WO2018133756A1 - 靶向自噬激动剂及其在神经退行性疾病治疗药物中的应用 - Google Patents
靶向自噬激动剂及其在神经退行性疾病治疗药物中的应用 Download PDFInfo
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- YXFVVABEGXRONW-UHFFFAOYSA-N Cc1ccccc1 Chemical compound Cc1ccccc1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 7
- WGUXTQDCAZNJIF-UHFFFAOYSA-N Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1 Chemical compound Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1 WGUXTQDCAZNJIF-UHFFFAOYSA-N 0.000 description 6
- 0 *NC(N[C@@](C(N*I)=O)c1ccccc1)=* Chemical compound *NC(N[C@@](C(N*I)=O)c1ccccc1)=* 0.000 description 5
- RWGFKTVRMDUZSP-UHFFFAOYSA-N CC(C)c1ccccc1 Chemical compound CC(C)c1ccccc1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 5
- FYGHSUNMUKGBRK-UHFFFAOYSA-N Cc1c(C)c(C)ccc1 Chemical compound Cc1c(C)c(C)ccc1 FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 description 3
- YXLFQKUIZVSIEP-UHFFFAOYSA-N CCCc(cc1OC)ccc1OC Chemical compound CCCc(cc1OC)ccc1OC YXLFQKUIZVSIEP-UHFFFAOYSA-N 0.000 description 2
- ODLMAHJVESYWTB-UHFFFAOYSA-N CCCc1ccccc1 Chemical compound CCCc1ccccc1 ODLMAHJVESYWTB-UHFFFAOYSA-N 0.000 description 2
- LRLRAYMYEXQKID-UHFFFAOYSA-N Cc1ccc(C(F)(F)F)cc1 Chemical compound Cc1ccc(C(F)(F)F)cc1 LRLRAYMYEXQKID-UHFFFAOYSA-N 0.000 description 2
- QPUYECUOLPXSFR-UHFFFAOYSA-N Cc1cccc2c1cccc2 Chemical compound Cc1cccc2c1cccc2 QPUYECUOLPXSFR-UHFFFAOYSA-N 0.000 description 2
- IBSQPLPBRSHTTG-UHFFFAOYSA-N Cc(cccc1)c1Cl Chemical compound Cc(cccc1)c1Cl IBSQPLPBRSHTTG-UHFFFAOYSA-N 0.000 description 1
- UOHMMEJUHBCKEE-UHFFFAOYSA-N Cc1c(C)c(C)c(C)cc1 Chemical compound Cc1c(C)c(C)c(C)cc1 UOHMMEJUHBCKEE-UHFFFAOYSA-N 0.000 description 1
- LJVVELIHWFQXGL-UHFFFAOYSA-N Cc1cc(Cc(cc2)ccc2OC)ccc1 Chemical compound Cc1cc(Cc(cc2)ccc2OC)ccc1 LJVVELIHWFQXGL-UHFFFAOYSA-N 0.000 description 1
- NVIOTXOJPTVJKZ-UHFFFAOYSA-N Cc1ccc(Cc2cc(C)cc(Cl)c2)cc1 Chemical compound Cc1ccc(Cc2cc(C)cc(Cl)c2)cc1 NVIOTXOJPTVJKZ-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
- C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
Definitions
- the invention relates to a targeted autophagy agonist and its application in the treatment of neurodegenerative diseases, and belongs to the technical field of therapeutic drug discovery of neurodegenerative diseases.
- Neurodegenerative disease is a disease state in which cellular neurons of the brain and spinal cord are lost.
- Typical neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and Huntington's disease, are common neurodegenerative diseases in the elderly and are the most common extrapyramidal diseases in the elderly.
- Parkinson's disease the number of patients in China is over one million. The prevalence rate of people over 65 years old is 1000/100,000. With the increase of age, men are slightly more than women. It is estimated that by 2030, the number of patients in China is close. 5000000.
- the main clinical features of the disease resting tremor, slowness and reduction of movement, increased muscle tone, and instability of posture are the main features. At present, drug replacement therapy is still the main method of treatment nowadays.
- levodopa replacement therapy can relieve the motor symptoms of most patients, but it can not prevent the apoptosis and necrosis of dopaminergic neurons. Decrease and the occurrence of side effects such as dyskinesia Therefore, it is of great clinical and social significance to elucidate the pathogenesis and to find effective interventions to develop early intervention and treatment of drugs to delay the development.
- Neurodegenerative diseases are mainly manifested as motor symptoms, including resting tremor, bradykinesia, muscle rigidity and posture gait abnormalities. In addition, there are some non-motor symptoms such as constipation, olfactory disorders, depression, etc. .
- Parkinson's disease the degeneration of dopaminergic neurons and the formation of Lewy bodies are the main pathological features. Among them, ⁇ -synuclein is the main component of Lewy bodies and one of the main markers of Parkinson's disease. .
- Current studies have shown that autophagy can effectively promote the clearance of aggregated proteins in cells, so activation of autophagy may be a potential Parkinson's treatment strategy.
- the technical problem solved by the present invention is to provide a novel compound as a ULK1 agonist.
- the present invention provides a compound of formula I or formula II or a pharmaceutically acceptable salt thereof:
- R 1 is R 11 is hydrogen, alkyl, alkoxy or halogen
- R 12 is hydrogen, alkyl, alkoxy or halogen
- R 13 is hydrogen, alkyl, alkoxy or halogen
- m is 1 or 2
- y is 1 or 2
- z is 1 or 2;
- R 2 is R 21 is hydrogen, alkyl, alkoxy, haloalkyl or halogen; n is 1 or 2;
- X is O or S.
- the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a neurodegenerative disease
- the therapeutic drug for neurodegenerative diseases is preferably an anti-Parkinson drug.
- the anti-Parkinson drug is preferably a ULK1 agonist drug, and the use thereof is for Parkinson's disease related treatment.
- the present invention also provides a pharmaceutical composition which is a preparation comprising an effective amount of the above compound or a pharmaceutically acceptable salt thereof.
- the compound prepared by the present invention or a pharmaceutically acceptable salt thereof can be used as a ULK1 agonist and has a more obvious Parkinson's therapeutic effect.
- Fig. 1A shows that SH-SY5Y cells were treated with 5 ⁇ M BL-918 for 24 hours, and a picture of autophagosomes was detected by transmission electron microscopy.
- Figure 1B shows that SH-SY5Y cells were treated with 5 ⁇ M BL-918 to detect the expression of ULK1, p-ULK1, mAtg13, p-mAtg13, FIP200, Atg101, LC3, Beclin-1 and SQSTM1/p62.
- Figure 1C is an immunoprecipitation map of the ULK complex.
- 1D shows that SH-SY5Y cells were transfected with GFP-LC3 and treated with siRNA-NC or siRNA-ULK1, and then incubated with 5 ⁇ M BL-918 for 24 hours, and the expression pattern of GFP-LC3 was observed using a fluorescence microscope.
- Figure 1E shows that SH-SY5Y cells were transfected with siRNA-NC or siRNA-ULK1 and incubated with 5 ⁇ M BL-918 for 24 hours to detect ULK1, p-ULK1, mAtg13, p-mAtg13, FIP200, Atg101, LC3, Beclin-1 and SQSTM1 The expression level of /p62.
- Figure 2A is a graph showing the protective effect of BL-918 on MPP+ injured cells by MTT cell survival assay.
- Figure 2B shows that treatment of cells with si-ULK1 reverses the protective effect of BL-918, and cell viability is determined by MTT assay.
- Figure 3A is a behavioral experiment of the time of rat swimming and climbing rod test.
- Figure 3B is a determination of dopamine content in rat striatum.
- Figure 3C is an immunofluorescence experiment of tyrosine hydroxylase in neurons.
- the invention provides a compound of formula I or formula II:
- R 1 is R 11 is hydrogen, alkyl, alkoxy or halogen;
- R 12 is hydrogen, alkyl, alkoxy or halogen;
- R 13 is hydrogen, alkyl, alkoxy or halogen;
- m is 1 or 2;
- y is 1 or 2;
- z is 1 or 2;
- R 2 is R 21 is hydrogen, alkyl, alkoxy, haloalkyl or halogen; n is 1 or 2;
- X is O or S.
- the chemical structure of the present invention is not required to be a chiral structure, and may be either R or S.
- the structure is as shown in formula I, that is, the chemical formula is
- X is O and R 1 is R 11 is hydrogen, alkyl, alkoxy or halogen; R 12 is hydrogen, alkyl, alkoxy or halogen; R 13 is hydrogen, alkyl, alkoxy or halogen; m is 1 or 2; y is 1 or 2; z is 1 or 2; R 2 is R 21 is hydrogen, alkyl, alkoxy, haloalkyl or halogen; n is 1 or 2.
- X is O and R 1 is R 13 is alkyl, alkoxy or halogen; z is 1 or 2; R 2 is R 21 is hydrogen, alkyl, alkoxy, haloalkyl or halogen; n is 1 or 2.
- X is O and R 1 is R 13 is an alkyl group, an alkoxy group or a halogen; R 2 is R 21 is hydrogen, C1-C3 alkyl, alkoxy, halogenated C1-C3 alkyl or halogen.
- X is O and R 1 is R 2 is More preferably, X is O and R 1 is R 2 is
- X is O and R 1 is R 12 is hydrogen, alkyl, alkoxy or halogen; y is 1 or 2; R 2 is R 21 is hydrogen, alkyl, alkoxy, haloalkyl or halogen; n is 1 or 2.
- X is O and R 1 is R 12 is hydrogen, alkyl, alkoxy or halogen; R 2 is R 21 is hydrogen, C1-C3 alkyl, alkoxy, halogenated C1-C3 alkyl or halogen. More preferably, X is O and R 1 is R 2 is More preferably, X is O and R 1 is R 2 is More preferably, X is O and R 1 is R 2 is
- X is O and R 1 is R 11 is hydrogen, alkyl, alkoxy or halogen; m is 1 or 2; R 2 is R 21 is hydrogen, alkyl, alkoxy, haloalkyl or halogen; n is 1 or 2.
- R 1 is R 111 is alkyl or alkoxy; R 112 is alkyl or alkoxy; R 2 is More preferably, X is O and R 1 is R 2 is
- X is S;
- R 1 is R 11 is hydrogen, alkyl, alkoxy or halogen;
- R 12 is hydrogen, alkyl, alkoxy or halogen;
- R 13 is hydrogen, alkyl, alkoxy or halogen;
- m is 1 or 2;
- y is 1 or 2;
- z is 1 or 2;
- R 2 is R 21 is hydrogen, alkyl, alkoxy, haloalkyl or halogen;
- n is 1 or 2.
