CN106256830B - A kind of deuterated IDO inhibitor and its preparation method and application - Google Patents
A kind of deuterated IDO inhibitor and its preparation method and application Download PDFInfo
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- CN106256830B CN106256830B CN201610436352.0A CN201610436352A CN106256830B CN 106256830 B CN106256830 B CN 106256830B CN 201610436352 A CN201610436352 A CN 201610436352A CN 106256830 B CN106256830 B CN 106256830B
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- deuterated
- indoles
- solvent
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- 239000003112 inhibitor Substances 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 208000002177 Cataract Diseases 0.000 claims abstract description 4
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 4
- 201000011510 cancer Diseases 0.000 claims abstract description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 3
- 206010052779 Transplant rejections Diseases 0.000 claims abstract description 3
- 208000036142 Viral infection Diseases 0.000 claims abstract description 3
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 3
- 210000000056 organ Anatomy 0.000 claims abstract description 3
- 230000009385 viral infection Effects 0.000 claims abstract description 3
- 239000003814 drug Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 5
- 230000009467 reduction Effects 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 3
- 230000000295 complement effect Effects 0.000 claims description 2
- 239000000470 constituent Substances 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 abstract description 22
- 239000013078 crystal Substances 0.000 abstract description 7
- 239000012453 solvate Substances 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 71
- 239000002904 solvent Substances 0.000 description 61
- 150000002518 isoindoles Chemical class 0.000 description 48
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 44
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 44
- 239000012044 organic layer Substances 0.000 description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 37
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 36
- -1 ion salt Chemical class 0.000 description 36
- 238000003756 stirring Methods 0.000 description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 33
- 230000015572 biosynthetic process Effects 0.000 description 31
- 235000019441 ethanol Nutrition 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 238000003786 synthesis reaction Methods 0.000 description 30
- 238000001819 mass spectrum Methods 0.000 description 26
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 24
- 238000000746 purification Methods 0.000 description 24
- 239000000741 silica gel Substances 0.000 description 24
- 229910002027 silica gel Inorganic materials 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 17
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 14
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 12
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 11
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
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- 239000000243 solution Substances 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 8
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- 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 7
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 7
- 229910052796 boron Inorganic materials 0.000 description 7
- 238000003810 ethyl acetate extraction Methods 0.000 description 7
- 210000002381 plasma Anatomy 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 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 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 5
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 4
- RIFKADJTWUGDOV-UHFFFAOYSA-N 1-cyclohexylethanone Chemical compound CC(=O)C1CCCCC1 RIFKADJTWUGDOV-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
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- 239000012043 crude product Substances 0.000 description 4
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
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- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 3
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- HWWVAHCWJLGKLW-UHFFFAOYSA-N n,n-dimethylhydroxylamine;hydron;chloride Chemical compound Cl.CN(C)O HWWVAHCWJLGKLW-UHFFFAOYSA-N 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
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- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
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- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 2
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- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 2
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
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- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 2
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- YGPSJZOEDVAXAB-UHFFFAOYSA-N kynurenine Chemical compound OC(=O)C(N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-UHFFFAOYSA-N 0.000 description 2
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- OSCBARYHPZZEIS-UHFFFAOYSA-N phenoxyboronic acid Chemical class OB(O)OC1=CC=CC=C1 OSCBARYHPZZEIS-UHFFFAOYSA-N 0.000 description 2
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- 238000001514 detection method Methods 0.000 description 1
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- 238000007710 freezing Methods 0.000 description 1
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- 229960001008 heparin sodium Drugs 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
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- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
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- 230000001900 immune effect Effects 0.000 description 1
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- 102000006639 indoleamine 2,3-dioxygenase Human genes 0.000 description 1
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- 238000006317 isomerization reaction Methods 0.000 description 1
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- 229940049920 malate Drugs 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
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
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- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
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- 231100000228 neurotoxicity Toxicity 0.000 description 1
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- 229910052763 palladium Inorganic materials 0.000 description 1
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- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
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- GJAWHXHKYYXBSV-UHFFFAOYSA-N quinolinic acid Chemical compound OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 description 1
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of deuterated IDO inhibitors and its preparation method and application, provide compound shown in formula I or its crystal form, pharmaceutically acceptable salt, hydrate or solvate.Compound prepared by the present invention or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, it can be used as IDO inhibitor, it can be used for the treatment of IDO related disease, especially cancer, viral infection, depression, neurodegenerative disease, wound, age-related cataract, organ transplant rejection and autoimmune disease.
Description
Technical field
The present invention relates to a kind of IDO inhibitors and its preparation method and application.
Background technique
Indoleamine 2,3- is bis- plus oxidizing ferment (indoleamine2,3-dioxygenase, IDO) is unique other than liver
Tryptophan is catalyzed along the rate-limiting enzyme of kynurenine pathway catabolism.IDO can pass through the concentration of tryptophan in reduction microenvironment
Have the function that inhibit pathogenic microorganism proliferation；IDO is also closely related with the nervous system disease, it can reduce the water of serotonin
It puts down and leads to depression, the accumulation of the metabolite with neurotoxicity such as quinolinic acid in brain can also be caused；IDO is inhibiting T cell
Important metabolic immunological regulation is played in immune and antineoplastic immune, induction Maternal-placental immune toler ance and graft immune tolerance
Effect.
It is closely related that IDO has been found a variety of mankind's major diseases such as Ahl tribulus sea silent sickness, cataract, cancer, therefore
IDO inhibitor is as important drug by increasingly extensive concern.
NLG919 is a kind of novel IDO inhibitor, has entered clinical experimental stage at present.But drug effect and medicine generation
Kinetic property, be still significantly improved space.
Summary of the invention
The purpose of the present invention is to provide a kind of IDO inhibitors and its preparation method and application.
Compound as follows or its crystal form, pharmaceutically acceptable salt, hydrate or solvate:
R1-R21It is respectively selected from H or D；
And R1-R21In at least one be D.
Further, R1And R2It is H or is simultaneously D simultaneously.
Further, R3-R6It is H or is simultaneously D simultaneously.
Further, R8And R9It is H or is simultaneously D simultaneously.
Further, R12-R21It is H or is simultaneously D simultaneously.
Further, R1And R2It is H or is simultaneously D simultaneously；And R3-R6It is H or is simultaneously D simultaneously；And R7For H or D；
And R8And R9It is H or is simultaneously D simultaneously；And R10For H or D；And R11For H or D；And R12-R21It is H or is simultaneously D simultaneously；
And R1-R21In at least one be D.
Further, R1And R2It is simultaneously D；And R3-R21In at least one be D.
Further, R1And R2It is simultaneously H；And R3-R6It is simultaneously D；And R7-R21In at least one be D.
Further, R1-R6It is simultaneously D；And R7-R21In at least one be D.
Further, R1-R6It is simultaneously H；And R7-R11In at least one be D.
Further, R1-R7It is simultaneously H；And R8-R11In at least one be D.
Further, R7Or/and R10For D.
