WO2024255856A1 - Compound for regulating tead activity, preparation method therefor, and use thereof - Google Patents

Abstract

The present application relates to a compound of formula (I) for regulating TEAD activity, a stereoisomer or tautomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, a pharmaceutical composition comprising same, and a use thereof for inhibiting TEAD activity.

Description

Translated fromChinese

一种调控TEAD活性的化合物、其制备方法及其用途A compound for regulating TEAD activity, preparation method and use thereof技术领域Technical Field

本申请涉及一种调控TEAD活性的化合物、其制备方法及其用途，具体涉及可用作药物的调控TEAD活性的化合物、及其药理学上可接受的盐、含有化合物或其盐的组合物以及其制备方法，及其用于制备药物的用途，属于医药化学领域。The present application relates to a compound for regulating TEAD activity, a preparation method and use thereof, and specifically to a compound for regulating TEAD activity that can be used as a drug, and a pharmacologically acceptable salt thereof, a composition containing the compound or its salt, and a preparation method thereof, and use thereof for preparing a drug, and belongs to the field of medicinal chemistry.

背景技术Background Art

Hippo信号通路是由一系列激酶级联组成的高度保守的信号通路，参与调节细胞增殖、细胞分化、细胞干性、细胞外间质沉积、损伤修复、器官发育等生理过程，是癌症生物发生和肿瘤维持的重要途径。在许多癌症适应症中，Hippo信号通路因为诸如NF2之类基因编码的蛋白功能缺失，导致下游共转录激活因子过度活化，这些转录因子包括YAP(Yes Associated Protein，Yes关联蛋白)和TAZ(Transcriptional coactivator with PDZ-binding motif，带有PDZ结合域的转录共激活因子)。YAP包括了多个结构域和特定的氨基酸序列，包括一个TEAD(Transcriptional Enhanced Associate Domains)结合区域，两个WW结构域，一个富含脯氨酸的N-末端结构域，一个C-末端的PDZ结合基序，一个SH3结合基序，一个卷曲螺旋结构域和一个转录激活结构域。TAZ与YAP同源，具有与YAP相似的结构域和功能，但缺少富含脯氨酸的结构域和第二个WW结构域。过度活化的YAP/TAZ转移到细胞核，在细胞核中与包括TEADs在内的几个核转录因子结合，形成转录复合物，促进包括CTGF(Connective tissue growth factor，结缔组织生长因子)、Cyr61(Mysteine rich angiogenic inducer61，富含半胱氨酸的血管生成诱导剂61)和AXL(AXL receptor tyrosine kinase，受体酪氨酸激酶AXL)等在内的几个下游靶基因的异常表达，进而引起机体的生理病理过程。The Hippo signaling pathway is a highly conserved signaling pathway composed of a series of kinase cascades. It is involved in regulating physiological processes such as cell proliferation, cell differentiation, cell stemness, extracellular matrix deposition, damage repair, and organ development. It is an important pathway for cancer biogenesis and tumor maintenance. In many cancer indications, the Hippo signaling pathway is caused by the loss of protein function encoded by genes such as NF2, which leads to the overactivation of downstream co-transcriptional activators, including YAP (Yes Associated Protein) and TAZ (Transcriptional coactivator with PDZ-binding motif). YAP includes multiple domains and specific amino acid sequences, including a TEAD (Transcriptional Enhanced Associate Domains) binding region, two WW domains, a proline-rich N-terminal domain, a C-terminal PDZ binding motif, an SH3 binding motif, a coiled-coil domain and a transcriptional activation domain. TAZ is homologous to YAP and has similar domains and functions to YAP, but lacks the proline-rich domain and the second WW domain. Overactivated YAP/TAZ translocates to the nucleus, where it binds to several nuclear transcription factors including TEADs to form a transcription complex, promoting the abnormal expression of several downstream target genes including CTGF (Connective tissue growth factor), Cyr61 (Mysteine rich angiogenic inducer 61) and AXL (AXL receptor tyrosine kinase), thereby causing physiological and pathological processes in the body.

TEADs/TEAD(转录增强相关结构域)是YAP和TAZ最重要的转录因子，也是Hippo信号通路的最终效应器。人类TEAD家族转录因子包括四个成员TEAD1/2/3/4。所有TEADs亚型N端都有一个与DNA结合的TEA结构域，在C末端都有一个与YAP/TAZ结合的结构域，DNA结合域和YAP/TAZ结合域在哺乳动物中高度保守，但在连接TEA结构域和反式激活结构域的连接子上有很大的不同，四个TEADs亚型的总体同源性介于61％至73％之间。TEADs的功能由其与核辅助激活因子的相互作用介导，YAP是与TEADs相互作用的主要核辅助激活因子。TEADs/TEAD (transcription enhancer associated domain) are the most important transcription factors of YAP and TAZ, and are also the final effectors of the Hippo signaling pathway. The human TEAD family transcription factors include four members, TEAD1/2/3/4. All TEADs subtypes have a DNA-binding TEA domain at the N-terminus and a YAP/TAZ-binding domain at the C-terminus. The DNA-binding domain and the YAP/TAZ-binding domain are highly conserved in mammals, but they differ greatly in the linker connecting the TEA domain and the transactivation domain. The overall homology of the four TEADs subtypes ranges from 61% to 73%. The function of TEADs is mediated by its interaction with nuclear coactivators, and YAP is the main nuclear coactivator that interacts with TEADs.

研究表明，在Hippo通路失调后，YAP/TAZ的过渡激活在肺癌、肝癌、胰腺癌、乳腺癌等癌症细胞中普遍高表达。在多种实体瘤的肿瘤干细胞中，YAP/TAZ可以促进肿瘤干细胞的存活，并且与肿瘤细胞转移和耐药性关系密切，促进多种肿瘤的发生和发展。在化疗药物治疗期间，抗微管药物、抗代谢药物和DNA损伤剂等可影响Hippo信号通路，导致YAP/TAZ激活和转录，从而产生耐药性。YAP/TAZ的过度激活会引起多种药物转运蛋白的高度表达，其可以将药物转移至胞外，导致抗凋亡蛋白如Bcl和survivin的上调，从而抑制细胞凋亡。许多研究表明，解除Hippo通路的下调引起YAP/TAZ的激活是多种靶向耐药的主要机制；YAP/TAZ的激活不仅与耐药性有关，研究表明YAP基因扩增还与结肠癌和胰腺癌的复发相关。Studies have shown that after the Hippo pathway is dysregulated, the transitional activation of YAP/TAZ is generally highly expressed in cancer cells such as lung cancer, liver cancer, pancreatic cancer, and breast cancer. In tumor stem cells of various solid tumors, YAP/TAZ can promote the survival of tumor stem cells, and is closely related to tumor cell metastasis and drug resistance, promoting the occurrence and development of various tumors. During chemotherapy drug treatment, anti-microtubule drugs, anti-metabolism drugs, and DNA damaging agents can affect the Hippo signaling pathway, leading to YAP/TAZ activation and transcription, thereby producing drug resistance. Excessive activation of YAP/TAZ can cause the high expression of various drug transporters, which can transfer drugs to the extracellular space, leading to the upregulation of anti-apoptotic proteins such as Bcl and survivin, thereby inhibiting cell apoptosis. Many studies have shown that the activation of YAP/TAZ caused by the downregulation of the Hippo pathway is the main mechanism of multiple targeted drug resistance; YAP/TAZ activation is not only related to drug resistance, but studies have shown that YAP gene amplification is also associated with the recurrence of colon cancer and pancreatic cancer.

YAP/TAZ-TEADs的激活对肿瘤发展具有明显的促进作用。在一些癌症中，如恶性间皮瘤、卵巢癌和胆管癌，YAP/TAZ-TEADs复合物经常过度激活或过度表达，导致癌症恶化发展。这种过度激活通常是由Hippo信号通路上游基因的改变引起的，尤其在恶性间皮瘤患者中，YAP/TAZ-TEADs复合物的过度激活有助于促进肿瘤细胞的增殖、转移、上皮向间充质转化(EMT)和肿瘤干细胞的维持。现有研究表明YAP/TAZ-TEADs的下游蛋白CTGF和CYR61能够诱导肿瘤细胞对紫杉醇等化疗药物产生耐药性。YAP/TAZ-TEADs已成为耐药癌细胞的替代生存途径。The activation of YAP/TAZ-TEADs has a significant promoting effect on tumor development. In some cancers, such as malignant mesothelioma, ovarian cancer, and cholangiocarcinoma, the YAP/TAZ-TEADs complex is often overactivated or overexpressed, leading to the deterioration and development of cancer. This overactivation is usually caused by changes in upstream genes of the Hippo signaling pathway. Especially in patients with malignant mesothelioma, the overactivation of the YAP/TAZ-TEADs complex helps promote tumor cell proliferation, metastasis, epithelial to mesenchymal transition (EMT), and maintenance of tumor stem cells. Existing studies have shown that the downstream proteins of YAP/TAZ-TEADs, CTGF and CYR61, can induce tumor cells to develop resistance to chemotherapeutic drugs such as paclitaxel. YAP/TAZ-TEADs has become an alternative survival pathway for drug-resistant cancer cells.

现有研究表明，YAP和TEADs的相互作用对于启动转录程序以促进肿瘤发生和增殖至关重要，DNA结合域缺陷的TEADs能够阻断Hippo信号通路上游基因突变介导的肿瘤形成。TEAD关键位置的点突变，尤其是与YAP和TEAD结合域相关的突变，显著抑制了YAP诱导基因的表达和功能。YAP/TAZ-TEAD相互作用的破坏可以消除YAP/TAZ的致癌特性，抑制YAP/TAZ与TEADs的相互作用后能明显抑制肿瘤细胞的增殖。因此抑制YAP/TAZ与TEADs的相互作用具有抗肿瘤、治疗肿瘤的潜力，特别是Hippo信号通路上游过度激活或突变的肿瘤。YAP/TAZ与TEADs相互作用的抑制是有希望的新型肿瘤治疗法。Existing studies have shown that the interaction between YAP and TEADs is essential for initiating transcriptional programs to promote tumorigenesis and proliferation, and TEADs with defects in the DNA binding domain can block tumor formation mediated by mutations in genes upstream of the Hippo signaling pathway. Point mutations at key positions of TEAD, especially mutations associated with the YAP and TEAD binding domains, significantly inhibit the expression and function of YAP-induced genes. Disruption of the YAP/TAZ-TEAD interaction can eliminate the oncogenic properties of YAP/TAZ, and inhibiting the interaction between YAP/TAZ and TEADs can significantly inhibit the proliferation of tumor cells. Therefore, inhibiting the interaction between YAP/TAZ and TEADs has the potential to be anti-tumor and treat tumors, especially tumors with overactivation or mutations in the upstream of the Hippo signaling pathway. Inhibition of the interaction between YAP/TAZ and TEADs is a promising new tumor therapy.

为靶向Hippo致癌途径，本申请提供一种TEAD抑制剂，防止TEAD棕榈酰化，选择性结合于TEAD并破坏其与YAP/TAZ的相互作用，由此下调YAP依赖性和TAZ依赖性转录，抑制YAP与TEAD之间的相互作用，抑制肿瘤细胞增殖(例如间皮瘤肿瘤细胞、恶性胸膜间皮瘤肿瘤细胞等)、抑制肿瘤的侵袭和转移、降低靶向药或化疗药物的耐药、降低肿瘤的免疫逃逸，实现治疗肿瘤的作用。To target the Hippo oncogenic pathway, the present application provides a TEAD inhibitor that prevents TEAD palmitoylation, selectively binds to TEAD and disrupts its interaction with YAP/TAZ, thereby downregulating YAP-dependent and TAZ-dependent transcription, inhibiting the interaction between YAP and TEAD, and They interact with each other, inhibit the proliferation of tumor cells (such as mesothelioma tumor cells, malignant pleural mesothelioma tumor cells, etc.), inhibit the invasion and metastasis of tumors, reduce the resistance of targeted drugs or chemotherapy drugs, and reduce the immune escape of tumors, thereby achieving the effect of treating tumors.

另外，本申请所描述的TEAD抑制剂抑制体外YAP/TAZ依赖性细胞增殖(即，Hippo途径缺陷型癌细胞系)，但不抑制Hippo途径野生型癌细胞系的增殖。In addition, the TEAD inhibitors described herein inhibit YAP/TAZ-dependent cell proliferation in vitro (ie, Hippo pathway-deficient cancer cell lines), but do not inhibit the proliferation of Hippo pathway wild-type cancer cell lines.

发明内容Summary of the invention

本申请提供一种式(I)所示的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物(例如水合物)、或其前药，
The present application provides a compound represented by formula (I), its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate (such as a hydrate), or its prodrug,

X、Y各自独立地选自CR⁰或N，X and Y are each independently selected from CR⁰ or N,

Z为C₁～C₆链状烃基，Z is a C₁ to C₆ chain hydrocarbon group,

W²、W³各自独立地选自C、CR²或N，W² and W³ are each independently selected from C, CR² or N,

W¹为不存在、CR¹或N，W⁴选自C或N，W⁵选自C＝O、CR³或N，且当W¹为不存在或者当W⁵为C＝O时，W⁴为N，^W1 is absent,^CR1 or N,^W4 is selected from C or N,^W5 is selected from C=O,^CR3 or N, and when^W1 is absent or when^W5 is C=O,^W4 is N,

表示芳香环， represents an aromatic ring,

环C为不存在、芳环、芳杂环、不饱和脂环或不饱和脂杂环，Ring C is absent, an aromatic ring, an aromatic heterocyclic ring, an unsaturated alicyclic ring or an unsaturated alicyclic heterocyclic ring,

环A选自芳环、芳杂环、饱和脂环、不饱和脂环、不饱和脂杂环、芳环与不饱和脂环构成的并环、芳杂环与不饱和脂环构成的并环、芳环与不饱和脂杂环构成的并环、芳杂环与不饱和脂杂环构成的并环，Ring A is selected from an aromatic ring, an aromatic heterocycle, a saturated alicyclic ring, an unsaturated alicyclic ring, an unsaturated alicyclic heterocycle, a cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, a cyclic ring consisting of an aromatic ring and an unsaturated alicyclic heterocycle, and a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic heterocycle.

环B选自芳环、芳杂环、饱和脂杂环、不饱和脂杂环、芳环与不饱和脂环构成的并环、芳杂环与不饱和脂环构成的并环、芳环与不饱和脂杂环构成的并环、芳杂环与不饱和脂杂环构成的并环，Ring B is selected from an aromatic ring, an aromatic heterocycle, a saturated alicyclic heterocycle, an unsaturated alicyclic heterocycle, a cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, a cyclic ring consisting of an aromatic ring and an unsaturated alicyclic heterocycle, and a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic heterocycle.

m、n、o各自独立地选自0、1、2、3、4，m, n, and o are each independently selected from 0, 1, 2, 3, and 4,

R^A、R^B、R⁰、R¹、R²、R³各自独立地选自氢、氘、氚、硝基、羟基、巯基、卤素、氰基、胺基、酯基、醛基、羧基、羰基、酰胺基、C₁～C₆烷基、C₁～C₆卤代烷基、C₁～C₆烷氧基、C₁～C₆卤代烷氧基，R^A , R^B , R⁰ , R¹ , R² , and R³ are each independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C₁ -C₆ alkyl, C₁ -C₆ haloalkyl, C₁ -C₆ alkoxy, C₁ -C₆ haloalkoxy,

其中，所述R⁰、R¹、R²、R³、R^A、R^B、环C各自任选地被氘、氚、硝基、羟基、醛基、胺基、亚胺基、卤素、氰基、酯基、羧基、酰胺基、＝O、C₁～C₆烷基、C₁～C₆烷氧基中的一个或两个以上取代，wherein each of R⁰ , R¹ , R² , R³ ,^RA ,^RB , and ring C is optionally substituted by one or more of deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano, ester, carboxyl, amide, =O, C₁ -C₆ alkyl, and C₁ -C₆ alkoxy groups,

所述Z任选地被氘、氚、硝基、羟基、醛基、胺基、亚胺基、卤素、氰基、酯基、羧基、酰胺基、＝O、C₁～C₆烷基、C₁～C₆烷氧基、3～8元环烷基、3～8元杂环烷基中的一个或两个以上取代，The Z is optionally substituted by one or more of deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano, ester, carboxyl, amide, =O, C₁ ～C₆ alkyl, C₁ ～C₆ alkoxy, 3～8-membered cycloalkyl, 3～8-membered heterocycloalkyl,

所述芳杂环、不饱和脂杂环、饱和脂杂环各自独立地包含1～4个杂原子，所述杂环烷基包含1～2个杂原子，所述杂原子独立地选自N、O、S。The aromatic heterocycle, unsaturated aliphatic heterocycle and saturated aliphatic heterocycle each independently contain 1 to 4 heteroatoms; the heterocycloalkyl group contains 1 to 2 heteroatoms, and the heteroatoms are independently selected from N, O and S.

本申请某些实施方案中，环C为不存在、芳环、芳杂环、不饱和脂环或不饱和脂杂环。In certain embodiments of the present application, ring C is absent, an aromatic ring, an aromatic heterocycle, an unsaturated alicyclic ring, or an unsaturated alicyclic heterocycle.

本申请某些实施方案中，所述环C不存在或者为5～10元芳杂环、优选5～6元芳杂环。优选地，所述环C不存在或者为包含1～3个杂原子(优选包含1～2个杂原子)的5～6元芳杂环，所述杂原子选自N、O、S(优选杂原子为N)，且W²、W³均选自C，所述环C任选地被独立地选自氘、氚、硝基、羟基、醛基、胺基、亚胺基、卤素、氰基、酯基、羧基、酰胺基、＝O、C₁～C₆烷基、C₁～C₆烷氧基中的一个或两个以上取代(优选地，所述环C任选地被独立地选自氘、氚、C₁～C₆烷基中的一个或两个以上取代)。In certain embodiments of the present application, the ring C does not exist or is a 5-10-membered aromatic heterocycle, preferably a 5-6-membered aromatic heterocycle. Preferably, the ring C does not exist or is a 5-6-membered aromatic heterocycle containing 1-3 heteroatoms (preferably containing 1-2 heteroatoms), the heteroatoms are selected from N, O, S (preferably the heteroatom is N), and^W2 and^W3 are both selected from C, and the ring C is optionally substituted by one or more independently selected from deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano, ester, carboxyl, amide, =O,_C1 -_C6 alkyl,_C1 -_C6 alkoxy (preferably, the ring C is optionally substituted by one or more independently selected from deuterium, tritium,_C1 -_C6 alkyl).

本申请某些实施方案中，所述环C不存在，且W²、W³各自独立地选自CR²或N，所述R²定义与前述一致；In certain embodiments of the present application, the ring C does not exist, and W² and W³ are each independently selected from CR² or N, and the definition of R² is consistent with the above;

本申请某些实施方案中，所述环C为5元芳杂环(例如包含1～3个杂原子的5元芳杂环，优选包含1～2个杂原子的芳杂环，所述杂原子选自N、O、S)，且W²、W³均选自C，所述环C任选地被独立地选自氘、氚、硝基、羟基、醛基、胺基、亚胺基、卤素、氰基、酯基、羧基、酰胺基、＝O、C₁～C₆烷基、C₁～C₆烷氧基中的一个或两个以上取代；In certain embodiments of the present application, the ring C is a 5-membered aromatic heterocycle (for example, a 5-membered aromatic heterocycle containing 1 to 3 heteroatoms, preferably an aromatic heterocycle containing 1 to 2 heteroatoms, wherein the heteroatoms are selected from N, O, and S), and W² and W³ are both selected from C, and the ring C is optionally independently selected from deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano, ester, carboxyl, amide, =O, C₁ to C₆ alkyl, C₁ to C₆ One or more substitutions in the alkoxy group;

本申请某些实施方案中，所述环C为3～8元不饱和脂杂环(例如包含1～2个杂原子的3～8元不饱和脂杂环，所述杂原子选自N、O、S)，且W²、W³均选自C，所述环C任选地被独立地选自氘、氚、硝基、羟基、醛基、胺基、亚胺基、卤素、氰基、酯基、羧基、酰胺基、＝O、C₁～C₆烷基、C₁～C₆烷氧基中的一个或两个以上取代；In certain embodiments of the present application, the ring C is a 3-8 membered unsaturated aliphatic heterocyclic ring (e.g., a 3-8 membered unsaturated aliphatic heterocyclic ring containing 1-2 heteroatoms, wherein the heteroatoms are selected from N, O, and S), and W² and W³ are both selected from C, and the ring C is optionally substituted by one or more of deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano, ester, carboxyl, amide, =O, C₁ -C₆ alkyl, and C₁ -C₆ alkoxy groups independently selected;

本申请某些实施方案中，所述环C为3～8元不饱和脂环(也称为C₃～C₈不饱和脂环)，且W²、W³均选自C，所述环C任选地被独立地选自氘、氚、硝基、羟基、醛基、胺基、亚胺基、卤素、氰基、酯基、羧基、酰胺基、＝O、C₁～C₆烷基、C₁～C₆烷氧基中的一个或两个以上取代；In certain embodiments of the present application, the ring C is a 3-8 membered unsaturated alicyclic ring (also referred to as a C₃ -C₈ unsaturated alicyclic ring), and W² and W³ are both selected from C, and the ring C is optionally substituted by one or more independently selected from deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano, ester, carboxyl, amide, =O, C₁ -C₆ alkyl, C₁ -C₆ alkoxy;

本申请某些实施方案中，W¹选自CR¹，W²、W³同时选自C或CR²，W⁴选自C，W⁵选自CR³，所述R¹、R²、R³与前述定义一致；In certain embodiments of the present application, W¹ is selected from CR¹ , W² and W³ are simultaneously selected from C or CR² , W⁴ is selected from C, W⁵ is selected from CR³ , and R¹ , R² , and R³ are consistent with the above definitions;

本申请某些实施方案中，W¹选自CR¹或N，W²、W³同时选自C或者W²、W³各自独立地选自CR²，W⁴选自C，W⁵选自CR³，所述R¹、R²、R³与前述定义一致；In certain embodiments of the present application, W¹ is selected from CR¹ or N, W² and W³ are simultaneously selected from C or W² and W³ are each independently selected from CR² , W⁴ is selected from C, and W⁵ is selected from CR³ , and R¹ , R² , and R³ are consistent with the above definitions;

本申请某些实施方案中，W¹为CR¹或N，R¹选自氢、氘、氚、羟基、卤素、胺基、C₁～C₆烷基和C₁～C₆卤代烷基(优选地，R¹选自氢、氘、氚和C₁～C₆烷基)；W²、W³均选自C或各自独立地选自CR²，每个R²独立地选自氢、氘、氚、硝基、羟基、巯基、卤素、氰基、胺基、C₁～C₆烷基、C₁～C₆卤代烷基、C₁～C₆烷氧基和C₁～C₆卤代烷氧基(优选地，W²、W³均选自C；或者W²选自CR²，R²选自氢、氘、氚、卤素、氰基、C₁～C₆烷基、C₁～C₆卤代烷基、C₁～C₆烷氧基和C₁～C₆卤代烷氧基，W³选自CR²，R²选自氢、氘、氚、卤素、C₁～C₆烷基、C₁～C₆卤代烷基、C₁～C₆烷氧基和C₁～C₆卤代烷氧基；更优选地，W²、W³均选自C；或者W²选自CR²，R²选自氢、氘、氚、卤素、氰基、C₁～C₆烷基和C₁～C₆烷氧基；W³选自CR²，R²选自氢、氘、氚、卤素、C₁～C₆烷基和C₁～C₆烷氧基)；W⁴为C；W⁵为CR³，R³选自氢、氘、氚、羟基、卤素、胺基、C₁～C₆烷基、C₁～C₆卤代烷基(优选地，R³选自氢、氘、氚、卤素和C₁～C₆烷基)；In certain embodiments of the present application, W¹ is CR¹ or N, R¹ is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, amine, C₁ ~ C₆ alkyl and C₁ ~ C₆ haloalkyl (preferably, R¹ is selected from hydrogen, deuterium, tritium and C₁ ~ C₆ alkyl); W² and W³ are both selected from C or are independently selected from CR² , and each R² is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, C₁ ~ C₆ alkyl, C₁ ~ C₆ haloalkyl, C 1 ~ C₆ alkoxy and C_1~ C₆ haloalkoxy (preferably, W² and W³ are both selected from C; or W² is selected from CR² , R² is selected from hydrogen, deuterium, tritium, halogen, cyano, C_{1 ~ C 6 alkyl, C 1~} C₆ haloalkyl ～C₆ haloalkyl, C₁ ～C₆ alkoxy and C₁ ～C₆ haloalkoxy, W³ is selected from CR² , R² is selected from hydrogen, deuterium, tritium, halogen, C₁ ～C₆ alkyl, C₁ ～C₆ haloalkyl, C₁ ～C₆ alkoxy and C₁ ～C₆ haloalkoxy; more preferably, W² and W³ are both selected from C; or W² is selected from CR² , R² is selected from hydrogen, deuterium, tritium, halogen, cyano, C₁ ～C₆ alkyl and C₁ ～C₆ alkoxy; W³ is selected from CR² , R² is selected from hydrogen, deuterium, tritium, halogen, C₁ ～C₆ alkyl and C₁ ～C₆ alkoxy); W⁴ is C; W⁵ is CR³ , R^{R 3} is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, amine, C₁ ～C₆ alkyl, C₁ ～C₆ haloalkyl (preferably, R³ is selected from hydrogen, deuterium, tritium, halogen and C₁ ～C₆ alkyl);

本申请某些实施方案中，W¹为CR¹，R¹选自氢、氘、氚、羟基、卤素、胺基、C₁～C₆烷基和C₁～C₆卤代烷基(优选地，R¹选自氢、氘、氚和C₁～C₆烷基)；W²、W³各自独立地选自CR²，每个R²独立地选自氢、氘、氚、硝基、羟基、巯基、卤素、氰基、胺基、C₁～C₆烷基、C₁～C₆卤代烷基、C₁～C₆烷氧基和C₁～C₆卤代烷氧基(优选地，W²选自CR²，R²选自氢、氘、氚、卤素、氰基、C₁～C₆烷基、C₁～C₆卤代烷基、C₁～C₆烷氧基和C₁～C₆卤代烷氧基，W³选自CR²，R²选自氢、氘、氚、卤素、C₁～C₆烷基、C₁～C₆卤代烷基、C₁～C₆烷氧基和C₁～C₆卤代烷氧基；更优选地，W²选自CR²，R²选自氢、氘、氚、卤素、氰基、C₁～C₆烷基和C₁～C₆烷氧基；W³选自CR²，R²选自氢、氘、氚、卤素、C₁～C₆烷基和C₁～C₆烷氧基)；W⁴为C；W⁵为CR³，R³选自氢、氘、氚、羟基、卤素、胺基、C₁～C₆烷基、C₁～C₆卤代烷基(优选地，R³选自氢、氘、氚、卤素和C₁～C₆烷基)；In certain embodiments of the present application, W¹ is CR¹ , R¹ is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, amine, C₁ ～C₆ alkyl and C₁ ～C₆ haloalkyl (preferably, R¹ is selected from hydrogen, deuterium, tritium and C₁ ～C₆ alkyl); W² and W³ are each independently selected from CR² , and each R² is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, C₁ ～C₆ alkyl, C₁ ～C₆ haloalkyl, C₁ ～C₆ alkoxy and C₁ ～C₆ haloalkoxy (preferably, W² is selected from CR² , R² is selected from hydrogen, deuterium, tritium, halogen, cyano, C₁ ～C₆ alkyl, C₁ ～C₆ haloalkyl, C₁ ～C 6 In_some embodiments,^W is selected from CR² , R² is selected from hydrogen, deuterium, tritium, halogen, C₁ ～ C₆ alkyl, C₁ ～ C₆ haloalkyl, C₁ ～ C₆ alkoxy and C₁ ～ C₆ haloalkoxy; more preferably, W² is selected from CR² , R² is selected from hydrogen, deuterium, tritium, halogen, cyano, C₁ ～ C₆^alkyl and C₁ ～ C₆ alkoxy; W³ is selected from CR₂ , R² is selected from hydrogen, deuterium, tritium, halogen, C₁ ～ C₆ alkyl and C₁ ～ C₆ alkoxy); W⁴ is C; W⁵ is CR³ , R³ is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, amine, C₁ ～ C₆ alkyl, C₁ ～ C₆ haloalkyl,₆ haloalkyl (preferably, R³ is selected from hydrogen, deuterium, tritium, halogen and C₁ -C₆ alkyl);

本申请某些实施方案中，所述Z选自其中*与环B相连，p选自0、1、2、3、4，R选自氢、氘、氚、硝基、羟基、醛基、胺基、卤素、氰基、酯基、羧基、酰胺基、C₁～C₆烷基、C₁～C₆烷氧基、C₁～C₆卤代烷基、C₁～C₆卤代烷氧基、C₁～C₆羟基烷基；或者本申请某些实施方案中，所述Z选自其中*与环B相连，p选自0、1、2、3、4，R选自3～8元环烷基、3～8元杂环烷基，所述杂环烷基包含1～2个独立地选自N、O、S的杂原子；In certain embodiments of the present application, Z is selected from wherein * is connected to ring B, p is selected from 0, 1, 2, 3, 4, R is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, aldehyde, amine, halogen, cyano, ester, carboxyl, amide, C₁ ～C₆ alkyl, C_{1 ～C 6 alkoxy, C 1～C 6haloalkyl,} C₁ ～C₆ haloalkoxy, C₁ ～C₆ hydroxyalkyl; or in certain embodiments of the present application, Z is selected from Wherein * is connected to ring B, p is selected from 0, 1, 2, 3, 4, R is selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, and the heterocycloalkyl contains 1-2 heteroatoms independently selected from N, O, and S;

本申请某些实施方案中，所述Z为C₁～C₆亚烷基(优选C₁～C₄亚烷基、C₁～C₃亚烷基，如-CH₂-、-CH₂CH₂-、-CH(CH₃)-、-CH(CH₂CH₃)-、-CH[CH(CH₃)₂]-)，所述Z任选地被氘、氚、硝基、羟基、醛基、胺基、亚胺基、卤素、氰基、＝O的任一个取代(优选，所述Z任选地被羟基取代)；In certain embodiments of the present application, the Z is C₁ -C₆ alkylene (preferably C₁ -C₄ alkylene, C₁ -C₃ alkylene, such as -CH₂ -, -CH₂ CH₂ -, -CH(CH₃ )-, -CH(CH₂ CH₃ )-, -CH[CH(CH₃ )₂ ]-), and the Z is optionally substituted by any one of deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano, =O (preferably, the Z is optionally substituted by hydroxyl);

本申请某些实施方案中，所述环A选自6～10元芳环(也称为C₆～C₁₀芳环)、5～10元芳杂环、3～14元饱和脂环(也称为C₃～C₁₄饱和脂环)、3～14元不饱和脂环(也称为C₃～C₁₄不饱和脂环)、3～14元不饱和脂杂环、芳环与不饱和脂环构成的7～14元并环、芳杂环与不饱和脂环构成的7～14元并环、芳环与不饱和脂杂环构成的7～14元并环、芳杂环与不饱和脂杂环构成的7～14元并环，所述芳杂环包含1～4个(优选包含1～3个)各自独立地选自N、O、S的杂原子，所述不饱和脂杂环包含1～2个各自独立地选自N、O、S的杂原子；优选地，所述环A选自6～10元芳环、5～10元芳杂环、3～14元饱和脂环、芳环与不饱和脂环构成的7～14元并环、芳杂环与不饱和脂环构成的7～14元并环；更优选地，所述环A选自6～10元芳环、5～10元芳杂环、芳环与不饱和脂环构成的7～14元并环。In certain embodiments of the present application, the ring A is selected from a 6- to 10-membered aromatic ring (also referred to as a C₆ -C₁₀ aromatic ring), a 5- to 10-membered aromatic heterocyclic ring, a 3- to 14-membered saturated alicyclic ring (also referred to as a C₃ -C₁₄ saturated alicyclic ring), a 3- to 14-membered unsaturated alicyclic ring (also referred to as a C₃ -C₁₄ unsaturated alicyclic ring), a 3- to 14-membered unsaturated alicyclic heterocyclic ring, a 7- to 14-membered cyclic ring composed of an aromatic ring and an unsaturated alicyclic ring, a 7- to 14-membered cyclic ring composed of an aromatic heterocyclic ring and an unsaturated alicyclic ring, and a 3- to 14-membered unsaturated alicyclic ring. and alicyclic rings, and a 7-14-membered cyclic ring composed of an aromatic heterocycle and an unsaturated alicyclic heterocycle, wherein the aromatic heterocycle contains 1-4 (preferably 1-3) heteroatoms independently selected from N, O, and S, and the unsaturated alicyclic heterocycle contains 1-2 heteroatoms independently selected from N, O, and S; preferably, the ring A is selected from a 6-10-membered aromatic ring, a 5-10-membered aromatic heterocycle, a 3-14-membered saturated alicyclic ring, a 7-14-membered cyclic ring composed of an aromatic ring and an unsaturated alicyclic ring, and a 7-14-membered cyclic ring composed of an aromatic heterocycle and an unsaturated alicyclic ring; more preferably, the ring A is selected from a 6-10-membered aromatic ring, a 5-10-membered aromatic heterocycle, and a 7-14-membered cyclic ring composed of an aromatic ring and an unsaturated alicyclic ring.

本申请某些实施方案中，所述环A选自C₆～C₁₀芳环、5～10元芳杂环、C₅～C₁₀饱和脂环、C₅～C₁₀不饱和脂环、C₆～C₁₀芳环与C₅～C₁₀不饱和脂环构成的并环、5～10元芳杂环与C₅～C₁₀不饱和脂环构成的并环；优选地，环A选自C₆～C₁₀芳环、6～10元芳杂环、C₅～C₈饱和脂环、C₆芳环与C₅～C₆不饱和脂环构成的并环，所述芳杂环包含1～3个(优选1～2个)各自独立地选自N、O、S的杂原子。更优选地，环A选自苯环、茚满、吡啶、环己烷、双环[1,1,1]戊基、嘧啶(例如环A选自苯环、茚满、吡啶、环己烷)。In certain embodiments of the present application, the ring A is selected from a C₆ -C₁₀ aromatic ring, a 5- to 10-membered aromatic heterocycle, a C₅ -C₁₀ saturated alicyclic ring, a C₅ -C₁₀ unsaturated alicyclic ring, a C₆ -C₁₀ aromatic ring and a C₅ -C₁₀ unsaturated alicyclic ring, and a C₆ -C₁₀ aromatic ring and a C 5 -C 10 unsaturated alicyclic ring. Preferably, the ring A is selected from a C₆ -C₁₀ aromatic ring, a 6 -10-membered aromatic heterocycle, a C₅ -C₈ saturated alicyclic ring, and a C₆ aromatic ring and a C₅ -C₆ unsaturated alicyclic ring, and the aromatic heterocycle contains 1 to 3 (preferably 1 to 2) heteroatoms independently selected from N, O, and S. More preferably, ring A is selected from benzene ring, indane, pyridine, cyclohexane, bicyclo[1,1,1]pentyl, pyrimidine (eg ring A is selected from benzene ring, indane, pyridine, cyclohexane).

本申请某些实施方案中，所述环B选自6～10元芳环、5～10元芳杂环、3～14元(优选3～12元)饱和脂杂环、3～14元(优选3～12元)不饱和脂杂环、芳环与不饱和脂环构成的7～14元并环、芳杂环与不饱和脂环构成的7～14元并环、芳环与不饱和脂杂环构成的7～14元并环、芳杂环与不饱和脂杂环构成的7～14元并环，所述芳杂环包含1～4个各自独立地选自N、O、S的杂原子，所述不饱和脂杂环、饱和脂杂环各自包含1～2个独立地选自N、O、S的杂原子；优选地，所述环B选自5～10元芳杂环、3～12元饱和脂杂环，所述芳杂环包含1～3个各自独立地选自N、O、S的杂原子，所述不饱和脂杂环、饱和脂杂环各自包含1个独立地选自N、O、S的杂原子。In certain embodiments of the present application, the ring B is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-14 membered (preferably 3-12 membered) saturated alicyclic ring, a 3-14 membered (preferably 3-12 membered) unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, and a 7-14 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring. The aromatic heterocycle contains 1 to 4 heteroatoms independently selected from N, O, and S, and the unsaturated aliphatic heterocycle and the saturated aliphatic heterocycle each contain 1 to 2 heteroatoms independently selected from N, O, and S; preferably, the ring B is selected from a 5-10 membered aromatic heterocycle and a 3-12 membered saturated aliphatic heterocycle, the aromatic heterocycle contains 1 to 3 heteroatoms independently selected from N, O, and S, and the unsaturated aliphatic heterocycle and the saturated aliphatic heterocycle each contain 1 heteroatom independently selected from N, O, and S.

本申请某些实施方案中，所述环B选自C₆～C₁₀芳环、5～10元芳杂环、C₃～C₁₀饱和脂杂环、5～10元不饱和脂杂环、5～10元芳杂环与C₅～C₁₀不饱和脂环构成的并环、C₆～C₁₀芳环与5～10元不饱和脂杂环构成的并环；优选地环B为5～10元芳杂环或C₄～C₈饱和脂杂环，所述芳杂环、不饱和脂杂环、饱和脂杂环各自包含1～3个(优选1～2个)各自独立地选自N、O、S的杂原子。更优选地，环B选自吡啶、吡唑、吡嗪、嘧啶、四氢吡喃、咪唑、噻唑、吡啶并咪唑、吡啶并吡唑、苯并咪唑、喹啉、哌啶、噁唑、异噁唑、吲唑和吖丁啶(例如，环B选自吡啶、吡唑、吡嗪、哌啶、噁唑、异噁唑、吲唑和吖丁啶)。In certain embodiments of the present application, the ring B is selected from a C₆ -C₁₀ aromatic ring, a 5-10 membered aromatic heterocycle, a C₃ -C₁₀ saturated alicyclic ring, a 5-10 membered unsaturated alicyclic ring, a cyclic ring formed by a 5-10 membered aromatic heterocycle and a C₅ -C₁₀ unsaturated alicyclic ring, and a cyclic ring formed by a C₆ -C₁₀ aromatic ring and a 5-10 membered unsaturated alicyclic ring; preferably, ring B is a 5-10 membered aromatic heterocycle or a C₄ -C₈ saturated alicyclic ring, and the aromatic heterocycle, unsaturated alicyclic ring, and saturated alicyclic ring each contain 1 to 3 (preferably 1 to 2) heteroatoms independently selected from N, O, and S. More preferably, Ring B is selected from pyridine, pyrazole, pyrazine, pyrimidine, tetrahydropyran, imidazole, thiazole, pyridoimidazole, pyridopyrazole, benzimidazole, quinoline, piperidine, oxazole, isoxazole, indazole and azetidine (e.g., Ring B is selected from pyridine, pyrazole, pyrazine, piperidine, oxazole, isoxazole, indazole and azetidine).

进一步，本申请某些实施方案中，所述环A选自苯环、环己烷、双环[1,1,1]戊烷、包含1～4个(优选包含1～3个)杂原子的5～10元芳杂环、由苯环与不饱和脂环构成的8～12元并环、由苯环与包含1～2个杂原子的不饱和脂杂环构成的8～12元并环，所述杂原子各自独立地选自N、O、S；所述环B选自苯环、包含1～4个杂原子的5～10元芳杂环、包含1～2个杂原子的3～10元饱和脂杂环、包含1～2个杂原子的3～10元不饱和脂杂环，所述杂原子各自独立地选自N、O、S。Furthermore, in certain embodiments of the present application, the ring A is selected from a benzene ring, a cyclohexane, a bicyclo[1,1,1]pentane, a 5-10 membered aromatic heterocycle containing 1 to 4 (preferably 1 to 3) heteroatoms, an 8-12 membered paracyclic ring consisting of a benzene ring and an unsaturated alicyclic ring, and an 8-12 membered paracyclic ring consisting of a benzene ring and an unsaturated alicyclic ring containing 1 to 2 heteroatoms, and the heteroatoms are each independently selected from N, O, and S; the ring B is selected from a benzene ring, a 5-10 membered aromatic heterocycle containing 1 to 4 heteroatoms, a 3-10 membered saturated alicyclic ring containing 1 to 2 heteroatoms, and a 3-10 membered unsaturated alicyclic ring containing 1 to 2 heteroatoms, and the heteroatoms are each independently selected from N, O, and S.

本申请某些实施方案中，m、n、o各自独立地选自0、1或2。In certain embodiments of the present application, m, n, and o are each independently selected from 0, 1 or 2.

本申请某些实施方案中，R^A选自氘、氚、羟基、卤素、C₁～C₆烷基、C₁～C₆卤代烷氧基和C₁～C₆卤代烷基；优选地，R^A选自氘、氚、卤素、C₁～C₆烷基和C₁～C₆卤代烷基；更优选地，R^A为氘、氚、甲基、氟、氯、溴、三氟甲基、三氟甲氧基、三氯甲基、三氯甲氧基、三溴甲氧基或三溴甲基。In certain embodiments of the present application,^RA is selected from deuterium, tritium, hydroxyl, halogen,_C1 ~_C6 alkyl,_C1 ~_C6 haloalkoxy and_C1 ~_C6 haloalkyl; preferably,^RA is selected from deuterium, tritium, halogen,_C1 ~_C6 alkyl and_C1 ~_C6 haloalkyl; more preferably,^RA is deuterium, tritium, methyl, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, trichloromethyl, trichloromethoxy, tribromomethoxy or tribromomethyl.

本申请某些实施方案中，R^B选自氘、氚、羟基、氰基、胺基、酰胺基、C₁～C₆烷基、C₁～C₆羟基烷基、C₁～C₆胺基烷基、C₁～C₆酰胺基烷基和C₁～C₆卤代烷基；优选地，R^B选自氘、氚、胺基和C₁～C₆烷基；更优选地，R^B为氘、氚、甲基、乙基、丙基或-NH₂；R^B任选地被氘、氚、或卤素取代。In certain embodiments of the present application,^RB is selected from deuterium, tritium, hydroxyl, cyano, amine, amide,_C1 -_C6 alkyl, C1-_C6 hydroxyalkyl,_C1 -_{C6 aminoalkyl, C1-C6amidoalkylandC1} -_C6 haloalkyl; preferably,^RB is selected from deuterium, tritium, amine_andC1 -_C6 alkyl; more preferably,^RB is deuterium, tritium, methyl, ethyl, propyl or_-NH2 ;^RB is optionally substituted by deuterium, tritium, or halogen.

本申请还提供一种式(II)所示的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物(例如水合物)、或其前药，
The present application also provides a compound represented by formula (II), its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate (such as a hydrate), or its prodrug,

X、Y各自独立地选自CR⁰或N且不同时为N，所述R⁰选自氢、氘、氚、硝基、羟基、巯基、卤素、氰基、胺基、酯基、醛基、羧基、羰基、酰胺基、C₁～C₆烷基、C₁～C₆卤代烷基、C₁～C₆烷氧基、C₁～C₆卤代烷氧基、C₁～C₆羟基烷基，X and Y are each independently selected from CR⁰ or N and are not N at the same time, and the R⁰ is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C₁ ～C₆ alkyl, C₁ ～C₆ haloalkyl, C₁ ～C₆ alkoxy, C₁ ～C₆ halogen alkyl, C₁ -C₆ hydroxyalkyl,

W²、W³各自独立地选自CH或N，W² and W³ are each independently selected from CH or N,

W¹为不存在、CH或N，W⁴选自C或N，W⁵选自C＝O、CH或N，且当W¹为不存在或者当W⁵为C＝O时，W⁴为N，^W1 is absent, CH or N,^W4 is selected from C or N,^W5 is selected from C=O, CH or N, and when^W1 is absent or when^W5 is C=O,^W4 is N,

R^C各自独立地选自氘、氚、硝基、羟基、巯基、卤素、氰基、胺基、酯基、醛基、羧基、羰基、酰胺基、C₁～C₆烷基、C₁～C₆卤代烷基、C₁～C₆烷氧基、C₁～C₆卤代烷氧基、C₁～C₆羟基烷基，q选自0、1、2、3，R and^C are each independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C₁ ～C₆ alkyl, C₁ ～C 6 haloalkyl, C₁ ～C₆ alkoxy, C₁ ～C₆ haloalkoxy, C₁ ～C₆ hydroxyalkyl, q is selected from 0,_1, 2, 3,

Z选自Z is selected from

环A选自芳环、芳杂环、饱和脂环、不饱和脂环、不饱和脂杂环、芳环与不饱和脂环构成的并环、芳杂环与不饱和脂环构成的并环、芳环与不饱和脂杂环构成的并环、芳杂环与不饱和脂杂环构成的并环，环B选自芳环、芳杂环、饱和脂杂环、不饱和脂杂环、芳环与不饱和脂环构成的并环、芳杂环与不饱和脂环构成的并环、芳环与不饱和脂杂环构成的并环、芳杂环与不饱和脂杂环构成的并环，所述芳杂环、不饱和脂杂环、饱和脂杂环各自独立地包含1～4个杂原子，所述杂原子独立地选自N、O、S，其中R、R^A、R^B、m、n、o、p、*、与前述定义一致。Ring A is selected from aromatic rings, aromatic heterocycles, saturated alicyclic rings, unsaturated alicyclic rings, unsaturated alicyclic rings, cyclic rings consisting of aromatic rings and unsaturated alicyclic rings, cyclic rings consisting of aromatic heterocyclic rings and unsaturated alicyclic rings, cyclic rings consisting of aromatic rings and unsaturated alicyclic rings, and cyclic rings consisting of aromatic heterocyclic rings and unsaturated alicyclic rings; Ring B is selected from aromatic rings, aromatic heterocyclic rings, saturated alicyclic rings, unsaturated alicyclic rings, cyclic rings consisting of aromatic rings and unsaturated alicyclic rings, cyclic rings consisting of aromatic rings and unsaturated alicyclic rings, and cyclic rings consisting of aromatic heterocyclic rings and unsaturated alicyclic rings; the aromatic heterocyclic rings, unsaturated alicyclic rings, and saturated alicyclic rings each independently contain 1 to 4 heteroatoms, and the heteroatoms are independently selected from N, O, and S, wherein R,^RA ,^RB , m, n, o, p, *, Consistent with the above definition.

本申请某些实施方案中，所述环A选自6～10元芳环、5～10元芳杂环、3～14元饱和脂环、3～14元不饱和脂环、3～14元不饱和脂杂环、芳环与不饱和脂环构成的7～14元并环、芳杂环与不饱和脂环构成的7～14元并环、芳环与不饱和脂杂环构成的7～14元并环、芳杂环与不饱和脂杂环构成的7～14元并环，所述芳杂环包含1～4个(优选包含1～3个)各自独立地选自N、O、S的杂原子，所述不饱和脂杂环包含1～2个各自独立地选自N、O、S的杂原子；In certain embodiments of the present application, the ring A is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-14 membered saturated alicyclic ring, a 3-14 membered unsaturated alicyclic ring, a 3-14 membered unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, and a 7-14 membered paracyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, wherein the aromatic heterocycle contains 1-4 (preferably 1-3) heteroatoms independently selected from N, O, and S, and the unsaturated alicyclic heterocycle contains 1-2 heteroatoms independently selected from N, O, and S;

本申请某些实施方案中，所述环B选自6～10元芳环、5～10元芳杂环、3～14元(优选3～12元)饱和脂杂环、3～14元(优选3～12元)不饱和脂杂环、芳环与不饱和脂环构成的7～14元并环、芳杂环与不饱和脂环构成的7～14元并环、芳环与不饱和脂杂环构成的7～14元并环、芳杂环与不饱和脂杂环构成的7～14元并环，所述芳杂环包含1～4个各自独立地选自N、O、S的杂原子，所述不饱和脂杂环、饱和脂杂环各自包含1～2个独立地选自N、O、S的杂原子；In certain embodiments of the present application, the ring B is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-14 membered (preferably 3-12 membered) saturated alicyclic ring, a 3-14 membered (preferably 3-12 membered) unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, and a 7-14 membered paracyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, wherein the aromatic heterocycle contains 1-4 heteroatoms independently selected from N, O, and S, and the unsaturated alicyclic heterocycle and the saturated alicyclic heterocycle each contain 1-2 heteroatoms independently selected from N, O, and S;

进一步，本申请某些实施方案中，所述环A选自苯环、环己烷、双环[1,1,1]戊烷、包含1～4个(优选包含1～3个)杂原子的5～10元芳杂环、由苯环与不饱和脂环构成的8～12元并环、由苯环与包含1～2个杂原子的不饱和脂杂环构成的8～12元并环，所述杂原子各自独立地选自N、O、S；所述环B选自苯环、包含1～4个杂原子的5～10元芳杂环、包含1～2个杂原子的3～10元饱和脂杂环、包含1～2个杂原子的3～10元不饱和脂杂环，所述杂原子各自独立地选自N、O、S。Furthermore, in certain embodiments of the present application, the ring A is selected from a benzene ring, a cyclohexane, a bicyclo[1,1,1]pentane, a 5-10 membered aromatic heterocycle containing 1 to 4 (preferably 1 to 3) heteroatoms, an 8-12 membered paracyclic ring consisting of a benzene ring and an unsaturated alicyclic ring, and an 8-12 membered paracyclic ring consisting of a benzene ring and an unsaturated alicyclic ring containing 1 to 2 heteroatoms, and the heteroatoms are each independently selected from N, O, and S; the ring B is selected from a benzene ring, a 5-10 membered aromatic heterocycle containing 1 to 4 heteroatoms, a 3-10 membered saturated alicyclic ring containing 1 to 2 heteroatoms, and a 3-10 membered unsaturated alicyclic ring containing 1 to 2 heteroatoms, and the heteroatoms are each independently selected from N, O, and S.

本申请某些具体实施方式中，本申请提供的式(II)所示的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物(例如水合物)、或其前药具有如下式(II-a)至(II-g)所示的任一结构、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物(例如水合物)、或其前药，In certain specific embodiments of the present application, the compound represented by formula (II) provided in the present application, its stereoisomer, its tautomer or its mixture form, or its pharmaceutically acceptable salt, or its solvate (e.g., hydrate), or its prodrug has any structure represented by the following formula (II-a) to (II-g), its stereoisomer, its tautomer or its mixture form, or its pharmaceutically acceptable salt, or its solvate (e.g., hydrate), or its prodrug,

其中R^A、R^B、R^C、环A、环B、m、n、o、q、X、Y、Z与前述定义一致。 wherein^RA ,^RB ,^RC , ring A, ring B, m, n, o, q, X, Y and Z are consistent with the above definitions.

本申请还提供一种式(III)所示的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物(例如水合物)、或其前药，
The present application also provides a compound represented by formula (III), its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate (such as a hydrate), or its prodrug,

X、Y各自独立地选自CR⁰或N且不同时为N，所述R⁰选自氢、氘、氚、硝基、羟基、巯基、卤素、氰基、胺基、酯基、醛基、羧基、羰基、酰胺基、C₁～C₆烷基、C₁～C₆卤代烷基、C₁～C₆烷氧基、C₁～C₆卤代烷氧基、C₁～C₆羟基烷基，X and Y are each independently selected from CR⁰ or N and are not N at the same time, and the R⁰ is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C₁ ～C₆ alkyl, C₁ ～C₆ haloalkyl, C₁ ～C₆ alkoxy, C₁ ～C₆ haloalkoxy, C₁ ～C₆ hydroxyalkyl,

W¹为不存在、CH或N，W⁴选自C或N，W⁵选自C＝O、CH或N，且当W¹为不存在或者当W⁵为C＝O时，W⁴为N，^W1 is absent, CH or N,^W4 is selected from C or N,^W5 is selected from C=O, CH or N, and when^W1 is absent or when^W5 is C=O,^W4 is N,

V¹、V²、V³各自独立地选自CH、N、NH、O、S，且V¹、V²、V³不同时为CH，V¹ , V² , and V³ are each independently selected from CH, N, NH, O, and S, and V¹ , V² , and V³ are not CH at the same time,

R^C各自独立地选自氘、氚、硝基、羟基、巯基、卤素、氰基、胺基、酯基、醛基、羧基、羰基、酰胺基、C₁～C₆烷基、C₁～C₆卤代烷基、C₁～C₆烷氧基、C₁～C₆卤代烷氧基、C₁～C₆羟基烷基，q选自0、1、2、3，R and^C are each independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C₁ ～C₆ alkyl, C₁ ～C 6 haloalkyl, C₁ ～C₆ alkoxy, C₁ ～C₆ haloalkoxy, C₁ ～C₆ hydroxyalkyl, q is selected from 0,_1, 2, 3,

Z选自Z is selected from

环A选自芳环、芳杂环、饱和脂环、不饱和脂环、不饱和脂杂环、芳环与不饱和脂环构成的并环、芳杂环与不饱和脂环构成的并环、芳环与不饱和脂杂环构成的并环、芳杂环与不饱和脂杂环构成的并环，环B选自芳环、芳杂环、饱和脂杂环、不饱和脂杂环、芳环与不饱和脂环构成的并环、芳杂环与不饱和脂环构成的并环、芳环与不饱和脂杂环构成的并环、芳杂环与不饱和脂杂环构成的并环，所述芳杂环、不饱和脂杂环、饱和脂杂环各自独立地包含1～4个杂原子，所述杂原子独立地选自N、O、S，其中R、R^A、R^B、m、n、o、p、*、与前述定义一致。Ring A is selected from aromatic rings, aromatic heterocycles, saturated alicyclic rings, unsaturated alicyclic rings, unsaturated alicyclic rings, cyclic rings consisting of aromatic rings and unsaturated alicyclic rings, cyclic rings consisting of aromatic heterocyclic rings and unsaturated alicyclic rings, cyclic rings consisting of aromatic rings and unsaturated alicyclic rings, and cyclic rings consisting of aromatic heterocyclic rings and unsaturated alicyclic rings; Ring B is selected from aromatic rings, aromatic heterocyclic rings, saturated alicyclic rings, unsaturated alicyclic rings, cyclic rings consisting of aromatic rings and unsaturated alicyclic rings, cyclic rings consisting of aromatic rings and unsaturated alicyclic rings, and cyclic rings consisting of aromatic heterocyclic rings and unsaturated alicyclic rings; the aromatic heterocyclic rings, unsaturated alicyclic rings, and saturated alicyclic rings each independently contain 1 to 4 heteroatoms, and the heteroatoms are independently selected from N, O, and S, wherein R,^RA ,^RB , m, n, o, p, *, Consistent with the above definition.

本申请某些实施方案中，所述W¹、W⁵均为CH，W⁴为C。In certain embodiments of the present application, W¹ and W⁵ are both CH, and W⁴ is C.

本申请某些实施方案中，所述环A选自6～10元芳环、5～10元芳杂环、3～14元饱和脂环、3～14元不饱和脂环、3～14元不饱和脂杂环、芳环与不饱和脂环构成的7～14元并环、芳杂环与不饱和脂环构成的7～14元并环、芳环与不饱和脂杂环构成的7～14元并环、芳杂环与不饱和脂杂环构成的7～14元并环，所述芳杂环包含1～4个(优选包含1～3个)各自独立地选自N、O、S的杂原子，所述不饱和脂杂环包含1～2个各自独立地选自N、O、S的杂原子；In certain embodiments of the present application, the ring A is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-14 membered saturated alicyclic ring, a 3-14 membered unsaturated alicyclic ring, a 3-14 membered unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, and a 7-14 membered paracyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, wherein the aromatic heterocycle contains 1-4 (preferably 1-3) heteroatoms independently selected from N, O, and S, and the unsaturated alicyclic heterocycle contains 1-2 heteroatoms independently selected from N, O, and S;

本申请某些实施方案中，所述环B选自6～10元芳环、5～10元芳杂环、3～14元(优选3～12元)饱和脂杂环、3～14元(优选3～12元)不饱和脂杂环、芳环与不饱和脂环构成的7～14元并环、芳杂环与不饱和脂环构成的7～14元并环、芳环与不饱和脂杂环构成的7～14元并环、芳杂环与不饱和脂杂环构成的7～14元并环，所述芳杂环包含1～4个各自独立地选自N、O、S的杂原子，所述不饱和脂杂环、饱和脂杂环各自包含1～2个独立地选自N、O、S的杂原子；In certain embodiments of the present application, the ring B is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-14 membered (preferably 3-12 membered) saturated alicyclic ring, a 3-14 membered (preferably 3-12 membered) unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, and a 7-14 membered paracyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, wherein the aromatic heterocycle contains 1-4 heteroatoms independently selected from N, O, and S, and the unsaturated alicyclic heterocycle and the saturated alicyclic heterocycle each contain 1-2 heteroatoms independently selected from N, O, and S;

进一步，本申请某些实施方案中，所述环A选自苯环、环己烷、双环[1,1,1]戊烷、包含1～4个(优选包含1～3个)杂原子的5～10元芳杂环、由苯环与不饱和脂环构成的8～12元并环、由苯环与包含1～2个杂原子的不饱和脂杂环构成的8～12元并环，所述杂原子各自独立地选自N、O、S；所述环B选自苯环、包含1～4个杂原子的5～10元芳杂环、包含1～2个杂原子的3～10元饱和脂杂环、包含1～2个杂原子的3～10元不饱和脂杂环，所述杂原子各自独立地选自N、O、S。Furthermore, in certain embodiments of the present application, the ring A is selected from a benzene ring, a cyclohexane, a bicyclo[1,1,1]pentane, a 5-10 membered aromatic heterocycle containing 1 to 4 (preferably 1 to 3) heteroatoms, an 8-12 membered paracyclic ring consisting of a benzene ring and an unsaturated alicyclic ring, and an 8-12 membered paracyclic ring consisting of a benzene ring and an unsaturated alicyclic ring containing 1 to 2 heteroatoms, and the heteroatoms are each independently selected from N, O, and S; the ring B is selected from a benzene ring, a 5-10 membered aromatic heterocycle containing 1 to 4 heteroatoms, a 3-10 membered saturated alicyclic ring containing 1 to 2 heteroatoms, and a 3-10 membered unsaturated alicyclic ring containing 1 to 2 heteroatoms, and the heteroatoms are each independently selected from N, O, and S.

本申请某些具体实施方式中，本申请提供的式(III)所示的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物(例如水合物)、或其前药具有如下式(III-a)至(III-f)所示的任一结构、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物(例如水合物)、或其前药，
In certain specific embodiments of the present application, the compound represented by formula (III) provided in the present application, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate (e.g., hydrate), or its prodrug has any structure represented by the following formula (III-a) to (III-f), its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate (e.g., hydrate), or its prodrug,

其中R^A、R^B、R^C、环A、环B、m、n、o、q、X、Y、Z与前述定义一致。wherein^RA ,^RB ,^RC , ring A, ring B, m, n, o, q, X, Y and Z are consistent with the above definitions.

本申请还提供一种式(IV)所示的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物(例如水合物)、或其前药，
The present application also provides a compound represented by formula (IV), its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate (such as a hydrate), or its prodrug,

X、Y、Z、W¹、W⁴、W⁵、环A、环B、R^A、R^B、m、n、o、同上述式(I)化合物和式(III)化合物中的定义；V⁴和V⁵各自独立地为CH或N，且V⁴、V⁵不同时为CH。X, Y, Z, W¹ , W⁴ , W⁵ , ring A, ring B, R^A , R^B , m, n, o, Same as the definitions in the above compounds of formula (I) and (III); V⁴ and V⁵ are each independently CH or N, and V⁴ and V⁵ are not CH at the same time.

本申请某些具体实施方式中，本申请提供的式(IV)所示的化合物选自式(III-a)至(III-f)所示的化合物：
其中X、Y、Z、W¹、W⁴、W⁵、环A、环B、R^A、R^B、m、n、o、同上述定义。In certain specific embodiments of the present application, the compound represented by formula (IV) provided in the present application is selected from the compounds represented by formula (III-a) to (III-f):
Among them, X, Y, Z, W¹ , W⁴ , W⁵ , ring A, ring B, R^A , R^B , m, n, o, Same as above definition.

本申请提供的式(I)、(II)、(III)、(II-a)、(II-b)、(II-c)、(II-d)、(II-e)、(II-f)、(II-g)、(III-a)、(III-b)、(III-c)、(III-d)、(III-e)、(III-f)、(IV)、(IV-a)、(IV-b)或(IV-c)所示的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物(例如水合物)、或其前药，在某些实施方案中，所述R⁰选自氢、氘、氚、硝基、羟基、巯基、氟、氯、溴、碘、氰基、醛基、羧基、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃、-N(CH₂CH₃)₂、-C(O)OCH₃、-C(O)OCH₂CH₃、-C(O)O(CH₂)₂CH₃、-C(O)OCH(CH₃)₂、-OC(O)CH₃、-OC(O)CH₂CH₃、-OC(O)(CH₂)₂CH₃、-OC(O)CH(CH₃)₂、-COCH₃、-COCH₂CH₃、-CO(CH₂)₂CH₃、-COCH(CH₃)₂、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-NHCOH、-NHCOCH₃、-N(CH₃)COCH₃、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、三氟甲基、三氟乙基、三氯甲基、三氯乙基、三氟甲氧基、三氟乙氧基、三氯甲氧基、三氯乙氧基、羟甲基、1-羟乙基、2-羟乙基、1-羟基正丙基、2-羟基正丙基、3-羟基正丙基。The compounds provided herein are represented by formula (I), (II), (III), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (IV), (IV-a), (IV-b) or (IV-c), their stereoisomers, their tautomers or mixtures thereof, or their pharmaceutically acceptable salts, or their solvates (e.g., hydrates), or their prodrugs. In certain embodiments, the R⁰ is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, -NH₂ , -NHCH₃ , -N(CH₃ )₂ , -NHCH₂ CH₃ , -N(CH₂ CH₃ )₂ , -C(O)OCH₃ , -C(O)OCH₂ CH₃ , -C(O)O(CH₂ )₂ CH₃ , -C(O)OCH(CH₃ )₂ , -OC(O)CH₃ , -OC(O)CH₂ CH₃ , -OC(O)(CH₂ )₂ CH₃ , -OC(O)CH(CH₃ )₂ , -COCH₃ , -COCH₂ CH₃ , -CO(CH₂ )₂ CH₃ , -COCH(CH₃ )₂ , -CONH₂ , -CONHCH₃ , -CON(CH₃ )₂ , -NHCOH, -NHCOCH₃ , -N(CH₃ )COCH₃ , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-n-propyl.

本申请提供的式(I)、(II)、(III)、(II-a)、(II-b)、(II-c)、(II-d)、(II-e)、(II-f)、(II-g)、(III-a)、(III-b)、(III-c)、(III-d)、(III-e)、(III-f)、(IV)、(IV-a)、(IV-b)或(IV-c)所示的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物(例如水合物)、或其前药，在某些实施方案中，所述R^A、R^B各自独立地选自氘、氚、硝基、羟基、巯基、氟、氯、溴、碘、氰基、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃、-N(CH₂CH₃)₂、-C(O)OCH₃、-C(O)OCH₂CH₃、-C(O)O(CH₂)₂CH₃、-C(O)OCH(CH₃)₂、-OC(O)CH₃、-OC(O)CH₂CH₃、-OC(O)(CH₂)₂CH₃、-OC(O)CH(CH₃)₂、醛基、羧基、-COCH₃、-COCH₂CH₃、-CO(CH₂)₂CH₃、-COCH(CH₃)₂、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-NHCOH、-NHCOCH₃、-N(CH₃)COCH₃、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、三氟甲基、三氟乙基、三氯甲基、三氯乙基、三氟甲氧基、三氟乙氧基、三氯甲氧基、三氯乙氧基、羟甲基、1-羟乙基、2-羟乙基、1-羟基正丙基、2-羟基正丙基、3-羟基正丙基。The compounds represented by formula (I), (II), (III), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (IV), (IV-a), (IV-b) or (IV-c) provided herein, their stereoisomers, their tautomers or their mixtures, or their pharmaceutically acceptable salts, or their solvates (e.g., hydrates), or their prodrugs, in certain embodiments, the^RA and^RB are each independently selected from deuterium, tritium, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine_,cyano , -NH2,_-NHCH3 , -N(_CH3 )₂ ,_-NHCH2CH3 ,_-N (_CH2CH3 )₂ , -C(O)_OCH3 , -C(O)_OCH2CH3. -C(O)O(CH₂ )₂ CH₃ , -C(O)OCH(CH₃ )₂ , -OC(O)CH₃ , -OC(O)CH₂ CH₃ , -OC(O)(CH₂ )₂ CH₃ , -OC(O)CH(CH₃ )₂ , aldehyde group, carboxyl group, -COCH₃ , -COCH₂ CH₃ , -CO(CH₂ )₂ CH₃ , -COCH(CH₃ )₂ , -CONH₂ , -CONHCH₃ , -CON(CH₃ )₂ , -NHCOH, -NHCOCH₃ , -N(CH₃ )COCH₃ , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-n-propyl.

本申请提供的式(I)、(II)、(III)、(II-a)、(II-b)、(II-c)、(II-d)、(II-e)、(II-f)、(II-g)、(III-a)、(III-b)、(III-c)、(III-d)、(III-e)、(III-f)、(IV)、(IV-a)、(IV-b)或(IV-c)所示的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物(例如水合物)、或其前药，在某些实施方案中，所述R选自氢、氘、氚、硝基、羟基、巯基、氟、氯、溴、碘、氰基、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃、-N(CH₂CH₃)₂、-C(O)OCH₃、-C(O)OCH₂CH₃、-C(O)O(CH₂)₂CH₃、-C(O)OCH(CH₃)₂、-OC(O)CH₃、-OC(O)CH₂CH₃、-OC(O)(CH₂)₂CH₃、-OC(O)CH(CH₃)₂、醛基、羧基、-COCH₃、-COCH₂CH₃、-CO(CH₂)₂CH₃、-COCH(CH₃)₂、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-NHCOH、-NHCOCH₃、-N(CH₃)COCH₃、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、三氟甲基、三氟乙基、三氯甲基、三氯乙基、三氟甲氧基、三氟乙氧基、三氯甲氧基、三氯乙氧基、羟甲基、1-羟乙基、2-羟乙基、1-羟基正丙基、2-羟基正丙基、3-羟基正丙基、环丙基、环丁基、环戊基、环己基、环丙氧基、环丁氧基、环戊氧基。The compounds provided herein, their stereoisomers, their tautomers or mixtures thereof, or their pharmaceutically acceptable salts, or their solvates (e.g., hydrates), or their prodrugs, in certain embodiments, wherein R is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine, cyano, -NH2, -NHCH3, -N(_{CH3)2,-NHCH2CH3, -N(CH2CH3)2,-C(O} )_OCH3 , -C(_O)OCH2CH3 . , -C(O)O(CH₂ )₂ CH₃ , -C(O)OCH(CH₃ )₂ , -OC(O)CH₃ , -OC(O)CH₂ CH₃ , -OC(O)(CH₂ )₂ CH₃ , -OC(O)CH(CH₃ )₂ , aldehyde group, carboxyl group, -COCH₃ , -COCH₂ CH₃ , -CO(CH₂ )₂ CH₃ , -COCH(CH₃ )₂ , -CONH₂ , -CONHCH₃ , -CON(CH₃ )₂ , -NHCOH, -NHCOCH₃ , -N(CH₃ )COCH₃ , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-n-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxy, and cyclopentyloxy.

本申请提供的式(II)、(III)、(II-a)、(II-b)、(II-c)、(II-d)、(II-e)、(II-f)、(II-g)、(III-a)、(III-b)、(III-c)、(III-d)、(III-e)、(III-f)所示的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物(例如水合物)、或其前药，在某些实施方案中，所述R^C选自氘、氚、硝基、羟基、巯基、氟、氯、溴、碘、氰基、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃、-N(CH₂CH₃)₂、-C(O)OCH₃、-C(O)OCH₂CH₃、-C(O)O(CH₂)₂CH₃、-C(O)OCH(CH₃)₂、-OC(O)CH₃、-OC(O)CH₂CH₃、-OC(O)(CH₂)₂CH₃、-OC(O)CH(CH₃)₂、醛基、羧基、-COCH₃、-COCH₂CH₃、-CO(CH₂)₂CH₃、-COCH(CH₃)₂、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-NHCOH、-NHCOCH₃、-N(CH₃)COCH₃、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、三氟甲基、三氟乙基、三氯甲基、三氯乙基、三氟甲氧基、三氟乙氧基、三氯甲氧基、三氯乙氧基、羟甲基、1-羟乙基、2-羟乙基、1-羟基正丙基、2-羟基正丙基、3-羟基正丙基。The compounds of formula (II), (III), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), their stereoisomers, their tautomers or mixtures thereof, or their pharmaceutically acceptable salts, or their solvates (e.g.,_hydrates ), or their prodrugs provided herein, in certain embodiments, the^RC is selected from deuterium, tritium, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine,_cyano ,_-NH2 , -NHCH3, -N(_CH3 )₂ ,_-NHCH2CH3 , -N_(CH2CH3)2,-C (O)_OCH3 ,_-C (_O )_OCH2CH3 , -C(O)O(_CH2 )_2CH3 , -C(O)OCH(CH₃ )₂ , -OC(O)CH₃ , -OC(O)CH₂ CH₃ , -OC(O)(CH₂ )₂ CH₃ , -OC(O)CH(CH₃ )₂ , aldehyde group, carboxyl group, -COCH₃ , -COCH₂ CH₃ , -CO(CH₂ )₂ CH₃ , -COCH(CH₃ )₂ , -CONH₂ , -CONHCH₃ , -CON(CH₃ )₂ , -NHCOH, -NHCOCH₃ , -N(CH₃ )COCH₃ , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-n-propyl.

本申请提供的式(I)、(II)、(III)、(II-a)、(II-b)、(II-c)、(II-d)、(II-e)、(II-f)、(II-g)、(III-a)、(III-b)、(III-c)、(III-d)、(III-e)、(III-f)、(IV)、(IV-a)、(IV-b)或(IV-c)所示的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物(例如水合物)、或其前药，在某些实施方案中，所述环A选自选自苯环、环己烷、双环[1,1,1]戊烷、包含1～3个(优选1～2个)杂原子的5～10元芳杂环、由苯环与不饱和脂环构成的8～12元并环、由苯环与包含1～2个杂原子的不饱和脂杂环构成的8～12元并环，所述杂原子各自独立地选自N、O、S；在某些实施方案中，所述环A选自The compounds provided herein are represented by formula (I), (II), (III), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (IV), (IV-a), (IV-b) or (IV-c), their stereoisomers, their tautomers or their mixtures, or A pharmaceutically acceptable salt thereof, or a solvate thereof (e.g., a hydrate), or a prodrug thereof, wherein in certain embodiments, the ring A is selected from a benzene ring, cyclohexane, bicyclo[1,1,1]pentane, a 5-10 membered aromatic heterocyclic ring containing 1-3 (preferably 1-2) heteroatoms, an 8-12 membered cyclic ring consisting of a benzene ring and an unsaturated alicyclic ring, and an 8-12 membered cyclic ring consisting of a benzene ring and an unsaturated alicyclic heterocyclic ring containing 1-2 heteroatoms, wherein the heteroatoms are each independently selected from N, O, and S; in certain embodiments, the ring A is selected from

本申请提供的式(I)、(II)、(III)、(II-a)、(II-b)、(II-c)、(II-d)、(II-e)、(II-f)、(II-g)、(III-a)、(III-b)、(III-c)、(III-d)、(III-e)、(III-f)、(IV)、(IV-a)、(IV-b)或(IV-c)所示的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物(例如水合物)、或其前药，在某些实施方案中，所述环B选自苯环、包含1～4个杂原子的5～10元芳杂环、包含1～2个杂原子的3～10元饱和脂杂环，所述杂原子各自独立地选自N、O、S；在某些实施方案中，所述环B选自优选地，所述环B选自包含1～3个杂原子的5～10元芳杂环、包含1个杂原子的3～10元饱和脂杂环，所述杂原子各自独立地选自N、O、S(例如所述环B选自The compounds provided herein are represented by formula (I), (II), (III), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (IV), (IV-a), (IV-b) or (IV-c), their stereoisomers, their tautomers or their mixtures, or their pharmaceutically acceptable salts, or their solvates (e.g., hydrates), or their prodrugs. In certain embodiments, the ring B is selected from a benzene ring, a 5-10 membered aromatic heterocycle containing 1 to 4 heteroatoms, or a 3-10 membered saturated aliphatic heterocycle containing 1 to 2 heteroatoms, and the heteroatoms are each independently selected from N, O, and S. In certain embodiments, the ring B is selected from Preferably, the ring B is selected from a 5- to 10-membered aromatic heterocycle containing 1 to 3 heteroatoms, a 3- to 10-membered saturated aliphatic heterocycle containing 1 heteroatom, wherein the heteroatoms are independently selected from N, O, S (for example, the ring B is selected from

本申请提供的式(I)、(II)、(III)、(II-a)、(II-b)、(II-c)、(II-d)、(II-e)、(II-f)、(II-g)、(III-a)、(III-b)、(III-c)、(III-d)、(III-e)、(III-f)、(IV)、(IV-a)、(IV-b)或(IV-c)所示的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物(例如水合物)、或其前药，在某些实施方案中，所述X、Y各自独立地选自N、CH、CCH₃、CCl、CCN、CCF₃，所述Z选自所述m、n、o、p、q各自独立地选自0或1，所述R选自氢、C₁～C₆烷基(例如甲基、乙基、正丙基、异丙基)、C₁～C₆羟基烷基(例如羟甲基、1-羟乙基、2-羟乙基等)，所述R^A选自卤素(例如氟、氯、溴)、C₁～C₆卤代烷基(例如三氟甲基)、C₁～C₆卤代烷氧基(例如三氟甲氧基)，所述R^B选自卤素(例如氟、氯、溴)、C₁～C₆烷基(例如甲基、乙基、正丙基、异丙基)、氨基、氰基，所述环A选自苯环、环己烷、双环[1,1,1]戊烷、包含1～2个杂原子的5～10元芳杂环、由苯环与不饱和脂环构成的8～12元并环、由苯环与包含1～2个杂原子的不饱和脂杂环构成的8～12元并环，所述杂原子各自独立地选自N、O、S(例如所述环A选自苯环、环己烷、双环[1,1,1]戊烷、吡啶、茚满等)，所述环B选自苯环、包含1～4个杂原子(例如包含1个、2个、3个或4个杂原子)的5～10元芳杂环、包含1～2个杂原子的3～10元饱和脂杂环，所述杂原子各自独立地选自N、O、S(例如环B选自吡唑、异噁唑、噁唑、咪唑、四氮唑、吡啶、吡嗪、四氢吡喃、吗啉、哌啶等)。The compounds provided herein are represented by formula (I), (II), (III), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (IV), (IV-a), (IV-b) or (IV-c), their stereoisomers, their tautomers or mixtures thereof, or their pharmaceutically acceptable salts, or their solvates (e.g., hydrates), or their prodrugs. In certain embodiments, X and Y are each independently selected from N, CH, CCH₃ , CCl, CCN, CCF₃ , and Z is selected from The m, n, o, p, q are each independently selected from 0 or 1, the R is selected from hydrogen, C₁ to C₆ alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), C₁ to C₆ hydroxyalkyl (e.g., hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, etc.), the^RA is selected from halogen (e.g., fluorine, chlorine, bromine), C₁ to C₆ haloalkyl (e.g., trifluoromethyl), C₁ to C₆ haloalkoxy (e.g., trifluoromethoxy), the^RB is selected from halogen (e.g., fluorine, chlorine, bromine), C₁ to C 6₆ alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), amino, cyano, the ring A is selected from a benzene ring, cyclohexane, bicyclo[1,1,1]pentane, a 5-10 membered aromatic heterocyclic ring containing 1-2 heteroatoms, an 8-12 membered cyclic ring consisting of a benzene ring and an unsaturated alicyclic ring, an 8-12 membered cyclic ring consisting of a benzene ring and an unsaturated alicyclic heterocyclic ring containing 1-2 heteroatoms, the heteroatoms are each independently selected from N, O, S (for example, the ring A is selected from a benzene ring, a cyclohexane, a bicyclo[1,1,1]pentane, a 5-10 membered aromatic heterocyclic ring containing 1-2 heteroatoms, The ring B is selected from a benzene ring, a 5-10 membered aromatic heterocycle containing 1-4 heteroatoms (e.g., containing 1, 2, 3 or 4 heteroatoms), and a 3-10 membered saturated aliphatic heterocycle containing 1-2 heteroatoms, and the heteroatoms are each independently selected from N, O, and S (e.g., the ring B is selected from pyrazole, isoxazole, oxazole, imidazole, tetrazole, pyridine, pyrazine, tetrahydropyran, morpholine, piperidine, etc.).

本申请提供的式(I)、(II)、(III)、(II-a)、(II-b)、(II-c)、(II-d)、(II-e)、(II-f)、(II-g)、(III-a)、(III-b)、(III-c)、(III-d)、(III-e)、(III-f)、(IV)、(IV-a)、(IV-b)或(IV-c)所示的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物(例如水合物)、或其前药，在某些优选实施方案中，环B选自包含1～3个杂原子的5～10元芳杂环(例如所述环B选自更优选地，所述环B选自例如)，环A选自6～10元芳环、5～10元芳杂环、3～10饱和脂肪环、芳环与不饱和脂环构成的7～10元并环、芳杂环与不饱和脂环构成的7～10元并环(例如所述环A选自)。The compounds provided herein are represented by formula (I), (II), (III), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (IV), (IV-a), (IV-b) or (IV-c), their stereoisomers, their tautomers or their mixtures, or their pharmaceutically acceptable salts, or their solvates (e.g., hydrates), or their prodrugs. In certain preferred embodiments, ring B is selected from a 5-10 membered aromatic heterocycle containing 1 to 3 heteroatoms (e.g., the ring B is selected from More preferably, the ring B is selected from ), Ring A is selected from a 6- to 10-membered aromatic ring, a 5- to 10-membered aromatic heterocyclic ring, a 3- to 10-membered saturated aliphatic ring, a 7- to 10-membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, and a 7- to 10-membered cyclic ring consisting of an aromatic heterocyclic ring and an unsaturated alicyclic ring (for example, Ring A is selected from ).

在本申请的一些实施方案中，在式(I)、(II)、(III)、(II-a)、(II-b)、(II-c)、(II-d)、(II-e)、(II-f)、(II-g)、(III-a)、(III-b)、(III-c)、(III-d)、(III-e)、(III-f)、(IV)、(IV-a)、(IV-b)或(IV-c)所示的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物(例如水合物)、或其前药中，In some embodiments of the present application, in the compound represented by formula (I), (II), (III), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (IV), (IV-a), (IV-b) or (IV-c), its stereoisomer, its tautomer or its mixture form, or its pharmaceutically acceptable salt, or its solvate (such as hydrate), or its prodrug,

X、Y各自独立地选自CR⁰或N(优选X和Y不同时为N)，R⁰选自氢、氘、氚、羟基、氟、氯、溴、胺基和甲基，优选R⁰选自氢、氘和氚；X, Y are each independently selected from CR⁰ or N (preferably X and Y are not N at the same time), R⁰ is selected from hydrogen, deuterium, tritium, hydroxyl, fluorine, chlorine, bromine, amino and methyl, preferably R⁰ is selected from hydrogen, deuterium and tritium;

Z为C₁～C₆亚烷基(优选C₁～C₄亚烷基、C₁～C₃亚烷基，如-CH₂-、-CH₂CH₂-、-CH(CH₃)-、-CH(CH₂CH₃)-、-CH[CH(CH₃)₂]-)，所述Z任选地被氘、氚、硝基、羟基、醛基、胺基、亚胺基、卤素、氰基或＝O中的任一个取代(优选，所述Z任选地被羟基取代)；Z is C₁ -C₆ alkylene (preferably C₁ -C₄ alkylene, C₁ -C₃ alkylene, such as -CH₂ -, -CH₂ CH₂ -, -CH(CH₃ )-, -CH(CH₂ CH₃ )-, -CH[CH(CH₃ )₂ ]-), and Z is optionally substituted by any one of deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano or =O (preferably, Z is optionally substituted by hydroxyl);

环A选自C₆～C₁₀芳环、5～10元芳杂环、C₅～C₁₀饱和脂环、C₅～C₁₀不饱和脂环、C₆～C₁₀芳环与C₅～C₁₀不饱和脂环构成的并环、6～10元芳杂环与C₅～C₁₀不饱和脂环构成的并环(优选地，环A选自C₆～C₁₀芳环、6～10元芳杂环、C₅～C₈饱和脂环、C₆芳环与C₅～C₆不饱和脂环构成的并环，更优选地，环A选自苯环、茚满、吡啶、环己烷、双环[1,1,1]戊基、嘧啶)；Ring A is selected from a C₆ ～C₁₀ aromatic ring, a 5-10 membered aromatic heterocycle, a C₅ ～C₁₀ saturated alicyclic ring, a C₅ ～C₁₀ unsaturated alicyclic ring, a C₆ ～C₁₀ aromatic ring and a C₅ ～C₁₀ unsaturated alicyclic ring, and a C₆ ～C₁₀ unsaturated alicyclic ring (preferably, Ring A is selected from a C₆ ～C₁₀ aromatic ring, a 6-10 membered aromatic heterocycle, a C₅ ～C₈ saturated alicyclic ring, and a C₆ aromatic ring and a C₅ ～C₆ unsaturated alicyclic ring. More preferably, Ring A is selected from a benzene ring, indane, pyridine, cyclohexane, bicyclo[1,1,1]pentyl, and pyrimidine);

环B选自C₆～C₁₀芳环、5～10元芳杂环、C₃～C₁₀饱和脂杂环、5～10元不饱和脂杂环、5～10元芳杂环与C₅～C₁₀不饱和脂环构成的并环、C₆～C₁₀芳环与5～10元不饱和脂杂环构成的并环(优选地环B为5～10元芳杂环或C₄～C₈饱和脂杂环，更优选地环B为含有1～3个选自N、O、S杂原子的5～10元芳杂环；具体地环B例如选自吡啶、吡唑、吡嗪、嘧啶、四氢吡喃、咪唑、噻唑、吡啶并咪唑、吡啶并吡唑、苯并咪唑、喹啉、哌啶、噁唑、异噁唑、嘧啶、吲唑和吖丁啶，优选自吡啶、吡唑、吡嗪、嘧啶、咪唑、噻唑、吡啶并咪唑、吡啶并吡唑、苯并咪唑、喹啉、噁唑、异噁唑、嘧啶、吲唑)；Ring B is selected from a C₆ ～C₁₀ aromatic ring, a 5～10 membered aromatic heterocycle, a C₃ ～C₁₀ saturated alicyclic heterocycle, a 5～10 membered unsaturated alicyclic heterocycle, a 5～10 membered aromatic heterocycle and a C₅ ～C₁₀ unsaturated alicyclic ring, a C₆ ～C₁₀ aromatic ring and a 5～10 membered unsaturated alicyclic heterocycle (preferably, Ring B is a 5～10 membered aromatic heterocycle or a C₄ ～C₈ saturated aliphatic heterocycle, more preferably ring B is a 5-10 membered aromatic heterocycle containing 1-3 heteroatoms selected from N, O and S; specifically, ring B is selected from pyridine, pyrazole, pyrazine, pyrimidine, tetrahydropyran, imidazole, thiazole, pyridoimidazole, pyridopyrazole, benzimidazole, quinoline, piperidine, oxazole, isoxazole, pyrimidine, indazole and azetidine, preferably pyridine, pyrazole, pyrazine, pyrimidine, imidazole, thiazole, pyridoimidazole, pyridopyrazole, benzimidazole, quinoline, oxazole, isoxazole, pyrimidine and indazole);

o为0、1或2(优选，o为0)；o is 0, 1 or 2 (preferably, o is 0);

m为0、1或2(优选，m为0或1)；m is 0, 1 or 2 (preferably, m is 0 or 1);

n为0、1或2(优选，n为0或1)；n is 0, 1 or 2 (preferably, n is 0 or 1);

R^A选自氘、氚、羟基、卤素、C₁～C₆烷基、C₁～C₆卤代烷氧基和C₁～C₆卤代烷基(优选地，R^A选自氘、氚、卤素、C₁～C₆烷基、C₁～C₆卤代烷氧基和C₁～C₆卤代烷基；更优选地，R^A为氘、氚、氟、氯、溴、三氟甲基、三氯甲基、三溴甲基、三氟甲氧基、三氯甲氧基或三溴甲氧基)；^RA is selected from deuterium, tritium, hydroxyl, halogen,_C1 -_C6 alkyl,_C1 -C6 haloalkoxy and_C1 -_C6 haloalkyl (preferably,^RA is selected from deuterium, tritium,_halogen ,_C1 -_C6 alkyl,_C1 -_C6 haloalkoxy and_C1 -_C6 haloalkyl; more preferably,^RA is deuterium, tritium, fluorine, chlorine, bromine, trifluoromethyl, trichloromethyl, tribromomethyl, trifluoromethoxy, trichloromethoxy or tribromomethoxy);

R^B选自氘、氚、羟基、氰基、胺基、酰胺基、C₁～C₆烷基、C₁～C₆羟基烷基、C₁～C₆胺基烷基、C₁～C₆酰胺基烷基和C₁～C₆卤代烷基(优选地，R^B选自氘、氚、胺基和C₁～C₆烷基；更优选地，R^B为氢、氘、氚、甲基、乙基、丙基或-NH₂)，R^B任选地被氘、氚或卤素取代；^RB is selected from deuterium, tritium, hydroxyl, cyano, amine, amide,_C1 -_C6 alkyl, C1-_C6 hydroxyalkyl,_C1-C6 aminoalkyl,_C1 -_C6 amidoalkyl and_C1 -_C6 haloalkyl (preferably,^RB is selected from deuterium, tritium, amine and_C1 -_C6 alkyl; more preferably,^RB is hydrogen, deuterium, tritium, methyl, ethyl, propyl or_-NH2 ),^RB is optionally substituted by deuterium, tritium or halogen;

所述芳杂环、不饱和脂杂环、饱和脂杂环各自独立地包含1～3个杂原子，所述杂原子独立地选自N、O、S。The aromatic heterocycle, unsaturated aliphatic heterocycle and saturated aliphatic heterocycle each independently contain 1 to 3 heteroatoms, and the heteroatoms are independently selected from N, O and S.

在本申请的一些实施方案中，在式(I)所示的化合物中，In some embodiments of the present application, in the compound represented by formula (I),

X、Y各自独立地选自CR⁰或N(优选X和Y不同时为N)，R⁰选自氢、氘、氚、羟基、氟、氯、溴、胺基和甲基，优选R⁰选自氢、氘和氚；X, Y are each independently selected from CR⁰ or N (preferably X and Y are not N at the same time), R⁰ is selected from hydrogen, deuterium, tritium, hydroxyl, fluorine, chlorine, bromine, amino and methyl, preferably R⁰ is selected from hydrogen, deuterium and tritium;

Z为C₁～C₆亚烷基(优选C₁～C₄亚烷基、C₁～C₃亚烷基，如-CH₂-、-CH₂CH₂-、-CH(CH₃)-、-CH(CH₂CH₃)-、-CH[CH(CH₃)₂]-)，所述Z任选地被氘、氚、硝基、羟基、醛基、胺基、亚胺基、卤素、氰基或＝O中的任一个取代(优选，所述Z任选地被羟基取代)；Z is C₁ -C₆ alkylene (preferably C₁ -C₄ alkylene, C₁ -C₃ alkylene, such as -CH₂ -, -CH₂ CH₂ -, -CH(CH₃ )-, -CH(CH₂ CH₃ )-, -CH[CH(CH₃ )₂ ]-), and Z is optionally substituted by any one of deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano or =O (preferably, Z is optionally substituted by hydroxyl);

W²、W³均为C，或者W²、W³各自独立地选自CR²，每个R²独立地选自氢、氘、氚、硝基、羟基、巯基、卤素、氰基、胺基、C₁～C₆烷基、C₁～C₆卤代烷基、C₁～C₆烷氧基和C₁～C₆卤代烷氧基(优选地，W²选自C或CR²，R²选自氢、氘、氚、卤素、氰基、C₁～C₆烷基、C₁～C₆卤代烷基、C₁～C₆烷氧基和C₁～C₆卤代烷氧基；W³选自C或CR²，R²选自氢、氘、氚、卤素、C₁～C₆烷基、C₁～C₆卤代烷基、C₁～C₆烷氧基和C₁～C₆卤代烷氧基；更优选地，W²选自C或CR²，R²选自氢、氘、氚、卤素、氰基、C₁～C₆烷基和C₁～C₆烷氧基；W³选自C或CR²，R²选自氢、氘、氚、卤素、C₁～C₆烷基和C₁～C₆烷氧基)；W² and W³ are both C, or W² and W³ are each independently selected from CR² , and each R² is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, mercapto, halogen, cyano, amine, C₁ to C₆ alkyl, C₁ to C₆ haloalkyl, C₁ to C₆ alkoxy and C₁ to C₆ haloalkoxy (preferably, W² is selected from C or CR² , R² is selected from hydrogen, deuterium, tritium, halogen, cyano, C₁ to C₆ alkyl, C₁ to C₆ haloalkyl, C₁ to C₆ alkoxy and C₁ to C₆ haloalkoxy; W³ is selected from C or CR² , R² is selected from hydrogen, deuterium, tritium, halogen, C_{1 to C 6 alkyl, C 1to C 6} haloalkyl, C₁ to C 6 alkoxy and C₁ to C₆ haloalkoxy More preferably, W² is selected from C or CR² , R² is selected from hydrogen, deuterium, tritium, halogen, cyano, C₁ ～C₆ alkyl and C₁ ～C₆ alkoxy; W₃ is selected from_C or CR² , R² is selected from hydrogen, deuterium, tritium, halogen^, C_{1～C 6alkyl} and C₁ ～C₆ alkoxy);

W¹为CR¹或N，R¹选自氢、氘、氚、羟基、卤素、胺基、C₁～C₆烷基和C₁～C₆卤代烷基(优选地，R¹选自氢、氘、氚和C₁～C₆烷基)；W¹ is CR¹ or N, R¹ is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, amine, C₁ ～C₆ alkyl and C₁ ～C₆ haloalkyl (preferably, R¹ is selected from hydrogen, deuterium, tritium and C₁ ～C₆ alkyl);

W⁴为C；W⁴ is C;

W⁵为CR³，R³选自氢、氘、氚、羟基、卤素、胺基、C₁～C₆烷基、C₁～C₆卤代烷基(优选地，R³选自氢、氘、氚、卤素和C₁～C₆烷基)；W⁵ is CR³ , R³ is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, amine, C₁ ～C₆ alkyl, C₁ ～C₆ haloalkyl (preferably, R³ is selected from hydrogen, deuterium, tritium, halogen and C₁ ～C₆ alkyl);

表示芳香环； represents an aromatic ring;

环C为不存在、5～6元芳杂环或5～6元不饱和脂杂环(优选地，环C为不存在或5～6元芳杂环；更优选地环C为不存在、吡唑、吡嗪或吡啶)，环C任选地被氘、氚或C₁～C₆烷基取代；Ring C is absent, a 5-6 membered aromatic heterocycle or a 5-6 membered unsaturated aliphatic heterocycle (preferably, ring C is absent or a 5-6 membered aromatic heterocycle; more preferably, ring C is absent, pyrazole, pyrazine or pyridine), and ring C is optionally substituted with deuterium, tritium or C₁ -C₆ alkyl;

环A选自C₆～C₁₀芳环、5～10元芳杂环、C₅～C₁₀饱和脂环、C₅～C₁₀不饱和脂环、C₆～C₁₀芳环与C₅～C₁₀不饱和脂环构成的并环、6～10元芳杂环与C₅～C₁₀不饱和脂环构成的并环(优选地，环A选自C₆～C₁₀芳环、6～10元芳杂环、C₅～C₈饱和脂环、C₆芳环与C₅～C₆不饱和脂环构成的并环，更优选地，环A选自苯环、茚满、吡啶、环己烷、双环[1,1,1]戊基、嘧啶)；Ring A is selected from a C₆ ～C₁₀ aromatic ring, a 5-10 membered aromatic heterocycle, a C₅ ～C₁₀ saturated alicyclic ring, a C₅ ～C₁₀ unsaturated alicyclic ring, a C₆ ～C₁₀ aromatic ring and a C₅ ～C₁₀ unsaturated alicyclic ring, and a C₆ ～C₁₀ unsaturated alicyclic ring (preferably, Ring A is selected from a C₆ ～C₁₀ aromatic ring, a 6-10 membered aromatic heterocycle, a C₅ ～C₈ saturated alicyclic ring, and a C₆ aromatic ring and a C₅ ～C₆ unsaturated alicyclic ring. More preferably, Ring A is selected from a benzene ring, indane, pyridine, cyclohexane, bicyclo[1,1,1]pentyl, and pyrimidine);

环B选自C₆～C₁₀芳环、5～10元芳杂环、C₃～C₁₀饱和脂杂环、5～10元不饱和脂杂环、5～10元芳杂环与C₅～C₁₀不饱和脂环构成的并环、C₆～C₁₀芳环与5～10元不饱和脂杂环构成的并环(优选地环B为5～10元芳杂环或C₄～C₈饱和脂杂环，更优选地环B为含有1～3个选自N、O、S杂原子的5～10元芳杂环，具体地环B例如优选自吡啶、吡唑、吡嗪、嘧啶、四氢吡喃、咪唑、噻唑、吡啶并咪唑、吡啶并吡唑、苯并咪唑、喹啉、哌啶、噁唑、异噁唑、嘧啶、吲唑和吖丁啶)；Ring B is selected from a C₆ -C₁₀ aromatic ring, a 5-10 membered aromatic heterocycle, a C₃ -C₁₀ saturated aliphatic heterocycle, a 5-10 membered unsaturated aliphatic heterocycle, a 5-10 membered aromatic heterocycle and a C₅ -C₁₀ unsaturated aliphatic heterocycle, and a C₆ -C₁₀ aromatic ring and a 5-10 membered unsaturated aliphatic heterocycle (preferably, Ring B is a 5-10 membered aromatic heterocycle or a C₄ -C₈ saturated aliphatic heterocycle, more preferably, Ring B is a 5-10 membered aromatic heterocycle containing 1 to 3 heteroatoms selected from N, O, and S. Specifically, Ring B is preferably selected from pyridine, pyrazole, pyrazine, pyrimidine, tetrahydropyran, imidazole, thiazole, pyridoimidazole, pyridopyrazole, benzimidazole, quinoline, piperidine, oxazole, isoxazole, pyrimidine, indazole, and azetidine);

o为0、1或2(优选，o为0)；o is 0, 1 or 2 (preferably, o is 0);

m为0、1或2(优选，m为0或1)；m is 0, 1 or 2 (preferably, m is 0 or 1);

n为0、1或2(优选，n为0或1)；n is 0, 1 or 2 (preferably, n is 0 or 1);

R^A选自氘、氚、羟基、卤素、C₁～C₆烷基和C₁～C₆卤代烷基(优选地，R^A选自氘、氚、卤素、C₁～C₆烷基和C₁～C₆卤代烷基；更优选地，R^A为氘、氚、氟、氯、溴、三氟甲基、三氯甲基或三溴甲基)；^RA is selected from deuterium, tritium, hydroxyl, halogen,_C1 -_C6 alkyl and_C1 -_C6 haloalkyl (preferably,^RA is selected from deuterium, tritium, halogen,_C1 -_C6 alkyl and_C1 -_C6 haloalkyl; more preferably,^RA is deuterium, tritium, fluorine, chlorine, bromine, trifluoromethyl, trichloromethyl or tribromomethyl);

R^B选自氘、氚、羟基、氰基、胺基、C₁～C₆烷基和C₁～C₆卤代烷基(优选地，R^B选自氘、氚、胺基和C₁～C₆烷基；更优选地，R^B为氘、氚、甲基、乙基、丙基或-NH₂)，R^B任选地被氘、氚或卤素取代；^RB is selected from deuterium, tritium, hydroxyl, cyano, amine, C₁ -C₆ alkyl and C₁ -C₆ haloalkyl (preferably,^RB is selected from deuterium, tritium, amine and C₁ -C₆ alkyl; more preferably,^RB is deuterium, tritium, methyl, ethyl, propyl or -NH₂ ),^RB is optionally substituted by deuterium, tritium or halogen;

所述芳杂环、不饱和脂杂环、饱和脂杂环各自独立地包含1～3个杂原子(优选包含1～2个杂原子)，所述杂原子独立地选自N、O、S。The aromatic heterocycle, unsaturated aliphatic heterocycle and saturated aliphatic heterocycle each independently contain 1 to 3 heteroatoms (preferably 1 to 2 heteroatoms), and the heteroatoms are independently selected from N, O and S.

在本申请的一些实施方案中，在式(I)所示的化合物中，In some embodiments of the present application, in the compound represented by formula (I),

X、Y各自独立地选自CR⁰或N且不同时为N，R⁰各自独立地选自氢、氘和氚，X, Y are each independently selected from CR⁰ or N and are not N at the same time, R⁰ are each independently selected from hydrogen, deuterium and tritium,

Z选自其中*与环B相连，p为0、1或2，R选自氢、氘、氚、羟基、C₁～C₆烷基和C₁～C₆羟基烷基，Z is selected from wherein * is connected to ring B, p is 0, 1 or 2, and R is selected from hydrogen, deuterium, tritium, hydroxyl, C₁ ～C₆ alkyl and C₁ ～C₆ hydroxyalkyl,

W²、W³均选自C，或者W²、W³各自独立地为CR²，每个R²独立地选自氢、氘、氚、卤素、氰基、C₁～C₆烷基、C₁～C₆卤代烷基、C₁～C₆烷氧基和C₁～C₆卤代烷氧基，W² and W³ are both selected from C, or W² and W³ are each independently CR² , and each R² is independently selected from hydrogen, deuterium, tritium, halogen, cyano, C₁ ～C₆ alkyl, C₁ ～C₆ haloalkyl, C₁ ～C₆ alkoxy and C₁ ～C₆ haloalkoxy,

W¹为CR¹或N，R¹独立地选自氢、氘、氚、卤素、C₁～C₆烷基和C₁～C₆卤代烷基，W¹ is CR¹ or N, R¹ is independently selected from hydrogen, deuterium, tritium, halogen, C₁ ～C₆ alkyl and C₁ ～C₆ haloalkyl,

W⁴为C，W⁴ is C,

W⁵为CR³，R³独立地选自氢、氘、氚、卤素、C₁～C₆烷基和C₁～C₆卤代烷基，W⁵ is CR³ , R³ is independently selected from hydrogen, deuterium, tritium, halogen, C₁ ～C₆ alkyl and C₁ ～C₆ haloalkyl,

表示芳香环， represents an aromatic ring,

环C为不存在或包含1～2个杂原子的5～6元芳杂环，所述杂原子选自N、O、S，所述环C任选地被氘、氚或C₁～C₆烷基取代，Ring C is a 5-6 membered aromatic heterocyclic ring without or containing 1-2 heteroatoms, wherein the heteroatoms are selected from N, O, and S, and the ring C is optionally substituted by deuterium, tritium, or C₁ -C₆ alkyl.

环A选自(优选)，Ring A is selected from (Preferred ),

环B选自(优选)，Ring B is selected from (Preferred ),

m、n、o各自为0、1或2(优选，o为0，m为0或1，n为0或1)，m, n, o are each 0, 1 or 2 (preferably, o is 0, m is 0 or 1, and n is 0 or 1),

R^A选自氘、氚、卤素、C₁～C₆烷基和C₁～C₆卤代烷基，^RA is selected from deuterium, tritium, halogen,_C1 -_C6 alkyl and_C1 -_C6 haloalkyl,

R^B选自氘、氚、胺基和C₁～C₆烷基。^RB is selected from deuterium, tritium, an amine group and a_C1 -_C6 alkyl group.

在本申请的一些具体实施方案中，本申请提供如下所示的化合物，其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物(例如水合物)、或其前药，


In some specific embodiments of the present application, the present application provides the compounds shown below, their stereoisomers, their tautomers or their mixtures, or their pharmaceutically acceptable salts, or their solvates (e.g., hydrates), or their prodrugs,

本申请的另一目的是提供一种药物组合物，包含至少一种前述化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药，和至少一种药学上可接受的辅料。Another object of the present application is to provide a pharmaceutical composition comprising at least one of the aforementioned compounds, their stereoisomers, their tautomers or their mixtures, or their pharmaceutically acceptable salts, or their solvates, or their prodrugs, and at least one pharmaceutically acceptable excipient.

本申请的另一目的是提供一种前述化合物、其立体异构体、或其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药、或药物组合物用于制备药物的用途。其中，所述药物是TEAD抑制剂，可用于治疗不需要的TEAD活性水平升高相关的疾病。或者，本申请提供了一种用作药物(优选TEAD抑制剂)的前述化合物、或其立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药、或药物组合物。或者，本申请提供了一种治疗或预防TEAD相关疾病的方法，包括向有需要的受试者给予前述化合物、或其立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药、或药物组合物。本文中的所述TEAD相关疾病是指通过抑制TEAD而达到缓解、改善、停止进展、减轻或者不再恶化等临床上有益的疗效的疾病或其并发症。Another object of the present application is to provide a use of the aforementioned compound, its stereoisomer, or its tautomer or its mixture form, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or a pharmaceutical composition for the preparation of a drug. Wherein, the drug is a TEAD inhibitor, which can be used to treat diseases associated with increased levels of unwanted TEAD activity. Alternatively, the present application provides a aforementioned compound, or its stereoisomer, tautomer or its mixture form, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or a pharmaceutical composition for use as a drug (preferably a TEAD inhibitor). Alternatively, the present application provides a method for treating or preventing a TEAD-related disease, comprising administering the aforementioned compound, or its stereoisomer, tautomer or its mixture form, or its pharmaceutically acceptable salt, or its solvate, to a subject in need thereof. Or its prodrug, or pharmaceutical composition. The TEAD-related disease herein refers to a disease or its complications that can achieve clinically beneficial effects such as alleviation, improvement, cessation of progression, alleviation or no longer deterioration by inhibiting TEAD.

在某些实施方案中，所述药物或方法用于治疗与TEAD表达增加或TEAD活性增加相关的疾病或病症。在某些实施方案中，所述药物或方法用于治疗与YAP表达增加或TAZ表达增加相关的疾病。在某些实施方案中，所述药物或方法用于治疗与YAP或TAZ与其他基因发生融合突变的相关疾病。在某些实施方案中，所述药物或方法用于治疗Hippo通路突变或失活相关的疾病。在某些具体实施方案中，所述药物或方法用于治疗肿瘤细胞增殖性疾病(例如间皮瘤肿瘤细胞、恶性胸膜间皮瘤肿瘤细胞等增殖性疾病)、抑制肿瘤的侵袭和转移、降低靶向药或化疗药物的耐药、降低肿瘤的免疫逃逸、治疗多囊肾病或肝纤维化；在某些具体实施方案中，所述药物或方法用于治疗听力神经瘤、急性白血病、急性淋巴细胞性白血病、急性骨髓性白血病(例如单核细胞性、粒细胞性、腺癌、血管肉瘤、星形细胞瘤、髓单核细胞和早幼粒细胞性)、急性T细胞白血病、基底细胞癌、胆管癌、膀胱癌、脑癌、乳腺癌、支气管癌、宫颈癌、软骨肉瘤、脊索瘤、绒毛膜癌、慢性白血病、慢性淋巴细胞性白血病、慢性骨髓细胞性白血病、慢性粒细胞性白血病、结肠癌、结直肠癌、颅咽管瘤、囊腺癌、弥漫性大B细胞淋巴瘤、不良增殖变化(发育异常和化生)、胚胎性癌、子宫内膜癌、内皮肉瘤、室管膜瘤、上皮癌、红白血病、食道癌、雌激素受体阳性乳腺癌、原发性血小板增多症、尤因氏肿瘤、纤维肉瘤、滤泡性淋巴瘤、生殖细胞睾丸癌、胶质瘤、成胶质细胞瘤、间皮瘤、肝细胞癌、脑膜瘤、恶性周围神经鞘瘤、施万细胞瘤、肺癌、膀胱癌、皮肤神经纤维瘤、前列腺癌、胰腺癌、胶质母细胞瘤、子宫内膜腺鳞状癌、未分化甲状腺癌、胃腺癌、食管腺癌、卵巢癌、卵巢浆液性腺癌、黑素瘤和乳腺癌。In certain embodiments, the drug or method is used to treat a disease or condition associated with increased TEAD expression or increased TEAD activity. In certain embodiments, the drug or method is used to treat a disease associated with increased YAP expression or increased TAZ expression. In certain embodiments, the drug or method is used to treat a disease associated with a fusion mutation of YAP or TAZ with other genes. In certain embodiments, the drug or method is used to treat a disease associated with a mutation or inactivation of the Hippo pathway. In certain specific embodiments, the drug or method is used to treat tumor cell proliferative diseases (such as mesothelioma tumor cells, malignant pleural mesothelioma tumor cells and other proliferative diseases), inhibit tumor invasion and metastasis, reduce the resistance of targeted drugs or chemotherapeutic drugs, reduce the immune escape of tumors, treat polycystic kidney disease or liver fibrosis; in certain specific embodiments, the drug or method is used to treat acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (such as monocytic, granulocytic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic Leukemia, chronic myeloid leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, adverse proliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial carcinoma, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, schwannoma, lung cancer, bladder cancer, cutaneous neurofibroma, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, undifferentiated thyroid cancer, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.

定义definition

除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义。一个特定的术语在没有特别定义的情况下不应被认为是不明确或不清楚的，而应该按照本领域的常规含义去理解。Unless otherwise stated, the following terms used in the specification and claims have the following meanings. A particular term should not be considered ambiguous or unclear without special definition, but should be understood according to the ordinary meaning in the art.

“链状烃基”是指脂肪族呈链状连接的只含碳、氢原子的基团。所述烃基可以是饱和的烃基，也可以是不饱和的烃基；所述链状可以是直链状，也可以是支链状。本申请中使用的C₁-C₆链状烃基是指由1～6个(例如1个、2个、3个、4个、5个或6个、或由任意两个前述数值组成的范围值)碳原子构成的直链烃基或者支链烃基，包括饱和的烃基与不饱和的烃基。常见的链状烃基包括但不限于甲基、乙基、正丙基、异丙基、-CH₂-、-CHCH₃-、-CHCH₂CH₃-、-CHCH(CH₃)₂-、-CH₂CH₂-、-CH(CH₃)CH₂-等。"Chained hydrocarbon group" refers to an aliphatic group that is connected in a chain and contains only carbon and hydrogen atoms. The hydrocarbon group may be a saturated hydrocarbon group or an unsaturated hydrocarbon group; the chain may be a straight chain or a branched chain. The C₁ -C₆ chained hydrocarbon group used in the present application refers to a straight chained hydrocarbon group or a branched chained hydrocarbon group consisting of 1 to 6 (e.g., 1, 2, 3, 4, 5 or 6, or a range consisting of any two of the aforementioned values) carbon atoms, including saturated hydrocarbon groups and unsaturated hydrocarbon groups. Common chained hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, -CH₂ -, -CHCH₃ -, -CHCH₂ CH₃ -, -CHCH(CH₃ )₂ -, -CH₂ CH₂ -, -CH(CH₃ )CH₂ -, etc.

“烷基”是一类饱和的脂肪族链状烃基团，包括直链烷基、支链烷基，是指链状烷烃分子中去掉一个氢原子而成的基团。例如本申请中使用的C₁-C₆烷基指由1～6个(例如1个、2个、3个、4个、5个或6个、或由任意两个前述数值组成的范围值)碳原子构成的直链烷基或支链烷基。典型的烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、特戊基、正己基等。"Alkyl" is a type of saturated aliphatic chain hydrocarbon group, including straight-chain alkyl and branched-chain alkyl, and refers to a group formed by removing a hydrogen atom from a chain alkane molecule. For example,_C1 -_C6 alkyl used in this application refers to a straight-chain alkyl or branched-chain alkyl composed of 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5 or 6, or a range consisting of any two of the aforementioned values). Typical alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, etc.

“亚烷基”是一类饱和的脂肪族链状烃基基团，包括直链亚烷基、支链亚烷基，是指烷烃分子中少掉两个氢原子而成的基团，其中少掉的氢原子可以是连接同一个碳原子，也可以是连接不同的碳原子。本申请中使用的C₁～C₆亚烷基是指由1～6个(例如1个、2个、3个、4个、5个或6个、或由任意两个前述数值组成的范围值)碳原子构成的直链亚烷基或支链亚烷基。典型的亚烷基包括但不限于-CH₂-、-CH(CH₃)-、-CH(CH₂CH₃)-、-CH[CH(CH₃)₂]-、-CH₂CH₂-、-CH(CH₃)CH₂-等。"Alkylene" is a type of saturated aliphatic chain hydrocarbon group, including straight-chain alkylene and branched-chain alkylene, and refers to a group formed by removing two hydrogen atoms from an alkane molecule, wherein the missing hydrogen atoms may be connected to the same carbon atom or to different carbon atoms. The C₁ -C₆ alkylene used in this application refers to a straight-chain alkylene or branched-chain alkylene composed of 1 to 6 (e.g., 1, 2, 3, 4, 5 or 6, or a range consisting of any two of the aforementioned values) carbon atoms. Typical alkylene includes, but is not limited to, -CH₂ -, -CH(CH₃ )-, -CH(CH₂ CH₃ )-, -CH[CH(CH₃ )₂ ]-, -CH₂ CH₂ -, -CH(CH₃ )CH₂ -, etc.

“烷氧基”是指-O-烷基；本申请中使用的C₁-C₆烷氧基指由1～6个(例如1个、2个、3个、4个、5个或6个、或由任意两个前述数值组成的范围值)碳原子构成的直链烷氧基或支链烷氧基。典型的烷氧基包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、正戊氧基、异戊氧基、特戊氧基、正己氧基等。"Alkoxy" refers to -O-alkyl;_C1 -_C6 alkoxy used in the present application refers to a straight chain alkoxy or branched alkoxy consisting of 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5 or 6, or a range consisting of any two of the foregoing values). Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentyloxy, tert-pentyloxy, n-hexyloxy, and the like.

“卤素”或“卤”是指氟、氯、溴或碘。"Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

“卤代烷基”是指烷基中至少一个氢被卤素原子置换，本申请中使用的C₁～C₆卤代烷基指由1～6个(例如1个、2个、3个、4个、5个或6个、或由任意两个前述数值组成的范围值)碳原子构成的直链烷基或支链烷基，且烷基上至少一个氢被卤素原子任意取代。常见的卤代烷基包括不限于一氟甲基、二氟甲基、三氟甲基、1-氟乙基、1,1-二氟乙基、2-氟乙基、2,2-二氟乙基、1,2-二氟乙基、2,2,2-三氟乙基、一氯甲基、二氯甲基、三氯甲基、1-氯乙基、1,1-二氯乙基、2-氯乙基、2,2-二氯乙基、1,2-二氯乙基、2,2,2-三氯乙基等。"Haloalkyl" refers to an alkyl group in which at least one hydrogen is replaced by a halogen atom. The_C1 -_C6 haloalkyl group used in this application refers to a straight-chain or branched alkyl group consisting of 1 to 6 (e.g., 1, 2, 3, 4, 5 or 6, or a range consisting of any two of the foregoing values) carbon atoms, and at least one hydrogen on the alkyl group is arbitrarily replaced by a halogen atom. Common haloalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 1-chloroethyl, 1,1-dichloroethyl, 2-chloroethyl, 2,2-dichloroethyl, 1,2-dichloroethyl, 2,2,2-trichloroethyl wait.

“卤代烷氧基”是指烷氧基中至少一个氢被卤素原子置换，本申请中使用的C₁～C₆卤代烷氧基是指由1～6个(例如1个、2个、3个、4个、5个或6个、或由任意两个前述数值组成的范围值)碳原子构成的直链烷氧基或支链烷氧基，且烷氧基上至少一个氢被卤素原子任意取代。常见的卤代烷氧基包括不限于一氟甲氧基、二氟甲氧基、三氟甲氧基、1-氟乙氧基、1,1-二氟乙氧基、2-氟乙氧基、2,2-二氟乙氧基、1,2-二氟乙氧基、2,2,2-三氟乙氧基、一氯甲氧基、二氯甲氧基、三氯甲氧基、1-氯乙氧基、1,1-二氯乙氧基、2-氯乙氧基、2,2-二氯乙氧基、1,2-二氯乙氧基、2,2,2-三氯乙氧基等。"Haloalkoxy" refers to an alkoxy group in which at least one hydrogen is replaced by a halogen atom. The_C1 -_C6 haloalkoxy group used in this application refers to a straight chain alkoxy group or a branched chain alkoxy group consisting of 1 to 6 (e.g., 1, 2, 3, 4, 5 or 6, or a range consisting of any two of the aforementioned values) carbon atoms, and at least one hydrogen on the alkoxy group is arbitrarily replaced by a halogen atom. Common haloalkoxy groups include, but are not limited to, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 1,2-difluoroethoxy, 2,2,2-trifluoroethoxy, monochloromethoxy, dichloromethoxy, trichloromethoxy, 1-chloroethoxy, 1,1-dichloroethoxy, 2-chloroethoxy, 2,2-dichloroethoxy, 1,2-dichloroethoxy, 2,2,2-trichloroethoxy, and the like.

“羟基烷基”是指烷基中任意一个氢被羟基置换，本申请中使用的C₁～C₆羟基烷基指由1～6个(例如1个、2个、3个、4个、5个或6个、或由任意两个前述数值组成的范围值)碳原子构成的直链烷基或支链烷基且烷基上任意一个氢被羟基取代。常见的羟基烷基包括不限于羟甲基、1-羟乙基、2-羟乙基、1-羟基正丙基、2-羟基正丙基、3-羟基正丙基、2-羟基异丙基、4-羟基正丁基等。"Hydroxyalkyl" means that any one hydrogen in an alkyl group is replaced by a hydroxyl group. The_C1 -_C6 hydroxyalkyl used in this application refers to a straight-chain alkyl or branched alkyl group consisting of 1 to 6 (e.g., 1, 2, 3, 4, 5 or 6, or a range consisting of any two of the aforementioned values) carbon atoms, and any one hydrogen on the alkyl group is replaced by a hydroxyl group. Common hydroxyalkyl groups include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-n-propyl, 2-hydroxyisopropyl, 4-hydroxy-n-butyl, and the like.

“环”是指任意的环状共价封闭结构，包括例如碳环(例如芳环或脂环)、杂环(例如芳杂环或脂杂环)。碳环是指仅由碳原子构成的环，杂环是指由碳原子、杂原子共价结合并形成的封闭结构。根据环的数量，“环”可以是单环、双环、三环或多环。环为双环、三环或多环时，各个环之间的关系可以包括并环、螺环、桥环。"Ring" refers to any cyclic covalently closed structure, including, for example, carbocycle (e.g., aromatic ring or alicyclic ring), heterocycle (e.g., aromatic heterocycle or alicyclic heterocycle). Carbocycle refers to a ring consisting of only carbon atoms, and heterocycle refers to a closed structure formed by covalent bonding of carbon atoms and heteroatoms. Depending on the number of rings, a "ring" can be a monocyclic, bicyclic, tricyclic or polycyclic ring. When the ring is bicyclic, tricyclic or polycyclic, the relationship between the rings may include fused rings, spirocyclic rings, and bridged rings.

“杂原子”是指除碳原子以外其他任意可与碳原子共价结合的原子。常见的杂原子包括但不限于O、S、N、P、Si等。"Heteroatom" refers to any atom other than a carbon atom that can be covalently bonded to a carbon atom. Common heteroatoms include, but are not limited to, O, S, N, P, Si, etc.

“元”是表示构成环的骨架原子的个数。典型的5元环可以包括但不限于环戊烷、吡咯、咪唑、噻唑、呋喃和噻吩等；典型的6元环包括但不限于环己烷、吡啶、吡喃、吡嗪、噻喃、哒嗪、嘧啶、苯等。"Member" refers to the number of atoms constituting the ring. Typical 5-membered rings include, but are not limited to, cyclopentane, pyrrole, imidazole, thiazole, furan, and thiophene; typical 6-membered rings include, but are not limited to, cyclohexane, pyridine, pyran, pyrazine, thiopyran, pyridazine, pyrimidine, benzene, and the like.

“脂环”或“脂环基”是指饱和或者部分不饱和的脂肪族碳环基团。饱和的脂肪族碳环称为例如饱和脂环，也可以称为“环烷基”；部分不饱和的碳环可以称为例如不饱和脂环。脂环可以为单环、螺环、并环或桥环，例如3～14元脂环即是指由3～14个骨架碳原子构成的脂肪族碳环基团。"Alicyclic ring" or "alicyclic group" refers to a saturated or partially unsaturated aliphatic carbocyclic group. A saturated aliphatic carbocyclic ring is called, for example, a saturated alicyclic ring, and may also be called a "cycloalkyl group"; a partially unsaturated carbocyclic ring may be called, for example, an unsaturated alicyclic ring. An alicyclic ring may be a monocyclic ring, a spirocyclic ring, a fused ring, or a bridged ring. For example, a 3- to 14-membered alicyclic ring refers to an aliphatic carbocyclic group consisting of 3 to 14 backbone carbon atoms.

“饱和脂环”又称为“环烷基”，是由饱和的碳原子作为骨架构成的脂肪族环状基团。本申请中使用的3～14元环烷基或3～14元饱和脂环是指由3～14个(例如3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个或由任意两个前述数值组成的范围值)饱和的碳原子构成的环状基团。典型的饱和脂环包括但不限于等。"Saturated alicyclic ring" is also called "cycloalkyl", which is an aliphatic cyclic group composed of saturated carbon atoms as the backbone. The 3-14-membered cycloalkyl or 3-14-membered saturated alicyclic ring used in this application refers to a cyclic group composed of 3-14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or a range consisting of any two of the foregoing values) saturated carbon atoms. Typical saturated alicyclic rings include but are not limited to wait.

“不饱和脂环”是由饱和碳原子和不饱和碳原子作为骨架构成的脂肪族环状基团。本申请中使用的3～14元不饱和脂环是指由3～14个(例如3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个或由任意两个前述数值组成的范围值)包含碳原子和不饱和碳原子作为骨架结构而构成的环状基团。典型的不饱和脂环包括但不限于等。"Unsaturated alicyclic ring" is an aliphatic cyclic group composed of saturated carbon atoms and unsaturated carbon atoms as a skeleton. The 3-14-membered unsaturated alicyclic ring used in this application refers to a cyclic group composed of 3-14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or a range consisting of any two of the foregoing values) carbon atoms and unsaturated carbon atoms as a skeleton structure. Typical unsaturated alicyclic rings include but are not limited to wait.

“脂杂环”或“脂杂环基”是指由一个或多个杂原子置换脂环中碳原子形成的没有芳香性的环状基团。脂杂环或脂杂环基可以包括饱和脂杂环和不饱和脂杂环。例如3～14元脂杂环基是指由3～14个(例如3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个或由任意两个前述数值组成的范围值)骨架原子构成的含有一个或多个杂原子的没有芳香性的环状基团，可以是饱和脂杂环基和不饱和脂杂环基。"Aliphatic heterocycle" or "aliphatic heterocyclic group" refers to a non-aromatic cyclic group formed by replacing carbon atoms in an alicyclic ring with one or more heteroatoms. Aliphatic heterocycles or aliphatic heterocyclic groups may include saturated aliphatic heterocycles and unsaturated aliphatic heterocycles. For example, a 3-14-membered aliphatic heterocyclic group refers to a non-aromatic cyclic group containing one or more heteroatoms and composed of 3-14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or a range consisting of any two of the foregoing) skeleton atoms, and may be a saturated aliphatic heterocyclic group or an unsaturated aliphatic heterocyclic group.

“饱和脂杂环”又称为“杂环烷基”，是指脂杂环中构成环骨架的碳原子均为饱和的。例如本申请中使用的3～14元饱和脂杂环是指由3～14个(例如3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个或由任意两个前述数值组成的范围值)原子构成环骨架形成的没有芳香性的环状基团，其中构成环骨架的原子由饱和碳原子和杂原子组成。典型的饱和脂杂环包括但不限于："Saturated heterocyclic alicyclic ring" is also called "heterocycloalkyl", which means that the carbon atoms constituting the ring skeleton of the heterocyclic alicyclic ring are all saturated. For example, the 3-14-membered saturated heterocyclic alicyclic ring used in this application refers to a 3-14-membered saturated heterocyclic alicyclic ring (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) A cyclic group without aromaticity formed by the ring skeleton of 1, 2, 3, 4 or a range consisting of any two of the above values) atoms, wherein the atoms constituting the ring skeleton are composed of saturated carbon atoms and heteroatoms. Typical saturated heterocyclic rings include but are not limited to:

等。 wait.

“不饱和脂杂环”或“不饱和脂杂环基”是指脂杂环中包含部分不饱和碳原子作为环骨架的不具有芳香性的环状结构。例如本申请某些实施例方式中，“不饱和脂杂环”是指构成脂杂环的骨架中含有不饱和碳原子。本申请中使用的3～14元不饱和脂杂环指由3～14个(例如3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个或由任意两个前述数值组成的范围值)骨架原子构成的没有芳香性的环状基团，其中构成环骨架的原子包括饱和碳原子、不饱和碳原子和杂原子，典型的不饱和脂杂环包括但不限于等。"Unsaturated heterocyclic ring" or "unsaturated heterocyclic group" refers to a non-aromatic cyclic structure containing some unsaturated carbon atoms as the ring skeleton in the heterocyclic ring. For example, in certain embodiments of the present application, "unsaturated heterocyclic ring" refers to the presence of unsaturated carbon atoms in the skeleton constituting the heterocyclic ring. The 3-14-membered unsaturated heterocyclic ring used in the present application refers to a non-aromatic cyclic group composed of 3-14 (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or a range consisting of any two of the foregoing values) skeleton atoms, wherein the atoms constituting the ring skeleton include saturated carbon atoms, unsaturated carbon atoms and heteroatoms. Typical unsaturated heterocyclic rings include but are not limited to wait.

“芳环”或“芳基”是指拥有共轭的平面环体系，完全由不饱和的碳原子构成的具有芳香性的环状结构，其平面环具有离域的π电子系统并且含有4n+2个π电子，其中n是整数。芳环可以由六、八、十或多于十个碳原子构成，芳环可以是单环也可以是多环(如双环、三环)。常见的芳环包括但不限于苯环、萘环、菲环、蒽环、四苯、芘环、五苯等。本申请中使用的6～10元芳环或6～10元芳基指由6～10个(例如6个、7个、8个、9个、10个或由任意两个前述数值组成的范围值)骨架碳原子构成的芳环基团。"Aromatic ring" or "aryl group" refers to a cyclic structure with aromaticity that has a conjugated planar ring system and is completely composed of unsaturated carbon atoms. Its planar ring has a delocalized π electron system and contains 4n+2 π electrons, where n is an integer. The aromatic ring can be composed of six, eight, ten or more carbon atoms, and the aromatic ring can be a monocyclic ring or a polycyclic ring (such as a bicyclic ring or a tricyclic ring). Common aromatic rings include, but are not limited to, benzene rings, naphthalene rings, phenanthrene rings, anthracene rings, tetraphenyl rings, pyrene rings, pentaphenyl rings, and the like. The 6-10 membered aromatic ring or 6-10 membered aryl group used in this application refers to an aromatic ring group composed of 6 to 10 (e.g., 6, 7, 8, 9, 10 or a range consisting of any two of the foregoing values) skeleton carbon atoms.

“芳杂环”或“杂芳基”是指由一个或多个杂原子置换芳环中的碳原子形成的芳香性环状结构。本申请中使用的5～10元芳杂环或5～10元杂芳基指由5～10个(例如5个、6个、7个、8个、9个、10个或由任意两个前述数值组成的范围值)骨架原子构成的含杂原子的芳香性环状基团。典型的芳杂环或杂芳基包括但不限于：等。"Aromatic heterocycle" or "heteroaryl" refers to an aromatic cyclic structure formed by replacing carbon atoms in an aromatic ring with one or more heteroatoms. The 5-10 membered aromatic heterocycle or 5-10 membered heteroaryl used in this application refers to an aromatic cyclic group containing heteroatoms composed of 5-10 (e.g., 5, 6, 7, 8, 9, 10 or a range consisting of any two of the foregoing values) backbone atoms. Typical aromatic heterocycles or heteroaryl groups include, but are not limited to: wait.

“芳香环”是指环状骨架依托环上的取代基整体共同形成的具有芳香性的基团，其平面环具有离域的π电子系统并且含有4n+2个π电子。”芳香环”可以是芳环或芳杂环，也可以是不饱和脂环或者不饱和脂杂环的饱和碳原子由＝O、＝S、＝NH等取代形成的具有芳香性的结构。例如吡啶酮即为一种”芳香环”基团。"Aromatic ring" refers to a group with aromatic properties formed by the cyclic skeleton relying on the substituents on the ring as a whole, and its planar ring has a delocalized π electron system and contains 4n+2 π electrons. "Aromatic ring" can be an aromatic ring or an aromatic heterocycle, or it can be an unsaturated alicyclic ring or an unsaturated alicyclic heterocycle with saturated carbon atoms substituted by =O, =S, =NH, etc. to form an aromatic structure. For example, pyridone is an "aromatic ring" group.

“并环”是指环与环之间共用两个相邻的环原子构成的环状结构。并环可以为双环、三环或多环。"Cyclic ring" refers to a cyclic structure formed by sharing two adjacent ring atoms between rings. Cyclic rings can be bicyclic, tricyclic or polycyclic.

本申请中“芳环与不饱和脂杂环构成的并环”是指芳环与不饱和脂杂环共用两个相邻的环原子形成的并环结构。“芳环与不饱和脂环构成的并环”是指芳环与不饱和脂环共用两个相邻的环原子形成的并环结构。“芳杂环与不饱和脂环构成的并环”是指芳杂环与不饱和脂环共用两个相邻的环原子形成的并环结构。“芳杂环与不饱和脂杂环构成的并环”是指芳杂环与不饱和脂杂环共用两个相邻的环原子形成的并环结构。本申请中“芳环与不饱和脂环构成的7～14元并环”是指由芳环与不饱和脂环共用两个相邻的环原子形成的具有7～14个(例如7个、8个、9个、10个、11个、12个、13个、14个或由任意两个前述数值组成的范围值)骨架环原子的并环结构。“芳杂环与不饱和脂环构成的7～14元并环”是指由芳杂环与不饱和脂环共用两个相邻的环原子形成的具有7～14个(例如7个、8个、9个、10个、11个、12个、13个、14个或由任意两个前述数值组成的范围值)骨架环原子的并环结构。本申请中“芳杂环与不饱和脂杂环构成的7～14元并环”是指由不饱和脂杂环与芳杂环共用两个相邻环原子形成的具有7～14个(例如7个、8个、9个、10个、11个、12个、13个、14个或由任意两个前述数值组成的范围值)骨架环原子的并环结构。本申请中“芳环与不饱和脂杂环构成的7～14元并环”是指由不饱和脂杂环与芳环共用两个相邻环原子形成的具有7～14个(例如7个、8个、9个、10个、11个、12个、13个、14个或由任意两个前述数值组成的范围值)骨架环原子的并环结构。常见的芳环与不饱和脂环构成的并环包含但不限于等。常见的芳环与不饱和脂杂环构成的并环包括但不限于常见的芳杂环与不饱和脂杂环构成的并环包括但不限于：In the present application, "a ring formed by an aromatic ring and an unsaturated alicyclic ring" refers to a ring structure formed by the aromatic ring and the unsaturated alicyclic ring sharing two adjacent ring atoms. "A ring formed by an aromatic ring and an unsaturated alicyclic ring" refers to a ring structure formed by the aromatic ring and the unsaturated alicyclic ring sharing two adjacent ring atoms. "A ring formed by an aromatic heterocyclic ring and an unsaturated alicyclic ring" refers to a ring structure formed by the aromatic heterocyclic ring and the unsaturated alicyclic ring sharing two adjacent ring atoms. "A ring formed by an aromatic heterocyclic ring and an unsaturated alicyclic ring" refers to a ring structure formed by the aromatic heterocyclic ring and the unsaturated alicyclic ring sharing two adjacent ring atoms. In the present application, "a 7-14-membered ring formed by an aromatic ring and an unsaturated alicyclic ring" refers to a ring structure having 7 to 14 (for example, 7, 8, 9, 10, 11, 12, 13, 14 or a range consisting of any two of the foregoing values) skeletal ring atoms formed by the aromatic ring and the unsaturated alicyclic ring sharing two adjacent ring atoms. "A 7- to 14-membered cyclic ring composed of an aromatic heterocycle and an unsaturated alicyclic ring" refers to a cyclic ring structure having 7 to 14 (e.g., 7, 8, 9, 10, 11, 12, 13, 14, or a range consisting of any two of the aforementioned values) skeletal ring atoms formed by the aromatic heterocycle and the unsaturated alicyclic ring sharing two adjacent ring atoms. In the present application, "a 7- to 14-membered cyclic ring composed of an aromatic heterocycle and an unsaturated alicyclic ring" refers to a cyclic ring structure having 7 to 14 (e.g., 7, 8, 9, 10, 11, 12, 13, 14, or a range consisting of any two of the aforementioned values) skeletal ring atoms formed by the unsaturated alicyclic ring and the aromatic heterocycle sharing two adjacent ring atoms. In the present application, "7- to 14-membered cyclic rings formed by aromatic rings and unsaturated alicyclic rings" refers to cyclic ring structures with 7 to 14 (e.g., 7, 8, 9, 10, 11, 12, 13, 14 or a range consisting of any two of the foregoing) skeleton ring atoms formed by unsaturated alicyclic rings and aromatic rings sharing two adjacent ring atoms. Common cyclic rings formed by aromatic rings and unsaturated alicyclic rings include but are not limited to etc. Common cyclic rings formed by aromatic rings and unsaturated heterocyclic rings include but are not limited to Common cyclic rings formed by aromatic heterocycles and unsaturated aliphatic heterocycles include but are not limited to:

“胺基”或“胺”是指具有-NR^SR^T的化学结构，其中R^S、R^T各自独立地选自氢、氘、氚、烷基、环烷基，常见的“胺基”包括但不限于-NH₂、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃、-N(CH₂CH₃)₂。"Amine" or "amine" refers to a chemical structure having -NR^S R^T , wherein^RS ,^RT are each independently selected from hydrogen, deuterium, tritium,_alkyl ,_cycloalkyl . Common "amine" includes but is not limited to_-NH2 ,_-NHCH3 , -N(_CH3 )₂ ,_-NHCH2CH3 , -N(_CH2CH3 )₂ .

“亚胺基”或“亚胺”是指具有＝NR^W的化学结构，其中R^W选自氢、氘、氚、烷基、环烷基。"Iminyl" or "imine" refers to a chemical structure having =^NRW , wherein^RW is selected from hydrogen, deuterium, tritium, alkyl, cycloalkyl.

“羰基”是指具有-COR^Z的化学结构，其中R^Z选自烷基、环烷基、杂环烷基，常见的羰基包括但不限于-COCH₃、-COCH₂CH₃、-CO(CH₂)₂CH₃、-COCH(CH₃)₂。"Carbonyl" refers to a chemical structure having -COR^Z , wherein R^Z is selected from alkyl, cycloalkyl, heterocycloalkyl. Common carbonyls include, but are not limited to, -COCH₃ , -COCH₂ CH₃ , -CO(CH₂ )₂ CH₃ , and -COCH(CH₃ )₂ .

“酰胺”或“酰胺基”是指具有-C(O)NR^UR^V或-NR^UC(O)R^V的化学结构，其中R^U、R^V各自独立地选自氢、氘、氚、烷基、环烷基、杂环烷基，常见的酰胺基包括但不限于-CONH₂、-CONHCH₃、-CON(CH₃)₂、-NHCOH、-NHCOCH₃、-N(CH₃)COCH₃。"Amide" or "amide group" refers to^a chemical structure having -C(O)^NRUR or^-NRUC (O)^RV , wherein R^U and^RV are each independently selected from hydrogen, deuterium, tritium, alkyl, cycloalkyl, heterocycloalkyl. Common amide groups include but are not limited to_-CONH2 ,_-CONHCH3 , -CON(_CH3 )₂ , -NHCOH,_-NHCOCH3 , -N(_CH3 )_COCH3 .

“胺基烷基”是指烷基中任意一个氢被胺基基团置换而成的基团，本申请中使用的C₁～C₆胺基烷基是指由1～6个(例如1个、2个、3个、4个、5个或6个、或由任意两个前述数值组成的范围值)碳原子构成的直链烷基或支链烷基，且烷基上任意一个氢被胺基取代。常见的胺基烷基包括不限于-CH₂N(CH₃)₂、-CH₂NH₂、-CH₂NHCH₃、-CH₂NHCH₂CH₃、-CH₂N(CH₂CH₃)₂等。"Aminoalkyl" refers to a group in which any hydrogen in an alkyl group is replaced by an amino group. The_C1 -_C6 aminoalkyl used in this application refers to a straight-chain or branched alkyl group consisting of 1 to 6 (e.g., 1, 2, 3, 4, 5 or 6, or a range consisting of any two of the foregoing values) carbon atoms, and any hydrogen on the alkyl group is replaced by an amino group. Common aminoalkyl groups_include but are not limited to_-CH2N (_CH3 )₂ ,_{-CH2NH2,-CH2NHCH3,-CH2NHCH2CH3} ,_-CH2N(CH2CH3 )_2, etc.

“酰胺基烷基”是指烷基中任意一个氢被酰胺基团置换而成的基团，本申请中使用的C₁～C₆酰胺基烷基是指由1～6个(例如1个、2个、3个、4个、5个或6个、或由任意两个前述数值组成的范围值)碳原子构成的直链烷基或支链烷基，且烷基上任意一个氢被酰胺基取代。常见的酰胺基烷基包括不限于-CH₂NHCOCH₃、-CH₂CONH₂等。"Acylamide alkyl" refers to a group in which any hydrogen in an alkyl group is replaced by an amide group. The C₁ -C₆ acylamide alkyl used in this application refers to a straight chain alkyl or branched chain alkyl consisting of 1 to 6 (e.g., 1, 2, 3, 4, 5 or 6, or a range consisting of any two of the aforementioned values) carbon atoms, and any hydrogen on the alkyl group is replaced by an amide group. Common acylamide alkyl groups include but are not limited to -CH₂ NHCOCH₃ , -CH₂ CONH₂ , etc.

“酯基”是指具有式-C(O)OR^a或-OC(O)R^b的化学结构，其中R^a、R^b选自烷基、环烷基、杂环烷基，常见的酯基包括但不限于-C(O)OCH₃、-C(O)OCH₂CH₃、-C(O)O(CH₂)₂CH₃、-C(O)OCH(CH₃)₂、-OC(O)CH₃、-OC(O)CH₂CH₃、-OC(O)(CH₂)₂CH₃、-OC(O)CH(CH₃)₂。"Ester group" refers to a chemical structure having the formula -C(O)OR^a or -OC(O)R^b , wherein^Ra and R^b are selected from alkyl, cycloalkyl, and heterocycloalkyl groups. Common ester groups include, but are not limited to, -C(O)OCH₃ , -C(O)OCH₂ CH₃ , -C(O)O(CH₂ )₂ CH₃ , -C(O)OCH(CH₃ )₂ , -OC(O)CH₃ , -OC(O)CH₂ CH₃ , -OC(O)(CH₂ )₂ CH₃ , and -OC(O)CH(CH₃ )₂ .

“取代”指基团中的一个或多个氢原子彼此独立地被相应数目的取代基所取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。各自并且独立地选自烷基、环烷基、芳基、杂芳基、杂环烷基、羟基、烷氧基、烷硫基、芳氧基、硝基、酰基、卤素、卤代烷基、氨基等等。"Replacement" refers to that one or more hydrogen atoms in a group are replaced by a corresponding number of substituents independently of one another. It goes without saying that substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible replacements without making too much effort. For example, amino or hydroxyl with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond. Each and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, alkoxy, alkylthio, aryloxy, nitro, acyl, halogen, haloalkyl, amino, etc.

“抑制剂”，是指使酶活性下降的物质。"Inhibitor" refers to a substance that reduces the activity of an enzyme.

“任选”或“任选地”意味着随后所描述地事件或环境可以但不必然发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选地被取代的”包括取代或未取代的，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally substituted" includes substitution or non-substitution, and "heterocyclic group optionally substituted with alkyl" means that alkyl may but need not be present, and the description includes instances where the heterocyclic group is substituted with alkyl and instances where the heterocyclic group is not substituted with alkyl.

“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

“可药用的”是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。"Pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, and are compatible with the intended use. The benefit/risk ratio is commensurate with the treatment.

作为可药用的盐，例如可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

“互变异构体”或“互变异构体形式”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-烯醇及亚胺-烯胺异构化。质子互变异构体的具体实例是咪唑部分，其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。互变异构体的非限制性实例包括但不限于，"Tautomers" or "tautomeric forms" refer to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, where the proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding electrons. Non-limiting examples of tautomers include, but are not limited to,

“立体异构体”是指具有相同分子式、官能团，由于分子中原子或官能团在空间上排列方式不同所产生的同分异构体现象，包括顺反异构体、手性异构体，其中手性异构体包括对映异构体和非对映异构体两大类。"Stereoisomers" refer to isomers with the same molecular formula and functional groups, which are produced by different spatial arrangements of atoms or functional groups in the molecule, including cis-trans isomers and chiral isomers. Chiral isomers include two major categories: enantiomers and diastereomers.

“对映异构体”是指具有相同分子式、官能团的化合物，由于原子或官能团在空间配置不同而引起的同分异构现象，同时所述化合物形成互为镜像而不可重叠的立体异构体。"Enantiomers" refer to compounds with the same molecular formula and functional groups, which exhibit isomerism due to different spatial configurations of atoms or functional groups. At the same time, the compounds form stereoisomers that are mirror images of each other and cannot be superimposed.

“非对映异构体”是指具有相同分子式、官能团的化合物，由于原子在空间配置不同而引起的同分异构现象，同时所述化合物彼此之间不呈实物与镜像关系的立体异构体。"Diastereoisomers" refer to compounds with the same molecular formula and functional groups, which are stereoisomers caused by different spatial configurations of atoms. At the same time, the compounds are not stereoisomers that are in a real-life mirror-image relationship with each other.

本申请中，化合物结构中的直线共价键“—”可以表示与纸共面。本申请中，当直线共价键连接的原子存在立体异构体时，则直线共价键表示其连接的原子的排列方式可以包括与纸共面、朝向纸面外、朝向纸面内，或者各种排列方式的混合。In the present application, a straight covalent bond "—" in a compound structure may represent being in the same plane as the paper. In the present application, when stereoisomers exist for atoms connected by a straight covalent bond, the straight covalent bond represents that the arrangement of the atoms connected by the straight covalent bond may include being in the same plane as the paper, facing outward from the paper, facing inward from the paper, or a mixture of various arrangements.

除非另有说明，本文使用的术语“包含、包括和含有(comprise、comprises和comprising)”或其等同物(contain、contains、containing、include、includes、including)为开放式表述，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。Unless otherwise specified, the terms "comprise, comprises and comprising" or their equivalents (contain, contains, containing, include, includes, including) used herein are open-ended expressions and mean that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included.

除非另有说明，本文所使用的表示成分的量、测量值或反应条件的所有数字应理解为在所有情况下均由术语“约”修饰。当与百分比相连时，术语“约”可以表示例如±1％、优选±0.5％、更优选±0.1％。Unless otherwise indicated, all numbers used herein expressing the amounts of ingredients, measurements or reaction conditions are to be understood as being modified in all cases by the term "about". When connected with a percentage, the term "about" can mean, for example, ±1%, preferably ±0.5%, more preferably ±0.1%.

除非上下文另有明确指示，本文中的单数术语涵盖复数的指示对象，反之亦然。类似地，除非上下文另有明确指示，本文中的词语“或”意在包括“和”。Unless the context clearly indicates otherwise, singular terms herein include plural referents and vice versa. Similarly, the word "or" herein is intended to include "and" unless the context clearly indicates otherwise.

显然，根据本申请的上述内容，按照本领域的普通技术知识和手段，在不脱离本申请上述基本技术思想前提下，还可以做出其他多种形式的修改、替换或变更。Obviously, based on the above content of this application, according to the common technical knowledge and means in this field, without departing from the above basic technical ideas of this application, other various forms of modifications, replacements or changes can be made.

本申请中的缩写具有如下所示的意义：
The abbreviations in this application have the following meanings:

具体实施方式DETAILED DESCRIPTION

合成方法Synthesis method

本申请还提供了上述化合物的合成方法，本申请的合成方法主要从化学文献中报道的制备方法或者以市售化学试剂为起始物料进行相关合成。The present application also provides a method for synthesizing the above-mentioned compounds. The method for synthesizing the present application is mainly based on the preparation methods reported in chemical literature or using commercially available chemical reagents as starting materials for related synthesis.

方法1
Method 1

步骤1)将式(i-a)所示化合物在缩合剂(例如偶氮二甲酸二乙酯)作用下，与式(i-d)所示化合物发生缩合反应得到式(i-b)所示化合物；步骤2)将式(i-b)所示化合物在硼酸化试剂(例如联硼酸频哪醇酯)作用下硼酸化得到式(i-c)所示化合物；步骤3)将式(i-c)所示化合物与式(i-e)所示化合物发生偶联反应得到式(I)所示化合物。Step 1) the compound represented by formula (i-a) is subjected to a condensation reaction with the compound represented by formula (i-d) under the action of a condensation agent (e.g., diethyl azodicarboxylate) to obtain a compound represented by formula (i-b); Step 2) the compound represented by formula (i-b) is subjected to borylation reaction with a borylation agent (e.g., bipyralidinol borate) to obtain a compound represented by formula (i-c); Step 3) the compound represented by formula (i-c) is subjected to a coupling reaction with the compound represented by formula (i-e) to obtain a compound represented by formula (I).

方法2
Method 2

步骤1)将方法1中式(i-e)所示化合物在硼酸化试剂(例如联硼酸频那醇酯)的作用下得到式(ii-e)所示化合物；步骤2)将式(ii-e)所示化合物与方法1中得到的式(i-b)所示化合物发生偶联反应得到式(I)所示化合物。Step 1) The compound represented by formula (i-e) in method 1 is subjected to the action of a boration reagent (e.g., biboric acid pinacol ester) to obtain a compound represented by formula (ii-e); Step 2) The compound represented by formula (ii-e) is subjected to a coupling reaction with the compound represented by formula (i-b) obtained in method 1 to obtain a compound represented by formula (I).

方法3
Method 3

步骤1)将式(iii-a)所示化合物在对甲苯磺酰肼作用下得到式(iii-b)所示化合物；步骤2)将式(iii-b)所示化合物在金属催化作用下偶联得到式(iii-c)所示化合物；步骤3)将式(iii-c)所示化合物与方法2中的式(ii-e)所示化合物发生偶联反应得到式(I)所示化合物。Step 1) The compound represented by formula (iii-a) is treated with p-toluenesulfonyl hydrazide to obtain the compound represented by formula (iii-b); Step 2) The compound represented by formula (iii-b) is coupled under the action of metal catalysis to obtain the compound represented by formula (iii-c); Step 3) The compound represented by formula (iii-c) is coupled with the compound represented by formula (ii-e) in method 2 to obtain the compound represented by formula (I).

方法1～3中，所述X、Y、Z、环A、环B、环C、W¹、W²、W³、W⁴、W⁵、m、n、o、p、R^A、R^B、与前述定义一致；所述L选自O、NH、NCH₃等；所述R’选自氢、氘、氚、硝基、氰基、C₁～C₆烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基)、C₁～C₆烷氧基(例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基)。所述式(I)所示化合物中具有氨基保护基团或羟基保护基团时(例如叔丁氧羰基、叔丁基羰基、叔丁基二甲基硅基、三甲基硅乙氧基甲基等)时，还可以进一步在三氟乙酸、盐酸等强酸作用下，脱去保护基团。In methods 1 to 3, X, Y, Z, ring A, ring B, ring C, W¹ , W² , W³ , W⁴ , W⁵ , m, n, o, p,^RA ,^RB , Consistent with the above definition; L is selected from O, NH,_NCH3 , etc.; R' is selected from hydrogen, deuterium, tritium, nitro, cyano,_C1 -_C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl),_C1 -_C6 alkoxy (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy). When the compound represented by formula (I) has an amino protecting group or a hydroxy protecting group (e.g., tert-butyloxycarbonyl, tert-butylcarbonyl, tert-butyldimethylsilyl, trimethylsilylethoxymethyl, etc.), the protecting group can be further removed under the action of a strong acid such as trifluoroacetic acid or hydrochloric acid.

本申请中，所述式(i-e)所示化合物可以是市售产品，也可以是本领域技术人员通过现有技术公开的制备方法制备获得。例如i-e可以通过以下方法i-e1、i-e2、i-e3、i-e4等方法制备得到，In the present application, the compound represented by formula (i-e) can be a commercially available product, or can be prepared by a person skilled in the art through a preparation method disclosed in the prior art. For example, i-e can be prepared by the following methods i-e1, i-e2, i-e3, i-e4, etc.,

方法i-e1
Method i-e1

式(i-1)所示化合物与式(i-2)所示化合物发生取代反应得到式(i-e)所示化合物，其中环A、环C、W¹、W²、W³、W⁴、W⁵、m、o、R^A、与前述定义一致；L”选自F、Cl或I；L’选自-OH、-NH₂、-NHCH₃，且当L’为-OH时L为O，当L’为-NH₂时L为-NH-，当L’为-NHCH₃时L为-NCH₃-。The compound represented by formula (i-1) undergoes substitution reaction with the compound represented by formula (i-2) to obtain the compound represented by formula (ie), wherein ring A, ring C, W¹ , W² , W³ , W⁴ , W⁵ , m, o,^RA , Consistent with the above definition; L" is selected from F, Cl or I; L' is selected from -OH,_-NH2 ,_-NHCH3 , and when L' is -OH, L is O, when L' is_-NH2, L is -NH-, and when L' is_-NHCH3, L is_-NCH3- .

方法i-e2
Method i-e2

式(i-3)所示化合物与式(i-4)所示化合物发生取代反应得到式(i-e)所示化合物，其中环C、W¹、W²、W³、W⁴、W⁵、m、R^A、与前述定义一致；环A选自芳环、芳杂环(例如苯环、包含1～3个杂原子的5～10元芳杂环，具体例如苯环、吡啶、嘧啶、吡嗪、噻吩、咪唑、吡唑等)；L”选自F、Cl或I；L’选自-OH、-NH₂、-NHCH₃，且当L’为-OH时L为O，当L’为-NH₂时L为-NH-，当L’为-NHCH₃时L为-NCH₃-。The compound represented by formula (i-3) undergoes substitution reaction with the compound represented by formula (i-4) to obtain the compound represented by formula (ie), wherein ring C, W¹ , W² , W³ , W⁴ , W⁵ , m,^RA , Consistent with the above definition; Ring A is selected from aromatic rings, aromatic heterocyclic rings (such as benzene rings, 5 to 10 rings containing 1 to 3 heteroatoms) wherein L" is selected from F, Cl or I; L' is selected from -OH,_-NH2 ,_-NHCH3 , and when L' is -OH, L is O, when L' is_-NH2 , L is -NH-, and when L' is_-NHCH3 , L is_-NCH3- .

方法i-e3
Method i-e3

式(i-5)所示化合物与式(i-6)所示化合物在缩合剂(例如DIAD、DEAD)作用下发生缩合反应得到式(i-e)所示化合物，其中环C、W¹、W²、W³、W⁴、W⁵、m、o、R^A、与前述定义一致；环A选自饱和脂环、不饱和脂环、不饱和脂杂环、芳环与不饱和脂环构成的并环、芳杂环与不饱和脂环构成的并环(例如环己烷、由苯环与不饱和脂环构成的8～12元并环，具体例如环己烷、环戊烷、茚满环等)。The compound represented by formula (i-5) and the compound represented by formula (i-6) undergo condensation reaction under the action of a condensing agent (such as DIAD, DEAD) to obtain a compound represented by formula (ie), wherein ring C, W¹ , W² , W³ , W⁴ , W⁵ , m, o,^RA , Consistent with the above definition; Ring A is selected from a saturated alicyclic ring, an unsaturated alicyclic ring, an unsaturated alicyclic heterocyclic ring, a cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, and a cyclic ring consisting of an aromatic heterocyclic ring and an unsaturated alicyclic ring (for example, cyclohexane, an 8-12-membered cyclic ring consisting of a benzene ring and an unsaturated alicyclic ring, such as cyclohexane, cyclopentane, indane ring, etc.).

方法i-e4
Method i-e4

式(i-7)所示化合物与式(i-6)所示化合物发生偶联反应得到式(i-e)所示化合物，其中环A、环C、W¹、W²、W³、W⁴、W⁵、m、o、R^A、与前述定义一致。The compound represented by formula (i-7) undergoes coupling reaction with the compound represented by formula (i-6) to obtain the compound represented by formula (ie), wherein ring A, ring C, W¹ , W² , W³ , W⁴ , W⁵ , m, o,^RA , Consistent with the above definition.

下面通过举例说明本申请的化合物和中间体的合成方法，下述举例仅作为本申请的示例，而不应作为对本申请范围的限制。除特殊说明外，本申请中所涉及的原料和试剂均可通过商业化渠道获得，具体渠道来源并不影响本申请技术方案的实施。The following examples are provided to illustrate the synthesis methods of the compounds and intermediates of the present application. The following examples are only used as examples of the present application and should not be used as limitations on the scope of the present application. Unless otherwise specified, the raw materials and reagents involved in the present application can be obtained through commercial channels, and the specific channel sources do not affect the implementation of the technical solution of the present application.

制备例1：3-溴-5-(4-三氟甲基)苯氧基吡啶的制备
Preparation Example 1: Preparation of 3-bromo-5-(4-trifluoromethyl)phenoxypyridine

将5-溴吡啶-3-醇(1.05g)溶于NMP(5mL)中，随后加入1-氟-4-三氟甲基苯(1g)和碳酸钾(1.26g)，将反应体系用微波加热至150℃搅拌4小时。LC-MS显示原料反应完全后，用水稀释反应液，使用乙酸乙酯萃取，合并有机相，减压浓缩，经硅胶柱层析分离纯化得标题化合物。MS(ESI)m/z(M+H)⁺＝318.0。5-Bromopyridin-3-ol (1.05 g) was dissolved in NMP (5 mL), followed by the addition of 1-fluoro-4-trifluoromethylbenzene (1 g) and potassium carbonate (1.26 g), and the reaction system was heated to 150° C. by microwave and stirred for 4 hours. After LC-MS showed that the reaction of the raw materials was complete, the reaction solution was diluted with water, extracted with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain the title compound. MS (ESI) m/z (M+H)⁺ = 318.0.

制备例2：2-溴-1-甲基-4-(4-三氟甲基)苯氧基苯的制备
Preparation Example 2: Preparation of 2-bromo-1-methyl-4-(4-trifluoromethyl)phenoxybenzene

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝331.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 331.0.

制备例3：1-溴-2-氯-3-(4-三氟甲基)苯氧基苯的制备
Preparation Example 3: Preparation of 1-bromo-2-chloro-3-(4-trifluoromethyl)phenoxybenzene

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝350.9。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 350.9.

制备例4：2-溴-4-(4-三氟甲基)苯氧基吡啶的制备
Preparation Example 4: Preparation of 2-bromo-4-(4-trifluoromethyl)phenoxypyridine

参考制备例1的制备方法，采用方法i-e1制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝318.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e1. MS (ESI) m/z (M+H)⁺ = 318.0.

制备例5：1-溴-2-甲基-3-(4-三氟甲基)苯氧基苯的制备
Preparation Example 5: Preparation of 1-bromo-2-methyl-3-(4-trifluoromethyl)phenoxybenzene

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝331.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 331.0.

制备例6：1-氯-2-溴-4-(4-三氟甲基)苯氧基苯的制备
Preparation Example 6: Preparation of 1-chloro-2-bromo-4-(4-trifluoromethyl)phenoxybenzene

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝350.9。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 350.9.

制备例7：4-溴-2-(4-三氟甲基)苯氧基吡啶的制备
Preparation Example 7: Preparation of 4-bromo-2-(4-trifluoromethyl)phenoxypyridine

参考制备例1的制备方法，采用方法i-e1制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝318.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e1. MS (ESI) m/z (M+H)⁺ = 318.0.

制备例8：4-溴-1-甲基-2-(4-三氟甲基)苯氧基苯的制备
Preparation Example 8: Preparation of 4-bromo-1-methyl-2-(4-trifluoromethyl)phenoxybenzene

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝331.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 331.0.

制备例9：4-溴-1-氯-2-(4-三氟甲基)苯氧基苯的制备
Preparation Example 9: Preparation of 4-bromo-1-chloro-2-(4-trifluoromethyl)phenoxybenzene

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝350.9。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 350.9.

制备例10：3-溴-N-甲基-N-(4-三氟甲基)苯基胺的制备
Preparation Example 10: Preparation of 3-bromo-N-methyl-N-(4-trifluoromethyl)phenylamine

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝330.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 330.0.

制备例11：2-溴-1-甲氧基-4-(4-三氟甲基)苯氧基苯的制备
Preparation Example 11: Preparation of 2-bromo-1-methoxy-4-(4-trifluoromethyl)phenoxybenzene

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝347.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 347.0.

制备例12：1-溴-2-甲氧基-3-(4-三氟甲基)苯氧基苯的制备
Preparation Example 12: Preparation of 1-bromo-2-methoxy-3-(4-trifluoromethyl)phenoxybenzene

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝347.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 347.0.

制备例13：1-溴-3-甲氧基-5-(4-三氟甲基)苯氧基苯的制备
Preparation Example 13: Preparation of 1-bromo-3-methoxy-5-(4-trifluoromethyl)phenoxybenzene

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝347.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 347.0.

制备例14：4-溴-1-甲氧基-2-(4-三氟甲基)苯氧基苯的制备
Preparation Example 14: Preparation of 4-bromo-1-methoxy-2-(4-trifluoromethyl)phenoxybenzene

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝347.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 347.0.

制备例15：2-溴-6-(4-三氟甲基)苯氧基苯腈的制备
Preparation Example 15: Preparation of 2-bromo-6-(4-trifluoromethyl)phenoxybenzonitrile

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝342.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 342.0.

制备例16：1-溴-3-氯-5-(4-三氟甲基)苯氧基苯的制备
Preparation Example 16: Preparation of 1-bromo-3-chloro-5-(4-trifluoromethyl)phenoxybenzene

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝350.9。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 350.9.

制备例17：3-溴-5-(4-三氟甲基)苯氧基苯腈的制备
Preparation Example 17: Preparation of 3-bromo-5-(4-trifluoromethyl)phenoxybenzonitrile

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝342.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 342.0.

制备例18：7-溴-2-甲基-5-(4-三氟甲基)苯氧基-2H-吲唑的制备
Preparation Example 18: Preparation of 7-bromo-2-methyl-5-(4-trifluoromethyl)phenoxy-2H-indazole

采用方法i-e1，将7-溴-5-碘-2-甲基-2H-吲唑(1.5g)、4-三氟甲基苯酚(938mg)、氯化亚铜(88.1mg)、2,2,6,6-四甲基-3,5-庚二酮(287mg)和碳酸铯(3.62g)溶于干燥NMP(24mL)中，体系升温至125℃反应20小时。LC-MS检测原料反应完全，硅藻土过滤，加入适量水，乙酸乙酯萃取，合并有机相，减压抽干溶剂，经硅胶柱层析分离纯化得标题化合物。MS(ESI)m/z(M+H)⁺＝371.0。Using method i-e1, 7-bromo-5-iodo-2-methyl-2H-indazole (1.5 g), 4-trifluoromethylphenol (938 mg), cuprous chloride (88.1 mg), 2,2,6,6-tetramethyl-3,5-heptanedione (287 mg) and cesium carbonate (3.62 g) were dissolved in dry NMP (24 mL), and the system was heated to 125°C for 20 hours. LC-MS detected that the raw material had reacted completely, filtered with diatomaceous earth, added with an appropriate amount of water, extracted with ethyl acetate, combined the organic phases, drained the solvent under reduced pressure, and separated and purified by silica gel column chromatography to obtain the title compound. MS (ESI) m/z (M+H)⁺ = 371.0.

制备例19：1-(3-溴苯氧基)-2,3-二氢-1H-茚的制备
Preparation Example 19: Preparation of 1-(3-bromophenoxy)-2,3-dihydro-1H-indene

采用方法i-e3，将2,3-二氢-1H-茚-1-醇(1.0g)、3-溴苯酚(1.42g)、Ph₃P(2.15g)溶于THF(50mL)中，向反应体系中缓慢滴加DIAD(1.81g)，加料完毕后，反应体系在室温下反应16小时。TLC检测原料反应完全，减压抽干溶剂，经硅胶柱层析分离纯化得标题化合物。MS(ESI)m/z(M+H)⁺＝289.0。Using method i-e3, 2,3-dihydro-1H-indene-1-ol (1.0 g), 3-bromophenol (1.42 g), and Ph₃ P (2.15 g) were dissolved in THF (50 mL), and DIAD (1.81 g) was slowly added dropwise to the reaction system. After the addition was completed, the reaction system was reacted at room temperature for 16 hours. TLC detected that the raw material had reacted completely, and the solvent was drained under reduced pressure. The title compound was separated and purified by silica gel column chromatography. MS (ESI) m/z (M+H)⁺ = 289.0.

制备例20：1-溴-3-(4-(三氟甲基)苄氧基)苯的制备
Preparation Example 20: Preparation of 1-bromo-3-(4-(trifluoromethyl)benzyloxy)benzene

参考制备例19的制备方法，采用方法i-e3制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝331.0。The title compound was prepared by referring to the preparation method of Preparation Example 19 using Method i-e3. MS (ESI) m/z (M+H)⁺ = 331.0.

制备例21：1-溴-3-(4-(三氟甲氧基)苯氧基)苯的制备
Preparation Example 21: Preparation of 1-bromo-3-(4-(trifluoromethoxy)phenoxy)benzene

采用方法i-e4，将(4-(三氟甲氧基)苯基)硼酸(500mg)溶于二氯甲烷(20mL)中，随后加入3-溴苯酚(455.5mg)、醋酸酮(483.2mg)和三乙胺(491.8mg)，反应体系室温反应12小时。TLC检测原料反应完全，加入适量水，二氯甲烷萃取，合并有机相，减压浓缩，经硅胶柱层析分离纯化得得到标题化合物。MS(ESI)m/z(M+H)⁺＝333.0。Using method i-e4, (4-(trifluoromethoxy)phenyl)boronic acid (500 mg) was dissolved in dichloromethane (20 mL), followed by the addition of 3-bromophenol (455.5 mg), acetic acid ketone (483.2 mg) and triethylamine (491.8 mg), and the reaction system was reacted at room temperature for 12 hours. TLC detected that the raw material had reacted completely, and an appropriate amount of water was added, and the dichloromethane was extracted. The organic phases were combined, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain the title compound. MS (ESI) m/z (M+H)⁺ = 333.0.

制备例22：2-(3-溴苯氧基)-4-三氟甲基吡啶的制备
Preparation Example 22: Preparation of 2-(3-bromophenoxy)-4-trifluoromethylpyridine

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝318.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 318.0.

制备例23：2-溴-4-(4-三氟甲基)苯氧基苯腈的制备
Preparation Example 23: Preparation of 2-bromo-4-(4-trifluoromethyl)phenoxybenzonitrile

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝342.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 342.0.

制备例24：1-溴-3-(4-三氟甲基)环己基氧基苯的制备
Preparation Example 24: Preparation of 1-bromo-3-(4-trifluoromethyl)cyclohexyloxybenzene

参考制备例19的制备方法，采用方法i-e3制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝323.0。The title compound was prepared by referring to the preparation method of Preparation Example 19 using Method i-e3. MS (ESI) m/z (M+H)⁺ = 323.0.

制备例27：2-(3-溴-5-甲基苯氧基)-5-(三氟甲基)吡啶的制备
Preparation Example 27: Preparation of 2-(3-bromo-5-methylphenoxy)-5-(trifluoromethyl)pyridine

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝332.0。The title compound was prepared by using method i-e2 with reference to the preparation method of Preparation Example 1. MS (ESI) m/z (M+H)⁺ = 332.0.

制备例28：2-(3-溴-2-氯苯氧基)-5-(三氟甲基)吡啶的制备
Preparation Example 28: Preparation of 2-(3-bromo-2-chlorophenoxy)-5-(trifluoromethyl)pyridine

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝352.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 352.0.

制备例29：2-((叔丁基二甲基硅基)氧基)-1-(吡嗪-2-基)乙烷-1-醇的制备
Preparation Example 29: Preparation of 2-((tert-butyldimethylsilyl)oxy)-1-(pyrazin-2-yl)ethan-1-ol

将1-(吡嗪-2-基)乙烷-1,2-二醇(0.7g)溶于二氯甲烷(20mL)中，加入N-甲基咪唑(1.2g)和叔丁基二甲基氯硅烷(1.5g)，加料完毕后将反应体系在常温下搅拌2小时。LC-MS显示反应完全后，向体系加入水，使用二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经硅胶柱层析分离纯化得0.82g标题化合物。MS(ESI)m/z(M+H)⁺＝255.1。1-(Pyrazine-2-yl)ethane-1,2-diol (0.7 g) was dissolved in dichloromethane (20 mL), and N-methylimidazole (1.2 g) and tert-butyldimethylsilyl chloride (1.5 g) were added. After the addition was completed, the reaction system was stirred at room temperature for 2 hours. After LC-MS showed that the reaction was complete, water was added to the system, and dichloromethane was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain 0.82 g of the title compound. MS (ESI) m/z (M+H)⁺ = 255.1.

制备例30：2-(3-溴-5-甲氧基苯氧基)-5-(三氟甲基)吡啶的制备
Preparation Example 30: Preparation of 2-(3-bromo-5-methoxyphenoxy)-5-(trifluoromethyl)pyridine

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝348.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 348.0.

制备例32：2-(3-溴-4-甲氧基苯氧基)-5-(三氟甲基)吡啶的制备
Preparation Example 32: Preparation of 2-(3-bromo-4-methoxyphenoxy)-5-(trifluoromethyl)pyridine

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝348.1。The title compound was prepared by referring to the preparation method of Preparation Example 1 using method i-e2. MS (ESI) m/z (M+H)⁺ = 348.1.

制备例33：2-(3-溴-2-甲基苯氧基)-5-(三氟甲基)吡啶的制备
Preparation Example 33: Preparation of 2-(3-bromo-2-methylphenoxy)-5-(trifluoromethyl)pyridine

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝332.0。The title compound was prepared by using method i-e2 with reference to the preparation method of Preparation Example 1. MS (ESI) m/z (M+H)⁺ = 332.0.

制备例34：2-(3-溴-5-氯氧基)-5-(三氟甲基)吡啶的制备
Preparation Example 34: Preparation of 2-(3-bromo-5-chlorooxy)-5-(trifluoromethyl)pyridine

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝352.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 352.0.

制备例37：2-(3-溴-4-氯苯氧基)-5-(三氟甲基)吡啶的制备
Preparation Example 37: Preparation of 2-(3-bromo-4-chlorophenoxy)-5-(trifluoromethyl)pyridine

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝352.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 352.0.

制备例41：2-(3-溴-4-氟苯氧基)-5-(三氟甲基)吡啶的制备
Preparation Example 41: Preparation of 2-(3-bromo-4-fluorophenoxy)-5-(trifluoromethyl)pyridine

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝336.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 336.0.

制备例42：8-溴-6-((5-(三氟甲基)吡啶-2-基)氧基)喹啉的制备
Preparation Example 42: Preparation of 8-bromo-6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinoline

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝369.1。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 369.1.

制备例45：1-(1-((2-(三甲基硅基)乙氧基)甲基)-1H-咪唑并[4,5-c]吡啶-7-基)乙烷-1-醇的制备
Preparation Example 45: Preparation of 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-7-yl)ethan-1-ol

步骤1：1-(1-((2-(三甲基硅基)乙氧基)甲基)-1H-咪唑并[4,5-c]吡啶-7-基)乙烷-1-酮的制备Step 1: Preparation of 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-7-yl)ethan-1-one

将7-溴-1-((2-(三甲基硅基)乙氧基)甲基)-1H-咪唑并[4,5-c]吡啶(1.5g)溶于四氢呋喃(15mL)，在氮气保护下，将反应体系降温至-78℃，缓慢滴加正丁基锂(3.5mL，1.6M in hexane)，搅拌0.5小时，再加入DMAc(1.19g)，加料完毕后将反应体系在-78℃下搅拌0.5小时。LCMS显示反应完全后，向体系加入氯化铵溶液，使用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经硅胶柱层析分离纯化得1.1g标题化合物。MS(ESI)m/z(M+H)⁺＝292.1。7-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridine (1.5 g) was dissolved in tetrahydrofuran (15 mL). Under nitrogen protection, the reaction system was cooled to -78°C, n-butyllithium (3.5 mL, 1.6 M in hexane) was slowly added dropwise, stirred for 0.5 hours, and DMAc (1.19 g) was added. After the addition was completed, the reaction system was stirred at -78°C for 0.5 hours. After LCMS showed that the reaction was complete, ammonium chloride solution was added to the system, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain 1.1 g of the title compound. MS (ESI) m/z (M+H)⁺ = 292.1.

步骤2：1-(1-((2-(三甲基硅基)乙氧基)甲基)-1H-咪唑并[4,5-c]吡啶-7-基)乙烷-1-醇的制备Step 2: Preparation of 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-7-yl)ethan-1-ol

将1-(1-((2-(三甲基硅基)乙氧基)甲基)-1H-咪唑并[4,5-c]吡啶-7-基)乙烷-1-酮(0.21g)溶于甲醇(10mL)，加入硼氢化钠(0.17g)，将反应体系在常温下搅拌1小时，LCMS显示反应完全后，减压浓缩，所得粗品经硅胶柱层析分离纯化得0.3g标题化合物。MS(ESI)m/z(M+H)⁺＝294.1。1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-7-yl)ethan-1-one (0.21 g) was dissolved in methanol (10 mL), sodium borohydride (0.17 g) was added, and the reaction system was stirred at room temperature for 1 hour. After LCMS showed that the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography to obtain 0.3 g of the title compound. MS (ESI) m/z (M+H)⁺ = 294.1.

制备例49：2-(3-溴-4-(三氟甲氧基)苯氧基)-5-(三氟甲基)吡啶的制备
Preparation Example 49: Preparation of 2-(3-bromo-4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)pyridine

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝402.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 402.0.

制备例52：1-(1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑[4,3-c]吡啶-7-基)乙烷-1-醇的制备
Preparation Example 52: Preparation of 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-7-yl)ethan-1-ol

参考制备例45步骤2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝294.2。The title compound was prepared according to Preparation Example 45, Step 2. MS (ESI) m/z (M+H)⁺ = 294.2.

制备例54：7-(1-羟乙基)-1H-苯并[d]咪唑-1-甲酸叔丁酯的制备
Preparation Example 54: Preparation of tert-butyl 7-(1-hydroxyethyl)-1H-benzo[d]imidazole-1-carboxylate

步骤1：1-(叔丁氧基羰基)-1H-苯并[d]咪唑-7-羧酸的制备Step 1: Preparation of 1-(tert-butoxycarbonyl)-1H-benzo[d]imidazole-7-carboxylic acid

将1H-苯并[d]咪唑-7-羧酸(2.4g)溶于二氯甲烷(30mL)中，随后加入三乙胺(3.0g)和二碳酸二叔丁酯(6.55g)，加料完毕后将反应体系在常温下搅拌16小时。LC-MS显示反应完全后，将反应液减压浓缩，得到2.5g标题化合物。MS(ESI)m/z(M+H)⁺＝263.2。1H-Benzo[d]imidazole-7-carboxylic acid (2.4 g) was dissolved in dichloromethane (30 mL), followed by the addition of triethylamine (3.0 g) and di-tert-butyl dicarbonate (6.55 g). After the addition was complete, the reaction system was stirred at room temperature for 16 hours. After LC-MS showed that the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain 2.5 g of the title compound. MS (ESI) m/z (M+H)⁺ = 263.2.

步骤2：7-(甲氧基(甲基)氨基甲酰基)-1H-苯并[d]咪唑-1-甲酸叔丁酯的制备
Step 2: Preparation of tert-butyl 7-(methoxy(methyl)carbamoyl)-1H-benzo[d]imidazole-1-carboxylate

将1-(叔丁氧基羰基)-1H-苯并[d]咪唑-7-羧酸(3.0g)溶于二氯甲烷(50mL)中，加入EDCI(2.6g)，HOBt(1.9g)和二甲羟胺盐酸盐(1.4g)，加料完毕后将反应体系在常温下搅拌16小时。LC-MS显示反应完全后，向体系加入水，使用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经硅胶柱层析分离纯化得3.0g标题化合物。MS(ESI)m/z(M+H)⁺＝306.2。1-(tert-Butyloxycarbonyl)-1H-benzo[d]imidazole-7-carboxylic acid (3.0 g) was dissolved in dichloromethane (50 mL), and EDCI (2.6 g), HOBt (1.9 g) and dimethylhydroxylamine hydrochloride (1.4 g) were added. After the addition was completed, the reaction system was stirred at room temperature for 16 hours. After LC-MS showed that the reaction was complete, water was added to the system, and ethyl acetate was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain 3.0 g of the title compound. MS (ESI) m/z (M+H)⁺ = 306.2.

步骤3：7-乙酰基-1H-苯并[d]咪唑-1-甲酸叔丁酯的制备
Step 3: Preparation of tert-butyl 7-acetyl-1H-benzo[d]imidazole-1-carboxylate

取7-(甲氧基(甲基)氨基甲酰基)-1H-苯并[d]咪唑-1-甲酸叔丁酯(3g)于三口烧瓶中，在氮气保护下，加入无水四氢呋喃(25mL)，将反应体系降温至0℃，缓慢滴加甲基溴化镁(11mL，在THF和Tol中1.4M)，加料完毕后将反应体系在0℃下搅拌2小时。LC-MS显示反应完全后，加入饱和氯化铵淬灭，使用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经硅胶柱层析分离纯化得1g标题化合物。MS(ESI)m/z(M+H)⁺＝261.1。7-(Methoxy(methyl)carbamoyl)-1H-benzo[d]imidazole-1-carboxylic acid tert-butyl ester (3 g) was placed in a three-necked flask. Anhydrous tetrahydrofuran (25 mL) was added under nitrogen protection. The reaction system was cooled to 0°C. Methylmagnesium bromide (11 mL, 1.4 M in THF and Tol) was slowly added dropwise. After the addition was completed, the reaction system was stirred at 0°C for 2 hours. After LC-MS showed that the reaction was complete, saturated ammonium chloride was added to quench, and ethyl acetate was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain 1 g of the title compound. MS (ESI) m/z (M+H)⁺ = 261.1.

步骤4：7-(1-羟乙基)-1H-苯并[d]咪唑-1-甲酸叔丁酯的制备
Step 4: Preparation of tert-butyl 7-(1-hydroxyethyl)-1H-benzo[d]imidazole-1-carboxylate

将7-乙酰基-1H-苯并[d]咪唑-1-甲酸叔丁酯(1.2g)溶于甲醇(10mL)，在0℃下加入硼氢化钠(0.35g)，加料完毕后将反应体系在常温下搅拌1小时。LC-MS显示反应完全后，向体系加入水，使用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经硅胶柱层析分离纯化得1g标题化合物。MS(ESI)m/z(M+H)⁺＝263.1。Dissolve tert-butyl 7-acetyl-1H-benzo[d]imidazole-1-carboxylate (1.2 g) in methanol (10 mL), add sodium borohydride (0.35 g) at 0°C, and stir the reaction system at room temperature for 1 hour after the addition is complete. After LC-MS shows that the reaction is complete, add water to the system, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting crude product is separated and purified by silica gel column chromatography to obtain 1 g of the title compound. MS (ESI) m/z (M+H)⁺ = 263.1.

制备例55：5-溴-7-((5-(三氟甲基)吡啶-2-基)氧基)喹喔啉的制备
Preparation Example 55: Preparation of 5-bromo-7-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinoxaline

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝370.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 370.0.

制备例58：2-(3-溴-2-氟苯氧基)-5-(三氟甲基)吡啶的制备
Preparation Example 58: Preparation of 2-(3-bromo-2-fluorophenoxy)-5-(trifluoromethyl)pyridine

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝336.0Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m/z (M+H)⁺ = 336.0

制备例61：2-(3-溴-2-氯苯氧基)-4-甲基-5-(三氟甲基)吡啶的制备
Preparation Example 61: Preparation of 2-(3-bromo-2-chlorophenoxy)-4-methyl-5-(trifluoromethyl)pyridine

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝366.0Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m/z (M+H)⁺ = 366.0

制备例63：2-(3-溴-4-(三氟甲基)苯氧基)-5-(三氟甲基)吡啶的制备
Preparation Example 63: Preparation of 2-(3-bromo-4-(trifluoromethyl)phenoxy)-5-(trifluoromethyl)pyridine

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝386.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using Method i-e2. MS (ESI) m/z (M+H)⁺ = 386.0.

制备例64：2-(3-溴-4-(二氟甲氧基)苯氧基)-5-(三氟甲基)吡啶的制备
Preparation Example 64: Preparation of 2-(3-bromo-4-(difluoromethoxy)phenoxy)-5-(trifluoromethyl)pyridine

将2-溴-4-((5-(三氟甲基)吡啶-2-基)氧基)苯酚(1.1g，3.29mmol)溶于乙腈和水的混合溶液(20mL)中，加入((二氟甲基)磺酰基)苯(1.9g)和叔丁醇钾(1.11g)，加料完毕后将反应体系在升温至100℃下搅拌16小时。LC-MS显示反应完全后，将反应液减压浓缩，所得粗品经硅胶柱层析分离纯化得0.4g标题化合物。MS(ESI)m/z(M+H)⁺＝384.0。2-Bromo-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenol (1.1 g, 3.29 mmol) was dissolved in a mixed solution of acetonitrile and water (20 mL), and ((difluoromethyl)sulfonyl)benzene (1.9 g) and potassium tert-butoxide (1.11 g) were added. After the addition was completed, the reaction system was stirred at 100° C. for 16 hours. After LC-MS showed that the reaction was complete, the reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography to obtain 0.4 g of the title compound. MS (ESI) m/z (M+H)⁺ = 384.0.

制备例65：2-(3-溴苯氧基)-5-(三氟甲基)嘧啶的制备
Preparation Example 65: Preparation of 2-(3-bromophenoxy)-5-(trifluoromethyl)pyrimidine

参考制备例1的制备方法，采用方法i-e2制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝319.0。The title compound was prepared by referring to the preparation method of Preparation Example 1 using method i-e2. MS (ESI) m/z (M+H)⁺ = 319.0.

实施例1：1-(1-(吡啶-2-基)乙基)-4-(3-(4-(三氟甲基)苯氧基)苯基)吡啶-2(1H)-酮的制备
Example 1: Preparation of 1-(1-(pyridin-2-yl)ethyl)-4-(3-(4-(trifluoromethyl)phenoxy)phenyl)pyridin-2(1H)-one

步骤1：4-溴-1-(1-(吡啶-2-基)乙基)吡啶-2(1H)-酮的制备
Step 1: Preparation of 4-bromo-1-(1-(pyridin-2-yl)ethyl)pyridin-2(1H)-one

将4-溴吡啶-2(1H)-酮(2.83g)溶于干燥THF(20mL)中，然后加入1-(吡啶-2-基)乙烷-1-醇(2g)和Ph₃P(8.52g)，随后缓慢滴加DIAD(6.57g)，反应体系在室温下搅拌1小时。LC-MS显示原料反应完全后，向体系加入水，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩。残余物经硅胶柱层析分离纯化得标题化合物。MS(ESI)m/z(M+H)⁺＝279.1。4-Bromopyridin-2(1H)-one (2.83 g) was dissolved in dry THF (20 mL), and then 1-(pyridin-2-yl)ethane-1-ol (2 g) and Ph₃ P (8.52 g) were added, followed by slow dropwise addition of DIAD (6.57 g), and the reaction system was stirred at room temperature for 1 hour. After LC-MS showed that the reaction of the raw materials was complete, water was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain the title compound. MS (ESI) m/z (M+H)⁺ = 279.1.

步骤2：(2-氧代-1-(1-(吡啶-2-基)乙基)-1,2-二氢吡啶-4-基)硼酸的制备
Step 2: Preparation of (2-oxo-1-(1-(pyridin-2-yl)ethyl)-1,2-dihydropyridin-4-yl)boronic acid

将4-溴-1-(1-(吡啶-2-基)乙基)-1,2-二氢吡啶-2-酮(200mg)溶于二氧六环(10mL)中，随后加入联硼酸频哪醇酯(219.40mg)、醋酸钾(105.99mg)和Pd(dppf)Cl₂(52.68mg)，加料完毕后将反应体系在氮气保护下升温至90℃搅拌2小时。LC-MS显示原料反应完全后，将反应液减压浓缩，得标题化合物。MS(ESI)m/z(M+H)⁺＝245.1。Dissolve 4-bromo-1-(1-(pyridin-2-yl)ethyl)-1,2-dihydropyridin-2-one (200 mg) in dioxane (10 mL), then add pinacol diboron (219.40 mg), potassium acetate (105.99 mg) and Pd(dppf)Cl₂ (52.68 mg). After the addition is complete, heat the reaction system to 90°C and stir for 2 hours under nitrogen protection. After LC-MS shows that the raw materials have reacted completely, concentrate the reaction solution under reduced pressure to obtain the title compound. MS (ESI) m/z (M+H)⁺ = 245.1.

步骤3：1-(1-(吡啶-2-基)乙基)-4-(3-(4-(三氟甲基)苯氧基)苯基)吡啶-2(1H)-酮的制备
Step 3: Preparation of 1-(1-(pyridin-2-yl)ethyl)-4-(3-(4-(trifluoromethyl)phenoxy)phenyl)pyridin-2(1H)-one

将(2-氧代-1-(1-(吡啶-2-基)乙基)-1,2-二氢吡啶-4-基)硼酸(205.5mg)溶于二氧六环(12mL)中，随后加入1-溴-3-(4-三氟甲基)苯氧基苯(200mg)、碳酸钾(174.1mg)和Pd(dppf)Cl₂(46.1mg)，氮气保护下，将反应体系加热至90℃搅拌2小时。LC-MS显示原料反应完全后，将反应液减压浓缩，所得粗品经硅胶过滤后减压浓缩。残余物经制备型高效液相色谱分离纯化得标题化合物。(2-Oxo-1-(1-(pyridin-2-yl)ethyl)-1,2-dihydropyridin-4-yl)boric acid (205.5 mg) was dissolved in dioxane (12 mL), followed by the addition of 1-bromo-3-(4-trifluoromethyl)phenoxybenzene (200 mg), potassium carbonate (174.1 mg) and Pd(dppf)Cl₂ (46.1 mg). Under nitrogen protection, the reaction system was heated to 90°C and stirred for 2 hours. After LC-MS showed that the raw material was completely reacted, the reaction solution was concentrated under reduced pressure, and the obtained crude product was filtered through silica gel and concentrated under reduced pressure. The residue was separated and purified by preparative high performance liquid chromatography to obtain the title compound.

MS(ESI)m/z(M+H)⁺＝437.1。MS (ESI) m/z (M+H)⁺ = 437.1.

¹H NMR(400MHz,DMSO-d₆)δ8.58–8.52(m,1H),7.83–7.72(m,4H),7.63–7.53(m,2H),7.50(t,J＝2.0Hz,1H),7.38–7.29(m,2H),7.24–7.16(m,3H),6.71(d,J＝2.0Hz,1H),6.62(dd,J＝7.2,2.0Hz,1H),6.18(q,J＝7.2Hz,1H),1.72(d,J＝7.2Hz,3H)。¹ H NMR (400MHz, DMSO-d₆ )δ8.58–8.52(m,1H),7.83–7.72(m,4H),7.63–7.53(m,2H),7.50(t,J＝2.0Hz,1H),7.38–7.29(m,2H) ,7.24–7 .16(m,3H),6.71(d,J＝2.0Hz,1H),6.62(dd,J＝7.2,2.0Hz,1H),6.18(q,J＝7.2Hz,1H),1.72(d, J=7.2Hz,3H).

实施例22：4-(2-氯-3-(4-(三氟甲基)苯氧基)苯基)-1-(1-(1-甲基-1H-吡唑-3-基)乙基)吡啶-2(1H)-酮的制备：
Example 22: Preparation of 4-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-1-(1-(1-methyl-1H-pyrazol-3-yl)ethyl)pyridin-2(1H)-one:

步骤1：2-(2-氯-3-(4-(三氟甲基)苯氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷的制备
Step 1: Preparation of 2-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

参考实施例1步骤2的试剂、条件，采用方法2步骤1的制备方法，将1-溴-2-氯-3-(4-(三氟甲基)苯氧基)苯溶于二氧六环(10mL)中，随后加入联硼酸频哪醇酯(219.40mg)、醋酸钾(105.99mg)和Pd(dppf)Cl₂(52.68mg)，加料完毕后将反应体系在氮气保护下升温至90℃搅拌2小时。LC-MS显示原料反应完全后，将反应液减压浓缩，得标题化合物制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝399.1。With reference to the reagents and conditions of step 2 of Example 1, the preparation method of step 1 of method 2 was adopted, 1-bromo-2-chloro-3-(4-(trifluoromethyl)phenoxy)benzene was dissolved in dioxane (10 mL), and then diboric acid pinacol ester (219.40 mg), potassium acetate (105.99 mg) and Pd(dppf)Cl₂ (52.68 mg) were added. After the addition was completed, the reaction system was heated to 90° C. and stirred for 2 hours under nitrogen protection. After LC-MS showed that the raw materials reacted completely, the reaction solution was concentrated under reduced pressure to obtain the title compound. MS (ESI) m/z (M+H)⁺ = 399.1.

步骤2：4-溴-1-(1-(1-甲基-1H-吡唑-3-基)乙基)吡啶-2(1H)-酮的制备
Step 2: Preparation of 4-bromo-1-(1-(1-methyl-1H-pyrazol-3-yl)ethyl)pyridin-2(1H)-one

参考实施例1步骤1的试剂、条件，采用方法1步骤1的制备方法得到标题化合物。MS(ESI)m/z(M+H)⁺＝282.0。Referring to the reagents and conditions of step 1 in example 1, the preparation method of step 1 in method 1 was used to obtain the title compound. MS (ESI) m/z (M+H)⁺ = 282.0.

步骤3：4-(2-氯-3-(4-(三氟甲基)苯氧基)苯基)-1-(1-(1-甲基-1H-吡唑-3-基)乙基)吡啶-2(1H)-酮的制备
Step 3: Preparation of 4-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-1-(1-(1-methyl-1H-pyrazol-3-yl)ethyl)pyridin-2(1H)-one

参考实施例1步骤3的试剂条件，采用方法2步骤2的制备方法，将2-(2-氯-3-(4-(三氟甲基)苯氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(205.5mg)溶于二氧六环(12mL)中，随后加入4-溴-1-(1-(1-甲基-1H-吡唑-3-基)乙基)吡啶-2(1H)-酮(145.1mg)、碳酸钾(174.1mg)和Pd(dppf)Cl₂(46.1mg)，氮气保护下，加热至90℃反应2小时。LC-MS显示原料反应完全后，将反应液减压浓缩，经制备型高效液相色谱分离纯化得标题化合物。MS(ESI)m/z(M+H)⁺＝474.1。¹H NMR(400MHz,DMSO-d₆)δ7.75(d,J＝8.4Hz,2H),7.69(d,J＝2.0Hz,1H),7.59(d,J＝7.2Hz,1H),7.51(t,J＝8.0Hz,1H),7.36(td,J＝8.0,1.6Hz,2H),7.15(d,J＝8.4Hz,2H),6.47(d,J＝2.0Hz,1H),6.37–6.26(m,2H),6.20(q,J＝7.2Hz,1H),3.83(s,3H),1.63(d,J＝7.2Hz,3H)。Referring to the reagent conditions of step 3 of Example 1, the preparation method of step 2 of method 2 was adopted to dissolve 2-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (205.5 mg) in dioxane (12 mL), followed by the addition of 4-bromo-1-(1-(1-methyl-1H-pyrazol-3-yl)ethyl)pyridin-2(1H)-one (145.1 mg), potassium carbonate (174.1 mg) and Pd(dppf)Cl₂ (46.1 mg), and the mixture was heated to 90° C. for 2 hours under nitrogen protection. After LC-MS showed that the raw materials reacted completely, the reaction solution was concentrated under reduced pressure and separated and purified by preparative high performance liquid chromatography to obtain the title compound. MS (ESI) m/z(M+H)⁺ =474.1.¹ H NMR (400MHz, DMSO-d₆ )δ7.75(d,J＝8.4Hz,2H),7.69(d,J＝2.0Hz,1H),7.59(d,J＝7.2Hz,1H),7.51(t,J＝8.0Hz,1H),7.36(td,J＝8.0,1.6Hz,2H), 7.15(d,J＝8.4Hz,2H),6.47(d,J＝2.0Hz,1H),6.37–6.26(m,2H),6.20(q,J＝7.2Hz,1H),3.83(s,3H),1.63(d,J＝7.2Hz,3H).

实施例24A：4-(1-(4-(2-氯-3-(4-(三氟甲基)苯氧基)苯基)-2-氧代吡啶-1(2H)基)乙基)哌啶-1-甲酸叔丁酯的制备
Example 24A: Preparation of tert-butyl 4-(1-(4-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-2-oxopyridin-1(2H)yl)ethyl)piperidine-1-carboxylate

步骤1：4-(1-对甲苯磺酰腙基乙基)哌啶-1-甲酸叔丁酯的制备
Step 1: Preparation of tert-butyl 4-(1-toluenesulfonylhydrazineethyl)piperidine-1-carboxylate

将4-乙酰哌啶-1-甲酸叔丁酯(2.0g)溶于甲醇(20mL)中，加入对甲苯磺酰肼(1.64g)，加料完毕后将反应体系升温至60℃反应1小时。LC-MS显示反应完全后，减压浓缩得到标题化合物。MS(ESI)m/z(M+H)⁺＝396.2。Dissolve tert-butyl 4-acetylpiperidine-1-carboxylate (2.0 g) in methanol (20 mL), add p-toluenesulfonyl hydrazide (1.64 g), and after the addition is complete, heat the reaction system to 60° C. and react for 1 hour. After LC-MS shows that the reaction is complete, concentrate under reduced pressure to obtain the title compound. MS (ESI) m/z (M+H)⁺ = 396.2.

步骤2：4-(1-(4-溴-2-氧代吡啶-1(2H)-基)乙基)哌啶-1-甲酸叔丁酯的制备
Step 2: Preparation of tert-butyl 4-(1-(4-bromo-2-oxopyridin-1(2H)-yl)ethyl)piperidine-1-carboxylate

将4-(1-对甲苯磺酰腙基乙基)哌啶-1-甲酸叔丁酯(400mg)和4-溴吡啶-2(1H)-酮(351.5mg)溶于1,4-二氧六环(10mL)中，加入碘化亚铜(38mg)和碳酸铯(658mg)，氮气保护下将反应体系加热至110℃反应16小时。LC-MS检测反应完全，硅藻土过滤，加入适量水，乙酸乙酯萃取，减压浓缩。经硅胶柱层析分离纯化得到标题化合物。MS(ESI)m/z(M+H)⁺＝385.1。Dissolve tert-butyl 4-(1-toluenesulfonylhydrazineethyl)piperidin-1-carboxylate (400 mg) and 4-bromopyridin-2(1H)-one (351.5 mg) in 1,4-dioxane (10 mL), add cuprous iodide (38 mg) and cesium carbonate (658 mg), and heat the reaction system to 110°C under nitrogen protection for 16 hours. LC-MS detected that the reaction was complete, filtered through diatomaceous earth, added appropriate amount of water, extracted with ethyl acetate, and concentrated under reduced pressure. Separate and purify by silica gel column chromatography to obtain the title compound. MS (ESI) m/z (M+H)⁺ = 385.1.

步骤3：4-(1-(4-(2-氯-3-(4-(三氟甲基)苯氧基)苯基)-2-氧代吡啶-1(2H)基)乙基)哌啶-1-甲酸叔丁酯的制备
Step 3: Preparation of tert-butyl 4-(1-(4-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-2-oxopyridin-1(2H)yl)ethyl)piperidine-1-carboxylate

将2-(2-氯-3-(4-(三氟甲基)苯氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(205.5mg)溶于二氧六环(12mL)中，随后加入4-(1-(4-溴-2-氧代吡啶-1(2H)-基)乙基)哌啶-1-甲酸叔丁酯(199mg)、碳酸钾(174.1mg)和Pd(dppf)Cl₂(46.1mg)，氮气保护下，将反应体系加热至90℃搅拌2小时。LC-MS显示原料反应完全后，将反应液减压浓缩，所得粗品经硅胶过滤后减压浓缩。残余物经制备型高效液相色谱分离纯化得标题化合物。MS(ESI)m/z(M+H)⁺＝577.2。2-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (205.5 mg) was dissolved in dioxane (12 mL), followed by the addition of tert-butyl 4-(1-(4-bromo-2-oxopyridin-1(2H)-yl)ethyl)piperidine-1-carboxylate (199 mg), potassium carbonate (174.1 mg) and Pd(dppf)Cl₂ (46.1 mg). Under nitrogen protection, the reaction system was heated to 90° C. and stirred for 2 hours. After LC-MS showed that the raw material was completely reacted, the reaction solution was concentrated under reduced pressure, and the obtained crude product was filtered through silica gel and concentrated under reduced pressure. The residue was separated and purified by preparative high performance liquid chromatography to obtain the title compound. MS (ESI) m/z (M+H)⁺ = 577.2.

实施例24：4-(2-氯-3-(4-(三氟甲基)苯氧基)苯基)-1-(1-(哌啶-4-基)乙基)吡啶-2(1H)-酮的制备
Example 24: Preparation of 4-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-1-(1-(piperidin-4-yl)ethyl)pyridin-2(1H)-one

将4-(1-(4-(2-氯-3-(4-(三氟甲基)苯氧基)苯基)-2-氧代吡啶-1(2H)基)乙基)哌啶-1-甲酸叔丁酯(实施例24A)(80mg)溶于二氯甲烷(5mL)中，加入三氟乙酸(1.53g)，反应体系在室温下反应1小时。LC-MS显示反应完全后，减压浓缩。经制备型高效液相色谱分离纯化得到标题化合物。MS(ESI)m/z(M+H)⁺＝477.2。¹HNMR(400MHz,DMSO-d₆)δ7.79–7.70(m,3H),7.51(t,J＝8.0Hz,1H),7.41–7.33(m,2H),7.15(d,J＝8.4Hz,2H),6.43(d,J＝2.0Hz,1H),6.36(dd,J＝7.2,2.0Hz,1H),4.73(s,1H),2.97(d,J＝12.4Hz,1H),2.86(d,J＝12.8Hz,1H),2.41(td,J＝12.0,2.4Hz,1H),2.30(td,J＝12.0,2.4Hz,1H),1.81–1.65(m,2H),1.31(d,J＝7.2Hz,3H),1.26–0.81(m,4H)。4-(1-(4-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-2-oxopyridin-1(2H)yl)ethyl)piperidine-1-carboxylic acid tert-butyl ester (Example 24A) (80 mg) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1.53 g) was added, and the reaction system was reacted at room temperature for 1 hour. After LC-MS showed that the reaction was complete, it was concentrated under reduced pressure. The title compound was separated and purified by preparative high performance liquid chromatography. MS (ESI) m/z (M+H)⁺ = 477.2.¹ HNMR (400 MHz, DMSO-d₆ )δ7.79–7.70(m,3H),7.51(t,J＝8.0Hz,1H),7.41–7.33(m,2H),7.15(d,J＝8.4H z,2H),6.43(d,J＝2.0Hz,1H),6.36(dd,J＝7.2,2.0Hz,1H),4.73(s,1H),2.97(d, J＝12.4Hz,1H),2.86(d,J＝12.8Hz,1H),2.41(td,J＝12.0,2.4Hz,1H),2.30(td,J ＝12.0,2.4Hz,1H),1.81–1.65(m,2H),1.31(d,J＝7.2Hz,3H),1.26–0.81(m,4H).

实施例50A：N-(6-(1-(4-(2-氯-3-(4-(三氟甲基)苯氧基)苯基)-2-氧代吡啶-1(2H)-基)乙基)吡啶-2-基)新戊酰胺的制备
Example 50A: Preparation of N-(6-(1-(4-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-2-oxopyridin-1(2H)-yl)ethyl)pyridin-2-yl)pivalamide

参考实施例1，采用方法1的制备方法制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝570.2。With reference to Example 1, the title compound was prepared using the preparation method of Method 1. MS (ESI) m/z (M+H)⁺ = 570.2.

实施例50：1-(1-(6-氨基吡啶-2-基)乙基)-4-(2-氯-3-(4-(三氟甲基)苯氧基)苯基)吡啶-2(1H)-酮的制备
Example 50: Preparation of 1-(1-(6-aminopyridin-2-yl)ethyl)-4-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)pyridin-2(1H)-one

将N-(6-(1-(4-(2-氯-3-(4-(三氟甲基)苯氧基)苯基)-2-氧代吡啶-1(2H)-基)乙基)吡啶-2-基)新戊酰胺(实施例50A)(325mg)溶于1,4-二氧六环(10.0mL)和浓盐酸(10.0mL)的混合溶剂中，将反应体系加热至90℃搅拌16小时。LC-MS显示反应完全，将反应液冷却至室温，氨水调pH至8～9，减压浓缩。经制备型高效液相色谱分离纯化后得标题化合物。MS(ESI)m/z(M+H)⁺＝486.1。¹H NMR(400MHz,DMSO-d₆)δ7.79–7.70(m,3H),7.51(t,J＝8.0Hz,1H),7.40–7.34(m,3H),7.15(d,J＝8.4Hz,2H),6.46(d,J＝7.2Hz,2H),6.42–6.32(m,2H),6.03–5.97(m,3H),1.63(d,J＝7.2Hz,3H)。N-(6-(1-(4-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-2-oxopyridin-1(2H)-yl)ethyl)pyridin-2-yl)pivalamide (Example 50A) (325 mg) was dissolved in a mixed solvent of 1,4-dioxane (10.0 mL) and concentrated hydrochloric acid (10.0 mL), and the reaction system was heated to 90°C and stirred for 16 hours. LC-MS showed that the reaction was complete, and the reaction solution was cooled to room temperature, the pH was adjusted to 8-9 with ammonia water, and concentrated under reduced pressure. The title compound was obtained after separation and purification by preparative high performance liquid chromatography. MS (ESI) m/z (M+H)⁺ = 486.1.¹ H NMR (400MHz, DMSO-d₆ )δ7.79–7.70(m,3H),7.51(t,J＝8.0Hz,1H),7.40–7.34(m,3H),7.15(d,J＝8.4Hz,2H) ,6.46(d,J＝7.2Hz,2H),6.42–6.32(m,2H),6.03–5.97(m,3H),1.63(d,J＝7.2Hz,3H).

实施例67A：1-(2-((叔丁基二甲基硅基)氧基)-1-(吡嗪-2-基)乙基)-4-(2-氯-3-((5-(三氟甲基)吡啶-2-基)氧基)苯基)吡啶-2(1H)-酮的制备
Example 67A: Preparation of 1-(2-((tert-butyldimethylsilyl)oxy)-1-(pyrazin-2-yl)ethyl)-4-(2-chloro-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)pyridin-2(1H)-one

参考实施例22，采用方法2的制备方法制备得到标题化合物。MS(ESI)m/z(M+H)⁺＝603.2。Referring to Example 22, the title compound was prepared using the preparation method of Method 2. MS (ESI) m/z (M+H)⁺ = 603.2.

实施例67：4-(2-氯-3-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-1-(2-羟基-1-(吡嗪-2-基)乙基)吡啶-2(1H)-酮的制备
Example 67: Preparation of 4-(2-chloro-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-(2-hydroxy-1-(pyrazin-2-yl)ethyl)pyridin-2(1H)-one

将1-(2-((叔丁基二甲基硅基)氧基)-1-(吡嗪-2-基)乙基)-4-(2-氯-3-((5-(三氟甲基)吡啶-2-基)氧基苯基)吡啶-2(1H)-酮(0.21g)溶于二氯甲烷(5mL)中，加入盐酸二氧六环溶液(5mL，4M)，加料完毕后将反应体系在常温下搅拌1小时。LC-MS显示反应完全后，减压浓缩，所得粗品经硅胶柱层析纯化得标题化合物。MS(ESI)m/z(M+H)⁺＝489.1。¹H NMR(400MHz,DMSO-d₆)δ8.72(d,J＝1.2Hz,1H),8.63–8.62(m,1H),8.59(d,J＝2.4Hz,1H),8.58–8.56(m,1H),8.28(dd,J＝8.8,2.4Hz,1H),7.92(d,J＝7.2Hz,1H),7.53–7.45(m,2H),7.40–7.37(m,2H),6.45(d,J＝2.0Hz,1H),6.38(dd,J＝7.2,2.0Hz,1H),6.12–6.08(m,1H),5.36(t,J＝5.2Hz,1H),4.22–4.11(m,2H)。1-(2-((tert-butyldimethylsilyl)oxy)-1-(pyrazin-2-yl)ethyl)-4-(2-chloro-3-((5-(trifluoromethyl)pyridin-2-yl)oxyphenyl)pyridin-2(1H)-one (0.21 g) was dissolved in dichloromethane (5 mL), and a hydrochloric acid dioxane solution (5 mL, 4 M) was added. After the addition was completed, the reaction system was stirred at room temperature for 1 hour. After LC-MS showed that the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the title compound. MS (ESI) m/z (M+H)⁺ = 489.1.¹ H NMR (400 MHz, DMSO-d₆ )δ8.72(d,J＝1.2Hz,1H),8.63–8.62(m,1H),8.59(d,J＝2.4Hz,1H),8.58–8.56(m,1H),8.28(dd,J＝8.8,2.4Hz,1H),7.92(d,J＝7.2Hz,1H),7.53– 7.45(m,2H),7.40–7.37(m,2H),6.45(d,J＝2.0Hz,1H),6.38(dd,J＝7.2, 2.0Hz, 1H), 6.12–6.08 (m, 1H), 5.36 (t, J = 5.2Hz, 1H), 4.22–4.11 (m, 2H).

采用相应的商品化试剂及前述制备例与实施例中产物为原料，使用上述实施例类似的制备方法，制备得到一系列化合物，所述化合物的结构及表征数据见表1，A series of compounds were prepared by using corresponding commercial reagents and the products of the above-mentioned preparation examples and embodiments as raw materials and using a preparation method similar to the above-mentioned embodiment. The structures and characterization data of the compounds are shown in Table 1.

表1















Table 1

生物试验Biological tests

测试例1：YAP-TEAD双荧光素酶报告基因实验。Test Example 1: YAP-TEAD dual luciferase reporter gene experiment.

1.实验材料：
1. Experimental materials:

2.实验方法2. Experimental Methods

a.用8xGTIIC-萤火虫荧光素酶、pRL-SV40-N质粒共转染对数生长期HEK293T细胞；a. HEK293T cells in logarithmic growth phase were co-transfected with 8xGTIIC-firefly luciferase and pRL-SV40-N plasmid;

b.实验孔：96孔板中铺12000个上述转染细胞，待测药物用含0.5％ DMSO的DMEM培养基进行梯度稀释，实验孔药物最高终浓度为5μM，5倍梯度稀释，共9个梯度浓度，将1～9每个浓度的待测药物溶液取50μL加入转染细胞孔中，每个浓度重复3个孔。按如下设置未加药对照孔：在96孔板中铺12000个上述转染细胞，在孔中加入0.5％ DMSO的DMEM培养基，重复8个孔。按如下设置未转染孔：在96孔板中铺上12000个未转染HEK293T细胞，然后在孔中加入0.5％DMSO的DMEM培养基，重复8个孔。b. Experimental wells: 12,000 transfected cells were plated in a 96-well plate. The drug to be tested was graded diluted with DMEM medium containing 0.5% DMSO. The highest final concentration of the drug in the experimental wells was 5 μM. The drug solution to be tested was graded diluted 5-fold, with a total of 9 graded concentrations. 50 μL of each concentration of the drug to be tested from 1 to 9 was added to the transfected cell wells. Each concentration was repeated for 3 wells. The untreated control wells were set as follows: 12,000 transfected cells were plated in a 96-well plate. DMEM medium containing 0.5% DMSO was added to the wells. The wells were repeated for 8 wells. The untransfected wells were set as follows: 12,000 untransfected HEK293T cells were plated in a 96-well plate. Then DMEM medium containing 0.5% DMSO was added to the wells. The wells were repeated for 8 wells.

c.药物作用24h后，参照Promega双荧光素酶检测试剂盒说明书，检测细胞荧光值。c. After 24 hours of drug action, refer to the instructions of the Promega Dual Luciferase Assay Kit to detect the cell fluorescence value.

d.使用以下公式计算抑制率％，d. Calculate the inhibition rate using the following formula:

抑制率％＝(未加药对照孔平均信号值-实验孔信号值)/(未加药对照孔平均信号值-未转染对照孔平均信号值)×100％Inhibition rate % = (average signal value of control wells without drug addition - signal value of experimental wells) / (average signal value of control wells without drug addition - average signal value of non-transfected control wells) × 100%

e.使用GraphPad Prism 9.0绘制抑制率-剂量曲线并计算IC50值。e. Use GraphPad Prism 9.0 to draw the inhibition rate-dose curve and calculate the IC50 value.

3.实验结果3. Experimental results

本申请中化合物在HEK293T细胞上具有的TEAD转录抑制活性如下表A所示。The TEAD transcriptional inhibitory activity of the compounds in the present application on HEK293T cells is shown in Table A below.

表A
Table A

表中，“A”代表对TEADs转录抑制活性的IC₅₀范围小于等于25nM；“B”代表对TEADs转录抑制活性的IC₅₀范围大于25nM且小于等于50nM；“C”代表对TEADs转录抑制活性的IC₅₀范围大于50nM且小于等于100nM；“H”代表对TEADs转录抑制活性的IC₅₀范围大于5μM或者无活性。In the table, "A" represents that the_IC50 range of TEADs transcriptional inhibitory activity is less than or equal to 25nM; "B" represents that the_IC50 range of TEADs transcriptional inhibitory activity is greater than 25nM and less than or equal to 50nM; "C" represents that the_IC50 range of TEADs transcriptional inhibitory activity is greater than 50nM and less than or equal to 100nM; "H" represents that the_IC50 range of TEADs transcriptional inhibitory activity is greater than 5μM or inactive.

本申请中化合物在HEK293T细胞上具有TEADs转录抑制活性。实验发现，本申请化合物对TEADs转录抑制活性的IC₅₀值小于等于100nM，本申请中某些化合物对TEADs转录抑制活性的IC₅₀值大于等于50nM且小于100nM，本申请中某些化合物对TEADs转录抑制活性的IC₅₀值大于等于30nM且小于50nM，本申请中某些化合物对TEADs转录抑制活性的IC₅₀值大于等于20nM且小于30nM，本申请中某些化合物TEADs转录抑制活性的IC50值大于等于10nM且小于20nM，本申请某些化合物对TEADs转录抑制活性的IC₅₀值小于10nM。The compounds in the present application have TEADs transcriptional inhibition activity on HEK293T cells. Experiments have found that the IC₅₀ value of the compounds in the present application for TEADs transcriptional inhibition activity is less than or equal to 100nM, the IC₅₀ value of some compounds in the present application for TEADs transcriptional inhibition activity is greater than or equal to 50nM and less than 100nM, the IC₅₀ value of some compounds in the present application for TEADs transcriptional inhibition activity is greater than or equal to 30nM and less than 50nM, the IC₅₀ value of some compounds in the present application for TEADs transcriptional inhibition activity is greater than or equal to 20nM and less than 30nM, the IC50 value of some compounds in the present application for TEADs transcriptional inhibition activity is greater than or equal to 10nM and less than 20nM, and the IC₅₀ value of some compounds in the present application for TEADs transcriptional inhibition activity is less than 10nM.

测试例2：细胞增殖抑制活性测定Test Example 2: Cell proliferation inhibitory activity assay

1.实验材料
1. Experimental Materials

2.实验方法2. Experimental Methods

a.将对数生长期的NCI-H226细胞接种于96孔板，每孔接种180μL；另在96孔板的空白孔中加入同体积空白培养基(PRMI 1640细胞培养基)；a. Inoculate NCI-H226 cells in the logarithmic growth phase into a 96-well plate, with 180 μL per well. Add the same volume of blank culture medium (PRMI 1640 cell culture medium) into the blank wells of the 96-well plate.

b.实验孔：用含0.5％ DMSO的PRMI 1640细胞培养基稀释待测药物，待测药物最高终浓度为10μM，进行三倍梯度稀释，共9个梯度浓度，将1～9各浓度的待测药物溶液20μL加入上述接种细胞的孔中，每浓度重复3个孔。按如下设置未加药对照孔：将0.5％ DMSO的PRMI 1640细胞培养基20μL加入上述接种细胞的孔中，重复8个孔。按如下设置空白对照孔：在上述空白培养基的孔中加入0.5％ DMSO的PRMI 1640细胞培养基20μL。b. Experimental wells: dilute the drug to be tested with PRMI 1640 cell culture medium containing 0.5% DMSO. The highest final concentration of the drug to be tested is 10μM. Perform three-fold gradient dilutions for a total of 9 gradient concentrations. Add 20μL of the drug solution of concentrations 1 to 9 to the wells inoculated with cells above. Repeat 3 wells for each concentration. Set up the untreated control wells as follows: dilute the PRMI 1640 with 0.5% DMSO. 20 μL of cell culture medium was added to the wells seeded with cells, and the same was repeated for 8 wells. Blank control wells were set up as follows: 20 μL of PRMI 1640 cell culture medium containing 0.5% DMSO was added to the wells containing blank culture medium.

c.作用168h后，用CellCounting-LiteTM 2.0试剂盒测定细胞活力，多功能酶标仪检测发光信号。c. After 168 hours of action, the cell viability was determined using the CellCounting-LiteTM 2.0 kit and the luminescent signal was detected using a multifunctional microplate reader.

d.使用以下公式计算抑制率％，d. Calculate the inhibition rate using the following formula:

抑制率％＝(未加药对照孔平均信号值-实验孔信号值)/(未加药对照孔平均信号值-空白对照孔平均信号值)×100％Inhibition rate % = (average signal value of control wells without drug addition - signal value of experimental wells) / (average signal value of control wells without drug addition - average signal value of blank control wells) × 100%

e.使用GraphPad Prism 9.0绘制抑制率-剂量曲线并计算IC50值。e. Use GraphPad Prism 9.0 to draw the inhibition rate-dose curve and calculate the IC50 value.

3.实验结果3. Experimental results

本申请中化合物细胞增殖抑制活性如下表2，The cell proliferation inhibition activity of the compounds in this application is shown in Table 2.

表2
Table 2

表中，“A”代表对NCI-H226细胞增殖抑制活性的IC₅₀范围小于等于25nM；“B”代表对NCI-H226细胞增殖抑制活性的IC₅₀范围大于25nM且小于等于50nM；“C”代表对NCI-H226细胞增殖抑制活性的IC₅₀范围大于50nM且小于等于100nM；“D”代表对NCI-H226细胞增殖抑制活性的IC₅₀范围大于100nM且小于等于500nM；“E”代表对NCI-H226细胞增殖抑制活性的IC₅₀范围大于500nM且小于等于1μM；“F”代表对NCI-H226细胞增殖抑制活性的IC₅₀范围大于1μM且小于等于3μM；“G”代表对NCI-H226细胞增殖抑制活性的IC₅₀范围大于3μM小于5μM；“H”代表对NCI-H226细胞增殖抑制活性的IC₅₀范围大于10μM或者无活性。In the table, "A" represents the_IC50 range of the inhibitory activity on the proliferation of NCI-H226 cells is less than or equal to 25nM; "B" represents the_IC50 range of the inhibitory activity on the proliferation of NCI-H226 cells is greater than 25nM and less than or equal to 50nM; "C" represents the_IC50 range of the inhibitory activity on the proliferation of NCI-H226 cells is greater than 50nM and less than or equal to 100nM; "D" represents the_IC50 range of the inhibitory activity on the proliferation of NCI-H226 cells is greater than 100nM and less than or equal to 500nM; "E" represents the_IC50 range of the inhibitory activity on the proliferation of NCI-H226 cells is greater than 500nM and less than or equal to 1μM; "F" represents the_IC50 range of the inhibitory activity on the proliferation of NCI-H226 cells is greater than 1μM and less than or equal to 3μM; "G" represents the IC50 range of the inhibitory activity on the proliferation of NCI-H226 cells is greater than 1μM and less than or equal to 3μM. "H" represents_theIC50 range of the inhibitory activity on the proliferation of NCI-H226 cells is greater than 10 μM or inactive.

本申请中化合物具有抑制NCI-H226细胞的增殖的作用。实验发现，本申请中某些化合物对NCI-H226细胞的增殖抑制活性的IC50值小于等于500nM，本申请中某些化合物对NCI-H226细胞的增殖抑制活性的IC₅₀值小于等于100nM，本申请中某些化合物对NCI-H226细胞的增殖抑制活性的IC₅₀值小于等于50nM，本申请中某些化合物对NCI-H226细胞的增殖抑制活性的IC₅₀值小于等于25nM，本申请某些化合物对NCI-H226细胞的增殖抑制活性的IC₅₀值小于等于10nM。The compounds in the present application have the effect of inhibiting the proliferation of NCI-H226 cells. Experiments have found that the IC50 value of the proliferation inhibition activity of some compounds in the present application on NCI-H226 cells is less than or equal to 500nM, the_IC50 value of the proliferation inhibition activity of some compounds in the present application on NCI-H226 cells is less than or equal to 100nM, the_IC50 value of the proliferation inhibition activity of some compounds in the present application on NCI-H226 cells is less than or equal to 50nM, the_IC50 value of the proliferation inhibition activity of some compounds in the present application on NCI-H226 cells is less than or equal to 25nM, and the_IC50 value of the proliferation inhibition activity of some compounds in the present application on NCI-H226 cells is less than or equal to 10nM.

测试例3：肝微粒体代谢稳定性测试Test Example 3: Liver microsome metabolic stability test

1.实验材料

1. Experimental Materials

2.实验方法2. Experimental Methods

将待测化合物用DMSO配制成10mM，取2μL加入198μL 50％乙腈/50％水溶液，得到100μM溶液。取肝微粒体，用PBS配制成0.5mg/mL，加入NADPH辅因子(终浓度为1mM)，混合物在37℃预热10min。取配制好的待测化合物2.5μL，分别加入222.5μL前述预热的混合物置于37℃水浴槽开始反应。在0.5、15、30和45min时间点将孵育的离心管取出后分别吸取25μL孵育后的肝微粒体悬液(含化合物)，加入5倍体积终止液终止反应，3220g离心40min，取上清后采用LC-MS/MS检测各时间点样品中剩余化合物含量。将剩余药量百分比-时间做非线性线性回归后，计算化合物在肝微粒体中的半衰期(t_1/2)。The test compound was prepared to 10mM with DMSO, 2μL was added to 198μL 50% acetonitrile/50% aqueous solution to obtain a 100μM solution. Liver microsomes were taken and prepared to 0.5mg/mL with PBS, NADPH cofactor (final concentration of 1mM) was added, and the mixture was preheated at 37℃ for 10min. 2.5μL of the prepared test compound was taken and added to 222.5μL of the above preheated mixture and placed in a 37℃ water bath to start the reaction. At 0.5, 15, 30 and 45min, the incubated centrifuge tubes were taken out and 25μL of the incubated liver microsome suspension (containing the compound) was taken out respectively, and 5 times the volume of the stop solution was added to terminate the reaction, and the supernatant was centrifuged at 3220g for 40min. After taking the supernatant, the remaining compound content in the sample at each time point was detected by LC-MS/MS. After nonlinear linear regression of the remaining drug percentage-time, the half-life (t_1/2 ) of the compound in liver microsomes was calculated.

本申请化合物在肝微粒体代谢中具有一定的稳定性。本申请某些化合物在肝微粒体中代谢时间较长或者不被肝微粒体代谢。The compounds of the present application have certain stability in liver microsome metabolism. Some compounds of the present application are metabolized in liver microsomes for a long time or are not metabolized by liver microsomes.

测试例3A：肝细胞代谢稳定性测试Test Example 3A: Hepatocyte Metabolic Stability Test

肝细胞来源：
Hepatocyte source:

将待测化合物用DMSO配制成10mM，取2μL加入198μL 50％乙腈/50％水溶液，得到100μM溶液。冻存的肝细胞复苏后，用培养基(William's E培养基，Gibco，货号：22551032)重悬成50万细胞每毫升的密度。取198μL肝细胞悬液至96孔板，分别加入2μL配制好的100μM待测化合物、阳性化合物溶液，置于培养箱进行孵育。在0.5、15、30、60、90和120分钟时间点将孵育的96孔板取出后分别吸取25μL孵育后的细胞悬液(含化合物)，加入6倍体积终止液终止反应，3220g离心45分钟，取上清后采用LC-MS/MS检测各时间点样品中剩余化合物含量。将％剩余药量-时间做非线性线性回归后，计算化合物在肝细胞中的半衰期(t_1/2)。The test compound was prepared to 10mM with DMSO, and 2μL was added to 198μL 50% acetonitrile/50% aqueous solution to obtain a 100μM solution. After the frozen hepatocytes were revived, they were resuspended in culture medium (William's E culture medium, Gibco, catalog number: 22551032) to a density of 500,000 cells per milliliter. 198μL of the hepatocyte suspension was added to a 96-well plate, and 2μL of the prepared 100μM test compound and positive compound solution were added respectively, and placed in an incubator for incubation. After the incubated 96-well plate was removed at 0.5, 15, 30, 60, 90 and 120 minutes, 25μL of the incubated cell suspension (containing the compound) was taken out, and 6 times the volume of the stop solution was added to terminate the reaction. The supernatant was taken and LC-MS/MS was used to detect the remaining compound content in the samples at each time point. The half-life (t_1/2 ) of the compound in hepatocytes was calculated by performing nonlinear linear regression on the relationship between % remaining drug and time.

本申请化合物在肝细胞代谢中具有稳定性。本申请化合物在肝细胞中半衰期较长，肝细胞代谢稳定性良好，例如实施例46和60的化合物的人源肝细胞的半衰期相比于现有化合物提高2～4倍。The compounds of the present application are stable in hepatocyte metabolism. The compounds of the present application have a long half-life in hepatocytes and good hepatocyte metabolic stability. For example, the half-life of the compounds of Examples 46 and 60 in human hepatocytes is 2 to 4 times higher than that of existing compounds.

测试例4：Caco-2细胞体外渗透性测试Test Example 4: Caco-2 cell in vitro permeability test

1.实验材料
1. Experimental Materials

2.实验方法2. Experimental Methods

a.细胞培养及接种铺板a. Cell culture and plating

在HTS Transwell^TM细胞培养板中接种Caco-2细胞，板孔中培养基体积为50μL，每24h更换一次培养基。Caco-2 cells were seeded in HTS Transwell^™ cell culture plates. The volume of culture medium in the wells was 50 μL, and the culture medium was replaced every 24 h.

b.检测电阻b. Detection resistor

Caco-2细胞培养14～16天后形成融合的单细胞层，检测电阻。单细胞层的跨膜电阻达到230Ω·cm²，可用于下一步渗透性测试。After 14-16 days of culture, Caco-2 cells formed a confluent monolayer, and the resistance was measured. The transmembrane resistance of the monolayer reached 230Ω·cm² , which can be used for the next permeability test.

c.渗透性测试c. Penetration test

首先配制化合物工作溶液，用DMSO将待测化合物配制成2mM，再以HBSS缓冲液(含4％ BSA的10mM HEPES缓冲液，pH 7.4)进一步稀释到10μM获得测试工作溶液。弃去Transwell^TM细胞培养板中培养液，用37℃HBSS清洗细胞表面3次，然后加入37℃HBSS液，置于37℃孵箱中孵育30min。A→B渗透性测试：吸去缓冲溶液，在上层小室(顶端，Apical，A面)加入含有受试药物的工作溶液，作为供给液，下层小室(基底端；Basolateral，B面)加入空白的HBSS液作为接收液。B→A渗透性(外排)测试：吸去缓冲溶液，在A面加入空白的HBSS液作为接收液，在B面加入含化合物的工作溶液作为给药端溶液。First, prepare the compound working solution. Use DMSO to prepare the test compound to 2mM, and then further dilute it to 10μM with HBSS buffer (10mM HEPES buffer containing 4% BSA, pH 7.4) to obtain the test working solution. Discard the culture medium in the Transwell^TM cell culture plate, wash the cell surface with 37℃ HBSS three times, then add 37℃ HBSS solution, and incubate in a 37℃ incubator for 30min. A→B permeability test: aspirate the buffer solution, add the working solution containing the test drug to the upper chamber (apical, A side) as the supply solution, and add blank HBSS solution to the lower chamber (basolateral, B side) as the receiving solution. B→A permeability (exfiltration) test: aspirate the buffer solution, add blank HBSS solution to the A side as the receiving solution, and add the working solution containing the compound to the B side as the dosing end solution.

d.采样和检测d. Sampling and testing

在Transwell^TM板中取适量的给药溶液作为T₀样品，然后置于37℃培养箱中温孵2h。孵育结束后，在接收端取样。样品采用LC-MS/MS方法进行检测。Take an appropriate amount of the dosing solution in the Transwell^TM plate as the_T0 sample, and then place it in a 37°C incubator for 2 hours. After the incubation, take a sample at the receiving end. The sample is detected by LC-MS/MS method.

e.数据分析e. Data analysis

表观渗透系数(P_app，单位：×10^-6cm/s)：Apparent permeability coefficient (P_app , unit: ×10^-6 cm/s):

V_R为接收端溶液的体积(A→B：接收端为基底端；B→A：接收端为顶端)，Area为Transwell-96孔板膜(0.0804cm²)，Time为孵育时间(单位：s)，C_R为样品接收端的药物浓度，C₀为样品最初T₀点时的药物浓度。_VR is the volume of the receiving end solution (A→B: the receiving end is the base end; B→A: the receiving end is the top end), Area is the Transwell-96 well plate membrane (0.0804^cm2 ), Time is the incubation time (unit: s),_CR is the drug concentration at the sample receiving end, and_C0 is the drug concentration at the initial_T0 point of the sample.

外排率(ER)：Efflux rate (ER):

P_app(B→A)为由基底端到顶端的表观渗透系数，P_app(A→B)为由顶端到基底端的表观渗透系数。P_app (B→A) is the apparent permeability from the base end to the apex, and P_app (A→B) is the apparent permeability from the apex to the base end.

本申请化合物具有一定的Caco-2细胞渗透性，Caco-2细胞外排作用不明显。本申请某些化合物的Caco-2细胞渗透性较高，且Caco-2细胞外排作用较低。例如本申请实施例1、实施例46、实施例60的化合物的表观渗透系数P_app(A→B)分别为3.01、4.65、4.85，细胞渗透性良好，相对于现有技术化合物提升了2～3倍，并且未见明显外排。The compounds of the present application have a certain Caco-2 cell permeability, and the Caco-2 cell efflux effect is not obvious. The Caco-2 cell permeability of some compounds of the present application is high, and the Caco-2 cell efflux effect is low. For example, the apparent permeability coefficients P_app (A→B) of the compounds of Examples 1, 46, and 60 of the present application are 3.01, 4.65, and 4.85, respectively, with good cell permeability, which is 2 to 3 times higher than that of the prior art compounds, and no obvious efflux is observed.

测试例5：化合物溶解性测试Test Example 5: Compound Solubility Test

1.实验材料
1. Experimental Materials

2.实验方法2. Experimental Methods

a.化合物准备。a. Compound preparation.

用DMSO将待测化合物配制成10mM溶液待用。The test compound was prepared into a 10 mM solution with DMSO.

b.溶解度测试b. Solubility test

取15μL浓度为10mM的待测化合物加入96孔板，加入485μL的PBS。板孔密封后置于摇床中，在25℃、1100rpm的条件下孵育2h。2h后，将孵育后的500μL样品转移到过滤板，使用真空歧管对样品进行过滤。从滤液中取5μL，与5μL DMSO混匀后，再加入490μL超纯水混匀，采用LC-MS测试化合物浓度。Take 15 μL of the compound to be tested at a concentration of 10 mM and add it to a 96-well plate, and add 485 μL of PBS. After the plate wells are sealed, place it in a shaker and incubate it for 2 hours at 25°C and 1100 rpm. After 2 hours, transfer 500 μL of the incubated sample to the filter plate and filter the sample using a vacuum manifold. Take 5 μL from the filtrate, mix it with 5 μL DMSO, and then add 490 μL ultrapure water to mix it. Use LC-MS to test the concentration of the compound.

c.标准品c. Standard products

取6μL浓度为10mM的待测化合物于96孔板，加入194μL DMSO溶液，混合均匀后，取5μL与5μL的PBS缓冲液混匀，再加入490μL超纯水混匀，与步骤2样品同步采用LC-MS测试化合物浓度。Take 6 μL of the test compound with a concentration of 10 mM into a 96-well plate, add 194 μL DMSO solution, mix evenly, take 5 μL and mix with 5 μL PBS buffer, then add 490 μL ultrapure water and mix well, and use LC-MS to test the compound concentration simultaneously with the sample in step 2.

d.数据分析d. Data analysis

已知标准品进样浓度为10μM，比较待测化合物与标准品在LC-MS中的峰面积计算溶解度，具体公式如下：The injection concentration of the standard is known to be 10 μM. The solubility is calculated by comparing the peak areas of the test compound and the standard in LC-MS. The formula is as follows:

本申请化合物可以具有一定的溶解性。本申请某些化合物具有较高的溶解性。本申请化合物可以具有>50μM的溶解度，本申请某些化合物还可以具有>100μM的溶解度。本申请化合物相比于现有技术化合物提升溶解性至少10倍，某些化合物提升超过100倍，某些化合物提升超过1000倍，例如实施例60、67的化合物的溶解度分别为63.0μM、112.2μM，折合溶解度分别为27.62μg/mL、54.85μg/mL，相比于现有技术的化合物的溶解性提升巨大。The compounds of the present application may have a certain solubility. Some compounds of the present application have a higher solubility. The compounds of the present application may have a solubility of >50μM, and some compounds of the present application may also have a solubility of >100μM. The compounds of the present application have an improvement in solubility of at least 10 times compared to the prior art compounds, some compounds have an improvement of more than 100 times, and some compounds have an improvement of more than 1000 times. For example, the solubility of the compounds in Examples 60 and 67 are 63.0μM and 112.2μM, respectively, and the equivalent solubility is 27.62μg/mL and 54.85μg/mL, respectively, which is a huge improvement in solubility compared to the compounds of the prior art.

测试例6：DMPK代谢试验Test Example 6: DMPK Metabolism Test

6周龄ICR雄鼠购买自集萃药康生物科技有限公司，小鼠(n＝3)静脉注射(IV)和口服灌胃(PO)的剂量分别为1mpk和10mpk，IV组的采血时间点为：0.083h、0.25h、0.5h、1h、2h、4h、8h、24h；PO组的采血时间点为：0.25h、0.5h、1h、2h、4h、6h、8h、24h。血液样本采集后置于冰上，并于1小时之内离心分离血浆(离心条件：6800g，6分钟，2-8℃)。血浆样本在分析前存放时则放于-80℃冰箱内。LC-MS/MS测定给予受试物后ICR小鼠血浆中受试物的浓度。运用Phoenix WinNonlin7.0计算药代动力学参数，提供AUC(0-t)、AUC(0-∞)、MRT(0-t)、MRT(0-∞)、Cmax、Tmax、和T1/2等参数及其平均值和标准差。Six-week-old ICR male mice were purchased from Jicui Yaokang Biotechnology Co., Ltd. The mice (n=3) were intravenously injected (IV) and orally gavaged (PO) with a dose of 1 mpk and 10 mpk, respectively. The blood sampling time points for the IV group were: 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 24h; the blood sampling time points for the PO group were: 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h. After blood collection, the blood samples were placed on ice and centrifuged within 1 hour to separate plasma (centrifugation conditions: 6800g, 6 minutes, 2-8℃). Plasma samples were stored in a -80℃ refrigerator before analysis. LC-MS/MS was used to determine the concentration of the test substance in the plasma of ICR mice after administration of the test substance. Phoenix WinNonlin7.0 was used to calculate the pharmacokinetic parameters, and parameters such as AUC(0-t), AUC(0-∞), MRT(0-t), MRT(0-∞), Cmax, Tmax, and T1/2 and their mean and standard deviations were provided.

本申请化合物小鼠PK暴露量较好，10mpk AUC(0-t)至少10000h*ng/mL以上，例如实施例46、66、90、92的化合物的10mpk AUC(0-t)分别为13000h*ng/mL、17000h*ng/mL、25000h*ng/mL、10500h*ng/mL，相比于现有化合物(例如≤2000h*ng/mL)提升至少5倍以上；同时现有的某些化合物在小鼠体内不代谢，可能存在体内蓄积毒性等安全性问题；本申请化合物在高暴露量的情况下，仍然能正常代谢，相比于现有化合物体内蓄积毒性更低、安全性更高。The mouse PK exposure of the compounds of the present application is good, and the 10mpk AUC (0-t) is at least 10000 h*ng/mL. For example, the 10mpk AUC (0-t) of the compounds of Examples 46, 66, 90, and 92 are 13000 h*ng/mL, 17000 h*ng/mL, 25000 h*ng/mL, and 10500 h*ng/mL, respectively, which is at least 5 times higher than that of existing compounds (e.g., ≤2000 h*ng/mL); at the same time, some existing compounds are not metabolized in mice, and there may be safety issues such as in vivo accumulation toxicity; the compounds of the present application can still be metabolized normally under high exposure, and have lower in vivo accumulation toxicity and higher safety than existing compounds.

Claims (15)

Translated fromChinese

一种式(I)所示的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药，
A compound represented by formula (I), its stereoisomer, its tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof,
X、Y各自独立地选自CR⁰或N，X and Y are each independently selected from CR⁰ or N,Z为C₁～C₆链状烃基，Z is a C₁ to C₆ chain hydrocarbon group,W²、W³各自独立地选自C、CR²或N，W² and W³ are each independently selected from C, CR² or N,W¹为不存在、CR¹或N，W⁴选自C或N，W⁵选自C＝O、CR³或N，且当W¹为不存在或者当W⁵为C＝O时，W⁴为N，^W1 is absent,^CR1 or N,^W4 is selected from C or N,^W5 is selected from C=O,^CR3 or N, and when^W1 is absent or when^W5 is C=O,^W4 is N,表示芳香环， represents an aromatic ring,环C为不存在、芳杂环、不饱和脂杂环或不饱和脂环，Ring C is absent, an aromatic heterocycle, an unsaturated alicyclic heterocycle or an unsaturated alicyclic ring,环A选自芳环、芳杂环、饱和脂环、不饱和脂环、不饱和脂杂环、芳环与不饱和脂环构成的并环、芳杂环与不饱和脂环构成的并环、芳环与不饱和脂杂环构成的并环、芳杂环与不饱和脂杂环构成的并环，Ring A is selected from an aromatic ring, an aromatic heterocycle, a saturated alicyclic ring, an unsaturated alicyclic ring, an unsaturated alicyclic heterocycle, a cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, a cyclic ring consisting of an aromatic ring and an unsaturated alicyclic heterocycle, and a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic heterocycle.环B选自芳环、芳杂环、饱和脂杂环、不饱和脂杂环、芳环与不饱和脂环构成的并环、芳杂环与不饱和脂环构成的并环、芳环与不饱和脂杂环构成的并环、芳杂环与不饱和脂杂环构成的并环，Ring B is selected from an aromatic ring, an aromatic heterocycle, a saturated alicyclic heterocycle, an unsaturated alicyclic heterocycle, a cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, a cyclic ring consisting of an aromatic ring and an unsaturated alicyclic heterocycle, and a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic heterocycle.m、n、o各自独立地选自0、1、2、3、4，m, n, and o are each independently selected from 0, 1, 2, 3, and 4,R^A、R^B、R⁰、R¹、R²、R³各自独立地选自氢、氘、氚、硝基、羟基、巯基、卤素、氰基、胺基、酯基、醛基、羧基、羰基、酰胺基、C₁～C₆烷基、C₁～C₆卤代烷基、C₁～C₆烷氧基、C₁～C₆卤代烷氧基，R^A , R^B , R⁰ , R¹ , R² , and R³ are each independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C₁ -C₆ alkyl, C₁ -C₆ haloalkyl, C₁ -C₆ alkoxy, C₁ -C₆ haloalkoxy,其中，所述R⁰、R¹、R²、R³、R^A、R^B、环C各自任选地被氘、氚、硝基、羟基、醛基、胺基、亚胺基、卤素、氰基、酯基、羧基、酰胺基、＝O、C₁～C₆烷基、C₁～C₆烷氧基中的一个或两个以上取代，wherein each of R⁰ , R¹ , R² , R³ ,^RA ,^RB , and ring C is optionally substituted by one or more of deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano, ester, carboxyl, amide, =O, C₁ -C₆ alkyl, and C₁ -C₆ alkoxy groups,所述Z任选地被氘、氚、硝基、羟基、醛基、胺基、亚胺基、卤素、氰基、酯基、羧基、酰胺基、＝O、C₁～C₆烷基、C₁～C₆烷氧基、3～8元环烷基、3～8元杂环烷基中的一个或两个以上取代，The Z is optionally substituted by one or more of deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano, ester, carboxyl, amide, =O, C₁ ～C₆ alkyl, C₁ ～C₆ alkoxy, 3～8-membered cycloalkyl, 3～8-membered heterocycloalkyl,所述芳杂环、不饱和脂杂环、饱和脂杂环各自独立地包含1～4个杂原子，所述杂环烷基包含1～2个杂原子，所述杂原子独立地选自N、O、S。The aromatic heterocycle, unsaturated aliphatic heterocycle and saturated aliphatic heterocycle each independently contain 1 to 4 heteroatoms; the heterocycloalkyl group contains 1 to 2 heteroatoms, and the heteroatoms are independently selected from N, O and S.根据权利要求1所述的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药，其中，所述环C不存在，且W²、W³各自独立地选自CR²或N；或者The compound according to claim 1, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein the ring C is absent, and W² and W³ are each independently selected from CR² or N; orW²、W³均选自C，所述环C为5元芳杂环，优选为包含1～3个杂原子的5元芳杂环，更优选为包含1～2个杂原子的芳杂环，所述杂原子选自N、O、S，所述环C任选地被氘、氚、硝基、羟基、醛基、胺基、亚胺基、卤素、氰基、酯基、羧基、酰胺基、＝O、C₁～C₆烷基、C₁～C₆烷氧基中的一个或两个以上取代。W² and W³ are both selected from C, the ring C is a 5-membered aromatic heterocycle, preferably a 5-membered aromatic heterocycle containing 1 to 3 heteroatoms, more preferably an aromatic heterocycle containing 1 to 2 heteroatoms, the heteroatoms are selected from N, O, and S, and the ring C is optionally substituted by one or more of deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano, ester, carboxyl, amide, =O, C₁ to C₆ alkyl, and C₁ to C₆ alkoxy.根据权利要求1或2所述的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药，其中，W¹选自CR¹，W²、W³同时选自C或CR²，W⁴选自C，W⁵选自CR³。The compound according to claim 1 or 2, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein^W1 is selected from^CR1 ,^W2 and^W3 are simultaneously selected from C or^CR2 ,^W4 is selected from C, and^W5 is selected from^CR3 .根据权利要求1～3任意一项所述的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药，其中，所述Z选自其中*与环B相连，p选自0、1、2、3、4，R选自氢、氘、氚、硝基、羟基、醛基、胺基、卤素、氰基、酯基、羧基、酰胺基、C₁～C₆烷基、C₁～C₆烷氧基、C₁～C₆卤代烷基、C₁～C₆卤代烷氧基、C₁～C₆羟基烷基；或者The compound according to any one of claims 1 to 3, its stereoisomer, its tautomer or its mixture form, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein Z is selected from wherein * is connected to ring B, p is selected from 0, 1, 2, 3, 4, and R is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, aldehyde, amine, halogen, cyano, ester, carboxyl, amide, C₁ ～C₆ alkyl, C₁ ～C₆ alkoxy, C₁ ～C₆ haloalkyl, C₁ ～C₆ haloalkoxy, C₁ ～C₆ hydroxyalkyl; or所述Z选自其中*与环B相连，p选自0、1、2、3、4，R选自3～8元环烷基、3～8元杂环烷基。The Z is selected from Wherein * is connected to ring B, p is selected from 0, 1, 2, 3, 4, and R is selected from 3-8 membered cycloalkyl and 3-8 membered heterocycloalkyl.根据权利要求1所述的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药，其中，所述化合物具有式(II)所示的结构，
The compound according to claim 1, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein the compound has a structure represented by formula (II),
X、Y各自独立地选自CR⁰或N且不同时为N，所述R⁰选自氢、氘、氚、硝基、羟基、巯基、卤素、氰基、胺基、酯基、醛基、羧基、羰基、酰胺基、C₁～C₆烷基、C₁～C₆卤代烷基、C₁～C₆烷氧基、C₁～C₆卤代烷氧基、C₁～C₆羟基烷基，X and Y are each independently selected from CR⁰ or N and are not N at the same time, and the R⁰ is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C₁ ～C₆ alkyl, C₁ ～C₆ haloalkyl, C₁ ～C₆ alkoxy, C₁ ～C₆ haloalkoxy, C₁ ～C₆ hydroxyalkyl,W²、W³各自独立地选自CH或N，W² and W³ are each independently selected from CH or N,W¹为不存在、CH或N，W⁴选自C或N，W⁵选自C＝O、CH或N，且当W¹为不存在或者当W⁵为C＝O时，W⁴为N，^W1 is absent, CH or N,^W4 is selected from C or N,^W5 is selected from C=O, CH or N, and when^W1 is absent or when^W5 is C=O,^W4 is N,R^C各自独立地选自氘、氚、硝基、羟基、巯基、卤素、氰基、胺基、酯基、醛基、羧基、羰基、酰胺基、C₁～C₆烷基、C₁～C₆卤代烷基、C₁～C₆烷氧基、C₁～C₆卤代烷氧基、C₁～C₆羟基烷基，q选自0、1、2、3，R and^C are each independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C₁ ～C₆ alkyl, C₁ ～C 6 haloalkyl, C₁ ～C₆ alkoxy, C₁ ～C₆ haloalkoxy, C₁ ～C₆ hydroxyalkyl, q is selected from 0,_1, 2, 3,Z选自其中*与环B相连，p选自0、1、2、3、4，R选自氢、氘、氚、硝基、羟基、醛基、胺基、卤素、氰基、酯基、羧基、酰胺基、C₁～C₆烷基、C₁～C₆烷氧基、C₁～C₆卤代烷基、C₁～C₆卤代烷氧基、C₁～C₆羟基烷基；Z is selected from wherein * is connected to ring B, p is selected from 0, 1, 2, 3, 4, and R is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, aldehyde, amine, halogen, cyano, ester, carboxyl, amide, C₁ ～C₆ alkyl, C₁ ～C₆ alkoxy, C₁ ～C₆ haloalkyl, C₁ ～C₆ haloalkoxy, C₁ ～C₆ hydroxyalkyl;优选地，所述化合物具有式(II-a)至(II-g)所示的任一结构，

Preferably, the compound has any structure shown in formula (II-a) to (II-g),

根据权利要求1所述的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药，其中，所述化合物具有式(III)所示的结构，
The compound according to claim 1, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein the compound has a structure represented by formula (III),
X、Y各自独立地选自CR⁰或N且不同时为N，所述R⁰选自氢、氘、氚、硝基、羟基、巯基、卤素、氰基、胺基、酯基、醛基、羧基、羰基、酰胺基、C₁～C₆烷基、C₁～C₆卤代烷基、C₁～C₆烷氧基、C₁～C₆卤代烷氧基、C₁～C₆羟基烷基，X and Y are each independently selected from CR⁰ or N and are not N at the same time, and the R⁰ is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C₁ ～C₆ alkyl, C₁ ～C₆ haloalkyl, C₁ ～C₆ alkoxy, C₁ ～C₆ haloalkoxy, C₁ ～C₆ hydroxyalkyl,W¹为不存在、CH或N，W⁴选自C或N，W⁵选自C＝O、CH或N，且当W¹为不存在或者当W⁵为C＝O时，W⁴为N，^W1 is absent, CH or N,^W4 is selected from C or N,^W5 is selected from C=O, CH or N, and when^W1 is absent or when^W5 is C=O,^W4 is N,V¹、V²、V³各自独立地选自CH、N、NH、O、S，且V¹、V²、V³不同时为CH，V¹ , V² , and V³ are each independently selected from CH, N, NH, O, and S, and V¹ , V² , and V³ are not CH at the same time,R^C各自独立地选自氘、氚、硝基、羟基、巯基、卤素、氰基、胺基、酯基、醛基、羧基、羰基、酰胺基、C₁～C₆烷基、C₁～C₆卤代烷基、C₁～C₆烷氧基、C₁～C₆卤代烷氧基、C₁～C₆羟基烷基，q选自0、1、2、3，R and^C are each independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C₁ ～C₆ alkyl, C₁ ～C 6 haloalkyl, C₁ ～C₆ alkoxy, C₁ ～C₆ haloalkoxy, C₁ ～C₆ hydroxyalkyl, q is selected from 0,_1, 2, 3,Z选自其中*与环B相连，p选自0、1、2、3、4，R选自氢、氘、氚、硝基、羟基、醛基、胺基、卤素、氰基、酯基、羧基、酰胺基、C₁～C₆烷基、C₁～C₆烷氧基、C₁～C₆卤代烷基、C₁～C₆卤代烷氧基、C₁～C₆羟基烷基；Z is selected from wherein * is connected to ring B, p is selected from 0, 1, 2, 3, 4, and R is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, aldehyde, amine, halogen, cyano, ester, carboxyl, amide, C₁ ～C₆ alkyl, C₁ ～C₆ alkoxy, C₁ ～C₆ haloalkyl, C₁ ～C₆ haloalkoxy, C₁ ～C₆ hydroxyalkyl;优选地，所述W¹、W⁵均为CH，W⁴为C。Preferably, W¹ and W⁵ are both CH, and W⁴ is C.根据权利要求6所述的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药，其中，所述化合物具有式(III-a)至(III-f)所示的任一结构，

The compound according to claim 6, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein the compound has any structure shown in formula (III-a) to (III-f),

根据权利要求1～7任意一项所述的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药，其中，所述R⁰选自氢、氘、氚、硝基、羟基、巯基、氟、氯、溴、碘、氰基、醛基、羧基、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃、-N(CH₂CH₃)₂、-C(O)OCH₃、-C(O)OCH₂CH₃、-C(O)O(CH₂)₂CH₃、-C(O)OCH(CH₃)₂、-OC(O)CH₃、-OC(O)CH₂CH₃、-OC(O)(CH₂)₂CH₃、-OC(O)CH(CH₃)₂、-COCH₃、-COCH₂CH₃、-CO(CH₂)₂CH₃、-COCH(CH₃)₂、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-NHCOH、-NHCOCH₃、-N(CH₃)COCH₃、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、三氟甲基、三氟乙基、三氯甲基、三氯乙基、三氟甲氧基、三氟乙氧基、三氯甲氧基、三氯乙氧基、羟甲基、1-羟乙基、2-羟乙基、1-羟基正丙基、2-羟基正丙基、3-羟基正丙基；和/或The compound according to any one of claims 1 to 7, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein the R⁰ is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, -NH₂ , -NHCH₃ , -N(CH₃ )₂ , -NHCH₂ CH₃ , -N(CH₂ CH₃ )₂ , -C(O)OCH₃ , -C(O)OCH₂ CH₃ , -C(O)O(CH₂ )₂ CH₃ , -C(O)OCH(CH₃ )₂ , -OC(O)CH₃ , -OC(O)CH₂ CH₃ , -OC(O)(CH₂ )₂ CH₃ , -OC(O)CH(CH₃ )₂ , -COCH₃ , -COCH₂ CH₃ , -CO(CH₂ )₂ CH₃ , -COCH(CH₃ )₂ , -CONH₂ , -CONHCH₃ , -CON(CH₃ )₂ , -NHCOH, -NHCOCH₃ , -N(CH₃ )COCH₃ , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-n-propyl; and/or所述R^A选自氘、氚、硝基、羟基、巯基、氟、氯、溴、碘、氰基、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃、-N(CH₂CH₃)₂、-C(O)OCH₃、-C(O)OCH₂CH₃、-C(O)O(CH₂)₂CH₃、-C(O)OCH(CH₃)₂、-OC(O)CH₃、-OC(O)CH₂CH₃、-OC(O)(CH₂)₂CH₃、-OC(O)CH(CH₃)₂、醛基、羧基、-COCH₃、-COCH₂CH₃、-CO(CH₂)₂CH₃、-COCH(CH₃)₂、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-NHCOH、-NHCOCH₃、-N(CH₃)COCH₃、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、三氟甲基、三氟乙基、三氯甲基、三氯乙基、三氟甲氧基、三氟乙氧基、三氯甲氧基、三氯乙氧基、羟甲基、1-羟乙基、2-羟乙基、1-羟基正丙基、2-羟基正丙基、3-羟基正丙基；和/或The^RA is selected from deuterium, tritium, nitro, hydroxyl, thiol,_fluorine , chlorine, bromine, iodine, cyano,_-NH2 , -NHCH3, -N(_CH3)2 ,_-NHCH2CH3 , -N(_CH2CH3 )₂ , -C(O)_OCH3 ,_-C (O)OCH2CH3, -C(_O )O(CH2_)2CH3, -C(O)OCH(_CH3 )₂ , -OC(_O )_CH3 , -OC(O_)CH2CH3, -OC(_O )(CH2)_2CH3 , -OC(O)CH(_CH3 )₂ , aldehyde, carboxyl,_-COCH3 ,_{-COCH2CH3,-CO(CH2)2CH3,-COCH} (_CH3)2 ,_-CONH2 ,_-CONHCH3 , -CON(_CH3 )₂ , -NHCOH,_-NHCOCH3 , -N(_CH3 )_COCH3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-n-propyl; and/or所述R^B选自氘、氚、硝基、羟基、巯基、氟、氯、溴、碘、氰基、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃、-N(CH₂CH₃)₂、-C(O)OCH₃、-C(O)OCH₂CH₃、-C(O)O(CH₂)₂CH₃、-C(O)OCH(CH₃)₂、-OC(O)CH₃、-OC(O)CH₂CH₃、-OC(O)(CH₂)₂CH₃、-OC(O)CH(CH₃)₂、醛基、羧基、-COCH₃、-COCH₂CH₃、-CO(CH₂)₂CH₃、-COCH(CH₃)₂、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-NHCOH、-NHCOCH₃、-N(CH₃)COCH₃、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、三氟甲基、三氟乙基、三氯甲基、三氯乙基、三氟甲氧基、三氟乙氧基、三氯甲氧基、三氯乙氧基、羟甲基、1-羟乙基、2-羟乙基、1-羟基正丙基、2-羟基正丙基、3-羟基正丙基、环丙基、环丁基、环戊基、环己基、环丙氧基、环丁氧基、环戊氧基。The^RB is selected from deuterium, tritium, nitro, hydroxyl, thiol,_fluorine , chlorine, bromine, iodine, cyano,_-NH2 , -NHCH3, -N(_CH3)2 ,_-NHCH2CH3 , -N(_CH2CH3 )₂ , -C(O)_OCH3 ,_-C (O)OCH2CH3, -C(_O )O(CH2_)2CH3, -C(O)OCH(_CH3 )₂ , -OC(_O )_CH3 , -OC(O_)CH2CH3, -OC(_O )(CH2)_2CH3 , -OC(O)CH(_CH3 )₂ , aldehyde, carboxyl,_-COCH3 ,_{-COCH2CH3,-CO(CH2)2CH3,-COCH} (_CH3)2 , -CONH₂ , -CONHCH₃ , -CON(CH₃ )₂ , -NHCOH, -NHCOCH₃ , -N(CH₃ )COCH₃ , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-n-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxy, and cyclopentyloxy.根据权利要求4-7任意一项所述的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药，其中，所述R选自氢、氘、氚、硝基、羟基、巯基、氟、氯、溴、碘、氰基、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃、-N(CH₂CH₃)₂、-C(O)OCH₃、-C(O)OCH₂CH₃、-C(O)O(CH₂)₂CH₃、-C(O)OCH(CH₃)₂、-OC(O)CH₃、-OC(O)CH₂CH₃、-OC(O)(CH₂)₂CH₃、-OC(O)CH(CH₃)₂、醛基、羧基、-COCH₃、-COCH₂CH₃、-CO(CH₂)₂CH₃、-COCH(CH₃)₂、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-NHCOH、-NHCOCH₃、-N(CH₃)COCH₃、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、三氟甲基、三氟乙基、三氯甲基、三氯乙基、三氟甲氧基、三氟乙氧基、三氯甲氧基、三氯乙氧基、羟甲基、1-羟乙基、2-羟乙基、1-羟基正丙基、2-羟基正丙基、3-羟基正丙基，优选地，所述R选自环丙基、环丁基、环戊基、环己基、环丙氧基、环丁氧基、环戊氧基。The compound according to any one of claims 4 to 7, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein R is selected from hydrogen, deuterium, tritium, nitro, hydroxyl_, thiol, fluorine, chlorine, bromine, iodine, cyano,_-NH2 , -NHCH3, -N(_CH3 )_2, -NHCH2CH3, -N(_CH2CH3 )₂ , -C(_O)OCH3 , -C(O)_OCH2CH3 , -C(O₎ O(CH2)_2CH3 , -C(O)OCH(_CH3 )₂ , -OC₍ O)_CH3 ,_-OC (O_)CH2CH3 , -OC(O)(_CH2 )_2CH3 , -OC(_O )CH(_CH3 )₂ , aldehyde group, carboxyl group, -COCH₃ , -COCH₂ CH₃ , -CO(CH₂ )₂ CH₃ , -COCH(CH₃ )₂ , -CONH₂ , -CONHCH₃ , -CON(CH₃ )₂ , -NHCOH, -NHCOCH₃ , -N(CH₃ )COCH₃ , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-n-propyl, preferably, R is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxy, and cyclopentyloxy.根据权利要求5～7任意一项所述的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药，其中，所述所述R^C选自氘、氚、硝基、羟基、巯基、氟、氯、溴、碘、氰基、-NH₂、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃、-N(CH₂CH₃)₂、-C(O)OCH₃、-C(O)OCH₂CH₃、-C(O)O(CH₂)₂CH₃、-C(O)OCH(CH₃)₂、-OC(O)CH₃、-OC(O)CH₂CH₃、-OC(O)(CH₂)₂CH₃、-OC(O)CH(CH₃)₂、醛基、羧基、-COCH₃、-COCH₂CH₃、-CO(CH₂)₂CH₃、-COCH(CH₃)₂、-CONH₂、-CONHCH₃、-CON(CH₃)₂、-NHCOH、-NHCOCH₃、-N(CH₃)COCH₃、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、三氟甲基、三氟乙基、三氯甲基、三氯乙基、三氟甲氧基、三氟乙氧基、三氯甲氧基、三氯乙氧基、羟甲基、1-羟乙基、2-羟乙基、1-羟基正丙基、2-羟基正丙基、3-羟基正丙基。The compound according to any one of claims 5 to 7, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein the^RC is selected from_deuterium , tritium, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine, cyano,_-NH2 ,_-NHCH3 , -N(_CH3 )₂ ,_-NHCH2CH3 , -N(_CH2CH3 )₂ , -C(_O)OCH3 , -C(O)_OCH2CH3 , -C(O)O(CH2)_2CH3 , -C(O)OCH(_CH3 )₂ , -OC(O)_CH3 ,_-OC (O_{)CH2CH3, -OC(O)(CH2)2CH3,-OC(O)} CH(_CH3 )₂ , aldehyde group, carboxyl group, -COCH₃ , -COCH₂ CH₃ , -CO(CH₂ )₂ CH₃ , -COCH(CH₃ )₂ , -CONH₂ , -CONHCH₃ , -CON(CH₃ )₂ , -NHCOH, -NHCOCH₃ , -N(CH₃ )COCH₃ , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-n-propyl.根据权利要求1～7任意一项所述的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药，其中，所述环A选自6～10元芳环、5～10元芳杂环、3～14元饱和脂环、3～14元不饱和脂环、3～14元不饱和脂杂环、芳环与不饱和脂环构成的7～14元并环、芳杂环与不饱和脂环构成的7～14元并环、芳环与不饱和脂杂环构成的7～14元并环、芳杂环与不饱和脂杂环构成的7～14元并环，所述芳杂环包含1～4个各自独立地选自N、O、S的杂原子，所述不饱和脂杂环包含1～2个各自独立地选自N、O、S的杂原子；优选地，所述环A选自和/或The compound according to any one of claims 1 to 7, its stereoisomer, its tautomer or mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein the ring A is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocyclic ring, a 3-14 membered saturated alicyclic ring, a 3-14 membered unsaturated alicyclic ring, a 3-14 membered unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic heterocyclic ring and an unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic heterocyclic ring and an unsaturated alicyclic ring, and a 7-14 membered paracyclic ring consisting of an aromatic heterocyclic ring and an unsaturated alicyclic ring, wherein the aromatic heterocyclic ring contains 1 to 4 heteroatoms independently selected from N, O, and S, and the unsaturated alicyclic heterocyclic ring contains 1 to 2 heteroatoms independently selected from N, O, and S; preferably, the ring A is selected from and/or所述环B选自6～10元芳环、5～10元芳杂环、3～14元饱和脂杂环、3～14元不饱和脂杂环、芳环与不饱和脂环构成的7～14元并环、芳杂环与不饱和脂环构成的7～14元并环、芳环与不饱和脂杂环构成的7～14元并环、芳杂环与不饱和脂杂环构成的7～14元并环，所述芳杂环包含1～4个各自独立地选自N、O、S的杂原子，所述饱和脂杂环、不饱和脂杂环各自包含1～2个独立地选自N、O、S的杂原子；优选地，所述环B选自The ring B is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-14 membered saturated alicyclic ring, a 3-14 membered unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, and a 7-14 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, wherein the aromatic heterocycle contains 1-4 heteroatoms independently selected from N, O, and S, and the saturated alicyclic heterocycle and the unsaturated alicyclic heterocycle each contain 1-2 heteroatoms independently selected from N, O, and S; preferably, the ring B is selected from据权利要求1～4任意一项所述的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药，其中，The compound according to any one of claims 1 to 4, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein:X、Y各自独立地选自CR⁰或N，R⁰选自氢、氘、氚、羟基、氟、氯、溴、胺基和甲基；X, Y are each independently selected from CR⁰ or N, R⁰ is selected from hydrogen, deuterium, tritium, hydroxyl, fluorine, chlorine, bromine, amino and methyl;Z为C₁～C₆亚烷基，所述Z任选地被氘、氚、硝基、羟基、醛基、胺基、亚胺基、卤素、氰基或＝O中的任一个取代；Z is a C₁ -C₆ alkylene group, and the Z is optionally substituted by any one of deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano or =O;W²、W³均为C，或者W²、W³各自独立地选自CR²，每个R²独立地选自氢、氘、氚、硝基、羟基、巯基、卤素、氰基、胺基、C₁～C₆烷基、C₁～C₆卤代烷基、C₁～C₆烷氧基和C₁～C₆卤代烷氧基；W² and W³ are both C, or W² and W³ are each independently selected from CR² , and each R² is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, C₁ ～C₆ alkyl, C₁ ～C₆ haloalkyl, C₁ ～C₆ alkoxy and C₁ ～C₆ haloalkoxy;W¹为CR¹或N，R¹选自氢、氘、氚、羟基、卤素、胺基、C₁～C₆烷基和C₁～C₆卤代烷基；W¹ is CR¹ or N, and R¹ is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, amine, C₁ ～C₆ alkyl and C₁ ～C₆ haloalkyl;W⁴为C；W⁴ is C;W⁵为CR³，R³选自氢、氘、氚、羟基、卤素、胺基、C₁～C₆烷基、C₁～C₆卤代烷基；W⁵ is CR³ , and R³ is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, amine, C₁ ～C₆ alkyl, C₁ ～C₆ haloalkyl;表示芳香环； represents an aromatic ring;环C为不存在、5～6元芳杂环或5～6元不饱和脂杂环，环C任选地被氘、氚或C₁～C₆烷基取代；Ring C is absent, a 5- to 6-membered aromatic heterocycle or a 5- to 6-membered unsaturated aliphatic heterocycle, and Ring C is optionally substituted by deuterium, tritium or C₁ -C₆ alkyl;环A选自C₆～C₁₀芳环、5～10元芳杂环、C₅～C₁₀饱和脂环、C₅～C₁₀不饱和脂环、C₆～C₁₀芳环与C₅～C₁₀不饱和脂环构成的并环、6～10元芳杂环与C₅～C₁₀不饱和脂环构成的并环；Ring A is selected from a C₆ ～C₁₀ aromatic ring, a 5- to₁₀ -membered aromatic heterocyclic ring, a C₅ ～C_{10 saturated alicyclic ring, a C 5 ～C 10unsaturated} alicyclic ring, a cyclic ring formed by a_{C 6～} C₁₀ aromatic ring and a C 5 ～C₁₀ unsaturated alicyclic ring, and a cyclic ring formed by a 6- to 10-membered aromatic heterocyclic ring and a C₅ ～C₁₀ unsaturated alicyclic ring;环B选自C₆～C₁₀芳环、5～10元芳杂环、C₃～C₁₀饱和脂杂环、5～10元不饱和脂杂环、5～10元芳杂环与C₅～C₁₀不饱和脂环构成的并环、C₆～C₁₀芳环与5～10元不饱和脂杂环构成的并环；Ring B is selected from a C₆ ～C₁₀ aromatic ring, a 5～10 membered aromatic heterocyclic ring, a C₃ ～C₁₀ saturated alicyclic heterocyclic ring, a 5～10 membered unsaturated alicyclic heterocyclic ring, a 5～10 membered aromatic heterocyclic ring and a C₅ ～C₁₀ unsaturated alicyclic ring, and a C₆ ～C₁₀ aromatic ring and a 5～10 membered unsaturated alicyclic heterocyclic ring.m、n、o各自独立地为0、1或2；m, n, and o are each independently 0, 1, or 2;R^A选自氘、氚、羟基、卤素、C₁～C₆烷基和C₁～C₆卤代烷基；^RA is selected from the group consisting of deuterium, tritium, hydroxyl, halogen,_C1 -_C6 alkyl and_C1 -_C6 haloalkyl;R^B选自氘、氚、羟基、氰基、胺基、C₁～C₆烷基和C₁～C₆卤代烷基，R^B任选地被氘、氚或卤素取代；^RB is selected from deuterium, tritium, hydroxyl, cyano, amine,_C1 -_C6 alkyl and_C1 -_C6 haloalkyl, and^RB is optionally substituted by deuterium, tritium or halogen;所述芳杂环、不饱和脂杂环、饱和脂杂环各自独立地包含1～3个杂原子，所述杂原子独立地选自N、O、S；The aromatic heterocycle, unsaturated aliphatic heterocycle, and saturated aliphatic heterocycle each independently contain 1 to 3 heteroatoms, and the heteroatoms are independently selected from N, O, and S;优选地，Preferably,X、Y各自独立地选自CR⁰或N且不同时为N，R⁰各自独立地选自氢、氘和氚，X, Y are each independently selected from CR⁰ or N and are not N at the same time, R⁰ are each independently selected from hydrogen, deuterium and tritium,Z选自其中*与环B相连，p为0、1或2，R选自氢、氘、氚、羟基、C₁～C₆烷基和C₁～C₆羟基烷基，Z is selected from wherein * is connected to ring B, p is 0, 1 or 2, and R is selected from hydrogen, deuterium, tritium, hydroxyl, C₁ ～C₆ alkyl and C₁ ～C₆ hydroxyalkyl,W²、W³均为C，或者W²、W³各自独立地选自CR²，每个R²独立地选自氢、氘、氚、卤素、氰基、C₁～C₆烷基、C₁～C₆卤代烷基、C₁～C₆烷氧基和C₁～C₆卤代烷氧基，W² and W³ are both C, or W² and W³ are each independently selected from CR² , and each R² is independently selected from hydrogen, deuterium, tritium, halogen, cyano, C₁ ～C₆ alkyl, C₁ ～C₆ haloalkyl, C₁ ～C₆ alkoxy and C₁ ～C₆ haloalkoxy,W¹为CR¹或N，R¹独立地选自氢、氘、氚、卤素、C₁～C₆烷基和C₁～C₆卤代烷基，W¹ is CR¹ or N, R¹ is independently selected from hydrogen, deuterium, tritium, halogen, C₁ ～C₆ alkyl and C₁ ～C₆ haloalkyl,W⁴为C，W⁴ is C,W⁵为CR³，R³独立地选自氢、氘、氚、卤素、C₁～C₆烷基和C₁～C₆卤代烷基，W⁵ is CR³ , R³ is independently selected from hydrogen, deuterium, tritium, halogen, C₁ ～C₆ alkyl and C₁ ～C₆ haloalkyl,表示芳香环， represents an aromatic ring,环C为不存在或包含1～2个杂原子的5～6元芳杂环，所述杂原子选自N、O、S，所述环C任选地被氘、氚或C₁～C₆烷基取代，Ring C is a 5-6 membered aromatic heterocyclic ring without or containing 1-2 heteroatoms, wherein the heteroatoms are selected from N, O, and S, and the ring C is optionally substituted by deuterium, tritium, or C₁ -C₆ alkyl.环A选自Ring A is selected from环B选自Ring B is selected fromm、n、o各自为0、1或2，m, n, o are each 0, 1 or 2,R^A选自氘、氚、卤素、C₁～C₆烷基、和C₁～C₆卤代烷基，^RA is selected from deuterium, tritium, halogen,_C1 -_C6 alkyl, and_C1 -_C6 haloalkyl,R^B选自氘、氚、胺基和C₁～C₆烷基。^RB is selected from deuterium, tritium, an amine group and a_C1 -_C6 alkyl group.据权利要求1～12任意一项所述的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药，其中，所述化合物选自：


The compound according to any one of claims 1 to 12, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein the compound is selected from:


一种药物组合物，包含至少一种权利要求1～13中任一项所述的化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药，和至少一种药学上可接受的辅料。A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 13, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, and at least one pharmaceutically acceptable excipient.用作药物的根据权利要求1～13中任一项所述的化合物、立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药、或根据权利要求14所述的药物组合物；A compound, stereoisomer, tautomer or mixture thereof according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, for use as a medicament, or a pharmaceutical composition according to claim 14;优选地，所述药物为TEAD抑制剂；Preferably, the drug is a TEAD inhibitor;更优选地，所述药物用于治疗与TEAD表达增加或TEAD活性增加相关的疾病或病症；More preferably, the medicament is used to treat a disease or condition associated with increased TEAD expression or increased TEAD activity;还更优选地，所述药物用于治疗肿瘤细胞增殖性疾病(例如间皮瘤肿瘤细胞增殖性疾病、恶性胸膜间皮瘤肿瘤细胞增殖性疾病)、抑制肿瘤的侵袭和转移、降低靶向药或化疗药物的耐药、降低肿瘤的免疫逃逸、治疗多囊肾病或肝纤维化；Still more preferably, the drug is used to treat tumor cell proliferative diseases (such as mesothelioma tumor cell proliferative diseases, malignant pleural mesothelioma tumor cell proliferative diseases), inhibit tumor invasion and metastasis, reduce resistance to targeted drugs or chemotherapeutic drugs, reduce tumor immune escape, treat polycystic kidney disease or liver fibrosis;甚至更优选地，所述药物用于治疗听力神经瘤、急性白血病、急性淋巴细胞性白血病、急性骨髓性白血病(例如单核细胞性、粒细胞性、腺癌、血管肉瘤、星形细胞瘤、髓单核细胞和早幼粒细胞性)、急性T细胞白血病、基底细胞癌、胆管癌、膀胱癌、脑癌、乳腺癌、支气管癌、宫颈癌、软骨肉瘤、脊索瘤、绒毛膜癌、慢性白血病、慢性淋巴细胞性白血病、慢性骨髓细胞性白血病、慢性粒细胞性白血病、结肠癌、结直肠癌、颅咽管瘤、囊腺癌、弥漫性大B细胞淋巴瘤、不良增殖变化(发育异常和化生)、胚胎性癌、子宫内膜癌、内皮肉瘤、室管膜瘤、上皮癌、红白血病、食道癌、雌激素受体阳性乳腺癌、原发性血小板增多症、尤因氏肿瘤、纤维肉瘤、滤泡性淋巴瘤、生殖细胞睾丸癌、胶质瘤、成胶质细胞瘤、间皮瘤、肝细胞癌、脑膜瘤、恶性周围神经鞘瘤、施万细胞瘤、肺癌、膀胱癌、皮肤神经纤维瘤、前列腺癌、胰腺癌、胶质母细胞瘤、子宫内膜腺鳞状癌、未分化甲状腺癌、胃腺癌、食管腺癌、卵巢癌、卵巢浆液性腺癌、黑素瘤和乳腺癌。Even more preferably, the medicament is used to treat acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (e.g. monocytic, granulocytic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, undesirable Proliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial carcinoma, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, schwannoma, lung cancer, bladder cancer, cutaneous neurofibroma, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid cancer, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.