WO2023045816A1 - Benzocycloheptane compound as axl inhibitor - Google Patents

Abstract

A benzocycloheptane compound as an AXL inhibitor and a preparation method therefor. The structure of the benzocycloheptane compound is represented by general formula I. The benzocycloheptane compound has AXL inhibitory activity, and can be used as an AXL inhibitor.

Description

作为AXL抑制剂的苯并环庚烷类化合物Benzocycloheptanes as AXL Inhibitors 技术领域technical field

本发明属于医药技术领域，特别涉及嘧啶类化合物，所述化合物是AXL激酶抑制剂。本发明还涉及使用该化合物治疗与AXL活性相关的疾病。The invention belongs to the technical field of medicine, and particularly relates to pyrimidine compounds, which are AXL kinase inhibitors. The invention also relates to the use of the compounds in the treatment of diseases associated with AXL activity.

背景技术Background technique

受体酪氨酸激酶(RTK)是多域跨膜蛋白，可作为细胞外配体的传感器。配体受体结合诱导受体二聚化并激活其胞内激酶结构域，继而导致多个下游信号级联反应的募集、磷酸化和激活(Robinson,D.R.等,Oncogene,19:5548-5557,2000)。迄今为止，已在人类基因组中鉴定出58个RTK，它们可调节多种细胞过程，包括细胞存活、生长、分化、增殖、粘附和运动(Segaliny,A.I.等,J.Bone Oncol,4:1-12,2015)。Receptor tyrosine kinases (RTKs) are multidomain transmembrane proteins that serve as sensors of extracellular ligands. Ligand-receptor binding induces receptor dimerization and activation of its intracellular kinase domain, which in turn leads to the recruitment, phosphorylation and activation of multiple downstream signaling cascades (Robinson, D.R. et al., Oncogene, 19:5548-5557, 2000). To date, 58 RTKs have been identified in the human genome that regulate a variety of cellular processes, including cell survival, growth, differentiation, proliferation, adhesion, and motility (Segaliny, A.I. et al., J. Bone Oncol, 4:1 -12, 2015).

AXL(又称为UFO、ARK和Tyro7)属于受体酪氨酸激酶TAM家族，该家族成员还包括Mer和Tyro3。其中，AXL和Tyro3具有最为相似的基因结构，而AXL和Mer具有最为相似的酪氨酸激酶域氨基酸序列。与其他受体酪氨酸激酶(RTKs)一样，TAM家族的结构包含胞外域、跨膜域和保守的胞内激酶域。AXL的细胞外结构域具有独特的使免疫球蛋白和III型纤维连接蛋白重复单元并置的结构并且使人联想到中性细胞粘附分子的结构。TAM家族成员有1个共同配体—生长抑制特异性蛋白6(Gas6)，该配体能够与所有TAM受体酪氨酸激酶结合。AXL与Gas6结合后，会导致受体二聚化和AXL自磷酸化，从而激活下游多条信号转导通路，并参与肿瘤发生的多个过程(Linger,R.M等，Ther.Targets，14(10),1073-1090，2010；Rescigno,J.等，Oncogene,6(10),1909-1913，1991)。AXL (also known as UFO, ARK, and Tyro7) belongs to the TAM family of receptor tyrosine kinases, which also includes Mer and Tyro3. Among them, AXL and Tyro3 have the most similar gene structure, while AXL and Mer have the most similar amino acid sequence of tyrosine kinase domain. Like other receptor tyrosine kinases (RTKs), the structure of the TAM family consists of an extracellular domain, a transmembrane domain, and a conserved intracellular kinase domain. The extracellular domain of AXL has a unique structure that juxtaposes immunoglobulin and type III fibronectin repeat units and is reminiscent of a neutrophil adhesion molecule. TAM family members have a common ligand—growth arrest specific protein 6 (Gas6), which can bind to all TAM receptor tyrosine kinases. After AXL binds to Gas6, it will lead to receptor dimerization and AXL autophosphorylation, thereby activating multiple downstream signal transduction pathways and participating in multiple processes of tumorigenesis (Linger, R.M et al., Ther.Targets, 14(10 ), 1073-1090, 2010; Rescigno, J. et al., Oncogene, 6(10), 1909-1913, 1991).

AXL广泛表达于人体正常组织，如单核细胞、巨噬细胞、血小板、内皮细胞、小脑、心脏、骨骼肌、肝脏和肾脏等，其中心肌和骨骼肌表达最高，骨髓CD34+细胞和基质细胞也有较高的表达，正常淋巴组织表达很低(Wu YM,Robinson DR,Kung HJ,Cancer Res,64(20),7311-7320,2004；hung BI等，DNA Cell Biol,22(8)，533-540，2003)。在对许多癌细胞的研究中发现，在造血细胞、***和内皮细胞中，AXL基因都存在着超表达或异位表达。在各类白血病和多数的实体瘤中，AXL激酶的超表达现象尤为突出。通过抑制AXL受体酪氨酸激酶可以降低肿瘤细胞的促存活信号、阻滞肿瘤的侵袭能力，增加靶向药物治疗和化疗敏感度。因此寻找有效的AXL抑制剂是当前肿瘤靶向药物研发的重要方向。AXL is widely expressed in normal tissues of the human body, such as monocytes, macrophages, platelets, endothelial cells, cerebellum, heart, skeletal muscle, liver, and kidney, among which the expression is highest in cardiac muscle and skeletal muscle, and bone marrow CD34+ cells and stromal cells also have a higher expression High expression, very low expression in normal lymphoid tissue (Wu YM, Robinson DR, Kung HJ, Cancer Res, 64(20), 7311-7320, 2004; hung BI et al., DNA Cell Biol, 22(8), 533-540 , 2003). In the study of many cancer cells, it was found that AXL gene was overexpressed or ectopically expressed in hematopoietic cells, mesenchymal cells and endothelial cells. In various leukemias and most solid tumors, the overexpression of AXL kinase is particularly prominent. Inhibition of AXL receptor tyrosine kinase can reduce the pro-survival signals of tumor cells, block the invasion ability of tumors, and increase the sensitivity of targeted drug therapy and chemotherapy. Therefore, finding effective AXL inhibitors is an important direction for the development of tumor-targeted drugs.

发明内容Contents of the invention

一方面，本发明提供了一种式I所示的苯并环庚烷类化合物或其药学上可接受的盐，In one aspect, the present invention provides a benzocycloheptane compound represented by formula I or a pharmaceutically acceptable salt thereof,

其中，R ¹、R ²为卤素； Wherein, R ¹ and R ² are halogen;

R ³独立的选自：氢、氘、卤素、C _1-6烷基、C _1-6烷氧基、

其中所述的C _1-6烷基或C _1-6烷氧基任选地被羟基、卤素、氰基或C _1-3烷氧基取代； R ³ is independently selected from: hydrogen, deuterium, halogen, C _1-6 alkyl, C _1-6 alkoxy,

Wherein said C _1-6 alkyl or C _1-6 alkoxy is optionally substituted by hydroxyl, halogen, cyano or C _1-3 alkoxy;

R ⁴、R ⁵独立的选自C _1-6烷基、羟基、C _2-6烯基或C _2-6炔基； R ⁴ and R ⁵ are independently selected from C _1-6 alkyl, hydroxyl, C _2-6 alkenyl or C _2-6 alkynyl;

m选自1-3的整数。m is an integer selected from 1-3.

在一些实施方案中，R ¹为氟。 In some embodiments, R ¹ is fluoro.

在一些实施方案中，R ²为氯。 In some embodiments, R ² is chloro.

在一些实施方案中，R ³独立的选自氘、卤素、C _1-6烷基、

In some embodiments, R ³ is independently selected from deuterium, halogen, C _1-6 alkyl,

在一些典型的实施方案中，R ³独立的选自C _1-6烷基或

In some typical embodiments, R ³ is independently selected from C _1-6 alkyl or

在一些典型实施方案中，R ³独立的选自C _1-3烷基或

In some typical embodiments, R ³ is independently selected from C _1-3 alkyl or

在一些更为典型的实施方案中，R ³独立的选自甲基或

In some more typical embodiments, R ³ is independently selected from methyl or

在一些实施方案中，R ⁴、R ⁵独立的选自C _1-6烷基。 In some embodiments, R ⁴ and R ⁵ are independently selected from C _1-6 alkyl groups.

在一些典型的实施方案中，R ⁴、R ⁵独立的选自C _1-3烷基。 In some typical embodiments, R ⁴ and R ⁵ are independently selected from C _1-3 alkyl groups.

在一些更为典型的实施方案中，R ⁴、R ⁵为甲基。 In some more typical embodiments, R ⁴ and R ⁵ are methyl.

在一些更为典型的实施方案中，R ³独立的选自甲基或

In some more typical embodiments, R ³ is independently selected from methyl or

在一些实施方案中，m为1或2。In some embodiments, m is 1 or 2.

在一些典型的实施方案中，m为2。In some exemplary embodiments, m is 2.

