CN114853814A - Plasmin inhibitor, preparation method and application thereof - Google Patents
Plasmin inhibitor, preparation method and application thereof Download PDFInfo
- Publication number
- CN114853814A CN114853814A CN202210060581.2A CN202210060581A CN114853814A CN 114853814 A CN114853814 A CN 114853814A CN 202210060581 A CN202210060581 A CN 202210060581A CN 114853814 A CN114853814 A CN 114853814A
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- Prior art keywords
- substituted
- unsubstituted
- alkyl
- tert
- preparation
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- 238000002360 preparation method Methods 0.000 title abstract description 85
- 229940122791 Plasmin inhibitor Drugs 0.000 title abstract description 5
- 239000002806 plasmin inhibitor Substances 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 110
- 239000000203 mixture Substances 0.000 claims abstract description 19
- -1 amino, hydroxy Chemical group 0.000 claims description 160
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 25
- 150000002431 hydrogen Chemical class 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 239000000651 prodrug Substances 0.000 claims description 13
- 229940002612 prodrug Drugs 0.000 claims description 13
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000003386 piperidinyl group Chemical group 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 150000004677 hydrates Chemical class 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 208000032843 Hemorrhage Diseases 0.000 claims description 9
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 8
- 125000001931 aliphatic group Chemical group 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000002757 morpholinyl group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 6
- 230000023555 blood coagulation Effects 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 4
- 229910003827 NRaRb Inorganic materials 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
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- 125000003566 oxetanyl group Chemical group 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
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- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 3
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- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 3
- 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 3
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 3
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- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
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- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 238000001356 surgical procedure Methods 0.000 claims description 3
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
- 230000002159 abnormal effect Effects 0.000 claims description 2
- 125000000131 cyclopropyloxy group Chemical group C1(CC1)O* 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000005958 tetrahydrothienyl group Chemical group 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
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- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 5
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 78
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- 239000007858 starting material Substances 0.000 description 55
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 40
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
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- 238000006243 chemical reaction Methods 0.000 description 36
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- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 24
- 230000002829 reductive effect Effects 0.000 description 24
- 238000004440 column chromatography Methods 0.000 description 23
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
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- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 15
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 14
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 13
- 229910052786 argon Inorganic materials 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 238000001514 detection method Methods 0.000 description 11
- 210000002381 plasma Anatomy 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- 125000006413 ring segment Chemical group 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 230000015556 catabolic process Effects 0.000 description 8
- 238000006731 degradation reaction Methods 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 8
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 8
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- 102000009123 Fibrin Human genes 0.000 description 7
- 108010073385 Fibrin Proteins 0.000 description 7
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 7
- 102000013566 Plasminogen Human genes 0.000 description 7
- 108010051456 Plasminogen Proteins 0.000 description 7
- 229950003499 fibrin Drugs 0.000 description 7
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 7
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 7
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 6
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 6
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- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
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- 230000005764 inhibitory process Effects 0.000 description 6
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- 125000006173 tetrahydropyranylmethyl group Chemical group 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
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- 229960000187 tissue plasminogen activator Drugs 0.000 description 5
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- WGWCJTNWUFFGFH-UHFFFAOYSA-N 3-[tert-butyl(dimethyl)silyl]oxypropanal Chemical compound CC(C)(C)[Si](C)(C)OCCC=O WGWCJTNWUFFGFH-UHFFFAOYSA-N 0.000 description 1
- DHYHYLGCQVVLOQ-UHFFFAOYSA-N 3-bromoaniline Chemical compound NC1=CC=CC(Br)=C1 DHYHYLGCQVVLOQ-UHFFFAOYSA-N 0.000 description 1
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- 108010039627 Aprotinin Proteins 0.000 description 1
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- 206010012735 Diarrhoea Diseases 0.000 description 1
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- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
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- 102000035195 Peptidases Human genes 0.000 description 1
- 206010051077 Post procedural haemorrhage Diseases 0.000 description 1
- 208000037486 Postoperative Hemorrhage Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- GYDJEQRTZSCIOI-UHFFFAOYSA-N Tranexamic acid Chemical compound NCC1CCC(C(O)=O)CC1 GYDJEQRTZSCIOI-UHFFFAOYSA-N 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
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- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
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- 229960003375 aminomethylbenzoic acid Drugs 0.000 description 1
- QCTBMLYLENLHLA-UHFFFAOYSA-N aminomethylbenzoic acid Chemical compound NCC1=CC=C(C(O)=O)C=C1 QCTBMLYLENLHLA-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical compound [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 description 1
- 229960004484 carbachol Drugs 0.000 description 1
- QJFKYVFGMFPPKM-UHFFFAOYSA-N carbonic acid;4-methylcyclohexan-1-amine Chemical compound OC(O)=O.CC1CCC(N)CC1 QJFKYVFGMFPPKM-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000007675 cardiac surgery Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 230000010102 embolization Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 208000030304 gastrointestinal bleeding Diseases 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
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- 230000003993 interaction Effects 0.000 description 1
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- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 150000002668 lysine derivatives Chemical class 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000002175 menstrual effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000004574 piperidin-2-yl group Chemical group N1C(CCCC1)* 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 230000033885 plasminogen activation Effects 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3834—Aromatic acids (P-C aromatic linkage)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/60—Quinoline or hydrogenated quinoline ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
- C07F9/65522—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
- C07F9/655363—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a six-membered ring
- C07F9/655372—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems
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Abstract
The invention relates to a plasmin inhibitor, a preparation method thereof and application thereof in the field of pharmacy. The invention also provides a method for preparing the compound, a composition containing the compound, application of the compound serving as a plasmin inhibitor and pharmaceutical application of the compound.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a plasmin inhibitor, a preparation method thereof and application thereof in the field of pharmacy.
Background
Plasmin is a proteolytic enzyme that degrades fibrin. When tissue damage causes vascular rupture, a hemostatic mechanism is triggered: vasoconstriction, platelet embolization, initiation of the clotting process, and final formation of stable fibrin. At the same time, the fibrinolytic system is activated due to fibrin deposition, and this system is responsible for fibrin formation and cleavageMaintains balance, and plays a role in maintaining the smoothness of blood vessels and remodeling damaged tissues in the process of repairing damaged blood vessel walls (Tengborn L,
M,Berntorp E.Thromb Res.2015Feb；135(2):231-42)。
the fibrinolytic system includes plasminogen, tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA). Plasminogen binds to lysine residues on the surface of fibrin and is converted to plasmin by an activator (i.e., tPA) released from endothelial cells. Fibrinolysis inhibition can be used to treat bleeding. The use of antifibrinolytics can reduce blood loss in cardiac surgery, trauma, orthopedic surgery, solid organ transplantation, obstetrics and gynecology, neurosurgery and non-surgical diseases (Ng W, JerathA,
m. analesthesol Intensive ther.2015; 47(4):339-50). In the early 1950 s, lysine amino acids were found to inhibit plasminogen activation, but were too weak to be used for the treatment of fibrinolytic hemorrhagic disease. In 1953, Shosuke Okamoto et al showed several thiol and amino carbonic acids to have plasma protein-resistant effects, and found that synthetic derivative of lysine, epsilon-aminocaproic acid (EACA), has a strong inhibitory effect on plasminogen. EACA has been widely used clinically, but requires larger doses in addition to mild gastrointestinal side effects such as nausea. In 1962, 4-amino-methyl-cyclohexane-carbonic acid (AMCHA) was found, which contains two stereoisomers, and further studies showed that its trans form (trans-4-aminomethylcyclohexanecarboxylic acid, i.e. tranexamic acid, TXA) has anti-fibrinolytic capacity, about 10 times higher activity than EACA, and proved to have stronger tolerance (Tengborn L,
M,Berntorp E.Thromb Res.2015 Feb；135(2):231-42)。
tranexamic acid is a synthetic lysine derivative and antifibrinolytic agent that forms reversible complexes with plasminogen. By combining with plasminogen, the interaction between plasminogen and plasmin heavy chain and fibrin lysine residue is blocked, so as to prevent the combination of plasminogen and fibrin surface and further delay fibrinolysis. Tranexamic acid has been approved for the treatment of severe menstrual bleeding and various surgical hemorrhagic diseases, and is currently the most clinically used hemostatic drug. However, a large number of literature reports show that the tranexamic acid is easy to cause gastrointestinal adverse reactions such as nausea, vomiting, diarrhea and dyspepsia after being orally taken, and the dosage of the tranexamic acid is large, so that patients may have epilepsy and other complications after being taken.
Other similar hemostatic drugs, such as aminocaproic acid, have the problems of rapid excretion in human body, weak hemostatic effect, short action duration, more toxic reaction and the like, and can form thrombus when the dosage is excessive, thereby limiting the application to patients with thrombosis tendency or thrombotic vascular disease history and renal insufficiency. The aminomethylbenzoic acid mechanism has 4-5 times stronger action with aminocaproic acid. Has obvious effect on common chronic bleeding, but has no hemostatic effect on wound bleeding and cancer bleeding. In addition, too large an amount may also promote thrombosis. Aprotinin, a commonly used hemostatic drug in heart bypass surgery, was withdrawn from the market by the FDA in 2008 because it can induce renal failure, myocardial infarction, heart failure, and the like.
Other mechanisms of hemostatic drugs, such as carbachol acting on blood vessels, can induce epilepsy after repeated use; the hemostatic thrombin for promoting the blood coagulation process can be only applied to gastrointestinal bleeding or local bleeding.
In view of the clinical limitations of available hemostatic drugs, more or less defects in terms of dosage, clinical indications, etc., and the problems of large dosage, more adverse reactions, easy occurrence of epilepsy and other complications of the existing similar drugs, a new hemostatic drug is needed to be developed to better meet the clinical requirements.
Disclosure of Invention
It is an object of the present invention to overcome the above-mentioned drawbacks of the prior art and to provide a new compound with blood clotting and hemostatic activities.
