WO2023186102A1 - Nav1.8 inhibitor and use thereof - Google Patents

Nav1.8 inhibitor and use thereof Download PDF

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WO2023186102A1
WO2023186102A1 PCT/CN2023/085508 CN2023085508W WO2023186102A1 WO 2023186102 A1 WO2023186102 A1 WO 2023186102A1 CN 2023085508 W CN2023085508 W CN 2023085508W WO 2023186102 A1 WO2023186102 A1 WO 2023186102A1
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substituted
alkyl
halogen
formula
pharmaceutically acceptable
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张学军
李金平
贾一民
陈浩民
李群
安丹
张博
杨俊�
李莉娥
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武汉人福创新药物研发中心有限公司
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
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    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
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    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The present invention provides a Nav1.8 inhibitor. Particularly, the present invention provides a compound represented by formula I, or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, a preparation method therefor, and use thereof in the preparation of a drug.

Description

Nav1.8抑制剂及其用途Nav1.8 inhibitors and their uses
本发明要求享有于2022年4月2日向中国国家知识产权局提交的，专利申请号为2022103513278，名称为“Nav1.8抑制剂及其用途”的在先申请的优先权。该在先申请的全文通过引用的方式结合于本申请中。The present invention claims the priority of the prior application submitted to the State Intellectual Property Office of China on April 2, 2022, with the patent application number 2022103513278 and the name "Nav1.8 inhibitors and their uses". The entirety of this prior application is incorporated by reference into this application.
技术领域Technical field
本发明属于医药领域，涉及Nav1.8抑制剂及其用途。具体地，本发明涉及苯甲酰胺化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药及其药物组合物作为Nav1.8抑制剂及其在制备治疗、缓解或预防疼痛药物中的用途。The invention belongs to the field of medicine and relates to Nav1.8 inhibitors and their uses. Specifically, the present invention relates to benzamide compounds, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs and pharmaceutical compositions thereof as Nav1.8 inhibitors and Its use in the preparation of medicaments for the treatment, relief or prevention of pain.
背景技术Background technique
疼痛是“一种令人不快的感觉和情绪上的感受，伴有实质上的或潜在的组织损伤，它是一种主观感受”。疼痛可以作为一种警戒信号，提醒机体注意潜在的危险，对机体正常的生命活动具有不可或缺的保护作用。同时，疼痛也是一种常见的临床症状，在引发疼痛的外界刺激消失后，强烈或持久的疼痛会造成生理功能的紊乱，严重影响生命体的生活质量。据统计，全世界约五分之一的人患有中度至重度慢性疼痛。2018年全球镇痛药市场约为360亿美元，预计2023年将达到560亿美元。其中急性中重度未来将以2.5％的年复合增长率稳定增长，慢性疼痛未来市场将18％左右的年复合增长率增长，慢性疼痛是驱动未来十年全球疼痛市场持续增长的主要推动力。Pain is “an unpleasant sensory and emotional sensation associated with actual or potential tissue damage that is subjective.” Pain can be used as a warning signal to remind the body to pay attention to potential dangers, and has an indispensable protective effect on the body's normal life activities. At the same time, pain is also a common clinical symptom. After the external stimulus that caused the pain disappears, strong or long-lasting pain will cause physiological function disorders and seriously affect the quality of life of the living body. According to statistics, approximately one in five people worldwide suffer from moderate to severe chronic pain. The global analgesic market was approximately US$36 billion in 2018 and is expected to reach US$56 billion in 2023. Among them, acute moderate to severe pain will grow steadily at a compound annual growth rate of 2.5% in the future, and the chronic pain market will grow at a compound annual growth rate of about 18% in the future. Chronic pain is the main driving force for the continued growth of the global pain market in the next ten years.
疼痛起源于周围神经系统的伤害感受器。这是一种游离的神经末梢，广泛分布于全身的皮肤、肌肉、关节和内脏组织中，它可以将感受到的热的、机械的或化学的刺激转化为神经冲动(动作电位)并经由传入神经纤维传递到其位于背根神经节(dorsal rootganglia，DRG)的胞体部分，最终传递到高级神经中枢，引起痛觉。而神经元中动作电位的产生和传导又依赖于细胞膜上的电压门控钠离子通道(voltage-gated sodium channels，NaV)。当细胞膜去极化时，钠离子通道激活，通道打开，引起钠离子内流，使细胞膜进一步去极化，导致动作电位的产生。因此，抑制异常的钠离子通道活动有助于疼痛的治疗、缓解。Pain originates from nociceptors in the peripheral nervous system. This is a kind of free nerve ending, which is widely distributed in the skin, muscles, joints and visceral tissues of the whole body. It can convert the thermal, mechanical or chemical stimulation it feels into nerve impulses (action potentials) and transmit them through The incoming nerve fibers are transmitted to the cell body part located in the dorsal root ganglion (DRG), and finally transmitted to the higher nerve center, causing pain. The generation and conduction of action potentials in neurons rely on voltage-gated sodium channels (NaV) on the cell membrane. When the cell membrane is depolarized, the sodium ion channel is activated and the channel opens, causing the influx of sodium ions, further depolarizing the cell membrane, resulting in the generation of an action potential. Therefore, inhibiting abnormal sodium ion channel activity contributes to the treatment and relief of pain.
人类钠离子是一类跨膜离子通道蛋白，由分子量260kD的α亚基和分子量为30-40kD的β亚基组成，根据α亚基的不同可以分为9种亚型，分别为Nav1.1～Nav1.9，Nav1.5、Nav1.8和Nav1.9是河豚毒素(tetrodotoxin，TTX)不敏感性钠通道，Nav1.5主要存在于心肌细胞中，Nav1.8、Navl.9存在于外周神经系统。其中Nav1.8是参与慢性疼痛、心房纤维性颤动、布加综合征的重要离子通道，是疼痛治疗的高选择性作用靶点。Human sodium ion is a type of transmembrane ion channel protein, consisting of an α subunit with a molecular weight of 260kD and a β subunit with a molecular weight of 30-40kD. It can be divided into 9 subtypes according to the different α subunits, namely Nav1.1 ~Nav1.9, Nav1.5, Nav1.8 and Nav1.9 are tetrodotoxin (TTX)-insensitive sodium channels. Nav1.5 mainly exists in cardiomyocytes, and Nav1.8 and Navl.9 exist in the periphery. nervous system. Among them, Nav1.8 is an important ion channel involved in chronic pain, atrial fibrillation, and Budd-Chiari syndrome, and is a highly selective target for pain treatment.
Nav1.8编码基因为SCN10A，位于人类染色体3p21-22区域，主要编码α亚单位。研究发现人与大鼠Nav1.8基因的同源性高达93％。Nav1.8主要存在于三叉神经节神经元和DRG神经元 中，具有慢速失活、迅速恢复的电生理特征。在表达Nav1.8的神经元内，动作电位的上升主要由Nav1.8电流构成。在神经性疼痛的模型中，神经损伤会使Nav1.8在轴突和神经元胞体中的表达水平上升。使用Nav1.8反义寡核苷酸在降低Nav1.8表达的同时可以明显地缓解疼痛。大鼠爪内注射角叉菜胶后，DRG神经元中Nav1.8的表达有所上升。Nav1.8敲除小鼠不能表现出正常的内脏炎症痛。人类的Nav1.8基因产生功能增益突变后，会导致外周神经痛。根据一系列动物实验以及人类基因证据，选择性抑制Nav1.8具有成为新型镇痛疗法的潜力，可以用于炎性疼痛、神经疼痛、手术后疼痛和癌痛等多种疼痛类型的治疗。The gene encoding Nav1.8 is SCN10A, which is located in the 3p21-22 region of human chromosomes and mainly encodes the α subunit. Studies have found that the homology between human and rat Nav1.8 genes is as high as 93%. Nav1.8 mainly exists in trigeminal ganglion neurons and DRG neurons , with electrophysiological characteristics of slow deactivation and rapid recovery. In neurons expressing Nav1.8, the rise in action potential is mainly composed of Nav1.8 currents. In models of neuropathic pain, nerve injury increases the expression levels of Nav1.8 in axons and neuronal cell bodies. The use of Nav1.8 antisense oligonucleotides can significantly relieve pain while reducing Nav1.8 expression. After intrapaw injection of carrageenan in rats, the expression of Nav1.8 in DRG neurons increased. Nav1.8 knockout mice do not exhibit normal visceral inflammatory pain. Gain-of-function mutations in the human Nav1.8 gene can cause peripheral neuralgia. According to a series of animal experiments and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a new analgesic therapy and can be used to treat various types of pain, such as inflammatory pain, neuralgia, post-operative pain and cancer pain.
一些已知的Nav’s抑制剂的主要缺点是它们的治疗窗口差，这可能是它们缺乏同种型选择性的结果。由于Navl.8主要限于感知疼痛的神经元，因此选择性Nav1.8阻断剂不太可能诱导非选择性Nav’s阻断剂常见的不良反应。因此，本领域仍然需要开发新的Nav1.8选择性抑制剂，优选对Nav1.8选择性更好、更有效、代谢稳定性增加、溶解度增加和副作用更少的Nav通道抑制剂。A major drawback of some known Nav’s inhibitors is their poor therapeutic window, which may be a result of their lack of isotype selectivity. Because Nav1.8 is primarily restricted to pain-sensing neurons, selective Nav1.8 blockers are less likely to induce the adverse effects common with non-selective Nav’s blockers. Therefore, there is still a need in this field to develop new Nav1.8 selective inhibitors, preferably Nav channel inhibitors that are more selective for Nav1.8, more effective, have increased metabolic stability, increased solubility and fewer side effects.
发明内容Contents of the invention
本发明旨在提出一种Nav1.8抑制剂，可用于制备治疗、缓解或预防疼痛的药物，所述疼痛包括急性疼痛、慢性疼痛、炎性疼痛、癌症疼痛、神经性疼痛、肌肉骨骼痛、原发性疼痛、肠痛和特发性疼痛等。The present invention aims to propose a Nav1.8 inhibitor that can be used to prepare drugs for treating, alleviating or preventing pain, including acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, Primary pain, intestinal pain and idiopathic pain, etc.
本发明的第一方面，本发明提出了一种化合物，为式(I)所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：
In the first aspect of the present invention, the present invention proposes a compound, which is a compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or Prodrugs:
其中，in,
X为N或CH；X is N or CH;
环A选自 Ring A is selected from
R1、R2、R3、R4、R5和R6各自独立地选自H、C1-C6烷基、被一个或多个氘取代的C1-C6烷基、被一个或多个R11取代的C1-C6烷基、-O-(C1-C6烷基)、被一个或多个R12取代的-O-(C1-C6烷基)、被一个或多个氘取代的-O-(C1-C6烷基)、C3-C6环烷基、被一个或多个R13取代的C3-C6环烷基、4-8元杂环烷基、被一个或多个R14取代的4-8元杂环烷基、6-10元芳基、被一个或多个R15取代的6-10元芳基、5-8元杂芳基、被一个或多个R16取代的5-8元杂芳基、-NR1aR1b、 卤素、羟基、氰基、硝基、-SF5，当取代基R11、R12、R13、R14、R15、R16为多个时，所述取代基相同或不同；R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more deuterium, substituted by one or multiple R 11 substituted C 1 -C 6 alkyl, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 alkyl) substituted by one or more R 12 , -O-(C 1 -C 6 alkyl) substituted by one or more deuteriums, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl substituted by one or more R 13 , 4- 8-membered heterocycloalkyl, 4-8-membered heterocycloalkyl substituted with one or more R 14 , 6-10-membered aryl, 6-10-membered aryl substituted with one or more R 15 , 5- 8-membered heteroaryl, 5-8-membered heteroaryl substituted by one or more R 16 , -NR 1a R 1b , Halogen, hydroxyl, cyano, nitro, -SF 5 , when the substituents R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are multiple, the substituents are the same or different;
R1a和R1b各自独立地选自H、C1-C6烷基、被一个或多个R1a1取代的C1-C6烷基，当取代基R1a、R1b、R1a1为多个时，所述取代基相同或不同；R 1a and R 1b are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 1a1 , when the substituents R 1a , R 1b , R 1a1 are multiple In each case, the substituents are the same or different;
R11、R12、R13、R14、R15、R16和R1a1各自独立地选自卤素、氨基、羟基、氰基或硝基。R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 1a1 are each independently selected from halogen, amino, hydroxyl, cyano or nitro.
在本发明一任选实施方案中，如式(I)所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药具有以下任一种或多种特征：In an optional embodiment of the present invention, the compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug has any of the following: One or more characteristics:
(1)R1为C1-C6烷基、被一个或多个氘取代的C1-C6烷基或被一个或多个卤素取代的C1-C6烷基；(1) R 1 is a C 1 -C 6 alkyl group, a C 1 -C 6 alkyl group substituted by one or more deuteriums, or a C 1 -C 6 alkyl group substituted by one or more halogens;
(2)R3为-SF5；(2) R 3 is -SF 5 ;
(3)R4为卤素；(3) R 4 is halogen;
(4)R6为C1-C6烷基；(4) R 6 is C 1 -C 6 alkyl;
(5)X为N，且R1为C1-C6烷基；(5) X is N, and R 1 is C 1 -C 6 alkyl;
(6)环A为 (6) Ring A is
在本发明一任选实施方案中：In an optional embodiment of the invention:
X为CH；X is CH;
