CN113874357A - 金属β内酰胺酶抑制剂 - Google Patents
金属β内酰胺酶抑制剂 Download PDFInfo
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- CN113874357A CN113874357A CN201980088215.4A CN201980088215A CN113874357A CN 113874357 A CN113874357 A CN 113874357A CN 201980088215 A CN201980088215 A CN 201980088215A CN 113874357 A CN113874357 A CN 113874357A
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- Prior art keywords
- compound
- dihydro
- phenyl
- triazol
- thioxo
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- 108060004734 metallo-beta-lactamase Proteins 0.000 title abstract description 47
- 102000020235 metallo-beta-lactamase Human genes 0.000 title abstract description 47
- 239000003112 inhibitor Substances 0.000 title abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 453
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 32
- 238000011282 treatment Methods 0.000 claims abstract description 23
- 208000035143 Bacterial infection Diseases 0.000 claims abstract description 17
- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 240
- 125000003118 aryl group Chemical group 0.000 claims description 135
- 125000001072 heteroaryl group Chemical group 0.000 claims description 111
- -1 ■OH Chemical compound 0.000 claims description 96
- 229910052736 halogen Inorganic materials 0.000 claims description 85
- 150000002367 halogens Chemical class 0.000 claims description 85
- 239000011737 fluorine Substances 0.000 claims description 80
- 229910052731 fluorine Inorganic materials 0.000 claims description 80
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 80
- 125000003545 alkoxy group Chemical group 0.000 claims description 78
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 72
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 68
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 67
- 125000005842 heteroatom Chemical group 0.000 claims description 62
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 59
- 125000006268 biphenyl-3-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C([H])C(*)=C([H])C([H])=C1[H] 0.000 claims description 51
- 239000005711 Benzoic acid Substances 0.000 claims description 43
- 235000010233 benzoic acid Nutrition 0.000 claims description 43
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 40
- 239000000460 chlorine Substances 0.000 claims description 38
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 35
- 229910052801 chlorine Inorganic materials 0.000 claims description 34
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 32
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 32
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 31
- 229910052794 bromium Inorganic materials 0.000 claims description 31
- 125000000623 heterocyclic group Chemical group 0.000 claims description 30
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 28
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 28
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 23
- 125000002252 acyl group Chemical group 0.000 claims description 20
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 18
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 16
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 16
- 125000001544 thienyl group Chemical group 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 13
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 13
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 125000002541 furyl group Chemical group 0.000 claims description 12
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 12
- 125000004104 aryloxy group Chemical group 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- RWYITADMELDNAG-UHFFFAOYSA-N 2-[2-(3-phenyl-5-sulfanylidene-1H-1,2,4-triazol-4-yl)ethylsulfanyl]propanoic acid Chemical compound C1(=CC=CC=C1)C1=NNC(N1CCSC(C(=O)O)C)=S RWYITADMELDNAG-UHFFFAOYSA-N 0.000 claims description 10
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 claims description 10
- 150000002466 imines Chemical class 0.000 claims description 10
- 229940124586 β-lactam antibiotics Drugs 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000005633 phthalidyl group Chemical group 0.000 claims description 9
- INTJMOGGQIJUAI-UHFFFAOYSA-N 2-[2-(3-phenyl-5-sulfanylidene-1H-1,2,4-triazol-4-yl)ethylsulfanyl]acetic acid Chemical compound C1(=CC=CC=C1)C1=NNC(N1CCSCC(=O)O)=S INTJMOGGQIJUAI-UHFFFAOYSA-N 0.000 claims description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000000586 2-(4-morpholinyl)ethoxy group Chemical group [H]C([H])(O*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 7
- 125000006269 biphenyl-2-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C(*)C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
- KUXXDQJCJKVMLF-UHFFFAOYSA-N 2-phenyl-2-[2-(3-phenyl-5-sulfanylidene-1H-1,2,4-triazol-4-yl)ethylsulfanyl]acetic acid Chemical compound C1(=CC=CC=C1)C(C(=O)O)SCCN1C(=NNC1=S)C1=CC=CC=C1 KUXXDQJCJKVMLF-UHFFFAOYSA-N 0.000 claims description 6
- 239000003782 beta lactam antibiotic agent Substances 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- IXAHDOYMCZRBFI-UHFFFAOYSA-N 2-[2-(5-sulfanylidene-3-thiophen-3-yl-1H-1,2,4-triazol-4-yl)ethyl]benzoic acid Chemical compound S1C=C(C=C1)C1=NNC(N1CCC1=C(C(=O)O)C=CC=C1)=S IXAHDOYMCZRBFI-UHFFFAOYSA-N 0.000 claims description 5
- VMCFDIHVJMDCDG-UHFFFAOYSA-N 2-[2-[3-(1H-pyrrol-2-yl)-5-sulfanylidene-1H-1,2,4-triazol-4-yl]ethyl]benzoic acid Chemical compound N1C(=CC=C1)C1=NNC(N1CCC1=C(C(=O)O)C=CC=C1)=S VMCFDIHVJMDCDG-UHFFFAOYSA-N 0.000 claims description 5
- HAQHGBQWHZKNEL-UHFFFAOYSA-N 3-[(3-phenyl-5-sulfanylidene-1H-1,2,4-triazol-4-yl)methyl]benzoic acid Chemical compound C1(=CC=CC=C1)C1=NNC(N1CC=1C=C(C(=O)O)C=CC=1)=S HAQHGBQWHZKNEL-UHFFFAOYSA-N 0.000 claims description 5
- RJDILCWGNNBNRJ-UHFFFAOYSA-N 4-[(3-phenyl-5-sulfanylidene-1H-1,2,4-triazol-4-yl)methyl]benzoic acid Chemical compound C1(=CC=CC=C1)C1=NNC(N1CC1=CC=C(C(=O)O)C=C1)=S RJDILCWGNNBNRJ-UHFFFAOYSA-N 0.000 claims description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 5
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 5
- 239000002132 β-lactam antibiotic Substances 0.000 claims description 5
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 4
- 239000004305 biphenyl Substances 0.000 claims description 4
- 235000010290 biphenyl Nutrition 0.000 claims description 4
- 229940127113 compound 57 Drugs 0.000 claims description 4
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims description 4
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims 1
- 241000894006 Bacteria Species 0.000 abstract description 20
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 296
- 238000005160 1H NMR spectroscopy Methods 0.000 description 80
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 80
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 78
- 239000000843 powder Substances 0.000 description 78
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 57
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- 238000000034 method Methods 0.000 description 24
- 239000003242 anti bacterial agent Substances 0.000 description 22
- 239000000203 mixture Substances 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 239000012453 solvate Substances 0.000 description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 201000010099 disease Diseases 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 229960002260 meropenem Drugs 0.000 description 10
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- VXEHYTTZIRUXJX-UHFFFAOYSA-N 4-[2-(4-hydroxyphenyl)ethyl]-3-phenyl-1H-1,2,4-triazole-5-thione Chemical compound OC1=CC=C(C=C1)CCN1C(=NNC1=S)C1=CC=CC=C1 VXEHYTTZIRUXJX-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 230000000844 anti-bacterial effect Effects 0.000 description 7
- 102000006635 beta-lactamase Human genes 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- PYRFHJUXDGQZPM-UHFFFAOYSA-N 1,2,4-triazole-3-thione Chemical group S=C1N=CN=N1 PYRFHJUXDGQZPM-UHFFFAOYSA-N 0.000 description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 241000588724 Escherichia coli Species 0.000 description 6
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 6
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 229940088710 antibiotic agent Drugs 0.000 description 6
- 230000001580 bacterial effect Effects 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 125000005493 quinolyl group Chemical group 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- BCUCPJUONAPFJS-UHFFFAOYSA-N 2-[2-(3-phenyl-5-sulfanylidene-1H-1,2,4-triazol-4-yl)ethyl]benzoic acid Chemical compound C1(=CC=CC=C1)C1=NNC(N1CCC1=C(C(=O)O)C=CC=C1)=S BCUCPJUONAPFJS-UHFFFAOYSA-N 0.000 description 5
- CXIYZCPODRYEPM-UHFFFAOYSA-N 3-(2-hydroxy-5-methoxyphenyl)-4-(2-phenylethyl)-1H-1,2,4-triazole-5-thione Chemical compound OC1=C(C=C(C=C1)OC)C1=NNC(N1CCC1=CC=CC=C1)=S CXIYZCPODRYEPM-UHFFFAOYSA-N 0.000 description 5
- ATHVVQOOZYRQFF-UHFFFAOYSA-N 4-(2-benzylsulfanylethyl)-3-phenyl-1H-1,2,4-triazole-5-thione Chemical compound C(C1=CC=CC=C1)SCCN1C(=NNC1=S)C1=CC=CC=C1 ATHVVQOOZYRQFF-UHFFFAOYSA-N 0.000 description 5
- SRMDEQXOBBCPEG-UHFFFAOYSA-N 4-benzyl-3-(2-hydroxy-5-methoxyphenyl)-1H-1,2,4-triazole-5-thione Chemical compound C(C1=CC=CC=C1)N1C(=NNC1=S)C1=C(C=CC(=C1)OC)O SRMDEQXOBBCPEG-UHFFFAOYSA-N 0.000 description 5
- FZIIOPOSBWZIPL-UHFFFAOYSA-N 5-hydroxy-2-[2-(3-phenyl-5-sulfanylidene-1H-1,2,4-triazol-4-yl)ethyl]benzoic acid Chemical compound OC=1C=CC(=C(C(=O)O)C=1)CCN1C(=NNC1=S)C1=CC=CC=C1 FZIIOPOSBWZIPL-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 230000003115 biocidal effect Effects 0.000 description 5
- 229960004261 cefotaxime Drugs 0.000 description 5
- GPRBEKHLDVQUJE-VINNURBNSA-N cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-VINNURBNSA-N 0.000 description 5
- 231100000135 cytotoxicity Toxicity 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 5
- 229960002182 imipenem Drugs 0.000 description 5
- 125000001041 indolyl group Chemical group 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 150000003952 β-lactams Chemical class 0.000 description 5
- LDLFBANONSBLLZ-UHFFFAOYSA-N 2-[2-[3-(2-hydroxy-5-methoxyphenyl)-5-sulfanylidene-1H-1,2,4-triazol-4-yl]ethyl]benzoic acid Chemical compound OC1=C(C=C(C=C1)OC)C1=NNC(N1CCC1=C(C(=O)O)C=CC=C1)=S LDLFBANONSBLLZ-UHFFFAOYSA-N 0.000 description 4
- DJLYPPYHDGPONB-UHFFFAOYSA-N 2-[2-[3-(3-methoxyphenyl)-5-sulfanylidene-1H-1,2,4-triazol-4-yl]ethyl]benzoic acid Chemical compound COC=1C=C(C=CC=1)C1=NNC(N1CCC1=C(C(=O)O)C=CC=C1)=S DJLYPPYHDGPONB-UHFFFAOYSA-N 0.000 description 4
- PSIKSHICRSARNJ-UHFFFAOYSA-N 4-[2-(2,4-dihydroxyphenyl)ethyl]-3-phenyl-1H-1,2,4-triazole-5-thione Chemical compound OC1=C(C=CC(=C1)O)CCN1C(NN=C1C1=CC=CC=C1)=S PSIKSHICRSARNJ-UHFFFAOYSA-N 0.000 description 4
- NXUULZDTTMJDAI-UHFFFAOYSA-N 4-benzyl-3-phenyl-1h-1,2,4-triazole-5-thione Chemical compound C=1C=CC=CC=1CN1C(S)=NN=C1C1=CC=CC=C1 NXUULZDTTMJDAI-UHFFFAOYSA-N 0.000 description 4
- 108090000204 Dipeptidase 1 Proteins 0.000 description 4
- 101000740455 Klebsiella pneumoniae Metallo-beta-lactamase type 2 Proteins 0.000 description 4
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 4
- 239000003781 beta lactamase inhibitor Substances 0.000 description 4
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
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- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 125000003838 furazanyl group Chemical group 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 125000002883 imidazolyl group Chemical group 0.000 description 4
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 125000002757 morpholinyl group Chemical group 0.000 description 4
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 4
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 4
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- RQPYHJGSNPEKCM-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-(3-phenyl-5-sulfanylidene-1H-1,2,4-triazol-4-yl)pentanoic acid Chemical compound C(C)(C)(C)OC(=O)NC(C(=O)O)CCCN1C(=NNC1=S)C1=CC=CC=C1 RQPYHJGSNPEKCM-UHFFFAOYSA-N 0.000 description 3
- BNCDIUBDLDFUDF-UHFFFAOYSA-N 2-[2-(5-sulfanylidene-3-thiophen-2-yl-1H-1,2,4-triazol-4-yl)ethyl]benzoic acid Chemical compound S1C(=CC=C1)C1=NNC(N1CCC1=C(C(=O)O)C=CC=C1)=S BNCDIUBDLDFUDF-UHFFFAOYSA-N 0.000 description 3
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Abstract
本发明涉及用作金属β内酰胺酶(MBL)抑制剂的新化合物。本发明还涉及包含此类MBL抑制剂的药物组合物,及其在治疗细菌感染中的用途。更一般地,本发明在任何必须除去产生MBL的细菌的领域中找到应用。
Description
本发明涉及用作金属β内酰胺酶(MBL)抑制剂的化合物。本发明还涉及包含此类MBL抑制剂的药物组合物,及其在治疗细菌感染中的用途。更一般地,本发明在任何必须除去产生微生物的MBL的领域中找到应用。
技术背景
由病原菌引起的感染在世界范围内很常见,并因此高度寻求对此类感染的抗菌治疗。然而,对抗生素具有耐药的(resistant)细菌的发展和传播是一个日益严重的公共卫生问题。它威胁到感染的有效治疗,并可能使现代医学的一些主要成就变得低效。目前,β-内酰胺抗菌药物是应用最广泛的抗菌治疗之一。尽管对抗生素的耐药性(resistance)是一种自然现象,但由于过度使用抗生素以及因旅行导致抗药性菌株在全球范围内传播的增加,情况变得更糟。在欧洲和其它发达社会,医院中发现的耐药细菌比例最高。今天,约70%在医院中引起感染的细菌对至少一种最常用于治疗的药物具有耐药性。
目前最令人担忧的抗生素耐药机制是酶催化水解β-内酰胺家族的β-内酰胺环,这是使用最广泛的一组抗菌药物,包括青霉素、头孢菌素、碳青霉烯类等。克服β-内酰胺酶介导的耐药性的一种高度相关的方法涉及组合治疗,其中β-内酰胺药物与β-内酰胺酶抑制剂一起给予,以保护前者免于失活。
β-内酰胺酶分为四个分子类别,A、B、C和D。类别A、C和D是丝氨酸酶,其中丝氨酸残基具有催化活性。它们中的大多数对碳青霉烯类药物没有活性。类别B代表MBL,其中一个或两个Zn原子促进β-内酰胺水解。虽然目前市场上有几种β-内酰胺酶抑制剂,但它们仅针对有限数量的丝氨酸催化类型的β-内酰胺酶。对于重要的金属β内酰胺酶(MBL)类别,情况仍然不是这样。MBL最令人担忧的特征是它们能够灭活所有类别的β-内酰胺类(单环β-内酰胺类除外),包括碳青霉烯类,所述碳青霉烯类对绝大多数丝氨酸-β-内酰胺酶稳定,是具有最广谱活性的抗生素,被认为是医院中的最后使用的抗菌药物。此外,MBL不会被市售的β-内酰胺酶抑制剂灭活,甚至可以降解其中的一些。
MBL由属于一些最重要的临床相关的细菌物种的临床分离株产生,引起大量的医院内感染(例如肺炎克雷伯菌、铜绿假单胞菌、气单胞菌、鲍氏不动杆菌、阴沟肠杆菌、大肠杆菌、粘质沙雷氏菌等)。此外,虽然MBL主要存在于医院内菌株中,但目前另一个严重的问题是它们出现在导致社区获得性感染的细菌中。MBL现在被认为是一个主要的治疗挑战。
因此,仍然存在对抗MBL介导的抗菌耐药性的新的治疗方法的需求。
发明概述
因此,本发明的目的是提供基于杂环分子的新化合物,该杂环分子含有在4和5位不同取代的1,2,4-三唑-3-硫酮部分,特别是有效对抗临床相关的MBL(包括NDM-型酶、VIM-型酶和IMP-型酶)的新化合物。已经开发了根据下式(II)并具有1,2,4-三唑-3-硫酮部分的化合物。然而,此类化合物对几种MBL(包括VIM-2和NDM-1)几乎没有或没有活性,并且不能恢复细菌菌株中β-内酰胺类抗生素的抗菌活性。为了获得活性,发明人开发了稳定的化合物,其中所述腙样键被饱和的N-C或C-C键替代。这种修饰导致化合物在临床细菌菌株中表现出增加的稳定性和对VIM型和NDM-1酶的广谱抑制作用和活性。
在一方面,本发明提供了如本文所定义的式(I)化合物或其药学上可接受的盐或溶剂合物。
在另一个方面,本发明提供了药物组合物,其包含如本文所定义的式(I)化合物或其药学上可接受的盐或溶剂合物,和一种或多种药学上可接受的赋形剂。
本发明还提供了组合物,其包含如本文所定义的式(I)化合物和任选地至少一种合适的抗微生物剂(抗细菌、抗真菌或抗病毒)。所述组合物有助于在药理学(人类和兽医治疗),植物检疫,农业和清洁(洗涤剂)应用中控制微生物(包括病毒、细菌和真菌)。
在另一个方面,本发明提供了如本文所定义的式(I)化合物或其药学上可接受的盐或溶剂合物,或如本文所定义的药物组合物,其用于治疗细菌感染。
在另一个方面,本发明提供了如本文所定义的式(I)化合物或其药学上可接受的盐或溶剂合物,或如本文所定义的药物组合物,与合适的抗细菌剂组合,其用于治疗细菌感染。
在另一个方面,本发明提供了在体外或体内抑制细菌金属β内酰胺酶的方法,所述方法包括使细胞与有效量的如本文所定义的式(I)化合物或其药学上可接受的盐或溶剂合物接触。
在另一个方面,本发明提供了在需要此类治疗的患者中治疗细菌感染的方法,所述方法包括向所述患者施用与合适的抗细菌剂组合的治疗有效量的如本文所定义的式(I)化合物或其药学上可接受的盐或溶剂合物,或如本文所定义的药物组合物。
在另一个方面,本发明提供了如本文所定义的式(I)化合物或其药学上可接受的盐或溶剂合物,其用于与合适的抗细菌剂组合使用,用于抑制MBL。
在另一个方面,本发明提供了除去产生细菌的MBL的方法,其中所述细菌与至少一种式(I)化合物和合适的抗细菌剂接触。
本发明还提供了试剂盒,其包括至少一种式(I)化合物和任选地至少一种合适的抗细菌剂。例如,所述试剂盒可用于体外测试,以评估抗细菌剂对产生细菌的MBL的效力。所述试剂盒还可以用于制备用于在有需要的患者种治疗细菌感染的药物组合物。
更具体地,本发明涉及式(I)化合物或其药学上可接受的盐,所述化合物如下所示,
其中,
■卤素,优选氯、氟或溴,
■OH、NO2、NR5R6、COOR8,
■(C1-C6)烷氧基、芳基氧基、芳基(C1-C6)烷氧基、环烷基(C1-C6)烷氧基、杂环烷基(C1-C6)烷氧基、杂芳基(C1-C6)烷氧基,其中所述芳基、环烷基、杂环烷基或杂芳基部分任选取代有至少一个(C1-C6)烷基,且所述烷氧基部分任选取代有至少一个卤素,优选氟,
■被NR3R4取代的(C1-C6)烷氧基,其中R3和R4独立地表示H、(C1-C12)酰基、(C1-C6)烷基、芳基(C1-C3)烷基、杂芳基(C1-C3)烷基、环烷基(C1-C3)烷基、杂环烷基(C1-C3)烷基、((C1-C6)烷基)-O-C(O)-、(芳基(C1-C6)烷基)-O-C(O)-、((C1-C6)烷基)-SO2-、((C1-C6)烷基芳基)-SO2-,
■(C1-C6)烷基,任选取代有至少一个卤素,优选氟,和
■芳基、杂芳基,它们任选取代有至少一个(C1-C6)烷基、至少一个(C1-C6)烷氧基、至少一个卤素原子、至少一个OH基团、至少一个NO2、至少一个-COOR8或至少一个NR5R6;
○选自以下的5-14元环:芳基、环烷基、杂环(所述杂环优选为杂芳基、杂环烷基、或杂环衍生物),所述5-14元环任选取代有至少一个选自以下的基团:
■卤素,优选氯、氟或溴,
■OH、NO2、NR5R6、COOR8,
■(C1-C6)烷基,任选取代有至少一个卤素,优选氟,或取代有COOR8,
■(C1-C6)烷氧基、芳基氧基、芳基(C1-C6)烷基氧基,和
■任选取代有NO2的芳基;
○选自下面的基团:
■COOR8,
■N3,
■NR1R2基团,其中R1和R2独立地表示H、(C1-C12)酰基、(C1-C6)烷基、芳基(C1-C3)烷基、杂芳基(C1-C3)烷基、环烷基(C1-C3)烷基、杂环烷基(C1-C3)烷基、((C1-C6)烷基)-O-C(O)-、(芳基(C1-C6)烷基)-O-C(O)-、((C1-C6)烷基)-SO2-、((C1-C6)烷基芳基)-SO2-,其中所述芳基、杂芳基、环烷基、杂环烷基部分任选地被至少一个选自下面的基团取代:卤素(优选氯、氟或溴)、OH、COOR8、NO2、NR5R6、脒基、NH-C(=NH)-NH2、(C1-C6)烷基氧基、和任选取代有至少一个卤素(优选氟)或取代有COOR8的(C1-C6)烷基,
或其中R1和R2与它们连接的氮一起形成含氮杂环或亚胺;
■SO2-R7,其中R7表示(C1-C6)烷基,或5-14元环,优选芳基,该5-14元环任选取代有(C1-C6)烷基,
■(C1-C12)酰基(优选苯甲酰基),和
■-NH(CO)-NHR9,其中R9为H、(C1-C6)烷基、芳基,优选苯基;或
○(C1-C6)烷基,任选取代有至少一个卤素,优选氟,或取代有COOR8,
其中R5和R6独立地为H、(C1-C6)烷基、芳基、杂芳基、(C3-C12)环烷基、(C3-C12)杂环烷基、(C1-C12)酰基、((C1-C6)烷基)-O-C(O)-、(芳基(C1-C6)烷基)-O-C(O)-、((C1-C6)烷基)-SO2-、((C1-C6)烷基芳基)-SO2-,或R5和R6与它们连接的氮一起形成含氮杂环或亚胺,且
R8独立地为H、(C1-C6)烷基、芳基、杂芳基、(C3-C12)环烷基、或(C3-C12)杂环烷基。
在一个优选实施方案中,式(I)的化合物选自:
-化合物1. 2-[2-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)乙基]苯甲酸;
-化合物2. 4-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)丁酸;
-化合物3. 2-{2-[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物4. 2-{2-[3-(2-羟基-5-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物5. 2-{[(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)氨基]甲基}苯甲酸;
-化合物6. 3-(2-甲基苯基)-4-(2-苯基乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物7. 4-苄基-3-(2-羟基-5-甲氧基苯基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物8. 3-苯基-4-(3-苯基丙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物9. 4-苄基-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物10. 3-(2-羟基-5-甲氧基苯基)-4-(2-苯基乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物11. 3-苯基-4-(2-苯基乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物12. 2-{2-[3-(呋喃-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物13. 2-{2-[3-(噻吩-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物14. 2-{2-[3-(2-甲基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物15. 5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;
-化合物16. 2-({[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]氨基}甲基)苯甲酸;
-化合物17. 2-{1-[(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)甲基]环己基}乙酸;
