CN107176956B - A kind of IDO inhibitor compound, Pharmaceutical composition, purposes - Google Patents
A kind of IDO inhibitor compound, Pharmaceutical composition, purposes Download PDFInfo
- Publication number
- CN107176956B CN107176956B CN201710405187.7A CN201710405187A CN107176956B CN 107176956 B CN107176956 B CN 107176956B CN 201710405187 A CN201710405187 A CN 201710405187A CN 107176956 B CN107176956 B CN 107176956B
- Authority
- CN
- China
- Prior art keywords
- substituted
- base
- compound
- alkyl
- cancer
- 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
- 150000001875 compounds Chemical class 0.000 title claims abstract description 71
- 239000003112 inhibitor Substances 0.000 title claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 11
- 101001037256 Homo sapiens Indoleamine 2,3-dioxygenase 1 Proteins 0.000 title description 5
- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 title description 4
- 102000006639 indoleamine 2,3-dioxygenase Human genes 0.000 claims abstract description 35
- 108020004201 indoleamine 2,3-dioxygenase Proteins 0.000 claims abstract description 35
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- 201000010099 disease Diseases 0.000 claims abstract description 9
- -1 nitro, hydroxyl Chemical group 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- 239000000460 chlorine Substances 0.000 claims description 14
- 239000011737 fluorine Substances 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 201000011510 cancer Diseases 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 230000001363 autoimmune Effects 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 208000030507 AIDS Diseases 0.000 claims description 4
- 208000002177 Cataract Diseases 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 208000019901 Anxiety disease Diseases 0.000 claims description 3
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 3
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 208000036142 Viral infection Diseases 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 208000019065 cervical carcinoma Diseases 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 210000003734 kidney Anatomy 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 201000001275 rectum cancer Diseases 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 230000009385 viral infection Effects 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 4
- 125000004432 carbon atom Chemical group C* 0.000 claims 4
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 2
- 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 claims 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 239000002585 base Substances 0.000 description 116
- 238000006243 chemical reaction Methods 0.000 description 59
- 239000000243 solution Substances 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 150000002518 isoindoles Chemical class 0.000 description 36
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Natural products CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
- 238000002360 preparation method Methods 0.000 description 27
- 235000002639 sodium chloride Nutrition 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 239000007787 solid Substances 0.000 description 25
- 238000004090 dissolution Methods 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 23
- 238000000605 extraction Methods 0.000 description 23
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 239000012074 organic phase Substances 0.000 description 20
- 239000011734 sodium Substances 0.000 description 20
- 239000011780 sodium chloride Substances 0.000 description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 12
- 150000002431 hydrogen Chemical class 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 150000001335 aliphatic alkanes Chemical class 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 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 9
- 239000004698 Polyethylene Substances 0.000 description 9
- 230000005496 eutectics Effects 0.000 description 9
- 229910052736 halogen Inorganic materials 0.000 description 9
- 150000002367 halogens Chemical class 0.000 description 9
- LGRQUXHYJBFGTM-UHFFFAOYSA-N 4H-imidazole Chemical class C1C=NC=N1 LGRQUXHYJBFGTM-UHFFFAOYSA-N 0.000 description 8
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 8
- 150000001721 carbon Chemical group 0.000 description 8
- 229960004799 tryptophan Drugs 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- YGACXVRLDHEXKY-WXRXAMBDSA-N O[C@H](C[C@H]1c2c(cccc2F)-c2cncn12)[C@H]1CC[C@H](O)CC1 Chemical compound O[C@H](C[C@H]1c2c(cccc2F)-c2cncn12)[C@H]1CC[C@H](O)CC1 YGACXVRLDHEXKY-WXRXAMBDSA-N 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- TWJVNKMWXNTSAP-UHFFFAOYSA-N azanium;hydroxide;hydrochloride Chemical class [NH4+].O.[Cl-] TWJVNKMWXNTSAP-UHFFFAOYSA-N 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- FFFAPZFZGCQOAY-UHFFFAOYSA-N n-cyclopropyl-n-methylformamide Chemical compound O=CN(C)C1CC1 FFFAPZFZGCQOAY-UHFFFAOYSA-N 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- YGPSJZOEDVAXAB-QMMMGPOBSA-N L-kynurenine Chemical compound OC(=O)[C@@H](N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-QMMMGPOBSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 3
- 108091005804 Peptidases Proteins 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 239000005864 Sulphur Substances 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 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
- 239000012230 colorless oil Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000857 drug effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 238000003674 kinase activity assay Methods 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 235000019833 protease Nutrition 0.000 description 3
- 239000011535 reaction buffer Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- GVHWLCYABLWGIR-UHFFFAOYSA-N (3-fluoro-2-formylphenyl)boronic acid Chemical compound OB(O)C1=CC=CC(F)=C1C=O GVHWLCYABLWGIR-UHFFFAOYSA-N 0.000 description 2
- NPZDCTUDQYGYQD-UHFFFAOYSA-N 1-tritylimidazole Chemical class C1=NC=CN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 NPZDCTUDQYGYQD-UHFFFAOYSA-N 0.000 description 2
- MXLMTQWGSQIYOW-UHFFFAOYSA-N 3-methyl-2-butanol Substances CC(C)C(C)O MXLMTQWGSQIYOW-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 102000016938 Catalase Human genes 0.000 description 2
- 108010053835 Catalase Proteins 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 229940072107 ascorbate Drugs 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Substances CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 125000006574 non-aromatic ring group Chemical group 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000012286 potassium permanganate Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- DGUWACLYDSWXRZ-UHFFFAOYSA-N (2-formylphenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1C=O DGUWACLYDSWXRZ-UHFFFAOYSA-N 0.000 description 1
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- WIHIUTUAHOZVLE-UHFFFAOYSA-N 1,3-diethoxypropan-2-ol Chemical compound CCOCC(O)COCC WIHIUTUAHOZVLE-UHFFFAOYSA-N 0.000 description 1
- CSRUMYQPYPNDPR-UHFFFAOYSA-N 2-bromo-1-tritylimidazole Chemical class BrC1=NC=CN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 CSRUMYQPYPNDPR-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000016680 Dioxygenases Human genes 0.000 description 1
- 108010028143 Dioxygenases Proteins 0.000 description 1
- 239000006145 Eagle's minimal essential medium Substances 0.000 description 1
- PSCXEUSWZWRCMQ-UHFFFAOYSA-N F[S](F)F Chemical compound F[S](F)F PSCXEUSWZWRCMQ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 241000720974 Protium Species 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 230000033540 T cell apoptotic process Effects 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 230000009876 antimalignant effect Effects 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 238000012754 cardiac puncture Methods 0.000 description 1
- 230000007969 cellular immunity Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 150000002012 dioxanes Chemical class 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- 102000012427 human indoleamine 2,3-dioxygenase 1 Human genes 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- HWWVAHCWJLGKLW-UHFFFAOYSA-N n,n-dimethylhydroxylamine;hydron;chloride Chemical compound Cl.CN(C)O HWWVAHCWJLGKLW-UHFFFAOYSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical compound OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 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
- 239000008354 sodium chloride injection Substances 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
The present invention provides a kind of noval chemical compound, which has certain inhibitory activity to indoleamine 2,3-dioxygenase (IDO), or can be used for treating associated disease.
Description
Technical field
The present invention relates to field of medicinal chemistry, more particularly to IDO inhibitor compound, Pharmaceutical composition, purposes.
Background technique
Diindyl amine 2 in majority tissue, 3- dioxygenase (IDO) is in silence state, but IDO is then in many tumour cells
In continuous expression shape, so that intracellular tryptophan levels decline and a series of generation of metabolins, and immune nerve is influenced in turn
Etc. system functions.IDO effect is to decompose tryptophan to kynurenin, and the exhaustion of tryptophan and its metabolite will lead to exempting from
The strong inhibition effect of epidemic disease reaction, causes the stopping of the growth of T cell, the activation of blocking t cell, induction of T cell apoptosis and increasing
Add the generation of regulatory T cells.To enhance body to the attacking ability of tumour cell, and IDO inhibitor can also be with chemotherapy
Drug combination, reduces the drug resistance of tumour cell, to enhance the anti-tumor activity of conventional cytotoxic therapy.
Studies have shown that IDO is in terms of tumor cell drug resistance in addition to other than playing an important role, also with many immunocytes
Activate relevant disease related.IDO is it is verified that infection relevant to cellular immunity activation, malignant tumour, autoimmune
The target of the major diseases such as disease, AIDS, cataract, Alzheimer disease.Therefore IDO inhibitor acts on important drug tool
There is wide potential applicability in clinical practice.
