CN107501272A - Imidazo isoindoles IDO1 inhibitor, its preparation method and application - Google Patents
Imidazo isoindoles IDO1 inhibitor, its preparation method and application Download PDFInfo
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- CN107501272A CN107501272A CN201710798280.9A CN201710798280A CN107501272A CN 107501272 A CN107501272 A CN 107501272A CN 201710798280 A CN201710798280 A CN 201710798280A CN 107501272 A CN107501272 A CN 107501272A
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- imidazoles
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
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- 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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to drug field, more particularly to a kind of imidazo isoindoles compound, its stereoisomer or its pharmaceutically acceptable salt with formula (I) architectural feature, its preparation method and they as indoleamine 2, the purposes of 3 dioxygenase 1 (IDO1) inhibitor.Test result indicates that, the compound of the present invention has to IDO1 activity significantly inhibits effect, T cell propagation can be effectively facilitated, suppress T cells and be divided into regulatory T cells, reverse the immunosupress of IDO1 mediations, it can be used for the relevant disease of the pathological characteristicses of kynurenine metabolism pathway of the treatment with IDO1 mediations, including cancer, viral infection, neurodegenerative disease, cataract, organ-graft refection, depression and autoimmune disease etc..
Description
Technical field
The invention belongs to drug field, and in particular to a kind of imidazo isoindoles compound, its stereoisomer or its
Pharmaceutically acceptable salt, its preparation method and their use as IDO 1 (IDO1) inhibitor
On the way.
Technical background
Tryptophan is that human body cell maintains amino acid necessary to propagation and survival, available for protein, nicotinic acid and 5- hydroxyls
The biosynthesis of tryptamines.Tryptophan typically absorbs from food, is metabolized more than 95% tryptophan along kynurenine approach, remaining color
Propylhomoserin converts 5-hydroxyryptophan and serotonin in nervous system and enteron aisle, or epiphysin is synthesized in pineal body.Indoles amine
2,3- dioxygenases 1 (indoleamine 2,3-dioxygenase, IDO1) are that tryptophan is catalyzed outside human liver along dog urinary ammonia
The rate-limiting enzyme of sour approach metabolism.(such as macrophage is thin in Various Tissues (such as lung, kidney, brain, placenta, thymus gland) and various kinds of cell by IDO1
Born of the same parents and BMDC) in express.IDO1 reduces the concentration of tryptophan in body microenvironment by oxicracking tryptophan, and
Produce a series of metabolites such as kynurenin, 3-hydroxykynurenine, 2- amino-3-hydroxies formic acid, quinolinic acid.Cell because
Son such as IFN-γ, TNF-α, IL-1 β and IL-6 can induce IDO1 up-regulated expressions (Bernhardt R.Chem Rev, 1996,96
(1)：2841-2888).
Substantial amounts of evidence shows that IDO1 can not only be catalyzed tryptophan oxidative metabolism, but also to the inherent immunity of body
There are important adjustment effect (Munn DH, et al.Trends Immunol, 2013,34 (3) with adaptive immunity：137-
143).IDO1 mainly causes tryptophan depletion and its metabolite to be built up to realize it to immune by being catalyzed tryptophan metabolism
The regulating and controlling effect of system：On the one hand, tryptophan depletion can be stranded in G1 by activating GCN2 path inducing T cell division cycles
Phase, so as to suppress the propagation of T cell, while also suppress initial CD4+T cell is divided into helper T lymphocyte 17 (Th17), and then
Produce immunosupress (Munn DH, et al.Immunity, 2005,22 (5)：633-642).On the other hand, the color such as kynurenin
Propylhomoserin metabolite has cytotoxicity, can kill T cell and NKT (NK) cell (Frumento G, et al.J
Exp Med, 2002,196 (4)：459-468；Munn DH, et al.J Clin Invest, 2004,114 (2)：280-290),
And these metabolites can also induce CD4 by activating aryl hydrocarbon receptor (AHR)+T cell is divided into regulatory T
(Treg) cell, and promote BMDC (DC) change into tolerogenesis DC (Mezrich JD, et al.J Immunol,
2010,185 (6)：3190-3198；Mezrich JD, et al.J Immunol, 2008,181 (8)：5396-5404)；In addition,
Tryptophan metabolite can suppress the function of NK cells by lowering the expression of NK cell receptors, and these can further press down
Immune response (Della Chiesa M, et al.Blood, 2006,108 (13) of body processed：4118-4125).
IDO1 is relevant with many pathological processes.Research shows that IDO1 is in host immune defenses and Maternal-placental immune toler ance
Etc. playing important immunoregulation effect in physiology course.In normal state, IDO1 expressions are relatively low for body, but in placenta
Development and the physiological such as inflammatory reaction stress in, cell factor such as IFN-γ secretion dramatically increases, so as to induce in IDO1 expression
Adjust, cause the metabolites such as tryptophan depletion and kynurenin to be built up, so as to suppress the t cell responses of parent, induce female tire to exempt from
Epidemic disease is resistant to, it is ensured that fetus is not repelled by the immune system of parent；Tryptophan depletion in host's microenvironment prevents it from for cause of disease
Microorganism replicates tryptophan necessary to offer, so as to cause pathogenic microorganism dead；At the same time the immune suppression of IDO1 mediations
System can avoid excessive activation (Mellor AL, et al.Nat Rev Immunol, 2008,8 (1) of body immune system：
74-80；Terness P, et al.Am J Reprod Immunol, 2007,58 (3)：238-254；Divanovic S, et
Al.J Infect Dis, 2012,205 (1)：152-161).After IDO1 inhibitor is applied to pregnant mouse, T cell can be caused
Embryo's rejection of mediation, causes mouse to be miscarried, and shows that IDO1 can make fetus from repulsion (the Munn DH, et of parent
Al.Science, 1998,281 (5380)：1191-1193).The survival that IDO1 is organized in new host to transplanting also plays immune
Inhibitory action (Radu CA, et al.Plast Reconstr Surg, 2007,119 (7)：2023-2028).These research knots
Fruit illustrates that IDO is a kind of immunological regulation enzyme, participates in the immune tolerance of body.
Numerous researchs show, the immune tolerances of IDO1 mediations and tumor immune escape, viral infection, neurodegenerative disease,
Closely related (the Munn DH, et of the diseases such as organ-graft refection, autoimmune disease, neuropsychiatric disease and cataract
Al.Trends Immunol, 2013,34 (3)：137-143；Nguyen NT, et al.Front Immunol, 2014,5：
551；Myint AM, et al.J Affect Disord, 2007,98 (1-2)：143-151；Mailankot M, et al.Lab
Invest, 2009,89 (5)：498-512).In these diseases, tryptophan depletion that the IDO1 of overexpression is mediated and its
The accumulation of metabolite can suppress the activation of T cell, cause the immune tolerance of body.
In the mouse model of virus infection, CD8 can be obviously promoted by giving IDO1 inhibitor+The propagation of T cell, recover T
The immune response of cell, suppress the mononuclear macrophage of viral infection host.In influenza infection, the IDO1 of overexpression
The immunosuppressive action of mediation is easily caused lung and superinfection (van der Sluijs KF, et al.J Infect occurs
Dis, 2006,193 (2)：214-222).In HIV, IDO1 can promote the propagation of Treg cells by up-regulated expression, and press down
The propagation of Th17 cells processed, cause Tregs/Th17 cell proportions to lack of proper care, cause immunosupress (the Favre D, et of patient
Al.Sci Transl Med, 2010,2 (32)：32ra36).In addition, the tryptophan depletion and its metabolite of IDO1 mediations are dense
Degree raises (Knubel CP, et al.FASEB J, 2010,24 (8) also relevant with parasitic infection：2689-2701).
Research shows that tryptophan metabolite such as kynurenin and quinolinic acid of IDO1 catalysis etc. have neurotoxicity, and
And these metabolites and neurodegenerative disease such as memory disorder, Alzheimer disease (AD), cognitive disorder disease, senile dementia
Disease, Parkinson's, parkinsonism and closely related (the Malpass K.Nat Rev of generation of dyskinetic disorder
Neurol, 2011,7 (8)：417；Maddison DC, et al.Semin Cell Dev Biol, 2015,40：134-141).
In AD brain in patients IDO1 expression and quinoline acid concentration is above normal person, wherein the microglia around senile plaque expelling and
Content highest in astrocyte.In addition, the Tryptophan concentration in AD blood samples of patients is less than normal person, and kynurenin concentration is then
Higher than normal person, and both ratio height and the understanding defect level of patient closely related (Guillemin GJ, et
Al.Neuropathol Appl Neurobiol, 2005,31 (4)：395-404；Widner B, et al.Adv Exp Med
Biol, 1999,467：133-138).Neuropsychiatric disease such as depression, schizophrenia, anxiety disorder also over-express with IDO1
It is relevant with the horizontal rise of the metabolite such as kynurenin.IDO1 overexpression causes tryptophan depletion, is used to close so as to reduce
Into the amount of the tryptophan of neurotransmitter serotonin, serotonin is caused to lack, along with the kynurenin with neurotoxicity
With the accumulation of the metabolite such as quinolinic acid, the generation of neuropsychiatric disease is collectively promoted, and be the factor of a variety of mood disorders
(Myint AM.FEBS J, 2012,279 (8)：1375-1385).Therefore, it is neurodegenerative disease and psychoneural to suppress IDO1
The critical treatment strategy of Disease.
