CN112105604A - 表现出肠肽酶抑制活性的新型化合物 - Google Patents
表现出肠肽酶抑制活性的新型化合物 Download PDFInfo
- Publication number
- CN112105604A CN112105604A CN201980031203.8A CN201980031203A CN112105604A CN 112105604 A CN112105604 A CN 112105604A CN 201980031203 A CN201980031203 A CN 201980031203A CN 112105604 A CN112105604 A CN 112105604A
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- China
- Prior art keywords
- amino
- thiazole
- carbonyl
- thiazol
- carboxylic acid
- Prior art date
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- Granted
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 225
- 102100029727 Enteropeptidase Human genes 0.000 title claims abstract description 33
- 108010013369 Enteropeptidase Proteins 0.000 title claims abstract description 32
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 27
- 230000001747 exhibiting effect Effects 0.000 title abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 40
- 208000008589 Obesity Diseases 0.000 claims abstract description 18
- 208000030159 metabolic disease Diseases 0.000 claims abstract description 18
- 235000020824 obesity Nutrition 0.000 claims abstract description 18
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 14
- 208000031226 Hyperlipidaemia Diseases 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 11
- -1 (5- ((4-carbamimidoyl-2-fluorophenoxy) carbonyl) thiazol-2-yl) (ethyl) amino Chemical group 0.000 claims description 242
- 239000000126 substance Substances 0.000 claims description 79
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 50
- 125000005605 benzo group Chemical group 0.000 claims description 49
- 229910052757 nitrogen Inorganic materials 0.000 claims description 49
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 40
- DMPZJACLHDWUFS-UHFFFAOYSA-N 1,3-benzothiazole-6-carboxylic acid Chemical compound OC(=O)C1=CC=C2N=CSC2=C1 DMPZJACLHDWUFS-UHFFFAOYSA-N 0.000 claims description 33
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 33
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical group NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 32
- 235000019260 propionic acid Nutrition 0.000 claims description 28
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 27
- 150000002148 esters Chemical class 0.000 claims description 24
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 23
- YZVFSQQHQPPKNX-UHFFFAOYSA-N 1,3-thiazole-5-carboxylic acid Chemical compound OC(=O)C1=CN=CS1 YZVFSQQHQPPKNX-UHFFFAOYSA-N 0.000 claims description 22
- 230000003287 optical effect Effects 0.000 claims description 22
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 22
- 229910052799 carbon Inorganic materials 0.000 claims description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Chemical group CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 16
- 150000003973 alkyl amines Chemical class 0.000 claims description 16
- 150000001408 amides Chemical group 0.000 claims description 16
- 150000001409 amidines Chemical group 0.000 claims description 16
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Chemical group CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 10
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 6
- 229910003827 NRaRb Inorganic materials 0.000 claims description 6
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 6
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- WKRDIRRBYUJLLA-CYBMUJFWSA-N (2R)-2-[3-[[5-(4-carbamimidoyl-2-fluorophenoxy)carbonyl-1,3-thiazol-2-yl]-ethylamino]propanoylamino]pentanedioic acid Chemical compound C(N)(=N)C1=CC(=C(OC(=O)C2=CN=C(S2)N(CCC(=O)N[C@H](CCC(=O)O)C(=O)O)CC)C=C1)F WKRDIRRBYUJLLA-CYBMUJFWSA-N 0.000 claims description 3
- MSPBXGXHQIAMCD-AWEZNQCLSA-N (2S)-2-[[1-[5-(4-carbamimidoylphenoxy)carbonyl-1,3-thiazol-2-yl]piperidine-4-carbonyl]amino]butanedioic acid Chemical compound C1CN(CCC1C(=O)N[C@@H](CC(=O)O)C(=O)O)C2=NC=C(S2)C(=O)OC3=CC=C(C=C3)C(=N)N MSPBXGXHQIAMCD-AWEZNQCLSA-N 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 3
- YBQKZEZXJRWODL-UHFFFAOYSA-N 1-[5-(4-carbamimidoyl-2-fluorophenoxy)carbonyl-1,3-thiazol-2-yl]piperidine-4-carboxylic acid Chemical compound C(N)(=N)C1=CC(=C(OC(=O)C2=CN=C(S2)N2CCC(CC2)C(=O)O)C=C1)F YBQKZEZXJRWODL-UHFFFAOYSA-N 0.000 claims description 3
- NOCYCOVDEPUBFR-UHFFFAOYSA-N 1-[5-[4-(diaminomethylideneamino)phenoxy]carbonyl-1,3-thiazol-2-yl]piperidine-4-carboxylic acid Chemical compound N(C(=N)N)C1=CC=C(OC(=O)C2=CN=C(S2)N2CCC(CC2)C(=O)O)C=C1 NOCYCOVDEPUBFR-UHFFFAOYSA-N 0.000 claims description 3
- IJNODRAQWJUAME-UHFFFAOYSA-N 4-[[1-[5-(4-carbamimidoylphenoxy)carbonyl-1,3-thiazol-2-yl]piperidine-4-carbonyl]-methylamino]butanoic acid Chemical compound CN(CCCC(O)=O)C(=O)C1CCN(CC1)C1=NC=C(S1)C(=O)OC1=CC=C(C=C1)C(N)=N IJNODRAQWJUAME-UHFFFAOYSA-N 0.000 claims description 3
- OYFZCFIMLBQBAO-UHFFFAOYSA-N 4-[[5-(4-carbamimidoyl-2-fluorophenoxy)carbonyl-1,3-thiazol-2-yl]-methylamino]butanoic acid Chemical compound C(N)(=N)C1=CC(=C(OC(=O)C2=CN=C(S2)N(CCCC(=O)O)C)C=C1)F OYFZCFIMLBQBAO-UHFFFAOYSA-N 0.000 claims description 3
- BKYSGUWJDIGFJT-UHFFFAOYSA-N 4-[[5-(4-carbamimidoylphenoxy)carbonyl-1,3-thiazol-2-yl]-methylamino]butanoic acid Chemical compound N(C)(C=1SC(=CN=1)C(=O)OC1=CC=C(C(=N)N)C=C1)CCCC(=O)O BKYSGUWJDIGFJT-UHFFFAOYSA-N 0.000 claims description 3
- MEYRAMNJVBQDRK-UHFFFAOYSA-N 4-[[6-(4-carbamimidoyl-2-fluorophenoxy)carbonyl-1,3-benzothiazol-2-yl]-methylamino]butanoic acid Chemical compound C(N)(=N)C1=CC(=C(OC(=O)C2=CC3=C(N=C(S3)N(CCCC(=O)O)C)C=C2)C=C1)F MEYRAMNJVBQDRK-UHFFFAOYSA-N 0.000 claims description 3
- HFMSFEJXNGLOPU-UHFFFAOYSA-N NC(=N)C1=CC=C(OC(=O)C2=CN=C(S2)N2CCC(CC2)C(=O)NCC(O)=O)C=C1 Chemical compound NC(=N)C1=CC=C(OC(=O)C2=CN=C(S2)N2CCC(CC2)C(=O)NCC(O)=O)C=C1 HFMSFEJXNGLOPU-UHFFFAOYSA-N 0.000 claims description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
- ATUPGUWJQKPHPN-UHFFFAOYSA-N [4-(diaminomethylideneamino)phenyl] 2-(4-methoxycarbonylpiperidin-1-yl)-1,3-thiazole-5-carboxylate Chemical compound COC(=O)C1CCN(CC1)C=1SC(=CN=1)C(=O)OC1=CC=C(C=C1)NC(=N)N ATUPGUWJQKPHPN-UHFFFAOYSA-N 0.000 claims description 3
- 229960005261 aspartic acid Drugs 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- JAEIBKXSIXOLOL-UHFFFAOYSA-N pyrrolidin-1-ium-3-carboxylate Chemical compound OC(=O)C1CCNC1 JAEIBKXSIXOLOL-UHFFFAOYSA-N 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- JISONMFIUAWROY-UHFFFAOYSA-N (4-carbamimidoylphenyl) 2-[(3-methoxy-2,2-dimethyl-3-oxopropyl)-methylamino]-1,3-benzothiazole-6-carboxylate Chemical compound COC(C(CN(C=1SC2=C(N=1)C=CC(=C2)C(=O)OC1=CC=C(C=C1)C(N)=N)C)(C)C)=O JISONMFIUAWROY-UHFFFAOYSA-N 0.000 claims description 2
- ZGECRJKCQKWHDV-UHFFFAOYSA-N (4-carbamimidoylphenyl) 2-[(3-methoxy-2,2-dimethyl-3-oxopropyl)-methylamino]-1,3-thiazole-5-carboxylate Chemical compound COC(C(CN(C=1SC(=CN=1)C(=O)OC1=CC=C(C=C1)C(N)=N)C)(C)C)=O ZGECRJKCQKWHDV-UHFFFAOYSA-N 0.000 claims description 2
- OVRYEIBSHZNFCZ-UHFFFAOYSA-N (4-carbamimidoylphenyl) 2-[4-[(3-methoxy-3-oxopropyl)carbamoyl]piperidin-1-yl]-1,3-thiazole-5-carboxylate Chemical compound COC(CCNC(=O)C1CCN(CC1)C=1SC(=CN=1)C(=O)OC1=CC=C(C=C1)C(N)=N)=O OVRYEIBSHZNFCZ-UHFFFAOYSA-N 0.000 claims description 2
- QIECPWHBWXFGHH-UHFFFAOYSA-N (4-carbamimidoylphenyl) 2-[4-[(4-methoxy-4-oxobutyl)-methylcarbamoyl]piperidin-1-yl]-1,3-thiazole-5-carboxylate Chemical compound COC(CCCN(C(=O)C1CCN(CC1)C=1SC(=CN=1)C(=O)OC1=CC=C(C=C1)C(N)=N)C)=O QIECPWHBWXFGHH-UHFFFAOYSA-N 0.000 claims description 2
- BKQYLYAIOFKTAN-UHFFFAOYSA-N (4-carbamimidoylphenyl) 2-[ethyl-(3-methoxy-2,2-dimethyl-3-oxopropyl)amino]-1,3-benzothiazole-6-carboxylate Chemical compound C(C)N(C=1SC2=C(N=1)C=CC(=C2)C(=O)OC1=CC=C(C=C1)C(N)=N)CC(C(=O)OC)(C)C BKQYLYAIOFKTAN-UHFFFAOYSA-N 0.000 claims description 2
- PZSKNYJVWUFRBS-UHFFFAOYSA-N (4-carbamimidoylphenyl) 2-[ethyl-(3-methoxy-3-oxopropyl)amino]-1,3-benzothiazole-6-carboxylate Chemical compound C(C)N(C=1SC2=C(N=1)C=CC(=C2)C(=O)OC1=CC=C(C=C1)C(N)=N)CCC(=O)OC PZSKNYJVWUFRBS-UHFFFAOYSA-N 0.000 claims description 2
- UEPHWPHJCUFJPX-UHFFFAOYSA-N 2-[[1-[5-(4-carbamimidoyl-2-fluorophenoxy)carbonyl-1,3-thiazol-2-yl]piperidine-4-carbonyl]amino]acetic acid Chemical compound C(N)(=N)C1=CC(=C(OC(=O)C2=CN=C(S2)N2CCC(CC2)C(=O)NCC(=O)O)C=C1)F UEPHWPHJCUFJPX-UHFFFAOYSA-N 0.000 claims description 2
- JXWLQVWYQVISCV-UHFFFAOYSA-N 3-[[6-(4-carbamimidoyl-2-fluorophenoxy)carbonyl-1,3-benzothiazol-2-yl]-ethylamino]-2,2-dimethylpropanoic acid Chemical compound C(N)(=N)C1=CC(=C(OC(=O)C2=CC3=C(N=C(S3)N(CC(C(=O)O)(C)C)CC)C=C2)C=C1)F JXWLQVWYQVISCV-UHFFFAOYSA-N 0.000 claims description 2
- YFOZKONHOLGXRH-UHFFFAOYSA-N 3-[[6-(4-carbamimidoyl-2-fluorophenoxy)carbonyl-1,3-benzothiazol-2-yl]-ethylamino]propanoic acid Chemical compound C(N)(=N)C1=CC(=C(OC(=O)C2=CC3=C(N=C(S3)N(CCC(=O)O)CC)C=C2)C=C1)F YFOZKONHOLGXRH-UHFFFAOYSA-N 0.000 claims description 2
- TZDVUEKRAZVVQW-UHFFFAOYSA-N 3-[[6-(4-carbamimidoyl-2-fluorophenoxy)carbonyl-1,3-benzothiazol-2-yl]-methylamino]propanoic acid Chemical compound C(N)(=N)C1=CC(=C(OC(=O)C2=CC3=C(N=C(S3)N(CCC(=O)O)C)C=C2)C=C1)F TZDVUEKRAZVVQW-UHFFFAOYSA-N 0.000 claims description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
