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WO2009094845A1 - 5-(3-heteroaromatic ring substituted phenyl) tetrazole compounds and their uses for anti-hiv/aids - Google Patents

5-(3-heteroaromatic ring substituted phenyl) tetrazole compounds and their uses for anti-hiv/aids Download PDF

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WO2009094845A1
WO2009094845A1 PCT/CN2008/002105 CN2008002105W WO2009094845A1 WO 2009094845 A1 WO2009094845 A1 WO 2009094845A1 CN 2008002105 W CN2008002105 W CN 2008002105W WO 2009094845 A1 WO2009094845 A1 WO 2009094845A1
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phenyl
compound
halogen
alkoxy
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Lan Xie
Kun Liu
Ling HOU
Shibo Jiang
Hong Lu
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Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D413/10—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 carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D417/10—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 carbon chain containing aromatic rings
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • the present invention relates to 5-(3-aromatic heterocyclic phenyl)-tetrazole compounds, a process for the preparation thereof, pharmaceutical compositions containing same and their preparation for the treatment or prevention of diseases or conditions associated with HIV infection Application in medicine. Background technique
  • HIV is an RNA retrovirus that selectively infects cells with CD4 receptors on the surface of the body's immune system, such as lymphocytes, monocyte macrophages, and dendritic cells.
  • the surface of the virus is a double lipid membrane with two important glycoproteins: gpl20 and gp41, pl20 is on the outside of the membrane to identify the CD4 receptor on the cell surface; gp41 spans the viral membrane, and the main function is to fuse the virus.
  • the membrane and cell membrane which in turn release the core internal material of the virus into the host cytoplasm.
  • the viral membrane contains two single-stranded RNAs and some important enzymes (such as reverse transcriptase, proteolytic enzyme, integrase) and structural proteins (p24, pl7, p7, etc.). HIV cannot be propagated in vitro and must be reproduced by means of human cells.
  • the replication process is roughly divided into seven steps: virus binding, fusing, reverse transcript ion, integration (integration) ), transcr ipt ion, trans lat ion, and assembly & budding cells.
  • HIV is continuously replicated in such a cyclical process, infecting human immune cells, destroying the body's immune system, and ultimately leading to the complete loss of the body's immune function, causing patients to be in danger of various infections without resilience, thus causing more Infectious diseases and tumors eventually lead to death.
  • drugs can inhibit the virus and treat diseases as long as they block any part of the virus replication process. of.
  • HI V invading cells There are three main steps in the process of HI V invading cells: adhesion, binding to co-receptors, Membrane fusion.
  • the viral envelope glycoprotein gpl20 first binds to the CD4 molecule on the cell surface (Gallaher WR, Ball JM, Garry RF, et al. A general model for the surface glycoproteins of HIV and other retroviruses. AIDS Res Hum Retrovir, 1995, 11: 191 -202), the conformation changes and then binds to a co-receptor (chemokine such as CXCR4 or CCR5) (Dragic T, Litwin V, All away GP, et al.
  • chemokine such as CXCR4 or CCR5
  • HIV-1 entry into CD4+ cells is mediated by The cheraokine receptor CC-CKR-5. Na ture, 1996, 381: 667 73 ); Subsequently, gp41 was inserted into the cell membrane to form a 6-helix, and the viral membrane was brought close to the cell membrane to fuse it. In this process, gpl20 and gp41, CD4 receptors, and co-receptors are all considered potential drug targets. Among them, gp41 plays a vital role in the whole process of fusion.
  • the amino acid sequence of Gp41 has four functional regions.
  • the transmembrane domain (TM) at the C-terminus immobilizes gp41 on the viral membrane; the C-terminal heptad repeat (CHR) and NHI3 ⁇ 4 (N-terminal heptad repeat, NHR) are functional parts of the gp41 structure; Fus ion pept ide (FP) is a highly hydrophobic sequence at the N-terminus that is inserted into the host cell membrane (Mel iky an GB, Markosyan RM, Hemmati H, et al. Evidence that the transition of HIV-1 Gp41 into a six-helix bundle, not the bundle configuration, induces membrane fusion.
  • gpl20 on the surface of the virus binds to the CD4 receptor and co-receptor on the cell surface, and its conformation changes.
  • the NHR helix of gp41 extends from the center, and the N-terminal melt peptide is inserted into the cell membrane (Coleman CI, Musial BL and Ross J. Enfuvirtide: The first fusion inhibitor for the treatment of patients with HIV-1 infection. Formulary, 2003, 38: 204 222). Subsequently, NHR and CHR close together, re-forming a parallel six-element spiral beam.
  • This conformational change provides the energy needed to bring the viral envelope closer to the hydration surface of the host cell membrane, thereby bringing the viral membrane closer to the cell membrane and promoting fusion.
  • the two functional regions of gp41, NHR and CHR can be targets of HIV fusion inhibitors.
  • the first fusion inhibitor drug, T-20 (Fuzeon), approved by the US FDA, is a 36 amino acid peptide that mimics the CHR helical structural sequence.
  • T20 is a peptide drug, there are insufficient oral bioavailability and high production cost, so it is necessary to find a high-efficiency, low-toxic non-peptide small molecule HIV fusion inhibitor lead.
  • T20 is a peptide drug, there are insufficient oral bioavailability and high production cost, so it is necessary to find a high-efficiency, low-toxic non-peptide small molecule HIV fusion inhibitor lead.
  • Two aryl carboxylic acid-substituted azole-based small molecule compounds NB-2 and NB-64 (Jiang) through targeted activity screening of structurally diverse small molecule compound libraries Sh-B, Lu H, Liu Sh- , et al. N-Substituted Pyrrole Derivatives as Novel Human Immunodeficiency Virus Type 1 Entry Inhibitors That Interfere with the gp41 Six-Helix Bundle Formation and Block Virus Fusion.
  • the present invention relates to a compound of the formula I having a 5-substituted phenyl-tetrazole skeleton structure which is effective for inhibiting the formation of the HIV-1 surface glycoprotein gp41 hexamer, thereby inhibiting HIV replication.
  • An in-depth study of this class of compounds will likely lead to the discovery of novel non-peptide small molecule HIV fusion inhibitors that will become new anti-AIDS drugs.
  • One aspect of the invention relates to a tetrazolium aryl heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof: among them,
  • R 2 - H, halogen, -N0 2 , —NH 2 , —leg, —N (R, ) 2 , —CN, —OH, d- 6 alkyl, d- 6 alkoxy, —CF 3 , -C00H, - S0 3 H, - C0NH 2 , -C0NHR' or -C00R';
  • Ar is a five-membered heteroaryl ring containing 1-3 hetero atoms selected from N, 0, S, selected from:
  • R 3 - CH0, COR', C00R, C00H, CF 3 , CH 2 R,, , halogen, 6 hydrocarbyl, 6 alkoxy, -NH 2 , -OH, -N0 2 , -CN, -HOCH- CN, - CH CH 2 ,
  • X and ⁇ are each independently selected from C, 0, S and ⁇ ;
  • R 4 -H, -CH 2 C00H, -CH 2 CH 2 C00H, -CH-CH- C00H, -CH 2 C00R' , - CH 2 CH 2 C00R, , -CH-CH- C00R, , d- 6 Hydrocarbyl group, phenyl group;
  • R 5 - H, halogen, -N0 2 , -NH 2 , - leg, - N (R, ) 2 , - CN, - 0H, hydrocarbyl, alkoxy, -CF 3 , CH0, - C00H, - S0 3 H, -C0NH 2 , -CONHR' or - C00R, ;
  • the above five-membered heteroaryl ring is optionally available at a ring position selected from the group consisting of an aldehyde group, a ketone group, an ester group, a carboxyl group, a cyano group, an ⁇ , an unsaturated ketone, an alkene, an alkyne, a d- 6 fluorenyl group, a substituent of alkoxy, halo, -NH 2 , -0H, -N0 2 and -CF 3 ;
  • R" is halogen, 0H or ( ⁇ alkoxy.
  • hydrocarbyl as used in the present invention includes alkyl, alkenyl and alkynyl groups.
  • the "lower heterocyclic group” referred to in the description of the substituent R 3 of the present invention includes, but is not limited to, 2,4-thiazolidinedione, 2-thio- 2,4-thiazolidinedione (circular tannin), Rhodanine ), succinimide, 2, 4 -imidazolidinone (hydantoin, hydantoin), 2-tuodihydantoin, pseudo-capinehydantoin (Pseudothiohydantoin) ) Wait.
  • a second aspect of the invention relates to a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • a third aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • Ar is a substituted pyrrole, as shown in formula II:
  • R 2 - H, halogen, -N0 2 , -NH 2 , - NHR, - N (R, ) 2 , - CN, -OH, d- 6 alkyl, alkoxy, -CF 3 , -C00H , -SO3H, -C0NH 2 , -C0NHR' or -C00R';
  • X and Y are each independently selected from C, 0, S and NH;
  • R 4 -H - CH 2 C00H, - CH 2 CH 2 COOH, - CH-CH-C00H, -CH 2 C00R' , - CH 2 CH 2 COOR, , - CH-CH- C00R, , Hydrocarbyl, Phenyl ;
  • R 5 - H, halogen, -N0 2 , - 2 , - leg, - N (R, ) 2 , - CN, -0H, d- 6 hydrocarbon, d- 6 alkoxy, -CF 3 , CH0, -C00H, -S0 3 H, -C0NH 2 , -CO wake up, or - C00R, ;
  • R 6 H, CH 3 , CF 3 , halogen or C 2 - 4 hydrocarbyl
  • R" is halogen, OH or ⁇ alkoxy.
  • Ar is 1,2,4-oxadiazole, as shown in the following formula III:
  • R 2 - H, halogen, -N0 2 , -NH 2 , - awake, -N (R, ) 2 , -CN, - 0H, d- 6 alkyl, d- 6 alkoxy, -CF 3 - C00H, - S0 3 H, - C0NH 2 , -CO leg, or -C00R';
  • X and Y are each independently selected from C, 0, S and NH;
  • R 5 HH, halogen, -N0 2 , -NH 2 , -NHR' , —N (R, ) 2 , —CN, —OH , d- 6 hydrocarbon, d— ⁇ alkoxy, —CF 3 , CH0 , ⁇ C00H, - S0 3 H, -C0NH 2 , -CONHR' or a C00R, ;
  • R' d- 6 hydrocarbyl
  • R" is halogen, OH or ( ⁇ 6 alkoxy.
  • Ar is a 5-substituted furan, as shown in the following formula IV:
  • X and Y are each independently selected from C, 0, S and NH;
  • R" is halogen, OH or 6 alkoxy.
  • the following compounds are more preferred in the present invention:
  • Route D For compounds in which Formula Ar is a five-membered heterocyclic ring (eg, pyrrole, furan, etc.) aldehyde:
  • Reaction conditions (vi) Suzuki coupling reaction, organoboric acid reagent, palladium catalyst; (vi i) condensation reaction (with ketone reagents shown or related in the figure), basic conditions: organic amine, strong inorganic base or weak acid Alkaline salt, methanol, ethanol, acetic acid, DMF or a mixed solvent of DMF and water, room temperature - 160 o C, 1-44 hours.
  • Ar, R!-R 4 , R 6 and X, Y in the above reaction scheme are as defined in the above formula I, and U, V and W each independently represent a hetero atom selected from N, 0, S or carbon. atom. Specifically,
  • Synthetic Route A The tetracycline ring can be synthesized by the action of the substituted phenyl cyanide compound (A) and sodium azide to obtain the target compound 1-1.
  • the nitrogen atom at the nitrogen position on the tetrazole ring reacts with the halogenated hydrocarbon.
  • Compound 1-2 can be obtained.
  • Scheme B Substituted 5-(3-amino)phenyl-tetrazolium (B) with 2, 5- Dimethoxytetrahydrofuran or ⁇ -substituted 1,4-butanone can be subjected to a 3 ⁇ 4orr reaction to obtain an arylpyrrole compound ( ⁇ -1), which is then reacted with a halogenated hydrocarbon to form a 1-substituted ⁇ tetrazole- Arylpyrroles ( ⁇ -2).
  • Synthetic route C using substituted 5-(3-cyano)phenyl-tetrazole (C) as a raw material, reacting with a few amines of hydrochloric acid to form an aminoguanidine intermediate (D), and then reacting with an acylating reagent to obtain 3 - aryl-1,2,4-oxadiazole compound ( ⁇ ⁇ -1 ), followed by halogenation of nitrogen to obtain the target compound 111-2.
  • non-peptide small molecule fusion inhibitors They act on HIV-1 gp41 and are expected to develop into a new class of anti-HIV drugs with specific targets: non-peptide small molecule fusion inhibitors.
  • the inhibitory activity of wild type HIV in the test was EC 5. The value was 7.70 ⁇ (SI>32), and it inhibited the replication of clinically isolated multiple types of HIV virus forests.
  • Known active compound NB-64 See the activity data of some related compounds. 1-2.
  • a compound represented by Il-la is a novel anti-HIV active compound having a broad antiviral spectrum which acts on the HIV-1 gp41 target, and can be developed into a non-peptide small molecule anti-peptide.
  • Inhibitors of HIV Fusion The compounds of the invention may be used either as such or in the form of pharmaceutically acceptable salts or solvates thereof.
  • the pharmaceutically acceptable salts of the compounds of formula I include pharmaceutically acceptable mineral acids Or an organic acid, or an inorganic base or a conventional salt formed by organic reduction.
  • suitable acid addition salts include with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, citric acid, lactic acid, maleic acid, Tartaric acid, citric acid, citric acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, a salt formed from benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, citric acid or the like.
  • Suitable base addition salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N,N,-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, B. a salt formed by a diamine, N-methylglucamine, and procaine.
  • the compound of the formula I of the present invention can be combined with a conventional pharmaceutical carrier or excipient to constitute a pharmaceutical composition.
  • the pharmaceutical composition can be administered orally or parenterally.
  • the pharmaceutical composition of the present invention can be prepared into various dosage forms including, but not limited to, tablets, capsules, solutions, suspensions, granules or injections, by a conventional method in the art, orally or parenterally.
  • the dosage and method of use of the compounds of the invention depend on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and the diagnosis and treatment. Subjective judgment of the physician.
  • the preferred dosage is between 0.01 and 100 mg/kg body weight per day. . detailed description
  • Example 7 1-Ethoxycarbonylmethyl-5-(3-(3-ethoxycarbonyl-2,5-dimethyl- 1 ⁇ pyrrole-1-yl)phenyl)-1 ⁇ tetrazole (II- 2c) (Synthesis Route A or B) Add sodium ethoxide (61 mg, 0.9 mmol) and methyl bromoacetate (0.06 mL, 0.6 mmol) to a solution of II-Id (93 mg, 0.3 mmol) in ethanol (5 mL) The reaction was refluxed for 4 hours.
  • Trifluoroacetic anhydride (0.21 mL, 1.5 mmol) was added to EtOAc (3 mL)EtOAc.
  • III-lb (76 mg, 0.29 mmol) was reacted in a 10% aqueous NaOH solution (2 mL) at room temperature for 1.5 hr.
  • the ELISA plate was coated with HIVIG (2 g/mL), blocked with 1% fat-free milk, added to the virus lysate, and incubated for 60 minutes at 37 °C. After extensive washing, anti-p24 monoclonal antibody-183-12H-5C, biotinylated goat anti-mouse antibody and avidin-labeled horseradish peroxidase were added. The color density was then measured at 450 nm using TMB color development. Calculated with CalcuSyn software compound virus half inhibition concentration (EC 50). Table 1. Inhibition of HIV replication and target molecule a
  • the compound of the formula I of the present invention is a non-peptide small molecule inhibitor having a novel skeleton structure and acting on HIV-1 gp41. They can effectively inhibit the formation of HIV-1 gp41 six-helix bundle (6-HB), thereby inhibiting HIV replication. These compounds also have inhibitory activity against clinically isolated multi-type HIV strains and have a broad spectrum of antiviral.
  • the compounds of the present invention are expected to develop into a new class of anti-HIV drugs: non-peptide small molecule HIV-1 fusion inhibitors targeting gp41.

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Abstract

5-(3-heteroaromatic ring substituted phenyl) tetrazole compounds of formula (I), pharmaceutically acceptable salts thereof, wherein the substituents are defined as same as claims. Preparation methods thereof, pharmaceutical compositions containing them and their medical uses in the manufacture of a medicament for use in the treatment or prophylaxis of a disease or disorder relating to HIV infection.

Description

5- ( 3-芳杂环取代苯基） 四氮唑类化合物  5-(3-aromatic heterocyclic phenyl) tetrazine
及其抗 H I V/A I DS的应用 技术领域  And its application against H I V/A I DS
本发明涉及 5- ( 3-芳杂环取代苯） -四氮唑类化合物、 其制 备方法， 含有它们的药物组合物及其在制备用于治疗或预防与 HIV感染的有关的疾病或病症的药物中的应用。 背景技术  The present invention relates to 5-(3-aromatic heterocyclic phenyl)-tetrazole compounds, a process for the preparation thereof, pharmaceutical compositions containing same and their preparation for the treatment or prevention of diseases or conditions associated with HIV infection Application in medicine. Background technique
艾滋病是人类免疫缺陷病毒（HIV )所引起的一种严重传染性 疾病。 HIV是一种 RNA逆转录病毒， 它选择性感染人体免疫系统 中表面带有 CD4受体的细胞， 如淋巴细胞、 单核巨噬细胞、 树突 状细胞等。 该病毒表面是层双脂膜， 膜上有两种重要的糖蛋白： gpl20和 gp41， pl20在膜的外面， 用于识别细胞表面的 CD4受 体； gp41横跨病毒膜， 主要作用是融合病毒膜与细胞膜， 继而将 病毒内部核心物质释放到宿主细胞质中。 病毒膜中包亵着 2个单 链 RNA和一些重要的酶（如逆转录酶、 蛋白水解酶、 整合酶）及 结构蛋白质 （p24， pl7， p7等） 。 HIV在体外不能繁殖， 必须借 助于人体细胞才能复制再生， 其复制过程大致分为 7个步骤： 病 毒进攻细胞 ( binding ) ， 融合 ( fus ing ) , 逆转录 ( reverse transcript ion ) ,整合 ( integrat ion )，转录 ( transcr ipt ion )， 转译 ( trans lat ion )和 重组并溢出 ( assembly & budding ) 细 胞。 艾滋病毒以这样一个循环过程不断地复制， 感染人体免疫细 胞， 破坏人体的免疫系统， 最终导致人体免疫功能的完全丧失， 使病人处于各类感染而毫无抵御能力的危险之中， 从而引起多种 感染性疾病和肿瘤， 最终导致患者死亡。 理论上讲， 药物只要阻 断病毒复制过程中的任一环节都会达到抑制病毒和治疗疾病的目 的。 AIDS is a serious infectious disease caused by human immunodeficiency virus (HIV). HIV is an RNA retrovirus that selectively infects cells with CD4 receptors on the surface of the body's immune system, such as lymphocytes, monocyte macrophages, and dendritic cells. The surface of the virus is a double lipid membrane with two important glycoproteins: gpl20 and gp41, pl20 is on the outside of the membrane to identify the CD4 receptor on the cell surface; gp41 spans the viral membrane, and the main function is to fuse the virus. The membrane and cell membrane, which in turn release the core internal material of the virus into the host cytoplasm. The viral membrane contains two single-stranded RNAs and some important enzymes (such as reverse transcriptase, proteolytic enzyme, integrase) and structural proteins (p24, pl7, p7, etc.). HIV cannot be propagated in vitro and must be reproduced by means of human cells. The replication process is roughly divided into seven steps: virus binding, fusing, reverse transcript ion, integration (integration) ), transcr ipt ion, trans lat ion, and assembly & budding cells. HIV is continuously replicated in such a cyclical process, infecting human immune cells, destroying the body's immune system, and ultimately leading to the complete loss of the body's immune function, causing patients to be in danger of various infections without resilience, thus causing more Infectious diseases and tumors eventually lead to death. In theory, drugs can inhibit the virus and treat diseases as long as they block any part of the virus replication process. of.
迄今为止， FDA批准用于治疗艾滋病的临床药物有 20个，分为 四类 ( Erik DC. Antiviral drugs in current clinical use. J Clin Virol, 2004, 30 (2): 115-133 ) : ( 1 ) 核苷类逆转录酶抑制剂 ( nucleoside reverse trascriptase inhibitors, NRTIs ) ， 8 个； ( 2 ) 非核苷类逆转录酶抑制剂 ( non- nucleoside reverse trascriptase inhibitors, NNRTIs ) , 3个； （ 3) 蛋白酶抑制 剂 ( rotease inhibitors, Pis )， 8个； ( 4 )融合抑制剂 ( fusion inhibitors, FIs) ， 1个。 临床上多采用不同作用机制的药物联 合治疗，如两种逆转录酶抑制剂和一种蛋白酶抑制剂（ Robbins GK， De GV, Shafer RW, et al. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med, 2003, 349: 2293 303.和 Shafer RW, Smeaton LM, Robbins GK, et al. Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med, 2003, 349: 2304 15 ) 。 该疗法虽能有效抑制感 染者体内的病毒载量， 降低其发病率和死亡率， 但仍存在易产生 抗药性、 毒副作用大等问题。 因此， 寻求病毒复制过程中的新药 物靶点， 并以此开发新型作用机制的抗 HIV药物是迫切需要的。 现有的抗 HIV药物都是针对病毒进入细胞后的复制过程发挥 抑制作用。然而随着对 HIV病毒与细胞融合机制研究的不断深入， 人们越来越关注能防止病毒侵入细胞、 在病毒复制早期发挥抗病 毒作用的药物研究。 该类药物既可以抑制病毒感染细胞， 又可以 抑制病毒复制， 有望为病人提供具有不同作用机制、 更为有效的 新型抗 HIV治疗药物。  To date, FDA has approved 20 clinical drugs for the treatment of AIDS, which are divided into four categories (Erik DC. Antiviral drugs in current clinical use. J Clin Virol, 2004, 30 (2): 115-133): (1) Nucleoside reverse transcriptase inhibitors (NRTIs), 8; (2) non-nucleoside reverse transcriptase inhibitors (NNRTIs), 3; (3) protease inhibition Rotease inhibitors (Pis), 8; (4) fusion inhibitors (FIs), one. Clinically, multiple combinations of drugs with different mechanisms of action, such as two reverse transcriptase inhibitors and one protease inhibitor (Robins GK, De GV, Shafer RW, et al. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med, 2003, 349: 2293 303. and Shafer RW, Smeaton LM, Robbins GK, et al. Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV- 1 infection. N Engl J Med, 2003, 349: 2304 15). Although this therapy can effectively inhibit the viral load in the infected person and reduce its morbidity and mortality, it still has problems such as easy drug resistance and large side effects. Therefore, it is urgent to seek new drug targets in the process of viral replication and to develop anti-HIV drugs with novel mechanisms of action. Existing anti-HIV drugs are directed against the replication process of the virus after it enters the cell. However, with the deepening of research on the mechanism of HIV virus and cell fusion, people are paying more and more attention to drug research that can prevent viruses from invading cells and exerting antiviral effects in the early stage of viral replication. These drugs can inhibit virus-infected cells and inhibit viral replication, and are expected to provide patients with new anti-HIV therapeutic drugs with different mechanisms of action.
HI V入侵细胞的过程主要有 3个步骤： 粘附、 与辅助受体结合、 膜融合。 病毒包膜糖蛋白 gpl20首先与细胞表面的 CD4分子结合 (Gallaher WR, Ball JM, Garry RF， et al. A general model for the surface glycoproteins of HIV and other retroviruses. AIDS Res Hum Retrovir, 1995， 11: 191-202 ) ， 构像发生变化后再与 辅助受体 （化学趋化因子， 如 CXCR4或 CCR5) 结合 （Dragic T， Litwin V, All away GP， et al. HIV-1 entry into CD4+ cells is mediated by the cheraokine receptor CC-CKR-5. Na ture, 1996， 381: 667 73 ) ； 随后由 gp41插入细胞膜形成 6螺旋体， 将病毒膜与细 胞膜拉近使之融合。 在该过程中， gpl20和 gp41、 CD4受体以及辅 助受体都被视作可能的药物作用靶点。 其中， gp41在整个融合过 程中起着至关重要的作用。 There are three main steps in the process of HI V invading cells: adhesion, binding to co-receptors, Membrane fusion. The viral envelope glycoprotein gpl20 first binds to the CD4 molecule on the cell surface (Gallaher WR, Ball JM, Garry RF, et al. A general model for the surface glycoproteins of HIV and other retroviruses. AIDS Res Hum Retrovir, 1995, 11: 191 -202), the conformation changes and then binds to a co-receptor (chemokine such as CXCR4 or CCR5) (Dragic T, Litwin V, All away GP, et al. HIV-1 entry into CD4+ cells is mediated by The cheraokine receptor CC-CKR-5. Na ture, 1996, 381: 667 73 ); Subsequently, gp41 was inserted into the cell membrane to form a 6-helix, and the viral membrane was brought close to the cell membrane to fuse it. In this process, gpl20 and gp41, CD4 receptors, and co-receptors are all considered potential drug targets. Among them, gp41 plays a vital role in the whole process of fusion.
Gp41的氨基酸序列有四个功能区。 位于 C端的跨膜区 ( transmembrane domain, TM ) 将 gp41固定在病毒膜上； CHR段 ( C- terminal heptad repeat, CHR )和 NHI¾( N- terminal heptad repeat, NHR )是 gp41结构的功能部分； 融膜肽（ fus ion pept ide， FP )是位于 N端的一段高度疏水的序列，主要作用是插入宿主细胞 膜中 (Mel iky an GB， Markosyan RM, Hemmati H, et al. Evidence that the transition of HIV-1 gp41 into a six-helix bundle, not the bundle configuration, induces membrane fusion. I Cell Biol, 2000, 151: 413 23 和 Munoz-Barroso I， Salzwedel K， Hunter E, et al. Role of the membrane-proximal domain in the initial stages of human immunodeficiency virus type 1 envelope glycoprotein- mediated membrane fusion. J Virol, 1999, 73: 6089 92 )。 病毒表面的 gp41的三段 NHR螺旋平行排列于中央， 三段 CHR螺 旋反平行地围绕在周围， 外面被 3个 gP120所包围。 当病毒感染细 胞时， 病毒表面的 gpl20与细胞表面的 CD4受体和辅助受体结合后 使其构像发生变化， gp41的 NHR螺旋就从中央伸展出来， 把 N端的 融膜肽插入细胞膜中 （ Coleman CI, Musial BL and Ross J. Enfuvirtide: The first fusion inhibitor for the treatment of patients with HIV— 1 infection. Formulary, 2003, 38: 204 222 ) 。 随后， NHR与 CHR相互靠拢， 重新形成平行的六元螺旋束。 这一构象变化为病毒包膜与宿主细胞膜的水化表面相互靠近提供 了所需要的能量，从而将病毒膜与细胞膜拉近，促使融合的发生。 ( Coo ley LA and Lew in SR， HIV-1 cell entry and advances in viral entry inhibitor therapy. J Clin Virol, 2003， 26: 121 132 和 Moore JP and Doms RW. The entry of entry inhibitors: A fusion of science and medicine. Proc Natl Acad Sci USA, 2003, 100: 10598 10602 ) 。 病毒表面诸多 gp41使两层膜形成膜间融合孔， 膜的流动性使之迅速扩大，最终实现 HIV包膜与宿主细胞膜的完全 融合， 病毒核心物质被释放到宿主细胞质中。 gp41的两段功能区 NHR和 CHR都可成为 HIV融合抑制剂的作用 靶点。 美国 FDA批准的第一个融合抑制剂药物 T-20 (Fuzeon) 是 一个模拟 CHR螺旋结构序列的 36个氨基酸的多肽。 它通过与 NHR结 合来阻断六元螺旋束的形成， 从而达到抑制病毒与细胞膜融合的 目的 ( Fung HB, BCPS and Guo Y. Enfuvirtide: A Fusion Inhibitor for the Treatment of HIV Infection. Clin Ther, 2004, 26 (3): 352-378 ) o ; 由于 T20是肽类药物， 存在着口服生物利用度差、 生 产成本高等不足，故寻找高效、低毒的非肽类小分子 HIV融合抑制 剂先导物是抗 HIV新药研究的主要方向之一。 通过对结构多样化的小分子化合物库进行靶向活性筛选， 两 个 ^芳基羧酸取代吡咯类小分子化合物 NB- 2 和 NB-64 (Jiang Sh-B, Lu H, Liu Sh- , et al. N-Substituted Pyrrole Derivatives as Novel Human Immunodeficiency Virus Type 1 Entry Inhibitors That Interfere with the gp41 Six-Helix Bundle Formation and Block Virus Fusion. Antimicrob Agents Chemother, 2004, 48: 4349-4359 )不仅在细胞模型中显示出良好的抗 HIV复制活性（ EC5。 值分别为 1.04 !^和 2.21 μΜ) ， 而且在病毒与细胞膜的融合试 猃（EC5。值分别为 6.74 μΜ和 29.92 μΜ) 和 gp41六元螺旋束形 成试验中 [IC5。 (6-HB) 值分别为 13.48 μΜ和 15.69 μΜ]均有明显 抑制活性。 这些试验结果表明 ΝΒ- 2和 ΝΒ- 64确为作用于 gp41的 小分子活性化合物。 基于结构与生物活性相关的基本原理， 对它 们的结构改造， 可能寻找到活性更好的小分子融合抑制剂。 The amino acid sequence of Gp41 has four functional regions. The transmembrane domain (TM) at the C-terminus immobilizes gp41 on the viral membrane; the C-terminal heptad repeat (CHR) and NHI3⁄4 (N-terminal heptad repeat, NHR) are functional parts of the gp41 structure; Fus ion pept ide (FP) is a highly hydrophobic sequence at the N-terminus that is inserted into the host cell membrane (Mel iky an GB, Markosyan RM, Hemmati H, et al. Evidence that the transition of HIV-1 Gp41 into a six-helix bundle, not the bundle configuration, induces membrane fusion. I Cell Biol, 2000, 151: 413 23 and Munoz-Barroso I, Salzwedel K, Hunter E, et al. Role of the membrane-proximal domain in The initial stages of human immunodeficiency virus type 1 envelope glycoprotein-mediated membrane fusion. J Virol, 1999, 73: 6089 92 ). The three-segment NHR helix of gp41 on the surface of the virus is arranged in parallel at the center, and the three-segment CHR spiral is surrounded by anti-parallel, surrounded by three g P 120s. When the virus is infected At the time of cell, gpl20 on the surface of the virus binds to the CD4 receptor and co-receptor on the cell surface, and its conformation changes. The NHR helix of gp41 extends from the center, and the N-terminal melt peptide is inserted into the cell membrane (Coleman CI, Musial BL and Ross J. Enfuvirtide: The first fusion inhibitor for the treatment of patients with HIV-1 infection. Formulary, 2003, 38: 204 222). Subsequently, NHR and CHR close together, re-forming a parallel six-element spiral beam. This conformational change provides the energy needed to bring the viral envelope closer to the hydration surface of the host cell membrane, thereby bringing the viral membrane closer to the cell membrane and promoting fusion. (Coo ley LA and Lew in SR, HIV-1 cell entry and advances in viral entry inhibitor therapy. J Clin Virol, 2003, 26: 121 132 and Moore JP and Doms RW. The entry of entry inhibitors: A fusion of science and Medicine. Proc Natl Acad Sci USA, 2003, 100: 10598 10602 ). Many gp41 on the surface of the virus cause the two membranes to form a fusion pore between the membranes, and the fluidity of the membrane rapidly expands, finally achieving complete fusion of the HIV envelope with the host cell membrane, and the viral core substance is released into the host cytoplasm. The two functional regions of gp41, NHR and CHR, can be targets of HIV fusion inhibitors. The first fusion inhibitor drug, T-20 (Fuzeon), approved by the US FDA, is a 36 amino acid peptide that mimics the CHR helical structural sequence. It binds to NHR to block the formation of a six-membered helix bundle, thereby achieving the purpose of inhibiting fusion of the virus and the cell membrane (Fung HB, BCPS and Guo Y. Enfuvirtide: A Fusion Inhibitor for the Treatment of HIV Infection. Clin Ther, 2004, 26 (3): 352-378 ) o ; Because T20 is a peptide drug, there are insufficient oral bioavailability and high production cost, so it is necessary to find a high-efficiency, low-toxic non-peptide small molecule HIV fusion inhibitor lead. One of the main directions of research on new anti-HIV drugs. Two aryl carboxylic acid-substituted azole-based small molecule compounds NB-2 and NB-64 (Jiang) through targeted activity screening of structurally diverse small molecule compound libraries Sh-B, Lu H, Liu Sh- , et al. N-Substituted Pyrrole Derivatives as Novel Human Immunodeficiency Virus Type 1 Entry Inhibitors That Interfere with the gp41 Six-Helix Bundle Formation and Block Virus Fusion. Antimicrob Agents Chemother, 2004, 48 : 4349-4359 ) Not only showed good anti-HIV replication activity in cell models (EC 5 values of 1.04 !^ and 2.21 μΜ, respectively), but also in the fusion test of virus and cell membrane (EC 5 values were 6.74, respectively). μΜ and 29.92 μΜ) and gp41 six-membered helical beam formation test [IC 5 . The (6-HB) values were 13.48 μΜ and 15.69 μΜ, respectively, with significant inhibitory activity. The results of these tests indicate that ΝΒ-2 and ΝΒ-64 are indeed small molecule active compounds acting on gp41. Based on the basic principles of structure and biological activity, it is possible to find a small molecule fusion inhibitor with better activity for their structural modification.
Figure imgf000007_0001
发明内容
Figure imgf000007_0001
Summary of the invention
本发明涉及式 I 的具有 5-取代苯基-四氮唑类骨架结构的化 合物， 它们可有效抑制 HIV- 1表面糖蛋白 gp41六聚体的形成，从 而抑制 HIV复制。 对该类化合物的深入研究， 将有可能发现新型 的非肽类小分子 HIV融合抑制剂， 成为新的抗 AIDS病药物。  The present invention relates to a compound of the formula I having a 5-substituted phenyl-tetrazole skeleton structure which is effective for inhibiting the formation of the HIV-1 surface glycoprotein gp41 hexamer, thereby inhibiting HIV replication. An in-depth study of this class of compounds will likely lead to the discovery of novel non-peptide small molecule HIV fusion inhibitors that will become new anti-AIDS drugs.
本发明笫一方面涉及式 I的四氮唑芳基杂环类化合物或其可 药用盐：
Figure imgf000008_0001
其中， One aspect of the invention relates to a tetrazolium aryl heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof:
Figure imgf000008_0001
among them,
R! - - H、 - CH2C00H、 -CH2CH2C00H、 -CH=CH-C00H、 -CH2C00R' 、 -CH2CH2COOR' 、 -CH=CH-C00R' 、 d—6烃基； R! - - H, - CH 2 C00H, -CH 2 CH 2 C00H, -CH=CH-C00H, -CH 2 C00R', -CH 2 CH 2 COOR' , -CH=CH-C00R' , d- 6 Hydrocarbyl group;
R2 = - H、 卤素、 -N02、 — NH2、 -腿， 、 - N (R， ）2、 — CN、 -OH, d-6烷基、 d-6烷氧基、 - CF3、 -C00H、 - S03H、 - C0NH2、 -C0NHR' 或 -C00R' ； R 2 = - H, halogen, -N0 2 , —NH 2 , —leg, —N (R, ) 2 , —CN, —OH, d- 6 alkyl, d- 6 alkoxy, —CF 3 , -C00H, - S0 3 H, - C0NH 2 , -C0NHR' or -C00R';
Ar为含 1-3个选自 N、 0、 S的杂原子的五元杂芳环， 选自：  Ar is a five-membered heteroaryl ring containing 1-3 hetero atoms selected from N, 0, S, selected from:
Figure imgf000008_0002
其中 R3 - CH0、 COR' 、 C00R， 、 C00H、 CF3、 CH2R，， 、 卤素、 6烃基、 6烷氧基、 - NH2、 -OH, -N02、 - CN、 -HOCH-CN、 - CH=CH2、
Figure imgf000008_0002
Wherein R 3 - CH0, COR', C00R, C00H, CF 3 , CH 2 R,, , halogen, 6 hydrocarbyl, 6 alkoxy, -NH 2 , -OH, -N0 2 , -CN, -HOCH- CN, - CH=CH 2 ,
-C≡CH、 - C≡CR， 、 -CH=CHR' 、 -CH=CHC0R' ， 或为任选在其环 结构的可利用位置上带有酯基、 羧基、 6烽基、 苯基取代的以下 杂环基团： -C≡CH, -C≡CR, , -CH=CHR', -CH=CHC0R', or optionally having an ester group, a carboxyl group, a 6- mercapto group, a phenyl group at the available positions of the ring structure The following heterocyclic groups:
Figure imgf000008_0003
Figure imgf000008_0003
其中， X和 Υ 各自独立地选自 C, 0， S和 ΝΗ;  Wherein X and Υ are each independently selected from C, 0, S and ΝΗ;
R4= -H、 -CH2C00H、 -CH2CH2C00H、 -CH-CH- C00H、 -CH2C00R' 、 - CH2CH2C00R， 、 -CH-CH- C00R， 、 d—6烃基、 苯基； R5= - H、 卤素、 - N02、 - NH2、 -腿， 、 - N (R， ）2、 - CN、 - 0H、 烃基、 烷氧基、 -CF3、 CH0、 - C00H、 - S03H、 -C0NH2, -CONHR' 或- C00R， ； R 4 = -H, -CH 2 C00H, -CH 2 CH 2 C00H, -CH-CH- C00H, -CH 2 C00R' , - CH 2 CH 2 C00R, , -CH-CH- C00R, , d- 6 Hydrocarbyl group, phenyl group; R 5 = - H, halogen, -N0 2 , -NH 2 , - leg, - N (R, ) 2 , - CN, - 0H, hydrocarbyl, alkoxy, -CF 3 , CH0, - C00H, - S0 3 H, -C0NH 2 , -CONHR' or - C00R, ;
上述五元杂芳环任选在其环上可利用位置带有选自醛基、 酮 基、 酯基、 羧基、 氰基、 α， Ρ不饱和酮、 烯、 炔、 d— 6烽基、 d-6 烷氧基、 卤素、 - NH2、 -0H、 - N02和 -CF3的取代基； The above five-membered heteroaryl ring is optionally available at a ring position selected from the group consisting of an aldehyde group, a ketone group, an ester group, a carboxyl group, a cyano group, an α, an unsaturated ketone, an alkene, an alkyne, a d- 6 fluorenyl group, a substituent of alkoxy, halo, -NH 2 , -0H, -N0 2 and -CF 3 ;
R' -Cw 烃基； 并且  R'-Cw hydrocarbyl;
R" 为卤素、 0H或（^烷氧基。  R" is halogen, 0H or (^ alkoxy.
本发明中所采用的术语 "烃基" 包括烷基、 烯基和炔基。 本发明对取代基 R3描述中所涉及的 "以下杂环基团" 包括但 不限于 2， 4-噻唑烷二酮、 2-硫代- 2， 4-噻唑烷二酮 （绕丹宁， Rhodanine ) 、 丁二酰亚胺、 2， 4 -咪唑啉二酮 （海因、 乙内酰脲， hydantoin ) 、 2 -梳代海因 ( 2-Thiohydantoin ) 、 假碗代乙内酰 脉 ( Pseudothiohydantoin ) 等。 本发明第二个方面涉及式 I 化合物或其可药用盐的制备方 法。 The term "hydrocarbyl" as used in the present invention includes alkyl, alkenyl and alkynyl groups. The "lower heterocyclic group" referred to in the description of the substituent R 3 of the present invention includes, but is not limited to, 2,4-thiazolidinedione, 2-thio- 2,4-thiazolidinedione (circular tannin), Rhodanine ), succinimide, 2, 4 -imidazolidinone (hydantoin, hydantoin), 2-tuodihydantoin, pseudo-capinehydantoin (Pseudothiohydantoin) ) Wait. A second aspect of the invention relates to a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof.
本发明第三个方面涉及含有至少一种式 I化合物或其可药用 盐以及一种或多种药用载体或赋形剂的药物組合物。  A third aspect of the invention relates to a pharmaceutical composition comprising at least one compound of formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
本发明笫四个方面涉及上述式 I化合物或其可药用盐用于制 备治疗与 HIV感染的有关的疾病或病症的药物的用途。 根据本发明的一个优选实施方式， Ar 为取代吡咯， 如式 II 所示：
Figure imgf000010_0001
Four aspects of the invention relate to the use of a compound of formula I above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or condition associated with HIV infection. According to a preferred embodiment of the invention, Ar is a substituted pyrrole, as shown in formula II:
Figure imgf000010_0001
其中，  among them,
RfH - CH2C00H、 -CH2CH2COOH、 - CH-CH- C00H、 -CH2C00R' 、 -CH2CH2COOR' 、 -CH=CH-C00R' 、 d— 6烃基； RfH - CH 2 C00H, -CH 2 CH 2 COOH, -CH-CH-C00H, -CH 2 C00R' , -CH 2 CH 2 COOR' , -CH=CH-C00R', d- 6 hydrocarbon group;
R2 = - H、 卤素、 -N02、 - NH2、 - NHR， 、 - N (R， ）2、 - CN、 -OH, d— 6烷基、 烷氧基、 - CF3、 -C00H、 -SO3H, -C0NH2、 -C0NHR' 或 -C00R' ； R 2 = - H, halogen, -N0 2 , -NH 2 , - NHR, - N (R, ) 2 , - CN, -OH, d- 6 alkyl, alkoxy, -CF 3 , -C00H , -SO3H, -C0NH 2 , -C0NHR' or -C00R';
R3 = CH0、 COR' 、 C00R， 、 C00H、 CF3、 CH2R" 、 卤素、 d-6 炫基、 d—6烷氧基、 -NH2、 - 0H、 -N02、 -CN、 - HC-CH-CN、 -CH=CH2、 - C≡CH、 -C≡CR， 、 -CH=CHR' 、 -CH=CHC0R' ， 或为任选在其环 结构上带有酯基、 羧基、 d— 6烽基、 苯基取代的以下杂环基团：
Figure imgf000010_0002
R 3 = CH0, COR' , C00R, , C00H, CF 3 , CH 2 R" , halogen, d- 6 cyclyl, d- 6 alkoxy, -NH 2 , - 0H, -N0 2 , -CN, - HC-CH-CN, -CH=CH 2 , -C≡CH, -C≡CR, , -CH=CHR', -CH=CHC0R', or optionally having an ester group in its ring structure, a heterocyclic group substituted with a carboxyl group, a d- 6 fluorenyl group, or a phenyl group:
Figure imgf000010_0002
其中， X和 Y 各自独立地选自 C, 0, S和 NH;  Wherein X and Y are each independently selected from C, 0, S and NH;
R4 = -H - CH2C00H、 - CH2CH2COOH、 - CH-CH-C00H、 -CH2C00R' , - CH2CH2COOR， 、 - CH-CH- C00R， 、 烃基、 苯基； R 4 = -H - CH 2 C00H, - CH 2 CH 2 COOH, - CH-CH-C00H, -CH 2 C00R' , - CH 2 CH 2 COOR, , - CH-CH- C00R, , Hydrocarbyl, Phenyl ;
R5= - H、 卤素、 - N02、 -冊2、 -腿， 、 - N (R， ）2、 - CN、 -0H、 d-6烃基、 d-6烷氧基、 -CF3、 CH0、 -C00H、 -S03H、 -C0NH2、 -CO醒， 或- C00R， ； R 5 = - H, halogen, -N0 2 , - 2 , - leg, - N (R, ) 2 , - CN, -0H, d- 6 hydrocarbon, d- 6 alkoxy, -CF 3 , CH0, -C00H, -S0 3 H, -C0NH 2 , -CO wake up, or - C00R, ;
R6 = H、 CH3、 CF3、 卤素或 C2— 4 烃基； R 6 = H, CH 3 , CF 3 , halogen or C 2 - 4 hydrocarbyl;
R， =d-6 烃基； 并且 R, =d- 6 hydrocarbon; and
R" 为卤素、 OH或 δ烷氧基。 根据本发明的另一个优选实施方式， Ar为 1 , 2， 4-噁二唑，如 下式 I I I所示： R" is halogen, OH or δ alkoxy. According to another preferred embodiment of the invention, Ar is 1,2,4-oxadiazole, as shown in the following formula III:
Figure imgf000011_0001
Figure imgf000011_0001
其中， among them,
- - H、 -CH2C00H、 -CH2CH2COOH - CH=CH- C00H、 -CH2C00R' 、 -CH2CH2COOR' 、 -CH=CH-C00R' 、 d—6烃基； - - H, -CH 2 C00H, -CH 2 CH 2 COOH - CH=CH-C00H, -CH 2 C00R' , -CH 2 CH 2 COOR' , -CH=CH-C00R', d- 6 hydrocarbon group;
R2 = - H、 卤素、 - N02、 - NH2、 -醒， 、 -N (R， ）2、 -CN、 - 0H、 d— 6烷基、 d— 6烷氧基、 -CF3、 - C00H、 - S03H、 - C0NH2、 -CO腿， 或 -C00R' ； R 2 = - H, halogen, -N0 2 , -NH 2 , - awake, -N (R, ) 2 , -CN, - 0H, d- 6 alkyl, d- 6 alkoxy, -CF 3 - C00H, - S0 3 H, - C0NH 2 , -CO leg, or -C00R';
R3 = CH0、 COR' 、 C00R， 、 C00H、 CF3、 CH2R" 、 卤素、 d-6 烃基、 CH烷氧基、 -NH2、 -OH , - N02、 -CN - HC=CH- CN、 -CH=CH2、 -C≡CH、 - C≡CR， 、 -CH=CHR' 、 -CH=CHC0R' , 或为任选在其环 结构上带有酯基、 羧基、 d— 6烃基、 苯基取代的以下杂环基团：
Figure imgf000011_0002
R 3 = CH0, COR', C00R, , C00H, CF 3 , CH 2 R" , halogen, d- 6 hydrocarbon, CH alkoxy, -NH 2 , -OH , - N0 2 , -CN - HC=CH - CN, -CH=CH 2 , -C≡CH, -C≡CR, , -CH=CHR', -CH=CHC0R', or optionally having an ester group, a carboxyl group, a d- 6 hydrocarbyl, phenyl substituted heterocyclic groups:
Figure imgf000011_0002
其中， X和 Y 各自独立地选自 C , 0， S和 NH;  Wherein X and Y are each independently selected from C, 0, S and NH;
R4 = -H、 -CH2C00H、 -CH2CH2C00H > -CH=CH-C00H、 -CH2C00R' 、R 4 = -H, -CH 2 C00H, -CH 2 CH 2 C00H > -CH=CH-C00H, -CH 2 C00R' ,
- CH2CH2COOR， 、 -CH-CH- C00R， 、 6烃基、 苯基； - CH 2 CH 2 COOR, , -CH-CH-C00R, , 6 hydrocarbyl, phenyl;
R5= HH、 卤素、 -N02、 -NH2、 -NHR' 、 — N (R， ）2、 - CN、 -OH , d-6烃基、 d— δ烷氧基、 -CF3、 CH0、 ~C00H、 - S03H、 -C0NH2、 -CONHR' 或一 C00R， ； R 5 = HH, halogen, -N0 2 , -NH 2 , -NHR' , —N (R, ) 2 , —CN, —OH , d- 6 hydrocarbon, d— δ alkoxy, —CF 3 , CH0 , ~C00H, - S0 3 H, -C0NH 2 , -CONHR' or a C00R, ;
R' =d-6 烃基； 并且 R' = d- 6 hydrocarbyl;
R" 为卤素、 OH或（^6烷氧基。 根椐本发明的另一个优选实施方式， Ar为 5-取代呋喃，如下 式 IV所示： R" is halogen, OH or (^ 6 alkoxy. According to another preferred embodiment of the invention, Ar is a 5-substituted furan, as shown in the following formula IV:
Figure imgf000012_0001
其中,
Figure imgf000012_0001
among them,
R^ -H, - CH2C00H、 -CH2CH2COOH -CH=CH-C00H, -CH2C00R' 、 -CH2CH2COOR' 、 -CH=CH-C00R' 、 烃基； R^-H, -CH 2 C00H, -CH 2 CH 2 COOH -CH=CH-C00H, -CH 2 C00R' , -CH 2 CH 2 COOR' , -CH=CH-C00R', hydrocarbon group;
R2 - -H、 卤素、 - N02、 -NH2、 - NHR， 、 - N (R， ）2、 - CN、 - 0H、 CH烷基、 CH烷氧基、 - CF3、 - C00H、 - S03H、 -C0NH2 -C0NHR' 或 -C00R' ； R 2 - -H, halogen, -N0 2 , -NH 2 , - NHR, - N (R, ) 2 , - CN, - 0H, CH alkyl, CH alkoxy, - CF 3 , - C00H, - S0 3 H, -C0NH 2 -C0NHR' or -C00R';
R3 = CH0、 COR' 、 C00R， 、 C00H、 CF3、 CH2R" 、 卤素、 d-6 烃基、 CH烷氧基、 -跳、 -OH , -N02、 - CN、 - HC=CH-CN、 -CH=CH2 , -C≡CH - C≡CR， 、 -CH=CHR' 、 - CH=CHC0R， ， 或为任选在其环 结构上带有酯基、 羧基、 d— 6烽基、 苯基取代的以下杂环基团：
Figure imgf000012_0002
R 3 = CH0, COR', C00R, , C00H, CF 3 , CH 2 R" , halogen, d- 6 hydrocarbon, CH alkoxy, -hop, -OH, -N0 2 , - CN, - HC=CH -CN, -CH=CH 2 , -C≡CH - C≡CR, , -CH=CHR', -CH=CHC0R, , or optionally having an ester group, a carboxyl group, a d- 6 The following heterocyclic groups substituted with fluorenyl and phenyl:
Figure imgf000012_0002
其中， X和 Y 各自独立地选自 C, 0, S和 NH;  Wherein X and Y are each independently selected from C, 0, S and NH;
R4 = - H、 - CH2C00H、 - CH2CH2C00H、 - CH=CH-C00H、 - CH2C00R， 、 -CH2CH2COOR， 、 - CH-CH- C00R， 、 d— 6烃基、 苯基； R 4 = - H, - CH 2 C00H, - CH 2 CH 2 C00H, - CH=CH-C00H, - CH 2 C00R, , -CH 2 CH 2 COOR, , - CH-CH- C00R, , d- 6 Hydrocarbyl group, phenyl group;
R5= - H、 卤素、 -N02、 -NH2、 -腿， 、 - N (R， ）2、 - CN、 - 0H、 烃基、 d-6烷氧基、 - CF3、 CH0> -C00H、 - S03H、 - C0NH2、 -CONHR' 或- C00R， ： R， =d,6 烃基； 并且 R 5 = - H, halogen, -N0 2 , -NH 2 , - leg, - N (R, ) 2 , - CN, - 0H, hydrocarbyl, d- 6 alkoxy, -CF 3 , CH0> - C00H, - S0 3 H, - C0NH 2 , -CONHR' or - C00R, : R, =d, 6 hydrocarbyl;
R" 为卤素、 OH或 6烷氧基 本发明更优选下列化合物： R" is halogen, OH or 6 alkoxy. The following compounds are more preferred in the present invention:
5-(3-(2，5-二甲基 -1^·吡咯 -1-基）苯基） -1^四氮唑 5-(3-(2,5-dimethyl-1^·pyrrole-1-yl)phenyl)-1^tetrazolium
( ΙΙ-la) ； ( ΙΙ-la) ;
5- (2-羟基 -5- (2， 5-二甲基 -I 吡咯 -1-基）苯基） -1 四氮唑 ( II - lb) ；  5-(2-hydroxy-5-(2,5-dimethyl-Ipyrrole-1-yl)phenyl)-1 tetrazolium (II-lb);
5- (2-氯- 5- (2， 5-二甲基 -1^吡咯- 1-基）苯基） -I 四氮唑 ( II-lc) ；  5-(2-Chloro-5-(2,5-dimethyl-l^pyrrole-1-yl)phenyl)-I tetrazolium (II-lc);
5-(3- (3-乙氧羰基 -2，5-二甲基-1^"吡咯-1-基）苯基） -I 四 氮唑 （II- Id) ；  5-(3-(3-ethoxycarbonyl-2,5-dimethyl-1^"pyrrol-1-yl)phenyl)-I tetrazolium (II-Id);
5- (3- (3-羧基- 2, 5-二甲基 -1^吡咯- 1-基）苯基） -I 四氮唑 ( ΙΙ-le) ；  5-(3-(3-carboxy- 2,5-dimethyl-l^pyrrole-1-yl)phenyl)-I tetrazolium ( ΙΙ-le);
5- (3- (I 吡咯 -1-基）苯基） -I 四氮唑 （II- If ) ；  5-(3-(Ipyrrole-1-yl)phenyl)-I tetrazolium (II-If);
1-羧甲基- 5- (3- (2， 5-二甲基 -1 吡咯- 1 -基）苯基） 1^四氮 唑 ( II- 2b) ；  1-carboxymethyl-5-(3-(2,5-dimethyl-1 -pyrrole-1-yl)phenyl) 1^tetrazole ( II-2b);
1-羧甲基 -5-(3-(3-羧基 -2，5-二甲基-1 吡咯-1 基）苯 基） -I 四氮唑（ II- 2d)  1-carboxymethyl-5-(3-(3-carboxy-2,5-dimethyl-1pyrrole-1yl)phenyl)-I tetrazole (II-2d)
5- (3- (5- (三氟甲基） -1， 2， 4-噁二唑 -3 -基）苯基） - 1^·四氮唑 5-(3-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)phenyl)-1 ^·tetrazolium
( ΙΙΙ-la) ； ( ΙΙΙ-la) ;
5- (3- (5- (氯甲基） -1, 2, 4-噁二唑 -3 -基）苯基） -1^四氮唑 ( ΙΙΙ-lb) ；  5-(3-(5-(Chloromethyl)-1,2,4-oxadiazole-3-yl)phenyl)-1^tetrazole (ΙΙΙ-lb);
5- (3- (5- (羟甲基) -1， 2, 4-噁二唑 -3 -基）苯基） - 1^四氮唑 ( III-lc) ；  5-(3-(5-(hydroxymethyl)-1,2,4-oxadiazole-3-yl)phenyl)-1 ^tetrazole ( III-lc) ;
1 -羧甲基 -5- (3- (5- (三氟甲基） -1， 2， 4 -噁二唑- 3-基）苯 基） -I 四氮唑 ( III-2b) ； 1-乙基- 5- (3- (5-次曱基- (绕丹宁 - 5-基）-呋喃- 2-基）苯 基）一1^~四氮唑（IV-2a ) ； 和 1-carboxymethyl-5-(3-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)phenyl)-I tetrazolium (III-2b); 1-ethyl-5-(3-(5-indolyl-(cyclodextrin-5-yl)-furan-2-yl)phenyl)- 1^~tetrazole (IV-2a);
1 -羧甲基- 5- (3- (5-次甲基 -（绕丹宁 -5-基) -呋喃 -2-基）苯 基）- 1^四氮唑（IV-2b ) 。 本发明化合物可通过多种反应路线和方法制备， 如图所示: 路线 A: 通用方法：
Figure imgf000014_0001
1-Carboxymethyl-5-(3-(5-methine-(cyclo-n-butyl-5-yl)-furan-2-yl)phenyl)- 1^tetrazole (IV-2b). The compounds of the invention can be prepared by a variety of reaction routes and methods, as shown: Route A: General Methods:
Figure imgf000014_0001
A 1-1 '-2  A 1-1 '-2
反应条件： （i)盐酸盐 （如氯化胺， 氯化锂等） ， DMF为溶剂， 室温至回流， 4- 24小时；（ i i )醇钠在甲醇或乙醇中，室温至 100。C， 4-32小时  Reaction conditions: (i) hydrochloride (such as ammonium chloride, lithium chloride, etc.), DMF as solvent, room temperature to reflux, 4- 24 hours; (i i) sodium alkoxide in methanol or ethanol, room temperature to 100. C, 4-32 hours
路线 B: 对于式 I中 Ar为吡咯环的化合物而言：  Route B: For compounds in formula I where Ar is a pyrrole ring:
Figure imgf000014_0002
Figure imgf000014_0002
反应条件： （i i i)微波反应， 以醋酸为溶剂或无溶剂，  Reaction conditions: (i i i) microwave reaction, using acetic acid as solvent or no solvent,
120 - 160。C， 5-20分钟； （ i i ) 同路线 A中第二步反应条件。 120 - 160. C, 5-20 minutes; (i i ) Same as the second reaction condition in route A.
路线 对于式 I中 Ar为噁二唑环的化合物而言：
Figure imgf000015_0001
For the compounds of formula I where Ar is an oxadiazole ring:
Figure imgf000015_0001
反应条件： （iv)在 8-羟喹啉存在下， 碳酸钠或碳酸钾，  Reaction conditions: (iv) sodium carbonate or potassium carbonate in the presence of 8-hydroxyquinoline,
80-100°C, 2-8小时， 乙醇为溶剂； （V )吡啶或四氢呋喃为溶剂， 室温到 120。C， 2-6小时； （ i i ) 同路线 A中第二步反应条件。 路线 D: 对于式 I中 Ar为五元杂环（如吡咯、 呋喃等）醛的 化合物而言： 80-100 ° C, 2-8 hours, ethanol as solvent; (V) pyridine or tetrahydrofuran as solvent, room temperature to 120. C, 2-6 hours; (i i ) The reaction conditions of the second step in the same route A. Route D: For compounds in which Formula Ar is a five-membered heterocyclic ring (eg, pyrrole, furan, etc.) aldehyde:
Figure imgf000015_0002
Figure imgf000015_0002
反应条件： (vi) Suzuki偶联反应， 有机硼酸试剂， 钯催化 剂； （vi i )缩合反应（与图中所示或相关酮类试剂），碱性条件： 有机胺， 无机强碱或弱酸强碱盐， 甲醇、 乙醇、 乙酸、 DMF或 DMF 与水的混合溶剂， 室温- 160oC, 1-44小时。 上述反应路线中的 Ar、 R!-R4, R6和 X、 Y的定义同前式 I所 述， U、 V、 W各自独立地表示选自 N、 0、 S的杂原子或为碳原子。 具体来说， Reaction conditions: (vi) Suzuki coupling reaction, organoboric acid reagent, palladium catalyst; (vi i) condensation reaction (with ketone reagents shown or related in the figure), basic conditions: organic amine, strong inorganic base or weak acid Alkaline salt, methanol, ethanol, acetic acid, DMF or a mixed solvent of DMF and water, room temperature - 160 o C, 1-44 hours. Ar, R!-R 4 , R 6 and X, Y in the above reaction scheme are as defined in the above formula I, and U, V and W each independently represent a hetero atom selected from N, 0, S or carbon. atom. Specifically,
合成路线 A: 取代苯氰化合物 （A ) 的氛基与叠氮化钠作用可 合成 四氮唑环，得到目标化合物 1-1， 四氮唑环上的 1位氮氢 与卤代烃反应即可得到化合物 1-2。  Synthetic Route A: The tetracycline ring can be synthesized by the action of the substituted phenyl cyanide compound (A) and sodium azide to obtain the target compound 1-1. The nitrogen atom at the nitrogen position on the tetrazole ring reacts with the halogenated hydrocarbon. Compound 1-2 can be obtained.
合成路线 B: 取代的 5- (3-氨基）苯基 - ^四氮唑（ B )与 2， 5- 二甲氧基四氢呋喃或 β位取代的 1， 4-二酮进行 ¾orr反应 可得到 ^芳基吡咯类化合物 （Π-1 ) ， 再与卤代烃反应生成 1- 取代的 ^ "四氮唑- 芳基吡咯类化合物 （Π-2 ) 。 Scheme B: Substituted 5-(3-amino)phenyl-tetrazolium (B) with 2, 5- Dimethoxytetrahydrofuran or β-substituted 1,4-butanone can be subjected to a 3⁄4orr reaction to obtain an arylpyrrole compound (Π-1), which is then reacted with a halogenated hydrocarbon to form a 1-substituted ^ tetrazole- Arylpyrroles (Π-2).
合成路线 C: 以取代的 5- (3-氰基)苯基- 四氮唑（ C )作原 料， 与盐酸幾胺反应生成氨基肟中间体（D ) , 再与酰化试剂作用 可得到 3 -芳基 -1， 2， 4-噁二唑类化合物（Π Ι-1 ) ， 继而氮的卤化 反应可得目标化合物 111-2。  Synthetic route C: using substituted 5-(3-cyano)phenyl-tetrazole (C) as a raw material, reacting with a few amines of hydrochloric acid to form an aminoguanidine intermediate (D), and then reacting with an acylating reagent to obtain 3 - aryl-1,2,4-oxadiazole compound (Π Ι-1 ), followed by halogenation of nitrogen to obtain the target compound 111-2.
合成路线 D: 取代的 5- (3-溴）零基- ^ ^"四氮唑（E )与芳杂环 的硼酸类化合物通过 Suzuki反应，偶联生成含有芳杂环的目标化 合物 IV- 1。 当芳杂环含有醛基时， 可经缩合、 卤代得到目标化合 物 IV-20 本发明涉及的取代的 5- ( 3-芳杂环取代苯基）四氮唑类化合 物 （式 I )是一类具有新骨架结构的抗 HIV活性化合物。 它们作 用于 HIV- 1 gp41 ,将有望发展成为一类具有特定靶标的新型抗 HIV 药物： 非肽类小分子融合抑制剂。 本发明的试验结果表明： 化合 物 I l-la抑制 6- HB结合的 IC5。值为 25. 61 μΜ, 高于相同试验中 所用的阳性对照化合物 ΝΒ- 64 ( IC50 = 58. 74 μΜ ) 。 该化合物在细 胞试验（ΜΤ- 2 淋巴细胞） 中对野生型 HIV 的抑制活性 EC5。值为 7. 70μΜ ( SI>32 )，并对临床分离的多类型的 HIV病毒林的复制均 有抑制活性， 明显优于已知活性化合物 NB-64。 部分相关化合物 的活性数据见表 1-2。 本发明结果表明以 I l-la为代表的化合物 为作用 HIV- 1 gp41靶点、 具有广泛的抗病毒谱的一类新型抗 HIV 活性化合物， 可发展为非肽类小分子抗 HIV融合的抑制剂。 本发明化合物既可以其本身也可以其可药用盐或溶剂化物的 形式使用。 式 I化合物的可药用盐包括与药学上可接受的无机酸 或有机酸、 或者无机碱或有机减形成的常规盐。 合适的酸加成盐 的例子包括与盐酸、 氢溴酸、 硫酸、 磷酸、 硝酸、 高氯酸、 富马 酸、 乙酸、 丙酸、 琥珀酸、 羟基乙酸、 曱酸、 乳酸、 马来酸、 酒 石酸、 柠檬酸、 朴酸、 丙二酸、 羟基马来酸、 苯乙酸、 谷氨酸、 苯甲酸、 水杨酸、 富马酸、 甲苯磺酸、 甲磺酸、 萘 -2-磺酸、 苯磺 酸、 羟基萘甲酸、 氢碘酸、 苹果酸、 鞣酸等形成的盐。 合适的碱 加成盐的例子包括与钠、 锂、 钾、 镁、 铝、 钙、 锌、 N，N， -二苄 基乙二胺、 氯代普鲁卡因、 胆碱、 二乙醇胺、 乙二胺、 N-甲基葡 糖胺和普鲁卡因等形成的盐。 本文中涉及到本发明化合物时， 包 括式 I化合物及其可药用盐或溶剂化物。 Synthetic Route D: Substituted 5-(3-bromo)-yl-(4)-tetrazole (E) and an aromatic heterocyclic boronic acid compound are coupled by Suzuki reaction to form the target compound IV-1 containing an aromatic heterocyclic ring. When the aromatic heterocyclic ring contains an aldehyde group, the target compound IV-2 0 can be obtained by condensation and halogenation. The substituted 5-(3-aromatic heterocyclic phenyl)tetrazole compound of the present invention (Formula I) It is a class of anti-HIV active compounds with a new backbone structure. They act on HIV-1 gp41 and are expected to develop into a new class of anti-HIV drugs with specific targets: non-peptide small molecule fusion inhibitors. The compound I l-la inhibits the IC 5 of 6-HB binding. The value is 25.61 μΜ, which is higher than the positive control compound ΝΒ-64 ( IC 50 = 58. 74 μΜ ) used in the same experiment. The inhibitory activity of wild type HIV in the test (ΜΤ-2 lymphocytes) was EC 5. The value was 7.70 μΜ (SI>32), and it inhibited the replication of clinically isolated multiple types of HIV virus forests. Known active compound NB-64. See the activity data of some related compounds. 1-2. The results of the present invention indicate that a compound represented by Il-la is a novel anti-HIV active compound having a broad antiviral spectrum which acts on the HIV-1 gp41 target, and can be developed into a non-peptide small molecule anti-peptide. Inhibitors of HIV Fusion. The compounds of the invention may be used either as such or in the form of pharmaceutically acceptable salts or solvates thereof. The pharmaceutically acceptable salts of the compounds of formula I include pharmaceutically acceptable mineral acids Or an organic acid, or an inorganic base or a conventional salt formed by organic reduction. Examples of suitable acid addition salts include with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, citric acid, lactic acid, maleic acid, Tartaric acid, citric acid, citric acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, a salt formed from benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, citric acid or the like. Examples of suitable base addition salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N,N,-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, B. a salt formed by a diamine, N-methylglucamine, and procaine. When reference is made herein to a compound of the invention, a compound of formula I, and pharmaceutically acceptable salts or solvates thereof, are included.
根据本发明， 本发明式 I化合物可与常规药用载体或赋形剂 组成药物组合物。 该药物组合物可通过口服或非肠道途径给药。 本发明的药物组合物可按本领域常规方法制备成各种剂型， 包括 但不限于片剂、 胶嚢、 溶液、 悬浮液、 颗粒剂或注射剂等， 经口 服或非肠道途径给药。  According to the present invention, the compound of the formula I of the present invention can be combined with a conventional pharmaceutical carrier or excipient to constitute a pharmaceutical composition. The pharmaceutical composition can be administered orally or parenterally. The pharmaceutical composition of the present invention can be prepared into various dosage forms including, but not limited to, tablets, capsules, solutions, suspensions, granules or injections, by a conventional method in the art, orally or parenterally.
另外需要指出， 本发明化合物使用剂量和使用方法取决于诸 多因素， 包括患者的年龄、 体重、 性别、 自然健康状况、 营养状 况、 化合物的活性强度、 服用时间、 代谢速率、 病症的严重程度 以及诊治医师的主观判断。优选的使用剂量介于 0. 01 ~ 100 mg/kg 体重 /天。 . 具体实施方式  It should also be noted that the dosage and method of use of the compounds of the invention depend on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and the diagnosis and treatment. Subjective judgment of the physician. The preferred dosage is between 0.01 and 100 mg/kg body weight per day. . detailed description
下面的实施例用于进一步说明本发明， 但其不意味着本发明 仅限于此。  The following examples are intended to further illustrate the invention, but are not intended to limit the invention thereto.
实施例 1 : 5- (3- (2， 5-二曱基 -I 吡咯 -1 -基）苯基） -1 ^四 氮唑（Il-la ) (合成路线 B )  Example 1 : 5-(3-(2,5-Dimercapto-Ipyrrole-1-yl)phenyl)-1^tetrazolium (Il-la) (Synthesis Route B)
2， 5-己二酮 （ 0. 13 mL )加到含有 3 -（1^四氮唑 -5-基）苯胺 ( 1 mmol ) 的冰醋酸（3 mL) 溶液中， 微波条件下， 150。C反应 10分钟。 冷至室温，反应物倒入水水中， 收集固体， 水洗至中性， 用制备色谱分离 （石油醚 /乙酸乙酯 /乙酸）得白色固体 124 mg， 收率 52%, mp 147-148 。C; NMR (DMS0-D6) ^ pm 8.14 (1H， d, = 8.4 Hz, ArH-6) , 7.87 (1H， s， ArH-2) , 7.76 (1H， t， / = 8.4 Hz, ArH-5), 7.53 (1H， d, /= 8.4 Hz, ArH-4) , 5.85 (2H， s， PyH), 2.02 (6H， s， Py-CH3 x 2) . 质谱（EI-MS): m/z (%) 239 (M+, 76) ， 211 (M-2 N, 100). 实施例 2: 5- (3- (l^吡咯- 1-基）苯基） -l^四氮唑（II- If ) 制备方法同 II- la (路线 B) 。 3- (I 四氮唑 -5 -基）苯胺（1 mmol )和 2， 5-二甲氧基四氢呋喃（ 0.14 mL)反应得化合物 II-lf， 白色固体 186 mg, 收率 88%, mp 210-212 °C; XH NMR (DMS0-D6) δ ppm 8.19 (1H， d, / = 2.0 Hz, ArH-2) , 7.92 (1H, d, / = 8.4 Hz, ArH-6) , 7.83 (1H, dd, / = 8.4 & 2.0 Hz, ArH-4) , 7.71 (1H， t, / = 8.4 Hz, ArH-5), 7.47 (2H, m， PyH— 2， 5), 6.35 (2H， t, /= 2.2 Hz, PyH-3, 4); 质谱（EI- MS): m/z (%) 211 (M+， 100)， 183 (M-2 x N, 98)， 168 (M-2 I -Nff, 37). 实施例 3: 5- (3- (3-乙氧叛基- 2， 5-二甲基 -1^·吡咯- 1-基）苯 基） -1 四氮唑（ Il-ld ) (合成路线 B ) 2, 5-hexanedione (0.13 mL) was added to contain 3-(1^tetrazolium-5-yl)aniline (1 mmol) in glacial acetic acid (3 mL) in a microwave condition, 150. C reaction for 10 minutes. After cooling to room temperature, the reaction mixture was poured into water, and the solid was collected, washed with water to neutral, and purified by preparative chromatography ( petroleum ether / ethyl acetate / acetic acid) to give a white solid 124 mg, yield 52%, mp 147-148. C; NMR (DMS0-D 6 ) ^ pm 8.14 (1H, d, = 8.4 Hz, ArH-6), 7.87 (1H, s, ArH-2), 7.76 (1H, t, / = 8.4 Hz, ArH- 5), 7.53 (1H, d, /= 8.4 Hz, ArH-4), 5.85 (2H, s, PyH), 2.02 (6H, s, Py-CH 3 x 2) . Mass Spectrometry (EI-MS): m /z (%) 239 (M+, 76), 211 (M-2 N, 100). Example 2: 5-(3-(l^pyrrole-1-yl)phenyl)-l^tetrazole ( II- If ) The preparation method is the same as II- la (route B). 3-(I-tetrazol-5-yl)aniline (1 mmol) and 2,5-dimethoxytetrahydrofuran (0.14 mL) gave Compound II-lf, white solid 186 mg, yield 88%, mp 210 -212 °C; X H NMR (DMS0-D 6 ) δ ppm 8.19 (1H, d, / = 2.0 Hz, ArH-2), 7.92 (1H, d, / = 8.4 Hz, ArH-6), 7.83 ( 1H, dd, / = 8.4 & 2.0 Hz, ArH-4), 7.71 (1H, t, / = 8.4 Hz, ArH-5), 7.47 (2H, m, PyH-2, 5), 6.35 (2H, t , /= 2.2 Hz, PyH-3, 4); Mass Spectrum (EI-MS): m/z (%) 211 (M+, 100), 183 (M-2 x N, 98), 168 (M-2 I -Nff, 37). Example 3: 5-(3-(3-Ethoxycarbo-2,5-dimethyl-1^-pyrrole-1-yl)phenyl)-1 Tetrazolium (I -ld ) (synthetic route B)
将甲醇钠 （1.65g， 30.6赚01)分次加入到 0。C的乙酰乙酸 乙酯 （4 g, 30.6讓 ol ) 的无水甲醇 （20 mL)溶液中， 保温反应 30分钟， 然后緩慢滴入溴丙酮 （2.2 mL, 25.5 mmol ) , 于室温 反应 10小时。 用盐酸水溶液调 ΡΗ值为中性， 用乙酸乙酯萃取， 干燥， 除去溶剂后用色谱柱分离 （石油醚 /乙酸乙酯 - 8: 1 )得 3 - 乙氧羰基 2， 5-己二酮， 淡黄色液体 2.9 g， 产物收率 61%。 新制备的 3 -乙氧叛基 -2， 5 -己二酮 05 mg)和 3 -（1H -四氮 唑- 5-基）苯胺 (1 mmol)在与制备 II- la相同的条件下反应得产 物 Π-ld, 淡黄色油状液体 256 rag, 收率 78%, rap 121-123 。C。 Sodium methoxide (1.65 g, 30.6 earned 01) was added to 0 in portions. The solution of ethyl acetoacetate (4 g, 30.6 EtOAc) in anhydrous methanol (20 mL) was warmed for 30 minutes, then bromoacetone (2.2 mL, 25.5 mmol) was slowly added dropwise and reacted at room temperature for 10 hours. The value was adjusted to neutral with aqueous hydrochloric acid, extracted with ethyl acetate, dried, and then evaporated to remove the solvent (ethyl ether/ethyl acetate - 8:1) to give 3-ethoxycarbonyl 2, 5-hexanedione. , pale yellow liquid 2.9 g, product yield 61%. The newly prepared 3-ethoxyxo-2,5-hexanedione 05 mg) and 3-(1H-tetrazol-5-yl)aniline (1 mmol) were reacted under the same conditions as in the preparation of II-la. The product obtained was Π-ld, pale yellow oily liquid 256 rag, yield 78%, rap 121-123. C.
^-NMR (CDC13) δ ppmll.66 (1Η， br, Tetrazole - Η)， 8.33 (1Η， d, / = 8.0 Hz, ArH-6) , 7.99 (1Η, s, ArH-2) , 7.68 (1H, t, /= 8.0 Hz, ArH-5), 7.34 (1H, d， / = 8.0 Hz, ArH-4) , 6.36 (1H, s, Py-H) , 4.29 (2H， q, -OCH2CH3) , 2.24 (3H, s， Py-CH3) , 1.97 (3H, s， Py-CHs) , 1.35 (3H， t， - CH2 ) . 实施例 4: 5- (3- (3 -羧基 -2， 5-二甲基 -1 吡咯- 1 -基)苯 基）- I 四氮唑（ II- le) (合成路线 B) ^-NMR (CDC1 3 ) δ ppmll.66 (1Η, br, Tetrazole - Η), 8.33 (1Η, d, / = 8.0 Hz, ArH-6) , 7.99 (1Η, s, ArH-2) , 7.68 ( 1H, t, /= 8.0 Hz, ArH-5), 7.34 (1H, d, / = 8.0 Hz, ArH-4) , 6.36 (1H, s, Py-H) , 4.29 (2H, q, -OCH2CH3) , 2.24 (3H, s, Py-CH 3 ), 1.97 (3H, s, Py-CHs), 1.35 (3H, t, - CH 2 ) . Example 4: 5-(3-(3-carboxy-2) , 5-dimethyl-1pyrrole-1-yl)phenyl)-I tetrazole (II-le) (Synthesis Route B)
ΙΙ-ld ( 100 mg, 0.32 mmol )在 1 NaOH水溶液（ 6 mL ) 中 室温反应 48小时， 用盐酸水溶液调 pH值为 3， 收集固体， 水洗 至中性， 用制备色谱分离 （石油醚 /乙酸乙酯 /乙酸）得白色固体 63 mg, 收率 69%, mp 250。C分解。 -NMR (CDC13) δ ppm 11.77 (1H， br, Tetrazole-H), 8.16 (1H, d, /= 8.0 Hz, ArH - 6)， 7.86 (1H， s， ArH-2) , 7.78 (1H, t, /= 8.0 Hz, ArH-5)， 7.55 (1H， d, / = 8.0 Hz, ArH-4), 6.24 (1H, s, Py-H) , 2.21 (3H, s， Py-CH3) , 1.87 (3H, s， Py-CH3) . 实施例 5: 1-甲氧羰基甲基 -5- (3- (2, 5-二甲基 -1 吡咯 -1- 基）苯基） -1^四氮唑（II-2a) (合成路线 B或 A) ΙΙ-ld (100 mg, 0.32 mmol) was reacted in 1 NaOH aqueous solution (6 mL) at room temperature for 48 hours, adjusted to pH 3 with aqueous hydrochloric acid, and the solid was collected, washed with water to neutral, and purified by preparative chromatography ( petroleum ether / acetic acid Ethyl acetate/acetic acid gave a white solid, 63 mg, yield 69%, mp 250. C decomposition. -NMR (CDC1 3 ) δ ppm 11.77 (1H, br, Tetrazole-H), 8.16 (1H, d, /= 8.0 Hz, ArH - 6), 7.86 (1H, s, ArH-2), 7.78 (1H, t, /= 8.0 Hz, ArH-5), 7.55 (1H, d, / = 8.0 Hz, ArH-4), 6.24 (1H, s, Py-H), 2.21 (3H, s, Py-CH 3 ) , 1.87 (3H, s, Py-CH 3 ) . Example 5: 1-methoxycarbonylmethyl-5-(3-(2,5-dimethyl-1pyrrol-1-yl)phenyl) 1^tetrazole (II-2a) (Synthesis Route B or A)
将甲醇钠（ 270 mg, 5 mmol)和溴乙酸甲酯（0.3 mL, 3.3 mmol) 加入到 Il-la (231 mg, 1 mmol) 的甲醇（10 mL)溶液中， 回流 反应 27小时。 蒸去溶剂， 残留物溶于乙酸乙酯中， 水洗、 干燥、 浓缩， 粗品用制备色谱分离 （石油醚 /乙酸乙酯 /乙酸）得白色固 体 205 mg, 产率 68%, mp 128-130。C。 lR NMR (DMS0-D6) ^ppm 8.15 (1H， d, /= 8.0 Hz, ArH-6) , 7.83 (1H, s， ArH-2) , 7.74 (1H， t， /= 8.0 Hz, ArH-5) , 7.50 (1H, d, /= 8.0 Hz, ArH-4) , 5.94 (2H， s， CH2) , 5.85 (2H， s， Py-H) , 3.76 (3H， s， OCH3)， 2.00 (6H， s， Py- CH3x 2). 实施例 6: 1-羧甲基 -5- (3-(2，
Figure imgf000020_0001
苯 基） -1^四氮唑（ II-2b) (合成路线 B) Sodium methoxide (270 mg, 5 mmol) and methyl bromoacetate (0.3 mL, 3.3 mmol). The solvent was evaporated, the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ C. l R NMR (DMS0-D 6 ) ^ppm 8.15 (1H, d, /= 8.0 Hz, ArH-6), 7.83 (1H, s, ArH-2), 7.74 (1H, t, /= 8.0 Hz, ArH-5) , 7.50 (1H, d, /= 8.0 Hz, ArH-4), 5.94 (2H, s, CH 2 ) , 5.85 (2H, s, Py-H) , 3.76 (3H, s, OCH 3 ), 2.00 (6H, s, Py- CH 3 x 2). Example 6: 1-carboxymethyl-5- (3-(2,
Figure imgf000020_0001
Phenyl) -1^tetrazole (II-2b) (Synthesis Route B)
将 lO NaOH水溶液 ( 1 raL)加入到 II - 2a ( 40 mg, 0.13 mmol) 的甲醇（2mL)溶液中， 室温反应 6小时。 将反应液倒入水水中， 用 10%盐酸水溶液调 PH至酸性， 收集固体， 用水洗至中性， 干燥 后得产物 II-2b 34 mg,收率 87%, mp 158-160。C。 ^-NMR (DMSO-DJ (J rn: 8.15 (1H, d, /- 8.0 Hz, ArH-6), 7.83 (1H， s， ArH-2), 7.74 (1H， t， /= 8.0 Hz, ArH-5) , 7.50 (1H, d, / = 8.0 Hz, ArH-4) , 5.84 (2H， s， CH2) , 5.78 (2H, s， Py-H) , 2.00 (6H， s, Py-CH3 x 2) . 质谱（ESI- MS): m/z ( ) 296 (M-H, 43), 252 (M-COOH, 31), 195 (M-H-CH2COOH-3 N, 100). 实施例 7: 1-乙氧羰基甲基 -5- (3- (3-乙氧羰基- 2， 5-二甲基 - 1^吡咯- 1-基）苯基） -1^·四氮唑 （II-2c) (合成路线 A或 B) 将乙醇钠 （61 mg, 0.9 mmol)和溴乙酸甲酯 （0.06 mL, 0.6 mmol )加入到 II- Id (93mg， 0.3 mmol ) 的乙醇 ( 5 mL)溶液中， 回流反应 4小时。 蒸去溶剂， 残留物溶于乙酸乙酯中， 水洗、 干 燥、 浓缩， 粗品用制备色谱分离 （石油醚 /乙酸乙酯）得 II-2c， 白色油状物 71 mg, 产率 60%。 NMR (CDC13) δ ppm 8.28 (1H, d, / = 8.0 Hz, ArH-6) , 8.01 (1H， s， ArH-2) , 7.64 (1H, t, /= 8.0 Hz；， ArH-5) , 7.32 (1H， d, / = 8.0 Hz, ArH-4) , 6.39 (1H， s, Py-H) , 5.47 (2H， s， CH2)， 4.31 (4H, m， -Oi¾CH3 2)， 2.33 (3H， s， Py-CH3) , 2.02 (3H, s， Py-CH3) , 1.34 (6H， m， -C^Cffs x 2) . 实施例 8: 5- (3-(5- (三氟甲基） -1，2，4-噁二唑 -3-基）苯 基）- I 四氮唑（ III- la) (合成路线 C) A 10% aqueous NaOH solution (1 raL) was added to a solution of II-2a (40 mg, 0.13 mmol) in methanol (2 mL) and allowed to react at room temperature for 6 hours. The reaction solution was poured into water, and the pH was made acidic with a 10% aqueous hydrochloric acid solution. The solid was collected, washed with water to neutral, and dried to give product II-2b 34 mg, yield 87%, mp 158-160. C. ^-NMR (DMSO-DJ (J rn: 8.15 (1H, d, /- 8.0 Hz, ArH-6), 7.83 (1H, s, ArH-2), 7.74 (1H, t, /= 8.0 Hz, ArH -5) , 7.50 (1H, d, / = 8.0 Hz, ArH-4) , 5.84 (2H, s, CH 2 ) , 5.78 (2H, s, Py-H) , 2.00 (6H, s, Py-CH 3 x 2). Mass Spectrum (ESI-MS): m/z ( ) 296 (MH, 43), 252 (M-COOH, 31), 195 (MH-CH 2 COOH-3 N, 100). Example 7 : 1-Ethoxycarbonylmethyl-5-(3-(3-ethoxycarbonyl-2,5-dimethyl- 1^pyrrole-1-yl)phenyl)-1^·tetrazole (II- 2c) (Synthesis Route A or B) Add sodium ethoxide (61 mg, 0.9 mmol) and methyl bromoacetate (0.06 mL, 0.6 mmol) to a solution of II-Id (93 mg, 0.3 mmol) in ethanol (5 mL) The reaction was refluxed for 4 hours. The solvent was evaporated, the residue was evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjj NMR (CDC1 3 ) δ ppm 8.28 (1H, d, / = 8.0 Hz, ArH-6) , 8.01 (1H, s, ArH-2) , 7.64 (1H, t, /= 8.0 Hz;, ArH-5) , 7.32 (1H, d, / = 8.0 Hz, ArH-4), 6.39 (1H, s, Py-H) , 5.47 (2H, s, CH 2 ), 4.31 (4H, m, -Oi3⁄4CH 3 2), 2.33 (3H, s, Py-CH 3 ) , 2.02 (3H, s, Py-CH 3 ) , 1.34 (6H, m, -C^Cffs x 2) . Example 8: 5- (3- (5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-I tetrazolium (III-la) (Synthesis Route C)
将 3- (1^·四氮唑 -5-基）苯胺（ 966 mg， 6 mmol ) 的盐酸盐溶 液（ 7 mL) 冷却到 0-5 °C, 滴加亚硝酸钠 ( 434 rag, 6.3 mmol ) 水溶液（4 mL)，生成重氮盐。另将 化钠水溶液（2 mL, 17.2腿 ol ) 加入到氣化亚铜 （ 592 mg, 6.6 mmol ) 和水（4 mL) 的混合物中， 形成 NaCu(CN)3复盐溶液， 加热到 60。C。 将重氮盐溶液緩慢加入 至 (；110^)3溶液中， 然后保温搅拌 2小时， 冷至室温。 反应体 系緩慢倒入冷的浓盐酸中， 用乙酸乙酯萃取， 干燥， 除去溶剂后 用制备色谱分离（石油醚 /乙酸乙酯 /水醋酸 =7: 3: 0.03)得 5- (3 - 氛基）苯基 -1^四氮唑（C) ， 白色固体 626 mg, 产物收率 61%, mp 145-147 °C。 Cool down the 3-(1^·tetrazolium-5-yl)aniline (966 mg, 6 mmol) hydrochloride solution (7 mL) to 0-5 ° C and add sodium nitrite ( 434 rag, 6.3 Methyl alcohol solution (4 mL) to form a diazonium salt. An aqueous solution of sodium sulphate (2 mL, 17.2 leg ol) was added to a mixture of cuprous copper (592 mg, 6.6 mmol) and water (4 mL) to form a NaCu(CN) 3 double salt solution and heated to 60. C. The diazonium salt solution was slowly added to the (;110^) 3 solution, and then stirred under stirring for 2 hours, and cooled to room temperature. The reaction system was slowly poured into cold concentrated hydrochloric acid, extracted with ethyl acetate, dried, and the solvent was removed, and then purified by preparative chromatography (petroleum ether / ethyl acetate / acetic acid = 7:3: 0.03) to give 5- (3 - atmosphere Phenyl-1^tetrazolium (C), white solid 626 mg, product yield 61%, mp 145-147 °C.
将 8-羟基喹啉( 1 mg, 0.0075 mmol )加入到 C( 513mg, 3 mmol ) 的乙醇溶液（ 30 mL )中，再依次加入盐酸羟胺（ 446 mg, 6.4匪 ol ) 和碳酸钠 （515 mg, 4.9 mmol) 的水溶液（各 5 mL), 加热回流 4 小时。 蒸去乙醇， 残留物加水（30 mL)溶解， 用盐酸水溶液调 PH至酸性， 收集固体， 用水洗至中性， 干燥后得 -5- (3-氨基 肟）苯基- 四氮唑（D) ， 白色固体 465 mg, 产物收率 76%， mp
Figure imgf000021_0001
Add 8-hydroxyquinoline (1 mg, 0.0075 mmol) to C (513 mg, 3 mmol) in ethanol (30 mL), then add hydroxylamine hydrochloride (446 mg, 6.4 匪ol) and sodium carbonate (515 mg) , 4.9 mmol) of aqueous solution (5 mL each), heated to reflux for 4 hours. Evaporate the ethanol, and the residue is dissolved in water (30 mL). The mixture is adjusted to acid with aqueous hydrochloric acid. The solid is collected, washed with water to neutral, and dried to give -5-(3-aminoindole)phenyl-tetrazole (D) ), white solid 465 mg, product yield 76%, mp
Figure imgf000021_0001
三氟醋酐 ( 0.21 mL, 1.5 mmol )加入到 D ( 102 mg, 0.5 mmol ) 的无水吡啶溶液（ 3 mL) 中， 加热回流 2小时。 反应物冷至室温 后倒入冰水中， 用盐酸水溶液调 PH至酸性， 收集固体， 用水洗至 中性， 干燥后得 III-la， 白色固体 121 mg, 产物收率 86%， mp 146-148。C。 ^ - NMR (DMS0-D6) ppm: 8.75 (1H， s， ArH-2) , 8.36 (1H, d， /= 8.0 Hz, ArH-6), 8.30 (1H, d, /= 8.0 Hz, ArH-4) ,Trifluoroacetic anhydride (0.21 mL, 1.5 mmol) was added to EtOAc (3 mL)EtOAc. The reaction mixture was cooled to room temperature, poured into ice water, and the pH was adjusted to acidic with aqueous hydrochloric acid. The solid was collected, washed with water to neutral, and dried to give a crystals of ss. . C. ^ - NMR (DMS0-D 6 ) ppm: 8.75 (1H, s, ArH-2) , 8.36 (1H, d, /= 8.0 Hz, ArH-6), 8.30 (1H, d, /= 8.0 Hz, ArH-4),
7.88 (1H， t, / = 8.0 Hz, ArH-5) . 质谱（ESI - MS) ： m/z ( ) 281 (M - H， 100) ， 137 (M -四氮唑-苯基， 23). 实施例 9 : 5-(3- (5- (氯甲基） - 1， 2,4-噁二唑 -3-基）苯 基） -I 四氟唑 （ III- lb) (合成路线 C) 7.88 (1H, t, / = 8.0 Hz, ArH-5). Mass Spectrum (ESI-MS): m/z ( ) 281 (M - H, 100), 137 (M -tetrazolyl-phenyl, 23) Example 9: 5-(3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-I tetrafluoroazole (III- lb) (Synthesis Route C) )
氯乙酰氯 ( 0.1 mL, 1.2 mraol )加入到 D ( 204 rag, 1 画 1 ) 的 THF溶液（ 10 mL) 中， 加热回流 4小时。 反应物冷至室温后倒 入水水中， 收集固体， 水洗至中性， 用制备色谱分离 （石油醚 / 乙酸乙酯 /水醋酸）得 III-lb， 白色固体 176 mg， 产物收率 67%, mp 160 - 162 。C。 ^-NMR (DMS0-D6) ^ pm: 8.71 (1H， s， ArH-2) ,Chloroacetyl chloride (0.1 mL, 1.2 mraol) was added to a D (204 rag, 1 draw 1) solution in THF (10 mL) and heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, poured into water, and the solid was collected, washed with water to neutral, and purified by preparative chromatography ( petroleum ether / ethyl acetate / water acetic acid) to give III-lb, white solid 176 mg, product yield 67%, Mp 160 - 162. C. ^-NMR (DMS0-D 6 ) ^ pm: 8.71 (1H, s, ArH-2),
8.30 (1H， d, / = 8.0 Hz, ArH-6) , 8.24 (1H, d, / = 8.0 Hz, ArH-4) , 7.84 (1H, t, /= 8.0 Hz, ArH-5)， 5.24 (2H, s， CH2) . 质谱（ESI-MS) ： m/z (%) 261 (M- H, 100), 263 (M-H+2, 28), 117 (M-四氮唑-苯基， 35). 实施例 10: 5-(3-（5- (羟甲基） -1， 2， 4-噁二唑 -3-基）苯 基）- 1^·四氮唑（ III- lc) (合成路线 C) 8.30 (1H, d, / = 8.0 Hz, ArH-6), 8.24 (1H, d, / = 8.0 Hz, ArH-4), 7.84 (1H, t, /= 8.0 Hz, ArH-5), 5.24 ( 2H, s, CH 2 ) . Mass Spectrometry (ESI-MS) : m/z (%) 261 (M-H, 100), 263 (M-H+2, 28), 117 (M-tetrazole-benzene Base, 35). Example 10: 5-(3-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)phenyl)- 1^·tetrazole (III- Lc) (synthetic route C)
III-lb ( 76 mg， 0.29 mmol )在 10% NaOH水溶液 ( 2 mL ) 中于室温反应 1.5小时。 将反应液倒入冰水中， 用 10%盐酸水溶 液调 PH至酸性， 用乙酸乙酯萃取， 干燥， 除去溶剂后用制备型 TLC分离 （石油醚 /乙酸乙酯 = 3: 2)得 III- lc， 白色固体 39 mg, 收率 55%， mp 120-122 。C。 ^-NMR (DMS0-D6) ^ ppm: 11.60 (1H， s, OH), 8.47 (1H， s， ArH-2) , 8.22 (1H， d, /= 8.0 Hz, ArH-6) , 7.96 (1H, d, /= 8.0 Hz, ArH-4) , 7.75 (1H， t, / = 8.0 Hz, ArH-5) , 4.44 (2H, s， CH2). 质谱 (ESI-MS) ： m/z (%) 243 (M - H， 100) ， 215 (M-H-2 x N, 34). 实施例 11: 1 -乙氧羰基甲基- 5- (3- (5- (三氟甲基) - 1， 2, 4 -噁 二唑- 3-基)苯基) 四氮唑（III- 2a) (合成路线 C或 A) III-lb (76 mg, 0.29 mmol) was reacted in a 10% aqueous NaOH solution (2 mL) at room temperature for 1.5 hr. The reaction solution was poured into ice water, and the mixture was acidified with 10% aqueous hydrochloric acid, and extracted with ethyl acetate, and dried, and the solvent was removed and then purified by preparative TLC ( petroleum ether / ethyl acetate = 3: 2) to give III- lc , white solid 39 mg, yield 55%, mp 120-122. C. ^-NMR (DMS0-D 6 ) ^ ppm: 11.60 (1H, s, OH), 8.47 (1H, s, ArH-2), 8.22 (1H, d, /= 8.0 Hz, ArH-6), 7.96 ( 1H, d, /= 8.0 Hz, ArH-4), 7.75 (1H, t, / = 8.0 Hz, ArH-5), 4.44 (2H, s, CH 2 ). Mass Spectrum (ESI-MS): m/z (%) 243 (M - H, 100), 215 (MH-2 x N, 34). Example 11: 1-Ethoxycarbonylmethyl-5-(3-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)phenyl)tetrazole (III- 2a) (synthetic route C or A)
制备方法同 II-2c。 以 Ill-la ( 50mg, 0.18 mmol )和溴乙酸 甲酯 （0.02 mL, 0.22 mmol )反应得 III-2a， 黄白色固体 35 mg, 收率 54%, mp 78-81。C。 ^ NMR (CDC13) ^ m 8.94 (1H， s， ArH-2)， 8.41 (1H， d， /= 8.0 Hz, ArH-6) , 8.26 (1H， d, / = 8.0 Hz, ArH-4) , 7.69 (1H, t, /= 8.0 Hz, ArH-5) , 5.49 (2H， s， CH2) , 4.31 (2H, q, -0^¾CH3) , 1.32 (3H， t， -CH2 β¾) . 实施例 12: 1-乙基 -5- (3- (5-醛基-呋喃- 2-基)苯基) - 1^四氮 唑（IV-la) (合成路线 D) The preparation method is the same as II-2c. Reaction of Ill-la (50 mg, 0.18 mmol) and methyl bromoacetate (0.02 mL, 0.22 mmol) afforded <RTI ID=0.0>> C. ^ NMR (CDC1 3 ) ^ m 8.94 (1H, s, ArH-2), 8.41 (1H, d, /= 8.0 Hz, ArH-6), 8.26 (1H, d, / = 8.0 Hz, ArH-4) , 7.69 (1H, t, /= 8.0 Hz, ArH-5) , 5.49 (2H, s, CH 2 ) , 4.31 (2H, q, -0^3⁄4CH 3 ) , 1.32 (3H, t, -CH 2 β3⁄4 Example 12: 1-Ethyl-5-(3-(5-aldehyde-furan-2-yl)phenyl)-1^tetrazole (IV-la) (Synthesis Route D)
将 3- (I 四氮唑 -5-基）苯胺 ( 322 mg, 2 mmol) 的氢溴酸溶液 (40%, 2mL)冷却到 0~5。C, 滴加亚硝酸钠 （ 166 mg， 2.4 mmol ) 的水溶液（2mL)， 生成重氮盐。 将此重氮盐溶液緩慢加入至溴化亚 铜 （ 344 mg, 2.4 mmol) 的氢溴酸溶液（40%, 1 mL) 中， 室温反 应过夜。 反应体系緩慢倒入冰水中， 收集固体， 水洗至中性， 干燥 后得 5- (3-溴)苯基- I 四氮唑， 黄色固体 362 mg (收率 80%)。 用此 中间体 ( 113mg, 0.5 mmol )和碘乙烷 ( 0.14 mL, 1.75 mmol )按照 II-2c的制备方法反应得 1-乙基 -5- (3-溴苯基 )-1^·四氮唑， 油状物 113 mg, 收率 89%。  3-(I tetrazolium-5-yl)aniline (322 mg, 2 mmol) in hydrobromic acid (40%, 2 mL) was cooled to 0~5. C, an aqueous solution (2 mL) of sodium nitrite (166 mg, 2.4 mmol) was added dropwise to give a diazonium salt. This diazonium salt solution was slowly added to a solution of copper bromide (344 mg, 2.4 mmol) in hydrobromic acid (40%, 1 mL) and allowed to react at room temperature overnight. The reaction system was slowly poured into ice water, the solid was collected, washed with water until neutral, and dried to give 5-(3-bromo)phenyl-I tetrazole as a yellow solid 362 mg (yield 80%). This intermediate (113 mg, 0.5 mmol) and ethyl iodide (0.14 mL, 1.75 mmol) were reacted according to the procedure of II-2c to give 1-ethyl-5-(3-bromophenyl)-1^·tetraz. Azole, oil 113 mg, yield 89%.
氮气保护下，将 Pd(PPh3)4( 22 mg, 0.02 mmol )加到 1 -乙基- 5-(3- 溴笨基)- I 四氮唑（113 mg, 0.45 mmol )的 DMF溶液 (5 mL) 中， 再分别加入二异丙基乙基胺 ( 0.22 mL, 1.35 mmol )的水溶液（ 10mL ) 和 5-甲酰基- 2-呋喃硼酸（ 75 mg, 0.54 mmol )的 DMF溶液（ 5 mL )， 100 。C反应 4小时。 反应体系被倒入冰水中， 用乙酸乙酯萃取， 干 燥， 除去溶剂后用制备色谱分离 （石油醚 /乙酸乙酯 = 3:1)得黄色 固体 88 rag, 收率 73%, mp 77-80 。C。 ^ NMR (CDC13) ^ ppm: 9.70 (1H， s， CHO), 8.59 (1H， s， ArH-2) , 8.20 (1H， d， / = 8.0 Hz, ArH-6) , 7.96 (1H， d, /= 8.0 Hz, ArH-4) , 7.59 (1H, t, /= 8.0 Hz, ArH-5) , 7.37 & 6.6.98 (each 1H, d, /= 4.0 Hz, FuranH-4 ' or -37 ), 4.74 (2H, q， -N ¾CH3) , 1.72 (3H， t， -CH2 β¾) . 实施例 13: 1-乙基- 5- (3- (5-次甲基 -（绕丹宁 -5-基）-呋喃 - 2 -基）苯基） -1^·四氮唑（ IV- 2a) (合成路线 D) Pd(PPh 3 ) 4 (22 mg, 0.02 mmol) was added to a solution of 1-ethyl-5-(3-bromophenyl)-I tetrazolium (113 mg, 0.45 mmol) in DMF under nitrogen. In 5 mL), diisopropylethylamine (0.22 mL, 1.35 mmol) in water (10 mL) and 5-formyl-2-furanboronic acid (75 mg, 0.54 mmol) in DMF (5 mL) ), 100. C reacted for 4 hours. The reaction system was poured into ice water, extracted with ethyl acetate, dried, and the solvent was removed and then purified by preparative chromatography ( petroleum ether / ethyl acetate = 3:1). Solid 88 rag, yield 73%, mp 77-80. C. ^ NMR (CDC1 3 ) ^ ppm: 9.70 (1H, s, CHO), 8.59 (1H, s, ArH-2) , 8.20 (1H, d, / = 8.0 Hz, ArH-6) , 7.96 (1H, d , /= 8.0 Hz, ArH-4), 7.59 (1H, t, /= 8.0 Hz, ArH-5) , 7.37 & 6.6.98 (each 1H, d, /= 4.0 Hz, FuranH-4 ' or -3 7 ), 4.74 (2H, q, -N 3⁄4CH 3 ) , 1.72 (3H, t, -CH 2 β3⁄4) . Example 13: 1-ethyl-5-(3-(5-methine-) Tannin-5-yl)-furan-2-yl)phenyl)-1^tetrazole (IV-2a) (Synthesis Route D)
IV - la ( 46 mg, 0.17 mmol ) 、 绕丹宁 （37 rag, 0, 28 mmol ) 和无水乙酸钠 （42 mg, 0.51 mmol )在无水甲醇 （ 5 mL ) 中回流 反应 13小时。 除去溶剂后用制备型 TLC分离（石油醚 /乙酸乙酯） 得 IV-2a， 红色固体 mg， 收率。 /。， mp 。C。 NMR (CDC13) δ ppm: 9.70 (1H， s, CHO), 8.59 (1H， s， ArH-2) , 8.20 (1H， d, / = 8.0 Hz, ArH-6) , 7.96 (1H， d, / = 8.0 Hz, ArH-4) , 7.59 (1H， t, / = 8.0 Hz, ArH-5), 7.58 (1H， s， OC-H)， 7.37 & 6.6.98 (each 1H, d, /= 4.0 Hz, FuranH-4' or -3, ), 4.74 (2H, q, -NC¾CH3), 1.72 (3H, t， -CH2 C¾) . 实施例 14: 抗 HIV活性试验（细胞模型） ， 用 EC 5。表示活 性。 IV-la (46 mg, 0.17 mmol), rhodanine (37 rag, 0, 28 mmol) and anhydrous sodium acetate (42 mg, 0.51 mmol) were refluxed in anhydrous methanol (5 mL) for 13 hr. After removal of the solvent, it was purified by preparative TLC ( petroleum ether / ethyl acetate). /. , mp. C. NMR (CDC1 3 ) δ ppm: 9.70 (1H, s, CHO), 8.59 (1H, s, ArH-2), 8.20 (1H, d, / = 8.0 Hz, ArH-6), 7.96 (1H, d, / = 8.0 Hz, ArH-4), 7.59 (1H, t, / = 8.0 Hz, ArH-5), 7.58 (1H, s, OC-H), 7.37 & 6.6.98 (each 1H, d, /= 4.0 Hz, Furan H-4' or -3, ), 4.74 (2H, q, -NC3⁄4CH 3 ), 1.72 (3H, t, -CH 2 C3⁄4) . Example 14: Anti-HIV activity test (cell model), used EC 5 . Indicates activity.
测定可参考的参照文献为 Jiang, S.， et al, Antimicrob. References for the determination are Jiang, S., et al, Antimicrob.
Agents Chemother. 2004, 48, 4349-4359。 Agents Chemother. 2004, 48, 4349-4359.
在 96孔细胞培养板中， 将 50 不同浓度的化合物溶液与 等体积的 HIV-1 病毒林 ( 100 TCID50) 混合， 于 37<C温育 30分 钟，然后加入 100 LMT- 2细胞（l x l05/mL,含 10%血清的 RPIM 1640培养液） ， 混合均匀， 37°C温育过夜。 笫 2天吸去 150 μΐ 上清液， 补入等体积新鲜培养液， 37Ό继续温育 3天， 于第四天 记录细胞病变 （CPE)效应。 然后吸取 100 的培养上清夜， 用 5 %的 Triton X- 100裂解病毒颗粒， 采用 ELISA方法检测其中 p24抗原。 简言之， 用 HIVIG (2 g/mL ) 包被酶标板， 再用 1% 的无脂牛奶封闭， 先后加入病毒裂解液， 37Ό温育 60分钟。 在充 分洗板之后，先后加入抗 p24单抗 -183- 12H-5C，生物素标记的羊 抗鼠抗体及卵白素标记的辣根过氧化物酶。 然后用 TMB显色， 在 450 nm处检测光密度。 用 CalcuSyn软件计算化合物的半数病毒 抑制浓度 ( EC50) 。 表 1. 抑制 HIV复制和靶分子 aIn a 96-well cell culture plate, mix 50 different concentrations of compound solution with an equal volume of HIV-1 virus forest (100 TCID 50 ), incubate for 30 minutes at 37 < C, then add 100 LMT-2 cells (lx L0 5 /mL, RPIM 1640 medium containing 10% serum), mix well and incubate overnight at 37 °C.吸 2 days to absorb 150 μΐ of the supernatant, add an equal volume of fresh medium, 37 Ό continue to incubate for 3 days, on the fourth day The cytopathic effect (CPE) effect was recorded. Then, 100 culture supernatants were aspirated, virus particles were lysed with 5% Triton X-100, and p24 antigen was detected by ELISA. Briefly, the ELISA plate was coated with HIVIG (2 g/mL), blocked with 1% fat-free milk, added to the virus lysate, and incubated for 60 minutes at 37 °C. After extensive washing, anti-p24 monoclonal antibody-183-12H-5C, biotinylated goat anti-mouse antibody and avidin-labeled horseradish peroxidase were added. The color density was then measured at 450 nm using TMB color development. Calculated with CalcuSyn software compound virus half inhibition concentration (EC 50). Table 1. Inhibition of HIV replication and target molecule a
D C gp41- 6聚体形成的活性数椐 Activity number of D C gp41- 6-mer
MT-2 Gp41 6-HB MT-2 Gp41 6-HB
· ·
Figure imgf000025_0001
CD
Figure imgf000025_0001
CD
NB-64 2.39 335.72 140 58.74 NB-64 2.39 335.72 140 58.74
II-la 7.70 249.46 >32 25.61II-la 7.70 249.46 >32 25.61
Il-lg 0.69 133.46 193.42 37.36Il-lg 0.69 133.46 193.42 37.36
Il-lh 9.66 >492.61 >51 48.72Il-lh 9.66 >492.61 >51 48.72
Π-lj 11.81 88.42 7.49 42.23Π-lj 11.81 88.42 7.49 42.23
ΙΙΙ-ld 152.73 >454.55 >3 26.50ΙΙΙ-ld 152.73 >454.55 >3 26.50
III - If 62.73 311.14 4.96 28.41III - If 62.73 311.14 4.96 28.41
IV - 2c 0.74 20.17 27.26 NDIV - 2c 0.74 20.17 27.26 ND
SI: '选择指数 CC5。 /EC5。； ND: 正在测试中 表 2. 抑制 HIV原代病毒林复制的活性数据 (细胞模型） SI: 'Select index CC 5 . /EC 5 . ND: Under test Table 2. Activity data (cell model) for inhibition of HIV primary virus forest replication
II-la NB-64 所用的复 BCso BC90 BC50 EC90 病毒 亚型 合受体 II-la NB-64 Complex BCso BC90 BC50 EC90 virus subtype receptor
g/mL g/mL g/mL g/mL g/mL g/mL g/mL g/mL
92UG103 A X4R5 1. 76 11. 00 93. 47 >10092UG103 A X4R5 1. 76 11. 00 93. 47 >100
92US957 B R5 24. 02 46. 96 >100 ― 92US957 B R5 24. 02 46. 96 >100 ―
93IN101 C R5 29. 63 61. 54 >100 ―  93IN101 C R5 29. 63 61. 54 >100 ―
92UG001 D X4R5 25. 80 72. 68 >100 ―  92UG001 D X4R5 25. 80 72. 68 >100 ―
92TH009 B R5 4. 09 15. 91 >100 ―  92TH009 B R5 4. 09 15. 91 >100 ―
寸  Inch
93BR020 F X4R5 >100 >100 ―  93BR020 F X4R5 >100 >100 ―
RU507 G R5 37. 73 90. 16 >100 ―  RU507 G R5 37. 73 90. 16 >100 ―
BCF02 0 R5 66. 54 >100 >100 ― 实施例 15: 化合物的细胞毒性试验， 用 CC 5。表示。 BCF02 0 R5 66. 54 >100 >100 ― Example 15: Cytotoxicity test of the compound, using CC 5 . Said.
测定可参考的参照文献为 Jiang, S. ， et a l. Ant imicrob. Agents Chemother. 2004， 48, 4349-4359。  References for the determination are Jiang, S., et a l. Ant imicrob. Agents Chemother. 2004, 48, 4349-4359.
在 96孔细胞培养板中， 将 50 不同浓度的化合物溶液与 等体积的 PBS混合，于 371；温育 30分钟，然后加入 100 μ L ΜΤ-2 细胞（l x l 05 /mL， 含 10 %血清的 RPIM 1640培养液） ， 混合均 匀， 37 Ό温育过夜。 第 2天吸去 150 上清液， 补入等体积新 鲜培养液， 37。C继续温育 3天后， 于笫四天加入 50 新鲜配制 的含 PMS的 XTT溶液（ 1 mg/mL ) ， 4 h后检测 450 nm处的光密 度。用 CalcuSyn软件计算化合物的半数细胞毒性浓度（CC5D；)。 结 果见表 1。 实施例 16: 抑制 gp41 六元螺旋束（6- HB )形成实验， 抑制 活性用 IC 5。表示。 In a 96-well cell culture plate, mix 50 different concentrations of compound solution with an equal volume of PBS at 371; incubate for 30 minutes, then add 100 μL of ΜΤ-2 cells (lxl 0 5 /mL, containing 10% serum) The RPIM 1640 medium was mixed well and incubated overnight for 37 Ό. On day 2, 150 supernatants were aspirated and an equal volume of fresh medium was added, 37. After continuing to incubate for 3 days, 50 freshly prepared PTT-containing XTT solution (1 mg/mL) was added for four days, and the optical density at 450 nm was measured after 4 hours. The half cytotoxic concentration (CC 5D ;) of the compound was calculated using CalcuSyn software. The results are shown in Table 1. Example 16: Inhibition of gp41 six yuan helix bundle (6- HB) formation assay, inhibitory activity with IC 5. Said.
测定可参考的参照文献为 Jiang, S. ， et al. J. Virol. Methods, 1999, 80， 85-96。 结果见表 1。 The reference reference for the determination is Jiang, S., et al. J. Virol. Methods, 1999, 80, 85-96. The results are shown in Table 1.
已有的结果表明： 本发明式 I化合物是一类具有新型骨架结 构、 作用于 HIV- 1 gp41的非肽类小分子抑制剂。 它们可有效抑制 HIV-1 gp41六元螺旋束体（6- HB )的形成， 从而抑制 HIV的复制。 该类化合物还对临床分离的多类型的 HIV病毒株灼有抑制活性， 具有广泛的抗病毒谱。 本发明涉及的化合物将有望发展成为一类 新型抗 HIV药物：以 gp41为靶点的非肽类小分子 HIV-1融合抑制 剂。  The results obtained indicate that the compound of the formula I of the present invention is a non-peptide small molecule inhibitor having a novel skeleton structure and acting on HIV-1 gp41. They can effectively inhibit the formation of HIV-1 gp41 six-helix bundle (6-HB), thereby inhibiting HIV replication. These compounds also have inhibitory activity against clinically isolated multi-type HIV strains and have a broad spectrum of antiviral. The compounds of the present invention are expected to develop into a new class of anti-HIV drugs: non-peptide small molecule HIV-1 fusion inhibitors targeting gp41.

Claims

权 利 要 求 Rights request
1. 式 I的四氮唑芳基杂环类化合物或其可药用盐：
Figure imgf000028_0001
其中， A tetrazolyl aryl heterocyclic compound of the formula I or a pharmaceutically acceptable salt thereof:
Figure imgf000028_0001
among them,
R! = -H、 -CH2C00H、 CH2CH2COOH、 -CH-CH- C00H、 -CH2C00R' 、 -CH2CH2COOR' 、 - CH-CH- C00R， 、 d— 6烃基； R! = -H, -CH 2 C00H, CH 2 CH 2 COOH, -CH-CH- C00H, -CH 2 C00R' , -CH 2 CH 2 COOR' , - CH-CH- C00R, , d- 6 hydrocarbon group ;
R2 = -H、 卤素、 - N02、 - NH2、 -NHR' 、 - N (R， ）2、 - CN、 -OH, d- 烷基、 CH烷氧基、 - CF3、 -C00H - S03H、 - C0NH2、 -CONHR' 或- C00R， ；R 2 = -H, halogen, -N0 2 , -NH 2 , -NHR' , - N (R, ) 2 , - CN, -OH, d-alkyl, CH alkoxy, -CF 3 , -C00H - S0 3 H, - C0NH 2 , -CONHR' or - C00R, ;
Ar为含 1-3个选自 N、 0、 S的杂原子的五元杂芳环， 选自： Ar is a five-membered heteroaryl ring containing 1-3 hetero atoms selected from N, 0, S, selected from:
Figure imgf000028_0002
其中的 R3 = CH0、 COR' 、 C00R' 、 C00H、 CF3> CH2R" 、 卤素、 ς— 6 烃基、 ς_6烷氧基、 - NH2、 -OH, - N02、 - CN、 -HOCH-CN、 - CH=CH2、 - C
Figure imgf000028_0002
Wherein R 3 = CH0, COR', C00R', C00H, CF 3 > CH 2 R" , halogen, ς- 6 hydrocarbon, ς 6 alkoxy, -NH 2 , -OH, - N0 2 , - CN, -HOCH-CN, - CH=CH 2 , - C
≡CH、 - C≡CR， 、 - CH=CHR， 、 -CH=CHC0R' ， 或为任选在其环结构的 可利用位置上带有酯基、 羧基、 ς_6烃基、 苯基取代的以下杂环基团： ≡CH, -C≡CR, , -CH=CHR, , -CH=CHC0R', or the following optionally having an ester group, a carboxyl group, a ς- 6 hydrocarbon group, or a phenyl group at the available positions of the ring structure Heterocyclic group:
Figure imgf000028_0003
Figure imgf000028_0003
其中， X和 Υ 各自独立地选自 C， 0， S和 NH;  Wherein X and Υ are each independently selected from C, 0, S and NH;
R4 = -H、 - CH2C00H、 - CH2CH2COOH、 - CH-CH - C00H、 - CH2C00R， 、 - CH2CH2COOR， 、 - CH-CH- C00R， 、 烃基、 苯基; R 4 = -H, - CH 2 C00H, - CH 2 CH 2 COOH, - CH-CH - C00H, - CH 2 C00R, - CH 2 CH 2 COOR, - CH-CH- C00R, , Hydrocarbyl, Benzene base;
R5= - H、 卤素、 -N02、 - NH2、 -NHR' 、 - N (R， ）2、 - CN、 -OH , d-, 烃基、 烷氧基、 - CF3、 CH0、 - C00H、一 S03H、一 C0NH2、 -CONHR'或一 C00R， ； 上述五元杂芳环任选在其环上可利用位置带有选自醛基、 酮基、 酯基、 羧基、 氣基、 ot， P不饱和酮、 烯、 炔、 d— 6径基、 d— 6烷氧基、 卤素、 - NH2、 -0H、 -N02和 -CF3的取代基； R 5 = - H, halogen, -N0 2 , -NH 2 , -NHR' , - N (R, ) 2 , - CN, -OH , d-, hydrocarbyl, alkoxy, -CF 3 , CH0, - C00H, a S0 3 H, a C0NH 2 , -CONHR' or a C00R,; The above five-membered heteroaryl ring is optionally available on its ring at a position selected from the group consisting of an aldehyde group, a ketone group, an ester group, a carboxyl group, a gas group, an ot, a P-unsaturated ketone, an alkene, an alkyne, a d- 6- diameter group, a substituent of d- 6 alkoxy, halogen, -NH 2 , -0H, -N0 2 and -CF 3 ;
R， =d-6 烃基； 并且 R, =d- 6 hydrocarbon; and
R" 为 ^素、 0H或 ς_6烷氧基。 R" is ^, 0H or ς 6 alkoxy.
2. 权利要求 1的化合物或其可药用盐， 其具有式 I I： 2. A compound of claim 1 or a pharmaceutically acceptable salt thereof having the formula I I:
Figure imgf000029_0001
Figure imgf000029_0001
其中，  among them,
= -H - CH2C00H、 -CH2CH2COOH, -CH=CH-C00H -CH2C00R' 、= -H - CH 2 C00H, -CH 2 CH 2 COOH, -CH=CH-C00H -CH 2 C00R' ,
-CH2CH2COOR' 、 -CH=CH-C00R' 、 d-6烃基； -CH 2 CH 2 COOR' , -CH=CH-C00R', d- 6 hydrocarbon group;
R2 = -H 卤素、 - N02、 - NH2、 -腿， 、 - N (R， ）2、 -CN、 -OH, d-6 烷基、 烷氧基、 - CF3、 - C00H、 - S03H、 -C0NH2、 -C0NHR' 或- C00R， ； R3 = CH0、 COR' 、 C00R， 、 C00H> CF3、 CH2R" 、 鹵素、 d— 6烃基、 d-6烷氧基、 - NH2、 -OH, - N02、 - CN、 - HOCH- CN、 - CH-CH2、 - C≡CH、 - C≡CR， 、 -CH=CHR' 、 -CH=CHC0R' ， 或为任选在其环结构上带有酯 基、 羧基、 d_6烃基、 苯基取代的以下杂环基团：
Figure imgf000029_0002
R 2 = -H halogen, -N0 2 , -NH 2 , -leg, -N (R, ) 2 , -CN, -OH, d- 6 alkyl, alkoxy, -CF 3 , - C00H, - S0 3 H, -C0NH 2 , -C0NHR' or - C00R, ; R 3 = CH0, COR', C00R, , C00H> CF 3 , CH 2 R" , halogen, d- 6 hydrocarbon, d- 6 alkoxy Base, -NH 2 , -OH, - N0 2 , - CN, - HOCH-CN, - CH-CH 2 , - C≡CH, - C≡CR, , -CH=CHR' , -CH=CHC0R' , Or the following heterocyclic group optionally having an ester group, a carboxyl group, a d- 6 hydrocarbon group, or a phenyl group substituted on its ring structure:
Figure imgf000029_0002
其中， X和 γ 各自独立地选自 C, 0， S和 NH;  Wherein X and γ are each independently selected from C, 0, S and NH;
R4 = - H、 -CH2C00H、 -CH2CH2COOH、 - CH-CH-C00H、 -CH2C00R' 、 - CH2CH2C00R， 、 - CH-CH- C00R， 、 C— 6烃基、 苯基； R 4 = - H, -CH 2 C00H, -CH 2 CH 2 COOH, - CH-CH-C00H, -CH 2 C00R', - CH 2 CH 2 C00R, , - CH-CH- C00R, , C- 6 Hydrocarbyl group, phenyl group;
R5= -H、 卤素、 - N02、 -NH2、 -丽， 、 -N (R' ) 2、 -CN、 -OH , ClH 烃基、 d—6烷氧基、 - CF3、 CH0、 -C00H、 - S03H、 -C0NH2、 -C0NHR'或 -C00R，；R 5 = -H, halogen, -N0 2 , -NH 2 , -Li, -N (R' ) 2 , -CN, -OH , C lH hydrocarbyl, d- 6 alkoxy, -CF 3 , CH0 , -C00H, - S0 3 H, -C0NH 2 , -C0NHR' or -C00R,;
R6 = H、 CH3、 CF3、 卤素或 C2-4 烃基； R' =d-6 烃基; 并且 R 6 = H, CH 3 , CF 3 , halogen or C 2 - 4 hydrocarbyl; R' = d- 6 hydrocarbyl;
R" 为卤素、 OH或 烷氧基。  R" is halogen, OH or alkoxy.
3. 权利要求 1的化合物或其可药用盐， 其具有式 I I I： 3. A compound of claim 1 or a pharmaceutically acceptable salt thereof having the formula I I I:
Figure imgf000030_0001
Figure imgf000030_0001
其中，  among them,
R, = - CH2C00H、 -CH2CH2COOH、 - CH=CH-C00H、 -CH2C00R' 、 -CH2CH2COOR' 、 - CH=CH- C00R， 、 d—6烃基； R, = - CH 2 C00H, -CH 2 CH 2 COOH, - CH=CH-C00H, -CH 2 C00R' , -CH 2 CH 2 COOR' , - CH=CH- C00R, , d- 6 hydrocarbon group;
R2 = - H、 卤素、 -N02、 - NH2、 -NHR' 、 -N (R， ）2、 -CN、 -0H、 d-6 烷基、 d-6烷氧基、 - CF3、 - C00H、 -S03H、 - C0NH2、 -C0NHR' 或 -C00R， ；R 2 = - H, halogen, -N0 2 , -NH 2 , -NHR' , -N (R, ) 2 , -CN, -0H, d- 6 alkyl, d- 6 alkoxy, - CF 3 - C00H, -S0 3 H, - C0NH 2 , -C0NHR' or -C00R, ;
R3 = CH0、 COR' 、 COOR' 、 C00H、 CF3、 CH2R" 、 卤素、 C】— 6烃基、 d-6烷氧基、 -NH2、 -OH, - N02、 -CN、 -HC=CH-CN, - CH-CH2、 -C≡CH、 -C≡CR， 、 -CH=CHR' 、 -CH=CHC0R' , 或为任选在其环结构上带有酯 基、 羧基、 6烃基、 苯基取代的以下杂环基团：
Figure imgf000030_0002
R 3 = CH0, COR', COOR', C00H, CF 3 , CH 2 R" , halogen, C] -6 hydrocarbon group, d- 6 alkoxy group, -NH 2 , -OH, - N0 2 , -CN, -HC=CH-CN, -CH-CH 2 , -C≡CH, -C≡CR, , -CH=CHR', -CH=CHC0R', or optionally having an ester group in its ring structure, a heterocyclic group substituted with a carboxyl group, a 6 hydrocarbon group, or a phenyl group:
Figure imgf000030_0002
其中， X和 Y 各自独立地选自 C， 0, S和 NH;  Wherein X and Y are each independently selected from C, 0, S and NH;
R4 = -Hv -CH2C00H、 -CH2CH2COOH、 -CH=CH-C00H, -CH2C00R' 、 -CH2CH2COOR' 、 -CH=CH- C00R， 、 d-6烽基、 苯基； R 4 = -Hv -CH 2 C00H, -CH 2 CH 2 COOH, -CH=CH-C00H, -CH 2 C00R' , -CH 2 CH 2 COOR' , -CH=CH- C00R, , d- 6烽Base, phenyl;
R5= -H、 卤素、 - N02、 -NH2、 -NHR' 、 -N (R' ) 2、 -CN -0H、 d -, 烃基、 d— 6烷氧基、 - CF3、 CH0、 - C00H、 - S03H、 - C0NH2、 -C0NHR'或- C00R，；R 5 = -H, halogen, -N0 2 , -NH 2 , -NHR' , -N (R' ) 2 , -CN -0H, d -, hydrocarbyl, d- 6 alkoxy, -CF 3 , CH0 - C00H, - S0 3 H, - C0NH 2 , -C0NHR' or - C00R,;
R' =d-6 烃基； 并且 R' = d- 6 hydrocarbyl;
R" 为卤素、 OH或 ς_6烷氧基。 R "is a halogen, OH or alkoxy ς_ 6.
4. 权利要求 1的化合物或其可药用盐， 其具有式 IV： 4. A compound of claim 1 or a pharmaceutically acceptable salt thereof, having the formula IV:
Figure imgf000031_0001
其中，
Figure imgf000031_0001
among them,
R, = -H、 -CH2C00H、 -CH2CH2COOH, -CH=CH-C00H, -CH2C00R' 、 - CH2CH2COOR， 、 -CH=CH-C00R' 、 d—6烃基； R, = -H, -CH 2 C00H, -CH 2 CH 2 COOH, -CH=CH-C00H, -CH 2 C00R' , - CH 2 CH 2 COOR, , -CH=CH-C00R' , d- 6 Hydrocarbyl group;
R2 = -H、 卤素、 -N02、 - NH2、 -腿， 、 - N (R， ）2、 - CN、 -OH, d— 6 烷基、 d—6烷氧基、 - CF3、 -C00H, - S03H、 -C0NH2、 -C0NHR' 或 -C00R， ；R 2 = -H, halogen, -N0 2 , -NH 2 , - leg, - N (R, ) 2 , - CN, -OH, d- 6 alkyl, d- 6 alkoxy, - CF 3 , -C00H, - S0 3 H, -C0NH 2 , -C0NHR' or -C00R, ;
R3 - CH0、 COR' 、 COOR' 、 C00H、 CF3、 CH2R" 、 卤素、 d— 6烃基、 d— 6烷氧基、 -跳、 - 0H、 -N02、 - CN、 -HC-CH-CN、 - CH=CH2、 -C≡CH -C≡CR， 、 - CH=CHR， 、 -CH=CHC0R' ， 或为任选在其环结构上带有酯 基、 羧基、 烃基、 苯基取代的以下杂环基团：
Figure imgf000031_0002
R 3 - CH0, COR' , COOR' , C00H, CF 3 , CH 2 R" , halogen, d- 6 hydrocarbon, d- 6 alkoxy, -hop, -0H, -N0 2 , - CN, -HC -CH-CN, -CH=CH 2 , -C≡CH -C≡CR, , - CH=CHR, , -CH=CHC0R', or optionally having an ester group, a carboxyl group, or a hydrocarbon group in its ring structure , the following heterocyclic groups substituted by phenyl:
Figure imgf000031_0002
其中， X和 Y 各自独立地选自 C， 0， S和 NH;  Wherein X and Y are each independently selected from C, 0, S and NH;
= - H、 - CH2C00H、 - CH2CH2COOH、 - CH==CH-C00H、 -CH2C00R' 、 -CH2CH2COOR' 、 -CH=CH-C00R' 、 d— 6烃基、 苯基； = - H, - CH 2 C00H, - CH 2 CH 2 COOH, - CH==CH-C00H, -CH 2 C00R', -CH 2 CH 2 COOR' , -CH=CH-C00R', d- 6 hydrocarbon group Phenyl group;
R5= - H、 卤素、 -N02、 -NH2、 - NHR， 、 -N (R， ）2、 -CN、 - OKU d-( 烃基、 d— fi烷氧基、 - CF3、 CH0、 -C00H、 -S03H、 -C0NH2、 -C0NHR'或- C00R，；R 5 = - H, halogen, -N0 2 , -NH 2 , - NHR, -N (R, ) 2 , -CN, - OKU d- ( hydrocarbyl, d- fi alkoxy, -CF 3 , CH0 , -C00H, -S0 3 H, -C0NH 2 , -C0NHR' or - C00R,;
R' -d_6 烃基； 并且 R'-d_ 6 hydrocarbyl;
R" 为卤素、 OH或 Cw烷氧基。 R" is halogen, OH or C w alkoxy.
5. 权利要求 1的化合物或其可药用盐， 选自： 5. A compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
5- (3- (2， 5-二甲基 -1^ "吡咯 -1-基）苯基） - 1 四氮唑；  5-(3-(2,5-dimethyl-l^"pyrrole-1-yl)phenyl)-1 tetrazolium;
5- (2-羟基 -5- (2， 5-二甲基 -I 吡咯 -1-基）苯基） -1^四氮唑； 5-(2-hydroxy-5-(2,5-dimethyl-Ipyrrolidin-1-yl)phenyl)-1^tetrazolium;
5-（2-氯 -5- (2， 5-二甲基 -1 ^吡咯 -1 -基）苯基） 四氮唑； 5- (3- (3-乙氧羰基- 2， 5 -二甲基- 1^"吡咯 -1 -基）苯基） -1^"四氮 唾； 5-(2-chloro-5-(2,5-dimethyl-1^pyrrole-1-yl)phenyl)tetrazole; 5-(3-(3-ethoxycarbonyl-2,5-dimethyl- 1^"pyrrole-1 -yl)phenyl) -1^"tetrazine;
5- (3- (3-羧基- 2， 5-二甲基 -I 吡咯 -1 -基）苯基） -I 四氮唑； 5-（3- 吡咯- 1-基)苯基) - I ^氮唑 （ Π- If )  5-(3-(3-carboxy-2,5-dimethyl-Ipyrrole-1-yl)phenyl)-Itetrazole; 5-(3-pyrrole-1-yl)phenyl)-I ^Azole ( Π- If )
1 -羧甲基- 5- (3- (2， 5-二甲基 - 1^吡咯- 1-基)苯基) -1^四氮唑； 1-羧曱基- 5- (3- (3-羧基- 2， 5-二甲基- I 吡咯 -1-基）苯基） -1B~ 四氮唑；  1-carboxymethyl-5-(3-(2,5-dimethyl-1^pyrrole-1-yl)phenyl)-1^tetrazole; 1-carboxymethyl- 5-(3- 3-carboxy- 2,5-dimethyl-I pyrrol-1-yl)phenyl)-1B~tetrazole;
5- (3- (5 - (三氟甲基) -1, 2， 4-噁二唑 -3-基）苯基） 四氮唑； 5- (3- (5- (氯甲基） -1, 2, 4-噁二唑 -3-基）苯基） -1^·四氮唑；  5-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)tetrazole; 5-(3-(5-(chloromethyl)- 1, 2, 4-oxadiazol-3-yl)phenyl)-1^·tetrazolium;
5- (3- (5- (羟甲基） -1， 2, 4-噁二唑 - 3-基）苯基） -I 四氮唑；  5-(3-(5-(hydroxymethyl)-1,2,4-oxadiazole-3-yl)phenyl)-I tetrazolium;
1-羧甲基 -5- (3- (5- (三氟甲基） -1, 2， 4-噁二唑 -3-基）苯基） - 1^ 四氮峻；  1-carboxymethyl-5-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-1 ^tetrazolium;
1 -乙基 -5- (3- (5-次甲基- (绕丹宁- 5-基） -呋喃 -2-基）苯基） -1H- 四氮峻； 和  1-ethyl-5-(3-(5-methine-(cyclodendron-5-yl)-furan-2-yl)phenyl)-1H-tetrazoline;
1-羧甲基 -5- (3- (5-次甲基 -（绕丹宁 -5-基）-呋喃- 2-基）苯 基） -I 四氮唑。  1-Carboxymethyl-5-(3-(5-methine-(cyclo)-penta-5-yl)-furan-2-yl)phenyl)-I tetrazole.
6. 如权利要求 1的化合物或其可药用盐制备方法， 其包括: 6. A method of preparing a compound of claim 1 or a pharmaceutically acceptable salt thereof, comprising:
路线 A: 通用方法
Figure imgf000032_0001
Route A: General Approach
Figure imgf000032_0001
A [-1 I-2 取代苯氣化合物（ A )的氛基与叠氮化钠作用可合成 1 氮唑环， 得到目标化合物 1-1， 四氮唑环上的 1位氮氢与卤代烃反应即可得到 化合物 I - 2;  A [-1 I-2 substituted benzene gas compound (A) can react with sodium azide to synthesize a azole ring to obtain the target compound 1-1, a nitrogen atom on the tetrazole ring and a halogen Hydrocarbon reaction to obtain compound I-2;
或者，  Or,
路线 B: 对于式 I中 Ar为吡咯环的化合物而言：
Figure imgf000033_0001
Route B: For compounds of formula I where Ar is a pyrrole ring:
Figure imgf000033_0001
取代的 5-(3-氨基）苯基^^四氮唑（B) 与 2， 5-二甲氧基四氢呋 喃或 β位取代的 1, 4-二酮进行 ¾«s - ¾orr反应可得到 芳基吡咯类 化合物（ Π-1 )， 再与卤代烃反应生成 1-取代的 四氮唑-^芳基吡 咯类化合物 （ Π-2) ；  Substituted 5-(3-amino)phenyl-tetrazole (B) with 2,5-dimethoxytetrahydrofuran or β-substituted 1,4-dione for 3⁄4«s - 3⁄4orr reaction a pyridole compound (Π-1), which is then reacted with a halogenated hydrocarbon to form a 1-substituted tetrazolium-ylarylpyrrole compound (Π-2);
或者，  Or,
路线 C: 对于式 I中 Ar为噁二唑环的化合物而言：  Route C: For compounds of formula I where Ar is an oxadiazole ring:
Figure imgf000033_0002
以取代的 5- (3-氰基)苯基 四氮唑（C)作原料， 与盐酸羟胺 反应生成氨基肟中间体（ D )，再与酰化试剂作用可得到 3-芳基- 1， 2， 4- 噁二唑类化合物（111-1)，继而氮的卤化反应可得目标化合物 III - 2;
Figure imgf000033_0002
The substituted 5-(3-cyano)phenyltetrazolium (C) is used as a raw material, and reacted with hydroxylamine hydrochloride to form an aminoguanidine intermediate (D), which is then reacted with an acylating reagent to obtain 3-aryl-1. 2, 4-oxadiazole compound (111-1), followed by halogenation of nitrogen to obtain the target compound III-2;
或者，  Or,
路线 D: 对于式 I中 Ar为五元杂环（如吡咯、 呋喃等）醛的化合 物而言：  Route D: For a compound of formula I where Ar is a five-membered heterocyclic ring (e.g., pyrrole, furan, etc.) aldehyde:
Figure imgf000033_0003
取代的 5- (3-溴）苯基^ 四氮唑（E ) 与芳杂环的硼酸类化合物 通过 Suzuki反应， 偶联生成含有芳杂环的目标化合物 IV-1。 当芳杂 环含有醛基时， 可经缩合、 卤代得到目标化合物 IV- 2;
Figure imgf000033_0003
The substituted 5-(3-bromo)phenyl^tetrazole (E) and the aromatic heterocyclic boronic acid compound are coupled by Suzuki reaction to form the target compound IV-1 containing an aromatic heterocyclic ring. When the aromatic heterocyclic ring contains an aldehyde group, the target compound IV-2 can be obtained by condensation and halogenation;
反应路线中的 R「R4、 R6和 X、 Y 的定义同前式 I 所述， ϋ、 V、 W 各自独立地表示选自 Ν、 0、 S的杂原子或为碳原子。 R "R 4 , R 6 and X, Y in the reaction scheme are as defined in the above formula I, and ϋ, V, W each independently represent a hetero atom selected from Ν, 0, S or a carbon atom.
7. 药物组合物， 其含有至少一种权利要求 1-5任一项所述的式 I 化合物或其可药用盐， 以及一种或多种药用载体或赋形剂。 7. A pharmaceutical composition comprising at least one compound of formula I according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
8. 权利要求 1-5任一项所述的式 I化合物或其可药用盐用于制备 治疗或预防与 HIV感染的有关的疾病或病症的药物的用途。 8. Use of a compound of formula I according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease or condition associated with HIV infection.
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