CN107501272A - Imidazo isoindoles IDO1 inhibitor, its preparation method and application - Google Patents

Abstract

The invention belongs to the field of medicines, and specifically relates to an imidazoisoindole compound having the structural characteristics of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, a preparation method thereof, and their use as indoleamine Use of a 2,3-dioxygenase 1 (IDO1) inhibitor. The experimental results show that the compound of the present invention has a significant inhibitory effect on the activity of IDO1, can effectively promote the proliferation of T cells, inhibit the differentiation of initial T cells into regulatory T cells, reverse the immune suppression mediated by IDO1, and can be used for the treatment of IDO1. Diseases associated with pathological features of kynurenine metabolic pathways, including cancer, viral infection, neurodegenerative diseases, cataracts, organ transplant rejection, depression and autoimmune diseases, etc.

Description

Imidazoloisoindole IDO1 inhibitor, its preparation method and application

technical field

The invention belongs to the field of medicine, and in particular relates to an imidazoisoindole compound, its stereoisomer or a pharmaceutically acceptable salt thereof, a preparation method thereof, and their function as indoleamine 2,3-dioxygenase 1 (IDO1) Inhibitor Uses.

technical background

Tryptophan is an essential amino acid for human cells to maintain proliferation and survival, and can be used for the biosynthesis of protein, niacin and 5-hydroxytryptamine. Tryptophan is generally ingested from food, more than 95% of tryptophan is metabolized along the kynurenic acid pathway, and the remaining tryptophan is converted into 5-hydroxytryptophan and 5-hydroxytryptophan in the nervous system and intestine, or in the pineal gland Synthetic melatonin. Indoleamine 2,3-dioxygenase 1 (indoleamine 2,3-dioxygenase, IDO1) is the rate-limiting enzyme that catalyzes the metabolism of tryptophan along the kynurenine pathway outside the human liver. IDO1 is expressed in various tissues (eg, lung, kidney, brain, placenta, thymus) and in various cells (eg, macrophages and dendritic cells). IDO1 reduces the concentration of tryptophan in the microenvironment of the body by oxidatively cracking tryptophan, and produces a series of metabolisms such as kynurenine, 3-hydroxykynurenine, 2-amino-3-hydroxybenzoic acid, and quinolinic acid. product. Cytokines such as IFN-γ, TNF-α, IL-1β and IL-6 can induce up-regulated expression of IDO1 (Bernhardt R. Chem Rev, 1996, 96(1):2841-2888).

A large amount of evidence shows that IDO1 can not only catalyze the oxidative metabolism of tryptophan, but also play an important role in regulating the body's innate immunity and adaptive immunity (Munn DH, et al.Trends Immunol, 2013, 34(3): 137- 143). IDO1 regulates the immune system mainly by catalyzing the metabolism of tryptophan leading to the depletion of tryptophan and the accumulation of its metabolites: on the one hand, depletion of tryptophan can induce the T cell division cycle to stay in the G1 phase by activating the GCN2 pathway , thereby inhibiting the proliferation of T cells, and at the same time inhibiting the differentiation of initial CD4 ⁺ T cells into helper T cells 17 (Th17), thereby producing immunosuppression (Munn DH, et al.Immunity, 2005, 22(5): 633-642 ). On the other hand, tryptophan metabolites such as kynurenine are cytotoxic and can kill T cells and natural killer (NK) cells (Frumento G, et al. JExp 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 ⁺ T cells to differentiate into regulatory T ( Treg) cells, and promote the conversion of dendritic cells (DC) into tolerogenic DC (Mezrich JD, et al.J Immunol, 2010, 185(6): 3190-3198; Mezrich JD, et al.J Immunol, 2008, 181 (8): 5396-5404); in addition, tryptophan metabolites can inhibit the function of NK cells by down-regulating the expression of NK cell receptors, which can further inhibit the body's immune response (Della Chiesa M, et al al. Blood, 2006, 108(13): 4118-4125).

IDO1 is related to many physiological and pathological processes. Studies have shown that IDO1 plays an important immune regulatory role in physiological processes such as host immune defense and maternal-fetal immune tolerance. Under normal conditions, the expression level of IDO1 is low, but in physiological stresses such as placental development and inflammatory response, the secretion of cytokines such as IFN-γ increases significantly, thereby inducing the upregulation of IDO1 expression, leading to tryptophan depletion and kynuria Accumulation of metabolites such as aminoacid acid, thereby inhibiting the mother's T cell response, inducing maternal-fetal immune tolerance, and ensuring that the fetus is not rejected by the mother's immune system; the depletion of tryptophan in the host microenvironment makes it unable to provide what is necessary for the replication of pathogenic microorganisms At the same time, IDO1-mediated immunosuppression can avoid excessive activation of the body's immune system (Mellor AL, et al. Nat Rev Immunol, 2008, 8(1): 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). When the IDO1 inhibitor is administered to pregnant mice, it will cause T cell-mediated embryo rejection, resulting in miscarriage of the mice, indicating that IDO1 can prevent the fetus from being rejected by the mother (Munn DH, et al.Science, 1998, 281 (5380 ): 1191-1193). IDO1 also exerts an immunosuppressive effect on the survival of transplanted tissues in new hosts (Radu CA, et al. Plast Reconstr Surg, 2007, 119(7):2023-2028). These findings indicate that IDO is an immunoregulatory enzyme involved in the body's immune tolerance.

Many studies have shown that immune tolerance mediated by IDO1 is closely related to tumor immune escape, viral infection, neurodegenerative diseases, organ transplant rejection, autoimmune diseases, neuropsychiatric diseases and cataracts (Munn DH, et 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. LabInvest, 2009, 89(5): 498-512). In these diseases, the depletion of tryptophan and the accumulation of its metabolites mediated by overexpressed IDO1 can inhibit the activation of T cells and lead to the body's immune tolerance.

In the mouse model of virus infection, administration of IDO1 inhibitors can significantly promote the proliferation of CD8 ⁺ T cells, restore the immune response of T cells, and inhibit the mononuclear macrophages of the virus-infected host. During influenza virus infection, the immunosuppressive effect mediated by overexpression of IDO1 easily leads to secondary infection in the lungs (van der Sluijs KF, et al. J InfectDis, 2006, 193(2): 214-222). During HIV infection, IDO1 will be up-regulated to promote the proliferation of Treg cells and inhibit the proliferation of Th17 cells, resulting in an imbalance in the ratio of Tregs/Th17 cells, leading to immunosuppression in patients (Favre D, et al.Sci Transl Med, 2010, 2 (32):32ra36). In addition, IDO1-mediated depletion of tryptophan and increased concentration of its metabolites are also associated with parasitic infection (Knubel CP, et al. FASEB J, 2010, 24(8): 2689-2701).

Studies have shown that tryptophan metabolites catalyzed by IDO1, such as kynurenine and quinolinic acid, are neurotoxic, and these metabolites are associated with neurodegenerative diseases such as memory impairment, Alzheimer's disease (AD), cognitive impairment Syndrome, Alzheimer's disease, Parkinson's disease, Parkinson's syndrome and movement disorders are closely related (Malpass K.Nat RevNeurol, 2011, 7(8): 417; Maddison DC, et al.Semin Cell Dev Biol, 2015, 40: 134-141). The expression of IDO1 and the concentration of quinolinic acid in the brain of AD patients were higher than those of normal people, and the highest content was in microglia and astrocytes around senile plaques. In addition, the concentration of tryptophan in the blood of AD patients is lower than that of normal people, while the concentration of kynurenine is higher than that of normal people, and the ratio of the two is closely related to the degree of cognitive impairment of patients (Guillemin GJ, et al.Neuropathol Appl Neurobiol, 2005, 31(4): 395-404; Widner B, et al. Adv Exp Med Biol, 1999, 467: 133-138). Neuropsychiatric disorders such as depression, schizophrenia, and anxiety are also associated with IDO1 overexpression and elevated levels of metabolites such as kynurenine. Overexpression of IDO1 causes tryptophan depletion, thereby reducing the amount of tryptophan used to synthesize the neurotransmitter serotonin, resulting in serotonin deficiency, coupled with neurotoxic kynurenine and quinolinic acid, etc. The accumulation of metabolites jointly promotes the occurrence of neuropsychiatric diseases, and is a factor of various mood disorders (Myint AM. FEBS J, 2012, 279(8): 1375-1385). Therefore, inhibition of IDO1 is an important therapeutic strategy for patients with neurodegenerative and neuropsychiatric disorders.

Excessive metabolism of tryptophan mediated by high expression of IDO1 also exists in various autoimmune diseases (NguyenNT, et al. Front Immunol, 2014, 5:551). In synovial joint DCs of patients with rheumatoid arthritis, IDO1 is highly expressed, and the concentration of tryptophan in the serum of patients is decreased, while the concentration of kynurenine is increased (Zhu L, et al. J Immunol, 2006, 177 (11): 8226-8233; Ozkan Y. et al. Clin Rheumatol, 2012, 31(1):29-34). IDO1 overexpression and enhanced tryptophan metabolism were also observed in patients with systemic lupus erythematosus. The concentration of tryptophan in the patient's serum decreased, and the concentration of the metabolite kynurenine and the ratio of kynurenine to tryptophan all increased significantly (Widner B, et al. Immunobiology, 2000, 201(5): 621-630). Therefore, inhibition of IDO1 is also an important therapeutic strategy for patients with autoimmune diseases.