- SDNLBFKDMVROCK-MHZLTWQESA-N C1CN(CCC1C(=O)N[C@@H](CC(=O)OCC2=CC=CC=C2)C(=O)OCC3=CC=CC=C3)C4=NC=C(S4)C(=O)OC5=C(C=C(C=C5)C(=N)N)F Chemical compound C1CN(CCC1C(=O)N[C@@H](CC(=O)OCC2=CC=CC=C2)C(=O)OCC3=CC=CC=C3)C4=NC=C(S4)C(=O)OC5=C(C=C(C=C5)C(=N)N)F SDNLBFKDMVROCK-MHZLTWQESA-N 0.000 claims description 2
- 208000016097 disease of metabolism Diseases 0.000 claims 5
- KKFGMAJUXXQGSO-UHFFFAOYSA-N CC(C)(CNC(C(CC1)CCN1C1=NC=C(C(O)=O)S1)=O)C(OC)=O Chemical compound CC(C)(CNC(C(CC1)CCN1C1=NC=C(C(O)=O)S1)=O)C(OC)=O KKFGMAJUXXQGSO-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 14
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 5
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- 108090000623 proteins and genes Proteins 0.000 abstract description 4
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- 206010041969 Steatorrhoea Diseases 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 154
- 238000002360 preparation method Methods 0.000 description 99
- 238000005160 1H NMR spectroscopy Methods 0.000 description 86
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 85
- 238000006243 chemical reaction Methods 0.000 description 68
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 239000003814 drug Substances 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
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- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 125000005599 alkyl carboxylate group Chemical group 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000006244 carboxylic acid protecting group Chemical group 0.000 description 3
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- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
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- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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Abstract
本发明涉及:表现出肠肽酶抑制活性的新型化合物;其药学上可接受的盐;用于代谢性疾病如肥胖症、糖尿病或高脂血症的药物组合物,所述药物组合物包含所述化合物或其药学上可接受的盐;以及使用所述新型化合物预防或治疗代谢性疾病的方法。当摄入的食物从体内排泄而未吸收时,本发明的化合物由于优异的肠肽酶抑制活性,使得脂肪和蛋白质都能够被排泄,从而导致较少副作用例如脂肪粪便,并且仅作用于胃肠道,因此降低了副作用例如抑郁。因此,本发明的化合物非常适合作为用于治疗或预防各种代谢性疾病如肥胖症、糖尿病和高脂血症的药剂。
Description
技术领域
相关申请的交叉引用
本申请要求于2018年5月9日向韩国知识产权局提交的韩国专利申请第10-2018-0053315号和第10-2018-0053316号的权益,所述韩国专利申请的公开内容通过引用整体并入本文中。
本发明涉及表现出肠肽酶抑制活性的新型化合物、其药学上可接受的盐,以及用于预防和治疗代谢性疾病如肥胖症、糖尿病或高脂血症等的药物组合物,所述药物组合物包含所述化合物或药学上可接受的盐。
背景技术
肠肽酶是一种丝氨酸蛋白酶,其将餐后从胰腺分泌的胰蛋白酶原转化为胰蛋白酶。由肠肽酶激活的胰蛋白酶然后激活蛋白酶前体,例如胰凝乳蛋白酶原、羧肽酶原和弹性蛋白酶原。这些蛋白酶的活性形式将膳食蛋白质降解为氨基酸单元,并且所得氨基酸从小肠吸收。因此,据报道肠肽酶抑制剂能够抑制蛋白质降解和吸收,并且可用作肥胖症的治疗药物。
在常规的口服肥胖症治疗药物中,西尼可(Xenical)具有抑制胃肠道中脂解酶作用的作用机理。由于这种作用,脂肪不会被吸收到体内,而是被提取到体外。此时,存在副作用,即患者在事先不知道的情况下有脂肪粪便运动。
另一方面,药物例如Belviq、Contrave和Qsymia通过在大脑中抑制食欲的作用而用作抗肥胖症药物,但它们具有严重的副作用,例如抑郁和自杀冲动。
在这方面,美国专利第9,346,821号公开了一种用于治疗或预防肥胖症的具有丝氨酸蛋白酶抑制活性的杂环羧酸酯衍生物,并且韩国未审查专利公布第10-2016-0113299号公开了一种具有肠肽酶抑制作用的稠合杂环化合物及其作为治疗或预防肥胖症和糖尿病等的药物的用途。
发明内容
技术问题
在这些情况下,持续需要开发仍表现出优异的肠肽酶抑制活性并且可用于预防或治疗代谢性疾病例如肥胖症、糖尿病或高脂血症等的化合物。
因此,本发明的一个目的是提供一种具有肠肽酶抑制活性并且可用于预防和治疗代谢性疾病例如肥胖症、糖尿病或高脂血症等的新型化合物或其药学上可接受的盐,包含它们的药物组合物,以及使用所述新型化合物或其药学上可接受的盐预防或治疗代谢性疾病的方法。
技术方案
为了实现上述目的,本文提供了一种化学式1的化合物、其光学异构体或其药学上可接受的盐。化学式1的化合物表现出优异的肠肽酶抑制活性,因此可用于治疗各种代谢性疾病,例如肥胖症、糖尿病和高脂血症等。
[化学式1]
其中,
Het是具有一个或两个选自N、O和S的杂原子的4元至10元单杂环或二杂环基团;
虚线表示存在或不存在键,
A1、A2、A3、A4和A5各自独立地是C或N;
Q是O或N;
R1和R6各自独立地是未取代或取代的烷基,或者R1和R6与它们所连接的氮原子一起形成未取代或取代的5元至7元杂环;
R2是氢或者未取代或取代的烷基;
R3和R4各自独立地是H,卤素或者未取代或取代的烷基;并且
R5是脒,胍,酰胺,或者未取代或取代的烷基胺。
关于化学式1中的“存在或不存在键”,当该键存在时,它是指Het的碳原子中与环外氮原子(即NR1R6的N)键合的碳原子与所述环外氮原子之间的键形成双键(其中与连接到NR1R6的Het基团中的碳原子键合的环外氮原子成为作为Het的取代基的亚氨基基团,并且不存在R6)。
此外,Het优选是具有一个或两个选自N和S的杂原子的5元至9元单杂环或二杂环基团,并且它更优选可以是噻唑或苯并噻唑。
此外,优选地,取代基可以是选自以下的一者至三者:-(CRa 2)nRb、-C(O)ORa、-(CH2)n-C(O)ORa、-(CH2)n-C(O)NRaRb、-C(O)NRaRb和-NRaC(O)Rb,其中Ra和Rb各自独立地是氢、卤素、-C(O)ORc、-C(O)NRcRd、C1-C4烷基或苯基,n是1至4的整数,所述C1-C4烷基或苯基是未取代的或被一个或两个选自-C(O)ORc和C1-C4烷氧基的基团取代,并且Rc可以是氢、C1-C4烷基或苄基。
有利效果
根据本发明的新型化合物通过优异的肠肽酶抑制活性降低了蛋白质、脂质和碳水化合物的消化能力,并且可用作用于各种代谢性疾病例如肥胖症或糖尿病和高脂血症的治疗性或预防性药物。
具体实施方式
下面更详细地描述本发明。
下面详细描述本说明书中使用的每种取代基的定义。除非另有说明,否则每个取代基具有以下定义。
在本说明书中,“卤素”的实例包括氟、氯、溴和碘。
在本说明书中,“烷基”是指直链或支链的脂族饱和烃基。优选地,它可以是具有1至6个碳的烷基,更优选是具有1至4个碳的烷基。这样的烷基的实例包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基和2-乙基丁基。
在本说明书中,“杂环”是指含有不同于碳原子的选自氮原子、硫原子和氧原子的杂原子作为环构成原子的芳族环或非芳族环,并且它包括含有1至4个杂原子的优选4元至10元、更优选5元至9元芳族环或非芳族环。这样的芳族环的实例包括噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、噻唑基、异噻唑基、唑基、异唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、1,2,4-二唑基、1,3,4-二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、三唑基、四唑基、三嗪基和苯并噻唑基。此外,这样的非芳族环的实例包括四氢噻吩基、四氢呋喃基、吡咯啉基、吡咯烷基、咪唑啉基、咪唑烷基、唑啉基、唑烷基、吡唑啉基、吡唑烷基、噻唑啉基、噻唑烷基、四氢异噻唑基、四氢唑基、四氢异唑基、哌啶基、哌嗪基、四氢吡啶基、二氢吡啶基、二氢噻喃基、四氢嘧啶基、四氢哒嗪基、二氢吡喃基、四氢吡喃基、四氢噻喃基、吗啉基、硫代吗啉基、氮杂环庚烷基、二氮杂环庚烷基和氮杂环庚烯基。
在本说明书中,“取代基”的实例包括卤素原子,氰基基团,硝基基团,未取代或取代的氨基基团,未取代或取代的烷基基团,未取代或取代的羧基基团,未取代或取代的烃基团,未取代或取代的杂环基团,酰基基团,未取代或取代的氨甲酰基基团,未取代或取代的硫代氨甲酰基基团,未取代或取代的氨磺酰基基团,未取代或取代的羟基基团,未取代或取代的硫烷基(SH)基团和未取代或取代的甲硅烷基基团。
在一个优选的实施方式中,化学式1的化合物可以是化学式1a的化合物。
[化学式1a]
其中,
A1、A2、A3、A4和A5各自独立地是C或N;
Q是O或N;
R1和R6各自独立地是未取代或取代的烷基,或者R1和R6与它们所连接的氮原子一起形成未取代或取代的5元至7元杂环;
R3和R4各自独立地是H,卤素或者未取代或取代的烷基;并且
R5是脒,胍,酰胺,或者未取代或取代的烷基胺。
在一个优选的实施方式中,在化学式1a中,A1、A2、A3、A4和A5可以各自独立地是C。
R1和R6可以各自独立地是H或者未取代或取代的C1-C6烷基,更优选是H或C1-C3烷基。
另外,R1和R6还可与它们所连接的氮原子一起形成未取代或取代的5元或6元杂环,更优选是吡咯烷基或哌啶基。
此外,R3和R4可以各自独立地是H,F,Cl,Br,I或者未取代或取代的C1-C6烷基,并且更优选地,它可以是H,F或者未取代或取代的C1-C3烷基。
此外,R5可以是脒,胍,酰胺,或者未取代或取代的C1-C4烷基胺。
此外,取代基可以是选自以下的一者或多者,优选一者至三者:-(CRa 2)nRb、-C(O)ORa、-(CH2)n-C(O)ORa、-(CH2)n-C(O)NRaRb、-C(O)NRaRb和-NRaC(O)Rb,其中Ra和Rb可以各自独立地是氢、卤素、-C(O)ORc、-C(O)NRcRd、C1-C4烷基或苯基,n可以是1至4的整数,所述C1-C4烷基或苯基可以是未取代的或被一个或两个选自-C(O)ORc和C1-C4烷氧基的基团取代,并且
Rc可以是氢、C1-C4烷基或苄基。
在另一个优选的实施方式中,化学式1的化合物可以是化学式1b的化合物:
[化学式1b]
其中,
虚线表示存在或不存在键,
A1、A2、A3、A4、A5、A6、A7和A8各自独立地是C或N;
Q是O或N;
R1和R6各自独立地是未取代或取代的烷基,或者R1和R6与它们所连接的氮原子一起形成未取代或取代的5元至7元杂环;
R2是未取代或取代的烷基;
R3和R4各自独立地是H,卤素或者未取代或取代的烷基;并且
R5是脒,胍,酰胺,或者未取代或取代的烷基胺。
化学式1b的化合物中的虚线表示存在或不存在键,并且当存在所述键时,在由与苯环结合的S和N组成的5元杂环中的S和N之间的碳原子与杂环中的氮原子之间形成双键(其中与碳原子结合的环外氮原子(即NR1R6的N)变为作为5元杂环的取代基的氨基基团,并且R2不存在),或者在5元杂环中的S与N之间的碳原子与环外氮原子之间形成双键,因此,所述环外氮原子成为亚氨基基团,并且R6不存在。
优选地,根据本发明的化学式1b可以是化学式1b-1的化合物:
[化学式1b-1]
其中,
A1、A2、A3、A4、A5、A6、A7和A8各自独立地是C或N;
Q是O或N;
R1和R6各自独立地是H或者未取代或取代的烷基;
R1和R2各自独立地是H或者未取代或取代的烷基;
R3和R4各自独立地是H,卤素或者未取代或取代的烷基;并且
R5是脒,胍,酰胺,或者未取代或取代的烷基胺。
此外,优选地,根据本发明的化学式1b可以是化学式1b-2的化合物:
[化学式1b-2]
其中,
A1、A2、A3、A4、A5、A6、A7和A8各自独立地是C或N;
Q是O或N;
R1和R6各自独立地是H或者未取代或取代的烷基,或者R1和R6与它们所连接的氮原子一起形成未取代或取代的5元至7元杂环;
R3和R4各自独立地是H,卤素或者未取代或取代的烷基;并且
R5是脒,胍,酰胺,或者未取代或取代的烷基胺。
在一个优选的实施方式中,在化学式1、1b-1和1b-2中,A1、A2、A3、A4、A5、A6、A7和A8可以各自独立地是C。
R1和R6可以各自独立地是H或者未取代或取代的C1-C6烷基,并且更优选是H或C1-C3烷基。
此外,R1和R6可以与它们所连接的氮原子一起形成未取代或取代的6元杂环,更优选是哌啶基。
此外,R2可以是H或者未取代或取代的C1-C6烷基,并且更优选是H或者未取代或取代的C1-C3烷基。
此外,R3和R4可以各自独立地是H,F,Cl,Br,I或者未取代或取代的C1-C6烷基,更优选是H,F或者未取代或取代的C1-C3烷基。
此外,R5可以是脒,胍,酰胺,或者未取代或取代的C1-C4烷基胺。
此外,取代基可以是C1-C4烷基、-C(O)OR'、-C(O)NR'R"或-NR'C(O)R",其中R'和R”可以各自独立地是氢、卤素、C1-C4烷基或苯基,并且这些取代基的数目可以是一个或多个,优选一个至三个。
根据本发明的化学式1的代表性化合物可包括以下化合物,但不限于此。
1]3-((5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酸;
2]1-(5-((4-甲脒基苯氧基)羰基)噻唑-2-基)哌啶-4-甲酸;
3]2-(4-(甲氧基羰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基苯酯;
4]2-(4-(甲氧基羰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
5]2-(4-(甲氧基羰基)哌啶-1-基)噻唑-5-甲酸4-胍基苯酯;
6]1-(5-((4-胍基苯氧基)羰基)噻唑-2-基)哌啶-4-甲酸;
7]1-(5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)哌啶-4-甲酸;
8]2-((3-甲氧基-3-氧代丙基)(甲基)氨基)噻唑-5-甲酸4-甲脒基苯酯;
9]3-((5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)(甲基)氨基)丙酸;
10]2-((3-甲氧基-3-氧代丙基)氨基)噻唑-5-甲酸4-甲脒基苯酯;
11]2-((4-甲氧基-4-氧代丁基)(甲基)氨基)噻唑-5-甲酸4-甲脒基苯酯;
12]2-(乙基(3-甲氧基-3-氧代丙基)氨基)噻唑-5-甲酸4-甲脒基苯酯;
13]3-((5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)氨基)丙酸;
14]3-((5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酸;
15]4-((5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)(甲基)氨基)丁酸;
16]2-(3-(甲氧基羰基)吡咯烷-1-基)噻唑-5-甲酸4-甲脒基苯酯;
17]1-(5-((4-甲脒基苯氧基)羰基)噻唑-2-基)吡咯烷-3-甲酸;
18]2-((3-甲氧基-2,2-二甲基-3-氧代丙基)(甲基)氨基)噻唑-5-甲酸4-甲脒基苯酯;
19]3-((5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)(甲基)氨基)-2,2-二甲基丙酸;
20]2-(乙基(3-甲氧基-3-氧代丙基)氨基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
21]2-((4-甲氧基-4-氧代丁基)(甲基)氨基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
22]4-((5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)(甲基)氨基)丁酸;
23]1-(5-((4-胍基苯基)氨甲酰基)噻唑-2-基)哌啶-4-甲酸甲酯;
24]2-((3-甲氧基-2,2-二甲基-3-氧代丙基)氨基)噻唑-5-甲酸4-甲脒基苯酯;
25](1-(5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)哌啶-4-羰基)-L-天冬氨酸;
26](1-(5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)哌啶-4-羰基)-L-天冬氨酸酯;
27]2-(4-(苯基氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基苯酯;
28]2-(4-苯甲酰胺基哌啶-1-基)噻唑-5-甲酸4-甲脒基苯酯;
29]2-(4-((2-甲氧基-2-氧代乙基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基苯酯;
30]2-(4-((3-甲氧基-3-氧代丙基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基苯酯;
31]2-(4-((4-甲氧基-4-氧代丁基)(甲基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基苯酯;
32]2-(4-((3-甲氧基-2,2-二甲基-3-氧代丙基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基苯酯;
33](1-(5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)哌啶-4-羰基)甘氨酸;
34]3-(1-(5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)哌啶-4-甲酰胺基)丙酸;
35]4-(1-(5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)-N-甲基哌啶-4-甲酰胺基)丁酸;
