CN107176956A - A kind of IDO inhibitor compound, Pharmaceutical composition, purposes - Google Patents
A kind of IDO inhibitor compound, Pharmaceutical composition, purposes Download PDFInfo
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- CN107176956A CN107176956A CN201710405187.7A CN201710405187A CN107176956A CN 107176956 A CN107176956 A CN 107176956A CN 201710405187 A CN201710405187 A CN 201710405187A CN 107176956 A CN107176956 A CN 107176956A
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- substituted
- unsubstituted
- alkyl
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- substitution
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- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- YGPSJZOEDVAXAB-QMMMGPOBSA-N L-kynurenine Chemical compound OC(=O)[C@@H](N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-QMMMGPOBSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- YRHQCMISQURDQB-UHFFFAOYSA-N N#CC(CC1C2)(C3)C11C2(CC(CC(c2ccccc2-2)[n]4c-2cnc4)O)CC3C1 Chemical compound N#CC(CC1C2)(C3)C11C2(CC(CC(c2ccccc2-2)[n]4c-2cnc4)O)CC3C1 YRHQCMISQURDQB-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 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
- 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
- 150000003869 acetamides Chemical class 0.000 description 1
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- 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
- 230000009876 antimalignant effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 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
- 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
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003795 chemical substances by application 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
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000001530 fumaric acid Substances 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
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004415 heterocyclylalkyl group Chemical group 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
- 208000015486 malignant pancreatic neoplasm Diseases 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 125000002950 monocyclic group Chemical group 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
- 230000001537 neural effect Effects 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
- 239000000575 pesticide Substances 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
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 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
- 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
- 229910052938 sodium sulfate Inorganic materials 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
- 229960005137 succinic acid Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000006228 supernatant Substances 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
Abstract
The invention provides a kind of noval chemical compound, the compound is to indoleamine 2, and 3 dioxygenases (IDO) have certain inhibitory activity, or available for treating associated disease.
Description
Technical field
The present invention relates to medicinal chemistry art, more particularly to IDO inhibitor compound, Pharmaceutical composition, purposes.
Background technology
Diindyl amine 2 in majority tissue, 3- dioxygenases (IDO) are 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 and then influence immune neural
Etc. systemic-function.IDO effects are to decompose tryptophan to kynurenin, the exhaustion of tryptophan and its metabolite to cause 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
Plus the generation of regulatory T cells.So as to strengthen attacking ability of the body to tumour cell, and IDO inhibitor can also be with chemotherapy
Drug combination, reduces the drug resistance of tumour cell, so as to strengthen the antitumor activity of conventional cytotoxic therapy.
Research shows that IDO in terms of tumor cell drug resistance except in addition to playing an important role, also with many immunocytes
Activate related disease related.IDO is it is verified that the infection related to cellular immunity activation, malignant tumour, LADA
The target of the major diseases such as disease, AIDS, cataract, Alzheimer disease.Therefore IDO inhibitor acts on important medicine tool
There is wide potential applicability in clinical practice.
WO2012142237 reports IDO inhibitor and its pharmaceutical composition, for regulating and controlling indoleamine 2,3- dioxygenases
Active 5H- imidazos [5,1-a] isoindoles compound.A keys are singly-bound or double bond；M is 0,1 or 2；P is 0 or 1；And
When a keys are 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 keys are 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 haloalkyls ,-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 compound structure of the invention and the present invention differ greatly, and are not considered as that it is of the invention one to be specifically described in this patent
Point, its general formula compound is as follows：
WO2016131380 and WO2016165613 also report 5H- imidazos [5,1-a] isoindoles compound conduct
The compound of IDO inhibitor.
NLG-919 is in clinical investigation phase as a kind of new IDO inhibitor at present, but its drug effect with
Pharmacokinetic property still has greatly improved space.
The content of the invention
It is an object of the invention to provide a kind of change of 5H- imidazos [5,1-a] isoindoles compound as IDO inhibitor
Compound, or its all stereoisomers, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug,
Its pharmaceutical composition of deuterated compound and its indole amine 2,3-dioxygenase (IDO) inhibitor purposes for lifting 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 0-4 integer；
Wherein R1From following substituent：Hydrogen, halogen, hydroxyl, cyano group, nitro, amino, substituted or unsubstituted C1-C6Alkane
Base, substituted or unsubstituted C1-C6Miscellaneous alkyl, substituted or unsubstituted C3-C6Cycloalkyl, substituted or unsubstituted C3-C6Heterocycle
Alkyl, substituted or unsubstituted C5-C6Aryl, substituted or unsubstituted C5-C6Heteroaryl；The substituent of above-mentioned group is selected from：
Nitro, hydroxyl, amino, sulfydryl, halogeno-group, cyano group, substituted or non-substituted C1-C10Alkyl, substituted or non-substituted C1-C10Miscellaneous alkane
Base, substitution or unsubstituted C3-C 10Cycloalkyl, substitution or unsubstituted C3-C10Heterocyclylalkyl；
R2Selected from following substituent：Hydrogen, halogen, cyano group, nitro, aryl, heteroaryl, OR3、N(R3)2、NCOR3；
R3Selected from following substituent：Substituted or non-substituted C1-C10Alkyl, substituted or non-substituted C1-C10Miscellaneous alkyl, substitution or
Unsubstituted C3-C10Cycloalkyl, substitution or unsubstituted C3-C10Heterocyclylalkyl, substituted or unsubstituted C5-C6Aryl, substitution or not
Substituted C5-C6Heteroaryl；
R4、R5Selected from following substituent：Hydrogen, halogen, hydroxyl, cyano group, nitro, amino, substituted or unsubstituted C1-C6Alkane
Base, substituted or unsubstituted C1-C6Miscellaneous alkyl, substituted or unsubstituted C3-C6Cycloalkyl, substituted or unsubstituted C3-C6Heterocycle
Alkyl；R4、R5Following group is collectively constituted with the carbon atom being connected：Substituted or unsubstituted C3-C8Alkyl, substitution or not
Substituted C3-C8Miscellaneous alkyl；The substituent of above-mentioned group be selected from nitro, hydroxyl, amino, sulfydryl, halogeno-group, cyano group, substitution or
Non-substituted C1-C10Alkyl, substituted or non-substituted C1-C10Miscellaneous alkyl, substitution or unsubstituted C3-C10Cycloalkyl, substitution 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 group, 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, substituted or non-substituted C1-C6 alkyl or collectively constitute substitution with the carbon atom being connected
Or non-substituted C3-C6 cycloalkyl；
Above-mentioned R1-R5The substituent of substituted radical is selected from group：Nitro, hydroxyl, amino, sulfydryl, halogeno-group, cyano group, substitution
Or non-substituted C1-C10 alkyl, substituted or non-substituted C1-C10 miscellaneous alkyls, substitution or unsubstituted C3-C10 cycloalkyl, substitution or not
Replace C3-C10 Heterocyclylalkyls.
