技术领域technical field
本发明属于药物开发领域，具体涉及吲哚胺2,3-双加氧酶抑制剂及其制备方法与应用。The invention belongs to the field of drug development, and specifically relates to an indoleamine 2,3-dioxygenase inhibitor and a preparation method and application thereof.
背景技术Background technique
吲哚胺2,3-双加氧酶(indoleamine 2,3-dioxygenase,简写IDO)是一种与色氨酸代谢有关的蛋白酶。色氨酸是八种必需氨基酸之一，在体内色氨酸可用来合成蛋白质，色氨酸还可作为前体底物通过甲氧基吲哚代谢途径合成5-羟色胺和褪黑激素(N-乙酰-5-甲氧基色胺)。5-羟色胺和褪黑激素是神经递质和神经内分泌激素，参与体内的多种神经与生理过程的调节。此外，色氨酸还可通过犬尿氨酸代谢途径产生犬尿氨酸等代谢产物。犬尿氨酸代谢途径的第一步是在吲哚胺2,3-双加氧酶或色氨酸2，3-双加氧酶(TDO)的催化作用下，色氨酸L-色氨酸降解为N-甲酰基-犬尿氨酸，N-甲酰基-犬尿氨酸在犬尿氨酸甲酰胺酶的催化作用下形成犬尿氨酸，犬尿氨酸还可被进一步代谢形成3-羟基邻氨基苯甲酸，喹啉酸，吡啶甲酸。喹啉酸具有神经毒性，而吡啶甲酸具有神经保护作用。犬尿氨酸和3-羟基邻氨基苯甲酸参与淋巴细胞活性调节从而引起免疫系統被抑制。Indoleamine 2,3-dioxygenase (IDO for short) is a protease related to tryptophan metabolism. Tryptophan is one of the eight essential amino acids. Tryptophan can be used to synthesize proteins in the body. Tryptophan can also be used as a precursor substrate to synthesize 5-hydroxytryptamine and melatonin (N- Acetyl-5-methoxytryptamine). Serotonin and melatonin are neurotransmitters and neuroendocrine hormones involved in the regulation of various neurological and physiological processes in the body. In addition, tryptophan can also produce metabolites such as kynurenine through the kynurenine metabolic pathway. The first step of the kynurenine metabolic pathway is catalyzed by indoleamine 2,3-dioxygenase or tryptophan 2,3-dioxygenase (TDO), tryptophan L-tryptophan Acid is degraded to N-formyl-kynurenine, and N-formyl-kynurenine is catalyzed by kynurenine formamidase to form kynurenine, which can be further metabolized to form 3-Hydroxyanthranilic acid, quinolinic acid, picolinic acid. Quinolinic acid is neurotoxic, while picolinic acid is neuroprotective. Kynurenine and 3-hydroxyanthranilic acid participate in the regulation of lymphocyte activity and thus cause the immune system to be suppressed.
除胎盘组织外，正常健康状况下吲哚胺2,3-双加氧酶在多数组织细胞内基本不表达。在炎症发生区域，干扰素γ等炎性细胞因子可诱导吲哚胺2,3-双加氧酶表达量升高。多方面的实验结果证明，吲哚胺2,3-双加氧酶在组织细胞中的高表达可导致该组织微环境的免疫系統被抑制，或称免疫被抑制或免疫检查点(immune checkpoint)。胎盘组织吲哚胺2,3-双加氧酶的高表达可防止对胎儿的免疫排斥反应。炎症区域吲哚胺2,3-双加氧酶的高表达可防止过度的免疫反应，防止细胞组织受到过度的损伤。导致免疫被抑制的机制之一是吲哚胺2,3-双加氧酶高表达造成局部L-色氨酸耗竭，从而被周围的淋巴细胞通过GCN2等机制感受到，引起CD8+细胞毒性T细胞发生细胞周期停滞或凋亡。导致免疫被抑制的另一种机制是吲哚胺2,3-双加氧酶高表达造成犬尿氨酸升高，犬尿氨酸形成后可离开细胞进入细胞外基质，然后进入附近的淋巴细胞通过结合AHR转录因子对CD8+T细胞和调节性Treg细胞进行调节,CD8+细胞毒性T细胞的活性被抑制，而调节性Treg细胞的数量增多并且被激活，从而导致免疫被抑制。Except for placental tissue, indoleamine 2,3-dioxygenase is basically not expressed in most tissue cells under normal health conditions. In the area of inflammation, inflammatory cytokines such as interferon-γ can induce the expression of indoleamine 2,3-dioxygenase to increase. Various experimental results have proved that the high expression of indoleamine 2,3-dioxygenase in tissue cells can lead to the suppression of the immune system in the microenvironment of the tissue, or immune suppression or immune checkpoint (immune checkpoint) . High expression of indoleamine 2,3-dioxygenase in placental tissue prevents immune rejection of the fetus. High expression of indoleamine 2,3-dioxygenase in inflammatory areas prevents excessive immune responses and prevents excessive tissue damage. One of the mechanisms leading to immune suppression is that the high expression of indoleamine 2,3-dioxygenase causes local depletion of L-tryptophan, which is sensed by surrounding lymphocytes through GCN2 and other mechanisms, causing CD8+ cytotoxic T cells Cell cycle arrest or apoptosis occurs. Another mechanism leading to immunosuppression is the high expression of indoleamine 2,3-dioxygenase, which causes an increase in kynurenine, which can leave the cell and enter the extracellular matrix, and then enter the nearby lymph Cells regulate CD8+ T cells and regulatory Treg cells by combining AHR transcription factors, the activity of CD8+ cytotoxic T cells is inhibited, and the number of regulatory Treg cells is increased and activated, resulting in immune suppression.
在很多不同类型的肿瘤中吲哚胺2,3-双加氧酶发生异常高表达，包括血液肿瘤和直结肠癌、肝癌、肺癌、胰腺癌、咽喉癌等实体瘤。吲哚胺2,3-双加氧酶异常高表达与肿瘤不良预后呈正相关。肿瘤细胞逃脱免疫监控是癌变和癌症进一步发展的关键一步，肿瘤中吲哚胺2,3-双加氧酶的异常高表达可能是肿瘤细胞逃脱免疫监控的一种主要机制，抑制吲哚胺2,3-双加氧酶的活性有可能激活被抑制的免疫系统，达到抑制肿瘤生长的效果，所以吲哚胺2,3-双加氧酶抑制剂作为一种免疫检查点抑制剂(immune checkpoint inhibitor)引起了医药界很大的兴趣。吲哚胺2,3-双加氧酶(IDO)有两种，IDO-1和IDO-2，参与上述免疫被抑制的主要是IDO-1，IDO-2在免疫被抑制中的作用还不是很清楚。色氨酸2，3-双加氧酶(TDO)也在很多类型的肿瘤中发生异常高表达，有的肿瘤还呈现IDO和TDO双阳性，所以有人认为也可通过抑制TDO免疫检查点起到肿瘤治疗的目的。因为正常肝脏细胞表达TDO，尚不清楚TDO抑制剂是否会影响肝脏功能和正常的色氨酸代谢，但TDO敲除得小鼠模型未见异常，表明TDO抑制剂可能不会影响肝脏功能和正常的色氨酸代谢。IDO和TDO导致免疫被抑制的机理基本相同，所以IDO/TDO双特异抑制剂也同样引起了医药界的兴趣，IDO/TDO双特异抑制剂将适用于IDO阳性、TDO阳性、IDO/TDO双阳性的病人。Indoleamine 2,3-dioxygenase is abnormally highly expressed in many different types of tumors, including hematological tumors and solid tumors such as colorectal cancer, liver cancer, lung cancer, pancreatic cancer, and throat cancer. Abnormally high expression of indoleamine 2,3-dioxygenase is positively correlated with poor prognosis of tumors. The escape of immune surveillance by tumor cells is a key step in carcinogenesis and the further development of cancer. Abnormally high expression of indoleamine 2,3-dioxygenase in tumors may be a major mechanism for tumor cells to escape immune surveillance. Inhibition of indoleamine 2 , The activity of 3-dioxygenase may activate the suppressed immune system to achieve the effect of inhibiting tumor growth, so indoleamine 2,3-dioxygenase inhibitor is used as an immune checkpoint inhibitor (immune checkpoint inhibitor) has aroused great interest in the medical field. There are two types of indoleamine 2,3-dioxygenase (IDO), IDO-1 and IDO-2. IDO-1 is mainly involved in the above-mentioned immune suppression, and the role of IDO-2 in immune suppression is not yet very clear. Tryptophan 2,3-dioxygenase (TDO) is also abnormally overexpressed in many types of tumors, and some tumors are also positive for both IDO and TDO, so some people think that it can also play a role in inhibiting TDO immune checkpoints. purpose of cancer treatment. Because normal liver cells express TDO, it is unclear whether TDO inhibitors will affect liver function and normal tryptophan metabolism, but TDO knockout mouse models have no abnormalities, indicating that TDO inhibitors may not affect liver function and normal metabolism. tryptophan metabolism. IDO and TDO have basically the same mechanism of immune suppression, so IDO/TDO dual-specific inhibitors have also attracted the interest of the medical community. IDO/TDO dual-specific inhibitors will be suitable for IDO-positive, TDO-positive, and IDO/TDO double-positive of patients.
色氨酸的犬尿氨酸代谢途径的很多代谢产物与精神分裂症，抑郁症，神经元退化有关，吲哚胺2,3-双加氧酶抑制剂可能也可用于这些疾病的治疗。犬尿氨酸在犬尿氨酸氨基转移酶的催化作用下可转化为犬尿喹啉酸，犬尿喹啉酸是一种NMDA拮抗剂，在精神分裂症病人的中枢神经中常见到较高的犬尿喹啉酸水平。喹啉酸具有神经毒性，可导致神经细胞凋亡和神经退化。吲哚胺2,3-双加氧酶不仅参与色氨酸代谢，还参与色氨等的代谢，5-羟色胺在吲哚胺2,3-双加氧酶的催化作用下可转化为5-羟吲哚乙酸，5-羟色胺下降可能是导致抑郁症的因素之一。Many metabolites of the kynurenine metabolic pathway of tryptophan are associated with schizophrenia, depression, and neuronal degeneration, and indoleamine 2,3-dioxygenase inhibitors may also be useful in the treatment of these diseases. Kynurenine can be converted into kynurenic acid under the catalysis of kynurenine aminotransferase, kynurenic acid is an NMDA antagonist, which is common in the central nervous system of patients with schizophrenia. kynurenic acid levels. Quinolinic acid is neurotoxic and can lead to neuronal apoptosis and neurodegeneration. Indoleamine 2,3-dioxygenase not only participates in the metabolism of tryptophan, but also participates in the metabolism of tryptophan, etc., under the catalysis of indoleamine 2,3-dioxygenase, 5-hydroxytryptamine can be converted into 5- Oxindoleacetic acid, decreased serotonin may be one of the factors leading to depression.
目前吲哚胺2,3-双加氧酶抑制剂的研发均处于早期，包括NewLink公司的Indoximod，NLG-919(IDO/TDO双特异性)，Incyte公司的Epacadostat(INCB 024360)，以及BMS，Flexus，Iomet,Iteos,Curadev等公司的IDO或TDO抑制剂。At present, the research and development of indoleamine 2,3-dioxygenase inhibitors are in the early stage, including NewLink's Indoximod, NLG-919 (IDO/TDO bispecific), Incyte's Epacadostat (INCB 024360), and BMS, IDO or TDO inhibitors from Flexus, Iomet, Iteos, Curadev and other companies.
发明内容Contents of the invention
为了解决现有技术存在的问题，发明人在一系列研究后发现(Z)-N'-羟基-N-苯基甲脒衍生物，对吲哚胺2,3-双加氧酶(IDO)具有很高的抑制活性，而对色氨酸2，3-双加氧酶(TDO)没有抑制活性，并且在PK动物模型中具有非常好的暴露量(AUC)。该类化合物能够有效抑制IDO的活性，也可用于抑制患者的免疫抑制。可广泛应用于治疗或预防癌症或肿瘤、病毒感染、抑郁症、神经变性病症、创伤、年龄相关的白内障、器官移植排斥或自身免疫疾病，有望开发成新一代免疫抑制剂。In order to solve the problems existing in the prior art, the inventors found after a series of studies that (Z)-N'-hydroxyl-N-phenylcarboxamidine derivatives, p-indoleamine 2,3-dioxygenase (IDO) It has very high inhibitory activity, but no inhibitory activity on tryptophan 2,3-dioxygenase (TDO), and has a very good exposure (AUC) in PK animal models. Such compounds can effectively inhibit the activity of IDO, and can also be used to suppress the immunosuppression of patients. It can be widely used in the treatment or prevention of cancer or tumors, viral infections, depression, neurodegenerative disorders, trauma, age-related cataracts, organ transplant rejection or autoimmune diseases, and is expected to be developed into a new generation of immunosuppressants.
本发明一方面提供一种具有如下式(I)结构的(Z)-N'-羟基-N-苯基甲脒衍生物、其立体异构体或其药学上可接受盐，One aspect of the present invention provides a (Z)-N'-hydroxy-N-phenylcarboxamidine derivative having the structure of the following formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof,
其中：in:
X选自-O-、-S-、-CH2-或-NR7-；X is selected from -O-, -S-, -CH2 - or -NR7 -;
Y选自C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C5-10芳基、5-10元杂芳基、-C1-4-O-C1-4-、-C0-4-C(O)O C1-4-、-C0-4-C(O)C0-4-、-C1-4-O-C(O)C0-4-、-C1-4-NR7R8-或-C0-4-C(O)NR7R8-，Y is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C5-10 aryl, 5 -10-membered heteroaryl, -C1-4 -OC1-4 -, -C0-4 -C(O)OC1-4 -, -C0-4 -C(O)C0-4 - , -C1-4 -OC(O)C0-4 -, -C1-4 -NR7 R8 - or -C0-4 -C(O)NR7 R8 -,
任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代；Optionally further selected from one or more groups selected from halogen, hydroxyl, mercapto, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halogen Substituted C1-8 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10 aryl , C5-10 aryloxy, C5-10 arylthio, 5-10 heteroaryl, 5-10 heteroaryloxy, 5-10 heteroarylthio, -C0 -8 -S(O)r R4 , -C0-8 -OR5 , -C0-8 -C(O)OR5 , -C0-8 -C(O)R6 , -C0- 8 -OC(O)R6 , -C0-8 -NR7 R8 , -C0-8 -C(O)NR7 R8 , -N(R7 )-C(O)R6 or - Substituents of N(R7 )-C(O)OR5 ;
R1选自氢、氘、卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5，R1 is selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3- 8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 -membered arylthio, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy, 5-10-membered heteroarylthio, -C0-8 -S(O)r R4 , -C0-8 -OR5 , -C0-8 -C(O)OR5 , -C0-8 -C(O)R6 , -C0-8 -OC(O)R6 , -C0-8 -NR7 R8 , -C0-8 -C(O)NR7 R8 , -N(R7 )-C(O)R6 or -N(R7 )-C(O)OR5 ,
任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代；Optionally further selected from one or more groups selected from halogen, hydroxyl, mercapto, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halogen Substituted C1-8 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10 aryl , C5-10 aryloxy, C5-10 arylthio, 5-10 heteroaryl, 5-10 heteroaryloxy, 5-10 heteroarylthio, -C0 -8 -S(O)r R4 , -C0-8 -OR5 , -C0-8 -C(O)OR5 , -C0-8 -C(O)R6 , -C0- 8 -OC(O)R6 , -C0-8 -NR7 R8 , -C0-8 -C(O)NR7 R8 , -N(R7 )-C(O)R6 or - Substituents of N(R7 )-C(O)OR5 ;
R2选自氢、氘、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C5-10芳基、5-10元杂芳基或C0-8烷基羰基，R2 is selected from hydrogen, deuterium, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C5- 10 aryl, 5-10 membered heteroaryl or C0-8 alkylcarbonyl,
任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代；Optionally further selected from one or more groups selected from halogen, hydroxyl, mercapto, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halogen Substituted C1-8 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10 aryl , C5-10 aryloxy, C5-10 arylthio, 5-10 heteroaryl, 5-10 heteroaryloxy, 5-10 heteroarylthio, -C0 -8 -S(O)r R4 , -C0-8 -OR5 , -C0-8 -C(O)OR5 , -C0-8 -C(O)R6 , -C0- 8 -OC(O)R6 , -C0-8 -NR7 R8 , -C0-8 -C(O)NR7 R8 , -N(R7 )-C(O)R6 or - Substituents of N(R7 )-C(O)OR5 ;
R3选自氢、氘、羟基、氨基、C1-8烷基、C2-8链烯基、C3-8环烷基、3-8元杂环基、C5-10芳基、5-10元杂芳基、C1-8烷氧基、C3-8环烷氧基、3-8元杂环基氧基、C5-10芳基氧基或5-10元杂芳基氧基，R is selected from hydrogen, deuterium, hydroxyl, amino, C1-8 alkyl, C2-8 alkenyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C5-10 aryl, 5-10 membered heteroaryl, C1-8 alkoxy, C3-8 cycloalkoxy, 3-8 membered heterocyclyloxy, C5-10 aryloxy or 5-10 membered heteroaryl base oxygen,
任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代；Optionally further selected from one or more groups selected from halogen, hydroxyl, mercapto, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halogen Substituted C1-8 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10 aryl , C5-10 aryloxy, C5-10 arylthio, 5-10 heteroaryl, 5-10 heteroaryloxy, 5-10 heteroarylthio, -C0 -8 -S(O)r R4 , -C0-8 -OR5 , -C0-8 -C(O)OR5 , -C0-8 -C(O)R6 , -C0- 8 -OC(O)R6 , -C0-8 -NR7 R8 , -C0-8 -C(O)NR7 R8 , -N(R7 )-C(O)R6 or - Substituents of N(R7 )-C(O)OR5 ;
R4选自氢、氘、C1-8烷基、C2-8链烯基、C3-8环烷基、卤取代C1-8烷基、苯基、对甲基苯基、氨基、单C1-8烷基氨基、二C1-8烷基氨基或C1-8烷酰氨基；R is selected from hydrogen, deuterium, C1-8 alkyl, C2-8 alkenyl, C3-8 cycloalkyl, halogen substituted C1-8 alkyl, phenyl, p- methylphenyl, amino , single C1-8 alkylamino, two C1-8 alkylamino or C1-8 alkanoylamino;
R5选自氢、氘、C1-8烷基、C3-8环烷基、卤取代C1-8烷基或羟取代C1-8烷基；R5 is selected from hydrogen, deuterium, C1-8 alkyl, C3-8 cycloalkyl, halogen substituted C1-8 alkyl or hydroxyl substituted C1-8 alkyl;
R6选自氢、氘、C1-8烷基、C1-8烷氧基、C3-8环烷基、C3-8环烷氧基、卤取代C1-8烷基、卤取代C1-8烷氧基、羟取代C1-8烷基或羟取代C1-8烷氧基；R is selected from hydrogen,deuterium , C1-8 alkyl, C1-8 alkoxy, C3-8 cycloalkyl, C3-8 cycloalkoxy, halogen substituted C1-8 alkyl, halogen Substituted C1-8 alkoxy, hydroxy substituted C1-8 alkyl or hydroxy substituted C1-8 alkoxy;
R7、R8各自独立的选自氢、氘、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C5-10芳基、5-10元杂芳基或C1-8烷酰基，R7 and R8 are each independently selected from hydrogen, deuterium, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3-8 membered hetero Cyclic group, C5-10 aryl, 5-10 membered heteroaryl or C1-8 alkanoyl,
任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、乙酰氨基、叠氮基、磺酰基、甲磺酰基、C1-8烷基、三氟甲基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C1-8烷氧基、C1-8烷氧羰基、C1-8烷基羰基、C1-8烷基羰基氧基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、氨基、单C1-8烷基氨基或二C1-8烷基氨基的取代基所取代；Optionally further selected from one or more groups selected from halogen, hydroxyl, mercapto, cyano, nitro, acetamido, azido, sulfonyl, methanesulfonyl, C1-8 alkyl, trifluoromethyl, C2 -8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C1-8 alkoxy, C1-8 alkoxycarbonyl, C1-8 Alkylcarbonyl, C1-8 alkylcarbonyloxy, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, amino, single C1-8 alkylamino or diC Substituted by1-8 alkylamino substituents;
m为0～5；m is 0-5;
r为0～2。r is 0-2.
作为进一步优选的方案，所述(Z)-N'-羟基-N-苯基甲脒衍生物、其立体异构体或其药学上可接受盐有两种光学异构体，分别指定为式(R-Ⅰ)化合物或式(S-Ⅰ)化合物，结构式如下：As a further preferred solution, the (Z)-N'-hydroxyl-N-phenylformamidine derivatives, their stereoisomers or pharmaceutically acceptable salts thereof have two optical isomers, respectively designated as formula (R-I) compound or formula (S-I) compound, structural formula is as follows:
作为进一步优选的方案，所述(Z)-N'-羟基-N-苯基甲脒衍生物、其立体异构体或其药学上可接受盐，X选自-O-或-S-；优选的，X选自-O-；As a further preferred solution, in the (Z)-N'-hydroxy-N-phenylformamidine derivative, its stereoisomer or a pharmaceutically acceptable salt thereof, X is selected from -O- or -S-; Preferably, X is selected from -O-;
Y选自C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C5-8芳基、5-8元杂芳基、-C1-2-O-C1-2-、-C0-2-C(O)O C1-2-、-C0-2-C(O)C0-2-、-C1-2-O-C(O)C0-2-、-C1-2-NR7R8-或-C0-2-C(O)NR7R8-，任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代；优选的，Y选自C2-3烷基、C2-3链烯基、C3-6环烷基、3-6元杂环基、C5-8芳基、5-8元杂芳基、-C1-2-NR7R8-或-C0-2-C(O)NR7R8-，任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代。Y is selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C5-8 aryl, 5 -8-membered heteroaryl, -C1-2 -OC1-2 -, -C0-2 -C(O)OC1-2 -, -C0-2 -C(O)C0-2 - , -C1-2 -OC(O)C0-2 -, -C1-2 -NR7 R8 - or -C0-2 -C(O)NR7 R8 -, optionally further replaced by one Or more selected from halogen, hydroxyl, mercapto, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halogen substituted C1-8 Alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10 aryl, C5-10 Aryloxy, C5-10 arylthio, 5-10 heteroaryl, 5-10 heteroaryloxy, 5-10 heteroarylthio, -C0-8 -S( O)r R4 , -C0-8 -OR5 , -C0-8 -C(O)OR5 , -C0-8 -C(O)R6 , -C0-8 -OC(O )R6 , -C0-8 -NR7 R8 , -C0-8 -C(O)NR7 R8 , -N(R7 )-C(O)R6 or -N(R7 ) -C(O)OR5 is replaced by a substituent; preferably, Y is selected from C2-3 alkyl, C2-3 alkenyl, C3-6 cycloalkyl, 3-6 membered heterocyclic group, C5-8 aryl, 5-8 membered heteroaryl, -C1-2 -NR7 R8 - or -C0-2 -C(O)NR7 R8 -, optionally further replaced by one or more One selected from halogen, hydroxyl, mercapto, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halogen substituted C1-8 alkyl , C3-8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10 aryl, C5-10 aryl Oxygen, C5-10 arylthio, 5-10 heteroaryl, 5-10 heteroaryloxy, 5-10 heteroarylthio, -C0-8 -S(O)r R4 , -C0-8 -OR5 , -C0-8 -C(O)OR5 , -C0-8 -C(O)R6 , -C0-8 -OC(O)R6 , -C0-8 -NR7 R8 , -C0-8 -C(O)NR7 R8 , -N(R7 )-C(O)R6 or -N(R7 )-C (O)OR5 is substituted by a substituent.
作为更进一步优选的方案，所述(Z)-N'-羟基-N-苯基甲脒衍生物、其立体异构体或其药学上可接受盐，X选自-O-；Y选自C2-3烷基、C2-3链烯基、C3-6环烷基、3-6元杂环基、C5-8芳基或5-8元杂芳基。As a further preferred solution, in the (Z)-N'-hydroxyl-N-phenylformamidine derivative, its stereoisomer or a pharmaceutically acceptable salt thereof, X is selected from -O-; Y is selected from C2-3 alkyl, C2-3 alkenyl, C3-6 cycloalkyl, 3-6 membered heterocyclic group, C5-8 aryl or 5-8 membered heteroaryl.
