CN110049973A - 1,4-二苯基-1h-咪唑和2，4-二苯基噻唑类衍生物及其制备方法和用途 - Google Patents

1,4-二苯基-1h-咪唑和2，4-二苯基噻唑类衍生物及其制备方法和用途 Download PDF

Info

Publication number
CN110049973A
CN110049973A CN201880004441.5A CN201880004441A CN110049973A CN 110049973 A CN110049973 A CN 110049973A CN 201880004441 A CN201880004441 A CN 201880004441A CN 110049973 A CN110049973 A CN 110049973A
Authority
CN
China
Prior art keywords
compound
och
room temperature
nmr
biotin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201880004441.5A
Other languages
English (en)
Other versions
CN110049973B (zh
Inventor
程魁
朱耿桢
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Southern Medical University
Original Assignee
Southern Medical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Southern Medical University filed Critical Southern Medical University
Publication of CN110049973A publication Critical patent/CN110049973A/zh
Application granted granted Critical
Publication of CN110049973B publication Critical patent/CN110049973B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D247/00—Heterocyclic compounds containing rings having two nitrogen atoms as the only ring hetero atoms, according to more than one of groups C07D229/00 - C07D245/00
    • C07D247/02—Heterocyclic compounds containing rings having two nitrogen atoms as the only ring hetero atoms, according to more than one of groups C07D229/00 - C07D245/00 having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明涉及1,4‑二苯基‑1H‑咪唑和2，4‑二苯基噻唑类衍生物及其制备方法和用途。其结构如下式所示：其中R1为H、OH、OCH3等中任意一个，R2为H、NO2、CH3、CF3、SO2CH3、COOCH3、CONHCH3中任意一个，R3为H、NO2、OCH3、CF3中任意一个，R4选自H、CF3、Cl，R5为H、Cl、CF3、NHCH3中任意一个，R6OCF3、CF3、CN中任意一个。V为C或N中任意一个，W为CH或N中任意一个，X为C原子，Y为CH或N中任意一个，Z为CH或S中任意一个。

