WO2021088787A1

WO2021088787A1 - Quinazoline compound used as axl inhibitor

Info

Publication number: WO2021088787A1
Application number: PCT/CN2020/126083
Authority: WO
Inventors: 李冬冬; 马昌友; 冯海威; 吴舰; 徐丹; 朱春霞; 田舟山
Original assignee: 南京正大天晴制药有限公司
Priority date: 2019-11-07
Filing date: 2020-11-03
Publication date: 2021-05-14
Also published as: CN114555588A

Abstract

Disclosed is a quinazoline compound used as an AXL inhibitor. The structure of the quinazoline compound is as shown in general formula (I), and the definition of each substituent is as described in the description. Further provided is a preparation method therefor. The quinazoline compound of the present invention has significant AXL inhibitory activity, and can be used as an AXL inhibitor.

Description

作为AXL抑制剂的喹唑啉类化合物Quinazolines as AXL inhibitors

本申请要求于2019年11月7日向国家知识产权局提交的发明专利申请CN201911081207.5(发明名称为：作为AXL抑制剂的喹唑啉类化合物)的优先权。This application claims the priority of the invention patent application CN201911081207.5 (the title of the invention: Quinazoline Compounds as AXL Inhibitors) submitted to the State Intellectual Property Office on November 7, 2019.

技术领域Technical field

本发明属于医药技术领域，特别涉及喹唑啉类化合物，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 present invention belongs to the field of medical technology, and particularly relates to quinazoline compounds, which are AXL kinase inhibitors. The present invention also relates to the use of the compound to treat diseases related to 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 kinase (RTK) is a multi-domain transmembrane protein that can be used as a sensor for 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 signal cascades (Robinson, DR et al., Oncogene, 19:5548-5557, 2000). So far, 58 RTKs have been identified in the human genome. They can regulate a variety of cellular processes, including cell survival, growth, differentiation, proliferation, adhesion, and movement (Segaliny, AI, etc., 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 structures, while AXL and Mer have the most similar tyrosine kinase domain amino acid sequences. Like other receptor tyrosine kinases (RTKs), the structure of the TAM family includes an extracellular domain, a transmembrane domain, and a conserved intracellular kinase domain. The extracellular domain of AXL has a unique structure in which immunoglobulin and type III fibronectin repeat units are juxtaposed and is reminiscent of a structure of neutrophil adhesion molecules. Members of the TAM family have a common ligand—growth inhibitory specific protein 6 (Gas6), which can bind to all TAM receptor tyrosine kinases. After the combination of AXL and Gas6, it will cause receptor dimerization and AXL autophosphorylation, thereby activating multiple downstream signal transduction pathways, and participating in multiple processes of tumorigenesis (Linger, RM, etc., 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 human tissues, such as monocytes, macrophages, platelets, endothelial cells, cerebellum, heart, skeletal muscle, liver and kidney, etc., among which myocardium and skeletal muscle have the highest expression, and bone marrow CD34+ cells and stromal cells are also relatively High expression, low expression in normal lymphoid tissues (Wu YM, Robinson DR, Kung HJ, Cancer Res, 64(20), 7311-7320, 2004; hung BI, etc., DNA Cell Biol, 22(8), 533-540 , 2003). In the study of many cancer cells, it is found that AXL gene is overexpressed or ectopic expressed in hematopoietic cells, mesenchymal cells and endothelial cells. In various types of leukemia and most solid tumors, the overexpression of AXL kinase is particularly prominent. By inhibiting the AXL receptor tyrosine kinase, the pro-survival signal of tumor cells can be reduced, the invasion ability of tumors can be blocked, and the sensitivity of targeted drug therapy and chemotherapy can be increased. Therefore, finding effective AXL inhibitors is an important direction of current tumor-targeted drug research and development.

发明内容Summary of the invention

一方面，本发明提供了一种式I所示的喹唑啉类化合物或其药学上可接受的盐，In one aspect, the present invention provides a quinazoline compound represented by formula I or a pharmaceutically acceptable salt thereof,

其中，X为CH或N；Among them, X is CH or N;

Y ¹为CH或N； Y ¹ is CH or N;

Y ²为CHR ¹、O或NR ²； Y ² is CHR ¹ , O or NR ² ;

选自

Selected from

R ¹为氢、C1-C6烷基、卤素、硝基、氨基或羟基； R ¹ is hydrogen, C1-C6 alkyl, halogen, nitro, amino or hydroxyl;

R ²为氢或C1-C6烷基； R ² is hydrogen or C1-C6 alkyl;

Q为NH；Q is NH;

m选自0或1；m is selected from 0 or 1;

n选自1、2或3；n is selected from 1, 2 or 3;

R ³选自苯基、5-6元杂芳基、9-12元苯并杂环基或9-12元苯并氧代杂环基，其中所述基团任选地被一个或多个R ⁵取代； R ^{3 is} selected from phenyl, 5-6 membered heteroaryl, 9-12 membered benzoheterocyclyl or 9-12 membered benzooxoheterocyclyl, wherein the group is optionally substituted by one or more R ⁵ replaced;

R ⁵选自卤素、C1-C4烷基、

R ^{5 is} selected from halogen, C1-C4 alkyl,

R ⁴选自苯基、5-6元杂芳基或9-12元苯并杂环基,其中所述基团任选地被一个或多个R ⁶取代； R ^{4 is} selected from phenyl, 5-6 membered heteroaryl or 9-12 membered benzoheterocyclyl, wherein said group is optionally substituted with one or more R ⁶ ;

R ⁶选自卤素、C1-C4烷基、

R ^{6 is} selected from halogen, C1-C4 alkyl,

R ^a为氢、C1-C4烷基或3-6元环烷基； R ^a is hydrogen, C1-C4 alkyl or 3-6 membered cycloalkyl;

R ^b为氢或C1-C4烷基； R ^b is hydrogen or C1-C4 alkyl;

或R ^a、R ^b与和它们相连接的N共同构成5-7元单环饱和杂环，所述基团可任选地被一个或多个卤素或C1-C3烷基取代； Or R ^a, R ^b and the N to which they are attached together form a 5-7 membered monocyclic saturated heterocyclic ring, the group may be optionally substituted with one or more halogen or C1-C3 alkyl substituent;

R ^c为C1-C4烷基或任选地被卤素或C1-C3烷基取代的苯基。 R ^c is C1-C4 alkyl or phenyl optionally substituted by halogen or C1-C3 alkyl.

在一些实施方案中，X为CH。In some embodiments, X is CH.

在一些实施方案中，X为N。In some embodiments, X is N.

在一些实施方案中，Y ¹为N。 In some embodiments, Y ¹ is N.

在一些实施方案中，Y ¹为CH。 In some embodiments, Y ¹ is CH.

在一些实施方案中，Y ²为CHR ¹或O，R ¹为氢、C1-C6烷基、卤素、硝基、氨基或羟基。 In some embodiments, Y ² is CHR ¹ or O, and R ¹ is hydrogen, C1-C6 alkyl, halogen, nitro, amino, or hydroxyl.

在一些实施方案中，Y ²为O。 In some embodiments, Y ² is O.

在一些实施方案中，Y ²为CHR ¹，且R ¹为氢、甲基、乙基、异丙基、氟、氯、溴、羟基或氨基；在一些典型的实施方案中，Y ²为CH ₂。 In some embodiments, Y ² is CHR ¹ , and R ¹ is hydrogen, methyl, ethyl, isopropyl, fluorine, chlorine, bromine, hydroxyl, or amino; in some typical embodiments, Y ² is CH ₂ .

在一些更为典型的实施方案中，X为CH，Y ¹为N且Y ²为CH ₂。 In some more typical embodiments, X is CH, Y ¹ is N and Y ² is CH ₂ .

在一些更为典型的实施方案中，X为N，Y ¹为CH且Y ²为O。 In some more typical embodiments, X is N, Y ¹ is CH, and Y ² is O.

在一些实施方案中，

为

In some embodiments,

for

在一些实施方案中，m为0，且n为1。In some embodiments, m is 0 and n is 1.

在一些实施方案中，m为0，且n为2。In some embodiments, m is 0 and n is 2.

在一些实施方案中，Q为NH，且m和n为1。In some embodiments, Q is NH, and m and n are 1.

在一些实施方案中，R ³选自苯基、5-6元杂芳基或9-12元苯并杂环基，其中所述基团任选地被一个或多个R ⁵取代； In some embodiments, R ^{3 is} selected from phenyl, 5-6 membered heteroaryl, or 9-12 membered benzoheterocyclyl, wherein the group is optionally substituted with one or more R ⁵ ;

R ⁵选自卤素、C1-C4烷基、

R ^{5 is} selected from halogen, C1-C4 alkyl,

在一些实施方案中，R ³选自苯基、吡啶基、噻吩基、呋喃基、1H-吡唑基、1,2,3-***基、1,2,4-***基、吡嗪基、

其中所述基团任选地被一个或多个R ⁵取代。 In some embodiments, R ^{3 is} selected from phenyl, pyridyl, thienyl, furyl, 1H-pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyrazine base,

Wherein the group is optionally substituted with one or more R ⁵ .

Wherein the group is optionally substituted with one or more R ⁵ .

在一些典型的实施方案中，R ³选自苯基、吡啶基、

其中所述基团任选地被一个或多个R ⁵取代。 In some typical embodiments, R ^{3 is} selected from phenyl, pyridyl,

Wherein the group is optionally substituted with one or more R ⁵ .

在一些典型的实施方案中，R ³选自苯基、吡啶基、

Wherein the group is optionally substituted with one or more R ⁵ .

在一些实施方案中，R ⁵选自氟、氯、溴、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、

In some embodiments, R ^{5 is} selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl,

在一些典型的实施方案中，R ⁵选自氟、氯、甲基、

In some typical embodiments, R ^{5 is} selected from fluorine, chlorine, methyl,

在一些实施方案中，R ⁴为任选地被一个或多个R ⁶取代的苯基。 In some embodiments, R ⁴ is phenyl optionally substituted with one or more R ^6.

在一些实施方案中，R ⁶选自

In some embodiments, R ^{6 is} selected from

在一些实施方案中，R ⁶为

In some embodiments, R ⁶ is

在一些实施方案中，R ^a为氢、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环丙基或环戊基。 In some embodiments, R ^a is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, cyclopropyl or cyclopentyl.

在一些实施方案中，R ^b为氢、甲基、乙基、正丙基或异丙基。 In some embodiments, R ^b is hydrogen, methyl, ethyl, n-propyl, or isopropyl.

在一些实施方案中，R ^a、R ^b与和它们相连接的N共同构成吗啉环基、吡咯烷基、哌嗪基或高哌嗪基，其中所述基团任选地被一个或多个氟、氯、溴、甲基或乙基取代。 In some embodiments, R ^a , R ^b and the N to which they are attached together form a morpholinyl, pyrrolidinyl, piperazinyl, or homopiperazinyl group, wherein the group is optionally composed of one or more One fluorine, chlorine, bromine, methyl or ethyl substitution.

在一些典型的实施方案中，R ^a为甲基，且R ^b为氢或甲基；或R ^a、R ^b与和它们相连接的N共同构成吗啉环基、吡咯烷基、哌嗪基或高哌嗪基，其中所述基团任选地被一个甲基取代。 In some exemplary embodiments, R ^a is methyl, and R ^b is hydrogen or methyl; or R ^a, R ^b and the N to which they are attached together form a morpholine ring, pyrrolidinyl, piperazinyl Or homopiperazinyl, where the group is optionally substituted with a methyl group.

在一些更为典型的实施方案中，R ^a为甲基，且R ^b为氢或甲基；或R ^a、R ^b与和它们相连接的N共同构成

In some of the more typical embodiments, R ^a is methyl, and R ^b is hydrogen or methyl; or R ^a, R ^b and the N to which they are attached together form

在一些实施方案中，R ^c为甲基、乙基、正丙基、异丙基、正丁基、叔丁基或任选地被一个或多个甲基取代的苯基。 In some embodiments, R ^c is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl optionally substituted with one or more methyl groups.

在一些典型的实施方案中，R ^c为甲基、异丙基或任选地被一个甲基取代的苯基。 In some typical embodiments, R ^c is methyl, isopropyl, or phenyl optionally substituted with one methyl.

在一些实施方案中，R ⁵选自氟、氯、甲基、

In some embodiments, R ^{5 is} selected from fluorine, chlorine, methyl,

在一些典型的实施方案中，R ⁵选自氟、氯、甲基、

在一些更为典型的实施方案中，R ⁵选自氟、氯、甲基、

In some more typical embodiments, R ^{5 is} selected from fluorine, chlorine, methyl,

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，In some embodiments, the aforementioned compound of formula I has a structure as shown in formula II,

其中，Q、m、R ³的定义如式I化合物中所定义的。 Wherein, the definitions of Q, m and R ³ are as defined in the compound of formula I.

在一些实施方案中，前述式I化合物具有如式III所示的结构，In some embodiments, the aforementioned compound of formula I has a structure as shown in formula III,

其中，R ³的定义如式I化合物中所定义的。 Wherein, ^{the definition of R 3} is as defined in the compound of formula I.

在一些实施方案中，R ³选自苯基、

其中所述基团任选地被一个或两个R ⁵取代，其中R ⁵选自氟、氯、甲基、

In some embodiments, R ^{3 is} selected from phenyl,

Wherein the group is optionally substituted with one or two R ⁵ , wherein R ^{5 is} selected from fluorine, chlorine, methyl,

在一些实施方案中，R ³选自苯基、

In some embodiments, R ^{3 is} selected from phenyl,

在一些典型的实施方案中，R ³选自苯基、

其中所述基团任选地被一个R ⁵取代，其中R ⁵选自氟、甲基、

In some typical embodiments, R ^{3 is} selected from phenyl,

Wherein said group is optionally substituted with a substituent R ^5, wherein R ⁵ is selected from fluoro, methyl,

在一些典型的实施方案中，R ³选自苯基、

In some typical embodiments, R ^{3 is} selected from phenyl,

在一些典型的实施方案中，R ³选自苯基、

In some typical embodiments, R ^{3 is} selected from phenyl,

在一些典型的实施方案中，R ³选自苯基、

In some typical embodiments, R ^{3 is} selected from phenyl,

在一些实施方案中，R ³选自

In some embodiments, R ^{3 is} selected from

在一些实施方案中，R ³选自

In some embodiments, R ^{3 is} selected from

在一些实施方案中，前述式I化合物具有如式IV所示的结构，In some embodiments, the aforementioned compound of formula I has a structure as shown in formula IV,

在一些典型的实施方案中，R ³为任选地被一个或多个R ⁵取代的苯基，其中R ⁵选自 In some typical embodiments, R ³ is phenyl optionally substituted with one or more R ⁵ , wherein R ^{5 is} selected from

在一些更为典型的实施方案中，R ³为被一个R ⁵取代的苯基，其中R ⁵为

In some more typical embodiments, R ³ is phenyl substituted with one R ⁵ ^{, wherein R 5} is

在一些实施方案中，前述式I化合物具有如式V所示的结构，In some embodiments, the aforementioned compound of formula I has a structure as shown in formula V,

其中，Q、m、R ⁴的定义如式I化合物中所定义的。 Wherein, the definitions of Q, m and R ⁴ are as defined in the compound of formula I.

在一些实施方案中，前述式I化合物具有如式VI所示的结构，In some embodiments, the aforementioned compound of formula I has a structure as shown in formula VI,

其中，R ⁴的定义如式I化合物中所定义的。 Wherein, ^{the definition of R 4} is as defined in the compound of formula I.

在一些实施方案中，前述式I化合物具有如式VII所示的结构，In some embodiments, the aforementioned compound of formula I has a structure as shown in formula VII,

在一些实施方案中，前述式I化合物具有如式VIII所示的结构，In some embodiments, the aforementioned compound of formula I has a structure as shown in formula VIII,

在一些实施方案中，R ³选自苯基，所述苯基任选被R ⁵取代，其中R ⁵选自

R ^a、R ^b和R ^c的定义同式I化合物。 In some embodiments, R ³ is selected from phenyl, said phenyl is optionally substituted with R ^5, wherein R ⁵ is selected from

With a compound of formula I R ^a, R ^b and R ^c are defined.

在一些实施方案中，R ^a为氢或C1-C4烷基。 In some embodiments, R ^a is hydrogen or C1-C4 alkyl.

在一些实施方案中，R ^a为氢或C1-C4烷基，且R ^b为氢。 In some embodiments, R ^a is hydrogen or C1-C4 alkyl, and R ^b is hydrogen.

在一些典型的实施方案中，R ^a为C1-C4烷基，且R ^b为氢。 In some exemplary embodiments, R ^a is C1-C4 alkyl, and R ^b is hydrogen.

在一些实施方案中，R ^c为C1-C4烷基。 In some embodiments, R ^c is C1-C4 alkyl.

在一些典型的实施方案中，R ^c为甲基、乙基、正丙基、异丙基、正丁基或叔丁基。 In some typical embodiments, R ^c is methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl.