作为更进一步优选的方案，所述(Z)-N'-羟基-N-苯基甲脒衍生物、其立体异构体或其药学上可接受盐，所述C3-6环烷基、3-6元杂环基、C5-8芳基或5-8元杂芳基选自如下结构：As a further preferred solution, the (Z)-N'-hydroxyl-N-phenylcarboxamidine derivatives, their stereoisomers or pharmaceutically acceptable salts thereof, theC3-6 cycloalkyl, 3-6 membered heterocyclyl, C5-8 aryl or 5-8 membered heteroaryl are selected from the following structures:
以上结构任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代；The above structure is optionally further replaced by one or more selected from halogen, hydroxyl, mercapto, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl , Halogen substituted C1-8 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10 Aryl, C5-10 aryloxy, C5-10 arylthio, 5-10 heteroaryl, 5-10 heteroaryloxy, 5-10 heteroarylthio, - C0-8 -S(O)r R4 , -C0-8 -OR5 , -C0-8 -C(O)OR5 , -C0-8 -C(O)R6 , -C0-8 -OC(O)R6 , -C0-8 -NR7 R8 , -C0-8 -C(O)NR7 R8 , -N(R7 )-C(O)R6 Or -N(R7 )-C(O)OR5 is substituted by a substituent;
R1选自氢、氘、卤素、羟基、巯基、氰基、硝基、叠氮基、C1-4烷基、C2-8链烯基、C3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C5-8芳基、C5-8芳基氧基、C5-8芳基硫基、5-8元杂芳基、5-8元杂芳基氧基、5-8元杂芳基硫基、-C0-4-S(O)rR4、-C0-4-O-R5、-C0-4-C(O)OR5、-C0-4-C(O)R6、-C0-4-O-C(O)R6、-C0-4-NR7R8、-C0-4-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5，R1 is selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, azido, C1-4 alkyl, C2-8 alkenyl, C3-6 cycloalkyl, 3-6 Member heterocyclyl, 3-6 member heterocyclyloxy, 3-6 member heterocyclylthio, C5-8 aryl, C5-8 aryloxy, C5-8 arylthio, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy, 5-8-membered heteroarylthio, -C0-4 -S(O)r R4 , -C0-4 -OR5 , -C0-4 -C(O)OR5 , -C0-4 -C(O)R6 , -C0-4 -OC(O)R6 , -C0-4 -NR7 R8 , -C0-4 -C(O)NR7 R8 , -N(R7 )-C(O)R6 or -N(R7 )-C(O)OR5 ,
任选进一步被一个或多个选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代；Optionally further selected from one or more groups selected from halogen, hydroxyl, mercapto, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halogen Substituted C1-8 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10 aryl , C5-10 aryloxy, C5-10 arylthio, 5-10 heteroaryl, 5-10 heteroaryloxy, 5-10 heteroarylthio, -C0 -8 -S(O)r R4 , -C0-8 -OR5 , -C0-8 -C(O)OR5 , -C0-8 -C(O)R6 , -C0- 8 -OC(O)R6 , -C0-8 -NR7 R8 , -C0-8 -C(O)NR7 R8 , -N(R7 )-C(O)R6 or - Substituents of N(R7 )-C(O)OR5 ;
R2选自氢、氘、C1-8烷基、卤取代C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C5-10芳基、5-10元杂芳基或C0-8烷基羰基；R2 is selected from hydrogen, deuterium, C1-8 alkyl, halogen substituted C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3- 8-membered heterocyclic group, C5-10 aryl, 5-10 membered heteroaryl or C0-8 alkylcarbonyl;
R3选自氢、氘、羟基、氨基、C1-8烷基、卤取代C1-8烷基、C2-8链烯基、C3-8环烷基、3-8元杂环基、C5-10芳基、5-10元杂芳基、C1-8烷氧基、C3-8环烷氧基、3-8元杂环基氧基、C5-10芳基氧基或5-10元杂芳基氧基。R is selected from hydrogen, deuterium, hydroxyl, amino, C1-8 alkyl, halogen substituted C1-8 alkyl, C2-8 alkenyl, C3-8 cycloalkyl, 3-8 membered heterocycle Base, C5-10 aryl, 5-10 heteroaryl, C1-8 alkoxy, C3-8 cycloalkoxy, 3-8 heterocyclyloxy, C5-10 aryl Oxygen or 5-10 membered heteroaryloxy.
作为更进一步优选的方案，所述(Z)-N'-羟基-N-苯基甲脒衍生物、其立体异构体或其药学上可接受盐，选自式(Ⅱ)化合物：As a further preferred solution, the (Z)-N'-hydroxy-N-phenylformamidine derivatives, their stereoisomers or pharmaceutically acceptable salts thereof are selected from compounds of formula (II):
其中，in,
R1选自氢、氘、卤素、羟基、氰基、硝基、叠氮基、甲基、乙基、异丙基、三氟甲基、烯丙基、环丙基、甲氧基、乙氧基、环丙氧基、甲氧甲基、苯基、磺酰基、甲磺酰基、异丙磺酰基、苯磺酰基、羧基、甲氧羰基、乙氧羰基、异丙氧羰基、乙酰氧基、乙酰基、氨基、二甲氨基、乙酰氨基或氨基羰基；优选的，R1选自氢、氘、氟、溴、羟基、氰基、三氟甲基、环丙基、磺酰基、甲磺酰基、异丙磺酰基、羧基、氨基或二甲氨基；更优选的，R1选自氢、氘、氟、溴或三氟甲基；R is selected from hydrogen,deuterium , halogen, hydroxyl, cyano, nitro, azido, methyl, ethyl, isopropyl, trifluoromethyl, allyl, cyclopropyl, methoxy, ethyl Oxy, cyclopropoxy, methoxymethyl, phenyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, benzenesulfonyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, acetoxy , acetyl, amino, dimethylamino, acetylamino or aminocarbonyl; preferably, R is selected from hydrogen, deuterium, fluorine, bromine, hydroxyl, cyano, trifluoromethyl, cyclopropyl, sulfonyl, methylsulfonyl Acyl, isopropylsulfonyl, carboxyl, amino or dimethylamino; more preferably, R is selected from hydrogen, deuterium, fluorine, bromine or trifluoromethyl;
R2选自氢、氘、C1-4烷基、卤取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C5-8芳基、5-8元杂芳基或C0-4烷基羰基；优选的，R2选自氢、氘、甲基、乙基、异丙基、三氟甲基、烯丙基、环丙基、苯基或乙酰基；R2 is selected from hydrogen, deuterium, C1-4 alkyl, halogen substituted C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, 3- 6-membered heterocyclic group, C5-8 aryl, 5-8 membered heteroaryl or C0-4 alkylcarbonyl; preferably, R2 is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, Trifluoromethyl, allyl, cyclopropyl, phenyl or acetyl;
R3选自氢、氘、羟基、氨基、C1-4烷基、卤取代C1-4烷基、C2-4链烯基、C3-6环烷基、3-6元杂环基、C5-8芳基、5-8元杂芳基、C1-4烷氧基、C3-6环烷氧基、3-6元杂环基氧基、C5-8芳基氧基或5-8元杂芳基氧基；优选的，R3选自氢、氘、羟基、甲基、乙基、异丙基、三氟甲基、烯丙基、环丙基、甲氧基、乙氧基、环丙氧基、苯基或乙酰基。R3 is selected from hydrogen, deuterium, hydroxyl, amino, C1-4 alkyl, halogen substituted C1-4 alkyl, C2-4 alkenyl, C3-6 cycloalkyl, 3-6 membered heterocycle Base, C5-8 aryl, 5-8 membered heteroaryl, C1-4 alkoxy, C3-6 cycloalkoxy, 3-6 membered heterocyclyloxy, C5-8 aryl Oxygen or 5-8 membered heteroaryloxy; Preferably,R is selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, allyl, cyclopropyl, methyl Oxy, ethoxy, cyclopropoxy, phenyl or acetyl.
n为1或2。n is 1 or 2.
作为最优选的方案，所述(Z)-N'-羟基-N-苯基甲脒衍生物、其立体异构体或其药学上可接受盐，选自如下化合物：As the most preferred solution, the (Z)-N'-hydroxyl-N-phenylcarboxamidine derivatives, their stereoisomers or pharmaceutically acceptable salts thereof are selected from the following compounds:
作为进一步优选的方案，所述(Z)-N'-羟基-N-苯基甲脒衍生物、其立体异构体或其药学上可接受盐，选自式(Ⅲ)化合物：As a further preferred solution, the (Z)-N'-hydroxy-N-phenylcarboxamidine derivatives, their stereoisomers or pharmaceutically acceptable salts thereof are selected from compounds of formula (III):
其中，m1、m2各自独立的选自0、1、2或3，且m1、m2不同时为0；Wherein, m1 and m2 are independently selected from 0, 1, 2 or 3, and m1 and m2 are not 0 at the same time;
Ra1、Ra2、Rb1、Rb2、Rc1、Rc2各自独立的选自氢、氘、卤素、羟基、巯基、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C5-8芳基、C5-8芳基氧基、C5-8芳基硫基、5-8元杂芳基、5-8元杂芳基氧基、5-8元杂芳基硫基、-C0-4-S(O)rR4、-C0-4-O-R5、-C0-4-C(O)OR5、-C0-4-C(O)R6、-C0-4-O-C(O)R6、-C0-4-NR7R8、-C0-4-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5；优选的，Ra1、Ra2、Rb1、Rb2、Rc1、Rc2各自独立的选自氢、氘、卤素、羟基、氰基、硝基、叠氮基、甲基、乙基、异丙基、三氟甲基、烯丙基、环丙基、甲氧基、乙氧基、环丙氧基、甲氧甲基、苯基、磺酰基、甲磺酰基、异丙磺酰基、苯磺酰基、羧基、甲氧羰基、乙氧羰基、异丙氧羰基、乙酰氧基、乙酰基、氨基、二甲氨基、乙酰氨基或氨基羰基；更优选的，Ra1、Ra2、Rb1、Rb2、Rc1、Rc2各自独立的选自氢、氘、氟、溴、羟基、氰基、三氟甲基、环丙基、磺酰基、甲磺酰基、异丙磺酰基、羧基、氨基或二甲氨基。Ra1 , Ra2 , Rb1 , Rb2 , Rc1 , and Rc2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, azido, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogen substituted C1-4 alkyl, C3-6 cycloalkyl, 3-6 heterocyclyl, 3-6 heterocyclyloxy, 3-6 membered heterocyclylthio, C5-8 aryl, C5-8 aryloxy, C5-8 arylthio, 5-8 membered heteroaryl, 5-8 membered heteroaryl Oxygen, 5-8 membered heteroarylthio, -C0-4 -S(O)r R4 , -C0-4 -OR5 , -C0-4 -C(O)OR5 , - C0-4 -C(O)R6 , -C0-4 -OC(O)R6 , -C0-4 -NR7 R8 , -C0-4 -C(O)NR7 R8 , -N(R7 )-C(O)R6 or -N(R7 )-C(O)OR5 ; preferably, each of Ra1 , Ra2 , Rb1 , Rb2 , Rc1 , and Rc2 independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, nitro, azido, methyl, ethyl, isopropyl, trifluoromethyl, allyl, cyclopropyl, methoxy, ethyl Oxy, cyclopropoxy, methoxymethyl, phenyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, benzenesulfonyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, acetoxy , acetyl, amino, dimethylamino, acetylamino or aminocarbonyl; more preferably, Ra1 , Ra2 , Rb1 , Rb2 , Rc1 , Rc2 are each independently selected from hydrogen, deuterium, fluorine, bromine, Hydroxy, cyano, trifluoromethyl, cyclopropyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, carboxy, amino or dimethylamino.
作为更进一步优选的方案，所述(Z)-N'-羟基-N-苯基甲脒衍生物、其立体异构体或其药学上可接受盐，选自如下化合物：As a further preferred solution, the (Z)-N'-hydroxy-N-phenylcarboxamidine derivatives, their stereoisomers or pharmaceutically acceptable salts thereof are selected from the following compounds:
其中，R1选自氢、氘、卤素、羟基、氰基、硝基、叠氮基、甲基、乙基、异丙基、三氟甲基、烯丙基、环丙基、甲氧基、乙氧基、环丙氧基、甲氧甲基、苯基、磺酰基、甲磺酰基、异丙磺酰基、苯磺酰基、羧基、甲氧羰基、乙氧羰基、异丙氧羰基、乙酰氧基、乙酰基、氨基、二甲氨基、乙酰氨基或氨基羰基；优选的，R1选自氢、氘、氟、溴、羟基、氰基、三氟甲基、环丙基、磺酰基、甲磺酰基、异丙磺酰基、羧基、氨基或二甲氨基；更优选的，R1选自氢、氘、氟、溴或三氟甲基；Wherein , R is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, azido, methyl, ethyl, isopropyl, trifluoromethyl, allyl, cyclopropyl, methoxy , ethoxy, cyclopropoxy, methoxymethyl, phenyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, benzenesulfonyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, acetyl Oxygen, acetyl, amino, dimethylamino, acetylamino or aminocarbonyl; Preferably, R is selected from hydrogen, deuterium, fluorine, bromine, hydroxyl, cyano, trifluoromethyl, cyclopropyl, sulfonyl, Methanesulfonyl, isopropylsulfonyl, carboxyl, amino or dimethylamino; more preferably, R is selected from hydrogen, deuterium, fluorine, bromine or trifluoromethyl;
R2选自氢、氘、C1-4烷基、卤取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C5-8芳基、5-8元杂芳基或C0-4烷基羰基；优选的，R2选自氢、氘、甲基、乙基、异丙基、三氟甲基、烯丙基、环丙基、苯基或乙酰基；R2 is selected from hydrogen, deuterium, C1-4 alkyl, halogen substituted C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, 3- 6-membered heterocyclic group, C5-8 aryl, 5-8 membered heteroaryl or C0-4 alkylcarbonyl; preferably, R2 is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, Trifluoromethyl, allyl, cyclopropyl, phenyl or acetyl;
R3选自氢、氘、羟基、氨基、C1-4烷基、卤取代C1-4烷基、C2-4链烯基、C3-6环烷基、3-6元杂环基、C5-8芳基、5-8元杂芳基、C1-4烷氧基、C3-6环烷氧基、3-6元杂环基氧基、C5-8芳基氧基或5-8元杂芳基氧基；优选的，R3选自氢、氘、羟基、甲基、乙基、异丙基、三氟甲基、烯丙基、环丙基、甲氧基、乙氧基、环丙氧基、苯基或乙酰基。R3 is selected from hydrogen, deuterium, hydroxyl, amino, C1-4 alkyl, halogen substituted C1-4 alkyl, C2-4 alkenyl, C3-6 cycloalkyl, 3-6 membered heterocycle Base, C5-8 aryl, 5-8 membered heteroaryl, C1-4 alkoxy, C3-6 cycloalkoxy, 3-6 membered heterocyclyloxy, C5-8 aryl Oxygen or 5-8 membered heteroaryloxy; Preferably,R is selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, allyl, cyclopropyl, methyl Oxy, ethoxy, cyclopropoxy, phenyl or acetyl.
作为进一步优选的方案，所述(Z)-N'-羟基-N-苯基甲脒衍生物、其立体异构体或其药学上可接受盐，选自式(Ⅳ)化合物：As a further preferred solution, the (Z)-N'-hydroxy-N-phenylcarboxamidine derivatives, their stereoisomers or pharmaceutically acceptable salts thereof are selected from compounds of formula (IV):
其中，n1选自0、1、2或3；n2、n3各自独立的选自0、1或2；Wherein, n1 is selected from 0, 1, 2 or 3; n2 and n3 are each independently selected from 0, 1 or 2;
每个Ra1、Ra2、Rb1、Rb2、Rc1、Rc2各自独立的选自氢、氘、卤素、羟基、巯基、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基硫基、C5-8芳基、C5-8芳基氧基、C5-8芳基硫基、5-8元杂芳基、5-8元杂芳基氧基、5-8元杂芳基硫基、-C0-4-S(O)rR4、-C0-4-O-R5、-C0-4-C(O)OR5、-C0-4-C(O)R6、-C0-4-O-C(O)R6、-C0-4-NR7R8、-C0-4-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5；优选的，每个Ra1、Ra2、Rb1、Rb2、Rc1、Rc2各自独立的选自氢、氘、卤素、羟基、氰基、硝基、叠氮基、甲基、乙基、异丙基、三氟甲基、烯丙基、环丙基、甲氧基、乙氧基、环丙氧基、甲氧甲基、苯基、磺酰基、甲磺酰基、异丙磺酰基、苯磺酰基、羧基、甲氧羰基、乙氧羰基、异丙氧羰基、乙酰氧基、乙酰基、氨基、二甲氨基、乙酰氨基或氨基羰基；更优选的，每个Ra1、Ra2、Rb1、Rb2、Rc1、Rc2各自独立的选自氢、氘、氟、溴、羟基、氰基、三氟甲基、环丙基、磺酰基、甲磺酰基、异丙磺酰基、羧基、氨基或二甲氨基。Each Ra1 , Ra2 , Rb1 , Rb2 , Rc1 , Rc2 is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, azido, C1-4 alkyl , C2-4 alkenyl, C2-4 alkynyl, halogen substituted C1-4 alkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy Base, 3-6 membered heterocyclylthio, C5-8 aryl, C5-8 aryloxy, C5-8 arylthio, 5-8 membered heteroaryl, 5-8 membered hetero Aryloxy, 5-8 membered heteroarylthio, -C0-4 -S(O)r R4 , -C0-4 -OR5 , -C0-4 -C(O)OR5 , -C0-4 -C(O)R6 , -C0-4 -OC(O)R6 , -C0-4 -NR7 R8 , -C0-4 -C(O)NR7 R8 , -N(R7 )-C(O)R6 or -N(R7 )-C(O)OR5 ; preferably, each of Ra1 , Ra2 , Rb1 , Rb2 , Rc1 , Rc2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, azido, methyl, ethyl, isopropyl, trifluoromethyl, allyl, cyclopropyl, methyl Oxy, ethoxy, cyclopropoxy, methoxymethyl, phenyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, benzenesulfonyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl , acetoxy, acetyl, amino, dimethylamino, acetylamino or aminocarbonyl; more preferably, each of Ra1 , Ra2 , Rb1 , Rb2 , Rc1 , Rc2 is independently selected from hydrogen, Deuterium, fluorine, bromine, hydroxy, cyano, trifluoromethyl, cyclopropyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, carboxy, amino or dimethylamino.
作为更进一步优选的方案，所述(Z)-N'-羟基-N-苯基甲脒衍生物、其立体异构体或其药学上可接受盐，选自如下化合物：As a further preferred solution, the (Z)-N'-hydroxy-N-phenylcarboxamidine derivatives, their stereoisomers or pharmaceutically acceptable salts thereof are selected from the following compounds:
其中，R1选自氢、氘、卤素、羟基、氰基、硝基、叠氮基、甲基、乙基、异丙基、三氟甲基、烯丙基、环丙基、甲氧基、乙氧基、环丙氧基、甲氧甲基、苯基、磺酰基、甲磺酰基、异丙磺酰基、苯磺酰基、羧基、甲氧羰基、乙氧羰基、异丙氧羰基、乙酰氧基、乙酰基、氨基、二甲氨基、乙酰氨基或氨基羰基；优选的，R1选自氢、氘、氟、溴、羟基、氰基、三氟甲基、环丙基、磺酰基、甲磺酰基、异丙磺酰基、羧基、氨基或二甲氨基；更优选的，R1选自氢、氘、氟、溴或三氟甲基；Wherein , R is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, azido, methyl, ethyl, isopropyl, trifluoromethyl, allyl, cyclopropyl, methoxy , ethoxy, cyclopropoxy, methoxymethyl, phenyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, benzenesulfonyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, acetyl Oxygen, acetyl, amino, dimethylamino, acetylamino or aminocarbonyl; Preferably, R is selected from hydrogen, deuterium, fluorine, bromine, hydroxyl, cyano, trifluoromethyl, cyclopropyl, sulfonyl, Methanesulfonyl, isopropylsulfonyl, carboxyl, amino or dimethylamino; more preferably, R is selected from hydrogen, deuterium, fluorine, bromine or trifluoromethyl;
R2选自氢、氘、C1-4烷基、卤取代C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C5-8芳基、5-8元杂芳基或C0-4烷基羰基；优选的，R2选自氢、氘、甲基、乙基、异丙基、三氟甲基、烯丙基、环丙基、苯基或乙酰基；R2 is selected from hydrogen, deuterium, C1-4 alkyl, halogen substituted C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, 3- 6-membered heterocyclic group, C5-8 aryl, 5-8 membered heteroaryl or C0-4 alkylcarbonyl; preferably, R2 is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, Trifluoromethyl, allyl, cyclopropyl, phenyl or acetyl;
R3选自氢、氘、羟基、氨基、C1-4烷基、卤取代C1-4烷基、C2-4链烯基、C3-6环烷基、3-6元杂环基、C5-8芳基、5-8元杂芳基、C1-4烷氧基、C3-6环烷氧基、3-6元杂环基氧基、C5-8芳基氧基或5-8元杂芳基氧基；优选的，R3选自氢、氘、羟基、甲基、乙基、异丙基、三氟甲基、烯丙基、环丙基、甲氧基、乙氧基、环丙氧基、苯基或乙酰基。R3 is selected from hydrogen, deuterium, hydroxyl, amino, C1-4 alkyl, halogen substituted C1-4 alkyl, C2-4 alkenyl, C3-6 cycloalkyl, 3-6 membered heterocycle Base, C5-8 aryl, 5-8 membered heteroaryl, C1-4 alkoxy, C3-6 cycloalkoxy, 3-6 membered heterocyclyloxy, C5-8 aryl Oxygen or 5-8 membered heteroaryloxy; Preferably,R is selected from hydrogen, deuterium, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl, allyl, cyclopropyl, methyl Oxy, ethoxy, cyclopropoxy, phenyl or acetyl.
本发明另一方面提供一种前所述(Z)-N’-羟基-N-苯基甲脒衍生物、其立体异构体或其药学上可接受盐的制备方法，包括如下制备步骤：Another aspect of the present invention provides a method for preparing the aforementioned (Z)-N'-hydroxy-N-phenylformamidine derivative, its stereoisomer or a pharmaceutically acceptable salt thereof, comprising the following preparation steps:
式(IA)化合物在酸性条件下进行反应得到通式(I)化合物；其中：X、Y、R1、R2、R3、R4、R5、R6、R7、R8、m、r如式(I)化合物所定义。The compound of formula (IA) is reacted under acidic conditions to obtain the compound of general formula (I); wherein: X, Y, R1 , R2 , R3 , R4 , R5 , R6 , R7 , R8 , m , r are as defined for the compound of formula (I).
本发明另一方面提供一种药物组合物，所述药物组合物包括治疗有效剂量的前述化合物、其立体异构体或其药学上可接受盐及可药用的载体。Another aspect of the present invention provides a pharmaceutical composition, which comprises a therapeutically effective dose of the aforementioned compound, its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
本发明另一方面提供一种前述化合物、其立体异构体或其药学上可接受盐、或前述药物组合物在制备药物中的应用，所述药物用于抑制吲哚胺2,3-双加氧酶的活性或者用于抑制患者的免疫抑制。Another aspect of the present invention provides the application of the aforementioned compound, its stereoisomer or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition in the preparation of a medicament for inhibiting indoleamine 2,3-bis Oxygenase activity or used to suppress immunosuppression in patients.
本发明另一方面提供一种前述化合物、其立体异构体或其药学上可接受盐、或前述药物组合物在制备药物中的应用，所述药物用于治疗或预防患者的癌症或肿瘤、病毒感染、抑郁症、神经变性病症、创伤、年龄相关的白内障、器官移植排斥或自身免疫疾病；优选的，其中所述癌症或肿瘤选自肺癌、骨癌、胃癌、胰腺癌、皮肤癌、头颈癌、子宫癌、卵巢癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、直肠癌、结肠癌、肛门区癌、乳腺癌、食管癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、尿道癌、阴茎癌、前列腺癌、胰腺癌、脑癌、睾丸癌、淋巴癌、移行细胞癌、膀胱癌、肾癌或输尿管癌、肾细胞癌、肾盂癌、霍奇金病、非霍奇金淋巴瘤、软组织肉瘤、儿童实体瘤、淋巴细胞性淋巴瘤、中枢神经系统(CNS)肿瘤、原发性中枢神经系统淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干神经胶质瘤、垂体腺瘤、黑素瘤、卡波西肉瘤、表皮样癌、鳞状细胞癌、T细胞淋巴瘤、慢性或急性白血病和所述癌的组合。Another aspect of the present invention provides the application of the aforementioned compound, its stereoisomer or pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition in the preparation of medicines, which are used to treat or prevent cancer or tumors in patients, Viral infection, depression, neurodegenerative disorders, trauma, age-related cataracts, organ transplant rejection or autoimmune disease; preferably, wherein the cancer or tumor is selected from lung cancer, bone cancer, gastric cancer, pancreatic cancer, skin cancer, head and neck Cancer, Uterine Cancer, Ovarian Cancer, Testicular Cancer, Uterine Cancer, Fallopian Tube Cancer, Endometrial Cancer, Cervical Cancer, Vaginal Cancer, Vulvar Cancer, Rectal Cancer, Colon Cancer, Anal Region Cancer, Breast Cancer, Esophagus Cancer, Small Intestine Cancer , endocrine system, thyroid, parathyroid, adrenal, urethra, penis, prostate, pancreas, brain, testis, lymph, transitional cell, bladder, kidney, or ureter, Renal Cell Carcinoma, Renal Pelvic Cancer, Hodgkin's Disease, Non-Hodgkin's Lymphoma, Soft Tissue Sarcoma, Pediatric Solid Tumors, Lymphoblastic Lymphoma, Central Nervous System (CNS) Tumors, Primary CNS Lymphoma, Tumors Angiogenesis, spinal tumors, brainstem gliomas, pituitary adenomas, melanomas, Kaposi's sarcoma, epidermoid carcinomas, squamous cell carcinomas, T-cell lymphomas, chronic or acute leukemias, and combinations of said carcinomas .