- R 1 is R 11 hydrogen, alkyl, alkoxy or halogen
- R 12 is hydrogen, alkyl, alkoxy or halogen
- m is 1 or 2
- y is 1 or 2
- R 2 is R 21 is hydrogen, alkyl, alkoxy, haloalkyl or halogen
- n is 1 or 2.
- X is S and R 1 is R 13 is alkyl, alkoxy or halogen; z is 1 or 2; R 2 is R 21 is hydrogen, alkyl, alkoxy, haloalkyl or halogen; n is 1 or 2.
- X is S, preferably, X is S, and R 1 is R 13 is an alkyl group, an alkoxy group or a halogen; R 2 is R 21 is hydrogen, C1-C3 alkyl, alkoxy, halogenated C1-C3 alkyl or halogen. More preferably, X is S and R 1 is R 2 is More preferably, R 1 is R 2 is More preferably, X is S and R 1 is R 2 is R 2 is
- X is S and R 1 is R 12 is hydrogen, alkyl, alkoxy or halogen; y is 1 or 2; R 2 is R 21 is hydrogen, alkyl, alkoxy, haloalkyl or halogen; n is 1 or 2.
- X is S and R 1 is R 12 is hydrogen, alkyl, alkoxy or halogen; R 2 is R 21 is hydrogen, C1-C3 alkyl, alkoxy, halogenated C1-C3 alkyl or halogen. More preferably, X is S and R 1 is R 2 is More preferably, X is S and R 1 is R 2 is More preferably, X is S and R 1 is R 2 is
- X is S and R 1 is R 11 is hydrogen, alkyl, alkoxy or halogen; m is 1 or 2; R 2 is R 21 is hydrogen, alkyl, alkoxy, haloalkyl or halogen; n is 1 or 2.
- X is S and R 1 is R 111 is alkyl or alkoxy; R 112 is alkyl or alkoxy; R 2 is More preferably, X is S and R 1 is R 2 is
- the invention also provides pharmaceutically acceptable salts of the compounds of the invention.
- the salt may be a nitrate, a hydrochloride, a sulfate or a phosphate or the like.
- the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a neurodegenerative disease.
- the neurodegenerative disease is preferably Parkinson's disease
- the drug for treating neurodegenerative diseases is an anti-Parkinson drug.
- the anti-Parkinson drug is preferably a ULK1 agonist drug for the related treatment of Parkinson's disease.
- the present invention also provides a pharmaceutical composition which is a preparation comprising an effective amount of the above compound or a pharmaceutically acceptable salt thereof.
- the compounds of the present invention can be formulated into the following forms by methods known in the art: tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, A suppository, a finely divided powder or aerosol or spray for inhalation, a sterile aqueous or oily solution or suspension or sterile emulsion for parenteral (including intravenous, intramuscular or infusion).
- the liquid preparation can be prepared using sterile water or a water-propylene glycol solution as a solvent, and the active ingredient can also be formulated in an aqueous polyethylene glycol solution.
- Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable coloring, flavoring, stabilizing and thickening agents as needed.
- Aqueous suspensions for oral use can be dispersed in water by dispersing the finely divided active component with viscous materials such as natural synthetic gums, resins, methylcellulose, carboxymethylcellulose and other pharmaceutical fields. Known suspending agents.
- the pharmaceutical composition can be in unit dosage form. In these forms, the composition is divided into unit doses containing appropriate quantities of the active ingredient.
- the unit dosage form can be a packaged preparation, the package including a divided amount of preparation such as a packaged tablet, a capsule, and a powder in a vial or ampoule.
- the unit dosage form can also be a capsule, cachet or tablet or it can be a suitable quantity of any such package.
- the pharmaceutical composition of the present invention may be an active ingredient of only the compound of the present invention or may be combined with other anti-Parkinson compounds as an active ingredient.
- the pharmaceutical composition of the present invention can be used in combination with other anti-Parkinson drugs.
- this combination therapy can be achieved by administering the various therapeutic ingredients simultaneously, sequentially or separately.
- Such combination products employ a compound of the invention within an effective dosage range and other pharmaceutically active agents within the approved dosage range.
- the intermediate 3 (1 mol) was dissolved in 100 ml of tetrahydrofuran at -20 ° C, and after adding a nitrogen methylmorpholine (1 mol) and chloroformyl isobutyl ester (1 mol) for half an hour, the aniline derivative (1.2 mol) was added.
- the reaction mixture was slowly added thereto, and after the reaction was kept for 2 hours, the reaction was quenched by taking 100 ml of a 5% aqueous sodium hydrogencarbonate solution. After stirring at room temperature for half an hour, it was extracted with methylene chloride (3 ⁇ 50 ml).
- the purpose of this experiment was to test the activity of the compounds of the present invention on ULK1 enzyme activation in vitro and autophagy activity on cells.
- BL-918 up-regulates the phosphorylation of ULK1 and mAtg13 and dephosphorylates the negative regulator mTOR upstream of the ULK complex. Further, it was found by immunoprecipitation experiments that the stability of BL-918 is a ULK complex (Fig. 1C). To verify whether compound BL-9184 induced autophagy was by targeting ULK1, siRNA was used to silence expression of ULK1. We found that the GFP-LC3 phosphor dot disappeared substantially (Fig. 1D, 1E). In summary, the compound BL-918 activated autophagy was achieved by targeting ULK1 to activate the ULK complex.
- BL-918 has induced autophagy, it has cytoprotective activity.
- MPP + induced SH-SY5Y cell injury model
- BL-918 can reverse the death of SH-SY5Y cells induced by MPP + to some extent (Fig. 2A).
- This protective activity can be reversed by the autophagy inhibitors 3-MA and si-ULK1 (Fig. 2B), further illustrating that BL-918 is a protective effect on cells by induction of autophagy.
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Abstract
本发明涉及靶向自噬激动剂及其在神经退行性疾病治疗药物中的应用，属于抗神经退行性疾病药学技术领域。本发明解决的技术问题是提供一种作为ULK1激动剂的化合物。该化合物包括如（I）（II）的化合物或其药学上可接受的盐。本发明的化合物或其药学上可接受的盐，可以作为ULK1激动剂，具有一定的抗神经退行性疾病活性。
Description
本发明涉及靶向自噬激动剂及其在神经退行性疾病治疗药物中的应用，属于神经退行性疾病治疗药物发现技术领域。
神经退行性疾病(Neurodegenerative disease)是一大脑和脊髓的细胞神经元丧失的疾病状态。典型的神经退行性疾病包括阿尔茨海默病，帕金森病和亨廷顿病等，是中老年人常见的神经系统变性疾病，也是中老年人最常见的锥体外系疾病。目前，以帕金森病为例，我国的患者已逾百万，65岁以上人群患病率为1000/10万，随年龄增高，男性稍多于女性，预计到2030年，我国的患者人数将近500万。该病的主要临床特点：静止性震颤、动作迟缓及减少、肌张力增高、姿势不稳等为主要特征。目前，药物替代治疗仍是现在治疗的主要方法，临床上采用左旋多巴替代治疗，虽然能够缓解大多患者的运动症状，但是不能阻止多巴胺能神经元进行性调亡、坏死，长期使用还存在疗效递减和产生运动障碍等副作用的发生因此，阐明的发病机制以及寻找有效的干预紀点从而研发出早期干预、治疗的药物来延缓的发展具有重要的临床价值和社会意义。
神经退行性疾病临床上主要表现为运动性症状，包括静止性震颤、运动迟缓、肌肉强直和姿势步态异常等，另外，还有一些非运动性的症状，例如便秘，嗅觉失常，抑郁症等。其中以帕金森病为例，黑质多巴胺能神经元变性缺失和路易小体形成为主要病理特征，其中α-突触核蛋白是路易小体的主要成分，也是帕金森病的主要标志物之一。目前研究表明自噬能够有效的促进细胞中已聚集蛋白的清除，因此通过激活自噬可能是一种有潜力的帕金森治疗策略。因此，在帕金森治疗中能够被小分子靶向激活自噬的调控子的发现显得极为迫切。UKL1作为自噬的启动子，显然是一个潜在的靶点。到目前为止还没有任何ULK1的小分子激动剂被发现。