Further, R1Selected from group：Hydrogen, halogen；R2 is selected from group：Halogen, hydroxyl, cyano group, N COR3；R3Selected from taking
Generation or non-substituted C1-C3 alkyl；
R4, R5 by hydrogen, substituted or non-substituted C1-C6 alkyl or with the carbon atom being connected collectively constitute substitution or
Non-substituted C3-C6 cycloalkyl.
Experiment finds that, when R1, R2 are selected from halogen, its activity has certain lifting, can be with by the specific embodiment of the invention
Find out, R1、R2Fluorine or chlorine can be independently selected from, but should not be construed as only limiting halogen herein for fluorine or chlorine.
In an embodiment of the invention, R1Selected from fluorine, R2It is independently selected from fluorine or chlorine.
It also found in present invention experiment, work as R4、R5Substituted or non-substituted C3-C6 is collectively constituted with the carbon atom being connected
During cycloalkyl, activity is more preferably.In an embodiment of the invention, cycloalkyl is selected from cyclopropyl at this, should not be construed as this
Only limitation C3-C6 cycloalkyl is cyclopropyl at place.
Further, the substituent of substituted radical is selected from：Hydroxyl, amino, sulfydryl, C1-C6 alkyl.
Present invention also offers a kind of Pharmaceutical composition, the Pharmaceutical composition active ingredient be selected from above-mentioned compound or its
Combination more than one or both 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 component
It is one or more kinds of.
Present invention also offers above-claimed cpd or its stereoisomer, solvate, hydrate, pharmaceutically acceptable
The purposes of salt or eutectic in indole amine 2,3-dioxygenase (IDO) inhibitor is prepared.
Wherein, above-mentioned inhibitor can treat and/or prevent the illness related to the tryptophan metabolic pathway that IDO is mediated.
It can by suppressing the IDO of unconventionality expression, so as to prevent the reduction of body cell tryptophan levels, and from treat or prevent because
IDO unconventionality expressions cause tryptophan levels to decline caused disease.
Wherein, the inhibitor is used to treat at least one disease as described below：Cancer, autoimmune conditions, virus
Sexy dye, depression, AIDS, RAEB, anxiety disorder, cataract, more preferably wherein described cancer
Selected from breast cancer, cervical carcinoma, colon cancer, liver cancer, stomach cancer, the carcinoma of the rectum, oophoroma, cancer of pancreas, carcinoma of urinary bladder, solid tumor, myeloma,
Non-small cell lung cancer, leukaemia, lymthoma, melanoma, osteocarcinoma, kidney.
In an 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 cycloalkyl with the carbon atom being connected,
Its Compound ira vitro IDO suppresses in Kinase activity assays, and compound is to people's source protein inhibition of enzyme activity IC50 test result datas
Respectively less than 49nM, and under identical test condition of the present invention, the new IDO inhibitor NLG- in clinical investigation phase
919 test result data is 159nM.
In an 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 cycloalkyl with the carbon atom being connected, and it is changed
The external IDO of compound suppresses in Kinase activity assays, and compound is small to people's source protein inhibition of enzyme activity IC50 test result datas
In 31nM.
In an 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 connected3-C6Cycloalkyl, its Compound ira vitro IDO suppresses kinase activity examination
In testing, compound is respectively less than 24nM to people's source protein inhibition of enzyme activity IC50 test result datas；Meanwhile, in pharmacokinetics examination
Middle discovery is tested, is compared with the Novel IDO inhibitor NLG-919 in clinical investigation phase, above-claimed cpd maximum plasma concentration
For 1.3-2.8 times of NLG-919.
Above-mentioned C1-C6Alkyl can be selected from methyl, ethyl, propyl group etc..
Above-mentioned C3-C6Cycloalkyl can be selected from cyclopropyl, cyclobutyl etc..
Involved carbon, hydrogen, oxygen, sulphur, nitrogen or F, Cl, Br, I include them in group of the present invention and compound
Isotope situation, and carbon, hydrogen, oxygen, sulphur or nitrogen involved in group of the present invention and compound is optionally further by one
Their individual or multiple corresponding isotopes are substituted, and the isotope of wherein carbon includes12C、13C and14C, the isotope of hydrogen includes protium
(H), deuterium (D is called heavy hydrogen), tritium (T is called superheavy hydrogen), the isotope of oxygen includes16O、17O and18O, the isotope of sulphur includes32S、33S、34S and36S, the isotope of nitrogen includes14N and15N, the isotope of fluorine includes17F and19F, the isotope of chlorine includes35Cl
With37Cl, the isotope of bromine includes79Br and81Br。
" miscellaneous alkyl " refers to the straight or branched saturated aliphatic hydrocarbons of 1 to 20 carbon atom, comprising 1 to 3 selected from N,
O or S hetero atom, N, S can be oxidized to various oxidation state.
" heterocyclic radical " refers to substituted or unsubstituted saturation or undersaturated aromatic rings or non-aromatic ring, aromatic rings or
Person's non-aromatic ring can be 3 to 8 yuan monocyclic, 4 to 12 membered bicyclics or 10 to 15 membered tricyclic systems, and be selected from comprising 1 to 3
N, the S selectively replaced in N, O or S hetero atom, preferably 3 to 8 circle heterocycles bases, the ring of heterocyclic radical 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
Or the biological effectiveness and characteristic of free alkali, and described 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.Generally, the acid bag of salt is pharmaceutically suitably formed
Include but be 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, butanedioic 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 acid such as aspartic acid, glutamic acid.
" carrier " refer to will not to organism produce obvious stimulation and will not eliminate given compound bioactivity and
The material of characteristic.
" excipient " refers to be added in pharmaceutical composition to promote the inert substance that compound is administered.It is non-limiting to implement
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 disintegrant.