Further, the compound is one of following compound:
Above compound or its crystal form, pharmaceutically acceptable salt, hydrate or molten are prepared the present invention also provides a kind of
The method of agent conjunction object, comprising the following steps:
Using II compound represented of formula as raw material, compound shown in formula I is obtained through carbonyl reduction.
Further, the preparation method is that, II compound represented of formula is dissolved in solvent, carbonyl reduction reagent is added
Reduction reaction is carried out, isolates and purifies to obtain compound shown in formula I.
Further, the solvent is selected from methanol.
Further, the carbonyl reduction reagent is selected from NaBH4Or NaBD4。
Further, the temperature of the reduction reaction is 0 DEG C.
The present invention also provides the compounds or its crystal form, pharmaceutically acceptable salt, hydrate or solvate to exist
Preparation is for treating and the purposes in IDO related disease drug.
Further, the compound or its crystal form, pharmaceutically acceptable salt, hydrate or solvate are IDO suppressions
Preparation.
Further, the IDO related disease includes cancer, viral infection, depression, neurodegenerative disease, wound
Wound, age-related cataract, organ transplant rejection, autoimmune disease.
The present invention also provides a kind of pharmaceutical composition, it is with the compound or its crystal form, pharmaceutically acceptable
Salt, hydrate or solvate are active constituent, in addition the system that pharmaceutically acceptable auxiliary material or/and complementary ingredient are prepared
Agent.
Term " pharmaceutically acceptable " refers to certain carrier, load, diluent, auxiliary material, and/or to be formed by salt usual
In chemistry or physically with constitute the other compatible at split-phase of certain pharmaceutical dosage form, and physiologically mutually compatible with receptor.
Term " salt " and " pharmaceutical salt " are by compound or its stereoisomer, with inorganic and/or organic bronsted lowry acids and bases bronsted lowry
The acid and/or basic salt of formation also include amphoteric ion salt (inner salt), further include quaternary ammonium salt, such as alkylammonium salt.These salt
It can be and directly obtained in being finally separating and purify of compound.It is also possible to by by compound or its stereoisomer,
It is obtained by mixing with a certain number of acid or alkali appropriate (such as equivalent).These salt may form precipitating in the solution
And it is collected with filter method, or recycle obtain after the solvent evaporates, or be freeze-dried and be made after reacting in an aqueous medium.This hair
Salt described in bright can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromate, hydrofluoride, the phosphorus of compound
Hydrochlorate, acetate, propionate, succinate, oxalates, malate, succinate, fumarate, maleate, tartaric acid
Salt or trifluoroacetate.
Test result shows that the compound of the present invention has significant inhibiting effect to IDO, and effect and NLG919 are quite very
To more excellent.Further pharmacokinetic trial is also shown, compared with NLG919, the compounds of this invention drug effect quite even more
In the case where height, also there is better pharmacokinetic property, have a vast market foreground.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically above content of the invention
It is bright.But this should not be interpreted as to the scope of the above subject matter of the present invention is limited to the following embodiments.It is all above-mentioned interior based on the present invention
Hold realized technology to all belong to the scope of the present invention.
Specific embodiment
The source of agents useful for same is as follows in following embodiments:
Chengdu Kingsoft chemical reagent Co., Ltd: hexahydrobenzoid acid, thionyl chloride, methylene chloride, dimethyl azanol hydrochloride,
Triethylamine, methyl-magnesium-bromide, ammonium chloride, imidazoles, sodium acetate, acetic acid, bromine, sodium sulphate, triphenylchloromethane, tetrahydrofuran,
2- formylphenylboronic acid, four triphenyl phosphorus palladiums, sodium carbonate, n,N-Dimethylformamide, sodium ethoxide, methanol, sodium borohydride.
Chengdu Ke Long chemical reagent factory: heavy water, palladium charcoal, deuterated methanol, boron deuterate sodium, potassium carbonate.
Chengdu Ruizhi Chemical Research Co., Ltd.: the deuterated formylphenylboronic acid of 2-, 3,4,5,6- tetra- deuterated -2- formoxyl deuteriums
For phenyl boric acid, the deuterated phenyl boric acid of the deuterated formoxyl-of 2-.
The synthesis of 1 1- cyclohexyl -2- of embodiment (5H- imidazo [5,1-a] iso-indoles -5-) ethyl alcohol (compound 10)
(1) synthesis of acetyl cyclohexane (intermediate 3)
Cyclohexanecarboxylic acid (5g, 39mmol) and methylene chloride (20ml) are added into the single port bottle of 100ml, stirs at room temperature
Under slowly instill thionyl chloride (5.67ml, 78mmol), react 5h, concentrated solvent.By dimethyl azanol hydrochloride (4.5g,
47mmol) mixed liquor of methylene chloride (10ml) and triethylamine (13ml, 96mmol) slowly instills wherein, stirs at room temperature
3h filters off solid, and 1N hydrochloric acid is instilled into liquid and removes excessive triethylamine, ethyl acetate extraction merges organic layer, and use is anhydrous
Sodium sulphate is dry, is spin-dried for solvent and obtains crude product 2 (5.3g).Crude Compound 2 (5g, 29mmol) is added into there-necked flask, tetrahydro
Furans (15ml), temperature control at 0 DEG C, are added under nitrogen protection, methyl-magnesium-bromide (10ml, 29mmol) are slowly added to, 0
2h is stirred at DEG C, ammonium chloride is added, methyl-magnesium-bromide is quenched, methylene chloride extraction is added, and is merged organic layer and is used anhydrous sodium sulfate
It is dry, it is spin-dried for methylene chloride and obtains compound 3 (4.2g, yield 85%).
(2) 2, the synthesis of 4,5- tribromoimidazoles (intermediate 5)
Imidazoles (29.24g, 0.43mol) is added into there-necked flask, sodium acetate (317.34g, 3.87mol) and acetic acid
(150ml), the bromine (65ml, 1.28mol) for being dissolved in acetic acid (100ml) are slowly dropped at room temperature by constant pressure separatory funnel,
It controls temperature and is no more than 40 DEG C, 3h is stirred at room temperature, reaction solution pours into the water of 1.5L, and solid is precipitated, and filters, is washed with water
Solid, drying obtain compound 5 (120g, yield 92%), mass spectrum: 305 (M+H+)。
(3) synthesis of 4- bromine imidazoles (intermediate 6)
Be added 2,4,5- tribromoimidazoles (49g, 161mmol) into single port bottle, sodium sulfite (101.5g, 806mmol) and
Water (500ml) stirs 6h at 110 DEG C, and ethyl acetate extraction is added, and merging organic layer is simultaneously dry with anhydrous sodium sulfate, is spin-dried for
Ethyl acetate obtains compound 6 (20.5g, yield 89%), mass spectrum: 148 (M+H+)。
(4) synthesis of the bromo- 1- trityl -1H- imidazoles (intermediate 7) of 4-
4- bromine imidazoles (30g, 205mmol) is added into single port bottle, methylene chloride: tetrahydrofuran=1:1 and triphenyl chlorine
Lower addition triethylamine (29ml) is stirred at room temperature in methane (62g, 226mmol), continues to stir 1h, water and 1N hydrochloric acid is added,
Methylene chloride extraction is added, merging organic layer is simultaneously dry with anhydrous sodium sulfate, is spin-dried for methylene chloride and obtains compound 7 (61g, receipts
Rate 72%).