WO2012142237 reports IDO inhibitor and its pharmaceutical composition, for regulating and controlling indoleamine 2,3- dioxygenase
Active 5H- imidazo [5,1-a] isoindoles compound.A key is singly-bound or double bond；M is 0,1 or 2；P is 0 or 1；And
When a key is singly-bound, then Z is-C (R36)2-、–C(R32)-、-N(R35)-or-O-, wherein R35For hydrogen, C1-6 alkyl ,-C (O)
R、-S(O)2R ,-C (O) OR or-C (O) N (R)2；With when a key is double bond, then Z is-C (R36)=or-N=；And each R36 is independent
Halogen, nitro, C1-6 alkyl ,-C1-6 alkyl-R are stood alone as hydrogen or R31, R3133, C1-6 halogenated alkyl ,-OR ,-N (R)2、-C
( O)OR、-C(O)N(R)2、-C(O)R、-S(O)2R、-N(R)C(O)R、-N(R)C(O)OR、-N(R)C( O)N(R)2, wherein R33
For-OR.The invention and the compound of the present invention architectural difference are larger, are not considered as that specifically describing in this patent is one of the invention
Point, general formula compound is as follows:
WO2016131380 and WO2016165613 also reports 5H- imidazo [5,1-a] isoindoles compound conduct
The compound of IDO inhibitor.
NLG-919 be in clinical investigation phase as a kind of novel IDO inhibitor at present, but its drug effect and
Pharmacokinetic property still has greatly improved space.
Summary of the invention
A kind of change the object of the present invention is to provide 5H- imidazo [5,1-a] isoindoles compound as IDO inhibitor
Object or its all stereoisomers, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug are closed,
Its pharmaceutical composition of deuterated compound and its indole amine 2,3-dioxygenase (IDO) inhibitor purposes be promoted IDO suppression
The drug effect and pharmacokinetic property of preparation.
The present invention provides a kind of compound or its stereoisomer, solvate, hydrate, prodrug, metabolite, deuterated
Compound, pharmaceutically acceptable salt or eutectic, the compound have formula (I) structure,
Wherein, n is the integer of 0-4；
Wherein R1From following substituent group: hydrogen, halogen, hydroxyl, cyano, nitro, amino, substituted or unsubstituted C1-C6Alkane
Base, substituted or unsubstituted C1-C6Miscellaneous alkyl, substituted or unsubstituted C3-C6Naphthenic base, substituted or unsubstituted C3-C6Heterocycle
Alkyl, substituted or unsubstituted C5-C6Aryl, substituted or unsubstituted C5-C6Heteroaryl；The substituent group of above-mentioned group is selected from:
Nitro, hydroxyl, amino, sulfydryl, halogeno-group, cyano, substituted or non-substituted C1-C10Alkyl, substituted or non-substituted C1-C10Miscellaneous alkane
Base, C substituted or unsubstituted3-C 10Naphthenic base, C substituted or unsubstituted3-C10Heterocyclylalkyl；
R2Selected from following substituent group: hydrogen, halogen, cyano, nitro, aryl, heteroaryl, OR3、N(R3)2、NCOR3；
R3Selected from following substituent group: substituted or non-substituted C1-C10Alkyl, substituted or non-substituted C1-C10Miscellaneous alkyl, replace or
Unsubstituted C3-C10Naphthenic base, C substituted or unsubstituted3-C10Heterocyclylalkyl, substituted or unsubstituted C5-C6Aryl, substitution or not
Substituted C5-C6Heteroaryl；
R4、R5Selected from following substituent group: hydrogen, halogen, hydroxyl, cyano, nitro, amino, substituted or unsubstituted C1-C6Alkane
Base, substituted or unsubstituted C1-C6Miscellaneous alkyl, substituted or unsubstituted C3-C6Naphthenic base, substituted or unsubstituted C3-C6Heterocycle
Alkyl；R4、R5Following group is collectively constituted with the carbon atom being connect: substituted or unsubstituted C3-C8Alkyl, replace or not
Substituted C3-C8Miscellaneous alkyl；The substituent group of above-mentioned group be selected from nitro, hydroxyl, amino, sulfydryl, halogeno-group, cyano, substitution or
Non-substituted C1-C10Alkyl, substituted or non-substituted C1-C10Miscellaneous alkyl, C substituted or unsubstituted3-C10Naphthenic base, it is substituted or unsubstituted
C3 -C10Heterocyclylalkyl.
Further, the compound has the structure of formula (II)
Wherein, R1Selected from following group: hydrogen, halogen；
R2Selected from group: hydrogen, halogeno-group, cyano, amino, hydroxyl, aryl, heteroaryl, OR3、N(R 3)2、NCOR3；
R3Selected from substituted or non-substituted C1-C6Alkyl or miscellaneous alkyl；
R4, R5 are selected from hydrogen, the alkyl of substituted or non-substituted C1-C6 or collectively constitute substitution with the carbon atom being connect
Or the naphthenic base of non-substituted C3-C6；
Above-mentioned R1-R5The substituent group of substituent group is selected from group: nitro, hydroxyl, amino, sulfydryl, halogeno-group, cyano, substitution
Or non-substituted C1-C10 alkyl, substituted or non-substituted C1-C10 miscellaneous alkyl, C3-C10 naphthenic base substituted or unsubstituted, replace or not
Replace C3-C10 Heterocyclylalkyl.
Further, R1Selected from group: hydrogen, halogen；R2 is selected from group: halogen, hydroxyl, cyano, N COR3；R3Selected from taking
Generation or non-substituted C1-C3 alkyl；
R4, R5 collectively constituted by hydrogen, substituted or non-substituted C1-C6 alkyl or with the carbon atom connecting substitution or
The naphthenic base of non-substituted C3-C6.
Experiment discovery, when R1, R2 are selected from halogen, activity has certain promotion, can be with by the specific embodiment of the invention
Find out, R1、R2It can be independently selected from fluorine or chlorine, but should not be construed as only limiting halogen herein being fluorine or chlorine.
In a specific embodiment of the invention, R1Selected from fluorine, R2It is independently selected from fluorine or chlorine.
It has also been found that, work as R in present invention experiment4、R5Substituted or non-substituted C3-C6 is collectively constituted with the carbon atom being connect
When naphthenic base, activity is more preferable.In a specific embodiment of the invention, naphthenic base is selected from cyclopropyl at this, should not be understood thus
Only limitation C3-C6 naphthenic base is cyclopropyl at place.
Further, the substituent group of substituent group is selected from: hydroxyl, amino, sulfydryl, C1-C6 alkyl.
The present invention also provides a kind of Pharmaceutical composition, the Pharmaceutical composition active ingredient be selected from above-mentioned compound or its
The combination of one or more of stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or eutectic.
" pharmaceutical composition ", can also be containing in pharmaceutically acceptable carrier, excipient in addition to containing active constituent
It is one or more kinds of.
The present invention also provides above compound or its stereoisomers, solvate, hydrate, pharmaceutically acceptable
Salt or eutectic are preparing the purposes in indole amine 2,3-dioxygenase (IDO) inhibitor.
Wherein, above-mentioned inhibitor can treat and/or prevent illness relevant to the tryptophan metabolic pathway that IDO is mediated.
It can by inhibiting the IDO of unconventionality expression, to prevent the reduction of body cell tryptophan levels, and from treat or prevent because
IDO unconventionality expression leads to disease caused by tryptophan levels decline.
Wherein, the inhibitor is for treating at least one disease as described below: cancer, autoimmune conditions, virus
Sexy dye, depression, AIDS, myelodysplastic syndrome, anxiety disorder, cataract, more preferably wherein described in cancer
Selected from breast cancer, cervical carcinoma, colon cancer, liver cancer, gastric cancer, the carcinoma of the rectum, oophoroma, cancer of pancreas, bladder cancer, solid tumor, myeloma,
Non-small cell lung cancer, leukaemia, lymthoma, melanoma, osteocarcinoma, kidney.
In a specific embodiment of the invention, the R in Formula II compound1、R2It is independently selected from fluorine or chlorine, R4、R5For
Hydrogen, substituted or non-substituted C1-C6 alkyl collectively constitute substituted or non-substituted C3-C6 naphthenic base with the carbon atom being connect,
Its Compound ira vitro IDO inhibits in Kinase activity assays, and compound inhibits IC50 test result data to source of people proteinase activity
Respectively less than 49nM, and under the identical test condition of the present invention, the novel IDO inhibitor NLG- in clinical investigation phase
919 test result data is 159nM.
In a specific embodiment of the invention, the R in Formula II compound1、R2It is independently selected from fluorine or chlorine； R4、R5For
Substituted or non-substituted C1-C6 alkyl collectively constitutes substituted or non-substituted C3-C6 naphthenic base with the carbon atom being connect, and changes
It closes the outer IDO of object to inhibit in Kinase activity assays, compound inhibits IC50 test result data small source of people proteinase activity
In 31nM.
In a specific embodiment of the invention, the R in Formula II compound1、R2It is independently selected from fluorine or chlorine, R4、R5For
Substituted or non-substituted C is collectively constituted with the carbon atom being connect3-C6Naphthenic base, Compound ira vitro IDO inhibit kinase activity examination
In testing, compound inhibits IC50 test result data to be respectively less than 24nM source of people proteinase activity；Meanwhile it being tried in pharmacokinetics
Middle discovery is tested, compared with the Novel IDO inhibitor NLG-919 in clinical investigation phase, above compound maximum plasma concentration
It is 1.3-2.8 times of NLG-919.