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、V、VI、VII或VIII化合物或其药学上可接受的盐。In another aspect, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, II, III, IV, V, VI, VII or VIII 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、V、VI、VII或式VIII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 a compound of formula I, II, III, IV, V, VI, VII or formula VIII or a pharmaceutically acceptable salt thereof, And one or more 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、V、VI、VII或VIII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 composition of the present invention can be administered by any suitable route or method, for example, oral or parenteral (for example, intravenous) administration. The therapeutically effective amount of the compound of formula I, II, III, IV, V, VI, VII or VIII 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 composition of the present invention is usually provided in the form of tablets, capsules or solutions. The tablet may contain the 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 lyophilized powder, and adjusted to suitable pH and isotonicity.

另一方面，本发明还提供了式I、II、III、IV、V、VI、VII或VIII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 the use of a compound of formula I, II, III, IV, V, VI, VII or VIII in the preparation of a medicament for the prevention and/or treatment of AXL protein kinase-mediated diseases or disease states .

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、V、VI、VII或VIII化合物或本发明的药物组合物。On the other hand, the present invention also provides a method for preventing and/or treating diseases or disease states mediated by AXL protein kinase, which comprises administering the formula I, II, III, IV, V of the present invention to an individual in need , VI, VII or VIII 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、V、VI、VII或VIII化合物或本发明的药物组合物。On the other hand, the present invention also provides the compound of formula I, II, III, IV, V, VI, VII or VIII of the present invention or the compound of the present invention for preventing and/or treating diseases or disease states mediated by AXL protein kinase Pharmaceutical composition.

本发明化合物对AXL具有明显抑制作用，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。The compound of the present invention has a significant inhibitory effect on AXL. Examples of diseases or disease states mediated by the AXL protein kinase include but are not limited to autoimmune diseases.

另一方面，本发明提供一种制备式III、IV、VI和VII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 method for preparing compounds of formula III, IV, VI and VII, including but not limited to the following synthetic schemes:

合成方案1：Synthesis scheme 1:

其中，R ³和R ⁴定义如上述式I定义所述； Wherein, the ^{definitions of R 3} and R ⁴ are as described in the definition of formula I above;

式1-1化合物和式1-2化合物在溶剂(例如四氢呋喃)、碱(例如二(三甲基硅基)氨基锂)的条件下制备式1-3化合物，式1-3和式i-1或ii-1在溶剂(例如二氧六环)中以碱(例碳酸铯)和钯催化剂(例如1,1'-双二苯基膦二茂铁二氯化钯)通过Suzuki偶联反应制备式III化合物；式1-3可以与式iii-1通过Buchwald–Hartwig偶联反应制备式IV化合物。同样地，式1-1化合物和式9-1化合物在溶剂(例如四氢呋喃)、碱(例如二(三甲基硅基)氨基锂)的条件下制备式9-2化合物，式9-2和式i-2或ii-2通过Suzuki偶联反应制备式VI化合物；式9-2可以与式iii-2通过Buchwald–Hartwig偶联反应制备式VII化合物。The compound of formula 1-1 and the compound of formula 1-2 are prepared under the conditions of a solvent (such as tetrahydrofuran) and a base (such as lithium bis(trimethylsilyl)amide), formula 1-3 and formula i- 1 or ii-1 in a solvent (e.g. dioxane) with a base (e.g. cesium carbonate) and a palladium catalyst (e.g. 1,1'-bisdiphenylphosphine ferrocene dichloride palladium) through the Suzuki coupling reaction The compound of formula III is prepared; the compound of formula IV can be prepared by Buchwald-Hartwig coupling reaction between formula 1-3 and formula iii-1. Similarly, the compound of formula 1-1 and the compound of formula 9-1 are prepared under the conditions of a solvent (such as tetrahydrofuran) and a base (such as lithium bis(trimethylsilyl)amide), and formula 9-2 and Formula i-2 or ii-2 is used to prepare formula VI compound by Suzuki coupling reaction; formula 9-2 can be used with formula iii-2 to prepare formula VII compound through Buchwald-Hartwig coupling reaction.

合成方案2：Synthesis scheme 2:

Z为苯基或5-6元杂芳基，R ^a和R ^b的定义如前式I所述；。 Z is a phenyl group or a 5-6 membered heteroaryl group, ^{and the definitions of Ra} and R ^b are as described in the previous formula I;.

式1-1化合物和式1-2化合物在碱(例如二(三甲基硅基)氨基锂)和溶剂(例如四氢呋喃)的存在下制备式1-3化合物，式1-3化合物与式vi化合物通过Suzuki偶联反应制备式vii化合物，式vii在碱性条件下水解制备得式viii化合物，式viii与式ix化合物在缩合剂(如HATU)、碱(如三乙胺)和溶剂(如DMF)条件下制备得式x。The compound of formula 1-1 and the compound of formula 1-2 are prepared in the presence of a base (for example, lithium bis(trimethylsilyl)amide) and a solvent (for example, tetrahydrofuran), and the compound of formula 1-3 and the compound of formula vi The compound is prepared by Suzuki coupling reaction to prepare the compound of formula vii. The compound of formula vii is hydrolyzed under alkaline conditions to prepare the compound of formula vii. The compound of formula viii and formula ix is used in condensing agent (such as HATU), base (such as triethylamine) and solvent (such as Formula x is prepared under the conditions of DMF).

相关定义Related definitions

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以上的立体异体的混合物的形式被分离得到。光学活性纯的形式可以从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。The "compounds" of the present invention may be asymmetric, for example, having one or more chiral centers. Unless otherwise specified, the "compound" in 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 compound containing asymmetric carbon atoms of the present invention can be isolated in an optically pure form or a mixture of two or more stereoisomers. The optically pure form can be resolved from a mixture of two or more stereoisomers, or synthesized by using chiral raw materials or chiral reagents.

本发明“化合物”还包括互变异构体形式。互变异构体形式来源于一个单键与相邻的双键交换并一起伴随一个质子的迁移。例如：

在一定条件下可以转变成

The "compounds" of the present invention also include tautomeric forms. The tautomeric form is derived from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton. E.g:

Under certain conditions, it can be transformed into

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 event or situation described later may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation.

本文中的数字范围，是指给定范围中的各个整数。例如，“C1-C6”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。The numerical range in this article refers to each integer in the given range. For example, "C1-C6" 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“元”是指组成环的骨架原子的数目。例如，“5-7元”是指组成环的骨架原子的数目为5个、6个或7个。因此，举例而言，吡啶、哌啶、哌嗪和苯为六元环，而噻吩、吡咯为五元环。The term "element" refers to the number of skeletal atoms that make up the ring. For example, "5-7 membered" means that the number of backbone atoms constituting the ring is 5, 6, or 7. Therefore, for example, pyridine, piperidine, piperazine, and benzene are six-membered rings, while thiophene and pyrrole are five-membered rings.

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“C1-C4烷基”包括C1烷基、C2烷基、C3烷基和C4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、叔丁基等。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 "C1-C4 alkyl" includes C1 alkyl, C2 alkyl, C3 alkyl and C4 alkyl. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl , Isobutyl, tert-butyl, etc.

术语“环烷基”指单环饱和烃体系，无杂原子，无双键。术语“3-6元环烷基”的实例包括，但不限于，环丙基、环丁基、环戊基、环己基。The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon system without heteroatoms or double bonds. Examples of the term "3-6 membered cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

术语“杂芳基”指包含至少一个独立地选自氮、氧和硫杂原子的一价芳基。例如“5-6元杂芳基”实例包括，但不限于，吡啶基、噻吩基、咪唑基、嘧啶基、吡啶基、呋喃基、吡嗪基、噻唑基。The term "heteroaryl" refers to a monovalent aryl group containing at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. For example, examples of "5-6 membered heteroaryl" include, but are not limited to, pyridyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, furyl, pyrazinyl, and thiazolyl.

术语“9-12元苯并杂环基”是指具有9～12个环原子的二环***，其中一个环为苯环，另一个为饱和、部分不饱和或不饱和的含有1-2个选自N、O、S杂原子的5-6元杂环基，二者共享一对相邻环原子。实例包括，但不限于

The term "9-12 membered benzoheterocyclyl" refers to a bicyclic ring system with 9-12 ring atoms, one of which is a benzene ring, and the other is saturated, partially unsaturated or unsaturated containing 1-2 A 5-6 membered heterocyclic group selected from N, O, and S heteroatoms, both of which share a pair of adjacent ring atoms. Examples include, but are not limited to

术语“9-12元苯并氧代杂环基”是指具有9～12个环原子的二环体系，其中一个环为苯环，另一个为饱和或部分不饱的含有1-2个选自N、O、S杂原子的5-6元杂环，且杂环上的至少一个环原子被基团

取代，只要满足化合价。实例包括，但不限于

The term "9-12 membered benzooxoheterocyclic group" refers to a bicyclic ring system with 9-12 ring atoms, one of which is a benzene ring, and the other is saturated or partially unsaturated containing 1-2 options. A 5-6 membered heterocyclic ring from N, O, S heteroatoms, and at least one ring atom on the heterocyclic ring is grouped

Replace as long as the valence is satisfied. Examples include, but are not limited to

术语“5-7元单环饱和杂环”是指包括5-7个环原子的饱和单环，其中含有1至2个相同的或不同的杂原子，所述杂原子独立地选自氮、硫或氧原子，其余环原子为碳。实例包括，但不限于吗啉环基、吡咯烷基、哌嗪基或高哌嗪基。The term "5-7 membered monocyclic saturated heterocyclic ring" refers to a saturated monocyclic ring comprising 5-7 ring atoms, which contains 1 to 2 identical or different heteroatoms, and the heteroatoms are independently selected from nitrogen, Sulfur or oxygen atoms, and the remaining ring atoms are carbon. Examples include, but are not limited to, morpholinyl, pyrrolidinyl, piperazinyl, or homopiperazinyl.

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

术语“羟基”指-OH。The term "hydroxyl" refers to -OH.

术语“硝基”指-NO ₂。 The term "nitro" refers to -NO ₂ .

术语“氨基”指-NH ₂。 The term "amino" refers to -NH ₂ .

取代基R ⁵、R ⁶可以与环上的任意原子相键合，只要原子价容许。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。本领域技术人员可以理解，对于包含一个或多个R ⁵或R ⁶取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。 The substituents R ⁵ and R ⁶ may be bonded to any atom on the ring, as long as the valence allows. Combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds. Those skilled in the art can understand that for ^{any group containing one or more R 5} or R ⁶ substituents, any substitution or substitution pattern that is impossible to exist in space and/or cannot be synthesized will not be introduced.

中的

及

中的

均是指化学键连接处。当双环或多环中出现

且连接位置不确定的情况下，表示连接位点仅限于

所在的单环上的任意原子，只要原子价容许。例如，

表示连接位点仅位于双环中的苯环上的任意碳原子，且需满足原子价键的要求，其具体指的是

middle

and

middle

Both refer to the chemical bond junction. When appearing in double or multiple rings

And when the connection location is uncertain, it means that the connection site is limited to

Any atom on the single ring, as long as the valence allows. E.g,

It means that the connection site is only located on any carbon atom on the benzene ring in the bicyclic ring, and must meet the requirements of atomic valence bonds, which specifically refers to

术语“药学上可接受的盐”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)加成盐或碱加成盐(包括有机碱和无机碱)。The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy of the free acid and base of a specific compound without biological adverse effects. For example, acid (including organic acid and inorganic acid) addition salt or base addition salt (including organic base and inorganic base).

本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or organic solvent or a mixture of both.

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 drug or medicament that is non-toxic but can 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用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 do not impair the biological activity and performance of the active compound. Including, but not limited to, any diluents, disintegrants, adhesives, glidants, and wetting agents approved by the State Food and Drug Administration that can be used for humans or animals.

术语“Suzuki偶联反应”是指钯配合物催化下，芳基或烯基硼酸或硼酸酯与氯、溴、碘代芳烃或烯烃发生交叉偶联。The term "Suzuki coupling reaction" refers to the cross-coupling of aryl or alkenyl boronic acid or boronic acid ester with chlorine, bromine, iodo aromatic hydrocarbon or alkene under the catalysis of palladium complex.

术语“Buchwald-Hartwig偶联反应”是指钯催化的胺与芳卤的交叉偶联反应，产生C-N键。The term "Buchwald-Hartwig coupling reaction" refers to the palladium-catalyzed cross-coupling reaction of amines and aromatic halides to produce C-N bonds.

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

M:mol/L；M:mol/L;

mM：mmol/L；mM: mmol/L;

μM：μmol/L；μM: μmol/L;

nM：nmol/L；nM: nmol/L;

HATU：2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐；HATU: 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate;

DIPEA：N,N-二异丙基乙胺；DIPEA: N,N-diisopropylethylamine;

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

DMSO：二甲基亚砜；DMSO: dimethyl sulfoxide;

Pd ₂(dba) ₃：三(二亚苄基丙酮)二钯； Pd ₂ (dba) ₃ : Tris(dibenzylideneacetone)dipalladium;

Pd(dppf)Cl ₂：1,1'-双二苯基膦二茂铁二氯化钯； Pd(dppf)Cl ₂ : 1,1'-bisdiphenylphosphinoferrocene palladium dichloride;

Xantphos：4,5-双二苯基膦-9,9-二甲基氧杂蒽；Xantphos: 4,5-bisdiphenylphosphine-9,9-dimethylxanthene;

h:小时；h: hour;

min:分；min: minutes;

DTT:二硫苏糖醇；DTT: Dithiothreitol;

HEPES:4-羟乙基哌嗪乙磺酸。HEPES: 4-hydroxyethylpiperazine ethanesulfonic acid.

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 on 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 specification or known in the art, and such combinations can be easily performed by those skilled in the art.

实施例1 (S)-8-(2-异丙氧基苯基)-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺Example 1 (S)-8-(2-isopropoxyphenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[ 7) annulen-2-yl) quinazolin-2-amine

a)(S)-8-溴-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺(1-3)a) (S)-8-Bromo-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annun-2-yl)quine Oxazoline-2-amine (1-3)

将化合物1-1(300mg,1.30mmol)及8-溴-2-氯喹唑啉1-2(350mg,1.44mmol)溶于四氢呋喃(20mL)中，温度降至0℃以下，滴加二(三甲基硅基)氨基锂的四氢呋喃溶液(1M，2.60mL,2.60mmol)，15min后停止反应，加入50mL饱和氯化铵水溶解淬灭反应，乙酸乙酯(100mL)萃取反应液，旋干后柱层析得化合物1-3(540mg)。Compound 1-1 (300mg, 1.30mmol) and 8-bromo-2-chloroquinazoline 1-2 (350mg, 1.44mmol) were dissolved in tetrahydrofuran (20mL), the temperature dropped below 0℃, and two (three (1M, 2.60mL, 2.60mmol) of lithium amide in tetrahydrofuran (1M, 2.60mL, 2.60mmol), stop the reaction after 15min, add 50mL saturated ammonium chloride water to dissolve and quench the reaction, extract the reaction solution with ethyl acetate (100mL), spin dry Column chromatography yielded compound 1-3 (540 mg).

¹H NMR(400MHz,DMSO-d ₆)δ10.07(s,1H),9.31(s,1H),8.22-8.07(m,2H),7.94(dd,J＝8.0,1.3Hz,1H),7.80(dd,J＝8.2,2.2Hz,1H),7.30(t,J＝7.7Hz,1H),7.10(d,J＝8.2Hz,1H),3.30-3.17(s,1H),2.90(s,5H),2.76–2.56(m,3H),2.18-1.99(m,2H),1.78(s,4H),1.53(s,2H).LC-MS:[M+H] ⁺:439.1. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.07(s,1H),9.31(s,1H),8.22-8.07(m,2H),7.94(dd,J=8.0,1.3Hz,1H), 7.80 (dd, J = 8.2, 2.2 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 3.30-3.17 (s, 1H), 2.90 (s ,5H),2.76-2.56(m,3H),2.18-1.99(m,2H),1.78(s,4H),1.53(s,2H).LC-MS:[M+H] ⁺ :439.1.

b)(S)-8-(2-异丙氧基苯基)-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺b) (S)-8-(2-isopropoxyphenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7 ]Ranen-2-yl)quinazolin-2-amine

将化合物1-3(50mg,0.11mmol)及(2-异丙氧基苯基)硼酸1-4(31mg,0.17mmol)，1,1'-双二苯基膦二茂铁二氯化钯(8.3mg,0.011mmol)，碳酸铯(74mg,0.23mmol)溶于二氧六环(10mL)/水(1mL)的混合溶剂中，氮气保护下回流反应7h。反应液旋干后柱层析得标题化合物(40mg)。Compound 1-3 (50mg, 0.11mmol) and (2-isopropoxyphenyl) boronic acid 1-4 (31mg, 0.17mmol), 1,1'-bisdiphenylphosphine ferrocene palladium dichloride (8.3mg, 0.011mmol), cesium carbonate (74mg, 0.23mmol) was dissolved in a mixed solvent of dioxane (10mL)/water (1mL), and the reaction was refluxed for 7h under nitrogen protection. The reaction mixture was spin-dried and column chromatography was performed to obtain the title compound (40 mg).