环A为 Ring A is
R1独立地选自C1-C6烷基、被一个或多个氘取代的C1-C6烷基、被一个或多个R11取代的C1-C6烷基、-O-(C1-C6烷基)、被一个或多个R12取代的-O-(C1-C6烷基)、被一个或多个氘取代的-O-(C1-C6烷基)、C3-C6环烷基、被一个或多个R13取代的C3-C6环烷基、4-8元杂环烷基、被一个或多个R14取代的4-8元杂环烷基、6-10元芳基、被一个或多个R15取代的6-10元芳基、5-8元杂芳基、被一个或多个R16取代的5-8元杂芳基、-NR1aR1b、氰基、硝基、-SF5，当取代基R11、R12、R13、R14、R15、R16为多个时，所述取代基相同或不同；R 1 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with one or more deuteriums, C 1 -C 6 alkyl substituted with one or more R 11 , -O- (C 1 -C 6 alkyl), -O-(C 1 -C 6 alkyl) substituted by one or more R 12 , -O-(C 1 -C 6 alkyl) substituted by one or more deuterium base), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl substituted by one or more R 13 , 4-8 membered heterocycloalkyl, 4- substituted by one or more R 14 8-membered heterocycloalkyl, 6-10-membered aryl, 6-10-membered aryl substituted with one or more R 15 , 5-8-membered heteroaryl, 5-8 substituted with one or more R 16 Metaheteroaryl, -NR 1a R 1b , cyano, nitro, -SF 5 , when the substituents R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are multiple, the substituents same or different;
R1a和R1b各自独立地选自H、C1-C6烷基、被一个或多个R1a1取代的C1-C6烷基，且R1a和R1b不同时为H；当取代基R1a、R1b、R1a1为多个时，所述取代基相同或不同；R 1a and R 1b are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 1a1 , and R 1a and R 1b are not H at the same time; when substituted When there are multiple groups R 1a , R 1b , and R 1a1 , the substituents are the same or different;
R11、R12、R13、R14、R15、R16和R1a1各自独立地选自卤素、氨基、羟基、氰基或硝基；R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 1a1 are each independently selected from halogen, amino, hydroxyl, cyano or nitro;
R2、R3、R4、R5和R6的定义如前文所述。R 2 , R 3 , R 4 , R 5 and R 6 are as defined above.
在本发明一任选实施方案中，R1为C1-C6烷基、被一个或多个氘取代的C1-C6烷基或被一个或多个卤素取代的C1-C6烷基；较佳地，R1为甲基、二氟甲基或-CD3。In an optional embodiment of the invention, R 1 is C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with one or more deuteriums, or C 1 -C 6 substituted with one or more halogens. Alkyl group; preferably, R 1 is methyl, difluoromethyl or -CD 3 .
在本发明一任选实施方案中，R2选自卤素、被一个或多个卤素取代的C1-C6烷基；较佳地，R2选自Cl或三氟甲基。 In an optional embodiment of the present invention, R 2 is selected from halogen, C 1 -C 6 alkyl substituted by one or more halogens; preferably, R 2 is selected from Cl or trifluoromethyl.
在本发明一任选实施方案中，R3选自H、被一个或多个卤素取代的C1-C6烷基；较佳地，R3选自H或三氟甲基。In an optional embodiment of the present invention, R 3 is selected from H, C 1 -C 6 alkyl substituted by one or more halogens; preferably, R 3 is selected from H or trifluoromethyl.
在本发明一任选实施方案中，R4为H。In an optional embodiment of the invention, R 4 is H.
在本发明一任选实施方案中，R5为卤素；较佳地，R5为F。In an optional embodiment of the present invention, R 5 is halogen; preferably, R 5 is F.
在本发明一任选实施方案中，R6为H。In an optional embodiment of the invention, R 6 is H.
在本发明一任选实施方案中，如式(I)所示的化合物为，
In an optional embodiment of the present invention, the compound represented by formula (I) is,
其中，R1、R2、R4、R5和R6具有前文所述的定义。Among them, R 1 , R 2 , R 4 , R 5 and R 6 have the definitions mentioned above.
在本发明一任选实施方案中，R1为H或卤素，R2为H或卤素，且R1和R2不同时为H或卤素；In an optional embodiment of the present invention, R 1 is H or halogen, R 2 is H or halogen, and R 1 and R 2 are not H or halogen at the same time;
R4为H，R5为卤素，R6为H；R 4 is H, R 5 is halogen, R 6 is H;
较佳地，所述卤素为F或Cl；Preferably, the halogen is F or Cl;
更佳地，R1为H，R2为Cl；或者R1为F，R2为H。More preferably, R 1 is H and R 2 is Cl; or R 1 is F and R 2 is H.
在本发明一任选实施方案中，R1为H或卤素；较佳地，R1为H或F。In an optional embodiment of the present invention, R 1 is H or halogen; preferably, R 1 is H or F.
在本发明一任选实施方案中，R2为H或卤素；较佳地，R2为H或Cl。In an optional embodiment of the present invention, R 2 is H or halogen; preferably, R 2 is H or Cl.
在本发明一任选实施方案中，R4为H。In an optional embodiment of the invention, R 4 is H.
在本发明一任选实施方案中，R5为卤素；较佳地，R5为F。In an optional embodiment of the present invention, R 5 is halogen; preferably, R 5 is F.
在本发明一任选实施方案中，R6为H。In an optional embodiment of the invention, R 6 is H.
在本发明一任选实施方案中：In an optional embodiment of the invention:
X为CH；X is CH;
环A为 Ring A is
R4独立地选自C1-C6烷基、被一个或多个R11取代的C1-C6烷基、被一个或多个氘取代的C1-C6烷基、-O-(C1-C6烷基)、被一个或多个R12取代的-O-(C1-C6烷基)、被一个或多个氘取代的-O-(C1-C6烷基)、C3-C6环烷基、被一个或多个R13取代的C3-C6环烷基、4-8元杂环烷基、被一个或多个R14取代的4-8元杂环烷基、6-10元芳基、被一个或多个R15取代的6-10元芳基、5-8元杂芳基、被一个或多个R16取代的5-8元杂芳基、-NR1aR1b、卤素、羟基、氰基、硝基、 -SF5，当取代基R11、R12、R13、R14、R15、R16为多个时，所述取代基相同或不同；R 4 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with one or more R 11 , C 1 -C 6 alkyl substituted with one or more deuterium, -O- (C 1 -C 6 alkyl), -O-(C 1 -C 6 alkyl) substituted by one or more R 12 , -O-(C 1 -C 6 alkyl) substituted by one or more deuterium base), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl substituted by one or more R 13 , 4-8 membered heterocycloalkyl, 4- substituted by one or more R 14 8-membered heterocycloalkyl, 6-10-membered aryl, 6-10-membered aryl substituted with one or more R 15 , 5-8-membered heteroaryl, 5-8 substituted with one or more R 16 Metaheteroaryl, -NR 1a R 1b , halogen, hydroxyl, cyano, nitro, -SF 5 , when there are multiple substituents R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 , the substituents are the same or different;
R1a和R1b各自独立地选自H、C1-C6烷基、被一个或多个R1a1取代的C1-C6烷基，当取代基R1a、R1b、R1a1为多个时，所述取代基相同或不同；R 1a and R 1b are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 1a1 , when the substituents R 1a , R 1b , R 1a1 are multiple In each case, the substituents are the same or different;
R11、R12、R13、R14、R15、R16和R1a1各自独立地选自卤素、氨基、羟基、氰基或硝基；R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 1a1 are each independently selected from halogen, amino, hydroxyl, cyano or nitro;
R1、R2、R3、R5和R6的定义如前文所述。R 1 , R 2 , R 3 , R 5 and R 6 are as defined above.
在本发明一任选实施方案中，R1为H、卤素或被一个或多个氘取代的C1-C6烷基；较佳地，R1为H、F或-CD3。In an optional embodiment of the present invention, R 1 is H, halogen or C 1 -C 6 alkyl substituted by one or more deuterium; preferably, R 1 is H, F or -CD 3 .
在本发明一任选实施方案中，R2为H、卤素或C1-C6烷基；较佳地，R2为H、Cl或甲基。In an optional embodiment of the present invention, R 2 is H, halogen or C 1 -C 6 alkyl; preferably, R 2 is H, Cl or methyl.
在本发明一任选实施方案中，R3为被一个或多个卤素取代的C1-C6烷基；较佳地，R3为三氟甲基。In an optional embodiment of the present invention, R 3 is C 1 -C 6 alkyl substituted by one or more halogens; preferably, R 3 is trifluoromethyl.
在本发明一任选实施方案中，R4为卤素；较佳地，R4为F。In an optional embodiment of the present invention, R 4 is halogen; preferably, R 4 is F.
在本发明一任选实施方案中，R5为卤素；较佳地，R5为F或Cl。In an optional embodiment of the present invention, R 5 is halogen; preferably, R 5 is F or Cl.
在本发明一任选实施方案中，R6为H。In an optional embodiment of the invention, R 6 is H.
在本发明一任选实施方案中：In an optional embodiment of the invention:
X为亚甲基；X is methylene;
环A为 Ring A is
R6独立地选自C1-C6烷基、被一个或多个R11取代的C1-C6烷基、-O-(C1-C6烷基)、被一个或多个R12取代的-O-(C1-C6烷基)、C3-C6环烷基、被一个或多个R13取代的C3-C6环烷基、4-8元杂环烷基、被一个或多个R14取代的4-8元杂环烷基、6-10元芳基、被一个或多个R15取代的6-10元芳基、5-8元杂芳基、被一个或多个R16取代的5-8元杂芳基、-NR1aR1b、卤素、羟基、氰基、硝基、-SF5，当取代基R11、R12、R13、R14、R15、R16为多个时，所述取代基相同或不同；R 6 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with one or more R 11 , -O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl substituted with one or more R 11 12- substituted -O-(C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl substituted by one or more R 13 , 4-8 membered heterocycloalkyl group, 4-8 membered heterocycloalkyl substituted by one or more R 14 , 6-10 membered aryl, 6-10 membered aryl substituted with one or more R 15 , 5-8 membered heteroaryl , 5-8 membered heteroaryl substituted by one or more R 16 , -NR 1a R 1b , halogen, hydroxyl, cyano, nitro, -SF 5 , when the substituent R 11 , R 12 , R 13 , When there are multiple R 14 , R 15 and R 16 , the substituents are the same or different;
R1a和R1b各自独立地选自H、C1-C6烷基、被一个或多个R1a1取代的C1-C6烷基，当取代基R1a、R1b、R1a1为多个时，所述取代基相同或不同；R 1a and R 1b are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 1a1 , when the substituents R 1a , R 1b , R 1a1 are multiple In each case, the substituents are the same or different;
R11、R12、R13、R14、R15、R16和R1a1各自独立地选自卤素、氨基、羟基、氰基或硝基；R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 1a1 are each independently selected from halogen, amino, hydroxyl, cyano or nitro;
R1、R2、R3、R4、R5和R6的定义如前文所述。R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined above.
在本发明一任选实施方案中，R1为卤素；较佳地，R1为F。In an optional embodiment of the present invention, R 1 is halogen; preferably, R 1 is F.
在本发明一任选实施方案中，R2为卤素；较佳地，R2为Cl。In an optional embodiment of the present invention, R 2 is halogen; preferably, R 2 is Cl.
在本发明一任选实施方案中，R3为被一个或多个卤素取代的C1-C6烷基；较佳地，R3为三氟甲基。In an optional embodiment of the present invention, R 3 is C 1 -C 6 alkyl substituted by one or more halogens; preferably, R 3 is trifluoromethyl.
在本发明一任选实施方案中，R4为H。In an optional embodiment of the invention, R 4 is H.
在本发明一任选实施方案中，R5为H或卤素；较佳地，R5为F。In an optional embodiment of the present invention, R 5 is H or halogen; preferably, R 5 is F.
在本发明一任选实施方案中，R6为C1-C6烷基；较佳地，R6为甲基。 In an optional embodiment of the present invention, R 6 is C 1 -C 6 alkyl; preferably, R 6 is methyl.
在本发明一任选实施方案中，式(I)所示的化合物为，
In an optional embodiment of the present invention, the compound represented by formula (I) is,
其中，R1、R2、R3、R4、R5和R6具有前文所述的定义，且R1不为H。Among them, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 have the definitions mentioned above, and R 1 is not H.
在本发明一任选实施方案中，R1为卤素或C1-C6烷基；较佳地，R1为F或甲基。In an optional embodiment of the present invention, R 1 is halogen or C 1 -C 6 alkyl; preferably, R 1 is F or methyl.
在本发明一任选实施方案中，R2为卤素；较佳地，R2为Cl。In an optional embodiment of the present invention, R 2 is halogen; preferably, R 2 is Cl.
在本发明一任选实施方案中，R3为被一个或多个卤素取代的C1-C6烷基；较佳地，R3为三氟甲基。In an optional embodiment of the present invention, R 3 is C 1 -C 6 alkyl substituted by one or more halogens; preferably, R 3 is trifluoromethyl.
在本发明一任选实施方案中，R4为H。In an optional embodiment of the invention, R 4 is H.
在本发明一任选实施方案中，R5为F。In an optional embodiment of the invention, R5 is F.
在本发明一任选实施方案中，R6为H。In an optional embodiment of the invention, R 6 is H.
在本发明一任选实施方案中，式(I)所示的化合物为，
In an optional embodiment of the present invention, the compound represented by formula (I) is,
其中，R1、R2、R3、R4、R5和R6具有前文所述的定义。Among them, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 have the definitions mentioned above.
在本发明一任选实施方案中，为 In an optional embodiment of the invention, for
在本发明一任选实施方案中，R1为卤素；较佳地，R1为F。In an optional embodiment of the present invention, R 1 is halogen; preferably, R 1 is F.
在本发明一任选实施方案中，R2为卤素；较佳地，R2为Cl。In an optional embodiment of the present invention, R 2 is halogen; preferably, R 2 is Cl.
在本发明一任选实施方案中，R3为被一个或多个卤素取代的C1-C6烷基；较佳地，R3为三氟甲基。In an optional embodiment of the present invention, R 3 is C 1 -C 6 alkyl substituted by one or more halogens; preferably, R 3 is trifluoromethyl.
在本发明一任选实施方案中，R4为被一个或多个氘取代的-O-(C1-C6烷基)；较佳地，R4为-O-CD3。 In an optional embodiment of the present invention, R 4 is -O-(C 1 -C 6 alkyl) substituted by one or more deuteriums; preferably, R 4 is -O-CD 3 .
在本发明一任选实施方案中，R5为F。In an optional embodiment of the invention, R5 is F.
在本发明一任选实施方案中，R6为H。In an optional embodiment of the invention, R 6 is H.
在本发明一任选实施方案中，式(I)所示的化合物选自下列化合物：

In an optional embodiment of the present invention, the compound represented by formula (I) is selected from the following compounds:

