CN107840826B - 1h-吲唑类衍生物及其作为ido抑制剂的用途 - Google Patents
1h-吲唑类衍生物及其作为ido抑制剂的用途 Download PDFInfo
- Publication number
- CN107840826B CN107840826B CN201610831550.7A CN201610831550A CN107840826B CN 107840826 B CN107840826 B CN 107840826B CN 201610831550 A CN201610831550 A CN 201610831550A CN 107840826 B CN107840826 B CN 107840826B
- Authority
- CN
- China
- Prior art keywords
- compound
- indazole
- substituted
- nmr
- ppm
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000003112 inhibitor Substances 0.000 title claims abstract description 10
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical class C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 title abstract description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 title description 2
- 229910052760 oxygen Inorganic materials 0.000 title description 2
- 239000001301 oxygen Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims abstract description 13
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 8
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000005934 immune activation Effects 0.000 claims abstract description 6
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 5
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 5
- 201000011510 cancer Diseases 0.000 claims abstract description 5
- 208000015181 infectious disease Diseases 0.000 claims abstract description 5
- 208000002177 Cataract Diseases 0.000 claims abstract description 4
- 208000030159 metabolic disease Diseases 0.000 claims abstract description 4
- 208000030507 AIDS Diseases 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 230000001413 cellular effect Effects 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 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
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 201000010099 disease Diseases 0.000 abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 4
- 239000007787 solid Substances 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 35
- 238000006243 chemical reaction Methods 0.000 description 34
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- 230000015572 biosynthetic process Effects 0.000 description 30
- 238000003786 synthesis reaction Methods 0.000 description 30
- 238000005160 1H NMR spectroscopy Methods 0.000 description 27
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 27
- 102000006639 indoleamine 2,3-dioxygenase Human genes 0.000 description 26
- 108020004201 indoleamine 2,3-dioxygenase Proteins 0.000 description 26
- 239000000243 solution Substances 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 13
- 230000000694 effects Effects 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 229960004799 tryptophan Drugs 0.000 description 8
- 239000012043 crude product Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 6
- AZOJNADMDJQIBV-UHFFFAOYSA-N 2,5-dimethyl-1,3-dinitrobenzene Chemical compound CC1=CC([N+]([O-])=O)=C(C)C([N+]([O-])=O)=C1 AZOJNADMDJQIBV-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- RGSIWCOYONWAJH-UHFFFAOYSA-N 2,5-dimethyl-3-nitroaniline Chemical compound CC1=CC(N)=C(C)C([N+]([O-])=O)=C1 RGSIWCOYONWAJH-UHFFFAOYSA-N 0.000 description 5
- UHMQLMVVZOTFDR-UHFFFAOYSA-N 4-nitro-6-(trifluoromethyl)-1h-indazole Chemical compound [O-][N+](=O)C1=CC(C(F)(F)F)=CC2=C1C=NN2 UHMQLMVVZOTFDR-UHFFFAOYSA-N 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 238000012512 characterization method Methods 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- LRLRAYMYEXQKID-UHFFFAOYSA-N 1-methyl-4-(trifluoromethyl)benzene Chemical compound CC1=CC=C(C(F)(F)F)C=C1 LRLRAYMYEXQKID-UHFFFAOYSA-N 0.000 description 4
- YKEVTSMJXUJEMX-UHFFFAOYSA-N 2-methyl-1,3-dinitro-5-(trifluoromethyl)benzene Chemical compound CC1=C([N+]([O-])=O)C=C(C(F)(F)F)C=C1[N+]([O-])=O YKEVTSMJXUJEMX-UHFFFAOYSA-N 0.000 description 4
- QAKVILZRKISYBX-UHFFFAOYSA-N 2-methyl-3-nitro-5-(trifluoromethyl)aniline Chemical compound CC1=C(N)C=C(C(F)(F)F)C=C1[N+]([O-])=O QAKVILZRKISYBX-UHFFFAOYSA-N 0.000 description 4
- IHQAYTCBMNCOKS-UHFFFAOYSA-N 6-(trifluoromethyl)-1h-indazol-4-amine Chemical compound NC1=CC(C(F)(F)F)=CC2=C1C=NN2 IHQAYTCBMNCOKS-UHFFFAOYSA-N 0.000 description 4