¹H NMR(400MHz,DMSO-d ₆)δ9.68(s,1H),9.29(s,1H),7.88(dd,J＝8.1,1.5Hz,1H),7.77–7.62(m,2H),7.42(dt,J＝15.0,7.2Hz,2H),7.34(dt,J＝7.5,2.7Hz,2H),7.16(d,J＝8.3Hz,1H),7.06(t,J＝7.4Hz,1H),6.86(d,J＝8.2Hz,1H),4.42(dp,J＝12.2,6.2,5.8Hz,2H),3.42–3.37(m,2H),3.17(d,J＝4.6Hz,1H)，2.74(s,1H),2.60(t,J＝12.9Hz,2H),2.46–2.37(m,2H),2.20(s,2H),1.87(s,4H),1.36(s,2H),0.99(dd,J＝6.1,1.7Hz,6H).LC-MS:[M+H] ⁺:493.3. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.68(s,1H),9.29(s,1H),7.88(dd,J=8.1,1.5Hz,1H),7.77–7.62(m,2H), 7.42 (dt, J = 15.0, 7.2 Hz, 2H), 7.34 (dt, J = 7.5, 2.7 Hz, 2H), 7.16 (d, J = 8.3 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H ), 6.86 (d, J = 8.2 Hz, 1H), 4.42 (dp, J = 12.2, 6.2, 5.8 Hz, 2H), 3.42–3.37 (m, 2H), 3.17 (d, J = 4.6 Hz, 1H) , 2.74(s,1H),2.60(t,J=12.9Hz,2H),2.46-2.37(m,2H),2.20(s,2H),1.87(s,4H),1.36(s,2H), 0.99(dd,J=6.1,1.7Hz,6H).LC-MS:[M+H] ⁺ :493.3.

实施例2 (S)-8-(3-异丙氧基苯基)-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺Example 2 (S)-8-(3-isopropoxyphenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[ 7) annulen-2-yl) quinazolin-2-amine

按照实施例1的方法，以化合物1-3(50mg,0.11mmol)和(3-异丙氧基苯基)硼酸(31mg,0.17mmol)为原料，得标题化合物(30mg)。According to the method of Example 1, using compound 1-3 (50 mg, 0.11 mmol) and (3-isopropoxyphenyl)boronic acid (31 mg, 0.17 mmol) as raw materials, the title compound (30 mg) was obtained.

¹H NMR(400MHz,DMSO-d ₆)δ9.79(s,1H),9.33(s,1H),7.92(d,J＝7.9Hz,1H),7.80(d,J＝7.1Hz,1H),7.76–7.67(m,1H),7.57(dd,J＝8.1,2.3Hz,1H),7.42(dt,J＝11.7,7.7Hz,2H),7.25(d,J＝7.5Hz,1H),7.18(d,J＝2.5Hz,1H),7.01(dd,J＝8.2,2.5Hz,1H),6.95(d,J＝8.2Hz,1H),4.64(h,J＝6.0Hz,1H),4.45(s,1H),3.43–3.35(m,4H),3.17(d,J＝4.8Hz,1H),2.76(s,1H),2.60(s,2H),2.23(s,2H),1.88(s,4H),1.47–1.31(m,2H),1.31–1.22(m,6H).LC-MS:[M+H] ⁺:493.2. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.79(s,1H),9.33(s,1H),7.92(d,J=7.9Hz,1H), 7.80(d,J=7.1Hz,1H) ,7.76–7.67(m,1H),7.57(dd,J=8.1,2.3Hz,1H),7.42(dt,J=11.7,7.7Hz,2H),7.25(d,J=7.5Hz,1H), 7.18(d,J=2.5Hz,1H), 7.01(dd,J=8.2,2.5Hz,1H), 6.95(d,J=8.2Hz,1H), 4.64(h,J=6.0Hz,1H), 4.45(s,1H),3.43–3.35(m,4H),3.17(d,J=4.8Hz,1H),2.76(s,1H),2.60(s,2H),2.23(s,2H),1.88 (s,4H),1.47–1.31(m,2H),1.31–1.22(m,6H).LC-MS:[M+H] ⁺ :493.2.

实施例3 (S)-8-(4-异丙氧基苯基)-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺Example 3 (S)-8-(4-isopropoxyphenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[ 7) annulen-2-yl) quinazolin-2-amine

按照实施例1的方法，以化合物1-3(50mg,0.11mmol)和(4-异丙氧基苯基)硼酸(31mg,0.17mmol)为原料，得标题化合物(40mg)。According to the method of Example 1, using compound 1-3 (50 mg, 0.11 mmol) and (4-isopropoxyphenyl)boronic acid (31 mg, 0.17 mmol) as raw materials, the title compound (40 mg) was obtained.

¹H NMR(400MHz,DMSO-d ₆)δ9.77(s,1H),9.32(s,1H),7.88(d,J＝7.9Hz,1H),7.79(dd,J＝10.2,4.6Hz,2H),7.65(d,J＝8.3Hz,2H),7.52(d,J＝8.0Hz,1H),7.43(t,J＝7.6Hz,1H),7.06(d,J＝8.4Hz,2H),6.97(d,J＝8.2Hz,1H),4.73(hept,J＝6.0Hz,1H),4.45(s,1H),3.40-3.39(m,4H)3.17(d,J＝4.2Hz,1H),2.78(dd,J＝14.8,7.4Hz,1H),2.67–2.56(m,2H),2.24(s,2H),1.98–1.73(m,4H),1.54–1.39(m,2H),1.35(dd,J＝6.0,2.2Hz,6H).LC-MS:[M+H] ⁺:493.3. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.77(s,1H),9.32(s,1H),7.88(d,J=7.9Hz,1H), 7.79(dd,J=10.2,4.6Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H) ,6.97(d,J=8.2Hz,1H),4.73(hept,J=6.0Hz,1H),4.45(s,1H),3.40-3.39(m,4H)3.17(d,J=4.2Hz,1H ), 2.78(dd,J=14.8,7.4Hz,1H), 2.67–2.56(m,2H),2.24(s,2H),1.98–1.73(m,4H),1.54–1.39(m,2H), 1.35(dd,J=6.0,2.2Hz,6H).LC-MS:[M+H] ⁺ :493.3.

实施例4 (S)-8-(4-氯-2-异丙氧基苯基)-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺Example 4 (S)-8-(4-chloro-2-isopropoxyphenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H -Benzo[7]annun-2-yl)quinazolin-2-amine

按照实施例1的方法，以化合物1-3(50mg,0.11mmol)和4-氯-2-异丙氧基苯硼酸(36.4mg,0.17mmol)为原料，得标题化合物(40mg)。According to the method of Example 1, using compound 1-3 (50 mg, 0.11 mmol) and 4-chloro-2-isopropoxyphenylboronic acid (36.4 mg, 0.17 mmol) as raw materials, the title compound (40 mg) was obtained.

¹H NMR(400MHz,DMSO-d ₆)δ9.73(s,1H),9.30(s,1H),7.90(d,J＝8.0Hz,1H),7.82(s,1H),7.68(d,J＝7.1Hz,1H),7.47–7.30(m,2H),7.25(d,J＝10.6Hz,2H),7.13(d,J＝8.2Hz,1H),6.91(d,J＝8.1Hz,1H),4.53-4.23(m,2H),3.44–3.36(m,2H),3.19–2.92(m,2H),2.75(s,1H),2.63–2.59(m,2H),2.43(s,1H),2.27(s,2H),1.89(s,4H),1.41(s,2H)，0.99(d,J＝5.9Hz,6H).LC-MS:[M+H] ⁺:527.2. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.73(s,1H),9.30(s,1H),7.90(d,J=8.0Hz,1H),7.82(s,1H),7.68(d, J = 7.1Hz, 1H), 7.47–7.30 (m, 2H), 7.25 (d, J = 10.6 Hz, 2H), 7.13 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 4.53-4.23(m, 2H), 3.44–3.36(m, 2H), 3.19–2.92(m, 2H), 2.75(s, 1H), 2.63–2.59(m, 2H), 2.43(s, 1H), 2.27 (s, 2H), 1.89 (s, 4H), 1.41 (s, 2H), 0.99 (d, J = 5.9 Hz, 6H). LC-MS: [M+H] ⁺ :527.2.

实施例5 (S)-N,N-二甲基-2-(2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)喹唑啉-8-基)苯磺酰胺Example 5 (S)-N,N-Dimethyl-2-(2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7 ]Ranthen-2-yl)amino)quinazolin-8-yl)benzenesulfonamide

按照实施例1的方法，以化合物1-3(50mg,0.11mmol)和(2-(N,N-二甲基氨磺酰基)苯基)硼酸(39mg,0.17mmol)为原料，得标题化合物(30mg)。According to the method of Example 1, using compound 1-3 (50mg, 0.11mmol) and (2-(N,N-dimethylsulfamoyl)phenyl)boronic acid (39mg, 0.17mmol) as starting materials, the title compound was obtained (30mg).

¹H NMR(400MHz,DMSO-d ₆)δ9.75(s,1H),9.31(s,1H),8.09(d,J＝6.7Hz,1H),7.94(d,J＝8.0Hz,1H),7.85–7.73(m,2H),7.70(d,J＝7.1Hz,1H),7.56(d,J＝34.6Hz,1H),7.43(q,J＝7.7Hz,2H),7.15(dd,J＝17.8,8.2Hz,1H),6.80(t,J＝9.1Hz,1H),3.17(d,J＝4.3Hz,1H),3.07(s,3H),2.74(d,J＝14.7Hz,1H),2.54(s,2H),2.41(s,2H),2.19(d,J＝13.0Hz,6H),2.11(s,2H),1.86(s,4H),1.33(s,2H).LC-MS:[M+H] ⁺:542.3. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.75(s,1H),9.31(s,1H), 8.09(d,J=6.7Hz,1H),7.94(d,J=8.0Hz,1H) ,7.85-7.73(m,2H),7.70(d,J=7.1Hz,1H),7.56(d,J=34.6Hz,1H),7.43(q,J=7.7Hz,2H),7.15(dd, J = 17.8, 8.2 Hz, 1H), 6.80 (t, J = 9.1 Hz, 1H), 3.17 (d, J = 4.3 Hz, 1H), 3.07 (s, 3H), 2.74 (d, J = 14.7 Hz, 1H), 2.54(s, 2H), 2.41(s, 2H), 2.19(d, J=13.0Hz, 6H), 2.11(s, 2H), 1.86(s, 4H), 1.33(s, 2H). LC-MS:[M+H] ⁺ :542.3.

实施例6 (S)-N,N-二甲基-3-(2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)喹唑啉-8-基)苯磺酰胺Example 6 (S)-N,N-Dimethyl-3-(2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7 ]Ranthen-2-yl)amino)quinazolin-8-yl)benzenesulfonamide

按照实施例1的方法，以化合物1-3(50mg,0.11mmol)和(3-(N,N-二甲基氨磺酰基)苯基)硼酸(39mg,0.17mmol)为原料，得标题化合物(30mg)。According to the method of Example 1, using compound 1-3 (50mg, 0.11mmol) and (3-(N,N-dimethylsulfamoyl)phenyl)boronic acid (39mg, 0.17mmol) as starting materials, the title compound was obtained (30mg).

¹H NMR(400MHz,DMSO-d ₆)δ9.84(s,1H),9.37(s,1H),8.11(d,J＝7.5Hz,1H), 8.03–7.96(m,1H),7.87(d,J＝6.8Hz,3H),7.81(t,J＝7.7Hz,1H),7.65(d,J＝2.3Hz,1H),7.49(t,J＝7.6Hz,1H),7.45(s,1H),6.94(d,J＝8.2Hz,1H),4.52–4.39(m,1H),3.40-3.39(m,2H),3.17(d,J＝4.9Hz,1H),2.78-2.73(m,1H),2.64(s,6H),2.60(s,1H),2.42(s,1H),2.23(s,2H),1.89(s,4H),1.38(q,J＝11.4Hz,2H),1.24(d,J＝7.0Hz,2H).LC-MS:[M+H] ⁺:542.3. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.84(s,1H),9.37(s,1H),8.11(d,J=7.5Hz,1H), 8.03–7.96(m,1H),7.87( d,J=6.8Hz,3H),7.81(t,J=7.7Hz,1H),7.65(d,J=2.3Hz,1H),7.49(t,J=7.6Hz,1H),7.45(s, 1H), 6.94(d,J=8.2Hz,1H),4.52-4.39(m,1H), 3.40-3.39(m,2H), 3.17(d,J=4.9Hz,1H), 2.78-2.73(m ,1H),2.64(s,6H),2.60(s,1H),2.42(s,1H),2.23(s,2H),1.89(s,4H),1.38(q,J=11.4Hz,2H) ,1.24(d,J=7.0Hz,2H).LC-MS:[M+H] ⁺ :542.3.

实施例7 (S)-N,N-二甲基-2-((2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)喹唑啉-8-基)氨基)苯磺酰胺Example 7 (S)-N,N-Dimethyl-2-((2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[ 7) annulen-2-yl)amino)quinazolin-8-yl)amino)benzenesulfonamide

将化合物1-3(50mg,0.11mmol)及化合物7-1(27.4mg,0.12mmol)，三(二亚苄基丙酮)二钯(10.4mg,0.011mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(6.6mg,0.011mmol)，碳酸铯(74mg,0.23mmol)溶于二氧六环(10mL)中，氮气保护下回流反应11h。反应液旋干后柱层析得标题化合物(30mg)。The compound 1-3 (50mg, 0.11mmol) and compound 7-1 (27.4mg, 0.12mmol), three (dibenzylideneacetone) two palladium (10.4mg, 0.011mmol), 4,5-bis diphenyl Phosphine-9,9-dimethylxanthene (6.6mg, 0.011mmol), cesium carbonate (74mg, 0.23mmol) were dissolved in dioxane (10mL), and the reaction was refluxed for 11h under nitrogen protection. The reaction solution was spin-dried and column chromatography was used to obtain the title compound (30 mg).

¹H NMR(400MHz,DMSO-d ₆)δ9.89(s,1H),9.28(s,1H),8.91(s,1H),7.82(ddd,J＝15.4,8.0,1.9Hz,2H),7.75–7.66(m,3H),7.66–7.59(m,1H),7.47(dd,J＝8.0,1.2Hz,1H),7.28(t,J＝7.8Hz,1H),7.20–7.12(m,1H),7.08(d,J＝8.2Hz,1H),3.50(t,J＝4.3Hz,1H),3.27–2.97(m,3H),2.81(q,J＝7.6,6.2Hz,2H),2.69(t,J＝12.1Hz,2H),2.60(s,6H),2.29(s,2H),1.88(s,4H),1.53–1.42(m,2H),1.23(s,1H).LC-MS:[M+H] ⁺:557.2. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.89 (s, 1H), 9.28 (s, 1H), 8.91 (s, 1H), 7.82 (ddd, J = 15.4, 8.0, 1.9 Hz, 2H), 7.75–7.66(m,3H), 7.66–7.59(m,1H), 7.47(dd,J=8.0,1.2Hz,1H), 7.28(t,J=7.8Hz,1H), 7.20–7.12(m, 1H), 7.08 (d, J = 8.2 Hz, 1H), 3.50 (t, J = 4.3 Hz, 1H), 3.27-2.97 (m, 3H), 2.81 (q, J = 7.6, 6.2 Hz, 2H), 2.69(t,J=12.1Hz,2H),2.60(s,6H),2.29(s,2H),1.88(s,4H),1.53-1.42(m,2H),1.23(s,1H).LC -MS:[M+H] ⁺ :557.2.

实施例8 (S)-N,N-二甲基-3-((2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)喹唑啉-8-基)氨基)苯磺酰胺Example 8 (S)-N,N-Dimethyl-3-((2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[ 7) annulen-2-yl)amino)quinazolin-8-yl)amino)benzenesulfonamide

按照实施例7的方法，以化合物1-3(50mg,0.11mmol)和3-氨基-N,N-二甲基苯磺酰胺(27.4mg,0.17mmol)为原料，得标题化合物(30mg)。According to the method of Example 7, using compound 1-3 (50 mg, 0.11 mmol) and 3-amino-N,N-dimethylbenzenesulfonamide (27.4 mg, 0.17 mmol) as raw materials, the title compound (30 mg) was obtained.

¹H NMR(400MHz,DMSO-d ₆)δ9.81(s,1H),9.30(s,1H),8.48(s,1H),7.81–7.63(m,2H),7.58(d,J＝7.9Hz,1H),7.51(t,J＝7.8Hz,1H),7.45(d,J＝8.1Hz,2H),7.34(t,J ＝7.7Hz,1H),7.27(s,1H),7.13(d,J＝7.6Hz,1H),6.92(d,J＝8.1Hz,1H),3.17(s,2H),3.01–2.68(m,6H),2.54(s,7H),2.06(s,2H),1.79(s,4H),1.43(s,2H). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.81(s,1H),9.30(s,1H),8.48(s,1H),7.81-7.63(m,2H),7.58(d,J=7.9 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.34 (t, J = 7.7 Hz, 1H), 7.27 (s, 1H), 7.13 ( d,J=7.6Hz,1H),6.92(d,J=8.1Hz,1H),3.17(s,2H),3.01-2.68(m,6H),2.54(s,7H),2.06(s,2H) ), 1.79(s, 4H), 1.43(s, 2H).

LC-MS:[M+H] ⁺:557.2. LC-MS:[M+H] ⁺ :557.2.