发明内容
本发明解决的技术问题是提供一种作为ULK1激动剂的新化合物。
本发明提供结构式如式Ⅰ或式Ⅱ所示的化合物或其药学上可接受的盐：
其中，R
1为
R
11为氢、烷基、烷氧基或卤素；R
12为氢、烷基、烷氧基或卤素；R
13为氢、烷基、烷氧基或卤素；m为1或2；y为1或2；z为1或2；
R
2为
R
21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
X为O或S。
本发明还提供上述化合物或其药学上可接受的盐在制备神经退行性疾病治疗药物中的用途
进一步的，所述神经退行性疾病治疗药物优选为抗帕金森药物。
进一步的，所述抗帕金森药物优选为ULK1激动剂类药物，其用途为用于帕金森疾病相关治疗。
本发明还提供一种药物组合物，它是包含有效剂量的上述化合物或其药学上可接受的盐的制剂。
本发明制备的化合物或其药学上可接受的盐，可以作为ULK1激动剂，具有较明显的帕金森治疗效果。
图1A为SH-SY5Y细胞用5μM BL-918处理24小时，透射电子显微镜检测自噬小体的图片。
图1B为SH-SY5Y细胞用5μM BL-918处理，检测ULK1,p-ULK1,mAtg13,p-mAtg13,FIP200,Atg101,LC3,Beclin-1和SQSTM1/p62的表达情况。
图1C为ULK复合体的免疫共沉淀图。
图1D为SH-SY5Y细胞转染GFP-LC3和用siRNA-NC或siRNA-ULK1处理后，再用5μM BL-918孵育24小时，使用荧光显微镜观察GFP-LC3的表达图。
图1E为SH-SY5Y细胞转染siRNA-NC或siRNA-ULK1,用5μM BL-918孵育24小时，检测ULK1,p-ULK1,mAtg13,p-mAtg13,FIP200,Atg101,LC3,Beclin-1 and SQSTM1/p62的表达水平。
图2A为通过MTT细胞存活实验检测BL-918对MPP+损伤细胞的保护作用图。
图2B为用si-ULK1处理细胞，可以逆转BL-918的保护作用，MTT法测定细胞存活率。
图3A为大鼠游泳和爬杆试验时间的行为学实验。
图3B为大鼠纹状体中多巴胺含量测定。
图3C为神经元中酪氨酸羟化酶的免疫荧光实验。
本发明提供如式Ⅰ或式Ⅱ所示的化合物：
R
1为
R
11为氢、烷基、烷氧基或卤素；R
12为氢、烷基、烷氧基或卤素；R
13为氢、烷基、烷氧基或卤素；m为1或2；y为1或2；z为1或2；R
2为
R
21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
X为O或S。
本发明的化学结构通式对手性结构没有要求，可以为R型也可以为S型。优选如式Ⅰ所示的结构，即化学通式为
作为一个优选方案，X为O，R
1为
R
11为氢、烷基、烷氧基或卤素；R
12为氢、烷基、烷氧基或卤素；R
13为氢、烷基、烷氧基或卤素；m为1或2；y为1或2；z为1或2；R
2为
R
21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2。
进一步优选的，X为O，R
1为
R
13为烷基、烷氧基或卤素；z为1或2；R
2为
R
21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2。优选的，X为O，R
1为
R
13为烷基、烷氧基或卤素；R
2为
R
21为氢、C1-C3烷基、烷氧基、卤代C1-C3烷基或卤素。优选的，X为O，R
1为
R
2为
更优选的，X为O，R
1为
R
2为
进一步优选的，X为O，R
1为
R
12为氢、烷基、烷氧基或卤素；y为1或2；R
2为
R
21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2。优选的，X为O，R
1为
R
12为氢、烷基、烷氧基或 卤素；R
2为
R
21为氢、C1-C3烷基、烷氧基、卤代C1-C3烷基或卤素。更优选的，X为O，R
1为
R
2为
更优选的，X为O，R
1为
R
2为
进一步优选的，X为O，R
1为
R
11为氢、烷基、烷氧基或卤素；m为1或2；R
2为
R
21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2。优选的，X为O，R
1为
R
111为烷基或烷氧基；R
112为烷基或烷氧基；R
2为
更优选的，X为O，R
1为
R
2为
作为另一个优选方案，X为S；R
1为
R
11为氢、烷基、烷氧基或卤素；R
12为氢、烷基、烷氧基或卤素；R
13为氢、烷基、烷氧基或卤素；m为1或2；y为1或2；z为1或2；R
2为
R
21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2。
优选的，R
1为
R
11氢、烷基、烷氧基或卤素；R
12为氢、烷基、烷氧基或卤素；m为1或2；y为1或2；R
2为
R
21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2。
作为其中的一个优选方案，X为S，R
1为
R
13为烷基、烷氧基或卤素；z为1或2；R
2为
R
21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2。优选的，X为S，优选的，X为S，R
1为
R
13为烷基、烷氧基或卤素；R
2为
R
21为氢、C1-C3烷基、烷氧基、卤代C1-C3烷基或卤素。更优选的，X为S，R
1为
R
2为
更优选的，R
1为
R
2为
更优选的，X为S，R
1为
R
2为
进一步优选的，X为S，R
1为
R
12为氢、烷基、烷氧基或卤素；y为1或2；R
2为
R
21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2。优选的，X为S，R
1为
R
12为氢、烷基、烷氧基或卤素；R
2为
R
21为氢、C1-C3烷基、烷氧基、卤代C1-C3烷基或卤素。更优选的，X为S，R
1为
R
2为
更优选的，X为S，R
1为
R
2为
进一步优选的，X为S，R
1为
R
11为氢、烷基、烷氧基或卤素；m为1或2；R
2为
R
21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2。优选的，X为S，R
1为
R
111为烷基或烷氧基；R
112为烷基或烷氧基；R
2为
更优选的，X为S，R
1为
R
2为
下面是本发明的化合物的一些优选结构。
本发明还提供本发明所述的化合物的药学上可接受的盐。所述盐可以为硝酸盐、盐酸盐、硫酸盐或磷酸盐等。
本发明还提供上述化合物或其药学上可接受的盐在制备治疗神经退行性疾病药物中的用途。进一步的，神经退行性疾病优选为帕金森疾病，治疗神经退行性疾病药物为抗帕金森药物。进一步的，所述抗帕金森药物优选为ULK1激动剂类药物，用于帕金森疾病的相关治疗。
本发明还提供一种药物组合物，它是包含有效剂量的上述化合物或其药学上可接受的盐的制剂。可以通过本领域已知的方法可将本发明化合物制成以下形式：片剂、胶囊剂、水性或油性溶液剂、混悬剂、乳剂、乳膏剂、软膏剂、凝胶剂、喷鼻剂、栓剂、用于吸入的细小分散的粉剂或气雾剂或喷雾剂、用于胃肠道外(包括静脉内、肌内或输注)的无菌水性或油性溶液或混悬剂或无菌乳剂。可采用无菌水或水-丙二醇溶液作为溶剂来制备液体制剂，还可将活性组分配制在聚乙二醇水溶液中。用于口服给予的水性溶液可通过将活性组分溶解在水中并按需要加入合适的着色剂、矫味剂、稳定剂和增稠剂来制备。口服使用的水性混悬剂可通过将细小分散的活性组分与粘性物质一道分散在水中，所述粘性物质如为天然合成胶、树脂、甲基纤维素、羧甲基纤维素和其他药剂领域已知的悬浮剂。
药物组合物可为单位剂量形式。在这些形式中，将所述组合物分成含适量活性组分的单位剂量。该单位剂量形式可为包装制剂，包装中包括分隔量的制剂，例如盒装片剂、胶囊剂和在管形瓶或安瓿中的粉剂。单位剂量形式还可为胶囊剂、扁囊剂或片剂或其可为适当数量的任何这些包装形式。
本发明的药物组合物，其活性成分可仅为本发明的化合物，也可与其他抗帕金森化合物组合作为活性成分。
在治疗帕金森的过程中，可采用本发明的药物组合物与其他抗帕金森药进行联合治疗。
在治疗帕金森时，可通过同时、序贯或单独给予各种治疗成分可实现这种联合治疗。此类组合产品应用有效剂量范围内的本发明化合物和准许剂量范围内的其他药学活性剂。
下面结合实施例对本发明的具体实施方式做进一步的描述，并不因此将本发明限制在所述的实施例范围之中。
实施例1 化合物1～45的合成
化合物1～12采用如下反应式合成：
Scheme 3 Reagents and conditions:(a)MeOH,1N NaOH；HCl pH＝3；(b)N-Methylmorpholine,iso-butylchloroformate,THF,-20℃,R
1NH
2；(c)HCl/MeOH,r.t.；(d)CH
2Cl
2,TEA,R
2NCO or R
2NCS,r.t.
中间体3制备
将原料2溶于10ml甲醇中，然后缓慢加入20ml 1N NaOH的水溶液和(Boc)
2O(2.18g,10mmol)。室温反应2小时后，用1N HCl溶液调节pH＝4-5。随后用氯仿萃取(3x30ml)，合并有机相，无水硫酸镁干燥得到粗产物。粗产物用硅胶色谱柱纯化，CH
2Cl
2/MeOH(10:1)作为流动相得到中间体5(955mg,76％)，为白色固体。1H-NMR(400MHz,CDCl
3),δ(ppm):12.76(1H,s),7.56(1H,d,J＝8.3Hz),7.41-7.29(6H,m),5.10(1H,d,J＝8.3Hz),1.38(9H,s)。
中间体4a-e合成通法
在–20℃将中间体3(1mol)溶于100ml四氢呋喃中，加入氮甲基吗啉(1mol)和氯甲酰异丁酯(1mol)保温反应半小时后，将苯胺衍生物(1.2mol)缓慢加入反应液中，保温反应2小时后，取100ml 5％的碳酸氢钠水溶液猝灭反应。室温搅拌半小时后，用二氯甲烷萃取(3×50ml)，合并有机相然后用5％的碳酸氢钠水溶液，稀盐酸，水，饱和食盐水洗涤，最后无水硫酸钠干燥。减压浓缩后用，硅胶柱层析纯化，CH
2Cl
2/MeOH(8:1)作为流动相得到中间体4a-4e，白色固体收率(70-90％)。
中间体(4a)
1H-NMR(400MHz,CDCl
3),δ(ppm):7.33-7.30(5H,m),7.18-7.03(3H,m),7.03-7.01(2H,m),5.20(1H,m),5.08(1H,m),1.45(3H,d,J＝6.7Hz),1.40(9H,s)；
中间体(4b)
1H-NMR(400MHz,CDCl
3),δ(ppm):8.16(1H,m),7.81(1H,s),7.40(5H,m),6.81(2H,m),5.67(1H,s),1.43(9H,s)；
中间体(4c)
1H-NMR(400MHz,CDCl
3),δ(ppm):7.74(1H,d,J＝7.8Hz),7.46-7.35(6H,m),7.18(1H,t,J＝7.2Hz),7.12(1H,d,J＝7.2Hz),7.05(1H,t,J＝7.2Hz),5.87(1H,s),2.01(3H,s),1.43(9H,s)
中间体(4d)
1H-NMR(400MHz,CDCl
3),δ(ppm):8.42(1H,br s),7.65(1H,d,J＝8.0Hz),7.46(2H,d,J＝7.0Hz),7.37-7.26(4H,m),7.16(1H,t,J＝7.0Hz),7.06(1H,dd,J＝7.8,7.6Hz),5.84(1H,s),1.44(9H,s)；
中间体(4e)
1H-NMR(400MHz,CDCl
3),δ(ppm):7.33-7.27(5H,m),6.71(1H,d,J＝8.0Hz),6.60(1H,d,J＝1.9Hz),6.50(1H,dd,J＝8.1,1.8Hz),5.79(2H,br s),5.05(1H,br s),3.85(3H,s),3.80(3H,s),3.53(1H,m),3.42(1H,m),2.68(2H,m),1.40(9H,s)；
中间体5a-e合成通法
取5倍量的乙酰氯在零摄氏度下缓慢滴加到110ml甲醇中，并搅拌30min。将中间体4(1eq)缓慢加入反应液中，升至室温后继续反应6-8小时。减压蒸出溶剂，得油状粗品，加入50ml水并用1N NaOH的水溶液体调节pH＝12，并用乙酸乙萃取，合并有机相，无水硫酸钠干燥，减压蒸干溶剂得产物不经纯化直接进行下一步。
中间体(5a)
1H-NMR(400MHz,CDCl
3),δ(ppm):7.42-7.25(11H,m),5.10(1H,m),4.50(1H,s),1.46(3H,d,J＝6.7Hz)；
中间体(5b)
1H-NMR(400MHz,CDCl3),δ(ppm):9.68(1H,s),8.30(1H,m),7.45-7.30(5H,m),6.90-6.81(2H,m),4.67(1H,s)
中间体(5c)
1H-NMR(400MHz,CDCl
3),δ(ppm):9.36(1H,s),8.06(1H,d,J＝8.0Hz),7.47(2H,d,J＝8.1Hz),7.40-7.28(3H,m),7.18(2H,m),7.03(1H,td,J＝7.5,1.0Hz),4.69(1H,s),2.27(3H,s),1.94(2H,s)
中间体(5d)
1H-NMR(400MHz,CDCl
3),δ(ppm):9.49(1H,s),7.86(1H,t,J＝1.9Hz),7.51(1H,ddd,J＝8.0,1.9,1.1Hz),7.41(2H,d,J＝8.0Hz),7.38-7.31(3H,m),7.22(1H,ddd,J＝8.0,1.7,1.2Hz),7.16(1H,t,J＝8.0Hz),4.62(1H,s),1.89(2H,s)
中间体(5e)
1H-NMR(400MHz,CDCl
3),δ(ppm):7.32-7.28(5H,m),7.08(1H,br s),6.78(1H,d,J＝8.1Hz),6.69-6.65(2H,m),4.48(1H,s),3.86(3H,s),3.83(3H,s),3.51(2H,m),2.75(2H,t,J＝7.1Hz),1.78(4H,s)；
化合物1-45合成通法
取1倍量的中间体5，和1.5倍量的三乙胺在零摄氏度溶于10ml，再缓慢滴加异氰酸酯或异硫氰酸酯，室温反应2小时，过滤并用甲醇洗涤得到产物白色固体，收率60-80％。以下为化合物1-45的核磁检测结果。
化合物1
1H-NMR(400MHz,DMSO-d6),δ(ppm):8.85(1H,d,J＝8.0Hz),8.64(1H,s),7.40(2H,d,J＝7.8Hz),7.33-7.29(2H,m),7.27-7.24(3H,m),7.18-7.14(3H,m),7.10(2H,dd,J＝7.3,1.0Hz),6.92(1H,d,J＝8.1Hz),6.81(1H,d,J＝7.0Hz),5.46(1H,d,J＝8.1Hz),4.92(1H,m),3.68(3H,s),1.39(3H,d,J＝7.0Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):169.8,154.8,154.5,144.6,140.5,133.8,128.7,128.7,128.6,128.6,127.8,127.0,127.0,126.1,126.1,119.6,119.6,114.4,114.4,56.7,55.6,48.3,23.2.HRMS(ESI)
+calculated for C
24H
25N
3O
3,[M+H]
+:m/z 404.1974,found 404.1976.
