WO2017088731A1

WO2017088731A1 - Octahydropyrrolo[3,4-c]pyrrole derivatives and use thereof

Info

Publication number: WO2017088731A1
Application number: PCT/CN2016/106785
Authority: WO
Inventors: 张英俊; 金传飞; 张
Original assignee: 广东东阳光药业有限公司
Priority date: 2015-11-24
Filing date: 2016-11-22
Publication date: 2017-06-01
Also published as: CN107207516A; CN107207516B

Abstract

The present invention relates to octahydropyrrolo[3,4-c]pyrrole derivatives and use thereof, and pharmaceutical compositions containing these compounds. The compounds or the pharmaceutical compositions are used for antagonizing orexin receptors. The present invention also relates to a method for preparing these compounds and pharmaceutical compositions, and use of these compounds and pharmaceutical compositions in preparing medicines for treating or preventing diseases related to orexin receptors.

Description

八氢吡咯并[3,4-c]吡咯衍生物及其用途Octahydropyrrolo[3,4-c]pyrrole derivatives and uses thereof

发明领域Field of invention

本发明属于药物技术领域，具体涉及八氢吡咯并[3,4-c]吡咯衍生物，包含该化合物的药物组合物，以及它们的使用方法和用途。更具体地说，本发明所述的化合物和药物组合物可作为食欲素受体拮抗剂用于治疗、预防或减轻与食欲素受体相关的疾病。The invention belongs to the technical field of medicines, and in particular relates to octahydropyrrolo[3,4-c]pyrrole derivatives, pharmaceutical compositions comprising the same, and methods and uses thereof. More specifically, the compounds and pharmaceutical compositions of the present invention are useful as orexin receptor antagonists for the treatment, prevention or alleviation of diseases associated with orexin receptors.

发明背景Background of the invention

食欲素(orexin)也称为下丘脑泌素、食欲肽，其包括食欲素A和食欲素B(或是下丘脑泌素-1和下丘脑泌素-2)，是一种由下丘脑分泌的神经肽，其主要的生理作用有：1.调节摄食，食欲素可以明显促进进食，并呈剂量依赖反应，且激活了调节进食的神经元；2.参与能量代谢的调节，食欲素可显著增加代谢率；3.参与睡眠-觉醒的调节，食欲素可抑制快速眼球运动睡眠，延长觉醒时间，阻断食欲素的作用可促进睡眠；4.参与内分泌调节，食欲素对垂体激素内分泌的影响很明显；5.与报酬感、学习和记忆相关；6.促进胃酸分泌；7.促进饮水增多；8.升高血压；9.在奖励***及药物成瘾机制中起重要作用，等(Piper et al.,The novel brain neuropeptide,orexin-A,modulates the sleep-wake cycle of rats.Eur.J.Neuroscience,2000,12(2),726-730；and Sakurai,T.,et al.,The neural circuit of orexin(hypocretin):Maintaining sleep and wakefulness.Nature Review Neuroscience,2007,8:171181)。Orexin, also known as hypothalamic and orexin, which includes orexin A and orexin B (or hypothalamic-1 and hypothalamic-2), is secreted by the hypothalamus The main physiological effects of neuropeptides are: 1. Regulating food intake, orexin can significantly promote eating, and dose-dependent response, and activate the neurons that regulate feeding; 2. Participate in the regulation of energy metabolism, orexin can be significant Increase the metabolic rate; 3. Participate in the regulation of sleep-wake, orexin can inhibit rapid eye movement sleep, prolong the time of awakening, block the effect of orexin can promote sleep; 4. Participate in endocrine regulation, the effect of orexin on pituitary hormone endocrine Obviously; 5. Relevant to sense of reward, learning and memory; 6. Promote gastric acid secretion; 7. Promote increased drinking water; 8. Increase high blood pressure; 9. Play an important role in reward system and drug addiction mechanism, etc. (Piper Et al., The novel brain neuropeptide, orexin-A, modulators the sleep-wake cycle of rats. Eur. J. Neuroscience, 2000, 12(2), 726-730; and Sakurai, T., et al., The Neural circuit of orexin(hypocretin):Maintain In sleep and wakefulness. Nature Review Neuroscience, 2007, 8: 171181).

食欲素通过作用于食欲素受体(orexin receptor,OXR)而产生生理效应。食欲素受体是一种G-蛋白偶联受体，有两种类型，分别称为OX₁受体和OX₂受体，其中OX₁受体对食欲素A具有选择性，而OX₂受体对食欲素A和食欲素B而言是非选择性受体(Sakurai T.et al.,Orexins and orexin receptors:a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior.Cell,1998,92(4):573-585)。OX₁受体和OX₂受体几乎仅存在于脑组织中，并选择性地表达于大脑中，其中OX₁受体以高密度表达于蓝斑(locus coeruleus)内，其为去甲肾上腺素能神经元的起核，而OX₂受体以高密度表达于结节***核中，其为组胺能神经元的起核。OX₁受体和OX₂受体二者的表达可见于中缝核内，其为血清素能神经元的起核，并可见于腹侧被盖区中，其为多巴胺能神经元的起核。此外，OX₂受体表达也可见于负责调节快速眼动睡眠的脑干胆碱能神经元中并对其核活动具有影响(Marcus,J.N.et al.,Differential expression of orexin receptors 1 and 2 in the rat brain.J.Comp.Neurol.,2001,435(1):6-25；and Trivedi,P.et al.,Distribution of orexin receptor mRNA in the rat brain.FEBS Lett.,1998,438(1-2):71-75)。Orexin produces a physiological effect by acting on the orexin receptor (OXR). The orexin receptor is a G-protein coupled receptor. There are two types, called OX ₁ receptor and OX ₂ receptor, respectively. The OX ₁ receptor is selective for orexin A, while OX _{2 is} affected. Sakurai T. et al., Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell, 1998, 92 (4): 573-585). OX ₁ receptor and OX ₂ receptor are almost exclusively found in brain tissue and are selectively expressed in the brain, wherein OX ₁ receptor is expressed in high density in locus coeruleus, which is norepinephrine. The nucleus of neurons can be nucleated, while the OX ₂ receptor is expressed in high density in the nodular papillary nucleus, which is the nucleation of histaminergic neurons. Expression of both the OX ₁ receptor and the OX ₂ receptor can be found in the nucleus raphe nucleus, which is the nucleation of serotonergic neurons and can be found in the ventral tegmental area, which is the nucleation of dopaminergic neurons. In addition, OX ₂ receptor expression can also be seen in brain stem cholinergic neurons responsible for regulating REM sleep and has an effect on their nuclear activity (Marcus, JNet al., Differential expression of orexin receptors 1 and 2 in the rat) brain.J.Comp.Neurol., 2001, 435(1): 6-25; and Trivedi, P. et al., Distribution of orexin receptor mRNA in the rat brain. FEBS Lett., 1998, 438 (1-2 ): 71-75).

由此可见，食欲素受体在病理学上具有重要的意义，涉及与多种疾病相关，例如睡眠障碍、抑郁症、焦虑症、恐慌症、强迫症、情感性神经病、抑郁性神经病、焦虑性神经病、心境障碍、惊恐发作障碍、行为失常、情绪紊乱、创伤后应激障碍、性功能障碍、精神病、精神***症、狂躁性抑郁、精神错乱、痴呆、药物依赖、成瘾、认知障碍、阿尔茨海默氏病、帕金森氏病、运动障碍、饮食失调、头痛、偏头痛、疼痛、消化***疾病、癫痫、炎症、心血管疾病、糖尿病、代谢疾病、免疫相关疾病、内分泌相关疾病和高血压等。但是，目前市场上与食欲素受体相关的药物仅有美国默克公司研发的抗失眠药苏沃雷生(Suvorexant)，其为食欲素受体拮抗剂，该药物还曾一度因为安全性问题而遭到美国FDA的拒绝批准。Thus, orexin receptors are important in pathology and are involved in a variety of diseases, such as sleep disorders, depression, anxiety, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety. Neuropathy, mood disorder, panic attack disorder, behavioral disorder, mood disorder, post-traumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, insanity, dementia, drug dependence, addiction, cognitive impairment, Alzheimer's disease, Parkinson's disease, dyskinesia, eating disorders, headache, migraine, pain, digestive diseases, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic diseases, immune-related diseases, endocrine-related diseases and High blood pressure, etc. However, the drugs currently associated with orexin receptors on the market are only Suvorexant, an anti-insomnia drug developed by Merck, which is an orexin receptor antagonist. It was once a safety issue. And the US FDA refused to approve quasi.

鉴于此，本发明提供了一类具有食欲素受体拮抗活性的化合物，与已有的同类化合物相比，本发明的化合物具有更好的药效活性，并且毒副作用更小，安全性更高，同时还具有优良的理化性质、药代性质和毒理特性，因此，具备较好的临床应用前景。In view of this, the present invention provides a class of compounds having orexin receptor antagonistic activity, and the compound of the present invention has better pharmacological activity, less toxic side effects and higher safety than the existing analogous compounds. At the same time, it also has excellent physical and chemical properties, pharmacokinetic properties and toxicological properties. Therefore, it has good clinical application prospects.

发明内容Summary of the invention

以下仅概括说明本发明的一些方面，并不局限于此。这些方面和其他部分在后面有更完整的说明。本说明书中的所有参考文献通过整体引用于此。当本说明书的公开内容与引用文献有差异时，以本说明书的公开内容为准。The following merely summarizes some aspects of the invention and is not limited thereto. These and other parts are more fully explained later. All references in this specification are hereby incorporated by reference in their entirety. In the event that the disclosure of the specification differs from the cited document, the disclosure of this specification shall control.

本发明提供了一类具有食欲素受体拮抗活性的化合物，具体涉及八氢吡咯并[3,4-c]吡咯衍生物，及其药物组合物，所述化合物和药物组合物可以用于制备预防或治疗与食欲素受体相关的疾病。The present invention provides a class of compounds having orexin receptor antagonistic activity, in particular to octahydropyrrolo[3,4-c]pyrrole derivatives, and pharmaceutical compositions thereof, which can be used in the preparation Prevent or treat diseases associated with orexin receptors.

本发明化合物对食欲素受体表现出良好的拮抗活性，具有更好的药效、药代性质和/或毒理特性，例如良好的脑/血浆比(brain plasma ratio)、良好的生物利用度、良好的代谢稳定性、低毒副作用和高安全性等。同时，本发明化合物在某些参数上的优良特性，如半衰期、清除率、选择性、生物利用度、化学稳定性、代谢稳定性、膜的渗透性、溶解性等，能够促使副作用的降低、治疗指数的扩大或耐受性的改进。The compounds of the present invention exhibit good antagonistic activity against orexin receptors, have better pharmacological, pharmacological and/or toxicological properties, such as good brain plasma ratio, good bioavailability. Good metabolic stability, low toxic side effects and high safety. At the same time, the excellent properties of the compounds of the present invention on certain parameters, such as half-life, clearance, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, solubility, etc., can promote the reduction of side effects, An increase in the therapeutic index or an improvement in tolerance.

具体地说：Specifically:

一方面，本发明涉及一种化合物，其为式(I)所示的化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In one aspect, the invention relates to a compound which is a compound of formula (I) or a stereoisomer, tautomer, oxynitride, solvate, metabolite, a pharmaceutically acceptable salt or prodrug,

其中：among them:

U为N或CR^3a；U is N or CR ^3a ;

V为N或CR^3b；V is N or CR ^3b ;

X为N或CR^3c；X is N or CR ^3c ;

Y为N或CR^3d；Y is N or CR ^3d ;

Hy为***基，所述***基任选地被一个或多个独立选自卤素、氧代(＝O)、C_1-6烷基、C_1-6卤代烷基、C_1-6烷氧基和苄基的取代基所取代；Hy is a triazolyl group, which is optionally selected from one or more independently selected from the group consisting of halogen, oxo (=O), C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkane. Substituted by a substituent of an oxy group and a benzyl group;

各R¹独立地为H、D、-CD₃、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6卤代烷基、C_1-6烷氧基、C_1-6卤代烷氧基、C_1-6烷氨基、C_1-6羟基取代的烷基、(C_1-6烷基)-C(＝O)-、(C_1-6烷氧基)-C(＝O)-、(C_1-6烷氨基)-C(＝O)-、C_3-6环烷基、C_2-9杂环基、C_6-10芳基或C_1-9杂芳基，或相邻的两个R¹和与它们相连的碳原子一起任选地形成C_3-10碳环、C_2-9杂环、C_6-10芳环或C_2-9杂芳环；Each R ^{1 is} independently H, D, -CD ₃ , F, Cl, Br, I, -CN, -NH ₂ , -OH, -NO ₂ , -COOH, -C(=O)NH ₂ , C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _1-6 hydroxy-substituted alkyl, (C _1-6 alkyl)-C(=O)-, (C _1-6 alkoxy)-C(=O)-, (C _1-6 alkylamino) -C(=O)-, C _3-6 cycloalkyl, C _2-9 heterocyclyl, C _6-10 aryl or C _1-9 heteroaryl, or two adjacent R ¹ and The linked carbon atoms together optionally form a C _3-10 carbocyclic ring, a C _2-9 heterocyclic ring, a C _6-10 aromatic ring or a C _2-9 heteroaryl ring;

各R^3a、R^3b、R^3c和R^3d独立地为H、D、-CD₃、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、烷基、烯基、炔基、卤代烷基、烷氧基、卤代烷氧基、烷氨基、羟基取代的烷基、烷基-C(＝O)-、烷氧基-C(＝O)-、烷氨基-C(＝O)-、环烷基、杂环基、芳基或杂芳基；Each of R ^3a , R ^3b , R ^3c and R ^{3d is} independently H, D, -CD ₃ , F, Cl, Br, I, -CN, -NH ₂ , -OH, -NO ₂ , -COOH, -C (=O)NH ₂ , alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, hydroxy substituted alkyl, alkyl-C(=O)-, alkoxy- C(=O)-, alkylamino-C(=O)-, cycloalkyl, heterocyclyl, aryl or heteroaryl;

各R²独立地为H、D、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6卤代烷基、C_1-6烷氧基、C_1-6卤代烷氧基、C_1-6烷氨基、C_1-6羟基取代的烷基、(C_1-6烷基)-C(＝O)-、(C_1-6烷氧基)-C(＝O)-、(C_1-6烷氨基)-C(＝O)-、C_3-6环烷基、C_2-9杂环基、C_6-10芳基或C_1-9杂芳基；Each R ^{2 is} independently H, D, F, Cl, Br, I, -CN, -NH ₂ , -OH, -NO ₂ , -COOH, -C(=O)NH ₂ , C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _1-6 hydroxy Substituted alkyl, (C _1-6 alkyl)-C(=O)-, (C _1-6 alkoxy)-C(=O)-, (C _1-6 alkylamino)-C (= O)-, C _3-6 cycloalkyl, C _2-9 heterocyclic, C _6-10 aryl or C _1-9 heteroaryl;

n为0、1、2、3、4或5；和n is 0, 1, 2, 3, 4 or 5; and

m为0、1、2、3或4。m is 0, 1, 2, 3 or 4.

在一实施方案中，本发明所述的化合物，其为式(II)所示的化合物或式(II)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In one embodiment, the compound of the present invention is a compound represented by formula (II) or a stereoisomer, tautomer, oxynitride, solvate, or a compound of formula (II). a metabolite, a pharmaceutically acceptable salt or a prodrug,

其中，V、R¹、R²、n和m具有本发明所述的含义。Wherein V, R ¹ , R ² , n and m have the meanings indicated in the present invention.

在一实施方案中，式(I)或式(II)中的各R¹独立地为H、D、-CD₃、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、C_1-4烷基、C_2-4烯基、C_2-4炔基、C_1-4卤代烷基、C_1-4烷氧基、C_1-4卤代烷氧基、C_1-4烷氨基、C_1-4羟基取代的烷基、(C_1-4烷基)-C(＝O)-、(C_1-4烷氧基)-C(＝O)-或(C_1-4烷氨基)-C(＝O)-。In one embodiment, each R ¹ in formula (I) or formula (II) is independently H, D, -CD ₃ , F, Cl, Br, I, -CN, -NH ₂ , -OH, - NO ₂ , -COOH, -C(=O)NH ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 alkoxy , C _1-4 haloalkoxy, C _1-4 alkylamino, C _1-4 hydroxy substituted alkyl, (C _1-4 alkyl)-C(=O)-, (C _1-4 alkoxy )-C(=O)- or (C _1-4 alkylamino)-C(=O)-.

在一实施方案中，式(I)或式(II)中的各R²独立地为H、D、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、C_1-4烷基、C_2-4烯基、C_2-4炔基、C_1-4卤代烷基、C_1-4烷氧基、C_1-4卤代烷氧基、C_1-4烷氨基、C_1-4羟基取代的烷基、(C_1-4烷基)-C(＝O)-、(C_1-4烷氧基)-C(＝O)-或(C_1-4烷氨基)-C(＝O)-。In one embodiment, each R ² in formula (I) or formula (II) is independently H, D, F, Cl, Br, I, -CN, -NH ₂ , -OH, -NO ₂ , - COOH, -C(=O)NH ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _{1- 4} -haloalkoxy, C _1-4 alkylamino, C _1-4 hydroxy substituted alkyl, (C _1-4 alkyl)-C(=O)-, (C _1-4 alkoxy)-C ( =O)- or (C _1-4 alkylamino)-C(=O)-.

在一实施方案中，式(I)或式(II)中的各R¹独立地为H、D、-CD₃、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、甲基、乙基、正丙基、异丙基、-CF₃、-CH₂CF₃、-CF₂CF₃、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-NHCH₃、-N(CH₃)₂、-CH₂OH、-C(＝O)NHCH₃或-C(＝O)N(CH₃)₂。In one embodiment, each R ¹ in formula (I) or formula (II) is independently H, D, -CD ₃ , F, Cl, Br, I, -CN, -NH ₂ , -OH, - NO ₂ , -COOH, -C(=O)NH ₂ , methyl, ethyl, n-propyl, isopropyl, -CF ₃ , -CH ₂ CF ₃ , -CF ₂ CF ₃ , methoxy, B Oxy, n-propyloxy, isopropyloxy, -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ OH, -C(=O)NHCH ₃ or -C(=O)N(CH ₃ ) ₂ .

在一实施方案中，式(I)或式(II)中的各R²独立地为H、D、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、甲基、乙基、正丙基、异丙基、-CF₃、-CH₂CF₃、-CF₂CF₃、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-NHCH₃、-N(CH₃)₂或-CH₂OH。In one embodiment, each R ² in formula (I) or formula (II) is independently H, D, F, Cl, Br, I, -CN, -NH ₂ , -OH, -NO ₂ , - COOH, -C(=O)NH ₂ , methyl, ethyl, n-propyl, isopropyl, -CF ₃ , -CH ₂ CF ₃ , -CF ₂ CF ₃ , methoxy, ethoxy, positive Propyloxy, isopropyloxy, -NHCH ₃ , -N(CH ₃ ) ₂ or -CH ₂ OH.

另一方面，本发明涉及一种药物组合物，其包含本发明所述的化合物和药学上可接受的载体、赋形剂、佐剂或它们的任意组合。In another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier, excipient, adjuvant or any combination thereof.

另一方面，本发明涉及本发明所述的化合物或药物组合物在制备药物中的用途，所述药物用于预防、治疗或减轻与食欲素受体相关的疾病。In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament for the prevention, treatment or alleviation of a disease associated with the orexin receptor.

在一实施方案中，所述与食欲素受体相关的疾病为睡眠障碍、抑郁症、焦虑症、恐慌症、强迫症、情感性神经病、抑郁性神经病、焦虑性神经病、心境障碍、惊恐发作障碍、行为失常、情绪紊乱、创伤后应激障碍、性功能障碍、精神病、精神***症、狂躁性抑郁、精神错乱、痴呆、药物依赖、成瘾、认知障碍、阿尔茨海默氏病、帕金森氏病、运动障碍、饮食失调、头痛、偏头痛、疼痛、消化***疾病、癫痫、炎症、心血管疾病、糖尿病、代谢疾病、免疫相关疾病、内分泌相关疾病或高血压。In one embodiment, the orexin receptor-related diseases are sleep disorders, depression, anxiety, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder , behavioral disorders, mood disorders, post-traumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, insanity, dementia, drug dependence, addiction, cognitive impairment, Alzheimer's disease, Pa Jinsen's disease, dyskinesia, eating disorders, headache, migraine, pain, digestive diseases, Epilepsy, inflammation, cardiovascular disease, diabetes, metabolic diseases, immune-related diseases, endocrine-related diseases, or high blood pressure.

另一方面，本发明涉及本发明所述的化合物或药物组合物在制备药物中的用途，所述药物用于拮抗食欲素受体。In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention for the preparation of a medicament for antagonizing an orexin receptor.

另一方面，本发明涉及式(I)或式(II)所包含的化合物的制备、分离和纯化的方法。In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound encompassed by formula (I) or formula (II).

生物试验结果表明，本发明提供的化合物对OX₁受体和OX₂受体均具有较好的拮抗作用，且在大鼠、犬和猴子体内具有很好的药代动力学性质，可作为较好的食欲素受体拮抗剂。The results of biological experiments show that the compounds provided by the present invention have good antagonistic effects on OX ₁ receptor and OX ₂ receptor, and have good pharmacokinetic properties in rats, dogs and monkeys, and can be used as a comparison. A good orexin receptor antagonist.

本发明的任一方面的任一实施方案，可以与其它实施方案进行组合，只要它们不会出现矛盾。此外，在本发明任一方面的任一实施方案中，任一技术特征可以适用于其它实施方案中的该技术特征，只要它们不会出现矛盾。Any of the embodiments of any of the aspects of the invention may be combined with other embodiments as long as they do not contradict each other. Furthermore, in any of the embodiments of any of the aspects of the invention, any of the technical features may be applied to the technical features in other embodiments as long as they do not contradict each other.

前面所述内容只概述了本发明的某些方面，但并不限于这些方面。这些方面及其他的方面的内容将在下面作更加具体完整的描述。The foregoing description merely summarizes certain aspects of the invention, but is not limited thereto. These and other aspects are described in more detail below.

发明内容Summary of the invention

定义和一般术语Definitions and general terms

现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本发明所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本发明所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。Some embodiments of the invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and formulas. The invention is intended to cover all alternatives, modifications, and equivalents, which are within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the invention. The invention is in no way limited to the methods and materials described herein. Where one or more of the incorporated literature, patents, and similar materials are different or inconsistent with the present application (including but not limited to defined terms, terminology applications, described techniques, etc.), The application shall prevail.

应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。It will be further appreciated that certain features of the invention are described in the various embodiments of the invention, and may be described in combination in a single embodiment. On the contrary, the various features of the invention are described in a single embodiment for the sake of brevity, but may be provided separately or in any suitable sub-combination.

除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。Unless otherwise stated, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art. All patents and publications related to the present invention are hereby incorporated by reference in their entirety.

除非另有说明或者上下文中有明显的冲突，本发明所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本发明所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一实施方案”指一个或多个实施方案。The articles "a", "an" and "sai" are used, and are meant to include "at least one" or "one or more", unless otherwise indicated. Thus, the articles used herein are used to refer to one or more than one (i. For example, "an embodiment" refers to one or more embodiments.

术语“任选”或“任选地”是指随后描述的事件或情形可以但不一定出现，并且该描述包括其中所述事件或情形出现的情况以及其中它不出现的情况。The term "optional" or "optionally" means that the subsequently described event or circumstance may, but does not necessarily, occur, and that the description includes instances in which the event or circumstance occurs and where it does not.

术语“任选地被……所取代”，可以与术语“未取代或被……所取代”交换使用，即所述结构或基团是未取代的或者被一个或多个本发明所述的取代基取代，其中所述取代发生在所给结构或基团上任何化合价允许的合理的位置。The term "optionally substituted with" can be used interchangeably with the term "unsubstituted or substituted by", ie the structure or group is unsubstituted or described by one or more of the present invention. Substituent substitution wherein the substitution occurs at a reasonable position permitted by any valence on the given structure or group.

一般而言，术语“取代的”表示所给结构或基团中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个取代基可以在基团各个可取代的合理的位置进行取代。当所给出的结构式中不只一个位置能被选自的一个或多个具体取代基所取代，那么取代基可以相同或不同地在结构式中各个合理的位置进行取代。本发明所述的取代基包括，但不限于D、F、Cl、Br、I、-N₃、-CN、-NO₂、-OH、-SH、-NH₂、烷基、烯基、炔基、卤代烷基、烷氧基、烷硫基、烷氨基、环烷基、杂环基、芳基、杂芳基，等等。In general, the term "substituted" means that one or more hydrogen atoms in a given structure or group are replaced by a particular substituent. Unless otherwise indicated, a substituent may be substituted at a reasonable position in which the groups are substitutable. When more than one position in the given formula can be substituted by one or more specific substituents selected from the substituents, the substituents may be substituted at the same or different positions in the structural formula. The substituents of the present invention include, but are not limited to, D, F, Cl, Br, I, -N ₃ , -CN, -NO ₂ , -OH, -SH, -NH ₂ , alkyl, alkenyl, alkyne Alkyl, haloalkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like.

术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。The term "comprising" is an open-ended expression that includes the subject matter of the invention, but does not exclude other aspects.

在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C_1-6烷基”特别指独立公开的甲基、乙基、C₃烷基、C₄烷基、C₅烷基和C₆烷基。In each part of the specification, the substituents of the compounds disclosed herein are disclosed in terms of the type or range of groups. In particular, the invention includes each individual sub-combination of each member of the group and range of such groups. For example, the term "C _1-6 alkyl" refers particularly to the disclosure independently methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl.