实施例9 (S)-N,N-二甲基-3-(2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)喹唑啉-7-基)苯磺酰胺Example 9 (S)-N,N-Dimethyl-3-(2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7 ]Ranutene-2-yl)amino)quinazolin-7-yl)benzenesulfonamide

a)(S)-7-溴-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺(9-2)a) (S)-7-Bromo-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annun-2-yl)quine Oxazoline-2-amine (9-2)

将化合物1-1(100mg,0.43mmol)及7-溴-2-氯喹唑啉9-1(116.3mg,0.48mmol)溶于四氢呋喃(5mL)中，温度降至0℃以下，滴加二(三甲基硅基)氨基锂的四氢呋喃溶液(1M/L，0.87mL,0.87mmol)，15min后停止反应，加入15mL饱和氯化铵水溶解淬灭反应，50mL乙酸乙酯萃取反应液，旋干后柱层析得化合物9-2(180mg)。Compound 1-1 (100mg, 0.43mmol) and 7-bromo-2-chloroquinazoline 9-1 (116.3mg, 0.48mmol) were dissolved in tetrahydrofuran (5mL), the temperature dropped below 0℃, and bis( Lithium trimethylsilyl)amide in tetrahydrofuran (1M/L, 0.87mL, 0.87mmol), stop the reaction after 15min, add 15mL saturated ammonium chloride water to dissolve and quench the reaction, extract the reaction solution with 50mL ethyl acetate, spin dry After column chromatography, compound 9-2 (180 mg) was obtained.

¹H NMR(400MHz,DMSO-d ₆)δ9.87(s,1H),9.29(s,1H),7.94–7.81(m,2H),7.69(d,J＝6.3Hz,2H),7.50(dd,J＝8.5,1.9Hz,1H),7.06(d,J＝8.6Hz,1H),3.45–3.34(m,2H),2.93(d,J＝11.6Hz,2H),2.65–2.54(m,5H),1.88(s,2H),1.72(s,4H),1.53(s,2H).LC-MS:[M+H] ⁺:437.0. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.87(s,1H),9.29(s,1H),7.94-7.81(m,2H),7.69(d,J=6.3Hz,2H),7.50( dd, J = 8.5, 1.9 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 3.45–3.34 (m, 2H), 2.93 (d, J = 11.6 Hz, 2H), 2.65–2.54 (m ,5H),1.88(s,2H),1.72(s,4H),1.53(s,2H).LC-MS:[M+H] ⁺ :437.0.

b)(S)-N,N-二甲基-3-(2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)喹唑啉-7-基)苯磺酰胺b) (S)-N,N-Dimethyl-3-(2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7] Ananthen-2-yl)amino)quinazolin-7-yl)benzenesulfonamide

将化合物9-2(50mg,0.11mmol)及化合物9-3(39mg,0.17mmol)，1,1'-双二苯基膦二茂铁二氯化钯(8.3mg,0.011mmol)，碳酸铯(74mg,0.23mmol)溶于二氧六环(10mL)/水(1mL)的混合溶剂中，氮气保护下回流反应8h。反应液旋干后柱层析得标题化合物(32mg)。The compound 9-2 (50mg, 0.11mmol) and compound 9-3 (39mg, 0.17mmol), 1,1'-bisdiphenylphosphine ferrocene palladium dichloride (8.3mg, 0.011mmol), cesium carbonate (74mg, 0.23mmol) was dissolved in a mixed solvent of dioxane (10mL)/water (1mL), and the reaction was refluxed for 8h under nitrogen protection. The reaction mixture was spin-dried and column chromatography was used to obtain the title compound (32 mg).

¹H NMR(400MHz,DMSO-d ₆)δ9.84(s,1H),9.35(s,1H),8.22(d,J＝6.6Hz,1H),8.13–7.98(m,2H),7.94(s,1H),7.84(d,J＝7.2Hz,3H),7.74(d,J＝8.1Hz,2H),7.13(d,J＝8.2Hz,1H),4.45(s,1H),3.39(d,J＝3.3Hz,3H),3.10(s,2H),2.85(s,2H),2.77(d,J＝12.6Hz,1H),2.50(s,6H),2.28(s,2H),1.87(s,4H),1.49(s,2H).LC-MS:[M+H] ⁺:542.2. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.84 (s, 1H), 9.35 (s, 1H), 8.22 (d, J = 6.6 Hz, 1H), 8.13-7.98 (m, 2H), 7.94 ( s, 1H), 7.84 (d, J = 7.2 Hz, 3H), 7.74 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 8.2 Hz, 1H), 4.45 (s, 1H), 3.39 ( d, J = 3.3Hz, 3H), 3.10 (s, 2H), 2.85 (s, 2H), 2.77 (d, J = 12.6 Hz, 1H), 2.50 (s, 6H), 2.28 (s, 2H), 1.87(s,4H),1.49(s,2H).LC-MS:[M+H] ⁺ :542.2.

实施例10 (S)-N,N-二甲基-3-((2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)喹唑啉-7-基)氨基)苯磺酰胺Example 10 (S)-N,N-Dimethyl-3-((2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[ 7) Annulen-2-yl)amino)quinazolin-7-yl)amino)benzenesulfonamide

将化合物9-2(50mg,0.11mmol)及化合物10-1(27.4mg,0.13mmol)，三(二亚苄基丙酮)二钯(10.4mg,0.011mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(6.6mg,0.011mmol)，碳酸铯(74mg,0.23mmol)溶于二氧六环(10mL)中，氮气保护下回流反应11h。反应液旋干后柱层析得标题化合物(40mg)。The compound 9-2 (50mg, 0.11mmol) and compound 10-1 (27.4mg, 0.13mmol), tris(dibenzylideneacetone) two palladium (10.4mg, 0.011mmol), 4,5-bisdiphenyl Phosphine-9,9-dimethylxanthene (6.6mg, 0.011mmol), cesium carbonate (74mg, 0.23mmol) were dissolved in dioxane (10mL), and the reaction was refluxed for 11h under nitrogen protection. The reaction mixture was spin-dried and column chromatography was used to obtain the title compound (40 mg).

¹H NMR(400MHz,DMSO-d ₆)δ9.54(s,1H),9.33(d,J＝3.3Hz,1H),8.98(s,1H),7.86–7.71(m,2H),7.70–7.47(m,4H),7.40–7.29(m,1H),7.18(d,J＝2.1Hz,1H),7.08(dd,J＝8.6,2.1Hz,2H),4.11–4.07(m,1H),3.39(d,J＝3.9Hz,2H),3.17(d,J＝4.9Hz,1H),3.10(s,2H),2.89–2.73(m,3H),2.70(s,6H),2.30(s,2H),1.88(s,4H),1.48(s,2H).LC-MS:[M+H] ⁺:557.3. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.54(s,1H),9.33(d,J=3.3Hz,1H),8.98(s,1H),7.86–7.71(m,2H),7.70– 7.47(m,4H),7.40–7.29(m,1H), 7.18(d,J=2.1Hz,1H), 7.08(dd,J=8.6,2.1Hz,2H), 4.11–4.07(m,1H) , 3.39 (d, J = 3.9 Hz, 2H), 3.17 (d, J = 4.9 Hz, 1H), 3.10 (s, 2H), 2.89-2.73 (m, 3H), 2.70 (s, 6H), 2.30 ( s,2H),1.88(s,4H),1.48(s,2H).LC-MS:[M+H] ⁺ :557.3.

实施例11 (S)-7-(3-异丙氧基苯基)-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺Example 11 (S)-7-(3-isopropoxyphenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[ 7) annulen-2-yl) quinazolin-2-amine

按照实施例9的方法，以化合物9-2(50mg,0.11mmol)和(3-异丙氧基苯基)硼酸(31mg,0.17mmol)为原料，得标题化合物(27mg)。According to the method of Example 9, using compound 9-2 (50 mg, 0.11 mmol) and (3-isopropoxyphenyl)boronic acid (31 mg, 0.17 mmol) as raw materials, the title compound (27 mg) was obtained.

¹H NMR(400MHz,DMSO-d ₆)δ9.79(s,1H),9.30(s,1H),7.98-7.67(m,5H),7.53–7.21(m,3H),7.12-7.01(m,2H),4.78(s,1H),4.46(s,1H),3.39(s,2H),3.12-3.11(m,2H),2.86(s,2H),2.79–2.61(m,2H),2.27(s,2H),1.87(s,4H),1.47(s,2H),1.38–1.23(m,6H).LC-MS:[M+H] ⁺:493.3. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.79(s,1H),9.30(s,1H),7.98-7.67(m,5H),7.53-7.21(m,3H),7.12-7.01(m , 2H), 4.78 (s, 1H), 4.46 (s, 1H), 3.39 (s, 2H), 3.12-3.11 (m, 2H), 2.86 (s, 2H), 2.79-2.61 (m, 2H), 2.27(s,2H),1.87(s,4H),1.47(s,2H),1.38-1.23(m,6H).LC-MS:[M+H] ⁺ :493.3.

实施例12 (S)-N,N-二甲基-4-(2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)喹唑啉-8-基)苯磺酰胺Example 12 (S)-N,N-Dimethyl-4-(2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7 ]Ranthen-2-yl)amino)quinazolin-8-yl)benzenesulfonamide

按照实施例1的方法，以化合物1-3(50mg,0.11mmol)和(4-(N,N-二甲基氨磺酰基)苯基)硼酸(39mg,0.17mmol)为原料，得标题化合物12(40mg)。According to the method of Example 1, using compound 1-3 (50mg, 0.11mmol) and (4-(N,N-dimethylsulfamoyl)phenyl)boronic acid (39mg, 0.17mmol) as starting materials, the title compound was obtained 12 (40mg).

¹H NMR(400MHz,DMSO-d ₆)δ9.85(s,1H),9.37(s,1H),8.08–7.94(m,3H),7.89(d,J＝7.9Hz,3H),7.72(s,1H),7.60–7.35(m,2H),6.94(d,J＝8.1Hz,1H),4.45(s,1H),3.50–3.49(m,4H),3.16(s,2H),2.76(s,6H),2.66–2.55(m,2H),2.25(s,2H),1.89(s,4H),1.54–1.31(m,2H).LC-MS:[M+H] ⁺:542.2. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.85 (s, 1H), 9.37 (s, 1H), 8.08-7.94 (m, 3H), 7.89 (d, J = 7.9 Hz, 3H), 7.72 ( s,1H), 7.60–7.35(m,2H), 6.94(d,J=8.1Hz,1H), 4.45(s,1H), 3.50–3.49(m,4H), 3.16(s,2H), 2.76 (s,6H),2.66-2.55(m,2H),2.25(s,2H),1.89(s,4H),1.54-1.31(m,2H).LC-MS:[M+H] ⁺ :542.2 .

实施例13 (S)-8-(4-苯氧基苯基)-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺Example 13 (S)-8-(4-phenoxyphenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7 ]Lylen-2-yl)quinazolin-2-amine

按照实施例1的方法，以化合物1-3(50mg,0.11mmol)和(4-苯氧基苯基)硼酸(36mg,0.17mmol)为原料，得标题化合物13(38mg)。According to the method of Example 1, using compound 1-3 (50 mg, 0.11 mmol) and (4-phenoxyphenyl)boronic acid (36 mg, 0.17 mmol) as raw materials, the title compound 13 (38 mg) was obtained.

¹H NMR(400MHz,DMSO-d ₆)δ9.79(s,1H),9.33(s,1H),7.92(d,J＝8.0Hz,1H),7.83(d,J＝7.2Hz,1H),7.78(d,J＝7.1Hz,3H),7.53(d,J＝8.3Hz,1H),7.46(q,J＝7.3Hz,3H),7.21(t,J＝7.5Hz,1H),7.15(t,J＝7.7Hz,4H),6.93(d,J＝8.2Hz,1H),4.46(s,1H),3.26–2.94(m,4H),2.80–2.75(m,1H),2.67–2.60(d,J＝14.3Hz,3H),2.19(s,2H),1.84(s,4H),1.58–1.33(m,2H).LC-MS:[M+H] ⁺:527.3. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.79(s,1H),9.33(s,1H),7.92(d,J=8.0Hz,1H),7.83(d,J=7.2Hz,1H) ,7.78(d,J=7.1Hz,3H),7.53(d,J=8.3Hz,1H),7.46(q,J=7.3Hz,3H),7.21(t,J=7.5Hz,1H),7.15 (t,J=7.7Hz,4H), 6.93(d,J=8.2Hz,1H), 4.46(s,1H), 3.26–2.94(m,4H), 2.80–2.75(m,1H), 2.67– 2.60(d,J=14.3Hz,3H),2.19(s,2H),1.84(s,4H),1.58–1.33(m,2H).LC-MS:[M+H] ⁺ :527.3.

实施例14 (S)-8-(2-苯氧基苯基)-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺Example 14 (S)-8-(2-phenoxyphenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7 ]Ranen-2-yl)quinazolin-2-amine

按照实施例1的方法，以化合物1-3(50mg,0.11mmol)和(2-苯氧基苯基)硼酸(36mg,0.17mmol)为原料，得标题化合物(45mg)。According to the method of Example 1, using compound 1-3 (50 mg, 0.11 mmol) and (2-phenoxyphenyl)boronic acid (36 mg, 0.17 mmol) as raw materials, the title compound (45 mg) was obtained.

¹H NMR(400MHz,DMSO-d ₆)δ9.72(s,1H),9.26(s,1H),7.86(d,J＝8.0Hz,1H),7.81(d,J＝2.2Hz,1H),7.72(d,J＝7.1Hz,1H),7.50(d,J＝7.4Hz,2H),7.40–7.27(m,3H),7.05(dt,J＝15.9,8.1Hz,3H),6.91(t,J＝6.8Hz,2H),6.79(d,J＝8.0Hz,2H),4.45(s,2H),3.40(s,2H),3.10–2.92(m,1H),2.81–2.75(m,1H),2.62-2.56(m,1H),2.44(s,2H),2.12(s,2H),1.83(s,4H),1.50–1.29(m,2H).LC-MS:[M+H] ⁺:527.3. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.72(s,1H),9.26(s,1H),7.86(d,J=8.0Hz,1H),7.81(d,J=2.2Hz,1H) ,7.72(d,J=7.1Hz,1H),7.50(d,J=7.4Hz,2H),7.40-7.27(m,3H),7.05(dt,J=15.9,8.1Hz,3H),6.91( t,J=6.8Hz,2H), 6.79(d,J=8.0Hz,2H), 4.45(s,2H), 3.40(s,2H), 3.10–2.92(m,1H), 2.81–2.75(m ,1H),2.62-2.56(m,1H),2.44(s,2H),2.12(s,2H),1.83(s,4H),1.50-1.29(m,2H).LC-MS:(M+ H) ⁺ :527.3.

实施例15 (S)-N,N-二甲基-3-(2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)喹唑啉-8-基)苯甲酰胺Example 15 (S)-N,N-Dimethyl-3-(2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7 ]Ranutene-2-yl)amino)quinazolin-8-yl)benzamide

按照实施例1的方法，以化合物1-3(50mg,0.11mmol)和(3-(二甲基氨基甲酰基)苯基)硼酸(33mg,0.17mmol)为原料，得标题化合物(38mg)。According to the method of Example 1, using compound 1-3 (50 mg, 0.11 mmol) and (3-(dimethylcarbamoyl)phenyl)boronic acid (33 mg, 0.17 mmol) as starting materials, the title compound (38 mg) was obtained.

¹H NMR(400MHz,DMSO-d ₆)δ9.78(s,1H),9.34(s,1H),7.95(d,J＝7.9Hz,1H),7.84(t,J＝8.6Hz,2H),7.63(d,J＝4.7Hz,2H),7.58(t,J＝7.6Hz,1H),7.55–7.50(m,2H),7.46(t,J＝7.6Hz,1H),6.94(d,J＝8.1Hz,1H),4.44(s,1H),3.39(s,3H),3.17(s,1H),2.99(s,6H),2.79-2.75(m,2H),2.64-2.58(m,2H),2.18-2.16(m,2H),1.85(s,4H),1.40-1.34(m,2H).LC-MS:[M+H] ⁺:506.3. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.78(s,1H),9.34(s,1H),7.95(d,J=7.9Hz,1H),7.84(t,J=8.6Hz,2H) ,7.63(d,J=4.7Hz,2H),7.58(t,J=7.6Hz,1H),7.55-7.50(m,2H),7.46(t,J=7.6Hz,1H),6.94(d, J = 8.1Hz, 1H), 4.44 (s, 1H), 3.39 (s, 3H), 3.17 (s, 1H), 2.99 (s, 6H), 2.79-2.75 (m, 2H), 2.64-2.58 (m ,2H),2.18-2.16(m,2H),1.85(s,4H),1.40-1.34(m,2H).LC-MS:[M+H] ⁺ :506.3.

实施例16 (S)-8-(2-氯-4-异丙氧基苯基)-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺Example 16 (S)-8-(2-chloro-4-isopropoxyphenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H -Benzo[7]annun-2-yl)quinazolin-2-amine

按照实施例1的方法，以化合物1-3(50mg,0.11mmol)和(2-氯-4-异丙氧基苯基)硼酸(36mg,0.17mmol)为原料，得标题化合物(38mg)。According to the method of Example 1, using compound 1-3 (50 mg, 0.11 mmol) and (2-chloro-4-isopropoxyphenyl)boronic acid (36 mg, 0.17 mmol) as raw materials, the title compound (38 mg) was obtained.

