WO2018161892A1 - 苯磺酰胺类ido1抑制剂、其制备方法及应用 - Google Patents

苯磺酰胺类ido1抑制剂、其制备方法及应用 Download PDF

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WO2018161892A1
WO2018161892A1 PCT/CN2018/078136 CN2018078136W WO2018161892A1 WO 2018161892 A1 WO2018161892 A1 WO 2018161892A1 CN 2018078136 W CN2018078136 W CN 2018078136W WO 2018161892 A1 WO2018161892 A1 WO 2018161892A1
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phenyl
aminesulfonyl
benzenesulfonamide
acetamide
amino
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French (fr)
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赖宜生
葛书山
郑英博
邹毅
王芳
徐强
郭文洁
王燕
胡月
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中国药科大学
南京大学
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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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    • C07C303/00—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
    • C07C303/40—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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    • 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
    • C07C311/30—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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    • 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
    • C07C311/30—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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    • 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
    • C07C311/30—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
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—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
    • 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
    • C07D317/46—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 condensed with one six-membered ring
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention belongs to the field of medicine, and in particular to a benzenesulfonamide compound or a pharmaceutically acceptable salt thereof, a preparation method thereof, and the use thereof as a guanamine 2,3-dioxygenase 1 (IDO1) inhibitor .
  • Tryptophan is an essential amino acid for human cells to maintain proliferation and survival, and can be used for biosynthesis of proteins, niacin and serotonin. Tryptophan is generally taken from food, more than 95% tryptophan is metabolized along the kynuric acid pathway, and the remaining tryptophan is converted to 5-hydroxytryptophan and serotonin in the nervous system and intestine, or in the pineal gland. Synthetic melatonin. Indoleamine 2,3-dioxygenase (IDO1) is a rate-limiting enzyme that catalyzes the metabolism of tryptophan along the kynurenine pathway in the human liver.
  • IDO1 Indoleamine 2,3-dioxygenase
  • IDO1 is expressed in a variety of tissues such as lung, kidney, brain, placenta, thymus, as well as a variety of cells such as macrophages and dendritic cells. IDO1 reduces the concentration of tryptophan in the body's microenvironment by oxidative cleavage of tryptophan, and produces a series of metabolisms such as kynurenine, 3-hydroxykynurenine, 2-amino-3-hydroxybenzoic acid, quinolinic acid, etc. product. Cytokines such as IFN- ⁇ , TNF- ⁇ , IL-1 ⁇ and IL-6 induce up-regulation of IDO1 (Bernhardt R. Chem Rev, 1996, 96(1): 2841-2888).
  • IDO1 not only catalyzes the oxidative metabolism of tryptophan, but also plays an important regulatory role in the body's innate and adaptive immunity (Munn DH, et al. Trends Immunol, 2013, 34(3): 137- 143). IDO1 mainly regulates the immune system by catalyzing the metabolism of tryptophan and causing the accumulation of tryptophan and its metabolites. On the one hand, tryptophan depletion can induce the T cell division cycle to remain in G1 phase by activating GCN2 pathway.
  • helper T cells 17 helper T cells 17 (Th17), thereby producing immunosuppression (Munn DH, et al. Immunity, 2005, 22(5): 633-642 ).
  • tryptophan metabolites such as kynurenine are cytotoxic and can kill T cells and natural killer (NK) cells (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 differentiation of CD4 + T cells into regulatory T by activating aromatic hydrocarbon receptors (AHR).
  • AHR aromatic hydrocarbon receptors
  • 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. Blood, 2006, 108(13): 4118-4125).
  • IDO1 is involved in many physiological and pathological processes. Studies have shown that IDO1 plays an important immunomodulatory 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 stress such as placental development and inflammatory reaction, the secretion of cytokines such as IFN- ⁇ is significantly increased, thereby inducing the up-regulation of IDO1, leading to tryptophan depletion and canine urine.
  • IDO1 is an immunomodulatory enzyme involved in the body's immune tolerance.
  • IDO1-mediated immune tolerance 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. Lab Invest, 2009, 89(5): 498-512).
  • overexpression of IDO1-mediated tryptophan depletion and accumulation of metabolites can inhibit T cell activation and lead to immune tolerance in the body.
  • IDO1-mediated immunosuppression tends to cause secondary infection in the lung (van der Sluijs KF, et al. J Infect Dis, 2006, 193(2): 214-222).
  • IDO1 is up-regulated, promotes the proliferation of Treg cells, inhibits the proliferation of Th17 cells, and causes the imbalance of Tregs/Th17 cells, leading to immunosuppression in patients (Favre D, et al. Sci Transl Med, 2010, 2 (32): 32ra36).
  • IDO1-mediated tryptophan depletion and elevated levels of metabolites are also associated with parasitic infections (Knubel CP, et al. FASEB J, 2010, 24(8): 2689-2701).
  • IDO1 catalyzed tryptophan metabolites such as kynurenine and quinolinic acid are neurotoxic, and these metabolites are associated with neurodegenerative diseases such as memory disorders, Alzheimer's disease (AD), and cognitive impairment.
  • AD Alzheimer's disease
  • disorders Alzheimer's disease, Parkinson's disease, Parkinson's disease, and the development of dyskinesia are closely related (Malpass K. Nat Rev Neurol, 2011, 7(8): 417; Maddison DC, et al. Semin Cell Dev Biol , 2015, 40: 134-141).
  • IDO1 and quinolinic acid in the brain of AD patients were higher than those in normal people, and the content of microglia and astrocytes in the periphery of senile plaques was the highest.
  • 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 proportion of the two is closely related to the degree of cognitive deficit 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 disorders are also associated with increased levels of IDO1 overexpression and increased levels of metabolites such as kynurenine.
  • Overexpression of IDO1 causes tryptophan depletion, which reduces the amount of tryptophan used to synthesize the neurotransmitter serotonin, resulting in a lack of serotonin, plus neurotoxic kynurenine and quinolinic acid.
  • the accumulation of metabolites promotes the development of neuropsychiatric disorders and is a factor in many mood disorders (Myint AM. FEBS J, 2012, 279(8): 1375-1385). Therefore, inhibition of IDO1 is an important therapeutic strategy for patients with neurodegenerative diseases and neuropsychiatric diseases.
  • IDO1 Excessive metabolism of tryptophan mediated by high expression of IDO1 is also present in various autoimmune diseases (Nguyen NT, et al. Front Immunol, 2014, 5: 551).
  • IDO1 In DCs with synovial joint tissue of rheumatoid arthritis, IDO1 is highly expressed, and the serum tryptophan concentration is decreased, while the kynurenine concentration 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 increased tryptophan metabolism are also present in patients with systemic lupus erythematosus.
  • IDO1-induced immunosuppression plays an important role in tumor immune escape.
  • IDO1 is overexpressed in various tumor cells and cells in its microenvironment such as DC and stromal cells, resulting in local tryptophan depletion and accumulation of tryptophan metabolites, thereby inducing tumor immune escape and helping tumor cells escape the immune system. Attack (Munn DH, et al. Trends Immunol, 2016, 37(3): 193-207).
  • Uyttenhove group uses immunohistochemical labeling methods in melanoma, lung cancer, breast cancer, stomach cancer, colon cancer, bladder cancer, pancreatic cancer, lymphoma, prostate cancer, kidney cancer, brain cancer, head and neck cancer, ovarian cancer, cervical cancer, uterus Expression of IDO1 was detected in 24 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).
  • tumor tissues such as ovarian cancer, melanoma, lung cancer and leukemia
  • the expression level of IDO1 in tumor tissues was closely related to the degree of malignancy of tumors 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; Okamoto A, et al. Clin Cancer Res, 2005, 11(16): 6030-6039; Ino K, et al.
  • IDO1 inhibitors can activate T cells, overcome the tumor immune escape mediated by IDO1, and can also improve the therapy of other tumor therapeutics (Koblish HK, et al. Mol Cancer Ther, 2010, 9(2): 489-498; Wainwright DA, et al. Clin Cancer Res, 2014, 20(20): 5290-5301).
  • IDO1 inhibitors can reduce the accumulation of tryptophan metabolism and kynurenine metabolites, thereby reversing IDO1-mediated immunosuppression, restoring proliferation and function of T cells and NK cells, and inhibiting The proliferation of Treg cells enhances 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 Symptoms and autoimmune diseases.
  • IDO1 inhibitors can be combined with other chemotherapeutic agents, targeted anti-tumor drugs, immunological checkpoint therapeutics, anti-tumor vaccines, antiviral agents, antiviral vaccines, cytokine therapies, adoptive cellular immunotherapy and radiation therapy.
  • chemotherapeutic agents targeted anti-tumor drugs, immunological checkpoint therapeutics, anti-tumor vaccines, antiviral agents, antiviral vaccines, cytokine therapies, adoptive cellular immunotherapy and radiation therapy.
  • chemotherapeutic agents targeted anti-tumor drugs, immunological checkpoint therapeutics, anti-tumor vaccines, antiviral agents, antiviral vaccines, cytokine therapies, adoptive cellular immunotherapy and radiation therapy.
  • IDO1 small molecule inhibitors are currently being developed to treat or prevent the above-mentioned diseases associated with IDO1.
  • an oxadiazole IDO1 inhibitor is reported in CN102164902B, which relates to the treatment of cancer, viral infections, neurodegenerative diseases, trauma, age-related cataracts, organ transplant rejection or by administering an IDO1 inhibitor or in combination with other therapeutic agents. Patients with autoimmune diseases.
  • IDO1 inhibitors are closely related to the pathogenesis of various diseases such as cancer, viral infection, neurodegenerative diseases, cataracts, organ transplant rejection, autoimmune diseases and depression. Therefore, IDO1 inhibitors can be used to inhibit the activity of IDO1, thereby reducing color. The accumulation of metabolites such as tyrosine and kynurenine restores the body's immune function and thus achieves the goal of treating the above diseases.
  • the compound of the present invention has IDO1 inhibitory activity and can be used for treating related diseases caused by IDO1 mediated immunosuppression, including cancer, viral infection, neurodegenerative disease, cataract, organ transplant rejection, autoimmune disease and depression. .
  • the technical problem to be solved by the present invention is to provide a benzenesulfonamide compound or a pharmaceutically acceptable salt thereof, a process for the preparation thereof, a pharmaceutical composition and use thereof.
  • the compounds of the present invention have good IDO1 inhibitory activity and can be used for the treatment and/or prevention of various related diseases caused by IDO1-mediated immunosuppression.
  • the present invention provides a benzenesulfonamide compound represented by the formula (I) or a pharmaceutically acceptable salt thereof:
  • n an integer from 0 to 8.
  • n an integer from 0 to 4.
  • R 1 represents hydrogen, cyano, nitro, hydroxy, halogen, amino, acetamido, trifluoromethyl or acrylamide
  • R 2 represents hydrogen, halogen, cyano, hydroxy, nitro, C 1 -C 8 alkyl, C 1 -C 8 alkoxy or methylenedioxy.
  • benzenesulfonamide compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is characterized in that:
  • n an integer from 0 to 4.
  • n an integer from 0 to 4.
  • R 1 represents a cyano group, a nitro group, an amino group, an acetamide group or an acrylamide group
  • R 2 represents hydrogen, 3-fluoro, 4-fluoro, 2-chloro, 3-chloro, 4-chloro, 3,4-dichloro, 3-bromo, 4-bromo, 3-chloro-4-fluoro, 3- Trifluoromethyl, 4-trifluoromethyl, 4-methyl, 3-isopropyl, 4-isopropyl, 4-cyano, 3-methoxy, 4-methoxy, 3,4- Dimethoxy or 3,4-methylenedioxy.
  • the imidazoisoindole compound represented by the formula (I) is preferably selected from the following compounds:
  • N-(4-(N-(4-Methoxybenzyl)aminesulfonyl)phenyl)acrylamide ( C19 ).
  • Another object of the present invention is to provide a process for the preparation of a compound of the formula (I), characterized in that:
  • n, m, R 1 and R 2 are as defined above;
  • n, m, R 1 and R 2 are as defined above;
  • R 1 is an acrylamide group
  • the compound of the formula (I) is prepared by reacting 2a, 2b, 2d, 2e, 2f and B 1-18 with acryloyl chloride, respectively, to obtain 3a-3d and C. 1 - 19 ; its synthetic route is as follows:
  • n, m, R 1 and R 2 are as defined above.
  • the pharmaceutically acceptable salts of the compounds of formula (I) can be synthesized by general chemical methods.
  • the preparation of the salt can be carried out by reacting the free base or acid with an equivalent stoichiometric or excess acid (inorganic or organic acid) or a base (inorganic or organic base) in a suitable solvent or solvent composition.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of an active ingredient and a pharmaceutically acceptable adjuvant; the active ingredient comprising a compound of formula (I) and pharmaceutically acceptable thereof One or more of the salts.
  • the adjuvant comprises a pharmaceutically acceptable carrier, diluent and/or excipient.
  • the pharmaceutical composition can be formulated into various types of dosage unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions), depending on the purpose of the treatment, Preference is given to tablets, capsules, liquids, suspensions, and injections (solutions and suspensions).
  • any excipient known and widely used in the art can be used.
  • the solution or suspension may be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerin) to prepare an isotonic injection with blood.
  • Any of the commonly used carriers in the art can also be used in the preparation of the injection.
  • a usual solvent, a buffer, or 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, and is usually from 5 to 95% by mass, preferably from 30 to 85% by mass.
  • the administration method of the pharmaceutical composition of the present invention is not particularly limited. Formulations of various dosage forms can be selected depending on the age, sex and other conditions and symptoms of the patient.
  • the invention further provides the use of a compound of the formula (I), a pharmaceutically acceptable salt thereof or the pharmaceutical composition for the preparation of a guanamine 2,3-dioxygenase 1 (IDO1) inhibitor.
  • the IDO1 inhibitor is for use in treating a patient associated with IDO1-mediated immunosuppression, including 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 formula (I), a pharmaceutically acceptable salt thereof or the pharmaceutical composition for the preparation of a medicament for the treatment of cancer, viral infection, neurodegenerative disease in a patient , cataracts, organ transplant rejection, depression or autoimmune diseases.
  • the cancer includes, but is not limited to, malignant melanoma, lung cancer, breast cancer, stomach cancer, colon cancer, bladder cancer, pancreatic cancer, lymphoma, leukemia, prostate cancer, testicular cancer, kidney cancer, brain cancer, head and neck cancer, ovary
  • malignant melanoma lung cancer, breast cancer, stomach cancer, colon cancer, bladder cancer, pancreatic cancer, lymphoma, leukemia, prostate cancer, testicular cancer, kidney cancer, brain cancer, head and neck cancer, ovary
  • cancer cervical cancer, endometrial cancer, mesothelioma, thyroid cancer, liver cancer, and esophageal cancer.
  • the viral infections include, but are not limited to, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, influenza virus, poliovirus, cytomegalovirus, coxsackie virus, human papilloma virus, love An infection caused by one or more of the Steiner-Barr virus and the varicella-zoster virus.
  • the neurodegenerative diseases include, but are not limited to, one or more of memory disorders, Alzheimer's disease, cognitive disorders, Alzheimer's disease, Parkinson's disease, Parkinson's disease, and dyskinetic diseases. .
  • the autoimmune diseases include, but are not limited to, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, scleroderma, nodular vasculitis, multiple sclerosis, nephropathy, myasthenia gravis, mixing One or more of connective tissue disease, psoriasis, liver disease, endocrine-related diseases, and autoimmune reactions due to infection.
  • the invention further provides that the compound of formula (I), a pharmaceutically acceptable salt thereof, or the pharmaceutical composition can be used in combination with one or more other types of therapeutic agents and/or therapeutic methods for treatment by IDO1 Mediated related diseases.
  • therapeutic agents and/or treatment methods include, but are not limited to, chemotherapeutic agents, targeted anti-tumor drugs, immunological checkpoint inhibitors, immunological checkpoint agonists, anti-tumor vaccines, antiviral agents, antiviral vaccines, Cytokine therapy, adoptive cellular immunotherapy or radiation therapy.
  • chemotherapeutic agents include, but are not limited to, alkylating agents, tubulin inhibitors, topoisomerase inhibitors, platinum drugs, antimetabolites or hormonal antitumor 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 immunological 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 inhibitor, A2AR inhibitor or VTCN1 inhibitor.
  • immunological checkpoint agonists include, but are not limited to, STING agonists, 4-1BB agonists, OX40 agonists, ROR gamma agonists or ICOS agonists.
  • P-cyanophenethylamine (1.00 g, 7.57 mmol) was dissolved in anhydrous dichloromethane (15 mL), triethylamine (1.26 mL, 8.75 mmol) was added and stirred for 20 min.
