CN103664996B - Indole derivatives and preparation method thereof - Google Patents
Indole derivatives and preparation method thereof Download PDFInfo
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- CN103664996B CN103664996B CN201310388834.XA CN201310388834A CN103664996B CN 103664996 B CN103664996 B CN 103664996B CN 201310388834 A CN201310388834 A CN 201310388834A CN 103664996 B CN103664996 B CN 103664996B
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- formula
- compound
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- pharmaceutically acceptable
- alkyl
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- 150000002475 indoles Chemical class 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 229940054051 antipsychotic indole derivative Drugs 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 348
- 150000003839 salts Chemical class 0.000 claims abstract description 57
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 32
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims description 111
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 72
- 125000000217 alkyl group Chemical group 0.000 claims description 53
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 41
- 229910052757 nitrogen Inorganic materials 0.000 claims description 38
- 229910052760 oxygen Inorganic materials 0.000 claims description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 35
- 230000008569 process Effects 0.000 claims description 32
- 125000003118 aryl group Chemical group 0.000 claims description 30
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 21
- 229910052717 sulfur Inorganic materials 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 241000304886 Bacilli Species 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 11
- 239000011261 inert gas Substances 0.000 claims description 10
- 239000003242 anti bacterial agent Substances 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 150000001721 carbon Chemical group 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 7
- 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 241000894006 Bacteria Species 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 claims description 6
- 125000006413 ring segment Chemical group 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 5
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 3
- 239000005695 Ammonium acetate Substances 0.000 claims description 3
- 241000193830 Bacillus <bacterium> Species 0.000 claims description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 3
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 3
- 229960000583 acetic acid Drugs 0.000 claims description 3
- 229940043376 ammonium acetate Drugs 0.000 claims description 3
- 235000019257 ammonium acetate Nutrition 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
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 3
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical class 0.000 claims 2
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 claims 2
- 125000002757 morpholinyl group Chemical group 0.000 claims 2
- 239000007789 gas Substances 0.000 claims 1
- 239000012453 solvate Substances 0.000 abstract description 9
- 229940088710 antibiotic agent Drugs 0.000 abstract description 3
- 239000004599 antimicrobial Substances 0.000 abstract 1
- -1 esters and amides Chemical class 0.000 description 170
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 152
- 239000000203 mixture Substances 0.000 description 132
- 238000005481 NMR spectroscopy Methods 0.000 description 71
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 45
- 150000003254 radicals Chemical class 0.000 description 40
- 238000005160 1H NMR spectroscopy Methods 0.000 description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 24
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
- 238000001035 drying Methods 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 230000000694 effects Effects 0.000 description 14
- 125000004494 ethyl ester group Chemical group 0.000 description 14
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 12
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 12
- 150000001412 amines Chemical class 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 10
- 239000010410 layer Substances 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- DKHFLDXCKWDVMF-UHFFFAOYSA-N 5-methyl-7-thia-2-azatricyclo[6.3.1.04,12]dodeca-1(12),3,8,10-tetraene-6-carboxylic acid Chemical compound CC1C(C(O)=O)SC2=CC=CC3=C2C1=CN3 DKHFLDXCKWDVMF-UHFFFAOYSA-N 0.000 description 7
- 125000002837 carbocyclic group Chemical group 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 7
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 7
- 229960001225 rifampicin Drugs 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 230000001580 bacterial effect Effects 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 125000004093 cyano group Chemical group *C#N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 5
- UEUGYIMGLFJGGX-UHFFFAOYSA-N 4-iodo-7h-pyrrolo[2,3-d]pyrimidine Chemical compound IC1=NC=NC2=C1C=CN2 UEUGYIMGLFJGGX-UHFFFAOYSA-N 0.000 description 5
- 241000588724 Escherichia coli Species 0.000 description 5
- 241000192125 Firmicutes Species 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229910019142 PO4 Inorganic materials 0.000 description 5
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 5
- 230000003115 biocidal effect Effects 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 150000004702 methyl esters Chemical class 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 5
- 239000010452 phosphate Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- SOVUOXKZCCAWOJ-HJYUBDRYSA-N (4s,4as,5ar,12ar)-9-[[2-(tert-butylamino)acetyl]amino]-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=C(NC(=O)CNC(C)(C)C)C(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O SOVUOXKZCCAWOJ-HJYUBDRYSA-N 0.000 description 4
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- GATNOFPXSDHULC-UHFFFAOYSA-N ethylphosphonic acid Chemical compound CCP(O)(O)=O GATNOFPXSDHULC-UHFFFAOYSA-N 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000002674 ointment Substances 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 125000004430 oxygen atom Chemical group O* 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229960004089 tigecycline Drugs 0.000 description 4
- KKFDCBRMNNSAAW-UHFFFAOYSA-N 2-(morpholin-4-yl)ethanol Chemical compound OCCN1CCOCC1 KKFDCBRMNNSAAW-UHFFFAOYSA-N 0.000 description 3
- IKTJMKYSKNYTJM-UHFFFAOYSA-N 3-(1h-indol-3-yl)butanoic acid Chemical compound C1=CC=C2C(C(CC(O)=O)C)=CNC2=C1 IKTJMKYSKNYTJM-UHFFFAOYSA-N 0.000 description 3
- XVRDITINKCASST-UHFFFAOYSA-N 4-iodo-1h-indole Chemical compound IC1=CC=CC2=C1C=CN2 XVRDITINKCASST-UHFFFAOYSA-N 0.000 description 3
- PCHGYPNRADCIKG-UHFFFAOYSA-N 4-iodo-1h-pyrrolo[2,3-b]pyridine Chemical compound IC1=CC=NC2=C1C=CN2 PCHGYPNRADCIKG-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 3
- 239000007868 Raney catalyst Substances 0.000 description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- 241000191967 Staphylococcus aureus Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 229960003085 meticillin Drugs 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- IKTJMKYSKNYTJM-QMMMGPOBSA-N (3s)-3-(1h-indol-3-yl)butanoic acid Chemical compound C1=CC=C2C([C@H](CC(O)=O)C)=CNC2=C1 IKTJMKYSKNYTJM-QMMMGPOBSA-N 0.000 description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- AETHSVNOUWYRPY-UHFFFAOYSA-N 1-(4-iodo-1h-indol-3-yl)ethanone Chemical compound C1=CC(I)=C2C(C(=O)C)=CNC2=C1 AETHSVNOUWYRPY-UHFFFAOYSA-N 0.000 description 2
- QMDFJHAAWUGVKQ-UHFFFAOYSA-N 2h-thiopyran Chemical group C1SC=CC=C1 QMDFJHAAWUGVKQ-UHFFFAOYSA-N 0.000 description 2
- QGXVGAKMSFELHC-UHFFFAOYSA-N 4-iodo-1h-pyrrolo[3,2-c]pyridine Chemical compound IC1=NC=CC2=C1C=CN2 QGXVGAKMSFELHC-UHFFFAOYSA-N 0.000 description 2
- AZXJOGUEZOBWKX-UHFFFAOYSA-N 4-iodo-6-methoxy-1h-indole Chemical compound COC1=CC(I)=C2C=CNC2=C1 AZXJOGUEZOBWKX-UHFFFAOYSA-N 0.000 description 2
- ITOSEVMXVPERCO-UHFFFAOYSA-N 4-iodo-6-methyl-1h-indole Chemical compound CC1=CC(I)=C2C=CNC2=C1 ITOSEVMXVPERCO-UHFFFAOYSA-N 0.000 description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 2
- CTXVMXNISQRMMN-UHFFFAOYSA-N 6-fluoro-4-iodo-1h-indole Chemical compound FC1=CC(I)=C2C=CNC2=C1 CTXVMXNISQRMMN-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- OPKOKAMJFNKNAS-UHFFFAOYSA-N N-methylethanolamine Chemical compound CNCCO OPKOKAMJFNKNAS-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
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- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/06—Peri-condensed systems
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/06—Peri-condensed systems
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- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
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Abstract
The present invention relates to the new antimicrobial compound of a class, i.e. a class indole derivatives, its alloisomerism or their officinal salt or solvate or hydrate;The preparation method of these compounds, the pharmaceutical composition containing these compounds, these compounds are for preparing the purposes in antibacterials.
Description
Technical Field
The invention relates to a new antibacterial compound, namely a class of indole derivatives, stereoisomers thereof or pharmaceutically acceptable salts, solvates or hydrates thereof; processes for the preparation of these compounds, pharmaceutical compositions containing these compounds, the use of these compounds for the preparation of an antibacterial medicament, preferably against bacilli or gram-bacteria, more preferably against tubercle bacilli or gram-negative or gram-positive bacteria.
Background
Resistance of drug-resistant strains to antibiotics, especially multidrug resistance, seriously compromises the treatment of anti-infective diseases and is one of the major public health concerns of global concern. In recent years, infection by drug-resistant strains has been one of the leading causes of high mortality in infectious diseases, such as methicillin-resistant staphylococcus aureus (MRSA) and staphylococcus epidermidis (MRSE), penicillin-resistant streptococcus pneumoniae (PRSP), vancomycin-resistant enterococci (VRE), which seriously jeopardize clinical treatment, rendering the use of antibacterial drugs very limited, even ineffective. The clinical demand for new effective antibacterial drugs is urgent, and people are actively searching and developing various new drugs capable of resisting drug-resistant bacteria without any residual force.
Innovative mycin is an antibacterial antibiotic with a novel chemical structure, which is produced by separating a Actinoplanes from soil in Shandong Jinan of China, has an inhibiting effect on partial gram-positive and gram-negative bacteria, has low toxicity, and has a protective effect on mice infected with dysentery bacillus or escherichia coli, abdominal cavities or oral administration. Innovative mycin has good curative effect on septicemia caused by escherichia coli and urinary system infection in clinic. The molecular structure of the desulfurization innovative mycin is beta-methylindolopropionic acid, which does not have a thiopyran ring in the innovative mycin and has the same antibacterial activity on E.coli B as the innovative mycin. Chiffon et al studied the antibacterial and primary antibacterial effects of desulphatoinnomycin on e.coli B, and the results showed that both innovate and desulphatoinnovate produced antibacterial activity by inhibiting bacterial tryptophan biosynthesis, and the antibacterial mechanism was antagonistic to inhibition of tryptophan pathway enzyme synthesis (chiffon et al, antibiotics 1984, 9 (5): 401). This result indicates that the thiopyran ring in the innovative mycin molecule does not appear to be an essential group. The inventive mycin has novel structure, and the main core of the inventive mycin is a novel heterocyclic ring system chemically. However, the antibacterial agent is not used in clinic until now, and the reason is that the antibacterial agent has narrow antibacterial spectrum, can be only orally taken and can not be injected into muscle, and the antibacterial activity is lower than that of other current clinical antibacterial agents. Therefore, scientists have carried out a lot of structural modification to the innovative mycin, and Sushenghui and the like have carried out the modification in the following aspects according to the chemical structural characteristics of the innovative mycin: several derivatives of carboxylic acids, including esters and amides, were synthesized; synthesizing a plurality of derivatives substituted on NH of indole; several substitutions were made throughout the ring system. These derivatives showed that, except for the fact that N-formyl Innovicin had an antibacterial effect close to that of Innovicin, no significant antibacterial effect was observed in any of the other derivatives [ Sushenghui et al, pharmaceutical industry, 1984, 139 (2): 17)].
Thus, there is also a need in the art for new antibacterial compounds.
Disclosure of Invention
The invention mainly solves the technical problem of screening and synthesizing a new antibacterial compound through the structure-effect research of innovative mycin derivatives. The compound has remarkable antibacterial activity, and has the advantages of small molecular weight, simple synthesis and small toxic and side effects.
The invention also provides a synthetic method of the indole derivative or the medicinal salt thereof, and the compound is obtained by selecting a reaction route.
The invention also provides application of the indole derivative or the medicinal salt thereof in the aspect of antibiosis, and research shows that the indole derivative or the medicinal salt thereof has remarkable antibacterial activity, so that an antibacterial pharmaceutical composition taking the indole derivative as an active ingredient is provided. The invention also provides the use of a compound of the invention for the preparation of an antibacterial medicament, preferably against bacilli or gram bacteria, more preferably against tubercle bacilli or gram negative or gram positive bacteria.
In one aspect, the present invention provides indole derivatives having the general formula (I), stereoisomers thereof, or pharmaceutically acceptable salts or solvates or hydrates thereof:
wherein,
R1is H, C1-6Alkyl radical, C1-6Alkanoyl or C1-6An alkylamino group;
R2is H, C1-6Alkyl radical, C3-6Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkanoyl, halogen, cyano, nitro, CF3Amino, N (R)5)2,COR6,CO2R6Or CON (R)6)2;
R3Is H, C1-6Alkyl radical, C3-6Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkanoyl, halogen, cyano, nitro, CF3Amino, N (R)5)2,COR6,CO2R6Or CON (R)6)2;
R4Is H, C1-6Alkyl radical, C3-6Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkanoyl, halogen, cyano, nitro, CF3Amino, N (R)5)2,COR6,CO2R6Or CON (R)6)2;
Each R5Independently of each other is H, C1-6Alkyl, or is COCH2N(R7)2;
Each R6Independently is H, or C1-6An alkyl group;
each R7Independently is H, or C1-6An alkyl group;
a, B and D are independently carbon or nitrogen atoms;
x is NH, O, S or absent;
y is OR8Or N (R)8)2;
Each R8Is independently selected from
(1) H or C1-6An alkyl group, a carboxyl group,
the wavy line indicates where the bond is formed,
R11represents H or C1-6An alkyl group;
R12represents
I) unsubstituted or substituted by 1-3R9Substituted C1-6An alkyl group;
ii) unsubstituted or substituted by halogen, C1-6Alkyl, C1-6 alkylamino, hydroxy or C1-6Alkoxy-substituted C3-8A cycloalkyl group;
iii) unsubstituted or substituted by 1-3R10A substituted 6 to 18 membered aryl or 5 to 14 membered heteroaryl;
iv) adamantyl;
each R8Can be independently substituted by 1-3R9The substitution is carried out by the following steps,
each R9Independently selected from halogen, C1-6Alkyl radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, hydroxy C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylcarbonyl group, C1-6Alkylcarbonyloxy, aminosulfonyl, carbamoyl, C1-6Alkylcarbamoyl, C3-8A cycloalkyl group; a 6 to 18 membered arylcarbonyloxy; 6-to 18-membered aryl or 5-to 14-membered heteroaryl, or R10A substituted 6 to 18 membered aryl or 5 to 14 membered heteroaryl; a non-aromatic heterocyclic group containing 5 or 6 ring atoms; butyrolactam-1-yl; and a phosphate group;
R10selected from halogen, hydroxy, amino, C1-6Alkylcarbonyl group, C1-6Alkyl, C1-6 alkoxy, C1-6 alkylamino and C1-6An alkylcarbonyloxy group;
with the proviso that the compounds of formula (I) do not include the following compounds:
the substituents of the above formula are shown in the following table
2) A compound of the following formula 3
Formula 3
R1Is methyl and R2Is a hydroxyl group; or
R1Is methyl and R2Is an ethoxy group; and
3) a compound of formula 4
Formula 4
R1Is methyl and R2Is a hydroxyl group.
In a preferred embodiment, the compounds of formula (I) have the following general formula (II)
R1、R2、R3、R4A, B, D, X, Y is as defined in formula (I).
In another preferred embodiment, R3Substituted on A.
In another preferred embodiment, R3Substituted on B.
In another preferred embodiment, R3Substitution on D.
In another preferred embodiment, the compounds of formula (I) have the following general formula XV
R1、R2、R3、R4A, B, D, Y is as defined in formula (I).
In another preferred embodiment, in the compounds of formula (I) or formula (II),
a, B and D are all carbon atoms;
b and D are carbon atoms, A is a nitrogen atom;
d is a carbon atom, A and B are nitrogen atoms;
a and D are carbon atoms, B is a nitrogen atom;
a and B are carbon atoms, D is a nitrogen atom; or
B is a carbon atom, and A and D are nitrogen atoms.
In another preferred embodiment, in the compounds of formula (I) or formula (II),
R1is H, C1-4Alkyl radical, C1-4Alkanoyl or C1-4An alkylamino group;
R2is H, C1-4Alkyl radical, C3-4Cycloalkyl radical, C1-4Alkoxy radical, C1-4Alkanoyl, halogen, cyano, nitro, CF3Amino, N (R)5)2,COR6,CO2R6Or CON (R)6)2;
R3Is H, C1-4Alkyl radical, C3-6Cycloalkyl radical, C1-6Alkoxy radical, C1-4Alkanoyl, halogen, cyano, nitro, CF3Amino, N (R)5)2,COR6,CO2R6Or CON (R)6)2;
R4Is H, C1-4Alkyl radical, C3-4Cycloalkyl radical, C1-4Alkoxy radical, C1-4Alkanoyl, halogen, cyano, nitro, CF3Amino, N (R)5)2,COR6,CO2R6Or CON (R)6)2;
Each R5Independently of each other is H, C1-4Alkyl, or is COCH2N(R7)2;
Each R6Independently of each other is H, C1-4An alkyl group;
each R7Independently of each other is H, C1-4An alkyl group;
a, B and D are carbon or nitrogen atoms;
x is NH, O, S or absent;
y is OR8Or N (R)8)2;
Each R8Is independently selected from
(1) H or C1-6An alkyl group, a carboxyl group,
the wavy line indicates where the bond is formed,
R11represents H or C1-6An alkyl group;
R12represents
I) unsubstituted or substituted by 1-3R9Substituted C1-6An alkyl group;
ii) unsubstituted or substituted by halogen, C1-6Alkyl, C1-6 alkylamino,Hydroxy or C1-6Alkoxy-substituted C3-8A cycloalkyl group;
iii) unsubstituted or substituted by 1-3R10A substituted 6 to 18 membered aryl or 5 to 14 membered heteroaryl;
iv) adamantyl;
each R8Can be independently substituted by 1-3R9The substitution is carried out by the following steps,
each R9Independently selected from halogen, C1-6Alkyl radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, hydroxy C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylcarbonyl group, C1-6Alkylcarbonyloxy, aminosulfonyl, carbamoyl, C1-6Alkylcarbamoyl, C3-8A cycloalkyl group; 6-to 18-membered arylcarbonyloxy, 6-to 18-membered aryl or 5-to 14-membered heteroaryl, or R10A substituted 6 to 18 membered aryl or 5 to 14 membered heteroaryl; a non-aromatic heterocyclic group containing 5 or 6 ring atoms; butyrolactam-1-yl and phosphate;
R10selected from halogen, hydroxy, amino, C1-6Alkylcarbonyl group, C1-6Alkyl, C1-6 alkoxy, C1-6 alkylamino and C1-6An alkylcarbonyloxy group.