Specifically, the invention provides compounds shown in the following formula I, and pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof:
wherein X is selected from CH 2 、NR 3 O, S; y is selected from CH and N; in certain specific embodiments, X is NR 3 Y is N;
R 1 selected from hydrogen, NRaRb, hydroxyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic heterocyclic group; wherein Ra and Rb are independently selected from hydrogen, alkyl and halogenated alkyl;
R 2 selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lipoheterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted arylheterocyclyl;
R 3 selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lipoheterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted arylheterocyclyl, - (CH) 2 ) mNRcRd, where m ═ 1,2,3,4, Rc, Rd are each independently selected from hydrogen, alkyl, haloalkyl;
in certain specific embodiments, R is as defined herein 1 Selected from hydrogen, NRaRb, hydroxyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted 6-10 membered aromatic heterocyclic group; wherein Ra and Rb are independently selected from hydrogen, alkyl and halogenated alkyl;
in certain specific embodiments, R is as defined herein 2 Selected from hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl radical, C 1 -C 4 Haloalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted 4-to 8-membered aliphatic heterocyclic group, substituted or unsubstituted 6-to 10-membered aromatic hydrocarbon groupA substituted or unsubstituted 6-10 membered aromatic heterocyclic group;
in certain specific embodiments, R is as defined herein 3 Selected from hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl radical, C 1 -C 4 Haloalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted 4-8 membered aliphatic heterocyclic group, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 6-10 membered aromatic heterocyclic group;
in certain specific embodiments, the alkyl groups of the present invention are selected from methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl; said alkyl group being optionally substituted with one or more groups selected from halogen, amino, hydroxy, cycloalkyl, lipoheterocyclyl;
in certain specific embodiments, the cycloalkyl groups of the present invention are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl;
in certain specific embodiments, the lipoheterocyclyl groups of the present invention are selected from the group consisting of oxetanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, piperidinyl, morpholinyl;
in certain specific embodiments, the aryl groups of the present invention are selected from phenyl, naphthyl;
in certain specific embodiments, the aromatic heterocyclic group of the present invention is selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl, thienyl, oxazolyl, isoxazolyl, 1,2, 4-oxadiazolyl;
in certain specific embodiments, R is as defined herein 1 Selected from the group consisting of hydroxy, said R 2 Selected from hydrogen;
in certain specific embodiments, X is selected from CH 2 、NR 3 O, S, wherein R is 3 Selected from hydrogen, -Q- (R) Q ) n And Q is selected from C 1 -C 4 Alkyl radical, C 3 -C 6 Cycloalkyl, 4-6 membered saturated aliphatic heterocyclic group, said n is 0 or 1, said R Q Selected from methyl, phenyl, tetrahydropyranyl, morpholinyl, piperidinyl, methylPiperidyl, o-chlorophenyl, carboxyl, hydroxyl, dimethylamino and halogen; further, Q is preferably selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropylalkyl, cyclobutylalkyl, cyclopentylalkyl, piperidinyl, tetrahydropyranyl, morpholinyl, cyclopropoxy;
in certain specific embodiments, X is preferably selected from CH 2 、NR 3 O, S, wherein R is 3 Selected from the group consisting of hydrogen, tetrahydropyranyl, tetrahydropyranylmethyl, methyl, ethyl, n-propyl, isopropyl, t-butyl, trifluoromethyl, trifluoroethyl, benzyl, phenethyl, phenyl, piperidinemethyl, methylpiperidinylmethyl, hydroxyethyl, hydroxymethyl, carboxymethyl, carboxyethyl, piperidinyl, methylpiperidinyl, piperidinylmethyl, cyclopropyl, cyclopentyl, cyclobutyl, dimethylaminopropyl, dimethylaminoethyl, epoxypropyl, o-chlorophenylethyl;
more preferably from CH 2 、NR 3 O, S, wherein R is 3 Selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, t-butyl, tetrahydropyranyl, tetrahydropyranylmethyl, trifluoromethyl, trifluoroethyl, benzyl, phenethyl, phenyl, piperidinylmethyl, methylpiperidinylmethyl, hydroxyethyl, hydroxymethyl, carboxymethyl, carboxyethyl, piperidinyl;
further preferably selected from CH 2 、NR 3 O, S, wherein R is 3 Selected from hydrogen, tetrahydropyranyl, tetrahydropyranylmethyl, methyl, ethyl, tert-butyl, carboxymethyl;
particularly preferably O, NR 3 Wherein said R is 3 Selected from hydrogen, tetrahydropyranyl, tetrahydropyranylmethyl.
In certain embodiments, Y of the present invention is preferably selected from N;
in certain embodiments, the tetrahydropyranylmethyl group of the present invention may be tetrahydropyran-4-ylmethyl, tetrahydropyran-2-ylmethyl, tetrahydropyran-3-ylmethyl; in certain embodiments, the tetrahydropyranylmethyl group of the present invention is preferably tetrahydropyran-4 ylmethyl;
in certain embodiments, the tetrahydropyranyl group of the present invention may be tetrahydropyran-4-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl; in certain embodiments, the tetrahydropyranyl group of the present invention is preferably tetrahydropyran-4 yl;
in certain embodiments, the piperidinyl groups of the present invention may be piperidin-4-yl, piperidin-2-yl, piperidin-3-yl; in certain embodiments, the piperidinyl groups of the present invention are preferably piperidin-4-yl;
in certain embodiments, the piperidinylmethyl group of the present invention can be piperidin-4-ylmethyl, piperidin-2-ylmethyl, piperidin-3-ylmethyl; in certain embodiments, the piperidinylmethyl group of the present invention is preferably piperidin-4-ylmethyl;
in certain embodiments, methylpiperidinylmethyl or methylpiperidinyl as described herein means that the methyl group is substituted at any position on the piperidine ring of the piperidinylmethyl or piperidinyl group; in certain embodiments, the methylpiperidinylmethyl or, preferably, N-methylpiperidinylmethyl, the methylpiperidinyl is, preferably, N-methylpiperidinyl;
in certain embodiments, the phenylethyl group of the present invention can be a 2-phenylethyl group, a 1-phenylethyl group; in certain embodiments, the phenethyl groups of the present invention are preferably 1-phenylethyl;
in certain embodiments, the trifluoroethyl group of the present invention can be a 2,2, 2-trifluoroethyl group, a 1,1, 2-trifluoroethyl group; in certain embodiments, the trifluoroethyl group of the present invention is preferably a 2,2, 2-trifluoroethyl group;
in certain specific embodiments, the compounds of the present invention have the following structure:
another object of the present invention is to provide a pharmaceutical composition, comprising at least one of the aforementioned compounds, or pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, and at least one pharmaceutically acceptable excipient.
Another object of the present invention is to provide a use of the aforementioned compound or a pharmaceutically acceptable salt, hydrate, isomer, prodrug and mixture thereof, or a pharmaceutical composition for preparing a medicament. The medicine has blood coagulation and hemostasis therapeutic activities, and can be used for treating abnormal hemorrhage caused by hyperfibrinolysis, surgical operation and postoperative hemorrhage, etc.
It is another object of certain of the present invention to provide a method of treating and/or ameliorating bleeding diseases or conditions comprising administering to a subject in need thereof one or more of the foregoing pharmaceutical compositions or a compound of formula i or a pharmaceutically acceptable salt, hydrate, isomer, prodrug or mixture thereof.
Definition of terms
As used herein, the following terms and phrases are intended to have the following meanings, unless otherwise indicated. A particular term or phrase, unless specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.
The term "pharmaceutically acceptable" as used herein, is intended to cover only those materials that are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, all of which are within the scope of the present invention.
"alkyl" refers to a straight or branched chain-containing saturated aliphatic hydrocarbon group such as: c 1 -C 4 Alkyl refers to saturated aliphatic hydrocarbon groups containing 1 to 4 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and the like, and their various isomers.
"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. For example, "C 3 -C 6 Cycloalkyl "refers to cycloalkyl groups containing 3 to 6 carbon atoms, typically C 3 -C 6 Cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and the like.
"Heterocyclyl" refers to a saturated, monocyclic hydrocarbon substituent in which one or more ring atoms are replaced with a heteroatom selected from N, O, S, the remaining ring atoms being carbon. For example: "3-8 membered heterocycloaliphatic" refers to a saturated cyclic hydrocarbon substituent containing 3-8 ring atoms, one or more of which is substituted with a heteroatom selected from N, O, S, with the remaining ring atoms being carbon. Specific examples include, but are not limited to: oxetanyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl and the like.
"Arylheterocyclyl" refers to an aromatic cyclic substituent in which one or more ring atoms are substituted with a heteroatom selected from N, O, S, the remaining ring atoms being carbon. For example: "5-6 membered aromatic heterocyclic ring" means an aromatic heterocyclic group containing 5 to 6 ring atoms, and specific examples include, but are not limited to, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2, 4-oxadiazolyl.
"Lipocyclyl" means a saturated cyclic substituent in which one or more ring atoms are substituted with a heteroatom selected from N, O, S, for example "3-5 membered heterocyclyl" means a saturated or unsaturated cyclic substituent comprising 3 to 5 ring atoms in which one or more ring atoms are substituted with a heteroatom selected from N, O, S, specific examples including but not limited to: oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, thiazolyl, and the like.
"aryl" refers to aromatic ring groups, e.g., "6-10 membered aryl" refers to aromatic ring groups containing 6 to 10 carbon ring atoms, and examples of aryl moieties include phenyl, naphthyl, and the like.
"optionally" means that the subsequently described event or circumstance may, but need not, occur.
Abbreviations used in this disclosure are known to those skilled in the art and, unless otherwise indicated, are intended to have the meaning reported in the art. For example: DMF means N, N-dimethylformamide; THF means tetrahydrofuran; me is methyl.
Experiments prove that the compound has excellent blood coagulation and hemostasis activities, is obviously superior to the hemostatic drug tranexamic acid which is the most widely clinically applied at present, and has great clinical application value.
Abbreviations in the present invention have the following meanings:
Detailed Description
The following examples, which are intended to be illustrative only and not to be limiting as to the scope of the invention, illustrate the synthesis of the compounds and intermediates of the invention. Except for special descriptions, the raw materials and reagents involved in the invention can be obtained from commercial sources, and the specific sources do not influence the implementation of the technical scheme of the invention.
EXAMPLE 1 preparation of (4-amino-3, 4-dihydro-2H-pyrano [2,3-b ] pyridin-7-yl) phosphonic acid hydrochloride
Step 1: preparation of (3- ((tert-butyldimethylsilyl) oxy) propylidene) -2-methylpropane-2-sulfinamide
3- ((tert-butyldimethylsilyl) oxy) propanal (5.6g) was dissolved in dichloromethane (50mL) and tert-butylsulfinamide (5.4g) and anhydrous copper sulfate (23.8g) were added and stirred at room temperature for 48 h. TLC showed complete consumption of starting material, filtered through celite, and purified by column chromatography to give the title compound (7.35 g).