本发明的第二方面，本发明提出了一种药物组合物，所述药物组合物包括治疗有效量的上述化合物，其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药以及药学上可接受的药用载体、稀释剂或赋形剂。In a second aspect of the present invention, the present invention proposes a pharmaceutical composition, which includes a therapeutically effective amount of the above compound, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable Acceptable salts or prodrugs and pharmaceutically acceptable pharmaceutical carriers, diluents or excipients.
根据本发明的具体实施例，可以将本发明的所述药物组合物包括治疗有效量的上述化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药以及药学上可接受的药用载体、稀释剂或赋形剂混合制备成药物制剂，以适合于经口或胃肠外给药。给药方法包括，但不限于皮内、肌内、腹膜内、静脉内、皮下、鼻内和经口途径。所述制剂可以通过任何途径施用，例如通过输注或推注，通过经上皮或皮肤粘膜(例如口腔粘膜或直肠等)吸收的途径施用。给药可以是全身的或局部的。经口施用制剂的实例包括固体或液体剂型，具体而言，包括片剂、丸剂、粒剂、粉剂、胶囊剂、糖浆、乳剂、混悬剂等。所述制剂可通过本领域已知的方法制备，且包含药物制剂领域常规使用的载体、稀释剂或赋形剂。According to specific embodiments of the present invention, the pharmaceutical composition of the present invention may include a therapeutically effective amount of the above-mentioned compounds, their tautomers, stereoisomers, hydrates, solvates, and pharmaceutically acceptable salts Or the prodrug and a pharmaceutically acceptable pharmaceutical carrier, diluent or excipient are mixed to prepare a pharmaceutical preparation suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The preparation may be administered by any route, such as by infusion or bolus injection, by absorption via epithelium or skin mucosa (eg, oral mucosa or rectum, etc.). Administration can be systemic or local. Examples of preparations for oral administration include solid or liquid dosage forms, specifically tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions, and the like. The preparation can be prepared by methods known in the art, and contains carriers, diluents or excipients conventionally used in the field of pharmaceutical preparations.
本发明的第三方面，本发明提出了上述化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或上述药物组合物在制备用于抑制电压门控钠离子通道相关药物中的用途，所述电压门控钠离子通道包括Nav1.1～Nav1.9，Nav1.5、Nav1.8和Nav1.9，优选为Nav1.8。In the third aspect of the present invention, the present invention provides the above-mentioned compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition in the preparation of Use in drugs related to inhibiting voltage-gated sodium ion channels. The voltage-gated sodium ion channels include Nav1.1 to Nav1.9, Nav1.5, Nav1.8 and Nav1.9, preferably Nav1.8.
根据本发明的具体实施例，上述化合物或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或上述药物组合物在制备药物中的用途，所述药物可用于治疗、缓解或预防疼痛，所述疼痛包括急性疼痛、慢性疼痛、炎性疼痛、癌症疼痛、神经性疼痛、肌肉骨骼痛、原发性疼痛、肠痛和特发性疼痛。According to specific embodiments of the present invention, the use of the above-mentioned compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs or the above-mentioned pharmaceutical compositions in the preparation of medicines, The medicaments may be used to treat, relieve or prevent pain, including acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.
本发明第四方面，提供一种抑制电压门控钠离子通道，或预防和/或治疗电压门控钠离子通道相关的疾病的方法，包括步骤：给需要的对象施用本发明第一方面所述的式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或本发明的第二方面所述的药物组合物。A fourth aspect of the present invention provides a method for inhibiting voltage-gated sodium ion channels, or preventing and/or treating diseases related to voltage-gated sodium ion channels, including the steps of: administering the first aspect of the present invention to a subject in need The compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the pharmaceutical composition according to the second aspect of the present invention.
所述电压门控钠离子通道包括Nav1.1～Nav1.9，Nav1.5、Nav1.8和Nav1.9，优选为Nav1.8。所述电压门控钠离子通道相关的疾病为疼痛，包括急性疼痛、慢性疼痛、炎性疼痛、癌症疼痛、神经性疼痛、肌肉骨骼痛、原发性疼痛、肠痛和特发性疼痛。The voltage-gated sodium ion channel includes Nav1.1 to Nav1.9, Nav1.5, Nav1.8 and Nav1.9, preferably Nav1.8. The diseases related to voltage-gated sodium ion channels are pain, including acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.
有益效果beneficial effects
根据本发明的实施例，本发明至少具有如下技术效果至少之一： According to the embodiments of the present invention, the present invention has at least one of the following technical effects:
1)提供了结构新颖、药代动力学性质优良、药效或成药性好的Nav1.8抑制剂，可以用于有效治疗Nav1.8相关的疾病、病症；1) Provides a Nav1.8 inhibitor with a novel structure, excellent pharmacokinetic properties, good efficacy or druggability, which can be used to effectively treat Nav1.8 related diseases and conditions;
2)本发明化合物具有较强的对Nav1.8离子通道抑制活性；2) The compound of the present invention has strong inhibitory activity on Nav1.8 ion channel;
3)本发明化合物在小鼠体内表现出优良的药代动力学性质。3) The compound of the present invention exhibits excellent pharmacokinetic properties in mice.
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
术语定义与说明Definitions and explanations of terms
除非另有说明，用于本发明申请，包括本申请说明书和权利要求书中记载的术语和定义如下。Unless otherwise stated, the terms and definitions used in this application, including the description and claims of this application, are as follows.
本领域技术人员可以理解，根据本领域中使用的惯例，在本申请的结构式中，用于描绘化学键，所述化学键为部分或取代基与核心结构或骨架结构相连的点。Those skilled in the art can understand that according to the conventions used in the art, in the structural formula of the present application, Used to depict chemical bonds, which are the points where a moiety or substituent is connected to the core or backbone structure.
术语“药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐，包括无机酸和碱、有机酸和碱的盐。The term "pharmaceutically acceptable salts" refers to pharmaceutically acceptable salts of nontoxic acids or bases, including salts of inorganic acids and bases, and organic acids and bases.
术语“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐或前体药物与其它化学组分的混合物，其它组分例如生理学/药学上可接受的载体和赋形剂。药物组合物的目的是促进化合物对生物体的给药。The term "pharmaceutical composition" means a mixture of one or more compounds described herein, or physiologically/pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of pharmaceutical compositions is to facilitate the administration of compounds to an organism.
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。The term "excipient" means a pharmaceutically acceptable inert ingredient. Examples of types of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling properties of pharmaceutical formulations, i.e. make the formulation more suitable for direct compression by increasing flowability and/or viscosity.
术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备，该修饰可以按常规的操作或者在体内被除去，而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物，当本发明化合物的前药被施予哺乳动物个体时，前药被割裂而分别形成游离的羟基、游离的氨基。The term "prodrug" refers to a compound of the invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. The prodrugs of the present invention are prepared by modifying the functional groups in the compound, and the modifications can be removed by conventional procedures or in vivo to obtain the parent compound. Prodrugs include compounds in which a hydroxyl group or amino group in the compound of the present invention is connected to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free hydroxyl groups and free hydroxyl groups, respectively. of amino.
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对应异构体和构象异构体。The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereoisomers and conformational isomers.
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible species. Proton transfer tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually yield a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is dominant; in phenols, the enol form is dominant. The present invention encompasses all tautomeric forms of the compounds.
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。 Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the invention.
本文中消旋体或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。The schematic representation of racemic or enantiopure compounds in this article is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise stated, wedge-shaped bonds and dashed-line bonds represent the absolute configuration of a stereocenter. When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of this invention.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、D-异构体、L-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, D-isomers, L-isomers, and racemic mixtures thereof and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which are within the scope of the present invention. within. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D-和L-异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的分步结晶法或色谱法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。Optically active (R)- and (S)-isomers as well as D- and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with a suitable optically active acid or base, and then the diastereomeric salts are formed by step-by-step procedures well known in the art. Diastereomers are resolved by crystallization or chromatography, and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally combined with chemical derivatization methods (e.g., generation of amino groups from amines). formate).
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a non-toxic amount of the drug or agent sufficient to achieve the desired effect. For the oral dosage form of the present invention, the "effective amount" of an active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease or condition.
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代。氧代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable . When the substituent is oxo (i.e. =O), it means that two hydrogen atoms are replaced. Oxygen does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical achievability.
前缀“Cu-Cv”表示接下来的基团具有从u至v个碳原子。例如，“C1-C6烷基”表示该烷基具有1至6个碳原子。The prefix "C u- C v " indicates that the following group has from u to v carbon atoms. For example, "C 1 -C 6 alkyl" means that the alkyl group has 1 to 6 carbon atoms.
术语“C1-C6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔 丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地，所述基团具有1、2或3个碳原子(“C1-C3烷基”)，例如甲基、乙基、正丙基或异丙基。The term "C 1 -C 6 alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert. Butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl base, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethyl Butyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethyl Butyl, etc. or their isomers. In particular, said groups have 1, 2 or 3 carbon atoms ("C 1 -C 3 alkyl"), for example methyl, ethyl, n-propyl or isopropyl.
术语“-O-(C1-C6烷基)”应理解为烷基基团通过氧原子与分子其余部分相连，其中“C1-C6烷基”具有上述定义。如-O-(甲基)、-O-(乙基)。The term "-O-(C 1 -C 6 alkyl)" is understood to mean that the alkyl group is attached to the remainder of the molecule through an oxygen atom, where "C 1 -C 6 alkyl" has the above definition. Such as -O-(methyl), -O-(ethyl).
术语“C3-C6环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3～6个碳原子，包括稠合或桥接的多环系统。如环丙基、环丁基、环戊基、环己基。The term "C 3 -C 6 cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
术语“4-8元杂环烷基”是指总共具有4、5、6、7或8个环原子且包含一个或两个相同或不同的环杂原子或含杂原子的基团的单环饱和杂环，所述环杂原子或含杂原子的基团选自：N、NH、O、S、SO和SO2，所述杂环烷基可通过任何一个碳原子或(如果存在)氮原子与分子的其余部分连接。所述杂环烷基可为4元环，例如氮杂环丁烷基、氧杂环丁烷基或硫杂环丁烷基；或者为5元环，例如四氢呋喃基、1,3-二氧戊环基、硫杂环戊基、吡咯烷基、咪唑烷基、吡唑烷基、1,1-二氧代硫杂环戊基、1,2-噁唑烷基、1,3-噁唑烷基或1,3-噻唑烷基；或者为6元环，例如四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基、1,3-二氧杂环己基、1,4-二氧杂环己基或1,2-氧氮杂环己基。The term "4-8 membered heterocycloalkyl" refers to a monocyclic ring having a total of 4, 5, 6, 7 or 8 ring atoms and containing one or two same or different ring heteroatoms or heteroatom-containing groups. Saturated heterocycle, the ring heteroatom or heteroatom-containing group is selected from: N, NH, O, S, SO and SO 2 , the heterocycloalkyl group can be passed through any carbon atom or (if present) nitrogen Atoms are connected to the rest of the molecule. The heterocycloalkyl group can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxanyl Pentyl, thiol, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxothiol, 1,2-oxazolidinyl, 1,3-oxazolidinyl oxazolidinyl or 1,3-thiazolidinyl; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, Piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl or 1,2-oxazanyl.
术语“6-10元芳基”应理解为具有6-10个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，特别是具有6个碳原子的环(“C6芳基”)，例如苯基；当所述6-10元芳基被取代时，其可以为单取代或者多取代。并且，对其取代位点没有限制，例如可以为邻位、对位或间位取代。The term "6-10 membered aryl" is understood to mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 10 carbon atoms, in particular a ring having 6 carbon atoms (" C 6 aryl"), such as phenyl; when the 6-10 membered aryl group is substituted, it can be mono-substituted or poly-substituted. Moreover, there is no restriction on the substitution position, for example, it may be ortho, para or meta substitution.
术语“5-8元杂芳基”应理解为具有5-8个环原子，特别是5或6个碳原子，且包含1-5个独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团。优选1-3个且独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团，并且，另外在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。The term "5-8 membered heteroaryl" is understood to mean a monovalent heteroaryl group having 5 to 8 ring atoms, in particular 5 or 6 carbon atoms, and containing 1 to 5 heteroatoms independently selected from N, O and S. Monocyclic, bicyclic or tricyclic aromatic ring groups. Preference is given to monovalent monocyclic, bicyclic or tricyclic aromatic ring radicals of 1 to 3 heteroatoms independently selected from N, O and S and, in addition, may in each case be benzo-fused. In particular, the heteroaryl group is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl Diazolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl base, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.
