CN106905256A - Benzo five-membered heterocyclic IDO1 inhibitor, its preparation method and application - Google Patents

Benzo five-membered heterocyclic IDO1 inhibitor, its preparation method and application Download PDF

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Publication number
CN106905256A
CN106905256A CN201710135045.3A CN201710135045A CN106905256A CN 106905256 A CN106905256 A CN 106905256A CN 201710135045 A CN201710135045 A CN 201710135045A CN 106905256 A CN106905256 A CN 106905256A
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inhibitor
alkyl
cancer
disease
aryl
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赖宜生
邹毅
王芳
徐强
郭文洁
王燕
罗明昊
李月珍
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China Pharmaceutical University
Nanjing University
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China Pharmaceutical University
Nanjing University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • 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

Abstract

The invention belongs to drug field, specifically related to a kind of benzo five-membered heterocycle compound with formula (I) architectural feature or its pharmaceutically acceptable salt, its preparation method and they as indoleamine 2, the purposes of 3 dioxygenase 1 (IDO1) inhibitor.Test result indicate that, compound of the invention has to the activity of IDO1 and 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, 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

Benzo five-membered heterocyclic IDO1 inhibitor, its preparation method and application
Technical field
The invention belongs to drug field, and in particular to a kind of benzo five-membered heterocycle compound or its is pharmaceutically acceptable Salt, its preparation method and they as IDO 1 (IDO1) inhibitor purposes.
Technical background
Tryptophan is that human body cell maintains propagation and amino acid necessary to survival, can be used for protein, nicotinic acid and 5- hydroxyls The biosynthesis of tryptamines.Tryptophan is general to be absorbed from food, is metabolized along kynurenine approach more than 95% tryptophan, remaining color Propylhomoserin converts 5-hydroxyryptophan and serotonin in nervous system and enteron aisle, or synthesizes epiphysin 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 for IDO1 Born of the same parents and BMDC) middle expression.The concentration that IDO1 passes through tryptophan in oxicracking tryptophan reduction body microenvironment, 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, the inducible IDO1 up-regulated expressions of IL-1 β and IL-6 (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 is important adjustment effect (Munn DH, et al.Trends Immunol, 2013,34 (3) with adaptive immunity：137- 143).IDO1 is mainly causes tryptophan depletion and its metabolite accumulation 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 that suppress the propagation of T cell, while also suppressing 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)；Additionally, 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, the 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 is dramatically increased, 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, the female tire of induction is exempted from Epidemic disease is tolerated, it is ensured that fetus is not repelled by the immune system of parent；Tryptophan depletion in host's microenvironment prevents it from being cause of disease Microorganism replicates tryptophan necessary to providing, so as to cause pathogenic microorganism dead；The immune suppression of at the same time IDO1 mediations System can avoid excessive activation (Mellor AL, the 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 repulsion (Munn DH, et that IDO1 can make fetus from parent Al.Science, 1998,281 (5380)：1191-1193).IDO1 also plays immune to the survival that transplanting is organized in new host Inhibitory action (Radu CA, et al.Plast Reconstr Surg, 2007,119 (7)：2023-2028).These research knots Fruit explanation IDO is a kind of immunological regulation enzyme, participates in the immune tolerance of body.
Numerous researchs show, the immune tolerance 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, giving IDO1 inhibitor can be obviously promoted CD8+The propagation of T cell, recovers T The immune response of cell, suppresses 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, causes Tregs/Th17 cell proportions to lack of proper care, and causes immunosupress (the Favre D, et of patient Al.Sci Transl Med, 2010,2 (32)：32ra36).Additionally, 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 (Malpass K.Nat Rev closely related with the generation of dyskinetic disorder Neurol, 2011,7 (8)：417；Maddison DC, et al.Semin Cell Dev Biol, 2015,40：134-141). IDO1 expression and quinoline acid concentration are above normal person in AD brain in patients, wherein microglia around senile plaque expelling and Content highest in astrocyte.Additionally, 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 (Guillemin GJs, et closely related with the understanding defect level of patient 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 are also over-expressed with IDO1 It is relevant with the metabolite level rising such as kynurenin.The overexpression of IDO1 causes tryptophan depletion, so as to reduce for closing 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 various 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 IDO1 expression high exists in (Nguyen in various autoimmune diseases NT, et al.Front Immunol, 2014,5：551).In the DCs of rheumatoid arthritis patients synovial joint tissue expression high IDO1, Tryptophan concentration reduction in patients serum, and the rising 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 IDO1 is there is also in lupus patient and over-expresses phenomenon enhanced with tryptophan metabolism.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 important autoimmune disease patient 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 with Tryptophan metabolite is built up, so that 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. Expression (Uyttenhove C, the et al.Nat Med, 2003,9 (10) of IDO1 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 The expression quantity of IDO1 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, recovers the propagation and function of T cell and NK cells, suppresses Treg The propagation of cell, so that strengthen the immune response of body, therefore IDO1 inhibitor can be used to treat the immune suppression 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.Additionally, 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 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 various diseases such as depression, therefore can suppress the work of IDO1 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 reach 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 there are provided a kind of benzo five-membered heterocycle compound or its pharmaceutically Acceptable salt, its preparation method, pharmaceutical composition and application.Compound of the invention has good IDO1 inhibitory activity, Can be used for treating and/or preventing the various relevant diseases caused by the immunosupress that IDO1 is mediated.
The invention provides benzo five-membered heterocyclic compound or its pharmaceutically acceptable salt shown in logical formula (I)：
Wherein：
α and β represent a singly-bound or double bond；When α is singly-bound, β is double bond；When α is double bond, β is singly-bound；
A represents C, O, S, NH or N；
B represents O, S or NH2；
R1Represent hydrogen, halogen, nitro, hydroxyl, cyano group, amino or C1-C10Alkyl；
R2Represent hydrogen, C1-C4Alkyl, C1-C10Alkyl C (O) R3、-C(O)NR4R5、-C(O)R3、C6-C10Aryl, (C1-C5) Alkyl (C6-C10) aryl, C1-C10Aromatic heterocyclic or-(C1-C5) alkyl (C1-C10) aromatic heterocyclic；Wherein described aromatic heterocyclic Group is optionally selected from other hetero atoms of O, S or N comprising one or more；Described alkyl, aryl or aromatic heterocyclic can appoint Selection of land is monosubstituted to five substitutions by substitution base that is following identical or differing, and described substitution base is selected from：Hydrogen, halogen, hydroxyl, first Epoxide or R3；
R3、R4、R5Hydrogen, C can be represented with identical or different1-C8Alkyl, C3-C6Cycloalkyl, C6-C10Aryl ,-(C1-C5) alkane Base (C6-C10) aryl, C1-C10Aromatic heterocyclic or (C1-C5) alkyl (C1-C10) aromatic heterocyclic；Wherein described heteroaromatic group can Other hetero atoms of O, S or N are optionally selected from comprising one or more；Described alkyl, aryl or aromatic heterocyclic are optionally Monosubstituted to five substitutions by substitution base that is following identical or differing, described substitution base is selected from：Hydrogen, halogen, hydroxyl or methoxy Base.