" prodrug " refers to can be the compounds of this invention with bioactivity through biotransformationin vivo.The prodrug of the present invention leads to
Prepared by the hydroxyl crossed in modification the compounds of this invention, the modification can be removed by conventional operation or in vivo, and
Obtain parent compound.When the prodrug of the present 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 pure state of the crystal being combined under, wherein API and CCF is the presence of fixation between solid, and each component at room temperature
Stoichiometric proportion.Eutectic is a kind of multicomponent crystal, both comprising the binary eutectic formed between two kinds of neutral solids, in also including
Property solid and salt or solvate formation multi-element eutectic.
" stereoisomer " refers to the isomers produced by spatially arrangement mode is different as atom in molecule, including suitable
Trans isomer, enantiomter and rotamer.
" optional " or " optionally " or " selective " or " optionally " refer to that then described event or situation can be with
But may not occur, the description includes the situation and wherein nonevent situation for wherein occurring the event or situation.For example, " selection
Property by alkyl-substituted heterocyclic radical " refer to the alkyl can with but may not exist, the description is taken including wherein heterocyclic radical by alkyl
The situation in generation, and wherein heterocyclic radical is not by alkyl-substituted situation.
Inventive compound is prepared into pharmaceutical preparation, physico-chemical property that can be according to active component and actual medication
Demand, prepares different dosage forms, such as solution, solid pharmaceutical preparation.
Embodiment
Embodiment 1
The conjunction of 1- ((3r, 5r, 7r)-adamantane -1- bases) -3- (5H- imidazos [5,1-a] iso-indoles -5- bases) -2- propyl alcohol
It is as follows into step：
Step 1：The preparation of 2- (1- trityl -1H- imidazoles -5- bases)-benzaldehyde
Weigh 2- formylphenylboronic acids (15.0g, 0.1mol), the bromo- 1- trityls -1H- imidazoles of 4- (38.8g,
0.1mol) and K2CO3(27.6g, 0.2mol) adds 200mL dioxanes and the dissolving of 20mL water in 500mL single port bottles.System is put
Change addition Pd (dppf) Cl after nitrogen2(1.5g, 2.3mmol).Reactant mixture stirs 4h in 90 DEG C under nitrogen protection.TLC
After detection reaction is finished, reaction solution is poured into 500mL water, EA (200mLx3) extractions, and saturation NaCl is used after merging organic phase
Washing, anhydrous Na 2SO4 is fully dried, and is purified to obtain 31g target compounds by column chromatography (PE/EA=20/1) after being spin-dried for, is
Yellow solid, yield is 75%.
Step 2：The preparation of 2- (1H- imidazoles -5- bases)-benzaldehyde
2- (1- trityl -1H- imidazoles -5- bases)-benzaldehyde (21.8g, 52.7mmol) is weighed in 500mL single port bottles
In, add 200mL formic acid and the dissolving of 50mL water.Reactant mixture stirs 4h in 45 DEG C, and TLC detection reactions are finished.Reaction solution revolves
200mL water is added after dry, dichloromethane (100mLx2) extraction, aqueous phase NaOH alkali tunes to pH=10 or so there are a large amount of solids to analyse
Go out.Suction filtration, filter cake is dried in vacuo to obtain 7.8g target compounds after being washed with water, be yellow solid, and yield is 86%.
Step 3：The preparation of 1- ((3r, 5r, 7r)-adamantane -1- bases) -2- acetone
2- ((3r, 5r, 7r)-adamantane -1- bases)-acetic acid (1.94g, 10mmol) is weighed in 50mL single port bottles, is added
20mL THF dissolve.Under nitrogen protection, to be cooled in 0 DEG C of system be added dropwise lithium methide THF solution (2M, 15mL,
30mmol).4h is stirred at room temperature in reaction system after completion of dropping, and TLC detection reactions are finished.Reaction solution is poured into 100mL saturations
In aqueous ammonium chloride solution, EA (50mLx3) extractions use saturated common salt water washing, anhydrous Na after merging organic phase2SO4Dry, be spin-dried for
1.26g target compounds are obtained by column chromatography (PE/EA=50/1) purifying afterwards, are colorless oil, yield is 66%.
Step 4：1- ((3r, 5r, 7r)-adamantane -1- bases) -3- (5H- imidazos [5,1-a] iso-indoles -5- bases) -2- third
The preparation of ketone
Weigh 1- ((3r, 5r, 7r)-adamantane -1- bases) -2- acetone (192mg, 1.0mmol) and 2- (1H- imidazoles -5-
Base)-benzaldehyde (172mg, 1.0mmol) is in 50mL single port bottles, and addition 5mL ethanol and the dissolving of 1mL water add NaOH
(100mg, 2.5mmol).Reactant mixture stirs 2h in 80 DEG C.After TLC detection reactions are finished, reaction solution pours into 20mL water
In, EA (10mLx3) extractions are washed, anhydrous Na after merging organic phase with saturation NaCl2SO4Dry, pass through column chromatography after being spin-dried for
(PE/EA=2/1) 270mg target compounds are purified to obtain, are yellow solid, yield is 78%.
Step 5：1- ((3r, 5r, 7r)-adamantane -1- bases) -3- (5H- imidazos [5,1-a] iso-indoles -5- bases) -2- third
The preparation of alcohol
Weigh 1- ((3r, 5r, 7r)-adamantane -1- bases) -3- (5H- imidazos [5,1-a] iso-indoles -5- bases) -2- acetone
(173 mg, 0.5mmol) add 5mL MeOH dissolvings, add NaBH in 50mL single port bottles4(76 mg, 2.0mmol).Instead
Answer mixture that 1h is stirred at room temperature.After TLC detection reactions are finished, reaction solution is poured into 20mL saturated aqueous ammonium chlorides, EA
(10mLx3) is extracted, and is washed after merging organic phase with saturation NaCl, anhydrous Na2SO4Dry, pass through column chromatography (PE/EA after being spin-dried for
=110mg target compounds 2/1) are purified to obtain, it is off-white powder, yield is 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- hydroxyls -3- (5H- imidazos [5,1-a]-iso-indoles -5- bases)-propyl group)-Buddha's warrior attendant
The synthesis step of alkane -1- alcohol is as follows：
Step 1：The preparation of 2- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- bases)-acetic acid
2- ((3r, 5r, 7r)-adamantane -1- bases)-acetic acid (1.94g, 10mmol) is taken in 50mL single port bottles, is added
20mL water dissolves.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 detection reactions are finished.By reaction solution acid adjustment to pH=4 or so, EA (20mLx5) extractions merge organic
Saturated common salt water washing is used after phase, anhydrous Na 2SO4 is dried, obtained after being spin-dried for by column chromatography (DCM/MeOH=20/1) purifying
960mg target compounds, are white solid, and yield is 46%.