The mediated tryptophan excessing metabolism of the high expression of IDO1 exists in (Nguyen in various autoimmune diseases
NT, et al.Front Immunol, 2014,5：551).In the high expression of the DCs of rheumatoid arthritis patients synovial joint tissue
IDO1, Tryptophan concentration reduces in patients serum, and the rise of kynurenin concentration (Zhu L, et al.J Immunol, 2006,
177(11)：8226-8233；Ozkan Y.et al.Clin Rheumatol, 2012,31 (1)：29-34).In systemic erythema
There is also the phenomenon of IDO1 overexpressions and tryptophan metabolism enhancing in lupus patient.Tryptophan concentration drop in patients serum
It is low, metabolite kynurenine concentration and kynurenin and tryptophan ratio significantly raised (Widner B, et
Al.Immunobiology, 2000,201 (5)：621-630).Therefore, it is also that autoimmune disease patient is important to suppress IDO1
Therapeutic strategy.
Substantial amounts of research shows that the immunosupress of IDO1 inductions plays an important role in tumor immune escape.IDO1 mistakes
Degree is expressed in cell such as DC and stroma cell in all kinds of tumour cells and its microenvironment, cause tumor by local tryptophan depletion and
Tryptophan metabolite is built up, and so as to induced tumor immunologic escape, helps tumour cell to escape the attack of body immune system
(Munn DH, et al.Trends Immunol, 2016,37 (3)：193-207).Uyttenhove groups utilize immuning tissue
Chemical marker method melanoma, lung cancer, breast cancer, stomach cancer, colon cancer, carcinoma of urinary bladder, cancer of pancreas, lymph cancer, prostate cancer,
24 kinds of kidney, the cancer of the brain, head and neck cancer, oophoroma, cervical carcinoma, carcinoma of endometrium, celiothelioma, thyroid cancer, the cancer of the esophagus and liver cancer etc.
IDO1 expression (Uyttenhove C, et al.Nat Med, 2003,9 (10) are detected in human tumor cell：1269-
1274).Then further it is confirmed in the tumor tissues such as oophoroma, melanoma, lung cancer, leukaemia, and it was found that swollen
IDO1 expression quantity and the grade malignancy of tumour are in close relations in tumor tissue, and influence tumor patient prognosis (Th é ate I,
Et al.Cancer Immunol Res, 2015,3 (2)：161-172；Curti A, et al.Blood, 2007,109 (7)：
2871-2877；De Jong RA, et al.Int J Gynecol Cancer, 2011,21 (7)：1320-1327；Okamoto
A, et al.Clin Cancer Res, 2005,11 (16)：6030-6039；Ino K, et al.Br J Cancer, 2006,95
(11)：1555-1561；Speeckaert R, et al.Eur.J.Cancer, 2012,48 (13)：2004-2011).IDO1 presses down
Preparation can activate T cell, overcome the tumor immune escape mediated by IDO1, but also can improve other tumor therapeutic agents
Therapy (Koblish HK, et al.Mol Cancer Ther, 2010,9 (2)：489-498；Wainwright DA, et
Al.Clin Cancer Res, 2014,20 (20)：5290-5301).
Multinomial preclinical and clinical research shows that IDO1 inhibitor can reduce the metabolism such as tryptophan metabolism and kynurenin
The accumulation of product, so as to reverse the immunosupress that IDO1 is mediated, recover T cell and the propagation and function of NK cells, suppress Treg
The propagation of cell, so as to strengthen the immune response of body, therefore IDO1 inhibitor can be used for the immune suppression that treatment is mediated by IDO1
The caused above-mentioned relevant disease of system, including cancer, viral infection, neurodegenerative disease, cataract, organ-graft refection, suppression
Strongly fragrant disease and autoimmune disease.In addition, IDO1 inhibitor can also be with other chemotherapeutics, anti-tumor drugs targeting, immune inspection
Make an inventory of therapeutic agent, anti-tumor vaccine, antivirotic, antiviral vaccine, cytokine therapy, adoptive cellular immunotherapy and put
Penetrate treatment synergy, play a part of cooperate with or strengthen therapy (Vacchelli E, et al.Oncoimmunology,
2014,3 (10)：e957994；Jochems C, et al.Oncotarget, 2016,7 (25)：37762-37772；Liu X, et
Al.Blood, 2010,115 (17)：3520-3530；Zamarin D, et al.Pharmacol Ther, 2015,150：23-
32)。
IDO1 micromolecular inhibitors are currently being deployed to be used for treating or preventing the above-mentioned disease related to IDO1.For example,
Bao oxadiazole class IDO1 inhibitor in CN102164902B, be related to by apply IDO1 inhibitor or with other therapeutic agents
Be used in combination come treating cancer, viral infection, neurodegenerative disease, wound, the cataract of age correlation, organ-graft refection or
Autoimmune disease patient.
Based on IDO1 and cancer, viral infection, neurodegenerative disease, cataract, organ-graft refection, LADA disease
Disease is closely related with the pathogenesis of a variety of diseases such as depression, therefore can suppress IDO1 work using IDO1 inhibitor
Property, so as to reduce the accumulation of the metabolites such as tryptophan metabolism and kynurenin, recover the immunologic function of body, and then
Treat the purpose of above-mentioned disease.Compound of the present invention has IDO1 inhibitory activity, can be used for treating IDO1 mediations
Relevant disease caused by immunosupress, including cancer, viral infection, neurodegenerative disease, cataract, organ-graft refection,
Autoimmune disease and depression.
The content of the invention
The technical problems to be solved by the invention are the provision of a kind of imidazo isoindoles compound, its alloisomerism
Body or its pharmaceutically acceptable salt, its preparation method, pharmaceutical composition and application.The compound of the present invention has good
IDO1 inhibitory activity, it can be used for treating and/or prevent the various relevant diseases caused by the immunosupress of IDO1 mediations.
The invention provides the imidazo isoindoles compound shown in logical formula (I), its stereoisomer or its pharmaceutically
Acceptable salt：
Wherein：
R1Representative represents hydrogen, NR3R4、C1-C8Alkyl, C3-C8Cycloalkyl, C5-C10Aryl or C1-C10Aromatic heterocyclic, wherein
Described heteroaromatic group is optionally comprising one or more other hetero atoms for being selected from O, S or N；Described alkyl, cycloalkanes
Base, aryl or aromatic heterocyclic are optionally monosubstituted to five substitutions, described substitution by substituent that is following identical or differing
Base is selected from：Halogen, trifluoromethyl, cyano group, nitro, hydroxyl or amino；
R2Represent O, S or NR5；
R3Represent hydrogen, C1-C8Alkyl or C3-C6Cycloalkyl；
R4Represent hydrogen, C1-C8Alkyl, C3-C6Cycloalkyl, C5-C10Aryl, C5-C10Aryl-(C1-C10Alkyl), C1-C10Virtue
Heterocyclic radical, C1-C10Heteroaromatic-(C1-C10Alkyl), C1-C12Condensed hetero ring base or C1-C12Condensed hetero ring-(C1-C10Alkyl), wherein institute
The heterocyclic group stated is optionally comprising one or more other hetero atoms for being selected from O, S or N；Wherein described alkyl, cycloalkanes
Base, aryl, heteroaromatic, condensed hetero ring are optionally monosubstituted to five substitutions by substituent that is following identical or differing, described
Substituent is selected from：C1-C5Alkyl, halogen, trifluoromethyl, carboxyl, cyano group, nitro, hydroxyl, amino or methoxyl group；
R5Represent hydrogen, hydroxyl or sulfydryl.
Further, have imidazo isoindoles compound shown in logical formula (I), its stereoisomer or its pharmaceutically
Acceptable salt, it is characterised in that：
R1Represent hydrogen, NR3R4、C3-C6Cycloalkyl, C5-C10Aryl or C1-C10Aromatic heterocyclic, wherein described aromatic heterocyclic
Group is optionally comprising one or more other hetero atoms for being selected from O, S or N；Wherein described cycloalkyl, aryl or heteroaromatic
Base is optionally monosubstituted to five substitutions by substituent that is following identical or differing, and described substituent is selected from：Halogen, cyanogen
Base, nitro, hydroxyl or amino；
R2Represent O or NR5；
R3Represent hydrogen or C1-C8Alkyl；
R4Represent C3-C6Cycloalkyl, C5-C10Aryl, C5-C10Aryl-(C1-C10Alkyl), C1-C10Aromatic heterocyclic, C1-C10
Heteroaromatic-(C1-C10Alkyl), C1-C12Condensed hetero ring base or C1-C12Condensed hetero ring-(C1-C10Alkyl), wherein described heterocycle can appoint
Selection of land includes one or more other hetero atoms for being selected from O, S or N；Wherein described cycloalkyl, aryl, heteroaromatic, condensed hetero ring
Optionally monosubstituted to five substitutions by substituent that is following identical or differing, described substituent is selected from：C1-C5Alkyl, halogen
Element, carboxyl, cyano group, nitro, hydroxyl, amino or methoxyl group；
R5Represent hydroxyl or sulfydryl.