(5) synthesis of 2- (1- trityl -1H- imidazoles -4-) benzaldehyde (intermediate 8)
The addition bromo- 1- trityl -1H- imidazoles (1.5g, 3.9mmol) of 4- into single port bottle, sodium carbonate (1.2g,
11.7mmol), 2- formylphenylboronic acid (864mg, 5.8mmol) and DMF (10ml), water (2ml) make reaction system full of nitrogen
Gas is added tetrakis triphenylphosphine palladium (242mg, 0.195mmol), and under nitrogen protection, water, acetic acid second is added in 90 DEG C of stirring 16h
Ester extraction, it is simultaneously dry with anhydrous sodium sulfate to merge organic layer, concentrated solvent, with silica gel cross column purification obtain compound 8 (930mg,
Yield 58%).
(6) synthesis of 1- cyclohexyl -2- (5H- imidazo [5,1-a] iso-indoles -5-) ethyl ketone (intermediate 9)
2- (1- trityl -1H- imidazoles -4-) benzaldehyde (400mg, 0.97mmol), acetyl group are added into there-necked flask
Hexamethylene (122mg, 0.97mmol) and anhydrous tetrahydro furan (5ml), under nitrogen protection, by sodium ethoxide (85mg,
Ethanol solution 1.25mmol) is added at room temperature, and 3h is stirred at room temperature, and is spin-dried for solvent, and saturated ammonium chloride is added
(10ml), is extracted with ethyl acetate, and merging organic layer is simultaneously dry with anhydrous sodium sulfate, is spin-dried for solvent, acetic acid (1ml) and second is added
Alcohol (5ml), stirs 3h at 90 DEG C, is cooled to room temperature, and saturated sodium carbonate is added and adjusts PH=10, is extracted with ethyl acetate, closes
And organic layer and dry with anhydrous sodium sulfate, concentrated solvent crosses column purification with silica gel and obtains compound 9 (210mg, yield
77%), mass spectrum: 281 (M+H+)。
(7) synthesis of cyclohexyl -2- (5H- imidazo [5,1-a] iso-indoles -5-) ethyl alcohol (compound 10)
Into single port bottle be added 1- cyclohexyl -2- (5H- imidazo [5,1-a] iso-indoles -5-) ethyl ketone (140mg,
0.5mmol) 1h is stirred, solvent is spin-dried for, 2N is added with methanol (3ml), addition sodium borohydride (57mg, 1.5mmol) at 0 DEG C
Hydrochloric acid (3ml), is extracted with ethyl acetate, and merging organic layer is simultaneously dry with anhydrous sodium sulfate, and concentrated solvent crosses column purification with silica gel
Compound 10 (105mg, yield 73%, LCMS purity 99.0%) is obtained,1H NMR(DMSO-d6, 400MHz): δ (ppm) 1.10-
1.37(m,6H),1.66-1.80(m,5H),2.05(m,2H),2.15(m,1H),3.72(m,1H),5.36-5.46(m,1H),
7.16 (s, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=7.6Hz), 7.80
(s,1H)；Mass spectrum: 283 (M+H+)。
2 1- cyclohexyl -2- of embodiment (bis- deuterated imidazo [5,1-a] iso-indoles -5- of 5H-7,8-) ethyl alcohol (compound 15
(D1)) synthesis
(1) synthesis of the deuterated -1H- imidazoles (intermediate 11) of the bromo- 1,2,5- tri- of 4-
Palladium carbon (2g, 10%Pd) stirs a hour in hydrogen at room temperature, then will be dissolved in pure heavy water (50g,
4- bromine imidazoles (10g, 69mmol) 2.5mol) is added, and after removing hydrogen, 1h is stirred at 100 DEG C, reaction solution, which is filtered to remove, urges
Agent is spin-dried for solvent and obtains compound 11 (9.2g, yield 91%), mass spectrum: 151 (M+H+)。
(2) bromo- trityl -2,5 1- 4-, the synthesis of-two deuterated -1H- imidazoles (intermediate 12)
4- bromo- 1,2,5- tri- deuterated -1H- imidazoles (30g, 205mmol), methylene chloride: tetrahydro furan are added into single port bottle
It mutters=1:1 and triphenylchloromethane (62g, 226mmol), lower addition triethylamine (29ml) is stirred at room temperature, continues to stir
Water and 1N hydrochloric acid is added in 1h, and methylene chloride extraction is added, and merging organic layer is simultaneously dry with anhydrous sodium sulfate, is spin-dried for dichloromethane
Alkane obtains compound 12 (61g, yield 72%).
(3) synthesis of 2- (deuterated -1H- imidazoles -4- of 1- trityl -2,5- bis-) benzaldehyde (intermediate 13)
The bromo- 1- trityl -2,5 of 4-,-two deuterated -1H- imidazoles (1.5g, 3.9mmol), carbonic acid are added into single port bottle
Sodium (1.2g, 11.7mmol), 2- formylphenylboronic acid (864mg, 5.8mmol) and DMF (10ml), water (2ml) make reaction system
Full of nitrogen, it is added tetrakis triphenylphosphine palladium (242mg, 0.195mmol), under nitrogen protection, water is added in 90 DEG C of stirring 16h,
Ethyl acetate extraction, merging organic layer is simultaneously dry with anhydrous sodium sulfate, and concentrated solvent crosses column purification with silica gel and obtains compound 13
(930mg, yield 58%).
