集团盛基药业(宿迁)有限公司 | 一种孟鲁司特钠侧链中间体的制备方法 |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4338327A (en) * | 1978-10-06 | 1982-07-06 | Janssen Pharmaceutica, N.V. | Substituted 1-(2-aryl-1,3-dioxolan-2-ylmethyl)-1H-1,2,4-triazoles |
| US4384879A (en) * | 1980-07-15 | 1983-05-24 | Ciba-Geigy Corporation | 4-(1H-Azolylmethyl)-1,3-dioxolan-5-one derivatives, production thereof and use thereof as growth regulators and/or microbicides |
| GB2095236B (en) * | 1981-03-18 | 1985-03-27 | Ici Plc | Heterocyclylmethyl-substituted dioxolanes and their use as fungicides |
| JPS58128383A (ja) * | 1982-01-26 | 1983-07-30 | Sumitomo Chem Co Ltd | トリアゾ−ル系化合物、その製造法およびこれを有効成分として含有する農園芸用殺菌剤、植物生長調節剤または除草剤 |
| EP0094167A3 (en) * | 1982-05-12 | 1984-07-04 | Fbc Limited | Azolyl fungicide and plant growth regulators and compositions containing them |
| US4785117A (en) * | 1987-10-02 | 1988-11-15 | Pennwalt Corporation | 5,5-disubstituted-3-phenyl-3-phenyl-3-[(1H-imidazol-1-ylmethyl) or (1H-1,2,4-triazol-1-ylmethyl)]-2-methylisoxazolidine derivatives (IR 3012) |
| US4835283A (en) * | 1988-03-07 | 1989-05-30 | Pennwalt Corporation | 3,5-diphenyl-3-[(1H-imidazol-1-ylmethyl) or (1H-1,2,4-triazol-1-ylmethyl)]-2 |
| DE4013723A1 (de) * | 1990-04-28 | 1991-10-31 | Basf Ag | 5-(1,2,4-triazol-1-ylmethyl)-isoxazoline |
| ES2038906B1 (es) * | 1991-09-04 | 1994-02-16 | Uriach & Cia Sa J | Procedimiento para la obtencion de nuevas oxazoilidinas. |
| JPH06263757A (ja) * | 1993-03-10 | 1994-09-20 | Kaken Pharmaceut Co Ltd | アゾール系化合物 |
| JPH0912574A (ja) * | 1995-06-28 | 1997-01-14 | Maruho Kk | 抗真菌剤 |
| BR0215702A (pt) * | 2002-04-12 | 2005-10-18 | Ranbaxy Lab Ltd | Derivados de tetraidrofurano 2,2,4-trisubstituìdo como agentes antifúngicos |
| JP2009286773A (ja) * | 2008-03-14 | 2009-12-10 | Bayer Cropscience Ag | 殺虫性縮環式アリール類 |
| CN104119322B (zh) * | 2014-07-11 | 2016-05-18 | 北京迪尔乐农业高新技术研发中心 | 一种用于杀菌的三唑类化合物及其制备方法和应用 |
| CN111848600B (zh) * | 2020-07-30 | 2021-12-07 | 沈阳药科大学 | 2,4,4-三取代二氢噁唑衍生物及其用途 |
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2021
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| WO2022022616A1 (zh) | 2022-02-03 |
| CN111848600A (zh) | 2020-10-30 |
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