化合物2
1H-NMR(400MHz,DMSO-d6),δ(ppm):8.85(1H,d,J＝8.0Hz),8.48(1H,s),8.12(1H,dd,J＝8.3,1.5Hz),8.02(2H,d,J＝8.1Hz),7.42(2H,d,J＝7.1Hz),7.39(1H,dd,J＝8.0,1.5Hz),7.33(2H,t,J＝7.0Hz),7.28(1H,dt,J＝7.2,1.2Hz),7.23(1H,m),7.21-7.14(3H,m),7.10(2H,dd,J＝7.3,1.0Hz),6.95(1H,td,J＝7.9,1.5Hz),5.50(1H,d,J＝8.1Hz),4.93(1H,m),1.39(3H,d,J＝7.0Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):169.6,154.5,144.7,140.1,137.1,129.6,128.7,128.7,128.6,128.6,127.9,127.8,127.2,127.2,127.0,126.1,126.1,123.0,121.7,57.0,48.3,23.2.HRMS(ESI)
+calculated for C
23H
22ClN
3O
2,[M+H]
+:m/z 408.1479,found 408.1473.
化合物3
1H-NMR(400MHz,DMSO-d6),δ(ppm):9.07(1H,s),8.87(1H,d,J＝8.0Hz),7.65(1H,t,J＝2.0Hz),7.40(2H,d,J＝7.7Hz),7.32(2H,d,J＝6.9Hz),7.27(1H,dt,J＝7.2,1.4Hz),7.23(1H,d,J＝8.1Hz),7.20-7.11(5H,m),7.08-7.06(2H,m),6.94(1H,ddd,J＝7.8,2.0,1.0Hz),5.45(1H,d,J＝8.0Hz),4.93(1H,m),1.39(3H,d,J＝7.1Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):169.5,154.4,144.6,142.2,140.2,133.7,128.7,128.7,128.6,128.6,127.9,127.0,127.0,126.1,126.1,121.3,117.3,116.4,56.7,48.3,23.1.HRMS(ESI)
+calculated for C
23H
22ClN
3O
2,[M+H]
+:m/z 408.1479,found 408.1473.
化合物4
1H-NMR(400MHz,DMSO-d6),δ(ppm):8.85(1H,d,J＝8.0Hz),8.72(1H,s),7.40(2H,d,J＝7.8,Hz),7.32(2H,t,J＝8.5Hz),7.25(3H,m),7.17-7.14(3H,m),7.10(2H,dd,J＝7.3,1.0Hz),7.00(3H,m),5.46(1H,d,J＝8.1Hz),4.92(1H,m),1.39(3H,d,J＝7.0Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):169.7,154.7,144.6,140.5,138.1,130.4,129.6,129.6,128.7,128.7,128.6,128.6,127.8,127.1,127.1,127.0,126.0,126.0,118.0,56.6,48.3,23.2,20.8.HRMS(ESI)
+calculated for C
24H
25N
3O
2,[M+H]
+:m/z 388.2025,found 388.2022.
化合物5
1H-NMR(400MHz,DMSO-d6),δ(ppm):8.83(1H,d,J＝8.0Hz),7.88(1H,s),7.41(2H,d,J＝7.3Hz),7.31(2H,t,J＝7.1Hz),7.26-7.14(4H,m),7.10(2H,dd,J＝7.3,1.0Hz),7.00(3H,m),5.45(1H,d,J＝8.1Hz),4.93(1H,m),2.13(6H,s),1.39(3H,d,J＝7.0Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):169.9,155.4,144.7,140.8,136.3,135.7,128.6,128.6,128.5,128.5,128.1,127.7,127.0,126.8,126.8,126.1,126.1,57.1,48.3,23.2,18.7,18.7.HRMS(ESI)
+calculated for C
25H
27N
3O
2,[M+H]
+:m/z 402.2182,found 402.2180.
化合物6
1H-NMR(400MHz,DMSO-d6),δ(ppm):9.26(1H,s),8.88(1H,d,J＝8.0Hz),7.57(4H,s),7.41(2H,d,J＝7.1Hz),7.33(2H,t,J＝7.1Hz),7.27(1H,m),7.17(4H,m),7.10(2H,dd,J＝7.3,1.0Hz),5.48(1H,d,J＝8.1Hz),4.93(1H,m),1.39(3H,d,J＝7.0Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):169.5,154.3,144.6,144.3,140.2,128.7,128.7,128.6,128.6,127.9,127.0,126.5,126.0,126.0,123.7,121.8,121.5,117.6,56.6,48.3,23.2.HRMS(ESI)
+calculated for C
24H
22F
3N
3O
2,[M+H]
+:m/z 442.1742,found 442.1742.
化合物7
1H-NMR(400MHz,DMSO-d6),δ(ppm):8.92(2H,s),8.19-7.12(18H,m),5.56(1H,d,J＝6.8Hz),4.96(1H,m),1.41(3H,d,J＝7.0Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):169.7,155.0,144.7,140.53,135.4,134.2,128.8,128.7,128.7,128.6,128.6,127.9,127.1,127.1,127.0,126.4,126.2,126.1,126.1,125.9,125.6,122.4,121.7,116.3,56.9,48.3,23.2.HRMS(ESI)
+calculated for C
27H
25N
3O
2,[M+H]
+:m/z 424.2025,found 424.2027.
化合物8
1H-NMR(400MHz,DMSO-d6),δ(ppm):10.00(1H,s),8.98(1H,d,J＝8.0Hz),8.36(1H,d, J＝7.8Hz),7.55(2H,d,J＝7.6Hz),7.42(2H,d,J＝7.1Hz),7.34-7.26(5H,m),7.17-7.04(6H,m),6.12(1H,d,J＝7.6Hz),4.93(1H,m),1.39(3H,d,J＝7.0Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):179.9,169.1,144.5,139.9,139.7,128.9,128.9,128.7,128.7,128.5,128.5,127.9,127.4,127.4,127.0,126.0,126.0,124.6,123.1,123.1,60.4,55.4,48.4,23.2.HRMS(ESI)
+calculated for C
23H
23N
3OS,[M+H]
+:m/z 390.1640,found 390.1646.
化合物9
1H-NMR(4e00MHz,DMSO-d6),δ(ppm):10.59(1H,s),9.02(1H,d,J＝8.0Hz),8.79(1H,d,J＝7.6Hz),8.35(2H,s),7.75(1H,s),7.45(2H,d,J＝7.8Hz),7.36-7.28(4H,m),7.18-7.14(3H,m),7.10(2H,dd,J＝7.3,1.0Hz),6.09(1H,d,J＝7.6Hz),4.95(1H,m),1.39(3H,d,J＝7.0Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):179.9,168.7,144.5,142.2,139.1,131.1,130.7,128.9,128.9,128.7,128.7,128.1,127.4,127.4,127.1,126.6,126.0,126.0,125.0,122.1,116.8,60.5,48.4,23.2.HRMS(ESI)
+calculated for C
25H
21F
6N
3OS,[M+H]
+:m/z 526.1388,found 526.1380.
化合物10
1H-NMR(400MHz,DMSO-d6),δ(ppm):10.26(1H,s),8.58(1H,s),7.74(1H,dd,J＝8.9,8.8Hz),7.51(2H,d,J＝8.0Hz),7.40(2H,t,J＝7.2Hz),7.26-7.34(4H,m),7.05(1H,t,J＝8.4Hz),7.00(1H,d,J＝8.2Hz),6.82(2H,d,J＝8.9Hz),5.69(1H,d,J＝8.0Hz),3.69(3H,s)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):170.4,159.3,154.9,154.8,154.5,139.7,133.7,129.0,129.0,128.2,127.3,127.3,126.4,122.6,119.7,119.7,114.4,114.4,111.6,104.7,56.9,55.6.HRMS(ESI)
+calculated for C
22H
19F
2N
3O
3,[M+H]
+:m/z 412.1473,found 412.1479.
化合物11
1H-NMR(400MHz,DMSO-d6),δ(ppm):10.26(1H,s),8.45(1H,s),8.15(1H,dd,J＝8.4,1.5Hz),8.06(1H,d,J＝7.8Hz),7.75(1H,m),7.54(2H,dd,J＝8.5,1.2Hz),7.41(3H,t,J＝7.5Hz),7.36-7.29(2H,m),7.23(1H,td,J＝7.8,1.4Hz),7.06(1H,t,J＝8.5Hz),6.95(1H,td,J＝7.8,1.5Hz),5.72(1H,d,J＝7.8Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):170.2,159.4,154.9,154.5,139.2,136.9,129.6,129.0,129.0,128.3,127.9,127.5,127.5,126.3,123.1,122.5,121.6,111.6,104.7,57.2.HRMS(ESI)
+calculated for C
21H
16ClF
2N
3O
2,[M+H]
+:m/z 416.0977,found 416.0975.