In another preferred embodiment, Y is OR8,R8Is C1-6Alkyl radical, each R8Can be independently substituted by 1-3R9Substituted, each R9Independently selected from halogen, C1-6Alkyl radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, hydroxy C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylcarbonyl group, C1-6Alkylcarbonyloxy, aminosulfonyl, carbamoyl, C1-6Alkylcarbamoyl, C3-8A cycloalkyl group; 6-to 18-membered arylcarbonyloxy, 6-to 18-membered aryl or 5-to 14-membered heteroaryl, or R10A substituted 6 to 18 membered aryl or 5 to 14 membered heteroaryl; non-aromatic hetero rings containing 5 or 6 ring atomsA cyclic group; butyrolactam-1-yl and phosphate.
In another preferred embodiment, Y is OR8,R8Is C1-6Alkyl radical, each R8Can be independently substituted by 1-3R9Substituted, each R9Independently selected from 6 to 18 membered arylcarbonyloxy.
In another preferred embodiment, in the compounds of formula (I) or formula (II), R12Represents unsubstituted C3-8Cycloalkyl radical, each R8Can be independently substituted by 1-3R9Substituted, each R9Independently selected from hydroxy, and C1-6Alkylamino, preferably R9Substituted at R12The above.
In another preferred embodiment, the present invention relates to an indole derivative represented by formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof:
wherein,
R1is H, C1-6Alkyl, or C1-6An alkanoyl group;
R2is H, C1-6Alkyl or halogen;
R3is H, C1-6Alkyl radical, C1-6Alkoxy, halogen, CF3Or N (R)5)2;
R4Is C1-6An alkyl group;
each R5Independently is H, or C1-6An alkyl group;
a, B and D are independently carbon or nitrogen atoms;
x is O, S, or absent;
y is OR8Or N (R)8)2;
Each R8Is independently selected from
(1) H, or C1-6An alkyl group, a carboxyl group,
the wavy line indicates where the bond is formed,
R11represents H or C1-6An alkyl group;
R12represents
I) unsubstituted or substituted by 1-3R9Substituted C1-6An alkyl group;
ii) unsubstituted or substituted by halogen, C1-6Alkyl radical, C1-6Alkylamino, hydroxy or C1-6Alkoxy-substituted C3-8A cycloalkyl group;
iii) unsubstituted or substituted by 1-3R10A substituted 6-to 18-membered aryl group,
iv) adamantyl;
v) unsubstituted 5-to 14-membered heteroaryl;
each R8Can be independently substituted by 1-3R9The substitution is carried out by the following steps,
each R9Independently selected from halogen, C1-6Alkyl radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, hydroxy, 6 to 18 membered arylcarbonyloxy, non-aromatic heterocyclyl containing 5 or 6 ring atoms, butyrolactam-1-yl, and phosphate;
R10selected from halogen, hydroxy, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical, C1-6Alkylamino and C1-6An alkylamino group;
with the proviso that the compounds of formula (I) do not include the following compounds:
1) a compound of formula 2
Formula 2
The substituents of the above formula are shown in the following table
2) A compound of the following formula 3
Formula 3
R1Is methyl and R2Is a hydroxyl group; or
R1Is methyl and R2Is an ethoxy group; and
3) a compound of the following formula 4
Formula 4
R1Is methyl and R2Is a hydroxyl group.
In another preferred embodiment, R1Is H, C1-6Alkyl, or C1-6An alkanoyl group.
In another preferred embodiment, R2Is H, C1-6Alkyl or halogen.
In another preferred embodiment, R3Is H, C1-6Alkyl radical, C1-6Alkoxy, halogen, CF3Or N (R)5)2。
In another preferred embodiment, R4Is C1-6An alkyl group.
In another preferred embodiment, each R is5Independently is H, or C1-6An alkyl group.
In another preferred embodiment, a, B, D are independently of each other a carbon or nitrogen atom.
In another preferred embodiment, X is O, S, or absent.
In another preferred embodiment, Y is OR8Or N (R)8)2,
Each R8Is independently selected from
(1) H, or C1-6An alkyl group, a carboxyl group,
the wavy line indicates where the bond is formed,
R11represents H or C1-6An alkyl group.
In another preferred embodiment, R12Represents
I) unsubstituted or substituted by 1-3R9Substituted C1-6An alkyl group;
ii) unsubstituted or substituted by halogen, C1-6Alkyl radical, C1-6Alkylamino, hydroxy or C1-6Alkoxy-substituted C3-8A cycloalkyl group;
iii) unsubstituted or substituted by 1-3R10SubstitutionThe 6-to 18-membered aryl group of (a),
iv) adamantyl;
v) an unsubstituted 5-to 14-membered heteroaryl.
In another preferred embodiment, each R is8Is independently selected from
(1) H, or C1-6An alkyl group, a carboxyl group,
the wavy line indicates where the bond is formed,
R11represents H or C1-6An alkyl group.
In another preferred embodiment, R12Represents
I) unsubstituted or substituted by 1-3R9Substituted C1-6An alkyl group;
ii) unsubstituted or substituted by halogen, C1-6Alkyl radical, C1-6Alkylamino, hydroxy or C1-6Alkoxy-substituted C3-8A cycloalkyl group;
iii) unsubstituted or substituted by 1-3R10A substituted 6-to 18-membered aryl group,
iv) adamantyl;
v) an unsubstituted 5-to 14-membered heteroaryl.
In another preferred embodiment, each R is8Is independently selected from
(1) H, or C1-6An alkyl group, a carboxyl group,
the wavy line indicates where the bond is formed,
R11represents H or C1-6An alkyl group;
R12represents
I) unsubstituted or substituted by 1-3R9Substituted C1-6An alkyl group;
ii) unsubstituted or substituted by halogen, C1-6Alkyl radical, C1-6Alkylamino, hydroxy or C1-6Alkoxy-substituted C3-8A cycloalkyl group;
iii) unsubstituted or substituted by 1-3R10A substituted 6-to 18-membered aryl group,
iv) adamantyl;
v) an unsubstituted 5-to 14-membered heteroaryl.
In another preferred embodiment, each R is8Can be independently substituted by 1-3R9Substituted, each R9Independently selected from halogen, C1-6Alkyl radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, hydroxy, 6 to 18 membered arylcarbonyloxy, non-aromatic heterocyclyl containing 5 or 6 ring atoms, butyrolactam-1-yl, and phosphate. In a preferred aspect, R9Substituted at R12The above.
In another preferred embodiment, R10Selected from halogen, hydroxy, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical, C1-6Alkylamino and C1-6An alkylamino group.
In another preferred embodiment, the compound of formula (I) has the structure of formula VIII
Wherein R is1、R2、R3、R4A, B, D are as defined for formula (I) and X isNH, O or S.
In another preferred embodiment, the compound of formula (I) has the structure of formula IX
Wherein R is1、R2、R3、R4A, B, D are as defined for formula (I).
In another preferred embodiment, the compounds of formula (I) have the structure of formula X
Wherein Z is O or N, and R8Is unsubstituted or substituted by 1 to 3R9Substituted C1-6Alkyl radical, R4、R9A, B, D is as defined for formula I, X is NH, O or S.
In another preferred embodiment, the compounds of formula (I) have the structure of formula XI
Wherein Z is O or N, and R8Is unsubstituted or substituted by 1 to 3R9Substituted C1-6Alkyl radical, R4、R9A, B, D are as defined for formula I.
In another preferred embodiment, the compound of formula (I) has the structure of formula XIII
Wherein R is1、R2、R3、R4、R11、R12A, B, D and X are as defined for formula I.
In another preferred embodiment, the compound of formula (I) has the structure of formula XIV
Wherein R is1、R2、R3、R4、R11、R12A, B and D are as defined for formula I.
Preferred compounds of the present invention are the compounds or stereoisomers in the following tables 1 and 2 and their pharmaceutically acceptable salts and solvates or hydrates.
TABLE 1
TABLE 2
The terms of the present invention are defined as follows.
The term "alkyl" as used in the present application is intended to designate a saturated, linear or branched hydrocarbon group, in particular a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl. Preferably methyl, ethyl or propyl. The substituted alkyl group can be a dihalogenated or trihaloalkyl group such as trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, tribromomethyl, tribromoethyl, and the like.
The terms "halogen", "halo" and "halo" denote F, Cl, Br or I.
The term "cycloalkyl" refers to a non-aromatic monocyclic carbon-containing ring, which may be saturated, having from 3 to 8 ring carbon atoms. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
The term "heterocyclyl" or "heterocycle" as used herein refers to aromatic and non-aromatic cyclic groups bearing at least one heteroatom as a ring member. Preferred heterocyclic groups are those containing 5 or 6 ring atoms including at least one heteroatom, more preferably a 5 or 6 membered heterocyclic group containing 1 nitrogen atom and1 oxygen atom, or a 5 or 6 membered heterocyclic group containing 1 nitrogen atom or 1 oxygen atom, or a 5 or 6 membered non-aromatic heterocyclic group containing 1 nitrogen atom and1 oxygen atom, or a 5 or 6 membered non-aromatic heterocyclic group containing 1 nitrogen atom or 1 oxygen atom, and the "heterocyclic group" includes: cyclic amine groups such as morpholino, preferably morpholino, piperidinyl, preferably piperidino, pyrrolidinyl, preferably pyrrolidino, and the like; and cyclic ether groups such as tetrahydrofuranyl, tetrahydropyranyl, and the like. Aromatic heterocyclyl groups, also referred to as "heteroaryl", are mono-cyclic hetero-aromatic groups that may include 1 to 3 heteroatoms, such as pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine groups and the like. The term "heteroatom" as used herein includes nitrogen, oxygen and sulfur atoms. The term heteroaryl as used herein also includes polycyclic hetero-aromatic systems with two or more rings in which two atoms are common to two adjacent rings (the rings are "fused"), wherein at least one of the rings is heteroaryl, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryls, heterocycles and/or heteroaryls. Heteroaryl includes 5 or 6 membered mono-cyclic hetero-aromatic groups containing 1 or 2 nitrogen, oxygen or sulfur atoms. Polycyclic hetero-aromatic systems with two rings include benzo five-membered heteroaryl groups containing one nitrogen, oxygen or sulfur atom. Examples of polycyclic heteroaromatic systems include quinoline, isoquinoline, tetrahydroisoquinoline, quinoxaline, benzeneAnd benzimidazoles, benzofurans, purines, imidazopyridines, benzotriazoles, and the like. Examples of heteroaryl groups also include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, etc,Azolyl radical, isoAzolyl group,Oxadiazolyl, thiazolyl, isothiazolyl or thiadiazolyl, including, for example, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isothiazolylAzolyl, 4-isoAzolyl, 5-isoAzolyl, 2-Oxadiazolyl, 5-Oxadiazolyl, 2-Azolyl, 4-Azolyl, 5-Azolyl, 3-pyrazolyl, 4-pyrazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidylA group, 5-pyrimidinyl group, 3-pyridazinyl group, 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, 2-triazolyl group, 5-triazolyl group, tetrazolyl group, 2-thienyl group, 3-thienyl group, carbazolyl group, benzimidazolyl group, benzothienyl group, benzofuranyl group, indolyl group, benzotriazolyl group, benzothiazolyl group, benzothiophenyl group, 2-thiazolyl group, 4-thiazolyl group, 5-triazolyl group, 2-thiazolyl groupAzolyl, benzimidazolyl, isoquinolyl, indolyl, isoindolyl, acridinyl, benzisoxazolylAzolyl, isothiazolyl, 1,2,3-Oxadiazolyl, 1,2,5-Oxadiazolyl, 1,2,4-Oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, purinyl, pyrazinyl, 1,3, 5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).
The term "phosphate group" as used in this application denotes-PO (OH)2。
The term "alkoxy" as used herein denotes an alkyl group as defined hereinbefore attached to the molecule via an oxygen ("alkoxy", e.g. -O-alkyl) atom. Specific examples include, but are not limited to, methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, n-hexoxy, isohexoxy, and the like, and when substituted alkoxy, the substituent may be, for example, halogen, amino, or the like.
The term "alkanoyl" means-C (O) R, wherein R is alkyl as defined herein. Specific examples include, but are not limited to, formyl, acetyl, isopropylacyl, n-propylacyl, n-butylacyl, isobutylacyl, sec-butylacyl, tert-butylacyl, n-pentylacyl, isopentylacyl, n-hexylacyl, isohexyl, and the like.
The term "aryl" refers to a carbocyclic aromatic ring group. The carbocyclic aromatic ring group has only carbon ring atoms (typically 6 to 18) and includes monocyclic aromatic rings such as phenyl and fused polycyclic aromatic ring systems in which one carbocyclic aromatic ring is fused to one or more aromatic rings, wherein the group or point of attachment is on a carbocyclic aromatic ring. Examples include 1-naphthyl, 2-naphthyl, 1-anthryl and 2-anthryl. Also included within the scope of the term "carbocyclic aromatic ring" as used herein are groups in which the aromatic ring is fused to one or more non-aromatic rings (carbocyclic or heterocyclic), such as indanyl, phthalimidyl, naphthaliminyl, phenanthridinyl or tetrahydronaphthyl, wherein the group or point of attachment is on the carbocyclic aromatic ring.
The term DMAP is 4-dimethylaminopyridine.
The term DIC is N, N-diisopropylcarbodiimide.
The term DMF is dimethylformamide.
The term "racemic mixture" means an equimolar mixture of two or more enantiomeric species without optical activity. The present invention includes all stereoisomers of the compounds described herein.
The present invention includes salts or solvates of the compounds described herein, including combinations thereof, such as solvates of the salts. The compounds of the invention may exist in solvated (e.g. hydrated) as well as unsolvated forms, and the invention includes all such forms.
Typically, but not exclusively, the salts of the invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of the present invention.
Examples of suitable pharmaceutically acceptable salts include inorganic acid addition salts such as hydrochloride, bromate, sulfate, phosphate and nitrate; organic acid addition salts such as acetate, galactarate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate and ascorbate; salts with acidic amino acids such as aspartate and glutamate; alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as magnesium and calcium salts; an ammonium salt; organic base salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt and N, N' -dibenzylethylenediamine salt; and salts with basic amino acids such as lysine salts and arginine salts. In some cases, the salt may be a hydrate or an ethanol solvate.
The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity).
The invention also provides a synthetic method of the compound shown in the formula (I).
The process may be carried out according to the following scheme to prepare the compound of formula (i).
Wherein R is1、R2、R3A, B, D, Y are as defined above for formula (I), wherein each R'1Independently is-COR4,R4As defined in formula (I), X is NH, O or S.
The process of the present invention may be carried out according to the following scheme for converting a compound of formula (I) having the structure of formula VIII to a compound of formula (I) having the structure of formula IX
Wherein R is1、R2、R3、R4A, B, D are as defined for formula (I).
The process of the present invention may also be carried out according to the following scheme, thereby converting the compound of formula VIII to the compound of formula X
Wherein Z is O or N, and R8Is unsubstituted or substituted by 1 to 3R9Substituted C1-6Alkyl radical, R1、R2、R3、R4、R9A, B, D is as defined for formula (I) and X is NH, O or S.
The process of the present invention may also be carried out according to the following scheme, thereby converting the compound of formula IX into the compound of formula XI
Wherein Z is O or N, and R8Is unsubstituted or substituted by 1 to 3R9Substituted C1-6Alkyl radical, R1、R2、R3、R4、R9A, B, D are as defined for formula (I).
The process of the invention may also be carried out according to the following scheme, thereby converting the compound of formula VIII into a compound of XIII
Wherein R is1、R2、R3、R4、R11、R12A, B and D are as defined for formula (I) and X is NH, O or S.
The process of the invention may also be carried out according to the following scheme, thereby converting the compound of formula IX into a compound of formula XIV
Wherein R is1、R2、R3、R4、R11、R12A, B and D are as defined for formula (I).
The method of the invention can comprise the following steps:
step 1) reacting a compound of formula III
With a compound of formula 1, and reacting the compound with a solvent,
(R’1)2o formula 1
Thereby producing the compound of the formula IV,
wherein each R'1Independently is-COR4,R1、R2、R3、R4A, B, D are as defined for formula (I), R13Is halogen or nitro;
step 2) reacting the compound of formula IV with HXCH2COY' to obtain the compound of the formula V,
wherein Y' is C1-6Alkoxy radical, R1、R2、R3、R4A, B, D is as defined for formula (I), X is NH, O or S;
step 3) reacting the compound of formula V with an acid or a salt thereof to obtain a compound of formula VI
Wherein Y' is as defined for formula V, R1、R2、R3、R4A, B, D is as defined for formula (I), X is NH, O or S;
step 4) hydrogenation of the compound of formula VI to give the compound of formula VII
Wherein Y' is as defined for formula V, R1、R2、R3、R4A, B, D is as defined for formula (I), X is NH, O or S;
step 5) reacting the compound of formula VII with a base to obtain a compound of formula (I) having the structure of formula VIII
Wherein R is1、R2、R3、R4A, B, D is as defined for formula (I) and X is NH, O or S.
The method of the invention can also comprise the following steps:
step 6) in the presence of a catalyst, a compound of formula (I) with a structure of formula VIII
Into a compound of formula (I) having the structure of formula IX
Wherein R is1、R2、R3、R4A, B, D are as defined for formula (I).
The method of the invention can also comprise the following steps:
step 7) reacting a compound of formula VIII in the presence of a suitable base
And R8ZH reaction to give the compound of formula X
Wherein Z is O or N, and R8Is unsubstituted or substituted by 1 to 3R9Substituted C1-6Alkyl radical, R1、R2、R3、R4、R9A, B, D is as defined for formula (I) and X is NH, O or S.
The method of the invention can also comprise the following steps:
step 8) reacting a compound of formula IX
And R8ZH reaction to give the compound of formula XI.
Wherein Z is O or N, and R8Is unsubstituted or substituted by 1 to 3R9Substituted C1-6Alkyl radical, R1、R2、R3、R4、R9A, B, D are as defined for formula (I).
The method of the invention can also comprise the following steps:
step 9) reacting a compound of formula VIII
Andreaction to give the compound of formula XIII
Wherein R is1、R2、R3、R4、R11、R12A, B, D and X are as defined for formula (I).