(4) conjunction of 1- cyclohexyl -2- (5H-7,8- bis- deuterated imidazo [5,1-a] iso-indoles -5-) ethyl ketone (intermediate 14)
At
Into there-necked flask be added 2- (deuterated -1H- imidazoles -4- of 1- trityl -2,5- bis-) benzaldehyde (400mg,
0.97mmol), acetyl cyclohexane (122mg, 0.97mmol) and anhydrous tetrahydro furan (5ml), under nitrogen protection, by ethyl alcohol
The ethanol solution of sodium (85mg, 1.25mmol) is added at room temperature, and 3h is stirred at room temperature, and is spin-dried for solvent, and saturation chlorination is added
Ammonium (10ml), is extracted with ethyl acetate, and it is simultaneously dry with anhydrous sodium sulfate to merge organic layer, is spin-dried for solvent, be added acetic acid (1ml) and
Ethyl alcohol (5ml), stirs 3h at 90 DEG C, is cooled to room temperature, and saturated sodium carbonate is added and adjusts PH=10, is extracted with ethyl acetate,
Merging organic layer is simultaneously dry with anhydrous sodium sulfate, and concentrated solvent crosses column purification with silica gel and obtains compound 14 (210mg, yield
77%), mass spectrum: 283 (M+H+)。
(5) conjunction of 1- cyclohexyl -2- (bis- deuterated imidazo [5,1-a] iso-indoles -5- of 5H-7,8-) ethyl alcohol (compound 15)
At
1- cyclohexyl -2- (5H-7,8- bis- deuterated imidazo [5,1-a] iso-indoles -5-) ethyl ketone is added into single port bottle
Sodium borohydride (57mg, 1.5mmol) is added at 0 DEG C in (140mg, 0.5mmol) and methanol (3ml), stirs 1h, is spin-dried for solvent,
It is added 2N hydrochloric acid (3ml), is extracted with ethyl acetate, merge organic layer and, concentrated solvent, with silica gel mistake dry with anhydrous sodium sulfate
Column purification obtains compound 15 (105mg, yield 78%, LCMS purity 99.4%),1H NMR(DMSO-d6, 400MHz): δ
(ppm)1.10-1.37(m,6H),1.66-1.80(m,5H),2.05(m,2H),2.15(m,1H),3.72(m,1H),5.36-
5.46 (m, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=7.6Hz)；Matter
Spectrum:
285(M+H+)。
Embodiment the 3 deuterated -2- of 1- cyclohexyl -1- (5H- imidazo [5,1-a] iso-indoles -5-) ethyl alcohol (compound 16
(D5)) synthesis
Into single port bottle be added 1- cyclohexyl -2- (5H- imidazo [5,1-a] iso-indoles -5-) ethyl ketone (140mg,
0.5mmol) with deuterated methanol (5ml), boron deuterate sodium (57mg, 1.5mmol) is added at 0 DEG C, stirs for 24 hours, is spin-dried at room temperature
Solvent is added 2N hydrochloric acid (3ml), is extracted with ethyl acetate, and merges organic layer and, concentrated solvent dry with anhydrous sodium sulfate, use
Silica gel crosses column purification and obtains compound 16 (105mg, yield 69%, LCMS purity 99.3%),1H NMR(DMSO-d6,
400MHz): δ (ppm) 1.10-1.37 (m, 6H), 1.66-1.80 (m, 5H), 2.05 (m, 2H), 3.72 (m, 1H), 5.36-5.46
(m, 1H), 7.16 (s, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=
7.6Hz),7.80(s,1H)；Mass spectrum: 284 (M+H+)。
4 deuterated-the 2- of 1- cyclohexyl -1- of embodiment (bis- deuterated imidazo [5,1-a] iso-indoles -5- of 5H-7,8-) ethyl alcohol
(compound 17 (D15))
1- cyclohexyl -2- (5H-7,8- bis- deuterated imidazo [5,1-a] iso-indoles -5-) ethyl ketone is added into single port bottle
(140mg, 0.5mmol) and deuterated methanol (5ml) is added boron deuterate sodium (57mg, 1.5mmol) at 0 DEG C, stirs at room temperature
For 24 hours, it is spin-dried for solvent, is added 2N hydrochloric acid (3ml), is extracted with ethyl acetate, merges organic layer and, concentration dry with anhydrous sodium sulfate
Solvent crosses column purification with silica gel and obtains compound 17 (105mg, yield 78%, LCMS purity 99.7%),1H NMR(DMSO-d6,
400MHz): δ (ppm) 1.10-1.37 (m, 6H), 1.66-1.80 (m, 5H), 2.05 (m, 2H), 3.72 (m, 1H), 5.36-5.46
(m, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=7.6Hz)；Mass spectrum: 286
(M+H+)。
The embodiment 5 deuterated -2- of 1- cyclohexyl -1- (5H- imidazo [5,1-a] -8,9,10,11- tetra- deuterated iso-indoles -
5-) ethyl alcohol (compound 20 (D25))
(1) synthesis of the deuterated benzaldehyde (intermediate 18) of 2- (1- trityl -1H- imidazoles -4-) -3,4,5,6- tetra-
The addition bromo- 1- trityl -1H- imidazoles (1.5g, 3.9mmol) of 4- into single port bottle, sodium carbonate (1.2g,
11.7mmol), 3,4,5,6- tetra- deuterated adjacent formylphenylboronic acids (864mg, 5.8mmol) and DMF (10ml), water (2ml), make anti-
It answers system full of nitrogen, is added tetrakis triphenylphosphine palladium (242mg, 0.195mmol), under nitrogen protection, 90 DEG C of stirring 16h,
Water is added, ethyl acetate extraction, merging organic layer is simultaneously dry with anhydrous sodium sulfate, and concentrated solvent is crossed column purification with silica gel and obtained
Compound 18 (930mg, yield 58%).
(2) 1- cyclohexyl -2- (the deuterated iso-indoles -5- of 5H- imidazo [5,1-a] 8,9,10,11- tetra-) ethyl ketone (intermediate
19) synthesis
It is added 2- (1- trityl -1H- imidazoles -4-) -3 into there-necked flask, 4,5,6- tetra- deuterated benzaldehydes (400mg,
0.97mmol), acetyl cyclohexane (122mg, 0.97mmol) and anhydrous tetrahydro furan (5ml), under nitrogen protection, by ethyl alcohol
The ethanol solution of sodium (85mg, 1.25mmol) is added at room temperature, and 3h is stirred at room temperature, and is spin-dried for solvent, and saturation chlorination is added
Ammonium (10ml), is extracted with ethyl acetate, and it is simultaneously dry with anhydrous sodium sulfate to merge organic layer, is spin-dried for solvent, be added acetic acid (1ml) and
Ethyl alcohol (5ml), stirs 3h at 90 DEG C, is cooled to room temperature, and saturated sodium carbonate is added and adjusts PH=10, is extracted with ethyl acetate,
Merging organic layer is simultaneously dry with anhydrous sodium sulfate, and concentrated solvent crosses column purification with silica gel and obtains compound 19 (210mg, yield
77%), mass spectrum: 285 (M+H+)。
(3) synthesis of cyclohexyl -2- (5H- imidazo [5,1-a] iso-indoles -5-) ethyl alcohol (compound 20)
1- cyclohexyl -2- (the deuterated iso-indoles -5- of 5H- imidazo [5,1-a] 8,9,10,11- tetra-) is added into single port bottle