36]3-(1-(5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)哌啶-4-甲酰胺基)-2,2-二甲基丙酸;
37]2-(4-((2-甲氧基-2-氧代乙基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
38]2-(4-((3-甲氧基-3-氧代丙基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
39]2-(4-((3-甲氧基-2,2-二甲基-3-氧代丙基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
40]2-(4-((3-甲氧基-2,2-二甲基-3-氧代丙基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
41]2-(4-((4-甲氧基-4-氧代丁基)(甲基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
42](1-(5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)哌啶-4-羰基)甘氨酸;
43]3-(1-(5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)哌啶-4-甲酰胺基)丙酸;
44]3-(1-(5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)哌啶-4-甲酰胺基)-2,2-二甲基丙酸;
45]3-(1-(5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)哌啶-4-甲酰胺基)-2,2-二甲基丙酸;
46](3-((5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酰基)-L-天冬氨酸二叔丁酯;
47](3-((5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酰基)-L-天冬氨酸;
48](3-((5-((4-甲脒基)-2-氟苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酰基)-D-谷氨酸二叔丁酯;
49](3-((5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酰基)-D-谷氨酸;
50]2-(乙基(3-((4-(甲氧基羰基)苯基)氨基)-3-氧代丙基)氨基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
51]2-(乙基(3-((3-(甲氧基羰基)苯基)氨基)-3-氧代丙基)氨基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
52]2-((3-((4-(叔丁氧羰基)苯基)氨基)-3-氧代丙基)(乙基)氨基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
53]2-((叔丁氧羰基)苯基)氨基)-3-氧代丙基)(乙基)氨基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
54]3-(3-((5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酰胺基)苯甲酸;
55]4-(3-((5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酰胺基)苯甲酸;
56]3-((6-((4-甲脒基-2-氟苯氧基)羰基)苯并[d]噻唑-2-基)氨基)-2,2-二甲基丙酸;
57]2-(4-(甲氧基羰基)哌啶-1-基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯;
58]1-(6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)哌啶-4-甲酸;
59]2-((3-甲氧基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯;
60]2-((3-甲氧基-3-氧代丙基)(甲基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯;
61]2-(乙基(3-甲氧基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯;
62]3-((6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)(甲基)氨基)丙酸;
63]2-((4-甲氧基-4-氧代丁基)(甲基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯;
64]4-((6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)(甲基)氨基)丁酸;
65]3-((6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)氨基)丙酸;
66]3-((6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)(乙基)氨基)丙酸;
67]2-((3-甲氧基-2,2-二甲基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯;
68]2-((3-甲氧基-2,2-二甲基-3-氧代丙基)(甲基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯;
69]2-(乙基(3-甲氧基-2,2-二甲基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯;
70]2-(乙基(3-甲氧基-2,2-二甲基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯;
71]2-((4-甲氧基-4-氧代丁基)(甲基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯;
72]2-((3-甲氧基-3-氧代丙基)(甲基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯;
73]3-((6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)氨基)-2,2-二甲基丙酸;
74]3-((6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)(乙基)氨基)-2,2-二甲基丙酸;
75]3-((6-((4-甲脒基-2-氟苯氧基)羰基)苯并[d]噻唑-2-基)(乙基)氨基)-2,2-二甲基丙酸;
76]4-((6-((4-甲脒基-2-氟苯氧基)羰基)苯并[d]噻唑-2-基)(甲基)氨基)丁酸;
77]3-((6-((4-甲脒基-2-氟苯氧基)羰基)苯并[d]噻唑-2-基)(甲基)氨基)丙酸;
78]2-(4-(甲氧基羰基哌啶-1-基)苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯;
79]1-(6-((4-甲脒基-2-氟苯氧基)羰基)苯并[d]噻唑-2-基)哌啶-4-甲酸;
80]2-(4-(苯基氨甲酰基)哌啶-1-基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯;
81]2-(4-(苯基氨甲酰基)哌啶-1-基)苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯;
82]2-(4-苯甲酰胺基哌啶-1-基)苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯;
83]2-(4-苯甲酰胺基哌啶-1-基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯;
84]2-(乙基(3-甲氧基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯;
85]3-((6-((4-甲脒基-2-氟苯氧基)羰基)苯并[d]噻唑-2-基)(乙基)氨基)丙酸;
86]3-((6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)(甲基)氨基)-2,2-二甲基丙酸;
87](Z)-3-((6-((4-甲脒基-2-氟苯氧基)羰基)-3-乙基苯并[d]噻唑-2(3H)-亚基)氨基)-2,2-二甲基丙酸;和
88](Z)-3-乙基-2-((3-甲氧基-2,2-二甲基-3-氧代丙基)亚氨基)-2,3-二氢苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯。
同时,根据一个实施方式的新型化合物可以具有不对称碳中心,并且可以作为外消旋体或单独的光学异构体存在。不言而喻,任何形式的异构体,包括这些光学异构体,也落入一个实施方式的化合物的范畴。如本文所用,术语“异构体”可以共同指代具有相同分子式的不同化合物,并且“光学异构体”可以指对于一个实施方式的化合物可能存在的任何立体异构体,包括相同的几何异构体在内。
应当理解,在根据一个实施方式的化学式1的化合物中,每个取代基可以连接至碳原子的手性中心。根据一个实施方式的化合物上的任何不对称碳原子可以以(R)-、(S)-或(R,S)-构型的任何形式存在。合适地,所述化合物可以以(R)-或(S)-构型存在。此外,根据一个实施方式的化合物可以采取任何可能的异构体或可能的异构体混合物的形式,例如,纯几何异构体、非对映异构体、对映异构体、外消旋体或其混合物。另外,当根据一个实施方式的化合物具有双键时,连接至所述双键的取代基可以采取E或Z构型。此外,当一个实施方式的化合物含有双取代的环烷基时,环烷基部分上的每个取代基可以采取顺式或反式构型。
同时,如本文所用的术语“药学上可接受的盐”是指具有与根据一个实施方式的化学式1的化合物相同的生物学活性和性质并且在药学、生物学或其它特性方面优选的任何盐。盐的非限制性实例包括化学式1的化合物的无机或有机碱加成盐或酸加成盐。适用于形成酸加成盐的有机酸的实例包括乙酸、丙酸、乙醇酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸和水杨酸。无机酸的实例可以包括盐酸、氢溴酸、磺酸、硝酸、磷酸等。
根据上述一个实施方式的化合物的药学上可接受的盐可以通过典型的化学方法从游离碱形式的化合物或由其衍生的碱性或酸性残基合成。此外,第二药学上可接受的盐可以由第一药学上可接受的盐合成。作为具体实例,可使游离碱形式的化合物与化学计量的量的合适的酸反应以得到一个实施方式的化合物的酸加成盐。在这方面,所述反应可以在水、有机溶剂或其混合物中,例如在非水介质如醚、乙酸乙酯、乙醇、异丙醇或乙腈中进行。此外,可以使用对本领域技术人员来说显而易见的典型反应来获得其它药学上可接受的盐。
本发明的化学式1的化合物表现出对肠肽酶的抑制活性,因此具有有效抑制胃肠道中的蛋白质消化酶以及脂肪的活性。所摄入的食物不被吸收到体内,而是排泄出体外。然而,由于蛋白质以及脂肪一起被排泄,因此几乎没有副作用如脂肪粪便。此外,由于其仅在胃肠道中起作用,因此其特征在于不具有副作用例如抑郁。
同时,根据本发明的另一个实施方式,提供了一种药物组合物,所述药物组合物包含化学式1的化合物、其异构体或其药学上可接受的盐作为活性成分,并表现出肠肽酶抑制活性。这样的药物组合物表现出优异的肠肽酶抑制活性,因此可以适合用于预防或治疗与肠肽酶活性相关的任何疾病,例如代谢性疾病如肥胖症和糖尿病。具体来说,本发明的化合物或其药学上可接受的盐可用作用于预防或治疗以下疾病的药物:基于症状性肥胖或单纯性肥胖的肥胖症,与肥胖相关的疾病状态或疾病,饮食失调,糖尿病(例如1型糖尿病、2型糖尿病、妊娠糖尿病、肥胖糖尿病),高脂血症(例如高甘油三酯血症、高胆固醇血症、高LDL-胆固醇血症、低HDL-胆固醇血症、餐后高脂血症),高血压,心力衰竭,糖尿病并发症[例如神经病,肾病,视网膜病,糖尿病性心肌病,白内障,大血管病变,骨质减少,高渗性糖尿病昏迷,感染性疾病(例如呼吸道感染、尿路感染、胃肠道感染、皮肤软组织感染、下肢感染),糖尿病性坏疽,口干症,听力减退,脑血管病症,外周血循环障碍],代谢综合症(具有选自高甘油三酸酯(TG)血症、低HDL胆固醇(HDL-C)血症、高血压、腹部肥胖和葡萄糖耐量受损中的3种或更多种的疾病状态),肌肉减少症,反流性食管炎等。
这样的药物组合物可以常规药物制剂的形式使用。也就是说,药物组合物可以在实际临床施用时以包括口服制剂和肠胃外制剂在内的各种制剂来施用,并且其可以以经口施用形式适当地施用。另外,取决于制剂,通过进一步包括稀释剂或赋形剂如常规填充剂、增量剂、粘合剂、润湿剂、崩解剂或表面活性剂来进行生产。
用于经口施用的固体制剂可以包括片剂、丸剂、粉末制剂、颗粒剂、胶囊剂等,并且可以通过将活性成分与淀粉、碳酸钙、蔗糖、乳糖或明胶等混合来提供这样的固体制剂。此外,除了赋形剂之外,还可以使用润滑剂如硬脂酸镁或滑石粉。此外,用于经口施用的液体制剂可以包括混悬剂、供内部使用的溶液制剂、乳剂、糖浆制剂等。用于经口施用的液体制剂除了包括水或液体石蜡作为常用的简单稀释剂以外,还可以包括各种媒介物,例如保湿剂、甜味剂、芳香剂或防腐剂。另外,用于肠胃外施用的制剂可以包括灭菌水溶液、不溶性试剂、悬浮剂、乳剂、冷冻干燥剂、栓剂等。这种用于肠胃外施用的制剂可以包括水不溶性溶剂,并且作为悬浮溶剂,可以使用丙二醇、聚乙二醇或植物油如橄榄油,和注射用酯如乙醇酸酯。作为栓剂用基质,可以使用维特索尔(witepsol)、聚乙二醇(macrogol)、吐温61(Tween 61)、可可脂、月桂酸酯、甘油、明胶等。
根据本发明的另一个实施方式,提供了一种抑制肠肽酶的方法,或一种预防或治疗代谢性疾病的方法,所述方法包括以上述药物组合物的形式施用药学上有效量的化学式1的化合物、其异构体或其药学上可接受的盐的步骤。如本文所用,术语“药学上有效量”是指足以以适用于任何药物治疗的合理的益处/风险比来治疗疾病的量。可以根据多种因素确定有效剂量水平,这些因素包括患者的健康状况,疾病类型,严重程度,药物活性,药物敏感性,施用方法,施用时间,施用途径,排泄率,治疗持续时间,组合或共同施用的药物以及医学领域中众所周知的其它因素。包含化学式1的化合物、其异构体或其药学上可接受的盐的本发明的药物组合物可以作为单独的治疗剂施用或与其它治疗剂组合施用,并且可以与常规的治疗剂依序或同时施用。所述组合物可以一次或多次施用。考虑到本领域技术人员可以容易确定的所有上述因素,重要的是以足以获得最大治疗效果而无副作用的最小可能量施用所述组合物。例如,由于可以根据施用途径、疾病的严重程度、性别、体重、年龄等增加或减少剂量,因此所述剂量不以任何方式限制本发明的范围。本发明化合物的优选剂量取决于患者的状况和体重、疾病的严重程度、药物类型、施用途径和持续时间,但是可以由本领域技术人员适当地选择。可以经由口服或肠胃外途径每天一次或以分开的剂量进行施用。
另外,当本发明的化学式1的化合物含有噻唑环时,它可以通过以下反应方案1的制备方法来制备。
[反应方案1]
如以上反应方案1所示,在碱如碳酸钾的存在下将作为起始原料的2-溴苯并[d]噻唑-6-甲酸叔丁酯(化学式2)和氨基链烷酸(化学式3)加热并进行偶联反应,得到化学式4的化合物,将其在碱如碳酸钾的存在下用烷基卤如碘乙烷进一步处理以合成化学式5的化合物。
此时,在有机酸或无机酸如三氟乙酸(TFA)的存在下处理所得化合物,以选择性地除去羧酸保护基团如叔丁基,从而获得化学式6的化合物。然后,使用偶联试剂如乙基碳二亚胺盐酸盐(EDCl)将所得化合物与化学式7的化合物进行偶联反应,以制备化学式8的化合物。在最后的步骤中,在酸的存在下将烷基羧酸酯选择性地水解,获得作为所需化合物的化学式1'的化合物。
另一方面,在其中R1和R6与它们所连接的氮原子一起形成未取代或取代的5元至7元杂环的化学式1的化合物的情况下,所述化合物是以与作为中间体的化学式4的制备方法相同的方式,使用仲氨基链烷酸例如化学式3-1的化合物来合成,以制备化学式4-2的化合物。可以通过使用与制备作为上述目标化合物的化学式1'的化合物的方法相似的方法来获得目标化合物。
另外,当本发明的化合物具有苯并噻唑环时,其可以通过以下反应方案2制备。
[反应方案2]
如以上反应方案2所示,在碱如碳酸钾的存在下将作为起始原料的2-溴苯并[d]噻唑-6-甲酸叔丁酯(化学式9)和氨基链烷酸(化学式10)加热并进行偶联反应,得到化学式11的化合物。此时,在有机酸或无机酸如三氟乙酸(TFA)的存在下处理所得化合物,以选择性地除去羧酸保护基团如叔丁基,从而获得化学式12的化合物。然后,使用偶联试剂如乙基碳二亚胺盐酸盐(EDCl)将所得化合物与化学式15的化合物进行偶联反应,以制备化学式16的化合物。在最后步骤中,在酸的存在下将烷基羧酸酯选择性地水解,获得作为所需化合物的化学式1”的化合物。
另一方面,为了制备具有被苯并噻唑环的氮取代或未取代的烷基作为取代基的苯并噻唑烷化合物,将反应方案2的取代或未取代的烷基卤化物如碘乙烷加入到作为中间体的化学式11的化合物中,并在碱如碳酸铯的存在下加热,获得化学式13的化合物。此时,将所得化合物在有机酸或无机酸如三氟甲酸的存在下进行处理,以选择性地除去羧酸保护基团如叔丁基,从而获得化学式7的化合物。然后,使用偶联试剂如乙基碳二亚胺盐酸盐(EDCl)使所得化合物与化学式15的化合物进行偶联反应,以制备化学式17的化合物。在最后的步骤中,在酸的存在下将烷基羧酸酯选择性地水解以获得所需化合物(化学式1”')。
实施例
在下文中,呈现了优选的实施例和实验例以促进对本发明的理解。然而,提供这些实施例和实验例只是为了更好地理解本发明,并且本发明的内容不限于此。
[制备例1]2-溴噻唑-5-甲酸
将20.0g(90.0mmol)的2-溴噻唑-5-甲酸甲酯溶解在250mL四氢呋喃和50mL水中后,在室温下向其中加入3.78g(90.0mmol)的氢氧化锂单水合物并搅拌12小时。将反应混合物减压浓缩直至除去四氢呋喃,并将1N氯化氢水溶液加入到剩余的水层直至达到pH 2。将乙酸乙酯加入到水溶液中,并且萃取反应混合物并合并有机层。将合并的有机层再次用硫酸钠干燥,然后减压浓缩,获得17.0g(91%)的目标化合物。
MS(ESI)m/z:209[M+H]+
[制备例2]2-溴噻唑-5-甲酸叔丁酯
将在[制备例1]中获得的4.86g(23.4mmol)的化合物2-溴噻唑-5-甲酸溶解在31mL叔丁醇和16mL二氯甲烷中后,在室温下向其中加入6.44mL(28.0mmol)的二碳酸二叔丁酯、0.285g(2.34mmol)的DMAP和0.756mL(9.34mmol)的吡啶并搅拌24小时。将反应混合物减压浓缩,加入乙酸乙酯和0.5N氯化氢水溶液直至达到pH 6。将反应混合物萃取两次并将有机层合并。将合并的有机层用0.5N氢氧化钠水溶液和盐水再次洗涤。合并的有机层经硫酸钠干燥,然后减压浓缩,获得4.89g(79%)的目标化合物。
MS(ESI)m/z:265[M+H]+
[实施例1]3-((5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酸
步骤1. 2-((3-甲氧基-3-氧代丙基)氨基)噻唑-5-甲酸叔丁酯
将[制备例2]中获得的2.0g(7.57mmol)的化合物2-溴噻唑-5-甲酸叔丁酯溶解在30mL二甲基甲酰胺中后,在室温下向其中加入1.16g(8.33mmol)的3-氨基丙酸甲酯盐酸盐和1.57g(11.36mmol)的碳酸钾并在60℃下搅拌16小时。将反应混合物冷却至室温后,将水倒入反应混合物中以终止反应。将反应混合物用乙酸乙酯萃取三次并将有机层合并。将合并的有机层用盐水洗涤,经硫酸钠干燥,然后减压浓缩,并通过MPLC纯化,得到1.8g(83%)的黄色固体状目标化合物。
MS(ESI)m/z:287[M+H]+
步骤2. 2-(乙基(3-甲氧基-3-氧代丙基)氨基)噻唑-5-甲酸叔丁酯
将在步骤1中获得的1.8g(6.29mmol)的化合物2-((3-甲氧基-3-氧代丙基)氨基)噻唑-5-甲酸叔丁酯溶解于25mL二甲基甲酰胺中后,向其中加入1.30g(9.43mmol)的碳酸钾和1.176g(7.54mmol)的碘乙烷并在50℃下搅拌5小时。将反应混合物冷却至室温后,将水倒入反应混合物中以终止反应。将反应混合物用乙酸乙酯萃取三次并将有机层合并。将合并的有机层用盐水洗涤,经硫酸钠干燥,然后减压浓缩,并通过MPLC纯化,得到1.5g(76%)的淡黄色液体状目标化合物。