Further, have imidazo isoindoles compound shown in logical formula (I), its stereoisomer or its pharmaceutically
Acceptable salt, it is characterised in that：
R1Representative represents NR3R4, cycloalkyl or rubigan；
R2Represent O or NR5；
R3Represent hydrogen or methyl；
R4Represent the chloro- 4- luorobenzyls of benzyl, 4- cyanobenzyls, 3,4- difluorobenzyls, 3- chlorobenzyls, 3-, 4- methoxybenzyls
Base, 4- hydroxybenzyls, α-methylbenzyl, 3,4- methylenedioxy benzyls, to carboxybenzyl, pyridine -3- methylene, to diaza
Benzene -2- methylene, phenyl, 1H- indazole -6- bases, 3,4- methylenedioxybenzenes, cyclohexyl, 3- methoxyphenethyls, phenethyl or
Pyridine -2- ethyls；
R5Represent hydroxyl.
Specifically, lead to the imidazo isoindoles compound shown in formula (I) and preferably be selected from following compounds：
N- benzyls -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide；
N- (4- cyanobenzyls) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide；
N- (3,4- difluorobenzylamine base -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamides；
N- (3- chlorobenzyls) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide；
N- (the chloro- 4- luorobenzyls of 3-) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide；
N- (4- methoxy-benzyls) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide；
N- (4- methoxy-benzyls) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide；
N- benzyls -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- methylacetamides；
2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- (1- phenylethyls) acetamide；
N- (benzo [d] [1,3] dioxy -5- methylene) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide；
N- (4- carboxybenzyls) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide；
2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- (pyridine -3- methylene) acetamide；
2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- (pyrazine -2- methylene) acetamide；
2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-phenyl acetanilide,Phenacetylaniline；
2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- (1H- indazole -6- bases) acetamide；
N- (benzo [d] [1,3] dioxy -5- bases) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide；
N- cyclohexyl -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide；
2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- (3- methoxyphenethyls) acetamide；
2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- phenethyl-acetamides；
2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- (2- (pyridine -2- bases) ethyl) acetamide；
(Z) -1- cyclohexyl -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetophenone oxime；
(Z) -1- (4- chlorphenyls) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetophenone oxime；
The compound numbers being related to below in pharmacological evaluation are equal to the compound corresponding to code name herein.
Another object of the present invention is to provide the preparation method of compound shown in logical formula (I), it is characterised in that：
A) R is worked as2For O when, the preparation method of compound is shown in logical formula (I)：Using 1H- imidazoles as raw material, through iodide reaction
1, the 1 ethanol solution backflow through sodium sulfite is made and sloughs introducing Trt protection groups on 1 N atom of 5 iodine atoms obtained 2,2
It is made 3,3 and is made 4 by Suzuki coupling reactions with adjacent formylphenylboronic acid, triphenylphosphine and the reaction of 2- bromoacetates is made
Witting reagents 5 are obtained, intermediate 4 and 5 is made 7,7 through cyclization through Witting reactions obtained 6,6 and is made through sodium hydroxide hydrolysis
8,8 and aminated compounds (NHR3R4) the obtained compound L A01-LA20 of reaction；Its synthetic route is as follows：
Wherein, R3And R4It is defined as described above；
B) R is worked as2For N-OH when, the preparation method of compound is shown in logical formula (I)：Intermediate 4 respectively with methylcyclohexyl
9a-b is made in ketone and the reaction of methyl rubigan ketone, and 10a-b, 10a-b and hydroxylamine hydrochloride is made by ring-closure reaction in 9a-b
LA21-LA22 is made in reaction；Its synthetic route is as follows：
The pharmaceutically acceptable salt of the logical formula (I) compound can be chemically synthesized by general.
Generally, the preparation of salt can by free alkali or acid with etc. chemical equivalent or excess acid (inorganic acid has
Machine acid) or alkali (inorganic base or organic base) react obtained in suitable solvent or solvent compositions.
Present invention also offers a kind of pharmaceutical composition, it is by treating the active component of upper effective dose and pharmaceutically acceptable
Auxiliary material composition；Described active component is included in logical formula (I) compound, its stereoisomer and its pharmaceutically acceptable salt
One or more.In described pharmaceutical composition, described auxiliary material includes pharmaceutically acceptable carrier, diluent and/or tax
Shape agent.
Pharmaceutical composition can be made to various types of administration unit dosage forms according to therapeutic purposes, such as tablet, pill, powder
Agent, liquid, suspension, emulsion, granule, capsule, suppository and injection (solution and suspension) etc., preferred tablet, capsule, liquid
Body, suspension and injection (solution and suspension).
In order that the pharmaceutical composition shaping of tablet, pill or suppository form, can be used this area any known and extensive
The excipient used.
In order to prepare the pharmaceutical composition of injection form, (appropriate chlorine can will be preferably added after solution or suspension liquid disinfectant
Change sodium, glucose or glycerine), it is made and the isotonic injection of blood.When preparing injection, can also use in the art any
Conventional carrier.Such as：Water, ethanol, propane diols, the isooctadecanol of ethoxylation, the isooctadecanol of polyethoxylated and poly- second
Fatty acid ester of alkene anhydro sorbitol etc..Further, it is also possible to add usual lytic agent and buffer etc..
Content of the composition of the present invention in pharmaceutical composition can be carried out without specifically limited in a wide range
Selection, generally can be the 5~95% of mass percent, is preferably the 30~85% of mass percent.
The medication of pharmaceutical composition of the present invention is not particularly limited.Can according to patient age, sex and its
Its condition and symptom, the preparation of various formulations is selected to be administered.
Invention additionally provides logical formula (I) compound, its stereoisomer, its pharmaceutically acceptable salt or the institute
State application of the pharmaceutical composition in IDO 1 (IDO1) inhibitor is prepared.Described IDO1 inhibitor is used
In the immunosuppressive related disorder patients for the treatment of IDO1 mediations, described relevant disease includes cancer, virus infects, nerve becomes
Property disease, cataract, organ-graft refection, depression and autoimmune disease.
Present invention also offers the logical formula (I) compound, its stereoisomer, its pharmaceutically acceptable salt or described
Purposes of the pharmaceutical composition in medicine is prepared, the medicine are used to treat the cancer of patient, virus infection, neurodegeneration disease
Disease, cataract, organ-graft refection, depression or autoimmune disease.
Described cancer includes but is not limited to：Malignant mela noma, lung cancer, breast cancer, stomach cancer, colon cancer, carcinoma of urinary bladder, pancreas
Gland cancer, lymph cancer, leukaemia, prostate cancer, carcinoma of testis, kidney, the cancer of the brain, head and neck cancer, oophoroma, cervical carcinoma, carcinoma of endometrium,
One or more in celiothelioma, thyroid cancer, liver cancer and the cancer of the esophagus.
Described virus infection includes but is not limited to：By human immunodeficiency virus, hepatitis type B virus, hepatitis C virus
Poison, influenza virus, poliovirus, cytomegalovirus, Coxsackie virus, HPV, Epstein-bar
Infected caused by one or more in your viral and varicella virus.
Described neurodegenerative disease includes but is not limited to：It is memory disorder, Alzheimer disease, cognitive disorder disease, old
One or more in dementia disease, Parkinson's, parkinsonism and dyskinetic disorder.
Described autoimmune disease includes but is not limited to：Rheumatoid arthritis, systemic loupus erythematosus, musculus cutaneus
Inflammation, chorionitis, nodular vasculitis, multiple sclerosis, nephrosis, myasthenia gravis, MCTD, psoriasis,
Hepatopathy, endocrine relevant disease and due to the one or more in autoimmune response caused by infection.
Present invention also offers the logical formula (I) compound, its stereoisomer, its pharmaceutically acceptable salt or described
Pharmaceutical composition can combine with the therapeutic agent and/or treatment method of one or more other species to be mediated for treating by IDO1
Relevant disease.
The therapeutic agent and/or treatment method of other species include but is not limited to：Chemotherapeutics, anti-tumor drugs targeting,
Immunologic test selects inhibitor, immunologic test selects activator, anti-tumor vaccine, antivirotic, antiviral vaccine, cell factor are treated
Method, adoptive cellular immunotherapy or radiotherapy.
Described chemotherapeutics includes but is not limited to：Alkylating agent, Antitubulin, topoenzyme inhibitor, platinum medicine,
Antimetabolitas or hormone series antineoplastic medicament.
Described anti-tumor drugs targeting includes but is not limited to：Kinases inhibitor, proteasome inhibitor, different lemon
Dehydrogenase inhibitor, the antineoplastic based on epigenetics or cell cycle signalling pathways inhibitor.
Described immunologic test point inhibitor includes but is not limited to：CTLA-4 inhibitor, PD-1 inhibitor, PD-L1 suppress
Agent, PD-L2 inhibitor, TIM-3 inhibitor, VISTA inhibitor, LAG3 inhibitor, TIGIT inhibitor, A2AR inhibitor or
VTCN1 inhibitor.
Described immunologic test point activator includes but is not limited to：STING activators, 4-1BB activators, OX40 excitements
Agent, ROR gamma agonists or ICOS activators.
Embodiment
In order to which the present invention is furture elucidated, a series of embodiments are given below, these embodiments be entirely it is illustrative, it
Only be used for the present invention specifically describe, be not construed as limitation of the present invention.