术语“卤代基”或“卤素”为氟、氯、溴和碘。The term "halo" or "halogen" is fluorine, chlorine, bromine and iodine.
术语“任选”或“任选地”意思是随后所述的事件或情形可发生或可不发生，且所述描述包括其中所述事件或情形发生的情况以及其中所述事件或情形不发生的情况。The term "optionally" or "optionally" means that the subsequently stated event or circumstance may or may not occur, and that the description includes instances where the stated event or circumstance occurs as well as instances where the stated event or circumstance does not occur Condition.
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“……独立地”应作广义理解，是指所描述的各个个体之间是相互独立的，可以独立地为相同或不同的具体基团。更详细地，描述方式“……独立地”既可以是指在不同基团中，相同符合之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。 In addition, it should be noted that, unless otherwise clearly stated, the description method "...independently" used in the present invention should be understood in a broad sense, meaning that each described individual is independent of each other and can be independent. Ground is the same or different specific groups. In more detail, the description "...independently" can mean that in different groups, the specific options expressed with the same symbols do not affect each other, or it can also mean that in the same group, the same symbols between The specific options expressed between them do not affect each other.
具体实施方式Detailed ways
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。The solutions of the present invention will be explained below with reference to examples. Those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. If specific techniques or conditions are not specified in the examples, the techniques or conditions described in literature in the field or product instructions will be followed. If the manufacturer of the reagents or instruments used is not indicated, they are all conventional products that can be purchased commercially.
如无特别说明，本发明的化合物均是通过核磁共振(NMR)和/或质谱(MS)来确定其结构的。NMR位移的单位为10-6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)。Unless otherwise stated, the structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The units of NMR shifts are 10 -6 (ppm). The solvents used for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
本发明的缩写定义如下：The abbreviations of the present invention are defined as follows:
M：摩尔浓度，如1M盐酸表示1mol/L盐酸溶液M: molar concentration, such as 1M hydrochloric acid represents 1mol/L hydrochloric acid solution
LC-MS：液质联用色谱LC-MS: liquid mass spectrometry
DMSO：二甲基亚砜DMSO: dimethyl sulfoxide
ACN：乙腈ACN: Acetonitrile
HATU：N,N,N’,N’-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲HATU: N,N,N’,N’-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate
DMF：N,N-二甲基甲酰胺DMF: N,N-dimethylformamide
DMAP：4-二甲氨基吡啶DMAP: 4-dimethylaminopyridine
LDA：二异丙基氨基锂LDA: lithium diisopropylamide
DCM：二氯甲烷DCM: dichloromethane
TFA：三氟乙酸TFA: trifluoroacetic acid
THF：四氢呋喃THF: Tetrahydrofuran
DIEA：也可写为DIEA，二异丙基乙胺，亦即N,N-二异丙基乙胺DIEA: can also be written as DIEA, diisopropylethylamine, also known as N,N-diisopropylethylamine
mCPBA：间氯过氧苯甲酸mCPBA: m-chloroperoxybenzoic acid
IC50：半数抑制浓度，指达到最大抑制效果一半时的浓度。IC 50 : Half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
制备1：中间体INT-1&INT-1-1的制备Preparation 1: Preparation of intermediate INT-1&INT-1-1
6-溴-3-氯-2-氟-N-(吡啶-3-基)-4-(三氟甲基)苯甲酰胺(INT-1)和2-溴-6-氟-N-(吡啶-3-基)-4-(三氟甲基)苯甲酰胺(INT-1-1)
6-Bromo-3-chloro-2-fluoro-N-(pyridin-3-yl)-4-(trifluoromethyl)benzamide (INT-1) and 2-bromo-6-fluoro-N-( Pyridin-3-yl)-4-(trifluoromethyl)benzamide (INT-1-1)
中间体INT-1&INT-1-1的合成路线如下所示：
The synthetic route of intermediate INT-1&INT-1-1 is as follows:
第一步：6-溴-3-氯-2-氟-4-(三氟甲基)苯甲酸甲酯和2-溴-6-氟-4-(三氟甲基)苯甲酸甲酯的合成
Step 1: 6-Bromo-3-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid methyl ester and 2-bromo-6-fluoro-4-(trifluoromethyl)benzoic acid methyl ester synthesis
将3-氨基-6-溴-2-氟-4-(三氟甲基)苯甲酸甲酯(5.0g，15.82mmol)加入到ACN(50mL)中，再将亚硝酸异戊酯(2.41g，20.57mmol)，CuCl2(2.77g，20.57mmol)加入到反应液中，室温搅拌2小时。将反应液浓缩，加入水(20mL)，用EtOAc(50mL×3)萃取，有机相用无水Na2SO4干燥，过滤，减压浓缩旋干，得到的粗品通过正相硅胶柱层析分离(EtOAc/PE＝10％-30％)得到3.20g中间体3和3-1的混合物，60.3％收率。3-Amino-6-bromo-2-fluoro-4-(trifluoromethyl)benzoic acid methyl ester (5.0g, 15.82mmol) was added to ACN (50mL), and then isoamyl nitrite (2.41g , 20.57mmol), CuCl 2 (2.77g, 20.57mmol) was added to the reaction solution, and stirred at room temperature for 2 hours. The reaction solution was concentrated, water (20 mL) was added, and extracted with EtOAc (50 mL × 3). The organic phase was dried over anhydrous Na 2 SO 4 , filtered, concentrated under reduced pressure and spun to dryness. The obtained crude product was separated by normal phase silica gel column chromatography. (EtOAc/PE=10%-30%) 3.20 g of a mixture of intermediates 3 and 3-1 were obtained, with a yield of 60.3%.
第二步：6-溴-3-氯-2-氟-4-(三氟甲基)苯甲酸和2-溴-6-氟-4-(三氟甲基)苯甲酸的合成
Step 2: Synthesis of 6-bromo-3-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid and 2-bromo-6-fluoro-4-(trifluoromethyl)benzoic acid
将6-溴-3-氯-2-氟-4-(三氟甲基)苯甲酸甲酯和2-溴-6-氟-4-(三氟甲基)苯甲酸甲酯的混合物(3.20g，9.54mmol)，NaOH(1.91g，47.7mmol)加入到H2O(8mL)、MeOH(16mL)和THF(8mL)的混合液中，室温中搅拌6小时。将反应液浓缩，加入水(20mL)，用EtOAc(30mL×3)萃取，然后向液相中加入2M盐酸，调pH为3，再用EtOAc(30mL×3)萃取，合并有机相，并用无水Na2SO4干燥，过滤，减压浓缩后得到2.70克中间体4和4-1的混合物，88％收率。The mixture of 6-bromo-3-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid methyl ester and 2-bromo-6-fluoro-4-(trifluoromethyl)benzoic acid methyl ester (3.20 g, 9.54 mmol), NaOH (1.91 g, 47.7 mmol) was added to the mixture of H 2 O (8 mL), MeOH (16 mL) and THF (8 mL), and stirred at room temperature for 6 hours. The reaction solution was concentrated, water (20 mL) was added, extracted with EtOAc (30 mL After drying over Na2SO4 , filtering and concentrating under reduced pressure, 2.70 g of a mixture of intermediates 4 and 4-1 were obtained, with a yield of 88%.
第三步：6-溴-3-氯-2-氟-N-(吡啶-3-基)-4-(三氟甲基)苯甲酰胺(INT-1)和2-溴-6-氟-N-(吡啶-3-基)-4-(三氟甲基)苯甲酰胺(INT-1-1)的合成
Step 3: 6-bromo-3-chloro-2-fluoro-N-(pyridin-3-yl)-4-(trifluoromethyl)benzamide (INT-1) and 2-bromo-6-fluoro Synthesis of -N-(pyridin-3-yl)-4-(trifluoromethyl)benzamide (INT-1-1)
将6-溴-3-氯-2-氟-4-(三氟甲基)苯甲酸和6-溴-2-氟-4-(三氟甲基)苯甲酸的混合物(2.70g，8.40mmol)，3-氨基吡啶(1.19g，12.60mmol)，HATU(6.39g，16.80mmol)和DIEA(3.26mg， 25.2mmol)加入到DMF(25mL)中，反应液在室温下反应16小时。LC-MS显示反应完成。向反应液中加入NH4Cl溶液(30mL)，用EtOAc(50mL×3)萃取，有机相用水洗3次，并用无水Na2SO4干燥，过滤，减压浓缩旋干，粗品通过正相硅胶柱柱层析分离(EtOAc/PE＝50％)并制备分离得到中间体INT-1 1.5g和INT-1-1 1.4g的混合物，收率90％。A mixture of 6-bromo-3-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid and 6-bromo-2-fluoro-4-(trifluoromethyl)benzoic acid (2.70g, 8.40mmol ), 3-aminopyridine (1.19g, 12.60mmol), HATU (6.39g, 16.80mmol) and DIEA (3.26mg, 25.2 mmol) was added to DMF (25 mL), and the reaction solution was reacted at room temperature for 16 hours. LC-MS showed the reaction was complete. Add NH 4 Cl solution (30 mL) to the reaction solution, extract with EtOAc (50 mL × 3), wash the organic phase with water 3 times, dry with anhydrous Na 2 SO 4 , filter, concentrate under reduced pressure and spin to dryness, the crude product is passed through the normal phase Silica gel column chromatography (EtOAc/PE=50%) was used to separate and prepare a mixture of 1.5g of intermediate INT-1 and 1.4g of INT-1-1, with a yield of 90%.
LC-MS,m/z：365.09和399.10[M+H]+。LC-MS, m/z: 365.09 and 399.10 [M+H] + .
实施例1：目标化合物I-1的制备Example 1: Preparation of target compound I-1
3-(3-氯-6-((7-氟-2,3-二氢-1H-茚-4-基)氧基)-2-甲基-4-(三氟甲基)苯甲酰胺基)吡啶1-氧化物
3-(3-Chloro-6-((7-fluoro-2,3-dihydro-1H-inden-4-yl)oxy)-2-methyl-4-(trifluoromethyl)benzamide pyridine 1-oxide
目标化合物I-1合成路线如下所示：
The synthetic route of target compound I-1 is as follows:
第一步：(2-溴-4-氟-6-(三氟甲基)苯基)(叔丁氧羰基)氨基甲酸叔丁酯(2)的合成
Step 1: Synthesis of (2-bromo-4-fluoro-6-(trifluoromethyl)phenyl)(tert-butoxycarbonyl)carbamic acid tert-butyl ester (2)
将中间体1(10g，39mmol)，(Boc)2O(25.5g，117mmol)和DMAP(4.8g,39mmol)加入到ACN(200mL)中，室温中搅拌16小时。向反应液中加入饱和NH4Cl溶液，用EtOAc(100mL×3)萃取，有机相用Na2SO4干燥，旋干经硅胶柱纯化得到15g中间体(2-溴-4-氟-6-(三氟甲基)苯基)(叔丁氧羰基)氨基甲酸叔丁酯(2)，84％收率。Intermediate 1 (10 g, 39 mmol), (Boc) 2 O (25.5 g, 117 mmol) and DMAP (4.8 g, 39 mmol) were added to ACN (200 mL), and stirred at room temperature for 16 hours. Saturated NH 4 Cl solution was added to the reaction solution, extracted with EtOAc (100 mL × 3), the organic phase was dried with Na 2 SO 4 , spin-dried and purified on a silica gel column to obtain 15 g of the intermediate (2-bromo-4-fluoro-6- (Trifluoromethyl)phenyl)(tert-butoxycarbonyl)carbamic acid tert-butyl ester (2), 84% yield.
第二步：3-(双(叔丁氧基羰基)氨基)-2-溴-6-氟-4-(三氟甲基)苯甲酸甲酯(3)的合成
Step 2: Synthesis of 3-(bis(tert-butoxycarbonyl)amino)-2-bromo-6-fluoro-4-(trifluoromethyl)benzoic acid methyl ester (3)
将中间体2(10.0g，22mmol)加入到THF(100mL)中，反应液降至-78℃，再将LDA(2M，13mL，26mmol)加入到反应液中，搅拌0.5小时。将氯氧化甲酯(2.5g，26mmol)于-78℃下加入到反应液中，继续在室温下搅拌6小时。向反应液中加入饱和NH4Cl溶液，用EtOAc(100mL×3)萃取，有机相用Na2SO4干燥，旋干经硅胶柱纯化得到8.0g中间体3-(双(叔丁氧基羰基)氨基)-2-溴-6-氟-4-(三氟甲基)苯甲酸甲酯(3)，70％收率。Intermediate 2 (10.0g, 22mmol) was added to THF (100mL), the reaction solution was lowered to -78°C, and LDA (2M, 13mL, 26mmol) was added to the reaction solution and stirred for 0.5 hours. Methyl oxychloride (2.5g, 26mmol) was added to the reaction solution at -78°C, and stirring was continued at room temperature for 6 hours. Saturated NH 4 Cl solution was added to the reaction solution, extracted with EtOAc (100 mL × 3), the organic phase was dried with Na 2 SO 4 , spin-dried and purified through a silica gel column to obtain 8.0 g of the intermediate 3-(bis(tert-butoxycarbonyl) )Amino)-2-bromo-6-fluoro-4-(trifluoromethyl)benzoic acid methyl ester (3), 70% yield.
第三步：3-(双(叔丁氧基羰基)氨基)-6-氟-2-甲基-4-(三氟甲基)苯甲酸甲酯(4)的合成
Step 3: Synthesis of 3-(bis(tert-butoxycarbonyl)amino)-6-fluoro-2-methyl-4-(trifluoromethyl)benzoic acid methyl ester (4)
将中间体3(8g，16mmol)，(A-taPhos)2PdCl2(1.1g，1.6mmol)和碳酸铯(10.4g,32mmol)以及三甲基环三硼氧烷(3.5M,13.7mL,48mmol)加入到1,4-Dioxane(100mL)中，80℃搅拌8小时。向反应液中加入饱和NH4Cl溶液，用EtOAc(100mL×3)萃取，有机相用Na2SO4干燥，旋干经硅胶柱纯化得到6g 3-(双(叔丁氧基羰基)氨基)-6-氟-2-甲基-4-(三氟甲基)苯甲酸甲酯(4)，86％收率。Intermediate 3 (8g, 16mmol), (A-taPhos) 2 PdCl 2 (1.1g, 1.6mmol) and cesium carbonate (10.4g, 32mmol) and trimethylcyclotriboroxane (3.5M, 13.7mL, 48 mmol) was added to 1,4-Dioxane (100 mL), and stirred at 80°C for 8 hours. Add saturated NH 4 Cl solution to the reaction solution, extract with EtOAc (100 mL×3), dry the organic phase with Na 2 SO 4 , spin dry and purify through silica gel column to obtain 6g of 3-(bis(tert-butoxycarbonyl)amino) -6-Fluoro-2-methyl-4-(trifluoromethyl)benzoic acid methyl ester (4), 86% yield.
第四步：3-氨基-6-氟-2-甲基-4-(三氟甲基)苯甲酸甲酯(5)的合成
Step 4: Synthesis of 3-amino-6-fluoro-2-methyl-4-(trifluoromethyl)benzoic acid methyl ester (5)
将中间体4(6g,14mmol)加入到100mL DCM中，向反应体系中加入TFA(32g,280mmol)，室温反应过夜，旋干，经硅胶柱纯化得到3g 3-氨基-6-氟-2-甲基-4-(三氟甲基)苯甲酸甲酯(5)，83％收率。 Add intermediate 4 (6g, 14mmol) to 100mL DCM, add TFA (32g, 280mmol) to the reaction system, react at room temperature overnight, spin to dryness, and purify through silica gel column to obtain 3g of 3-amino-6-fluoro-2- Methyl-4-(trifluoromethyl)benzoate (5), 83% yield.
第五步：3-氯-6-氟-2-甲基-4-(三氟甲基)苯甲酸乙酯(6)的合成
Step 5: Synthesis of ethyl 3-chloro-6-fluoro-2-methyl-4-(trifluoromethyl)benzoate (6)
将中间体5(2.8g，11mmol)加入到ACN(50mL)中，再将亚硝酸异戊酯(2.5g，22mmol)，CuCl2(2.2g，22mmol)加入到反应液中，室温搅拌6小时。将反应液浓缩，加入水，用EtOAc(50mL×3)萃取，有机相用Na2SO4干燥，旋干经硅胶柱纯化得到2.6g中间体3-氯-6-氟-2-甲基-4-(三氟甲基)苯甲酸甲酯(6)，87％收率。Add intermediate 5 (2.8g, 11mmol) to ACN (50mL), then add isoamyl nitrite (2.5g, 22mmol) and CuCl 2 (2.2g, 22mmol) to the reaction solution, and stir at room temperature for 6 hours. . The reaction solution was concentrated, water was added, and extracted with EtOAc (50 mL × 3). The organic phase was dried with Na 2 SO 4 , spin-dried, and purified on a silica gel column to obtain 2.6 g of the intermediate 3-chloro-6-fluoro-2-methyl- Methyl 4-(trifluoromethyl)benzoate (6), 87% yield.
第六步：3-氯-6-氟-2-甲基-4-(三氟甲基)苯甲酸(7)的合成
Step 6: Synthesis of 3-chloro-6-fluoro-2-methyl-4-(trifluoromethyl)benzoic acid (7)
将中间体6(2.0g，7.0mmol)，LiOH(672mg，28.0mmol)加入到H2O(10mL)、MeOH(20mL)和THF(10mL)的混合液中，室温中搅拌6小时。向反应液中加入2M盐酸，调pH为酸性，将反应液浓缩，加入水，用EtOAc(40mL×3)萃取，有机相用Na2SO4干燥浓缩后得到1.8g中间体3-氯-6-氟-2-甲基-4-(三氟甲基)苯甲酸(7)，100％收率。Intermediate 6 (2.0 g, 7.0 mmol) and LiOH (672 mg, 28.0 mmol) were added to the mixture of H 2 O (10 mL), MeOH (20 mL) and THF (10 mL), and the mixture was stirred at room temperature for 6 hours. Add 2M hydrochloric acid to the reaction solution to adjust the pH to acidic. Concentrate the reaction solution, add water, and extract with EtOAc (40mL×3). The organic phase is dried with Na 2 SO 4 and concentrated to obtain 1.8g of intermediate 3-chloro-6. -Fluoro-2-methyl-4-(trifluoromethyl)benzoic acid (7), 100% yield.
第七步：3-氯-6-氟-2-甲基-N-(吡啶-3-基)-4-(三氟甲基)苯甲酰胺(8)的合成
Step 7: Synthesis of 3-chloro-6-fluoro-2-methyl-N-(pyridin-3-yl)-4-(trifluoromethyl)benzamide (8)
将中间体6(1.8g，7mmol)，3-氨基吡啶(794mg，8.4mmol)，HATU(5.3g，14mmol)和DIEA(1.8g，14mmol)加入到DMF(30mL)中，反应液在室温下反应12小时。向反应液中加入NH4Cl溶液(40mL)，用EtOAc(50mL×3)萃取，有机相用水洗3次，用Na2SO4干燥，旋干经硅胶柱纯化得到1.5g中间体3-氯-6-氟-2-甲基-N-(吡啶-3-基)-4-(三氟甲基)苯甲酰胺(8)，65％收率。Intermediate 6 (1.8g, 7mmol), 3-aminopyridine (794mg, 8.4mmol), HATU (5.3g, 14mmol) and DIEA (1.8g, 14mmol) were added to DMF (30mL), and the reaction solution was at room temperature. Reaction time is 12 hours. Add NH 4 Cl solution (40 mL) to the reaction solution, extract with EtOAc (50 mL × 3), wash the organic phase with water 3 times, dry with Na 2 SO 4 , spin dry and purify through silica gel column to obtain 1.5 g of intermediate 3-chloro -6-Fluoro-2-methyl-N-(pyridin-3-yl)-4-(trifluoromethyl)benzamide (8), 65% yield.