¹H NMR(400MHz,DMSO-d ₆)δ9.75(s,1H),9.32(s,1H),7.94(dd,J＝8.0,1.5Hz,1H),7.76–7.64(m,2H),7.43(t,J＝7.6Hz,1H),7.34(t,J＝7.7Hz,2H),7.18(d,J＝2.5Hz,1H),7.04(dd,J＝8.4,2.5Hz,1H),6.87(d,J＝8.2Hz,1H),4.75(hept,J＝6.0Hz,1H),4.44(s,2H),3.33(s,2H),3.07(s,2H),2.78-2.72(m,1H),2.63-2.57(m,2H),2.18(t,J＝7.3Hz,2H),1.86(s,4H),1.47-1.42(m,2H),1.36(d,J＝6.0Hz,6H).LC-MS:[M+H] ⁺:527.3. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.75(s,1H),9.32(s,1H),7.94(dd,J=8.0,1.5Hz,1H),7.76-7.64(m,2H), 7.43 (t, J = 7.6 Hz, 1H), 7.34 (t, J = 7.7 Hz, 2H), 7.18 (d, J = 2.5 Hz, 1H), 7.04 (dd, J = 8.4, 2.5 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 4.75 (hept, J = 6.0 Hz, 1H), 4.44 (s, 2H), 3.33 (s, 2H), 3.07 (s, 2H), 2.78-2.72 (m ,1H),2.63-2.57(m,2H),2.18(t,J=7.3Hz,2H),1.86(s,4H),1.47-1.42(m,2H),1.36(d,J=6.0Hz, 6H).LC-MS:[M+H] ⁺ :527.3.

实施例17 (S)-8-(3-氯-4-异丙氧基苯基)-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺Example 17 (S)-8-(3-chloro-4-isopropoxyphenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H -Benzo[7]annun-2-yl)quinazolin-2-amine

按照实施例1的方法，以化合物1-3(50mg,0.11mmol)和(3-氯-4-异丙氧基苯基)硼酸(36mg,0.17mmol)为原料，得标题化合物(41mg)。According to the method of Example 1, using compound 1-3 (50 mg, 0.11 mmol) and (3-chloro-4-isopropoxyphenyl)boronic acid (36 mg, 0.17 mmol) as raw materials, the title compound (41 mg) was obtained.

¹H NMR(400MHz,DMSO-d ₆)δ9.81(s,1H),9.33(s,1H),7.91(dd,J＝8.0,1.4Hz,1H),7.86–7.74(m,2H),7.71–7.52(m,3H),7.43(t,J＝7.6Hz,1H),7.32(d,J＝8.6Hz,1H),6.98(d,J＝8.3Hz,1H),4.79(hept,J＝6.0Hz,1H),4.47–4.40(m,2H),3.42–3.38(m,3H),3.09(s,1H),2.80–2.75(m,1H),2.72–2.56(m,2H),2.34–2.11(m,2H),1.87(s,4H),1.46-1.44(m,2H),1.39(dd,J＝6.0Hz,6H).LC-MS:[M+H] ⁺:527.2. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.81(s,1H),9.33(s,1H),7.91(dd,J=8.0,1.4Hz,1H),7.86-7.74(m,2H), 7.71–7.52 (m, 3H), 7.43 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 4.79 (hept, J =6.0Hz,1H), 4.47–4.40(m,2H),3.42–3.38(m,3H),3.09(s,1H), 2.80–2.75(m,1H), 2.72–2.56(m,2H), 2.34–2.11(m,2H),1.87(s,4H),1.46-1.44(m,2H),1.39(dd,J=6.0Hz,6H).LC-MS:[M+H] ⁺ :527.2.

实施例18 (S)-8-(3-(吗啉代磺酰基)苯基)-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺Example 18 (S)-8-(3-(morpholinosulfonyl)phenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H- Benzo[7]ananthen-2-yl)quinazolin-2-amine

按照实施例1的方法，以化合物1-3(50mg,0.11mmol)和(3-(吗啉磺酰基)苯基)硼酸(39mg,0.17mmol)为原料，得标题化合物(46mg)。According to the method of Example 1, using compound 1-3 (50 mg, 0.11 mmol) and (3-(morpholinesulfonyl)phenyl)boronic acid (39 mg, 0.17 mmol) as starting materials, the title compound (46 mg) was obtained.

¹H NMR(400MHz,DMSO-d ₆)δ9.85(s,1H),9.37(s,1H),8.13(dt,J＝7.2,1.7Hz,1H),8.00(dd,J＝7.9,1.4Hz,1H),7.94–7.77(m,4H),7.67(d,J＝2.2Hz,1H),7.49(t,J＝7.6Hz,1H),7.42(dd,J＝8.2,2.2Hz,1H),6.95(d,J＝8.2Hz,1H),4.48–4.41(m,3H),3.70–3.56(m,4H),3.39(d,J＝2.6Hz,2H),3.10(s,1H),2.91(t,J＝4.7Hz,4H),2.81–2.73(m,1H),2.63(t,J＝12.4Hz,1H),2.38(s,1H),2.24(s,2H),1.88(s,4H),1.38(s,2H).LC-MS:[M+H] ⁺:584.2. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.85(s,1H),9.37(s,1H),8.13(dt,J=7.2,1.7Hz,1H),8.00(dd,J=7.9,1.4 Hz,1H),7.94-7.77(m,4H),7.67(d,J=2.2Hz,1H),7.49(t,J=7.6Hz,1H),7.42(dd,J=8.2,2.2Hz,1H ), 6.95(d,J=8.2Hz,1H), 4.48–4.41(m,3H), 3.70–3.56(m,4H), 3.39(d,J=2.6Hz,2H), 3.10(s,1H) ,2.91(t,J=4.7Hz,4H),2.81-2.73(m,1H),2.63(t,J=12.4Hz,1H),2.38(s,1H),2.24(s,2H),1.88( s,4H),1.38(s,2H).LC-MS:[M+H] ⁺ :584.2.

实施例19 (S)-N ⁸-(4-异丙氧基苯基)-N ²-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2,8二胺 Example 19 (S)-N ⁸ -(4-isopropoxyphenyl)-N ² -(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzene And [7] annulen-2-yl) quinazoline-2,8 diamine

按照实施例7的方法，以化合物1-3(50mg,0.11mmol)和4-异丙氧基苯胺(26mg,0.17mmol)为原料，得标题化合物(16mg)。According to the method of Example 7, using compound 1-3 (50 mg, 0.11 mmol) and 4-isopropoxyaniline (26 mg, 0.17 mmol) as raw materials, the title compound (16 mg) was obtained.

¹H NMR(400MHz,DMSO-d ₆)δ9.77(s,1H),9.23(s,1H),8.24(s,1H),7.81–7.66(m,1H),7.68–7.53(m,2H),7.33(d,J＝7.5Hz,1H),7.24(d,J＝8.3Hz,2H),7.18(t,J＝7.8Hz,1H),7.09(d,J＝8.1Hz,1H),6.94(d,J＝8.5Hz,2H),4.55(hept,J＝6.1Hz,1H),2.86(s,7H),2.66(t,J＝13.6Hz,2H),2.18–1.98(m,2H),1.78(d,J＝5.6Hz,4H),1.49(s,2H),1.27(d,J＝6.1Hz,6H).LC-MS:[M+H] ⁺:509.3. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.77(s,1H),9.23(s,1H),8.24(s,1H),7.81-7.66(m,1H),7.68-7.53(m,2H) ), 7.33 (d, J = 7.5 Hz, 1H), 7.24 (d, J = 8.3 Hz, 2H), 7.18 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 8.1 Hz, 1H), 6.94(d,J=8.5Hz,2H),4.55(hept,J=6.1Hz,1H), 2.86(s,7H), 2.66(t,J=13.6Hz,2H), 2.18–1.98(m,2H ), 1.78(d,J=5.6Hz,4H),1.49(s,2H),1.27(d,J=6.1Hz,6H).LC-MS:[M+H] ⁺ :509.3.

实施例20 (S)-N ²-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)-N ⁸-(4-(邻甲苯氧基)苯基)喹唑啉-2,8-二胺 Example 20 (S)-N ² -(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annun-2-yl)-N ⁸ -(4-(o-tolyloxy)phenyl)quinazoline-2,8-diamine

按照实施例7的方法，以化合物1-3(50mg,0.11mmol)和2-(邻甲苯基氧基)苯胺(34mg,0.17mmol)为原料，得标题化合物(47mg)。According to the method of Example 7, using compound 1-3 (50 mg, 0.11 mmol) and 2-(o-tolyloxy)aniline (34 mg, 0.17 mmol) as raw materials, the title compound (47 mg) was obtained.

¹H NMR(400MHz,DMSO-d ₆)δ9.84(s,1H),9.26(s,1H),8.24(s,1H),7.91(dd,J＝8.1,2.2Hz,1H),7.81–7.67(m,2H),7.41–7.24(m,5H),7.15(dtd,J＝19.6,7.6,1.4Hz,2H),7.04(dd,J＝8.1,1.2Hz,1H),6.91(td,J＝7.8,1.4Hz,1H),6.69(dd,J＝8.1,1.4Hz,1H),6.39(d,J＝8.2Hz,1H),3.38(s,5H),3.09(s,2H),2.67(s,2H),2.25(d,J＝4.7Hz,2H),2.08(s,3H),1.88(s,4H),1.46–1.30(m,2H).LC-MS:[M+H] ⁺:556.3. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.84 (s, 1H), 9.26 (s, 1H), 8.24 (s, 1H), 7.91 (dd, J = 8.1, 2.2 Hz, 1H), 7.81- 7.67(m,2H),7.41–7.24(m,5H),7.15(dtd,J=19.6,7.6,1.4Hz,2H),7.04(dd,J=8.1,1.2Hz,1H),6.91(td, J = 7.8, 1.4 Hz, 1H), 6.69 (dd, J = 8.1, 1.4 Hz, 1H), 6.39 (d, J = 8.2 Hz, 1H), 3.38 (s, 5H), 3.09 (s, 2H), 2.67(s,2H),2.25(d,J=4.7Hz,2H),2.08(s,3H),1.88(s,4H),1.46-1.30(m,2H).LC-MS:[M+H ] ⁺ :556.3.

实施例21 (S)-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)-8-(3-(吡咯烷-1-基磺酰基)苯基)喹唑啉-2-胺Example 21 (S)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]ronen-2-yl)-8-( 3-(pyrrolidin-1-ylsulfonyl)phenyl)quinazolin-2-amine

按照实施例1的方法，以化合物1-3(50mg,0.11mmol)和(3-(吡咯烷-1-基磺酰基)苯基)硼酸(44mg,0.17mmol)为原料，得标题化合物(32mg)。According to the method of Example 1, using compound 1-3 (50mg, 0.11mmol) and (3-(pyrrolidin-1-ylsulfonyl)phenyl)boronic acid (44mg, 0.17mmol) as starting materials, the title compound (32mg ).

¹H NMR(400MHz,DMSO-d ₆)δ9.81(s,1H),9.35(s,1H),8.10(d,J＝7.7Hz,1H),7.98(d,J＝7.9Hz,1H),7.94–7.89(m,2H),7.88–7.84(m,1H),7.77(t,J＝8.0Hz,1H),7.62(d,J＝2.3Hz,1H),7.48(t,J＝7.6Hz,1H),7.40(dd,J＝8.1,2.2Hz,1H),6.90(d,J＝8.2Hz,1H),3.24–3.12(m,4H),2.91(s,5H),2.78(s,1H),2.60–2.53(m,1H),2.46(s,2H),2.16–1.97(m,2H),1.80(s,4H),1.68–1.55(m,4H),1.41(s,2H).LC-MS:[M+H] ⁺:568.3. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.81(s,1H),9.35(s,1H), 8.10(d,J=7.7Hz,1H),7.98(d,J=7.9Hz,1H) ,7.94–7.89(m,2H),7.88–7.84(m,1H),7.77(t,J=8.0Hz,1H),7.62(d,J=2.3Hz,1H),7.48(t,J=7.6 Hz, 1H), 7.40 (dd, J = 8.1, 2.2 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 3.24-3.12 (m, 4H), 2.91 (s, 5H), 2.78 (s ,1H),2.60--2.53(m,1H),2.46(s,2H),2.16-1.97(m,2H),1.80(s,4H),1.68-1.55(m,4H),1.41(s,2H) ).LC-MS:[M+H] ⁺ :568.3.

实施例22 (S)-8-(3-((1,4-二氮杂环庚烷-1-基)磺酰基)苯基)-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺盐酸盐Example 22 (S)-8-(3-((1,4-diazepan-1-yl)sulfonyl)phenyl)-N-(7-(pyrrolidin-1-yl)- 6,7,8,9-Tetrahydro-5H-benzo[7] annulen-2-yl)quinazolin-2-amine hydrochloride

a)4-((3-溴苯基)磺酰基)-1,4-二氮杂环庚烷-1-羧酸叔丁酯(22-3)a) tert-butyl 4-((3-bromophenyl)sulfonyl)-1,4-diazepan-1-carboxylate (22-3)

将化合物22-1(1.0g,3.9mmol)溶于二氯甲烷(10mL)，加入三乙胺(0.79g,7.8mmol)后温度降低到0℃，滴加化合物22-2(0.48g,4.7mmol)的二氯甲烷(5mL)溶液，滴加完毕升温至室温搅拌1h。反应液加入50mL二氯甲烷稀释后用饱和食盐水(20mL)洗涤两次，取有机层，旋干得化合物22-3(1.3g)。Compound 22-1 (1.0g, 3.9mmol) was dissolved in dichloromethane (10mL), triethylamine (0.79g, 7.8mmol) was added, and the temperature was lowered to 0°C, compound 22-2 (0.48g, 4.7 mmol) in dichloromethane (5 mL), after adding dropwise, warm to room temperature and stir for 1 h. The reaction solution was diluted with 50 mL of dichloromethane and washed twice with saturated brine (20 mL). The organic layer was taken and spin-dried to obtain compound 22-3 (1.3 g).

b)4-((3-(苯硼酸频哪醇酯基)磺酰基)-1,4-二氮杂-1-甲酸叔丁基酯(22-5)b) 4-((3-(phenylboronic acid pinacol ester)sulfonyl)-1,4-diaza-1-carboxylate tert-butyl ester (22-5)

将化合物22-3(1.0g，2.38mmol)及联频哪醇酯22-4(0.79g，3.10mmol)，1,1'-双二苯基膦基二茂铁二氯化钯(0.18g，0.24mmol)，醋酸钾(0.47g，4.76mmol)溶于二氧六环(20mL)中，氮气保护下加热至回流，7h后停止加热，反应液旋干后柱层析得化合物22-5(1.02g)。The compound 22-3 (1.0g, 2.38mmol) and bipinacol ester 22-4 (0.79g, 3.10mmol), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (0.18g , 0.24mmol), potassium acetate (0.47g, 4.76mmol) was dissolved in dioxane (20mL), heated to reflux under nitrogen protection, stopped heating after 7h, the reaction solution was spin-dried and column chromatography to obtain compound 22-5 (1.02g).

c)叔丁基(S)-4-((3-(2-((7-(吡咯烷基-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基]氨基)喹唑啉-8-基)苯基)磺酰基)-1,4-二氮杂环庚烷-1-羧酸酯(22-6)c) tert-Butyl(S)-4-((3-(2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7] Annulen-2-yl)amino)quinazolin-8-yl)phenyl)sulfonyl)-1,4-diazepan-1-carboxylate (22-6)

将化合物1-3(50mg，0.11mmol)及22-5(107mg，0.17mmol)，1,1'-双二苯基膦二茂铁二氯化钯(8.3mg，0.011mmol)，碳酸铯(74mg，0.22mmol)溶于二氧六环(10mL)/水(1mL)的混合溶剂中，氮气保护下回流反应10h。反应液旋干后柱层析得化合物22-6(65mg)。LC-MS:[M+H] ⁺:697.4. Compound 1-3 (50mg, 0.11mmol) and 22-5 (107mg, 0.17mmol), 1,1'-bisdiphenylphosphine ferrocene dichloride palladium (8.3mg, 0.011mmol), cesium carbonate ( 74 mg, 0.22 mmol) was dissolved in a mixed solvent of dioxane (10 mL)/water (1 mL), and the reaction was refluxed for 10 h under the protection of nitrogen. The reaction solution was spin-dried and column chromatography was used to obtain compound 22-6 (65 mg). LC-MS: [M+H] ⁺ :697.4.

d)(S)-8-(3-((1,4-二氮杂环庚烷-1-基)磺酰基)苯基)-N-(7-(吡咯烷-1-基)-6,7,8,9- 四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺盐酸盐d) (S)-8-(3-((1,4-diazepan-1-yl)sulfonyl)phenyl)-N-(7-(pyrrolidin-1-yl)-6 ,7,8,9-Tetrahydro-5H-benzo[7]annun-2-yl)quinazolin-2-amine hydrochloride

将化合物22-6(60mg，0.086mmol)溶于二氧六环(5mL)，加入盐酸二氧六环溶液(4M,5mL)后室温搅拌4h。旋干反应液，制备分离得标题化合物(23mg)。Compound 22-6 (60 mg, 0.086 mmol) was dissolved in dioxane (5 mL), and dioxane hydrochloride solution (4M, 5 mL) was added and stirred at room temperature for 4 h. The reaction solution was spin-dried to prepare and isolate the title compound (23 mg).