Step 2：The preparation of 1- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- bases) -2- acetone
2- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- bases)-acetic acid (840mg, 4mmol) is taken in 50mL single port bottles
In, add 10mL THF dissolvings.Under nitrogen protection, to be cooled in 0 DEG C of system be added dropwise lithium methide THF solution (2M,
8mL, 16mmol).4h is stirred at room temperature in reaction system after completion of dropping, and TLC detection reactions are finished.Reaction solution is poured into 50mL to satisfy
In aqueous ammonium chloride solution, EA (20 mLx3) extractions merge and saturated common salt water washing are used after organic phase, and anhydrous Na 2SO4 is dried,
720mg target compounds are obtained by column chromatography (PE/EA=5/1) purifying after being spin-dried for, are colorless oil, yield is 87%.
Step 3：1- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- bases) -3- (5H- imidazos [5,1-a] iso-indoles -
5- yls) -2- acetone preparation
Weigh 1- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- bases) -2- acetone (624mg, 3.0mmol) and 2-
(1H- imidazoles -5- bases)-benzaldehyde (516mg, 3.0mmol) adds 20mL ethanol and the dissolving of 4mL water in 50mL single port bottles, then
Add NaOH (300mg, 7.5mmol).Reactant mixture stirs 2h in 80 DEG C.After TLC detection reactions are finished, reaction solution is poured into
In 50mL water, EA (30mLx3) extractions are washed, anhydrous Na 2SO4 is dried, and is passed through after being spin-dried for after merging organic phase with saturation NaCl
Column chromatography (DCM/EA=2/1) purifies to obtain 630mg target compounds, is yellow solid, and yield is 58%.
Step 4：(1s, 3r, 5R, 7S) -3- (2- hydroxyls -3- (5H- imidazos [5,1-a]-iso-indoles -5- bases)-propyl group) -
The preparation of adamantane -1- alcohol
Weigh 1- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- bases) -3- (5H- imidazos [5,1-a] iso-indoles -5-
Base) -2- acetone (181mg, 0.5mmol) in 50mL single port bottles, adds 5mL MeOH dissolving, add NaBH4 (76mg,
2.0mmol).1h is stirred at room temperature in reactant mixture.After TLC detection reactions are finished, reaction solution pours into 20mL saturated ammonium chloride water
In solution, EA (10mLx3) extractions are washed, anhydrous Na 2SO4 is dried, and passes through post after being spin-dried for after merging organic phase with saturation NaCl
Chromatography (DCM/EA=1/1) purifies to obtain 95mg target compounds, is off-white powder, yield is 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- bases) -3- (5H- imidazos [5,1-a] iso-indoles -5- bases) -2-
The synthesis step of propyl alcohol is as follows：
Step 1：1- ((1s, 3s, 5R, 7S) -3- fluorine adamantane -1- bases) -3- (5H- imidazos [5,1-a] iso-indoles -5-
Base) -2- acetone preparation
Weigh 1- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- bases) -3- (5H- imidazos [5,1-a] iso-indoles -5-
Base) -2- acetone (181mg, 0.5mmol) is in 50mL single port bottles, and addition 5mL DCM dissolvings add DAST under nitrogen protection
(diethylin sulfur trifluoride) (97mg, 0.6mmol).Reactant mixture stirs 2h in 0 DEG C.After TLC detection reactions are finished,
Reaction solution is poured into 20mL water, DCM (10mL x3) extractions, is washed after merging organic phase with saturation NaCl, anhydrous Na 2SO4 is done
It is dry, 170mg target compounds are purified to obtain by column chromatography (PE/EA=2/1) after being spin-dried for, are white solid, yield is 93%.
Step 2：1- ((1s, 3s, 5R, 7S) -3- fluorine adamantane -1- bases) -3- (5H- imidazos [5,1-a] iso-indoles -5-
Base) -2- propyl alcohol preparation
Weigh 1- ((1s, 3s, 5R, 7S) -3- fluorine adamantane -1- bases) -3- (5H- imidazos [5,1-a] iso-indoles -5-
Base) -2- acetone (36mg, 0.1mmol) in 50mL single port bottles, adds 5mL MeOH dissolving, add NaBH4 (19mg,
0.5mmol).1h is stirred at room temperature in reactant mixture.After TLC detection reactions are finished, reaction solution pours into 20mL saturated ammonium chloride water
In solution, EA (10mLx3) extractions are washed, anhydrous Na 2SO4 is dried, and passes through post after being spin-dried for after merging organic phase with saturation NaCl
Chromatography (DCM/EA=1/1) purifies to obtain 55mg target compounds, is off-white powder, yield is 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- bases) -3- (5H- imidazos [5,1-a] iso-indoles -5- bases) -2-
The synthesis step of propyl alcohol is as follows：
Step 1：1- ((1s, 3s, 5R, 7S) -3- chlorine adamantane -1- bases) -3- (5H- imidazos [5,1-a] iso-indoles -5-
Base) -2- acetone preparation
Weigh 1- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- bases) -3- (5H- imidazos [5,1-a] iso-indoles -5-
Base) -2- acetone (181mg, 0.5mmol) is in 50mL single port bottles, and addition 5mL SOCl2 simultaneously stir 2h in 50 DEG C.TLC detections are anti-
It should finish, reaction solution adds 20mL water and with NaOH alkali tunes to pH=10 or so after being spin-dried for.EA (10mLx3) is extracted, and is associated with
Washed after machine phase with saturation NaCl, anhydrous Na 2SO4 is dried, and 180mg is purified to obtain by column chromatography (DCM/EA=5/1) after being spin-dried for
Target compound, is yellow solid, and yield is 95%.
