WO2023236263A1 - Benzoxazole derivative, preparation method therefor, and application thereof - Google Patents
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- WO2023236263A1 WO2023236263A1 PCT/CN2022/101058 CN2022101058W WO2023236263A1 WO 2023236263 A1 WO2023236263 A1 WO 2023236263A1 CN 2022101058 W CN2022101058 W CN 2022101058W WO 2023236263 A1 WO2023236263 A1 WO 2023236263A1
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- 238000002360 preparation method Methods 0.000 title claims abstract description 90
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D263/57—Aryl or substituted aryl radicals
Definitions
- the present invention relates to the technical field of medicinal chemistry, and in particular to a benzoxazole derivative and its preparation method and application.
- P2Y 14 receptor is a member of the P2Y receptor. After being specifically activated by uridine 5'-diphosphate glucose (UDPG) and other endogenous UDP-sugar, it can pass Gi/o The protein inhibits adenylyl cyclase (AC), thereby reducing intracellular production of 3',5'-cyclic adenosine monophosphate (cAMP).
- UDPG uridine 5'-diphosphate glucose
- AC adenylyl cyclase
- cAMP 3',5'-cyclic adenosine monophosphate
- P2Y 14 R is widely expressed in tissues and organs such as the heart, placenta, adipose tissue, gastrointestinal tract, bone marrow, and thymus, especially in the immune system.
- P2Y 14 R When P2Y 14 R is stimulated, it can promote the release of mediators from mast cells and inflammation of renal leap cells, increase the hypersensitivity of microglia and the motility of neutrophils; and can inhibit the release of metals from astrocytes Proteases and tumor necrosis factor.
- the high expression level of purinergic receptor P2Y 14 in immune cells and tissues indicates that it may participate in the regulation of immune inflammatory responses as an inflammatory mediator.
- P2Y 14 receptor antagonists have good innovation and application prospects in the field of drug development for related diseases such as acute gouty arthritis, drug-induced liver injury, acute kidney injury, and neural pain.
- P2Y 14 R activation is closely related to intracellular cAMP content, and cAMP can prevent the activation of NLRP3 inflammasome. Therefore, P2Y 14 R may regulate the inflammatory response through NLRP3 inflammasome.
- the latest research proves the key role of P2Y 14 R in the pathogenesis of acute gouty arthritis and its ability to alleviate inflammation by regulating NLRP3-mediated macrophage pyroptosis.
- Blocking P2Y14R with selective inhibitors or ablating the P2Y14R gene in ICs reduces renal inflammation, alleviates proximal tubular (PT) injury, and improves renal function after renal IRI. That is, inhibiting the UDPG/P2Y 14 R pathway in ICs can play a protective role in renal inflammation suffering from ischemic injury. Activation of P2Y 14 R causes the activation of SGCs and increases the secretion of IL-1 ⁇ and CCL2 through the ERK and p38 pathways. Therefore, P2Y 14 R in SGCs can be used as an innovative drug target for analgesic treatment of trigeminal nerve-related pain conditions (such as migraine, nerve injury, maxillofacial inflammation, etc.).
- trigeminal nerve-related pain conditions such as migraine, nerve injury, maxillofacial inflammation, etc.
- Benzoxazole is an important pharmacophore in modern drug discovery.
- a large number of benzoxazole compounds have been successfully developed, sold and widely used in the prevention and treatment of various diseases. They have low toxicity, high bioavailability, and good Biocompatibility and efficacy.
- Benzoxazoles have a wide range of biological activities.
- Research shows that benzoxazole heterocyclic compounds have good biological activity. Due to their unique structure, low toxicity and excellent biological activity, they have been widely used in many fields such as chemistry, medicine, biology and materials science. . Using the principle of activity superposition, the activity of many small molecule drugs is greatly improved after the benzoxazole group is introduced. It is precisely because benzoxazole derivatives have many excellent properties that they have become a hot topic in drug research and development.
- the object of the present invention is to provide a benzoxazole derivative and its preparation method and application.
- the benzoxazole derivatives provided by the invention have better antagonistic activity against P2Y 14 receptors and can treat P2Y 14 receptor-related diseases (such as acute gouty arthritis, drug-induced liver injury, acute kidney injury, neuralgia, etc.) activity.
- the invention provides a benzoxazole derivative having a structure represented by formula (I):
- R 1 is selected from: hydrogen, unsubstituted alkyl, unsubstituted aryl.
- the alkyl group is preferably a C1-C3 alkyl group. More preferably, R 1 is selected from: hydrogen, propyl or phenyl.
- R 2 is selected from: substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen.
- the alkyl group is preferably a C1-C3 alkyl group; the alkoxy group is preferably a C1-C3 alkoxy group.
- each substituent is independently selected from halogen (that is, when there are multiple substituents, each substituent can be the same halogen or different halogen).
- R 2 is selected from: methyl, methoxy, fluorine atom, chlorine atom, trifluoromethyl or trifluoromethoxy.
- the benzoxazole derivative has any of the following structures:
- the present invention also provides a preparation method of the benzoxazole derivative described in the above technical solution, which includes the following steps:
- R 1 and R 2 are consistent with those described in the previous technical solutions, and will not be repeated here.
- reaction route of the above preparation method is as follows:
- R 1 and R 2 are consistent with those described in the previous technical solutions, and will not be repeated here.
- the molar ratio of the above-mentioned compound having the structure of formula (II): the compound having the structure of formula (III) is preferably 1:1.5.
- the temperature of the reaction is preferably 100-110°C, and more preferably 110°C.
- the reaction time is preferably 1 hour.
- the reaction is preferably carried out in an organic solvent medium.
- the organic solvent is preferably toluene.
- the following post-processing is preferably carried out: cooling to precipitate and separate the precipitate, and then washing and drying the precipitate to obtain pure benzoxazole represented by formula (I) derivative.
- the present invention also provides a benzoxazole derivative described in the above technical solution or a benzoxazole derivative prepared by the preparation method described in the above technical solution in the preparation of drugs for treating P2Y 14 receptor related diseases. applications in. Among them, diseases related to P2Y 14 receptors include acute gouty arthritis, drug-induced liver injury, acute kidney injury or neuralgia.
- the invention also provides a drug for treating P2Y 14 receptor-related diseases, including benzoxazole derivatives and auxiliary materials;
- the benzoxazole derivative is the benzoxazole derivative described in the above technical solution or the benzoxazole derivative prepared by the preparation method described in the above technical solution.
- the excipients are pharmaceutically acceptable excipients.
- the above-mentioned medicines provided by the present invention can also be used in combination with other medicines for treating related diseases.
- HE staining test results show that the compound provided by the invention can significantly alleviate hepatocyte ballooning degeneration and necrosis, improve the tissue morphology of the liver portal area, and reduce inflammatory cell infiltration, proving that it can significantly alleviate liver damage caused by APAP.
- Figure 1 shows the effects of different doses of I-1 (5 mg/kg, 10 mg/kg) and PPTN (5 mg/kg) on the liver function biochemical index AST in APAP model C57BL/6J mice;
- Figure 2 shows the effects of different doses of I-1 (5mg/kg, 10mg/kg) and PPTN (5mg/kg) on the biochemical index ALT of liver function in APAP model C57BL/6J mice;
- Figure 3 shows the effect of HE staining on the liver tissue of APAP model C57BL/6J mice.
- Benzo[d]oxazole-6-amine (0.134g, 1mmol) was dissolved in toluene (10mL), and the temperature was raised to 110°C.
- 1-isocyanato-2-methoxybenzene (0.2 mL, 1.5 mmol) dropwise to the reaction mixture, stir the resulting solution under reflux for 1 hour, let it cool to precipitate, filter the precipitate, wash the precipitate with dichloromethane, and dry , to obtain the pure target product.
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was followed, except that 1-chloro-3-isocyanatobenzene was used as the compound of formula (III).
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was followed, except that 1-chloro-2-isocyanatobenzene was used as the compound of formula (III).
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was followed, except that 1-chloro-4-isocyanatobenzene was used as the compound of formula (III).
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was followed, except that 1-isocyanato-2-methylbenzene was used as the compound of formula (III).
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was followed, except that 1-isocyanato-3-methylbenzene was used as the compound of formula (III).
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was followed, except that 1-isocyanato-2-(trifluoromethyl)benzene was used as the compound of formula (III).
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was followed, except that 1-isocyanato-4-toluene was used as the compound of formula (III).
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was followed, except that 1-isocyanato-4-(trifluoromethoxy)benzene was used as the compound of formula (III).
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was followed, except that 1-fluoro-4-benzene isocyanate was used as the compound of formula (III).
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was followed, except that 1-isocyanato-3-methoxybenzene was used as the compound of formula (III).
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was followed, except that 1-isocyanato-4-methoxybenzene was used as the compound of formula (III).
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was followed, except that 1-isocyanato-3-(trifluoromethyl)benzene was used as the compound of formula (III).
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was followed, except that 1-isocyanato-4-(trifluoromethyl)benzene was used as the compound of formula (III).
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 is carried out, except that 2-propylbenzo[d]oxazole-6-amine is used for the compound of formula (II), and 1-isocyanato-2-methyl is used for the compound of formula (III). Oxybenzene.
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was followed, except that 2-propylbenzo[d]oxazole-6-amine was used for the compound of formula (II) and 1-chloro-3-isocyanatobenzene was used for the compound of formula (III).
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was followed, except that 2-propylbenzo[d]oxazole-6-amine was used for the compound of formula (II) and 1-chloro-4-isocyanatobenzene was used for the compound of formula (III).
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was carried out, except that 2-propylbenzo[d]oxazole-6-amine was used for the compound of formula (II), and 1-isocyanato-3-methyl was used for the compound of formula (III). Benzene.
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 is carried out, except that 2-propylbenzo[d]oxazole-6-amine is used for the compound of formula (II), and 1-isocyanato-4-toluene is used for the compound of formula (III). .
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was carried out, except that 2-propylbenzo[d]oxazole-6-amine was used for the compound of formula (II), and 1-isocyanate-4-( was used for the compound of formula (III). Trifluoromethoxy)benzene.
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 is carried out, except that 2-propylbenzo[d]oxazole-6-amine is used for the compound of formula (II), and 1-fluoro-4-isocyanate is used for the compound of formula (III). benzene.
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was carried out, except that 2-propylbenzo[d]oxazole-6-amine was used for the compound of formula (II), and 1-isocyanato-3-methyl was used for the compound of formula (III). Oxybenzene.
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was carried out, except that 2-propylbenzo[d]oxazole-6-amine was used for the compound of formula (II), and 1-isocyanato-4-methyl was used for the compound of formula (III). Oxybenzene.
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 is carried out, except that 2-propylbenzo[d]oxazole-6-amine is used for the compound of formula (II), and 1-isocyanato-3-( is used for the compound of formula (III). Trifluoromethyl)benzene.
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was carried out, except that the compound of formula (II) used 2-propylbenzo[d]oxazole-6-amine, and the compound of formula (III) used 1-isocyanato-4-( Trifluoromethyl)benzene.
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was carried out, except that 2-phenylbenzo[d]oxazole-6-amine was used for the compound of formula (II), and 1-isocyanato-2-methyl was used for the compound of formula (III). Oxybenzene.
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was followed, except that 2-phenylbenzo[d]oxazole-6-amine was used as the compound of formula (II), and 1-chloro-3-isocyanatobenzene was used as the compound of formula (III).
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was followed, except that 2-phenylbenzo[d]oxazole-6-amine was used as the compound of formula (II), and 1-chloro-4-isocyanatobenzene was used as the compound of formula (III).
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was followed, except that 2-phenylbenzo[d]oxazole-6-amine was used as the compound of formula (II), and 1-chloro-2-isocyanatobenzene was used as the compound of formula (III).
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was carried out, except that 2-phenylbenzo[d]oxazole-6-amine was used for the compound of formula (II), and 1-isocyanato-2-methyl was used for the compound of formula (III). Benzene.
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 is carried out, except that 2-phenylbenzo[d]oxazole-6-amine is used for the compound of formula (II), and 1-isocyanato-3-methyl is used for the compound of formula (III). Benzene.
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was carried out, except that 2-phenylbenzo[d]oxazole-6-amine was used for the compound of formula (II), and 1-isocyanato-4-methyl was used for the compound of formula (III). Benzene.
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was carried out, except that the compound of formula (II) used 2-phenylbenzo[d]oxazole-6-amine, and the compound of formula (III) used 1-isocyanato-2-( Trifluoromethyl)benzene.
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was carried out, except that the compound of formula (II) used 2-phenylbenzo[d]oxazole-6-amine, and the compound of formula (III) used 1-isocyanato-4-( Trifluoromethoxy)benzene.
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 is carried out, except that 2-phenylbenzo[d]oxazole-6-amine is used for the compound of formula (II), and 1-fluoro-4-isocyanate is used for the compound of formula (III). benzene.
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 is carried out, except that 2-phenylbenzo[d]oxazole-6-amine is used for the compound of formula (II), and 1-isocyanato-3-methyl is used for the compound of formula (III). Oxybenzene.
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was carried out, except that the compound of formula (II) used 2-phenylbenzo[d]oxazole-6-amine, and the compound of formula (III) used 1-isocyanato-3-( Trifluoromethyl)benzene.
- the NMR data are as follows:
- Example 1 The preparation process of Example 1 was carried out, except that the compound of formula (II) used 2-phenylbenzo[d]oxazole-6-amine, and the compound of formula (III) used 1-isocyanato-4-( Trifluoromethyl)benzene.
- the NMR data are as follows:
- the HEK293 cell line stably transduced with P2Y 14 R was purchased from Keygen Biotech. Approximately 24 hours before assay, cells were seeded in 384-well plates at a density of 10,000 cells per well. Prior to the assay, cells were briefly washed with phosphate-buffered saline solution to remove traces of serum, and then inoculated with 7.5 ⁇ L of induction buffer containing 30 ⁇ M Forskolin, 10 ⁇ M UDPG, and a 100 nM concentration of the test compound. Place at 37°C for 30 minutes and repeat 3 times.
- P2Y 14 R inhibitory activity was then assessed by detecting cAMP levels in HEK293 cell lysates using a cAMP-Glo TM Assay Kit (Promega, WI, USA) following the manufacturer's instructions. See Table 1 for test results.
- the drug-induced liver injury model was constructed by intraperitoneal injection of APAP (350 mg/kg).
- mice were sacrificed 24 hours after modeling, and the livers were separated. After being washed with physiological saline, they were fixed with 4% paraformaldehyde and then embedded in paraffin and sliced. The thickness of the slices was 4-8 ⁇ m. The slices were dewaxed in xylene and immersed in gradient ethanol. Carry out rehydration. Hydrated samples were washed with PBS and stained with hematoxylin for 10 minutes.
- distilled water absorbed excess staining solution, differentiated with 1% hydrochloric acid ethanol for a few seconds, rinsed with distilled water, reversed blue with 0.6% ammonia, rinsed with running water, and stained in eosin staining solution After 1-3 minutes, dehydrate the sections and seal them, and examine the tissue condition under a microscope.