A large number of studies have shown that IDO1-induced immunosuppression plays an important role in tumor immune escape. IDO1 is overexpressed in various tumor cells and cells in their microenvironment, such as DC and stromal cells, leading to local tryptophan depletion and accumulation of tryptophan metabolites in the tumor, thereby inducing tumor immune escape and helping tumor cells evade the body's immune system. Attack (Munn DH, et al. Trends Immunol, 2016, 37(3):193-207). Uyttenhove group used immunohistochemical labeling method in melanoma, lung cancer, breast cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, lymphatic cancer, prostate cancer, kidney cancer, brain cancer, head and neck cancer, ovarian cancer, cervical cancer, uterus The expression of IDO1 was detected in 24 kinds of human tumor cells including endometrial cancer, mesothelioma, thyroid cancer, esophageal cancer and liver cancer (Uyttenhove C, et al. Nat Med, 2003, 9(10): 1269-1274). It was further confirmed in ovarian cancer, melanoma, lung cancer, leukemia and other tumor tissues, and it was found that the expression of IDO1 in tumor tissues was closely related to the malignancy of the tumor, and affected the prognosis of tumor patients (Théate 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; OkamotoA, 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 inhibitors can activate T cells, overcome tumor immune escape mediated by IDO1, and can also improve the therapy of other tumor therapeutic agents (Koblish HK, et al. Mol Cancer Ther, 2010, 9(2): 489-498; Wainwright DA, et al. Clin Cancer Res, 2014, 20(20):5290-5301).

A number of preclinical and clinical studies have shown that IDO1 inhibitors can reduce the accumulation of metabolites such as tryptophan metabolism and kynurenine, thereby reversing IDO1-mediated immunosuppression, restoring the proliferation and function of T cells and NK cells, and inhibiting The proliferation of Treg cells, thereby enhancing the body's immune response, so IDO1 inhibitors can be used to treat the above-mentioned related diseases caused by IDO1-mediated immunosuppression, including cancer, viral infection, neurodegenerative diseases, cataracts, organ transplant rejection, depression syndrome and autoimmune diseases. In addition, IDO1 inhibitors can also be used in combination with other chemotherapeutic agents, targeted anticancer drugs, immune checkpoint therapeutics, antitumor vaccines, antiviral agents, antiviral vaccines, cytokine therapy, adoptive cellular immunotherapy and radiation therapy , play the role of synergistic or enhanced therapy (Vacchelli E, et al. Oncoimmunology, 2014, 3(10): e957994; Jochems C, et al. . Blood, 2010, 115(17): 3520-3530; Zamarin D, et al. Pharmacol Ther, 2015, 150: 23-32).

Small molecule inhibitors of IDO1 are currently being developed to treat or prevent the above-mentioned IDO1-related diseases. For example, oxadiazole IDO1 inhibitors are reported in CN102164902B, involving the treatment of cancer, viral infection, neurodegenerative disease, trauma, age-related cataract, organ transplant rejection or Patients with autoimmune diseases.

Based on the fact that IDO1 is closely related to the pathogenesis of various diseases such as cancer, viral infection, neurodegenerative disease, cataract, organ transplant rejection, autoimmune disease and depression, IDO1 inhibitors can be used to inhibit the activity of IDO1, thereby reducing color Amino acid metabolism and the accumulation of metabolites such as kynurenine, restore the body's immune function, and then achieve the purpose of treating the above diseases. The compound described in the present invention has IDO1 inhibitory activity, and can be used to treat related diseases caused by IDO1-mediated immunosuppression, including cancer, viral infection, neurodegenerative disease, cataract, organ transplant rejection, autoimmune disease and depression .

Contents of the invention

The technical problem to be solved by the present invention is to provide an imidazoisoindole compound, its stereoisomer or its pharmaceutically acceptable salt, its preparation method, pharmaceutical composition and application. The compound of the present invention has good IDO1 inhibitory activity, and can be used for treating and/or preventing various related diseases caused by IDO1-mediated immunosuppression.

The present invention provides imidazoisoindole compounds represented by general formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof:

in:

R ₁ represents hydrogen, NR ₃ R ₄ , C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₁₀ aryl or C ₁ -C ₁₀ aromatic heterocyclic group, wherein said The heteroaryl ring group may optionally contain one or more other heteroatoms selected from O, S or N; the alkyl, cycloalkyl, aryl or heteroaryl ring group may be optionally represented by the following The same or different substituents are monosubstituted to pentasubstituted, and the substituents are selected from: halogen, trifluoromethyl, cyano, nitro, hydroxyl or amino;

R ₂ represents O, S or NR ₅ ;

R ₃ represents hydrogen, C ₁ -C ₈ alkyl or C ₃ -C ₆ cycloalkyl;

R ₄ represents hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₆ cycloalkyl, C ₅ -C ₁₀ aryl, C ₅ -C ₁₀ aryl-(C ₁ -C ₁₀ alkyl), C ₁ -C ₁₀ aromatic heterocyclic group, C ₁ -C ₁₀ aromatic heterocyclic ring-(C ₁ -C ₁₀ alkyl), C ₁ -C ₁₂ fused heterocyclic group or C ₁ -C ₁₂ fused heterocyclic ring-(C ₁ - C ₁₀ alkyl), wherein the heterocyclic group may optionally contain one or more other heteroatoms selected from O, S or N; wherein the alkyl, cycloalkyl, aryl, aryl Heterocyclic rings and fused heterocyclic rings can be optionally monosubstituted to pentasubstituted by the following identical or different substituents selected from: C ₁ -C ₅ alkyl, halogen, trifluoromethyl, carboxyl , cyano, nitro, hydroxyl, amino or methoxy;

R ₅ represents hydrogen, hydroxyl or mercapto.

Further, the imidazoisoindole compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that:

R ₁ represents hydrogen, NR ₃ R ₄ , C ₃ -C ₆ cycloalkyl, C ₅ -C ₁₀ aryl or C ₁ -C ₁₀ aromatic heterocyclic group, wherein the aromatic heterocyclic group can optionally Contains one or more other heteroatoms selected from O, S or N; wherein the cycloalkyl, aryl or aromatic heterocyclic group can be optionally monosubstituted by the following same or different substituents up to five Substitution, the substituent is selected from: halogen, cyano, nitro, hydroxyl or amino;

R ₂ represents O or NR ₅ ;

R ₃ represents hydrogen or C ₁ -C ₈ alkyl;

R ₄ represents C ₃ -C ₆ cycloalkyl, C ₅ -C ₁₀ aryl, C ₅ -C ₁₀ aryl-(C ₁ -C ₁₀ alkyl), C ₁ -C ₁₀ aromatic heterocyclic group, C ₁ -C ₁₀ aromatic heterocycle-(C ₁ -C ₁₀ alkyl), C ₁ -C ₁₂ fused heterocyclic group or C ₁ -C ₁₂ fused heterocycle-(C ₁ -C ₁₀ alkyl), wherein the The heterocycle may optionally contain one or more other heteroatoms selected from O, S or N; wherein said cycloalkyl, aryl, aromatic heterocycle, and condensed heterocycle may be optionally represented by the following identical or Different substituents are monosubstituted to pentasubstituted, and the substituents are selected from: C ₁ -C ₅ alkyl, halogen, carboxyl, cyano, nitro, hydroxyl, amino or methoxy;

R ₅ represents hydroxyl or mercapto.

Further, the imidazoisoindole compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that:

R ₁ represents NR ₃ R ₄ , cycloalkyl or p-chlorophenyl;

R ₂ represents O or NR ₅ ;

R ₃ represents hydrogen or methyl;

R ₄ represents benzyl, 4-cyanobenzyl, 3,4-difluorobenzyl, 3-chlorobenzyl, 3-chloro-4-fluorobenzyl, 4-methoxybenzyl, 4-hydroxybenzyl Base, α-methylbenzyl, 3,4-methylenedioxybenzyl, p-carboxybenzyl, pyridine-3-methylene, p-diazepine-2-methylene, phenyl, 1H - indazol-6-yl, 3,4-methylenedioxybenzene, cyclohexyl, 3-methoxyphenethyl, phenethyl or pyridine-2-ethyl;

R ₅ represents a hydroxyl group.