第八步：3-氯-6-((7-氟-2,3-二氢-1H-茚-4-基)氧基)-2-甲基-N-(吡啶-3-基)-4-(三氟甲基)苯甲酰胺(8)的合成
Step 8: 3-chloro-6-((7-fluoro-2,3-dihydro-1H-inden-4-yl)oxy)-2-methyl-N-(pyridin-3-yl)- Synthesis of 4-(trifluoromethyl)benzamide (8)
室温下，向50毫升单口瓶中加入中间体8(200mg，0.6mmol)，7-氟-2,3-二氢-1H-茚-4-醇(110mg，0.72mmol)，碳酸铯(390mg，1.2mmol)和DMF(10mL)，随后100℃反应5小时。冷却至室温，向反应液中加入NH4Cl溶液(40mL)，用EtOAc(50mL×3)萃取，有机相用水洗3次，用Na2SO4干燥，旋干经硅胶柱纯化得到200mg的中间体3-氯-6-氟-2-甲基-4-(三氟甲基)苯甲酸乙酯(9)，72％收率。 At room temperature, add intermediate 8 (200mg, 0.6mmol), 7-fluoro-2,3-dihydro-1H-inden-4-ol (110mg, 0.72mmol), cesium carbonate (390mg, 1.2 mmol) and DMF (10 mL), followed by reaction at 100°C for 5 hours. Cool to room temperature, add NH 4 Cl solution (40 mL) to the reaction solution, extract with EtOAc (50 mL × 3), wash the organic phase with water 3 times, dry with Na 2 SO 4 , spin dry and purify on a silica gel column to obtain 200 mg of the intermediate 3-Chloro-6-fluoro-2-methyl-4-(trifluoromethyl)benzoic acid ethyl ester (9), 72% yield.
第九步：3-(3-氯-6-((7-氟-2,3-二氢-1H-茚-4-基)氧基)-2-甲基-4-(三氟甲基)苯甲酰胺基)吡啶1-氧化物(I-1)的合成
Step 9: 3-(3-chloro-6-((7-fluoro-2,3-dihydro-1H-inden-4-yl)oxy)-2-methyl-4-(trifluoromethyl )Synthesis of benzamido)pyridine 1-oxide (I-1)
室温下，向25毫升单口瓶中加入中间体9(200mg，0.43mmol)，DCM(5mL)和mCPBA(111mg，0.65mmol)。室温反应2小时。反应完成后，饱和碳酸氢钠水洗，有机相用Na2SO4干燥，浓缩后送制备得到80mg的3-(3-氯-6-((7-氟-2,3-二氢-1H-茚-4-基)氧基)-2-甲基-4-(三氟甲基)苯甲酰胺基)吡啶1-氧化物(I-1)，收率39％。Intermediate 9 (200 mg, 0.43 mmol), DCM (5 mL) and mCPBA (111 mg, 0.65 mmol) were added to a 25 ml single-neck bottle at room temperature. React at room temperature for 2 hours. After the reaction is completed, wash with saturated sodium bicarbonate water, dry the organic phase with Na 2 SO 4 , concentrate and send to prepare 80 mg of 3-(3-chloro-6-((7-fluoro-2,3-dihydro-1H- Inden-4-yl)oxy)-2-methyl-4-(trifluoromethyl)benzamido)pyridine 1-oxide (I-1), yield 39%.
1H NMR(400MHz,CDCl3)δ10.51(s,1H),8.56(s,1H),8.15(s,1H),7.20(s,1H),6.92-6.60(m,3H),2.93(t,J＝7.4Hz,2H),2.70(t,J＝7.3Hz,2H),2.43(s,3H),2.04(dd,J＝14.8,7.6Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ10.51(s,1H),8.56(s,1H),8.15(s,1H),7.20(s,1H),6.92-6.60(m,3H),2.93( t,J＝7.4Hz,2H),2.70(t,J＝7.3Hz,2H),2.43(s,3H),2.04(dd,J＝14.8,7.6Hz,2H).
LC-MS,M/Z(ESI):961.0[2M+H]+。LC-MS, M/Z(ESI):961.0[2M+H] + .
实施例2：目标化合物I-2的制备Example 2: Preparation of target compound I-2
3-(6-((7-氟-2,3-二氢-1H-茚-4-基)氧基)-2-甲基-3-(三氟甲基)苯甲酰胺基)吡啶1-氧化物
3-(6-((7-fluoro-2,3-dihydro-1H-inden-4-yl)oxy)-2-methyl-3-(trifluoromethyl)benzamido)pyridine 1 -oxide
目标化合物I-2合成路线如下所示：
The synthetic route of target compound I-2 is as follows:
第一步：2-溴-6-氟-3-(三氟甲基)苯甲酸(2)的合成
Step 1: Synthesis of 2-bromo-6-fluoro-3-(trifluoromethyl)benzoic acid (2)
将中间体1(10.0g，41mmol)加入到THF(150mL)中，反应液降至-78℃，再将LDA(2M，25mL，50mmol)加入到反应液中，搅拌0.5小时。将干冰通过导管通入到到反应体系中，继续在-78℃搅拌2小时。升至室温，向反应液中加入饱和NH4Cl溶液，用EtOAc(100mL×3)萃取，有机相用Na2SO4干燥，旋干经硅胶柱纯化得到10.0g中间体2-溴-6-氟-3-(三氟甲基)苯甲酸(2)，70％收率。Intermediate 1 (10.0g, 41mmol) was added to THF (150mL), the reaction solution was lowered to -78°C, and LDA (2M, 25mL, 50mmol) was added to the reaction solution and stirred for 0.5 hours. Dry ice was introduced into the reaction system through the catheter, and stirring was continued at -78°C for 2 hours. Warm to room temperature, add saturated NH 4 Cl solution to the reaction solution, extract with EtOAc (100 mL×3), dry the organic phase with Na 2 SO 4 , spin dry and purify on silica gel column to obtain 10.0 g of intermediate 2-bromo-6- Fluoro-3-(trifluoromethyl)benzoic acid (2), 70% yield.
第二步：2-溴-6-氟-N-(吡啶-3-基)-3-(三氟甲基)苯甲酰胺(3)的合成
Step 2: Synthesis of 2-bromo-6-fluoro-N-(pyridin-3-yl)-3-(trifluoromethyl)benzamide (3)
将中间体2(2.0g，7mmol)，3-氨基吡啶(790mg，8.4mmol)，HATU(5.4g，14mmol)和DIEA(1.8g，14mmol)加入到DMF(30mL)中，反应液在室温下反应12小时。向反应液中加入NH4Cl溶液(40mL)，用EtOAc(50mL×3)萃取，有机相用水洗3次，用Na2SO4干燥，旋干经硅胶柱纯化得到2g中间体2-溴-6-氟-N-(吡啶-3-基)-3-(三氟甲基)苯甲酰胺(3)，79％收率。Intermediate 2 (2.0g, 7mmol), 3-aminopyridine (790mg, 8.4mmol), HATU (5.4g, 14mmol) and DIEA (1.8g, 14mmol) were added to DMF (30mL), and the reaction solution was at room temperature. Reaction time is 12 hours. NH 4 Cl solution (40 mL) was added to the reaction solution, extracted with EtOAc (50 mL × 3), the organic phase was washed three times with water, dried with Na 2 SO 4 , spin-dried and purified by a silica gel column to obtain 2 g of the intermediate 2-bromo- 6-Fluoro-N-(pyridin-3-yl)-3-(trifluoromethyl)benzamide (3), 79% yield.
第三步：6-氟-2-甲基-N-(吡啶-3-基)-3-(三氟甲基)苯甲酰胺(4)的合成
Step 3: Synthesis of 6-fluoro-2-methyl-N-(pyridin-3-yl)-3-(trifluoromethyl)benzamide (4)
将中间体3(1g，2.8mmol)，(A-taPhos)2PdCl2(213mg，0.3mmol)和碳酸铯(1.8g,5.6mmol)以及三甲基环三硼氧烷(3.5M,1.6mL,5.6mmol)加入到1,4-Dioxane(20mL)中，80℃搅拌8小时。向反应液中加入饱和NH4Cl溶液，用EtOAc(30mL×3)萃取，有机相用Na2SO4干燥，旋干经硅胶柱纯化得到0.4g 6-氟-2-甲基-N-(吡啶-3-基)-3-(三氟甲基)苯甲酰胺(4)，48％收率。Intermediate 3 (1g, 2.8mmol), (A-taPhos) 2 PdCl 2 (213mg, 0.3mmol) and cesium carbonate (1.8g, 5.6mmol) and trimethylcyclotriboroxane (3.5M, 1.6mL ,5.6mmol) was added to 1,4-Dioxane (20mL), and stirred at 80°C for 8 hours. Saturated NH 4 Cl solution was added to the reaction solution, extracted with EtOAc (30 mL × 3), the organic phase was dried with Na 2 SO 4 , spin-dried and purified through a silica gel column to obtain 0.4g of 6-fluoro-2-methyl-N-( Pyridin-3-yl)-3-(trifluoromethyl)benzamide (4), 48% yield.
第四步：6-((7-氟-2,3-二氢-1H-茚-4-基)氧基)-2-甲基-N-(吡啶-3-基)-3-(三氟甲基)苯甲酰胺(5)的合成
Step 4: 6-((7-fluoro-2,3-dihydro-1H-inden-4-yl)oxy)-2-methyl-N-(pyridin-3-yl)-3-(tris Synthesis of fluoromethyl)benzamide (5)
室温下，向50毫升单口瓶中加入中间体4(200mg，0.67mmol)，7-氟-2,3-二氢-1H-茚-4-醇(123mg，0.80mmol)，碳酸铯(435mg，1.34mmol)和DMF(10mL)，随后100℃反应5小时。冷却至室温，向反应液中加入NH4Cl溶液(40mL)，用EtOAc(50mL×3)萃取，有机相用水洗3次，用Na2SO4干燥，旋干经硅胶柱纯化得到230mg的中间体6-((7-氟-2,3-二氢-1H-茚-4-基)氧基)-2-甲基-N-(吡啶-3-基)-3-(三氟甲基)苯甲酰胺(5)，74％收率。At room temperature, add intermediate 4 (200mg, 0.67mmol), 7-fluoro-2,3-dihydro-1H-inden-4-ol (123mg, 0.80mmol), cesium carbonate (435mg, 1.34 mmol) and DMF (10 mL), followed by reaction at 100°C for 5 hours. Cool to room temperature, add NH 4 Cl solution (40 mL) to the reaction solution, extract with EtOAc (50 mL × 3), wash the organic phase with water 3 times, dry with Na 2 SO 4 , spin dry and purify on a silica gel column to obtain 230 mg of the intermediate 6-((7-Fluoro-2,3-dihydro-1H-inden-4-yl)oxy)-2-methyl-N-(pyridin-3-yl)-3-(trifluoromethyl ) benzamide (5), 74% yield.
第五步：3-(6-((7-氟-2,3-二氢-1H-茚-4-基)氧基)-2-甲基-3-(三氟甲基)苯甲酰胺基)吡啶1-氧化物(I-2)的合成
Step 5: 3-(6-((7-fluoro-2,3-dihydro-1H-inden-4-yl)oxy)-2-methyl-3-(trifluoromethyl)benzamide Synthesis of pyridine 1-oxide (I-2)
室温下，向25毫升单口瓶中加入中间体5(170mg，0.37mmol)，DCM(5mL)和mCPBA(94mg，0.55mmol)。室温反应2小时。反应完成后，饱和碳酸氢钠水洗，有机相用Na2SO4干燥，浓缩后送制备得到40mg的3-(6-((7-氟-2,3-二氢-1H-茚-4-基)氧基)-2-甲基-3-(三氟甲基)苯甲酰胺基)吡啶1-氧化物(I-2)，39％收率。Intermediate 5 (170 mg, 0.37 mmol), DCM (5 mL) and mCPBA (94 mg, 0.55 mmol) were added to a 25 ml single-neck bottle at room temperature. React at room temperature for 2 hours. After the reaction is completed, wash with saturated sodium bicarbonate water, dry the organic phase with Na 2 SO 4 , concentrate and prepare 40 mg of 3-(6-((7-fluoro-2,3-dihydro-1H-indene-4- (yl)oxy)-2-methyl-3-(trifluoromethyl)benzamido)pyridine 1-oxide (I-2), 39% yield.
1H NMR(400MHz,CDCl3)δ9.98(s,1H),8.70(s,1H),8.23(d,J＝8.1Hz,1H),7.56(d,J＝8.9Hz,1H),7.21–7.02(m,2H),6.83(d,J＝6.2Hz,2H),6.56(d,J＝8.8Hz,1H),2.99–2.86(m,2H),2.71(t,J＝7.5Hz,2H),2.49(s,3H),2.05(p,J＝7.5Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ9.98 (s, 1H), 8.70 (s, 1H), 8.23 (d, J = 8.1Hz, 1H), 7.56 (d, J = 8.9Hz, 1H), 7.21 –7.02(m,2H),6.83(d,J＝6.2Hz,2H),6.56(d,J＝8.8Hz,1H),2.99–2.86(m,2H),2.71(t,J＝7.5Hz, 2H), 2.49 (s, 3H), 2.05 (p, J = 7.5Hz, 2H).
LC-MS,M/Z(ESI):893.3[2M+H]+。LC-MS, M/Z(ESI):893.3[2M+H] + .
实施例3：目标化合物I-3的制备Example 3: Preparation of target compound I-3
3-(2-((6,7-二氟-2,3-二氢-1H-茚-4-基)氧基)-6-氟-4-(三氟甲基)苯甲酰胺基)吡啶1-氧化物
3-(2-((6,7-difluoro-2,3-dihydro-1H-inden-4-yl)oxy)-6-fluoro-4-(trifluoromethyl)benzamide) Pyridine 1-oxide
目标化合物I-3的合成路线如下：
The synthetic route of target compound I-3 is as follows:
第一步：2-((6,7-二氟-2,3-二氢-1H-茚-4-基)氧基)-6-氟-N-(吡啶-3-基)-4-(三氟甲基)苯甲酰胺(2)的合成
Step 1: 2-((6,7-difluoro-2,3-dihydro-1H-inden-4-yl)oxy)-6-fluoro-N-(pyridin-3-yl)-4- Synthesis of (trifluoromethyl)benzamide (2)
室温下，向5毫升微波管中加入中间体INT-1-1(150mg，0.41mmol)，7-氟-2,3-二氢-1H-茚-4-醇(76mg，0.50mmol)，碳酸铯(266mg，0.82mmol)，CuI(7.6mg,0.04mmol)和甲苯(2mL)， 随后100℃微波反应0.5小时。冷却至室温，向反应液中加入NH4Cl溶液(10mL)，用EtOAc(10mL×3)萃取，有机相用水洗3次，用Na2SO4干燥，旋干经硅胶柱纯化得到75mg的中间体2-((6,7-二氟-2,3-二氢-1H-茚-4-基)氧基)-6-氟-N-(吡啶-3-基)-4-(三氟甲基)苯甲酰胺(2)，40％收率。At room temperature, add intermediate INT-1-1 (150 mg, 0.41 mmol), 7-fluoro-2,3-dihydro-1H-inden-4-ol (76 mg, 0.50 mmol), and carbonic acid into a 5 ml microwave tube. Cesium (266 mg, 0.82 mmol), CuI (7.6 mg, 0.04 mmol) and toluene (2 mL), Subsequently, the microwave reaction was carried out at 100°C for 0.5 hours. Cool to room temperature, add NH 4 Cl solution (10 mL) to the reaction solution, extract with EtOAc (10 mL × 3), wash the organic phase with water three times, dry with Na 2 SO 4 , spin to dryness, and purify on a silica gel column to obtain 75 mg of the intermediate 2-((6,7-Difluoro-2,3-dihydro-1H-inden-4-yl)oxy)-6-fluoro-N-(pyridin-3-yl)-4-(trifluoro Methyl)benzamide (2), 40% yield.
第二步：3-(3-氯-6-((6,7-二氟-2,3-二氢-1H-茚-4-基)氧基)-2-氟-4-(三氟甲基)苯甲酰胺基)吡啶1-氧化物(I-3)的合成
Step 2: 3-(3-chloro-6-((6,7-difluoro-2,3-dihydro-1H-inden-4-yl)oxy)-2-fluoro-4-(trifluoro Synthesis of methyl)benzamido)pyridine 1-oxide (I-3)
室温下，向25毫升单口瓶中加入中间体2(75mg，0.17mmol)，DCM(5mL)和mCPBA(58mg，0.34mmol)。室温反应2小时。反应完成后饱和碳酸氢钠水洗，有机相用Na2SO4干燥，浓缩后送制备得到12mg的3-(2-((6,7-二氟-2,3-二氢-1H-茚-4-基)氧基)-6-氟-4-(三氟甲基)苯甲酰胺基)吡啶1-氧化物(I-3)，15％收率。Intermediate 2 (75 mg, 0.17 mmol), DCM (5 mL) and mCPBA (58 mg, 0.34 mmol) were added to a 25 ml single-neck bottle at room temperature. React at room temperature for 2 hours. After the reaction is completed, wash with saturated sodium bicarbonate water, dry the organic phase with Na 2 SO 4 , concentrate and then send to prepare 12 mg of 3-(2-((6,7-difluoro-2,3-dihydro-1H-indene- 4-yl)oxy)-6-fluoro-4-(trifluoromethyl)benzamido)pyridine 1-oxide (I-3), 15% yield.
1H NMR(400MHz,CDCl3)δ10.28(s,1H),8.54(s,1H),8.07(s,1H),7.40(s,1H),7.23(s,1H),7.12(d,J＝8.3Hz,1H),6.85-6.66(m,2H),2.99(t,J＝7.4Hz,2H),2.70(t,J＝7.3Hz,2H),2.25-1.97(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ10.28(s,1H),8.54(s,1H),8.07(s,1H),7.40(s,1H),7.23(s,1H),7.12(d, J＝8.3Hz,1H),6.85-6.66(m,2H),2.99(t,J＝7.4Hz,2H),2.70(t,J＝7.3Hz,2H),2.25-1.97(m,2H).
LC-MS,M/Z(ESI):469.3[M+H]+。LC-MS, M/Z(ESI): 469.3[M+H] + .
实施例4：目标化合物I-4的制备Example 4: Preparation of target compound I-4
3-(3-氯-6-((6,7-二氟-2,3-二氢-1H-茚-4-基)氧基)-2-氟-4-(三氟甲基)苯甲酰胺基)吡啶1-氧化物
3-(3-Chloro-6-((6,7-difluoro-2,3-dihydro-1H-inden-4-yl)oxy)-2-fluoro-4-(trifluoromethyl)benzene Carboxamido)pyridine 1-oxide
目标化合物I-4的合成路线如下：
The synthetic route of target compound I-4 is as follows:
第一步：3-氯-6-((6,7-二氟-2,3-二氢-1H-茚-4-基)氧基)-2-氟-N-(吡啶-3-基)-4-(三氟甲基)苯甲酰胺(2)的合成
Step 1: 3-chloro-6-((6,7-difluoro-2,3-dihydro-1H-inden-4-yl)oxy)-2-fluoro-N-(pyridin-3-yl) Synthesis of )-4-(trifluoromethyl)benzamide (2)
室温下，向5毫升微波管中加入中间体INT-1(150mg，0.3mmol)，7-氟-2,3-二氢-1H-茚-4-醇(55mg，0.36mmol)，碳酸铯(195mg，0.6mmol)，CuI(5.7mg,0.03mmol)和甲苯(2mL)，随后100℃微波反应0.5小时。冷却至室温，向反应液中加入NH4Cl溶液(10mL)，用EtOAc(10mL×3)萃取，有机相用水洗3次，用Na2SO4干燥，旋干经硅胶柱纯化得到75mg的中间体3-氯-6-((6,7-二氟-2,3-二氢-1H-茚-4-基)氧基)-2-氟-N-(吡啶-3-基)-4-(三氟甲基)苯甲酰胺(2)，50％收率。At room temperature, intermediate INT-1 (150 mg, 0.3 mmol), 7-fluoro-2,3-dihydro-1H-inden-4-ol (55 mg, 0.36 mmol), cesium carbonate ( 195 mg, 0.6 mmol), CuI (5.7 mg, 0.03 mmol) and toluene (2 mL), followed by microwave reaction at 100°C for 0.5 hours. Cool to room temperature, add NH 4 Cl solution (10 mL) to the reaction solution, extract with EtOAc (10 mL × 3), wash the organic phase with water three times, dry with Na 2 SO 4 , spin to dryness, and purify on a silica gel column to obtain 75 mg of the intermediate 3-Chloro-6-((6,7-difluoro-2,3-dihydro-1H-inden-4-yl)oxy)-2-fluoro-N-(pyridin-3-yl)-4 -(Trifluoromethyl)benzamide (2), 50% yield.
第二步：3-(3-氯-6-((6,7-二氟-2,3-二氢-1H-茚-4-基)氧基)-2-氟-4-(三氟甲基)苯甲酰胺基)吡啶1-氧化物(I-4)的合成
Step 2: 3-(3-chloro-6-((6,7-difluoro-2,3-dihydro-1H-inden-4-yl)oxy)-2-fluoro-4-(trifluoro Synthesis of methyl)benzamido)pyridine 1-oxide (I-4)
室温下，向25毫升单口瓶中加入中间体2(75mg，0.15mmol)，DCM(5mL)和mCPBA(51mg，0.3mmol)。室温反应2小时。反应完成后饱和碳酸氢钠水洗，有机相用Na2SO4干燥，浓缩后送制备得到10mg的3-(6-((7-氟-2,3-二氢-1H-茚-4-基)氧基)-2-甲基-3-(三氟甲基)苯甲酰胺基)吡啶1-氧化物(I-4)，13％收率。Intermediate 2 (75 mg, 0.15 mmol), DCM (5 mL) and mCPBA (51 mg, 0.3 mmol) were added to a 25 ml single-neck bottle at room temperature. React at room temperature for 2 hours. After the reaction is completed, wash with saturated sodium bicarbonate water, dry the organic phase with Na 2 SO 4 , concentrate and prepare 10 mg of 3-(6-((7-fluoro-2,3-dihydro-1H-indene-4-yl) )oxy)-2-methyl-3-(trifluoromethyl)benzamido)pyridine 1-oxide (I-4), 13% yield.
1H NMR(400MHz,CDCl3)δ10.24(s,1H),8.58(s,1H),8.10(d,J＝8.7Hz,1H),7.59(d,J＝6.2Hz,1H),7.27-7.19(m,1H),6.88-6.72(m,2H),3.00(t,J＝7.3Hz,2H),2.72(t,J＝7.2Hz,2H),2.18-2.07(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ10.24 (s, 1H), 8.58 (s, 1H), 8.10 (d, J = 8.7Hz, 1H), 7.59 (d, J = 6.2Hz, 1H), 7.27 -7.19(m,1H),6.88-6.72(m,2H),3.00(t,J＝7.3Hz,2H),2.72(t,J＝7.2Hz,2H),2.18-2.07(m,2H).
LC-MS,M/Z(ESI):503.2[M+H]+。LC-MS, M/Z(ESI):503.2[M+H] + .
以下目标化合物参照化合物I-1的合成方法类似制备得到。