作为进一步优选的方案，所述的应用是指将治疗有效剂量的前述的化合物、其立体异构体或其药学上可接受盐、或前述药物组合物与抗CTLA-4抗体、抗PD-1抗体、抗PD-L1抗体、抗病毒剂、化疗剂、免疫抑制剂、辐射、抗肿瘤疫苗、抗病毒疫苗、细胞因子疗法或酪氨酸激酶抑制剂进行联合用药；优选的，所述细胞因子优选IL-2、IL-3、IL-4或IL-5，所述化疗剂优选细胞毒性剂，所述抗PD-1抗体优选Keytruda抗体。As a further preferred solution, the application refers to combining the therapeutically effective dose of the aforementioned compound, its stereoisomer or its pharmaceutically acceptable salt, or the aforementioned pharmaceutical composition with anti-CTLA-4 antibody, anti-PD-1 Antibody, anti-PD-L1 antibody, antiviral agent, chemotherapeutic agent, immunosuppressant, radiation, antitumor vaccine, antiviral vaccine, cytokine therapy or tyrosine kinase inhibitor are used in combination; preferably, the cytokine Preferably IL-2, IL-3, IL-4 or IL-5, the chemotherapeutic agent is preferably a cytotoxic agent, and the anti-PD-1 antibody is preferably a Keytruda antibody.
本发明另一方面提供一种调节吲哚胺2,3-双加氧酶活性的方法，所述方法包括将治疗有效剂量的前述化合物、其立体异构体或其药学上可接受盐、或前述药物组合物与吲哚胺2,3-双加氧酶接触；优选的，所述调节优选为抑制作用。Another aspect of the present invention provides a method for modulating the activity of indoleamine 2,3-dioxygenase, the method comprising administering a therapeutically effective dose of the aforementioned compound, its stereoisomer or a pharmaceutically acceptable salt thereof, or The aforementioned pharmaceutical composition is contacted with indoleamine 2,3-dioxygenase; preferably, the adjustment is preferably inhibition.
本发明另一方面提供一种抑制患者的免疫抑制的方法，所述方法包括将治疗有效剂量的前述化合物、其立体异构体或其药学上可接受盐、或前述药物组合物给予患者。Another aspect of the present invention provides a method for suppressing immunosuppression in a patient, the method comprising administering a therapeutically effective dose of the aforementioned compound, its stereoisomer or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition to the patient.
具体实施方式detailed description
详细说明：除非有相反陈述，下列用在说明书和权利要求书中的术语具有下述含义。DETAILED DESCRIPTION: Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
“C1-8烷基”指包括1至8个碳原子的直链烷基和含支链烷基，烷基指饱和的脂族烃基团，C0-8是指不含碳原子或者C1-8烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2，3-二甲基戊基、2，4-二甲基戊基、2，2-二甲基戊基、3，3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2，3-二甲基己基、2，4-二甲基己基、2，5-二甲基己基、2，2-二甲基己基、3，3-二甲基己基、4，4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基或其各种支链异构体等。"C1-8 alkyl" refers to straight chain alkyl and branched chain alkyl including 1 to 8 carbon atoms, alkyl refers to saturated aliphatic hydrocarbon group, C0-8 refers to no carbon atoms or C1-8 Alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 , 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 - ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof, and the like.
烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代；Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from halogen, hydroxy, mercapto, Cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halogen substituted C1-8 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 aryl Thio, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy, 5-10-membered heteroarylthio, -C0-8 -S(O)r R4 , -C0-8 -OR5 , -C0-8 -C(O)OR5 , -C0-8 -C(O)R6 , -C0-8 -OC(O)R6 , -C0-8 -NR7 R8 , -C0-8 -C(O)NR7 R8 , -N(R7 )-C(O)R6 or -N(R7 )-C(O)OR5 replace;
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，“C3-8环烷基”指包括3至8个碳原子的环烷基，“5-10元环烷基”指包括5至10个碳原子的环烷基，例如："Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, "C3-8 cycloalkyl" refers to a cycloalkyl group comprising 3 to 8 carbon atoms, and "5-10 membered ring "Alkyl" means a cycloalkyl group comprising 5 to 10 carbon atoms, for example:
单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl alkenyl, cyclooctyl, etc.
多环环烷基包括螺环、稠环和桥环的环烷基。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基基或多螺环烷基，螺环烷基的非限制性实施例包含：Multicyclic cycloalkyls include spiro, fused and bridged cycloalkyls. "Spirocycloalkyl" refers to polycyclic groups in which single rings share one carbon atom (called a spiro atom), these may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Spirocycloalkyl groups are classified as single spirocycloalkyl, double spirocycloalkyl or multiple spirocycloalkyl according to the number of spiro atoms shared between the rings, non-limiting examples of spirocycloalkyl include:
“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，稠环烷基的非限制性实施例包含："fused cycloalkyl" means an all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, one or more of which may contain one or more double bonds, but None of the rings have a fully conjugated π-electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups. Non-limiting examples of fused cycloalkyl groups include:
“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，桥环烷基的非限制性实施例包含："Bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms not directly attached, these may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system . According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实施例包括茚满基、四氢萘基、苯并环庚烷基等。The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring where the ring attached to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydro Naphthyl, benzocycloheptyl, etc.
环烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代；Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido , C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halogen substituted C1-8 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, 3 -8-membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 arylthio, 5-10 membered heteroaryl radical, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8 -S(O)r R4 , -C0-8 -OR5 , -C0-8 -C(O)OR5 , -C0-8 -C(O)R6 , -C0-8 -OC(O)R6 , -C0-8 -NR7 R8 , -C0-8 Substituents of -C(O)NR7 R8 , -N(R7 )-C(O)R6 or -N(R7 )-C(O)OR5 ;
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。“5-10元杂环基”指包含5至10个环原子的环基，“3-8元杂环基”指包含3至8个环原子的环基。"Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O)r (where r is an integer 0, 1, 2 ), but excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. "5-10 membered heterocyclic group" refers to a ring group containing 5 to 10 ring atoms, and "3-8 membered heterocyclic group" refers to a ring group containing 3 to 8 ring atoms.
单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
多环杂环基包括螺环、稠环和桥环的杂环基。“螺杂环基”指单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环基、双螺杂环基或多螺杂环基。螺环烷基的非限制性实施例包含：Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls. "Spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O)r (where r is an integer 0, 1, 2), and the remaining ring atoms are carbon. These can contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. According to the number of spiro atoms shared between rings, spirocycloalkyl groups are classified as single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl. Non-limiting examples of spirocycloalkyl groups include:
“稠杂环基”指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基，稠杂环基的非限制性实施例包含："fused heterocyclyl" means a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none The ring has a fully conjugated π-electron system, with one or more ring atoms selected from nitrogen, oxygen, or a heteroatom of S(O)r (where r is an integer 0, 1, 2), and the remaining ring atoms being carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups. Non-limiting examples of fused heterocyclyl groups include:
“桥杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，桥环烷基的非限制性实施例包含："Bridged heterocyclyl" means a polycyclic heterocyclic group in which any two rings share two atoms not directly connected, these may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system, One or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)r (wherein r is an integer of 0, 1, 2), and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，非限制性实施例包含：The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl, non-limiting examples include:
杂环基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代；Heterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido , C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halogen substituted C1-8 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, 3 -8-membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 arylthio, 5-10 membered heteroaryl radical, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8 -S(O)r R4 , -C0-8 -OR5 , -C0-8 -C(O)OR5 , -C0-8 -C(O)R6 , -C0-8 -OC(O)R6 , -C0-8 -NR7 R8 , -C0-8 Substituents of -C(O)NR7 R8 , -N(R7 )-C(O)R6 or -N(R7 )-C(O)OR5 ;
“芳基”指全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，具有共轭的π电子体系的多环(即其带有相邻对碳原子的环)基团，“C5-10芳基”指含有5-10个碳的全碳芳基，“5-10元芳基”指含有5-10个碳的全碳芳基，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，非限制性实施例包含："Aryl" means an all-carbon monocyclic or fused polycyclic (that is, rings that share adjacent pairs of carbon atoms) group, a polycyclic (that is, its rings with adjacent pairs of carbon atoms) having a conjugated π-electron system ) group, "C5-10 aryl" refers to a full-carbon aryl group containing 5-10 carbons, and "5-10 membered aryl" refers to a full-carbon aryl group containing 5-10 carbons, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is an aryl ring, non-limiting examples include:
芳基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代；Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferablyone or more of the following groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halogen substituted C1-8 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered Heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 arylthio, 5-10 membered heteroaryl, 5 -10-membered heteroaryloxy, 5-10-membered heteroarylthio, -C0-8 -S(O)r R4 , -C0-8 -OR5 , -C0-8 -C( O)OR5 , -C0-8 -C(O)R6 , -C0-8 -OC(O)R6 , -C0-8 -NR7 R8 , -C0-8 -C( Substituents of O) NR7 R8 , -N(R7 )-C(O)R6 or -N(R7 )-C(O)OR5 ;
“杂芳基”指包含1至4个杂原子的杂芳族体系，所述杂原子包括氮、氧和S(O)r(其中r是整数0、1、2)的杂原子，5-7元杂芳基指含有5-7个环原子的杂芳族体系，5-10元杂芳基指含有5-10个环原子的杂芳族体系，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包含："Heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, including nitrogen, oxygen, and S(O)r (where r is an integer 0, 1, 2) heteroatoms, 5- 7-membered heteroaryl refers to a heteroaromatic system containing 5-7 ring atoms, and 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, such as furyl, thienyl, pyridyl, Pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples include:
杂芳基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代；Heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halogen substituted C1-8 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, 3- 8-membered heterocyclyloxy, 3-8-membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 arylthio, 5-10-membered heteroaryl , 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8 -S(O)r R4 , -C0-8 -OR5 , -C0-8 - C(O)OR5 , -C0-8 -C(O)R6 , -C0-8 -OC(O)R6 , -C0-8 -NR7 R8 , -C0-8 - Substituents of C(O)NR7 R8 , -N(R7 )-C(O)R6 or -N(R7 )-C(O)OR5 ;
“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上述定义的烷基，C2-8链烯基指含有2-8个碳的直链或含支链烯基。例如乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等。"Alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, and C2-8 alkenyl means a straight or branched alkenyl group containing 2 to 8 carbons base. For example vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl and the like.
烯基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代；Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferablyone or more of the following groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halogen substituted C1-8 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered Heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 arylthio, 5-10 membered heteroaryl, 5 -10-membered heteroaryloxy, 5-10-membered heteroarylthio, -C0-8 -S(O)r R4 , -C0-8 -OR5 , -C0-8 -C( O)OR5 , -C0-8 -C(O)R6 , -C0-8 -OC(O)R6 , -C0-8 -NR7 R8 , -C0-8 -C( Substituents of O) NR7 R8 , -N(R7 )-C(O)R6 or -N(R7 )-C(O)OR5 ;
“炔基”指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基，C2-8链炔基指含有2-8个碳的直链或含支链炔基。例如乙炔基、1-丙炔基、2-丙炔基、1-，2-或3-丁炔基等。"Alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, and C2-8 alkynyl refers to a straight-chain or branched-chain alkynyl group containing 2-8 carbons . For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and the like.
炔基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代；Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferablyone or more of the following groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halogen substituted C1-8 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered Heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 arylthio, 5-10 membered heteroaryl, 5 -10-membered heteroaryloxy, 5-10-membered heteroarylthio, -C0-8 -S(O)r R4 , -C0-8 -OR5 , -C0-8 -C( O)OR5 , -C0-8 -C(O)R6 , -C0-8 -OC(O)R6 , -C0-8 -NR7 R8 , -C0-8 -C( Substituents of O) NR7 R8 , -N(R7 )-C(O)R6 or -N(R7 )-C(O)OR5 ;
“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。C1-8烷氧基指含1-8个碳的烷基氧基，非限制性实施例包含甲氧基、乙氧基、丙氧基、丁氧基等。"Alkoxy" means -O-(alkyl), wherein alkyl is as defined above. C1-8 alkoxy refers to an alkyloxy group containing 1-8 carbons, non-limiting examples include methoxy, ethoxy, propoxy, butoxy and the like.
烷氧基可以是任选取代的或未取代的，当被取代时，取代基，优选为一个或多个以下基团，独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代；Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituents, preferably one or more of the following groups, are independently selected from halogen, hydroxy, mercapto, cyano, nitro, azide Base, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halogen substituted C1-8 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10 aryl, C5-10 aryloxy, C5-10 arylthio, 5-10 membered hetero Aryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8 -S(O)r R4 , -C0-8 -OR5 , -C0- 8 -C(O)OR5 , -C0-8 -C(O)R6 , -C0-8 -OC(O)R6 , -C0-8 -NR7 R8 , -C0- 8 -C(O)NR7 R8 , -N(R7 )-C(O)R6 or -N(R7 )-C(O)OR5 are substituted by substituents;
“卤取代的C1-8烷基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-8个碳烷基基团，例如二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基等。"Halogen substituted C1-8 alkyl" refers to 1-8 carbon alkyl groups whose hydrogen on the alkyl is optionally substituted by fluorine, chlorine, bromine, iodine atoms, such as difluoromethyl, dichloromethane group, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
“卤取代的C1-8烷氧基”烷基上的氢任选的被氟、氯、溴、碘原子取代的1-8个碳烷氧基基团。例如二氟甲氧基、二氯甲氧基、二溴甲氧基、三氟甲氧基、三氯甲氧基、三溴甲氧基等。"Halogen-substituted C1-8 alkoxy" is an alkoxy group of 1-8 carbons in which the hydrogen on the alkyl group is optionally substituted by fluorine, chlorine, bromine, or iodine atoms. For example, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.
“卤素”指氟、氯、溴或碘。"Halogen" means fluorine, chlorine, bromine or iodine.
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, a "heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和键(如烯属)的碳原子结合时可能是不稳定的。"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated bond (eg, olefinic).
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
下面结合实施例对本发明做进一步详细、完整地说明，但决非限制本发明，本发明也并非仅局限于实施例的内容。The present invention will be described in further detail and completely below in conjunction with the examples, but it is by no means limiting the present invention, and the present invention is not limited only to the content of the examples.
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代甲醇(CD3OD)和氘代氯仿(CDCl3)内标为四甲基硅烷(TMS)。The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). The determination of NMR is carried out with Bruker AVANCE-400 nuclear magnetic apparatus, and the determination solvent is deuterated methanol (CD3 OD) and deuterated chloroform (CDCl3 ), and the internal standard is tetramethylsilane (TMS).
液质联用色谱LC-MS的测定用Agilent 1200Infinity Series质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。Agilent 1200 Infinity Series mass spectrometer was used for liquid chromatography-mass chromatography LC-MS determination. The determination of HPLC uses Agilent 1200DAD high pressure liquid chromatography (Sunfire C18 150×4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6mm chromatographic column).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin-layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。The starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or following methods known in the art.
在无特殊说明的情况下，本发明的所有反应均在连续的磁搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂。Unless otherwise specified, all reactions in the present invention are carried out under a dry nitrogen or argon atmosphere under continuous magnetic stirring, and the solvent is a dry solvent.
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。氢气氛是指反应瓶连接一个约1L容积的氢气气球。The argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L. The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
在无特殊说明的情况下，实施例中的溶液是指水溶液。反应的温度为室温。室温为最适宜的反应温度，为20℃～30℃。Unless otherwise specified, the solutions in the examples refer to aqueous solutions. The reaction temperature is room temperature. Room temperature is the most suitable reaction temperature, which is 20°C to 30°C.
实施例中的反应进程的监测采用薄层色谱法(TLC)或液质联用色谱(LC-MS)反应所使用的展开剂体系有：二氯甲烷和甲醇体系，正己烷和乙酸乙酯体系，石油醚和乙酸乙酯体系，丙酮，溶剂的体积比可根据化合物的极性不同而进行调节。柱层析的洗脱剂的体系包括：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：二氯甲烷和乙酸乙酯体系，D：乙酸乙酯和甲醇，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的氨水和醋酸等进行调节。The monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC) or liquid chromatography-mass chromatography (LC-MS). , Petroleum ether and ethyl acetate system, acetone, the volume ratio of the solvent can be adjusted according to the polarity of the compound. The eluent system of column chromatography includes: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and ethyl acetate system, D: ethyl acetate and methanol, solvent The volume ratio is adjusted according to the polarity of the compound, and can also be adjusted by adding a small amount of ammonia and acetic acid.
实施例一Embodiment one
(Z)-N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(S-甲基磺亚胺酰基)乙基)氨基)-1,2,(Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(S-methylsulfonimidoyl)ethyl)amino)-1,2,5-噁二唑-3-碳杂氧杂脒(1)5-oxadiazole-3-carbaoxamidine (1)
步骤一:4-氨基-N'-羟基-1,2,5-噁二唑-3-碳杂氧杂脒1bStep 1: 4-Amino-N'-hydroxy-1,2,5-oxadiazole-3-carbaoxamidine 1b
将丙二氰(20g,303mmol)溶于350ml水中,45℃加热5分钟,然后冰浴下加入亚硝酸钠(23g,333.3mmol),当温度升到10℃时加入6N HCl(3.4ml),温度升到16℃,保持温度在16-18℃下搅拌1.5小时,冷却到13℃,一次性加入50％羟胺水溶液(61.7g,909mmol),温度急剧升高到27℃,在此温度下搅拌一个小时,然后再回流2小时,冷却至室温搅拌过夜,在冰浴下滴加6N HCl(49ml),调节PH至7，继续冰浴下搅拌，析出固体，过滤，滤饼用水洗，干燥得到化合物4-氨基-N'-羟基-1,2,5-噁二唑-3-碳杂氧杂脒1b(40g，92％)。MS m/z(ESI):143.9。Dissolve malondicyanide (20g, 303mmol) in 350ml of water, heat at 45°C for 5 minutes, then add sodium nitrite (23g, 333.3mmol) under ice-cooling, add 6N HCl (3.4ml) when the temperature rises to 10°C, The temperature rose to 16°C, kept the temperature at 16-18°C and stirred for 1.5 hours, cooled to 13°C, added 50% hydroxylamine aqueous solution (61.7g, 909mmol) at one time, the temperature rose sharply to 27°C, and stirred at this temperature One hour, then reflux for 2 hours, cool to room temperature and stir overnight, add 6N HCl (49ml) dropwise under ice bath, adjust the pH to 7, continue stirring under ice bath, precipitate solid, filter, wash the filter cake with water, and dry to obtain Compound 4-amino-N'-hydroxy-1,2,5-oxadiazole-3-carbaoxamidine 1b (40 g, 92%). MS m/z (ESI): 143.9.
13CNMR(400MHz,CD3OD,ppm):δ154.5,144.4,139.7。13 CNMR (400MHz, CD3OD, ppm): δ154.5, 144.4, 139.7.
步骤二:4-氨基-N-羟基-1,2,5-噁二唑-3-碳杂亚胺酰基氯化1cStep 2: 4-Amino-N-hydroxyl-1,2,5-oxadiazole-3-carbaimide acyl chloride 1c
将化合物4-氨基-N'-羟基-1,2,5-噁二唑-3-碳杂氧杂脒(8.4g,59mmol)溶于100ml水和冰醋酸(60ml)中,加入6N HCl(29ml),加热至完全溶解,然后加入NaCl(10.36g,59.5mmol),再在冰浴下加入亚硝酸钠(3.99g,5.78mmol)的水溶液(14ml),保持温度在0℃搅拌1.5小时，然后搅拌至室温，析出固体，过滤，滤饼用水洗，干燥得到化合物4-氨基-N-羟基-1,2,5-噁二唑-3-碳杂亚胺酰基氯化1c(4g，42％)。MS m/z(ESI):162.9。Compound 4-amino-N'-hydroxyl-1,2,5-oxadiazole-3-carbaoxamidine (8.4g, 59mmol) was dissolved in 100ml water and glacial acetic acid (60ml), and 6N HCl ( 29ml), heated until completely dissolved, then added NaCl (10.36g, 59.5mmol), then added an aqueous solution (14ml) of sodium nitrite (3.99g, 5.78mmol) under ice-cooling, kept the temperature at 0°C and stirred for 1.5 hours, Then stirred to room temperature, precipitated solid, filtered, washed the filter cake with water, dried to obtain the compound 4-amino-N-hydroxyl-1,2,5-oxadiazole-3-carbaimide acid chloride 1c (4g, 42 %). MS m/z (ESI): 162.9.
13CNMR(400MHz,CD3OD,ppm):δ154.3,141.9,127.0。13 CNMR (400MHz, CD3OD, ppm): δ154.3, 141.9, 127.0.
步骤三:4-氨基-N'-羟基-N-(2-甲氧基乙基)-1,2,5-噁二唑-3-碳杂氧杂脒1dStep 3: 4-amino-N'-hydroxy-N-(2-methoxyethyl)-1,2,5-oxadiazole-3-carbaoxamidine 1d
将化合物4-氨基-N-羟基-1,2,5-噁二唑-3-碳杂亚胺酰基氯化(4.0g,24.7mmol)溶于乙酸乙酯(40ml)中,冰浴下加入2-甲氧基乙烷-1-胺(2.29ml,25.9mmol)搅拌5分钟,再加入三乙胺(5.16ml,37.05mmol)搅拌二小时至反应完全,水洗，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得到化合物4-氨基-N'-羟基-N-(2-甲氧基乙基)-1,2,5-噁二唑-3-碳杂氧杂脒1d(4.5g，92％)。MS m/z(ESI):202.1。The compound 4-amino-N-hydroxyl-1,2,5-oxadiazole-3-carbaimide acid chloride (4.0g, 24.7mmol) was dissolved in ethyl acetate (40ml), and added under ice-cooling 2-Methoxyethane-1-amine (2.29ml, 25.9mmol) was stirred for 5 minutes, then triethylamine (5.16ml, 37.05mmol) was added and stirred for 2 hours until the reaction was complete, washed with water, washed with saturated brine, anhydrous sulfuric acid The organic phase was dried over sodium and concentrated under reduced pressure to obtain the compound 4-amino-N'-hydroxy-N-(2-methoxyethyl)-1,2,5-oxadiazole-3-carbaoxamidine 1d (4.5 g, 92%). MS m/z (ESI): 202.1.
1H NMR(400MHz,DMSO,ppm):δ10.67(s,1H),6.28(s,2H),6.14(s,1H),3.56(m,2H),3.44(m,2H),3.28(s,3H)。1 H NMR (400MHz, DMSO, ppm): δ10.67(s,1H),6.28(s,2H),6.14(s,1H),3.56(m,2H),3.44(m,2H),3.28( s, 3H).
步骤四:N'-羟基-4-((2-甲氧基乙基)氨基)-1,2,5-噁二唑-3-碳杂氧杂脒1eStep 4: N'-Hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazole-3-carbaoxamidine 1e
将化合物4-氨基-N'-羟基-N-(2-甲氧基乙基)-1,2,5-噁二唑-3-碳杂氧杂脒(4.5g,22.3mmol)溶于水(40ml)中,加入氢氧化钾(4.15g,74.1mmol)回流48小时至反应完全,用乙酸乙酯萃取,水洗有机相，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得到化合物N'-羟基-4-((2-甲氧基乙基)氨基)-1,2,5-噁二唑-3-碳杂氧杂脒1e(2.8g，62％)。MS m/z(ESI):202.1。The compound 4-amino-N'-hydroxyl-N-(2-methoxyethyl)-1,2,5-oxadiazole-3-carbaoxamidine (4.5g, 22.3mmol) was dissolved in water (40ml), add potassium hydroxide (4.15g, 74.1mmol), reflux for 48 hours until the reaction is complete, extract with ethyl acetate, wash the organic phase with water, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain Compound N'-hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazole-3-carbaoxamidine 1e (2.8 g, 62%). MS m/z (ESI): 202.1.
1H NMR(400MHz,DMSOd6,ppm):δ10.53(s,1H),6.22(s,2H),6.15(s,1H),3.56(m,2H),3.50(m,2H),3.37(s,3H)。1 H NMR(400MHz,DMSOd6 ,ppm):δ10.53(s,1H),6.22(s,2H),6.15(s,1H),3.56(m,2H),3.50(m,2H),3.37 (s,3H).
步骤五:N-羟基-4-((2-甲氧基乙基)氨基)-1,2,5-噁二唑-3-碳杂亚胺酰基氯化Step 5: N-hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazole-3-carboimide acyl chloride1f1f
将化合物N'-羟基-4-((2-甲氧基乙基)氨基)-1,2,5-噁二唑-3-碳杂氧杂脒(2.8g,13.93mmol)溶于6N HCl(14ml)待溶液澄清后加入氯化钠水(2.2g,41.79mmol),然后再加水(14ml)和乙酸乙酯(14ml),冰浴下滴加亚硝酸钠(1.0g,13.3mmol)冰浴下搅拌2小时，然后室温搅拌过夜至反应完全,用乙酸乙酯萃取,水洗有机相，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得固体用乙酸乙酯：石油醚(3/20)洗得到化合物N-羟基-4-((2-甲氧基乙基)氨基)-1,2,5-噁二唑-3-碳杂亚胺酰基氯化1f(2.2g，72％)。MS m/z(ESI):221.1。The compound N'-hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazole-3-carbaoxamidine (2.8g, 13.93mmol) was dissolved in 6N HCl (14ml) After the solution is clarified, add sodium chloride water (2.2g, 41.79mmol), then add water (14ml) and ethyl acetate (14ml), add sodium nitrite (1.0g, 13.3mmol) dropwise under ice bath Stir in the bath for 2 hours, then stir overnight at room temperature until the reaction is complete, extract with ethyl acetate, wash the organic phase with water, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a solid. Use ethyl acetate:petroleum ether ( 3/20) was washed to obtain the compound N-hydroxyl-4-((2-methoxyethyl)amino)-1,2,5-oxadiazole-3-carbaimidoyl chloride 1f (2.2g, 72%). MS m/z (ESI): 221.1.