Further, with the benzo five-membered heterocycle compound or its pharmaceutically acceptable salt shown in logical formula (I), its It is characterised by：
α and β represent a singly-bound or double bond；When α is singly-bound, β is double bond；When α is double bond, β is singly-bound；
A represents O, NH or N；
B represents O or NH2；
R1Represent hydrogen, halogen, nitro, hydroxyl or amino；
R2Represent hydrogen, C1-C4Alkyl, C1-C10Alkyl C (O) R3、-C(O)NR4R5、-C(O)R3、C6-C10Aryl ,-(C1-C5) Alkyl (C6-C10) aryl, C1-C10Aromatic heterocyclic or-(C1-C5) alkyl (C1-C10) aromatic heterocyclic；Wherein described aromatic heterocyclic Group is optionally selected from other hetero atoms of O, S or N comprising one or more；Described alkyl, aryl or aromatic heterocyclic can appoint Selection of land is monosubstituted to five substitutions by substitution base that is following identical or differing, and described substitution base is selected from：Hydrogen, halogen, hydroxyl, first Epoxide or R3；
R3、R4、R5Hydrogen, C can be represented with identical or different1-C8Alkyl, C3-C6Cycloalkyl, C6-C10Aryl, (C1-C5) alkane Base (C6-C10) aryl, C1-C10Aromatic heterocyclic or (C1-C5) alkyl (C1-C10) aromatic heterocyclic；Wherein described heteroaromatic group can Other hetero atoms of O, S or N are optionally selected from comprising one or more；Described alkyl, aryl or aromatic heterocyclic are optionally Monosubstituted to five substitutions by substitution base that is following identical or differing, described substitution base is selected from：Hydrogen, halogen, hydroxyl or methoxy Base.
Further, with the benzo five-membered heterocycle compound or its pharmaceutically acceptable salt shown in logical formula (I), its It is characterised by：
α and β represent a singly-bound or double bond；When α is singly-bound, β is double bond；When α is double bond, β is singly-bound；
A represents O, NH or N；
B represents O or NH2；
R1Represent hydrogen, chlorine, fluorine, nitro or amino；
R2Optionally certainly：
Specifically, lead to the benzo five-membered heterocycle compound shown in formula (I) and preferably be selected from following compounds：
The compound numbers being related in pharmacological evaluation below are equal to the compound corresponding to code name herein.
Present invention also offers the preparation method of compound shown in logical formula (I), it is characterised in that：
A) when A is O, and B is O, the preparation method of compound is shown in logical formula (I)：Difference substitution o-aminophenols with There is condensation reaction and intermediate 1,1 and the different substituted prepared 2a-f of alpha-chloro acetophenone reaction be obtained in CDI, 2a-f is through hydroboration Sodium reduction is obtained 3a-f；1 is obtained 4a-j from different substituted aralkyl chlorine reactions, and 4i is reduced prepared 5；1 from different acyl chlorides Reaction is obtained 6a-c；1 is obtained 7a-c from the reaction of different aminated compounds；Its synthetic route is as follows：
Wherein, R1And R2It is defined as described above；
B) when A is NH, and B is O, the preparation method of compound is shown in logical formula (I)：2- benzimidazolones and alpha-chloro- The reaction of 4 '-fluoro acetophenone is obtained 8,8 and is obtained 9 through sodium borohydride reduction；Its synthetic route is as follows：
Wherein, R1And R2It is defined as described above；
C) when A is N, B is NH2When, the preparation method of compound is shown in logical formula (I)：1H-2- aminobenzimidazoles are passed through Boc protections prepared 10,10 are sloughed Boc substitution bases and are obtained 12 with acyl chloride reaction prepared 11,11；Its synthetic route is as follows：
Wherein, R1And R2It is defined as described above.
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 prepared in suitable solvent or solvent compositions.
Present invention also offers a kind of pharmaceutical composition, it is by the active component of the upper effective dose for the treatment of and pharmaceutically acceptable Auxiliary material composition；Described active component includes one or more in logical formula (I) compound and its pharmaceutically acceptable salt. In described pharmaceutical composition, described auxiliary material includes pharmaceutically acceptable carrier, diluent and/or excipient.
Pharmaceutical composition can be made various types of administration unit dosage forms, such as tablet, pill, powder according to therapeutic purposes 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 for using.
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 injection is prepared, it is also possible to using in the art any Conventional carrier.For example：Water, ethanol, propane diols, the isooctadecanol of ethoxylation, the isooctadecanol and polyethylene of polyoxy Fatty acid ester of 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 in a wide range without specifically limited Selection, generally can be the 5~95% of mass percent, be 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, select the preparation administration of various formulations.
Invention additionally provides the logical formula (I) compound, its pharmaceutically acceptable salt or described pharmaceutical composition Application in IDO 1 (IDO1) inhibitor is prepared.Described IDO1 inhibitor is used to treat IDO1 Jie The immunosuppressant related disorder patients for leading, described relevant disease includes cancer, viral infection, neurodegenerative disease, white interior Barrier, organ-graft refection, depression and autoimmune disease.
Exist present invention also offers the logical formula (I) compound, its pharmaceutically acceptable salt or described pharmaceutical composition The purposes in medicine is prepared, the medicine is used to treat the cancer of patient, viral infection, neurodegenerative disease, cataract, organ Graft rejection, depression or autoimmune disease.
Described cancer is included 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 is included 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 The infection for causing for one or more in your viral and varicella virus.
Described neurodegenerative disease is included 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 is included but is not limited to：Rheumatoid arthritis, systemic loupus erythematosus, musculus cutaneus Inflammation, chorionitis, nodular vasculitis, multiple sclerosis, ephrosis, myasthenia gravis, MCTD, psoriasis, One or more in hepatopathy, endocrine relevant disease and the autoimmune response caused due to infection.
Can present invention also offers the logical formula (I) compound, its pharmaceutically acceptable salt or described pharmaceutical composition Combined for treating the relevant disease mediated by IDO1 with the therapeutic agent and/or treatment method with one or more other species.
The therapeutic agent and/or treatment method of other species are included but is not limited to：Chemotherapeutics, anti-tumor drugs targeting, It is the inhibitor of immunologic test point Co inhibitor, the activator of immunologic test point costimulatory molecules, anti-tumor vaccine, antiviral Agent, antiviral vaccine, cytokine therapy, adoptive cellular immunotherapy or radiotherapy.
Described chemotherapeutics is included but is not limited to：Alkylating agent, Antitubulin, topoenzyme inhibitor, platinum medicine, Antimetabolitas or hormone series antineoplastic medicament.
Described anti-tumor drugs targeting is included 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 is included 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 is included but is not limited to：STING activators, 4-1BB activators, OX40 are exciting Agent, ROR gamma agonists or ICOS activators.
Specific embodiment
In order to 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 synthesis of 2- benzoxazoles quinolines ketone (1a)
O-aminophenol (1.00g, 9.16mmol) and CDI (1.78g, 10.99mmol) 30mL dry DMFs are dissolved, Nitrogen is protected, and 5h is reacted at 80 DEG C, is down to room temperature, add water (10mL) be quenched reaction, ethyl acetate (3 × 7mL) is extracted, and is used respectively Saturated ammonium chloride and saturated common salt water washing organic layer, anhydrous magnesium sulfate are dried, column chromatography for separation (petroleum ether: ethyl acetate=7 : 1), obtain light red solid 1.10g, yield 89%, mp 137-141 DEG C.1H NMR (300MHz, Chloroform-d) δ 9.81 (s, 1H), 8.00-6.85 (m, 4H)
The synthesis of 3- (4- fluorophenethyls ketone group) -2- benzoxazoles quinolines ketone (2a)
2- benzoxazoles quinolines ketone (0.10g, 0.74mmol) and potassium carbonate (0.31g, 2.22mmol) are mixed with 10mL DMF Close, 1h is reacted at 80 DEG C, then cool the temperature to 60 DEG C, add alpha-chloro -4 '-fluoro acetophenone (0.38g, 2.22mmol), instead 3h is answered, room temperature is down to, adds saturated ammonium chloride solution (10mL) that reaction, ethyl acetate extraction (3 × 7mL), saturated common salt is quenched Water washing, anhydrous magnesium sulfate is dried, and (petroleum ether: ethyl acetate=10: 1), obtains faint yellow solid 0.17g, receive column chromatography for separation Rate 83%, mp 148-150 DEG C.ESI-MS：294.1[M+Na]+；1H NMR (300MHz, Chloroform-d) δ 8.08 (ddd, J =9.0,5.2,2.1Hz, 2H), 7.39-6.96 (m, 5H), 6.85 (dq, J=4.8,3.3,2.1Hz, 1H), 5.22 (d, J= 2.0Hz, 2H) .IR (KBr)：3074,1763,1694,1601,1487,1232cm-1.
Embodiment 2
The synthesis of 3- (4- chloro-acetophenones base) -2- benzoxazoles quinolines ketone (2b)
The synthetic method of reference object compound 2a, with 2- benzoxazoles quinoline ketone and alpha-chloro -4 '-chloro-acetophenone as raw material It is obtained, yield 85%, mp 193-195 DEG C.ESI-MS：288.6[M+H]+；1H NMR (300MHz, Chloroform-d) δ 8.14-7.86 (m, 2H), 7.53 (d, J=8.0Hz, 2H), 7.40-7.05 (m, 3H), 6.86 (s, 1H), 5.23 (d, J= 3.1Hz, 2H) .IR (KBr)：3065,1763,1691,1587,1487,1246cm-1.
Embodiment 3
The synthesis of 3- (3- chloro-acetophenones base) -2- benzoxazoles quinolines ketone (2c)
The synthetic method of reference object compound 2a, with 2- benzoxazoles quinoline ketone and alpha-chloro -3 '-chloro-acetophenone as raw material It is obtained, yield 85%, mp 150-152 DEG C.ESI-MS：288.6[M+H]+；1H NMR (300MHz, Chloroform-d) δ 8.34-7.84 (m, 2H), 7.83-7.43 (m, 2H), 7.42-7.07 (m, 3H), 7.02-6.76 (m, 1H), 5.23 (qd, J= 8.4,4.9,4.3Hz, 2H) .IR (KBr)：3071,1722,1683,1601,1512,1229cm-1.
Embodiment 4
The synthesis of the chloro- 2- benzoxazoles quinoline ketone (1b) of 5-
With reference to the synthetic method of 1a, it is obtained by raw material of the chloro- Ortho-Aminophenols of 4-, yield 87%, mp 189-193 DEG C.1H NMR (300MHz, Chloroform-d) δ 8.87 (s, 1H), 7.28 (d, J=1.8Hz, 1H), 7.13 (dp, J=8.0,2.1Hz, 2H).
The synthesis of the chloro- 3- of 5- (4- fluorophenethyls ketone group) -2- benzoxazoles quinolines ketone (2d)
The synthetic method of reference object compound 2a, is obtained, yield by raw material of 1b and alpha-chloro -4 '-fluoro acetophenone 153-155 DEG C of 89%, mp.ESI-MS：306.7[M+H]+；1H NMR (300MHz, Chloroform-d) δ 8.08 (d, J= 7.4Hz, 2H), 7.20 (dd, J=30.4,9.8Hz, 4H), 6.85 (s, 1H), 5.20 (s, 2H) .IR (KBr)：3076,1771, 1690,1599,1487,1232cm-1.
Embodiment 5
The synthesis of the chloro- 3- of 5- (4- chloro-acetophenones base) -2- benzoxazoles quinolines ketone (2e)
The synthetic method of reference object compound 2a, is obtained, yield by raw material of 1b and alpha-chloro -4 '-chloro-acetophenone 167-169 DEG C of 87%, mp.ESI-MS：323.1[M+H]+；1H NMR (300MHz, Chloroform-d) δ 8.05-7.93 (m, 2H), (s, the 2H) .IR (KBr) of 7.60-7.50 (m, 2H), 7.24-7.12 (m, 2H), 6.85 (d, J=2.0Hz, 1H), 5.21： 3067,1772,1719,1589,1485,1246cm-1.
Embodiment 6
The synthesis of the chloro- 3- of 5- (3- chloro-acetophenones base) -2- benzoxazoles quinolines ketone (2f)
The synthetic method of reference object compound 2a, is obtained, yield by raw material of 1b and alpha-chloro -3 '-chloro-acetophenone 134-136 DEG C of 87%, mp.ESI-MS：323.1[M+H]+；1H NMR (300MHz, Chloroform-d) δ 7.97 (d, J= 27.1Hz, 2H), 7.68 (s, 1H), 7.54 (s, 1H), 7.17 (d, J=10.9Hz, 2H), 6.84 (s, 1H), 5.22 (s, 2H) .IR(KBr)：3067,1778,1703,1614,1487,1223cm-1.
Embodiment 7
The synthesis of 3- (2- (4- fluorophenyls) -2- hydroxyls) ethyl -2- benzoxazoles quinolines ketone (3a)
Target compound 2a (0.10g, 0.37mmol) 10mL anhydrous tetrahydro furans are dissolved, hydroboration is added under ice bath Sodium (0.04g, 1.11mmol), reacts 1h under ice bath, add 10mL saturated ammonium chlorides to be quenched, ethyl acetate extraction (3 × 7mL), Anhydrous magnesium sulfate is dried, and (petroleum ether: ethyl acetate=5: 1), obtains white solid 0.10g, yield 99%, mp for column chromatography purifying 111-113℃.ESI-MS：274.3[M+H]+；1H NMR (300MHz, Chloroform-d) δ 7.89 (s, 1H), 7.53-7.37 (m, 2H), 7.26-6.86 (m, 5H), 5.79 (t, 1H), 4.41 (t, 1H), 4.10 (t, 1H) .IR (KBr)：3645,3071, 1722,1601,1512,1229,1103cm-1.
Embodiment 8
The synthesis of 3- (2- (4- chlorphenyls) -2- hydroxyls) ethyl -2- benzoxazoles quinolines ketone (3b)
Reference object compound 3a synthetic methods, are obtained, yield 99%, mp 140-142 DEG C by raw material of 2b.ESI-MS： 290.7[M+H]+；1H NMR (300MHz, Chloroform-d) δ 7.36 (q, J=7.5,6.4Hz, 4H), 7.15 (dq, J= 14.1,6.9Hz, 3H), 6.99 (d, J=7.0Hz, 1H), 5.14 (s, 1H), 3.95 (d, J=10.8Hz, 2H), 3.06 (s, 1H).IR(KBr)：3645,3063,1748,1593,1485,1240,1090cm-1.
Embodiment 9
The synthesis of 3- (2- (3- chlorphenyls) -2- hydroxyls) ethyl -2- benzoxazoles quinolines ketone (3c)
Reference object compound 3a synthetic methods, are obtained, yield 99%, mp 113-115 DEG C by raw material of 2c.ESI-MS： 290.7[M+H]+；1H NMR (300MHz, Chloroform-d) δ 7.52-7.42 (m, 1H), 7.28 (d, J=2.2Hz, 3H), 7.20-7.05 (m, 3H), 7.01 (dd, J=7.9,1.7Hz, 1H), 5.11 (dd, J=8.2,4.0Hz, 1H), 4.13-3.83 (m, 3H), 3.54 (s, 1H) .IR (KBr)：3646,3063,1759,1599,1485,1240,1103cm-1.
Embodiment 10
The synthesis of the chloro- 3- of 5- (2- (4- fluorophenyls) -2- hydroxyls) ethyl -2- benzoxazoles quinolines ketone (3d)
Reference object compound 3a synthetic methods, are obtained, yield 99%, mp 142-144 DEG C by raw material of 2d.ESI-MS： 308.7[M+H]+；1H NMR (300MHz, Chloroform-d) δ 7.42 (dd, J=8.4,5.3Hz, 2H), 7.18-6.87 (m, 5H), (s, the 1H) .IR (KBr) of 5.14 (dd, J=8.4,3.7Hz, 1H), 4.17-3.79 (m, 2H), 2.94：3646,3089, 1771,1607,1485,1223,1096cm-1.
Embodiment 11
The synthesis of the chloro- 3- of 5- (2- (4- chlorphenyls) -2- hydroxyls) ethyl -2- benzoxazoles quinolines ketone (3e)
Reference object compound 3a synthetic methods, are obtained, yield 99%, mp 127-129 DEG C by raw material of 2e.ESI-MS： 325.1[M+H]+；1H NMR (300MHz, Chloroform-d) δ 7.42-7.32 (m, 4H), 7.09 (d, J=1.1Hz, 1H), 7.08 (s, 1H), 7.03 (dd, J=1.8,0.8Hz, 1H), 5.12 (dd, J=8.3,3.6Hz, 1H), 3.99 (dd, J=14.6, 3.6Hz, 1H), 3.87 (dd, J=14.5,8.3Hz, 1H), 2.97 (s, 1H) .IR (KBr)：3626,3063,1767,1614, 1485,1252,1092cm-1.
Embodiment 12
The synthesis of the chloro- 3- of 5- (2- (3- chlorphenyls) -2- hydroxyls) ethyl -2- benzoxazoles quinolines ketone (3f)
Reference object compound 3a synthetic methods, are obtained, yield 99%, mp 157-159 DEG C by raw material of 2f.ESI-MS： 325.1[M+H]+；1H NMR (300MHz, Chloroform-d) δ 7.45 (dq, J=1.6,0.9Hz, 1H), 7.43-7.37 (m, 2H), 7.37-7.31 (m, 1H), 7.16-7.05 (m, 2H), 6.95 (d, J=8.5Hz, 1H), 5.74 (t, J=8.3Hz, 1H), 4.38 (t, J=8.9Hz, 1H), 4.01 (dd, J=9.1,7.9Hz, 1H) .IR (KBr)：3647,3078,1728,1599, 1506,1261,1099cm-1.
Embodiment 13
The synthesis of 3- phenethyls -2- benzoxazoles quinolines ketone (4a)
2- benzoxazoles quinolines ketone (0.10g, 0.74mmol) and potassium carbonate (0.31g, 2.22mmol) are mixed with 10mL DMF Close, 1h is reacted at 80 DEG C, then cool the temperature to 60 DEG C, add Beta-bromo vinylbenzene (0.41g, 2.22mmol), react 6h, drop To room temperature, add 10mL saturated ammonium chloride solutions that reaction is quenched, ethyl acetate extraction (3 × 7mL), saturated common salt washing is organic Layer, anhydrous magnesium sulfate is dried, and (petroleum ether: ethyl acetate=10: 1), obtains white solid 0.15g, yield 86%, mp to column chromatography 116-118℃.ESI-MS：240.3[M+H]+；1H NMR (300MHz, Chloroform-d) δ 7.29 (d, J=7.7Hz, 3H), 7.20 (s, 3H), 7.10 (t, J=5.9Hz, 2H), 6.79 (d, J=7.1Hz, 1H), 4.06 (t, J=7.4Hz, 2H), 3.08 (t, J=7.2Hz, 2H) .IR (KBr)：3061,1767,1614,1489,1258cm-1.
Embodiment 14
The synthesis of 3- (3- luorobenzyls) -2- benzoxazoles quinolines ketone (4b)
Reference object compound 4a synthetic methods, are obtained, yield 88%, mp 119-121 DEG C with 1a and 3- fluorobenzyl chlorides. ESI-MS：244.2[M+H]+；1H NMR (300MHz, DMSO-d6) δ 7.48-7.31 (m, 2H), 7.30-6.86 (m, 6H), 5.12-4.86 (m, 2H) .IR (KBr)：3042,1757,1589,1487,1252cm-1.
Embodiment 15
The synthesis of 3- (4- chlorobenzyls) -2- benzoxazoles quinolines ketone (4c)
Reference object compound 4a synthetic methods, are obtained, yield 87%, mp 145-147 DEG C with 1a and 4- chlorobenzyl chlorides. ESI-MS：260.7[M+H]+；1H NMR (300MHz, Chloroform-d) δ 7.57-7.25 (m, 4H), 7.23 (s, 1H), 7.18-7.01 (m, 2H), 6.95-6.74 (m, 1H), 5.26-4.79 (m, 2H) .IR (KBr)：3005,1771,1597,1485, 1275cm-1.
Embodiment 16
The synthesis of the chloro- 3- phenethyls -2- benzoxazoles quinoline ketone (4d) of 5-
Reference object compound 4a synthetic methods, are obtained, yield 88%, mp 102-104 with 1b and Beta-bromo vinylbenzene ℃.ESI-MS：274.7[M+H]+；1H NMR (300MHz, Chloroform-d) δ 7.36-7.24 (m, 3H), 7.24-7.15 (m, 2H), 7.14-6.99 (m, 2H), 6.67 (d, J=2.0Hz, 1H), 4.03 (t, J=7.3Hz, 2H), 3.06 (t, J=7.3Hz, 2H).IR(KBr)：3057,1759,1610,1485,1246cm-1.
Embodiment 17
The synthesis of the chloro- 3- of 5- (3- luorobenzyls) -2- benzoxazoles quinolines ketone (4e)
Reference object compound 4a synthetic methods, are obtained, yield 92%, mp 134-136 DEG C with 1b and 3- fluorobenzyl chlorides. ESI-MS：278.7[M+H]+；1H NMR (300MHz, Chloroform-d) δ 7.36 (q, J=11.9,9.7Hz, 1H), 7.22- (d, J=9.4Hz, the 2H) .IR (KBr) of 6.92 (m, 5H), 6.81 (d, J=14.5Hz, 1H), 4.96：3065,1772,1589, 1506,1256cm-1.
Embodiment 18
The synthesis of the chloro- 3- of 5- (4- chlorobenzyls) -2- benzoxazoles quinolines ketone (4f)
Reference object compound 4a synthetic methods, are obtained, yield 91%, mp 122-124 DEG C with 1b and 4- chlorobenzyl chlorides. ESI-MS：295.1[M+H]+；1H NMR (300MHz, Chloroform-d) δ 7.32 (q, J=8.1Hz, 4H), 7.23-6.97 (m, 3H), 6.90-6.73 (m, 1H), 4.95 (s, 2H) .IR (KBr)：3067,1767,1601,1483,1252cm-1.
Embodiment 19
The synthesis of the fluoro- 2- benzoxazoles quinoline ketone (1c) of 5-
With reference to the synthetic method of 1a, by the fluoro- Ortho-Aminophenols of 4- for raw material is obtained, yield 90%, mp 174-176 DEG C.1H NMR (300MHz, Chloroform-d) δ 9.60 (s, 1H), 7.13 (dd, J=8.7,4.2Hz, 1H), 6.93-6.68 (m, 2H)
The synthesis of the fluoro- 3- of 5- (3- luorobenzyls) -2- benzoxazoles quinolines ketone (4g)
Reference object compound 4a synthetic methods, are obtained, yield 88%, mp 156-158 DEG C with 1c and 3- fluorobenzyl chlorides.1H NMR (300MHz, Chloroform-d) δ (ppm) 7.37 (td, J=8.3,5.6Hz, 1H), 7.23-7.11 (m, 2H), 7.06 (dd, J=10.2,4.0Hz, 2H), 6.83 (td, J=9.2,2.6Hz, 1H), 6.59 (dd, J=7.7,2.6Hz, 1H), 5.00 [the M+H]+.IR (KBr) of (s, 2H) .MS (EI) m/z 262.1：3063,1765,1591,1487,1250cm-1.
Embodiment 20
The synthesis of the fluoro- 3- of 5- (4- chlorobenzyls) -2- benzoxazoles quinolines ketone (4h)
Reference object compound 4a synthetic methods, are obtained, yield 82%, mp 103-105 DEG C with 1c and 4- chlorobenzyl chlorides.1H NMR (300MHz, Chloroform-d) δ (ppm) 7.46-7.21 (m, 4H), 7.13 (dd, J=8.8,4.2Hz, 1H), 6.79 (td, J=9.2,2.6Hz, 1H), 6.57 (dd, J=7.6,2.6Hz, 1H), 4.94 (s, 2H) .MS (EI) m/z 278.2 [M+H ]+.IR(KBr)：3061,1778,1614,1489,1250cm-1.
Embodiment 21
The synthesis of 5- nitros -3- (3- luorobenzyls) -2- benzoxazoles quinolines ketone (4i)
Reference object compound 4a synthetic methods, are obtained, yield with 5- nitro -2- benzoxazoles quinoline ketone and 3- fluorobenzyl chlorides 116-118 DEG C of 81%, mp.1H NMR (300MHz, Chloroform-d) δ (ppm) 8.42 (d, J=1.8Hz, 1H), 8.10 (dd, J=7.5,2.0Hz, 1H), 7.40 (d, J=7.5Hz, 1H), 7.35-7.25 (m, 2H), 7.19 (dt, J=8.7, 1.8Hz, 1H), 6.97 (ddt, J=8.9,6.8,2.3Hz, 1H), 5.56 (d, J=1.3Hz, 2H) .MS (EI) m/z 289.1 [M +H]+.IR(KBr)：3065,1792,1614,1506,1261cm-1.
Embodiment 22
The synthesis of 5- nitros -3- (4- chlorobenzyls) -2- benzoxazoles quinolines ketone (4j)
Reference object compound 4a synthetic methods, are obtained, yield with 5- nitro -2- benzoxazoles quinoline ketone and 4- chlorobenzyl chlorides 165-167 DEG C of 77%, mp.1H NMR (300MHz, Chloroform-d) δ (ppm) 8.14 (dd, J=8.8,2.3Hz, 1H), 7.76 (d, J=2.3Hz, 1H), 7.48-7.29 (m, 5H), 5.05 (s, 2H) .MS (EI) m/z 303.1 [M-H]+.IR(KBr)： 3080,1784,1595,1522,1260cm-1.
Embodiment 23
The synthesis of 5- amino -3- (3- luorobenzyls) -2- benzoxazoles quinolines ketone (5)
4i (0.10g, 0.35mmol) 10mL industrial alcohols are dissolved, ammonium chloride (0.19g, 3.47mmol) is dissolved in 2mL water adds reaction system.Zinc powder (0.23g, 3.47mmol) is slowly added under ice bath cooling, ice bath reaction 1h recovers to room temperature Reaction 2h, removes ethanol, and ethyl acetate extraction, anhydrous magnesium sulfate is dried, column chromatography for separation (petroleum ether: ethyl acetate=5: 1), Obtain faint yellow solid 0.70g, yield 78%, mp 179-181 DEG C.1H NMR (300MHz, Chloroform-d) δ (ppm) 7.29 (d, J=21.3Hz, 2H), 7.10 (d, J=7.7Hz, 1H), 7.03-6.96 (m, 2H), 6.37 (dd, J=8.5,2.4Hz, 1H), 6.15 (d, J=2.2Hz, 1H), 4.92 (s, 2H), 3.59 (s, 2H) .MS (EI) m/z 257.1 [M-H]+.IR(KBr)： 3356,3048,1746,1591,1489,1254cm-1.
Embodiment 24
The synthesis of 3- (2- (4- fluorophenyls) acetyl group) -2- benzoxazoles quinolines ketone (6a)
1a (0.10g, 0.74mmol) 10mL anhydrous tetrahydro furans are dissolved, triethylamine (0.22g, 2.22mmol) is added Acid is tied up, the anhydrous tetrahydrofuran solution (0.15g, 0.89mmol) to fluorophenylacetyl chloride is added dropwise under ice bath, drop finishes will react liquid temperature Degree is warmed to room temperature, and is again heated to 70 DEG C, reacts 6h, plus 10mL water quenchings are gone out reaction, and ethyl acetate extracts (3 × 7mL).Column chromatography is pure (petroleum ether: ethyl acetate=10: 1), obtains white solid 0.17g, yield 86%, mp 180-182 DEG C for change.ESI-MS：272.2 [M+H]+；1H NMR (300MHz, DMSO-d6) δ 7.98-7.89 (m, 1H), 7.50-7.41 (m, 1H), 7.41-7.28 (m, 4H), 7.24-7.14 (m, 2H), 4.41 (s, 2H) .IR (KBr)：3067,1796,1721,1601,1514,1248cm-1.
Embodiment 25
The synthesis of 3- benzoyls -2- benzoxazoles quinolines ketone (6b)
The synthetic method of reference object compound 6a, is obtained, yield 89%, mp 185- by raw material of 1a and chlorobenzoyl chloride 187℃.ESI-MS：240.2[M+H]+；1H NMR (300MHz, DMSO-d6) δ 7.95-7.85 (m, 2H), 7.84-7.75 (m, 1H), 7.67 (t, J=7.4Hz, 1H), 7.53 (t, J=7.6Hz, 2H), 7.49-7.42 (m, 1H), 7.40-7.26 (m, 2H) .IR(KBr)：3069,1805,1697,1599,1481,1250cm-1.
Embodiment 26
The synthesis of the chloro- 3- of 5- (2- (4- fluorophenyls) acetyl group) -2- benzoxazoles quinolines ketone (6c)
The synthetic method of reference object compound 6a, with 1b with to fluorophenylacetyl chloride as raw material be obtained, yield 87%, mp193-195℃.ESI-MS：306.7[M+H]+；1H NMR (300MHz, Chloroform-d) δ 7.99 (d, J=8.2Hz, 2H), (s, the 2H) .IR (KBr) of 7.56 (d, J=8.0Hz, 2H), 7.35-6.99 (m, 2H), 6.85 (s, 1H), 3.51：3063, 1755,1715,1611,1485,1246cm-1.
Embodiment 27
The synthesis of 3- (4- methoxybenzyls) carbamyl -2- benzoxazoles quinolines ketone (7a)
Solid phosgene (0.22g, 0.74mmol) 5mL anhydrous methylene chlorides are dissolved, 2- benzoxazoles is added dropwise under ice bath The anhydrous methylene chloride solution (5mL) of quinoline ketone (0.10g, 0.74mmol) and triethylamine (0.30g, 2.96mmol), drop finishes immediately Nitrogen protect, at room temperature stir 1h after, under ice bath be added dropwise 4-Methoxybenzylamine (0.15g, 1.11mmol) and triethylamine (0.11g, Anhydrous methylene chloride solution (5mL) 1.11mmol), reacts 3h at room temperature, plus 10mL saturated ammonium chlorides are quenched, dichloromethane extraction Take (3 × 7mL), anhydrous magnesium sulfate is dried, and (petroleum ether: ethyl acetate=7: 1), obtains white solid 0.18g, yield to column chromatography 82-84 DEG C of 83%, mp.ESI-MS：299.4[M+H]+；1H NMR (300MHz, DMSO-d6) δ 8.56 (s, 1H), 7.89 (d, 1H), (s, the 3H) .IR (KBr) of 7.43 (s, 1H), 7.41-7.25 (m, 4H), 6.90 (d, 2H), 4.45 (d, 2H), 3.73：3266, 3009,2951,2870,1761,1722,1612,1514,1275,1260,1034cm-1.
Embodiment 28
The synthesis of the chloro- 3- of 5- (3- methoxybenzyls) carbamyl -2- benzoxazoles quinolines ketone (7b)
The synthetic method of reference object compound 7a, is obtained, yield with 1b and solid phosgene, O-methoxy benzylamine as raw material 120-122 DEG C of 90%, mp.ESI-MS：333.7[M+H]+；1H NMR (300MHz, Chloroform-d) δ 8.37 (s, 1H), (s, the 3H) .IR (KBr) of 8.15 (d, 1H), 7.33-7.16 (m, 3H), 6.97-6.84 (m, 3H), 4,60 (d, 2H), 3.83： 3354,3048,1771,1724,1601,1477,1265,1252,1042cm-1.
Embodiment 29
The synthesis of the chloro- 3- of 5- (4- anisyls) carbamyl -2- benzoxazoles quinolines ketone (7c)
The synthetic method of reference object compound 7a, is obtained, yield with 1b and solid phosgene, P-nethoxyaniline as raw material 162-164 DEG C of 86%, mp.ESI-MS：319.7[M+H]+；1H NMR (300MHz, DMSO-d6) δ 9.85 (s, 1H), 7.89 (d, J=2.3Hz, 1H), 7.53 (dd, J=8.8,2.4Hz, 3H), 7.41-7.28 (m, 2H), 7.22-7.07 (m, 2H), 7.03- (s, the 1H) .IR (KBr) of 6.79 (m, 3H), 3.77 (s, 3H), 3.35：3291,3036,2957,2866,1784,1734,1609, 1477,1246,1182,1034cm-1.
Embodiment 30
The synthesis of 1- (2- (4- fluorophenyls) -2 carbonyl ethyls) -1,3- dihydro -2H- benzo [d] imidazoles -2- ketone (8)
Reference object compound 2a synthetic methods, with 2- benzimidazolones and alpha-chloro -4 '-fluoro acetophenone as raw material system , yield 78%, mp 280-282 DEG C1H NMR (300MHz, Chloroform-d) δ (ppm) 8.22-8.03 (m, 2H), 7.43-7.31 (dd, J=7.9,1.5Hz, 1H), 7.26-7.14 (m, 3H), 7.12-7.06 (td, J=7.6,1.5Hz, 1H), 7.05-6.97 (td, J=7.6,1.5Hz, 1H), 5.61 (s, 2H) .MS (EI) m/z 273.3 [M+H]+.IR(KBr)：3323, 3018,1687,1520,1439cm-1.
The synthesis of 1- (2- (4- fluorophenyls) -2- ethoxys) -1,3- dihydro -2H- benzo [d] imidazoles -2- ketone (9)
Reference object compound 3a synthetic methods, are that raw material is obtained yield 73%, mp 276-278 DEG C with 81H NMR (300MHz, Chloroform-d) δ (ppm) 7.49-7.43 (m, 2H), 7.39-7.35 (m, 1H), 7.13-7.07 (m, 3H), 7.06-7.01 (td, J=7.6,1.5Hz, 1H), 7.00-6.96 (dd, J=7.8,1.5Hz, 1H), 5.25-5.17 (d, J= 6.4Hz, 1H), 5.14-5.07 (m, 1H), 4.38-4.27 (d, J=4.9Hz, 2H) .MS (EI) m/z 273.3 [M+H]+.IR (KBr)：3570,3343,3028,1670,1521,1449cm-1.
Embodiment 31
The synthesis of the tert-butyl group (1H- benzos [d] imidazoles -2- bases) carbamate (10)
Boc is added in THF (30mL) solution of 1H-2- aminobenzimidazoles (2.00g, 15.02mmol)2O (3.61g, 16.52mmol) with TEA (3.04g, 30.04mmol), 3h then is stirred at 60 DEG C, be cooled to room temperature, remove solvent oil Ether washing obtains white solid crude product 10 (3g, 85.62%), is directly used in next step reaction.
The synthesis of the tert-butyl group (1- (2- (4- fluorophenyls) acetyl group) -1H- benzos [d] imidazoles -2- bases) carbamate (11)
Reference object compound 6a synthetic methods, with 10 for raw material is obtained, yield 53%, mp 310-312 DEG C1H NMR (300MHz, Chloroform-d) δ (ppm) 8.53 (s, 1H), 7.92-7.80 (m, 1H), 7.76-7.64 (dd, J=7.7, 1.4Hz, 1H), 7.41-7.21 (m, 4H), 7.11-6.99 (m, 2H), 4.04-3.88 (t, J=1.0Hz, 2H), 1.46 (s, 9H).MS(EI)m/z 370.4[M+H]+.IR(KBr)：3353,3038,1680,1531,1423,1370cm-1.
The synthesis of 1- (2- amino -1H- benzo [d] imidazoles -1- bases) -2- (4- fluorophenyls) ethane (12)
To being slowly added dropwise HCl solution (4M in dioxane (5mL) solution containing 11 (0.5g, 1.35mmol) under ice bath HCl, 6.8mL), 2h is stirred at room temperature, white solid to be filtered, dioxane washing obtains hydrochloride, and 12 are obtained after dissociation (0.26g, 71.33%), mp 237-239 DEG C1H NMR (300MHz, Chloroform-d) δ (ppm) 7.84-7.69 (m, 2H), 7.36-7.22 (m, 4H), 7.14-7.02 (m, 2H), 6.15-6.08 (d, J=5.9Hz, 1H), 6.06-6.00 (d, J= 5.9Hz, 1H), 4.03-3.93 (t, J=1.0Hz, 2H) .MS (EI) m/z 270.2 [M+H]+.IR(KBr)：3356,3148, 3048,1646,1591,1419cm-1.
Embodiment 32
1. the IDO1 inhibitory activity based on Hela cells is tested
1.1 experiment materials and key instrument
1.2 experimental techniques
From ATCC purchase Hela cells be stored in minimum essential medium (2mM Glus and be tuned into containing The EarleShi BSS of 1.5g/L sodium acid carbonates, 0.1mM nonessential amino acid, the bronze medals of 1mM third acid sodium and 10% hyclone) in. Hela cells are stored in offer 5%CO at 37 DEG C2The wet incubator of control in.
By 5 × 103Be seeded in Hela cells in 96 well culture plates by the density in/hole, and overnight incubation.Second day, will The serial dilutions (the μ L culture mediums of cumulative volume 200) of IFN-γ (final concentration 100ng/mL) and compound add to cell.Incubate 24 During 140 μ L of supernatant liquid/hole moved into 96 new orifice plates after hour, the trichloroacetic acid of 10 μ L 6.1mol/L is added, in constant temperature oven In 50 DEG C incubate 30min so that produce N- formoxyl kynurenins be hydrolyzed to kynurenin.Then will react mixed with 4000rpm Compound is centrifuged 10min to remove sediment.During 100 μ L of supernatant liquid/hole moved into 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 is calculated.Experiment sets 3 multiple holes.
1.3 experimental results
Experimental result is as shown in table 1.Result shows that the compounds of this invention there is significant suppression to make the activity of IDO1 With.Wherein, the most strong (IC of the activity of compound 4f50：6.08μM).
Inhibitory activity of the compounds of this invention of table 1 to IDO1
The proliferation experiment of 2.T lymphocytes
2.1 experimental techniques
The treatment 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, be transferred in 1.5mL centrifuge tubes, be centrifuged, suck supernatant, plus Enter 1mL DMEM culture mediums suspension cell again.Mitomycin C (the μ g/ml of final concentration 25) is added, piping and druming is mixed to be hooked, 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, aseptic taking-up spleen be put into containing 2mL without In the culture dish of the 35mm of the culture mediums of precooling RPMI 1640 of bacterium, 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, blows, stands 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 (irritates 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 (irritates cell+reacting cells+correspondence compound), and blank (only adds reacting cells), mould Type group (irritates cell+reacting cells), in addition to blank, other group 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) 4h is cultivated in continuation in adding 20 μ L MTT (final concentration 4mg/ml) incubators, and 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 results
In mixed lymphocyte reaction (MLP) system, B16F1 cells expression IDO1 high, the propagation to T lymphocytes can be produced Raw inhibitory action.As addition compound 4e, 4f and 6c (3 times of IC50Concentration) after culture 48h, using MTT detection T lymphocytes Propagation, proliferation rate is 29.96%, 52.25% and 27.22%, illustrates that compound 4e, 4f and 6c can dramatically increase T lymphocytes Propagation.
3. the influence of pair Autoimmune disease
3.1 experimental techniques
By treated B16F1 cells (8 × 104Individual hole), (106 holes use the ConA of 5 μ g/mL to spleen lymphocyte Stimulate) add 24 orifice plates in, add corresponding concentration compound after 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 results
When original T lymphocytes and melanoma cells line B16 F1 are co-cultured, the quantity of Autoimmune disease and Only the experimental group (5.1%) containing original T lymphocytes is compared to rising 2 times (11.7%).As (3 times of compound 4e, 4f and 6c IC50Concentration) in addition system after can substantially reverse this effect (dropping to 6.0%, 8.7% and 7.1% respectively), explanation Compound 4e, 4f and 6c can reverse conversion of the original T lymphocytes to Autoimmune disease by suppressing IDO1.
4. the influence pair IDO1 expression
4.1 experimental techniques
Hela cells are with 2 × 105Per hole density kind in 6 orifice plate cultures, in 37 DEG C, 5%CO2Under the conditions of cultivate 12h.It is empty White control (only adding culture medium), model group (adds IFN-γ, correspondence 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 results
Test result indicate that, compound 4e, 4f and 6c do not influence the expression of IDO1 in Hela cells, illustrate compound 4e, 4f and 6c are the immunosupress for reversing IDO1 to mediate by suppressing the activity of IDO1.

Claims (10)

1. the benzo five-membered heterocycle compound or its pharmaceutically acceptable salt shown in formula (I) are led to：
Wherein：
α and β represent a singly-bound or double bond；When α is singly-bound, β is double bond；When α is double bond, β is singly-bound；
A represents C, O, S, NH or N；
B represents O, S or NH2；
R1Represent hydrogen, halogen, nitro, hydroxyl, cyano group, amino or C1-C10Alkyl；
R2Represent hydrogen, C1-C4Alkyl, C1-C10Alkyl C (O) R3、-C(O)NR4R5、-C(O)R3、C6-C10Aryl, (C1-C5) alkyl (C6-C10) aryl, C1-C10Aromatic heterocyclic or-(C1-C5) alkyl (C1-C10) aromatic heterocyclic；Wherein described heteroaromatic group can Other hetero atoms of O, S or N are optionally selected from comprising one or more；Described alkyl, aryl or aromatic heterocyclic are optionally Monosubstituted to five substitutions by substitution base that is following identical or differing, described substitution base is selected from：Hydrogen, halogen, hydroxyl, methoxyl group Or R3；
R3、R4、R5Hydrogen, C can be represented with identical or different1-C8Alkyl, C3-C6Cycloalkyl, C6-C10Aryl ,-(C1-C5) alkyl (C6-C10) aryl, C1-C10Aromatic heterocyclic or (C1-C5) alkyl (C1-C10) aromatic heterocyclic；Wherein described heteroaromatic group can appoint Selection of land is selected from other hetero atoms of O, S or N comprising one or more；Described alkyl, aryl or aromatic heterocyclic optionally by Substitution base that is following identical or differing is monosubstituted to five substitutions, and described substitution base is selected from：Hydrogen, halogen, hydroxyl or methoxyl group.
2. benzo five-membered heterocycle compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that：
α and β represent a singly-bound or double bond；When α is singly-bound, β is double bond；When α is double bond, β is singly-bound；
A represents O, NH or N；
B represents O or NH2；
R1Represent hydrogen, halogen, nitro, hydroxyl or amino；
R2Represent hydrogen, C1-C4Alkyl, C1-C10Alkyl C (O) R3、-C(O)NR4R5、-C(O)R3、C6-C10Aryl ,-(C1-C5) alkyl (C6-C10) aryl, C1-C10Aromatic heterocyclic or-(C1-C5) alkyl (C1-C10) aromatic heterocyclic；Wherein described heteroaromatic group can Other hetero atoms of O, S or N are optionally selected from comprising one or more；Described alkyl, aryl or aromatic heterocyclic are optionally Monosubstituted to five substitutions by substitution base that is following identical or differing, described substitution base is selected from：Hydrogen, halogen, hydroxyl, methoxyl group Or R3；
R3、R4、R5Hydrogen, C can be represented with identical or different1-C8Alkyl, C3-C6Cycloalkyl, C6-C10Aryl, (C1-C5) alkyl (C6- C10) aryl, C1-C10Aromatic heterocyclic or (C1-C5) alkyl (C1-C10) aromatic heterocyclic；Wherein described heteroaromatic group can be optional Ground is selected from other hetero atoms of O, S or N comprising one or more；Described alkyl, aryl or aromatic heterocyclic are optionally by under State substitution base that is identical or differing monosubstituted to five substitutions, described substitution base is selected from：Hydrogen, halogen, hydroxyl or methoxyl group.
3. benzo five-membered heterocycle compound according to claim 2 or its pharmaceutically acceptable salt, it is characterised in that：
α and β represent a singly-bound or double bond；When α is singly-bound, β is double bond；When α is double bond, β is singly-bound；
A represents O, NH or N；
B represents O or NH2；
R1Represent hydrogen, chlorine, fluorine, nitro or amino；
R2Optionally certainly：
4. benzo five-membered heterocycle compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that The compound is selected from：
5. the preparation method of benzo five-membered heterocycle compound according to claim 1, it is characterised in that：
A) when A is O, and B is O, the preparation method of compound is shown in logical formula (I)：The o-aminophenol of difference substitution is sent out with CDI Raw condensation reaction is obtained intermediate 1,1 and different substituted alpha-chloro acetophenones reactions and is obtained 2a-f, 2a-f through sodium borohydride also The prepared 3a-f of original；1 is obtained 4a-j from different substituted aralkyl chlorine reactions, and 4i is reduced prepared 5；1 from different acyl chloride reactions 6a-c is obtained；1 is obtained 7a-c from the reaction of different aminated compounds；Its synthetic route is as follows：
Wherein, R1And R2Definition it is as claimed in claim 1；
B) when A is NH, and B is O, the preparation method of compound is shown in logical formula (I)：2- benzimidazolones and alpha-chloro -4 '-fluorine Acetophenone reaction is obtained 8,8 and is obtained 9 through sodium borohydride reduction；Its synthetic route is as follows：
Wherein, R1And R2Definition it is as claimed in claim 1；
C) when A is N, B is NH2When, the preparation method of compound is shown in logical formula (I)：1H-2- aminobenzimidazoles are protected through Boc It is obtained 10,10 and sloughs Boc substitutions base prepared 12 with acyl chloride reaction prepared 11,11；Its synthetic route is as follows：
Wherein, R1And R2Definition it is as claimed in claim 1.
6. a kind of pharmaceutical composition, it is made up of active component and pharmaceutically acceptable auxiliary material of the upper effective dose for the treatment of；It is described Active component include benzo five-membered heterocycle compound (I) as any one of claim 1-4 or its pharmaceutically may be used The salt of receiving；Described pharmaceutically acceptable auxiliary material includes pharmaceutically acceptable carrier, diluent and/or excipient.
7. compound any one of claim 1-4, its stereoisomer, its pharmaceutically acceptable salt or right will Ask application of the pharmaceutical composition described in 6 in the inhibitor of IDO 1 is prepared, described indoleamine 2,3- The inhibitor of dioxygenase 1 is used to treat the immunosuppressant related disorder patients of the mediation of IDO 1, the Yin Diindyl amine 2, the immunosuppressant relevant disease of the mediation of 3- dioxygenases 1 is cancer, viral infection, neurodegenerative disease, cataract, Organ-graft refection, depression or autoimmune disease.
8. the group described in its pharmaceutically acceptable salt of the compound any one of claim 1-4 or claim 6 Purposes of the compound in medicine is prepared, the medicine is used to treating the cancer of patient, viral infection, neurodegenerative disease, white interior Barrier, organ-graft refection, depression or autoimmune disease.
9. the application according to 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 is 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 various infection for causing；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 cause itself One or more in immune response.
10. the application according to claim 7-9, it is characterised in that：Further give the Disease apply it is a kind of or It is various 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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