术语“D”表示单个氘原子。The term "D" denotes a single ruthenium atom.

术语“杂原子”表示氧(O)，硫(S)，氮(N)，磷(P)或硅(Si)，包括氮(N)，硫(S)和磷(P)任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3,4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR)。The term "heteroatom" means oxygen (O), sulfur (S), nitrogen (N), phosphorus (P) or silicon (Si), including nitrogen (N), sulfur (S) and phosphorus (P) in any oxidation state. a form; a form of a primary, secondary, tertiary amine or a quaternary ammonium salt; or a form in which a hydrogen on a nitrogen atom in a heterocyclic ring is substituted, for example, N (like N in a 3,4-dihydro-2H-pyrrolyl group), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).

术语“卤素”和“卤代”在本发明中可互换使用，是指氟(F)、氯(Cl)、溴(Br)或碘(I)。The terms "halogen" and "halo" are used interchangeably herein and refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

本发明使用的术语“烷基”或“烷基基团”，表示含有1-20个碳原子，饱和的直链或支链一价烃基基团，其中，所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。在一实施方案中，烷基基团含有1-6个碳原子；在另一实施方案中，烷基基团含有1-4个碳原子；还在一实施方案中，烷基基团含有1-3个碳原子。烷基基团的实例包含，但并不限于，甲基(Me、-CH₃)，乙基(Et、-CH₂CH₃)，正丙基(n-Pr、-CH₂CH₂CH₃)，异丙基(i-Pr、-CH(CH₃)₂)，正丁基(n-Bu、-CH₂CH₂CH₂CH₃)，异丁基(i-Bu、-CH₂CH(CH₃)₂)，仲丁基(s-Bu、-CH(CH₃)CH₂CH₃)，叔丁基(t-Bu、-C(CH₃)₃)，等等。The term "alkyl" or "alkyl group" as used herein, denotes a saturated straight or branched monovalent hydrocarbon group containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally selected The ground is replaced by one or more substituents described herein. In one embodiment, the alkyl group contains from 1 to 6 carbon atoms; in another embodiment, the alkyl group contains from 1 to 4 carbon atoms; and in one embodiment, the alkyl group contains 1 - 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH) (CH ₃ ) ₂ ), sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu, -C(CH ₃ ) ₃ ), and the like.

术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少含有一个碳-碳sp²双键，其包括“cis”和“trans”的定位，或者“E”和“Z”的定位。所述烯基基团任选地被一个或多个本发明所描述的取代基所取代。The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, which contains at least one carbon-carbon sp ² double bond, including the positioning of "cis" and "trans", or "E""and the positioning of the "Z". The alkenyl group is optionally substituted with one or more substituents described herein.

术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少含有一个碳-碳sp三键；所述炔基基团任选地被一个或多个本发明所描述的取代基所取代。The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, which contains at least one carbon-carbon sp triple bond; said alkynyl group optionally being one or more of the inventions Substituted substituents are substituted.

术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述烷氧基基团含有1-12个碳原子。在一实施方案中，烷氧基基团含有1-6个碳原子；在另一实施方案中，烷氧基基团含有1-4个碳原子；在又一实施方案中，烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。The term "alkoxy" denotes an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains from 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains from 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains from 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group can be optionally substituted with one or more substituents described herein.

烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH₃)，乙氧基(EtO、-OCH₂CH₃)，1-丙氧基(n-PrO、n-丙氧基、-OCH₂CH₂CH₃)，2-丙氧基(i-PrO、i-丙氧基、-OCH(CH₃)₂)，1-丁氧基(n-BuO、n-丁氧基、-OCH₂CH₂CH₂CH₃)，2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH₂CH(CH₃)₂)，2-丁氧基(s-BuO、s-丁氧基、-OCH(CH₃)CH₂CH₃)，2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH₃)₃)，等等。Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃ ), ethoxy (EtO, -OCH ₂ CH ₃ ), 1-propoxy (n-PrO, n- Propyloxy, -OCH ₂ CH ₂ CH ₃ ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH ₃ ) ₂ ), 1-butoxy (n-BuO, n- Butoxy, -OCH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH ₂ CH(CH ₃ ) ₂ ), 2-butyl Oxygen (s-BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) ₃ ) ₃ ), and so on.

术语“卤代烷基”表示烷基基团被一个或多个卤素原子所取代，其中烷基基团具有如本发明所述的含义，这样的实例包含，但并不限于，-CF₃、-CF₂CF₃、-CH₂CF₂CHF₂等。在一实施方案中，“卤代烷基”为较低级的C_1-4卤代烷基，其中所述“C_1-4卤代烷基”包含氟取代的C_1-4烷基、氯取代的C_1-4烷基、溴取代的C_1-4烷基、碘取代的C_1-4烷基，等等。具体的，氟取代的C_1-4烷基包含-CH₂F、-CHF₂、-CF₃、-CH₂Cl、-CHCl₂、-CCl₃、-CH₂Br、-CHBr₂、-CBr₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CF₂CH₂F、-CF₂CHF₂、-CF₂CF₃、-CHFCF₃、-CHFCHF₂、-CHFCH₂F、-CH₂CH₂CF₃、-CH₂CF₂CHF₂等等。所述卤代烷基任选地被一个或多个本发明所描述的取代基所取代。 The term "haloalkyl" denotes an alkyl group is substituted with one or more halogen atoms, wherein the alkyl group is as defined in the present invention, such examples include, but are not limited to, -CF _3, -CF ₂ CF ₃ , -CH ₂ CF ₂ CHF ₂ and the like. In one embodiment, "haloalkyl" is a lower level of C _1-4 haloalkyl groups, wherein the "C _1-4 haloalkyl" includes C _1-4 alkyl substituted by fluorine, chlorine-substituted C _{1- 4-} alkyl, bromo-substituted C _1-4 alkyl, iodine-substituted C _1-4 alkyl, and the like. Specifically, the fluorine-substituted C _1-4 alkyl group includes -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ Cl, -CHCl ₂ , -CCl ₃ , -CH ₂ Br, -CHBr ₂ , -CBr. ₃ , -CH ₂ CH ₂ F, -CH ₂ CHF ₂ , -CH ₂ CF ₃ , -CF ₂ CH ₂ F, -CF ₂ CHF ₂ , -CF ₂ CF ₃ , -CHFCF ₃ , -CHFCHF ₂ , -CHFCH ₂ F, -CH ₂ CH ₂ CF ₃ , -CH ₂ CF ₂ CHF ₂ and the like. The haloalkyl group is optionally substituted with one or more substituents described herein.

术语“卤代烷氧基”表示烷氧基基团被一个或多个卤素原子所取代，其中烷氧基基团具有如本发明所述的含义，这样的实例包含，但并不限于，-OCF₃、-OCF₂CF₃、-OCH₂CF₂CHF₂等。所述卤代烷氧基任选地被一个或多个本发明所描述的取代基所取代。The term "haloalkoxy" denotes that the alkoxy group is substituted by one or more halogen atoms, wherein the alkoxy group has the meaning as described herein, such examples include, but are not limited to, -OCF ₃ -OCF ₂ CF ₃ , -OCH ₂ CF ₂ CHF ₂ and the like. The haloalkoxy group is optionally substituted with one or more substituents described herein.

术语“烷氨基”或“烷基氨基”包括“N-烷基氨基”和“N,N-二烷基氨基”，其中氨基基团分别独立地被一个或两个烷基基团所取代，其中烷基基团具有如本发明所述的含义。The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino groups are each independently substituted with one or two alkyl groups, Wherein the alkyl group has the meaning as described herein.

术语“羟基取代的烷基”表示烷基基团被一个或多个羟基基团所取代，其中烷基基团具有本发明所述的含义。这样的实例包含，但并不限于羟甲基，羟乙基，1,2-二羟基乙基，等等。The term "hydroxy substituted alkyl" denotes an alkyl group substituted by one or more hydroxy groups, wherein the alkyl group has the meanings indicated herein. Such examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, and the like.

术语“碳环基”或“碳环”在此处可交换使用，表示含有3-12个环碳原子的，单价或多价的单环、双环或者三环体系，其中环可以是完全饱和的或包含一个或多个不饱和度，但一个芳香性环都不能有。The term "carbocyclyl" or "carbocyclic" is used interchangeably herein to refer to a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring carbon atoms, wherein the ring may be fully saturated. Or contain one or more degrees of unsaturation, but an aromatic ring cannot.

术语“杂环基”和“杂环”在此处可交换使用，表示包含3-12个环原子的，单价或多价的单环、双环或三环体系，其中环上一个或多个原子独立地被杂原子所替换，所述杂原子具有如本发明所述的含义，环可以是完全饱和的或包含一个或多个不饱和度，但一个芳香性环都不能有。The terms "heterocyclyl" and "heterocycle" are used interchangeably herein to refer to a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring atoms, wherein one or more atoms on the ring Independently replaced by a heteroatom having the meaning as described herein, the ring may be fully saturated or contain one or more unsaturations, but none of the aromatic rings may be present.

术语“环烷基”表示含有3-12个环碳原子的，单价或多价的饱和单环、双环或三环体系。The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic system containing from 3 to 12 ring carbon atoms.

术语“芳基”表示含有6-14个环原子，或6-10个环原子，或6个环原子的，单价或多价的单环、双环或三环的碳环体系，其中至少一个环是芳香族的。芳基基团通常，但不必须地通过芳基基团的芳香性环与母体分子连接。术语“芳基”可以和术语“芳香环”或“芳环”交换使用。芳基基团的实例可以包括苯基、萘基、蒽基，等等。所述芳基基团任选地被一个或多个本发明所描述的取代基所取代。The term "aryl" denotes a monovalent or polyvalent monocyclic, bicyclic or tricyclic carbocyclic ring system containing 6 to 14 ring atoms, or 6 to 10 ring atoms, or 6 ring atoms, wherein at least one ring It is aromatic. The aryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the aryl group. The term "aryl" can be used interchangeably with the terms "aromatic ring" or "aromatic ring". Examples of the aryl group may include a phenyl group, a naphthyl group, an anthracenyl group, and the like. The aryl group is optionally substituted with one or more substituents described herein.

术语“杂芳基”表示含有5-14个环原子，或5-10个环原子，或5-6个环原子的，单价或多价的单环、双环或三环体系，其中至少一个环是芳香族的，且至少一个环包含一个或多个杂原子。杂芳基基团通常，但不必须地通过杂芳基基团的芳香性环与母体分子连接。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。The term "heteroaryl" denotes a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system containing from 5 to 14 ring atoms, or from 5 to 10 ring atoms, or from 5 to 6 ring atoms, wherein at least one ring It is aromatic and at least one ring contains one or more heteroatoms. A heteroaryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of a heteroaryl group. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein.

术语“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。The term "stereoisomer" refers to a compound that has the same chemical structure but differs in the way the atoms or groups are spatially aligned. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotomers), geometric isomers (cis/trans) isomers, atropisomers, etc. .

本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S,“Stereochemistry of Organic Compounds”,John Wiley&Sons,Inc,New York,1994。许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时，使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号，其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，可出现这种情况。The stereochemical definitions and rules used in the present invention generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate a plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light caused by the compound, wherein (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。The resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography, depending on the difference in physicochemical properties of the components. Method and / or step crystallization.

可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2^nd Ed.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。The racemate of any of the resulting end products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art by known methods, for example, by obtaining the diastereomeric salts thereof. Separation. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 ^nd Ed. Robert) E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p. 268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that are interconvertible by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton transfer, such as keto-enol isomerization and imine-ene Amine isomerization.

“药学上可接受的”是指这样一些化合物、原料、组合物和/或剂型，它们在合理医学判断的范围内，适用于与患者组织接触而无过度毒性、刺激性、***反应或与合理的利益/风险比相对称的其他问题和并发症，并有效用于既定用途。"Pharmaceutically acceptable" means a compound, material, composition, and/or dosage form that, within the scope of sound medical judgment, is suitable for contact with a patient's tissue without undue toxicity, irritation, allergies, or reasonable The benefits/risk ratios are commensurate with other problems and complications and are effectively used for the intended use.

本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)或(II)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C_1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：Higuchi et al.,Pro-drugs as Novel Delivery Systems,Vol.14,A.C.S.Symposium Series；Roche et al.,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987；Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Reviews Drug Discovery,2008,7,255-270,and Hecker et al,Prodrugs of Phosphates and Phosphonates,J.Med.Chem.,2008,51,2328-2345,每篇文献通过引用包含于此。The term "prodrug" as used in the present invention denotes a compound which is converted in vivo to a compound of formula (I) or (II). Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug-like compound of the present invention may be an ester. In the prior invention, the ester may be used as a prodrug such as a phenyl ester, an aliphatic (C _1-24 ) ester, an acyloxymethyl ester, or a carbonate. , carbamates and amino acid esters. For example, a compound of the invention comprises a hydroxyl group, i.e., it can be acylated to give a compound in the form of a prodrug. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxy group on the parent. A discussion of the completeness of prodrugs can be found in Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, ACSSymposium Series; Roche et al., ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery, 2008, 7, 255-270, and Hecker et al, Prodrugs of Phosphates and Phosphonates, J. Med. Chem., 2008, 51, 2328-2345, each of which is incorporated herein by reference.

“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。"Metabolic product" refers to a product obtained by metabolism of a specific compound or a salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such a product may be obtained by administering a compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like. Accordingly, the invention includes metabolites of a compound, including metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.

本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N⁺(C_1-4烷基)₄的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C₁-₈磺酸化物和芳香磺酸化物。The "pharmaceutically acceptable salt" as used in the present invention means an organic salt and an inorganic salt of the compound of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, mineral acid salts formed by reaction with amino groups, hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or by other methods described in the literature, such as ion exchange These salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid Salt, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained by appropriate bases include the alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates quaternary ammonium salts formed from any of the compounds comprising a group of N. Water soluble or oil soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C ₁ - ₈ sulfonate and aromatic sulfonate.

本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸、乙醇胺或其混合物。术语“水合物”是指溶剂分子是水所形成的缔合物。"Solvate" as used herein refers to an association of one or more solvent molecules with a compound of the invention. Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine or mixtures thereof. The term "hydrate" means that the solvent molecule is an association formed by water.

当所述溶剂为水时，可以使用术语“水合物”。在一实施方案中，一个本发明化合物分子可以与一个水分子相结合，比如一水合物；在另一实施方案中，一个本发明化合物分子可以与多于一个的水分子相结合，比如二水合物，在又一实施方案中，一个本发明化合物分子可以与少于一个的水分子相结合，比如半水合物。应注意，本发明所述的水合物保留有非水合形式的所述化合物的生物有效性。When the solvent is water, the term "hydrate" can be used. In one embodiment, a molecule of the compound of the invention may be combined with a water molecule, such as a monohydrate; in another embodiment, a molecule of the invention may be combined with more than one water molecule, such as dihydrate. In yet another embodiment, a molecule of the compound of the invention may be combined with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the compounds in a non-hydrated form.

如本发明所使用的术语“治疗有效量”或“治疗有效剂量”是指能够引发个体的生物学或医学响应(例如降低或抑制酶或蛋白质活性，或改善症状、缓解病症、减缓或延迟疾病发展，或预防疾病等)的本发明化合物的量。The term "therapeutically effective amount" or "therapeutically effective amount" as used in the present invention refers to a biological or medical response capable of eliciting an individual (eg, reducing or inhibiting enzyme or protein activity, or ameliorating symptoms, alleviating a condition, slowing or delaying a disease). The amount of the compound of the invention that develops, or prevents disease, etc.).

本发明化合物的描述Description of the compounds of the invention

本发明涉及取代的(八氢吡咯并[3,4-c]吡咯-2(1H)-基)苯基甲酮化合物、其药学上可接受的盐、其药物组合物及其药物制剂，它们具有食欲素受体拮抗作用，可作为食欲素受体拮抗剂用于预防或治疗与食欲素受体相关的疾病，例如睡眠障碍、精神病学、神经病学和神经变性障碍、药物依赖、成瘾、认知障碍、运动障碍、饮食失调，等。The present invention relates to a substituted (octahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)phenyl ketone compound, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, and a pharmaceutical preparation thereof, which It has orexin receptor antagonism and can be used as an orexin receptor antagonist for the prevention or treatment of diseases associated with orexin receptors, such as sleep disorders, psychiatry, neurology and neurodegenerative disorders, drug dependence, addiction, Cognitive impairment, dyskinesia, eating disorders, etc.

其中：among them:

U为N或CR^3a；U is N or CR ^3a ;

V为N或CR^3b；V is N or CR ^3b ;

X为N或CR^3c；X is N or CR ^3c ;

Y为N或CR^3d； Y is N or CR ^3d ;

Hy为***基，所述***基任选地被一个或多个独立选自卤素、氧代(＝O)、C_1-6烷基、C_1-6卤代烷基、C_1-6烷氧基和苄基的取代基所取代；和Hy is a triazolyl group, which is optionally selected from one or more independently selected from the group consisting of halogen, oxo (=O), C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkane. Substituted by a substituent of an oxy group and a benzyl group;

R¹、R²、R^3a、R^3b、R^3c、R^3d、n和m具有本发明所述的含义。R ¹ , R ² , R ^3a , R ^3b , R ^3c , R ^3d , n and m have the meanings indicated in the present invention.

在一实施方案中，Hy为以下i-1至i-14所示的子结构式：In one embodiment, Hy is a substructure of the following i-1 to i-14:

其中i-1至i-14所示的子结构式任选地被一个或多个独立选自卤素、氧代(＝O)、C_1-6烷基、C_1-6卤代烷基、C_1-6烷氧基或苄基的取代基所取代。

Wherein the substructures represented by i-1 to i-14 are optionally one or more independently selected from the group consisting of halogen, oxo (=O), C _1-6 alkyl, C _1-6 haloalkyl, C _1- Substituted by a ₆ alkoxy or benzyl substituent.

其中，V为N或CR^3b；和Where V is N or CR ^3b ; and

R¹、R²、R^3b、n和m具有本发明所述的含义。R ¹ , R ² , R ^3b , n and m have the meanings as described herein.

在一实施方案中，式(I)中的R^3a、R^3b、R^3c和R^3d各自独立地为H、D、-CD₃、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、烷基、烯基、炔基、卤代烷基、烷氧基、卤代烷氧基、烷氨基、羟基取代的烷基、烷基-C(＝O)-、烷氧基-C(＝O)-、烷氨基-C(＝O)-、环烷基、杂环基、芳基或杂芳基；In one embodiment, R ^3a , R ^3b , R ^3c and R ^3d in formula (I) are each independently H, D, -CD ₃ , F, Cl, Br, I, -CN, -NH ₂ , -OH, -NO ₂ , -COOH, -C(=O)NH ₂ , alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, hydroxy substituted alkyl, alkyl -C(=O)-, alkoxy-C(=O)-, alkylamino-C(=O)-, cycloalkyl, heterocyclyl, aryl or heteroaryl;

或R^3a和R^3b，和与它们相连的碳原子一起任选地形成碳环、杂环、芳环或杂芳环；Or R ^3a and R ^3b , together with the carbon atom to which they are attached, optionally form a carbocyclic, heterocyclic, aromatic or heteroaryl ring;

或R^3c和R^3d，和与它们相连的碳原子一起任选地形成碳环、杂环、芳环或杂芳环。Or R ^3c and R ^3d , together with the carbon atom to which they are attached, optionally form a carbocyclic, heterocyclic, aromatic or heteroaryl ring.

在一实施方案中，式(II)中的R^3b为H、D、-CD₃、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、烷基、烯基、炔基、卤代烷基、烷氧基、卤代烷氧基、烷氨基、羟基取代的烷基、烷基-C(＝O)-、烷氧基-C(＝O)-、烷氨基-C(＝O)-、环烷基、杂环基、芳基或杂芳基。In one embodiment, R ^3b in formula (II) is H, D, -CD ₃ , F, Cl, Br, I, -CN, -NH ₂ , -OH, -NO ₂ , -COOH, -C (=O)NH ₂ , alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, hydroxy substituted alkyl, alkyl-C(=O)-, alkoxy- C(=O)-, alkylamino-C(=O)-, cycloalkyl, heterocyclyl, aryl or heteroaryl.

在一实施方案中，式(I)中的R^3a、R^3b、R^3c和R^3d各自独立地为H、D、-CD₃、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6卤代烷基、C_1-6烷氧基、C_1-6卤代烷氧基、C_1-6烷氨基、C_1-6羟基取代的烷基、(C_1-6烷基)-C(＝O)-、(C_1-6烷氧基)-C(＝O)-、(C_1-6烷氨基)-C(＝O)-、C_3-6环烷基、C_2-9杂环基、C_6-10芳基或C_1-9杂芳基；In one embodiment, R ^3a , R ^3b , R ^3c and R ^3d in formula (I) are each independently H, D, -CD ₃ , F, Cl, Br, I, -CN, -NH ₂ , -OH, -NO ₂ , -COOH, -C(=O)NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _{1- 6} alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _1-6 hydroxy substituted alkyl, (C _1-6 alkyl)-C(=O)-, (C _{1- 6} alkoxy)-C(=O)-, (C _1-6 alkylamino)-C(=O)-, C _3-6 cycloalkyl, C _2-9 heterocyclic, C _6-10 aryl Or a C _1-9 heteroaryl group;

或R^3a和R^3b，和与它们相连的碳原子一起形成C_3-10碳环、C_2-9杂环、C_6-10芳环或C_2-9杂芳环；Or R ^3a and R ^3b , together with the carbon atom to which they are attached, form a C _3-10 carbocyclic ring, a C _2-9 heterocyclic ring, a C _6-10 aromatic ring or a C _2-9 heteroaryl ring;

或R^3c和R^3d，和与它们相连的碳原子一起形成C_3-10碳环、C_2-9杂环、C_6-10芳环或C_2-9杂芳环。 Or R ^3c and R ^3d , together with the carbon atom to which they are attached, form a C _3-10 carbocyclic ring, a C _2-9 heterocyclic ring, a C _6-10 aromatic ring or a C _2-9 heteroaryl ring.

在一实施方案中，式(II)中的R^3b为H、D、-CD₃、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6卤代烷基、C_1-6烷氧基、C_1-6卤代烷氧基、C_1-6烷氨基、C_1-6羟基取代的烷基、(C_1-6烷基)-C(＝O)-、(C_1-6烷氧基)-C(＝O)-、(C_1-6烷氨基)-C(＝O)-、C_3-6环烷基、C_2-9杂环基、C_6-10芳基或C_1-9杂芳基。In one embodiment, R ^3b in formula (II) is H, D, -CD ₃ , F, Cl, Br, I, -CN, -NH ₂ , -OH, -NO ₂ , -COOH, -C (=O)NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy , C _1-6 alkylamino, C _1-6 hydroxy substituted alkyl, (C _1-6 alkyl)-C(=O)-, (C _1-6 alkoxy)-C(=O)- (C _1-6 alkylamino)-C(=O)-, C _3-6 cycloalkyl, C _2-9 heterocyclic, C _6-10 aryl or C _1-9 heteroaryl.

在一实施方案中，式(I)中的R^3a、R^3b、R^3c和R^3d各自独立地为H、D、-CD₃、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、甲基、乙基、正丙基、异丙基、-CF₃、-CH₂CF₃、-CF₂CF₃、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-NHCH₃、-N(CH₃)₂、-CH₂OH、-C(＝O)NHCH₃或-C(＝O)N(CH₃)₂。In one embodiment, R ^3a , R ^3b , R ^3c and R ^3d in formula (I) are each independently H, D, -CD ₃ , F, Cl, Br, I, -CN, -NH ₂ , -OH, -NO ₂ , -COOH, -C(=O)NH ₂ , methyl, ethyl, n-propyl, isopropyl, -CF ₃ , -CH ₂ CF ₃ , -CF ₂ CF ₃ , A Oxy, ethoxy, n-propyloxy, isopropyloxy, -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ OH, -C(=O)NHCH ₃ or -C(=O ) N(CH ₃ ) ₂ .

在一实施方案中，式(II)中的R^3b为H、D、-CD₃、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、甲基、乙基、正丙基、异丙基、-CF₃、-CH₂CF₃、-CF₂CF₃、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-NHCH₃、-N(CH₃)₂、-CH₂OH、-C(＝O)NHCH₃或-C(＝O)N(CH₃)₂。In one embodiment, R ^3b in formula (II) is H, D, -CD ₃ , F, Cl, Br, I, -CN, -NH ₂ , -OH, -NO ₂ , -COOH, -C (=O)NH ₂ ,methyl, ethyl, n-propyl, isopropyl, —CF ₃ , —CH ₂ CF ₃ , —CF ₂ CF ₃ , methoxy, ethoxy, n-propyloxy , isopropyloxy, -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ OH, -C(=O)NHCH ₃ or -C(=O)N(CH ₃ ) ₂ .

在一实施方案中，式(I)或式(II)中的各R¹独立地为H、D、-CD₃、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、烷基、烯基、炔基、卤代烷基、烷氧基、卤代烷氧基、烷氨基、羟基取代的烷基、烷基-C(＝O)-、烷氧基-C(＝O)-、烷氨基-C(＝O)-、环烷基、杂环基、芳基或杂芳基。In one embodiment, each R ¹ in formula (I) or formula (II) is independently H, D, -CD ₃ , F, Cl, Br, I, -CN, -NH ₂ , -OH, - NO ₂ , -COOH, -C(=O)NH ₂ , alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, hydroxy substituted alkyl, alkyl-C (= O)-, alkoxy-C(=O)-, alkylamino-C(=O)-, cycloalkyl, heterocyclyl, aryl or heteroaryl.

