WO2019195972A1 - 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

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WO2019195972A1
WO2019195972A1 PCT/CN2018/082243 CN2018082243W WO2019195972A1 WO 2019195972 A1 WO2019195972 A1 WO 2019195972A1 CN 2018082243 W CN2018082243 W CN 2018082243W WO 2019195972 A1 WO2019195972 A1 WO 2019195972A1
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compound
och
room temperature
preparation
biotin
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程魁
朱耿桢
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南方医科大学
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Priority to US17/043,646 priority patent/US11472815B2/en
Priority to CN201880004441.5A priority patent/CN110049973B/zh
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  • the invention relates to the fields of medicine hygiene and chemical industry, and particularly relates to a series of compounds of TLR1/2 agonists, which can be used in the fields of scientific research, medical treatment and chemical industry.
  • the immune system is an important system for the body to perform immune responses and immune functions. It consists of immune organs, immune cells and immune molecules. The function of the immune system is to identify and exclude antigenic foreign bodies to maintain environmental stability and physiological balance in the body. Autoimmune diseases are mainly caused by the accumulation of a large number of immune cells and immunoglobulins produced by excessive immune responses.
  • pattern recognition receptors are a class of predominantly expressed on innate immune cell surface, non-clonal distribution, recognizing one or more pathogen-associated molecular patterns (PAMP) or host-derived risk-related molecular patterns (DAMP) and Activating immune cells that mediate recognition molecules of innate immunity.
  • PAMP pathogen-associated molecular patterns
  • DAMP host-derived risk-related molecular patterns
  • Toll-like receptors TLRs
  • RLRs retinoic acid-induced gene I-like receptors
  • NLRs NOD-like receptors
  • CLRs C-type lectin receptors
  • TLR3 recognizes double-stranded RNA
  • TLR4 recognizes lipopolysaccharide
  • TLR5 recognizes bacterial flagellin
  • TLR7 and 8 recognizes viral or bacterial single-stranded RNA
  • TLR9 recognizes cytosine-guanosine monophosphate (CpG).
  • TLR modulators have agonists and inhibitors for the treatment of immune inflammation.
  • TLR2 is the most widely recognized pathogen spectrum, including Gram-positive bacteria such as Staphylococcus, Streptococcus pneumoniae, Mycoplasma, Yeast, and Escherichia coli, which primarily mediate signals of lipoproteins infected by Gram-positive bacteria.
  • Transduction which increases the expression of IL-1 and IL-12-associated protein kinases, tumor necrosis factor-related factors and other signal transduction molecules, and further promotes the synthesis and release of IL-1 and 12 and other effector factors, triggers inflammatory response, induces The expression of genes such as cell proliferation and apoptosis, which mediates the natural immune defense of the body.
  • the regulation of TLR1 and 2 activity is both a goal of clinical treatment and a very meaningful research topic.
  • One aspect of the invention provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula I;
  • any one of NHCH 3 , R 6 is selected from any one of H, OCF 3 , CF 3 , CN; V is any one of C or N, W is selected from any one of CH or N, and X is C, Y is Any one of CH or N, Z is any one of CH or S.
  • the compound of formula I is selected from the structure of formula I-1 or I-2,
  • the compound has the following structural formula
  • the present invention provides a process for the preparation of a compound of the formula I-1, wherein the process for the preparation of the compound of the formula I-1 comprises the steps of:
  • the preparation method of the compound 1-20 comprises the following steps:
  • R 1 OH
  • R 3 CF 3
  • R 6 CF 3 ;
  • R 1 OH
  • R 3 OCH 3
  • R 6 CF 3 ;
  • R 1 OH
  • R 3 NO 2
  • R 6 CF 3 ;
  • R 1 OH
  • R 2 CH 3
  • R 6 CF 3 .
  • Another aspect of the invention provides a process for the preparation of a compound of formula 1-2, comprising the steps of:
  • step 5 the product obtained in step 5 is subjected to chlorine substitution under thionyl chloride conditions to give the compound of formula I-2.
  • the intermediate compounds A3, B1, B2, B3, B4, B5 of the respective compounds and R 1 , R 2 and R 6 in the corresponding product compounds 21-27 are as follows:
  • Another aspect of the invention provides a process for the preparation of a compound of formula 1-2, comprising the steps of:
  • the X is a halogen (preferably Cl, Br, I).
  • the preparation method of the compound 1-2 includes the following steps:
  • R 8 is (CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 I or (CH 2 ) 2 O(CH 2 ) 2 I.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, which further comprises a pharmaceutically acceptable carrier or adjuvant.
  • Another aspect of the invention provides the use of a compound as described above for the preparation of an anti-inflammatory adjuvant, an agonist of TLR1 or TLR2, an anti-tumor drug.
  • a further aspect of the invention provides a method of modulating the level of activation of TLR1 and 2 alkaline phosphatase activity in vitro, in vivo, comprising administering to a subject a compound of formula I.
  • the present invention provides the use of a compound of formula I for TLR 1, 2 and the like.
  • the compounds 1-47 of the present invention can be structurally modified to obtain more active compounds and are useful for the treatment of TLR1, 2 related diseases.
