WO2023125707A1

WO2023125707A1 - P38 mapk/mk2 pathway regulator, composition thereof, preparation method therefor and use thereof

Info

Publication number: WO2023125707A1
Application number: PCT/CN2022/142965
Authority: WO
Inventors: 栾林波; 姚元山; 陈永凯; 王朝东
Original assignee: 上海美悦生物科技发展有限公司
Priority date: 2021-12-29
Filing date: 2022-12-28
Publication date: 2023-07-06
Also published as: TW202334119A; CN116444492A

Abstract

Disclosed in the present disclosure are a compound as shown in formula I, a racemate, a stereoisomer, a tautomer, an isotope label, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, and a composition thereof, a preparation method therefor and the use thereof. The compound has a good regulation effect on a p38 MAPK/MK2 pathway, good selectivity, and good pharmacokinetic properties. Furthermore, the compound can be used for treating diseases mediated by a p38 kinase inhibitor, and for preparing a medicament for such conditions or diseases.

Description

一种p38 MAPK/MK2通路调节剂及其组合物、制备方法和用途A p38 MAPK/MK2 pathway regulator and its composition, preparation method and use

本公开要求享有于2021年12月29日向中国国家知识产权局提交的，专利申请号为202111642855.0，名称为“一种p38 MAPK/MK2通路调节剂及其组合物、制备方法和用途”的在先申请的优先权。该在先申请的全文通过引用的方式结合于本公开中。This disclosure claims to enjoy the patent application number 202111642855.0, which was submitted to the State Intellectual Property Office of China on December 29, 2021, and is entitled "a p38 MAPK/MK2 pathway modulator and its composition, preparation method and use". Application priority. The entirety of this prior application is incorporated by reference into this disclosure.

技术领域technical field

本公开属于医药领域，具体涉及一种p38 MAPK/MK2通路调节剂及其组合物、制备方法和用途。The disclosure belongs to the field of medicine, and in particular relates to a p38 MAPK/MK2 pathway regulator and its composition, preparation method and application.

背景技术Background technique

生物信号转导涉及特异性的蛋白-蛋白相互作用和翻译后修饰、调节遗传和表观遗传过程以应对内外环境的作用。丝裂原活化蛋白激酶MAPK(mitogen-activated protein kinase)是一组能被不同的细胞内外部应激激活的丝氨酸-苏氨酸蛋白激酶，是信号从细胞表面传导到细胞核内部的重要传递者。应激因素包括细胞因子、神经递质、激素、细胞应激和细胞黏附等。Biological signal transduction involves specific protein-protein interactions and post-translational modifications, regulating genetic and epigenetic processes in response to internal and external environments. Mitogen-activated protein kinase MAPK (mitogen-activated protein kinase) is a group of serine-threonine protein kinases that can be activated by different intracellular and external stresses, and is an important transmitter of signals from the cell surface to the interior of the nucleus. Stress factors include cytokines, neurotransmitters, hormones, cell stress, and cell adhesion.

作为MAPK家族的一个亚族，p38 MAPK在细胞对外界信号和炎性细胞因子的作用作出响应，p38 MAPK被激活后磷酸化并激活下游多种蛋白激酶和转录因子，从而发挥复杂的生物学作用。p38 MAPK包括四个成员，即p38α、p38β、p38γ和p38δ。其中，p38α被认为在炎症过程的信号通路中起着重要作用，而其它异构体的生物学功能尚未完全被发现，但它们具有多效性。研究表明，p38β在细胞保护机制中起着重要的作用，而丝裂原活化蛋白激酶MKK3(MAP Kinase Kinase 3)介导p38δ对晚期结直肠癌(CRC)细胞的增殖和存活有作用。作为药物开发领域一个有吸引力的靶点，p38 MAPK有多个抑制剂药物进入临床研究，截至目前还没有药物被批准上市。根据***息，部分候选化合物在临床研究阶段失败，临床失败的主要原因包括剂量受限制以避免毒性从到导致药物分子在作用靶点暴露量不足抗炎通路下调、信号网络冗余或参与其它MAPK通路反馈调节的关键蛋白受到抑制等，而抑制反馈机制可能上调其他促炎症途径，导致炎症增加。因此，开发一款安全有效的p38 MAPK抑制剂是目前该领域药物开发面临的主要挑战。As a subfamily of the MAPK family, p38 MAPK responds to external signals and inflammatory cytokines in cells. After p38 MAPK is activated, it phosphorylates and activates a variety of downstream protein kinases and transcription factors, thereby playing complex biological roles . p38 MAPK includes four members, namely p38α, p38β, p38γ and p38δ. Among them, p38α is considered to play an important role in the signaling pathway of the inflammatory process, while the biological functions of other isoforms have not been fully discovered, but they have pleiotropic effects. Studies have shown that p38β plays an important role in the mechanism of cell protection, while mitogen-activated protein kinase MKK3 (MAP Kinase Kinase 3) mediates p38δ to play a role in the proliferation and survival of advanced colorectal cancer (CRC) cells. As an attractive target in the field of drug development, several inhibitors of p38 MAPK have entered clinical research, but so far no drug has been approved for marketing. According to public information, some candidate compounds fail in the clinical research stage. The main reasons for clinical failure include dose limitation to avoid toxicity, resulting in insufficient exposure of drug molecules at the target site, downregulation of anti-inflammatory pathways, redundant signaling networks, or involvement of other MAPKs Key proteins of pathway feedback regulation are inhibited, etc., and inhibition of feedback mechanisms may upregulate other pro-inflammatory pathways, leading to increased inflammation. Therefore, developing a safe and effective p38 MAPK inhibitor is the main challenge facing drug development in this field.

p38 MAPK可调控超过60种底物并行使不同的生理学功能[Cell 2013(152),924]，所以选择性地抑制p38 MAPK下游效应物的激活，是避免由于p38 MAPK的整体抑制而导致的副作用/药效不足的主要策略。MAPK激活蛋白激酶2(MAPK-activated protein kinase 2，MK2)是p38 MAPK下游的直接作用底物，可被p38α和p38β激活。作为第一个被发现的p38 MAPK底物，MK2可在转录和转录后水平调节炎症因子的表达，从而在多个炎症性疾病的调节中发挥重要作用。研究表明，MK2可通过稳定mRNA的AU-rich元件，从而使TNF-α、IL-6、IL-8和COX-2等炎症因子表达增加。在小鼠的术后肠梗阻模型中[The Journal of surgical research 2013(185),102]，MK2抑制剂可减少炎症因子MIP-1α、TNF-α、IL-6和IL-1β等的表达，同时发现多形核白细胞、肥大细胞、单核巨噬细胞浸润的减少和肠平滑肌收缩性能的改善。在小鼠的胶原诱发性关节炎(CIA)模型中[Journal ofimmunology 2006(177),1913]，敲除MK2基因可以减少胶原诱发性关节炎的发生，与野生型小鼠相比，MK2-/-和MK2+/-小鼠胶原诱发性关节炎的发病率减少、严重程度降低，且炎症因子TNF-α和IL-6表达也有不同程度的减少。在MK2敲除的高胆固醇血症小鼠模型中[Circ Res 2007(101),1104]，小鼠的大动脉的脂质沉积和巨噬细胞减少，而且VCAM-1和MCP-1等炎症因子表达减少。另外，有研究表明抑制MK2可以用于抗肿瘤药物的开发[Cancer cell 2007(11),175]。p38 MAPK can regulate more than 60 substrates and perform different physiological functions [Cell 2013(152), 924], so selectively inhibiting the activation of downstream effectors of p38 MAPK is to avoid the side effects caused by the overall inhibition of p38 MAPK /Primary strategy for underpowered drugs. MAPK-activated protein kinase 2 (MAPK-activated protein kinase 2, MK2) is the direct downstream substrate of p38 MAPK, which can be activated by p38α and p38β. As the first discovered p38 MAPK substrate, MK2 can regulate the expression of inflammatory factors at the transcriptional and post-transcriptional levels, thus playing an important role in the regulation of multiple inflammatory diseases. Studies have shown that MK2 can increase the expression of inflammatory factors such as TNF-α, IL-6, IL-8 and COX-2 by stabilizing the AU-rich element of mRNA. In the postoperative intestinal obstruction model in mice [The Journal of surgical research 2013(185), 102], MK2 inhibitors can reduce the expression of inflammatory factors MIP-1α, TNF-α, IL-6 and IL-1β, etc., It was also found that the infiltration of polymorphonuclear leukocytes, mast cells, and mononuclear macrophages was reduced and the contractility of intestinal smooth muscle was improved. In the mouse collagen-induced arthritis (CIA) model [Journal ofimmunology 2006(177), 1913], knocking out the MK2 gene can reduce the occurrence of collagen-induced arthritis, compared with wild-type mice, MK2-/ The incidence and severity of collagen-induced arthritis in - and MK2+/- mice were reduced, and the expressions of inflammatory factors TNF-α and IL-6 were also reduced to varying degrees. In the MK2 knockout mouse model of hypercholesterolemia [Circ Res 2007(101), 1104], the lipid deposition and macrophages in the aorta of the mice were reduced, and inflammatory factors such as VCAM-1 and MCP-1 were expressed reduce. In addition, studies have shown that inhibiting MK2 can be used in the development of anti-tumor drugs [Cancer cell 2007(11), 175].

许多疾病与p38 MAPK/MK2通路相关，这些疾病包括(但不限于)自体免疫疾病和炎症性疾病(例如类风湿性关节炎、发脓性汗腺炎、银屑病、炎症性肠病、特发性皮炎、***性红斑狼疮等)、骨骼疾病、代谢疾病、神经和神经退化性疾病、癌症、心血管疾病、过敏症和哮喘、阿尔茨海默氏病和激素相关疾病等。选择性的抑制p38 MAPK/MK2通路减少了对p38 MAPK其它下游通路的影响，进而降低了药物开发中的潜在毒副作用和药效不充分的问题；满足与p38 MAPK/MK2通路相关疾病领域存在的未被满足的临床需求。Many diseases are associated with the p38 MAPK/MK2 pathway, these diseases include (but are not limited to) autoimmune diseases and inflammatory diseases (such as rheumatoid arthritis, hidradenitis suppurativa, psoriasis, inflammatory bowel disease, idiopathic dermatitis, systemic lupus erythematosus, etc.), skeletal diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone-related diseases, etc. Selective inhibition of the p38 MAPK/MK2 pathway reduces the impact on other downstream pathways of p38 MAPK, thereby reducing the potential side effects and insufficient drug efficacy in drug development; meeting the existing needs in the field of diseases related to the p38 MAPK/MK2 pathway Unmet clinical needs.

发明内容Contents of the invention

为了改善现有技术存在的问题，本公开提供了一种如式I所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药：In order to improve the problems existing in the prior art, the present disclosure provides a compound as shown in formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable Salts or prodrugs thereof:

其中，W为CH或N；m为0-5的整数；n为0-3的整数；Wherein, W is CH or N; m is an integer of 0-5; n is an integer of 0-3;

环A为3-20元的含氮杂环基，除与母核

连接的N原子以外，还任选地含有1个、2个或更多个选自O、N或S的杂原子； Ring A is a nitrogen-containing heterocyclic group of 3-20 members, except for the parent nucleus

In addition to the attached N atom, it optionally contains 1, 2 or more heteroatoms selected from O, N or S;

R ¹选自H、卤素、CN和C _1-6烷基； R ¹ is selected from H, halogen, CN and C _1-6 alkyl;

R ²选自-OR ⁸¹、-NH-C(O)R ⁸²、-NHR ⁸³和-C(O)NHR ⁸⁴； R ² is selected from -OR ⁸¹ , -NH-C(O)R ⁸² , -NHR ⁸³ and -C(O)NHR ⁸⁴ ;

R ³选自H、C _1-10烷基和C _3-20环烷基； R ³ is selected from H, C _1-10 alkyl and C _3-20 cycloalkyl;

R ⁴选自H、卤素和C _1-10烷基； R ⁴ is selected from H, halogen and C _1-10 alkyl;

R ⁵分别独立地选自H、卤素、-OH、-C _1-6烷基、-C _1-6烷氧基、氧代(＝O)、-C(O)C _1-6烷基、羟基取代的C ₁- ₁₀烷基、-C(O)OH、-C(O)NR ^91aR ^91b、-S(O) ₂R ⁹²和-S(O) ₂NR ^93aR ^93b； R ⁵ are independently selected from H, halogen, -OH, -C _1-6 alkyl, -C _1-6 alkoxy, oxo (=O), -C(O)C _1-6 alkyl, Hydroxyl substituted C ₁ - ₁₀ alkyl, -C(O)OH, -C(O)NR ^91a R ^91b , -S(O) ₂ R ⁹² and -S(O) ₂ NR ^93a R ^93b ;

R ⁶选自H、卤素和甲基； ^R is selected from H, halogen and methyl;

R ⁷分别独立地选自H、卤素、未取代或被Ra取代的C _1-10烷基和C _3-20环烷基；Ra选自卤素和C _3-20环烷基； R ⁷ are independently selected from H, halogen, unsubstituted or substituted C _1-10 alkyl and C _3-20 cycloalkyl; Ra is selected from halogen and C _3-20 cycloalkyl;

R ⁸¹、R ⁸²、R ⁸³、R ⁸⁴相同或不同，彼此独立地选自无取代或任选被1、2、3、4或5个Rb取代的C _6-14芳基-C _1-10烷基、5-14元杂芳基-C _1-10烷基、C _6-14芳基和5-14元杂芳基；每个Rb相同或不同，彼此独立地选自卤素、卤代C _1-10烷基、C _1-10烷基和C _1-10烷氧基； R ⁸¹ , R ⁸² , R ⁸³ , and R ⁸⁴ are the same or different, and are independently selected from C _6-14 aryl-C _1-10 unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 Rb Alkyl, 5-14 membered heteroaryl-C _1-10 alkyl, C _6-14 aryl and 5-14 membered heteroaryl; each Rb is the same or different, independently selected from halogen, halogenated C _1-10 alkyl, C _1-10 alkyl and C _1-10 alkoxy;

R ^91a、R ^91b、R ⁹²、R ^93a、R ^93b相同或不同，彼此独立地选自H、C _1-6烷基和C _3-20环烷基。 R ^91a , R ^91b , R ⁹² , R ^93a , and R ^93b are the same or different, and are independently selected from H, C _1-6 alkyl, and C _3-20 cycloalkyl.

根据本公开的实施方案，W为CH或N；m为0-5的整数；n为0-3的整数；According to an embodiment of the present disclosure, W is CH or N; m is an integer of 0-5; n is an integer of 0-3;

环A为3-20元的含氮杂环基，除与所述母核连接的N原子以外，还任选地含有1个、2个或更多个选自O、N或S的杂原子；Ring A is a 3-20 membered nitrogen-containing heterocyclic group, which optionally contains 1, 2 or more heteroatoms selected from O, N or S in addition to the N atom connected to the parent nucleus ;

R ⁵分别独立地选自H、卤素、-OH、C _1-6烷基、C _1-6烷氧基、氧代(＝O)、-C(O)C _1-6烷基、羟基取代的C _1-6烷基、-C(O)OH、-C(O)NR ^91aR ^91b、-S(O) ₂R ⁹²和-S(O) ₂NR ^93aR ^93b； R ⁵ are independently selected from H, halogen, -OH, C _1-6 alkyl, C _1-6 alkoxy, oxo (=O), -C(O)C _1-6 alkyl, hydroxy substituted C _1-6 alkyl, -C(O)OH, -C(O)NR ^91a R ^91b , -S(O) ₂ R ⁹² and -S(O) ₂ NR ^93a R ^93b ;

R ⁶选自H、卤素和甲基； ^R is selected from H, halogen and methyl;

R ⁷分别独立地选自H、卤素、C _1-10烷基和C _3-20环烷基； R ⁷ are independently selected from H, halogen, C _1-10 alkyl and C _3-20 cycloalkyl;

R ⁸¹、R ⁸²、R ⁸³、R ⁸⁴相同或不同，彼此独立地选自C _6-14芳基-C _1-10烷基、5-14元杂芳基-C _1-10烷基、C _6-14芳基和5-14元杂芳基；其中C _6-14芳基或5-14元杂芳基各自无取代或任选被1、2、3、4或5个彼此独立地选自卤素、卤代C _1-10烷基、C _1-10烷基和C _1-6烷氧基取代； R ⁸¹ , R ⁸² , R ⁸³ , and R ⁸⁴ are the same or different, and are independently selected from C _6-14 aryl-C _1-10 alkyl, 5-14 membered heteroaryl-C _1-10 alkyl, C _6-14 aryl and 5-14 membered heteroaryl; wherein C _6-14 aryl or 5-14 membered heteroaryl are each unsubstituted or optionally 1, 2, 3, 4 or 5 independently selected from each other Substituted from halogen, halogenated C _1-10 alkyl, C _1-10 alkyl and C _1-6 alkoxy;

根据本公开的实施方案，W为CH或N；m为0、1、2、3、4或5；n为0、1、2、3；According to an embodiment of the present disclosure, W is CH or N; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3;

环A为3-12元的含氮杂环基，除与所述母核连接的N原子以外，还任选地含有1个、2个或更多个选自O、N或S的杂原子；Ring A is a 3-12 membered nitrogen-containing heterocyclic group, which optionally contains 1, 2 or more heteroatoms selected from O, N or S in addition to the N atom connected to the parent nucleus ;

R ³选自H、C _1-6烷基和C _3-12环烷基； R ³ is selected from H, C _1-6 alkyl and C _3-12 cycloalkyl;

R ⁴选自H、卤素和C _1-6烷基； R ⁴ is selected from H, halogen and C _1-6 alkyl;

R ⁶选自H、卤素和甲基； ^R is selected from H, halogen and methyl;

R ⁷分别独立地选自H、卤素、C _1-6烷基和C _3-12环烷基； R ⁷ are independently selected from H, halogen, C _1-6 alkyl and C _3-12 cycloalkyl;

R ⁸¹、R ⁸²、R ⁸³、R ⁸⁴相同或不同，彼此独立地选自C _6-14芳基-C _1-6烷基、5-14元杂芳基-C _1-6烷基、C _6-14芳基和5-14元杂芳基；其中芳基或杂芳基各自无取代或任选被1、2、3、4或5个彼此独立地选自卤素、卤代C _1-6烷基、C _1-6烷基和C _1-3烷氧基取代； R ⁸¹ , R ⁸² , R ⁸³ , and R ⁸⁴ are the same or different, and are independently selected from C _6-14 aryl-C _1-6 alkyl, 5-14 membered heteroaryl-C _1-6 alkyl, C _6-14 aryl and 5-14 membered heteroaryl; wherein each aryl or heteroaryl is unsubstituted or optionally 1, 2, 3, 4 or 5 independently selected from halogen, halogenated C _{1- 6} alkyl, C _1-6 alkyl and C _1-3 alkoxy are substituted;

R ^91a、R ^91b、R ⁹²、R ^93a、R ^93b相同或不同，彼此独立地选自H、C _1-6烷基和C _3-10环烷基。 R ^91a , R ^91b , R ⁹² , R ^93a , and R ^93b are the same or different, and are independently selected from H, C _1-6 alkyl, and C _3-10 cycloalkyl.

环A为3-9元的含氮杂环基，除与所述母核连接的N原子以外，还任选地含有1个、2个或更多个选自O、N或S的杂原子；Ring A is a 3-9 membered nitrogen-containing heterocyclic group, which optionally contains 1, 2 or more heteroatoms selected from O, N or S in addition to the N atom connected to the parent nucleus ;

R ¹选自卤素； R ¹ is selected from halogen;

R ³选自C _1-3烷基和C _3-6环烷基； R ³ is selected from C _1-3 alkyl and C _3-6 cycloalkyl;

R ⁴为C _1-3烷基或卤素； R ⁴ is C _1-3 alkyl or halogen;

R ⁵分别独立地选自卤素、-OH、-C _1-3烷基、-C _1-3烷氧基、氧代(＝O)、-C(O)C _1-3烷基、羟基取代的C _1-3烷基、-C(O)OH、-C(O)NR ^91aR ^91b、-S(O) ₂R ⁹²和-S(O) ₂NR ^93aR ^93b； R ⁵ are independently selected from halogen, -OH, -C _{1-3 alkyl, -C 1-3} _alkoxy , oxo (=O), -C(O)C _1-3 alkyl, hydroxy substituted C _1-3 alkyl, -C(O)OH, -C(O)NR ^91a R ^91b , -S(O) ₂ R ⁹² and -S(O) ₂ NR ^93a R ^93b ;

R ⁶选自H、卤素和甲基； ^R is selected from H, halogen and methyl;

R ⁷分别独立地选自H、卤素和C _1-3烷基； R ⁷ are independently selected from H, halogen and C _1-3 alkyl;

R ⁸¹、R ⁸²、R ⁸³、R ⁸⁴相同或不同，彼此独立地选自C _6-8芳基-C _1-3烷基、5-6元杂芳基-C _1-3烷基、C _6-8芳基、5-6元杂芳基；其中芳基或杂芳基各自无取代或任选被1、2、3、4或5个彼此独立地选自卤素、卤代C _1-3烷基、C _1-3烷基和C _1-3烷氧基取代； R ⁸¹ , R ⁸² , R ⁸³ , and R ⁸⁴ are the same or different, and are independently selected from C _6-8 aryl-C _1-3 alkyl, 5-6 membered heteroaryl-C _1-3 alkyl, C _6-8 aryl, 5-6 membered heteroaryl; wherein each aryl or heteroaryl is unsubstituted or optionally 1, 2, 3, 4 or 5 independently selected from halogen, halogenated C _{1- 3} alkyl, C _1-3 alkyl and C _1-3 alkoxy are substituted;

R ^91a、R ^91b、R ⁹²、R ^93a、R ^93b相同或不同，彼此独立地选自H、C _1-3烷基和C _3-7环烷基。 R ^91a , R ^91b , R ⁹² , R ^93a , and R ^93b are the same or different, and are independently selected from H, C _1-3 alkyl, and C _3-7 cycloalkyl.

根据本公开的实施方案，W为CH或N；m为0、1、2或3；n为0或1；According to an embodiment of the present disclosure, W is CH or N; m is 0, 1, 2 or 3; n is 0 or 1;

环A选自以下结构：Ring A is selected from the following structures:

R ¹为Cl或Br； R ¹ is Cl or Br;

R ³为甲基或环丙基； R ³ is methyl or cyclopropyl;

R ⁴为甲基； R ⁴ is methyl;

R ⁵选自F、-OH、甲基、甲氧基、乙氧基、氧代(＝O)、-C(O)C _1-3烷基、2-羟基异丙基、-C(O)OH、-C(O)NH ₂、-C(O)NHCH ₃、-S(O) ₂CH ₃、S(O) ₂CH ₂CH ₃和-S(O) ₂-环丙烷； R ^is selected from F, -OH, methyl, methoxy, ethoxy, oxo (=O), -C(O)C _1-3 alkyl, 2-hydroxyisopropyl, -C(O )OH, -C(O)NH ₂ , -C(O)NHCH ₃ , -S(O) ₂ CH ₃ , S(O) ₂ CH ₂ CH ₃ and -S(O) ₂ -cyclopropane;

R ⁶选自H、F和Cl； ^R is selected from H, F and Cl;

R ⁷为H； ^R7 is H;

R ⁸¹、R ⁸²、R ⁸³、R ⁸⁴相同或不同，彼此独立地选自无取代或任选被1、2或3个Rb取代的苯基甲基、吡啶基甲基、吡啶基乙基、苯基和吡啶基；每个Rb相同或不同，彼此独立地选自F、Cl和CF ₃。 R ⁸¹ , R ⁸² , R ⁸³ , and R ⁸⁴ are the same or different, and are independently selected from phenylmethyl, pyridylmethyl, pyridylethyl, unsubstituted or optionally substituted by 1, 2 or 3 Rb, Phenyl and pyridyl; each Rb is the same or different, independently selected from F, Cl and _CF3 .

根据本公开的实施方案，R ₅和环A形成的结构可以选自： According to an embodiment of the present disclosure, the structure formed by R _and ring A may be selected from:

在一种优选的实施方案中，式Ⅰ化合物具有式Ⅰa或Ⅰb所示的结构：In a preferred embodiment, the compound of formula I has the structure shown in formula Ia or Ib:

其中，R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、R ⁷、A、W、m和n具有上文所述的定义，加粗的化学键表示化合物中存在轴手性。 Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , A, W, m and n have the above-mentioned definitions, and the chemical bonds in bold indicate the existence of axial chirality in the compound.