Embodiment 1
The preparation of 4,5- bis- iodo- 1H- imidazoles (1)
1H- imidazoles (3g, 44.1mmol) is dissolved in 2M NaOH (10.6g, 265.0mmol) solution, adds KI
(29.3g, 176.0mmol) and I2The aqueous solution 100mL of (22.4g, 88.0mmol), react at room temperature 3 hours, 6M dilute salt is added dropwise
Reacting liquid pH value is adjusted to neutrality by acid, produces a large amount of solids, is filtered, ethyl alcohol recrystallization, obtains off-white powder, yield 99.0%,
mp 166-168℃。1H NMR (300MHz, DMSO-d6) δ (ppm) 7.8 (br s, 1H), 12.75 (br s, 1H)；MS(EI)m/z
320.8[M+H]+.
The preparation of the iodo- 1H- imidazoles (2) of 4-
1 (12.0g, 37.5mmol) is dissolved in the reaction system of ethanol (120mL) and water (20mL), adds Na2SO3
Ethanol, ethyl acetate extraction is removed under reduced pressure in (23.6g, 188.0mmol), back flow reaction 72 hours, and anhydrous magnesium sulfate is dried, removed
Solvent is removed, recrystallize with dichloromethane obtains white solid, yield 48.1%.1H NMR (300MHz, Chloroform-d) δ (ppm)
7.0 (s, 1H), 7.5 (s, 1H)；MS(EI)m/z 194.9[M+H]+.
The preparation of the iodo- 1- trityls -1H- imidazoles (3) of 4-
2 (3.5g, 18.0mmol) are dissolved in DMF (70mL), triethylamine (3.0mL, 21.6mmol) is added dropwise, add triphen first
Base chlorine (5.5g, 19.7mmol), react at room temperature 24 hours, pour into 200mL water, separate out a large amount of solids, filter, ether crosses diafiltration
Wash, be dried to obtain white solid, yield 94.0%, mp 214-216 DEG C.1H NMR (300MHz, Chloroform-d) δ (ppm)
6.9 (m, 1H), 7.0-7.2 (m, 6H), 7.25-7.4 (m, 10H)；MS(EI)m/z 437.1[M+H]+.2- (1- trityls-
1H- imidazoles) benzaldehyde (4) preparation
By 3 (3.0g, 6.9mmol), 2- formylphenylboronic acids (1.6g, 10.7mmol), K3PO4(4.4g, 20.8mmol) is molten
In DMF (30mL) and water (6mL), Pd (PPh are added3)4(0.6g, 0.5mmol), N2Reacted 16 hours in 90 DEG C under protection, it is cold
But, filter, add water (50mL), ethyl acetate extraction, anhydrous magnesium sulfate is dried, and column chromatography obtains white solid, yield
147-149 DEG C of 66.7%, mp.1H NMR (300MHz, Chloroform-d) δ (ppm) 7.97 (dd, J=7.8,1.4Hz,
1H), 7.72-7.54 (m, 3H), 7.38 (h, J=3.2Hz, 11H), 7.25-7.19 (m, 6H), 7.07 (d, J=1.3Hz, 1H)；
MS(EI)m/z 415.2[M+H]+.
The preparation of Witting reagents (5)
Triphenylphosphine (25.9g, 98.8mmol) is dissolved in dichloromethane (300mL), is slowly added to 2- bromoacetates
(15.0g, 89.8mmol), react at room temperature 3 days, remove solvent, solid is washed to obtain white solid product, yield with dichloromethane
90.6%.(E) preparation of -3- (2- (1- trityl -1H- imidazol-4 yls) phenyl) ethyl acrylate (6)
5 (3.3g, 7.7mmol) are dissolved in dichloromethane (10mL), 0 DEG C of addition NaOH (0.6g, 15.4mmol) is water-soluble
Liquid (1mL), it is stirred at room temperature 40 minutes.2- (1- trityl -1H- imidazoles) benzaldehyde (3.2g, 7.7mmol) is dissolved in dichloromethane
In alkane (1mL), it is slowly dropped into above-mentioned system, is stirred at room temperature 12 hours at 0 DEG C, adds water (50mL), dichloromethane extraction, nothing
Water magnesium sulfate is dried, and column chromatography purifies to obtain faint yellow solid, yield 77.5%.1H NMR (300MHz, Chloroform-d) δ
(ppm) 8.17 (d, J=15.9Hz, 1H), 7.77 (dd, J=7.8,1.4Hz, 1H), 7.61-7.51 (m, 3H), 7.45-7.33
(m, 14H), 7.21 (td, J=7.2,6.6,4.1Hz, 8H), 7.06-6.89 (m, 2H), 6.32 (d, J=15.9Hz, 1H),
4.23 (q, J=7.1Hz, 2H), 4.07 (q, J=7.1Hz, 1H), 1.29-1.24 (m, 3H), 1.15 (t, J=7.1Hz, 1H)；
MS(EI)m/z 485.3[M+H]+.
The preparation of 2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) ethyl acetate (7)
6 (5.0g, 10.3mmol) are dissolved in methanol (5mL), then add acetic acid (12.5mL), 90 DEG C are reacted 3 hours.
Room temperature is cooled to, unsaturated carbonate potassium solution is added and reaction system pH is adjusted to 10, methanol, ethyl acetate extraction, nothing is removed under reduced pressure
Water magnesium sulfate is dried, and is removed solvent and is obtained crude product, column chromatography purifies to obtain gray solid, yield 76.0%.1H NMR
(300MHz, Chloroform-d) δ (ppm) 7.81 (s, 1H), 7.57 (dt, J=7.6,1.0Hz, 1H), 7.49-7.42 (m,
2H), 7.35 (dd, J=1.7,1.0Hz, 1H), 7.21 (s, 1H), 5.58 (s, 1H), 4.30 (q, J=7.1Hz, 2H), 3.12
(dd, J=17.3,3.9Hz, 1H), 2.73 (dd, J=17.3,9.7Hz, 1H), 1.33 (t, J=7.2Hz, 3H)；MS(EI)m/z
243.1[M+H]+.
The preparation of 2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetic acid (8)
7 (1.0g, 4.1mmol) are dissolved in methanol (50mL), NaOH (0.8g, 20.6mmol) aqueous solution 2mL are added, by this
60 DEG C of reaction system heats 3 hours.Room temperature is cooled to, the pH value of reaction is adjusted to 5-6 with 10% watery hydrochloric acid.Water is removed under reduced pressure
And methanol, solid crude product is obtained, is direct plungeed into next step without purifying.
The preparation of N- benzyls -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide (LA01)
Crude product 8 (0.2g, about 0.6mmol) is dissolved in DMF (5mL), adds EDCI (0.14g, 0.75mmol), HOBt
(0.11g, 0.75mmol) and TEA (0.26mL, 1.86mmol), is stirred at room temperature 15 minutes.Addition benzylamine (0.07g,
0.65mmol), react at room temperature 12 hours.Water 10mL, ethyl acetate extraction are added, anhydrous magnesium sulfate is dried, and is removed solvent and is obtained
Solid crude product, column chromatography purify to obtain white solid 0.08g, yield 67.2%, mp 140-142 DEG C.1H NMR (300MHz,
Chloroform-d) δ (ppm) 7.61 (s, 1H), 7.51 (d, J=7.5Hz, 1H), 7.43-7.32 (m, 7H), 7.24 (d, J=
8.1Hz, 1H), 7.08 (s, 1H), 6.55 (s, 1H), 5.67 (dd, J=9.4,4.5Hz, 1H), 4.62-4.40 (m, 2H), 2.94
(dd, J=15.4,4.4Hz, 1H), 2.50 (dd, J=15.4,9.5Hz, 1H)；MS(EI)m/z 304.2[M+H]+.
Embodiment 2
The preparation of N- (4- cyanobenzyls) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide (LA02)
With reference to LA01 preparation method, it is made using 10 and to cyano group benzylamine as raw material, yield 60.4%, mp 198-200
℃。1H NMR (300MHz, DMSO-d6) δ (ppm) 8.70 (t, J=5.9Hz, 1H), 7.87-7.74 (m, 2H), 7.69-7.52
(m, 2H), 7.5-7.33 (m, 4H), 7.26 (td, J=7.6,1.2Hz, 1H), 7.13 (s, 1H), 5.62 (dd, J=8.7,
5.2Hz, 1H), 4.60-4.37 (m, 2H), 3.07 (dd, J=15.4,5.2Hz, 1H), 2.69 (dd, J=15.5,8.8Hz,
1H)；MS(EI)m/z 329.1[M+H]+.
Embodiment 3
N- (the preparations of 3,4- difluorobenzylamine base -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide (LA03)
With reference to LA01 preparation method, with 10 and 3,4- difluorobenzylamines are made for raw material, yield 78.0%, mp 88-90
℃。1H NMR (300MHz, Chloroform-d) δ (ppm) 7.60 (s, 1H), 7.51 (d, J=7.6Hz, 1H), 7.36 (dd, J
=21.6,7.5Hz, 2H), 7.24 (t, J=7.7Hz, 1H), 7.19-6.97 (m, 4H), 6.91 (s, 1H), 5.66 (dd, J=
9.2,4.5Hz, 1H), 4.53 (dd, J=14.9,5.9Hz, 1H), 4.37 (dd, J=14.9,5.4Hz, 1H), 2.96 (dd, J=
15.9,4.2Hz, 1H), 2.56 (dd, J=15.5,9.2Hz, 1H)；MS(EI)m/z 340.1[M+H]+.