化合物12
1H-NMR(400MHz,DMSO-d6),δ(ppm):10.29(1H,s),8.99(1H,s),7.74(1H,m),7.66(1H,d,J＝1.9Hz),7.52(2H,dd,J＝7.6,1.3Hz),7.41(2H,t,J＝7.2Hz),7.35-7.28(2H,m),7.25(1H,t,J＝8.1Hz),7.19(1H,d,J＝7.8Hz),7.14(1H,d,J＝7.6Hz),7.06(1H,t,J＝8.5Hz),6.96(1H,dd,J＝7.9,2.1Hz),5.69(1H,d,J＝7.8Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):170.1,159.3,154.9,154.5,142.1,139.4,133.7,130.8,129.0,129.0,128.3,127.4,127.4,126.3,122.4,121.5,117.3,116.4,111.6,104.8,56.9.HRMS(ESI)
+calculated for C
21H
16ClF
2N
3O
2,[M+H]
+:m/z 416.0977,found 416.0975.
化合物13
1H-NMR(400MHz,DMSO-d6),δ(ppm):10.26(1H,s),8.58(1H,s),7.74(1H,dd,J＝8.9,8.8Hz),7.51(2H,d,J＝8.0Hz),7.40(2H,t,J＝7.2Hz),7.26-7.34(4H,m),7.08-7.02(4H,m),5.69(1H,d,J＝8.0Hz),2.21(3H,s)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):170.4,159.3,154.9,154.8,139.6,138.0,130.5,129.6,129.6,129.0,129.0,128.2,127.4,127.4,126.4,122.4,118.1,118.1,111.6,104.7,56.9,20.7.HRMS(ESI)
+calculated for C
22H
19F
2N
3O
2,[M+H]
+:m/z 396.1524,found 396.1525.
化合物14
1H-NMR(400MHz,DMSO-d6),δ(ppm):10.23(1H,s),7.88(1H,s),7.75(1H,dd,J＝8.9,8.8Hz),7.53(2H,d,J＝7.5Hz),7.40(2H,t,J＝7.3Hz),7.31(2H,m),7.04(5H,m),5.69(1H,d,J＝8.5Hz),2.14(6H,s)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):170.5,159.3,155.6,154.9,139.8,136.2,135.8,128.9,128.9,128.1,128.1,127.2,127.2,126.2,122.6,111.6,104.8,57.4,18.7,18.7.HRMS(ESI)
+calculated for C
23H
21F
2N
3O
2,[M+H]
+:m/z 410.1680,found 410.1680.
化合物15
1H-NMR(400MHz,DMSO-d6),δ(ppm):10.30(1H,s),9.20(1H,s),7.74(1H,dd,J＝8.9,8.8Hz),7.51(2H,d,J＝8.0Hz),7.40(2H,t,J＝7.2Hz),7.26-7.34(4H,m),7.06(1H,t,J＝8.5Hz),5.69(1H,d,J＝8.0Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):170.4,159.3,154.9,154.8,144.2, 139.6,129.0,129.0,128.4,127.4,127.4,126.4,124.7,122.4,121.9,121.6,117.7,111.8,104.7,56.9.HRMS(ESI)
+calculated for C
22H
16F
5N
3O
2,[M+H]
+:m/z 450.1241,found 450.1240.
化合物16
1H-NMR(400MHz,DMSO-d6),δ(ppm):10.32(1H,s),8.89(1H,s),8.16(1H,d,J＝8.3,Hz),8.06(1H,dd,J＝7.6,1.0Hz),7.89(1H,dd,J＝7.8,1.3Hz),7.77(1H,m),7.71(1H,d,J＝7.9Hz),7.59-7.50(5H,m),7.44-7.39(3H,m),7.36-7.29(2H,m),7.07(1H,t,J＝7.0Hz),5.79(1H,d,J＝7.9Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):170.4,159.4,158.0,154.9,139.7,135.3,134.2,129.1,129.1,128.9,128.3,127.4,127.4,126.4,126.3,126.2,125.9,125.6,122.6,122.5,121.6,116.3,111.6,104.7,57.2.HRMS(ESI)
+calculated for C
25H
19F
2N
3O
2,[M+H]
+:m/z 432.1524,found 432.1522.
化合物17
1H-NMR(400MHz,DMSO-d6),δ(ppm):10.37(1H,s),9.94(1H,s),8.41(1H,d,J＝7.6Hz),7.70(1H,m),7.55(4H,t,J＝8.9Hz),7.40(2H,t,J＝7.2Hz),7.35-7.28(4H,m),7.12-7.03(2H,m),6.33(1H,d,J＝7.6Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):180.3,169.7,159.4,154.9,139.9,138.8,129.0,129.0,128.9,128.9,128.4,127.7,127.7,126.6,124.6,123.1,123.1,122.4,111.6,104.7,60.7.HRMS(ESI)
+calculated for C
21H
17F
2N
3OS,[M+H]
+:m/z 398.1139,found 398.1137.
化合物18
1H-NMR(400MHz,CDCl
3),δ(ppm):10.55(1H,s),9.98(1H,s),8.89(1H,d,J＝7.0Hz),8.36(2H,s),7.76(1H,s),7.59(2H,d,J＝7.5Hz),7.44-7.27(5H,m),7.17(3H,dd,J＝7.7,6.8Hz),7.10(1H,td,J＝7.3,1.3Hz),6.24(1H,d,J＝7.6Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):180.2,168.9,142.2,138.9,135.9,132.9,130.9,130.8,130.5,128.9,128.9,128.4,127.6,127.6,126.5,126.3,125.9,122.3,122.1,116.9,60.9.HRMS(ESI)
+calculated for C
23H
15F
8N
3OS,[M+H]
+:m/z 534.0886,found 534.0883.
化合物19
1H-NMR(400MHz,DMSO-d6),δ(ppm):9.82(1H,s),8.64(1H,s),7.53(2H,d,J＝7.4Hz),7.40(2H,t,J＝7.7Hz),7.33-7.26(4H,m),7.16(2H,dd,J＝7.7,7.1Hz),7.09(1H,td,J＝7.3,1.3Hz),7.03(1H,d,J＝8.0Hz),6.28(2H,d,J＝9.0Hz),5.64(1H,d,J＝8.0Hz),3.68(3H,s),2.03(3H,s)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):169.8,154.9,154.5,140.4,136.0,133.8,132.6,130.8,128.9,128.9,128.1,127.2,127.2,126.5,126.1,125.7,119.7,119.7,114.4,114.4,57.2,55.6,18.0.HRMS(ESI)
+calculated for C
23H
23N
3O
3,[M+H]
+:m/z 390.1818,found 390.1814.
化合物20
1H-NMR(400MHz,DMSO-d6),δ(ppm):9.83(1H,s),8.49(1H,s),8.15(1H,dd,J＝8.4,1.5Hz),8.11(1H,d,J＝7.9Hz),7.56(2H,d,J＝7.3Hz),7.44-7.37(3H,m),7.35-7.29(2H,m),7.23(1H,td,J＝7.9,1.5Hz),7.17(3H,dd,J＝7.7,6.8Hz),7.09(1H,td,J＝7.3,1.3Hz),6.96(1H,td,J＝7.8,1.5Hz),5.67(1H,d,J＝7.8Hz),2.03(3H,s)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):169.7,154.5,139.9,137.0,136.1,132.7,130.8,129.6,128.9,128.2,127.9,127.4,126.5,126.1,125.7,123.1,121.7,121.2,57.5,18.0.HRMS(ESI)
+calculated for C
22H
20ClN
3O
2,[M+H]
+:m/z 394.1322,found 394.1324.
化合物21
1H-NMR(400MHz,DMSO-d6),δ(ppm):9.85(1H,s),9.08(1H,s),7.66(1H,t,J＝2.0Hz),7.54(2H,d,J＝7.8Hz),7.41(2H,t,J＝7.7Hz),7.34-7.26(2H,m),7.24(2H,d,J＝7.9Hz),7.17(3H,dd,J＝7.7,6.8Hz),7.09(1H,td,J＝7.3,1.3Hz),5.64(1H,d,J＝7.8Hz),2.03(3H,s)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):169.5,154.5,142.1,140.1,135.9,133.7,132.7,130.8,130.8,128.9,128.9,128.2,127.2,127.2,126.5,126.2,125.7,121.4,117.3,116.4,57.1,18.0.HRMS(ESI)
+calculated for C
22H
20ClN
3O
2,[M+H]
+:m/z 394.1322,found 394.1324.
化合物22
1H-NMR(400MHz,DMSO-d6),δ(ppm):9.82(1H,s),8.72(1H,s),7.53(2H,d,J＝7.4Hz),7.40(2H,t,J＝7.7Hz),7.31(2H,t,J＝7.6Hz),7.26(2H,d,J＝8.4Hz),7.09(2H,td,J＝7.3,1.3Hz),7.03(2H,d,J＝8.0Hz),5.64(1H,d,J＝8.0Hz),2.21(3H,s),2.03(3H,s)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):169.8,154.8,140.4,138.1,136.0,132.7,130.8,130.5,129.6,129.6,128.9, 128.9,128.1,127.2,127.2,126.5,126.1,125.7,118.1,118.1,57.1,20.8,18.0.HRMS(ESI)
+calculated for C
23H
23N
3O
2,[M+H]
+:m/z 374.1869,found 374.1865.
化合物23
1H-NMR(400MHz,DMSO-d6),δ(ppm):9.81(1H,s),7.88(1H,s),7.55(2H,d,J＝7.2Hz),7.40(2H,t,J＝7.3Hz),7.32(2H,d,J＝7.5Hz),7.19-7.07(4H,m),7.01(3H,s),5.64(1H,d,J＝7.8Hz),2.14(6H,s),2.03(3H,s)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):169.9,155.6,140.5,136.2,136.1,135.8,132.7,130.8,128.9,128.9,128.1,128.1,128.0,127.0,127.0,126.5,126.1,125.7,57.5,18.7,18.0.HRMS(ESI)
+calculated for C
24H
25N
3O
2,[M+H]
+:m/z 388.2025,found 388.2020.
化合物24
1H-NMR(400MHz,DMSO-d6),δ(ppm):9.86(1H,s),9.27(1H,s),7.58-7.54(6H,m),7.40(2H,t,J＝7.7Hz),7.35-7.29(3H,m),7.17(2H,dd,J＝7.7,6.8Hz),7.09(1H,td,J＝7.3,1.3Hz),5.67(1H,d,J＝7.8Hz),2.03(3H,s)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):169.8,154.8,144.3,140.4,138.1,136.0,132.7,130.8,128.9,128.9,128.1,127.2,127.2,126.5,126.5,126.1,125.7,121.6,117.7,117.7,57.1,18.0.HRMS(ESI)
+calculated for C
23H
20F
3N
3O
2,[M+H]
+:m/z 428.1586,found 428.1590.