在一种优选的实施方案中，式Ⅰ化合物具有式Ⅱ所示的结构：In a preferred embodiment, the compound of formula I has the structure shown in formula II:

其中R ¹、R ³、R ⁴、R ⁵、R ⁶、R ⁷、m、n、W和环A彼此独立地具有上文所述的定义； wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , m, n, W and ring A independently of each other have the definitions stated above;

R ¹⁰选自H、卤素、未取代或任选被1个、2个或更多个卤素、OH、NH ₂取代的下列基团：C _1-10烷基、C _1-10烷氧基、卤代C _1-10烷基、卤代C _1-10烷氧基、C _2-10烯基、C _2-10烯基氧基、C _2-10炔基和C _2-10炔基氧基； R ¹⁰ is selected from H, halogen, unsubstituted or optionally substituted by 1, 2 or more halogens, OH, NH ₂ from the following groups: C _1-10 alkyl, C _1-10 alkoxy, Halogenated C _1-10 alkyl, halogenated C _1-10 alkoxy, C _2-10 alkenyl, C _2-10 alkenyloxy, C _2-10 alkynyl and C _2-10 alkynyloxy ;

每个R ¹¹相同或不同，彼此独立地选自H、卤素、C _1-6烷基和卤代C _1-10烷基； Each R ¹¹ is the same or different, independently selected from H, halogen, C _1-6 alkyl and halogenated C _1-10 alkyl;

p为0-4的整数。p is an integer of 0-4.

根据本公开的实施方案，R ¹⁰选自H、卤素、未取代或任选被1个、2个或更多个卤素、OH、NH ₂取代的下列基团：C _1-6烷基、C _1-6烷氧基、卤代C _1-6烷基、卤代C _1-6烷氧基、C _2-6烯基、C _2-6烯基氧基、C _2-6炔基和C _2-6炔基氧基； According to an embodiment of the present disclosure, R ¹⁰ is selected from the following groups H, halogen, unsubstituted or optionally substituted by 1, 2 or more halogens, OH, NH ₂ : C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkenyloxy, C _2-6 alkynyl and C _2-6 alkynyloxy;

每个R ¹¹相同或不同，彼此独立地选自H、卤素、C _1-6烷基和卤代C _1-6烷基； Each R ¹¹ is the same or different, independently selected from H, halogen, C _1-6 alkyl and halogenated C _1-6 alkyl;

p为0、1、2、3或4。p is 0, 1, 2, 3 or 4.

根据本公开的实施方案，R ¹⁰选自H、卤素、C _1-3烷基和卤代C _1-3烷基；p为0、1或2； According to an embodiment of the present disclosure, R ¹⁰ is selected from H, halogen, C _1-3 alkyl and halogenated C _1-3 alkyl; p is 0, 1 or 2;

每个R ¹¹相同或不同，彼此独立地选自H、卤素、C _1-3烷基和卤代C _1-3烷基。 Each R ¹¹ is the same or different and is independently selected from H, halogen, C _1-3 alkyl and halogenated C _1-3 alkyl.

根据本公开的实施方案，R ¹⁰为H或甲基；p为0、1或2； According to an embodiment of the present disclosure, R ¹⁰ is H or methyl; p is 0, 1 or 2;

每个R ¹¹相同或不同，彼此独立地选自F、Cl和CF ₃。 Each R ¹¹ is the same or different and is independently selected from F, Cl and CF ₃ .

在一种更优选的实施方案中，式Ⅱ化合物具有式Ⅱa或式Ⅱb所示的结构：In a more preferred embodiment, the compound of formula II has the structure shown in formula IIa or formula IIb:

其中，R ¹、R ³、R ⁴、R ⁵、R ⁶、R ⁷、R ¹⁰、R ¹¹、A、W、m、n和p具有上文所述的定义，加粗的化学键表示存在轴手性。 Among them, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ , A, W, m, n and p have the above definitions, and the chemical bonds in bold indicate the presence of axes Chirality.

在一些实施方案中，式I、式Ia、式Ib、式II、式IIa或式IIb所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其中W为N。In some embodiments, the compound represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, its racemate, stereoisomer, tautomer, isotopic label, solvate . A pharmaceutically acceptable salt or a prodrug thereof, wherein W is N.

在一些实施方案中，式I、式Ia或式Ib所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其中R ²为-OR ⁸¹或-NHR ⁸³；R ⁸¹和R ⁸³相同或不同，彼此独立地为C _6-8芳基-C ₁- ₃烷基-或5-6元杂芳基-C ₁- ₃烷基-；其中C _6-8芳基、5-6元杂芳基无取代或任选被1、2、3、4或5个彼此独立地选自卤素、卤代C ₁- ₃烷基、C ₁- ₃烷基和C _1-3烷氧基取代，C ₁- ₃烷基部分与O或NH相连。 In some embodiments, the compound represented by Formula I, Formula Ia or Formula Ib, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or Prodrug, wherein R ² is -OR ⁸¹ or _-NHR ⁸³ ; R ⁸¹ and R ⁸³ are the same or different, independently of each other C _6-8 aryl-C _1-3 alkyl- or 5-6 membered heteroaryl -C ₁ - ₃ alkyl-; wherein C _6-8 aryl, 5-6 membered heteroaryl is unsubstituted or optionally 1, 2, 3, 4 or 5 independently selected from halogen, halogenated C _1-3 alkyl, _C _1-3 alkyl and C _1-3 alkoxy are _substituted , _and the C _1-3 alkyl part is connected with O or NH.

在一些实施方案中，式I、式Ia或式Ib所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其中R ²为-OR ⁸¹；R ⁸¹为C _6-8芳基-C ₁- ₃烷基或5-6元杂芳基-C ₁- ₃烷基；其中C _6-8芳基和5-6元杂芳基无取代或任选被1、2、3、4或5个彼此独立地选自卤素、卤代C ₁- ₃烷基、C ₁- ₃烷基和C _1-3烷氧基取代；C ₁- ₃烷基部分与O相连。在一些实施方案中，式I、式Ia或式Ib所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其中R ²为-OR ⁸¹；R ⁸¹为-CH ₂-吡啶基；其中，吡啶基无取代或任选被1、2、3、4或5个彼此独立地选自卤素、卤代C ₁- ₃烷基、C ₁- ₃烷基和C _1-3烷氧基取代。 In some embodiments, the compound represented by Formula I, Formula Ia or Formula Ib, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or Prodrug, wherein R ² is -OR ⁸¹ _; R ⁸¹ is C _6-8 aryl-C _1-3 alkyl _or 5-6 membered heteroaryl-C _1-3 alkyl; wherein C _6-8 aryl And the 5-6 membered heteroaryl is unsubstituted or optionally 1, 2, 3, 4 or 5 independently selected from halogen, halogenated C ₁ - ₃ alkyl, C ₁ - ₃ alkyl and C _{1- 3} alkoxy substitutions; C ₁ - ₃ alkyl moieties are connected to O. In some embodiments, the compound represented by Formula I, Formula Ia or Formula Ib, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or Prodrug, wherein R ² is -OR ⁸¹ ; R ⁸¹ is -CH ₂ -pyridyl; wherein, pyridyl is unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 independently selected from halogen, halogen C _1-3 alkyl, C _1-3 alkyl and C _1-3 alkoxy _are substituted _.

在一些实施方案中，式I、式Ia、式Ib、式II、式IIa或式IIb所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其中R ⁵分别独立地选自H、-OH、-C _1-6烷基、-C _1-6烷氧基、-C(O)C _1-6烷基、羟基取代的C ₁- ₁₀烷基、-C(O)OH、-C(O)NR ^91aR ^91b和-S(O) ₂R ⁹²；R ^91a、R ^91b和R ⁹²相同或不同，彼此独立地选自H、C _1-6烷基和C _3-10环烷基。 In some embodiments, the compound represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, its racemate, stereoisomer, tautomer, isotopic label, solvate , a pharmaceutically acceptable salt or a prodrug thereof, wherein R ⁵ are independently selected from H, -OH, -C _1-6 alkyl, -C _1-6 alkoxy, -C(O)C _{1- 6} alkyl, hydroxyl substituted C ₁ - ₁₀ alkyl, -C (O) OH, -C (O) NR ^91a R ^91b and -S (O) ₂ R ⁹² ; R ^91a , R ^91b and R ⁹² are the same or different, independently selected from H, C _1-6 alkyl and C _3-10 cycloalkyl.

在一些实施方案中，式I、式Ia、式Ib、式II、式IIa或式IIb所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其中R ¹为卤素。 In some embodiments, the compound represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, its racemate, stereoisomer, tautomer, isotopic label, solvate , A pharmaceutically acceptable salt or a prodrug thereof, wherein R ¹ is halogen.

在一些实施方案中，式I、式Ia、式Ib、式II、式IIa或式IIb所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其中R ³为C _1-3烷基。 In some embodiments, the compound represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, its racemate, stereoisomer, tautomer, isotopic label, solvate . A pharmaceutically acceptable salt or a prodrug thereof, wherein R ³ is C _1-3 alkyl.

在一些实施方案中，式I、式Ia、式Ib、式II、式IIa或式IIb所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其中R ⁴为卤素或C ₁- ₃烷基。 In some embodiments, the compound represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, its racemate, stereoisomer, tautomer, isotopic label, solvate . A pharmaceutically acceptable salt or a prodrug thereof, wherein R ⁴ is halogen or C ₁ - ₃ alkyl.

在一些实施方案中，式I、式Ia、式Ib、式II、式IIa或式IIb所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其中R ⁶为H或卤素。 In some embodiments, the compound represented by Formula I, Formula Ia, Formula Ib, Formula II, Formula IIa or Formula IIb, its racemate, stereoisomer, tautomer, isotopic label, solvate , a pharmaceutically acceptable salt or a prodrug thereof, wherein R ⁶ is H or halogen.

根据本公开的实施方案，式Ⅰ化合物包括但不限于以下结构：According to embodiments of the present disclosure, compounds of formula I include but are not limited to the following structures:

根据本公开的实施方案，式I所示化合物包括但不限于以下结构：According to an embodiment of the present disclosure, compounds represented by formula I include but are not limited to the following structures:

本公开还提供一种式Ⅰ化合物的制备方法，包括：The present disclosure also provides a preparation method of the compound of formula I, comprising:

方案一：化合物a1与化合物a2发生偶联反应得到式Ⅰ化合物。Scheme 1: compound a1 and compound a2 undergo a coupling reaction to obtain a compound of formula I.

反应式如下：The reaction formula is as follows:

其中，Y为Cl或Br；W、R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、R ⁷、m、n和环A彼此独立地具有上文所述定义； Wherein, Y is Cl or Br; W, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , m, n and ring A are independently defined above;

方案二：当W为N，R ₇为H时，化合物b1与化合物b2反应得到式Ⅱ化合物； Scheme 2: When W is N and R ₇ is H, compound b1 reacts with compound b2 to obtain a compound of formula II;

反应式如下：The reaction formula is as follows:

其中R ¹、R ³、R ⁴、R ⁵、R ⁶、R ⁷、R ¹⁰、R ¹¹、m、n、p和环A彼此独立地具有上文所述的定义； wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ , m, n, p and ring A independently of one another have the definitions stated above;

根据本公开的实施方案，所述反应在无机碱的存在下进行；所述无机碱选自碳酸钠、碳酸钾、碳酸铯、氢氧化钠和氢氧化钾中的一种。According to an embodiment of the present disclosure, the reaction is carried out in the presence of an inorganic base; the inorganic base is selected from one of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide.

根据本公开的实施方案，当R ₅为OH时，化合物b2中的OH可以被硅保护基保护，所述硅保护基可以为叔丁基二苯基硅基；所述硅保护基在所述反应中会脱除，得到脱保护的OH。 According to an embodiment of the present disclosure, when R ₅ is OH, the OH in compound b2 can be protected by a silicon protecting group, and the silicon protecting group can be tert-butyldiphenylsilyl; the silicon protecting group is in the It will be removed during the reaction to obtain the deprotected OH.

本公开还提供式I所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药化合物中的至少一种在制备药物中的用途。The present disclosure also provides at least one of the compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug compound Use in the preparation of medicines.

根据本公开的实施方案，所述药物可以为治疗和/或预防与p38激酶抑制剂有关的疾病的药物，例如可以为MK2抑制剂或p38 MAPK/MK2通路调节剂。According to an embodiment of the present disclosure, the drug may be a drug for treating and/or preventing diseases related to p38 kinase inhibitors, for example, it may be an MK2 inhibitor or a p38 MAPK/MK2 pathway modulator.

本公开还提供一种药物组合物，其包含治疗有效量的式I所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药化合物中的至少一种。The present disclosure also provides a pharmaceutical composition, which comprises a therapeutically effective amount of a compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable At least one of the salts or prodrug compounds thereof.

根据本公开的实施方案，所述药物组合物还包括至少一种药学上可接受的载体。According to an embodiment of the present disclosure, the pharmaceutical composition further includes at least one pharmaceutically acceptable carrier.

根据本公开的实施方案，所述药物组合物还可以进一步含有一种或多种额外的治疗剂。According to embodiments of the present disclosure, the pharmaceutical composition may further contain one or more additional therapeutic agents.

所述的载体包括崩解剂，例如甲基纤维素、羧甲基纤维素钠、羧甲基纤维素钙、交联羧甲基纤维素钠、聚乙烯基吡咯烷酮、羧丙基纤维素、淀粉等；润滑剂，包括硬脂酸钙、硬脂酸锌、硬脂酸镁、硬脂酰醇富马酸钠等；粘合剂，包括明胶、聚乙二醇、糖、树胶、淀粉、羟丙基纤维素等；稀释剂，包括甘露醇、木糖醇、乳糖、右旋糖、蔗糖、山梨糖醇和淀粉；表面活性剂，包括聚山梨酯80、十二烷基硫酸钠、滑石粉和二氧化硅。可通过使用本领域中已知的方法配制本公开组合物，以便在给予患者后提供速释、缓释或延迟释放活性成分的作用。The carrier includes a disintegrant, such as methylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, polyvinylpyrrolidone, carboxypropylcellulose, starch etc.; lubricants, including calcium stearate, zinc stearate, magnesium stearate, sodium stearyl fumarate, etc.; binders, including gelatin, polyethylene glycol, sugar, gum, starch, hydroxyl Propyl cellulose, etc.; diluents, including mannitol, xylitol, lactose, dextrose, sucrose, sorbitol and starch; surfactants, including polysorbate 80, sodium lauryl sulfate, talc and silica. Compositions of the present disclosure can be formulated so as to provide immediate, sustained or delayed release of the active ingredient after administration to the patient by employing methods known in the art.

本公开还提供式I所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药化合物，在治疗和/或预防与p38激酶抑制剂介导有关的疾病中的用途。The present disclosure also provides the compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug compound, in the treatment and/or Or the use in preventing diseases mediated by p38 kinase inhibitors.

本公开还提供治疗和/或预防与p38激酶抑制剂介导有关的疾病的方法，包括给予患者治疗或预防有效量的式I所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药化合物中的至少一种。The present disclosure also provides a method for treating and/or preventing diseases mediated by p38 kinase inhibitors, comprising administering to a patient an effective dose of a compound represented by formula I, its racemate, stereoisomer, tautomer At least one of isomers, isotope labels, solvates, pharmaceutically acceptable salts or prodrug compounds thereof.

根据本公开的实施方案，所述疾病可以为与p38 MAPK/MK2通路相关的疾病，例如可以为自体免疫疾病和炎症性疾病(如类风湿性关节炎、发脓性汗腺炎、银屑病、炎症性肠病、特发性皮炎、***性红斑狼疮等)、骨骼疾病、代谢疾病、神经和神经退化性疾病、癌症、心血管疾病、过敏症和哮喘、阿尔茨海默氏病和激素相关疾病。According to an embodiment of the present disclosure, the disease may be a disease related to the p38 MAPK/MK2 pathway, such as an autoimmune disease and an inflammatory disease (such as rheumatoid arthritis, hidradenitis suppurativa, psoriasis, Inflammatory bowel disease, idiopathic dermatitis, systemic lupus erythematosus, etc.), bone disease, metabolic disease, neurological and neurodegenerative disease, cancer, cardiovascular disease, allergy and asthma, Alzheimer's disease and hormone-related disease.

有益效果Beneficial effect

本公开的化合物对p38 MAPK/MK2通路具有良好的调节作用，并具有良好的选择性。另外，本公开的化合物药代动力学等性能良好。还有，本公开的化合物可用于治疗与p38激酶抑制剂介导有关的疾病，以及制备用于此类病症或疾病的药物。The disclosed compound has a good regulating effect on the p38 MAPK/MK2 pathway and has good selectivity. In addition, the compounds of the present disclosure have good properties such as pharmacokinetics. Also, the disclosed compounds are useful in the treatment of diseases associated with the mediation of p38 kinase inhibitors, and in the preparation of medicaments for such conditions or diseases.

术语定义与说明Definition and Explanation of Terms

除非另有说明，本公开说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当被理解为本公开说明书和/或权利要求书记载的范围内。Unless otherwise stated, the definitions of groups and terms described in the specification and claims of this disclosure include their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples etc., can be arbitrarily combined and combined with each other. Such combinations and combined group definitions and compound structures should be understood as falling within the scope of the present disclosure and/or claims.

除非另有说明，本说明书和权利要求书记载的数值范围相当于至少记载了其中每一个具体的整数数值。例如，数值范围“1-20”相当于记载了数值范围“1-20”中的每一个整数数值即1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20。此外，当某些数值范围被定义为“数”时，应当理解为记载了该范围的两个端点、该范围内的每一个整数以及该范围内的每一个小数。例如，“0～10的数”应当理解为不仅记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数，还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。Unless otherwise stated, the numerical ranges described in the specification and claims are equivalent to at least recording each specific integer value therein. For example, the numerical range "1-20" is equivalent to recording every integer value in the numerical range "1-20", that is, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20. Additionally, when certain numerical ranges are defined as "numbers," it should be understood that both endpoints of the range, each integer within the range, and each decimal within the range are recited. For example, "the number from 0 to 10" should be understood as not only recording each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least recording each of the integers respectively Sum with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.

应当理解，本文在描述一个、两个或更多个中，“更多个”应当是指大于2，例如大于等于3的整数，例如3、4、5、6、7、8、9或10。It should be understood that in describing one, two or more herein, "more" shall refer to an integer greater than 2, such as greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10 .

应当理解，术语“任选地含有1个、2个或更多个选自O、N或S的杂原子”表示不含有杂原子的情形，或含有1个、2个或更多个选自O、N或S的杂原子的情形。It should be understood that the term "optionally containing 1, 2 or more heteroatoms selected from O, N or S" means that no heteroatoms are contained, or that 1, 2 or more heteroatoms selected from The case of O, N or S heteroatoms.

术语“卤素”表示氟、氯、溴和碘。The term "halogen" denotes fluorine, chlorine, bromine and iodine.

术语“C _1-10烷基”应理解为表示具有1～10个碳原子的直链或支链饱和一价烃基。例如，表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链和支链烷基，“C _1-6烷基”表示具有1、2、3、4、5或6个碳原子的直链和支链烷基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、 1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。 The term "C _1-10 alkyl" is understood to mean a linear or branched saturated monovalent hydrocarbon group having 1 to 10 carbon atoms. For example, means straight chain and branched chain alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C _1-6 alkyl" means having 1, 2, 3 , straight-chain and branched-chain alkyl groups of 4, 5 or 6 carbon atoms. The alkyl group is for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, 1,2-dimethylbutyl, etc. or their isomers.

术语“烷氧基”指-O-(烷基)，其中烷基的定义如本文中所述。优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子的烷氧基(C _1-12烷氧基)，更优选含有1至6个碳原子的烷氧基(C _1-6烷氧基)。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基和丁氧基。烷氧基可以是取代的或未取代的。 The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined herein. Alkoxy groups containing 1 to 12 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (C _1-12 alkoxy) are preferred, more Alkoxy having 1 to 6 carbon atoms (C _1-6 alkoxy) is preferred. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy and butoxy. Alkoxy groups can be substituted or unsubstituted.

术语“C _2-10烯基”应理解为优选表示直连或支链的一价烃基，其包含一个或多个双键并且具有2、3、4、5、6、7、8、9或10个碳原子，更优选“C _2-8烯基”。“C _2-10烯基”应理解为优选表示直连或支链的一价烃基，其包含一个或多个双键并且具有2、3、4、5、6、7或8个碳原子，例如，具有2、3、4、5或6个碳原子(即，C _2-6烯基)，具有2或3个碳原子(即，C _2-3烯基)。应理解，在所述烯基包含多于一个双键的情况下，所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基。 The term "C _2-10 alkenyl" is understood to preferably mean a straight or branched monovalent hydrocarbon radical comprising one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably "C _2-8 alkenyl". "C _2-10 alkenyl" is understood to mean preferably a straight or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5, 6, 7 or 8 carbon atoms, For example, having 2, 3, 4, 5 or 6 carbon atoms (ie, _C2-6 alkenyl), having 2 or 3 carbon atoms (ie, _C2-3 alkenyl). It is understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)- But-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z) -pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl Base, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3- Alkenyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl , 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, ( Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methyl But-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2- Alkenyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E )-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methyl 1-butylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

术语“C _2-10炔基”应理解为优选表示直连或支链的一价烃基，其包含一个或多个三键并且具有2、3、4、5、6、7、8、9或10个碳原子，例如，具有2、3、4、5、6、7或8个碳原子(即，“C _2-8炔基”)，具有2、3、4、5或6个碳原子(即，“C _2-6炔基”)，具有2或3个碳原子(“C _2-3炔基”)。所述炔基是例如乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基、戊-1-炔基、戊-2-炔基、戊-3-炔基、戊-4-炔基、己-1-炔基、己-2-炔基、己-3-炔基、己-4-炔基、己-5-炔基、1-甲基丙-2-炔基、2-甲基丁-3-炔基、1-甲基丁-3-炔基、1-甲基丁-2-炔基、3-甲基丁-1-炔基、1-乙基丙-2-炔基、3-甲基戊-4-炔基、2-甲基戊-4-炔基、1-甲基戊-4-炔基、2-甲基戊-3-炔基、1-甲基戊-3-炔基、4-甲基戊-2-炔基、1-甲基戊-2-炔基、4-甲基戊-1-炔基、3-甲基戊-1-炔基、2-乙基丁-3-炔基、1-乙基丁-3-炔基、1-乙基丁-2-炔基、1-丙基丙-2-炔基、1-异丙基丙-2-炔基、2,2-二甲基丁-3-炔基、1,1-二甲基丁-3-炔基、1,1-二甲基丁-2-炔基或3,3-二甲基丁-1-炔基。特别地，所述炔基是乙炔基、丙-1-炔基或丙-2-炔基。 The term "C _2-10 alkynyl" is understood to preferably mean a straight or branched monovalent hydrocarbon radical comprising one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, e.g., having 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e., "C _alkynyl ") having 2, 3, 4, 5 or 6 carbon atoms (ie, "C _2-6 alkynyl"), having 2 or 3 carbon atoms ("C _2-3 alkynyl"). The alkynyl group is for example ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl , Pent-2-ynyl, Pent-3-ynyl, Pent-4-ynyl, Hex-1-ynyl, Hex-2-ynyl, Hex-3-ynyl, Hex-4-ynyl, Hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl , 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpentyl -4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut- 2-alkynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbutanyl -3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

术语“C _3-20环烷基”应理解为表示饱和的一价单环、二环(如并环、螺环、桥环)烃环或三环烷烃，其具有3～20个碳原子，优选“C _3-12环烷基”，更优选优选“C _3-8环烷基”。术语“C _3-12环烷基”应理解为表示饱和的一价单环、双环(如桥环、螺环)烃环或三环烷烃，其具有3、4、5、6、7、8、9、10、11或12个碳原子。所述C _3-12环烷基可以是单环烃基，如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如龙脑基、吲哚基、六氢吲哚基、四氢萘基、十氢萘基、二环[2.1.1]己基、二环[2.2.1]庚基、二环[2.2.1]庚烯基、6,6-二甲基二环 [3.1.1]庚基、2,6,6-三甲基二环[3.1.1]庚基、二环[2.2.2]辛基、2,7-二氮杂螺[3,5]壬烷基、2,6-二氮杂螺[3,4]辛烷基，或者是三环烃基如金刚烷基。 The term "C _3-20 cycloalkyl" should be understood as meaning a saturated monovalent monocyclic, bicyclic (such as double ring, spiro ring, bridged ring) hydrocarbon ring or tricycloalkane, which has 3 to 20 carbon atoms, Preferable is "C _3-12 cycloalkyl", more preferably "C _3-8 cycloalkyl". The term "C _3-12 cycloalkyl" should be understood as meaning a saturated monovalent monocyclic, bicyclic (such as bridged, spiro) hydrocarbon ring or tricycloalkane, which has 3, 4, 5, 6, 7, 8 , 9, 10, 11 or 12 carbon atoms. The C _3-12 cycloalkyl group can be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic Hydrocarbon groups such as bornyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2. 1] Heptenyl, 6,6-Dimethylbicyclo[3.1.1]heptyl, 2,6,6-Trimethylbicyclo[3.1.1]heptyl, Bicyclo[2.2.2]octyl 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl, or a tricyclic hydrocarbon group such as adamantyl.