- Gently shake the 96-well plate to mix, place it at room temperature for 15 minutes, set the wavelength to 510nm, measure the OD value of each well with the microplate reader, use the absolute value the OD value of the measurement well minus the OD value of the control well, check the standard curve, and obtain the corresponding ALT/AST vitality units.
- the new inhibitor of P2Y 14 R receptor I-1 and the positive drug PPTN were used to verify whether I-1 has the same effect as PPTN in alleviating acetaminophen liver damage.
- Different doses of I-1 (5 mg/kg, 10 mg/kg) and PPTN (5 mg/kg) were administered to the administration group 1 hour in advance.
- the test results are shown in Figure 1-2.
- Figure 1 shows the effects of different doses of I-1 (5 mg/kg, 10 mg/kg) and PPTN (5 mg/kg) on the liver function biochemical index AST of APAP model C57BL/6J mice.
- benzoxazole derivatives prepared in the present invention have good antagonistic activity related to P2Y 14 receptors.
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Abstract
The present invention provides a benzoxazole derivative, a preparation method therefor, and an application thereof. The benzoxazole derivative provided by the present invention has a structure as represented by formula (I). Experimental results show that the benzoxazole derivative provided by the present invention has good P2Y14 receptor antagonistic activity, and can be used for preparing a therapeutic drug for P2Y14 receptor related diseases.
Description
本申请要求于2022年06月06日提交中国专利局、申请号为202210628424.7、发明名称为“一种苯并恶唑衍生物及其制备方法和应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。This application requires the priority of the Chinese patent application submitted to the China Patent Office on June 6, 2022, with the application number 202210628424.7 and the invention title "A benzoxazole derivative and its preparation method and application", and its entire content incorporated herein by reference.
本发明涉及药物化学技术领域，特别涉及一种苯并恶唑衍生物及其制备方法和应用。The present invention relates to the technical field of medicinal chemistry, and in particular to a benzoxazole derivative and its preparation method and application.
P2Y
14受体(P2Y
14R)是P2Y受体的成员之一，其被尿苷5'-二磷酸葡萄糖(UDPG)和其他内源性UDP-糖类特异性激活后，可通过Gi/o蛋白抑制腺苷酸环化酶(AC)，从而减少细胞内3',5'-环腺苷单磷酸(cAMP)的产生。P2Y
14R广泛在心脏、胎盘、脂肪组织、胃肠道、骨髓和胸腺等组织和器官中表达，在免疫系统中尤其明显。当P2Y
14R受到激动时，能够促进肥大细胞释放介质和肾闰细胞炎症，提高小神经胶质细胞的超敏性和中性粒细胞的趋动性；并且能够抑制星形胶质细胞释放金属蛋白酶和肿瘤坏死因子。嘌呤受体P2Y
14在免疫细胞和组织中的高表达水平表明其作为炎症介质可能参与免疫炎症反应的调节。
P2Y 14 receptor (P2Y 14 R) is a member of the P2Y receptor. After being specifically activated by uridine 5'-diphosphate glucose (UDPG) and other endogenous UDP-sugar, it can pass Gi/o The protein inhibits adenylyl cyclase (AC), thereby reducing intracellular production of 3',5'-cyclic adenosine monophosphate (cAMP). P2Y 14 R is widely expressed in tissues and organs such as the heart, placenta, adipose tissue, gastrointestinal tract, bone marrow, and thymus, especially in the immune system. When P2Y 14 R is stimulated, it can promote the release of mediators from mast cells and inflammation of renal leap cells, increase the hypersensitivity of microglia and the motility of neutrophils; and can inhibit the release of metals from astrocytes Proteases and tumor necrosis factor. The high expression level of purinergic receptor P2Y 14 in immune cells and tissues indicates that it may participate in the regulation of immune inflammatory responses as an inflammatory mediator.
P2Y
14受体拮抗剂在急性痛风性关节炎、药源性肝损伤、急性肾损伤和神经疼痛等相关疾病药物开发领域有很好的创新性和应用前景。P2Y
14R激活与细胞内cAMP含量密切相关，而cAMP能阻止NLRP3炎性小体的活化，因此P2Y
14R可能通过NLRP3炎性小体对炎症反应进行调控。最新的研究证明了P2Y
14R在急性痛风性关节炎发病机理中的关键作用，能够通过调节NLRP3介导的巨噬细胞焦亡实现对炎症的缓解作用。在ICs中用选择性抑制剂阻断P2Y14R或消融P2Y
14R基因可减少肾脏炎症，减轻近端肾小管(PT)损伤，并改善肾脏IRI后的肾功能。即抑制ICs中的UDPG/P2Y
14R途径可在遭受缺血性损伤的肾脏炎症中起到保护作用。P2Y
14R的激活引起SGCs的激活，并且通过ERK和p38途径增加了IL-1β和CCL2的分泌。因此，SGCs中的P2Y
14R 可用作镇痛治疗三叉神经相关疼痛状态(例如偏头痛，神经损伤，颌面炎症等)的创新药物靶标。
P2Y 14 receptor antagonists have good innovation and application prospects in the field of drug development for related diseases such as acute gouty arthritis, drug-induced liver injury, acute kidney injury, and neural pain. P2Y 14 R activation is closely related to intracellular cAMP content, and cAMP can prevent the activation of NLRP3 inflammasome. Therefore, P2Y 14 R may regulate the inflammatory response through NLRP3 inflammasome. The latest research proves the key role of P2Y 14 R in the pathogenesis of acute gouty arthritis and its ability to alleviate inflammation by regulating NLRP3-mediated macrophage pyroptosis. Blocking P2Y14R with selective inhibitors or ablating the P2Y14R gene in ICs reduces renal inflammation, alleviates proximal tubular (PT) injury, and improves renal function after renal IRI. That is, inhibiting the UDPG/P2Y 14 R pathway in ICs can play a protective role in renal inflammation suffering from ischemic injury. Activation of P2Y 14 R causes the activation of SGCs and increases the secretion of IL-1β and CCL2 through the ERK and p38 pathways. Therefore, P2Y 14 R in SGCs can be used as an innovative drug target for analgesic treatment of trigeminal nerve-related pain conditions (such as migraine, nerve injury, maxillofacial inflammation, etc.).
苯并恶唑是现代药物发现中的重要药效团，大量苯并恶唑类化合物已经被成功开发，销售和广泛应用于预防和治疗各种疾病，其具有低毒性，高生物利用度，良好生物相容性和疗效。苯并恶唑类化合物具有广泛的生物活性。研究表明，苯并恶唑类杂环化合物具有很好的生物活性，由于具有独特的结构、低毒性和优良的生物活性，因此在化学、医学、生物学和材料科学等众多领域得到了广泛应用。利用活性叠加原理，在许多小分子药物中引入苯并恶唑基团后，其活性得到很大的提高。正是由于苯并恶唑类衍生物具有众多优良特性，使得它成为药物研发中的一大热点。Benzoxazole is an important pharmacophore in modern drug discovery. A large number of benzoxazole compounds have been successfully developed, sold and widely used in the prevention and treatment of various diseases. They have low toxicity, high bioavailability, and good Biocompatibility and efficacy. Benzoxazoles have a wide range of biological activities. Research shows that benzoxazole heterocyclic compounds have good biological activity. Due to their unique structure, low toxicity and excellent biological activity, they have been widely used in many fields such as chemistry, medicine, biology and materials science. . Using the principle of activity superposition, the activity of many small molecule drugs is greatly improved after the benzoxazole group is introduced. It is precisely because benzoxazole derivatives have many excellent properties that they have become a hot topic in drug research and development.
发明内容Contents of the invention
有鉴于此，本发明的目的在于提供一种苯并恶唑衍生物及其制备方法和应用。本发明提供的苯并恶唑衍生物具有较好的拮抗P2Y
14受体活性以及治疗P2Y
14受体相关疾病(如急性痛风性关节炎、药源性肝损伤、急性肾损伤和神经疼痛等)的活性。
In view of this, the object of the present invention is to provide a benzoxazole derivative and its preparation method and application. The benzoxazole derivatives provided by the invention have better antagonistic activity against P2Y 14 receptors and can treat P2Y 14 receptor-related diseases (such as acute gouty arthritis, drug-induced liver injury, acute kidney injury, neuralgia, etc.) activity.
本发明提供了一种苯并恶唑衍生物，具有式(I)所示结构：The invention provides a benzoxazole derivative having a structure represented by formula (I):
其中：in:
R
1选自：氢、未取代的烷基、未取代的芳基。其中的烷基优选为C1～C3的烷基。更优选的，R
1选自：氢、丙基或苯基。
R 1 is selected from: hydrogen, unsubstituted alkyl, unsubstituted aryl. The alkyl group is preferably a C1-C3 alkyl group. More preferably, R 1 is selected from: hydrogen, propyl or phenyl.
R
2选自：取代或未取代的烷基、取代或未取代的烷氧基、卤素。其中的烷基优选为C1～C3的烷基；其中的烷氧基为C1～C3的烷氧基。其中，取代的烷基中，取代基至少为一个，且各取代基独立的选自卤素(即当有多个取代基时，各取代基可以为相同的卤素或不同的卤素)。取代的烷氧基中，取代基至少为一个，且各取代基独立的选自卤素(即当有多个取代基时，各取代基可以为相同的卤素或不同的卤素)。更优选的，R
2选自：甲基、甲氧基、氟原子、氯原子、三氟甲基或三氟甲氧基。
R 2 is selected from: substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen. The alkyl group is preferably a C1-C3 alkyl group; the alkoxy group is preferably a C1-C3 alkoxy group. Wherein, in the substituted alkyl group, there is at least one substituent, and each substituent is independently selected from halogen (that is, when there are multiple substituents, each substituent can be the same halogen or different halogen). In the substituted alkoxy group, there is at least one substituent, and each substituent is independently selected from halogen (that is, when there are multiple substituents, each substituent can be the same halogen or different halogen). More preferably, R 2 is selected from: methyl, methoxy, fluorine atom, chlorine atom, trifluoromethyl or trifluoromethoxy.
在本发明的一些实施例中，所述苯并恶唑衍生物，具有以下任一结构：In some embodiments of the present invention, the benzoxazole derivative has any of the following structures:
本发明还提供了一种上述技术方案中所述的苯并恶唑衍生物的制备方法，包括以下步骤：The present invention also provides a preparation method of the benzoxazole derivative described in the above technical solution, which includes the following steps:
将式(II)结构的化合物和式(III)结构的化合物反应，得到式(I)所示的苯并恶唑衍生物；React a compound with a structure of formula (II) and a compound with a structure of formula (III) to obtain a benzoxazole derivative represented by formula (I);
其中，R
1、R
2的种类与前文技术方案中所述一致，在此不再一一赘述。
Among them, the types of R 1 and R 2 are consistent with those described in the previous technical solutions, and will not be repeated here.
上述制备方法的反应路线如下：The reaction route of the above preparation method is as follows:
其中，R
1、R
2的种类与前文技术方案中所述一致，在此不再一一赘述。
Among them, the types of R 1 and R 2 are consistent with those described in the previous technical solutions, and will not be repeated here.
本发明中，上述式(II)结构化合物∶式(III)结构化合物的摩尔比优选为1∶1.5。In the present invention, the molar ratio of the above-mentioned compound having the structure of formula (II): the compound having the structure of formula (III) is preferably 1:1.5.
本发明中，所述反应的温度优选为100～110℃，更优选为110℃。所述反应的时间优选为1h。In the present invention, the temperature of the reaction is preferably 100-110°C, and more preferably 110°C. The reaction time is preferably 1 hour.
本发明中，所述反应优选在有机溶剂介质中进行。所述有机溶剂优选为甲苯。In the present invention, the reaction is preferably carried out in an organic solvent medium. The organic solvent is preferably toluene.
本发明中，在上述制备过程中，优选先将式(II)化合物溶于溶剂中，然后升温至目标温度，而后再向体系中滴加式(III)化合物，之后再继续保温反应。In the present invention, in the above preparation process, it is preferred to dissolve the compound of formula (II) in a solvent first, then raise the temperature to the target temperature, and then drop the compound of formula (III) into the system, and then continue the heat preservation reaction.
本发明中，在上述反应后，优选还进行如下后处理：冷却析出沉淀并将沉淀物分离出来，再对沉淀物进行洗涤和干燥，从而得到纯净的式(I)所示的苯并恶唑衍生物。In the present invention, after the above reaction, the following post-processing is preferably carried out: cooling to precipitate and separate the precipitate, and then washing and drying the precipitate to obtain pure benzoxazole represented by formula (I) derivative.
本发明还提供了一种上述技术方案中所述的苯并恶唑衍生物或上述技术方案中所述的制备方法制得的苯并恶唑衍生物在制备治疗P2Y
14受体相关疾病的药物中的应用。其中，P2Y
14受体相关的疾病包括急性痛风性关节炎、药源性肝损伤、急性肾损伤或神经疼痛等疾病。
The present invention also provides a benzoxazole derivative described in the above technical solution or a benzoxazole derivative prepared by the preparation method described in the above technical solution in the preparation of drugs for treating P2Y 14 receptor related diseases. applications in. Among them, diseases related to P2Y 14 receptors include acute gouty arthritis, drug-induced liver injury, acute kidney injury or neuralgia.
本发明还提供了一种治疗P2Y
14受体相关疾病的药物，包括苯并恶唑衍生物以及辅料；
The invention also provides a drug for treating P2Y 14 receptor-related diseases, including benzoxazole derivatives and auxiliary materials;
其中，所述苯并恶唑衍生物为上述技术方案中所述的苯并恶唑衍生物或上 述技术方案中所述的制备方法制得的苯并恶唑衍生物。所述辅料为药学上可接受的辅料。Wherein, the benzoxazole derivative is the benzoxazole derivative described in the above technical solution or the benzoxazole derivative prepared by the preparation method described in the above technical solution. The excipients are pharmaceutically acceptable excipients.
本发明提供的上述药物还可以与其他治疗相关疾病药物联合使用。The above-mentioned medicines provided by the present invention can also be used in combination with other medicines for treating related diseases.
实验结果表明，本发明提供的苯并恶唑衍生物具有较好的治疗P2Y
14受体相关的炎症性疾病如急性痛风性关节炎、药源性肝损伤、急性肾损伤和神经疼痛等的活性。100nM浓度下苯并恶唑衍生物对P2Y
14R抑制率达到50％以上，对P2Y
14R有较好的抑制作用。对APAP造模C57BL/6J小鼠肝功能生化指标的影响的测试结果显示，本发明提供的化合物能够显著的下调血清中的AST及ALT水平，缓解对乙酰氨基酚引起的药源性肝损伤。HE染色检测结果显示，本发明提供的化合物能够使肝细胞气球样变性以及坏死显著缓解，肝脏汇管区组织形态改善，且炎症细胞浸润减少，证明其能够显著缓解APAP引起的肝脏损伤。
Experimental results show that the benzoxazole derivatives provided by the present invention have good activity in treating P2Y 14 receptor-related inflammatory diseases such as acute gouty arthritis, drug-induced liver injury, acute kidney injury, and neuralgia. . At a concentration of 100 nM, the inhibition rate of benzoxazole derivatives on P2Y 14 R reaches more than 50%, and it has a good inhibitory effect on P2Y 14 R. The test results of the impact on biochemical indicators of liver function in APAP model C57BL/6J mice show that the compounds provided by the invention can significantly reduce the levels of AST and ALT in serum and alleviate drug-induced liver damage caused by acetaminophen. HE staining test results show that the compound provided by the invention can significantly alleviate hepatocyte ballooning degeneration and necrosis, improve the tissue morphology of the liver portal area, and reduce inflammatory cell infiltration, proving that it can significantly alleviate liver damage caused by APAP.