-化合物18. 4-[3-(2-羟基-5-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸;
-化合物19. 4-[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸;
-化合物20. 3-苯基-4-[(1R,2S)-2-苯基环丙基]-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物21. 3-(4-氯苯基)-4-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)丁酸;
-化合物22. 2-{2-[3-(3-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物23. 2-{2-[3-(4-甲基-1,2,3-噻二唑-5-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物24. 4-[3-(3-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸;
-化合物25. 2-{[(叔丁氧基)羰基]氨基}-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;
-化合物26. 4-己基-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物27. 2-{2-[3-(5-氯噻吩-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物28. 3-苯基-4-(2-{[2-(三氟甲基)喹啉-4-基]硫基}乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物29. 5-[3-(2-羟基-5-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]戊酸;
-化合物30. 5-[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]戊酸;
-化合物31. 4-[2-(4-羟基苯基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物32. 4-丁基-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物33. 4-[2-(苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物34. 4-[(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)甲基]环己烷-1-甲酸;
-化合物35. 2-{2-[3-(金刚烷-1-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物36. 2-{2-[3-(喹啉-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物37. 5-苯基-4-[(3-苯酞基)甲基]-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物38. 5-(3-联苯基)-4-[3-羧基丙基]-1,2,4-三唑-3-硫酮;
-化合物39. 5-(3-联苯基)-4-[2-(2-羧基苯基)乙基]-1,2,4-三唑-3-硫酮;
-化合物40. 5-(4-苄基氧基苯基)-4-[2-(2-羧基苯基)乙基]-1,2,4-三唑-3-硫酮;
-化合物41. 4-[2-(2,4-二羟基苯基)乙基]-5-苯基-1,2,4-三唑-3-硫酮;
-化合物42. 5-(3-联苯基)-4-[2-(2,4-二羟基苯基)乙基]-1,2,4-三唑-3-硫酮;
-化合物43. 5-(2-联苯基)-4-[2-(2,4-二羟基苯基)乙基]-1,2,4-三唑-3-硫酮;
-化合物44.邻-{2-[1-甲基-1H-吡咯-2-基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物45. 6-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)己酸;
-化合物46. 3-苯基-4-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)丁酸;
-化合物47. 3-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)环己烷-1-甲酸;
-化合物48. 4-[3-(1-甲基-1H-吡咯-2-基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]丁酸;
-化合物49. 4-(2-叠氮基乙基)-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物50. 4-[3-(喹啉-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸;
-化合物51.邻-{[3-(3-联苯基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基氨基]甲基}苯甲酸;
-化合物52.间-[(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)甲基]苯甲酸;
-化合物53. 5-羟基-2-[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基]苯甲酸;
-化合物54. 4-[4-(苄基氧基)苯基乙基]-5-苯基-1,2,4-三唑-3-硫酮;
-化合物55.对-[(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)甲基]苯甲酸;
-化合物56. 2-{2-[3-(喹啉-6-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物57.邻-{2-[3-(1H-吡咯-2-基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物58.邻-{2-[3-(3-噻吩基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物59. 8-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)辛酸;
-化合物60.苯基[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]乙酸;
-化合物61. 5-氨基-2-[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基]苯甲酸;
-化合物62.邻-(2-{3-[间-(2-吗啉代乙氧基)苯基]-5-硫代-1,4-二氢-1,2,4-三唑-4-基}乙基)苯甲酸;
-化合物63.邻-[2-(3-{间-[2-(4-甲基-1-哌嗪基)乙氧基]苯基}-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基]苯甲酸;
-化合物64. 4-[2-(苄硫基)乙基]-5-(1-甲基-1H-吡咯-2-基)-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物65.[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]乙酸;
-化合物66.[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]丙酸;
-化合物67. 2-[[2,3-二羟基苯基)甲基]氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;
-化合物68. 2-[二(苯基甲基)氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;
-化合物69. 2-[二(1H-咪唑-5-基甲基)氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;
-化合物70. 5-苯基-4-[2-(苯基硫基)乙基]-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物71. 4-[2-(2-氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物72. 4-[2-(4-氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物73. 4-[2-(2,4-二氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物74. 4-[2-(4-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物75. 4-[2-(2-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物76. 4-[2-(2-羟基-5-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物77. 4-[2-(2-苯基乙基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物78. 2-苯基-3-[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]-丙酸;
-化合物79. 5-苯基-4-[3-(苯基硫基)丙基]-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物80. 4-[2-(苄硫基)乙基]-5-(邻-甲苯基)-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物81. 3-{2-[3-(3-联苯基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基硫基}-氢化阿托酸。
在一个具体实施方案中,式(I)的化合物选自:
-化合物1. 2-[2-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)乙基]苯甲酸;
-化合物2. 4-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)丁酸;
-化合物4. 2-{2-[3-(2-羟基-5-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物5. 2-{[(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)氨基]甲基}苯甲酸;
-化合物12. 2-{2-[3-(呋喃-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物13. 2-{2-[3-(噻吩-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物14. 2-{2-[3-(2-甲基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物15. 5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸。
在一个具体实施方案中,式(I)的化合物选自:
-化合物33. 4-[2-(苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物37. 5-苯基-4-[(3-苯酞基)甲基]-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物39. 5-(3-联苯基)-4-[2-(2-羧基苯基)乙基]-1,2,4-三唑-3-硫酮;和
-化合物42. 5-(3-联苯基)-4-[2-(2,4-二羟基苯基)乙基]-1,2,4-三唑-3-硫酮。
在一个具体实施方案中,式(I)的化合物选自:
-化合物12. 2-{2-[3-(呋喃-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物13. 2-{2-[3-(噻吩-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物14. 2-{2-[3-(2-甲基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸。
发明详述
定义
本文提及的带有前缀如C1-C3、C1-C6或C2-C6的术语也可以与碳原子数较少的如C1-C2、C1-C5或C2-C5一起使用。例如,如果使用术语C1-C3,则意指相应的烃链可以包含1至3个碳原子,尤其是1、2或3个碳原子。例如,如果使用术语C1-C6,则意指相应的烃链可以包含1至6个碳原子,尤其是1、2、3、4、5或6个碳原子。例如,如果使用术语C2-C6,则意指相应的烃链可以包含2至6个碳原子,尤其是2、3、4、5或6个碳原子。
术语“烷基”是指饱和的,直链或支链的脂族基团。术语“(C1-C3)烷基”更具体地意指甲基、乙基、丙基或异丙基。术语“(C1-C6)烷基”更具体地是指甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基或己基。除非另有说明,否则术语“烷基”还包括全卤代烷基,特别是全氟代烷基,如CF3。
术语“烯基”是指具有至少一个碳-碳双键的不饱和,直链或支链的脂族基团。术语“(C2-C10)烯基”更具体地包括乙烯基、丙烯基、丁烯基、戊烯基、己烯基、庚烯基、辛烯基、壬烯基或癸烯基。术语“(C2-C6)烯基”更具体地包括乙烯基、丙烯基、丁烯基、戊烯基或己烯基。术语“烷氧基”或“烷基氧基”对应于如上面所定义的烷基通过-O-(醚)键与分子键合。(C1-C3)烷氧基包括甲氧基、乙氧基、丙氧基和异丙氧基。(C1-C6)烷氧基包括甲氧基、乙氧基、丙基氧基、异丙基氧基、丁基氧基、异丁基氧基、叔丁基氧基、戊基氧基和己基氧基。在优选的实施方案中,所述烷氧基是甲氧基。
术语“环烷基”对应于饱和的或非芳族不饱和的,单环、双环或三环烷基,其包含3至20个碳原子。它还包括稠合、桥连或螺连接的环烷基。术语“环烷基”包括例如环丙基、环丁基、环戊基和环己基。术语“环烷基”还可以指5-10元桥连的碳环基,如双环[2,2,1]庚基、双环[2,2,2]辛基或金刚烷基。在优选的实施方案中,所述环烷基是金刚烷基或环己基。
术语“杂环烷基”对应于如上面所定义的饱和或非芳族不饱和环烷基,其进一步包含至少一个杂原子,例如氮(N),氧(O)或硫(S)原子。它还包括稠合、桥连或螺连接的杂环烷基。表示性的杂环烷基包括,但不限于3-二氧杂环戊烷、苯并[1,3]二氧杂环戊烯基、吡唑啉基、吡喃基、硫吗啉基、吡唑烷基、哌啶基、哌嗪基、1,4-二氧杂环己基、咪唑啉基、氮杂环庚基、吡咯啉基、吡咯烷基、哌啶基、咪唑烷基、吗啉基、1,4-二噻烷基、吡咯烷基、喹嗪基、噁唑啉基(oxozoliny)、噁唑烷基、异噁唑啉基、异噁唑烷基、噻唑啉基、噻唑烷基、异噻唑啉基、异噻唑烷基、二氢吡喃基、四氢-2H-呋喃基、四氢呋喃基和四氢噻吩基。术语“杂环烷基”还可以指5-10元桥连的杂环基,如7-氧杂双环[2,2,1]庚基。在优选的实施方案中,所述杂环烷基是吗啉基。
术语“芳基”对应于具有5至14个碳原子的单环或双环芳族烃。优选地,术语“芳基”是指苯基、联苯基或萘基。术语“联苯”可以用于“被苯基取代的苯基”。
本文所用术语“杂芳基”对应于芳族单环或多环基团,其包含5至14个原子并且包含一个或多个杂原子,如氮(N),氧(O)或硫(S)原子。这些单环和多环杂芳基的实例可以是:吡啶基、噻唑基、噻吩基、呋喃基、吡咯基、咪唑基、三唑基、四唑基、苯并呋喃基、噻萘基(thianaphthalenyl)、吲哚基、二氢吲哚基、喹啉基、异喹啉基、苯并咪唑基、三嗪基、噻二唑基、噻蒽基、异苯并呋喃基、吩噁噻基(phenoxanthinyl)、异噻唑基、异噁唑基、吡嗪基、哒嗪基、吲嗪基、异吲哚基、吲唑基、嘌呤基、酞嗪基(phtalazinyl)、萘啶基、喹喔啉基、喹唑啉基、噌啉基、碟啶基、咔唑基、β-咔啉基、菲啶基、吖啶基、嘧啶基、菲咯啉基、吩嗪基、吩噻嗪基、呋咱基(furazanyl)、吩噁嗪基、苯并三唑基、苯并噁唑基、苯并异噁唑基、羟吲哚基、苯并噻吩基、苯并噻唑基、s-三嗪基、噁唑基或噻吩基。在优选的实施方案中,所述杂芳基是呋喃基、吡咯基、咪唑基、噻吩基或喹啉基。
术语“杂环”对应于脂环族或芳族单环或多环烃,其包含一个或多个杂原子,如氮(N),氧(O)或硫原子(S),并且任选地包含一个或多个氧代基团。杂环包括,但不限于杂芳基、杂环烷基和杂环衍生物。所述“杂环衍生物”更具体地选自异二氢吲哚基、二氢吲哚基、色满基、异色满基、酞基、邻苯二甲酰亚胺基、吡咯烷酮基、咪唑烷酮基、色烯基、四氢喹啉基、四氢异喹啉基、呫吨基、苯并噁唑啉基、isatinyl和二氢吡啶基,优选地邻苯二甲酰亚胺基或酞基。
术语“含氮杂环”对应于如上所定义的杂环,其具有至少一个氮原子。含氮杂环的实例是邻苯二甲酰亚胺基。
术语“亚胺”对应于具有下式的部分的基团:
特别地,所述亚胺可以是式-N=CRxRy,其中Rx和Ry独立地选自H、烷基、芳基、环烷基、杂芳基和杂环烷基,并且其中所述亚胺通过其N原子与分子键合。
术语“芳基氧基”对应于如上面所定义的芳基通过-O-(醚)键与分子键合。芳基氧基的实例是苯氧基。
本文所用术语“烷基芳基”对应于如上所定义的芳基,其取代有至少一个如上所定义的烷基。更具体地,术语“(C1-C6)烷基芳基”对应于烷基芳基,其烷基为(C1-C6)烷基。在优选的实施方案中,所述“(C1-C6)烷基芳基”是甲苯基。
本文所用术语“芳基烷基”或“芳烷基”对应于如上所定义的烷基,其取代有至少一个如上所定义的芳基。更具体地,术语“芳基(C1-C6)烷基”对应于芳基烷基,其烷基为(C1-C6)烷基。在优选的实施方案中,所述“芳基(C1-C6)烷基”是苄基、苯乙基或三苯甲基,更优选地苄基和苯乙基。
本文所用的术语“环烷基烷基”对应于如上所定义的烷基,其取代有至少一个如上所定义的环烷基。更具体地,术语“环烷基(C1-C3)烷基”对应于环烷基烷基,其烷基为(C1-C3)烷基。
本文所用的术语“杂环烷基烷基”对应于如上所定义的烷基,其取代有至少一个如上所定义的杂环烷基。更具体地,术语“杂环烷基(C1-C3)烷基”对应于杂环烷基烷基,其所述烷基为(C1-C3)烷基。
本文所用的术语“杂芳基烷基”对应于如上所定义的烷基,其取代有至少一个如上所定义的杂芳基。更具体地,术语“杂芳基(C1-C3)烷基”对应于杂芳基烷基,其烷基为(C1-C3)烷基。
本文所用的术语“芳基烷基氧基”或“芳基烷氧基”对应于如上定义的烷氧基,其取代有至少一个如上定义的芳基。更具体地,术语“芳基(C1-C6)烷基氧基”对应于芳基烷基氧基,其烷基氧基为(C1-C6)烷基氧基。在优选的实施方案中,所述“芳基(C1-C6)烷基氧基”是苄基氧基。
本文所用的术语“环烷基烷氧基”对应于如上定义的烷氧基,其取代有至少一个如上定义的环烷基。更具体地,术语“环烷基(C1-C6)烷氧基”对应于环烷基烷氧基,其烷氧基为(C1-C6)烷氧基。
如本文所用,术语“杂环烷基烷氧基”对应于如上所定义的烷氧基,其取代有至少一个如上所定义的杂环烷基。更具体地,术语“杂环烷基(C1-C6)烷氧基”对应于杂环烷基烷氧基,其烷氧基为(C1-C6)烷氧基。在优选的实施方案中,所述“杂环烷基(C1-C6)烷氧基”是吗啉基乙氧基或(甲基哌嗪基)乙氧基。
本文所用的术语“杂芳基烷氧基”对应于如上定义的烷氧基,其取代有至少一个如上定义的杂芳基。更具体地,术语“杂芳基(C1-C6)烷氧基”对应于杂芳基烷氧基,其烷氧基为(C1-C6)烷氧基。
本文所用的术语“酰基”对应于烃链或碳环,其通过-(CO)-基团键合到分子上。优选的酰基是烷基-(CO)-、芳基-(CO)-、杂芳基-(CO)-、环烷基-(CO)-、杂环烷基-(CO)-、芳基烷基-(CO)-,其中所述烷基、芳基、杂芳基、环烷基、杂环烷基和烷基方法如上所定义。
例如,酰基可以是CH3-(CO)-、CF3-(CO)-或苄基-(CO)-。
((C1-C6)烷基)-O-C(O)-的实例是Boc(叔丁氧基羰基)。
((芳基(C1-C6)烷基)-O-C(O)-的实例是(苄基)-O-C(O)-或(芴基甲基)-O-C(O)-。
((C1-C6)烷基芳基)-SO2-的实例是甲苯基-SO2-。
术语“卤素”对应于氟、氯、溴或碘原子,优选地氟、氯或溴原子。
术语“杂原子”是指非金属原子,其不同于碳和氢并且具有至少一对电子。优选的杂原子为N、O、S、Se、Si和P,更优选地N、O和S。
表述“被至少一个取代”或“包含至少一个”意指基团(radical/group)被列表中的一个、两个、三个或几个基团取代,或包含列表中的一个,两个,三个或几个基团,优选地,被列表中的一个或两个基团取代,或包含列表中的一个或两个基团。
本文所用的术语“治疗”(treatment/treat/treating)是指旨在改善患者健康状况的任何行为,如治疗、防止、预防和延缓疾病,特别是细菌感染。在某些实施方案中,此类术语是指疾病或与之相关的症状的改善或根除。在其它的实施方案中,该术语是指使由于向患有这种疾病的受试者施用一种或多种治疗剂,而最小化疾病的扩散或恶化。
本文所用的术语“受试者”、“个体”或“患者”是可互换的,并且是指动物,优选地是哺乳动物,甚至更优选地是人,包括在成年人、儿童、新生儿和产前期的人。但是,术语“受试者”也可以指非人类动物,特别是哺乳动物,如狗、猫、马、牛、猪、绵羊和非人类灵长类动物等。
术语“数量”、“量”和“剂量”在本文可互换使用,并且可以指分子的绝对定量。
本文所用的术语“有效成分”、“活性成分”和“活性药物成分”是等同的,并且是指具有治疗效果的药物组合物的组分。
如本文所用,术语“治疗效果”是指通过根据本发明的活性成分或药物组合物诱导的效果,其能够防止或延迟疾病的出现,或能够治愈或减弱该疾病的影响(effects)。
如本文所用,术语“有效量”是指防止、去除或减少疾病的有害影响的活性成分或药物组合物的量。显而易见的是,本领域技术人员可以根据待治疗的受试者,疾病的性质等来调整给药的量。特别地,给药剂量和给药方案可以是待治疗疾病的性质、阶段和严重程度以及待治疗受试者的体重、年龄和整体健康,以及医生的判断的函数。。
如本文所用,术语“赋形剂或药学上可接受的载体”是指除活性成分外的任何组分,所述活性成分存在于药物组合物中。其添加可以旨在赋予最终产品特别的稠度或其它物理或味觉特性。赋形剂或药学上可接受的载体必须与活性成分没有任何相互作用,特别是化学相互作用。
化合物
本发明的目的是提供化合物或其药学上可接受的盐,特别是用于用作MBL抑制剂的化合物或其药学上可接受的盐,所述化合物具有如下所示的式(I),
其中:
■卤素,优选氯、氟或溴,
■OH、NO2、NR5R6、COOR8,
■(C1-C6)烷氧基、芳基氧基、芳基(C1-C6)烷氧基、环烷基(C1-C6)烷氧基、杂环烷基(C1-C6)烷氧基、杂芳基(C1-C6)烷氧基,其中所述芳基、环烷基、杂环烷基或杂芳基部分任选取代有至少一个(C1-C6)烷基,且所述烷氧基部分任选取代有至少一个卤素,优选氟,
■被NR3R4取代的(C1-C6)烷氧基,其中R3和R4独立地表示H、(C1-C12)酰基、(C1-C6)烷基、芳基(C1-C3)烷基、杂芳基(C1-C3)烷基、环烷基(C1-C3)烷基、杂环烷基(C1-C3)烷基、((C1-C6)烷基)-O-C(O)-、(芳基(C1-C6)烷基)-O-C(O)-、((C1-C6)烷基)-SO2-、((C1-C6)烷基芳基)-SO2-,
■(C1-C6)烷基,任选取代有至少一个卤素,优选氟,和
■芳基、杂芳基,它们任选取代有至少一个(C1-C6)烷基、(C1-C6)烷氧基、至少一个卤素原子、至少一个OH基团、至少一个NO2、-COOR8、或NR5R6;
○5-14元环,其选自芳基、环烷基、杂环(所述杂环优选为杂芳基、杂环烷基、或杂环衍生物),所述5-14元环任选取代有至少一个选自以下的基团:
■卤素,优选氯、氟或溴,
■OH、NO2、NR5R6、COOR8,
■(C1-C6)烷基,任选取代有至少一个卤素,优选氟,或取代有COOR8,
■(C1-C6)烷氧基、芳基氧基、芳基(C1-C6)烷基氧基,和
■任选取代有NO2的芳基;
○选自下面的基团:
■COOR8,
■N3,
■NR1R2基团,其中R1和R2独立地表示H、(C1-C12)酰基、(C1-C6)烷基、芳基(C1-C3)烷基、杂芳基(C1-C3)烷基、环烷基(C1-C3)烷基、杂环烷基(C1-C3)烷基、((C1-C6)烷基)-O-C(O)-、(芳基(C1-C6)烷基)-O-C(O)-、((C1-C6)烷基)-SO2-、((C1-C6)烷基芳基)-SO2-,其中所述芳基、杂芳基、环烷基、杂环烷基部分任选地被至少一个选自下面的基团取代:卤素(优选氯、氟或溴)、OH、COOR8、NO2、NR5R6、脒基、NH-C(=NH)-NH2、(C1-C6)烷基氧基、和任选取代有至少一个卤素(优选氟)或取代有COOR8的(C1-C6)烷基,
或其中R1和R2与它们连接的氮一起形成含氮杂环或亚胺;
■SO2-R7,其中R7表示(C1-C6)烷基,或5-14元环,优选芳基,该5-14元环任选取代有(C1-C6)烷基,
■(C1-C12)酰基(优选苯甲酰基),和
■-NH(CO)-NHR9,其中R9为H、(C1-C6)烷基、芳基,优选苯基;或
○(C1-C6)烷基,任选取代有至少一个卤素,优选氟,或取代有COOR8,
其中R5和R6独立地为H、(C1-C6)烷基、芳基、杂芳基、(C3-C12)环烷基、(C3-C12)杂环烷基、(C1-C12)酰基、((C1-C6)烷基)-O-C(O)-、(芳基(C1-C6)烷基)-O-C(O)-、((C1-C6)烷基)-SO2-、((C1-C6)烷基芳基)-SO2-,或R5和R6与它们连接的氮一起形成含氮杂环或亚胺,且
R8独立地为H、(C1-C6)烷基、芳基、杂芳基、(C3-C12)环烷基、或(C3-C12)杂环烷基。
在本申请中,当n是1且l是1时,部分(X)n-(A)l如下表示:
其中X是任选地包含至少一个杂原子的(C1-C3)烷基链,并且如上面定义的A替代所述(C1-C3)烷基链中的任意一个氢。
优选地,X是任选地包含至少一个杂原子的直链(C1-C3)烷基链。
在本申请中,当n是1且l是1时,部分(X)n-(A)l如下所示:
其中X是任选地包含至少一个杂原子的(C1-C3)烷基链并且如上面定义的各A独立地替代所述(C1-C3)烷基链中的任意一个氢。
优选地,A在所述(C1-C3)烷基链的末端位置,即在所述(C1-C3)烷基链的末端碳上,或当杂原子在所述(C1-C3)烷基链的末端碳上时,A在该杂原子上。
例如,当:
-X是甲基时,X-A是-CH2-A且X-(A)2是-CH(A)2;
-X是乙基时,X-A是-CH2-CH2-A且X-(A)2是-CH2-CH(A)2;
-X是丙基时,X-A是-CH2-CH2-CH2-A且X-(A)2是-CH2-CH2-CH(A)2。
同样,在本申请中,当o为1时,部分Y-(Z)o如下所示:
其中Y是任选地包含至少一个杂原子的(C1-C10)烷基链,任选地包含至少一个杂原子的(C3-C12)环烷基,或(C2-C10)烯基,并且其中如上所定义的Z取代所述(C1-C10)烷基、(C3-C12)环烷基或(C2-C10)烯基中的任意一个氢。
当o为2时,部分Y-(Z)o如下所示:
其中Y是任选地包含至少一个杂原子的(C1-C10)烷基链,任选地包含至少一个杂原子的(C3-C12)环烷基,或(C2-C10)烯基,并且其中如上所定义的各Z独立地替代所述(C1-C10)烷基链、(C3-C12)环烷基或(C2-C10)烯基中的任意一个氢。
优选地,当Y为(C1-C10)烷基链时,所述(C1-C10)烷基链是直链。
优选地,当Y为(C1-C10)烷基链时,Z在所述(C1-C10)烷基链的末端位置,即在所述(C1-C10)烷基链的末端碳上或当杂原子在所述(C1-C10)烷基链的末端碳上时,Z在该杂原子上。
优选地,当Y为(C2-C10)烯基时,Z在所述(C2-C10)烯基链的末端位置,即在所述(C2-C10)烯基链的末端碳上。
一般来讲:
-当n为0时,则l为1,因此,A直接连接至1,2,4-三唑-5-硫酮环;
-当l为2时,则n为1。
在本申请中,Y可以表示(C1-C10)烷基链,其任选地包含至少一个杂原子。应当理解,所述杂原子可以在所述(C1-C10)烷基链的任何位置。杂原子可以在(C1-C10)烷基链的一个或两个末端上,即该杂原子将式(I)化合物的1,2,4-三唑-5-硫酮部分与所述(C1-C10)烷基链连接,或该杂原子将所述(C1-C10)烷基链与一个(如果o=1)或两个(如果o=2)Z基团连接。可选地,或另外,所述杂原子可以在所述(C1-C10)烷基链的任意位置,即,所述杂原子可以插入(interrupt)所述(C1-C10)烷基链。同样适用于当Y表示任选地包含至少一个杂原子的(C3-C12)环烷基的情况。因此,它可以对应于如上所定义的杂环烷基。同样适用于X,所述X表示任选地包含至少一个杂原子的(C1-C3)烷基链。
式(I)化合物可以以另一种互变异构形式存在或与另一种互变异构形式平衡,其由下式(I’)表示:
因此,本发明还涵盖式(I)化合物的此类互变异构形式。
在具体的实施方案中,式(I)化合物选自:
-化合物1. 2-[2-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)乙基]苯甲酸;
-化合物2. 4-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)丁酸;
-化合物3. 2-{2-[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物4. 2-{2-[3-(2-羟基-5-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物5. 2-{[(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)氨基]甲基}苯甲酸;
-化合物6. 3-(2-甲基苯基)-4-(2-苯基乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物7. 4-苄基-3-(2-羟基-5-甲氧基苯基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物8. 3-苯基-4-(3-苯基丙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物9. 4-苄基-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物10. 3-(2-羟基-5-甲氧基苯基)-4-(2-苯基乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物11. 3-苯基-4-(2-苯基乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物12. 2-{2-[3-(呋喃-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物13. 2-{2-[3-(噻吩-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物14. 2-{2-[3-(2-甲基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物15. 5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;
-化合物16. 2-({[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]氨基}甲基)苯甲酸;
-化合物17. 2-{1-[(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)甲基]环己基}乙酸;
-化合物18. 4-[3-(2-羟基-5-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸;
-化合物19. 4-[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸;
-化合物20. 3-苯基-4-[(1R,2S)-2-苯基环丙基]-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物21. 3-(4-氯苯基)-4-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)丁酸;
-化合物22. 2-{2-[3-(3-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物23. 2-{2-[3-(4-甲基-1,2,3-噻二唑-5-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物24. 4-[3-(3-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸;
-化合物25. 2-{[(叔丁氧基)羰基]氨基}-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;
-化合物26. 4-己基-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物27. 2-{2-[3-(5-氯噻吩-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物28. 3-苯基-4-(2-{[2-(三氟甲基)喹啉-4-基]硫基}乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物29. 5-[3-(2-羟基-5-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]戊酸;
-化合物30. 5-[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]戊酸;
-化合物31. 4-[2-(4-羟基苯基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物32. 4-丁基-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物33. 4-[2-(苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物34. 4-[(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)甲基]环己烷-1-甲酸;
-化合物35. 2-{2-[3-(金刚烷-1-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物36. 2-{2-[3-(喹啉-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物37. 5-苯基-4-[(3-苯酞基)甲基]-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物38. 5-(3-联苯基)-4-[3-羧基丙基]-1,2,4-三唑-3-硫酮;
-化合物39. 5-(3-联苯基)-4-[2-(2-羧基苯基)乙基]-1,2,4-三唑-3-硫酮;
-化合物40. 5-(4-苄基氧基苯基)-4-[2-(2-羧基苯基)乙基]-1,2,4-三唑-3-硫酮;
-化合物41. 4-[2-(2,4-二羟基苯基)乙基]-5-苯基-1,2,4-三唑-3-硫酮;
-化合物42. 5-(3-联苯基)-4-[2-(2,4-二羟基苯基)乙基]-1,2,4-三唑-3-硫酮;
-化合物43. 5-(2-联苯基)-4-[2-(2,4-二羟基苯基)乙基]-1,2,4-三唑-3-硫酮;
-化合物44.邻-{2-[1-甲基-1H-吡咯-2-基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物45. 6-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)己酸;
-化合物46. 3-苯基-4-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)丁酸;
-化合物47. 3-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)环己烷-1-甲酸;
-化合物48. 4-[3-(1-甲基-1H-吡咯-2-基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]丁酸;
-化合物49. 4-(2-叠氮基乙基)-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物50. 4-[3-(喹啉-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸;
-化合物51.邻-{[3-(3-联苯基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基氨基]甲基}苯甲酸;
-化合物52.间-[(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)甲基]苯甲酸;
-化合物53. 5-羟基-2-[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基]苯甲酸;
-化合物54. 4-[4-(苄基氧基)苯基乙基]-5-苯基-1,2,4-三唑-3-硫酮;
-化合物55.对-[(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)甲基]苯甲酸;
-化合物56. 2-{2-[3-(喹啉-6-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物57.邻-{2-[3-(1H-吡咯-2-基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物58.邻-{2-[3-(3-噻吩基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物59. 8-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)辛酸;
-化合物60.苯基[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]乙酸;
-化合物61. 5-氨基-2-[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基]苯甲酸.