术语“3-20元的含氮杂环基”是指饱和的或不饱和的含氮的非芳族的环或环系，例如，其是4-、5-、6-或7-元的单环、7-、8-、9-、10-、11-、12-、13-或14-元的二环(如并环、螺环、桥环)或者三环环系，并且含有至少一个N，还可以不含或含有例如1、2、3、4、5个或更多个选自O和S和的杂原子，其中N和S还可以任选被氧化成各种氧化状态，以形成氮氧化物、-S(O)-或-S(O) ₂-的状态。优选地，所述杂环基可以选自“3-12元的含氮杂环基”。术语“3-12元的含氮杂环基”意指饱和的或不饱和的含氮的非芳族的环或环系，并且含有至少一个N原子，不含或含有选自O和S和的杂原子。所述杂环基通过N原子与母核连接，可以通过所述碳原子中的任一个或其他氮原子(如果存在的话)与分子的其余部分连接。所述杂环基可以包括稠合的或桥连的环以及螺环的环。特别地，所述杂环基可以包括但不限于：4元环，如氮杂环丁烷基；5元环，如吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基；或6元环，如哌啶基、吗啉基、硫代吗啉基或哌嗪基；或7元环，如二氮杂环庚烷基。任选地，所述杂环基可以是苯并稠合的。所述杂环基可以是双环的，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。杂环基可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、1,2,3,5-四氢噁唑基或4H-[1,4]噻嗪基，或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基。所述3-12元的含氮杂环基与其它基团相连构成本公开的化合物时，可以为3-12元的含氮杂环基上的N原子与母核相连，碳原子与其它基团相连。例如当3-12元的含氮杂环基选自哌嗪基时，可以为哌嗪基上的氮原子与母核相连。或当3-12元的含氮杂环基选自哌啶基时，可以为哌啶基环上的氮原子与母核相连。 The term "3-20 membered nitrogen-containing heterocyclic group" refers to a saturated or unsaturated nitrogen-containing non-aromatic ring or ring system, for example, which is 4-, 5-, 6- or 7-membered Monocyclic, 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered bicyclic rings (such as double rings, spiro rings, bridged rings) or tricyclic ring systems, and contain at least A N, which may also contain or contain, for example, 1, 2, 3, 4, 5 or more heteroatoms selected from O and S and wherein N and S may also optionally be oxidized to various oxidation states, To form nitrogen oxides, -S(O)- or -S(O) ₂ -state. Preferably, the heterocyclic group may be selected from "3-12 membered nitrogen-containing heterocyclic groups". The term "3-12 membered nitrogen-containing heterocyclic group" means a saturated or unsaturated nitrogen-containing non-aromatic ring or ring system, and contains at least one N atom, does not contain or contains a group selected from O and S and of heteroatoms. The heterocyclyl is attached to the parent nucleus through an N atom and may be attached to the remainder of the molecule through any of the carbon atoms or other nitrogen atoms, if present. The heterocyclyl may include fused or bridged rings as well as spirocyclic rings. In particular, the heterocyclic group may include but not limited to: 4-membered rings, such as azetidinyl; 5-membered rings, such as pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6 A membered ring such as piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclyl group may be benzo-fused. The heterocyclic group can be bicyclic, such as but not limited to 5,5-membered rings, such as hexahydrocyclopenta[c]pyrrol-2(1H)-yl rings, or 5,6-membered bicyclic rings, such as hexahydropyrrole And[1,2-a]pyrazin-2(1H)-yl ring. A heterocyclyl group may be partially unsaturated, i.e. it may contain one or more double bonds, such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl , 1,2,3,5-tetrahydrooxazolyl or 4H-[1,4]thiazinyl, alternatively, it may be benzo-fused such as but not limited to dihydroisoquinolinyl. When the 3-12 membered nitrogen-containing heterocyclic group is connected with other groups to form the compound of the present disclosure, it can be that the N atom on the 3-12 membered nitrogen-containing heterocyclic group is connected with the mother nucleus, and the carbon atom is connected with other groups. Group connected. For example, when the 3- to 12-membered nitrogen-containing heterocyclic group is selected from piperazinyl, the nitrogen atom on the piperazinyl may be connected to the parent nucleus. Or when the 3-12 membered nitrogen-containing heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring may be connected to the parent nucleus.

术语“螺环”是指两个环共用1个成环原子的环系。The term "spiro" refers to a ring system in which two rings share 1 ring-forming atom.

术语“并环”是指两个环共用2个成环原子的环系。The term "merged ring" refers to a ring system in which two rings share 2 ring-forming atoms.

术语“桥环”是指两个环共用3个以上成环原子的环系。The term "bridged ring" refers to a ring system in which two rings share more than 3 ring-forming atoms.

术语“C _6-14芳基-C _1-10烷基”指被C _6-14芳基取代的C _1-10烷基，连接位点在C _1-10烷基。 The term "C _6-14 aryl-C _1-10 alkyl" refers to a C _1-10 alkyl substituted by a C _6-14 aryl, and the connection point is at the C _1-10 alkyl.

术语“5-14元杂芳基-C _1-10烷基”指被5-14元杂芳基取代的C _1-10烷基，连接位点在C _1-10烷基。 The term "5-14 membered heteroaryl-C _1-10 alkyl" refers to a C _1-10 alkyl group substituted by a 5-14 membered heteroaryl group, and the attachment point is at the C _1-10 alkyl group.

术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(稠合多环是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环包括如本文中所述的芳基环稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (a fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6 to 10 membered , such as phenyl and naphthyl. The aryl ring includes an aryl ring fused to a heteroaryl, heterocyclyl, or cycloalkyl ring as described herein, wherein the ring bonded to the parent structure is an aryl ring, which is not limiting Examples include:

芳基可以是取代的或未取代的。

Aryl groups can be substituted or unsubstituted.

术语“杂芳基”指包含1至4个(例如1、2、3和4个)杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元(例如5、6、7、8、9或10元)，更优选为5 元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、***基、四唑基等。所述杂芳基环包括如本文中所述的杂芳基稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (eg 1, 2, 3 and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered (eg 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered, eg furyl, thienyl, pyridyl, pyrrolyl, N-alkyl Pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl rings include heteroaryl fused to aryl, heterocyclyl or cycloalkyl rings as described herein, where the ring attached to the parent structure is a heteroaryl ring, without limitation Sexual examples include:

杂芳基可以是取代的或未取代的。

Heteroaryl groups can be substituted or unsubstituted.

本文中的术语“烷基”、“烷氧基”、“环烷基”、“杂环基”、“芳基”和“杂芳基”等可以是取代的或未取代的；当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个相同或不同的取代基。The terms "alkyl", "alkoxy", "cycloalkyl", "heterocyclyl", "aryl" and "heteroaryl" etc. herein may be substituted or unsubstituted; when substituted , which may be substituted at any available point of attachment, said substituents are preferably independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano One or more of the same or different substituents among , amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

本公开中所述化合物的药学上可接受的盐可为无机盐或有机盐，如果这些化合物具有碱性中心，则其可以形成酸加成盐；如果这些化合物具有酸性中心，则其可以形成碱加成盐；如果这些化合物既包含酸性中心(例如羧基)又包含碱性中心(例如氨基)，则其还可以形成内盐。The pharmaceutically acceptable salts of the compounds described in this disclosure may be inorganic salts or organic salts, and if these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form bases. Addition salts; these compounds can also form internal salts if they contain both an acidic center (eg carboxyl group) and a basic center (eg amino group).

本公开化合物可以存在特定的几何或立体异构体形式。例如顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，外消旋混合物和其他混合物，以及对映异构体或非对映体富集的混合物，所有这些混合物都属于本公开的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本公开的范围之内。Compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. For example cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers isomers, (L)-isomers, racemic and other mixtures, as well as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure.

本公开所述化合物的化学结构中，键

表示未指定构型，

或

表示绝对构型，即如果化学结构中存在手性异构体，键

可以为

或

或者同时包含

和

两种构型，

表示存在轴手性。 In the chemical structures of the compounds described in this disclosure, the bond

means unspecified configuration,

or

Indicates the absolute configuration, i.e. if chiral isomers exist in the chemical structure, the bond

can be

or

or both

and

two configurations,

Indicates the presence of axial chirality.

键

表示未指定构型，包括顺式(E)或反式(Z)构型。 key

Denotes unassigned configuration, including cis (E) or trans (Z) configuration.

另外，本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。“互变异构体”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇异构化、亚胺-烯胺异构化和内酰胺-内酰亚胺异构化。本公开中的所有化合物的所有的互变异构形式均在本公开的范围内。用单一方式命名的化合物的名称不排除任何互变异构体。In addition, the compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. "Tautomer" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactam imide isomerization. All tautomeric forms of all compounds in the disclosure are within the scope of the disclosure. The names of compounds named in a single way do not exclude any tautomers.

本公开还包括一些与本文中记载的结构相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 ²H、 ³H、 ¹¹C、 ¹³C、 ¹⁴C、 ¹³N、 ¹⁵N、 ¹⁵O、 ¹⁷O、 ¹⁸O、 ³¹P、 ³²P、 ³⁵S、 ¹⁸F、 ¹²³I、 ¹²⁵I和 ³⁶Cl等。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。 The present disclosure also includes some isotopically labeled compounds of the disclosure having the same structure as described herein, but wherein one or more atoms are replaced by an atom with an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I, ¹²⁵ I and ³⁶ Cl, etc. All permutations of isotopic composition of the disclosed compounds, whether radioactive or not, are included within the scope of the present disclosure.

除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即，至少10％的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘、至少2000倍的丰度的氘、至少3000倍的丰度的氘、至少4000倍的丰度的氘、至少5000倍的丰度的氘、至少6000倍的丰度的氘或更高丰度的氘。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的化合物。在制备氘代形式的化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (i.e., at least 10 % deuterium incorporation). Exemplary compounds having a natural abundance greater than deuterium can be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 5000 times more abundant deuterium, at least 6000 times more abundant deuterium, or more abundant deuterium. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize the deuterated form of the compound. Commercially available deuterated starting materials can be used in the preparation of deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including but not limited to deuterated borane, trideuterioborane in tetrahydrofuran , deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.

本公开的“治疗有效量”是指研究人员、兽医、医师或其它临床医师等在组织、***、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量，它包括以下一项或多项：(1)预防疾病：例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。(2)抑制疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转病理和/或症状)。针对药物或药理学活性剂而言，“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。The "therapeutically effective amount" in the present disclosure refers to the amount of active compound or drug that researchers, veterinarians, physicians or other clinicians look for in tissues, systems, animals, individuals or humans to cause biological or medical responses, including One or more of the following: (1) Preventing a disease: eg, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or developed disease pathology or symptoms. (2) Inhibiting a disease: For example, inhibiting a disease, disorder or condition (ie preventing further development of the pathology and/or symptoms) in an individual experiencing or developing pathology or symptoms of the disease, disorder or condition. (3) Alleviating disease: For example, alleviating a disease, disorder or condition (ie reversing the pathology and/or symptoms) in an individual experiencing or developing the pathology or symptoms of the disease, disorder or condition. For a drug or a pharmacologically active agent, "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.

本公开“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。"Pharmaceutically acceptable" in the present disclosure means that these compounds, materials, compositions and/or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without undue toxicity, irritation, allergic response or other problems or complications, have a reasonable benefit/risk ratio, and are effective for the intended use.

本公开的“患者”是指包括哺乳动物在内的任何动物，优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物，最优选人。"Patient" in the present disclosure refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, most preferably people.

具体实施方式Detailed ways

下文将结合具体实施例对本公开的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本公开，而不应被解释为对本公开保护范围的限制。凡基于本公开上述内容所实现的技术均涵盖在本公开旨在保护的范围内。The technical solution of the present disclosure will be further described in detail in conjunction with specific embodiments below. It should be understood that the following examples are only for illustrating and explaining the present disclosure, and should not be construed as limiting the protection scope of the present disclosure. All technologies implemented based on the above contents of the present disclosure are covered within the intended protection scope of the present disclosure.

除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 ^-6(ppm)的单位给出。NMR的测定是用Bruker ASCEND ^TM-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d ₆)、氘代氯仿(CDCl ₃)、氘代甲醇(CD ₃OD)，内标为四甲基硅烷(TMS)。 Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). The determination of NMR is to use Bruker ASCEND ^™ -400 nuclear magnetic instrument, and the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard is Tetramethylsilane (TMS).

MS的测定用Agilent 6110，Agilent 1100，Agilent 6120，AgilentG6125B液相质谱联用仪。Agilent 6110, Agilent 1100, Agilent 6120, Agilent G6125B liquid phase mass spectrometer were used for the determination of MS.

HPLC的测定使用岛津HPLC-2010C高效液相色谱仪(XBRIDGE 2.1*50mm,3.5um色谱柱)。The determination of HPLC uses Shimadzu HPLC-2010C high performance liquid chromatography (XBRIDGE 2.1*50mm, 3.5um chromatographic column).

手性HPLC分析测定使用THARSFC X5。Chiral HPLC analysis was performed using THARSFC X5.

薄层层析硅胶板使用烟台青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。The thin-layer chromatography silica gel plate uses Yantai Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm-0.5mm. .

柱层析一般使用青岛海洋硅胶200～300目硅胶为载体。Column chromatography generally uses Qingdao Ocean Silica gel 200-300 mesh silica gel as the carrier.

高效液相制备使用Waters 2767、Waters 2545、和创新恒通LC3000制备型色谱仪。High-performance liquid phase preparation uses Waters 2767, Waters 2545, and innovative Hengtong LC3000 preparative chromatography.

手性制备柱层析使用，Shimadzu LC-20AP、THARSFC PREP 80。For chiral preparative column chromatography, Shimadzu LC-20AP and THARSFC PREP 80 were used.

CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。The CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

加压氢化反应使用北京佳维科创科技GCD-500G型氢气发生器。The pressurized hydrogenation reaction uses Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.

微波反应使用Biotage initiator+型微波反应器。The microwave reaction uses a Biotage initiator+ type microwave reactor.

实验例中如无特殊说明，反应均在氩气氛或者氮气氛下进行。In the experimental examples, unless otherwise specified, the reactions were all carried out under an argon or nitrogen atmosphere.

氩气氛或者氮气氛是指反应瓶连接一个约1升容积的氩气或者氮气气球。The argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 liter.

氢气氛是指反应瓶连接一个约1升容积的氢气气球。The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1 liter.

实验例中如无特殊说明，反应温度均为室温，温度范围是20℃-30℃。In the experimental example, unless otherwise specified, the reaction temperature is room temperature, and the temperature range is 20°C-30°C.

中间体化合物A-5的合成Synthesis of intermediate compound A-5

第一步：化合物A-5b的合成The first step: the synthesis of compound A-5b

将氯化亚砜(22.43g,188.5mmol)缓慢滴加到化合物A-5a(20.00g,125mol)的乙醇(60mL)溶液中，反应混合物在60℃下进行3小时。反应结束后，反应液直接减压浓缩除去溶剂后得到化合物A-5b(20.00g)粗品，该粗品直接用于下一步反应。Thionyl chloride (22.43 g, 188.5 mmol) was slowly added dropwise to a solution of compound A-5a (20.00 g, 125 mol) in ethanol (60 mL), and the reaction mixture was carried out at 60° C. for 3 hours. After the reaction, the reaction solution was directly concentrated under reduced pressure to remove the solvent to obtain a crude compound A-5b (20.00 g), which was directly used for the next reaction.

MS m/z(ESI):187.9[M+1] ⁺。 MS m/z (ESI): 187.9 [M+1] ⁺ .

第二步：化合物A-5c的合成The second step: the synthesis of compound A-5c

将化合物A-5b(16.00g,85.6mmol)溶于乙醇(60mL)中，再将硼氢化钠(6.48g,171.2mmol)在0℃分批缓慢加入溶液中。将所得混合物在室温下搅拌3小时。反应结束后，减压浓缩除去溶剂，所得残余物通过硅胶柱层析(石油醚:乙酸乙酯＝1:5)纯化得到化合物A-5c(16.00g,收率：73.5％)。Compound A-5b (16.00 g, 85.6 mmol) was dissolved in ethanol (60 mL), and sodium borohydride (6.48 g, 171.2 mmol) was slowly added to the solution in batches at 0°C. The resulting mixture was stirred at room temperature for 3 hours. After the reaction, the solvent was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:5) to obtain compound A-5c (16.00 g, yield: 73.5%).

MS m/z(ESI):146.1[M+1] ⁺。 MS m/z (ESI): 146.1 [M+1] ⁺ .

第三步:化合物A-5的合成The third step: the synthesis of compound A-5

在室温下，将氯化亚砜(1.77g,0.015mol)缓慢加入到化合物A-5c(1.80g,0.012mol)和N,N-二甲基甲酰胺(5滴)的二氯甲烷(50mL)溶液中，反应在室温下进行1小时。反应结束后，向反应液中加入氯化铵溶液(100mL,4M)调节pH值至中性，然后加入水(20mL)并用二氯甲烷(10mL×3)萃取，合并的有机相用无水硫酸钠干燥并过滤，过滤液减压浓缩除去溶剂，所得残余物经柱层析(石油醚:乙酸乙酯＝1:0～5:1)纯化得到化合物A-5(1.80g,收率：84.68％)。Thionyl chloride (1.77 g, 0.015 mol) was slowly added to compound A-5c (1.80 g, 0.012 mol) and N,N-dimethylformamide (5 drops) in dichloromethane (50 mL ) solution, the reaction was carried out at room temperature for 1 hour. After the reaction was over, ammonium chloride solution (100mL, 4M) was added to the reaction solution to adjust the pH to neutral, then water (20mL) was added and extracted with dichloromethane (10mL×3), and the combined organic phase was washed with anhydrous sulfuric acid Sodium was dried and filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:0 ~ 5:1) to obtain compound A-5 (1.80g, yield: 84.68 %).

¹H NMR(400MHz,CDCl ₃)δ8.35(d,J＝2.4Hz,1H),7.26(ddd,J＝9.1,8.0,2.6Hz,1H),4.72(d,J＝2.1Hz,2H). ¹ H NMR (400MHz, CDCl ₃ ) δ8.35 (d, J = 2.4Hz, 1H), 7.26 (ddd, J = 9.1, 8.0, 2.6Hz, 1H), 4.72 (d, J = 2.1Hz, 2H) .

化合物A的合成Synthesis of Compound A

第一步：化合物A-2的合成The first step: the synthesis of compound A-2

在-78℃，将双(三甲基硅基)胺基锂的四氢呋喃溶液(141mL,141mmol)慢慢加入到化合物A-1(20g,141mmol)的四氢呋喃(500mL)溶液中，反应液在-78℃搅拌1小时后再慢慢滴加乙酰氯(6.6g,844mmol)，得到的混合物在-78℃继续搅拌1小时。反应结束后，反应液缓慢倒入饱和氯化铵水溶液中(500mL),用乙酸乙酯萃取(300mL×3)。合并的有机相用饱和食盐水洗涤(300mL×2)，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物用柱层析(石油醚:乙酸乙酯＝1:0～2:1)纯化得到化合物A-2(6.6g,收率：30％)。At -78°C, a tetrahydrofuran solution (141mL, 141mmol) of bis(trimethylsilyl)amide lithium was slowly added to a solution of compound A-1 (20g, 141mmol) in tetrahydrofuran (500mL), and the reaction solution was in- After stirring at 78°C for 1 hour, acetyl chloride (6.6 g, 844 mmol) was slowly added dropwise, and the resulting mixture was stirred at -78°C for 1 hour. After the reaction, the reaction solution was slowly poured into a saturated aqueous ammonium chloride solution (500 mL), and extracted with ethyl acetate (300 mL×3). The combined organic phases were washed with saturated brine (300mL×2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to column chromatography (petroleum ether:ethyl acetate=1:0～2: 1) Purification to obtain compound A-2 (6.6 g, yield: 30%).

MS m/z(ESI):185.1[M+1] ⁺。 MS m/z (ESI): 185.1 [M+1] ⁺ .

第二步：化合物A-4的合成The second step: the synthesis of compound A-4

将化合物A-2(8.98g,48.7mmol)和化合物A-3(4.63g,32.5mmol)的1,4-二氧六环(150mL)溶液加热至90℃并搅拌3.5小时。反应液自然冷却至室温后，加入甲磺酸(3.12g,32.5mmol)，然后反应加热至50℃继续搅拌3小时。反应结束后，反应混合液自然冷却到室温并过滤，滤饼收集后干燥得到化合物A-4(5.60g，收率：69％)。A solution of compound A-2 (8.98 g, 48.7 mmol) and compound A-3 (4.63 g, 32.5 mmol) in 1,4-dioxane (150 mL) was heated to 90° C. and stirred for 3.5 hours. After the reaction solution was naturally cooled to room temperature, methanesulfonic acid (3.12 g, 32.5 mmol) was added, and then the reaction was heated to 50° C. and stirred for 3 hours. After the reaction, the reaction mixture was naturally cooled to room temperature and filtered, and the filter cake was collected and dried to obtain compound A-4 (5.60 g, yield: 69%).

MS m/z(ESI):251.0[M+1] ⁺。 MS m/z (ESI): 251.0 [M+1] ⁺ .

第三步：化合物A-6的合成The third step: the synthesis of compound A-6

将化合物A-5(4.01g,24.6mmol)加到化合物A-4(5.60g,22.3mmol)，碳酸钾(7.69g,55.7mmol)和18-冠-6(1.18g,4.4mmol)的N,N-二甲基甲酰胺(80mL)混合液中，反应在室温搅拌16小时。反应结束后，反应液倒入水中(100mL),用乙酸乙酯萃取(80mL×3)。合并的有机相用食盐水洗涤(20mL×3)，无水硫酸钠干燥并过滤，过滤液减压浓缩得到化合物A-6(8.40g,收率80％)粗品，该粗品直接用于下一步反应。Compound A-5 (4.01g, 24.6mmol) was added to the N , N-dimethylformamide (80 mL) mixture, the reaction was stirred at room temperature for 16 hours. After the reaction, the reaction solution was poured into water (100 mL), and extracted with ethyl acetate (80 mL×3). The combined organic phases were washed with brine (20mL×3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound A-6 (8.40g, yield 80%), which was directly used in the next step reaction.

MS m/z(ESI):378.0[M+1] ⁺。 MS m/z (ESI): 378.0 [M+1] ⁺ .

第四步：化合物A-8的合成The fourth step: the synthesis of compound A-8

将双三苯基膦二氯化钯(1.56g,2.22mmol)加到化合物A-6(8.4g,22.2mmol)和三丁基 (1-乙氧基乙烯)锡(化合物A-7)(10.21g,24.2mmol)的1,4-二氧六环(100mL)溶液中，反应液加热到130℃并搅拌4小时。然后反应液过滤，滤液直接减压浓缩，残余物中加入四氢呋喃(100mL)溶解，再滴入5mL浓盐酸并搅拌1小时。反应结束后，反应液减压浓缩，所得残余物经柱层析(乙酸乙酯)纯化得到化合物A-8(5g,收率：60％)。Bistriphenylphosphine palladium dichloride (1.56 g, 2.22 mmol) was added to compound A-6 (8.4 g, 22.2 mmol) and tributyl(1-ethoxyethylene) tin (compound A-7) ( 10.21g, 24.2mmol) in 1,4-dioxane (100mL) solution, the reaction solution was heated to 130°C and stirred for 4 hours. Then the reaction solution was filtered, and the filtrate was directly concentrated under reduced pressure. The residue was dissolved by adding tetrahydrofuran (100 mL), and then 5 mL of concentrated hydrochloric acid was added dropwise and stirred for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate) to obtain compound A-8 (5 g, yield: 60%).

MS m/z(ESI):386.0[M+1] ⁺。 MS m/z (ESI): 386.0 [M+1] ⁺ .