The following target compounds were prepared similarly by referring to the synthetic method of compound I-1.


测试例1：化合物对Nav1.8离子通道抑制活性检测Test Example 1: Detection of Inhibitory Activity of Compounds on Nav1.8 Ion Channel
试剂除用于酸碱滴定的NaOH和KOH外，均从Sigma(St.Louis,MO)公司购买。测试化合物的最终浓度均在当天配制，再溶于细胞外液。细胞外液(mM)为:NaCl,137；KCl,4；CaCl2,1.8；MgCl2,1；HEPES,10；glucose 10；pH 7.4(NaOH滴定)。所有测试化合物和对照化合物溶液均含1μM TTX。细胞内液(mM)为：天冬氨酸，140；氯化镁，2；乙二醇四乙酸(EGTA)，11；N-2-羟乙基哌嗪-N’-2-乙磺酸(HEPES)，10。用氢氧化铯调整pH到7.4。Reagents, except NaOH and KOH used for acid-base titration, were purchased from Sigma (St. Louis, MO). The final concentrations of test compounds were prepared on the same day and redissolved in the extracellular fluid. Extracellular fluid (mM) is: NaCl, 137; KCl, 4; CaCl 2 , 1.8; MgCl 2 , 1; HEPES, 10; glucose 10; pH 7.4 (NaOH titration). All test compound and control compound solutions contained 1 μM TTX. The intracellular fluid (mM) is: aspartic acid, 140; magnesium chloride, 2; ethylene glycol tetraacetic acid (EGTA), 11; N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) ), 10. Adjust pH to 7.4 with cesium hydroxide.
测试化合物溶于二甲基亚砜(DMSO)，浓度为9mM。测试当天再溶于细胞外液，配制 成要求浓度。Test compounds were dissolved in dimethyl sulfoxide (DMSO) at a concentration of 9mM. On the day of testing, dissolve in extracellular fluid and prepare into the required concentration.
电生理实验步骤：Electrophysiological experiment steps:
将细胞转移到灌流槽中，用细胞外液进行灌流。细胞内液实验当天融化。电极用PC–10(Narishige，Japan)拉制。全细胞膜片钳记录，噪音用采样频率的五分之一进行过滤。电极内加入1/4电极管长的细胞内液，将电极安装在探针上。设置好所需要的Protocol，将界面调成Membrane test，Stage调成Bath。电极内施加正压，将电极尖端接触到细胞，抽气装置三通阀调成三通状态，然后对电极施加负压，使得电极与细胞形成高阻封接。Stage调成Patch，leak控制在-200pA内，继续施加负压，使得细胞膜破裂，形成电流通路。打开抽滤装置和细胞外液阀门进行灌流，观察细胞电流，待细胞电流稳定开始加药(至少3个sweep的电流曲线重叠)。从低浓度往高浓度加药，每个浓度加药时间不少于2min且等到电流稳定再更换浓度加药。Transfer the cells to a perfusion tank and perfuse with extracellular fluid. The intracellular fluid was thawed on the day of the experiment. The electrodes were drawn from PC-10 (Narishige, Japan). Whole-cell patch-clamp recordings with noise filtered at one fifth of the sampling frequency. Add 1/4 of the electrode tube length of intracellular fluid into the electrode, and install the electrode on the probe. Set the required Protocol, adjust the interface to Membrane test, and adjust the Stage to Bath. Apply positive pressure to the electrode, bring the tip of the electrode into contact with the cells, adjust the three-way valve of the air extraction device to the three-way state, and then apply negative pressure to the electrode to form a high-resistance seal between the electrode and the cells. Stage is set to Patch, leak is controlled within -200pA, and negative pressure is continued to be applied to rupture the cell membrane and form a current path. Open the suction filtration device and the extracellular fluid valve for perfusion, observe the cell current, and start adding medicine when the cell current is stable (the current curves of at least 3 sweeps overlap). Dosing from low concentration to high concentration, the dosing time of each concentration should be no less than 2 minutes, and wait until the current is stable before changing the concentration of dosing.
供试品给药采用利用自身重力的灌流系统进行灌流。在初始记录期间，观察峰值电流幅度至少1分钟直到其稳定。在此期间，所有峰值电流幅度的CV％应小于10％以排除初始电流的上下波动。初始记录期间最后10次记录的峰值电流幅度的平均值作为阴性对照的电流峰值。待初始电流稳定后，试验样品从低浓度开始给药直到10次记录的峰值电流再次稳定或者持续给药5min后，给药后和给药前峰值电流“不变”。我们将下面两种情况定义为“稳定”或者“不变”：1)如果连续10次扫描的峰值电流的绝对平均值超过200pA而CV值小于10％；2)或者连续10次扫描的峰值电流的平均值在200pA和50pA之间而且CV值小于30％。然后给予下一个更高浓度的检测。The test product is administered using a perfusion system that utilizes its own gravity for perfusion. During the initial recording, observe the peak current amplitude for at least 1 min until it stabilizes. During this period, the CV% of all peak current amplitudes should be less than 10% to exclude up and down fluctuations in the initial current. The average of the peak current amplitudes of the last 10 recordings during the initial recording period was used as the current peak value of the negative control. After the initial current is stabilized, the test sample is administered from a low concentration until the peak current recorded 10 times stabilizes again or after continuous administration for 5 minutes, the peak current after administration and before administration is "unchanged". We define the following two situations as "stable" or "unchanged": 1) if the absolute average of the peak current for 10 consecutive scans exceeds 200pA and the CV value is less than 10%; 2) or if the peak current for 10 consecutive scans The average value is between 200pA and 50pA and the CV value is less than 30%. The next higher concentration is then tested.
每个浓度最后10次扫描的峰值电流平均值作为该浓度的峰值电流，用于数据分析。如果5分钟内不能达到稳定状态，那么此时的最后10次扫描的峰值电流平均值作为该浓度的峰值电流用于数据分析。同时该细胞要丢弃，不再用于更高浓度的检测。化合物每个浓度至少测试两个细胞。The average value of the peak current of the last 10 scans of each concentration was used as the peak current of that concentration for data analysis. If a steady state cannot be reached within 5 minutes, the average peak current of the last 10 scans at this time is used as the peak current of that concentration for data analysis. At the same time, the cells are discarded and no longer used for higher concentration detection. Compounds were tested on at least two cells per concentration.
电压脉冲程序：Voltage pulse program:
将细胞钳制在–80mV，然后用持续10毫秒方波去极化到10mV，以得到NaV1.8电流。这一程序每5秒重复一次。检测方波引发的最大电流，待其稳定后，灌流测试化合物，当反应稳定后，计算阻断的强度。Cells were clamped at –80 mV and then depolarized to 10 mV with a square wave lasting 10 ms to obtain NaV1.8 current. This procedure is repeated every 5 seconds. The maximum current induced by the square wave is detected. After it stabilizes, the test compound is perfused. When the reaction is stable, the intensity of the blockage is calculated.
数据处理和拟合Data processing and fitting
资料采集和分析将用pCLAMP 10(Molecular Devices,Union City,CA)。电流稳定指的是电流随时间变化在有限的范围内。通过绘制药物的梯度稀释系列浓度和其作用在HEK293/Nav1.8上产生的稳定电流值之间的量效关系，Data acquisition and analysis will use pCLAMP 10 (Molecular Devices, Union City, CA). Current stability means that the current changes within a limited range over time. By plotting the dose-effect relationship between the gradient dilution series concentration of the drug and the stable current value generated by its action on HEK293/Nav1.8,
进而计算该药物对Nav1.8离子通道的抑制活性(IC50)。Then the inhibitory activity (IC 50 ) of the drug on Nav1.8 ion channel was calculated.
表1：化合物对于Nav1.8离子通道的抑制活性