Description

1,4-二苯基-1H-咪唑和2，4-二苯基噻唑类衍生物及其制备方 法和用途
技术领域
本发明涉及医药卫生和化工领域，具体涉及TLR1/2激动剂的一系列化合物，可用于科研、医疗和化工等领域。
背景技术
免疫系统是机体执行免疫应答及免疫功能的重要系统。由免疫器官、免疫细胞和免疫分子组成。免疫系统的功能在于识别和排除抗原性异物来维持机体内环境稳定和生理平衡。自身免疫性疾病主要是由过度免疫反应所产生的大量免疫细胞和免疫球蛋白堆积所致。
在哺乳动物的生长发育过程伴随着免疫系统紊乱和炎症反应，炎症反应是通过激活先天性和适应性免疫应答来保护机体清除有害刺激和入侵病的原体从而修复受损组织的免疫系统。在此过程中模式识别受体是一类主要表达于固有免疫细胞表面、非克隆性分布、可识别一种或多种病原体相关分子模式(PAMP)或宿主衍生的危险相关分子模式(DAMP)并活化免疫细胞，介导固有免疫的识别分子。其可分为四个亚家族：Toll样受体(TLRs)，维甲酸诱导基因I样受体(RLRs)，NOD样受体(NLRs)和C型凝集素受体(CLRs)。其中Toll样受体是识别病原微生物中最具代表性的一类。
从1997年Medzhitov发现Toll样受体以来，哺乳动物中已被确认的TLR家族成员有13个，在人类基因组中有超过10个功能成员配体与TLR配对。其中TLR3识别双链RNA，TLR4识别脂多糖，TLR5识别细菌鞭毛蛋白，TLR7和8识别病毒或细菌单链RNA，TLR9识别胞嘧啶-鸟苷单磷酸(CpG)。同时TLR家族成员可与其自身或其他TLR二聚化以形成同型或异型二聚体，连同衔接蛋白介导下游信号传导，例如TLR1/2和TLR2/6。目前，TLR的调节剂对于免疫炎症的治疗有激动剂和抑制剂。
在TLR家族中，TLR2是识别病原体谱最广的，包括格兰阳性菌如葡萄球菌、肺炎链球菌、支原体、酵母和大肠埃希菌，主要介导格兰阳性菌感染的脂蛋白等的信号转导，使IL-1和IL-12相关蛋白激酶、肿瘤坏死因子相关因子等信号转导分子的表达增加，并进一步促进IL-1和12等效应因子的合成和释放增加引发炎症反应，诱导细胞增殖转化和凋亡等基因的表达，从而介导机体的天然免疫防御作用。对TLR1、2活性的调节既是临床治疗的目标，也是十分有意义的科研论题。
发明内容
本发明的目的在于提供1,4-二苯基-1H-咪唑和2，4-二苯基噻唑类衍生物，如式I所示，所述多种化合物能激活TLR1/2受体活性，抵抗一系列肿瘤的发生与发展，如乳腺癌、膀胱癌。从而为这些疾病的治疗提供一种新的手段和途径，具有重要的研发价值和开发意义。
本发明的一个方面提供了一种化合物或其药学上可接受的盐，所述化合物具有式I所示的结构；
其中R1选自H、OH、OCH3、OCH2CH3、OCH2C6H5、O(CH2)2Br、O(CH2)3Br、O(CH2)2O(CH2)2Br、O(CH2)2O(CH2)2OH、OCOCH3、OCO(CH2)6CH3、OCO(CH2)10CH3、OCOC6H5、OCOCH＝CHC6H5、OSO3H、O(CH2)2O(CH2)2O(CH)2I、OCH2CONH2、O(CH2)2NH2、O(CH2)2NH-Biotin、O(CH2)2O-Biotin、O(CH2)2O(CH2)2O-Biotin中任意一个，R2选自H、NO2、CH3、CF3、SO2CH3、COOCH3、CONHCH3、-N+O-O-中任意一个，R3选自H、NO2、OCH3、CF3中任意一个，R4选自H、CF3、Cl，R5选自H、Cl、CF3、NHCH3中任意一个，R6选自H、OCF3、CF3、CN中任意一个；V为C或N中任意一个，W选自CH或N中任意一个，X为C，Y为CH或N中任意一个，Z为CH或S中任意一个。
在本发明的技术方案中，式I化合物选自式I-1或I-2的结构，
其中R1-R6取代基与上述相同。
在本发明的技术方案中，所述化合物具有如下结构式
本发明另一个方面提供了式I-1所述化合物的制备方法，其中化合物式I-1所示的化合物的制备方法包括下述步骤：
1)将化合物A1在甲机锂催化条件下，反应得到化合物A2
2)将化合物A2在四丁基三溴化铵作用下，反应得到化合物A3
3)将化合物A3与化合物A4反应得到式I-1所示的化合物；
其中，R1选自H、OH、OCH3、OCH2CH3、OCH2C6H5、O(CH2)2Br、O(CH2)3Br、O(CH2)2O(CH2)2Br、O(CH2)2O(CH2)2OH、OCOCH3、OCO(CH2)6CH3、OCO(CH2)10CH3、OCOC6H5、OCOCH＝CHC6H5、OSO3H、O(CH2)2O(CH2)2O(CH)2I、OCH2CONH2、O(CH2)2NH2、O(CH2)2NH-Biotin、O(CH2)2O-Biotin、O(CH2)2O(CH2)2O-Biotin中任意一个，R2选自H、NO2、CH3、CF3、SO2CH3、COOCH3、CONHCH3、-N+O-O-中任意一个，R3选自H、NO2、OCH3、CF3中任意一个，R4选自H、CF3、Cl，R5选自H、Cl、CF3、NHCH3中任意一个，R6选自H、OCF3、CF3、CN中任意一个；V为C或N中任意一个，W选自CH或N中任意一个，X为C，Y为CH或N中任意一个，Z为CH或S中任意一个。
所述化合物1-20的制备方法，包括下述步骤：
1)将化合物A1在有机锂催化条件下，反应得到化合物A2
2)将化合物A2在四丁基三溴化铵作用下，反应得到化合物A33)将化合物A3与化合物A4反应得到化合物1-20；
其中，制备各化合物的中间体化合物A1，A2，A3，A4及其相应产物化合物1-20中的R1-R6
如下所示：
1:R1＝R3＝R4＝H,R2＝NO2,R5＝Cl,R6＝CF3；
2:R1＝R3＝R4＝H,R2＝NO2,R5＝NHCH3,R6＝CF3；
3:R1＝R2＝R3＝R4＝R5＝H,R6＝CF3；
4:R1＝R3＝R4＝R5＝H,R2＝CF3,R6＝CF3；
5:R1＝R2＝R4＝R5＝H,R3＝CF3,R6＝CF3；
6:R1＝R2＝R3＝R4＝H,R5＝CF3,R6＝CF3；
7:R1＝R3＝R5＝H,R2＝R4＝CF3,R6＝CF3；
8:R1＝R2＝R4＝R5＝H,R3＝OCH3,R6＝CF3；
9:R1＝R2＝R4＝R5＝H,R3＝NO2,R6＝CF3；
10:R1＝R3＝R4＝R5＝H,R2＝CH3,R6＝CF3；
11:R1＝OH,R2＝NO2,R3＝R4＝H,R5＝Cl,R6＝CF3；
12:R1＝OH,R2＝NO2,R3＝R4＝H,R5＝NHCH3,R6＝CF3；
13:R1＝OH,R2＝R3＝R4＝R5＝H,R6＝CF3；
14:R1＝OH,R2＝CF3,R3＝R4＝R5＝H,R6＝CF3；
15:R1＝OH,R2＝R4＝R5＝H,R3＝CF3,R6＝CF3；
16:R1＝OH,R2＝R3＝R4＝H,R5＝CF3,R6＝CF3；
17:R1＝OH,R2＝R4＝CF3,R3＝R5＝H,R6＝CF3；
18:R1＝OH,R2＝R4＝R5＝H,R3＝OCH3,R6＝CF3；
19:R1＝OH,R2＝R4＝R5＝H,R3＝NO2,R6＝CF3；
20:R1＝OH,R2＝CH3,R3＝R4＝R5＝H,R6＝CF3。
本发明另一个方面提供了式I-2化合物的制备方法，包括下述步骤：
1)将化合物A1在甲机锂催化条件下，反应得到化合物A2将化合物A2在四丁基三溴化铵作用下，反应得到化合物A3
2)将化合物B1在甲胺中反应生成氨基取代的化合物B2还原化合物B2得到化合物B3
或者将化合物B5氨甲基化得到化合物B3；
3)将化合物B3和原甲酸三乙酯反应成环，得到化合物B4
4)将化合物B4和化合物A3反应得到化合物B6
5)将化合物B6在酸性条件下回流，得到式I-2所示化合物；
可选地，将步骤5)所得产物在氯化亚砜条件下进行氯取代，得到式I-2所示化合物。
其中，R1选自H、OH、OCH3、OCH2CH3、OCH2C6H5、O(CH2)2Br、O(CH2)3Br、O(CH2)2O(CH2)2Br、O(CH2)2O(CH2)2OH、OCOCH3、OCO(CH2)6CH3、OCO(CH2)10CH3、OCOC6H5、OCOCH＝CHC6H5、OSO3H、O(CH2)2O(CH2)2O(CH)2I、OCH2CONH2、O(CH2)2NH2、O(CH2)2NH-Biotin、O(CH2)2O-Biotin、O(CH2)2O(CH2)2O-Biotin中任意一个，R2选自H、NO2、CH3、CF3、SO2CH3、COOCH3、CONHCH3、-N+O-O-中任意一个，R6选自H、OCF3、CF3、CN中任意一个；
优选地，制备各化合物的中间体化合物A3，B1，B2，B3，B4，B5及其相应产物化合物21-27中的R1，R2和R6如下所示：
21:R1＝OH,R6＝OCF3,R2＝NO2；
22:R1＝OH,R6＝CF3,R2＝NO2；
23:R1＝OH,R6＝CF3,R2＝SO2CH3；
24:R1＝OH,R6＝CF3,R2＝COOCH3；
25:R1＝OH,R6＝CF3,R2＝CONHCH3；
26:R1＝OH,R6＝CF3,R2＝NO2；
27:R1＝H,R6＝CN,R2＝NO2。
本发明另一个方面提供了式I-2所示化合物的制备方法，包括下述步骤：
1)制备化合物22
2)将化合物22与R7X反应获得化合物
所述R7选自R7＝CH3、CH3CH2、C6H5CH2、C2H4Br、C3H6Br、(CH2)2O(CH2)2Br、(CH2)2O(CH2)2OH、COCH3、C7H15CO、C11H23CO、C6H5CO、C6H5CH＝CHCO、SO3H、(CH2)2O(CH2)2O(CH2)2I、NH2COCH；
所述X为卤素(优选为Cl,Br,I)。
在本发明的技术方案中，化合物I-2的制备方法，包括下述步骤：
1)制备化合物22将化合物22与1,2-二溴乙烷反应获得化合物31
2)将化合物31与NH3.H2O以及KI反应制备得到化合物43
可选地，将化合物43与化合物反应得到化合物44，
或者
2)将化合物31与生物素反应，得到化合物45，46或47
或者
2)将生物素与I(CH2)2O(CH2)2O(CH2)2I或I(CH2)2O(CH2)2I反应，得到再与化合物22反应得到化合物45，46或47；
其中,R8为(CH2)2O(CH2)2O(CH2)2I或(CH2)2O(CH2)2I。
(i)28:CH3I,丙酮,K2CO3,室温12h；29:CH3CH2I,丙酮,K2CO3,室温,12h；30:C6H5CH2Br,丙酮,K2CO3,室温12h；31:1,2-二溴乙烷,丙酮,K2CO3,室温12h；32:1,3-二溴乙烷,丙酮,K2CO3,室温,12h；33:Br(CH2)2O(CH2)2Br,丙酮,K2CO3,室温,12h；34:Cl(CH2)2O(CH2)2OH,丙酮,K2CO3,室温,12h；35:CH3COCl,Et3N,DCM,0℃,1h；36:C7H15COCl,Et3N,DCM,0℃,1h；37:C11H23COCl,Et3N,DCM,0℃,1h；38:C6H5COCl,Et3N,DCM,0℃,1h；39:C6H5CH＝CHCOCl,Et3N,DCM,0℃,1h；40:SO3/吡啶,Et3N,THF,室温,6h；41:I(CH2)2O(CH2)2O(CH2)2I,丙酮,K2CO3,室温,12h；42:NH2COCH2Cl,2-丁酮,KI,室温12h；(ii)31,NH3·H2O,KI,THF,12h；(iii)HATU,DIPEA,室温,12h.(iv)NaH,KI,DMSO,室温,12h；(v)NaH,DMSO,室温,12h；(vi)K2CO3,acetone,室温,12h
本发明另一方面提供了一种药物组合物，其包括本发明所述的化合物或其药学上可接受的盐，其还包括药学上可接受的载体或辅料。
本发明另一方面提供了上述的化合物在制备抗炎佐剂、TLR1或TLR 2的激动剂、抗肿瘤的药物中的应用。
本发明再一个方面提供了一种在体外、体内调节TLR1和2碱性磷酸酶活性激活水平的方法，其包括给予受试者式I所式的化合物。
本发明提供了式I所示化合物在TLR1、2等方面应用。
本发明所述的化合物1-47能进行结构修饰，获得活性更好的化合物，并用于治疗TLR1、2相关疾病。
本发明一个具体的技术方案提供了化合物的制备方法，其包括以下步骤：
1.将2-羟基-4-(三氟甲基)苯甲酸在冰浴下溶于THF，将1.6M甲基锂逐滴加入，反应混合物在室温下拌4小时。然后加蒸馏水淬灭并用稀HCl调节至pH＝7并用乙酸乙酯萃取。将收集的有机层用无水Na2SO4干燥并减压浓缩。通过柱层析法(石油醚)纯化，得到油状的1-(2-羟基-4-(三氟甲基)苯基)乙酮等相对应的产物。
2.常温下将油状的1-(2-羟基-4-(三氟甲基)苯基)乙酮溶于MeOH和DCM中，四丁基三溴化铵溶于DCM后滴入前述的混合溶液中，常温下反应24小时，反应完毕减压旋干有机相并通过柱层析法(石油醚-乙酸乙酯＝8:1)纯化，得到黄色油状的2-溴-1-(2-羟基-4-(三氟甲基)苯基)乙酮的方法。
3.将不同取代基的硫代苯甲酰胺分别和溴代苯乙酮在EtOH回流过夜，冷却后析出结晶并抽滤的方法。
4.将取代的苯胺溶于DMF中，加入原甲酸三乙酯在浓HCl的条件下形成沉淀后过滤得到取代的咪唑并在甲醇冰浴下重结晶的方法。
5.将取代的咪唑和溴代苯乙酮在MeOH溶剂中回流12小时，旋干溶剂后用丙酮超声出现沉淀，将沉淀过滤后干燥，然后将滤饼在甲醇的条件下重结晶制备取代的溴盐的方法。
6.表示将取代的溴盐在醋酸和醋酸铵条件下回流过夜，加蒸馏水后析出过滤制备1,4-二苯基-1H-咪唑的方法。
7.表示将1,4-二苯基-1H-咪唑和碱在非质子性溶剂中反应，加卤代烷烃制备以1,4-二苯基-1H-咪唑为母核的中间体的方法。
8.表示将1,4-二苯基-1H-咪唑为母核的中间体和碱在非质子性溶剂中反应，加生物素制备以1,4-二苯基-1H-咪唑为母核标记的生物素的方法。
上述所示的部分化合物能剂量依赖性的激活TLR1/2受体。
本发明所述的化合物22可用于制成TLR1、2相关佐剂、药物等。结合现代常用药物制剂手段，可将所述化合物制成注射剂、片剂、粉剂、颗粒剂、胶囊，从而采用比较方便的给药形式，其中本发明化合物在所述药物中的质量百分比含量为1～20％。
上述各种剂型的药物均可按照药学领域的常规方法制备。
附图说明
图1化合物22呈浓度依赖的激活TLR1/2活性。
具体实施方式
为了更好地理解本发明的内容，下面结合具体实施方法对本发明内容作进一步说明，但本发明的保护内容不局限以下实施例。
实施例1：化合物1的制备
1-(2-羟基-4-(三氟甲基)苯基)乙酮的制备。
将2-羟基-4-(三氟甲基)苯甲酸(1.0g,4.85mmol)在冰浴下溶于THF(10mL)，将1.6M(10mL)甲基锂逐滴加入，反应混合物在室温下搅拌4小时。然后加蒸馏水淬灭并用稀HCl调节至pH＝7并用乙酸乙酯萃取(3×50mL)。将收集的有机层用无水Na2SO4干燥并减压浓缩。通过柱层析法(石油醚)纯化，得到油状的1-(2-羟基-4-(三氟甲基)苯基)乙酮(750mg,75.8％)相对应的产物。
2-溴-1-(2-羟基-4-(三氟甲基)苯基)乙酮的制备。
常温下将油状的1-(2-羟基-4-(三氟甲基)苯基)乙酮(1.0g，0.0049mmol)溶于MeOH(12mL)和DCM(6mL)中，四丁基三溴化铵(2.59g，0.0054mmol)溶于DCM(12mL)后滴入前述的混合溶液中，常温下反应24小时，反应完毕减压旋干有机相并通过柱层析法(石油醚-乙酸乙酯)纯化，得到黄色油状的2-溴-1-(2-羟基-4-(三氟甲基)苯基)乙酮(1.32g，95％)的方法。
化合物1的制备。
将2-氯-5-硝基硫代苯甲酰胺(243mg,1.12mmol)和2-溴-1-(4-(三氟甲基)苯基)乙酮(300mg,1.12mmol)溶于EtOH(5mL).反应液在回流的条件下反应4小时，通过薄层板检测反应进程。反应结束后降温析出沉淀，过滤沉淀后得到化合物2-(2-氯-5-硝基苯基)-5-(4-(三氟甲基)苯基)噻唑，产率100％。
实施例2：化合物2的制备
将化合物2-(2-氯-5-硝基苯基)-5-(4-(三氟甲基)苯基)噻唑(300mg,0.78mmol)和40％甲胺水溶液(263mg,3.9mmol)溶于EtOH(15mL),室温下反应并用薄层板检测反应进程，反应结束用乙酸乙酯萃取(3×50mL)后水洗去甲胺。将收集的有机层用无水Na2SO4干燥并减压浓缩。通过柱层析法(石油醚-乙酸乙酯＝4:1)纯化，得到N-甲基-4-硝基-2-(5-(4-(三氟甲基)苯基)噻唑-2-基)苯胺，产率100％。
将化合物2-(甲氨基)-5-硝基苯并硫代酰胺(211.2mg,1mmol)和2-溴-1-(4-(三氟甲基)苯基)乙酮(300mg,1.12mmol)溶于EtOH(5mL).反应液在回流的条件下反应4小时，通过薄层板检测反应进程。反应结束后降温析出沉淀，过滤沉淀后得到化合物2-(2-氯-5-硝基苯基)-5-(4-(三氟甲基)苯基)噻唑，产率100％。
实施例3：化合物3-20的制备
实施例3中分别制备了化合物3-20。化合物3-20制备步骤与化合物1的制备中相同，除了所用原料有所区别。不同之处如下面的表1所示：
表1：化合物3-20与化合物1的区别
实施例4：化合物22的制备
1、1-(2-羟基-4-(三氟甲基)苯基)乙酮的制备。
将2-羟基-4-(三氟甲基)苯甲酸(1.0g,4.85mmol)在冰浴下溶于THF(10mL)，将1.6M(10mL)甲基锂逐滴加入，反应混合物在室温下搅拌4小时。然后加蒸馏水淬灭并用稀HCl调节至pH＝7并用乙酸乙酯萃取(3×50mL)。将收集的有机层用无水Na2SO4干燥并减压浓缩。通过柱层析法(石油醚)纯化，得到油状的1-(2-羟基-4-(三氟甲基)苯基)乙酮(750mg,75.8％)相对应的产物。
2、2-溴-1-(2-羟基-4-(三氟甲基)苯基)乙酮的制备。
常温下将油状的1-(2-羟基-4-(三氟甲基)苯基)乙酮(1.0g，0.0049mmol)溶于MeOH(12mL)和DCM(6mL)中，四丁基三溴化铵(2.59g，0.0054mmol)溶于DCM(12mL)后滴入前述的混合溶液中，常温下反应24小时，反应完毕减压旋干有机相并通过柱层析法(石油醚-乙酸乙酯)纯化，得到黄色油状的2-溴-1-(2-羟基-4-(三氟甲基)苯基)乙酮(1.32g，95％)的方法。
3、1-甲基-5-硝基-1H-苯并[d]咪唑的制备
将N1-甲基-4-硝基苯-1,2-二胺(251mg,1.5mmol)溶于DMF(4mL)中，加入原甲酸三乙酯(10mL)在浓HCl(12N solution,167μL,5mmol)的条件下形成淡黄色沉淀后过滤得到1-甲基-5-硝基-1H-苯并[d]咪唑(90mg,33.7％)并在甲醇冰浴下重结晶的方法。
4、3-(2-(2-羟基-4-(三氟甲基)苯基)-2-氧代乙基)-1-甲基-5-硝基-1H-苯并[d]咪唑-3-鎓溴化物的制备
将2-溴-1-(2-羟基-4-(三氟甲基)苯基)乙酮(566mg，2mmol)与1-甲基-5-硝基-1H-苯并[d]咪唑(354mg，2mmol)在MeOH(20mL)溶剂中回流12小时，旋干溶剂后用丙酮超声出现沉淀，将沉淀过滤后干燥，然后将滤饼在甲醇的条件下重结晶制备3-(2-(2-羟基-4-(三氟甲基)苯基)-2-氧代乙基)-1-甲基-5-硝基-1H-苯并[d]咪唑-3-鎓溴化物(920mg，100％)的方法。
5、2-(1-(2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲基)苯酚的制备将3-(2-(2-羟基-4-(三氟甲基)苯基)-2-氧代乙基)-1-甲基-5-硝基-1H-苯并[d]咪唑-3-鎓溴化物(920mg，12mmol)在醋酸(10mL)和醋酸铵(770mg，10mmol)条件下回流过夜，反应完毕后加入蒸馏水(100mL)，析出黄色固体，抽滤后重结晶得到纯净的制备2-(1-(2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲基)苯酚(378mg,50％)的方法。
实施例5：化合物21,23,24,25的制备
表2：化合物21,23,24,25与化合物22的区别
实施例6：化合物26的制备
将2-(1-(2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲基)苯酚(30mg,0.08mmol)溶于氯化亚砜(4mL)并在室温下反应。薄层板检测反应进程，反应结束后将氯化亚砜旋干，通过柱层析法(石油醚-乙酸乙酯＝2:1)纯化，得到黄色的2-(1-(3-氯-2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲基)苯酚(750mg,75.8％)。
实施例7：化合物27的制备
表3：化合物27与化合物26的区别
实施例8：化合物28的制备
将2-(1-(2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲基)苯酚(30mg,0.082mmol)和K2CO3溶于(101.8mg,0.738mmol)丙酮(3ml)，并搅拌20分钟。再加入碘甲烷(34.9mg,0.246mmol).50℃下反应并用薄层板检测反应进程。反应结束后加水淬灭并用乙酸乙酯(3×50mL)萃取，将收集的有机层用无水Na2SO4干燥并减压浓缩。通过柱层析法(石油醚-乙酸乙酯＝1:1)纯化，得到黄色的2-(4-(2-甲氧基-4-(三氟甲基)苯基)-1H-咪唑-1-基)-N-甲基-4-硝基苯胺(28.6mg,92％)。
实施例9：化合物29、30、31、32、33、34、40、41、42的制备
表4：化合物27与化合物26的区别
化合物编号 与化合物22步骤不同之处
29 将原料CH<sub>3</sub>I替换为CH<sub>3</sub>CH<sub>2</sub>I
30 将原料CH<sub>3</sub>I替换为C<sub>6</sub>H<sub>5</sub>CH<sub>2</sub>I
31 将原料CH<sub>3</sub>替换为C<sub>2</sub>H<sub>4</sub>Br<sub>2</sub>
32 将原料CH<sub>3</sub>I替换为C<sub>3</sub>H<sub>6</sub>Br<sub>2</sub>
33 将原料CH<sub>3</sub>I替换为(CH<sub>2</sub>)<sub>2</sub>O(CH<sub>2</sub>)<sub>2</sub>Br<sub>2</sub>
34 将原料CH<sub>3</sub>I替换为Cl(CH<sub>2</sub>)<sub>2</sub>O(CH<sub>2</sub>)<sub>2</sub>OH
40 将原料CH<sub>3</sub>I替换为SO<sub>3</sub>-Py
41 将原料CH<sub>3</sub>I替换为(CH<sub>2</sub>)<sub>2</sub>O(CH<sub>2</sub>)<sub>2</sub>O(CH<sub>2</sub>)<sub>2</sub>I<sub>2</sub>
42 将原料CH<sub>3</sub>I替换为NH<sub>2</sub>COCH<sub>2</sub>Cl
实施例10：化合物35的制备
将2-(1-(2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲基)苯酚(10mg,0.026mmol)溶于DCM(20ml)，加入三乙胺(200uL)并在冰浴下搅拌10分钟，再逐滴加入乙酰氯(2ml)，并用薄层板检测反应进程。反应结束后旋干溶剂并通过柱层析法(石油醚-乙酸乙酯＝1:1)纯化，得到黄色的(1-(2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲基)苯基乙酸酯(9.2mg，85％)。
实施例11：化合物36、37、38、39的制备
表5：化合物36、37、38、39与化合物35的区别
化合物编号 与化合物22步骤不同之处
36 将原料CH<sub>3</sub>COCl替换为C<sub>7</sub>H<sub>15</sub>COCl
37 将原料CH<sub>3</sub>COCl替换为C<sub>11</sub>H<sub>23</sub>COCl
38 将原料CH<sub>3</sub>COCl替换为C<sub>6</sub>H<sub>5</sub>COCl
39 将原料CH<sub>3</sub>COCl替换为C<sub>7</sub>H<sub>15</sub>COCl
实施例12：化合物43的制备
将2-(4-(2-(2-溴乙氧基)-4-(三氟甲基)苯基)-1H-咪唑-1-基)-N-甲基-4-硝基苯胺(35mg,0.082mmol)，碘化钾(68mg,0.41mmol)溶于THF(4ml)和30％氨水(4mL)，密闭回流过夜并用薄层板检测反应进程。反应结束后萃取并通过柱层析法(二氯甲烷-甲醇＝9:1)纯化，得到黄色2-(4-(3-(2-氨基乙氧基)-4-(三氟甲基)苯基)-1H-咪唑-1-基)-N-甲基-4-硝基苯胺(24.5mg，71％)。
实施例13：化合物44的制备
将生物素(34.8mg,0.14mmol)溶于DMF(4mL)，再加入HATU(80.94mg,0.213mmol)和DIPEA(2mL)并混合搅拌30分钟，再加入2-(4-(3-(2-氨基乙氧基)-4-(三氟甲基)苯基)-1H-咪唑-1-基)-N-甲基-4-硝基苯胺(30mg,0.071mmol)。45℃过夜并用薄层板检测反应进程。反应结束后萃取并通过柱层析法(乙酸乙酯-甲醇＝9:1)纯化，得到黄色N-(2-(2-(1-(2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲基)苯氧基)乙基)-5-((3AS，4S，6AR)-2-氧代六氢-1H-噻吩并[3,4-d]咪唑-4-基)戊酰胺(42.76mg,93％)。
实施例14：化合物45、46、47的制备
表6：化合物45、46、47与化合物35的区别
化合物编号 与化合物44步骤不同之处
45 将连接链(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub>替换为CH<sub>2</sub>CH<sub>2</sub>
46 将连接链(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub>替换为(CH<sub>2</sub>)<sub>2</sub>O(CH<sub>2</sub>)<sub>2</sub>
47 将连接链(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub>替换为(CH<sub>2</sub>)<sub>2</sub>O(CH<sub>2</sub>)<sub>2</sub>O(CH<sub>2</sub>)<sub>2</sub>
实施例15：化合物的结构验证
化合物1
2-(2-氯-5-硝基苯基)-5-(4-(三氟甲基)苯基)噻唑。
白色固体(276.2mg,64.1％).m.p.169.2-170.2℃.1H NMR(400MHz,CDCl3)δ9.34(d,J＝2.8Hz,1H),8.23(dd,J＝8.8,2.8Hz,1H),8.16(d,J＝8.1Hz,2H),7.86(s,1H),7.74(dd,J＝12.4,8.5Hz,3H).13C NMR(101MHz,CDCl3)δ99.97,160.97,153.95,146.81,137.96,136.88,132.89,131.83,130.50,126.68,125.84,124.31,117.21.MS(ESI-TOF)forC16H8ClF3N2O2S[M+H]+calculated 385.76,found 385.96.
化合物2
N-甲基-4-硝基-2-(5-(4-(三氟甲基)苯基)噻唑-2-基)苯胺。
黄色固体(284.9mg,96.3％).m.p.145.3-145.9℃.1H NMR(400MHz,DMSO)δ9.40(d,J＝5.0Hz,1H),8.57–8.37(m,2H),8.24(d,J＝8.2Hz,2H),8.19(dd,J＝9.3,2.5Hz,1H),7.85(d,J＝8.3Hz,2H),6.97(d,J＝9.5Hz,1H),3.14(d,3H).13C NMR(101MHz,DMSO)δ167.39,152.95,151.80,137.26,135.79,127.21,126.27,125.45,116.73,113.68,111.54,30.35.MS(ESI-TOF)for C17H12F3N3O2S[M+H]+calculated 380.36,found 380.32.
化合物3
2-苯基-4-(4-(三氟甲基)苯基)噻唑。
白色固体(299.2mg,98.2％).m.p.126.1-127.0℃.1H NMR(400MHz,CDCl3)δ8.14(d,J＝8.2Hz,2H),8.07(dd,J＝7.4,2.1Hz,2H),7.73(d,J＝8.3Hz,2H),7.61(s,1H),7.50(dd,J＝5.0,2.3Hz,3H).13C NMR(101MHz,CDCl3)δ168.34,154.65,137.65,133.41,130.28,130.03,129.70,128.96,126.60,125.68,122.84,114.32.MS(ESI-TOF)for C16H10F3NS[M+H]+calculated 306.32,found 305.59.
化合物4
2-(3-(三氟甲基)苯基)-4-(4-(三氟甲基)苯基)噻唑。
白色固体(302.1mg,80.9％).m.p.91.7-95.2℃.1H NMR(400MHz,CDCl3)δ8.14(d,J＝8.2Hz,2H),8.07(dd,J＝7.4,2.1Hz,2H),7.73(d,J＝8.3Hz,2H),7.61(s,1H),7.50(dd,J＝5.0,2.3Hz,3H).13C NMR(101MHz,CDCl3)δ168.34,154.65,137.65,133.41,130.28,130.03,129.70,128.96,126.60,125.68,122.84,114.32.MS(ESI-TOF)for C17H9F6NS[M+H]+calculated 374.32,found 375.11.
化合物5
2,5-双(4-(三氟甲基)苯基)噻唑。
白色固体(282mg,75.6％).m.p.126.3-127.8℃.1H NMR(400MHz,CDCl3)δ8.14(dd,J＝17.3,8.1Hz,96H),7.74(t,J＝7.3Hz,96H),7.65(s,18H),7.28(s,3H).13C NMR(101MHz,CDCl3)δ166.40,155.17,137.27,136.42,131.69,130.32,126.77,125.94,125.76,122.75,115.24.MS(ESI-TOF)for C17H9F6NS[M+H]+calculated 374.32,found374.29.
化合物6
2-(2-(三氟甲基)苯基)-5-(4-(三氟甲基)苯基)噻唑。
白色固体(303.1mg,81.2％).m.p.123.4-126.2℃.1H NMR(400MHz,CDCl3)δ8.11(d,J＝8.2Hz,2H),7.89(d,J＝7.5Hz,1H),7.82–7.56(m,6H).13C NMR(101MHz,CDCl3)δ164.64,154.31,137.39,132.40,132.14,131.73,130.17,129.84,129.05,128.74,127.00,126.64,125.71,125.49,124.98,122.79,122.26,116.25.MS(ESI-TOF)for C17H9F6NS[M+H]+calculated 374.32,found 374.78.
化合物7
2-(3,5-双(三氟甲基)苯基)-4-(4-(三氟甲基)苯基)噻唑。
白色固体(319.1mg,72.3％).m.p.125.7-126.4℃.1H NMR(400MHz,CDCl3)δ8.49(s,2H),8.15(d,J＝8.1Hz,2H),7.98(s,1H),7.84–7.66(m,3H).13C NMR(101MHz,CDCl3)δ164.58,155.51,136.84,135.20,132.72,130.59,130.27,127.03,126.49,125.78,125.38,124.32,123.38,122.68,121.61,118.89,115.69.MS(ESI-TOF)for C18H8F9NS[M+H]+calculated 440.31,found 440.95.
化合物8
4-(4-甲氧基苯基)-2-(3-(三氟甲基)苯基)噻唑。
白色固体(320.58mg,95.6％).m.p.128.7-129.9℃.1H NMR(400MHz,CDCl3)δ8.12(d,J＝7.7Hz,2H),8.05–7.91(m,2H),7.71(d,J＝8.0Hz,2H),7.52(s,1H),7.06–6.88(m,2H),3.90(d,3H).13C NMR(101MHz,CDCl3)δ168.20,161.33,154.38,137.76,128.09,126.52,125.60,114.27,113.45,55.37.MS(ESI-TOF)for C17H12F3NOS[M+H]+calculated336.34,found 337.08.
化合物9
4-(4-硝基苯基)-2-(3-(三氟甲基)苯基)噻唑。
黄色固体(349.6mg,99.8％).m.p.120.8-121.5℃.1H NMR(400MHz,DMSO)δ8.51(s,1H),8.26(dd,J＝33.7,6.1Hz,6H),7.80(d,J＝6.3Hz,2H).13C NMR(101MHz,DMSO)δ165.01,154.53,148.36,137.46,127.50,127.04,126.03,124.75,123.24,119.59.MS(ESI-TOF)for C16H9F3N2O2S[M+H]+calculated 351.32,found 351.32.
化合物10
2-(间甲苯基)-4-(4-(三氟甲基)苯基)-2,5-二氢噻唑。
白色固体(299.8mg,93.9％).m.p.94.8-95.5℃.1H NMR(400MHz,CDCl3)δ8.13(d,J＝8.0Hz,2H),7.90(s,1H),7.85(d,J＝7.7Hz,1H),7.72(d,J＝8.2Hz,2H),7.59(s,1H),7.39(t,J＝7.6Hz,1H),7.30(d,J＝7.6Hz,1H),2.48(s,3H).13C NMR(101MHz,CDCl3)δ168.59,154.58,138.77,137.69,133.31,131.11,129.99,128.86,127.13,126.56,125.63,123.84,122.85,114.23,21.33.MS(ESI-TOF)for C17H14F3NS[M+H]+calculated 322.36,found 333.01.
化合物11
2-(2-(2-氯-5-硝基苯基)噻唑-5-基)-5-(三氟甲基)苯酚。
白色固体(560.4mg,81.6％).m.p.187.4-188.6℃.1H NMR(400MHz,CDCl3)δ11.54(s,1H),8.93(d,J＝2.7Hz,1H),8.30(dd,J＝8.8,2.7Hz,1H),7.94(s,1H),7.80(d,J＝8.8Hz,2H),7.35(d,J＝1.2Hz,1H),7.28(s,1H),7.21(dd,J＝8.2,1.2Hz,1H).13C NMR(101MHz,CDCl3)δ156.09,132.32,126.75,125.44,125.10,116.47.MS(ESI-TOF)forC16H8ClF3N2O3S[M+H]+calculated 401.76,found 401.21.
化合物12
2-(2-(2-(甲基氨基)-5-硝基苯基)噻唑-5-基)-5-(三氟甲基)苯酚。
黄色固体(192.3mg,45.8％).m.p.194.6-198.7℃.1H NMR(400MHz,DMSO)δ11.08(s,1H),9.50(d,J＝4.8Hz,1H),8.48(d,J＝2.2Hz,1H),8.39(s,1H),8.27–8.10(m,2H),7.29(d,J＝7.3Hz,2H),6.96(d,J＝9.4Hz,1H),3.13(d,3H).13C NMR(101MHz,DMSO)δ165.55,155.57,151.83,149.65,135.73,130.27,127.26,125.34,123.97,119.10,116.21,113.81,112.90,111.35,30.28.MS(ESI-TOF)for C17H12F3N3O3S[M+H]+calculated 396.36,found 397.25.
化合物13
2-(2-苯基噻唑-4-基)-5-(三氟甲基)苯酚。
白色固体(427.6mg,90.7％).m.p.132.5-134.2℃.1H NMR(400MHz,CDCl3)δ12.13(s,1H),7.97–7.88(m,2H),7.69(d,J＝8.1Hz,1H),7.60(s,1H),7.50(s,3H),7.32(s,1H),7.14(d,J＝8.1Hz,1H).13C NMR(101MHz,CDCl3)δ168.17,156.17,153.04,131.79,130.96,129.17,126.40,125.17,122.51,122.31,120.09,115.78,115.09,113.31.MS(ESI-TOF)forC16H10F3NOS[M+H]+calculated 322.32,found 322.30.
化合物14
5-(三氟甲基)-2-(2-(3-(三氟甲基)苯基)噻唑-4-基)苯酚。
白色固体(302.5mg,74.6％).m.p.108.5-109.8℃.1H NMR(400MHz,CDCl3)δ11.81(s,1H),8.16(d,J＝7.6Hz,2H),7.76(dd,J＝13.9,9.4Hz,3H),7.67(t,J＝7.8Hz,1H),7.33(s,1H),7.18(d,J＝8.2Hz,1H).13C NMR(101MHz,CDCl3)δ166.43,156.05,153.60,132.60,129.89,129.51,127.42,126.56,123.17,122.15,119.81,115.97,115.16,114.23.MS(ESI-TOF)for C17H9F6NOS[M+H]+calculated 390.31,found 390.39.
化合物15
5-(三氟甲基)-2-(2-(4-(三氟甲基)苯基)噻唑-5-基)苯酚。
白色固体(387.6mg,70.3％).m.p.138.6-139.2℃.1H NMR(400MHz,CDCl3)δ11.80(s,1H),8.09(d,J＝8.1Hz,2H),7.88–7.69(m,4H),7.34(s,1H),7.19(d,J＝8.2Hz,1H).13CNMR(101MHz,CDCl3)δ166.36,156.11,153.77,134.92,132.75,132.34,132.01,126.74,126.45,125.05,122.35,119.80,116.03,115.22,114.50.MS(ESI-TOF)for C17H9F6NOS[M+H]+calculated 390.31,found 389.14.
化合物16
5-(三氟甲基)-2-(2-(2-(三氟甲基)苯基)噻唑-5-基)苯酚。
白色固体(391.3mg,71.2％).m.p.138.9-140.7℃.1H NMR(400MHz,CDCl3)δ11.68(s,1H),7.91(d,J＝7.1Hz,1H),7.83(s,1H),7.78(d,J＝8.2Hz,1H),7.75–7.64(m,3H),7.32(s,1H),7.18(d,J＝8.2Hz,1H).13C NMR(101MHz,CDCl3)δ164.76,156.17,153.10,132.11,132.02,130.44,127.25,126.54,119.92,115.79,115.41,115.35.MS(ESI-TOF)forC17H9F6NOS[M+H]+calculated 390.31,found 391.21.
化合物17
2-(2-(3,5-双(三氟甲基)苯基)噻唑-4-基)-5-(三氟甲基)苯酚。
白色固体(117.2mg,75.6％).m.p.157.6-158.2℃.1H NMR(400MHz,CDCl3)δ11.48(s,1H),8.36(s,2H),8.03(s,1H),7.82(s,1H),7.77(d,J＝8.2Hz,1H),7.33(s,1H),7.20(d,J＝8.1Hz,1H).13C NMR(101MHz,CDCl3)δ164.62,155.91,154.13,133.82,133.51,133.17,132.49,132.26,126.71,126.24,124.96,124.08,122.25,121.37,119.52,118.66,116.18,115.24.MS(ESI-TOF)for C18H8F9NOS[M+H]+calculated 456.31,found 456.02.
化合物18
2-(4-(4-甲氧基苯基)噻唑-2-基)-5-(三氟甲基)苯酚。
白色固体(342.7mg,86.4％).m.p.146.2-147.3℃.1H NMR(400MHz,CDCl3)δ12.25(s,1H),7.91(d,J＝8.5Hz,2H),7.74(d,J＝8.2Hz,1H),7.58(s,1H),7.32(s,1H),7.16(d,J＝8.1Hz,1H),7.02(d,J＝8.6Hz,2H),3.91(s,3H).13C NMR(101MHz,CDCl3)δ168.10,161.84,156.19,152.75,131.49,128.02,126.37,124.73,120.24,115.76,115.06,115.02,114.50,112.29,55.42.MS(ESI-TOF)for C17H12F3NO2S[M+H]+calculated 352.34,found351.94.
化合物19
2-(4-(4-硝基苯基)噻唑-2-基)-5-(三氟甲基)苯酚。
黄色固体(186.5mg,90.7％).m.p.144.9-145.3℃.1H NMR(400MHz,DMSO)δ11.16(s,1H),8.54(d,J＝4.3Hz,1H),8.46–8.39(m,1H),8.40–8.33(m,2H),8.33–8.23(m,2H),7.30(s,2H).13C NMR(101MHz,DMSO)δ163.54,157.58,157.48,155.61,151.53,148.49,138.56,132.26,130.40,129.76,127.70,124.95,124.00,122.18,116.10,113.10.MS(ESI-TOF)for C16H9F3N2O3S[M+H]+calculated 367.31,found 368.55.
化合物20
2-(2-(间甲苯基)-2,5-二氢噻唑-4-基)-5-(三氟甲基)苯酚。
白色固体(277.6mg,69.4％).m.p.100.7-101.1℃.1H NMR(400MHz,CDCl3)δ12.17(s,1H),7.78(d,J＝6.7Hz,3H),7.65(d,J＝6.1Hz,1H),7.46–7.35(m,1H),7.33(dd,J＝13.6,9.7Hz,2H),7.18(d,J＝7.8Hz,1H),2.48(d,3H).13C NMR(101MHz,CDCl3)δ168.41,156.18,152.96,139.07,131.77,129.06,126.91,126.39,125.18,123.65,122.47,120.15,115.77,115.06,113.16,21.30.MS(ESI-TOF)for C17H14F3NOS[M+H]+calculated 378.36,found 377.66.
化合物21
2-(1-(2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲氧基)苯酚。
黄色固体(203mg,86％).m.p.194.4-195.1℃.1H NMR(400MHz,DMSO)δ8.23(dd,J＝9.2,2.5Hz,1H),8.02(d,J＝2.7Hz,1H),8.01–7.92(m,4H),7.40(dd,J＝8.9,0.9Hz,2H),6.87(d,J＝9.4Hz,1H),6.71(q,J＝4.5Hz,1H),2.83(s,3H).13C NMR(101MHz,DMSO)δ150.69,147.38,140.61,139.15,135.55,134.04,127.08,126.54,124.11,121.89,121.67,121.63,119.35,118.28,110.45,30.27.MS(ESI-TOF)for C17H13F3N4O3[M+H]+calculated379.31,found 378.02.
化合物22
2-(1-(2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲基)苯酚。
黄色固体(378mg,50％).1H NMR(400MHz,DMSO)δ11.83(s,1H),8.25(dd,J＝9.3,2.6Hz,1H),8.13(d,J＝1.0Hz,1H),8.10–7.97(m,3H),7.21(d,J＝8.0Hz,2H),6.88(d,J＝9.4Hz,1H),6.73(d,J＝4.8Hz,1H),2.82(d,3H).13C NMR(101MHz,DMSO)δ155.24),150.74,138.46,137.90,135.48,128.30,127.25,126.96,125.95,124.43,122.83,121.23,120.09,115.89,113.10,110.44,30.17.MS(ESI-TOF)for C17H13F3N4O3[M+H]-calculated 377.31,found 377.52.
化合物23
2-(1-(2-(甲基氨基)-5-(甲基磺酰基)苯基)-1H-咪唑-4-基)-5-(三氟甲基)苯酚。
粉色固体(284mg,55％).m.p.179.4-180.1℃.1H NMR(400MHz,DMSO)δ11.90(s,1H),8.22–7.96(m,3H),7.83(dd,J＝8.8,2.0Hz,1H),7.67(d,J＝2.0Hz,1H),7.22(d,J＝6.3Hz,2H),6.91(d,J＝8.9Hz,1H),6.23(d,J＝4.7Hz,1H),3.17(s,3H),2.78(d,3H).13CNMR(101MHz,DMSO)δ155.34,149.00,138.52,137.79,130.07,128.40,128.09,127.18,126.93,126.42,125.97,123.27,122.74,121.69,120.00,115.90,113.18,110.84,44.61,30.01.MS(ESI-TOF)for C18H16F3N3O3S[M+H]+calculated 412.40,found 412.44.
化合物24
3-(4-(2-羟基-4-(三氟甲基)苯基)-1H-咪唑-1-基)-4-(甲基氨基)苯甲酸甲酯。
灰色固体(64mg,34％).m.p.182.2-183.5℃.1H NMR(400MHz,DMSO)δ11.99(s,1H),8.14–7.98(m,3H),7.94(dd,J＝8.7,1.5Hz,1H),7.68(d,J＝1.8Hz,1H),7.21(d,J＝6.9Hz,2H),6.84(d,J＝8.8Hz,1H),6.12(d,J＝4.8Hz,1H),4.26(d,J＝7.1Hz,1H),3.80(s,2H),2.77(d,3H).13C NMR(101MHz,DMSO)δ166.06,155.36,148.95,137.76,132.25,129.03,126.87,122.68,121.74,119.95,116.16,113.17,110.67,79.59,60.48,51.96,29.95,14.65.MS(ESI-TOF)for C19H16F3N3O3[M+H]+calculated 392.34,found 392.39.
化合物25
3-(4-(2-羟基-4-(三氟甲基)苯基)-1H-咪唑-1-基)-N-甲基-4-(甲基氨基)苯甲酰胺。灰色固体(64mg,34％).m.p.194.9-195.6℃.1H NMR(400MHz,DMSO)δ12.00(s,1H),8.19(d,J＝4.5Hz,1H),8.13–7.97(m,3H),7.88(dd,J＝8.6,1.9Hz,1H),7.70(d,J＝2.0Hz,1H),7.21(d,J＝6.8Hz,2H),6.80(d,J＝8.7Hz,1H),5.78(d,1H),2.75(t,6H).13C NMR(101MHz,DMSO)δ166.00,155.33,147.17,138.34,137.79,130.01,128.26,126.86,125.97,123.27,122.73,121.52,120.09,115.87,113.13,110.50,30.07,26.52.MS(ESI-TOF)forC19H17F3N4O2[M+H]+calculated 391.36,found 391.06.
化合物26
2-(1-(3-氯-2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲基)苯酚。
黄色固体(28.39mg,86％).m.p.130.8-131.9℃.1H NMR(400MHz,DMSO)δ11.53(s,1H),8.31(d,J＝2.7Hz,1H),8.21(d,J＝1.1Hz,1H),8.16–8.06(m,3H),7.21(d,J＝6.4Hz,2H),6.87(d,J＝5.3Hz,1H),2.40(d,3H).13C NMR(101MHz,DMSO)δ155.06,147.76,139.87,137.31,135.04,128.39,128.08,127.21,126.37,125.78,122.93,120.51,120.11,115.95,112.88,30.06.MS(ESI-TOF)for C17H12ClF3N4O3[M+H]+calculated 411.75,found 411.83.
化合物27
4-(1-(3-氯-2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)苄腈。
黄色固体(34.2mg,62％).m.p.210.8-212.6℃.1H NMR(400MHz,DMSO)δ8.31(d,J＝2.5Hz,1H),8.25(s,1H),8.11(s,1H),8.08(d,J＝2.4Hz,1H),8.02(d,J＝8.2Hz,2H),7.85(d,J＝8.2Hz,2H),6.89(s,1H),2.41(s,3H).13C NMR(101MHz,DMSO)δ147.70,141.57,139.64,138.83,135.03,133.09,126.26,125.77,125.39,122.46,120.56,120.08,119.55,109.23,30.20.MS(ESI-TOF)for C17H12ClN5O2[M+H]+calculated 354.76,found 355.23.
化合物28
2-(4-(2-甲氧基-4-(三氟甲基)苯基)-1H-咪唑-1-基)-N-甲基-4-硝基苯胺。
黄色固体(28.6mg,92％).m.p.201.5-202.2℃.1H NMR(400MHz,DMSO)δ8.39(d,J＝8.0Hz,1H),8.23(dd,J＝9.3,2.7Hz,1H),8.01(d,J＝2.7Hz,1H),7.97(d,J＝1.2Hz,1H),7.88(d,J＝1.1Hz,1H),7.40(d,J＝8.2Hz,1H),7.35(s,1H),6.87(d,J＝9.4Hz,1H),6.67(q,J＝4.5Hz,1H),3.99(s,3H),2.82(d,3H).13C NMR(101MHz,DMSO)δ156.00,150.93,138.41,136.21,135.45,128.22,127.96,127.65,127.33,127.11,126.79,126.12,124.43,123.42,122.35,121.53,117.59,110.33,108.13,56.16,30.18.MS(ESI-TOF)forC18H15F3N4O3[M+H]+calculated 393.33,found 393.10.
化合物29
2-(4-(2-乙氧基-4-(三氟甲基)苯基)-1H-咪唑-1-基)-N-甲基-4-硝基苯胺。
黄色固体(95mg,82％).m.p.208.8-209.8℃.1H NMR(400MHz,DMSO)δ8.39(d,J＝8.0Hz,1H),8.23(dd,J＝9.3,2.6Hz,1H),8.00(dd,J＝9.9,1.8Hz,2H),7.81(d,J＝0.8Hz,1H),7.39(d,J＝8.2Hz,1H),7.33(s,1H),6.88(d,J＝9.4Hz,1H),6.68(d,J＝4.8Hz,1H),4.27(q,2H),2.83(d,3H),1.42(t,J＝6.9Hz,3H).13C NMR(101MHz,DMSO)δ155.19,150.77,138.43,136.35,135.54,127.55,127.05,126.78,124.19,121.83,121.54,117.53,110.44,108.86,64.59,30.19,14.88.MS(ESI-TOF)for C19H17F3N4O3[M+H]+calculated 407.36,found 407.65.
化合物30
2-(4-(2-(苄氧基)-4-(三氟甲基)苯基)-1H-咪唑-1-基)-N-甲基-4-硝基苯胺。
黄色固体(159mg,92％).m.p.217.3-218.4℃.1H NMR(400MHz,DMSO)δ8.40(d,J＝8.0Hz,1H),8.21(dd,J＝9.3,2.6Hz,1H),7.99(dd,J＝16.5,2.0Hz,2H),7.77(d,J＝1.1Hz,1H),7.54(d,J＝6.9Hz,2H),7.46(s,1H),7.41(d,J＝8.1Hz,1H),7.39–7.24(m,3H),6.85(d,J＝9.4Hz,1H),6.72(d,J＝4.8Hz,1H),5.39(s,2H),2.82(d,3H).13C NMR(101MHz,DMSO)δ154.90,150.48,138.34,136.92,136.26,135.50,128.85,128.50,128.30,127.53,127.12,126.97,123.84,122.05,121.46,117.91,110.38,109.72,70.53,30.24.MS(ESI-TOF)for C24H19F3N4O3[M+H]+calculated 467.43,found 467.52.
化合物31
2-(4-(2-(2-溴乙氧基)-4-(三氟甲基)苯基)-1H-咪唑-1-基)-N-甲基-4-硝基苯胺。
黄色固体(109mg,90％).m.p.209.3-210.5℃.1H NMR(400MHz,DMSO)δ8.40(d,J＝8.0Hz,1H),8.22(d,J＝9.2Hz,1H),8.07(s,1H),8.03(s,2H),7.49–7.31(m,2H),6.88(d,J＝9.2Hz,1H),6.74(d,J＝3.5Hz,1H),4.58(s,2H),3.98(s,2H),2.83(d,3H).13C NMR(101MHz,DMSO)δ154.55,150.50,138.34,135.99,135.50,128.00,127.59,126.95,126.02,123.88,123.32,122.51,121.56,118.13,110.42,109.20,68.99,32.13,30.22.MS(ESI-TOF)for C19H16BrF3N4O3[M+H]+calculated 486.25,found 486.28.
化合物32
2-(4-(2-(3-溴丙氧基)-4-(三氟甲基)苯基)-1H-咪唑-1-基)-N-甲基-4-
硝基苯胺。
黄色固体(153mg,90％).m.p.213.3-214.8℃.1H NMR(400MHz,DMSO)δ8.39(d,J＝7.8Hz,1H),8.23(d,J＝9.1Hz,1H),8.02(s,2H),7.82(s,1H),7.41(d,J＝13.2Hz,2H),6.87(d,J＝9.2Hz,1H),6.73(s,1H),4.34(s,2H),3.70(d,2H),2.83(d,3H),2.45–2.21(m,2H).13C NMR(101MHz,DMSO)δ154.99,150.76,138.48,136.19,135.57,127.79,127.75,124.13,121.95,121.61,117.92,117.88,110.47,109.05,66.90,40.61,40.41,40.20,39.99,39.78,39.57,39.36,32.09,31.83,30.28.MS(ESI-TOF)for C20H18BrF3N4O3[M+H]+calculated 500.28,found500.99.
化合物33
2-(4-(2-(3-溴丙氧基)-4-(三氟甲基)苯基)-1H-咪唑-1-基)-N-甲基-4-
硝基苯胺。
黄色固体(178mg,92％).m.p.188.1-189.9℃.1H NMR(400MHz,DMSO)δ8.38(d,J＝8.0Hz,1H),8.23(dd,J＝9.3,2.5Hz,1H),8.06–7.92(m,3H),7.46–7.31(m,2H),6.86(d,J＝9.4Hz,1H),6.67(d,J＝4.7Hz,1H),4.39–4.25(m,2H),3.92–3.81(m,2H),3.73(t,2H),3.42(t,2H),2.82(d,3H).13C NMR(101MHz,DMSO)δ155.16,150.95,138.46,136.31,135.53,127.47,127.16,126.14,124.36,123.44,122.53,121.62,117.85,110.44,109.14,70.64,68.94,67.99,32.11,30.26.MS(ESI-TOF)for C21H20BrF3N4O4[M+H]+calculated 530.31,found 530.11.
化合物34
2-(2-(2-(1-(2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲基)苯氧基)
乙氧基)乙醇。
黄色固体(141mg,76％).m.p.172.5-173.6℃.1H NMR(400MHz,DMSO)δ8.37(d,J＝7.9Hz,1H),8.23(dd,J＝9.2,2.2Hz,1H),7.99(t,J＝4.3Hz,3H),7.40(d,J＝10.8Hz,2H),6.87(d,J＝9.3Hz,1H),6.68(d,J＝4.7Hz,1H),4.46(t,1H),4.33(d,2H),3.84(d,2H),3.42(t,2H),3.32(s,2H),2.83(d,3H).13C NMR(101MHz,DMSO)δ155.18,150.69,138.32,136.30,135.50,127.35,124.03,122.49,121.57,117.79,110.38,72.66,69.24,68.08,60.49,30.19.MS(ESI-TOF)for C21H21F3N4O5[M+H]+calculated 465.41,found 466.56.
化合物35
(1-(2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲基)苯基乙酸酯。
黄色固体(178mg,92％).m.p.134.7-136.1℃.1H NMR(400MHz,DMSO)δ8.34(d,J＝8.2Hz,1H),8.23(dd,J＝9.3,2.6Hz,1H),8.03(d,J＝2.7Hz,2H),7.83(s,1H),7.75–7.62(m,2H),6.88(d,J＝9.3Hz,1H),6.73(d,J＝4.7Hz,1H),2.82(d,3H),2.38(s,3H).13C NMR(101MHz,DMSO)δ169.42,150.75,146.94,139.09,135.54,130.99,128.81,127.07,124.32,122.96,121.41,110.43,30.17,21.71.MS(ESI-TOF)for C19H15F3N4O4[M+H]+calculated421.34,found 421.34.
化合物36
2-(1-(2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲基)辛酸苯酯。
黄色固体(105mg,91％).m.p.150.6-152.2℃.1H NMR(400MHz,DMSO)δ8.34(d,J＝8.2Hz,1H),8.23(dd,J＝9.3,2.4Hz,1H),8.05–7.95(m,2H),7.77(s,1H),7.70(d,J＝8.3Hz,1H),7.62(s,1H),6.87(d,J＝9.3Hz,1H),6.74(d,J＝4.7Hz,1H),2.82(d,3H),2.71(t,2H),1.70–1.55(m,2H),1.26(ddd,8H),0.82(t,3H).13C NMR(101MHz,DMSO)δ171.95,150.68,146.97,139.05,135.86,135.52,131.04,128.81,127.85,127.53,127.06,125.60,124.17,122.99,121.38,110.44,34.06,31.41,30.14,28.73,24.40,22.40,14.22.MS(ESI-TOF)for C25H27F3N4O4[M+H]+calculated 505.50,found 505.48.
化合物37
2-(1-(2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲基)十二烷酸苯酯。
黄色固体(154mg,90％).m.p.158.3-159.6℃.1H NMR(400MHz,DMSO)δ8.34(d,J＝8.2Hz,1H),8.21(dd,J＝9.2,2.1Hz,1H),8.05–7.94(m,2H),7.76(s,1H),7.69(d,J＝8.3Hz,1H),7.61(s,1H),6.87(d,J＝9.3Hz,1H),6.75(d,J＝4.6Hz,1H),2.81(d,3H),2.70(t,2H),1.69–1.54(m,2H),1.27–1.12(m,17H),0.84(t,4H).13C NMR(101MHz,DMSO)δ171.91,150.66,146.96,139.02,135.86,135.51,131.02,128.81,127.85,127.53,127.03,125.59,124.13,123.01,121.35,121.31,121.09,110.42,34.05,31.69,30.12,29.37,29.17,29.11,29.04,28.78,24.38,22.49,14.28.MS(ESI-TOF)for C29H35F3N4O4[M+H]+calculated 561.61,found 561.83.
化合物38
2-(1-(2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲基)苯基苯甲酸酯。
黄色固体(186mg,90％).m.p.203.3-204.3℃.1H NMR(400MHz,DMSO)δ8.37(d,J＝8.3Hz,1H),8.22(t,J＝7.9Hz,2H),8.14(d,J＝9.2Hz,1H),8.00(d,J＝9.3Hz,1H),7.89–7.80(m,2H),7.75(dd,J＝18.0,8.6Hz,2H),7.65(d,J＝9.1Hz,1H),7.60(t,J＝7.8Hz,2H),6.77(d,J＝9.3Hz,1H),6.62(s,1H),2.65(d,3H).13C NMR(101MHz,DMSO)δ164.63,150.23,147.06,139.06,135.91,135.46,134.55,131.23,130.37,129.39,129.26,128.99,126.95,123.73,121.15,110.40,30.04.MS(ESI-TOF)for C24H17F3N4O4[M+H]+calculated 483.41,found 483.25.
化合物39
(1-(2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲基)苯基肉桂酸酯。
黄色固体(119mg,85％).m.p.209.3-210.2℃.1H NMR(400MHz,DMSO)δ8.40(d,J＝8.1Hz,1H),8.16(d,J＝9.2Hz,1H),8.03(s,1H),7.98(s,1H),7.93(d,J＝16.0Hz,1H),7.85(s,1H),7.82–7.68(m,4H),7.44(d,J＝6.8Hz,3H),7.07(d,J＝16.0Hz,1H),6.77(d,J＝9.3Hz,1H),6.67(d,J＝4.6Hz,1H),2.67(d,3H).13C NMR(101MHz,DMSO)δ164.92,150.52,147.46,146.88,139.11,135.80,135.50,134.27,131.35,131.15,129.31,129.09,128.82,127.90,127.58,127.01,124.04,123.18,121.52,121.30,117.65,110.38,30.07.MS(ESI-TOF)for C26H19F3N4O4[M+H]+calculated 509.45,found 509.38.
化合物40
(1-(2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲基)苯基硫酸氢盐。
黄色固体(186mg,90％).m.p.173.3-175.6℃.1H NMR(400MHz,DMSO)δ8.36(d,J＝8.2Hz,1H),8.24(dd,J＝9.3,2.6Hz,1H),8.08–7.95(m,2H),7.89(d,J＝20.3Hz,2H),7.49(d,J＝7.8Hz,1H),6.88(d,J＝9.4Hz,1H),6.65(d,J＝4.8Hz,1H),2.83(d,3H).13C NMR(101MHz,DMSO)δ150.73,150.19,138.37,136.28,135.51,129.33,127.44,127.18,124.09,122.23,121.41,119.86,117.08,110.50,30.20.MS(ESI-TOF)for C17H13F3N4O6S[M+H]-calculated 455.37,found 455.30.
化合物41
2-(4-(2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)-4-(三氟甲基)苯基)-1H-咪唑-1-基)-N-甲基-4-硝基苯胺。
黄色固体(81mg,84％).m.p.166.7-168.2℃.1H NMR(400MHz,CDCl3)δ8.33(d,J＝7.0Hz,2H),8.16(d,J＝2.4Hz,1H),7.97(s,1H),7.82(s,1H),7.34(d,J＝7.9Hz,1H),7.17(s,1H),6.81(d,J＝9.3Hz,1H),5.19(s,1H),4.39–4.24(m,2H),4.03–3.88(m,2H),3.72–3.62(m,2H),3.58(t,2H),3.55–3.47(m,2H),3.13(t,2H),3.01(d,3H).13C NMR(101MHz,CDCl3)δ154.82,149.79,136.90,136.53,127.34,127.01,125.43,123.71,121.49,109.50,71.72,70.16,69.48,67.31,30.02,2.66.MS(ESI-TOF)for C23H24F3IN4O5[M+H]+calculated621.36,found 620.81.
化合物42
(2-(1-(2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲基)苯氧基)乙酰胺。黄色固体(52mg,92％).m.p.226.7-228.9℃.1H NMR(400MHz,DMSO)δ8.37(d,J＝8.0Hz,1H),8.24(dd,J＝9.3,2.6Hz,1H),8.19(s,1H),8.05–7.96(m,2H),7.59(s,1H),7.43(d,J＝8.2Hz,1H),7.35(s,1H),7.24(s,1H),6.88(d,J＝9.4Hz,1H),6.68(d,J＝4.7Hz,1H),4.74(s,2H),2.83(d,3H).13C NMR(101MHz,DMSO)δ169.81,154.54,150.78,138.40,136.24,135.52,127.69,127.13,124.20,123.00,121.61,110.44,99.98,67.58,30.26.MS(ESI-TOF)for C19H16F3N5O4[M+H]+calculated 436.36,found 436.57.
化合物43
2-(4-(3-(2-氨基乙氧基)-4-(三氟甲基)苯基)-1H-咪唑-1-基)-N-甲基-4-硝基苯胺。
黄色固体(39mg,80％).m.p.136.9-139.5℃.1H NMR(400MHz,DMSO)δ8.37(d,J＝8.0Hz,1H),8.24(dd,J＝9.3,2.5Hz,1H),8.04(d,J＝2.6Hz,1H),8.01(s,1H),7.96(s,1H),7.49–7.39(m,2H),6.89(d,J＝9.4Hz,1H),6.63(d,J＝4.4Hz,1H),4.37(t,2H),3.28(d,4H),2.83(d,3H).13C NMR NMR(101MHz,DMSO)δ154.97,150.74,138.40,136.16,135.52,127.91,127.76,127.22,127.01,126.03,124.16,123.33,122.28,121.59,118.05,110.44,109.44,68.90,30.21.MS(ESI-TOF)for C19H18F3N5O3[M+H]+calculated 422.37,found422.02.
化合物44
N-(2-(2-(1-(2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲基)苯氧基)
乙基)-5-((3AS，4S，6AR)-2-氧代六氢-1H-噻吩并[3,4-d]咪唑-4-基)戊酰胺。
黄色固体(42.76mg,93％).m.p.118.7-120.5℃.1H NMR(400MHz,CDCl3)δ8.34–8.19(m,2H),8.12(d,J＝2.4Hz,1H),7.74(d,J＝25.4Hz,2H),7.33(d,J＝8.2Hz,1H),7.14(dd,J＝13.3,8.0Hz,2H),6.76(d,J＝9.3Hz,1H),6.31(s,1H),5.28(d,J＝4.3Hz,1H),5.12(s,1H),4.35–4.27(m,1H),4.24(t,2H),4.13–4.04(m,1H),3.75(d,2H),2.98(d,4H),2.78(dd,1H),2.54(d,1H),2.11(t,2H),1.50(d,4H),1.28(d,3H).13C NMR(101MHz,DMSO)δ172.71,163.12,155.07,150.90,138.36,136.06,135.44,127.57,124.42,121.62,117.76,110.33,108.93,79.62,67.67,61.40,59.59,55.82,53.74,42.03,38.31,35.56,31.37,30.22,28.55,25.41,22.47,14.36,12.75.MS(ESI-TOF)for C29H32F3N7O5S[M+H]+calculated648.67,found 647.57.
化合物45
2-(2-(1-(2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲基)苯氧基)5-((3aS，4S，6aR)-2-氧代六氢-1H-噻吩并[3,4-d]咪唑-4-基)戊酸乙酯。
黄色固体(67mg,71％).m.p.79.1-80.5℃.1H NMR(400MHz,CDCl3)δ8.34–8.24(m,2H),8.12(d,J＝2.5Hz,1H),7.78(s,1H),7.71(s,1H),7.35(d,J＝8.0Hz,1H),7.10(s,1H),6.79(d,J＝9.3Hz,1H),5.88(s,1H),5.51(d,1H),5.26(s,1H),4.54(d,2H),4.47–4.37(m,1H),4.30(t,2H),4.24–4.15(m,1H),3.00(t,4H),2.84(dd,1H),2.65(d,1H),2.20(t,2H),2.03(s,2H),1.52–1.42(m,3H),1.28(d,3H).13C NMR(101MHz,CDCl3)δ173.17,154.50,150.05,137.01,136.62,127.45,127.15,123.89,121.58,121.18,118.06,109.65,108.12,66.49,61.96,59.95,55.37,40.42,33.60,29.95,28.13,24.55.MS(ESI-TOF)forC29H31F3N6O6S[M+H]+calculated 649.65,found 649.68.
化合物46
((3aS，4S，6aR)-2-(2-(2-(2-(2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲基)苯氧基)乙氧基)基)-2-氧代六氢-1H-噻吩并[3,4-d]咪唑-4-基)戊酸乙酯。
黄色固体(85mg,63％).m.p.53.2-54.7℃.1H NMR(400MHz,CDCl3)δ8.26(dd,J＝9.2,2.4Hz,1H),8.17(d,J＝7.9Hz,1H),8.10(d,J＝2.5Hz,1H),7.88(s,1H),7.73(s,1H),7.32(d,J＝8.2Hz,1H),7.07(s,1H),6.79(d,J＝9.4Hz,1H),6.08(d,J＝48.6Hz,3H),5.76(s,1H),4.49(t,2H),4.30(s,1H),4.25–4.16(m,3H),4.07(s,2H),3.89(s,2H),3.68–3.60(m,2H),3.10(d,2H),3.01(d,3H),2.86(d,3H),2.17(s,2H),1.66(s,3H),1.53(d,J＝7.0Hz,4H).13C NMR(101MHz,CDCl3)δ173.38,164.72,154.68,150.17,137.18,136.44,127.13,125.47,123.82,121.84,121.23,117.80,109.74,108.16,71.64,68.86,67.12,63.08,62.12,60.32,55.55,40.61,33.57,31.52,30.01,28.37,24.51,22.58,14.05,2.93.MS(ESI-TOF)for C31H35F3N6O7S[M+H]+calculated 693.71,found 693.01.
化合物47
5-(2-(2-(2-(2-(甲基氨基)-5-硝基苯基)-1H-咪唑-4-基)-5-(三氟甲基)苯氧基)乙氧基)乙氧基)乙基5-(3AS，4S，6AR)-2-氧代六氢-1H-噻吩并[3,4-d]咪唑-4-基)戊。
黄色固体(22.6mg,75％).m.p.73.1-74.4℃.1H NMR(400MHz,CDCl3)δ8.30(dd,J＝9.1,2.7Hz,2H),8.15(d,J＝2.6Hz,1H),7.92(d,J＝1.2Hz,1H),7.76(d,J＝0.9Hz,1H),7.36(d,J＝7.5Hz,1H),7.17(s,1H),6.78(d,J＝9.3Hz,1H),5.66(s,1H),5.39(d,1H),5.04(s,1H),4.46(dd,1H),4.34–4.27(m,2H),4.25(dd,1H),4.15–4.06(m,2H),3.98–3.88(m,2H),3.65(dd,2H),3.51(td,4H),3.10(ddd,1H),2.98(t,3H),2.88(d,1H),2.71(d,1H),2.28(t,2H),1.68–1.53(m,4H),1.45–1.30(m,2H).13C NMR(101MHz,CDCl3)δ173.52,163.75,154.76,150.12,137.29,136.60,129.20,127.05,125.59,123.79,122.74,121.74,121.34,117.74,109.47,108.20,70.28,69.36,68.94,67.27,63.07,61.83,60.02,55.48,40.42,33.58,29.87,28.21,24.58.MS(ESI-TOF)for C33H39F3N6O8S[M+H]+calculated737.76,found 738.86.
实施例16化合物22以及其余化合物的TLR1/2激活活性检测
TLR1/2激活活性采用TLR1/2 HEK BLUE细胞进行检测。TLR1/2 HEK BLUE细胞培养于含10％胎牛血清，1％青霉素、链霉素的DMEM培养基中，置于含5％CO2的37℃细胞培养箱中培养。
HEK BLUE TLR1/2细胞以20000个/孔铺于384孔板中，37℃，5％CO2中培养24小时，每孔25μL。待细胞长势良好时，加入100μM浓度的化合物并倍比稀释11个浓度梯度。再于CO2培养箱中放置24小时后在板中每孔避光加入40μL孔定蓝溶液，在620nm吸光度下15分钟为单位读数4次，以检测细胞上清中SEAP的信号强度。
如图1所示，化合物22能显著激活TLR1/2碱性磷酸酶(SEAP)信号强度，在化合物在低浓度(15nM)时，其能显著激活TLR1/2碱性磷酸酶信号强度。其他化合物结果参见表7.
该结果显示该系列化合物具有很好的激活TLR1/2的能力，具有良好的开发潜力。
表7：所有化合物的TLR1/2激活活性检测
表示最高浓度为100μM依然没有激活效果。
最高SEAP信号数值小于化合物22的激活数值的50％。
NA：没有激活。

Claims (11)

1.一种化合物或其药学上可接受的盐，所述化合物具有式I所示的结构；
其中R1选自H、OH、OCH3、OCH2CH3、OCH2C6H5、O(CH2)2Br、O(CH2)3Br、O(CH2)2O(CH2)2Br、O(CH2)2O(CH2)2OH、OCOCH3、OCO(CH2)6CH3、OCO(CH2)10CH3、OCOC6H5、OCOCH＝CHC6H5、OSO3H、O(CH2)2O(CH2)2O(CH)2I、OCH2CONH2、O(CH2)2NH2、O(CH2)2NH-Biotin、O(CH2)2O-Biotin、O(CH2)2O(CH2)2O-Biotin中任意一个，R2选自H、NO2、CH3、CF3、SO2CH3、COOCH3、CONHCH3、中任意一个，R3选自H、NO2、OCH3、CF3中任意一个，R4选自H、CF3、Cl，R5选自H、Cl、CF3、NHCH3中任意一个，R6选自H、OCF3、CF3、CN中任意一个；V为C或N中任意一个，W选自CH或N中任意一个，X为C，Y为CH或N中任意一个，Z为CH或S中任意一个。
2.根据权利要求1所述的化合物或其药学上可接受的盐，其中，式I化合物选自式I-1或I-2的结构，
所述的R1-R6取代基与权利要求1相同。
3.根据权利要求1所述的化合物或其药学上可接受的盐，所述化合物具有如下结构式
4.权利要求2中所述化合物I-1的制备方法，包括下述步骤：
1)将化合物A1在甲机锂催化条件下，反应得到化合物A2
2)将化合物A2在四丁基三溴化铵作用下，反应得到化合物A3
3)将化合物A3与化合物A4反应得到式I-1所示的化合物；
其中，R1选自H、OH、OCH3、OCH2CH3、OCH2C6H5、O(CH2)2Br、O(CH2)3Br、O(CH2)2O(CH2)2Br、O(CH2)2O(CH2)2OH、OCOCH3、OCO(CH2)6CH3、OCO(CH2)10CH3、OCOC6H5、OCOCH＝CHC6H5、OSO3H、O(CH2)2O(CH2)2O(CH)2I、OCH2CONH2、O(CH2)2NH2、O(CH2)2NH-Biotin、O(CH2)2O-Biotin、O(CH2)2O(CH2)2O-Biotin中任意一个，R2选自H、NO2、CH3、CF3、SO2CH3、COOCH3、CONHCH3、-N+O-O-中任意一个，R3选自H、NO2、OCH3、CF3中任意一个，R4选自H、CF3、Cl，R5选自H、Cl、CF3、NHCH3中任意一个，R6选自H、OCF3、CF3、CN中任意一个。
5.权利要求3中所述化合物1-20的制备方法，包括下述步骤：
1)将化合物A1在甲机锂催化条件下，反应得到化合物A2
2)将化合物A2在四丁基三溴化铵作用下，反应得到化合物A3
3)将化合物A3与化合物A4反应得到化合物1-20；
其中，制备各化合物的中间体化合物A1，A2，A3，A4及其相应产物化合物1-20中的R1-R6
如下所示：
1:R1＝R3＝R4＝H,R2＝NO2,R5＝Cl,R6＝CF3；
2:R1＝R3＝R4＝H,R2＝NO2,R5＝NHCH3,R6＝CF3；
3:R1＝R2＝R3＝R4＝R5＝H,R6＝CF3；
4:R1＝R3＝R4＝R5＝H,R2＝CF3,R6＝CF3；
5:R1＝R2＝R4＝R5＝H,R3＝CF3,R6＝CF3；
6:R1＝R2＝R3＝R4＝H,R5＝CF3,R6＝CF3；
7:R1＝R3＝R5＝H,R2＝R4＝CF3,R6＝CF3；
8:R1＝R2＝R4＝R5＝H,R3＝OCH3,R6＝CF3；
9:R1＝R2＝R4＝R5＝H,R3＝NO2,R6＝CF3；
10:R1＝R3＝R4＝R5＝H,R2＝CH3,R6＝CF3；
11:R1＝OH,R2＝NO2,R3＝R4＝H,R5＝Cl,R6＝CF3；
12:R1＝OH,R2＝NO2,R3＝R4＝H,R5＝NHCH3,R6＝CF3；
13:R1＝OH,R2＝R3＝R4＝R5＝H,R6＝CF3；
14:R1＝OH,R2＝CF3,R3＝R4＝R5＝H,R6＝CF3；
15:R1＝OH,R2＝R4＝R5＝H,R3＝CF3,R6＝CF3；
16:R1＝OH,R2＝R3＝R4＝H,R5＝CF3,R6＝CF3；
17:R1＝OH,R2＝R4＝CF3,R3＝R5＝H,R6＝CF3；
18:R1＝OH,R2＝R4＝R5＝H,R3＝OCH3,R6＝CF3；
19:R1＝OH,R2＝R4＝R5＝H,R3＝NO2,R6＝CF3；
20:R1＝OH,R2＝CH3,R3＝R4＝R5＝H,R6＝CF3。
6.权利要求2中所述化合物I-2的制备方法，包括下述步骤：
1)将化合物A1在甲机锂催化条件下，反应得到化合物A2将化合物A2在四丁基三溴化铵作用下，反应得到化合物A3
2)将化合物B1在甲胺中反应生成氨基取代的化合物B2还原化合物B2得到化合物B3
或者将化合物B5氨甲基化得到化合物B3；
3)将化合物B3和原甲酸三乙酯反应成环，得到化合物B4
4)将化合物B4和化合物A3反应得到化合物B6
5)将化合物B6在酸性条件下回流，得到式I-2所示化合物；
可选地，将步骤5)所得产物在氯化亚砜条件下进行氯取代，得到式I-2所示化合物26、27；
在I-2中，R1选自H、OH、OCH3、OCH2CH3、OCH2C6H5、O(CH2)2Br、O(CH2)3Br、O(CH2)2O(CH2)2Br、O(CH2)2O(CH2)2OH、OCOCH3、OCO(CH2)6CH3、OCO(CH2)10CH3、OCOC6H5、OCOCH＝CHC6H5、OSO3H、O(CH2)2O(CH2)2O(CH)2I、OCH2CONH2、O(CH2)2NH2、O(CH2)2NH-Biotin、O(CH2)2O-Biotin、O(CH2)2O(CH2)2O-Biotin中任意一个，R2选自H、NO2、CH3、CF3、SO2CH3、COOCH3、CONHCH3、-N+O-O-中任意一个，R6选自H、OCF3、CF3、CN中任意一个；
优选地，制备各化合物的中间体化合物A3，B1，B2，B3，B4，B5及其相应产物化合物21-27中的R1，R2和R6如下所示：
21:R1＝OH,R6＝OCF3,R2＝NO2；
22:R1＝OH,R6＝CF3,R2＝NO2；
23:R1＝OH,R6＝CF3,R2＝SO2CH3；
24:R1＝OH,R6＝CF3,R2＝COOCH3；
25:R1＝OH,R6＝CF3,R2＝CONHCH3；
26:R1＝OH,R6＝CF3,R2＝NO2
27:R1＝H,R6＝CN,R2＝NO2。
7.权利要求6中所述化合物I-2的制备方法，包括下述步骤：
1)制备化合物22
2)将化合物22与R7X反应获得化合物
所述R7选自CH3、CH3CH2、C6H5CH2、C2H4Br、C3H6Br、(CH2)2O(CH2)2Br、(CH2)2O(CH2)2OH、COCH3、C7H15CO、C11H23CO、C6H5CO、C6H5CH＝CHCO、SO3H、(CH2)2O(CH2)2O(CH2)2I、NH2COCH；
所述X为卤素(优选为Cl,Br,I)。
8.权利要求6中所述化合物I-2的制备方法，包括下述步骤：
1)制备化合物22将化合物22与1,2-二溴乙烷反应获得化合物31
2)将化合物31与NH3.H2O以及KI反应制备得到化合物43
可选地，将化合物43与化合物反应得到化合物44，
或者
2)将化合物31与生物素反应，得到化合物45，46或47
或者
2)将生物素与I(CH2)2O(CH2)2O(CH2)2I或I(CH2)2O(CH2)2I反应，得到再与化合物22反应得到化合物45，46或47；
其中,R8为(CH2)2O(CH2)2O(CH2)2I或(CH2)2O(CH2)2I；
(i)28:CH3I,丙酮,K2CO3,室温12h；29:CH3CH2I,丙酮,K2CO3,室温,12h；30:C6H5CH2Br,丙酮,K2CO3,室温12h；31:1,2-二溴乙烷,丙酮,K2CO3,室温12h；32:1,3-二溴乙烷,丙酮,K2CO3,室温,12h；33:Br(CH2)2O(CH2)2Br,丙酮,K2CO3,室温,12h；34:Cl(CH2)2O(CH2)2OH,丙酮,K2CO3,室温,12h；35:CH3COCl,Et3N,DCM,0℃,1h；36:C7H15COCl,Et3N,DCM,0℃,1h；37:C11H23COCl,Et3N,DCM,0℃,1h；38:C6H5COCl,Et3N,DCM,0℃,1h；39:C6H5CH＝CHCOCl,Et3N,DCM,0℃,1h；40:SO3/吡啶,Et3N,THF,室温,6h；41:I(CH2)2O(CH2)2O(CH2)2I,丙酮,K2CO3,室温,12h；42:NH2COCH2Cl,2-丁酮,KI,室温12h；(ii)31,NH3.H2O,KI,THF,12h；(iii)HATU,DIPEA,室温,12h.(iv)NaH,KI,DMSO,室温,12h；(v)NaH,DMSO,室温,12h；(vi)K2CO3,acetone,室温,12h。
9.一种药物组合物，其包括权利要求1-3任一项所述的化合物或其药学上可接受的盐，其还包括药学上可接受的载体或辅料。
10.根据权利要求1-3任一项所述的化合物在制备抗炎佐剂、TLR1或TLR2的激动剂、抗肿瘤的药物中的应用。
11.一种在体外、体内调节TLR1和2碱性磷酸酶活性激活水平的方法，其包括给予受试者权利要求1-3任一项所述的化合物。
CN201880004441.5A 2018-04-09 2018-04-09 1,4-二苯基-1h-咪唑和2，4-二苯基噻唑类衍生物及其制备方法和用途 Active CN110049973B (zh)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2018/082243 WO2019195972A1 (zh) 2018-04-09 2018-04-09 1,4-二苯基-1h-咪唑和2，4-二苯基噻唑类衍生物及其制备方法和用途

Publications (2)

Publication Number Publication Date
CN110049973A true CN110049973A (zh) 2019-07-23
CN110049973B CN110049973B (zh) 2023-02-17

Family

ID=67273982

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201880004441.5A Active CN110049973B (zh) 2018-04-09 2018-04-09 1,4-二苯基-1h-咪唑和2，4-二苯基噻唑类衍生物及其制备方法和用途

Country Status (3)

Country Link
US (1) US11472815B2 (zh)
CN (1) CN110049973B (zh)
WO (1) WO2019195972A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111909110A (zh) * 2020-08-31 2020-11-10 浙江工业大学 一种2,4-二取代噻唑类化合物的制备方法
WO2021126281A1 (en) * 2019-12-20 2021-06-24 Nammi Therapeutics, Inc. Formulated and/or co-formulated liposome compositions containing toll-like receptor ("tlr") agonist prodrugs useful in the treatment of cancer and methods thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120129811A1 (en) * 2010-11-18 2012-05-24 Aihua Wang Tricyclic inhibitors of pro-matrix metalloproteinase activation
WO2015171951A1 (en) * 2014-05-07 2015-11-12 The Regents Of The University Of Colorado, A Body Corporate 2-(4-aryl-1h-imidazol-1-yl)aniline compounds
JP2018135270A (ja) * 2017-02-20 2018-08-30 大日本住友製薬株式会社 イミダゾール誘導体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120129811A1 (en) * 2010-11-18 2012-05-24 Aihua Wang Tricyclic inhibitors of pro-matrix metalloproteinase activation
WO2015171951A1 (en) * 2014-05-07 2015-11-12 The Regents Of The University Of Colorado, A Body Corporate 2-(4-aryl-1h-imidazol-1-yl)aniline compounds
JP2018135270A (ja) * 2017-02-20 2018-08-30 大日本住友製薬株式会社 イミダゾール誘導体

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
NORIHIRO IKEMOTO ET AL.,: "Practical routes to the triarylsulfonyl chloride intermediate of a β3 adrenergic receptor agonist", 《TETRAHEDRON》 *
REGISTRY: "化合物RN 1387473-42-8等", 《STNEXT》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021126281A1 (en) * 2019-12-20 2021-06-24 Nammi Therapeutics, Inc. Formulated and/or co-formulated liposome compositions containing toll-like receptor ("tlr") agonist prodrugs useful in the treatment of cancer and methods thereof
CN114901275A (zh) * 2019-12-20 2022-08-12 纳米医疗有限公司 可用于治疗癌症的含有Toll样受体(“TLR”)激动剂前药的配制和/或共同配制的脂质体组合物及其方法
CN111909110A (zh) * 2020-08-31 2020-11-10 浙江工业大学 一种2,4-二取代噻唑类化合物的制备方法

Also Published As

Publication number Publication date
CN110049973B (zh) 2023-02-17
US20210017189A1 (en) 2021-01-21
US11472815B2 (en) 2022-10-18
WO2019195972A1 (zh) 2019-10-17

Similar Documents

Publication Publication Date Title
Dharavath et al. Microwave-assisted synthesis, biological evaluation and molecular docking studies of new coumarin-based 1, 2, 3-triazoles
JP4338217B2 (ja) 置換可能な８―シアノ―１―シクロプロピル―７―（２，８―ジアザビシクロ―［４．３．０］―ノナン―８―イル）―６―フルオロ―１，４―ジヒドロ―４―オキソ―３―キノリンカルボン酸およびそれらの誘導体
TWI518084B (zh) 哌喃酮與吡啶酮衍生物之製造方法
CN104010501B (zh) 含src同源区2蛋白酪胺酸磷酸酶-1增效剂及其治疗方法
WO2021037179A1 (zh) Sting通路调节剂及其用途
CN110049973A (zh) 1,4-二苯基-1h-咪唑和2，4-二苯基噻唑类衍生物及其制备方法和用途
EA032434B1 (ru) Применение изохинолонов для получения лекарственных средств, изохинолоны и способ их синтеза
Rohini et al. Synthesis and antimicrobial activities of a new class of 6-arylbenzimidazo [1, 2-c] quinazolines
CN110105279A (zh) 一种喹啉类stat3特异性抑制剂及其制备方法和应用
Kajfez et al. 1-Substitution in 2-methyl-4 (5)-nitroimidazole. I. Synthesis of compounds with potential antitrichomonal activity
WO2015171951A1 (en) 2-(4-aryl-1h-imidazol-1-yl)aniline compounds
CN109369623B (zh) 一种取代1,2,3三氮唑类二芳基嘧啶衍生物及其制备方法与应用
EP3475260A1 (en) Compounds for use as an anti-bacterial or anti-fungal agent and as a zinc sensor
CN105777610A (zh) 一种制备4-氯-2-(三氟乙酰基)苯胺盐酸盐水合物的方法
CN112679409B (zh) 一种4-吲哚-取代硫半脲衍生物及其制备方法和应用
CN111675694B (zh) 一种含肟基团的二芳基嘧啶类hiv-1逆转录酶抑制剂及其制备方法与应用
CN111057004B (zh) 一种n-邻取代苯基苯甲酰胺-4-甲氨基吖啶类化合物及其制备方法和用途
CN108947961B (zh) 吲唑类衍生物及其制备方法和用途
CN113164482A (zh) 显示抗胞内作用毒素、胞内病毒和细菌的保护活性的新二氢喹唑啉酮
CN113501826A (zh) 作为tdp2的抑制剂的呋喃并喹啉二酮
CN112624972A (zh) 吖啶酮类化合物及医药用途
Khalifa et al. Biological evaluation of newly synthesized quinazolinyl-chalcone derivatives
Dharshan et al. Synthesis, characterization, antimicrobial, antioxidant and larvicidal activities of novel [1-(5, 7-Dichloro-1, 3-Benzoxazol-2-YL)-3-Substituted Phenyl-1H-Pyrazol-4-L][Methylene] aniline derivatives
WO2024138292A1 (zh) 一种新型具有抗菌和抗癌功能的苯基喹诺酮类化合物及其制备
US12024508B2 (en) Dihydroquinazolinones exhibiting protective activity against intracellular-acting toxins, intracellular viruses and bacteria

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
CB03 Change of inventor or designer information
CB03 Change of inventor or designer information

Inventor after: Cheng Kui

Inventor after: Liu Shuwen

Inventor after: Zhu Gengzhen

Inventor before: Cheng Kui

Inventor before: Zhu Gengzhen

GR01 Patent grant
GR01 Patent grant