WO2020253802A1 - 二芳基酰胺类化合物及其应用 - Google Patents

二芳基酰胺类化合物及其应用 Download PDF

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WO2020253802A1
WO2020253802A1 PCT/CN2020/096939 CN2020096939W WO2020253802A1 WO 2020253802 A1 WO2020253802 A1 WO 2020253802A1 CN 2020096939 W CN2020096939 W CN 2020096939W WO 2020253802 A1 WO2020253802 A1 WO 2020253802A1
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carboxamide
nitrofuran
group
alkyl
edema
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PCT/CN2020/096939
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English (en)
French (fr)
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杨宝学
李润涛
李敏
张顺
赵岩
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Peking University
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Peking University
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Priority to EP20827138.7A priority Critical patent/EP3984534A4/en
Priority to US17/619,174 priority patent/US12428389B2/en
Priority to JP2021575322A priority patent/JP7677912B2/ja
Publication of WO2020253802A1 publication Critical patent/WO2020253802A1/zh
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the field of diuretics, in particular to diarylamide compounds, their pharmaceutically acceptable salts and their use in preparing drugs as urea channel protein inhibitors.
  • Diuretics act on the kidneys to increase the excretion of water. Clinically, it is mainly used to treat edema caused by various reasons. It can also be used to treat some non-edematous diseases. For example, as a first-line drug, it can be used alone or in combination with other drugs to treat hypertension, and reduce the incidence of cardiovascular and cerebrovascular diseases and death rate. Diuretics can be divided into potassium-sparing diuretics, thiazide diuretics, loop diuretics, and carbonic anhydrase inhibitors according to the different sites of diuretics. Potassium-sparing diuretics represented by amiloride and triamterene mainly exert diuretic activity directly by blocking the exchange of Na + , K + and H + .
  • potassium-sparing diuretics can also indirectly regulate the level of aldosterone to exert diuretic activity.
  • Thiazide diuretics mainly exert diuretic activity by acting on the Na + -Cl - cotransporter of the distal convoluted tubules and collecting ducts to hinder the reabsorption of NaCl.
  • Loop diuretics act on the Na + -K + -2Cl - cotransporter of the medullary loop and hinder the reabsorption of NaCl to exert diuretic activity. Since this part is the main part of NaCl reabsorption, it has a significant effect on urine concentration. Therefore, loop diuretics have strong diuretic activity.
  • Vasopressin V2 receptor antagonists are a class of drugs that specifically antagonize the binding of vasopressin to its receptor, which can phosphorylate aquaporin 2 (AQP2) in the vesicles in the main cells of the collecting duct of the kidney and make it inserted into the cell
  • the apical plasma membrane increases the reabsorption of water in the collecting duct, thereby exerting a diuretic effect. It is suitable for diseases such as normal volume and hypervolemic hyponatremia.
  • the downstream pathways of V2 receptors are more complicated, which can cause liver toxicity and other adverse effects. Reaction, so it is not entirely ideal as a diuretic. Therefore, we hope to find a new type of diuretic that can exert diuretic effects without causing side effects such as electrolyte disturbance.
  • Urea channel protein (urea transporter, UT) is a transmembrane protein that specifically permeates urea and plays a very important role in the mechanism of urine concentration. Selectively knocking out the urea channel can block the urea circulation pathway in the kidney and reduce urine concentration. Ability to produce urea selective diuresis without affecting the excretion of Na + , K + , and Cl - .
  • urea channel protein inhibitors can be used as diuretics to reduce the intrarenal osmotic pressure difference established by the intrarenal urea cycle without significantly affecting the body's electrolyte balance, thereby producing diuretic effects and being used to treat different causes (such as congestion) Patients with edema diseases such as heart failure, liver cirrhosis, nephrotic syndrome, etc.) and patients with non-edema diseases (such as heart failure, cardiovascular and cerebrovascular diseases, etc.).
  • edema diseases such as heart failure, liver cirrhosis, nephrotic syndrome, etc.
  • non-edema diseases such as heart failure, cardiovascular and cerebrovascular diseases, etc.
  • Urea is the most abundant solute in urine, accounting for 40-50% of the total solute in urine.
  • the concentration of urea in urine can be as high as 100 times the concentration of plasma urea [Yang Band and Bankir L. Renal handling of urea in transgenic mice lacking the urea transporter UT-B, Am J Physiol Renal Physiol, 2005, 288: F881-F896].
  • Urea is the main solute involved in the mechanism of urine concentration.
  • the mechanism of urea circulation in the kidney specifically includes: (1) Water reabsorption and impermeability of urea in the collecting duct under the control of vasopressin, resulting in high concentration of urea in the collecting duct; (2) Urea at the end of the inner medullary collecting duct The increase in permeability allows high-concentration urea to penetrate into the interstitial tissue of the inner medulla; (3) Medullary urea passes through the ascending branches of the inner medulla and is continuously carried by the blood to the renal cortex, and then passes through the descending branches of the small blood vessels.
  • Urea channel is a membrane channel protein that specifically permeates urea.
  • 7 members have been cloned, belonging to two subfamily UT-A and UT-B.
  • the UT-A subfamily includes 6 members (UT-A1 to UT-A6) from the same gene (Slc14a2) via different promoters Regulation and post-transcriptional shearing [Bagnasco SM. Gene structure of urea transporters, Am J Physiol, 2003, 284: F3-F10; Shayakul C and Hediger MA.
  • the SLC14 gene family of urea transporters, Pfluegers Arch, 2004447:603 -609] the UT-B subfamily has only one member, UT-B.
  • UT-A1, UT-A3, and UT-A4 are expressed in the epithelial cells of the renal collecting duct, and UT-A2 descends in the renal loop UT-A5 and UT-A6 are expressed in the testis and colon respectively.
  • UT-B is expressed by another gene (Slc14a1), which is located in the endothelial cells of the descending branches of the straight small blood vessels of the kidney, red blood cells, and multiple tissues and organs.
  • UT-A1, UT-A2, UT-A3, UT-A4 and UT-B mediate the urea permeability of the corresponding parts of the urea cycle in the kidney, play an important role in the process of the urea cycle in the kidney, and participate in the mechanism of urine concentration.
  • kidneys can block renal circulation passage urea, reduced ability to concentrate the urine, without affecting Na +, K +, Cl - in the case of generating selective urea Diuretic effect. Therefore, urea channel protein inhibitors can act on the kidneys as diuretics and increase the excretion of water, which can be used clinically to treat water retention diseases such as congestive heart failure, nephrotic syndrome, and edema.
  • the present invention discovers a class of diarylamide compounds and their pharmaceutically acceptable salts, which have good urea channel protein inhibitory activity and excellent druggability.
  • the present invention describes the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of drugs as urea channel inhibitors,
  • Ring A and Ring B are each independently a 5- to 6-membered heteroaryl group or a 5- to 6-membered aryl group;
  • Said ring A and ring B are optionally substituted by R 1 and R 2 respectively;
  • R 1 is selected from the group consisting of the following groups: nitro, halogen, alkyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonyl and pyrido;
  • R 2 is selected from the group consisting of halogen, hydroxy, amino, cyano, alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy, alkylcarbonyl, alkoxy carbonyl group, and pyridyl group
  • R 5 is optionally substituted alkyl carbonyl group
  • R 5 is optionally substituted heterocyclic group or cycloalkyl group
  • R 5 is optionally substituted heteroarylcarbonyl group, N -Alkylamino, N,N-di(alkyl)amino, and aminocarbonyl substituted by R 3 and R 4 ;
  • R 3 and R 4 are each independently selected from the group consisting of H, hydroxyl, alkyl, heterocyclic group or cyclic group optionally substituted by R 5 , and optionally R 5 Substituted heterocyclyl or cycloalkyl, heteroaryl or arylalkyl optionally substituted by R 5 , N-(alkyl)aminoalkyl, and N,N-bis(alkyl)aminoalkyl Base; and
  • R 5 is selected from the group consisting of: alkyl, nitro, alkylcarbonylamino, N-(alkyl)amino, N,N-bis(alkyl)amino, N,N-bis( Alkyl)aminoalkylamino, and heterocyclic group or cyclic group.
  • the present invention also describes a method for treating or preventing diseases associated with urea channel protein inhibitors, the method comprising administering to a patient in need a therapeutically effective amount of the formula according to the present invention ( I) The compound shown in or a pharmaceutically acceptable salt thereof.
  • the present invention also describes the compound represented by formula (I) according to the present invention, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of diseases related to urea channel protein inhibitors.
  • the present invention also describes the compound represented by formula (I) according to the present invention, or a pharmaceutically acceptable salt thereof, as a urea channel protein inhibitor.
  • the present invention also describes the use of the compound represented by formula (I) according to the present invention or a pharmaceutically acceptable salt thereof in the treatment of diseases related to urea channel protein inhibitors.
  • the present invention describes a diarylamide compound or a pharmaceutically acceptable salt thereof, the diarylamide compound or a pharmaceutically acceptable salt thereof is selected from The group consisting of the following compounds, or pharmaceutically acceptable salts thereof:
  • the present invention describes a pharmaceutical composition
  • a pharmaceutical composition comprising: the diarylamide compound according to the sixth aspect of the present invention or a pharmaceutically acceptable salt thereof; and A pharmaceutically acceptable carrier.
  • the present invention uses computer simulation screening to screen 1040 compounds from small molecule compound libraries, uses red blood cell lysis model to screen out compounds with UT-B inhibitory activity, and combines structural transformation and optimization to obtain a class with stronger UT-B Inhibiting activity of diaryl amide compounds.
  • This type of diarylamide compound has a strong activity of inhibiting UT-B and UT-A permeating urea, and its half effective dose for inhibiting urea channel UT-B in vitro is below the micromolar level, and has no obvious cytotoxicity .
  • diarylamide compounds can significantly increase the urine output of rats and mice, reduce the level of urea, and reduce the urine osmotic pressure, indicating that it has a good selective diuretic effect of urea, and this Compounds do not affect body fluid and electrolyte balance.
  • the diarylamide compound of the present invention has the potential to develop into a new type of diuretic, and can avoid the side effects such as electrolyte disturbances common to conventional diuretics, and can be used to treat different causes (such as congestive heart failure, liver cirrhosis, and kidney disease). Patients with edema diseases and non-edema diseases (heart failure, cardiovascular and cerebrovascular diseases, etc.).
  • Figure 1 is a schematic diagram of a screening model for erythrocyte urea channel inhibitors.
  • Figure 2 exemplarily shows the inhibitory effect of the compound of Example 3 of the present invention (hereinafter referred to as the compound of Example 3 or Example 3) on UT-B and UT-A1 permeation of urea.
  • A The chemical structure of the compound of Example 3;
  • B The dose-effect relationship of the compound of Example 3 on human and rat UT-B inhibition in the red blood cell lysis model;
  • C In wild type or UT-B knockout mice In, the dose-effect relationship of PU-48 on the inhibition of red blood cell urea permeability.
  • D The inhibitory effect of the compound of Example 3 on the urea transport ability of MDCK cells stably transfected with UT-B.
  • E The inhibitory effect of the compound of Example 3 on the urea transport ability of MDCK cells stably transfected with UT-A1.
  • Figure 3 exemplarily shows the diuretic effect and non-urea excretion of a single subcutaneous injection of the compound of Example 3 of the present invention in rats. Put the rat into a metabolic cage, and collect 0 ⁇ 2h urine as the basal urine output. Then 100 mg/kg of the compound of Example 3 was subcutaneously administered to the experimental group, and corn oil was administered to the control group.
  • Figure 4 exemplarily shows the diuretic effect and non-urea excretion of a single subcutaneous injection of the compound of Example 3 of the present invention in mice. Place the mice in the metabolic cage, and collect the urine for 0 ⁇ 2h as the baseline urine output. Then 100 mg/kg of the compound of Example 3 was subcutaneously administered to the experimental group, and corn oil was administered to the control group.
  • Figure 5 exemplarily shows the diuretic effect and non-urea excretion of the compound of Example 3 of the present invention after a single intragastric administration in rats. Put the rat into a metabolic cage, and receive 0 ⁇ 2h urine as the basal urine output. Then, 100 mg/kg of the compound of Example 3 was administered to the experimental group by gavage, and sodium carboxymethyl cellulose was administered to the control group.
  • the compound of Example 3 is compared with the base level.
  • Figure 7 exemplarily shows the diuretic effect of the compound of Example 3 of the present invention after long-term gastric administration of rats and mice.
  • Rats and mice were placed in metabolic cages, and one day’s urine was taken as the basic level of urine output.
  • the experimental group was given 100 mg/kg of the compound of Example 3 by gavage, and the control group was given sodium carboxymethyl cellulose three times a day (first (Doubling the dose), continuously administered for 7 days, and after the last administration, the renal inner and outer medulla were taken for analysis.
  • A Mouse urine volume (left); mouse urine osmolality (right).
  • B Rat urine volume (left); rat urine osmolality (right).
  • C Urea excretion in rats (left); non-urea solute excretion in rats (right).
  • Figure 8 exemplarily shows the verification of the toxicity of the compound of Example 3 of the present invention.
  • CCK-8 was used to detect cell viability. Rats and mice were placed in metabolic cages. The experimental group was given 100 mg/kg of the compound of Example 3 by gavage, and the control group was given carboxymethyl cellulose sodium three times a day (the first dose was doubled) for 7 consecutive days and the body weight was observed After the last administration, blood, kidney, and liver tissues were taken for analysis.
  • A: cell survival rate; B: body weight of rats and mice; C: rat blood urea; D: rat kidney index (left), rat liver weight index (right); E: rat kidney morphology. Data are expressed as mean ⁇ standard error; n 8; *P ⁇ 0.05, ***P ⁇ 0.001 represents compared with the control group.
  • alkyl refers to a group consisting only of carbon atoms and hydrogen atoms and having no unsaturation (such as double bonds, triple bonds or rings), which covers various possible geometric differences. Structural groups and stereoisomeric groups. This group is connected to the rest of the molecule through a single bond.
  • alkyl groups the following linear or branched groups can be cited: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl , N-pentyl and its other seven isomers, n-hexyl and its other sixteen isomers.
  • C 1-6 alkyl includes methyl, ethyl, propyl, butyl, pentyl, hexyl and all of them isomer.
  • alkenyl refers to a linear, branched or cyclic unsaturated hydrocarbon radical atomic group having at least one carbon-carbon double bond.
  • C 2-6 alkenyl includes alkenyl groups having a chain of 2 to 6 carbons and at least one double bond (e.g., vinyl, allyl, propenyl, isopropenyl, 1-butenyl, 2 -Butenyl, 3-butenyl, 2-methylallyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, etc.).
  • alkynyl used in the present invention refers to an unsaturated hydrocarbon group atomic group having at least one carbon-carbon triple bond.
  • C 2-6 alkynyl groups include alkynyl groups having a chain of 2 to 6 carbons and at least one triple bond (e.g., ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, Isopentynyl, 1,3-hexadiynyl, n-hexynyl, 3-pentynyl, 1-hexen-3-ynyl, etc.).
  • cyclic group used in the present invention refers to a saturated non-aromatic ring system composed of at least 3 carbon atoms.
  • the ring system can be monocyclic, bicyclic, polycyclic, fused, bridged, or spirocyclic.
  • cycloalkyl groups the following groups can be cited: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; and those formed by two or more of the above-mentioned monocyclic rings through a common edge and a common carbon atom Condensed ring, bridged ring or spiro ring group.
  • alkoxy used in the present invention refers to a group in which an oxygen atom is connected to the above-mentioned alkyl group and is connected to the rest of the molecule by a single bond through the oxygen atom, which covers various possible geometrically isomeric groups With stereoisomeric groups.
  • alkoxy groups the following linear or branched groups can be cited: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, S-butoxy, tert-butoxy, n-pentoxy and its other seven isomers, n-hexyloxy and its other sixteen isomers.
  • aryl used in the present invention refers to an aromatic 5-membered to 10-membered monocyclic ring, an 8-membered to 12-membered fused bicyclic ring or an 11-membered to 14-membered fused tricyclic ring system.
  • a 5-membered or 6-membered aryl group means that the number of carbon atoms in the ring system is 5 or 6.
  • 1, 2, 3, or 4 hydrogen atoms in each ring may be substituted with substituents.
  • heteroaryl refers to a 5-14 membered aromatic heterocyclic ring system having one or more heteroatoms independently selected from N, O or S.
  • the ring system may be monocyclic, Bicyclic and polycyclic rings, among which the bicyclic and polycyclic rings can be formed by single rings connected by single bonds or condensed.
  • heteroaryl groups the following groups can be cited: oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl , Tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, Benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pterridinyl, purinyl, quinoxalinyl, thiol Diazolyl, indolazinyl, acri
  • heterocyclic group refers to a non-aromatic 3-15 membered ring system composed of carbon atoms and heteroatoms independently selected from N, O or S.
  • the ring system can be monocyclic, bicyclic or
  • a polycyclic ring may also be a fused ring, a bridged ring, or a spiro ring, and may optionally contain one or more double bonds.
  • heterocyclic groups the following groups can be cited: oxirane, sulfiethane, aziridinyl, oxetanyl, thietane, aza Cyclobutanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathiolane Hexyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathiocyclohexyl, 3,4-dihydro-2H-pyranyl, 5,6- Dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyridyl, 1,2,5,6-tetrahydropyridyl.
  • halogen used in the present invention means fluorine, chlorine, bromine or iodine.
  • N-(alkyl)amino or N,N-di(alkyl)amino used in the present invention means -NH alkyl or -N (alkyl) 2 respectively , for example, -NHCH 3 , -N( CH 3 ) 2 and so on.
  • an alkylsulfonyl group is a sulfonyl group further substituted by an alkyl group, where the alkane
  • the base is as defined above.
  • prevention or treatment means administering the compound or formulation described in this application to prevent, ameliorate or eliminate a disease or one or more symptoms related to the disease, and includes:
  • terapéuticaally effective amount means capable of (i) treating or preventing a specific disease, condition or disorder, (ii) reducing, ameliorating or eliminating one or more symptoms of a specific disease, condition or disorder, or (iii) preventing or The amount of the compound of the present application that delays the onset of one or more symptoms of the specific disease, condition, or disorder described herein.
  • the amount of the compound of the present application that constitutes a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but it can be routinely determined by those skilled in the art. Determined by its own knowledge and this disclosure.
  • the present invention describes the use of the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, in the preparation of drugs as urea channel inhibitors,
  • Ring A and Ring B are each independently a 5- to 6-membered heteroaryl group or a 5- to 6-membered aryl group;
  • Said ring A and ring B are optionally substituted by R 1 and R 2 respectively;
  • R 1 is selected from the group consisting of the following groups: nitro, halogen, alkyl, alkylcarbonyl, alkylcarbonylamino, alkylsulfonyl and pyrido;
  • R 2 is selected from the group consisting of halogen, hydroxy, amino, cyano, alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy, alkylcarbonyl, alkoxy carbonyl group, and pyridyl group
  • R 5 is optionally substituted alkyl carbonyl group
  • R 5 is optionally substituted heterocyclic group or cycloalkyl group
  • R 5 is optionally substituted heteroarylcarbonyl group, N -Alkylamino, N,N-di(alkyl)amino, and aminocarbonyl substituted by R 3 and R 4 ;
  • R 3 and R 4 are each independently selected from the group consisting of H, hydroxyl, alkyl, heterocyclic group or cyclic group optionally substituted by R 5 , and optionally R 5 Substituted heterocyclyl or cycloalkyl, heteroaryl or arylalkyl optionally substituted by R 5 , N-(alkyl)aminoalkyl, and N,N-bis(alkyl)aminoalkyl Base; and
  • R 5 is selected from the group consisting of: alkyl, nitro, alkylcarbonylamino, N-(alkyl)amino, N,N-bis(alkyl)amino, N,N-bis( Alkyl)aminoalkylamino, and heterocyclic group or cyclic group.
  • each group above satisfies one or more of the following:
  • R 1 is selected from the group consisting of the following groups: nitro, halogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonyl Acyl and pyrido groups;
  • R 2 is selected from the group consisting of the following groups: halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxy C 1-6 alkane Group, amino C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, pyrido, C 1- optionally substituted by R 5 6 alkylcarbonylamino, R 5 is optionally substituted 5- to 6-membered heterocyclic group or cycloalkyl group, R 5 is optionally substituted 5- to 6-membered heteroaryl carbonyl amino, N- (C 1-6 Alkyl)amino, N,N-bis(C 1-6 alkyl)amino, and aminocarbonyl substituted by R 3 and R 4 ;
  • R 3 and R 4 are each independently selected from the group consisting of H, hydroxyl, C 1-6 alkyl, 5- to 6-membered heterocyclic group optionally substituted by R 5 or ring group, R 5 is optionally substituted 5- to 6-membered heterocyclic group or cyclic C 1-6 alkyl group, R 5 is optionally substituted 5 to 6 membered heteroaryl or aryl C 1-6 alkyl Group, N-(C 1-6 alkyl)amino C 1 -C 6 alkyl, and N,N-bis(C 1-6 alkyl)amino C 1-6 alkyl; and
  • R 5 is selected from the group consisting of the following groups: C 1-6 alkyl, nitro, C 1-6 alkylcarbonylamino, N-(C 1-6 alkyl)amino, N,N-di (C 1-6 alkyl)amino, N,N-bis(C 1-6 alkyl)amino, C 1-6 alkylamino, and 5- to 6-membered heterocyclic group or cyclic group.
  • the heteroatoms of the heteroaryl group and the heterocyclic group are independently selected from O, S, and/or N, and the number of heteroatoms is an integer selected from 1, 2, and 3.
  • the heteroaryl group is selected from the group consisting of furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, oxazolyl, isooxanyl Azolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzofuranyl, benzo Thienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, indolyl.
  • the heterocyclic group is selected from the group consisting of piperidinyl, dioxanyl, oxathinyl, morpholinyl, piperazinyl .
  • the cyclic group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • the ring A and ring B are each independently selected from the group consisting of the following heteroaryl groups or aryl groups: furyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, Pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl.
  • the definitions of ring A and ring B satisfy one or more of the following:
  • the ring A is selected from the group consisting of the following heteroaryl or aryl groups: furyl, thienyl, pyrrolyl, oxazolyl, pyrazolyl, phenyl; and
  • the ring B is selected from the group consisting of thienyl, oxazolyl, isoxazolyl, pyrazolyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl.
  • R 6 is selected from the group consisting of the following groups consisting of: hydroxy, halogen, C 1 -C 6 alkyl, C 1 - C 6 alkoxycarbonyl, C 1 -C 6 alkylaminocarbonyl, or R 6 forms an oxo 5-membered or 6-membered nitrogen heterocycle with the ring on which it is located through a covalent bond, and the nitrogen heterocycle is optionally R 5 Replace.
  • the compound represented by formula (I), or a pharmaceutically acceptable salt thereof is selected from the following compounds (1) to (79), or a pharmaceutically acceptable salt thereof Group:
  • the drug is a drug used to treat or prevent a disease related to a urea channel protein inhibitor; preferably, the drug is a diuretic, an antihypertensive drug and/or a drug used to study urea channel protein Tool medicine;
  • the urea channel protein is UT-B protein or UT-A protein.
  • the disease related to the channel urea channel protein inhibitor of the present invention is an edema disease related to the channel urea channel protein inhibitor; wherein, the edema disease preferably includes: cardiogenic edema, preferably The cardiogenic edema is cardiogenic edema due to congestive heart failure and/or constrictive pericarditis; nephrogenic edema, preferably the renal edema is due to acute glomerulonephritis , Chronic glomerulonephritis, nephrotic syndrome, renal arteriosclerosis and/or nephrogenic edema of renal tubular disease; hepatogenic edema, preferably the hepatogenic edema is due to liver cirrhosis, liver necrosis, Hepatogenic edema of liver cancer and/or acute hepatitis; dystrophic edema, preferably said dystrophic edema is due to primary food intake, secondary malnutrition, digestion and absorption
  • the diseases related to urea channel protein inhibitors of the present invention are non-edematous diseases related to urea channel protein inhibitors; wherein, the non-edematous diseases preferably include: heart failure, preferably congestion Heart failure, acute heart failure, chronic heart failure; cardiovascular and cerebrovascular diseases, preferably mild hypertension, moderate hypertension, senile systolic hypertension, hypertension combined with heart failure.