The method of the invention can also comprise the following steps:
step 10) reacting a compound of formula IX
Andreaction to give the compound of formula XIV
Wherein R is1、R2、R3、R4、R11、R12A, B and D are as defined for formula (I).
In one embodiment of the process of the present invention, step 1) is carried out by reacting a compound of formula III with a compound of formula 1 in the presence of an inert gas, preferably nitrogen, in an organic solvent, preferably dichloromethane, in the presence of a catalyst, preferably tin tetrachloride, and/or nitromethane, preferably at room temperature, to produce a compound of formula IV.
In one embodiment of the process of the invention, step 2) is carried out by reacting a compound of the formula IV, HXCH in the presence of an inert gas, preferably nitrogen2COY' and a suitable base, such as anhydrous pyridine, in a suitable solvent, such as anhydrous methanol, preferably at a suitable temperature, such as about 90 deg.C, for a suitable time, such as 48h, to give the compound of formula V.
In one embodiment of the process of the present invention, step 3) is carried out by reacting the compound of formula V with an acid or a salt thereof, preferably ammonium acetate and glacial acetic acid, in the presence of an inert gas, preferably nitrogen, to give the compound of formula VI.
In one embodiment of the process of the invention, step 4) is carried out by hydrogenating the compound of formula VI in the presence of a catalyst, e.g. 10% Pd — C, in an organic solvent, e.g. ethyl acetate, preferably at a suitable pressure, e.g. 45 atm, to obtain the compound of formula VII.
In one embodiment of the process of the present invention, step 5) is carried out by reacting the compound of formula VII with a suitable base, such as sodium hydroxide, in a suitable solvent, such as ethanol, water and/or tetrahydrofuran, preferably at a suitable temperature, such as room temperature, for a suitable time, such as 5h, to give the compound of formula (I), having the structure of formula VIII.
In one embodiment of the process of the present invention, the process further comprises the following step 6):
the compound of formula (I) having the structure of formula VIII is converted to the compound of formula (I) having the structure of formula IX in the presence of a catalyst, such as raney nickel, preferably in a suitable base, such as sodium hydroxide, in a suitable solvent, such as water.
In one embodiment of the process of the present invention, the process further comprises the following step 7):
reacting a compound of formula VIII with R in the presence of DIC and DMAP8ZH reaction to obtain the compound of formula X.
In one embodiment of the process of the present invention, the process further comprises the following step 8):
a compound of formula IX is reacted with R in the presence of an inert gas such as nitrogen, a suitable base such as triethylamine, in a suitable solvent such as DMF8ZH reaction to give the compound of formula XI.
In one embodiment of the process of the present invention, the process further comprises the following step 9):
reacting a compound of formula VIII with an inert gas, preferably nitrogen, in the presence of a suitable base, such as triethylamine, in a suitable solvent, such as DMF, preferably at a suitable temperature, such as room temperature, for a suitable time, such as 5minReaction to give the compound of formula XIII.
In one embodiment of the process of the present invention, the process further comprises the following step 10):
in the presence of an inert gas, preferably nitrogen, in the presence of a suitable base, for example triethylamineWhen a compound of formula IX is reacted with a solvent, e.g. DMF, preferably at a suitable temperature, e.g. room temperatureThe reaction is carried out for a suitable time, e.g., 5min, to give the compound of formula XIV.
Preparation of stereoisomers
Stereoisomers of the compounds of the present invention can be prepared by conventional techniques of the prior art, for example, the search of the innovative full synthetic route to mycin of Guxia Ling et al and the study of its stereoisomers (Proc. Pharmacology, 1987, 22 (9): 671-678). Specifically, according to the above method, stereoisomers of the compounds in table 1 having the stereoconfiguration as described in formula (II) or XV, especially the compounds of table 2, are prepared.
The skilled person knows how to prepare salts or solvates of the compounds of the present invention.
The present invention also provides an antibacterial composition comprising the compound of formula (i) as defined above or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition contains 0.7-99.9% by weight of indole derivative and 0.1-99.9% by weight of pharmaceutically acceptable carrier. The pharmaceutical composition is in the form of a formulation suitable for pharmaceutical use. The medicinal preparation can be in the form of tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, capsules, hard capsules, soft capsules, sustained-release capsules, oral liquid, mixture, buccal preparation, granules, medicinal granules, pills, powder, ointment, pellets, suspension, solution, injection, powder injection, freeze-dried powder injection, cachets, suppositories, ointment, plaster, cream, spray, aerosol, drops and patches.
The pharmaceutical composition of the present invention, as a preparation form, contains the compound of the present invention in an effective amount of 0.1 to 1000mg per dose, which means per preparation unit, such as per tablet of tablet, per capsule, or per dose, such as 100mg per dose.
The pharmaceutical compositions of the present invention may be formulated as solid or semi-solid pharmaceutical preparations in the form of powders, tablets, dispersible powders, capsules, cachets, suppositories, and ointments, using a solid carrier. Solid carriers which may be used are preferably one or more substances selected from diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, bulking agents, and the like, or may be encapsulating substances in powder formulations containing from 5% to 70% of the micronized active ingredient in the carrier. Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sucrose, lactose, fructose, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, low boiling waxes, cocoa butter, and the like. Because of their ease of administration, tablets, powders, cachets, and capsules represent the most advantageous oral solid form of benefit.
Liquid formulations of the present invention include solutions, suspensions and emulsions. For example, an injection preparation for parenteral administration may be in the form of water or a water-propylene glycol solution, and its isotonicity, pH, etc. are adjusted to suit the physiological conditions of a living body; the liquid preparation can also be prepared into solution in polyethylene glycol or water solution. Aqueous solutions for oral administration can be prepared by dissolving the active ingredient in water, followed by the addition of suitable amounts of coloring, flavoring, stabilizing and thickening agents. Aqueous suspensions suitable for oral administration can be prepared by dispersing the micronized active ingredient in viscous materials such as natural and synthetic gums, methylcellulose, sodium carboxymethylcellulose, and other known suspending agents.
It is particularly advantageous to formulate the above pharmaceutical preparations in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form of a formulation refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect. Such dosage unit forms may be in the form of a pack, such as a tablet, capsule or powder in a small tube or vial, or an ointment, gel or cream in a tube or bottle.
Although the amount of active ingredient contained in the dosage unit form may vary, it is generally adjusted within the range of 1-800mg, depending on the potency of the active ingredient selected.
When the active compounds of formula (I) according to the invention are used as medicaments for the treatment of bacterial infections, they are preferably administered in an amount of 6 to 14mg/kg body weight. The dosage administered may vary with the needs of the patient, the severity of the infection to be treated, the compound selected, and the like.
The preferred dosage for a given situation can be determined by one skilled in the art in a routine manner. Generally, the amount of the active ingredient to be initially treated is lower than the optimum dose of the active ingredient, and then the dose to be administered is gradually increased until the optimum therapeutic effect is achieved. For convenience, the total daily dose may be divided into several portions and administered in fractions.
Detailed Description
The present invention is further illustrated in detail by the following examples, which will enable those skilled in the art to more fully understand the present invention, but the practice of the present invention is not limited to these examples, which are not intended to limit the present invention in any way. The corresponding nuclear magnetic, mass spectral data, and the like, are written below the corresponding product, and the title compound in the form of the racemic mixture has the same nuclear magnetic and mass spectral data as the corresponding specific isomer. The specific isomer structures related to the title compounds mentioned in the preparation examples below are the compounds represented in table 2, and the numbers of the title compounds and their corresponding specific isomers are specified as follows: the title compound is numbered with a "'" in the upper right hand corner to give the title compound the corresponding specific isomer number. For example, the particular isomer number of compound 1 is compound 1'.
Example 1: 2-Carboxylic acid-3-methyl-3, 5-dihydro-2H-Thiopyrano [4,3,2-cd ] indole (Compound C)
Step 1) to a 0 ℃ solution of 4-iodoindole (7.5 g,30 mmol) in dichloromethane (75ml) under nitrogen protection, tin tetrachloride (4.5 ml,36 mmol) was slowly added, the reaction was carried out at room temperature for 30min, and then Ac was added2O (2.9 g,30 mmol) and nitromethane (46.5 ml) were reacted at room temperature for 1h, quenched with ice water, filtered, the filter cake was washed with a little ether, the organic layer was extracted with ethyl acetate, anhydrous Na2SO4Drying, spin-drying of the solvent and recrystallization from ethyl acetate and petroleum ether gave the compound 3-acetyl-4-iodoindole (6.9g, 78%).
1HNMR(500MHz,DMSO-d6):12.07(s,1H),8.32(d,J=3.0Hz,1H),7.67(dd,J=7.5Hz,1.0Hz,1H),7.49(dd,J=8.0Hz,1.0Hz,1H),6.92(t,J=8.0Hz,1H),2.49(s,3H)。MS(ESI+)m/z:286.0[M+H]+。
Step 2) under the protection of nitrogen, 3-acetyl-4-iodoindole (2.85 g,10 mmol), ethyl thioglycolate (3.84 g, 16 mmol) and anhydrous pyridine (2.61 g, 17 mmol) in anhydrous methanol (100ml) are reacted at 90 ℃ for 48h, after the reaction is finished, the methanol is evaporated to dryness, 100ml ethyl acetate is added to dissolve the residue, the ethyl acetate layer (80 ml × 3) is washed with water, and the ethyl acetate layer is treated with anhydrous Na2SO4Drying, spin-drying the solvent and recrystallizing with ethyl acetate and petroleum ether gave the compound 3-acetyl-4-ethoxycarbonylmethylthioindole (1.93g, 70%).
1HNMR(500MHz,DMSO-d6):12.00(s,1H),8.28(s,1H),7.24(d,J=8.0Hz,1H),7.14(t,J=8.0Hz,1H),6.96(d,J=8.0Hz,1H),4.08(q,J=7.5Hz,2H),3.80(s,2H),2.45(s,3H),1.13(t,J=7.5Hz,3H)。MS(ESI+)m/z:278.1[M+H]+。
Step 3) under the protection of nitrogen, 3-acetyl-4-ethoxycarbonyl methylthioindole (2.63 g,10 mmol), ammonium acetate (3.51 g, 46 mmol) and glacial acetic acid (5.54 g, 93 mmol) are reacted at 110 ℃ for 15h, water is added after the reaction is finished, an aqueous layer (80 ml × 3) is extracted by ethyl acetate, an ethyl acetate layer (80 ml × 3) is washed by water, and the ethyl acetate layer is dried by anhydrousNa2SO4Drying, spin-drying solvent, and separating with petroleum ether and ethyl acetate column chromatography to obtain 3-methyl-5H-thiopyrano [4,3,2-cd]Indole-2-carboxylic acid ethyl ester (1.23g, 50%).
1HNMR(500MHz,DMSO-d6):11.20(s,1H),7.32(s,1H),6.84(d,J=8.0Hz,1H),6.77(t,J=8.0Hz,1H),6.44(d,J=7.0Hz,1H),4.18(q,J=7.5Hz,2H),2.49(s,3H),1.24(t,J=7.5Hz,3H)。MS(ESI+)m/z:259.1[M]+。
Step 4) to 3-methyl-5H-thiopyrano [4,3,2-cd]Adding 10% Pd-C (324 mg, 0.30 mmol) into ethyl acetate (50ml) solution of indole-2-carboxylic acid ethyl ester (1.23g, 5mmol), then carrying out catalytic hydrogenation reaction for 20H under 45 atmospheric pressure, filtering through diatomite after the reaction is finished, washing a filter cake with ethyl acetate, concentrating a solvent of the filtrate, and carrying out column chromatography separation on petroleum ether and ethyl acetate to obtain a compound 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd]Indole-2-carboxylic acid ethyl ester (0.74g, 60%).1HNMR(500MHz,DMSO-d6):12.85(s,1H),10.80(s,1H),7.15(d,J=2.0Hz,1H),7.12(d,J=8.0Hz,1H),6.92(t,J=7.5Hz,1H),6.73(d,J=7.0Hz,1H),4.29(d,J=3.0Hz,1H),4.16(q,J=7.5Hz,2H),3.66(dq,J=3.5Hz,7.0Hz,1H),1.23(t,J=7.0Hz,3H)。MS(ESI+)m/z:261.3[M]+。
Step 5) Ethyl 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylate (0.5 g, 2 mmol) and a solution of sodium hydroxide (1.21 g,30 mmol) in ethanol (30 ml), water (18 ml) and tetrahydrofuran (80 ml) were reacted at room temperature for 5H. After completion of the reaction, the reaction mixture was diluted with brine, followed by addition of 2M hydrochloric acid solution (20 ml), extraction with methylene chloride (80 ml. times.3), drying over anhydrous magnesium sulfate, washing of the cake with ethyl acetate, spin-drying of the solvent, and recrystallization with methylene chloride and toluene to give a racemic mixture of 2-carboxylic acid-3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole (0.30g, 66%).
The racemic mixture of 2-carboxylic acid-3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole (0.3g) obtained above was dissolved in anhydrous methanol (8 ml), heated to boiling, and (— α -phenylethylamine (0.18 ml) was added dropwise, followed by filtration while hot and cooling to precipitate (S) - α -phenylethylamine (2R,3S) -2-carboxylic acid-3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole as white rod crystals (0.20 g). And (5) reserving the mother liquor. The crystals were recrystallized twice from anhydrous methanol and weighed 0.17 g.