Specifically, the imidazoisoindole compounds represented by the general formula (I) are preferably selected from the following compounds:

N-benzyl-2-(5H-imidazol[5,1-a]isoindol-5-yl)acetamide;

N-(4-cyanobenzyl)-2-(5H-imidazol[5,1-a]isoindol-5-yl)acetamide;

N-(3,4-difluorobenzylamino-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide;

N-(3-chlorobenzyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide;

N-(3-chloro-4-fluorobenzyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide;

N-(4-methoxybenzyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide;

N-(4-methoxybenzyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide;

N-benzyl-2-(5H-imidazol[5,1-a]isoindol-5-yl)-N-methylacetamide;

2-(5H-imidazol[5,1-a]isoindol-5-yl)-N-(1-phenylethyl)acetamide;

N-(benzo[d][1,3]dioxo-5-methylene)-2-(5H-imidazol[5,1-a]isoindol-5-yl)acetamide;

N-(4-carboxybenzyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide;

2-(5H-imidazo[5,1-a]isoindol-5-yl)-N-(pyridine-3-methylene)acetamide;

2-(5H-imidazo[5,1-a]isoindol-5-yl)-N-(p-diazepine-2-methylene)acetamide;

2-(5H-imidazo[5,1-a]isoindol-5-yl)-N-phenylacetamide;

2-(5H-imidazol[5,1-a]isoindol-5-yl)-N-(1H-indazol-6-yl)acetamide;

N-(benzo[d][1,3]dioxo-5-yl)-2-(5H-imidazol[5,1-a]isoindol-5-yl)acetamide;

N-cyclohexyl-2-(5H-imidazol[5,1-a]isoindol-5-yl)acetamide;

2-(5H-imidazol[5,1-a]isoindol-5-yl)-N-(3-methoxyphenethyl)acetamide;

2-(5H-imidazol[5,1-a]isoindol-5-yl)-N-phenethylacetamide;

2-(5H-imidazol[5,1-a]isoindol-5-yl)-N-(2-(pyridin-2-yl)ethyl)acetamide;

(Z)-1-cyclohexyl-2-(5H-imidazol[5,1-a]isoindol-5-yl)ethanone oxime;

(Z)-1-(4-chlorophenyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanone oxime;

The compound codes involved in the following pharmacological experiments are equal to the compounds corresponding to the codes here.

Another object of the present invention is to provide the preparation method of the compound shown in general formula (I), it is characterized in that:

a) When R ₂ is O, the preparation method of the compound shown in general formula (I) is: take 1H-imidazole as raw material, obtain 1 through iodination reaction; The Trt protecting group was introduced into the 1-position N atom of 2 and 2 to obtain 3, 3 and o-formylphenylboronic acid were prepared by Suzuki coupling reaction to obtain 4, and triphenylphosphine was reacted with ethyl 2-bromoacetate to obtain Witting reagent 5, intermediates 4 and 5 were prepared by Witting reaction 6, 6 was cyclized to obtain 7, 7 was hydrolyzed by sodium hydroxide to obtain 8, 8 was reacted with amine compound (NHR ₃ R ₄ ) to obtain compound LA01 -LA20; its synthetic route is as follows:

Wherein, R ₃ and R ₄ are as defined above;

b) when R2 is N _- OH, the preparation method of the compound shown in general formula (I) is: intermediate 4 reacts with methyl cyclohexyl ketone and methyl p-chlorophenyl ketone respectively to obtain 9a-b , 9a-b undergoes a cyclization reaction to obtain 10a-b, 10a-b reacts with hydroxylamine hydrochloride to obtain LA21-LA22; its synthetic route is as follows:

The pharmaceutically acceptable salts of the compounds of general formula (I) can be synthesized by general chemical methods.

In general, salts can be prepared by reacting free bases or acids with equivalent or excess amounts of acids (inorganic or organic) or bases (inorganic or organic) in a suitable solvent or solvent composition.

The present invention also provides a pharmaceutical composition, which is composed of a therapeutically effective amount of an active component and a pharmaceutically acceptable adjuvant; the active component includes a compound of general formula (I), its stereoisomer and One or more of its pharmaceutically acceptable salts. In the pharmaceutical composition, the auxiliary materials include pharmaceutically acceptable carriers, diluents and/or excipients.

According to the purpose of treatment, the pharmaceutical composition can be made into various types of administration unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions), etc., Tablets, capsules, liquids, suspensions, and injections (solutions and suspensions) are preferred.

For shaping pharmaceutical compositions in the form of tablets, pills or suppositories, any excipient known and widely used in the art may be used.

In order to prepare the pharmaceutical composition in the form of injection, the solution or suspension can be sterilized (preferably adding an appropriate amount of sodium chloride, glucose or glycerin) to make an injection with isotonic pressure with blood. When preparing injections, any commonly used carrier in the art can also be used. For example: water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyethoxylated isostearyl alcohol, fatty acid esters of polyethylene sorbitan, and the like. In addition, general dissolving agents, buffering agents and the like may be added.

The content of the composition of the present invention in the pharmaceutical composition is not particularly limited, and can be selected within a wide range, usually 5-95% by mass, preferably 30-85% by mass.

The administration method of the pharmaceutical composition of the present invention is not particularly limited. Preparations in various dosage forms can be selected and administered according to the patient's age, sex and other conditions and symptoms.

The present invention additionally provides the compound of general formula (I), its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutical composition in the preparation of indoleamine 2,3-dioxygenase 1 (IDO1) application of inhibitors. The IDO1 inhibitor is used for treating patients with diseases related to IDO1-mediated immunosuppression, and the related diseases include cancer, viral infection, neurodegenerative disease, cataract, organ transplant rejection, depression and autoimmune disease.

The present invention also provides the use of the compound of the general formula (I), its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutical composition in the preparation of medicines for the treatment of patients with cancer, Viral infection, neurodegenerative disease, cataracts, organ transplant rejection, depression, or autoimmune disease.

The cancers include, but are not limited to: malignant melanoma, lung cancer, breast cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, lymphoma, leukemia, prostate cancer, testicular cancer, kidney cancer, brain cancer, head and neck cancer, ovarian cancer One or more of cancer, cervical cancer, endometrial cancer, mesothelioma, thyroid cancer, liver cancer and esophageal cancer.

The virus infection includes but not limited to: caused by human immunodeficiency virus, hepatitis B virus, hepatitis C virus, influenza virus, poliovirus, cytomegalovirus, Coxsackie virus, human papilloma virus, HIV Infection caused by one or more of Predstein-Barr virus and Varicella-Zoster virus.

The neurodegenerative diseases include, but are not limited to: one or more of memory impairment, Alzheimer's disease, cognitive impairment, senile dementia, Parkinson's disease, Parkinson's syndrome and movement disorders .

The autoimmune diseases include, but are not limited to: rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, scleroderma, nodular vasculitis, multiple sclerosis, kidney disease, myasthenia gravis, mixed One or more of sexual connective tissue disease, psoriasis, liver disease, endocrine-related disease, and autoimmune response due to infection.

The present invention also provides that the compound of general formula (I), its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutical composition can be combined with one or more other types of therapeutic agents and/or treatment methods Combined for the treatment of related diseases mediated by IDO1.

The other types of therapeutic agents and/or treatment methods include, but are not limited to: chemotherapy agents, targeted anti-tumor drugs, immune checkpoint inhibitors, immune checkpoint agonists, anti-tumor vaccines, antiviral agents, antiviral vaccines, Cytokine therapy, adoptive cellular immunotherapy or radiation therapy.

The chemotherapeutic agents include, but are not limited to: alkylating agents, tubulin inhibitors, topoase inhibitors, platinum drugs, anti-metabolite drugs or hormone anti-tumor drugs.

The targeted anti-tumor drugs include, but are not limited to: protein kinase inhibitors, proteasome inhibitors, isocitrate dehydrogenase inhibitors, epigenetic-based anti-tumor drugs or cell cycle signaling pathway inhibitors.

The immune checkpoint inhibitors include but are not limited to: CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, TIM-3 inhibitors, VISTA inhibitors, LAG3 inhibitors , TIGIT inhibitors, A2AR inhibitors, or VTCN1 inhibitors.

The immune checkpoint agonists include but not limited to: STING agonists, 4-1BB agonists, OX40 agonists, RORγ agonists or ICOS agonists.

detailed description

In order to further clarify the present invention, a series of examples are given below, these examples are completely illustrative, they are only used to specifically describe the present invention, and should not be construed as limiting the present invention.

Example 1

Preparation of 4,5-diiodo-1H-imidazole (1)

Dissolve 1H-imidazole (3g, 44.1mmol) in 2M NaOH (10.6g, 265.0mmol) solution, add KI (29.3g, 176.0mmol) and I ₂ (22.4g, 88.0mmol) aqueous solution 100mL, react at room temperature for 3 After 1 hour, 6M dilute hydrochloric acid was added dropwise to adjust the pH value of the reaction solution to neutral, resulting in a large amount of solid, which was filtered by suction and recrystallized from ethanol to obtain an off-white solid with a yield of 99.0%, mp 166-168°C. ¹ H NMR (300MHz, DMSO-d ₆ ) δ (ppm) 7.8 (br s, 1H), 12.75 (br s, 1H); MS (EI) m/z 320.8[M+H] ⁺ .

Preparation of 4-iodo-1H-imidazole (2)

Dissolve 1 (12.0g, 37.5mmol) in the reaction system of ethanol (120mL) and water (20mL), add Na ₂ SO ₃ (23.6g, 188.0mmol), reflux for 72 hours, remove ethanol under reduced pressure, ethyl acetate Extract the ester, dry over anhydrous magnesium sulfate, remove the solvent, and recrystallize from dichloromethane to obtain a white solid with a yield of 48.1%. ¹ H NMR (300MHz, Chloroform-d) δ (ppm) 7.0 (s, 1H), 7.5 (s, 1H); MS (EI) m/z 194.9[M+H] ⁺ .