图1为不同剂量的Ⅰ-1(5mg/kg，10mg/kg)、PPTN(5mg/kg)对APAP造模C57BL/6J小鼠肝功能生化指标AST的影响的效果图；Figure 1 shows the effects of different doses of I-1 (5 mg/kg, 10 mg/kg) and PPTN (5 mg/kg) on the liver function biochemical index AST in APAP model C57BL/6J mice;
图2为不同剂量的Ⅰ-1(5mg/kg，10mg/kg)、PPTN(5mg/kg)对APAP造模C57BL/6J小鼠肝功能生化指标ALT的影响的效果图；Figure 2 shows the effects of different doses of I-1 (5mg/kg, 10mg/kg) and PPTN (5mg/kg) on the biochemical index ALT of liver function in APAP model C57BL/6J mice;
图3为HE染色检测PPTN(5mg/kg)、Ⅰ-1(5mg/kg、10mg/kg)对APAP造模C57BL/6J小鼠肝脏组织的影响的效果图。Figure 3 shows the effect of HE staining on the liver tissue of APAP model C57BL/6J mice.
为了进一步理解本发明，下面结合实施例对本发明优选实施方案进行描述，但是应当理解，这些描述只是为进一步说明本发明的特征和优点，而不是对本发明权利要求的限制。In order to further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only to further illustrate the features and advantages of the present invention, rather than to limit the claims of the present invention.
实施例1：制备式(I-1)化合物Example 1: Preparation of compound of formula (I-1)
1-(苯并[d]恶唑-6-基)-3-(2-甲氧基苯基)脲的合成：Synthesis of 1-(benzo[d]oxazol-6-yl)-3-(2-methoxyphenyl)urea:
将苯并[d]恶唑-6-胺(0.134g,1mmol)溶于甲苯(10mL)，升温至110℃。在 反应混合物中滴加入1-异氰酸根-2-甲氧基苯(0.2mL,1.5mmol)，将得到的溶液回流搅拌1h，放冷析出沉淀，过滤沉淀，用二氯甲烷洗涤沉淀，干燥，得到纯净目标产物。Benzo[d]oxazole-6-amine (0.134g, 1mmol) was dissolved in toluene (10mL), and the temperature was raised to 110°C. Add 1-isocyanato-2-methoxybenzene (0.2 mL, 1.5 mmol) dropwise to the reaction mixture, stir the resulting solution under reflux for 1 hour, let it cool to precipitate, filter the precipitate, wash the precipitate with dichloromethane, and dry , to obtain the pure target product.
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ9.44(s,1H),9.23(s,1H),8.38(d,J＝9.1Hz,1H),8.09(dd,J＝8.0,1.5Hz,1H),7.75(dd,J＝9.1,2.6Hz,1H),7.67(d,J＝2.6Hz,1H),7.03(dd,J＝8.1,1.7Hz,1H),7.01–6.96(m,1H),6.91(td,J＝7.7,1.7Hz,1H),3.87(s,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ9.44 (s, 1H), 9.23 (s, 1H), 8.38 (d, J = 9.1Hz, 1H), 8.09 (dd, J = 8.0, 1.5Hz, 1H),7.75(dd,J＝9.1,2.6Hz,1H),7.67(d,J＝2.6Hz,1H),7.03(dd,J＝8.1,1.7Hz,1H),7.01–6.96(m,1H ),6.91(td,J＝7.7,1.7Hz,1H),3.87(s,3H).
13C NMR(101MHz,DMSO-d
6)δ152.28,148.47,145.59,140.57,135.60,128.22,122.59,120.45,119.44,117.00,115.88,110.95,108.56,55.71,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
13 C NMR (101MHz, DMSO-d 6 ) δ152.28,148.47,145.59,140.57,135.60,128.22,122.59,120.45,119.44,117.00,115.88,110.95,108.56,55.71,40.15 ,39.94,39.73,39.52,39.31,39.10 ,38.89.
实施例2：制备式(I-2)化合物Example 2: Preparation of compound of formula (I-2)
1-(苯并[d]恶唑-6-基)-3-(3-氯苯基)脲的合成：Synthesis of 1-(benzo[d]oxazol-6-yl)-3-(3-chlorophenyl)urea:
按照实施例1的制备过程进行，不同的是，式(III)化合物采用1-氯-3-异氰酸酯苯。The preparation process of Example 1 was followed, except that 1-chloro-3-isocyanatobenzene was used as the compound of formula (III).
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ9.77(s,1H),8.77(s,1H),8.36(d,J＝9.1Hz,1H),7.78–7.73(m,2H),7.67(d,J＝2.6Hz,1H),7.33(t,J＝8.0Hz,1H),7.24(dd,J＝7.9,5.9Hz,1H),7.06(ddd,J＝7.9,1.9,0.9Hz,1H).
1 H NMR (400MHz, DMSO-d 6 ) δ9.77 (s, 1H), 8.77 (s, 1H), 8.36 (d, J = 9.1Hz, 1H), 7.78–7.73 (m, 2H), 7.67 ( d,J＝2.6Hz,1H),7.33(t,J＝8.0Hz,1H),7.24(dd,J＝7.9,5.9Hz,1H),7.06(ddd,J＝7.9,1.9,0.9Hz,1H ).
13C NMR(101MHz,DMSO-d
6)δ151.80,145.31,140.84,140.77,134.97,133.33,130.52,128.89,128.19,121.95,117.55,116.62,115.95,108.51,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
13 C NMR (101MHz, DMSO-d 6 ) δ151.80,145.31,140.84,140.77,134.97,133.33,130.52,128.89,128.19,121.95,117.55,116.62,115.95,108.51,40.1 5,39.94,39.73,39.52,39.31,39.10 ,38.89.
实施例3：制备式(I-3)化合物Example 3: Preparation of compound of formula (I-3)
1-(苯并[d]恶唑-6-基)-3-(2-氯苯基)脲的合成：Synthesis of 1-(benzo[d]oxazol-6-yl)-3-(2-chlorophenyl)urea:
按照实施例1的制备过程进行，不同的是，式(III)化合物采用1-氯-2-异氰酸酯苯。The preparation process of Example 1 was followed, except that 1-chloro-2-isocyanatobenzene was used as the compound of formula (III).
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ9.51(s,1H),9.26(s,1H),8.37(d,J＝9.1Hz,1H),8.07(d,J＝7.7Hz,1H),7.75(dd,J＝9.1,2.5Hz,1H),7.68(d,J＝2.5Hz,1H),7.47(d,J＝7.9Hz,1H),7.32(t,J＝7.7Hz,1H),7.08(t,J＝7.3Hz,1H).
1 H NMR (400MHz, DMSO-d 6 ) δ9.51 (s, 1H), 9.26 (s, 1H), 8.37 (d, J = 9.1Hz, 1H), 8.07 (d, J = 7.7Hz, 1H) ,7.75(dd,J＝9.1,2.5Hz,1H),7.68(d,J＝2.5Hz,1H),7.47(d,J＝7.9Hz,1H),7.32(t,J＝7.7Hz,1H) ,7.08(t,J＝7.3Hz,1H).
13C NMR(101MHz,DMSO-d
6)δ152.11,145.70,140.90,135.55,135.14,129.35,127.46,124.11,123.12,122.73,117.19,115.82,108.61,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
13 C NMR (101MHz, DMSO-d 6 ) δ152.11,145.70,140.90,135.55,135.14,129.35,127.46,124.11,123.12,122.73,117.19,115.82,108.61,40.15,39.94 ,39.73,39.52,39.31,39.10,38.89 .
实施例4：制备式(I-4)化合物Example 4: Preparation of compound of formula (I-4)
1-(苯并[d]恶唑-6-基)-3-(4-氯苯基)脲的合成：Synthesis of 1-(benzo[d]oxazol-6-yl)-3-(4-chlorophenyl)urea:
按照实施例1的制备过程进行，不同的是，式(III)化合物采用1-氯-4-异氰酸酯苯。The preparation process of Example 1 was followed, except that 1-chloro-4-isocyanatobenzene was used as the compound of formula (III).
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ9.71(s,1H),8.74(s,1H),8.36(d,J＝9.1Hz,1H),7.76(dd,J＝9.1,2.4Hz,1H),7.67(d,J＝2.4Hz,1H),7.50(d,J＝8.8Hz,2H),7.36(d,J＝8.8Hz,2H).
1 H NMR (400MHz, DMSO-d 6 ) δ9.71 (s, 1H), 8.74 (s, 1H), 8.36 (d, J = 9.1 Hz, 1H), 7.76 (dd, J = 9.1, 2.4 Hz, 1H),7.67(d,J＝2.4Hz,1H),7.50(d,J＝8.8Hz,2H),7.36(d,J＝8.8Hz,2H).
13C NMR(101MHz,DMSO-d
6)δ151.81,145.25,140.74,138.23,135.11,128.76,125.85,119.69,116.49,115.97,108.49,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
13 C NMR (101MHz, DMSO-d 6 ) δ151.81,145.25,140.74,138.23,135.11,128.76,125.85,119.69,116.49,115.97,108.49,40.15,39.94,39.73,39.52,3 9.31,39.10,38.89.
实施例5：制备式(I-5)化合物Example 5: Preparation of compound of formula (I-5)
1-(苯并[d]恶唑-6-基)-3-(邻甲苯基)脲的合成：Synthesis of 1-(benzo[d]oxazol-6-yl)-3-(o-tolyl)urea:
按照实施例1的制备过程进行，不同的是，式(III)化合物采用1-异氰酸根-2-甲基苯。The preparation process of Example 1 was followed, except that 1-isocyanato-2-methylbenzene was used as the compound of formula (III).
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ9.16(s,1H),8.82(s,1H),8.38(d,J＝9.1Hz,1H),7.81–7.72(m,2H),7.68(d,J＝2.3Hz,1H),7.17(dd,J＝16.1,7.8Hz,2H),6.99(t,J＝7.4Hz,1H),2.26(s,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ9.16 (s, 1H), 8.82 (s, 1H), 8.38 (d, J = 9.1Hz, 1H), 7.81–7.72 (m, 2H), 7.68 ( d,J＝2.3Hz,1H),7.17(dd,J＝16.1,7.8Hz,2H),6.99(t,J＝7.4Hz,1H),2.26(s,3H).
13C NMR(101MHz,DMSO-d
6)δ152.33,145.31,140.51,136.85,135.60,130.28,128.37,126.10,123.30,121.87,116.68,115.97,108.51,40.15,39.94,39.73,39.52,39.31,39.10,38.89,18.05.
13 C NMR (101MHz, DMSO-d 6 ) δ152.33,145.31,140.51,136.85,135.60,130.28,128.37,126.10,123.30,121.87,116.68,115.97,108.51,40.15,39.94 ,39.73,39.52,39.31,39.10,38.89 ,18.05.
实施例6：制备式(I-6)化合物Example 6: Preparation of compound of formula (I-6)
1-(苯并[d]恶唑-6-基)-3-(间甲苯基)脲的合成：Synthesis of 1-(benzo[d]oxazol-6-yl)-3-(m-tolyl)urea:
按照实施例1的制备过程进行，不同的是，式(III)化合物采用1-异氰酸根-3-甲基苯。The preparation process of Example 1 was followed, except that 1-isocyanato-3-methylbenzene was used as the compound of formula (III).
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ9.51(s,1H),8.73(s,1H),8.37(d,J＝9.1Hz,1H),7.75(dd,J＝9.1,2.4Hz,1H),7.67(d,J＝2.4Hz,1H),7.32(s,1H),7.25(d,J＝8.2Hz,1H),7.18(t,J＝7.7Hz,1H),6.83(d,J＝7.3Hz,1H),2.29(s,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ9.51 (s, 1H), 8.73 (s, 1H), 8.37 (d, J = 9.1 Hz, 1H), 7.75 (dd, J = 9.1, 2.4 Hz, 1H),7.67(d,J＝2.4Hz,1H),7.32(s,1H),7.25(d,J＝8.2Hz,1H),7.18(t,J＝7.7Hz,1H),6.83(d, J＝7.3Hz,1H),2.29(s,3H).
13C NMR(101MHz,DMSO-d
6)δ151.89,145.17,140.56,139.17,138.10,135.38,128.73,123.05,118.72,116.40,116.00,115.39,108.46,40.15,39.94,39.73,39.52,39.31,39.10,38.89,21.21.
13 C NMR (101MHz, DMSO-d 6 ) δ151.89,145.17,140.56,139.17,138.10,135.38,128.73,123.05,118.72,116.40,116.00,115.39,108.46,40.15,39.94 ,39.73,39.52,39.31,39.10,38.89 ,21.21.
实施例7：制备式(I-7)化合物Example 7: Preparation of compound of formula (I-7)
1-(苯并[d]恶唑-6-基)-3-(2-(三氟甲基)苯基)脲的合成：Synthesis of 1-(benzo[d]oxazol-6-yl)-3-(2-(trifluoromethyl)phenyl)urea:
按照实施例1的制备过程进行，不同的是，式(III)化合物采用1-异氰酸根-2-(三氟甲基)苯。The preparation process of Example 1 was followed, except that 1-isocyanato-2-(trifluoromethyl)benzene was used as the compound of formula (III).
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ9.41(s,1H),9.07(s,1H),8.35(d,J＝9.1 Hz,1H),7.82(d,J＝8.2Hz,1H),7.77–7.69(m,2H),7.67(dd,J＝12.9,4.8Hz,2H),7.35(t,J＝7.6Hz,1H).
1 H NMR (400MHz, DMSO-d 6 ) δ9.41 (s, 1H), 9.07 (s, 1H), 8.35 (d, J = 9.1 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H) ,7.77–7.69(m,2H),7.67(dd,J＝12.9,4.8Hz,2H),7.35(t,J＝7.6Hz,1H).
13C NMR(101MHz,DMSO-d6)δ152.59,145.58,140.88,135.68,135.19,132.84,127.43,126.01,125.96,124.68,121.61,121.32,117.07,115.84,108.61,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
13 C NMR (101MHz, DMSO-d6) δ152.59,145.58,140.88,135.68,135.19,132.84,127.43,126.01,125.96,124.68,121.61,121.32,117.07,115.84,108.6 1,40.15,39.94,39.73,39.52,39.31, 39.10,38.89.