- DLKUQAHLXGZFPM-UHFFFAOYSA-N 6-methyl-4-nitro-1h-indazole Chemical compound CC1=CC([N+]([O-])=O)=C2C=NNC2=C1 DLKUQAHLXGZFPM-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 3
- OVDGUTHABMXVMI-UHFFFAOYSA-N 3-nitro-4-(propylamino)benzoic acid Chemical compound CCCNC1=CC=C(C(O)=O)C=C1[N+]([O-])=O OVDGUTHABMXVMI-UHFFFAOYSA-N 0.000 description 3
- AHEMYGJJCOXPSP-UHFFFAOYSA-N 6-bromo-4-nitro-1h-indazole Chemical compound [O-][N+](=O)C1=CC(Br)=CC2=C1C=NN2 AHEMYGJJCOXPSP-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 229940126657 Compound 17 Drugs 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 3
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940125758 compound 15 Drugs 0.000 description 3
- 229940126142 compound 16 Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000009987 spinning Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- MAACLNKBFOTDTC-UHFFFAOYSA-N 6-bromo-N-[(4-nitrophenyl)methyl]-1H-indazol-4-amine Chemical compound BrC=1C=C(C=2C=NNC=2C=1)NCC1=CC=C(C=C1)[N+](=O)[O-] MAACLNKBFOTDTC-UHFFFAOYSA-N 0.000 description 2
- ALKXLVRDXHYCOA-UHFFFAOYSA-N 6-chloro-4-nitro-1h-indazole Chemical compound [O-][N+](=O)C1=CC(Cl)=CC2=C1C=NN2 ALKXLVRDXHYCOA-UHFFFAOYSA-N 0.000 description 2
- JGZBDXTVJJTZOR-UHFFFAOYSA-N 6-methyl-1h-indol-4-amine Chemical compound CC1=CC(N)=C2C=CNC2=C1 JGZBDXTVJJTZOR-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-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
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- -1 Dihydropyridine ester Chemical class 0.000 description 2
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 2
- BYHJHXPTQMMKCA-QMMMGPOBSA-N N-formyl-L-kynurenine Chemical compound [O-]C(=O)[C@@H]([NH3+])CC(=O)C1=CC=CC=C1NC=O BYHJHXPTQMMKCA-QMMMGPOBSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- OOKFCQHMHNKVKJ-UHFFFAOYSA-N 5-bromo-2-methyl-3-nitroaniline Chemical compound CC1=C(N)C=C(Br)C=C1[N+]([O-])=O OOKFCQHMHNKVKJ-UHFFFAOYSA-N 0.000 description 1
- JWKMYCQSTYOSPG-UHFFFAOYSA-N 6-(trifluoromethyl)-N-[[3-(trifluoromethyl)phenyl]methyl]-1H-indazol-4-amine Chemical compound FC(C=1C=C(C=2C=NNC=2C=1)NCC1=CC(=CC=C1)C(F)(F)F)(F)F JWKMYCQSTYOSPG-UHFFFAOYSA-N 0.000 description 1
- XHWQIUNDWUOLTJ-UHFFFAOYSA-N 6-bromo-N-[[3-(trifluoromethyl)phenyl]methyl]-1H-indazol-4-amine Chemical compound BrC=1C=C(C=2C=NNC=2C=1)NCC1=CC(=CC=C1)C(F)(F)F XHWQIUNDWUOLTJ-UHFFFAOYSA-N 0.000 description 1
- KGBIIGJZQFBLNK-UHFFFAOYSA-N 6-chloro-N-[[3-(trifluoromethyl)phenyl]methyl]-1H-indazol-4-amine Chemical compound ClC=1C=C(C=2C=NNC=2C=1)NCC1=CC(=CC=C1)C(F)(F)F KGBIIGJZQFBLNK-UHFFFAOYSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 102000016938 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241001248537 Eurema daira Species 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- FBKMWOJEPMPVTQ-UHFFFAOYSA-N N'-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[2-(sulfamoylamino)ethylamino]-1,2,5-oxadiazole-3-carboximidamide Chemical compound NS(=O)(=O)NCCNC1=NON=C1C(=NO)NC1=CC=C(F)C(Br)=C1 FBKMWOJEPMPVTQ-UHFFFAOYSA-N 0.000 description 1
- TZCCKCLHNUSAMQ-DUGSHLAESA-N NC(=O)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)Cc5cccs5)C(=O)N Chemical compound NC(=O)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)Cc5cccs5)C(=O)N TZCCKCLHNUSAMQ-DUGSHLAESA-N 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 150000001555 benzenes Chemical group 0.000 description 1
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229940105657 catalase Drugs 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 235000013905 glycine and its sodium salt Nutrition 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- IFGCUJZIWBUILZ-UHFFFAOYSA-N sodium 2-[[2-[[hydroxy-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyphosphoryl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid Chemical compound [Na+].C=1NC2=CC=CC=C2C=1CC(C(O)=O)NC(=O)C(CC(C)C)NP(O)(=O)OC1OC(C)C(O)C(O)C1O IFGCUJZIWBUILZ-UHFFFAOYSA-N 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000003760 tallow Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229940021747 therapeutic vaccine Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种式(Ⅰ)所示的1H‑吲唑类衍生物，还公开了所述化合物的制备方法和作为IDO抑制剂的用途。本发明的化合物可以用于预防和/或治疗多种疾病，如阿尔茨海默病、白内障、细胞免疫激活相关的感染、自身免疫性疾病、艾滋病、癌症、抑郁症或色氨酸代谢异常等。