-化合物62.邻-(2-{3-[间-(2-吗啉代乙氧基)苯基]-5-硫代-1,4-二氢-1,2,4-三唑-4-基}乙基)苯甲酸;
-化合物63.邻-[2-(3-{间-[2-(4-甲基-1-哌嗪基)乙氧基]苯基}-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基]苯甲酸;
-化合物64. 4-[2-(苄硫基)乙基]-5-(1-甲基-1H-吡咯-2-基)-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物65.[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]乙酸;
-化合物66.[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]丙酸;
-化合物67. 2-[[2,3-二羟基苯基)甲基]氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;
-化合物68. 2-[二(苯基甲基)氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;
-化合物69. 2-[二(1H-咪唑-5-基甲基)氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;
-化合物70. 5-苯基-4-[2-(苯基硫基)乙基]-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物71. 4-[2-(2-氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物72. 4-[2-(4-氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物73. 4-[2-(2,4-二氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物74. 4-[2-(4-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物75. 4-[2-(2-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物76. 4-[2-(2-羟基-5-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物77. 4-[2-(2-苯基乙基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物78. 2-苯基-3-[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]-丙酸;
-化合物79. 5-苯基-4-[3-(苯基硫基)丙基]-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物80. 4-[2-(苄硫基)乙基]-5-(邻-甲苯基)-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物81. 3-{2-[3-(3-联苯基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基硫基}-氢化阿托酸。
在具体的实施方案中,本发明的化合物是式(I)化合物,其中:
■卤素,优选氯、氟或溴,
■OH,
■(C1-C6)烷氧基,任选取代有杂环烷基,优选甲氧基或吗啉基乙氧基,
·(C1-C6)烷基,任选取代有至少一个卤素,优选氟,和
■芳基(优选苯基)或芳基(C1-C6)烷基氧基(优选苄基氧基);
○ 5-14元环,其选自芳基(优选苯基)、环烷基(优选环己基或环丙基),杂环(所述杂环优选为杂芳基(优选喹啉基)、杂环烷基(优选吗啉基)或杂环衍生物(优选酞基)),所述5-14元环任选取代有至少一个选自以下的基团:
■卤素,优选氯、氟或溴,
■OH、COOH、NO2、NH2,
■(C1-C6)烷基,任选取代有至少一个卤素,优选氟,或取代有COOH,
■芳基(优选苯基),任选取代有NO2,和
■芳基(C1-C6)烷基氧基(优选苄基氧基);
○选自下面的基团:
■COOH,
■N3,
■NR1R2基团,其中R1和R2独立地表示H、Boc、(C1-C6)烷基
■SO2-R7,其中R7表示(C1-C6)烷基,或5-14元环,优选芳基,该5-14元环任选取代有(C1-C6)烷基,
■苯甲酰基,和
■N-苯基脲;或
○(C1-C6)烷基,任选取代有至少一个卤素,优选氟,或取代有COOH。
根据本发明,当n是0时,Y是-CH2-且A是杂芳基,所述杂芳基优选地具有一个或两个杂原子,如N、O或S。
根据另一个实施方案,当A是杂芳基时,所述杂芳基优选地选自吡啶基、噻唑基、噻吩基、呋喃基、吡咯基、咪唑基、三唑基、四唑基、苯并呋喃基、噻萘基(thianaphthalenyl)、吲哚基、二氢吲哚基、喹啉基、苯并咪唑基、三嗪基、噻蒽基、异苯并呋喃基、吩噁噻基(phenoxanthinyl)、异噻唑基、异噁唑基、吡嗪基、哒嗪基、吲嗪基、异吲哚基、吲唑基、嘌呤基、酞嗪基(phtalazinyl)、萘啶基、喹喔啉基、喹唑啉基、噌啉基、碟啶基、咔唑基、β-咔啉基、菲啶基、吖啶基、嘧啶基、菲咯啉基、吩嗪基、吩噻嗪基、呋咱基(furazanyl)、吩噁嗪基、苯并三唑基、苯并噁唑基、苯并异噁唑基、羟吲哚基、苯并噻吩基、苯并噻唑基、s-三嗪基、噁唑基和噻吩基(thiofuranyl)。在更优选的实施方案中,当A是杂芳基时,所述杂芳基是呋喃基、吡咯基、噻吩基或喹啉基。
在具体的实施方案中,本发明的化合物是式(I)化合物,其中n是1且X是甲基或乙基。
在另一个具体的实施方案中,本发明的化合物是式(I)化合物,其中n是0。根据所述具体的实施方案,A可以是任意杂芳基,除了当Y是-CH2-时。根据更具体的实施方案(不管Y的定义),A是具有一个或两个杂原子的杂芳基。当A是具有一个或两个杂原子的杂芳基时,所述杂芳基优选地选自吡啶基,噻唑基,噻吩基,呋喃基,吡咯基,咪唑基,苯并呋喃基,噻萘基(thianaphthalenyl),吲哚基,吲哚啉基,喹啉基,苯并咪唑基,噻蒽基,异苯并呋喃基,吩噁噻基(phenoxanthinyl),异噻唑基,异噁唑基,吡嗪基,哒嗪基,吲嗪基,异吲哚基,吲唑基,嘌呤基,酞嗪基,萘啶基,喹喔啉基,喹唑啉基,噌啉基,咔唑基,β-咔啉基,菲啶基,吖啶基,嘧啶基,菲咯啉基,吩嗪基,吩噻嗪基,呋咱基,吩噁嗪基,苯并噁唑基,苯并异噁唑基,羟吲哚基,苯并噻吩基,苯并噻唑基,噁唑基和噻吩基。在更优选的实施方案中,当A是杂芳基时,所述杂芳基是呋喃基、吡咯基、噻吩基或喹啉基。
在具体的实施方案中,本发明的化合物是式(I)化合物,其中Y是任选地包含至少一个杂原子的(C1-C10)烷基链,或任选地包含至少一个杂原子的(C3-C12)环烷基。在更具体的实施方案中,本发明的化合物是式(I)化合物,其中Y是任选地包含至少一个杂原子的(C2-C10)烷基链或任选地包含至少一个杂原子的(C3-C12)环烷基。
优选地,Y是任选地包含至少一个杂原子的(C2-C7)烷基链或任选地包含至少一个杂原子的(C3-C12)环烷基。更优选地,Y是任选地包含至少一个杂原子的(C2-C7)烷基链。
在另一个具体的实施方案中,本发明的化合物是式(I)化合物,其中(A)表示选自芳基和杂芳基的5-14元环,所述5-14元环任选地被至少一个选自下面的基团取代:
■卤素,优选氯、氟或溴,
■OH、NO2、NR5R6、COOR8,
■(C1-C6)烷氧基、芳基氧基、芳基(C1-C6)烷氧基、环烷基(C1-C6)烷氧基、杂环烷基(C1-C6)烷氧基、杂芳基(C1-C6)烷氧基,其中所述芳基、环烷基、杂环烷基或杂芳基部分任选取代有至少一个(C1-C6)烷基,且所述烷氧基部分任选取代有至少一个卤素,优选氟,
■被NR3R4取代的(C1-C6)烷氧基,其中R3和R4独立地表示H、(C1-C12)酰基、(C1-C6)烷基、芳基(C1-C3)烷基、杂芳基(C1-C3)烷基、环烷基(C1-C3)烷基、杂环烷基(C1-C3)烷基、((C1-C6)烷基)-O-C(O)-、(芳基(C1-C6)烷基)-O-C(O)-、((C1-C6)烷基)-SO2-、((C1-C6)烷基芳基)-SO2-,
■(C1-C6)烷基,任选取代有至少一个卤素,优选氟,和
■芳基、杂芳基,它们任选取代有至少一个(C1-C6)烷基、(C1-C6)烷氧基、至少一个卤素原子、至少一个OH基团、至少一个NO2、-COOR8、或NR5R6;
且当n为0时,Y为-CH2-且A为杂芳基,所述杂芳基具有一个或两个杂原子。
优选地,所述5-14元环任选地被至少一个选自下面的基团取代:
■卤素,优选氯、氟或溴,
■OH,
■(C1-C6)烷氧基(例如甲氧基)、芳基(C1-C6)烷氧基(例如苄基氧基)、杂环烷基(C1-C6)烷氧基(例如吗啉代乙氧基或哌嗪基乙氧基),其中所述基团的芳基或杂环烷基部分任选取代有至少一个(C1-C6)烷基,且所述基团的烷氧基部分任选取代有至少一个卤素,优选氟,
■(C1-C6)烷基,任选取代有至少一个卤素,优选氟,(例如甲基或CF3),和
■芳基(例如苯基),其任选取代有至少一个(C1-C6)烷基、(C1-C6)烷氧基、卤素原子、OH基团、NO2、-COOR8、或NR5R6。
在另一个具体的实施方案中,本发明的化合物是式(I)化合物,其中(A)表示选自芳基、杂芳基、环烷基和杂环烷基的5-14元环,所述5-14元环任选地被至少一个选自下面的基团取代:
■卤素,优选氯、氟或溴,
■OH,
■(C1-C6)烷氧基(例如甲氧基)、芳基(C1-C6)烷氧基(例如苄基氧基)、杂环烷基(C1-C6)烷氧基(例如吗啉代乙氧基或哌嗪基乙氧基),其中所述基团的芳基或杂环烷基部分任选取代有至少一个(C1-C6)烷基,且所述基团的烷氧基部分任选取代有至少一个卤素,优选氟,
·(C1-C6)烷基,任选取代有至少一个卤素,优选氟,(例如甲基或CF3),和
■芳基(例如苯基),其任选取代有至少一个(C1-C6)烷基、(C1-C6)烷氧基、卤素原子、OH基团、NO2、-COOR8、或NR5R6;
且当n为0时,Y为-CH2-且A为杂芳基,所述杂芳基具有一个或两个杂原子。
在另一个具体的实施方案中,本发明的化合物是式(I)化合物,其中A是具有一个或两个杂原子的杂芳基,其任选地被至少一个(C1-C6)烷基取代。具有最多两个杂原子的杂芳基的优选的实例是呋喃基、吡咯基、噻吩基或喹啉基。
在另一个具体的实施方案中,本发明的化合物是式(I)化合物,其中A是苯基或萘基(优选地苯基),其任选地被至少一个选自下面的基团取代:
■卤素,优选氯、氟或溴,
■OH,
■(C1-C6)烷氧基(例如甲氧基)、芳基(C1-C6)烷氧基(例如苄基氧基)、杂环烷基(C1-C6)烷氧基(例如吗啉代乙氧基或哌嗪基乙氧基),其中所述芳基或杂环烷基任选取代有至少一个(C1-C6)烷基,
■(C1-C6)烷基,任选取代有至少一个卤素,优选氟,(例如甲基或CF3),和
■芳基(例如苯基),其任选取代有至少一个(C1-C6)烷基、(C1-C6)烷氧基、卤素原子、OH基团、NO2、-COOR8、或NR5R6。
在更具体的实施方案中,A是任选地被甲氧基、(甲基哌嗪基)乙氧基或吗啉基乙氧基取代的苯基。
在具体的实施方案中,R5和R6独立地为H、(C1-C6)烷基、芳基、杂芳基、(C3-C12)环烷基、(C3-C12)杂环烷基、(C1-C12)酰基、((C1-C6)烷基)-O-C(O)-、(芳基(C1-C6)烷基)-O-C(O)-、((C1-C6)烷基)-SO2-或((C1-C6)烷基芳基)-SO2-,优选地H或(C1-C6)烷基,更优选地R5和R6是H。
在具体的实施方案中,R8是H或(C1-C6)烷基,优选地R8是H。
在具体的实施方案中,R1和R2独立地表示H、(C1-C12)酰基、(C1-C6)烷基、芳基(C1-C3)烷基、杂芳基(C1-C3)烷基、环烷基(C1-C3)烷基、杂环烷基(C1-C3)烷基、((C1-C6)烷基)-O-C(O)-、(芳基(C1-C6)烷基)-O-C(O)-、((C1-C6)烷基)-SO2-、((C1-C6)烷基芳基)-SO2-,其中所述芳基、杂芳基、环烷基、杂环烷基部分任选地被至少一个选自下面的基团取代:卤素(优选地氯、氟或溴)、OH、COOR8、NO2、NR5R6、NH-C(=NH)-NH2、(C1-C6)烷基氧基和任选地被至少一个卤素(优选地氟)或被COOR8取代的(C1-C6)烷基。优选地,R1和R2独立地表示H、Boc(叔丁基-O-C(O)-)、(C1-C6)烷基、芳基(C1-C3)烷基(例如苄基)、杂芳基(C1-C3)烷基(例如咪唑基甲基),其中所述芳基和杂芳基任选地被至少一个OH取代。
在另一个具体的实施方案中,本发明的化合物是式(I)化合物,其中Z表示:
○5-14元环,其选自芳基(例如苯基、联苯基或萘基)、环烷基(例如环己基、环丙基)、杂环(所述杂环优选为杂芳基(例如喹啉基)、或杂环衍生物(例如酞基)),所述5-14元环任选取代有至少一个选自以下的基团:
■卤素,优选氯、氟或溴,
·OH、COOH、NO2、NH2,
■(C1-C6)烷基(例如甲基),任选取代有至少一个卤素,优选氟,或取代有COOH;
○选自下面的基团:
■COOH,
■N3,
■NR1R2基团,其中R1和R2独立地表示H、Boc、(C1-C6)烷基、芳基(C1-C3)烷基(例如苄基)、杂芳基(C1-C3)烷基(例如咪唑基甲基),其中所述芳基和杂芳基任选取代有至少一个OH;或
○(C1-C6)烷基,任选取代有至少一个卤素,优选氟,或取代有COOH。
在具体的实施方案中,本发明的化合物是式(I)化合物,其中Z表示任选地被至少一个选自下面的基团取代的芳基(优选地苯基):
■卤素,优选氯、氟或溴,
■OH、NO2、NR5R6、COOR8,
■(C1-C6)烷基,任选取代有至少一个卤素,优选氟,或取代有COOR8,
■(C1-C6)烷氧基、芳基氧基、芳基(C1-C6)烷基氧基,和
■芳基,如苯基,任选取代有NO2。
在另一个具体的实施方案中,Z是杂环,优选地杂环烷基、杂芳基或杂环衍生物,更优选地杂芳基(例如喹啉基、呋喃基、噻吩基、吡咯基,优选地喹啉基)或杂环衍生物(例如酞基(phtalidyl))。在此类实施方案中,所述杂环任选地被至少一个选自下面的基团取代:
■卤素,优选氯、氟或溴,
■OH、NO2、NR5R6、COOR8,
■(C1-C6)烷基,任选取代有至少一个卤素,优选氟,或取代有COOR8,
■(C1-C6)烷氧基、芳基氧基、芳基(C1-C6)烷基氧基,和
■芳基,如苯基,任选取代有NO2。
在另一个具体的实施方案中,Z是选自下面的基团:
■COOR8,
■N3,
■NR1R2基团,其中R1和R2独立地表示H、(C1-C12)酰基、(C1-C6)烷基、芳基(C1-C3)烷基、杂芳基(C1-C3)烷基、环烷基(C1-C3)烷基、杂环烷基(C1-C3)烷基、((C1-C6)烷基)-O-C(O)-、(芳基(C1-C6)烷基)-O-C(O)-、((C1-C6)烷基)-SO2-、((C1-C6)烷基芳基)-SO2-,其中所述芳基、杂芳基、环烷基、杂环烷基部分任选地被至少一个选自下面的基团取代:卤素(优选氯、氟或溴)、OH、COOR8、NO2、NR5R6、脒基、NH-C(=NH)-NH2、(C1-C6)烷基氧基、和任选取代有至少一个卤素(优选氟)或取代有COOR8的(C1-C6)烷基,
或其中R1和R2与它们连接的氮一起形成含氮杂环或亚胺;
■(C1-C12)酰基(优选苯甲酰基),和
■(C1-C6)烷基,任选取代有至少一个卤素,优选氟,或取代有COOR8。
在具体的实施方案中,其中R7是5-14元环,所述5-14元环选自芳基、杂芳基、环烷基和杂环烷基,并且所述5-14元环任选地被(C1-C6)烷基取代。优选地,R7是任选地被(C1-C6)烷基取代的芳基。
在另一个具体的实施方案中,本发明的化合物是式(I)化合物,其中:
■卤素,优选氯、氟或溴,
■OH、NO2、COOR8,
■(C1-C6)烷氧基、杂环烷基(C1-C6)烷氧基(例如吗啉代乙氧基或哌嗪基乙氧基),其中所述基团的杂环烷基部分任选取代有至少一个(C1-C6)烷基,且所述基团的烷氧基部分任选取代有至少一个卤素,优选氟,
■(C1-C6)烷基(例如甲基),任选取代有至少一个卤素,优选氟,和
■芳基(例如苯基);
○5-14元环,其选自芳基(例如苯基)、环烷基、杂环(所述杂环优选为杂芳基、杂环烷基、或杂环衍生物(例如酞基)),所述5-14元环任选取代有至少一个选自以下的基团:
■卤素,优选氯、氟或溴,
■OH、NO2、COOR8,
·(C1-C6)烷基,任选取代有至少一个卤素,优选氟,或取代有COOR8,
■(C1-C6)烷氧基,
○选自下面的基团:
■COOR8,
■NR1R2基团,其中R1和R2独立地表示H、(C1-C6)烷基、芳基(C1-C3)烷基、杂芳基(C1-C3)烷基,其中所述芳基和杂芳基任选地被至少一个选自下面的基团取代:卤素(优选氯、氟或溴)、OH和NO2;
○(C1-C6)烷基,任选取代有至少一个卤素,优选氟,或取代有COOR8,
R8独立地为H、(C1-C6)烷基、芳基、杂芳基、(C3-C12)环烷基、或(C3-C12)杂环烷基,优选R8为H。
在另一个具体的实施方案中,本发明的化合物是式(I)化合物,其中:
■杂环烷基(C1-C6)烷氧基(例如吗啉代乙氧基或哌嗪基乙氧基),其中所述杂环烷基部分任选取代有至少一个(C1-C6)烷基,
■(C1-C6)烷基(例如甲基),和
■芳基(例如苯基);
○5-14元环,其选自芳基(例如苯基),和杂环(优选杂环衍生物(例如酞基)),所述5-14元环任选取代有至少一个选自以下的基团:
■卤素,优选氯、氟或溴,
■OH、NO2、COOR8,
■(C1-C6)烷基,任选取代有至少一个卤素,优选氟,或取代有COOR8,
○选自下面的基团:
■COOR8,
■NR1R2基团,其中R1和R2独立地表示H、(C1-C6)烷基、芳基(C1-C3)烷基、杂芳基(C1-C3)烷基,其中所述芳基和杂芳基任选地被至少一个选自下面的基团取代:卤素(优选氯、氟或溴)、OH和NO2;
○(C1-C6)烷基,任选取代有至少一个卤素,优选氟,或取代有COOR8,
R8独立地为H、(C1-C6)烷基、芳基、杂芳基、(C3-C12)环烷基、或(C3-C12)杂环烷基,优选R8为H。
在具体的实施方案中,式(I)化合物选自:
-化合物33. 4-[2-(苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物37. 5-苯基-4-[(3-苯酞基)甲基]-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物39. 5-(3-联苯基)-4-[2-(2-羧基苯基)乙基]-1,2,4-三唑-3-硫酮;
-化合物42. 5-(3-联苯基)-4-[2-(2,4-二羟基苯基)乙基]-1,2,4-三唑-3-硫酮;
-化合物62. 邻-(2-{3-[间-(2-吗啉代乙氧基)苯基]-5-硫代-1,4-二氢-1,2,4-三唑-4-基}乙基)苯甲酸;
-化合物63.邻-[2-(3-{间-[2-(4-甲基-1-哌嗪基)乙氧基]苯基}-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基]苯甲酸;
-化合物64. 4-[2-(苄硫基)乙基]-5-(1-甲基-1H-吡咯-2-基)-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物66.[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]丙酸;
-化合物67. 2-[[2,3-二羟基苯基)甲基]氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;
-化合物68. 2-[二(苯基甲基)氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;
-化合物69. 2-[二(1H-咪唑-5-基甲基)氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;
-化合物70. 5-苯基-4-[2-(苯基硫基)乙基]-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物71. 4-[2-(2-氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物72. 4-[2-(4-氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物73. 4-[2-(2,4-二氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物74. 4-[2-(4-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物75. 4-[2-(2-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物76. 4-[2-(2-羟基-5-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物77. 4-[2-(2-苯基乙基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物78. 2-苯基-3-[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]-丙酸;
-化合物80. 4-[2-(苄硫基)乙基]-5-(邻-甲苯基)-2,4-二氢-1,2,4-三唑-3-硫酮;和
-化合物81. 3-{2-[3-(3-联苯基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基硫基}-氢化阿托酸。
在另一个具体的实施方案中,本发明的化合物是式(I)化合物,其中:
○芳基(例如苯基),任选地被至少一个选自下面的基团取代:卤素(优选氟)、OH、NO2和COOR8,
○选自下面的基团:
■COOR8,
■NR1R2基团,其中R1和R2独立地表示H、(C1-C6)烷基、或杂芳基(C1-C3)烷基;
○(C1-C6)烷基,任选取代有至少一个卤素,优选氟,或取代有COOR8,
R8独立地为H、(C1-C6)烷基、芳基、杂芳基、(C3-C12)环烷基、或(C3-C12)杂环烷基,优选R8为H。
在优选的实施方案中,式(I)化合物选自:
-化合物39. 5-(3-联苯基)-4-[2-(2-羧基苯基)乙基]-1,2,4-三唑-3-硫酮;
-化合物42. 5-(3-联苯基)-4-[2-(2,4-二羟基苯基)乙基]-1,2,4-三唑-3-硫酮;
-化合物64. 4-[2-(苄硫基)乙基]-5-(1-甲基-1H-吡咯-2-基)-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物66.[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]丙酸;
-化合物69. 2-[二(1H-咪唑-5-基甲基)氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;
-化合物70. 5-苯基-4-[2-(苯基硫基)乙基]-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物71. 4-[2-(2-氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物73. 4-[2-(2,4-二氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物74. 4-[2-(4-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物75. 4-[2-(2-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物76. 4-[2-(2-羟基-5-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;和
-化合物77. 4-[2-(2-苯基乙基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮。
在更优选实施方案中,式(I)的化合物选自:
-化合物42. 5-(3-联苯基)-4-[2-(2,4-二羟基苯基)乙基]-1,2,4-三唑-3-硫酮;
-化合物69. 2-[二(1H-咪唑-5-基甲基)氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;和
-化合物70. 5-苯基-4-[2-(苯基硫基)乙基]-2,4-二氢-1,2,4-三唑-3-硫酮。
在另一具体实施方案中,n为0且A为芳基,其选自任选取代有苯基或苄基氧基的苯基、和萘基。优选地,式(I)的化合物选自:2-[2-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)乙基]苯甲酸;4-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)丁酸;2-{2-[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;2-{[(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)氨基]甲基}苯甲酸;3-苯基-4-(3-苯基丙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-苄基-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;2-({[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]氨基}甲基)苯甲酸;4-[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸;3-(4-氯苯基)-4-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)丁酸;2-{[(叔丁氧基)羰基]氨基}-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;4-己基-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;5-[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]戊酸;4-[2-(4-羟基苯基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-丁基-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-[2-(苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;5-苯基-4-[(3-苯酞基)甲基]-2,4-二氢-1,2,4-三唑-3-硫酮;5-(3-联苯基)-4-[3-羧基丙基]-1,2,4-三唑-3-硫酮;5-(3-联苯基)-4-[2-(2-羧基苯基)乙基]-1,2,4-三唑-3-硫酮;5-(4-苄基氧基苯基)-4-[2-(2-羧基苯基)乙基]-1,2,4-三唑-3-硫酮;5-(3-联苯基)-4-[2-(2,4-二羟基苯基)乙基]-1,2,4-三唑-3-硫酮;6-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)己酸;间-[(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)甲基]苯甲酸;5-羟基-2-[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基]苯甲酸;对-[(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)甲基]苯甲酸;8-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)辛酸;苯基[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]乙酸;[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]乙酸;[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]丙酸;2-[[2,3-二羟基苯基)甲基]氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;2-[二(苯基甲基)氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;2-[二(1H-咪唑-5-基甲基)氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;5-苯基-4-[2-(苯基硫基)乙基]-2,4-二氢-1,2,4-三唑-3-硫酮;4-[2-(2-氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-[2-(4-氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-[2-(2,4-二氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-[2-(4-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-[2-(2-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-[2-(2-羟基-5-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-[2-(2-苯基乙基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;2-苯基-3-[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]-丙酸;5-苯基-4-[3-(苯基硫基)丙基]-2,4-二氢-1,2,4-三唑-3-硫酮;和3-{2-[3-(3-联苯基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基硫基}-氢化阿托酸。
在一个具体实施方案中,式(I)的化合物选自4-[2-(苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;5-(3-联苯基)-4-[2-(2-羧基苯基)乙基]-1,2,4-三唑-3-硫酮或5-(3-联苯基)-4-[2-(2,4-二羟基苯基)乙基]-1,2,4-三唑-3-硫酮。
在一个具体实施方案中,n为0且A为苯基,其取代有至少一个选自以下的基团:甲基、甲氧基、CF3、OH、卤素(优选Cl)。优选地,式(I)的化合物选自2-{2-[3-(2-羟基-5-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;3-(2-甲基苯基)-4-(2-苯基乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-苄基-3-(2-羟基-5-甲氧基苯基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;3-(2-羟基-5-甲氧基苯基)-4-(2-苯基乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;2-{2-[3-(2-甲基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;4-[3-(2-羟基-5-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸;2-{2-[3-(3-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;4-[3-(3-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸;和5-[3-(2-羟基-5-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]戊酸。