  • a specific technical solution of the present invention provides a method for preparing a compound, which comprises the following steps:
  • the substituted aniline is dissolved in DMF, and a solution of triethyl orthoformate is added to form a precipitate under concentrated HCl, followed by filtration to obtain a substituted imidazole and recrystallization under an ice bath in methanol.
  • Some of the compounds shown above activate the TLR1/2 receptor in a dose-dependent manner.
  • the compound 22 of the present invention can be used to prepare TLR1, 2 related adjuvants, drugs and the like.
  • the compound can be prepared into an injection, a tablet, a powder, a granule, or a capsule in combination with a conventional pharmaceutical preparation, thereby adopting a convenient administration form, wherein the compound of the present invention has a mass percentage of 1 in the drug. ⁇ 20%.
  • the above various dosage forms of the drug can be prepared according to a conventional method in the pharmaceutical field.
  • Compound 22 of Figure 1 exhibits a concentration-dependent activation of TLR1/2 activity.
  • Compound 3-20 was prepared in Example 3, respectively.
  • the preparation procedure of Compound 3-20 was the same as in the preparation of Compound 1, except that the materials used were different. The differences are shown in Table 1 below:
  • N1-Methyl-4-nitrobenzene-1,2-diamine (251 mg, 1.5 mmol) was dissolved in DMF (4 mL) EtOAc (EtOAc) A pale yellow precipitate formed under the conditions of 5 mmol), which was filtered to give 1-methyl-5-nitro-1H-benzo[d]imidazole (90 mg, 33.7%) and recrystallized from methanol ice bath.
  • Biotin (34.8 mg, 0.14 mmol) was dissolved in DMF (4 mL), then HATU (80.94 mg, 0.213 mmol) and DIPEA (2 mL) was added and stirred for 30 min, then 2-(4-(3-(2) -Aminoethoxy)-4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)-N-methyl-4-nitroaniline (30 mg, 0.071 mmol). The reaction was progressed overnight at 45 ° C with a thin layer of plate.
  • TLR1/2 activation activity was detected using TLR1/2HEK BLUE cells.
  • TLR1/2HEK BLUE cells were cultured in DMEM medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and cultured in a 37 ° C cell culture incubator containing 5% CO 2 .
  • HEK BLUE TLR1/2 cells were plated at 20,000 cells/well in 384-well plates and incubated at 37 ° C, 5% CO 2 for 24 hours at 25 ⁇ L per well.
  • a compound at a concentration of 100 ⁇ M was added and diluted 11 concentration gradients.
  • 40 ⁇ L of the well blue solution was added to each well in the plate in the dark, and the unit reading was performed 4 times at 620 nm absorbance for 15 minutes to detect the signal intensity of SEAP in the cell supernatant.
  • Compound 22 significantly activated the TLR1/2 alkaline phosphatase (SEAP) signal intensity, which significantly activated the TLR1/2 alkaline phosphatase signal intensity at low concentrations (15 nM). See Table 7 for the results of other compounds.
  • SEAP TLR1/2 alkaline phosphatase
  • the highest SEAP signal value is less than 50% of the activation value of Compound 22.

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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。其结构如式（I）所示其中R 1 为H、OH、OCH 3 等中任意一个，R 2 为H、NO 2、CH 3、CF 3、SO 2CH 3、COOCH 3、CONHCH 3 中任意一个，R 3为H、NO 2、OCH 3、CF 3 中任意一个，R 4 选自H、CF 3、Cl，R 5为H、Cl、CF 3、NHCH 3 中任意一个，R 6 OCF 3、CF 3、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；
Figure PCTCN2018082243-appb-000001