Preparation of 4-iodo-1-trityl-1H-imidazole (3)

Dissolve 2 (3.5g, 18.0mmol) in DMF (70mL), drop triethylamine (3.0mL, 21.6mmol), add trityl chloride (5.5g, 19.7mmol), react at room temperature for 24 hours, pour In 200 mL of water, a large amount of solid precipitated out, which was suction filtered, washed with diethyl ether, and dried to obtain a white solid with a yield of 94.0%, mp 214-216°C. ¹ H NMR (300MHz, Chloroform-d) δ (ppm) 6.9 (m, 1H), 7.0-7.2 (m, 6H), 7.25-7.4 (m, 10H); MS (EI) m/z 437.1 [M+ H] ⁺ Preparation of 2-(1-trityl-1H-imidazole)benzaldehyde (4)

3 (3.0 g, 6.9 mmol), 2-formylphenylboronic acid (1.6 g, 10.7 mmol), K ₃ PO ₄ (4.4 g, 20.8 mmol) were dissolved in DMF (30 mL) and water (6 mL), and Pd was added (PPh ₃ ) ₄ (0.6g, 0.5mmol), reacted at 90°C for 16 hours under the protection of N ₂ , cooled, filtered with suction, added water (50mL), extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and obtained by column chromatography White solid, 66.7% yield, mp 147-149°C. ¹ H NMR (300MHz, Chloroform-d) δ (ppm) 7.97 (dd, J=7.8, 1.4Hz, 1H), 7.72-7.54 (m, 3H), 7.38 (h, J=3.2Hz, 11H), 7.25 -7.19(m, 6H), 7.07(d, J=1.3Hz, 1H); MS(EI) m/z 415.2[M+H] ⁺ .

Preparation of Witting reagent (5)

Dissolve triphenylphosphine (25.9g, 98.8mmol) in dichloromethane (300mL), slowly add ethyl 2-bromoacetate (15.0g, 89.8mmol), react at room temperature for 3 days, remove the solvent, and wash the solid with dichloro Washing with methane gave a white solid product with a yield of 90.6%. Preparation of (E)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)ethyl acrylate (6)

5 (3.3g, 7.7mmol) was dissolved in dichloromethane (10mL), NaOH (0.6g, 15.4mmol) aqueous solution (1mL) was added at 0°C, and stirred at room temperature for 40 minutes. Dissolve 2-(1-trityl-1H-imidazole)benzaldehyde (3.2g, 7.7mmol) in dichloromethane (1mL), slowly drop into the above system at 0°C, stir at room temperature for 12 hours, add Water (50 mL), extracted with dichloromethane, dried over anhydrous magnesium sulfate, and purified by column chromatography to obtain a light yellow solid with a yield of 77.5%. ¹ H NMR (300MHz, Chloroform-d) δ (ppm) 8.17 (d, J = 15.9Hz, 1H), 7.77 (dd, J = 7.8, 1.4Hz, 1H), 7.61-7.51 (m, 3H), 7.45 -7.33(m, 14H), 7.21(td, J=7.2, 6.6, 4.1Hz, 8H), 7.06-6.89(m, 2H), 6.32(d, J=15.9Hz, 1H), 4.23(q, J =7.1Hz, 2H), 4.07(q, J=7.1Hz, 1H), 1.29-1.24(m, 3H), 1.15(t, J=7.1Hz, 1H); MS(EI) m/z 485.3 [M +H] ⁺ .

Preparation of ethyl 2-(5H-imidazo[5,1-a]isoindol-5-yl)acetate (7)

6 (5.0 g, 10.3 mmol) was dissolved in methanol (5 mL), then acetic acid (12.5 mL) was added, and reacted at 90° C. for 3 hours. Cool to room temperature, add saturated potassium carbonate solution to adjust the pH of the reaction system to 10, remove methanol under reduced pressure, extract with ethyl acetate, dry over anhydrous magnesium sulfate, remove the solvent to obtain a crude product, and purify by column chromatography to obtain a gray solid with a yield of 76.0%. . ¹ H NMR (300MHz, Chloroform-d) δ (ppm) 7.81 (s, 1H), 7.57 (dt, J=7.6, 1.0Hz, 1H), 7.49-7.42 (m, 2H), 7.35 (dd, J= 1.7, 1.0Hz, 1H), 7.21(s, 1H), 5.58(s, 1H), 4.30(q, J=7.1Hz, 2H), 3.12(dd, J=17.3, 3.9Hz, 1H), 2.73( dd, J=17.3, 9.7Hz, 1H), 1.33(t, J=7.2Hz, 3H); MS(EI) m/z243.1[M+H] ⁺ .

Preparation of 2-(5H-imidazo[5,1-a]isoindol-5-yl)acetic acid (8)

7 (1.0 g, 4.1 mmol) was dissolved in methanol (50 mL), NaOH (0.8 g, 20.6 mmol) aqueous solution 2 mL was added, and the reaction system was heated at 60° C. for 3 hours. After cooling to room temperature, the pH of the reaction was adjusted to 5-6 with 10% dilute hydrochloric acid. Water and methanol were removed under reduced pressure to give a crude solid which was used in the next step without purification.

Preparation of N-benzyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide (LA01)

The crude product 8 (0.2g, about 0.6mmol) was dissolved in DMF (5mL), EDCI (0.14g, 0.75mmol), HOBt (0.11g, 0.75mmol) and TEA (0.26mL, 1.86mmol) were added, and stirred at room temperature for 15 minutes . Add benzylamine (0.07g, 0.65mmol) and react at room temperature for 12 hours. 10 mL of water was added, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was removed to obtain a crude solid, which was purified by column chromatography to obtain 0.08 g of a white solid with a yield of 67.2%, mp 140-142°C. ¹ H NMR (300MHz, Chloroform-d) δ (ppm) 7.61 (s, 1H), 7.51 (d, J = 7.5Hz, 1H), 7.43-7.32 (m, 7H), 7.24 (d, J = 8.1Hz , 1H), 7.08(s, 1H), 6.55(s, 1H), 5.67(dd, J=9.4, 4.5Hz, 1H), 4.62-4.40(m, 2H), 2.94(dd, J=15.4, 4.4 Hz, 1H), 2.50 (dd, J=15.4, 9.5Hz, 1H); MS(EI) m/z 304.2[M+H] ⁺ .

Example 2

Preparation of N-(4-cyanobenzyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide (LA02)

Referring to the preparation method of LA01, it is prepared from 10 and p-cyanobenzylamine, with a yield of 60.4%, mp 198-200°C. ¹ H NMR (300MHz, DMSO-d ₆ ) δ (ppm) 8.70 (t, J=5.9Hz, 1H), 7.87-7.74 (m, 2H), 7.69-7.52 (m, 2H), 7.5-7.33 (m , 4H), 7.26(td, J=7.6, 1.2Hz, 1H), 7.13(s, 1H), 5.62(dd, J=8.7, 5.2Hz, 1H), 4.60-4.37(m, 2H), 3.07( dd, J=15.4, 5.2Hz, 1H), 2.69 (dd, J=15.5, 8.8Hz, 1H); MS(EI) m/z 329.1[M+H] ⁺ .

Example 3

Preparation of N-(3,4-difluorobenzylamino-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide (LA03)

Referring to the preparation method of LA01, it is prepared by using 10 and 3,4-difluorobenzylamine as raw materials, the yield is 78.0%, and the mp is 88-90°C. ¹ H NMR (300MHz, Chloroform-d) δ (ppm) 7.60(s, 1H), 7.51(d, J=7.6Hz, 1H), 7.36(dd, J=21.6, 7.5Hz, 2H), 7.24(t , J=7.7Hz, 1H), 7.19-6.97(m, 4H), 6.91(s, 1H), 5.66(dd, J=9.2, 4.5Hz, 1H), 4.53(dd, J=14.9, 5.9Hz, 1H), 4.37(dd, J=14.9, 5.4Hz, 1H), 2.96(dd, J=15.9, 4.2Hz, 1H), 2.56(dd, J=15.5, 9.2Hz, 1H); MS(EI)m /z 340.1[M+H] ⁺ .

Example 4

Preparation of N-(3-chlorobenzyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide (LA04)

Referring to the preparation method of LA01, it is prepared by using 10 and 3-chlorobenzylamine as raw materials, with a yield of 66.0% and a mp of 73-75°C. ¹ HNMR (300MHz, Chloroform-d) δ (ppm) 7.65 (s, 1H), 7.53 (d, J = 7.6Hz, 1H), 7.44-7.29 (m, 4H), 7.29-7.16 (m, 3H), 7.12(d, J=1.7Hz, 1H), 6.33(s, 1H), 5.71(dd, J=9.4, 4.5Hz, 1H), 4.59(dd, J=14.6, 5.8Hz, 1H), 4.43(dd , J=15.0, 5.0Hz, 1H), 3.08-2.86(m, 1H), 2.66-2.41(m, 1H); MS(EI) m/z 338.1[M+H] ⁺ .