Above-mentioned C1-C6Alkyl can be selected from methyl, ethyl, propyl etc..
Above-mentioned C3-C6Naphthenic base can be selected from cyclopropyl, cyclobutyl etc..
Carbon involved in group and compound of the present invention, hydrogen, oxygen, sulphur, nitrogen or F, Cl, Br, I include them
Isotope situation and group of the present invention and compound involved in carbon, hydrogen, oxygen, sulphur or nitrogen optionally further by one
Their a or multiple corresponding isotopes are substituted, and wherein the isotope of carbon includes12C、13C and14C, the isotope of hydrogen include protium
(H), deuterium (D is called heavy hydrogen), tritium (T is called superheavy hydrogen), the isotope of oxygen include16O、17O and18The isotope of O, sulphur includes32S、33S、34S and36The isotope of S, nitrogen includes14N and15The isotope of N, fluorine includes17F and19The isotope of F, chlorine includes35Cl
With37The isotope of Cl, bromine includes79Br and81Br。
" miscellaneous alkyl " refers to the linear chain or branched chain saturated aliphatic hydrocarbons of 1 to 20 carbon atom, comprising 1 to 3 selected from N,
The hetero atom of O or S, N, S can be oxidized to various oxidation state.
" heterocycle " refers to substituted or unsubstituted saturated or unsaturated aromatic rings or non-aromatic ring, aromatic rings or
Person's non-aromatic ring can be 3 to 8 yuan of monocycle, 4 to 12 membered bicyclics or 10 to 15 membered tricyclic systems, and includes 1 to 3 and be selected from
N, the hetero atom of O or S, preferably 3 to 8 circle heterocyclic ring bases, N, the S selectively replaced in the ring of heterocycle can be oxidized to various oxidations
State.
" pharmaceutically acceptable salt " or " its pharmaceutically acceptable salt " refers to that the compounds of this invention keeps free acid
Perhaps the biological effectiveness and characteristic of free alkali and the free acid by with nontoxic inorganic base or organic base, it is described
Free alkali pass through the salt obtained with nontoxic inorganic acid or organic acid reaction.In general, pharmaceutically suitably forming the acid packet of salt
It includes but is not limited to: the inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, third
Diacid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzene methanesulfonic acid, benzene
The organic acids such as sulfonic acid；And the acidic amino acids such as aspartic acid, glutamic acid.
" carrier " refer to will not to organism generate obvious stimulation and will not eliminate given compound bioactivity and
The material of characteristic.
" excipient " refers to the inert substance being added in pharmaceutical composition to promote compound to be administered.Non-limiting implementation
Example includes calcium carbonate, calcium phosphate, sugar, starch, cellulose derivative (including microcrystalline cellulose), gelatin, vegetable oil, polyethylene glycol
Class, diluent, granulating agent, lubricant, adhesive and disintegrating agent.
" prodrug ", which refers to, to be biologically active the compounds of this invention through biotransformationin vivo.Prodrug of the invention is logical
Prepared by the hydroxyl crossed in modification the compounds of this invention, which can be removed by conventional operation or in vivo, and
Obtain parent compound.When prodrug of the invention is delivered to mammalian subject, prodrug to form free hydroxyl by isolating.
" eutectic " refers to active pharmaceutical ingredient (API) and eutectic formation (CCF) in hydrogen bond or the work of other non-covalent bonds
The crystal being combined under, wherein the pure state of API and CCF is solid at room temperature, and there is fixation between each component
Stoichiometric ratio.Eutectic is a kind of multicomponent crystal, both comprising the binary eutectic formed between two kinds of neutral solids, also includes
Property the multi-element eutectic that is formed of solid and salt or solvate.
" stereoisomer " refers to the isomers as caused by the spatially arrangement mode difference of atom in molecule, including suitable
Trans isomer, enantiomter and conformer.
" optional " or " optionally " or " selective " " selectively " refer to that then described event or situation can be with
But it may not occur, which includes the case where that the event or situation and wherein nonevent situation wherein occurs.For example, " selection
Property by alkyl-substituted heterocycle " refer to the alkyl can with but may not exist, the description include wherein heterocycle taken by alkyl
For the case where, and wherein heterocycle not by alkyl-substituted situation.
Inventive compound is prepared into pharmaceutical preparation, it can physico-chemical property according to active constituent and actual medication
Demand prepares different dosage forms, such as solution, solid pharmaceutical preparation.
Specific embodiment
Embodiment 1
The conjunction of 1- ((3r, 5r, 7r)-adamantane -1- base) -3- (5H- imidazo [5,1-a] iso-indoles -5- base) -2- propyl alcohol
Shown in steps are as follows:
The preparation of step 1:2- (1- trityl -1H- imidazoles -5- base)-benzaldehyde
It weighs 2- formylphenylboronic acid (15.0g, 0.1mol), the bromo- 1- trityl -1H- imidazoles of 4- (38.8g,
0.1mol) and K2CO3200mL dioxanes and the dissolution of 20mL water is added in 500mL single port bottle in (27.6g, 0.2mol).System is set
Pd (dppf) Cl is added after changing nitrogen2(1.5g, 2.3mmol).Reaction mixture is under nitrogen protection in 90 DEG C of stirring 4h.TLC
After detecting end of reaction, reaction solution is poured into 500mL water, EA (200mLx3) extraction, uses saturation NaCl after merging organic phase
Washing, anhydrous Na 2SO4 is sufficiently dry, purifies to obtain 31g target compound by column chromatography (PE/EA=20/1) after being spin-dried for, is
Yellow solid, yield 75%.
The preparation of step 2:2- (1H- imidazoles -5- base)-benzaldehyde
2- (1- trityl -1H- imidazoles -5- base)-benzaldehyde (21.8g, 52.7mmol) is weighed in 500mL single port bottle
In, 200mL formic acid and the dissolution of 50mL water is added.Reaction mixture detects end of reaction in 45 DEG C of stirrings 4h, TLC.Reaction solution rotation
200mL water, methylene chloride (100mLx2) extraction are added after dry, water phase NaOH alkali tune to pH=10 or so there are a large amount of solids to analyse
Out.It filters, filter cake is dried in vacuo to obtain 7.8g target compound after being washed with water, be yellow solid, yield 86%.
The preparation of step 3:1- ((3r, 5r, 7r)-adamantane -1- base) -2- acetone
2- ((3r, 5r, 7r)-adamantane -1- base)-acetic acid (1.94g, 10mmol) is weighed in 50mL single port bottle, is added
20mL THF dissolution.Under nitrogen protection, into the system for be cooled to 0 DEG C be added dropwise lithium methide THF solution (2M, 15mL,
30mmol).Rear reaction system is added dropwise, 4h is stirred at room temperature, TLC detects end of reaction.Reaction solution is poured into 100mL saturation
In aqueous ammonium chloride solution, EA (50mLx3) extraction uses saturated common salt water washing, anhydrous Na after merging organic phase2SO4It is dry, it is spin-dried for
1.26g target compound is obtained by column chromatography (PE/EA=50/1) purifying afterwards, is colorless oil, yield 66%.
Step 4:1- ((3r, 5r, 7r)-adamantane -1- base) -3- (5H- imidazo [5,1-a] iso-indoles -5- base) -2- third
The preparation of ketone
Weigh 1- ((3r, 5r, 7r)-adamantane -1- base) -2- acetone (192mg, 1.0mmol) and 2- (1H- imidazoles -5-
Base) for-benzaldehyde (172mg, 1.0mmol) in 50mL single port bottle, addition 5mL ethyl alcohol and the dissolution of 1mL water add NaOH
(100mg, 2.5mmol).Reaction mixture is in 80 DEG C of stirring 2h.After TLC detects end of reaction, reaction solution pours into 20mL water
In, EA (10mLx3) extraction is washed after merging organic phase with saturation NaCl, anhydrous Na2SO4It is dry, it is chromatographed after being spin-dried for by column
(PE/EA=2/1) 270mg target compound is purified to obtain, is yellow solid, yield 78%.
Step 5:1- ((3r, 5r, 7r)-adamantane -1- base) -3- (5H- imidazo [5,1-a] iso-indoles -5- base) -2- third
The preparation of alcohol
Weigh 1- ((3r, 5r, 7r)-adamantane -1- base) -3- (5H- imidazo [5,1-a] iso-indoles -5- base) -2- acetone
(173 mg, 0.5mmol) are added 5mL MeOH dissolution, add NaBH in 50mL single port bottle4(76 mg, 2.0mmol).Instead
Answer mixture that 1h is stirred at room temperature.After TLC detects end of reaction, reaction solution is poured into 20mL saturated aqueous ammonium chloride, EA
(10mLx3) extraction is washed after merging organic phase with saturation NaCl, anhydrous Na2SO4It is dry, (PE/EA is chromatographed by column after being spin-dried for
=2/1) 110mg target compound is purified to obtain, is off-white powder, yield 63%.