在一实施方案中，式(I)或式(II)中相邻的两个R¹和与它们相连的碳原子一起任选地形成碳环、杂环、芳环或杂芳环。In one embodiment, in Formula (I) or formula (II) R ¹ and two adjacent carbon atoms to which they are attached optionally form together with the carbon ring, heterocyclic ring, aryl or heteroaryl ring.

在一实施方案中，式(I)或式(II)中的各R²独立地为H、D、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、烷基、烯基、炔基、卤代烷基、烷氧基、卤代烷氧基、烷氨基、羟基取代的烷基、烷基-C(＝O)-、烷氧基-C(＝O)-、烷氨基-C(＝O)-、环烷基、杂环基、芳基或杂芳基。In one embodiment, each R ² in formula (I) or formula (II) is independently H, D, F, Cl, Br, I, -CN, -NH ₂ , -OH, -NO ₂ , - COOH, -C(=O)NH ₂ , alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, hydroxy substituted alkyl, alkyl-C(=O)-, alkoxy-C(=O)-, alkylamino-C(=O)-, cycloalkyl, heterocyclyl, aryl or heteroaryl.

在一实施方案中，式(I)或式(II)中的n为0、1、2、3、4或5。In one embodiment, n in formula (I) or formula (II) is 0, 1, 2, 3, 4 or 5.

在一实施方案中，式(I)或式(II)中的m为0、1、2、3或4。In one embodiment, m in formula (I) or formula (II) is 0, 1, 2, 3 or 4.

在一实施方案中，式(I)或式(II)中的各R¹独立地为H、D、-CD₃、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6卤代烷基、C_1-6烷氧基、C_1-6卤代烷氧基、C_1-6烷氨基、C_1-6羟基取代的烷基、(C_1-6烷基)-C(＝O)-、(C_1-6烷氧基)-C(＝O)-、(C_1-6烷氨基)-C(＝O)-、C_3-6环烷基、C_2-9杂环基、C_6-10芳基或C_1-9杂芳基。In one embodiment, each R ¹ in formula (I) or formula (II) is independently H, D, -CD ₃ , F, Cl, Br, I, -CN, -NH ₂ , -OH, - NO ₂ , -COOH, -C(=O)NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkoxy , C _1-6 haloalkoxy, C _1-6 alkylamino, C _1-6 hydroxy substituted alkyl, (C _1-6 alkyl)-C(=O)-, (C _1-6 alkoxy )-C(=O)-, (C _1-6 alkylamino)-C(=O)-, C _3-6 cycloalkyl, C _2-9 heterocyclic, C _6-10 aryl or C _{1 -9} heteroaryl.

在一实施方案中，式(I)或式(II)中相邻的两个R¹和与它们相连的碳原子一起任选地形成C_3-10碳环、C_2-9杂环、C_6-10芳环或C_2-9杂芳环。In one embodiment, two adjacent R ¹ in formula (I) or formula (II), together with the carbon atom to which they are attached, optionally form a C _3-10 carbocyclic ring, a C _2-9 heterocyclic ring, C _6-10 aromatic ring or C _2-9 heteroaryl ring.

在一实施方案中，式(I)或式(II)中的各R²独立地为H、D、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6卤代烷基、C_1-6烷氧基、C_1-6卤代烷氧基、C_1-6烷氨基、C_1-6羟基取代的烷基、(C_1-6烷基)-C(＝O)-、(C_1-6烷氧基)-C(＝O)-、(C_1-6烷氨基)-C(＝O)-、C_3-6环烷基、C_2-9杂环基、C_6-10芳基或C_1-9杂芳基。In one embodiment, each R ² in formula (I) or formula (II) is independently H, D, F, Cl, Br, I, -CN, -NH ₂ , -OH, -NO ₂ , - COOH, -C(=O)NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _{1- 6} haloalkoxy, C _1-6 alkylamino, C _1-6 hydroxy substituted alkyl, (C _1-6 alkyl)-C(=O)-, (C _1-6 alkoxy)-C ( =O)-, (C _1-6 alkylamino)-C(=O)-, C _3-6 cycloalkyl, C _2-9 heterocyclic, C _6-10 aryl or C _1-9 heteroaryl base.

在一实施方案中，本发明所述的化合物，其为具有下列之一结构的化合物或具有下列之一结构的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In one embodiment, the compound of the present invention is a stereoisomer, tautomer, oxynitride, solvate, metabolism of a compound having one of the following structures or a compound having one of the following structures a product, a pharmaceutically acceptable salt or a prodrug,

除非另作说明，本发明的化合物所有合适的同位素变化、立体异构体、互变异构体、溶剂化物、代谢产物、盐和药学上可接受的前药都包含在本发明范围内。All suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are included within the scope of the invention unless otherwise stated.

式(I)或式(II)所示化合物可以以不同的互变异构体形式存在，并且所有这些互变异构体都包括在本发明范围内。The compounds of formula (I) or formula (II) may exist in different tautomeric forms, and all such tautomers are included within the scope of the invention.

本发明化合物的氮氧化物也包含在本发明的范围之内。可以通过在升温下使用常用氧化剂(例如过氧化氢)，在有例如乙酸的酸存在下，氧化相应的含氮碱性物质，或者通过在适合的溶剂中与过酸反应，例如在二氯甲烷、乙酸乙酯或乙酸甲酯中与过乙酸反应，或在氯仿或二氯甲烷中与3-氯过氧苯甲酸反应，制备本发明化合物的氮氧化物。 Nitrogen oxides of the compounds of the invention are also included within the scope of the invention. The corresponding nitrogen-containing basic substance can be oxidized by using a usual oxidizing agent (for example, hydrogen peroxide) at elevated temperature, in the presence of an acid such as acetic acid, or by reacting with a peracid in a suitable solvent, for example, in methylene chloride. The oxynitride of the compound of the present invention is prepared by reacting with peracetic acid in ethyl acetate or methyl acetate or by reacting with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

此外，当本发明的化合物形成水合物或溶剂化物时，它们也包括在本发明的范围内。类似地，本发明化合物的水合物或溶剂合物的药学上可接受的盐也包括在本发明的范围内。Furthermore, when the compounds of the invention form hydrates or solvates, they are also included within the scope of the invention. Similarly, pharmaceutically acceptable salts of hydrates or solvates of the compounds of the invention are also included within the scope of the invention.

式(I)或式(II)所示化合物可以以盐的形式存在。在一实施方案中，所述盐是指药学上可接受的盐。本发明的药学上可接受的盐可以用常规化学方法由母体化合物、碱性或酸性部分来合成。一般而言，该类盐可以通过使这些化合物的游离酸形式与化学计量量的适宜碱(如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应，或者通过使这些化合物的游离碱形式与化学计量量的适宜酸反应来进行制备。该类反应通常在水或有机溶剂或二者的混合物中进行。一般地，在适当的情况中，需要使用非水性介质如***、乙酸乙酯、乙醇、异丙醇或乙腈。在例如“Remington′s Pharmaceutical Sciences”，第20版，Mack Publishing Company,Easton,Pa.,(1985)；和“药用盐手册：性质、选择和应用(Handbook of Pharmaceutical Salts:Properties,Selection,and Use)”,Stahl and Wermuth(Wiley-VCH，Weinheim，Germany，2002)中可找到另外一些适宜盐的列表。The compound of the formula (I) or the formula (II) may exist in the form of a salt. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety by conventional chemical methods. In general, such salts can be obtained by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base such as a hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg or K. The free base form of these compounds is prepared by reaction with a stoichiometric amount of a suitable acid. This type of reaction is usually carried out in water or an organic solvent or a mixture of the two. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. For example, "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and A list of additional suitable salts can be found in Use), Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

本发明化合物是碱性的，因此一般能够通过用合适的酸处理来形成药学上可接受的酸加成盐。合适的酸包括药学上可接受的无机酸和药学上可接受的有机酸。代表性的药学上可接受的酸加成盐包括盐酸盐、氢溴酸盐、硝酸盐、甲基硝酸盐、硫酸盐、硫酸氢盐、氨基磺酸盐、磷酸盐、乙酸盐、羟基乙酸盐、苯基乙酸盐、丙酸盐、丁酸盐、异丁酸盐、戊酸盐、马来酸盐、羟基马来酸盐、丙烯酸盐、富马酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、水杨酸盐、对氨基水杨酸盐、乙醇酸盐、乳酸盐、庚酸盐、邻苯二甲酸盐、草酸盐、琥珀酸盐、苯甲酸盐、邻乙酰氧基苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、扁桃酸盐、单宁酸盐、甲酸盐、硬脂酸盐、抗坏血酸盐、棕榈酸盐、油酸盐、丙酮酸盐、扑酸盐、丙二酸盐、月桂酸盐、戊二酸盐、谷氨酸盐、依托酸盐、甲磺酸盐、已磺酸盐、2-羟基乙磺酸盐、苯磺酸盐、对氨基苯磺酸盐、对甲苯磺酸盐和萘-2-磺酸盐，等。The compounds of the invention are basic and therefore can generally be formed into a pharmaceutically acceptable acid addition salt by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable mineral acids and pharmaceutically acceptable organic acids. Representative pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methyl nitrate, sulfate, hydrogen sulfate, sulfamate, phosphate, acetate, hydroxyl Acetate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, Tartrate, citrate, salicylate, p-aminosalicylate, glycolate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate , o-acetoxybenzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, single Nitrate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate , relying on acid salts, methanesulfonate, sulfonate, 2-hydroxyethanesulfonate, besylate, p-aminobenzenesulfonate, p-toluenesulfonate and naphthalene-2-sulfonate, etc. .

本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构，除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，如²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl和¹²⁵I。Any structural formula given by the present invention is also intended to indicate that these compounds are not isotopically enriched and isotopically enriched. Isotopically enriched compounds have the structure depicted by the general formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I.

另一方面，本发明所述化合物包括同位素富集的本发明所定义的化合物，例如，其中存在放射性同位素，如³H、¹⁴C和¹⁸F的那些化合物，或者其中存在非放射性同位素，如²H和¹³C。该类同位素富集的化合物可用于代谢研究(使用¹⁴C)、反应动力学研究(使用例如²H或³H)、检测或成像技术，如正电子发射断层扫描术(PET)或包括药物或底物组织分布测定的单光子发射计算机断层成像术(SPECT)，或可用于患者的放疗中。¹⁸F富集的化合物对PET或SPECT研究而言是特别理想的。同位素富集的式(I)或式(II)所示化合物可以通过本领域技术人员熟悉的常规技术或本发明中的实施例和制备过程所描述使用合适的同位素标记试剂替代原来使用过的未标记试剂来制备。In another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, for example, those in which a radioisotope such as ³ H, ¹⁴ C and ¹⁸ F is present, or in which a non-radioactive isotope is present, such as ² H and ¹³ C. Such isotopically enriched compounds can be used for metabolic studies (using ¹⁴ C), reaction kinetic studies (using, for example, ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or including drugs or Single photon emission computed tomography (SPECT) of substrate tissue distribution assays, or may be used in patient radiation therapy. ¹⁸ F enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) or formula (II) may be replaced by conventional isotopically labeled reagents as described in the conventional techniques familiar to those skilled in the art or in the examples and preparations of the present invention. Label the reagent to prepare.

另一方面，本发明涉及制备式(I)或式(II)所示化合物的中间体。In another aspect, the invention relates to an intermediate for the preparation of a compound of formula (I) or formula (II).

另一方面，本发明涉及式(I)或式(II)所示化合物的制备、分离和纯化的方法。In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound of formula (I) or formula (II).

本发明化合物的药物组合物、制剂和给药Pharmaceutical compositions, formulations and administrations of the compounds of the invention

本发明提供一种药物组合物，包括式(I)或式(II)所示化合物或式(I)或式(II)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药。所述药物组合物进一步包含至少一种药学上可接受的载体、佐剂或赋形剂，以及任选地，其它的治疗和/或预防成分。The present invention provides a pharmaceutical composition comprising a compound represented by formula (I) or formula (II) or a stereoisomer, tautomer, oxynitride of a compound of formula (I) or formula (II) , solvates, metabolites, pharmaceutically acceptable salts or prodrugs. The pharmaceutical composition Further comprising at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally other therapeutic and/or prophylactic ingredients.

合适的载体、佐剂和赋形剂对于本领域技术人员是熟知的并且详细描述于例如Ansel H.C.et al.,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems(2004)Lippincott,Williams&Wilkins,Philadelphia；Gennaro A.R.et al.,Remington：The Science and Practice of Pharmacy(2000)Lippincott,Williams&Wilkins,Philadelphia；和Rowe R.C.,Handbook of Pharmaceutical Excipients(2005)Pharmaceutical Press,Chicago中。Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel HC et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro AR et al Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe RC, Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.

本发明所用“药学上可接受的赋形剂”意指与给药剂型或药物组合物一致性相关的药学上可接受的材料、混合物或溶媒。每种赋形剂在混合时必须与药物组合物的其它成分相容，以避免对患者给药时会大大降低本发明化合物的功效的相互作用和会导致不是药学上可接受的药物组合物的相互作用。此外，每种赋形剂必须是药学上可接受的，例如，具有足够高的纯度。As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle that is associated with the administration of a dosage form or pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions which would greatly reduce the efficacy of the compounds of the invention when administered to a patient and result in a pharmaceutical composition that is not pharmaceutically acceptable. interaction. In addition, each excipient must be pharmaceutically acceptable, for example, of sufficiently high purity.

合适的药学上可接受的赋形剂会依所选具体剂型而不同。此外，可根据它们在组合物中的特定功能来选择药学上可接受的赋形剂。例如，可选择能有助于生产均一剂型的某些药学上可接受的赋形剂。可选择能有助于生产稳定剂型的某些药学上可接受的赋形剂。可选择对患者给药时有助于携带或运输本发明化合物从身体的一个器官或部分到身体的另一个器官或部分的某些药学上可接受的赋形剂。可选择增强患者依从性的某些药学上可接受的赋形剂。Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen. In addition, pharmaceutically acceptable excipients can be selected based on their particular function in the composition. For example, certain pharmaceutically acceptable excipients can be selected which can aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients can be selected which can aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients that facilitate carrying or transporting a compound of the invention from one organ or part of the body to another organ or part of the body upon administration to a patient may be selected. Certain pharmaceutically acceptable excipients that enhance patient compliance may be selected.

合适的药学上可接受的赋形剂包括以下类型的赋形剂：稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、造粒剂、包衣剂、润湿剂、溶剂、共溶剂、助悬剂、乳化剂、甜味剂、矫味剂、掩味剂、着色剂、防结块剂、保湿剂、螯合剂、塑化剂、增粘剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂。本领域技术人员可认识到，某些药学上可接受的赋形剂可提供不止一种功能，并提供可供选择的功能，这取决于制剂中存在多少该赋形剂和制剂中存在哪些其他赋形剂。Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents , solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, Preservatives, stabilizers, surfactants and buffers. One skilled in the art will recognize that certain pharmaceutically acceptable excipients may provide more than one function and provide alternative functionality depending on how much of the excipient and the formulation are present in the formulation. excipient.

技术人员掌握本领域的知识和技能，以使他们能选择用于本发明的适当量的合适的药学上可接受的赋形剂。此外，存在大量技术人员可获得的资源，他们描述药学上可接受的赋形剂，并用于选择合适的药学上可接受的赋形剂。实例包括Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。The skilled artisan will have the knowledge and skill in the art to enable them to select the appropriate amount of suitable pharmaceutically acceptable excipient for use in the present invention. In addition, there are a number of resources available to the skilled artisan who describe pharmaceutically acceptable excipients and are used to select suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

在Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York中披露了用于配置药学上可接受的组合物的各种载体，和用于其制备的公知技术，这些文献各自的内容通过引用并入本发明。除任何诸如因产生任何不期望的生物作用，或以有害方式与药学上可接受组合物中的任何其它成分发生相互作用而与本发明化合物不相容的任何常用载体外，关注其应用属于本发明的范围。In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York Various carriers for the formulation of pharmaceutically acceptable compositions, and well-known techniques for their preparation are disclosed, the respective contents of which are incorporated herein by reference. In addition to any conventional carrier that is incompatible with the compounds of the present invention, such as by any undesired biological action, or in a deleterious manner in interaction with any other component of the pharmaceutically acceptable composition, The scope of the invention.

本发明化合物通常被配制成适合于通过所需途径对患者给药的剂型。例如，剂型包括那些适合于以下给药途径的剂型：(1)口服给药，例如片剂、胶囊剂、囊片剂、丸剂、含片剂、粉剂、糖浆剂、酏剂、混悬剂、溶液剂、乳剂、香包剂和扁囊剂；(2)胃肠外给药，例如无菌溶液剂、混悬剂和复溶粉末；(3)透皮给药，例如透皮贴片剂；(4)直肠给药，例如栓剂；(5)吸入，例如气雾剂、溶液剂和干粉剂；和(6)局部给药，例如乳膏剂、油膏剂、洗剂、溶液剂、糊剂、喷雾剂、泡沫剂和凝胶剂。 The compounds of the invention are typically formulated in a dosage form suitable for administration to a patient by the desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, for example, tablets, capsules, caplets, pills, tablets, powders, syrups, elixirs, suspensions, Solution, emulsion, sachet and cachet; (2) parenteral administration, such as sterile solutions, suspensions and reconstituted powders; (3) transdermal administration, such as transdermal patches (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes , sprays, foams and gels.

也应认识到，本发明的某些化合物可以以游离形式存在用于治疗，或者如果适当可以以其药学上可接受的衍生物的形式存在。药学上可接受衍生物的一些非限制性的实施方案包括药学上可接受的前药，盐，酯，这些酯的盐，或者对有需要的患者给药时能直接或间接提供本发明所述化合物或其代谢产物或残留物的任何另外的加合物或衍生物。It will also be appreciated that certain compounds of the invention may exist in free form for treatment or, if appropriate, in the form of their pharmaceutically acceptable derivatives. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or can be provided directly or indirectly to a patient in need thereof. Any additional adduct or derivative of the compound or its metabolite or residue.

在一实施方案中，本发明化合物可以配制成口服剂型。在另一实施方案中，本发明化合物可以配制成吸入剂型。在另一实施方案中，本发明化合物可以配制成经鼻给药剂型。在又一实施方案中，本发明化合物可以配制成透皮给药剂型。还在一实施方案中，本发明化合物可以配制成局部给药剂型。In one embodiment, the compounds of the invention may be formulated into oral dosage forms. In another embodiment, the compounds of the invention may be formulated in an inhaled dosage form. In another embodiment, the compounds of the invention may be formulated for nasal administration. In yet another embodiment, the compounds of the invention may be formulated for transdermal administration. In still another embodiment, the compounds of the invention may be formulated in a topical dosage form.

本发明提供的药物组合物可以以压制片、研制片、可咀嚼锭剂、速溶片、复压片、或肠溶片、糖衣或薄膜衣片来提供。肠溶片是用能抗胃酸作用但在肠中溶解或崩解的物质包衣的压制片，从而防止了活性成分接触胃的酸性环境。肠包衣包括，但不限于，脂肪酸、脂肪、水杨酸苯酯、蜡、紫胶、氨化紫胶和邻苯二甲酸乙酸纤维素酯。糖衣片为糖衣包围的压制片，其可利于掩盖令人不愉快的味道或气味并且能防止片剂氧化。薄膜包衣片为用水溶性物质的薄层或薄膜覆盖的压制片。薄膜包衣包括，但不限于，羟乙基纤维素、羧甲基纤维素钠、聚乙二醇4000和邻苯二甲酸乙酸纤维素酯。薄膜包衣赋有和糖包衣相同的一般特性。复压片为经过超过一个压缩周期制备的压制片，包括多层片、和压制包衣或干包衣片。The pharmaceutical composition provided by the present invention can be provided as a compressed tablet, a developed tablet, a chewable tablet, a fast-dissolving tablet, a reconstituted tablet, or an enteric coated tablet, a sugar-coated tablet or a film-coated tablet. The enteric coated tablet is a compressed tablet coated with a substance which is resistant to gastric acid but which dissolves or disintegrates in the intestine, thereby preventing the active ingredient from contacting the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. The sugar-coated tablet is a compressed tablet surrounded by a sugar coating which can be used to mask an unpleasant taste or odor and to prevent oxidation of the tablet. The film coated tablet is a compressed tablet covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. The film coating imparts the same general characteristics as the sugar coating. The compressed tablet is a compressed tablet prepared over more than one compression cycle, including a multilayer tablet, and a press-coated or dry-coated tablet.

片剂剂型可以由呈粉末、结晶或颗粒状的活性成分单独的或与本发明描述的一种或多种载体或赋形剂组合来制备，所述载体和赋形剂包括粘合剂、崩解剂、控释聚合物、润滑剂、稀释剂和/或着色剂。增香剂和甜味剂在形成咀嚼片和锭剂时特别有用。The tablet dosage form can be prepared from the active ingredient in powder, crystalline or granular form, alone or in combination with one or more carriers or excipients described herein, including carriers Decomposing agents, controlled release polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are particularly useful in forming chewable tablets and lozenges.

本发明提供的药物组合物可以以软胶囊或硬胶囊来提供，其可以由明胶、甲基纤维素、淀粉或海藻酸钙来制备。所述硬明胶胶囊也称为干填充胶囊(DFC)，由两段组成，一段塞入另一段中，因此完全包封了活性成分。软弹性胶囊(SEC)是软的、球形壳，比如明胶壳，其通过加入甘油、山梨醇或类似的多元醇塑化。软明胶壳可以包含防腐剂来预防微生物生长。合适的防腐剂为如本发明所述的那些，包括尼泊金甲酯和尼泊金丙酯，以及山梨酸。本发明提供的液体、半固体和固体剂型可以包囊在胶囊中。合适的液体和半固体剂型包括在碳酸丙烯酯、植物油或甘油三酯中的溶液和混悬剂。包含这样的溶液的胶囊可以如在美国专利U.S.Pat.Nos.4,328,245；4,409,239和4,410,545中描述的来制备。所述胶囊也可以采用如本领域技术人员已知的涂层，从而改善或维持活性成分的溶出。The pharmaceutical composition provided by the present invention may be provided in a soft capsule or a hard capsule, which may be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsule, also known as dry-filled capsule (DFC), consists of two sections, one section being inserted into the other section, thus completely encapsulating the active ingredient. Soft elastic capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerin, sorbitol or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those according to the invention, including methylparaben and propylparaben, and sorbic acid. The liquid, semi-solid and solid dosage forms provided herein can be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such a solution can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239 and 4,410,545. The capsules may also employ coatings as known to those skilled in the art to improve or maintain dissolution of the active ingredient.

本发明提供的药物组合物可以以液体和半固体剂型来提供，包括乳剂、溶液、混悬剂、酏剂和糖浆剂。乳剂为二相***，其中一种液体以小球形式完全分散在另一种液体中，其可以是水包油型或油包水型。乳剂可以包括药学上可接受的非水液体和溶剂、乳化剂和防腐剂。混悬剂可以包括药学上可接受的助悬剂和防腐剂。含水醇溶液可以包括药学上可接受的缩醛，比如低级烷基醛的二(低级烷基)缩醛，例如乙醛二乙基缩醛；和具有一个或多个羟基的水溶性溶剂，比如丙二醇和乙醇。酏剂是透明的、甜味的水醇溶液。糖浆剂是浓的糖例如蔗糖的水溶液，并且还可以包含防腐剂。对于液体剂型，例如，在聚乙二醇中的溶液可以用足量的药学上可接受的液体载体例如水稀释，以精确方便地给药。The pharmaceutical compositions provided herein can be provided in liquid and semisolid dosage forms including emulsions, solutions, suspensions, elixirs, and syrups. The emulsion is a two-phase system in which one liquid is completely dispersed in the form of pellets in another liquid, which may be an oil-in-water or water-in-oil type. The emulsions may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers, and preservatives. Suspensions can include pharmaceutically acceptable suspending agents and preservatives. The aqueous alcohol solution may include a pharmaceutically acceptable acetal such as a di(lower alkyl) acetal of a lower alkyl aldehyde such as acetaldehyde diethyl acetal; and a water soluble solvent having one or more hydroxyl groups, such as Propylene glycol and ethanol. The tincture is a clear, sweet, hydroalcoholic solution. A syrup is an aqueous solution of a concentrated sugar such as sucrose, and may also contain a preservative. For liquid dosage forms, for example, solutions in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier such as water for precise and convenient administration.

本发明提供的药物组合物可以配制成适于对患者吸入给药的任何剂型，例如干粉剂、气雾剂、混悬剂或溶液组合物。在一实施方案中，本发明所公开的药物组合物可以配制成适于用干粉剂对患者吸入给药的剂型。在又一实施方案中，本发明所公开的药物组合物可以配制成适于通过喷雾器对患者吸入给药的剂型。通过吸入递送至肺的干粉组合物通常包含精细粉末状得本发明所公开的化合物和一种或多种精细粉末状的药学上可接受的赋形剂。特别适合用作干粉剂的药学上可接受的赋形剂为本领域技术人员所知晓，其包括乳糖、淀粉、甘露醇、和单-、二-和多糖。精细粉末可通过例如微粉化和研磨制备得到。一般来说，尺寸减小的(如微粉化的)化合物可以通过约1至10微米的D₅₀值(例如，用激光衍射法测量的)来定义。The pharmaceutical compositions provided herein can be formulated into any dosage form suitable for inhalation administration to a patient, such as a dry powder, aerosol, suspension or solution composition. In one embodiment, the disclosed pharmaceutical compositions can be formulated in a dosage form suitable for inhalation administration to a patient with a dry powder. In yet another embodiment, the disclosed pharmaceutical compositions can be formulated in a dosage form suitable for inhalation administration to a patient by a nebulizer. Dry powder compositions for delivery to the lung by inhalation typically comprise a finely divided powder of the compound disclosed herein and one or more finely divided pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients which are particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di- and polysaccharides. Fine powders can be prepared, for example, by micronization and milling. Generally, the size-reduced (e.g. micronised) compound can be (e.g., as measured by laser diffraction method) is defined by the D ₅₀ value from about 1 to 10 microns.