Example 5

Preparation of N-(3-chloro-4-fluorobenzyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide (LA05)

Referring to the preparation method of LA01, it is prepared from 10 and 3-chloro-4-fluorobenzylamine, with a yield of 67.2%, and mp 143-145°C. ¹ H NMR (300MHz, Chloroform-d) δ (ppm) 7.67 (s, 1H), 7.54 (d, J = 7.6Hz, 1H), 7.37 (dt, J = 14.1, 7.3Hz, 2H), 7.30-7.22 (m, 2H), 7.14(q, J=8.2, 7.3Hz, 2H), 6.29(s, 1H), 5.79-5.63(m, 1H), 4.54(d, J=5.9Hz, 1H), 4.41( d, J=4.9Hz, 1H), 2.99 (dd, J=15.3, 4.5Hz, 1H), 2.58 (dd, J=15.4, 9.1Hz, 1H); MS(EI) m/z 356.1 [M+H ] ⁺ .

Example 6

Preparation of N-(4-methoxybenzyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide (LA06)

Referring to the preparation method of LA01, it is prepared from 10 and p-methoxybenzylamine, with a yield of 72.3% and a mp of 74-76°C. ¹ H NMR (300MHz, DMSO-d ₆ )δ(ppm) 8.52(s, 1H), 7.77-7.55(m, 2H), 7.47(d, J=7.6Hz, 1H), 7.39(t, J=7.5 Hz, 1H), 7.32-7.18(m, 3H), 7.13(s, 1H), 6.97-6.84(m, 2H), 5.62(dd, J=8.9, 5.2Hz, 1H), 4.31(d, J= 5.8Hz, 2H), 3.74(s, 3H), 3.01(dd, J=15.3, 5.3Hz, 1H), 2.61(dd, J=15.3, 9.0Hz, 1H); MS(EI) m/z 334.2[ M+H] ⁺ .

Example 7

Preparation of N-(4-hydroxybenzyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide (LA07)

Referring to the preparation method of LA01, it is prepared from 10 and p-hydroxybenzylamine, with a yield of 65.8%, mp 232-234°C. ¹ H NMR (300MHz, DMSO-d ₆ ) δ (ppm) 9.33 (d, J = 1.2Hz, 1H), 8.46 (s, 1H), 7.70-7.55 (m, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.39(t, J=7.4Hz, 1H), 7.26(dd, J=7.5, 1.2Hz, 1H), 7.17-7.01(m, 3H), 6.79-6.63(m, 2H), 5.62 (dd, J=9.0, 5.2Hz, 1H), 4.26(d, J=5.7Hz, 2H), 3.00(dd, J=15.2, 5.3Hz, 1H), 2.74-2.56(m, 1H); MS( EI)m/z 320.2[M+H] ⁺ .

Example 8

Preparation of N-benzyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)-N-methylacetamide (LA08)

Referring to the preparation method of LA01, it is prepared from 10 and p-N-methylbenzylamine, with a yield of 69.1%, and a mp of 208-210°C. ¹ H NMR (300MHz, Chloroform-d) δ (ppm) 7.86 (d, J = 3.5Hz, 1H), 7.66-6.99 (m, 10H), 5.79 (d, J = 9.3Hz, 1H), 4.81-4.62 (m, 1H), 4.45(s, 1H), 3.22-3.01(m, 2H), 2.86(s, 3H); MS(EI) m/z 318.2[M+H] ⁺ .

Example 9

Preparation of 2-(5H-imidazo[5,1-a]isoindol-5-yl)-N-(1-phenylethyl)acetamide (LA09)

Referring to the preparation method of LA01, it is prepared from 10 and α-methylbenzylamine, with a yield of 60.2%, and mp 144-146°C. ¹ H NMR (300MHz, Chloroform-d) δ (ppm) 7.59 (d, J = 7.8Hz, 2H), 7.51-7.37 (m, 3H), 7.36-7.16 (m, 5H), 7.15-7.02 (m, 1H), 6.90(d, J=11.5Hz, 1H), 5.51(dd, J=9.2, 4.9Hz, 1H), 5.18(dd, J=7.2, 2.8Hz, 1H), 2.95-2.67(m, 1H ), 2.58-2.30(m, 1H), 1.48(t, J=6.0Hz, 3H); MS(EI) m/z 318.2[M+H] ⁺ .

Example 10

N-(Benzo[d][1,3]dioxo-5-methylene)-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide (LA10) preparation

Referring to the preparation method of LA01, it is prepared by using 10 and 3,4-methylenedioxybenzylamine as raw materials, with a yield of 74.3%, and mp88-90°C. ¹ H NMR (300MHz, Chloroform-d) δ (ppm) 7.81 (s, 1H), 7.66-7.09 (m, 6H), 6.73 (s, 2H), 6.34 (s, 1H), 5.81 (d, J= 75.2Hz, 2H), 4.39(d, J=28.1Hz, 2H), 2.98(d, J=15.9Hz, 1H), 2.59(dd, J=15.5, 8.9Hz, 1H); MS(EI)m/ z 348.1[M+H] ⁺ .

Example 11

Preparation of N-(4-carboxybenzyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide (LA11)

Referring to the preparation method of LA01, it is prepared from 10 and p-carboxybenzylamine, with a yield of 79.2% and a mp of 260-262°C. ¹ H NMR (300MHz, DMSO-d ₆ ) δ (ppm) 12.84 (s, 2H), 8.68 (s, 1H), 8.03-7.81 (m, 2H), 7.72-7.53 (m, 2H), 7.49 (d , J=7.4Hz, 1H), 7.39(d, J=7.5Hz, 2H), 7.25(t, J=7.7Hz, 1H), 7.13(d, J=2.3Hz, 1H), 5.62(d, J =6.6Hz, 1H), 4.45(s, 2H), 3.07(dd, J=15.2, 5.3Hz, 1H), 2.68(dd, J=15.5, 8.9Hz, 1H); MS(EI) m/z 348.1 [M+H] ⁺ .

Example 12

Preparation of 2-(5H-imidazo[5,1-a]isoindol-5-yl)-N-(pyridine-3-methylene)acetamide (LA12)

Referring to the preparation method of LA01, it is prepared by using 10 and 3-aminomethylpyridine as raw materials, with a yield of 59.1%, and mp 119-121°C. ¹ H NMR (300MHz, Chloroform-d) δ(ppm) 8.56-8.44(m, 1H), 7.86(d, J=42.9Hz, 1H), 7.68(d, J=8.0Hz, 1H), 7.54(d , J=7.5Hz, 1H), 7.46-7.23(m, 5H), 7.14(s, 2H), 5.75(dd, J=9.0, 4.4Hz, 1H), 4.52(dd, J=20.6, 5.7Hz, 2H), 3.09(dd, J=15.7, 4.8Hz, 1H), 2.66(s, 1H); MS(EI) m/z 305.1[M+H] ⁺ .

Example 13

Preparation of 2-(5H-imidazo[5,1-a]isoindol-5-yl)-N-(p-diazabenzene-2-methylene)acetamide (LA13)

Referring to the preparation method of LA01, it is prepared by using 10 and 2-aminomethylpyrazine as raw materials, the yield is 64.1%, and the mp is 163-165°C. ¹ H NMR (300MHz, Chloroform-d) δ(ppm) 8.65(d, J=4.1Hz, 1H), 8.57-8.45(m, 2H), 7.72(s, 1H), 7.54(d, J=8.0Hz , 1H), 7.38(dd, J=15.2, 7.7Hz, 2H), 7.26(dd, J=11.4, 5.0Hz, 1H), 7.13(d, J=4.4Hz, 1H), 7.04(s, 1H) , 5.84-5.54(m, 1H), 4.72(t, J=4.9Hz, 2H), 3.13-2.95(m, 1H), 2.63(dd, J=15.5, 9.7Hz, 1H); MS(EI)m /z 306.1[M+H] ⁺ .

Example 14

Preparation of 2-(5H-imidazo[5,1-a]isoindol-5-yl)-N-phenylacetamide (LA14)

Referring to the preparation method of LA01, it is prepared from 10 and aniline, with a yield of 77.1%, and mp227-229°C. ¹ H NMR (300MHz, Chloroform-d) δ (ppm) 7.95 (s, 1H), 7.74 (s, 1H), 7.56 (t, J=7.9Hz, 2H), 7.47-7.30 (m, 4H), 7.28 (d, J=2.6Hz, 2H), 7.17(dd, J=15.5, 7.7Hz, 2H), 5.90-5.64(m, 1H), 3.13(d, J=15.3Hz, 1H), 2.73(dd, J=15.5, 9.5Hz, 1H); MS(EI) m/z 290.2[M+H] ⁺ .

Example 15

Preparation of 2-(5H-imidazo[5,1-a]isoindol-5-yl)-N-(1H-indazol-6-yl)acetamide (LA15)

Referring to the preparation method of LA01, it is prepared from 10 and 6-aminoindazole as raw materials, with a yield of 68.3% and a mp of 280-282°C. ¹ H NMR (300MHz, DMSO-d ₆ ) δ (ppm) 8.23(s, 1H), 7.99(s, 1H), 7.67(dd, J=14.8, 8.3Hz, 2H), 7.57(d, J=7.4 Hz, 1H), 7.40(d, J=7.3Hz, 1H), 7.31(d, J=7.5Hz, 1H), 7.20-7.02(m, 2H), 5.73(s, 1H), 2.89(dd, J =16.0, 9.2Hz, 1H); MS(EI) m/z 330.2[M+H] ⁺ .