Embodiment 4
The preparation of N- (3- chlorobenzyls) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide (LA04)
With reference to LA01 preparation method, it is made using 10 and 3- chlorobenzylamines as raw material, yield 66.0%, mp 73-75 DEG C.1H
NMR (300MHz, Chloroform-d) δ (ppm) 7.65 (s, 1H), 7.53 (d, J=7.6Hz, 1H), 7.44-7.29 (m, 4H),
7.29-7.16 (m, 3H), 7.12 (d, J=1.7Hz, 1H), 6.33 (s, 1H), 5.71 (dd, J=9.4,4.5Hz, 1H), 4.59
(dd, J=14.6,5.8Hz, 1H), 4.43 (dd, J=15.0,5.0Hz, 1H), 3.08-2.86 (m, 1H), 2.66-2.41 (m,
1H)；MS(EI)m/z 338.1[M+H]+.
Embodiment 5
The preparation of N- (the chloro- 4- luorobenzyls of 3-) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide (LA05)
With reference to LA01 preparation method, it is made using the chloro- 4- fluorin benzyl amines of 10 and 3- as raw material, yield 67.2%, mp 143-
145℃。1H NMR (300MHz, Chloroform-d) δ (ppm) 7.67 (s, 1H), 7.54 (d, J=7.6Hz, 1H), 7.37
(dt, J=14.1,7.3Hz, 2H), 7.30-7.22 (m, 2H), 7.14 (q, J=8.2,7.3Hz, 2H), 6.29 (s, 1H),
5.79-5.63 (m, 1H), 4.54 (d, J=5.9Hz, 1H), 4.41 (d, J=4.9Hz, 1H), 2.99 (dd, J=15.3,
4.5Hz, 1H), 2.58 (dd, J=15.4,9.1Hz, 1H)；MS(EI)m/z 356.1[M+H]+.
Embodiment 6
The preparation of N- (4- methoxy-benzyls) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide (LA06)
With reference to LA01 preparation method, it is made using 10 and 4-Methoxybenzylamine as raw material, yield 72.3%, mp 74-76
℃。1H NMR (300MHz, DMSO-d6) δ (ppm) 8.52 (s, 1H), 7.77-7.55 (m, 2H), 7.47 (d, J=7.6Hz, 1H),
7.39 (t, J=7.5Hz, 1H), 7.32-7.18 (m, 3H), 7.13 (s, 1H), 6.97-6.84 (m, 2H), 5.62 (dd, J=
8.9,5.2Hz, 1H), 4.31 (d, J=5.8Hz, 2H), 3.74 (s, 3H), 3.01 (dd, J=15.3,5.3Hz, 1H), 2.61
(dd, J=15.3,9.0Hz, 1H)；MS(EI)m/z 334.2[M+H]+.
Embodiment 7
The preparation of N- (4- hydroxybenzyls) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide (LA07)
With reference to LA01 preparation method, it is made using 10 and gumbix as raw material, yield 65.8%, mp 232-234
℃。1H NMR (300MHz, DMSO-d6) δ (ppm) 9.33 (d, J=1.2Hz, 1H), 8.46 (s, 1H), 7.70-7.55 (m, 2H),
7.47 (d, J=7.6Hz, 1H), 7.39 (t, J=7.4Hz, 1H), 7.26 (dd, J=7.5,1.2Hz, 1H), 7.17-7.01 (m,
3H), 6.79-6.63 (m, 2H), 5.62 (dd, J=9.0,5.2Hz, 1H), 4.26 (d, J=5.7Hz, 2H), 3.00 (dd, J=
15.2,5.3Hz, 1H), 2.74-2.56 (m, 1H)；MS(EI)m/z 320.2[M+H]+.
Embodiment 8
The preparation of N- benzyls -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- methylacetamides (LA08)
With reference to LA01 preparation method, it is made using 10 and to N- methylbenzylamines as raw material, yield 69.1%, mp 208-210
℃。1H NMR (300MHz, Chloroform-d) δ (ppm) 7.86 (d, J=3.5Hz, 1H), 7.66-6.99 (m, 10H), 5.79
(d, J=9.3Hz, 1H), 4.81-4.62 (m, 1H), 4.45 (s, 1H), 3.22-3.01 (m, 2H), 2.86 (s, 3H)；MS(EI)
m/z 318.2[M+H]+.
Embodiment 9
The preparation of 2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- (1- phenylethyls) acetamides (LA09)
With reference to LA01 preparation method, it is made using 10 and Alpha-Methyl benzylamine as raw material, yield 60.2%, mp 144-146
℃。1H NMR (300MHz, Chloroform-d) δ (ppm) 7.59 (d, J=7.8Hz, 2H), 7.51-7.37 (m, 3H), 7.36-
7.16 (m, 5H), 7.15-7.02 (m, 1H), 6.90 (d, J=11.5Hz, 1H), 5.51 (dd, J=9.2,4.9Hz, 1H), 5.18
(dd, J=7.2,2.8Hz, 1H), 2.95-2.67 (m, 1H), 2.58-2.30 (m, 1H), 1.48 (t, J=6.0Hz, 3H)；MS
(EI)m/z 318.2[M+H]+.
Embodiment 10
N- (benzo [d] [1,3] dioxy -5- methylene) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide
(LA10) preparation
With reference to LA01 preparation method, with 10 and 3,4- methylene-dioxy benzylamines are made for raw material, yield 74.3%,
mp88-90℃。1H NMR (300MHz, Chloroform-d) δ (ppm) 7.81 (s, 1H), 7.66-7.09 (m, 6H), 6.73 (s,
2H), 6.34 (s, 1H), 5.81 (d, J=75.2Hz, 2H), 4.39 (d, J=28.1Hz, 2H), 2.98 (d, J=15.9Hz,
1H), 2.59 (dd, J=15.5,8.9Hz, 1H)；MS(EI)m/z 348.1[M+H]+.
Embodiment 11
The preparation of N- (4- carboxybenzyls) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide (LA11)
With reference to LA01 preparation method, it is made using 10 and para-amino-methyl-benzoic acid as raw material, yield 79.2%, mp 260-262
℃。1H NMR (300MHz, DMSO-d6) δ (ppm) 12.84 (s, 2H), 8.68 (s, 1H), 8.03-7.81 (m, 2H), 7.72-
7.53 (m, 2H), 7.49 (d, J=7.4Hz, 1H), 7.39 (d, J=7.5Hz, 2H), 7.25 (t, J=7.7Hz, 1H), 7.13
(d, J=2.3Hz, 1H), 5.62 (d, J=6.6Hz, 1H), 4.45 (s, 2H), 3.07 (dd, J=15.2,5.3Hz, 1H), 2.68
(dd, J=15.5,8.9Hz, 1H)；MS(EI)m/z 348.1[M+H]+.
Embodiment 12
The preparation of 2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- (pyridine -3- methylene) acetamide (LA12)
With reference to LA01 preparation method, it is made using 10 and 3- aminomethyl-pyridines as raw material, yield 59.1%, mp 119-121
℃。1H NMR (300MHz, Chloroform-d) δ (ppm) 8.56-8.44 (m, 1H), 7.86 (d, J=42.9Hz, 1H), 7.68
(d, J=8.0Hz, 1H), 7.54 (d, J=7.5Hz, 1H), 7.46-7.23 (m, 5H), 7.14 (s, 2H), 5.75 (dd, J=
9.0,4.4Hz, 1H), 4.52 (dd, J=20.6,5.7Hz, 2H), 3.09 (dd, J=15.7,4.8Hz, 1H), 2.66 (s, 1H)；
MS(EI)m/z305.1[M+H]+.
Embodiment 13
The system of 2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- (pyrazine -2- methylene) acetamide (LA13)
It is standby
With reference to LA01 preparation method, it is made using 10 and 2- amine methylpyrazines as raw material, yield 64.1%, mp 163-165
℃。1H NMR (300MHz, Chloroform-d) δ (ppm) 8.65 (d, J=4.1Hz, 1H), 8.57-8.45 (m, 2H), 7.72
(s, 1H), 7.54 (d, J=8.0Hz, 1H), 7.38 (dd, J=15.2,7.7Hz, 2H), 7.26 (dd, J=11.4,5.0Hz,
1H), 7.13 (d, J=4.4Hz, 1H), 7.04 (s, 1H), 5.84-5.54 (m, 1H), 4.72 (t, J=4.9Hz, 2H), 3.13-
2.95 (m, 1H), 2.63 (dd, J=15.5,9.7Hz, 1H)；MS(EI)m/z 306.1[M+H]+.
Embodiment 14
The preparation of 2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-phenyl acetanilide,Phenacetylaniline (LA14)
With reference to LA01 preparation method, it is made using 10 and aniline as raw material, yield 77.1%, mp227-229 DEG C.1H NMR
(300MHz, Chloroform-d) δ (ppm) 7.95 (s, 1H), 7.74 (s, 1H), 7.56 (t, J=7.9Hz, 2H), 7.47-
7.30 (m, 4H), 7.28 (d, J=2.6Hz, 2H), 7.17 (dd, J=15.5,7.7Hz, 2H), 5.90-5.64 (m, 1H), 3.13
(d, J=15.3Hz, 1H), 2.73 (dd, J=15.5,9.5Hz, 1H)；MS(EI)m/z 290.2[M+H]+.