适合于透皮给药的药物组合物可制备成不连续的贴片剂，意在与患者的表皮保持紧密接触一段延长的时间。例如，可通过离子渗透从贴片剂中递送活性成分，如Pharmaceutical Research,3(6),318(1986)中的一般描述。Pharmaceutical compositions suitable for transdermal administration can be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient can be delivered from the patch by ion permeation as generally described in Pharmaceutical Research, 3(6), 318 (1986).

适合于局部给药的药物组合物可以被配制成油膏剂、乳膏剂、混悬剂、洗剂、粉剂、溶液剂、糊剂、凝胶剂、喷雾剂、气雾剂或油剂。例如，油膏剂、乳膏剂和凝胶剂可以用水或油基质，和适合的增稠剂和/或凝胶剂和/或溶剂来配置。这样的基质可以包括，水，和/或油例如液体液体石蜡和植物油(例如花生油或蓖麻油)，或溶剂例如聚乙二醇。根据基质性质使用的增稠剂和凝胶剂包括软石蜡、硬脂酸铝、鲸蜡硬脂醇、聚乙二醇、羊毛脂、蜂蜡、聚羧乙烯和纤维素衍生物，和/或单硬脂酸甘油脂和/或非离子型乳化剂。Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For example, ointments, creams, and gels can be formulated with a water or oil base, and a suitable thickening and/or geling agent and/or solvent. Such a matrix may include water, and/or oils such as liquid liquid paraffin and vegetable oils (such as peanut oil or castor oil), or solvents such as polyethylene glycol. Thickeners and gels for use depending on the nature of the matrix include soft paraffin, aluminum stearate, cetearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or single Stearic acid glycerides and/or nonionic emulsifiers.

本发明化合物也可以与作为靶向药物载体的可溶性聚合物结合。这样的聚合物包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰胺-苯酚、聚羟乙基天冬酰胺苯酚或棕榈酰残基取代的聚氧乙烯聚赖氨酸。此外，本发明所公开的化合物可以与在实现药物的控制释放中使用的一类生物可降解的聚合物结合，例如，聚乳酸、聚ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯和水凝胶的交联或两亲嵌段共聚物。The compounds of the invention may also be combined with soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or palmitoyl residue substituted polyoxyethylene polylysine. Furthermore, the compounds disclosed herein can be combined with a class of biodegradable polymers used in the controlled release of drugs, for example, polylactic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters. Crosslinked or amphiphilic block copolymers of polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels.

本发明提供的药物组合物可以通过注射、输注或植入肠胃外给药，用于局部或全身给药。如本发明使用的肠胃外给药包括静脉内、动脉内、腹膜内、鞘内、心室内、尿道内、胸骨内、颅内、肌内、滑膜内和皮下给药。The pharmaceutical compositions provided by the present invention can be administered parenterally by injection, infusion or implantation for topical or systemic administration. Parenteral administration as used in the present invention includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.

本发明提供的药物组合物可以配制成适于肠胃外给药的任何剂型，包括溶液、混悬剂、乳剂、胶束、脂质体、微球、纳米体系和适于在注射前在液体中制成溶液或混悬液的固体形式。这样的剂型可以根据药物科学领域的技术人员已知的常规方法来制备(参见Remington:The Science和Practice of Pharmacy,同上)。The pharmaceutical compositions provided herein can be formulated into any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and in liquids prior to injection. A solid form of the solution or suspension. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see Remington: The Science and Practice of Pharmacy, supra).

预期用于肠胃外给药的药物组合物可以包括一种或多种药学上可接受的载体和赋形剂，包括，但不限于，含水运载体、水混溶性运载体、非水运载体、抗微生物剂或抗微生物生长的防腐剂、稳定剂、溶解增强剂、等渗剂、缓冲剂、抗氧剂、局部麻醉剂、助悬剂和分散剂、湿润剂或乳化剂、络合剂、多价螯合剂或螯合剂、防冻剂、冷冻保护剂、增稠剂、pH调节剂和惰性气体。Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients including, but not limited to, aqueous carriers, water miscible vehicles, nonaqueous vehicles, antibiotics Microbial or antimicrobial growth preservatives, stabilizers, dissolution enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, multivalent Chelating or chelating agents, antifreeze agents, cryoprotectants, thickeners, pH adjusters, and inert gases.

本发明提供的药物组合物可以配制成立即或改性释放剂型，包括延迟-、缓释-、脉冲-、控制-、靶向-和程序化释放形式。The pharmaceutical compositions provided herein can be formulated as immediate or modified release dosage forms, including delayed-, sustained-release, pulse-, controlled-, targeted-, and programmed release forms.

本发明提供的药物组合物可以配制成单剂量或多剂量给药。所述单剂量制剂被包装在安瓿剂、小瓶或注射器中。所述多剂量肠胃外制剂必须包含抑菌或抑真菌浓度的抗微生物剂。所有的肠胃外制剂都必须是无菌的，如本领域已知和实践的。The pharmaceutical compositions provided by the present invention may be formulated for administration in single or multiple doses. The single dose formulation is packaged in an ampoule, vial or syringe. The multi-dose parenteral formulation must contain an antimicrobial agent at a bacteriostatic or fungistatic concentration. All parenteral formulations must be sterile, as is known and practiced in the art.

本发明提供的药物组合物可以与不会损害预期的治疗作用的其它活性成分共同配制，或者与补充预期的作用的物质共同配制。 The pharmaceutical compositions provided herein can be formulated with other active ingredients that do not impair the intended therapeutic effect, or with a substance that complements the intended effect.

在一实施方案中，本发明的治疗方法包括对有需要的患者给予安全有效量的本发明化合物或包含本发明化合物的药物组合物。本发明各实施方案包括通过对有需要的患者给予安全有效量的本发明化合物或包含本发明化合物的药物组合物，来治疗本发明提及的疾病。In one embodiment, the method of treatment of the invention comprises administering to a patient in need thereof a safe and effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention. Embodiments of the invention include treating a disease referred to in the invention by administering to a patient in need thereof a safe and effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

在一实施方案中，本发明化合物或包含本发明化合物的药物组合物可以通过任何适合的给药途径来给药，包括全身给药和局部给药。全身给药包括口服给药、胃肠外给药、透皮给药和直肠给药。典型的胃肠外给药是指通过注射或输注给药，包括静脉内、肌内和皮下注射或输注给药。局部给药包括施用于皮肤以及眼内、耳、***内、吸入和鼻内给药。在一个实施方案中，本发明化合物或包含本发明化合物的药物组合物可以是口服给药。在另一实施方案中，本发明化合物或包含本发明化合物的药物组合物可以是吸入给药。还有一实施例中，本发明化合物或包含本发明化合物可以是经鼻内给药。In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention may be administered by any suitable route of administration, including systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes administration to the skin as well as intraocular, otic, intravaginal, inhalation, and intranasal administration. In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention may be administered orally. In another embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention may be administered by inhalation. In still another embodiment, the compound of the invention or a compound comprising a compound of the invention may be administered intranasally.

在一实施方案中，本发明化合物或包含本发明化合物的药物组合物可以一次性给药，或者根据给药方案，在指定时间段内，在不同的时间间隔给药若干次。例如，每天给药一次、两次、三次或四次。在一实施方案中，每天给药一次。在又一实施方案中，每天给药两次。可以给药直至达到想要的治疗效果或无限期地维持想要的治疗效果。本发明化合物或包含本发明化合物的药物组合物的合适给药方案取决于该化合物的药代动力学性质，例如吸收、分布和半衰期，这些可以由技术人员测定。此外，本发明化合物或包含本发明化合物的药物组合物的合适给药方案，包括实施该方案的持续时间，取决于被治疗的疾病，被治疗疾病的严重程度、被治疗患者的年龄和身体状况、被治疗患者的医疗史、同时疗法的性质、想要的治疗效果等在技术人员知识和经验范围内的因素。这样的技术人员还应该理解，对于个体患者对给药方案的反应，或随着时间推移个体患者需要变化时，可要求调整事宜的给药方案。In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention may be administered at a time, or several times at different time intervals, over a specified period of time, depending on the dosage regimen. For example, administration once, twice, three times or four times a day. In one embodiment, it is administered once a day. In yet another embodiment, the administration is twice daily. It can be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for the compounds of the invention or pharmaceutical compositions comprising the compounds of the invention depend on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, as determined by the skilled artisan. Furthermore, a suitable dosage regimen of a compound of the invention or a pharmaceutical composition comprising a compound of the invention, including the duration of implementation of the regimen, depends on the disease being treated, the severity of the condition being treated, the age and condition of the patient being treated The medical history of the patient being treated, the nature of the concurrent therapy, the desired therapeutic effect, and the like within the knowledge and experience of the skilled person. Such skilled artisans will also appreciate that the dosage regimen for the adjustment may be required for individual patient responses to the dosage regimen, or for individual patient needs to change over time.

本发明化合物可以与一种或多种其它治疗剂同时，或在其之前或之后给药。本发明化合物可以与其他治疗剂通过相同或不同给药途径分别给药，或与之以同以药物组合物形式给药。The compounds of the invention may be administered simultaneously with, or before or after, one or more other therapeutic agents. The compounds of the invention may be administered separately or in combination with other therapeutic agents by the same or different routes of administration.

本发明化合物可以与镇静剂、***、抗焦虑药、抗精神病药、抗焦虑剂、环吡咯酮、咪唑并吡啶、吡唑并嘧啶、弱安定剂、褪黑激素激动剂和拮抗剂、褪色素能药剂、苯二氮革、巴比妥酸盐、5HT-2拮抗剂等等联合使用，例如：阿地***、二烯丙巴比妥、螺旋萘哌酮、阿普***、阿米替林、异戊巴比妥、阿莫沙平、苯他西泮、太息定、溴替***、丁氨苯丙酮、丁螺环酮、布塔巴比妥、布塔比妥、卡普脲、卡波氯醛、甜菜碱氯醛、水合氯醛、利眠宁、氯米帕明、氯硝西泮、氯哌酮、氯氮革、氯乙双酯、氯氮平、环丙西泮、去郁敏、环庚吡喹醇、安定、氯醛柳胺、双丙戊酸、可他敏、多虑平、艾司***、氯乙基戊烯炔醇、甲苄咪唑、非诺班、氟硝西泮、氟西泮、氟伏沙明、氟苯氧丙胺、磷安定、导眠能、哈拉西泮、羟嗪、丙咪嗪、锂、氯羟去甲安定、氯甲西泮、马普替林、氯***、褪黑激素、甲***、安宁、***、咪达氟、咪达***、尼法唑酮、尼索氨酯、硝基安定、去甲替林、去甲羟基安定、仲醛、帕罗昔汀、戊巴比妥、哌拉平、奋乃静、苯乙肼、***、环丙二氮革、异丙嗪、异丙酚、普罗替林、四氟硫安定、瑞氯西泮、咯利普兰、司可巴比妥、舍曲林、舒普罗酮、替马西泮、硫利哒嗪、曲卡唑酯、反苯环丙胺、曲唑酮、***苯二氮、曲匹泮、三甲氧苯醋酰胺、三氯乙磷酸、三氟拉嗪、三甲氧苯酰吗啉、三甲丙咪嗪、乌达西泮、文拉法新、扎来普隆、唑拉西泮、唑吡坦以及它们的盐和组合物等等，或者本发明化合物可以在给药的同时联合使用物理方法例如光疗法或电刺激。The compound of the present invention can be used with sedatives, hypnotics, anxiolytics, antipsychotics, anxiolytics, cyclopyrrolidone, imidazopyridine, pyrazolopyrimidine, weak tranquilizers, melatonin agonists and antagonists, and fading A combination of a pharmaceutical agent, benzodiazepine, barbiturate, a 5HT-2 antagonist, etc., for example: aldezazole, diphenobarbital, spironaphthyl, alprazolam, amitripty Forest, barbital, barbital, amoxapine, benzocycline, benzodiazepine, bromozolam, bupropion, buspirone, butabarbital, butabutrol, captopril , carbopol chloral, betaine chloral, chloral hydrate, chlordiazepoxide, clomipramine, clonazepam, chloropentazone, chloroform, chloroethylene diester, clozapine, ciprofloxacin , decoction, cycloheptamol, diazepam, chloralil, divalproic acid, ketamine, doxepin, estazolam, chloroethylpentenyl alcohol, mebendazole, fifenol Class, flunitrazepam, flurazepam, fluvoxamine, fluphenoxypropylamine, phosphorus diazepam, inducing sleep energy, haloxicam, hydroxyzine, imipramine, lithium, chlorohydroxyl for example, Methicillin, Maprotiline, Chlorpheniramine, Melatonin, Toluene Barbital, Tranquility, Diarrhea, Midazolam, Midazolam, Nifaxone, Nissocarbamide, Nitrodiazepine, Go Metatelin, noroxylamine, paraformaldehyde, paroxetine, pentobarbital, piperazine, perphenazine, phenelzine, phenobarbital, cyprodinil, promethazine, isopropyl Phenol, protriptyline, tetraflusulfuron, reclosan, rolipram, spartabarbital, sertraline, spiroxone, temazepam, thioridazine, trazodazole, anti-benzene ring Propylamine, trazodone, triazole benzodiazepine, triclopidine, trimethoxy benzene acetamide, trichloroethylene phosphate, trifluoperazine, trimethoxybenzoylmorpholine, lampromazine, urethane oxime, text Rafaxine, zaleplon, zoloxazepine, zolpidem, and salts and compositions thereof, or the like, or a compound of the invention may be used in combination with physical methods such as phototherapy or electrical stimulation.

此外，本发明化合物可以以前药形式给药。在本发明中，本发明化合物的“前药”是对患者给药时，最终能在体内释放出本发明化合物的功能性衍生物。以前药形式给予本发明化合物时，本领域技术人员可实施下列方式中的一种及以上：(a)变更化合物的体内起效时间；(b)变更化合物的体内作用持续时间；(c)变更化合物的体内输送或分布；(d)变更化合物的体内溶解度；及(e)克服化合物所面临的副作用或其他难点。用于制备前药的典型的功能性衍生物，包含在体内以化学方式或酶的方式裂解的化合物的变体。包含制备磷酸盐、酰胺、酯、硫代酯、碳酸盐及氨基甲酸盐的这些变体对本领域技术人员来讲是众所周知的。Furthermore, the compounds of the invention may be administered in the form of a prodrug. In the present invention, a "prodrug" of a compound of the present invention is a functional derivative which, when administered to a patient, ultimately releases the compound of the present invention in vivo. Those skilled in the art when administering the compounds of the invention in the form of a prodrug One or more of the following may be practiced: (a) altering the in vivo onset time of the compound; (b) altering the duration of in vivo action of the compound; (c) altering the in vivo delivery or distribution of the compound; (d) altering the compound In vivo solubility; and (e) overcoming the side effects or other difficulties faced by the compound. Typical functional derivatives for the preparation of prodrugs, including variants of compounds which are cleaved chemically or enzymatically in vivo. These variants comprising the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates are well known to those skilled in the art.

本发明化合物及药物组合物的用途Use of the compounds of the invention and pharmaceutical compositions

本发明所述的化合物和药物组合物作为食欲素受体拮抗剂，对预防或治疗与食欲素受体相关的疾病是有效的，可用于制备拮抗食欲素受体的药品。The compounds and pharmaceutical compositions of the present invention are effective as orexin receptor antagonists for preventing or treating diseases associated with orexin receptors, and can be used for the preparation of a medicament for antagonizing orexin receptors.

与食欲素受体相关的疾病可选自所有类型的睡眠障碍、所有类型的精神病学、神经病学和神经变性障碍、所有类型的压力相关综合症、所有类型的成瘾(尤其是精神活性物质的使用、滥用、寻求和恢复)、所有类型的在健康人群中和在精神疾病患者和神经***疾病患者中的认知功能障碍、所有类型的进食或饮水障碍，等。Diseases associated with orexin receptors may be selected from all types of sleep disorders, all types of psychiatry, neurology and neurodegenerative disorders, all types of stress related syndromes, all types of addiction (especially psychoactive substances) Use, abuse, seeking and recovery), all types of cognitive dysfunction in healthy people and in patients with mental illness and neurological diseases, all types of eating or drinking disorders, and the like.

在一实施方案中，与食欲素受体相关的疾病包含睡眠障碍、抑郁症、焦虑症、恐慌症、强迫症、情感性神经病、抑郁性神经病、焦虑性神经病、心境障碍、惊恐发作障碍、行为失常、情绪紊乱、创伤后应激障碍、性功能障碍、精神病、精神***症、狂躁性抑郁、精神错乱、痴呆、药物依赖、成瘾、认知障碍、阿尔茨海默氏病、帕金森氏病、运动障碍、饮食失调、头痛、偏头痛、疼痛、消化***疾病、癫痫、炎症、心血管疾病、糖尿病、代谢疾病、免疫相关疾病、内分泌相关疾病或高血压。In one embodiment, the disease associated with the orexin receptor comprises sleep disorders, depression, anxiety, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder, behavior Disorders, mood disorders, post-traumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, insanity, dementia, drug dependence, addiction, cognitive impairment, Alzheimer's disease, Parkinson's disease Disease, dyskinesia, eating disorders, headache, migraine, pain, digestive diseases, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic diseases, immune-related diseases, endocrine-related diseases or high blood pressure.

在一实施方案中，与食欲素受体相关的疾病可选自睡眠障碍，其包含所有类型的失眠症、发作性嗜睡症和其他的过度嗜睡疾病、深眠状态、睡眠相关的肌张力障碍、不宁腿综合症、睡眠性呼吸暂停综合症、昼夜节律障碍、时差综合征、轮班工作综合征与睡眠时相延迟或提前综合征或精神疾病相关的失眠，等。In one embodiment, the disease associated with the orexin receptor may be selected from the group consisting of sleep disorders, including all types of insomnia, narcolepsy and other excessive sleepiness disorders, deep sleep states, sleep related dystonia, Restless leg syndrome, sleep apnea syndrome, circadian rhythm disorder, jet lag syndrome, shift work syndrome and sleep phase delay or early syndrome or mental illness related insomnia, etc.

在一实施方案中，与食欲素受体相关的疾病可选自精神病学、神经病学和神经变性障碍，其包含抑郁症、焦虑症、恐慌症、强迫症、情感性神经病、抑郁性神经病、焦虑性神经病、心境障碍、惊恐发作障碍、创伤后应激障碍、性功能障碍、精神病、帕金森氏病、痴呆或精神发育迟缓，等。In one embodiment, the disease associated with the orexin receptor may be selected from the group consisting of psychiatry, neurology, and neurodegenerative disorders, including depression, anxiety, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety Sexual neuropathy, mood disorder, panic attack disorder, post-traumatic stress disorder, sexual dysfunction, psychosis, Parkinson's disease, dementia or mental retardation, etc.

在一实施方式中，与食欲素受体相关的疾病可选自认知功能障碍，其包含在正常的、健康的、年轻的、成人的或者老年的人群中瞬间发作或慢性发作的所有类型的注意、学习和记忆功能下降，或者在精神病、神经病、心血管和免疫***疾病患者中瞬间发作或慢性发作的所有类型的注意、学习和记忆功能下降，等。In one embodiment, the disease associated with the orexin receptor may be selected from cognitive dysfunction, which includes all types of transient or chronic episodes in a normal, healthy, young, adult, or elderly population. Attention, learning and memory decline, or all types of attention, learning and memory decline in transient or chronic episodes in patients with psychosis, neuropathy, cardiovascular and immune system disorders, etc.

应当理解的是，在如压力或恐惧等某些环境条件(其中，压力可能具有社会来源如社会压力或具有生理来源如生理压力，包括由恐惧产生的压力)促进或加速任何如前所述的病症或疾病的情况下，本发明的化合物对治疗这些环境调节的病症或疾病是特别有用的。It should be understood that in certain environmental conditions such as stress or fear (where stress may have social sources such as social stress or have physiological sources such as physiological stress, including stress generated by fear), promote or accelerate any of the aforementioned In the case of a condition or disease, the compounds of the invention are particularly useful for treating such environmentally conditioned conditions or diseases.

本发明的化合物及药物组合物除了对人类治疗有益以外，还可应用于兽医治疗宠物、引进品种的动物和农场的动物中的哺乳动物。另外一些动物的实例包括马、狗和猫。在此，本发明的化合物包括其药学上可接受的衍生物。In addition to being useful for human therapy, the compounds and pharmaceutical compositions of the present invention are also useful in veterinary treatment of pets, introduced species of animals, and mammals in farm animals. Other examples of animals include horses, dogs, and cats. Herein, the compounds of the invention include pharmaceutically acceptable derivatives thereof.

本发明化合物的一般合成方法General method for synthesizing the compounds of the invention

为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的方法。For the purpose of describing the invention, the examples are set forth below. However, it should be understood that the present invention is not limited to the embodiments, but merely provides the practice of the present invention. Methods.

一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)或式(II)所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。In general, the compounds of the present invention can be prepared by the methods described herein, unless otherwise stated, wherein the substituents are as defined for formula (I) or formula (II). The following reaction schemes and examples are provided to further illustrate the contents of the present invention.

所属领域的专业人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare a number of other compounds of the invention, and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention. Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by modifications by those skilled in the art, such as appropriate protection of the interfering group, by the use of other known reagents in addition to those described herein, or The reaction conditions are subject to some conventional modifications. Additionally, the reactions or known reaction conditions disclosed herein are also recognized to be suitable for the preparation of other compounds of the invention.

下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company，使用时都没有经过进一步纯化，除非其他方面表明。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，天津市福晨化学试剂厂，武汉鑫华远科技发展有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂购买得到。The examples described below, unless otherwise indicated, all temperatures are set to degrees Celsius. The reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents from Shantou Xiqiao Chemical Plant, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant purchased it.

无水四氢呋喃，二氧六环，甲苯，***是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯，石油醚，正己烷，N,N-二甲基乙酰胺和N,N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by refluxing with sodium metal. Anhydrous dichloromethane and chloroform were obtained by reflux drying of calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were previously dried over anhydrous sodium sulfate.

以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿都是干燥过的。The following reaction is generally carried out under a positive pressure of nitrogen or argon or on a dry solvent (unless otherwise indicated), the reaction bottle is stoppered with a suitable rubber stopper, and the substrate is driven through a syringe. The glassware is dry.

色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。The column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

¹H NMR谱使用Bruker 400MHz或600MHz核磁共振谱仪记录。¹H NMR谱以CDC1₃、DMSO-d₆、CD₃OD或丙酮-d₆为溶剂(以ppm为单位)，用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)、d(doublet，双峰)、t(triplet，三重峰)、m(multiplet，多重峰)、br(broadened，宽峰)、dd(doublet of doublets，双二重峰)、dt(doublet of triplets，双三重峰)。偶合常数，用赫兹(Hz)表示。 ¹ H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz NMR spectrometer. ^{The 1} H NMR spectrum was determined by using CDC1 ₃ , DMSO-d ₆ , CD ₃ OD or acetone-d ₆ as a solvent (in ppm) using TMS (0 ppm) or chloroform (7.26 ppm) as a reference standard. When multiple peaks appear, the following abbreviations are used: s (singlet, single peak), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), br (broadened, wide) Peak), dd (doublet of doublets), dt (doublet of triplets). Coupling constant, expressed in Hertz (Hz).

低分辨率质谱(MS)数据的测定条件是：Agilent 6120四级杆HPLC-MS(柱子型号：Zorbax SB-C18,2.1x 30mm,3.5微米,6min,流速为0.6mL/min。流动相：5％-95％(含0.1％甲酸的CH₃CN)在(含0.1％甲酸的H₂O)中的比例，采用电喷雾电离(ESI)，在210nm/254nm下，用UV检测。The conditions for the determination of low resolution mass spectrometry (MS) data were: Agilent 6120 quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 micron, 6 min, flow rate 0.6 mL/min. Mobile phase: 5 ratio of 95% (0.1% formic acid in CH ₃ CN) in (H containing 0.1% formic acid ₂ O) in using electrospray ionization (ESI), at 210nm / 254nm, with UV detection.

纯的化合物使用Agilent 1260pre-HPLC或Calesep pump 250pre-HPLC(柱子型号：NOVASEP 50/80mm DAC)，在210nm/254nm下，用UV检测。The pure compound was detected by UV using an Agilent 1260 pre-HPLC or a Calesep pump 250 pre-HPLC (column model: NOVASEP 50/80 mm DAC) at 210 nm / 254 nm.