¹H NMR(400MHz,DMSO-d ₆)δ9.79(s,1H),9.35(s,1H),8.28(s,2H),8.08(d,J＝7.7Hz,1H),7.98(dd,J＝8.0,1.4Hz,1H),7.94–7.83(m,3H),7.75(t,J＝7.7Hz,1H),7.60(d,J＝2.2Hz,1H),7.48(t,J＝7.6Hz,1H),7.41(dd,J＝8.1,2.2Hz,1H),6.91(d,J＝8.2Hz,1H),3.30(t,J＝5.7Hz,5H),2.95–2.73(m,10H),2.43(d,J＝11.1Hz,2H),1.99(s,2H),1.75(d,J＝13.7Hz,6H),1.43(s,2H).LC-MS:[M+H] ⁺:597.3. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.79(s,1H), 9.35(s,1H), 8.28(s,2H), 8.08(d,J=7.7Hz,1H), 7.98(dd, J = 8.0, 1.4 Hz, 1H), 7.94–7.83 (m, 3H), 7.75 (t, J = 7.7 Hz, 1H), 7.60 (d, J = 2.2 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.41 (dd, J = 8.1, 2.2 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 3.30 (t, J = 5.7 Hz, 5H), 2.95-2.73 (m, 10H ),2.43(d,J=11.1Hz,2H),1.99(s,2H),1.75(d,J=13.7Hz,6H),1.43(s,2H).LC-MS:[M+H] ⁺ :597.3.

实施例23 (S)-8-(2,3-二氢苯并[b][1,4]二恶英-6-基)-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺Example 23 (S)-8-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-N-(7-(pyrrolidin-1-yl)-6 ,7,8,9-Tetrahydro-5H-benzo[7]annun-2-yl)quinazolin-2-amine

按照实施例1的方法，以化合物1-3(50mg，0.11mmol)和(2,3-二氢苯并[b][1,4]二恶英-6-基)硼酸(44mg，0.17mmol)为原料，得标题化合物(38mg)。According to the method of Example 1, with compound 1-3 (50mg, 0.11mmol) and (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid (44mg, 0.17mmol) ) Was used as the starting material to obtain the title compound (38 mg).

¹H NMR(400MHz,DMSO-d ₆)δ9.71(s,1H),9.30(s,1H),8.24(s,1H),7.80–7.69(m,2H),7.54(dd,J＝8.1,2.2Hz,1H),7.41(t,J＝7.6Hz,1H),7.18(d,J＝7.6Hz,2H),6.97(dd,J＝10.4,8.2Hz,2H),4.33(s,4H),3.01–2.74(m,7H),2.62(s,2H),2.05(s,2H),1.80(d,J＝5.8Hz,4H),1.44(s,2H).LC-MS:[M+H] ⁺:493.3. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.71(s,1H),9.30(s,1H),8.24(s,1H),7.80-7.69(m,2H),7.54(dd,J=8.1 ,2.2Hz,1H),7.41(t,J=7.6Hz,1H),7.18(d,J=7.6Hz,2H),6.97(dd,J=10.4,8.2Hz,2H),4.33(s,4H ),3.01–2.74(m,7H),2.62(s,2H),2.05(s,2H),1.80(d,J=5.8Hz,4H),1.44(s,2H).LC-MS:[M +H] ⁺ :493.3.

实施例24 (S)-8-(3,4-二甲氧基苯基)-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺Example 24 (S)-8-(3,4-Dimethoxyphenyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzene And [7] annulen-2-yl) quinazolin-2-amine

按照实施例1的方法，以化合物1-3(50mg，0.11mmol)和(3,4-二甲氧基苯基)硼酸(42mg，0.17mmol)为原料，得标题化合物(40mg)。According to the method of Example 1, using compound 1-3 (50 mg, 0.11 mmol) and (3,4-dimethoxyphenyl)boronic acid (42 mg, 0.17 mmol) as starting materials, the title compound (40 mg) was obtained.

¹H NMR(400MHz,DMSO-d ₆)δ9.72(s,1H),9.31(s,1H),7.87(dd,J＝8.0,1.5Hz,1H),7.84–7.73(m,2H),7.50–7.36(m,2H),7.31(d,J＝2.0Hz,1H),7.22(dd,J＝8.2,2.0Hz,1H),7.10(d,J＝8.3Hz,1H),6.90(d,J＝8.1Hz,1H),3.86(s,3H),3.70(s,3H),2.83(d,J＝11.4Hz,1H),2.70(s,5H),2.57–2.51(m,1H),2.39(s,2H),1.90(s,2H),1.74(s,4H),1.46(s,2H).LC-MS:[M+H] ⁺:495.2. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.72(s,1H),9.31(s,1H),7.87(dd,J=8.0,1.5Hz,1H),7.84-7.73(m,2H), 7.50–7.36(m,2H), 7.31(d,J=2.0Hz,1H), 7.22(dd,J=8.2,2.0Hz,1H), 7.10(d,J=8.3Hz,1H), 6.90(d ,J=8.1Hz,1H),3.86(s,3H),3.70(s,3H),2.83(d,J=11.4Hz,1H),2.70(s,5H),2.57–2.51(m,1H) ,2.39(s,2H),1.90(s,2H),1.74(s,4H),1.46(s,2H).LC-MS:[M+H] ⁺ :495.2.

实施例25 (S)-8-(1-甲基-1H-吲唑-5-基)-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺Example 25 (S)-8-(1-methyl-1H-indazol-5-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro- 5H-Benzo[7]Annun-2-yl)quinazolin-2-amine

按照实施例1的方法，以化合物1-3(50mg，0.11mmol)和(1-甲基-1H-吲唑-5-基)硼酸(30mg，0.17mmol)为原料，得标题化合物(10mg)。According to the method of Example 1, using compound 1-3 (50mg, 0.11mmol) and (1-methyl-1H-indazol-5-yl)boronic acid (30mg, 0.17mmol) as raw materials, the title compound (10mg) was obtained .

¹H NMR(400MHz,DMSO-d ₆)δ9.70(s,1H),9.33(s,1H),8.11(s,1H),8.01(s,1H),7.91(dd,J＝8.0,1.4Hz,1H),7.83(dd,J＝7.2,1.4Hz,1H),7.78–7.70(m,2H),7.68(d,J＝2.1Hz,1H),7.49–7.42(m,1H),7.37(dd,J＝8.1,2.0Hz,1H),6.82(d,J＝8.2Hz,1H),4.14(s,3H),2.81(d,J＝13.0Hz,1H),2.67(s,1H),2.60(s,4H),2.41(s,2H),2.33(p,J＝1.9Hz,1H),2.07(s,2H),1.72(s,4H),1.60(s,2H).LC-MS:[M+H] ⁺:489.1. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.70(s,1H),9.33(s,1H),8.11(s,1H),8.01(s,1H),7.91(dd,J=8.0,1.4 Hz,1H),7.83(dd,J=7.2,1.4Hz,1H),7.78–7.70(m,2H),7.68(d,J=2.1Hz,1H),7.49–7.42(m,1H),7.37 (dd,J=8.1,2.0Hz,1H), 6.82(d,J=8.2Hz,1H), 4.14(s,3H), 2.81(d,J=13.0Hz,1H), 2.67(s,1H) ,2.60(s,4H),2.41(s,2H),2.33(p,J=1.9Hz,1H),2.07(s,2H),1.72(s,4H),1.60(s,2H).LC- MS:[M+H] ⁺ :489.1.

实施例26 (S)-(4-甲基哌嗪-1-基)(5-(2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)喹唑啉-8-基)吡啶-3-基)甲酮Example 26 (S)-(4-Methylpiperazin-1-yl)(5-(2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H -Benzo[7]Annun-2-yl)amino)quinazolin-8-yl)pyridin-3-yl)methanone

a)(S)-5-(2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)喹唑啉-8-基)烟酸甲酯(26-2)a) (S)-5-(2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]ronen-2-yl)amino )Quinazolin-8-yl)nicotinic acid methyl ester (26-2)

将化合物1-3(300mg,0.69mmol)，化合物26-1(270mg,1.02mmol)，1,1'-双二苯基膦二茂铁二氯化钯(50mg，0.068mmol)及碳酸铯(444mg,1.36mmol)溶于二氧六环(10ml)/水(1mL)混合溶剂中，加热回流反应5h后。反应液旋干、柱层析纯化得化合物26-2(212mg)。LC-MS:[M+H] ⁺:494.1。 Compound 1-3 (300mg, 0.69mmol), compound 26-1 (270mg, 1.02mmol), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (50mg, 0.068mmol) and cesium carbonate ( 444mg, 1.36mmol) was dissolved in a mixed solvent of dioxane (10ml)/water (1mL) and heated to reflux for 5h after reaction. The reaction solution was spin-dried and purified by column chromatography to obtain compound 26-2 (212 mg). LC-MS: [M+H] ⁺ : 494.1.

b)((S)-5-(2-(((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基]氨基]喹唑啉-8-基)烟酸(26-3)b)((S)-5-(2-(((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annun-2-yl ]Amino]quinazolin-8-yl)nicotinic acid (26-3)

将化合物(S)-5-(2-(((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基]氨基]氨基)喹唑啉-8-烟酸甲酯26-2(212mg,0.43mmol)溶于四氢呋喃(3mL)和水(2mL)中，室温条件下加入一水合氢氧化锂(46mg，1.08mmol)，升温至50℃反应2h。反应完毕用1M的盐酸将反应液调制pH＝2，旋干反应液，得化合物26-3(171mg)。LC-MS:[M+H] ⁺:480.1。 The compound (S)-5-(2-(((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annun-2-yl] Amino]amino)quinazoline-8-nicotinic acid methyl ester 26-2 (212mg, 0.43mmol) was dissolved in tetrahydrofuran (3mL) and water (2mL), and lithium hydroxide monohydrate (46mg, 1.08mmol) was added at room temperature. ), the temperature was raised to 50°C and reacted for 2 hours. After the reaction, the pH of the reaction solution was adjusted to 2 with 1M hydrochloric acid, and the reaction solution was spin-dried to obtain compound 26-3 (171 mg). LC-MS: [M+H] ⁺ : 480.1.

c)((S)-(4-甲基哌嗪-1-基)(5-(2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)喹唑啉-8-基)吡啶-3-基)甲酮c)((S)-(4-Methylpiperazin-1-yl)(5-(2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H -Benzo[7]Annun-2-yl)amino)quinazolin-8-yl)pyridin-3-yl)methanone

将化合物26-3(171mg,0.36mmol)，2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐HATU(167mg,0.54mmol)，干燥三乙胺(73mg,0.72mmol)溶于DMF(10mL)中，搅拌30min后加入N-甲基哌嗪(55mg,0.54mmol)。反应液在室温下搅拌反应12h后，加入50mL乙酸乙酯稀释，饱和食盐水洗涤5次后取有机相并旋干，制备液相纯化后得标题化合物(20mg)。Compound 26-3 (171mg, 0.36mmol), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate HATU (167mg, 0.54mmol) , Dry triethylamine (73mg, 0.72mmol) was dissolved in DMF (10mL), stirred for 30min and then added with N-methylpiperazine (55mg, 0.54mmol). After the reaction solution was stirred and reacted at room temperature for 12 hours, it was diluted with 50 mL of ethyl acetate, washed with saturated brine for 5 times, and the organic phase was taken and spin-dried to obtain the title compound (20 mg) after liquid phase purification.

¹H NMR(400MHz,DMSO-d ₆)δ9.81(s,1H),9.36(s,1H),9.02(d,J＝2.1Hz,1H),8.69(d,J＝2.0Hz,1H),8.04(t,J＝2.1Hz,1H),8.00(dd,J＝8.0,1.4Hz,1H),7.91(dd,J＝7.2,1.4Hz,1H),7.57(d,J＝2.0Hz,1H),7.53–7.46(m,1H),7.40(dd,J＝8.1,2.2Hz,1H),6.92(d,J＝8.2Hz,1H),2.81(s,7H),2.65–2.52(m,5H),2.43–2.28(m,3H),2.20(s,2H),2.16(s,3H),1.99(s,2H),1.77(s,4H),1.42(s,2H).LC-MS:[M+H] ⁺:562.1. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.81(s,1H),9.36(s,1H),9.02(d,J=2.1Hz,1H),8.69(d,J=2.0Hz,1H) ,8.04(t,J=2.1Hz,1H),8.00(dd,J=8.0,1.4Hz,1H),7.91(dd,J=7.2,1.4Hz,1H),7.57(d,J=2.0Hz, 1H), 7.53–7.46 (m, 1H), 7.40 (dd, J = 8.1, 2.2 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 2.81 (s, 7H), 2.65–2.52 (m ,5H),2.43-2.28(m,3H),2.20(s,2H),2.16(s,3H),1.99(s,2H),1.77(s,4H),1.42(s,2H).LC- MS:[M+H] ⁺ :562.1.

实施例27 (S)-8-(苯并[d][1,3]二氧杂-5-基)-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺Example 27 (S)-8-(benzo[d][1,3]dioxa-5-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9 -Tetrahydro-5H-benzo[7]ananthen-2-yl)quinazolin-2-amine

按照实施例1的方法，以化合物1-3(50mg，0.11mmol)和苯并[d][1,3]二氧杂-5-基硼酸(38mg，0.17mmol)为原料，得标题化合物(35mg)。According to the method of Example 1, using compound 1-3 (50mg, 0.11mmol) and benzo[d][1,3]dioxa-5-ylboronic acid (38mg, 0.17mmol) as starting materials, the title compound ( 35mg).

¹H NMR(400MHz,DMSO-d ₆)δ9.78(s,1H),9.32(s,1H),7.89(dd,J＝7.9,1.5Hz,1H),7.85–7.71(m,2H),7.54(dd,J＝8.1,2.3Hz,1H),7.42(t,J＝7.6Hz,1H),7.29(d,J＝1.7Hz,1H),7.16(dd,J＝8.0,1.7Hz,1H),7.07(d,J＝8.0Hz,1H),6.99(d,J＝8.2Hz,1H),6.14(d,J＝6.9Hz,2H),4.46-4.43(m,1H),3.40–3.39(m,2H),3.18-3.16(m,2H),2.83–2.77(m,1H),2.69-2.63(m,2H),2.57(s,1H),2.26(s,2H),1.90(d,J＝7.5Hz,4H),1.44-1.34(m,2H).LC-MS:[M+H] ⁺:479.1. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.78(s,1H),9.32(s,1H),7.89(dd,J=7.9,1.5Hz,1H),7.85-7.71(m,2H), 7.54(dd,J＝8.1,2.3Hz,1H),7.42(t,J＝7.6Hz,1H),7.29(d,J＝1.7Hz,1H),7.16(dd,J＝8.0,1.7Hz,1H ), 7.07 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.14 (d, J = 6.9 Hz, 2H), 4.46-4.43 (m, 1H), 3.40–3.39 (m,2H),3.18-3.16(m,2H),2.83-2.77(m,1H),2.69-2.63(m,2H),2.57(s,1H),2.26(s,2H),1.90(d ,J=7.5Hz,4H),1.44-1.34(m,2H).LC-MS:[M+H] ⁺ :479.1.

实施例28 (S)-8-(2,2-二氟苯并[d][1,3]二氧杂-5-基)-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺Example 28 (S)-8-(2,2-Difluorobenzo[d][1,3]dioxa-5-yl)-N-(7-(pyrrolidin-1-yl)-6 ,7,8,9-Tetrahydro-5H-benzo[7]annun-2-yl)quinazolin-2-amine

按照实施例1的方法，以化合物1-3(50mg，0.11mmol)和(2,2-二氟苯并[d][1,3]二氧杂-5-基)硼酸(46mg，0.17mmol)为原料，得标题化合物(35mg)。According to the method of Example 1, with compound 1-3 (50mg, 0.11mmol) and (2,2-difluorobenzo[d][1,3]dioxa-5-yl)boronic acid (46mg, 0.17mmol) ) Was used as the starting material to obtain the title compound (35 mg).

¹H NMR(400MHz,DMSO-d ₆)δ9.81(s,1H),9.34(s,1H),7.95(dd,J＝8.0,1.5Hz,1H),7.83(dd,J＝7.3,1.5Hz,1H),7.78(d,J＝1.6Hz,1H),7.62(d,J＝2.3Hz,1H),7.58–7.41(m,4H),6.94(d,J＝8.2Hz,1H),3.39(s,2H),3.00(s,3H),2.78(d,J＝8.2Hz,2H),2.59(d,J＝13.6Hz,2H),2.24–1.94(m,2H),1.83(s,4H),1.45(s,2H).LC-MS:[M+H] ⁺:515.2. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.81(s,1H),9.34(s,1H),7.95(dd,J=8.0,1.5Hz,1H),7.83(dd,J=7.3,1.5 Hz, 1H), 7.78 (d, J = 1.6 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.58-7.41 (m, 4H), 6.94 (d, J = 8.2 Hz, 1H), 3.39 (s, 2H), 3.00 (s, 3H), 2.78 (d, J = 8.2 Hz, 2H), 2.59 (d, J = 13.6 Hz, 2H), 2.24-1.94 (m, 2H), 1.83 (s ,4H),1.45(s,2H).LC-MS:[M+H] ⁺ :515.2.