第五步：化合物A-9的合成The fifth step: the synthesis of compound A-9

将醋酸(2mL)滴加到化合物A-8(5g,13mmol)和N-氯代丁二酰亚胺(1.90g,14.3mmol)的异丙醇(100mL)溶液中，反应在60℃条件下搅拌16小时。反应结束后，反应液减压浓缩，所得残余物用柱层析(乙酸乙酯)纯化得到化合物A-9(3.60g,收率：70％)。Acetic acid (2mL) was added dropwise to a solution of compound A-8 (5g, 13mmol) and N-chlorosuccinimide (1.90g, 14.3mmol) in isopropanol (100mL), reacted at 60°C Stir for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate) to obtain compound A-9 (3.60 g, yield: 70%).

MS m/z(ESI):420.0[M+1] ⁺。 MS m/z (ESI): 420.0 [M+1] ⁺ .

第六步：化合物A的合成Step 6: Synthesis of Compound A

将N，N-二甲基甲酰胺二甲基缩醛(0.85g,7.2mmol)加入到化合物A-9(1.30g,3.1mmol)的N，N-二甲基甲酰胺(15mL)溶液中，反应混合物在100℃条件下搅拌3小时。反应结束后，反应混合液倒入水中(50mL),用乙酸乙酯萃取(30mL×3)。合并的有机相用饱和食盐水洗涤(30mL×3)，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物用柱层析(二氯甲烷:甲醇＝1:0～50:1)纯化得到化合物A(900mg,收率：78％)。N,N-Dimethylformamide dimethyl acetal (0.85g, 7.2mmol) was added to a solution of compound A-9 (1.30g, 3.1mmol) in N,N-dimethylformamide (15mL) , and the reaction mixture was stirred at 100° C. for 3 hours. After the reaction, the reaction mixture was poured into water (50 mL), and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with saturated brine (30mL×3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to column chromatography (dichloromethane:methanol=1:0～50:1 ) was purified to obtain compound A (900 mg, yield: 78%).

MS m/z(ESI):474.9[M+H] ⁺。 MS m/z (ESI): 474.9 [M+H] ⁺ .

中间体化合物B的合成：Synthesis of Intermediate Compound B:

第一步：化合物B-2的合成The first step: the synthesis of compound B-2

将叠氮磷酸二苯酯(23.5g,0.085mol)加入到化合物B-1(10g,0.057mol)和三乙胺(17.3 g,0.17mol)的叔丁醇/甲苯(50mL/50mL)的混合溶液中，反应混合物在110℃进行16小时。反应结束后，将反应液倒入水中，用二氯甲烷(200mL×3)萃取。合并的有机相用水(30mL)洗涤，无水硫酸钠干燥并过滤，过滤液减压浓缩除去溶剂，所得残余物通过硅胶柱层析(石油醚:乙酸乙酯＝1:0～10:1)纯化得到化合物B-2(3.6g，收率：25％)。Diphenylphosphoryl azide (23.5 g, 0.085 mol) was added to a mixture of compound B-1 (10 g, 0.057 mol) and triethylamine (17.3 g, 0.17 mol) in tert-butanol/toluene (50 mL/50 mL) In solution, the reaction mixture was carried out at 110°C for 16 hours. After the reaction, the reaction solution was poured into water and extracted with dichloromethane (200 mL×3). The combined organic phases were washed with water (30 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the resulting residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate=1:0～10:1) Purification gave compound B-2 (3.6 g, yield: 25%).

MS m/z(ESI):247.0[M+1] ⁺。 MS m/z (ESI): 247.0 [M+1] ⁺ .

第二步：化合物B-3的合成The second step: the synthesis of compound B-3

将化合物B-2(3.6g,14.5mol)加入到三氟乙酸/二氯甲烷(15mL/30mL)的混合溶液中，反应混合物在室温下搅拌16小时。反应结束后，反应液减压浓缩除去溶剂，所得残余物经柱层析(二氯甲烷:甲醇＝1:0～20:1)纯化得到化合物B-3粗品(3.1g)。Compound B-2 (3.6 g, 14.5 mol) was added to a mixed solution of trifluoroacetic acid/dichloromethane (15 mL/30 mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by column chromatography (dichloromethane:methanol=1:0~20:1) to obtain crude compound B-3 (3.1 g).

MS m/z(ESI):147.0[M+1] ⁺。 MS m/z (ESI): 147.0 [M+1] ⁺ .

第三步：化合物B-4的合成The third step: the synthesis of compound B-4

将硫酸银(6.61g,0.02mol)和碘(5.38g,0.02mol)加入到化合物B-3(3.1g,0.02mol)的乙醇(50mL)溶液中，反应混合物在50℃条件下搅拌16小时。反应结束后，反应液减压浓缩除去溶剂，得到的残余物通过硅胶柱层析(二氯甲烷:甲醇＝1:0～10:1)纯化得到化合物B-4(4.9g,收率：65％)。MS m/z(ESI):272.7[M+1] ⁺。 Silver sulfate (6.61g, 0.02mol) and iodine (5.38g, 0.02mol) were added to a solution of compound B-3 (3.1g, 0.02mol) in ethanol (50mL), and the reaction mixture was stirred at 50°C for 16 hours . After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography (dichloromethane:methanol=1:0～10:1) to obtain compound B-4 (4.9g, yield: 65 %). MS m/z (ESI): 272.7 [M+1] ⁺ .

第四步：化合物B-6的合成The fourth step: the synthesis of compound B-6

在氮气保护下，将甲基硼酸(530mg,8.8mmol)，碳酸铯(8.96g,27.5mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(450mg,0.55mmol)依次加入到化合物B-4(1.5g,5.5mmol)的1，4-二氧六环(30mL)溶液中，反应混合物在100℃进行1.5小时。反应结束后，向反应液中加入碳酸氢钠水溶液进行稀释，用乙酸乙酯(50mL×3)萃取，合并的有机相用饱和食盐水洗一次，无水硫酸钠干燥并过滤，过滤液减压浓缩除去溶剂，所得残余物通过硅胶柱层析法(石油醚:乙酸乙酯＝2:3)纯化得到化合物B-6(0.43g,收率：48％)。Under nitrogen protection, methylboronic acid (530mg, 8.8mmol), cesium carbonate (8.96g, 27.5mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (450mg , 0.55mmol) were sequentially added to a solution of compound B-4 (1.5g, 5.5mmol) in 1,4-dioxane (30mL), and the reaction mixture was carried out at 100°C for 1.5 hours. After the reaction, add aqueous sodium bicarbonate solution to the reaction solution for dilution, extract with ethyl acetate (50mL×3), wash the combined organic phase once with saturated brine, dry over anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure The solvent was removed, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:3) to obtain compound B-6 (0.43 g, yield: 48%).

MS m/z(ESI):161.0[M+1] ⁺。 MS m/z (ESI): 161.0 [M+1] ⁺ .

第五步：化合物B-7的合成The fifth step: the synthesis of compound B-7

将化合物B-6(1.20g,6.88mmol)加入到化合物A-2(850mg,5.29mmol)的无水1，4-二氧六环(8mL)溶液中，反应加热到110℃并在该温度下搅拌1小时。反应液自然降温至50℃后，加入甲基磺酸(285mg,2.96mmol)，然后反应在50℃继续进行1小时。反应结束后，向反应液中加入水(50mL)进行稀释，用乙酸乙酯萃取(100mL×3)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥并过滤，过滤液通过减压浓缩除去溶剂，所得残余物通过硅胶柱层析(二氯甲烷)纯化得到化合物B-7(530mg,收率：66％)。Compound B-6 (1.20g, 6.88mmol) was added to compound A-2 (850mg, 5.29mmol) in anhydrous 1,4-dioxane (8mL) solution, the reaction was heated to 110°C and at this temperature Stir for 1 hour. After the reaction solution was naturally cooled to 50°C, methanesulfonic acid (285mg, 2.96mmol) was added, and the reaction was continued at 50°C for 1 hour. After the reaction, water (50 mL) was added to the reaction solution for dilution, and extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography (dichloromethane) to obtain compound B-7 (530 mg, harvested rate: 66%).

MS m/z(ESI):269.0[M+1] ⁺。 MS m/z (ESI): 269.0 [M+1] ⁺ .

第六步：化合物B-8的合成Step 6: Synthesis of Compound B-8

将碳酸钾(1.14g,8.28mmol)，18-冠-6(175mg,0.66mmol)加入到化合物A-5(702mg,4.30mmol)和化合物B-7(890mg,3.31mmol)的N,N-二甲基甲酰胺(15mL)溶液中，反应加热到40℃并在该温度下搅拌16小时。反应结束后，反应液冷却至室温，加入水(50mL)进行稀释，用乙酸乙酯(50mL×3)萃取，合并的有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥并过滤，过滤液通过减压浓缩得到化合物B-8(1.5g,纯度：84％,收率：96％)粗品，该粗品直接用于下一步反应。Potassium carbonate (1.14g, 8.28mmol), 18-crown-6 (175mg, 0.66mmol) was added to the N,N- In dimethylformamide (15 mL), the reaction was heated to 40°C and stirred at this temperature for 16 hours. After the reaction, the reaction solution was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (50 mL×3), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude compound B-8 (1.5 g, purity: 84%, yield: 96%), which was directly used in the next reaction.

MS m/z(ESI):395.8[M+1] ⁺。 MS m/z (ESI): 395.8 [M+1] ⁺ .

第七步:化合物B-9的合成The seventh step: the synthesis of compound B-9

将化合物A-7(2.01g,5.55mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(257mg,0.37mmol)加入到化合物B-8(1.45g,3.70mmol)的1，4-二氧六环(20mL)溶液中，反应在130℃搅拌1.5小时。反应结束后，反应液直接减压浓缩得到化合物B-9(3.90g)粗品，该粗品直接用于下一步。Compound A-7 (2.01g, 5.55mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (257mg, 0.37mmol) was added to compound B-8 (1.45g , 3.70 mmol) in 1,4-dioxane (20 mL), the reaction was stirred at 130°C for 1.5 hours. After the reaction, the reaction solution was directly concentrated under reduced pressure to obtain a crude compound B-9 (3.90 g), which was directly used in the next step.

MS m/z(ESI):431.9[M+1] ⁺。 MS m/z (ESI): 431.9 [M+1] ⁺ .

第八步:化合物B-10的合成The eighth step: the synthesis of compound B-10

将化合物B-9(1.45g,3.40mmol)加入到四氢呋喃(15mL)和浓盐酸(0.50mL)溶液中，反应在室温搅拌1小时。反应结束后，将反应液减压浓缩除去溶剂，所得残余物通过硅胶柱层析(石油醚:乙酸乙酯＝3:2)纯化得到B-10(910mg,收率：66％)。Compound B-9 (1.45 g, 3.40 mmol) was added to a solution of tetrahydrofuran (15 mL) and concentrated hydrochloric acid (0.50 mL), and the reaction was stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:2) to obtain B-10 (910 mg, yield: 66%).

MS m/z(ESI):403.9[M+1] ⁺。 MS m/z (ESI): 403.9 [M+1] ⁺ .

第九步：化合物B-11的合成Step 9: Synthesis of compound B-11

将N-氯代丁二酰亚胺(330mg,2.48mmol)和冰醋酸(0.20mL)依次加入到化合物B-10(910mg,2.25mmol)的异丙醇(12mL)溶液中，反应在60℃搅拌3小时。反应结束后，反应液减压浓缩除去溶剂，所得残余物通过硅胶柱层析法(乙酸乙酯)纯化得到化合物B-11(1.13g)。N-chlorosuccinimide (330mg, 2.48mmol) and glacial acetic acid (0.20mL) were successively added to a solution of compound B-10 (910mg, 2.25mmol) in isopropanol (12mL) and reacted at 60°C Stir for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain Compound B-11 (1.13 g).

MS m/z(ESI):437.8[M+1] ⁺。 MS m/z (ESI): 437.8 [M+1] ⁺ .

第十步：化合物B的合成Step 10: Synthesis of Compound B

将N,N-二甲基甲酰胺二甲基缩醛(600mg,5.0mmol)加入到化合物B-11(1.08g,2.5mmol)的N,N-二甲基甲酰胺(15mL)溶液中，反应在100℃条件下搅拌3小时。反应结束后，反应液自然冷却至室温，加入水(50mL)稀释，用乙酸乙酯(50mL×3)萃取。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥并过滤，过滤液减压浓缩除去溶剂，得到的残余物通过硅胶柱层析(石油醚:乙酸乙酯＝2:1)纯化得到化合物B(900mg,收率：72％)。N,N-dimethylformamide dimethyl acetal (600mg, 5.0mmol) was added to a solution of compound B-11 (1.08g, 2.5mmol) in N,N-dimethylformamide (15mL), The reaction was stirred at 100°C for 3 hours. After the reaction, the reaction solution was naturally cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=2:1) to obtain the compound B (900 mg, yield: 72%).

MS m/z(ESI):492.7[M+1] ⁺。 MS m/z (ESI): 492.7 [M+1] ⁺ .

实施例1化合物2，2-P1和2-P2的合成The synthesis of embodiment 1 compound 2,2-P1 and 2-P2

第一步：化合物2-3的合成The first step: the synthesis of compound 2-3

将化合物2-1(300mg,2.42mmol)，化合物2-2(753mg,2.42mmol)和N,N-二异丙基乙胺(627mg,4.85mmol)溶于乙腈(15mL)中，室温搅拌12小时。反应完成后，反应液减压浓缩，所得残余物经硅胶柱层析(石油醚:乙酸乙酯＝1:0～4:1)纯化得到化合物2-3(620mg,收率：77.3％)。Compound 2-1 (300mg, 2.42mmol), compound 2-2 (753mg, 2.42mmol) and N,N-diisopropylethylamine (627mg, 4.85mmol) were dissolved in acetonitrile (15mL), stirred at room temperature for 12 Hour. After the reaction was completed, the reaction liquid was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-4:1) to obtain compound 2-3 (620 mg, yield: 77.3%).

MS m/z(ESI):330.0[M+1] ⁺。 MS m/z (ESI): 330.0 [M+1] ⁺ .

第二步：化合物2-4的合成The second step: the synthesis of compound 2-4

室温下，将氯化氢的1,4-二氧六环溶液(1.9mL,4M)缓慢加入化合物2-3(500mg,1.52mmol)的二氯甲烷(10mL)中，室温反应12小时。反应结束后，减压浓缩除去溶剂，得到化合物2-4(200mg,粗品)。该粗品直接进行下一步反应。MS m/z(ESI):130.1[M+1] ⁺。 At room temperature, hydrogen chloride solution in 1,4-dioxane (1.9 mL, 4M) was slowly added to compound 2-3 (500 mg, 1.52 mmol) in dichloromethane (10 mL), and reacted at room temperature for 12 hours. After the reaction, the solvent was concentrated under reduced pressure to obtain compound 2-4 (200 mg, crude product). The crude product was directly subjected to the next reaction. MS m/z (ESI): 130.1 [M+1] ⁺ .

第三步：化合物2的合成The third step: the synthesis of compound 2

将化合物A(100mg,0.21mmol)，化合物2-4(70mg,0.42mmol)和碳酸钾(87mg,0.63mmol)溶于N,N-二甲基甲酰胺(10mL)中，反应混合物加热至90℃搅拌16小时。反应结束后，加水(30mL)稀释，乙酸乙酯萃取(20mL×3)。合并有机相，用饱和食盐水洗涤(20mL×2)，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物经高效液相制备色谱(色谱柱：Gemini-C18,150×21.2mm，5μm；流动相：乙腈-水(0.1％甲酸)；梯度：30-70％；柱温：25℃；流速：14mL/min；波长：214nm；柱压：80bar)纯化得到化合物2(40mg,收率35.0％)。Compound A (100mg, 0.21mmol), compound 2-4 (70mg, 0.42mmol) and potassium carbonate (87mg, 0.63mmol) were dissolved in N,N-dimethylformamide (10mL), and the reaction mixture was heated to 90 °C and stirred for 16 hours. After the reaction was completed, it was diluted with water (30 mL), and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (20mL×2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to preparative high performance liquid chromatography (chromatographic column: Gemini-C18, 150×21.2mm , 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-70%; column temperature: 25 ° C; flow rate: 14mL/min; wavelength: 214nm; Yield 35.0%).

MS m/z(ESI):540.8[M+1] ⁺； ¹H NMR(400MHz,CD ₃OD)δ8.84(s,1H),8.48(dd,J＝12.2,4.1Hz,2H),8.41(s,1H),7.83–7.72(m,2H),6.79(s,1H),5.51(d,J＝1.8Hz,2H),4.20–4.11(m,4H),2.17(d,J＝3.7Hz,3H),1.99(s,3H),1.55(s,3H)。 MS m/z (ESI): 540.8[M+1] ⁺ ; ¹ H NMR (400MHz, CD ₃ OD) δ8.84 (s, 1H), 8.48 (dd, J=12.2, 4.1Hz, 2H), 8.41 (s,1H),7.83–7.72(m,2H),6.79(s,1H),5.51(d,J=1.8Hz,2H),4.20–4.11(m,4H),2.17(d,J=3.7 Hz,3H), 1.99(s,3H), 1.55(s,3H).

将化合物A(300mg，0.63mmol)，化合物2-4(314mg，1.89mmol)和碳酸钾(175mg，1.26mmol)溶于N,N-二甲基甲酰胺(10mL)溶液中，反应混合物加热至90℃搅拌16小时。反应结束后，反应液加水(30mL)稀释，乙酸乙酯萃取(20mL×3)。合并的有机相用饱和食盐水洗涤(20mL×2)，无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析 (二氯甲烷/甲醇＝1/0～20/1)纯化得到粗品化合物2，粗品化合物2经超临界流体手性色谱((设备：SFC Thar prep 80,柱子：CHIRALPAK WHELK-01 250mm*21.1mm，5μm，流动相：40％MeOH/CO ₂(NH ₄OH 0.2％)，总流速：40g/min)拆分得到化合物2-P1(29.1mg，收率8.5％)和化合物2-P2(40.2mg，收率11.7％)。 Compound A (300mg, 0.63mmol), compound 2-4 (314mg, 1.89mmol) and potassium carbonate (175mg, 1.26mmol) were dissolved in N,N-dimethylformamide (10mL) solution, and the reaction mixture was heated to Stir at 90°C for 16 hours. After the reaction, the reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated brine (20mL×2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane/methanol=1/0～20/1 ) was purified to obtain crude compound 2, which was subjected to supercritical fluid chiral chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK WHELK-01 250mm*21.1mm, 5 μm, mobile phase: 40% MeOH/CO ₂ (NH ₄ OH 0.2%), total flow rate: 40 g/min) to obtain compound 2-P1 (29.1 mg, yield 8.5%) and compound 2-P2 (40.2 mg, yield 11.7%).

化合物2-P1:Compound 2-P1:

ESI-MS[M+H] ⁺:541.2。SFC：保留时间＝4.84min； ¹H NMR(400MHz,CD ₃OD)δ8.69(s,1H),8.42(d,J＝5.2Hz,1H),8.39(d,J＝2.4Hz,1H),8.30(s,1H),7.61(d,J＝5.2Hz,1H),7.32(ddd,J＝9.0,8.0,2.4Hz,1H),6.33(s,1H),5.38(t,J＝2.2Hz,2H),4.15–4.03(m,4H),2.12(s,3H),1.83(s,3H),1.54(s,3H)。 ESI-MS [M+H] ⁺ : 541.2. SFC: retention time=4.84min; ¹ H NMR (400MHz, CD ₃ OD) δ8.69(s, 1H), 8.42(d, J=5.2Hz, 1H), 8.39(d, J=2.4Hz, 1H) ,8.30(s,1H),7.61(d,J=5.2Hz,1H),7.32(ddd,J=9.0,8.0,2.4Hz,1H),6.33(s,1H),5.38(t,J=2.2 Hz, 2H), 4.15–4.03(m, 4H), 2.12(s, 3H), 1.83(s, 3H), 1.54(s, 3H).

化合物2-P2:Compound 2-P2:

ESI-MS[M+H] ⁺:541.0。SFC：保留时间＝6.79min； ¹H NMR(400MHz,CD ₃OD)δ8.71(s,1H),8.42(d,J＝5.3Hz,1H),8.39(d,J＝2.4Hz,1H),8.24(s,1H),7.62(d,J＝5.3Hz,1H),7.32(ddd,J＝9.0,8.0,2.4Hz,1H),6.35(s,1H),5.39(s,2H),4.12(dt,J＝15.3,6.2Hz,4H),2.14(s,3H),1.87(s,3H),1.55(s,3H)。 ESI-MS [M+H] ⁺ : 541.0. SFC: retention time = 6.79min; ¹ H NMR (400MHz, CD ₃ OD) δ8.71 (s, 1H), 8.42 (d, J = 5.3Hz, 1H), 8.39 (d, J = 2.4Hz, 1H) ,8.24(s,1H),7.62(d,J=5.3Hz,1H),7.32(ddd,J=9.0,8.0,2.4Hz,1H),6.35(s,1H),5.39(s,2H), 4.12 (dt, J = 15.3, 6.2 Hz, 4H), 2.14 (s, 3H), 1.87 (s, 3H), 1.55 (s, 3H).

实施例2化合物6的合成The synthesis of embodiment 2 compound 6

第一步：化合物6-2的合成The first step: the synthesis of compound 6-2

将S-甲基异硫脲硫酸盐(799mg,4.25mol)加入化合物6-1(500mg,5.74mol)的水溶液(5mL)中,反应混合物在90℃下搅拌1小时。反应结束后，将反应混合物减压浓缩，残余物经乙醇洗涤后得到化合物6-2(900mg,收率：92.80％)。S-methylisothiourea sulfate (799 mg, 4.25 mol) was added to an aqueous solution (5 mL) of compound 6-1 (500 mg, 5.74 mol), and the reaction mixture was stirred at 90°C for 1 hour. After the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was washed with ethanol to obtain compound 6-2 (900 mg, yield: 92.80%).

MS m/z(ESI)：130.2[M+1] ⁺。 MS m/z (ESI): 130.2 [M+1] ⁺ .

第二步：化合物6的合成The second step: the synthesis of compound 6

将化合物6-2(383mg,1.68mmol)和碳酸钾(233mg,1.68mmol)加入化合物A(200mg,0.42mmol)的N，N-二甲基甲酰胺(5mL)溶液中，反应混合物在60℃下搅拌16小时。反应结束后，加水(50mL)稀释，用乙酸乙酯(50mL×3)萃取。合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经过高效液相制备色谱(色谱柱：Gemini-C18，150×21.2mm，5μm；流动相：乙腈-水(0.1％甲酸)；梯度：25-50％；柱温：25℃；流速：14mL/min；波长：214nm；柱压：80bar)纯化得到化合物6(60mg，收率：26.3％)。Compound 6-2 (383mg, 1.68mmol) and potassium carbonate (233mg, 1.68mmol) were added to compound A (200mg, 0.42mmol) in N,N-dimethylformamide (5mL) solution, and the reaction mixture was heated at 60°C Stirring was continued for 16 hours. After the reaction was completed, it was diluted with water (50 mL), and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to preparative high performance liquid chromatography (column: Gemini-C18, 150×21.2 mm, 5 μm; Mobile phase: acetonitrile-water (0.1% formic acid); Gradient: 25-50%; Column temperature: 25°C; Flow rate: 14mL/min; Wavelength: 214nm; Column pressure: 80bar) Compound 6 (60mg, yield: 26.3%).

MS m/z(ESI)：541.2[M+1] ⁺； ¹H NMR(400MHz,DMSO-d6)：δ8.80(s,1H),8.61(d,J＝2.3Hz,1H),8.52(d,J＝5.0Hz,1H),8.28(s,1H),8.14-8.06(m,1H),7.51(d,J＝5.0Hz,1H),6.83(s, 1H),5.49(d,J＝1.2Hz,2H),5.05-4.82(m,1H),4.50-4.25(m,1H),3.82-3.45(m,4H),2.10-1.85(m,8H)。 MS m/z (ESI): 541.2[M+1] ⁺ ; ¹ H NMR (400MHz, DMSO-d6): δ8.80(s, 1H), 8.61(d, J=2.3Hz, 1H), 8.52( d,J=5.0Hz,1H),8.28(s,1H),8.14-8.06(m,1H),7.51(d,J=5.0Hz,1H),6.83(s,1H),5.49(d,J =1.2Hz, 2H), 5.05-4.82(m, 1H), 4.50-4.25(m, 1H), 3.82-3.45(m, 4H), 2.10-1.85(m, 8H).

实施例3化合物10的合成The synthesis of embodiment 3 compound 10

将碳酸钾(87.32mg,0.63mmol)，化合物10-2(54.4mg,0.42mmol)加入到化合物A(100mg,0.21mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应混合物在90℃下搅拌反应12小时。反应结束后，加水(50mL)稀释，乙酸乙酯萃取(50mL×3)，合并有机相，用饱和食盐水洗(50mL×3)，无水硫酸钠干燥，减压浓缩除去溶剂，残余物经高效液相制备色谱(色谱柱：Xbridge-C18；150×21.2mm，5μm；柱温：25℃；流速：20mL/min；波长：214nm；柱压：80bar；流动项：乙腈-水(0.1％甲酸)；梯度：40-60％)纯化得到化合物10(30.5mg,收率：25.4％)。Potassium carbonate (87.32mg, 0.63mmol), compound 10-2 (54.4mg, 0.42mmol) was added to compound A (100mg, 0.21mmol) in N,N-dimethylformamide (10mL) solution, the reaction mixture The reaction was stirred at 90°C for 12 hours. After the reaction, dilute with water (50mL), extract with ethyl acetate (50mL×3), combine the organic phases, wash with saturated brine (50mL×3), dry over anhydrous sodium sulfate, concentrate under reduced pressure to remove the solvent, and the residue is subjected to high-efficiency Preparative liquid chromatography (column: Xbridge-C18; 150×21.2mm, 5 μm; column temperature: 25°C; flow rate: 20mL/min; wavelength: 214nm; column pressure: 80bar; flow item: acetonitrile-water (0.1% formic acid ); gradient: 40-60%) was purified to obtain compound 10 (30.5 mg, yield: 25.4%).

MS m/z(ESI)：540.8[M+1] ⁺； ¹H NMR(400MHz,CD ₃OD)：δ8.74(s,1H),8.48(d,J＝5.1Hz,1H),8.44(d,J＝2.3Hz,1H),8.25(s,1H),7.75-7.68(m,1H),7.58(d,J＝5.1Hz,1H),6.80(s,1H),5.48(d,J＝1.5Hz,2H),3.85-3.78(m,4H),3.76-3.68(m,4H),2.13(s,3H),2.03(s,3H)。 MS m/z (ESI): 540.8[M+1] ⁺ ; ¹ H NMR (400MHz, CD ₃ OD): δ8.74(s, 1H), 8.48(d, J=5.1Hz, 1H), 8.44( d,J=2.3Hz,1H),8.25(s,1H),7.75-7.68(m,1H),7.58(d,J=5.1Hz,1H),6.80(s,1H),5.48(d,J =1.5Hz, 2H), 3.85-3.78(m, 4H), 3.76-3.68(m, 4H), 2.13(s, 3H), 2.03(s, 3H).

实施例4化合物11的合成The synthesis of embodiment 4 compound 11

第一步：化合物11-2的合成The first step: the synthesis of compound 11-2

将化合物11-1(1g,9.90mmol)，S-甲基异硫脲硫酸盐(0.93g,4.95mmol)，溶于水(15mL)中，反应混合物于90℃下搅拌1小时。加入乙醇(20mL)搅拌30分钟，过滤，滤饼干燥得化合物11-2(0.88g，收率：74.1％)。Compound 11-1 (1 g, 9.90 mmol), S-methylisothiourea sulfate (0.93 g, 4.95 mmol), was dissolved in water (15 mL), and the reaction mixture was stirred at 90° C. for 1 hour. Add ethanol (20 mL) and stir for 30 minutes, filter, and dry the filter cake to obtain compound 11-2 (0.88 g, yield: 74.1%).

MS m/z(ESI):144.1[M+H] ⁺。 MS m/z (ESI): 144.1 [M+H] ⁺ .

第二步：化合物11的合成The second step: the synthesis of compound 11

将化合物A(119mg,0.25mmol)，化合物11-2(200mg,1.40mmol)，碳酸钾(116mg,0.84mmol)溶于N,N-二甲基甲酰胺(5mL)溶液中，90℃搅拌12小时反应结束后，加入水(10mL)，用乙酸乙酯萃取(20mL×3)，合并有机相，饱和食盐水(30mL)洗涤，无水硫酸钠干燥并过滤，滤液减压浓缩后经硅胶柱层析(二氯甲烷:甲醇＝1:0～10:1)纯化得到粗品，粗品经高效液相制备色谱(色谱柱：Gemini-C18；150×21.2mm，5μm；流动相：乙腈-水(0.1％甲酸)；梯度：30-70％；柱温：25℃；流速：20mL/min；波长：214nm；柱压：80bar)纯化得化合物11(37mg,收率：26.7％)。Compound A (119mg, 0.25mmol), compound 11-2 (200mg, 1.40mmol), potassium carbonate (116mg, 0.84mmol) were dissolved in N,N-dimethylformamide (5mL) solution, stirred at 90°C for 12 After 1 hour of reaction, add water (10mL), extract with ethyl acetate (20mL×3), combine the organic phases, wash with saturated brine (30mL), dry over anhydrous sodium sulfate and filter, and the filtrate is concentrated under reduced pressure and passed through a silica gel column. Chromatography (dichloromethane:methanol=1:0～10:1) was purified to obtain the crude product, and the crude product was subjected to preparative high performance liquid chromatography (chromatographic column: Gemini-C18; 150×21.2mm, 5 μm; mobile phase: acetonitrile-water ( 0.1% formic acid); gradient: 30-70%; column temperature: 25°C; flow rate: 20mL/min; wavelength: 214nm; column pressure: 80bar) to obtain compound 11 (37mg, yield: 26.7%).

MS m/z(ESI):555.2[M+1] ⁺； ¹H NMR(400MHz,CD ₃OD)δ8.78(s,1H),8.49–8.46(m,2H),8.29(s,1H),7.78–7.72(m,1H),7.56(d,J＝5.1Hz,1H),6.84(s,1H),5.53(d,J＝1.9Hz,2H),4.54(d,J＝13.7Hz,2H),3.93–3.84(m,1H),3.36(s,1H),3.31(s,1H),2.17(s,3H),2.07(s,3H),1.98–1.90(m,2H),1.50(d,J＝10.7Hz,2H)。 MS m/z (ESI): 555.2[M+1] ⁺ ; ¹ H NMR (400MHz, CD ₃ OD) δ8.78 (s, 1H), 8.49–8.46 (m, 2H), 8.29 (s, 1H) ,7.78–7.72(m,1H),7.56(d,J=5.1Hz,1H),6.84(s,1H),5.53(d,J=1.9Hz,2H),4.54(d,J=13.7Hz, 2H),3.93–3.84(m,1H),3.36(s,1H),3.31(s,1H),2.17(s,3H),2.07(s,3H),1.98–1.90(m,2H),1.50 (d, J=10.7Hz, 2H).

实施例5化合物12、12-P1和12-P2的合成The synthesis of embodiment 5 compound 12, 12-P1 and 12-P2

第一步：化合物12-2的合成The first step: the synthesis of compound 12-2

室温下，将S-甲基异硫脲硫酸盐(351mg,1.86mmol)加入化合物12-1(430mg,3.73mmol)的水溶液(5.0mL)中。反应混合物在90℃下搅拌1小时。反应混合物减压浓缩，得到化合物12-2(600mg,粗品)。产物不经纯化直接进行下一步反应。S-methylisothiourea sulfate (351 mg, 1.86 mmol) was added to an aqueous solution (5.0 mL) of compound 12-1 (430 mg, 3.73 mmol) at room temperature. The reaction mixture was stirred at 90°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain compound 12-2 (600 mg, crude product). The product was directly subjected to the next reaction without purification.

MS m/z(ESI):158.1[M+1] ⁺。 MS m/z (ESI): 158.1 [M+1] ⁺ .

第二步：化合物12-P1和12-P2的合成The second step: the synthesis of compounds 12-P1 and 12-P2

将化合物12-2(559mg,2.19mmol)，化合物A(260mg,0.55mmol)和碳酸钾(302mg,2.19mmol)的N,N-二甲基甲酰胺(15mL)溶液加热至60℃，反应12小时。反应混合物加水(20mL)稀释，乙酸乙酯萃取(20mL×3)。合并有机相，用饱和食盐水洗涤(20mL×3)，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物经硅胶柱层析(二氯甲烷:甲醇＝1:0～10:1)纯化得到含量为80％的粗品。该粗品经高效液相制备色谱(色谱柱：Gemini-C18；150×21.2mm，5μm；流动相：乙腈-水(0.1％甲酸)；梯度：30-60％；柱温：25℃流速：14mL/min；波长：214nm；柱压:80bar)纯化得到化合物12(45mg,收率：14.3％)。Compound 12-2 (559mg, 2.19mmol), compound A (260mg, 0.55mmol) and potassium carbonate (302mg, 2.19mmol) in N,N-dimethylformamide (15mL) was heated to 60°C, reaction 12 Hour. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (20mL×3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (dichloromethane:methanol=1:0～10: 1) purification to obtain a crude product with a content of 80%. The crude product was subjected to preparative high-performance liquid chromatography (chromatographic column: Gemini-C18; 150 × 21.2mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-60%; column temperature: 25 ° C, flow rate: 14 mL /min; wavelength: 214nm; column pressure: 80bar) was purified to obtain compound 12 (45mg, yield: 14.3%).

MS m/z(ESI):569.1[M+H] ⁺； ¹H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.62(d,J＝2.3Hz,1H),8.51(d,J＝5.0Hz,1H),8.28(s,1H),8.14–8.08(m,1H),7.49(d,J＝5.0Hz,1H),6.83(s,1H),5.48(s,2H),4.39(s,1H),4.28(d,J＝12.3Hz,2H),3.50–3.42(m,2H),2.06(s,3H),1.95(s, 3H),1.52–1.43(m,4H),1.15(s,3H)。 MS m/z (ESI): 569.1[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d6) δ8.80(s, 1H), 8.62(d, J=2.3Hz, 1H), 8.51(d ,J=5.0Hz,1H),8.28(s,1H),8.14–8.08(m,1H),7.49(d,J=5.0Hz,1H),6.83(s,1H),5.48(s,2H) ,4.39(s,1H),4.28(d,J＝12.3Hz,2H),3.50–3.42(m,2H),2.06(s,3H),1.95(s,3H),1.52–1.43(m,4H ), 1.15(s,3H).

化合物12经过超临界流体制备色谱(设备：SFC Thar prep 80；柱子：CHIRALPAK AD-H，250mm×20mm，5μm；流动相：40％乙醇(乙醇/二氧化碳，0.2％的氨水)；流速：12.5g/min)拆分得到化合物12-P1(15.4mg)和化合物12-P2(15.8mg)。Compound 12 was subjected to supercritical fluid preparative chromatography (equipment: SFC Thar prep 80; column: CHIRALPAK AD-H, 250mm×20mm, 5 μm; mobile phase: 40% ethanol (ethanol/carbon dioxide, 0.2% ammonia water); flow rate: 12.5g /min) to obtain compound 12-P1 (15.4 mg) and compound 12-P2 (15.8 mg).

化合物12-P1：Compound 12-P1:

MS m/z(ESI):568.8[M+1] ⁺；SFC：保留时间＝3.50min； ¹H NMR(400MHz,CD ₃OD)δ8.73(s,1H),8.43(t,J＝4.1Hz,2H),8.24(s,1H),7.75–7.67(m,1H),7.50(d,J＝5.1Hz,1H),6.79(s,1H),5.48(d,J＝1.8Hz,2H),4.33–4.24(m,2H),3.54(ddd,J＝13.5,10.1,3.8Hz,2H),2.13(s,3H),2.02(s,3H),1.63-1.54(m,4H),1.22(s,3H)。 MS m/z (ESI): 568.8[M+1] ⁺ ; SFC: retention time = 3.50min; ¹ H NMR (400MHz, CD ₃ OD) δ8.73 (s, 1H), 8.43 (t, J = 4.1 Hz, 2H), 8.24(s, 1H), 7.75–7.67(m, 1H), 7.50(d, J=5.1Hz, 1H), 6.79(s, 1H), 5.48(d, J=1.8Hz, 2H ),4.33–4.24(m,2H),3.54(ddd,J＝13.5,10.1,3.8Hz,2H),2.13(s,3H),2.02(s,3H),1.63-1.54(m,4H), 1.22(s,3H).

化合物12-P2：Compound 12-P2:

MS m/z(ESI):568.8[M+1] ⁺；SFC：保留时间＝5.76min； ¹H NMR(400MHz,CD ₃OD)δ8.66(s,1H),8.36(dd,J＝5.2,3.7Hz,2H),8.17(s,1H),7.67–7.59(m,1H),7.43(d,J＝5.1Hz,1H),6.72(s,1H),5.40(d,J＝1.8Hz,2H),4.21(dd,J＝13.5,4.5Hz,2H),3.53–3.43(m,2H),2.05(s,3H),1.95(s,3H),1.56–1.47(m,4H),1.15(s,3H)。 MS m/z (ESI): 568.8[M+1] ⁺ ; SFC: retention time = 5.76min; ¹ H NMR (400MHz, CD ₃ OD) δ8.66 (s, 1H), 8.36 (dd, J = 5.2 ,3.7Hz,2H),8.17(s,1H),7.67–7.59(m,1H),7.43(d,J＝5.1Hz,1H),6.72(s,1H),5.40(d,J＝1.8Hz ,2H),4.21(dd,J＝13.5,4.5Hz,2H),3.53–3.43(m,2H),2.05(s,3H),1.95(s,3H),1.56–1.47(m,4H), 1.15(s,3H).

实施例6化合物13的合成The synthesis of embodiment 6 compound 13

第一步：化合物13-2的合成The first step: the synthesis of compound 13-2

将13-1(1g,7.8mmol)和S-甲基异硫脲硫酸盐(730mg,3.90mmol)的水溶液(50ml)加热至90℃，搅拌1小时。反应液减压浓缩，所得残余物中加入20mL乙醇，搅拌30分钟，过滤，滤饼干燥得化合物13-2(0.5g,收率：36％)。An aqueous solution (50 ml) of 13-1 (1 g, 7.8 mmol) and S-methylisothiourea sulfate (730 mg, 3.90 mmol) was heated to 90° C. and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, 20 mL of ethanol was added to the obtained residue, stirred for 30 minutes, filtered, and the filter cake was dried to obtain compound 13-2 (0.5 g, yield: 36%).

¹H NMR(400MHz,CD ₃OD)δ3.76–3.68(m,4H),3.67–3.52(m,4H),2.15(d,J＝7.8Hz,3H)。 ¹ H NMR (400 MHz, CD ₃ OD) δ 3.76-3.68 (m, 4H), 3.67-3.52 (m, 4H), 2.15 (d, J=7.8 Hz, 3H).

第二步：化合物13的合成The second step: the synthesis of compound 13

将化合物A(100mg,0.21mmol),化合物13-2(72mg,0.42mmol)和碳酸钾(58mg,0.42mmol)的N，N-二甲基甲酰胺(10mL)溶液加热至90℃搅拌12小时。反应混合物加水(50mL)稀释，二氯甲烷萃取(30mL×3)。合并有机相，用饱和食盐水洗涤(20mL×2)，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物经高效液相制备色谱(色谱柱：Gemini-C18，150×21.2mm，5μm；流动相：乙腈-水(0.1％三氟乙酸)；梯度：30-50％，柱温：25℃；流速:14mL/min；波长:214nm；柱压:80bar)纯化得到化合物13(14.9mg,收率：12.2％)。MS m/z(ESI):582.1[M+H] ⁺； ¹H NMR(400MHz,CD ₃OD)δ8.80(s,1H),8.54(d,J＝5.2Hz,1H), 8.49(d,J＝2.4Hz,1H),8.36(s,1H),7.76(ddd,J＝9.6,8.6,2.4Hz,1H),7.67(d,J＝5.2Hz,1H),6.84(s,1H),5.53(d,J＝1.9Hz,2H),4.03–3.96(m,2H),3.96–3.89(m,2H),3.73–3.62(m,4H),2.19(s,3H),2.17(s,3H),2.07(s,3H)。 Compound A (100mg, 0.21mmol), compound 13-2 (72mg, 0.42mmol) and potassium carbonate (58mg, 0.42mmol) in N,N-dimethylformamide (10mL) was heated to 90°C and stirred for 12 hours . The reaction mixture was diluted with water (50 mL), extracted with dichloromethane (30 mL×3). The organic phases were combined, washed with saturated brine (20mL×2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to preparative high performance liquid chromatography (chromatographic column: Gemini-C18, 150×21.2mm , 5 μm; mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); gradient: 30-50%, column temperature: 25 ° C; flow rate: 14mL/min; wavelength: 214nm; column pressure: 80bar) purification to obtain compound 13 ( 14.9 mg, yield: 12.2%). MS m/z (ESI): 582.1[M+H] ⁺ ; ¹ H NMR (400MHz, CD ₃ OD) δ8.80(s, 1H), 8.54(d, J=5.2Hz, 1H), 8.49(d ,J=2.4Hz,1H),8.36(s,1H),7.76(ddd,J=9.6,8.6,2.4Hz,1H),7.67(d,J=5.2Hz,1H),6.84(s,1H) ,5.53(d,J＝1.9Hz,2H),4.03–3.96(m,2H),3.96–3.89(m,2H),3.73–3.62(m,4H),2.19(s,3H),2.17(s ,3H), 2.07(s,3H).

实施例7化合物33、33-P1和33-P2的合成The synthesis of embodiment 7 compound 33, 33-P1 and 33-P2

第一步：化合物33-2的合成The first step: the synthesis of compound 33-2

将化合物33-1(3.60g,23.75mmol)，化合物2-2(7.37g,23.75mmol,)和N,N-二异丙基乙胺(6.14g,47.50mmol)加入到乙腈(50mL)中，室温搅拌12小时。反应完成后，反应液减压浓缩，所得残余物经硅胶柱层析法(石油醚:乙酸乙酯＝1:0～5:1)纯化得到化合物33-2(7.5g,收率：84.8％)。Compound 33-1 (3.60g, 23.75mmol), Compound 2-2 (7.37g, 23.75mmol,) and N,N-diisopropylethylamine (6.14g, 47.50mmol) were added to acetonitrile (50mL) , stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 ~ 5:1) to obtain compound 33-2 (7.5g, yield: 84.8% ).

MS m/z(ESI):358.2[M+1] ⁺。 MS m/z (ESI): 358.2 [M+1] ⁺ .

第二步：化合物33-3的合成The second step: the synthesis of compound 33-3

室温下，将氯化氢的二氧六环溶液(26mL,4M)缓慢加入化合物33-2(7.5g,21mmol)的二氯甲烷(100mL)溶液中，室温搅拌12小时。反应液减压浓缩得化合物33-3(6g,粗品)。产物不经纯化直接进行下一步反应。At room temperature, a solution of hydrogen chloride in dioxane (26 mL, 4M) was slowly added to a solution of compound 33-2 (7.5 g, 21 mmol) in dichloromethane (100 mL), and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain compound 33-3 (6 g, crude product). The product was directly subjected to the next reaction without purification.

MS m/z(ESI):158.1[M+1] ⁺。 MS m/z (ESI): 158.1 [M+1] ⁺ .

第三步：化合物33-4的合成The third step: the synthesis of compound 33-4

将化合物A(500mg,1.05mmol)，化合物33-3(4.07g,粗品)和碳酸钾(1.45g,10.53mmol)的N,N-二甲基甲酰胺(10mL)溶液加热至90℃搅拌16小时。反应液加水(30mL)稀释，乙酸乙酯萃取(20mL×3)。合并有机相，用饱和食盐水洗涤(20mL×2)，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物经硅胶柱层析(二氯甲烷:甲醇＝1:0～20:1)纯化得到化合物33-4(150mg,收率：22.54％)。Compound A (500mg, 1.05mmol), compound 33-3 (4.07g, crude product) and potassium carbonate (1.45g, 10.53mmol) in N,N-dimethylformamide (10mL) solution was heated to 90°C and stirred for 16 Hour. The reaction solution was diluted with water (30 mL), extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (20mL×2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (dichloromethane:methanol=1:0～20: 1) Purified to obtain compound 33-4 (150 mg, yield: 22.54%).

MS m/z(ESI):568.8[M+1] ⁺。 MS m/z (ESI): 568.8 [M+1] ⁺ .

第四步：化合物33的合成The fourth step: the synthesis of compound 33

将化合物33-4(150mg,0.27mmol)和氢氧化锂水合物(37mg,0.81mmol)溶于10mL四氢呋喃和水(V:V＝1:1)混合溶剂中，室温下搅拌反应12小时。反应结束后，向反应液中滴加1M的盐酸至pH＝7。过滤，滤饼干燥得粗品。该粗品经高效液相制备色谱(色谱柱：Gemini-C18；150×21.2mm，5μm；流动相：乙腈-水(0.1％甲酸)；梯度：40-50％；柱温：25℃；流速：20mL/min；波长：214nm；柱压：80bar)纯化得到化合物33(23.2mg，收率：15.5％)。Compound 33-4 (150 mg, 0.27 mmol) and lithium hydroxide hydrate (37 mg, 0.81 mmol) were dissolved in 10 mL of tetrahydrofuran and water (V:V=1:1) mixed solvent, and stirred at room temperature for 12 hours. After the reaction was completed, 1M hydrochloric acid was added dropwise to the reaction liquid until pH=7. Filter and dry the filter cake to obtain the crude product. The crude product was subjected to preparative high-performance liquid chromatography (chromatographic column: Gemini-C18; 150 × 21.2mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-50%; column temperature: 25 ° C; flow rate: 20 mL/min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 33 (23.2 mg, yield: 15.5%).

MS m/z(ESI):554.6[M+1] ⁺； ¹H NMR(400MHz,CD ₃OD)δ8.85(s,1H),8.49(t,J＝4.2Hz,2H),8.41(s,1H),7.84(d,J＝5.8Hz,1H),7.80–7.71(m,1H),6.81(s,1H),5.52(d,J＝1.7Hz,2H),4.50(td,J＝9.1,3.3Hz,2H),4.42(td,J＝8.9,6.0Hz,2H),3.70–3.63(m,1H),2.19(s,3H),2.03(s,3H)。 MS m/z (ESI): 554.6[M+1] ⁺ ; ¹ H NMR (400MHz, CD ₃ OD) δ8.85 (s, 1H), 8.49 (t, J = 4.2Hz, 2H), 8.41 (s ,1H),7.84(d,J=5.8Hz,1H),7.80–7.71(m,1H),6.81(s,1H),5.52(d,J=1.7Hz,2H),4.50(td,J= 9.1, 3.3Hz, 2H), 4.42 (td, J = 8.9, 6.0Hz, 2H), 3.70–3.63 (m, 1H), 2.19 (s, 3H), 2.03 (s, 3H).

取放大批次的化合物33(30mg)经超临界流体手性色谱((设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO ₂(NH ₄OH 0.2％),总流速：40g/min)拆分得到化合物33-P1(12.6mg)和化合物33-P2(10.4mg)。 The amplified batch of compound 33 (30 mg) was subjected to supercritical fluid chiral chromatography ((equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5 μm, mobile phase: 40% EtOH/CO ₂ (NH ₄ OH 0.2%), total flow rate: 40g/min) to obtain compound 33-P1 (12.6mg) and compound 33-P2 (10.4mg).

化合物33-P1：Compound 33-P1:

MS m/z(ESI):554.8[M+1] ⁺。SFC：保留时间＝3.03min；UV＝254nm。 ¹H NMR(400MHz,DMSO-d ₆)δ8.81(s,1H),8.61(d,J＝2.3Hz,1H),8.54(d,J＝5.1Hz,1H),8.23(s,1H),8.14–8.07(m,1H),7.61(d,J＝5.1Hz,1H),6.82(s,1H),5.48(d,J＝1.1Hz,2H),4.31–4.08(m,4H),3.51(s,1H),2.07(s,3H),1.93(s,3H)。 MS m/z (ESI): 554.8 [M+1] ⁺ . SFC: retention time = 3.03 min; UV = 254 nm. ¹ H NMR (400MHz,DMSO-d ₆ )δ8.81(s,1H),8.61(d,J=2.3Hz,1H),8.54(d,J=5.1Hz,1H),8.23(s,1H) ,8.14–8.07(m,1H),7.61(d,J＝5.1Hz,1H),6.82(s,1H),5.48(d,J＝1.1Hz,2H),4.31–4.08(m,4H), 3.51(s,1H), 2.07(s,3H), 1.93(s,3H).

化合物33-P2：Compound 33-P2:

MS m/z(ESI):554.8[M+1] ⁺。SFC：保留时间＝3.57min；UV＝254nm。 ¹H NMR(400MHz,DMSO-d ₆)δ8.81(s,1H),8.61(d,J＝2.3Hz,1H),8.54(d,J＝5.1Hz,1H),8.23(s,1H),8.10(td,J＝9.9,2.3Hz,1H),7.61(d,J＝5.1Hz,1H),6.82(s,1H),5.48(s,2H),4.29–4.15(m,4H),3.50(s,1H),2.07(s,3H),1.95(s,3H)。 MS m/z (ESI): 554.8 [M+1] ⁺ . SFC: retention time = 3.57min; UV = 254nm. ¹ H NMR (400MHz,DMSO-d ₆ )δ8.81(s,1H),8.61(d,J=2.3Hz,1H),8.54(d,J=5.1Hz,1H),8.23(s,1H) ,8.10(td,J=9.9,2.3Hz,1H),7.61(d,J=5.1Hz,1H),6.82(s,1H),5.48(s,2H),4.29–4.15(m,4H), 3.50(s,1H), 2.07(s,3H), 1.95(s,3H).

实施例8化合物35、35-P1和35-P2的合成The synthesis of embodiment 8 compound 35, 35-P1 and 35-P2

路线1：Route 1:

将化合物33(150mg,0.27mmol)，甲胺盐酸盐(109mg,1.35mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(155mg,0.81mmol)，1-羟基苯并***(110mg,0.81mmol)和三乙胺(82mg,0.81mmol)溶于二氯甲烷(20mL)中，反应混合物在室温下搅拌12小时。反应完成后，加水(10mL)稀释，二氯甲烷萃取(20mL×3)。合并有机相，用饱和食盐水洗涤(20mL×2)，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物经硅胶柱层析(二氯甲烷:甲醇＝1:0～20:1)纯化得到粗品，将粗品经高效液相制备色谱(色谱柱:Gemini-C18 150 x 21.2mm，5μm流动项:ACN--H ₂O(0.1％FA)，梯度:20-60，温度：45℃；压力：80bar；波长：214/254nm；流速：20mL/min)纯化得到化合物35(2.7mg,收率：1.74％)。 Compound 33 (150mg, 0.27mmol), methylamine hydrochloride (109mg, 1.35mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (155mg, 0.81mmol ), 1-hydroxybenzotriazole (110mg, 0.81mmol) and triethylamine (82mg, 0.81mmol) were dissolved in dichloromethane (20mL), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, it was diluted with water (10 mL), and extracted with dichloromethane (20 mL×3). The organic phases were combined, washed with saturated brine (20mL×2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (dichloromethane:methanol=1:0～20: 1) The crude product was purified, and the crude product was subjected to preparative high performance liquid chromatography (column: Gemini-C18 150 x 21.2 mm, 5 μm flow item: ACN--H ₂ O (0.1% FA), gradient: 20-60, temperature: 45° C.; pressure: 80 bar; wavelength: 214/254 nm; flow rate: 20 mL/min) to obtain compound 35 (2.7 mg, yield: 1.74%).

MS m/z(ESI):567.7[M+1] ⁺； ¹H NMR(400MHz,CD ₃OD)δ8.79(s,1H),8.50–8.45(m,2H),8.26(s,1H),7.75(s,1H),7.68(d,J＝5.2Hz,1H),6.83(s,1H),5.52(d,J＝1.9Hz,2H),4.34–4.25(m,4H),3.96(s,1H),2.78(s,3H),2.17(s,3H),2.06(s,3H)。 MS m/z (ESI): 567.7[M+1] ⁺ ; ¹ H NMR (400MHz, CD ₃ OD) δ8.79 (s, 1H), 8.50–8.45 (m, 2H), 8.26 (s, 1H) ,7.75(s,1H),7.68(d,J=5.2Hz,1H),6.83(s,1H),5.52(d,J=1.9Hz,2H),4.34–4.25(m,4H),3.96( s,1H), 2.78(s,3H), 2.17(s,3H), 2.06(s,3H).

路线2：Route 2:

第一步：化合物35-2的合成The first step: the synthesis of compound 35-2

将化合物35-1(1.7g,7.9mmol)加入到氯化氢的1,4-二氧六环溶液(10mL,4M)中，反应混合物室温搅拌4小时。反应结束后，反应液减压浓缩得到化合物35-2(1.5g，粗品)。MS m/z(ESI):115.1[M+1] ⁺。 Compound 35-1 (1.7 g, 7.9 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (10 mL, 4M), and the reaction mixture was stirred at room temperature for 4 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain compound 35-2 (1.5 g, crude product). MS m/z (ESI): 115.1 [M+1] ⁺ .

第二步：化合物35-3的合成The second step: the synthesis of compound 35-3

将化合物35-2(1.5g,9.96mmol)加入到化合物2-2(3.4g,10.96mmol)和N,N-二异丙基乙胺(2.57g,19.92mmol)的乙腈(30mL)溶液中，反应混合物室温搅拌12小时。反应结束后，反应液减压浓缩，残余物经硅胶柱层析(石油醚：乙酸乙酯＝1:0～3:1)纯化得到化合物35-3(3g，收率：84.5％)。MS m/z(ESI):357.0.[M+1] ⁺。 Compound 35-2 (1.5g, 9.96mmol) was added to a solution of compound 2-2 (3.4g, 10.96mmol) and N,N-diisopropylethylamine (2.57g, 19.92mmol) in acetonitrile (30mL) , and the reaction mixture was stirred at room temperature for 12 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-3:1) to obtain compound 35-3 (3 g, yield: 84.5%). MS m/z (ESI): 357.0.[M+1] ⁺ .

第三步：化合物35-4的合成The third step: the synthesis of compound 35-4

将化合物35-3(500mg,1.40mmol)加入到氯化氢的1,4-二氧六环溶液(10mL,4M)中，反应混合物室温搅拌16小时。反应结束后，反应液减压浓缩得到化合物35-4(300mg，粗品)。MS m/z(ESI):157.1[M+1] ⁺。 Compound 35-3 (500 mg, 1.40 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (10 mL, 4M), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain compound 35-4 (300 mg, crude product). MS m/z (ESI): 157.1 [M+1] ⁺ .

第四步：化合物35的合成The fourth step: the synthesis of compound 35

将化合物35-4(300mg,1.92mmol)加入到化合物A(182.43mg,0.38mmol)和碳酸钾 (530.94mg，3.84mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应混合物在90℃下搅拌12小时，反应结束后，反应液加水(20mL)稀释，用乙酸乙酯萃取(30mL×3)，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩后经硅胶柱层析(二氯甲烷：甲醇＝1:0～10:1)纯化得到化合物35，化合物35通过超临界流体手性色谱(设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO ₂(NH ₄OH 0.2％),总流速：40g/min)拆分得到化合物35-P1(48.6mg，收率4.5％)和化合物35-P2(59.8mg，收率5.5％)。 Compound 35-4 (300mg, 1.92mmol) was added to compound A (182.43mg, 0.38mmol) and potassium carbonate (530.94mg, 3.84mmol) in N,N-dimethylformamide (10mL) solution, the reaction mixture Stir at 90°C for 12 hours. After the reaction, the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (30 mL×3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Compound 35 was purified by silica gel column chromatography (dichloromethane:methanol=1:0～10:1), and compound 35 was purified by supercritical fluid chiral chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm* 20mm, 5μm, mobile phase: 40%EtOH/CO ₂ (NH ₄ OH 0.2%), total flow rate: 40g/min) resolved to obtain compound 35-P1 (48.6mg, yield 4.5%) and compound 35-P2 ( 59.8 mg, yield 5.5%).

化合物35-P1：Compound 35-P1:

MS m/z(ESI):568.2[M+1] ⁺。SFC：保留时间＝2.76min,UV＝254nm。 ¹H NMR(400MHz,DMSO-d ₆)δ8.81(s,1H),8.61(d,J＝2.3Hz,1H),8.54(d,J＝5.0Hz,1H),8.21(s,1H),8.16–8.06(m,1H),7.98(d,J＝4.7Hz,1H),7.59(d,J＝5.1Hz,1H),6.82(s,1H),5.48(s,2H),4.21(t,J＝8.6Hz,2H),4.12(dd,J＝14.9,8.7Hz,2H),3.41(td,J＝8.5,4.2Hz,1H),2.61(d,J＝4.6Hz,3H),2.08(s,3H),1.95(s,3H)。 MS m/z (ESI): 568.2 [M+1] ⁺ . SFC: retention time = 2.76min, UV = 254nm. ¹ H NMR (400MHz,DMSO-d ₆ )δ8.81(s,1H),8.61(d,J=2.3Hz,1H),8.54(d,J=5.0Hz,1H),8.21(s,1H) ,8.16–8.06(m,1H),7.98(d,J＝4.7Hz,1H),7.59(d,J＝5.1Hz,1H),6.82(s,1H),5.48(s,2H),4.21( t,J=8.6Hz,2H),4.12(dd,J=14.9,8.7Hz,2H),3.41(td,J=8.5,4.2Hz,1H),2.61(d,J=4.6Hz,3H), 2.08(s,3H),1.95(s,3H).

化合物35-P2：Compound 35-P2:

MS m/z(ESI):568.2[M+1] ⁺。SFC：保留时间＝3.2min,UV＝254nm。 ¹H NMR(400MHz,DMSO-d ₆)δ8.81(s,1H),8.61(d,J＝2.3Hz,1H),8.54(d,J＝5.1Hz,1H),8.21(s,1H),8.15–8.08(m,1H),7.98(d,J＝4.6Hz,1H),7.59(d,J＝5.1Hz,1H),6.82(s,1H),5.49(d,J＝1.1Hz,2H),4.21(t,J＝8.5Hz,2H),4.12(dd,J＝14.8,8.7Hz,2H),3.49–3.36(m,1H),2.61(d,J＝4.6Hz,3H),2.08(s,3H),1.95(s,3H)。 MS m/z (ESI): 568.2 [M+1] ⁺ . SFC: retention time = 3.2min, UV = 254nm. ¹ H NMR (400MHz,DMSO-d ₆ )δ8.81(s,1H),8.61(d,J=2.3Hz,1H),8.54(d,J=5.1Hz,1H),8.21(s,1H) ,8.15–8.08(m,1H),7.98(d,J＝4.6Hz,1H),7.59(d,J＝5.1Hz,1H),6.82(s,1H),5.49(d,J＝1.1Hz, 2H), 4.21(t, J＝8.5Hz, 2H), 4.12(dd, J＝14.8, 8.7Hz, 2H), 3.49–3.36(m, 1H), 2.61(d, J＝4.6Hz, 3H), 2.08(s,3H),1.95(s,3H).

实施例9化合物38的合成The synthesis of embodiment 9 compound 38

第一步：化合物38-2的合成The first step: the synthesis of compound 38-2

将化合物38-1(500mg,2.17mmol)，甲胺盐酸盐(161mg,2.39mmol)，HATU(O-(7-氮杂苯并***-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐)(1.65g,4.34mmol)，N,N-二异丙基乙胺(840mg,6.51mmol)溶于N,N-二甲基甲酰胺(10mL)中，氮气保护下在室温搅拌16小时。反应结束后，加水(10mL)稀释，用乙酸乙酯萃取(20mL×3)。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷:甲醇＝1:0～20:1)纯化得到化合物38-2(550mg,纯度75％,收率：78.1％)。Compound 38-1 (500mg, 2.17mmol), methylamine hydrochloride (161mg, 2.39mmol), HATU(O-(7-azabenzotriazol-1-yl)-N,N,N', N'-tetramethyluronium hexafluorophosphate) (1.65g, 4.34mmol), N,N-diisopropylethylamine (840mg, 6.51mmol) was dissolved in N,N-dimethylformamide (10mL) , stirred at room temperature for 16 hours under nitrogen protection. After the reaction was completed, it was diluted with water (10 mL), and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=1:0～20:1) to obtain compound 38 -2 (550 mg, purity 75%, yield: 78.1%).

MS m/z(ESI):265.0[M+23] ⁺。 MS m/z (ESI): 265.0 [M+23] ⁺ .

第二步：化合物38-3的合成The second step: the synthesis of compound 38-3

将氯化氢的1,4-二氧六环溶液(3mL,4M)加入到化合物38-2(600mg,2.48mmol)的二氯甲烷(10mL)溶液中，室温下搅拌2小时。反应结束后，减压浓缩得到化合物38-3(600mg,粗品)。产物不经纯化直接进行下一步反应。A solution of hydrogen chloride in 1,4-dioxane (3 mL, 4M) was added to a solution of compound 38-2 (600 mg, 2.48 mmol) in dichloromethane (10 mL), and stirred at room temperature for 2 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain compound 38-3 (600 mg, crude product). The product was directly subjected to the next reaction without purification.

MS m/z(ESI):143.1[M+1] ⁺。 MS m/z (ESI): 143.1 [M+1] ⁺ .

第三步：化合物38-4的合成The third step: the synthesis of compound 38-4

将化合物38-3(300mg,1.68mmol)，化合物2-2(520mg,1.68mmol)，N,N-二异丙基乙胺(434mg,3.35mmol)溶于乙腈(5mL)中，反应混合物在40℃下搅拌16小时。反应结束后，减压浓缩，残余物经硅胶柱层析(二氯甲烷:甲醇＝1:0～20:1)纯化得到化合物38-4(650mg,收率：80.7％)。Compound 38-3 (300mg, 1.68mmol), compound 2-2 (520mg, 1.68mmol), N,N-diisopropylethylamine (434mg, 3.35mmol) were dissolved in acetonitrile (5mL), and the reaction mixture was Stir at 40°C for 16 hours. After the reaction, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=1:0~20:1) to obtain compound 38-4 (650 mg, yield: 80.7%).

MS m/z(ESI):385.0[M+1] ⁺。 MS m/z (ESI): 385.0 [M+1] ⁺ .

第四步：化合物38-5的合成The fourth step: the synthesis of compound 38-5

将氯化氢的1,4-二氧六环溶液(3mL,4M)加入到化合物38-4(550mg,1.43mmol)的二氯甲烷(5mL)溶液中，反应液在室温下搅拌12小时。反应结束后，减压浓缩，得到化合物38-5(500mg,粗品)。产物不经纯化直接进行下一步反应。A solution of hydrogen chloride in 1,4-dioxane (3 mL, 4M) was added to a solution of compound 38-4 (550 mg, 1.43 mmol) in dichloromethane (5 mL), and the reaction solution was stirred at room temperature for 12 hours. After the reaction, it was concentrated under reduced pressure to obtain compound 38-5 (500 mg, crude product). The product was directly subjected to the next reaction without purification.

MS m/z(ESI):185.2[M+1] ⁺。 MS m/z (ESI): 185.2 [M+1] ⁺ .

第五步：化合物38的合成The fifth step: the synthesis of compound 38

将化合物38-5(264mg,1.20mmol),化合物A(171mg,0.36mmol)和碳酸钾(247mg,1.79mmol)溶于N-N二甲基甲酰胺(10mL)中，在65℃下搅拌16小时。反应结束后，加水稀释(100mL)，用乙酸乙酯萃取(50mL×3)。合并有机相，无水硫酸钠干燥并过滤，滤液减压浓缩，所得残余物经硅胶柱层析(石油醚:乙酸乙酯＝1:0～2:1)纯化得到粗品，该粗品经高效液相制备色谱(色谱柱：Gemini-C18，150×21.2mm，5μm；流动相：乙腈-水(0.1％甲酸)；梯度：30-50％；柱温：25℃；流速：20mL/min；波长：214nm；柱压：80bar)纯化得到化合物38(40mg,收率：18.6％)。Compound 38-5 (264 mg, 1.20 mmol), compound A (171 mg, 0.36 mmol) and potassium carbonate (247 mg, 1.79 mmol) were dissolved in N-N dimethylformamide (10 mL), stirred at 65°C for 16 hours. After the reaction, it was diluted with water (100 mL), and extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 ~ 2:1) to obtain a crude product, which was purified by high-efficiency liquid Phase preparative chromatography (column: Gemini-C18, 150×21.2mm, 5μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-50%; column temperature: 25°C; flow rate: 20mL/min; wavelength : 214nm; column pressure: 80bar) was purified to obtain compound 38 (40mg, yield: 18.6%).

MS m/z(ESI):596.2[M+1] ⁺； ¹H NMR(400MHz,CD ₃OD)δ8.79(s,1H),8.49(d,J＝3.1Hz,1H),8.48(s,1H),8.31(s,1H),7.79–7.71(m,1H),7.60(d,J＝5.2Hz,1H),6.84(s,1H),5.52(d,J＝1.9Hz,2H),2.99(t,J＝12.3Hz,3H),2.73(s,3H),2.55–2.45(m,1H),2.18(s,3H),2.07(s,3H),1.86(d,J＝10.8Hz,2H),1.68(dd,J＝25.0,12.4Hz,3H)。 MS m/z (ESI): 596.2[M+1] ⁺ ; ¹ H NMR (400MHz, CD ₃ OD) δ8.79 (s, 1H), 8.49 (d, J = 3.1Hz, 1H), 8.48 (s ,1H),8.31(s,1H),7.79–7.71(m,1H),7.60(d,J=5.2Hz,1H),6.84(s,1H),5.52(d,J=1.9Hz,2H) ,2.99(t,J=12.3Hz,3H),2.73(s,3H),2.55–2.45(m,1H),2.18(s,3H),2.07(s,3H),1.86(d,J=10.8 Hz, 2H), 1.68 (dd, J=25.0, 12.4Hz, 3H).

实施例10化合物41、41-P1和41-P2的合成The synthesis of embodiment 10 compound 41, 41-P1 and 41-P2

第一步：化合物41-2的合成The first step: the synthesis of compound 41-2

将化合物41-1(400mg,2.33mmol)，化合物2-2(723mg,2.33mmol,)和N,N-二异丙基乙胺(602mg,4.66mmol)溶于乙腈(20mL)中，反应液室温搅拌12小时。反应完成后，减压浓缩，所得残余物经硅胶柱层析(石油醚:乙酸乙酯＝1:0～4:1)纯化得到化合物41-2(600mg,收率：64.8％)。Compound 41-1 (400mg, 2.33mmol), compound 2-2 (723mg, 2.33mmol), and N,N-diisopropylethylamine (602mg, 4.66mmol) were dissolved in acetonitrile (20mL), and the reaction solution Stir at room temperature for 12 hours. After the reaction was completed, it was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-4:1) to obtain compound 41-2 (600 mg, yield: 64.8%).

MS m/z(ESI):377.9[M+1] ⁺。 MS m/z (ESI): 377.9 [M+1] ⁺ .

第二步：化合物41-3的合成The second step: the synthesis of compound 41-3

将氯化氢的1,4-二氧六环溶液(1.7mL,4M)缓慢加入化合物41-2(500mg,1.32mmol)的二氯甲烷(10mL)溶液中。反应液室温搅拌12小时，反应完成后，反应液减压浓缩得化合物41-3(220mg,粗品)。产物不经纯化直接进行下一步反应。A solution of hydrogen chloride in 1,4-dioxane (1.7 mL, 4M) was slowly added to a solution of compound 41-2 (500 mg, 1.32 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 41-3 (220 mg, crude product). The product was directly subjected to the next reaction without purification.

MS m/z(ESI):178.0[M+1] ⁺。 MS m/z (ESI): 178.0 [M+1] ⁺ .

第三步：化合物41的合成The third step: the synthesis of compound 41

将化合物A(150mg,0.31mmol)，化合物41-3(135mg,粗品)和碳酸钾(128mg,0.93mmol)的N,N-二甲基甲酰胺(15mL)溶液加热至90℃搅拌16小时。反应完成后，加水(30mL)稀释，乙酸乙酯萃取(20mL×3)。合并有机相，用饱和食盐水洗涤(20mL×2)，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物经高效液相制备色谱(色谱柱：Gemini-C18，150x 21.2mm，5μm；流动相:乙腈-水(0.1％甲酸)；梯度:20-50％，柱温：25℃流速:14mL/min；波长:214nm；柱压:80bar)纯化得到化合物41(41.6mg,收率21.9％)。A solution of compound A (150 mg, 0.31 mmol), compound 41-3 (135 mg, crude product) and potassium carbonate (128 mg, 0.93 mmol) in N,N-dimethylformamide (15 mL) was heated to 90°C and stirred for 16 hours. After the reaction was completed, it was diluted with water (30 mL) and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (20mL×2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to preparative high performance liquid chromatography (column: Gemini-C18, 150×21.2mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-50%, column temperature: 25 ℃ flow rate: 14mL/min; wavelength: 214nm; rate 21.9%).

MS m/z(ESI):588.8[M+1] ⁺； ¹H NMR(400MHz,DMSO-d ₆)δ8.79(s,1H),8.58(d,J＝2.4Hz,1H),8.55(d,J＝5.1Hz,1H),8.22(s,1H),8.07(ddd,J＝10.0,9.0,2.4Hz,1H),7.64(d,J＝5.1Hz,1H),6.80(s,1H),5.45(d,J＝1.5Hz,2H),4.45–4.21(m,5H),3.02(s,3H),2.04(s,3H),1.92(s,3H)。 MS m/z (ESI): 588.8[M+1] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.79 (s, 1H), 8.58 (d, J=2.4Hz, 1H), 8.55 ( d,J=5.1Hz,1H),8.22(s,1H),8.07(ddd,J=10.0,9.0,2.4Hz,1H),7.64(d,J=5.1Hz,1H),6.80(s,1H ), 5.45 (d, J=1.5Hz, 2H), 4.45–4.21 (m, 5H), 3.02 (s, 3H), 2.04 (s, 3H), 1.92 (s, 3H).

取放大批次的化合物41经超临界流体手性色谱((设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO ₂(NH ₄OH 0.2％),总流速：40g/min)拆分得到化合物41-P1(33.3mg，收率10.5％)和化合物41-P2(29.8mg，收率9.3％)。 The amplified batch of compound 41 was subjected to supercritical fluid chiral chromatography ((equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5 μm, mobile phase: 40% EtOH/CO ₂ (NH ₄ OH 0.2% ), total flow rate: 40g/min) to obtain compound 41-P1 (33.3mg, yield 10.5%) and compound 41-P2 (29.8mg, yield 9.3%).

化合物41-P1:Compound 41-P1:

MS m/z(ESI):588.7[M+1] ⁺。SFC：保留时间＝6.92min,UV＝254nm。 ¹H NMR(400MHz,CD ₃OD)δ8.68(s,1H),8.42(d,J＝5.2Hz,1H),8.36(d,J＝2.4Hz,1H),8.20(s,1H),7.68–7.58(m,2H),6.71(s,1H),5.40(d,J＝1.9Hz,2H),4.42–4.29(m,4H),4.29–4.22(m,1H),2.90(s,3H),2.06(s,3H),1.93(s,3H)。 MS m/z (ESI): 588.7 [M+1] ⁺ . SFC: retention time = 6.92min, UV = 254nm. ¹ H NMR (400MHz, CD ₃ OD) δ8.68(s, 1H), 8.42(d, J=5.2Hz, 1H), 8.36(d, J=2.4Hz, 1H), 8.20(s, 1H), 7.68–7.58(m,2H),6.71(s,1H),5.40(d,J＝1.9Hz,2H),4.42–4.29(m,4H),4.29–4.22(m,1H),2.90(s, 3H), 2.06(s,3H), 1.93(s,3H).

化合物41-P2:Compound 41-P2:

MS m/z(ESI):588.7[M+1] ⁺。SFC：保留时间＝8.76min,UV＝254nm。 ¹H NMR(400MHz,CD ₃OD)δ8.68(s,1H),8.42(d,J＝5.2Hz,1H),8.36(d,J＝2.3Hz,1H),8.20(s,1H),7.69–7.59(m,2H),6.71(s,1H),5.40(d,J＝1.8Hz,2H),4.43–4.30(m,4H),4.26(d,J＝8.2Hz,1H),2.89(d,J＝5.7Hz,3H),2.06(s,3H),1.93(s,3H)。 MS m/z (ESI): 588.7 [M+1] ⁺ . SFC: retention time = 8.76min, UV = 254nm. ¹ H NMR (400MHz, CD ₃ OD) δ8.68(s, 1H), 8.42(d, J=5.2Hz, 1H), 8.36(d, J=2.3Hz, 1H), 8.20(s, 1H), 7.69–7.59(m,2H),6.71(s,1H),5.40(d,J=1.8Hz,2H),4.43–4.30(m,4H),4.26(d,J=8.2Hz,1H),2.89 (d, J=5.7Hz, 3H), 2.06(s, 3H), 1.93(s, 3H).

实施例11化合物45的合成The synthesis of embodiment 11 compound 45

第一步：化合物45-2的合成The first step: the synthesis of compound 45-2

将化合物45-1(500mg,3.86mmol),化合物2-2(1.2g,3.86mmol)和N,N-二异丙基乙胺(998mg,7.72mmol)溶于乙腈(15mL)中，室温搅拌12小时。反应完成后，反应液减压浓缩，所得残余物经硅胶柱层析(石油醚:乙酸乙酯＝1:0～4:1)纯化得到化合物45-2(1.2g,收率：88％)Compound 45-1 (500mg, 3.86mmol), compound 2-2 (1.2g, 3.86mmol) and N,N-diisopropylethylamine (998mg, 7.72mmol) were dissolved in acetonitrile (15mL), stirred at room temperature 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 ~ 4:1) to obtain compound 45-2 (1.2 g, yield: 88%)

MS m/z(ESI):335.9[M+1] ⁺。 MS m/z (ESI): 335.9 [M+1] ⁺ .

第二步：化合物45-3的合成The second step: the synthesis of compound 45-3

将氯化氢的1,4-二氧六环溶液(1.8mL,4M)加入到化合物45-2(800mg,2.38mmol)的二氯甲烷(15mL)溶液中，室温搅拌12小时。反应完成后，反应液减压浓缩得化合物45-3(200mg,粗品)。产物不经纯化直接进行下一步反应。A solution of hydrogen chloride in 1,4-dioxane (1.8 mL, 4M) was added to a solution of compound 45-2 (800 mg, 2.38 mmol) in dichloromethane (15 mL), and stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 45-3 (200 mg, crude product). The product was directly subjected to the next reaction without purification.

MS m/z(ESI):136.1[M+1] ⁺。 MS m/z (ESI): 136.1 [M+1] ⁺ .

第三步：化合物45的合成The third step: the synthesis of compound 45

将化合物A(100mg,0.21mmol)，化合物45-3(72mg,0.42mmol)和碳酸钾(87mg,0.63 mmol)的N,N-二甲基甲酰胺(8mL)溶液加热至90℃搅拌16小时。反应混合液加水(30mL)稀释，乙酸乙酯萃取(20mL×3)。合并有机相，用饱和食盐水洗涤(20mL×2)，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物经高效液相制备色谱(色谱柱：Gemini-C18；150×21.2mm，5μm；流动相：乙腈-水(0.1％甲酸)；梯度：30-60％；柱温：25℃；流速：14mL/min；波长：214nm；柱压：80bar)纯化得到化合物体45(20.2mg,收率16.6％)。Compound A (100 mg, 0.21 mmol), compound 45-3 (72 mg, 0.42 mmol) and potassium carbonate (87 mg, 0.63 mmol) in N,N-dimethylformamide (8 mL) was heated to 90°C and stirred for 16 hours . The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (20mL×2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to preparative high performance liquid chromatography (column: Gemini-C18; 150×21.2mm , 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-60%; column temperature: 25 ° C; flow rate: 14mL/min; wavelength: 214nm; mg, yield 16.6%).

MS m/z(ESI):546.8[M+1] ⁺； ¹H NMR(400MHz,DMSO-d ₆)δ8.83(s,1H),8.62(dd,J＝8.6,3.7Hz,2H),8.26(s,1H),8.11(td,J＝10.0,2.3Hz,1H),7.74(d,J＝5.1Hz,1H),6.84(s,1H),5.50(s,2H),4.56(t,J＝12.5Hz,4H),2.09(s,3H),1.96(s,3H)。 MS m/z (ESI): 546.8[M+1] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.83 (s, 1H), 8.62 (dd, J=8.6, 3.7Hz, 2H), 8.26(s,1H),8.11(td,J=10.0,2.3Hz,1H),7.74(d,J=5.1Hz,1H),6.84(s,1H),5.50(s,2H),4.56(t , J=12.5Hz, 4H), 2.09(s, 3H), 1.96(s, 3H).

实施例12化合物34、34-P1和34-P2的合成The synthesis of embodiment 12 compound 34, 34-P1 and 34-P2

第一步：化合物34-2的合成The first step: the synthesis of compound 34-2

将氯甲酸异丁酯(2.7g,19.78mmol)加入到化合物34-1(2.0g,9.88mmol)和N-甲基吗啉(1.5g,14.83mmol)的四氢呋喃(50mL)溶液中，反应混合物在-10℃下搅拌1小时，然后加入氨的甲醇溶液(20mL)，继续搅拌1.5小时。反应结束后，反应液减压浓缩，残余物经硅胶柱层析(石油醚：乙酸乙酯＝1:0～1:1)纯化得到化合物34-2(2.1g，收率：84.41％)。MS m/z(ESI):145.1[M+1] ⁺。 Isobutyl chloroformate (2.7g, 19.78mmol) was added to a solution of compound 34-1 (2.0g, 9.88mmol) and N-methylmorpholine (1.5g, 14.83mmol) in tetrahydrofuran (50mL), and the reaction mixture Stir at -10°C for 1 hour, then add ammonia in methanol (20 mL) and continue stirring for 1.5 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-1:1) to obtain compound 34-2 (2.1 g, yield: 84.41%). MS m/z (ESI): 145.1 [M+1] ⁺ .

第二步：化合物34-3的合成The second step: the synthesis of compound 34-3

将氯化氢的1,4-二氧六环溶液(15mL,4M)加入到化合物34-2(2.1g,10.43mmol)的二氯甲烷(15mL)溶液中，反应混合物室温搅拌2小时。反应结束后，反应液减压浓缩得到化合物34-3(1.5g,收率：86.14％)。MS m/z(ESI):101.1[M+1] ⁺。 A solution of hydrogen chloride in 1,4-dioxane (15 mL, 4M) was added to a solution of compound 34-2 (2.1 g, 10.43 mmol) in dichloromethane (15 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain compound 34-3 (1.5 g, yield: 86.14%). MS m/z (ESI): 101.1 [M+1] ⁺ .

第三步：化合物34-4的合成The third step: the synthesis of compound 34-4

将化合物2-2(3.1g,9.99mmol)加入到化合物34-3(1.0g,9.99mmol)和N,N-二异丙基乙胺(2.58g,19.98mmol)的乙腈(15mL)溶液中，反应混合物室温搅拌12小时。反应结束后，反应液减压浓缩，残余物经硅胶柱层析(石油醚：乙酸乙酯＝1:0～1:1)纯化得到化合物34-4(1.0g，收率：26.32％)。MS m/z(ESI):342.9.[M+1] ⁺。 Compound 2-2 (3.1 g, 9.99 mmol) was added to a solution of compound 34-3 (1.0 g, 9.99 mmol) and N,N-diisopropylethylamine (2.58 g, 19.98 mmol) in acetonitrile (15 mL) , and the reaction mixture was stirred at room temperature for 12 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-1:1) to obtain compound 34-4 (1.0 g, yield: 26.32%). MS m/z (ESI): 342.9.[M+1] ⁺ .

第四步：化合物34-5的合成The fourth step: the synthesis of compound 34-5

将氯化氢的1,4-二氧六环溶液(3mL,4M)加入到化合物34-4(1.0g,2.92mmol)的二氯甲烷(3mL)溶液中，反应混合物在室温下搅拌2小时。反应结束后，反应液减压浓缩得到化合物34-5(450mg,收率：97.55％)。MS m/z(ESI):143.0.[M+1] ⁺。 A solution of hydrogen chloride in 1,4-dioxane (3 mL, 4M) was added to a solution of compound 34-4 (1.0 g, 2.92 mmol) in dichloromethane (3 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain compound 34-5 (450 mg, yield: 97.55%). MS m/z (ESI): 143.0.[M+1] ⁺ .

第五步：化合物34的合成The fifth step: the synthesis of compound 34

将化合物34-5(449mg,3.16mmol)加入到化合物A(300mg,0.63mmol)和碳酸钾(523.84mg，3.79mmol)的N,N-二甲基甲酰胺(5mL)溶液中，反应混合物在90℃下搅拌16小时，反应结束后，反应液减压浓缩，残余物加水(20mL)稀释，用乙酸乙酯萃取(30mL×3)，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷：甲醇＝1:0～10:1)纯化得到化合物34，化合物34经超临界流体手性色谱((设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO ₂(NH ₄OH0.2％),总流速：40g/min)拆分得到化合物34-P1(40.5mg，收率11.3％)和化合物34-P2(47.1mg，收率13.1％)。 Compound 34-5 (449mg, 3.16mmol) was added to compound A (300mg, 0.63mmol) and potassium carbonate (523.84mg, 3.79mmol) in N,N-dimethylformamide (5mL) solution, and the reaction mixture was Stir at 90°C for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure. The residue was diluted with water (20 mL), extracted with ethyl acetate (30 mL×3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=1:0～10:1) to obtain compound 34. Compound 34 was subjected to supercritical fluid chiral chromatography ((equipment: SFC Thar prep 80, Column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO ₂ (NH ₄ OH0.2%), total flow rate: 40g/min) to obtain compound 34-P1 (40.5mg, yield 11.3%) and compound 34-P2 (47.1 mg, yield 13.1%).

化合物34-P1:Compound 34-P1:

MS m/z(ESI):[M+1] ⁺553.8。SFC：保留时间＝3.81min,UV＝214nm。 ¹H NMR(400MHz,CD ₃OD)δ8.74(s,1H),8.43(dd,J＝3.8,1.3Hz,2H),8.24(s,1H),7.75–7.68(m,1H),7.63(d,J＝5.2Hz,1H),6.77(s,1H),5.47(d,J＝1.8Hz,2H),4.35–4.17(m,4H),3.59–3.46(m,1H),2.12(s,3H),2.00(s,3H)。 MS m/z (ESI): [M+1] ^+553.8 . SFC: retention time = 3.81 min, UV = 214nm. ¹ H NMR (400MHz, CD ₃ OD)δ8.74(s,1H),8.43(dd,J＝3.8,1.3Hz,2H),8.24(s,1H),7.75–7.68(m,1H),7.63 (d,J=5.2Hz,1H),6.77(s,1H),5.47(d,J=1.8Hz,2H),4.35–4.17(m,4H),3.59–3.46(m,1H),2.12( s,3H), 2.00(s,3H).

化合物34-P2:Compound 34-P2:

ESI-MS[M+H] ⁺:553.8。SFC：保留时间＝4.6min,UV＝214nm。1H NMR(400MHz,CD ₃OD)δ8.74(s,1H),8.43(dd,J＝3.9,1.1Hz,2H),8.24(s,1H),7.75–7.67(m,1H),7.63(d,J＝5.2Hz,1H),6.77(s,1H),5.47(d,J＝1.6Hz,2H),4.35–4.18(m,4H),3.59–3.46(m,1H),2.13(s,3H),2.00(s,3H)。 ESI-MS [M+H] ⁺ : 553.8. SFC: retention time = 4.6min, UV = 214nm. 1H NMR (400MHz, CD ₃ OD) δ8.74(s, 1H), 8.43(dd, J=3.9, 1.1Hz, 2H), 8.24(s, 1H), 7.75–7.67(m, 1H), 7.63( d,J=5.2Hz,1H),6.77(s,1H),5.47(d,J=1.6Hz,2H),4.35–4.18(m,4H),3.59–3.46(m,1H),2.13(s ,3H), 2.00(s,3H).

实施例13化合物29、29-P1和29-P2的合成The synthesis of embodiment 13 compound 29, 29-P1 and 29-P2

将化合物2-4(303mg，1.83mmol)加入到化合物B(300mg，0.61mmol)和碳酸钾(168mg，1.22mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应混合物加热至90℃搅拌16小时。反应结束后，反应液倒入水中(30mL)，乙酸乙酯萃取(20mL×3)。合并的有机相用饱和食盐水洗涤(20mL×2)，无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到粗品化合物29，粗品化合物29经超临界流体手性色谱((设备：SFC Thar prep 80,柱子：CHIRALPAK IC 250mm*4.6mm，5μm，流动相： 40％MeOH/CO ₂(NH ₄OH 0.2％)，总流速：40g/min)拆分得到化合物29-P1(19.5mg，收率5.7％)和化合物29-P2(22.6mg，收率6.6％)。 Compound 2-4 (303mg, 1.83mmol) was added to compound B (300mg, 0.61mmol) and potassium carbonate (168mg, 1.22mmol) in N,N-dimethylformamide (10mL) solution, and the reaction mixture was heated to Stir at 90°C for 16 hours. After the reaction, the reaction solution was poured into water (30 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated brine (20mL×2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane/methanol=1/0～20/1 ) was purified to obtain crude compound 29, which was subjected to supercritical fluid chiral chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK IC 250mm*4.6mm, 5 μm, mobile phase: 40% MeOH/CO ₂ (NH ₄ OH 0.2%), total flow rate: 40g/min) to obtain compound 29-P1 (19.5mg, yield 5.7%) and compound 29-P2 (22.6mg, yield 6.6%).

化合物29-P1：Compound 29-P1:

ESI-MS[M+H] ⁺:559.1。SFC：保留时间＝5.44min,UV＝214nm。 ¹H NMR(400MHz,CD ₃OD)δ8.63(s,1H),8.44(dd,J＝3.8,1.3Hz,2H),7.71(ddd,J＝9.6,8.6,2.4Hz,1H),7.27(d,J＝5.1Hz,1H),6.85(d,J＝0.5Hz,1H),5.49(d,J＝1.9Hz,2H),4.09–3.91(m,4H),2.19(s,3H),2.10(s,3H),1.51(s,3H)。 ESI-MS [M+H] ⁺ : 559.1. SFC: retention time = 5.44min, UV = 214nm. ¹ H NMR (400MHz, CD ₃ OD) δ8.63 (s, 1H), 8.44 (dd, J = 3.8, 1.3Hz, 2H), 7.71 (ddd, J = 9.6, 8.6, 2.4Hz, 1H), 7.27 (d,J=5.1Hz,1H),6.85(d,J=0.5Hz,1H),5.49(d,J=1.9Hz,2H),4.09–3.91(m,4H),2.19(s,3H) , 2.10(s,3H), 1.51(s,3H).

化合物29-P2：Compound 29-P2:

ESI-MS[M+H] ⁺:559.1。SFC：保留时间＝15.16min,UV＝214nm。 ¹H NMR(400MHz,CD ₃OD)δ8.63(s,1H),8.44(dd,J＝3.8,1.3Hz,2H),7.71(ddd,J＝9.6,8.6,2.4Hz,1H),7.32–7.21(m,1H),6.85(s,1H),5.49(d,J＝1.9Hz,2H),4.10–3.93(m,4H),2.19(s,3H),2.10(s,3H),1.51(s,3H)。 ESI-MS [M+H] ⁺ : 559.1. SFC: retention time = 15.16min, UV = 214nm. ¹ H NMR (400MHz, CD ₃ OD) δ8.63 (s, 1H), 8.44 (dd, J = 3.8, 1.3Hz, 2H), 7.71 (ddd, J = 9.6, 8.6, 2.4Hz, 1H), 7.32 –7.21(m,1H),6.85(s,1H),5.49(d,J＝1.9Hz,2H),4.10–3.93(m,4H),2.19(s,3H),2.10(s,3H), 1.51(s,3H).

根据上述实施例，制备如下化合物：According to the above examples, the following compounds were prepared:

生物学评价biological evaluation

1.p38 MAPK/MK2体外活性的测定1. Determination of in vitro activity of p38 MAPK/MK2

化合物对p38 MAPK/MK2的抑制作用采用Z-LYTE激酶检测试剂盒(Thermo,PV3177)进行检测。DMSO溶解受试化合物至10mM母液，-20℃保存待用。化合物起始浓度为10μM，1％DMSO,5倍倍比稀释，8个浓度，双复孔；50mM HEPES pH 7.5,10mM MgCl ₂,0.01％Brij-35,1mM EGTA作为反应缓冲液用来配置2x active p38a/inactive MK2/Ser/Thr 4混合液，最终10μL的反应体系在384孔板(Corning,4514)中进行，含有500ng/mL inactive MK2(abcam,79910),8ng/mL active p38a(Carna,04-152),2μM Ser/Thr 4；20℃反应1小时后，每孔加入稀释2048倍后的Development Reagent A，室温孵育1小时后加入5μL终止缓冲溶液终止反应，酶标仪检测 (Ex.400nm,Em.445nm；Ex.400nm,Em.520nm)。用GraphPad Prism 8软件拟合浓度-效应曲线，并计算50％抑制效果的化合物浓度，即IC ₅₀。结果如表1所示。 The inhibitory effect of compounds on p38 MAPK/MK2 was detected by Z-LYTE Kinase Assay Kit (Thermo, PV3177). The test compound was dissolved in DMSO to 10 mM stock solution and stored at -20°C until use. The initial concentration of the compound is 10 μM, 1% DMSO, 5-fold dilution, 8 concentrations, duplicate holes; 50mM HEPES pH 7.5, 10mM MgCl ₂ , 0.01% Brij-35, 1mM EGTA as the reaction buffer to configure 2x active p38a/inactive MK2/Ser/Thr 4 mixture, the final 10 μL reaction system was carried out in a 384-well plate (Corning, 4514), containing 500ng/mL inactive MK2 (abcam, 79910), 8ng/mL active p38a (Carna, 04-152), 2 μM Ser/Thr 4; after 1 hour of reaction at 20°C, add Development Reagent A diluted 2048 times to each well, incubate at room temperature for 1 hour, add 5 μL of stop buffer solution to terminate the reaction, and detect with a microplate reader (Ex. 400nm, Em.445nm; Ex.400nm, Em.520nm). The concentration-effect curve was fitted with GraphPad Prism 8 software, and the concentration of the compound with 50% inhibitory effect was calculated, ie IC ₅₀ . The results are shown in Table 1.

表1Table 1

化合物compound	p38 MAPK/MK2 IC ₅₀(nM) p38 MAPK/MK2 IC ₅₀ (nM)
化合物2Compound 2	4.754.75
化合物2-P1Compound 2-P1	0.410.41
化合物6Compound 6	10.9210.92
化合物10Compound 10	16.5916.59
化合物11Compound 11	2.682.68
化合物12Compound 12	4.694.69
化合物12-P2Compound 12-P2	0.550.55
化合物13Compound 13	10.0410.04
化合物29-P2Compound 29-P2	0.180.18
化合物33Compound 33	3.763.76
化合物35Compound 35	1.261.26
化合物38Compound 38	31.2931.29
化合物41Compound 41	3.203.20
化合物45Compound 45	203.70203.70
化合物33-P2Compound 33-P2	2.112.11
化合物34-P2Compound 34-P2	6.336.33
化合物35-P2Compound 35-P2	1.241.24
化合物41-P2Compound 41-P2	1.061.06

从表1可知，本公开的化合物对p38 MAPK/MK2具有良好的抑制活性。It can be seen from Table 1 that the compounds of the present disclosure have good inhibitory activity on p38 MAPK/MK2.

2.p38 MAPK/MK5体外活性测定2. Determination of in vitro activity of p38 MAPK/MK5

化合物对p38 MAPK/MK5的抑制作用采用Z-LYTE激酶检测试剂盒(Thermo,PV3177)进行检测。DMSO溶解受试化合物至10mM母液，-20℃保存待用。化合物起始浓度为10μM，1％DMSO,5倍倍比稀释，8个浓度，双复孔；50mM HEPES pH 7.5,10mM MgCl ₂,0.01％Brij-35,1mM EGTA作为反应缓冲液用来配置2x active p38a/inactive MK5/Ser/Thr 4混合液，最终10μL的反应体系在384孔板(Corning,4514)中进行，含有10μg/mL inactive MK5(abcam,217826),1ng/mL active p38a(Carna,04-152),2μM Ser/Thr 4；20℃反应4小时后，每孔加入稀释2048倍后的Development Reagent A，室温孵育1小时后加入5μL终止缓冲溶液终止反应，酶标仪检测(Ex.400nm,Em.445nm；Ex.400nm,Em.520nm)。用GraphPad Prism 8软件拟合浓度-效应曲线，并计算50％抑制效果的化合物浓度，即IC ₅₀。结果如表2所示。 The inhibitory effect of compounds on p38 MAPK/MK5 was detected by Z-LYTE Kinase Assay Kit (Thermo, PV3177). The test compound was dissolved in DMSO to 10 mM stock solution and stored at -20°C until use. The initial concentration of the compound is 10 μM, 1% DMSO, 5-fold dilution, 8 concentrations, duplicate holes; 50mM HEPES pH 7.5, 10mM MgCl ₂ , 0.01% Brij-35, 1mM EGTA as the reaction buffer to configure 2x active p38a/inactive MK5/Ser/Thr 4 mixture, the final 10 μL reaction system was carried out in a 384-well plate (Corning, 4514), containing 10 μg/mL inactive MK5 (abcam, 217826), 1ng/mL active p38a (Carna, 04-152), 2 μM Ser/Thr 4; after 4 hours of reaction at 20°C, add Development Reagent A diluted 2048 times to each well, incubate at room temperature for 1 hour, add 5 μL of stop buffer solution to stop the reaction, and detect with a microplate reader (Ex. 400nm, Em.445nm; Ex.400nm, Em.520nm). The concentration-effect curve was fitted with GraphPad Prism 8 software, and the concentration of the compound with 50% inhibitory effect was calculated, ie IC ₅₀ . The results are shown in Table 2.

表2Table 2

化合物compound	p38 MAPK/MK5 IC ₅₀(nM) p38 MAPK/MK5 IC ₅₀ (nM)
化合物2Compound 2	84438443
化合物6Compound 6	22382238
化合物10Compound 10	>10000>10000
化合物12Compound 12	>10000>10000
化合物13Compound 13	32063206
化合物41Compound 41	87468746

从表2可知，本公开的化合物对p38 MAPK/MK5抑制活性均大于2μM。这进一步说明本公开的化合物对p38 MAPK/MK2具有良好的选择性。It can be seen from Table 2 that the inhibitory activity of the compounds of the present disclosure on p38 MAPK/MK5 is greater than 2 μM. This further shows that the compound of the present disclosure has good selectivity to p38 MAPK/MK2.

3.p38 MAPK/ATF2体外活性的测定3. Determination of in vitro activity of p38 MAPK/ATF2

化合物对p38a催化ATF2的抑制作用采用HTRF方法进行检测。DMSO溶解受试化合物至10mM母液，-20℃保存待用。化合物起始浓度为10μM，0.25％DMSO,5倍倍比稀释，8个浓度，双复孔；40mM Tris pH 7.5,20mM MgCl2,0.1mg/mL BSA,50μM DTT作为反应缓冲液用来配置3.5 x p38a(MAPK14,Carna Biosciences,04-152)蛋白工作液、3.5x Human ATF2 Protein(Sino Biological,11599-H20B)工作液和3.5 x ATP工作液，10mM的EDTA用来终止反应，最终14μL的反应体系在96孔板(cisbio，66PL96025)中进行，含有0.29ng/μL p38a,0.29μM Human ATF2 Protein；25μM ATP。20℃反应35min后，每孔加入预先配置好的抗体溶液(cibio,63ADK015PEG,Phospho-ATF2 Eu Cryptate antibody,Phospho-ATF2 d2 antibody,用Detection buffer稀释40倍)室温孵育过夜，酶标仪检测(HTRF compatible reader)。用GraphPad Prism 8软件拟合浓度-效应曲线，并计算50％抑制效果的化合物浓度，即IC ₅₀。结果如表3所示。 The inhibitory effect of compounds on p38a-catalyzed ATF2 was detected by HTRF method. The test compound was dissolved in DMSO to 10 mM stock solution and stored at -20°C until use. The initial concentration of the compound is 10 μM, 0.25% DMSO, 5-fold dilution, 8 concentrations, double-well; 40mM Tris pH 7.5, 20mM MgCl2, 0.1mg/mL BSA, 50μM DTT are used as the reaction buffer to configure 3.5 x p38a (MAPK14, Carna Biosciences, 04-152) protein working solution, 3.5x Human ATF2 Protein (Sino Biological, 11599-H20B) working solution and 3.5 x ATP working solution, 10mM EDTA was used to stop the reaction, and the final 14μL reaction system Carried out in 96-well plate (cisbio, 66PL96025), containing 0.29ng/μL p38a, 0.29μM Human ATF2 Protein; 25μM ATP. After reacting at 20°C for 35 minutes, add a pre-configured antibody solution (cibio, 63ADK015PEG, Phospho-ATF2 Eu Cryptate antibody, Phospho-ATF2 d2 antibody, diluted 40 times with Detection buffer) to each well and incubate overnight at room temperature, and detect with a microplate reader (HTRF compatible reader). The concentration-effect curve was fitted with GraphPad Prism 8 software, and the concentration of the compound with 50% inhibitory effect was calculated, ie IC ₅₀ . The results are shown in Table 3.

表3table 3

化合物compound	p38 MAPK/ATF2 IC ₅₀(nM) p38 MAPK/ATF2 IC ₅₀ (nM)
化合物6Compound 6	37063706
化合物10Compound 10	56895689
化合物41Compound 41	80498049

从表3可知，本公开的化合物对p38 MAPK/ATF2抑制活性均大于3.7μM。这进一步说明本公开的化合物对p38 MAPK/MK2具有良好的选择性。It can be seen from Table 3 that the inhibitory activity of the compounds of the present disclosure on p38 MAPK/ATF2 is greater than 3.7 μM. This further shows that the compound of the present disclosure has good selectivity to p38 MAPK/MK2.

4.对人PBMC细胞上清TNF-α体外活性测定4. Determination of TNF-α in vitro activity of human PBMC cell supernatant

化合物对人PBMC细胞上清TNF-α的抑制作用实验方案用Elisa检测试剂盒(碧云天，PI518)进行检测。DMSO溶解受试化合物至10mM母液，-20℃保存待用。化合物起始浓度为2μM，5倍倍比稀释，6个浓度，细胞铺板双复孔，Elisa检测为单孔，DMSO终浓度为0.4％，也可根据化合物筛选的实际情况，变更化合物起始浓度、倍比稀释倍数、梯度浓度数量和复孔数。The inhibitory effect of compounds on human PBMC cell supernatant TNF-α was detected by Elisa detection kit (Beiyuntian, PI518). The test compound was dissolved in DMSO to 10 mM stock solution and stored at -20°C until use. The initial concentration of the compound is 2 μM, 5-fold dilution, 6 concentrations, the cells are plated in double wells, the Elisa is detected as a single well, and the final concentration of DMSO is 0.4%. The initial concentration of the compound can also be changed according to the actual situation of compound screening , ratio dilution factor, gradient concentration quantity and duplicate hole number.

新鲜人外周血单个核细胞(PBMC)(赛笠生物)以2*10^5的数量铺在96孔板(Corning,3599)中，每孔含有100μL的RPMI-1640(Gibco#A1049101)+10％FBS(Gibco,10099141C),37℃，5％CO ₂过夜培养；待测化合物已25μL/孔的体积加入96孔培养板中，1h后，加入5μL的LPS，使其终浓度为100ng/mL，阴性对照孔不加LPS及化合物，阳性对照孔中不加化合物，37℃，5％CO ₂继续培养24h后，500rcf离心8min收集细胞培养上清，按照Elisaa试剂盒中操作手册进行操作，检测TNF-α的浓度。用GraphPad Prism 8软件拟合浓度-效应曲线，并计算50％抑制效果的化合物浓度，即IC ₅₀。结果如表4所示。 Fresh human peripheral blood mononuclear cells (PBMC) (Sai Li Biological) were plated in 96-well plates (Corning, 3599) in a quantity of 2*10^5, and each well contained 100 μL of RPMI-1640 (Gibco#A1049101)+10 %FBS (Gibco, 10099141C), culture overnight at 37°C, 5% CO ₂ ; the compound to be tested was added to a 96-well culture plate in a volume of 25 μL/well, and after 1 hour, 5 μL of LPS was added to make the final concentration 100 ng/mL , no LPS and compounds were added to the negative control wells, no compound was added to the positive control wells, after 37°C, 5% CO ₂ continued to culture for 24 hours, the cell culture supernatant was collected by centrifugation at 500rcf for 8 minutes, and the operation was carried out according to the operation manual in the Elisaa kit, and the detection Concentration of TNF-α. The concentration-effect curve was fitted with GraphPad Prism 8 software, and the concentration of the compound with 50% inhibitory effect was calculated, ie IC ₅₀ . The results are shown in Table 4.

表4Table 4

化合物compound	TNF-α IC ₅₀(nM) TNF-α _IC50 (nM)
化合物6Compound 6	34.1534.15
化合物10Compound 10	72.9972.99
化合物12Compound 12	24.6424.64
化合物13Compound 13	56.8056.80
化合物41Compound 41	5050
化合物34-P2Compound 34-P2	96.3996.39
化合物35-P2Compound 35-P2	77.7477.74
化合物41-P1Compound 41-P1	38.1838.18

从表4可知，本公开的化合物对人PBMC细胞的TNF-α具有良好的抑制作用。It can be known from Table 4 that the compounds of the present disclosure have good inhibitory effect on TNF-α of human PBMC cells.

以上，对本公开的实施方式进行了说明。但是，本公开不限定于上述实施方式。凡在本公开的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本公开的保护范围之内。The embodiments of the present disclosure have been described above. However, the present disclosure is not limited to the above-mentioned embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present disclosure shall be included within the protection scope of the present disclosure.

Claims

一种如式I所示的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药：A compound as shown in formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug:

其中，W为CH或N；m为0-5的整数；n为0-3的整数；Wherein, W is CH or N; m is an integer of 0-5; n is an integer of 0-3;

环A为3-20元的含氮杂环基，除与母核
连接的N原子以外，还任选地含有1个、2个或更多个选自O、N或S的杂原子； Ring A is a nitrogen-containing heterocyclic group of 3-20 members, except for the parent nucleus
In addition to the attached N atom, it optionally contains 1, 2 or more heteroatoms selected from O, N or S;

R ¹选自H、卤素、CN和C _1-6烷基； R ¹ is selected from H, halogen, CN and C _1-6 alkyl;

R ²选自-OR ⁸¹、-NH-C(O)R ⁸²、-NHR ⁸³和-C(O)NHR ⁸⁴； R ² is selected from -OR ⁸¹ , -NH-C(O)R ⁸² , -NHR ⁸³ and -C(O)NHR ⁸⁴ ;

R ³选自H、C _1-10烷基和C _3-20环烷基； R ³ is selected from H, C _1-10 alkyl and C _3-20 cycloalkyl;

R ⁴选自H、卤素和C _1-10烷基； R ⁴ is selected from H, halogen and C _1-10 alkyl;

R ⁵分别独立地选自H、卤素、-OH、-C _1-6烷基、-C _1-6烷氧基、氧代(＝O)、-C(O)C _1-6烷基、羟基取代的C _1-10烷基、-C(O)OH、-C(O)NR ^91aR ^91b、-S(O) ₂R ⁹²和-S(O) ₂NR ^93aR ^93b； R ⁵ are independently selected from H, halogen, -OH, -C _1-6 alkyl, -C _1-6 alkoxy, oxo (=O), -C(O)C _1-6 alkyl, Hydroxyl substituted C _1-10 alkyl, -C(O)OH, -C(O)NR ^91a R ^91b , -S(O) ₂ R ⁹² and -S(O) ₂ NR ^93a R ^93b ;

R ⁶选自H、卤素和甲基； ^R is selected from H, halogen and methyl;

R ⁷分别独立地选自H、卤素、未取代或被Ra取代的C _1-10烷基、C _3-20环烷基；Ra选自卤素和C _3-20环烷基； R ⁷ are independently selected from H, halogen, unsubstituted or substituted C _1-10 alkyl, C _3-20 cycloalkyl; Ra is selected from halogen and C _3-20 cycloalkyl;

R ⁸¹、R ⁸²、R ⁸³、R ⁸⁴相同或不同，彼此独立地选自无取代或任选被1、2、3、4或5个Rb取代的C _6-14芳基-C _1-10烷基、5-14元杂芳基-C _1-10烷基、C _6-14芳基和5-14元杂芳基；每个Rb相同或不同，彼此独立地选自卤素、卤代C _1-10烷基、C _1-10烷基和C _1-10烷氧基； R ⁸¹ , R ⁸² , R ⁸³ , and R ⁸⁴ are the same or different, and are independently selected from C _6-14 aryl-C _1-10 unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 Rb Alkyl, 5-14 membered heteroaryl-C _1-10 alkyl, C _6-14 aryl and 5-14 membered heteroaryl; each Rb is the same or different, independently selected from halogen, halogenated C _1-10 alkyl, C _1-10 alkyl and C _1-10 alkoxy;

R ^91a、R ^91b、R ⁹²、R ^93a、R ^93b相同或不同，彼此独立地选自H、C _1-6烷基和C _3-20环烷基。 R ^91a , R ^91b , R ⁹² , R ^93a , and R ^93b are the same or different, and are independently selected from H, C _1-6 alkyl, and C _3-20 cycloalkyl.
根据权利要求1所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其特征在于，The compound according to claim 1, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug, is characterized in that,

W为CH或N；m为0、1、2、3、4或5；n为0、1、2、3；W is CH or N; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3;

环A为3-12元的含氮杂环基，除与所述母核连接的N原子以外，还任选地含有1个、2个或更多个选自O、N或S的杂原子；Ring A is a 3-12 membered nitrogen-containing heterocyclic group, which optionally contains 1, 2 or more heteroatoms selected from O, N or S in addition to the N atom connected to the parent nucleus ;

R ¹选自H、卤素、CN和C _1-6烷基； R ¹ is selected from H, halogen, CN and C _1-6 alkyl;

R ²选自-OR ⁸¹、-NH-C(O)R ⁸²、-NHR ⁸³和-C(O)NHR ⁸⁴； R ² is selected from -OR ⁸¹ , -NH-C(O)R ⁸² , -NHR ⁸³ and -C(O)NHR ⁸⁴ ;

R ³选自H、C _1-6烷基和C _3-12环烷基； R ³ is selected from H, C _1-6 alkyl and C _3-12 cycloalkyl;

R ⁴选自H、卤素和C _1-6烷基； R ⁴ is selected from H, halogen and C _1-6 alkyl;

R ⁵分别独立地选自H、卤素、-OH、C _1-6烷基、C _1-6烷氧基、氧代(＝O)、-C(O)C _1-6烷基、羟基取代的C _1-6烷基、-C(O)OH、-C(O)NR ^91aR ^91b、-S(O) ₂R ⁹²和-S(O) ₂NR ^93aR ^93b； R ⁵ are independently selected from H, halogen, -OH, C _1-6 alkyl, C _1-6 alkoxy, oxo (=O), -C(O)C _1-6 alkyl, hydroxy substituted C _1-6 alkyl, -C(O)OH, -C(O)NR ^91a R ^91b , -S(O) ₂ R ⁹² and -S(O) ₂ NR ^93a R ^93b ;

R ⁶选自H、卤素和甲基； ^R is selected from H, halogen and methyl;

R ⁷分别独立地选自H、卤素、C _1-6烷基和C _3-12环烷基； R ⁷ are independently selected from H, halogen, C _1-6 alkyl and C _3-12 cycloalkyl;

R ⁸¹、R ⁸²、R ⁸³、R ⁸⁴相同或不同，彼此独立地选自C _6-14芳基-C _1-6烷基、5-14元杂芳基-C _1-6烷基、C _6-14芳基、5-14元杂芳基；其中芳基或杂芳基各自无取代或任选被1、2、3、4或5个彼此独立地选自卤素、卤代C _1-6烷基、C _1-6烷基和C _1-3烷氧基取代； R ⁸¹ , R ⁸² , R ⁸³ , and R ⁸⁴ are the same or different, and are independently selected from C _6-14 aryl-C _1-6 alkyl, 5-14 membered heteroaryl-C _1-6 alkyl, C _6-14 aryl, 5-14 membered heteroaryl; wherein each aryl or heteroaryl is unsubstituted or optionally 1, 2, 3, 4 or 5 independently selected from halogen, halogenated C _{1- 6} alkyl, C _1-6 alkyl and C _1-3 alkoxy are substituted;

R ^91a、R ^91b、R ⁹²、R ^93a、R ^93b相同或不同，彼此独立地选自H、C _1-6烷基和C _3-10环烷基。 R ^91a , R ^91b , R ⁹² , R ^93a , and R ^93b are the same or different, and are independently selected from H, C _1-6 alkyl, and C _3-10 cycloalkyl.
根据权利要求1或2所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，W为CH或N；m为0、1、2、3、4或5；n为0、1、2、3；The compound according to claim 1 or 2, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug, W is CH or N ; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3;

环A为3-9元的含氮杂环基，除与所述母核连接的N原子以外，还任选地含有1个、2个或更多个选自O、N或S的杂原子；Ring A is a 3-9 membered nitrogen-containing heterocyclic group, which optionally contains 1, 2 or more heteroatoms selected from O, N or S in addition to the N atom connected to the parent nucleus ;

R ¹选自卤素； R ¹ is selected from halogen;

R ²选自-OR ⁸¹、-NH-C(O)R ⁸²、-NHR ⁸³和-C(O)NHR ⁸⁴； R ² is selected from -OR ⁸¹ , -NH-C(O)R ⁸² , -NHR ⁸³ and -C(O)NHR ⁸⁴ ;

R ³选自C _1-3烷基和C _3-6环烷基； R ³ is selected from C _1-3 alkyl and C _3-6 cycloalkyl;

R ⁴为C _1-3烷基或卤素； R ⁴ is C _1-3 alkyl or halogen;

R ⁵分别独立地选自卤素、-OH、-C _1-3烷基、-C _1-3烷氧基、氧代(＝O)、-C(O)C _1-3烷基、羟基取代的C _1-3烷基、-C(O)OH、-C(O)NR ^91aR ^91b、-S(O) ₂R ⁹²和-S(O) ₂NR ^93aR ^93b； R ⁵ are independently selected from halogen, -OH, -C _{1-3 alkyl, -C 1-3} _alkoxy , oxo (=O), -C(O)C _1-3 alkyl, hydroxy substituted C _1-3 alkyl, -C(O)OH, -C(O)NR ^91a R ^91b , -S(O) ₂ R ⁹² and -S(O) ₂ NR ^93a R ^93b ;

R ⁶选自H、卤素和甲基； ^R is selected from H, halogen and methyl;

R ⁷分别独立地选自H、卤素和C _1-3烷基； R ⁷ are independently selected from H, halogen and C _1-3 alkyl;

R ⁸¹、R ⁸²、R ⁸³、R ⁸⁴相同或不同，彼此独立地选自C _6-8芳基-C _1-3烷基、5-6元杂芳基-C _1-3烷基、C _6-8芳基、5-6元杂芳基；其中芳基或杂芳基各自无取代或任选被1、2、3、4或5个彼此独立地选自卤素、卤代C _1-3烷基、C _1-3烷基和C _1-3烷氧基取代； R ⁸¹ , R ⁸² , R ⁸³ , and R ⁸⁴ are the same or different, and are independently selected from C _6-8 aryl-C _1-3 alkyl, 5-6 membered heteroaryl-C _1-3 alkyl, C _6-8 aryl, 5-6 membered heteroaryl; wherein each aryl or heteroaryl is unsubstituted or optionally 1, 2, 3, 4 or 5 independently selected from halogen, halogenated C _{1- 3} alkyl, C _1-3 alkyl and C _1-3 alkoxy are substituted;

R ^91a、R ^91b、R ⁹²、R ^93a、R ^93b相同或不同，彼此独立地选自H、C _1-3烷基和C _3-7环烷基。 R ^91a , R ^91b , R ⁹² , R ^93a , and R ^93b are the same or different, and are independently selected from H, C _1-3 alkyl, and C _3-7 cycloalkyl.
根据权利要求1-3任一项所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其特征在于，W为CH或N；m为0、1、2或3；n为0或1；The compound according to any one of claims 1-3, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein In that, W is CH or N; m is 0, 1, 2 or 3; n is 0 or 1;

所述环A选自以下结构：The ring A is selected from the following structures:

R ¹为Cl或Br； R ¹ is Cl or Br;

R ²选自-OR ⁸¹、-NH-C(O)R ⁸²、-NHR ⁸³和-C(O)NHR ⁸⁴； R ² is selected from -OR ⁸¹ , -NH-C(O)R ⁸² , -NHR ⁸³ and -C(O)NHR ⁸⁴ ;

R ³为甲基或环丙基； R ³ is methyl or cyclopropyl;

R ⁴为甲基； R ⁴ is methyl;

R ⁵选自F、-OH、甲基、甲氧基、乙氧基、氧代(＝O)、-C(O)C _1-3烷基、2-羟基异丙基、-C(O)OH、-C(O)NH ₂、-C(O)NHCH ₃、-S(O) ₂CH ₃、S(O) ₂CH ₂CH ₃和-S(O) ₂-环丙烷； R ^is selected from F, -OH, methyl, methoxy, ethoxy, oxo (=O), -C(O)C _1-3 alkyl, 2-hydroxyisopropyl, -C(O )OH, -C(O)NH ₂ , -C(O)NHCH ₃ , -S(O) ₂ CH ₃ , S(O) ₂ CH ₂ CH ₃ and -S(O) ₂ -cyclopropane;

R ⁶选自H、F和Cl； ^R is selected from H, F and Cl;

R ⁷为H； ^R7 is H;

R ⁸¹、R ⁸²、R ⁸³、R ⁸⁴相同或不同，彼此独立地选自无取代或任选被1、2或3个Rb取代的苯基甲基、吡啶基甲基、吡啶基乙基、苯基和吡啶基；每个Rb相同或不同，彼此独立地选自F、Cl和CF ₃。 R ⁸¹ , R ⁸² , R ⁸³ , and R ⁸⁴ are the same or different, and are independently selected from phenylmethyl, pyridylmethyl, pyridylethyl, unsubstituted or optionally substituted by 1, 2 or 3 Rb, Phenyl and pyridyl; each Rb is the same or different, independently selected from F, Cl and _CF3 .
根据权利要求1-4任一项所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其特征在于，所述R ₅和环A形成的结构可以选自： The compound according to any one of claims 1-4, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug thereof, characterized in In that, the structure formed by said R ₅ and ring A can be selected from:

优选地，式Ⅰ化合物具有式Ⅰa或Ⅰb所示的结构：Preferably, the compound of formula I has the structure shown in formula Ia or Ib:

其中，R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、R ⁷、A、W、m和n具有权利要求1-4任一项所述的定义。 Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , A, W, m and n have the definitions described in any one of claims 1-4.
根据权利要求1-5任一项所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其特征在于，式Ⅰ化合物具有式Ⅱ所示的结构：The compound according to any one of claims 1-5, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein In that, the compound of formula I has the structure shown in formula II:

其中R ¹、R ³、R ⁴、R ⁵、R ⁶、R ⁷、m、n、W和环A彼此独立地具有权利要求1-5任一项所述的定义； Wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , m, n, W and ring A independently have the definition described in any one of claims 1-5;

R ¹⁰选自H、卤素、未取代或任选被1个、2个或更多个卤素、OH、NH ₂取代的下列基团：C _1-10烷基、C _1-10烷氧基、卤代C _1-10烷基、卤代C _1-10烷氧基、C _2-10烯基、C _2-10烯基氧基、C _2-10炔基和C _2-10炔基氧基； R ¹⁰ is selected from H, halogen, unsubstituted or optionally substituted by 1, 2 or more halogens, OH, NH ₂ from the following groups: C _1-10 alkyl, C _1-10 alkoxy, Halogenated C _1-10 alkyl, halogenated C _1-10 alkoxy, C _2-10 alkenyl, C _2-10 alkenyloxy, C _2-10 alkynyl and C _2-10 alkynyloxy ;

每个R ¹¹相同或不同，彼此独立地选自H、卤素、C _1-6烷基和卤代C _1-10烷基； Each R ¹¹ is the same or different, independently selected from H, halogen, C _1-6 alkyl and halogenated C _1-10 alkyl;

p为0-4的整数；p is an integer of 0-4;

优选地，R ¹⁰选自H、卤素、C _1-3烷基、卤代C _1-3烷基；p为0、1或2； Preferably, R ¹⁰ is selected from H, halogen, C _1-3 alkyl, halogenated C _1-3 alkyl; p is 0, 1 or 2;

每个R ¹¹相同或不同，彼此独立地选自H、卤素、C _1-3烷基、卤代C _1-3烷基；更优选地，R ¹⁰为H或甲基；p为0、1或2； Each R ¹¹ is the same or different, independently selected from H, halogen, C _1-3 alkyl, halogenated C _1-3 alkyl; more preferably, R ¹⁰ is H or methyl; p is 0, 1 or 2;

每个R ¹¹相同或不同，彼此独立地选自F、Cl和CF ₃； Each R ¹¹ is the same or different, independently selected from F, Cl and CF ₃ ;

优选地，式Ⅱ化合物具有式Ⅱa或式Ⅱb：Preferably, the compound of formula II has formula IIa or formula IIb:

其中，R ¹、R ³、R ⁴、R ⁵、R ⁶、R ⁷、R ¹⁰、R ¹¹、A、W、m、n和p具有权利要求1-5任一项所述的定义。 Wherein, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ , A, W, m, n and p have the definitions described in any one of claims 1-5.
根据权利要求1-6任一项所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药，其特征在于，所述化合物具有以下结构：The compound according to any one of claims 1-6, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein In that, the compound has the following structure:

优选地，式I所示化合物具有以下结构：Preferably, the compound shown in formula I has the following structure:
权利要求1-7任一项所述化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药的制备方法，其特征在于，包括以下步骤：The preparation method of the compound described in any one of claims 1-7, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug, which It is characterized in that it comprises the following steps:

方案一：化合物a1与化合物a2发生偶联反应得到式Ⅰ化合物。Scheme 1: compound a1 and compound a2 undergo a coupling reaction to obtain a compound of formula I.

反应式如下：The reaction formula is as follows:

其中，Y为Cl或Br；W、R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、R ⁷、m、n和环A彼此独立地具有权利要求1-7任一项所述定义； Wherein, Y is Cl or Br; W, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , m, n and ring A independently have the following properties as defined in any one of claims 1-7. definition;

方案二：当W为N，R ₇为H时，化合物b1与化合物b2反应得到式Ⅱ化合物； Scheme 2: When W is N and R ₇ is H, compound b1 reacts with compound b2 to obtain a compound of formula II;

反应式如下：The reaction formula is as follows:

其中R ¹、R ³、R ⁴、R ⁵、R ⁶、R ⁷、R ¹⁰、R ¹¹、m、n、p和环A彼此独立地具有权利要求1-7任一项所述的定义； Wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ , m, n, p and ring A independently have the definition described in any one of claims 1-7;

优选地，所述反应在无机碱的存在下进行；所述无机碱选自碳酸钠、碳酸钾、碳酸铯、氢氧化钠和氢氧化钾中的一种；Preferably, the reaction is carried out in the presence of an inorganic base; the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide;

优选地，当R ₅为OH时，化合物b2中的OH可以被硅保护基保护，所述硅保护基可以为叔丁基二苯基硅基；所述硅保护基在所述反应中会脱除，得到脱保护的OH。 Preferably, when R ₅ is OH, the OH in compound b2 can be protected by a silicon protecting group, and the silicon protecting group can be tert-butyldiphenylsilyl; the silicon protecting group will be removed in the reaction In addition, the deprotected OH is obtained.
一种药物组合物，其包含治疗有效量的权利要求1-7任一项所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药化合物中的至少一种，以及一种或多种药学上可接受的载体。A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-7, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically At least one of acceptable salts or prodrug compounds thereof, and one or more pharmaceutically acceptable carriers.
权利要求1-7任一项所述的化合物、其消旋体、立体异构体、互变异构体、同位素标记物、溶剂化物、药学上可接受的盐或其前药化合物中的至少一种，或如权利要求9所述的药物组合物在制备药物中的用途；At least one of the compound described in any one of claims 1-7, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug compound One, or the purposes of the pharmaceutical composition as claimed in claim 9 in the preparation of medicine;

优选地，所述药物为治疗和/或预防与p38激酶抑制剂有关的疾病的药物，例如可以为MK2抑制剂或p38 MAPK/MK2通路调节剂；Preferably, the drug is a drug for treating and/or preventing diseases related to p38 kinase inhibitors, such as MK2 inhibitors or p38 MAPK/MK2 pathway regulators;

优选地，所述疾病为与p38 MAPK/MK2通路相关的疾病，例如可以为自体免疫疾病和炎症性疾病(如类风湿性关节炎、发脓性汗腺炎、银屑病、炎症性肠病、特发性皮炎、***性红斑狼疮等)、骨骼疾病、代谢疾病、神经和神经退化性疾病、癌症、心血管疾病、过敏症和哮喘、阿尔茨海默氏病和激素相关疾病。Preferably, the disease is a disease related to the p38 MAPK/MK2 pathway, for example, it can be an autoimmune disease and an inflammatory disease (such as rheumatoid arthritis, hidradenitis suppurativa, psoriasis, inflammatory bowel disease, idiopathic dermatitis, systemic lupus erythematosus, etc.), bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone-related diseases.