实施例8：制备式(I-8)化合物Example 8: Preparation of compound of formula (I-8)
1-(苯并[d]恶唑-6-基)-3-(对甲苯基)脲的合成：Synthesis of 1-(benzo[d]oxazol-6-yl)-3-(p-tolyl)urea:
按照实施例1的制备过程进行，不同的是，式(III)化合物采用1-异氰酸根-4-甲苯。The preparation process of Example 1 was followed, except that 1-isocyanato-4-toluene was used as the compound of formula (III).
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),8.69(s,1H),8.37(d,J＝9.1Hz,1H),7.75(dd,J＝9.1,2.5Hz,1H),7.66(d,J＝2.5Hz,1H),7.35(d,J＝8.3Hz,2H),7.11(d,J＝8.2Hz,2H),2.25(s,3H).
1 H NMR (400MHz, DMSO-d6) δ9.48(s,1H),8.69(s,1H),8.37(d,J＝9.1Hz,1H),7.75(dd,J＝9.1,2.5Hz,1H ),7.66(d,J＝2.5Hz,1H),7.35(d,J＝8.3Hz,2H),7.11(d,J＝8.2Hz,2H),2.25(s,3H).
13C NMR(101MHz,DMSO-d6)δ151.92,145.14,140.50,136.67,135.46,131.19,129.29,118.28,116.35,116.02,108.45,40.15,39.94,39.73,39.52,39.31,39.10,38.89,20.35.
13 C NMR (101MHz, DMSO-d6) δ151.92,145.14,140.50,136.67,135.46,131.19,129.29,118.28,116.35,116.02,108.45,40.15,39.94,39.73,39.52,39 .31,39.10,38.89,20.35.
实施例9：制备式(I-9)化合物Example 9: Preparation of compound of formula (I-9)
1-(苯并[d]恶唑-6-基)-3-(4-(三氟甲氧基)苯基)脲的合成：Synthesis of 1-(benzo[d]oxazol-6-yl)-3-(4-(trifluoromethoxy)phenyl)urea:
按照实施例1的制备过程进行，不同的是，式(III)化合物采用1-异氰酸根-4-(三氟甲氧基)苯。The preparation process of Example 1 was followed, except that 1-isocyanato-4-(trifluoromethoxy)benzene was used as the compound of formula (III).
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ11.13(s,1H),9.78(s,1H),8.75(s,1H),8.37(d,J＝9.1Hz,1H),7.76(dd,J＝9.1,2.6Hz,1H),7.67(d,J＝2.6Hz,1H),7.60–7.55(m,2H),7.31(d,J＝8.4Hz,2H).
1 H NMR (400MHz, DMSO-d 6 ) δ11.13 (s, 1H), 9.78 (s, 1H), 8.75 (s, 1H), 8.37 (d, J = 9.1Hz, 1H), 7.76 (dd, J＝9.1,2.6Hz,1H),7.67(d,J＝2.6Hz,1H),7.60–7.55(m,2H),7.31(d,J＝8.4Hz,2H).
13C NMR(101MHz,DMSO-d6)δ151.87,145.27,142.93,140.78,138.52,135.09,121.83,121.45,119.38,118.91,116.52,115.96,108.50,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
13 C NMR (101MHz, DMSO-d6) δ151.87,145.27,142.93,140.78,138.52,135.09,121.83,121.45,119.38,118.91,116.52,115.96,108.50,40.15,39.94, 39.73,39.52,39.31,39.10,38.89.
实施例10：制备式(I-10)化合物Example 10: Preparation of compounds of formula (I-10)
1-(苯并[d]恶唑-6-基)-3-(4-氟苯基)脲的合成：Synthesis of 1-(benzo[d]oxazol-6-yl)-3-(4-fluorophenyl)urea:
按照实施例1的制备过程进行，不同的是，式(III)化合物采用1-氟-4-异氰酸苯。The preparation process of Example 1 was followed, except that 1-fluoro-4-benzene isocyanate was used as the compound of formula (III).
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ11.10(s,1H),9.62(s,1H),8.71(s,1H),8.36(d,J＝9.1Hz,1H),7.76(dd,J＝9.1,2.6Hz,1H),7.67(d,J＝2.6Hz,1H),7.51–7.45(m,2H),7.18–7.12(m,2H).
1 H NMR (400MHz, DMSO-d 6 ) δ11.10 (s, 1H), 9.62 (s, 1H), 8.71 (s, 1H), 8.36 (d, J = 9.1Hz, 1H), 7.76 (dd, J＝9.1,2.6Hz,1H),7.67(d,J＝2.6Hz,1H),7.51–7.45(m,2H),7.18–7.12(m,2H).
13C NMR(101MHz,DMSO-d6)δ158.76,156.39,151.96,145.18,140.63,135.58,135.28,119.96,119.88,116.42,116.00,115.55,115.33,108.48,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
13 C NMR (101MHz, DMSO-d6) δ158.76,156.39,151.96,145.18,140.63,135.58,135.28,119.96,119.88,116.42,116.00,115.55,115.33,108.48,40.15 ,39.94,39.73,39.52,39.31,39.10, 38.89.
实施例11：制备式(I-11)化合物Example 11: Preparation of compound of formula (I-11)
1-(苯并[d]恶唑-6-基)-3-(3-甲氧基苯基)脲的合成：Synthesis of 1-(benzo[d]oxazol-6-yl)-3-(3-methoxyphenyl)urea:
按照实施例1的制备过程进行，不同的是，式(III)化合物采用1-异氰酸根-3-甲氧基苯。The preparation process of Example 1 was followed, except that 1-isocyanato-3-methoxybenzene was used as the compound of formula (III).
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ11.10(s,1H),9.60(s,1H),8.73(s,1H),8.38(d,J＝9.1Hz,1H),7.76(dd,J＝9.1,2.6Hz,1H),7.67(d,J＝2.6Hz,1H),7.21(dt,J＝11.2,5.5Hz,2H),6.96–6.92(m,1H),6.59(ddd,J＝8.2,2.4,0.6Hz,1H),3.75(s,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ11.10 (s, 1H), 9.60 (s, 1H), 8.73 (s, 1H), 8.38 (d, J = 9.1Hz, 1H), 7.76 (dd, J＝9.1,2.6Hz,1H),7.67(d,J＝2.6Hz,1H),7.21(dt,J＝11.2,5.5Hz,2H),6.96–6.92(m,1H),6.59(ddd,J =8.2,2.4,0.6Hz,1H),3.75(s,3H).
13C NMR(101MHz,DMSO-d6)δ159.73,151.85,145.20,140.63,140.46, 135.27,129.68,116.46,116.01,110.49,108.47,107.77,103.93,54.94,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
13 C NMR (101MHz, DMSO-d6) δ159.73,151.85,145.20,140.63,140.46, 135.27,129.68,116.46,116.01,110.49,108.47,107.77,103.93,54.94,40.15 ,39.94,39.73,39.52,39.31,39.10, 38.89.
实施例12：制备式(I-12)化合物Example 12: Preparation of compound of formula (I-12)
1-(苯并[d]恶唑-6-基)-3-(4-甲氧基苯基)脲的合成：Synthesis of 1-(benzo[d]oxazol-6-yl)-3-(4-methoxyphenyl)urea:
按照实施例1的制备过程进行，不同的是，式(III)化合物采用1-异氰酸根-4-甲氧基苯。The preparation process of Example 1 was followed, except that 1-isocyanato-4-methoxybenzene was used as the compound of formula (III).
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ11.06(s,1H),9.41(s,1H),8.65(s,1H),8.37(d,J＝9.1Hz,1H),7.75(dd,J＝9.1,2.6Hz,1H),7.67(d,J＝2.6Hz,1H),7.40–7.36(m,2H),6.92–6.87(m,2H),3.73(s,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ11.06 (s, 1H), 9.41 (s, 1H), 8.65 (s, 1H), 8.37 (d, J = 9.1Hz, 1H), 7.75 (dd, J＝9.1,2.6Hz,1H),7.67(d,J＝2.6Hz,1H),7.40–7.36(m,2H),6.92–6.87(m,2H),3.73(s,3H).
13C NMR(101MHz,DMSO-d6)δ154.77,152.01,145.07,140.42,135.57,132.24,119.94,116.28,116.05,114.11,108.44,55.18,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
13 C NMR (101MHz, DMSO-d6) δ154.77,152.01,145.07,140.42,135.57,132.24,119.94,116.28,116.05,114.11,108.44,55.18,40.15,39.94,39.73,39 .52,39.31,39.10,38.89.
实施例13：制备式(I-13)化合物Example 13: Preparation of compound of formula (I-13)
1-(苯并[d]恶唑-6-基)-3-(3-(三氟甲基)苯基)脲的合成：Synthesis of 1-(benzo[d]oxazol-6-yl)-3-(3-(trifluoromethyl)phenyl)urea:
按照实施例1的制备过程进行，不同的是，式(III)化合物采用1-异氰酸根-3-(三氟甲基)苯。The preparation process of Example 1 was followed, except that 1-isocyanato-3-(trifluoromethyl)benzene was used as the compound of formula (III).
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ11.16(s,1H),9.93(s,1H),8.79(s,1H),8.39–8.36(m,1H),8.04(s,1H),7.76(dd,J＝9.1,2.6Hz,1H),7.68(d,J＝2.6Hz,1H),7.55(dd,J＝3.4,1.7Hz,2H),7.35(ddd,J＝3.3,1.9,0.9Hz,1H).
1 H NMR (400MHz, DMSO-d 6 ) δ11.16(s,1H),9.93(s,1H),8.79(s,1H),8.39–8.36(m,1H),8.04(s,1H), 7.76(dd,J＝9.1,2.6Hz,1H),7.68(d,J＝2.6Hz,1H),7.55(dd,J＝3.4,1.7Hz,2H),7.35(ddd,J＝3.3,1.9, 0.9Hz,1H).
13C NMR(101MHz,DMSO-d6)δ151.92,145.33,140.90,140.09,134.88,130.08,129.82,129.51,121.76,118.59,116.66,115.93,114.04,114.00,108.52,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
13 C NMR (101MHz, DMSO-d6) δ151.92,145.33,140.90,140.09,134.88,130.08,129.82,129.51,121.76,118.59,116.66,115.93,114.04,114.00,108.5 2,40.15,39.94,39.73,39.52,39.31, 39.10,38.89.
实施例14：制备式(I-14)化合物Example 14: Preparation of compounds of formula (I-14)
1-(苯并[d]恶唑-6-基)-3-(4-(三氟甲基)苯基)脲的合成：Synthesis of 1-(benzo[d]oxazol-6-yl)-3-(4-(trifluoromethyl)phenyl)urea:
按照实施例1的制备过程进行，不同的是，式(III)化合物采用1-异氰酸根-4-(三氟甲基)苯。The preparation process of Example 1 was followed, except that 1-isocyanato-4-(trifluoromethyl)benzene was used as the compound of formula (III).
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ11.20(s,1H),10.00(s,1H),8.86(s,1H),8.41(d,J＝9.1Hz,1H),7.80(dd,J＝9.1,2.6Hz,1H),7.73–7.69(m,5H).
1 H NMR (400MHz, DMSO-d 6 ) δ11.20 (s, 1H), 10.00 (s, 1H), 8.86 (s, 1H), 8.41 (d, J = 9.1Hz, 1H), 7.80 (dd, J＝9.1,2.6Hz,1H),7.73–7.69(m,5H).
13C NMR(101MHz,DMSO-d6)δ151.75,145.38,142.97,140.95,134.85,126.21,126.18,125.83,117.90,116.66,115.92,108.54,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
13 C NMR (101MHz, DMSO-d6) δ151.75,145.38,142.97,140.95,134.85,126.21,126.18,125.83,117.90,116.66,115.92,108.54,40.15,39.94,39.73,3 9.52,39.31,39.10,38.89.
实施例15：制备式(I-15)化合物Example 15: Preparation of compound of formula (I-15)
1-(2-甲氧基苯基)-3-(2-丙基苯并[d]恶唑-6-基)脲的合成：Synthesis of 1-(2-methoxyphenyl)-3-(2-propylbenzo[d]oxazol-6-yl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-丙基苯并[d]恶唑-6-胺，式(III)化合物采用1-异氰酸根-2-甲氧基苯。The preparation process of Example 1 is carried out, except that 2-propylbenzo[d]oxazole-6-amine is used for the compound of formula (II), and 1-isocyanato-2-methyl is used for the compound of formula (III). Oxybenzene.
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ9.53(s,1H),8.27(s,1H),8.15(dd,J＝7.8,1.8Hz,1H),8.01(d,J＝1.8Hz,1H),7.56(d,J＝8.5Hz,1H),7.16(dd,J＝8.6,2.0Hz,1H),7.06–6.86(m,4H),2.87(t,J＝7.3Hz,2H),1.81(q,J＝7.4Hz,2H),0.98(t,J＝7.4Hz,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ9.53 (s, 1H), 8.27 (s, 1H), 8.15 (dd, J = 7.8, 1.8Hz, 1H), 8.01 (d, J = 1.8Hz, 1H),7.56(d,J＝8.5Hz,1H),7.16(dd,J＝8.6,2.0Hz,1H),7.06–6.86(m,4H),2.87(t,J＝7.3Hz,2H), 1.81(q,J＝7.4Hz,2H),0.98(t,J＝7.4Hz,3H).
13C NMR(101MHz,DMSO-d6)δ165.86,152.43,150.65,147.66,137.16,135.47,128.55,121.90,120.57,118.99,118.34,114.93,110.73,99.91,55.78,40.15,39.94,39.73,39.52,39.31,39.10,38.89,29.57,19.66,13.50.
13 C NMR (101MHz, DMSO-d6) δ165.86,152.43,150.65,147.66,137.16,135.47,128.55,121.90,120.57,118.99,118.34,114.93,110.73,99.91,55.78, 40.15,39.94,39.73,39.52,39.31, 39.10,38.89,29.57,19.66,13.50.
实施例16：制备式(I-16)化合物Example 16: Preparation of compound of formula (I-16)
1-(3-氯苯基)-3-(2-丙基苯并[d]恶唑-6-基)脲的合成：Synthesis of 1-(3-chlorophenyl)-3-(2-propylbenzo[d]oxazol-6-yl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-丙基苯并[d]恶唑-6-胺，式(III)化合物采用1-氯-3-异氰酸酯苯。The preparation process of Example 1 was followed, except that 2-propylbenzo[d]oxazole-6-amine was used for the compound of formula (II) and 1-chloro-3-isocyanatobenzene was used for the compound of formula (III).
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ8.95(d,J＝19.4Hz,2H),7.96(d,J＝1.9Hz,1H),7.73(s,1H),7.57(d,J＝8.5Hz,1H),7.32–7.27(m,2H),7.21(dd,J＝8.6,1.9Hz,1H),7.03(dt,J＝7.1,2.0Hz,1H),2.88(d,J＝14.7Hz,2H),1.81(q,J＝7.4Hz,2H),0.98(t,J＝7.4Hz,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ8.95 (d, J＝19.4Hz, 2H), 7.96 (d, J＝1.9Hz, 1H), 7.73 (s, 1H), 7.57 (d, J＝ 8.5Hz,1H),7.32–7.27(m,2H),7.21(dd,J＝8.6,1.9Hz,1H),7.03(dt,J＝7.1,2.0Hz,1H),2.88(d,J＝14.7 Hz, 2H), 1.81 (q, J = 7.4Hz, 2H), 0.98 (t, J = 7.4Hz, 3H).