下面简写词的使用贯穿本发明：The following abbreviations are used throughout the invention:

Boc 叔丁氧羰基Boc tert-butoxycarbonyl

CH₂Cl₂、DCM 二氯甲烷CH ₂ Cl ₂ , DCM dichloromethane

Cs₂CO₃ 碳酸铯Cs ₂ CO ₃ strontium carbonate

CDC1₃ 氘代氯仿CDC1 ₃ deuterated chloroform

CuI 碘化亚铜CuI cuprous iodide

DMF N,N-二甲基甲酰胺 DMF N,N-dimethylformamide

DMSO 二甲基亚砜DMSO dimethyl sulfoxide

Et₃N、TEA 三乙胺Et ₃ N, TEA triethylamine

EtOAc、EA 乙酸乙酯EtOAc, EA ethyl acetate

EtOH 乙醇EtOH ethanol

g 克g g

h 小时h hours

KOH 氢氧化钾KOH potassium hydroxide

K₂CO₃ 碳酸钾K ₂ CO ₃ potassium carbonate

MeCN、CH₃CN 乙腈MeCN, CH ₃ CN acetonitrile

Na₂CO₃ 碳酸钠Na ₂ CO ₃ sodium carbonate

NaOH 氢氧化钠NaOH sodium hydroxide

Na₂SO₄ 硫酸钠Na ₂ SO ₄ sodium sulfate

MgSO₄ 硫酸镁MgSO ₄ magnesium sulfate

mL、ml 毫升mL, ml ml

PE 石油醚(60-90℃)PE petroleum ether (60-90 ° C)

RT、rt、r.t. 室温RT, rt, r.t. room temperature

下列合成方案描述了制备本发明化合物的步骤。除非另外说明，R¹、R²、n和m具有如本发明所述的定义。The following synthetic schemes describe the steps in the preparation of the compounds of the invention. Unless otherwise stated, R ¹ , R ² , n and m have the definitions as described herein.

合成方案1Synthetic scheme 1

本发明化合物(10)可以通过合成方案1中描述的一般合成方法制备得到，并在具体实施例中详细描述：首先任选取代的邻碘苯甲酸(1)与2H-1,2,3-三氮唑在适当的碱存在和加热条件下通过催化剂(如 CuI)的作用反应得到化合物(2)，化合物(2)与氯代试剂在加热条件下反应得到化合物(3)，然后化合物(3)在适当的碱存在下与2-Boc-六氢吡咯并[3,4-c]吡咯(4)反应得到化合物(5)，化合物(5)再在适当的条件下(如在酸的存在下或在加热的条件下)脱掉Boc保护基得到相应的化合物(6)，化合物(6)与2-氯-5-溴嘧啶(7)在适当的碱存在和加热条件下反应得到化合物(8)，最后化合物(8)与任选取代的苯硼酸(9)偶联得到目标化合物(10)。The compound ( 10 ) of the present invention can be produced by the general synthetic method described in the synthesis scheme 1, and is described in detail in the specific examples: first optionally substituted o-iodobenzoic acid ( 1 ) and 2H- 1 , 2, 3- The triazole is reacted by a catalyst (such as CuI) in the presence of a suitable base to obtain a compound ( 2 ), and the compound ( 2 ) is reacted with a chlorinating reagent under heating to obtain a compound ( 3 ), and then the compound ( 3) ) in the presence of a suitable base to 2-Boc- hexahydro-pyrrolo [3,4-c] pyrrole (4) to give compound (5), the compound (5) and then (e.g., the presence of an acid under appropriate conditions The Boc protecting group is removed under heating or under heating to give the corresponding compound ( 6 ), and the compound ( 6 ) is reacted with 2-chloro-5-bromopyrimidine ( 7 ) in the presence of a suitable base and heating to obtain a compound ( 8 ), the final compound ( 8 ) is coupled with an optionally substituted phenylboronic acid ( 9 ) to give the target compound ( 10 ).

以下结合实施例对本发明提供的化合物、药物组合物及其应用进行进一步说明。The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in conjunction with the examples.

实施例1:(5-(5-(4-氟苯基)嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(5-甲基-2-(2H-1,2,3-三氮唑-2-基)苯基)甲酮Example 1: (5-(5-(4-Fluorophenyl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)(5-methyl-2) -(2H-1,2,3-triazol-2-yl)phenyl)methanone

步骤1)5-甲基-2-(2H-1,2,3-三氮唑-2-基)苯甲酸的合成Step 1) Synthesis of 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid

将2H-1,2,3-三氮唑(3.45g,50mmol)、2-碘-5-甲基苯甲酸(5.24g,20mmol)、碳酸铯(11.72g,36mmol)、反式-N,N'-二甲基-1,2-环己二胺(0.51g,3.6mmol)和碘化亚铜(0.38g,2mmol)依次加入到N,N-二甲基甲酰胺(30mL)中。反应液在氮气保护下逐渐升温至100℃，反应4小时后冷却至室温，加入水(60mL)稀释并用乙酸乙酯(200mL×2)萃取。水层用浓盐酸酸化至pH为1～2，然后加入乙酸乙酯(200mL×2)萃取，所得有机层用无水硫酸钠干燥，过滤，滤液减压旋干后经柱层析分离纯化(二氯甲烷/甲醇(v/v)＝50/1)得到标题化合物为黄色固体(2.76g,68％)。2H-1,2,3-triazole (3.45 g, 50 mmol), 2-iodo-5-methylbenzoic acid (5.24 g, 20 mmol), cesium carbonate (11.72 g, 36 mmol), trans-N, N'-Dimethyl-1,2-cyclohexanediamine (0.51 g, 3.6 mmol) and cuprous iodide (0.38 g, 2 mmol) were added sequentially to N,N-dimethylformamide (30 mL). The reaction solution was gradually warmed to 100 ° C under a nitrogen atmosphere. After 4 hours, the mixture was cooled to room temperature, diluted with water (60 mL), and extracted with ethyl acetate (200 mL×2). The aqueous layer was acidified with concentrated hydrochloric acid to pH 1-2, then ethyl acetate (200 mL×2) was evaporated. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. Methylene chloride/methanol (v/v) = 50/1)

MS(ESI,neg.ion)m/z:202.1[M-H]^-；MS (ESI, neg.ion) m/z: 202.1 [MH] ^- ;

¹H NMR(CD₃OD,600MHz)δ(ppm):7.88(s,2H),7.66(d,1H),7.59(d,J＝8.2Hz,1H),7.50-7.48(dd,J＝8.1Hz,1.1Hz,1H),2.45(s,3H)； ¹ H NMR (CD ₃ OD, 600 MHz) δ (ppm): 7.88 (s, 2H), 7.66 (d, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.50-7.48 (dd, J = 8.1 Hz, 1.1 Hz, 1H), 2.45 (s, 3H);

¹³C NMR(CD₃OD,151MHz)δ(ppm):169.8,140.7,137.5,136.7,133.5,131.5,129.3,126.0,21.0. ¹³ C NMR (CD ₃ OD, 151 MHz) δ (ppm): 169.8, 140.7, 137.5, 136.7, 133.5, 131.5, 129.3, 126.0, 21.0.

步骤2)5-甲基-2-(2H-1,2,3-三氮唑-2-基)苯甲酰氯的合成Step 2) Synthesis of 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl chloride

将5-甲基-2-(2H-1,2,3-三氮唑-2-基)苯甲酸(2.03g,10mmol)用无水二氯甲烷(20mL)溶解，再缓缓加入氯化亚砜(15mL,200mmol)和吡啶(0.15mL,2mmol)。反应液逐渐升温至回流，反应3小时后冷却，然后减压缓缓蒸去溶剂，所得产物直接用于下一步。Dissolve 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (2.03 g, 10 mmol) in anhydrous dichloromethane (20 mL) and slowly add chlorin Sulfoxide (15 mL, 200 mmol) and pyridine (0.15 mL, 2 mmol). The reaction solution was gradually warmed to reflux, and the mixture was cooled for 3 hours, then the solvent was evaporated slowly under reduced pressure, and the obtained product was used directly to the next step.

步骤3)5-(5-甲基-2-(2H-1,2,3-三氮唑-2-基)苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-甲酸叔丁酯的合成Step 3) 5-(5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2 (1H Synthesis of tert-butyl formate

冰水浴条件下，将2-Boc-六氢吡咯并[3,4-c]吡咯(0.99g,4.66mmol)用无水二氯甲烷(20mL)溶解，再依次缓缓加入三乙胺(5.0mL,36mmol)和5-甲基-2-(2H-1,2,3-三氮唑-2-基)苯甲酰氯(1.25g,5.64mmol)的二氯甲烷(15mL)溶液。反应液在冰水浴条件下搅拌10min后，转移至室温下反应12小时。向反应液中加入二氯甲烷(50mL)，并依次用水(50mL)和饱和食盐水(50mL)洗涤。有机层用无水硫酸钠干燥，过滤，滤液减压旋干后经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1.2)得到标题化合物为黄色粘稠物(1.79mg,96.7％)。2-Boc-hexahydropyrrolo[3,4-c]pyrrole (0.99 g, 4.66 mmol) was dissolved in anhydrous dichloromethane (20 mL) under ice-water bath, and then triethylamine (5.0) A solution of mL, 36 mmol) and 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl chloride (1.25 g, 5.64 mmol) in dichloromethane (15 mL). The reaction solution was stirred for 10 min in an ice water bath, and then transferred to room temperature for 12 hours. Dichloromethane (50 mL) was added to the reaction mixture, which was washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate (MgSO4). 1.79 mg, 96.7%).

MS(ESI,pos.ion)m/z:398.1[M+H]⁺；MS (ESI, pos.) m/z: 398.1 [M+H] ⁺

¹H NMR(CDCl₃,600MHz)δ(ppm):7.84(d,J＝7.4Hz,1H),7.77(s,2H),7.30(d,J＝8.0Hz,1H),7.20(s, 1H),3.78-3.76(m,1H),3.64-3.53(m,2H),3.45-3.38(m,1H),3.27-3.25(m,2H),3.16-3.07(m,1H),2.93-2.87(m,2H),2.76(s,1H),2.39(s,3H),1.44(d,J＝19.3Hz,9H). ¹ H NMR (CDCl ₃ , 600 MHz) δ (ppm): 7.84 (d, J = 7.4 Hz, 1H), 7.77 (s, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H) ), 3.78-3.76 (m, 1H), 3.64-3.53 (m, 2H), 3.45-3.38 (m, 1H), 3.27-3.25 (m, 2H), 3.16-3.07 (m, 1H), 2.93-2.87 (m, 2H), 2.76 (s, 1H), 2.39 (s, 3H), 1.44 (d, J = 19.3 Hz, 9H).

步骤4)(六氢吡咯并[3,4-c]吡咯-2(1H)-基)(5-甲基-2-(2H-1,2,3-三氮唑-2-基)苯基)甲酮的合成Step 4) (hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzene Synthesis of ketone

将5-(5-甲基-2-(2H-1,2,3-三氮唑-2-基)苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-甲酸叔丁酯(1.79g,4.5mmol)用无水二氯甲烷(15mL)溶解，然后加入氯化氢-乙酸乙酯溶液(15mL,3M)。反应液在室温下反应1小时后，向其中缓缓加入水(30mL)和碳酸钾(0.83g,6.0mmol)。所得混合物在室温下搅拌0.5小时，然后减压旋干，粘稠物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝10/1)得到标题化合物为黄色油状物(1.28g,95.6％)。5-(5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- tert-Butyl carboxylic acid (1.79 g, 4.5 mmol) was dissolved in methylene chloride (15 mL). After the reaction solution was allowed to react at room temperature for 1 hour, water (30 mL) and potassium carbonate (0.83 g, 6.0 mmol) were gradually added thereto. The obtained mixture was stirred at room temperature for 0.5 hr then EtOAc (mjjjjjjjj g, 95.6%).

MS(ESI,pos.ion)m/z:298.4[M+H]⁺；MS (ESI, pos.) m/z: 298.4 [M+H] ⁺

¹H NMR(CDCl₃,600MHz)δ(ppm):7.81-7.79(m,3H),7.30(d,J＝7.9Hz,1H),7.17(s,1H),3.72-3.64(m,2H),3.37(s,1H),3.35-3.31(m,1H),3.21-3.18(m,1H),3.09-3.06(m,1H),2.97-2.95(m,2H),2.85-2.77(m,2H),2.38(s,3H). ¹ H NMR (CDCl ₃ , 600 MHz) δ (ppm): 7.81-7.79 (m, 3H), 7.30 (d, J = 7.9 Hz, 1H), 7.17 (s, 1H), 3.72-3.64 (m, 2H) , 3.37 (s, 1H), 3.35-3.31 (m, 1H), 3.21-3.18 (m, 1H), 3.09-3.06 (m, 1H), 2.97-2.95 (m, 2H), 2.85-2.77 (m, 2H), 2.38 (s, 3H).

步骤5)(5-(5-溴嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(5-甲基-2-(2H-1,2,3-三氮唑-2-基)苯基)甲酮的Step 5) (5-(5-Bromopyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)(5-methyl-2-(2H-1,2) , 3-triazol-2-yl)phenyl)methanone 合成synthesis

将2-氯-5-溴嘧啶(0.29g,1.50mmol)、(六氢吡咯并[3,4-c]吡咯-2(1H)-基)(5-甲基-2-(2H-1,2,3-三氮唑-2-基)苯基)甲酮(0.30g,1.01mmol)和碳酸钾(0.56g,4.01mmol)依次加入到乙腈(25mL)中，反应液在氮气保护下逐渐升温至回流，反应9小时后冷却，然后减压蒸除溶剂。所得粘稠物用二氯甲烷(30mL)溶解，并依次用水(20mL)和饱和食盐水(20mL)萃取。有机层用无水硫酸钠干燥，过滤，滤液减压旋干后经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/2)得到标题化合物为淡黄色固体(0.270g,58.92％)。2-Chloro-5-bromopyrimidine (0.29 g, 1.50 mmol), (hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)(5-methyl-2-(2H-1) , 2,3-triazol-2-yl)phenyl)methanone (0.30 g, 1.01 mmol) and potassium carbonate (0.56 g, 4.01 mmol) were sequentially added to acetonitrile (25 mL). The temperature was gradually raised to reflux, and the reaction was cooled after 9 hours, and then the solvent was evaporated under reduced pressure. The obtained viscous material was dissolved in dichloromethane (30 mL) and extracted with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate (MgSO4). g, 58.92%).

MS(ESI,pos.ion)m/z:454.0[M+H]⁺；MS (ESI, pos.) m/z: 454.0 [M+H] ⁺

¹H NMR(CDCl₃,400MHz)δ(ppm):8.31(s,2H),7.84(d,J＝8.3Hz,1H),7.72(s,2H),7.31(d,J＝8.3Hz,1H),7.21(s,1H),3.89-3.79(m,2H),3.70-3.63(m,2H),3.51(dd,J＝11.7Hz,5.3Hz,1H),3.44-3.38(m,2H),3.08-2.92(m,3H),2.40(s,3H). ¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm): 8.31 (s, 2H), 7.84 (d, J = 8.3 Hz, 1H), 7.72 (s, 2H), 7.31 (d, J = 8.3 Hz, 1H) ), 7.21 (s, 1H), 3.89-3.79 (m, 2H), 3.70-3.63 (m, 2H), 3.51 (dd, J = 11.7 Hz, 5.3 Hz, 1H), 3.44 - 3.38 (m, 2H) , 3.08-2.92 (m, 3H), 2.40 (s, 3H).

步骤6)(5-(5-(4-氟苯基)嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(5-甲基-2-(2H-1,2,3-三氮唑-2-基)苯Step 6) (5-(5-(4-Fluorophenyl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)(5-methyl-2- (2H-1,2,3-triazol-2-yl)benzene 基)甲酮的合成Synthesis of ketone

将(5-(5-溴嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(5-甲基-2-(2H-1,2,3-三氮唑-2-基)苯基)甲酮(0.454g,1.0mmol)、4-氟苯硼酸(0.154g,1.1mmol)和碳酸铯(0.652g,2.0mmol)用1,4-二氧六环(15mL)和水(3mL)溶解，再在氮气保护下向其中加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(73mg,0.1mmol)。反应液逐渐升温至80℃，反应6小时后冷却，然后减压蒸去溶剂。粘稠物用二氯甲烷(30mL)溶解，并依次用水(30mL)和饱和食盐水(30mL)洗涤。二氯甲烷层用无水硫酸钠干燥，过滤，滤液减压旋干后经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/2)得到标题化合物为白色固体(0.302g,64.3％)。(5-(5-Bromopyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)(5-methyl-2-(2H-1,2,3) -Triazol-2-yl)phenyl)methanone (0.454 g, 1.0 mmol), 4-fluorophenylboronic acid (0.154 g, 1.1 mmol) and cesium carbonate (0.652 g, 2.0 mmol) with 1,4-di Ethoxycyclohexane (15 mL) and water (3 mL) were dissolved, and then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.1 mmol) was added thereto under a nitrogen atmosphere. The reaction liquid was gradually heated to 80 ° C, and after reacting for 6 hours, it was cooled, and then the solvent was evaporated under reduced pressure. The viscous material was dissolved in dichloromethane (30 mL) and washed sequentially with water (30mL) and brine (30mL). The methylene chloride layer was dried over anhydrous sodium sulfate (MgSO4). 0.302g, 64.3%).

MS(ESI,pos.ion)m/z:470.2[M+H]⁺；MS (ESI, pos.) m/z: 470.2 [M+H] ⁺

¹H NMR(CDCl₃,400MHz)δ(ppm):8.51(s,2H),7.85(d,J＝8.3Hz,1H),7.73(s,2H),7.44-7.41(m,2H),7.31(d,J＝8.3Hz,1H),7.23(s,1H),7.14(t,J＝8.6Hz,2H),3.93-3.87(m,2H),3.76-3.68(m,2H),3.62(dd, J＝11.6Hz,5.3Hz,1H),3.50(dd,J＝11.6Hz,3.8Hz,1H),3.40(s,1H),3.10-2.96(m,3H),2.41(s,3H). ¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm): 8.51 (s, 2H), 7.85 (d, J = 8.3 Hz, 1H), 7.73 (s, 2H), 7.44-7.41 (m, 2H), 7.31 (d, J = 8.3 Hz, 1H), 7.23 (s, 1H), 7.14 (t, J = 8.6 Hz, 2H), 3.93 - 3.87 (m, 2H), 3.76 - 3.68 (m, 2H), 3.62 ( Dd, J = 11.6 Hz, 5.3 Hz, 1H), 3.50 (dd, J = 11.6 Hz, 3.8 Hz, 1H), 3.40 (s, 1H), 3.10-2.96 (m, 3H), 2.41 (s, 3H) .

实施例2:(2-(2H-1,2,3-三氮唑-2-基)苯基)(5-(5-(4-氟苯基)嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮Example 2: (2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-(4-fluorophenyl)pyrimidin-2-yl)hexahydropyrrole [3,4-c]pyrrole-2(1H)-yl)methanone

步骤1)2-(2H-1,2,3-三氮唑-2-基)苯甲酸的合成Step 1) Synthesis of 2-(2H-1,2,3-triazol-2-yl)benzoic acid

本步骤标题化合物参照实施例1步骤1所描述的方法制备得到，即将2H-1,2,3-三氮唑(0.7g,10.08mmol)、2-碘苯甲酸(1g,4.03mmol)、碳酸铯(2.36g,7.2mmol)、反式-N,N'-二甲基-1,2-环己二胺(0.103g,0.752mmol)和碘化亚铜(0.077g,0.403mmol)在N,N-二甲基甲酰胺(18mL)中反应制备，粗产品经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)得到标题化合物为黄色固体(0.511g,67％)。The title compound of this step was prepared by the method described in the first step of Example 1, that is, 2H-1,2,3-triazole (0.7 g, 10.08 mmol), 2-iodobenzoic acid (1 g, 4.03 mmol), carbonic acid.铯 (2.36 g, 7.2 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (0.103 g, 0.752 mmol) and cuprous iodide (0.077 g, 0.403 mmol) in N The title compound was obtained as a yellow solid (0.511 g, m. m. 67%).

MS(ESI,neg.ion)m/z:188.1[M-H]^-；MS (ESI, neg.ion) m/z: 188.1 [MH] ^- ;

¹H NMR(DMSO-d₆,600MHz)δ(ppm):13.06(s,1H),8.08(s,2H),7.78-7.75(m,2H),7.72-7.68(m,1H),7.60-7.57(m,1H)； ^{_{1 H NMR (DMSO-d 6}} , 600MHz) δ (ppm): 13.06 (s, 1H), 8.08 (s, 2H), 7.78-7.75 (m, 2H), 7.72-7.68 (m, 1H), 7.60- 7.57 (m, 1H);

¹³C NMR(DMSO-d₆,151MHz)δ(ppm):167.7,137.5,136.3,131.7,129.6,128.9,128.5,124.4. ¹³ C NMR (DMSO-d ₆ , 151 MHz) δ (ppm): 167.7, 137.5, 136.3, 131.7, 129.6, 128.9, 128.5, 124.4.

步骤2)2-(2H-1,2,3-三氮唑-2-基)苯甲酰氯的合成Step 2) Synthesis of 2-(2H-1,2,3-triazol-2-yl)benzoyl chloride

将2-(2H-1,2,3-三氮唑-2-基)苯甲酸(0.37g,1.96mmol)用无水二氯甲烷(20mL)溶解，再缓缓加入氯化亚砜(6mL,82.7mmol)和吡啶(0.04mL,0.5mmol)。反应液逐渐升温至回流，反应3小时后冷却，然后减压缓缓蒸去溶剂，所得产物直接用于下一步。2-(2H-1,2,3-Triazol-2-yl)benzoic acid (0.37 g, 1.96 mmol) was dissolved in anhydrous dichloromethane (20 mL) and then th , 82.7 mmol) and pyridine (0.04 mL, 0.5 mmol). The reaction solution was gradually warmed to reflux, and the mixture was cooled for 3 hours, then the solvent was evaporated slowly under reduced pressure, and the obtained product was used directly to the next step.

步骤3)5-(2-(2H-1,2,3-三氮唑-2-基)苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-甲酸叔丁酯的合成Step 3) 5-(2-(2H-1,2,3-Triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl Ester synthesis

本步骤标题化合物参照实施例1步骤3所描述的方法制备得到，即将2-(2H-1,2,3-三氮唑-2-基)苯甲酰氯(1.12g,5.39mmol)、2-Boc-六氢吡咯并[3,4-c]吡咯(0.96g,4.52mmol)和三乙胺(2.55mL,18.1mmol)在无水二氯甲烷(30mL)中反应制备，粗产品经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)得到标题化合物为橙黄色粘稠物(1.33g,76.6％)。The title compound of this step was prepared by the method described in Step 3 of Example 1, that is, 2-(2H-1,2,3-triazol-2-yl)benzoyl chloride (1.12 g, 5.39 mmol), 2- Preparation of Boc-hexahydropyrrolo[3,4-c]pyrrole (0.96 g, 4.52 mmol) and triethylamine (2.55 mL, 18.1 mmol) in anhydrous dichloromethane (30 mL). The title compound was obtained as an orange-yellow viscous material (1.33 g, 76.6%).

MS(ESI,pos.ion)m/z:384.3[M+H]⁺；MS (ESI, pos.) m/z: 384.3 [M+H] ⁺

¹H NMR(CDCl₃,400MHz)δ(ppm):8.00(d,J＝8.1Hz,1H),7.81(s,2H),7.55-7.50(m,1H),7.45-7.42(m,2H),3.83-3.79(m,1H),3.64-3.56(m,2H),3.48-3.39(m,1H),3.36-3.27(m,2H),3.20-3.13(m,1H),2.98-2.90(m,2H),2.82-2.78(m,1H),1.46-1.44(m,9H). ¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm): 8.00 (d, J = 8.1 Hz, 1H), 7.81 (s, 2H), 7.55-7.50 (m, 1H), 7.45-7.42 (m, 2H) , 3.83-3.79 (m, 1H), 3.64-3.56 (m, 2H), 3.48-3.39 (m, 1H), 3.36-3.27 (m, 2H), 3.20-3.13 (m, 1H), 2.98-2.90 ( m, 2H), 2.82-2.78 (m, 1H), 1.46-1.44 (m, 9H).

步骤4)(2-(2H-1,2,3-三氮唑-2-基)苯基)(六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮的合成Step 4) (2-(2H-1,2,3-triazol-2-yl)phenyl)(hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methanone synthesis

本步骤标题化合物参照实施例1步骤4所描述的方法制备得到，即将5-(2-(2H-1,2,3-三氮唑-2-基)苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-甲酸叔丁酯(1.31g,3.42mmol)、氯化氢-乙酸乙酯溶液(10mL,35mmol)在无水二氯甲烷(20mL)中反应制备，粗产品经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝15/1)得到标题化合物为橙黄色粘稠物(0.94g,97.1％)。The title compound of this step was prepared by the method described in Step 4 of Example 1, that is, 5-(2-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3 , 4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (1.31 g, 3.42 mmol), hydrogen chloride-ethyl acetate solution (10 mL, 35 mmol) The title compound was obtained as an orange yellow viscous material (0.94 g, 97.1%).

MS(ESI,pos.ion)m/z:284.2[M+H]⁺；MS (ESI, pos. ion) m/z: 284.2 [M+H] ⁺

¹H NMR(CDCl₃,400MHz)δ(ppm):7.97(d,J＝8.1Hz,1H),7.83(s,2H),7.54-7.50(m,1H),7.44-7.38(m,2H),3.79-3.67(m,2H),3.31-3.26(m,2H),3.15(dd,J＝11.2Hz,7.3Hz,1H),3.08(dd,J＝11.4Hz,3.4Hz, 1H),2.95(d,J＝8.4Hz,2H),2.83-2.75(m,2H). ¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm): 7.97 (d, J = 8.1 Hz, 1H), 7.83 (s, 2H), 7.54 - 7.50 (m, 1H), 7.44 - 7.38 (m, 2H) , 3.79-3.67 (m, 2H), 3.31-3.26 (m, 2H), 3.15 (dd, J = 11.2 Hz, 7.3 Hz, 1H), 3.08 (dd, J = 11.4 Hz, 3.4 Hz, 1H), 2.95 (d, J = 8.4 Hz, 2H), 2.83 - 2.75 (m, 2H).