Table 1: Inhibitory activity of compounds on Nav1.8 ion channel

试验结果表明，本发明化合物具有较强的对Nav1.8离子通道抑制活性。The test results show that the compound of the present invention has strong inhibitory activity on Nav1.8 ion channel.
测试例2：小鼠药代动力学Test Example 2: Mouse Pharmacokinetics
按照下述实验方法测定对照化合物和本发明化合物的小鼠药代动力学性质。The mouse pharmacokinetic properties of control compounds and compounds of the present invention were determined according to the following experimental methods.
采用雄性CD-1小鼠3只，剂量为10mg/kg，给药途径为灌胃，溶媒为5％DMSO+10％聚氧乙烯蓖麻油+85％Saline，禁食过夜，采血时间点为给药前和在给药后15、30分钟以及1、2、4、6、24小时，收集血液至EDTA-2K抗凝管中，6800g 2-8℃离心6分钟，收集血浆，于-80℃保存。取20μL的样品加入300μL含内标乙腈溶液，涡旋混匀约10min，5500g离心10min；转移150μL上清到新的96孔板中，再加入150μL超纯水混匀。LC-MS/MS进样分析，检测的各个时间点的血药浓度，采用WinNonlin软件PK参数计算。Three male CD-1 mice were used. The dose was 10 mg/kg. The administration route was intragastric administration. The solvent was 5% DMSO + 10% polyoxyethylene castor oil + 85% Saline. They were fasted overnight. The blood collection time point was Before drug administration and at 15, 30 minutes and 1, 2, 4, 6, and 24 hours after administration, collect blood into EDTA-2K anticoagulant tubes, centrifuge at 6800g for 6 minutes at 2-8°C, collect plasma, and store at -80°C save. Take 20 μL of sample and add 300 μL of acetonitrile solution containing internal standard, vortex and mix for about 10 min, and centrifuge at 5500g for 10 min; transfer 150 μL of supernatant to a new 96-well plate, then add 150 μL of ultrapure water and mix. LC-MS/MS sample injection analysis, the blood drug concentration at each time point detected was calculated using WinNonlin software PK parameters.
试验结果表明，本发明化合物在小鼠体内表现出优良的药代动力学性质。The test results show that the compound of the present invention exhibits excellent pharmacokinetic properties in mice.
以上对本公开技术方案的实施方式进行了示例性的说明。应当理解，本公开的保护范围不拘囿于上述实施方式。凡在本公开的精神和原则之内，本领域技术人员所做的任何修改、等同替换、改进等，均应包含在本申请权利要求书的保护范围之内。 The above has provided an exemplary description of the embodiments of the technical solution of the present disclosure. It should be understood that the protection scope of the present disclosure is not limited to the above-described embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of this disclosure shall be included in the protection scope of the claims of this application.

Claims (20)