The crystals are reacted with H2O (9 ml) mixture at 49% H2SO4—H2Treating with ethyl ether, washing with water to pH5, and removing anhydrous MgSO4And (5) drying. Concentrating, recrystallizing with chloroform-diethyl ether to obtain (2R,3S) -2-carboxylic acid-3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd]Indole 0.1g, white amorphous crystal. The relevant data are as follows:
1HNMR(500MHz,DMSO-d6):12.99(s,1H),10.89(s,1H),7.14(d,J=2.0Hz,1H),7.09(d,J=8.0Hz,1H),6.98(t,J=7.5Hz,1H),6.77(d,J=7.0Hz,1H),4.24(d,J=3.0Hz,1H),3.66(dq,J=3.5Hz,7.0Hz,1H),1.21(d,J=7.0Hz,3H)。MS(ESI+)m/z:233.1[M]+。
example 2: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid benzoyloxymethyl ester (CV2)
Under the protection of nitrogen, racemic mixture 2-carboxylic acid-3-methyl-3, 5-dihydro-2H-sulfur pyrano [4,3,2-cd]Indole or (2R,3S) -2-carboxylic acid 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd]Indole (0.23g, 1 mmol) and triethylamine (0.10 g,1 mmol) were dissolved in DMF solution (6ml) and reacted at room temperature for 5min, then chloromethyl benzoate (0.17 g,1 mmol) was added and reacted at room temperature for 24h, after completion of the reaction, ethyl acetate 50ml was added, the ethyl acetate layer (80 ml × 3) was washed with water, and the ethyl acetate layer was washed with anhydrous Na2SO4Drying, spin-drying solvent, recrystallizing with ethanol and petroleum ether to obtain racemic mixture 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd]Indole-2-carboxylic acid benzoyloxymethyl ester or (2R,3S) -3-methyl-3, 5-dihydro-2H-Thiopyrano [4,3,2-cd]Indole-2-carboxylic acid benzoyloxymethyl ester (0.22g, 60%), the data for which are as follows:
1HNMR(500MHz,DMSO-d6):10.91(s,1H),7.94(d,J=7.5Hz2H),7.71(d,J=7.5Hz,2H),7.56(t,J=7.5Hz,1H),7.18(s,1H),7.11(d,J=8.5Hz,1H),6.98(t,J=7.5Hz,1H),6.76(d,J=7.0Hz,1H),6.01(t,J=6.5Hz,1H),5.94(d,J=6.5Hz,1H),4.42(d,J=3.5Hz,1H),3.61(dd,J=3.5Hz,6.5Hz,1H),1.23(d,J=7.0Hz,3H)。MS(ESI+)m/z:367.1[M+H]+。
example 3: 3- (indol-3-yl) -butyric acid (compound 20)
Dissolving sodium hydroxide (0.19g,4.8mmol) in water (50ml), adding a racemic mixture of 2-carboxylic acid-3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole or (2R,3S) -2-carboxylic acid-3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole (1g,4.3mmol) under stirring, adding freshly prepared Raney nickel (Raney nickel) (10 g, wet weight, containing anhydrous ethanol) and water (50ml), heating under reflux for 1 hour, cooling and filtering, washing with 0.02% sodium hydroxide solution (20 ml. times.2), combining the washing solution with the filtrate, decolorizing with 0.2 g of activated carbon, filtering, acidifying the filtrate with concentrated hydrochloric acid, extracting with ethyl ether (20 ml. times.3), the ether extract was washed with water (10 ml. times.3), dried over anhydrous sodium sulfate overnight, the solvent was concentrated and recrystallized from ether and petroleum ether to give yellow crystals as a racemic mixture of 3- (indol-3-yl) -butyric acid or (S) -3- (indol-3-yl) -butyric acid (0.46 g, 52%), with the following data:
1HNMR(400MHz,DMSO-d6):12.00(s,1H),10.76(s,1H),7.53(d,J=8.0Hz,1H),7.31(d,J=8.0Hz,1H),7.09(d,J=2.4Hz,1H),7.04(t,J=7.2Hz,1H),6.95(t,J=7.2Hz,1H),3.42(m,1H),2.65(m,1H),2.46(m,1H),1.31(d,J=6.8Hz,3H)。MS(ESI+)m/z:204.3[M+H]+。
example 4:3- (indol-3-yl) -butyric acid benzoyloxymethyl ester (Compound DSCV)
Dissolving racemic mixture of 3- (indol-3-yl) -butyric acid or (S) -3- (indol-3-yl) -butyric acid (0.20 g,1 mmol) and triethylamine (0.10 g,1 mmol) in DMF solution (6ml) under nitrogen, reacting at room temperature for 5min, adding chloromethyl benzoate (0.17 g,1 mmol), reacting at room temperature for 24h, adding ethyl acetate 50ml after the reaction, washing ethyl acetate layer with water (80 ml × 3), and reacting the ethyl acetate layer with anhydrous Na2SO4Drying, spin-drying of the solvent and column fractionation gave the title compound, benzoyl oxymethyl 3- (indol-3-yl) -butyrate (0.23g, 70%) as a racemic mixture or as the (S) isomer, with the following data:
1HNMR(400MHz,DMSO-d6):10.79(s,1H),7.90(d,J=8.4Hz,1H),7.69(t,J=7.6Hz,1H),7.53(t,J=7.6Hz,1H),7.16(d,J=8.0Hz,1H),7.12(d,J=2.4Hz,1H),7.03(m,1H),6.93(m,1H),5.92(q,2H),3.45(m,1H),2.84(m,1H),2.69(m,1H),1.30(d,J=6.8Hz,3H)。MS(ESI+)m/z:338.1[M+H]+。
example 5: 2-Carboxylic acid-3-methyl-3, 5-dihydro-2H-Thiopyrano [4,3,2-cd ] -6-azaindole (Compound 1)
The title compound was prepared in analogy to example 1, starting from 4-iodo-1H-pyrrolo [3,2-c ] pyridine, as racemic mixture or (2R,3S) isomer, with the following relevant data:
1h NMR (500MHz, chloroform) 11.73(s,1H),7.63(s,1H),7.31(s,1H), 6.93(s,1H),6.37(s,1H),4.04(s,1H),3.50(m,1H),1.44(d, J =6.5Hz, 3H). MS (ESI)+)m/z:234.05[M]+。
Example 6: 2-Carboxylic acid-3-methyl-3, 5-dihydro-2H-Thiopyrano [4,3,2-cd ] -6, 7-diazaindole (Compound 2)
The title compound was prepared in analogy to example 1, starting from 4-iodo-1H-pyrrolo [3,2-d ] pyridazine, as racemic mixture or (2R,3S) isomer, with the following relevant data:
1h NMR (500MHz, chloroform) 11.77(s,1H),8.96(s,1H),7.92(s,1H),6.37(s,1H),4.04(s,1H),3.50(m,1H),1.46(d, J =6.5Hz, 3H). MS (ESI)+)m/z:235.04[M]+。
Example 7: 2-Carboxylic acid-3-methyl-3, 5-dihydro-2H-pyrano [4,3,2-cd ] -6, 7-diazaindole (Compound 3)
The title compound was prepared by a method analogous to example 1 starting from 4-iodo-1H-pyrrolo [3,2-d ] pyridazine, as racemic mixture or (2R,3S) isomer, with the following relevant data:
1h NMR (500MHz, chloroform) 11.78(s,1H),8.90(s,1H),7.88(s,1H),6.37(s,1H),4.47(s,1H),3.70(m,1H),1.53(d, J =6.5Hz, 3H). MS (ESI)+)m/z:219.06[M]+。
Example 8: 3-methyl-6-methoxy-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (Compound 4)
The title compound was prepared by an analogous method to example 1 starting from 4-iodo-7-methoxy-1H-indole as racemic mixture or (2R,3S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 12.53(s,1H),11.68(s,1H),9.82(s,1H),7.15(s,1H),6.89(s,1H),4.13(s,1H),4.07(s,3H),3.50(m,1H),1.41(d, J =6.5Hz, 3H). MS (ESI)+)m/z:263.06[M]+。
Example 9: 3-methyl-6-methylamino-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (Compound 5)
Starting from 4-iodo-N-methyl-1H-indol-7-amine, the title compound was prepared by a method analogous to example 1, as racemic mixture or (2R,3S) isomer, with the following data:
1h NMR (500MHz, chloroform) 12.78(s,1H),11.31(s,1H),9.86(s,1H),7.02(s,1H),6.97(s,1H),4.04(s,1H),3.50(m,1H),2.88(s,3H),1.54(d, J =6.5Hz, 3H). MS (ESI)+)m/z:262.08[M]+。
Example 11: 2-Carboxylic acid-3, 4-dimethyl-7-trifluoromethyl-3, 5-dihydro-2H-pyrano [4,3,2-cd ] indole (Compound 7)
Starting from 2-methyl-4-iodo-6- (trifluoromethyl) -1H-indole, the title compound was prepared by a method analogous to example 1 as racemic mixture or (2R,3S) isomer with the following data:
1h NMR (500MHz, chloroform) 12.17(s,1H),11.86(s,1H),8.37(s,1H),6.92(s,1H),4.47(s,1H),3.70(m,1H),2.49(s,3H),1.45(d, J =6.5Hz, 3H). MS (ESI)+)m/z:299.08[M]+。
Example 12: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (3' -morpholino) propyl ester (Compound 75)
Dissolving 2-carboxylic acid-3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole or (2R,3S) -2-carboxylic acid-3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole (2.55 g,11 mmol) in dichloromethane (50ml), adding DIC (1.51g,11.98mmol), stirring at normal temperature for 1H, adding DMAP (0.24g,1.96mmol) and 3-morpholino-propanol (1.59g,10.95mmol), heating and refluxing for 6H, washing the reaction solution with water and saturated water, drying anhydrous magnesium sulfate, filtering, evaporating to dryness, recrystallizing with ethyl acetate petroleum ether system to obtain 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (3 '-morpholino) propyl ester or (2R,3S) -3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (3' -morpholino) propyl ester 2.97g (75%), the data for this are as follows:
1H NMR (500MHz, chloroform) 11.86(s,1H),9.65(s,1H),7.18(s,1H),7.11(s,1H),7.02(s,1H),4.18(m,2H),4.00(s,1H),3.81(m,1H),3.69(m,2H),2.62(m,2H),2.49(s,2H),2.39(m,2H),1.78(s,2H),1.57(d, J =6.5Hz, 3H). MS (ESI)+)m/z:360.15[M]+。
Example 13: 3-methyl-7-fluoro-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (2' -morpholino) ethyl ester (Compound 76)
Starting from the compound 2-morpholinoethanol and 2-carboxylic acid-3-methyl-7-fluoro-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole, as racemic mixture or (2R,3S) isomer, the title compound, as racemic mixture or (2R,3S) isomer, was prepared according to a method analogous to example 12, with the following data:
1h NMR (500MHz, chloroform) 11.84(s,1H),9.79(s,1H),7.02(s,1H),6.89(s,1H),4.27(s,2H),4.00(s,1H),3.81(m,1H),3.71(m,4H),2.83(m,4H),2.59(m,2H),1.52(d, J =6.5Hz, 3H). MS (ESI)+)m/z:364.13[M]+。
Example 14: 3-methyl-3, 5-dihydro-2H-pyrano [4,3,2-cd ] indole-2-carboxylic acid (2' -morpholino) ethyl ester (Compound 77)
Starting from the compounds 2-morpholinoethanol and 2-carboxylic acid-3-methyl-3, 5-dihydro-2H-pyrano [4,3,2-cd ] indole, as racemic mixture or (2R,3S) isomer, the title compound, as racemic mixture or (2R,3S) isomer, was prepared in analogy to example 12 with the following data:
1h NMR (500MHz, chloroform) 11.36(s,1H),9.80(s,1H),7.18(s,1H),7.02(s,1H),6.80(s,1H),4.31(s,2H),4.30(s,1H),4.01(m,1H),3.70(m,4H),2.86(s,4H),2.82(m,2H),1.40(d, J =6.5Hz, 3H). MS (ESI)+)m/z:330.16[M]+。
Example 15: 3-methyl-7-methoxy-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (2' -dimethylamino) ethyl ester (Compound 78)
Starting from the compound 2-methylaminoethanol and 2-carboxylic acid-3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole, as racemic mixture or (2R,3S) isomer, the title compound, as racemic mixture or (2R,3S) isomer, was prepared by reaction in analogy to example 12, with the following data:
1h NMR (500MHz, chloroform) 11.66(s,1H),9.78(s,1H),7.02(s,1H),6.79(s,1H),4.23(m,2H),4.00(s,1H),3.88(s,3H),3.81(m,1H),3.16(m,2H),2.81(s,6H),1.41(d, J =6.0Hz, 3H). MS (ESI)+)m/z:334.14[M]+。
Example 16: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] -6, 8-diazaindole-2-carboxylic acid (2' -dimethylaminoethyl) amine (compound 79)
Starting from the compound N, N-dimethylethylenediamine and 2-carboxylic acid-3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] -6, 8-diazaindole as racemic mixture or (2R,3S) isomer, the title compound was prepared in analogy to example 12 as racemic mixture or (2R,3S) isomer with the following data:
1h NMR (500MHz, chloroform) 11.53(s,1H),9.05(s,1H),7.30(s,1H), 4.11(s,1H),3.48(s,1H),3.40(m,1H),3.35(m,2H),2.64(m,2H),2.32(s,6H),1.61(d, J =6.5Hz, 3H). MS (ESI)+)m/z:305.13[M]+。
Example 17: 2- (3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] -8-azaindole-2-carbonyloxy) ethylphosphonic acid (Compound 80)
Dissolving 2-carboxylic acid-3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] -8-azaindole or (2R,3S) -2-carboxylic acid-3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] -8-azaindole (2.57 g,11 mmol) in dichloromethane (50ml), adding DIC (1.51g,11.98mmol), stirring at normal temperature for 1H, adding DMAP (0.24g,1.96mmol) and dimethyl hydroxyethyl phosphonate (1.84g,10.95mmol), heating and refluxing for 6H, washing with water, drying with saturated salt reaction solution, anhydrous magnesium sulfate, filtering, evaporating to dryness, recrystallizing with ethyl acetate petroleum ether system to obtain 3-methyl-3, 5-dihydro-2H-thiopyrano [4 ], 3,2-cd ] -8-azaindole-2-carboxylic acid (dimethyl 2' -phosphonate) ethyl ester 3.50g, dissolved in dichloromethane (50ml), added trimethylbromosilane (9.85g, 64.8mmol), stirred at ambient temperature for 3H, quenched with methanol, evaporated to dryness to give the product 2- (3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] -8-azaindole-2-carbonyloxy) ethylphosphonic acid 2.53g (68%) as racemic mixture or (2R,3S) isomer with the following data:
1h NMR (500MHz, chloroform) 11.58(s,1H),8.12(s,1H),7.21(s,1H),6.37(s,1H),4.31(m,2H),4.00(s,1H),3.81(m,3H),2.02(m,2H),1.42(d, J =6.0Hz, 3H). MS (ESI)+)m/z:342.04[M]+。
Example 18: n-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] -7-azaindole-2-carboxylic acid methyl ester (Compound 8)
Starting from 4-iodo-1-methyl-1H-pyrrolo [3,2-c ] pyridine, the title compound, as a racemic mixture or as the (2R,3S) isomer, was prepared by a method analogous to examples 1 and 12, with the following relevant data:
1h NMR (500MHz, chloroform) 7.71(s,1H),6.90(s,1H),6.29(s,1H),5.32(m,1H),4.00(s,1H),3.78(m,1H),3.62(s,3H),1.42(d, J =6.5Hz, 3H). MS (ESI)+)m/z:262.08[M]+。
Example 19: n-acetyl-3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] -7-azaindole-2-carboxylic acid ethyl ester (Compound 9)
The title compound was prepared by a method analogous to examples 1 and 12 starting from 1- (4-iodo-1H-pyrrolo [2,3-c ] pyridin-1-yl) ethanone as racemic mixture or as (2R,3S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 8.65(s,1H),8.30(s,1H),7.12(s,1H),4.12(m,2H),4.01(s,1H),3.81(m,1H),2.70(s,3H),1.54(d, J =6.5Hz,3H),1.01(m, 3H). MS (ESI)+)m/z:304.09[M]+。
Example 20: 3-methyl-3, 5-dihydro-2H-pyrano [4,3,2-cd ] -6, 7-diazaindole-2-carboxylic acid ethyl ester (Compound 10)
The title compound was prepared by a method analogous to examples 1 and 12 starting from 4-iodo-1H-pyrrolo [3,2-d ] pyridazine, as racemic mixture or (2R,3S) isomer, with the following relevant data:
1h NMR (500MHz, chloroform) 11.32(s,1H),8.88(s,1H),6.28(s,1H),4.15(m,2H),3.98(s,1H),3.84(m,1H),1.53(d, J =6.5Hz,3H),0.99(m, 3H). MS (ESI)+)m/z:247.10[M]+。
Example 21: 3-methyl-3, 5-dihydro-2H-pyrano [4,3,2-cd ] -7-azaindole-2-carboxylic acid ethyl ester (Compound 11)
The title compound was prepared by a method analogous to examples 1 and 12 starting from 4-iodo-1H-pyrrolo [2,3-c ] pyridine as a racemic mixture or as the (2R,3S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 11.33(s,1H),8.86(s,1H),8.36(s,1H),6.37(s,1H),4.43(s,1H),4.26(m,2H),4.01(m,1H),1.42(d,J=6.5Hz,3H),1.30(m,3H)。MS(ESI+)m/z:246.10[M]+。
example 22: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] -6, 7-diazaindole-2-carboxylethylamine (Compound 12)
The title compound was prepared by a method analogous to examples 1 and 12 starting from 4-iodo-1H-pyrrolo [3,2-d ] pyridazine, as racemic mixture or (2R,3S) isomer, with the following relevant data:
1h NMR (500MHz, chloroform) 11.43(s,1H),8.32(s,1H),7.83(s,1H),6.37(s,1H),4.43(s,1H),4.26(m,2H),4.01(m,1H),1.42(d, J =6.5Hz,3H),1.30(m, 3H). MS (ESI)+)m/z:262.09[M]+。
Example 23: 3-methyl-7-fluoro-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid tert-butyl ester (Compound 13)
Starting from 4-iodo-6-fluoro-1H-indole, the title compound was prepared by a method analogous to examples 1 and 12 as racemic mixture or (2R,3S) isomer with the following data:
1h NMR (500MHz, chloroform) 11.36(s,1H),8.95(s,1H),7.36(s,1H),6.37(s,1H),3.56(s,1H),3.48(m,1H),1.40(s,9H),1.34(d, J =6.5Hz, 3H). MS (ESI)+)m/z:307.10[M]+。
Example 24: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid tert-butylamine (Compound 14)