其中R 1选自H、OH、OCH 3、OCH 2CH 3、OCH 2C 6H 5、O(CH 2) 2Br、O(CH 2) 3Br、O(CH 2) 2O(CH 2) 2Br、O(CH 2) 2O(CH 2) 2OH、OCOCH 3、OCO(CH 2) 6CH 3、OCO(CH 2) 10CH 3、OCOC 6H 5、OCOCH＝CHC 6H 5、OSO 3H、O(CH 2) 2O(CH 2) 2O(CH) 2I、OCH 2CONH 2、O(CH 2) 2NH 2、O(CH 2) 2NH-Biotin、O(CH 2) 2O-Biotin、O(CH 2) 2O(CH 2) 2O-Biotin中任意一个，R 2选自H、NO 2、CH 3、CF 3、SO 2CH 3、COOCH 3、CONHCH 3、-N +O-O -中任意一个，R 3选自H、NO 2、OCH 3、CF 3中任意一个，R 4选自H、CF 3、Cl，R 5选自H、Cl、CF 3、NHCH 3中任意一个，R 6选自H、OCF 3、CF 3、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，
Figure PCTCN2018082243-appb-000002
其中R 1-R 6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
Figure PCTCN2018082243-appb-000003
Figure PCTCN2018082243-appb-000004
Figure PCTCN2018082243-appb-000005
Figure PCTCN2018082243-appb-000006
Figure PCTCN2018082243-appb-000007
Figure PCTCN2018082243-appb-000008
Figure PCTCN2018082243-appb-000009
Figure PCTCN2018082243-appb-000010
Figure PCTCN2018082243-appb-000011
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
Figure PCTCN2018082243-appb-000012
在甲机锂催化条件下，反应得到化合物A2
Figure PCTCN2018082243-appb-000013
2)将化合物A2
Figure PCTCN2018082243-appb-000014
在四丁基三溴化铵作用下，反应得到化合物A3
Figure PCTCN2018082243-appb-000015
3)将化合物A3
Figure PCTCN2018082243-appb-000016
与化合物A4
Figure PCTCN2018082243-appb-000017
反应得到式I-1所示的化合物；
其中，R 1选自H、OH、OCH 3、OCH 2CH 3、OCH 2C 6H 5、O(CH 2) 2Br、O(CH 2) 3Br、O(CH 2) 2O(CH 2) 2Br、O(CH 2) 2O(CH 2) 2OH、OCOCH 3、OCO(CH 2) 6CH 3、OCO(CH 2) 10CH 3、OCOC 6H 5、OCOCH＝CHC 6H 5、OSO 3H、O(CH 2) 2O(CH 2) 2O(CH) 2I、OCH 2CONH 2、O(CH 2) 2NH 2、O(CH 2) 2NH-Biotin、O(CH 2) 2O-Biotin、O(CH 2) 2O(CH 2) 2O-Biotin中任意一个，R 2选自H、NO 2、CH 3、CF 3、SO 2CH 3、COOCH 3、CONHCH 3、-N +O-O -中任意一个，R 3选自H、NO 2、OCH 3、CF 3中任意一个，R 4选自H、CF 3、Cl，R 5选自H、Cl、CF 3、NHCH 3中任意一个，R 6选自H、OCF 3、CF 3、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。
Figure PCTCN2018082243-appb-000018
所述化合物1-20的制备方法，包括下述步骤：
1)将化合物A1
Figure PCTCN2018082243-appb-000019
在有机锂催化条件下，反应得到化合物A2
Figure PCTCN2018082243-appb-000020
2)将化合物A2
Figure PCTCN2018082243-appb-000021
在四丁基三溴化铵作用下，反应得到化合物A3
Figure PCTCN2018082243-appb-000022
3)将化合物A3
Figure PCTCN2018082243-appb-000023
与化合物A4
Figure PCTCN2018082243-appb-000024
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R 1-R 6 如下所示：
1:R 1＝R 3＝R 4＝H,R 2＝NO 2,R 5＝Cl,R 6＝CF 3；
2:R 1＝R 3＝R 4＝H,R 2＝NO 2,R 5＝NHCH 3,R 6＝CF 3；
3:R 1＝R 2＝R 3＝R 4＝R 5＝H,R 6＝CF 3；
4:R 1＝R 3＝R 4＝R 5＝H,R 2＝CF 3,R 6＝CF 3；
5:R 1＝R 2＝R 4＝R 5＝H,R 3＝CF 3,R 6＝CF 3；
6:R 1＝R 2＝R 3＝R 4＝H,R 5＝CF 3,R 6＝CF 3；
7:R 1＝R 3＝R 5＝H,R 2＝R 4＝CF 3,R 6＝CF 3；
8:R 1＝R 2＝R 4＝R 5＝H,R 3＝OCH 3,R 6＝CF 3；
9:R 1＝R 2＝R 4＝R 5＝H,R 3＝NO 2,R 6＝CF 3；
10:R 1＝R 3＝R 4＝R 5＝H,R 2＝CH 3,R 6＝CF 3；
11:R 1＝OH,R 2＝NO 2,R 3＝R 4＝H,R 5＝Cl,R 6＝CF 3；
12:R 1＝OH,R 2＝NO 2,R 3＝R 4＝H,R 5＝NHCH 3,R 6＝CF 3；
13:R 1＝OH,R 2＝R 3＝R 4＝R 5＝H,R 6＝CF 3；
14:R 1＝OH,R 2＝CF 3,R 3＝R 4＝R 5＝H,R 6＝CF 3；
15:R 1＝OH,R 2＝R 4＝R 5＝H,R 3＝CF 3,R 6＝CF 3；
16:R 1＝OH,R 2＝R 3＝R 4＝H,R 5＝CF 3,R 6＝CF 3；
17:R 1＝OH,R 2＝R 4＝CF 3,R 3＝R 5＝H,R 6＝CF 3；
18:R 1＝OH,R 2＝R 4＝R 5＝H,R 3＝OCH 3,R 6＝CF 3；
19:R 1＝OH,R 2＝R 4＝R 5＝H,R 3＝NO 2,R 6＝CF 3；
20:R 1＝OH,R 2＝CH 3,R 3＝R 4＝R 5＝H,R 6＝CF 3。
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
Figure PCTCN2018082243-appb-000025
在甲机锂催化条件下，反应得到化合物A2
Figure PCTCN2018082243-appb-000026
将化合物A2
Figure PCTCN2018082243-appb-000027
在四丁基三溴化铵作用下，反应得到化合物A3
Figure PCTCN2018082243-appb-000028
2)将化合物B1
Figure PCTCN2018082243-appb-000029
在甲胺中反应生成氨基取代的化合物B2
Figure PCTCN2018082243-appb-000030
还原化合物B2得到化合物B3
Figure PCTCN2018082243-appb-000031
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
Figure PCTCN2018082243-appb-000032
4)将化合物B4和化合物A3反应得到化合物B6
Figure PCTCN2018082243-appb-000033
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，R 1选自H、OH、OCH 3、OCH 2CH 3、OCH 2C 6H 5、O(CH 2) 2Br、O(CH 2) 3Br、O(CH 2) 2O(CH 2) 2Br、O(CH 2) 2O(CH 2) 2OH、OCOCH 3、OCO(CH 2) 6CH 3、OCO(CH 2) 10CH 3、OCOC 6H 5、OCOCH＝CHC 6H 5、OSO 3H、O(CH 2) 2O(CH 2) 2O(CH) 2I、OCH 2CONH 2、O(CH 2) 2NH 2、O(CH 2) 2NH-Biotin、O(CH 2) 2O-Biotin、O(CH 2) 2O(CH 2) 2O-Biotin中任意一个，R 2选自H、NO 2、CH 3、CF 3、SO 2CH 3、COOCH 3、CONHCH 3、-N +O-O -中任意一个，R 6选自H、OCF 3、CF 3、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R 1，R 2和R 6如下所示：