MS(ESI)m/z(M+H) + ＝292.1.
Step 2: preparation of 3- ((tert-butyldimethylsilyl) oxy) -1- (2, 6-dichloropyridin-3-yl) propyl) -2-methylpropane-2-sulfinamide
2, 6-dichloropyridine (3.74g) was weighed into a 250mL three-necked flask, dissolved in tetrahydrofuran (50mL), replaced with argon three times, cooled to-78 ℃, then lithium diisopropylamide (LDA,12.5mL) was added slowly over 10min, stirred for 30min, and then a solution of N- (3- ((tert-butyldimethylsilyl) oxy) propylene) -2-methylpropane-2-sulfinamide (7.35g) dissolved in 10mL tetrahydrofuran was added slowly dropwise with a syringe, and reacted at-78 ℃ for 2 h. TLC showed complete consumption of starting material, quenched with water, extracted 2 times with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography to afford the title compound (2.6 g).
MS(ESI)m/z(M+H) + ＝438.9.
And step 3: preparation of 1- (2, 6-dichloropyridin-3-yl) -3-hydroxypropyl) -2-methylpropane-2-sulfinamide
3- ((tert-Butyldimethylsilyl) oxy) -1- (2, 6-dichloropyridin-3-yl) propyl) -2-methylpropane-2-sulfinamide (2.6g) was weighed out and dissolved in tetrahydrofuran (30mL) and cooled to 0 ℃.1M tetrabutylammonium fluoride solution (17.8mL) was added and the reaction was carried out at 0 ℃ for 1 h. TLC showed complete consumption of starting material, quenched with water, extracted 2 times with ethyl acetate, washed 2 times with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to afford the title compound (1.6 g).
MS(ESI)m/z(M+H) + ＝325.0.
And 4, step 4: preparation of 7-chloro-3, 4-dihydro-2H-pyrano [2,3-b ] pyridin-4-yl) -2-methylpropan-2-sulfinamide
1- (2, 6-dichloropyridin-3-yl) -3-hydroxypropyl) -2-methylpropane-2-sulfinamide (200mg), potassium tert-butoxide (173mg) in tert-butanol (5mL) was weighed and reacted at 85 ℃ for 2 h. TLC showed complete consumption of starting material, quenched with water, extracted 2 times with dichloromethane, dried over anhydrous sodium sulfate, and purified by column chromatography to afford the title compound (133 mg).
MS(ESI)m/z(M+H) + ＝289.1.
And 5: preparation of diethyl 4- ((-tert-butylsulfinyl) amino) -3, 4-dihydro-2H-pyrano [2,3-b ] pyridin-7-yl) phosphonate
weighing-N- (7-chloro-3, 4-dihydro-2H-pyrano [2,3-b ] pyridin-4-yl) -2-methylpropane-2-sulfinamide (50mg) and dissolving in toluene (2mL), sequentially adding tris (dibenzylideneacetone) dipalladium (16mg), 1,1' -bis (diphenylphosphino) ferrocene (19mg), triethylamine (53mg), diethyl phosphite (48mg) and argon replacing for 3 times, and reacting at 120 ℃ for 2.5H. TLC showed complete consumption of starting material, quenched with water, extracted 2 times with ethyl acetate, dried over anhydrous sodium sulfate, and purified by Prep-TLC to give the title compound (13 mg).
MS(ESI)m/z(M+H) + ＝391.0.
Step 6: preparation of (4-amino-3, 4-dihydro-2H-pyrano [2,3-b ] pyridin-7-yl) phosphonic acid hydrochloride
Diethyl (4- ((tert-butylsulfinyl) amino) -3, 4-dihydro-2H-pyrano [2,3-b ] pyridin-7-yl) phosphonate (13mg) was weighed out, dissolved in concentrated hydrochloric acid (3mL) and reacted at 100 ℃ for 3H. LCMS indicated complete consumption of starting material, concentrated under reduced pressure and purified by pre-HPLC to give the title compound (6.5 mg).
MS(ESI)m/z(M+H) + ＝231.0.
1 H NMR(400MHz,Deuterium Oxide)δ8.34(dd,J＝8.0,3.1Hz,1H),7.70(t,J＝7.3Hz,1H), 4.78(s,1H),4.72(q,J＝3.9,3.2Hz,2H),2.57(ddd,J＝13.4,9.5,5.8Hz,1H),2.39(ddt,J＝15.7, 10.8,4.7Hz,1H).
Example 2 preparation of (4-amino-3, 4-dihydro-2H-benzopyran-7-yl) phosphonic acid hydrochloride
Step 1: preparation of N- (7-bromobenzopyran-4-alkylidene) -2-methylpropane-2-sulfinamide
7-bromo-4-dihydrochromone (2.5g) was dissolved in tetrahydrofuran (4mL), tert-butylsulfinamide (2.0g) and tetraethyl titanate (4mL) were added in sequence, the reaction was allowed to proceed overnight at 85 deg.C, and TLC indicated complete reaction of the starting materials. Quenched by addition of water, filtered, the filter cake washed with ethyl acetate, the filtrate backwashed 2 times with saturated brine (2X 15mL), the organic phases combined, dried over anhydrous sodium sulfate, and purified by column chromatography to give the title compound (2.1 g).
MS(ESI)m/z(M+H) + ＝329.9.
Step 2: preparation of N- (7-bromobenzopyran-4-yl) -2-methylpropane-2-sulfinamide
Weighing N- (7-bromobenzopyran-4-alkylidene) -2-methylpropane-2-sulfinamide (1.4g) and dissolving the N- (7-bromobenzopyran-4-alkylidene) -2-methylpropane-2-sulfinamide in tetrahydrofuran (10mL), slowly adding 1.0M lithium tri-sec-butylborohydride (10.6mL) at the temperature of 0 ℃, slowly heating the system to room temperature for reaction for 3h, and adding ammonium chloride aqueous solution to quench after TLC shows that the raw materials are completely reacted. Extraction with ethyl acetate was performed 2 times, dried over anhydrous sodium sulfate, and purified by column chromatography to give the title compound (738 mg).
MS(ESI)m/z(M+H) + ＝332.0.
And 3, step 3: preparation of diethyl (4- ((tert-butylsulfinyl) amino) chroman-7-yl) phosphonate
Weighing N- (7-bromobenzopyran-4-yl) -2-methylpropane-2-sulfinamide (0.32g) into a microwave reaction, sequentially adding N, N-diisopropylethylamine (0.21mL), diethyl phosphite (0.16mL), palladium acetate (8mg), dppf (21mg), replacing with argon for three times, adding 3mL of anhydrous N, N-dimethylformamide/ethylene glycol dimethyl ether (9:1, v/v), reacting at 115 ℃ for 25min in the microwave reactor, and displaying that the raw materials are completely reacted by TLC. After quenching with water, extraction with ethyl acetate was performed 2 times, dried over anhydrous sodium sulfate, and purified by column chromatography to give the title compound (233 mg).
MS(ESI)m/z(M+H) + ＝390.0.
And 4, step 4: preparation of (4-amino-3, 4-dihydro-2H-benzopyran-7-yl) phosphonic acid hydrochloride
Diethyl (4- ((tert-butylsulfinyl) amino) chroman-7-yl) phosphonate (0.145g) was weighed out and dissolved in 12M concentrated hydrochloric acid (4mL), the system was warmed to 100 ℃ and reacted overnight, LC-MS showed complete reaction of the starting material, and after concentration under reduced pressure, the title compound (39mg) was purified by pre-HPLC.
MS(ESI)m/z(M-H) - ＝227.9.
1 H NMR(400MHz,Deuterium Oxide)δ7.32(dd,J＝7.9,4.4Hz,1H),7.20(dd,J＝12.5,7.9Hz, 1H),7.11(d,J＝14.7Hz,1H),4.52(d,J＝5.6Hz,1H),4.17(tdt,J＝12.1,9.1,3.6Hz,2H),2.29 (ddd,J＝14.4,9.5,4.7Hz,1H),2.12-2.01(m,1H).
EXAMPLE 3 preparation of (4-amino-1, 2,3, 4-tetrahydroquinolin-7-yl) phosphonic acid hydrochloride
Step 1: preparation of methyl 3- ((3-bromophenyl) amino) propionate
M-bromoaniline (9g), methyl acrylate (4.6g) and glacial acetic acid (297. mu.L) were placed in a sealed tube and reacted at 110 ℃ for 12 h. After TLC detection of the material consumption, diluted with ethyl acetate, washed three times with water, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to give the title compound (10 g).
MS(ESI)m/z(M+H) + ＝257.9.
Step 2: preparation of methyl 3- (N- (3-bromophenyl) -4-methylphenylsulfonamido) propionate
Methyl 3- ((3-bromophenyl) amino) propionate (10g) and 4-toluenesulfonyl chloride (8.1g) were dissolved in pyridine (20mL) and reacted at room temperature for 2 h. After the consumption of the starting material by TLC, the reaction mixture was concentrated to dryness, diluted with ethyl acetate, washed once with hydrochloric acid (1N) and saturated brine in this order, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to give the title compound (15.6 g).
MS(ESI)m/z(M+H) + ＝411.9.
And step 3: preparation of 3- (N- (3-bromophenyl) -4-methylphenylsulfonamido) propionic acid
Methyl 3- (N- (3-bromophenyl) -4-methylphenylsulfonamido) propionate (15.6g) was dissolved in dioxane/water/concentrated hydrochloric acid (180/60/20 mL) and reacted at 110 ℃ overnight. After completion of the reaction, the reaction solution was concentrated to dryness, diluted with water, extracted three times with ethyl acetate, then dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by column chromatography to give the title compound (12 g).
MS(ESI)m/z(M+H) + ＝397.9.
And 4, step 4: preparation of 7-bromo-2, 3-dihydroisoquinolin-4-one
3- (N- (3-bromophenyl) -4-methylphenylsulfonamido) propionic acid (12g) was dissolved in anhydrous dichloromethane (100mL), and thionyl chloride (10.8mL) and 2-3 drops of N, N-dimethylformamide were added to conduct a reaction at 40 ℃ under reflux for 2 hours. After the consumption of the starting material was detected by LC-MS, the reaction was concentrated to dryness and diluted with anhydrous dichloromethane (50 mL). Then, aluminum chloride (8g) was dissolved in anhydrous dichloromethane, and the above solution was dropwise added to the aluminum chloride solution in an ice bath. After the addition was complete, the reaction was carried out overnight at room temperature. After TLC detection of the material consumption, the reaction was quenched with ice-water, neutralized with sodium hydroxide solution, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by column chromatography to give the title compound (3.5 g).