Embodiment 15
The preparation of 2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- (1H- indazole -6- bases) acetamide (LA15)
With reference to LA01 preparation method, it is made using 10 and 6- Aminoindazoles as raw material, yield 68.3%, mp 280-282
℃。1H NMR (300MHz, DMSO-d6) δ (ppm) 8.23 (s, 1H), 7.99 (s, 1H), 7.67 (dd, J=14.8,8.3Hz,
2H), 7.57 (d, J=7.4Hz, 1H), 7.40 (d, J=7.3Hz, 1H), 7.31 (d, J=7.5Hz, 1H), 7.20-7.02 (m,
2H), 5.73 (s, 1H), 2.89 (dd, J=16.0,9.2Hz, 1H)；MS(EI)m/z 330.2[M+H]+.
Embodiment 16
N- (benzo [d] [1,3] dioxy -5- bases) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide (LA16)
Prepare
With reference to LA01 preparation method, with 10 and 3,4- methylene dioxo group anilines are made for raw material, yield 65.9%,
mp210-212℃。1H NMR (300MHz, Chloroform-d) δ (ppm) 8.43 (s, 1H), 7.68 (s, 1H), 7.53 (s,
2H), 7.41 (s, 1H), 7.30 (s, 2H), 7.05 (s, 1H), 6.88 (s, 1H), 6.76 (s, 1H), 6.11-5.91 (m, 2H),
5.74 (s, 1H), 3.08 (s, 1H), 2.69 (s, 1H)；MS(EI)m/z 334.1[M+H]+.
Embodiment 17
The preparation of N- cyclohexyl -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide (LA17)
With reference to LA01 preparation method, it is made using 10 and cyclohexylamine as raw material, yield 69.3%, mp 84-86 DEG C.1H
NMR (300MHz, DMSO-d6) δ (ppm) 7.98 (d, J=7.8Hz, 1H), 7.68 (s, 1H), 7.61 (d, J=7.5Hz, 1H),
7.51 (d, J=7.6Hz, 1H), 7.39 (t, J=7.4Hz, 1H), 7.28 (td, J=7.5,1.2Hz, 1H), 7.14 (s, 1H),
5.60 (dd, J=9.1,5.2Hz, 1H), 2.94 (dd, J=15.1,5.2Hz, 1H), 1.63 (ddd, J=64.8,31.0,
9.4Hz, 6H), 1.18-1.10 (m, 2H)；MS(EI)m/z 296.2[M+H]+.
Embodiment 18
The preparation of 2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- (3- methoxyphenethyls) acetamides (LA18)
With reference to LA01 preparation method, it is made using 10 and 3- methoxyphenethylamines as raw material, yield 78.2%, mp 94-96
℃。1H NMR (300MHz, Chloroform-d) δ (ppm) 7.67 (s, 1H), 7.52 (d, J=7.6Hz, 1H), 7.43-7.17
(m, 4H), 7.12 (d, J=1.5Hz, 1H), 6.85-6.69 (m, 3H), 5.91 (d, J=7.2Hz, 1H), 5.68 (dd, J=
9.6,4.3Hz, 1H), 3.79 (s, 3H), 3.64 (qd, J=6.9,3.1Hz, 2H), 2.93 (d, J=4.4Hz, 1H), 2.85
(td, J=7.5,7.0,2.5Hz, 2H), 2.42 (dd, J=15.5,9.5Hz, 1H)；MS(EI)m/z 348.2[M+H]+.
Embodiment 19
The preparation of 2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- phenethyl-acetamides (LA19)
With reference to LA01 preparation method, it is made using 10 and phenyl ethylamine as raw material, yield 77.2%, mp 167-169 DEG C.1H
NMR (300MHz, Chloroform-d) δ (ppm) 7.70 (s, 1H), 7.53 (d, J=7.6Hz, 1H), 7.43-7.12 (m,
10H), 5.81 (s, 1H), 5.69 (dd, J=9.5,4.3Hz, 1H), 3.65 (tt, J=6.7,3.3Hz, 2H), 2.92-2.85
(m, 2H), 2.43 (dd, J=15.5,9.5Hz, 1H)；MS(EI)m/z 318.2[M+H]+.
Embodiment 20
The preparation of 2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- (2- (pyridine -2- bases) ethyl) acetamide (LA20)
With reference to LA01 preparation method, it is made using 10 and 2- (2- aminoethyls) pyridine as raw material, yield 85.2%, mp
140-142℃。1H NMR (300MHz, DMSO-d6) δ (ppm) 8.50 (d, J=4.3Hz, 1H), 8.21 (s, 1H), 7.83-7.66
(m, 2H), 7.60 (d, J=7.5Hz, 1H), 7.47 (d, J=7.6Hz, 1H), 7.38 (t, J=7.4Hz, 1H), 7.25 (dd, J
=14.8,5.8Hz, 3H), 7.15 (s, 1H), 5.59 (dd, J=9.3,5.6Hz, 1H), 3.54 (q, J=6.5Hz, 2H), 2.93
(td, J=8.0,7.2,3.5Hz, 2H), 2.55 (d, J=10.0Hz, 2H)；MS(EI)m/z 319.2[M+H]+.
Embodiment 21
(E) system of -1- cyclohexyls -3- (2- (1- trityl -1H- imidazol-4 yls) phenyl) -2- propylene -1- ketone (9a)
It is standby
At 0 DEG C, Na (0.6g, 23.9mmol) is slowly added to alcohol sodium solution is made in ethanol (15mL), adds first
Base cyclohexyl ketone (1.5g, 11.9mmol), 4 (5.0g, 11.9mmol).Room temperature reaction 3 hours, add saturated ammonium chloride solution
Extract reaction of going out, removal of solvent under reduced pressure, add water 15mL, dichloromethane extraction, anhydrous magnesium sulfate is dried, and removal of solvent under reduced pressure obtains
Crude white solid.1H NMR (300MHz, Chloroform-d) δ (ppm) 8.10-7.97 (m, 2H), 7.64-7.48 (m,
4H), 7.40-7.26 (m, 9H), 7.18 (d, J=7.2Hz, 6H), 6.50 (d, J=15.0Hz, 1H), 2.91 (s, 1H), 2.28
(dt, J=13.2,7.0Hz, 2H), 1.94 (dt, J=13.2,6.9Hz, 2H), 1.89-1.69 (m, 3H), 1.58-1.39 (m,
3H).
The preparation of 1- cyclohexyl -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) ethyl -1- ketone (10a)
With reference to the preparation method of intermediate 7, it is made by intermediate 9a for raw material, yield 50.8%.1H NMR (300MHz,
Chloroform-d) δ (ppm) 7.69-7.62 (s, 1H), 7.58-7.53 (dt, J=7.6,0.9Hz, 1H), 7.43-7.36 (m,
1H), 7.28-7.21 (m, 2H), 7.21-7.15 (s, 1H), 5.73-5.59 (dd, J=9.5,3.6Hz, 1H), 3.26-3.16
(dd, J=18.4,3.6Hz, 1H), 3.04-2.76 (dd, J=18.4,9.5Hz, 1H), 2.49-2.24 (m, 1H), 1.97-
1.59 (m, 5H), 1.40-1.19 (m, 5H)
(Z) preparation of -1- cyclohexyl -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetophenone oxime (LA21)
10a (0.07g, 0.25mmol) is dissolved in ethanol (5mL), room temperature addition hydroxylamine hydrochloride (0.05g,
0.75mmol), react 12 hours at 50 DEG C.Room temperature is cooled to, removal of solvent under reduced pressure obtains crude product, and column chromatography purifies to obtain white
Solid, yield 54.2%, mp 126-128 DEG C.1H NMR (300MHz, DMSO-d6) δ (ppm) 0.99-1.15 (m, 5H), 1.45-
1.72 (m, 6H), 2.43and 2.58 (two m, 1H), 2.70and 2.91 (m, 1H), 4.69 (m, 1H), 7.23-7.29 (m,
3H), 7.40and7.46 (two m, 1H), 7.53and 7.58 (two m, 1H), 7.75and 7.76 (two s, 1H),
10.34and 10.41 (two s, 1H)；MS(EI)m/z 296.2[M+H]+.
Embodiment 22
(E) -1- (4- chlorphenyls) -3- (2- (1- trityl -1H- imidazol-4 yls) phenyl) -2- propylene -1- ketone (9b)
Preparation
With reference to intermediate 9a preparation method, it is made by methyl rubigan ketone and 4.1H NMR (300MHz,
Chloroform-d) δ (ppm) 8.12 (dd, J=7.5,2.0Hz, 1H), 8.09 (s, 1H), 7.96-7.86 (m, 2H), 7.84-
7.68 (m, 2H), 7.59 (s, 1H), 7.52-7.42 (m, 4H), 7.49-7.26 (m, 10H), 7.19-7.11 (m, 6H)
The preparation of 1- (4- chlorphenyls) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) ethyl -1- ketone (10b)
With reference to the preparation method of intermediate 7, it is made by intermediate 9b for raw material, yield 59.9%.1H NMR (300MHz,
Chloroform-d) δ (ppm) 8.01-7.85 (m, 2H), 7.66-7.25 (m, 8H), 6.30 (t, J=7.0Hz, 1H), 3.43
(dd, J=12.5,6.9Hz, 1H), 3.20 (dd, J=12.4,7.0Hz, 1H)
(Z) preparation of -1- (4- chlorphenyls) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetophenone oxime (LA22)
With reference to LA21 preparation method, it is made by 10b and hydroxylamine hydrochloride for raw material, yield 49.9%, mp 89-91 DEG C.1H
NMR (300MHz, Chloroform-d) δ (ppm) 7.86-6.94 (m, 11H), 6.21-5.65 (m, 1H), 3.83-3.14 (m,
2H)；MS(EI)m/z 324.1[M+H]+.