21:R 1＝OH,R 6＝OCF 3,R 2＝NO 2；
22:R 1＝OH,R6＝CF 3,R 2＝NO 2；
23:R 1＝OH,R 6＝CF 3,R 2＝SO 2CH 3；
24:R 1＝OH,R 6＝CF 3,R 2＝COOCH 3；
25:R 1＝OH,R 6＝CF 3,R 2＝CONHCH 3；
26:R 1＝OH,R 6＝CF 3,R 2＝NO 2；
27:R 1＝H,R 6＝CN,R 2＝NO 2。
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
Figure PCTCN2018082243-appb-000034
2)将化合物22与R 7X反应获得化合物
Figure PCTCN2018082243-appb-000035
所述R 7选自R 7＝CH 3、CH 3CH 2、C 6H 5CH 2、C 2H 4Br、C 3H 6Br、(CH 2) 2O(CH 2) 2Br、(CH 2) 2O(CH 2) 2OH、COCH 3、C 7H 15CO、C 11H 23CO、C 6H 5CO、C 6H 5CH＝CHCO、SO 3H、(CH 2) 2O(CH 2) 2O(CH 2) 2I、NH 2COCH；
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
Figure PCTCN2018082243-appb-000036
将化合物22与1,2-二溴乙烷反应获得化合物 31
Figure PCTCN2018082243-appb-000037
2)将化合物31与NH 3.H 2O以及KI反应制备得到化合物43
Figure PCTCN2018082243-appb-000038
可选地，将化合物43与化合物
Figure PCTCN2018082243-appb-000039
反应得到化合物44，
Figure PCTCN2018082243-appb-000040
或者
2)将化合物31与生物素
Figure PCTCN2018082243-appb-000041
反应，得到化合物45，46或47
Figure PCTCN2018082243-appb-000042
或者
2)将生物素与I(CH 2) 2O(CH 2) 2O(CH 2) 2I或I(CH 2) 2O(CH 2) 2I反应，得到
Figure PCTCN2018082243-appb-000043
再与化合物22反应得到化合物45，46或47；
其中,R 8为(CH 2) 2O(CH 2) 2O(CH 2) 2I或(CH 2) 2O(CH 2) 2I。
Figure PCTCN2018082243-appb-000044
(i)28:CH 3I,丙酮,K 2CO 3,室温12h；29:CH 3CH 2I,丙酮,K 2CO 3,室温,12h；30:C 6H 5CH 2Br,丙酮,K 2CO 3,室温12h；31:1,2-二溴乙烷,丙酮,K 2CO 3,室温12h；32:1,3-二溴乙烷,丙酮,K 2CO 3,室温,12h；33:Br(CH 2) 2O(CH 2) 2Br,丙酮,K 2CO 3,室温,12h；34:Cl(CH 2) 2O(CH 2) 2OH,丙酮,K 2CO 3,室温,12h；35:CH 3COCl,Et 3N,DCM,0℃,1h；36:C 7H 15COCl,Et 3N,DCM,0℃,1h；37:C 11H 23COCl,Et 3N,DCM,0℃,1h；38:C 6H 5COCl,Et 3N,DCM,0℃,1h；39:C 6H 5CH＝CHCOCl,Et 3N,DCM,0℃,1h；40:SO 3/吡啶,Et 3N,THF,室温,6h；41:I(CH 2) 2O(CH 2) 2O(CH 2) 2I,丙酮,K 2CO 3,室温,12h；42:NH 2COCH 2Cl,2-丁酮,KI,室温12h；(ii)31,NH 3 .H 2O,KI,THF,12h；(iii)HATU,DIPEA,室温,12h.(iv)NaH,KI,DMSO,室温,12h；(v)NaH,DMSO,室温,12h；(vi)K 2CO 3,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TLR2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Na 2SO 4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Na 2SO 4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Na 2SO 4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
Figure PCTCN2018082243-appb-000045
Figure PCTCN2018082243-appb-000046
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Na 2SO 4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
Figure PCTCN2018082243-appb-000047
Figure PCTCN2018082243-appb-000048
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
Figure PCTCN2018082243-appb-000049
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K 2CO 3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Na 2SO 4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 3I替换为CH 3CH 2I
30 将原料CH 3I替换为C 6H 5CH 2I
31 将原料CH 3替换为C 2H 4Br 2
32 将原料CH 3I替换为C 3H 6Br 2
33 将原料CH 3I替换为(CH 2) 2O(CH 2) 2Br 2
34 将原料CH 3I替换为Cl(CH 2) 2O(CH 2) 2OH
40 将原料CH 3I替换为SO 3-Py
41 将原料CH 3I替换为(CH 2) 2O(CH 2) 2O(CH 2) 2I 2
42 将原料CH 3I替换为NH 2COCH 2Cl
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,0.026 mmol)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 3COCl替换为C 7H 15COCl
37 将原料CH 3COCl替换为C 11H 23COCl
38 将原料CH 3COCl替换为C 6H 5COCl
39 将原料CH 3COCl替换为C 7H 15COCl
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 2) 2NH 2替换为CH 2CH 2
46 将连接链(CH 2) 2NH 2替换为(CH 2) 2O(CH 2) 2
47 将连接链(CH 2) 2NH 2替换为(CH 2) 2O(CH 2) 2O(CH 2) 2
实施例15：化合物的结构验证
化合物1
Figure PCTCN2018082243-appb-000050
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)for C 16H 8ClF 3N 2O 2S[M+H] +calculated 385.76,found 385.96.