  • a white solid was obtained from m-methoxyphenylethylamine and m-nitrobenzenesulfonyl chloride in a yield of 86%, mp 105-107 °C.
  • HeLa cells were seeded in 96-well culture plates at a density of 5 x 10 3 /well and cultured overnight. The next day, IFN- ⁇ (final concentration 100 ng/mL) and serial dilutions of the compound (total volume 200 ⁇ L medium) were added to the cells. After 24 hours of incubation, 140 ⁇ L of the supernatant/well was transferred to a new 96-well plate, 10 ⁇ L of 6.1 mol/L trichloroacetic acid was added, and incubation was carried out for 30 min at 50 ° C in a constant temperature oven to produce the N-formyl canine. Hydrolysis of uridine is kynurenine.
  • the reaction mixture was then centrifuged at 4000 rpm for 10 min to remove the precipitate. 100 ⁇ L of the supernatant/well was transferred to another 96-well plate and mixed with an equal volume of 2% (w/v) p-dimethylaminobenzaldehyde in acetic acid. The absorbance was measured at 480 nm using a microplate reader, and the results were calculated using an IC 50 calculator. The experiment set up 3 duplicate holes.
  • Range of IC 50 values reported are: A represents less than 10 ⁇ M, B represents 10-20 ⁇ M, C represents 20-50 ⁇ M, D represents greater than 50 ⁇ M.
  • B16F1 cell treatment aspirate the medium (high glucose DMEM, 10% FBS), and wash PBS 1-2 times. Add 0.25% trypsin digestion. The trypsin was aspirated, the medium was added, the cells were blown down, transferred to a 1.5 mL centrifuge tube, centrifuged, the supernatant was aspirated, and the cells were resuspended by adding 1 mL of DMEM medium. Add mitomycin C (final concentration 25 ⁇ g / ml), pipet and mix, 37 ° C, water bath for 30 min, RP1640 wash 3 times, cell count, set aside.
  • mitomycin C final concentration 25 ⁇ g / ml
  • spleen cells C57/BL6 mice were taken, and the eyeballs were sacrificed by exsanguination. The spleens were aseptically removed and placed in a 35 mm Petri dish containing 2 mL of sterile pre-chilled RPMI 1640 medium. The spleen was gently spleened with a 5 mL syringe needle. The cells are extruded. Add 2 mL of the medium and repeatedly blow with a 5 mL pipette until the suspension is homogeneous. The cell suspension was filtered through a 70 ⁇ m filter and centrifuged at 300 g for 5 min (4 ° C).
  • Treated B16F1 cells 2 ⁇ 10 4 / well (stimulator cells), spleen lymphocytes 1 ⁇ 10 6 / well (reactive cells), add 96-well plates, add RP1640 (10% FBS), make up Up to 200 ⁇ L.
  • T lymphocyte proliferation rate (%) [administration well (T lymphocyte + B16F1 cell + IDO1 inhibitor) OD value - control well (T lymphocyte + B16F1 cell) OD value] / control well (T lymphocyte + B16F1 Cell) OD value ⁇ 100%
  • B16F1 cells highly express IDO1, which can inhibit the proliferation of T lymphocytes.
  • the compounds 1h, 3a, C 10 , C 11 and C 14 (3 times IC 50 concentration) were added for 48 hours, the proliferation of T lymphocytes was detected by MTT, and the proliferation rates were 34.77%, 39.83%, 33.21%, 36.72%, respectively. And 42.21%, indicating that these compounds can significantly increase the proliferation of T lymphocytes.
  • Treated B16F1 cells (8 ⁇ 10 4 wells), spleen lymphocytes (10 6 wells, stimulated with 5 ⁇ g / mL of ConA) were added to a 24-well plate, and the corresponding concentration of the compound was added and placed at 37 ° C, humidity.
  • the cells were cultured for 48 hours in a 95%, 5% CO 2 incubator; the supernatant was collected and tested for ELISA, stained with anti-CD4, anti-CD25, anti-FOCP3 antibodies, and T cell differentiation was detected in a flow cytometer.
  • Hela cells were cultured in a 6-well plate at a density of 2 ⁇ 10 5 per well, and cultured at 37 ° C, 5% CO 2 for 12 h.
  • Blank control only medium
  • model group add IFN- ⁇ , corresponding positive drug
  • drug treatment group add IFN- ⁇ , corresponding compound
  • culture at 37 ° C, 5% CO 2 for 24 h collect cells Western blot was used to detect IDO1 expression.

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Abstract

一种具有式(I)结构特征的苯磺酰胺类化合物或其药学上可接受的盐、其制备方法、以及它们作为吲哚胺2,3-双加氧酶1(IDO1)抑制剂的用途。实验结果表明，化合物对IDO1的活性具有显著抑制作用，能够有效地促进T细胞增殖，抑制初始T细胞分化成调节性T细胞，逆转IDO1介导的免疫抑制，可以用于治疗具有IDO1介导的犬尿氨酸代谢途径的病理学特征的相关疾病，包括癌症、病毒感染、神经变性疾病、白内障、器官移植排斥、抑郁症和自身免疫性疾病等。

Description

苯磺酰胺类IDO1抑制剂、其制备方法及应用 技术领域
本发明属于药物领域，具体涉及一种苯磺酰胺类化合物或其药学上可接受的盐、其制备方法、以及它们作为吲哚胺2,3-双加氧酶1(IDO1)抑制剂的用途。
技术背景
色氨酸是人体细胞维持增殖和存活所必需的氨基酸，可用于蛋白质、烟酸和5-羟色胺的生物合成。色氨酸一般从食物中摄取，超过95％色氨酸沿犬尿酸途径代谢，余下的色氨酸在神经系统和肠道中转化5-羟色氨酸和5-羟色胺，或在松果体中合成褪黑素。吲哚胺2,3-双加氧酶1(indoleamine 2,3-dioxygenase,IDO1)是人体肝脏外催化色氨酸沿犬尿氨酸途径代谢的限速酶。IDO1在多种组织(如肺、肾、脑、胎盘、胸腺)以及多种细胞(如巨噬细胞和树突状细胞)中表达。IDO1通过氧化裂解色氨酸降低机体微环境中色氨酸的浓度，并且产生犬尿氨酸、3-羟基犬尿氨酸、2-氨基-3-羟基苯甲酸、喹啉酸等一系列代谢产物。细胞因子如IFN-γ、TNF-α、IL-1β和IL-6可诱导IDO1上调表达(Bernhardt R.Chem Rev,1996,96(1):2841-2888)。
大量的证据表明，IDO1不仅可以催化色氨酸氧化代谢，而且还对机体的固有免疫和适应性免疫具有重要的调节作用(Munn DH,et al.Trends Immunol,2013,34(3):137-143)。IDO1主要是通过催化色氨酸代谢导致色氨酸耗竭及其代谢产物聚积来实现其对免疫系统的调控作用：一方面，色氨酸耗竭可通过激活GCN2通路诱导T细胞分裂周期滞留于G1期，从而抑制T细胞的增殖，同时还抑制初始CD4 +T细胞分化成辅助性T细胞17(Th17)，进而产生免疫抑制(Munn DH,et al.Immunity,2005,22(5):633-642)。另一方面，犬尿氨酸等色氨酸代谢产物具有细胞毒性，可以杀灭T细胞和自然杀伤(NK)细胞(Frumento G,et al.J Exp Med,2002,196(4):459-468；Munn DH,et al.J Clin Invest,2004,114(2):280-290)，而且这些代谢产物还可以通过激活芳香烃受体(AHR)来诱导CD4 +T细胞分化成调节性T(Treg)细胞，并促进树突状细胞(DC)转化成致耐受性DC(Mezrich JD,et al.J Immunol,2010,185(6):3190-3198；Mezrich JD,et al.J Immunol,2008,181(8):5396-5404)；此外，色氨酸代谢产物可通过下调NK细胞受体的表达来抑制NK细胞的功能，这些都可以进一步抑制机体的免疫反应(Della Chiesa M,et al.Blood,2006,108(13):4118-4125)。
IDO1与很多生理病理过程有关。研究表明，IDO1在宿主免疫防御和母胎免疫耐受等生理过程中发挥重要的免疫调节作用。机体在正常状态下，IDO1表达水平较低，但在胎盘发育 和炎症反应等生理性应激中，细胞因子如IFN-γ分泌显著增加，从而诱导IDO1表达上调，导致色氨酸耗竭和犬尿氨酸等代谢产物聚积，从而抑制母体的T细胞反应，诱导母胎免疫耐受，确保胎儿不被母体的免疫系统排斥；宿主微环境中的色氨酸耗竭使其不能为病原微生物复制提供所必需的色氨酸，从而导致病原微生物死亡；与此同时IDO1介导的免疫抑制可以避免机体免疫系统的过度激活(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)。当给妊娠小鼠施用IDO1抑制剂后，会引起T细胞介导的胚胎排斥反应，导致小鼠流产，表明IDO1可以使胎儿免于母体的排斥(Munn DH,et al.Science,1998,281(5380):1191-1193)。IDO1对移植组织在新宿主中的存活也发挥免疫抑制作用(Radu CA,et al.Plast Reconstr Surg,2007,119(7):2023-2028)。这些研究结果说明IDO是一种免疫调节酶，参与机体的免疫耐受。
众多研究表明，IDO1介导的免疫耐受与肿瘤免疫逃逸、病毒感染、神经变性疾病、器官移植排斥、自身免疫性疾病、神经精神疾病和白内障等疾病的密切相关(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.Lab Invest,2009,89(5):498-512)。在这些疾病中，过度表达的IDO1所介导的色氨酸耗竭及其代谢产物的聚积可以抑制T细胞的激活，导致机体的免疫耐受。
在病毒感染的小鼠模型中，给予IDO1抑制剂可明显促进CD8 +T细胞的增殖，恢复T细胞的免疫应答，抑制病毒感染宿主的单核巨噬细胞。在流感病毒感染时，过度表达的IDO1介导的免疫抑制作用易导致肺部发生二次感染(van der Sluijs KF,et al.J Infect Dis,2006,193(2):214-222)。在HIV感染时，IDO1会被上调表达，促进Treg细胞的增殖，而抑制Th17细胞的增殖，造成Tregs/Th17细胞比例失调，导致患者的免疫抑制(Favre D,et al.Sci Transl Med,2010,2(32):32ra36)。此外，IDO1介导的色氨酸耗竭及其代谢产物浓度升高还与寄生虫感染有关(Knubel CP,et al.FASEB J,2010,24(8):2689-2701)。
研究表明，IDO1催化的色氨酸代谢产物如犬尿氨酸和喹啉酸等具有神经毒性，并且这些代谢产物与神经变性疾病如记忆障碍症、阿尔茨海默病(AD)、认知障碍症、老年痴呆症、帕金森病、帕金森综合症和运动障碍性疾病的发生密切相关(Malpass K.Nat Rev Neurol,2011,7(8):417；Maddison DC,et al.Semin Cell Dev Biol,2015,40:134-141)。在AD患者大脑中IDO1表达和喹啉酸浓度均高于正常人，其中在老年斑周围的小胶质细胞和星形细胞中含量最高。此外，在AD患者血液中的色氨酸浓度低于正常人，而犬尿氨酸浓度则高于正常人，而且两者的比例高低与患者的认识缺陷程度密切相关(Guillemin GJ,et al.Neuropathol Appl Neurobiol, 2005,31(4):395-404；Widner B,et al.Adv Exp Med Biol,1999,467:133-138)。神经精神疾病如抑郁症、精神分裂症、焦虑症也与IDO1过度表达和犬尿氨酸等代谢产物水平升高有关。IDO1的过度表达造成色氨酸耗竭，从而减少用于合成神经递质5-羟色胺的色氨酸的量，导致5-羟色胺缺乏，再加上具有神经毒性的犬尿氨酸和喹啉酸等代谢产物的聚积，共同促进神经精神疾病的发生，而且是多种心境障碍的因素(Myint AM.FEBS J,2012,279(8):1375-1385)。因此，抑制IDO1是神经变性疾病和神经精神疾病患者的重要治疗策略。
IDO1高表达所介导的色氨酸过度代谢也存在于各种自身免疫性疾病中(Nguyen NT,et al.Front Immunol,2014,5:551)。在类风湿关节炎患者滑膜关节组织的DCs高表达IDO1，患者血清中色氨酸浓度降低，而犬尿氨酸浓度升高(Zhu L,et al.J Immunol,2006,177(11):8226-8233；Ozkan Y.et al.Clin Rheumatol,2012,31(1):29-34)。在系统性红斑狼疮患者中也存在IDO1过度表达和色氨酸代谢增强的现象。患者血清中的色氨酸浓度降低，代谢产物犬尿酸浓度和犬尿氨酸和色氨酸比值均明显升高(Widner B,et al.Immunobiology,2000,201(5):621-630)。因此，抑制IDO1也是自身免疫性疾病患者重要的治疗策略。