Ethyl ketone (140mg, 0.5mmol) and deuterated methanol (5ml) are added boron deuterate sodium (57mg, 1.5mmol) at 0 DEG C, stir at room temperature
It mixes for 24 hours, is spin-dried for solvent, be added 2N hydrochloric acid (3ml), be extracted with ethyl acetate, merging organic layer is simultaneously dry with anhydrous sodium sulfate, dense
Contracting solvent crosses column purification with silica gel and obtains compound 20 (105mg, yield 72%, LCMS purity 99.5%),1H NMR(DMSO-
d6, 400MHz): δ (ppm) 1.10-1.37 (m, 6H), 1.66-1.80 (m, 5H), 2.05 (m, 2H), 3.72 (m, 1H), 5.36-
5.46(m,1H),7.16(s,1H),7.80(s,1H)；Mass spectrum: 288 (M+H+)。
6 1- of embodiment (the deuterated cyclohexyl of 1-) -2- (5H- imidazo [5,1-a] iso-indoles -5-) ethyl alcohol (compound 24
(D6)) synthesis
(1) synthesis of the deuterated hexamethylene of acetyl group 1- (intermediate 22)
Cyclohexanecarboxylic acid (5g, 39mmol) and methylene chloride (20ml) are added into the single port bottle of 100ml, stirs at room temperature
Under slowly instill thionyl chloride (5.67ml, 78mmol), react 5h, concentrated solvent.By dimethyl azanol hydrochloride (4.5g,
47mmol) mixed liquor of methylene chloride (10ml) and triethylamine (13ml, 96mmol) slowly instills wherein, stirs at room temperature
3h filters off solid, and 1N hydrochloric acid is instilled into liquid and removes excessive triethylamine, ethyl acetate extraction merges organic layer, and use is anhydrous
Sodium sulphate is dry, is spin-dried for solvent and obtains crude product 2 (5.3g).Crude product 2 (4g, 23mmol) is added into there-necked flask, potassium carbonate
48h is stirred at (9.5g, 69mmol) and 80 DEG C of heavy water (5ml), ethyl acetate extraction merges the drying of organic layer anhydrous sodium sulfate,
It is spin-dried for solvent to obtain crude product 23 (5g), crude Compound 23 (5g, 29mmol) is added in there-necked flask, tetrahydrofuran (15ml), temperature
Degree control is added under nitrogen protection at 0 DEG C, is slowly added to methyl-magnesium-bromide (10ml, 29mmol), stirs 2h at 0 DEG C, add
Enter ammonium chloride and methyl-magnesium-bromide is quenched, methylene chloride extraction is added, merging organic layer is simultaneously dry with anhydrous sodium sulfate, is spin-dried for dichloro
Methane obtains compound 22 (4.2g, yield 85%)
(2) synthesis of 1- (the deuterated cyclohexyl of 1-) -2- (5H- imidazo [5,1-a] iso-indoles -5-) ethyl ketone (intermediate 23)
2- (1- trityl -1H- imidazoles -4-) benzaldehyde (400mg, 0.97mmol), acetyl group are added into there-necked flask
The deuterated hexamethylene of 1- (122mg, 0.97mmol) and anhydrous tetrahydro furan (5ml), under nitrogen protection, by sodium ethoxide (85mg,
Ethanol solution 1.25mmol) is added at room temperature, and 3h is stirred at room temperature, and is spin-dried for solvent, is added saturated ammonium chloride (10ml),
It is extracted with ethyl acetate, merging organic layer is simultaneously dry with anhydrous sodium sulfate, is spin-dried for solvent, acetic acid (1ml) and ethyl alcohol is added
(5ml) stirs 3h at 90 DEG C, is cooled to room temperature, and saturated sodium carbonate is added and adjusts PH=10, is extracted with ethyl acetate, merges
Organic layer is simultaneously dry with anhydrous sodium sulfate, and concentrated solvent crosses column purification with silica gel and obtains compound 23 (210mg, yield 77%),
Mass spectrum: 282 (M+H+)。
(3) synthesis of 1- (the deuterated cyclohexyl of 1-) -2- (5H- imidazo [5,1-a] iso-indoles -5-) ethyl alcohol (compound 24)
1- (the deuterated cyclohexyl of 1-) -2- (5H- imidazo [5,1-a] iso-indoles -5-) ethyl ketone is added into single port bottle
Sodium borohydride (57mg, 1.5mmol) is added at 0 DEG C in (140mg, 0.5mmol) and methanol (3ml), stirs 1h, is spin-dried for solvent,
It is added 2N hydrochloric acid (3ml), is extracted with ethyl acetate, merge organic layer and, concentrated solvent, with silica gel mistake dry with anhydrous sodium sulfate
Column purification obtains compound 24 (105mg, yield 72%, LCMS purity 99.6%),1H NMR(DMSO-d6, 400MHz): δ
(ppm)1.10-1.37(m,6H),1.66-1.80(m,4H),2.05(m,2H),2.15(m,1H),3.72(m,1H),5.36-
5.46 (m, 1H), 7.16 (s, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=
7.6Hz),7.80(s,1H)；Mass spectrum: 284 (M+H+)。
7 1- of embodiment (the deuterated cyclohexyl of 1-) deuterated -2- of -1- (5H- imidazo [5,1-a] iso-indoles -5-) ethyl alcohol (is changed
It closes object 25 (D56))
1- (the deuterated cyclohexyl of 1-) -2- (5H- imidazo [5,1-a] iso-indoles -5-) ethyl ketone is added into single port bottle
(140mg, 0.5mmol) and deuterated methanol (5ml) is added boron deuterate sodium (57mg, 1.5mmol) at 0 DEG C, stirs at room temperature
For 24 hours, it is spin-dried for solvent, is added 2N hydrochloric acid (3ml), is extracted with ethyl acetate, merges organic layer and, concentration dry with anhydrous sodium sulfate
Solvent crosses column purification with silica gel and obtains compound 25 (105mg, yield 78%, LCMS purity 99.1%),1H NMR(DMSO-d6,
400MHz): δ (ppm) 1.10-1.37 (m, 6H), 1.66-1.80 (m, 4H), 2.05 (m, 2H), 3.72 (m, 1H), 5.36-5.46
(m, 1H), 7.16 (s, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=
7.6Hz),7.80(s,1H)；Mass spectrum: 285 (M+H+)。
8 1- of embodiment (the deuterated cyclohexyl of 1-) -2- (bis- deuterated imidazo [5,1-a] iso-indoles -5- of 5H-7,8-) ethyl alcohol
(compound 27 (D16))
(1) 1- (the deuterated cyclohexyl of 1-) -2- (5H-7,8- bis- deuterated imidazo [5,1-a] iso-indoles -5-) ethyl ketone is (intermediate
Body 26) synthesis
Into there-necked flask be added 2- (deuterated -1H- imidazoles -4- of 1- trityl -2,5- bis-) benzaldehyde (400mg,
0.97mmol), the deuterated hexamethylene of acetyl group 1- (122mg, 0.97mmol) and anhydrous tetrahydro furan (5ml), under nitrogen protection,
The ethanol solution of sodium ethoxide (85mg, 1.25mmol) is added at room temperature, 3h is stirred at room temperature, is spin-dried for solvent, is added full
It with ammonium chloride (10ml), is extracted with ethyl acetate, merging organic layer is simultaneously dry with anhydrous sodium sulfate, is spin-dried for solvent, acetic acid is added