1HNMR(400MHz,DMSOd6,ppm):δ13.47(s,1H),6.22(s,2H),5.99(s,1H),3.43(m,2H),3.53(m,2H),3.28(s,3H)。1 HNMR (400MHz, DMSOd6 , ppm): δ13.47(s,1H),6.22(s,2H),5.99(s,1H),3.43(m,2H),3.53(m,2H),3.28( s, 3H).
步骤六:N-(3-溴-4-氟苯基)-N'-羟基-4-((2-甲氧基乙基)氨基)-1,2,5-噁二唑-Step 6: N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazole-3-碳杂氧杂脒1g3-carbaoxaamidine 1g
将化合物N-羟基-4-((2-甲氧基乙基)氨基)-1,2,5-噁二唑-3-碳杂亚胺酰基氯化(2.2g,10mmol)加入水(14ml)加热至60℃，加入3-溴-4-氟苯胺(2.06g,11mmol),搅拌10分钟，然后再加碳酸氢钠(1.26g,15mmol)60℃下搅拌30分钟，至反应完全,用乙酸乙酯萃取,水洗有机相，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得化合物1g(3.9g，100％)。MS m/z(ESI):374.0。The compound N-hydroxyl-4-((2-methoxyethyl)amino)-1,2,5-oxadiazole-3-carbaimide acid chloride (2.2g, 10mmol) was added to water (14ml ) to 60°C, add 3-bromo-4-fluoroaniline (2.06g, 11mmol), stir for 10 minutes, then add sodium bicarbonate (1.26g, 15mmol) and stir at 60°C for 30 minutes until the reaction is complete, use Extracted with ethyl acetate, washed the organic phase with water and saturated brine, dried the organic phase with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 1g (3.9g, 100%). MS m/z (ESI): 374.0.
1H NMR(400MHz,DMSOd6,ppm):δ11.54(s,1H),8.86(s,2H),7.10(m,1H),6.81(m,1H),6.15(m,1H)3.53(m,2H),3.39(m,2H),3.29(m,3H)。1 H NMR(400MHz,DMSOd6,ppm):δ11.54(s,1H),8.86(s,2H),7.10(m,1H),6.81(m,1H),6.15(m,1H)3.53(m ,2H), 3.39(m,2H), 3.29(m,3H).
步骤七:4-(3-溴-4-氟苯基)-3-(4-((2-甲氧基乙基)氨基)-1,2,5-噁二唑-3-Step 7: 4-(3-bromo-4-fluorophenyl)-3-(4-((2-methoxyethyl)amino)-1,2,5-oxadiazole-3-基)-1,2,4-噁二唑-5(4H)-酮1hbase)-1,2,4-oxadiazol-5(4H)-one 1h
将化合物N-(3-溴-4-氟苯基)-N'-羟基-4-((2-甲氧基乙基)氨基)-1,2,5-噁二唑-3-碳杂氧杂脒(3.9g,10.4mmol)加入乙酸乙酯(50ml),加热至60℃，加入1,1'-羰基二咪唑(2.53g,15.6mmol),搅拌30分钟，1N HCl洗有机相，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得化合物1h(4.0g，96％)。The compound N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazole-3-carba Add ethyl acetate (50ml) to oxamidine (3.9g, 10.4mmol), heat to 60°C, add 1,1'-carbonyldiimidazole (2.53g, 15.6mmol), stir for 30 minutes, wash the organic phase with 1N HCl, Wash with saturated brine, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain compound 1h (4.0 g, 96%).
步骤八:4-(3-溴-4-氟苯基)-3-(4-((2-羟基乙基)氨基)-1,2,5-噁二唑-3-基)-Step 8: 4-(3-bromo-4-fluorophenyl)-3-(4-((2-hydroxyethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-噁二唑-5(4H)-酮1i1,2,4-Oxadiazol-5(4H)-one 1i
将化合物8(4g,10mmol)加入二氯甲烷(25ml)在-78℃滴加三溴化硼的二氯甲烷溶液(25ml,25mmol),搅拌至室温，LC-MS监测原料原料转化完全，停止反应，冰浴下用饱和碳酸氢钠溶液调pH至中性，有机相用水洗，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得化合物1i(2.0g，96％)。MS m/z(ESI):385.9。Add compound 8 (4g, 10mmol) into dichloromethane (25ml) and add boron tribromide in dichloromethane (25ml, 25mmol) dropwise at -78°C, stir to room temperature, LC-MS monitors that the conversion of the raw material is complete, stop For the reaction, the pH was adjusted to neutral with saturated sodium bicarbonate solution under an ice bath, the organic phase was washed with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 1i (2.0 g, 96%). MS m/z (ESI): 385.9.
步骤九:2-((4-(4-(3-溴-4-氟苯基)-5-羰基-4,5-二氢-1,2,4-噁二唑-3-基)-1,Step 9: 2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)- 1,2,5-噁二唑-3-基)氨基)乙基甲磺酸酯1j2,5-oxadiazol-3-yl)amino)ethyl methanesulfonate 1j
将化合物4-(3-溴-4-氟苯基)-3-(4-((2-羟基乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(2g,5.2mmol)加入乙酸乙酯(15ml)室温下加入甲磺酰氯(593mg,5.2mmol),再加三乙胺(526mg,5.2mmol)，LC-MS监测原料原料转化完全，停止反应，有机相用水洗，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得化合物1j(2.0g，82％)。MSm/z(ESI):463.9。The compound 4-(3-bromo-4-fluorophenyl)-3-(4-((2-hydroxyethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2 , 4-Oxadiazol-5(4H)-one (2g, 5.2mmol) was added to ethyl acetate (15ml) and methanesulfonyl chloride (593mg, 5.2mmol) was added at room temperature, followed by triethylamine (526mg, 5.2mmol) , LC-MS monitored the complete conversion of raw materials, stopped the reaction, washed the organic phase with water, washed with saturated brine, dried the organic phase with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 1j (2.0 g, 82%). MS m/z (ESI): 463.9.
步骤十:4-(3-溴-4-氟苯基)-3-(4-((2-(甲硫基)乙基)氨基)-1,2,5-噁二唑-3-Step 10: 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(methylthio)ethyl)amino)-1,2,5-oxadiazole-3-基)-1,2,4-噁二唑-5(4H)-酮1kbase)-1,2,4-oxadiazol-5(4H)-one 1k
在100mL单口瓶中将2-((4-(4-(3-溴-4-氟苯基)-5-羰基-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)乙基甲磺酸酯1a(2.6g，5.60mmol)溶于N，N-二甲基甲酰胺(25mL)，用冰浴冷却至0℃,加入甲硫醇钠(43.1mg,6.16mmol),在冰浴条件下搅拌20min。LC-MS监测原料转化完全，停止反应，加入水(50mL)淬灭反应,用乙酸乙酯(50mL*2)萃取，合并有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液加硅胶，直接旋干柱层析，石油醚/乙酸乙酯(5/1到3/1)，得4-(3-溴-4-氟苯基)-3-(4-((2-(甲硫基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮1k(1.0g，42.8％)。2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3- Base)-1,2,5-oxadiazol-3-yl)amino)ethyl methanesulfonate 1a (2.6g, 5.60mmol) was dissolved in N,N-dimethylformamide (25mL) and washed with ice Cool the bath to 0°C, add sodium methyl mercaptide (43.1 mg, 6.16 mmol), and stir for 20 min under ice bath conditions. LC-MS monitored the complete conversion of raw materials, stopped the reaction, added water (50mL) to quench the reaction, extracted with ethyl acetate (50mL*2), combined organic phases were washed with saturated sodium chloride (50mL), dried over anhydrous sodium sulfate, Filtrate, add silica gel to the filtrate, spin dry column chromatography directly, petroleum ether/ethyl acetate (5/1 to 3/1), get 4-(3-bromo-4-fluorophenyl)-3-(4-( (2-(Methylthio)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 1k (1.0g, 42.8%).
MS m/z(ESI):416.0,418.0(M,M+2)。MS m/z (ESI): 416.0, 418.0 (M, M+2).
1H NMR(400MHz,CDCl3,ppm)δ7.62(dd,J1＝5.6Hz,J2＝2.4Hz,1H),7.33(m,2H),5.68(t,J＝5.2Hz,1H),3.60(dd,J1＝12.8Hz,J2＝6.4Hz,2H),2.80(t,J＝6.4Hz,2H),2.15(s,3H)。1 H NMR (400MHz, CDCl3 , ppm) δ7.62 (dd, J1 =5.6Hz, J2 =2.4Hz, 1H), 7.33 (m, 2H), 5.68 (t, J = 5.2Hz, 1H) , 3.60 (dd, J1 =12.8 Hz, J2 =6.4 Hz, 2H), 2.80 (t, J = 6.4 Hz, 2H), 2.15 (s, 3H).
步骤十一：4-(3-溴-4-氟苯基)-3-(4-((2-(甲基亚硫酰基)乙基)氨基)-1,2,5-噁Step 11: 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(methylsulfinyl)ethyl)amino)-1,2,5-oxa二唑-3-基)-1,2,4-噁二唑-5(4H)-酮1lOxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 1l
在100mL单口瓶中将4-(3-溴-4-氟苯基)-3-(4-((2-(甲硫基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(1.0g，2.41mmol)溶于二氯甲烷(30mL)，用干冰丙酮浴冷却至-40℃,将间氯过氧化苯甲酸(457mg,2.65mmol)溶于5mL二氯甲烷滴加入上述溶液中，滴加完后撤去干冰丙酮浴，大约20分钟后温度缓慢升至室温，然后室温下继续搅拌40分钟，LC-MS监测原料转化完全，停止反应，加入水(50mL),用乙酸乙酯(50mL*2)萃取，合并有机相用饱和氯化钠(60mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干得4-(3-溴-4-氟苯基)-3-(4-((2-(甲基亚硫酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮1l(0.9g，90％)。MS m/z(ESI):432.0,434.0(M,M+2)。4-(3-bromo-4-fluorophenyl)-3-(4-((2-(methylthio)ethyl)amino)-1,2,5-oxadiazole- 3-yl)-1,2,4-oxadiazol-5(4H)-one (1.0g, 2.41mmol) was dissolved in dichloromethane (30mL), cooled to -40°C with a dry ice acetone bath, and m-chloro Benzoic acid peroxide (457mg, 2.65mmol) was dissolved in 5mL of dichloromethane and added dropwise to the above solution. After the dropwise addition, the dry ice acetone bath was removed. After about 20 minutes, the temperature rose slowly to room temperature, and then continued to stir at room temperature for 40 minutes. LC - MS monitors that the conversion of raw materials is complete, stop the reaction, add water (50mL), extract with ethyl acetate (50mL*2), combine the organic phases, wash with saturated sodium chloride (60mL), dry over anhydrous sodium sulfate, filter, and spin the filtrate 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(methylsulfinyl)ethyl)amino)-1,2,5-oxadiazole-3- base)-1,2,4-oxadiazol-5(4H)-one 1 l (0.9 g, 90%). MS m/z (ESI): 432.0, 434.0 (M, M+2).
步骤十二：4-(3-溴-4-氟苯基)-3-(4-((2-(S-甲基磺亚胺酰基)乙基)氨基)-1,2,Step 12: 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(S-methylsulfonimidoyl)ethyl)amino)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮1m5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 1m
在100mL单口瓶中将4-(3-溴-4-氟苯基)-3-(4-((2-(甲基亚硫酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(0.9g，2.08mmol)溶于氯仿(30mL)，加入叠氮化钠(275.0mg,4.16mmol),用冰浴冷却至0℃,加入浓硫酸(0.5mL),撤去冰浴，用油浴加热到42℃,搅拌反应过夜。LC-MS监测原料转化完全，停止反应，加入饱和碳酸氢钠溶液(50mL),用乙酸乙酯(50mL*2)萃取，合并有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干得4-(3-溴-4-氟苯基)-3-(4-((2-(S-甲基磺亚胺酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮1m(0.7g，75.3％)。MS m/z(ESI):447.0,449.0(M,M+2)。In a 100mL single-necked bottle, 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(methylsulfinyl)ethyl)amino)-1,2,5-oxadi Azol-3-yl)-1,2,4-oxadiazol-5(4H)-one (0.9g, 2.08mmol) was dissolved in chloroform (30mL), sodium azide (275.0mg, 4.16mmol) was added, Cool to 0°C with an ice bath, add concentrated sulfuric acid (0.5 mL), remove the ice bath, heat to 42°C with an oil bath, and stir the reaction overnight. LC-MS monitored the complete conversion of raw materials, stopped the reaction, added saturated sodium bicarbonate solution (50mL), extracted with ethyl acetate (50mL*2), combined organic phases were washed with saturated sodium chloride (50mL), and dried over anhydrous sodium sulfate , filtered, and the filtrate was spin-dried to give 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(S-methylsulfonimidoyl)ethyl)amino)-1,2, 5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 1m (0.7 g, 75.3%). MS m/z (ESI): 447.0, 449.0 (M, M+2).
步骤十三：(Z)-N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(S-甲基磺亚胺酰基)乙基)Step 13: (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(S-methylsulfonimidoyl)ethyl)氨基)-1,2,5-噁二唑-3-碳杂氧杂脒1Amino)-1,2,5-oxadiazole-3-carbaoxamidine 1
在100mL单口瓶中将4-(3-溴-4-氟苯基)-3-(4-((2-(S-甲基磺亚胺酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(0.7g，1.57mmol)溶于四氢呋喃/甲醇(8mL/8mL)，将氢氧化钠(250mg,6.28mmol)溶于水(4mL)加入上述溶液中，室温下反应2小时。LC-MS监测原料转化完全，停止反应，加入饱和氯化铵溶液(30mL),用乙酸乙酯(30mL*2)萃取，合并有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液加硅胶，直接旋干柱层析，乙酸乙酯/甲醇(30/1到20/1)，得(Z)-N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(S-甲基磺亚胺酰基)乙基)氨基)-1,2,5-噁二唑-3-碳杂氧杂脒1(0.39g，59.0％)。MS m/z(ESI):421.0,423.0(M,M+2)。4-(3-bromo-4-fluorophenyl)-3-(4-((2-(S-methylsulfonimidoyl)ethyl)amino)-1,2,5 -oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (0.7g, 1.57mmol) was dissolved in tetrahydrofuran/methanol (8mL/8mL), sodium hydroxide (250mg , 6.28mmol) was dissolved in water (4mL) and added to the above solution, and reacted at room temperature for 2 hours. LC-MS monitored the complete conversion of raw materials, stopped the reaction, added saturated ammonium chloride solution (30mL), extracted with ethyl acetate (30mL*2), combined organic phases were washed with saturated sodium chloride (50mL), and dried over anhydrous sodium sulfate , filter, add silica gel to the filtrate, spin dry column chromatography directly, ethyl acetate/methanol (30/1 to 20/1), get (Z)-N-(3-bromo-4-fluorophenyl)-N' -Hydroxy-4-((2-(S-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carbaoxamidine 1 (0.39g, 59.0%) . MS m/z (ESI): 421.0, 423.0 (M, M+2).
1H NMR(400MHz,DMSO-d6,ppm)δ11.47(s,1H),8.88(s,1H),7.18(t,J＝8.8Hz,1H),7.10(dd,J1＝6.0Hz,J2＝2.8Hz,1H),6.75(m,1H),6.57(t,J＝6.0Hz,1H),3.85(s,1H),3.66(dd,J1＝12.8Hz,J2＝6.4Hz,2H),3.36(dd,J1＝12.8Hz,J2＝6.4Hz,2H),2.96(s,3H)。1 H NMR (400MHz, DMSO-d6, ppm) δ11.47 (s, 1H), 8.88 (s, 1H), 7.18 (t, J = 8.8Hz, 1H), 7.10 (dd, J1 = 6.0Hz, J2 =2.8Hz, 1H), 6.75(m, 1H), 6.57(t, J=6.0Hz, 1H), 3.85(s, 1H), 3.66(dd, J1 =12.8Hz, J2 =6.4Hz , 2H), 3.36 (dd, J1 =12.8 Hz, J2 =6.4 Hz, 2H), 2.96 (s, 3H).
实施例二Embodiment two
(Z)-N-(3-溴-4-氟苯基)-4-((2-(N,S-二甲基磺亚胺酰基)乙基)氨基)-N'-羟基-(Z)-N-(3-bromo-4-fluorophenyl)-4-((2-(N,S-dimethylsulfonimidoyl)ethyl)amino)-N'-hydroxyl-1,2,5-噁二唑-3-碳杂氧杂脒(2)1,2,5-oxadiazole-3-carbaoxamidine (2)
步骤一:4-(3-溴-4-氟苯基)-3-(4-((2-(N,S-二甲基磺亚胺酰基)乙基)氨基)-1,Step 1: 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(N,S-dimethylsulfonimidoyl)ethyl)amino)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮2a2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 2a
100mL单口瓶中加入4-(3-溴-4-氟苯基)-3-(4-((2-(S-甲基磺亚胺酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(40mg,0.09mmol)，三甲基氧鎓四氟硼酸(20mg,0.13mmol)，二氯甲烷(8mL),室温下搅拌15分钟，加入碳酸钠(57.3mg,0.54mmol),室温反应过夜。停止反应，加入水(20mL),用乙酸乙酯(20mL*2)萃取，合并有机相用饱和氯化钠(30mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，通过制备硅胶板分离纯化(展开剂：二氯甲烷/甲醇＝10/1；洗脱剂：乙酸乙酯/甲醇＝10/1)得4-(3-溴-4-氟苯基)-3-(4-((2-(N,S-二甲基磺亚胺酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮2a(20mg，50％)。MS m/z(ESI):461.0,463.0(M,M+2)。Add 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(S-methylsulfonimidoyl)ethyl)amino)-1,2,5- Oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (40mg, 0.09mmol), trimethyloxonium tetrafluoroboric acid (20mg, 0.13mmol), dichloromethane (8 mL), stirred at room temperature for 15 minutes, added sodium carbonate (57.3 mg, 0.54 mmol), and reacted overnight at room temperature. Stop the reaction, add water (20mL), extract with ethyl acetate (20mL*2), combine organic phases, wash with saturated sodium chloride (30mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate, separate and purify by preparing a silica gel plate (developing solvent: dichloromethane/methanol=10/1; eluent: ethyl acetate/methanol=10/1) to get 4-(3-bromo-4-fluorophenyl)-3-(4-(( 2-(N,S-Dimethylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazole-5(4H) - Ketone 2a (20 mg, 50%). MS m/z (ESI): 461.0, 463.0 (M, M+2).
1H NMR(400MHz,DMSO-d6,ppm)δ8.11(dd,J1＝6.4Hz,J2＝2.8Hz,1H),7.74(m,1H),7.60(t,J＝8.8Hz,1H),7.05(t,J＝6.0Hz,1H),3.66(dd,J1＝12.4Hz,J2＝6.4Hz,2H),3.37(t,J2＝6.4Hz,2H),2.99(s,3H),2.65(s,3H)。1 H NMR (400MHz, DMSO-d6, ppm) δ8.11 (dd, J1 = 6.4Hz, J2 = 2.8Hz, 1H), 7.74 (m, 1H), 7.60 (t, J = 8.8Hz, 1H ), 7.05(t, J=6.0Hz, 1H), 3.66(dd, J1 =12.4Hz, J2 =6.4Hz, 2H), 3.37(t, J2 =6.4Hz, 2H), 2.99(s, 3H), 2.65(s, 3H).
步骤二:(Z)-N-(3-溴-4-氟苯基)-4-((2-(N,S-二甲基磺亚胺酰基)乙基)氨基)-Step 2: (Z)-N-(3-bromo-4-fluorophenyl)-4-((2-(N,S-dimethylsulfonimidoyl)ethyl)amino)-N'-羟基-1,2,5-噁二唑-3-碳杂氧杂脒2N'-Hydroxy-1,2,5-oxadiazole-3-carbaoxamidine 2
在100mL单口瓶中将4-(3-溴-4-氟苯基)-3-(4-((2-(N,S-二甲基磺亚胺酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(20mg，0.43mmol)溶于四氢呋喃/甲醇(6mL/6mL)，将氢氧化钠(9mg,0.22mmol)溶于水(2mL)加入上述溶液中，室温下反应2小时。LC-MS监测原料转化完全，停止反应，加入饱和氯化铵溶液(10mL),用乙酸乙酯(15mL*2)萃取，合并有机相用饱和氯化钠(20mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，通过制备硅胶板分离纯化(展开剂：二氯甲烷/甲醇＝10/1；洗脱剂：乙酸乙酯/甲醇＝10/1)得(Z)-N-(3-溴-4-氟苯基)-4-((2-(N,S-二甲基磺亚胺酰基)乙基)氨基)-N'-羟基-1,2,5-噁二唑-3-碳杂氧杂脒2(13.0mg，68％)。MS m/z(ESI):435.0,437.0(M,M+2)。In a 100mL single-necked bottle, 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(N,S-dimethylsulfonimidoyl)ethyl)amino)-1, 2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (20mg, 0.43mmol) was dissolved in tetrahydrofuran/methanol (6mL/6mL), and sodium hydroxide (9mg, 0.22mmol) dissolved in water (2mL) was added to the above solution, and reacted at room temperature for 2 hours. LC-MS monitored the complete conversion of raw materials, stopped the reaction, added saturated ammonium chloride solution (10mL), extracted with ethyl acetate (15mL*2), combined organic phases were washed with saturated sodium chloride (20mL), and dried over anhydrous sodium sulfate , filtered, and the filtrate was concentrated, separated and purified by preparing a silica gel plate (developing solvent: dichloromethane/methanol=10/1; eluent: ethyl acetate/methanol=10/1) to obtain (Z)-N-(3- Bromo-4-fluorophenyl)-4-((2-(N,S-dimethylsulfonimidoyl)ethyl)amino)-N'-hydroxy-1,2,5-oxadiazole-3 - Carbaxamidine 2 (13.0 mg, 68%). MS m/z (ESI): 435.0, 437.0 (M, M+2).
1H NMR(400MHz,CDCl3,ppm)δ7.18(dd,J1＝6.0Hz,J2＝3.6Hz,1H),7.18(dd,J1＝5.6Hz,J2＝2.8Hz,1H),7.02(t,J＝8.4Hz,1H),6.90(m,1H),6.76(t,J＝6.0Hz,1H),3.90(m,2H),3.58(m,2H),3.09(s,3H),2.83(s,3H)。1 H NMR (400MHz, CDCl3 , ppm) δ7.18 (dd, J1 = 6.0Hz, J2 = 3.6Hz, 1H), 7.18 (dd, J1 = 5.6Hz, J2 = 2.8Hz, 1H) ,7.02(t,J=8.4Hz,1H),6.90(m,1H),6.76(t,J=6.0Hz,1H),3.90(m,2H),3.58(m,2H),3.09(s, 3H), 2.83(s, 3H).
实施例三Embodiment three
(Z)-N-(3-溴-4-氟苯基)-4-((2-(乙基磺亚胺酰基)乙基)氨基)-N'-羟基-1,2,5-(Z)-N-(3-bromo-4-fluorophenyl)-4-((2-(ethylsulfonimidoyl)ethyl)amino)-N'-hydroxyl-1,2,5-噁二唑-3-碳杂氧杂脒(3)Oxadiazole-3-carbaoxamidine (3)
步骤一:4-(3-溴-4-氟苯基)-3-(4-((2-(乙硫基)乙基)氨基)-1,2,5-噁二唑-3-Step 1: 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(ethylthio)ethyl)amino)-1,2,5-oxadiazole-3-基)-1,2,4-噁二唑-5(4H)-酮3bbase)-1,2,4-oxadiazol-5(4H)-one 3b
在100mL单口瓶中将2-((4-(4-(3-溴-4-氟苯基)-5-羰基-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)乙基甲磺酸酯3a(928mg，2.0mmol)溶于N，N-二甲基甲酰胺(8mL)，加入乙硫醇钠(205mg,2.2mmol),在室温下搅拌20min。LC-MS监测原料转化完全，停止反应，加入水(50mL)淬灭反应,用乙酸乙酯(50mL*2)萃取，合并有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液加硅胶，直接旋干柱层析，石油醚/乙酸乙酯(5/1到3/1)，得4-(3-溴-4-氟苯基)-3-(4-((2-(乙硫基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮3b(380mg，44％)。MS m/z(ESI):430.0,432.0(M,M+2)。2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3- yl)-1,2,5-oxadiazol-3-yl)amino)ethyl methanesulfonate 3a (928mg, 2.0mmol) was dissolved in N,N-dimethylformamide (8mL), added ethylsulfide Sodium alkoxide (205mg, 2.2mmol), stirred at room temperature for 20min. LC-MS monitored the complete conversion of raw materials, stopped the reaction, added water (50mL) to quench the reaction, extracted with ethyl acetate (50mL*2), combined organic phases were washed with saturated sodium chloride (50mL), dried over anhydrous sodium sulfate, Filtrate, add silica gel to the filtrate, spin dry column chromatography directly, petroleum ether/ethyl acetate (5/1 to 3/1), get 4-(3-bromo-4-fluorophenyl)-3-(4-( (2-(Ethylthio)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 3b (380mg, 44 %). MS m/z (ESI): 430.0, 432.0 (M, M+2).