化合物2
Figure PCTCN2018082243-appb-000051
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 C 17H 12F 3N 3O 2S[M+H] +calculated 380.36,found 380.32.
化合物3
Figure PCTCN2018082243-appb-000052
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 C 16H 10F 3NS[M+H] +calculated 306.32,found 305.59.
化合物4
Figure PCTCN2018082243-appb-000053
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 C 17H 9F 6NS[M+H] +calculated 374.32,found 375.11.
化合物5
Figure PCTCN2018082243-appb-000054
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 C 17H 9F 6NS[M+H] +calculated 374.32,found 374.29.
化合物6
Figure PCTCN2018082243-appb-000055
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 C 17H 9F 6NS[M+H] +calculated 374.32,found 374.78.
化合物7
Figure PCTCN2018082243-appb-000056
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 C 18H 8F 9NS[M+H] +calculated440.31,found 440.95.
化合物8
Figure PCTCN2018082243-appb-000057
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 C 17H 12F 3NOS[M+H] +calculated 336.34,found 337.08.
化合物9
Figure PCTCN2018082243-appb-000058
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 C 16H 9F 3N 2O 2S[M+H] +calculated 351.32,found 351.32.
化合物10
Figure PCTCN2018082243-appb-000059
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 C 17H 14F 3NS[M+H] +calculated 322.36,found 333.01.
化合物11
Figure PCTCN2018082243-appb-000060
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)for C 16H 8ClF 3N 2O 3S[M+H] +calculated 401.76,found 401.21.
化合物12
Figure PCTCN2018082243-appb-000061
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 C 17H 12F 3N 3O 3S[M+H] +calculated 396.36,found 397.25.
化合物13
Figure PCTCN2018082243-appb-000062
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)for C 16H 10F 3NOS[M+H] +calculated 322.32,found 322.30.
化合物14
Figure PCTCN2018082243-appb-000063
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 C 17H 9F 6NOS[M+H] +calculated 390.31,found 390.39.
化合物15
Figure PCTCN2018082243-appb-000064
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). 13C NMR(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 C 17H 9F 6NOS[M+H] +calculated 390.31,found 389.14.
化合物16
Figure PCTCN2018082243-appb-000065
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)for C 17H 9F 6NOS[M+H] +calculated 390.31,found 391.21.
化合物17
Figure PCTCN2018082243-appb-000066
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 C 18H 8F 9NOS[M+H] +calculated 456.31,found 456.02.
化合物18
Figure PCTCN2018082243-appb-000067
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 C 17H 12F 3NO 2S[M+H] +calculated 352.34,found 351.94.
化合物19
Figure PCTCN2018082243-appb-000068
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 C 16H 9F 3N 2O 3S[M+H] +calculated 367.31,found 368.55.
化合物20
Figure PCTCN2018082243-appb-000069
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 C 17H 14F 3NOS[M+H] +calculated 378.36,found 377.66.
化合物21
Figure PCTCN2018082243-appb-000070
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 C 17H 13F 3N 4O 3[M+H] +calculated 379.31,found 378.02.
化合物22
Figure PCTCN2018082243-appb-000071
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 C 17H 13F 3N 4O 3[M+H] -calculated 377.31,found 377.52.
化合物23
Figure PCTCN2018082243-appb-000072
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). 13C NMR(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 C 18H 16F 3N 3O 3S[M+H] +calculated 412.40,found 412.44.
化合物24
Figure PCTCN2018082243-appb-000073
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 C 19H 16F 3N 3O 3[M+H] +calculated 392.34,found 392.39.
化合物25
Figure PCTCN2018082243-appb-000074
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)for C 19H 17F 3N 4O 2[M+H] +calculated 391.36,found 391.06.
化合物26
Figure PCTCN2018082243-appb-000075
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 C 17H 12ClF 3N 4O 3[M+H] +calculated 411.75,found 411.83.
化合物27
Figure PCTCN2018082243-appb-000076
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 C 17H 12ClN 5O 2[M+H] +calculated 354.76,found 355.23.