Example 16

Preparation of N-(benzo[d][1,3]diox-5-yl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide (LA16)

Referring to the preparation method of LA01, it is prepared by using 10 and 3,4-methylenedioxyaniline as raw materials, with a yield of 65.9%, and mp210-212°C. ¹ H NMR (300MHz, Chloroform-d) δ (ppm) 8.43 (s, 1H), 7.68 (s, 1H), 7.53 (s, 2H), 7.41 (s, 1H), 7.30 (s, 2H), 7.05 (s, 1H), 6.88(s, 1H), 6.76(s, 1H), 6.11-5.91(m, 2H), 5.74(s, 1H), 3.08(s, 1H), 2.69(s, 1H); MS(EI)m/z 334.1[M+H] ⁺ .

Example 17

Preparation of N-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide (LA17)

Referring to the preparation method of LA01, it is prepared by using 10 and cyclohexylamine as raw materials, with a yield of 69.3%, mp 84-86°C. ¹ HNMR (300MHz, DMSO-d ₆ ) δ (ppm) 7.98 (d, J = 7.8Hz, 1H), 7.68 (s, 1H), 7.61 (d, J = 7.5Hz, 1H), 7.51 (d, J =7.6Hz, 1H), 7.39(t, J=7.4Hz, 1H), 7.28(td, J=7.5, 1.2Hz, 1H), 7.14(s, 1H), 5.60(dd, J=9.1, 5.2Hz , 1H), 2.94 (dd, J=15.1, 5.2Hz, 1H), 1.63 (ddd, J=64.8, 31.0, 9.4Hz, 6H), 1.18-1.10 (m, 2H); MS(EI) m/z 296.2[M+H] ⁺ .

Example 18

Preparation of 2-(5H-imidazo[5,1-a]isoindol-5-yl)-N-(3-methoxyphenethyl)acetamide (LA18)

Referring to the preparation method of LA01, it is prepared from 10 and 3-methoxyphenethylamine, with a yield of 78.2% and a mp of 94-96°C. ¹ H NMR (300MHz, Chloroform-d) δ (ppm) 7.67(s, 1H), 7.52(d, J=7.6Hz, 1H), 7.43-7.17(m, 4H), 7.12(d, J=1.5Hz , 1H), 6.85-6.69(m, 3H), 5.91(d, J=7.2Hz, 1H), 5.68(dd, J=9.6, 4.3Hz, 1H), 3.79(s, 3H), 3.64(qd, J=6.9, 3.1Hz, 2H), 2.93(d, J=4.4Hz, 1H), 2.85(td, J=7.5, 7.0, 2.5Hz, 2H), 2.42(dd, J=15.5, 9.5Hz, 1H ); MS(EI) m/z 348.2[M+H] ⁺ .

Example 19

Preparation of 2-(5H-imidazo[5,1-a]isoindol-5-yl)-N-phenylethylacetamide (LA19)

Referring to the preparation method of LA01, it was prepared from 10 and phenethylamine, with a yield of 77.2% and a mp of 167-169°C. ¹ HNMR (300MHz, Chloroform-d) δ (ppm) 7.70 (s, 1H), 7.53 (d, J = 7.6Hz, 1H), 7.43-7.12 (m, 10H), 5.81 (s, 1H), 5.69 ( dd, J=9.5, 4.3Hz, 1H), 3.65(tt, J=6.7, 3.3Hz, 2H), 2.92-2.85(m, 2H), 2.43(dd, J=15.5, 9.5Hz, 1H); MS (EI)m/z 318.2[M+H] ⁺ .

Example 20

Preparation of 2-(5H-imidazo[5,1-a]isoindol-5-yl)-N-(2-(pyridin-2-yl)ethyl)acetamide (LA20)

Referring to the preparation method of LA01, it is prepared from 10 and 2-(2-aminoethyl)pyridine as raw materials, with a yield of 85.2%, and mp140-142°C. ¹ H NMR (300MHz, DMSO-d ₆ ) δ (ppm) 8.50 (d, J = 4.3Hz, 1H), 8.21 (s, 1H), 7.83-7.66 (m, 2H), 7.60 (d, J = 7.5 Hz, 1H), 7.47(d, J=7.6Hz, 1H), 7.38(t, J=7.4Hz, 1H), 7.25(dd, J=14.8, 5.8Hz, 3H), 7.15(s, 1H), 5.59(dd, J=9.3, 5.6Hz, 1H), 3.54(q, J=6.5Hz, 2H), 2.93(td, J=8.0, 7.2, 3.5Hz, 2H), 2.55(d, J=10.0Hz , 2H); MS(EI) m/z 319.2[M+H] ⁺ .

Example 21

Preparation of (E)-1-cyclohexyl-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)-2-propen-1-one (9a)

At 0°C, slowly add Na (0.6g, 23.9mmol) into ethanol (15mL) to prepare sodium ethoxide solution, add methylcyclohexyl ketone (1.5g, 11.9mmol), 4 (5.0g, 11.9mmol ). React at room temperature for 3 hours, add saturated ammonium chloride solution to extract the reaction, remove the solvent under reduced pressure, add 15 mL of water, extract with dichloromethane, dry over anhydrous magnesium sulfate, remove the solvent under reduced pressure to obtain a white solid crude product. ¹ H NMR (300MHz, Chloroform-d) δ (ppm) 8.10-7.97 (m, 2H), 7.64-7.48 (m, 4H), 7.40-7.26 (m, 9H), 7.18 (d, J=7.2Hz, 6H), 6.50(d, J=15.0Hz, 1H), 2.91(s, 1H), 2.28(dt, J=13.2, 7.0Hz, 2H), 1.94(dt, J=13.2, 6.9Hz, 2H), 1.89-1.69(m, 3H), 1.58-1.39(m, 3H).

Preparation of 1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl-1-one (10a)

Referring to the preparation method of Intermediate 7, it was prepared from Intermediate 9a with a yield of 50.8%. ¹ H NMR (300MHz, Chloroform-d) δ (ppm) 7.69-7.62 (s, 1H), 7.58-7.53 (dt, J=7.6, 0.9Hz, 1H), 7.43-7.36 (m, 1H), 7.28- 7.21(m, 2H), 7.21-7.15(s, 1H), 5.73-5.59(dd, J=9.5, 3.6Hz, 1H), 3.26-3.16(dd, J=18.4, 3.6Hz, 1H), 3.04- 2.76(dd, J=18.4, 9.5Hz, 1H), 2.49-2.24(m, 1H), 1.97-1.59(m, 5H), 1.40-1.19(m, 5H).

Preparation of (Z)-1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanone oxime (LA21)

10a (0.07g, 0.25mmol) was dissolved in ethanol (5mL), hydroxylamine hydrochloride (0.05g, 0.75mmol) was added at room temperature, and reacted at 50°C for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a white solid with a yield of 54.2%, mp 126-128°C. ¹ H NMR (300MHz, DMSO-d ₆ ) δ(ppm) 0.99-1.15(m, 5H), 1.45-1.72(m, 6H), 2.43and 2.58(two m, 1H), 2.70and 2.91(m, 1H) ), 4.69(m, 1H), 7.23-7.29(m, 3H), 7.40and7.46(two m, 1H), 7.53and 7.58(two m, 1H), 7.75and 7.76(two s, 1H), 10.34 and 10.41(two s, 1H); MS(EI) m/z 296.2[M+H] ⁺ .

Example 22

(E)-1-(4-chlorophenyl)-3-(2-(1-trityl-1H-imidazol-4-yl)phenyl)-2-propen-1-one (9b) preparation

Prepared from methyl-p-chlorophenyl ketone and 4 according to the preparation method of intermediate 9a. ¹ H NMR (300MHz, Chloroform-d) δ (ppm) 8.12 (dd, J=7.5, 2.0Hz, 1H), 8.09 (s, 1H), 7.96-7.86 (m, 2H), 7.84-7.68 (m, 2H), 7.59(s, 1H), 7.52-7.42(m, 4H), 7.49-7.26(m, 10H), 7.19-7.11(m, 6H).

Preparation of 1-(4-chlorophenyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethyl-1-one (10b)

Referring to the preparation method of intermediate 7, it was prepared from intermediate 9b with a yield of 59.9%. ¹ H NMR (300MHz, Chloroform-d) δ (ppm) 8.01-7.85 (m, 2H), 7.66-7.25 (m, 8H), 6.30 (t, J=7.0Hz, 1H), 3.43 (dd, J= 12.5, 6.9Hz, 1H), 3.20 (dd, J=12.4, 7.0Hz, 1H).