步骤二：4-(3-溴-4-氟苯基)-3-(4-((2-(乙基亚硫酰基)乙基)氨基)-1,2,5-噁二Step 2: 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(ethylsulfinyl)ethyl)amino)-1,2,5-oxadi唑-3-基)-1,2,4-噁二唑-5(4H)-酮3cAzol-3-yl)-1,2,4-oxadiazol-5(4H)-one 3c
在100mL单口瓶中将4-(3-溴-4-氟苯基)-3-(4-((2-(乙硫基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(380mg，0.88mmol)溶于二氯甲烷(30mL)，用干冰丙酮浴冷却至-40℃,将间氯过氧化苯甲酸(152.5mg,0.88mmol)溶于5mL二氯甲烷滴加入上述溶液中，滴加完后撤去干冰丙酮浴，大约20分钟后温度缓慢升至室温，然后室温下继续搅拌40分钟，LC-MS监测原料转化完全，停止反应，加入水(50mL),用乙酸乙酯(50mL*2)萃取，合并有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干得4-(3-溴-4-氟苯基)-3-(4-((2-(乙基亚硫酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮3c(360mg，91.7％)。MS m/z(ESI):446.0,448.0(M,M+2)。4-(3-bromo-4-fluorophenyl)-3-(4-((2-(ethylthio)ethyl)amino)-1,2,5-oxadiazole- 3-yl)-1,2,4-oxadiazol-5(4H)-one (380mg, 0.88mmol) was dissolved in dichloromethane (30mL), cooled to -40°C with a dry ice acetone bath, and m-chloro Oxidized benzoic acid (152.5mg, 0.88mmol) was dissolved in 5mL of dichloromethane and added dropwise to the above solution. After the dropwise addition, the dry ice acetone bath was removed. After about 20 minutes, the temperature rose slowly to room temperature, and then continued to stir at room temperature for 40 minutes. LC - MS monitors that the conversion of raw materials is complete, stop the reaction, add water (50mL), extract with ethyl acetate (50mL*2), combine the organic phases, wash with saturated sodium chloride (50mL), dry over anhydrous sodium sulfate, filter, and spin the filtrate 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(ethylsulfinyl)ethyl)amino)-1,2,5-oxadiazole-3- (yl)-1,2,4-oxadiazol-5(4H)-one 3c (360 mg, 91.7%). MS m/z (ESI): 446.0, 448.0 (M, M+2).
步骤三：4-(3-溴-4-氟苯基)-3-(4-((2-(S-乙基磺亚胺酰基)乙基)氨基)-1,2,5-Step 3: 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(S-ethylsulfonimidoyl)ethyl)amino)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮3dOxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 3d
在100mL单口瓶中将4-(3-溴-4-氟苯基)-3-(4-((2-(乙基亚硫酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(360mg，0.81mmol)溶于氯仿(30mL)，加入叠氮化钠(105.0mg,1.62mmol),用冰浴冷却至0℃,加入浓硫酸(0.5mL),撤去冰浴，用油浴加热到42℃,搅拌反应过夜。LC-MS监测原料转化完全，停止反应，加入饱和碳酸氢钠溶液(30mL),用乙酸乙酯(30mL*2)萃取，合并有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干得4-(3-溴-4-氟苯基)-3-(4-((2-(S-乙基磺亚胺酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮3d(280mg，75.0％)。MS m/z(ESI):461.0,463.0(M,M+2)。4-(3-bromo-4-fluorophenyl)-3-(4-((2-(ethylsulfinyl)ethyl)amino)-1,2,5-oxadi Azol-3-yl)-1,2,4-oxadiazol-5(4H)-one (360mg, 0.81mmol) was dissolved in chloroform (30mL), sodium azide (105.0mg, 1.62mmol) was added, and the Cool in an ice bath to 0°C, add concentrated sulfuric acid (0.5 mL), remove the ice bath, heat to 42°C with an oil bath, and stir the reaction overnight. LC-MS monitored the complete conversion of raw materials, stopped the reaction, added saturated sodium bicarbonate solution (30mL), extracted with ethyl acetate (30mL*2), combined organic phases were washed with saturated sodium chloride (50mL), and dried over anhydrous sodium sulfate , filtered, and the filtrate was spin-dried to give 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(S-ethylsulfonimidoyl)ethyl)amino)-1,2, 5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 3d (280 mg, 75.0%). MS m/z (ESI): 461.0, 463.0 (M, M+2).
步骤四：((Z)-N-(3-溴-4-氟苯基)-4-((2-(乙基磺亚胺酰基)乙基)氨基)-N'-羟Step 4: ((Z)-N-(3-bromo-4-fluorophenyl)-4-((2-(ethylsulfonimidoyl)ethyl)amino)-N'-hydroxyl基-1,2,5-噁二唑-3-碳杂氧杂脒3Base-1,2,5-oxadiazole-3-carbaoxamidine 3
在100mL单口瓶中将4-(3-溴-4-氟苯基)-3-(4-((2-(S-乙基磺亚胺酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(200mg，0.43mmol)溶于四氢呋喃/甲醇(8mL/8mL)，将氢氧化钠(50mg,2.0mmol)溶于水(4mL)加入上述溶液中，室温下反应2小时。LC-MS监测原料转化完全，停止反应，加入饱和氯化铵溶液(30mL),用乙酸乙酯(30mL*2)萃取，合并有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，通过制备硅胶板分离纯化(展开剂：二氯甲烷/甲醇＝10/1；洗脱剂：乙酸乙酯/甲醇＝10/1)得(Z)-N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(S-甲基磺亚胺酰基)乙基)氨基)-1,2,5-噁二唑-3-碳杂氧杂脒3(85.0mg，45.4％)。MS m/z(ESI):434.0,436.0(M,M+2)。4-(3-bromo-4-fluorophenyl)-3-(4-((2-(S-ethylsulfonimidoyl)ethyl)amino)-1,2,5 -Oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (200mg, 0.43mmol) was dissolved in tetrahydrofuran/methanol (8mL/8mL), and sodium hydroxide (50mg, 2.0 mmol) was dissolved in water (4 mL) and added to the above solution, and reacted at room temperature for 2 hours. LC-MS monitored the complete conversion of raw materials, stopped the reaction, added saturated ammonium chloride solution (30mL), extracted with ethyl acetate (30mL*2), combined organic phases were washed with saturated sodium chloride (50mL), and dried over anhydrous sodium sulfate , filtered, and the filtrate was concentrated, separated and purified by preparing a silica gel plate (developing solvent: dichloromethane/methanol=10/1; eluent: ethyl acetate/methanol=10/1) to obtain (Z)-N-(3- Bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(S-methylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carba Oxamidine 3 (85.0 mg, 45.4%). MS m/z (ESI): 434.0, 436.0 (M, M+2).
1H NMR(400M,DMSO-d6,ppm)δ11.47(s,1H),8.88(s,1H),7.18(t,J＝8.4Hz,1H),7.10(dd,J1＝6.0Hz,J2＝2.8Hz,1H),6.76(m,1H),6.56(t,J＝6.0Hz,1H),3.80(s,1H),3.64(dd,J1＝12.8Hz,J2＝6.4Hz,2H),3.28(m,2H),2.10(dd,J1＝14.4Hz,J2＝7.2Hz,1H),1.20(t,J＝4.0Hz,3H)。1 H NMR (400M, DMSO-d6 , ppm) δ11.47(s, 1H), 8.88(s, 1H), 7.18(t, J=8.4Hz, 1H), 7.10(dd, J1 =6.0Hz ,J2 =2.8Hz,1H), 6.76(m,1H),6.56(t,J=6.0Hz,1H),3.80(s,1H),3.64(dd,J1 =12.8Hz,J2 =6.4 Hz, 2H), 3.28 (m, 2H),2.10 (dd, J1= 14.4Hz, J2 = 7.2Hz, 1H), 1.20 (t, J = 4.0Hz, 3H).
实施例四Embodiment four
(Z)-N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(N-甲基乙基磺亚胺酰基)乙基)氨基)-(Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxyl-4-((2-(N-methylethylsulfonimidoyl)ethyl)amino)-1,2,5-噁二唑-3-碳杂氧杂脒(4)1,2,5-oxadiazole-3-carbaoxamidine (4)
步骤一:4-(3-溴-4-氟苯基)-3-(4-((2-(N-甲基乙基磺亚胺酰基)乙基)氨基)-1,Step 1: 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(N-methylethylsulfonimidoyl)ethyl)amino)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮4a2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 4a
100mL单口瓶中加入4-(3-溴-4-氟苯基)-3-(4-((2-(S-乙基磺亚胺酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(300mg,0.65mmol)，三甲基氧鎓四氟硼酸(115mg,0.78mmol)，二氯甲烷(30mL),室温下搅拌15分钟，加入碳酸钠(414mg,3.9mmol),室温反应过夜。停止反应，加入水(50mL),用乙酸乙酯(50mL*2)萃取，合并有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，通过制备硅胶板分离纯化(展开剂：二氯甲烷/甲醇＝15/1；洗脱剂：乙酸乙酯/甲醇＝15/1)得4-(3-溴-4-氟苯基)-3-(4-((2-(N-甲基乙基磺亚胺酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮4a(130mg，42.1％)。MS m/z(ESI):475.0,477.0(M,M+2)。Add 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(S-ethylsulfonimidoyl)ethyl)amino)-1,2,5- Oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (300mg, 0.65mmol), trimethyloxonium tetrafluoroboric acid (115mg, 0.78mmol), dichloromethane (30 mL), stirred at room temperature for 15 minutes, added sodium carbonate (414 mg, 3.9 mmol), and reacted overnight at room temperature. Stop the reaction, add water (50mL), extract with ethyl acetate (50mL*2), combine organic phases, wash with saturated sodium chloride (50mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate, separate and purify by preparing a silica gel plate (developing solvent: dichloromethane/methanol=15/1; eluent: ethyl acetate/methanol=15/1) to get 4-(3-bromo-4-fluorophenyl)-3-(4-(( 2-(N-Methylethylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazole-5(4H)- Ketone 4a (130 mg, 42.1%). MS m/z (ESI): 475.0, 477.0 (M, M+2).
1H NMR(400MHz,DMSO-d6,ppm)δ8.12(dd,J1＝6.0Hz,J2＝2.8Hz,1H),7.74(m,1H),7.60(t,J＝8.8Hz,1H),7.00(t,J＝6.0Hz,1H),3.63(dd,J1＝12.8Hz,J2＝6.4Hz,2H),3.40(m,1H),3.30(m,1H),3.16(m,2H),2.64(s,3H),1.22(t,J＝7.2Hz,3H)。1 H NMR (400MHz, DMSO-d6 , ppm) δ8.12 (dd, J1 = 6.0Hz, J2 = 2.8Hz, 1H), 7.74 (m, 1H), 7.60 (t, J = 8.8Hz, 1H) ,7.00(t,J=6.0Hz,1H),3.63(dd,J1 ＝12.8Hz,J2 ＝6.4Hz,2H),3.40(m,1H),3.30(m,1H),3.16(m, 2H), 2.64(s, 3H), 1.22(t, J=7.2Hz, 3H).
步骤二:(Z)-N-(3-溴-4-氟苯基)-4-((2-(N,S-二甲基磺亚胺酰基)乙基)氨基)-Step 2: (Z)-N-(3-bromo-4-fluorophenyl)-4-((2-(N,S-dimethylsulfonimidoyl)ethyl)amino)-N'-羟基-1,2,5-噁二唑-3-碳杂氧杂脒4N'-Hydroxy-1,2,5-oxadiazole-3-carbaoxamidine 4
在100mL单口瓶中将4-(3-溴-4-氟苯基)-3-(4-((2-(N-甲基乙基磺亚胺酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(130mg，0.27mmol)溶于四氢呋喃/甲醇(8mL/8mL)，将氢氧化钠(55mg,1.36mmol)溶于水(5mL)加入上述溶液中，室温下反应2小时。LC-MS监测原料转化完全，停止反应，加入饱和氯化铵溶液(30mL),用乙酸乙酯(30mL*2)萃取，合并有机相用饱和氯化钠(30mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，通过制备硅胶板分离纯化(展开剂：二氯甲烷/甲醇＝10/1；洗脱剂：乙酸乙酯/甲醇＝10/1)得(Z)-N-(3-溴-4-氟苯基)-4-((2-(N,S-二甲基磺亚胺酰基)乙基)氨基)-N'-羟基-1,2,5-噁二唑-3-碳杂氧杂脒4(76.6mg，63.2％)。MS m/z(ESI):448.0,450.0(M,M+2)。4-(3-bromo-4-fluorophenyl)-3-(4-((2-(N-methylethylsulfonimidoyl)ethyl)amino)-1,2 ,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (130mg, 0.27mmol) was dissolved in tetrahydrofuran/methanol (8mL/8mL), and sodium hydroxide ( 55mg, 1.36mmol) was dissolved in water (5mL) and added to the above solution, and reacted at room temperature for 2 hours. LC-MS monitored the complete conversion of raw materials, stopped the reaction, added saturated ammonium chloride solution (30mL), extracted with ethyl acetate (30mL*2), combined organic phases were washed with saturated sodium chloride (30mL), and dried over anhydrous sodium sulfate , filtered, and the filtrate was concentrated, separated and purified by preparing a silica gel plate (developing solvent: dichloromethane/methanol=10/1; eluent: ethyl acetate/methanol=10/1) to obtain (Z)-N-(3- Bromo-4-fluorophenyl)-4-((2-(N,S-dimethylsulfonimidoyl)ethyl)amino)-N'-hydroxy-1,2,5-oxadiazole-3 - Carbaxamidine 4 (76.6 mg, 63.2%). MS m/z (ESI): 448.0, 450.0 (M, M+2).
1H NMR(400MHz,DMSO-d6,ppm)δ11.45(s,1H),8.89(s,1H),7.18(t,J＝8.8Hz,1H),7.10(dd,J1＝6.0Hz,J2＝2.8Hz,1H),6.76(m,1H),6.56(t,J＝6.0Hz,1H),3.58(dd,J1＝12.8Hz,J2＝6.4Hz,2H),3.31(m,2H),2.63(s,3H),1.22(t,J＝7.2Hz,3H)。1 H NMR (400MHz, DMSO-d6 , ppm) δ11.45(s, 1H), 8.89(s, 1H), 7.18(t, J=8.8Hz, 1H), 7.10(dd, J1 = 6.0Hz , J2 =2.8Hz, 1H), 6.76(m, 1H), 6.56(t, J=6.0Hz, 1H), 3.58(dd, J1 =12.8Hz, J2 =6.4Hz, 2H), 3.31( m, 2H), 2.63 (s, 3H), 1.22 (t, J=7.2Hz, 3H).
实施例五Embodiment five
(Z)-N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(苯基磺亚胺酰基)乙基)氨基)-1,2,5-(Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(phenylsulfonimidoyl)ethyl)amino)-1,2,5-噁二唑-3-碳杂氧杂脒(5)Oxadiazole-3-carbaoxamidine (5)
步骤一:4-(3-溴-4-氟苯基)-3-(4-((2-(苯基硫代)乙基)氨基)-1,2,5-噁二唑-Step 1: 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(phenylthio)ethyl)amino)-1,2,5-oxadiazole-3-基)-1,2,4-噁二唑-5(4H)-酮5b3-yl)-1,2,4-oxadiazol-5(4H)-one 5b
在100mL单口瓶中将2-((4-(4-(3-溴-4-氟苯基)-5-羰基-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)乙基甲磺酸酯5a(464mg，1.00mmol)溶于N，N-二甲基甲酰胺(8mL)，加入苯硫醇钠(158.4mg,1.2mmol),在室温下搅拌20min。LC-MS监测原料转化完全，停止反应，加入水(30mL)淬灭反应,用乙酸乙酯(30mL*2)萃取，合并有机相用饱和氯化钠(40mL)洗涤，无水硫酸钠干燥，过滤，滤液加硅胶，直接旋干柱层析，石油醚/乙酸乙酯(5/1到3/1)，得4-(3-溴-4-氟苯基)-3-(4-((2-(苯基硫代)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮5b(400mg，83.6％)。MS m/z(ESI):476.0,478.0(M,M+2)。2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3- yl)-1,2,5-oxadiazol-3-yl)amino)ethyl methanesulfonate 5a (464mg, 1.00mmol) was dissolved in N,N-dimethylformamide (8mL), added phenylthio Sodium alkoxide (158.4mg, 1.2mmol), stirred at room temperature for 20min. LC-MS monitored the complete conversion of raw materials, stopped the reaction, added water (30mL) to quench the reaction, extracted with ethyl acetate (30mL*2), combined organic phases were washed with saturated sodium chloride (40mL), dried over anhydrous sodium sulfate, Filtrate, add silica gel to the filtrate, spin dry column chromatography directly, petroleum ether/ethyl acetate (5/1 to 3/1), get 4-(3-bromo-4-fluorophenyl)-3-(4-( (2-(Phenylthio)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 5b (400mg, 83.6%). MS m/z (ESI): 476.0, 478.0 (M, M+2).
1H NMR(400MHz,DMSO-d6,ppm)δ8.09(dd,J1＝6.0Hz,J2＝2.4Hz,1H),7.73(m,1H),7.60(t,J＝8.8Hz,1H),7.35(m,4H),7.22(m,1H),6.80(m,1H),3.48(m,2H),3.21(dd,J1＝8.8Hz,J2＝6.0Hz,2H)。1 H NMR (400MHz, DMSO-d6 , ppm) δ8.09 (dd, J1 = 6.0Hz, J2 = 2.4Hz, 1H), 7.73 (m, 1H), 7.60 (t, J = 8.8Hz, 1H), 7.35 (m, 4H), 7.22 (m, 1H), 6.80 (m, 1H), 3.48 (m, 2H), 3.21 (dd, J1 =8.8 Hz, J2 =6.0 Hz, 2H).
步骤二：4-(3-溴-4-氟苯基)-3-(4-((2-(苯基亚硫酰基)乙基)氨基)-1,2,5-噁二Step 2: 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(phenylsulfinyl)ethyl)amino)-1,2,5-oxadi唑-3-基)-1,2,4-噁二唑-5(4H)-酮5cAzol-3-yl)-1,2,4-oxadiazol-5(4H)-one 5c
在100mL单口瓶中将4-(3-溴-4-氟苯基)-3-(4-((2-(苯基硫代)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(400mg，0.84mmol)溶于二氯甲烷(25mL)，用干冰丙酮浴冷却至-20℃,将间氯过氧化苯甲酸(173mg,1.00mmol)溶于5mL二氯甲烷滴加入上述溶液中，滴加完后撤去干冰丙酮浴，大约20分钟后温度缓慢升至室温，然后室温下继续搅拌40分钟，LC-MS监测原料转化完全，停止反应，加入水(40mL),用乙酸乙酯(40mL*2)萃取，合并有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干得4-(3-溴-4-氟苯基)-3-(4-((2-(苯基亚硫酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮5c(380mg，92.0％)。MS m/z(ESI):494.0,496.0(M,M+2)。4-(3-bromo-4-fluorophenyl)-3-(4-((2-(phenylthio)ethyl)amino)-1,2,5-oxadiazole -3-yl)-1,2,4-oxadiazol-5(4H)-one (400mg, 0.84mmol) was dissolved in dichloromethane (25mL), cooled to -20°C with a dry ice acetone bath, and m-chloro Benzoic acid peroxide (173mg, 1.00mmol) was dissolved in 5mL of dichloromethane and added dropwise to the above solution. After the dropwise addition, the dry ice acetone bath was removed. After about 20 minutes, the temperature rose slowly to room temperature, and then continued to stir at room temperature for 40 minutes. LC - MS monitors that the conversion of raw materials is complete, stop the reaction, add water (40mL), extract with ethyl acetate (40mL*2), combine the organic phases, wash with saturated sodium chloride (50mL), dry over anhydrous sodium sulfate, filter, and spin the filtrate 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(phenylsulfinyl)ethyl)amino)-1,2,5-oxadiazole-3- (yl)-1,2,4-oxadiazol-5(4H)-one 5c (380 mg, 92.0%). MS m/z (ESI): 494.0, 496.0 (M, M+2).
步骤三：4-(3-溴-4-氟苯基)-3-(4-((2-(苯基磺亚胺酰基)乙基)氨基)-1,2,5-噁Step 3: 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(phenylsulfonimidoyl)ethyl)amino)-1,2,5-oxa二唑-3-基)-1,2,4-噁二唑-5(4H)-酮5dOxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 5d
在100mL单口瓶中将4-(3-溴-4-氟苯基)-3-(4-((2-(苯基亚硫酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(380mg，0.77mmol)溶于氯仿(30mL)，加入叠氮化钠(102mg,1.54mmol),用冰浴冷却至0℃,加入浓硫酸(0.5mL),撤去冰浴，用油浴加热到42℃,搅拌反应过夜。LC-MS监测原料转化完全，停止反应，加入饱和碳酸氢钠溶液(50mL),用乙酸乙酯(50mL*2)萃取，合并有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干得4-(3-溴-4-氟苯基)-3-(4-((2-(苯基磺亚胺酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮5d(320mg，81.6％)。MS m/z(ESI):509.0,511.0(M,M+2)。4-(3-Bromo-4-fluorophenyl)-3-(4-((2-(phenylsulfinyl)ethyl)amino)-1,2,5-oxadi Azol-3-yl)-1,2,4-oxadiazol-5(4H)-one (380mg, 0.77mmol) was dissolved in chloroform (30mL), sodium azide (102mg, 1.54mmol) was added, and the The bath was cooled to 0°C, concentrated sulfuric acid (0.5 mL) was added, the ice bath was removed, heated to 42°C with an oil bath, and the reaction was stirred overnight. LC-MS monitored the complete conversion of raw materials, stopped the reaction, added saturated sodium bicarbonate solution (50mL), extracted with ethyl acetate (50mL*2), combined organic phases were washed with saturated sodium chloride (50mL), and dried over anhydrous sodium sulfate , filtered, and the filtrate was spin-dried to give 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(phenylsulfonimidoyl)ethyl)amino)-1,2,5- Oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 5d (320 mg, 81.6%). MS m/z (ESI): 509.0, 511.0 (M, M+2).
步骤四：(Z)-N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(苯基磺亚胺酰基)乙基)氨Step 4: (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(phenylsulfonimidoyl)ethyl)ammonia基)-1,2,5-噁二唑-3-碳杂氧杂脒5base)-1,2,5-oxadiazole-3-carbaoxamidine 5
在100mL单口瓶中将4-(3-溴-4-氟苯基)-3-(4-((2-(苯基磺亚胺酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(320mg，0.63mmol)溶于四氢呋喃/甲醇(8mL/8mL)，将氢氧化钠(125mg,3.15mmol)溶于水(4mL)加入上述溶液中，室温下反应2小时。LC-MS监测原料转化完全，停止反应，加入饱和氯化铵溶液(30mL),用乙酸乙酯(30mL*2)萃取，合并有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，通过制备硅胶板分离纯化(展开剂：二氯甲烷/甲醇＝10/1；洗脱剂：乙酸乙酯/甲醇＝10/1)得(Z)-N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(苯基磺亚胺酰基)乙基)氨基)-1,2,5-噁二唑-3-碳杂氧杂脒5(104.0mg，34.2％)。MS m/z(ESI):483.0,485.0(M,M+2)。4-(3-bromo-4-fluorophenyl)-3-(4-((2-(phenylsulfonimidoyl)ethyl)amino)-1,2,5-oxa Oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (320mg, 0.63mmol) was dissolved in tetrahydrofuran/methanol (8mL/8mL), sodium hydroxide (125mg, 3.15mmol ) dissolved in water (4 mL) was added to the above solution, and reacted at room temperature for 2 hours. LC-MS monitored the complete conversion of raw materials, stopped the reaction, added saturated ammonium chloride solution (30mL), extracted with ethyl acetate (30mL*2), combined organic phases were washed with saturated sodium chloride (50mL), and dried over anhydrous sodium sulfate , filtered, and the filtrate was concentrated, separated and purified by preparing a silica gel plate (developing solvent: dichloromethane/methanol=10/1; eluent: ethyl acetate/methanol=10/1) to obtain (Z)-N-(3- Bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(phenylsulfonimidoyl)ethyl)amino)-1,2,5-oxadiazole-3-carbaoxa Amidine 5 (104.0 mg, 34.2%). MS m/z (ESI): 483.0, 485.0 (M, M+2).
1H NMR(400MHz,DMSO-d6,ppm)δ11.46(s,1H),8.83(s,1H),7.91(d,J＝7.2Hz,2H),7.64(m,3H),7.17(t,J＝8.4Hz,1H),7.06(t,J＝3.2Hz,1H),6.74(m,1H),6.44(m,1H),4.46(s,1H),3.47(m,4H)。1 H NMR (400MHz, DMSO-d6 , ppm) δ11.46(s, 1H), 8.83(s, 1H), 7.91(d, J=7.2Hz, 2H), 7.64(m, 3H), 7.17( t,J=8.4Hz,1H), 7.06(t,J=3.2Hz,1H), 6.74(m,1H), 6.44(m,1H), 4.46(s,1H), 3.47(m,4H).