实施例29 (S)-8-(1H-苯并[d]咪唑-5-基)-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺Example 29 (S)-8-(1H-benzo[d]imidazol-5-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H -Benzo[7]annun-2-yl)quinazolin-2-amine

按照实施例1的方法，以化合物1-3(50mg，0.11mmol)和(1H-苯并[d]咪唑-5-基)硼酸(46mg，0.17mmol)为原料，得标题化合物(23mg)。According to the method of Example 1, using compound 1-3 (50 mg, 0.11 mmol) and (1H-benzo[d]imidazol-5-yl)boronic acid (46 mg, 0.17 mmol) as starting materials, the title compound (23 mg) was obtained.

¹H NMR(400MHz,DMSO-d ₆)δ9.71(d,J＝5.4Hz,1H),9.33(s,1H),8.29(s,2H), 7.90(dd,J＝8.0,1.5Hz,1H),7.88–7.80(m,2H),7.79–7.67(m,2H),7.52(dd,J＝8.3,1.6Hz,1H),7.45(t,J＝7.6Hz,1H),7.39(dd,J＝8.1,2.3Hz,1H),6.82(d,J＝8.1Hz,1H),2.76(s,6H),2.49-2.46(m,2H),2.25-2.14(m,2H),1.92(s,1H),1.76(s,4H),1.39–1.27(m,2H).LC-MS:[M+H] ⁺:475.3. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.71(d,J=5.4Hz,1H),9.33(s,1H),8.29(s,2H), 7.90(dd,J=8.0,1.5Hz, 1H),7.88–7.80(m,2H),7.79–7.67(m,2H),7.52(dd,J=8.3,1.6Hz,1H),7.45(t,J=7.6Hz,1H),7.39(dd ,J=8.1,2.3Hz,1H),6.82(d,J=8.1Hz,1H),2.76(s,6H),2.49-2.46(m,2H),2.25-2.14(m,2H),1.92( s,1H),1.76(s,4H),1.39–1.27(m,2H).LC-MS:[M+H] ⁺ :475.3.

实施例30 (S)-8-(苯并[d]噻唑-5-基)-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺Example 30 (S)-8-(benzo[d]thiazol-5-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzene And [7] annulen-2-yl) quinazolin-2-amine

按照实施例1的方法，以化合物1-3(50mg，0.11mmol)和苯并[d]噻唑-5-基硼酸(30.5mg，0.17mmol)为原料，得标题化合物30(35mg)。According to the method of Example 1, using compound 1-3 (50 mg, 0.11 mmol) and benzo[d]thiazol-5-ylboronic acid (30.5 mg, 0.17 mmol) as raw materials, the title compound 30 (35 mg) was obtained.

¹H NMR(400MHz,DMSO-d ₆)δ9.75(s,1H),9.48(s,1H),9.35(s,1H),8.33–8.22(m,2H),7.96(dd,J＝8.0,1.5Hz,1H),7.90(dd,J＝7.2,1.5Hz,1H),7.83(dd,J＝8.3,1.6Hz,1H),7.74(d,J＝2.2Hz,1H),7.54–7.44(m,1H),7.32(dd,J＝8.1,2.3Hz,1H),6.82(d,J＝8.1Hz,1H),2.78-2.75(m,1H),2.66(s,4H),2.54(s,2H),2.47–2.41(m,1H),2.28(s,1H),2.07-1.85(m,2H),1.75(d,J＝5.7Hz,4H),1.42–1.29(m,2H).LC-MS:[M+H] ⁺:492.2. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.75(s,1H),9.48(s,1H),9.35(s,1H),8.33-8.22(m,2H),7.96(dd,J=8.0 ,1.5Hz,1H),7.90(dd,J=7.2,1.5Hz,1H),7.83(dd,J=8.3,1.6Hz,1H),7.74(d,J=2.2Hz,1H),7.54-7.44 (m, 1H), 7.32 (dd, J = 8.1, 2.3 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 2.78-2.75 (m, 1H), 2.66 (s, 4H), 2.54 ( s,2H),2.47–2.41(m,1H),2.28(s,1H),2.07-1.85(m,2H),1.75(d,J=5.7Hz,4H),1.42–1.29(m,2H) .LC-MS:[M+H] ⁺ :492.2.

实施例31 (S)-8-(1H-吲唑-5-基)-N-(7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺Example 31 (S)-8-(1H-indazol-5-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[ 7) annulen-2-yl) quinazolin-2-amine

按照实施例1的方法，以化合物1-3(50mg，0.11mmol l)和(1H-吲唑-5-基)硼酸(50mg，0.17mmol)为原料，得标题化合物(40mg)。According to the method of Example 1, using compound 1-3 (50 mg, 0.11 mmol) and (1H-indazol-5-yl)boronic acid (50 mg, 0.17 mmol) as starting materials, the title compound (40 mg) was obtained.

¹H NMR(400MHz,DMSO)δ9.71(s,1H),9.33(s,1H),8.29(s,1H),8.14(d,J＝0.5Hz,1H),8.01(s,1H),7.91(dd,J＝8.0,1.4Hz,1H),7.83(dd,J＝7.2,1.4Hz,1H),7.70(dd,J＝8.5,1.3Hz,2H),7.64(d,J＝8.6Hz,1H),7.49–7.42(m,1H),7.38(dd,J＝8.1,2.2Hz,1H),6.80(d,J＝8.2Hz,1H),2.86–2.54(m,6H),2.35(dd,J＝19.4,17.6Hz,2H),2.12(s,1H),1.87(s,1H),1.74(s,5H),1.34(d,J＝46.6Hz,2H).LC-MS:[M+H] ⁺:475.3.. ¹ H NMR(400MHz,DMSO)δ9.71(s,1H),9.33(s,1H),8.29(s,1H), 8.14(d,J=0.5Hz,1H), 8.01(s,1H), 7.91(dd,J=8.0,1.4Hz,1H),7.83(dd,J=7.2,1.4Hz,1H),7.70(dd,J=8.5,1.3Hz,2H),7.64(d,J=8.6Hz ,1H),7.49–7.42(m,1H),7.38(dd,J=8.1,2.2Hz,1H),6.80(d,J=8.2Hz,1H),2.86-2.54(m,6H),2.35( dd,J＝19.4,17.6Hz,2H),2.12(s,1H),1.87(s,1H),1.74(s,5H),1.34(d,J＝46.6Hz,2H).LC-MS:[ M+H] ⁺ :475.3..

实施例32 (S)-(2-氟-5-(2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)喹唑啉-8-基)苯基)(4-甲基哌嗪-1-基)甲酮Example 32 (S)-(2-Fluoro-5-(2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene -2-yl)amino)quinazolin-8-yl)phenyl)(4-methylpiperazin-1-yl)methanone

a)(S)-2-氟-5-(2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)喹唑啉-8-基)苯甲酸甲酯(32-2)a) (S)-2-Fluoro-5-(2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2 -Yl)amino)quinazolin-8-yl)methyl benzoate (32-2)

将化合物1-3(150mg,0.34mmol)及(4-氟-3-(甲氧基羰基)苯基)硼酸32-1(101mg,0.51mmol)，1,1'-双二苯基膦二茂铁二氯化钯(25mg，0.034mmol)，碳酸铯(222mg,0.68mmol)溶于二氧六环(10mL)/水(1mL)的混合溶剂中，氮气保护下回流反应5h。反应液旋干后柱层析得标题化合物32-2(149mg)。LC-MS:[M+H] ⁺:511.1。 Compound 1-3 (150mg, 0.34mmol) and (4-fluoro-3-(methoxycarbonyl)phenyl) boronic acid 32-1 (101mg, 0.51mmol), 1,1'-bisdiphenylphosphine two Ferrocene palladium dichloride (25 mg, 0.034 mmol) and cesium carbonate (222 mg, 0.68 mmol) were dissolved in a mixed solvent of dioxane (10 mL)/water (1 mL), and the reaction was refluxed for 5 hours under nitrogen protection. The reaction solution was spin-dried and column chromatography was used to obtain the title compound 32-2 (149 mg). LC-MS: [M+H] ⁺ : 511.1.

b)(S)-2-氟-5-(2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)喹唑啉-8-基)苯甲酸(32-3)b) (S)-2-Fluoro-5-(2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2 -Yl)amino)quinazolin-8-yl)benzoic acid (32-3)

将化合物32-2(149mg,0.29mmol)溶于四氢呋喃(3ml)和水(2ml)的混合溶剂中，加入一水合氢氧化锂(31mg，0.72mmol)，80℃反应2h。反应完毕用1M的盐酸调节pH＝2后浓缩至干，得化合物32-3(144mg)。LC-MS:[M+H] ⁺:497.0。 Compound 32-2 (149mg, 0.29mmol) was dissolved in a mixed solvent of tetrahydrofuran (3ml) and water (2ml), lithium hydroxide monohydrate (31mg, 0.72mmol) was added, and the reaction was carried out at 80°C for 2h. After the reaction, the pH was adjusted to 2 with 1M hydrochloric acid and concentrated to dryness to obtain compound 32-3 (144 mg). LC-MS: [M+H] ⁺ : 497.0.

c)(S)-(2-氟-5-(2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)喹唑啉-8-基)苯基)(4-甲基哌嗪-1-基)甲酮c) (S)-(2-Fluoro-5-(2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene- 2-yl)amino)quinazolin-8-yl)phenyl)(4-methylpiperazin-1-yl)methanone

将化合物32-3(144mg,0.29mmol)，HATU(135mg,0.35mmol)，DIPEA(75mg,0.58mmol)溶于DMF(5mL)，室温下搅拌30min后缓慢加入N-甲基哌嗪(45mg,0.44mmol)，反应液室温下搅拌12h后，加入乙酸乙酯(50mL)稀释，饱和食盐水(30mL)洗涤后取有机相旋干，柱层析纯化得标题化合物(69mg)。Compound 32-3 (144mg, 0.29mmol), HATU (135mg, 0.35mmol), DIPEA (75mg, 0.58mmol) were dissolved in DMF (5mL), stirred at room temperature for 30min, and then slowly added N-methylpiperazine (45mg, 0.44mmol), the reaction solution was stirred at room temperature for 12h, then diluted with ethyl acetate (50mL), washed with saturated brine (30mL), the organic phase was spin-dried, and purified by column chromatography to obtain the title compound (69mg).

¹H NMR(400MHz,DMSO-d ₆)δ9.77(s,1H),9.33(s,1H),7.97–7.86(m,2H),7.81(dd,J＝7.2,1.2Hz,1H),7.71–7.67(m,1H),7.53(dd,J＝6.5,2.2Hz,1H),7.48–7.35(m,3H),6.94(d,J＝8.2Hz,1H),3.65(s,4H),3.28(s,2H),2.77(s,6H),2.35(s,3H),2.21(s,2H),2.17(s,3H),1.96(s,2H),1.76(s,4H),1.45(s,2H).LC-MS:[M+H] ⁺:579.1 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.77(s,1H),9.33(s,1H),7.97-7.86(m,2H),7.81(dd,J=7.2,1.2Hz,1H), 7.71–7.67 (m, 1H), 7.53 (dd, J = 6.5, 2.2 Hz, 1H), 7.48–7.35 (m, 3H), 6.94 (d, J = 8.2 Hz, 1H), 3.65 (s, 4H) , 3.28(s, 2H), 2.77(s, 6H), 2.35(s, 3H), 2.21(s, 2H), 2.17(s, 3H), 1.96(s, 2H), 1.76(s, 4H), 1.45(s,2H).LC-MS:[M+H] ⁺ :579.1

实施例33 (S)-N-甲基-5-(2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)喹唑啉-8-基)烟酰胺Example 33 (S)-N-methyl-5-(2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene -2-yl)amino)quinazolin-8-yl)nicotinamide

将化合物26-3(80mg,0.17mmol)溶于DMF(5mL)，加入HATU(82mg,0.21mmol)，干燥DIPEA(4mg,0.34mmol),室温下活化30min后加入甲胺四氢呋喃溶液(0.13mL,0.26mmol)，室温下搅拌反应12h。反应完毕加入乙酸乙酯(50mL)稀释，饱和食盐水(30mL)洗涤后分离有机相并旋干，柱层析纯化后得标题化合物(20mg)。Compound 26-3 (80mg, 0.17mmol) was dissolved in DMF (5mL), HATU (82mg, 0.21mmol) was added, DIPEA (4mg, 0.34mmol) was dried, activated at room temperature for 30min and then methylamine tetrahydrofuran solution (0.13mL, 0.26mmol), the reaction was stirred at room temperature for 12h. After the reaction was completed, ethyl acetate (50 mL) was added for dilution, washed with saturated brine (30 mL), the organic phase was separated and spin-dried, and purified by column chromatography to obtain the title compound (20 mg).

¹H NMR(400MHz,DMSO-d ₆)δ9.84(s,1H),9.37(s,1H),9.09(d,J＝2.1Hz,1H),9.03(d,J＝2.1Hz,1H),8.71(q,J＝4.5Hz,1H),8.52(t,J＝2.1Hz,1H),8.01(dd,J＝8.0,1.5Hz,1H),7.94(dd,J＝7.2,1.5Hz,1H),7.57(d,J＝2.2Hz,1H),7.55–7.47(m,1H),7.44(dd,J＝8.1,2.2Hz,1H),6.88(d,J＝8.2Hz,1H),2.96(s,6H),2.82(d,J＝4.5Hz,3H),2.79–2.70(m,1H),2.58(t,J＝12.6Hz,2H),2.08(s,2H),1.82(s,4H),1.37(s,2H).LC-MS:[M+H] ⁺:494.2. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.84(s,1H),9.37(s,1H),9.09(d,J=2.1Hz,1H),9.03(d,J=2.1Hz,1H) ,8.71(q,J=4.5Hz,1H),8.52(t,J=2.1Hz,1H), 8.01(dd,J=8.0,1.5Hz,1H),7.94(dd,J=7.2,1.5Hz, 1H), 7.57 (d, J = 2.2 Hz, 1H), 7.55-7.47 (m, 1H), 7.44 (dd, J = 8.1, 2.2 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 2.96(s,6H), 2.82(d,J=4.5Hz,3H),2.79–2.70(m,1H),2.58(t,J=12.6Hz,2H),2.08(s,2H),1.82(s ,4H),1.37(s,2H).LC-MS:[M+H] ⁺ :494.2.

实施例34 (S)-2-氟-N-甲基-5-(2-((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)氨基)喹唑啉-8-基)苯甲酰胺Example 34 (S)-2-Fluoro-N-methyl-5-(2-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[ 7) annulen-2-yl)amino)quinazolin-8-yl)benzamide

将化合物32-3(38mg,0.077mmol)，HATU(35mg,0.09mmol)，DIPEA(20mg,0.15mmol)溶于DMF(4mL)，室温下活化30min后缓慢加入甲胺的四氢呋喃溶液(1M,0.12mL,0.12mmol)。反应液室温下反应12h后，加入乙酸乙酯(50mL)稀释，饱和食盐水(30mL)洗涤后分离有机相并旋干，柱层析纯化后得黄色固体产物得标题化合物(5mg)。Compound 32-3 (38mg, 0.077mmol), HATU (35mg, 0.09mmol), DIPEA (20mg, 0.15mmol) was dissolved in DMF (4mL), activated at room temperature for 30min, then slowly added methylamine in tetrahydrofuran solution (1M, 0.12 mL, 0.12mmol). After reacting for 12 hours at room temperature, the reaction solution was diluted with ethyl acetate (50 mL), washed with saturated brine (30 mL), the organic phase was separated and spin-dried, purified by column chromatography to obtain a yellow solid product to obtain the title compound (5 mg).

¹H NMR(400MHz,DMSO-d ₆)δ9.83(s,1H),9.35(s,1H),8.34(dt,J＝5.9,3.1Hz,1H),8.02–7.82(m,4H),7.58(d,J＝7.1Hz,2H),7.51–7.36(m,2H),6.98(d,J＝8.3Hz,1H),3.45(s,3H),2.80(d,J＝4.6Hz,3H),2.74(d,J＝6.9Hz,1H),2.72–2.61(m,3H),2.54(s,2H),2.37–2.15(m,2H),1.91(s,4H),1.42-1.30(m,2H).LC-MS:[M+H] ⁺:511.2. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.83(s,1H),9.35(s,1H),8.34(dt,J=5.9,3.1Hz,1H),8.02-7.82(m,4H), 7.58(d,J=7.1Hz,2H), 7.51–7.36(m,2H), 6.98(d,J=8.3Hz,1H), 3.45(s,3H), 2.80(d,J=4.6Hz,3H ), 2.74(d,J=6.9Hz,1H), 2.72–2.61(m,3H),2.54(s,2H),2.37–2.15(m,2H),1.91(s,4H),1.42-1.30( m,2H).LC-MS:[M+H] ⁺ :511.2.