13C NMR(101MHz,DMSO-d6)δ166.03,152.45,150.55,141.18,136.68,135.77,133.20,130.40,121.52,118.93,117.63,116.72,115.47,100.51,40.15,39.94,39.73,39.52,39.31,39.10,38.89,29.57,19.65,13.49.
13 C NMR (101MHz, DMSO-d6) δ166.03,152.45,150.55,141.18,136.68,135.77,133.20,130.40,121.52,118.93,117.63,116.72,115.47,100.51,40.15 ,39.94,39.73,39.52,39.31,39.10, 38.89,29.57,19.65,13.49.
实施例17：制备式(I-17)化合物Example 17: Preparation of compound of formula (I-17)
1-(4-氯苯基)-3-(2-丙基苯并[d]恶唑-6-基)脲的合成：Synthesis of 1-(4-chlorophenyl)-3-(2-propylbenzo[d]oxazol-6-yl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-丙基苯并[d]恶唑-6-胺，式(III)化合物采用1-氯-4-异氰酸酯苯。The preparation process of Example 1 was followed, except that 2-propylbenzo[d]oxazole-6-amine was used for the compound of formula (II) and 1-chloro-4-isocyanatobenzene was used for the compound of formula (III).
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ8.92(s,1H),8.84(s,1H),7.95(d,J＝1.8Hz,1H),7.56(d,J＝8.5Hz,1H),7.50(d,J＝2.1Hz,1H),7.49(d,J＝2.1Hz,1H),7.34(d,J＝2.1Hz,1H),7.32(d,J＝2.0Hz,1H),7.20(dd,J＝8.6,2.0Hz,1H),2.86(d,J＝7.4Hz,2H),1.80(q,J＝7.4Hz,2H),0.97(t,J＝7.4Hz,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ8.92 (s, 1H), 8.84 (s, 1H), 7.95 (d, J = 1.8Hz, 1H), 7.56 (d, J = 8.5Hz, 1H) ,7.50(d,J＝2.1Hz,1H),7.49(d,J＝2.1Hz,1H),7.34(d,J＝2.1Hz,1H),7.32(d,J＝2.0Hz,1H),7.20 (dd,J＝8.6,2.0Hz,1H),2.86(d,J＝7.4Hz,2H),1.80(q,J＝7.4Hz,2H),0.97(t,J＝7.4Hz,3H).
13C NMR(101MHz,DMSO-d6)δ166.13,152.62,150.64,138.67,136.87,135.77,128.73,125.57,119.94,119.01,115.53,100.54,40.15,39.94,39.73,39.52,39.31,39.10,38.89,29.65,19.74,13.57.
13 C NMR (101MHz, DMSO-d6) δ166.13,152.62,150.64,138.67,136.87,135.77,128.73,125.57,119.94,119.01,115.53,100.54,40.15,39.94,39.73,3 9.52,39.31,39.10,38.89,29.65, 19.74,13.57.
实施例18：制备式(I-18)化合物Example 18: Preparation of compound of formula (I-18)
1-(2-丙基苯并[d]恶唑-6-基)-3-(间甲苯基)脲的合成：Synthesis of 1-(2-propylbenzo[d]oxazol-6-yl)-3-(m-tolyl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-丙基苯并[d]恶唑-6-胺，式(III)化合物采用1-异氰酸根-3-甲基苯。The preparation process of Example 1 was carried out, except that 2-propylbenzo[d]oxazole-6-amine was used for the compound of formula (II), and 1-isocyanato-3-methyl was used for the compound of formula (III). Benzene.
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ8.87(s,1H),8.62(s,1H),7.98(s,1H),7.56(d,J＝8.5Hz,1H),7.31(s,1H),7.25(d,J＝7.9Hz,1H),7.21–7.14(m,2H),6.80(d,J＝7.2Hz,1H),2.88(t,J＝7.3Hz,2H),2.29(s,3H),1.82(dt,J＝14.6,7.2Hz,2H),0.98(t,J＝7.3Hz,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ8.87 (s, 1H), 8.62 (s, 1H), 7.98 (s, 1H), 7.56 (d, J = 8.5Hz, 1H), 7.31 (s, 1H),7.25(d,J＝7.9Hz,1H),7.21–7.14(m,2H),6.80(d,J＝7.2Hz,1H),2.88(t,J＝7.3Hz,2H),2.29( s,3H),1.82(dt,J＝14.6,7.2Hz,2H),0.98(t,J＝7.3Hz,3H).
13C NMR(101MHz,DMSO-d6)δ165.88,152.57,150.60,139.51,137.96,137.05,135.52,128.63,122.66,118.90,118.77,115.46,115.22,100.19,40.15,39.94,39.73,39.52,39.31,39.10,38.89,29.57,21.23,19.66,13.49,-19.92.
13 C NMR (101MHz, DMSO-d6) δ165.88,152.57,150.60,139.51,137.96,137.05,135.52,128.63,122.66,118.90,118.77,115.46,115.22,100.19,40.15 ,39.94,39.73,39.52,39.31,39.10, 38.89,29.57,21.23,19.66,13.49,-19.92.
实施例19：制备式(I-19)化合物Example 19: Preparation of compound of formula (I-19)
1-(2-丙基苯并[d]恶唑-6-基)-3-(对甲苯基)脲的合成：Synthesis of 1-(2-propylbenzo[d]oxazol-6-yl)-3-(p-tolyl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-丙基苯并[d]恶唑-6-胺，式(III)化合物采用1-异氰酸根-4-甲苯。The preparation process of Example 1 is carried out, except that 2-propylbenzo[d]oxazole-6-amine is used for the compound of formula (II), and 1-isocyanato-4-toluene is used for the compound of formula (III). .
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ8.84(s,1H),8.59(s,1H),7.97(d,J＝1.7Hz,1H),7.55(d,J＝8.5Hz,1H),7.35(d,J＝8.4Hz,2H),7.18(dd,J＝8.5,1.9Hz,1H),7.10(d,J＝8.2Hz,2H),2.88(t,J＝7.3Hz,2H),2.25(s,3H),1.81(dd,J＝14.7,7.4Hz,2H),0.98(t,J＝7.4Hz,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ8.84 (s, 1H), 8.59 (s, 1H), 7.97 (d, J = 1.7Hz, 1H), 7.55 (d, J = 8.5Hz, 1H) ,7.35(d,J＝8.4Hz,2H),7.18(dd,J＝8.5,1.9Hz,1H),7.10(d,J＝8.2Hz,2H),2.88(t,J＝7.3Hz,2H) ,2.25(s,3H),1.81(dd,J＝14.7,7.4Hz,2H),0.98(t,J＝7.4Hz,3H).
13C NMR(101MHz,DMSO-d6)δ165.84,152.63,150.60,137.13,137.00,135.46,130.73,129.18,118.89,118.37,115.19,100.15,40.15,39.94,39.73,39.52,39.31,39.10,38.89,29.57,20.34,19.65,13.49.
13 C NMR (101MHz, DMSO-d6) δ165.84,152.63,150.60,137.13,137.00,135.46,130.73,129.18,118.89,118.37,115.19,100.15,40.15,39.94,39.73,3 9.52,39.31,39.10,38.89,29.57, 20.34,19.65,13.49.
实施例20：制备式(I-20)化合物Example 20: Preparation of compounds of formula (I-20)
1-(2-丙基苯并[d]恶唑-6-基)-3-(4-(三氟甲氧基)苯基)脲的合成：Synthesis of 1-(2-propylbenzo[d]oxazol-6-yl)-3-(4-(trifluoromethoxy)phenyl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-丙基苯并[d]恶唑-6-胺，式(III)化合物采用1-异氰酸根-4-(三氟甲氧基)苯。The preparation process of Example 1 was carried out, except that 2-propylbenzo[d]oxazole-6-amine was used for the compound of formula (II), and 1-isocyanate-4-( was used for the compound of formula (III). Trifluoromethoxy)benzene.
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ8.93(d,J＝10.0Hz,2H),7.97(d,J＝1.6Hz,1H),7.57(dd,J＝8.7,4.0Hz,3H),7.30(d,J＝8.6Hz,2H),7.21(dd,J＝8.6,1.8Hz,1H),2.88(t,J＝7.3Hz,2H),1.86–1.76(m,2H),0.98(t,J＝7.4Hz,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ8.93 (d, J = 10.0 Hz, 2H), 7.97 ( d, J = 1.6 Hz, 1H), 7.57 ( dd, J = 8.7, 4.0 Hz, 3H) ,7.30(d,J＝8.6Hz,2H),7.21(dd,J＝8.6,1.8Hz,1H),2.88(t,J＝7.3Hz,2H),1.86–1.76(m,2H),0.98( t,J＝7.4Hz,3H).
13C NMR(101MHz,DMSO-d6)δ165.98,152.56,150.57,142.66,138.92,136.80,135.71,121.73,121.47,119.48,118.93,115.41,100.43,40.15,39.94,39.73,39.52,39.31,39.10,38.89,29.57,19.65,13.48.
13 C NMR (101MHz, DMSO-d6) δ165.98,152.56,150.57,142.66,138.92,136.80,135.71,121.73,121.47,119.48,118.93,115.41,100.43,40.15,39.94, 39.73,39.52,39.31,39.10,38.89, 29.57,19.65,13.48.
实施例21：制备式(I-21)化合物Example 21: Preparation of compound of formula (I-21)
1-(4-氟苯基)-3-(2-丙基苯并[d]恶唑-6-基)脲的合成：Synthesis of 1-(4-fluorophenyl)-3-(2-propylbenzo[d]oxazol-6-yl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-丙基苯并[d]恶唑-6-胺，式(III)化合物采用1-氟-4-异氰酸苯。The preparation process of Example 1 is carried out, except that 2-propylbenzo[d]oxazole-6-amine is used for the compound of formula (II), and 1-fluoro-4-isocyanate is used for the compound of formula (III). benzene.
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ8.88(s,1H),8.73(s,1H),7.96(d,J＝1.8Hz,1H),7.56(d,J＝8.5Hz,1H),7.48(ddd,J＝10.5,5.3,2.8Hz,2H),7.20(dd,J＝8.6,2.0Hz,1H),7.16–7.10(m,2H),2.87(t,J＝7.3Hz,2H),1.81(h,J＝7.4Hz,2H),0.98(t,J＝7.4Hz,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ8.88 (s, 1H), 8.73 (s, 1H), 7.96 (d, J = 1.8Hz, 1H), 7.56 (d, J = 8.5Hz, 1H) ,7.48(ddd,J＝10.5,5.3,2.8Hz,2H),7.20(dd,J＝8.6,2.0Hz,1H),7.16–7.10(m,2H),2.87(t,J＝7.3Hz,2H ), 1.81 (h, J = 7.4Hz, 2H), 0.98 (t, J = 7.4Hz, 3H).
13C NMR(101MHz,DMSO-d6)δ165.91,158.58,152.71,150.58,136.99,135.94,135.58,120.11,120.04,118.90,115.40,115.31,115.18,100.31,40.15,39.94,39.73,39.52,39.31,39.10,38.89,29.57,19.65,13.49.
13 C NMR (101MHz, DMSO-d6) δ165.91,158.58,152.71,150.58,136.99,135.94,135.58,120.11,120.04,118.90,115.40,115.31,115.18,100.31,40.15 ,39.94,39.73,39.52,39.31,39.10, 38.89,29.57,19.65,13.49.
实施例22：制备式(I-22)化合物Example 22: Preparation of compound of formula (I-22)
1-(3-甲氧基苯基)-3-(2-丙基苯并[d]恶唑-6-基)脲的合成：Synthesis of 1-(3-methoxyphenyl)-3-(2-propylbenzo[d]oxazol-6-yl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-丙基苯并[d]恶唑-6-胺，式(III)化合物采用1-异氰酸根-3-甲氧基苯。The preparation process of Example 1 was carried out, except that 2-propylbenzo[d]oxazole-6-amine was used for the compound of formula (II), and 1-isocyanato-3-methyl was used for the compound of formula (III). Oxybenzene.
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ8.87(s,1H),8.71(s,1H),7.97(d,J＝1.8Hz,1H),7.57–7.54(m,1H),7.20(ddd,J＝11.8,5.1,3.7Hz,3H),6.98–6.94(m,1H),6.57(ddd,J＝8.2,2.4,0.6Hz,1H),3.74(s,3H),2.87(t,J＝7.3Hz,2H),1.81(h,J＝7.4Hz,2H),0.98(t,J＝7.4Hz,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ8.87 (s, 1H), 8.71 (s, 1H), 7.97 (d, J = 1.8Hz, 1H), 7.57–7.54 (m, 1H), 7.20 ( ddd,J＝11.8,5.1,3.7Hz,3H),6.98–6.94(m,1H),6.57(ddd,J＝8.2,2.4,0.6Hz,1H),3.74(s,3H),2.87(t, J＝7.3Hz,2H),1.81(h,J＝7.4Hz,2H),0.98(t,J＝7.4Hz,3H).
13C NMR(101MHz,DMSO-d6)δ165.92,159.70,152.53,150.59,140.82,136.94,135.60,129.56,118.91,115.31,110.60,107.28,104.08,100.31,54.93,40.15,39.94,39.73,39.52,39.31,39.10,38.89,29.58,19.66,13.49.
13 C NMR (101MHz, DMSO-d6) δ165.92,159.70,152.53,150.59,140.82,136.94,135.60,129.56,118.91,115.31,110.60,107.28,104.08,100.31,54.93 ,40.15,39.94,39.73,39.52,39.31, 39.10,38.89,29.58,19.66,13.49.
实施例23：制备式(I-23)化合物Example 23: Preparation of compounds of formula (I-23)
1-(4-甲氧基苯基)-3-(2-丙基苯并[d]恶唑-6-基)脲的合成：Synthesis of 1-(4-methoxyphenyl)-3-(2-propylbenzo[d]oxazol-6-yl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-丙基苯并[d]恶唑-6-胺，式(III)化合物采用1-异氰酸根-4-甲氧基苯。The preparation process of Example 1 was carried out, except that 2-propylbenzo[d]oxazole-6-amine was used for the compound of formula (II), and 1-isocyanato-4-methyl was used for the compound of formula (III). Oxybenzene.
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ8.80(s,1H),8.50(s,1H),7.96(d,J＝1.9Hz,1H),7.55(d,J＝8.5Hz,1H),7.39–7.35(m,2H),7.18(dd,J＝8.6,2.0Hz,1H),6.90–6.86(m,2H),3.72(s,3H),2.87(t,J＝7.3Hz,2H),1.81(dd,J＝14.7,7.4Hz,2H),0.98(t,J＝7.4Hz,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ8.80 (s, 1H), 8.50 (s, 1H), 7.96 (d, J = 1.9 Hz, 1H), 7.55 ( d, J = 8.5 Hz, 1H) ,7.39–7.35(m,2H),7.18(dd,J＝8.6,2.0Hz,1H),6.90–6.86(m,2H),3.72(s,3H),2.87(t,J＝7.3Hz,2H ), 1.81 (dd, J = 14.7, 7.4Hz, 2H), 0.98 (t, J = 7.4Hz, 3H).