大量的研究表明，IDO1诱导的免疫抑制在肿瘤免疫逃逸中起重要的作用。IDO1过度表达于各类肿瘤细胞及其微环境中的细胞如DC和基质细胞，导致肿瘤局部色氨酸耗竭和色氨酸代谢产物聚积，从而诱导肿瘤免疫逃逸，帮助肿瘤细胞逃避机体免疫系统的攻击(Munn DH,et al.Trends Immunol,2016,37(3):193-207)。Uyttenhove小组利用免疫组织化学标记方法在黑色素瘤、肺癌、乳腺癌、胃癌、结肠癌、膀胱癌、胰腺癌、淋巴癌、前列腺癌、肾癌、脑癌、头颈癌、卵巢癌、宫颈癌、子宫内膜癌、间皮瘤、甲状腺癌、食管癌和肝癌等24种人类肿瘤细胞中检测到了IDO1的表达(Uyttenhove C,et al.Nat Med,2003,9(10):1269-1274)。随后在卵巢癌、黑色素瘤、肺癌、白血病等肿瘤组织中进一步得到证实，并且发现肿瘤组织内IDO1的表达量与肿瘤的恶性程度关系密切，并且影响肿瘤患者的预后(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；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抑制剂可以激活T细胞，克服由IDO1介导的肿瘤免疫逃逸，而且还可以提高其它肿瘤治疗剂的疗法(Koblish HK,et al.Mol Cancer Ther,2010,9(2):489-498；Wainwright DA,et al.Clin Cancer Res,2014,20(20):5290-5301)。
多项临床前和临床研究表明，IDO1抑制剂可以降低色氨酸代谢和犬尿氨酸等代谢产物的聚积，从而逆转IDO1介导的免疫抑制，恢复T细胞和NK细胞的增殖和功能，抑制Treg细胞的增殖，从而增强机体的免疫应答，因此IDO1抑制剂可用于治疗由IDO1介导的免疫抑制 所引起的上述相关疾病，包括癌症、病毒感染、神经变性疾病、白内障、器官移植排斥、抑郁症和自身免疫性疾病。此外，IDO1抑制剂还可以和其它化疗剂、靶向抗肿瘤药物、免疫检查点治疗剂、抗肿瘤疫苗、抗病毒剂、抗病毒疫苗、细胞因子疗法、过继性细胞免疫治疗和放射治疗联合作用，起到协同或增强疗法的作用(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)。
目前正在开发IDO1小分子抑制剂用来治疗或预防上述与IDO1相关的疾病。例如，在CN102164902B中报道了噁二唑类IDO1抑制剂，涉及通过施用IDO1抑制剂或与其它治疗剂联合使用来治疗癌症、病毒感染、神经变性疾病、创伤、年龄相关的白内障、器官移植排斥或自身免疫性疾病患者。
基于IDO1与癌症、病毒感染、神经变性疾病、白内障、器官移植排斥、自身免疫性疾病和抑郁症等多种疾病的发病机制密切相关，因此可以采用IDO1抑制剂来抑制IDO1的活性，从而降低色氨酸代谢以及犬尿氨酸等代谢产物的聚积，恢复机体的免疫功能，进而达到治疗上述疾病的目的。本发明所述的化合物具有IDO1抑制活性，可以用于治疗IDO1介导的免疫抑制所引起的相关疾病，包括癌症、病毒感染、神经变性疾病、白内障、器官移植排斥、自身免疫性疾病和抑郁症。
发明内容
本发明所要解决的技术问题在于提供了一种苯磺酰胺类化合物或其药学上可接受的盐、其制备方法、药物组合物及应用。本发明的化合物具有良好的IDO1抑制活性，可以用于治疗和/或预防IDO1介导的免疫抑制所引起的各种相关疾病。
本发明提供了通式(I)所示的苯磺酰胺类化合物或其药学上可接受的盐：
Figure PCTCN2018078136-appb-000001
其中：
n代表0～8的整数；
m代表0～4的整数；
R 1代表氢、氰基、硝基、羟基、卤素、氨基、乙酰胺基、三氟甲基或丙烯酰胺基；
R 2代表氢、卤素、氰基、羟基、硝基、C 1-C 8烷基、C 1-C 8烷氧基或亚甲二氧基。
进一步地，具有通式(I)所示的苯磺酰胺类化合物或其药学上可接受的盐，其特征在于：
n代表0～4的整数；
m代表0～4的整数；
R 1代表氰基、硝基、氨基、乙酰胺基或丙烯酰胺基；
R 2代表氢、3-氟、4-氟、2-氯、3-氯、4-氯、3,4-二氯、3-溴、4-溴、3-氯-4-氟、3-三氟甲基、4-三氟甲基、4-甲基、3-异丙基、4-异丙基、4-氰基、3-甲氧基、4-甲氧基、3,4-二甲氧基或3,4-亚甲二氧基。
具体来说，通式(I)所示的咪唑并异吲哚类化合物优选自下列化合物：
N-(4-(N-(4-氰苄基)胺磺酰基)苯基)乙酰胺(1a)；
N-(4-(N-(3-氯苄基)胺磺酰基)苯基)乙酰胺(1b)；
N-(4-(N-(4-甲氧基苄基)胺磺酰基)苯基)乙酰胺(1c)；
N-(4-(N-(4-甲氧基苯基)胺磺酰基)苯基)乙酰胺(1d)；
N-(4-(N-(4-氟苯基)胺磺酰基)苯基)乙酰胺(1e)；
N-(4-(N-(3-甲氧基苯乙基)胺磺酰基)苯基)乙酰胺(1f)；
N-(4-(N-(3,4-二甲氧基苯乙基)胺磺酰基)苯基)乙酰胺(1g)；
N-(4-氰苄基)-3-硝基苯磺酰胺(1h)；
N-(3-氯苄基)-3-硝基苯磺酰胺(1i)；
N-(3-甲氧基苯乙基)-3-硝基苯磺酰胺(1j)；
N-(4-甲氧基苄基)-3-硝基苯磺酰胺(1k)；
N-(4-甲氧基苯基)-3-硝基苯磺酰胺(1l)；
4-氰基-N-(4-甲氧基苄基)苯磺酰胺(1m)；
4-氰基-N-(3-氟苄基)苯磺酰胺(1n)；
N-(苯并[d][1,3]二氧-5-亚甲基)-4-氰基苯磺酰胺(1o)；
4-氰基-N-(3-甲氧基苯乙基)苯磺酰胺(1p)；
4-氨基-N-(3-氯苄基)苯磺酰胺(2a)；
4-氨基-N-(4-甲氧基苯基)苯磺酰胺(2b)；
4-氨基-N-(4-氟苯基)苯磺酰胺(2c)；
4-氨基-N-(4-甲氧基苄基)苯磺酰胺(2d)；
4-氨基-N-(3-甲氧基苯乙基)苯磺酰胺(2e)；
4-氨基-N-(3,4-二甲氧基苯乙基)苯磺酰胺(2f)；
N-(4-(N-(3-氯苄基)胺磺酰基)苯基)丙烯酰胺(3a)；
N-(4-(N-(4-甲氧基苯基)胺磺酰基)苯基)丙烯酰胺(3b)；
N-(4-(N-(3,4-二甲氧基苯乙基)胺磺酰基)苯基)丙烯酰胺(3c)；
N-(4-(N-(3-甲氧基苯乙基)胺磺酰基)苯基)丙烯酰胺(3d)；
N-(4-(N-苯基胺磺酰基)苯基)乙酰胺(A 1)；
N-(4-(N-(3-氟苯基)胺磺酰基)苯基)乙酰胺(A 2)；
N-(4-(N-(3-氯-4-氟苯基)胺磺酰基)苯基)乙酰胺(A 3)；
N-(4-(N-(4-甲基苯基)胺磺酰基)苯基)乙酰胺(A 4)；
N-(4-(N-(3-异丙苯基)胺磺酰基)苯基)乙酰胺(A 5)；
N-(4-(N-(4-异丙苯基)胺磺酰基)苯基)乙酰胺(A 6)；
N-(4-(N-(3-甲氧基苯基)胺磺酰基)苯基)乙酰胺(A 7)；
N-(4-(N-苄基胺磺酰基)苯基)乙酰胺(A 8)；
N-(4-(N-(3-氟苄基)胺磺酰基)苯基)乙酰胺(A 9)；
N-(4-(N-(4-氟苄基)胺磺酰基)苯基)乙酰胺(A 10)；
N-(4-(N-(2-氯苄基)胺磺酰基)苯基)乙酰胺(A 11)；
N-(4-(N-(4-氯苄基)胺磺酰基)苯基)乙酰胺(A 12)；
N-(4-(N-(3,4-二氯苄基)胺磺酰基)苯基)乙酰胺(A 13)；
N-(4-(N-(3-溴苄基)胺磺酰基)苯基)乙酰胺(A 14)；
N-(4-(N-(4-溴苄基)胺磺酰基)苯基)乙酰胺(A 15)；
N-(4-(N-(3-三氟甲基苄基)胺磺酰基)苯基)乙酰胺(A 16)；
N-(4-(N-(4-三氟甲基苄基)胺磺酰基)苯基)乙酰胺(A 17)；
N-(4-(N-苯乙基胺磺酰基)苯基)乙酰胺(A 18)；
N-苄基-3-硝基苯磺酰胺(A 19)；
N-(2-氯苄基)-3-硝基苯磺酰胺(A 20)；
N-(4-氯苄基)-3-硝基苯磺酰胺(A 21)；
N-(3,4-二氯苄基)-3-硝基苯磺酰胺(A 22)；
N-(3-三氟甲基苄基)-3-硝基苯磺酰胺(A 23)；
N-(4-三氟甲基苄基)-3-硝基苯磺酰胺(A 24)；
N-苯基-4-硝基苯磺酰胺(A 25)；
N-(2-氯苯基)-4-硝基苯磺酰胺(A 26)；
N-苄基-4-硝基苯磺酰胺(A 27)；
N-(2-氯苄基)-4-硝基苯磺酰胺(A 28)；
N-(3-氯苄基)-4-硝基苯磺酰胺(A 29)；
N-(4-氯苄基)-4-硝基苯磺酰胺(A 30)；
N-(3,4-二氯苄基)-4-硝基苯磺酰胺(A 31)；
N-(3-三氟甲基苄基)-4-硝基苯磺酰胺(A 32)；
N-(4-三氟甲基苄基)-4-硝基苯磺酰胺(A 33)；
N-(4-甲氧基苄基)-4-硝基苯磺酰胺(A 34)；
N-苯乙基-4-硝基苯磺酰胺(A 35)；
N-苄基-3-氰基苯磺酰胺(A 36)；
N-(2-氯苄基)-3-氰基苯磺酰胺(A 37)；
N-(3-氯苄基)-3-氰基苯磺酰胺(A 38)；
N-(4-氯苄基)-3-氰基苯磺酰胺(A 39)；
N-(3,4-二氯苄基)-3-氰基苯磺酰胺(A 40)；
N-(3-三氟甲基苄基)-3-氰基苯磺酰胺(A 41)；
N-(4-三氟甲基苄基)-3-氰基苯磺酰胺(A 42)；
N-(4-甲氧基苄基)-3-氰基苯磺酰胺(A 43)；
N-苯乙基-3-氰基苯磺酰胺(A 44)；
N-苄基-4-氰基苯磺酰胺(A 45)；
N-(2-氯苄基)-4-氰基苯磺酰胺(A 46)；
N-(3-氯苄基)-4-氰基苯磺酰胺(A 47)；
N-(4-氯苄基)-4-氰基苯磺酰胺(A 48)；
N-(3,4-二氯苄基)-4-氰基苯磺酰胺(A 49)；
N-(3-三氟甲基苄基)-4-氰基苯磺酰胺(A 50)；
N-(4-三氟甲基苄基)-4-氰基苯磺酰胺(A 51)；
N-苯乙基-4-氰基苯磺酰胺(A 52)；
4-氨基-N-苯基苯磺酰胺(B 1)；
4-氨基-N-(3-氟苯基)苯磺酰胺(B 2)；
4-氨基-N-(3-氯-4-氟苯基)苯磺酰胺(B 3)；
4-氨基-N-(4-甲基苯基)苯磺酰胺(B 4)；
4-氨基-N-(3-异丙基苯基)苯磺酰胺(B 5)；
4-氨基-N-(4-异丙基苯基)苯磺酰胺(B 6)；
4-氨基-N-(3-甲氧基苯基)苯磺酰胺(B 7)；
4-氨基-N-苄基苯磺酰胺(B 8)；
4-氨基-N-(3-氟苄基)苯磺酰胺(B 9)；
4-氨基-N-(4-氟苄基)苯磺酰胺(B 10)；
4-氨基-N-(2-氯苄基)苯磺酰胺(B 11)；
4-氨基-N-(4-氯苄基)苯磺酰胺(B 12)；
4-氨基-N-(3,4-二氯苄基)苯磺酰胺(B 13)；
4-氨基-N-(3-溴苄基)苯磺酰胺(B 14)；
4-氨基-N-(4-溴苄基)苯磺酰胺(B 15)；
4-氨基-N-(3-三氟甲基苄基)苯磺酰胺(B 16)；
4-氨基-N-(4-三氟甲基苄基)苯磺酰胺(B 17)；
4-氨基-N-苯乙基苯磺酰胺(B 18)；
N-(4-(N-苯基胺磺酰基)苯基)丙烯酰胺(C 1)；
N-(4-(N-(3-氟苯基)胺磺酰基)苯基)丙烯酰胺(C 2)；
N-(4-(N-(3-氯-4-氟苯基)胺磺酰基)苯基)丙烯酰胺(C 3)；
N-(4-(N-(4-甲基苯基)胺磺酰基)苯基)丙烯酰胺(C 4)；
N-(4-(N-(3-异丙苯基)胺磺酰基)苯基)丙烯酰胺(C 5)；
N-(4-(N-(4-异丙苯基)胺磺酰基)苯基)丙烯酰胺(C 6)；
N-(4-(N-(3-甲氧基苯基)胺磺酰基)苯基)丙烯酰胺(C 7)；
N-(4-(N-苄基胺磺酰基)苯基)丙烯酰胺(C 8)；
N-(4-(N-(3-氟苄基)胺磺酰基)苯基)丙烯酰胺(C 9)；
N-(4-(N-(4-氟苄基)胺磺酰基)苯基)丙烯酰胺(C 10)；
N-(4-(N-(2-氯苄基)胺磺酰基)苯基)丙烯酰胺(C 11)；
N-(4-(N-(4-氯苄基)胺磺酰基)苯基)丙烯酰胺(C 12)；
N-(4-(N-(3,4-二氯苄基)胺磺酰基)苯基)丙烯酰胺(C 13)；
N-(4-(N-(3-溴苄基)胺磺酰基)苯基)丙烯酰胺(C 14)；
N-(4-(N-(4-溴苄基)胺磺酰基)苯基)丙烯酰胺(C 15)；
N-(4-(N-(3-三氟甲基苄基)胺磺酰基)苯基)丙烯酰胺(C 16)；
N-(4-(N-(4-三氟甲基苄基)胺磺酰基)苯基)丙烯酰胺(C 17)；
N-(4-(N-苯乙基胺磺酰基)苯基)丙烯酰胺(C 18)；
N-(4-(N-(4-甲氧基苄基)胺磺酰基)苯基)丙烯酰胺(C 19)。
下面药理实验中涉及的化合物代号等同于此处代号所对应的化合物。
本发明的另一目的在于提供通式(I)所示化合物的制备方法，其特征在于：
a)当R 1为氰基、硝基或乙酰胺基时，通式(I)所示化合物的制备方法为：以不同取代的苯磺酰氯和胺类化合物发生缩合反应制得化合物1a-p和A 1- 52；其合成路线如下：
Figure PCTCN2018078136-appb-000002
其中，n、m、R 1和R 2的定义如前所述；
b)当R 1为胺基时，通式(I)所示化合物的制备方法为：1b-g和A 1-18在浓盐酸作用下水解脱去乙酰基制得2a-f和B 1-18；其合成路线如下：
Figure PCTCN2018078136-appb-000003
其中，n、m、R 1和R 2的定义如前所述；
c)当R 1为丙烯酰胺基时，通式(I)所示化合物的制备方法为：2a、2b、2d、2e、2f以及B 1-18分别与丙烯酰氯反应制得3a-3d和C 1- 19；其合成路线如下：
Figure PCTCN2018078136-appb-000004
其中，n、m、R 1和R 2的定义如前所述。
所述通式(I)化合物的药学上可接受的盐可通过一般的化学方法合成。
一般情况下，盐的制备可以通过游离碱或酸与等化学当量或过量酸(无机酸或有机酸)或碱(无机碱或有机碱)在合适的溶剂或溶剂组合物中反应制得。
本发明还提供了一种药物组合物，其由治疗上有效量的活性组分和药学上可接受的辅料组成；所述的活性组分包括通式(I)化合物和其药学上可接受的盐中的一种或多种。所述药物组合物中，所述的辅料包括药学上可接受的载体、稀释剂和/或赋形剂。
根据治疗目的可将药物组合物制成各种类型的给药单位剂型，如片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、胶囊、栓剂和针剂(溶液和悬浮液)等，优选片剂、胶囊、液体、悬浮液、和针剂(溶液和悬浮液)。
为了使片剂、丸剂或栓剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋形剂。
为了制备针剂形式的药物组合物，可将溶液或悬浮液消毒后(最好加入适量的氯化钠，葡萄糖或甘油)，制成与血液等渗压的针剂。在制备针剂时，也可以使用本领域内任何常用的载体。例如：水、乙醇、丙二醇、乙氧基化的异硬脂醇、聚乙氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外，还可以加入通常溶解剂和缓冲剂等。
本发明所述的组合物在药物组合物中的含量无特殊限制，可在很宽的范围内进行选择，通常可为质量百分比的5～95％，优先为质量百分比的30～85％。
本发明所述的药物组合物的给药方法没有特殊限制。可根据患者年龄、性别和其它条件及症状，选择各种剂型的制剂给药。
本发明另外提供了所述通式(I)化合物、其药学上可接受的盐或所述药物组合物在制备吲哚胺2,3-双加氧酶1(IDO1)抑制剂中的应用。所述的IDO1抑制剂用于治疗IDO1介导的免疫抑制的相关疾病患者，所述的相关疾病包括癌症、病毒感染、神经变性疾病、白内障、器官移植排斥、抑郁症和自身免疫性疾病。
本发明还提供了所述通式(I)化合物、其药学上可接受的盐或所述药物组合物在制备药物中的用途，所述药物用于治疗患者的癌症、病毒感染、神经变性疾病、白内障、器官移植排斥、抑郁症或自身免疫性疾病。
所述的癌症包括但不限于：恶性黑色素瘤、肺癌、乳腺癌、胃癌、结肠癌、膀胱癌、胰腺癌、淋巴癌、白血病、前列腺癌、睾丸癌、肾癌、脑癌、头颈癌、卵巢癌、宫颈癌、子宫内膜癌、间皮瘤、甲状腺癌、肝癌和食管癌中的一种或多种。
所述的病毒感染包括但不限于：由人类免疫缺陷病毒、乙型肝炎病毒、丙型肝炎病毒、流感病毒、脊髓灰质炎病毒、巨细胞病毒、柯萨奇病毒、人类乳头状瘤病毒、爱泼斯坦-巴尔病毒和水痘-带状疱疹病毒中的一种或多种引起的感染。
所述的神经变性疾病包括但不限于：记忆障碍症、阿尔茨海默病、认知障碍症、老年痴呆症、帕金森病、帕金森综合症和运动障碍性疾病中的一种或多种。
所述的自身免疫性疾病包括但不限于：类风湿性关节炎、系统性红斑狼疮、皮肌炎、硬皮病、结节性脉管炎、多发性硬化症、肾病、重症肌无力、混合性结缔组织病、银屑病、肝病、内分泌相关疾病和由于感染引起的自身免疫反应中的一种或多种。
本发明还提供了所述通式(I)化合物、其药学上可接受的盐或所述药物组合物可以和一种或多种其它种类的治疗剂和/或治疗方法联合用于治疗由IDO1介导的相关疾病。
所述其它种类的治疗剂和/或治疗方法包括但不限于：化疗剂、靶向抗肿瘤药物、免疫检查点抑制剂、免疫检查点激动剂、抗肿瘤疫苗、抗病毒剂、抗病毒疫苗、细胞因子疗法、过继性细胞免疫治疗或放射治疗。
所述的化疗剂包括但不限于：烷化剂、微管蛋白抑制剂、拓扑酶抑制剂、铂类药物、抗代谢类药物或激素类抗肿瘤药物。
所述的靶向抗肿瘤药物包括但不限于：蛋白激酶抑制剂、蛋白酶体抑制剂、异柠檬酸脱氢酶抑制剂、基于表观遗传学的抗肿瘤药物或细胞周期信号通路抑制剂。
所述的免疫检查点抑制剂包括但不限于：CTLA-4抑制剂、PD-1抑制剂、PD-L1抑制剂、PD-L2抑制剂、TIM-3抑制剂、VISTA抑制剂、LAG3抑制剂、TIGIT抑制剂、A2AR抑制剂或VTCN1抑制剂。
所述的免疫检查点激动剂包括但不限于：STING激动剂、4-1BB激动剂、OX40激动剂、RORγ激动剂或ICOS激动剂。
具体实施方式
为了进一步阐明本发明，下面给出一系列实施例，这些实施例完全是例证性的，它们仅用来对本发明具体描述，不应当理解为对本发明的限制。
实施例1
N-(4-(N-(4-氰苄基)氨磺酰)苯基)乙酰胺(1a)的合成
Figure PCTCN2018078136-appb-000005
将对氰基苯乙胺(1.00g,7.57mmol)溶于无水二氯甲烷(15mL)中，加入三乙胺(1.26mL,8.75mmol)，搅拌20分钟，冰浴冷却，滴加对乙酰氨基苯磺酰氯(1.93g,8.32mmol)的无水二氯甲烷溶液(5mL)，滴加完毕后冰浴搅拌30分钟，撤去冰浴，室温反应4小时，加水(25mL)，二氯甲烷萃取，无水硫酸镁干燥，柱层析纯化得到白色固体2.18g，产率87％，mp211-213℃。 1H NMR(300MHz,DMSO-d 6)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/z328[M-H] -.
实施例2
N-(4-(N-(3-氯苄基)氨磺酰)苯基)乙酰胺(1b)的合成
Figure PCTCN2018078136-appb-000006
参照1a的合成方法，由间氯苄胺和对乙酰氨基苯磺酰氯制得白色固体，收率90％，mp 185-187℃。 1H NMR(300MHz,DMSO-d 6)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[M-H] -.
实施例3
N-(4-(N-(4-甲氧基苄基)氨磺酰)苯基)乙酰胺(1c)的合成
Figure PCTCN2018078136-appb-000007
参照1a的合成方法，由对甲氧基苄胺和对乙酰氨基苯磺酰氯制得白色固体，收率80％，mp 188-190℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)10.38(s,1H),7.96(s,1H),7.76-7.68(m,4H),7.13(d,J＝8.3Hz,2H),6.83(d,J＝8.3Hz,2H),3.86(s,2H),3.71(s,3H),2.09(s,3H).MS(EI)m/z 333[M-H] -.
实施例4
N-(4-(N-(4-甲氧基苯基)氨磺酰)苯基)乙酰胺(1d)的合成
Figure PCTCN2018078136-appb-000008
参照1a的合成方法，由对甲氧基苯胺和对乙酰氨基苯磺酰氯制得白色固体，收率88％，mp 206-208℃。 1H NMR(300MHz,DMSO-d 6)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[M-H] -.
实施例5
N-(4-(N-(4-氟苯基)氨磺酰)苯基)乙酰胺(1e)的合成
Figure PCTCN2018078136-appb-000009
参照1a的合成方法，由对氟苯胺和对乙酰氨基苯磺酰氯制得白色固体，收率91％，mp190-192℃。 1H NMR(300MHz,DMSO-d 6)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[M-H] -.
实施例6
N-(4-(N-(3-甲氧基苯乙基)氨磺酰)苯基)乙酰胺(1f)的合成
Figure PCTCN2018078136-appb-000010
参照1a的合成方法，由间甲氧基苯乙胺和对乙酰氨基苯磺酰氯制得白色固体，收率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[M-H] -.
实施例7
N-(4-(N-(3,4-二甲氧基苯乙基)氨磺酰)苯基)乙酰胺(1g)的合成
Figure PCTCN2018078136-appb-000011
参照1a的合成方法，由3,4-二甲氧基苯乙胺和对乙酰氨基苯磺酰氯制得白色固体，收率70％，mp 139-141℃。 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[M-H] -.
实施例8
N-(4-氰苄基)-3-硝基苯磺酰胺(1h)的合成
Figure PCTCN2018078136-appb-000012
参照1a的合成方法，由对氰基苄胺和间硝基苯磺酰氯制得白色固体，收率90％，mp153-155℃。 1H NMR(300MHz,DMSO-d 6)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[M-H] -.
实施例9
N-(3-氯苄基)-3-硝基苯磺酰胺(1i)的合成
Figure PCTCN2018078136-appb-000013
参照1a的合成方法，由间氯苄胺和间硝基苯磺酰氯制得白色固体，收率89％，mp 103-105℃。 1H NMR(300MHz,DMSO-d 6)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 325[M-H] -.
实施例10
N-(3-甲氧基苯乙基)-3-硝基苯磺酰胺(1j)的合成
Figure PCTCN2018078136-appb-000014
参照1a的合成方法，由间甲氧基苯乙胺和间硝基苯磺酰氯制得白色固体，收率86％，mp105-107℃。 1H NMR(300MHz,Chloroform-d)δ(ppm)8.59(t,J＝2.0Hz,1H),8.49-8.33(m,1H),8.12(d,J＝7.8Hz,1H),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[M-H] -.
实施例11
N-(4-甲氧基苄基)-3-硝基苯磺酰胺(1k)的合成
Figure PCTCN2018078136-appb-000015
参照1a的合成方法，由对甲氧基苄胺和间硝基苯磺酰氯制得白色固体，收率80％，mp103-105℃。 1H NMR(300MHz,DMSO-d 6)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[M-H] -.
实施例12
N-(4-甲氧基苯基)-3-硝基苯磺酰胺(1l)的合成
Figure PCTCN2018078136-appb-000016
参照1a的合成方法，由对甲氧基苯胺和间硝基苯磺酰氯制得白色固体，收率86％，mp130-132℃。 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[M-H] -.
实施例13
4-氰基-N-(4-甲氧基苄基)苯磺酰胺(lm)的合成
Figure PCTCN2018078136-appb-000017
参照1a的合成方法，由对甲氧基苄胺和对氰基苯磺酰氯制得白色固体，收率75％，mp137-139℃。 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[M-H] -.
实施例14
4-氰基-N-(3-氟苄基)苯磺酰胺(1n)的合成
Figure PCTCN2018078136-appb-000018
参照1a的合成方法，由间氟苄胺和对氰基苯磺酰氯制得白色固体，收率82％，mp122-124℃。 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[M-H] -.
实施例15
N-(苯并[d][1,3]二氧-5-亚甲基)-4-氰基苯磺酰胺(1o)的合成
Figure PCTCN2018078136-appb-000019
参照1a的合成方法，由3,4-亚甲二氧基苄胺和对氰基苯磺酰氯制得白色固体，收率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[M-H] -.
实施例16
4-氰基-N-(3-甲氧基苯乙基)苯磺酰胺(1p)的合成
Figure PCTCN2018078136-appb-000020
参照1a的合成方法，由2-甲氧基苯乙胺和对氰基苯磺酰氯制得白色固体，收率89％，mp88-90℃。 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[M-H] -.
实施例17
4-氨基-N-(3-氯苄基)苯磺酰胺(2a)的合成
Figure PCTCN2018078136-appb-000021
将1b(0.50g,1.48mmol)溶于乙醇(10mL)中，加入浓盐酸(3mL)，70℃下反应12小时，冷却至室温，加入饱和碳酸钾溶液将反应液pH调到10。减压除去乙醇，乙酸乙酯萃取，无水硫酸镁干燥，除去溶剂，得到白色固体，产率90％，mp 119-121℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)7.70(s,1H),7.42(d,J＝8.6Hz,2H),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[M-H] -.
实施例18
4-氨基-N-(4-甲氧基苯基)苯磺酰胺(2b)的合成
Figure PCTCN2018078136-appb-000022
参照2a的合成方法，由1d制得白色固体，收率89％，mp 131-133℃。 1H NMR(300MHz,DMSO-d 6)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[M-H] -.
实施例19
4-氨基-N-(4-氟苯基)苯磺酰胺(2c)的合成
Figure PCTCN2018078136-appb-000023
参照2a的合成方法，由1f制得白色固体，收率78％，mp 151-153℃。 1H NMR(300MHz,DMSO-d 6)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[M-H] -.
实施例20
4-氨基-N-(4-甲氧基苄基)苯磺酰胺(2d)的合成
Figure PCTCN2018078136-appb-000024
参照2a的合成方法，由1c制得白色固体，收率75％，mp 94-96℃。 1H NMR(300MHz,DMSO-d 6)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[M-H] -.
实施例21
4-氨基-N-(3-甲氧基苯乙基)苯磺酰胺(2e)的合成
Figure PCTCN2018078136-appb-000025
参照2a的合成方法，由1f制得白色固体，收率90％，mp 88-90℃。 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[M+H] +.
实施例22
4-氨基-N-(3,4-二甲氧基苯乙基)苯磺酰胺(2f)的合成
Figure PCTCN2018078136-appb-000026
参照2a的合成方法，由1g制得白色固体，收率92％，mp 127-129℃。 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[M-H] -.
实施例23
N-(4-(N-(3-氯苄基)胺磺酰基)苯基)丙烯酰胺(3a)的合成
Figure PCTCN2018078136-appb-000027
将2a(0.10g,0.34mmol)溶于无水二氯甲烷(15mL)，冰浴下滴加丙烯酰氯(0.03mL,0.37mmol)的二氯甲烷溶液(5mL)，冰浴搅拌1小时，恢复室温搅拌2小时，加水(5mL)淬灭反应，二氯甲烷萃取，无水硫酸镁干燥，柱层析纯化得到白色固体0.06g，产率51％，mp157-159℃。 1H NMR(300MHz,DMSO-d 6)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 349[M-H] -.
实施例24
N-(4-(N-(4-甲氧基苯基)胺磺酰基)苯基)丙烯酰胺(3b)的合成
Figure PCTCN2018078136-appb-000028
参照3a的合成方法，由2b制得白色固体，收率45％，mp 209-211℃。 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[M-H] -.
实施例25
N-(4-(N-(3,4-二甲氧基苯乙基)胺磺酰基)苯基)丙烯酰胺(3c)的合成
Figure PCTCN2018078136-appb-000029
参照3a的合成方法，由2f制得白色固体，收率40％，mp 146-148℃。 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[M-H] -.
实施例26
N-(4-(N-(3-甲氧基苯乙基)胺磺酰基)苯基)丙烯酰胺(3d)的合成
Figure PCTCN2018078136-appb-000030
参照3a的合成方法，由2d制得白色固体，收率52％，mp 134-136℃。 1H NMR(300MHz,DMSO-d 6)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[M-H] -.
实施例27
N-(4-(N-苯基胺磺酰基)苯基)乙酰胺(A 1)的合成
Figure PCTCN2018078136-appb-000031
参照1a的合成方法，由苯胺和对乙酰氨基苯磺酰氯制得白色固体，收率90％，mp204-206℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)10.17(s,1H),10.04(s,1H),7.54(s,4H),7.08(t,J＝7.8Hz,2H),6.94-6.84(m,3H),1.92(s,3H).MS(EI)m/z 289[M-H] -.
实施例28
N-(4-(N-(3-氟苯基)胺磺酰基)苯基)乙酰胺(A 2)的合成
Figure PCTCN2018078136-appb-000032
参照1a的合成方法，由3-氟苯胺和对乙酰氨基苯磺酰氯制得淡黄色固体，收率87％，mp142-144℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)10.35(s,1H),10.20(s,1H),7.58(s,4H),7.12(q,J＝8.0Hz,1H),6.78-6.67(m,3H),1.92(s,3H).MS(EI)m/z 307[M-H] -.
实施例29
N-(4-(N-(3-氯-4-氟苯基)胺磺酰基)苯基)乙酰胺(A 3)的合成
Figure PCTCN2018078136-appb-000033
参照1a的合成方法，由3-氯-4-氟苯胺和对乙酰氨基苯磺酰氯制得白色固体，收率86％， mp 218-220℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)10.26(s,1H),10.21(s,1H),7.56(q,J＝8.6Hz,4H),7.17(t,J＝9.0Hz,1H),7.06(dd,J＝2.7,2.7Hz,1H),6.92(s,1H),1.93(s,3H).MS(EI)m/z 341[M-H] -.
实施例30
N-(4-(N-(4-甲基苯基)胺磺酰基)苯基)乙酰胺(A 4)的合成
Figure PCTCN2018078136-appb-000034
参照1a的合成方法，由4-甲基苯胺和对乙酰氨基苯磺酰氯制得白色固体，收率87％，mp>250℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)10.45(s,1H),9.89(s,1H),7.69(d,J＝8.1Hz,2H),7.57(d,J＝8.4Hz,2H),7.08(d,J＝7.8Hz,2H),6.73(d,J＝7.8Hz,2H),2.19(s,3H),1.92(s,3H).MS(EI)m/z 303[M-H] -.
实施例31
N-(4-(N-(3-异丙苯基)胺磺酰基)苯基)乙酰胺(A 5)的合成
Figure PCTCN2018078136-appb-000035
参照1a的合成方法，由3-异丙基苯胺和对乙酰氨基苯磺酰氯制得白色固体，收率89％，mp 158-160℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)10.17(s,1H),9.95(s,1H),7.55(s,4H),6.98(t,J＝7.7Hz,1H),6.79-6.72(m,3H),2.63-2.58(m,1H),1.92(s,3H),0.95(d,J＝6.9Hz,6H).MS(EI)m/z 331[M-H] -.
实施例32
N-(4-(N-(4-异丙苯基)胺磺酰基)苯基)乙酰胺(A 6)的合成
Figure PCTCN2018078136-appb-000036
参照1a的合成方法，由4-异丙基苯胺和对乙酰氨基苯磺酰氯制得淡黄色固体，收率90％，mp 186-188℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)10.16(s,1H),9.91(s,1H),7.54(s,4H),6.95(d,J＝8.1Hz,2H),6.94(d,J＝8.1Hz,2H),2.65-2.58(m,1H),1.92(d,J＝2.4Hz,3H),0.97(dd,J＝2.1,2.7Hz,6H).MS(EI)m/z 331[M-H] -.
实施例33
N-(4-(N-(3-甲氧基苯基)胺磺酰基)苯基)乙酰胺(A 7)的合成
Figure PCTCN2018078136-appb-000037
参照1a的合成方法，由3-甲氧基苯胺和对乙酰氨基苯磺酰氯制得白色固体，收率88％，mp 186-188℃。 1H NMR(300 MHz,DMSO-d 6)δ(ppm)10.18(s,1H),10.05(s,1H),7.57(s,4H),6.97(t,J＝8.3 Hz,1H),6.53-6.43(m,3H),3.52(s,3H),1.92(s,3H).MS(EI)m/z 319[M-H] -.
实施例34
N-(4-(N-苄基胺磺酰基)苯基)乙酰胺(A 8)的合成
Figure PCTCN2018078136-appb-000038
参照1a的合成方法，由苄胺和对乙酰氨基苯磺酰氯制得白色固体，收率90％，mp140-142℃。 1H NMR(300 MHz,DMSO-d 6)δ(ppm)10.20(s,1H),7.89(t,J＝6.3 Hz,1H),7.64-7.57(m,4H),7.18-7.07(m,5H),3.81(d,J＝6.3 Hz,2H),1.96(s,3H).MS(EI)m/z 303[M-H] -.
实施例35
N-(4-(N-(3-氟苄基)胺磺酰基)苯基)乙酰胺(A 9)的合成
Figure PCTCN2018078136-appb-000039
参照1a的合成方法，由3-氟苄胺和对乙酰氨基苯磺酰氯制得白色固体，收率91％，mp140-142℃。 1H NMR(300 MHz,DMSO-d 6)δ(ppm)10.20(s,1H),7.96(s,1H),7.63-7.56(m,4H),7.18(q,J＝7.7 Hz,1H),6.96-6.89(m,3H),3.85(s,2H),1.96(s,3H).MS(EI)m/z 321[M-H] -.
实施例36
N-(4-(N-(4-氟苄基)胺磺酰基)苯基)乙酰胺(A 10)的合成
Figure PCTCN2018078136-appb-000040
参照1a的合成方法，由4-氟苄胺和对乙酰氨基苯磺酰氯制得白色固体，收率90％，mp 160-162℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)10.19(s,1H),7.91(t,J＝6.3Hz,1H),7.63-7.56(m,4H),7.17-7.11(m,2H),7.00-6.94(m,2H),3.90(d,J＝6.3Hz,2H),1.95(s,3H).MS(EI)m/z 321[M-H] -.
实施例37
N-(4-(N-(2-氯苄基)胺磺酰基)苯基)乙酰胺(A 11)的合成
Figure PCTCN2018078136-appb-000041
参照1a的合成方法，由2-氯苄胺和对乙酰氨基苯磺酰氯制得白色固体，收率92％，mp154-156℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)10.20(s,1H),7.97(d,J＝6.3Hz,1H),7.61(s,4H),7.27-7.24(m,2H),7.17-7.14(m,2H),3.99(d,J＝6.3Hz,2H),1.95(s,3H).MS(EI)m/z 337[M-H] -.
实施例38
N-(4-(N-(4-氯苄基)胺磺酰基)苯基)乙酰胺(A 12)的合成
Figure PCTCN2018078136-appb-000042
参照1a的合成方法，由4-氯苄胺和对乙酰氨基苯磺酰氯制得白色固体，收率90％，mp172-174℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)10.20(s,1H),7.95(t,J＝6.5Hz,1H),7.63-7.56(m,4H),7.17(dd,J＝8.1,8.4Hz,4H),3.81(d,J＝6.3Hz,2H),1.95(s,3H).MS(EI)m/z 337[M-H] -.
实施例39
N-(4-(N-(3,4-二氯苄基)胺磺酰基)苯基)乙酰胺(A 13)的合成
Figure PCTCN2018078136-appb-000043
参照1a的合成方法，由3,4-二氯苄胺和对乙酰氨基苯磺酰氯制得白色固体，收率92％，mp 160-162℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)10.20(s,1H),8.01(t,J＝6.3Hz,1H),7.62-7.54(m,4H),7.40(d,J＝17.4Hz,1H),7.30(d,J＝2.1Hz,1H),7.11-7.08(m,1H),3.85(d,J＝6.3Hz,2H),1.95(s,3H).MS(EI)m/z 371[M-H] -.
实施例40
N-(4-(N-(3-溴苄基)胺磺酰基)苯基)乙酰胺(A 14)的合成
Figure PCTCN2018078136-appb-000044
参照1a的合成方法，由3-溴苄胺和对乙酰氨基苯磺酰氯制得白色固体，收率89％，mp178-180℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)10.19(s,1H),7.97(t,J＝6.5Hz,1H),7.62-7.55(m,4H),7.27(d,J＝4.5Hz,2H),7.11-7.10(m,2H),3.84(d,J＝6.3Hz,2H),1.95(s,3H).MS(EI)m/z 381[M-H] -.
实施例41
N-(4-(N-(4-溴苄基)胺磺酰基)苯基)乙酰胺(A 15)的合成
Figure PCTCN2018078136-appb-000045
参照1a的合成方法，由4-溴苄胺和对乙酰氨基苯磺酰氯制得白色固体，收率90％，mp192-194℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)10.21(s,1H),7.95(t,J＝6.5Hz,1H),7.63-7.56(m,4H),7.34(d,J＝8.1Hz,2H),7.06(d,J＝8.1Hz,2H),3.79(d,J＝6.3Hz,2H),1.95(s,3H).MS(EI)m/z 381[M-H] -.
实施例42
N-(4-(N-(3-三氟甲基苄基)胺磺酰基)苯基)乙酰胺(A 16)的合成
Figure PCTCN2018078136-appb-000046
参照1a的合成方法，由3-三氟甲基苄胺和对乙酰氨基苯磺酰氯制得白色固体，收率88％，mp 154-156℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)10.19(s,1H),8.05(t,J＝6.3Hz,1H),7.61-7.54(m,4H),7.46-7.35(m,4H),3.95(d,J＝6.3Hz,2H),1.95(s,3H).MS(EI)m/z 371[M-H] -.
实施例43
N-(4-(N-(4-三氟甲基苄基)胺磺酰基)苯基)乙酰胺(A 17)的合成
Figure PCTCN2018078136-appb-000047
参照1a的合成方法，由4-三氟甲基苄胺和对乙酰氨基苯磺酰氯制得白色固体，收率89％， mp 186-188℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)10.19(s,1H),8.04(t,J＝6.0Hz,1H),7.62-7.56(m,4H),7.50(d,J＝8.1Hz,2H),7.33(d,J＝8.1Hz,2H),3.93(d,J＝5.7Hz,2H),1.95(s,3H).MS(EI)m/z 371[M-H] -.
实施例44
N-(4-(N-苯乙基胺磺酰基)苯基)乙酰胺(A 18)的合成
Figure PCTCN2018078136-appb-000048
参照1a的合成方法，由苯乙胺和对乙酰氨基苯磺酰氯制得白色固体，收率85％，mp130-132℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)10.19(s,1H),7.59(q,J＝8.5Hz,4H),7.46(t,J＝5.9Hz,1H),7.16-7.00(m,5H),2.72-2.85(m,2H),2.52(t,J＝7.5Hz,2H),1.95(s,3H).MS(EI)m/z 317[M-H] -.
实施例45
N-苄基-3-硝基苯磺酰胺(A 19)的合成
Figure PCTCN2018078136-appb-000049
参照1a的合成方法，由苄胺和间硝基苯磺酰氯制得白色固体，收率90％，mp 84-86℃。 1H NMR(500MHz,DMSO-d 6)δ(ppm)8.53(s,1H),8.43-8.40(m,2H),8.18-8.15(m,1H),7.86-7.80(m,1H),7.25-7.14(m,5H),4.09(s,2H).MS(EI)m/z 291[M-H] -.
实施例46
N-(2-氯苄基)-3-硝基苯磺酰胺(A 20)的合成
Figure PCTCN2018078136-appb-000050
参照1a的合成方法，由2-氯苄胺和间硝基苯磺酰氯制得白色固体，收率91％，mp104-106℃。 1H NMR(500MHz,DMSO-d 6)δ(ppm)8.61(s,1H),8.44-8.40(m,2H),8.20-8.16(m,1H),7.87-7.82(m,1H),7.40-7.19(m,4H),4.19(s,2H).MS(EI)m/z 325[M-H] -.
实施例47
N-(4-氯苄基)-3-硝基苯磺酰胺(A 21)的合成
Figure PCTCN2018078136-appb-000051
参照1a的合成方法，由4-氯苄胺和间硝基苯磺酰氯制得白色固体，收率92％，mp114-116℃。 1H NMR(500MHz,DMSO-d 6)δ(ppm)8.55(s,1H),8.45-8.38(m,2H),8.18-8.14(m,1H),7.84(t,J＝13.5Hz,1H),7.29-7.20(m,4H),4.09(s,2H).MS(EI)m/z 325[M-H] -.
实施例48
N-(3,4-二氯苄基)-3-硝基苯磺酰胺(A 22)的合成
Figure PCTCN2018078136-appb-000052
参照1a的合成方法，由3,4-二氯苄胺和间硝基苯磺酰氯制得白色固体，收率90％，mp108-110℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.50(s,1H),8.46-8.38(m,2H),8.19-8.12(m,1H),7.88-7.80(m,1H),7.65-7.20(m,3H),4.09(s,2H).MS(EI)m/z 359[M-H] -.
实施例49
N-(3-三氟甲基苄基)-3-硝基苯磺酰胺(A 23)的合成
Figure PCTCN2018078136-appb-000053
参照1a的合成方法，由3-三氟甲基苄胺和间硝基苯磺酰氯制得类白色固体，收率88％，mp 102-104℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.59(s,1H),8.44-8.36(m,2H),8.17-8.13(m,1H),7.87-7.81(m,1H),7.54-7.31(m,4H),4.09(s,2H).MS(EI)m/z 359[M-H] -.
实施例50
N-(4-三氟甲基苄基)-3-硝基苯磺酰胺(A 24)的合成
Figure PCTCN2018078136-appb-000054
参照1a的合成方法，由4-三氟甲基苄胺和间硝基苯磺酰氯制得白色固体，收率89％，mp 78-80℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.52(s,1H),8.46-8.36(m,2H),8.17-8.13(m,1H),7.90-7.85(m,1H),7.54-7.25(m,4H),4.09(s,2H).MS(EI)m/z 359[M-H] -.
实施例51
N-苯基-4-硝基苯磺酰胺(A 25)的合成
Figure PCTCN2018078136-appb-000055
参照1a的合成方法，由苯胺和对硝基苯磺酰氯制得白色固体，收率87％，mp 168-170℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)10.33(s,1H),8.30-8.05(m,4H),7.15-6.96(m,5H).MS(EI)m/z 277[M-H] -.
实施例52
N-(2-氯苯基)-4-硝基苯磺酰胺(A 26)的合成
Figure PCTCN2018078136-appb-000056
参照1a的合成方法，由2-氯苯胺和对硝基苯磺酰氯制得白色固体，收率90％，mp240-242℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)10.27(s,1H),8.29-8.14(m,4H),7.25-7.02(m,4H).MS(EI)m/z 311[M-H] -.
实施例53
N-苄基-4-硝基苯磺酰胺(A 27)的合成
Figure PCTCN2018078136-appb-000057
参照1a的合成方法，由苄胺和对硝基苯磺酰氯制得淡黄色色固体，收率87％，mp 90-92℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.60(s,1H),8.43-8.40(m,2H),8.21-8.12(m,2H),7.25-7.14(m,5H),4.09(s,2H).MS(EI)m/z 291[M-H] -.
实施例54
N-(2-氯苄基)-4-硝基苯磺酰胺(A 28)的合成
Figure PCTCN2018078136-appb-000058
参照1a的合成方法，由2-氯苄胺和对硝基苯磺酰氯制得白色固体，收率90％，mp136-138℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.51(s,1H),8.24(d,J＝8.7Hz,2H),7.89(d,J＝8.4Hz,2H),7.27-7.22(m,2H),7.17-7.12(m,2H),4.01(s,2H).MS(EI)m/z 325[M-H] -.
实施例55
N-(3-氯苄基)-4-硝基苯磺酰胺(A 29)的合成
Figure PCTCN2018078136-appb-000059
参照1a的合成方法，由3-氯苄胺和对硝基苯磺酰氯制得白色固体，收率89％，mp124-126℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.31(s,1H),8.26(d,J＝8.4Hz,2H),7.85(d,J＝8.1Hz,2H),7.13(s,2H),7.06(s,2H),3.97(s,2H).MS(EI)m/z 325[M-H] -.
实施例56
N-(4-氯苄基)-4-硝基苯磺酰胺(A 30)的合成
Figure PCTCN2018078136-appb-000060
参照1a的合成方法，由4-氯苄胺和对硝基苯磺酰氯制得白色固体，收率91％，mp168-170℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.39(s,1H),8.23(d,J＝8.7Hz,2H),7.86(d,J＝9.0Hz,2H),7.18(d,J＝8.1Hz,2H),7.09(d,J＝8.4Hz,2H),3.93(s,2H).MS(EI)m/z 325[M-H] -.
实施例57
N-(3,4-二氯苄基)-4-硝基苯磺酰胺(A 31)的合成
Figure PCTCN2018078136-appb-000061
参照1a的合成方法，由3,4-二氯苄胺和对硝基苯磺酰氯制得淡黄色固体，收率89％，mp106-108℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.63(s,1H),8.31(d,J＝8.7Hz,2H),7.92(d,J＝9.0Hz,2H),7.48(d,J＝8.4Hz,2H),7.33(s,1H),7.17(d,J＝8.1Hz,2H),4.07(s,2H).MS(EI)m/z 359[M-H] -.
实施例58
N-(3-三氟甲基苄基)-4-硝基苯磺酰胺(A 32)的合成
Figure PCTCN2018078136-appb-000062
参照1a的合成方法，由3-三氟甲基苄胺和对硝基苯磺酰氯制得白色固体，收率86％， mp 80-82℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.59(s,1H),8.19(d,J＝8.7Hz,2H),7.83(d,J＝8.4Hz,2H),7.40(s,3H),7.33(s,1H),4.08(s,2H).MS(EI)m/z 359[M-H] -.
实施例59
N-(4-三氟甲基苄基)-4-硝基苯磺酰胺(A 33)的合成
Figure PCTCN2018078136-appb-000063
参照1a的合成方法，由4-三氟甲基苄胺和对硝基苯磺酰氯制得白色固体，收率88％，mp 160-162℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.46(s,1H),8.20(d,J＝11.1Hz,2H),7.84(d,J＝8.4Hz,2H),7.46(d,J＝8.1Hz,2H),7.28(d,J＝8.1Hz,2H),4.06(s,2H).MS(EI)m/z 359[M-H] -.
实施例60
N-(4-甲氧基苄基)-4-硝基苯磺酰胺(A 34)的合成
Figure PCTCN2018078136-appb-000064
参照1a的合成方法，由4-甲氧基苄胺和对硝基苯磺酰氯制得白色固体，收率90％，mp108-110℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.41(s,1H),8.31(d,J＝9.0Hz,2H),7.93(d,J＝9.0Hz,2H),7.06(d,J＝8.7Hz,2H),6.75(d,J＝8.7Hz,2H),3.95(s,2H),3.64(s,3H).MS(EI)m/z 321[M-H] -.
实施例61
N-苯乙基-4-硝基苯磺酰胺(A 35)的合成
Figure PCTCN2018078136-appb-000065
参照1a的合成方法，由苯乙胺和对硝基苯磺酰氯制得淡黄色固体，收率86％，mp 80-82℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.14(d,J＝8.4Hz,2H),8.00(t,J＝5.1Hz,1H),7.86(d,J＝8.7Hz,2H),7.13-7.00(m,5H),2.90(q,J＝6.6Hz,2H),2.55(t,J＝7.2,2H).MS(EI)m/z 305[M-H] -.
实施例62
N-苄基-3-氰基苯磺酰胺(A 36)的合成
Figure PCTCN2018078136-appb-000066
参照1a的合成方法，由苄胺和间氰基苯磺酰氯制得白色固体，收率85％，mp 74-76℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.30(t,J＝6.3Hz,2H),7.93(t,J＝6.6Hz,3H),7.62(t,J＝8.1Hz,1H),7.14-7.05(m,5H),3.93(d,J＝5.4Hz,2H).MS(EI)m/z 271[M-H] -.
实施例63
N-(2-氯苄基)-3-氰基苯磺酰胺(A 37)的合成
Figure PCTCN2018078136-appb-000067
参照1a的合成方法，由2-氯苄胺和间氰基苯磺酰氯制得类白色固体，收率87％，mp132-134℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.10(s,1H),7.98-7.92(m,3H),7.63(t,J＝7.8Hz,1H),7.25-7.20(m,2H),7.14(d,J＝3.3Hz,2H),4.02(s,2H).MS(EI)m/z 305[M-H] -.
实施例64
N-(3-氯苄基)-3-氰基苯磺酰胺(A 38)的合成
Figure PCTCN2018078136-appb-000068
参照1a的合成方法，由3-氯苄胺和间氰基苯磺酰氯制得白色固体，收率85％，mp 76-78℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.36(s,1H),7.96-7.88(m,3H),7.62(t,J＝7.5Hz,1H),7.18-7.03(m,4H),3.97(s,2H).MS(EI)m/z 305[M-H] -.
实施例65
N-(4-氯苄基)-3-氰基苯磺酰胺(A 39)的合成
Figure PCTCN2018078136-appb-000069
参照1a的合成方法，由4-氯苄胺和间氰基苯磺酰氯制得白色固体，收率88％，mp104-106℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.34(s,1H),7.96-7.89(m,3H),7.63(t,J＝8.1Hz,1H),7.17(d,J＝8.4Hz,2H),7.09(d,J＝8.1Hz,2H),3.94(s,2H).MS(EI)m/z 305[M-H] -.
实施例66
N-(3,4-二氯苄基)-3-氰基苯磺酰胺(A 40)的合成
Figure PCTCN2018078136-appb-000070
参照1a的合成方法，由3,4-二氯苄胺和间氰基苯磺酰氯制得白色固体，收率87％，mp132-134℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.47(s,1H),8.04(s,2H),7.98(d,J＝7.8Hz,1H),7.71(t,J＝7.8Hz,1H),7.47(d,J＝8.4Hz,1H),7.35(s,1H),7.17(d,J＝9.3Hz,1H),4.07(s,2H).MS(EI)m/z 339[M-H] -.
实施例67
N-(3-三氟甲基苄基)-3-氰基苯磺酰胺(A 41)的合成
Figure PCTCN2018078136-appb-000071
参照1a的合成方法，由3-三氟甲基苄胺和间氰基苯磺酰氯制得白色固体，收率85％，mp 74-76℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.54(s,1H),8.03-7.96(m,3H),7.68(t,J＝7.8Hz,1H),7.52-7.42(m,4H),4.18(s,2H).MS(EI)m/z 339[M-H] -.
实施例68
N-(4-三氟甲基苄基)-3-氰基苯磺酰胺(A 42)的合成
Figure PCTCN2018078136-appb-000072
参照1a的合成方法，由4-三氟甲基苄胺和间氰基苯磺酰氯制得白色固体，收率88％，mp 112-114℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.42(s,1H),7.92(t,J＝7.8Hz,3H),7.62(t,J＝7.8Hz,1H),7.48(d,J＝8.1Hz,2H),7.30(d,J＝8.1Hz,2H),4.05(s,2H).MS(EI)m/z 339[M-H] -.
实施例69
N-(4-甲氧基苄基)-3-氰基苯磺酰胺(A 43)的合成
Figure PCTCN2018078136-appb-000073
参照1a的合成方法，由4-甲氧基苄胺和间氰基苯磺酰氯制得白色固体，收率90％，mp118-120℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.16(s,1H),7.90(t,J＝8.4Hz,3H),7.60(t,J＝8.4Hz,1H),6.95(d,J＝8.4Hz,2H),6.64(d,J＝8.4Hz,2H),3.86(s,2H),3.57(s,3H).MS(EI) m/z 301[M-H] -.
实施例70
N-苯乙基-3-氰基苯磺酰胺(A 44)的合成
Figure PCTCN2018078136-appb-000074
参照1a的合成方法，由苯乙胺和间氰基苯磺酰氯制得白色固体，收率85％，mp 70-72℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.11-8.01(m,3H),7.93(t,J＝5.1Hz,1H),7.75(t,J＝8.1Hz,1H),7.24-7.10(m,5H),3.00(q,J＝6.3Hz,2H),2.64(t,J＝7.2,2H).MS(EI)m/z 285[M-H] -.
实施例71
N-苄基-4-氰基苯磺酰胺(A 45)的合成
Figure PCTCN2018078136-appb-000075
参照1a的合成方法，由苄胺和对氰基苯磺酰氯制得白色固体，收率82％，mp 140-142℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.23(s,1H),7.90(d,J＝8.4Hz,2H),7.78(d,J＝8.4Hz,2H),7.23-7.06(m,5H),3.91(s,2H).MS(EI)m/z 271[M-H] -.
实施例72
N-(2-氯苄基)-4-氰基苯磺酰胺(A 46)的合成
Figure PCTCN2018078136-appb-000076
参照1a的合成方法，由2-氯苄胺和对氰基苯磺酰氯制得白色固体，收率89％，mp116-118℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.39(s,1H),7.92(d,J＝8.1Hz,2H),7.79(d,J＝8.1Hz,2H),7.24-7.22(m,2H),7.15-7.12(m,2H),4.00(s,2H).MS(EI)m/z 305[M-H] -.
实施例73
N-(3-氯苄基)-4-氰基苯磺酰胺(A 47)的合成
Figure PCTCN2018078136-appb-000077
参照1a的合成方法，由3-氯苄胺和对氰基苯磺酰氯制得白色固体，收率90％，mp114-116℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.44(s,1H),7.90(d,J＝8.4Hz,2H),7.75(d,J ＝8.4Hz,2H),7.18-7.12(m,2H),7.07-7.03(m,2H),3.96(s,2H).MS(EI)m/z 305[M-H] -.
实施例74
N-(4-氯苄基)-4-氰基苯磺酰胺(A 48)的合成
Figure PCTCN2018078136-appb-000078
参照1a的合成方法，由4-氯苄胺和对氰基苯磺酰氯制得类白色固体，收率92％，mp110-112℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.41(s,1H),7.90(d,J＝8.1Hz,2H),7.76(d,J＝8.1Hz,2H),7.18(d,J＝8.4Hz,2H),7.08(d,J＝8.4Hz,2H),3.92(s,2H).MS(EI)m/z 305[M-H] -.
实施例75
N-(3,4-二氯苄基)-4-氰基苯磺酰胺(A 49)的合成
Figure PCTCN2018078136-appb-000079
参照1a的合成方法，由3,4-二氯苄胺和对氰基苯磺酰氯制得白色固体，收率90％，mp124-126℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.46(s,1H),7.89(d,J＝8.7Hz,2H),7.74(d,J＝8.4Hz,2H),7.39(d,J＝8.4Hz,1H),7.24(s,1H),7.07(d,J＝9Hz,1H),3.96(s,2H).MS(EI)m/z 339[M-H] -.
实施例76
N-(3-三氟甲基苄基)-4-氰基苯磺酰胺(A 50)的合成
Figure PCTCN2018078136-appb-000080
参照1a的合成方法，由3-三氟甲基苄胺和对氰基苯磺酰氯制得白色固体，收率86％，mp 104-106℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.61(s,1H),7.96(d,J＝8.7Hz,2H),7.83(d,J＝7.5Hz,2H),7.55-7.42(m,4H),4.16(s,2H).MS(EI)m/z 339[M-H] -.
实施例77
N-(4-三氟甲基苄基)-4-氰基苯磺酰胺(A 51)的合成
Figure PCTCN2018078136-appb-000081
参照1a的合成方法，由4-三氟甲基苄胺和对氰基苯磺酰氯制得白色固体，收率88％，mp 136-138℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.51(s,1H),7.86(d,J＝8.1Hz,2H),7.74(d,J＝8.4Hz,2H),7.47(d,J＝7.8Hz,2H),7.28(d,J＝8.1Hz,4H),4.04(s,2H).MS(EI)m/z339[M-H] -.
实施例78
N-苯乙基-4-氰基苯磺酰胺(A 52)的合成
Figure PCTCN2018078136-appb-000082
参照1a的合成方法，由苯乙胺和对氰基苯磺酰氯制得白色固体，收率85％，mp 102-104℃。 1H NMR(300MHz,DMSO-d 6)δ(ppm)8.02(d,J＝8.4Hz,3H),7.88(d,J＝8.4Hz,2H),7.24-7.10(m,5H),7.24-7.10(m,5H),2.98(q,J＝6.9Hz,2H),2.64(t,J＝7.2,2H).MS(EI)m/z 285[M-H] -.
实施例79
4-氨基-N-苯基苯磺酰胺(B 1)的合成
Figure PCTCN2018078136-appb-000083
参照2a的合成方法，由A 1制得淡黄色固体，收率89％，mp 188-190℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)9.81(s,1H),7.34(d,J＝8.6Hz,2H),7.15(t,J＝7.8Hz,2H),7.01(d,J＝7.7Hz,2H),6.94(d,J＝7.3Hz,1H),6.48(d,J＝8.7Hz,2H),5.92(s,2H).MS(EI)m/z 247[M-H] -.
实施例80
4-氨基-N-(3-氟苯基)苯磺酰胺(B 2)的合成
Figure PCTCN2018078136-appb-000084
参照2a的合成方法，由A 2制得白色固体，收率92％，mp 160-162℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)10.15(s,1H),7.38(d,J＝8.5Hz,2H),7.20(dd,J＝8.3,8.1Hz,1H),6.76(m,3H),6.53(d,J＝8.6Hz,2H),5.97(s,2H).MS(EI)m/z 265[M-H] -.
实施例81
4-氨基-N-(3-氯-4-氟苯基)苯磺酰胺(B 3)的合成
Figure PCTCN2018078136-appb-000085
参照2a的合成方法，由A 3制得白色固体，收率90％，mp 166-168℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)10.0(s,1H),7.31(m,2H),7.25(d,J＝8.9Hz,1H),7.12(d,J＝8.4Hz,2H),6.50(d,J＝8.1Hz,2H),6.02(s,2H).MS(EI)m/z 299[M-H] -.
实施例82
4-氨基-N-(4-甲基苯基)苯磺酰胺(B 4)的合成
Figure PCTCN2018078136-appb-000086
参照2a的合成方法，由A 4制得白色固体，收率89％，mp 188-190℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)9.55(s,1H),7.21(d,J＝8.5Hz,2H),6.83(dd,J＝8.0,8.3Hz,4H),6.37(d,J＝8.6Hz,2H),5.82(s,2H),2.31(s,3H).MS(EI)m/z 261[M-H] -.
实施例83
4-氨基-N-(3-异丙基苯基)苯磺酰胺(B 5)的合成
Figure PCTCN2018078136-appb-000087
参照2a的合成方法，由A 5制得白色固体，收率90％，mp 82-84℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)9.6(s,1H),7.24(d,J＝8.6Hz,2H),6.95(t,J＝7.6Hz,1H),6.72(m,3H),6.38(d,J＝8.6Hz,2H),5.83(s,2H),2.61(m,1H),0.96(d,J＝6.8Hz,6H).MS(EI)m/z 289[M-H] -.
实施例84
4-氨基-N-(4-异丙基苯基)苯磺酰胺(B 6)的合成
Figure PCTCN2018078136-appb-000088
参照2a的合成方法，由A 6制得淡黄色固体，收率92％，mp152-154℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)9.71(s,1H),7.33(d,J＝8.6Hz,2H),6.97(dd,J＝8.4,8.3Hz,4H),6.48(d,J＝8.6Hz,2H),5.93(s,2H),2.72(m,1H),1.07(d,J＝6.9Hz,6H).MS(EI)m/z 289[M-H] -.
实施例85
4-氨基-N-(3-甲氧基苯基)苯磺酰胺(B 7)的合成
Figure PCTCN2018078136-appb-000089
参照2a的合成方法，由A 7制得白色固体，收率94％，mp158-160℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)9.56(s,1H),7.36(d,J＝8.7Hz,2H),7.05(t,J＝8.4Hz,1H),6.54(dd,J＝6.0,8.6Hz,2H),5.97(s,2H),3.55(s,3H).MS(EI)m/z 277[M-H] -.
实施例86
4-氨基-N-苄基苯磺酰胺(B 8)的合成
Figure PCTCN2018078136-appb-000090
参照2a的合成方法，由A 8制得白色固体，收率93％，mp116-118℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)7.53(t,J＝6.1Hz,1H),7.32(d,J＝8.6Hz,2H),7.09-7.18(m,5H),6.49(d,J＝8.6Hz,2H),3.73(d,J＝5.9Hz,2H).MS(EI)m/z 261[M-H] -.
实施例87
4-氨基-N-(3-氟苄基)苯磺酰胺(B 9)的合成
Figure PCTCN2018078136-appb-000091
参照2a的合成方法，由A 9制得白色固体，收率95％，mp 102-104℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)7.69(s,1H),7.39(d,J＝8.3Hz,2H),7.18-7.29(m,1H),7.03(t,J＝9.2Hz,3H),6.56(d,J＝8.4Hz,2H),5.91(s,2H),3.87(d,J＝5.9Hz,2H).MS(EI)m/z 279[M-H] -.
实施例88
4-氨基-N-(4-氟苄基)苯磺酰胺(B 10)的合成
Figure PCTCN2018078136-appb-000092
参照2a的合成方法，由A 10制得淡黄色固体，收率93％，mp 130-132℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)7.64(d,J＝6.6Hz,1H),7.38(d,J＝8.4Hz,2H),7.22(d,J＝7.5Hz,2H),7.08(d,J＝8.7Hz,2H),6.55(d,J＝8.4Hz,2H),5.91(s,2H),3.81(d,J＝6.4Hz,2H).MS(EI)m/z 279[M-H] -.
实施例89
4-氨基-N-(2-氯苄基)苯磺酰胺(B 11)的合成
Figure PCTCN2018078136-appb-000093
参照2a的合成方法，由A 11制得白色固体，收率94％，mp 110-112℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)7.69(t,J＝6.2Hz,1H),7.24-7.42(m,5H),6.57(d,J＝8.6Hz,2H),5.93(s,2H),3.90(d,J＝6.3Hz,2H).MS(EI)m/z 295[M-H] -.
实施例90
4-氨基-N-(4-氯苄基)苯磺酰胺(B 12)的合成
Figure PCTCN2018078136-appb-000094
参照2a的合成方法，由A 12制得白色固体，收率95％，mp 172-174℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)7.66(t,J＝6.2Hz,1H),7.21-7.40(m,6H),6.56(d,J＝8.4Hz,2H),5.91(s,2H),3.83(d,J＝6.2Hz,2H).MS(EI)m/z 295[M-H] -.
实施例91
4-氨基-N-(3,4-二氯苄基)苯磺酰胺(B 13)的合成
Figure PCTCN2018078136-appb-000095
参照2a的合成方法，由A 13制得白色固体，收率93％，mp 148-150℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)7.73(s,1H),7.21-7.52(m,4H),7.22(s,1H),6.56(d,J＝8.9Hz,2H),5.93(s,2H),3.87(d,J＝6.0Hz,2H).MS(EI)m/z 329[M-H] -.
实施例92
4-氨基-N-(3-溴苄基)苯磺酰胺(B 14)的合成
Figure PCTCN2018078136-appb-000096
参照2a的合成方法，由A 14制得白色固体，收率92％，mp 100-102℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)7.693(s,1H),7.30(dd,J＝8.1,3.1Hz,5H),6.56(d,J＝8.6Hz,2H),5.92(s,2H),3.85(d,J＝6.1Hz,2H).MS(EI)m/z 339[M-H] -.
实施例93
4-氨基-N-(4-溴苄基)苯磺酰胺(B 15)的合成
Figure PCTCN2018078136-appb-000097
参照2a的合成方法，由A 15制得淡黄色固体，收率95％，mp 184-186℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)7.66(s,1H),7.40-7.64(m,3H),7.10(d,J＝8.1Hz,2H),6.57(d,J＝8.4Hz,2H),5.93(s,2H),3.81(d,J＝6.3Hz,2H).MS(EI)m/z 339[M-H] -.
实施例94
4-氨基-N-(3-三氟甲基苄基)苯磺酰胺(B 16)的合成
Figure PCTCN2018078136-appb-000098
参照2a的合成方法，由A 16制得白色固体，收率93％，mp 126-128℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)7.76(t,J＝6.3Hz 1H),7.50-7.64(m,3H),7.41(d,J＝8.5Hz,2H),6.57(d,J＝8.4Hz,2H),5.91(s,2H),3.96(d,J＝6.3Hz,2H).MS(EI)m/z 329[M-H] -.
实施例95
4-氨基-N-(4-三氟甲基苄基)苯磺酰胺(B 17)的合成
Figure PCTCN2018078136-appb-000099
参照2a的合成方法，由A 17制得类白色固体，收率94％，mp 176-178℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)7.76(s,1H),7.62(d,J＝8.0Hz,2H),7.41(dd,J＝8.1,8.6Hz,4H),6.56(d,J＝8.6Hz,2H),5.91(s,2H),3.94(d,J＝6.3Hz,2H).MS(EI)m/z 329[M-H] -.
实施例96
4-氨基-N-苯乙基苯磺酰胺(B 18)的合成
Figure PCTCN2018078136-appb-000100
参照2a的合成方法，由A 18制得白色固体，收率90％，mp 138-140℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)7.37(d,J＝8.4Hz,2H),7.14-7.25(m,5H),6.56(d,J＝8.5Hz,2H),2.82(m,2H),2.60(t,J＝7.4Hz,2H).MS(EI)m/z 275[M-H] -.
实施例97
N-(4-(N-苯基胺磺酰基)苯基)丙烯酰胺(C 1)的合成
Figure PCTCN2018078136-appb-000101
参照3a的合成方法，由B 1制得白色固体，收率50％。 1H NMR(300MHz,DMSO-d6)δ(ppm)10.55(s,1H),8.15(t,J＝6.0Hz,1H),7.98(d,J＝7.3Hz,2H),7.84(d,J＝7.5Hz,2H),7.48-7.30(m,2H),7.12-7.02(m,3H),6.49-6.40(m,1H),6.30(d,J＝16.8Hz,1H),5.83(d,J＝10.2Hz,1H).MS(EI)m/z 301[M-H] -.
实施例98
N-(4-(N-(3-氟苯基)胺磺酰基)苯基)丙烯酰胺(C 2)的合成
Figure PCTCN2018078136-appb-000102
参照3a的合成方法，由B 2制得白色固体，收率54％。 1H NMR(300MHz,DMSO-d6)δ(ppm)10.48(s,1H),8.03(t,J＝6.3Hz,1H),7.88(d,J＝8.7Hz,2H),7.73(d,J＝8.4Hz,2H),7.46-7.24(m,1H),7.12-6.98(m,3H),6.50-6.40(m,1H),6.31(d,J＝15.9Hz,1H),5.84(d,J＝9.9Hz,1H).MS(EI)m/z 319[M-H] -.
实施例99
N-(4-(N-(3-氯-4-氟苯基)胺磺酰基)苯基)丙烯酰胺(C 3)的合成
Figure PCTCN2018078136-appb-000103
参照3a的合成方法，由B 3制得白色固体，收率50％。 1H NMR(300MHz,DMSO-d6)δ(ppm)10.41(s,1H),7.98(t,J＝6.2Hz,1H),7.84(d,J＝7.8Hz,2H),7.74(d,J＝8.7Hz,2H),7.32-7.15(m,1H),7.12-6.88(m,2H),6.49-6.39(m,1H),6.30(d,J＝15.6Hz,1H),5.84(d,J＝9.9Hz,1H).MS(EI)m/z 353[M-H] -.
实施例100
N-(4-(N-(4-甲基苯基)胺磺酰基)苯基)丙烯酰胺(C 4)的合成
Figure PCTCN2018078136-appb-000104
参照3a的合成方法，由B 4制得白色固体，收率58％。 1H NMR(300MHz,DMSO-d6)δ(ppm)10.40(s,1H),8.02(t,J＝6.0Hz,1H),7.86(d,J＝8.7Hz,2H),7.76(d,J＝8.7Hz,2H),7.18(d,J＝7.8Hz,2H),6.98(d,J＝7.8Hz,2H),6.48-6.39(m,1H),6.31(d,J＝15.2Hz,1H),5.84(d,J＝10.2Hz,1H).2.32(s,3H).MS(EI)m/z 325[M-H] -.
实施例101
N-(4-(N-(3-异丙苯基)胺磺酰基)苯基)丙烯酰胺(C 5)的合成
Figure PCTCN2018078136-appb-000105
参照3a的合成方法，由B 5制得白色固体，收率55％。 1H NMR(300MHz,DMSO-d6)δ(ppm)10.41(s,1H),8.01(t,J＝6.0Hz,1H),7.84(d,J＝7.8Hz,2H),7.74(d,J＝8.4Hz,2H),7.28-7.12(m,1H),6.98-6.86(m,3H),6.47-6.38(m,1H),6.30(d,J＝17.2Hz,1H),5.84(d,J＝9.9Hz,1H),2.87-2.80(m,1H),1.20(d,J＝7.2Hz,6H).MS(EI)m/z 343[M-H] -.
实施例102
N-(4-(N-(4-异丙苯基)胺磺酰基)苯基)丙烯酰胺(C 6)的合成
Figure PCTCN2018078136-appb-000106
参照3a的合成方法，由B 6制得白色固体，收率56％。 1H NMR(300MHz,DMSO-d6)δ(ppm)10.40(s,1H),8.03(t,J＝6.3Hz,1H),7.85(d,J＝8.7Hz,2H),7.76(d,J＝8.7Hz,2H),7.38(d,J＝8.4,2H),6.98(d,J＝8.4Hz,2H),6.48-6.39(m,1H),6.31(d,J＝15.9Hz,1H),5.84(d,J＝9.9Hz,1H),2.89-2.82(m,1H),1.21(d,J＝7.2Hz,6H).MS(EI)m/z 343[M-H] -.
实施例103
N-(4-(N-(3-甲氧基苯基)胺磺酰基)苯基)丙烯酰胺(C 7)的合成
Figure PCTCN2018078136-appb-000107
参照3a的合成方法，由B 7制得白色固体，收率52％。 1H NMR(300MHz,DMSO-d6)δ(ppm)10.41(s,1H),7.98(t,J＝6.3Hz,1H),7.84(d,J＝8.1Hz,2H),7.75(d,J＝8.7Hz,2H),7.18-7.04(t,J＝8.4,1H),6.86-6.74(m,3H),6.49-6.34(m,1H),6.30(d,J＝15.9Hz,1H),5.83(d,J＝9.9Hz,1H),3.74(s,3H),.MS(EI)m/z 331[M-H] -.
实施例104
N-(4-(N-苄基胺磺酰基)苯基)丙烯酰胺(C 8)的合成
Figure PCTCN2018078136-appb-000108
参照3a的合成方法，由B 8制得白色固体，收率75％，mp 116-118℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)10.50(s,1H),8.02(t,J＝6.2Hz,1H),7.81(d,J＝8.7Hz,2H),7.72(d,J＝8.7Hz,2H),7.27-7.16(m,5H),6.48-6.39(m,1H),6.28(d,J＝15.6Hz,1H),5.79(d,J＝9.9Hz,1H),3.92(d,J＝6.0Hz,2H).MS(EI)m/z 315[M-H] -.
实施例105
N-(4-(N-(3-氟苄基)胺磺酰基)苯基)丙烯酰胺(C 9)的合成
Figure PCTCN2018078136-appb-000109
参照3a的合成方法，由B 9制得白色固体，收率80％，mp 152-154℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)10.39(s,1H),8.01(t,J＝6.3Hz,1H),7.70(d,J＝8.4Hz,2H),7.61(d,J＝5.7Hz,2H),7.22-7.15(m,1H),6.95-6.89(m,3H),6.37-6.28(m,1H),6.18(d,J＝16.8Hz,1H),5.69(d,J＝9.9Hz,1H),3.87(d,J＝6.3Hz,2H).MS(EI)m/z 333[M-H] -.
实施例106
N-(4-(N-(4-氟苄基)胺磺酰基)苯基)丙烯酰胺(C 10)的合成
Figure PCTCN2018078136-appb-000110
参照3a的合成方法，由B 10制得白色固体，收率82％，mp 178-180℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)10.40(s,1H),7.95(t,J＝6.0Hz,1H),7.70(d,J＝8.7Hz,2H),7.61(d,J＝8.4Hz,2H),7.14(t,J＝6.8Hz,1H),6.97(t,J＝8.6Hz,2H),6.37-6.28(m,1H),6.18(d,J＝17.1Hz,1H),5.70(d,J＝9.9Hz,1H),3.82(d,J＝6.0Hz,2H).MS(EI)m/z 333[M-H] -.
实施例107
N-(4-(N-(2-氯苄基)胺磺酰基)苯基)丙烯酰胺(C 11)的合成
Figure PCTCN2018078136-appb-000111
参照3a的合成方法，由B 11制得白色固体，收率78％，mp 178-180℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)10.41(s,1H),8.00(s,1H),7.71(d,J＝7.5Hz,2H),7.64(d,J＝8.7Hz,2H),7.28-7.15(m,4H),6.39-6.29(m,1H),6.18(d,J＝17.4Hz,1H),5.69(d,J＝2.7Hz,1H),3.91(d,J＝4.5Hz,2H).MS(EI)m/z 349[M-H] -.
实施例108
N-(4-(N-(4-氯苄基)胺磺酰基)苯基)丙烯酰胺(C 12)的合成
Figure PCTCN2018078136-appb-000112
参照3a的合成方法，由B 12制得白色固体，收率80％，mp 190-192℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)10.40(s,1H),7.98(t,J＝6.3Hz,1H),7.70(d,J＝8.4Hz,2H),7.61(d,J＝8.4Hz,2H),7.17(dd,J＝8.4,8.1Hz,4H),6.37-6.28(m,1H),6.18(d,J＝16.5Hz,1H),5.69(d,J＝2.7Hz，1H),3.82(d,J＝6.0Hz,2H).MS(EI)m/z 349[M-H] -.
实施例109
N-(4-(N-(3,4-二氯苄基)胺磺酰基)苯基)丙烯酰胺(C 13)的合成
Figure PCTCN2018078136-appb-000113
参照3a的合成方法，由B 13制得白色固体，收率82％，mp 148-150℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)10.41(s,1H),8.05(s,1H),7.65(d,J＝29.4Hz,4H),7.34(d,J＝30.0Hz,2H),7.11(s,1H),6.38-6.15(m,2H),5.70(s,1H),3.82(d,J＝6.0Hz,2H).MS(EI)m/z 383[M-H] -.
实施例110
N-(4-(N-(3-溴苄基)胺磺酰基)苯基)丙烯酰胺(C 14)的合成
Figure PCTCN2018078136-appb-000114
参照3a的合成方法，由B 14制得白色固体，收率81％，mp 156-158℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)10.40(s,1H),8.01(t,J＝6.0Hz,1H),7.70(d,J＝8.4Hz,2H),7.60(d,J＝8.7Hz,2H),7.26(s,2H),7.11(d,J＝3.9Hz,2H),6.38-6.29(m,1H),6.18(d,J＝15.9Hz,1H),5.69(d,J＝10.2Hz,1H),3.86(d,J＝6.0Hz,2H).MS(EI)m/z 393[M-H] -.
实施例111
N-(4-(N-(4-溴苄基)胺磺酰基)苯基)丙烯酰胺(C 15)的合成
Figure PCTCN2018078136-appb-000115
参照3a的合成方法，由B 15制得白色固体，收率83％，mp 194-196℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)10.44(s,1H),7.98(t,J＝6.2Hz,1H),7.71(d,J＝8.4Hz,2H),7.61(d,J＝8.7Hz,2H),7.34(d,J＝7.8Hz,2H),7.07(d,J＝7.8Hz,2H),6.38-6.29(m,1H),6.17(d,J＝15.9Hz,1H),5.69(d,J＝10.2Hz,1H),3.80(d,J＝6.3Hz,2H).MS(EI)m/z 393[M-H] -.
实施例112
N-(4-(N-(3-三氟甲基苄基)胺磺酰基)苯基)丙烯酰胺(C 16)的合成
Figure PCTCN2018078136-appb-000116
参照3a的合成方法，由B 16制得白色固体，收率77％，mp 152-154℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)10.55(s,1H),8.19(t,J＝6.2Hz,1H),7.79(d,J＝8.7Hz,2H),7.69(d,J＝8.7Hz,2H),7.55-7.44(m,4H),6.49-6.40(m,1H),6.27(d,J＝16.8Hz,1H),5.78(d,J＝3.9Hz,1H),4.06(d,J＝6.0Hz,2H).MS(EI)m/z 383[M-H] -.
实施例113
N-(4-(N-(4-三氟甲基苄基)胺磺酰基)苯基)丙烯酰胺(C 17)的合成
Figure PCTCN2018078136-appb-000117
参照3a的合成方法，由B 17制得白色固体，收率80％，mp 198-200℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)10.38(s,1H),8.07(s,1H),7.69(d,J＝7.8Hz,2H),7.61(d,J＝8.1Hz,2H),7.50(d,J＝7.2Hz,4H),7.33(d,J＝7.2Hz,2H),6.37-6.15(m,1H),6.18(d,J＝16.5Hz,1H),5.69(d,J＝9.9Hz,1H),3.94(d,J＝4.5Hz,2H).MS(EI)m/z 383[M-H] -.
实施例114
N-(4-(N-苯乙基胺磺酰基)苯基)丙烯酰胺(C 18)的合成
Figure PCTCN2018078136-appb-000118
参照3a的合成方法，由B 18制得白色固体，收率75％，mp 154-156℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)10.39(s,1H),7.70(d,J＝8.1Hz,2H),7.61(d,J＝7.5Hz,2H),7.49(s,1H),7.09(m,4H),6.37-6.28(m,1H),6.17(d,J＝15.6Hz,1H),5.69(d,J＝8.7Hz,1H),2.80(s,1H),2.53(s,1H).MS(EI)m/z 329[M-H] -.
实施例115
N-(4-(N-(4-甲氧基苄基)胺磺酰基)苯基)丙烯酰胺(C 19)的合成
Figure PCTCN2018078136-appb-000119
参照3a的合成方法，由2d制得白色固体，收率81％，mp 156-158℃。 1H NMR(300MHz,DMSO-d6)δ(ppm)10.38(s,1H),7.82(t,J＝6.0Hz,1H),7.70(d,J＝8.7Hz,2H),7.61(d,J＝8.7Hz,2H),7.00(d,J＝8.4Hz,4H),6.69(d,J＝8.7Hz,2H),6.38-6.29(m,1H),6.18(d,J＝17.1Hz,1H),5.69(d,J＝9.9Hz,1H),3.75(d,J＝6.0Hz,2H),3.57(s,3H).MS(EI)m/z 345[M-H] -.