在一个具体实施方案中,n为0且A为5-元环,其选自呋喃基,任选取代有卤素的噻吩基,和任选取代有甲基的吡咯基。优选地,式(I)的化合物选自:2-{2-[3-(呋喃-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;2-{2-[3-(噻吩-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;2-{2-[3-(4-甲基-1,2,3-噻二唑-5-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;2-{2-[3-(5-氯噻吩-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;邻-{2-[1-甲基-1H-吡咯-2-基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基}苯甲酸;4-[3-(1-甲基-1H-吡咯-2-基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]丁酸;邻-{2-[3-(1H-吡咯-2-基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基}苯甲酸;邻-{2-[3-(3-噻吩基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基}苯甲酸;或4-[2-(苄硫基)乙基]-5-(1-甲基-1H-吡咯-2-基)-2,4-二氢-1,2,4-三唑-3-硫酮。
在一个具体实施方案中,n为0且A为喹啉基。优选地,式(I)的化合物选自:4-[3-(喹啉-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸;2-{2-[3-(喹啉-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;或2-{2-[3-(喹啉-6-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸。
在一个具体实施方案中,Y选自(C1-C7)烷基链,其任选包含至少一个杂原子。
在一个具体实施方案中,Y为(C1-C7)烷基链,其任选包含至少一个杂原子,o为1,且Z为COOH。优选地,式(I)的化合物选自4-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)丁酸;5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;4-[3-(2-羟基-5-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸;4-[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸;4-[3-(3-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸;5-[3-(2-羟基-5-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]戊酸;5-[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]戊酸;5-(3-联苯基)-4-[3-羧基丙基]-1,2,4-三唑-3-硫酮;6-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)己酸;4-[3-(1-甲基-1H-吡咯-2-基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]丁酸;4-[3-(喹啉-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸;8-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)辛酸;[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]乙酸;和[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]丙酸。
在一个具体实施方案中,Y为(C1-C7)烷基链,其任选包含至少一个杂原子,o为2且Z选自:
-(C1-C3)烷基,优选甲基,任选取代有COOH,
-任选取代有Cl的苯基,
-NH-Boc、N(咪唑基甲基)2、N(苄基)2和COOH,所述苄基任选取代有至少一个OH。
优选地,式(I)的化合物选自:3-(4-氯苯基)-4-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)丁酸;2-{[(叔丁氧基)羰基]氨基}-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;3-苯基-4-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)丁酸;苯基[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]乙酸;2-[[2,3-二羟基苯基)甲基]氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;2-[二(苯基甲基)氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;2-[二(1H-咪唑-5-基甲基)氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;和3-{2-[3-(3-联苯基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基硫基}-氢化阿托酸。
在一个具体实施方案中,Y为(C1-C7)烷基链,其任选包含至少一个杂原子,o为1,且Z为苯基,该苯基取代有COOH,且任选取代有OH或NH2。优选地,式(I)的化合物选自:2-[2-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)乙基]苯甲酸;2-{2-[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;2-{2-[3-(2-羟基-5-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;2-{[(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)氨基]甲基}苯甲酸;2-{2-[3-(呋喃-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;2-{2-[3-(噻吩-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;2-{2-[3-(2-甲基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;2-{2-[5-硫代-3-(噻吩-2-基)-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;2-{2-[3-(2,2-二苯基乙基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;2-{2-[3-(3-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;2-{2-[3-(5-氯噻吩-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;5-(3-联苯基)-4-[2-(2-羧基苯基)乙基]-1,2,4-三唑-3-硫酮;5-(4-苄基氧基苯基)-4-[2-(2-羧基苯基)乙基]-1,2,4-三唑-3-硫酮;邻-{2-[1-甲基-1H-吡咯-2-基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基}苯甲酸;邻-[2-(3-苯乙基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基]苯甲酸;间-[(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)甲基]苯甲酸;5-羟基-2-[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基]苯甲酸;对-[(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)甲基]苯甲酸;2-{2-[3-(喹啉-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;2-{2-[3-(喹啉-6-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;邻-{2-[3-(1H-吡咯-2-基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基}苯甲酸;邻-{2-[3-(3-噻吩基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基}苯甲酸;5-(2-联苯基)-4-[2-(2-羧基苯基)乙基]-1,2,4-三唑-3-硫酮;2-({[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]氨基}甲基)苯甲酸;邻-{[3-(3-联苯基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基氨基]甲基}苯甲酸;2-{2-[3-(金刚烷-1-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;2-{[(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)氨基]甲基}苯甲酸;5-氨基-2-[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基]苯甲酸;邻-(2-{3-[间-(2-吗啉代乙氧基)苯基]-5-硫代-1,4-二氢-1,2,4-三唑-4-基}乙基)苯甲酸;和邻-[2-(3-{间-[2-(4-甲基-1-哌嗪基)乙氧基]苯基}-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基]苯甲酸。
更优选地,式(I)的化合物为5-(3-联苯基)-4-[2-(2-羧基苯基)乙基]-1,2,4-三唑-3-硫酮。
在一个具体实施方案中,o为1且Z为取代有至少一个OH的苯基。在一个优选实施方案中,所述苯基取代有两个OH。优选地,式(I)的化合物选自:4-[2-(4-羟基苯基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-[2-(2,4-二羟基苯基)乙基]-5-苯基-1,2,4-三唑-3-硫酮;5-(3-联苯基)-4-[2-(2,4-二羟基苯基)乙基]-1,2,4-三唑-3-硫酮;5-(2-联苯基)-4-[2-(2,4-二羟基苯基)乙基]-1,2,4-三唑-3-硫酮;或5-羟基-2-[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基]苯甲酸.更优选地,式(I)的化合物为4-[2-(4-羟基苯基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮或5-(3-联苯基)-4-[2-(2,4-二羟基苯基)乙基]-1,2,4-三唑-3-硫酮。
在一个具体实施方案中,o为1且Z为取代有苄基氧基的苯基。优选地,式(I)的化合物为4-[4-(苄基氧基)苯基乙基]-5-苯基-1,2,4-三唑-3-硫酮。
在一个具体实施方案中,Y为(C1-C5)烷基链,其包含至少一个杂原子。优选地,所述杂原子为S。优选地,式(I)的化合物选自:4-[2-(苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮,苯基[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]乙酸,4-[2-(苄硫基)乙基]-5-(1-甲基-1H-吡咯-2-基)-2,4-二氢-1,2,4-三唑-3-硫酮;[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]乙酸;[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]丙酸;5-苯基-4-[2-(苯基硫基)乙基]-2,4-二氢-1,2,4-三唑-3-硫酮;4-[2-(2-氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-[2-(4-氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-[2-(2,4-二氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-[2-(4-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-[2-(2-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-[2-(2-羟基-5-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-[2-(2-苯基乙基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;2-苯基-3-[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]-丙酸;5-苯基-4-[3-(苯基硫基)丙基]-2,4-二氢-1,2,4-三唑-3-硫酮;4-[2-(苄硫基)乙基]-5-(邻-甲苯基)-2,4-二氢-1,2,4-三唑-3-硫酮;和3-{2-[3-(3-联苯基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基硫基}-氢化阿托酸。
在一个具体实施方案中,l和o为1,A为任选取代有至少一个选自以下的基团的苯基:甲基、OMe、OH、卤素和CF3,且Z为任选取代有至少一个选自以下的基团的苯基:COOH和OH。优选地,式(I)的化合物选自:4-苄基-3-(2-羟基-5-甲氧基苯基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-苄基-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;间-[(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)甲基]苯甲酸;和对-[(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)甲基]苯甲酸;2-[2-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)乙基]苯甲酸;2-{2-[3-(2-羟基-5-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;3-(2-羟基-5-甲氧基苯基)-4-(2-苯基乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;3-苯基-4-(2-苯基乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;2-{2-[3-(3-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;4-[2-(4-羟基苯基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-[2-(2,4-二羟基苯基)乙基]-5-苯基-1,2,4-三唑-3-硫酮;5-羟基-2-[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基]苯甲酸;2-{[(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)氨基]甲基}苯甲酸;3-苯基-4-(3-苯基丙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;2-{2-[3-(2-甲基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;3-苯基-4-[(1R,2S)-2-苯基环丙基]-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-[2-(苄硫基)乙基]-5-(邻-甲苯基)-2,4-二氢-1,2,4-三唑-3-硫酮和4-[2-(苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮。
在一个更具体实施方案中,l和o为1,A为任选取代有至少一个选自以下的基团的苯基:OMe和OH,Z为任选取代有COOH或至少一个OH的苯基,且Y为乙基或甲基。优选地,式(I)的化合物选自:4-苄基-3-(2-羟基-5-甲氧基苯基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-苄基-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;间-[(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)甲基]苯甲酸;和对-[(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)甲基]苯甲酸;2-[2-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)乙基]苯甲酸;2-{2-[3-(2-羟基-5-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;3-(2-羟基-5-甲氧基苯基)-4-(2-苯基乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;3-苯基-4-(2-苯基乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;2-{2-[3-(3-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;4-[2-(4-羟基苯基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-[2-(2,4-二羟基苯基)乙基]-5-苯基-1,2,4-三唑-3-硫酮;和5-羟基-2-[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基]苯甲酸。
更优选地,式(I)的化合物为3-(2-羟基-5-甲氧基苯基)-4-(2-苯基乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;4-[2-(4-羟基苯基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮或4-苄基-3-(2-羟基-5-甲氧基苯基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮。
在一个具体实施方案中,l和o为1,A为取代有苯基的苯基,且Z为COOH或任选取代有至少一个选自以下的基团的苯基:COOH和OH。优选地,式(I)的化合物选自:5-(3-联苯基)-4-[3-羧基丙基]-1,2,4-三唑-3-硫酮;5-(3-联苯基)-4-[2-(2-羧基苯基)乙基]-1,2,4-三唑-3-硫酮;5-(3-联苯基)-4-[2-(2,4-二羟基苯基)乙基]-1,2,4-三唑-3-硫酮;5-(2-联苯基)-4-[2-(2,4-二羟基苯基)乙基]-1,2,4-三唑-3-硫酮;和邻-{[3-(3-联苯基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基氨基]甲基}苯甲酸。
在另外的具体的实施方案中,本发明的化合物由式(I)表示,其中:
-l和o是1,A是被苯基取代的苯基,且Z是COOH或任选地被至少一个选自下面的基团取代的苯基:COOH和OH;以及
-Y是具有由N组成的杂原子的(C1-C7)烷基链。
优选地,式(I)化合物是邻-{[3-(3-联苯基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基氨基]甲基}苯甲酸。
在具体的实施方案中,本发明的化合物由式(I)表示,其中:
所述5-14元环任选地被至少一个选自下面的基团取代:氯、OH、甲氧基、甲基、CF3、吗啉基乙氧基、(甲基哌嗪基)乙氧基、二甲基氨基乙氧基、苯基、苄基氧基;
○5-14元环,其选自苯基、环己基、环丙基、喹啉基、吗啉基、酞基,所述5-14元环任选取代有至少一个选自以下的基团:氯、OH、COOH、NO2、NH2、甲基、CF3、CH2-COOH、苄基氧基、和任选取代有NO2的苯基;
○选自下面的基团:COOH、N3、NR1R2,其中R1和R2独立地表示H、Boc、任选取代有至少一个OH的苄基、(咪唑基)甲基;或
○CF3或CH2-COOH。
在具体的实施方案中,本发明的化合物选自:
化合物7. 4-苄基-3-(2-羟基-5-甲氧基苯基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
化合物10. 3-(2-羟基-5-甲氧基苯基)-4-(2-苯基乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
化合物31。4-[2-(4-羟基苯基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
化合物33. 4-[2-(苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
化合物37. 5-苯基-4-[(3-苯酞基)甲基]-2,4-二氢-1,2,4-三唑-3-硫酮;
化合物39. 5-(3-联苯基)-4-[2-(2-羧基苯基)乙基]-1,2,4-三唑-3-硫酮;和
化合物42. 5-(3-联苯基)-4-[2-(2,4-二羟基苯基)乙基]-1,2,4-三唑-3-硫酮。
在一个具体实施方案中,式(I)的化合物选自:
-化合物33. 4-[2-(苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物37. 5-苯基-4-[(3-苯酞基)甲基]-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物39. 5-(3-联苯基)-4-[2-(2-羧基苯基)乙基]-1,2,4-三唑-3-硫酮;
-化合物42. 5-(3-联苯基)-4-[2-(2,4-二羟基苯基)乙基]-1,2,4-三唑-3-硫酮。
-化合物62.邻-(2-{3-[间-(2-吗啉代乙氧基)苯基]-5-硫代-1,4-二氢-1,2,4-三唑-4-基}乙基)苯甲酸;
-化合物63.邻-[2-(3-{间-[2-(4-甲基-1-哌嗪基)乙氧基]苯基}-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基]苯甲酸;
-化合物64. 4-[2-(苄硫基)乙基]-5-(1-甲基-1H-吡咯-2-基)-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物65.[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]乙酸;
-化合物66.[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]丙酸;
-化合物67. 2-[[2,3-二羟基苯基)甲基]氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;
-化合物68. 2-[二(苯基甲基)氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;
-化合物69. 2-[二(1H-咪唑-5-基甲基)氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;
-化合物70. 5-苯基-4-[2-(苯基硫基)乙基]-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物71. 4-[2-(2-氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物72. 4-[2-(4-氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物73. 4-[2-(2,4-二氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物74. 4-[2-(4-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物75. 4-[2-(2-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物76. 4-[2-(2-羟基-5-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物77. 4-[2-(2-苯基乙基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物78. 2-苯基-3-[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]-丙酸;
-化合物79. 5-苯基-4-[3-(苯基硫基)丙基]-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物80. 4-[2-(苄硫基)乙基]-5-(邻-甲苯基)-2,4-二氢-1,2,4-三唑-3-硫酮;和
-化合物81. 3-{2-[3-(3-联苯基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基硫基}-氢化阿托酸。
本发明化合物的合适的药学上可接受的盐是指,例如,具有足够碱性的本发明的化合物的酸加成盐。例如,与例如无机酸或有机酸的酸加成盐,例如盐酸、氢溴酸、硫酸、磷酸、三氟乙酸、甲酸、柠檬酸、甲烷磺酸或马来酸。另外,足够酸性的本发明化合物的合适的药学上可接受的盐为碱金属盐如钠盐或钾盐,碱土金属盐如钙盐或镁盐,铵盐或与可提供药学上可接受的阳离子的有机碱形成的盐,例如与甲胺、二甲胺、三甲胺、哌啶、吗啉或三-(2-羟乙基)胺形成的盐。
具有相同分子式但其原子的键合性质或顺序或其原子在空间中的排列不同的化合物称为“异构体”。其原子空间排列不同的异构体称为“立体异构体”。彼此不是镜像的立体异构体被称为“非对映异构体”,彼此是不可重叠的镜像的立体异构体被称为“对映异构体”。例如,当化合物的中心不对称时,它与四个不同的基团键合,则一对对映异构体是可能的。对映异构体可以通过其不对称中心的绝对构型来表征,并由卡恩-英格尔—普雷洛格(Cahn-Lngold-Prelog)的R和S排序规则进行描述,或通过分子旋转偏振光平面的方式来描述,并被指定为右旋或左旋(即分别表示为(+)或(-)-异构体)。手性化合物可以单一的对映异构体或其混合物存在。包含相等比例的对映异构体的混合物称为“外消旋混合物”。
本发明的化合物可以具有一个或多个不对称中心;因此,此类化合物可以作为单独的(R)-或(S)-立体异构体或其混合物生产。除非另有说明,否则本说明书和权利要求书中具体化合物的描述或命名旨在包括单一对映异构体及其混合物,外消旋或其它形式。测定立体化学和分离立体异构体的方法是本领域众所周知的(参见"Advanced OrganicChemistry",第4版J.March,John Wiley and Sons,New York,2001的第4章的讨论),例如通过从旋光活性原料合成或通过拆分外消旋形式。本发明的某些化合物可以具有几何异构中心(E-和Z-异构体。应当理解,本发明涵盖具有抗增殖活性的所有光学异构体、非对映异构体和几何异构体及其混合物。
还应理解,某些式(I)化合物可以以溶剂合物和非溶剂合物形式存在,例如水合形式。应该理解,本发明包括所有具有抗菌活性的溶剂合物形式。
还应理解,某些式(I)化合物可以具有多晶型,并且本发明涵盖具有抗菌活性的所有此类形式。
治疗用途和应用
本发明的化合物是金属β内酰胺酶抑制剂(MBL)。许多细菌已发展出对β-内酰胺抗细菌剂(BLA)的耐药性,并且主要的耐药性机制之一是MBL对BLA的水解作用。因此,当与本发明的化合物一起施用时,本发明的化合物对细菌MBL的抑制可以显著增强BLA的活性。
本发明提供了起金属β内酰胺酶抑制剂作用的化合物。
因此,本发明提供了在体外或体内抑制细菌金属β内酰胺酶活性的方法,所述方法包括使细胞与有效量的如本文所定义的化合物或其药学上可接受的盐、水合物或溶剂合物或药物组合物接触。
本发明还提供了在有需要治疗的患者中预防或治疗细菌感染的方法,所述方法包括向所述患者施用与合适的抗细菌剂组合的治疗有效量的如本文定义的化合物或其药学上可接受的盐、水合物或溶剂合物或药物组合物。
本发明还提供了如上所定义的化合物或其药学上可接受的盐、合物或溶剂合物在制备如本文所定义的药物组合物中的用途,所述药物组合物用于在患者中预防或治疗细菌感染,任选地与合适的抗细菌剂组合。
在优选的实施方案中、所述抗细菌剂是β-内酰胺抗细菌剂或其类似物。合适的β-内酰胺抗细菌剂的非限制性实例包括碳青霉烯类(例如美罗培南、亚胺培南、厄他培南、多利培南、帕尼培南/倍他米隆和比阿培南以及拉唑培南(razupenem)、替比培南、来那培南和托莫培南)、脲基青霉素(例如哌拉西林)、青霉烯类(例如法罗培南)、碳头孢烯类(例如氯碳头孢)和头孢菌素类(例如头孢泊肟、头孢他啶、头孢噻肟、头孢曲松、头孢吡普、头孢洛林)。合适的β-内酰胺抗细菌剂的特定实例包括、例如、替莫西林、哌拉西林、头孢泊肟、头孢他啶、头孢噻肟、头孢曲松、美罗培南、法罗培南、亚胺培南、氯碳头孢等。
本发明还提供了在体外或体内抑制细菌感染的方法,所述方法包括使细胞与有效量的如本文所定义的化合物或其药学上可接受的盐、水合物或溶剂合物与合适的抗细菌剂的组合接触。
本发明还提供了用于治疗的如本文定义的化合物或其药学上可接受的盐、水合物或溶剂合物或药物组合物。
本发明还提供了用于治疗细菌感染的如本文定义的化合物或其药学上可接受的盐、水合物或溶剂合物或药物组合物。在一个实施方案中,所述治疗可以是预防性的(即旨在预防疾病)。
本发明还提供了用于抑制金属β内酰胺酶活性的如本文定义的化合物或其药学上可接受的盐、水合物或溶剂合物。
此外,本发明还提供了用于治疗涉及金属β内酰胺酶活性的疾病或障碍的如本文定义的化合物或其药学上可接受的盐、水合物或溶剂合物。
本发明还提供了多部分试剂盒,其包含如本文所定义的化合物或其药学上可接受的盐、水合物或溶剂合物或药物组合物,以及BLA和/或与式(I)化合物连接的BLA。
术语“细菌感染”应理解为是指任何增殖的致病细菌对身体组织的入侵,从而导致可能发展为疾病的组织损伤。所述细菌感染可能是由革兰氏阴性细菌引起的。例如,所述细菌感染可能是由以下一个或多个属细菌引起的;假单胞菌,埃希杆菌,克雷伯菌,肠杆菌,沙雷氏菌,不动杆菌,寡养单胞菌,伯克霍尔德氏菌。
本领域技术人员将理解,有需要的患者合适地是人类,但也可以包括,但不限于灵长类动物(例如猴子),商业化养农场动物(例如马、牛、绵羊或猪)和家养宠物(例如狗、猫、豚鼠、兔子、仓鼠或沙鼠)。因此,有需要的患者可以是能够被细菌感染的任何哺乳动物。
方案和施用
根据本发明的化合物或根据本发明的药物组合物可以通过任何常规的施用途径来施用。具体地,本发明的化合物或药物组合物可以通过局部、肠内、口服、肠胃外、鼻内、静脉内、动脉内、肌内、皮下或眼内施用等方式施用。具体地,根据本发明的化合物或根据本发明的药物组合物可以配制用于局部、肠内、口服、肠胃外、鼻内、静脉内、动脉内、肌内、皮下或眼内施用等。
优选地,本发明的化合物或本发明的药物组合物通过肠内或肠胃外给药途径来施用。当肠胃外施用时,优选通过静脉内施用途径来施用根据本发明的化合物或根据本发明的药物组合物。当肠内施用时,本发明的化合物或本发明的药物组合物优选通过口服施用。
对于口服施用,可以将所述组合物配制成常规的口服剂型,例如片剂、胶囊、粉末、颗粒和液体制剂,例如糖浆、酏剂和浓缩滴剂。可以使用无毒的固体载体或稀释剂,其包括例如药用级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、滑石粉、纤维素、葡萄糖、蔗糖、镁、碳酸盐等。对于压缩的片剂,还需要粘合剂,其是赋予粉末状材料粘结性的试剂。例如,淀粉、明胶、糖(如乳糖或右旋糖)和天然或合成树胶可以用作粘合剂。在片剂中,促进片剂分解的崩解剂也是必需的。崩解剂包括淀粉、粘土、纤维素、藻类、树胶和交联聚合物。此外,片剂中还包含润滑剂和助流剂,以防止在制造过程中将片剂材料粘附到表面上并改善制造过程中粉末材料的流动特性。胶质二氧化硅最常用作助流剂,而化合物如滑石粉或硬脂酸最常用作润滑剂。
对于透皮施用,可以将组合物配制成软膏剂、乳膏剂或凝胶形式,并且可以使用适当的渗透剂或去污剂(如二甲亚砜、二甲基乙酰胺和二甲基甲酰胺)以促进渗透。