1H NMR(400MHz,CDCl3)δ1.23-1.27(2H,m),1.55-1.73(12H,m), 1.93-1.99(4H,
M), 2.14-2.21 (1H, m), 4.20-4.26 (1H, m), 5.33 (0.8H, t, J=6.0Hz), 5.41 (0.2H, t, J=
6.0Hz),7.18-7.20(0.8H,m),7.25-7.29(1.2H,m),7.32-7.39(1.2H, m),7.44(0.8H,dd,J
=7.6Hz, 4.4Hz), 7.53-7.56 (1H, m), 7.80 (0.8H, s), 7.86 (0.2H, s)
EMEM (calculated value): 348.2；MS (ESI) m/e (M+1H)+: 349.2
Embodiment 2
(1s, 3r, 5R, 7S) -3- (2- hydroxyl -3- (5H- imidazo [5,1-a]-iso-indoles -5- base)-propyl)-Buddha's warrior attendant
The synthesis step of alkane -1- alcohol is as follows:
The preparation of step 1:2- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- base)-acetic acid
It takes 2- ((3r, 5r, 7r)-adamantane -1- base)-acetic acid (1.94g, 10mmol) in 50mL single port bottle, is added
The dissolution of 20mL water.Then KOH (1.12g, 20mmol) and KMnO4 (1.58 g, 10mmol) is sequentially added.Finish rear reaction system
50 DEG C are stirred overnight, and TLC detects end of reaction.By reaction solution tune acid to pH=4 or so, EA (20mLx5) extraction merges organic
Xiang Houyong saturated common salt water washing, anhydrous Na 2SO4 is dry, is obtained after being spin-dried for by column chromatography (DCM/MeOH=20/1) purifying
960mg target compound is white solid, yield 46%.
The preparation of step 2:1- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- base) -2- acetone
Take 2- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- base)-acetic acid (840mg, 4mmol) in 50mL single port bottle
In, 10mL THF dissolution is added.Under nitrogen protection, into the system for be cooled to 0 DEG C be added dropwise lithium methide THF solution (2M,
8mL, 16mmol).Rear reaction system is added dropwise, 4h is stirred at room temperature, TLC detects end of reaction.Reaction solution is poured into 50mL to satisfy
In aqueous ammonium chloride solution, EA (20 mLx3) extraction uses saturated common salt water washing after merging organic phase, and anhydrous Na 2SO4 is dry,
720mg target compound is obtained by column chromatography (PE/EA=5/1) purifying after being spin-dried for, is colorless oil, yield 87%.
Step 3:1- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- base) -3- (5H- imidazo [5,1-a] iso-indoles -
5- yl) -2- acetone preparation
Weigh 1- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- base) -2- acetone (624mg, 3.0mmol) and 2-
20mL ethyl alcohol and the dissolution of 4mL water is added in 50mL single port bottle in (1H- imidazoles -5- base)-benzaldehyde (516mg, 3.0mmol), then
It is added NaOH (300mg, 7.5mmol).Reaction mixture is in 80 DEG C of stirring 2h.After TLC detects end of reaction, reaction solution is poured into
In 50mL water, EA (30mLx3) extraction is washed after merging organic phase with saturation NaCl, and anhydrous Na 2SO4 is dry, passes through after being spin-dried for
Column chromatography (DCM/EA=2/1) purifies to obtain 630mg target compound, is yellow solid, yield 58%.
Step 4:(1s, 3r, 5R, 7S) -3- (2- hydroxyl -3- (5H- imidazo [5,1-a]-iso-indoles -5- base)-propyl) -
The preparation of adamantane -1- alcohol
Weigh 1- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- base) -3- (5H- imidazo [5,1-a] iso-indoles -5-
Base) -2- acetone (181mg, 0.5mmol) in 50mL single port bottle, be added 5mL MeOH dissolution, add NaBH4 (76mg,
2.0mmol).1h is stirred at room temperature in reaction mixture.After TLC detects end of reaction, reaction solution pours into 20mL saturated ammonium chloride water
In solution, EA (10mLx3) extraction is washed after merging organic phase with saturation NaCl, and anhydrous Na 2SO4 is dry, passes through column after being spin-dried for
Chromatography (DCM/EA=1/1) purifies to obtain 95mg target compound, is off-white powder, yield 52%.
1H NMR(400MHz,CDCl3)δ1.23-1.26(2H,m),1.42-1.85(12H,m),1.95-2.06(3H,
m),2.14-2.20(1H,m),4.20-4.26(1H,m),5.31-5.34(1H,m),7.17-7.21(0.75H,m), 7.26-
7.29(1.25H,m),7.31-7.37(1.25H,m),7.43-7.46(0.75H,m),7.53-7.55(1H,m), 7.80
(0.75H, s), 7.85 (0.25H, s) .EM (calculated value): 364.2；MS(ESI)m/e (M+1H)+: 365.2
Embodiment 3
1- ((1s, 3s, 5R, 7S) -3- fluorine adamantane -1- base) -3- (5H- imidazo [5,1-a] iso-indoles -5- base) -2-
The synthesis step of propyl alcohol is as follows:
Step 1:1- ((1s, 3s, 5R, 7S) -3- fluorine adamantane -1- base) -3- (5H- imidazo [5,1-a] iso-indoles -5-
Base) -2- acetone preparation
Weigh 1- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- base) -3- (5H- imidazo [5,1-a] iso-indoles -5-
Base) -2- acetone (181mg, 0.5mmol) is in 50mL single port bottle, addition 5mL DCM dissolution, DAST is added under nitrogen protection
(diethylin sulfur trifluoride) (97mg, 0.6mmol).Reaction mixture is in 0 DEG C of stirring 2h.After TLC detects end of reaction,
Reaction solution pours into 20mL water, DCM (10mL x3) extraction, is washed after merging organic phase with saturation NaCl, anhydrous Na 2SO4 is dry
It is dry, 170mg target compound is purified to obtain by column chromatography (PE/EA=2/1) after being spin-dried for, is white solid, yield 93%.
Step 2:1- ((1s, 3s, 5R, 7S) -3- fluorine adamantane -1- base) -3- (5H- imidazo [5,1-a] iso-indoles -5-
Base) -2- propyl alcohol preparation
Weigh 1- ((1s, 3s, 5R, 7S) -3- fluorine adamantane -1- base) -3- (5H- imidazo [5,1-a] iso-indoles -5-
Base) -2- acetone (36mg, 0.1mmol) in 50mL single port bottle, be added 5mL MeOH dissolution, add NaBH4 (19mg,
0.5mmol).1h is stirred at room temperature in reaction mixture.After TLC detects end of reaction, reaction solution pours into 20mL saturated ammonium chloride water
In solution, EA (10mLx3) extraction is washed after merging organic phase with saturation NaCl, and anhydrous Na 2SO4 is dry, passes through column after being spin-dried for
Chromatography (DCM/EA=1/1) purifies to obtain 55mg target compound, is off-white powder, yield 60%.
1H NMR(400MHz,CDCl3)δ1.21-1.25(2H,m),1.44-1.80(12H,m),1.93-2.19(4H,
M), 4.22-4.26 (1H, m), 5.32 (0.8H, t, J=6.0Hz), 5.41 (0.2H, t, J=6.0Hz), 7.17-7.20
(0.8H,m),7.26-7.29(1.2H,m),7.33-7.37(1.2H,m),7.44-7.46(0.8H,m),7.53-7.56 (1H,
m),7.81(0.8H,s),7.85(0.2H,s).
EM (calculated value): 366.2；MS(ESI)m/e(M+1H)+: 367.2
Embodiment 4
1- ((1s, 3s, 5R, 7S) -3- chlorine adamantane -1- base) -3- (5H- imidazo [5,1-a] iso-indoles -5- base) -2-
The synthesis step of propyl alcohol is as follows:
Step 1:1- ((1s, 3s, 5R, 7S) -3- chlorine adamantane -1- base) -3- (5H- imidazo [5,1-a] iso-indoles -5-
Base) -2- acetone preparation
Weigh 1- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- base) -3- (5H- imidazo [5,1-a] iso-indoles -5-
Base) in 50mL single port bottle, 5mL SOCl2 and in 50 DEG C of stirring 2h is added in -2- acetone (181mg, 0.5mmol).TLC detection is anti-
It should finish, reaction solution is added 20mL water and with NaOH alkali tune to pH=10 or so after being spin-dried for.EA (10mLx3) extraction, is associated with
It is washed after machine phase with saturation NaCl, anhydrous Na 2SO4 is dry, purifies to obtain 180mg by column chromatography (DCM/EA=5/1) after being spin-dried for
Target compound is yellow solid, yield 95%.