化合物28
Figure PCTCN2018082243-appb-000077
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)for C 18H 15F 3N 4O 3[M+H] +calculated 393.33,found 393.10.
化合物29
Figure PCTCN2018082243-appb-000078
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 C 19H 17F 3N 4O 3[M+H] +calculated 407.36,found 407.65.
化合物30
Figure PCTCN2018082243-appb-000079
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 C 24H 19F 3N 4O 3[M+H] +calculated 467.43,found 467.52.
化合物31
Figure PCTCN2018082243-appb-000080
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 C 19H 16BrF 3N 4O 3[M+H] +calculated 486.25,found 486.28.
化合物32
Figure PCTCN2018082243-appb-000081
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 C 20H 18BrF 3N 4O 3[M+H] +calculated 500.28,found500.99.
化合物33
Figure PCTCN2018082243-appb-000082
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 C 21H 20BrF 3N 4O 4[M+H] +calculated 530.31,found530.11.
化合物34
Figure PCTCN2018082243-appb-000083
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 C 21H 21F 3N 4O 5[M+H] +calculated 465.41,found 466.56.
化合物35
Figure PCTCN2018082243-appb-000084
(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 C 19H 15F 3N 4O 4[M+H] +calculated 421.34,found421.34.
化合物36
Figure PCTCN2018082243-appb-000085
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 C 25H 27F 3N 4O 4[M+H] +calculated 505.50,found 505.48.
化合物37
Figure PCTCN2018082243-appb-000086
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 C 29H 35F 3N 4O 4[M+H] +calculated 561.61,found 561.83.
化合物38
Figure PCTCN2018082243-appb-000087
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 C 24H 17F 3N 4O 4[M+H] +calculated 483.41,found 483.25.
化合物39
Figure PCTCN2018082243-appb-000088
(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 C 26H 19F 3N 4O 4[M+H] +calculated 509.45,found 509.38.
化合物40
Figure PCTCN2018082243-appb-000089
(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 C 17H 13F 3N 4O 6S[M+H] -calculated455.37,found 455.30.
化合物41
Figure PCTCN2018082243-appb-000090
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,CDCl 3)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,CDCl 3)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 C 23H 24F 3IN 4O 5[M+H] +calculated 621.36,found620.81.
化合物42
Figure PCTCN2018082243-appb-000091
(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 C 19H 16F 3N 5O 4[M+H] +calculated 436.36,found 436.57.
化合物43
Figure PCTCN2018082243-appb-000092
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 C 19H 18F 3N 5O 3[M+H] +calculated 422.37,found 422.02.
化合物44
Figure PCTCN2018082243-appb-000093
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,CDCl 3)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 C 29H 32F 3N 7O 5S[M+H] +calculated 648.67,found 647.57.
化合物45
Figure PCTCN2018082243-appb-000094
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,CDCl 3)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,CDCl 3)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)for C 29H 31F 3N 6O 6S[M+H] +calculated 649.65,found 649.68.
化合物46
Figure PCTCN2018082243-appb-000095
((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,CDCl 3)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,CDCl 3)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 C 31H 35F 3N 6O 7S[M+H] +calculated 693.71,found 693.01.
化合物47
Figure PCTCN2018082243-appb-000096