Starting from 4-iodo-1H-indole, the title compound was prepared by a method analogous to examples 1 and 12 as racemic mixture or (2R,3S) isomer with the following data:
1h NMR (500MHz, chloroform) 11.66(s,1H),9.79(s,1H),8.00(s,1H),7.02(s,1H),6.90(s,1H),6.85(s,1H),4.00(s,1H),3.81(m,1H),1.50(s,9H),1.34(d, J =6.5Hz, 3H). MS (ESI)+)m/z:288.13[M]+。
Example 25: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] -6, 8-diazaindole-2-carboxamidine (Compound 15)
The title compound was prepared by a method analogous to examples 1 and 12 starting from 4-iodo-7H-pyrrolo [2,3-d ] pyrimidine as racemic mixture or (2R,3S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 11.75(s,1H),9.80(s,1H),8.21(s,1H),7.02(s,1H),4.11(s,1H),3.48(m,1H),1.53(s,3H),1.29(d, J =6.5Hz, 3H). MS (ESI)+)m/z:248.07[M]+。
Example 26: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] -6-azaindole-2-carboxyethylamine (Compound 16)
The title compound was prepared by a method analogous to examples 1 and 12 starting from 4-iodo-1H-pyrrolo [3,2-c ] pyridine as a racemic mixture or as the (2R,3S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 11.66(s,1H),9.05(s,1H),8.03(s,1H),7.43(s,1H),6.37(s,1H),4.11(s,1H),3.48(m,1H),2.92(m,2H),1.34(d, J =6.5Hz,3H),1.20(s, 3H). MS (ESI)+)m/z:261.09[M]+。
Example 27: 3-methyl-3, 5-dihydro-2H-pyrano [4,3,2-cd ] -6, 7-diazaindole-2-formylisopropylamine (Compound 17)
The title compound was prepared by a method analogous to examples 1 and 12 starting from 4-iodo-1H-pyrrolo [3,2-d ] pyridazine, as racemic mixture or (2R,3S) isomer, with the following relevant data:
1h NMR (500MHz, chloroform) 11.88(s,1H),8.92(s,1H),8.02(s,1H),6.01(s,1H),6.37(s,1H),4.11(s,1H),3.84(m,1H),1.31(d, J =6.5Hz,3H),1.07(s, 6H). MS (ESI)+)m/z:260.13[M]+。
Example 30: 3- (1-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) butanoic acid (Compound 21)
Starting from 1-methyl-4-iodo-1H-pyrrolo [2,3-c ] pyridine, the title compound, as a racemic mixture or (S) isomer, was prepared by a method analogous to examples 1 and 3, with the following relevant data:
1h NMR (500MHz, chloroform) 11.78(s,1H),8.45(s,1H),8.28(d, J =6.5Hz,1H), 7.22(d, J =6.5Hz,1H),6.45(s,1H),3.36(s,1H),3.20(m,1H),2.51(m,2H),1.39(d, J =6.5Hz, 3H). MS (ESI)+)m/z:218.11[M]+。
Example 32: 3- (7-methoxy-1-methyl-1H-pyrrolo [3,2-c ] pyridin-3-yl) butanoic acid (Compound 22)
The title compound was prepared by a method analogous to examples 1 and 3 starting from 4-iodo-7-methoxy-1-methyl-1H-pyrrolo [3,2-c ] pyridine as racemic mixture or (S) isomer with the following data:
1h NMR (500MHz, chloroform) 11.06(s,1H),7.98(s,1H),7.85(s,1H),6.14(s,1H),3.91(s,3H),3.66(s,1H),3.20(m,1H),2.50(m,2H),1.39(d, J =6.5Hz, 3H). MS (ESI)+)m/z:248.12[M]+。
Example 33: 3- (7-fluoro-1H-pyrrolo [2,3-c ] pyridin-3-yl) butanoic acid (Compound 23)
Starting from 4-iodo-7-fluoro-1H-pyrrolo [2,3-c ] pyridine, the title compound, as a racemic mixture or as the (S) isomer, was prepared by a method analogous to examples 1 and 3, with the relevant data as follows
1H NMR (500MHz, chloroform) 11.36(s,1H),10.55(s,1H),8.00(s,1H),7.58(s,1H),6.83(s,1H),3.20(m,1H),2.51(m,2H),1.40(d, J =6.5Hz, 3H). MS (ESI)+)m/z:222.08[M]+。
Example 34: ethyl 3- (7-fluoro-1-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) butanoate (Compound 24)
Starting from 1-methyl-4-iodo-7-fluoro-1H-pyrrolo [2,3-c ] pyridine, the title compound, as a racemic mixture or (S) isomer, was prepared by a method analogous to examples 1,3 and 12, with the following relevant data:
1h NMR (500MHz, chloroform) 7.96(s,1H),7.50(s,1H),6.27(s,1H),4.01(m,2H),3.84(s,3H),3.51(m,1H),2.54(m,2H),1.39(d, J =6.5Hz,3H),1.15(m, 3H). MS (ESI)+)m/z:264.13[M]+。
Example 35: N-Ethyl-3- (5-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) butanoylethylamine (compound 25)
Starting from 4-iodo-5-methyl-1H-pyrrolo [2,3-c ] pyridine, the title compound was prepared in analogy to examples 1,3 and 12 as racemic mixture or (S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 11.39(s,1H),8.29(s,1H),7.32(s,1H),6.84(s,1H),3.26(m,2H),3.18(m,1H),2.66(m,2H),2.57(s,3H),2.49(s,1H),1.39(d, J =6.5Hz,3H),1.08(m, 3H). MS (ESI)+)m/z:245.15[M]+。
Example 36: 3- (7H-pyrrolo [2,3-c ] pyridazin-5-yl) butanoic acid tert-butyl ester (Compound 26)
The title compound was prepared by a method analogous to example 12 starting from 4-iodo-7H-pyrrolo [2,3-c ] pyridazine, as racemic mixture or (S) isomer, with the following relevant data:
1h NMR (500MHz, chloroform) 9.08(s,1H),7.57(s,2H),6.38(s,1H),3.51(m,1H),2.54(m,2H),1.40(d, J =6.5Hz,3H),1.36(s, 9H). MS (ESI)+)m/z:261.15[M]+。
Example 37: 3- (7-methyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) butanoic acid tert-butyl ester (compound 27)
The title compound was prepared in analogy to examples 1,3 and 12 starting from 4-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine as racemic mixture or (S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 9.25(s,1H),8.52(s,1H),6.15(s,1H),3.78(s, 3H),3.51(m,1H),2.53(m,2H),1.38(d, J =6.0Hz,3H),1.33(s, 9H). MS (ESI)+)m/z:275.16[M]+。
Example 38: N-Ethyl-3- (5- (methylamino) -1H-indol-3-yl) butanamide (Compound 28)
Starting from 4-iodo-5- (methylamino) -1H-indole, the title compound was prepared in analogy to the methods of examples 1,3 and 12 as racemic mixture or (S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 11.30(s,1H),9.52(s,1H),8.03(s,1H),7.26(s,1H),7.17(s,1H),6.50(s,1H),6.37(s,1H),3.27(m,2H),3.18(m,1H),2.80(s,3H),2.55(m,2H),1.39(d, J =6.0Hz,3H),1.05(m, 3H). MS (ESI)+)m/z:259.17[M]+。
Example 39: 3- (1-acetyl-6-methyl-1H-indol-3-yl) butyric acid isopropyl ester (Compound 29)
Starting from 1-acetyl-4-iodo-6-methyl-1H-indole, the title compound was prepared in analogy to examples 1,3 and 12 as racemic mixture or (S) isomer with the following data:
1h NMR (500MHz, chloroform) 7.68(s,1H),7.37(s,1H),7.00(s,1H),6.98(s,1H),4.92(m,1H),3.51(m,1H),2.70(s,3H),2.50(m,1H),2.27(m,2H),2.20(s,3H),1.42(d, J =6.0Hz,3H),1.15(s, 6H). MS (ESI)+)m/z:301.17[M]+。
Example 40: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (4' -methylcyclohexanecarbonyloxy) methyl ester (Compound 30)
The title compound was prepared by a method analogous to example 2 as a racemic mixture or as the (2R,3S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 9.65(s,1H),7.11(d, J =7.0Hz,3H),6.04(d, J =6.5Hz,1H),5.91(t, J =6.5Hz,1H),4.00(s,1H),3.81(m,1H),2.28(m,1H),1.66(m,3H),1.56(m,3H),1.38(d, J =6.0Hz,3H),1.26(m,4H),1.01(m, 3H). MS (ESI)+)m/z:387.15[M]+。
Example 41: (3-methyl-7-fluoro-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid 4-methoxycyclohexanecarbonyloxy) methyl ester (Compound 31)
Starting from 4-iodo-6-fluoro-1H-indole, the title compound was prepared by a method analogous to examples 1 and 2 as racemic mixture or (2R,3S) isomer with the following data:
1h NMR (500MHz, chloroform) 9.79(s,1H),7.02(s,1H),6.89(s,2H),6.52(d, J =6.5Hz,1H),6.05(d, J =6.5Hz,1H),4.00(s,1H),3.81(m,1H),3.45(s,3H),2.97(m,1H),2.02(m,4H),1.50(m,2H),1.40(m,3H),1.38(d, J =6.0Hz, 3H). MS (ESI)+)m/z:421.14[M]+。
Example 42: 3-methyl-7-methoxy-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (cyclopropanecarbonyloxy) methyl ester (Compound 32)
Starting from 4-iodo-6-methoxy-1H-indole, the title compound was prepared by a method analogous to examples 1 and 2, as racemic mixture or (2R,3S) isomer, with the following data:
1h NMR (500MHz, chloroform) 9.64(s,1H),7.02(s,1H),6.78(s,2H),6.05(d, J =6.5Hz,1H),5.93(d, J =6.5Hz,1H),4.10(s,1H),3.83(m,1H),3.73(s,3H),1.43(m,1H),1.38(d, J =6.0Hz,3H),1.11(m,2H),0.83(m, 2H). MS (ESI)+)m/z:361.10[M]+。
Example 43: 3-methyl-3, 5-dihydro-2H-pyrano [4,3,2-cd ] -6, 8-diazaindole-2-carboxylic acid (cyclopentanecarboxyloxy) methyl ester (Compound 33)
The title compound was prepared in analogy to examples 1 and 2, starting from 4-iodo-7H-pyrrolo [2,3-d ] pyrimidine, as racemic mixture or (2R,3S) isomer, with the following relevant data:
1h NMR (500MHz, chloroform) 11.98(s,1H),9.05(s,1H),7.36(s,1H),6.37(d, J =6.5Hz,1H),5.73(d, J =6.5Hz,1H),4.00(s,1H),3.81(m,1H),2.57(m,1H),2.10(m,2H),1.84(m,2H),1.75(m,2H),1.69(m,2H),1.46(d, J =6.0Hz, 3H). MS (ESI)+)m/z:361.11[M]+。
Example 44: 3-methyl-3, 5-dihydro-2H-pyrano [4,3,2-cd ] -8-azaindole-2-carboxylic acid (cyclobutanecarbonyloxy) methyl ester (Compound 34)
The title compound was prepared by a method analogous to examples 1 and 2 starting from 4-iodo-1H-pyrrolo [2,3-b ] pyridine as a racemic mixture or as the (2R,3S) isomer, with the following relevant data:
1h NMR (500MHz, chloroform) 8.45(s,1H),7.63(s,1H),6.57(d, J =6.5Hz,1H),6.49(s,1H),5.92(d, J =6.5Hz,1H),3.82(s,2H),3.74(m,1H),2.91(m,1H),2.50(m,2H),2.35(m,2H),2.16(m,2H),1.38(d, J =6.0Hz, 3H). MS (ESI)+)m/z:346.10[M]+。
Example 45: 3-methyl-3, 5-dihydro-2H-pyrano [4,3,2-cd ] -8-azaindole-2-carboxylic acid (4' -hydroxycyclohexanecarbonyloxy) methyl ester (Compound 35)
The title compound was prepared by a method analogous to examples 1 and 2 starting from 4-iodo-1H-pyrrolo [2,3-b ] pyridine as a racemic mixture or as the (2R,3S) isomer, with the following relevant data:
1h NMR (500MHz, chloroform) 8.23(s,1H),7.40(s,1H),6.67(d, J =6.0Hz,1H),6.37(s,1H),5.82(d, J =6.0Hz,1H),4.00(s,1H),3.81(m,1H),3.25(m,1H),2.90(s,1H),2.76(m,2H),2.27(s,2H),1.95(m,2H),1.63(m,2H),1.42(m,2H),1.38(d, J =6.5Hz, 3H). MS (ESI)+)m/z:390.12[M]+。
Example 46: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (1' -methylcyclohexanecarbonyloxy) methyl ester (Compound 36)
The title compound, as a racemic mixture or as the (2R,3S) isomer, was prepared by a method analogous to example 2, with the relevant data as follows
1H NMR (500MHz, chloroform) 9.80(s,1H),7.12(s,1H),7.02(s,1H),6.67(d, J =6.0Hz,1H),5.82(d, J =6.0Hz,1H),4.00(s,1H),3.83(m,1H),2.07(m,2H),1.66(m,4H),1.56(m,3H),1.44(d, J =6.5Hz,3H),1.35(m,1H),1.09(s, 3H). MS (ESI)+)m/z:387.15[M]+。
Example 47: 3-methyl-7- (methylamino) -3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (4' -methoxycyclohexanecarbonyloxy) methyl ester (Compound 37)
Starting from 4-iodo-N-methyl-1H-indol-6-amine, the title compound was prepared in analogy to examples 1 and 2 as racemic mixture or (2R,3S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 7.02(s,1H),6.75(d, J =6.0Hz,1H),6.45(s,1H),6.24(s,1H),5.83(d, J =6.0Hz,1H),4.02(s,1H),3.84(m,1H),3.47(s,3H),2.84(s,3H),2.79(m,1H),2.57(m,1H),2.21(m,3H),1.82(m,3H),1.50(m,4H),1.38(d, J =6.5Hz, 3H). MS (ESI)+)m/z:432.17[M]+。
Example 48: 3, 6-dimethyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (4' -methylcyclohexanecarbonyloxy) methyl ester (Compound 38)
Starting from 4-iodo-7-methyl-1H-indole, the title compound was prepared by a method analogous to examples 1 and 2 as racemic mixture or (2R,3S) isomer with the following data:
1h NMR (500MHz, chloroform) 8.80(s,1H),7.08(s,1H),7.02(s,1H),6.75(d, J =6.0Hz,1H),5.83(d, J =6.0Hz,1H),4.02(s,1H),3.83(m,1H),2.84(s,3H),2.57(m,1H),1.85(m,2H),1.73(m,4H),1.53(m,1H),1.52(m,4H),1.38(d, J =6.5Hz,3H),1.02(m, 3H). MS (ESI)+)m/z:401.17[M]+。
Example 49: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] -6, 8-diazaindole-2-carboxylic acid (4' -methoxycyclohexanecarbonyloxy) methyl ester (Compound 39)
The title compound was prepared in analogy to examples 1 and 2, starting from 4-iodo-7H-pyrrolo [2,3-d ] pyrimidine, as racemic mixture or (2R,3S) isomer, with the following relevant data:
1H NMR(500MHz, chloroform) 9.05(s,1H),6.76(d, J =6.0Hz,1H),6.37(s,1H),5.88(d, J =6.0Hz,1H),4.00(s,1H),3.81(m,1H),3.47(s,3H),2.84(m,1H),2.37(m,1H),2.36(m,3H),2.25(m,2H),2.07(m,2H),1.65(m,2H),1.56(m,2H),1.47(d, J =6.5Hz, 3H). MS (ESI)+)m/z:405.14[M]+。
Example 50: 3-methyl-3, 5-dihydro-2H-pyrano [4,3,2-cd ] -8-azaindole-2-carboxylic acid (4' -hydroxycyclohexanecarbonyloxy) methyl ester (Compound 40)
The title compound was prepared by a method analogous to examples 1 and 2 starting from 4-iodo-1H-pyrrolo [2,3-b ] pyridine as a racemic mixture or as the (2R,3S) isomer, with the following relevant data:
1h NMR (500MHz, chloroform) 8.16(s,1H),6.96(s,1H),6.86(d, J =6.0Hz,1H),6.64(s,1H),5.78(d, J =6.0Hz,1H),4.81(s,1H),4.01(s,1H),3.68(m,1H),3.42(m,2H),2.66(m,2H),1.95(m,2H),1.71(m,2H),1.52(m,3H),1.43(d, J =6.5Hz, 3H). MS (ESI)+)m/z:374.15[M]+。
Example 51: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] -6, 8-diazaindole-2-carboxylic acid (4' -hydroxycyclohexanecarbonyloxy) methyl ester (Compound 41)
The title compound was prepared by a method analogous to examples 1 and 2 starting from 4-iodo-1H-pyrrolo [2,3-b ] pyrimidine as racemic mixture or (2R,3S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 11.20(s,1H),8.23(s,1H),7.26(s,1H),6.86(d, J =6.0Hz,1H),5.78(d, J =6.0Hz,1H),4.05(s,1H),3.81(m,1H),3.75(s,1H),2.90(m,1H),2.76(m,2H),2.06(m,2H),1.75(m,2H),1.55(m,3H),1.39(d, J =6.5Hz, 3H). MS (ESI)+)m/z:390.12[M]+。
Example 52: 3-methyl-8-methoxy-3, 5-dihydro-2H-pyrano [4,3,2-cd ] indole-2-carboxylic acid (4' -methylcyclohexanecarbonyloxy) methyl ester (Compound 42)
Starting from 4-iodo-5-methoxy-1H-indole, the title compound was prepared by a method analogous to examples 1 and 2 as racemic mixture or (2R,3S) isomer with the following data:
1h NMR (500MHz, chloroform) 11.23(s,1H),7.02(s,1H),6.88(s,1H),6.80(s,1H),6.56(d, J =6.0Hz,1H),5.68(d, J =6.0Hz,1H),4.81(s,1H),4.01(m,1H),3.91(s,3H),2.52(m,2H),1.67(m,2H),1.53(t, J =5.5Hz,3H),1.40(m,2H),1.34(d, J =6.5Hz,3H),1.03(m, 2H). MS (ESI)+)m/z:401.18[M]+。
Example 53: 3-methyl-3, 5-dihydro-2H-pyrano [4,3,2-cd ] indole-2-carboxylic acid (4-fluorocyclohexanecarbonyloxy) methyl ester (Compound 43)
The title compound was prepared by a method analogous to example 2 as a racemic mixture or as the (2R,3S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 11.31(s,1H),7.14(s,1H),7.02(s,1H),6.98(s,1H),6.82(s,1H),6.66(d, J =6.0Hz,1H),5.73(d, J =6.0Hz,1H),4.81(s,1H),4.49(m,1H),2.69(m,2H),1.51(m,3H),1.49(m,4H),1.34(d, J =6.5Hz, 3H). MS (ESI)+)m/z:375.15[M]+。
Example 54: 3, 7-dimethyl-3, 5-dihydro-2H-pyrano [4,3,2-cd ] indole-2-carboxylic acid (4' -chlorocyclohexanecarbonyloxy) methyl ester (Compound 44)
Starting from 4-iodo-6-methyl-1H-indole, the title compound was prepared by a method analogous to examples 1 and 2 as racemic mixture or (2R,3S) isomer with the following data:
1h NMR (500MHz, chloroform) 11.28(s,1H),6.82(s,1H),6.38(s,1H),6.14(s,1H),6.06(d, J =6.0Hz,1H),5.83(d, J =6.0Hz,1H),4.33(s,1H),3.88(m,1H),3.11(m,1H),2.38(s,3H),2.23(m,4H),1.75(m,3H),1.35(m,2H),1.26(d,J=6.5Hz,3H)。MS(ESI+)m/z:405.13[M]+。
Example 55: 3-methyl-3, 5-dihydro-2H-pyrano [4,3,2-cd ] -6, 8-diazaindole-2-carboxylic acid (4' -methylaminocyclohexanecarbonyloxy) methyl ester (Compound 45)
The title compound was prepared in analogy to examples 1 and 2, starting from 4-iodo-7H-pyrrolo [2,3-d ] pyrimidine, as racemic mixture or (2R,3S) isomer, with the following relevant data:
1h NMR (500MHz, chloroform) 11.19(s,1H),9.12(s,1H),6.37(s,1H),6.26(d, J =6.0Hz,1H),5.83(d, J =6.0Hz,1H),4.03(s,1H),3.98(m,1H),2.48(s,3H),2.12(m,1H),1.82(m,3H),1.56(m,3H),1.43(m,3H),1.26(d, J =6.5Hz, 3H). MS (ESI)+)m/z:386.20[M]+。
Example 56: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (isobutyryloxy) methyl ester (Compound 46)