13C NMR(101MHz,DMSO-d6)δ165.80,154.54,152.80,150.60,137.24,135.39,132.58,120.14,118.87,115.16,113.99,100.10,55.17,40.15,39.94,39.73,39.52,39.31,39.10,38.89,29.57,19.66,13.49.
13 C NMR (101MHz, DMSO-d6) δ165.80,154.54,152.80,150.60,137.24,135.39,132.58,120.14,118.87,115.16,113.99,100.10,55.17,40.15,39.94,3 9.73,39.52,39.31,39.10,38.89, 29.57,19.66,13.49.
实施例24：制备式(I-24)化合物Example 24: Preparation of compounds of formula (I-24)
1-(2-丙基苯并[d]恶唑-6-基)-3-(3-(三氟甲基)苯基)脲的合成：Synthesis of 1-(2-propylbenzo[d]oxazol-6-yl)-3-(3-(trifluoromethyl)phenyl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-丙基苯并[d]恶唑-6-胺，式(III)化合物采用1-异氰酸根-3-(三氟甲基)苯。The preparation process of Example 1 is carried out, except that 2-propylbenzo[d]oxazole-6-amine is used for the compound of formula (II), and 1-isocyanato-3-( is used for the compound of formula (III). Trifluoromethyl)benzene.
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ9.08(s,1H),9.01(s,1H),8.03(s,1H),7.97(d,J＝1.8Hz,1H),7.59(t,J＝9.0Hz,2H),7.52(t,J＝7.9Hz,1H),7.32(d,J＝7.6Hz,1H),7.23(dd,J＝8.6,2.0Hz,1H),2.88(t,J＝7.3Hz,2H),1.80(dt,J＝14.5,7.3Hz,2H),0.99(t,J＝7.4Hz,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ9.08 (s, 1H), 9.01 (s, 1H), 8.03 (s, 1H), 7.97 (d, J = 1.8Hz, 1H), 7.59 (t, J＝9.0Hz,2H),7.52(t,J＝7.9Hz,1H),7.32(d,J＝7.6Hz,1H),7.23(dd,J＝8.6,2.0Hz,1H),2.88(t, J＝7.3Hz,2H),1.80(dt,J＝14.5,7.3Hz,2H),0.99(t,J＝7.4Hz,3H).
13C NMR(101MHz,DMSO-d6)δ166.07,152.59,150.55,140.51,136.61,135.84,129.92,129.69,129.37,121.91,118.93,118.12,115.58,114.21,100.65,40.15,39.94,39.73,39.52,39.31,39.10,38.89,29.57,19.65,13.48.
13 C NMR (101MHz, DMSO-d6) δ166.07,152.59,150.55,140.51,136.61,135.84,129.92,129.69,129.37,121.91,118.93,118.12,115.58,114.21,100.6 5,40.15,39.94,39.73,39.52,39.31, 39.10,38.89,29.57,19.65,13.48.
实施例25：制备式(I-25)化合物Example 25: Preparation of compounds of formula (I-25)
1-(2-丙基苯并[d]恶唑-6-基)-3-(4-(三氟甲基)苯基)脲的合成：Synthesis of 1-(2-propylbenzo[d]oxazol-6-yl)-3-(4-(trifluoromethyl)phenyl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-丙基苯并[d]恶唑-6-胺，式(III)化合物采用1-异氰酸根-4-(三氟甲基)苯。The preparation process of Example 1 was carried out, except that the compound of formula (II) used 2-propylbenzo[d]oxazole-6-amine, and the compound of formula (III) used 1-isocyanato-4-( Trifluoromethyl)benzene.
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ9.14(s,1H),9.02(s,1H),7.97(d,J＝1.8Hz,1H),7.68(d,J＝8.9Hz,2H),7.64(d,J＝9.0Hz,2H),7.58(d,J＝8.5Hz,1H),7.23(dd,J＝8.6,2.0Hz,1H),2.88(t,J＝7.3Hz,2H),1.80(dt,J＝14.7,7.4Hz,2H),0.98(t,J＝7.4Hz,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ9.14 (s, 1H), 9.02 (s, 1H), 7.97 (d, J = 1.8Hz, 1H), 7.68 (d, J = 8.9Hz, 2H) ,7.64(d,J＝9.0Hz,2H),7.58(d,J＝8.5Hz,1H),7.23(dd,J＝8.6,2.0Hz,1H),2.88(t,J＝7.3Hz,2H) ,1.80(dt,J＝14.7,7.4Hz,2H),0.98(t,J＝7.4Hz,3H).
13C NMR(101MHz,DMSO-d6δ166.08,152.36,150.54,143.38,136.56,135.87,126.11,126.07,125.91,118.97,117.92,115.53,100.59,40.15,39.94,39.73,39.52,39.31,39.10,38.89,29.57,19.64,13.48.
13 C NMR (101MHz, DMSO-d6δ166.08,152.36,150.54,143.38,136.56,135.87,126.11,126.07,125.91,118.97,117.92,115.53,100.59,40.15,39.94,3 9.73,39.52,39.31,39.10,38.89,29.57, 19.64,13.48.
实施例26：制备式(I-26)化合物Example 26: Preparation of compound of formula (I-26)
1-(2-甲氧基苯基)-3-(2-苯基苯并[d]恶唑-6-基)脲的合成：Synthesis of 1-(2-methoxyphenyl)-3-(2-phenylbenzo[d]oxazol-6-yl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-苯基苯并[d]恶唑-6-胺，式(III)化合物采用1-异氰酸根-2-甲氧基苯。The preparation process of Example 1 was carried out, except that 2-phenylbenzo[d]oxazole-6-amine was used for the compound of formula (II), and 1-isocyanato-2-methyl was used for the compound of formula (III). Oxybenzene.
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ9.64(s,1H),8.31(s,1H),8.17(dq,J＝7.8,2.7Hz,4H),7.71(d,J＝8.6Hz,1H),7.61(dd,J＝6.8,2.9Hz,3H),7.23(dd,J＝8.6,2.0Hz,1H),7.04(dd,J＝8.0,1.5Hz,1H),6.97(td,J＝7.7,1.8Hz,1H),6.92(td,J＝7.6,1.6Hz,1H),3.90(s,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ9.64 (s, 1H), 8.31 (s, 1H), 8.17 (dq, J = 7.8, 2.7Hz, 4H), 7.71 (d, J = 8.6Hz, 1H),7.61(dd,J＝6.8,2.9Hz,3H),7.23(dd,J＝8.6,2.0Hz,1H),7.04(dd,J＝8.0,1.5Hz,1H),6.97(td,J ＝7.7,1.8Hz,1H),6.92(td,J＝7.6,1.6Hz,1H),3.90(s,3H).
13C NMR(101MHz,DMSO-d6)δ161.44,152.38,150.78,147.70,138.05,136.02,131.51,129.27,128.48,126.90,126.62,121.98,120.57,119.70,118.38,115.70,110.76,99.94,55.79,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
13 C NMR (101MHz, DMSO-d6) δ161.44,152.38,150.78,147.70,138.05,136.02,131.51,129.27,128.48,126.90,126.62,121.98,120.57,119.70,118.3 8,115.70,110.76,99.94,55.79,40.15, 39.94,39.73,39.52,39.31,39.10,38.89.
实施例27：制备式(I-27)化合物Example 27: Preparation of compound of formula (I-27)
1-(3-氯苯基)-3-(2-苯基苯并[d]恶唑-6-基)脲的合成：Synthesis of 1-(3-chlorophenyl)-3-(2-phenylbenzo[d]oxazol-6-yl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-苯基苯并[d]恶唑-6-胺，式(III)化合物采用1-氯-3-异氰酸酯苯。The preparation process of Example 1 was followed, except that 2-phenylbenzo[d]oxazole-6-amine was used as the compound of formula (II), and 1-chloro-3-isocyanatobenzene was used as the compound of formula (III).
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ9.08(s,1H),8.97(s,1H),8.22–8.14(m,2H),8.11(d,J＝1.8Hz,1H),7.77–7.68(m,2H),7.62(dd,J＝5.0,1.7Hz,3H),7.35–7.26(m,4H),7.08–7.00(m,1H).
1 H NMR (400MHz, DMSO-d 6 ) δ9.08 (s, 1H), 8.97 (s, 1H), 8.22–8.14 (m, 2H), 8.11 (d, J = 1.8Hz, 1H), 7.77– 7.68(m,2H),7.62(dd,J＝5.0,1.7Hz,3H),7.35–7.26(m,4H),7.08–7.00(m,1H).
13C NMR(101MHz,DMSO-d6)δ161.59,152.41,150.68,141.12,137.59,136.31,133.21,131.57,130.41,129.28,126.93,126.58,121.60,119.64,117.69,116.77,116.21,100.53,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
13 C NMR (101MHz, DMSO-d6) δ161.59,152.41,150.68,141.12,137.59,136.31,133.21,131.57,130.41,129.28,126.93,126.58,121.60,119.64,117.6 9,116.77,116.21,100.53,40.15,39.94, 39.73,39.52,39.31,39.10,38.89.
实施例28：制备式(I-28)化合物Example 28: Preparation of compound of formula (I-28)
1-(4-氯苯基)-3-(2-苯基苯并[d]恶唑-6-基)脲的合成：Synthesis of 1-(4-chlorophenyl)-3-(2-phenylbenzo[d]oxazol-6-yl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-苯基苯并[d]恶唑-6-胺，式(III)化合物采用1-氯-4-异氰酸酯苯。The preparation process of Example 1 was followed, except that 2-phenylbenzo[d]oxazole-6-amine was used as the compound of formula (II), and 1-chloro-4-isocyanatobenzene was used as the compound of formula (III).
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ9.04(s,1H),8.90(s,1H),8.20–8.16(m,2H),8.11(d,J＝1.8Hz,1H),7.71(d,J＝8.6Hz,1H),7.63–7.59(m,3H),7.54–7.50(m,2H),7.37–7.33(m,2H),7.29(dd,J＝8.6,2.0Hz,1H).
1 H NMR (400MHz, DMSO-d 6 ) δ9.04 (s, 1H), 8.90 (s, 1H), 8.20–8.16 (m, 2H), 8.11 (d, J = 1.8Hz, 1H), 7.71 ( d,J＝8.6Hz,1H),7.63–7.59(m,3H),7.54–7.50(m,2H),7.37–7.33(m,2H),7.29(dd,J＝8.6,2.0Hz,1H) .
13C NMR(101MHz,DMSO-d6)δ161.54,152.46,150.69,138.55,137.72,136.22,131.56,129.27,128.64,126.92,126.59,125.51,119.86,119.64,116.13,100.42,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
13 C NMR (101MHz, DMSO-d6) δ161.54,152.46,150.69,138.55,137.72,136.22,131.56,129.27,128.64,126.92,126.59,125.51,119.86,119.64,116.1 3,100.42,40.15,39.94,39.73,39.52, 39.31,39.10,38.89.
实施例29：制备式(I-29)化合物Example 29: Preparation of compounds of formula (I-29)
1-(2-氯苯基)-3-(2-苯基苯并[d]恶唑-6-基)脲的合成：Synthesis of 1-(2-chlorophenyl)-3-(2-phenylbenzo[d]oxazol-6-yl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-苯基苯并[d]恶唑-6-胺，式(III)化合物采用1-氯-2-异氰酸酯苯。The preparation process of Example 1 was followed, except that 2-phenylbenzo[d]oxazole-6-amine was used as the compound of formula (II), and 1-chloro-2-isocyanatobenzene was used as the compound of formula (III).
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ9.72(s,1H),8.39(s,1H),8.24–8.13(m,5H),7.73(d,J＝8.6Hz,1H),7.62(dd,J＝5.0,1.7Hz,4H),7.48(dd,J＝8.0,1.4Hz,1H),7.38–7.23(m,2H),7.06(td,J＝7.9,1.5Hz,1H).
1 H NMR (400MHz, DMSO-d 6 ) δ9.72 (s, 1H), 8.39 (s, 1H), 8.24–8.13 (m, 5H), 7.73 (d, J = 8.6Hz, 1H), 7.62 ( dd,J＝5.0,1.7Hz,4H),7.48(dd,J＝8.0,1.4Hz,1H),7.38–7.23(m,2H),7.06(td,J＝7.9,1.5Hz,1H).
13C NMR(101MHz,DMSO-d6)δ161.60,152.16,150.73,137.59,136.32,135.81,131.57,129.27,129.23,127.61,126.93,126.57,123.47,122.07,121.43,119.76,115.96,100.32,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
13 C NMR (101MHz, DMSO-d6) δ161.60,152.16,150.73,137.59,136.32,135.81,131.57,129.27,129.23,127.61,126.93,126.57,123.47,122.07,121.4 3,119.76,115.96,100.32,40.15,39.94, 39.73,39.52,39.31,39.10,38.89.
实施例30：制备式(I-30)化合物Example 30: Preparation of compounds of formula (I-30)
1-(2-苯基苯并[d]恶唑-6-基)-3-(邻甲苯基)脲的合成：Synthesis of 1-(2-phenylbenzo[d]oxazol-6-yl)-3-(o-tolyl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-苯基苯并[d]恶唑-6-胺，式(III)化合物采用1-异氰酸根-2-甲基苯。The preparation process of Example 1 was carried out, except that 2-phenylbenzo[d]oxazole-6-amine was used for the compound of formula (II), and 1-isocyanato-2-methyl was used for the compound of formula (III). Benzene.
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ9.33(s,1H),8.19–8.16(m,3H),8.01(s,1H),7.86(d,J＝7.4Hz,1H),7.73–7.70(m,1H),7.63–7.60(m,3H),7.26(dd,J＝8.6,2.0Hz,1H),7.18(dd,J＝13.4,7.5Hz,2H),6.98(td,J＝7.4,1.1Hz,1H),2.27(s,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ9.33 (s, 1H), 8.19–8.16 (m, 3H), 8.01 (s, 1H), 7.86 (d, J = 7.4Hz, 1H), 7.73– 7.70(m,1H),7.63–7.60(m,3H),7.26(dd,J＝8.6,2.0Hz,1H),7.18(dd,J＝13.4,7.5Hz,2H),6.98(td,J＝ 7.4,1.1Hz,1H),2.27(s,3H).
13C NMR(101MHz,DMSO-d6)δ161.44,152.68,150.78,138.12,137.21,136.00,131.52,130.21,129.27,127.77,126.90,126.62,126.18,122.89,121.26,119.69,115.81,100.05,40.15,39.94,39.73,39.52,39.31,39.10,38.89,17.88.
13 C NMR (101MHz, DMSO-d6) δ161.44,152.68,150.78,138.12,137.21,136.00,131.52,130.21,129.27,127.77,126.90,126.62,126.18,122.89,121.2 6,119.69,115.81,100.05,40.15,39.94, 39.73,39.52,39.31,39.10,38.89,17.88.