Step 2:1- ((1s, 3s, 5R, 7S) -3- chlorine adamantane -1- base) -3- (5H- imidazo [5,1-a] iso-indoles -5-
Base) -2- propyl alcohol preparation
Weigh 1- ((1s, 3s, 5R, 7S) -3- chlorine adamantane -1- base) -3- (5H- imidazo [5,1-a] iso-indoles -5-
Base) -2- acetone (38mg, 0.1mmol) in 50mL single port bottle, be added 5mL MeOH dissolution, add NaBH4 (19mg,
0.5mmol).1h is stirred at room temperature in reaction mixture.After TLC detection reaction is completed, reaction solution pours into 20mL saturated ammonium chloride water
In solution, EA (10mLx3) extraction is washed after merging organic phase with saturation NaCl, and anhydrous Na 2SO4 is dry, passes through column after being spin-dried for
Chromatography (DCM/EA=1/1) purifies to obtain 64mg target compound, is yellow solid, yield 67%.
1H NMR(400MHz,CDCl3)δ1.23-1.27(2H,m),1.51-1.82(12H,m),1.92-2.00(3H,
m),2.14-2.18(1H,m),4.22-4.26(1H,m),5.29-5.33(1H,m),7.17-7.20(0.7H,m), 7.26-
7.28(1.3H,m),7.33-7.37(1.3H,m),7.42-7.46(0.7H,m),7.52-7.55(1H,m),7.80 (0.7H,
s),7.86(0.3H,s).
EM (calculated value): 382.2；MS(ESI)m/e(M+1H)+: 383.2
Embodiment 5
N- ((1s, 3r, 5R, 7S) -3- (2- hydroxyl -3- (5H- imidazoles [5,1-a] iso-indoles -5- base)-propyl)-Buddha's warrior attendant
Alkane -1- base) acetamide synthesis step it is as follows:
Step 1:N- ((1s, 3r, 5R, 7S) -3- (3- (5H- imidazoles [5,1-a] iso-indoles -5- base) -2- oxopropyl) -
Adamantane-1-yl) acetamide preparation
Weigh 1- ((1s, 3s, 5R, 7S) -3- chlorine adamantane -1- base) -3- (5H- imidazo [5,1-a] iso-indoles -5-
Base) -2- acetone (65mg, 0.17mmol) is in 50mL single port bottle, and mixture is in 140 DEG C of stirring 1h after 1mL acetamide is added.
After TLC detects end of reaction, reaction solution directly purifies to obtain 28mg target compound by column chromatography (DCM/MeOH=20/1),
For yellow solid, yield 41%.
Step 2:N- ((1s, 3r, 5R, 7S) -3- (2- hydroxyl -3- (5H- imidazoles [5,1-a] iso-indoles -5- base)-propyl) -
Adamantane -1- base) acetamide preparation
N- ((1s, 3r, 5R, 7S) -3- (3- (5H- imidazoles [5,1-a] iso-indoles -5- base) -2- oxopropyl)-adamantane -
1- yl) acetamide (28mg, 0.07mmol) in 50mL single port bottle, be added 3mL MeOH dissolution, add NaBH4 (15mg,
0.4mmol).1h is stirred at room temperature in reaction mixture.After TLC detection reaction is completed, reaction solution pours into 10mL saturated ammonium chloride water
In solution, EA (10mLx3) extraction is washed after merging organic phase with saturation NaCl, and anhydrous Na 2SO4 is dry, passes through column after being spin-dried for
Chromatography (DCM/MeOH=10/1) purifies to obtain 15mg target compound, is yellow solid, yield 54%.
1H NMR(400MHz,CDCl3)δ1.24-1.27(2H,m),1.46-1.79(12H,m),1.93-2.02(6H,
M), 2.14-2.20 (1H, m), 4.21-4.26 (1H, m), 5.31 (0.8H, t, J=6.0Hz), 5.39 (0.2H, t, J=
6.0Hz),5.64(1H,brs),7.18-7.19(0.8H,m),7.25-7.28(1.2H,m),7.32-7.37(1.2H,m),
7.44 (0.8H, dd, J=7.6Hz, 4.4Hz), 7.53-7.55 (1H, m), 7.80 (0.8H, s), 7.85 (0.2H, s)
EM (calculated value): 405.2；MS(ESI)m/e(M+1H)+: 406.3
Embodiment 6
(1s, 3r, 5R, 7S) -3- (2- hydroxyl -3- (5H- imidazoles [5,1-a] iso-indoles -5- base)-propyl)-adamantane -1-
The synthesis step of nitrile is as follows:
Step 1:(1s, 3r, 5R, 7S) -3- (3- (5H- imidazoles [5,1-a] iso-indoles -5- base) -2- oxopropyl)-Buddha's warrior attendant
The preparation of alkane -1- nitrile
Weigh 1- ((1s, 3s, 5R, 7S) -3- chlorine adamantane -1- base) -3- (5H- imidazo [5,1-a] iso-indoles -5-
Base) -2- acetone (65mg, 0.17mmol) in 50mL single port bottle, be added 3mL THF dissolution after add NaCN (25mg,
0.51mmol).Mixture is stirred overnight in 70 DEG C.After TLC detects end of reaction, reaction solution is poured into 10mL water, EA
(10mLx3) extraction is washed after merging organic phase with saturation NaCl, and anhydrous Na 2SO4 is dry, chromatographs (DCM/ by column after being spin-dried for
EA=5/1 42mg target compound) is purified to obtain, is white solid, yield 67%.
Step 2:(1s, 3r, 5R, 7S) -3- (2- hydroxyl -3- (5H- imidazoles [5,1-a] iso-indoles -5- base)-propyl)-gold
The preparation of rigid alkane -1- nitrile
Weigh (1s, 3r, 5R, 7S) -3- (3- (5H- imidazoles [5,1-a] iso-indoles -5- base) -2- oxopropyl)-Buddha's warrior attendant
Alkane -1- nitrile (37mg, 0.1mmol) in 50mL single port bottle, be added 3mL MeOH dissolution, add NaBH4 (15mg,
0.4mmol).1h is stirred at room temperature in reaction mixture.After TLC detection reaction is completed, reaction solution pours into 10mL saturated ammonium chloride water
In solution, EA (10mLx3) extraction is washed after merging organic phase with saturation NaCl, and anhydrous Na 2SO4 is dry, passes through column after being spin-dried for
Chromatography (DCM/MeOH=10/1) purifies to obtain 19mg target compound, is white solid, yield 51%.
1H NMR(400MHz,CDCl3)δ1.25-1.82(14H,m),1.94-2.02(3H,m),2.14-2.21(1H,
m),4.23-4.26(1H,m),5.32-5.38(1H,m),7.18-7.20(0.8H,m),7.25-7.27(1.2H,m), 7.34-
7.37 (1.2H, m), 7.45 (0.8H, dd, J=7.6Hz, 4.4Hz), 7.53-7.55 (1H, m), 7.79 (0.8H, s), 7.85
(0.2H,s).
EM (calculated value): 373.2；MS(ESI)m/e(M+1H)+: 374.2
Embodiment 7
1- (fluoro- 5H- imidazo [5,1-a] iso-indoles -5- base of 6-) -3- ((1s, 3s, 5R, 7S) -3- fluorine adamantane -1-
Base) -2- propyl alcohol synthesis:
According to embodiment 1 (step 1 and step 2), embodiment 2 (step 1, step 2 and step 3) and 3 (step of embodiment
1 process similar with step 2), by 2- ((3r, 5r, 7r)-adamantane -1- base)-acetic acid and the fluoro- 2- formylphenylboronic acid system of 3-
Standby desired product.
1H NMR(400MHz,CDCl3)δ1.21-1.24(2H,m),1.49-1.79(12H,m),1.93-2.17(4H,
M), 4.23-4.26 (1H, m), 5.31 (0.85H, t, J=6.0Hz), 5.40 (0.15H, t, J=6.0Hz), 7.17-7.20
(0.85H,m),7.26-7.29(0.15H,m),7.37-7.43(2H,m),7.49-7.51(1H,m),7.81(0.85H, s),
7.86(0.15H,s).
EM (calculated value): 384.2；MS(ESI)m/e(M+1H)+: 385.2
Embodiment 8
1- (chloro- 5H- imidazo [5,1-a] iso-indoles -5- base of 6-) -3- ((1s, 3s, 5R, 7S) -3- fluorine adamantane -1-
Base) -2- propyl alcohol synthesis:
According to embodiment 1 (step 1 and step 2), embodiment 2 (step 1, step 2 and step 3) and 4 (step of embodiment
1 process similar with step 2), by 2- ((3r, 5r, 7r)-adamantane -1- base)-acetic acid and the fluoro- 2- formylphenylboronic acid system of 3-
Standby desired product.
1H NMR(400MHz,CDCl3)δ1.21-1.24(2H,m),1.43-1.79(12H,m),1.92-1.99(3H,
M), 2.08-2.10 (1H, m), 4.24-4.26 (1H, m), 5.32 (0.8H, t, J=6.0Hz), 5.40 (0.2H, t, J=
6.0Hz),7.18-7.20(0.8H,m),7.26-7.28(0.2H,m),7.37-7.45(2H,m),7.49-7.51(1H, m),
7.82(0.8H,s),7.87(0.2H,s).