在一些实施方案中，前述式I化合物具有如式II所示的结构或其药学上可接受的盐：In some embodiments, the aforementioned compound of formula I has a structure as shown in formula II or a pharmaceutically acceptable salt thereof:

其中，R ¹、R ²、R ³的定义与式I化合物中的定义一致； Wherein, the definitions of R ¹ , R ² , and R ³ are consistent with those in the compound of formula I;

R ⁶选自：氘、卤素、C _1-6烷基或C _1-6烷氧基，其中所述的C _1-6烷基或C _1-6烷氧基任选地可以被一个或多个氘、甲氧基、羟基、卤素或氰基所取代。 R ⁶ is selected from: deuterium, halogen, C _1-6 alkyl or C _1-6 alkoxy, wherein said C _1-6 alkyl or C _1-6 alkoxy can optionally be replaced by one or more Deuterium, methoxy, hydroxyl, halogen or cyano are substituted.

在一些实施方案中，R ⁶选自：氘、卤素或C _1-6烷基。 In some embodiments, R ⁶ is selected from: deuterium, halogen, or C _1-6 alkyl.

在一些实施方案中，R ⁶为C _1-6烷基。 In some embodiments, R ⁶ is C _1-6 alkyl.

在一些典型实施方案中，R ⁶为C _1-3烷基。 In some typical embodiments, R ⁶ is C _1-3 alkyl.

在一些更为典型实施方案中，R ⁶为甲基。 In some more typical embodiments, R ⁶ is methyl.

在一些实施方案中，前述式II化合物具有如式Ⅲ所示的结构或其药学上可接受的盐：In some embodiments, the aforementioned compound of formula II has a structure as shown in formula III or a pharmaceutically acceptable salt thereof:

其中，R ¹的定义与式I化合物中的定义一致。 Wherein, the definition of ^R is consistent with the definition in the compound of formula I.

在一些典型的实施方案中，R ¹为氟。 In some typical embodiments, R ¹ is fluoro.

在一些实施方案中，前述式III化合物具有如式IV所示的结构或其药学上可接受的盐：In some embodiments, the aforementioned compound of formula III has a structure as shown in formula IV or a pharmaceutically acceptable salt thereof:

其中，R ¹定义与式I化合物中的定义一致。 Wherein, the definition of ^R is consistent with the definition in the compound of formula I.

在一些典型的实施方案中，R ¹为氟。在一些实施方案中，前述式III化合物具有如式V所示的结构或其药学上可接受的盐： In some typical embodiments, R ¹ is fluoro. In some embodiments, the aforementioned compound of formula III has a structure as shown in formula V or a pharmaceutically acceptable salt thereof:

其中，R ¹定义与式I化合物中的定义一致。 Wherein, the definition of ^R is consistent with the definition in the compound of formula I.

在一些典型的实施方案中，R ¹为氟。 In some typical embodiments, R ¹ is fluoro.

在一些实施方案中，前述式IV化合物具有如式IV-I所示的结构或其药学上可接受的盐：In some embodiments, the aforementioned compound of formula IV has a structure as shown in formula IV-I or a pharmaceutically acceptable salt thereof:

其中，R ¹定义与式I化合物中的定义一致。 Wherein, the definition of ^R is consistent with the definition in the compound of formula I.

在一些实施方案中，前述式IV-I的化合物具有如式IV-I-I或IV-I-II所示的结构或其药学上可接受的盐：In some embodiments, the aforementioned compound of formula IV-I has a structure as shown in formula IV-I-I or IV-I-II or a pharmaceutically acceptable salt thereof:

其中，R ¹定义与式I化合物中的定义一致。 Wherein, the definition of ^R is consistent with the definition in the compound of formula I.

在一些实施方案中，前述式IV化合物具有如式IV-II所示的结构或其药学上可接受的盐：In some embodiments, the aforementioned compound of formula IV has a structure as shown in formula IV-II or a pharmaceutically acceptable salt thereof:

其中，R ¹定义与式I化合物中的定义一致。 Wherein, the definition of ^R is consistent with the definition in the compound of formula I.

在一些实施方案中，前述式IV-II化合物具有如式IV-II-I或IV-II-II所示的结构或其药学上可接受的盐：In some embodiments, the aforementioned compound of formula IV-II has a structure as shown in formula IV-II-I or IV-II-II or a pharmaceutically acceptable salt thereof:

其中，R ¹定义与式I化合物中的定义一致。 Wherein, the definition of ^R is consistent with the definition in the compound of formula I.

在一些实施方案中，前述式V化合物具有如式V-I所示的结构或其药学上可接受的盐：In some embodiments, the aforementioned compound of formula V has a structure as shown in formula V-I or a pharmaceutically acceptable salt thereof:

其中，R ¹定义与式I化合物中的定义一致。 Wherein, the definition of ^R is consistent with the definition in the compound of formula I.

在一些实施方案中，前述式V-I化合物具有如式V-I-I或式V-I-II所示的结构或其药学上可接受的盐：In some embodiments, the aforementioned compound of formula V-I has a structure as shown in formula V-I-I or formula V-I-II or a pharmaceutically acceptable salt thereof:

其中，R ¹定义与式I化合物中的定义一致。 Wherein, the definition of ^R is consistent with the definition in the compound of formula I.

在一些实施方案中，前述式V化合物具有如式V-II所示的结构或其药学上可接受的盐：In some embodiments, the aforementioned compound of formula V has a structure as shown in formula V-II or a pharmaceutically acceptable salt thereof:

其中，R ¹定义与式I化合物中的定义一致。 Wherein, the definition of ^R is consistent with the definition in the compound of formula I.

在一些实施方案中，前述式V-II化合物具有如式V-II-I或式V-II-II所示的结构或其药学上可接受的盐：In some embodiments, the aforementioned compound of formula V-II has a structure as shown in formula V-II-I or formula V-II-II or a pharmaceutically acceptable salt thereof:

其中，R ¹定义与式I化合物中的定义一致。 Wherein, the definition of ^R is consistent with the definition in the compound of formula I.

在一些特定的实施方案中，本发明提供了以下化合物，或其药学上可接受的盐，In some specific embodiments, the present invention provides the following compounds, or pharmaceutically acceptable salts thereof,

在一些特定的实施方案中，本发明提供了以下化合物，或其药学上可接受的盐，In some specific embodiments, the present invention provides the following compounds, or pharmaceutically acceptable salts thereof,

另一方面，本发明还提供了一种药物组合物，其包含治疗有效量的式I、II、III、IV、IV-I、IV-II、IV-I-I、IV-I-II、IV-II-I、IV-II-II、V、V-I、V-II、V-I-I、V-I-II、V-II-I或V-II-II化合物或其药学上可接受的盐。On the other hand, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of formula I, II, III, IV, IV-I, IV-II, IV-I-I, IV-I-II, IV- II-I, IV-II-II, V, V-I, V-II, V-I-I, V-I-II, V-II-I or V-II-II compound or a pharmaceutically acceptable salt thereof.

在一些实施方案中，本发明还提供了一种药物组合物，其包含治疗有效量的式I、II、III、IV、IV-I、IV-II、IV-I-I、IV-I-II、IV-II-I、IV-II-II、V、V-I、V-II、V-I-I、V-I-II、V-II-I或V-II-II化合物或其药学上可接受的盐，以及一种或多种药学上可接受的载体。In some embodiments, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of formula I, II, III, IV, IV-I, IV-II, IV-I-I, IV-I-II, IV-II-I, IV-II-II, V, V-I, V-II, V-I-I, V-I-II, V-II-I or V-II-II compound or a pharmaceutically acceptable salt thereof, and a or multiple pharmaceutically acceptable carriers.

本发明所述的药物组合物可以通过任何适用的途径或方法给药，例如通过口服或肠胃外(例如，静脉内)给药。式I、II、III、IV、IV-I、IV-II、IV-I-I、IV-I-II、IV-II-I、IV-II-II、V、V-I、V-II、V-I-I、V-I-II、V-II-I或V-II-II化合物的治疗有效量为从约0.001mg到50mg/Kg体重/天，优选从0.01mg到50mg/Kg体重/天。The pharmaceutical compositions described herein may be administered by any suitable route or method, such as orally or parenterally (eg, intravenously). Formula I, II, III, IV, IV-I, IV-II, IV-I-I, IV-I-II, IV-II-I, IV-II-II, V, V-I, V-II, V-I-I, V-I - The therapeutically effective amount of compound II, V-II-I or V-II-II is from about 0.001 mg to 50 mg/Kg body weight/day, preferably from 0.01 mg to 50 mg/Kg body weight/day.

对于口服途径给药，本发明的药物组合物通常以片剂、胶囊剂或溶液的形式提供。片剂可以包含本发明的化合物或其药学上可接受的盐以及药学上可接受的载体。所述载体包括但不限于稀释剂、崩解剂、粘合剂、润滑剂、着色剂或防腐剂。胶囊剂包括硬胶囊剂和软胶囊剂。For oral administration, the pharmaceutical compositions of the present invention are generally provided in the form of tablets, capsules or solutions. Tablets may contain a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The carrier includes, but is not limited to, diluents, disintegrants, binders, lubricants, colorants or preservatives. Capsules include hard capsules and soft capsules.