(1ml) and ethyl alcohol (5ml), stirs 3h at 90 DEG C, is cooled to room temperature, and saturated sodium carbonate is added and adjusts PH=10, with acetic acid second
Ester extraction, merging organic layer is simultaneously dry with anhydrous sodium sulfate, and concentrated solvent crosses column purification with silica gel and obtains compound 26
(210mg, yield 77%), mass spectrum: 284 (M+H+)。
(2) 1- (the deuterated cyclohexyl of 1-) -2- (bis- deuterated imidazo [5,1-a] iso-indoles -5- of 5H-7,8-) ethyl alcohol (chemical combination
Object 27) synthesis
1- (the deuterated cyclohexyl of 1-) -2- (5H-7,8- bis- deuterated imidazo [5,1-a] iso-indoles-is added into single port bottle
Sodium borohydride (57mg, 1.5mmol) is added at 0 DEG C in 5-) ethyl ketone (140mg, 0.5mmol) and methanol (3ml), stirs 1h, rotation
Dry solvent is added 2N hydrochloric acid (3ml), is extracted with ethyl acetate, and merges organic layer and, concentrated solvent dry with anhydrous sodium sulfate,
Column purification, which is crossed, with silica gel obtains compound 27 (105mg, yield 68%, LCMS purity 99.9%),1H NMR(DMSO-d6,
400MHz): δ (ppm) 1.10-1.37 (m, 6H), 1.66-1.80 (m, 4H), 2.05 (m, 2H), 2.15 (m, 1H), 3.72 (m,
1H), 5.36-5.46 (m, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=
7.6Hz)；Mass spectrum: 286 (M+H+)。
Deuterated ethyl alcohol (the compound of 9 1- cyclohexyl -2- of embodiment (5H- imidazo [5,1-a] iso-indoles -5-) -2,2- two
29(D4))
(1) 1- cyclohexyl -2- (5H- imidazo [5,1-a] iso-indoles -5-) -2,2- bis- deuterated ethyl ketone (intermediate 28)
Synthesis
Into there-necked flask be added 1- cyclohexyl -2- (5H- imidazo [5,1-a] iso-indoles -5-) ethyl ketone (140mg,
0.5mmol), potassium carbonate (207mg, 1.5mmol) and heavy water (5ml) stir 48h at 80 DEG C, are extracted with ethyl acetate, anhydrous sulphur
Sour sodium is dry, is spin-dried for solvent and obtains compound 28 (130mg, yield 92%), mass spectrum: 283 (M+H+)。
(2) 1- cyclohexyl -2- (5H- imidazo [5,1-a] iso-indoles -5-) -2,2- bis- deuterated ethyl alcohol (compound 29)
Synthesis
The deuterated ethyl ketone of 1- cyclohexyl -2- (5H- imidazo [5,1-a] iso-indoles -5-) -2,2- two is added into single port bottle
Sodium borohydride (57mg, 1.5mmol) is added at 0 DEG C in (140mg, 0.5mmol) and methanol (3ml), stirs 1h, is spin-dried for solvent,
It is added 2N hydrochloric acid (3ml), is extracted with ethyl acetate, merge organic layer and, concentrated solvent, with silica gel mistake dry with anhydrous sodium sulfate
Column purification obtains compound 29 (105mg, yield 71%, LCMS purity 99.7%),1H NMR(DMSO-d6, 400MHz): δ
(ppm)1.10-1.37(m,6H),1.66-1.80(m,5H),2.15(m,1H),3.72(m,1H),5.36-5.46(m,1H),
7.16 (s, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=7.6Hz), 7.80
(s,1H)；Mass spectrum: 285 (M+H+)。
The deuterated ethyl alcohol of embodiment the 10 deuterated -2- of 1- cyclohexyl -1- (5H- imidazo [5,1-a] iso-indoles -5-) -2,2- two
(compound 30 (D45))
The deuterated ethyl ketone of 1- cyclohexyl -2- (5H- imidazo [5,1-a] iso-indoles -5-) -2,2- bis- is added into single port bottle
(140mg, 0.5mmol) and deuterated methanol (5ml) is added boron deuterate sodium (57mg, 1.5mmol) at 0 DEG C, stirs at room temperature
For 24 hours, it is spin-dried for solvent, is added 2N hydrochloric acid (3ml), is extracted with ethyl acetate, merges organic layer and, concentration dry with anhydrous sodium sulfate
Solvent crosses column purification with silica gel and obtains compound 30 (105mg, yield 80%, LCMS purity 99.2%),1H NMR(DMSO-
D6,400MHz): δ (ppm) 1.10-1.37 (m, 6H), 1.66-1.80 (m, 5H), 3.72 (m, 1H), 5.36-5.46 (m, 1H),
7.16 (s, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=7.6Hz), 7.80
(s,1H)；Mass spectrum: 285 (M+H+)。
11 1- cyclohexyl -2- of embodiment (bis- deuterated imidazo [5,1-a] iso-indoles -5- of 5H-7,8-) -2,2- two is deuterated
Ethyl alcohol (compound 32 (D14))
(1) 1- cyclohexyl -2- (5H-7,8- bis- deuterated imidazo [5,1-a] iso-indoles -5-) -2,2 two deuterated ethyl ketones (in
Mesosome 31) synthesis
1- cyclohexyl -2- (5H-7,8- bis- deuterated imidazo [5,1-a] iso-indoles -5-) ethyl ketone is added into there-necked flask
(140mg, 0.5mmol), potassium carbonate (207mg, 1.5mmol) and heavy water (5ml) stir 48h at 80 DEG C, are extracted with ethyl acetate
It takes, anhydrous sodium sulfate is dry, is spin-dried for solvent and obtains compound 31 (130mg, yield 92%), mass spectrum: 285 (M+H+)。
(2) 1- cyclohexyl -2- (5H-7,8- bis- deuterated imidazo [5,1-a] iso-indoles -5-) -2,2 two deuterated ethyl alcohol (are changed
Close object 32) synthesis
1- cyclohexyl -2- (bis- deuterated imidazo [5,1-a] iso-indoles -5- of 5H-7,8-) -2,2- two is added into single port bottle
Sodium borohydride (57mg, 1.5mmol) is added at 0 DEG C in deuterated ethyl ketone (140mg, 0.5mmol) and methanol (3ml), stirs 1h,
It is spin-dried for solvent, is added 2N hydrochloric acid (3ml), is extracted with ethyl acetate, merging organic layer is simultaneously dry with anhydrous sodium sulfate, is concentrated molten
Agent crosses column purification with silica gel and obtains compound 32 (105mg, yield 75%, LCMS purity 99.4%),1H NMR(DMSO-d6,
400MHz): δ (ppm) 1.10-1.37 (m, 6H), 1.66-1.80 (m, 5H), 2.15 (m, 1H), 3.72 (m, 1H), 5.36-5.46
(m, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=7.6Hz)；Mass spectrum: 287
(M+H+)。
12 1- of embodiment (the deuterated cyclohexyl of 1-) deuterated -2- of -1- (5H- imidazo [5,1-a] iso-indoles -5-) -2,2- two
Deuterated ethyl alcohol (compound 34 (D456))
(1) the deuterated ethyl ketone of 1- (the deuterated cyclohexyl of 1-) -2- (5H- imidazo [5,1-a] iso-indoles -5-) -2,2- bis- is (intermediate
Body 33) synthesis
1- (the deuterated cyclohexyl of 1-) -2- (5H- imidazo [5,1-a] iso-indoles -5-) ethyl ketone is added into there-necked flask
(140mg, 0.5mmol), potassium carbonate (207mg, 1.5mmol) and heavy water (5ml) stir 48h at 80 DEG C, are extracted with ethyl acetate
It takes, anhydrous sodium sulfate is dry, is spin-dried for solvent and obtains compound 33 (130mg, yield 92%), mass spectrum: 284 (M+H+)。