Step 2：1- ((1s, 3s, 5R, 7S) -3- chlorine adamantane -1- bases) -3- (5H- imidazos [5,1-a] iso-indoles -5-
Base) -2- propyl alcohol preparation
Weigh 1- ((1s, 3s, 5R, 7S) -3- chlorine adamantane -1- bases) -3- (5H- imidazos [5,1-a] iso-indoles -5-
Base) -2- acetone (38mg, 0.1mmol) in 50mL single port bottles, adds 5mL MeOH dissolving, add NaBH4 (19mg,
0.5mmol).1h is stirred at room temperature in reactant mixture.After TLC detection reactions are completed, reaction solution pours into 20mL saturated ammonium chloride water
In solution, EA (10mLx3) extractions are washed, anhydrous Na 2SO4 is dried, and passes through post after being spin-dried for after merging organic phase with saturation NaCl
Chromatography (DCM/EA=1/1) purifies to obtain 64mg target compounds, is yellow solid, yield is 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- hydroxyls -3- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-propyl group)-Buddha's warrior attendants
Alkane -1- bases) acetamide synthesis step it is as follows：
Step 1：N- ((1s, 3r, 5R, 7S) -3- (3- (5H- imidazoles [5,1-a] iso-indoles -5- bases) -2- oxopropyls) -
Adamantane-1-yl) acetamide preparation
Weigh 1- ((1s, 3s, 5R, 7S) -3- chlorine adamantane -1- bases) -3- (5H- imidazos [5,1-a] iso-indoles -5-
Base) -2- acetone (65mg, 0.17mmol) is in 50mL single port bottles, and mixture stirs 1h in 140 DEG C after addition 1mL acetamides.
After TLC detection reactions are finished, reaction solution directly purifies to obtain 28mg target compounds by column chromatography (DCM/MeOH=20/1),
For yellow solid, yield is 41%.
Step 2：N- ((1s, 3r, 5R, 7S) -3- (2- hydroxyls -3- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-propyl group) -
Adamantane -1- bases) acetamide preparation
N- ((1s, 3r, 5R, 7S) -3- (3- (5H- imidazoles [5,1-a] iso-indoles -5- bases) -2- oxopropyls)-adamantane -
1- yls) acetamide (28mg, 0.07mmol) in 50mL single port bottles, adds 3mL MeOH dissolving, add NaBH4 (15mg,
0.4mmol).1h is stirred at room temperature in reactant mixture.After TLC detection reactions are completed, reaction solution pours into 10mL saturated ammonium chloride water
In solution, EA (10mLx3) extractions are washed, anhydrous Na 2SO4 is dried, and passes through post after being spin-dried for after merging organic phase with saturation NaCl
Chromatography (DCM/MeOH=10/1) purifies to obtain 15mg target compounds, is yellow solid, yield is 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- hydroxyls -3- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-propyl group)-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- bases) -2- oxopropyls)-Buddha's warrior attendant
The preparation of alkane -1- nitriles
Weigh 1- ((1s, 3s, 5R, 7S) -3- chlorine adamantane -1- bases) -3- (5H- imidazos [5,1-a] iso-indoles -5-
Base) -2- acetone (65mg, 0.17mmol) in 50mL single port bottles, add added after 3mL THF dissolving NaCN (25mg,
0.51mmol).Mixture is stirred overnight in 70 DEG C.After TLC detection reactions are finished, reaction solution is poured into 10mL water, EA
(10mLx3) is extracted, and is washed after merging organic phase with saturation NaCl, and anhydrous Na 2SO4 is dried, and passes through column chromatography (DCM/ after being spin-dried for
EA=5/1 42mg target compounds) are purified to obtain, are white solid, yield is 67%.
Step 2：(1s, 3r, 5R, 7S) -3- (2- hydroxyls -3- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-propyl group)-gold
The preparation of firm alkane -1- nitriles
Weigh (1s, 3r, 5R, 7S) -3- (3- (5H- imidazoles [5,1-a] iso-indoles -5- bases) -2- oxopropyls)-Buddha's warrior attendant
Alkane -1- nitriles (37mg, 0.1mmol) add 3mL MeOH dissolving in 50mL single port bottles, add NaBH4 (15mg,
0.4mmol).1h is stirred at room temperature in reactant mixture.After TLC detection reactions are completed, reaction solution pours into 10mL saturated ammonium chloride water
In solution, EA (10mLx3) extractions are washed, anhydrous Na 2SO4 is dried, and passes through post after being spin-dried for after merging organic phase with saturation NaCl
Chromatography (DCM/MeOH=10/1) purifies to obtain 19mg target compounds, is white solid, yield is 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- imidazos [5,1-a] iso-indoles -5- bases of 6-) -3- ((1s, 3s, 5R, 7S) -3- fluorine adamantane -1-
Base) -2- propyl alcohol synthesis：
According to embodiment 1 (step 1 with step 2), embodiment 2 (step 1, step 2 and step 3) and (step of embodiment 3
1 with step 2) similar process, by 2- ((3r, 5r, 7r)-adamantane -1- bases)-acetic acid and the fluoro- 2- formylphenylboronic acid systems 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- imidazos [5,1-a] iso-indoles -5- bases of 6-) -3- ((1s, 3s, 5R, 7S) -3- fluorine adamantane -1-
Base) -2- propyl alcohol synthesis：
According to embodiment 1 (step 1 with step 2), embodiment 2 (step 1, step 2 and step 3) and (step of embodiment 4
1 with step 2) similar process, by 2- ((3r, 5r, 7r)-adamantane -1- bases)-acetic acid and the fluoro- 2- formylphenylboronic acid systems 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- imidazos [5,1-a] iso-indoles -5- bases of 6-) -1- (1- ((1s, 3s, 5R, 7S) -3- fluorine adamantane -
1- yls)-cyclopropyl)-ethanol synthesis step it is as follows：
Step 1：The preparation of 2- ((3r, 5r, 7r)-adamantane -1- bases)-N- methoxy N-methylacetamides
Weigh 2- ((3r, 5r, 7r)-adamantane -1- bases)-acetic acid (9.7g, 50mmol), dimethyl azanol hydrochloride (5.4
G, 55mmol) and TEA (15.2g, 150mmol) in 250mL single port bottles, add 100mL THF dissolving, add HBTU
(22.8g, 60mmol).4h is stirred at room temperature in reactant mixture.After TLC detection reactions are finished, reaction solution slowly pours into 300mL water
In, there is solid precipitation.Suction filtration, filter cake is dried in vacuo to obtain 9.6g target compounds after being washed with water, be white solid, and yield is
81%.