Description
技术领域
本发明涉及1H-吲唑类衍生物，还涉及其制备方法和作为IDO抑制剂的用途。
背景技术
吲哚胺2,3-双加氧酶(Indoleamine 2,3-dioxygenase，IDO)是催化色氨酸等吲哚胺类分子中吲哚环氧化裂解，使其按犬尿酸途径分解代谢的限速酶。
IDO在肿瘤免疫豁免及肿瘤发生过程中起着重要作用。正常情况下，IDO在体内呈低水平表达，而大多数肿瘤细胞则会组成的高表达IDO，将L-色氨酸转化为N-甲酰犬尿氨酸，降低了细胞微环境中的色氨酸浓度，使得色氨酸依赖的T细胞合成停滞于G1期，T细胞增殖受到抑制，从而抑制了机体免疫系统对肿瘤组织的杀伤作用。同时，IDO作用下色氨酸的代谢产物存在细胞毒性，可对T细胞产生直接溶解作用。
因此，抑制IDO的活性可以有效地阻止肿瘤细胞周围色氨酸的降解，促进T细胞的增殖，从而增强机体对肿瘤细胞的攻击能力。并且，IDO抑制剂还可以与化疗药物合用，降低肿瘤细胞的耐药性，从而增强常规细胞毒疗法的抗肿瘤活性。同时服用IDO抑制剂也可提高癌症病人的治疗性疫苗的疗效。
除了在肿瘤细胞耐药性方面发挥着重要作用，IDO还与多种与细胞免疫激活相关的疾病的发病机制密切相关。IDO已被证实是与细胞免疫激活相关的感染、恶性肿瘤、自身免疫性疾病、艾滋病等重大疾病的靶标。同时，抑制IDO还是对于患有神经系统疾病如抑郁症，阿尔茨海默病的病人的重要治疗策略。因此，IDO抑制剂具有广阔的临床应用前景。
发明内容
为解决上述问题，本发明提供了一种1H-吲唑类衍生物或其药学上可接受的盐或其溶剂合物，所述化合物的结构如式(Ⅰ)所示：
其中，
R1选自H、卤素、C1～C6烷基或C1～C6卤代烷基；
R2选自取代的或非取代的芳基、杂芳基、环烷基或杂环基，所述取代的芳基、杂芳基、环烷基或杂环基分别独立地被一个或多个选自卤素、-NH2、-(CH2)aOH、-COOH、硝基、C1～C6烷基、C1～C6卤代烷基、-CONH-R3或-NH-R4的取代基所取代；
R3选自C1～C6烷基；
R4选-CH2COOH或5-6元的环烷基或C1～C6烷基取代的环烷基；
a＝0或1。
进一步地，所述R1选自H、Cl、Br、-CF3、-CHX2、-CH2X或-CH3。
进一步地，所述C1～C6烷基选自甲基。
进一步地，所述C1～C6卤代烷基为三氟甲基。
进一步地，所述芳基选自苯基，杂芳基选自苯并噻吩，环烷基选自环己基，杂环基选自4～6元的氮杂环基。
进一步地，所述R2选自下述基团之一：
进一步地，所述化合物选自如下化合物之一：
本发明还提供了前述式(Ⅰ)化合物、式(Ⅱ)所示化合物、或其药学上可接受的盐、或其前药、或其溶剂合物在制备IDO抑制剂类药物上的用途，
R1如前述所定义。
进一步地，所述药物是预防和/或治疗阿尔茨海默病、白内障、细胞免疫激活相关的感染、自身免疫性疾病、艾滋病、癌症、抑郁症或色氨酸代谢异常的药物。
本发明还提供了一种药物组合物，其特征在于：它是前述的化合物或其药学上可接受的盐为活性成分，加上药学上可接受的辅料制备而成的制剂。
所述C1～C6烷基是指C1、C2、C3、C4、C5、C6的烷基，即具有1～6个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、己基等等。
本发明中，英文缩写的涵义如下所示：
DHP：1,4-Dihydropyridine，二氢吡啶酯。
DMF：Dimethylformamide，二甲基甲酰胺。
DCC：Dicyclohexylcarbodiimide，二环己基碳二亚胺。
DIBAL-H：Diisobutylaluminum bydride，二异丁基氢化铝
DIEA：N,N-Diisopropylethylamine，N,N-二异丙基乙胺。
EA：Ethyl acetate，乙酸乙酯。
EDCI：1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐。
Et3N：Triethylamine，三乙胺。
HOBT：1-Hydroxybenzotriazole，1-羟基苯并三氮唑。
HATU：2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯。
PE：Petroleum ether，石油醚。
TFA：Tallow Fatty Acid，三氟乙酸。
THF：Tetrahydrofuran，四氢呋喃。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
所述试剂和原料均来自市售的商品，除专门标注了来源的起始原料外，其余试剂购于成都科龙化学试剂公司。
实施例1中间体原料的合成
(1)5a和5b的合成
2,5-二甲基-1，3-二硝基苯(2a)的合成
取干燥的50mL梨形瓶，以20mL浓硫酸将二甲苯(1a)(2.00mL，16.23mmol)溶解，室温搅拌下缓慢加入硝酸钾(4.91g，48.68mmol)，加毕，室温搅拌反应2h，将反应液缓慢倒入冰水中，过滤，滤饼真空干燥，再经柱层析(PE:EA＝80：1)纯化得淡黄色固体(2a)(1.62g，收率51％)。结构鉴定：1H-NMR(400MHz,CDCl3,ppm):δ13.0(br,1H,NH),7.42(s,2H,Ar-H),2.45(s,6H,CH3).ESI-MS:197.05[M+H].
2-甲基-5-三氟甲基-1,3-二硝基苯(2b)的合成
以4-三氟甲基-甲苯(1b)(CAS：6140-17-6，购于成都瑞欧克试剂公司)为原料，按照制备2,5-二甲基-1，3-二硝基苯(2a)的方法，制备得到2-甲基-5-三氟甲基-1,3-二硝基苯(2b)，黄色固体，收率75％。结构鉴定：1H-NMR(400MHz,CDCl3,ppm):δ13.0(br,1H,NH),8.29(s,2H,Ar-H),2.69(s,3H,CH3).ESI-MS:251.02[M+H].
2,5-二甲基-3-硝基苯胺(3a)的合成
将2,5-二甲基-1,3-二硝基苯(2a)(196.0mg,1.00mmol)溶于MeOH(6mL)和二氧六环(3mL)中，加入浓盐酸(0.60mL)和Fe(168.90mg,3.00mmol)，升至80℃搅拌反应12h。先过滤，再将反应液旋干，饱和NaHCO3溶液将pH调至7～8，EA提取三次，有机层用饱和食盐水洗涤，无水硫酸镁干燥，旋干得淡黄色固体142.8mg，收率86％。
2-甲基-5-三氟甲基-3-硝基苯胺(3b)的合成
按照实施例1中制备5-溴-2-甲基-3-硝基苯胺(3a)的方法，制备得到2-甲基-5-三氟甲基-3-硝基苯胺(3b)，黄色固体，收率68％。
6-甲基-4-硝基-1H-吲唑(4a)的合成
将2,5-二甲基-3-硝基苯胺(9a)(83.0mg,0.50mmol)溶于冰醋酸(3mL)中，再将NaNO2(69.0mg,1.00mmol)溶于水(0.5mL)中，室温搅拌下将NaNO2的水溶液缓慢滴加到2,5-二甲基-3-硝基苯胺(3a)的冰醋酸溶液中，有固体析出，室温搅拌反应13h后，将反应液倒入冰水中，过滤，滤饼真空干燥箱干燥12h，得黄色固体79.6mg，收率90％。纯度经HPLC测试为98％；结构鉴定：1H-NMR(400MHz,d6-DMSO,ppm):δ12.46(br,1H),8.20(s,1H),8.10(s,1H),7.87(s,1H),2.35(s,3H).ESI-MS:178.18[M+H].
6-三氟甲基-4硝基-1H-吲唑(4b)的合成
按照制备6-溴-4硝基-1H-吲唑(4a)的方法，制备得到6-三氟甲基-4硝基-1H-吲唑(4b)，收率79％。纯度经HPLC测试为98％。结构鉴定：1H-NMR(400MHz,d6-DMSO,ppm):δ12.46(br,1H),8.20(s,1H),8.12(s,1H),7.80(s,1H).ESI-MS:232.13[M+H].
6-甲基-1H-吲哚-4-胺(5a)的合成
将原料6-甲基-4-硝基-1H-吲唑(4a)(50mg,0.28mmol)溶于乙醇(2mL)和水(1mL)的混合溶剂中，加入氯化铵(1.6mg,0.03mmol)，再加入铁粉(79.1mg,1.41mmol)，升温至80℃搅拌反应0.5h后，将反应液趁热过滤，滤渣用乙醇洗。减压旋去乙醇，用EA萃取水层三次。合并有机相，用饱和食盐水洗涤，无水硫酸镁干燥，旋干，过柱(PE:EA＝10:1)，得34.9mg淡黄色固体，收率84％。纯度经HPLC测试为98％；1H-NMR(400MHz,d6-DMSO,ppm):δ12.46(br,1H),7.70(s,1H),7.16(s,1H),6.85(s,1H),4.60(br,2H),2.21(s,3H).ESI-MS:148.10[M+H].
6-三氟甲基-1H-吲唑-4-胺(5b)的合成
以化合物4-三氟甲基-甲苯(4b)为原料。参照化合物5a的合成方法得化合物5b。黄色固体，收率95％。纯度经HPLC测试为98％；1H-NMR(400MHz,CDCl3,ppm):δ13.0(br,1H,NH),8.10(s,1H,indazole-H),7.21(s,1H,indazole-H),6.58(s,1H,indazole-H),4.37(br,2H,NH2).ESI-MS:202.05[M+H].