  • heart failure preferably congestion Heart failure, acute heart failure, chronic heart failure
  • cardiovascular and cerebrovascular diseases preferably mild hypertension, moderate hypertension, senile systolic hypertension, hypertension combined with heart failure.
  • the present invention also describes a method for treating or preventing diseases associated with urea channel protein inhibitors, the method comprising administering to a patient in need a therapeutically effective amount of formula (I) according to the present invention
  • the compound shown, or a pharmaceutically acceptable salt thereof is administered to a patient in need a therapeutically effective amount of formula (I) according to the present invention.
  • the present invention also describes the compound represented by formula (I) according to the present invention, or a pharmaceutically acceptable salt thereof, for the treatment of diseases related to urea channel protein inhibitors.
  • the present invention also describes the compound represented by formula (I) according to the present invention, or a pharmaceutically acceptable salt thereof, used as a urea channel protein inhibitor.
  • the present invention also describes the use of the compound represented by formula (I) according to the present invention, or a pharmaceutically acceptable salt thereof, in the treatment of diseases related to urea channel protein inhibitors.
  • the present invention describes a diarylamide compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of The group consisting of the following compounds, or pharmaceutically acceptable salts thereof:
  • the present invention describes a pharmaceutical composition
  • a pharmaceutical composition comprising: the above-mentioned diarylamide compound or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • pharmaceutical composition refers to a mixture comprising one or more of the compounds of the application or their salts and a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound of the present application to the organism.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reactions or other problems or complications of the disease are commensurate with a reasonable benefit/risk ratio.
  • the pharmaceutically acceptable salts of the diarylamide compounds of the present invention include acid addition salts formed with inorganic or organic acids, such as nitric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, Phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, fumaric acid, lactic acid, oxalic acid, malonic acid, malic acid, maleic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonate Acid, isethionine and salicylic acid.
  • inorganic or organic acids such as nitric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, Phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, fumaric acid, lactic acid, oxalic acid, malonic acid, malic acid, maleic
  • the pharmaceutically acceptable salts of the diarylamide compounds of the present invention also include salts formed with inorganic or organic bases, such as alkali metals or alkaline earth metals, especially sodium, potassium, calcium, ammonium or Magnesium hydroxide, carbonate or bicarbonate, acyclic or cyclic amines, preferably methylamine, ethylamine, diethylamine, triethylamine, piperidine and the like.
  • alkali metals or alkaline earth metals especially sodium, potassium, calcium, ammonium or Magnesium hydroxide, carbonate or bicarbonate, acyclic or cyclic amines, preferably methylamine, ethylamine, diethylamine, triethylamine, piperidine and the like.
  • the pharmaceutically acceptable carrier of the present invention includes but is not limited to: water, salt solution, alcohol, polyethylene glycol, polyhydroxy ethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, gypsum powder , Sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or cellulose lower alkyl ether, silicic acid, Fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid ethers, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the pharmaceutical composition may further include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifiers, suspending agents, preservatives, osmotic pressure regulators, buffers, sweeteners. Agent, flavoring agent, coloring agent or any combination of the above.
  • composition of the present invention can be prepared into any form of preparations, such as capsules, tablets, aerosols, solutions, suspensions, sugar coatings, lozenges, syrups, emulsions, ointments, ointments, injections, powders , Granules, pastes, sustained release agents, foams.
  • the medicament of the present invention can be made into oral administration preparations, nasal administration preparations, pulmonary administration preparations, oral cavity preparations, subcutaneous administration preparations, intradermal administration preparations, transdermal administration preparations , Parenteral administration preparations, rectal administration preparations, reservoir administration preparations, intravenous administration preparations, intraurethral administration preparations, intramuscular administration preparations, intranasal administration preparations, ocular administration preparations, Epidural formulations or topical formulations.
  • the compound of the present invention and its composition can inhibit the permeation of urea channel protein UT-B-mediated red blood cell membrane to urea, and its effect is in a dose-dependent relationship; in vivo test results show that the compound of the present invention is administered by intragastric or subcutaneous administration After the drug, it can significantly increase the urine output of rats and mice, reduce its osmotic pressure, and does not cause changes in the excretion of non-urea solutes; it can reduce the concentration of urea in the renal medulla of rats and mice, but does not cause changes in the concentration of non-urea solutes This indicates that the compound of the present invention can produce urea-selective diuretic effect in the body without obvious toxicity.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 81%, melting point 233-234°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 63%, melting point 178-180°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 56%, melting point 296°C (decomposition).
  • the synthesis method is the same as in Example 10. The yield is 63%, and the melting point is 205-208°C.
  • the synthesis method is the same as in Example 10.
  • the yield is 45%, and the melting point is 230-232°C.
  • the synthesis method is the same as in Example 10.
  • the yield is 36%, and the melting point is 211-212°C.
  • the synthesis method is the same as in Example 10.
  • the yield is 22%, and the melting point is 207-208°C.
  • the synthesis method is the same as in Example 10.
  • the yield was 51%, and the melting point was 209-211°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 65%, melting point 214-215°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 57%, melting point 212-214°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 85%, melting point 218-219°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 87%, melting point 209-211°C.
  • the synthesis method is the same as in Example 1. Yellow crystal, yield 64%, melting point 212-213°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 77%, melting point 212-214°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 72%, melting point 142-144°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 91%, melting point 123-124°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 72%, melting point 185-187°C.
  • the synthesis method is the same as in Example 5A. Ethanol was recrystallized to obtain a yellow solid with a yield of 89% and a melting point of 226-228°C.
  • the synthesis method is the same as in Example 5A. Yellow solid, yield 86%, melting point 247-249°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 86%, melting point 153-154°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 80%, melting point 179-180°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 58%, melting point 193-194°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 77%, melting point 221-223°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 84%, melting point 238-240°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 87%, melting point 297°C (decomposition).
  • the synthesis method is the same as in Example 1. Yellow solid, yield 95%, melting point 182-183°C.
  • the synthesis method is the same as in Example 1. Brown solid, yield 63%, melting point 202-205°C.
  • the synthesis method is the same as in Example 1. Brown solid, yield 35%, melting point 208-209°C.
  • the synthesis method is the same as in Example 1. Brown solid, yield 71%, melting point 185-186°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 70%, melting point 250-252°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 85%, melting point 197-199°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 45%, melting point 191-192°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 48%, melting point 249-252°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 69%, melting point 165-167°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 85%, melting point 149-150°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 68%, melting point 156-158°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 65%, melting point 225-226°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 63%, melting point 195-198°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 35%, melting point 195-198°C.
  • Example 5A The synthesis method is the same as in Example 5A. Yellow solid, yield 30%, melting point 260-262°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 55%, melting point 151-153°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 50%, melting point 252-254°C.
  • Example 71 The synthesis method of Example 71 is the same as that of Example 5A. Yellow solid, yield 68%, melting point 207-209°C.
  • the synthesis method is the same as in Example 72. Yellow solid, yield 32%, melting point 255-257°C.
  • the synthesis method is the same as in Example 71. Yellow solid, yield 30%, melting point 213-215°C.
  • the synthesis method is the same as in Example 1. Yellow solid, yield 89%, melting point 214-215°C.
  • Example 5A The synthesis method is the same as in Example 5A. Yellow solid, yield 48%, melting point 174-175°C.
  • the synthesis method is the same as in Example 5A. Yellow solid, yield 30%.
  • the red blood cell suspension is incubated at room temperature for 2 hours to balance the urea concentration inside and outside the cell, and mix with a pipette regularly;
  • Each microplate has a positive control well (non-specific UT-B inhibitor phloretin) and a negative control well (PBS).
  • Photometric value, A pos is the absorbance value of the positive control well.
  • the red blood cell lysis rate is calculated by measuring the absorption wavelength 710.
  • the present invention first screened 1,040 compounds that may have UT-B inhibitory activity based on the molecular structure of UT-B protein by computer simulation.
  • the above compounds were dissolved in DMSO and placed in 96-well micropores.
  • the application solution diluted to 1mM in the plate is used as a screening compound library.
  • red blood cells of three species of human, rat (SD rat) and mouse (C57 mouse) were taken, and the red blood cell urea channel inhibitor screening model was used to conduct preliminary screening of urea channel inhibitors on the above-mentioned screening compound library to screen compounds
  • concentration is 10 ⁇ M, and the screening is repeated once to determine the lead compound.
  • the clue compound specifically inhibits the urea channel
  • red blood cells were equilibrated with isotonic PBS or PBS containing 1.25M urea, and the clue compound (10 ⁇ M) was incubated with the clue compound (10 ⁇ M) and quickly transferred to isotonic PBS to detect the lysis rate of red blood cells.
  • the result is that the red blood cells incubated with isotonic PBS did not see obvious lysis, while the red blood cells incubated with 1.25M urea PBS were lysed. It indicates that the rupture of red blood cells is caused by the clue compound specifically inhibiting the urea permeability of urea channel protein.
  • Example 3 After analysis and comparison, the compound of Example 3, which has a good inhibitory effect on the three species, was selected as an exemplary preferred compound (Figure 2A to Figure 2C).
  • Example 3 In order to determine the inhibitory effect of the compound of Example 3 on UT-A, MDCK cells stably expressing UT-A1 were cultured into a compact monolayer in Transwell, and forskolin was used to stimulate the transfer of UT-A protein to the plasma membrane, using Example 3 After the compound was incubated for 15 minutes, the culture medium under the Transwell was replaced with a culture medium containing 15 mM urea, and the urea concentration in the culture medium on the Transwell was detected at a specific time to evaluate the inhibitory effect of the compound of Example 3 on the permeability of UT-A urea.
  • the compound of Example 3 shows obvious diuretic effect.
  • the urine output began to increase 2h after administration, the peak of diuretic effect was 4h after administration, and the duration of diuretic effect was about 6-8h.
  • the collected urine is measured with a freezing point osmometer. Using time as the abscissa and urine osmotic pressure as the ordinate, the curve is drawn, and the result is shown in Fig. 5B; compared with the solvent control group, the compound of Example 3 can significantly reduce the urine osmotic pressure.
  • the peak of action was 4h after administration, and returned to the level before administration at 6-8h after administration.
  • the present inventors further observed the long-term diuretic effect of the compound of Example 3.
  • 100 mg/kg of the compound of Example 3 was administered intragastrically (doubled for the first dose), once every 8 hours, solvent control: 0.5% sodium carboxymethyl cellulose (CMC-Na).
  • Urine was collected every 24h and transferred to a pre-weighed test tube. The drug was administered for 7 days, and the body weight was recorded. The results are shown in Figure 7.
  • the weight loss method measures the weight of urine and converts it to volume (1g ⁇ 1ml).
  • the urine output of the compound of Example 3 began to increase on the first day after administration and continued until the 7th day.
  • the osmotic pressure of urine was measured using a freezing point osmometer. Using time as the abscissa and urine osmotic pressure as the ordinate, the curve is drawn, and the results are shown in Figure 7B.
  • the urine osmotic pressure of the compound administration group of Example 3 began to decrease on the first day and continued until day 7. , Indicating that the continuous administration of the compound of Example 3 can reduce the osmotic pressure of the rat's urine.
  • the CCK-8 kit was used to complete the MDCK cytotoxicity test. The result is shown in Figure 8A, which shows that the compound of Example 3 has no significant cytotoxic effect.
  • the CCK-8 kit was used to detect compound cytotoxicity: MDCK cell suspension in logarithmic growth phase was inoculated into 96-well culture plate (1 ⁇ 10 4 cells/well/100 ⁇ l), and 100 ⁇ l containing 10% fetus was given to each well. Bovine serum, 100U/ml penicillin and 100 ⁇ g/ml streptomycin in DMEM culture solution were cultured in a 37°C, 5% CO 2 incubator.
  • the urea kit was used to detect the effect of the compound of Example 3 on the serum urea level after long-term administration, and it was found that there was no significant statistical difference compared with the control group (Figure 8C).
  • the kidney tissue was immersed in a fixative solution (4% paraformaldehyde), embedded in a paraffin embedding machine, and then cut into 6 ⁇ m thick paraffin sections using a paraffin microtome.
  • the sections were observed under an optical microscope.
  • the inner medulla, outer medulla, and cortex of each kidney were compared and observed with an optical microscope. It was found that the compound of Example 3 did not significantly affect the histological morphology of the kidney. However, because the compound of Example 3 exerts a significant diuretic effect, the compound of Example 3 was administered internally. Tubule swelling appeared in the marrow. Blood was collected by cardiac puncture, serum was obtained after centrifugation, and the instrument was used to measure serological indicators. It was found that the compound of Example 3 did not affect glucose metabolism and lipid metabolism (Table 2).
  • * "++++” means that the compound's IC 50 value to human UT-B is ⁇ 10 ⁇ M, and the inhibitory activity is "strong”;
  • +++” means that the compound's IC 50 value to human UT-B is >10 ⁇ M and ⁇ 20 ⁇ M, which inhibits "Strong”activity;
  • ++” indicates that the compound has an IC 50 value of >20 ⁇ M and ⁇ 80 ⁇ M against human UT-B, and the inhibitory activity is "moderate”; and “+” indicates that the compound has an IC 50 value of human UT-B >80 ,
  • the inhibitory activity is "weak", and the lysis rate of mouse red blood cells of the compound of Example 6 at 80 ⁇ m is 40%.

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Abstract

具有式(I)所示结构的二芳基酰胺类化合物、其药学上可接受的盐在制备作为尿素通道蛋白抑制剂的药物中的用途以及一类新型的二芳基酰胺类化合物，所述二芳基酰胺类化合物具有尿素通道蛋白抑制剂作用，能够在体内产生尿素选择性利尿并且没有明显的毒性作用。

Description

二芳基酰胺类化合物及其应用
相关申请的交叉引用
本申请要求于2019年6月19日向中国国家知识产权局提交的第201910531710.X号中国专利申请的优先权和权益，所述申请公开的内容通过引用整体并入本文中。
技术领域
本发明涉及利尿药领域，具体涉及二芳基酰胺类化合物、其药学上可接受的盐及其在制备作为尿素通道蛋白抑制剂的药物中的用途。
背景技术
1.利尿药目前应用和研发热点
利尿药作用于肾脏，可增加水的排出。临床上主要用于治疗各种原因引起的水肿，也可用于治疗一些非水肿性疾病，如作为一线药可单独使用或与其他药物配伍使用治疗高血压，降低心脑血管疾病的发生率和病死率。按照利尿药作用部位的不同，可以将利尿药分为保钾利尿药、噻嗪类利尿药、袢利尿药和碳酸酐酶抑制剂。以阿米洛利和氨苯蝶啶为代表的保钾利尿药主要是直接通过阻碍Na +、K +和H +的交换，发挥利尿活性。另外，保钾利尿药还可以通过间接调节醛固酮的水平发挥利尿活性。噻嗪类利尿药主要是通过作用于远曲小管和集合管的Na +-Cl -共转运体，阻碍NaCl的重吸收发挥利尿活性。袢利尿药作用于髓袢的Na +-K +-2Cl -共转运体，阻碍NaCl的重吸收发挥利尿活性。由于该部位是NaCl重吸收的主要部分，对尿浓缩具有显著的影响。因此，袢利尿药具有较强效的利尿活性。但在发挥利尿作用的同时会导致Na +、K +、Cl -排出增多，因此长期使用利尿药会导致水电解质失衡、血容量不足、代谢性酸碱失衡和血脂血糖紊乱等不良反应。所以研发不引起电解质紊乱的新型利尿药是利尿药物研发领域的热点。
血管加压素V2受体拮抗药是一类特异性拮抗加压素与其受体结合的药物，可使肾脏集合管主细胞内囊泡中水通道蛋白2(AQP2)磷酸化并使其插入细胞顶质膜，增加集合管中水的重吸收，从而发挥利尿作用，适用于正常容量性及高容量性低钠血症等疾病，但由于V2受体下游通路较为复杂，会引起肝毒性等不良反应，因此其作为一种利尿药也不完全理想。因此，我们希望寻找一种新型利尿药，其在发挥利尿作用的同时且不引起电解质紊乱等副作用。
尿素通道蛋白(urea transporter，UT)是一种特异性通透尿素的跨膜蛋白，在尿浓缩机制中发挥非常重要作用，选择性敲除尿素通道可阻断肾内尿素循环通路，降低尿浓缩能力，在不影响Na +、K +、Cl -排泄的情况下，产生尿素选择性利尿作用。因此，尿素通道蛋白抑制剂可作为利尿药，在不明显影响机体电解质平衡的情况下，减低肾内尿素循环建立的肾内渗透压差，从而产生利尿作用，用于治疗不同病因(如充血性心力衰竭、肝硬化、肾病综合征等)的水肿疾病患者和非水肿性疾病(如心力衰竭、心脑血管疾病等)患者。
2.尿浓缩机制和肾内尿素循环过程
正常人每天形成的原尿约有180升，而实际每天排出的终尿量只有1.5升左右。尿素是尿液中含量最丰富的溶质，占尿中溶质总量的40～50％，尿中尿素浓度可高达血浆尿素浓度的100倍以上[Yang B and Bankir L.Renal handling of urea in transgenic mice lacking the urea transporter UT-B,Am J Physiol Renal Physiol,2005,288:F881-F896]。尿素是参与尿浓缩机制的主要溶质，其以肾内尿素循环机制，通过逆流倍增和逆流交换过程，浓度由外髓向内髓组织逐渐增加，和氯化钠一起形成肾皮质至肾髓质的渗透压梯度，从而使肾脏能够有效地浓缩尿液使水和某些溶质有效地被回吸收。肾脏内尿素循环机制具体包括：(1)集合管在加压素调控下对水的重吸收和对尿素的不通透，导致尿素在集合管内高度浓缩；(2)内髓集合管末端对尿素渗透性的增加，使高浓度的尿素渗透到内髓的间质组织；(3)髓质尿素通过内髓的直小血管升支不断的被血液带向肾脏皮质，又通过直小血管降支和髓袢降支细段特定区段对尿素的通透被重新带回髓质，从而维持从肾皮质至肾髓质的尿素梯度和渗 透压梯度，此过程在尿浓缩机制中具有非常重要的作用[Sands JM.Renal urea transporters,Curr Opin Nephrol Hypertens,2004,13:525–532]，除内髓的直小血管升支内皮细胞以微孔方式通透尿素外，上述各部分对尿素的通透性均由尿素通道介导[Smith CP and Rousselet G.Facilitative Urea transporters,J MembrancBiol,2001,183:1-14]。
尿素通道是特异性通透尿素的膜通道蛋白。目前已经克隆了7个成员，分别属于UT-A和UT-B两个亚家族，UT-A亚家族包括6个成员(UT-A1至UT-A6)由同一基因(Slc14a2)经不同启动子调控和转录后剪切所产生[Bagnasco SM.Gene structure of urea transporters,Am J Physiol,2003,284:F3–F10；Shayakul C and Hediger MA.The SLC14 gene family of urea transporters,Pfluegers Arch,2004447:603–609]，UT-B亚家族只有一个成员UT-B。有5个尿素通道蛋白在肾脏不同部位的表达，UT-A1、UT-A3和UT-A4(UT-A4仅在大鼠表达)在肾脏集合管上皮细胞表达，UT-A2在肾脏髓袢降支细段表达，UT-A5、UT-A6分别在睾丸、结肠中表达。UT-B由另一基因(Slc14a1)表达，定位于肾脏直小血管降支内皮细胞、红细胞和多个组织器官。UT-A1、UT-A2、UT-A3、UT-A4和UT-B介导肾内尿素循环相应部位的尿素通透性，在肾内尿素循环过程中起重要作用，参与尿浓缩机制。
3.尿素通道功能性敲除可产生尿素选择性利尿和降低血压
利用尿素通道基因敲除小鼠模型[Yang B,Bankir L,Gillepsie A.Urea-selective concentrating defect in transgenic mice lacking urea transporter UT-B,J Biol Chem,2002,277:10633-10637]进行的肾脏生理学研究结果表明，缺失UT-B的小鼠未表现出生长发育异常。UT-B敲除不影响肾小球滤过率、肾脏重量以及尿中尿素以外其他主要溶质(Na +、K +、Cl -)的清除率。但其尿浓缩能力发生了明显改变：尿量增加、尿渗透压降低、尿尿素和血尿素浓度比值仅为野生型小鼠的50％。实验结果表明，UT-B在肾脏直小血管介导的尿素转运占肾脏总尿浓缩能力的三分之一[Bankir L,Chen K and Yang B.Renal handling of urea in transgenic mice lacking the urea transporter UT-B,Am J Physiol,2004,286:F144-F151]。UT-Al/UT-A3基因缺失小鼠在基础条件下，尿浓缩能力下降到野生型小鼠尿浓缩能力的35％，其尿量比野生型小鼠高3倍。而且在严格控制摄入液体5天后，它们的尿渗透压并没有提高。UT-A1/UT-A3基因敲除小鼠尿素在肾脏内髓的积聚也显著减少(为正常水平的1/3)[Fenton RA,Chou CL,Stewart GS.Urinary concentrating defect in mice with selective deletion of phloretin-sensitive urea transporters in the renal collecting duct,Proc Natl Acad Sci,2004,101:7469-7474；Fenton,R.A.,Flynn A,Shodeinde A.Renal phenotype of UT-A urea transporter knockout mice,J Am Soc Nephrol.2005,16:1583-1592]。全部UT敲除小鼠表现出显著性的多尿，日均尿量大约为野生型小鼠的3倍；禁水后，野生型小鼠的尿渗透压升高明显，而全部UT敲除小鼠的尿渗透压升高较平缓。因此，HE染色切片显示，野生型小鼠和全部UT敲除小鼠的肾脏皮质和外髓没有任何组织学异常，在全部UT敲除小鼠的肾脏内髓可以观察到集合管扩张，而野生型小鼠则没有这种现象[Jiang,T.,Li,Y.,Layton,A.T.,Wang,W.,Sun,Y.,Li,M.,Zhou,H.,and Yang,B.(2017).Generation and phenotypic analysis of mice lacking all urea transporters.Kidney Int 91,338-351]。因此，选择性敲除UT-B或UT-A1/UT-A3可阻断肾内尿素循环通路，降低尿浓缩能力，在不影响Na +、K +、Cl -的情况下，产生尿素选择性利尿作用。因此，尿素通道蛋白抑制剂可以作为利尿药作用于肾脏，可增加水的排出，从而在临床上用来治疗充血性心衰、肾病综合征、水肿等水潴留性疾病。
发明内容
本发明通过计算机高通量筛选和合理的药物设计方式，发现一类二芳基酰胺类化合物、其药学上可接受的盐，该类化合物具有良好的尿素通道蛋白抑制活性和优异的成药性。
作为本发明的第一方面，本发明描述了式(I)所示的化合物、或其药学上可接受的盐在制备作为尿素通道蛋白抑制剂的药物中的用途，
Figure PCTCN2020096939-appb-000001
其中，
环A和环B分别独立地为5～6元杂芳基或5～6元芳基；
所述环A和环B分别任选地被R 1和R 2取代；
R 1选自于由如下基团所组成的组：硝基、卤素、烷基、烷基羰基、烷基羰基氨基、烷基磺酰基以及吡啶并基；
R 2选自于由如下基团所组成的组：卤素、羟基、氨基、氰基、烷基、烯基、炔基、羟基烷基、氨基烷基、烷氧基、烷基羰基、烷氧基羰基、吡啶并基、任选地被R 5取代的烷基羰基氨基、任选地被R 5取代的杂环基或环基、任选地被R 5取代的杂芳基羰基氨基、N-烷基氨基、N,N-二(烷基)氨基、以及被R 3和R 4取代的氨基羰基；
其中，R 3和R 4各自独立地选自于由如下基团所组成的组：H、羟基、烷基、任选地被R 5取代的杂环基或环基、任选地被R 5取代的杂环基或环基烷基、任选地被R 5取代的杂芳基或芳基烷基、N-(烷基)氨基烷基、以及N,N-二(烷基)氨基烷基；以及
R 5选自于由如下基团所组成的组：烷基、硝基、烷基羰基氨基、N-(烷基)氨基、N,N-二(烷基)氨基、N,N-二(烷基)氨基烷基氨基、以及杂环基或环基。
作为本发明的第二方面，本发明还描述了一种治疗或预防与尿素通道蛋白抑制剂相关的疾病的方法，所述方法包括向有需要的患者给予治疗有效量的根据本发明的式(I)所示的化合物、或其药学上可接受的盐。
作为本发明的第三方面，本发明还描述了用于治疗或预防与尿素通道蛋白抑制剂相关的疾病的根据本发明的式(I)所示的化合物、或其药学上可接受的盐。
作为本发明的第四方面，本发明还描述了用作尿素通道蛋白抑制剂的根据本发明的式(I)所示的化合物、或其药学上可接受的盐。
作为本发明的第五方面，本发明还描述了根据本发明的式(I)所示的化合物、或其药学上可接受的盐在治疗与尿素通道蛋白抑制剂相关的疾病中的用途。
作为本发明的第六方面，本发明描述了一种二芳基酰胺类化合物、或其药学上可接受的盐，所述二芳基酰胺类化合物、或其药学上可接受的盐选自于由下述化合物、或其药学上可接受的盐所组成的组：
(15)N-(哒嗪-3-基)-5-硝基呋喃-2-甲酰胺；
(17)N-(噻吩-3-基)-5-硝基呋喃-2-甲酰胺；
(25)N-(4-乙酰氨基苯基)-5-甲磺酰基呋喃-2-甲酰胺；
(26)N-(2-乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
(51)N-(4-氨甲基苯基)-5-硝基呋喃-2-甲酰胺；
(53)N-(3-(甲氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(55)N-(3-(乙氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(56)N-(3-(异丙氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(57)N-(3-(异丁氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(58)N-(3-(环己氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(59)N-(3-(苄氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(60)N-(3-((2-二甲氨基乙基)氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(61)N-(3-((2-吗啉基乙基)氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(62)N-(3-((3-吗啉基丙基)氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(63)N-(4-甲基-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
(64)N-(5-甲基-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
(65)N-(4-氟-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
(66)N-(5-氟-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
(67)N-(4-羟基-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
(68)N 1,N 3-二甲基-5-(5-硝基呋喃-2-甲酰胺基)间苯二甲酰胺；
(69)N-(2-甲基-1,3-二氢-1,3-二氧代-2H-异吲哚-5-基)-5-硝基呋喃-2-甲酰胺；
(70)N-(4-乙酰氨基苯基)-5-乙酰基呋喃-2-甲酰胺；
(71)N-(4-(2-二甲氨基)乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
(72)N-(4-(2-吗啉基)乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
(73)N-(4-(3-二甲氨基)丙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
(74)N-(4-((2-二甲氨基)乙基氨基)乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
(75)2-乙酰氨基-5-(5-硝基呋喃-2-甲酰胺)苯甲酸乙酯；
(76)5-(5-硝基呋喃-2-甲酰胺)-1H-吡唑-4-羧酸乙酯；
(77)5-(5-硝基呋喃-2-甲酰胺)-1H-吡唑-3-羧酸乙酯；以及
(78)3-(5-乙酰基-2-呋喃甲酰基)氨基甲酰胺。
作为本发明的第七方面，本发明描述了一种药物组合物，所述药物组合物包含：本发明的第六方面所述的二芳基酰胺类化合物或其药学上可接受的盐；以及药学上可接受的载体。
本发明利用计算机模拟筛选从小分子化合物库中筛选出1040种化合物，利用红细胞裂解模型从中筛出具有UT-B抑制活性的化合物，并结合结构的改造和优化，获得一类具有较强UT-B抑制活性的二芳基酰胺化合物。这类二芳基酰胺化合物具有较强的抑制UT-B及UT-A通透尿素的活性，其在体外对尿素通道UT-B抑制的半数有效剂量在微摩尔水平以下，且没有明显细胞毒性。体内实验发现：皮下和口服给予这类二芳基酰胺化合物可显著增加大鼠和小鼠尿量，降低尿尿素水平，同时降低尿渗透压，表明具有很好的尿素选择性利尿作用，且这类化合物不影响体液电解质平衡。本发明的这类二芳基酰胺化合物具有发展成为新型利尿剂的潜力，且可以避免常规利尿剂常见的电解质紊乱等副作用，可以用来治疗不同病因(如充血性心力衰竭、肝硬化、肾病综合征等)的水肿疾病患者和非水肿性疾病(心力衰竭、心脑血管疾病等)患者。
附图说明
图1为红细胞尿素通道抑制剂筛选模型的示意图。
图2示例性地示出了本发明的实施例3化合物(以下称为实施例3或实施例3化合物)对UT-B及UT-A1通透尿素的抑制作用。A：实施例3化合物的化学结构；B：在红细胞裂解模型中，实施例3化合物对人和大鼠UT-B抑制作用的剂量效应关系；C：在野生型或UT-B敲除小鼠中，PU-48对红细胞尿素通透性抑制的剂量效应关系。D：实施例3化合物对稳定转染UT-B的MDCK细胞尿素转运能力的抑制作用。E：实施例3化合物对稳定转染UT-A1的MDCK细胞尿素转运能力的抑制作用。F：实施例3化合物对稳定转染UT-B或UT-A1的MDCK细胞尿素转运的抑制率。数据表示为平均值±标准误，n＝3；*P＜0.01，代表实施例3化合物对稳定转染UT-B的MDCK细胞的尿素转运的抑制率与对稳定转染UT-A1的MDCK细胞的尿素转运的抑制率相比。
图3示例性地示出了大鼠单次皮下注射本发明实施例3化合物的利尿作用及非尿素的排泄量。将大鼠放入代谢笼中，收集0～2h的尿液作为基础水平尿量。然后皮下给予实验组100mg/kg的实施例3化合物，给予对照组玉米油。A：尿量；B：渗透压；C：非尿素溶质排泄量。结果以平均值±标准误表示，n＝6，*P＜0.05，**P<0.01，***P<0.001代表给实施例3化合物组大鼠相比溶剂对照组大鼠；#P＜0.05，###P＜0.001代表给实施例3化合物后与基础水平相比。
图4示例性地示出了小鼠单次皮下注射本发明实施例3化合物的利尿作用及非尿素的排泄量。将小鼠放入代谢笼中，收集0～2h的尿液作为基础水平尿量。然后皮下给予实验组100mg/kg的实施例3化合物，给予对照组玉米油。A：尿量；B：渗透压；C：非尿素溶质排泄量。结果以平均值±标准误表示，n＝6，*P＜0.05，**P<0.01给实施例3化合物组小鼠相比溶剂对照组小鼠；#P＜0.05是给实施例3化合物后与基础水平相比。
图5示例性地示出了大鼠单次灌胃给药后本发明实施例3化合物的利尿作用及非尿素的排泄量。将大鼠放入代谢笼中，接0～2h的尿液作为基础水平尿量。然后灌胃给予实验组100mg/kg的实施例3化合物，给予对照组羧甲基纤维素钠。A：尿量；B：渗透压；C：非尿素溶质排泄量。结果以平均值±标准误表示，n＝6，*P＜0.05，**P<0.01给实施例3化合物组大鼠相比溶剂对照组大鼠；#P＜0.05，##P＜0.01给实施例3化合物后与基础水平相比。
图6示例性地示出了小鼠单次灌胃给药后本发明实施例3化合物的利尿作用及非尿素的排泄量。将小鼠放入代谢笼中，接0～2h的尿液作为基础水平尿量。然后灌胃给予实验组100mg/kg的实施例3化合物，给予对照组羧甲基纤维素钠。A：尿量。B：渗透压。C：非尿素溶质排泄量。结果以平均值±标准误表示，n＝6，*P＜0.05给实施例3化合物组小鼠相比溶剂对照组小鼠；#P＜0.05是给实施例3化合物后与基础水平相比。
图7示例性地示出了大、小鼠灌长期胃给药后本发明实施例3化合物利尿作用。将大、小鼠放置于代谢笼中，取一天的尿液作为基础水平尿量，实验组灌胃给予100mg/kg的实施例3化合物，对照组给予羧甲基纤维素钠，每天三次(首剂加倍)，连续给药7天，并于末次给药后取肾内髓、外髓进行分析。A：小鼠尿量(左)；小鼠尿渗透压(右)。B：大鼠尿量(左)；大鼠尿渗透压(右)。C：大鼠尿素排泄(左)；大鼠非尿素溶质排泄(右)。D：内、外髓渗透压(左)；内、外髓尿素浓度；内、外髓非尿素浓度。数据表示为平均值±标准误；n＝8；*P<0.05，**P<0.01代表与对照组相比。
图8示例性地示出了本发明实施例3化合物毒性作用的验证。在MDCK细胞中加入实施例3化合物观察24h后，利用CCK-8进行细胞活力检测。大、小鼠放置于代谢笼中，实验组灌胃给予100mg/kg的实施例3化合物，对照组给予羧甲基纤维素钠，每天三次(首剂加倍)，连续给药7天，观察体重并于末次给药后取血、肾脏、肝脏组织进行分析。A：细胞存活率；B：大、小鼠体重；C：大鼠血尿素；D：大鼠肾脏指数(左)，大鼠肝重指数(右)；E：大鼠肾脏形态。数据表示为平均值±标准误；n＝8；*P<0.05，***P<0.001代表与对照组相比。
具体实施方式
以下对本发明的实施方式进行详细说明。但是，本发明不局限于以下说明，所属技术领域的普通技术人员可以很容易地理解其方式和详细内容可以被变换为各种形式。另外，本发明不应该被解释为仅限定在以下所示的实施方式所记载的内容中。
本发明中使用的术语“烷基”是指仅由碳原子和氢原子组成、且不具有不饱和度(例如双键、三键或环)的基团，其涵盖了各种可能的几何异构基团与立体异构基团。该基团通过单键与分子的其余部分相连。作为烷基的非限制性实例，可以列举以下直链或支链的基团：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基及其另外七种异构体、正己基及其另外十六种异构体。本发明中对于碳原子数的描述包括两个端点以及位于其间的所有整数值，例如：C 1-6烷基包括了甲基、乙基、丙基、丁基、戊基、己基及其全部异构体。
本发明中使用的术语“烯基”是指具有至少一个碳碳双键的直链、支链或环状的不饱和烃基原子团。例如，C 2-6烯基包括具有2个碳至6个碳的链以及至少一个双键的烯基(例如乙烯基、烯丙基、丙烯基、异丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-甲基烯丙基、1-己烯基、2-己烯基、3-己烯基等)。
本发明中使用的术语“炔基”是指具有至少一个碳碳三键的不饱和烃基原子团。例如C 2-6炔基 包括具有2个碳至6个碳的链以及至少一个三键的炔基(例如，乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、异戊炔基、1,3-己二炔基、正己炔基、3-戊炔基、1-己烯-3-炔基等)。
本发明中使用的术语“环基”是指由至少3个碳原子组成的饱和非芳香环系，该环系可以是单环、双环、多环，也可以是稠环、桥环、螺环。作为环烷基的非限制性实例，可以列举以下基团：环丙基、环丁基、环戊基、环己基；以及由两个或多个上述单环通过公共边和公共碳原子形成的稠环、桥环或螺环基团。
本发明中使用的术语“烷氧基”是指氧原子与上述烷基相连、并且通过该氧原子以单键连接至分子其余部分的基团，其涵盖了各种可能的几何异构基团与立体异构基团。作为烷氧基的非限制性实例，可以列举以下直链或支链的基团：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基及其另外七种异构体、正己氧基及其另外十六种异构体。
本发明中使用的术语“芳基”是指芳香族5元-10元单环、8元-12元稠合双环或11元-14元稠合三环环系。例如，5元或6元芳基表示环系中的碳原子数为5或6。在一些实施方式中，每个环的1个、2个、3个或4个氢原子可被取代基取代。
本发明中使用的术语“杂芳基”是指具有一个或多个独立地选自N、O或S的杂原子的5-14元芳香族杂环环系，该环系可以是单环、双环、多环，其中双环和多环可以由单环通过单键连接方式或稠合方式形成。作为杂芳基的非限制性实例，可以列举以下基团：噁唑基、异噁唑基、咪唑基、呋喃基、吲哚基、异吲哚基、吡咯基、三唑基、三嗪基、四唑基、噻吩基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并呋喃基、苯并噻唑基、苯并噁唑基、苯并咪唑基、苯并噻吩基、苯并吡喃基、咔唑基、喹啉基、异喹啉基、喹唑啉基、噌啉基、萘啶基、蝶啶基、嘌呤基、喹噁啉基、噻二唑基、吲哚嗪基、吖啶基、吩嗪基、酞嗪基、香豆素基、吡唑并吡啶基、吡啶并哒嗪基、吡咯并吡啶基、咪唑并吡啶基、吡唑并哒嗪基；以及由上述杂芳基通过单键连接方式或稠合方式形成的基团。
本发明中使用的术语“杂环基”是指由碳原子和独立选自N、O或S的杂原子组成的非芳香族3-15元环系，该环系可以是单环、双环或多环，也可以是稠环、桥环、螺环，并且可以任选地包含一个或多个双键。作为杂环基的非限制性实例，可以列举以下基团：环氧乙烷基、环硫乙烷基、氮杂环丙烷基、氧杂环丁烷基、硫杂环丁烷基、氮杂环丁烷基、四氢呋喃基、四氢噻吩基、吡咯烷基、四氢吡喃基、四氢呋喃基、哌啶基、1,4-二氧杂环己烷基、1,4-氧硫杂环己烷基、吗啉基、1,4-二噻烷基、哌嗪基、1,4-氮硫杂环己烷基、3,4-二氢-2H-吡喃基、5,6-二氢-2H-吡喃基、1,2,3,4-四氢吡啶基、1,2,5,6-四氢吡啶基。
本发明中使用的术语“卤素”是指氟、氯、溴或碘。
本发明中使用的术语“N-(烷基)氨基或N,N-二(烷基)氨基”分别表示-NH烷基或-N(烷基) 2，例如，-NHCH 3、-N(CH 3) 2等。
通过所有如上描述，技术人员清楚，任何名称为复合名称的基团按惯例应当意指由通过衍生其的部分构成，例如，烷基磺酰基为进一步被烷基取代的磺酰基基团，其中烷基如上文所定义。
术语“预防或者治疗”意为将本申请所述化合物或制剂进行给药以预防、改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时；
(ii)抑制疾病或疾病状态，即遏制其发展；
(iii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“治疗有效量”意指能够(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于 该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
在一些实施方式中，本发明描述了式(I)所示的化合物、或其药学上可接受的盐在制备作为尿素通道蛋白抑制剂的药物中的用途，
Figure PCTCN2020096939-appb-000002
其中，
环A和环B分别独立地为5～6元杂芳基或5～6元芳基；
所述环A和环B分别任选地被R 1和R 2取代；
R 1选自于由如下基团所组成的组：硝基、卤素、烷基、烷基羰基、烷基羰基氨基、烷基磺酰基以及吡啶并基；
R 2选自于由如下基团所组成的组：卤素、羟基、氨基、氰基、烷基、烯基、炔基、羟基烷基、氨基烷基、烷氧基、烷基羰基、烷氧基羰基、吡啶并基、任选地被R 5取代的烷基羰基氨基、任选地被R 5取代的杂环基或环基、任选地被R 5取代的杂芳基羰基氨基、N-烷基氨基、N,N-二(烷基)氨基、以及被R 3和R 4取代的氨基羰基；
其中，R 3和R 4各自独立地选自于由如下基团所组成的组：H、羟基、烷基、任选地被R 5取代的杂环基或环基、任选地被R 5取代的杂环基或环基烷基、任选地被R 5取代的杂芳基或芳基烷基、N-(烷基)氨基烷基、以及N,N-二(烷基)氨基烷基；以及
R 5选自于由如下基团所组成的组：烷基、硝基、烷基羰基氨基、N-(烷基)氨基、N,N-二(烷基)氨基、N,N-二(烷基)氨基烷基氨基、以及杂环基或环基。
在一些实施方式中，上述各基团的定义满足以下的一项或多项：
R 1选自于由如下基团所组成的组：硝基、卤素、C 1-6烷基、C 1-6烷基羰基、C 1-6烷基羰基氨基、C 1-6烷基磺酰基以及吡啶并基；
R 2选自于由如下基团所组成的组：卤素、羟基、氨基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷基羰基、C 1-6烷氧基羰基、吡啶并基、任选地被R 5取代的C 1-6烷基羰基氨基、任选地被R 5取代的5～6元杂环基或环基、任选地被R 5取代的5～6元杂芳基羰基氨基、N-(C 1-6烷基)氨基、N,N-二(C 1-6烷基)氨基、以及被R 3和R 4取代的氨基羰基；
其中，R 3和R 4各自独立地选自于由如下基团所组成的组：H、羟基、C 1-6烷基、任选地被R 5取代的5～6元杂环基或环基、任选地被R 5取代的5～6元杂环基或环基C 1-6烷基、任选地被R 5取代的5～6元杂芳基或芳基C 1-6烷基、N-(C 1-6烷基)氨基C 1-C 6烷基、以及N,N-二(C 1-6烷基)氨基C 1-6烷基；以及
R 5选自于由如下基团所组成的组：C 1-6烷基、硝基、C 1-6烷基羰基氨基、N-(C 1-6烷基)氨基、N,N-二(C 1-6烷基)氨基、N,N-二(C 1-6烷基)氨基C 1-6烷基氨基、以及5～6元杂环基或环基。
在一些实施方式中，所述杂芳基和杂环基的杂原子独立地选自O、S和/或N，杂原子的数目为选自1、2、3的整数。
在一些实施方式中，所述杂芳基选自于由如下基团所组成的组：呋喃基、噻吩基、噻唑基、异噻唑基、噻二唑基、吡咯基、噁唑基、异噁唑基、吡唑基、咪唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、喹啉基、异喹啉基、喹喔啉基、喹唑啉基、苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、吲哚基。
在一些实施方式中，所述杂环基选自于由如下基团所组成的组：哌啶基、二氧杂环己烷基、氧硫杂环己烷基、吗啉基、哌嗪基。
在一些实施方式中，所述环基选自于由如下基团所组成的组：环丙基、环丁基、环戊基、环己基。
在一些实施方式中，所述环A和环B各自独立地选自于由如下杂芳基或芳基所组成的组：呋喃基、噻吩基、噻唑基、异噻唑基、噻二唑基、吡咯基、噁唑基、异噁唑基、吡唑基、咪唑基、苯基、吡啶基、吡嗪基、嘧啶基、哒嗪基。
在一些实施方式中，所述环A和环B的定义满足以下的一项或多项：
所述环A选自于由如下杂芳基或芳基所组成的组：呋喃基、噻吩基、吡咯基、噁唑基、吡唑基、苯基；以及
所述环B选自于由如下基团所组成的组：噻吩基、噁唑基、异噁唑基、吡唑基、苯基、吡啶基、吡嗪基、嘧啶基、哒嗪基。
在一些实施方式中，所述环A和/或环B进一步被R 6取代，R 6选自于由如下基团所组成的组：羟基、卤素、C 1-C 6烷基、C 1-C 6烷氧基羰基、C 1-C 6烷基氨基羰基、或R 6通过共价键与其所在的环形成氧代5元或6元氮杂环，所述氮杂环任选地被R 5取代。
在一些实施方式中，所述式(I)所示的化合物、或其药学上可接受的盐选自于由下述化合物(1)至(79)、或其药学上可接受的盐所组成的组：
(1)N-(4-乙酰氨基苯基)-4-硝基苯甲酰胺；
(2)N-(4-乙酰基苯基)-5-硝基呋喃-2-甲酰胺；
(3)N-(4-乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
(4)N-(4-乙酰氨基苯基)呋喃-2-甲酰胺；
(5)N-苯基-5-硝基呋喃-2-甲酰胺；
(6)N-(4-乙酰氨基苯基)噻吩-2-甲酰胺；
(7)N-(4-乙酰氨基苯基)-1H-吡咯-2-甲酰胺；
(8)N-(4-乙酰氨基苯基)噁唑-5-甲酰胺；
(9)N-(4-乙酰氨基苯基)-5-硝基噻吩-2-甲酰胺；
(10)N-(吡啶-2-基)-5-硝基呋喃-2-甲酰胺；
(11)N-(吡啶-3-基)-5-硝基呋喃-2-甲酰胺；
(12)N-(吡啶-4-基)-5-硝基呋喃-2-甲酰胺；
(13)N-(吡嗪-2-基)-5-硝基呋喃-2-甲酰胺；
(14)N-(嘧啶-2-基)-5-硝基呋喃-2-甲酰胺；
(15)N-(哒嗪-3-基)-5-硝基呋喃-2-甲酰胺；
(16)N-(喹啉-6-基)-5-硝基呋喃-2-甲酰胺；
(17)N-(噻吩-3-基)-5-硝基呋喃-2-甲酰胺；
(18)N-(噻吩-2-基)-5-硝基呋喃-2-甲酰胺；
(19)N-(异噁唑-3-基)-5-硝基呋喃-2-甲酰胺；
(20)N-(1H-吡唑-5-基)-5-硝基呋喃-2-甲酰胺；
(21)N-(1-甲基-1H-吡唑-3-基)-5-硝基呋喃-2-甲酰胺；
(22)N-(1-甲基-1H-吡唑-4-基)-5-硝基呋喃-2-甲酰胺；
(23)N-(4-乙酰氨基苯基)-5-溴呋喃-2-甲酰胺；
(24)N-(4-乙酰氨基苯基)-5-乙酰氨基呋喃-2-甲酰胺；
(25)N-(4-乙酰氨基苯基)-5-甲磺酰基呋喃-2-甲酰胺；
(26)N-(2-乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
(27)N-(3-乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
(28)N-(3-甲基苯基)-5-硝基呋喃-2-甲酰胺；
(29)N-(2-甲氧基苯基)-5-硝基呋喃-2-甲酰胺；
(30)N-(3-甲氧基苯基)-5-硝基呋喃-2-甲酰胺；
(31)N-(4-甲氧基苯基)-5-硝基呋喃-2-甲酰胺；
(32)N-(3-羟基苯基)-5-硝基呋喃-2-甲酰胺；
(33)N-(4-羟基苯基)-5-硝基呋喃-2-甲酰胺；
(34)N-(3-氨基苯基)-5-硝基呋喃-2-甲酰胺；
(35)N-(2-氟苯基)-5-硝基呋喃-2-甲酰胺；
(36)N-(3-氟苯基)-5-硝基呋喃-2-甲酰胺；
(37)N-(4-氟苯基)-5-硝基呋喃-2-甲酰胺；
(38)N-(3-氯苯基)-5-硝基呋喃-2-甲酰胺；
(39)N-(4-氯苯基)-5-硝基呋喃-2-甲酰胺；
(40)N-(3-氰基苯基)-5-硝基呋喃-2-甲酰胺；
(41)N-(4-氰基苯基)-5-硝基呋喃-2-甲酰胺；
(42)3-(5-硝基呋喃-2-甲酰胺基)苯甲酸乙酯；
(43)4-(5-硝基呋喃-2-甲酰胺基)苯甲酸乙酯；
(44)N-(3-氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
(45)N-(4-氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
(46)N-(3-乙酰基苯基)-5-硝基呋喃-2-甲酰胺；
(47)N-(4-二甲氨基苯基)-5-硝基呋喃-2-甲酰胺；
(48)N-(4-吗啉基苯基)-5-硝基呋喃-2-甲酰胺；
(49)N-(4-(4-乙基哌嗪-1-基)苯基)-5-硝基呋喃-2-甲酰胺；
(50)N-(4-(2-羟乙基)苯基)-5-硝基呋喃-2-甲酰胺；
(51)N-(4-氨甲基苯基)-5-硝基呋喃-2-甲酰胺；
(52)N,N’-(1,4-亚苯基)二(5-硝基呋喃-2-甲酰胺)；
(53)N-(3-(甲氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(54)N-(3-(二甲基氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(55)N-(3-(乙氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(56)N-(3-(异丙氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(57)N-(3-(异丁氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(58)N-(3-(环己氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(59)N-(3-(苄氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(60)N-(3-((2-二甲氨基乙基)氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(61)N-(3-((2-吗啉基乙基)氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(62)N-(3-((3-吗啉基丙基)氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(63)N-(4-甲基-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
(64)N-(5-甲基-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
(65)N-(4-氟-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
(66)N-(5-氟-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
(67)N-(4-羟基-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
(68)5-(5-硝基呋喃-2-甲酰胺基)间苯二甲酰(N-甲基)胺；
(69)N-(2-甲基-1,3-二氢-1,3-二氧代-2H-异吲哚-5-基)-5-硝基呋喃-2-甲酰胺；
(70)N-(4-乙酰氨基苯基)-5-乙酰基呋喃-2-甲酰胺；
(71)N-(4-(2-二甲氨基)乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
(72)N-(4-(2-吗啉基)乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
(73)N-(4-(3-二甲氨基)丙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
(74)N-(4-((2-二甲氨基)乙基氨基)乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
(75)2-乙酰氨基-5-(5-硝基呋喃-2-甲酰胺)苯甲酸乙酯；
(76)5-(5-硝基呋喃-2-甲酰胺)-1H-吡唑-4-羧酸乙酯；
(77)5-(5-硝基呋喃-2-甲酰胺)-1H-吡唑-3-羧酸乙酯；
(78)3-(5-乙酰基-2-呋喃甲酰基)氨基甲酰胺；以及
(79)N-3-(乙炔基苯基)-5-硝基呋喃-2-甲酰胺。
在一些实施方式中，所述药物为用于治疗或预防与尿素通道蛋白抑制剂相关的疾病的药物；优选地，所述药物为利尿药、降压药和/或用于研究尿素通道蛋白的工具药；优选地，所述尿素通道蛋白为UT-B蛋白或UT-A蛋白。
在一些实施方式中，本发明所述的与尿素通道蛋白抑制剂相关的疾病为与尿素通道蛋白抑制剂相关的水肿性疾病；其中，所述水肿性疾病优选包括：心源性水肿，优选地所述心源性水肿为归因于充血性心力衰竭和/或缩窄性心包炎的心源性水肿；肾源性水肿，优选地所述肾源性水肿为归因于急性肾小球肾炎、慢性肾小球肾炎、肾病综合征、肾动脉硬化症和/或肾小管病变的肾源性水肿；肝源性水肿，优选地所述肝源性水肿为归因于肝硬化、肝坏死、肝癌和/或急性肝炎的肝源性水肿；营养不良性水肿，优选地所述营养不良性水肿为归因于原发性食物摄人不足、继发性营养不良性、消化吸收障碍和/或蛋白质合成功能受损的营养不良性水肿；结缔组织病所致的水肿；变态反应性水肿；内分泌性水肿；特发性水肿；静脉梗阻性水肿；淋巴梗阻性水肿；炎症性水肿；变态反应性水肿；血管神经性水肿；脑水肿；喉头水肿；肺水肿和/或下肢水肿。
在一些实施方式中，本发明所述的与尿素通道蛋白抑制剂相关的疾病为与尿素通道蛋白抑制剂相关的非水肿性疾病；其中，所述非水肿性疾病优选包括：心力衰竭，优选充血性心力衰竭、急性心力衰竭、慢性心力衰竭；心脑血管疾病，优选轻度高血压、中度高血压、老年收缩期高血压、高血压合并心力衰竭。
在一些实施方式中，本发明还描述了一种治疗或预防与尿素通道蛋白抑制剂相关的疾病的方法，所述方法包括向有需要的患者给予治疗有效量的根据本发明的式(I)所示的化合物、或其药学上可接受的盐。
在一些实施方式中，本发明还描述了用于治疗与尿素通道蛋白抑制剂相关的疾病的根据本发明的式(I)所示的化合物、或其药学上可接受的盐。
在一些实施方式中，本发明还描述了用作尿素通道蛋白抑制剂的根据本发明的式(I)所示的化合物、或其药学上可接受的盐。
在一些实施方式中，本发明还描述了根据本发明的式(I)所示的化合物、或其药学上可接受的盐在治疗与尿素通道蛋白抑制剂相关的疾病中的用途。
在另一些实施方式中，本发明描述了一种二芳基酰胺类化合物、或其药学上可接受的盐，所述二芳基酰胺类化合物、或其药学上可接受的盐选自于由下述化合物、或其药学上可接受的盐所组成的组：
(15)N-(哒嗪-3-基)-5-硝基呋喃-2-甲酰胺；
(17)N-(噻吩-3-基)-5-硝基呋喃-2-甲酰胺；
(25)N-(4-乙酰氨基苯基)-5-甲磺酰基呋喃-2-甲酰胺；
(26)N-(2-乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
(51)N-(4-氨甲基苯基)-5-硝基呋喃-2-甲酰胺；
(53)N-(3-(甲氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(55)N-(3-(乙氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(56)N-(3-(异丙氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(57)N-(3-(异丁氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(58)N-(3-(环己氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(59)N-(3-(苄氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(60)N-(3-((2-二甲氨基乙基)氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(61)N-(3-((2-吗啉基乙基)氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(62)N-(3-((3-吗啉基丙基)氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
(63)N-(4-甲基-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
(64)N-(5-甲基-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
(65)N-(4-氟-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
(66)N-(5-氟-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
(67)N-(4-羟基-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
(68)N 1,N 3-二甲基-5-(5-硝基呋喃-2-甲酰胺基)间苯二甲酰胺；
(69)N-(2-甲基-1,3-二氢-1,3-二氧代-2H-异吲哚-5-基)-5-硝基呋喃-2-甲酰胺；
(70)N-(4-乙酰氨基苯基)-5-乙酰基呋喃-2-甲酰胺；
(71)N-(4-(2-二甲氨基)乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
(72)N-(4-(2-吗啉基)乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
(73)N-(4-(3-二甲氨基)丙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
(74)N-(4-((2-二甲氨基)乙基氨基)乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
(75)2-乙酰氨基-5-(5-硝基呋喃-2-甲酰胺)苯甲酸乙酯；
(76)5-(5-硝基呋喃-2-甲酰胺)-1H-吡唑-4-羧酸乙酯；
(77)5-(5-硝基呋喃-2-甲酰胺)-1H-吡唑-3-羧酸乙酯；以及
(78)3-(5-乙酰基-2-呋喃甲酰基)氨基甲酰胺。
在又一些实施方式中，本发明描述了一种药物组合物，所述药物组合物包含：上述二芳基酰胺类化合物或其药学上可接受的盐；以及药学上可接受的载体。
术语“药物组合物”是指包含一种或多种本申请的化合物或其盐与药学上可接受的载体的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。
术语“药学上可接受的”是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
本发明所述的二芳基酰胺类化合物的药学上可接受的盐包括与无机酸或有机酸形成的酸加成盐，所述酸例如硝酸、盐酸、氢溴酸、硫酸、高氯酸、磷酸、乙酸、三氟乙酸、丙酸、羟乙酸、富马酸、乳酸、草酸、丙二酸、苹果酸、马来酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、苦杏仁酸、甲磺酸、羟乙磺酸和水杨酸。本发明所述的二芳基酰胺类化合物的药学上可接受的盐也包含与无机碱或有机碱形成的盐，所述碱例如碱金属或碱土金属，特别是钠、钾、钙、铵或镁的氢氧化物、碳酸盐或碳酸氢盐，非环状或环状胺类，优选甲胺、乙胺、二乙胺、三乙基胺、哌啶等。
本发明所述的药学上可接受的载体，包括但不限于：水、盐溶液、醇、聚乙二醇、多羟基乙氧基化的蓖麻油、花生油、橄榄油、明胶、乳糖、石膏粉、蔗糖、糊精、碳酸镁、糖、环糊精、直链淀粉、硬脂酸镁、滑石、明胶、琼脂、果胶、阿拉伯胶、硬脂酸或纤维素低烷基醚、硅酸、脂肪酸、脂肪酸胺、脂肪酸单甘油酯和二甘油酯、季戊四醇脂肪酸醚、聚氧乙烯、羟甲基纤维素和聚乙烯吡咯烷酮。
在一些实施方式中，所述药物组合物还可包含一种或多种药学上可接受的辅助剂、润湿剂、乳化剂、悬浮剂、防腐剂、渗透压调节剂、缓冲剂、甜味剂、矫味剂、着色剂或上述的任意组合。
本发明的药物组合物可以制成任何形式的制剂，例如胶囊剂、片剂、气雾剂、溶液剂、悬浮剂、糖衣剂、锭剂、糖浆剂、乳剂、软膏剂、膏剂、注射剂、散剂、颗粒剂、糊剂、缓释剂、泡沫剂。根据给药途径，本发明的药物可以制成口服给药制剂、鼻部给药制剂、肺部给药制剂、口腔含化制 剂、皮下给药制剂、皮内给药制剂、经皮给药制剂、胃肠外给药制剂、直肠给药制剂、储库式给药制剂、静脉内给药制剂、尿道内给药制剂、肌内给药制剂、鼻内给药制剂、眼部给药制剂、硬膜外给药制剂或局部给药制剂。
本发明的化合物及其组合物可抑制尿素通道蛋白UT-B介导的红细胞膜对尿素的通透，且其作用呈剂量依赖关系；体内试验结果表明，本发明的化合物经灌胃或皮下给药后，可显著增多大、小鼠排尿量，降低其渗透压，且不引起非尿素溶质排泄的改变；可降低大、小鼠肾内髓尿素的浓度，但不引起非尿素溶质浓度的改变，表明本发明的化合物能够在体内产生尿素选择性利尿作用且没有明显的毒性作用。
在本文中，除非另有说明，否则术语“包含、包括和含有(comprise、comprises和comprising)”或等同物为开放式表述，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
实施例
接着，将通过以下实施例对本发明进行详细说明。本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂、化合物或仪器未注明生产厂商者或来源者，均为可以通过购买获得的常规产品或可以通过已知方法获得的已知产品。
实施例1 N-(4-乙酰氨基苯基)-4-硝基苯甲酰胺
Figure PCTCN2020096939-appb-000003
将对硝基苯甲酸(3-1a,167mg,1mmol)混悬于二氯甲烷(5mL)中，加入2滴DMF，冰水浴冷却到0℃。缓慢滴加草酰氯(190mg,0.13mL,1.5mmol)，滴毕，室温搅拌2小时。反应液浓缩除去溶剂及过量草酰氯，得对硝基苯甲酰氯(3-2a)，不经纯化，加入四氢呋喃(1mL)备用。将对乙酰氨基苯胺(3-3a,150mg,1mmol)溶于四氢呋喃(5mL)，加入三乙胺(152mg,1.5mmol)后，于冰浴下滴加上述酰氯3-2a的四氢呋喃溶液。滴毕，室温反应至TLC(CH 2Cl 2:MeOH＝15:1)显示反应完全。向反应体系中加入30mL水，继续搅拌10分钟后抽滤，滤饼依次以5％盐酸、蒸馏水各10mL洗涤，干燥后得黄色固体，收率80％，熔点301-303℃(文献值 [93]293℃(分解))。
1H NMR(400MHz,DMSO-d 6)δ10.51(s,1H),9.95(s,1H),8.36(d,J＝8.4Hz,2H),8.17(d,J＝8.4Hz,2H),7.69(d,J＝8.4Hz,2H),7.57(d,J＝8.4Hz,2H),2.04(s,3H). 13C NMR(101MHz,DMSO-d 6)δ168.54,163.98,149.54,141.12,134.27,129.60,124.00,121.40,119.65,24.39。
实施例2 N-(4-乙酰基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000004
合成方法同实施例1。黄色固体，收率81％，熔点233-234℃。
1H NMR(400MHz,DMSO-d 6)δ10.91(s,1H),7.99(d,J＝8.0Hz,2H),7.90(d,J＝8.0Hz,2H), 7.82(d,J＝2.4Hz,1H),7.69(d,J＝2.4Hz,1H),2.55(s,3H)； 13C NMR(101MHz,DMSO-d 6)δ197.13,155.33,152.36,147.92,142.68,133.14,129.84,120.31,117.57,113.90,26.98.
实施例3 N-(4-乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000005
合成方法同实施例1。桔黄色固体，收率80％，熔点233-234℃。
1H NMR(400MHz,DMSO-d 6)δ10.59(s,1H),9.97(s,1H),7.81(d,J＝4.0Hz,1H),7.62-7.66(m,3H),7.57(d,J＝8.8Hz,2H),2.04(s,3H)； 13C NMR(101MHz,DMSO-d 6)δ168.61,154.79,152.20,148.56,136.49,133.32,121.66,119.71,116.77,113.97,24.40.HRMS m/z:calcd for C 16H 13N 3O 4,([M+H]+):285.08698,Found:285.08696.
实施例4 N-(4-乙酰氨基苯基)呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000006
合成方法同实施例1。白色固体232mg，收率68％，熔点212-214℃。
1H NMR(400MHz,DMSO-d 6)δ10.11(s,1H),9.91(s,1H),7.92(d,J＝1.7Hz,1H),7.64(d,J＝8.9Hz,2H),7.53(d,J＝8.9Hz,2H),7.30(d,J＝3.4Hz,1H),6.69(dd,J＝3.4,1.7Hz,1H),2.03(s,3H). 13C NMR(101MHz,DMSO-d 6)δ168.46,156.44,148.06,146.02,135.77,134.07,121.28,119.65,114.89,112.55,24.37.HRMS m/z:calcd for C 13H 13N 2O 3[M+H] +:245.09207；found:244.10848.
实施例5 N-苯基-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000007
合成方法同实施例1。黄色固体，收率63％，熔点178-180℃。
1H NMR(400MHz,DMSO-d 6)δ10.63(s,1H),7.82(d,J＝3.9Hz,1H),7.74(d,J＝7.7Hz,2H),7.64(d,J＝3.9Hz,1H),7.39(t,J＝7.9Hz,2H),7.17(t,J＝7.4Hz,1H). 13C NMR(101MHz,DMSO-d 6)δ165.05,152.22,148.39,138.26,129.29,125.04,121.17,116.98,113.93.HRMS m/z:calcd for C 11H 9N 2O 4[M+H] +:233.05568；found:233.05517.
实施例5A N-甲基-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000008
将4-5a(141mg,1mmol)混悬于二氯甲烷(5mL)中，加入EDCI(230mg,1.2mmol)，HOBT(148mg,1.1mmol)，室温搅拌30min。随后加入4-7d(74mg,1.1mmol)，三乙胺(253mg,2.5mmol)，室温搅拌过夜。旋蒸除去溶剂，残余物中加入2N盐酸(5mL)，剧烈搅拌后析出固体，抽滤，固体用水洗涤，干燥，得淡黄色粉末100mg，收率59％，熔点187-190℃。
实施例6 N-(4-乙酰氨基苯基)噻吩-2-甲酰胺
Figure PCTCN2020096939-appb-000009
合成方法同实施例1。白色固体，收率55％，熔点247-248℃。
1H NMR(400MHz,DMSO-d 6)δ10.17(s,1H),9.91(s,1H),7.99(d,J＝3.5Hz,1H),7.84(d,J＝4.9 Hz,1H),7.62(d,J＝8.8Hz,2H),7.54(d,J＝8.8Hz,2H),7.22(t,J＝4.3Hz,1H),2.03(s,3H). 13C NMR(101MHz,DMSO-d 6)δ168.57,160.16,140.71,135.88,134.34,132.20,129.40,128.59,121.43,119.76,24.47.HRMS m/z:calcd for C 13H 13N 2O 2S[M+H] +:261.06992；found:261.06953.
实施例7 N-(4-乙酰氨基苯基)-1H-吡咯-2-甲酰胺
Figure PCTCN2020096939-appb-000010
合成方法同实施例5A。白色固体，收率56％，熔点260-262℃。
1H NMR(400MHz,DMSO-d 6)δ11.61(s,1H),9.87(s,1H),9.68(s,1H),7.62(d,J＝8.8Hz,2H),7.51(d,J＝8.8Hz,2H),7.03(s,1H),6.94(s,1H),6.15(d,J＝2.9Hz,1H),2.03(s,3H). 13C NMR(101MHz,DMSO-d 6)δ168.37,159.39,135.13,134.95,126.56,122.77,120.80,119.70,111.50,109.27,24.35.HRMS m/z:calcd for C 13H 14N 3O 2[M+H] +:244.10805；found:244.10848.
实施例8 N-(4-乙酰氨基苯基)噁唑-5-甲酰胺
Figure PCTCN2020096939-appb-000011
合成方法同实施例1。白色固体，收率62％，熔点255-257℃。
1H NMR(400MHz,DMSO-d 6)δ10.37(s,1H),9.94(s,1H),8.64(s,1H),7.96(s,1H),7.63(d,J＝9.0Hz,2H),7.56(d,J＝9.0Hz,2H),2.04(s,3H). 13C NMR(101MHz,DMSO-d 6)δ168.55,155.16,154.21,145.74,136.17,133.59,130.29,121.45,119.71,24.39.HRMS m/z:calcd for C 12H 14N 3O 3[M+H] +:246.08732；found:246.08681.
实施例9 N-(4-乙酰氨基苯基)-5-硝基噻吩-2-甲酰胺
Figure PCTCN2020096939-appb-000012
合成方法同实施例1。黄色固体，收率56％，熔点296℃(分解)。
1H NMR(400MHz,DMSO-d 6)δ10.61(s,1H),9.97(s,1H),8.21(d,J＝4.4Hz,1H),8.04(d,J＝4.4Hz,1H),7.64(d,J＝9.0Hz,2H),7.58(d,J＝9.0Hz,2H),2.04(s,3H). 13C NMR(101MHz,DMSO-d 6)δ168.61,158.37,153.67,147.07,136.54,133.38,130.62,128.57,121.61,119.71,24.40.HRMS m/z:calcd for C 13H 12N 3O 4S[M+H] +:306.05430；found:306.05418.
实施例10 N-(吡啶-2-基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000013
将4-6a(263mg,1.5mmol)溶于二氯乙烷(1mL)，在冰水浴冷却下，滴加至4-12a(141mg,1.5mmol)的二氯乙烷(4mL)溶液中。滴毕，升温至65℃搅拌3h，TLC(CH 2Cl 2:MeOH＝15:1)检测反应基本完全。反应液冷却至室温后，加入水、乙酸乙酯各15mL，充分混匀后分层。水相用乙酸乙酯萃取(15mL×2)，有机相合并后，依次用饱和NaHCO 3溶液、10％柠檬酸、饱和NaCl溶液萃洗，无水硫酸钠干燥，浓缩。硅胶柱层析(PE:EA＝5:1)分离得黄色固体160mg，收率46％，熔点189-190℃。
1H NMR(400MHz,CDCl 3)δ8.94(s,1H),8.38(d,J＝4.6Hz,1H),8.29(d,J＝8.4Hz,1H),7.79(t,J＝7.8Hz,1H),7.42(s,2H),7.15(t,J＝6.0Hz,1H). 13C NMR(101MHz,CDCl 3)δ154.15,150.10,148.30,147.23,138.64,120.90,117.22,114.49,112.42.HRMS m/z:calcd for C 10H 8N 3O 4[M+H] +:234.05093；found:234.05065.
实施例11 N-(吡啶-3-基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000014
合成方法同实施例10。收率63％，熔点205-208℃。
1H NMR(400MHz,DMSO-d 6)δ10.87(s,1H),8.91(s,1H),8.37(d,J＝3.8Hz,1H),8.15(d,J＝8.2Hz,1H),7.84(d,J＝3.2Hz,1H),7.66(d,J＝3.2Hz,1H),7.44(dd,J＝8.2,3.8Hz,1H). 13C NMR(101MHz,DMSO-d 6)δ155.45,152.30,147.89,145.88,142.69,135.04,128.33,124.16,117.50,113.93.HRMS m/z:calcd for C 10H 8N 3O 4[M+H] +:234.05093；found:234.05086.
实施例12 N-(吡啶-4-基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000015
合成方法同实施例10。收率45％，熔点230-232℃。
1H NMR(400MHz,DMSO-d 6)δ10.94(s,1H),8.52(d,J＝5.2Hz,2H),7.83(d,J＝3.2Hz,1H),7.75(d,J＝5.2Hz,2H),7.70(d,J＝3.2Hz,1H). 13C NMR(101MHz,DMSO-d 6)δ155.78,152.42,150.96,147.54,145.26,117.91,114.72,113.84.HRMS m/z:calcd for C 10H 8N 3O 4[M+H] +:234.05093；found:234.05038.
实施例13 N-(吡嗪-2-基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000016
合成方法同实施例10。收率36％，熔点211-212℃。
1H NMR(400MHz,DMSO-d 6)δ11.60(s,1H),9.38(s,1H),8.53(s,1H),8.48(d,J＝2.4Hz,1H),7.91(d,J＝4.0Hz,1H),7.83(d,J＝4.0Hz,1H). 13C NMR(101MHz,DMSO-d 6)δ155.59,152.72,148.63,147.10,143.27,137.86,118.16,113.70.HRMS m/z:calcd for C 9H 7N 4O 4[M+H] +:235.04618；found:235.04610.
实施例14 N-(嘧啶-2-基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000017
合成方法同实施例10。收率22％，熔点207-208℃。
1H NMR(400MHz,DMSO-d 6)δ11.43(s,1H),8.93-8.63(m,2H),7.82(d,J＝2.0Hz,2H),7.32(t,J＝4.8Hz,1H). 13C NMR(101MHz,DMSO-d 6)δ159.11,157.78,154.77,152.64,147.71,118.42,117.86,113.70.HRMS m/z:calcd for C 9H 7N 4O 4[M+H] +:235.04618；found:235.04607.
实施例15 N-(哒嗪-3-基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000018
合成方法同实施例10。收率51％，熔点209-211℃。
1H NMR(400MHz,DMSO-d 6)δ11.91(s,1H),9.07(d,J＝4.2Hz,1H),8.36(d,J＝9.0Hz,1H),7.95(d,J＝3.2Hz,1H),7.84(d,J＝3.2Hz,1H),7.80-7.77(m,1H). 13C NMR(101MHz,DMSO-d 6)δ156.10,155.61,152.67,149.67,147.13,129.17,120.06,118.10,113.65.HRMS m/z:calcd for C 9H 7N 4O 4[M+H] +:235.04618；found:235.04607.
实施例16 N-(喹啉-6-基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000019
合成方法同实施例1。甲醇重结晶得黄色晶体，收率42％，熔点193-195℃。
1H NMR(400MHz,DMSO-d 6)δ10.96(s,1H),8.85(dd,J＝4.0,1.2Hz,1H),8.47(s,1H),8.37(d,J＝8.4Hz,1H),8.05(s,2H),7.86(d,J＝4.0Hz,1H),7.72(d,J＝4.0Hz,1H),7.53(q,J＝4.0Hz,1H). 13C NMR(101MHz,DMSO-d 6)δ155.38,152.34,150.19,148.18,145.61,136.28,130.06,128.55,124.60,122.41,117.61,117.32,113.96.HRMS m/z:calcd for C 14H 10N 3O 4[M+H] +:284.06658；found:284.06597.
实施例17 N-(噻吩-3-基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000020
合成方法同实施例1。黄色固体，收率65％，熔点214-215℃。
1H NMR(400MHz,DMSO-d 6)δ11.11(s,1H),7.81(s,1H),7.74(s,1H),7.58(d,J＝2.8Hz,1H),7.53(t,J＝2.4Hz,1H),7.34(d,J＝5.0Hz,1H). 13C NMR(101MHz,DMSO-d 6)δ154.21,152.21,148.31,136.07,125.57,122.41,116.88,114.03,111.54.HRMS m/z:calcd for C 9H 7N 2O 4S[M+H] +:239.01210；found:239.01212.
实施例18 N-(噻吩-2-基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000021
合成方法同实施例1。黄色固体，收率57％，熔点212-214℃。
1H NMR(400MHz,DMSO-d 6)δ12.01(s,1H),7.82(d,J＝4.0Hz,1H),7.60(d,J＝4.0Hz,1H),7.10(d,J＝5.4Hz,1H),7.02(d,J＝3.1Hz,1H),6.94(dd,J＝5.4Hz,4.0Hz,1H). 13C NMR(101MHz,DMSO-d 6)δ153.14,152.33,147.58,139.05,124.88,119.04,117.31,114.08,114.04.HRMS m/z:calcd for C 9H 7N 2O 4S[M+H] +:239.01210；found:239.01156.
实施例18A N-(噻唑-2-基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000022
将4-12j(100mg,1mmol)溶于二氯甲烷(5mL)中，加入三乙胺(151mg,1.5mmol)。将4-6a(175mg,1mmol)溶于二氯甲烷(1mL)中，冰浴下滴加至上述溶液当中。滴毕，升至室温反应过夜，TLC(CH 2Cl 2:MeOH＝15:1)检测反应完全。旋蒸除去溶剂，残余物加入水(5mL)，剧烈搅拌30min，抽滤。固体用少量甲醇洗涤，干燥，得棕色固体180mg，收率75％，熔点265-268℃。
实施例19 N-(异噁唑-3-基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000023
合成方法同实施例18A。浅棕色固体，收率58％，熔点230-232℃。
1H NMR(400MHz,DMSO-d 6)δ11.96(s,1H),8.90(s,1H),7.81(q,J＝4.0Hz,2H),7.02(s,1H). 13C NMR(101MHz,DMSO-d 6)δ161.07,157.59,155.00,152.63,146.93,118.02,113.65,100.10.HRMS m/z:calcd for C 8H 6N 3O 5[M+H] +:224.03020；found:224.03009.
实施例20 N-(1H-吡唑-5-基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000024
合成方法同实施例18A。橘黄色固体，收率32％，熔点197-198℃。
1H NMR(400MHz,DMSO-d 6)δ8.25(d,J＝3.0Hz,1H),8.08(d,J＝3.9Hz,1H),7.84(d,J＝3.9Hz,1H),6.11(d,J＝3.0Hz,1H),5.96(s,2H). 13C NMR(101MHz,DMSO-d 6)δ160.53,153.13,152.08,145.52,131.76,124.39,113.32,104.04.HRMS m/z:calcd for C 8H 7N 4O 4[M+H] +:223.04618；found:223.04568.
实施例21 N-(1-甲基-1H-吡唑-3-基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000025
合成方法同实施例1。黄色固体，收率85％，熔点218-219℃。
1H NMR(400MHz,DMSO-d 6)δ11.36(s,1H),7.79(d,J＝3.8Hz,1H),7.73(d,J＝3.8Hz,1H),7.65(d,J＝1.8Hz,1H),6.56(d,J＝1.8Hz,1H),3.80(s,3H). 13C NMR(101MHz,DMSO-d 6)δ154.10,152.37,148.05,146.24,131.76,116.57,113.79,97.94,38.90.HRMS m/z:calcd for C 9H 9N 4O 4[M+H] +:237.06183；found:237.06160.
实施例22 N-(1-甲基-1H-吡唑-4-基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000026
合成方法同实施例1。黄色固体，收率87％，熔点209-211℃。
1H NMR(400MHz,DMSO-d 6)δ10.93(s,1H),8.04(s,1H),7.80(d,J＝3.8Hz,1H),7.60(s,1H),7.51(d,J＝3.8Hz,1H),3.84(s,3H). 13C NMR(101MHz,DMSO-d 6)δ153.32,152.05,148.44,130.81,122.58,120.87,116.46,114.09,39.22.HRMS m/z:calcd for C 9H 9N 4O 4[M+H] +:237.06183；found:237.06160.
实施例23 N-(4-乙酰氨基苯基)-5-溴呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000027
合成方法同实施例1。淡黄色固体，收率85％，熔点217-219℃。
1H NMR(400MHz,DMSO-d 6)δ10.15(s,1H),9.92(s,1H),7.62(d,J＝9.0Hz,2H),7.53(d,J＝9.0Hz,2H),7.34(d,J＝3.6Hz,1H),6.83(d,J＝3.6Hz,1H),2.03(s,3H). 13C NMR(101MHz,DMSO-d 6)δ168.50,155.35,149.84,135.94,133.81,125.61,121.39,119.67,117.32,114.69,24.38.HRMS m/z:calcd for C 13H 12BrN 2O 3[M+H] +:323.00258；found:323.00219.
实施例24 N-(4-乙酰氨基苯基)-5-乙酰氨基呋喃-2-甲酰胺
5-乙酰氨基呋喃-2-甲酸(4-14c)
Figure PCTCN2020096939-appb-000028
将4-18(171mg,1mmol)溶于甲醇(10mL),加入Pd/C(10％,17mg)，置于氢化仪中室温反应2h，TLC(PE:EA＝3:1)检测反应完全。反应液经硅藻土过滤，滤液浓缩得黄色油状物(3-27)。
于4-17中加入醋酸酐(2mL)，室温搅拌1h，反应液变混浊，TLC(PE:EA＝3:1)检测反应完成。加入水(10mL)，继续搅拌15min，抽滤，固体用水洗涤，得白色固体(4-16)。
在未干燥的4-16中加入甲醇(4mL)，LiOH溶液(4N,1mL)，室温搅拌至水解完全。反应液加水(5mL×3)，有机相合并后用无水Na 2SO 4干燥，浓缩后得4-14c，白色固体80mg，三步总收率47％。
N-(4-乙酰氨基苯基)-5-乙酰氨基呋喃-2-甲酰胺(实施例24)
Figure PCTCN2020096939-appb-000029
合成方法同实施例1。淡黄色固体，收率85％，熔点250-251℃。
1H NMR(400MHz,DMSO-d 6)δ10.37(s,1H),9.95(s,1H),7.64(d,J＝8.8Hz,2H),7.58-7.54(m,3H),7.45(d,J＝3.6Hz,1H),2.53(s,3H),2.04(s,3H). 13C NMR(101MHz,DMSO-d 6)δ187.18,168.55,155.92,152.90,150.25,136.25,133.57,121.69,119.67,119.37,116.04,26.78,24.40.HRMS m/z:calcd for C 15H 15N 2O 4[M+H] +:287.10263；found:287.10235.
实施例25 N-(4-乙酰氨基苯基)-5-甲磺酰基呋喃-2-甲酰胺
N-(4-乙酰氨基苯基)-5-甲磺酰基呋喃-2-甲酰胺5-甲磺酰基呋喃-2-甲酸(4-14d)
Figure PCTCN2020096939-appb-000030
反应瓶中加入4-21(205mg,1mmol)，甲基磺酸钠(510mg,5mmol),无水DMSO(5mL)，110℃搅拌20h。TLC(PE:EA＝4:1)检测反应仍有少量原料未反应。反应液冷却至室温，加入乙酸乙酯(20mL)，用饱和NaCl溶液萃洗(15mL×3)，无水Na 2SO 4干燥，浓缩。硅胶柱层析(PE:EA＝4:1)分离得4-19，淡黄色固体72mg，收率35％。
1H NMR(400MHz,CDCl 3)δ10.37(s,1H),9.95(s,1H),7.64(d,J＝8.8Hz,2H),7.58-7.54(m,3H),7.45(d,J＝3.6Hz,1H),2.53(s,3H),2.04(s,3H). 13C NMR(101MHz,CDCl 3)δ157.89,151.99,147.77,117.82,117.70,52.68,43.07.
于4-19(72mg,0.35mmol)中加入四氢呋喃(4mL)，LiOH水溶液(3N,1mL)，室温搅拌5min，TLC(PE:EA＝2:1)检测反应完成。旋蒸除去大部分溶剂，残余物加水(5mL)，以4N盐酸调pH＝3，乙酸乙酯萃取(5mL×3)，有机相合并后以饱和NaCl洗涤，无水Na 2SO 4干燥，浓缩得4-14d，白色固体63mg，收率95％。
N-(4-乙酰氨基苯基)-5-甲磺酰基呋喃-2-甲酰胺(实施例25)
Figure PCTCN2020096939-appb-000031
合成方法同实施例5A。灰白色固体，收率37％，熔点251-253℃。
1H NMR(400MHz,DMSO-d 6)δ10.40(s,1H),9.96(s,1H),7.62(d,J＝8.8Hz,2H),7.57(d,J＝8.8Hz,2H),7.48(d,J＝3.6Hz,1H),7.44(d,J＝3.6Hz,1H),3.43(s,3H),2.04(s,3H). 13C NMR(101MHz,DMSO-d 6)δ168.58,155.31,151.01,150.91,136.39,133.32,121.76,119.70,118.23,115.31,43.28,24.40.HRMS m/z:calcd for C 14H 15N 2O 5S[M+H] +:323.06962；found:323.06897.
实施例26 N-(2-乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000032
合成方法同实施例1。黄色晶体，收率64％，熔点212-213℃。
1H NMR(400MHz,DMSO-d 6)δ10.16(s,1H),9.73(s,1H),7.83(d,J＝3.7Hz,1H),7.60-7.56(m, 3H),7.27-7.20(m,2H),2.10(s,3H). 13C NMR(101MHz,DMSO-d 6)δ169.66,155.28,152.01,148.57,132.47,129.03,126.66,125.28,124.85,116.89,114.01,23.99.HRMS m/z:calcd for C 13H 12N 3O 5[M+H] +:290.07715；found:290.07695.
实施例27 N-(3-乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000033
合成方法同实施例1。黄色固体，收率77％，熔点212-214℃。
1H NMR(400MHz,DMSO-d 6)δ10.63(s,1H),10.03(s,1H),8.09(s,1H),7.82(d,J＝3.9Hz,1H),7.67(d,J＝3.9Hz,1H),7.44(d,J＝7.8Hz,1H),7.35-7.27(m,2H),2.06(s,3H). 13C NMR(101MHz,DMSO-d 6)δ168.87,155.05,152.27,148.41,140.15,138.57,129.39,116.95,115.93,115.76,113.89,111.87,24.52.HRMS m/z:calcd for C 13H 12N 3O 5[M+H] +:290.07715；found:290.07690.
实施例28 N-(3-甲基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000034
合成方法同实施例1。硅胶柱分离(PE:EA＝6:1)得黄色固体，收率62％，熔点144-145℃。
1H NMR(400MHz,CDCl 3)δ8.15(s,1H),7.50-7.46(m,2H),7.41(d,J＝3.8Hz,1H),7.37(d,J＝3.8Hz,1H),7.29(d,J＝7.6Hz,1H),7.03(d,J＝7.6Hz,1H),2.38(s,3H). 13C NMR(101MHz,CDCl 3)δ153.89,147.94,139.31,136.24,129.10,126.40,120.99,117.49,116.70,112.68,21.48.HRMS m/z:calcd for C 12H 11N 2O 4[M+H] +:247.07133；found:247.07116.
实施例29 N-(2-甲氧基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000035
合成方法同实施例1。黄色固体，收率72％，熔点142-144℃。
1H NMR(400MHz,CDCl 3)δ8.86(s,1H),8.41(d,J＝8.0Hz,1H),7.41(d,J＝3.7Hz,1H),7.35(d,J＝3.7Hz,1H),7.15(t,J＝7.8Hz,1H),7.02(t,J＝7.8Hz,1H),6.96(d,J＝8.0Hz,1H),3.98(s,3H). 13C NMR(101MHz,CDCl 3)δ153.70,148.39,148.21,126.24,125.14,121.14,120.26,116.39,112.57,110.18,55.95.HRMS m/z:calcd for C 12H 11N 2O 5[M+H] +:263.06625；found:263.06540.
实施例30 N-(3-甲氧基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000036
合成方法同实施例1。黄色固体，收率91％，熔点123-124℃。
1H NMR(400MHz,CDCl 3)δ8.25(s,1H),7.42-7.37(m,3H),7.29(t,J＝8.0Hz,1H),7.17(d,J＝7.2Hz,1H),6.76(dd,J＝8.0,1.8Hz,1H),3.84(s,3H).. 13C NMR(101MHz,CDCl 3)δ160.27,153.94,147.83,137.53,129.98,116.80,112.70,112.53,111.45,106.09,55.40.HRMS m/z:calcd for C 12H 11N 2O 5[M+H] +:263.06625；found:263.06565.
实施例31 N-(4-甲氧基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000037
合成方法同实施例1。黄色固体，收率72％，熔点185-187℃。
1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),7.82(d,J＝3.8Hz,1H),7.65(d,J＝8.8Hz,2H),7.61(d,J＝3.8Hz,1H),6.96(d,J＝8.8Hz,2H),3.76(s,3H). 13C NMR(101MHz,DMSO-d 6)δ156.61,154.71,152.14,148.85,131.21,122.78,116.63,114.40,113.98,55.67.HRMS m/z:calcd for C 12H 11N 2O 5[M+H] +:263.06625；found:263.06567.
实施例32 N-(3-羟基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000038
合成方法同实施例5A。乙醇重结晶得黄色固体，收率89％，熔点226-228℃。
1H NMR(400MHz,DMSO-d 6)δ10.47(s,1H),9.52(s,1H),7.81(d,J＝3.9Hz,1H),7.64(d,J＝3.9Hz,1H),7.30(d,J＝2.0Hz,1H),7.18-7.12(m,2H),6.56(dt,J＝7.6,2.0Hz,1H). 13C NMR(101MHz,DMSO-d 6)δ158.06,154.91,152.20,148.47,139.29,129.92,116.83,113.88,112.15,111.78,108.17.HRMS m/z:calcd for C 11H 9N 2O 5[M+H] +:249.05060；found:249.05046.
实施例33 N-(4-羟基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000039
合成方法同实施例5A。黄色固体，收率86％，熔点247-249℃。
1H NMR(400MHz,DMSO-d 6)δ10.42(s,1H),9.39(s,1H),7.80(d,J＝3.9Hz,1H),7.58(d,J＝3.9Hz,1H),7.50(d,J＝8.8Hz,2H),6.77(d,J＝8.8Hz,2H). 13C NMR(101MHz,DMSO-d 6)δ154.89,154.59,152.10,148.82,129.67,123.03,116.42,115.64,113.97.HRMS m/z:calcd for C 12H 11N 2O 5[M+H] +:263.06625；found:263.06567.
实施例34 N-(3-氨基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000040
间苯二胺(108mg,1mmol)溶于四氢呋喃(5mL)，加入三乙胺(151mg,1.5mmol)，冰水浴冷却至0℃。将4-6a(175mg,1mmol)溶于四氢呋喃(1mL)，分批滴加至上述溶液中，滴毕，升至室温反应至TLC(CH 2Cl 2:MeOH＝15:1)检测反应完全。反应液中加入2N HCl溶液10mL，继续搅拌10min。抽滤，除去不溶物，滤液用饱和碳酸钠水溶液调pH＝9，用乙酸乙酯(8mL×3)萃取，有机相浓缩得黄色固体，用少量水/甲醇洗涤，干燥后得纯品100mg，收率41％，熔点191-193℃。
1H NMR(400MHz,DMSO-d 6)δ10.30(s,1H),7.80(d,J＝3.9Hz,1H),7.62(d,J＝3.9Hz,1H),7.03-6.97(m,2H),6.83(d,J＝8.0Hz,1H),6.36(dd,J＝8.0,1.2Hz,1H),5.17(s,2H). 13C NMR(101MHz,DMSO-d 6)δ154.75,152.17,149.57,148.69,138.86,129.47,116.57,113.88,111.00,108.85,106.57.HRMS m/z:calcd for C 11H 10N 3O 4[M+H] +:248.06658；found:248.06640.
实施例35 N-(2-氟苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000041
合成方法同实施例1。淡黄色固体，收率92％，熔点164-165℃。
1H NMR(400MHz,DMSO-d 6)δ10.57(s,1H),7.82(d,J＝3.9Hz,1H),7.64(d,J＝3.9Hz,1H),7.58(t,J＝7.8Hz,1H),7.35-7.32(m,2H),7.27-7.23(m,1H). 13C NMR(101MHz,DMSO-d 6)δ157.46,155.33,154.99,152.28,147.88,128.33,128.25,127.68,125.01,124.98,124.63,124.51,117.35,116.60,116.40,113.85.HRMS m/z:calcd for C 11H 8FN 2O 4[M+H] +:251.04626；found:251.04616.
实施例36 N-(3-氟苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000042
合成方法同实施例1。硅胶柱层析分离(PE:EA＝5:1)得黄色固体，收率50％，熔点164-165℃。
1H NMR(400MHz,CDCl 3)δ8.24(s,1H),7.65(d,J＝10.6Hz,1H),7.41(dd,J＝11.4,3.8Hz,2H),7.36-7.31(m,2H),6.92(t,J＝8.0Hz,1H). 13C NMR(101MHz,CDCl 3)δ164.21,161.76,153.93,147.42,137.84,137.73,130.47,130.38,117.11,115.64,115.61,112.65,112.48,112.27,108.11,107.84.HRMS m/z:calcd for C 11H 8FN 2O 4[M+H] +:251.04626；found:251.04602.
实施例37 N-(4-氟苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000043
合成方法同实施例1。硅胶柱层析分离(PE:EA＝5:1)得黄色固体，收率46％，熔点173-174℃。
1H NMR(400MHz,CDCl 3)δ8.18(s,1H),7.66-7.63(m,2H),7.42(d,J＝3.8Hz,1H),7.38(d,J＝3.8Hz,1H),7.10(t,J＝8.6Hz,2H). 13C NMR(101MHz,CDCl 3)δ161.31,158.86,153.93,147.65,132.29,122.35,122.27,116.87,116.18,115.95,112.64.HRMS m/z:calcd for C 11H 7FN 2O 4[M+H] +:251.04626；found:251.04611.
实施例38 N-(3-氯苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000044
合成方法同实施例1。黄色固体，收率86％，熔点153-154℃。
1H NMR(400MHz,CDCl 3)δ8.21(s,1H),7.82(t,J＝1.8Hz,1H),7.52(d,J＝8.0Hz,1H),7.43(d,J＝4.0Hz,1H),7.39(d,J＝4.0Hz,1H),7.33(t,J＝8.0Hz,1H),7.19(d,J＝8.0Hz,1H). 13C NMR(101MHz,CDCl 3)δ153.94,147.38,137.43,135.00,130.26,125.65,120.52,118.33,117.14,112.64.HRMS m/z:calcd for C 11H 8ClN 2O 4[M+H] +:267.01671；found:267.01600.
实施例39 N-(4-氯苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000045
合成方法同实施例1。黄色固体，收率80％，熔点179-180℃。
1H NMR(400MHz,DMSO-d 6)δ10.76(s,1H),7.83(d,J＝3.7Hz,1H),7.78(d,J＝8.6Hz,2H),7.64(d,J＝3.7Hz,1H),7.45(d,J＝8.6Hz,2H). 13C NMR(101MHz,DMSO-d 6)δ155.09,152.26,148.11,137.26,129.22,128.70,122.67,117.24,113.93.HRMS m/z:calcd for C 11H 7FN 2O 4[M+H] +:251.04626；found:251.04611.
实施例40 N-(3-氰基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000046
合成方法同实施例1。黄色固体，收率58％，熔点193-194℃。
1H NMR(400MHz,DMSO-d 6)δ10.93(s,1H),8.19(s,1H),8.03(d,J＝7.2Hz,1H),7.83(d,J＝4.0Hz,1H),7.67–7.60(m,3H). 13C NMR(101MHz,DMSO-d 6)δ155.41,152.34,147.77,139.14,130.80,128.51,125.74,123.96,118.97,117.66,113.91,112.11.HRMS m/z:calcd for C 12H 8N 3O 4[M+H] +: 258.05093；found:258.05055.
实施例41 N-(4-氰基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000047
合成方法同实施例1。淡黄色固体，收率65％，熔点229-231℃。
1H NMR(400MHz,DMSO-d 6)δ10.99(s,1H),7.96(d,J＝8.8Hz,2H),7.87(d,J＝8.8Hz,2H),7.83(d,J＝4.0Hz,1H),7.70(d,J＝4.0Hz,1H). 13C NMR(101MHz,DMSO-d 6)δ155.47,152.39,147.68,142.64,133.74,121.07,119.31,117.84,113.88,106.76.HRMS m/z:calcd for C 12H 8N 3O 4[M+H] +:258.05093；found:258.05055.
实施例42 3-(5-硝基呋喃-2-甲酰胺基)苯甲酸乙酯
Figure PCTCN2020096939-appb-000048
合成方法同实施例1。硅胶柱层析分离(PE:EA＝4:1)得黄色固体，收率66％，熔点126-128℃。
1H NMR(400MHz,CDCl 3)δ8.43(s,1H),8.22(s,1H),8.03(d,J＝8.0Hz,1H),7.88(d,J＝8.0Hz,1H),7.48(t,J＝8.0Hz,1H),7.42-7.40(m,2H),4.40(q,J＝6.8Hz,2H),1.41(t,J＝6.8Hz,3H). 13C NMR(101MHz,CDCl 3)δ165.93,154.21,151.40,147.61,136.64,131.68,129.46,126.59,124.76,121.37,117.11,112.72,61.40,14.37.HRMS m/z:calcd for C 14H 13N 2O 6[M+H] +:305.07681；found:305.07662.
实施例43 4-(5-硝基呋喃-2-甲酰胺基)苯甲酸乙酯
Figure PCTCN2020096939-appb-000049
合成方法同实施例1。黄色固体，收率77％，熔点221-223℃。
1H NMR(400MHz,DMSO-d 6)δ10.92(s,1H),7.99(d,J＝8.8Hz,2H),7.91(d,J＝8.8Hz,2H),7.84(d,J＝3.9Hz,1H),7.70(d,J＝3.9Hz,1H),4.31(q,J＝7.2Hz,2H),1.33(t,J＝7.2Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ165.67,155.31,152.36,147.89,142.72,130.64,125.84,120.41,117.55,113.89,61.05,14.66.HRMS m/z:calcd for C 14H 13N 2O 6[M+H] +:305.07681；found:305.07648.
实施例44 N-(3-氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000050
合成方法同实施例1。黄色固体，收率84％，熔点238-240℃。
1H NMR(400MHz,DMSO-d 6)δ10.76(s,1H),8.20(s,1H),7.99-7.94(m,2H),7.82(d,J＝4.0Hz,1H),7.69-7.66(m,2H),7.47(t,J＝8.0Hz,2H),7.40(s,1H). 13C NMR(101MHz,DMSO-d 6)δ168.06,155.14,152.29,148.21,138.35,135.57,129.16,123.80,123.69,120.81,117.10,113.91.HRMS m/z:calcd for C 12H 10N 3O 5[M+H] +:276.06150；found:276.06126.
实施例45 N-(4-氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000051
合成方法同实施例1。黄色固体，收率87％，熔点297℃(分解)。
1H NMR(400MHz,DMSO-d 6)δ10.85(s,1H),7.96-7.91(m,3H),7.85-7.82(m,3H),7.72-7.70(m,1H),7.37(s,1H). 13C NMR(101MHz,DMSO-d 6)δ167.71,155.21,152.31,148.93,130.46,128.81,120.20,117.37,113.92.HRMS m/z:calcd for C 12H 10N 3O 5[M+H] +:276.06150；found:276.06125.
实施例46 N-(3-乙酰基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000052
合成方法同实施例1。黄色固体，收率95％，熔点182-183℃。
1H NMR(400MHz,DMSO-d 6)δ10.82(s,1H),8.29(t,J＝2.0Hz,1H),8.06(dd,J＝8.4,1.2Hz,1H),7.83(d,J＝3.9Hz,1H),7.78(d,J＝7.8Hz,1H),7.67(d,J＝3.9Hz,1H),7.56(t,J＝7.8Hz,1H),2.60(s,3H). 13C NMR(101MHz,DMSO-d 6)δ197.99,155.26,152.30,148.11,138.73,129.77,125.53,125.03,120.32,117.26,113.92,27.23.HRMS m/z:calcd for C 13H 11N 2O 5[M+H] +:275.06625；found:275.06598.
实施例47 N-(4-二甲氨基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000053
合成方法同实施例1。棕色固体，收率63％，熔点202-205℃。
1H NMR(400MHz,CDCl 3)δ8.09(s,1H),7.52(d,J＝8.8Hz,2H),7.40(d,J＝3.6Hz,1H),7.34(d,J＝3.6Hz,1H),6.74(d,J＝8.8Hz,2H),2.96(s,6H). 13C NMR(101MHz,CDCl 3)δ153.58,148.61,148.45,125.77,122.02,121.91,116.19,112.80,112.73,40.68.HRMS m/z:calcd for C 14H 10N 3O 4[M+H] +:284.06658；found:284.06597.
实施例48 N-(4-吗啉基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000054
合成方法同实施例1。棕色固体，收率35％，熔点208-209℃。
1H NMR(400MHz,CDCl 3)δ8.11(s,1H),7.58(d,J＝8.4Hz,2H),7.41(s,1H),7.36(s,1H),6.94(d,J＝8.4Hz,2H),3.87(s,4H),3.17(s,4H). 13C NMR(101MHz,CDCl 3)δ153.69,151.25,149.06,148.11,128.70,121,74,116.49,116.08,112.81,66.84,49.32.HRMS m/z:calcd for C 14H 10N 3O 4[M+H] +:284.06658；found:284.06597.
实施例49 N-(4-(4-乙基哌嗪-1-基)苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000055
合成方法同实施例1。棕色固体，收率71％，熔点185-186℃。
1H NMR(400MHz,CDCl 3)δ8.10(s,1H),7.55(d,J＝8.4Hz,2H),7.41(s,1H),7.35(s,1H),6.95(d,J＝8.4Hz,2H),3.23(s,4H),2.62(s,4H),2.49(q,J＝7.0Hz,2H),1.14(t,J＝7.0Hz,3H). 13C NMR(101MHz,CDCl 3)δ153.73,151.21,149.10,148.24,128.38,121.75,116.43,116.28,112.86,52.76,52.38,49.10,12.05.HRMS m/z:calcd for C 14H 10N 3O 4[M+H] +:284.06658；found:284.06597.
实施例50 N-(4-(2-羟乙基)苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000056
合成方法同实施例1。硅胶柱层析分离(CH 2Cl 2:MeOH＝25:1)得黄色固体，收率35％，熔点147-148℃。
1H NMR(400MHz,DMSO-d 6)δ10.55(s,1H),7.81(d,J＝4.0Hz,1H),7.64-7.62(m,3H),7.23(d,J＝8.4Hz,2H),4.62(t,J＝5.2Hz,1H),3.60(dd,J＝12.4,6.8Hz,2H),2.71(t,J＝6.8Hz,2H). 13C NMR(101MHz,DMSO-d 6)δ154.90,152.17,148.53,136.40,136.13,129.61,121.11,116.80,113.93,62.59,38.96.HRMS m/z:calcd for C 13H 13N 2O 5[M+H] +:277.08190；found:277.08177.
实施例51 N-(4-氨甲基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000057
4-24的合成方法同实施例1。将4-24加入浓度为4N的HCl乙酸乙酯溶液(2mL)中，室温搅拌至TLC(CH 2Cl 2:MeOH＝15:1)检测反应完全。抽滤，得淡黄色固体232mg，为实施例52的盐酸盐。收率60％，熔点249-252℃。
1H NMR(400MHz,D 2O)δ7.84(d,J＝8.2Hz,2H),7.59(d,J＝3.6Hz,1H),7.50-7.48(m,3H),4.12(s,2H). 13C NMR(101MHz,D 2O)δ155.49,152.14,147.75,138.34,129.55,129.39,121.15,116.39,111.98,42.48.HRMS m/z:calcd for C 14H 10N 3O 4[M+H] +:284.06658；found:284.06597.
实施例52 N,N’-(1,4-亚苯基)二(5-硝基呋喃-2-甲酰胺)
Figure PCTCN2020096939-appb-000058
将间苯二胺(108mg,1mmol)溶于四氢呋喃(5mL)中，加入三乙胺(302mg,3mmol)，冰水浴冷却。将4-6a(350mg,2mmol)溶于四氢呋喃(1mL)，滴加至上述溶液中。滴毕升至室温搅拌过夜，TLC(CH 2Cl 2:MeOH＝15:1)检测反应完全。反应液中加入水(20mL)，充分搅拌后抽滤，干燥后得黄色固体232mg，收率60％，熔点185-186℃。
1H NMR(400MHz,CDCl 3)δ10.73(s,2H),8.26(s,1H),7.82(s,2H),7.68(s,2H),7.54(s,1H),7.52(s,1H),7.40(t,J＝8.0Hz,1H). 13C NMR(101MHz,CDCl 3)δ155.12,152.30,148.30,138.68,129.59,117.40,117.10,113.92,113.46.HRMS m/z:calcd for C 14H 10N 3O 4[M+H] +:284.06658；found:284.06597.
实施例53 N-(3-(甲氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺
3-氨基-N-甲基苯甲酰胺(4-25a)
Figure PCTCN2020096939-appb-000059
4-26a合成方法同实施例5A。将4-26a(180mg,1mmol)溶于甲醇(10mL)，加入Pd/C(10％,18mg)，置于氢化仪中室温反应2h，TLC(CH 2Cl 2:MeOH＝15:1)检测反应完全。反应液经硅藻土过滤，滤液浓缩得4-25a，黄色固体，收率70％。同法合成4-25b和4-32a～n。
N-(3-(甲氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺(实施例53)
Figure PCTCN2020096939-appb-000060
合成方法同实施例1。黄色固体，收率70％，熔点250-252℃。
1H NMR(400MHz,DMSO-d 6)δ10.79(s,1H),8.49(s,1H),8.19(s,1H),7.95(d,J＝7.8Hz,1H),7.83(s,1H),7.70(s,1H),7.61(d,J＝7.8Hz,1H),7.48(t,J＝7.8Hz,1H),2.80(d,J＝2.8Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ166.74,155.13,152.28,148.16,138.42,135.71,129.22,123.51,123.12,120.40,117.11,113.90,26.76.HRMS m/z:calcd for C 13H 12N 3O 5[M+H] +:290.07715；found:290.07696.
实施例54 N-(3-(二甲基氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000061
合成方法同实施例1。硅胶柱层析分离(PE:EA＝1:3)得黄色固体，收率56％，熔点157-159℃。
1H NMR(400MHz,CDCl 3)δ9.45(s,1H),7.77(d,J＝8.0Hz,1H),7.66(s,1H),7.38-7.30(m,3H),7.16(d,J＝8.0Hz,1H),3.12(s,1H),3.00(s,1H). 13C NMR(101MHz,CDCl 3)δ171.19,154.47,151.41,148.06,137.06,136.77,129.12,123.17,121.73,119.46,116.73,112.60,39.57,35.36.HRMS m/z:calcd for C 14H 14N 3O 5[M+H] +:304.09280；found:304.09265.
实施例55 N-(3-(乙氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000062
合成方法同实施例1。黄色固体，收率85％，熔点197-199℃。
1H NMR(400MHz,DMSO-d 6)δ10.77(s,1H),8.50(t,J＝5.2Hz,1H),8.16(t,J＝1.8Hz,1H),7.94(dd,J＝8.0,1.2Hz,1H),7.83(d,J＝3.9Hz,1H),7.68(d,J＝3.9Hz,1H),7.62(d,J＝8.0Hz,1H),7.47(t,J＝8.0Hz,1H),3.32-3.26(m,2H),1.13(t,J＝7.2Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ166.08,155.15,152.30,148.18,138.37,135.94,129.19,123.53,123.26,120.47,117.12,113.92,34.55,15.24.HRMS m/z:calcd for C 14H 14N 3O 5[M+H] +:304.09280；found:304.09286.
实施例56 N-(3-(异丙氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000063
合成方法同实施例1。黄色固体，收率31％，熔点196-198℃。
1H NMR(400MHz,DMSO-d 6)δ10.77(s,1H),8.26(d,J＝8.0Hz,1H),8.12(t,J＝1.6Hz,1H),7.95(dd,J＝8.0,1.6Hz,1H),7.83(d,J＝3.9Hz,1H),7.68(d,J＝3.9Hz,1H),7.63(d,J＝8.0Hz,1H),7.46(t,J＝8.0Hz,1H),4.14-4.07(m,1H),1.17(d,J＝6.8Hz,6H). 13C NMR(101MHz,DMSO-d 6)δ165.53,155.14,152.29,148.17,138.27,136.14,129.09,123.48,120.55,117.10,113.92,41.50,22.77.HRMS m/z:calcd for C 15H 16N 3O 5[M+H] +:318.10845；found:318.10893.
实施例57 N-(3-(异丁氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000064
合成方法同实施例1。黄色固体，收率45％，熔点191-192℃。
1H NMR(400MHz,DMSO-d 6)δ10.78(s,1H),8.50(t,J＝5.4Hz,1H),8.15(s,1H),7.94(d,J＝8.0Hz,1H),7.83(d,J＝3.9Hz,1H),7.68(d,J＝3.9Hz,1H),7.62(d,J＝8.0Hz,1H),7.47(t,J＝8.0Hz,1H),3.08(t,J＝6.4Hz,2H),1.88-1.81(m,1H),0.89(d,J＝6.4Hz,6H). 13C NMR(101MHz,DMSO-d 6)δ166.48,155.16,152.31,148.20,138.37,136.11,129.19,123.53,123.35,120.19,117.13,113.94,47.21,28.57,20.69.HRMS m/z:calcd for C 15H 16N 3O 5[M+H] +:318.10845；found:318.10893.
实施例58 N-(3-(环己氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000065
合成方法同实施例1。黄色固体，收率48％，熔点249-252℃。
1H NMR(400MHz,DMSO-d 6)δ10.78(s,1H),8.25(d,J＝7.8Hz,1H),8.12(s,1H),7.97(d,J＝7.8Hz,1H),7.84(d,J＝3.9Hz,1H),7.70(d,J＝3.9Hz,1H),7.64(d,J＝7.8Hz,1H),7.46(d,J＝7.8Hz,1H),3.78(s,1H),1.88-1.72(m,4H),1.62(d,J＝11.8Hz,1H),1.38-1.24(m,4H),1.20-1.10(m,1H). 13C NMR(101MHz,DMSO-d 6)δ165.54,155.15,152.31,148.20,138.28,136.17,129.09,123.51,120.59,117.11,113.93,48.86,32.85,25.73,25.41.HRMS m/z:calcd for C 15H 16N 3O 5[M+H] +:318.10845；found:318.10893.
实施例59 N-(3-(苄氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000066
合成方法同实施例1。黄色固体，收率69％，熔点165-167℃。
1H NMR(400MHz,DMSO-d 6)δ10.80(s,1H),9.10(s,1H),8.21(s,1H),7.97(d,J＝7.8Hz,1H),7.82(d,J＝3.2Hz,1H),7.70-7.68(m,2H),7.49(t,J＝7.8Hz,1H),7.40-7.19(m,5H),4.49(d,J＝5.4Hz,2H). 13C NMR(101MHz,DMSO-d 6)δ166.39,155.15,152.29,148.15,140.06,138.44,135.60,129.30,128.75,127.65,127.21,123.76,123.37,120.57,117.14,113.91,43.09.HRMS m/z:calcd for C 15H 16N 3O 5[M+H] +:318.10845；found:318.10893.
实施例60 N-(3-((2-二甲氨基乙基)氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000067
合成方法同实施例1。黄色固体，收率85％，熔点149-150℃。
1H NMR(400MHz,CDCl 3)δ8.71(s,1H),8.02(s,1H),7.97(dd,J＝8.0,1.2Hz,1H),7.60(d,J＝8.0Hz,1H),7.46(t,J＝8.0Hz,1H),7.42(d,J＝3.8Hz,1H),7.39(d,J＝3.8Hz,1H),6.97(s,1H),3.53(q,J＝5.6Hz,2H),2.53(t,J＝5.6Hz,2H),2.28(s,6H). 13C NMR(101MHz,DMSO-d 6)δ166.24,155.18,152.27,148.28,138.53,135.77,129.20,123.64,123.24,120.46,117.09,113.93,58.62,45.74,37.91.HRMS m/z:calcd for C 15H 16N 3O 5[M+H] +:318.10845；found:318.10893.
实施例61 N-(3-((2-吗啉基乙基)氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000068
合成方法同实施例1。白色固体，收率49％，熔点193-194℃。
1H NMR(400MHz,DMSO-d 6)δ10.78(s,1H),8.44(t,J＝5.6Hz,1H),8.16(t,J＝1.6Hz,1H),7.94(dd,J＝8.0,1.2Hz,1H),7.82(d,J＝3.9Hz,1H),7.67(d,J＝3.9Hz,1H),7.60(d,J＝8.0Hz,1H),7.47(t,J＝8.0Hz,1H),3.57(t,J＝4.4Hz,4H),3.40(q,J＝6.4Hz,3H),2.52-2.40(m,6H). 13C NMR(101MHz,DMSO-d 6)δ166.32,155.22,152.26,148.41,138.69,135.79,129.21,123.69,123.18,120.51,117.04,113.94,66.66,57.80,53.76,37.05.HRMS m/z:calcd for C 18H 21N 4O 6[M+H] +:389.14556；found:389.14653.
实施例62 N-(3-((3-吗啉基丙基)氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000069
合成方法同实施例1。黄色固体，收率68％，熔点156-158℃。
1H NMR(400MHz,CDCl 3)δ8.44(s,1H),8.10(s,1H),8.03(s,1H),7.92(d,J＝8.0Hz,1H),7.61(d,J＝8.0Hz,1H),7.48(t,J＝8.0Hz,1H),7.41(d,J＝8.0Hz,2H),3.69(s,4H),3.59(d,J＝5.2Hz,2H), 2.66-2.42(m,6H),1.80(s,2H). 13C NMR(101MHz,CDCl 3)δ166.63,154.12,147.49,136.91,136.19,129.48,123.57,122.97,119.06,117.01,112.63,66.95,58.70,53.83,40.74,24.13.HRMS m/z:calcd for C 18H 21N 4O 6[M+H] +:389.14556；found:389.14653.
实施例63 N-(4-甲基-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000070
合成方法同实施例1。黄色固体，收率65％，熔点225-226℃。
1H NMR(400MHz,DMSO-d 6)δ10.65(s,1H),8.20(d,J＝4.4Hz,1H),7.82(d,J＝3.6Hz,1H),7.72(s,2H),7.64(d,J＝3.6Hz,1H),7.25(d,J＝8.8Hz,1H),2.76(d,J＝4.4Hz,3H),2.29(s,3H). 13C NMR(101MHz,DMSO-d 6)δ169.59,154.96,148.27,138.14,135.84,131.51,131.22,121.59,119.67,116.97,113.94,26.37,19.27.HRMS m/z:calcd for C 18H 21N 4O 6[M+H] +:389.14556；found:389.14653.
实施例64 N-(5-甲基-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000071
合成方法同实施例1。黄色固体，收率63％，熔点195-198℃。
1H NMR(400MHz,DMSO-d 6)δ10.69(s,1H),8.42(d,J＝4.8Hz,1H),7.97(s,1H),7.82(d,J＝3.9Hz,1H),7.76(s,1H),7.67(d,J＝3.9Hz,1H),7.44(s,1H),2.78(d,J＝4.4Hz,3H),2.37(s,3H). 13C NMR(101MHz,DMSO-d 6)δ166.89,155.07,152.29,148.20,138.60,138.30,135.73,123.97,117.73,117.04,113.92,26.76,21.64.HRMS m/z:calcd for C 18H 21N 4O 6[M+H] +:389.14556；found:389.14653.
实施例65 N-(4-氟-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000072
合成方法同实施例1。黄色固体，收率35％，熔点195-198℃。
1H NMR(400MHz,DMSO-d 6)δ10.69(s,1H),8.42(d,J＝4.8Hz,1H),7.97(s,1H),7.82(d,J＝3.9Hz,1H),7.76(s,1H),7.67(d,J＝3.9Hz,1H),7.44(s,1H),2.78(d,J＝4.4Hz,3H),2.37(s,3H). 13C NMR(101MHz,DMSO-d 6)δ166.89,155.07,152.29,148.20,138.60,138.30,135.73,123.97,117.73,117.04,113.92,26.76,21.64.HRMS m/z:calcd for C 18H 21N 4O 6[M+H] +:389.14556；found:389.14653.
实施例66 N-(5-氟-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000073
合成方法同实施例1。硅胶柱层析分离(CH 2Cl 2:MeOH＝25:1)得黄色固体，收率40％，熔点211-213℃。
1H NMR(400MHz,DMSO-d 6)δ10.97(s,1H),8.58(d,J＝4.2Hz,1H),8.05(s,1H),7.92(d,J＝10.8Hz,1H),7.85(d,J＝3.9Hz,1H),7.71(d,J＝3.9Hz,1H),7.47(d,J＝9.2Hz,1H),2.82(d,J＝4.4Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ165.48,163.31,160.90,155.31,152.36,147.75,140.07,139.95,137.41,137.33,117.51,116.29,113.88,110.26,110.00,109.82,109.59,26.80.HRMS m/z:calcd for C 18H 21N 4O 6[M+H] +:389.14556；found:389.14653.
实施例67 N-(4-羟基-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000074
合成方法同实施例5A。黄色固体，收率30％，熔点260-262℃。
1H NMR(400MHz,DMSO-d 6)δ12.16(s,1H),10.60(s,1H),8.73(d,J＝3.6Hz,1H),8.09(s,1H),7.82(d,J＝3.6Hz,1H),7.66-7.59(m,2H),6.94(d,J＝8.8Hz,1H),2.82(d,J＝4.0Hz,3H). 13C NMR(101MHz,DMSO-d 6)δ168.45,156.53,154.94,152.21,148.50,129.13,127.72,122.35,117.81,116.70,114.00,26.61.HRMS m/z:calcd for C 18H 21N 4O 6[M+H] +:389.14556；found:389.14653.
实施例68 N 1,N 3-二甲基-5-(5-硝基呋喃-2-甲酰胺基)间苯二甲酰胺
Figure PCTCN2020096939-appb-000075
合成方法同实施例1。黄色固体，收率55％，熔点151-153℃。
1H NMR(400MHz,DMSO-d 6)δ10.92(s,1H),8.56(d,J＝4.4Hz,2H),8.35(s,2H),8.06(s,1H),7.86(d,J＝3.9Hz,1H),7.73(d,J＝3.9Hz,1H),2.83(d,J＝4.4Hz,6H). 13C NMR(101MHz,DMSO-d 6)δ166.59,155.23,152.36,147.96,138.50,135.99,122.46,121.86,117.30,113.92,26.82.HRMS m/z:calcd for C 18H 21N 4O 6[M+H] +:389.14556；found:389.14653.
实施例69 N-(2-甲基-1,3-二氢-1,3-二氧代-2H-异吲哚-5-基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000076
合成方法同实施例1。黄色固体，收率50％，熔点252-254℃。
1H NMR(400MHz,DMSO-d 6)δ11.09(s,1H),8.26(d,J＝1.6Hz,1H),8.09(dd,J＝8.2,1.6Hz,1H),7.87(d,J＝8.2Hz,1H),7.83(d,J＝3.9Hz,1H),7.69(d,J＝3.9Hz,1H),3.02(s,3H). 13C NMR(101MHz,DMSO-d 6)δ168.11,168.01,155.52,152.42,147.61,143.68,133.64,127.29,125.09,124.50,117.92,114.60,113.90,24.24.HRMS m/z:calcd for C 18H 21N 4O 6[M+H] +:389.14556；found:389.14653.
实施例70 N-(4-乙酰氨基苯基)-5-乙酰基呋喃-2-甲酰胺
5-乙酰基呋喃-2-甲酸(4-14e)
Figure PCTCN2020096939-appb-000077
将4-21(205mg,1mmol)溶于无水DMF(5mL),加入4-33(361mg,1.5mmol)、PdCl 2(PPh 3) 2(70mg,0.1mmol)。氩气保护下于115℃搅拌18h。TLC(PE:EA＝3:1)检测反应基本完全。反应液冷却至室温，加入盐酸(4N,0.5mL)，搅拌30min。反应体系中加入水15mL，用乙酸乙酯萃取(15mL×3)，有机相合并后用无水Na 2SO 4干燥，浓缩。硅胶柱层析(PE:EA＝10:1)得4-34，白色固体100mg，收率60％。
于4-34(100mg,6mmol)中加入四氢呋喃(4mL)，LiOH水溶液(3N,1mL)，室温搅拌5min，TLC(PE:EA＝3:1)检测反应完成。旋蒸除去大部分溶剂，残余物加水(5mL)，以4N盐酸调pH＝3-4，乙酸乙酯萃取(5mL×3)，有机相合并后以饱和NaCl洗涤，无水Na 2SO 4干燥，浓缩得4-14e，白色固体90mg，收率98％。
N-(4-乙酰氨基苯基)-5-乙酰基呋喃-2-甲酰胺(实施例70)
Figure PCTCN2020096939-appb-000078
合成方法同实施例5A。淡黄色固体，收率82％，熔点250-251℃。
1H NMR(400MHz,DMSO-d 6)δ10.37(s,1H),9.95(s,1H),7.64(d,J＝8.8Hz,2H),7.58-7.54(m,3H),7.45(d,J＝3.6Hz,1H),2.53(s,3H),2.04(s,3H). 13C NMR(101MHz,DMSO-d 6)δ187.18,168.55,155.92,152.90,150.25,136.25,133.57,121.69,119.67,119.37,116.04,26.78,24.40.HRMS m/z:calcd for C 15H 15N 2O 4[M+H] +:287.10263；found:287.10235.
实施例71 N-(4-(2-二甲氨基)乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000079
将对硝基苯胺(276mg,2mmol)、三乙胺(303mg,3mmol)加入四氢呋喃(10mL)中，冰水浴下滴加氯乙酰氯(226mg,2mmol)。滴毕，室温搅拌2h，TLC(CH 2Cl 2:MeOH＝10:1)检测反应完成。反应液中加入1N HCl(20mL)，继续搅拌15min，抽滤，干燥，得黄色粉末4-35a，408mg,收率95％。
将4-36a(214mg,1mmol)，二甲胺盐酸盐(163mg,2mmol)，无水碳酸钾(414mg,3mmol)，碘化钠(165mg,1.1mmol)，乙腈(15mL)加入反应瓶，80℃搅拌3h，TLC(CH 2Cl 2:MeOH＝10:1)检测反应完成。反应液冷却后抽滤，滤液浓缩，残余物加入水和乙酸乙酯各15mL，混匀后静置分层，弃去水相，有机相以2N盐酸萃取(3mL×3)，萃取液合并后以饱和碳酸氢钠水溶液调pH＝9，析出黄色固体，抽滤、干燥得4-35a，150mg，收率64％。
4-37a的合成方法同4-25a，不经分离直接用于下一步反应。
实施例71的合成方法同实施例5A。黄色固体，收率68％，熔点207-209℃。
1H NMR(400MHz,DMSO-d 6)δ10.61(s,1H),9.76(s,1H),7.82(d,J＝3.5Hz,1H),7.71-7.49(m,5H),3.06(s,2H),2.27(s,6H). 13C NMR(101MHz,DMSO-d 6)δ168.98,154.79,152.19,148.50,135.81,133.60,121.53,120.23,116.80,113.98,63.73,45.83.HRMS m/z:calcd for C 15H 16N 4O 5[M+H] +:333.11935；found:333.11900.
实施例72 N-(4-(2-吗啉基)乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000080
合成方法同实施例72。黄色固体，收率32％，熔点255-257℃。
1H NMR(400MHz,DMSO-d 6)δ10.63(s,1H),9.80(s,1H),7.83(d,J＝3.8Hz,1H),7.69-7.61(m,5H),3.64(t,J＝4.0Hz,4H),3.13(s,2H),2.51(t,J＝4.0Hz,4H). 13C NMR(101MHz,DMSO-d 6)δ168.41,154.81,152.20,148.49,135.68,133.71,121.55,120.29,116.82,113.99,66.53,62.48,53.64.HRMS m/z:calcd for C 17H 18N 4O 6[M+H] +:375.12991；found:375.13017.
实施例73 N-(4-(3-二甲氨基)丙酰氨基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000081
合成方法同实施例71。黄色固体，收率30％，熔点213-215℃。
1H NMR(400MHz,DMSO-d 6)δ10.78(s,1H),10.18(s,1H),7.81(d,J＝1.5Hz,2H),7.70(d,J＝8.8Hz,2H),7.60(d,J＝8.8Hz,2H),2.54(t,J＝6.9Hz,2H),2.44(t,J＝6.9Hz,2H),2.16(s,6H). 13C NMR(101MHz,DMSO-d 6)δ170.55,154.79,152.22,148.58,136.44,133.45,121.59,119.68,116.92,113.95,55.61,45.44,35.16.HRMS m/z:calcd for C 16H 18N 4O 5[M+H] +:347.13500；found:347.13491.
实施例74 N-(4-((2-二甲氨基)乙基氨基)乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000082
合成方法同实施例71。橘黄色固体，收率28％，熔点160-162℃。
1H NMR(400MHz,CDCl 3)δ9.80(s,1H),8.24(s,1H),7.80–7.53(m,4H),7.42(d,J＝3.6Hz,1H),7.37(d,J＝3.6Hz,1H),3.41(d,J＝2.2Hz,2H),2.78(s,2H),2.45(s,2H),2.28(d,J＝2.2Hz,6H). 13C NMR(101MHz,CDCl 3)δ170.42,153.79,147.94,135.58,132.19,121.06,120.08,116.68,112.73,58.77,53.09,47.43,45.34.HRMS m/z:calcd for C 17H 21N 5O 5[M+H] +:376.16155；found:376.16271.
实施例75 2-乙酰氨基-5-(5-硝基呋喃-2-甲酰胺)苯甲酸乙酯
Figure PCTCN2020096939-appb-000083
合成方法同实施例1。黄色固体，收率89％，熔点214-215℃。
1H NMR(400MHz,DMSO-d 6)δ10.79(s,1H),10.46(s,1H),8.34(d,J＝2.5Hz,1H),8.19(d,J＝9.0Hz,1H),7.98(dd,J＝9.0,2.5Hz,1H),7.82(d,J＝3.9Hz,1H),7.64(d,J＝3.9Hz,1H),3.88(s,3H),2.13(s,3H). 13C NMR(101MHz,DMSO-d 6)δ168.81,167.57,155.00,152.25,148.15,136.39,133.54,126.29,122.46,117.08,113.91,52.84,25.01.HRMS m/z:calcd for C 15H 13N 3O 7[M+H] +:348.08263；found:348.08242.
实施例76 5-(5-硝基呋喃-2-甲酰胺)-1H-吡唑-4-羧酸乙酯
Figure PCTCN2020096939-appb-000084
合成方法同实施例5A。黄色固体，收率48％，熔点174-175℃。
1H NMR(400MHz,CDCl 3)δ8.15(d,J＝3.8Hz,1H),7.80(s,1H),7.41(d,J＝3.8Hz,1H),4.32(q,J＝7.1Hz,2H),1.37(t,J＝7.1Hz,3H). 13C NMR(101MHz,CDCl 3)δ163.67,156.79,154.70,153.38,144.86,144.32,125.33,111.45,94.67,60.22,14.48.
实施例77 5-(5-硝基呋喃-2-甲酰胺)-1H-吡唑-3-羧酸乙酯
Figure PCTCN2020096939-appb-000085
合成方法同实施例5A。黄色固体，收率30％。
1H NMR(400MHz,DMSO-d 6)δ13.79(s,1H),11.62(s,1H),7.81(d,J＝3.8Hz,1H),7.75(d,J＝3.8Hz,1H),7.06(s,1H),4.33(q,J＝7.1Hz,2H),1.33(t,J＝7.1Hz,3H).
实施例78 3-(5-乙酰基-2-呋喃甲酰基)氨基甲酰胺
Figure PCTCN2020096939-appb-000086
合成方法同实施例5A。白色固体，收率36％。
1H NMR(400MHz,CDCl 3)δ8.63(s,1H),8.09(s,1H),7.85(d,J＝8.0Hz,1H),7.59(d,J＝8.0Hz,1H),7.44(t,J＝8.0Hz,1H),7.31(d,J＝3.8Hz,1H),7.26(d,J＝3.8Hz,1H),6.38(s,1H),3.02(d,J＝4.8Hz,3H),2.56(s,3H). 13C NMR(101MHz,CDCl 3)δ186.51,167.56,155.52,152.33,149.69,137.27,135.60,129.53,123.50,122.91,119.12,118.47,116.52,26.90,26.29.HRMS m/z:calcd for C 15H 14N 2O 4[M+H] +:287.10263；found:287.10218.
实施例79 N-3-(乙炔基苯基)-5-硝基呋喃-2-甲酰胺
Figure PCTCN2020096939-appb-000087
合成方法同实施例1。硅胶柱层析分离(PE:EA＝5:1)得黄色固体，收率46％，熔点173-174℃。
1H NMR(400MHz,CDCl 3)δ8.20(s,1H),7.82(s,1H),7.69(dt,J＝7.4,2.0Hz,1H),7.42(d,J＝3.8Hz,1H),7.39(d,J＝3.8Hz,1H),7.34-7.31(m,2H),3.11(s,1H). 13C NMR(101MHz,CDCl 3)δ153.96,147.53,136.39,129.31,129.22,123.78,123.28,120.81,117.02,112.63,82.72,78.03。
试验例
UT-B抑制剂的筛选和药效学评价
1.筛选试验方法
1)取血，置于15ml刻度离心管(悬于含有肝素钠的PBS)中，离心，3000r/min，10min，弃上清；
2)加入与血等量的PBS，离心，3000r/min，10min，弃上清；
3)用含1.25M尿素的高渗PBS稀释红细胞至比容为2％的细胞悬液；
4)红细胞悬液置于室温孵育2h使细胞内外尿素浓度平衡，定时用移液器进行混合；
5)取99μl上述红细胞悬液置于96孔圆底微孔板各孔中，然后加入1μl待测化合物，混匀，室温孵育6min(待测化合物终浓度为20μM，DMSO终浓度为1％)；
6)另取96孔平底黑壁微孔板，每孔加入180μl等渗PBS(含1％DMSO)；
7)取上述步骤5)红细胞悬液20μl，迅速加入96孔板中，快速混匀；
8)5min内用酶标仪测吸光度值，波长710nm；
9)每块微孔板均设阳性对照孔(非特异性UT-B抑制剂phloretin)、阴性对照孔(PBS)。
Figure PCTCN2020096939-appb-000088
光度值，A pos是阳性对照孔的吸光度值。通过测吸收波长710计算红细胞裂解率。
2.发现尿素通道抑制剂苗头化合物
为增加发现尿素通道线索化合物的机会，本发明首先根据UT-B蛋白分子结构，利用计算机模拟筛选了1040种可能具有UT-B抑制活性的化合物，将上述化合物溶于DMSO，在96孔微孔板中稀释成1mM浓度应用液作为筛选化合物库。
取人、大鼠(SD大鼠)、小鼠(C57小鼠)三个种属的红细胞，以红细胞尿素通道抑制剂筛选模型，对上述筛选化合物库进行尿素通道抑制剂的初步筛选，筛选化合物浓度为10μM，重复筛选一次，确定线索化合物。
3.线索化合物特异性抑制尿素通道
为了确定线索化合物作用特异性，分别用等渗PBS或含1.25M尿素PBS平衡红细胞，线索化合物(10μM)孵育后，快速转移至等渗PBS中，检测红细胞裂解率。结果为：用等渗PBS孵育的红细胞，未见红细胞明显裂解，而用1.25M尿素PBS孵育的红细胞，红细胞裂解。表明红细胞的破裂是线索化合物特异性抑制尿素通道蛋白的尿素通透性所致。
4.确定最佳线索化合物
以所获得的线索化合物结构的母核为基础，进行取代基的替换化学结构类似物，建立二次筛选小分子库，应用上述模型和方法筛选和确定活性，获得剂量效应实验结果(表3)(注：表3中的IC 50分别是小鼠、大鼠、人红细胞溶解率为50％时的浓度)。如表3所示，本发明的化合物均具有尿素通道蛋白抑制作用，可以作为尿素通道蛋白抑制剂使用。
经分析比较，选择对三个种属均有较好抑制作用的实施例3化合物实施例3化合物作为示例性的优选化合物(图2A～图2C)。
5.实施例3化合物对尿素通道UT-A的抑制作用
为确定实施例3化合物对UT-A的抑制作用，将稳定表达UT-A1的MDCK细胞在Transwell中培养成紧密的单细胞层，用forskolin刺激UT-A蛋白转移至细胞质膜，用实施例3化合物孵育15min，将Transwell下面的培养液换成含有15mM尿素的培养液，在特定时间检测Transwell上面培养液中的尿素浓度，评价实施例3化合物对UT-A尿素通透性的抑制作用。
实验结果表明，本发明示例性的实施例3化合物显著抑制UT-A1介导的尿素通透性(图2D)，且实施例3化合物对UT-A抑制活性强于UT-B(图2E，图2F)。
6.实施例3化合物具有明显的利尿作用
(1)取SD大鼠，雄性，每组6只，体重200g左右。实验前将动物放入代谢笼中适应三天，标准饮食，自由饮水。尿液收集系统提前进行硅化处理，以防尿液丢失。适应完成后，收集两h尿液，转移至事先称量好的EP管中，皮下注射100mg/kg实施例3化合物，每两h收集一次尿液，共收集12h。溶剂对照：玉米油。减重法测量尿液重量，换算为体积(1g≈1ml)。以时间为横坐标，尿量作为纵坐标，绘制曲线，结果见图4A；和溶剂对照组相比，实施例3化合物表现出明显的利尿作用。利尿作用的高峰在给药后4h，利尿作用持续时间约6～8h。结果显示means±SEM，n＝6。收集的尿液使用冰点渗透压仪测量尿液渗透压仪。以时间为横坐标，尿渗透压作为纵坐标，绘制曲线，结果见图4B；和溶剂对照组相比，实施例3化合物能明显地降低尿渗透压。作用的高峰在给药后4h，并于给药后6～8h恢复到给药前的水平，结果显示means±SEM，n＝6。所取的尿样应用尿素试剂盒检测尿中尿素的水平，根据之前测得的每2h尿量、尿渗透压和尿素排泄量，计算出每2h非尿素溶质的排泄量。与对照组比较，各剂量组每2h非尿素溶质排泄量无显著变化(图3C)。结果显示means±SEM，n＝6。
(2)取C57BL/6J小鼠，雄性，每组6只，体重20～22克。实验前将动物放入代谢笼中适应三天，标准饮食，自由饮水。尿液收集系统提前进行硅化处理，以防尿液丢失。适应完成后， 收集两h尿液，转移至事先称量好的试管中，皮下注射100mg/kg实施例3化合物，每两h收集一次尿液，共收集12h。溶剂对照：40％玉米油。减重法测量尿液重量，换算为体积(1g≈1ml)。以时间为横坐标，尿量作为纵坐标，绘制曲线，结果见图4A；和溶剂对照组相比，实施例3化合物表现出明显的利尿作用。结果显示means±SEM，n＝6。收集的尿液使用冰点渗透压仪测量尿液渗透压仪。以时间为横坐标，尿渗透压作为纵坐标，绘制曲线，结果见图4B；和溶剂对照组相比，实施例3化合物能明显地降低尿渗透压。结果显示means±SEM，n＝6。所取的尿样应用尿素试剂盒检测尿中尿素的水平，根据之前测得的每2h尿量、尿渗透压和尿素排泄量，计算出每2h非尿素溶质的排泄量。与对照组比较，各剂量组每2h非尿素溶质排泄量无显著变化(图4C)。结果显示means±SEM，n＝6。
(3)取SD大鼠，雄性，每组6只，体重200g左右，实验前将动物放入代谢笼中适应三天，标准饮食，自由饮水。尿液收集系统提前进行硅化处理，以防尿液丢失。适应完成后，收集两h尿液，转移至事先称量好的试管中，灌胃给药100mg/kg实施例3化合物，每两h收集一次尿液，共收集12h。溶剂对照：0.5％羧甲基纤维素钠(CMC-Na)。减重法测量尿液重量，换算为体积(1g≈1ml)。以时间为横坐标，尿量作为纵坐标，绘制曲线，结果见图5A；和溶剂对照组相比，实施例3化合物表现出明显的利尿作用。在给药后2h尿量便开始升高，利尿作用的高峰在给药后4h，利尿作用持续时间约6～8h。结果显示means±SEM，n＝6。收集的尿液使用冰点渗透压仪测量尿液渗透压仪。以时间为横坐标，尿渗透压作为纵坐标，绘制曲线，结果见图5B；和溶剂对照组相比，实施例3化合物能明显地降低尿渗透压。作用的高峰在给药后4h，并于给药后6～8h恢复到给药前的水平，结果显示means±SEM，n＝6。所取的尿样应用尿素试剂盒检测尿中尿素的水平，根据之前测得的每2h尿量、尿渗透压和尿素排泄量，计算出每2h尿中非尿素排泄量。与对照组比较，各剂量组每2h非尿素溶质排泄量无显著变化，如图5C。C57BL/6J小鼠，雄性，每组6只，体重20～22g，实验前将动物放入代谢笼中适应三天，标准饮食，自由饮水。尿液收集系统提前进行硅化处理，以防尿液丢失。适应完成后，收集两h尿液，转移至事先称量好的试管中，灌胃给药100mg/kg实施例3化合物，每两h收集一次尿液，共收集12h。溶剂对照：CMC-Na。减重法测量尿液重量，换算为体积(1g≈1ml)。以时间为横坐标，尿量作为纵坐标，绘制曲线，结果见图6A；和溶剂对照组相比，实施例3化合物表现出明显的利尿作用。结果显示means±SEM，n＝6。收集的尿液使用冰点渗透压仪测量尿液渗透压仪。以时间为横坐标，尿渗透压作为纵坐标，绘制曲线，结果见图6B；和溶剂对照组相比，实施例3化合物能明显地降低尿渗透压。结果显示means±SEM，n＝6。所取的尿样应用尿素试剂盒检测尿中尿素的水平，根据之前测得的每2h尿量、尿渗透压和尿素排泄量，计算出每2h非尿素溶质的排泄量。与对照组比较，各剂量组每2h非尿素溶质排泄量无显著变化(图6C)。结果显示means±SEM，n＝6。
随后，因此本发明人进一步观察实施例3化合物的长期利尿作用。正常C57BL/6J小鼠，8周，雄性，每组8只，实验前将动物放入代谢笼中适应三天，标准饮食，自由饮水。适应完成后，灌胃给药100mg/kg实施例3化合物(首剂加倍)，每8h一次，溶剂对照：0.5％羧甲基纤维素钠(CMC-Na)。每24h收集一次尿液，转移至事先称量好的试管中。共给药7天，并记录体重，结果见图7。减重法测量尿液重量，换算为体积(1g≈1ml)。以时间为横坐标，尿量作为纵坐标，绘制曲线，结果见图7A；和溶剂对照组相比，实施例3化合物给药第一天尿量开始增多，一直持续到第7天，较溶剂对照组，具有明显的利尿作用，结果显示means±SEM，n＝8。使用冰点渗透压仪测量尿液渗透压。以时间为横坐标，尿渗透压作为纵坐标，绘制曲线，结果见图7A；和溶剂对照组相比，实施例3化合物给药组第一天尿渗透压开始下降，一直持续到第7天，说明连续给实施例3化合物后，可以降低小鼠尿的渗透压，结果显示means±SEM，n＝8。
正常SD大鼠，8周，雄性，每组8只，实验前将动物放入代谢笼中适应三天，标准饮食， 自由饮水。适应完成后，灌胃给药100mg/kg实施例3化合物(首剂加倍)，每8h一次，溶剂对照：0.5％羧甲基纤维素钠(CMC-Na)。每24h收集一次尿液，转移至事先称量好的试管中。共给药7天并记录体重，结果见图7。减重法测量尿液重量，换算为体积(1g≈1ml)。以时间为横坐标，尿量作为纵坐标，绘制曲线，结果见图7B；和溶剂对照组相比，实施例3化合物给药第一天尿量开始增多，一直持续到第7天，较溶剂对照组，具有明显的利尿作用，结果显示means±SEM，n＝8。使用冰点渗透压仪测量尿液渗透压。以时间为横坐标，尿渗透压作为纵坐标，绘制曲线，结果见图7B；和溶剂对照组相比，实施例3化合物给药组第一天尿渗透压开始下降，一直持续到第7天，说明连续给予实施例3化合物后，可以降低大鼠尿的渗透压，结果显示means±SEM，n＝8。根据之前测得的每24h尿量、尿渗透压和尿素排泄量，计算出每24h非尿素溶质的排泄量。与对照组比较，各剂量组每24h尿素和非尿素溶质排泄量无显著变化(图7C)。结果显示means±SEM，n＝8。正常SD大鼠，8周，雄性，每组8只，实验前将动物放入代谢笼中适应三天，标准饮食，自由饮水。适应完成后，灌胃给药100mg/kg实施例3化合物(首剂加倍)，每8h一次，溶剂对照：0.5％羧甲基纤维素钠(CMC-Na)，连续给药并记录7天，第七天，戊巴比妥钠麻醉大鼠，检测肾内髓和外髓组织中渗透压、尿素及非尿素溶质浓度的变化，结果见图7D，肾内髓组织液渗透压明显降低，其主要原因是由于尿素浓度的降低，而非尿素溶质的浓度没有明显的变化。
7.实施例3化合物无明显毒性
为了研究本发明化合物的细胞毒性，利用CCK-8试剂盒，完成了MDCK细胞毒性试验，结果见图8A，表明实施例3化合物无显著细胞毒作用。本研究用CCK-8试剂盒检测化合物细胞毒性：将对数生长期的MDCK细胞悬液接种于96孔培养板(1×10 4个细胞/孔/100μl)，每孔给予100μl含有10％胎牛血清、100U/ml青霉素和100μg/ml链霉素的DMEM培养液，置37℃、5％CO 2培养箱中培养。当细胞70％～80％融合时，血清饥饿12h进行同步化。然后每孔给予100μl含有不同浓度(7.8，15.6，31.3，62.5和125μM)化合物的DMEM培养液，培养12h。每孔给予10μl CCK-8检测液，37℃避光孵育1h，检测470nm OD值。同时设置空白孔(培养基、CCK-8)，对照孔(细胞、相同浓度化合物的溶解介质、培养基、CCK-8)，每组设3复孔。计算细胞存活率：细胞存活率(％)＝[(OD实验孔－OD空白孔)/(OD对照孔－OD空白孔)]×100％，其中，OD是指各孔的吸光度值。
取正常SD大鼠，8周，雄性，每组8只。实验前将动物放入代谢笼中适应三天，标准饮食，自由饮水。适应完成后，灌胃给药100mg/kg实施例3化合物(首剂加倍)，每8h一次，溶剂对照：0.5％羧甲基纤维素钠(CMC-Na)，连续给药7天，第七天，戊巴比妥钠麻醉大鼠，取肝脏及肾脏，称重，计算肾重指数及肝重指数，发现与对照相比没有明显的差异(图8B，图8D)。使用尿素试剂盒检测长期给药后实施例3化合物对血清尿素水平的影响，发现与对照组相比无明显的统计学差异(图8C)。取肾脏组织浸于固定液(4％多聚甲醛)中，经石蜡包埋机包埋后采用石蜡切片机将组织切成6μm厚的石蜡切片，切片经二甲苯处理15min两次，二甲苯：无水乙醇＝1：1，处理2min，100％乙醇5min两次，80％乙醇5min，蒸馏水5min后先给予苏木精液染色5min，随后流水稍洗去苏木精液(1～3s)，用1％盐酸乙醇处理1～3s，水洗10～30s，蒸馏水过洗1～2s后用0.5％伊红液染色1～3min，随后用蒸馏水洗1～2s，80％乙醇洗1～2s，95％乙醇(I)2～3s，95％乙醇(II)3～5s，无水乙醇5～10min，石炭酸二甲苯5～10min二甲苯2min三次后用中性树胶封固。切片置于光学显微镜下观察。每只肾脏选择内髓、外髓、皮质使用光学显微镜对比观察，发现实施例3化合物不显著影响肾脏组织学形态，但由于实施例3化合物发挥明显的利尿作用，实施例3化合物给药后内髓出现小管肿胀现象。经心脏穿刺取血，离心后获得血清，使用仪器测量血清学指标，发现实施例3化合物不影响糖代谢、脂代谢(表2)。
表1本发明实施例1-实施例79的化合物结构
Figure PCTCN2020096939-appb-000089
Figure PCTCN2020096939-appb-000090
Figure PCTCN2020096939-appb-000091
表2实施例3化合物处理组大鼠和对照组大鼠血生化指标
Figure PCTCN2020096939-appb-000092
表3本发明的化合物及其对UT-B的IC 50值
Figure PCTCN2020096939-appb-000093
Figure PCTCN2020096939-appb-000094
*“++++”表示化合物对人UT-B的IC 50值≤10μM，抑制活性“强”；“+++”表示化合物对人UT-B的IC 50值>10μM且≤20μM，抑制活性“较强”；“++”表示化合物对人UT-B的IC 50值>20μM且≤80μM，抑制活性“中等”；以及“+”表示化合物对人UT-B的IC 50值>80，抑制活性“弱”，其中实施例6化合物在80μm下的小鼠红细胞裂解率为40％。

Claims (18)

  1. 式(I)所示的化合物、或其药学上可接受的盐在制备作为尿素通道蛋白抑制剂的药物中的用途，
    Figure PCTCN2020096939-appb-100001
    其中，
    环A和环B分别独立地为5～6元杂芳基或5～6元芳基；
    所述环A和环B分别任选地被R 1和R 2取代；
    R 1选自于由如下基团所组成的组：硝基、卤素、烷基、烷基羰基、烷基羰基氨基、烷基磺酰基以及吡啶并基；
    R 2选自于由如下基团所组成的组：卤素、羟基、氨基、氰基、烷基、烯基、炔基、羟基烷基、氨基烷基、烷氧基、烷基羰基、烷氧基羰基、吡啶并基、任选地被R 5取代的烷基羰基氨基、任选地被R 5取代的杂环基或环基、任选地被R 5取代的杂芳基羰基氨基、N-烷基氨基、N,N-二(烷基)氨基、以及被R 3和R 4取代的氨基羰基；
    其中，R 3和R 4各自独立地选自于由如下基团所组成的组：H、羟基、烷基、任选地被R 5取代的杂环基或环基、任选地被R 5取代的杂环基或环基烷基、任选地被R 5取代的杂芳基或芳基烷基、N-(烷基)氨基烷基、以及N,N-二(烷基)氨基烷基；以及
    R 5选自于由如下基团所组成的组：烷基、硝基、烷基羰基氨基、N-(烷基)氨基、N,N-二(烷基)氨基、N,N-二(烷基)氨基烷基氨基、以及杂环基或环基。
  2. 根据权利要求1所述的用途，其中，各基团的定义满足以下的一项或多项：
    R 1选自于由如下基团所组成的组：硝基、卤素、C 1-6烷基、C 1-6烷基羰基、C 1-6烷基羰基氨基、C 1-6烷基磺酰基以及吡啶并基；
    R 2选自于由如下基团所组成的组：卤素、羟基、氨基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷基羰基、C 1-6烷氧基羰基、吡啶并基、任选地被R 5取代的C 1-6烷基羰基氨基、任选地被R 5取代的5～6元杂环基或环基、任选地被R 5取代的5～6元杂芳基羰基氨基、N-(C 1-6烷基)氨基、N,N-二(C 1-6烷基)氨基、以及被R 3和R 4取代的氨基羰基；
    其中，R 3和R 4各自独立地选自于由如下基团所组成的组：H、羟基、C 1-6烷基、任选地被R 5取代的5～6元杂环基或环基、任选地被R 5取代的5～6元杂环基或环基C 1-6烷基、任选地被R 5取代的5～6元杂芳基或芳基C 1-6烷基、N-(C 1-6烷基)氨基C 1-C 6烷基、以及N,N-二(C 1-6烷基)氨基C 1-6烷基；以及
    R 5选自于由如下基团所组成的组：C 1-6烷基、硝基、C 1-6烷基羰基氨基、N-(C 1-6烷基)氨基、N,N-二(C 1-6烷基)氨基、N,N-二(C 1-6烷基)氨基C 1-6烷基氨基、以及5～6元杂环基或环基。
  3. 根据权利要求1或2所述的用途，其中，所述杂芳基和杂环基的杂原子独立地选自O、S和/或N，杂原子的数目为选自1、2、3的整数；
    优选地，所述杂芳基选自于由如下基团所组成的组：呋喃基、噻吩基、噻唑基、异噻唑基、噻二唑基、吡咯基、噁唑基、异噁唑基、吡唑基、咪唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、喹啉基、异喹啉基、喹喔啉基、喹唑啉基、苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、吲哚基；
    优选地，所述杂环基选自于由如下基团所组成的组：哌啶基、二氧杂环己烷基、氧硫杂环己烷基、吗啉基、哌嗪基。
  4. 根据权利要求1-3中任一项所述的用途，其中，所述环A和环B各自独立地选自于由如下杂芳基或芳基所组成的组：呋喃基、噻吩基、噻唑基、异噻唑基、噻二唑基、吡咯基、噁唑基、异噁唑基、吡唑基、咪唑基、苯基、吡啶基、吡嗪基、嘧啶基、哒嗪基。
  5. 根据权利要求1-4中任一项所述的用途，其中，所述环A和环B的定义满足以下的一项或多项：
    所述环A选自于由如下杂芳基或芳基所组成的组：呋喃基、噻吩基、吡咯基、噁唑基、吡唑基、苯基；以及
    所述环B选自于由如下基团所组成的组：噻吩基、噁唑基、异噁唑基、吡唑基、苯基、吡啶基、吡嗪基、嘧啶基、哒嗪基。
  6. 根据权利要求1-5中任一项所述的用途，其中，所述环A和/或环B进一步被R 6取代，R 6选自于由如下基团所组成的组：羟基、卤素、C 1-C 6烷基、C 1-C 6烷氧基羰基、C 1-C 6烷基氨基羰基、或R 6通过共价键与其所在的环形成氧代5元或6元氮杂环，所述氮杂环任选地被R 5取代。
  7. 根据权利要求1-6中任一项所述的用途，其中，所述式(I)所示的化合物、或其药学上可接受的盐选自于由下述化合物(1)至(79)、或其药学上可接受的盐所组成的组：
    (1)N-(4-乙酰氨基苯基)-4-硝基苯甲酰胺；
    (2)N-(4-乙酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (3)N-(4-乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (4)N-(4-乙酰氨基苯基)呋喃-2-甲酰胺；
    (5)N-苯基-5-硝基呋喃-2-甲酰胺；
    (6)N-(4-乙酰氨基苯基)噻吩-2-甲酰胺；
    (7)N-(4-乙酰氨基苯基)-1H-吡咯-2-甲酰胺；
    (8)N-(4-乙酰氨基苯基)噁唑-5-甲酰胺；
    (9)N-(4-乙酰氨基苯基)-5-硝基噻吩-2-甲酰胺；
    (10)N-(吡啶-2-基)-5-硝基呋喃-2-甲酰胺；
    (11)N-(吡啶-3-基)-5-硝基呋喃-2-甲酰胺；
    (12)N-(吡啶-4-基)-5-硝基呋喃-2-甲酰胺；
    (13)N-(吡嗪-2-基)-5-硝基呋喃-2-甲酰胺；
    (14)N-(嘧啶-2-基)-5-硝基呋喃-2-甲酰胺；
    (15)N-(哒嗪-3-基)-5-硝基呋喃-2-甲酰胺；
    (16)N-(喹啉-6-基)-5-硝基呋喃-2-甲酰胺；
    (17)N-(噻吩-3-基)-5-硝基呋喃-2-甲酰胺；
    (18)N-(噻吩-2-基)-5-硝基呋喃-2-甲酰胺；
    (19)N-(异噁唑-3-基)-5-硝基呋喃-2-甲酰胺；
    (20)N-(1H-吡唑-5-基)-5-硝基呋喃-2-甲酰胺；
    (21)N-(1-甲基-1H-吡唑-3-基)-5-硝基呋喃-2-甲酰胺；
    (22)N-(1-甲基-1H-吡唑-4-基)-5-硝基呋喃-2-甲酰胺；
    (23)N-(4-乙酰氨基苯基)-5-溴呋喃-2-甲酰胺；
    (24)N-(4-乙酰氨基苯基)-5-乙酰氨基呋喃-2-甲酰胺；
    (25)N-(4-乙酰氨基苯基)-5-甲磺酰基呋喃-2-甲酰胺；
    (26)N-(2-乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (27)N-(3-乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (28)N-(3-甲基苯基)-5-硝基呋喃-2-甲酰胺；
    (29)N-(2-甲氧基苯基)-5-硝基呋喃-2-甲酰胺；
    (30)N-(3-甲氧基苯基)-5-硝基呋喃-2-甲酰胺；
    (31)N-(4-甲氧基苯基)-5-硝基呋喃-2-甲酰胺；
    (32)N-(3-羟基苯基)-5-硝基呋喃-2-甲酰胺；
    (33)N-(4-羟基苯基)-5-硝基呋喃-2-甲酰胺；
    (34)N-(3-氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (35)N-(2-氟苯基)-5-硝基呋喃-2-甲酰胺；
    (36)N-(3-氟苯基)-5-硝基呋喃-2-甲酰胺；
    (37)N-(4-氟苯基)-5-硝基呋喃-2-甲酰胺；
    (38)N-(3-氯苯基)-5-硝基呋喃-2-甲酰胺；
    (39)N-(4-氯苯基)-5-硝基呋喃-2-甲酰胺；
    (40)N-(3-氰基苯基)-5-硝基呋喃-2-甲酰胺；
    (41)N-(4-氰基苯基)-5-硝基呋喃-2-甲酰胺；
    (42)3-(5-硝基呋喃-2-甲酰胺基)苯甲酸乙酯；
    (43)4-(5-硝基呋喃-2-甲酰胺基)苯甲酸乙酯；
    (44)N-(3-氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (45)N-(4-氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (46)N-(3-乙酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (47)N-(4-二甲氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (48)N-(4-吗啉基苯基)-5-硝基呋喃-2-甲酰胺；
    (49)N-(4-(4-乙基哌嗪-1-基)苯基)-5-硝基呋喃-2-甲酰胺；
    (50)N-(4-(2-羟乙基)苯基)-5-硝基呋喃-2-甲酰胺；
    (51)N-(4-氨甲基苯基)-5-硝基呋喃-2-甲酰胺；
    (52)N,N’-(1,4-亚苯基)二(5-硝基呋喃-2-甲酰胺)；
    (53)N-(3-(甲氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (54)N-(3-(二甲基氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (55)N-(3-(乙氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (56)N-(3-(异丙氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (57)N-(3-(异丁氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (58)N-(3-(环己氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (59)N-(3-(苄氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (60)N-(3-((2-二甲氨基乙基)氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (61)N-(3-((2-吗啉基乙基)氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (62)N-(3-((3-吗啉基丙基)氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (63)N-(4-甲基-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (64)N-(5-甲基-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (65)N-(4-氟-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (66)N-(5-氟-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (67)N-(4-羟基-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (68)N 1,N 3-二甲基-5-(5-硝基呋喃-2-甲酰胺基)间苯二甲酰胺；
    (69)N-(2-甲基-1,3-二氢-1,3-二氧代-2H-异吲哚-5-基)-5-硝基呋喃-2-甲酰胺；
    (70)N-(4-乙酰氨基苯基)-5-乙酰基呋喃-2-甲酰胺；
    (71)N-(4-(2-二甲氨基)乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (72)N-(4-(2-吗啉基)乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (73)N-(4-(3-二甲氨基)丙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (74)N-(4-((2-二甲氨基)乙基氨基)乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (75)2-乙酰氨基-5-(5-硝基呋喃-2-甲酰胺)苯甲酸乙酯；
    (76)5-(5-硝基呋喃-2-甲酰胺)-1H-吡唑-4-羧酸乙酯；
    (77)5-(5-硝基呋喃-2-甲酰胺)-1H-吡唑-3-羧酸乙酯；
    (78)3-(5-乙酰基-2-呋喃甲酰基)氨基甲酰胺；以及
    (79)N-3-(乙炔基苯基)-5-硝基呋喃-2-甲酰胺。
  8. 根据权利要求1-7中任一项所述的用途，其中，所述药物为用于治疗或预防与尿素通道蛋白抑制剂相关的疾病的药物；优选地，所述药物为利尿药、降压药和/或用于研究尿素通道蛋白的工具药；优选地，所述尿素通道蛋白为UT-B蛋白或UT-A蛋白；
    优选地，所述与尿素通道蛋白抑制剂相关的疾病为与尿素通道蛋白抑制剂相关的水肿性疾病；优选地，所述水肿性疾病包括：心源性水肿，优选地所述心源性水肿为归因于充血性心力衰竭和/或缩窄性心包炎的心源性水肿；肾源性水肿，优选地所述肾源性水肿为归因于急性肾小球肾炎、慢性肾小球肾炎、肾病综合征、肾动脉硬化症和/或肾小管病变的肾源性水肿；肝源性水肿，优选地所述肝源性水肿为归因于肝硬化、肝坏死、肝癌和/或急性肝炎的肝源性水肿；营养不良性水肿，优选地所述营养不良性水肿为归因于原发性食物摄人不足、继发性营养不良性、消化吸收障碍和/或蛋白质合成功能受损的营养不良性水肿；结缔组织病所致的水肿；变态反应性水肿；内分泌性水肿；特发性水肿；静脉梗阻性水肿；淋巴梗阻性水肿；炎症性水肿；变态反应性水肿；血管神经性水肿；脑水肿；喉头水肿；肺水肿和/或下肢水肿；
    优选地，所述与尿素通道蛋白抑制剂相关的疾病为与尿素通道蛋白抑制剂相关的非水肿性疾病；优选地，所述非水肿性疾病包括：心力衰竭，优选充血性心力衰竭、急性心力衰竭、慢性心力衰竭；心脑血管疾病，优选轻度高血压、中度高血压、老年收缩期高血压、高血压合并心力衰竭。
  9. 一种治疗或预防与尿素通道蛋白抑制剂相关的疾病的方法，所述方法包括向有需要的患者给予治疗有效量的式(I)所示的化合物、或其药学上可接受的盐，
    Figure PCTCN2020096939-appb-100002
    其中，
    环A和环B分别独立地为5～6元杂芳基或5～6元芳基；
    所述环A和环B分别任选地被R 1和R 2取代；
    R 1选自于由如下基团所组成的组：硝基、卤素、烷基、烷基羰基、烷基羰基氨基、烷基磺酰基以及吡啶并基；
    R 2选自于由如下基团所组成的组：卤素、羟基、氨基、氰基、烷基、烯基、炔基、羟基烷基、氨基烷基、烷氧基、烷基羰基、烷氧基羰基、吡啶并基、任选地被R 5取代的烷基羰基氨基、任选地被R 5取代的杂环基或环基、任选地被R 5取代的杂芳基羰基氨基、N-烷基氨基、N,N-二(烷基)氨基、以及被R 3和R 4取代的氨基羰基；
    其中，R 3和R 4各自独立地选自于由如下基团所组成的组：H、羟基、烷基、任选地被R 5取代的杂环基或环基、任选地被R 5取代的杂环基或环基烷基、任选地被R 5取代的杂芳基或芳基烷基、N-(烷基)氨基烷基、以及N,N-二(烷基)氨基烷基；以及
    R 5选自于由如下基团所组成的组：烷基、硝基、烷基羰基氨基、N-(烷基)氨基、N,N-二(烷基)氨基、N,N-二(烷基)氨基烷基氨基、以及杂环基或环基。
  10. 根据权利要求9所述的方法，其中，各基团的定义满足以下的一项或多项：
    R 1选自于由如下基团所组成的组：硝基、卤素、C 1-6烷基、C 1-6烷基羰基、C 1-6烷基羰基氨基、C 1-6烷基磺酰基以及吡啶并基；
    R 2选自于由如下基团所组成的组：卤素、羟基、氨基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、C 1-6烷基羰基、C 1-6烷氧基羰基、吡啶并基、任选地被R 5取代的C 1-6烷基羰基氨基、任选地被R 5取代的5～6元杂环基或环基、任选地被R 5取代的5～6元杂芳基羰基氨基、N-(C 1-6烷基)氨基、N,N-二(C 1-6烷基)氨基、以及被R 3和R 4取代的氨基羰基；
    其中，R 3和R 4各自独立地选自于由如下基团所组成的组：H、羟基、C 1-6烷基、任选地被R 5取代的5～6元杂环基或环基、任选地被R 5取代的5～6元杂环基或环基C 1-6烷基、任选地被R 5取代的5～6元杂芳基或芳基C 1-6烷基、N-(C 1-6烷基)氨基C 1-C 6烷基、以及N,N-二(C 1-6烷基)氨基C 1-6烷基；以及
    R 5选自于由如下基团所组成的组：C 1-6烷基、硝基、C 1-6烷基羰基氨基、N-(C 1-6烷基)氨基、N,N-二(C 1-6烷基)氨基、N,N-二(C 1-6烷基)氨基C 1-6烷基氨基、以及5～6元杂环基或环基。
  11. 根据权利要求9或10所述的方法，其中，所述杂芳基和杂环基的杂原子独立地选自O、S和/或N，杂原子的数目为选自1、2、3的整数；
    优选地，所述杂芳基选自于由如下基团所组成的组：呋喃基、噻吩基、噻唑基、异噻唑基、噻二唑基、吡咯基、噁唑基、异噁唑基、吡唑基、咪唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、喹啉基、异喹啉基、喹喔啉基、喹唑啉基、苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、吲哚基；
    优选地，所述杂环基选自于由如下基团所组成的组：哌啶基、二氧杂环己烷基、氧硫杂环己烷基、吗啉基、哌嗪基。
  12. 根据权利要求9-11中任一项所述的方法，其中，所述环A和环B各自独立地选自于由如下杂芳基或芳基所组成的组：呋喃基、噻吩基、噻唑基、异噻唑基、噻二唑基、吡咯基、噁唑基、异噁唑基、吡唑基、咪唑基、苯基、吡啶基、吡嗪基、嘧啶基、哒嗪基。
  13. 根据权利要求9-12中任一项所述的方法，其中，所述环A和环B的定义满足以下的一项或多项：
    所述环A选自于由如下杂芳基或芳基所组成的组：呋喃基、噻吩基、吡咯基、噁唑基、吡唑基、苯基；以及
    所述环B选自于由如下基团所组成的组：噻吩基、噁唑基、异噁唑基、吡唑基、苯基、吡啶基、吡嗪基、嘧啶基、哒嗪基。
  14. 根据权利要求9-13中任一项所述的方法，其中，所述环A和/或环B进一步被R 6取代，R 6选自于由如下基团所组成的组：羟基、卤素、C 1-C 6烷基、C 1-C 6烷氧基羰基、C 1-C 6烷基氨基羰基、或R 6通过共价键与其所在的环形成氧代5元或6元氮杂环，所述氮杂环任选地被R 5取代。
  15. 根据权利要求9-14中任一项所述的方法，其中，所述式(I)所示的化合物、或其药学上可接受的盐选自于由下述化合物(1)至(79)、或其药学上可接受的盐所组成的组：
    (1)N-(4-乙酰氨基苯基)-4-硝基苯甲酰胺；
    (2)N-(4-乙酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (3)N-(4-乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (4)N-(4-乙酰氨基苯基)呋喃-2-甲酰胺；
    (5)N-苯基-5-硝基呋喃-2-甲酰胺；
    (6)N-(4-乙酰氨基苯基)噻吩-2-甲酰胺；
    (7)N-(4-乙酰氨基苯基)-1H-吡咯-2-甲酰胺；
    (8)N-(4-乙酰氨基苯基)噁唑-5-甲酰胺；
    (9)N-(4-乙酰氨基苯基)-5-硝基噻吩-2-甲酰胺；
    (10)N-(吡啶-2-基)-5-硝基呋喃-2-甲酰胺；
    (11)N-(吡啶-3-基)-5-硝基呋喃-2-甲酰胺；
    (12)N-(吡啶-4-基)-5-硝基呋喃-2-甲酰胺；
    (13)N-(吡嗪-2-基)-5-硝基呋喃-2-甲酰胺；
    (14)N-(嘧啶-2-基)-5-硝基呋喃-2-甲酰胺；
    (15)N-(哒嗪-3-基)-5-硝基呋喃-2-甲酰胺；
    (16)N-(喹啉-6-基)-5-硝基呋喃-2-甲酰胺；
    (17)N-(噻吩-3-基)-5-硝基呋喃-2-甲酰胺；
    (18)N-(噻吩-2-基)-5-硝基呋喃-2-甲酰胺；
    (19)N-(异噁唑-3-基)-5-硝基呋喃-2-甲酰胺；
    (20)N-(1H-吡唑-5-基)-5-硝基呋喃-2-甲酰胺；
    (21)N-(1-甲基-1H-吡唑-3-基)-5-硝基呋喃-2-甲酰胺；
    (22)N-(1-甲基-1H-吡唑-4-基)-5-硝基呋喃-2-甲酰胺；
    (23)N-(4-乙酰氨基苯基)-5-溴呋喃-2-甲酰胺；
    (24)N-(4-乙酰氨基苯基)-5-乙酰氨基呋喃-2-甲酰胺；
    (25)N-(4-乙酰氨基苯基)-5-甲磺酰基呋喃-2-甲酰胺；
    (26)N-(2-乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (27)N-(3-乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (28)N-(3-甲基苯基)-5-硝基呋喃-2-甲酰胺；
    (29)N-(2-甲氧基苯基)-5-硝基呋喃-2-甲酰胺；
    (30)N-(3-甲氧基苯基)-5-硝基呋喃-2-甲酰胺；
    (31)N-(4-甲氧基苯基)-5-硝基呋喃-2-甲酰胺；
    (32)N-(3-羟基苯基)-5-硝基呋喃-2-甲酰胺；
    (33)N-(4-羟基苯基)-5-硝基呋喃-2-甲酰胺；
    (34)N-(3-氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (35)N-(2-氟苯基)-5-硝基呋喃-2-甲酰胺；
    (36)N-(3-氟苯基)-5-硝基呋喃-2-甲酰胺；
    (37)N-(4-氟苯基)-5-硝基呋喃-2-甲酰胺；
    (38)N-(3-氯苯基)-5-硝基呋喃-2-甲酰胺；
    (39)N-(4-氯苯基)-5-硝基呋喃-2-甲酰胺；
    (40)N-(3-氰基苯基)-5-硝基呋喃-2-甲酰胺；
    (41)N-(4-氰基苯基)-5-硝基呋喃-2-甲酰胺；
    (42)3-(5-硝基呋喃-2-甲酰胺基)苯甲酸乙酯；
    (43)4-(5-硝基呋喃-2-甲酰胺基)苯甲酸乙酯；
    (44)N-(3-氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (45)N-(4-氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (46)N-(3-乙酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (47)N-(4-二甲氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (48)N-(4-吗啉基苯基)-5-硝基呋喃-2-甲酰胺；
    (49)N-(4-(4-乙基哌嗪-1-基)苯基)-5-硝基呋喃-2-甲酰胺；
    (50)N-(4-(2-羟乙基)苯基)-5-硝基呋喃-2-甲酰胺；
    (51)N-(4-氨甲基苯基)-5-硝基呋喃-2-甲酰胺；
    (52)N,N’-(1,4-亚苯基)二(5-硝基呋喃-2-甲酰胺)；
    (53)N-(3-(甲氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (54)N-(3-(二甲基氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (55)N-(3-(乙氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (56)N-(3-(异丙氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (57)N-(3-(异丁氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (58)N-(3-(环己氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (59)N-(3-(苄氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (60)N-(3-((2-二甲氨基乙基)氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (61)N-(3-((2-吗啉基乙基)氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (62)N-(3-((3-吗啉基丙基)氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (63)N-(4-甲基-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (64)N-(5-甲基-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (65)N-(4-氟-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (66)N-(5-氟-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (67)N-(4-羟基-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (68)N 1,N 3-二甲基-5-(5-硝基呋喃-2-甲酰胺基)间苯二甲酰胺；
    (69)N-(2-甲基-1,3-二氢-1,3-二氧代-2H-异吲哚-5-基)-5-硝基呋喃-2-甲酰胺；
    (70)N-(4-乙酰氨基苯基)-5-乙酰基呋喃-2-甲酰胺；
    (71)N-(4-(2-二甲氨基)乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (72)N-(4-(2-吗啉基)乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (73)N-(4-(3-二甲氨基)丙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (74)N-(4-((2-二甲氨基)乙基氨基)乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (75)2-乙酰氨基-5-(5-硝基呋喃-2-甲酰胺)苯甲酸乙酯；
    (76)5-(5-硝基呋喃-2-甲酰胺)-1H-吡唑-4-羧酸乙酯；
    (77)5-(5-硝基呋喃-2-甲酰胺)-1H-吡唑-3-羧酸乙酯；
    (78)3-(5-乙酰基-2-呋喃甲酰基)氨基甲酰胺；以及
    (79)N-3-(乙炔基苯基)-5-硝基呋喃-2-甲酰胺。
  16. 根据权利要求9-15中任一项所述的方法，其中，所述式(I)所示的化合物、或其药学上可接受的盐为用于治疗或预防与尿素通道蛋白抑制剂相关的疾病的药物；优选地，所述药物为利尿药、降压药和/或用于研究尿素通道蛋白的工具药；优选地，所述尿素通道蛋白为UT-B蛋白或UT-A蛋白；
    优选地，所述与尿素通道蛋白抑制剂相关的疾病为与尿素通道蛋白抑制剂相关的水肿性疾病；优选地，所述水肿性疾病包括：心源性水肿，优选地所述心源性水肿为归因于充血性心力衰竭和/或缩窄性心包炎的心源性水肿；肾源性水肿，优选地所述肾源性水肿为归因于急性肾小球肾炎、慢性肾小球肾炎、肾病综合征、肾动脉硬化症和/或肾小管病变的肾源性水肿；肝源性水肿，优选地所述肝源性水肿为归因于肝硬化、肝坏死、肝癌和/或急性肝炎的肝源性水肿；营养不良性水肿，优选地所述营养不良性水肿为归因于原发性食物摄人不足、继发性营养不良性、消化吸收障碍和/或蛋白质合成功能受损的营养不良性水肿；结缔组织病所致的水肿；变态反应性水肿；内分泌性水肿；特发性水肿；静脉梗阻性水肿；淋巴梗阻性水肿；炎症性水肿；变态反应性水肿；血管神经性水肿；脑水肿；喉头水肿；肺水肿和/或下肢水肿；
    优选地，所述与尿素通道蛋白抑制剂相关的疾病为与尿素通道蛋白抑制剂相关的非水肿性疾病；优选地，所述非水肿性疾病包括：心力衰竭，优选充血性心力衰竭、急性心力衰竭、慢性心力衰竭；心脑血管疾病，优选轻度高血压、中度高血压、老年收缩期高血压、高血压合并心力衰竭。
  17. 一种二芳基酰胺类化合物、或其药学上可接受的盐，所述二芳基酰胺类化合物、或其药学上可接受的盐选自于由下述化合物、或其药学上可接受的盐所组成的组：
    (15)N-(哒嗪-3-基)-5-硝基呋喃-2-甲酰胺；
    (17)N-(噻吩-3-基)-5-硝基呋喃-2-甲酰胺；
    (25)N-(4-乙酰氨基苯基)-5-甲磺酰基呋喃-2-甲酰胺；
    (26)N-(2-乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (51)N-(4-氨甲基苯基)-5-硝基呋喃-2-甲酰胺；
    (53)N-(3-(甲氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (55)N-(3-(乙氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (56)N-(3-(异丙氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (57)N-(3-(异丁氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (58)N-(3-(环己氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (59)N-(3-(苄氨基甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (60)N-(3-((2-二甲氨基乙基)氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (61)N-(3-((2-吗啉基乙基)氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (62)N-(3-((3-吗啉基丙基)氨甲酰基)苯基)-5-硝基呋喃-2-甲酰胺；
    (63)N-(4-甲基-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (64)N-(5-甲基-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (65)N-(4-氟-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (66)N-(5-氟-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (67)N-(4-羟基-3-甲氨甲酰基苯基)-5-硝基呋喃-2-甲酰胺；
    (68)N 1,N 3-二甲基-5-(5-硝基呋喃-2-甲酰胺基)间苯二甲酰胺；
    (69)N-(2-甲基-1,3-二氢-1,3-二氧代-2H-异吲哚-5-基)-5-硝基呋喃-2-甲酰胺；
    (70)N-(4-乙酰氨基苯基)-5-乙酰基呋喃-2-甲酰胺；
    (71)N-(4-(2-二甲氨基)乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (72)N-(4-(2-吗啉基)乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (73)N-(4-(3-二甲氨基)丙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (74)N-(4-((2-二甲氨基)乙基氨基)乙酰氨基苯基)-5-硝基呋喃-2-甲酰胺；
    (75)2-乙酰氨基-5-(5-硝基呋喃-2-甲酰胺)苯甲酸乙酯；
    (76)5-(5-硝基呋喃-2-甲酰胺)-1H-吡唑-4-羧酸乙酯；
    (77)5-(5-硝基呋喃-2-甲酰胺)-1H-吡唑-3-羧酸乙酯；以及
    (78)3-(5-乙酰基-2-呋喃甲酰基)氨基甲酰胺。
  18. 一种药物组合物，所述药物组合物包含：权利要求17所述化合物或其药学上可接受的盐；以及药学上可接受的载体。
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