Step 2：The preparation of 1- ((3r, 5r, 7r)-adamantane -1- bases)-N- methoxy-. N-methyl ring propyl formamides
Weigh 2- ((3r, 5r, 7r)-adamantane -1- bases)-N- methoxy N-methylacetamides (4.74g, 20mmol) in
In 100mL single port bottles, 50mL THF dissolvings are added.LDA (2M in are added dropwise into the system for be cooled to -70 DEG C under nitrogen protection
THF, 30mL, 60mmol).Completion of dropping after -70 DEG C stir 1h, be added dropwise at a temperature of this 1,2- Bromofumes (3.76g,
20mmol).Returned naturally after completion of dropping and warm to room temperature and stir 1h.After TLC detection reactions are finished, reaction solution pours into 200mL
In water, EA (50mLx 3) extractions are washed, anhydrous Na 2SO4 is dried after merging organic phase with saturation NaCl, pass through post layer after being spin-dried for
Analysis (PE/EA=5/1) purifies to obtain 2.7g target compounds, is white solid, yield is 51%.
Step 3：1- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- bases)-N- methoxy-. N-methyl ring propyl formamides
Prepare
Weigh 1- ((3r, 5r, 7r)-adamantane -1- bases)-N- methoxy-. N-methyl ring propyl formamides (2.63g, 10
Mmol) in 100mL single port bottles, the dissolving of 30mL water is added.Then KOH (1.12g, 20mmol) and KMnO4 is sequentially added
(1.58g, 10mmol).Finish rear 40 DEG C of reaction system to be stirred overnight, TLC is detected after completion of the reaction, EA (20mLx3) extractions,
Merge and saturated common salt water washing is used after organic phase, anhydrous Na 2SO4 is dried, and is purified after being spin-dried for by column chromatography (DCM/EA=4/1)
1.04g target compounds are obtained, are yellow solid, yield is 37%.
Step 4：The preparation of 1- (1- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- bases)-cyclopropyl)-ethyl ketone
Weigh 1- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- bases)-N- methoxy-. N-methyl rings propyl formamide (1g,
3.58mmol) in 50mL single port bottles, 20mL THF dissolvings are added.Under nitrogen protection, to be cooled in 0 DEG C of system be added dropwise
The THF solution (2M, 4.5mL, 9.00mmol) of methyl-magnesium-bromide.4h, TLC detections is stirred at room temperature in reaction system after completion of dropping
Reaction is finished.Reaction solution is poured into 50mL saturated aqueous ammonium chlorides, EA (30mLx3) extractions use saturation after merging organic phase
Brine It, anhydrous Na 2SO4 is dried, and 460mg target chemical combination is obtained by column chromatography (PE/EA=2/1) purifying after being spin-dried for
Thing, is colorless oil, and yield is 55%.
Step 5：2- (fluoro- 5H- imidazos [5,1-a] iso-indoles -5- bases of 6-) -1- (1- ((1s, 3s, 5R, 7S) -3- hydroxyls
Adamantane -1- bases)-cyclopropyl)-ethyl ketone preparation
Weigh 1- (1- ((1r, 3s, 5R, 7S) -3- hydroxyadamantane -1- bases)-cyclopropyl)-ethyl ketone (234mg, 1.0
Mmol) and the fluoro- 6- of 2- (1H- imidazoles -5- bases)-benzaldehyde (190mg, 1.0mmol) is in 50mL single port bottles, 5mL ethanol is added
And the dissolving of 1mL water, add NaOH (100mg, 2.5mmol).Reactant mixture stirs 2h in 80 DEG C.TLC detection reactions are finished
After, reaction solution is poured into 20mL water, EA (10mLx3) extractions, is washed after merging organic phase with saturation NaCl, anhydrous Na 2SO4
Dry, 220mg target compounds are purified to obtain by column chromatography (DCM/EA=1/1) after being spin-dried for, are white solid, yield is
54%.
Step 6：2- (fluoro- 5H- imidazos [5,1-a] iso-indoles -5- bases of 6-) -1- (1- ((1s, 3s, 5R, 7S) -3- fluorine gold
Firm alkane -1- bases)-cyclopropyl)-ethyl ketone preparation
Weigh 2- (fluoro- 5H- imidazos [5,1-a] iso-indoles -5- bases of 6-) -1- (1- ((1s, 3s, 5R, 7S) -3- hydroxyls gold
Firm alkane -1- bases)-cyclopropyl)-ethyl ketone (203mg, 0.5mmol) is in 50mL single port bottles, and addition 5mL DCM dissolvings, nitrogen is protected
DAST (97mg, 0.6mmol) is added under shield.Reactant mixture stirs 2h in 0 DEG C.After TLC detection reactions are finished, reaction
Liquid is poured into 20mL water, DCM (10mLx3) extractions, is washed after merging organic phase with saturation NaCl, anhydrous Na 2SO4 is dried, and is spin-dried for
185mg target compounds are purified to obtain by post layer (DCM/EA=5/1) afterwards, are white solid, yield is 91%.