(2)5c和5d的合成
将原料6-溴-4-硝基-1H-吲唑(4c)或6-氯-4-硝基-1H-吲唑(4d)(8.26mmol，购于江苏南通生物科技有限公司)溶于乙醇(20mL)和水(10mL)的混合溶剂中，加入氯化铵(221.5mg,4.13mmol)，先将一部分铁粉(1.3g,23.46mmol)加入其中，升温至80℃搅拌反应45分钟，再将另剩余铁粉(1.0g,17.86mmol)加入，继续搅拌反应20分钟。TLC检测原料反应完全后，将反应液趁热过滤，滤渣用乙醇(10mL)洗。减压旋去乙醇，用EA(20mL)萃取水层三次。合并有机相，用饱和食盐水洗涤，无水硫酸镁干燥，旋干，过柱(PE:EA＝8:1)，得淡黄色固体，收率为92-94％。纯度经HPLC测试均为98％；5c的结构表征：1H-NMR(400MHz,d6-DMSO,ppm):δ12.46(br,1H),8.15(s,1H),7.56(s,1H),6.88(s,1H),5.80(br,2H).ESI-MS:213.05[M+H].5d的结构表征：1H-NMR(400MHz,d6-DMSO,ppm):δ12.46(br,1H),8.14(s,1H),7.54(s,1H),6.89(s,1H),5.78(br,2H).ESI-MS:168.03[M+H].
实施例2本发明化合物N1、N2、N3、N4和N5的合成
6-溴-N-(3-三氟甲基苄基)-1H-吲唑-4-胺(N1).
将胺5c(0.28mmol)和苯甲醛6(0.24mmol)溶于二氯甲烷(DCM，3mL)中，加入DHP(83.5mg,0.33mmol)和适量
(840.2mg)，滴入三氟醋酸(TFA，17.6μL,0.24mmol)，40℃回流12小时，将反应液过滤，旋干，过柱(PE:EA＝10:1)得化合物N1。收率53.9％；红色粉末状固体；1H-NMR(400MHz,d6-CDCl3,ppm):δ8.00(s,1H,indazole-H3),7.69(s,1H,Ar-H),7.63-7.50(m,3H,Ar-H),7.06(s,1H,Ar-H),6.34(s,1H,Ar-H),4.56(d,2H,J＝4.4Hz,benzyl-CH2).13C-NMR(100MHz,d6-CDCl3,ppm):δ141.9,141.7,139.2,131.7,131.4,130.8,129.4,124.6,124.3,122.9,112.5,103.5,102.2,47.6.ESI-MS:370.01[M+H].
选择相应的醛原料，按照类似的方法制备得到化合物N2、N3、N4、N5，结果和表征如下：
4-((6-溴-1H-吲唑-4-氨基)甲基)苯并噻吩(N2).收率31.8％；黄色固体；1H-NMR(400MHz,d6-DMSO,ppm):δ14.09(s,1H,indazole-NH),7.90(d,1H,J＝7.0Hz,Ar-H),7.80(d,1H,J＝7.0Hz,Ar-H),7.48(s,1H,NH),7.44(s,1H,Ar-H),7.22(s,1H,Ar-H),6.70(s,1H,Ar-H),6.59(s,1H,Ar-H),4.76(d,2H,J＝5.0Hz,benzyl-CH2).ESI-MS:356.99[M+H].
3-((6-溴-1H-吲唑-4-氨基)甲基)苯酚(N3).收率49.6％；淡黄色固体；1H-NMR(400MHz,d6-DMSO,ppm):δ12.97(s,1H,indazole-NH),9.63(s,1H,OH),8.23(s,1H,indazole-H),7.12(t,2H,J＝7.7Hz,NH),6.82-6.78(m,3H,Ar-H),6.03(d,1H,J＝0.9Hz,Ar-H),5.77(s,1H,Ar-H),4.36(d,2H,J＝5.8Hz,benzyl-CH2).13C-NMR(100MHz,d6-DMSO,ppm):δ158.0,143.2,141.4,132.6,129.9,121.8,118.0,115.3,114.2,114.0,112.6,101.1,100.1,46.3.ESI-MS:318.02[M+H].
4-((6-溴-1H-吲唑-4-氨基)甲基)苯甲醇(N4).收率49.6％；淡黄色固体；1H-NMR(400MHz,d6-DMSO,ppm):δ12.84(s,1H,indazole-NH),8.22(s,1H,indazole-H3),7.35-7.27(m,5H,Ar-H),6.82(s,1H,NH),6.03(d,1H,J＝1.1Hz,Ar-H),5.15(s,1H,OH),4.47(s,2H,CH 2NH),4.42(s,2H,CH 2COOH).13C-NMR(100MHz,d6-DMSO,ppm):δ143.2,142.2,141.6,138.2,132.6,127.2,127.1,121.7,112.6,101.2,100.3,63.2,48.2.ESI-MS:332.03[M-H].
6-溴-N-(4-硝基苄基)-1H-吲唑-4-胺(N5).淡棕色固体；收率63.1％；1H-NMR(400MHz,d6-DMSO,ppm):δ12.90(s,1H,indazole-NH),8.23(d,2H,J＝3.8Hz,Ar-H),8.22(s,1H,indazole-H),7.65(d,2H,J＝8.6Hz,Ar-H),7.48(s,1H,-NH),6.86(s,1H,Ar-H),6.01(s,1H,Ar-H),4.62(d,2H,J＝4.8Hz,benzyl-CH2).13C-NMR(100MHz,d6-DMSO,ppm):δ148.5,147.8,147.0,142.7,132.5,128.5,124.1,121.7,112.6,101.3,45.8.ESI-MS:347.01[M+H].
实施例3本发明化合物N6和N7的合成
4-((6-甲基-1H-吲唑-4-氨基)甲基)苯甲酸(N6).
按照实施例2中类似的方法合成化合物N6，区别在于以化合物5a替代化合物5c，得化合物N6。收率42.0％；淡黄色粉末状固体；1H-NMR(400MHz,d6-DMSO,ppm):δ12.72(s,2H,COOH and indazole-NH),8.12(s,2H,indazole-H3and NH),7.91(d,2H,J＝8.1Hz,Ar-H),7.50(d,2H,J＝8.1Hz,Ar-H),6.47(s,1H,Ar-H),5.77(s,1H,Ar-H),4.50(s,2H,benzyl-CH2),2.21(s,3H,CH3),ESI-MS:282.12[M+H].