MS(ESI)m/z(M+H) + ＝225.9.
And 5: preparation of 7-bromo-4-oxo-3, 4-dihydroquinoline-1 (2H) -carboxylic acid tert-butyl ester
7-bromo-2, 3-dihydroisoquinolin-4-one (762mg) was dissolved in 20mL of anhydrous dichloromethane, and 4-dimethylaminopyridine (830mg) and di-tert-butyl dicarbonate (873mg) were added to the solution in an ice bath to react at room temperature for 4 hours. After TLC detection of the starting material consumption, the reaction was concentrated to dryness and the crude product was purified by column chromatography to give the title compound (795 mg).
MS(ESI)m/z(M+H) + ＝326.0.
Step 6: preparation of tert-butyl 7-bromo-4- ((tert-butylsulfinyl) imino) -3, 4-dihydroquinoline-1 (2H) -carboxylate
7-bromo-4-oxo-3, 4-dihydroquinoline-1 (2H) -carboxylic acid tert-butyl ester (795mg) and tert-butylsulfinamide (443mg) were dissolved in 2-methyltetrahydrofuran (10mL), 1mL of tetraethyl titanate was added, and the mixture was transferred to 80 ℃ and reacted overnight. After TLC detection of the end of consumption of starting material, it was diluted with ethyl acetate, added 1mL of water, filtered, concentrated and the crude product was purified by column chromatography to give the title compound (907 mg).
MS(ESI)m/z(M+H) + ＝429.1
And 7: preparation of tert-butyl 7-bromo-4- (1, 1-dimethylethylenesulfonamido) -3, 4-dihydroquinoline-1 (2H) -carboxylic acid salt
Tert-butyl 7-bromo-4- ((tert-butylsulfinyl) imino) -3, 4-dihydroquinoline-1 (2H) -carboxylic acid salt (907mg) was dissolved in 10mL of anhydrous tetrahydrofuran, and lithium tri-sec-butylborohydride (6.3mL) was slowly added in an ice bath, followed by reaction at room temperature for 2H. After TLC detection of the starting material consumption, the reaction was concentrated to dryness and the crude product was purified by column chromatography to give the title compound (380 mg).
MS(ESI)m/z(M+Na) + ＝453.0.
And 8: preparation of tert-butyl 7- (diethoxyphosphoryl) -4- ((R) -1, 1-dimethylethylenesulfonamido) -3, 4-dihydroquinoline-1 (2H) -carboxylate
Tert-butyl 7-bromo-4- ((R) -1, 1-dimethylethylsulphinylideneamino) -3, 4-dihydroquinoline-1 (2H) -carboxylate (300mg), diethyl phosphite (193mg), tris (dibenzylideneacetone) dipalladium (64mg), 1' -bis (diphenylphosphino) ferrocene (dppf,77.6mg) and triethylamine (141mg) were dissolved in 10mL of toluene, transferred to 125 ℃ under nitrogen and reacted overnight. After TLC detection of complete consumption of starting material, it was diluted with ethyl acetate, filtered and concentrated, and the crude product was purified by pre-TLC to give the title compound (96 mg).
MS(ESI)m/z(M+Na) + ＝511.0.
And step 9: preparation of (4-amino-1, 2,3, 4-tetrahydroquinolin-7-yl) phosphonic acid hydrochloride
Tert-butyl 7- (diethoxyphosphoryl) -4- (1, 1-dimethylethylenesulfonamido) -3, 4-dihydroquinoline-1 (2H) -carboxylic acid salt (96mg) was added to concentrated hydrochloric acid (20mL) and stirred at 100 ℃ overnight. After complete consumption of starting material by LC-MS assay, it was concentrated under reduced pressure and purified by pre-HPLC to give the title compound (22.6 mg).
MS(ESI)m/z(M-16) + ＝211.9.
1 H NMR(400MHz,Deuterium Oxide)δ7.22(dd,J＝7.7,3.8Hz,1H),7.05(td,J＝15.3,13.0,9.6 Hz,2H),4.45(d,J＝4.3Hz,1H),3.24(dt,J＝7.3,3.3Hz,2H),2.16-1.94(m,2H).
EXAMPLE 4 preparation of (5-amino-8- (2-hydroxyethyl) -5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonic acid hydrochloride
Step 1: preparation of 3- ((-tert-butylsulfinyl) amino) -3- (2, 6-dichloropyridin-3-yl) propyl methanesulfonate
N- (1- (2, 6-dichloropyridin-3-yl) -3-hydroxypropyl) -2-methylpropane-2-sulfinamide (200mg) was weighed out and dissolved in dichloromethane (4mL), and placed at 0 ℃ to react with triethylamine (0.17mL) and methanesulfonyl chloride (48. mu.L) sequentially added thereto at 0 ℃ for 1.5 h. TLC showed complete consumption of starting material, quenched with water, extracted 2 times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (240 mg).
MS(ESI)m/z(M+H) + ＝402.9
Step 2: preparation of N- (7-chloro-1- (2-hydroxyethyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridin-4-yl) -2-methylpropane-2-sulfinamide
3- ((tert-Butylsulfinyl) amino) -3- (2, 6-dichloropyridin-3-yl) propyl methanesulfonate (240mg) was weighed, dissolved in N, N-dimethylformamide (5mL), and then ethanolamine (109mg) and triethylamine (0.25mL) were added thereto to react at 70 ℃ for 1.5 hours. TLC indicated complete consumption of starting material, quenched with water, extracted 2 times with ethyl acetate, washed 2 times with saturated brine, dried over anhydrous sodium sulfate, and purified by Prep-TLC to give the title compound (127 mg).
MS(ESI)m/z(M+H) + ＝332.0.
And step 3: preparation of N- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -7-chloro-1, 2,3, 4-tetrahydro-1, 8-naphthyridin-4-yl) -2-methylpropane-2-sulfinamide
N- (7-chloro-1- (2-hydroxyethyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridin-4-yl) -2-methylpropane-2-sulfinamide (110mg, N) was weighed out and dissolved in dichloromethane (4mL) and cooled to 0 ℃. Imidazole (45mg), tert-butyldimethylsilyl chloride (100mg) were added thereto, and the mixture was warmed to room temperature to react for 2 hours. TLC indicated complete consumption of starting material, quenched with water, extracted 3 times with ethyl acetate, dried over anhydrous sodium sulfate, and purified by Prep-TLC to give the title compound (139 mg).
MS(ESI)m/z(M+H) + ＝446.2
And 4, step 4: preparation of diethyl (8- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -5- ((tert-butylsulfinyl) amino) -5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonate
N- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -7-chloro-1, 2,3, 4-tetrahydro-1, 8-naphthyridin-4-yl) -2-methylpropane-2-sulfinamide ((139mg) was weighed out and dissolved in toluene (4mL), tris (dibenzylideneacetone) dipalladium (29mg), 1,1' -bis (diphenylphosphino) ferrocene (35mg), triethylamine (95mg), diethyl phosphite (87mg) were added in this order and replaced with argon 3 times, and reaction was carried out at 120 ℃ for 3 h.TLC, showing complete consumption of the starting material, quenched with water, extracted with ethyl acetate 2 times, dried over anhydrous sodium sulfate, and purified by Prep-TLC to give the title compound (32 mg).
MS(ESI)m/z(M+H) + ＝548.2
And 5: preparation of (5-amino-8- (2-hydroxyethyl) -5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonic acid hydrochloride
Diethyl (8- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -5- ((tert-butylsulfinyl) amino) -5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonate (32mg) was weighed out and dissolved in concentrated hydrochloric acid (4mL) and reacted at 100 ℃ for 3 h. LCMS indicated complete consumption of starting material, concentrated under reduced pressure and purified by pre-HPLC to give the title compound (5.23 mg).
MS(ESI)m/z(M+H) + ＝274.0
1 H NMR(400MHz,Deuterium Oxide)δ7.87(dd,J＝7.4,2.9Hz,1H),7.09(t,J＝8.1Hz,1H), 4.63(t,J＝5.2Hz,1H),3.87(t,J＝4.4Hz,2H),3.75-3.57(m,4H),2.29(ddt,J＝14.2,9.5,4.8Hz, 1H),2.19(dq,J＝15.0,5.4Hz,1H).
EXAMPLE 5 preparation of (5-amino-8-benzyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonic acid hydrochloride
Step 1: preparation of 3- ((tert-butylsulfinyl) amino) -3- (2, 6-dichloropyridin-3-yl) propyl methanesulfonate
N- (1- (2, 6-dichloropyridin-3-yl) -3-hydroxypropyl) -2-methylpropane-2-sulfinamide (250mg) was weighed out and dissolved in dichloromethane (4mL), placed at 0 ℃ and triethylamine (0.21mL) and methanesulfonyl chloride (60. mu.L) were added in that order to react at 0 ℃ for 1.5 h. TLC showed complete consumption of starting material, quenched with water, extracted 2 times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (300 mg).
MS(ESI)m/z(M+H) + ＝402.9
Step 2: preparation of N- (1-benzyl-7-chloro-1, 2,3, 4-tetrahydro-1, 8-naphthyridin-4-yl) -2-methylpropane-2-sulfinamide
3- ((tert-butylsulfinyl) amino) -3- (2, 6-dichloropyridin-3-yl) propyl methanesulfonate (300mg) was weighed, dissolved in N, N-dimethylformamide (6mL), and reacted at 70 ℃ for 2 hours with benzylamine (160mg) and triethylamine (0.30 mL). TLC showed complete consumption of the starting material, quenched with water, extracted 2 times with ethyl acetate, washed 2 times with saturated brine, dried over anhydrous sodium sulfate and purified by column chromatography to give the title compound (356 mg).
MS(ESI)m/z(M+H) + ＝378.0
And step 3: preparation of diethyl (8-benzyl-5- ((tert-butylsulfinyl) amino) -5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonate
N- (1-benzyl-7-chloro-1, 2,3, 4-tetrahydro-1, 8-naphthyridin-4-yl) -2-methylpropane-2-sulfinamide ((180mg) was weighed and dissolved in toluene (2mL), tris (dibenzylideneacetone) dipalladium (44mg), 1,1' -bis (diphenylphosphino) ferrocene (53mg), triethylamine (0.2mL), diethyl phosphite (132mg) was added in this order, and after replacement with argon gas for 3 times, the reaction was carried out at 120 ℃ for 9 h.TLC showing that the starting material was consumed, water was added for quenching, ethyl acetate was extracted 2 times, dried over anhydrous sodium sulfate, and purified by Prep-TLC to obtain the title compound (32 mg).