对于经粘膜施用,可以使用鼻喷雾剂、直肠或阴道栓剂。可以通过本领域已知的方法将活性化合物掺入任何已知的栓剂基质中。此类基质的实例包括可可脂、聚乙二醇(碳蜡)、聚氧乙烯山梨醇酐单硬脂酸酯,以及这些与其它相容材料的混合物,以改变熔点或溶解速率。
可以配制根据本发明的药物组合物以在施用后或在施用后的任何预定时间或时间段基本上立即释放活性药物。
根据本发明的化合物或根据本发明的药物组合物可以以单一剂量或多剂量施用。
优选地,所述治疗定期施用,优选地在每天和每月之间,更优选地在每天和每两周之间,更优选地在每天和每周之间,甚至更优选地所述治疗每天施用。在具体的实施方案中,所述治疗每天施用数次,优选每天2或3次,甚至更优选每天3次。
使用根据本发明的化合物或根据本发明的药物组合物的治疗的持续时间优选地包括1天至20周,更优选地5天至10周,更优选地5天至4周,甚至更优选地5天至2周。在具体的实施方案中,所述治疗的持续时间是至少1周。可选的,只要细菌感染存在,所述治疗即可以持续。
根据本发明的化合物或根据本发明的药物组合物的施用量必须通过本领域普通技术人员众所周知的标准方法来确定。为了确定合适的剂量,必须考虑患者的生理数据(例如年龄、大小和体重)和施用途径,以便向患者施用治疗有效量。
药物组合物的形式、施用途径、根据本发明的化合物或根据本发明的药物组合物的施用剂量可以由本领域技术人员根据疾病的类型和严重程度,并且根据患者,特别是其年龄、体重、性别和总体身体情况,来调节。
生物活性
伴随实施例部分或文献其它部分中描述的酶和体外基于细胞的测定可以用于测量本发明化合物的药理学作用。
尽管式I化合物的药理学性质随结构变化而变化,如所预期的,但发现本发明化合物在这些酶测定中具有活性。
诊断用途
本发明的化合物或包含这些化合物与合适的抗细菌剂组合的药物组合物还可以用于检测金属β内酰胺酶的方法中。可以理解,可以修饰式(I)化合物以使文献中已知的各种类型的测定成为可能,如使用光谱(如荧光或基于发光的方法)的那些测定。因此,在一种变化中,含有细菌的样品(其被怀疑表达MBL)可以(a)在β-内酰胺抗生素试剂存在下进行培养;和(b)在本发明的抗生素组合存在下进行培养。如果发现细菌在条件(a)下生长,则表明能够水解抗生素试剂的β-内酰胺酶正在引起细菌对抗生素的耐药性。但是,如果细菌在条件(b)下不生长,即在本发明化合物和合适的抗细菌剂存在下,则存在的β-内酰胺酶被抑制了。这样的结果表明β-内酰胺酶是金属β内酰胺酶。该方法可以用于确定细菌是否表达金属β内酰胺酶。
在以下实施例中将描述本发明的其它方面和优点,这些实施例应被认为是说明性的而不是限制性的。
实施例
实施例1:一般合成
根据Maingot等人[Maingot L.,Leroux F.,Landry V.,Dumont J.,Nagase H.,Villoutreix B.,Sperandio O.,Deprez-Poulain R.&Deprez B.(2010)Bioorg.Med.Chem.Letters 20,6213-6],稳定类似物的合成(A途径)(其中腙样键被C-C键替代)分两个主要步骤进行。第一步是生成氨基硫脲前体,其通过胺衍生物与O,O’-二-2-吡啶基硫代碳酸酯(DPT)反应,生成硫代氨基甲酸酯,然后与酰肼反应。第二步是氨基硫脲在热碱性条件下的环化(方案1)。
方案1.用于合成在4和5位取代的1,2,4-三唑-3-硫酮类似物所遵循的一般途径A。
酰肼衍生物以前是通过用热肼水合物处理相应的羧酸乙酯或羧酸甲酯而获得的。
稳定类似物的合成(B途径)呈现在方案2中,其中腙样键被还原的N-C键替代。首先根据两条众所周知的途径(取决于位置5的取代基)获得4-氨基-1,2,4-三唑-3-硫酮前体。然后将这些前体与各种苯甲醛缩合,得到具有腙样键的类似物。其使用NaBH4还原得到具有NH-CH2连接的稳定化合物(方案2)。
方案2.合成在4和5位取代的1,2,4-三唑-3-硫酮类似物所遵循的一般途径B。
实施例2:化学合成的实验细节。
合成途径A(方案1).将胺化合物(1mmol,1当量)(如果所述胺是盐酸盐,则加入1.5当量Na2CO3)和DPT(1.05当量)溶解在DMF(4mL)中,并将混合物在55℃搅拌90分钟。然后,直接加入酰肼化合物(1.1当量),并继续温热90分钟。在真空下蒸发后,将获得的残留物不经纯化直接用于环化步骤。
将残留物在KOH(3当量,3mmol)存在下,在水/乙醇(40:60-10mL)混合物中取出,并将反应回流2小时。使用1M KHSO4水溶液中和该溶液,并用二氯甲烷萃取两次。用MgSO4干燥、过滤并蒸发有机相后,将获得的残留物通过硅胶柱色谱法进行纯化。
合成途径B(方案2).合成4-氨基-1,2,4-三唑-3-硫酮衍生物的两条途径。
用于烷酸(n=1)的途径1:一步(Beyer法)。小心地将羧酸(1当量)和硫代卡巴肼(thiocarbohydrazide)(1当量)一起研磨,并通过在160℃温热90分钟将混合物熔化。冷却至室温后,加入Na2CO3水溶液(20g/L,10mL/mmol),并将混合物在回流下搅拌1h。冷却后,将形成的沉淀物过滤并用水洗涤。干燥后,将化合物从EtOH中重结晶。
用于芳酸和杂芳酸(n=0)的途径2:从乙酯开始的三步。将酯溶解在含有肼、水合物(5当量)的乙醇中,并将混合物回流3h30。冷却后,将形成的沉淀物过滤,用二乙基醚洗涤并干燥,以得到酰肼产物。将后者溶解在乙醇中,并加入CS2(5当量)和KOH(1.7当量)。将混合物回流5小时。加水,将混合物置于冰浴中,并用4N HCl中和。过滤形成的沉淀,用水洗涤并干燥,得到1,2,4-噁二唑-3-硫酮中间体。将后者溶解在乙醇中。加入水合肼(10当量),并将混合物回流过夜。在真空下蒸发后,将残留物在二乙基醚中取出,过滤并从乙醇中重结晶,得到1,2,4-三唑-3-硫酮化合物。
然后在密封管中,将1,2,4-三唑-3-硫酮类似物溶于乙酸(10mL/mmol)中。加入苯甲醛衍生物(2至5当量)并将混合物在110℃搅拌(5小时至过夜)。冷却后,过滤形成的沉淀物,干燥并从乙醇中重结晶,得到具有腙样键的类似物。
最后,将腙样化合物(0.5mmol,1当量)溶解在MeOH(5mL)中。加入NaBH4(10当量)并将混合物在惰性气氛下回流1小时。蒸发后,将残留物在硅胶柱上纯化。
实施例3:根据一般化学合成制备的化合物
化合物1:2-[2-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)乙基]苯甲酸
白色粉末,82mg,产率:52%LC-MS tR:1.27min;m/z(ES+)326.1(M+H+);Mp=220-221℃;1H NMR(400MHz,DMSO-d6):13.90(bs,1H),12.72(bs,1H),7.68(dd,J=7.6,1.2Hz,1H),7.48(t,J=7.4Hz,1H),7.44-7.33(m,3H),7.28(t,J=7.6Hz,1H),7.21(d,J=7.6Hz,2H),6.93(d,J=7.6Hz,2H),4.36(d,J=6.6Hz,2H),3.32(d,J=6.6Hz,2H);13C NMR(100MHz,DMSO-d6):167.7,166.8,151.5,138.6,131.8,131.7,130.7,130.2(2C),128.5,128.3,126.8,125.6,44.4,31.4;HRMS(ESI+)计算值:C17H16N3O2S(M+H)+326.0963,实测值:326.0965。
化合物2:4-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)丁酸
白色粉末,186mg,产率:61%LC-MS tR:0.95min;m/z(ES+)250.2(M+H+);1H NMR(400MHz,DMSO-d6):13.92(bs,1H),12.11(bs,1H),7.72-7.67(m,2H),7.63-7.53(m,3H),4.06(t,J=7.4Hz,2H),2.14(t,J=7.4Hz,2H),1.78(quint,J=7.4Hz,2H);13C NMR(100MHz,DMSO-d6):173.5,167.1,151.1,130.6,128.9,128.5,125.9,43.1,30.4,23.0;HRMS(ESI+)计算值:C12H14N3O2S(M+H)+264.0807,实测值:264.0804。
化合物3:2-{2-[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸
浅棕色粉末,181mg,产率:48%LC-MS tR:1.57min;m/z(ES+)376.1(M+H+);Mp=240-241℃;1H NMR(400MHz,DMSO-d6):13.98(bs,1H),12.40(bs,1H),7.99-7.90(m,3H),7.75(s,1H),7.64-7.56(m,3H),7.42-7.35(m,2H),7.25(t,J=7.6Hz,1H),6.99(d,J=7.6Hz,1H),4.46(t,J=6.6Hz,2H),3.38(t,J=7.6Hz,1H);13C NMR(100MHz,DMSO-d6):167.7,167.0,151.3,138.7,133.1,132.0,131.8,131.2,130.6,130.3,128.4,128.3,128.2,127.5,127.4,126.8,126.7,124.9,122.9,44.7,31.3;HRMS(ESI+)计算值:C21H18N3O2S(M+H)+376.1120,实测值:376.1123。
化合物4:2-{2-[3-(2-羟基-5-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸
黄色粉末,160mg,产率:43%;LC-MS tR:1.28min;m/z(ES+)372.1(M+H+);Mp=88-89℃;1H NMR(400MHz,DMSO-d6):13.72(bs,1H),12.33(bs,1H),9.72(bs,1H),7.67(dd,J=7.6,1.6Hz,1H),7.36(td,J=7.4,1.6Hz,1H),7.26(td,J=7.6,1.6Hz,1H),6.90-6.85(m,1H),6.81-6.76(m,2H),5.90(d,J=3.2Hz,1H),4.25(t,J=6.4Hz,2H),3.60(s,3H),3.27(t,J=6.4Hz,2H);13C NMR(100MHz,DMSO-d6):167.5,166.2,151.5,150.2,148.7,139.0,131.6,131.1,130.7,130.1,126.6,118.2,116.4,114.7,55.2,44.5,31.3;HRMS(ESI+)计算值:C18H18N3O4S(M+H)+372.1018,实测值:372.1021。
化合物5:2-{[(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)氨基]甲基}苯甲酸
白色粉末,68mg,产率:69%;LC-MS tR:1.45min;m/z(ES+)327.1(M+H+);Mp=161-162℃;1H NMR(400MHz,DMSO-d6):13.92(bs,1H),12.94(bs,1H),7.88-7.84(m,2H),7.73(dd,J=8,1.2Hz,1H),7.51-7.36(m,4H),7.30(td,J=7.6,1.2Hz,1H),7.19(d,J=7.6Hz,1H),6.77(t,J=4Hz,1H),4.55(d,J=4Hz,2H);13C NMR(100MHz,DMSO-d6):168.1,166.2,148.8,136.9,131.5,130.7,130.4,130.3(2C),128.3,127.5,127.5,125.2,50.8;HRMS(ESI+)计算值:C16H15N4O2S(M+H)+327.0916,实测值:327.0919。
化合物6:3-(2-甲基苯基)-4-(2-苯基乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮
浅黄色粉末,247mg,产率:47%;LC-MS tR:1.68min;m/z(ES+)296.2(M+H+);Mp=156-157℃;1H NMR(400MHz,DMSO-d6):13.95(bs,1H),7.47(t,J=7.4Hz,1H),7.36(d,J=7.6Hz,1H),7.27(t,J=7.4Hz,1H),7.21-7.17(m,3H),7.05(d,J=7.6Hz,1H),6.90-6.83(m,2H),3.95(t,J=7.6Hz,1H),2.90(t,J=7.6Hz,1H),2.02(s,3H);13C NMR(100MHz,DMSO-d6):166.2,150.5,137.6,137.2,130.6,130.3,129.9,128.4(2C),126.5,125.8,125.1,44.8,32.6,18.9;HRMS(ESI+)计算值:C17H18N3S(M+H)+296.1221,实测值:296.1220。
化合物7:4-苄基-3-(2-羟基-5-甲氧基苯基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮
灰白色粉末,134mg,产率:43%;LC-MS tR:1.47min;m/z(ES+)314.1(M+H+);Mp=211-212℃;1H NMR(400MHz,DMSO-d6):13.93(bs,1H),12.96(bs,1H),7.90–7.82(m,2H),7.73(dd,J=7.8,1.4Hz,1H),7.53–7.34(m,4H),7.31(d,J=7.6Hz,1H),7.18(d,J=7.5Hz,1H),6.77(t,J=5.8Hz,1H),4.54(d,J=4.5Hz,2H);13C NMR(100MHz,DMSO-d6):168.17,166.34,148.93,137.05,131.60,130.85,130.50,130.39,128.44,127.64,127.58,125.33,50.92,28.99;HRMS(ESI+)计算值:C16H16N3O2S(M+H)+314.0963,实测值:314.0967。
化合物8:3-苯基-4-(3-苯基丙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮
灰白色粉末,207mg,产率:67%;LC-MS tR:1.67min;m/z(ES+)296.2(M+H+);Mp=160-161℃;n1H NMR(400MHz,DMSO-d6):13.94(bs,1H),7.62-7.45(m,5H),7.25-7.03(m,5H),4.02(t,J=7.8Hz,2H),2.48(t,J=7.6Hz,2H),1.88(quint,J=7.6Hz,2H);13C NMR(100MHz,DMSO-d6):167.0,151.0,140.3,130.6,128.9,128.4,128.2,127.9,126.0,125.8,43.3,31.7,28.9;HRMS(ESI+)计算值:C17H18N3S(M+H)+296.1221,实测值:296.1222。
化合物9:4-苄基-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮
白色粉末,159mg,产率:62%;LC-MS tR:1.51min;m/z(ES+)268.2(M+H+);Mp=186-187℃;1H NMR(400MHz,DMSO-d6):14.12(bs,1H),7.52-7.46(m,5H),7.28-7.19(m,3H),7.04-6.99(m,2H),5.35(s,2H);13C NMR(100MHz,DMSO-d6):167.9,151.3,135.6,103.6,128.8,128.4,128.2,127.4,126.4,125.9,46.6;HRMS(ESI+)计算值:C15H14N3S(M+H)+268.0908,实测值:268.0910。
化合物10:3-(2-羟基-5-甲氧基苯基)-4-(2-苯基乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮
白色粉末,282mg,产率:43%;LC-MS tR:1.51min;m/z(ES+)328.1(M+H+);Mp=132-133℃;1H NMR(400MHz,DMSO-d6):13.85(bs,1H),9.84(s,1H),7.23–7.11(m,3H),6.98(dd,J=8.9,3.1Hz,1H),6.94-6.83(m,3H),6.39(d,J=3.0Hz,1H),4.04(t,J=8.0Hz,2H),3.65(s,3H),2.91(t,J=8.0Hz,2H);13C NMR(100MHz,DMSO-d6):166.2,151.8,150.0,149.1,137.6,128.5,128.4,126.5,118.6,116.7,115.2,113.2,55.4,45.4,32.8;HRMS(ESI+)计算值:C17H18N3O2S(M+H)+328.1120,实测值:328.1122。
化合物11:3-苯基-4-(2-苯基乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮
白色粉末,323mg,产率:61%;LC-MS tR:1.59min;m/z(ES+)282.3(M+H+);Mp=204-205℃;1H NMR(400MHz,DMSO-d6):13.95(bs,1H),7.59-7.54(m,1H),7.53-7.47(m,2H),7.44-7.40(m,2H),7.22-7.16(m,2H),4.20(t,J=7.6Hz,2H),2.93(t,J=7.6Hz,2H);13CNMR(100MHz,DMSO-d6):166.9,151.5,137.2,130.5,128.8,128.6,128.5(2C),126.6,125.9,45.1,32.9;HRMS(ESI+)计算值:C16H16N3S(M+H)+282.1065,实测值:282.1065。
化合物12:2-{2-[3-(呋喃-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸
浅黄色粉末,54mg,产率:17%;LC-MS tR:1.34min;m/z(ES+)316.1(M+H+);Mp=210-211℃;1H NMR(400MHz,DMSO-d6):13.99(bs,1H),12.96(bs,1H),7.80(d,J=1.6Hz,1H),7.77(dd,J=8,1.2Hz,1H),7.41(td,J=7.4,1.2Hz,1H),7.28(td,J=7.4,1.2Hz,1H),7.09(d,J=7.6Hz,1H),6.94(d,J=3.6Hz,1H),6.63-6.60(m,1H),4.49(t,J=7Hz,2H),3.36(d,J=7Hz,2H);13C NMR(100MHz,DMSO-d6):168.2,167.0,145.1;139.6,138.5,131.8,131.1,130.4,130.3,126.8,112.3,111.6,44.9,31.7;HRMS(ESI+)计算值:C18H18N3O2S(M+H)+340.1120,实测值:340.1119。
化合物13:2-{2-[3-(噻吩-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸
灰白色粉末,101mg,产率:30%;LC-MS tR:1.37min;m/z(ES+)332.2(M+H+);Mp=195-196℃;1H NMR(400MHz,DMSO-d6):13.97(bs,1H),12.94(bs,1H),7.77-7.73(m,2H),7.53-7.50(m,1H),7.46-7.40(m,1H),7.15-7.09(m,2H),4.48(t,J=7Hz,2H),3.37(t,J=7Hz,2H);13C NMR(100MHz,DMSO-d6):168.1,167.3,146.1,138.6,131.9,131.1,130.5,130.4,129.5,128.8,127.9,126.8,126.0,44.8,31.5;HRMS(ESI+)计算值:C15H14N3O2S(M+H)+332.0527,实测值:332.0526。
化合物14:2-{2-[3-(2-甲基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸
白色粉末,193mg,产率:57%;LC-MS tR:1.45min;m/z(ES+)340.1(M+H+);Mp=180-181℃;1H NMR(400MHz,DMSO-d6):13.90(bs,1H),12.65(bs,1H),7.75(dd,J=7.6,1.2Hz,1H),7.45-7.36(m,2H),7.33(td,J=4.4,1.2Hz,1H),7.28(d,J=7.6Hz,1H),7.13(t,J=7.2Hz,1H),7.95(d,J=7.6Hz,1H),6.64(d,J=7.6Hz,1H),4.12(t,J=6.4Hz,2H),3.32(t,J=6.4Hz,2H);13C NMR(100MHz,DMSO-d6):167.5,166.3,150.8,138.8,137.3,131.8,131.2,130.8,130.4,130.3,130.1,129.7,126.8,125.6,124.8,44.2,30.9,19.9;HRMS(ESI+)计算值:C15H14N3O3S(M+H)+316.0756,实测值:316.0759。
化合物15:5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸
灰白色粉末,107mg,产率:37%;LC-MS tR:1.20min;m/z(ES+)278.2(M+H+);Mp=176-177℃;1H NMR(400MHz,DMSO-d6):13.93(bs,1H),11.98(bs,1H),7.69-7.65(m,2H),7.62-7.53(m,3H),4.04(t,J=7.4Hz,2H),2.10(t,J=7.4Hz,2H),1.53(quint,J=7.4Hz,2H),1.33(quint,J=7.4Hz,2H);13C NMR(100MHz,DMSO-d6):173.9,167.0,151.0,130.7,128.9,128.4,126.0,43.2,32.7,26.9,21.1;HRMS(ESI+)计算值:C13H16N3O2S(M+H)+278.0963,实测值:278.0965。
化合物16:2-({[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]氨基}甲基)苯甲酸
白色粉末,34mg,产率:45%;LC-MS tR:1.65min;m/z(ES+)377.2(M+H+);Mp=213-214℃;1H NMR(400MHz,DMSO-d6):14.01(bs,1H),12.98(bs,1H),8.60(s,1H),7.94(bs,3H),7.89(d,J=8.8Hz,1H),7.70(d,J=8.8Hz,1H),7.63-7.54(m,2H),7.39-7.34(m,1H),7.29-7.23(m,2H),6.90-6.84(m,1H),4.63(d,J=5.2Hz,2H);13C NMR(100MHz,DMSO-d6):168.1,166.5,148.6,137.1,133.2,132.0,131.5,130.8,130.6,130.3,128.6,127.9,127.6,127.5,127.4,127.3,126.6,124.1,122.6,50.9;HRMS(ESI+)计算值:C20H17N4O2S(M+H)+377.1072,实测值:377.1070。
化合物17:2-{1-[(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)甲基]环己基}乙酸
浅黄色粉末,113mg,产率:34%;LC-MS tR:1.52min;m/z(ES+)332.3(M+H+);Mp=80-81℃;1H NMR(400MHz,DMSO-d6):13.91(bs,1H),12.08(bs,1H),7.69-7.47(m,5H),4.38(s,2H),2.23(s,2H),1.39-1.10(m,8H),1.01-0.85(m,2H);13C NMR(100MHz,DMSO-d6):172.4,168.8,151.8,130.6,129.1,128.7,50.6,38.7,38.5,33.1,24.9,20.8;HRMS(ESI+)计算值:C17H22N3O2S(M+H)+332.1433,实测值:332.1433。
化合物18:4-[3-(2-羟基-5-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸
浅黄色粉末,99mg,产率:32%;LC-MS tR:1.03min;m/z(ES+)310.1(M+H+);Mp=155-156℃;1H NMR(400MHz,DMSO-d6):13.81(bs,1H),11.95(bs,1H),9.80(s,1H),7.04-6.98(m,1H),6.94-6.89(m,2H),3.89(t,J=7.2Hz,2H),2.07(t,J=7.2Hz,2H),1.73(quint,J=7.2Hz,2H);13C NMR(100MHz,DMSO-d6):173.4,166.4,151.9,149.6,149.4,118.5,116.8,115.6,113.2,55.5,43.1,30.5,23.0;HRMS(ESI+)计算值:C13H16N3O4S(M+H)+310.0862,实测值:310.0864。
化合物19:4-[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸
黄色粉末,101mg,产率:32%;LC-MS tR:1.39min;m/z(ES+)314.2(M+H+);Mp=220-221℃;1H NMR(400MHz,DMSO-d6):14.01(bs,1H),12.12(bs,1H),8.36(d,J=1.6Hz,1H),8.12-7.99(m,3H),7.80(dd,J=8.4,1.6Hz,1H),7.68-7.60(m,2H),4.18(t,J=7.2Hz,2H),2.19(t,J=7.2Hz,2H),1.85(quint,J=7.2Hz,2H);13C NMR(100MHz,DMSO-d6):173.5,167.3,151.0,133.4,132.3,128.7,128.6,128.3,127.7,127.6,126.9,125.1,123.2,43.4,30.3,23.0;HRMS(ESI+)计算值:C16H16N3O2S(M+H)+314.0963,实测值:314.0965。
化合物20:3-苯基-4-[(1R,2S)-2-苯基环丙基]-4,5-二氢-1H-1,2,4-三唑-5-硫酮
黄色粉末,132mg,产率:45%;LC-MS tR:1.72min;m/z(ES+)294.2(M+H+);Mp=185-186℃;1H NMR(400MHz,DMSO-d6):13.82(bs,1H),7.75-7.71(m,2H),7.57-7.51(m,1H),7.47-7.42(m,2H),7.29-7.13(m,3H),7.04-7.00(m,2H),3.53-3.48(m,1H),2.26-2.19(m,1H),1.50-1.43(m,1H),1.21-1.14(m,1H);13C NMR(100MHz,DMSO-d6):168.6,151.0,139.3,130.1,128.6,128.4,128.0,127.8,127.8,126.3,125.9,34.9,26.0,17.3;HRMS(ESI+)计算值:C17H16N3S(M+H)+294.1065,实测值:294.1064。
化合物21:3-(4-氯苯基)-4-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)丁酸
白色粉末,230mg,产率:77%;LC-MS tR:1.53min;m/z(ES+)374.0(M+H+);Mp=153-154℃;1H NMR(400MHz,DMSO-d6):13.89(bs,1H),12.09(bs,1H),7.55(tt,J=7.4,1.2Hz,1H),7.46(t,J=7.6Hz,2H),7.32(d,J=7.2Hz,2H),7.10(d,J=8.8Hz,2H),6.81(d,J=8.8Hz,2H),4.39(dd,J=14.4,9.2Hz,1H),4.22 39(dd,J=14.0,6.4Hz,1H),3.56-3.45(m,1H),2.61-2.43(m,2H);13C NMR(100MHz,DMSO-d6):171.9,167.1,151.1,138.7,131.4,130.3,129.2,128.5,128.3,128.3,128.0,125.8,48.3,38.8,36.8;HRMS(ESI+)计算值:C18H17N3O2SCl(M+H)+374.0730,实测值:374.0732。
化合物22:2-{2-[3-(3-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸
白色粉末,91mg,产率:26%;LC-MS tR:1.40min;m/z(ES+)356.1(M+H+);Mp=197-198℃;1H NMR(400MHz,DMSO-d6):13.88(bs,1H),12.71(bs,1H),7.66(dd,J=8.0,1.6Hz,1H),7.37(td,J=7.6,1.6Hz,1H),7.30-7.22(m,2H),7.05-6.99(m,1H),6.87(d,J=7.6Hz,1H),6.74(d,J=7.6Hz,1H),6.71-6.68(m,1H),4.41(t,J=6.4Hz,2H),3.74(s,3H),3.29(t,J=6.4Hz,2H);13C NMR(100MHz,DMSO-d6):167.6,166.8,159.9,151.4,138.6,131.7,131.1,130.7,130.1,126.7(2C),120.5,116.3,113.5,55.1,44.2,31.4;HRMS(ESI+)计算值:C18H18N3O3S(M+H)+356.1069,实测值:356.1071。
化合物23:2-{2-[3-(4-甲基-1,2,3-噻二唑-5-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸
黄色粉末,134mg,产率:39%;LC-MS tR:1.28min;m/z(ES+)348.0(M+H+);Mp=195-196℃;1H NMR(400MHz,DMSO-d6):14.35(bs,1H),12.88(bs,1H),7.64(dd,J=8.0,1.2Hz,1H),7.37(td,J=7.6,1.6Hz,1H),7.25 7.37(td,J=7.6,1.2Hz,1H),6.94(dd,J=8.0,1.6Hz,1H),4.32 7.37(t,J=6.4Hz,2H),3.28(t,J=6.4Hz,2H),2.43(s,3H);13C NMR(100MHz,DMSO-d6):167.8,167.5,159.4,142.2,138.1,132.9,131.9,131.4,130.5,130.1,127.0,445.1,31.3,13.1;HRMS(ESI+)计算值:C14H14N5O2S2(M+H)+348.0589,实测值:348.0592。
化合物24:4-[3-(3-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸
白色粉末,249mg,产率:85%;LC-MS tR:1.17min;m/z(ES+)294.1(M+H+);Mp=159-160℃;1H NMR(400MHz,DMSO-d6):13.91(bs,1H),12.09(bs,1H),7.47(t,J=8.0Hz,1H),7.29-7.12(m,3H),4.07(t,J=7.3Hz,2H),3.81(s,3H);2.15(t,J=7.3Hz,2H),1.77(quint,J=7.3Hz,2H);13C NMR(100MHz,DMSO-d6):173.4,167.1,159.3,150.9,130.1,127.2,120.7,116.6,113.8,55.3,43.2,30.4,23.1;HRMS(ESI+)计算值:C13H16N3O3S(M+H)+294.0912,实测值:294.0912。
化合物25:2-{[(叔丁氧基)羰基]氨基}-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸
白色粉末,312mg,产率:53%;LC-MS tR:1.41min;m/z(ES+)393.2(M+H+);Mp=105-106℃;1H NMR(400MHz,DMSO-d6):13.92(bs,1H),12.40(bs,1H),7.70-7.51(m,5H),6.99(d,J=8.0Hz,1H),4.03(t,J=7.2Hz,2H),3.77-3.68(m,1H),1.64-1.35(m,4H),1.34(s,9H);13C NMR(100MHz,DMSO-d6):173.,167.1,155.4,151.0,130.6,128.9,128.5,126.0,77.9,52.9,43.3,28.1,27.7,24.6;HRMS(ESI+)计算值:C18H25N4O4S(M+H)+393.1597,实测值:393.1595。