4-((6-甲基-1H-吲唑-4-氨基)甲基)苯甲醇(N7).
选择相应的醛原料，按照类似的方法制备得到化合物N7，收率53.7％；淡黄色粉末状固体；1H-NMR(400MHz,d6-DMSO,ppm):δ9.23(s,2H,indazole-NH and OH),8.12(s,1H,indazole-H),7.19(d,2H,J＝8.4Hz,Ar-H),6.72(d,2H,J＝8.4Hz,Ar-H),6.47(s,1H,Ar-H),5.87(s,1H,Ar-H),4.29(d,2H,J＝8.4Hz,benzyl-CH2),4.29(s,3H,CH3).ESI-MS:254.12[M+H].
实施例4本发明化合物N8、N9、N10、N11和N12的合成
6-三氟甲基-N-(3-三氟甲基苄基)-1H-吲唑-4-胺(N8).
按照实施例2中类似的方法合成化合物N1，区别在于以化合物5b替代化合物5c，得化合物N8。收率34.5％；黄色固体；1H-NMR(400MHz,d6-CDCl3,ppm):δ10.92(s,1H,indazole-NH),8.11(s,1H,indazole-H3),7.72(s,1H,Ar-H),7.65-7.51(m,2H,Ar-H andNH),7.20(s,1H,Ar-H),6.41(s,1H,Ar-H),4.61(d,2H,J＝5.2Hz,benzyl-CH2).13C-NMR(100MHz,d6-CDCl3,ppm):δ166.0,162.2,141.8,141.0,140.4,139.1,131.7,130.9,129.4,124.7,124.6,124.5,124.4,123.1,114.9,97.1,96.0,61.5.ESI-MS:360.09[M+H].
选择相应的醛原料，按照类似的方法制备得到化合物N9、N10、N11和N12。结果和表征如下:
4-((6-三氟甲基-1H-吲唑-4-氨基)甲基)苯并噻吩(N9).收率54.7％；黄色固体；1H-NMR(400MHz,d6-DMSO,ppm):δ13.21(s,1H,indazole-NH),8.37(s,1H,indazole-H3),7.88(d,1H,J＝7.8Hz,Ar-H),7.78(d,1H,J＝7.6Hz,Ar-H),7.60(s,1H,NH),7.05(s,1H,Ar-H),6.36(s,1H,Ar-H),4.82(d,2H,J＝5.9Hz,benzyl-CH2).13C-NMR(100MHz,d6-DMSO,ppm):δ145.3,142.7,140.5,140.0,139.2,132.7,128.6,126.7,124.8,124.4,123.7,122.9,121.8,115.3,95.8,94.0,42.6.ESI-MS:348.07[M+H].
N-甲基-3-(((6-三氟甲基-1H-吲哚-4-)氨基)甲基)苯甲酰胺(N10).收率60.5％；黄色固体；1H-NMR(400MHz,d6-DMSO,ppm):δ13.18(s,1H,indazole-NH),8.43(s,1H,CONH),8.37(s,1H,indazole-H),7.91(s,1H,Ar-H),7.72(d,1H,J＝7.7Hz,Ar-H).7.55(d,1H,J＝7.7Hz,Ar-H).7.46-7.41(m,2H,Ar-H),6.15(s,1H,Ar-H),4.55(d,2H,J＝5.8Hz,benzyl-CH2),2.78(d,3H,J＝4.5Hz,-CH3).13C-NMR(100MHz,d6-DMSO,ppm):δ167.1,143.1,140.5,140.1,135.2,132.7,130.2,128.6,125.9,124.0,115.1,95.4,93.7,46.5,31.1.ESI-MS:349.12[M+H].
(1S,2S)-2-((6-溴-1H-吲唑-4-氨基)甲基)环己醇N11.收率52.7％；米黄色固体；1H-NMR(400MHz,d6-DMSO,ppm):δ13.10(s,1H,indazole-NH),8.34(s,1H,indazole-H),6.95(s,1H,Ar-H),6.27(s,1H,Ar-H)),3.69-3.65(m,1H,cyclohexanol-H),3.24-3.18(m,1H,cyclohexanol-H),2.98-2.92(m,1H,cyclohexanol-H),1.97-1.88(m,2H,CH2NH),1.59-0.98(m,8H,cyclohexanol-H).13C-NMR(100MHz,d6-DMSO,ppm):δ143.8,140.7,132.6,129.1,126.9,124.2,114.9,93.0,71.7,46.3,44.7,36.0,29.7,25.5,24.9.ESI-MS:314.15[M+H].
3-((6-三氟甲基-1H-吲唑-4-氨基)甲基)苯甲酸(N12).收率81.2％；黄色固体；1H-NMR(400MHz,d6-DMSO,ppm):δ13.11(s,2H,COOH and indazole-NH),8.36(d,1H,J＝0.6Hz,Ar-H),8.01(s,1H,Ar-H),7.84(d,1H,J＝7.7Hz,Ar-H),7.66(d,1H,J＝7.7Hz,Ar-H),7.51-7.46(m,2H,NH and Ar-H),7.00(s,1H,Ar-H),6.15(s,1H,Ar-H),4.58(d,2H,J＝6.0Hz,).ESI-MS:336.09[M+H].
实施例5本发明化合物N13的合成
6-氯-N-(3-三氟甲基苄基)-1H-吲唑-4-胺(N13).
按照实施例2中类似的方法合成化合物N13，区别在于以化合物5d替代化合物5c，得化合物N13。收率58％；黄色固体；1H-NMR(400MHz,d6-DMSO,ppm):δ12.42(s,2H,COOH andindazole-NH),8.14(s,2H,indazole-H3and NH),8.05(d,2H,J＝8.1Hz,Ar-H),7.76(d,2H,J＝8.1Hz,Ar-H),6.58(s,1H,Ar-H),5.79(s,1H,Ar-H),4.58(s,2H,benzyl-CH2)；ESI-MS:302.02[M+H].