MS(ESI)m/z(M+H) + ＝480.1
And 4, step 4: preparation of (5-amino-8-benzyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonic acid hydrochloride
Diethyl (8-benzyl-5- ((tert-butylsulfinyl) amino) -5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonate (27mg) was weighed out, dissolved in concentrated hydrochloric acid (4mL) and reacted at 100 ℃ for 3 h. LCMS indicated complete consumption of starting material, concentrated under reduced pressure and purified by pre-HPLC to give the title compound (3.44 mg).
MS(ESI)m/z(M+H) + ＝320.2
1 H NMR(400MHz,Deuterium Oxide)δ7.91(dd,J＝6.9,2.7Hz,1H),7.33(q,J＝7.5,7.0Hz, 5H),7.09(t,J＝8.2Hz,1H),4.95–4.80(m,2H),4.67(s,1H),3.84–3.72(m,2H),2.35(tt,J＝9.5, 4.8Hz,1H),2.23(dq,J＝15.1,5.4Hz,1H).
EXAMPLE 6 preparation of (5-amino-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonic acid hydrochloride
Step 1: preparation of 3- ((-tert-butylsulfinyl) amino) -3- (2, 6-dichloropyridin-3-yl) propyl methanesulfonate
N- (1- (2, 6-dichloropyridin-3-yl) -3-hydroxypropyl) -2-methylpropane-2-sulfinamide (270mg) was weighed out and dissolved in dichloromethane (5mL), and placed at 0 ℃ to react with triethylamine (0.21mL) and methanesulfonyl chloride (64. mu.L) for 1.5h at 0 ℃. TLC showed complete consumption of starting material, quenched with water, extracted 2 times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (330 mg).
MS(ESI)m/z(M+H) + ＝402.9
Step 2: preparation of N- (7-chloro-1- (4-methoxybenzyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridin-4-yl) -2-methylpropane-2-sulfinamide
3- ((tert-butylsulfinyl) amino) -3- (2, 6-dichloropyridin-3-yl) propyl methanesulfonate (330mg) was weighed, dissolved in N, N-dimethylformamide (6mL), and p-methoxybenzylamine (338mg) and triethylamine (0.34mL) were added to react at 70 ℃ for 3 hours. TLC showed complete consumption of the starting material, quenched with water, extracted 2 times with ethyl acetate, washed 2 times with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to give the title compound (336 mg).
MS(ESI)m/z(M+H) + ＝408.1
And step 3: preparation of diethyl (5- ((tert-butylsulfinyl) amino) -8- (4-methoxybenzyl) -5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonate
N- (7-chloro-1- (4-methoxybenzyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridin-4-yl) -2-methylpropane-2-sulfinamide (336mg) was weighed out and dissolved in toluene (6mL), and tris (dibenzylideneacetone) dipalladium (76mg), 1,1' -bis (diphenylphosphino) ferrocene (92 mg), triethylamine (0.35mL), diethyl phosphite (0.21mL), argon-substituted 3 times, and reacted at 120 ℃ overnight. TLC indicated complete consumption of starting material, quenched with water, extracted 2 times with ethyl acetate, dried over anhydrous sodium sulfate, and purified by Prep-TLC to give the title compound (110 mg).
MS(ESI)m/z(M+H) + ＝510.2
And 4, step 4: preparation of (5-amino-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonic acid hydrochloride
Diethyl (5- ((tert-butylsulfinyl) amino) -8- (4-methoxybenzyl) -5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonate (65mg) was weighed out and dissolved in concentrated hydrochloric acid (4mL) and reacted at 100 ℃ overnight. LCMS indicated complete consumption of starting material, concentrated under reduced pressure and purified by pre-HPLC to give the title compound (17.5 mg).
MS(ESI)m/z(M+H) + ＝230.1
1 H NMR(400MHz,Deuterium Oxide)δ7.87(dd,J＝7.4,2.8Hz,1H),7.02(dd,J＝9.0,7.3Hz, 1H),4.63(t,J＝5.0Hz,1H),3.59(dt,J＝13.9,5.2Hz,1H),3.45(ddd,J＝13.9,9.2,4.8Hz,1H), 2.15(dq,J＝10.3,5.0Hz,2H).
EXAMPLE 7 preparation of (5-amino-5, 6,7, 8-tetrahydronaphthalen-2-yl) phosphonic acid hydrochloride
Step 1: preparation of N- (6-bromo-3, 4-dihydronaphthalen-1 (2H) -alkylidene) -2-methylpropane-2-sulfinamide
6-bromo-3, 4-dihydronaphthalen-1 (2H) -one (300mg,1.33mmol), 2-methylpropane-2-sulfinamide (242mg) was dissolved in 2-methylfuran, added to tetraethoxytitanate (1mL) and reacted at 85 ℃ for 4H under nitrogen protection, and TLC monitored for completion of the reaction. After cooling to room temperature, the reaction mixture was dropped into a mixed solution of ethyl acetate and saturated brine, suction-filtered through celite, and the filtrate was concentrated and then column-purified to obtain the title compound (399 mg).
MS(ESI)m/z(M+H) + ＝328.0/330.0.
Step 2: preparation of N- (6-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) -2-methylpropane-2-sulfinamide
N- (6-bromo-3, 4-dihydronaphthalene-1 (2H) -alkylene) -2-methylpropane-2-sulfinamide (399mg) was added dropwise to a lithium tri-sec-butylborohydride solution (3.7mL) at-15 ℃ under nitrogen protection, the reaction was carried out for 1H at the temperature, and the completion of the reaction was monitored by TLC. Quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate of the organic phase, concentrated and purified by column to give the title compound (316 mg).
MS(ESI)m/z(M+H) + ＝330.0/332.0.
And step 3: preparation of (5- ((tert-butylsulfinyl) amino) diethyl) -5,6,7, 8-tetrahydronaphthalen-2-yl) phosphonate
N- (6-bromo-1, 2,3, 4-tetrahydronaphthalen-1-yl) -2-methylpropane-2-sulfinamide (158mg) was weighed and dissolved in toluene (5mL), and diethyl phosphite (133mg), triethylamine (200uL), tris (dibenzylideneacetone) dipalladium (44mg), 1,1' -bis (diphenylphosphino) ferrocene (54mg) were added in this order, and then replaced with argon for 3 times, followed by reaction at 120 ℃ for 2 hours. TLC indicated complete consumption of starting material, quenched with water, extracted 2 times with ethyl acetate, dried over anhydrous sodium sulfate, and purified by Prep-TLC to give the title compound (112 mg).
MS(ESI)m/z(M+H) + ＝388.1.
And 4, step 4: preparation of (5-amino-5, 6,7, 8-tetrahydronaphthalen-2-yl) phosphonic acid hydrochloride
(5- ((tert-butylsulfinyl) amino) diethyl) -5,6,7, 8-tetrahydronaphthalen-2-yl) phosphonate (112mg) was weighed out and dissolved in concentrated hydrochloric acid (10mL) and reacted at 100 ℃ overnight. LCMS showed complete consumption of starting material, concentrated under reduced pressure and isolated by pre-HPLC to afford the title compound (30 mg).
MS(ESI)m/z(M-H) - ＝226.0.
1 H NMR(400MHz,Deuterium Oxide)δ7.47(t,J＝11.2Hz,2H),7.32(dd,J＝7.8,3.4Hz, 1H),4.50(t,J＝5.4Hz,1H),2.77(dtd,J＝24.6,17.2,6.5Hz,2H),2.08(dt,J＝13.5,6.9Hz,1H), 1.92(dq,J＝14.2,5.2Hz,1H),1.79(p,J＝6.7Hz,2H).
EXAMPLE 8 preparation of (5-amino-5, 6,7, 8-tetrahydroquinolin-2-yl) phosphonic acid hydrochloride
Step 1: preparation of N- (2-chloro-7, 8-dihydroquinolin-5 (6H) -alkylidene) -2-methylpropane-2-sulfinamide
2-chloro-7, 8-dihydroquinolin-5 (6H) -one (300mg) and 2-methylpropane-2-sulfinamide (300mg) were dissolved in 2-methylfuran (10mL), added to tetraethoxytitanate (1mL), and reacted at 85 ℃ for 4H under nitrogen protection, and the completion of the reaction was monitored by TLC. After cooling to room temperature, the reaction mixture was dropped into a mixed solution of ethyl acetate and saturated brine, suction-filtered through celite, and the filtrate was concentrated and then column-purified to obtain the title compound (433 mg).
MS(ESI)m/z(M+H) + ＝285.9.
Step 2: preparation of N- ((S) -2-chloro-5, 6,7, 8-tetrahydroquinolin-5-yl) -2-methylpropane-2-sulfinamide
N- (2-chloro-7, 8-dihydroquinolin-5 (6H) -alkylene) -2-methylpropane-2-sulfinamide (433mg) was added dropwise to a lithium tri-sec-butylborohydride solution (4.5mL) at-15 ℃ under nitrogen protection, the reaction was carried out at that temperature for 1H, and the completion of the reaction was monitored by TLC. Quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate of the organic phase, concentrated and purified on a column to give the title compound (276 mg).
MS(ESI)m/z(M+H) + ＝287.0.
And step 3: preparation of (5- ((tert-butylsulfinyl) amino) diethyl) -5,6,7, 8-tetrahydroquinolin-2-yl) phosphonate
N- (2-chloro-5, 6,7, 8-tetrahydroquinolin-5-yl) -2-methylpropane-2-sulfinamide (100mg) was weighed and dissolved in toluene (5mL), and diethyl phosphite (97mg), triethylamine (98. mu.L), tris (dibenzylideneacetone) dipalladium (32mg), 1,1' -bis (diphenylphosphino) ferrocene (39mg) were added in this order, and then replaced with argon for 3 times, followed by reaction at 120 ℃ for 2 hours. TLC showed complete consumption of starting material, quenched with water, extracted 2 times with ethyl acetate, dried over anhydrous sodium sulfate, and purified by Prep-TLC to afford the title compound (68mg, 50% yield).