Step 7：2- (fluoro- 5H- imidazos [5,1-a] iso-indoles -5- bases of 6-) -1- (1- ((1s, 3s, 5R, 7S) -3- fluorine gold
Firm alkane -1- bases)-cyclopropyl)-ethanol preparation
Weigh 2- (fluoro- 5H- imidazos [5,1-a] iso-indoles -5- bases of 6-) -1- (1- ((1s, 3s, 5R, 7S) -3- fluorine Buddha's warrior attendants
Alkane -1- bases)-cyclopropyl)-ethyl ketone (102mg, 0.25mmol) is in 20mL single port bottles, and addition 5mL MeOH dissolvings are added
NaBH4 (38mg, 1.0mmol).1h is stirred at room temperature in reactant mixture.After TLC detection reactions are finished, reaction solution pours into 20mL and satisfied
In aqueous ammonium chloride solution, EA (10mLx3) extractions are washed, anhydrous Na 2SO4 is dried, rotation after merging organic phase with saturation NaCl
85mg target compounds are purified to obtain by column chromatography (DCM/EA=1/1) after dry, are white solid, yield is 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- bases)-cyclopropyl) -2- (fluoro- 5H- imidazos [5,1-a] of 6-
Iso-indoles -5- bases)-ethanol synthesis：
According to the process similar with embodiment 4 (step 1 and step 2), by 2- (the different Yin of the fluoro- 5H- imidazos [5,1-a] of 6-
Diindyl -5- bases) -1- (1- ((1s, 3s, 5R, 7S) -3- hydroxyadamantane -1- bases)-cyclopropyl)-ethanol (embodiment 9, produce by step 5
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- imidazos [5,1-a] iso-indoles -5- bases of 6-) -8- ((1s, 3s, 5R, 7S) -3- fluorine adamantane -1-
Base) -3- methyl -2- butanol synthesis step it is as follows：
Step 1：The preparation of 2- ((3r, 5r, 7r)-adamantane -1- bases)-N- methoxyl groups-N, 2- dimethylpropionamide
Weigh 2- ((3r, 5r, 7r)-adamantane -1- bases)-N- methoxy N-methylacetamides (2.37g, 10mmol) in
In 50mL single port bottles, 30mL THF dissolvings are added.LDA (2M in are added dropwise into the system for be cooled to -70 DEG C under nitrogen protection
THF, 15mL, 30mmol).Completion of dropping stirs 1h after -70 DEG C, and MeI (2.84g, 20mmol) is added dropwise at a temperature of this.Drop
Add to return naturally after finishing and warm to room temperature and stir 1h.After TLC detection reactions are finished, reaction solution is poured into 100mL water, EA
(50mLx3) is extracted, and is washed after merging organic phase with saturation NaCl, and anhydrous Na 2SO4 is dried, and passes through column chromatography (PE/EA after being spin-dried for
=1.8g target compounds 5/1) are purified to obtain, it is white solid, yield is 68%.
Step 2：1- (fluoro- 5H- imidazos [5,1-a] iso-indoles -5- bases of 6-) -8- ((1s, 3s, 5R, 7S) -3- fluorine Buddha's warrior attendants
Alkane -1- bases) -3- methyl -2- butanol preparation
According to the process similar with embodiment 9 (step 3 to step 7), by 2- ((3r, 5r, 7r)-adamantane -1- bases) -
N- methoxyl groups-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
The test of pesticide effectiveness
Experiment 1：External IDO suppresses Kinase activity assays
1：Test material：
Human IDO1 (ChemPartner products, lot number 20160706)；
L-tryptophan (Sigma products, article No. 93659-10G, lot number 1400132V)；
Ascorbate (Sigma products, article No. 11140-250G, lot number BCBM0369V)；
Methylenum careuleum (Sigma products, article No. M9140-100G, lot number 056K0739V)；
Catalase (Sigma products, article No. C9322-1G, lot number 010M1010)；
DMSO (Sigma products, article No. D2650, lot number WXBC3124V)；
96- orifice plates (Corning products, article No. 3635, lot number 12016021)；
Positive compound：NLG-919 (Selleckchem products, article No. S7111, lot number 01)；
Detecting instrument：SpectraMax
2：Test principle：
It is N- formoxyl kynurenins by tryptophan substrate oxidation to measure employment restructuring IDO1 enzymes, and UV absorption signal exists
321nM wavelength absorptions are associated in the amount of IDO1 oxidation product N- formoxyl kynurenins.
3：Test method：
(1) testing sample is configured：100 times i.e. 100umol/L of reaction final concentration is diluted to 100%DMSO；
(2) positive compound is configured：100 times i.e. 1000umol/L of reaction final concentration is diluted to 100%DMSO；
(3) dilute：Testing sample is using 100umol/L as initial concentration, with 4 times of concentration dilutions, dilutes 7 concentration gradients；
Positive control is using 1000umol/L as initial concentration, with 4 times of concentration dilutions, dilutes 10 concentration gradients；
(4) positive compound of each testing sample of prepare 7 concentration and 10 concentration is separately added into 96 orifice plates
In, it is separately added into 100%DMSO in positive control and negative control hole；
(5) 2 times of enzyme solutions are prepared：IDO1 enzymes are added into 1 times of reaction buffer, 2 times of enzyme solutions are formed；Wherein reaction is buffered
Liquid is the phosphate buffer (pH 6.5) of improvement；
(6) enzyme solutions are added into 96 orifice plates：The testing sample of existing 2 μ l 100%DMSO dissolvings in 96 hole reaction plates
And positive compound, then add 100 μ l 2 times of enzyme solutions；Also 100 μ l 2 times of enzyme solutions are added in Positive control wells, it is cloudy
100 μ l reaction buffer is added in property control wells；It is incubated 15 minutes at room temperature；
(7) substrate solution of 2 times of preparation：L-tryptophan, ascorbate, methylenum careuleum, catalase etc. are 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-
Should；
(9) OD321 is read in real time with SpectraMax at room temperature.
(10) inhibiting rate calculates the replicate data from SpectraMax.Data are changed into inhibiting rate data, wherein max is
Refer to the data of DMSO controls, 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
Experiment 2：The pharmacokinetics test of the compounds of this invention
SD rats, male (being purchased from the western pul-Bi Kai experimental animals Co., Ltd in Shanghai).Each test-compound is with oral
The administering mode single of (10mg/kg, every group 3) gives SD rats and carries out pharmacokinetic, and test-compound is used
DMSO/9% sodium chloride injection=5/95 (V/V) dissolving, and through vortex 1min, administration is configured to after ultrasonic 1min molten
Liquid.Animal needs fasting 12 hours before being administered orally, and recovers after being administered 2 hours to food.SD rat orals take and intravenously administrable
Afterwards, through jugular vein or cardiac puncture collection pharmacokinetics sample, acquisition time is：Before administration, administration after 0.25h, 0.5h,
1h, 2h, 3h, 4h, 6h, 8h and 24h, each time point gather 3 whole blood samples through rat eye rear vein beard, and collection capacity is about
0.3mL, and handled through liquaemin anti-freezing.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 before the plasma analysis of collection.Take 50 μ L plasma samples
Into 1.5mL centrifuge tubes, 250 μ L inner mark solutions (blank is not added with the methanol that internal standard adds same volume) are added, is vortexed and mixes,
15000 revs/min centrifuge 5 minutes, take 200 μ L of supernatant liquid to be added to 96 holes and enter in model, are analyzed through LC-MS/MS sample introductions.