实施例6本发明化合物N14的合成
化合物(9)的合成
将原料(5b)(150mg,0.746mmol)和原料(8)(185.4mg,0.896mmol)溶于DCM(7mL)中，加入DHP(264.2mg,1.04mmol)，滴入三氟醋酸(55.8uL,0.746mmol)，40℃回流反应12小时，将反应液过滤，旋干，过柱(DCM:MeOH＝80:1)，得化合物(9)203.8mg黄色固体，收率72.3％。
(3-((6-(三氟甲基)-1H-吲哚-4-)氨基)苯基)氨基乙酸(N14)的合成
将化合物(9)(100mg,0.255mmol)溶于乙醇和水(3:3mL)中，加入氢氧化钠(30.6mg,0.765mmol)，室温搅拌反应12小时，减压将反应液中乙醇旋走，用1N盐酸调pH为4左右，EA萃取，无水硫酸镁干燥，旋干过柱(DCM:MeOH＝30:1)得黄色固体化合物N14。收率42.3％；黄色固体；1H-NMR(400MHz,d6-DMSO,ppm):δ13.12(s,1H,indazole-NH),8.36(s,1H,indazole-H3),7.33-6.61(m,5H,Ar-H),6.41(s,1H,Ar-H),6.27(s,1H,NH),4.36(d,2H,J＝5.8Hz,benzyl-CH2),3.75(s,2H,NHCH2).13C-NMR(100MHz,d6-DMSO,ppm):δ173.0,148.8,143.4,140.6,140.4,129.4,128.9,124.5,120.0,115.6,115.1,111.6,111.0,95.2,93.6.ESI-MS:365.12[M+H].
实施例7本发明化合物N15和N16的合成
化合物(11)的合成
将原料(5b)(200.0mg,1.0mmol)和原料(10)(181.2mg,1.2mmol)溶于DCM(10mL)中，加入DHP(354.2mg,1.4mmol)，滴入三氟醋酸(74.5uL,1.0mmol)，40℃回流反应12小时。将反应液过滤，旋干，过柱(DCM 60mL,DCM:MeOH＝50：1)，得化合物(11)278.8mg黄色固体，收率83.0％。
化合物(N15)的合成
将化合物(11)(200mg,0.595mmol)溶于乙醇和水(1:1)中，加入氯化铵(16.5mg,0.3mmol)，分批加入铁粉(166.7mg,2.98mmol)，于80℃反应30分钟，将反应液趁热过滤，减压旋干溶剂，过柱(DCM:MeOH＝30:1)，得化合物(N15)155.9mg淡黄色固体,收率85.6％。
化合物(13)的合成
将原料(N15)(68.3mg,0.223mmol)和原料(12)(30.0mg,0.268mmol)溶于DCM(2mL)中，加入DHP(79.1mg,0.312mmol)，滴入三氟醋酸(16.6uL,0.223mmol)，40℃回流反应12小时。将反应液过滤，旋干，过柱(DCM:MeOH＝100:1)，得化合物(13)57.3mg淡黄色固体，收率66.2％。
3-((3-((6-(三氟甲基)-1H-吲哚-4-)氨基)苯基)氨基)-1-环己醇(N16)的合成
将化合物(13)(55mg,0.137mmol)溶于乙醇(1mL)中，置于0℃，加入硼氢化钠(76.6mg,0.684mmol)，升至室温搅拌反应12小时，将反应液降温至0℃，加入丙酮(2mL)淬灭多余的硼氢化钠，将反应液旋干过柱(DCM:MeOH＝20:1)，得淡黄色固体化合物(N16)。收率68.7％；淡黄色固体；1H-NMR(400MHz,d6-DMSO,ppm):δ13.13(s,1H,indazole-NH),8.37(s,1H,indazole-H),7.32(t,1H,J＝5.2Hz,NH),7.01-6.42(m,5H,Ar-H),6.18(s,1H,Ar-H),4.59(s,1H,NH),4.42(s,1H,OH),4.35(d,2H,J＝5.6Hz,benzyl-CH2),3.57(t,1H,J＝4.1Hz,CH),2.51(d,1H,J＝1.8Hz,CH),1.66-0.89(m,8H,CH2).13C-NMR(100MHz,d6-DMSO,ppm):δ148.5,143.4,140.5,140.4,132.8,128.7,126.8,124.1,115.1,114.7,111.5,111.4,95.0,93.7,68.3,65.3,50.0,42.8,35.6,32.2,19.6.ESI-MS:405.19[M+H].
实施例8本发明化合物N17、N18、N19和N20的合成
化合物15的合成
将化合物14(2.47g,24.46mmol)溶解于无水甲醇(30mL)中,冰浴下滴加SOCl2(8.78mL,122.30mmol),加毕，升温至室温搅拌12h后，旋干反应液，得到粗产品为白色固体化合物15，直接投下步反应，收率99％。
化合物16的合成
将化合物15(3.68g,24.46mmol)溶解于乙腈(25mL)中,冰浴下滴加Et3N(3.39mL,24.46mmol)。将(Boc)2O(5.87g,26.91mmol)溶解于乙腈(5mL)中，滴加到反应液中。加毕，升温至室温搅拌4h后，滤去反应液中的固体，旋干滤液，加水溶解残余物。用EA萃取3次，合并有机层，用饱和氯化钠水溶液洗涤一次，用无水硫酸镁干燥有机层，过滤，旋干得粗产品。粗产品经柱层析纯化(PE:EA＝20:1)得淡黄色油状液体化合物16(3.00g,9.73mmol),收率为65％。
化合物17的合成
将化合物16(2.00g,10.64mmol)置于三颈瓶中，氩气保护下加入DCM使之溶解，后置于-78℃下搅拌。10min后，缓慢滴加DIBAL-H(2.3mL,1M)。加毕，保持-78℃搅拌30min后，用2mL无水甲醇淬灭反应。5min后，移至冰浴。向反应液中加入200mL的10％柠檬酸水溶液，有固体析出。冰浴下搅拌30min至固体消失，用EA萃取水层3次，合并有机层，用饱和氯化钠水溶液洗涤一次，无水硫酸镁干燥。过滤，旋干滤液，得粗产品淡黄色透明油状液体化合物17。直接投下步反应，收率99％。
化合物18的合成
将化合物5b(200mg,1.00mmol)、化合物17(471mg,2.99mmol)和DHP(352mg,1.39mmol)溶解于DCM中，搅拌下滴加TFA(74μl,1.00mmol)。加毕，升温至回流搅拌12h后，旋干反应液，得粗品。粗品经柱层析(DCM:MeOH＝60:1)纯化得橘黄色固体化合物18(100mg,0.27mg)。收率为27％。
N-(3-甲基-杂氮环丁烷)-6-三氟甲基-1H-吲哚-4-胺(N17)的合成
将化合物18(50mg,0.14mmol)溶解于DCM(2mL)中，搅拌下滴加TFA(0.30mL,2.63mmol)。加毕，室温下搅拌3h后，旋干反应液得粗品，经柱层析(DCM:MeOH＝20:1)纯化得黄色固体化合物N17。收率63.0％；土黄色固体；1H-NMR(400MHz,d6-DMSO,ppm):δ8.31(s,1H,indazole-H),6.99(s,1H,Ar-H),6.74(t,1H,J＝5.3Hz,NH),6.19(s,1H,Ar-H),3.59(m,2H,CH2),3.45-3.42(m,2H,CH2),3.28(d,2H,J＝6.5Hz,benzyl-CH2),2.97-2.90(m,2H,CH andNH).13C-NMR(100MHz,d6-DMSO,ppm):δ143.5,140.6,132.6,128.8,126.8,124.1,114.9,95.0,92.9,50.7,47.0,33.9.ESI-MS:271.11[M+H].