The title compound was prepared by a method analogous to example 2 as a racemic mixture or as the (2R,3S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 11.21(s,1H),8.66(s,1H),7.17(s,1H),7.05(s,1H),7.02(s,1H),6.86(d, J =6.0Hz,1H),5.63(d, J =6.0Hz,1H),4.00(s,1H),3.81(m,1H),2.66(m,1H),1.41(d, J =6.5Hz,3H),1.15(s, 6H). MS (ESI)+)m/z:333.10[M]+。
Example 57: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (pivaloyloxy) methyl ester (Compound 47)
The title compound was prepared by a method analogous to example 2 as a racemic mixture or as the (2R,3S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 11.80(s,1H),8.60(s,1H),7.56(m,1H),7.16(m,1H),7.02(s,1H),6.36(d, J =6.0Hz,1H),5.23(d, J =6.0Hz,1H),4.06(s,1H),3.83(m,1H),1.46(d, J =6.5Hz,3H),1.27(s, 9H). MS (ESI)+)m/z:347.12[M]+。
Example 58: 3, 7-dimethyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (pivaloyloxy) methyl ester (Compound 48)
Starting from 4-iodo-6-methyl-1H-indole, the title compound was prepared by a method analogous to examples 1 and 2 as racemic mixture or (2R,3S) isomer with the following data:
1h NMR (500MHz, chloroform) 11.77(s,1H),7.65(s,1H),7.01(s,1H),6.37(s,1H),6.29(d, J =6.0Hz,1H),5.73(d, J =6.0Hz,1H),3.85(s,1H),3.71(m,1H),2.47(s,3H),1.40(d, J =6.5Hz,3H),1.26(s, 9H). MS (ESI)+)m/z:361.13[M]+。
Example 59: 3-methyl-6-fluoro-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (1' - (pivaloyloxy)) ethyl ester (Compound 49)
Starting from 4-iodo-7-fluoro-1H-indole, the title compound was prepared by a method analogous to examples 1 and 2 as racemic mixture or (2R,3S) isomer with the following data:
1h NMR (500MHz, chloroform) 11.69(s,1H),7.94(s,1H),7.11(s,1H),7.02(s,1H),6.87(m,1H),4.08(s,1H),3.80(m,1H),1.74(m,3H),1.46(d, J =6.5Hz,3H),1.27(s, 9H). MS (ESI)+)m/z:379.13[M]+。
Example 60: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] -6, 8-diazaindole-2-carboxylic acid (1' - (pivaloyloxy)) ethyl ester (Compound 50)
The title compound was prepared in analogy to examples 1 and 2, starting from 4-iodo-7H-pyrrolo [2,3-d ] pyrimidine, as racemic mixture or (2R,3S) isomer, with the following relevant data:
1h NMR (500MHz, chloroform) 11.51(s,1H),9.05(s,1H),7.34(s,1H),6.37(m,1H),3.89(s,1H),3.71(m,1H),1.75(s,3H),1.47(d, J =6.5Hz,3H),1.26(s, 9H). MS (ESI)+)m/z:363.13[M]+。
Example 61: 3-methyl-6-methoxy-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (1' - (propionyloxy)) ethyl ester (Compound 51)
The title compound was prepared by a method analogous to example 2 starting from compound 4 as racemic mixture or (2R,3S) isomer with the following data:
1h NMR (500MHz, chloroform) 11.28(s,1H),7.94(s,1H),7.13(s,1H),7.02(s,1H),6.67(s,1H),4.10(s,3H),4.01(s,1H),3.81(s,1H),2.54(m,2H),1.75(m,3H),1.41(d, J =6.5Hz,3H),1.28(m, 3H). MS (ESI)+)m/z:363.11[M]+。
Example 62: 3-methyl-3, 5-dihydro-2H-pyrano [4,3,2-cd ] -6, 8-diazaindole-2-carboxylic acid (1' - (pivaloyloxy)) ethyl ester (Compound 52)
The title compound was prepared by an analogous method to example 43 as a racemic mixture or as the (2R,3S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 11.30(s,1H),9.02(s,1H),6.57(s,1H),6.39(d, J =6.0Hz,1H),5.63(d, J =6.0Hz,1H),4.43(s,1H),4.01(m,1H),1.54(d, J =6.5Hz,3H),1.28(s, 9H). MS (ESI)+)m/z:333.13[M]+。
Example 65: 3-methyl-3, 5-dihydro-2H-pyrano [4,3,2-cd ] indole-2-carboxylic acid benzoyloxymethyl ester (Compound 55)
The title compound was prepared by a method analogous to example 2 as a racemic mixture or as the (2R,3S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 11.39(s,1H),7.89(m,2H),7.71(m,2H),7.28(s,1H),7.10(m,2H),6.80(m,2H),6.12(d, J =6.0Hz,1H),5.82(d, J =6.0Hz,1H),4.40(s,1H),3.81(m,1H),1.26(d, J =7.0Hz, 3H). MS (ESI)+)m/z:351.35[M]+。
Example 66: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (4' -methoxybenzoyloxy) methyl ester (Compound 56)
Starting from compound C, which is the racemic mixture or the (2R,3S) isomer, the title compound, which is the racemic mixture or the (2R,3S) isomer, is prepared by a method analogous to example 2, with the following relevant data:
1h NMR (500MHz, chloroform) 11.33(s,1H),9.80(s,1H),7.14(m,2H),7.04(m,2H),6.93(m,4H),6.89(d, J =6.0Hz,1H),5.83(d, J =6.0Hz,1H),3.89(s,3H),3.77(s,1H),3.64(m,1H),1.22(d, J =7.0Hz, 3H). MS (ESI)+)m/z:397.10[M]+。
Example 67: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (4' -methylbenzoyloxy) methyl ester (Compound 57)
Starting from compound C, which is the racemic mixture or the (2R,3S) isomer, the title compound, which is the racemic mixture or the (2R,3S) isomer, is prepared by a method analogous to example 2, with the following relevant data:
1h NMR (500MHz, chlorine)Imitation) 7.98(m,2H),7.75(m,2H),7.13(m, 3H),6.81(d, J =6.0Hz,1H),5.76(d, J =6.0Hz,1H),3.96(s,1H), 3.81(m,1H),2.47(s,3H),1.28(d, J =7.0Hz, 3H). MS (ESI)+)m/z:381.10[M]+。
Example 68: 3-methyl-7-fluoro-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (3' -fluorobenzoyloxy) methyl ester (Compound 58)
The title compound was prepared by a method analogous to example 41 as racemic mixture or (2R,3S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 11.71(s,1H),7.77(m,3H),7.37(m,1H),6.92(m,3H),7.09(d, J =6.0Hz,1H),5.80(d, J =6.0Hz,1H),3.86(s,1H),3.81(m,1H),1.26(d, J =7.0Hz, 3H). MS (ESI)+)m/z:403.07[M]+。
Example 69: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (4' -methylaminobenzoyloxy) methyl ester (Compound 59)
Starting from compound C, which is the racemic mixture or the (2R,3S) isomer, the title compound, which is the racemic mixture or the (2R,3S) isomer, is prepared by a method analogous to example 2, with the following relevant data:
1h NMR (500MHz, chloroform) 11.82(s,1H),8.36(m,1H),7.78(m,2H),7.12(m,2H),7.09(m,2H),6.68(m,2H),6.79(d, J =6.0Hz,1H),5.63(d, J =6.0Hz,1H),4.21(s,1H),4.00(m,1H),2.90(s,3H),1.31(d, J =7.0Hz, 3H). MS (ESI)+)m/z:396.11[M]+。
Example 70: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (4' -hydroxybenzoyloxy) methyl ester (Compound 60)
The title compound was prepared by a method analogous to example 2 as a racemic mixture or as the (2R,3S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 11.61(s,1H),7.87(s,2H),7.14(m,2H),6.93(m,4H),6.64(d, J =6.0Hz,1H),5.57(d, J =6.0Hz,1H),4.13(s,1H),3.84(s,1H),3.81(m,1H),1.42(d, J =7.0Hz, 3H). MS (ESI)+)m/z:383.42[M]+。
Example 71: 3-methyl-3, 5-dihydro-2H-pyrano [4,3,2-cd ] indole-2-carboxylic acid (4' -methylbenzoyloxy) methyl ester (Compound 61)
Starting from compound C, which is the racemic mixture or the (2R,3S) isomer, the title compound, which is the racemic mixture or the (2R,3S) isomer, is prepared by a method analogous to example 2, with the following relevant data:
1h NMR (500MHz, chloroform) 11.83(s,1H),7.89(m,2H),7.21(m,2H),7.13(m,2H),6.80(m,2H),6.72(d, J =6.0Hz,1H),5.62(d, J =6.0Hz,1H),4.01(s,1H),3.81(m,1H),2.47(s,3H),1.28(d, J =7.0Hz, 3H). MS (ESI)+)m/z:365.38[M]+。
Example 72: 3-methyl-7-methoxy-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (1' - (4 "-methylbenzoyloxy)) ethyl ester (Compound 62)
Starting from 4-iodo-6-methoxy-1H-indole, the title compound was prepared by a method analogous to examples 1 and 2, as racemic mixture or (2R,3S) isomer, with the following data:
1h NMR (500MHz, chloroform) 11.81(s,1H),7.89(m,2H),7.20(m,2H),6.80(s,1H),6.68(m,2H),6.58(m,1H),4.00(s,1H),3.88(s,3H),3.81(m,1H),2.46(s,3H),1.81(m,3H),1.52(d, J =7.0Hz, 3H). MS (ESI)+)m/z:425.13[M]+。
Example 73: 3-methyl-7-methoxy-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] -6, 8-diazaindole-2-carboxylic acid (1' - (4 "-ethylbenzoyloxy)) ethyl ester (Compound 63)
Starting from 2-methoxy-4-iodo-7H-pyrrolo [2,3-d ] pyrimidine, the title compound was prepared in analogy to examples 1 and 2 as racemic mixture or (2R,3S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 7.94(m,2H),7.53(m,2H),6.61(m,1H),6.28(s,1H),4.38(s,1H),3.87(m,1H),3.74(s,3H),2.71(s,3H),1.82(m,3H),1.26(d, J =7.0Hz,3H),1.19(m, 3H). MS (ESI)+)m/z:441.14[M]+。
Example 74: 3, 7-dimethyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] -8-azaindole-2-carboxylic acid (1 ' - (4 ' ' -methoxybenzoyloxy)) ethyl ester (Compound 64)
Starting from 4-iodo-6-methyl-1H-pyrrolo [2,3-b ] pyridine, the title compound was prepared in analogy to examples 1 and 2, as racemic mixture or (2R,3S) isomer, with the following relevant data:
1h NMR (500MHz, chloroform) 11.77(s,1H),7.94(m,2H),7.19(s,1H),6.92(m,2H),6.61(m,1H),6.28(s,1H),4.13(s,1H),3.84(m,1H),3.81(s, 3H),1.78(m,3H),1.54(d, J =7.0Hz, 3H). MS (ESI)+)m/z:426.12[M]+。
Example 75: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] -7, 8-diazaindole-2-carboxylic acid (1' -benzoyloxy) ethyl ester (Compound 65)
The title compound was prepared by a method analogous to examples 1 and 2 starting from 4-iodo-7H-pyrrolo [2,3-c ] pyridazine, as racemic mixture or (2R,3S) isomer, with the following relevant data:
1h NMR (500MHz, chloroform) 11.77(s,1H),9.16(m,1H),8.01(m,2H),7.60(m,3H),6.65(m,1H),6.22(s,1H),4.38(s,1H),3.79(m,1H),1.80(m,3H),1.34(d, J =7.0Hz, 3H). MS (ESI)+)m/z:383.09[M]+。
Example 76: 3, 7-dimethyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] -6, 8-diazaindole-2-carboxylic acid (1' -benzoyloxy) ethyl ester (Compound 66)
The title compound was prepared by a method analogous to examples 1 and 2 starting from 2-methyl-4-iodo-7H-pyrrolo [2,3-d ] pyrimidine as a racemic mixture or as the (2R,3S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 11.81(s,1H),8.01(m,2H),7.72(m,2H),7.57(s,2H),6.54(m,1H),6.37(m,1H),4.86(s,1H),3.81(m,1H),2.48(s,3H),1.81(m,3H),1.29(d, J =7.0Hz, 3H). MS (ESI)+)m/z:397.11[M]+。
Example 77: 3-methyl-7-fluoro-3, 5-dihydro-2H-pyrano [4,3,2-cd ] indole-2-carboxylic acid (3' -fluorobenzoyloxy) methyl ester (Compound 67)
The title compound was prepared by a method analogous to example 41 as racemic mixture or (2R,3S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 7.71(m,2H),7.38(m,2H),6.80(s,1H),6.64(d, J =6.0Hz,1H),6.59(s,1H),6.51(s,2H),5.57(d, J =6.0Hz,1H),4.81(s,1H),4.01(m,1H),1.24(d, J =7.0Hz, 3H). MS (ESI)+)m/z:387.09[M]+。
Example 78: 3-methyl-3, 5-dihydro-2H-pyrano [4,3,2-cd ] indole-2-carboxylic acid (4' -methoxybenzoyloxy) methyl ester (Compound 68)
Starting from 4-iodo-1H-indole, the title compound was prepared by a method analogous to examples 1 and 2 as racemic mixture or (2R,3S) isomer with the following data:
1h NMR (500MHz, chloroform) 11.75(s,1H),7.98(m,2H),7.13(m,1H),6.98(m,3H),6.75(m,2H),6.72(d, J =6.0Hz,1H),5.65(d, J =6.0Hz,1H),4.43(s,1H),4.01(m,1H), 3.87(s,3H),1.55(d, J =7.0Hz, 3H). MS (ESI)+)m/z:381.12[M]+。
Example 79: benzoic acid (3- (1H-indol-3-yl) butyryloxy) methyl ester (Compound 69)
The title compound was prepared by a method analogous to example 4 as racemic mixture or (2R,3S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 11.68(s,1H),8.04(m,2H),7.59(m,4H),7.29(m,2H),6.97(m,1H),6.80(s,1H),6.62(d, J =6.0Hz,1H),5.83(d, J =6.0Hz,1H),3.51(m,1H),2.64(m,2H),1.38(d, J =7.0Hz, 3H). MS (ESI)+)m/z:337.13[M]+。
Example 80: 4-Methylbenzoic acid (3- (1H-indol-3-yl) butyryloxy) methyl ester (Compound 70)
The title compound was prepared by a method analogous to example 4 as racemic mixture or (2R,3S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 11.81(s,1H),7.89(m,2H),7.49(m,2H),7.25(m,3H),6.97(m,1H),6.80(s,1H),6.72(d, J =6.5Hz,1H),5.63(d, J =6.5Hz,1H),3.58(m,1H),2.43(m,2H),1.30(d, J =7.0Hz, 3H). MS (ESI)+)m/z:351.15[M]+。
Example 81: 4-Methoxybenzoic acid (3- (1H-indol-3-yl) butyryloxy) methyl ester (Compound 71)
The title compound was prepared by a method analogous to example 4 as racemic mixture or (2R,3S) isomer with the following relevant data:
h NMR (500MHz, chloroform) 11.90(s,1H),7.98(m,2H),7.44(m,2H),7.20(m,2H),6.90(m,2H),6.80(s,1H),6.68(d, J =6.5Hz,1H),5.59(d, J =6.5Hz,1H),3.56(m,1H),2.37(m,2H),2.11(m,3H),1.32(d, J =7.0Hz, 3H). MS (ESI)+)m/z:367.14[M]+。
Example 82: 4-Methoxycyclohexanecarboxylic acid (3- (6-methyl-1H-indol-3-yl) butyryloxy) methyl ester (Compound 72)
Starting from 2-iodo-6-methyl-1H-indole, the title compound was prepared by a method analogous to examples 1,3 and 4 as racemic mixture or (2R,3S) isomer with the following data:
1h NMR (500MHz, chloroform) 11.69(s,1H),7.72(s,1H),6.98(m,2H), 6.80(m,1H),6.74(d, J =6.5Hz,1H),5.62(d, J =6.5Hz,1H),3.51(m,1H),3.45(s,3H),2.83(m,2H),2.35(m,3H),1.93(m,2H),1.88(m,3H),1.66(m,4H),1.45(m,2H),1.39(d, J =7.0Hz, 3H). MS (ESI)+)m/z:387.20[M]+。
Example 83: cyclohexanecarboxylic acid (3- (7H-pyrrolo [2,3-d ] pyrimidin-5-yl) butanoyloxy) methyl ester (compound 73)
The title compound was prepared by a method analogous to examples 1,3 and 4 starting from 6-iodo-7H-pyrrolo [2,3-d ] pyrimidine as racemic mixture or (2R,3S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 11.39(s,1H),9.25(s,1H),8.74(s,1H),6.73(s,1H),6.34(d, J =6.5Hz,1H),5.53(d, J =6.5Hz,1H),3.51(m,1H),2.48(m,3H),1.92(m,2H),1.72(m,2H),1.48(m,6H),1.35(d, J =7.0Hz, 3H). MS (ESI)+)m/z:345.17[M]+。
Example 84: 3- (7H-pyrrolo [2,3-d ] pyrimidin-5-yl) butanoic acid (pivaloyloxy) methyl ester (compound 74)
The title compound was prepared by an analogous method to example 83 as a racemic mixture or as the (2R,3S) isomer with the following relevant data:
1h NMR (500MHz, chloroform) 11.53(s,1H),9.25(s,1H),8.71(s,1H),6.79(s,1H),6.29(d, J =6.5Hz,1H),5.33(d, J =6.5Hz,1H),3.51(m,1H),2.52(m,2H),1.39(d, J =7.0Hz,3H),1.11(s, 9H). MS (ESI)+)m/z:319.15[M]+。
Example 85: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (pyridin-2-ylcarbonyloxy) methyl ester (Compound 81)
The title compound was prepared by a method analogous to example 2 as a racemic mixture or as the (2R,3S) isomer with the following relevant data:
1H NMR (500MHz, chloroform) 11.91(s,1H),9.65(s,1H),8.27(m,2H),8.04(s,1H),7.14(m,2H),7.92(m,2H),6.29(d, J =6.5Hz,1H),5.33(d, J =6.5Hz,1H),4.00(s,1H),3.81(m,1H),1.18(d, J =7.0Hz, 3H). MS (ESI)+)m/z:368.08[M]+。
Example 86: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (benzofuran-2-ylcarbonyloxy) methyl ester (Compound 82)
The title compound was prepared by a method analogous to example 2 as a racemic mixture or as the (2R,3S) isomer with the following relevant data:
1H NMR (500MHz, chloroform) 11.09(s,1H),7.49(m,4H),7.12(m,3H),7.04(m,2H),6.65(d, J =6.5Hz,1H),5.53(d, J =6.5Hz,1H),4.86(s,1H),3.81(m,1H),1.46(d, J =7.0Hz, 3H). MS (ESI)+)m/z:407.08[M]+。
Example 87: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (indol-3-ylcarbonyloxy) methyl ester (Compound 83)
The title compound was prepared by a method analogous to example 2 as a racemic mixture or as the (2R,3S) isomer with the following relevant data:
1H NMR (500MHz, chloroform) 11.81(s,1H),9.90(m,1H),8.84(s,1H),7.92(s,1H),7.44(m,2H),7.11(m,3H),7.02(m,2H),6.72(d, J =6.5Hz,1H),5.65(d, J =6.5Hz,1H),4.00(s,1H),3.81(m,1H),1.18(d, J =7.0Hz, 3H). MS (ESI)+)m/z:406.10[M]+。
Example 88: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (2' -morpholinoethyl) amine (compound 84)
Starting from compound 2-morpholino-ethylamine and compound C as racemic mixture or (2R,3S) isomer, the title compound was prepared in analogy to example 12 as racemic mixture or (2R,3S) isomer with the following data:
1H NMR(400MHz,DMSO)10.88(s,1H),7.87(s,1H),7.15(d,J=2.0Hz,1H),7.09(d,J=8.0Hz,1H),6.99(t,J=7.6Hz,1H),6.76(d,J=7.2Hz,1H),4.10(d,J=3.6Hz,1H),3.59(m,1H),3.54(t,J=4.4Hz,4H),3.29(m,1H),3.11(m,1H),2.32(t,J=2.4Hz,6H),1.26(d,J=6.4Hz,3H)。MS(ESI+)m/z:346.2[M+H]+。