Preparation of (Z)-1-(4-chlorophenyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanone oxime (LA22)

Referring to the preparation method of LA21, it is prepared from 10b and hydroxylamine hydrochloride as raw materials, the yield is 49.9%, and the mp is 89-91°C. ¹ HNMR (300MHz, Chloroform-d) δ (ppm) 7.86-6.94 (m, 11H), 6.21-5.65 (m, 1H), 3.83-3.14 (m, 2H); MS (EI) m/z 324.1 [M +H]+.

Example 23

1. IDO1 inhibitory activity test based on Hela cells

1.1 Experimental materials and main instruments

Hela cell line ATCC

Centrifuge Eppendorf(CHINA)

Electric constant temperature blast drying oven (DHG-924385-III) Shanghai Xinmiao Medical Instrument Manufacturing Co., Ltd.

Acetic acid (glacial acetic acid) Nanjing Chemical Reagent Co., Ltd.

Trichloroacetic acid (CAS: 76-03-9) Shanghai Lingfeng Chemical Reagent Co., Ltd.

Electronic balance Sartorius

p-Dimethylaminobenzaldehyde (CAS: 100-10-7) Aladdin

Recombinant Human IFN-γ(Catalog#AF-300-02) PEPROTECH

1.2 Experimental method

Hela cells purchased from ATCC were stored in minimal basal medium (2mM L-glutamine and Earle's supplemented with 1.5g/L sodium bicarbonate, 0.1mM non-essential amino acids, 1mM sodium propupuprate and 10% fetal calf serum). 's BSS). Store Hela cells at 37 °C in a humidified incubator supplied with 5% _CO2 .

Hela cells were seeded in a 96-well culture plate at a density of 5×10 ³ /well and cultured overnight. The next day, IFN-γ (final concentration 100 ng/mL) and compound serial dilutions (total volume 200 μL medium) were added to the cells. After 24 hours of incubation, transfer 140 μL of supernatant/well to a new 96-well plate, add 10 μL of 6.1 mol/L trichloroacetic acid, and incubate in a constant temperature oven at 50°C for 30 minutes to make the produced N-formyl canine Uridine is hydrolyzed to kynurenine. The reaction mixture was then centrifuged at 4000 rpm for 10 min to remove the precipitate. 100 μL of supernatant/well was transferred to another 96-well plate, and mixed with an equal volume of 2% (w/v) p-dimethylaminobenzaldehyde in acetic acid solution. The absorbance was detected at 480 nm using a microplate reader, and the obtained results were calculated using an IC ₅₀ calculator. Three replicate wells were set up in the experiment.

1.3 Experimental results

The experimental results are shown in Table 1. The results show that the compound of the present invention has significant inhibitory effect on the activity of IDO1. Among them, compound LA18 has the strongest activity (IC ₅₀ : 0.84 μM).

Table 1 Inhibitory activity of compounds of the present invention on IDO1

2. Proliferation experiment of T lymphocytes

2.1 Experimental method

B16F1 cell treatment: Aspirate the medium (high glucose DMEM, 10% FBS), wash with PBS 1-2 times. Add 0.25% trypsin for digestion. Aspirate the trypsin, add medium, blow down the cells, transfer to a 1.5mL centrifuge tube, centrifuge, aspirate the supernatant, add 1mL DMEM medium to resuspend the cells. Add mitomycin C (final concentration 25 μg/ml), pipette to mix, 37°C, water bath for 30 minutes, wash 3 times with RP1640, count cells, and set aside.

Preparation of spleen cells: Take C57/BL6 mice, remove their eyeballs, and kill them by bloodletting. Aseptically remove the spleen and put it into a 35mm culture dish containing 2 mL of sterile pre-cooled RPMI 1640 medium. Cell extrusion. Then add 2 mL of culture medium, and pipette repeatedly with a 5 mL pipette until the suspension is uniform. The cell suspension was filtered with a 70 μm filter, and centrifuged at 300 g for 5 min (4° C.). After discarding the supernatant, add 10mL Tris-NH ₄ Cl to the splenocytes, blow evenly, let stand for 2-3min, and centrifuge at 300g for 5min (4°C) to remove red blood cells. After discarding the supernatant, wash twice with PRMI 1640 and set aside.

1) Add ² ×104/well of treated B16F1 cells (stimulator cells) and ¹ ×106 cells/well of spleen lymphocytes (response cells) to a 96-well plate, add RP1640 (10% FBS), and fill to 200 μL.

2) Grouping: drug administration group (stimulator cells + response cells + corresponding compound), blank control (only response cells), model group (stimulation cells + response cells), except for blank control, other groups were added with ConA (final concentration 5 μg/ml), placed in an incubator at 37°C, 95% humidity, and 5% CO ₂ for 48 hours.

3) Add 20 μL of MTT (final concentration 4 mg/ml) into the incubator to continue culturing for 4 hours, measure the absorbance value at 570 nm wavelength with a microplate reader; calculate the proliferation rate of T lymphocytes:

T lymphocyte proliferation rate (%)=[administration hole (T lymphocyte+B16F1 cell+IDO1 inhibitor) OD value-control hole (T lymphocyte+B16F1 cell) OD value]/control hole (T lymphocyte+B16F1 Cell) OD value × 100%

2.2 Experimental results

In the mixed lymphocyte reaction system, B16F1 cells highly express IDO1, which can inhibit the proliferation of T lymphocytes. After adding compounds LA16 and LA18 (3 times _IC50 concentration) and culturing for 48 hours, using MTT to detect the proliferation of T lymphocytes, the proliferation rates were 48.61% and 26.53%, respectively, indicating that compounds LA16 and LA18 can significantly increase the proliferation of T lymphocytes.

3. Effects on regulatory T lymphocytes

3.1 Experimental method

Add the treated B16F1 cells (8×10 ⁴ wells) and spleen lymphocytes (10 ⁶ wells, stimulated with 5 μg/mL ConA) into a 24-well plate, add the corresponding concentration of the compound and place it at 37°C in humidity Cultivate in an incubator with 95% and 5% CO ₂ for 48 hours; collect the supernatant to test ELISA, stain with anti-CD4, anti-CD25, and anti-FOCP3 antibodies, and detect the differentiation of T cells in a flow cytometer.

3.2 Experimental results

When primitive T lymphocytes were co-cultured with melanoma cell line B16F1, the number of regulatory T lymphocytes increased 2.7 times (14.7%) compared with the experimental group containing only primitive T lymphocytes (5.4%). When compounds LA16 and LA18 (3 times IC ₅₀ concentration) were added to the system, this effect could be significantly reversed (7.9% and 10.1%, respectively), indicating that compounds LA16 and LA18 could reverse the regulation of primitive T lymphocytes by inhibiting IDO1. transformation of T lymphocytes.

4. Effect on IDO1 expression

4.1 Experimental method

Hela cells were cultured in a 6-well plate at a density of 2×10 ⁵ per well, and cultured at 37° C. and 5% CO ₂ for 12 hours. Blank control (add medium only), model group (add IFN-γ, corresponding positive drug), drug treatment group (add IFN-γ, corresponding compound), culture at 37°C, 5% CO ₂ for 24h, and collect cells , Western blot detection of IDO1 expression.

4.2 Experimental results

The experimental results showed that compounds LA16 and LA18 did not affect the expression of IDO1 in Hela cells, indicating that compounds LA16 and LA18 reversed IDO1-mediated immunosuppression by inhibiting the activity of IDO1.

Claims (10)