化合物25
1H-NMR(400MHz,DMSO-d6),δ(ppm):9.88(1H,s),8.93(1H,s),8.18(2H,d,J＝8.6Hz),8.06(1H,dd,J＝7.7,0.9Hz),7.89(2H,dd,J＝8.0,1.5Hz),7.76(1H,d,J＝7.9Hz),7.62-7.52(5H,m),7.42(3H,m),7.34(2H,m),7.17(2H,dd,J＝7.7,7.1Hz),7.09(1H,td,J＝7.3,1.3Hz),5.73(1H,d,J＝7.8Hz),2.07(3H,s)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):169.8,155.1,140.4,136.1,135.4,134.2,132.7,130.9,128.9,128.9,128.8,128.2,127.3,127.3,126.5,126.4,126.3,126.1,126.0,125.7,125.6,122.5,121.7,116.3,57.4,18.0.HRMS(ESI)
+calculated for C
26H
23N
3O
2,[M+H]
+:m/z 410.1869,found 410.1870.
化合物26
1H-NMR(400MHz,DMSO-d6),δ(ppm):9.99(1H,s),8.94(1H,s),8.45(1H,d,J＝7.6Hz),7.57(4H,m),7.41(2H,t,J＝7.7Hz),7.35-7.26(4H,m),7.18-7.08(4H,m),6.26(1H,d,J＝7.6Hz),2.03(3H,s)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):180.2,169.1,139.9,139.4,135.9,132.9,130.8,128.9,128.9,128.2,127.6,127.6,126.5,126.1,125.9,124.6,123.1,123.1,60.9,18.0.HRMS(ESI)
+calculated for C
22H
21N
3OS,[M+H]
+:m/z 376.1484,found 376.1486.
化合物27
1H-NMR(400MHz,DMSO-d6),δ(ppm):10.55(1H,s),9.98(1H,s),8.89(1H,d,J＝7.0Hz),8.36(2H,s),7.76(1H,s),7.59(2H,d,J＝7.5Hz),7.44-7.27(5H,m),7.17(3H,dd,J＝7.7,6.8Hz),7.10(1H,td,J＝7.3,1.3Hz),6.24(1H,d,J＝7.6Hz),2.03(3H,s)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):180.2,168.9,142.2,138.9,135.9,132.9,130.9,130.8,130.5,128.9,128.9,128.4,127.6,127.6,126.5,126.3,125.9,122.3,122.1,116.9,60.9,18.0.HRMS(ESI)
+calculated for C
24H
19F
6N
3OS,[M+H]
+:m/z 512.1231,found 512.1233.
化合物28
1H-NMR(400MHz,DMSO-d6),δ(ppm):10.60(1H,s),8.58(1H,s),7.95(1H,s),7.50(3H,m),7.40(2H,t,J＝7.2Hz),7.34-7.26(5H,m),7.01(1H,d,J＝7.9Hz),6.82(2H,d,J＝9.1Hz),5.53(1H,d,J＝7.9Hz),3.69(3H,s)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):170.3,155.0,154.6,140.8,139.3,113.6,131.4,129.2,128.4,127.4,126.7,122.1,122.0,119.7,119.7,118.5,114.4,114.4,57.8,55.6.HRMS(ESI)
+calculated for C
22H
20BrN
3O
3,[M+H]
+:m/z 454.0766,found 454.0762.
化合物29
1H-NMR(400MHz,DMSO-d6),δ(ppm):10.61(1H,s),8.44(1H,s),8.14(1H,dd,J＝8.5,1.5Hz),8.07(1H,d,J＝7.7Hz),7.95(1H,s),7.52(3H,d,J＝7.2Hz),7.42(3H,t,J＝7.3Hz),7.36-7.20(4H,m),6.96(1H,td,J＝7.7,1.6Hz),5.53(1H,d,J＝7.8Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):170.1,154.6,140.7,138.8,136.9,131.4,129.6,129.2,129.2,128.5,127.5,127.5,126.7,123.2,122.1,121.9,121.6,121.2,118.5,58.1.HRMS(ESI)
+calculated for C
21H
17BrClN
3O
2,[M+H]
+:m/z 458.0271,found 458.0276.
化合物30
1H-NMR(400MHz,DMSO-d6),δ(ppm):10.63(1H,s),8.98(1H,s),7.93(1H,s),7.65(1H,s),7.51(3H,m),7.41(2H,t,J＝7.3Hz),7.35-7.19(5H,m),7.14(1H,d,J＝8.4Hz),6.96(1H,d,J＝ 7.8Hz),5.51(1H,d,J＝7.8Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):169.9,154.6,141.9,140.6,138.9,133.7,131.4,130.8,129.2,129.2,128.5,127.4,127.4,126.8,122.1,122.0,121.5,118.5,117.4,116.5,57.8.HRMS(ESI)
+calculated for C
21H
17BrClN
3O
2,[M+H]
+:m/z 458.0271,found 458.0276.
化合物31
1H-NMR(400MHz,DMSO-d6),δ(ppm):10.60(1H,s),8.58(1H,s),7.95(1H,s),7.50(3H,m),7.40(2H,t,J＝7.2Hz),7.34-7.26(5H,m),7.07-7.00(3H,m),5.53(1H,d,J＝7.9Hz),2.21(3H,s)；
13C-NMR(100MHz,CDCl
3),δ(ppm):
13C-NMR(100MHz,DMSO-d6),δ(ppm):170.3,155.0,154.6,140.8,139.3,113.6,131.4,129.2,128.4,127.4,126.7,122.1,122.0,119.7,119.7,118.5,114.4,114.4,57.8,55.6.HRMS(ESI)
+calculated for C
22H
20BrN
3O
2,[M+H]
+:m/z 438.0817,found 438.0819.
化合物32
1H-NMR(400MHz,DMSO-d6),δ(ppm):10.59(1H,s),7.94(1H,s),7.83(1H,s),7.51(3H,d,J＝7.4Hz),7.41(2H,t,J＝7.3Hz),7.34-7.25(3H,m),7.02(3H,m),5.53(1H,d,J＝8.2Hz),2.14(6H,s)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):170.4,155.7,140.7,139.5,136.1,135.8,131.4,129.1,129.1,128.3,128.1,127.2,127.2,126.7,126.2,122.0,121.9,118.5,58.1,18.7,18.7.HRMS(ESI)
+calculated for C
23H
22BrN
3O
2,[M+H]
+:m/z 452.0974,found 452.0975.
化合物33
1H-NMR(400MHz,DMSO-d6),δ(ppm):10.63(1H,s),9.19(1H,s),7.94(1H,s),7.58(4H,s),7.51(3H,m),7.41(2H,t,J＝7.3Hz),7.35(1H,tt,J＝7.4,1.3Hz),7.31-7.26(3H,m),5.54(1H,d,J＝7.8Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):169.9,154.5,144.1,140.6,138.9,131.4,129.2,129.2,128.5,127.4,127.4,126.8,126.6,126.4,123.7,122.1,122.0,118.5,117.7,117.7,57.7.HRMS(ESI)
+calculated for C
22H
17BrF
3N
3O
2,[M+H]
+:m/z 492.0534,found 492.0530.
化合物34
1H-NMR(400MHz,DMSO-d6),δ(ppm):10.66(1H,s),8.88(1H,s),8.16(1H,s),8.05(1H,dd,J＝7.8,1.0Hz),7.97(1H,t,J＝1.8Hz),7.90(1H,dd,J＝8.1,1.4Hz),7.71(1H,d,J＝7.8Hz),7.58-7.52(6H,m),7.42(3H,m),7.35(1H,tt,J＝7.4,1.3Hz),7.28(2H,m),5.61(1H,d,J＝7.8Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):170.2,155.2,140.7,139.2,135.2,134.2,131.4,129.2,129.2,128.9,128.5,127.4,127.4,126.8,126.4,126.3,126.0,125.6,122.6,122.1,122.0,121.6,118.5,116.4,58.0.HRMS(ESI)
+calculated for C
25H
20BrN
3O
2,[M+H]
+:m/z 474.0817,found474.0815.
化合物35
1H-NMR(400MHz,DMSO-d6),δ(ppm):10.70(1H,s),9.94(1H,s),8.43(1H,d,J＝7.4Hz),7.95(1H,s),7.58-7.26(13H,m),7.11(1H,tt,J＝7.4,1.0Hz),6.17(1H,d,J＝7.4Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):180.4,169.5,140.7,139.8,138.4,131.4,129.2,129.2,128.9,128.9,128.6,127.7,127.7,126.8,124.7,123.1,123.1,122.1,122.0,118.5,61.5.HRMS(ESI)
+calculated for C
21H
18BrN
3OS,[M+H]
+:m/z 440.0432,found 440.0430.
化合物36
1H-NMR(400MHz,DMSO-d6),δ(ppm):10.74(1H,s),10.46(1H,s),8.90(1H,d,J＝7.4Hz),8.34(2H,s),7.95(1H,s),7.77(1H,s),7.55-7.50(3H,m),7.42(2H,t,J＝7.1Hz),7.35(1H,t,J＝7.2Hz),7.31-7.26(2H,m),6.17(1H,d,J＝7.2Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):180.4,169.0,142.1,140.6,131.9,131.4,130.8,130.5,129.2,129.2,128.7,127.8,127.8,126.9,125.0,122.3,122.1,122.0,118.5,61.6.HRMS(ESI)
+calculated for C
23H
16BrF
6N
3OS,[M+H]
+:m/z 576.0180,found 576.0180.
化合物37
1H-NMR(400MHz,DMSO-d6),δ(ppm):8.60(1H,s),8.44(1H,t,J＝5.4Hz),7.37-7.24(7H,m),6.88(1H,d,J＝8.8Hz),6.81(2H,d,J＝9.0Hz),6.77(2H,d,J＝8.0Hz),6.61(1H,dd,J＝8.1,1.8Hz),5.32(1H,d,J＝8.1Hz),3.68(9H,s),3.27(2H,q,J＝6.8Hz),2.26(2H,t,J＝7.1Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):170.7,154.8,154.5,149.0,147.7,140.6,133.8,132.2,128.7,128.7,127.8,127.1,127.1,120.9,120.4,119.6,119.6,114.4,114.4,112.9,112.3,56.8,55.9,55.8,55.6,40.9,34.9.HRMS(ESI)
+calculated for C
26H
29N
3O
5,[M+H]
+:m/z 464.2185,found 464.2180.
化合物38
1H-NMR(400MHz,DMSO-d6),δ(ppm):8.45(2H,s),8.12(1H,d,J＝8.2Hz),7.98(1H,d,J＝7.0Hz),7.40-7.37(3H,m),7.34(2H,t,J＝7.0Hz),7.30-7.27(1H,m),7.22(1H,td,J＝7.8,1.5Hz),6.94(1H,td,J＝7.9,1.5Hz),6.78(1H,d,J＝6.8Hz),6.76(1H,s),6.62(1H,dd,J＝8.2,1.5Hz),5.35(1H,dd,J＝7.8,3.0Hz),3.69(6H,s),3.28(2H,q,J＝6.8Hz),2.63(2H,t,J＝6.9Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):170.5,154.4,149.0,147.7,140.1,137.1,132.2,129.6,128.8,128.8,127.9,127.2,127.2,123.0,121.6,121.2,120.9,112.9,112.3,57.1,55.9,55.8,40.9,34.9.HRMS(ESI)
+calculated for C
25H
26ClN
3O
4,[M+H]
+:m/z 468.1690,found 468.1692.