EM (calculated value): 400.2；MS(ESI)m/e(M+1H)+: 401.2
Embodiment 9
2- (fluoro- 5H- imidazo [5,1-a] iso-indoles -5- base of 6-) -1- (1- ((1s, 3s, 5R, 7S) -3- fluorine adamantane -
1- yl)-cyclopropyl)-ethyl alcohol synthesis step it is as follows:
The preparation of step 1:2- ((3r, 5r, 7r)-adamantane -1- base)-N- methoxy N-methylacetamide
Weigh 2- ((3r, 5r, 7r)-adamantane -1- base)-acetic acid (9.7g, 50mmol), dimethyl azanol hydrochloride (5.4
G, 55mmol) and TEA (15.2g, 150mmol) in 250mL single port bottle, be added 100mL THF dissolution, add HBTU
(22.8g, 60mmol).4h is stirred at room temperature in reaction mixture.After TLC detects end of reaction, reaction solution slowly pours into 300mL water
In, there is solid precipitation.It filters, filter cake is dried in vacuo to obtain 9.6g target compound after being washed with water be white solid, and yield is
81%.
The preparation of step 2:1- ((3r, 5r, 7r)-adamantane -1- base)-N- methoxy-. N-methyl cyclopropyl formamide
Weigh 2- ((3r, 5r, 7r)-adamantane -1- base)-N- methoxy N-methylacetamide (4.74g, 20mmol) in
In 100mL single port bottle, 50mL THF dissolution is added.LDA (2M in is added dropwise under nitrogen protection into the system for be cooled to -70 DEG C
THF, 30mL, 60mmol).In -70 DEG C of stirring 1h after being added dropwise, be added dropwise at a temperature of this 1,2- Bromofume (3.76g,
20mmol).It is returned naturally after being added dropwise and warms to room temperature and stir 1h.After TLC detects end of reaction, reaction solution pours into 200mL
In water, EA (50mLx 3) extraction is washed after merging organic phase with saturation NaCl, and anhydrous Na 2SO4 is dry, passes through column layer after being spin-dried for
Analysis (PE/EA=5/1) purifies to obtain 2.7g target compound, is white solid, yield 51%.
Step 3:1- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- base)-N- methoxy-. N-methyl cyclopropyl formamide
Preparation
Weigh 1- ((3r, 5r, 7r)-adamantane -1- base)-N- methoxy-. N-methyl cyclopropyl formamide (2.63g, 10
Mmol) in 100mL single port bottle, the dissolution of 30mL water is added.Then KOH (1.12g, 20mmol) and KMnO4 is sequentially added
(1.58g, 10mmol).40 DEG C of rear reaction system is finished to be stirred overnight, TLC is detected after completion of the reaction, EA (20mLx3) extraction,
Saturated common salt water washing is used after merging organic phase, anhydrous Na 2SO4 is dry, passes through column chromatography (DCM/EA=4/1) purifying after being spin-dried for
1.04g target compound is obtained, is yellow solid, yield 37%.
The preparation of step 4:1- (1- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- base)-cyclopropyl)-ethyl ketone
Weigh 1- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- base)-N- methoxy-. N-methyl cyclopropyl formamide (1g,
3.58mmol) in 50mL single port bottle, 20mL THF dissolution is added.Under nitrogen protection, it is added dropwise into the system for being cooled to 0 DEG C
The THF solution (2M, 4.5mL, 9.00mmol) of methyl-magnesium-bromide.Rear reaction system is added dropwise, 4h, TLC detection is stirred at room temperature
End of reaction.Reaction solution is poured into 50mL saturated aqueous ammonium chloride, EA (30mLx3) extraction uses saturation after merging organic phase
Brine It, anhydrous Na 2SO4 is dry, obtains 460mg target chemical combination by column chromatography (PE/EA=2/1) purifying after being spin-dried for
Object is colorless oil, yield 55%.
Step 5:2- (fluoro- 5H- imidazo [5,1-a] iso-indoles -5- base of 6-) -1- (1- ((1s, 3s, 5R, 7S) -3- hydroxyl
Adamantane -1- base)-cyclopropyl)-ethyl ketone preparation
Weigh 1- (1- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- base)-cyclopropyl)-ethyl ketone (234mg, 1.0
Mmol) and the fluoro- 6- of 2- (1H- imidazoles -5- base)-benzaldehyde (190mg, 1.0mmol) is in 50mL single port bottle, and 5mL ethyl alcohol is added
And the dissolution of 1mL water, add NaOH (100mg, 2.5mmol).Reaction mixture is in 80 DEG C of stirring 2h.TLC detects end of reaction
After, reaction solution pours into 20mL water, EA (10mLx3) extraction, is washed after merging organic phase with saturation NaCl, anhydrous Na 2SO4
It is dry, 220mg target compound is purified to obtain by column chromatography (DCM/EA=1/1) after being spin-dried for, is white solid, yield is
54%.
Step 6:2- (fluoro- 5H- imidazo [5,1-a] iso-indoles -5- base of 6-) -1- (1- ((1s, 3s, 5R, 7S) -3- fluorine gold
Rigid alkane -1- base)-cyclopropyl)-ethyl ketone preparation
Weigh 2- (fluoro- 5H- imidazo [5,1-a] iso-indoles -5- base of 6-) -1- (1- ((1s, 3s, 5R, 7S) -3- hydroxyl gold
Rigid alkane -1- base)-cyclopropyl)-ethyl ketone (203mg, 0.5mmol) in 50mL single port bottle, protect by addition 5mL DCM dissolution, nitrogen
DAST (97mg, 0.6mmol) is added under shield.Reaction mixture is in 0 DEG C of stirring 2h.After TLC detects end of reaction, reaction
Liquid pours into 20mL water, DCM (10mLx3) extraction, is washed after merging organic phase with saturation NaCl, anhydrous Na 2SO4 is dry, is spin-dried for
185mg target compound is purified to obtain by column layer (DCM/EA=5/1) afterwards, is white solid, yield 91%.
Step 7:2- (fluoro- 5H- imidazo [5,1-a] iso-indoles -5- base of 6-) -1- (1- ((1s, 3s, 5R, 7S) -3- fluorine gold
Rigid alkane -1- base)-cyclopropyl)-ethyl alcohol preparation
Weigh 2- (fluoro- 5H- imidazo [5,1-a] iso-indoles -5- base of 6-) -1- (1- ((1s, 3s, 5R, 7S) -3- fluorine Buddha's warrior attendant
Alkane -1- base)-cyclopropyl) in 20mL single port bottle, addition 5mL MeOH dissolution adds-ethyl ketone (102mg, 0.25mmol)
NaBH4 (38mg, 1.0mmol).1h is stirred at room temperature in reaction mixture.After TLC detects end of reaction, it is full that reaction solution pours into 20mL
In aqueous ammonium chloride solution, EA (10mLx3) extraction is washed after merging organic phase with saturation NaCl, and anhydrous Na 2SO4 is dry, rotation
85mg target compound is purified to obtain by column chromatography (DCM/EA=1/1) after dry, is white solid, yield 83%.
1H NMR(400MHz,CDCl3)δ0.03-0.08(2H,m),0.28-0.32(2H,m),1.45-1.79(12H,
M), 1.94-2.00 (3H, m), 2.19-2.24 (1H, m), 4.36-4.39 (1H, m), 5.31 (0.85H, t, J=6.0 Hz),
5.41 (0.15H, t, J=6.0Hz), 7.18-7.20 (0.85H, m), 7.26-7.28 (0.15H, m), 7.37-7.43 (2H,
m),7.47-7.50(1H,m),7.80(0.85H,s),7.84(0.15H,s).
EM (calculated value): 410.2；MS(ESI)m/e(M+1H)+: 411.2
Embodiment 10
1- (1- ((1r, 3s, 5R, 7S) -3- chlorine adamantane -1- base)-cyclopropyl) -2- (fluoro- 5H- imidazo [5,1-a] of 6-
Iso-indoles -5- base)-ethyl alcohol synthesis:
According to (step 1 process similar with step 2), by 2- (the different Yin of the fluoro- 5H- imidazo [5,1-a] of 6- of embodiment 4
Diindyl -5- base) (embodiment 9, step 5 produce -1- (1- ((1s, 3s, 5R, 7S) -3- hydroxyadamantane -1- base)-cyclopropyl)-ethyl alcohol
Product) prepare desired product.
1H NMR(400MHz,CDCl3)δ0.03-0.09(2H,m),0.26-0.31(2H,m),1.49-1.76(12H,
m),1.94-1.99(3H,m),2.19-2.22(1H,m),4.35-4.38(1H,m),5.31-5.41(1H,m), 7.18-7.22
(0.8H,m),7.25-7.28(0.2H,m),7.37-7.42(2H,m),7.47-7.51(1H,m),7.79 (0.8H,s),7.84
(0.2H,s).