实施例六Embodiment six
(Z)-N-(3-溴-4-氟苯基)-N'-羟基-4-((3-(S-甲基磺亚胺酰基)丙基)氨基)-1,2,(Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((3-(S-methylsulfonimidoyl)propyl)amino)-1,2,5-噁二唑-3-碳杂氧杂脒(6)5-oxadiazole-3-carbaoxamidine (6)
步骤一:4-氨基-N'-羟基-N-(3-甲氧基丙基)-1,2,5-噁二唑-3-碳杂氧杂脒6bStep 1: 4-amino-N'-hydroxy-N-(3-methoxypropyl)-1,2,5-oxadiazole-3-carbaoxamidine 6b
化合物4-氨基-N-羟基-1,2,5-噁二唑-3-碳杂亚胺酰基氯化(4.0g,24.7mmol)溶于乙酸乙酯(40ml)中,冰浴下加入2-甲氧基乙烷-1-胺(3.3g,37.0mmol)搅拌5分钟,再加入三乙胺(7.2ml,49.4mmol)搅拌2小时至反应完全,水洗，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得到化合物6b(4.3g，81％)。MS m/z(ESI):216.2(M+1)。Compound 4-amino-N-hydroxyl-1,2,5-oxadiazole-3-carbaimide acid chloride (4.0g, 24.7mmol) was dissolved in ethyl acetate (40ml), and 2 -Methoxyethane-1-amine (3.3g, 37.0mmol) was stirred for 5 minutes, then triethylamine (7.2ml, 49.4mmol) was added and stirred for 2 hours until the reaction was complete, washed with water, washed with saturated brine, anhydrous sodium sulfate The organic phase was dried and concentrated under reduced pressure to obtain compound 6b (4.3 g, 81%). MS m/z (ESI): 216.2 (M+1).
步骤二:N'-羟基-4-((3-甲氧基丙基)氨基)-1,2,5-噁二唑-3-碳杂氧杂脒6cStep 2: N'-Hydroxy-4-((3-methoxypropyl)amino)-1,2,5-oxadiazole-3-carbaoxamidine 6c
将化合物4-氨基-N'-羟基-N-(3-甲氧基丙基)-1,2,5-噁二唑-3-碳杂氧杂脒(4.3g,20.0mmol)溶于水(40ml)中,加入氢氧化钾(4.15g,74.1mmol)回流48小时，TLC检测反应完全,用乙酸乙酯萃取,水洗有机相，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得到化合物N'-羟基-4-((3-甲氧基丙基)氨基)-1,2,5-噁二唑-3-碳杂氧杂脒6c(3.5g，81.4％)。MS m/z(ESI):216.1。The compound 4-amino-N'-hydroxyl-N-(3-methoxypropyl)-1,2,5-oxadiazole-3-carbaoxamidine (4.3g, 20.0mmol) was dissolved in water (40ml), add potassium hydroxide (4.15g, 74.1mmol) and reflux for 48 hours, TLC detects that the reaction is complete, extract with ethyl acetate, wash the organic phase with water, wash with saturated saline, dry the organic phase with anhydrous sodium sulfate, and vacuum the Concentration gave the compound N'-hydroxy-4-((3-methoxypropyl)amino)-1,2,5-oxadiazole-3-carbaoxamidine 6c (3.5 g, 81.4%). MS m/z (ESI): 216.1.
步骤三:N-羟基-4-((3-甲氧基丙基)氨基)-1,2,5-噁二唑-3-碳杂亚胺酰基氯6dStep 3: N-hydroxy-4-((3-methoxypropyl)amino)-1,2,5-oxadiazole-3-carbaimide acid chloride 6d
将化合物N'-羟基-4-((3-甲氧基丙基)氨基)-1,2,5-噁二唑-3-碳杂氧杂脒(3.5g,16.3mmol)溶于6NHCl(16.5ml)待溶液澄清后加入氯化钠水(2.86g,48.9mmol),然后再加水(20ml)和乙酸乙酯(20ml),冰浴下滴加亚硝酸钠(1.1g,16.3mmol)冰浴下搅拌2小时，然后室温搅拌过夜至反应完全,用乙酸乙酯萃取,水洗有机相，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得固体用乙酸乙酯：石油醚(3：20)洗得N-羟基-4-((3-甲氧基丙基)氨基)-1,2,5-噁二唑-3-碳杂亚胺酰基氯化6d(2.5g，65.2％)。MS m/z(ESI):235.1。The compound N'-hydroxy-4-((3-methoxypropyl)amino)-1,2,5-oxadiazole-3-carbaoxamidine (3.5 g, 16.3 mmol) was dissolved in 6N HCl ( 16.5ml) After the solution is clarified, add sodium chloride water (2.86g, 48.9mmol), then add water (20ml) and ethyl acetate (20ml), add sodium nitrite (1.1g, 16.3mmol) dropwise under ice bath Stir in the bath for 2 hours, then stir overnight at room temperature until the reaction is complete, extract with ethyl acetate, wash the organic phase with water, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a solid. Use ethyl acetate:petroleum ether ( 3:20) to N-hydroxy-4-((3-methoxypropyl)amino)-1,2,5-oxadiazole-3-carbaimide acyl chloride 6d (2.5g, 65.2 %). MS m/z (ESI): 235.1.
步骤四:N-(3-溴-4-氟苯基)-N'-羟基-4-((3-甲氧基丙基)氨基)-1,2,5-噁二唑-Step 4: N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((3-methoxypropyl)amino)-1,2,5-oxadiazole-3-碳杂氧杂脒6e3-carbaoxaamidine 6e
将化合物N-羟基-4-((3-甲氧基丙基)氨基)-1,2,5-噁二唑-3-碳杂亚胺酰基氯化(2.5g,10.64mmol)加入水(14ml)加热至60℃，加入3-溴-4-氟苯胺(2.06g,11mmol),搅拌10分钟，然后再加碳酸氢钠(1.26g,15mmol)60℃下搅拌30分钟，至反应完全,用乙酸乙酯萃取,水洗有机相，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得N-(3-溴-4-氟苯基)-N'-羟基-4-((3-甲氧基丙基)氨基)-1,2,5-噁二唑-3-碳杂氧杂脒6e(3.9g，94.0％)。MS m/z(ESI):388.0,390.0(M,M+2)。The compound N-hydroxy-4-((3-methoxypropyl)amino)-1,2,5-oxadiazole-3-carbaimidoyl chloride (2.5 g, 10.64 mmol) was added to water ( 14ml) was heated to 60°C, added 3-bromo-4-fluoroaniline (2.06g, 11mmol), stirred for 10 minutes, then added sodium bicarbonate (1.26g, 15mmol) and stirred at 60°C for 30 minutes until the reaction was complete. Extract with ethyl acetate, wash the organic phase with water, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain N-(3-bromo-4-fluorophenyl)-N'-hydroxyl-4-(( 3-methoxypropyl)amino)-1,2,5-oxadiazole-3-carbaoxamidine 6e (3.9 g, 94.0%). MS m/z (ESI): 388.0, 390.0 (M, M+2).
1H NMR(400MHz,DMSO-d6,ppm)δ11.41(s,1H),8.86(s,1H),7.18(t,J＝8.4Hz,1H),7.11(dd,J1＝6.0Hz,J2＝2.8Hz,1H),6.76(m,1H),6.21(t,J＝5.6Hz,1H),3.36(t,J＝6.4Hz,2H),3.23(m,5H),1.78(m,2H)。1 H NMR (400MHz, DMSO-d6 , ppm) δ11.41(s, 1H), 8.86(s, 1H), 7.18(t, J=8.4Hz, 1H), 7.11(dd, J1 = 6.0Hz ,J2 =2.8Hz,1H),6.76(m,1H),6.21(t,J=5.6Hz,1H),3.36(t,J=6.4Hz,2H),3.23(m,5H),1.78( m,2H).
步骤五:4-(3-溴-4-氟苯基)-3-(4-((3-甲氧基丙基)氨基)-1,2,5-噁二唑-3-Step 5: 4-(3-bromo-4-fluorophenyl)-3-(4-((3-methoxypropyl)amino)-1,2,5-oxadiazole-3-基)-1,2,4-噁二唑-5(4H)-酮6fbase)-1,2,4-oxadiazol-5(4H)-one 6f
将化合物N-(3-溴-4-氟苯基)-N'-羟基-4-((3-甲氧基丙基)氨基)-1,2,5-噁二唑-3-碳杂氧杂脒(3.9g,10.0mmol)加入乙酸乙酯(50ml)加热至60℃，加入1,1'-羰基二咪唑(2.43g,15.0mmol),搅拌30分钟，1NHCl洗有机相，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得4-(3-溴-4-氟苯基)-3-(4-((3-甲氧基丙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮6f(4.0g，96.6％)。MS m/z(ESI):414.0,416.0(M,M+2)。The compound N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((3-methoxypropyl)amino)-1,2,5-oxadiazole-3-carba Add ethyl acetate (50ml) to oxamidine (3.9g, 10.0mmol) and heat to 60°C, add 1,1'-carbonyldiimidazole (2.43g, 15.0mmol), stir for 30 minutes, wash the organic phase with 1N HCl, and wash with saturated salt Wash with water, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 4-(3-bromo-4-fluorophenyl)-3-(4-((3-methoxypropyl)amino)-1,2 ,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 6f (4.0 g, 96.6%). MS m/z (ESI): 414.0, 416.0 (M, M+2).
步骤六:4-(3-溴-4-氟苯基)-3-(4-((3-羟基丙基)氨基)-1,2,5-噁二唑-3-基)-Step 6: 4-(3-bromo-4-fluorophenyl)-3-(4-((3-hydroxypropyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-噁二唑-5(4H)-酮6g1,2,4-Oxadiazol-5(4H)-one 6g
将4-(3-溴-4-氟苯基)-3-(4-((3-甲氧基丙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(4g,9.66mmol)加入二氯甲烷(100ml)在-78℃滴加1N三溴化硼的二氯甲烷溶液(25ml,25mmol),搅拌至室温，LC-MS监测原料转化完全，停止反应，冰浴下用饱和碳酸氢钠溶液调PH至中性，有机相用水洗，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得化合物6g(3.5g，88.0％)。MS m/z(ESI):400.0,402(M,M+2)。4-(3-bromo-4-fluorophenyl)-3-(4-((3-methoxypropyl)amino)-1,2,5-oxadiazol-3-yl)-1, Add dichloromethane (100ml) to 2,4-oxadiazol-5(4H)-one (4g, 9.66mmol) and add 1N boron tribromide solution in dichloromethane (25ml, 25mmol) dropwise at -78°C, stirring To room temperature, LC-MS monitors the complete conversion of raw materials, stop the reaction, adjust the pH to neutral with saturated sodium bicarbonate solution under ice bath, wash the organic phase with water, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, and concentrate in vacuo under reduced pressure Compound 6g (3.5g, 88.0%) was obtained. MS m/z (ESI): 400.0,402 (M,M+2).
步骤七:3-((4-(4-(3-溴-4-氟苯基)-5-羰基-4,5-二氢-1,2,4-噁二唑-3-基)-1,Step 7: 3-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)- 1,2,5-噁二唑-3-基)氨基)丙基甲磺酸酯6h2,5-oxadiazol-3-yl)amino)propyl methanesulfonate 6h
将化合物4-(3-溴-4-氟苯基)-3-(4-((3-羟基丙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(1.8g,4.5mmol)加入二氯甲烷(30ml)室温下加入甲磺酰氯(1.0mL,11.25mmol),再加三乙胺(1.0mL,11.25mmol)，LC-MS监测原料转化完全，停止反应，有机相用水洗，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得化合物6h(1.9g，88.3％)。MS m/z(ESI):477.9,479.9(M,M+2)。The compound 4-(3-bromo-4-fluorophenyl)-3-(4-((3-hydroxypropyl)amino)-1,2,5-oxadiazol-3-yl)-1,2 , 4-Oxadiazol-5(4H)-one (1.8g, 4.5mmol) was added into dichloromethane (30ml), methanesulfonyl chloride (1.0mL, 11.25mmol) was added at room temperature, and triethylamine (1.0mL, 11.25 mmol), LC-MS monitored the complete conversion of raw materials, stopped the reaction, washed the organic phase with water, washed with saturated brine, dried the organic phase with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 6h (1.9 g, 88.3%). MS m/z (ESI): 477.9, 479.9 (M, M+2).
步骤八:4-(3-溴-4-氟苯基)-3-(4-((3-(甲硫基)丙基)氨基)-1,2,5-噁二唑-3-Step 8: 4-(3-bromo-4-fluorophenyl)-3-(4-((3-(methylthio)propyl)amino)-1,2,5-oxadiazole-3-基)-1,2,4-噁二唑-5(4H)-酮6ibase)-1,2,4-oxadiazol-5(4H)-one 6i
在100mL单口瓶中将2-((4-(4-(3-溴-4-氟苯基)-5-羰基-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)乙基甲磺酸酯6h(500mg，1.05mmol)溶于N，N-二甲基甲酰胺(6mL)，加入甲硫醇钠(90mg,1.25mmol),在室温下搅拌20min。LC-MS监测原料转化完全，停止反应，加入水(30mL)淬灭反应,用乙酸乙酯(50mL*2)萃取，合并有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液加硅胶，直接旋干柱层析，石油醚/乙酸乙酯(5/1到3/1)，得4-(3-溴-4-氟苯基)-3-(4-((2-(甲硫基)丙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮6i(200mg，44.3％)。MS m/z(ESI):430.0,432.0(M,M+2)。2-((4-(4-(3-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3- Base)-1,2,5-oxadiazol-3-yl)amino)ethyl methanesulfonate 6h (500mg, 1.05mmol) was dissolved in N,N-dimethylformamide (6mL), added methylsulfide Sodium alkoxide (90mg, 1.25mmol), stirred at room temperature for 20min. LC-MS monitored the complete conversion of raw materials, stopped the reaction, added water (30mL) to quench the reaction, extracted with ethyl acetate (50mL*2), combined organic phases were washed with saturated sodium chloride (50mL), dried over anhydrous sodium sulfate, Filtrate, add silica gel to the filtrate, spin dry column chromatography directly, petroleum ether/ethyl acetate (5/1 to 3/1), get 4-(3-bromo-4-fluorophenyl)-3-(4-( (2-(methylthio)propyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 6i (200mg, 44.3 %). MS m/z (ESI): 430.0, 432.0 (M, M+2).
1H NMR(400MHz,DMSO-d6,ppm)δ8.07(dd,J1＝6.0Hz,J2＝2.4Hz,1H),7.71(m,1H),7.59(t,J＝8.8Hz,1H),6.59(t,J＝9.6Hz,1H),3.30(dd,J1＝12.8Hz,J2＝6.8Hz,2H),2.49(m,2H),2.04(s,3H),1.83(dd,J1＝14.0Hz,J2＝7.2Hz,2H)。1 H NMR (400MHz, DMSO-d6 , ppm) δ8.07 (dd, J1 = 6.0Hz, J2 = 2.4Hz, 1H), 7.71 (m, 1H), 7.59 (t, J = 8.8Hz, 1H), 6.59(t, J=9.6Hz, 1H), 3.30(dd, J1 =12.8Hz, J2 =6.8Hz, 2H), 2.49(m, 2H), 2.04(s, 3H), 1.83( dd, J1 =14.0 Hz, J2 =7.2 Hz, 2H).
步骤九：4-(3-溴-4-氟苯基)-3-(4-((2-(甲基亚硫酰基)丙基)氨基)-1,2,5-噁二Step 9: 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(methylsulfinyl)propyl)amino)-1,2,5-oxadi唑-3-基)-1,2,4-噁二唑-5(4H)-酮6jAzol-3-yl)-1,2,4-oxadiazol-5(4H)-one 6j
在100mL单口瓶中将4-(3-溴-4-氟苯基)-3-(4-((2-(甲硫基)丙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(200mg，0.47mmol)溶于二氯甲烷(20mL)，用干冰丙酮浴冷却至-40℃,将间氯过氧化苯甲酸(96.3mg,2.65mmol)溶于5mL二氯甲烷滴加入上述溶液中，滴加完后撤去干冰丙酮浴，大约20分钟后温度缓慢升至室温，然后室温下继续搅拌40分钟，LC-MS监测原料转化完全，停止反应，加入水(30mL),用乙酸乙酯(30mL*2)萃取，合并有机相用饱和氯化钠(40mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干得4-(3-溴-4-氟苯基)-3-(4-((2-(甲基亚硫酰基)丙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮6j(200mg，96％)。MS m/z(ESI):446.0,448.0(M,M+2)。4-(3-Bromo-4-fluorophenyl)-3-(4-((2-(methylthio)propyl)amino)-1,2,5-oxadiazole- 3-yl)-1,2,4-oxadiazol-5(4H)-one (200mg, 0.47mmol) was dissolved in dichloromethane (20mL), cooled to -40°C with a dry ice acetone bath, and m-chloro Oxidized benzoic acid (96.3 mg, 2.65 mmol) was dissolved in 5 mL of dichloromethane and added dropwise to the above solution. After the dropwise addition, the dry-ice acetone bath was removed. After about 20 minutes, the temperature slowly rose to room temperature, and then continued to stir at room temperature for 40 minutes. LC - MS monitors that the conversion of raw materials is complete, stop the reaction, add water (30mL), extract with ethyl acetate (30mL*2), combine the organic phases, wash with saturated sodium chloride (40mL), dry over anhydrous sodium sulfate, filter, and spin the filtrate 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(methylsulfinyl)propyl)amino)-1,2,5-oxadiazole-3- (yl)-1,2,4-oxadiazol-5(4H)-one 6j (200 mg, 96%). MS m/z (ESI): 446.0, 448.0 (M, M+2).
步骤十：4-(3-溴-4-氟苯基)-3-(4-((2-(S-甲基磺亚胺酰基)丙基)氨基)-1,2,5-Step 10: 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(S-methylsulfonimidoyl)propyl)amino)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮6kOxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 6k
在100mL单口瓶中将4-(3-溴-4-氟苯基)-3-(4-((2-(甲基亚硫酰基)丙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(200mg，0.45mmol)溶于氯仿(20mL)，加入叠氮化钠(59.0mg,0.90mmol),用冰浴冷却至0℃,加入浓硫酸(0.5mL),撤去冰浴，用油浴加热到42℃,搅拌反应过夜。LC-MS监测原料转化完全，停止反应，加入饱和碳酸氢钠溶液(30mL),用乙酸乙酯(30mL*2)萃取，合并有机相用饱和氯化钠(30mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干得4-(3-溴-4-氟苯基)-3-(4-((2-(S-甲基磺亚胺酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮6k(150mg，72.6％)。MS m/z(ESI):461.0,463.0(M,M+2)。In a 100mL single-necked bottle, 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(methylsulfinyl)propyl)amino)-1,2,5-oxadi Azol-3-yl)-1,2,4-oxadiazol-5(4H)-one (200mg, 0.45mmol) was dissolved in chloroform (20mL), sodium azide (59.0mg, 0.90mmol) was added, and the Cool in an ice bath to 0°C, add concentrated sulfuric acid (0.5 mL), remove the ice bath, heat to 42°C with an oil bath, and stir the reaction overnight. LC-MS monitored the complete conversion of raw materials, stopped the reaction, added saturated sodium bicarbonate solution (30mL), extracted with ethyl acetate (30mL*2), combined organic phases were washed with saturated sodium chloride (30mL), and dried over anhydrous sodium sulfate , filtered, and the filtrate was spin-dried to give 4-(3-bromo-4-fluorophenyl)-3-(4-((2-(S-methylsulfonimidoyl)ethyl)amino)-1,2, 5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 6k (150 mg, 72.6%). MS m/z (ESI): 461.0, 463.0 (M, M+2).
步骤十一：(Z)-N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(S-甲基磺亚胺酰基)丙基)Step 11: (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(S-methylsulfonimidoyl)propyl)氨基)-1,2,5-噁二唑-3-碳杂氧杂脒6Amino)-1,2,5-oxadiazole-3-carbaoxamidine 6
在100mL单口瓶中将4-(3-溴-4-氟苯基)-3-(4-((2-(S-甲基磺亚胺酰基)丙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(150mg，0.33mmol)溶于四氢呋喃/甲醇(6mL/6mL)，将氢氧化钠(65.1mg,1.65mmol)溶于水(4mL)加入上述溶液中，室温下反应2小时。LC-MS监测原料转化完全，停止反应，加入饱和氯化铵溶液(30mL),用乙酸乙酯(30mL*2)萃取，合并有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，过滤，滤液浓缩，通过制备硅胶板分离纯化(展开剂：二氯甲烷/甲醇＝10/1；洗脱剂：乙酸乙酯/甲醇＝10/1)得(Z)-N-(3-溴-4-氟苯基)-N'-羟基-4-((2-(S-甲基磺亚胺酰基)丙基)氨基)-1,2,5-噁二唑-3-碳杂氧杂脒6(60.0mg，41.8％)。MS m/z(ESI):435.0,437.0(M,M+2)。4-(3-bromo-4-fluorophenyl)-3-(4-((2-(S-methylsulfonimidoyl)propyl)amino)-1,2,5 -oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (150mg, 0.33mmol) was dissolved in tetrahydrofuran/methanol (6mL/6mL), sodium hydroxide (65.1mg , 1.65mmol) dissolved in water (4mL) was added to the above solution, and reacted at room temperature for 2 hours. LC-MS monitored the complete conversion of raw materials, stopped the reaction, added saturated ammonium chloride solution (30mL), extracted with ethyl acetate (30mL*2), combined organic phases were washed with saturated sodium chloride (50mL), and dried over anhydrous sodium sulfate , filtered, filtered, the filtrate was concentrated, separated and purified by preparing a silica gel plate (developing solvent: dichloromethane/methanol=10/1; eluent: ethyl acetate/methanol=10/1) to obtain (Z)-N-( 3-Bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(S-methylsulfonimidoyl)propyl)amino)-1,2,5-oxadiazole-3- Carbaoxamidine 6 (60.0 mg, 41.8%). MS m/z (ESI): 435.0, 437.0 (M, M+2).
1H NMR(400MHz,MeOD-d4,ppm)δ7.15(dd,J1＝6.0Hz,J2＝2.4Hz,1H),7.07(t,J＝8.8Hz,1H),6.87(m,1H),3.49(t,J＝6.4Hz,2H),3.27(t,J＝8.0Hz,2H),3.03(s,3H),2.19(m,1H)。1 H NMR (400MHz, MeOD-d4 , ppm) δ7.15 (dd, J1 = 6.0Hz, J2 = 2.4Hz, 1H), 7.07 (t, J = 8.8Hz, 1H), 6.87 (m, 1H) , 3.49 (t, J = 6.4Hz, 2H), 3.27 (t, J = 8.0Hz, 2H), 3.03 (s, 3H), 2.19 (m, 1H).
实施例七Embodiment seven
(Z)-N-(2-溴-4-氟苯基)-N'-羟基-4-((2-(S-甲基磺亚胺酰基)乙基)氨基)-1,2,(Z)-N-(2-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(S-methylsulfonimidoyl)ethyl)amino)-1,2,5-噁二唑-3-碳杂氧杂脒(7)5-oxadiazole-3-carbaoxamidine (7)
步骤一:N-(2-溴-4-氟苯基)-N'-羟基-4-((2-甲氧基乙基)氨基)-1,2,5-噁二唑-Step 1: N-(2-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazole-3-碳杂氧杂脒7b3-carbaoxaamidine 7b
将化合物N-羟基-4-((2-甲氧基乙基)氨基)-1,2,5-噁二唑-3-碳杂亚胺酰基氯化(2.2g,10mmol)加入水(14ml)加热至60℃，加入2-溴-4-氟苯胺(2.06g,11mmol),搅拌10分钟，然后再加碳酸氢钠(1.26g,15mmol)60℃下搅拌30分钟，至反应完全,用乙酸乙酯萃取,水洗有机相，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得化合物7b(3.9g，100％)。MS m/z(ESI):374.0。The compound N-hydroxyl-4-((2-methoxyethyl)amino)-1,2,5-oxadiazole-3-carbaimide acid chloride (2.2g, 10mmol) was added to water (14ml ) to 60°C, add 2-bromo-4-fluoroaniline (2.06g, 11mmol), stir for 10 minutes, then add sodium bicarbonate (1.26g, 15mmol) and stir at 60°C for 30 minutes until the reaction is complete, use Extracted with ethyl acetate, washed the organic phase with water and saturated brine, dried the organic phase with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 7b (3.9 g, 100%). MS m/z (ESI): 374.0.
步骤二:4-(2-溴-4-氟苯基)-3-(4-((2-甲氧基乙基)氨基)-1,2,5-噁二唑-3-Step 2: 4-(2-bromo-4-fluorophenyl)-3-(4-((2-methoxyethyl)amino)-1,2,5-oxadiazole-3-基)-1,2,4-噁二唑-5(4H)-酮7cbase)-1,2,4-oxadiazol-5(4H)-one 7c
将化合物N-(2-溴-4-氟苯基)-N'-羟基-4-((2-甲氧基乙基)氨基)-1,2,5-噁二唑-3-碳杂氧杂脒(840mg,2.25mmol)加入乙酸乙酯(10ml)加热至60℃，加入1,1'-羰基二咪唑(547m g,3.37mmol),搅拌30分钟，1NHCl洗有机相，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得化合物7c(800mg，89％)。MS m/z(ESI):400.0。The compound N-(2-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazole-3-carba Add ethyl acetate (10ml) to oxamidine (840mg, 2.25mmol) and heat to 60°C, add 1,1'-carbonyldiimidazole (547mg, 3.37mmol), stir for 30 minutes, wash the organic phase with 1N HCl, and wash with saturated brine , dried the organic phase over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 7c (800 mg, 89%). MS m/z (ESI): 400.0.