步骤5)(2-(2H-1,2,3-三氮唑-2-基)苯基)(5-(5-溴嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮的合成Step 5) (2-(2H-1,2,3-Triazol-2-yl)phenyl)(5-(5-bromopyrimidin-2-yl)hexahydropyrrolo[3,4-c] Synthesis of pyrrole-2(1H)-yl)methanone

本步骤标题化合物参照实施例1步骤5所描述的方法制备得到，即将2-氯-5-溴嘧啶(0.35g,1.81mmol)、(2-(2H-1,2,3-三氮唑-2-基)苯基)(六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮(0.34g,1.20mmol)和碳酸钾(0.67g,4.80mmol)在乙腈(25mL)中反应制备，粗产品经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/2)得到标题化合物为淡黄色固体(0.324g,61.29％)。The title compound of this step was prepared by the method described in Step 5 of Example 1, that is, 2-chloro-5-bromopyrimidine (0.35 g, 1.81 mmol), (2-(2H-1,2,3-triazole)- 2-yl)phenyl)(hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methanone (0.34 g, 1.20 mmol) and potassium carbonate (0.67 g, 4.80 mmol) in acetonitrile ( The title compound was obtained as a pale yellow solid (0.324 g, 61.29%).

MS(ESI,pos.ion)m/z:440.4[M+H]⁺；MS (ESI, pos.) m/z: 440.4 [M+H] ⁺

¹H NMR(CDCl₃,400MHz)δ(ppm):8.31(s,2H),7.98(d,J＝8.2Hz,1H),7.75(s,2H),7.54-7.50(m,1H),7.44-7.41(m,2H),3.90-3.80(m,2H),3.72-3.62(m,2H),3.54(dd,J＝11.7Hz,5.3Hz,1H),3.44-3.38(m,2H),3.10-2.95(m,3H). ¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm): 8.31 (s, 2H), 7.98 (d, J = 8.2 Hz, 1H), 7.75 (s, 2H), 7.54 - 7.50 (m, 1H), 7.44 -7.41 (m, 2H), 3.90-3.80 (m, 2H), 3.72-3.62 (m, 2H), 3.54 (dd, J = 11.7 Hz, 5.3 Hz, 1H), 3.44 - 3.38 (m, 2H), 3.10-2.95 (m, 3H).

步骤6)(2-(2H-1,2,3-三氮唑-2-基)苯基)(5-(5-(4-氟苯基)嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮Step 6) (2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-(4-fluorophenyl)pyrimidin-2-yl)hexahydropyrrolo[ 3,4-c]pyrrole-2(1H)-yl)methanone 的合成Synthesis

本步骤标题化合物参照实施例1步骤6所描述的方法制备得到，即将(2-(2H-1,2,3-三氮唑-2-基)苯基)(5-(5-溴嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮(0.440g,1.0mmol)、4-氟苯硼酸(0.154g,1.1mmol)、碳酸铯(0.652g,2.0mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(73mg,0.1mmol)在1,4-二氧六环(15mL)和水(3mL)中反应制备，粗产品经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/3)得到标题化合物为白色固体(0.273g,59.9％)。The title compound of this step was prepared by the method described in the step 6 of Example 1, that is, (2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-bromopyrimidine)- 2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methanone (0.440 g, 1.0 mmol), 4-fluorophenylboronic acid (0.154 g, 1.1 mmol), cesium carbonate ( 0.652 g, 2.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.1 mmol) in 1,4-dioxane (15 mL) and water ( The title compound was obtained as a white solid (0.273 g, 59.9%).

MS(ESI,pos.ion)m/z:456.5[M+H]⁺；MS (ESI, pos.) m/z: 456.5 [M+H] ⁺

¹H NMR(CDCl₃,600MHz)δ(ppm):8.51(s,2H),7.99(d,J＝8.1Hz,1H),7.76(s,2H),7.54-7.51(m,1H),7.43-7.41(m,4H),7.14(t,J＝8.5Hz,2H),3.91-3.89(m,2H),3.75-3.72(m,2H),3.64(dd,J＝11.4Hz,5.1Hz,1H),3.53-3.51(m,1H),3.42(s,1H),3.11-2.99(m,3H). ^{_{1 H NMR (CDCl 3, 600MHz}} ) δ (ppm): 8.51 (s, 2H), 7.99 (d, J = 8.1Hz, 1H), 7.76 (s, 2H), 7.54-7.51 (m, 1H), 7.43 -7.41 (m, 4H), 7.14 (t, J = 8.5 Hz, 2H), 3.91-3.89 (m, 2H), 3.75-3.72 (m, 2H), 3.64 (dd, J = 11.4 Hz, 5.1 Hz, 1H), 3.53-3.51 (m, 1H), 3.42 (s, 1H), 3.11-2.99 (m, 3H).

实施例3:(2-氟-6-(2H-1,2,3-三氮唑-2-基)苯基)(5-(5-(4-氟苯基)嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮Example 3: (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-(4-fluorophenyl)pyrimidin-2-yl) Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methanone

步骤1)2-氟-6-(2H-1,2,3-三氮唑-2-基)苯甲酸的合成Step 1) Synthesis of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid

本步骤标题化合物参照实施例1步骤1所描述的方法制备得到，即将2H-1,2,3-三氮唑(1.947g,28.19mmol)、2-氟-6-碘苯甲酸(3g,11.28mmol)、碳酸铯(6.616g,20.31mmol)、反式-N,N'-二甲基-1,2-环己二胺(0.289g,2.03mmol)和碘化亚铜(0.215g,1.13mmol)在N,N-二甲基甲酰胺(12mL)中反应制备，粗产品经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝100/1)得到标题化合物为淡黄色固体(1.503g,64.33％)。The title compound of this step was prepared by the method described in the first step of Example 1, that is, 2H-1,2,3-triazole (1.947 g, 28.19 mmol), 2-fluoro-6-iodobenzoic acid (3 g, 11.28). Ment), cesium carbonate (6.616 g, 20.31 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (0.289 g, 2.03 mmol) and cuprous iodide (0.215 g, 1.13) Methyl acetate (m/v) (m/m) (m. Solid (1.503 g, 64.33%).

MS(ESI,pos.ion)m/z:208.2[M+H]⁺；MS (ESI, pos.) m/z: 208.2 [M+H] ⁺

¹H NMR(DMSO-d₆,600MHz)δ(ppm):8.15(s,2H),7.79(d,J＝8.22Hz,1H),7.70-7.65(m,1H),7.44(t,J＝8.75Hz,1H). ^{_{1 H NMR (DMSO-d 6}} , 600MHz) δ (ppm): 8.15 (s, 2H), 7.79 (d, J = 8.22Hz, 1H), 7.70-7.65 (m, 1H), 7.44 (t, J = 8.75Hz, 1H).

步骤2)2-氟-6-(2H-1,2,3-三氮唑-2-基)苯甲酰氯的合成Step 2) Synthesis of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl chloride

将2-氟-6-(2H-1,2,3-三氮唑-2-基)苯甲酸(1.026g,4.953mmol)用无水二氯甲烷(20mL)溶解，再缓缓加入氯化亚砜(11mL,150mmol)和吡啶(0.08mL,1mmol)。反应液逐渐升温至回流，反应3小时后冷却，然后减压缓缓蒸去溶剂，所得产物直接用于下一步。2-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (1.026 g, 4.953 mmol) was dissolved in anhydrous dichloromethane (20 mL). Sulfoxide (11 mL, 150 mmol) and pyridine (0.08 mL, 1 mmol). The reaction solution was gradually warmed to reflux, and the mixture was cooled for 3 hours, then the solvent was evaporated slowly under reduced pressure, and the obtained product was used directly to the next step.

步骤3)5-(2-氟-6-(2H-1,2,3-三氮唑-2-基)苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-甲酸叔丁酯的合成Step 3) 5-(2-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2 (1H) Synthesis of tert-butyl formate

本步骤标题化合物参照实施例1步骤3所描述的方法制备得到，即将2-氟-6-(2H-1,2,3-三氮唑-2-基)苯甲酰氯(1.11g,4.92mmol)、2-Boc-六氢吡咯并[3,4-c]吡咯(0.87g,4.10mmol)和三乙胺(2.35mL,16.7mmol)在无水二氯甲烷(30mL)中反应制备，粗产品经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)得到标题化合物为橙黄色粘稠物(1.45g,88.15％)。The title compound of this step was prepared by the method described in Step 3 of Example 1, that is, 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl chloride (1.11 g, 4.92 mmol). , 2-Boc-hexahydropyrrolo[3,4-c]pyrrole (0.87g, 4.10mmol) and triethylamine (2.35mL, 16.7mmol) were prepared by reaction in anhydrous dichloromethane (30mL), crude The product was purified by silica gel column chromatography eluting elut elut elut elut elut

MS(ESI,pos.ion)m/z:346.3[M+H-56]⁺；MS (ESI, pos.) m/z: 346.3 [M+H - 56] ⁺ ;

¹H NMR(CDCl₃,400MHz)δ(ppm):7.84-7.78(m,3H),7.50-7.44(m,1H),7.13(td,J＝8.4Hz,2.7Hz,1H),3.86-3.64(m,3H),3.58-3.54(m,1H),3.51-3.47(m,1H),3.40-3.37(m,1H),3.32-3.15(m,2H),2.95-2.82(m,2H),1.45-1.41(m,9H). ¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm): 7.84-7.78 (m, 3H), 7.50-7.44 (m, 1H), 7.13 (td, J = 8.4 Hz, 2.7 Hz, 1H), 3.86-3.64 (m, 3H), 3.58-3.54 (m, 1H), 3.51-3.47 (m, 1H), 3.40-3.37 (m, 1H), 3.32-3.15 (m, 2H), 2.95-2.82 (m, 2H) , 1.45-1.41 (m, 9H).

步骤4)(2-氟-6-(2H-1,2,3-三氮唑-2-基)苯基)(六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮的合成Step 4) (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl ) Synthesis of ketone

本步骤标题化合物参照实施例1步骤4所描述的方法制备得到，即将5-(2-氟-6-(2H-1,2,3-三氮唑-2-基)苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-甲酸叔丁酯(1.41g,3.51mmol)、氯化氢-乙酸乙酯溶液(10mL,35mmol)在无水二氯甲烷(10mL)中反应制备，粗产品经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20/1)得到标题化合物为黄色粘稠物(0.977g,92.27％)。The title compound of this step is prepared by the method described in the step 4 of Example 1, that is, 5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydro Pyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (1.41 g, 3.51 mmol), hydrogen chloride-ethyl acetate solution (10 mL, 35 mmol) The title compound was obtained as a yellow viscous (0.977 g, 92.27%).

MS(ESI,pos.ion)m/z:302.4[M+H]⁺；MS (ESI, pos.) m/z: 302.4 [M+H] ⁺

¹H NMR(CDCl₃,400MHz)δ(ppm):7.87-7.79(m,3H),7.51-7.45(m,1H),7.15(t,J＝8.4Hz,1H),3.77-3.59(m,3H),3.25-3.08(m,3H),3.03-2.91(m,2H),2.90-2.74(m,2H). ¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm): 7.87-7.79 (m, 3H), 7.51-7.45 (m, 1H), 7.15 (t, J = 8.4 Hz, 1H), 3.77-3.59 (m, 3H), 3.25-3.08 (m, 3H), 3.03-2.91 (m, 2H), 2.90-2.74 (m, 2H).

步骤5)(5-(5-溴嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三氮唑-2-基)苯基)甲酮的合Step 5) (5-(5-Bromopyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)(2-fluoro-6-(2H-1,2, Combination of 3-triazol-2-yl)phenyl)methanone 成to make

本步骤标题化合物参照实施例1步骤5所描述的方法制备得到，即将2-氯-5-溴嘧啶(0.29g,1.50mmol)、(2-氟-6-(2H-1,2,3-三氮唑-2-基)苯基)(六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮(0.302g,1.0mmol)和碳酸钾(0.56g,4.01mmol)在乙腈(25mL)中反应制备，粗产品经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/1)得到标题化合物为淡黄色固体(0.328g,71.6％)。The title compound of this step was prepared by the method described in the step 5 of Example 1, that is, 2-chloro-5-bromopyrimidine (0.29 g, 1.50 mmol), (2-fluoro-6-(2H-1,2,3- Triazol-2-yl)phenyl)(hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methanone (0.302 g, 1.0 mmol) and potassium carbonate (0.56 g, 4.01 mmol) The title compound was obtained as a pale yellow solid (0.328 g, 71.6%). .

MS(ESI,pos.ion)m/z:458.1[M+H]⁺；MS (ESI, pos.) m/z: 458.1 [M+H] ⁺

¹H NMR(CDCl₃,400MHz)δ(ppm):8.31(d,J＝1.9Hz,2H),7.86-7.83(m,1H),7.81(s,1H),7.73(s,1H),7.51-7.45(m,1H),7.17-7.11(m,1H),3.92-3.82(m,2H),3.78(dd,J＝12.5Hz,4.4Hz,1H),3.71-3.53(m,4H),3.26(dd,J＝10.7Hz,5.2Hz,1H),3.15-2.99(m,2H). ¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm): 8.31 (d, J = 1.9 Hz, 2H), 7.86-7.83 (m, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 7.51 -7.45 (m, 1H), 7.17-7.11 (m, 1H), 3.92-3.82 (m, 2H), 3.78 (dd, J = 12.5 Hz, 4.4 Hz, 1H), 3.71-3.53 (m, 4H), 3.26 (dd, J = 10.7 Hz, 5.2 Hz, 1H), 3.15-2.99 (m, 2H).

步骤6)(2-氟-6-(2H-1,2,3-三氮唑-2-基)苯基)(5-(5-(4-氟苯基)嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)Step 6) (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-(4-fluorophenyl)pyrimidin-2-yl)6 Hydropyrrolo[3,4-c]pyrrole-2(1H)-yl) 甲酮的合成Synthesis of ketone

本步骤标题化合物参照实施例1步骤6所描述的方法制备得到，即将(5-(5-溴嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三氮唑-2-基)苯基)甲酮(0.458g,1.0mmol)、4-氟苯硼酸(0.154g,1.1mmol)、碳酸铯(0.652g,2.0mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(73mg,0.1mmol)在1,4-二氧六环(15mL)和水(3mL)中反应制备，粗产品经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v) ＝1/2)得到标题化合物为淡黄色固体(0.294g,62.1％)。The title compound of this step was prepared by the method described in the step 6 of Example 1, that is, (5-(5-bromopyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl. (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (0.458 g, 1.0 mmol), 4-fluorophenylboronic acid (0.154 g, 1.1 mmol) , cesium carbonate (0.652 g, 2.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.1 mmol) in 1,4-dioxane (15 mL) Prepared by reaction with water (3mL), and the crude product was purified by silica gel column chromatography ( petroleum ether / ethyl acetate (v / v) The title compound was obtained as a pale yellow solid (0.294 g, 62.1%).

MS(ESI,pos.ion)m/z:474.2[M+H]⁺；MS (ESI, pos.) m/z: 474.2 [M+H] ⁺

¹H NMR(CDCl₃,600MHz)δ(ppm):8.50(s,2H),7.85-7.83(m,1H),7.80(s,1H),7.73(s,1H),7.48-7.44(m,1H),7.40(dd,J＝8.4Hz,5.3Hz,2H),7.15-7.10(m,3H),4.00-3.89(m,2H),3.80-3.71(m,2H),3.69-3.61(m,2H),3.59-3.55(m,1H),3.28-3.26(m,1H),3.15-3.01(m,2H). ^{_{1 H NMR (CDCl 3, 600MHz}} ) δ (ppm): 8.50 (s, 2H), 7.85-7.83 (m, 1H), 7.80 (s, 1H), 7.73 (s, 1H), 7.48-7.44 (m, 1H), 7.40 (dd, J=8.4 Hz, 5.3 Hz, 2H), 7.15-7.10 (m, 3H), 4.00-3.89 (m, 2H), 3.80-3.71 (m, 2H), 3.69-3.61 (m) , 2H), 3.59-3.55 (m, 1H), 3.28-3.26 (m, 1H), 3.15-3.01 (m, 2H).

实施例4:(5-(5-(2,4-二氟苯基)嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(5-甲基-2-(2H-1,2,3-三氮唑-2-基)苯基)甲酮Example 4: (5-(5-(2,4-Difluorophenyl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)(5-A Keto-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

本步骤标题化合物参照实施例1步骤6所描述的方法制备得到，即将(5-(5-溴嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(5-甲基-2-(2H-1,2,3-三氮唑-2-基)苯基)甲酮(0.454g,1.0mmol)、2,4-二氟苯硼酸(0.174g,1.1mmol)、碳酸铯(0.652g,2.0mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(73mg,0.1mmol)在1,4-二氧六环(15mL)和水(3mL)中反应制备，粗产品经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/2)得到标题化合物为淡黄色固体(0.281g,57.6％)。The title compound of this step was prepared by the method described in the step 6 of Example 1, that is, (5-(5-bromopyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl. (5-Methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (0.454 g, 1.0 mmol), 2,4-difluorophenylboronic acid (0.174 g) , 1.1 mmol), cesium carbonate (0.652 g, 2.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.1 mmol) in 1,4-dioxane The title compound was obtained as a pale yellow solid (0.281 g). , 57.6%).

MS(ESI,pos.ion)m/z:488.5[M+H]⁺；MS (ESI, pos.) m/z: 488.5 [M+H] ⁺

¹H NMR(CDCl₃,400MHz)δ(ppm):8.46(s,2H),7.83(d,J＝8.4Hz,1H),7.72(s,2H),7.34-7.27(m,2H),7.22(s,1H),7.01-6.83(m,2H),3.91-3.82(m,2H),3.76-3.67(m,2H),3.64(dd,J＝11.7Hz,5.4Hz,1H),3.51(dd,J＝11.7Hz,3.9Hz,1H),3.43(s,1H),3.09-2.97(m,3H),2.40(s,3H)。 ¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm): 8.46 (s, 2H), 7.83 (d, J = 8.4 Hz, 1H), 7.72 (s, 2H), 7.34 - 7.27 (m, 2H), 7.22 (s, 1H), 7.01-6.83 (m, 2H), 3.91-3.82 (m, 2H), 3.76-3.67 (m, 2H), 3.64 (dd, J = 11.7 Hz, 5.4 Hz, 1H), 3.51 ( Dd, J = 11.7 Hz, 3.9 Hz, 1H), 3.43 (s, 1H), 3.09-2.97 (m, 3H), 2.40 (s, 3H).

实施例5:(2-(2H-1,2,3-三氮唑-2-基)苯基)(5-(5-(2,4-二氟苯基)嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮Example 5: (2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-(2,4-difluorophenyl)pyrimidin-2-yl)6 Hydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methanone

本步骤标题化合物参照实施例1步骤6所描述的方法制备得到，即将(2-(2H-1,2,3-三氮唑-2-基)苯基)(5-(5-溴嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮(0.440g,1.0mmol)、2,4-二氟苯硼酸(0.174g,1.1mmol)、碳酸铯(0.652g,2.0mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(73mg,0.1mmol)在1,4-二氧六环(15mL)和水(3mL)中反应制备，粗产品经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/3)得到标题化合物为白色固体(0.354g,74.8％)。The title compound of this step was prepared by the method described in the step 6 of Example 1, that is, (2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-bromopyrimidine)- 2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methanone (0.440 g, 1.0 mmol), 2,4-difluorophenylboronic acid (0.174 g, 1.1 mmol), Barium carbonate (0.652 g, 2.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.1 mmol) in 1,4-dioxane (15 mL) The title compound was obtained as a white solid (0.354 g, 74.8%).

MS(ESI,pos.ion)m/z:474.2[M+H]⁺；MS (ESI, pos.) m/z: 474.2 [M+H] ⁺

¹H NMR(CDCl₃,600MHz)δ(ppm):8.46(s,2H),7.97(d,J＝8.1Hz,1H),7.75(s,2H),7.60-7.46(m,1H),7.42(s,1H),7.41(s,1H),7.31(td,J＝8.5Hz,6.4Hz,1H),6.98-6.88(m,2H),3.92-3.87(m,2H),3.77-3.67(m,2H),3.63(dd,J＝11.6Hz,5.4Hz,1H),3.53-3.50(m,1H),3.41(s,1H),3.11-2.97(m,3H). ¹ H NMR (CDCl ₃ , 600 MHz) δ (ppm): 8.46 (s, 2H), 7.97 (d, J = 8.1 Hz, 1H), 7.75 (s, 2H), 7.60-7.46 (m, 1H), 7.42 (s, 1H), 7.41 (s, 1H), 7.31 (td, J = 8.5 Hz, 6.4 Hz, 1H), 6.98-6.88 (m, 2H), 3.92-3.87 (m, 2H), 3.77-3.67 ( m, 2H), 3.63 (dd, J = 11.6 Hz, 5.4 Hz, 1H), 3.53-3.50 (m, 1H), 3.41 (s, 1H), 3.11-2.97 (m, 3H).

实施例6:(5-(5-(2,4-二氟苯基)嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三氮唑-2-基)苯基)甲酮 Example 6: (5-(5-(2,4-Difluorophenyl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)(2-fluoro -6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

本步骤标题化合物参照实施例1步骤6所描述的方法制备得到，即将(5-(5-溴嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三氮唑-2-基)苯基)甲酮(0.458g,1.0mmol)、2,4-二氟苯硼酸(0.174g,1.1mmol)、碳酸铯(0.652g,2.0mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(73mg,0.1mmol)在1,4-二氧六环(15mL)和水(3mL)中反应制备，粗产品经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1/2)得到标题化合物为黄色固体(0.314g,63.9％)。The title compound of this step was prepared by the method described in the step 6 of Example 1, that is, (5-(5-bromopyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl. (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (0.458 g, 1.0 mmol), 2,4-difluorophenylboronic acid (0.174 g, 1.1 mmol), cesium carbonate (0.652 g, 2.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.1 mmol) in 1,4-dioxane The title compound was obtained as a yellow solid (0.314 g, 63.9). %).

MS(ESI,pos.ion)m/z:492.2[M+H]⁺；MS (ESI, pos.) m/z: 492.2 [M+H] ⁺

¹H NMR(CDCl₃,400MHz)δ(ppm):8.46(s,2H),7.88-7.76(m,2H),7.73(s,1H),7.45(dt,J＝14.3Hz,7.2Hz,1H),7.30(dd,J＝15.0Hz,8.5Hz,1H),7.12(dd,J＝14.3Hz,8.2Hz,1H),6.99-6.85(m,2H),4.02-3.87(m,2H),3.86-3.78(m,1H),3.77-3.69(m,1H),3.68-3.50(m,3H),3.33-3.22(m,1H),3.19-2.99(m,2H). ¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm): 8.46 (s, 2H), 7.88-7.76 (m, 2H), 7.73 (s, 1H), 7.45 (dt, J = 14.3 Hz, 7.2 Hz, 1H) ), 7.30 (dd, J = 15.0 Hz, 8.5 Hz, 1H), 7.12 (dd, J = 14.3 Hz, 8.2 Hz, 1H), 6.99-6.85 (m, 2H), 4.02-3.87 (m, 2H), 3.86-3.78(m,1H), 3.77-3.69(m,1H), 3.68-3.50(m,3H),3.33-3.22(m,1H), 3.19-2.99(m,2H).

实施例7:2-(2-(5-(5-甲基-2-(2H-1,2,3-三氮唑-2-基)苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)嘧啶-5-基)苯甲酰胺Example 7: 2-(2-(5-(5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-yl)pyrimidin-5-yl)benzamide

本步骤标题化合物参照实施例1步骤6所描述的方法制备得到，即将(5-(5-溴嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(5-甲基-2-(2H-1,2,3-三氮唑-2-基)苯基)甲酮(0.454g,1.0mmol)、2-氨基甲酰基苯硼酸(0.181g,1.1mmol)、碳酸铯(0.652g,2.0mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(73mg,0.1mmol)在1,4-二氧六环(15mL)和水(3mL)中反应制备，粗产品经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)得到标题化合物为淡黄色固体(0.406g,82.1％)。The title compound of this step was prepared by the method described in the step 6 of Example 1, that is, (5-(5-bromopyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl. (5-Methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (0.454 g, 1.0 mmol), 2-carbamoylbenzeneboronic acid (0.181 g, 1.1 mmol), cesium carbonate (0.652 g, 2.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.1 mmol) in 1,4-dioxane The title compound (m.p. %).

MS(ESI,pos.ion)m/z:495.2[M+H]⁺；MS (ESI, pos.) m/z: 495.2 [M+H] ⁺

¹H NMR(DMSO-d₆,600MHz)δ(ppm):8.39(s,2H),7.94(s,2H),7.79(s,1H),7.75(d,J＝8.2Hz,1H),7.53-7.46(m,2H),7.42-7.39(m,4H),7.32(s,1H),3.81(dd,J＝11.3Hz,7.9Hz,1H),3.70-3.60(m,2H),3.44-3.38(m,4H),3.08-2.86(m,3H),2.39(s,3H). ^{_{1 H NMR (DMSO-d 6}} , 600MHz) δ (ppm): 8.39 (s, 2H), 7.94 (s, 2H), 7.79 (s, 1H), 7.75 (d, J = 8.2Hz, 1H), 7.53 -7.46 (m, 2H), 7.42-7.39 (m, 4H), 7.32 (s, 1H), 3.81 (dd, J = 11.3 Hz, 7.9 Hz, 1H), 3.70-3.60 (m, 2H), 3.44 3.38 (m, 4H), 3.08-2.86 (m, 3H), 2.39 (s, 3H).