1. The imidazoisoindole compound represented by general formula (I), its stereoisomer or its pharmaceutically acceptable salt: in: R ₁ represents hydrogen, NR ₃ R ₄ , C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₁₀ aryl or C ₁ -C ₁₀ aromatic heterocyclic group, wherein said The heteroaryl ring group may optionally contain one or more other heteroatoms selected from O, S or N; the alkyl, cycloalkyl, aryl or heteroaryl ring group may be optionally represented by the following The same or different substituents are monosubstituted to pentasubstituted, and the substituents are selected from: halogen, trifluoromethyl, cyano, nitro, hydroxyl or amino; R ₂ represents O, S or NR ₅ ; R ₃ represents hydrogen, C ₁ -C ₈ alkyl or C ₃ -C ₆ cycloalkyl; R ₄ represents hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₆ cycloalkyl, C ₅ -C ₁₀ aryl, C ₅ -C ₁₀ aryl-(C ₁ -C ₁₀ alkyl), C ₁ -C ₁₀ aromatic heterocyclic group, C ₁ -C ₁₀ aromatic heterocyclic ring-(C ₁ -C ₁₀ alkyl), C ₁ -C ₁₂ fused heterocyclic group or C ₁ -C ₁₂ fused heterocyclic ring-(C ₁ - C ₁₀ alkyl), wherein said heterocyclic group may optionally contain one or more other heteroatoms selected from O, S or N; wherein said alkyl, cycloalkyl, aryl, aryl Heterocyclic rings and fused heterocyclic rings can optionally be monosubstituted to pentasubstituted by the following identical or different substituents selected from: C ₁ -C ₅ alkyl, halogen, trifluoromethyl, carboxyl , cyano, nitro, hydroxyl, amino or methoxy; R ₅ represents hydrogen, hydroxyl or mercapto. 2. the imidazoisoindole compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that: R ₁ represents hydrogen, NR ₃ R ₄ , C ₃ -C ₆ cycloalkyl, C ₅ -C ₁₀ aryl or C ₁ -C ₁₀ aromatic heterocyclic group, wherein the aromatic heterocyclic group can optionally Contains one or more other heteroatoms selected from O, S or N; wherein the cycloalkyl, aryl or aromatic heterocyclic group can be optionally monosubstituted by the following same or different substituents up to five Substitution, the substituent is selected from: halogen, cyano, nitro, hydroxyl or amino; R ₂ represents O or NR ₅ ; R ₃ represents hydrogen or C ₁ -C ₈ alkyl; R ₄ represents C ₃ -C ₆ cycloalkyl, C ₅ -C ₁₀ aryl, C ₅ -C ₁₀ aryl-(C ₁ -C ₁₀ alkyl), C ₁ -C ₁₀ aromatic heterocyclic group, C ₁ -C ₁₀ aromatic heterocycle-(C ₁ -C ₁₀ alkyl), C ₁ -C ₁₂ fused heterocyclic group or C ₁ -C ₁₂ fused heterocycle-(C ₁ -C ₁₀ alkyl), wherein the The heterocycle may optionally contain one or more other heteroatoms selected from O, S or N; wherein the cycloalkyl, aryl, aromatic heterocycle, and condensed heterocycle may be optionally represented by the following identical or Different substituents are monosubstituted to pentasubstituted, and the substituents are selected from: C ₁ -C ₅ alkyl, halogen, carboxyl, cyano, nitro, hydroxyl, amino or methoxy; R ₅ represents hydroxyl or mercapto. 3. the imidazoisoindole compound according to claim 2, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that: R ₁ represents NR ₃ R ₄ , cycloalkyl or p-chlorophenyl; R ₂ represents O or NR ₅ ; R ₃ represents hydrogen or methyl; R ₄ represents benzyl, 4-cyanobenzyl, 3,4-difluorobenzyl, 3-chlorobenzyl, 3-chloro-4-fluorobenzyl, 4-methoxybenzyl, 4-hydroxybenzyl Base, α-methylbenzyl, 3,4-methylenedioxybenzyl, p-carboxybenzyl, pyridine-3-methylene, p-diazepine-2-methylene, phenyl, 1H - indazol-6-yl, 3,4-methylenedioxybenzene, cyclohexyl, 3-methoxyphenethyl, phenethyl or pyridine-2-ethyl; R ₅ represents a hydroxyl group. 4. The imidazoisoindole compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that said compound is selected from: N-benzyl-2-(5H-imidazol[5,1-a]isoindol-5-yl)acetamide; N-(4-cyanobenzyl)-2-(5H-imidazol[5,1-a]isoindol-5-yl)acetamide; N-(3,4-difluorobenzylamino-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide; N-(3-chlorobenzyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide; N-(3-chloro-4-fluorobenzyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide; N-(4-methoxybenzyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide; N-(4-methoxybenzyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide; N-benzyl-2-(5H-imidazol[5,1-a]isoindol-5-yl)-N-methylacetamide; 2-(5H-imidazol[5,1-a]isoindol-5-yl)-N-(1-phenylethyl)acetamide; N-(benzo[d][1,3]dioxo-5-methylene)-2-(5H-imidazol[5,1-a]isoindol-5-yl)acetamide; N-(4-carboxybenzyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)acetamide; 2-(5H-imidazo[5,1-a]isoindol-5-yl)-N-(pyridine-3-methylene)acetamide; 2-(5H-imidazo[5,1-a]isoindol-5-yl)-N-(p-diazepine-2-methylene)acetamide; 2-(5H-imidazo[5,1-a]isoindol-5-yl)-N-phenylacetamide; 2-(5H-imidazol[5,1-a]isoindol-5-yl)-N-(1H-indazol-6-yl)acetamide; N-(benzo[d][1,3]dioxo-5-yl)-2-(5H-imidazol[5,1-a]isoindol-5-yl)acetamide; N-cyclohexyl-2-(5H-imidazol[5,1-a]isoindol-5-yl)acetamide; 2-(5H-imidazol[5,1-a]isoindol-5-yl)-N-(3-methoxyphenethyl)acetamide; 2-(5H-imidazol[5,1-a]isoindol-5-yl)-N-phenethylacetamide; 2-(5H-imidazol[5,1-a]isoindol-5-yl)-N-(2-(pyridin-2-yl)ethyl)acetamide; (Z)-1-cyclohexyl-2-(5H-imidazol[5,1-a]isoindol-5-yl)ethanone oxime; (Z)-1-(4-Chlorophenyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanone oxime. 5. the preparation method of pyrimidine compound according to claim 1, is characterized in that: a) When R ₂ is O, the preparation method of the compound shown in general formula (I) is: take 1H-imidazole as raw material, obtain 1 through iodination reaction; The Trt protecting group was introduced into the 1-position N atom of 2 and 2 to obtain 3, 3 and o-formylphenylboronic acid were prepared by Suzuki coupling reaction to obtain 4, and triphenylphosphine was reacted with ethyl 2-bromoacetate to obtain Witting reagent 5, intermediates 4 and 5 were prepared by Witting reaction 6, 6 was cyclized to obtain 7, 7 was hydrolyzed by sodium hydroxide to obtain 8, 8 was reacted with amine compound (NHR ₃ R ₄ ) to obtain compound LA01 -LA20; its synthetic route is as follows: Wherein, R ₃ and R ₄ are as defined in claim 1; b) when R2 is N _- OH, the preparation method of the compound shown in general formula (I) is: intermediate 4 reacts with methyl cyclohexyl ketone and methyl p-chlorophenyl ketone respectively to obtain 9a-b , 9a-b undergoes a cyclization reaction to obtain 10a-b, 10a-b reacts with hydroxylamine hydrochloride to obtain LA21-LA22; its synthetic route is as follows: 6. A pharmaceutical composition, it is made up of the active ingredient of therapeutically effective amount and pharmaceutically acceptable adjuvant; Described active ingredient comprises the imidazoisoisocyanurate as described in any one in claim 1-4 Indole compounds (I), their stereoisomers or pharmaceutically acceptable salts thereof; the pharmaceutically acceptable adjuvants include pharmaceutically acceptable carriers, diluents and/or excipients. 7. The compound described in any one of claims 1-4, its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutical composition described in claim 6 are used in the preparation of indoleamine 2,3-bis Application of oxygenase 1 inhibitor, said indoleamine 2,3-dioxygenase 1 inhibitor is used for the treatment of indoleamine 2,3-dioxygenase 1-mediated immunosuppressive related diseases In a patient, the disease related to the immunosuppression mediated by indoleamine 2,3-dioxygenase 1 is cancer, viral infection, neurodegenerative disease, cataract, organ transplant rejection, depression or autoimmune disease. 8. The compound described in any one of claims 1-4, its stereoisomer, its pharmaceutically acceptable salt or the purposes of the pharmaceutical composition described in claim 6 in preparing medicine, described medicine For the treatment of cancer, viral infection, neurodegenerative disease, cataract, organ transplant rejection, depression or autoimmune disease in patients. 9. The application according to claim 7-8, wherein said cancer is malignant melanoma, lung cancer, breast cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, lymphoma, leukemia, prostate cancer, testicular cancer, One or more of kidney cancer, brain cancer, head and neck cancer, ovarian cancer, cervical cancer, endometrial cancer, mesothelioma, thyroid cancer, liver cancer and esophageal cancer; the virus infection is human immunodeficiency virus, One of the hepatitis B virus, hepatitis C virus, influenza virus, polio virus, cytomegalovirus, coxsackie virus, human papilloma virus, Epstein-Barr virus, and varicella-zoster virus or multiple infections; the neurodegenerative disease is one of memory impairment, Alzheimer's disease, cognitive impairment, senile dementia, Parkinson's disease, Parkinson's syndrome and movement disorders or more; the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, scleroderma, nodular vasculitis, multiple sclerosis, nephropathy, myasthenia gravis, mixed One or more of sexual connective tissue disease, psoriasis, liver disease, endocrine-related disease, and autoimmune response due to infection. 10. The application according to claims 7-9, characterized in that: one or more chemotherapeutic agents, targeted anti-tumor drugs, immune checkpoint inhibitors, immune checkpoint agonists, Antitumor vaccines, antiviral agents, antiviral vaccines, cytokine therapy, adoptive cellular immunotherapy or radiotherapy; the chemotherapeutic agents are alkylating agents, tubulin inhibitors, topoase inhibitors, platinum drugs, Antimetabolite drugs or hormonal antineoplastic drugs; the targeted antineoplastic drugs are protein kinase inhibitors, proteasome inhibitors, isocitrate dehydrogenase inhibitors, epigenetic-based antineoplastic drugs or cell Cyclic signal pathway inhibitors; the immune checkpoint inhibitors are CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, TIM-3 inhibitors, VISTA inhibitors, LAG3 Inhibitors, TIGIT inhibitors, A2AR inhibitors or VTCN1 inhibitors; the immune checkpoint agonists are STING agonists, 4-1BB agonists, OX40 agonists, RORγ agonists or ICOS agonists.