实施例31：制备式(I-31)化合物Example 31: Preparation of compound of formula (I-31)
1-(2-苯基苯并[d]恶唑-6-基)-3-(间甲苯基)脲的合成：Synthesis of 1-(2-phenylbenzo[d]oxazol-6-yl)-3-(m-tolyl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-苯基苯并[d]恶唑-6-胺，式(III)化合物采用1-异氰酸根-3-甲基苯。The preparation process of Example 1 is carried out, except that 2-phenylbenzo[d]oxazole-6-amine is used for the compound of formula (II), and 1-isocyanato-3-methyl is used for the compound of formula (III). Benzene.
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ8.98(s,1H),8.66(s,1H),8.19–8.16(m,2H),8.13(d,J＝1.8Hz,1H),7.72–7.69(m,1H),7.63–7.60(m,3H),7.32(s,1H),7.27(dd,J＝8.6,2.0Hz,2H),7.18(t,J＝7.7Hz,1H),6.81(d,J＝7.4Hz,1H),2.30(s,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ8.98 (s, 1H), 8.66 (s, 1H), 8.19–8.16 (m, 2H), 8.13 (d, J = 1.8Hz, 1H), 7.72– 7.69(m,1H),7.63–7.60(m,3H),7.32(s,1H),7.27(dd,J＝8.6,2.0Hz,2H),7.18(t,J＝7.7Hz,1H),6.81 (d,J＝7.4Hz,1H),2.30(s,3H).
13C NMR(101MHz,DMSO-d6)δ161.46,152.53,150.74,139.44,137.97,136.07,131.52,129.27,128.64,126.90,126.62,122.74,119.62,118.84,115.98,115.52,100.21,40.15,39.94,39.73,39.52,39.31,39.10,38.89,21.22.
13 C NMR (101MHz, DMSO-d6) δ161.46,152.53,150.74,139.44,137.97,136.07,131.52,129.27,128.64,126.90,126.62,122.74,119.62,118.84,115.9 8,115.52,100.21,40.15,39.94,39.73, 39.52,39.31,39.10,38.89,21.22.
实施例32：制备式(I-32)化合物Example 32: Preparation of compound of formula (I-32)
1-(2-苯基苯并[d]恶唑-6-基)-3-(对甲苯基)脲的合成：Synthesis of 1-(2-phenylbenzo[d]oxazol-6-yl)-3-(p-tolyl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-苯基苯并[d]恶唑-6-胺，式(III)化合物采用1-异氰酸根-4-甲基苯。The preparation process of Example 1 was carried out, except that 2-phenylbenzo[d]oxazole-6-amine was used for the compound of formula (II), and 1-isocyanato-4-methyl was used for the compound of formula (III). Benzene.
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ8.95(s,1H),8.63(s,1H),8.19–8.16(m,2H),8.12(d,J＝1.8Hz,1H),7.70(d,J＝8.6Hz,1H),7.63–7.59(m,3H),7.37(d,J＝8.4Hz,2H),7.26(dd,J＝8.6,2.0Hz,1H),7.11(d,J＝8.2Hz,2H),2.26(s,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ8.95 (s, 1H), 8.63 (s, 1H), 8.19–8.16 (m, 2H), 8.12 (d, J = 1.8Hz, 1H), 7.70 ( d,J＝8.6Hz,1H),7.63–7.59(m,3H),7.37(d,J＝8.4Hz,2H),7.26(dd,J＝8.6,2.0Hz,1H),7.11(d,J =8.2Hz,2H),2.26(s,3H).
13C NMR(101MHz,DMSO-d6)δ161.43,152.59,150.73,138.04,136.94,136.01,131.52,130.83,129.27,129.19,126.90,126.62,119.61,118.43,115.95,100.16,40.15,39.94,39.73,39.52,39.31,39.10,38.89,20.34.
13 C NMR (101MHz, DMSO-d6) δ161.43,152.59,150.73,138.04,136.94,136.01,131.52,130.83,129.27,129.19,126.90,126.62,119.61,118.43,115.9 5,100.16,40.15,39.94,39.73,39.52, 39.31,39.10,38.89,20.34.
实施例33：制备式(I-33)化合物Example 33: Preparation of compound of formula (I-33)
1-(2-苯基苯并[d]恶唑-6-基)-3-(2-(三氟甲基)苯基)脲的合成：Synthesis of 1-(2-phenylbenzo[d]oxazol-6-yl)-3-(2-(trifluoromethyl)phenyl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-苯基苯并[d]恶唑-6-胺，式(III)化合物采用1-异氰酸根-2-(三氟甲基)苯。The preparation process of Example 1 was carried out, except that the compound of formula (II) used 2-phenylbenzo[d]oxazole-6-amine, and the compound of formula (III) used 1-isocyanato-2-( Trifluoromethyl)benzene.
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ9.68(s,1H),8.18(dd,J＝6.6,3.3Hz,3H),8.14(d,J＝1.9Hz,1H),7.98(d,J＝8.2Hz,1H),7.72(t,J＝9.5Hz,2H),7.66(d,J＝7.8Hz,1H),7.63–7.59(m,3H),7.31(t,J＝7.7Hz,1H),7.27(dd,J＝8.6,2.0Hz,1H).
1 H NMR (400MHz, DMSO-d 6 ) δ9.68 (s, 1H), 8.18 (dd, J = 6.6, 3.3Hz, 3H), 8.14 (d, J = 1.9Hz, 1H), 7.98 (d, J＝8.2Hz,1H),7.72(t,J＝9.5Hz,2H),7.66(d,J＝7.8Hz,1H),7.63–7.59(m,3H),7.31(t,J＝7.7Hz, 1H),7.27(dd,J＝8.6,2.0Hz,1H).
13C NMR(101MHz,DMSO-d6)δ161.61,152.53,150.73,137.65,136.31,136.16,132.94,131.58,129.28,126.94,126.57,125.93,125.84,123.89,120.21,119.92,119.76,115.95,100.34,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
13 C NMR (101MHz, DMSO-d6) δ161.61,152.53,150.73,137.65,136.31,136.16,132.94,131.58,129.28,126.94,126.57,125.93,125.84,123.89,120.2 1,119.92,119.76,115.95,100.34,40.15, 39.94,39.73,39.52,39.31,39.10,38.89.
实施例34：制备式(I-34)化合物Example 34: Preparation of compounds of formula (I-34)
1-(2-苯基苯并[d]恶唑-6-基)-3-(4-(三氟甲氧基)苯基)脲的合成：Synthesis of 1-(2-phenylbenzo[d]oxazol-6-yl)-3-(4-(trifluoromethoxy)phenyl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-苯基苯并[d]恶唑-6-胺，式(III)化合物采用1-异氰酸根-4-(三氟甲氧基)苯。The preparation process of Example 1 was carried out, except that the compound of formula (II) used 2-phenylbenzo[d]oxazole-6-amine, and the compound of formula (III) used 1-isocyanato-4-( Trifluoromethoxy)benzene.
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ9.01(d,J＝36.7Hz,2H),8.20–8.16(m,2H),8.11(d,J＝1.8Hz,1H),7.73–7.70(m,1H),7.63–7.60(m,4H),7.59–7.57(m,1H),7.33–7.28(m,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ9.01 (d, J = 36.7Hz, 2H), 8.20–8.16 (m, 2H), 8.11 (d, J = 1.8Hz, 1H), 7.73–7.70 ( m,1H),7.63–7.60(m,4H),7.59–7.57(m,1H),7.33–7.28(m,3H).
13C NMR(101MHz,DMSO-d6)δ161.55,152.51,150.70,142.70,138.85,137.71,136.25,131.53,129.25,126.91,126.60,121.72,119.63,119.54,118.93,116.13,100.44,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
13 C NMR (101MHz, DMSO-d6) δ161.55,152.51,150.70,142.70,138.85,137.71,136.25,131.53,129.25,126.91,126.60,121.72,119.63,119.54,118.9 3,116.13,100.44,40.15,39.94,39.73, 39.52,39.31,39.10,38.89.
实施例35：制备式(I-35)化合物Example 35: Preparation of compound of formula (I-35)
1-(4-氟苯基)-3-(2-苯基苯并[d]恶唑-6-基)脲的合成：Synthesis of 1-(4-fluorophenyl)-3-(2-phenylbenzo[d]oxazol-6-yl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-苯基苯并[d]恶唑-6-胺，式(III)化合物采用1-氟-4-异氰酸苯。The preparation process of Example 1 is carried out, except that 2-phenylbenzo[d]oxazole-6-amine is used for the compound of formula (II), and 1-fluoro-4-isocyanate is used for the compound of formula (III). benzene.
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ8.99(s,1H),8.78(s,1H),8.19–8.16(m,2H),8.11(d,J＝1.8Hz,1H),7.72–7.69(m,1H),7.63–7.60(m,3H),7.52–7.47(m,2H),7.28(dd,J＝8.6,2.0Hz,1H),7.17–7.12(m,2H).
1 H NMR (400MHz, DMSO-d 6 ) δ8.99 (s, 1H), 8.78 (s, 1H), 8.19–8.16 (m, 2H), 8.11 (d, J = 1.8Hz, 1H), 7.72– 7.69(m,1H),7.63–7.60(m,3H),7.52–7.47(m,2H),7.28(dd,J=8.6,2.0Hz,1H),7.17–7.12(m,2H).
13C NMR(101MHz,DMSO-d6)δ161.49,158.63,156.26,152.66,150.71,137.90,136.12,135.87,135.85,131.53,129.26,126.91,126.61,120.18,120.10,119.62,116.06,115.41,115.19,100.32,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
13 C NMR (101MHz, DMSO-d6) δ161.49,158.63,156.26,152.66,150.71,137.90,136.12,135.87,135.85,131.53,129.26,126.91,126.61,120.18,120.1 0,119.62,116.06,115.41,115.19,100.32, 40.15,39.94,39.73,39.52,39.31,39.10,38.89.
实施例36：制备式(I-36)化合物Example 36: Preparation of compounds of formula (I-36)
1-(3-甲氧基苯基)-3-(2-苯基苯并[d]恶唑-6-基)脲的合成：Synthesis of 1-(3-methoxyphenyl)-3-(2-phenylbenzo[d]oxazol-6-yl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-苯基苯并[d]恶唑-6-胺，式(III)化合物采用1-异氰酸根-3-甲氧基苯。The preparation process of Example 1 is carried out, except that 2-phenylbenzo[d]oxazole-6-amine is used for the compound of formula (II), and 1-isocyanato-3-methyl is used for the compound of formula (III). Oxybenzene.
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ8.99(s,1H),8.76(s,1H),8.18(dd,J＝6.1,2.5Hz,2H),8.12(s,1H),7.71(d,J＝8.6Hz,1H),7.64–7.59(m,3H),7.28(dd,J＝8.6,1.2Hz,1H),7.21(dd,J＝10.8,5.0Hz,2H),6.98(d,J＝8.0Hz,1H),6.58(dd,J＝8.2,2.1Hz,1H),3.75(s,3H).
1 H NMR (400MHz, DMSO-d 6 ) δ8.99 (s, 1H), 8.76 (s, 1H), 8.18 (dd, J = 6.1, 2.5Hz, 2H), 8.12 (s, 1H), 7.71 ( d,J＝8.6Hz,1H),7.64–7.59(m,3H),7.28(dd,J＝8.6,1.2Hz,1H),7.21(dd,J＝10.8,5.0Hz,2H),6.98(d ,J＝8.0Hz,1H),6.58(dd,J＝8.2,2.1Hz,1H),3.75(s,3H).
13C NMR(101MHz,DMSO-d6)δ161.50,159.70,152.48,150.72,140.75,137.85,136.13,131.54,129.57,129.28,126.91,126.61,119.62,116.06,110.65,107.36,104.14,100.32,54.94,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
13 C NMR (101MHz, DMSO-d6) δ161.50,159.70,152.48,150.72,140.75,137.85,136.13,131.54,129.57,129.28,126.91,126.61,119.62,116.06,110.6 5,107.36,104.14,100.32,54.94,40.15, 39.94,39.73,39.52,39.31,39.10,38.89.
实施例37：制备式(I-37)化合物Example 37: Preparation of compounds of formula (I-37)
1-(2-苯基苯并[d]恶唑-6-基)-3-(3-(三氟甲基)苯基)脲的合成：Synthesis of 1-(2-phenylbenzo[d]oxazol-6-yl)-3-(3-(trifluoromethyl)phenyl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-苯基苯并[d]恶唑-6-胺，式(III)化合物采用1-异氰酸根-3-(三氟甲基)苯。The preparation process of Example 1 was carried out, except that the compound of formula (II) used 2-phenylbenzo[d]oxazole-6-amine, and the compound of formula (III) used 1-isocyanato-3-( Trifluoromethyl)benzene.
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ9.13(s,2H),8.18(dd,J＝6.2,2.6Hz,2H),8.12(s,1H),8.04(s,1H),7.72(d,J＝8.6Hz,1H),7.64–7.60(m,4H),7.54(t,J＝7.9Hz,1H),7.32(dd,J＝10.3,3.8Hz,2H).
1 H NMR (400MHz, DMSO-d 6 ) δ9.13 (s, 2H), 8.18 (dd, J = 6.2, 2.6Hz, 2H), 8.12 (s, 1H), 8.04 (s, 1H), 7.72 ( d,J＝8.6Hz,1H),7.64–7.60(m,4H),7.54(t,J＝7.9Hz,1H),7.32(dd,J＝10.3,3.8Hz,2H).
13C NMR(101MHz,DMSO-d6)δ161.62,152.55,150.67,140.45,137.52,136.38,131.58,129.93,129.70,129.39,129.28,126.93,126.58,121.97,119.64,118.20,116.31,114.24,100.67,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
13 C NMR (101MHz, DMSO-d6) δ161.62,152.55,150.67,140.45,137.52,136.38,131.58,129.93,129.70,129.39,129.28,126.93,126.58,121.97,119.6 4,118.20,116.31,114.24,100.67,40.15, 39.94,39.73,39.52,39.31,39.10,38.89.
实施例38：制备式(I-38)化合物Example 38: Preparation of compound of formula (I-38)
1-(2-苯基苯并[d]恶唑-6-基)-3-(4-(三氟甲基)苯基)脲的合成：Synthesis of 1-(2-phenylbenzo[d]oxazol-6-yl)-3-(4-(trifluoromethyl)phenyl)urea:
按照实施例1的制备过程实施，不同的是，式(II)化合物采用2-苯基苯并[d]恶唑-6-胺，式(III)化合物采用1-异氰酸根-4-(三氟甲基)苯。The preparation process of Example 1 was carried out, except that the compound of formula (II) used 2-phenylbenzo[d]oxazole-6-amine, and the compound of formula (III) used 1-isocyanato-4-( Trifluoromethyl)benzene.
核磁数据如下：The NMR data are as follows:
1H NMR(400MHz,DMSO-d
6)δ9.16(d,J＝20.4Hz,2H),8.18(dd,J＝6.4,2.8Hz,2H),8.12(d,J＝1.6Hz,1H),7.74–7.68(m,3H),7.66(d,J＝8.9Hz,2H),7.63–7.60(m,3H),7.32(dd,J＝8.6,1.7Hz,1H).