实施例8:2-(2-(5-(2-(2H-1,2,3-三氮唑-2-基)苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)嘧啶-5-基)苯甲酰胺Example 8: 2-(2-(5-(2-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2 (1H)-yl)pyrimidin-5-yl)benzamide

本步骤标题化合物参照实施例1步骤6所描述的方法制备得到，即将(2-(2H-1,2,3-三氮唑-2-基)苯基)(5-(5-溴嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮(0.440g,1.0mmol)、2-氨基甲酰基苯硼酸(0.181g,1.1mmol)、碳酸铯(0.652g,2.0mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(73mg,0.1 mmol)在1,4-二氧六环(15mL)和水(3mL)中反应制备，粗产品经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝25/1)得到标题化合物为黄色固体(0.385g,80.2％)。The title compound of this step was prepared by the method described in the step 6 of Example 1, that is, (2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-bromopyrimidine)- 2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methanone (0.440 g, 1.0 mmol), 2-carbamoylbenzeneboronic acid (0.181 g, 1.1 mmol), carbonic acid Bismuth (0.652 g, 2.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.1 Methyl acetate (m/v) (m/v) The compound was a yellow solid (0.385 g, 80.2%).

MS(ESI,pos.ion)m/z:481.3[M+H]⁺；MS (ESI, pos.) m/z: 481.3 [M+H] ⁺

¹H NMR(DMSO-d₆,600MHz)δ(ppm):8.39(s,2H),7.98(s,2H),7.88(d,J＝8.0Hz,1H),7.79(s,1H),7.62(t,J＝7.5Hz,1H),7.55-7.47(m,4H),7.42-7.39(m,3H),3.86-3.58(m,4H),3.44-3.38(m,2H),3.25-2.75(m,4H). ¹ H NMR (DMSO-d ₆ , 600 MHz) δ (ppm): 8.39 (s, 2H), 7.98 (s, 2H), 7.88 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.55-7.47 (m, 4H), 7.42 - 7.39 (m, 3H), 3.86-3.58 (m, 4H), 3.44 - 3.38 (m, 2H), 3.25 - 2.75 (m, 4H).

实施例9:2-(2-(5-(2-氟-6-(2H-1,2,3-三氮唑-2-基)苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)嘧啶-5-基)苯甲酰胺Example 9: 2-(2-(5-(2-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c Pyrrole-2(1H)-yl)pyrimidin-5-yl)benzamide

本步骤标题化合物参照实施例1步骤6所描述的方法制备得到，即将(5-(5-溴嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三氮唑-2-基)苯基)甲酮(0.458g,1.0mmol)、2-氨基甲酰基苯硼酸(0.181g,1.1mmol)、碳酸铯(0.652g,2.0mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(73mg,0.1mmol)在1,4-二氧六环(15mL)和水(3mL)中反应制备，粗产品经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝25/1)得到标题化合物为黄色固体(0.393g,78.9％)。The title compound of this step was prepared by the method described in the step 6 of Example 1, that is, (5-(5-bromopyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl. (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (0.458 g, 1.0 mmol), 2-carbamoylbenzeneboronic acid (0.181 g, 1.1) Methyl), cesium carbonate (0.652 g, 2.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.1 mmol) in 1,4-dioxane (15 mL) and EtOAc (3 mL) (EtOAc) .

MS(ESI,pos.ion)m/z:499.2[M+H]⁺；MS (ESI, pos.) m/z: 499.2 [M+H] ⁺

¹H NMR(CDCl₃,600MHz)δ(ppm):8.41(s,2H),7.89-7.69(m,3H),7.68-7.61(m,1H),7.55-7.43(m,2H),7.39(t,J＝7.6Hz,1H),7.32(d,J＝7.6Hz,1H),7.19-7.12(m,1H),6.10(d,J＝9.9Hz,1H),5.91(d,J＝16.2Hz,1H),4.00-3.82(m,2H),3.78-3.50(m,5H),3.31-3.22(m,1H),3.15-2.99(m,2H). ^{_{1 H NMR (CDCl 3, 600MHz}} ) δ (ppm): 8.41 (s, 2H), 7.89-7.69 (m, 3H), 7.68-7.61 (m, 1H), 7.55-7.43 (m, 2H), 7.39 ( t, J = 7.6 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.19-7.12 (m, 1H), 6.10 (d, J = 9.9 Hz, 1H), 5.91 (d, J = 16.2) Hz, 1H), 4.00-3.82 (m, 2H), 3.78-3.50 (m, 5H), 3.31-3.22 (m, 1H), 3.15-2.99 (m, 2H).

实施例10:3-(2-(5-(5-甲基-2-(2H-1,2,3-三氮唑-2-基)苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)嘧啶-5-基)苯甲酰胺Example 10: 3-(2-(5-(5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-yl)pyrimidin-5-yl)benzamide

本步骤标题化合物参照实施例1步骤6所描述的方法制备得到，即将(5-(5-溴嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(5-甲基-2-(2H-1,2,3-三氮唑-2-基)苯基)甲酮(0.261g,0.575mmol)、3-氨基甲酰基苯硼酸(0.100g,0.606mmol)、碳酸铯(0.380g,1.17mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(44mg,0.058mmol)在1,4-二氧六环(15mL)和水(3mL)中反应制备，粗产品经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)得到标题化合物为橙黄色固体(0.222g,78.1％)。The title compound of this step was prepared by the method described in the step 6 of Example 1, that is, (5-(5-bromopyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl. (5-Methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (0.261 g, 0.575 mmol), 3-carbamoylbenzeneboronic acid (0.100 g, 0.606 mmol), cesium carbonate (0.380 g, 1.17 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (44 mg, 0.058 mmol) in 1,4-dioxane The title compound (yield: m. %).

MS(ESI,pos.ion)m/z:495.3[M+H]⁺；MS (ESI, pos.) m/z: 495.3 [M+H] ⁺

¹H NMR(CDCl₃,600MHz)δ(ppm):8.59(s,2H),7.99(s,1H),7.85(d,J＝8.3Hz,1H),7.74(s,2H),7.72(s,1H),7.64(d,J＝7.8Hz,1H),7.52(t,J＝7.7Hz,1H),7.31(dd,J＝8.4Hz,0.8Hz,1H),7.22(s,1H),6.22(s,1H),5.69(s,1H),3.91(dt,J＝17.7Hz,8.9Hz,2H),3.77-3.69(m,2H),3.63(dd,J＝11.5Hz,5.2Hz,1H),3.52(dd,J＝11.6Hz,3.7Hz,1H),3.40(s,1H),3.10-2.96(m,3H),2.41(s,3H). ^{_{1 H NMR (CDCl 3, 600MHz}} ) δ (ppm): 8.59 (s, 2H), 7.99 (s, 1H), 7.85 (d, J = 8.3Hz, 1H), 7.74 (s, 2H), 7.72 (s , 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.31 (dd, J = 8.4 Hz, 0.8 Hz, 1H), 7.22 (s, 1H), 6.22(s,1H), 5.69(s,1H), 3.91 (dt, J=17.7Hz, 8.9Hz, 2H), 3.77-3.69(m, 2H), 3.63 (dd, J=11.5Hz, 5.2Hz, 1H), 3.52 (dd, J = 11.6 Hz, 3.7 Hz, 1H), 3.40 (s, 1H), 3.10-2.96 (m, 3H), 2.41 (s, 3H).

实施例11:3-(2-(5-(2-(2H-1,2,3-三氮唑-2-基)苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)嘧啶-5-基)苯甲酰胺Example 11: 3-(2-(5-(2-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2 (1H)-yl)pyrimidin-5-yl)benzamide

本步骤标题化合物参照实施例1步骤6所描述的方法制备得到，即将(2-(2H-1,2,3-三氮唑-2-基)苯基)(5-(5-溴嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮(0.260g,0.59mmol)、3-氨基甲酰基苯硼酸(0.110g,0.667mmol)、碳酸铯(0.39g,1.2mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(45mg,0.059mmol)在1,4-二氧六环(15mL)和水(3mL)中反应制备，粗产品经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20/1)得到标题化合物为灰色固体(0.252g,88.8％)。The title compound of this step was prepared by the method described in the step 6 of Example 1, that is, (2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-bromopyrimidine)- 2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methanone (0.260 g, 0.59 mmol), 3-carbamoylbenzeneboronic acid (0.110 g, 0.667 mmol), carbonic acid铯 (0.39 g, 1.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (45 mg, 0.059 mmol) in 1,4-dioxane (15 mL) and The title compound was obtained as a gray solid (0.252 g, 88.8%).

MS(ESI,pos.ion)m/z:481.5[M+H]⁺；MS (ESI, pos.) m/z: 481.5 [M+H] ⁺

¹H NMR(DMSO-d₆,400MHz)δ(ppm):8.77(s,2H),8.12(s,1H),8.06(s,1H),7.99(s,2H),7.88(d,J＝8.0Hz,1H),7.83-7.78(m,2H),7.63-7.59(m,1H),7.54-7.49(m,3H),7.44(s,1H),3.83(dd,J＝11.4Hz,7.6Hz,1H),3.72-3.65(m,2H),3.53(dd,J＝11.7Hz,4.9Hz,1H),3.47-3.40(m,3H),3.10-2.96(m,3H). ^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ (ppm): 8.77 (s, 2H), 8.12 (s, 1H), 8.06 (s, 1H), 7.99 (s, 2H), 7.88 (d, J = 8.0 Hz, 1H), 7.83-7.78 (m, 2H), 7.63-7.59 (m, 1H), 7.54-7.49 (m, 3H), 7.44 (s, 1H), 3.83 (dd, J = 11.4 Hz, 7.6 Hz, 1H), 3.72-3.65 (m, 2H), 3.53 (dd, J = 11.7 Hz, 4.9 Hz, 1H), 3.47-3.40 (m, 3H), 3.10-2.96 (m, 3H).

实施例12:3-(2-(5-(2-氟-6-(2H-1,2,3-三氮唑-2-基)苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)嘧啶-5-基)苯甲酰胺Example 12: 3-(2-(5-(2-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c Pyrrole-2(1H)-yl)pyrimidin-5-yl)benzamide

本步骤标题化合物参照实施例1步骤6所描述的方法制备得到，即将(5-(5-溴嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三氮唑-2-基)苯基)甲酮(0.324g,0.707mmol)、3-氨基甲酰基苯硼酸(0.123g,0.746mmol)、碳酸铯(0.460g,1.41mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(54mg,0.07mmol)在1,4-二氧六环(15mL)和水(3mL)中反应制备，粗产品经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20/1)得到标题化合物为橙黄色固体(0.340g,96.4％)。The title compound of this step was prepared by the method described in the step 6 of Example 1, that is, (5-(5-bromopyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl. (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (0.324 g, 0.707 mmol), 3-carbamoylbenzeneboronic acid (0.123 g, 0.746) Ment), cesium carbonate (0.460 g, 1.41 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (54 mg, 0.07 mmol) in 1,4-dioxane (15 mL) and EtOAc (3 mL) (EtOAc, m. ).

MS(ESI,pos.ion)m/z:499.5[M+H]⁺；MS (ESI, pos.) m/z: 499.5 [M+H] ⁺

¹H NMR(CDCl₃,400MHz)δ(ppm):8.59(s,2H),7.99-7.98(m,1H),7.85-7.79(m,2H),7.75-7.69(m,2H),7.61(d,J＝7.4Hz,1H),7.52-7.44(m,2H),7.16-7.10(m,1H),6.45(s,1H),5.90(s,1H),4.02-3.84(m,2H),3.82-3.72(m,2H),3.69-3.54(m,3H),3.30-3.27(m,1H),3.15-3.01(m,2H). ^{_{1 H NMR (CDCl 3, 400MHz}} ) δ (ppm): 8.59 (s, 2H), 7.99-7.98 (m, 1H), 7.85-7.79 (m, 2H), 7.75-7.69 (m, 2H), 7.61 ( d, J=7.4 Hz, 1H), 7.52-7.44 (m, 2H), 7.16-7.10 (m, 1H), 6.45 (s, 1H), 5.90 (s, 1H), 4.02-3.84 (m, 2H) , 3.82-3.72 (m, 2H), 3.69-3.54 (m, 3H), 3.30-3.27 (m, 1H), 3.15-3.01 (m, 2H).

实施例13:4-(2-(5-(5-甲基-2-(2H-1,2,3-三氮唑-2-基)苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)嘧啶-5-基)苯甲酰胺Example 13: 4-(2-(5-(5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-yl)pyrimidin-5-yl)benzamide

本步骤标题化合物参照实施例1步骤6所描述的方法制备得到，即将(5-(5-溴嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(5-甲基-2-(2H-1,2,3-三氮唑-2-基)苯基)甲酮(0.370g,0.814mmol)、4-氨基甲酰基苯硼酸(0.126g,0.774mmol)、碳酸铯(0.530g,1.63mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(56mg,0.077mmol)在1,4-二氧六环(15mL)和水(3mL)中反应制备，粗产品经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)得到标题化合物为土黄色固体(0.252g,62.6％)。The title compound of this step was prepared by the method described in the step 6 of Example 1, that is, (5-(5-bromopyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl. (5-Methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (0.370 g, 0.814 mmol), 4-carbamoylbenzene Boric acid (0.126 g, 0.774 mmol), cesium carbonate (0.530 g, 1.63 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (56 mg, 0.077 mmol) at 1, 4-Dioxane (15 mL) and EtOAc (3 mL) (0.252g, 62.6%).

MS(ESI,pos.ion)m/z:495.3[M+H]⁺；MS (ESI, pos.) m/z: 495.3 [M+H] ⁺

¹H NMR(DMSO-d₆,400MHz)δ(ppm):8.78(s,2H),7.99(s,2H),7.97(s,1H),7.95(d,J＝8.3Hz,2H),7.75(d,J＝8.2Hz,2H),7.70(d,J＝8.1Hz,1H),7.63(d,J＝8.1Hz,1H),7.36(s,1H),7.22(s,1H),3.94-3.89(m,2H),3.78-3.69(m,2H),3.62(dd,J＝11.6Hz,5.3Hz,1H),3.53(dd,J＝11.5Hz,3.8Hz,1H),3.41(s,1H),3.10-2.97(m,3H),2.40(s,3H). ^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ (ppm): 8.78 (s, 2H), 7.99 (s, 2H), 7.97 (s, 1H), 7.95 (d, J = 8.3Hz, 2H), 7.75 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.36 (s, 1H), 7.22 (s, 1H), 3.94 -3.89 (m, 2H), 3.78-3.69 (m, 2H), 3.62 (dd, J = 11.6 Hz, 5.3 Hz, 1H), 3.53 (dd, J = 11.5 Hz, 3.8 Hz, 1H), 3.41 (s) , 1H), 3.10-2.97 (m, 3H), 2.40 (s, 3H).

实施例14:4-(2-(5-(2-(2H-1,2,3-三氮唑-2-基)苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)嘧啶-5-基)苯甲酰胺Example 14: 4-(2-(5-(2-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2 (1H)-yl)pyrimidin-5-yl)benzamide

本步骤标题化合物参照实施例1步骤6所描述的方法制备得到，即将(2-(2H-1,2,3-三氮唑-2-基)苯基)(5-(5-溴嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮(0.350g,0.795mmol)、4-氨基甲酰基苯硼酸(0.124g,0.755mmol)、碳酸铯(0.517g,1.59mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.56mg,0.076mmol)在1,4-二氧六环(15mL)和水(3mL)中反应制备，粗产品经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝25/1)得到标题化合物为灰色固体(0.280g,73.3％)。The title compound of this step was prepared by the method described in the step 6 of Example 1, that is, (2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-bromopyrimidine)- 2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methanone (0.350 g, 0.795 mmol), 4-carbamoylbenzeneboronic acid (0.124 g, 0.755 mmol), carbonic acid铯 (0.517 g, 1.59 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.56 mg, 0.076 mmol) in 1,4-dioxane (15 mL) Prepared by reaction with water (3 mL) EtOAc (EtOAc:EtOAc:

MS(ESI,pos.ion)m/z:481.3[M+H]⁺；MS (ESI, pos.) m/z: 481.3 [M+H] ⁺

¹H NMR(DMSO-d₆,400MHz)δ(ppm):8.79(s,2H),7.99(s,2H),7.97(s,1H),7.94(d,J＝8.3Hz,2H),7.76(d,J＝8.3Hz,2H),7.65-7.60(m,1H),7.54-7.48(m,3H),7.36(s,1H),3.87(dd,J＝11.5Hz,7.5Hz,1H),3.74-3.66(m,2H),3.57-3.50(m,1H),3.46-3.40(m,3H),3.10-2.97(m,3H). ^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ (ppm): 8.79 (s, 2H), 7.99 (s, 2H), 7.97 (s, 1H), 7.94 (d, J = 8.3Hz, 2H), 7.76 (d, J = 8.3 Hz, 2H), 7.65-7.60 (m, 1H), 7.54-7.48 (m, 3H), 7.36 (s, 1H), 3.87 (dd, J = 11.5 Hz, 7.5 Hz, 1H) , 3.74-3.66 (m, 2H), 3.57-3.50 (m, 1H), 3.46-3.40 (m, 3H), 3.10-2.97 (m, 3H).

实施例15:4-(2-(5-(2-氟-6-(2H-1,2,3-三氮唑-2-基)苯甲酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)嘧啶-5-基)苯甲酰胺Example 15: 4-(2-(5-(2-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c Pyrrole-2(1H)-yl)pyrimidin-5-yl)benzamide

本步骤标题化合物参照实施例1步骤6所描述的方法制备得到，即将(5-(5-溴嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三氮唑-2-基)苯基)甲酮(0.367g,0.800mmol)、4-氨基甲酰基苯硼酸(0.138g,0.84mmol)、碳酸铯(0.522g,1.6mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(59mg,0.08mmol)在1,4-二氧六环(15mL)和水(3mL)中反应制备，粗产品经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)得到标题化合物为土黄色固体(0.291g,73.0％)。The title compound of this step was prepared by the method described in the step 6 of Example 1, that is, (5-(5-bromopyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl. (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (0.367 g, 0.800 mmol), 4-carbamoylbenzeneboronic acid (0.138 g, 0.84) Methyl), cesium carbonate (0.522 g, 1.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (59 mg, 0.08 mmol) in 1,4-dioxane (15 mL) and water (3 mL), EtOAc (m. ).

MS(ESI,pos.ion)m/z:499.3[M+H]⁺；MS (ESI, pos.) m/z: 499.3 [M+H] ⁺

¹H NMR(DMSO-d₆,400MHz)δ(ppm):8.77(s,2H),8.03-7.99(m,2H),7.96(s,1H),7.93(d,J＝8.2Hz,2H),7.77(d,J＝8.2Hz,2H),7.50-7.45(m,2H),7.35(s,1H),7.15-7.10(m,1H),3.92-3.83(m,2H),3.80-3.72(m,2H),3.68-3.56(m,3H),3.31-3.28(m,1H),3.15-3.04(m,2H). ^{_{1 H NMR (DMSO-d 6}} , 400MHz) δ (ppm): 8.77 (s, 2H), 8.03-7.99 (m, 2H), 7.96 (s, 1H), 7.93 (d, J = 8.2Hz, 2H) , 7.77 (d, J = 8.2 Hz, 2H), 7.50-7.45 (m, 2H), 7.35 (s, 1H), 7.15-7.10 (m, 1H), 3.92-3.83 (m, 2H), 3.80-3.72 (m, 2H), 3.68-3.56 (m, 3H), 3.31-3.28 (m, 1H), 3.15-3.04 (m, 2H).

实施例16至实施例21中的化合物可以由相应的原料参照实施例1所描述的方法制备得到，其中所用的原料均能从市面上经采购或通过本领域技术人员公知的方法进行简单处理得到。The compounds of Examples 16 to 21 can be prepared from the corresponding starting materials by the method described in Example 1, wherein the starting materials used can be purchased commercially or simply by methods well known to those skilled in the art. .

实施例16:(5-(5-(4-氯苯基)嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(5-甲基-2-(2H-1,2,3-三氮唑-2-基)苯基)甲酮Example 16: (5-(5-(4-Chlorophenyl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)(5-methyl-2) -(2H-1,2,3-triazol-2-yl)phenyl)methanone

MS(ESI,pos.ion)m/z:486.1[M+H]⁺.MS (ESI, pos.) m/z: 486.1 [M+H] ⁺ .

实施例17:(2-(2H-1,2,3-三氮唑-2-基)苯基)(5-(5-(4-氯苯基)嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮Example 17: (2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-(4-chlorophenyl)pyrimidin-2-yl)hexahydropyrrole [3,4-c]pyrrole-2(1H)-yl)methanone

MS(ESI,pos.ion)m/z:472.5[M+H]⁺.MS (ESI, pos.) m/z: 472.5 [M+H] ⁺ .

实施例18:(5-(5-(4-氯苯基)嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三氮唑-2-基)苯基)甲酮Example 18: (5-(5-(4-Chlorophenyl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)(2-fluoro-6- (2H-1,2,3-triazol-2-yl)phenyl)methanone

MS(ESI,pos.ion)m/z:490.9[M+H]⁺.MS (ESI, pos.) m/z: 490.9 [M+H] ⁺ .

实施例19:(5-(5-(4-甲氧基苯基)嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(5-甲基-2-(2H-1,2,3-三氮唑-2-基)苯基)甲酮Example 19: (5-(5-(4-Methoxyphenyl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)(5-methyl -2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

MS(ESI,pos.ion)m/z:482.5[M+H]⁺.MS (ESI, pos.ion) m / z: 482.5 [M + H] +.

实施例20:(2-(2H-1,2,3-三氮唑-2-基)苯基)(5-(5-(4-甲氧基苯基)嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮Example 20: (2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-(4-methoxyphenyl)pyrimidin-2-yl)hexahydro Pyrrolo[3,4-c]pyrrole-2(1H)-yl)methanone

MS(ESI,pos.ion)m/z:468.6[M+H]⁺.MS (ESI, pos.) m/z: 468.6 [M+H] ⁺ .

实施例21:(2-氟-6-(2H-1,2,3-三氮唑-2-基)苯基)(5-(5-(4-甲氧基苯基)嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮 Example 21: (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-(4-methoxyphenyl)pyrimidin-2- Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methanone

MS(ESI,pos.ion)m/z:486.3[M+H]⁺.MS (ESI, pos.) m/z: 486.3 [M+H] ⁺ .

生物试验Biological test

实施例A本发明化合物对人源化OX₁受体的拮抗作用实验Example A Antagonistic Effects of the Compounds of the Invention on Humanized OX ₁ Receptors

试验方法experiment method

运用荧光检测法检测本发明化合物对激动剂诱导的细胞钙流的影响来评价本发明化合物对表达在中国仓鼠卵巢细胞(CHO)上的人源化OX₁受体的拮抗能力。将细胞悬浮于DMEM培养基(invitrogen)中，然后以2×10⁴细胞/孔的密度分布在微孔反应板中。将含有荧光探针(Fluo4NW,Invitrogen)、丙磺舒与20mM羟乙基哌嗪乙硫磺酸(invitrogen)的Hank平衡盐溶液(HBSS,invitrogen)(pH＝7.4)加入到上述微孔反应板中，然后与细胞一起于37℃孵育60min，再于22℃孵育15min。将反应板置于细胞荧光工作站中(CellLux,PerkinElmer)，并加入测试化合物或参照拮抗剂或Hank平衡盐溶液，5min后再加入3nM食欲素A或Hank平衡盐缓冲液(空白对照)，然后测量荧光强度的变化，其与细胞内游离钙离子浓度的变化成正相关。实验结果以相对于对照组(加入3nM食欲素A的组别)的抑制百分比表示。Effect detected using fluorescence detection method of the present invention, the compounds of the agonist-induced calcium flux in cells to evaluate compounds of the present invention is expressed on human Chinese hamster ovary cells (CHO) the ability to antagonize the humanized OX ₁ receptor. The cells were suspended in DMEM medium (invitrogen) and then distributed in a microwell reaction plate at a density of 2 × 10 ⁴ cells/well. Add a Hank's balanced salt solution (HBSS, invitrogen) (pH=7.4) containing a fluorescent probe (Fluo4NW, Invitrogen), probenecid and 20 mM hydroxyethylpiperazine ethanesulfuric acid (invitrogen) to the above microporous reaction plate. Then, it was incubated with the cells at 37 ° C for 60 min and then at 22 ° C for 15 min. Place the reaction plate in a cell fluorescence workstation (CellLux, PerkinElmer) and add the test compound or reference antagonist or Hank's balanced salt solution. After 5 minutes, add 3nM orexin A or Hank's balanced salt buffer (blank control) and measure. A change in fluorescence intensity that is positively correlated with changes in intracellular free calcium ion concentration. The experimental results are expressed as a percentage of inhibition relative to the control group (group of 3 nM orexin A added).

标准参照拮抗剂为SB334867，通过系列浓度的实验测试获得量效曲线，从而计算出IC₅₀值。Standard reference antagonist SB334867, dose-response curve obtained by concentration series of experimental tests to calculate the ₅₀ value IC.

实验结果表明，本发明化合物对OX₁受体表现出较好的拮抗作用。The experimental results show that the compound of the present invention shows a good antagonistic effect on the OX ₁ receptor.