MS(ESI)m/z(M+H) + ＝389.2.
And 4, step 4: preparation of (5-amino-5, 6,7, 8-tetrahydroquinolin-2-yl) phosphonic acid hydrochloride
(5- ((tert-butylsulfinyl) amino) diethyl) -5,6,7, 8-tetrahydroquinolin-2-yl) phosphonate (68mg) was weighed out and dissolved in concentrated hydrochloric acid (5mL) and reacted at 100 ℃ overnight. LCMS indicated complete consumption of starting material, concentrated under reduced pressure and isolated by pre-HPLC to give the title compound (25 mg).
MS(ESI)m/z(M+H) + ＝229.0.
1 H NMR(400MHz,Deuterium Oxide)δ8.49(dd,J＝8.0,2.5Hz,1H),8.02(t,J＝7.8Hz,1H), 4.75(d,J＝4.6Hz,1H),3.15(tdd,J＝19.1,12.9,5.9Hz,2H),2.19(tt,J＝12.2,6.2Hz,1H),2.00 (ddq,J＝11.3,7.9,4.9,4.1Hz,3H).
EXAMPLE 9 preparation of (4-Aminothiopyran-7-yl) phosphonic acid hydrochloride
Step 1: preparation of 2- ((3-bromophenyl) thio) propionic acid
After M-bromophenylthiol (0.27mL) was dissolved in 5mL of 2M aqueous sodium hydroxide solution and reacted at 100 ℃ for 2 hours, the temperature of the reaction system was lowered to 60 ℃, 3-chloropropionic acid (302mg) was added and reacted at 60 ℃ overnight, and the completion of the reaction was monitored by TLC. After cooling to room temperature, the pH of the system was adjusted to 2 with 3M aqueous hydrochloric acid in an ice bath, a large amount of solid precipitated, which was filtered off, the filter cake was washed three times with water, the filter cake was taken out and dried under reduced pressure to give the title compound (500 mg).
MS(ESI)m/z(M-H) - ＝258.8/260.8.
Step 2: preparation of 7-bromothiochroman-4-ones
2- ((3-bromophenyl) thio) propionic acid (500mg) was dissolved in cold concentrated sulfuric acid (10mL), stirred for half an hour in an ice water bath, then moved to room temperature and stirred for 3h, and the reaction was monitored by TLC for completion. The system was slowly poured into ice, extracted three times with ethyl acetate, the organic phases were combined, washed successively with saturated sodium bicarbonate solution, saturated brine once, dried over anhydrous sodium sulfate, concentrated and column-purified to give the title compound (320 mg).
MS(ESI)m/z(M+H) + ＝242.9/244.8.
1 H NMR(400MHz,Chloroform-d)δ7.98-7.96(d,J＝8.5Hz,1H),7.48-7.47(d,J＝1.9Hz, 1H),7.33-7.30(dd,J＝8.5,1.9Hz,1H),3.28-3.25(m,2H),3.01-2.96(m,2H).
And step 3: preparation of N- (7-bromothiopyran-4-alkylidene) -2-methylpropane-2-sulfinamide
7-Bromothiochroman-4-one (320mg), 2-methylpropane-2-sulfinamide (240mg) was dissolved in tetraethyl titanate (3mL), reacted at 100 ℃ for 1h under nitrogen protection, and the completion of the reaction was monitored by TLC. After cooling to room temperature, the reaction mixture was dropped into a mixed solution of ethyl acetate and saturated brine, suction-filtered through celite, and the filtrate was concentrated and then column-purified to give the title compound (320 mg).
MS(ESI)m/z(M+H) + ＝345.9/348.0.
And 4, step 4: preparation of N- (7-bromothiochroman-4-yl) -2-methylpropane-2-sulfinamide
N- (7-bromothiopyran-4-alkylidene) -2-methylpropane-2-sulfinamide (320mg) was taken, under the protection of nitrogen, lithium tri-sec-butylborohydride solution (2.8mL) was added dropwise at-15 ℃ and reacted at that temperature for 1h, and the completion of the reaction was monitored by TLC. Quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate of the organic phase, concentrated and purified by column to give the title compound (260 mg).
MS(ESI)m/z(M+H) + ＝369.8/371.9.
1 H NMR(400MHz,Chloroform-d)δ7.29(d,J＝2.7Hz,1H),7.23-7.15(m,2H),4.53-4.49 (ddd,J＝9.1,5.9,3.6Hz,1H),3.49-3.47(d,J＝8.7Hz,1H),3.22-3.15(ddd,J＝12.9,10.5,3.6Hz, 1H),3.06-3.00(ddd,J＝12.8,6.4,3.9Hz,1H),2.48-2.32(m,2H),1.25(s,9H).
And 5: preparation of diethyl (4- ((tert-butylsulfinyl) amino) thiopyran-7-yl) phosphonate
N- (7-Bromothiochroman-4-yl) -2-methylpropane-2-sulfinamide (50mg) was weighed and dissolved in toluene (3mL), and diethyl phosphite (39mg), triethylamine (58. mu.L), tris (dibenzylideneacetone) dipalladium (13mg), 1,1' -bis (diphenylphosphino) ferrocene (16mg) were added in this order, and the mixture was substituted with argon for 3 times, followed by reaction at 120 ℃ for 2 hours. TLC indicated complete consumption of starting material, quenched with water, extracted 2 times with ethyl acetate, dried over anhydrous sodium sulfate, and purified by Prep-TLC to give the title compound (50 mg).
MS(ESI)m/z(M+H) + ＝406.1.
And 6: preparation of (4-aminothiopyran-7-yl) phosphonic acid hydrochloride
Diethyl (4- ((tert-butylsulfinyl) amino) thiopyran-7-yl) phosphonate (50mg) was weighed out and dissolved in concentrated hydrochloric acid (4mL) and reacted at 100 ℃ overnight. LCMS indicated complete consumption of starting material, concentrated under reduced pressure and isolated by pre-HPLC to afford the title compound (4.1 mg).
MS(ESI)m/z(M-H) - ＝243.9.
1 H NMR(400MHz,Deuterium Oxide)δ7.44-7.41(d,J＝13.2Hz,1H),7.39-7.27(m,2H), 4.60-4.58(t,J＝4.3Hz,1H),3.12-2.97(m,2H),2.43-2.34(m,1H),2.28-2.20(m,1H).
EXAMPLE 10 preparation of (4-amino-3, 4-dihydro-2H-thiopyrano [2,3-b ] pyridin-7-yl) phosphonate hydrochloride
Step 1: preparation of 3- ((tert-butylsulfinyl) amino) -3- (2, 6-dichloropyridin-3-yl) propyl methanesulfonate
N- (1- (2, 6-dichloropyridin-3-yl) -3-hydroxypropyl) -2-methylpropane-2-sulfinamide (360mg) was weighed out and dissolved in dichloromethane (6mL), and placed at 0 ℃ to react with triethylamine (0.46mL) and methanesulfonyl chloride (86. mu.L) for 1.5h at 0 ℃. TLC showed complete consumption of starting material, quenched with water, extracted 2 times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (440 mg).
MS(ESI)m/z(M+H) + ＝402.9.
Step 2: preparation of (-) -3- ((tert-butylsulfinyl) amino) -3- (2, 6-dichloropyridin-3-yl) propyl) ethanol thioester
3- ((tert-butylsulfinyl) amino) -3- (2, 6-dichloropyridin-3-yl) propyl methanesulfonate (200mg) was weighed out, dissolved in N, N-dimethylformamide (4mL), and reacted with potassium thioacetate (57mg) at 40 ℃ for 2 hours. TLC showed complete consumption of starting material, quenched with water, extracted 2 times with ethyl acetate, washed 2 times with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (220 mg).
MS(ESI)m/z 0(M+H) + ＝383..
And step 3: preparation of N- (7-chloro-3, 4-dihydro-2H-thiopyrano [2,3-b ] pyridin-4-yl) -2-methylpropane-2-sulfinamide
(3- ((tert-butylsulfinyl) amino) -3- (2, 6-dichloropyridin-3-yl) propyl) ethanethiolate (220mg) was weighed out and dissolved in tetrahydrofuran (4mL), and 4mL of a 2M aqueous solution of sodium hydroxide was added to the solution to conduct a reaction at 60 ℃ for 2 hours. TLC showed complete consumption of starting material, quenched with water, extracted 3 times with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography to give the title compound (108 mg).
MS(ESI)m/z(M+H) + ＝305.0.
And 4, step 4: preparation of diethyl (4- ((tert-butylsulfinyl) amino) -3, 4-dihydro-2H-thiopyrano [2,3-b ] pyridin-7-yl) phosphonate
N- (7-chloro-3, 4-dihydro-2H-thiopyrano [2,3-b ] pyridin-4-yl) -2-methylpropane-2-sulfinamide (108mg) was weighed and dissolved in toluene (3mL), and tris (dibenzylideneacetone) dipalladium (33mg), 1,1' -bis (diphenylphosphino) ferrocene (40mg), triethylamine (148. mu.L), diethyl phosphite (92. mu.L) were added in this order, and then replaced with argon gas for 6 hours at 120 ℃. TLC indicated complete consumption of starting material, quenched with water, extracted 2 times with ethyl acetate, dried over anhydrous sodium sulfate, and purified by Prep-TLC to give the title compound (45 mg).
MS(ESI)m/z(M+H) + ＝407.1.
And 5: preparation of (4-amino-3, 4-dihydro-2H-thiopyrano [2,3-b ] pyridin-7-yl) phosphonate hydrochloride
Diethyl (4- ((tert-butylsulfinyl) amino) -3, 4-dihydro-2H-thiopyrano [2,3-b ] pyridin-7-yl) phosphonate (45mg) was weighed out, dissolved in concentrated hydrochloric acid (4mL) and reacted at 100 ℃ overnight. LCMS indicated complete consumption of starting material, concentrated under reduced pressure and isolated by pre-HPLC to give the title compound (5.49 mg).
MS(ESI)m/z(M+H) + ＝247.0.
1 H NMR(400MHz,Deuterium Oxide)δ7.87(dd,J＝7.4,2.8Hz,1H),7.02(dd,J＝9.0,7.3Hz, 1H),4.63(t,J＝5.0Hz,1H),3.59(dt,J＝13.9,5.2Hz,1H),3.45(ddd,J＝13.9,9.2,4.8Hz,1H), 2.15(dq,J＝10.3,5.0Hz,2H).