example 89: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (2' -morpholino) ethyl ester (Compound 85)
Starting from compound 2-morpholino-ethanol and compound C as racemic mixture or (2R,3S) isomer, the title compound is prepared in analogy to example 12 as racemic mixture or (2R,3S) isomer with the following relevant data:
1H NMR(400MHz,DMSO)10.91(s,1H),7.17(d,J=2.0Hz,1H),7.11(d,J=8.4Hz,1H),7.00(t,J=7.6Hz,1H),6.78(d,J=7.2Hz,1H),4.29(d,J=3.6Hz,1H),4.12(m,2H),3.55(m,1H),3.52(m,4H),2.39(m,2H),2.31(m,4H),1.27(d,J=6.8Hz,3H)。MS(ESI+)m/z:347.2[M+H]+。
example 90-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (3' -dimethylaminopropyl) amine (Compound 86)
Starting from N, N-dimethyl-1, 3-propanediamine and compound C, as racemic mixture or (2R,3S) isomer, the title compound was prepared in analogy to example 12, as racemic mixture or (2R,3S) isomer, with the following relevant data:
1H NMR(400MHz,DMSO)10.87(s,1H),8.07(t,J=3.6Hz,1H),7.14(d,J=2.0Hz,1H),7.09(d,J=8.0Hz,1H),6.98(t,J=7.6Hz,1H),6.75(d,J=7.2Hz,1H),4.11(d,J=3.6Hz,1H),3.59(m,1H),3.16(m,1H),3.04(m,1H),2.19(t,J=7.2Hz,2H),2.11(s,6H),1.53(m,2H),1.19(d,J=6.8Hz,3H)。MS(ESI+)m/z:318.2[M+H]+。
EXAMPLE 91 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (2' -dimethylaminoethyl) amine (compound 87)
Starting from N, N-dimethylethylenediamine and compound C as racemic mixture or (2R,3S) isomer, the title compound was prepared in analogy to example 12, as racemic mixture or (2R,3S) isomer, with the following relevant data:
1H NMR(400MHz,DMSO)10.87(s,1H),7.95(s,1H),7.14(d,J=2.0Hz,1H),7.09(d,J=8.0Hz,1H),6.98(t,J=7.6Hz,1H),6.75(d,J=7.2Hz,1H),4.11(d,J=3.2Hz,1H),3.58(m,1H),3.22(m,1H),3.09(m,1H),2.26(t,J=6.8Hz,2H),2.10(d,J=3.6Hz,6H),1.19(d,J=6.8Hz,3H)。MS(ESI+)m/z:304.1[M+H]+。
example 92: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (4' -fluorobenzoyloxy) methyl ester (Compound 88)
Starting from chloromethyl 4-fluorobenzoate and compound C as racemic mixture or (2R,3S) isomer, the title compound was prepared in analogy to example 2 as racemic mixture or (2R,3S) isomer with the following relevant data:
1H NMR(400MHz,DMSO)10.92(s,1H),7.99(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,2H),7.16(s,1H),7.12(d,J=8.0Hz,1H),7.00(t,J=7.6Hz,1H),6.77(d,J=7.2Hz,1H),6.00(d,J=6.0Hz,1H),5.92(d,J=6.0Hz,1H),4.42(d,J=3.6Hz,1H),3.62(m,1H),1.24(d,J=6.8Hz,3H)。MS(ESI+)m/z:408.1[M+Na]+,424.0[M+Ka]+。
example 93: 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (adamantane-1-formyloxy) methyl ester (Compound 89)
Starting from chloroalkyl amantadine-1-ylcarboxylate and compound C, as racemic mixture or (2R,3S) isomer, the title compound was prepared in analogy to example 2, as racemic mixture or (2R,3S) isomer, with the following data:
1H NMR(400MHz,DMSO)10.93(s,1H),7.18(d,J=1.2Hz,1H),7.13(d,J=8.0Hz,1H),7.00(t,J=7.6Hz,1H),6.77(d,J=7.2Hz,1H),5.73(d,J=5.6Hz,1H),5.67(d,J=5.6Hz,1H),4.34(d,J=4.0Hz,1H),3.58(m,1H),1.97(s,3H),1.77(d,J=2.4Hz,6H),1.66(m,6H),1.27(d,J=6.8Hz,3H)。MS(ESI+)m/z:448.2[M+Na]+,464.1[M+Ka]+。
EXAMPLE 94 Cyclohexanecarbonyloxymethyl 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylate (Compound 90)
Starting from chloromethyl cyclohexanecarboxylate and compound C, as racemic mixture or (2R,3S) isomer, the title compound was prepared by a method analogous to example 2, as racemic mixture or (2R,3S) isomer, with the following relevant data:
1H NMR(400MHz,DMSO)10.93(s,1H),7.18(s,1H),7.13(d,J=8.4Hz,1H),7.00(t,J=7.6Hz,1H),6.78(d,J=7.2Hz,1H),5.73(d,J=6.0Hz,1H),5.67(d,J=6.0Hz,1H),4.35(d,J=3.6Hz,1H),3.59(m,1H),2.31(m,1H),1.79(m,2H),1.67(m,2H),1.57(d,J=10.4Hz,1H),1.26(m,8H)。MS(ESI+)m/z:396.1[M+Na]+,412.1[M+Ka]+。
EXAMPLE 95 (1' -benzoyloxy) ethyl 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylate (Compound 91)
Starting from chloroethyl 1-benzoate and compound C, as racemic mixture or (2R,3S) isomer, the title compound was prepared by a method analogous to example 2, as racemic mixture or (2R,3S) isomer, with the following relevant data:
1H NMR(400MHz,DMSO)10.85(s,1H),8.01(d,J=8.0Hz,2H),7.66(t,J=7.2Hz,1H),7.55(d,J=8.0Hz,2H),7.16(s,1H),7.12(d,J=8.0Hz,1H),7.00(t,J=7.6Hz,1H),6.77(d,J=7.2Hz,1H),6.76(m,1H),4.34(d,J=4.0Hz,1H),3.58(m,1H),1.40(m,3H),1.24(d,J=6.8Hz,3H)。MS(ESI+)m/z:404.1[M+Na]+,420.1[M+Ka]+。
EXAMPLE 96 (1' -Cyclohexanecarbonyloxy) ethyl 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylate (Compound 92)
Starting from chloroethyl 1-cyclohexanecarboxylate and compound C, as racemic mixture or (2R,3S) isomer, the title compound was prepared by a method analogous to example 2, as racemic mixture or (2R,3S) isomer, with the following relevant data:
H NMR(400MHz,DMSO)10.92(s,1H),7.18(s,1H),7.13(d,J=8.4Hz,1H),7.00(t,J=7.6Hz,1H),6.78(d,J=7.2Hz,1H),6.76(m,1H),2.31(m,3H),1.40(m,14H)。MS(ESI+)m/z:410.1[M+Na]+,426.1[M+Ka]+。
example 97-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (3' -imidazol-1-ylpropyl) amine (Compound 93)
Starting from the compound 3-imidazol-1-ylpropylamine and the compound C, as racemic mixture or (2R,3S) isomer, the title compound was prepared in analogy to example 12, as racemic mixture or (2R,3S) isomer, with the following relevant data:
1H NMR(400MHz,DMSO)10.88(s,1H),8.19(t,J=3.2Hz,1H),7.60(s,1H),7.15(t,J=3.6Hz,2H),7.09(d,J=8.0Hz,1H),6.98(t,J=7.6Hz,1H),6.89(s,1H),6.76(d,J=7.2Hz,1H),4.14(d,J=3.6Hz,1H),3.96(t,J=7.6Hz,2H),3.63(m,1H),3.09(m,1H),3.01(m,1H),1.84(m,2H),1.19(d,J=6.8Hz,3H)。MS(ESI+)m/z:341.1[M+H]+,363.1[M+Na]+。
EXAMPLE 98 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylic acid (3' -butyrolactam-1-ylpropyl) amine (Compound 94)
Starting from the compound 3-butyrolactam-1-ylpropylamine and compound C, as racemic mixture or (2R,3S) isomer, the title compound was prepared in analogy to example 12, as racemic mixture or (2R,3S) isomer, with the following data:
1H NMR(400MHz,DMSO)10.87(s,1H),8.13(t,J=4.8Hz,1H),7.14(s,1H),7.08(d,J=8.0Hz,1H),6.98(t,J=7.6Hz,1H),6.75(d,J=7.2Hz,1H),4.12(d,J=3.2Hz,1H),3.61(m,1H),3.23(m,3H),3.06(m,1H),2.20(t,J=8.0Hz,2H),1.92(m,2H),1.57(t,J=6.8Hz,2H),1.18(d,J=6.8Hz,3H)。MS(ESI+)m/z:358.2[M+H]+,380.2[M+Na]+。
EXAMPLE 99 (2-benzoyloxy) ethyl 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylate (Compound 95)
Starting from chloroethyl 2-benzoate and compound C, as racemic mixture or (2R,3S) isomer, the title compound was prepared by a method analogous to example 2, as racemic mixture or (2R,3S) isomer, with the following relevant data:
1H NMR(400MHz,DMSO)10.90(s,1H),7.97(d,J=7.2Hz,1H),7.68(t,J=7.6Hz,1H),7.54(t,J=7.7Hz,2H),7.12(m,2H),6.96(t,J=7.2Hz,1H),6.76(d,J=7.2Hz,1H),4.45(m,2H),4.36(d,J=3.6Hz,1H),3.63(m,1H),1.22(d,J=6.8Hz,3H).MS(ESI+)m/z:404.2[M+Na]+,420.0[M+Ka]+。
EXAMPLE 100 (3-benzoyloxy) propyl 3-methyl-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylate (Compound 96)
Starting from chloropropyl 3-benzoate and compound C as racemic mixture or (2R,3S) isomer, the title compound is prepared by a method analogous to example 2 as racemic mixture or (2R,3S) isomer with the following data:
1H NMR(400MHz,DMSO)10.92(s,1H),7.97(m,2H),7.65(d,J=7.4Hz,1H),7.53(t,J=7.7Hz,2H),7.13(dd,J=9.5,4.9Hz,2H),6.96(m,1H),6.78(d,J=7.1Hz,1H),4.32(d,J=3.7Hz,1H),4.24(dd,J=13.7,7.5Hz,4H),3.63(m,1H),2.00(t,J=6.2Hz,2H),1.23(d,J=6.8Hz,3H)。MS(ESI+)m/z:418.0[M+Na]+,434.0[M+Ka]+
EXAMPLE 101 benzoyloxymethyl 3-methyl-4, 7, 8-tribromo-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylate (Compound 97)
Starting from the compound chloromethyl benzoate and 2-carboxylic acid 3-methyl-4, 7, 8-tribromo-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole, as racemic mixture or (2R,3S) isomer, the title compound, as racemic mixture or (2R,3S) isomer, was prepared in analogy to example 2, with the following data
1H NMR(400MHz,DMSO)12.34(s,1H),8.01(d,J=8.0Hz,1H),7.74(m,2H),7.53(m,3H),5.85(q,J=5.9Hz,2H),4.49(d,J=4.0Hz,1H),3.57(m,1H),1.23(d,J=8.0Hz,3H)。MS(ESI+)m/z:,622.9[M+Na]+。
EXAMPLE 102 benzoyloxymethyl 3-methyl-4-bromo-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole-2-carboxylate (Compound 98)
Starting from the compound chloromethyl benzoate and 2-carboxylic acid 3-methyl-4-bromo-3, 5-dihydro-2H-thiopyrano [4,3,2-cd ] indole, as racemic mixture or (2R,3S) isomer, the title compound, as racemic mixture or (2R,3S) isomer, was prepared in analogy to example 2, with the following data
1H NMR(400MHz,DMSO)11.68(s,1H),7.80(dd,J=8.3,1.2Hz,2H),7.69(d,J=7.5Hz,1H),7.53(t,J=7.8Hz,2H),7.04(dd,J=8.1,0.7Hz,1H),6.98(m,1H),6.78(dd,J=7.1,0.7Hz,1H),5.84(s,2H),4.28(d,J=2.2Hz,1H),3.55(m,1H),1.26(d,J=6.9Hz,3H)。MS(ESI+)m/z:,523.9[M+H]+。
Activity testing of Compounds of the invention
The antibacterial activity of the compounds of the invention was determined by determining the minimum inhibitory concentration (MlC, mg/L) against a standard strain, a clinically isolated strain and a resistant strain to some antibacterial agents: in this experiment, the newly marketed glycin cyclinsThe antibiotic tigecycline (Tige) was used as a control drug. The minimum inhibitory concentration was determined as follows: adding 1ml of the liquid medicine into a sterile plate, adding 14ml of a melted MH culture medium at 50 ℃, and uniformly mixing to ensure that the final concentration of the medicine contained in each plate is 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06 and 0.03mg/L in sequence; cooling, inoculating gram-negative or gram-positive bacteria with a multi-point inoculator (Denley A400, England) in an amount of about 105CFU/ml, and the dish cover is covered. Culturing the strain in an incubator at 35-37 deg.C for 18-20h, and observing and recording the result; the minimum concentration of drug contained in the plate for aseptic growth was the Minimum Inhibitory Concentration (MIC).
Table 3 lists the in vitro antibacterial activity against gram strains of representative compounds of formula (I) of the present application, and compared to the recent new marketed glycine-tetracycline antibiotic tigecycline. As can be seen from Table 3, the in vitro activity of the compound of formula (I) of the present invention against these gram bacteria is superior to or comparable to that of the newly marketed glycine-ring antibiotic tigecycline, and the compound of formula (I) of the present invention also shows very good activity against clinically increasing MRSA (methicillin-resistant Staphylococcus aureus) and MRSE (methicillin-resistant Staphylococcus epidermidis). Against fungi, in particular gram-bacteria, preferably gram-negative or gram-positive bacteria.
TABLE 3 in vitro antibacterial Activity of preferred Compounds of the invention against clinically isolated gram bacteria (MIC. mu.g/ml)
The applicant also carried out comparative tests using the above method with innovatory mycin (CD) and desulphatoneomycin (DSC, corresponding to compound No. 20 of the invention) as positive controls, the results of which are shown in tables 4 to 8.
TABLE 4
TABLE 5
TABLE 6
TABLE 7
As described above, the compounds of the present invention have a stronger antibacterial activity and a broad antibacterial spectrum against various pathogenic microorganisms including gram-negative and gram-positive bacteria. The antibacterial activity of the compound of the invention on gram strains, particularly staphylococcus including MRSA and MRSE is superior to or equivalent to that of the recently marketed antibiotic tigecycline in the glycine cyclins. The compound of the invention has better antibacterial activity on gram strains, particularly staphylococcus aureus MRSA12-1, ATCC25923, MSSE12-8, Klebsiella pneumoniae E-12-1, pseudomonas aeruginosa 12-20 and streptococcus pneumoniae 10-11 than positive control innovated mycin and desulfurization innovated mycin.
The antibacterial activity of the compounds of the invention against bacillus, preferably against mycobacterium tuberculosis, is determined by determining their minimum inhibitory concentration (MlC, mg/L) against the standard strain H37 Rv: rifampicin (RFP) was used as a control in this experiment. The minimum inhibitory concentration was determined as follows: adding 200 μ l of sterilized water into each well of 96-well plate to prevent evaporation of components in each experimental well during culture, precisely weighing 1mg of each compound, and adding 1ml of sterilized distilled water to obtain 1000 μ g/ml stock solution; RFP was dissolved in dimethylformamide; filtering with 0.22 μm microporous membrane. The final concentrations of the test agents (compounds of the invention, especially those of table 1 or table 2) were: 128.0, 64.0, 32.0, 16.0, 8.0, 4.0, 2.0, 1.0, 0.5, 0.25, 0.125, 0.0625 μ g/ml. The final control RFP concentrations were: 32.0, 16.0, 8.0, 4.0, 2.0, 1.0, 0.5, 0.25, 0.125, 0.0625, 0.032 μ g/ml. Selecting each strain culture which grows vigorously on an improved Roche medium to prepare a bacterial suspension, inoculating the bacterial suspension into a 7H9 liquid medium, incubating for 10-14 hours at 37 ℃ to ensure that the bacterial suspension grows to have turbidity of McFarland1 (equivalent to 107CUF/ml), inoculating 100 mu l of the bacterial suspension into each hole after dilution, and finally, obtaining the bacterial suspension with the final concentration2 growth control wells without antimicrobial were placed and incubated at 37 ℃. After day 5, 20. mu.l of growth control wells were addedBlue (Setotec corporation) and 5% Tween 8050. mu.l were mixed and incubated at 37 ℃ for 24 hours, and if the color changed from Blue to pink, the drug was added to each experimentThe above amount of AlamarBlue and Tween 80 mixture was added to the wells, incubated at 37 ℃ for 24h, and the color of each well was recorded and the MIC was defined as the lowest drug concentration that prevented the color change (from blue to pink). The results show that the compound has obvious effect on resisting bacillus, preferably mycobacterium tuberculosis.
Table 8 lists the in vitro antibacterial activity of the representative compound CV2 of the compounds of formula (I) of the present application against bacilli, preferably Mycobacterium tuberculosis, and compared to rifampicin. As can be seen from Table 4, the in vitro activity of the compounds of formula (I) according to the invention on bacilli, preferably tubercle bacilli, is comparable to that of rifampicin. The MIC of the compounds of formula (I) according to the invention, in particular of the compounds of Table 1, for in vitro activity against bacilli, preferably tubercle bacilli, is between 0.25 and 8. mu.g/ml, and the MIC of the stereoisomers of the compounds of Table 1, in particular of the compounds of Table 2, having the particular configuration shown by formula (II) or formula XV, for in vitro activity against bacilli, preferably tubercle bacilli, is between 0.125 and 4. mu.g/ml. Compared with Innovamycin (CD) and desulphatoneomycin (DSC, corresponding to compound number 20 in the present invention), the compounds of the present invention have better antibacterial activity.