实施例B本发明化合物对人源化OX₂受体的拮抗作用实验Example B Antagonistic effect of the compounds of the invention on humanized OX ₂ receptor

试验方法experiment method

运用荧光检测法检测本发明化合物对激动剂诱导的细胞钙流的影响来评价本发明化合物对表达在HEK-293细胞上的人源化OX₂受体的拮抗能力。将细胞悬浮于DMEM培养基(invitrogen)中，然后以3×10⁴细胞/孔的密度分布在微孔反应板中。将含有荧光探针(Fluo4NW,Invitrogen)、丙磺舒和20mM羟乙基哌嗪乙硫磺酸的Hank平衡盐缓冲液(HBSS,invitrogen)(PH＝7.4)加入到上述微孔反应板中，然后与细胞一起于37℃孵育60min，再于22℃孵育15min。将反应板置于细胞荧光工作站中(CellLux,PerkinElmer)，并加入测试化合物或参照拮抗剂或Hank平衡盐溶液，5min后再加入10nM食欲素B或Hank平衡盐缓冲液(空白对照)，然后测量荧光强度的变化，其与细胞内游离钙离子浓度的变化成正相关。实验结果以相对于对照组(加入10nM食欲素B的组别)的抑制百分比表示。Effect detected using fluorescence detection method of the present invention, the compounds of the agonist-induced calcium flux in a cell to evaluate compounds of the invention expressed in human HEK-293 cells the ability to antagonize the humanized OX ₂ receptor. The cells were suspended in DMEM medium (invitrogen) and then distributed in a microwell reaction plate at a density of 3 × 10 ⁴ cells/well. Add a Hank's balanced salt buffer (HBSS, invitrogen) (PH=7.4) containing a fluorescent probe (Fluo4NW, Invitrogen), probenecid and 20 mM hydroxyethylpiperazine ethanesulfonic acid to the above microporous reaction plate, and then Incubate with cells for 60 min at 37 ° C and then for 15 min at 22 ° C. The reaction plate was placed in a cell fluorescence workstation (CellLux, PerkinElmer), and the test compound or reference antagonist or Hank balanced salt solution was added. After 5 min, 10 nM orexin B or Hank's balanced salt buffer (blank control) was added, and then measured. A change in fluorescence intensity that is positively correlated with changes in intracellular free calcium ion concentration. The experimental results are expressed as a percentage of inhibition relative to the control group (group of 10 nM orexin B added).

标准参照拮抗剂为JNJ10397049，通过系列浓度的实验测试获得量效曲线，从而计算出IC₅₀值。The standard reference antagonist was JNJ10397049, and the dose-response curve was obtained by a series of experimental tests to calculate the IC ₅₀ value.

表1本发明部分实施例提供的化合物对OX₂受体的拮抗作用实验结果Table 1 Experimental results of antagonism of compounds provided by some embodiments of the present invention on OX ₂ receptor

实验结果表明，本发明化合物对OX₂受体的表现出较好的拮抗作用。The experimental results show that the compound of the present invention exhibits a good antagonistic effect on the OX ₂ receptor.

实施例C大鼠、犬和猴子静注或灌胃定量本发明化合物后的药代动力学评价Example C Pharmacokinetic Evaluation of Rats, Canines, and Monkeys After Quantification of Compounds of the Invention by Intravenous or Oral Administration

本发明对本发明化合物在大鼠、犬和猴子体内的药代动力学研究进行了评估，动物信息详见表A。The present invention evaluates the pharmacokinetic study of the compounds of the present invention in rats, dogs and monkeys, and the animal information is shown in Table A.

表A本发明受试动物信息表Table A The test animal information table of the present invention

试验方法experiment method

将本发明化合物以5％DMSO+5％Kolliphor HS 15+2％(2％HCl)+88％Saline的盐水溶液或10％DMSO+10％Kolliphor HS 15+80％生理盐水溶液的形式，对受试动物进行给药。对于静脉注射给药组，给药剂量为1mg/kg或2mg/kg，然后在给药后的时间点为0.083、0.25、0.5、1.0、2.0、4.0、6.0、8.0和24小时时静脉取血(0.3mL)，并在3,000或4,000rpm下离心10分钟，收集血浆溶液，并于-20℃或-70℃下保存。对于灌胃给药组，给药剂量为2.5mg/kg或5mg/kg，然后在给药后的时间点为0.25、0.5、1.0、2.0、4.0、6.0、8.0和24小时时静脉取血(0.3mL)，并在3,000或4,000rpm下离心10分钟，收集血浆溶液，并于-20℃或-70℃下保存。阳性对照为suvorexant。The compound of the present invention is in the form of 5% DMSO + 5% Kolliphor HS 15 + 2% (2% HCl) + 88% Saline saline solution or 10% DMSO + 10% Kolliphor HS 15 + 80% physiological saline solution. The test animals were administered. For the intravenous administration group, the dose is 1 mg/kg or 2 mg/kg, and then the blood is taken intravenously at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours after the administration. (0.3 mL), and centrifuged at 3,000 or 4,000 rpm for 10 minutes, the plasma solution was collected and stored at -20 ° C or -70 ° C. For the intragastric administration group, the dose was 2.5 mg/kg or 5 mg/kg, and then venous blood was taken at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours after the administration ( 0.3 mL), and centrifuged at 3,000 or 4,000 rpm for 10 minutes, the plasma solution was collected and stored at -20 ° C or -70 ° C. The positive control was suvorexant.

对上述各组收集获得的血浆溶液进行LC/MS/MS分析。分析结果表明，本发明化合物在大鼠、犬和猴子体内具有较好的药代动力学性质，其中实施例2、实施例3、实施例5、实施例6、实施例9、实施例14和实施例15提供的化合物在大鼠体内的药代动力学参数详见表2。The plasma solutions obtained from each of the above groups were subjected to LC/MS/MS analysis. The analysis results show that the compound of the present invention has better pharmacokinetic properties in rats, dogs and monkeys, wherein Example 2, Example 3, Example 5, Example 6, Example 9, Example 14 and The pharmacokinetic parameters of the compounds provided in Example 15 in rats are detailed in Table 2.

表2本发明部分实施例化合物在大鼠体内的药代动力学参数Table 2 Pharmacokinetic parameters of some of the compounds of the present invention in rats

“--”表示无检测数据。"--" means no test data.

由表2的实验结果可知，本发明部分实施例化合物在大鼠体内的暴露量和生物利用度均较阳性对照suvorexant高，具有很好的药代动力学性质。It can be seen from the experimental results of Table 2 that the exposure amount and bioavailability of some of the compounds of the present invention in rats are higher than that of the positive control suvorexant, and have good pharmacokinetic properties.

实施例D本发明化合物潜在的致QT间期延长作用的评估Example D Assessment of Potential QT Interval Prolongation of Compounds of the Invention

试验方法experiment method

通过检测本发明化合物是否阻滞hERG通道来评估本发明化合物潜在的致QT间期延长作用，具体实验方法如下：The potential QT interval prolongation of the compounds of the invention can be assessed by detecting whether the compounds of the invention block the hERG channel, as follows:

将精确称取的本发明化合物溶解在二甲基亚砜(DMSO)中，配制成10.0mM的最高浓度的溶液，然后用hERG FP Assay Buffer(Invitrogen)稀释成初始浓度为120.0μM的溶液；将hERG Tracer Red原液(Invitrogen)和阳性对照品E-4031原液(Invitrogen)分别用hERG FP Assay Buffer(Invitrogen)稀释成初始浓度为4.0nM和120.0μM的溶液。往384孔板中，加入2.5μL初始浓度的本发明化合物或2.5μL初始浓度的阳性对照品E-4031(阳性对照组)或2.5μL hERG FP Assay Buffer(阴性对照组)、5μL hERG Membrane和2.5μL hERG Tracer Red溶液，空白对照组加入5μL hERG FP Assay Buffer和5μL hERG Membrane，使得本发明化合物、E-4031和hERG Tracer Red的测试终浓度分别为30.0μM、30.0μM和1.0nM，每一组测试做4个复孔。然后将384孔板放入25℃，250rpm的震荡仪(PHMP-4,Grant-sio)中孵育4小时，用多功能酶标仪(PHERAStarFS,BMG LABTECH)测量各孔的荧光偏振值，计算化合物对hERG通道的相对抑制率和50％抑制浓度(IC₅₀)。The accurately weighed compound of the present invention was dissolved in dimethyl sulfoxide (DMSO) to prepare a solution of the highest concentration of 10.0 mM, and then diluted with a hERG FP Assay Buffer (Invitrogen) to a solution having an initial concentration of 120.0 μM; The hERG Tracer Red stock solution (Invitrogen) and the positive control E-4031 stock solution (Invitrogen) were diluted with hERG FP Assay Buffer (Invitrogen) to a solution having an initial concentration of 4.0 nM and 120.0 μM, respectively. To a 384-well plate, add 2.5 μL of the initial concentration of the compound of the invention or 2.5 μL of the initial concentration of the positive control E-4031 (positive control) or 2.5 μL of hERG FP Assay Buffer (negative control), 5 μL of hERG Membrane and 2.5 μL hERG Tracer Red solution, 5 μL of hERG FP Assay Buffer and 5 μL of hERG Membrane were added to the blank control group, so that the final concentrations of the compounds of the present invention, E-4031 and hERG Tracer Red were 30.0 μM, 30.0 μM and 1.0 nM, respectively. Test to make 4 duplicate holes. The 384-well plate was then incubated for 4 hours at 25 ° C in a 250 rpm shaker (PHMP-4, Grant-sio), and the fluorescence polarization values of each well were measured using a multi-function microplate reader (PHERAStarFS, BMG LABTECH) to calculate the compound. hERG channel inhibition rate relative and 50% inhibitory concentration (IC _50).

在E-4031作为阳性对照的情况下，若30.0μM的本发明化合物对hERG通道的相对抑制率小于50％，则本发明化合物对hERG通道的IC₅₀大于30.0μM。若30.0μM的本发明化合物对hERG通道的相对抑制率大于50％，则需对本发明化合物做剂量曲线滴定，具体方法如下：In the case of E-4031 as a positive control, the compounds of the present invention is 30.0 m when the relative inhibition of the hERG channel rate is less than 50%, the compound of the present invention for the hERG channel IC ₅₀ is greater than 30.0μM. If the relative inhibition rate of the 30.0 μM compound of the present invention to the hERG channel is greater than 50%, the dose curve titration of the compound of the present invention is required, as follows:

将上述初始浓度为120μM的本发明化合物溶液和E-4031溶液，分别用hERG FP Assay Buffer进行5倍梯度稀释，稀释成120.0μM、24.0μM、4.8μM、960.0nM、192.0nM、38.4nM、7.7nM和1.5nM共8个待测浓度，每个待测浓度做2个复孔。往384孔板中加入2.5μL待测浓度的本发明化合物或2.5μL待测浓度的阳性对照品E-4031(阳性对照组)或2.5μL hERG FP Assay Buffer(阴性对照组)、5μL hERG FP Membrane和2.5μL hERG Tracer Red溶液，空白对照组加入5μL hERG FP Assay Buffer和5μL hERG Membrane。然后将384孔板放入25℃，250rpm的震荡仪(PHMP-4,Grant-sio)中孵育4小时，用多功能酶标仪(PHERAStarFS,BMG LABTECH)测量各孔的荧光偏振值，以E-4031荧光偏振值的最大值和最小值进行校正，GraphPad软件计算本发明化合物的IC₅₀。The above-mentioned compound solution of the present invention having an initial concentration of 120 μM and the E-4031 solution were subjected to 5-fold gradient dilution with hERG FP Assay Buffer, and diluted to 120.0 μM, 24.0 μM, 4.8 μM, 960.0 nM, 192.0 nM, 38.4 nM, 7.7. There are 8 concentrations to be measured at nM and 1.5nM, and 2 duplicate wells are made for each concentration to be tested. Add 2.5 μL of the compound of the present invention to the 384-well plate or 2.5 μL of the test positive concentration E-4031 (positive control group) or 2.5 μL of hERG FP Assay Buffer (negative control group), 5 μL of hERG FP Membrane With 2.5 μL of hERG Tracer Red solution, 5 μL of hERG FP Assay Buffer and 5 μL of hERG Membrane were added to the blank control group. The 384-well plate was then incubated in a 250 rpm shaker (PHMP-4, Grant-sio) for 4 hours at 25 ° C. The fluorescence polarization values of each well were measured using a multi-plate reader (PHERAStarFS, BMG LABTECH) to E. -4031 maximum and minimum values are corrected fluorescence polarization, GraphPad software calculates the compounds of the invention IC _50.

实验结果表明，本发明化合物对hERG通道基本没有抑制活性。其中实施例4、实施例6、实施例9、实施例13、实施例14和实施例15提供的化合物对hERG通道的50％抑制浓度大于30.0μM，提示这些化合物引起QT间期延长的风险小。 The experimental results show that the compound of the present invention has substantially no inhibitory activity on the hERG channel. The compounds provided in Example 4, Example 6, Example 9, Example 13, Example 14 and Example 15 have a 50% inhibitory concentration on the hERG channel of greater than 30.0 μM, suggesting that these compounds have a small risk of prolonging the QT interval. .

实施例E：评价本发明化合物在人肝微粒体中的稳定性Example E: Evaluation of the stability of the compounds of the invention in human liver microsomes

在37℃条件下，将本发明化合物和人肝微粒体置于0.1M磷酸钾缓冲液(含1.0mM EDTA，pH＝7.4)中共同孵育，通过测定不同孵育时间的样品浓度，在GraphPad Prism5.01中以“化合物相对含量”对“孵育时间”作图求算出化合物的半衰期，并计算内在清除率。实验体系参见表5：The compound of the present invention and human liver microsomes were incubated in a 0.1 M potassium phosphate buffer (containing 1.0 mM EDTA, pH=7.4) at 37 ° C, and the sample concentration at different incubation times was determined by GraphPad Prism 5. In 01, the "incubation of the compound" is plotted against the "incubation time" to calculate the half-life of the compound, and the intrinsic clearance rate is calculated. See Table 5 for the experimental system:

表5实验体系Table 5 experimental system

样品经LC/MS/MS(采用ESI放射源和waters xbridge C18EB-A-1420色谱柱)进行分析，分析使用的流动相为2mM甲酸铵和0.1％甲酸的水溶液(流动相A)与2mM甲酸铵和0.1％甲酸的甲醇溶液(流动相B)；流速为0.4mL/min；柱温保持在40℃。经LC/MS/MS分析得出样品峰面积与内标峰面积比值，将0min点的化合物含量看作100％，计算出各时间点化合物的相对含量。以“化合物相对含量”对“孵育时间”作图求算出化合物的半衰期，并计算内在清除率。The samples were analyzed by LC/MS/MS (using an ESI source and a waters xbridge C18EB-A-1420 column) using a mobile phase of 2 mM ammonium formate and 0.1% formic acid in aqueous solution (mobile phase A) and 2 mM ammonium formate. And 0.1% formic acid in methanol (mobile phase B); flow rate was 0.4 mL/min; column temperature was maintained at 40 °C. The ratio of peak area to internal standard peak area was obtained by LC/MS/MS analysis. The compound content at 0 min was regarded as 100%, and the relative content of the compound at each time point was calculated. The half-life of the compound was calculated by plotting the "relative content of the compound" on the "incubation time" and the intrinsic clearance rate was calculated.

实验结果表明，本发明所述化合物在人肝微粒体中稳定性较高。The experimental results show that the compound of the present invention has high stability in human liver microsomes.

在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。In the description of the present specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example" or "some examples" and the like means a specific feature described in connection with the embodiment or example, A structure, material or feature is included in at least one embodiment or example of the invention. In the present specification, the schematic representation of the above terms is not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in a suitable manner in any one or more embodiments or examples. In addition, various embodiments or examples described in the specification, as well as features of various embodiments or examples, may be combined and combined.

尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。 Although the embodiments of the present invention have been shown and described, it is understood that the above-described embodiments are illustrative and are not to be construed as limiting the scope of the invention. The embodiments are subject to variations, modifications, substitutions and variations.

Claims

一种化合物，其为式(I)所示的化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，a compound which is a stereoisomer, a tautomer, an oxynitride, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of the formula (I) or a compound of the formula (I). Or a prodrug,

其中：among them:

U为N或CR^3a；U is N or CR ^3a ;

V为N或CR^3b；V is N or CR ^3b ;

X为N或CR^3c；X is N or CR ^3c ;

Y为N或CR^3d；Y is N or CR ^3d ;

Hy为***基，所述***基任选地被一个或多个独立选自卤素、氧代(＝O)、C_1-6烷基、C_1-6卤代烷基、C_1-6烷氧基和苄基的取代基所取代；Hy is a triazolyl group, which is optionally selected from one or more independently selected from the group consisting of halogen, oxo (=O), C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkane. Substituted by a substituent of an oxy group and a benzyl group;

各R¹独立地为H、D、-CD₃、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6卤代烷基、C_1-6烷氧基、C_1-6卤代烷氧基、C_1-6烷氨基、C_1-6羟基取代的烷基、(C_1-6烷基)-C(＝O)-、(C_1-6烷氧基)-C(＝O)-、(C_1-6烷氨基)-C(＝O)-、C_3-6环烷基、C_2-9杂环基、C_6-10芳基或C_1-9杂芳基，或相邻的两个R¹和与它们相连的碳原子一起任选地形成C_3-10碳环、C_2-9杂环、C_6-10芳环或C_2-9杂芳环；Each R ^{1 is} independently H, D, -CD ₃ , F, Cl, Br, I, -CN, -NH ₂ , -OH, -NO ₂ , -COOH, -C(=O)NH ₂ , C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _1-6 hydroxy-substituted alkyl, (C _1-6 alkyl)-C(=O)-, (C _1-6 alkoxy)-C(=O)-, (C _1-6 alkylamino) -C(=O)-, C _3-6 cycloalkyl, C _2-9 heterocyclyl, C _6-10 aryl or C _1-9 heteroaryl, or two adjacent R ¹ and The linked carbon atoms together optionally form a C _3-10 carbocyclic ring, a C _2-9 heterocyclic ring, a C _6-10 aromatic ring or a C _2-9 heteroaryl ring;

各R^3a、R^3b、R^3c和R^3d独立地为H、D、-CD₃、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、烷基、烯基、炔基、卤代烷基、烷氧基、卤代烷氧基、烷氨基、羟基取代的烷基、烷基-C(＝O)-、烷氧基-C(＝O)-、烷氨基-C(＝O)-、环烷基、杂环基、芳基或杂芳基；Each of R ^3a , R ^3b , R ^3c and R ^{3d is} independently H, D, -CD ₃ , F, Cl, Br, I, -CN, -NH ₂ , -OH, -NO ₂ , -COOH, -C (=O)NH ₂ , alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, hydroxy substituted alkyl, alkyl-C(=O)-, alkoxy- C(=O)-, alkylamino-C(=O)-, cycloalkyl, heterocyclyl, aryl or heteroaryl;

各R²独立地为H、D、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6卤代烷基、C_1-6烷氧基、C_1-6卤代烷氧基、C_1-6烷氨基、C_1-6羟基取代的烷基、(C_1-6烷基)-C(＝O)-、(C_1-6烷氧基)-C(＝O)-、(C_1-6烷氨基)-C(＝O)-、C_3-6环烷基、C_2-9杂环基、C_6-10芳基或C_1-9杂芳基；Each R ^{2 is} independently H, D, F, Cl, Br, I, -CN, -NH ₂ , -OH, -NO ₂ , -COOH, -C(=O)NH ₂ , C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _1-6 hydroxy Substituted alkyl, (C _1-6 alkyl)-C(=O)-, (C _1-6 alkoxy)-C(=O)-, (C _1-6 alkylamino)-C (= O)-, C _3-6 cycloalkyl, C _2-9 heterocyclic, C _6-10 aryl or C _1-9 heteroaryl;

n为0、1、2、3、4或5；和n is 0, 1, 2, 3, 4 or 5; and

m为0、1、2、3或4。m is 0, 1, 2, 3 or 4.
根据权利要求1所述的化合物，其为式(II)所示的化合物或式(II)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药， The compound according to claim 1, which is a compound represented by the formula (II) or a stereoisomer, a tautomer, an oxynitride, a solvate, a metabolite, or a pharmaceutically acceptable compound of the compound of the formula (II). Acceptable salt or prodrug,
根据权利要求1或2所述的化合物，其中各R¹独立地为H、D、-CD₃、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、C_1-4烷基、C_2-4烯基、C_2-4炔基、C_1-4卤代烷基、C_1-4烷氧基、C_1-4卤代烷氧基、C_1-4烷氨基、C_1-4羟基取代的烷基、(C_1-4烷基)-C(＝O)-、(C_1-4烷氧基)-C(＝O)-或(C_1-4烷氨基)-C(＝O)-。The compound according to claim 1 or 2, wherein each R ^{1 is} independently H, D, -CD ₃ , F, Cl, Br, I, -CN, -NH ₂ , -OH, -NO ₂ , -COOH , -C(=O)NH ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 Haloalkoxy, C _1-4 alkylamino, C _1-4 hydroxy substituted alkyl, (C _1-4 alkyl)-C(=O)-, (C _1-4 alkoxy)-C (= O)- or (C _1-4 alkylamino)-C(=O)-.
根据权利要求1或2所述的化合物，其中各R²独立地为H、D、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、C_1-4烷基、C_2-4烯基、C_2-4炔基、C_1-4卤代烷基、C_1-4烷氧基、C_1-4卤代烷氧基、C_1-4烷氨基、C_1-4羟基取代的烷基、(C_1-4烷基)-C(＝O)-、(C_1-4烷氧基)-C(＝O)-或(C_1-4烷氨基)-C(＝O)-。The compound according to claim 1 or 2, wherein each R ^{2 is} independently H, D, F, Cl, Br, I, -CN, -NH ₂ , -OH, -NO ₂ , -COOH, -C ( =O)NH ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylamino, C _1-4 hydroxy substituted alkyl, (C _1-4 alkyl)-C(=O)-, (C _1-4 alkoxy)-C(=O)- or (C _1-4 alkylamino)-C(=O)-.
根据权利要求1或2所述的化合物，其中各R¹独立地为H、D、-CD₃、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、甲基、乙基、正丙基、异丙基、-CF₃、-CH₂CF₃、-CF₂CF₃、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-NHCH₃、-N(CH₃)₂、-CH₂OH、-C(＝O)NHCH₃或-C(＝O)N(CH₃)₂。The compound according to claim 1 or 2, wherein each R ^{1 is} independently H, D, -CD ₃ , F, Cl, Br, I, -CN, -NH ₂ , -OH, -NO ₂ , -COOH , -C(=O)NH ₂ , methyl, ethyl, n-propyl, isopropyl, -CF ₃ , -CH ₂ CF ₃ , -CF ₂ CF ₃ , methoxy, ethoxy, n-propyl Alkoxy, isopropyloxy, -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ OH, -C(=O)NHCH ₃ or -C(=O)N(CH ₃ ) ₂ .
根据权利要求1或2所述的化合物，其中各R²独立地为H、D、F、Cl、Br、I、-CN、-NH₂、-OH、-NO₂、-COOH、-C(＝O)NH₂、甲基、乙基、正丙基、异丙基、-CF₃、-CH₂CF₃、-CF₂CF₃、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-NHCH₃、-N(CH₃)₂或-CH₂OH。The compound according to claim 1 or 2, wherein each R ^{2 is} independently H, D, F, Cl, Br, I, -CN, -NH ₂ , -OH, -NO ₂ , -COOH, -C ( =O)NH ₂ ,methyl, ethyl, n-propyl, isopropyl, -CF ₃ , -CH ₂ CF ₃ , -CF ₂ CF ₃ , methoxy, ethoxy, n-propyloxy, Isopropyloxy, -NHCH ₃ , -N(CH ₃ ) ₂ or -CH ₂ OH.
根据权利要求1所述的化合物，其为具有下列之一结构的化合物或具有下列之一结构的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，The compound according to claim 1, which is a compound having one of the following structures or a stereoisomer, tautomer, oxynitride, solvate, metabolite, pharmaceutically of a compound having one of the following structures; Acceptable salt or prodrug,
一种药物组合物，其包含权利要求1-7任意一项所述的化合物和药学上可接受的载体、赋形剂、佐剂或它们的任意组合。A pharmaceutical composition comprising a compound of any of claims 1-7 and a pharmaceutically acceptable carrier, excipient, adjuvant, or any combination thereof.
权利要求1-7任意一项所述的化合物或权利要求8所述的药物组合物在制备药物中的用途，所述药物用于预防、治疗或减轻与食欲素受体相关的疾病。Use of a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 for the preparation of a medicament for the prevention, treatment or alleviation of a disease associated with orexin receptors.
根据权利要求9所述的用途，其中所述与食欲素受体相关的疾病为睡眠障碍、抑郁症、焦虑症、恐慌症、强迫症、情感性神经病、抑郁性神经病、焦虑性神经病、心境障碍、惊恐发作障碍、行为失常、情绪紊乱、创伤后应激障碍、性功能障碍、精神病、精神***症、狂躁性抑郁、精神错乱、痴呆、药物依赖、成瘾、认知障碍、阿尔茨海默氏病、帕金森氏病、运动障碍、饮食失调、头痛、偏头痛、疼痛、消化***疾病、癫痫、炎症、心血管疾病、糖尿病、代谢疾病、免疫相关疾病、内分泌相关疾病或高血压。 The use according to claim 9, wherein the diseases associated with orexin receptors are sleep disorders, depression, anxiety, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder , panic attacks, behavioral disorders, mood disorders, post-traumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, insanity, dementia, drug dependence, addiction, cognitive impairment, Alzheimer Disease, Parkinson's disease, dyskinesia, eating disorders, headache, migraine, pain, digestive diseases, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic diseases, immune-related diseases, endocrine-related diseases or high blood pressure.