The embodiment of the present invention 9, the pharmacokinetics of the prepare compound of embodiment 10 (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 |
Can be seen that the compounds of this invention from the studies above data has obvious inhibitory action to IDO activity, with having located
The NLG-919 studied in clinical stage is compared, and also has obvious advantage in terms of drug effect, medicine are for power, can be used as IDO suppression
Agent, with wide anti-malignant tumor disease, autoimmune conditions, viral infection, depression, AIDS, myelosis
The application prospects such as abnormal syndrome, anxiety disorder, cataract.
Embodiments of the invention are the foregoing is only, are not intended to limit the scope of the invention, it is every to utilize this hair
Bright principle and description, improvements introduced, modification, equivalent structure or equivalent flow conversion, or be directly or indirectly used in
Other related technical fields, are included within the scope of the present invention.
Claims (10)
1. a kind of compound or its stereoisomer, solvate, hydrate, pharmaceutically acceptable salt, eutectic, its feature exist
In, the compound has formula (I) structure,
Wherein, n is 0-4 integer；
Wherein R1From following substituent：Hydrogen, halogen, hydroxyl, cyano group, nitro, amino, substituted or unsubstituted C1-C6Alkyl, take
Generation or unsubstituted C1-C6Miscellaneous alkyl, substituted or unsubstituted C3-C6Cycloalkyl, substituted or unsubstituted C3-C6Heterocyclylalkyl,
Substituted or unsubstituted C5-C6Aryl, substituted or unsubstituted C5-C6Heteroaryl；The substituent of above-mentioned group is selected from：Nitro, hydroxyl
Base, amino, sulfydryl, halogeno-group, cyano group, substituted or non-substituted C1-C10Alkyl, substituted or non-substituted C1-C10Miscellaneous alkyl, substitution or
Unsubstituted C3-C10Cycloalkyl, substitution or unsubstituted C3-C10Heterocyclylalkyl；
R2Selected from following substituent：Hydrogen, halogen, cyano group, nitro, aryl, heteroaryl, OR3、N(R3)2、NCOR3；
R3Selected from following substituent：Substituted or non-substituted C1-C10Alkyl, substituted or non-substituted C1-C10Miscellaneous alkyl, replaces or does not take
For C3-C10Cycloalkyl, substitution or unsubstituted C3-C10Heterocyclylalkyl, substituted or unsubstituted C5-C6It is aryl, substituted or unsubstituted
C5-C6Heteroaryl；
R4、R5Selected from following substituent：Hydrogen, halogen, hydroxyl, cyano group, nitro, amino, substituted or unsubstituted C1-C6Alkyl, take
Generation or unsubstituted C1-C6Miscellaneous alkyl, substituted or unsubstituted C3-C6Cycloalkyl, substituted or unsubstituted C3-C6Heterocyclylalkyl；
R4、R5Following group is collectively constituted with the carbon atom being connected：Substituted or unsubstituted C3-C8Alkyl, substituted or unsubstituted
C3-C8Miscellaneous alkyl；The substituent of above-mentioned group is selected from nitro, hydroxyl, amino, sulfydryl, halogeno-group, cyano group, substituted or non-substituted
C1-C10Alkyl, substituted or non-substituted C1-C10Miscellaneous alkyl, substitution or unsubstituted C3-C10Cycloalkyl, substitution or unsubstituted C3-C10It is miscellaneous
Cycloalkyl.
2. a kind of compound according to claim 1, it is characterised in that the compound has the structure of formula (II)
Wherein, R1Selected from following group：Hydrogen, halogen；
R2Selected from group：Hydrogen, halogeno-group, cyano group, amino, hydroxyl, aryl, heteroaryl, OR3、N(R3)2、NCOR3；
R3Selected from substituted or non-substituted C1-C6Alkyl or miscellaneous alkyl；
R4、R5Selected from hydrogen, substituted or non-substituted C1-C6Alkyl or collectively constitute substitution with the carbon atom being connected or non-take
For C3-C6Cycloalkyl；
Above-mentioned R1-R5The substituent of substituted radical is selected from group：Nitro, hydroxyl, amino, sulfydryl, halogeno-group, cyano group, substitution or non-
Replace C1-C10Alkyl, substituted or non-substituted C1-C10Miscellaneous alkyl, substitution or unsubstituted C3-C10Cycloalkyl, substitution or unsubstituted C3-
C10Heterocyclylalkyl.
3. compound according to claim 2, it is characterised in that：R1Selected from group：Hydrogen, halogen；R2Selected from group：Halogen,
Hydroxyl, cyano group, NCOR3；R3Selected from substituted or non-substituted C1-C3Alkyl；
R4、R5For hydrogen, substituted or non-substituted C1-C6Alkyl or with the carbon atom being connected collectively constitute substitution or
Non-substituted C3-C6Cycloalkyl.
4. compound according to claim 3, it is characterised in that：R1、R2It is independently selected from fluorine or chlorine.
5. compound according to claim 4, it is characterised in that：R1Selected from fluorine, R2It is independently selected from fluorine or chlorine.
6. the compound according to claim 3-5 any one, it is characterised in that：R4、R5It is common with the carbon atom being connected
The substituted or non-substituted cyclopropyl of composition.
7. compound according to claim 3, it is characterised in that：The substituent of substituted radical is selected from：Hydroxyl, amino, sulfydryl,
C1-C6 alkyl.
8. a kind of Pharmaceutical composition, it is characterised in that the Pharmaceutical composition active ingredient will selected from any rights of claim 1-6
Ask described compound or one kind in its stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or eutectic or
Two or more combinations.
9. compound described in claim 1-7 any one or its stereoisomer, solvate, hydrate, it can pharmaceutically connect
Purposes of the salt or eutectic received in indole amine 2,3-dioxygenase (IDO) inhibitor is prepared.
10. purposes according to claim 9, it is characterised in that the inhibitor is used to treat at least one as described below
Disease：Cancer, autoimmune conditions, viral infection, depression, AIDS, RAEB, anxiety disorder,
Cataract；Further, described cancer is selected from breast cancer, cervical carcinoma, colon cancer, liver cancer, stomach cancer, the carcinoma of the rectum, oophoroma, pancreas
Gland cancer, carcinoma of urinary bladder, solid tumor, myeloma, non-small cell lung cancer, leukaemia, lymthoma, melanoma, osteocarcinoma, kidney.
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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 |
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