对于胃肠道外途径给药，本发明的药物组合物可以通过静脉内注射、肌内注射或皮下注射给药。其通常以无菌水溶液或混悬液或冻干粉末提供，并调节合适的pH和等渗性。For parenteral administration, the pharmaceutical composition of the present invention can be administered by intravenous injection, intramuscular injection or subcutaneous injection. It is usually provided as a sterile aqueous solution or suspension, or as a lyophilized powder, adjusted to appropriate pH and isotonicity.

另一方面，本发明还提供了式I、II、III、IV、IV-I、IV-II、IV-I-I、IV-I-II、IV-II-I、IV-II-II、V、V-I、V-II、V-I-I、V-I-II、V-II-I或V-II-II化合物在制备用于预防和/或治疗AXL蛋白激酶介导的疾病或疾病状态的药物中的用途。On the other hand, the present invention also provides formula I, II, III, IV, IV-I, IV-II, IV-I-I, IV-I-II, IV-II-I, IV-II-II, V, Use of compounds V-I, V-II, V-I-I, V-I-II, V-II-I or V-II-II in the preparation of medicines for preventing and/or treating diseases or disease states mediated by AXL protein kinase.

另一方面，本发明还提供了用于预防和/或治疗AXL蛋白激酶介导的疾病或疾病状态的方法，其包括向有需要的个体给予本发明的式I、II、III、IV、IV-I、IV-II、IV-I-I、IV-I-II、IV-II-I、IV-II-II、V、V-I、V-II、V-I-I、V-I-II、V-II-I或V-II-II化合物或本发明的药物组合物。On the other hand, the present invention also provides methods for preventing and/or treating diseases or disease states mediated by AXL protein kinase, which comprises administering the formula I, II, III, IV, IV of the present invention to individuals in need -I, IV-II, IV-I-I, IV-I-II, IV-II-I, IV-II-II, V, V-I, V-II, V-I-I, V-I-II, V-II-I or V -II-II compound or the pharmaceutical composition of the present invention.

另一方面，本发明还提供了用于预防和/或治疗AXL蛋白激酶介导的疾病或疾病状态的本发明的式I、II、III、IV、IV-I、IV-II、IV-I-I、IV-I-II、IV-II-I、IV-II-II、V、V-I、V-II、V-I-I、V-I-II、V-II-I或V-II-II化合物或本发明的药物组合物。On the other hand, the present invention also provides the formula I, II, III, IV, IV-I, IV-II, IV-I-I of the present invention for preventing and/or treating AXL protein kinase-mediated diseases or disease states , IV-I-II, IV-II-I, IV-II-II, V, V-I, V-II, V-I-I, V-I-II, V-II-I or V-II-II compound or the medicine of the present invention combination.

所述AXL蛋白激酶介导的疾病或疾病状态的实例包括但不限于自身免疫性疾病。Examples of such AXL protein kinase mediated diseases or conditions include, but are not limited to, autoimmune diseases.

另一方面，本发明提供一种制备式I、II、III、IV、IV-I、IV-II、IV-I-I、IV-I-II、IV-II-I、IV-II-II、V、V-I、V-II、V-I-I、V-I-II、V-II-I或V-II-II化合物的方法，包括但不限于以下合成方案：On the other hand, the present invention provides a kind of preparation formula I, II, III, IV, IV-I, IV-II, IV-I-I, IV-I-II, IV-II-I, IV-II-II, V , V-I, V-II, V-I-I, V-I-II, V-II-I or V-II-II compound methods, including but not limited to the following synthetic schemes:

其中，R ¹、R ²、R ³、m的定义与式I化合物中的定义一致， Wherein, the definitions of R ¹ , R ² , R ³ , and m are consistent with those in the compound of formula I,

R ^a、R ^b独立的选自卤素。 R ^a and R ^b are independently selected from halogen.

在一些实施方案中R ^a为氯。 In some embodiments R ^a is chloro.

在一些实施方案中R ^b为氯。 In some embodiments ^Rb is chloro.

式H-1、式H-2的化合物在溶剂(例如N,N-二甲基甲酰胺或四氢呋喃)、碱(例如N,N-二异丙基乙基胺或六甲基二硅基胺基锂)的条件下制备式H-3化合物，H-4化合物在溶剂(例如乙腈中)制备发生氟代反应制备H-5化合物,H-5化合物在还原剂(例如钯碳)发生反应制备H-6化合物,化合物H-3与化合物H-6在溶剂(例如异丙醇)发生亲核取代反应生成H-7化合物,H-7在溶剂(例如二氯甲烷)中与吡咯烷反应制备式I化合物。The compound of formula H-1, formula H-2 is in solvent (for example N,N-dimethylformamide or tetrahydrofuran), base (for example N, N-diisopropylethylamine or hexamethyldisilazylamine Formula H-3 compound is prepared under the condition of lithium base), H-4 compound is prepared in a solvent (such as acetonitrile) by fluorination reaction to prepare H-5 compound, and H-5 compound is prepared by reacting in a reducing agent (such as palladium carbon) Compound H-6, compound H-3 and compound H-6 undergo a nucleophilic substitution reaction in a solvent (such as isopropanol) to generate compound H-7, and H-7 is prepared by reacting with pyrrolidine in a solvent (such as dichloromethane) Compound of formula I.

进一步的，本发明提供以下化合物作为合成式I化合物的中间体：Further, the present invention provides the following compounds as intermediates for the synthesis of compounds of formula I:

相关定义related definition

除非有特定说明，下列用在说明书和权利要求书中的术语具有下述含义：Unless otherwise specified, the following terms used in the specification and claims have the following meanings:

本发明“化合物”可以是不对称的，例如，具有一个或多个手性中心。除非另有说明，本发明的“化合物”指的是任意一种立体异构体或两种或两种以上的立体异构体的混合物。立体异构体包括但不限于对映异构体和非对映异构体。本发明的含有不对称碳原子的化合物可以以光学活性纯的形式或两种或两种以上的立体异构体的混合物的形式被分离出来。光学活性纯的形式可以从两种或两种以上的立体异构体的混合物中进行拆分，或通过使用手性原料或手性试剂合成。A "compound" of the invention may be asymmetric, eg, possess one or more chiral centers. Unless otherwise specified, the "compound" of the present invention refers to any one stereoisomer or a mixture of two or more stereoisomers. Stereoisomers include, but are not limited to, enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of the present invention can be isolated in an optically active pure form or in the form of a mixture of two or more stereoisomers. Optically pure forms can be resolved from mixtures of two or more stereoisomers, or synthesized by using chiral starting materials or reagents.

本发明，当式I化合物的m为2或3时，R ³可以独立的选自相同或者不同的基团，例如，m为2时，一个R ³可以为甲基，另一个R ³可以为氯。 In the present invention, when the m of the compound of formula I is 2 or 3, R ³ can be independently selected from the same or different groups, for example, when m is 2, one R ³ can be methyl, and the other R ³ can be chlorine.

术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes that said event or circumstance occurs and that it does not.

本文中的数字范围，是指给定范围中的各个整数。例如，“C _1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。 Numerical ranges herein refer to individual integers within a given range. For example, "C _1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

术语“取代”是指特定原子或基团上的任意一个或多个氢原子被取代基取代，只要特定原子或基团的价态是正常的并且取代后的化合物是稳定的。The term "substituted" means that any one or more hydrogen atoms on a specific atom or group are replaced by a substituent, as long as the valence of the specific atom or group is normal and the substituted compound is stable.

当任何变量(例如R ³)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被一个或多个R ³所取代，则在每种情况下的R ³都有独立的选项。例如，当式I化合物的m为2时，一个R ³可以为甲基，另一个R ³可以为氯。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。 When any variable (eg ^R3 ) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. Thus, for example, if a group is substituted by one or more ^R3 , there are independent options for ^R3 in each case. For example, when m of the compound of formula I is 2, one ^R3 can be methyl and the other ^R3 can be chloro. Also, combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.

术语“烷基”指饱和的脂族烃基团，包括直链的或支链的饱和烃基，所述烃基具有所示出的碳原子数。如术语“C _1-6烷基”包括C ₁烷基、C ₂烷基、C ₃烷基、C ₄烷基、C ₅烷基、C ₆烷基，实例包括，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、2-戊基、3-戊基、正己基、2-己基、3-己基等。其可以是二价的，例如亚甲基、亚乙基。 The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight or branched chain saturated hydrocarbon groups, having the indicated number of carbon atoms. For example, the term "C _1-6 alkyl" includes C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, C ₆ alkyl, examples include, but are not limited to, methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, 3-hexyl, etc. It can be divalent, eg methylene, ethylene.

术语“烷氧基”指具有烷基-O-结构的基团，烷基为包括直链的或支链的饱和一价烃基。如“C ₁₃烷氧基”包括甲氧基、乙氧基、正丙氧基、异丙氧基。 The term "alkoxy" refers to a group having an alkyl-O-structure, and the alkyl group includes a linear or branched saturated monovalent hydrocarbon group. For example, "C ₁₃ alkoxy" includes methoxy, ethoxy, n-propoxy, isopropoxy.

术语

中的

是指化学键连接处。 the term

middle

Refers to the chemical bond connection.

术语“卤素”指氟、氯、溴和碘。The term "halogen" refers to fluorine, chlorine, bromine and iodine.

术语“C _2-6烯基”用于表示直链或支链的包含至少一个碳-碳双键的由2至6个碳原子组成的碳氢基团，碳-碳双键可以位于该基团的任何位置上。实例包括但不限于乙烯基、丙烯基、丁烯基、戊烯基、己烯基等。 The term " _C2-6 alkenyl" is used to denote a straight or branched chain hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond which may be located in the group anywhere in the regiment. Examples include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, and the like.

术语“C _2-6炔基”用于表示直链或支链的包含至少一个碳-碳三键的由2至6个碳原子组成的碳氢基团，碳-碳三键可以位于该基团的任何位置上。实例包括但不限于乙炔基、丙炔基、丁炔基等。术语“氘取代”是指化合物或基团中的一个或多个C-H键被C-D键取代，氘取代可以是一取代、二取代、多取代或全取代。所述“氘代”方法采用本领域的常规方法，例如，可使用商品化氘代原料，或按照现有技术中公开的方法在化合物中引入氘。 The term " _C2-6 alkynyl" is used to denote a straight or branched chain hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond which may be located in the group anywhere in the regiment. Examples include, but are not limited to, ethynyl, propynyl, butynyl, and the like. The term "deuterium substitution" means that one or more CH bonds in a compound or group are replaced by CD bonds, and the deuterium substitution can be monosubstitution, disubstitution, multiple substitution or full substitution. The "deuteration" method adopts conventional methods in the art, for example, commercially available deuterated raw materials can be used, or deuterium can be introduced into the compound according to the method disclosed in the prior art.

术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。The term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a non-toxic drug or agent to achieve the desired effect.

术语“药学上可接受的载体”是指对机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些载体。包括但不限于国家食品药品监督管理局许可的可于人或动物的任何稀释剂、崩解剂、粘合剂、助流剂、润湿剂。The term "pharmaceutically acceptable carrier" refers to those carriers that have no obvious stimulating effect on the body and will not impair the biological activity and performance of the active compound. Including but not limited to any diluents, disintegrants, binders, glidants, and wetting agents approved by the State Food and Drug Administration that can be used on humans or animals.

术语“药学上可接受盐”是指保留了特定化合物的游离酸和碱的生物学效力而没有生物学不良作用的盐。例如酸(包括有机酸和无机酸)加成盐或碱(包括有机碱和无机碱)加成盐。The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acids and bases of the specified compound without adverse biological effects. For example acid (including organic and inorganic acids) addition salts or base (including organic and inorganic bases) addition salts.

如无特殊说明，本发明的简称具有如下含义：Unless otherwise specified, the abbreviation of the present invention has the following meanings:

M：mol/LM: mol/L

mM：mmol/LmM: mmol/L

nM：nmol/LnM: nmol/L

¹H NMR：核磁共振氢谱 ¹ H NMR: Proton Magnetic Resonance Spectroscopy

MS(ESI+)：质谱MS(ESI+): mass spectrum

DMSO-d ₆:氘代二甲基亚砜 DMSO-d ₆ : deuterated dimethyl sulfoxide

CDCl _3:氘代氯仿 CDCl _3: deuterated chloroform

DTT：二硫苏糖醇DTT: Dithiothreitol

SEB：Supplemented Enzymatic Buffer(补充酶缓冲液)SEB: Supplemented Enzymatic Buffer (Supplemented Enzymatic Buffer)

IMDM(Iscove's Modified Dulbecco's Medium):Iscove(人名)改良的Dulbecco(人名)培养基。IMDM (Iscove's Modified Dulbecco's Medium): Iscove (person's name) modified Dulbecco (person's name) medium.

室温：25℃。Room temperature: 25°C.

具体实施方式Detailed ways

下面更具体地描述本发明的化合物的制备方法，但这些具体的制备方法不对本发明的范围构成任何限制。此外，反应条件如反应物、溶剂、碱、所用化合物的量、反应温度、反应时间等不限于下面的实例。The preparation methods of the compounds of the present invention are described in more detail below, but these specific preparation methods do not constitute any limitation to the scope of the present invention. In addition, reaction conditions such as reactants, solvents, bases, amounts of compounds used, reaction temperature, reaction time, etc. are not limited to the following examples.

本发明的化合物还可以任选地将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便制得，这样的组合可由本领域的技术人员容易地进行。The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this description or known in the art, and such combinations can be easily performed by those skilled in the art.

第一部分制备Part I preparation

制备例1(2-((2,5-二氯嘧啶-4-基)氨基)-5-甲基苯基)二甲基氧化膦的制备Preparation Example 1 Preparation of (2-((2,5-dichloropyrimidin-4-yl)amino)-5-methylphenyl)dimethylphosphine oxide

a)(2-氨基-5-甲基苯基)二甲基氧化膦的制备a) Preparation of (2-amino-5-methylphenyl) dimethylphosphine oxide

依次向反应瓶中加入2-碘-4-甲基苯胺(1g)，二甲基氧化磷(505mg)，醋酸钯(97mg)，4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(249mg)，磷酸钾(1.35g)，15mL N,N-二甲基甲酰胺和3mL水溶解，氮气保护升温至110℃反应3h。反应完毕后冷却至室温，过滤除去不溶性无机盐和催化剂，滤液减压浓缩后加入30mL水稀释，用1M的盐酸调节pH至2，过滤除去不溶物，滤液经二氯甲烷洗涤后分出水层，水层以1M的氢氧化钠溶液调节pH至9后以二氯甲烷萃取，分出有机相，无水硫酸钠干燥，抽滤，减压浓缩至干，得标题产物0.6g。MS(ESI+):184.1(M+H).Add 2-iodo-4-methylaniline (1g), dimethylphosphorus oxide (505mg), palladium acetate (97mg), 4,5-bis(diphenylphosphine)-9,9- Dimethylxanthene (249mg), potassium phosphate (1.35g), 15mL N,N-dimethylformamide and 3mL water were dissolved, and the temperature was raised to 110°C under nitrogen protection for 3 hours. Cool to room temperature after the reaction is complete, filter to remove insoluble inorganic salts and catalysts, concentrate the filtrate under reduced pressure and add 30 mL of water to dilute, adjust the pH to 2 with 1M hydrochloric acid, filter to remove insoluble matter, and separate the water layer after washing the filtrate with dichloromethane. The aqueous layer was adjusted to pH 9 with 1M sodium hydroxide solution and extracted with dichloromethane. The organic phase was separated, dried over anhydrous sodium sulfate, filtered with suction, and concentrated to dryness under reduced pressure to obtain 0.6 g of the title product. MS(ESI+):184.1(M+H).

b)(2-((2,5-二氯嘧啶-4-基)氨基)-5-甲基苯基)二甲基氧化膦的制备b) Preparation of (2-((2,5-dichloropyrimidin-4-yl)amino)-5-methylphenyl)dimethylphosphine oxide

依次向反应瓶中加入(2-氨基-5-甲基苯基)二甲基氧化膦(0.55g)，2,4,5-三氯嘧啶(0.73g)，N,N-二异丙基乙基胺(0.65g)，N,N-二甲基甲酰胺(20ml)，80℃下搅拌反应5小时，反应完减压蒸馏蒸干，残余物用乙醇(8ml)结晶得到标题产物(0.6g)。MS(ESI+):330.1(M+H).Add (2-amino-5-methylphenyl) dimethylphosphine oxide (0.55g), 2,4,5-trichloropyrimidine (0.73g), N,N-diisopropyl Ethylamine (0.65g), N,N-dimethylformamide (20ml), stirred and reacted at 80°C for 5 hours, evaporated to dryness under reduced pressure after the reaction, and the residue was crystallized with ethanol (8ml) to obtain the title product (0.6 g). MS(ESI+):330.1(M+H).

制备例2 2-氨基-8-氟-5,6,8,9-四氢-7H-苯并[7]轮烯-7-酮和2-氨基-6-氟-5,6,8,9-四氢-7H-苯并[7]轮烯-7-酮的制备Preparation Example 2 2-amino-8-fluoro-5,6,8,9-tetrahydro-7H-benzo[7]annulen-7-one and 2-amino-6-fluoro-5,6,8, Preparation of 9-tetrahydro-7H-benzo[7]annulen-7-one

a)8-氟-2-硝基-5,6,8,9-四氢-7H-苯并[7]轮烯-7-酮和6-氟-2-硝基-5,6,8,9-四氢-7H-苯并[7]轮烯-7-酮的制备a) 8-fluoro-2-nitro-5,6,8,9-tetrahydro-7H-benzo[7]annulen-7-one and 6-fluoro-2-nitro-5,6,8 , Preparation of 9-tetrahydro-7H-benzo[7]annulen-7-one

室温下向反应瓶中加入2-硝基-5,6,8,9-四氢苯并[7]环烯-7-酮(3.0g)，乙腈(45ml)，1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)盐(15.54g)，80℃条件下搅拌过夜。反应液在室温下用水(200ml)淬灭，然后用乙酸乙酯萃取3次(60mL×3)，乙酸乙酯层用饱和氯化钠溶液洗涤3次(15mL×3)，有机层用无水硫酸钠干燥，浓缩至干得标题化合物的混合物(2.0g)。MS(ESI+):224.1(M+H)。Add 2-nitro-5,6,8,9-tetrahydrobenzo[7]cycloen-7-one (3.0g), acetonitrile (45ml), 1-chloromethyl-4 -Fluoro-1,4-diazidebicyclo2.2.2octanebis(tetrafluoroborate) salt (15.54g), stirred overnight at 80°C. The reaction solution was quenched with water (200ml) at room temperature, then extracted 3 times with ethyl acetate (60mL×3), the ethyl acetate layer was washed 3 times with saturated sodium chloride solution (15mL×3), and the organic layer was washed with anhydrous Dry over sodium sulfate and concentrate to dryness to give a mixture of title compounds (2.0 g). MS (ESI+): 224.1 (M+H).

b)2-氨基-8-氟-5,6,8,9-四氢-7H-苯并[7]轮烯-7-酮和2-氨基-6-氟-5,6,8,9-四氢-7H-苯并[7]轮烯 -7-酮的制备b) 2-Amino-8-fluoro-5,6,8,9-tetrahydro-7H-benzo[7]annulen-7-one and 2-amino-6-fluoro-5,6,8,9 -Preparation of tetrahydro-7H-benzo[7]annulen-7-one

向反应瓶中加入甲醇(6ml)，8-氟-2-硝基-5,6,8,9-四氢-7H-苯并[7]轮烯-7-酮和6-氟-2-硝基-5,6,8,9-四氢-7H-苯并[7]轮烯-7-酮的混合物(200mg)，钯碳(40mg，10％w/w)，反应液在40℃、氢气氛围下搅拌3小时。反应液冷却至室温后用硅藻土过滤，乙酸乙酯洗涤滤饼(3ml×3)，滤液减压条件下浓缩，再用乙酸乙酯(10ml)稀释，氯化氢水溶液(1M)调节至pH＝3，减压浓缩，得到标题产物的混合物(100mg)。MS(ESI+):194.1(M+H).Add methanol (6ml), 8-fluoro-2-nitro-5,6,8,9-tetrahydro-7H-benzo[7]annolene-7-one and 6-fluoro-2- Nitro-5,6,8,9-tetrahydro-7H-benzo[7]annolene-7-one mixture (200mg), palladium on carbon (40mg, 10%w/w), the reaction solution at 40°C , and stirred under a hydrogen atmosphere for 3 hours. After the reaction solution was cooled to room temperature, it was filtered with diatomaceous earth, the filter cake was washed with ethyl acetate (3ml×3), the filtrate was concentrated under reduced pressure, diluted with ethyl acetate (10ml), and adjusted to pH = 3. Concentrate under reduced pressure to obtain a mixture of title products (100 mg). MS(ESI+):194.1(M+H).

实施例1化合物1-8的制备The preparation of embodiment 1 compound 1-8

a)2-((5-氯-4-((2-(二甲基磷酰基)-4-甲基苯基)氨基)嘧啶-2-基)氨基)-8-氟-5,6,8,9-四氢-7H-苯并[7]轮烯-7-酮和2-((5-氯-4-((2-(二甲基磷酰基)-4-甲基苯基)氨基)嘧啶-2-基)氨基)-6-氟-5,6,8,9-四氢-7H-苯并[7]轮烯-7-酮的制备a) 2-((5-chloro-4-((2-(dimethylphosphoryl)-4-methylphenyl)amino)pyrimidin-2-yl)amino)-8-fluoro-5,6, 8,9-tetrahydro-7H-benzo[7]annulen-7-one and 2-((5-chloro-4-((2-(dimethylphosphoryl)-4-methylphenyl) Preparation of amino)pyrimidin-2-yl)amino)-6-fluoro-5,6,8,9-tetrahydro-7H-benzo[7]annulen-7-one

向反应瓶中依次加入异丙醇(10ml)，2,5-二氯-N-[2-(二甲基磷酰基)-4-甲基苯基]嘧啶-4-胺(300mg)，2-氨基-8-氟-5,6,8,9-四氢-7H-苯并[7]轮烯-7-酮和2-氨基-6-氟-5,6,8,9-四氢-7H-苯并[7]轮烯-7-酮的混合物(220mg)，搅拌下滴入氯化氢的二氧六环溶液(0.5ml，4N)，氮气保护，反应混合物在130℃下用微波辐射照射30分钟，减压浓缩得 标题产物的混合物(370mg)。MS(ESI+):487.2(M+H).In the reaction flask, add isopropanol (10ml), 2,5-dichloro-N-[2-(dimethylphosphoryl)-4-methylphenyl]pyrimidin-4-amine (300mg), 2 -Amino-8-fluoro-5,6,8,9-tetrahydro-7H-benzo[7]annulen-7-one and 2-amino-6-fluoro-5,6,8,9-tetrahydro -7H-benzo[7]annulen-7-one mixture (220mg), hydrogen chloride dioxane solution (0.5ml, 4N) was added dropwise under stirring, under nitrogen protection, the reaction mixture was irradiated with microwave at 130°C Irradiated for 30 minutes, concentrated under reduced pressure to obtain a mixture of title products (370 mg). MS(ESI+):487.2(M+H).

b)(2-((5-氯-2-((7S，8S)-8-氟-7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-甲基苯基)二甲基氧化膦和(2-((5-氯-2-((7S，8S)-6-氟-7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)嘧啶-4-基)氨基)-5-甲基苯基)二甲基氧化膦的制备b) (2-((5-chloro-2-((7S,8S)-8-fluoro-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo [7] annulen-2-yl)amino)pyrimidin-4-yl)amino)-5-methylphenyl)dimethylphosphine oxide and (2-((5-chloro-2-((7S, 8S )-6-fluoro-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)amino)pyrimidin-4-yl) Preparation of amino)-5-methylphenyl)dimethylphosphine oxide

向反应瓶中依次加入2-((5-氯-4-((2-(二甲基磷酰基)-4-甲基苯基)氨基)嘧啶-2-基)氨基)-8-氟-5,6,8,9-四氢-7H-苯并[7]轮烯-7-酮和2-((5-氯-4-((2-(二甲基磷酰基)-4-甲基苯基)氨基)嘧啶-2-基)氨基)-6-氟-5,6,8,9-四氢-7H-苯并[7]轮烯-7-酮的混合物(370mg)，二氯甲烷(8ml)，吡咯烷(108mg)，无水硫酸镁(300mg)，氮气保护，35℃反应1小时，向反应液中加入氰基硼氢化钠(143mg)，室温下搅拌2小时。过滤所得混合物，用二氯甲烷(3x 10mL)洗涤滤饼。母液减压浓缩，所得残余物采用反相高效液相色谱法纯化(柱：XBridge-Prep-OBD C18柱，30×150mm，填料粒径5μm；流动相A:10mmol/L碳酸氢铵水溶液，流动相B:乙腈；流速：60mL/min；梯度：25％B～53％B，10min；检测波长：220nm；，得到了标题产物的混合物A(4个异构体混合物，保留时间:9.57min)和混合物B(4个异构体混合物，保留时间:10.07min)。Add 2-((5-chloro-4-((2-(dimethylphosphoryl)-4-methylphenyl)amino)pyrimidin-2-yl)amino)-8-fluoro- 5,6,8,9-tetrahydro-7H-benzo[7]annulen-7-one and 2-((5-chloro-4-((2-(dimethylphosphoryl)-4-methan A mixture of (370 mg) di Chloromethane (8ml), pyrrolidine (108mg), anhydrous magnesium sulfate (300mg), under nitrogen protection, react at 35°C for 1 hour, add sodium cyanoborohydride (143mg) to the reaction solution, and stir at room temperature for 2 hours. The resulting mixture was filtered and the filter cake was washed with dichloromethane (3 x 10 mL). The mother liquor was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase high-performance liquid chromatography (column: XBridge-Prep-OBD C18 column, 30 × 150mm, packing particle size 5 μm; mobile phase A: 10mmol/L ammonium bicarbonate aqueous solution, mobile Phase B: acetonitrile; Flow rate: 60mL/min; Gradient: 25%B～53%B, 10min; Detection wavelength: 220nm;, obtained mixture A of the title product (4 isomer mixture, retention time: 9.57min) and mixture B (mixture of 4 isomers, retention time: 10.07 min).

混合物A:MS(ESI+):542.2(M+H)Mixture A: MS(ESI+):542.2(M+H)

混合物B:MS(ESI+):542.2(M+H)Mixture B: MS(ESI+):542.2(M+H)

步骤c)异构体的拆分Step c) resolution of isomers

异构体混合物A用手性液相色谱进行了手性拆分(柱：Chiralpak IF，2x25cm，填料粒径5μm；流动相A:甲基叔丁基醚(0.1％二乙胺)，流动相B:甲醇；流速：20ml/min；梯度：9min内50％B等梯度；检测波长：220/254nm)，分别得到了异构体1，异构体2，以及异构体3、4的混合物30mg。Isomer mixture A was chirally resolved by chiral liquid chromatography (column: Chiralpak IF, 2x25cm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: Methanol; Flow rate: 20ml/min; Gradient: 50% B isogradient within 9min; Detection wavelength: 220/254nm), obtained isomer 1, isomer 2, and the mixture of isomer 3, 4 respectively 30mg.

异构体1(13.5mg)，手性HPLC保留时间为4.6min。Isomer 1 (13.5mg), chiral HPLC retention time is 4.6min.

¹HNMR(400MHz,DMSO-d6,ppm):δ10.94(s,1H),9.28(s,1H),8.40(s,1H),8.15(s,1H),7.46(m,1H),7.41(m,1H),7.34(m,2H),6.98(m,1H),4.96(m,1H),3.23(m,1H),2.95–2.76(m,2H),2.64(m,6H),2.34(s,3H),1.76(m,7H),1.68(s,5H).MS(ESI+):542.2(M+H) ¹ HNMR(400MHz,DMSO-d6,ppm):δ10.94(s,1H),9.28(s,1H),8.40(s,1H),8.15(s,1H),7.46(m,1H),7.41 (m,1H),7.34(m,2H),6.98(m,1H),4.96(m,1H),3.23(m,1H),2.95–2.76(m,2H),2.64(m,6H), 2.34(s,3H),1.76(m,7H),1.68(s,5H).MS(ESI+):542.2(M+H)

异构体2(7.6mg)，手性HPLC保留时间为5.9min。Isomer 2 (7.6mg), chiral HPLC retention time is 5.9min.

¹HNMR(400MHz,DMSO-d6,ppm):δ10.92(s,1H),9.29(s,1H),8.39(s,1H),8.15(s,1H),7.53–7.38(m,2H),7.31(m,2H),7.02(m,1H),4.95(m,1H),3.30(m,1H), 3.00–2.80(m,1H),2.74(m,1H),2.68–2.56(m,5H),2.34(m,4H),1.76(m,7H),1.68(m,5H).MS(ESI+):542.2(M+H) ^1HNMR (400MHz,DMSO-d6,ppm):δ10.92(s,1H),9.29(s,1H),8.39(s,1H),8.15(s,1H),7.53–7.38(m,2H) ,7.31(m,2H),7.02(m,1H),4.95(m,1H),3.30(m,1H), 3.00–2.80(m,1H),2.74(m,1H),2.68–2.56(m ,5H),2.34(m,4H),1.76(m,7H),1.68(m,5H).MS(ESI+):542.2(M+H)

异构体3、4的混合物30mg用手性液相色谱进行了手性拆分(Chiralpak IF，2x25cm，填料粒径5μm；流动相A:甲基叔丁基醚(0.1％二乙胺)，流动相B:乙醇；流速：20ml/min；梯度：25min内10％B等梯度；检测波长：220/254nm)，分别得到了异构体3，异构体4。30 mg of the mixture of isomers 3 and 4 was subjected to chiral resolution by chiral liquid chromatography (Chiralpak IF, 2×25 cm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), Mobile phase B: ethanol; flow rate: 20ml/min; gradient: 10% B isogradient within 25min; detection wavelength: 220/254nm), obtained isomer 3 and isomer 4 respectively.

异构体3(11.2mg)，手性HPLC保留时间为18.2min。Isomer 3 (11.2mg), chiral HPLC retention time is 18.2min.

¹HNMR(400MHz,DMSO-d6,ppm):δ10.94(s,1H),9.29(s,1H),8.41(s,1H),8.15(s,1H),7.53–7.39(m,2H),7.34(m,2H),6.98(m,1H),5.10–4.81(m,1H),3.24(m,1H),2.96–2.75(m,2H),2.71–2.55(m,6H),2.34(s,3H),1.76(m,7H),1.68(s,5H).MS(ESI+):542.2(M+H) ¹ HNMR(400MHz,DMSO-d6,ppm):δ10.94(s,1H),9.29(s,1H),8.41(s,1H),8.15(s,1H),7.53–7.39(m,2H) ,7.34(m,2H),6.98(m,1H),5.10–4.81(m,1H),3.24(m,1H),2.96–2.75(m,2H),2.71–2.55(m,6H),2.34 (s,3H),1.76(m,7H),1.68(s,5H).MS(ESI+):542.2(M+H)

异构体4(4.4mg)，手性HPLC保留时间为22.2min。Isomer 4 (4.4mg), chiral HPLC retention time is 22.2min.

¹HNMR(400MHz,DMSO-d6,ppm):δ10.92(s,1H),9.29(s,1H),8.39(s,1H),8.15(s,1H),7.53–7.38(m,2H),7.31(m,2H),7.02(m,1H),4.95(m,1H),3.30(m,1H),3.00–2.80(m,1H),2.74(m,1H),2.68–2.56(m,6H),2.34(s,3H),1.76(m,7H),1.68(m,5H).MS(ESI+):542.2(M+H) ^1HNMR (400MHz,DMSO-d6,ppm):δ10.92(s,1H),9.29(s,1H),8.39(s,1H),8.15(s,1H),7.53–7.38(m,2H) ,7.31(m,2H),7.02(m,1H),4.95(m,1H),3.30(m,1H),3.00–2.80(m,1H),2.74(m,1H),2.68–2.56(m ,6H),2.34(s,3H),1.76(m,7H),1.68(m,5H).MS(ESI+):542.2(M+H)

异构体混合物B用手性液相色谱进行了手性拆分(Chiralpak IF，2x25cm，填料粒径5μm；流动相A:甲基叔丁基醚(0.1％二乙胺)，流动相B:甲醇；流速：20ml/min；梯度：17min内50％B等梯度；检测波长：220/254nm)，分别得到了异构体5，异构体6，以及异构体7、8的混合物30mg。Isomer mixture B was chirally resolved by chiral liquid chromatography (Chiralpak IF, 2x25cm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: Methanol; flow rate: 20ml/min; gradient: 50% B isogradient within 17min; detection wavelength: 220/254nm), obtained isomer 5, isomer 6, and 30mg of the mixture of isomers 7 and 8 respectively.

异构体5(16.9mg)，手性HPLC保留时间为4.9minIsomer 5 (16.9mg), chiral HPLC retention time is 4.9min

¹H NMR(400MHz,DMSO-d6,ppm):δ10.90(s,1H),9.29(s,1H),8.37(s,1H),8.15(s,1H),7.43(m,2H),7.36–7.25(m,2H),7.04(m,1H),4.72(m,1H),3.18(m,1H),3.06–3.02(m,1H),2.98-2.85(m,2H),2.70-2.80(m,1H),2.68–2.56(m,4H),2.34(s,3H),1.83-1.74(m,7H),1.69(m,5H).MS(ESI+):542.2(M+H). ¹ H NMR(400MHz,DMSO-d6,ppm):δ10.90(s,1H),9.29(s,1H),8.37(s,1H),8.15(s,1H),7.43(m,2H), 7.36–7.25(m,2H),7.04(m,1H),4.72(m,1H),3.18(m,1H),3.06–3.02(m,1H),2.98-2.85(m,2H),2.70- 2.80(m,1H),2.68–2.56(m,4H),2.34(s,3H),1.83-1.74(m,7H),1.69(m,5H).MS(ESI+):542.2(M+H) .

异构体6(10.5mg)，手性HPLC保留时间为6.3min。Isomer 6 (10.5mg), chiral HPLC retention time is 6.3min.

¹HNMR(400MHz,DMSO-d6,ppm):δ10.90(s,1H),9.29(s,1H),8.37(s,1H),8.15(s,1H),7.43(m,2H),7.36–7.25(m,2H),7.04(m,1H),4.72(m,1H),3.18(m,2H),3.06–3.02(m,1H),2.98-2.85(m,1H),2.70-2.80(m,1H),2.68–2.56(m,4H),2.34(s,3H),1.90-1.82(m,1H),1.78(m,3H),1.75(m,3H),1.69(m,5H).MS(ESI+):542.2(M+H) ¹ HNMR(400MHz,DMSO-d6,ppm):δ10.90(s,1H),9.29(s,1H),8.37(s,1H),8.15(s,1H),7.43(m,2H),7.36 –7.25(m,2H),7.04(m,1H),4.72(m,1H),3.18(m,2H),3.06–3.02(m,1H),2.98-2.85(m,1H),2.70-2.80 (m,1H),2.68–2.56(m,4H),2.34(s,3H),1.90-1.82(m,1H),1.78(m,3H),1.75(m,3H),1.69(m,5H ).MS(ESI+):542.2(M+H)

异构体7、8的混合物用手性液相色谱进行了手性拆分(Chiralpak ID，2x25cm，填料粒径5μm；流动相A:甲基叔丁基醚(0.1％二乙胺)，流动相B:甲醇；流速：20ml/min；梯度：19min内10％B等梯度；检测波长：220/254nm)，分别得到了异构体7，异构体8。The mixture of isomers 7 and 8 was chirally resolved by chiral liquid chromatography (Chiralpak ID, 2x25cm, filler particle size 5 μm; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile Phase B: methanol; flow rate: 20ml/min; gradient: 10% B isogradient within 19min; detection wavelength: 220/254nm), and isomer 7 and isomer 8 were obtained respectively.

异构体7(7.9mg)，手性HPLC保留时间为14.0min。Isomer 7 (7.9mg), chiral HPLC retention time is 14.0min.

¹HNMR(400MHz,DMSO-d6,ppm):δ10.90(s,1H),9.29(s,1H),8.37(s,1H),8.15(s,1H),7.43(m,2H),7.36–7.25(m,2H),7.04(m,1H),4.72(m,1H),3.18(m,1H),3.06–2.94(m,1H),2.87(m,1H),2.74(m,1H),2.68–2.56(m,4H),2.42(m,1H),2.34(s,3H),1.83(m,1H),1.78(s,3H),1.74(s,3H),1.69(s,5H).MS(ESI+):542.2(M+H) ¹ HNMR(400MHz,DMSO-d6,ppm):δ10.90(s,1H),9.29(s,1H),8.37(s,1H),8.15(s,1H),7.43(m,2H),7.36 –7.25(m,2H),7.04(m,1H),4.72(m,1H),3.18(m,1H),3.06–2.94(m,1H),2.87(m,1H),2.74(m,1H ),2.68–2.56(m,4H),2.42(m,1H),2.34(s,3H),1.83(m,1H),1.78(s,3H),1.74(s,3H),1.69(s, 5H).MS(ESI+):542.2(M+H)

异构体8(13.5mg)，手性HPLC保留时间为16.8min。Isomer 8 (13.5mg), chiral HPLC retention time is 16.8min.

¹HNMR(400MHz,DMSO-d6,ppm):δ10.93(s,1H),9.29(s,1H),8.39(s,1H),8.16(s,1H),7.50(m,1H),7.43(m,1H),7.33(m,2H),6.97(m,1H),4.89–4.55(m,1H),3.12(m,1H),2.92(m,2H),2.76(m,1H),2.69–2.57(m,5H),2.33(s,3H),1.90-1.82(m,1H),1.78(m,3H),1.75(m,3H),1.69(m,5H).MS(ESI+):542.2(M+H)。 ^1HNMR (400MHz,DMSO-d6,ppm):δ10.93(s,1H),9.29(s,1H),8.39(s,1H),8.16(s,1H),7.50(m,1H),7.43 (m,1H),7.33(m,2H),6.97(m,1H),4.89–4.55(m,1H),3.12(m,1H),2.92(m,2H),2.76(m,1H), 2.69–2.57(m,5H),2.33(s,3H),1.90-1.82(m,1H),1.78(m,3H),1.75(m,3H),1.69(m,5H).MS(ESI+) :542.2(M+H).

第二部分生物活性测试Part II Biological Activity Test

活性测试中所使用的阳性药(BGB324)具体结构如下：The specific structure of the positive drug (BGB324) used in the activity test is as follows:

以上化合物均从上海升泓生物科技有限公司购买。All the above compounds were purchased from Shanghai Shenghong Biotechnology Co., Ltd.

测试1：化合物AXL激酶抑制活性Test 1: Compound AXL Kinase Inhibitory Activity

1.实验流程1. Experimental process

a)AXL酶(Carna，08-107)配置及加入：用1×酶缓冲液(用200μL的Enzymatic buffer kinase 5X,10μL的500mM的MgCl2，10μL的100mM的DTT，6.26μL的2500nM的SEB，加入773.75μL的H2O，配置成1ml的1×酶缓冲液。)将AXL酶33.33ng/uL稀释到0.027ng/μL(1.67×，final conc.＝0.016ng/uL)，使用BioTek(MultiFlo FX)自动分液仪，化合物孔和阳性对照孔分别加6μL的1.67倍终浓度的酶溶液；在阴性对照孔中加6μL的1×Enzymatic buffer。a) AXL enzyme (Carna, 08-107) configuration and addition: use 1× enzyme buffer (200 μL of Enzymatic buffer kinase 5X, 10 μL of 500 mM MgCl2, 10 μL of 100 mM DTT, 6.26 μL of 2500 nM SEB, add 773.75μL of H2O, configured into 1ml of 1× enzyme buffer.) Dilute AXL enzyme 33.33ng/uL to 0.027ng/μL (1.67×, final conc.=0.016ng/uL), use BioTek (MultiFlo FX) to automatically Add 6 μL of enzyme solution with a final concentration of 1.67 times to the dispenser, compound wells and positive control wells; add 6 μL of 1×Enzymatic buffer to the negative control wells.

b)化合物配制及加入：使用DMSO将实施例中制备的化合物及阳性药从10mM稀释到100 μM，用化合物滴定仪(Tecan，D300e)进行滴定，滴定仪自动喷入每孔所需浓度，第1个浓度为1μM，1/2log梯度稀释，共8个浓度。2500rpm离心30s，室温孵育15min。b) Compound preparation and addition: use DMSO to dilute the compounds and positive drugs prepared in the examples from 10 mM to 100 μM, and titrate with a compound titrator (Tecan, D300e), and the titrator will automatically spray the required concentration into each well. 1 concentration is 1μM, 1/2 log gradient dilution, a total of 8 concentrations. Centrifuge at 2500rpm for 30s and incubate at room temperature for 15min.

c)ATP、底物配制及加入：ATP(Sigma，A7699)用1×酶缓冲液进行稀释，从10mM稀释到75μM(5×)，终浓度为15μM；底物TK Substrate 3-biotin(Cisbio，61TK0BLC)用1×酶缓冲液，从500μM稀释到5μM(5×)，终浓度为1μM,；ATP同底物等体积混合，使用BioTek自动分液仪4μL加入每孔；2500rpm离心30s，25℃反应45min。c) ATP, substrate preparation and addition: ATP (Sigma, A7699) was diluted with 1× enzyme buffer, from 10 mM to 75 μM (5×), and the final concentration was 15 μM; substrate TK Substrate 3-biotin (Cisbio, 61TK0BLC) was diluted with 1× enzyme buffer solution from 500 μM to 5 μM (5×), and the final concentration was 1 μM; ATP was mixed with the substrate in equal volume, and 4 μL was added to each well using a BioTek automatic liquid dispenser; centrifuged at 2500 rpm for 30 s, at 25 ° C React for 45 minutes.

d)检测试剂配制及加入：Streptavidin-XL665(Cisbio，610SAXLG)用HTRF KinEASE detection buffer(cisbio)从16.67μM稀释到250nM(4×)，终浓度为62.5nM；TK Antibody-Cryptate(Cisbio)用HTRF KinEASE detection buffer(cisbio)从100×稀释到5×，终浓度为1×；XL665同Antibody等体积混合，使用BioTek自动分液仪10μL加入每孔，2500rpm离心30s，25℃反应1小时。反应结束后，用多功能读板仪HTRF进行检测。d) Detection reagent preparation and addition: Streptavidin-XL665 (Cisbio, 610SAXLG) was diluted from 16.67μM to 250nM (4×) with HTRF KinEASE detection buffer (cisbio), and the final concentration was 62.5nM; TK Antibody-Cryptate (Cisbio) was diluted with HTRF KinEASE detection buffer (cisbio) was diluted from 100× to 5×, and the final concentration was 1×; XL665 was mixed with Antibody in equal volume, 10 μL was added to each well using a BioTek automatic dispenser, centrifuged at 2500 rpm for 30 seconds, and reacted at 25°C for 1 hour. After the reaction, the multifunctional plate reader HTRF was used for detection.

2.数据分析2. Data Analysis

使用GraphPad Prism 5软件log(inhibitor)vs.response-Variable slope拟合量效曲线，得到化合物对AXL激酶抑制的IC50值。Use GraphPad Prism 5 software log(inhibitor) vs. response-Variable slope to fit the dose-effect curve, and obtain the IC50 value of the compound on AXL kinase inhibition.

抑制率计算公式如下：The formula for calculating the inhibition rate is as follows:

Conversion％_sample：是样品的转化率读数；Conversion%_sample: is the conversion rate reading of the sample;

Conversion％_min：代表没有酶活孔的转化率读数；Conversion%_min: represents the conversion rate reading of the well without enzyme activity;

Conversion％_max：代表没有化合物抑制孔的转化率读数。Conversion%_max: Represents the conversion reading for wells with no compound inhibition.

3.实验结果3. Experimental results

实验结果如表1所示。The experimental results are shown in Table 1.

表1.AXL IC50数据Table 1. AXL IC50 data

实施例标题化合物Example title compound	AXL抑制活性IC50(nM)AXL inhibitory activity IC50(nM)
实施例1异构体1Example 1 Isomer 1	14.8214.82
实施例1异构体2Example 1 Isomer 2	22.4222.42
实施例1异构体3Example 1 Isomer 3	0.940.94
实施例1异构体4Example 1 Isomer 4	0.680.68
实施例1异构体5Example 1 Isomer 5	31.6531.65
实施例1异构体6Example 1 Isomer 6	44.1444.14

实施例1异构体7Example 1 Isomer 7	3.473.47
实施例1异构体8Example 1 Isomer 8	4.994.99
阳性药(BGB324)Positive drug (BGB324)	2.252.25

测试2：化合物对细胞增殖抑制检测Test 2: Detection of compound's inhibition of cell proliferation

MV-4-11(人髓性单核细胞白血病细胞株，培养基：IMDM+10％胎牛血清)，置于37℃,5％CO ₂的培养箱中培养。取对数生长期的细胞分别以8000个/孔、6000个/孔、2000个/孔、2000个/孔和3000个/孔的细胞密度铺在96孔板中，并同时设置空白对照组。 MV-4-11 (human myelomonocytic leukemia cell line, culture medium: IMDM+10% fetal bovine serum) was cultured in an incubator at 37°C and 5% CO ₂ . Cells in the logarithmic growth phase were plated in 96-well plates at cell densities of 8000/well, 6000/well, 2000/well, 2000/well and 3000/well, and a blank control group was set at the same time.

将待测化合物以及阳性药溶解在二甲基亚砜中以制备10mM的储液，并置于-80℃冰箱中长期保存。细胞铺板24h后，用二甲基亚砜稀释10mM的化合物储液得到200倍浓度的工作液(最高浓度200或2000μM，3倍梯度，共10个浓度)，每个浓度各取3μL加入到197μL的完全培养基中，稀释得到3倍浓度的工作液，然后取50μL加入到100μL的细胞培养液中，每个浓度设置两个复孔。加药处理72h后，每孔加入50μl的

按照说明书的操作流程在Envision(PerkinElmer)上测定荧光信号，使用计算机软件拟合量效曲线，得到化合物对细胞增殖抑制的IC ₅₀值。 Dissolve the test compound and the positive drug in dimethyl sulfoxide to prepare a 10 mM stock solution, and store it in a -80°C refrigerator for long-term storage. 24 hours after cell plating, dilute the 10 mM compound stock solution with dimethyl sulfoxide to obtain a 200-fold working solution (maximum concentration 200 or 2000 μM, 3-fold gradient, 10 concentrations in total), and add 3 μL of each concentration to 197 μL Diluted in the complete culture medium of 3-fold working solution, then took 50 μL and added it to 100 μL cell culture medium, and set up two replicate wells for each concentration. After 72 hours of drug treatment, add 50 μl of

Fluorescent signals were measured on Envision (PerkinElmer) according to the operating procedure of the manual, and the dose-effect curve was fitted using computer software to obtain the IC ₅₀ value of the compound for inhibiting cell proliferation.

实施例1的异构体1-8对MV-4-11细胞有好的抗增殖活性。Isomers 1-8 of Example 1 have good antiproliferative activity on MV-4-11 cells.

测试3化合物的MV4-11体内药效Test the MV4-11 in vivo efficacy of 3 compounds

测试化合物以及阳性药对人急性单核细胞白血病细胞MV-4-11裸鼠移植瘤模型肿瘤体内生长的抑制作用。The inhibitory effect of the test compound and the positive drug on the growth of human acute monocytic leukemia cell MV-4-11 xenografted tumor model in nude mice in vivo.

1.小鼠模型的构建1. Construction of mouse model

收取对数生长期MV-4-11细胞，细胞计数后重悬后，调整细胞浓度至7.0×10 ⁷细胞/mL；注射到裸鼠前右侧腋窝皮下，每只动物接种200μL(14×10 ⁶细胞/只)，建立MV-4-11移植瘤模型。待瘤体积达到100～300mm ³，挑选健康状况良好、肿瘤体积相近的荷瘤鼠。 Collect MV-4-11 cells in the logarithmic growth phase, count the cells and resuspend, adjust the cell concentration to 7.0×10 ⁷ cells/mL; inject 200 μL (14×10 ⁶ cells/only) to establish the MV-4-11 xenograft tumor model. When the tumor volume reaches 100-300 mm ³ , tumor-bearing mice with good health and similar tumor volume are selected.

2.化合物的配置2. Compound Configuration

将化合物以及阳性药，用适当的溶剂涡旋振荡后超声使化合物完全溶解后缓慢加入适量体积缓冲液，涡旋振荡，使液体混合均匀，得到不同浓度的给药制剂。The compound and positive drug were vortexed with an appropriate solvent and ultrasonically dissolved to completely dissolve the compound, then an appropriate volume of buffer solution was slowly added, vortexed to mix the liquid evenly, and drug preparations of different concentrations were obtained.

溶剂对照组：缓冲液(20:80，v:v)。Solvent Control: Buffer (20:80, v:v).

3.动物分组及给药3. Grouping and administration of animals

将建模的小鼠随机分组(n＝6)，于分组当天开始给予相关化合物和阳性药，21天后或溶 剂对照组肿瘤体积达到2000mm ³结束实验(以先达到指标为准)，给药体积均为10mL·kg ^-1。化合物以及阳性药均采取灌胃方式给予，每天给予一次。实验开始后每周测量2次瘤径和动物体重，计算肿瘤体积。 The modeled mice were randomly grouped (n=6), and related compounds and positive drugs were administered on the day of grouping, and the experiment was ended after 21 days or when the tumor volume of the solvent control group reached 2000 ^mm (whichever was reached first), and the administration volume Both are 10 mL·kg ^-1 . Both the compound and the positive drug were administered by intragastric administration, once a day. After the experiment started, the tumor diameter and animal body weight were measured twice a week, and the tumor volume was calculated.

实施例1的异构体1-8有较好的体内活性。Isomers 1-8 of Example 1 have better activity in vivo.

Claims (10)

1. 一种式I所示的苯并环庚烷类化合物或其药学上可接受的盐，A benzocycloheptane compound represented by formula I or a pharmaceutically acceptable salt thereof,

   

   

   其中，R ¹、R ²为卤素； Wherein, R ¹ and R ² are halogen;

   R ³独立的选自：氢、氘、卤素、C _1-6烷基、C _1-6烷氧基、

   

   其中所述的C _1-6烷基或C _1-6烷氧基任选地被羟基、卤素、氰基或C _1-3烷氧基取代； R ³ is independently selected from: hydrogen, deuterium, halogen, C _1-6 alkyl, C _1-6 alkoxy,

   

   Wherein said C _1-6 alkyl or C _1-6 alkoxy is optionally substituted by hydroxyl, halogen, cyano or C _1-3 alkoxy;

   R ⁴、R ⁵独立的选自C _1-6烷基、羟基、C _2-6烯基或C _2-6炔基； R ⁴ and R ⁵ are independently selected from C _1-6 alkyl, hydroxyl, C _2-6 alkenyl or C _2-6 alkynyl;

   m选自1-3的整数。m is an integer selected from 1-3.
2. 根据权利要求1所述的式I化合物，其特征在于，R ¹为氟，R ²为氯。 The compound of formula I according to claim 1, wherein R ¹ is fluorine and R ² is chlorine.
3. 根据权利要求1所述的式I化合物，其特征在于，R ³独立的选自氘、卤素、C _1-6烷基、

   

   

   The compound of formula I according to claim 1, wherein R ^{is independently} selected from deuterium, halogen, C _1-6 alkyl,

   

   
4. 根据权利要求1所述的式I化合物，其特征在于，R ³独立的选自C _1-6烷基或

   

   The compound of formula I according to claim 1, wherein R ^is independently selected from C _1-6 alkyl or

   
5. 根据权利要求1所述的式I化合物，其特征在于，式I化合物具有如式II所示的结构或其药学上可接受的盐：The compound of formula I according to claim 1, wherein the compound of formula I has a structure as shown in formula II or a pharmaceutically acceptable salt thereof:

   

   

   其中，R ¹、R ²、R ³的定义与式I化合物中的定义一致。 Wherein, the definitions of R ¹ , R ² , and R ³ are consistent with those in the compound of formula I.
6. 根据权利要求1所述的式I化合物，其特征在于，式I化合物具有如式Ⅲ所示的结构或其药学上可接受的盐：The compound of formula I according to claim 1, wherein the compound of formula I has a structure as shown in formula III or a pharmaceutically acceptable salt thereof:

   

   

   

   

   其中，R ¹的定义与式I化合物中的定义一致。 Wherein, the definition of ^R is consistent with the definition in the compound of formula I.
7. 根据权利要求1所述的式I化合物，其特征在于，式I化合物具有如式IV所示的结构或其药学上可接受的盐：The compound of formula I according to claim 1, wherein the compound of formula I has a structure as shown in formula IV or a pharmaceutically acceptable salt thereof:

   

   

   其中，R ¹定义与式I化合物中的定义一致。 Wherein, the definition of ^R is consistent with the definition in the compound of formula I.
8. 一种选自以下化合物，或其药学上可接受的盐，A compound selected from the following, or a pharmaceutically acceptable salt thereof,

   

   
9. 一种选自以下化合物，或其药学上可接受的盐，A compound selected from the following, or a pharmaceutically acceptable salt thereof,

   

   

   

   
10. 一种药物组合物，其包含治疗有效量的式I、II、III、IV的化合物或其药学上可接受的盐。A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, II, III, IV or a pharmaceutically acceptable salt thereof.