(2) the deuterated second of 1- (the deuterated cyclohexyl of 1-) deuterated -2- of -1- (5H- imidazo [5,1-a] iso-indoles -5-) -2,2- two
Alcohol (compound 34)
Bis- deuterium of 1- (the deuterated cyclohexyl of 1-) -2- (5H- imidazo [5,1-a] iso-indoles -5-) -2,2- is added into single port bottle
For ethyl ketone (140mg, 0.5mmol) and deuterated methanol (5ml), boron deuterate sodium (57mg, 1.5mmol) is added at 0 DEG C, at room temperature
Stirring for 24 hours, is spin-dried for solvent, is added 2N hydrochloric acid (3ml), is extracted with ethyl acetate, and merging organic layer is simultaneously dry with anhydrous sodium sulfate,
Concentrated solvent crosses column purification with silica gel and obtains compound 34 (105mg, yield 70%, LCMS purity 99.8%),1H NMR
(DMSO-d6, 400MHz): δ (ppm) 1.10-1.37 (m, 6H), 1.66-1.80 (m, 4H), 3.72 (m, 1H), 5.36-5.46
(m, 1H), 7.16 (s, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=
7.6Hz),7.80(s,1H)；Mass spectrum: 287 (M+H+)。
13 1- cyclohexyl -2- of embodiment (the deuterated iso-indoles -5- of 5H- imidazo [5,1-a] -6-) ethyl alcohol (compound 37
(D3))
(1) synthesis of 2- (1- trityl -1H- imidazoles -4-) deuterated benzaldehyde (intermediate 35)
The addition bromo- 1- trityl -1H- imidazoles (1.5g, 3.9mmol) of 4- into single port bottle, sodium carbonate (1.2g,
11.7mmol), the deuterated phenyl boric acid of the deuterated formoxyl of 2- (864mg, 5.8mmol) and DMF (10ml), water (2ml) make reaction system
It full of nitrogen, is added tetrakis triphenylphosphine palladium (242mg, 0.195mmol), under nitrogen protection, 90 DEG C of stirring 16h are added
Water, ethyl acetate extraction, merging organic layer is simultaneously dry with anhydrous sodium sulfate, and concentrated solvent crosses column purification with silica gel and obtains chemical combination
Object 35 (930mg, yield 58%), mass spectrum: 415 (M+H+)。
(2) synthesis of 1- cyclohexyl -2- (the deuterated iso-indoles -5- of 5H- imidazo [5,1-a] -6-) ethyl ketone (intermediate 36)
2- (1- trityl -1H- imidazoles -4-) deuterated benzaldehyde (400mg, 0.97mmol), 1- are added into there-necked flask
Acetyl cyclohexane (122mg, 0.97mmol) and anhydrous tetrahydro furan (5ml), under nitrogen protection, by sodium ethoxide (85mg,
Ethanol solution 1.25mmol) is added at room temperature, and 3h is stirred at room temperature, and is spin-dried for solvent, is added saturated ammonium chloride (10ml),
It is extracted with ethyl acetate, merging organic layer is simultaneously dry with anhydrous sodium sulfate, is spin-dried for solvent, acetic acid (1ml) and ethyl alcohol is added
(5ml) stirs 3h at 90 DEG C, is cooled to room temperature, and saturated sodium carbonate is added and adjusts PH=10, is extracted with ethyl acetate, merges
Organic layer is simultaneously dry with anhydrous sodium sulfate, and concentrated solvent crosses column purification with silica gel and obtains compound 36 (210mg, yield 77%),
Mass spectrum: 283 (M+H+)。
(3) synthesis of 1- cyclohexyl -2- (the deuterated iso-indoles -5- of 5H- imidazo [5,1-a] -6-) ethyl alcohol (compound 37)
1- cyclohexyl -2- (the deuterated iso-indoles -5- of 5H- imidazo [5,1-a] -6-) ethyl ketone is added into there-necked flask
Sodium borohydride (57mg, 1.5mmol) is added at 0 DEG C in (140mg, 0.5mmol), methanol (5ml), stirs at room temperature for 24 hours, rotation
Dry solvent is added 2N hydrochloric acid (3ml), is extracted with ethyl acetate, and merges organic layer and, concentrated solvent dry with anhydrous sodium sulfate,
Column purification, which is crossed, with silica gel obtains compound 37 (105mg, yield 82%, LCMS purity 99.3%),1H NMR(DMSO-d6,
400MHz): δ (ppm) 1.10-1.37 (m, 6H), 1.66-1.80 (m, 5H), 2.05 (m, 2H), 2.15 (m, 1H), 3.72 (m,
1H), 7.16 (s, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=7.6Hz),
7.80(s,1H)；Mass spectrum: 284 (M+H+)。
Embodiment the 14 deuterated -2- of 1- cyclohexyl -1- (the deuterated iso-indoles -5- of 5H- imidazo [5,1-a] -6-) ethyl alcohol (is changed
Close object 3 (D35) 8)
1- cyclohexyl -2- (the deuterated iso-indoles -5- of 5H- imidazo [5,1-a] -6-) ethyl ketone is added into there-necked flask
Sodium borohydride (57mg, 1.5mmol) is added at 0 DEG C in (140mg, 0.5mmol), methanol (5ml), stirs at room temperature for 24 hours, rotation
Dry solvent is added 2N hydrochloric acid (3ml), is extracted with ethyl acetate, and merges organic layer and, concentrated solvent dry with anhydrous sodium sulfate,
Column purification, which is crossed, with silica gel obtains compound 37 (105mg, yield 79%, LCMS purity 99.2%),1H NMR(DMSO-d6,
400MHz): δ (ppm) 1.10-1.37 (m, 6H), 1.66-1.80 (m, 5H), 2.05 (m, 2H), 3.72 (m, 1H), 7.16 (s,
1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=7.6Hz), 7.80 (s, 1H)；
Mass spectrum: 284 (M+H+)。
The pharmacodynamic test of 15 the compounds of this invention of embodiment
The test of IDO inhibiting compound: the IC of each compound is carried out by IDO enzyme test50It is by PH=6.5
The activity of IDO is tested in 50mM kaliumphosphate buffer.Mankind's IDO albumen of 70nM purifying, 200 μM of L-Trps,
20mM ascorbate, 20 μM of methylenum careuleum, 0.1%DMSO.Inhibitor first dilutes in the DMSO of 100mM, then in the phosphorus of 50mM
Diluted in sour potassium, last solubility is added in reaction solution between 1mM to 5nM, at 25 DEG C with enzyme preculture 5 minutes.Reaction
Addition L-Trp, which reaches 200 μM and then cultivates 30min at 60 DEG C, is hydrolyzed to kynurenin for N- formoxyl kynurenin.Instead
5 minutes removing protein precipitations should be centrifuged at 3400g, supernatant liquor is anti-to dimethylamine benzaldehyde with 2% (w/v) in acetic acid
It answers.Reaction cultivates 10min at 25 DEG C, and 480nm is read in spectrophotometer.Control sample with do not have IDO inhibitor, or
There is no IDO enzyme, or is used with reference inhibitor 1- methyl tryptophan (200 μM) and menadione (1.2 μM) as control group
In pair it needs to be determined that each compound IC50Nonlinear regression be arranged parameter.Nonlinear regression and IC50It is to pass through
GraphPad Prism 4 software determines.As a result as shown in table 1 below.