TABLE 8 in vitro antibacterial Activity of Compounds against Mycobacterium tuberculosis (MIC. mu.g/ml)
Compound numbering | Activity of | Compound numbering | Activity of | Compound numbering | Activity of | Compound numbering | Activity of |
RFP | 0.108 | 57 | 0.90 | 12' | 2.62 | 70' | 1.26 |
CD | 6.00 | 58 | 0.72 | 13' | 2.90 | 71' | 1.20 |
CV2 | 0.78 | 59 | 0.70 | 14' | 2.86 | 72' | 1.34 |
1 | 3.62 | 60 | 0.71 | 15' | 2.17 | 73' | 1.38 |
2 | 3.54 | 61 | 2.48 | 16' | 2.43 | 74' | 1.52 |
3 | 4.21 | 62 | 1.01 | 17' | 2.95 | 75' | 1.84 |
4 | 3.84 | 63 | 1.32 | 20' | 4.00 | 76' | 1.80 |
5 | 4.38 | 64 | 1.42 | 21' | 3.51 | 77' | 3.39 |
7 | 4.86 | 65 | 1.58 | 22' | 2.62 | 78' | 1.95 |
8 | 5.23 | 66 | 1.60 | 23' | 2.69 | 79' | 2.11 |
9 | 5.06 | 67 | 3.07 | 24' | 4.18 | 80' | 1.64 |
10 | 4.82 | 68 | 2.40 | 25' | 4.14 | 81' | 0.48 |
11 | 3.82 | 69 | 2.38 | 26' | 4.19 | 82' | 0.64 |
12 | 5.23 | 70 | 2.52 | 27' | 4.26 | 83' | 0.58 |
13 | 5.80 | 71 | 2.40 | 28' | 3.83 | 84' | 1.88 |
14 | 5.72 | 72 | 2.68 | 29' | 3.83 | 85' | 1.86 |
15 | 4.33 | 73 | 2.76 | 30' | 0.42 | 86' | 2.01 |
16 | 4.85 | 74 | 3.04 | 31' | 0.39 | 87' | 1.93 |
17 | 5.90 | 75 | 3.68 | 32' | 1.13 | 88' | 0.39 |
20 | 8.00 | 76 | 3.60 | 33' | 0.63 | 89' | 0.58 |
21 | 7.02 | 77 | 6.77 | 34' | 0.99 | 90' | 0.40 |
22 | 5.23 | 78 | 3.89 | 35' | 0.40 | 91' | 0.54 |
23 | 5.37 | 79 | 4.22 | 36' | 0.54 | 92' | 0.56 |
24 | 8.35 | 80 | 3.28 | 37' | 0.38 | 93' | 1.94 |
25 | 8.28 | 81 | 0.96 | 38' | 0.61 | 94' | 1.91 |
26 | 8.37 | 82 | 1.28 | 39' | 0.37 | 95' | 0.46 |
27 | 8.52 | 83 | 1.16 | 40' | 1.19 | 96' | 0.52 |
28 | 7.66 | 84 | 3.76 | 41' | 0.45 | 97' | 1.17 |
29 | 7.66 | 85 | 3.72 | 42' | 1.27 | 98' | 0.84 |
30 | 0.83 | 86 | 4.01 | 43' | 1.19 | ||
31 | 0.78 | 87 | 3.85 | 44' | 1.71 | ||
32 | 2.25 | 88 | 0.78 | 45' | 1.28 | ||
33 | 1.26 | 89 | 1.16 | 46' | 0.63 | ||
34 | 1.98 | 90 | 0.80 | 47' | 0.69 | ||
35 | 0.80 | 91 | 1.08 | 48' | 0.84 | ||
36 | 1.08 | 92 | 1.12 | 49' | 0.65 | ||
37 | 0.76 | 93 | 3.87 | 50' | 0.68 | ||
38 | 1.22 | 94 | 3.82 | 51' | 0.94 | ||
39 | 0.74 | 95 | 0.92 | 52' | 0.73 | ||
40 | 2.38 | 96 | 1.03 | 55' | 1.18 | ||
41 | 0.90 | 97 | 2.33 | 56' | 0.36 | ||
42 | 2.54 | 98 | 1.68 | 57' | 0.45 | ||
43 | 2.38 | 58' | 0.36 |
44 | 3.42 | CV2’ | 0.39 | 59' | 0.35 | ||
45 | 2.55 | 1' | 1.81 | 60' | 0.36 | ||
46 | 1.26 | 2' | 1.77 | 61' | 1.24 | ||
47 | 1.38 | 3' | 2.11 | 62' | 0.51 | ||
48 | 1.67 | 4' | 1.92 | 63' | 0.66 | ||
49 | 1.29 | 5' | 2.19 | 64' | 0.71 | ||
50 | 1.35 | 7' | 2.43 | 65' | 0.79 | ||
51 | 1.88 | 8' | 2.62 | 66' | 0.80 | ||
52 | 1.46 | 9' | 2.53 | 67' | 1.54 | ||
55 | 2.36 | 10' | 2.41 | 68' | 1.20 | ||
56 | 0.72 | 11' | 1.91 | 69' | 1.19 |
Test for toxic side effects
Acute toxicity test: the compounds of the invention, preferably those of tables 1 and 2, are administered to ICR mice at a body weight of 18-22g, in each case in male and female halves. A total of 20 animals. The compound was separately gavaged at the dose and the number of abnormal reactions and dead animals within 14 days was recorded. The test result shows that the compound CV2 is administrated to the mice by one-time gavage at 2g/kg, no animal death is seen, and LD50 of the ICR mice administrated with the gavage CV2 is more than 2.0 g/kg. The compounds of the invention, preferably the compounds of tables 1 and 2, correspond to LD50 of compound CV2, with the exception of compound CV 2.
Claims (45)
1. An indole derivative represented by formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein,
R1is H, C1-6Alkyl or C1-6An alkanoyl group;
R2is H;
R3is H, C1-6Alkyl, or C1-6An alkoxy group;
R4is C1-6An alkyl group;
b and D are carbon atoms, A is a nitrogen atom;
d is a carbon atom, A and B are nitrogen atoms;
a and D are carbon atoms, B is a nitrogen atom;
a and B are carbon atoms, D is a nitrogen atom;
a is a carbon atom, B and D are nitrogen atoms; or
B is a carbon atom, A and D are nitrogen atoms;
x is O, or S;
y is OR8;
R8Is H or C1-6Alkyl radical, said R8Can be independently substituted by 1-3R9Substituted, each R9Is a phosphate group;
or
R8Is composed of
The wavy line indicates where the bond is formed,
R11represents H or C1-6An alkyl group;
R12represents
Ii) unsubstituted or substituted by C1-6Alkylamino, hydroxy or C1-6Alkoxy-substituted C3-8Cycloalkyl, said cycloalkyl being cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
iii) unsubstituted or substituted by 1-3R10A substituted 6-membered aryl group;
R10is selected from C1-6Alkyl and C1-6An alkoxy group; the stereoisomers have the following general formula (II)
R1、R2、R3、R4A, B, D, X, Y is as defined for formula (I),
with the proviso that the compounds of formula (I) do not include the following compounds:
1) a compound of the following formula 4
R1Is methyl and R2Is a hydroxyl group.
2. An indole derivative represented by formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein,
R1is a compound of formula (I) in the formula (H),
R2is a compound of formula (I) in the formula (H),
R3is a compound of formula (I) in the formula (H),
R4is C1-6An alkyl group;
b and D are carbon atoms, A is a nitrogen atom;
d is a carbon atom, A and B are nitrogen atoms;
a and D are carbon atoms, B is a nitrogen atom;
a and B are carbon atoms, D is a nitrogen atom;
a is a carbon atom, B and D are nitrogen atoms; or
B is a carbon atom, A and D are nitrogen atoms;
x is O, or S;
y is N (R)8)2,
The R is8Is H and C1-6Alkyl radical, said C1-6Alkyl unsubstituted or substituted by 1 to 3R9The substitution is carried out by the following steps,
each R9Is C1-6An alkylamino group;
the stereoisomers have the following general formula (II)
R1、R2、R3、R4A, B, D, X, Y is as defined in formula (I).
3. An indole derivative represented by formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein,
R1is a compound of formula (I) in the formula (H),
R2is a compound of H, or a halogen,
R3is H, C1-6Alkyl radical, C1-6Alkoxy, halogen or N (R)5)2,
R4Is C1-6An alkyl group, a carboxyl group,
each R5Independently is H or C1-6An alkyl group, a carboxyl group,
a, B and D are all carbon atoms;
x is O, or S;
y is OR8,
Each R8Is independently selected from
(1)C1-6Alkyl substituted by 1R9Substituted, each R9Is a non-aromatic heterocyclic group containing 6 ring atoms, said non-aromatic heterocyclic group being morpholinyl;
(2)
the wavy line indicates where the bond is formed,
R11represents H or C1-6An alkyl group;
R12represents
I) unsubstituted or substituted by 1-3R9’Substituted C1-6An alkyl group;
ii) unsubstituted or substituted by C1-6Alkyl, halogen or C1-6Alkoxy-substituted C3-8Cycloalkyl, which is cyclopropyl, or cyclohexyl;
iii) is unsubstituted orBy 1R10A substituted 6-membered aryl or 5-to 14-membered heteroaryl, said heteroaryl being pyridine, benzofuranyl, indolyl, or isoindolyl;
iv) adamantyl;
each R9’Is a 6-membered arylcarbonyloxy group,
R10selected from halogen, hydroxy, C1-6Alkyl radical, C1-6Alkoxy, and C1-6An alkylamino group;
the stereoisomers have the following general formula (II)
R1、R2、R3、R4A, B, D, X, Y is as defined in formula (I).
4. An indole derivative represented by formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein,
R1is a compound of formula (I) in the formula (H),
R2is a compound of formula (I) in the formula (H),
R3is C1-6An alkoxy group,
R4is C1-6An alkyl group, a carboxyl group,
a, B and D are all carbon atoms;
x is O, or S;
y is OR8,
R8Is C1-6Alkyl substituted by 1R9Substituted, each R9Is two (C)1-6Alkyl) amino.
5. An indole derivative represented by formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein,
R1is a compound of formula (I) in the formula (H),
R2is a compound of formula (I) in the formula (H),
R3is a compound of formula (I) in the formula (H),
R4is C1-6An alkyl group, a carboxyl group,
a, B and D are all carbon atoms;
x is O, or S;
y is N (R)8)2,
The R is8Is H and C1-6Alkyl radical, said C1-6Alkyl is substituted by 1-3R9The substitution is carried out by the following steps,
each R9Independently selected from C1-6Alkylamino, morpholinyl, imidazole and butyrolactam-1-yl,
the stereoisomers have the following general formula (II)
R1、R2、R3、R4A, B, D, X, Y is as defined in formula (I).
6. An indole derivative represented by formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein
R1Is a compound of formula (I) in the formula (H),
R2is H, or C1-6Alkyl radical
R3Is C1-6Alkoxy radical, CF3Or N (R)5)2,
R4Is C1-6An alkyl group, a carboxyl group,
each R5Independently is H or C1-6An alkyl group, a carboxyl group,
a, B and D are all carbon atoms;
x is O, or S;
y is OR8;
Each R8Is H;
the stereoisomers have the following general formula (II)
R1、R2、R3、R4A, B, D, X, Y is as defined in formula (I).
7. An indole derivative represented by formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein
R1Is a compound of formula (I) in the formula (H),
R2is a compound of formula (I) in the formula (H),
R3is a halogen, and the halogen is a halogen,
R4is C1-6An alkyl group, a carboxyl group,
a, B and D are all carbon atoms;
x is O, or S;
y is OR8;
Each R8Is C1-6An alkyl group;
the stereoisomers have the following general formula (II)
R1、R2、R3、R4A, B, D, X, Y is as defined in formula (I).
8. An indole derivative represented by formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein
R1Is a compound of formula (I) in the formula (H),
R2is a compound of formula (I) in the formula (H),
R3is a compound of formula (I) in the formula (H),
R4is C1-6An alkyl group, a carboxyl group,
a, B and D are all carbon atoms;
x is O, or S;
y is N (R)8)2;
The R is8Is H and C1-6An alkyl group;
the stereoisomers have the following general formula (II)
R1、R2、R3、R4A, B, D, X, Y is as defined in formula (I).
9. A compound according to any one of claims 1 to 2, 6, and 8, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein,
said C is1-6Alkyl is C1-4An alkyl group.
10. A compound according to claim 3 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein,
said C is1-6Alkyl is C1-4An alkyl group.
11. The compound of claim 5 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein,
said C is1-6Alkyl is C1-4An alkyl group.
12. A compound according to any one of claims 4 and 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein,
said C is1-6Alkyl is C1-4An alkyl group.
13. A compound according to claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein, the C1-6Alkanoyl is C1-4An alkanoyl group.
14. The compound of any one of claims 1 and 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein, the C1-6Alkoxy is C1-4An alkoxy group.
15. The compound of claim 4 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein, the C1-6Alkoxy is C1-4An alkoxy group.
16. A compound according to claim 3 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein, the C1-6Alkoxy is C1-4An alkoxy group.
17. A compound according to claim 3 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein the halogen is selected from F, Cl, or Br.
18. The compound of claim 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein the halogen is selected from F, Cl, or Br.
19. A compound according to any one of claims 1 to 2, 6 and 8, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein,
the alkyl group is selected from the group consisting of methyl, ethyl, isopropyl, n-propyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl.
20. A compound according to claim 3 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein,
the alkyl group is selected from the group consisting of methyl, ethyl, isopropyl, n-propyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl.
21. The compound of claim 5 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein,
the alkyl group is selected from the group consisting of methyl, ethyl, isopropyl, n-propyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl.
22. The compound of any one of claims 4 and 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein,
the alkyl group is selected from the group consisting of methyl, ethyl, isopropyl, n-propyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl.
23. The compound of any one of claims 10, 16 and 20, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein the halogen is selected from F, Cl, or Br.
24. A compound according to claim 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein the halogen is selected from F, Cl, or Br.
25. A compound according to claim 22 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein the halogen is selected from F, Cl, or Br.
26. The compound of any one of claims 10, 16, 17, and 20, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein,
the heterocyclic group is selected from morpholino.
27. A compound selected from the following table
28. A process for the preparation of a compound according to any one of claims 1 to 27, and pharmaceutically acceptable salts thereof, or isomers thereof, characterized in that it comprises the steps of:
step 1) reacting a compound of formula III
With a compound of formula 1, and reacting the compound with a solvent,
(R’1)2o formula 1
Thereby producing the compound of the formula IV,
wherein each R'1Independently is-COR4,R1、R2、R3、R4A, B, D as in any one of 1 to 19As defined by the formula (I) in the description, R13Is halogen;
step 2) reacting the compound of formula IV with HXCH2COY' to obtain the compound of the formula V,
wherein Y' is C1-6Alkoxy radical, R1、R2、R3、R4A, B, D are as defined for formula (I) as defined in any one of claims 1 to 19, X is O or S;
step 3) reacting the compound of formula V with an acid or a salt thereof to obtain a compound of formula VI
Wherein Y' is as defined for formula V, R1、R2、R3、R4A, B, D are as defined for formula (I) as defined in any one of claims 1 to 19, X is O or S;
step 4) hydrogenation of the compound of formula VI to give the compound of formula VII
Wherein Y' is as defined for formula V, R1、R2、R3、R4A, B, D are as defined for formula (I) as defined in any one of claims 1 to 19, X is O or S; and
step 5) reacting the compound of formula VII with a base to obtain a compound of formula (I) having the structure of formula VIII
Wherein R is1、R2、R3、R4A, B, D are as defined for formula (I) in any one of claims 1 to 19, X is O or S.
29. The method of claim 28, further comprising the step of:
step 7) reacting a compound of formula VIII in the presence of DIC and DMAP
And R8ZH reaction to give the compound of formula X
Wherein Z is O or N, and R8Is unsubstituted or substituted by 1 to 3R9Substituted C1-6Alkyl radical, R1、R2、R3、R4、R9A, B, D are as defined for formula (I) in any one of claims 1 to 19, X is O or S.
30. The method of claim 28, further comprising the step of:
step 9) reacting a compound of formula VIII
Andreaction to give the compound of formula XIII
Wherein R is1、R2、R3、R4、R11、R12A, B, D and X are as defined for formula (I) in any one of claims 1 to 19.
31. The process of any one of claims 28 to 30, wherein step 1) is carried out by reacting the compound of formula III with the compound of formula 1 in the presence of an inert gas, in an organic solvent, in the presence of a catalyst, to produce the compound of formula IV.
32. The process of claim 31, wherein step 1) is carried out by reacting the compound of formula III with the compound of formula 1 in the presence of nitrogen, in dichloromethane, in the presence of tin tetrachloride, and/or nitromethane at room temperature to produce the compound of formula IV.
33. A process according to any one of claims 28 to 30, wherein step 2) is carried out by reacting a compound of formula IV, HXCH in the presence of an inert gas2COY' and anhydrous pyridine in anhydrous methanol at 90 ℃ for 48h to obtain the compound of formula V.
34. The process of claim 33, wherein step 2) is carried out by reacting the compound of formula IV, HXCH in the presence of nitrogen gas2COY' and anhydrous pyridine in anhydrous methanol at 90 ℃ for 48h to obtain the compound of formula V.
35. A process according to any one of claims 28 to 30, wherein step 3) is carried out by reacting the compound of formula V with an acid or a salt thereof in the presence of an inert gas to give the compound of formula VI.
36. The process of claim 28, wherein step 3) is carried out by reacting the compound of formula V with ammonium acetate and glacial acetic acid in the presence of nitrogen to provide the compound of formula VI.
37. The process of any one of claims 28 to 30, wherein step 4) is carried out by hydrogenating the compound of formula VI in the presence of a catalyst in an organic solvent at 45 atmospheres to give the compound of formula VII.
38. The process of claim 37, wherein step 4) is carried out by hydrogenating the compound of formula VI in the presence of 10% Pd-C in ethyl acetate at 45 atmospheres to obtain the compound of formula VII.
39. The process of any one of claims 28 to 30, wherein step 5) is carried out by reacting the compound of formula VII with sodium hydroxide in ethanol, water and/or tetrahydrofuran at room temperature for 5h to give the compound of formula (I) having the structure of formula VIII.
40. The method of claim 30, wherein,
the method step 9) is carried out as follows: reacting the compound of formula VIII with a compound of formula VIII in the presence of an inert gas, triethylamine and DMF at room temperature for 5minReaction to give the compound of formula XIII.
41. The method of claim 40, wherein,
the method step 9) is carried out as follows: reacting the compound of formula VIII with a compound of formula VIII in the presence of nitrogen, triethylamine and DMF at room temperature for 5minReaction to give the compound of formula XIII.
42. A pharmaceutical composition comprising a therapeutically effective amount of an indole derivative of any one of claims 1 to 27, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers.
43. Use of an indole derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27 in the manufacture of an antibacterial medicament.
44. The use of claim 43, wherein the antibacterial agent is an antibacterial agent against bacilli or gram bacteria.
45. The use according to claim 43, wherein the antibacterial agent is an anti-tubercle bacillus or gram-negative or gram-positive agent.
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