化合物39
1H-NMR(400MHz,DMSO-d6),δ(ppm):9.02(1H,s),8.46(1H,s),7.64(1H,s),7.35-7.22(6H,m),7.12(1H,d,J＝7.6Hz),7.08(1H,d,J＝7.4Hz),6.94(1H,d,J＝7.2Hz),6.76(2H,brs),6.60(1H,d,J＝7.4Hz),5.32(1H,d,J＝7.4Hz),3.69(6H,s),3.28(2H,q,J＝6.8Hz),2.62(2H,t,J＝6.9Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):170.4,154.4,149.0,147.7,142.2,140.3,133.7,132.1,130.8,128.8,128.8,127.9,127.1,127.1,121.3,120.9,117.2,116.3,112.9,112.3,57.1,55.9,55.8,40.9,34.9.HRMS(ESI)
+calculated for C
25H
26ClN
3O
4,[M+H]
+:m/z 468.1690,found 468.1692.化合物40
1H-NMR(400MHz,DMSO-d6),δ(ppm):8.68(1H,s),8.44(1H,t,J＝5.5Hz),7.37-7.30(4H,m),7.28-7.22(3H,m),7.02(2H,d,J＝8.3Hz),6.93(1H,d,J＝8.2Hz),6.78(1H,d,J＝6.8Hz),6.76(1H,s),6.60(1H,dd,J＝8.2,1.5Hz),5.32(1H,d,J＝8.0Hz),3.69(3H,s),3.68(3H,s),3.27(2H,q,J＝6.8Hz),2.62(2H,t,J＝6.9Hz),2.20(3H,s)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):170.7,154.8,149.0,147.7,140.6,138.2,132.2,130.4,129.6,129.6,128.7,128.7,127.8,127.1,127.1,120.9,118.0,118.0,112.9,112.3,56.8,55.9,55.8,40.9,34.9,20.8.HRMS(ESI)
+calculated for C
26H
29N
3O
4,[M+H]
+:m/z 448.2236,found 448.2240.
化合物41
1H-NMR(400MHz,DMSO-d6),δ(ppm):8.44(1H,t,J＝5.4Hz),7.85(1H,s),7.37(2H,d,J＝7.1Hz),7.32(2H,t,J＝7.1Hz),7.26(1H,m),7.05-6.98(4H,m),6.79(1H,d,J＝8.1Hz),6.77(1H,d,J＝1.8Hz),6.62(1H,dd,J＝8.1,1.8Hz),5.33(1H,d,J＝8.1Hz),3.70(3H,s),3.69(3H,s),3.27(2H,q,J＝6.8Hz),2.63(2H,t,J＝7.1Hz),2.12(6H,s)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):170.7,155.4,149.1,147.7,140.9,136.3,135.7,132.2,128.6,128.6,128.1,127.6,126.8,126.8,126.1,120.9,112.9,112.3,57.1,55.9,55.8,40.9,34.9,18.7,18.7.HRMS(ESI)
+calculated for C
27H
31N
3O
4,[M+H]
+:m/z 462.2393,found 462.2396.
化合物42
1H-NMR(400MHz,DMSO-d6),δ(ppm):8.89(1H,s),8.50(1H,t,J＝5.5Hz),8.17(1H,d,J＝8.3Hz),8.04(1H,dd,J＝7.7,0.7Hz),7.88(1H,dd,J＝8.0,1.5Hz),7.64(1H,d,J＝8.0Hz),7.57-7.49(3H,m),7.44-7.33(5H,m),7.30-7.27(1H,m),6.79-6.77(2H,m),6.63(1H,dd,J＝8.2,1.9Hz),5.42(1H,d,J＝8.0Hz),3.69(3H,s),3.68(3H,s),3.31(2H,q,J＝6.8Hz),2.65(2H,t,J＝6.9Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):170.3,154.0,149.0,147.7,144.3,140.2,132.1,128.8,128.8,127.9,127.1,127.1,126.5,120.9,117.6,117.6,112.9,112.2,56.8,55.9,55.8,40.9,34.9.HRMS(ESI)
+calculated for C
26H
26F
3N
3O
4,[M+H]
+:m/z 502.1954,found 502.1950.
化合物43
1H-NMR(400MHz,DMSO-d6),δ(ppm):8.89(1H,s),8.50(1H,t,J＝5.5Hz),8.17(1H,d,J＝8.3Hz),8.04(1H,dd,J＝7.7,0.7Hz),7.88(1H,dd,J＝8.0,1.5Hz),7.64(1H,d,J＝8.0Hz),7.57-7.49(3H,m),7.44-7.33(5H,m),7.30-7.27(1H,m),6.79-6.77(2H,m),6.63(1H,dd,J＝8.2,1.9Hz),5.42(1H,d,J＝8.0Hz),3.69(3H,s),3.68(3H,s),3.31(2H,q,J＝6.8Hz),2.65(2H,t,J＝6.9Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):170.6,155.0,149.0,147.7,140.5,135.5,134.2,132.2,128.9,128.8,128.8,127.8,127.1,126.4,126.2,125.9,125.5,122.4,121.7,120.9,116.2,112.9,112.3,57.1,55.9,55.8,40.9,34.9.HRMS(ESI)
+calculated for C
29H
29N
3O
4,[M+H]
+:m/z 484.2236,found 484.2240.
化合物44
1H-NMR(400MHz,DMSO-d6),δ(ppm):9.96(1H,s),8.57(1H,t,J＝5.4Hz),8.33(1H,d,J＝7.7Hz),7.54(2H,d,J＝8.3Hz),7.39-7.26(7H,m),7.10(1H,t,J＝7.4Hz),6.78(1H,d,J＝8.4Hz), 6.76(1H,d,J＝1.9Hz),6.60(1H,dd,J＝8.2,1.8Hz),5.99(1H,d,J＝7.7Hz),3.69(6H,s),3.28(2H,q,J＝6.8Hz),2.62(2H,t,J＝6.9Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):179.9,169.9,149.0,147.7,139.9,139.7,132.1,128.9,128.9,128.7,128.7,127.9,127.3,127.3,124.6,123.1,123.1,120.9,112.9,112.3,60.5,55.9,55.8,40.9,34.9.HRMS(ESI)
+calculated for C
25H
27N
3O
3S,[M+H]
+:m/z 450.1851,found 450.1856.
化合物45
1H-NMR(400MHz,DMSO-d6),δ(ppm):10.55(1H,s),8.76(1H,d,J＝7.6Hz),8.61(1H,t,J＝5.4Hz),8.34(2H,br s),7.75(1H,br s),7.42-7.27(5H,m),6.78(1H,d,J＝8.4Hz),6.76(1H,d,J＝1.9Hz),6.60(1H,dd,J＝8.2,1.8Hz),5.96(1H,d,J＝7.7Hz),3.70(3H,s),3.69(3H,s),3.31(2H,q,J＝6.8Hz),2.64(2H,t,J＝6.9Hz)；
13C-NMR(100MHz,DMSO-d6),δ(ppm):179.9,169.6,149.0,147.7,142.2,139.1,132.1,130.8,130.5,128.8,128.8,128.1,1127.4,127.4,125.0,122.3,120.9,112.9,112.2,60.5,55.9,55.8,40.9,34.9.HRMS(ESI)
+calculated for C
27H
25F
6N
3O
3S,[M+H]
+:m/z 586.1599,found 586.1592.
实施例2 式Ⅱ化合物的合成通法
式Ⅱ化合物的合成与实施例1类似，仅将原料(R)-苯甘氨酸替换为(S)-苯甘氨酸。以下面化合物46为例。
Scheme 2 Reagents and conditions：(a)MeOH,1N NaOH；HCl pH＝3；(b)N-Methylmorpholine,iso-butylchloroformate，THF，-20℃，2，4-difluoroanilie；(c)HCl/MeOH，r.t.；(d)CH
2Cl
2，TEA，isothiocyanates，r.t.