Table 1
The medicine generation test of 16 the compounds of this invention of embodiment
(1) pharmacokinetic parameter of compound 10,16,37,38
In detection SD rat plasma respectively stomach-filling give after 25mg/kg compound 10,16,37,38 compound 10,16,37,
38 concentration simultaneously draws the pharmacokinetic parameter that Drug-time curve calculates the medicine.
Experiment is provided using healthy male SD rat, weight 180-220g, the animal center as tested by the drug of Shanghai, is used
Credit number SYXK (river) 2011-178.Feeding environment room temperature is controlled at 16-26 DEG C.Relative humidity 40-70%, artificial light,
12 hours light and shade alternatings, the feed of capital Hu Kang Experimental Animal Center particular formulation, free water to the north of feeding.Animal subject is in reality
Day the last week is tested in experimental place progress adaptive feeding.
Experimental animal carries out euthanasia processing according to SOP after sample acquires.
Experimental animal grouping and dosage regimen:
According to the requirement of experiment purpose and experimental design, 25mg/kg compound 10,16,37,38 is given in stomach-filling respectively, administration
Volume is 25ml/kg, administration concentration 1mg/kg.SD rat 16, male is randomly divided into 4 groups, every group 4, stomach-filling is given respectively
Give subject compound.Fasting 12h before testing, free water, 2h is unified after administration feeds.Unification is fed after 2h is administered.
The desired amount of test sample is weighed in 10ml import centrifuge tube (BD), is added after high-temperature sterilization while stirring
0.5%HPMC (hydroxymethyl cellulose) aqueous solution is formulated as suspension, mixes before being administered to required concentration.After administration 0.25,
0.5,1.0,2.0,3.0,4.0,6.0,8.0 and 24 hour acquisition sample.Blood 0.3ml is taken through rat eye rear vein beard.Blood sample
With heparin sodium anticoagulation, 3500rpm is centrifuged about 200 μ L of separated plasma (being protected from light) after ten minutes in 4 DEG C of centrifuges.Freezing is protected
It is to be detected to be stored in -80 DEG C of refrigerators.
Pharmacokinetic parameter is analyzed with DAS2.1 software, and non-compartment model is selected to calculate pharmacokinetic parameters.Using
Each time point blood concentration average value is calculated.Up to Cmax CmaxWith peak time TmaxFor measured value；Below Drug-time curve
Product AUC0-tValue: it is calculated using trapezoidal method；AUC0-∞=AUC0-t+Ct/ke, CtThe blood medicine that time point can be measured for the last one is dense
Degree, keFor elimination rate constant；Eliminate half-life period t1/2=0.693/ke.As a result as shown in table 2 below.
PK data when 2 rat oral gavage 25mg/kg of table
| Compound | Cmax(ng/ml) | AUC0-t(ng*h/ml) | AUC0-∞(ng*h/ml) | T1/2(h) |
| 10 | 6512 | 7954 | 8063 | 1.2 |
| 16 | 6353 | 13657 | 14543 | 1.9 |
| 37 | 6406 | 9651 | 10075 | 1.8 |
| 38 | 6309 | 14142 | 15895 | 2.6 |
(2) metabolism of the compound 10,16,37,38 in rat plasma
The rat plasma sample in above-mentioned pharmacokinetic studies is temporally put into isometric merging respectively, obtains each time
Point (0h, 9h and 48h) merges plasma sample.It takes and merges 100 μ L of blood plasma, 300 μ L acetonitriles are added, be vortexed 1min, centrifugation
(14000rpm) 5min takes the 40 DEG C of nitrogen stream dryings of whole supernatants, adds 100 μ L acetonitrile/waters (1:1, v/v) to dissolve, centrifugation
5min (14000rpm) takes 7.0 μ L to carry out UPLC-UV/Q-TOFMS analysis.Measure the content of each metabolin.As a result such as the following table 3
Shown
3 rat plasma metabolin of table
| Compound | Raw medicine | Isomerization metabolin | Oxidative metabolites | Dehydrogenation metabolin |
| 10 | 52 | 15.8 | 2.5 | 27.5 |
| 16 | 71.1 | 9.8 | 2.6 | 16.5 |
| 37 | 63 | 10.2 | 2.1 | 24.7 |
| 38 | 81.4 | 2.7 | 2.8 | 13.1 |
Test result shows that the compound of the present invention has significant inhibiting effect to IDO, and effect and NLG919 are quite very
To more excellent.Further pharmacokinetic trial is also shown, compared with NLG919, the compounds of this invention drug effect quite even more
In the case where height, also there is better pharmacokinetic property, have a vast market foreground.
Claims (7)
1. compound as follows or its pharmaceutically acceptable salt:
R7For D, R10For H, R1-R6、R8-R9、R11-R21It is selected from H；
Or, R7For H, R10For D, R1-R6、R8-R9、R11-R21It is selected from H；
Or, R7And R10It is D, R1-R6、R8-R9、R11-R21It is selected from H.
2. compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that: the compound is such as
One of lower compound:
3. a kind of method for preparing compound or its pharmaceutically acceptable salt as claimed in claim 1 or 2, comprising the following steps:
Using II compound represented of formula as raw material, compound shown in formula I is obtained through carbonyl reduction.
4. compound as claimed in claim 1 or 2 or its pharmaceutically acceptable salt are in preparation for treating and IDO related disease medicine
Purposes in object.
5. purposes according to claim 4, it is characterised in that: the compound or its pharmaceutically acceptable salt are IDO
Inhibitor.
6. purposes according to claim 4, it is characterised in that: the IDO related disease include cancer, viral infection,
Depression, neurodegenerative disease, wound, age-related cataract, organ transplant rejection, autoimmune disease
Disease.
7. a kind of pharmaceutical composition, it is characterised in that: it be with compound of any of claims 1 or 2 or its can pharmaceutically connect
The salt received is active constituent, in addition the preparation that pharmaceutically acceptable auxiliary material or/and complementary ingredient are prepared.
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