EM (calculated value): 426.2；MS(ESI)m/e(M+1H)+: 427.2
Embodiment 11
1- (fluoro- 5H- imidazo [5,1-a] iso-indoles -5- base of 6-) -8- ((1s, 3s, 5R, 7S) -3- fluorine adamantane -1-
Base) -3- methyl -2- butanol synthesis step it is as follows:
The preparation of step 1:2- ((3r, 5r, 7r)-adamantane -1- base)-N- methoxyl group-N, 2- dimethylpropionamide
Weigh 2- ((3r, 5r, 7r)-adamantane -1- base)-N- methoxy N-methylacetamide (2.37g, 10mmol) in
In 50mL single port bottle, 30mL THF dissolution is added.LDA (2M in is added dropwise under nitrogen protection into the system for be cooled to -70 DEG C
THF, 15mL, 30mmol).In -70 DEG C of stirring 1h after being added dropwise, MeI (2.84g, 20mmol) is added dropwise at a temperature of this.Drop
It is returned naturally after adding and warms to room temperature and stir 1h.After TLC detects end of reaction, reaction solution is poured into 100mL water, EA
(50mLx3) extraction is washed after merging organic phase with saturation NaCl, and anhydrous Na 2SO4 is dry, chromatographs (PE/EA by column after being spin-dried for
=5/1) 1.8g target compound is purified to obtain, is white solid, yield 68%.
Step 2:1- (fluoro- 5H- imidazo [5,1-a] iso-indoles -5- base of 6-) -8- ((1s, 3s, 5R, 7S) -3- fluorine Buddha's warrior attendant
Alkane -1- base) -3- methyl -2- butanol preparation
According to embodiment 9 (step 3 to the similar process of step 7), by 2- ((3r, 5r, 7r)-adamantane -1- base) -
N- methoxyl group-N, 2- dimethylpropionamide (embodiment 11, step 1 product) prepare desired product
1H NMR(400MHz,CDCl3)δ1.04-1.09(6H,m),1.45-1.78(12H,m),1.95-2.17(4H,
M), 4.32-4.34 (1H, m), 5.32 (0.8H, t, J=6.0Hz), 5.40 (0.2H, t, J=6.0Hz), 7.17-7.20
(0.8H,m),7.26-7.29(0.2H,m),7.38-7.43(2H,m),7.49-7.52(1H,m),7.79(0.8H,s), 7.85
(0.2H,s).
EM (calculated value): 412.2；MS(ESI)m/e(M+1H)+: 413.2
Embodiment 12
Pharmacodynamic test
Test 1: external IDO inhibits Kinase activity assays
1: test material:
Human IDO1 (ChemPartner product, lot number 20160706)；
L-tryptophan (Sigma product, article No. 93659-10G, lot number 1400132V)；
Ascorbate (Sigma product, article No. 11140-250G, lot number BCBM0369V)；
Methylenum careuleum (Sigma product, article No. M9140-100G, lot number 056K0739V)；
Catalase (Sigma product, article No. C9322-1G, lot number 010M1010)；
DMSO (Sigma product, article No. D2650, lot number WXBC3124V)；
96- orifice plate (Corning product, article No. 3635, lot number 12016021)；
Positive compound: NLG-919 (Selleckchem product, article No. S7111, lot number 01)；
Detecting instrument: SpectraMax
2: test principle:
It is N- formoxyl kynurenin that employment recombination IDO1 enzyme, which is measured, by tryptophan substrate oxidation, and UV absorption signal exists
321nM wavelength absorption is associated in the amount of IDO1 oxidation product N- formoxyl kynurenin.
3: test method:
(1) it configures sample to be tested: being diluted to 100 times i.e. 100umol/L of reaction final concentration with 100%DMSO；
(2) it configures positive compound: being diluted to 100 times i.e. 1000umol/L of reaction final concentration with 100%DMSO；
(3) dilute: sample to be tested, with 4 times of concentration dilutions, dilutes 7 concentration gradients using 100umol/L as initial concentration；
Positive control, with 4 times of concentration dilutions, dilutes 10 concentration gradients using 1000umol/L as initial concentration；
(4) positive compound of each sample to be tested of prepare 7 concentration and 10 concentration is separately added into 96 orifice plates
In, 100%DMSO is separately added into positive control and negative control hole；
(5) 2 times of enzyme solutions are prepared: 1 times of reaction buffer is added in IDO1 enzyme, forms 2 times of enzyme solutions；Wherein reaction buffering
Liquid is the phosphate buffer (pH 6.5) of improvement；
(6) enzyme solutions are added into 96 orifice plates: having the sample to be tested of the 100%DMSO dissolution of 2 μ l in 96 hole reaction plates
And positive compound, then add 2 times of enzyme solutions of 100 μ l；Also 2 times of enzyme solutions of 100 μ l are added in Positive control wells, yin
The reaction buffer of 100 μ l is added in property control wells；It is incubated for 15 minutes at room temperature；
(7) it prepares 2 times of substrate solution: L-tryptophan, ascorbate, methylenum careuleum, catalase etc. is added 1
Times reaction buffer, forms 2 times of substrate solutions；
(8) substrate solution is added into 96 orifice plates: 2 times of substrate solutions starting that 100 μ l are added in 96 hole reaction plates is anti-
It answers；
(9) OD321 is read in real time with SpectraMax at room temperature.
(10) inhibiting rate calculates the replicate data from SpectraMax.Data are converted to inhibiting rate data, wherein max is
Refer to the data of DMSO control, min is the data of no enzyme activity control.
Percent inhibition=(max-Signal)/(max-min) * 100.
Inhibiting rate data are used5 obtain IC by nonlinear regression50Value.
Table 1
Test 2: the pharmacokinetics test of the compounds of this invention
SD rat, male (being purchased from Shanghai western Poole-Bi Kai experimental animal Co., Ltd).Each test-compound is with oral
The administration mode of (10mg/kg, every group 3) is given in a single dose SD rat and carries out pharmacokinetic, and test-compound uses
Sodium chloride injection=5/95 (V/V) of DMSO/9% is dissolved, and is configured to be administered later molten through vortex 1min, ultrasonic 1min
Liquid.Animal needs fasting 12 hours before being administered orally, and restores after administration 2 hours to food.SD rat oral clothes and intravenously administrable
Afterwards, pharmacokinetics sample, acquisition time are acquired through jugular vein or cardiac puncture are as follows: before administration, 0.25h, 0.5h after administration,
1h, 2h, 3h, 4h, 6h, 8h and for 24 hours, each time point acquire 3 whole blood samples through rat eye rear vein beard, and collection capacity is about
0.3mL, and through heparin sodium anticoagulation.It is immediately placed on after Blood specimen collection on ice, the centrifugal separation plasma within 30 minutes
(centrifugal condition: 8000 revs/min, 6 minutes, 2-8 DEG C).- 70 DEG C are deposited in front of the plasma analysis of collection.Take 50 μ L plasma samples
Into 1.5mL centrifuge tube, 250 μ L inner mark solutions (methanol that internal standard adds same volume is not added in blank) are added, is vortexed and mixes,
15000 revs/min are centrifuged 5 minutes, take 200 μ L supernatants to be added in 96 hole sample introduction plates, sample introduction is analyzed through LC-MS/MS.
The embodiment of the present invention 9, the pharmacokinetics of 10 prepare compound of embodiment (hereinafter referred to as compound 9, compound 10)
Test result such as table 2
Table 2
| Embodiment | T1/2(h) | Tmax(h) | Cmax(ng/ml) | AUC(ng/ml*h) |
| Compound 9 | 0.76 | 0.35 | 791 | 722 |
| Compound 10 | 0.98 | 0.33 | 1687 | 1150 |
| NLG-919 | 0.81 | 0.53 | 609 | 642 |
It can be seen that the compounds of this invention from the studies above data to significantly inhibit IDO activity, and locate
It is compared in the NLG-919 of clinical stage research, also there is apparent advantage in terms of drug effect, medicine are for power, can be used as IDO inhibition
Agent has wide anti-malignant tumor disease, autoimmune conditions, viral infection, depression, AIDS, myelosis
The application prospects such as abnormal syndrome, anxiety disorder, cataract.
The above description is only an embodiment of the present invention, is not intended to limit the scope of the invention, all to utilize this hair
Bright principle and description, improvements introduced, modification, equivalent structure or equivalent flow shift, are applied directly or indirectly in
Other related technical areas are included within the scope of the present invention.
Claims (11)
1. a kind of IDO inhibitor compound or its pharmaceutically acceptable salt, which is characterized in that the compound is tied with formula (I)
Structure,
Wherein, 1 n；
R1、R2It is independently selected from fluorine or chlorine；
R4、R5Substitution or non-is collectively constituted selected from hydrogen, the alkyl of substituted or non-substituted C1~C6 or with the carbon atom being connect
Replace the naphthenic base of C3~C6；
Above-mentioned R4、R5The substituent group of substituent group is selected from group: nitro, hydroxyl, amino, sulfydryl, halogeno-group, cyano, C1~C10
Alkyl, C1~C10 miscellaneous alkyl, C3~C10 naphthenic base, C3~C10 Heterocyclylalkyl.