MS(ESI)m/z:315[M+H]+
步骤3. 2-(乙基(3-甲氧基-3-氧代丙基)氨基)噻唑-5-甲酸
将在步骤2中获得的1.5g(4.77mmol)的化合物2-(乙基(3-甲氧基-3-氧代丙基)氨基)噻唑-5-甲酸叔丁酯溶解在10mL二氯甲烷中后,加入5.0mL(65.3mmol)的三氟乙酸,然后在室温下搅拌1小时。减压浓缩反应混合物,得到1.7g(定量)的黄色液体状目标化合物,无需纯化步骤。
MS(ESI)m/z:259[M+H]+
步骤4. 2-(乙基(3-甲氧基-3-氧代丙基)氨基)噻唑-5-甲酸4-甲脒基-2-氟苯酯
将在步骤3中获得的1.7g(6.58mmol)的化合物2-(乙基(3-甲氧基-3-氧代丙基)氨基)噻唑-5-甲酸溶解在7mL吡啶中后,向其中加入1.38g(7.24mmol)的3-氟-4-羟基苯甲脒盐酸盐和2.27g(11.85mmol)的EDCI并在50℃下搅拌3小时。减压浓缩反应混合物,并通过制备型HPLC纯化,得到2.0g(77%)的白色固体状目标化合物。
MS(ESI)m/z:395[M+H]+
步骤5. 3-((5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酸
在室温下向在步骤4中获得的1.2g(3.04mmol)的化合物2-(乙基(3-甲氧基-3-氧代丙基)氨基)噻唑-5-甲酸4-甲脒基-2-氟苯酯中加入4mL HCL(4N的H2O溶液)和4mL HCl(4N的二烷溶液),并将混合物在40℃下搅拌4小时。反应完成后,将反应混合物减压浓缩,并通过制备型HPLC纯化,得到0.68g(58%)的白色固体状目标化合物。
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.48(br s,1H),9.41(br s,2H),9.15(br s,2H),8.20(s,1H)7.93-7.88(m,1H),7.74-7.67(m,2H),3.75(t,J=6.7Hz,2H),3.60-3.53(m,2H),2.66(t,J=7.1Hz,2H),1.20(t,J=7.1Hz,2H);MS(ESI)m/z:381[M+H]+
[实施例2]1-(5-((4-甲脒基苯氧基)羰基)噻唑-2-基)哌啶-4-甲酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:48%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.43(br s,1H),9.33(s,2H),9.11-8.98(m,2H),8.14(s,1H),7.87(d,J=8.6Hz,2H),7.51(d,J=8.7Hz,2H),3.97(d,J=13.0Hz,2H),3.31-3.27(m,2H),2.64-2.56(m,1H),1.96(dd,J=3.2,13.6Hz,2H),1.66-1.56(m,2H);MS(ESI)m/z:375[M+H]+
[实施例3]2-(4-(甲氧基羰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:53%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.33(br s,2H),9.05(br s,2H),8.13(s,1H),7.86(d,J=8.7Hz,2H),7.50(d,J=8.8Hz,2H),3.96(d,J=13.0Hz,2H),3.62(s,3H),3.34-3.27(m,2H),2.75-2.65(m,1H),1.96(dd,J=3.2,13.4Hz,2H),1.67-1.57(m,2H);MS(ESI)m/z:389[M+H]+
[实施例4]2-(4-(甲氧基羰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基-2-氟苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:6%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.41(br s,2H),9.15(br s,2H),8.19(s,1H),7.91-7.88(m,1H),7.73-7.68(m,2H),3.98(d,J=13.1Hz,2H),3.63(s,3H),3.34-3.30(m,2H),2.77-2.70(m,1H),1.98(dd,J=3.1,13.4Hz,2H),1.68-1.58(m,2H);MS(ESI)m/z:407[M+H]+
[实施例5]2-(4-(甲氧基羰基)哌啶-1-基)噻唑-5-甲酸4-胍基苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:46%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.68(br s,1H),8.10(s,1H),7.43(br s,4H),7.30(br s,4H),3.97(d,J=13.2Hz,2H),3.63(s,3H),3.34-3.27(m,2H),2.76-2.69(m,1H),1.97(dd,J=3.2,13.4Hz,2H),1.68-1.58(m,2H);MS(ESI)m/z:404[M+H]+
[实施例6]1-(5-((4-胍基苯氧基)羰基)噻唑-2-基)哌啶-4-甲酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:12%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.42(br s,1H),9.78(br s,1H),8.10(s,1H),7.47(br s,4H),7.30(br s,4H),3.96(d,J=13.1Hz,2H),3.30-3.26(m,2H),2.62-2.60(m,1H),1.96(dd,J=3.0,13.4Hz,2H),1.66-1.56(m,2H);MS(ESI)m/z:390[M+H]+
[实施例7]1-(5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)哌啶-4-甲酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:39%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.43(br s,1H),9.40(br s,2H),9.16(br s,2H),8.19(s,1H),7.90(d,J=11.0Hz,1H),7.75-7.68(m,2H),3.97(d,J=12.8Hz,2H),3.16-3.15(m,2H),2.63-2.56(m,1H),1.98-1.95(m,2H),1.66-1.56(m,2H);MS(ESI)m/z:393[M+H]+
[实施例8]2-((3-甲氧基-3-氧代丙基)(甲基)氨基)噻唑-5-甲酸4-甲脒基苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:36%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.34(br s,2H),9.07(br s,2H),8.16(s,1H),7.88(d,J=8.7Hz,2H),7.52(d,J=8.7Hz,2H),3.84(t,J=6.9Hz,2H),3.60(s,3H),3.14(s,3H),2.73(t,J=7.0Hz,2H);MS(ESI)m/z:363[M+H]+
[实施例9]3-((5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)(甲基)氨基)丙酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:10%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.36(br s,2H),9.17(br s,2H),8.16(s,1H),7.88(d,J=6.84Hz,2H),7.51(d,J=6.92Hz,2H),3.79(m,2H),3.15(s,3H),2.64(m,2H);MS(ESI)m/z:349[M+H]+
[实施例10]2-((3-甲氧基-3-氧代丙基)氨基)噻唑-5-甲酸4-甲脒基苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:50%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.34(br s,2H),9.16(br s,2H),8.87(s,1H),8.07(s,1H),7.88(d,J=7.1Hz,2H),7.50(d,J=6.9Hz,2H),3.62(s,3H),3.62-3.54(m,2H),2.70-2.65(m,2H);MS(ESI)m/z:349[M+H]+
[实施例11]2-((4-甲氧基-4-氧代丁基)(甲基)氨基)噻唑-5-甲酸4-甲脒基苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:21%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.33(br s,2H),9.09(br s,2H),8.14(s,1H),7.88(d,J=8.7Hz,2H),7.52(d,J=8.6Hz,2H),3.64-3.57(m,2H),3.62(s,3H),3.13(s,3H),2.37(t,J=8.2Hz,2H),1.93-1.85(m,2H);MS(ESI)m/z:377[M+H]+
[实施例12]2-(乙基(3-甲氧基-3-氧代丙基)氨基)噻唑-5-甲酸4-甲脒基苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:21%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.34(br s,2H),9.16(br s,2H),8.15(s,1H),7.88(d,J=8.4Hz,2H),7.51(d,J=8.3Hz,2H),3.79(t,J=6.7Hz,2H),3.61(s,3H),3.58-3.52(m,2H),2.75(t,J=7.0Hz,2H),1.19(t,J=7.0Hz,3H);MS(ESI)m/z:377[M+H]+
[实施例13]3-((5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)氨基)丙酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:29%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.36(br s,1H),9.34(br s,2H),9.19(br s,2H),8.86(t,J=5.0Hz,1H),8.07(s,1H),7.86(d,J=8.6Hz,2H),7.50(d,J=8.3Hz,2H),3.56-3.49(m,2H),2.58(t,J=6.5Hz,2H);MS(ESI)m/z:335[M+H]+
[实施例14]3-((5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:16%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.5(br s,1H),9.34(br s,2H),9.18(brs,2H),8.15(s,1H),7.88(d,J=8.5Hz,2H),7.51(d,J=8.6Hz,2H),3.75(t,J=6.8Hz,2H),3.60-3.54(m,2H),2.66(t,J=7.0Hz,2H),1.23-1.15(m,3H);MS(ESI)m/z:363[M+H]+
[实施例15]4-((5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)(甲基)氨基)丁酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:17%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.2(br s,1H),9.34(br s,2H),9.11(brs,2H),8.14(s,1H),7.88(d,J=8.6Hz,2H),7.51(d,J=8.6Hz,2H),3.60(t,J=5.8Hz,2H),3.13(s,3H),2.27(t,J=7.2Hz,2H),1.90-1.82(m,2H);MS(ESI)m/z:363[M+H]+
[实施例16]2-(3-(甲氧基羰基)吡咯烷-1-基)噻唑-5-甲酸4-甲脒基苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:5%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.34(br s,2H),9.05(br s,2H),8.18(s,1H),8.18(d,J=8.76Hz,2H),7.52(d,J=8.76Hz,2H),3.67(s,3H),3.46-3.42(m,2H),2.37-2.21(m,2H);MS(ESI)m/z:375[M+H]+
[实施例17]1-(5-((4-甲脒基苯氧基)羰基)噻唑-2-基)吡咯烷-3-甲酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:50%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.78(brs,1H),9.34(br s,2H),9.03(brs,2H),8.17(s,1H),7.88(d,J=8.68Hz,2H),7.52(d,J=8.68Hz,2H),2.72-2.67(m,2H),2.23-2.23(m,2H);MS(ESI)m/z:361[M+H]+
[实施例18]2-((3-甲氧基-2,2-二甲基-3-氧代丙基)(甲基)氨基)噻唑-5-甲酸4-甲脒基苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:37%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.31(br s,2H),9.10(br s,2H),8.14(s,1H),7.87(d,J=8.7Hz,2H),7.52(d,J=8.7Hz,2H),3.85(s,2H),3.61(s,3H),3.09(s,3H),1.19(s,6H);MS(ESI)m/z:391[M+H]+
[实施例19]3-((5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)(甲基)氨基)-2,2-二甲基丙酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:27%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.34(br s,2H),9.14(br s,2H),8.14(s,1H),7.86(d,J=8.6Hz,2H),7.51(d,J=8.7Hz,2H),3.84(s,2H),3.11(s,3H),1.15(s,6H);MS(ESI)m/z:377[M+H]+
[实施例20]2-(乙基(3-甲氧基-3-氧代丙基)氨基)噻唑-5-甲酸4-甲脒基-2-氟苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:40%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.40(br s,2H),9.30(br s,2H),8.20(s,1H),7.92-7.89(m,1H),7.74-7.67(m,2H),3.80(t,J=6.8Hz,2H),3.61(s,3H),3.58-3.52(m,2H),2.75(t,J=7.1Hz,2H),1.19(t,J=7.1Hz,3H);MS(ESI)m/z:395[M+H]+
[实施例21]2-((4-甲氧基-4-氧代丁基)(甲基)氨基)噻唑-5-甲酸4-甲脒基-2-氟苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:51%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.35(br s,4H),8.19(s,1H),7.90(d,J=11.5Hz,1H),7.72-7.68(m,2H),3.65-3.59(m,2H),3.58(s,3H),3.13(s,3H),2.35(t,J=8.8Hz,2H),1.93-1.83(m,2H);MS(ESI)m/z:395[M+H]+
[实施例22]4-((5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)(甲基)氨基)丁酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:36%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.19(br s,1H),9.40(br s,4H),9.12(br s,1H),8.19(s,1H)7.91(d,J=9.9Hz,1H),7.74-7.68(m,2H),3.64-3.58(m,2H),3.14(s,3H),2.28(t,J=7.2Hz,2H),1.92-1.82(m,2H);MS(ESI)m/z:381[M+H]+
[实施例23]1-(5-((4-胍基苯基)氨甲酰基)噻唑-2-基)哌啶-4-甲酸甲酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:39%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ10.10(br s,1H),9.53(br s,2H),8.06(s,1H),7.72(d,J=8.7Hz,2H),7.30(br s,4H),7.19(d,J=8.7Hz,2H),3.65(d,J=13.0Hz,2H),3.62(s,3H),3.24-3.16(m,2H),2.71-2.66(m,1H),1.95-1.90(m,2H),1.65-1.55(m,2H);MS(ESI)m/z:403[M+H]+
[实施例24]2-((3-甲氧基-2,2-二甲基-3-氧代丙基)氨基)噻唑-5-甲酸4-甲脒基苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:28%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.33(br s,2H),9.09(br s,2H),8.73(t,J=6.1Hz,1H),8.03(s,1H),7.87(d,J=8.7Hz,2H),7.50(d,J=8.6Hz,2H),3.61(s,3H),3.57(d,J=6.2Hz,2H),1.17(s,6H);MS(ESI)m/z:377[M+H]+
[实施例25](1-(5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)哌啶-4-羰基)-L-天冬氨酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:5%)
MS(ESI)m/z:490[M+H]+
[实施例26](1-(5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)哌啶-4-羰基)-L-天冬氨酸酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:22%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.39(br s,2H),9.13(br s,2H),8.48(d,J=7.9Hz,1H),8.19(s,1H),7.91-7.88(m,1H),7.71-7.70(m,2H),7.34-7.30(m,10H),5.11-5.04(m,4H)4.69(q,J=7.7Hz,1H),3.97(d,J=11.6Hz,2H),3.24(t,J=11.8Hz,2H),2.91(dd,J=5.8,16.4Hz,1H),2.78(dd,J=7.8,16.4Hz,1H),1.76-1.70(m,2H),1.59-1.49(m,2H);MS(ESI)m/z:688[M+H]+