化合物26:4-己基-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮
白色粉末,138mg,产率:53%;LC-MS tR:1.84min;m/z(ES+)262.0(M+H+);Mp=98-99℃;1H NMR(400MHz,DMSO-d6):13.92(bs,1H),7.70-7.53(m,5H),4.02(t,J=7.6Hz,2H),1.50(quint,J=7.6Hz,2H),1.32-1.05(m,6H),0.76(t,J=7.0Hz,3H);13C NMR(100MHz,DMSO-d6):166.9,151.1,130.6,128.9,128.5,126.2,43.4,30.2,27.2,25.2,21.6,13.6;HRMS(ESI+)计算值:C14H20N3S(M+H)+262.1378,实测值:262.1379。
化合物27:2-{2-[3-(5-氯噻吩-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸
白色粉末,177mg,产率:48%;LC-MS tR:1.54min;m/z(ES+)366.0(M+H+);Mp=240-241℃;1H NMR(400MHz,DMSO-d6):14.03(bs,1H),12.97(bs,1H),7.77(dd,J=8.0,1.2Hz,1H),7.42(td,J=7.4,1.2Hz,1H),7.35(d,J=4.0Hz,1H),7.30(td,J=7.6,1.2Hz,1H),7.13(d,J=4.0Hz,1H),7.06(d,J=7.6Hz,1H),4.46(t,J=6.8Hz,2H),3.53(t,J=6.8Hz,2H);13C NMR(100MHz,DMSO-d6):168.2,167.4,145.0,138.5,131.9,131.4,131.3,130.6,130.4,128.8,127.6,126.9,125.0,44.7,31.5;HRMS(ESI+)计算值:C15H13N3O2S2Cl(M+H)+366.0138,实测值:366.0139。
化合物28:3-苯基-4-(2-{[2-(三氟甲基)喹啉-4-基]硫基}乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮
白色粉末,166mg,产率:38%;LC-MS tR:1.86min;m/z(ES+)433.1(M+H+);Mp=184-185℃;1H NMR(400MHz,DMSO-d6):14.05(bs,1H),8.10(d,J=8.0Hz,1H),7.97(d,J=8.0Hz,1H),7.92(t,J=7.6Hz,1H),7.78-7.74(m,2H),7.36-7.32(m,2H),7.16(t,J=7.4Hz,1H),6.99(t,J=7.6Hz,2H);13C NMR(100MHz,DMSO-d6):166.6,151.7,148.5,145.8,145.3(q,J=33.5Hz,1C),145.1,131.4,130.0,129.9,128.8,128.5,128.0,126.0,125.3,123.2,122.6,119.9,110.9,41.4,26.5;19F NMR(376MHz,DMSO-d6):-65.9;HRMS(ESI+)计算值:C20H16F3N4S2(M+H)+433.0768,实测值:433.0770。
化合物29:5-[3-(2-羟基-5-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]戊酸
白色粉末,26mg,产率:8%;LC-MS tR:1.11min;m/z(ES+)324.1(M+H+);Mp=155-156℃;1H NMR(400MHz,DMSO-d6):13.81(bs,1H),11.85(bs,3H),9.89(bs,1H),7.04-6.85(m,3H),3.87(t,J=7.0Hz,2H),3.70(s,3H),2.03(t,J=7.4Hz,2H),1.50(q,J=7.2Hz,2H),1.27(q,J=7.2Hz,2H);13C NMR(100MHz,DMSO-d6):174.0,166.4,149.7,149.4,118.6,116.9,115.4,113.3,55.5,43.2,32.9,26.9,21.2;HRMS(ESI+)计算值:C14H18N3O4S(M+H)+324.1018,实测值:324.1018。
化合物30:5-[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]戊酸
白色粉末,83mg,产率:25%;LC-MS tR:1.44min;m/z(ES+)328.0(M+H+);Mp=170-171℃;1H NMR(400MHz,DMSO-d6):14.01(bs,1H),11.96(bs,1H),8.29(bs,1H),8.12-8.01(m,3H),7.80-7.75(m,1H),7.69-7.61(m,2H),4.15(t,J=7.4Hz,2H),2.12(t,J=7.2Hz,2H);,1.60(q,J=7.6Hz,2H);,1.236(q,J=7.4Hz,2H);13C NMR(100MHz,DMSO-d6):173.9,167.2,151.0,133.3,132.3,128.7,128.5,128.3,127.7,127.0,125.0,123.4,43.4,32.7,27.1,21.2;HRMS(ESI+)计算值:C17H18N3O2S(M+H)+328.1120,实测值:328.1122。
化合物31:4-[2-(4-羟基苯基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮
白色粉末,109mg,产率:37%;LC-MS tR:1.38min;m/z(ES+)298.1(M+H+);Mp=208-209℃;1H NMR(400MHz,DMSO-d6):13.92(bs,1H),9.22(bs,1H),7.59-7.43(m,5H),6.73(d,J=8.4Hz,2H),6.58(d,J=8.4Hz,2H),4.14(t,J=7.4Hz,2H),2.79(t,J=7.4Hz,2H);13CNMR(100MHz,DMSO-d6):166.7,155.9,151.4,130.4,129.3,128.7,128.5,127.1,125.9,115.2,45.4,32.1;HRMS(ESI+)计算值:C16H16N3OS(M+H)+298.1014,实测值:.298.1016。
化合物32:4-丁基-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮
白色泡沫,132mg,产率:57%;LC-MS tR:1.59min;m/z(ES+)234.1(M+H+);Mp=128-129℃;1H NMR(400MHz,DMSO-d6):13.91(bs,1H),7.68-7.54(m,5H),4.03(t,J=7.6Hz,2H),1.51(q,J=7.5Hz,2H),1.11(st,J=7.4Hz,2H),0.73(t,J=7.8Hz,3H);13C NMR(100MHz,DMSO-d6):167.0,151.1,130.6,129.0,128.5,126.2,43.2,29.4,18.9,13.1;HRMS(ESI+)计算值:C12H16N3S(M+H)+234.1065,实测值:324.1065。
化合物33:4-[2-(苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮
白色粉末,212mg,产率:65%;LC-MS tR:1.79min;m/z(ES+)328.0(M+H+);Mp=108-109℃;1H NMR(400MHz,DMSO-d6):13.99(bs,1H),7.69-7.56(m,5H),7.27-7.10(m,5H),4.24(t,J=7.2Hz,2H),3.51(s,2H),2.64(t,J=7.2Hz,2H);13C NMR(100MHz,DMSO-d6):166.9,151.3,137.9,130.7,129.0,128.8,128.6,128.3,126.8,126.0,43.0,34.4,28.0;HRMS(ESI+)计算值:C17H18N3O2S2(M+H)+328.0942,实测值:328.0946。
化合物34:4-[(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)甲基]环己烷-1-甲酸
白色粉末,71mg,产率:22%;LC-MS tR:1.32min;m/z(ES+)318.2(M+H+);Mp=207-208℃;1H NMR(400MHz,DMSO-d6):13.94(bs,1H),11.95(bs,1H),7.70-7.53(m,5H),3.98(d,J=7.6Hz,2H),2.04-1.96(m,1H),1.77-1.72(m,2H),1.60-1.47(m,1H),1.46-1.36(m,2H),1.07-0.95(m,2H),0.80-0.68(m,2H);13C NMR(100MHz,DMSO-d6):176.3,167.4,151.3,130.6,128.9,128.7,126.3,48.8,41.8,35.4,28.7,27.8;HRMS(ESI+)计算值:C16H20N3O2S(M+H)+318.1276,实测值:318.1275。
化合物35:2-{2-[3-(金刚烷-1-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸
白色粉末,72mg,产率:19%;LC-MS tR:1.75min;m/z(ES+)384.4(M+H+);Mp>250℃;1H NMR(400MHz,DMSO-d6):13.63(bs,1H),13.03(bs,1H),7.83(d,J=7.6Hz,1H),7.62(d,J=7.2Hz,1H),7.54(t,J=7.6Hz,1H),7.36(t,J=7.2Hz,1H),4.36(t,J=7.6Hz,1H),3.40(t,J=7.6Hz,1H),2.05-1.93(m,9H),1.78-1.66(m,6H);13C NMR(100MHz,DMSO-d6):168.6,167.5,157.2,138.8,131.8,131.3,131.1,130.0,126.7,36.1,38.8,35.6,34.6,31.6,27.3;HRMS(ESI+)计算值:C21H26N3O2S(M+H)+384.1746,实测值:384.1748。
化合物36:2-{2-[3-(喹啉-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸
白色粉末,111mg,产率:35%;LC-MS tR:1.40min;m/z(ES+)315.1(M+H+);Mp=238-239℃;1H NMR(400MHz,DMSO-d6):14.20(bs,1H),11.74(bs,1H),8.55(d,J=8.4Hz,1H),8.17-8.04(m,3H),7.87(t,J=7.6Hz,1H),7.72(t,J=7.6Hz,1H),4.73(t,J=7.4Hz,1H),2.37(t,J=7.4Hz,1H),2.10(quint,J=7.4Hz,1H);13C NMR(100MHz,DMSO-d6):173.9,168.5,148.3,147.0,146.4,145.8,137.6,130.5,129.2,127.9,127.6,119.6,44.7,31.1,23.8;HRMS(ESI+)计算值:C15H15N4O2S(M+H)+315.0916,实测值:315.0919。
化合物37:5-苯基-4-[(3-苯酞基)甲基]-2,4-二氢-1,2,4-三唑-3-硫酮
白色粉末,385mg,产率:40%;LC-MS tR:1.46min;m/z(ES+)324.1(M+H+);1H NMR(500MHz,DMSO-d6):14.16(bs,1H),7.82-7.74(m,2H),7.69-7.45(m,7H),6.08(dd,J=11.0,4.0Hz,1H),4.77(dd,J=18.5,4.0Hz,1H),4.24(dd,J=18.5,11.0Hz,1H);13C NMR(125MHz,DMSO-d6):168.5,167.2,151.6,146.1,134.5,130.6,129.8,128.8,128.7,125.6,125.1,125.0,122.7,76.9,47.4;HRMS(ESI+)计算值:C17H14N3O2S(M+H)+324.0807,实测值:324.0809。
化合物38:5-(3-联苯基)-4-[3-羧基丙基]-1,2,4-三唑-3-硫酮
白色粉末,61mg,产率:33%;LC-MS tR:1.51min;m/z(ES+)340.1(M+H+);1H NMR(500MHz,DMSO-d6):δ(ppm)13.97(s,1H),12.07(s,1H),7.95(s,1H),7.93-7.87(m,1H),7.78-7.72(m,2H),7.71-7.63(m,2H),7.49(t,J=7.6Hz,2H),7.41(t,J=7.4Hz),4.19-4.07(m,2H),2.16(t,J=7.2Hz,2H),1.87-1.76(m,2H);13C NMR(125MHz,DMSO-d6):δ(ppm)173.5,167.2,151.2,140.9,139.1,129.7,129.1,129.0,128.0,127.7,126.9,126.8,43.3,30.6,23.2;HRMS(ESI+)计算值:C18H18N3O2S(M+H)+340.1120,实测值:340.1119。
化合物39:5-(3-联苯基)-4-[2-(2-羧基苯基)乙基]-1,2,4-三唑-3-硫酮
白色粉末,84mg,产率40%;LC-MS tR:1.67min;m/z(ES+)402.1(M+H+);1H NMR(500MHz,DMSO-d6):δ(ppm)13.93(s,1H),12.67(s,1H),7.77-7.72(m,1H),7.65-7.60(m,2H),7.55-7.47(m,3H),7.47-7.39(m,2H),7.37-7.31(m,2H),7.18-7.10(m,2H),6.83(d,J=6.9Hz,1H),4.46(t,J=6.3Hz,2H),3.32(t,J=6.3Hz,2H);13C NMR(125MHz,DMSO-d6):δ(ppm)167.7,167.0,151.7,140.5,139.1,138.7,131.8,131.3,130.8,130.2,129.2,129.0,128.5,127.8,127.4,126.9,126.7,126.3,44.4,31.5;HRMS(ESI+)计算值:C23H20N3O2S(M+H)+402.1276,实测值:402.1274。
化合物40:5-(4-苄基氧基苯基)-4-[2-(2-羧基苯基)乙基]-1,2,4-三唑-3-硫酮
白色粉末,27mg,产率40%;LC-MS tR:1.72min;m/z(ES+)432.2(M+H+);1H NMR(500MHz,DMSO-d6):δ(ppm)13.81(s,1H),12.74(s,1H),7.69(dd,J=7.6,1.1Hz,1H),7.50-7.33(m,6H),7.28-7.23(m,1H),7.18(d,J=8.8Hz,2H),7.01(d,J=8.8Hz,2H),6.96(d,J=7.6Hz,1H),5.15(s,2H),4.34(t,J=6.7Hz,2H),3.32(t,J=6.3Hz,2H);13C NMR(125MHz,DMSO-d6):δ(ppm)167.9,166.8,159.8,151.5,138.8,136.7,131.9,131.2,130.9,130.2,130.0,128.5,128.0,127.7,126.9,118.1,114.9,69.4,44.5,31.5;HRMS(ESI+)计算值:C24H22N3O3S(M+H)+432.1382,实测值:432.1375。
化合物41:4-[2-(2,4-二羟基苯基)乙基]-5-苯基-1,2,4-三唑-3-硫酮
白色粉末,27mg,产率18%;LC-MS tR:1.04min;m/z(ES+)314.2(M+H+);1H NMR(500MHz,DMSO-d6):δ(ppm)13.87(s,1H),9.12(s,1H),9.02(s,1H),7.57-7.52(m,1H),7.51-7.45(m,4H),6.54(d,J=8.1Hz,1H),6.14(d,J=2.4Hz,1H),6.06(dd,J=8.1,2.4Hz,1H),4.11(t,J=7.4Hz,2H),2.78(t,J=7.4Hz,2H);13C NMR(125MHz,DMSO-d6):δ(ppm)167.0,157.2,156.2,151.6,130.4,130.4,128.7,128.6,126.0,113.8,106.1,102.3,44.1,27.6;HRMS(ESI+)计算值:C16H16N3O2S(M+H)+314.0963,实测值:314.0964。
化合物42:5-(3-联苯基)-4-[2-(2,4-二羟基苯基)乙基]-1,2,4-三唑-3-硫酮
白色粉末,16mg,产率1%;LC-MS tR:1.30min;m/z(ES+)390.0(M+H+);1H NMR(400MHz,DMSO-d6):δ(ppm)13.90(s,1H),9.05(s,1H),8.99(s,1H),7.85-7.81(m,1H),7.75-7.68(m,3H),7.58-7.53(m,1H),7.52-7.38(m,4H),6.52(d,J=8.2Hz,1H),6.11(d,J=2.3Hz,1H),6.04(dd,J=8.2,2.3Hz,1H),4.19(t,J=7.2Hz,2H),2.81(t,J=7.2Hz,2H);13C NMR(101MHz,DMSO-d6):δ(ppm)167.0,157.1,156.2,151.5,140.6,139.1,130.3,129.3,129.0,128.6,127.8,127.5,126.9,126.7,113.8,106.0,102.3,44.1,27.6;HRMS(ESI+)计算值:C22H20N3O2S(M+H)+390.1276,实测值:390.1281。
化合物43:5-(2-联苯基)-4-[2-(2,4-二羟基苯基)乙基]-1,2,4-三唑-3-硫酮
白色粉末,186mg,产率68%;LC-MS tR:1.27min;m/z(ES+)390.1(M+H+);1H NMR(500MHz,DMSO-d6):δ(ppm)13.77(s,1H,NH),9.01(s,1H,OH),8.93(s,1H,OH),7.66(td,J=7.6,1.2Hz,1H),7.53(dd,J=7.8,0.9Hz,1H),7.41(td,J=7.6,1.2Hz,1H),7.38-7.31(m,3H),7.21-7.10(m,3H),6.38(d,J=8.1Hz,1H),6.10(d,J=2.4Hz,1H),6.03(dd,J=8.1,2.4Hz,1H),3.44(t,J=7.1Hz,2H),2.53-2.50(m,2H);13C NMR(125MHz,DMSO-d6):δ(ppm)166.1,157.1,156.2,151.2,141.1,139.2,131.2,130.2,129.9,128.6,128.4,127.8,127.6,124.2,113.8,105.9,102.4,43.2,27.2;HRMS(ESI+)计算值:C22H20N3O2S(M+H)+390.1276,实测值:390.1280。
化合物44:邻-{2-[1-甲基-1H-吡咯-2-基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基}苯甲酸
白色粉末,37mg,产率24%;LC-MS tR:1.39min;m/z(ES+)329.2(M+H+);1H NMR(500MHz,DMSO-d6):13.83(bs,1H),12.79(bs,1H),7.77(dd,J=7.8,1.3Hz,1H),7.41(dt,J=7.5,1.3Hz,1H),7.29(dt,J=7.6,1.1Hz,1H),7.08(dd,J=7.6,0.8Hz,1H),6.89(dd,J=2.3,1.8Hz,1H),6.40(dd,J=3.9,1.7Hz,1H),6.06(dd,J=3.8,2.6Hz,1H),4.37(t,J=6.86Hz,1H),3.45-3.32(m,5H);13C NMR(125MHz,DMSO-d6):168.0,166.3,144.8,138.9,131.6,131.0,130.5,130.4,126.7,126.4,116.5,112.4,107.7,44.6,34.9,31.2;HRMS(ESI+)计算值:C16H17N4O2S(M+H)+329.1072,实测值:329.1076。
化合物45:6-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)己酸
灰白色粉末,215mg,产率:74%;LC-MS tR:1.28min;m/z(ES+)292.1(M+H+);Mp=136-137℃;1H NMR(400MHz,DMSO-d6):13.92(bs,1H),11.98(bs,1H),7.69-7.64(m,2H),7.62-7.54(m,3H),4.01(t,J=6.0Hz,2H),2.08(t,J=5.8Hz,2H),1.56-1.16(m,2H),1.39-1.31(m,2H),1.15-1.06(m,2H);13C NMR(100MHz,DMSO-d6):174.1,167.0,151.1,130.6,129.0,128.5,126.1,43.4,33.2,27.1,25.1,23.6;HRMS(ESI+)计算值:C14H18N3O2S(M+H)+292.1121,实测值:292.1120。
化合物46:3-苯基-4-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)丁酸
白色固体,27mg,产率38%;LC-MS tR:1.42min;m/z(ES+)340.1(M+H+);1H NMR(400MHz,DMSO-d6):δ13.87(s,1H),12.02(s,1H),7.56(t,J=7.4Hz),7.47(t,J=7.6Hz,2H),7.15-7.08(m,3H),6.82(m,2H),4.39(dd,J=14,7.2Hz,1H),4.18(dd,J=14.0,8.5Hz,1H),3.60-3.52(m,1H),2.56-2.52(m,1H),2.47-2.41(m,1H);13C NMR(101MHz,DMSO-d6):δ172.6,167.7,151.8,140.4,130.9,129.2,129.1,128.8,127.9,127.4,126.5,49.0,40.6,37.4;HRMS(ESI+)计算值:C18H18N3O2S(M+H)+340.1120,实测值:340.1119。
化合物47:3-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)环己烷-1-甲酸
灰白色粉末,171mg,产率:38%;LC-MS tR:1.32min;m/z(ES+)304.1(M+H+);Mp=234-235℃;HRMS(ESI+)计算值:C15H18N3O2S(M+H)+304.1122,实测值:304.1120。
化合物48:4-[3-(1-甲基-1H-吡咯-2-基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]丁酸
白色粉末,121mg,产率:45%;LC-MS tR:1.10min;m/z(ES+)267.2(M+H+);1H NMR(500MHz,DMSO-d6):13.89(bs,1H),11.82(bs,1H),7.05(s,1H),6.67(s,1H),6.29(s,1H),4.05(t,J=7.4Hz,2H),3.68(s,3H),2.21(t,J=7.4Hz,2H),1.84(q,J=7.4Hz,2H);13C NMR(125MHz,DMSO-d6):173.5,166.4,140.8,126.8,112.4,107.9,104.7,43.3,35.3,30.5,22.9;HRMS(ESI+)计算值:C11H15N4O2S(M+H)+267.0916,实测值:267.0919。
化合物49:4-(2-叠氮基乙基)-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮
白色粉末,94mg,产率:38%;LC-MS tR:1.40min;m/z(ES+)247.1(M+H+);Mp=108-109℃;1H NMR(400MHz,DMSO-d6):14.04(bs,1H),7.74-7.67(m,2H),7.64-7.54(m,3H),4.1(t,J=6Hz,2H),3.64(t,J=6Hz,2H);13C NMR(100MHz,DMSO-d6):166.9,151.6,130.7,128.9,128.8,128.7,47.6,43.2;HRMS(ESI+)计算值:C10H11N6S(M+H)+247.0766,实测值:247.0769。
化合物50:4-[3-(喹啉-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸
白色粉末,111mg,产率:35%;LC-MS tR:1.40min;m/z(ES+)315.1(M+H+);Mp=238-239℃;1H NMR(400MHz,DMSO-d6):14.20(bs,1H),11.74(bs,1H),8.55(d,J=8.4Hz,1H),8.17-8.04(m,3H),7.87(t,J=7.6Hz,1H),7.72(t,J=7.6Hz,1H),4.73(t,J=7.4Hz,1H),2.37(t,J=7.4Hz,1H),2.10(quint,J=7.4Hz,1H);13C NMR(100MHz,DMSO-d6):173.9,168.5,148.3,147.0,146.4,145.8,137.6,130.5,129.2,127.9,127.6,119.6,44.7,31.1,23.8;HRMS(ESI+)计算值:C15H15N4O2S(M+H)+315.0916,实测值:315.0919。
化合物51:邻-{[3-(3-联苯基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基氨基]甲基}苯甲酸
白色粉末,163mg,产率:81%;LC-MS tR:1.76min;m/z(ES+)403.0(M+H+);1H NMR(500MHz,DMSO-d6):13.98(bs,1H),12.94(bs,1H),8.08(t,J=1.5Hz,1H),7.83(dt,J=7.5,1.5Hz,1H),7.77-7.71(m,2H),7.58-7.19(m,9H),6.87(t,J=6.0Hz,1H),4.60(d,J=6.0Hz,2H);13C NMR(125MHz,DMSO-d6):168.0,166.4,148.8,140.2,139.2,137.2,131.6,130.4,130.3,130.2,129.1,128.9,128.6,127.7,127.4,126.7,126.6,125.9,125.7,50.9;HRMS(ESI+)计算值:C22H19N4O2S(M+H)+403.1229,实测值:403.1233。
化合物52:间-[(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)甲基]苯甲酸
白色粉末,27mg,产率:9%;LC-MS tR:1.23min;m/z(ES+)312.0(M+H+);1H NMR(500MHz,DMSO-d6):14.15(bs,1H),12.91(bs,1H),7.78(d,J=8.0Hz,1H),7.59(s,1H),7.55-7.42(m,5H),7.38(t,J=7.8Hz,1H),7.24(d,J=8.0Hz,1H),5.41(s,2H);13C NMR(125MHz,DMSO-d6):167.9,166.8,151.3,136.1,131.0,130.9,128.9,128.8,128.4,128.3,127.3,125.8,46.4;HRMS(ESI+)计算值:C16H14N3O2S(M+H)+312.0807,实测值:312.0809。
化合物53:5-羟基-2-[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基]苯甲酸
白色固体,58mg,产率75%;LC-MS tR:1.18min;m/z 342.0(M+H)+;1H NMR(500MHz,DMSO-d6):δ13.88(s,1H),12.53(s,1H),9.57(s,1H),7.51-7.48(m,1H),7.40(t,J=7.7Hz,2H),7.26(dd,J=8.2,1.1Hz,2H),7.09(d,J=2.7Hz,1H,Har),6.78(dd,J=8.3,2.7Hz,1H),6.70(d,J=8.3Hz,1H),4.30(t,J=6.6Hz,2H),3.20(t,J=6.6Hz,2H);13C NMR(125MHz,DMSO-d6):δ168.2,167.4,156.4,152.2,132.8,131.4,130.8,129.3,129.0,126.3,119.4,117.8,45.3,31.2;HRMS(ESI+)计算值:C17H16N3O3S(M+H)+342.0912,实测值:342.0915。
化合物54:4-[4-(苄基氧基)苯基乙基]-5-苯基-1,2,4-三唑-3-硫酮
白色粉末,87mg,产率66%;LC-MS tR:1.98min;m/z(ES+)388.2(M+H+);1H NMR(400MHz,DMSO-d6):δ(ppm)13.92(s,1H),7.57-7.52(m,1H),7.50-7.35(m,8H),7.35-7.29(m,1H),6.82(s,4H),5.05(s,2H),4.23-4.11(m,2H),2.93-2.79(m,2H);13C NMR(101MHz,DMSO-d6):δ(ppm)166.9,157.1,151.5,137.2,130.5,129.5,129.3,128.8,128.6,128.4,127.8,127.6,126.0,114.8,69.1,45.3,32.1;HRMS(ESI+)计算值:C23H22N3OS(M+H)+388.1484,实测值:388.1490。
化合物55:对-[(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)甲基]苯甲酸
白色粉末,47mg,产率:30%;LC-MS tR:1.34min;m/z(ES+)312.2(M+H+);Mp=232-233℃;1H NMR(500MHz,DMSO-d6):14.16(bs,1H),12.60(bs,1H),7.82(d,J=8.0Hz,2H),7.54-7.42(m,5H),7.12(d,J=8.0Hz,2H),5.40(s,2H);13C NMR(125MHz,DMSO-d6):167.9,151.3,140.3,130.7,129.5,129.5,128.8,128.2,126.4,126.4,125.8,46.5;HRMS(ESI+)计算值:C16H14N3O2S(M+H)+312.0811,实测值:312.0807。
化合物56:2-{2-[3-(喹啉-6-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸
白色粉末,201mg,产率:53%;LC-MS tR:1.04min;m/z(ES+)377.0(M+H+);1H NMR(500MHz,DMSO-d6):14.05(bs,1H),12.63(bs,1H),8.98(dd,J=4.0,1.5Hz,1H),8.42(d,J=8.5Hz,1H),7.99(d,J=8.5Hz,1H),7.86(d,J=8.5Hz,1H),7.65-7.58(m,2H),7.51(dd,J=8.0,1.5Hz,1H),7.37(td,J=7.5,1.0Hz,1H),7.22(td,J=7.5,1.0Hz,1H),6.98(d,J=7.5Hz,1H),4.47(t,J=6.5Hz,2H),3.37(t,J=6.5Hz,2H);13C NMR(125MHz,DMSO-d6):167.8,167.1,151.9,150.9,147.8,138.5,136.7,131.6,131.2,130.8,130.5,129.3,128.7,128.6,127.2,126.8,123.5,122.1,44.7,31.4;HRMS(ESI+)计算值:C20H17N4O2S(M+H)+337.1072,实测值:377.1072。
化合物57:邻-{2-[3-(1H-吡咯-2-基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基}苯甲酸