合成方法：将实施例1中的(R)-苯甘氨酸替换为(S)-本甘氨酸，合成方法同实施例1。
试验例1 化合物1～46的激酶激动活性及自噬率活性
本实验的目的是检测本发明的化合物对体外ULK1酶激活活性，及对细胞的自噬率活性。
ULK1酶活实验是利用ADP-Glo
TMKinase Assay+ULK1 Kinase Enzyme System(Promega,Madison,WI,USA)测得，通过GraphPad Prism5 software(San Diego,CA,USA)处理数据，结果见表1。细胞的自噬率活性是通过MDC荧光染色分析实验方法测定。
表1 化合物1～46激酶激动活性及自噬率活性
实验结果表明，本发明的化合物均对ULK1具有激动活性及自噬活性，其中，化合物6、化合物15、化合物18、化合物27、化合物36、化合物46的效果较好，最优的，化合物18(记为BL-918)对ULK1具有较强的激动活性及自噬活性。
试验例2 化合物18(BL-918)诱导自噬机制研究
为了进一步研究BL-918诱导自噬的分子机制，我们首先利用透射电子显微镜对BL-918处理过得SH-SY5Y细胞进行了观测(图1A)，结果表明BL-918不仅使Beclin-1和LC3-II的表达上调，同时使SQSTM1/p62发生了下调；并且在Bafilomycin A1存在下，LC3-II和SQSTM1/p62发生了明显的聚集(图1B)，以上实验结果表明BL-918加强了自噬流的产生。
由于ULK复合体与自噬小体的形成密切相关，因此我们接下来检测了ULK复合体相关蛋白的表达。BL-918使ULK1和mAtg13的磷酸化上调，并且使ULK复合体上游的负调控因子mTOR发生了去磷酸化。进一步，通过免疫共沉淀实验发现BL-918是ULK复合体的稳定性得到了增强(图1C)。为了验证化合物BL-9184诱导的自噬是否是通过靶向ULK1，siRNA被用于沉默ULK1的表达。我们发现GFP-LC3荧光点基本消失了(图1D，1E)，综上结果表明化合物BL-918激活自噬是通过靶向ULK1激活ULK复合体实现的。
试验例3 化合物BL-918的细胞保护活性
为了检测BL-918有诱导的自噬是否具有细胞保护活性。我们建立了MPP
+诱导的SH-SY5Y细胞损伤模型，实验结果表明，BL-918能够一定程度上逆转由MPP
+诱导的SH-SY5Y细胞的死亡(图2A)。这种保护活性能够被自噬抑制剂3-MA和si-ULK1逆转(图2B)，进一步说明BL-918是通过诱导自噬对细胞产生的保护效应。
试验例4 化合物BL-918的体内活性评价
为了检测BL-918在体内的保护活性，我们进而建立了由MPP
+诱导的大鼠PD模型。我们测定了大鼠的爬杆和游泳实验的行为学(图3A)。实验结果表明BL-918治疗的大鼠在行为学上显示了明显的改善。并且我们进一步测定了大鼠纹状体的多巴胺水平(图3B)，发现BL-918治疗组一定程度上改善了纹状体多巴胺的下降，并且BL-918能够使纹状体中的酪氨酸羟化酶含量提高(图3C)，并没有表现出明显的毒性。
Claims (23)
- 结构式如式Ⅰ或式Ⅱ所示的化合物，或者该化合物在药学上可接受的盐在制备抗帕金森药物中的用途：
其中，R 1为R 11为氢、烷基、烷氧基或卤素；R 12为氢、烷基、烷氧基或卤素；R 13为氢、烷基、烷氧基或卤素；m为1或2；y为1或2；z为1或2；
R 2为R 21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
X为O或S。 - 根据权利要求1所述的用途，其特征在于：所述抗帕金森药物为ULK1激动剂类药物。
- 根据权利要求1或2所述的用途，其特征在于：结构式如式Ⅰ所示。
- 根据权利要求1～3任一项所述的用途，其特征在于：X为O。
- 根据权利要求4所述的用途，其特征在于：R 1为R 13为烷基、烷氧基或卤素；z为1或2；
R 2为R 21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
优选R 1为R 13为烷基、烷氧基或卤素；
R 2为R 21为氢、C1-C3烷基、烷氧基、卤代C1-C3烷基或卤素；
更优选R 1为
R 2为
更优选R 1为R 2为
- 根据权利要求4所述的用途，其特征在于：R 1为R 12为氢、烷基、烷氧基或卤素；y为1或2；
R 2为R 21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
优选R 1为R 12为氢、烷基、烷氧基或卤素；
R 2为R 21为氢、C1-C3烷基、烷氧基、卤代C1-C3烷基或卤素；
更优选R 1为
R 2为
更优选R 1为R 2为
- 根据权利要求4所述的用途，其特征在于：R 1为R 11为氢、烷基、烷氧基或卤素；m为1或2；
R 2为R 21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
优选R 1为R 111为烷基或烷氧基；R 112为烷基或烷氧基；
R 2为
更优选R 1为
R 2为
- 根据权利要求1～3任一项所述的用途，其特征在于：X为S。
- 根据权利要求8所述的用途，其特征在于：R 1为R 13为烷基、烷氧基或卤素；y为1或2；
R 2为R 21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
优选R 1为R 13为烷基、烷氧基或卤素；
R 2为R 21为氢、C1-C3烷基、烷氧基、卤代C1-C3烷基或卤素；
更优选R 1为
R 2为
更优选R 1为R 2为
- 根据权利要求8所述的用途，其特征在于：R 1为R 12为氢、烷基、烷氧基或卤素；y为1或2；
R 2为R 21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
优选R 1为R 12为氢、烷基、烷氧基或卤素；
R 2为R 21为氢、C1-C3烷基、烷氧基、卤代C1-C3烷基或卤素；
更优选R 1为
R 2为
更优选R 1为R 2为
- 根据权利要求8所述的用途，其特征在于：R 1为R 11为氢、烷基、烷氧基或卤素；m为1或2；
R 2为R 21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
优选R 1为R 111为烷基或烷氧基；R 112为烷基或烷氧基；
R 2为
更优选R 1为R 2为
- 根据权利要求1或2所述的用途，其特征在于：化合物的结构式如下：结构式如下所示的化合物或其药学上可接受的盐：
- 结构式如式Ⅰ或式Ⅱ所示的化合物或其药学上可接受的盐：
其中，R 1为R 11氢、烷基、烷氧基或卤素；R 12为氢、烷基、烷氧基或卤素；m为1或2；y为1或2；
R 2为R 21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
X为S。 - 根据权利要求13所述的化合物或其药学上可接受的盐，其特征在于：结构式如式Ⅰ所示。
- 根据权利要求13或14所述的化合物或其药学上可接受的盐，其特征在于：R 1为
R 2为
优选R 1为R 2为
- 根据权利要求13或14所述的化合物或其药学上可接受的盐，其特征在于：R 1为R 12为氢、烷基、烷氧基或卤素；y为1或2；
R 2为R 21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
优选R 1为R 12为氢、烷基、烷氧基或卤素；
R 2为R 21为氢、C1-C3烷基、烷氧基、卤代C1-C3烷基或卤素；
更优选R 1为
R 2为
更优选R 1为R 2为
- 根据权利要求13或14所述的化合物或其药学上可接受的盐，其特征在于：R 1为R 11为氢、烷基、烷氧基或卤素；m为1或2；
R 2为R 21为氢、烷基、烷氧基、卤代烷基或卤素；n为1 或2；
优选R 1为R 111为烷基或烷氧基；R 112为烷基或烷氧基；
R 2为
更优选R 1为R 2为
- 结构式如式Ⅰ或式Ⅱ所示的化合物或其药学上可接受的盐：
其中，R 1为R 11为氢、烷基、烷氧基或卤素；R 12为氢、烷基、烷氧基或卤素；R 13为氢、烷基、烷氧基或卤素；m为1或2；y为1或2；z为1或2；
R 2为R 21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
X为O。 - 根据权利要求18所述的化合物或其药学上可接受的盐，其特征在于：结构式如式Ⅰ所示。
- 根据权利要求18或19所述的化合物或其药学上可接受的盐，其特征在于：R 1为R 13为烷基、烷氧基或卤素；z为1或2；
R 2为R 21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
优选R 1为R 13为烷基、烷氧基或卤素；
R 2为R 21为氢、C1-C3烷基、烷氧基、卤代C1-C3烷基或卤素；
更优选R 1为
R 2为
更优选R 1为R 2为
- 根据权利要求18或19所述的化合物或其药学上可接受的盐，其特征在于：R 1为R 12为氢、烷基、烷氧基或卤素；y为1或2；
R 2为R 21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
优选R 1为R 12为氢、烷基、烷氧基或卤素；
R 2为R 21为氢、C1-C3烷基、烷氧基、卤代C1-C3烷基或卤素；
更优选R 1为
R 2为
更优选R 1为R 2为
- 根据权利要求18或19所述的化合物或其药学上可接受的盐，其特征在于：R 1为R 11为氢、烷基、烷氧基或卤素；m为1或2；
R 2为R 21为氢、烷基、烷氧基、卤代烷基或卤素；n为1或2；
优选R 1为R 111为烷基或烷氧基；R 112为烷基或烷氧基；
R 2为
更优选R 1为
R 2为
- 结构式如下所示的化合物或其药学上可接受的盐：
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| CN201710038351.5 | 2017-01-18 | ||
| CN201710038351.5A CN106748892B (zh) | 2017-01-18 | 2017-01-18 | 靶向自噬激动剂及其在神经退行性疾病治疗药物中的应用 |
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| WO2024030332A1 (en) * | 2022-08-01 | 2024-02-08 | Verge Analytics, Inc. | Methods of treating neurological disorders with activators of unc51-like autophagy activating kinase 1 (ulk1) |
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| CN112057442A (zh) * | 2020-08-27 | 2020-12-11 | 四川大学 | 一种硫脲类化合物的抗肌萎缩侧索硬化作用 |
| CN119700734B (zh) * | 2025-02-11 | 2025-11-21 | 山东大学齐鲁医院 | Bl-918在制备治疗腓骨肌萎缩症2k药物中的应用 |
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|---|---|---|---|---|
| US6391917B1 (en) * | 1998-01-21 | 2002-05-21 | Zymogenetics, Inc. | Dialkyl ureas as calcitonin mimetics |
| WO2004022528A2 (en) * | 2002-09-09 | 2004-03-18 | Nps Allelix Corp. | Arylglycine derivatives and their use as glycine transport inhibitors |
| WO2004022534A1 (en) * | 2002-09-09 | 2004-03-18 | Nps Allelix Corp. | Arylglycine derivatives for use as glycine transport inhibitors |
| WO2006063293A2 (en) * | 2004-12-07 | 2006-06-15 | Portola Pharmaceuticals, Inc. | THIOUREAS AS FACTOR Xa INHIBITORS |
| WO2006063113A2 (en) * | 2004-12-07 | 2006-06-15 | Portola Pharmaceuticals, Inc. | Ureas as factor xa inhibitors |
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| JP2004502664A (ja) * | 2000-06-30 | 2004-01-29 | イーラン ファーマスーティカルズ、インコーポレイテッド | アルツハイマー病処置用化合物 |
| PE20020276A1 (es) * | 2000-06-30 | 2002-04-06 | Elan Pharm Inc | COMPUESTOS DE AMINA SUSTITUIDA COMO INHIBIDORES DE ß-SECRETASA PARA EL TRATAMIENTO DE ALZHEIMER |
| WO2004031145A2 (en) * | 2002-10-02 | 2004-04-15 | Bristol-Myers Squibb Company | Lactam-containing diaminoalkyl, beta-aminoacids, alpha-aminoacids and derivatives thereof as factor xa inhibitors |
| FR2937973B1 (fr) * | 2008-11-04 | 2010-11-05 | Galderma Res & Dev | Modulateurs des recepteurs de la melanocortine, leur procede de preparation et leur utilisation en medecine humaine ainsi qu'en cosmetique |
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- 2017-01-18 CN CN201710038351.5A patent/CN106748892B/zh active Active
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6391917B1 (en) * | 1998-01-21 | 2002-05-21 | Zymogenetics, Inc. | Dialkyl ureas as calcitonin mimetics |
| WO2004022528A2 (en) * | 2002-09-09 | 2004-03-18 | Nps Allelix Corp. | Arylglycine derivatives and their use as glycine transport inhibitors |
| WO2004022534A1 (en) * | 2002-09-09 | 2004-03-18 | Nps Allelix Corp. | Arylglycine derivatives for use as glycine transport inhibitors |
| WO2006063293A2 (en) * | 2004-12-07 | 2006-06-15 | Portola Pharmaceuticals, Inc. | THIOUREAS AS FACTOR Xa INHIBITORS |
| WO2006063113A2 (en) * | 2004-12-07 | 2006-06-15 | Portola Pharmaceuticals, Inc. | Ureas as factor xa inhibitors |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024030332A1 (en) * | 2022-08-01 | 2024-02-08 | Verge Analytics, Inc. | Methods of treating neurological disorders with activators of unc51-like autophagy activating kinase 1 (ulk1) |
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| CN106748892A (zh) | 2017-05-31 |
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