[实施例27]2-(4-(苯基氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:34%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.98(br s,1H),9.31(br s,2H),8.98(brs,2H),8.14(s,1H),7.87-7.85(m,2H),7.58(d,J=7.7Hz,2H),7.50(d,J=8.7,2H),7.29(t,J=7.6Hz,2H),7.50(d,J=8.7Hz,2H),7.29(t,J=7.6Hz,2H),7.01(t,J=7.4Hz,1H),4.08(d,J=13.0Hz,2H),3.31-3.25(m,2H),2.71-2.47(m,1H),1.94-1.88(m,2H),1.74-1.64(m,2H);MS(ESI)m/z:450[M+H]+
[实施例28]2-(4-苯甲酰胺基哌啶-1-基)噻唑-5-甲酸4-甲脒基苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:32%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.32(br s,2H),9.03(br s,2H),8.35(d,J=7.6Hz,1H)8.16(s,1H),7.88-7.82(m,4H),7.54-7.50(m,3H),7.47-7.44(m,2H),4.18-4.10(m,1H),4.06(d,J=12.9Hz,2H),3.40-3.37(m,2H),1.97-1.94(m,2H),1.69-1.59(m,2H);MS(ESI)m/z:450[M+H]+
[实施例29]2-(4-((2-甲氧基-2-氧代乙基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:55%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.26(br s,2H),9.12(br s,2H),8.38(t,J=5.8Hz,1H),8.14(s,1H),7.87(d,J=8.7Hz,2H),7.51(d,J=8.7Hz,2H),4.02(d,J=13.0Hz,2H),3.82(d,J=5.9Hz,2H),3.61(s,3H),3.31-3.24(m,2H),2.59-2.54(m,1H),1.86-1.82(m,2H),1.67-1.56(m,2H);MS(ESI)m/z:446[M+H]+
[实施例30]2-(4-((3-甲氧基-3-氧代丙基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:51%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.32(br s,2H),8.97(br s,2H),8.14(s,1H),8.01(t,J=5.6Hz,1H),7.87(d,J=8.7Hz,2H),7.51(d,J=8.7Hz,2H),4.02(d,J=12.6Hz,2H),3.58(s,3H),3.29-3.15(m,4H),2.49-2.43(m,3H),1.80-1.76(m,2H),1.64-1.53(m,2H);MS(ESI)m/z:460[M+H]+
[实施例31]2-(4-((4-甲氧基-4-氧代丁基)(甲基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:33%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.32(br s,2H),9.02(br s,2H),8.14(s,1H),7.88-7.86(m,2H),7.52-7.50(m,2H),4.03-3.95(m,2H),3.60(s,1H,旋转异构体,-OCH3),3.57(s,2H,旋转异构体-OCH3),3.38-3.31(m,2H),3.30-3.26(m,2H),3.02(s,2H,旋转异构体-CH3),2.99-2.93(m,1H),2.78(s,1H,旋转异构体-CH3),2.37(t,J=7.2Hz,1H),2.24(t,J=7.4Hz,1H),1.82-1.70(m,2H),1.69-1.62(m,2H),1.59-1.52(m,2H);MS(ESI)m/z:488[M+H]+
[实施例32]2-(4-((3-甲氧基-2,2-二甲基-3-氧代丙基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:4%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.32(br s,2H),9.02(br s,2H),8.14(s,1H),7.90-7.86(m,3H),7.51(d,J=8.7Hz,2H),4.03(d,J=12.5Hz,2H),3.56(s,3H),3.27-3.20(m,4H),2.55-2.53(m,1H),1.80-1.77(m,2H),1.65-1.55(m,2H),1.06(s,6H);MS(ESI)m/z:488[M+H]+
[实施例33](1-(5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)哌啶-4-羰基)甘氨酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:48%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.55(br s,1H),9.33(br s,2H),9.01(br s,2H),8.26(t,J=5.8Hz,1H),8.15(s,1H),7.88(d,J=8.7Hz,2H),7.52(d,J=8.7Hz,2H),4.04(d,J=12.8Hz,2H),3.74(d,J=5.9Hz,2H),3.30-3.24(m,2H),1.86-1.83(m,2H),1.67-1.57(m,2H);MS(ESI)m/z:432[M+H]+
[实施例34]3-(1-(5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)哌啶-4-甲酰胺基)丙酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:53%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.33(br s,2H),9.04(br s,2H),8.15(s,1H),7.99(t,J=5.5Hz,1H),7.89-7.86(m,2H),7.53-7.50(m,2H),4.03(d,J=12.8Hz,2H),3.26-3.20(m,4H),2.46-2.41(m,1H),2.37(t,J=6.8Hz,2H),1.81-1.77(m,2H),1.65-1.55(m,2H);MS(ESI)m/z:446[M+H]+
[实施例35]4-(1-(5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)-N-甲基哌啶-4-甲酰胺基)丁酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:56%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.33(br s,2H),9.03(br s,2H),8.15(s,1H),7.89-7.87(m,2H),7.53-7.51(m,2H),4.04-3.96(m,2H),3.39-3.35(m,2H),3.34-3.26(m,2H),3.04(s,2H,旋转异构体-CH3),3.00-2.94(m,1H),2.80(s,1H,旋转异构体-CH3),2.29(t,J=7.1Hz,1H),2.15(t,J=7.4Hz,1H),1.80-1.74(m,2H),1.70-1.65(m,2H),1.64-1.54(m,2H);MS(ESI)m/z:474[M+H]+
[实施例36]3-(1-(5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)哌啶-4-甲酰胺基)-2,2-二甲基丙酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:41%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.24(br s,1H),9.32(br s,2H),9.01(br s,2H),8.14(s,1H),7.87(d,J=8.8Hz,2H),7.79(t,J=6.1Hz,1H),7.51(d,J=8.7Hz,2H),4.03(d,J=12.5Hz,2H),3.26-3.19(m,4H),2.58-2.53(m,1H),1.80-1.77(m,2H),1.65-1.55(m,2H),1.03(s,6H);MS(ESI)m/z:474[M+H]+
[实施例37]2-(4-((2-甲氧基-2-氧代乙基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基-2-氟苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:23%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.30(br s,4H),8.39(t,J=5.9Hz,1H),8.21(s,1H)7.93-7.90(m,1H),7.74-7.69(m,2H),4.04(d,J=12.6Hz,2H),3.84(d,J=5.9Hz,2H),3.63(s,3H),3.30-3.26(m,2H),2.61-2.52(m,1H),1.90-1.84(m,2H)1.68-1.58(m,2H);MS(ESI)m/z:464[M+H]+
[实施例38]2-(4-((3-甲氧基-3-氧代丙基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基-2-氟苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:50%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.37(br s,2H),9.24(br s,2H),8.19(s,1H),8.01(t,J=5.6Hz,1H),7.91-7.88(m,1H),7.73-7.68(m,2H),4.03(d,J=12.3Hz,2H),3.58(s,3H),3.29-3.21(m,4H),2.46-2.43(m,3H),1.81-1.77(m,2H),1.64-1.54(m,2H);MS(ESI)m/z:478[M+H]+
[实施例39]2-(4-((3-甲氧基-2,2-二甲基-3-氧代丙基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基-2-氟苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:50%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.40(br s,2H),9.20(br s,2H),8.19(s,1H),7.91-7.87(m,2H),7.73-7.68(m,2H),4.04(d,J=12.4Hz,2H),3.57(s,3H),3.28-3.20(m,4H),2.49-2.48(m,1H),1.81-1.77(m,2H),1.65-1.55(m,2H),1.06(s,6H);MS(ESI)m/z:506[M+H]+
[实施例40]2-(4-((3-甲氧基-2,2-二甲基-3-氧代丙基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基-2-氟苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:9%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.86(br s,2H),9.34(br s,2H),9.10-8.96(m,2H),8.16(s,1H),7.88(d,J=8.6Hz,2H),7.55-7.48(m,4H),6.87(d,J=9.0Hz,2H),4.14-4.06(m,2H),3.71(s,3H),3.35-3.25(m,2H),2.70-2.64(m,1H),1.96-1.90(m,2H),1.77-1.64(m,2H);MS(ESI)m/z:480[M+H]+
[实施例41]2-(4-((4-甲氧基-4-氧代丁基)(甲基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基-2-氟苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:16%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.41(br s,2H),9.19(br s,2H),8.21(s,1H),7.93-7.90(m,1H),7.77-7.70(m,2H),4.05-3.96(m,2H),3.62(s,1H,旋转异构体,-OCH3),3.58(s,2H,旋转异构体-OCH3),3.39-3.32(m,2H),3.31-3.28(m,2H),3.04(s,2H,旋转异构体-CH3),3.02-2.95(m,1H),2.79(s,1H,旋转异构体-CH3),2.39(t,J=7.2Hz,1H),2.25(t,J=7.5Hz,1H),1.86-1.77(m,2H),1.74-1.67(m,2H),1.64-1.54(m,2H);MS(ESI)m/z:506[M+H]+
[实施例42](1-(5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)哌啶-4-羰基)甘氨酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:15%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.54(br s,1H),9.42(br s,2H),9.15(br s,2H),8.27(t,J=5.8Hz,1H),8.21(s,1H),7.93-7.90(m,1H),7.75-7.70(m,2H),4.05(d,J=12.4Hz,2H),3.75(d,J=5.9Hz,2H),3.30-3.27(m,2H),2.59-2.50(m,1H),1.87-1.84(m,2H),1.68-1.58(m,2H);MS(ESI)m/z:450[M+H]+
[实施例43]3-(1-(5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)哌啶-4-甲酰胺基)丙酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:17%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.21(br s,1H),9.40(br s,2H),9.17(br s,2H),8.19(s,1H),7.98(t,J=5.4Hz,1H),7.92-7.89(m,1H),7.71-7.70(m,2H),4.03(d,J=12.3Hz,2H),3.28-3.21(m,4H),2.49-2.41(m,1H),2.36(t,J=6.8Hz,2H),1.81-1.78(m,2H),1.65-1.55(m,2H);MS(ESI)m/z:464[M+H]+
[实施例44]3-(1-(5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)哌啶-4-甲酰胺基)-2,2-二甲基丙酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:56%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.40(br s,2H),9.13(br s,2H),8.19(s,1H),7.92-7.89(m,1H),7.73-7.68(m,2H),4.03-3.94(m,2H),3.38-3.34(m,2H),3.32-3.27(m,2H),3.03(s,2H,旋转异构体-CH3),2.99-2.94(m,1H),2.79(s,1H,旋转异构体-CH3),2.28(t,J=7.1Hz,1H),2.14(t,J=7.4Hz,1H),1.79-1.73(m,2H),1.69-1.64(m,2H),1.62-1.51(m,2H);MS(ESI)m/z:492[M+H]+
[实施例45]3-(1-(5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)哌啶-4-甲酰胺基)-2,2-二甲基丙酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:36%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.39(br s,2H),9.15(br s,2H),8.19(s,1H),7.91-7.89(m,1H),7.80(t,J=6.2Hz,1H),7.78-7.68(m,2H),4.04(d,J=12.6Hz,2H),3.27-3.20(m,4H),2.59-2.53(m,1H),1.81-1.78(m,2H),1.66-1.56(m,2H),1.04(s,6H);MS(ESI)m/z:492[M+H]+
[实施例46](3-((5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酰基)-L-天冬氨酸二叔丁酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:48%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.40(br s,2H),9.14(br s,2H),8.42(d,J=8.0Hz,1H),8.19(s,1H),7.92-7.89(m,1H),7.74-7.67(m,2H),4.51-4.45(m,1H),3.73-3.72(m,2H),3.56-3.50(m,2H),2.67-2.58(m,1H),2.56-2.51(m,3H),1.38(s,9H),1.38(s,9H),1.18(t,J=7.0Hz,3H);MS(ESI)m/z:608[M+H]+
[实施例47](3-((5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酰基)-L-天冬氨酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:37%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.41(br s,2H),9.16(br s,2H),8.41(d,J=7.9Hz,1H),8.20(s,1H),7.92-7.89(m,1H),7.75-7.68(m,2H),4.56-4.51(m,1H),3.74-3.72(m,2H),3.53-3.51(m,2H),2.71-2.65(m,1H),2.60-2.54(m,3H),1.18(t,J=7.0Hz,3H);MS(ESI)m/z:496[M+H]+
[实施例48](3-((5-((4-甲脒基)-2-氟苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酰基)-D-谷氨酸二叔丁酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:44%)