EXAMPLE 11 preparation of (5-amino-8-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonate hydrochloride
Step 1: preparation of 3- ((tert-butylsulfinyl) amino) -3- (2, 6-dichloropyridin-3-yl) propyl methanesulfonate
N- (1- (2, 6-dichloropyridin-3-yl) -3-hydroxypropyl) -2-methylpropane-2-sulfinamide (360mg) was weighed out and dissolved in dichloromethane (6mL), and placed at 0 ℃ to react with triethylamine (0.46mL) and methanesulfonyl chloride (86. mu.L) for 1.5h at 0 ℃. TLC showed complete consumption of starting material, quenched with water, extracted 2 times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (440 mg).
MS(ESI)m/z(M+H) + ＝402.9.
Step 2: preparation of N- (7-chloro-1-methyl-1, 2,3, 4-tetrahydro-1, 8-naphthyridin-4-yl) -2-methylpropane-2-sulfinamide
3- ((tert-Butylsulfinyl) amino) -3- (2, 6-dichloropyridin-3-yl) propyl methanesulfonate (220mg) was weighed into a sealed tube, dissolved by adding tetrahydrofuran (5mL), and reacted with a 2M tetrahydrofuran solution of methylamine (1.64mL) and triethylamine (0.23mL) at 100 ℃ overnight. TLC showed complete consumption of starting material, quenched with water, extracted 2 times with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography to give the title compound (110 mg).
MS(ESI)m/z(M+H) + ＝302.1.
And step 3: preparation of diethyl (5- ((tert-butylsulfinyl) amino) -8-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonate
Weighing N- (7-chloro-1-methyl-1, 2,3, 4-tetrahydro-1, 8-naphthyridin-4-yl) -2-methylpropane-2-sulfinamide (110mg) and dissolving in toluene (3mL), sequentially adding tris (dibenzylideneacetone) dipalladium (34mg,0.037mmol), 1,1' -bis (diphenylphosphino) ferrocene (41 mg), triethylamine (0.15mL), diethyl phosphite (94 μ L), replacing with argon for 3 times, and reacting at 120 ℃ for 6 h. TLC indicated complete consumption of starting material, quenched with water, extracted 2 times with ethyl acetate, dried over anhydrous sodium sulfate, and purified by Prep-TLC to give the title compound (73 mg).
MS(ESI)m/z 404.1(M+H) + .
And 4, step 4: preparation of (5-amino-8-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonate hydrochloride
Diethyl (5- ((tert-butylsulfinyl) amino) -8-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonate (73mg) was weighed out and dissolved in concentrated hydrochloric acid (4mL) and reacted at 100 ℃ for 8 h. LCMS indicated complete consumption of material, concentration under reduced pressure and isolation by pre-HPLC afforded the title compound (26.7 mg).
MS(ESI)m/z(M+H) + ＝244.0.
1 H NMR(400MHz,Deuterium Oxide)δ7.82(dd,J＝7.4,2.9Hz,1H),7.06(dd,J＝9.3,7.2Hz, 1H),4.62(t,J＝5.1Hz,1H),3.66(dt,J＝8.5,5.2Hz,2H),3.21(s,3H),2.31–2.11(m,2H).
EXAMPLE 12 preparation of (5-amino-8-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonate hydrochloride
Step 1: preparation of 3- ((tert-butylsulfinyl) amino) -3- (2, 6-dichloropyridin-3-yl) propyl methanesulfonate
N- (1- (2, 6-dichloropyridin-3-yl) -3-hydroxypropyl) -2-methylpropane-2-sulfinamide (500mg) was weighed out and dissolved in dichloromethane (8 mL), and placed at 0 ℃ to react with triethylamine (0.64mL) and methanesulfonyl chloride (119. mu.L) for 1.5h at 0 ℃. TLC showed complete consumption of starting material, quenched with water, extracted 2 times with dichloromethane, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (600 mg).
MS(ESI)m/z(M+H) + ＝402.9
Step 2: preparation of N- (7-chloro-1-isopropyl-1, 2,3, 4-tetrahydro-1, 8-naphthyridin-4-yl) -2-methylpropane-2-sulfinamide
3- ((tert-butylsulfinyl) amino) -3- (2, 6-dichloropyridin-3-yl) propyl methanesulfonate (200mg) was weighed into a sealed tube, dissolved by adding tetrahydrofuran (4mL), and reacted at 120 ℃ overnight with isopropylamine (127. mu.L) and triethylamine (0.20 mL). TLC showed complete consumption of starting material, quenched with water, extracted 2 times with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography to give the title compound (34 mg).
MS(ESI)m/z(M+H) + ＝330.1.
And step 3: preparation of diethyl (5-amino-8-isopropyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonate
N- (7-chloro-1-isopropyl-1, 2,3, 4-tetrahydro-1, 8-naphthyridin-4-yl) -2-methylpropane-2-sulfinamide (34mg) was weighed and dissolved in toluene (1.5mL), and tris (dibenzylideneacetone) dipalladium (10mg), 1,1' -bis (diphenylphosphino) ferrocene (12mg), triethylamine (43. mu.L), diethyl phosphite (40. mu.L) were added in this order, and then replaced with argon gas for 3 times, and reacted at 120 ℃ overnight. TLC indicated complete consumption of starting material, concentrated under reduced pressure in vacuo and purified by Prep-TLC to give the title compound (18 mg).
MS(ESI)m/z(M+H) + ＝328.1.
And 4, step 4: preparation of (5-amino-8-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonate hydrochloride
Diethyl (5-amino-8-isopropyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonate (18mg) was weighed out and dissolved in concentrated hydrochloric acid (4mL) and reacted at 100 ℃ overnight. LCMS indicated complete consumption of starting material, concentrated under reduced pressure and isolated by pre-HPLC to give the title compound (5.2 mg).
MS(ESI)m/z(M+H) + ＝272.1.
1 H NMR(400MHz,Deuterium Oxide)δ7.77(dd,J＝7.4,2.8Hz,1H),6.96(t,J＝7.5Hz,1H), 4.57(s,1H),4.43(p,J＝6.6Hz,1H),3.63(dt,J＝13.8,5.1Hz,1H),3.45(ddd,J＝14.1,8.4,5.9 Hz,1H),2.16(q,J＝5.2,4.3Hz,2H),1.24(dd,J＝8.7,6.6Hz,6H).
Example 13
Step 1: preparation of 3- ((tert-butylsulfinyl) amino) -3- (2, 6-dichloropyridin-3-yl) propyl methanesulfonate
N- (1- (2, 6-dichloropyridin-3-yl) -3-hydroxypropyl) -2-methylpropane-2-sulfinamide (300mg) was weighed out and dissolved in dichloromethane (5mL), and placed at 0 ℃ to react with triethylamine (0.38mL) and methanesulfonyl chloride (71. mu.L) for 1.5h at 0 ℃. TLC showed complete consumption of starting material, quenched with water, extracted 2 times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (372 mg).
MS(ESI)m/z 402.9(M+H) +
Step 2: preparation of N- (7-chloro-1-isobutyl-1, 2,3, 4-tetrahydro-1, 8-naphthyridin-4-yl) -2-methylpropane-2-sulfinamide
3- ((tert-butylsulfinyl) amino) -3- (2, 6-dichloropyridin-3-yl) propyl methanesulfonate (186mg) was weighed into a sealed tube, and N, N-dimethylformamide (4mL) was added thereto for dissolution, and isobutylamine (0.14mL) and triethylamine (0.19mL) were added thereto and reacted at 70 ℃ for 3 hours. TLC showed complete consumption of starting material, quenched with water, extracted 2 times with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography to give the title compound (70 mg).
MS(ESI)m/z(M+H) + ＝344.1.
And step 3: preparation of diethyl (5- ((tert-butylsulfinyl) amino) -8-isobutyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonate
Weighing N- (7-chloro-1-isobutyl-1, 2,3, 4-tetrahydro-1, 8-naphthyridin-4-yl) -2-methylpropane-2-sulfinamide (70mg) and dissolving in toluene (2mL), sequentially adding tris (dibenzylideneacetone) dipalladium (19mg), 1,1' -bis (diphenylphosphino) ferrocene (23mg), triethylamine (85 muL), diethyl phosphite (52 muL) and replacing for 3 times with argon, and reacting at 120 ℃ for 10 h. TLC indicated complete consumption of starting material, quenched with water, extracted 2 times with ethyl acetate, dried over anhydrous sodium sulfate, and purified by Prep-TLC to give the title compound (20 mg).
MS(ESI)m/z(M+H) + ＝446.1.
And 4, step 4: preparation of (5-amino-8-isobutyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonate hydrochloride
Diethyl (5- ((tert-butylsulfinyl) amino) -8-isobutyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) phosphonate (20mg) was weighed out and dissolved in concentrated hydrochloric acid (4mL) and reacted at 100 ℃ overnight. LCMS indicated complete consumption of material, concentration under reduced pressure and isolation of the title compound by pre-HPLC (12 mg).
MS(ESI)m/z(M+H) + ＝286.1
1 H NMR(400MHz,Deuterium Oxide)δ7.82(dd,J＝7.5,2.7Hz,1H),6.99(t,J＝7.6Hz,1H), 4.62(t,J＝5.1Hz,1H),3.65(tdd,J＝17.9,10.1,4.6Hz,2H),3.49(dd,J＝15.2,7.5Hz,1H),3.34 (dd,J＝15.3,7.9Hz,1H),2.32–2.04(m,3H),0.91(dd,J＝6.7,1.6Hz,6H).
The following compounds of the examples were prepared using conventional commercially available starting materials and reagents, according to the preparation methods of the preceding examples in combination with conventional means of separation and purification in the art:
example 33
Step 1: preparation of 7-bromo-4-oxo-2, 3-dihydroisoquinoline-1 (2H) -carboxylic acid tert-butyl ester
7-bromo-2, 3-dihydroisoquinolin-4-one (762mg) was dissolved in 20mL of anhydrous dichloromethane, and 4-dimethylaminopyridine (830mg) and di-tert-butyl dicarbonate (873mg) were added to the solution in an ice bath to react at room temperature for 4 hours. After TLC detection of the starting material consumption, the reaction was concentrated to dryness and the crude product was purified by column chromatography to give the title compound (795 mg).
MS(ESI)m/z(M+H) + ＝326.0.