实施例116
1.基于Hela细胞的IDO1抑制活性测试
1.1实验材料和主要仪器
Figure PCTCN2018078136-appb-000120
1.2实验方法
从ATCC购买的Hela细胞保存在最低基础培养基(2mM L-谷氨酰胺和调成含有1.5g/L碳酸氢钠、0.1mM非必需氨基酸、1mM丙铜酸钠和10％胎牛血清的Earle氏BSS)中。在37℃下将Hela细胞保存在提供5％CO 2的控湿培养箱中。
按5×10 3/孔的密度将Hela细胞接种在96孔培养板中，并培养过夜。第二天，将IFN-γ(终浓度100ng/mL)和化合物的系列稀释液(总体积200μL培养基)加给细胞。温育24小时后将140μL上清液/孔移至新的96孔板中，加入10μL 6.1mol/L的三氯乙酸，在恒温烘箱中50℃温育30min以使产生的N-甲酰基犬尿氨酸水解为犬尿氨酸。然后以4000rpm将反应混合物离心10min以去除沉淀物。将100μL上清液/孔移至另一96孔板中，与等体积2％(w/v)对-二甲氨基苯甲醛的乙酸溶液混合。使用酶标仪在480nm处检测吸光值，所得结果利用IC 50计算器计算。实验设3个复孔。
IC 50值报告的范围为：A表示小于10μM，B表示10-20μM，C表示20-50μM，D表示 大于50μM。
1.3实验结果
实验结果如表1所示。结果表明，本发明化合物对IDO1的活性具有显著的抑制作用。其中，化合物C 14的活性最强(IC 50:1.72μM)。
表1 本发明化合物对IDO1的抑制活性
Figure PCTCN2018078136-appb-000121
2.T淋巴细胞的增殖实验
2.1实验方法
B16F1细胞处理：吸去培养基(高糖DMEM，10％FBS)，PBS洗1-2次。加入0.25％胰酶消化。吸去胰酶，加入培养基，将细胞吹打下来，转移至1.5mL离心管中，离心，吸去上清，加入1mL DMEM培养基重新悬浮细胞。加入丝裂霉素C(终浓度25μg/ml)，吹打混勾，37℃，水浴30min，RP1640洗3次，细胞计数，待用。
脾脏细胞的制备：取C57/BL6小鼠，摘眼球放血处死，无菌取出脾脏放入含有2mL无菌的预冷RPMI 1640培养基的35mm的培养皿中，用5mL注射器针芯轻轻将脾细胞挤出。再加入2mL培养基，用5mL移液管反复吹打直至悬液均匀。将细胞悬液用70μm滤器过滤，300g离心5min(4℃)。弃上清后脾细胞加入10mL Tris-NH 4Cl，吹均，静置2-3min，300g离心5min(4℃)，去除红细胞。弃上清后，再用PRMI 1640洗涤两次，待用。
1)将处理过的B16F1细胞2×10 4个/孔(剌激细胞)，脾脏淋巴细胞1×10 6个/孔(反应细胞)，加入96孔板，加入RP1640(10％FBS)，补齐至200μL。
2)分组：给药组(剌激细胞+反应细胞+对应化合物)，空白对照(只加反应细胞)，模型组(剌激细胞+反应细胞)，除空白对照外，其他组均加入ConA(终浓度5μg/ml)，置于37℃、湿度95％、5％CO 2的培养箱中培养，培养48h。
3)加入20μL MTT(终浓度4mg/ml)培养箱中继续培养4h，酶标仪测定570nm波长处吸光度值；计算T淋巴细胞增殖率：
T淋巴细胞增殖率(％)＝[给药孔(T淋巴细胞+B16F1细胞+IDO1抑制剂)OD值一对照孔(T淋巴细胞+B16F1细胞)OD值]/对照孔(T淋巴细胞+B16F1细胞)OD值×100％
2.2实验结果
在混合淋巴细胞反应体系中，B16F1细胞高表达IDO1，对T淋巴细胞的增殖能够产生抑制作用。当加入化合物1h、3a、C 10、C 11和C 14(3倍IC 50浓度)培养48h后，利用MTT检测T淋巴细胞的增殖，增殖率分别为34.77％、39.83％、33.21％、36.72％和42.21％，说明这些化合物都能显著增加T淋巴细胞的增殖。
3.对调节性T淋巴细胞的影响
3.1实验方法
将处理过的B16F1细胞(8×10 4个孔)，脾脏淋巴细胞(10 6个孔，使用5μg/mL的ConA刺激)加入24孔板中，加入对应浓度的化合物后置于37℃、湿度95％、5％CO 2的培养箱中培养48h；收集上清液测试ELISA，使用抗CD4、抗CD25、抗FOCP3抗体染色，在流式细胞仪中检测T细胞的分化。
3.2实验结果
当原始T淋巴细胞与黑色素瘤细胞株B16F1共培养时，调节性T淋巴细胞的数量和仅含原始T淋巴细胞的实验组(3.2％)相比上升了4倍(12％)。当化合物1c、1h、3a、C 10、C 11和C 14(3倍IC 50浓度)加入体系中后能够明显逆转了这种效应(分别下降为7.8％、7.6％、2.1％、8.2％、7.3％、11.5％)，说明这些化合物都能够通过抑制IDO1逆转原始T淋巴细胞向 调节性T淋巴细胞的转化。
4.对IDO1表达的影响
4.1实验方法
Hela细胞以2×10 5每孔的密度种于6孔板培养，于37℃，5％CO 2条件下培养12h。空白对照(只加培养基)，模型组(加入IFN-γ、对应阳性药)，药物处理组(加入IFN-γ、对应化合物)，于37℃，5％CO 2条件下培养24h，收集细胞，Western blot检测IDO1表达。4.2实验结果
实验结果表明，化合物1c、1h、3a、C 10、C 11和C 14不影响Hela细胞中IDO1的表达，说明这些化合物都是通过抑制IDO1的活性来逆转IDO1介导的免疫抑制。

Claims (10)

  1. 通式(I)所示的苯磺酰胺类化合物或其药学上可接受的盐：
    Figure PCTCN2018078136-appb-100001
    其中：
    n代表0～8的整数；
    m代表0～4的整数；
    R 1代表氢、氰基、硝基、羟基、卤素、氨基、乙酰胺基、三氟甲基或丙烯酰胺基；
    R 2代表氢、卤素、氰基、羟基、硝基、C 1-C 8烷基、C 1-C 8烷氧基或亚甲二氧基。
  2. 根据权利要求2所述的苯磺酰胺类化合物或其药学上可接受的盐，其特征在于：
    n代表0～4的整数；
    m代表0～4的整数；
    R 1代表氰基、硝基、氨基、乙酰胺基或丙烯酰胺基；
    R 2代表氢、3-氟、4-氟、2-氯、3-氯、4-氯、3,4-二氯、3-溴、4-溴、3-氯-4-氟、3-三氟甲基、4-三氟甲基、4-甲基、3-异丙基、4-异丙基、4-氰基、3-甲氧基、4-甲氧基、3,4-二甲氧基或3,4-亚甲二氧基。
  3. 根据权利要求1所述的苯磺酰胺类化合物或其药学上可接受的盐，其特征在于所述化合物选自：
    N-(4-(N-(4-氰苄基)胺磺酰基)苯基)乙酰胺；
    N-(4-(N-(3-氯苄基)胺磺酰基)苯基)乙酰胺；
    N-(4-(N-(4-甲氧基苄基)胺磺酰基)苯基)乙酰胺；
    N-(4-(N-(4-甲氧基苯基)胺磺酰基)苯基)乙酰胺；
    N-(4-(N-(4-氟苯基)胺磺酰基)苯基)乙酰胺；
    N-(4-(N-(3-甲氧基苯乙基)胺磺酰基)苯基)乙酰胺；
    N-(4-(N-(3,4-二甲氧基苯乙基)胺磺酰基)苯基)乙酰胺；
    N-(4-氰苄基)-3-硝基苯磺酰胺；
    N-(3-氯苄基)-3-硝基苯磺酰胺；
    N-(3-甲氧基苯乙基)-3-硝基苯磺酰胺；
    N-(4-甲氧基苄基)-3-硝基苯磺酰胺；
    N-(4-甲氧基苯基)-3-硝基苯磺酰胺；
    4-氰基-N-(4-甲氧基苄基)苯磺酰胺；
    4-氰基-N-(3-氟苄基)苯磺酰胺；
    N-(苯并[d][1,3]二氧-5-亚甲基)-4-氰基苯磺酰胺；
    4-氰基-N-(3-甲氧基苯乙基)苯磺酰胺；
    4-氨基-N-(3-氯苄基)苯磺酰胺；
    4-氨基-N-(4-甲氧基苯基)苯磺酰胺；
    4-氨基-N-(4-氟苯基)苯磺酰胺；
    4-氨基-N-(4-甲氧基苄基)苯磺酰胺；
    4-氨基-N-(3-甲氧基苯乙基)苯磺酰胺；
    4氨基-N-(3,4-二甲氧基苯乙基)苯磺酰胺；
    N-(4-(N-(3-氯苄基)胺磺酰基)苯基)丙烯酰胺；
    N-(4-(N-(4-甲氧基苯基)胺磺酰基)苯基)丙烯酰胺；
    N-(4-(N-(3,4-二甲氧基苯乙基)胺磺酰基)苯基)丙烯酰胺；
    N-(4-(N-(3-甲氧基苯乙基)胺磺酰基)苯基)丙烯酰胺；
    N-(4-(N-苯基胺磺酰基)苯基)乙酰胺；
    N-(4-(N-(3-氟苯基)胺磺酰基)苯基)乙酰胺；
    N-(4-(N-(3-氯-4-氟苯基)胺磺酰基)苯基)乙酰胺；
    N-(4-(N-(4-甲基苯基)胺磺酰基)苯基)乙酰胺；
    N-(4-(N-(3-异丙苯基)胺磺酰基)苯基)乙酰胺；
    N-(4-(N-(4-异丙苯基)胺磺酰基)苯基)乙酰胺；
    N-(4-(N-(3-甲氧基苯基)胺磺酰基)苯基)乙酰胺；
    N-(4-(N-苄基胺磺酰基)苯基)乙酰胺；
    N-(4-(N-(3-氟苄基)胺磺酰基)苯基)乙酰胺；
    N-(4-(N-(4-氟苄基)胺磺酰基)苯基)乙酰胺；
    N-(4-(N-(2-氯苄基)胺磺酰基)苯基)乙酰胺；
    N-(4-(N-(4-氯苄基)胺磺酰基)苯基)乙酰胺；
    N-(4-(N-(3,4-二氯苄基)胺磺酰基)苯基)乙酰胺；
    N-(4-(N-(3-溴苄基)胺磺酰基)苯基)乙酰胺；
    N-(4-(N-(4-溴苄基)胺磺酰基)苯基)乙酰胺；
    N-(4-(N-(3-三氟甲基苄基)胺磺酰基)苯基)乙酰胺；
    N-(4-(N-(4-三氟甲基苄基)胺磺酰基)苯基)乙酰胺；
    N-(4-(N-苯乙基胺磺酰基)苯基)乙酰胺；
    N-苄基-3-硝基苯磺酰胺；
    N-(2-氯苄基)-3-硝基苯磺酰胺；
    N-(4-氯苄基)-3-硝基苯磺酰胺；
    N-(3,4-二氯苄基)-3-硝基苯磺酰胺；
    N-(3-三氟甲基苄基)-3-硝基苯磺酰胺；
    N-(4-三氟甲基苄基)-3-硝基苯磺酰胺；
    N-苯基-4-硝基苯磺酰胺；
    N-(2-氯苯基)-4-硝基苯磺酰胺；
    N-苄基-4-硝基苯磺酰胺；
    N-(2-氯苄基)-4-硝基苯磺酰胺；
    N-(3-氯苄基)-4-硝基苯磺酰胺；
    N-(4-氯苄基)-4-硝基苯磺酰胺；
    N-(3,4-二氯苄基)-4-硝基苯磺酰胺；
    N-(3-三氟甲基苄基)-4-硝基苯磺酰胺；
    N-(4-三氟甲基苄基)-4-硝基苯磺酰胺；
    N-(4-甲氧基苄基)-4-硝基苯磺酰胺；
    N-苯乙基-4-硝基苯磺酰胺；
    N-苄基-3-氰基苯磺酰胺；
    N-(2-氯苄基)-3-氰基苯磺酰胺；
    N-(3-氯苄基)-3-氰基苯磺酰胺；
    N-(4-氯苄基)-3-氰基苯磺酰胺；
    N-(3,4-二氯苄基)-3-氰基苯磺酰胺；
    N-(3-三氟甲基苄基)-3-氰基苯磺酰胺；
    N-(4-三氟甲基苄基)-3-氰基苯磺酰胺；
    N-(4-甲氧基苄基)-3-氰基苯磺酰胺；
    N-苯乙基-3-氰基苯磺酰胺；
    N-苄基-4-氰基苯磺酰胺；
    N-(2-氯苄基)-4-氰基苯磺酰胺；
    N-(3-氯苄基)-4-氰基苯磺酰胺；
    N-(4-氯苄基)-4-氰基苯磺酰胺；
    N-(3,4-二氯苄基)-4-氰基苯磺酰胺；
    N-(3-三氟甲基苄基)-4-氰基苯磺酰胺；
    N-(4-三氟甲基苄基)-4-氰基苯磺酰胺；
    N-苯乙基-4-氰基苯磺酰胺；
    4-氨基-N-苯基苯磺酰胺；
    4-氨基-N-(3-氟苯基)苯磺酰胺；
    4-氨基-N-(3-氯-4-氟苯基)苯磺酰胺；
    4-氨基-N-(4-甲基苯基)苯磺酰胺；
    4-氨基-N-(3-异丙基苯基)苯磺酰胺；
    4-氨基-N-(4-异丙基苯基)苯磺酰胺；
    4-氨基-N-(3-甲氧基苯基)苯磺酰胺；
    4-氨基-N-苄基苯磺酰胺；
    4-氨基-N-(3-氟苄基)苯磺酰胺；
    4-氨基-N-(4-氟苄基)苯磺酰胺；
    4-氨基-N-(2-氯苄基)苯磺酰胺；
    4-氨基-N-(4-氯苄基)苯磺酰胺；
    4-氨基-N-(3,4-二氯苄基)苯磺酰胺；
    4-氨基-N-(3-溴苄基)苯磺酰胺；
    4-氨基-N-(4-溴苄基)苯磺酰胺；
    4-氨基-N-(3-三氟甲基苄基)苯磺酰胺；
    4-氨基-N-(4-三氟甲基苄基)苯磺酰胺；
    4-氨基-N-苯乙基苯磺酰胺；
    N-(4-(N-苯基胺磺酰基)苯基)丙烯酰胺；
    N-(4-(N-(3-氟苯基)胺磺酰基)苯基)丙烯酰胺；
    N-(4-(N-(3-氯-4-氟苯基)胺磺酰基)苯基)丙烯酰胺；
    N-(4-(N-(4-甲基苯基)胺磺酰基)苯基)丙烯酰胺；
    N-(4-(N-(3-异丙苯基)胺磺酰基)苯基)丙烯酰胺；
    N-(4-(N-(4-异丙苯基)胺磺酰基)苯基)丙烯酰胺；
    N-(4-(N-(3-甲氧基苯基)胺磺酰基)苯基)丙烯酰胺；
    N-(4-(N-苄基胺磺酰基)苯基)丙烯酰胺；
    N-(4-(N-(3-氟苄基)胺磺酰基)苯基)丙烯酰胺；
    N-(4-(N-(4-氟苄基)胺磺酰基)苯基)丙烯酰胺；
    N-(4-(N-(2-氯苄基)胺磺酰基)苯基)丙烯酰胺；
    N-(4-(N-(4-氯苄基)胺磺酰基)苯基)丙烯酰胺；
    N-(4-(N-(3,4-二氯苄基)胺磺酰基)苯基)丙烯酰胺；
    N-(4-(N-(3-溴苄基)胺磺酰基)苯基)丙烯酰胺；
    N-(4-(N-(4-溴苄基)胺磺酰基)苯基)丙烯酰胺；
    N-(4-(N-(3-三氟甲基苄基)胺磺酰基)苯基)丙烯酰胺；
    N-(4-(N-(4-三氟甲基苄基)胺磺酰基)苯基)丙烯酰胺；
    N-(4-(N-苯乙基胺磺酰基)苯基)丙烯酰胺；
    N-(4-(N-(4-甲氧基苄基)胺磺酰基)苯基)丙烯酰胺。
  4. 根据权利要求1所述的苯磺酰胺类化合物的制备方法，其特征在于：
    a)当R 1为氰基、硝基或乙酰胺基时，通式(I)所示化合物的制备方法为：以不同取代的苯磺酰氯和胺类化合物发生缩合反应制得化合物1a-p和A 1-52；其合成路线如下：
    Figure PCTCN2018078136-appb-100002
    其中，n、m、R 1和R 2的定义如前所述；
    b)当R 1为胺基时，通式(I)所示化合物的制备方法为：1b-g和A 1-18在浓盐酸作用下水解脱去乙酰基制得2a-f和B 1-18；其合成路线如下：
    Figure PCTCN2018078136-appb-100003
    其中，n、m、R 1和R 2的定义如前所述；
    c)当R 1为丙烯酰胺基时，通式(I)所示化合物的制备方法为：2a、2b、2d、2e、2f以及B 1-18分别与丙烯酰氯反应制得3a-3d和C 1-19；其合成路线如下：
    Figure PCTCN2018078136-appb-100004
    其中，n、m、R 1和R 2的定义如权利要求1所述。
  5. 一种药物组合物，其由治疗上有效量的活性组分和药学上可接受的辅料组成；所述的活性组分包括如权利要求1-3中任一项所述的苯磺酰胺类化合物(I)或其药学上可接受的盐；所述的药学上可接受的辅料包括药学上可接受的载体、稀释剂和/或赋形剂。
  6. 权利要求1-3中任一项所述的化合物、其药学上可接受的盐或权利要求5中所述的组合物在制备吲哚胺2,3-双加氧酶1抑制剂中的应用。
  7. 权利要求1-3中任一项所述的化合物、其药学上可接受的盐或权利要求5中所述的组合物在制备药物中的用途，所述药物用于治疗患者的免疫抑制。
  8. 权利要求1-3中任一项所述的化合物其药学上可接受的盐或权利要求5中所述的组合物在制备药物中的用途，所述药物用于治疗患者的癌症、病毒感染、神经变性疾病、白内障、器官移植排斥、抑郁症或自身免疫性疾病。
  9. 根据权利要求8所述的应用，其中所述的癌症为恶性黑色素瘤、肺癌、乳腺癌、胃癌、结肠癌、膀胱癌、胰腺癌、淋巴癌、白血病、前列腺癌、睾丸癌、肾癌、脑癌、头颈癌、卵巢癌、宫颈癌、子宫内膜癌、间皮瘤、甲状腺癌、肝癌和食管癌中的一种或多种；所述的病毒感染为人类免疫缺陷病毒、乙型肝炎病毒、丙型肝炎病毒、流感病毒、脊髓灰质炎病毒、巨细胞病毒、柯萨奇病毒、人类乳头状瘤病毒、爱泼斯坦-巴尔病毒和水痘-带状疱疹病毒中的一种或多种引起的感染；所述的神经变性疾病为记忆障碍症、阿尔茨海默病、认知障碍症、老年痴呆症、帕金森病、帕金森综合症和运动障碍性疾病中的一种或多种；所述的自身免疫性疾病为类风湿性关节炎、系统性红斑狼疮、皮肌炎、硬皮病、结节性脉管炎、多发性硬化症、肾病、重症肌无力、混合性结缔组织病、银屑病、肝病、内分泌相关疾病和由于感染引起的自身免疫反应中的一种或多种。
  10. 根据权利要求8-9所述的应用，其特征在于：进一步给予所述疾病患者施用一种或多种化疗剂、靶向抗肿瘤药物、免疫检查点抑制剂、免疫检查点激动剂、抗肿瘤疫苗、抗病毒剂、抗病毒疫苗、细胞因子疗法、过继性细胞免疫治疗或放射治疗；所述的化疗剂为烷化剂、微管蛋白抑制剂、拓扑酶抑制剂、铂类药物、抗代谢类药物或激素类抗肿瘤药物；所述的靶向抗肿瘤药物为蛋白激酶抑制剂、蛋白酶体抑制剂、异柠檬酸脱氢酶抑制剂、基于表观遗传学的抗肿瘤药物或细胞周期信号通路抑制剂；所述的免疫检查点抑制剂为CTLA-4抑制剂、PD-1抑制剂、PD-L1抑制剂、PD-L2抑制剂、TIM-3抑制剂、VISTA抑制剂、LAG3抑制剂、TIGIT抑制剂、A2AR抑制剂或VTCN1抑制剂；所述的免疫检查点激动剂为STING激动剂、4-1BB激动剂、OX40激动剂、RORγ激动剂或ICOS激动剂。
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