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,CDCl 3)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,CDCl 3)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 C 33H 39F 3N 6O 8S[M+H] +calculated 737.76,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TLR1/2HEK BLUE细胞进行检测。TLR1/2HEK 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％CO 2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％CO 2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CO 2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
Figure PCTCN2018082243-appb-000097
Figure PCTCN2018082243-appb-000098
Figure PCTCN2018082243-appb-000099
：表示最高浓度为100μM依然没有激活效果。
Figure PCTCN2018082243-appb-000100
：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；
    Figure PCTCN2018082243-appb-100001
    其中R 1选自H、OH、OCH 3、OCH 2CH 3、OCH 2C 6H 5、O(CH 2) 2Br、O(CH 2) 3Br、O(CH 2) 2O(CH 2) 2Br、O(CH 2) 2O(CH 2) 2OH、OCOCH 3、OCO(CH 2) 6CH 3、OCO(CH 2) 10CH 3、OCOC 6H 5、OCOCH＝CHC 6H 5、OSO 3H、O(CH 2) 2O(CH 2) 2O(CH) 2I、OCH 2CONH 2、O(CH 2) 2NH 2、O(CH 2) 2NH-Biotin、O(CH 2) 2O-Biotin、O(CH 2) 2O(CH 2) 2O-Biotin中任意一个，R 2选自H、NO 2、CH 3、CF 3、SO 2CH 3、COOCH 3、CONHCH 3、中任意一个，R 3选自H、NO 2、OCH 3、CF 3中任意一个，R 4选自H、CF 3、Cl，R 5选自H、Cl、CF 3、NHCH 3中任意一个，R 6选自H、OCF 3、CF 3、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，
    Figure PCTCN2018082243-appb-100002
    所述的R 1-R 6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
    Figure PCTCN2018082243-appb-100003
    Figure PCTCN2018082243-appb-100004
    Figure PCTCN2018082243-appb-100005
    Figure PCTCN2018082243-appb-100006
    Figure PCTCN2018082243-appb-100007
    Figure PCTCN2018082243-appb-100008
    Figure PCTCN2018082243-appb-100009
    Figure PCTCN2018082243-appb-100010
  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
    Figure PCTCN2018082243-appb-100011
    在甲机锂催化条件下，反应得到化合物A2
    Figure PCTCN2018082243-appb-100012
    2)将化合物A2
    Figure PCTCN2018082243-appb-100013
    在四丁基三溴化铵作用下，反应得到化合物A3
    Figure PCTCN2018082243-appb-100014
    3)将化合物A3
    Figure PCTCN2018082243-appb-100015
    与化合物A4
    Figure PCTCN2018082243-appb-100016
    反应得到式I-1所示的化合物；
    其中，R 1选自H、OH、OCH 3、OCH 2CH 3、OCH 2C 6H 5、O(CH 2) 2Br、O(CH 2) 3Br、O(CH 2) 2O(CH 2) 2Br、O(CH 2) 2O(CH 2) 2OH、OCOCH 3、OCO(CH 2) 6CH 3、OCO(CH 2) 10CH 3、OCOC 6H 5、OCOCH＝CHC 6H 5、OSO 3H、O(CH 2) 2O(CH 2) 2O(CH) 2I、OCH 2CONH 2、O(CH 2) 2NH 2、O(CH 2) 2NH-Biotin、O(CH 2) 2O-Biotin、O(CH 2) 2O(CH 2) 2O-Biotin中任意一个，R 2选自H、NO 2、CH 3、CF 3、SO 2CH 3、COOCH 3、CONHCH 3、-N +O-O -中任意一个，R 3选自H、NO 2、OCH 3、CF 3中任意一个，R 4选自H、CF 3、Cl，R 5选自H、Cl、CF 3、NHCH 3中任意一个，R 6选自H、OCF 3、CF 3、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
    Figure PCTCN2018082243-appb-100017
    在甲机锂催化条件下，反应得到化合物A2
    Figure PCTCN2018082243-appb-100018
    2)将化合物A2
    Figure PCTCN2018082243-appb-100019
    在四丁基三溴化铵作用下，反应得到化合物A3
    Figure PCTCN2018082243-appb-100020
    3)将化合物A3
    Figure PCTCN2018082243-appb-100021
    与化合物A4
    Figure PCTCN2018082243-appb-100022
    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R 1-R 6如下所示：
    1:R 1＝R 3＝R 4＝H,R 2＝NO 2,R 5＝Cl,R 6＝CF 3；
    2:R 1＝R 3＝R 4＝H,R 2＝NO 2,R 5＝NHCH 3,R 6＝CF 3；
    3:R 1＝R 2＝R 3＝R 4＝R 5＝H,R 6＝CF 3；
    4:R 1＝R 3＝R 4＝R 5＝H,R 2＝CF 3,R 6＝CF 3；
    5:R 1＝R 2＝R 4＝R 5＝H,R 3＝CF 3,R 6＝CF 3；
    6:R 1＝R 2＝R 3＝R 4＝H,R 5＝CF 3,R 6＝CF 3；
    7:R 1＝R 3＝R 5＝H,R 2＝R 4＝CF 3,R 6＝CF 3；
    8:R 1＝R 2＝R 4＝R 5＝H,R 3＝OCH 3,R 6＝CF 3；
    9:R 1＝R 2＝R 4＝R 5＝H,R 3＝NO 2,R 6＝CF 3；
    10:R 1＝R 3＝R 4＝R 5＝H,R 2＝CH 3,R 6＝CF 3；
    11:R 1＝OH,R 2＝NO 2,R 3＝R 4＝H,R 5＝Cl,R 6＝CF 3；
    12:R 1＝OH,R 2＝NO 2,R 3＝R 4＝H,R 5＝NHCH 3,R 6＝CF 3；
    13:R 1＝OH,R 2＝R 3＝R 4＝R 5＝H,R 6＝CF 3；
    14:R 1＝OH,R 2＝CF 3,R 3＝R 4＝R 5＝H,R 6＝CF 3；
    15:R 1＝OH,R 2＝R 4＝R 5＝H,R 3＝CF 3,R 6＝CF 3；