2. compound according to claim 1, it is characterised in that: R1Selected from fluorine, R2It is independently selected from fluorine or chlorine；R4、R5It is selected from
Hydrogen, the alkyl of substituted or non-substituted C1~C6 or the ring that substituted or non-substituted C3-C6 is collectively constituted with the carbon atom being connect
Alkyl；
Above-mentioned R4、R5The substituent group of substituent group is selected from group: nitro, hydroxyl, amino, sulfydryl, halogeno-group, cyano, C1~C10
Alkyl, C1~C10 miscellaneous alkyl take C3~C10 naphthenic base, C3~C10 Heterocyclylalkyl.
3. compound according to claim 1, it is characterised in that: when n is the R in 1 formula (I) compound1、R2It is independently selected from fluorine
Or chlorine；R4、R5Collectively constituted by substituted or non-substituted C1~C6 alkyl or with the carbon atom connecting substituted or non-substituted C3~
The naphthenic base of C6.
4. compound according to claim 1, it is characterised in that: the alkyl of the C1~C6 is selected from methyl, ethyl, propyl.
5. compound described in any one according to claim 1~4, it is characterised in that: R4、R5It is total with the carbon atom being connect
With the substituted or non-substituted cyclopropyl of composition.
6. compound according to claim 1, it is characterised in that: the substituent group of substituent group is selected from: hydroxyl, amino, sulfydryl,
C1~C6 alkyl.
7. a kind of Pharmaceutical composition, which is characterized in that the Pharmaceutical composition active ingredient is selected from any right of claim 1~6
It is required that the combination of the compound or one or both of its pharmaceutically acceptable salt.
8. compound described in claim 1~6 any one or its pharmaceutically acceptable salt are as claimed in claim 7 medicinal
Composition is preparing the purposes in indole amine 2,3-dioxygenase (IDO) inhibitor.
9. purposes according to claim 8, which is characterized in that the inhibitor is for treating at least one disease as described below
Disease: cancer, autoimmune conditions, viral infection, depression, myelodysplastic syndrome, anxiety disorder, cataract.
10. purposes according to claim 9, which is characterized in that the autoimmune conditions are selected from AIDS.
11. purposes according to claim 9, which is characterized in that the cancer is selected from solid tumor, leukaemia, the reality
Body tumor is selected from breast cancer, cervical carcinoma, colon cancer, liver cancer, gastric cancer, the carcinoma of the rectum, oophoroma, cancer of pancreas, bladder cancer, myeloma, non-
Small Cell Lung Cancer, lymthoma, melanoma, osteocarcinoma, kidney.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710405187.7A CN107176956B (en) | 2017-05-31 | 2017-05-31 | A kind of IDO inhibitor compound, Pharmaceutical composition, purposes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710405187.7A CN107176956B (en) | 2017-05-31 | 2017-05-31 | A kind of IDO inhibitor compound, Pharmaceutical composition, purposes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107176956A CN107176956A (en) | 2017-09-19 |
| CN107176956B true CN107176956B (en) | 2019-11-12 |
Family
ID=59835978
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710405187.7A Active CN107176956B (en) | 2017-05-31 | 2017-05-31 | A kind of IDO inhibitor compound, Pharmaceutical composition, purposes |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107176956B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108424414A (en) * | 2017-12-08 | 2018-08-21 | 苏州国匡医药科技有限公司 | Indoleamine 2,3-dioxygenase modulating compound of the one kind containing heterocycle and its purposes in pharmacy |
| CN109053751A (en) * | 2018-08-30 | 2018-12-21 | 成都海博锐药业有限公司 | FXR regulator with spirane structure |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012142237A1 (en) * | 2011-04-15 | 2012-10-18 | Newlink Geneticks Corporation | Fused imidazole derivatives useful as ido inhibitors |
| CN105884780A (en) * | 2015-02-16 | 2016-08-24 | 上海迪诺医药科技有限公司 | Polycyclic compound and pharmaceutical composition and application thereof |
| WO2016165613A1 (en) * | 2015-04-12 | 2016-10-20 | Hangzhou Innogate Pharma Co., Ltd. | Heterocycles useful as ido and tdo inhibitors |
| CN106478634A (en) * | 2015-09-01 | 2017-03-08 | 上海璎黎药业有限公司 | Condensed imidazole compound, its preparation method, pharmaceutical composition and purposes |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CR20130565A (en) * | 2013-11-04 | 2014-05-26 | Newlink Genetics Corp | FUSIONATES DERIVED FROM USEFUL IMIDAZOL AS IDO INHIBITORS |
-
2017
- 2017-05-31 CN CN201710405187.7A patent/CN107176956B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012142237A1 (en) * | 2011-04-15 | 2012-10-18 | Newlink Geneticks Corporation | Fused imidazole derivatives useful as ido inhibitors |
| CN105884780A (en) * | 2015-02-16 | 2016-08-24 | 上海迪诺医药科技有限公司 | Polycyclic compound and pharmaceutical composition and application thereof |
| CN105884828A (en) * | 2015-02-16 | 2016-08-24 | 上海迪诺医药科技有限公司 | Polycyclic compound, pharmaceutical composition and application thereof |
| WO2016165613A1 (en) * | 2015-04-12 | 2016-10-20 | Hangzhou Innogate Pharma Co., Ltd. | Heterocycles useful as ido and tdo inhibitors |
| CN106478634A (en) * | 2015-09-01 | 2017-03-08 | 上海璎黎药业有限公司 | Condensed imidazole compound, its preparation method, pharmaceutical composition and purposes |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107176956A (en) | 2017-09-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110256440B (en) | Phthalazine isoxazole alkoxy derivative, preparation method, pharmaceutical composition and application thereof | |
| CN109311900A (en) | Simple function intermediate for the degradation of ligand dependent target protein | |
| CN105682661A (en) | Certain chemical entities, compositions, and methods | |
| JP2008526761A (en) | Polycyclic bis-amide MMP inhibitor | |
| CN108069929B (en) | 3-substituted coumarin derivative and application thereof, and GPR35 receptor agonist | |
| CN110511219A (en) | The dihydronaphthridine class compound and application thereof that phenyl replaces | |
| AU2017287553A1 (en) | Imidazopyrazinamine phenyl derivative and use thereof | |
| TW201734021A (en) | Inhibitors of BRUTON's tyrosine kinase and methods of their use | |
| WO2020056072A1 (en) | 1h-indazole carboxamides as receptor-interacting protein kinase 1 inhibitors (ripk1) | |
| CN105658641B (en) | Benzazole amide derivatives, its preparation method and its application in medicine | |
| CN114591352B (en) | Triazolopyridazine compound and application thereof | |
| CN107176956B (en) | A kind of IDO inhibitor compound, Pharmaceutical composition, purposes | |
| CA3029086C (en) | Chiral heterocyclic compound with hedgehog pathway antagonist activity, method and use thereof | |
| CN104230952A (en) | Compound containing pyrimidine skeleton, and preparation method and use of compound | |
| TWI723480B (en) | Fused ring derivatives used as fgfr4 inhibitors | |
| CN107304211A (en) | A kind of selective FGFR4 kinase inhibitors | |
| CN108727343A (en) | Quinazolinones PARP-1/2 inhibitor containing 3- amino nafoxidines and preparation method thereof, pharmaceutical composition and purposes | |
| CN112457305A (en) | Aromatic heterocyclic compound containing tricyclic structure, and preparation method and application thereof | |
| WO2023208174A1 (en) | Deubiquitinase inhibitor and use thereof | |
| CN104804017B (en) | Oxazolidinone compounds and its application in medicine | |
| CN114591318B (en) | Pyrazolo heterocyclic compound, preparation method thereof, pharmaceutical composition and application | |
| CN110294742A (en) | And ring class ASK1 inhibitor and its application | |
| CN108864080B (en) | Tetracyclic compounds as selective estrogen receptor down-regulating agents and application thereof | |
| CN109384727B (en) | Phthalazinone compound, preparation method, pharmaceutical composition and application thereof | |
| CN105085359A (en) | Nitrogen-containing heterocyclic substituted pyrrolidine formyl thiomorpholin DPP-IV inhibitor |
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 | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 610041 No. 902, floor 9, building 12, No. 88, Keyuan South Road, high tech Zone, Chengdu, Sichuan Patentee after: Sano Hubble Pharmaceutical (Chengdu) Co.,Ltd. Patentee after: Chengdu Beite Pharmaceutical Co., Ltd Address before: 610041 No. 902, floor 9, building 12, No. 88, Keyuan South Road, high tech Zone, Chengdu, Sichuan Patentee before: CHENGDU HIGHBRED PHARMACEUTICAL Co.,Ltd. Patentee before: Chengdu Beite Pharmaceutical Co., Ltd |