步骤三:4-(2-溴-4-氟苯基)-3-(4-((2-羟基乙基)氨基)-1,2,5-噁二唑-3-基)-Step 3: 4-(2-bromo-4-fluorophenyl)-3-(4-((2-hydroxyethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-噁二唑-5(4H)-酮7d1,2,4-Oxadiazol-5(4H)-one 7d
将化合物4-(2-溴-4-氟苯基)-3-(4-((2-甲氧基乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(800mg,2mmol)加入二氯甲烷(15ml)在-78℃滴加三溴化硼的二氯甲烷溶液(5ml,2.5mmol),搅拌至室温，LC-MS监测原料原料转化完全，停止反应，冰浴下用饱和碳酸氢钠溶液调PH至中性，有机相用水洗，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得化合物7d(300mg，39％)。MS m/z(ESI):385.9。Compound 4-(2-bromo-4-fluorophenyl)-3-(4-((2-methoxyethyl)amino)-1,2,5-oxadiazol-3-yl)-1 , 2,4-Oxadiazol-5(4H)-ketone (800mg, 2mmol) was added to dichloromethane (15ml) at -78°C, a solution of boron tribromide in dichloromethane (5ml, 2.5mmol) was added dropwise, stirring To room temperature, LC-MS monitors the complete conversion of the raw materials, stop the reaction, adjust the pH to neutral with saturated sodium bicarbonate solution under ice bath, wash the organic phase with water, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, reduce the pressure and vacuum Concentration gave compound 7d (300 mg, 39%). MS m/z (ESI): 385.9.
步骤四:2-((4-(4-(2-溴-4-氟苯基)-5-羰基-4,5-二氢-1,2,4-噁二唑-3-基)-1,Step 4: 2-((4-(4-(2-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)- 1,2,5-噁二唑-3-基)氨基)乙基甲磺酸酯7e2,5-oxadiazol-3-yl)amino)ethyl methanesulfonate 7e
将化合物4-(2-溴-4-氟苯基)-3-(4-((2-羟基乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(300mg,0.78mmol)加入乙酸乙酯(5ml)室温下加入甲磺酰氯(89mg,0.78mmol),再加三乙胺(79mg,0.78mmol)，LC-MS监测原料原料转化完全，停止反应，有机相用水洗，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得化合物7e(320mg，88％)。MS m/z(ESI):463.9。The compound 4-(2-bromo-4-fluorophenyl)-3-(4-((2-hydroxyethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2 , 4-Oxadiazol-5(4H)-one (300mg, 0.78mmol) was added to ethyl acetate (5ml) and methanesulfonyl chloride (89mg, 0.78mmol) was added at room temperature, and triethylamine (79mg, 0.78mmol) was added , LC-MS monitored the complete conversion of raw materials, stopped the reaction, washed the organic phase with water, washed with saturated brine, dried the organic phase with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 7e (320 mg, 88%). MS m/z (ESI): 463.9.
步骤五:4-(2-溴-4-氟苯基)-3-(4-((2-(甲硫基)乙基)氨基)-1,2,5-噁二唑-3-Step 5: 4-(2-bromo-4-fluorophenyl)-3-(4-((2-(methylthio)ethyl)amino)-1,2,5-oxadiazole-3-基)-1,2,4-噁二唑-5(4H)-酮7fbase)-1,2,4-oxadiazol-5(4H)-one 7f
在25mL单口瓶中将2-((4-(4-(2-溴-4-氟苯基)-5-羰基-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)乙基甲磺酸酯(320mg，0.69mmol)溶于N，N-二甲基甲酰胺(3mL)，用冰浴冷却至0℃,加入甲硫醇钠(48mg,0.69mmol),在冰浴条件下搅拌20min。LC-MS监测原料转化完全，停止反应，加入水(25mL)淬灭反应,用乙酸乙酯(25mL*2)萃取，合并有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液加硅胶，直接旋干柱层析，石油醚/乙酸乙酯(5/1到3/1)，得4-(3-溴-4-氟苯基)-3-(4-((2-(甲硫基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮7f(170mg,59.3％)。MS m/z(ESI):416.0。2-((4-(4-(2-bromo-4-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3- Base)-1,2,5-oxadiazol-3-yl)amino)ethyl methanesulfonate (320mg, 0.69mmol) was dissolved in N,N-dimethylformamide (3mL) and cooled in an ice bath To 0 ° C, sodium methyl mercaptide (48 mg, 0.69 mmol) was added, and stirred for 20 min under ice-bath conditions. LC-MS monitored the complete conversion of raw materials, stopped the reaction, added water (25mL) to quench the reaction, extracted with ethyl acetate (25mL*2), combined organic phases were washed with saturated sodium chloride (50mL), dried over anhydrous sodium sulfate, Filtrate, add silica gel to the filtrate, spin dry column chromatography directly, petroleum ether/ethyl acetate (5/1 to 3/1), get 4-(3-bromo-4-fluorophenyl)-3-(4-( (2-(Methylthio)ethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 7f (170mg, 59.3 %). MS m/z (ESI): 416.0.
步骤六：4-(2-溴-4-氟苯基)-3-(4-((2-(甲基亚硫酰基)乙基)氨基)-1,2,5-噁二Step 6: 4-(2-bromo-4-fluorophenyl)-3-(4-((2-(methylsulfinyl)ethyl)amino)-1,2,5-oxadi唑-3-基)-1,2,4-噁二唑-5(4H)-酮7gAzol-3-yl)-1,2,4-oxadiazol-5(4H)-one 7g
在25mL单口瓶中将4-(2-溴-4-氟苯基)-3-(4-((2-(甲硫基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(170mg，0.41mmol)溶于二氯甲烷(10mL)，用干冰丙酮浴冷却至-40℃,将间氯过氧化苯甲酸(78mg,0.45mmol)溶于5mL二氯甲烷滴加入上述溶液中，滴加完后撤去干冰丙酮浴，大约20分钟后温度缓慢升至室温，然后室温下继续搅拌40分钟，LC-MS监测原料转化完全，停止反应，加入水(20mL),用乙酸乙酯(20mL*2)萃取，合并有机相用饱和氯化钠(60mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干得7g(160mg，90.7％)。MS m/z(ESI):431.9。4-(2-bromo-4-fluorophenyl)-3-(4-((2-(methylthio)ethyl)amino)-1,2,5-oxadiazole- 3-yl)-1,2,4-oxadiazol-5(4H)-one (170mg, 0.41mmol) was dissolved in dichloromethane (10mL), cooled to -40°C with a dry ice acetone bath, and m-chloro Oxidized benzoic acid (78mg, 0.45mmol) was dissolved in 5mL of dichloromethane and added dropwise to the above solution. After the dropwise addition, the dry ice acetone bath was removed. After about 20 minutes, the temperature slowly rose to room temperature, and then continued to stir at room temperature for 40 minutes. LC- Complete conversion of raw materials was monitored by MS, and the reaction was stopped. Add water (20mL), extract with ethyl acetate (20mL*2), combine organic phases, wash with saturated sodium chloride (60mL), dry over anhydrous sodium sulfate, filter, and spin the filtrate to dry Yield 7 g (160 mg, 90.7%). MS m/z (ESI): 431.9.
步骤七：4-(2-溴-4-氟苯基)-3-(4-((2-(S-甲基磺亚胺酰基)乙基)氨基)-1,2,5-Step 7: 4-(2-bromo-4-fluorophenyl)-3-(4-((2-(S-methylsulfonimidoyl)ethyl)amino)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)7hOxadiazol-3-yl)-1,2,4-oxadiazole-5(4H)7h
在50mL单口瓶中将4-(2-溴-4-氟苯基)-3-(4-((2-(甲基亚硫酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(160mg,0.41mmol)溶于氯仿(6mL)，加入叠氮化钠(80.0mg,1.23mmol),用冰浴冷却至0℃,加入浓硫酸(0.5mL),撤去冰浴，用油浴加热到42℃,搅拌反应过夜。LC-MS监测原料转化完全，停止反应，加入饱和碳酸氢钠溶液(25mL),用乙酸乙酯(25mL*2)萃取，合并有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干,经TLC薄层色谱纯化(DCM:MeOH＝10:1)得7h(40mg，22％)。MS m/z(ESI):446.9。4-(2-bromo-4-fluorophenyl)-3-(4-((2-(methylsulfinyl)ethyl)amino)-1,2,5-oxadi Azol-3-yl)-1,2,4-oxadiazol-5(4H)-one (160mg, 0.41mmol) was dissolved in chloroform (6mL), sodium azide (80.0mg, 1.23mmol) was added, and the Cool in an ice bath to 0°C, add concentrated sulfuric acid (0.5 mL), remove the ice bath, heat to 42°C with an oil bath, and stir the reaction overnight. LC-MS monitored the complete conversion of raw materials, stopped the reaction, added saturated sodium bicarbonate solution (25mL), extracted with ethyl acetate (25mL*2), combined organic phases were washed with saturated sodium chloride (50mL), and dried over anhydrous sodium sulfate , filtered, the filtrate was spin-dried, and purified by TLC (DCM:MeOH=10:1) to obtain 7h (40mg, 22%). MS m/z (ESI): 446.9.
步骤八：(Z)-N-(2-溴-4-氟苯基)-N'-羟基-4-((2-(S-甲基磺亚胺酰基)乙基)氨Step 8: (Z)-N-(2-bromo-4-fluorophenyl)-N'-hydroxy-4-((2-(S-methylsulfonimidoyl)ethyl)ammonia基)-1,2,5-噁二唑-3-碳杂氧杂脒7base)-1,2,5-oxadiazole-3-carbaoxamidine 7
在50mL单口瓶中将4-(2-溴-4-氟苯基)-3-(4-((2-(S-甲基磺亚胺酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮2h(40mg，0.089mmol)溶于四氢呋喃/甲醇(4mL/4mL)，将2N氢氧化钠(0.3ml)加入上述溶液中，室温下反应2小时。LC-MS监测原料转化完全，停止反应，加入饱和氯化铵溶液(15mL),用乙酸乙酯(30mL*2)萃取，合并有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干,经TLC薄层色谱纯化(DCM:MeOH＝10:1)得化合物7(24mg，64％)。MS m/z(ESI):421.0。4-(2-bromo-4-fluorophenyl)-3-(4-((2-(S-methylsulfonimidoyl)ethyl)amino)-1,2,5 -oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 2h (40mg, 0.089mmol) was dissolved in tetrahydrofuran/methanol (4mL/4mL), and 2N sodium hydroxide ( 0.3ml) was added to the above solution, and reacted at room temperature for 2 hours. LC-MS monitored the complete conversion of raw materials, stopped the reaction, added saturated ammonium chloride solution (15mL), extracted with ethyl acetate (30mL*2), combined organic phases were washed with saturated sodium chloride (50mL), and dried over anhydrous sodium sulfate , filtered, the filtrate was spin-dried, and purified by TLC (DCM:MeOH=10:1) to obtain compound 7 (24 mg, 64%). MS m/z (ESI): 421.0.
1H NMR(400MHz,DMSOd6,ppm):δ7.37(m,1H),7.08(m,1H),7.04(m,1H),3.83(m,2H),3.55(m,2H),3.10(s,3H)。1 H NMR(400MHz,DMSOd6 ,ppm):δ7.37(m,1H),7.08(m,1H),7.04(m,1H),3.83(m,2H),3.55(m,2H),3.10 (s,3H).
实施例八Embodiment eight
((Z)-N-(4-溴-3-氟苯基)-N'-羟基-4-((2-(S-甲基磺亚胺酰基)乙基)氨基)-1,((Z)-N-(4-bromo-3-fluorophenyl)-N'-hydroxy-4-((2-(S-methylsulfonimidoyl)ethyl)amino)-1,2,5-噁二唑-3-碳杂氧杂脒(8)2,5-oxadiazole-3-carbaoxamidine (8)
步骤一:N-(4-溴-3-氟苯基)-N'-羟基-4-((2-甲氧基乙基)氨基)-1,2,5-噁二唑-Step 1: N-(4-bromo-3-fluorophenyl)-N'-hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazole-3-碳杂氧杂脒8b3-carbaoxaamidine 8b
将化合物N-羟基-4-((2-甲氧基乙基)氨基)-1,2,5-噁二唑-3-碳杂亚胺酰基氯化(500mg,2.27mmol)加入水(5ml)加热至60℃，加入4-溴-3-氟苯胺(472mg,2.49mmol),搅拌10分钟，然后再加碳酸氢钠(286mg,3.4mmol)60℃下搅拌30分钟，至反应完全,用乙酸乙酯萃取,水洗有机相，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得化合物8b(800mg)。MS m/z(ESI):374.0。The compound N-hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazole-3-carbaimide acid chloride (500mg, 2.27mmol) was added to water (5ml ) was heated to 60°C, added 4-bromo-3-fluoroaniline (472mg, 2.49mmol), stirred for 10 minutes, then added sodium bicarbonate (286mg, 3.4mmol) and stirred at 60°C for 30 minutes until the reaction was complete. Extracted with ethyl acetate, washed the organic phase with water and saturated brine, dried the organic phase with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8b (800 mg). MS m/z (ESI): 374.0.
步骤二:4-(4-溴-3-氟苯基)-3-(4-((2-甲氧基乙基)氨基)-1,2,5-噁二唑-3-Step 2: 4-(4-bromo-3-fluorophenyl)-3-(4-((2-methoxyethyl)amino)-1,2,5-oxadiazole-3-基)-1,2,4-噁二唑-5(4H)-酮8cbase)-1,2,4-oxadiazol-5(4H)-one 8c
将化合物N-(4-溴-3-氟苯基)-N'-羟基-4-((2-甲氧基乙基)氨基)-1,2,5-噁二唑-3-碳杂氧杂脒(800mg,2.25mmol)加入乙酸乙酯(10ml)加热至60℃，加入1,1'-羰基二咪唑(547mg,3.37mmol),搅拌30分钟，1NHCl洗有机相，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩,通过快速色谱柱纯化得化合物8c(400mg，47％)。MS m/z(ESI):400.0。The compound N-(4-bromo-3-fluorophenyl)-N'-hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazole-3-carba Add ethyl acetate (10ml) to oxamidine (800mg, 2.25mmol) and heat to 60°C, add 1,1'-carbonyldiimidazole (547mg, 3.37mmol), stir for 30 minutes, wash the organic phase with 1N HCl and saturated brine, The organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo under reduced pressure, and purified by flash chromatography to obtain compound 8c (400 mg, 47%). MS m/z (ESI): 400.0.
步骤三:4-(4-溴-3-氟苯基)-3-(4-((2-羟基乙基)氨基)-1,2,5-噁二唑-3-基)-Step 3: 4-(4-bromo-3-fluorophenyl)-3-(4-((2-hydroxyethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2,4-噁二唑-5(4H)-酮8d1,2,4-Oxadiazol-5(4H)-one 8d
将化合物4-(4-溴-3-氟苯基)-3-(4-((2-甲氧基乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(400mg,2mmol)加入二氯甲烷(15ml)在-78℃滴加三溴化硼的二氯甲烷溶液(2.5ml,1.25mmol),搅拌至室温，LC-MS监测原料原料转化完全，停止反应，冰浴下用饱和碳酸氢钠溶液调PH至中性，有机相用水洗，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得化合物8d(330mg，86％)。MS m/z(ESI):385.9。Compound 4-(4-bromo-3-fluorophenyl)-3-(4-((2-methoxyethyl)amino)-1,2,5-oxadiazol-3-yl)-1 , 2,4-oxadiazol-5(4H)-one (400mg, 2mmol) was added to dichloromethane (15ml) and boron tribromide in dichloromethane (2.5ml, 1.25mmol) was added dropwise at -78°C, Stir to room temperature, LC-MS monitors the complete conversion of raw materials, stop the reaction, adjust the pH to neutral with saturated sodium bicarbonate solution under ice bath, wash the organic phase with water, wash with saturated saline, dry the organic phase with anhydrous sodium sulfate, and reduce pressure Concentration in vacuo afforded compound 8d (330 mg, 86%). MS m/z (ESI): 385.9.
步骤四:2-((4-(4-(4-溴-3-氟苯基)-5-羰基-4,5-二氢-1,2,4-噁二唑-3-基)-1,Step 4: 2-((4-(4-(4-bromo-3-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)- 1,2,5-噁二唑-3-基)氨基)乙基甲磺酸酯8e2,5-oxadiazol-3-yl)amino)ethyl methanesulfonate 8e
将化合物4-(4-溴-3-氟苯基)-3-(4-((2-羟基乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(330mg,0.85mmol)加入乙酸乙酯(5ml)室温下加入甲磺酰氯(118mg,1.03mmol),再加三乙胺(129mg,1.27mmol)，LC-MS监测原料原料转化完全，停止反应，有机相用水洗，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得化合物8e(280mg)。MS m/z(ESI):463.9。The compound 4-(4-bromo-3-fluorophenyl)-3-(4-((2-hydroxyethyl)amino)-1,2,5-oxadiazol-3-yl)-1,2 , 4-Oxadiazol-5(4H)-one (330mg, 0.85mmol) was added to ethyl acetate (5ml) and methanesulfonyl chloride (118mg, 1.03mmol) was added at room temperature, and triethylamine (129mg, 1.27mmol) was added , LC-MS monitored the complete conversion of raw materials, stopped the reaction, washed the organic phase with water, washed with saturated brine, dried the organic phase with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8e (280 mg). MS m/z (ESI): 463.9.
步骤五:4-(4-溴-3-氟苯基)-3-(4-((2-(甲硫基)乙基)氨基)-1,2,5-噁二唑-3-Step 5: 4-(4-bromo-3-fluorophenyl)-3-(4-((2-(methylthio)ethyl)amino)-1,2,5-oxadiazole-3-基)-1,2,4-噁二唑-5(4H)-酮8fbase)-1,2,4-oxadiazol-5(4H)-one 8f
在25mL单口瓶中将2-((4-(4-(4-溴-3-氟苯基)-5-羰基-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)乙基甲磺酸酯(280mg，0.60mmol)溶于N，N-二甲基甲酰胺(3mL)，用冰浴冷却至0℃,加入甲硫醇钠(48mg,0.69mmol),在冰浴条件下搅拌20min,LC-MS监测原料转化完全，停止反应，加入水(25mL)淬灭反应,用乙酸乙酯(25mL*2)萃取，合并有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液加硅胶，直接旋干柱层析，石油醚/乙酸乙酯(5/1到3/1)，得8f(170mg,68％)。MS m/z(ESI):416.0。2-((4-(4-(4-bromo-3-fluorophenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3- Base)-1,2,5-oxadiazol-3-yl)amino)ethyl methanesulfonate (280mg, 0.60mmol) was dissolved in N,N-dimethylformamide (3mL) and cooled in an ice bath To 0 ℃, add sodium methyl mercaptide (48mg, 0.69mmol), stir in ice bath for 20min, LC-MS monitors the complete conversion of raw materials, stop the reaction, add water (25mL) to quench the reaction, and ethyl acetate (25mL *2) Extraction, the combined organic phases were washed with saturated sodium chloride (50mL), dried over anhydrous sodium sulfate, filtered, the filtrate was added to silica gel, and directly spin-dried for column chromatography, petroleum ether/ethyl acetate (5/1 to 3/ 1), to obtain 8f (170 mg, 68%). MS m/z (ESI): 416.0.
步骤六：4-(4-溴-3-氟苯基)-3-(4-((2-(甲基亚硫酰基)乙基)氨基)-1,2,5-噁二Step 6: 4-(4-bromo-3-fluorophenyl)-3-(4-((2-(methylsulfinyl)ethyl)amino)-1,2,5-oxadi唑-3-基)-1,2,4-噁二唑-5(4H)-酮8gAzol-3-yl)-1,2,4-oxadiazol-5(4H)-one 8g
在25mL单口瓶中将4-(4-溴-3-氟苯基)-3-(4-((2-(甲硫基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(170mg，0.41mmol)溶于二氯甲烷(10mL)，用干冰丙酮浴冷却至-40℃,将间氯过氧化苯甲酸(78mg,0.45mmol)溶于5mL二氯甲烷滴加入上述溶液中，滴加完后撤去干冰丙酮浴，大约20分钟后温度缓慢升至室温，然后室温下继续搅拌40分钟，LC-MS监测原料转化完全，停止反应，加入水(20mL),用乙酸乙酯(20mL*2)萃取，合并有机相用饱和氯化钠(60mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干得8g(160mg，90.7％)。MS m/z(ESI):431.9。4-(4-bromo-3-fluorophenyl)-3-(4-((2-(methylthio)ethyl)amino)-1,2,5-oxadiazole- 3-yl)-1,2,4-oxadiazol-5(4H)-one (170mg, 0.41mmol) was dissolved in dichloromethane (10mL), cooled to -40°C with a dry ice acetone bath, and m-chloro Oxidized benzoic acid (78mg, 0.45mmol) was dissolved in 5mL of dichloromethane and added dropwise to the above solution. After the dropwise addition, the dry ice acetone bath was removed. After about 20 minutes, the temperature slowly rose to room temperature, and then continued to stir at room temperature for 40 minutes. LC- Complete conversion of raw materials was monitored by MS, and the reaction was stopped. Add water (20mL), extract with ethyl acetate (20mL*2), combine organic phases, wash with saturated sodium chloride (60mL), dry over anhydrous sodium sulfate, filter, and spin the filtrate to dry Yield 8 g (160 mg, 90.7%). MS m/z (ESI): 431.9.
步骤七：4-(4-溴-3-氟苯基)-3-(4-((2-(S-甲基磺亚胺酰基)乙基)氨基)-1,2,5-Step 7: 4-(4-bromo-3-fluorophenyl)-3-(4-((2-(S-methylsulfonimidoyl)ethyl)amino)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮8hOxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 8h
在50mL单口瓶中将4-(4-溴-3-氟苯基)-3-(4-((2-(甲基亚硫酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(160mg,0.41mmol)溶于氯仿(6mL)，加入叠氮化钠(80.0mg,1.23mmol),用冰浴冷却至0℃,加入浓硫酸(0.5mL),撤去冰浴，用油浴加热到42℃,搅拌反应过夜。LC-MS监测原料转化完全，停止反应，加入饱和碳酸氢钠溶液(25mL),用乙酸乙酯(25mL*2)萃取，合并有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干,经TLC薄层色谱纯化(DCM:MeOH＝10:1)得8h(40mg，22％)。MS m/z(ESI):446.9。4-(4-bromo-3-fluorophenyl)-3-(4-((2-(methylsulfinyl)ethyl)amino)-1,2,5-oxadi Azol-3-yl)-1,2,4-oxadiazol-5(4H)-one (160mg, 0.41mmol) was dissolved in chloroform (6mL), sodium azide (80.0mg, 1.23mmol) was added, and the Cool in an ice bath to 0°C, add concentrated sulfuric acid (0.5 mL), remove the ice bath, heat to 42°C with an oil bath, and stir the reaction overnight. LC-MS monitored the complete conversion of raw materials, stopped the reaction, added saturated sodium bicarbonate solution (25mL), extracted with ethyl acetate (25mL*2), combined organic phases were washed with saturated sodium chloride (50mL), and dried over anhydrous sodium sulfate , filtered, the filtrate was spin-dried, and purified by TLC (DCM:MeOH=10:1) to obtain 8h (40mg, 22%). MS m/z (ESI): 446.9.
步骤八：(Z)-N-(4-溴-3-氟苯基)-N'-羟基-4-((2-(S-甲基磺亚胺酰基)乙基)氨Step 8: (Z)-N-(4-bromo-3-fluorophenyl)-N'-hydroxy-4-((2-(S-methylsulfonimidoyl)ethyl)ammonia基)-1,2,5-噁二唑-3-碳杂氧杂脒8base)-1,2,5-oxadiazole-3-carbaoxamidine 8
在50mL单口瓶中将4-(4-溴-3-氟苯基)-3-(4-((2-(S-甲基磺亚胺酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮3h(40mg，0.089mmol)溶于四氢呋喃/甲醇(4mL/4mL)，将2N氢氧化钠(0.3ml)加入上述溶液中，室温下反应2小时。LC-MS监测原料转化完全，停止反应，加入饱和氯化铵溶液(15mL),用乙酸乙酯(30mL*2)萃取，合并有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干,经TLC薄层色谱纯化(DCM:MeOH＝10:1)得化合物8(24mg，64％)。MS m/z(ESI):421.0。4-(4-bromo-3-fluorophenyl)-3-(4-((2-(S-methylsulfonimidoyl)ethyl)amino)-1,2,5 -oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 3h (40mg, 0.089mmol) was dissolved in tetrahydrofuran/methanol (4mL/4mL), and 2N sodium hydroxide ( 0.3ml) was added to the above solution, and reacted at room temperature for 2 hours. LC-MS monitored the complete conversion of raw materials, stopped the reaction, added saturated ammonium chloride solution (15mL), extracted with ethyl acetate (30mL*2), combined organic phases were washed with saturated sodium chloride (50mL), and dried over anhydrous sodium sulfate , filtered, the filtrate was spin-dried, and purified by TLC (DCM:MeOH=10:1) to obtain compound 8 (24 mg, 64%). MS m/z (ESI): 421.0.