白色粉末,99mg,产率:63%;LC-MS tR:1.33min;m/z(ES+)315.1(M+H+);1H NMR(500MHz,DMSO-d6):13.78(bs,1H),12.57(bs,1H),11.58(bs,1H),7.82(dd,J=7.8,1.2Hz,1H),7.47(dt,J=7.5,1.3Hz,1H),7.37-7.23(m,2H),6.94(s,1H),6.73(s,1H),6.16(dd,J=6.0,2.5Hz,1H),4.43(t,J=7.2Hz,2H),3.37(t,J=7.2Hz,2H);13C NMR(125MHz,DMSO-d6):168.4,166.6,145.5,138.9,131.9,131.1,130.4,130.3,126.8,121.7,116.2,110.0,109.1,44.8,31.6;HRMS(ESI+)计算值:C15H15N4O2S(M+H)+315.0916,实测值:315.0917。
化合物58:邻-{2-[3-(3-噻吩基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基}苯甲酸
白色粉末,118mg,产率:36%;LC-MS tR:1.35min;m/z(ES+)332.1(M+H+);1H NMR(500MHz,DMSO-d6):13.88(bs,1H),12.94(bs,1H),7.88-7.86(m,1H),7.75(dd,J=9.5,1.0Hz,1H),7.66-7.63(m,1H),7.64(td,J=9.5,1.5Hz,1H),7.29(td,J=9.5,1.0Hz,1H),7.18(dd,J=6.0,1.5Hz,1H),7.07(d,J=9.5Hz,1H),4.42(t,J=8.8Hz,2H),3.34(t,J=8.8Hz,2H);13C NMR(125MHz,DMSO-d6):168.1,166.9,147.4,138.7,131.8,131.2,130.6,130.2,127.3,127.1,126.9,126.8,125.9,44.7,31.6;HRMS(ESI+)计算值:C15H14N3O2S2(M+H)+332.0527,实测值:332.0529。
化合物59:8-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)辛酸
白色粉末,132mg,产率:60%;LC-MS tR:1.38min;m/z(ES+)320.1(M+H+);1H NMR(500MHz,DMSO-d6):13.92(bs,1H),12.03(bs,1H),7.70-7.53(m,5H),4.02(t,J=9.5Hz,2H),2.12(t,J=9.5Hz,2H),1.52(sext,J=9.5Hz,2H),1.39(sext,J=9.5Hz,2H),1.19-1.05(m,6H);13C NMR(125MHz,DMSO-d6):174.3,166.9,151.1,130.6,128.9,128.5,126.2,43.4,33.5,28.1,27.7,27.1,25.4,24.2;HRMS(ESI+)计算值:C16H22N3O2S(M+H)+320.1433,实测值:320.1437。
化合物60:苯基[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]乙酸
白色粉末,417mg,产率:56%;LC-MS tR:1.52min;m/z(ES+)372.0(M+H+);1H NMR(600MHz,DMSO-d6):13.32(bs,1H),11.62(bs,1H),7.64-7.53(m,5H),7.32-7.24(m,5H),4.59(s,1H),4.27-4.14(m,2H),2.77-2.70(m,1H),2.62-2.56(m,1H);13C NMR(150MHz,DMSO-d6):171.2,166.9,151.1,136.7,130.7,129.0,128.6,128.4,128.1,127.8,125.8,51.2,,43.0,28.2;HRMS(ESI+)计算值:C18H18N3O2S2(M+H)+372.0840,实测值:372.0846。
化合物61:5-氨基-2-[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基]苯甲酸
白色泡沫,38mg,产率34%;LC-MS tR:0.97min;m/z 341.1(M+H)+;1HNMR(600MHz,DMSO-d6):δ13.87(s,1H),12.58(s,1H),7.52-7.48(m,1H),7.43-7.39(m,2H),7.25(dt,J=8.3,1.5Hz,2H),7.13(s,2H),6.78(d,J=7.1Hz,1H),6.69(d,J=8.1Hz,2H),4.28(t,J=6.6Hz,2H),3.81-3.69(m,2H),3.19(t,J=6.6Hz,2H);HRMS(ESI+)计算值:C17H17N4O2S(M+H)+341.1072,实测值:341.1077。
化合物62:邻-(2-{3-[间-(2-吗啉代乙氧基)苯基]-5-硫代-1,4-二氢-1,2,4-三唑-4-基}乙基)苯甲酸
白色粉末,64mg,产率:20%;LC-MS tR:1.09min;m/z(ES+)455.1(M+H+);1H NMR(500MHz,DMSO-d6):13.96(bs,1H),12.76(bs,1H),10.22(bs,1H),7.68-7.64(m,1H),7.44-7.24(m,3H),7.16-7.08(m,1H),6.90-6.78(m,3H),4.40(t,J=7.5Hz,2H),4.33(t,J=6.0Hz,2H),4.01-3.65(m,6H),3.60-3.35(m,4H),3.29(t,J=7.5Hz,2H);13C NMR(125MHz,DMSO-d6):167.9,167.0,157.4,151.3,138.7,131.9,131.3,130.9,130.2,130.0,127.0,126.9,121.5,117.1,114.6,63.4,62.3,55.0,51.8,44.4,31.6;HRMS(ESI+)计算值:C23H27N4O4S(M+H)+455.1753,实测值:455.1757。
化合物63:邻-[2-(3-{间-[2-(4-甲基-1-哌嗪基)乙氧基]苯基}-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基]苯甲酸
白色粉末,249mg,产率:75%;LC-MS tR:1.05min;m/z(ES+)468.2(M+H+);1H NMR(500MHz,DMSO-d6):13.94(bs,1H),12.70(bs,1H),9.81(bs,1H),7.68-7.63(m,1H),7.41-7.36(m,1H),7.32-7.24(m,2H),7.08-7.03(m,1H),6.88-6.85(m,1H),6.82-6.77(m,1H),6.70(s,1H),4.40(t,J=7.5Hz,2H),4.16-4.12(m,2H),3.58-3.36(m,4H),3.29(t,J=7.5Hz,2H),3.20-3.01(m,6H),2.80(s,3H);13C NMR(125MHz,DMSO-d6):167.8,166.9,157.9,151.5,138.8,131.9,131.3,130.9,130.2,129.9(2C),126.9,121.0,116.9,114.3,64.5,55.1,51.7,49.4,44.4,42.2,31.6;HRMS(ESI+)计算值:C24H30N5O3S(M+H)+468.2069,实测值:468.2073。
化合物64:4-[2-(苄硫基)乙基]-5-(1-甲基-1H-吡咯-2-基)-2,4-二氢-1,2,4-三唑-3-硫酮
微黄色粉末,117mg,产率:35%;LC-MS tR:1.81min;m/z(ES+)331.1(M+H+);1H NMR(400MHz,DMSO-d6):13.96(bs,1H),7.31-7.17(m,5H),7.08(t,J=2.0Hz,1H),6.60(dd,J=4.0,2.0Hz,1H),6.21(dd,J=4.0,2.0Hz,1H),4.23(t,J=7.0Hz,2H),3.65(s,3H),3.52(s,2H),2.69(t,J=7.0Hz,2H);13CNMR(100MHz,DMSO-d6):166.2,144.8,137.8,128/.6,128.2,126.8,126.6,116.8,112.6,107.9,42.8,34.8,34.2,27.9;HRMS(ESI+)计算值:C16H19N4S2(M+H)+331.1051,实测值:331.1055。
化合物65:[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]乙酸
微黄色粉末,121mg,产率:20%;LC-MS tR:1.19min;m/z(ES+)296.1(M+H+);1H NMR(600MHz,DMSO-d6):13.98(bs,1H),12.53(bs,1H),7.69-7.65(m,2H),7.62-7.54(3H),4.22(t,J=7.2Hz,2H),3.05(s,2H),2.86(t,J=7.2Hz,2H);13C NMR(150MHz,DMSO-d6):170.8,166.9,151.3,130.7,128.9,128.7,125.8,42.7,32.6,28.8;HRMS(ESI+)计算值:C12H14N3O2S2(M+H)+296.0527,实测值:296.0533。
化合物66:[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]丙酸
微黄色粉末,84mg,产率:44%;LC-MS tR:1.24min;m/z(ES+)310.0(M+H+);1H NMR(500MHz,DMSO-d6):14.01(s,1H),12.26(s,1H),7.69–7.67(m,2H),7.61–7.55(m,3H),4.16(t,J=7.0,14.5Hz,2H),2.77(t,J=7.0,14.5Hz,2H),2.42(t,J=7.0,14.5Hz,2H),2.35(t,J=7.0,14.5Hz,2H);13C NMR(125MHz,DMSO-d6):172.8,166.9,151.6,130.8,129.1,129.0,126.1,43.2,34.1,28.0,25.7;HRMS(ESI+)计算值:C13H16N3O2S2(M+H)+310.0684,实测值:310.0690。
化合物67:2-[[2,3-二羟基苯基)甲基]氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸
白色粉末,63mg,产率:44%;LC-MS tR:0.90min;m/z(ES+)415.0(M+H+);1H NMR(400MHz,DMSO-d6):13.97(s,1H),9.52,(s,1H),7.67-7.56(m,5H),6.80(dd,J=1.4,7.7Hz,2H),6.69(dd,J=1.4,7.7Hz,2H),6.66-6.62(m,1H),4.08-4.04(m,2H),4.01-3.94(m,2H),3.62-3.60(m,1H),3.35(bs,2H),1.76-1.55(m,4H);13C NMR(101MHz,DMSO-d6):170.1,167.2,151.1,145.3,144.5,130.8,129.1,128.6,126.0,121.2,119.2,118.9,116.0,58.6,45.1,43.2,26.5,23.9;HRMS(ESI+)计算值:C20H23N4O4S(M+H)+415.1440,实测值:415.1447。
化合物68:2-[二(苯基甲基)氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸
白色粉末,30mg,产率:29%;UPLC-MS tR:3.15min;m/z(ES+)473.4(M+H+);1H NMR(500MHz,DMSO-d6):13.98(s,1H),12.35(bs,1H),7.61-7.49(m,5H),7.31-7.24(m,10H),4.03-3.90(m,2H),3.74-3.60(m,4H)3.01(s,1H),1.69-1.42(m,4H);13C NMR(125MHz,DMSO-d6):172.9,167.2,151.2,130.8,129.1,129.0,128.6,128.4,127.4,126.2,60.2,54.1,43.4,25.4,25.0;HRMS(ESI+)计算值:C27H29N4O2S(M+H)+473.2011,实测值:473.2009。
化合物69:2-[二(1H-咪唑-5-基甲基)氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸
白色粉末,26mg,产率:21%;LC-MS tR:1.32min;m/z(ES+)453.3(M+H+);1H NMR(500MHz,DMSO-d6):13.98(s,1H),12.08(s,1H),9.00(s,2H),7.62-7.46(m,7H),4.05–3.93(m,2H),3.79(s,4H)3.17-3.14(m,1H),1.68-1.48(m,4H);13C NMR(125MHz,DMSO-d6):173.4,167.2,151.2,134.5,131.0,130.1,129.1,128.5,126.2,117.5,61.3(1C,CH),44.6(1C,Ca),43.3,26.0,24.7;HRMS(ESI+)计算值:C21H25N8O2S(M+H)+453.1821,实测值:453.1821。
化合物70:5-苯基-4-[2-(苯基硫基)乙基]-2,4-二氢-1,2,4-三唑-3-硫酮
白色粉末,32mg,产率:48%;LC-MS tR:1.77min;m/z(ES+)314.0(M+H+);1H NMR(600MHz,DMSO-d6):13.96(bs,1H),7.61-7.54(m,3H),7.51-7.46(m,2H),7.23-7.18(m,2H),7,17-7.12(m,3H),4.16-1.13(m,2H),3.31-3.27(m,2H);13C NMR(150MHz,DMSO-d6):166.8,151.3,134.0,130.6,128.9,128.8(2C),127.9,125.9,125.7,43.3,28.9;HRMS(ESI+)计算值:C16H16N3S2(M+H)+314.0786,实测值:314.0790。
化合物71:4-[2-(2-氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮
白色粉末,100mg,产率:30%;LC-MS tR:1.77min;m/z(ES+)346.0(M+H+);1H NMR(500MHz,CDCl3):11.76(s,1H),7.58–7.51(m,5H),7.27(t,J=7.5,15.0Hz,1H),7.22–7.19(m,1H),7.06(t,J=7.5,15.0Hz,1H),7.02–6.98(m,1H),4.32(t,J=7.2,14.0Hz,2H),2.81(t,J=7.2,14.0Hz,2H);13C NMR(125MHz,CDCl3):167.8,160.9,152.5,131.3,131.1,131.0,129.4,129.1,129.0,125.8,125.3,124.4,155.6,43.9,28.9,28.8;HRMS(ESI+)计算值:C17H17FN3S2(M+H)+346.0848,实测值:346.0854。
化合物72:4-[2-(4-氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮
白色粉末,75mg,产率:27%;LC-MS tR:1.82min;m/z(ES+)346.0(M+H+);1H NMR(500MHz,CDCl3):10.78(s,1H),8.15–8.12(m,2H),7.60–7.53(m,5H),7.45–7.44(m,2H),4.29(t,J=7.4,14.9Hz,2H),3.72(s,2H),2.73(t,J=7.4,14.9Hz,2H);13C NMR(125MHz,CDCl3):168.3,152.3,147.3,145.7,131.5,130.0,129.5,128.9,125.7,124.0,44.0,35.4,28.8;HRMS(ESI+)计算值:C17H17FN3S2(M+H)+346.0848,实测值:346.0854。
化合物73:4-[2-(2,4-二氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮
白色粉末,32mg,产率:11%;LC-MS tR:1.85min;m/z(ES+)364.1(M+H+);1H NMR(500MHz,CDCl3):11.26(s,1H),7.59–7.52(m,5H),7.30-7.25(m,1H),6.82–6.74(m,2H),4.31(t,J=7.3,14.5Hz,2H),3.53(s,1H),2.79(t,J=7.3,14.5Hz,2H);13C NMR(125MHz,CDCl3):168.0,162.6,160.6,152.5,131.7,131.4,129.4,128.9,125.7,121.2,111.5,104.1,43.9,29.8,28.7;HRMS(ESI+)计算值:C17H16F2N3S2(M+H)+364.0754,实测值:364.0761。
化合物74:4-[2-(4-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮
白色粉末,38mg,产率:21%;LC-MS tR:1.79min;m/z(ES+)372.9(M+H+);1H NMR(500MHz,CDCl3):11.74(s,1H),7.59–7.53(m,5H),7.21–7.19(m,2H),6.97–6.93(m,2H),4.27(t,J=7.4,13.8Hz,2H),3.57(s,1H),2.73(t,J=7.4,13.8Hz,2H);13C NMR(125MHz,CDCl3):167.9,163.0,161.1,152.3,133.6,131.4,130.6,129.4,128.9,125.8,115.6,115.5,44.1,35.2,28.7;HRMS(ESI+)计算值:C17H17N4O2S2(M+H)+373.0793,实测值:373.0793。
化合物75:4-[2-(2-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮
白色粉末,67mg,产率:17%;LC-MS tR:1.73min;m/z(ES+)373.1(M+H+);1H NMR(500MHz,CDCl3):10.90(s,1H),7.98(d,J=7.9Hz,1H),7.58–7.53(m,7H),7.43–7.40(m,1H),4.28(t,J=7.5,15.0Hz,2H),3.98(s,2H),2.78(t,J=7.5,15.0Hz,2H);13C NMR(125MHz,CDCl3):168.2,152.5,148.4,134.1,133.5,132.4,131.5,129.6,129.5,128.9,128.6,125.7,125.6,44.2,33.5,29.3;HRMS(ESI+)计算值:C17H17N4O2S2(M+H)+373.0793,实测值:373.0793。
化合物76:4-[2-(2-羟基-5-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮
白色粉末,72mg,产率:10%;LC-MS tR:1.57min;m/z(ES+)389.0(M+H+);1H NMR(500MHz,DMSO-d6):14.02(s,1H),11.33(s,1H),8.09(d,J=3.0Hz,1H),8.05(dd,J=3.0,9.0Hz,1H),7.71–7.69(m,2H),7.62–7.57(m,5H),6.98(d,J=9.0Hz,1H),4.29(t,J=7.5,14.5Hz,2H),2.79(t,J=7.5,14.5Hz,2H);13C NMR(125MHz,DMSO-d6):167.0,161.7,151.6,139.3,130.8,129.1,128.9,125.9,125.8,124.8,115.4,43.2,28.8,28.6;HRMS(ESI+)计算值:C17H17N4O3S2(M+H)+389.0742,实测值:389.0742。
化合物77:4-[2-(2-苯基乙基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮
白色粉末,118mg,产率:53%;LC-MS tR:1.86min;m/z(ES+)342.1(M+H+);1H NMR(400MHz,CDCl3):12.29(s,1H),7.59–7.50(m,5H),7.31–7.27(m,2H),7.23–7.15(m,3H),4.28(t,J=15.1,7.5Hz,2H),2.90(t,J=15.1,7.5Hz,2H),2.82(t,J=15.5,7.2Hz,2H),2.68(t,J=15.5,7.2Hz,2H);13C NMR(100MHz,CDCl3):167.1,152.4,140.2,131.3,129.4,129.0,128.6,128.5,126.5,44.4,36.2,33.4,29.4;HRMS(ESI+)计算值:C18H20N3S2(M+H)+342.1099,实测值:342.1101。
化合物78:2-苯基-3-[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]-丙酸
灰白色粉末,47mg,产率:12%;LC-MS tR:1.57min;m/z(ES+)386.0(M+H+);1H NMR(400MHz,DMSO-d6):13.96(bs,1H),12.50(bs,1H),7.68-7.64(m,2H),7.59-7.49(m,3H),7.34-7.19(m,5H),4.15(t,J=7.4Hz,2H),3.64(2d,J=9.2Hz和J=9.2Hz,2H),2.90-2.77(m,3H),2.56-2.52(m,1H);13C NMR(100MHz,DMSO-d6):166.8,151.4,140.5,130.6,128.9,128.8,128.4,127.6,127.2,51.1,43.3,33.6,28.3;HRMS(ESI+)计算值:C19H20N3O2S2(M+H)+386.0997,实测值:386.1001。
化合物79:5-苯基-4-[3-(苯基硫基)丙基]-2,4-二氢-1,2,4-三唑-3-硫酮
白色粉末,399mg,产率:61%;LC-MS tR:1.82min;m/z(ES+)328.1(M+H+);1H NMR(500MHz,DMSO-d6):13.97(bs,1H),7.64-7.56(m,3H),7.55-7.50(m,2H),7.33-7.25(m,2H),7.20-7.15(m,3H),4.16(t,J=7.5Hz,2H),2.86(t,J=7.5Hz,2H),1.83(t,J=7.5Hz,2H);,13C NMR(125MHz,DMSO-d6):167.1,151.2,135.5,130.8,129.1,128.7,128.2,127.8,126.0,125.8,24.8,29.1,27.1;HRMS(ESI+)计算值:C17H18N3S2(M+H)+328.0942,实测值:328.0951。
化合物80:4-[2-(苄硫基)乙基]-5-(邻-甲苯基)-2,4-二氢-1,2,4-三唑-3-硫酮
白色粉末,151mg,产率:44%;LC-MS tR:1.87min;m/z(ES+)342.0(M+H+);1H NMR(500MHz,DMSO-d6):13.99(bs,1H),7.55-7.36(m,4H),7.27-7.17(m,3H),7.09-7.05(m,2H),3.99(t,J=7.2Hz,2H),3.42(s,2H),2.57(t,J=7.2Hz,2H);13C NMR(125MHz,DMSO-d6):166.3,150.4,137.9,130.8,130.7,130.2,128.5,128.4,128.3,126.8,126.1,125.3,42.6,34.3,27.9,19.1;HRMS(ESI+)计算值:C18H20N3S2(M+H)+342.1099,实测值:342.1100。
化合物81:3-{2-[3-(3-联苯基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基硫基}-氢化阿托酸
白色粉末,72mg,产率:8%;LC-MS tR:1.78min;m/z(ES+)462.1(M+H+);1H NMR(500MHz,DMSO-d6):14.06(bs,1H),12.46(bs,1H),7.94(bs,1H),7.87-7.83(m,1H),7.71-7.60(m,4H),7.51-7.37(3H),7.28-7.23(m,3H),7.17-7.13(m,2H),4.25-4.14(m,2H),3.64-3.58(m,1H),2.90-2.75(m,3H),2.48-2.42(m,1H);,13C NMR(125MHz,DMSO-d6):173.4,166.8,151.6,140.9,139.0,138.2,129.7,129.1,129.0,128.5,128.1,127.7,127.4,127.2,127.0,126.9,126.8,51.1,43.4,33.5,28.4;HRMS(ESI+)计算值:C25H24N3O2S2(M+H)+462.1310,实测值:462.1317。
实施例4:生物学评价的实验细节
1-用于测定抑制常数的酶法测定。
化合物的抑制能力已通过报告底物方法评估,特别是在不存在和存在几种浓度的抑制剂(最终浓度,0.5–1,000μM)情况下,通过测量报告底物(如150μM亚胺培南,150μM美罗培南,120μM头孢噻肟或100μM头孢硝噻吩)的水解速率进行评估。
反应速率通过在紫外-可见分光光度计或酶标仪中于300nm(亚胺培南、美罗培南)、260nm(头孢噻肟)或482nm(头孢硝噻吩)的波长下在50mM HEPES缓冲液(pH 7.5)中以及存在纯化的MBL酶(如VIM-1、VIM-2、VIM-4、NDM-1和IMP-1,最终浓度范围为1-70nM)的情况下,在底物水解后观察到的吸光度变化来衡量。
在竞争性抑制模型的基础上,通过分析比值v0/vi(v0,不存在抑制剂时的水解速度;vi,存在抑制剂时的水解速度)作为[I]的函数的相关性,确定抑制常数(Ki),其已经描述在[Docquier J.D.,Lamotte-Brasseur J.,Galleni M.,Amicosante G.,Frère J.M.,Rossolini G.M.(2003)J.Antimicrob.Chemother.51,257-266]。v0/vi vs[I]的曲线的斜率,对应于Km S/(Km S+[S])Ki(其中Km S是报告底物的Km值,[S]是反应混合物中的浓度)且允许计算Ki值。或者,通过在不同浓度的抑制剂和底物存在下测量初始水解速率来进行Dixon作图分析。这允许确定Ki值并支持各种化合物作为各种测试酶的竞争性抑制剂。
抑制试验结果见表1。多种化合物显现出对至少一种重要的MBL(如VIM-型或NDM-型酶(例如,NDM-1))在微摩尔(micromolar)或亚微摩尔范围的Ki或在100μM>85%的抑制作用。其中,有几种表现出大范围的抑制作用。
表1:MBL抑制剂及其对分离的MBL的抑制能力。
aND=没有确定;-=无显著抑制作用或Ki>100μM;+=10μM<Ki≤100μM;++=1μM<Ki≤10μM;+++=Ki≤1μM
当未评估Ki时,指示最大测试浓度下的%抑制作用。
2-微生物测定以确定MBL抑制剂与β-内酰胺的协同活性。
微生物测定使用不同的方法进行:
A]使用其中将抑制剂(40-320μg)加入到含有限定量β-内酰胺抗生素(如30μg头孢西丁)的盘中的盘扩散试验(disk-diffusion test),与单独抗生素进行比较,评价组合用药的抗微生物活性(对应于生长抑制区直径,单位为mm)。
这些试验是在用含有编码功能性金属β内酰胺酶的克隆基因的pLB-II质粒衍生物(如pLBII-VIM-2)转化后产生限定的MBL的等基因实验室菌株(如大肠杆菌DH5α或XL-1)上进行的[Borgianni L.,Vandenameele J.,Matagne A.,Bini L.,Bonomo R.A.,FrèreJ.M.,Rossolini G.M.,Docquier J.D.(2010)Antimicrob.Agents Chemother.54,3197-3204]。或者,用高渗菌株(如大肠杆菌AS19)代替大肠杆菌DH5α或XL-1。
结果见表2。在产生重组VIM-2的细菌上进行的这些首次微生物试验是非常有前景的,因为几种化合物显示出恢复对头孢西丁敏感性的能力。
表2:微生物测定——MBL抑制剂与头孢西丁在组合试验设置中的体外抗菌协同活性
对大肠杆菌AS19和LZ2310[pLBII-VIM2](大肠杆菌K12ΔnorEΔmdfA N43 acrA1)的活性
a将可变体积的化合物添加到盘,以获得40μg的最终抑制剂量。
bEUCAST抗性转效点(resistance breakpoint)=18mm(即+4),对于LZ2310而言
c测量的直径和没有化合物的直径间的差异
dN.A.=不适用;++=1μM<Ki≤10μM;+++=Ki≤1μM
B]微量肉汤稀释法,其中在不存在和存在固定浓度的(如16μg/ml、32μg/ml或64μg/ml)各种抑制剂的情况下,测量β-内酰胺抗生素(如亚胺培南、美罗培南或头孢他啶)的最小抑菌浓度(MIC)。
这种方法是按照CLSI的建议进行的(文件M07-A10,2015,“Methods for DilutionAntimicrobial Susceptibility Tests for Bacteria That Grow Aerobically”)。
与单独的抗生素相比,该组合的较低MIC表明受试化合物增强了抗生素活性。使用产生上述定义的MBL的等基因实验室菌株或显示多重抗药性(multi-drug resistance)表型的临床分离株进行此类测试,并且其中金属β内酰胺酶的产生通过分子方法得到证实。
在不存在和存在固定浓度的MBL抑制剂(32μg/ml)的情况下,按照CLSI(文件M07-A10,2015)的建议,在Mueller-Hinton肉汤中一式两份测定美罗培南(MEM)的MIC值。显示增强倍数≥3.log2稀释的化合物在下表3中以粗体表示。化合物33、37、39、42、62-64、66、69-78、80和81显著降低了美罗培南对产生VIM的克雷伯氏菌属临床分离株的MIC。
表3:在不存在和存在MBL抑制剂的情况下,美罗培南(MEM)的MIC测定。(指示增强倍数x.log2稀释)
值x≥3.log2稀释以粗体显示
3-在真核细胞上的细胞膜完整性测定以评估化合物细胞毒性。
测试所选化合物诱导真核细胞裂解的能力,其通过在化合物不存在和存在0.001至1.2mM浓度范围的化合物的情况下,在添加了10%胎牛血清、4.5mg/ml葡萄糖和2mM L-谷氨酰胺的Dulbecco修饰的Eagle培养基中孵育这些细胞24小时(37℃,5%CO2)后,测量由HeLa细胞中释放的乳酸脱氢酶(LDH)。LDH活性是在样品中使用商业试剂盒(如CytoToxNon-Radioactive Cytotoxicity Assay,Promega,Madison,Wisconsin,U.S.A.)测定的,所述样品中含有与不同浓度的被测化合物或用于重悬此类化合物的溶剂或缓冲液(载体对照(vehicle control))一起孵育的HeLa细胞。
进一步的对照包括仅含有培养基的样品(培养基对照)或其中通过加入9%TritonX-100(最大LDH释放对照)诱导细胞裂解的样品。细胞毒性的百分比计算为100x(样品LDH释放)/(最大LDH释放)。细胞毒性百分比的变化通常取决于化合物浓度,并允许计算对应于诱导50%细胞毒性的化合物浓度的IC50值。
通过使用这一操作,化合物12(2-{2-[3-(呋喃-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸)、13(2-{2-[3-(噻吩-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸)和14(2-{2-[3-(2-甲基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸)显示具有非常低的细胞毒性,具有估算的IC50值>1.2mM。
Claims (23)
1.式(I)的化合物或其药学上可接受的盐,所述化合物如下式所示,
其中:
■卤素,优选氯、氟或溴,
■OH、NO2、NR5R6、COOR8,