1 H NMR (400MHz, DMSO-d 6 ) δ9.16 (d, J = 20.4Hz, 2H), 8.18 (dd, J = 6.4, 2.8Hz, 2H), 8.12 (d, J = 1.6Hz, 1H) ,7.74–7.68(m,3H),7.66(d,J＝8.9Hz,2H),7.63–7.60(m,3H),7.32(dd,J＝8.6,1.7Hz,1H).
13C NMR(101MHz,DMSO-d6)δ161.64,152.33,150.67,143.32,137.47,136.41,131.59,129.28,126.94,126.57,126.12,126.08,122.06,119.68,117.98,116.27,100.61,40.15,39.94,39.73,39.52,39.31,39.10,38.89.
13 C NMR (101MHz, DMSO-d6) δ161.64,152.33,150.67,143.32,137.47,136.41,131.59,129.28,126.94,126.57,126.12,126.08,122.06,119.68,117.9 8,116.27,100.61,40.15,39.94,39.73, 39.52,39.31,39.10,38.89.
实施例39：测试Example 39: Test
1、P2Y
14R拮抗活性测试
1. P2Y 14 R antagonist activity test
稳转P2Y
14R的HEK293细胞系购自Keygen Biotech公司。在测定前约24小时，将细胞以每孔10,000个细胞的密度接种在384孔板中。在测定之前，用磷酸盐缓冲盐溶液短暂洗涤细胞以去除痕量血清，然后加入7.5μL的诱导缓冲液进行接种，其中含有30μM Forskolin、10μM UDPG和100nM浓度的待测化合物。在37℃下放置30分钟，重复3次。然后按照制造商的说明，通过使用cAMP-Glo
TM检测试剂盒(Promega，WI，USA)检测HEK293细胞裂解物中的cAMP水平来评估P2Y
14R抑制活性。测试结果参见表1。
The HEK293 cell line stably transduced with P2Y 14 R was purchased from Keygen Biotech. Approximately 24 hours before assay, cells were seeded in 384-well plates at a density of 10,000 cells per well. Prior to the assay, cells were briefly washed with phosphate-buffered saline solution to remove traces of serum, and then inoculated with 7.5 μL of induction buffer containing 30 μM Forskolin, 10 μM UDPG, and a 100 nM concentration of the test compound. Place at 37°C for 30 minutes and repeat 3 times. P2Y 14 R inhibitory activity was then assessed by detecting cAMP levels in HEK293 cell lysates using a cAMP-Glo ™ Assay Kit (Promega, WI, USA) following the manufacturer's instructions. See Table 1 for test results.
表1：100nM浓度下部分化合物对P2Y
14R抑制率
Table 1: Inhibition rate of some compounds on P2Y 14 R at 100nM concentration
由表1测试结果可以看出，受测化合物在100nM浓度下对P2Y
14R的抑制率均在50％以上，证明本发明化合物对P2Y
14R有较好的抑制作用。
It can be seen from the test results in Table 1 that the inhibitory rates of the tested compounds on P2Y 14 R at a concentration of 100 nM are all above 50%, proving that the compounds of the present invention have a good inhibitory effect on P2Y 14 R.
2、P2Y
14R新型抑制剂缓解药源性肝损伤实验
2. Experiment on new inhibitors of P2Y 14 R alleviating drug-induced liver injury
利用腹腔注射APAP(350mg/kg)构建药源性肝损伤模型。The drug-induced liver injury model was constructed by intraperitoneal injection of APAP (350 mg/kg).
造模后24h处死小鼠，分离肝脏肝脏，生理盐水冲洗后用4％多聚甲醛固定，随后石蜡包埋切片，切片厚度4-8μm，切片在二甲苯中进行脱蜡，并在梯度乙醇中进行复水。水化的样品用PBS清洗，染苏木素10min，染色完后蒸馏水吸去多于染色液，1％的盐酸乙醇分化数秒，蒸馏水冲洗，0.6％氨水反蓝，流水冲洗，在伊红染液中染色1-3min，切片脱水封片，显微镜对组织病例情况镜检。The mice were sacrificed 24 hours after modeling, and the livers were separated. After being washed with physiological saline, they were fixed with 4% paraformaldehyde and then embedded in paraffin and sliced. The thickness of the slices was 4-8 μm. The slices were dewaxed in xylene and immersed in gradient ethanol. Carry out rehydration. Hydrated samples were washed with PBS and stained with hematoxylin for 10 minutes. After staining, distilled water absorbed excess staining solution, differentiated with 1% hydrochloric acid ethanol for a few seconds, rinsed with distilled water, reversed blue with 0.6% ammonia, rinsed with running water, and stained in eosin staining solution After 1-3 minutes, dehydrate the sections and seal them, and examine the tissue condition under a microscope.
摘眼球取血后将血液在低温离心机中以3000rpm，4℃，离心10min，随后弃去沉淀，保留血清，每组设置测定孔，对照孔，按说明书操作(参见表2)。After removing the eyeballs to collect blood, centrifuge the blood in a low-temperature centrifuge at 3000 rpm and 4°C for 10 minutes. Then discard the precipitate and retain the serum. Set measurement holes and control holes in each group and operate according to the instructions (see Table 2).
表2：操作规定Table 2: Operating regulations
轻轻摇动96孔板混匀，室温放置15min，设置波长510nm，酶标仪测得每孔OD值，以绝对值＝测定孔OD值减去对照孔OD值，查标准曲线，求得相应的ALT/AST活力单位。Gently shake the 96-well plate to mix, place it at room temperature for 15 minutes, set the wavelength to 510nm, measure the OD value of each well with the microplate reader, use the absolute value = the OD value of the measurement well minus the OD value of the control well, check the standard curve, and obtain the corresponding ALT/AST vitality units.
采用了P2Y
14R受体的新型抑制剂Ⅰ-1以及阳性药PPTN，验证Ⅰ-1是否也有像PPTN一样的缓解对乙酰氨基酚肝损伤的效果。提前1h给予给药组不同剂量的Ⅰ-1(5mg/kg，10mg/kg)以及PPTN(5mg/kg)。测试结果参见图1-2，图1为不同剂量的Ⅰ-1(5mg/kg，10mg/kg)、PPTN(5mg/kg)对APAP造模C57BL/6J小鼠肝功能生化指标AST的影响的效果图(
N＝3)；
*P<0.05，
**P<0.01，
***P<0.001；图2为不同剂量的Ⅰ-1(5mg/kg，10mg/kg)、PPTN(5mg/kg)对APAP造模C57BL/6J小鼠肝功能生化指标ALT的影响的效果图(
N＝3)；
*P<0.05，
**P<0.01，
***P<0.001。可以看出，不同剂量的式Ⅰ-1化合物都能够显著的下调血清中的AST及ALT水平，缓解对乙酰氨基酚引起的药源性肝损伤。
The new inhibitor of P2Y 14 R receptor I-1 and the positive drug PPTN were used to verify whether I-1 has the same effect as PPTN in alleviating acetaminophen liver damage. Different doses of I-1 (5 mg/kg, 10 mg/kg) and PPTN (5 mg/kg) were administered to the administration group 1 hour in advance. The test results are shown in Figure 1-2. Figure 1 shows the effects of different doses of I-1 (5 mg/kg, 10 mg/kg) and PPTN (5 mg/kg) on the liver function biochemical index AST of APAP model C57BL/6J mice. Rendering ( N=3); * P<0.05, ** P<0.01, *** P<0.001; Figure 2 shows the effects of different doses of I-1 (5mg/kg, 10mg/kg) and PPTN (5mg/kg) on APAP Rendering of the influence of ALT on the biochemical index of liver function in C57BL/6J mice ( N=3); * P<0.05, ** P<0.01, *** P<0.001. It can be seen that different doses of the compound of formula I-1 can significantly reduce the levels of AST and ALT in serum and alleviate drug-induced liver injury caused by acetaminophen.
HE染色的结果参见图3，图3为HE染色检测PPTN(5mg/kg)、Ⅰ-1(5mg/kg、10mg/kg)对APAP造模C57BL/6J小鼠肝脏组织的影响的效果图(N＝3)。可以看出，给予PPTN以及式Ⅰ-1化合物之后再造模，与模型组相比，肝细胞气球样变性以及坏死显著缓解，肝脏汇管区组织形态改善，且炎症细胞浸润减少。说明式Ⅰ-1化合物以及PPTN都能够显著缓解APAP引起的肝脏损伤。The results of HE staining are shown in Figure 3. Figure 3 shows the effect of HE staining on the liver tissue of APAP model C57BL/6J mice ( N=3). It can be seen that after administration of PPTN and the compound of formula Ⅰ-1, the model was reestablished. Compared with the model group, the ballooning degeneration and necrosis of liver cells were significantly alleviated, the tissue morphology of the liver portal area was improved, and the infiltration of inflammatory cells was reduced. It shows that both the compound of formula I-1 and PPTN can significantly alleviate the liver damage caused by APAP.
对式Ⅰ-2～式Ⅰ-38化合物同样进行上述实验测试，结果显示，这些化合物同样能够显著的下调血清中的AST及ALT水平，缓解对乙酰氨基酚引起的药源性肝损伤；以及缓解APAP引起的肝脏损伤。The above experimental tests were also conducted on the compounds of Formula I-2 to Formula I-38. The results showed that these compounds can also significantly reduce the levels of AST and ALT in serum, alleviate drug-induced liver damage caused by acetaminophen; and alleviate Liver damage caused by APAP.
由上述实施例可知，本发明制备的苯并恶唑衍生物具有较好的拮抗P2Y
14受体相关的活性。
It can be seen from the above examples that the benzoxazole derivatives prepared in the present invention have good antagonistic activity related to P2Y 14 receptors.
本文中应用了具体个例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其核心思想，包括最佳方式，并且也使得本领域的任何技术人员都能够实践本发明，包括制造和使用任何装置或系统，和实施任何结合的方法。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。本发明专利保护的范围通过权利要求来限定，并可包括本领域技术人员能够想到的其他实施例。如果这些其他实施例具有近似于权利要求文字表述的结构要素，或者如果它们包括与 权利要求的文字表述无实质差异的等同结构要素，那么这些其他实施例也应包含在权利要求的范围内。This article uses specific examples to illustrate the principles and implementation methods of the present invention. The description of the above embodiments is only used to help understand the method of the present invention and its core ideas, including the best way, and also makes any technology in this field Any person can practice the invention, including making and using any devices or systems and performing any incorporated methods. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the scope of the claims of the present invention. The scope of patent protection of the present invention is defined by the claims, and may include other embodiments that occur to those skilled in the art. These other embodiments shall also be included within the scope of the claims if they have structural elements that are similar to the literal expressions of the claims, or if they include equivalent structural elements with insubstantial differences from the literal expressions of the claims.
Claims (10)
- 一种苯并恶唑衍生物，具有式(I)所示结构：A benzoxazole derivative having a structure shown in formula (I):
其中：in:R 1选自：氢、未取代的烷基、未取代的芳基； R 1 is selected from: hydrogen, unsubstituted alkyl, unsubstituted aryl;R 2选自：取代或未取代的烷基、取代或未取代的烷氧基、卤素。 R 2 is selected from: substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen. - 根据权利要求1所述的苯并恶唑衍生物，其特征在于，R 1中，所述未取代的烷基为C1～C3的烷基； The benzoxazole derivative according to claim 1, wherein in R 1 , the unsubstituted alkyl group is a C1-C3 alkyl group;R 2中，所述取代或未取代的烷基为C1～C3的烷基；所述取代或未取代的烷氧基为C1～C3的烷氧基。 In R 2 , the substituted or unsubstituted alkyl group is a C1-C3 alkyl group; the substituted or unsubstituted alkoxy group is a C1-C3 alkoxy group.
- 根据权利要求1所述的苯并恶唑衍生物，其特征在于，R 2中： The benzoxazole derivative according to claim 1, characterized in that, in R 2 :所述取代的烷基中，取代基至少为一个，且各取代基独立的选自卤素；In the substituted alkyl group, there is at least one substituent, and each substituent is independently selected from halogen;所述取代的烷氧基中，取代基至少为一个，且各取代基独立的选自卤素。In the substituted alkoxy group, there is at least one substituent, and each substituent is independently selected from halogen.
- 根据权利要求1所述的苯并恶唑衍生物，其特征在于，R 1选自：氢、丙基或苯基； The benzoxazole derivative according to claim 1, wherein R1 is selected from: hydrogen, propyl or phenyl;R 2选自：甲基、甲氧基、氟原子、氯原子、三氟甲基或三氟甲氧基。 R 2 is selected from: methyl, methoxy, fluorine atom, chlorine atom, trifluoromethyl or trifluoromethoxy.
- 根据权利要求1～4中任一项所述的苯并恶唑衍生物，其特征在于，具有以下任一结构：The benzoxazole derivative according to any one of claims 1 to 4, characterized in that it has any one of the following structures:
- 一种权利要求1～5中任一项所述的苯并恶唑衍生物的制备方法，包括以下步骤：A method for preparing the benzoxazole derivative according to any one of claims 1 to 5, comprising the following steps:将式(II)结构的化合物和式(III)结构的化合物反应，得到式(I)所示的苯并恶唑衍生物；React a compound with a structure of formula (II) and a compound with a structure of formula (III) to obtain a benzoxazole derivative represented by formula (I);
其中：in:R 1选自：氢、未取代的烷基、未取代的芳基； R 1 is selected from: hydrogen, unsubstituted alkyl, unsubstituted aryl;R 2选自：取代或未取代的烷基、取代或未取代的烷氧基、卤素。 R 2 is selected from: substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen. - 根据权利要求6所述的制备方法，其特征在于，所述反应的温度为100～110℃。The preparation method according to claim 6, characterized in that the temperature of the reaction is 100-110°C.
- 权利要求1～5中任一项所述的苯并恶唑衍生物或权利要求6～7中任一项所述的制备方法制得的苯并恶唑衍生物在制备治疗P2Y 14受体相关疾病的 药物中的应用。 The benzoxazole derivative according to any one of claims 1 to 5 or the benzoxazole derivative prepared by the preparation method according to any one of claims 6 to 7 is relevant in the preparation and treatment of P2Y 14 receptors. Applications in medicines for diseases.
- 根据权利要求8所述的应用，其特征在于，所述P2Y 14受体相关疾病包括急性痛风性关节炎、药源性肝损伤、急性肾损伤或神经疼痛。 The application according to claim 8, wherein the P2Y 14 receptor-related diseases include acute gouty arthritis, drug-induced liver injury, acute kidney injury or neuralgia.
- 一种治疗P2Y 14受体相关疾病的药物，包括苯并恶唑衍生物以及辅料； A drug for treating P2Y 14 receptor-related diseases, including benzoxazole derivatives and excipients;所述苯并恶唑衍生物为权利要求1～5中任一项所述的苯并恶唑衍生物或权利要求6～7中任一项所述的制备方法制得的苯并恶唑衍生物。The benzoxazole derivative is a benzoxazole derivative according to any one of claims 1 to 5 or a benzoxazole derivative prepared by the preparation method according to any one of claims 6 to 7. things.
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