1H NMR(400MHz,三氟乙酸盐,甲醇-d4)δ8.10(s,1H),7.77(dd,J=2.0,10.3Hz,1H),7.71-7.69(m,1H),7.58(t,J=7.7Hz,1H),4.31-4.28(m,1H),3.87-3.86(m,2H),3.61(q,J=14.1Hz,2H),2.68(t,J=6.8Hz,2H),2.29(t,J=7.5Hz,2H),2.10-2.01(m,1H),1.88-1.78(m,1H),1.46(s,9H),1.44(s,9H),1.27(t,J=7.0Hz,3H);MS(ESI)m/z:622[M+H]+
[实施例49](3-((5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酰基)-D-谷氨酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:30%)
1H NMR(400MHz,三氟乙酸盐,甲醇-d4)δ8.10(s,1H),7.77(dd,J=2.0,10.3Hz,1H),7.71-7.69(m,1H),7.58(t,J=7.7Hz,1H),4.31-4.28(m,1H),3.87-3.86(m,2H),3.61(q,J=14.1Hz,2H),2.68(t,J=6.8Hz,2H),2.29(t,J=7.5Hz,2H),2.10-2.01(m,1H),1.88-1.78(m,1H),1.46(s,9H),1.44(s,9H),1.27(t,J=7.0Hz,3H);MS(ESI)m/z:510[M+H]+
[实施例50]2-(乙基(3-((4-(甲氧基羰基)苯基)氨基)-3-氧代丙基)氨基)噻唑-5-甲酸4-甲脒基-2-氟苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:20%)
1H NMR(400MHz,三氟乙酸盐,甲醇-d4)δ8.12(s,1H),7.98(d,J=8.7Hz,2H),7.80(d,J=10.4Hz,1H),7.73-7.69(m,2H),7.62-7.58(m,1H),3.99(t,J=6.8Hz,2H),3.90(s,3H),3.70-3.65(m,2H),2.87(t,J=6.8Hz,2H),1.33(t,J=7.1Hz,3H);MS(ESI)m/z:514[M+H]+
[实施例51]2-(乙基(3-((3-(甲氧基羰基)苯基)氨基)-3-氧代丙基)氨基)噻唑-5-甲酸4-甲脒基-2-氟苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:25%)
1H NMR(400MHz,三氟乙酸盐,甲醇-d4)δ8.26(s,1H),8.24(s,1H),8.12-7.71(m,4H),7.62-7.58(m,1H),7.44(t,J=8.0Hz,1H),3.99(t,J=6.8Hz,2H),3.92(s,3H),3.70-3.65(m,2H),2.85(t,J=6.8Hz,2H),1.33(t,J=7.1Hz,3H);MS(ESI)m/z:514[M+H]+
[实施例52]2-((3-((4-(叔丁氧羰基)苯基)氨基)-3-氧代丙基)(乙基)氨基)噻唑-5-甲酸4-甲脒基-2-氟苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:59%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ11.21(s,1H),10.23(br s,2H),10.00(brs,2H),9.03(s,1H),8.72(d,J=10.1Hz,1H),8.66(d,J=8.7Hz,1H),8.53-8.50(m,4H),4.69-4.65(m,2H),4.50-4.30(m,2H),3.63(t,J=6.8Hz,2H),2.34(s,9H),2.03(t,J=7.1Hz,3H);MS(ESI)m/z:556[M+H]+
[实施例53]2-((叔丁氧羰基)苯基)氨基)-3-氧代丙基)(乙基)氨基)噻唑-5-甲酸4-甲脒基-2-氟苯酯
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:62%)
1H NMR(400MHz,三氟乙酸盐,甲醇-d4)δ8.03(s,1H),8.02(s,1H),7.71-7.67(m,2H),7.62-7.58(m,2H),7.48(t,J=7.7Hz,1H),7.29(t,J=7.9Hz,1H),3.88(t,J=6.8Hz,2H),3.58-3.53(m,2H),2.73(t,J=6.8Hz,2H),1.49(s,9H),1.21(t,J=7.1Hz,3H);MS(ESI)m/z:556[M+H]+
[实施例54]3-(3-((5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酰胺基)苯甲酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:23%)
1H NMR(400MHz,三氟乙酸盐,甲醇-d4)δ8.23(s,1H),8.13(s,1H),7.84-7.71(m,4H),7.60(t,J=8.2Hz,1H),7.43(t,J=8.0Hz,1H),3.99(t,J=6.7Hz,2H),3.71-3.65(m,2H),2.86(t,J=6.8Hz,2H),1.33(t,J=7.1Hz,3H);MS(ESI)m/z:500[M+H]+
[实施例55]4-(3-((5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酰胺基)苯甲酸
以与[实施例1]中相同的方式从[制备例2]中获得的化合物2-溴噻唑-5-甲酸叔丁酯进行反应,得到标题化合物。(产率:20%)
1H NMR(400MHz,三氟乙酸盐,甲醇-d4)δ8.12(s,1H),7.99(d,J=8.6Hz,2H),7.82-7.78(m,1H),7.73-7.69(m,3H),7.60-7.58(m,1H),3.99(t,J=6.8Hz,2H),3.69-3.65(m,2H),2.87(t,J=6.6Hz,2H),1.33(t,J=7.1Hz,3H);MS(ESI)m/z:500[M+H]+
[制备例3]2-溴苯并[d]噻唑-6-甲酸叔丁酯
将7.0g(27.1mmol)的2-溴苯并[d]噻唑-6-甲酸溶解在60mL叔丁醇和30mL四氢呋喃中后,在室温下向其中添加7.48mL(32.5mmol)的二碳酸二叔丁酯、0.663g(5.42mmol)的DMAP和6.58mL(81.0mmol)的吡啶,然后在70℃下搅拌5小时。将反应混合物减压浓缩,加入乙酸乙酯、水和1N氯化氢水溶液直至达到pH 6,然后搅拌1小时,并且过滤沉淀的固体。萃取滤液乙酸乙酯和水层并合并有机层。将合并的有机层再次用硫酸钠干燥,减压浓缩,并通过MPLC纯化,得到3.4g(40%)的黄色固体状目标化合物。
MS(ESI)m/z:315[M+H]+
[实施例56]3-((6-((4-甲脒基-2-氟苯氧基)羰基)苯并[d]噻唑-2-基)氨基)-2,2-二甲基丙酸
步骤1. 2-((3-甲氧基-2,2-二甲基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸叔丁
酯
将[制备例3]中获得的2.5g(7.96mmol)的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯溶解在30mL二甲基甲酰胺中后,在室温下向其中加入1.39g(8.35mmol)的3-氨基-2,2-二甲基丙酸甲酯盐酸盐和1.65g(11.94mmol)的碳酸钾,然后在60℃下搅拌16小时。将反应混合物冷却至室温后,将其用乙酸乙酯和盐水萃取,并将有机层合并。合并的有机层经硫酸钠干燥,减压浓缩,并通过MPLC纯化,得到3.0g(72%)的黄色固体状目标化合物。
MS(ESI)m/z:365[M+H]+
步骤2. 2-((3-甲氧基-2,2-二甲基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸
将在步骤1中获得的2.3g(6.31mmol)的化合物2-((3-甲氧基-2,2-二甲基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸叔丁酯溶解在10mL二氯甲烷中后,向其中加入5mL(65.3mmol)的三氟乙酸,然后在室温下搅拌1小时。将反应混合物减压浓缩,得到2.6g(定量)的淡黄色液体状目标化合物,无需纯化。
MS(ESI)m/z:309[M+H]+
步骤3. 2-((3-甲氧基-2,2-二甲基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸4-甲
脒基-2-氟苯酯
将在步骤2中获得的1.3g(3.08mmol)的化合物2-((3-甲氧基-2,2-二甲基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸溶解在7mL吡啶中后,向其中添加0.65g(3.39mmol)的3-氟-4-羟基苯甲脒盐酸盐和1.06g(5.54mmol)的EDCI,然后在50℃下搅拌4小时。减压浓缩反应混合物,并通过制备型HPLC纯化,得到0.8g(59%)的乳白色固体状目标化合物。
MS(ESI)m/z:445[M+H]+
步骤4. 3-((6-((4-甲脒基-2-氟苯氧基)羰基)苯并[d]噻唑-2-基)氨基)-2,2-二
甲基丙酸
向步骤3中获得的0.8g(1.43mmol)的化合物2-((3-甲氧基-2,2-二甲基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯中加入3mL HCL(4N的H2O溶液)和3mLHCl(4N的二烷溶液),然后在40℃下搅拌3小时。将反应混合物减压浓缩并通过制备型HPLC纯化,得到0.6g(77%)的白色固体状目标化合物。
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.48(br s,1H),9.43(br s,2H),9.22(br s,2H),8.57-8.52(m,2H),7.99(dd,J=1.8,8.5Hz,1H),7.96-7.91(m,1H),7.79-7.73(m,2H),7.51(d,J=8.5Hz,1H),3.63(d,J=5.4Hz,2H),1.18(s,6H);MS(ESI)m/z:431[M+H]+
[实施例57]2-(4-(甲氧基羰基)哌啶-1-基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:5%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.34(br s,2H),9.04(br s,2H),8.61(d,J=1.8Hz,1H),8.03(dd,J=1.8,8.5Hz,1H),7.90(d,J=8.7Hz,2H)7.58-7.54(m,3H),4.04(d,J=12.8Hz,2H),3.63(s,3H),3.39-3.38(m,2H),2.78-2.70(m,1H),2.00(dd,J=3.2,13.4Hz,2H),1.70-1.61(m,2H);MS(ESI)m/z:439[M+H]+
[实施例58]1-(6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)哌啶-4-甲酸
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:10%)
MS(ESI)m/z:425[M+H]+
[实施例59]2-((3-甲氧基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:40%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.35(br s,2H),9.04(br s,2H),8.68(t,J=5.0Hz,1H),8.53(s,1H),8.01(d,J=8.4Hz,1H),7.91(d,J=8.6Hz,2H),7.58(d,J=8.6Hz,2H),7.53(d,J=8.4Hz,1H),3.69-3.63(m,2H),3.63(s,3H),2.71(t,J=6.5Hz,1H);MS(ESI)m/z:399[M+H]+
[实施例60]2-((3-甲氧基-3-氧代丙基)(甲基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:27%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.34(br s,2H),9.03(br s,2H),8.63(d,J=1.8Hz,1H),8.04(dd,J=1.8,8.5Hz,1H),7.91(d,J=8.7Hz,2H),7.58(d,J=8.6Hz,3H),3.87(t,J=8.0Hz,2H),3.61(s,3H),3.19(s,3H),2.78(t,J=7.0Hz,2H);MS(ESI)m/z:413[M+H]+
[实施例61]2-(乙基(3-甲氧基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:33%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.35(br s,2H),9.11(br s,2H),8.61(s,1H),8.04(d,J=8.6Hz,1H),7.91(d,J=8.4Hz,2H),7.58(d,J=7.4Hz,3H),3.84(t,J=6.6Hz,2H),3.62(s,3H),3.61-3.55(m,2H),2.79(t,J=7.0Hz,2H),1.23(t,J=7.0Hz,3H);MS(ESI)m/z:427[M+H]+
[实施例62]3-((6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)(甲基)氨基)丙酸
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:34%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.35(br s,2H),9.01(br s,2H),8.62(s,1H),8.04(d,J=8.4Hz,1H),7.91(d,J=8.6Hz,2H),7.58(d,J=8.6Hz,3H),3.86-3.79(m,2H),3.20(s,3H),2.69(t,J=7.2Hz,2H);MS(ESI)m/z:399[M+H]+
[实施例63]2-((4-甲氧基-4-氧代丁基)(甲基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:16%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.35(br s,2H),9.03(br s,2H),8.61(d,J=1.8Hz,1H),8.03(dd,J=1.9,8.5Hz,1H),7.91(d,J=8.6Hz,2H),7.58(d,J=8.7Hz,2H),7.55(d,J=8.6Hz,1H),3.66-3.60(m,2H),3.58(s,3H),3.18(s,3H),2.40(t,J=7.2Hz,2H),1.97-1.89(m,2H);MS(ESI)m/z:427[M+H]+
[实施例64]4-((6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)(甲基)氨基)丁酸
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:58%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.16(br s,1H),9.35(br s,2H),9.11(br s,2H),8.60(d,J=1.8Hz,1H),8.03(dd,J=1.8,8.5Hz,1H),7.91(d,J=8.6Hz,2H),7.60-7.54(m,3H),3.66-3.58(m,2H),3.19(s,3H),2.31(t,J=7.2Hz,2H),1.94-1.86(m,2H);MS(ESI)m/z:413[M+H]+
[实施例65]3-((6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)氨基)丙酸
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:40%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.38(br s,1H),9.35(br s,2H),9.09(br s,2H),8.65(br s,1H),8.52(s,1H),8.00(dd,J=1.7,8.5Hz,1H),7.91(d,J=8.6Hz,2H),7.57(d,J=8.6Hz,2H),7.53(d,J=8.5Hz,1H),3.66-3.59(m,2H),2.63(t,J=6.4Hz,2H);MS(ESI)m/z:385[M+H]+
[实施例66]3-((6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)(乙基)氨基)丙酸
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:48%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.48(br s,1H),9.34(br s,2H),8.93(br s,2H),8.61(d,J=1.8Hz,1H),8.03(dd,J=1.8,8.5Hz,1H),7.91(d,J=8.7Hz,2H),7.58(dd,J=2.1,8.7Hz,1H),3.82-3.76(m,2H),3.65-3.57(m,2H),2.71(t,J=7.1Hz,2H),1.24(t,J=7.0Hz,3H);MS(ESI)m/z:413[M+H]+
[实施例67]2-((3-甲氧基-2,2-二甲基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:49%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.35(br s,2H),9.05(br s,2H),8.57-8.50(m,2H),7.99(d,J=8.5Hz,1H),7.91(d,J=8.6Hz,2H),7.57(d,J=8.6Hz,2H),7.50(d,J=8.4Hz,1H),3.66-3.63(m,2H),3.60(s,3H),1.20(s,6H);MS(ESI)m/z:427[M+H]+
[实施例68]2-((3-甲氧基-2,2-二甲基-3-氧代丙基)(甲基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:15%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.35(br s,2H),9.01(br s,2H),8.63(d,J=1.7Hz,1H),8.04(dd,J=1.8,8.6Hz,1H),7.91(d,J=8.7Hz,2H),7.59-7.55(m,3H),3.86(s,2H),3.60(s,3H),3.16(s,3H),1.22(s,6H);MS(ESI)m/z:441[M+H]+
[实施例69]2-(乙基(3-甲氧基-2,2-二甲基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:19%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.35(br s,2H),9.04(br s,2H),8.61(s,1H),8.03(d,J=8.8Hz,1H),7.91(d,J=8.5Hz,2H),7.59-7.54(m,3H),3.82(s,2H),3.61(s,3H),3.54-3.47(m,2H),1.23(s,6H),1.22-1.17(m,3H);MS(ESI)m/z:455[M+H]+