以类似的方法合成N18、N19和N20，区别是将初始原料换成19、20、21。结果和表征如下：
(R)-N-(吡咯-2-甲基-)-6-(三氟甲基)-1H-吲哚-4-胺(N18).收率50.0％；黄色固体；1H-NMR(400MHz,d6-DMSO,ppm):δ8.33(s,1H,indazole-H),6.98(s,1H,NH),6.95(s,1H,Ar-H),6.65(t,1H,NH),6.22(s,1H,Ar-H),3.37-3.31(m,2H,benzyl-CH2)),3.21-3.09(m,3H,CH2and CH),2.89-2.76(m,1H,NH)1.89-1.38(m,6H,CH2).13C-NMR(100MHz,d6-DMSO,ppm):δ143.5,410.7,132.5,129.1,128.8,114.9,95.0,93.0,57.1,48.7,46.3,29.9,25.4.ESI-MS:285.13[M+H].
(R)-N-(哌啶-2-甲基)-6-(三氟甲基)-1H-吲哚-4-胺(N19).收率57.0％；淡黄色固体；1H-NMR(400MHz,d6-DMSO,ppm):δ13.23(s,1H,indazole-NH),8.43(s,1H,indazole-H3),7.05(s,2H,NH and Ar-H),6.30(s,1H,Ar-H),3.51-3.18(m,6H,CH2and NH)1.92-1.43(m,6H,CH2).ESI-MS:399.14[M+H].
(S)-N-(哌啶-2-甲基)-6-(三氟甲基)-1H-吲哚-4-胺(N20).收率57.0％；淡黄色固体；1H-NMR(400MHz,d6-DMSO,ppm):δ13.26(s,1H,indazole-NH),8.48(s,1H,indazole-H),7.14(t,1H,J＝5.5Hz,NH),7.06(s,1H,Ar-H),6.30(s,1H,Ar-H),3.56-3.40(m,2H,CH),2.90-2.85(m,2H,benzyl-CH2),1.92(m,1H,NH)1.70-1.44(m,5H,CH2),1.12(m,2H,CH2)13C-NMR(100MHz,d6-DMSO,ppm):δ142.9,140.6,132.9,129.0,115.3,100.0,96.0,93.2,55.2,45.9,44.5,27.1,22.7,22.2.ESI-MS:299.15[M+H].
实施例9本发明化合物对IDO蛋白的抑制活性
重组人IDO蛋白经大肠杆菌表达，镍亲合层析纯化而得。化合物对IDO抑制活性实验采用L-色氨酸作为底物。待测化合物溶解在10％DMSO溶液中配制成稀释液。取5uL稀释液加入到100μL反应体系中。100μL反应体系中含有0.5％DMSO，40nmol/LIDO，900μmol/L L-色氨酸，以及其他反应共存物(磷酸钾缓冲液、抗坏血酸、过氧化氢酶，亚甲基蓝)。反应混合物于37度下培育180分钟，再加入三氯乙酸终止反应。使用Tecan Infinite M1000酶标仪在321nm处测定产生的N-甲酰基犬尿氨酸的浓度，从而评价化合物对IDO的抑制活性。阴性对照物是以5μL的缓冲液代替IDO。临床III期的IDO抑制剂INCB024360作为阳性对照，验证本实验建立的IDO活性检测体系是否有效。
每个浓度设立三复孔。使用软件Graphpad Prism进行数据分析。在不含待测化合物的反应液中，吸光度(At)定义为100％活性。在不含IDO的反应液中，吸光度(Ab)定义为0％活性。对于待测化合物，活性的计算公式为：％activity＝[(A-Ab)/(At-Ab)]×100，其中A为含待测化合物的反应液的吸光度。抑制率的计算公式为：％inhibition＝100-％activity.
通过以上实验方法，测试了本发明中的部分化合物针对IDO的抑制活性。具体部化合物在1μM、10μM、100μM浓度下的抑制活性见表1。
其中A表示抑制率大于90％、B表示抑制率为70-89％，C表示抑制率为40-69％；D表示抑制率为10-39％，E表示抑制率小于10％；阳性对照物在浓度为0.05μM时的抑制率为46％。
表1本发明化合物对IDO的抑制活性
构效关系显示：当R1对活性的影响依次为：卤素>烷烃>卤代烷烃；R2结构较长时，活性明显降低；R2宜为取代苯环或者取代的脂肪环，并且含有极性基团，如OH，COOH，NH2，NO2时，化合物的活性显著增加。
经试验证明，本发明提供的1H-吲唑类衍生物对IDO具有优异的抑制作用，可以用于预防和/或治疗多种疾病，如阿尔茨海默病、白内障、细胞免疫激活相关的感染、自身免疫性疾病、艾滋病、癌症、抑郁症或色氨酸代谢异常等。
Claims (9)
1.一种化合物或其药学上可接受的盐，所述化合物的结构如式(Ⅰ)所示：
其中，
R1选自卤素、C1～C6烷基或C1～C6卤代烷基；
R2选自取代的苯基、取代的环己基或非取代的5～6元的氮杂环基，所述取代的苯基、取代的环己基分别独立地被一个或多个选自-NH2、-(CH2)aOH、硝基、-CONH-R3或-NH-R4的取代基所取代；所述非取代的5～6元的氮杂环基为：
R3选自C1～C6烷基；
R4选自5-6元的环烷基或C1～C6烷基取代的5-6元环烷基；
a＝0或1。
2.根据权利要求1所述的化合物，其特征在于：所述R1选自Cl、-Br、CF3-或-CH3。
3.根据权利要求1所述的化合物，其特征在于：所述C1～C6烷基选自甲基。
4.根据权利要求1所述的化合物，其特征在于：所述C1～C6卤代烷基为三氟甲基。
5.根据权利要求1-4任一项所述的化合物，其特征在于：所述R2选自下述基团之一：
6.一种化合物或其药学上可接受的盐，其特征在于：所述化合物选自如下化合物之一：
7.权利要求1-6任一项所述化合物、式(Ⅱ)所示化合物、或其药学上可接受的盐在制备IDO抑制剂类药物上的用途，
R1如权利要求1-4任一项所定义。
8.根据权利要求7所述的用途，其特征在于：所述药物是预防和/或治疗阿尔茨海默病、白内障、细胞免疫激活相关的感染、自身免疫性疾病、艾滋病、癌症、抑郁症或色氨酸代谢异常的药物。
9.一种药物组合物，其特征在于：它是以权利要求1-6任一项所述的化合物或其药学上可接受的盐为活性成分，加上药学上可接受的辅料制备而成的制剂。
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610831550.7A CN107840826B (zh) | 2016-09-19 | 2016-09-19 | 1h-吲唑类衍生物及其作为ido抑制剂的用途 |
| PCT/CN2016/099845 WO2017133258A1 (zh) | 2016-02-04 | 2016-09-23 | 1h-吲唑类衍生物及其作为ido抑制剂的用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610831550.7A CN107840826B (zh) | 2016-09-19 | 2016-09-19 | 1h-吲唑类衍生物及其作为ido抑制剂的用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107840826A CN107840826A (zh) | 2018-03-27 |
| CN107840826B true CN107840826B (zh) | 2021-07-09 |
Family
ID=61656406