1H NMR(400MHz,DMSO,ppm):δ7.28(m,1H),6.56(m,1H),6.46(m,1H),3.73(m,2H),3.45(m,2H),2.98(s,3H)。1 H NMR (400MHz, DMSO, ppm): δ7.28(m,1H),6.56(m,1H),6.46(m,1H),3.73(m,2H),3.45(m,2H),2.98( s, 3H).
实施例九Embodiment nine
(Z)-N-(4-氟-3-(三氟甲基)苯基)-N'-羟基-4-((2-(S-甲基磺亚胺酰基)乙基)氨(Z)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-4-((2-(S-methylsulfonimidoyl)ethyl)amine基)-1,2,5-噁二唑-3-碳杂氧杂脒(9)base)-1,2,5-oxadiazole-3-carbaoxamidine (9)
步骤一:N-(4-氟-3-(三氟甲基)苯基)-N'-羟基-4-((2-甲氧基乙基)氨基)-1,2,Step 1: N-(4-fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxyl-4-((2-methoxyethyl)amino)-1,2,5-噁二唑-3-碳杂氧杂脒9b5-oxadiazole-3-carbaoxamidine 9b
将化合物N-羟基-4-((2-甲氧基乙基)氨基)-1,2,5-噁二唑-3-碳杂亚胺酰基氯化(500mg,2.27mmol)加入水(5ml)加热至60℃，加入4-氟-3-(三氟甲基)苯胺(472mg,2.49mmol),搅拌10分钟，然后再加碳酸氢钠(286mg,3.4mmol)60℃下搅拌30分钟，至反应完全,用乙酸乙酯萃取,水洗有机相，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得化合物9b(800mg)。MS m/z(ESI):364.0。The compound N-hydroxy-4-((2-methoxyethyl)amino)-1,2,5-oxadiazole-3-carbaimide acid chloride (500mg, 2.27mmol) was added to water (5ml ) to 60°C, add 4-fluoro-3-(trifluoromethyl)aniline (472mg, 2.49mmol), stir for 10 minutes, then add sodium bicarbonate (286mg, 3.4mmol) and stir at 60°C for 30 minutes, When the reaction was complete, it was extracted with ethyl acetate, the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 9b (800 mg). MS m/z (ESI): 364.0.
步骤二:4-(4-氟-3-(三氟甲基)苯基)-3-(4-((2-甲氧基乙基)氨基)-1,2,5-噁二Step 2: 4-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((2-methoxyethyl)amino)-1,2,5-oxadi唑-3-基)-1,2,4-噁二唑-5(4H)-酮9cAzol-3-yl)-1,2,4-oxadiazol-5(4H)-one 9c
将化合物N-(4-氟-3-(三氟甲基)苯基)-N'-羟基-4-((2-甲氧基乙基)氨基)-1,2,5-噁二唑-3-碳杂氧杂脒(800mg,2.25mmol)加入乙酸乙酯(10ml)加热至60℃，加入1,1'-羰基二咪唑(547mg,3.37mmol),搅拌30分钟，1NHCl洗有机相，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩,通过快速色谱柱纯化得化合物9c(400mg，47％)。MS m/z(ESI):390.0。The compound N-(4-fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxyl-4-((2-methoxyethyl)amino)-1,2,5-oxadiazole - Add ethyl acetate (10ml) to 3-carbaoxaamidine (800mg, 2.25mmol) and heat to 60°C, add 1,1'-carbonyldiimidazole (547mg, 3.37mmol), stir for 30 minutes, wash the organic phase with 1N HCl , washed with saturated brine, dried the organic phase with anhydrous sodium sulfate, concentrated under reduced pressure in vacuo, and purified by flash chromatography to obtain compound 9c (400 mg, 47%). MS m/z (ESI): 390.0.
步骤三:4-(4-氟-3-(三氟甲基)苯基)-3-(4-((2-羟基乙基)氨基)-1,2,5-噁二Step 3: 4-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((2-hydroxyethyl)amino)-1,2,5-oxadi唑-3-基)-1,2,4-噁二唑-5(4H)-酮9dAzol-3-yl)-1,2,4-oxadiazol-5(4H)-one 9d
将化合物4-(4-氟-3-(三氟甲基)苯基)-3-(4-((2-甲氧基乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(400mg,2mmol)加入二氯甲烷(15ml)在-78℃滴加三溴化硼的二氯甲烷溶液(2.5ml,1.25mmol),搅拌至室温，LC-MS监测原料原料转化完全，停止反应，冰浴下用饱和碳酸氢钠溶液调PH至中性，有机相用水洗，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得化合物9d(330mg，86％)。MS m/z(ESI):376.0。The compound 4-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((2-methoxyethyl)amino)-1,2,5-oxadiazole-3 -yl)-1,2,4-oxadiazol-5(4H)-one (400mg, 2mmol) was added to dichloromethane (15ml) at -78°C, and a solution of boron tribromide in dichloromethane (2.5ml , 1.25mmol), stirred to room temperature, LC-MS monitored the complete conversion of raw materials, stopped the reaction, adjusted the pH to neutral with saturated sodium bicarbonate solution under ice bath, washed the organic phase with water, washed with saturated brine, and dried over anhydrous sodium sulfate The organic phase was concentrated under reduced pressure to obtain compound 9d (330 mg, 86%). MS m/z (ESI): 376.0.
步骤四:2-((4-(4-(4-氟-3-(三氟甲基)苯基)-5-羰基-4,5-二氢-1,2,4-噁二唑-Step 4: 2-((4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3-基)-1,2,5-噁二唑-3-基)氨基)乙基甲磺酸酯9e3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl methanesulfonate 9e
将化合物4-(4-氟-3-(三氟甲基)苯基)-3-(4-((2-羟基乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(330mg,0.85mmol)加入乙酸乙酯(5ml)室温下加入甲磺酰氯(118mg,1.03mmol),再加三乙胺(129mg,1.27mmol)，LC-MS监测原料原料转化完全，停止反应，有机相用水洗，饱和食盐水洗,无水硫酸钠干燥有机相,减压真空浓缩得化合物9e(280mg)。MS m/z(ESI):454.0。The compound 4-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((2-hydroxyethyl)amino)-1,2,5-oxadiazol-3-yl )-1,2,4-oxadiazol-5(4H)-ketone (330mg, 0.85mmol) was added to ethyl acetate (5ml) and methanesulfonyl chloride (118mg, 1.03mmol) was added at room temperature, and triethylamine ( 129mg, 1.27mmol), LC-MS monitored the complete conversion of raw materials, stopped the reaction, washed the organic phase with water, washed with saturated brine, dried the organic phase with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 9e (280mg). MS m/z (ESI): 454.0.
步骤五:4-(4-氟-3-(三氟甲基)苯基)-3-(4-((2-(甲硫基)乙基)氨基)-1,2,5-噁Step 5: 4-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((2-(methylthio)ethyl)amino)-1,2,5-oxa二唑-3-基)-1,2,4-噁二唑-5(4H)-酮9fOxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 9f
在25mL单口瓶中将2-((4-(4-(4-氟-3-(三氟甲基)苯基)-5-羰基-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)乙基甲磺酸酯(280mg，0.60mmol)溶于N，N-二甲基甲酰胺(3mL)，用冰浴冷却至0℃,加入甲硫醇钠(48mg,0.69mmol),在冰浴条件下搅拌20min,LC-MS监测原料转化完全，停止反应，加入水(25mL)淬灭反应,用乙酸乙酯(25mL*2)萃取，合并有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液加硅胶，直接旋干柱层析，石油醚/乙酸乙酯(5/1到3/1)，得9f(60mg,24％)。MS m/z(ESI):406.0。2-((4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-5-carbonyl-4,5-dihydro-1,2,4-oxa Oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl methanesulfonate (280 mg, 0.60 mmol) dissolved in N,N-dimethylformamide (3 mL) , cooled to 0°C with an ice bath, added sodium methyl mercaptide (48mg, 0.69mmol), stirred for 20min under ice bath conditions, LC-MS monitored the complete conversion of raw materials, stopped the reaction, added water (25mL) to quench the reaction, and used Extract with ethyl acetate (25mL*2), wash the combined organic phases with saturated sodium chloride (50mL), dry over anhydrous sodium sulfate, filter, add silica gel to the filtrate, spin dry column chromatography directly, petroleum ether/ethyl acetate (5 /1 to 3/1), yielding 9f (60 mg, 24%). MS m/z (ESI): 406.0.
步骤六：4-(4-氟-3-(三氟甲基)苯基)-3-(4-((2-(甲基亚硫酰基)乙基)氨基)-1,Step 6: 4-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((2-(methylsulfinyl)ethyl)amino)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮9g2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 9g
在25mL单口瓶中将4-(4-氟-3-(三氟甲基)苯基)-3-(4-((2-(甲硫基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(60mg，0.14mmol)溶于二氯甲烷(10mL)，用干冰丙酮浴冷却至-40℃,将间氯过氧化苯甲酸(26mg,0.14mmol)溶于5mL二氯甲烷滴加入上述溶液中，滴加完后撤去干冰丙酮浴，大约20分钟后温度缓慢升至室温，然后室温下继续搅拌40分钟，LC-MS监测原料转化完全，停止反应，加入水(20mL),用乙酸乙酯(20mL*2)萃取，合并有机相用饱和氯化钠(60mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干得9g(30mg，48％)。MS m/z(ESI):422.0。4-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((2-(methylthio)ethyl)amino)-1,2,5 -Oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (60mg, 0.14mmol) was dissolved in dichloromethane (10mL) and cooled to -40°C with a dry ice acetone bath , Dissolve m-chloroperoxybenzoic acid (26mg, 0.14mmol) in 5mL of dichloromethane and add dropwise to the above solution. After the dropwise addition, remove the dry ice acetone bath. After about 20 minutes, the temperature rises slowly to room temperature, and then continues to stir at room temperature After 40 minutes, LC-MS monitored the complete conversion of raw materials, stopped the reaction, added water (20 mL), extracted with ethyl acetate (20 mL*2), combined organic phases were washed with saturated sodium chloride (60 mL), dried over anhydrous sodium sulfate, After filtration, the filtrate was spin-dried to obtain 9 g (30 mg, 48%). MS m/z (ESI): 422.0.
步骤七：4-(4-氟-3-(三氟甲基)苯基)-3-(4-((2-(S-甲基磺亚胺酰基)乙基)氨Step 7: 4-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((2-(S-methylsulfonimidoyl)ethyl)ammonia基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮9hBase) -1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one 9h
在50mL单口瓶中将4-(4-氟-3-(三氟甲基)苯基)-3-(4-((2-(甲基亚硫酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(35mg,0.071mmol)溶于氯仿(6mL)，加入叠氮化钠(18.0mg.0.27mmol),用冰浴冷却至0℃,加入浓硫酸(0.2mL),撤去冰浴，用油浴加热到42℃,搅拌反应过夜。LC-MS监测原料转化完全，停止反应，加入饱和碳酸氢钠溶液(25mL),用乙酸乙酯(25mL*2)萃取，合并有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干,经TLC薄层色谱纯化(DCM:MeOH＝10:1)得9h(25mg，80％)。MS m/z(ESI):436.9。4-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((2-(methylsulfinyl)ethyl)amino)-1,2 ,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (35mg, 0.071mmol) was dissolved in chloroform (6mL), and sodium azide (18.0mg. 0.27mmol), cooled to 0°C with an ice bath, added concentrated sulfuric acid (0.2mL), removed the ice bath, heated to 42°C with an oil bath, and stirred overnight. LC-MS monitored the complete conversion of raw materials, stopped the reaction, added saturated sodium bicarbonate solution (25mL), extracted with ethyl acetate (25mL*2), combined organic phases were washed with saturated sodium chloride (50mL), and dried over anhydrous sodium sulfate , filtered, the filtrate was spin-dried, and purified by TLC (DCM:MeOH=10:1) to obtain 9h (25 mg, 80%). MS m/z (ESI): 436.9.
步骤八：(Z)-N-(4-氟-3-(三氟甲基)苯基)-N'-羟基-4-((2-(S-甲基磺亚胺酰基)Step 8: (Z)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-4-((2-(S-methylsulfonimide)乙基)氨基)-1,2,5-噁二唑-3-碳杂氧杂脒9Ethyl)amino)-1,2,5-oxadiazole-3-carbaoxamidine 9
在50mL单口瓶中将4-(4-氟-3-(三氟甲基)苯基)-3-(4-((2-(S-甲基磺亚胺酰基)乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(25mg，0.057mmol)溶于四氢呋喃/甲醇(4mL/4mL)，将2N氢氧化钠(0.1ml)加入上述溶液中，室温下反应2小时。LC-MS监测原料转化完全，停止反应，加入饱和氯化铵溶液(15mL),用乙酸乙酯(30mL*2)萃取，合并有机相用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干,经TLC薄层色谱纯化(DCM:MeOH＝10:1)得化合物9(16mg，68％)。MS m/z(ESI):411.0。4-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((2-(S-methylsulfonimidoyl)ethyl)amino)- 1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (25mg, 0.057mmol) was dissolved in tetrahydrofuran/methanol (4mL/4mL), and 2N Sodium hydroxide (0.1 ml) was added to the above solution and reacted at room temperature for 2 hours. LC-MS monitored the complete conversion of raw materials, stopped the reaction, added saturated ammonium chloride solution (15mL), extracted with ethyl acetate (30mL*2), combined organic phases were washed with saturated sodium chloride (50mL), and dried over anhydrous sodium sulfate , filtered, the filtrate was spin-dried, and purified by TLC (DCM:MeOH=10:1) to obtain compound 9 (16 mg, 68%). MS m/z (ESI): 411.0.
1H NMR(400MHz,DMSO,ppm):δ7.01-7.08(m,2H),6.97(m,1H),3.73(m,2H),3.42(m,2H),2.90(s,3H)。1 H NMR (400MHz, DMSO, ppm): δ7.01-7.08 (m, 2H), 6.97 (m, 1H), 3.73 (m, 2H), 3.42 (m, 2H), 2.90 (s, 3H).
生物学评价biological evaluation
一、IDO活性抑制的酶学测试1. Enzyme test for IDO activity inhibition
人的吲哚胺2,3-双加氧酶(IDO)购自BPS Bioscience Inc。人吲哚胺(idoleamine)2,3-双加氧酶(IDO)酶学反应在96孔板进行，反应体积为20μL，反应条件为：40nM IDO酶，0.2mM L-色氨酸，50mM KPB(pH6.5)缓冲液，20mM L-抗坏血酸钠，10μM亚甲蓝，0.2mg/mL过氧化氢酶，溶剂为二甲基亚砜的<1％不同浓度的化合物。在30℃反应60分钟后，每孔加入5μL 30％(W/V)三氯乙酸(50mM KPB缓冲液配制)，50℃孵育30分钟使N-甲酰基-犬尿氨酸水解为犬尿氨酸。每孔加入25μL 2％(W/V)p-(二甲基氨基)苯甲醛(p-DMBA)/冰醋酸溶液，用BioTek Synergy H1酶标仪(Molecular Devices)读取490nm吸光值。Human indoleamine 2,3-dioxygenase (IDO) was purchased from BPS Bioscience Inc. The enzymatic reaction of human indoleamine 2,3-dioxygenase (IDO) was carried out in a 96-well plate, the reaction volume was 20 μL, and the reaction conditions were: 40 nM IDO enzyme, 0.2 mM L-tryptophan, 50 mM KPB (pH 6.5) buffer, 20 mM L-sodium ascorbate, 10 μM methylene blue, 0.2 mg/mL catalase, solvent < 1% of different concentrations of compounds in dimethyl sulfoxide. After reacting at 30°C for 60 minutes, add 5 μL of 30% (W/V) trichloroacetic acid (prepared in 50mM KPB buffer) to each well, and incubate at 50°C for 30 minutes to hydrolyze N-formyl-kynurenine into kynurenine acid. 25 μL of 2% (W/V) p-(dimethylamino)benzaldehyde (p-DMBA)/glacial acetic acid solution was added to each well, and the absorbance at 490 nm was read with a BioTek Synergy H1 microplate reader (Molecular Devices).
待测化合物贮备溶液用二甲基亚砜配制为10mM，实验时用用二甲基亚砜稀释至试验最高浓度，然后进行1：3梯度稀释，一般稀释成8到10个浓度点，每个浓度点设复孔，每次实验均包含1个参照化合物。分析酶标仪读取490nm吸光值原始数据，计算受试化合物不同浓度点对IDO酶活性的抑制，采用GraphPad Prism软件对抑制百分比数据进行非线性拟合分析得到化合物的半数抑制浓度IC50值。The stock solution of the compound to be tested was prepared to 10mM with dimethyl sulfoxide, and was diluted with dimethyl sulfoxide to the highest test concentration during the experiment, and then a 1:3 gradient dilution was performed, generally diluted to 8 to 10 concentration points, each Concentration points were set up as duplicate wells, and each experiment contained a reference compound. The original data of absorbance at 490nm was read by the microplate reader, and the inhibition of IDO enzyme activity at different concentration points of the test compound was calculated. The GraphPad Prism software was used to perform nonlinear fitting analysis on the inhibition percentage data to obtain the half maximal inhibitory concentration IC50 value of the compound.
二、IDO活性抑制的细胞模型测试2. Cell model test of IDO activity inhibition
干扰素γ可诱导Hela细胞表达IDO，这一模型被用来测试化合物对吲哚胺2,3-双加氧酶(IDO)的抑制活性。Hela细胞(ATCC)的培养液为含100μM L-色氨酸的不含酚红的RPMI-1640。待测化合物贮备溶液用二甲基亚砜配制为10mM，实验时用二甲基亚砜稀释至试验最高浓度，实验时用培养基进行3倍系列稀释，一般稀释成8到10个浓度点，每个浓度点设复孔。DMSO终浓度为0.5％，每次实验均包含内参化合物。Interferon-γ can induce the expression of IDO in Hela cells, and this model was used to test the inhibitory activity of compounds on indoleamine 2,3-dioxygenase (IDO). The culture medium of Hela cells (ATCC) was RPMI-1640 without phenol red containing 100 μM L-tryptophan. The stock solution of the compound to be tested is prepared as 10 mM with dimethyl sulfoxide, diluted to the highest concentration of the test with dimethyl sulfoxide during the experiment, and carried out 3-fold serial dilution with the medium during the experiment, generally diluted to 8 to 10 concentration points, Multiple wells were set up for each concentration point. The final concentration of DMSO was 0.5%, and each experiment contained internal reference compounds.
试验的程序为：在96孔培养板上每孔加入20，000个Hela细胞(ATCC)过夜培养，24小时后将干扰素γ(终浓度为50ng/mL)和不同浓度的待测化合物和内参化合物加到培养的细胞。24时后，将140μL上清液/孔转移至一个新的96孔板中，每孔加入10μL6.1N的三氯乙酸，50℃孵育30分钟使N-甲酰基-犬尿氨酸水解为犬尿氨酸。反应混合物离心(转速为2500转/分钟离心10分钟)去除沉淀物，将上清液100μL转移至另一个新的96孔板中，每孔加入100μL 2％(W/V)p-(二甲基氨基)苯甲醛(p-DMBA)/冰醋酸溶液，用BioTek Synergy H1酶标仪(Molecular Devices)读取490nm吸光值。The procedure of the test is: 20,000 Hela cells (ATCC) are added to each well of a 96-well culture plate for overnight culture, and after 24 hours, interferon gamma (final concentration is 50ng/mL) and different concentrations of the test compound and internal reference Compounds are added to cultured cells. After 24 hours, transfer 140 μL of supernatant/well to a new 96-well plate, add 10 μL of 6.1N trichloroacetic acid to each well, and incubate at 50°C for 30 minutes to hydrolyze N-formyl-kynurenine into canine uric acid. The reaction mixture was centrifuged (2500 rpm for 10 minutes) to remove the precipitate, and 100 μL of the supernatant was transferred to another new 96-well plate, and 100 μL of 2% (W/V) p-(dimethylformaldehyde) was added to each well Amino) benzaldehyde (p-DMBA)/glacial acetic acid solution, and the absorbance at 490 nm was read with a BioTek Synergy H1 microplate reader (Molecular Devices).
分析酶标仪读取490nm吸光值原始数据，计算受试化合物不同浓度点对IDO酶活性的抑制，采用GraphPad Prism软件对抑制百分比数据进行非线性拟合分析得到化合物的半数抑制浓度IC50值。The original data of absorbance at 490nm was read by the microplate reader, and the inhibition of IDO enzyme activity at different concentration points of the test compound was calculated. The GraphPad Prism software was used to perform nonlinear fitting analysis on the inhibition percentage data to obtain the half maximal inhibitory concentration IC50 value of the compound.
本发明实施例化合物及参照化合物(INCB-24360)的活性通过以上两个试验方法分别进行测定，酶学及细胞学IDO抑制活性IC50值结果见下表：The activities of the compounds of the embodiments of the present invention and the reference compound (INCB-24360) are measured respectively by the above two test methods, and the enzymatic and cytological IDO inhibitory activityIC50 values are shown in the following table:
试验结果证明：本发明实施例化合物同参照化合物(INCB-24360)一样均具有类似的酶学及细胞学IDO抑制活性。The test results prove that: the compound of the embodiment of the present invention has similar enzymatic and cytological IDO inhibitory activities as the reference compound (INCB-24360).
三、大鼠血浆PK分析3. Rat plasma PK analysis
测试化合物的药物代谢动力学试验是用SD大鼠(上海史莱克)进行的。Pharmacokinetic experiments of test compounds were carried out with SD rats (Shanghai Shrek).
■给药方式：单次灌胃给药。■Administration method: single gavage administration.
■给药剂量：20mg/10mL/kg。■Dosage: 20mg/10mL/kg.
■制剂处方：3％二甲基乙酰胺和20％羟丙基-β-环糊精。■ Preparation prescription: 3% dimethylacetamide and 20% hydroxypropyl-β-cyclodextrin.
■取样点：给药前和给药后15分钟、0.5、1、2、4、6、8、24小时。■Sampling points: before administration and 15 minutes, 0.5, 1, 2, 4, 6, 8, 24 hours after administration.
■血浆采样与样品处理：■Plasma sampling and sample processing:
1)颈静脉采血0.2ml，置于EDTA-2K试管中，4℃下以转速6000转/分钟离心5分钟分离血浆，于-80℃保存。1) Collect 0.2ml of blood from the jugular vein, place it in an EDTA-2K test tube, centrifuge at 6000 rpm for 5 minutes at 4°C to separate the plasma, and store it at -80°C.
2)将160μL乙腈加入到40μL血浆样品、标品、和内参，涡旋3分钟，转速4000转/分钟离心10分钟，取100μL上清液，然后再加入100μL无离子水混匀，取10μL进行LC/MS/MS分析，血浆LC/MS/MS分析所用仪器为AB Sciex API 4000。2) Add 160 μL of acetonitrile to 40 μL of plasma samples, standards, and internal reference, vortex for 3 minutes, and centrifuge at 4000 rpm for 10 minutes, take 100 μL of supernatant, then add 100 μL of deionized water to mix, take 10 μL for LC/MS/MS analysis, the instrument used for plasma LC/MS/MS analysis is AB Sciex API 4000.
■液相分析：■Liquid phase analysis:
●液相条件：Shimadzu LC-20AD泵●Liquid phase conditions: Shimadzu LC-20AD pump
●色谱柱：phenomenex Gemiu 5um C18 50X 4.6mm●Column: phenomenonex Gemiu 5um C18 50X 4.6mm
●移动相：A液为0.1％甲酸水溶液，B液为乙腈●Mobile phase: liquid A is 0.1% formic acid aqueous solution, liquid B is acetonitrile
●流速：0.8mL/min●Flow rate: 0.8mL/min
●洗脱时间：0-3.01分钟，洗脱液如下：●Elution time: 0-3.01 minutes, the eluent is as follows:
■质谱分析：质谱仪设置条件：阳离子电喷雾电离(ESI)模式。■Mass spectrometry: mass spectrometer setting conditions: positive ion electrospray ionization (ESI) mode.
■试验结果：药代动力学的主要参数用WinNonlin 6.1计算得到，实验结果见下表：■Test results: The main parameters of pharmacokinetics are calculated by WinNonlin 6.1, and the experimental results are shown in the table below:
试验结果证明：本发明部分实施例化合物明显优于参照化合物(INCB-24360)，具有更好的药代动力学，主要药代动力学参数最大血药浓度(Cmax)、药物暴露量(AUC)相对于参照化合物均有很大幅度的提高，尤其实施例1化合物更是提高了数十倍。Test result proves: the compound of some embodiments of the present invention is obviously better than reference compound (INCB-24360), has better pharmacokinetics, and main pharmacokinetic parameter maximum blood drug concentration (Cmax), drug exposure (AUC) Compared with the reference compounds, all have greatly improved, especially the compound of Example 1 has improved tens of times.
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| PCT/CN2016/111484WO2017101884A1 (en) | 2015-12-15 | 2016-12-22 | Indolamine 2,3-dioxygenase inhibitor and preparation method and use thereof |
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| CN201510936832.9ACN106883193B (en) | 2015-12-15 | 2015-12-15 | Indoleamine 2,3-dioxygenase inhibitor and preparation method and application thereof |
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| CN201510936832.9AActiveCN106883193B (en) | 2015-12-15 | 2015-12-15 | Indoleamine 2,3-dioxygenase inhibitor and preparation method and application thereof |
| CN201680072729.7APendingCN108884063A (en) | 2015-12-15 | 2016-12-22 | Indole amine 2,3-dioxygenase inhibitor and the preparation method and application thereof |
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