[实施例70]2-(乙基(3-甲氧基-2,2-二甲基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:21%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.43(br s,2H),9.16(br s,2H),8.63(s,J=1.4Hz,1H),8.05-8.02(m,1H),7.94(d,J=10.4Hz,1H),7.80-7.75(m,2H),7.56(d,J=8.5Hz,1H),3.82(s,2H),3.61(s,3H),3.54-3.48(m,2H),1.22(s,6H),1.22-1.17(m,3H);MS(ESI)m/z:473[M+H]+
[实施例71]2-((4-甲氧基-4-氧代丁基)(甲基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:18%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.42(br s,2H),9.11(br s,2H),8.63(d,J=1.8Hz,1H),8.03(dd,J=1.9,8.5Hz,1H),7.96-7.91(m,1H),7.80-7.73(m,2H),7.56(d,J=8.6Hz,1H),3.67-3.61(m,2H),3.58(s,3H),3.18(s,3H),2.40(t,J=7.2Hz,2H),1.97-1.89(m,2H);MS(ESI)m/z:445[M+H]+
[实施例72]2-((3-甲氧基-3-氧代丙基)(甲基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:16%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.43(br s,2H),9.24(br s,2H),8.65(d,J=1.8Hz,1H),8.04(dd,J=1.8,8.5Hz,1H),7.96-7.92(m,1H),7.80-7.73(m,2H),7.59(d,J=8.6Hz,1H),3.90-3.84(m,2H),3.61(s,3H),3.19(s,3H),2.77(t,J=7.0Hz,2H);MS(ESI)m/z:431[M+H]+
[实施例73]3-((6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)氨基)-2,2-二甲基丙酸
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:42%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.46(br s,1H),9.35(br s,2H),9.05(br s,2H),8.53-8.48(m,2H),7.99(dd,J=1.8,8.5Hz,1H),7.91(d,J=8.7Hz,2H),7.57(d,J=8.7Hz,2H),7.50(d,J=8.5Hz,1H),3.63(d,J=5.6Hz,2H),1.18(s,6H);MS(ESI)m/z:413[M+H]+
[实施例74]3-((6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)(乙基)氨基)-2,2-二甲基丙酸
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:38%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.70(br s,1H),9.36(br s,2H),9.21(br s,2H),8.60(d,J=1.8Hz,1H),8.03(dd,J=1.8,8.5Hz,1H),7.92(d,J=8.6Hz,2H),7.60-7.55(m,3H),3.82(s,2H),3.60-3.53(m,2H),1.24-1.18(m,9H);MS(ESI)m/z:441[M+H]+
[实施例75]3-((6-((4-甲脒基-2-氟苯氧基)羰基)苯并[d]噻唑-2-基)(乙基)氨基)-2,2-二甲基丙酸
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:41%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.71(br s,1H),9.43(br s,2H),9.22(br s,2H),8.63(d,J=1.8Hz,1H),8.04(dd,J=1.8,8.6Hz,1H),7.97-7.92(m,1H),7.80-7.73(m,2H),7.58(d,J=8.5Hz,1H),3.83(s,2H),3.60-3.52(m,2H),1.24-1.18(m,9H);MS(ESI)m/z:459[M+H]+
[实施例76]4-((6-((4-甲脒基-2-氟苯氧基)羰基)苯并[d]噻唑-2-基)(甲基)氨基)丁酸
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:30%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.19(br s,1H),9.43(br s,2H),9.22(br s,2H),8.63(d,J=1.8Hz,1H),8.03(dd,J=1.9,8.5Hz,1H),7.96-7.92(m,1H),7.80-7.73(m,2H),7.56(d,J=8.5Hz,1H),3.66-3.58(m,2H),3.19(s,3H),2.31(t,J=7.3Hz,2H),1.90(p,J=7.2,14.4Hz,2H);MS(ESI)m/z:431[M+H]+
[实施例77]3-((6-((4-甲脒基-2-氟苯氧基)羰基)苯并[d]噻唑-2-基)(甲基)氨基)丙酸
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:34%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.47(br s,1H),9.43(br s,2H),9.23(br s,2H),8.65(d,J=1.8Hz,1H),8.04(dd,J=1.9,8.5Hz,1H),7.96-7.92(m,1H),7.80-7.73(m,2H),7.59(d,J=8.5Hz,1H),3.86-3.79(m,2H),3.20(s,3H),2.69(t,J=7.2Hz,2H);MS(ESI)m/z:417[M+H]+
[实施例78]2-(4-(甲氧基羰基哌啶-1-基)苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:53%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ11.30(br s,1H),10.93(br s,2H),8.61(d,J=1.8Hz,1H),8.04(dd,J=1.4,8.5Hz,1H),7.96(dd,J=2.0,11.9Hz,1H),7.76(d,J=7.7Hz,1H),7.54(d,J=8.5Hz,1H),7.16(t,J=8.6Hz,1H),4.04(d,J=12.8Hz,2H),3.63(s,3H),3.36-3.33(m,2H),2.78-2.71(m,1H),2.02-1.98(m,2H),1.70-1.60(m,2H);MS(ESI)m/z:457[M+H]+
[实施例79]1-(6-((4-甲脒基-2-氟苯氧基)羰基)苯并[d]噻唑-2-基)哌啶-4-甲酸
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:33%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ11.29(br s,1H),10.97(br s,2H),8.61(d,J=1.7Hz,1H),8.04(d,J=8.6Hz,1H),7.83(d,J=1.8Hz,1H),7.81-7.76(m,1H),7.54(d,J=8.5Hz,1H),7.14(t,J=8.6Hz,1H),4.04(d,J=12.1Hz,2H),3.38-3.32(m,2H),2.64-2.58(m,1H),2.00-1.96(m,2H),1.68-1.58(m,2H);MS(ESI)m/z:443[M+H]+
[实施例80]2-(4-(苯基氨甲酰基)哌啶-1-基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:70%)
1H NMR(400MHz,三氟乙酸盐,甲醇-d4)δ8.43(s,1H),8.04(d,J=8.6Hz,1H),7.82(d,J=8.6Hz,2H),7.47-7.42(m,5H),7.22(t,,J=7.9Hz,2H),7.00(t,J=7.4Hz,1H),4.24-4.14(m,2H),3.33-3.23(m,2H),2.70-2.60(m,1H),1.99-1.88(m,2H),1.89-1.75(m,2H);MS(ESI)m/z:500[M+H]+
[实施例81]2-(4-(苯基氨甲酰基)哌啶-1-基)苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:8%)
1H NMR(400MHz,三氟乙酸盐,甲醇-d4)δ8.36(s,1H),7.94(d,J=8.6Hz,1H),7.73(d,J=9.0Hz,1H),7.61(d,J=8.6Hz,1H),7.42-7.47(m,3H),7.20(t,J=7.6Hz,2H),7.10(t,J=6.4Hz,1H),6.99(t,J=7.4Hz,1H),4.20(m,2H),3.30(m,2H),2.67(m,1H),1.94(m,2H),1.84(m,2H);MS(ESI)m/z:518[M+H]+
[实施例82]2-(4-苯甲酰胺基哌啶-1-基)苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:29%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.40(br,2H),9.14(br,2H),8.65(d,1.8Hz,1H),8.36(d,J=7.7Hz,1H),8.07-8.04(m,1H),7.96-7.93(m,1H),7.86-7.84(m,2H),7.80-7.74(m,2H),7.59(d,8.56Hz,1H),7.55-7.51(m,1H),7.48-7.44(m,2H),4.18-4.14(m,3H),3.46-3.40(m,2H),2.01-1.98(m,2H),1.73-1.63(m,2H);MS(ESI)m/z:518[M+H]+
[实施例83]2-(4-苯甲酰胺基哌啶-1-基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:4%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.35(s,2H),9.06(s,2H),8.63-8.63(d,1H),8.36-8.34(s,J=7.7Hz,1H),8.06-8.04(d,J=8Hz,1H),7.93-7.91(d,J=8.6Hz,2H),7.86-7.84(d,J=7.2Hz,2H),7.59-7.57(d,J=8.6Hz,3H),7.53-7.51(d,J=7.2Hz,1H),7.48-7.44(t,2H),4.15-4.13(d,3H),3.45-3.39(t,2H),2.00-1.97(d,J=12Hz,2H),1.73-1.63(m,2H);MS(ESI)m/z:500[M+H]+
[实施例84]2-(乙基(3-甲氧基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:50%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.42(br s,2H),9.20(br s,2H),8.64(d,J=1.8Hz,1H),8.04(dd,J=1.8,8.5Hz,1H),7.96-7.91(m,1H),7.80-7.73(m,2H),7.58(d,J=8.6Hz,1H),3.84(t,J=6.9Hz,2H),3.62(s,3H),3.62-3.54(m,2H),2.79(t,J=7.1Hz,2H),2.23(t,J=7.1Hz,3H);MS(ESI)m/z:445[M+H]+
[实施例85]3-((6-((4-甲脒基-2-氟苯氧基)羰基)苯并[d]噻唑-2-基)(乙基)氨基)丙酸
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:64%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.43(br s,2H),9.33(br s,2H),8.63(s,1H),8.07-8.01(m,1H),7.97-7.91(m,1H),7.80-7.73(m,2H),7.58(d,J=8.5Hz,1H),3.81-3.77(m,2H),3.63-3.58(m,2H),2.71(t,J=7.1Hz,2H),1.24(t,J=7.0Hz,3H);MS(ESI)m/z:431[M+H]+
[实施例86]3-((6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)(甲基)氨基)-2,2-二甲基丙酸
以与[实施例56]中相同的方式从[制备例3]中获得的化合物2-溴苯并[d]噻唑-6-甲酸叔丁酯进行反应,得到标题化合物。(产率:37%)
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.68(br s,1H),9.36(br s,2H),9.24(br s,2H),8.62(d,J=1.7Hz,1H),8.04(dd,J=1.8,8.5Hz,1H),7.92(d,J=8.6Hz,2H),7.60-7.55(m,3H),3.85(s,2H),3.18(s,3H),1.19(s,6H);MS(ESI)m/z:427[M+H]+
[实施例87](Z)-3-((6-((4-甲脒基-2-氟苯氧基)羰基)-3-乙基苯并[d]噻唑-2(3H)-亚基)氨基)-2,2-二甲基丙酸
步骤1.(Z)-3-乙基-2-((3-甲氧基-2,2-二甲基-3-氧代丙基)亚氨基)-2,3-二氢
苯并[d]噻唑-6-甲酸叔丁酯
将在[实施例56]的步骤2中获得的4.67g(12.82mmol)的化合物2-((3-甲氧基-2,2-二甲基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸叔丁酯溶解在26mL的二甲基甲酰胺中后,向其中加入8.35g(25.60mmol)的碳酸铯和1.55ml(19.23mmol)的碘乙烷,然后在90℃下搅拌16小时。将反应混合物冷却至室温,然后用乙酸乙酯和盐水萃取,并且合并有机层。合并的有机层经硫酸钠干燥,减压浓缩,并通过MPLC纯化,得到2.10g(41%)的淡黄色固体状目标化合物。
MS(ESI)m/z:393[M+H]+
步骤2.(Z)-3-乙基-2-((3-甲氧基-2,2-二甲基-3-氧代丙基)亚氨基)-2,3-二氢
苯并[d]噻唑-6-甲酸
将在步骤1中获得的2.10g(5.36mmol)的化合物(Z)-3-乙基-2-((3-甲氧基-2,2-二甲基-3-氧代丙基)亚氨基)-2,3-二氢苯并[d]噻唑-6-甲酸叔丁酯溶解在25mL二氯甲烷中后,向其中加入6ml(78mmol)的三氟乙酸,然后在室温下搅拌1小时。将反应混合物减压浓缩,得到1.80g(定量)的黄色液体状目标化合物,而无需纯化步骤。
MS(ESI)m/z:337[M+H]+
步骤3.(Z)-3-乙基-2-((3-甲氧基-2,2-二甲基-3-氧代丙基)亚氨基)-2,3-二氢
苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯
将在步骤2中获得的1.80g(5.36mmol)的化合物(Z)-3-乙基-2-((3-甲氧基-2,2-二甲基-3-氧代丙基)亚氨基)-2,3-二氢苯并[d]噻唑-6-甲酸溶解在18mL吡啶中后,向其中加入1.12g(5.89mmol)的3-氟-4-羟基苯甲脒盐酸盐和1.85g(9.64mmol)的EDCI,并在50℃下搅拌16小时。减压浓缩反应混合物,并通过制备型HPLC纯化,得到白色固体状目标化合物。回收反应后残留的起始原料,并重复上述反应程序,得到总产率为1.28g(51%)的所需化合物。
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ9.42(br s,2H),9.18(br s,2H),8.39(s,1H),8.07(d,2H J=8.56Hz),7.94(d,2H J=10.16Hz),7.76(s,2H),7.36(d,1H J=8.64Hz),4.06-4.01(m,2H),3.58(s,3H),3.21(s,2H),1.21(s,6H)1.12-1.17(m,3H);MS(ESI)m/z:473[M+H]+
[实施例88](Z)-3-((6-((4-甲脒基-2-氟苯氧基)羰基)-3-乙基苯并[d]噻唑-2(3H)-亚基)氨基)-2,2-二甲基丙酸
向[实施例87的步骤3]中获得的1.284g(2.72mmol)的化合物(Z)-3-乙基-2-((3-甲氧基-2,2-二甲基-3-氧代丙基)亚氨基)-2,3-二氢苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯中加入4mL HCL(4N的H2O溶液)和4mL HCl(4N的二烷溶液),并且将混合物在室温下搅拌4小时,然后在70℃下搅拌1小时。减压浓缩反应混合物并通过制备型HPLC纯化,得到0.66g(53%)的白色固体状目标化合物。
1H NMR(400MHz,三氟乙酸盐,DMSO-d6)δ12.19(br s,1H),9.43(br s,2H),9.30(br s,2H),8.41(s,1H),8.0(d,2H J=6.8Hz),7.93(d,2H J=10.12Hz),7.76(s,2H),7.39(d,1H J=8.68Hz),4.08-4.06(m,2H),3.22(s,2H),1.19(s,6H)1.18-1.15(m,3H);MS(ESI)m/z:459[M+H]+
[实验例]证实本发明化合物的肠肽酶抑制活性
进行以下测试以测量本发明化合物的肠肽酶抑制活性。
肠肽酶抑制测定
使用纯化的重组人肠肽酶和底物乙酰基-Asp-Asp-Asp-Asp-Lys-AFC(BioVision)测量了合成的肠肽酶抑制剂的抑制活性。将用缓冲液(20mM Tris,50mM NaCl,pH 7.5)稀释的7.2ng/mL肠肽酶、30μM乙酰基-Asp-Asp-Asp-Asp-Lys-AFC、几种浓度的肠肽酶抑制剂(1%DMSO浓度)分配在96孔板(Costar)中,以使最终体积为100μL,然后使酶反应在30℃下进行1小时。同时,将1%DMSO、底物和肠肽酶代替所述化合物分配到阳性对照孔上,并将1%DMSO和底物分配到阴性对照孔上。在荧光光谱仪中使用380nm的激发波长和500nm的发射波长开始酶反应,然后测量20至60分钟之间的荧光增加速率(毫单位/分钟)。
将在每种浓度下稀释的抑制剂所降低的荧光测量值转换为阳性对照组(100%反应性)和阴性对照组(0%反应性)的相对值%,并用于计算IC50值。IC50是将酶活性抑制50%的抑制剂浓度,并且使用PRISM(GraphPad)计算得出。Ki值是使用Cheng-Prusoff方程从IC50值计算得出的。
【表1】肠肽酶抑制活性
实施例 | 肠肽酶(Ki,nM) | 实施例 | 肠肽酶(Ki,nM) |
1 | 0.68 | 31 | 17 |
2 | 4.9 | 32 | 18 |
3 | 17.0 | 33 | 8.2 |
4 | 0.92 | 34 | 8.9 |
5 | 510.0 | 35 | 9.7 |
6 | 220.0 | 36 | 9.7 |
7 | 0.6 | 37 | 1.8 |
8 | 28.0 | 38 | 2.6 |
9 | 28.0 | 39 | 2.5 |
10 | 11.0 | 40 | 9.7 |
11 | 21.0 | 41 | 1.8 |
12 | 9.7 | 42 | 1.0 |
13 | 4.8 | 43 | 1.7 |
14 | 5.1 | 44 | 1.6 |
15 | 5.7 | 45 | 1.5 |