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610831550.7A Active CN107840826B (zh) | 2016-02-04 | 2016-09-19 | 1h-吲唑类衍生物及其作为ido抑制剂的用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107840826B (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108689937B (zh) * | 2017-04-10 | 2021-09-17 | 西华大学 | 吲唑类化合物及其在制备ido抑制剂类药物上的用途 |
| CN108689938B (zh) * | 2017-04-10 | 2021-07-30 | 西华大学 | 多取代的吲唑类化合物及其作为ido抑制剂的用途 |
| CN111285808B (zh) * | 2018-12-07 | 2023-06-23 | 西华大学 | 4位芳杂环取代的吲唑类化合物及其作为ido/tdo双重抑制剂的用途 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103298460A (zh) * | 2010-12-14 | 2013-09-11 | 电泳有限公司 | 酪蛋白激酶1δ(CK1δ)抑制剂 |
| WO2015123365A1 (en) * | 2014-02-11 | 2015-08-20 | Mitokinin Llc | Compositions and methods using the same for treatment of neurodegenerative and mitochondrial disease |
| WO2016071293A2 (en) * | 2014-11-03 | 2016-05-12 | Iomet Pharma Ltd | Pharmaceutical compound |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107033087B (zh) * | 2016-02-04 | 2020-09-04 | 西华大学 | 1h-吲唑-4-胺类化合物及其作为ido抑制剂的用途 |
-
2016
- 2016-09-19 CN CN201610831550.7A patent/CN107840826B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103298460A (zh) * | 2010-12-14 | 2013-09-11 | 电泳有限公司 | 酪蛋白激酶1δ(CK1δ)抑制剂 |
| WO2015123365A1 (en) * | 2014-02-11 | 2015-08-20 | Mitokinin Llc | Compositions and methods using the same for treatment of neurodegenerative and mitochondrial disease |
| WO2016071293A2 (en) * | 2014-11-03 | 2016-05-12 | Iomet Pharma Ltd | Pharmaceutical compound |
Non-Patent Citations (1)
| Title |
|---|
| "RN1525839-79-5等";Registry;《STN Columbus》;20140121 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107840826A (zh) | 2018-03-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2019240616B2 (en) | N-((het)arylmethyl)-heteroaryl-carboxamides compounds as plasma kallikrein inhibitors | |
| TWI766882B (zh) | 新穎化合物類 | |
| CN107033087B (zh) | 1h-吲唑-4-胺类化合物及其作为ido抑制剂的用途 | |
| DK2152692T3 (en) | EXTERNAL anti-cancer activity | |
| CN105358550B (zh) | 组蛋白脱乙酰基酶抑制剂 | |
| JP6117430B2 (ja) | 選択的ヒストン脱アセチル化酵素抑制剤としての新規化合物およびこれを含む薬剤学的組成物 | |
| JP5596139B2 (ja) | 二置換フタラジンヘッジホッグ経路アンタゴニスト | |
| WO2011007819A1 (ja) | ラクタムまたはベンゼンスルホンアミド化合物を含有する医薬 | |
| CA2920815A1 (en) | Inhibitors of plasma kallikrein | |
| TW202017916A (zh) | 新穎緩激肽ｂ２受體拮抗劑及其用途 | |
| KR20110105792A (ko) | 페닐피리미돈을 함유하는 화합물, 그 약물 조성물 및 그 제조방법과 용도 | |
| CN107840826B (zh) | 1h-吲唑类衍生物及其作为ido抑制剂的用途 | |
| CN108689937B (zh) | 吲唑类化合物及其在制备ido抑制剂类药物上的用途 | |
| JP7397072B2 (ja) | ウイルス感染を処置するための２，６－ジメチル－Ｎ－（（ピリジン－４－イル）メチル）イミダゾ［１，２－ｂ］ピリダジン－８－アミンおよび２，５－ジメチル－Ｎ－［（ピリジン－４－イル）メチル］ピラゾロ［１，５－ａ］ピリミジン－７－アミン誘導体 | |
| JP2023529570A (ja) | Ｕｓｐ３０阻害剤としての活性を有するｎ－シアノピロリジン | |
| CN106986874B (zh) | (1H-吡唑[3,4-d]嘧啶)-4-氨基衍生物及其作为IDO抑制剂在药物制备中的用途 | |
| WO2014062204A1 (en) | Matrix metalloproteinase inhibitors and methods for the treatment of pain and other diseases | |
| CN107118209A (zh) | 吡啶骈[3,4-b]吲哚脲类化合物及其作为IDO抑制剂的用途 | |
| RU2821520C2 (ru) | N-((гет)арилметил)-гетероарил-карбоксамидные соединения в качестве ингибиторов плазменного калликреина | |
| CN113527261A (zh) | 吡啶酮或嘧啶酮类衍生物及其制备方法和用途 | |
| CN116134025A (zh) | 酰胺膦氧类衍生物及其制备方法和用途 | |
| JP2023541309A (ja) | ピペラジン誘導体、その製造方法、およびその使用 | |
| NZ770256B2 (en) | N-((het)arylmethyl)-heteroaryl-carboxamides compounds as plasma kallikrein inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |