CN106928101A - Benzene sulfonamide IDO1 inhibitor, its preparation method and application - Google Patents

Benzene sulfonamide IDO1 inhibitor, its preparation method and application Download PDF

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Publication number
CN106928101A
CN106928101A CN201710135502.9A CN201710135502A CN106928101A CN 106928101 A CN106928101 A CN 106928101A CN 201710135502 A CN201710135502 A CN 201710135502A CN 106928101 A CN106928101 A CN 106928101A
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inhibitor
cancer
compound
phenyl
ido1
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赖宜生
王芳
邹毅
徐强
郭文洁
王燕
孙其锐
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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Priority to CN201710135502.9A priority Critical patent/CN106928101A/en
Publication of CN106928101A publication Critical patent/CN106928101A/en
Priority to PCT/CN2018/078136 priority patent/WO2018161892A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
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    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/17—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/40—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
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Abstract

The invention belongs to drug field, specifically related to a kind of benzenesulfonamides 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

Benzene sulfonamide IDO1 inhibitor, its preparation method and application
Technical field
The invention belongs to drug field, and in particular to a kind of benzenesulfonamides or its 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 (MezrichJD, 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；TernessP, 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 (MunnDH, the 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 the propagation of CD8+T cells, recover 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 be easily caused lung occur superinfection (van der Sluijs KF, et al.JInfect Dis, 2006,193 (2)：214-222).In HIV, IDO1 can promote the propagation of Treg cells by up-regulated expression, and suppress The propagation of Th17 cells, 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 (MyintAM.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 CN102164902 B, be related to treat by applying IDO1 inhibitor or with other Agent is used in combination and comes treating cancer, viral infection, neurodegenerative disease, wound, cataract, the organ-graft refection of age correlation 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 benzenesulfonamides or its and can pharmaceutically connect Salt, its preparation method, pharmaceutical composition and the application received.Compound of the invention has good IDO1 inhibitory activity, can be with For treat and/or prevent IDO1 mediate immunosupress caused by various relevant diseases.
The invention provides the benzenesulfonamides shown in logical formula (I) or its pharmaceutically acceptable salt：
Wherein：
N represents 0~8 integer；
M represents 0~4 integer；
R1Represent hydrogen, cyano group, nitro, hydroxyl, halogen, amino, acetamido, trifluoromethyl or acrylamido；
R2Represent hydrogen, halogen, cyano group, hydroxyl, nitro, C1-C8Alkoxy or methylene-dioxy.
Further, with the benzenesulfonamides shown in logical formula (I) or its pharmaceutically acceptable salt, its feature It is：
N represents 0~4 integer；
M represents 0~4 integer；
R1Represent cyano group, nitro, amino, acetamido or acrylamido；
R2Represent 3- fluorine, 4- fluorine, 3- chlorine, 4- cyano group, 3- methoxyl groups, 4- methoxyl groups, 3,4- dimethoxys or 3,4- methylene Two epoxides.
Specifically, lead to the imidazo isoindoles compound shown in formula (I) and preferably be selected from following compounds：
N- (4- (N- (4- cyanobenzyls) sulfamic) phenyl) acetamide (1a)；
N- (4- (N- (3- chlorobenzyls) sulfamic) phenyl) acetamide (1b)；
N- (4- (N- (4- methoxy-benzyls) sulfamic) phenyl) acetamide (1c)；
N- (4- (N- (4- methoxyphenyls) sulfamic) phenyl) acetamide (1d)；
N- (4- (N- (4- fluorophenyls) sulfamic) phenyl) acetamide (1e)；
N- (4- (N- (3- methoxyphenethyls) sulfamic) phenyl) acetamide (1f)；
N- (4- (N- (3,4- Dimethoxyphenethyl) sulfamic) phenyl) acetamide (1g)；
N- (4- cyanobenzyls) -3- nitrobenzene sulfonamides (1h)；
N- (3- chlorobenzyls) -3- nitrobenzene sulfonamides (1i)；
N- (3- methoxyphenethyls) -3- nitrobenzene sulfonamides (1j)；
N- (4- methoxy-benzyls) -3- nitrobenzene sulfonamides (1k)；
N- (4- methoxyphenyls) -3- nitrobenzene sulfonamides (1l)；
4- cyano group-N- (4- methoxy-benzyls) benzsulfamide (1m)；
4- cyano group-N- (3- luorobenzyls) benzsulfamide (1n)；
N- (benzo [d] [1,3] dioxy -5- methylene) -4- cvanobenzenesulfonamides (1o)；
4- cyano group-N- (3- methoxyphenethyls) benzsulfamide (1p)；
4- amino-N- (3- chlorobenzyls) benzsulfamide (2a)；
4- amino-N- (4- methoxyphenyls) benzsulfamide (2b)；
4- amino-N- (4- fluorophenyls) benzsulfamide (2c)；
4- amino-N- (4- methoxy-benzyls) benzsulfamide (2d)；
4- amino-N- (3- methoxyphenethyls) benzsulfamide (2e)；
4- amino-N- (3,4- Dimethoxyphenethyl) benzsulfamide (2f)；
N- (4- (N- (3- chlorobenzyls) sulfamic) phenyl) acrylamide (3a)；
N- (4- (N- (4- methoxyphenyls) sulfamic) phenyl) acrylamide (3b)；
N- (4- (N- (3,4- Dimethoxyphenethyl) sulfamic) phenyl) acrylamide (3c)；
N- (4- (N- (3- methoxyphenethyls) sulfamic) phenyl) acrylamide (3d).
The compound numbers being related in pharmacological evaluation below are equal to the compound corresponding to code name herein.
Preparation method another object of the present invention is to provide compound shown in logical formula (I), it is characterised in that：
A) R is worked as1During for cyano group, nitro or acetamido, the preparation method of compound is shown in logical formula (I)：Taken with difference There is condensation reaction and compound 1a-p be obtained in the benzene sulfonyl chloride and aminated compounds in generation；Its synthetic route is as follows：
Wherein, n, m, R1And R2It is defined as described above；
B) R is worked as1During for amido, the preparation method of compound is shown in logical formula (I)：1b-g hydrolysis under concentrated hydrochloric acid effect is de- Deacetylate is obtained 2a-f；Its synthetic route is as follows：
Wherein, n, m, R1And R2It is defined as described above；
C) R is worked as1During for acrylamido, the preparation method of compound is shown in logical formula (I)：2a, 2b, 2e, 2f respectively with Acryloyl chloride reaction is obtained 3a-3d；Its synthetic route is as follows：
Wherein, n, m, 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 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 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, Immunologic test selects inhibitor, immunologic test and selects activator, anti-tumor vaccine, antivirotic, antiviral vaccine, cell factor treatment Method, 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 N- (4- (N- (4- cyanobenzyls) sulfonamides) phenyl) acetamide (1a)
Cyano group phenyl ethylamine (1.00g, 7.57mmol) will be dissolved in anhydrous methylene chloride (15mL), add triethylamine (1.26mL, 8.75mmol), stirs 20 minutes, and ice bath is added dropwise the anhydrous of N-acetylsulfanilyl chloride (1.93g, 8.32mmol) Dichloromethane solution (5mL), ice bath is stirred 30 minutes after completion of dropping, removes ice bath, room temperature reaction 4 hours, and add water (25mL), Dichloromethane is extracted, and anhydrous magnesium sulfate is dried, and column chromatography purifying obtains white solid 2.18g, yield 87%, mp 211-213 ℃。1H NMR (300MHz, DMSO-d6) δ (ppm) 10.31 (s, 1H), 8.18 (s, 1H), 7.71 (q, J=9.8,8.8Hz, 6H), 7.44 (dd, J=8.3,4.3Hz, 2H), 4.05 (d, J=7.0Hz, 2H), 2.25-1.99 (m, 3H) .MS (EI) m/z 328.0 [M-H]+.
Embodiment 2
The synthesis of N- (4- (N- (3- chlorobenzyls) sulfonamides) phenyl) acetamide (1b)
With reference to the synthetic method of 1a, it is obtained by a chlorobenzylamine and N-acetylsulfanilyl chloride, yield 90%, mp 185- 187℃。1H NMR (300MHz, DMSO-d6) δ (ppm) 10.31 (s, 1H), 8.09 (s, 1H), 7.86-7.61 (m, 4H), 7.24 (d, J=24.5Hz, 4H), 3.97 (d, J=6.8Hz, 2H), 2.26-1.96 (m, 3H) .MS (EI) m/z 337.0 [M-H]+.
Embodiment 3
The synthesis of N- (4- (N- (4- methoxy-benzyls) sulfonamides) phenyl) acetamide (1c)
With reference to the synthetic method of 1a, it is obtained by 4-Methoxybenzylamine and N-acetylsulfanilyl chloride, yield 80%, mp 188-190℃。1H NMR (300MHz, DMSO-d6) δ (ppm) 10.38 (s, 1H), 7.96 (s, 1H), 7.76-7.68 (m, 4H), (s, the 3H) .MS of 7.13 (d, J=8.3Hz, 2H), 6.83 (d, J=8.3Hz, 2H), 3.86 (s, 2H), 3.71 (s, 3H), 2.09 (EI)m/z 333.0[M-H]+.
Embodiment 4
The synthesis of N- (4- (N- (4- methoxyphenyls) sulfonamides) phenyl) acetamide (1d)
With reference to the synthetic method of 1a, it is obtained by P-nethoxyaniline and N-acetylsulfanilyl chloride, yield 88%, mp 206-208℃。1H NMR (300MHz, DMSO-d6) δ (ppm) 10.29 (s, 1H), 9.77 (s, 1H), 7.78-7.49 (m, 4H), 6.95 (dq, J=8.2,3.2Hz, 2H), 6.86-6.70 (m, 2H), 3.66 (q, J=2.2Hz, 3H), 2.06 (p, J=3.5Hz, 3H).MS(EI)m/z 319.0[M-H]+.
Embodiment 5
The synthesis of N- (4- (N- (4- fluorophenyls) sulfonamides) phenyl) acetamide (1e)
With reference to the synthetic method of 1a, it is obtained by para-fluoroaniline and N-acetylsulfanilyl chloride, yield 91%, mp 190- 192℃。1H NMR (300MHz, DMSO-d6) δ (ppm) 10.32 (d, J=5.5Hz, 1H), 10.13 (s, 1H), 7.78-7.56 (m, 4H), 7.20-6.97 (m, 4H), 2.06 (d, J=5.2Hz, 3H) .MS (EI) m/z 307.0 [M-H]+.
Embodiment 6
The synthesis of N- (4- (N- (3- methoxyphenethyls) sulfonamides) phenyl) acetamide (1f)
With reference to the synthetic method of 1a, it is obtained by meta-methoxy phenyl ethylamine and N-acetylsulfanilyl chloride, yield 78%, mp 133-135℃。1H NMR (300MHz, Chloroform-d) δ (ppm) 7.90 (s, 1H), 7.76-7.68 (m, 2H), 7.64 (d, J=8.9Hz, 2H), 7.20 (t, J=7.9Hz, 1H), 6.77 (dd, J=8.1,2.5Hz, 1H), 6.71-6.65 (m, 1H), 6.63 (t, J=2.0Hz, 1H), 4.67 (s, 1H), 3.78 (s, 3H), 3.21 (q, J=6.7Hz, 2H), 2.75 (t, J= 6.9Hz, 2H), 2.22 (s, 3H) .MS (EI) m/z 347.0 [M-H]+.
Embodiment 7
The synthesis of N- (4- (N- (3,4- Dimethoxyphenethyl) sulfonamides) phenyl) acetamide (1g)
With reference to the synthetic method of 1a, it is obtained by 3,4- dimethoxy-phenylethylamines and N-acetylsulfanilyl chloride, yield 139-141 DEG C of 70%, mp.1H NMR (300MHz, Chloroform-d) δ (ppm) 7.93 (s, 1H), 7.83-7.44 (m, 4H), 6.90-6.44 (m, 3H), 4.68 (s, 1H), 3.81 (d, J=12.0Hz, 6H), 3.17 (q, J=6.8Hz, 2H), 2.71 (t, J=6.8Hz, 2H), 2.19 (s, 3H) .MS (EI) m/z 377.0 [M+H]+.
Embodiment 8
The synthesis of N- (4- cyanobenzyls) -3- nitrobenzene sulfonamides (1h)
With reference to the synthetic method of 1a, it is obtained by cyano group benzylamine and m-nitrobenzene sulfonyl chloride, yield 90%, mp 153-155 ℃。1H NMR (300MHz, DMSO-d6) δ (ppm) 8.85-8.32 (m, 3H), 8.14 (s, 1H), 7.99-7.61 (m, 3H), 7.39 (s, 2H), 4.16 (s, 2H) .MS (EI) m/z 316.0 [M-H]+.
Embodiment 9
The synthesis of N- (3- chlorobenzyls) -3- nitrobenzene sulfonamides (1i)
With reference to the synthetic method of 1a, it is obtained by a chlorobenzylamine and m-nitrobenzene sulfonyl chloride, yield 89%, mp 103-105 ℃。1H NMR (300MHz, DMSO-d6) δ (ppm) 8.64 (s, 1H), 8.49-8.32 (m, 2H), 8.12 (d, J=7.7Hz, 1H), 7.81 (dd, J=9.1,6.8Hz, 1H), 7.30-7.10 (m, 4H), 4.11 (d, J=2.3Hz, 2H) .MS (EI) m/z 324.9 [M-H]+.
Embodiment 10
The synthesis of N- (3- methoxyphenethyls) -3- nitrobenzene sulfonamides (1j)
With reference to the synthetic method of 1a, it is obtained by meta-methoxy phenyl ethylamine and m-nitrobenzene sulfonyl chloride, yield 86%, mp 105-107℃。1H NMR (300MHz, Chloroform-dd) δ (ppm) 8.59 (t, J=2.0Hz, 1H), 8.49-8.33 (m, 1H), 8.12 (d, J=7.8Hz, 1HH), 7.71 (t, J=8.0Hz, 1H), 7.17 (t, J=7.9Hz, 1H), 6.80-6.62 (m, 2H), 6.57 (t, J=2.2Hz, 1H), 4.83 (t, J=6.1Hz, 1H), 3.77 (s, 3H), 3.33 (q, J=6.5Hz, 2H), 2.79 (t, J=6.7Hz, 2H) .MS (EI) m/z 335.0 [M-H]+.
Embodiment 11
The synthesis of N- (4- methoxy-benzyls) -3- nitrobenzene sulfonamides (1k)
With reference to the synthetic method of 1a, it is obtained by 4-Methoxybenzylamine and m-nitrobenzene sulfonyl chloride, yield 80%, mp 103- 105℃。1H NMR (300MHz, DMSO-d6) δ (ppm) 8.45 (s, 1H), 8.37 (ddd, J=8.3,2.3,1.0Hz, 1H), 8.30 (t, J=2.0Hz, 1H), 8.10 (ddd, J=7.9,1.8,1.0Hz, 1H), 7.79 (t, J=8.0Hz, 1H), 7.09- 7.00 (m, 2H), 6.76-6.65 (m, 2H), 3.98 (s, 2H), 3.64 (s, 3H) .MS (EI) m/z 321.0 [M-H]+.
Embodiment 12
The synthesis of N- (4- methoxyphenyls) -3- nitrobenzene sulfonamides (1l)
With reference to the synthetic method of 1a, it is obtained by P-nethoxyaniline and m-nitrobenzene sulfonyl chloride, yield 86%, mp 130- 132℃。1H NMR (300MHz, Chloroform-d) δ (ppm) 8.61 (t, J=2.0Hz, 1H), 8.43 (ddd, J=8.3, 2.2,1.1Hz, 1H), 7.99 (ddd, J=7.8,1.8,1.1Hz, 1H), 7.68 (t, J=8.0Hz, 1H), 7.06-6.98 (m, 2H), 6.87-6.71 (m, 2H), 6.52 (s, 1H), 3.80 (s, 3H) .MS (EI) m/z 307.0 [M-H]+.
Embodiment 13
The synthesis of 4- cyano group-N- (4- methoxy-benzyls) benzsulfamide (lm)
With reference to the synthetic method of 1a, it is obtained by 4-Methoxybenzylamine and to cyanobenzenesulfonyl chloride, yield 75%, mp 137- 139℃。1H NMR (300MHz, Chloroform-d) δ (ppm) 7.99-7.90 (m, 2H), 7.85-7.75 (m, 2H), 7.15- 7.04 (m, 2H), 6.86-6.75 (m, 2H), 4.94 (t, J=5.9Hz, 1H), 4.16 (d, J=5.9Hz, 2H), 3.80 (s, 3H).MS(EI)m/z 301.0[M-H]+.
Embodiment 14
The synthesis of 4- cyano group-N- (3- luorobenzyls) benzsulfamide (1n)
With reference to the synthetic method of 1a, it is obtained by a fluorin benzyl amine and to cyanobenzenesulfonyl chloride, yield 82%, mp 122-124 ℃。1H NMR (300MHz, Chloroform-d) δ (ppm) 8.02-7.90 (m, 2H), 7.86-7.74 (m, 2H), 7.34-7.18 (m, 1H), 7.10-6.77 (m, 3H), 5.28 (t, J=6.2Hz, 1H), 4.21 (d, J=6.0Hz, 2H) .MS (EI) m/z 289.0[M-H]+.
Embodiment 15
The synthesis of N- (benzo [d] [1,3] dioxy -5- methylene) -4- cvanobenzenesulfonamides (1o)
With reference to the synthetic method of 1a, it is obtained by 3,4- methylene-dioxies benzylamine and to cyanobenzenesulfonyl chloride, yield 82%, mp 149-151℃。1H NMR (300MHz, Chloroform-d) δ (ppm) 8.01-7.89 (m, 2H), 7.87-7.76 (m, 2H), 6.75-6.68 (m, 1H), 6.64 (d, J=7.4Hz, 2H), 5.97 (s, 2H), 4.94 (t, J=6.1Hz, 1H), 4.13 (d, J= 6.0Hz, 2H) .MS (EI) m/z 315.0 [M-H]+.
Embodiment 16
The synthesis of 4- cyano group-N- (3- methoxyphenethyls) benzsulfamide (1p)
With reference to the synthetic method of 1a, it is obtained by 2- methoxyphenethylamines and to cyanobenzenesulfonyl chloride, yield 89%, mp 88- 90℃。1H NMR (300MHz, Chloroform-d) δ (ppm) 7.89-7.82 (m, 2H), 7.76-7.70 (m, 2H), 7.18- 7.08 (m, 1H), 6.76-6.53 (m, 3H), 5.39 (t, J=6.0Hz, 1H), 3.73 (s, 3H), 3.23 (q, J=6.7Hz, 2H), 2.73 (t, J=7.0Hz, 2H) .MS (EI) m/z 315.0 [M-H]+.
Embodiment 17
The synthesis of 4- amino-N- (3- chlorobenzyls) benzsulfamide (2a)
1b (0.50g, 1.48mmol) is dissolved in ethanol (10mL), concentrated hydrochloric acid (3mL) is added, 12 is reacted at 70 DEG C small When, room temperature is cooled to, add unsaturated carbonate potassium solution that reaction solution pH is transferred into 10.Ethanol, ethyl acetate extraction, nothing is removed under reduced pressure Water magnesium sulfate is dried, and removes solvent, obtains white solid, yield 90%, mp 119-121 DEG C.1H NMR (300MHz, DMSO- d6) δ (ppm) 7.70 (s, 1H), 7.42 (d, J=8.6Hz, 2HH), 7.36-7.11 (m, 4H), 6.60 (d, J=8.4Hz, 2H), 5.92 (s, 2H), 3.90 (d, J=5.0Hz, 2H) .MS (EI) m/z 295.0 [M+H]+.
Embodiment 18
The synthesis of 4- amino-N- (4- methoxyphenyls) benzsulfamide (2b)
With reference to the synthetic method of 2a, it is obtained by 1d, yield 89%, mp 131-133 DEG C.1H NMR (300MHz, DMSO-d6) δ (ppm) 9.48 (s, 1H), 7.40-7.19 (m, 2H), 7.06-6.86 (m, 2H), 6.84-6.70 (m, 2H), 6.59-6.42 (m, 2H), 5.95 (s, 2H), 3.66 (d, J=2.3Hz, 3H) .MS (EI) m/z 277.0 [M-H]+.
Embodiment 19
The synthesis of 4- amino-N- (4- fluorophenyls) benzsulfamide (2c)
With reference to the synthetic method of 2a, it is obtained by 1f, yield 78%, mp 151-153 DEG C.1H NMR (300MHz, DMSO-d6) δ (ppm) 9.81 (s, 1H), 7.38-7.29 (m, 2H), 7.06 (dd, J=7.0,3.2Hz, 4H), 6.52 (dd, J=8.9, 3.1Hz, 2H), 5.99 (s, 2H) .MS (EI) m/z 265.0 [M-H]+.
Embodiment 20
The synthesis of 4- amino-N- (4- methoxy-benzyls) benzsulfamide (2d)
With reference to the synthetic method of 2a, it is obtained by 1c, yield 75%, mp 94-96 DEG C.1H NMR (300MHz, DMSO-d6) δ (ppm) 7.54 (s, 1H), 7.43 (d, J=8.3Hz, 2H), 7.19-7.09 (m, 2H), 6.91-6.79 (m, 2H), 6.65-6.54 (m, 2H), 5.94 (s, 2H), 3.79 (s, 2H), 3.72 (s, 3H) .MS (EI) m/z 291.0 [M-H]+.
Embodiment 21
The synthesis of 4- amino-N- (3- methoxyphenethyls) benzsulfamide (2e)
With reference to the synthetic method of 2a, it is obtained by 1f, yield 90%, mp 88-90 DEG C.1H NMR (300MHz, Chloroform-d) δ (ppm) 7.46 (s, 1H), 7.42-7.33 (m, 2H), 7.21 (t, J=7.5Hz, 1H), 6.85 (ddt, J =7.2,1.9,1.0Hz, 1H), 6.76 (dt, J=7.5,2.0Hz, 1H), 6.68-6.60 (m, 2H), 6.56 (td, J=2.0, 1.0Hz, 1H), 4.82 (s, 2H), 3.71 (s, 3H), 3.49 (t, J=5.2Hz, 2H), 2.79 (tt, J=5.1,1.1Hz, 2H) .MS(EI)m/z 307.0[M+H]+.
Embodiment 22
The synthesis of 4- amino-N- (3,4- Dimethoxyphenethyl) benzsulfamide (2f)
With reference to the synthetic method of 2a, it is obtained by 1g, yield 92%, mp 127-129 DEG C.1H NMR (300MHz, Chloroform-d) δ (ppm) 7.62-7.50 (m, 2H), 6.79 (d, J=8.1Hz, 1H), 6.71-6.62 (m, 3H), 6.59 (d, J=2.0Hz, 1H), 4.32 (t, J=6.3Hz, 1H), 4.15 (s, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 3.17 (q, J =6.7Hz, 2H), 2.72 (t, J=6.8Hz, 2H) .MS (EI) m/z 335.0 [M-H]+.
Embodiment 23
The synthesis of N- (4- (N- (3- chlorobenzyls) sulfamic) phenyl) acrylamide (3a)
2a (0.10g, 0.34mmol) is dissolved in anhydrous methylene chloride (15mL), under ice bath be added dropwise acryloyl chloride (0.03mL, Dichloromethane solution (5mL) 0.37mmol), ice bath stir 1 hour, recovery be stirred at room temperature 2 hours, add water (5mL) be quenched instead Should, dichloromethane extraction, anhydrous magnesium sulfate is dried, and column chromatography purifying obtains white solid 0.06g, yield 51%, mp157-159 ℃。1H NMR (300MHz, DMSO-d6) δ (ppm) 10.58 (s, 1H), 8.15 (s, 1H), 7.83 (dd, J=9.0,3.2Hz, 2H), 7.78-7.65 (m, 2H), 7.47-7.06 (m, 4H), 6.44 (dd, J=9.8,3.4Hz, 1H), 6.37-6.22 (m, 1H), 5.88-5.74 (m, 1H), 3.99 (d, J=3.3Hz, 2H) .MS (EI) m/z 348.9 [M-H]+.
Embodiment 24
The synthesis of N- (4- (N- (4- methoxyphenyls) sulfamic) phenyl) acrylamide (3b)
With reference to the synthetic method of 3a, it is obtained by 2b, yield 45%, mp 209-211 DEG C.1H NMR (300MHz, Chloroform-d) δ (ppm) 8.09 (s, 1H), 7.78-7.72 (m, 2H), 7.69-7.63 (m, 2H), 6.91-6.85 (m, 2H), 6.78-6.72 (m, 2H), 6.48 (dd, J=16.8,10.0Hz, 1H), 6.11 (dd, J=13.8,10.0Hz, 1H), 6.02 (s, 1H), 5.65 (dd, J=16.8,13.8Hz, 1H), 3.80 (s, 3H) .MS (EI) m/z 331.0 [M-H]+.
Embodiment 25
The synthesis of N- (4- (N- (3,4- Dimethoxyphenethyl) sulfamic) phenyl) acrylamide (3c)
With reference to the synthetic method of 3a, it is obtained by 2f, yield 40%, mp 146-148 DEG C.1H NMR (300MHz, Chloroform-d) δ (ppm) 7.71 (s, 5H), 6.77 (d, J=8.1Hz, 1H), 6.63 (dd, J=8.1,2.0Hz, 1H), 6.57 (d, J=2.0Hz, 1H), 6.49 (dd, J=16.9,1.2Hz, 1H), 6.28 (dd, J=16.8,10.2Hz, 1H), 5.85 (d, J=10.2Hz, 1H), 4.45 (s, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.20 (q, J=6.6Hz, 2H), 2.72 (t, J=6.8Hz, 2H) .MS (EI) m/z 389.0 [M-H]+.
Embodiment 26
The synthesis of N- (4- (N- (3- methoxyphenethyls) sulfamic) phenyl) acrylamide (3d)
With reference to the synthetic method of 3a, it is obtained by 2d, yield 52%, mp 134-136 DEG C.1H NMR (300MHz, DMSO-d6) δ (ppm) 10.53 (s, 1H), 7.90-7.81 (m, 2H), 7.78-7.70 (m, 2H), 7.61 (t, J=5.8Hz, 1H), 7.17 (t, J=8.0Hz, 1H), 6.84-6.67 (m, 3H), 6.47 (dd, J=17.0,9.9Hz, 1H), 6.31 (dd, J=17.0,2.2Hz, 1H), 5.83 (dd, J=9.9,2.2Hz, 1H), 3.71 (s, 3H), 3.03-2.84 (m, 2H), 2.64 (t, J=7.5Hz, 2H) .MS(EI)m/z 359.0[M-H]+.
Embodiment 27
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/I 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.
IC50Value report scope be：A represents less than 10 μM, and B represents 10-20 μM, and C represents 20-50 μM, and D is represented more than 50 μM。
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 1c50：5.88μM).
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 LMTT (final concentration 4mg/ml) incubators, and ELIASA determined and inhaled at 570nm wavelength Shading value；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 1h (3 times of IC50Concentration) culture 48h after, using MTT detect T lymphocytes propagation, increase It is 34.77% to grow rate, illustrates that compound 1h can dramatically increase the propagation of T lymphocytes.
3. the influence of pair Autoimmune disease
3.1 experimental techniques
By treated B16F1 cells (8 × 104Individual hole), spleen lymphocyte (106Individual hole, uses the ConA of 5 μ g/mL 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 (3.2%) containing original T lymphocytes is compared to rising 4 times (12%).As compound 1c, 1h and 3a (3 times of IC50 Concentration) in addition system after can substantially reverse this effect (dropping to 7.8%, 7.6%, 2.1% respectively), illustrate chemical combination Thing 1c, 1h and 3a 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 1c, 1h and 3a do not influence the expression of IDO1 in Hela cells, illustrate compound 1c, 1h and 3a are the immunosupress for reversing IDO1 to mediate by suppressing the activity of IDO1.

Claims (10)

1. the benzenesulfonamides or its pharmaceutically acceptable salt shown in formula (I) are led to：
Wherein：
N represents 0~8 integer；
M represents 0~4 integer；
R1Represent hydrogen, cyano group, nitro, hydroxyl, halogen, amino, acetamido, trifluoromethyl or acrylamido；
R2Represent hydrogen, halogen, cyano group, hydroxyl, nitro, C1-C8Alkoxy or methylene-dioxy.
2. benzenesulfonamides according to claim 2 or its pharmaceutically acceptable salt, it is characterised in that：
N represents 0~4 integer；
M represents 0~4 integer；
R1Represent cyano group, nitro, amino, acetamido or acrylamido；
R2Represent 3- fluorine, 4- fluorine, 3- chlorine, 4- cyano group, 3- methoxyl groups, 4- methoxyl groups, 3,4- dimethoxys or 3,4- (methylenedioxy) Base.
3. benzenesulfonamides according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that described Compound is selected from：
N- (4- (N- (4- cyanobenzyls) sulfamic) phenyl) acetamide；
N- (4- (N- (3- chlorobenzyls) sulfamic) phenyl) acetamide；
N- (4- (N- (4- methoxy-benzyls) sulfamic) phenyl) acetamide；
N- (4- (N- (4- methoxyphenyls) sulfamic) phenyl) acetamide；
N- (4- (N- (4- fluorophenyls) sulfamic) phenyl) acetamide；
N- (4- (N- (3- methoxyphenethyls) sulfamic) phenyl) acetamide；
N- (4- (N- (3,4- Dimethoxyphenethyl) sulfamic) phenyl) acetamide；
N- (4- cyanobenzyls) -3- nitrobenzene sulfonamides；
N- (3- chlorobenzyls) -3- nitrobenzene sulfonamides；
N- (3- methoxyphenethyls) -3- nitrobenzene sulfonamides；
N- (4- methoxy-benzyls) -3- nitrobenzene sulfonamides；
N- (4- methoxyphenyls) -3- nitrobenzene sulfonamides；
4- cyano group-N- (4- methoxy-benzyls) benzsulfamide；
4- cyano group-N- (3- luorobenzyls) benzsulfamide；
N- (benzo [d] [1,3] dioxy -5- methylene) -4- cvanobenzenesulfonamides；
4- cyano group-N- (3- methoxyphenethyls) benzsulfamide；
4- amino-N- (3- chlorobenzyls) benzsulfamide；
4- amino-N- (4- methoxyphenyls) benzsulfamide；
4- amino-N- (4- fluorophenyls) benzsulfamide；
4- amino-N- (4- methoxy-benzyls) benzsulfamide；
4- amino-N- (3- methoxyphenethyls) benzsulfamide；
4- amino-N- (3,4- Dimethoxyphenethyl) benzsulfamide；
N- (4- (N- (3- chlorobenzyls) sulfamic) phenyl) acrylamide；
N- (4- (N- (4- methoxyphenyls) sulfamic) phenyl) acrylamide；
N- (4- (N- (3,4- Dimethoxyphenethyl) sulfamic) phenyl) acrylamide；
N- (4- (N- (3- methoxyphenethyls) sulfamic) phenyl) acrylamide.
4. the preparation method of benzenesulfonamides according to claim 1, it is characterised in that：
A) R is worked as1During for cyano group, nitro or acetamido, the preparation method of compound is shown in logical formula (I)：With different substituted benzene There is condensation reaction and compound 1a-p be obtained in sulfonic acid chloride and aminated compounds；Its synthetic route is as follows：
Wherein, n, m, R1And R2Definition it is as claimed in claim 1；
B) R is worked as1During for amido, the preparation method of compound is shown in logical formula (I)：Second is sloughed in 1b-g hydrolysis under concentrated hydrochloric acid effect Acyl group is obtained 2a-f；Its synthetic route is as follows：
Wherein, n, m, R1And R2Definition it is as claimed in claim 1；
C) R is worked as1During for acrylamido, the preparation method of compound is shown in logical formula (I)：2a, 2b, 2e, 2f respectively with acryloyl Chlorine reaction is obtained 3a-3d；Its synthetic route is as follows：
Wherein, n, m, R1And R2Definition it is as claimed in claim 1.
5. 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 benzenesulfonamides (I) as any one of claim 1-3 or its is pharmaceutically acceptable Salt；Described pharmaceutically acceptable auxiliary material includes pharmaceutically acceptable carrier, diluent and/or excipient.
6. the group described in compound any one of claim 1-3, its pharmaceutically acceptable salt or claim 5 Application of the compound in the inhibitor of IDO 1 is prepared.
7. the group described in compound any one of claim 1-3, its pharmaceutically acceptable salt or claim 5 Purposes of the compound in medicine is prepared, the medicine is used to treat the immunosupress of patient.
8. the group described in its pharmaceutically acceptable salt of the compound any one of claim 1-3 or claim 5 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. application according to claim 8, wherein described cancer be 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, oophoroma, palace One or more in neck cancer, carcinoma of endometrium, celiothelioma, thyroid cancer, liver cancer and the cancer of the esophagus；Described virus infection is people Para-immunity defective virus, hepatitis type B virus, HCV, influenza virus, poliovirus, cytomegalovirus, One kind or many in Coxsackie virus, HPV, epstein-Barr virus and varicella virus Plant the infection for causing；Described neurodegenerative disease is memory disorder, Alzheimer disease, cognitive disorder disease, senile dementia One or more in disease, Parkinson's, parkinsonism and dyskinetic disorder；Described autoimmune disease is Rheumatoid arthritis, systemic loupus erythematosus, dermatomyositis, chorionitis, nodular vasculitis, multiple sclerosis, ephrosis, weight Disease myasthenia, MCTD, psoriasis, hepatopathy, endocrine relevant disease and due to the autoimmunity that causes of infection One or more in reaction.
10. the application according to claim 8-9, 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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