Embodiment 23
1. the IDO1 inhibitory activity test based on Hela cells
1.1 experiment materials and key instrument
Hela cell lines ATCC
Centrifuge Eppendorf (CHINA)
The new talent medicine equipment manufacture of electric heating constant-temperature blowing drying box (DHG-924385-III) Shanghai is limited
Company
Acetic acid (glacial acetic acid) Nanjing chemical reagent limited company
Trichloroacetic acid (CAS：76-03-9) Shanghai Ling Feng chemical reagent Co., Ltd
Electronic balance Sartorius
To dimethylamino benzaldehyde (CAS：100-10-7) Aladdin
Recombinant Human IFN-γ(Catalog#AF-300-02) PEPROTECH
1.2 experimental method
From ATCC purchase Hela cells be stored in minimum essential medium (2mM Glus and be tuned into containing
1.5g/L sodium acid carbonates, 0.1mM nonessential amino acid, the EarleShi BSS of 1mM the third bronze medal acid sodium and 10% hyclone) in.
Hela cells are stored at 37 DEG C 5%CO is provided2The wet incubator of control in.
By 5 × 103Hela cells are seeded in 96 well culture plates by the density in/hole, and overnight incubation.Second day, will
The serial dilutions of IFN-γ (final concentration 100ng/mL) and compound (the μ L culture mediums of cumulative volume 200) add to cell.Incubate 24
140 μ L of supernatant liquid/hole is moved in 96 new orifice plates after hour, 10 μ L 6.1mol/L trichloroacetic acid is added, in constant temperature oven
In 50 DEG C incubate 30min so that caused N- formoxyls kynurenin is hydrolyzed to kynurenin.Then it will react mixed with 4000rpm
Compound centrifuges 10min to remove sediment.100 μ L of supernatant liquid/hole is moved in another 96 orifice plate, with isometric 2% (w/v)
The acetic acid solution mixing of p- dimethylaminobenzaldehyde.Light absorption value is detected at 480nm using ELIASA, acquired results utilize IC50
Calculator calculates.Experiment sets 3 multiple holes.
1.3 experimental result
Experimental result is as shown in table 1.As a result show, the compounds of this invention there is significant suppression to make IDO1 activity
With.Wherein, the most strong (IC of compound L A18 activity50：0.84μM).
Inhibitory activity of the compounds of this invention of table 1 to IDO1
The proliferation experiment of 2.T lymphocytes
2.1 experimental method
The processing of B16F1 cells：Culture medium (DMEM in high glucose, 10%FBS) is sucked, PBS is washed 1-2 times.Add 0.25% pancreatin
Digestion.Pancreatin is sucked, culture medium is added, cell is blown and beaten, is transferred in 1.5mL centrifuge tubes, is centrifuged, is sucked supernatant, add
Enter 1mLDMEM culture mediums suspension cell again.Mitomycin C (the μ g/ml of final concentration 25) is added, blows and beats and mixes hook, 37 DEG C, water-bath
30min, RP1640 are washed 3 times, and cell count is stand-by.
The preparation of spleen cell：Take C57/BL6 mouse, pluck eyeball sacrificed by exsanguination, sterile taking-up spleen be put into containing 2mL without
In the 35mm of the culture mediums of precooling RPMI 1640 of bacterium culture dish, gently splenocyte is extruded with 5mL syringes nook closing member.Again plus
Enter 2mL culture mediums, blown and beaten repeatedly with 5mL pipettes until suspension is uniform.Cell suspension is filtered with 70 μm of filters, 300g centrifugations
5min(4℃).Splenocyte adds 10mL Tris-NH after abandoning supernatant4Cl, blow, stand 2-3min, 300g centrifugations 5min (4
DEG C), remove red blood cell.After abandoning supernatant, then washed twice with PRMI 1640, it is stand-by.
1) by treated B16F1 cells 2 × 104Individual/hole (stimulation cell), spleen lymphocyte 1 × 106Individual/hole is (anti-
Answer cell), 96 orifice plates are added, add RP1640 (10%FBS), polishing to 200 μ L.
2) it is grouped：Administration group (stimulates cell+reacting cells+correspondence compound), blank control (only plus reacting cells), mould
Type group (stimulate cell+reacting cells), in addition to blank control, other groups add ConA (the μ g/ml of final concentration 5), be placed in 37 DEG C,
Humidity 95%, 5%CO2Incubator in cultivate, cultivate 48h.
3) add in 20 μ L MTT (final concentration 4mg/ml) incubators and continue to cultivate 4h, ELIASA is determined at 570nm wavelength
Absorbance；Calculate T lymphocytic proliferation rates：
T lymphocytic proliferation rates (%)=[a pair of dosing holes (T lymphocyte+B16F1 cell+IDO1 inhibitor) OD values
According to hole (T lymphocyte+B16F1 cells) OD values]/control wells (T lymphocyte+B16F1 cells) OD value × 100%
2.2 experimental result
In mixed lymphocyte reaction (MLP) system, the high expression IDO1 of B16F1 cells, the propagation of T lymphocytes can be produced
Raw inhibitory action.As addition compound L A16 and LA18 (3 times of IC50Concentration) after culture 48h, utilize MTT detection T lymphocytes
Propagation, proliferation rate is respectively 48.61% and 26.53%, illustrates that compound L A16 and LA18 can dramatically increase the increasing of T lymphocytes
Grow.
3. the influence of pair Autoimmune disease
3.1 experimental method
By treated B16F1 cells (8 × 104Individual hole), spleen lymphocyte (106Individual hole, use 5 μ g/mL ConA
Stimulate) add in 24 orifice plates, add after the compound of corresponding concentration be placed in 37 DEG C, humidity 95%, 5%CO2Incubator in train
Support 48h；Supernatant test ELISA is collected, using anti-CD4, anti-CD25, anti-FOCP3 antibody stainings, is detected in flow cytometer
The differentiation of T cell.
3.2 experimental result
When original T lymphocytes and melanoma cells line B16 F1 are co-cultured, the quantity of Autoimmune disease and
Only the experimental group (5.4%) containing original T lymphocytes is compared and risen 2.7 times (14.7%).As compound L A16 and LA18 (3
Times IC50Concentration) in addition system after can substantially reverse this effect (dropping to 7.9% and 10.1% respectively), explanation
Compound LA16 and LA18 can reverse conversion of the original T lymphocytes to Autoimmune disease by suppressing IDO1.
4. the influence pair IDO1 expression
4.1 experimental method
Hela cells are with 2 × 105Density kind per hole is in 6 orifice plate cultures, in 37 DEG C, 5%CO2Under the conditions of cultivate 12h.It is empty
White control (only plus culture medium), model group (add IFN-γ, corresponding positive drug), and drug-treated group (adds IFN-γ, correspondenceization
Compound), in 37 DEG C, 5%CO2Under the conditions of cultivate 24h, collect cell, Western blot detection IDO1 expression.
4.2 experimental result
Test result indicates that compound L A16 and LA18 do not influence the expression of IDO1 in Hela cells, illustrate compound
LA16 and LA18 is to reverse the immunosupress that IDO1 is mediated by suppressing IDO1 activity.
Claims (10)
1. imidazo isoindoles compound, its stereoisomer or its pharmaceutically acceptable salt shown in logical formula (I)：
Wherein：
R1Representative represents hydrogen, NR3R4、C1-C8Alkyl, C3-C8Cycloalkyl, C5-C10Aryl or C1-C10Aromatic heterocyclic, wherein described
Heteroaromatic group is optionally comprising one or more other hetero atoms for being selected from O, S or N；Described alkyl, cycloalkyl, aryl
Or aromatic heterocyclic is optionally monosubstituted to five substitutions by substituent that is following identical or differing, described substituent is selected from：
Halogen, trifluoromethyl, cyano group, nitro, hydroxyl or amino；
R2Represent O, S or NR5；
R3Represent hydrogen, C1-C8Alkyl or C3-C6Cycloalkyl；
R4Represent hydrogen, C1-C8Alkyl, C3-C6Cycloalkyl, C5-C10Aryl, C5-C10Aryl-(C1-C10Alkyl), C1-C10Heteroaromatic
Base, C1-C10Heteroaromatic-(C1-C10Alkyl), C1-C12Condensed hetero ring base or C1-C12Condensed hetero ring-(C1-C10Alkyl), wherein described
Heterocyclic group is optionally comprising one or more other hetero atoms for being selected from O, S or N；Wherein described alkyl, cycloalkyl, virtue
Base, heteroaromatic, condensed hetero ring are optionally monosubstituted to five substitutions, described substituent by substituent that is following identical or differing
It is selected from：C1-C5Alkyl, halogen, trifluoromethyl, carboxyl, cyano group, nitro, hydroxyl, amino or methoxyl group；
R5Represent hydrogen, hydroxyl or sulfydryl.