■(C1-C6)烷氧基、芳基氧基、芳基(C1-C6)烷氧基、环烷基(C1-C6)烷氧基、杂环烷基(C1-C6)烷氧基、杂芳基(C1-C6)烷氧基,其中所述芳基、环烷基、杂环烷基或杂芳基部分任选取代有至少一个(C1-C6)烷基,且所述烷氧基部分任选取代有至少一个卤素,优选氟,
■被NR3R4取代的(C1-C6)烷氧基,其中R3和R4独立地表示H、(C1-C12)酰基、(C1-C6)烷基、芳基(C1-C3)烷基、杂芳基(C1-C3)烷基、环烷基(C1-C3)烷基、杂环烷基(C1-C3)烷基、((C1-C6)烷基)-O-C(O)-、(芳基(C1-C6)烷基)-O-C(O)-、((C1-C6)烷基)-SO2-、((C1-C6)烷基芳基)-SO2-,
■(C1-C6)烷基,任选取代有至少一个卤素,优选氟,和
■芳基、杂芳基,它们任选取代有至少一个(C1-C6)烷基、至少一个(C1-C6)烷氧基、至少一个卤素原子、至少一个OH基团、至少一个NO2、至少一个-COOR8、或至少一个NR5R6;
○5-14元环,其选自芳基、环烷基、杂环(所述杂环优选为杂芳基、杂环烷基、或杂环衍生物),所述5-14元环任选取代有至少一个选自以下的基团:
■卤素,优选氯、氟或溴,
■OH、NO2、NR5R6、COOR8,
■(C1-C6)烷基,任选取代有至少一个卤素,优选氟,或取代有COOR8,
■(C1-C6)烷氧基、芳基氧基、芳基(C1-C6)烷基氧基,和
■任选取代有NO2的芳基;
○选自下面的基团:
■COOR8,
■N3,
■NR1R2基团,其中R1和R2独立地表示H、(C1-C12)酰基、(C1-C6)烷基、芳基(C1-C3)烷基、杂芳基(C1-C3)烷基、环烷基(C1-C3)烷基、杂环烷基(C1-C3)烷基、((C1-C6)烷基)-O-C(O)-、(芳基(C1-C6)烷基)-O-C(O)-、((C1-C6)烷基)-SO2-、((C1-C6)烷基芳基)-SO2-,其中所述芳基、杂芳基、环烷基、杂环烷基部分任选地被至少一个选自下面的基团取代:卤素(优选氯、氟或溴)、OH、COOR8、NO2、NR5R6、脒基、NH-C(=NH)-NH2、(C1-C6)烷基氧基、和任选取代有至少一个卤素(优选氟)或取代有COOR8的(C1-C6)烷基,或其中R1和R2与它们连接的氮一起形成含氮杂环或亚胺;
■SO2-R7,其中R7表示(C1-C6)烷基,或5-14元环,优选芳基,该5-14元环任选取代有(C1-C6)烷基,
■(C1-C12)酰基(优选苯甲酰基),和
■-NH(CO)-NHR9,其中R9为H、(C1-C6)烷基、芳基,优选苯基;或
○(C1-C6)烷基,任选取代有至少一个卤素,优选氟,或取代有COOR8,其中R5和R6独立地为H、(C1-C6)烷基、芳基、杂芳基、(C3-C12)环烷基、(C3-C12)杂环烷基、(C1-C12)酰基、((C1-C6)烷基)-O-C(O)-、(芳基(C1-C6)烷基)-O-C(O)-、((C1-C6)烷基)-SO2-、((C1-C6)烷基芳基)-SO2-,或R5和R6与它们连接的氮一起形成含氮杂环或亚胺,且
R8独立地为H、(C1-C6)烷基、芳基、杂芳基、(C3-C12)环烷基、或(C3-C12)杂环烷基。
2.根据权利要求1的化合物,其中(A)表示5-14元环,其选自芳基、杂芳基、环烷基和杂环烷基,所述5-14元环任选地被至少一个选自下面的基团取代:
■卤素,优选氯、氟或溴,
■OH,
■(C1-C6)烷氧基(例如甲氧基)、芳基(C1-C6)烷氧基(例如苄基氧基)、杂环烷基(C1-C6)烷氧基(例如吗啉代乙氧基或哌嗪基乙氧基),其中所述基团的芳基或杂环烷基部分任选取代有至少一个(C1-C6)烷基,且所述基团的烷氧基部分任选取代有至少一个卤素,优选氟,
■(C1-C6)烷基,任选取代有至少一个卤素,优选氟,(例如甲基或CF3),和
■芳基(例如苯基),其任选取代有至少一个(C1-C6)烷基、(C1-C6)烷氧基、卤素原子、OH基团、NO2、-COOR8、或NR5R6;
当n为0时,Y为-CH2-且A为杂芳基,所述杂芳基具有一个或两个杂原子。
3.根据权利要求1或2的化合物,其中Z表示:
○5-14元环,其选自芳基(例如苯基、联苯基或萘基)、环烷基(例如环己基、环丙基)、杂环(所述杂环优选为杂芳基(例如喹啉基)、或杂环衍生物(例如酞基)),所述5-14元环任选取代有至少一个选自以下的基团:
■卤素,优选氯、氟或溴,
■OH、COOH、NO2、NH2,
■(C1-C6)烷基(例如甲基),任选取代有至少一个卤素,优选氟,或取代有COOH;
○选自下面的基团:
■COOH,
■N3,
■NR1R2基团,其中R1和R2独立地表示H、Boc、(C1-C6)烷基、芳基(C1-C3)烷基(例如苄基)、杂芳基(C1-C3)烷基(例如咪唑基甲基),其中所述芳基和杂芳基任选取代有至少一个OH;或
○(C1-C6)烷基,任选取代有至少一个卤素,优选氟,或取代有COOH。
4.根据权利要求1至3任一项的化合物,其中n=1且X为甲基或乙基。
5.根据权利要求1的化合物,其中n=0且其中A为芳基,其选自任选取代有苯基或苄基氧基的苯基、和萘基。
6.根据权利要求1的化合物,其中n=0且其中A为苯基,其取代有至少一个选自以下的基团:甲基、甲氧基、CF3、OH、卤素。
7.根据权利要求1的化合物,其中n=0且其中A为5-元环,其选自呋喃基、任选取代有卤素的噻吩基、任选取代有甲基的吡咯基。
8.根据权利要求1的化合物,其中n=0且其中A为喹啉基。
9.根据权利要求1至8的化合物,其中Y选自(C1-C7)烷基链,其任选包含至少一个杂原子。
10.根据权利要求1至9的化合物,其中Y为(C1-C7)烷基链,且其中o=1且Z为COOH。
11.根据权利要求1至9的化合物,其中Y为(C1-C7)烷基链,其任选包含至少一个杂原子,且其中o=2且Z选自
-(C1-C3)烷基,优选甲基,任选取代有COOH,
-任选取代有Cl的苯基,
-NH-Boc、N(咪唑基甲基)2、N(苄基)2和COOH,所述苄基任选取代有至少一个OH。
12.根据权利要求1至9的化合物,其中Y为(C1-C7)烷基链,其任选包含至少一个杂原子,且其中o=1且Z为苯基,该苯基取代有COOH,且任选取代有OH或NH2。
13.根据权利要求1至9的化合物,其中o=1且Z为苯基,其取代有至少一个OH,优选取代有两个OH。
14.根据权利要求1至9的化合物,其中o=1且Z为苯基,其取代有苄基氧基。
15.根据权利要求1至9的化合物,其中Y为(C1-C5)烷基链,其包含至少一个杂原子,所述杂原子优选为S。
16.根据权利要求1至9的化合物,其中o为1,A为任选取代有至少一个选自以下的基团的苯基:甲基、OMe、OH、卤素和CF3,且Z为任选取代有至少一个选自以下的基团的苯基:COOH、OH。
17.根据权利要求16的化合物,其中A为任选取代有至少一个选自以下的基团的苯基:OMe和OH,Z为任选取代有COOH或至少一个OH的苯基,Y为乙基或甲基。
18.根据权利要求1至8的化合物,其中o为1,A为取代有苯基的苯基,且Z为COOH或任选取代有至少一个选自以下的基团的苯基:COOH、OH。
19.根据权利要求1的化合物,其中:
■卤素,优选氯、氟或溴,
■OH、NO2、COOR8,
■(C1-C6)烷氧基、杂环烷基(C1-C6)烷氧基(例如吗啉代乙氧基或哌嗪基乙氧基),其中所述基团的杂环烷基部分任选取代有至少一个(C1-C6)烷基,且所述基团的烷氧基部分任选取代有至少一个卤素,优选氟,
■(C1-C6)烷基(例如甲基),任选取代有至少一个卤素,优选氟,和
■芳基(例如苯基);
○5-14元环,其选自芳基(例如苯基)、环烷基、杂环(所述杂环优选为杂芳基、杂环烷基、或杂环衍生物(例如酞基)),所述5-14元环任选取代有至少一个选自以下的基团:
■卤素,优选氯、氟或溴,
■OH、NO2、COOR8,
■(C1-C6)烷基,任选取代有至少一个卤素,优选氟,或取代有COOR8,
■(C1-C6)烷氧基,
○选自下面的基团:
■COOR8,
■NR1R2基团,其中R1和R2独立地表示H、(C1-C6)烷基、芳基(C1-C3)烷基、杂芳基(C1-C3)烷基,其中所述芳基和杂芳基任选地被至少一个选自下面的基团取代:卤素(优选氯、氟或溴)、OH和NO2;
○(C1-C6)烷基,任选取代有至少一个卤素,优选氟,或取代有COOR8,R8独立地为H、(C1-C6)烷基、芳基、杂芳基、(C3-C12)环烷基、或(C3-C12)杂环烷基,优选R8为H。
20.根据上述权利要求任一项的化合物或其药学上可接受的盐,所述化合物选自:
-化合物1.2-[2-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)乙基]苯甲酸;
-化合物2.4-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)丁酸;
-化合物3.2-{2-[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物4.2-{2-[3-(2-羟基-5-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物5.2-{[(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)氨基]甲基}苯甲酸;
-化合物6.3-(2-甲基苯基)-4-(2-苯基乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物7.4-苄基-3-(2-羟基-5-甲氧基苯基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物8.3-苯基-4-(3-苯基丙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物9.4-苄基-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物10.3-(2-羟基-5-甲氧基苯基)-4-(2-苯基乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物11.3-苯基-4-(2-苯基乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物12.2-{2-[3-(呋喃-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物13.2-{2-[3-(噻吩-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物14.2-{2-[3-(2-甲基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物15.5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;
-化合物16.2-({[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]氨基}甲基)苯甲酸;
-化合物17.2-{1-[(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)甲基]环己基}乙酸;
-化合物18.4-[3-(2-羟基-5-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸;
-化合物19.4-[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸;
-化合物20.3-苯基-4-[(1R,2S)-2-苯基环丙基]-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物21.3-(4-氯苯基)-4-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)丁酸;
-化合物22.2-{2-[3-(3-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物23.2-{2-[3-(4-甲基-1,2,3-噻二唑-5-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物24.4-[3-(3-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸;
-化合物25.2-{[(叔丁氧基)羰基]氨基}-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;
-化合物26.4-己基-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物27.2-{2-[3-(5-氯噻吩-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物28.3-苯基-4-(2-{[2-(三氟甲基)喹啉-4-基]硫基}乙基)-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物29.5-[3-(2-羟基-5-甲氧基苯基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]戊酸;
-化合物30.5-[3-(萘-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]戊酸;
-化合物31.4-[2-(4-羟基苯基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物32.4-丁基-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物33.4-[2-(苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物34.4-[(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)甲基]环己烷-1-甲酸;
-化合物35.2-{2-[3-(金刚烷-1-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物36.2-{2-[3-(喹啉-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物37.5-苯基-4-[(3-苯酞基)甲基]-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物38.5-(3-联苯基)-4-[3-羧基丙基]-1,2,4-三唑-3-硫酮;
-化合物39.5-(3-联苯基)-4-[2-(2-羧基苯基)乙基]-1,2,4-三唑-3-硫酮;
-化合物40.5-(4-苄基氧基苯基)-4-[2-(2-羧基苯基)乙基]-1,2,4-三唑-3-硫酮;
-化合物41.4-[2-(2,4-二羟基苯基)乙基]-5-苯基-1,2,4-三唑-3-硫酮;
-化合物42.5-(3-联苯基)-4-[2-(2,4-二羟基苯基)乙基]-1,2,4-三唑-3-硫酮;
-化合物43.5-(2-联苯基)-4-[2-(2,4-二羟基苯基)乙基]-1,2,4-三唑-3-硫酮;
-化合物44.邻-{2-[1-甲基-1H-吡咯-2-基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物45.6-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)己酸;
-化合物46.3-苯基-4-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)丁酸;
-化合物47.3-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)环己烷-1-甲酸;
-化合物48.4-[3-(1-甲基-1H-吡咯-2-基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]丁酸;
-化合物49.4-(2-叠氮基乙基)-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物50.4-[3-(喹啉-2-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]丁酸;
-化合物51.邻-{[3-(3-联苯基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基氨基]甲基}苯甲酸;
-化合物52.间-[(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)甲基]苯甲酸;
-化合物53.5-羟基-2-[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基]苯甲酸;
-化合物54.4-[4-(苄基氧基)苯基乙基]-5-苯基-1,2,4-三唑-3-硫酮;
-化合物55.对-[(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)甲基]苯甲酸;
-化合物56.2-{2-[3-(喹啉-6-基)-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物57.邻-{2-[3-(1H-吡咯-2-基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物58.邻-{2-[3-(3-噻吩基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基}苯甲酸;
-化合物59.8-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)辛酸;
-化合物60.苯基[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]乙酸;和
-化合物61.5-氨基-2-[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基]苯甲酸;
-化合物62.邻-(2-{3-[间-(2-吗啉代乙氧基)苯基]-5-硫代-1,4-二氢-1,2,4-三唑-4-基}乙基)苯甲酸;
-化合物63.邻-[2-(3-{间-[2-(4-甲基-1-哌嗪基)乙氧基]苯基}-5-硫代-1,4-二氢
-1,2,4-三唑-4-基)乙基]苯甲酸;
-化合物64.4-[2-(苄硫基)乙基]-5-(1-甲基-1H-吡咯-2-基)-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物65.[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]乙酸;
-化合物66.[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]丙酸;
-化合物67.2-[[2,3-二羟基苯基)甲基]氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;
-化合物68.2-[二(苯基甲基)氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;
-化合物69.2-[二(1H-咪唑-5-基甲基)氨基]-5-(3-苯基-5-硫代-4,5-二氢-1H-1,2,4-三唑-4-基)戊酸;
-化合物70.5-苯基-4-[2-(苯基硫基)乙基]-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物71.4-[2-(2-氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物72.4-[2-(4-氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物73.4-[2-(2,4-二氟苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物74.4-[2-(4-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物75.4-[2-(2-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物76.4-[2-(2-羟基-5-硝基苄基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物77.4-[2-(2-苯基乙基硫基)乙基]-3-苯基-4,5-二氢-1H-1,2,4-三唑-5-硫酮;
-化合物78.2-苯基-3-[2-(3-苯基-5-硫代-1,4-二氢-1,2,4-三唑-4-基)乙基硫基]-丙酸;
-化合物79.5-苯基-4-[3-(苯基硫基)丙基]-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物80.4-[2-(苄硫基)乙基]-5-(邻-甲苯基)-2,4-二氢-1,2,4-三唑-3-硫酮;
-化合物81.3-{2-[3-(3-联苯基)-5-硫代-1,4-二氢-1,2,4-三唑-4-基]乙基硫基}-氢化阿托酸。
21.根据前述权利要求中任一项的化合物或其药学上可接受的盐,其用于与β-内酰胺抗生素组合治疗细菌感染。
22.药物组合物,其包含与药学上可接受的稀释剂或载体混合的根据权利要求1至21的化合物或其药学上可接受的盐。
23.根据权利要求22所述的药物组合物,其用于与β-内酰胺抗生素组合治疗细菌感染。
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EP18306493.0A EP3653611A1 (en) | 2018-11-15 | 2018-11-15 | Inhibitors of metallo-beta-lactamases |
EP18306493.0 | 2018-11-15 | ||
PCT/EP2019/081508 WO2020099645A1 (en) | 2018-11-15 | 2019-11-15 | Inhibitors of metallo-beta-lactamases |
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US (1) | US20220000841A1 (zh) |
EP (2) | EP3653611A1 (zh) |
CN (1) | CN113874357A (zh) |
BR (1) | BR112021009362A8 (zh) |
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Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3832186A (en) * | 1972-04-26 | 1974-08-27 | Fuji Photo Film Co Ltd | Heat developing-out photosensitive materials |
US5489598A (en) * | 1994-06-08 | 1996-02-06 | Warner-Lambert Company | Cytoprotection utilizing aryltriazol-3-thiones |
CN1134147A (zh) * | 1993-10-29 | 1996-10-23 | 默里尔药物公司 | 用作记忆增强剂的3-芳基-4-烷基及4,5-二烷基-4h-1,2,4-三唑 |
JP2000066349A (ja) * | 1998-08-25 | 2000-03-03 | Fuji Photo Film Co Ltd | 熱現像カラー画像形成方法 |
WO2002066447A1 (en) * | 2001-02-21 | 2002-08-29 | Ono Pharmaceutical Co., Ltd. | 4h-1,2,4-triazole-3(2h)-thione deratives as sphingomyelinase inhibitors |
JP2007025241A (ja) * | 2005-07-15 | 2007-02-01 | Fujifilm Corp | 感光性組成物およびこれを用いた画像記録方法 |
JP2007269886A (ja) * | 2006-03-30 | 2007-10-18 | Fujifilm Corp | 感光性重合体、感光性組成物及び平版印刷版原版 |
CN101154045A (zh) * | 2006-09-29 | 2008-04-02 | 富士胶片株式会社 | 光聚合型光敏平版印刷版原版 |
CN101160291A (zh) * | 2005-03-09 | 2008-04-09 | 日本化药株式会社 | 新颖的hsp90抑制剂 |
US20110065704A1 (en) * | 2009-06-26 | 2011-03-17 | Ryder Sean | Compounds for modulating rna binding proteins and uses therefor |
US20130072461A1 (en) * | 2006-05-25 | 2013-03-21 | Synta Pharmaceuticals Corp. | Triazole compounds that modulate hsp90 activity |
WO2017197210A1 (en) * | 2016-05-13 | 2017-11-16 | Yale University | Identification of small molecule inhibitors of jumonji at-rich interactive domain 1a (jarid1a) histone demethylase |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2546887B1 (fr) * | 1983-05-30 | 1985-08-30 | Paris 7 Universite | Procede de preparation de dihydro-2,4 triazol-1,2,4 thiones-3 disubstituees en positions 4 et 5 et nouveaux composes pouvant etre prepares par ce procede |
AU2948189A (en) * | 1987-12-31 | 1989-08-01 | Smithkline Beckman Corporation | 4-aralkyl-5-substituted-1,2,4-triazole-5-thiols |
JPH10301219A (ja) * | 1997-04-25 | 1998-11-13 | Konica Corp | ハロゲン化銀写真感光材料及びその処理方法 |
WO2006055760A1 (en) * | 2004-11-18 | 2006-05-26 | Synta Pharmaceuticals Corp. | Triazole compounds that modulate hsp90 activity |
TWI446910B (zh) * | 2005-08-18 | 2014-08-01 | Synta Pharmaceuticals Corp | 調節hsp90活性的三唑化合物 |
JP2013537229A (ja) * | 2010-09-13 | 2013-09-30 | シンタ ファーマシューティカルズ コーポレーション | 野生型egfr及び/又はkras患者において非小細胞肺癌を処置するためのhsp90阻害剤 |
EP2527335B1 (en) * | 2011-04-26 | 2013-09-18 | King Saud University | Triazole compounds as anti-inflammatory agents |
-
2018
- 2018-11-15 EP EP18306493.0A patent/EP3653611A1/en not_active Withdrawn
-
2019
- 2019-11-15 CN CN201980088215.4A patent/CN113874357A/zh active Pending
- 2019-11-15 CA CA3118626A patent/CA3118626A1/en active Pending
- 2019-11-15 BR BR112021009362A patent/BR112021009362A8/pt unknown
- 2019-11-15 EP EP19806164.0A patent/EP3880665A1/en active Pending
- 2019-11-15 WO PCT/EP2019/081508 patent/WO2020099645A1/en unknown
- 2019-11-15 US US17/293,496 patent/US20220000841A1/en active Pending
Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3832186A (en) * | 1972-04-26 | 1974-08-27 | Fuji Photo Film Co Ltd | Heat developing-out photosensitive materials |
CN1134147A (zh) * | 1993-10-29 | 1996-10-23 | 默里尔药物公司 | 用作记忆增强剂的3-芳基-4-烷基及4,5-二烷基-4h-1,2,4-三唑 |
US5489598A (en) * | 1994-06-08 | 1996-02-06 | Warner-Lambert Company | Cytoprotection utilizing aryltriazol-3-thiones |
JP2000066349A (ja) * | 1998-08-25 | 2000-03-03 | Fuji Photo Film Co Ltd | 熱現像カラー画像形成方法 |
WO2002066447A1 (en) * | 2001-02-21 | 2002-08-29 | Ono Pharmaceutical Co., Ltd. | 4h-1,2,4-triazole-3(2h)-thione deratives as sphingomyelinase inhibitors |
CN101160291A (zh) * | 2005-03-09 | 2008-04-09 | 日本化药株式会社 | 新颖的hsp90抑制剂 |
JP2007025241A (ja) * | 2005-07-15 | 2007-02-01 | Fujifilm Corp | 感光性組成物およびこれを用いた画像記録方法 |
JP2007269886A (ja) * | 2006-03-30 | 2007-10-18 | Fujifilm Corp | 感光性重合体、感光性組成物及び平版印刷版原版 |
US20130072461A1 (en) * | 2006-05-25 | 2013-03-21 | Synta Pharmaceuticals Corp. | Triazole compounds that modulate hsp90 activity |
CN101154045A (zh) * | 2006-09-29 | 2008-04-02 | 富士胶片株式会社 | 光聚合型光敏平版印刷版原版 |
US20110065704A1 (en) * | 2009-06-26 | 2011-03-17 | Ryder Sean | Compounds for modulating rna binding proteins and uses therefor |
WO2017197210A1 (en) * | 2016-05-13 | 2017-11-16 | Yale University | Identification of small molecule inhibitors of jumonji at-rich interactive domain 1a (jarid1a) histone demethylase |
Non-Patent Citations (7)
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US20220000841A1 (en) | 2022-01-06 |
WO2020099645A1 (en) | 2020-05-22 |
EP3880665A1 (en) | 2021-09-22 |
EP3653611A1 (en) | 2020-05-20 |
BR112021009362A2 (pt) | 2021-08-17 |
BR112021009362A8 (pt) | 2021-08-31 |
CA3118626A1 (en) | 2020-05-22 |
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