  1. 式(I)所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：
    Compounds represented by formula (I), their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:
    其中，in,
    X为N或CH；X is N or CH;
    环A选自 Ring A is selected from
    R1、R2、R3、R4、R5和R6各自独立地选自H、C1-C6烷基、被一个或多个氘取代的C1-C6烷基、被一个或多个R11取代的C1-C6烷基、-O-(C1-C6烷基)、被一个或多个R12取代的-O-(C1-C6烷基)、被一个或多个氘取代的-O-(C1-C6烷基)、C3-C6环烷基、被一个或多个R13取代的C3-C6环烷基、4-8元杂环烷基、被一个或多个R14取代的4-8元杂环烷基、6-10元芳基、被一个或多个R15取代的6-10元芳基、5-8元杂芳基、被一个或多个R16取代的5-8元杂芳基、-NR1aR1b、卤素、羟基、氰基、硝基、-SF5，当取代基R11、R12、R13、R14、R15、R16为多个时，所述取代基相同或不同；R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more deuterium, substituted by one or multiple R 11 substituted C 1 -C 6 alkyl, -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 alkyl) substituted by one or more R 12 , -O-(C 1 -C 6 alkyl) substituted by one or more deuteriums, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl substituted by one or more R 13 , 4- 8-membered heterocycloalkyl, 4-8-membered heterocycloalkyl substituted with one or more R 14 , 6-10-membered aryl, 6-10-membered aryl substituted with one or more R 15 , 5- 8-membered heteroaryl, 5-8-membered heteroaryl substituted by one or more R 16 , -NR 1a R 1b , halogen, hydroxyl, cyano, nitro, -SF 5 , when the substituent R 11 , R 12. When R 13 , R 14 , R 15 and R 16 are multiple, the substituents are the same or different;
    R1a和R1b各自独立地选自H、C1-C6烷基、被一个或多个R1a1取代的C1-C6烷基，当取代基R1a、R1b、R1a1为多个时，所述取代基相同或不同；R 1a and R 1b are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 1a1 , when the substituents R 1a , R 1b , R 1a1 are multiple In each case, the substituents are the same or different;
    R11、R12、R13、R14、R15、R16和R1a1各自独立地选自卤素、氨基、羟基、氰基或硝基。R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 1a1 are each independently selected from halogen, amino, hydroxyl, cyano or nitro.
  2. 如权利要求1所述的如式(I)所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，其具有以下任一种或多种特征：The compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 1, characterized in that, Have any one or more of the following characteristics:
    (1)R1为C1-C6烷基、被一个或多个氘取代的C1-C6烷基或被一个或多个卤素取代的C1-C6烷基；(1) R 1 is a C 1 -C 6 alkyl group, a C 1 -C 6 alkyl group substituted by one or more deuteriums, or a C 1 -C 6 alkyl group substituted by one or more halogens;
    (2)R3为-SF5；(2) R 3 is -SF 5 ;
    (3)R4为卤素；(3) R 4 is halogen;
    (4)R6为C1-C6烷基；(4) R 6 is C 1 -C 6 alkyl;
    (5)X为N，且R1为C1-C6烷基； (5) X is N, and R 1 is C 1 -C 6 alkyl;
    (6)环A为 (6) Ring A is
  3. 如权利要求1所述的如式(I)所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，The compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 1, characterized in that,
    X为CH；X is CH;
    环A为 Ring A is
    R1独立地选自C1-C6烷基、被一个或多个氘取代的C1-C6烷基、被一个或多个R11取代的C1-C6烷基、-O-(C1-C6烷基)、被一个或多个R12取代的-O-(C1-C6烷基)、被一个或多个氘取代的-O-(C1-C6烷基)、C3-C6环烷基、被一个或多个R13取代的C3-C6环烷基、4-8元杂环烷基、被一个或多个R14取代的4-8元杂环烷基、6-10元芳基、被一个或多个R15取代的6-10元芳基、5-8元杂芳基、被一个或多个R16取代的5-8元杂芳基、-NR1aR1b、氰基、硝基、-SF5，当取代基R11、R12、R13、R14、R15、R16为多个时，所述取代基相同或不同；R 1 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with one or more deuteriums, C 1 -C 6 alkyl substituted with one or more R 11 , -O- (C 1 -C 6 alkyl), -O-(C 1 -C 6 alkyl) substituted by one or more R 12 , -O-(C 1 -C 6 alkyl) substituted by one or more deuterium base), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl substituted by one or more R 13 , 4-8 membered heterocycloalkyl, 4- substituted by one or more R 14 8-membered heterocycloalkyl, 6-10-membered aryl, 6-10-membered aryl substituted with one or more R 15 , 5-8-membered heteroaryl, 5-8 substituted with one or more R 16 Metaheteroaryl, -NR 1a R 1b , cyano, nitro, -SF 5 , when the substituents R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are multiple, the substituents same or different;
    R1a和R1b各自独立地选自H、C1-C6烷基、被一个或多个R1a1取代的C1-C6烷基，且R1a和R1b不同时为H；当取代基R1a、R1b、R1a1为多个时，所述取代基相同或不同；R 1a and R 1b are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 1a1 , and R 1a and R 1b are not H at the same time; when substituted When there are multiple groups R 1a , R 1b , and R 1a1 , the substituents are the same or different;
    R11、R12、R13、R14、R15、R16和R1a1各自独立地选自卤素、氨基、羟基、氰基或硝基；R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 1a1 are each independently selected from halogen, amino, hydroxyl, cyano or nitro;
    R2、R3、R4、R5和R6的定义如权利要求1中所述。R 2 , R 3 , R 4 , R 5 and R 6 are as defined in claim 1 .
  4. 如权利要求3所述的如式(I)所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，The compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 3, characterized in that,
    R1为C1-C6烷基、被一个或多个氘取代的C1-C6烷基或被一个或多个卤素取代的C1-C6烷基；较佳地，R1为甲基、二氟甲基或-CD3；R 1 is a C 1 -C 6 alkyl group, a C 1 -C 6 alkyl group substituted by one or more deuteriums, or a C 1 -C 6 alkyl group substituted by one or more halogens; preferably, R 1 is Methyl, difluoromethyl or -CD 3 ;
    和/或，R2选自卤素、被一个或多个卤素取代的C1-C6烷基；较佳地，R2选自Cl或三氟甲基；And/or, R 2 is selected from halogen, C 1 -C 6 alkyl substituted by one or more halogens; preferably, R 2 is selected from Cl or trifluoromethyl;
    和/或，R3选自H、被一个或多个卤素取代的C1-C6烷基；较佳地，R3选自H或三氟甲基；And/or, R 3 is selected from H, C 1 -C 6 alkyl substituted by one or more halogens; preferably, R 3 is selected from H or trifluoromethyl;
    和/或，R4为H；and/or, R 4 is H;
    和/或，R5为卤素；较佳地，R5为F；And/or, R 5 is halogen; preferably, R 5 is F;
    和/或，R6为H。and/or, R 6 is H.
  5. 如权利要求1所述的如式(I)所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，如式(I)所示的化合物为，
    The compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 1, characterized in that, as The compound represented by formula (I) is,
    其中，R1、R2、R4、R5和R6具有如权利要求1所述的定义。Wherein, R 1 , R 2 , R 4 , R 5 and R 6 have the definitions as claimed in claim 1 .
  6. 如权利要求5所述的如式(II)所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，The compound represented by formula (II), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 5, characterized in that,
    R1为H或卤素；较佳地，R1为H或F；R 1 is H or halogen; preferably, R 1 is H or F;
    和/或，R2为H或卤素；较佳地，R2为H或Cl；And/or, R 2 is H or halogen; preferably, R 2 is H or Cl;
    和/或，R4为H；and/or, R 4 is H;
    和/或，R5为卤素；较佳地，R5为F；And/or, R 5 is halogen; preferably, R 5 is F;
    和/或，R6为H。and/or, R 6 is H.
  7. 如权利要求1所述的如式(I)所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，The compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 1, characterized in that,
    X为CH；X is CH;
    环A为 Ring A is
    R4独立地选自C1-C6烷基、被一个或多个R11取代的C1-C6烷基、被一个或多个氘取代的C1-C6烷基、-O-(C1-C6烷基)、被一个或多个R12取代的-O-(C1-C6烷基)、被一个或多个氘取代的-O-(C1-C6烷基)、C3-C6环烷基、被一个或多个R13取代的C3-C6环烷基、4-8元杂环烷基、被一个或多个R14取代的4-8元杂环烷基、6-10元芳基、被一个或多个R15取代的6-10元芳基、5-8元杂芳基、被一个或多个R16取代的5-8元杂芳基、-NR1aR1b、卤素、羟基、氰基、硝基、-SF5，当取代基R11、R12、R13、R14、R15、R16为多个时，所述取代基相同或不同；R 4 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with one or more R 11 , C 1 -C 6 alkyl substituted with one or more deuterium, -O- (C 1 -C 6 alkyl), -O-(C 1 -C 6 alkyl) substituted by one or more R 12 , -O-(C 1 -C 6 alkyl) substituted by one or more deuterium base), C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl substituted by one or more R 13 , 4-8 membered heterocycloalkyl, 4- substituted by one or more R 14 8-membered heterocycloalkyl, 6-10-membered aryl, 6-10-membered aryl substituted with one or more R 15 , 5-8-membered heteroaryl, 5-8 substituted with one or more R 16 Metaheteroaryl, -NR 1a R 1b , halogen, hydroxyl, cyano, nitro, -SF 5 , when there are multiple substituents R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 , The substituents are the same or different;
    R1a和R1b各自独立地选自H、C1-C6烷基、被一个或多个R1a1取代的C1-C6烷基，当取代基R1a、R1b、R1a1为多个时，所述取代基相同或不同；R 1a and R 1b are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 1a1 , when the substituents R 1a , R 1b , R 1a1 are multiple In each case, the substituents are the same or different;
    R11、R12、R13、R14、R15、R16和R1a1各自独立地选自卤素、氨基、羟基、氰基或硝基；R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 1a1 are each independently selected from halogen, amino, hydroxyl, cyano or nitro;
    R1、R2、R3、R5和R6的定义如权利要求1中所述。R 1 , R 2 , R 3 , R 5 and R 6 are as defined in claim 1 .
  8. 如权利要求7所述的如式(I)所示的化合物、其互变异构体、立体异构体、水合物、溶 剂化物、药学上可接受的盐或前药，其特征在于，The compound represented by formula (I) as claimed in claim 7, its tautomer, stereoisomer, hydrate, solution Agent compound, pharmaceutically acceptable salt or prodrug, characterized in that,
    R1为H、卤素或被一个或多个氘取代的C1-C6烷基；较佳地，R1为H、F或-CD3；R 1 is H, halogen or C 1 -C 6 alkyl substituted by one or more deuteriums; preferably, R 1 is H, F or -CD 3 ;
    和/或，R2为H、卤素或C1-C6烷基；较佳地，R2为H、Cl或甲基；And/or, R 2 is H, halogen or C 1 -C 6 alkyl; preferably, R 2 is H, Cl or methyl;
    和/或，R3为被一个或多个卤素取代的C1-C6烷基；较佳地，R3为三氟甲基；And/or, R 3 is C 1 -C 6 alkyl substituted by one or more halogens; preferably, R 3 is trifluoromethyl;
    和/或，R4为卤素；较佳地，R4为F；And/or, R 4 is halogen; preferably, R 4 is F;
    和/或，R5为卤素；较佳地，R5为F；And/or, R 5 is halogen; preferably, R 5 is F;
    和/或，R6为H。and/or, R 6 is H.
  9. 如权利要求1所述的如式(I)所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，The compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 1, characterized in that,
    X为CH；X is CH;
    环A为 Ring A is
    R6独立地选自C1-C6烷基、被一个或多个R11取代的C1-C6烷基、-O-(C1-C6烷基)、被一个或多个R12取代的-O-(C1-C6烷基)、被一个或多个氘取代的-O-(C1-C6烷基)、C3-C6环烷基、被一个或多个R13取代的C3-C6环烷基、4-8元杂环烷基、被一个或多个R14取代的4-8元杂环烷基、6-10元芳基、被一个或多个R15取代的6-10元芳基、5-8元杂芳基、被一个或多个R16取代的5-8元杂芳基、-NR1aR1b、卤素、羟基、氰基、硝基、-SF5，当取代基R11、R12、R13、R14、R15、R16为多个时，所述取代基相同或不同；R 6 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with one or more R 11 , -O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl substituted with one or more R 11 12Substituted -O-(C 1 -C 6 alkyl), -O-(C 1 -C 6 alkyl) substituted by one or more deuterium, C 3 -C 6 cycloalkyl, substituted by one or more deuterium C 3 -C 6 cycloalkyl substituted by R 13 , 4-8 membered heterocycloalkyl, 4-8 membered heterocycloalkyl substituted by one or more R 14 , 6-10 membered aryl, substituted by one or multiple 6-10-membered aryl groups substituted by R 15 , 5-8-membered heteroaryl groups, 5-8-membered heteroaryl groups substituted by one or more R 16 , -NR 1a R 1b , halogen, hydroxyl, cyanide group, nitro, -SF 5 , when the substituents R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are multiple, the substituents are the same or different;
    R1a和R1b各自独立地选自H、C1-C6烷基、被一个或多个R1a1取代的C1-C6烷基，当取代基R1a、R1b、R1a1为多个时，所述取代基相同或不同；R 1a and R 1b are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 1a1 , when the substituents R 1a , R 1b , R 1a1 are multiple In each case, the substituents are the same or different;
    R11、R12、R13、R14、R15、R16和R1a1各自独立地选自卤素、氨基、羟基、氰基或硝基；R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 1a1 are each independently selected from halogen, amino, hydroxyl, cyano or nitro;
    R1、R2、R3、R4和R5的定义如权利要求1中所述。R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 1 .
  10. 如权利要求9所述的如式(I)所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，The compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 9, characterized in that,
    R1为卤素；较佳地，R1为F；R 1 is halogen; preferably, R 1 is F;
    和/或，R2为卤素；较佳地，R2为Cl；And/or, R 2 is halogen; preferably, R 2 is Cl;
    和/或，R3为被一个或多个卤素取代的C1-C6烷基；较佳地，R3为三氟甲基；And/or, R 3 is C 1 -C 6 alkyl substituted by one or more halogens; preferably, R 3 is trifluoromethyl;
    和/或，R4为H；and/or, R 4 is H;
    和/或，R5为卤素；较佳地，R5为F；And/or, R 5 is halogen; preferably, R 5 is F;
    和/或，R6为C1-C6烷基；较佳地，R6为甲基。And/or, R 6 is C 1 -C 6 alkyl; preferably, R 6 is methyl.
  11. 如权利要求1所述的如式(I)所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，式(I)所示的化合物为，
    The compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 1, characterized in that the formula The compound shown in (I) is,
    其中，R1、R2、R3、R4、R5和R6具有如权利要求1所述的定义，且R1不为H。Wherein, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 have the definitions as described in claim 1, and R 1 is not H.
  12. 如权利要求11所述的如式(III)所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，The compound represented by formula (III), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 11, characterized in that,
    R1为C1-C6烷基；较佳地，R1为甲基；R 1 is C 1 -C 6 alkyl; preferably, R 1 is methyl;
    和/或，R2为卤素；较佳地，R2为Cl；And/or, R 2 is halogen; preferably, R 2 is Cl;
    和/或，R3为被一个或多个卤素取代的C1-C6烷基；较佳地，R3为三氟甲基；And/or, R 3 is C 1 -C 6 alkyl substituted by one or more halogens; preferably, R 3 is trifluoromethyl;
    和/或，R4为H；and/or, R 4 is H;
    和/或，R5为F；and/or, R 5 is F;
    和/或，R6为H。and/or, R 6 is H.
  13. 如权利要求1所述的如式(I)所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，式(I)所示的化合物为，
    The compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 1, characterized in that the formula The compound shown in (I) is,
    其中，R1、R2、R3、R4、R5和R6具有如权利要求1所述的定义。Wherein, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 have the definitions as claimed in claim 1 .
  14. 如权利要求13所述的如式(IV’)所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，The compound represented by formula (IV'), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 13, characterized in that,
    为 for
    和/或，R1为卤素；较佳地，R1为F； And/or, R 1 is halogen; preferably, R 1 is F;
    和/或，R2为卤素；较佳地，R2为Cl；And/or, R 2 is halogen; preferably, R 2 is Cl;
    和/或，R3为被一个或多个卤素取代的C1-C6烷基；较佳地，R3为三氟甲基；And/or, R 3 is C 1 -C 6 alkyl substituted by one or more halogens; preferably, R 3 is trifluoromethyl;
    和/或，R4为被一个或多个氘取代的-O-(C1-C6烷基)；较佳地，R4为-O-CD3；And/or, R 4 is -O-(C 1 -C 6 alkyl) substituted by one or more deuteriums; preferably, R 4 is -O-CD 3 ;
    和/或，R5为F；and/or, R 5 is F;
    和/或，R6为H。and/or, R 6 is H.
  15. 如权利要求1所述的式(I)所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述式(I)所示的化合物选自下列化合物：

    The compound represented by formula (I) according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that, The compound represented by formula (I) is selected from the following compounds:

  16. 一种药物组合物，其特征在于，其包括权利要求1-15中任一项所述的式(I)所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药和药学上可接受的赋形剂。A pharmaceutical composition, characterized in that it includes the compound represented by formula (I) according to any one of claims 1 to 15, its tautomers, stereoisomers, hydrates, and solvates , pharmaceutically acceptable salts or prodrugs and pharmaceutically acceptable excipients.
  17. 如权利要求1-15中任一项所述的式(I)所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，或如权利要求16所述的组合物在制备抑制电压门控钠离子通道药物中的用途。The compound represented by formula (I) according to any one of claims 1 to 15, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, Or the use of the composition according to claim 16 in the preparation of drugs that inhibit voltage-gated sodium ion channels.
  18. 如权利要求17所述的用途，其特征在于，所述电压门控钠离子通道为Nav1.8。The use according to claim 17, characterized in that the voltage-gated sodium ion channel is Nav1.8.
  19. 如权利要求1-15中任一项所述的式(I)所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，或如权利要求16所述的组合物在制备治疗、缓解或预防疼痛药物中的用途。The compound represented by formula (I) according to any one of claims 1 to 15, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, Or the use of the composition according to claim 16 in the preparation of medicaments for treating, relieving or preventing pain.
  20. 如权利要求19所述的用途，其特征在于，所述疼痛包括急性疼痛、慢性疼痛、炎性疼痛、癌症疼痛、神经性疼痛、肌肉骨骼痛、原发性疼痛、肠痛和特发性疼痛。 The use according to claim 19, wherein the pain includes acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain. .
PCT/CN2023/085508 2022-04-02 2023-03-31 Nav1.8 inhibitor and use thereof WO2023186102A1 (en)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111065383A (en) * 2017-07-11 2020-04-24 沃泰克斯药物股份有限公司 Carboxamides useful as sodium channel modulators
CN112225695A (en) * 2020-12-15 2021-01-15 上海济煜医药科技有限公司 Oxynitride and preparation method and application thereof
CN112479996A (en) * 2019-09-12 2021-03-12 上海济煜医药科技有限公司 Pyridine oxynitride and preparation method and application thereof
CN112689633A (en) * 2018-07-09 2021-04-20 利伯研究所公司 For inhibiting Nav1.8 pyridine carboxamide Compounds
WO2022192487A2 (en) * 2021-03-11 2022-09-15 Latigo Biotherapeutics, Inc. Methyl-substituted pyridine and pyridazine compounds, derivatives thereof, and methods of their use
WO2022188872A1 (en) * 2021-03-11 2022-09-15 上海济煜医药科技有限公司 Crystal form of pyridine nitrogen oxide compound and use thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111065383A (en) * 2017-07-11 2020-04-24 沃泰克斯药物股份有限公司 Carboxamides useful as sodium channel modulators
CN112689633A (en) * 2018-07-09 2021-04-20 利伯研究所公司 For inhibiting Nav1.8 pyridine carboxamide Compounds
CN112479996A (en) * 2019-09-12 2021-03-12 上海济煜医药科技有限公司 Pyridine oxynitride and preparation method and application thereof
CN112225695A (en) * 2020-12-15 2021-01-15 上海济煜医药科技有限公司 Oxynitride and preparation method and application thereof
WO2022192487A2 (en) * 2021-03-11 2022-09-15 Latigo Biotherapeutics, Inc. Methyl-substituted pyridine and pyridazine compounds, derivatives thereof, and methods of their use
WO2022188872A1 (en) * 2021-03-11 2022-09-15 上海济煜医药科技有限公司 Crystal form of pyridine nitrogen oxide compound and use thereof

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