2. imidazo isoindoles compound according to claim 1, its stereoisomer or its is pharmaceutically acceptable
Salt, it is characterised in that：
R1Represent hydrogen, NR3R4、C3-C6Cycloalkyl, C5-C10Aryl or C1-C10Aromatic heterocyclic, wherein described heteroaromatic group can
Optionally comprising one or more other hetero atoms for being selected from O, S or N；Wherein described cycloalkyl, aryl or aromatic heterocyclic can
Optionally monosubstituted to five substitutions by substituent that is following identical or differing, described substituent is selected from：Halogen, cyano group, nitre
Base, hydroxyl or amino；
R2Represent O or NR5；
R3Represent hydrogen or C1-C8Alkyl；
R4Represent C3-C6Cycloalkyl, C5-C10Aryl, C5-C10Aryl-(C1-C10Alkyl), C1-C10Aromatic heterocyclic, C1-C10Virtue is miscellaneous
Ring-(C1-C10Alkyl), C1-C12Condensed hetero ring base or C1-C12Condensed hetero ring-(C1-C10Alkyl), wherein described heterocycle is optionally
Include one or more other hetero atoms for being selected from O, S or N；Wherein described cycloalkyl, aryl, heteroaromatic, condensed hetero ring can appoint
Selection of land is monosubstituted to five substitutions by substituent that is following identical or differing, and described substituent is selected from：C1-C5Alkyl, halogen,
Carboxyl, cyano group, nitro, hydroxyl, amino or methoxyl group；
R5Represent hydroxyl or sulfydryl.
3. imidazo isoindoles compound according to claim 2, its stereoisomer or its is pharmaceutically acceptable
Salt, it is characterised in that：
R1Representative represents NR3R4, cycloalkyl or rubigan；
R2Represent O or NR5；
R3Represent hydrogen or methyl；
R4Represent the chloro- 4- luorobenzyls of benzyl, 4- cyanobenzyls, 3,4- difluorobenzyls, 3- chlorobenzyls, 3-, 4- methoxy-benzyls, 4-
Hydroxybenzyl, α-methylbenzyl, 3,4- methylenedioxy benzyls, to carboxybenzyl, pyridine -3- methylene, pyrazine -2-
Methylene, phenyl, 1H- indazole -6- bases, 3,4- methylenedioxybenzenes, cyclohexyl, 3- methoxyphenethyls, phenethyl or pyridine -
2- ethyls；
R5Represent hydroxyl.
4. imidazo isoindoles compound according to claim 1, its stereoisomer or its is pharmaceutically acceptable
Salt, it is characterised in that the compound is selected from：
N- benzyls -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide；
N- (4- cyanobenzyls) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide；
N- (3,4- difluorobenzylamine base -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamides；
N- (3- chlorobenzyls) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide；
N- (the chloro- 4- luorobenzyls of 3-) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide；
N- (4- methoxy-benzyls) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide；
N- (4- methoxy-benzyls) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide；
N- benzyls -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- methylacetamides；
2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- (1- phenylethyls) acetamide；
N- (benzo [d] [1,3] dioxy -5- methylene) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide；
N- (4- carboxybenzyls) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide；
2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- (pyridine -3- methylene) acetamide；
2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- (pyrazine -2- methylene) acetamide；
2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-phenyl acetanilide,Phenacetylaniline；
2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- (1H- indazole -6- bases) acetamide；
N- (benzo [d] [1,3] dioxy -5- bases) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide；
N- cyclohexyl -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetamide；
2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- (3- methoxyphenethyls) acetamide；
2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- phenethyl-acetamides；
2- (5H- imidazoles [5,1-a] iso-indoles -5- bases)-N- (2- (pyridine -2- bases) ethyl) acetamide；
(Z) -1- cyclohexyl -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetophenone oxime；
(Z) -1- (4- chlorphenyls) -2- (5H- imidazoles [5,1-a] iso-indoles -5- bases) acetophenone oxime.
5. the preparation method of pyrimidines according to claim 1, it is characterised in that：
A) R is worked as2For O when, the preparation method of compound is shown in logical formula (I)：Using 1H- imidazoles as raw material, 1 is made through iodide reaction,
The 1 ethanol solution backflow through sodium sulfite sloughs 5 iodine atoms and introducing Trt protection groups obtained 3,3 on 2,21 N atom is made
4 are made by Suzuki coupling reactions with adjacent formylphenylboronic acid, triphenylphosphine and 2- bromoacetates are reacted and are made
Witting reagents 5, intermediate 4 and 5 are made 7,7 through cyclization through Witting reactions obtained 6,6 and are made 8,8 through sodium hydroxide hydrolysis
With aminated compounds (NHR3R4) the obtained compound L A01-LA20 of reaction；Its synthetic route is as follows：
Wherein, R3And R4Definition it is as claimed in claim 1；
B) R is worked as2For N-OH when, the preparation method of compound is shown in logical formula (I)：Intermediate 4 respectively with methylcyclohexyl ketone and
9a-b is made in the reaction of methyl rubigan ketone, and 10a-b is made by ring-closure reaction in 9a-b, and 10a-b makes with hydroxylamine hydrochloride reaction
Obtain LA21-LA22；Its synthetic route is as follows：
6. a kind of pharmaceutical composition, it is made up of the active component and pharmaceutically acceptable auxiliary material for treating upper effective dose；It is described
Active component include imidazo isoindoles compound (I) as any one of claim 1-4, its stereoisomer
Or its pharmaceutically acceptable salt；Described pharmaceutically acceptable auxiliary material include pharmaceutically acceptable carrier, diluent and/
Or excipient.
7. the compound, its stereoisomer, its pharmaceutically acceptable salt or right any one of claim 1-4 will
Ask application of the pharmaceutical composition in the inhibitor of IDO 1 is prepared described in 6, described indoleamine 2,3-
The inhibitor of dioxygenase 1 is used for the immunosuppressive related disorder patients for treating the mediation of IDO 1, the Yin
Diindyl amine 2, the immunosuppressive relevant disease that 3- dioxygenases 1 mediate is cancer, viral infection, neurodegenerative disease, cataract,
Organ-graft refection, depression or autoimmune disease.
8. the compound, its stereoisomer, its pharmaceutically acceptable salt or right any one of claim 1-4 will
Purposes of the pharmaceutical composition described in 6 in medicine is prepared is sought, the medicine is for treating the cancer of patient, virus infects,
Neurodegenerative disease, cataract, organ-graft refection, depression or autoimmune disease.
9. according to the application described in claim 7-8, wherein described cancer is malignant mela noma, lung cancer, breast cancer, stomach
Cancer, colon cancer, carcinoma of urinary bladder, cancer of pancreas, lymph cancer, leukaemia, prostate cancer, carcinoma of testis, kidney, the cancer of the brain, head and neck cancer, ovary
One or more in cancer, cervical carcinoma, carcinoma of endometrium, celiothelioma, thyroid cancer, liver cancer and the cancer of the esophagus；Described virus sense
Contaminate for human immunodeficiency virus, hepatitis type B virus, HCV, influenza virus, poliovirus, giant cell
One kind in virus, Coxsackie virus, HPV, epstein-Barr virus and varicella virus
Or a variety of caused infection；Described neurodegenerative disease is memory disorder, Alzheimer disease, cognitive disorder disease, old age
One or more in dementia, Parkinson's, parkinsonism and dyskinetic disorder；Described LADA disease
Disease is rheumatoid arthritis, systemic loupus erythematosus, dermatomyositis, chorionitis, nodular vasculitis, multiple sclerosis, kidney
Disease, myasthenia gravis, MCTD, psoriasis, hepatopathy, endocrine relevant disease and due to infection caused by itself
One or more in immune response.
10. according to the application described in claim 7-9, it is characterised in that：Further give the Disease apply it is a kind of or
It is a variety of chemotherapeutics, anti-tumor drugs targeting, immunologic test point inhibitor, immunologic test point activator, anti-tumor vaccine, antiviral
Agent, antiviral vaccine, cytokine therapy, adoptive cellular immunotherapy or radiotherapy；Described chemotherapeutics be alkylating agent,
Antitubulin, topoenzyme inhibitor, platinum medicine, antimetabolitas or hormone series antineoplastic medicament；Described target
To antineoplastic be kinases inhibitor, proteasome inhibitor, isocitric dehydrogenase inhibitor, based on epigenetic
Antineoplastic or cell cycle signalling pathways inhibitor；Described immunologic test point inhibitor be CTLA-4 inhibitor,
PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, TIM-3 inhibitor, VISTA inhibitor, LAG3 inhibitor, TIGIT suppressions
Preparation, A2AR inhibitor or VTCN1 inhibitor；Described immunologic test point activator be STING activators, 4-1BB activators,
OX40 activators, ROR gamma agonists or ICOS activators.
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| CN110221068A (en) * | 2018-03-02 | 2019-09-10 | 中国医学科学院基础医学研究所 | Detect the application of the reagent of Kyn content |
| CN110221068B (en) * | 2018-03-02 | 2020-09-18 | 中国医学科学院基础医学研究所 | Application of reagent for detecting Kyn content |
| CN113248491A (en) * | 2020-02-11 | 2021-08-13 | 中国科学院上海药物研究所 | Substituted indole urea derivatives, synthesis method and application thereof |
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