    16:R 1＝OH,R 2＝R 3＝R 4＝H,R 5＝CF 3,R 6＝CF 3；
    17:R 1＝OH,R 2＝R 4＝CF 3,R 3＝R 5＝H,R 6＝CF 3；
    18:R 1＝OH,R 2＝R 4＝R 5＝H,R 3＝OCH 3,R 6＝CF 3；
    19:R 1＝OH,R 2＝R 4＝R 5＝H,R 3＝NO 2,R 6＝CF 3；
    20:R 1＝OH,R 2＝CH 3,R 3＝R 4＝R 5＝H,R 6＝CF 3。
  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
    Figure PCTCN2018082243-appb-100023
    在甲机锂催化条件下，反应得到化合物A2
    Figure PCTCN2018082243-appb-100024
    将化合物A2
    Figure PCTCN2018082243-appb-100025
    在四丁基三溴化铵作用下，反应得到化合物A3
    Figure PCTCN2018082243-appb-100026
    2)将化合物B1
    Figure PCTCN2018082243-appb-100027
    在甲胺中反应生成氨基取代的化合物B2
    Figure PCTCN2018082243-appb-100028
    还原 化合物B2得到化合物B3
    Figure PCTCN2018082243-appb-100029
    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
    Figure PCTCN2018082243-appb-100030
    4)将化合物B4和化合物A3反应得到化合物B6
    Figure PCTCN2018082243-appb-100031
    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，R 1选自H、OH、OCH 3、OCH 2CH 3、OCH 2C 6H 5、O(CH 2) 2Br、O(CH 2) 3Br、O(CH 2) 2O(CH 2) 2Br、O(CH 2) 2O(CH 2) 2OH、OCOCH 3、OCO(CH 2) 6CH 3、OCO(CH 2) 10CH 3、OCOC 6H 5、OCOCH＝CHC 6H 5、OSO 3H、O(CH 2) 2O(CH 2) 2O(CH) 2I、OCH 2CONH 2、O(CH 2) 2NH 2、O(CH 2) 2NH-Biotin、O(CH 2) 2O-Biotin、O(CH 2) 2O(CH 2) 2O-Biotin中任意一个，R 2选自H、NO 2、CH 3、CF 3、SO 2CH 3、COOCH 3、CONHCH 3、-N +O-O -中任意一个，R 6选自H、OCF 3、CF 3、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R 1，R 2和R 6如下所示：
    21:R 1＝OH,R 6＝OCF 3,R 2＝NO 2；
    22:R 1＝OH,R6＝CF 3,R 2＝NO 2；
    23:R 1＝OH,R 6＝CF 3,R 2＝SO 2CH 3；
    24:R 1＝OH,R 6＝CF 3,R 2＝COOCH 3；
    25:R 1＝OH,R 6＝CF 3,R 2＝CONHCH 3；
    26:R 1＝OH,R 6＝CF 3,R 2＝NO 2
    27:R 1＝H,R 6＝CN,R 2＝NO 2。
  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
    Figure PCTCN2018082243-appb-100032
    2)将化合物22与R 7X反应获得化合物
    Figure PCTCN2018082243-appb-100033
    所述R 7选自CH 3、CH 3CH 2、C 6H 5CH 2、C 2H 4Br、C 3H 6Br、(CH 2) 2O(CH 2) 2Br、(CH 2) 2O(CH 2) 2OH、COCH 3、C 7H 15CO、C 11H 23CO、C 6H 5CO、C 6H 5CH＝CHCO、SO 3H、 (CH 2) 2O(CH 2) 2O(CH 2) 2I、NH 2COCH；
    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
    Figure PCTCN2018082243-appb-100034
    将化合物22与1,2-二溴乙烷反应获得化合物
    Figure PCTCN2018082243-appb-100035
    2)将化合物31与NH 3·H 2O以及KI反应制备得到化合物43
    Figure PCTCN2018082243-appb-100036
    可选地，将化合物43与化合物
    Figure PCTCN2018082243-appb-100037
    反应得到化合物44，
    Figure PCTCN2018082243-appb-100038
    或者
    2)将化合物31与生物素
    Figure PCTCN2018082243-appb-100039
    反应，得到化合物45，46或
    Figure PCTCN2018082243-appb-100040
    或者
    2)将生物素与I(CH 2) 2O(CH 2) 2O(CH 2) 2I或I(CH 2) 2O(CH 2) 2I反应，得到
    Figure PCTCN2018082243-appb-100041
    再与化合物22反应得到化合物45，46或47；
    其中,R 8为(CH 2) 2O(CH 2) 2O(CH 2) 2I或(CH 2) 2O(CH 2) 2I。
    Figure PCTCN2018082243-appb-100042
    (i)28:CH 3I,丙酮,K 2CO 3,室温12h；29:CH 3CH 2I,丙酮,K 2CO 3,室温,12h；30:C 6H 5CH 2Br,丙酮,K 2CO 3,室温12h；31:1,2-二溴乙烷,丙酮,K 2CO 3,室温12h；32:1,3-二溴乙烷,丙酮,K 2CO 3,室温,12h；33:Br(CH 2) 2O(CH 2) 2Br,丙酮,K 2CO 3,室温,12h；34:Cl(CH 2) 2O(CH 2) 2OH,丙酮,K 2CO 3,室温,12h；35:CH 3COCl,Et 3N,DCM,0℃,1h；36:C 7H 15COCl,Et 3N,DCM,0℃,1h；37:C 11H 23COCl,Et 3N,DCM,0℃,1h；38:C 6H 5COCl,Et 3N,DCM,0℃,1h；39:C 6H 5CH＝CHCOCl,Et 3N,DCM,0℃,1h；40:SO 3/吡啶,Et 3N,THF,室温,6h；41:I(CH 2) 2O(CH 2) 2O(CH 2) 2I,丙酮,K 2CO 3,室温,12h；42:NH 2COCH 2Cl,2-丁酮,KI,室温12h；(ii)31,NH 3·H 2O,KI,THF,12h；(iii)HATU,DIPEA,室温,12h.(iv)NaH,KI,DMSO,室温,12h；(v)NaH,DMSO,室温,12h；(vi)K 2CO 3,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TLR 2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。
PCT/CN2018/082243 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 WO2019195972A1 (zh)

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