Step 2: preparation of tert-butyl 7-bromo-4- ((tert-butylsulfinyl) imino) -3, 4-dihydroisoquinoline-1 (2H) -carboxylate
7-bromo-4-oxo-3, 4-dihydroisoquinoline-1 (2H) -carboxylic acid tert-butyl ester (795mg) and tert-butylsulfinamide (443mg) were dissolved in 2-methyltetrahydrofuran (10mL), and 1mL of tetraethyl titanate was added and the mixture was transferred to 80 ℃ for reaction overnight. After TLC detection of the end of consumption of starting material, it was diluted with ethyl acetate, added 1mL of water, filtered, concentrated and the crude product was purified by column chromatography to give the title compound (907 mg).
MS(ESI)m/z(M+H) + ＝429.1
And step 3: preparation of tert-butyl 7-bromo-4- (1, 1-dimethylethylenesulfonamido) -3, 4-dihydroisoquinoline-1 (2H) -carboxylate
Tert-butyl 7-bromo-4- ((tert-butylsulfinyl) imino) -3, 4-dihydroisoquinoline-1 (2H) -carboxylate (907mg) was dissolved in 10mL of anhydrous tetrahydrofuran, and lithium tri-sec-butylborohydride (6.3mL) was slowly added in an ice bath, followed by reaction at room temperature for 2H. After TLC detection of the starting material consumption, the reaction was concentrated to dryness and the crude product was purified by column chromatography to give the title compound (380 mg).
MS(ESI)m/z(M+Na) + ＝453.0.
And 4, step 4: preparation of tert-butyl 7- (diethoxyphosphoryl) -4- ((R) -1, 1-dimethylethylenesulfonamido) -3, 4-dihydroisoquinoline-1 (2H) -carboxylate
Tert-butyl 7-bromo-4- ((R) -1, 1-dimethylethylenesulfonamido) -3, 4-dihydroisoquinoline-1 (2H) -carboxylate (300mg), diethyl phosphite (193mg), tris (dibenzylideneacetone) dipalladium (64mg), 1' -bis (diphenylphosphino) ferrocene (dppf,77.6mg), and triethylamine (141mg) were dissolved in 10mL of toluene, transferred to 125 ℃ under nitrogen protection, and reacted overnight. After TLC detection of complete consumption of starting material, it was diluted with ethyl acetate, filtered and concentrated, and the crude product was purified by pre-TLC to give the title compound (96 mg).
MS(ESI)m/z(M+Na) + ＝511.0.
And 5: preparation of (4-amino-1, 2,3, 4-tetrahydroquinolin-7-yl) phosphonic acid hydrochloride
Tert-butyl 7- (diethoxyphosphoryl) -4- (1, 1-dimethylethylenesulfonamido) -3, 4-dihydroisoquinoline-1 (2H) -carboxylate (96mg) was added to concentrated hydrochloric acid (20mL), and stirred at 100 ℃ overnight. After complete consumption of starting material by LC-MS assay, it was concentrated under reduced pressure and purified by pre-HPLC to give the title compound (22.6 mg).
MS(ESI)m/z(M-16) + ＝211.9。
1 H NMR(400MHz,Deuterium Oxide)：δ7.74–7.63(m,1H),7.58–7.45(m,2H),4.96(t,J＝5.8Hz,1H),4.58–4.33(m,2H),3.88(dd,J＝13.8,5.8Hz,1H),3.66(dd,J＝13.8,5.9Hz,1H).
Biological assay
Test example 1: plasma clot degradation experiments
1. Purpose of experiment
The inhibition of human plasma clot degradation by the compounds of the invention was determined.
2. Experimental materials and instruments
3. Experimental procedure
3.1 collecting fresh healthy human blood, using 0.109M trisodium citrate as anticoagulant, mixing 1 part anticoagulant and 9 parts blood, centrifuging at 2000Xg for 20 minutes at room temperature, collecting supernatant (blood plasma), subpackaging and storing at-80 ℃ for later use.
3.2 day of experiment, plasma was thawed in a 37 ℃ water bath and all reagents except tPA were pre-warmed at 37 ℃.
3.3 Add 12.5. mu.L, 80mM CaCl to 96-well plates 2 (HEPES buffer, pH 7.4), and then 25. mu.L of a solution diluted with physiological saline was added theretoFor test compounds of different concentrations, equal volumes of saline were added to the negative control wells.
3.4 mu.L of pre-warmed plasma was mixed with 12.5. mu.L of tPA at 4nM (HEPES buffer, pH 7.4), immediately added to a 96-well plate, absorbance was measured at 405nM, and the reading was taken every 2 minutes for 15 hours continuously.
3.5 the absorption value changes with time, and rises first and then falls, and the time corresponding to the median of the absorption value in the descending section and the time corresponding to the median of the absorption value in the ascending section are the plasma Clot degradation time (Clot lysis time). Calculating the plasma clot degradation time relative to the plasma clot degradation time in the wells with different concentrations of compound by taking the plasma clot degradation time of the negative control wells as a reference to obtain the inhibition rate:
inhibition% Clot lysis time Compound pore Clot lysis time )100％
3.6 fitting dose-response curves
The log values of the compound concentrations were taken as the X-axis and the percent inhibition as the Y-axis, and the dose-effect curves were fitted using the analysis software GraphPad Prism 5 log (inhibitor) vs. response-Variable slope (Variable slope), to derive the IC of each compound on cell activity 50 The value is obtained.
Calculating the formula: y ═ min + (max-min)/(1+10^ ((Logicc) 50 -X)×Hillslope))。
Inhibition of plasma clot degradation by Compounds of the invention the IC of the compounds of the examples of the invention was calculated by the assay described above 50 The values are all greatly lower than the currently most widely used hemostatic drug tranexamic acid (IC under the same test conditions) 50 4.75. mu.M).
IC of Compounds in examples of the invention 50 ratio value (IC) 50 ratio ═ Compound IC of the invention 50 Value/tranexamic acid IC 50 Values) are as follows:
| example numbering | IC 50 ratio(uM) | Example numbering | IC 50 ratio(uM) |
| 1 | 0.06 | 18 | / |
| 2 | 0.11 | 19 | 0.11 |
| 3 | 0.64 | 20 | 0.49 |
| 4 | 0.51 | 21 | / |
| 5 | 0.39 | 22 | 0.95 |
| 6 | 0.22 | 23 | 0.15 |
| 7 | 0.54 | 24 | 0.73 |
| 8 | 0.48 | 25 | 0.73 |
| 9 | 0.62 | 26 | / |
| 10 | 0.37 | 27 | 0.33 |
| 11 | 0.53 | 28 | / |
| 12 | 0.82 | 29 | / |
| 13 | 0.28 | 30 | 0.97 |
| 14 | 0.67 | 31 | / |
| 15 | 0.24 | 32 | 0.3 |
| 16 | 0.42 | 33 | 2.19 |
| 17 | / |
Note: "/" indicates no detection.
Test data show that the compound can effectively inhibit the degradation of plasma clot, has excellent blood coagulation and hemostatic activities, has an effective dose far lower than that of the most frequently used hemostatic medicament in clinic at present, can effectively avoid adverse reactions and complications caused by high-dose medicament administration, and has excellent medicament prospect.
Claims (10)
1. A compound having the structure of formula I, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof:
wherein X is selected from CH 2 、NR 3 O, S; y is selected from CH and N;
R 1 selected from hydrogen, NRaRb, hydroxy, substituted or unsubstitutedSubstituted or unsubstituted alkyl, substituted or unsubstituted aromatic heterocyclic group; wherein Ra and Rb are independently selected from hydrogen, alkyl and halogenated alkyl;
R 2 selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lipoheterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted arylheterocyclyl;
R 3 selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lipoheterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted arylheterocyclyl, - (CH) 2 ) mNrcRd, wherein m ═ 1,2,3,4, Rc, Rd are each independently selected from hydrogen, alkyl, haloalkyl.
2. The compound of claim 1, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, wherein R is 1 Selected from hydrogen, NRaRb, hydroxyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted 6-10 membered aromatic heterocyclic group; wherein Ra and Rb are independently selected from hydrogen, alkyl and halogenated alkyl.
3. The compound of claim 1 or 2, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, wherein R is 2 Selected from hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl radical, C 1 -C 4 Haloalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted 4-8 membered aliphatic heterocyclic group, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 6-10 membered aromatic heterocyclic group.
4. The compound of any one of claims 1-3, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, wherein R is 3 Selected from hydrogen, substituted or unsubstituted C 1 -C 4 Alkyl radical, C 1 -C 4 Haloalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted 4-8 membered aliphatic heterocyclic group, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 6-10 membered aromatic heterocyclic group.
5. The compound according to any one of claims 1 to 4, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, wherein the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl; said alkyl group being optionally substituted with one or more groups selected from halogen, amino, hydroxy, cycloalkyl, lipoheterocyclyl; the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl; the lipid heterocyclic group is selected from oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, piperidinyl, morpholinyl; the aryl is selected from phenyl and naphthyl; the aromatic heterocyclic group is selected from pyridyl, pyrimidyl, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl, thienyl, oxazolyl, isoxazolyl and 1,2, 4-oxadiazolyl.
6. The compound according to any one of claims 1-4, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, wherein X is selected from CH 2 、NR 3 O, S, wherein R is 3 Selected from hydrogen, -Q- (R) Q ) n And Q is selected from C 1 -C 4 Alkyl radical, C 3 -C 6 Cycloalkyl, 4-6 membered saturated aliphatic heterocyclic group, said n is 0 or 1, said R Q Selected from methyl, phenyl, tetrahydropyranyl, morpholinyl, piperidinyl, methylpiperidinyl, o-chlorophenyl, carboxy, hydroxy, dimethylamino, halogen;
preferably, Q is selected from Q, preferably from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropylalkyl, cyclobutylalkyl, cyclopentylalkyl, piperidinyl, tetrahydropyranyl, morpholinyl, cyclopropoxy.
7. The compound of any one of claims 1-6, pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, wherein the compound of formula I has the structure:
8. a pharmaceutical composition comprising at least one compound of any one of claims 1-7, or pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, and at least one pharmaceutically acceptable excipient.
9. Use of a compound of any one of claims 1-8, or pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof, or a pharmaceutical composition, for the manufacture of a medicament.
10. Use according to claim 9, characterized in that the medicament has the therapeutic activity of blood coagulation, hemostasis; can be used for treating abnormal hemorrhage due to hyperfibrinolysis, and hemorrhage after surgery and operation.
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