16 | 19.0 | 46 | 40 |
17 | 5.4 | 47 | 0.52 |
18 | 8.9 | 48 | 37 |
19 | 4.8 | 49 | 0.57 |
20 | 2.5 | 50 | 14 |
21 | 3.0 | 51 | 9.7 |
22 | 0.57 | 52 | 82 |
23 | 53 | 12 | |
24 | 8.9 | 54 | 2.5 |
25 | 4.7 | 55 | 8.2 |
26 | 8.2 | ||
27 | 12.0 | ||
28 | 6.5 | ||
29 | 18.0 | ||
30 | 18.0 |
(ND:已测量但未检测到值,空白:未测量)
【表2】肠肽酶抑制活性
实施例 | 肠肽酶(Ki,nM) | 实施例 | 肠肽酶(Ki,nM) |
56 | 0.59 | 76 | 0.57 |
57 | 13.0 | 77 | 0.57 |
58 | 7.4 | 78 | |
59 | 14.0 | 79 | |
60 | 10.0 | 80 | 23.0 |
61 | 10.0 | 81 | |
62 | 4.3 | 82 | 1.9 |
63 | 13.0 | 83 | 9.7 |
64 | 6.4 | 84 | 2.2 |
65 | 5.7 | 85 | 0.55 |
66 | 4.8 | 86 | 10.0 |
67 | 19.0 | 87 | 4.0 |
68 | 06.0 | 88 | 0.16 |
69 | 21.0 | ||
70 | 3.5 | ||
71 | 1.1 | ||
72 | 1.3 | ||
73 | 0.89 | ||
74 | 8.9 | ||
75 | 0.7 |
(ND:已测量但未检测到值,空白:未测量)
从表1和表2可以看出,已证实本发明的化合物表现出TMPRSS15抑制活性。
因而,证实了本发明的化合物表现出优异的肠肽酶抑制活性。因此,具有肠肽酶抑制活性的本发明的化合物降低了蛋白质、脂质和碳水化合物的消化能力,同时具有较少的副作用如脂肪粪便,并且可有效作为用于各种代谢性疾病如肥胖症、糖尿病或高脂血症的治疗性或预防性药物。
Claims (19)
2.根据权利要求1所述的化合物、其光学异构体或其药学上可接受的盐,
其中所述Het是具有一个或两个选自N和S的杂原子的5元至9元单杂环或二杂环基团。
3.根据权利要求1所述的化合物、其光学异构体或其药学上可接受的盐,
其中所述Het是噻唑或苯并噻唑。
5.根据权利要求4所述的化合物、其光学异构体或其药学上可接受的盐,
其中所述R1和R6各自独立地是H或者未取代或取代的C1-C6烷基,或者R1和R6与它们所连接的氮原子一起形成未取代或取代的5元或6元杂环,
R3和R4各自独立地是H,F,Cl,Br,I或者未取代或取代的C1-C6烷基;并且
R5是脒,胍,酰胺,或者未取代或取代的C1-C4烷基胺。
6.根据权利要求4所述的化合物、其光学异构体或其药学上可接受的盐,
其中所述R1和R6是H或C1-C3烷基,或者R1和R2与它们所连接的氮原子一起形成吡咯烷基或哌啶基;
R3和R4是H,F或者未取代或取代的C1-C3烷基;
R5是脒,胍,酰胺,或者未取代或取代的C1-C4烷基胺;
所述取代基是选自以下的一者至三者:-(CRa 2)nRb、-C(O)ORa、-(CH2)n-C(O)ORa、-(CH2)n-C(O)NRaRb、-C(O)NRaRb和-NRaC(O)Rb,其中Ra和Rb各自独立地是氢、卤素、-C(O)ORc、-C(O)NRcRd、C1-C4烷基或苯基,n是1至4的整数,所述C1-C4烷基或苯基是未取代的或被一个或两个选自-C(O)ORc和C1-C4烷氧基的基团取代,并且Rc是氢、C1-C4烷基或苄基。
7.根据权利要求4所述的化合物、其光学异构体或其药学上可接受的盐,
其中所述A1、A2、A3、A4和A5各自独立地是C或N。
8.根据权利要求1所述的化合物、其光学异构体或其药学上可接受的盐,
其中所述化学式1的化合物是化学式1b的化合物:
[化学式1b]
其中,
虚线表示存在或不存在键,
A1、A2、A3、A4、A5、A6、A7和A8各自独立地是C或N;
Q是O或N;
R1和R6各自独立地是未取代或取代的烷基,或者R1和R6与它们所连接的氮原子一起形成未取代或取代的5元至7元杂环;
R2是未取代或取代的烷基;
R3和R4各自独立地是H,卤素或者未取代或取代的烷基;并且
R5是脒,胍,酰胺,或者未取代或取代的烷基胺。
根据权利要求1所述的化合物、其光学异构体或其药学上可接受的盐,
其中所述R1和R6各自独立地是H或者未取代或取代的C1-C6烷基,或者R1和R6与它们所连接的氮原子一起形成未取代或取代的6元杂环;
R2是H或者未取代或取代的C1-C6烷基;
R3和R4各自独立地是H,F,Cl,Br,I,或者未取代或取代的C1-C6烷基;并且
R5是脒,胍,酰胺,或者未取代或取代的C1-C4烷基胺。
9.根据权利要求8所述的化合物、其光学异构体或其药学上可接受的盐,
其中所述R1和R6各自独立地是H或者未取代或取代的C1-C3烷基,或者所述R1和R6与它们所连接的氮原子一起形成哌啶基;
R2是H或者未取代或取代的C1-C3烷基;
R3和R4各自独立地是H,F,或者未取代或取代的C1-C3烷基;并且
R5是脒,胍,酰胺,或者未取代或取代的C1-C4烷基胺;并且
所述取代基是选自以下的一者至三者:C1-C4烷基、-C(O)OR'、-C(O)NR'R"或-NR'C(O)R"(其中R'和R"各自独立地是氢、卤素、C1-C4烷基或苯基)。
10.根据权利要求8所述的化合物、其光学异构体或其药学上可接受的盐,
其中A1、A2、A3、A4、A5、A6、A7和A8各自独立地是C。
13.根据权利要求1所述的化合物、其光学异构体或其药学上可接受的盐,所述化合物选自以下化合物1]至88]:
1]3-((5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酸;
2]1-(5-((4-甲脒基苯氧基)羰基)噻唑-2-基)哌啶-4-甲酸;
3]2-(4-(甲氧基羰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基苯酯;
4]2-(4-(甲氧基羰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
5]2-(4-(甲氧基羰基)哌啶-1-基)噻唑-5-甲酸4-胍基苯酯;
6]1-(5-((4-胍基苯氧基)羰基)噻唑-2-基)哌啶-4-甲酸;
7]1-(5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)哌啶-4-甲酸;
8]2-((3-甲氧基-3-氧代丙基)(甲基)氨基)噻唑-5-甲酸4-甲脒基苯酯;
9]3-((5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)(甲基)氨基)丙酸;
10]2-((3-甲氧基-3-氧代丙基)氨基)噻唑-5-甲酸4-甲脒基苯酯;
11]2-((4-甲氧基-4-氧代丁基)(甲基)氨基)噻唑-5-甲酸4-甲脒基苯酯;
12]2-(乙基(3-甲氧基-3-氧代丙基)氨基)噻唑-5-甲酸4-甲脒基苯酯;
13]3-((5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)氨基)丙酸;
14]3-((5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酸;
15]4-((5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)(甲基)氨基)丁酸;
16]2-(3-(甲氧基羰基)吡咯烷-1-基)噻唑-5-甲酸4-甲脒基苯酯;
17]1-(5-((4-甲脒基苯氧基)羰基)噻唑-2-基)吡咯烷-3-甲酸;
18]2-((3-甲氧基-2,2-二甲基-3-氧代丙基)(甲基)氨基)噻唑-5-甲酸4-甲脒基苯酯;
19]3-((5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)(甲基)氨基)-2,2-二甲基丙酸;
20]2-(乙基(3-甲氧基-3-氧代丙基)氨基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
21]2-((4-甲氧基-4-氧代丁基)(甲基)氨基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
22]4-((5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)(甲基)氨基)丁酸;
23]1-(5-((4-胍基苯基)氨甲酰基)噻唑-2-基)哌啶-4-甲酸甲酯;
24]2-((3-甲氧基-2,2-二甲基-3-氧代丙基)氨基)噻唑-5-甲酸4-甲脒基苯酯;
25](1-(5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)哌啶-4-羰基)-L-天冬氨酸;
26](1-(5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)哌啶-4-羰基)-L-天冬氨酸酯;
27]2-(4-(苯基氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基苯酯;
28]2-(4-苯甲酰胺基哌啶-1-基)噻唑-5-甲酸4-甲脒基苯酯;
29]2-(4-((2-甲氧基-2-氧代乙基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基苯酯;
30]2-(4-((3-甲氧基-3-氧代丙基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基苯酯;
31]2-(4-((4-甲氧基-4-氧代丁基)(甲基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基苯酯;
32]2-(4-((3-甲氧基-2,2-二甲基-3-氧代丙基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基苯酯;
33](1-(5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)哌啶-4-羰基)甘氨酸;
34]3-(1-(5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)哌啶-4-甲酰胺基)丙酸;
35]4-(1-(5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)-N-甲基哌啶-4-甲酰胺基)丁酸;
36]3-(1-(5-((4-甲脒基)苯氧基)羰基)噻唑-2-基)哌啶-4-甲酰胺基)-2,2-二甲基丙酸;
37]2-(4-((2-甲氧基-2-氧代乙基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
38]2-(4-((3-甲氧基-3-氧代丙基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
39]2-(4-((3-甲氧基-2,2-二甲基-3-氧代丙基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
40]2-(4-((3-甲氧基-2,2-二甲基-3-氧代丙基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
41]2-(4-((4-甲氧基-4-氧代丁基)(甲基)氨甲酰基)哌啶-1-基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
42](1-(5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)哌啶-4-羰基)甘氨酸;
43]3-(1-(5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)哌啶-4-甲酰胺基)丙酸;
44]3-(1-(5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)哌啶-4-甲酰胺基)-2,2-二甲基丙酸;
45]3-(1-(5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)哌啶-4-甲酰胺基)-2,2-二甲基丙酸;
46](3-((5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酰基)-L-天冬氨酸二叔丁酯;
47](3-((5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酰基)-L-天冬氨酸;
48](3-((5-((4-甲脒基)-2-氟苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酰基)-D-谷氨酸二叔丁酯;
49](3-((5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酰基)-D-谷氨酸;
50]2-(乙基(3-((4-(甲氧基羰基)苯基)氨基)-3-氧代丙基)氨基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
51]2-(乙基(3-((3-(甲氧基羰基)苯基)氨基)-3-氧代丙基)氨基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
52]2-((3-((4-(叔丁氧羰基)苯基)氨基)-3-氧代丙基)(乙基)氨基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
53]2-((叔丁氧羰基)苯基)氨基)-3-氧代丙基)(乙基)氨基)噻唑-5-甲酸4-甲脒基-2-氟苯酯;
54]3-(3-((5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酰胺基)苯甲酸;
55]4-(3-((5-((4-甲脒基-2-氟苯氧基)羰基)噻唑-2-基)(乙基)氨基)丙酰胺基)苯甲酸;
56]3-((6-((4-甲脒基-2-氟苯氧基)羰基)苯并[d]噻唑-2-基)氨基)-2,2-二甲基丙酸;
57]2-(4-(甲氧基羰基)哌啶-1-基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯;
58]1-(6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)哌啶-4-甲酸;
59]2-((3-甲氧基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯;
60]2-((3-甲氧基-3-氧代丙基)(甲基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯;
61]2-(乙基(3-甲氧基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯;
62]3-((6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)(甲基)氨基)丙酸;
63]2-((4-甲氧基-4-氧代丁基)(甲基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯;
64]4-((6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)(甲基)氨基)丁酸;
65]3-((6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)氨基)丙酸;
66]3-((6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)(乙基)氨基)丙酸;
67]2-((3-甲氧基-2,2-二甲基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯;
68]2-((3-甲氧基-2,2-二甲基-3-氧代丙基)(甲基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯;
69]2-(乙基(3-甲氧基-2,2-二甲基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯;
70]2-(乙基(3-甲氧基-2,2-二甲基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯;
71]2-((4-甲氧基-4-氧代丁基)(甲基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯;
72]2-((3-甲氧基-3-氧代丙基)(甲基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯;
73]3-((6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)氨基)-2,2-二甲基丙酸;
74]3-((6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)(乙基)氨基)-2,2-二甲基丙酸;
75]3-((6-((4-甲脒基-2-氟苯氧基)羰基)苯并[d]噻唑-2-基)(乙基)氨基)-2,2-二甲基丙酸;
76]4-((6-((4-甲脒基-2-氟苯氧基)羰基)苯并[d]噻唑-2-基)(甲基)氨基)丁酸;
77]3-((6-((4-甲脒基-2-氟苯氧基)羰基)苯并[d]噻唑-2-基)(甲基)氨基)丙酸;
78]2-(4-(甲氧基羰基哌啶-1-基)苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯;
79]1-(6-((4-甲脒基-2-氟苯氧基)羰基)苯并[d]噻唑-2-基)哌啶-4-甲酸;
80]2-(4-(苯基氨甲酰基)哌啶-1-基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯;
81]2-(4-(苯基氨甲酰基)哌啶-1-基)苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯;
82]2-(4-苯甲酰胺基哌啶-1-基)苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯;
83]2-(4-苯甲酰胺基哌啶-1-基)苯并[d]噻唑-6-甲酸4-甲脒基苯酯;
84]2-(乙基(3-甲氧基-3-氧代丙基)氨基)苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯;
85]3-((6-((4-甲脒基-2-氟苯氧基)羰基)苯并[d]噻唑-2-基)(乙基)氨基)丙酸;
86]3-((6-((4-甲脒基苯氧基)羰基)苯并[d]噻唑-2-基)(甲基)氨基)-2,2-二甲基丙酸;
87](Z)-3-((6-((4-甲脒基-2-氟苯氧基)羰基)-3-乙基苯并[d]噻唑-2(3H)-亚基)氨基)-2,2-二甲基丙酸;和
88](Z)-3-乙基-2-((3-甲氧基-2,2-二甲基-3-氧代丙基)亚氨基)-2,3-二氢苯并[d]噻唑-6-甲酸4-甲脒基-2-氟苯酯。
14.一种用于抑制肠肽酶的药物组合物,所述药物组合物包含根据权利要求1至13中任一项所述的化合物、其光学异构体或其药学上可接受的盐。
15.一种用于预防或治疗代谢性疾病的药物组合物,所述药物组合物包含根据权利要求1至13中任一项所述的化合物、其光学异构体或其药学上可接受的盐。
16.根据权利要求15所述的用于预防或治疗代谢性疾病的药物组合物,其中所述代谢性疾病是肥胖症、糖尿病或高脂血症。
17.一种用于抑制肠肽酶的方法,所述方法包括施用根据权利要求1至13中任一项所述的化合物、其光学异构体或其药学上可接受的盐。
18.一种用于预防或治疗代谢性疾病的方法,所述方法包括施用根据权利要求1至13中任一项所述的化合物、其光学异构体或其药学上可接受的盐。
19.根据权利要求18所述的用于预防或治疗代谢性疾病的方法,其中所述代谢性疾病是肥胖症、糖尿病或高脂血症。
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