实施例35 N-甲基-3-(2-((3-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-7-基)氨基)喹唑啉-8-基)苯甲酰胺Example 35 N-Methyl-3-(2-((3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]nitrogen Hetero-7-yl)amino)quinazolin-8-yl)benzamide

(a)N-(8-溴喹唑啉-2-基)-3-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-7-胺(a) N-(8-Bromoquinazolin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[ d]Aza-7-amine

将化合物3-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-7-胺x(275mg,1.12mmol)及8-溴-2-氯喹唑啉1-2(300mg,1.23mmol)溶于无水四氢呋喃(10mL)，降温至-10℃后缓慢滴加双-(三甲基硅基)氨基锂的四氢呋喃溶液(1M,2.24mL,2.24mmol)，-10℃下反应1h后，向反应液中加入2mL饱和氯化铵溶液淬灭反应，乙酸乙酯(100mL)萃取反应液，柱层析纯化后得化合物x-1(346mg)。LCMS:(M+1+):453.1。Compound 3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo(d)aza-7-amine x (275mg, 1.12mmol) and 8-Bromo-2-chloroquinazoline 1-2 (300mg, 1.23mmol) was dissolved in anhydrous tetrahydrofuran (10mL). After cooling to -10℃, slowly add dropwise the tetrahydrofuran solution of lithium bis-(trimethylsilyl)amide (1M, 2.24mL, 2.24mmol), after reacting at -10°C for 1 hour, 2mL of saturated ammonium chloride solution was added to the reaction solution to quench the reaction, the reaction solution was extracted with ethyl acetate (100mL), and the compound was purified by column chromatography x-1 (346mg). LCMS: (M+1+): 453.1.

(b)N-甲基-3-(2-((3-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-7-基)氨基)喹唑啉-8-基)苯甲酰胺(b) N-methyl-3-(2-((3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo(d)nitrogen Hetero-7-yl)amino)quinazolin-8-yl)benzamide

将化合物N-(8-溴喹唑啉-2-基)-3-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-7-胺x-1(229mg,0.51mmol)、(3-(甲基氨基甲酰基)苯基)硼酸x-2(138mg，0.77mmol)、Pd(dppf)Cl ₂(38mg，0.051mmol)和Cs ₂CO ₃(333mg，1.02mmol)溶于1,4-二氧六环(5mL)和水(0.5mL)混合溶液中，氮气保护下回流反应6h。反应完毕将反应液减压浓缩至干，柱层析纯化后得标题化合物(55mg)。 The compound N-(8-bromoquinazolin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo(d ] Aza-7-amine x-1 (229mg, 0.51mmol), (3-(methylcarbamoyl)phenyl)boronic acid x-2 (138mg, 0.77mmol), Pd(dppf)Cl ₂ (38mg, 0.051 mmol) and Cs ₂ CO ₃ (333 mg, 1.02 mmol) were dissolved in a mixed solution of 1,4-dioxane (5 mL) and water (0.5 mL), and the reaction was refluxed for 6 hours under nitrogen protection. After the reaction, the reaction solution was concentrated to dryness under reduced pressure, and purified by column chromatography to obtain the title compound (55 mg).

¹H NMR(400MHz,DMSO)δ9.88(s,1H),9.37(s,1H),8.52(d,J＝4.6Hz,1H),8.16(s,1H),7.97(dd,J＝8.0,1.5Hz,2H),7.87(ddd,J＝4.4,3.4,1.4Hz,2H),7.69(s,1H),7.62(t,J＝7.7Hz,1H),7.55(d,J＝7.8Hz,1H),7.49(t,J＝7.6Hz,1H),6.95(d,J＝8.2Hz,1H),4.35(t,J＝5.1Hz,10H),3.44(qd,J＝7.0,5.1Hz,6H),1.06(t,J＝7.0Hz,4H).LCMS:(M+1 ⁺):508.3。 ¹ H NMR (400MHz, DMSO) δ 9.88 (s, 1H), 9.37 (s, 1H), 8.52 (d, J = 4.6 Hz, 1H), 8.16 (s, 1H), 7.97 (dd, J = 8.0 ,1.5Hz,2H),7.87(ddd,J=4.4,3.4,1.4Hz,2H),7.69(s,1H),7.62(t,J=7.7Hz,1H),7.55(d,J=7.8Hz ,1H),7.49(t,J=7.6Hz,1H),6.95(d,J=8.2Hz,1H), 4.35(t,J=5.1Hz,10H),3.44(qd,J=7.0,5.1Hz , 6H), 1.06 (t, J=7.0 Hz, 4H). LCMS: (M+1 ⁺ ): 508.3.

实施例36 N-(8-(3-异丙氧基苯基)喹唑啉-2-基)-3-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂7-胺Example 36 N-(8-(3-isopropoxyphenyl)quinazolin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5 -Tetrahydro-1H-benzo[d]aza 7-amine

按照实施例35的方法，以化合物x-1(102mg,0.23mmol)、3-异丙氧基苯硼酸(64mg,0.35mmol)为原料，得标题化合物(44mg)。According to the method of Example 35, using compound x-1 (102 mg, 0.23 mmol) and 3-isopropoxyphenylboronic acid (64 mg, 0.35 mmol) as raw materials, the title compound (44 mg) was obtained.

¹H NMR(400MHz,DMSO)δ9.72(s,1H),9.31(s,1H),7.90(dd,J＝8.0,1.2Hz,1H),7.78(dd,J＝7.2,1.3Hz,1H),7.68(d,J＝2.0Hz,1H),7.51(dd,J＝8.2,2.2Hz,1H),7.46–7.36(m,2H),7.22(d,J＝7.7Hz,1H),7.16(s,1H),7.00(dd,J＝8.2,2.1Hz,1H),6.88(d,J＝8.2Hz,1H),4.64(dt,J＝12.0,6.0Hz,1H),4.34(t,J＝5.1Hz,4H),3.44(qd,J＝7.0,5.1Hz,9H),1.06(t,J＝7.0Hz,10H).LCMS:(M+1 ⁺):509.3。 ¹ H NMR(400MHz,DMSO)δ9.72(s,1H),9.31(s,1H),7.90(dd,J=8.0,1.2Hz,1H),7.78(dd,J=7.2,1.3Hz,1H ), 7.68(d,J=2.0Hz,1H),7.51(dd,J=8.2,2.2Hz,1H),7.46-7.36(m,2H),7.22(d,J=7.7Hz,1H),7.16 (s, 1H), 7.00 (dd, J = 8.2, 2.1 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 4.64 (dt, J = 12.0, 6.0 Hz, 1H), 4.34 (t, J = 5.1 Hz, 4H), 3.44 (qd, J = 7.0, 5.1 Hz, 9H), 1.06 (t, J = 7.0 Hz, 10H). LCMS: (M+1 ⁺ ): 509.3.

实施例37 N-(8-(4-异丙氧基苯基)喹唑啉-2-基)-3-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂7-胺Example 37 N-(8-(4-isopropoxyphenyl)quinazolin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5 -Tetrahydro-1H-benzo[d]aza 7-amine

按照实施例35的方法，以化合物x-1(261mg,0.58mmol)、4-异丙氧基苯硼酸(157mg,0.87mmol)为原料，得标题化合物(205mg)。According to the method of Example 35, using compound x-1 (261 mg, 0.58 mmol) and 4-isopropoxyphenylboronic acid (157 mg, 0.87 mmol) as raw materials, the title compound (205 mg) was obtained.

¹H NMR(400MHz,DMSO)δ9.72(s,1H),9.31(s,1H),7.90–7.83(m,2H),7.77(dd,J＝7.2,1.2Hz,1H),7.63(d,J＝8.6Hz,2H),7.41(dd,J＝14.3,6.7Hz,2H),7.04(d,J＝8.7Hz,2H),6.93(d,J＝8.0Hz,1H),4.73(dt,J＝12.1,6.0Hz,1H),3.90(d,J＝7.9Hz,2H),2.86–2.54(m,10H),1.70–1.46(m,5H),1.35(d,J＝6.0Hz,6H).LCMS:(M+1 ⁺):509.3。 ¹ H NMR(400MHz,DMSO)δ9.72(s,1H),9.31(s,1H),7.90-7.83(m,2H),7.77(dd,J=7.2,1.2Hz,1H),7.63(d ,J=8.6Hz,2H),7.41(dd,J=14.3,6.7Hz,2H),7.04(d,J=8.7Hz,2H),6.93(d,J=8.0Hz,1H),4.73(dt ,J=12.1,6.0Hz,1H),3.90(d,J=7.9Hz,2H), 2.86–2.54(m,10H),1.70–1.46(m,5H),1.35(d,J=6.0Hz, 6H). LCMS: (M+1 ⁺ ): 509.3.

实施例38 (S)-2-甲基-6-(2-(((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基]氨基)喹唑啉-8-基)异吲哚-1-酮Example 38 (S)-2-Methyl-6-(2-(((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7] round (En-2-yl)amino)quinazolin-8-yl)isoindol-1-one

按照实施例1的方法，以化合物1-3(153mg,0.35mmol)、2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)异吲哚啉-1-酮(143mg，0.52mmol)为原料，得标题化合物(15mg)。 ¹H NMR(400MHz,DMSO)δ9.74(s,1H),9.34(s,1H),8.29(s,1H),7.94(dd,J＝8.0,1.3Hz,1H),7.93–7.87(m,1H),7.83(dd,J＝7.2,1.3Hz,1H),7.73(d,J＝8.3Hz,1H),7.68(d,J＝2.0Hz,1H),7.46(t,J＝7.6Hz,1H),7.35(dd,J＝8.0,2.1Hz,1H),6.86(d,J＝8.2Hz,1H),5.76(s,1H),4.57(s,2H),3.14(s,4H),2.61(s,6H),1.72(s,6H),1.56–1.31(m,3H).LCMS:(M+1 ⁺):504.3. According to the method of Example 1, the compound 1-3 (153mg, 0.35mmol), 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)isoindolin-1-one (143 mg, 0.52 mmol) was used as the starting material to obtain the title compound (15 mg). ¹ H NMR(400MHz,DMSO)δ9.74(s,1H),9.34(s,1H),8.29(s,1H),7.94(dd,J=8.0,1.3Hz,1H),7.93-7.87(m ,1H),7.83(dd,J=7.2,1.3Hz,1H),7.73(d,J=8.3Hz,1H),7.68(d,J=2.0Hz,1H),7.46(t,J=7.6Hz ,1H),7.35(dd,J=8.0,2.1Hz,1H),6.86(d,J=8.2Hz,1H),5.76(s,1H),4.57(s,2H),3.14(s,4H) ,2.61(s,6H),1.72(s,6H),1.56--1.31(m,3H).LCMS:(M+1 ⁺ ):504.3

实施例39 (S)-2-甲基-5-(2-(((7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基]氨基)喹唑啉-8-基)异吲哚-1-酮Example 39 (S)-2-Methyl-5-(2-(((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7] round (En-2-yl)amino)quinazolin-8-yl)isoindol-1-one

按照实施例1的方法，以化合物1-3(92mg,0.21mmol)、2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)异吲哚啉-1-酮(88mg，0.32mmol)为原料，得标题化合物(40mg)。 ¹H NMR(400MHz,DMSO)δ9.77(s,1H),9.34(s,1H),8.25(s,1H),7.96(dd,J＝8.0,1.4Hz,1H),7.81(ddd,J＝23.5,11.0,1.6Hz,4H),7.52–7.41(m,1H),7.27(dd,J＝8.1,2.2Hz,1H),6.86(d,J＝8.1Hz,1H),4.50(s,3H),3.20–3.04(m,5H),2.72–2.56(m,5H),1.74(s,6H),1.40(s,3H).LCMS:(M+1 ⁺):504.3. According to the method of Example 1, with compound 1-3 (92mg, 0.21mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)isoindolin-1-one (88 mg, 0.32 mmol) was used as the starting material to obtain the title compound (40 mg). ¹ H NMR(400MHz,DMSO)δ9.77(s,1H),9.34(s,1H),8.25(s,1H),7.96(dd,J=8.0,1.4Hz,1H),7.81(ddd,J = 23.5, 11.0, 1.6 Hz, 4H), 7.52–7.41 (m, 1H), 7.27 (dd, J = 8.1, 2.2 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 4.50 (s, 3H), 3.20-3.04(m,5H), 2.72-2.56(m,5H), 1.74(s,6H), 1.40(s,3H) ^{.LCMS:(M+1 +} ): 504.3

实施例40 (S)-8-(3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基)-N-(7-(吡咯烷-1-基)-6,7,8，9-四氢-5H-苯并[7]轮烯-2-基)喹唑啉-2-胺Example 40 (S)-8-(3,4-Dihydro-2H-benzo[b][1,4]oxazine-6-yl)-N-(7-(pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzo[7] annulen-2-yl)quinazolin-2-amine

按照实施例1的方法，以化合物1-3(188mg,0.43mmol)、6-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)-3,4-二氢-2H-苯并[b][1,4]恶嗪(166mg，0.64mmol)为原料，得标题化合物(60mg)。 ¹H NMR(400MHz,DMSO)δ9.66(s,1H),9.28(s,1H),8.26(s,1H),7.89–7.77(m,2H),7.68(dd,J＝7.2,1.4Hz,1H),7.50(dd,J＝8.1,2.2Hz,1H),7.44–7.34(m,1H),6.93(d,J＝8.1Hz,1H),6.89–6.78(m,2H),6.76(d,J＝8.1Hz,1H),5.79(s,1H),4.28–4.11(m,2H),2.67(d,J＝1.8Hz,7H),1.92(s,3H),1.73(s,5H),1.48(s,3H).LCMS:(M+1 ⁺):492.3。 According to the method of Example 1, the compound 1-3 (188mg, 0.43mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaboroborin-2-yl )-3,4-dihydro-2H-benzo[b][1,4]oxazine (166mg, 0.64mmol) as starting material to obtain the title compound (60mg). ¹ H NMR(400MHz,DMSO)δ9.66(s,1H),9.28(s,1H),8.26(s,1H),7.89–7.77(m,2H),7.68(dd,J=7.2,1.4Hz ,1H),7.50(dd,J=8.1,2.2Hz,1H),7.44-7.34(m,1H),6.93(d,J=8.1Hz,1H),6.89-6.78(m,2H),6.76( d, J = 8.1 Hz, 1H), 5.79 (s, 1H), 4.28-4.11 (m, 2H), 2.67 (d, J = 1.8 Hz, 7H), 1.92 (s, 3H), 1.73 (s, 5H) ), 1.48 (s, 3H). LCMS: (M+1 ⁺ ): 492.3.

生物活性测试1 喹唑啉类化合物体外对AXL激酶IC ₅₀测试： _{Biological activity test 1 The IC 50} test of quinazoline compounds against AXL kinase in vitro:

1.实验流程1. Experimental procedure

采用迁移率改变法(Mobility shift assay)建立AXL激酶活性检测平台，进行化合物活性测定。The Mobility shift assay was used to establish an AXL kinase activity detection platform for compound activity determination.

a)化合物配制：将化合物粉末溶解在100％DMSO(购买于Sigma，Cat：D8418-1L)中，配制成10mM储存液。a) Compound preparation: The compound powder is dissolved in 100% DMSO (purchased from Sigma, Cat: D8418-1L) to prepare a 10 mM stock solution.

b)激酶反应过程：将10mM储存液用100％DMSO稀释至100μM后，用1×激酶反应缓冲液将化合物从起始浓度1000nM进行3倍稀释，共10个浓度。再使用分液器Echo 550向目的板OptiPlate-384F转移250nL终浓度的化合物。用1×激酶反应缓冲液(含50mM HEPES，10mM MgCl ₂，2mM DTT)配制6.25nM的AXL激酶(购买于Carna，08-107；AXL激酶反应终浓度为2.5nM)溶液。在化合物孔和阳性对照孔分别加10μL的6.25nM的激酶溶液；在阴性对照孔中加10μL的1×激酶反应缓冲液，加完后1000rpm离心30秒，反应板振荡混匀后室温孵育10分钟。再用1×激酶反应缓冲液配制53μM的ATP(购买于Sigma,Cat.A7699-5G,Lot.SLBT6850,ATP终浓度为31.7μM)和激酶底物22(购买于GL,Cat：112393，底物终浓度为3μM)的混合溶液。向上述酶和待测化合物的孔中加入15μL的53μM的ATP和底物的混合溶液，总反应体积25μL。1000rpm离心30秒，振荡混匀后室温孵育，开始反应。40分钟后加入30μL终止检测液1000rpm离心30秒，振荡混匀，停止激酶反应。用Caliper EZ Reader仪器读取转化率。 b) Kinase reaction process: After diluting the 10 mM stock solution with 100% DMSO to 100 μM, the compound was diluted 3-fold from the initial concentration of 1000 nM with 1×kinase reaction buffer to a total of 10 concentrations. Then use a dispenser Echo 550 to transfer 250 nL of the final concentration of the compound to the target plate OptiPlate-384F. A 6.25 nM AXL kinase (purchased from Carna, 08-107; AXL kinase reaction final concentration 2.5 nM) solution was prepared with 1× kinase reaction buffer (containing 50 mM HEPES, 10 mM MgCl _{2, 2 mM DTT).} Add 10μL of 6.25nM kinase solution to the compound well and positive control well respectively; add 10μL of 1× kinase reaction buffer to the negative control well, centrifuge at 1000rpm for 30 seconds after adding, shake and mix the reaction plate and incubate at room temperature for 10 minutes . Then prepare 53μM ATP (purchased from Sigma, Cat.A7699-5G, Lot.SLBT6850, final concentration of ATP is 31.7μM) and kinase substrate 22 (purchased from GL, Cat: 112393, substrate) with 1× kinase reaction buffer The final concentration is 3μM) mixed solution. Add 15 μL of a mixed solution of 53 μM ATP and substrate to the wells of the enzyme and the test compound, and the total reaction volume is 25 μL. Centrifuge at 1000 rpm for 30 seconds, shake and mix and incubate at room temperature to start the reaction. After 40 minutes, add 30 μL of stop detection solution and centrifuge at 1000 rpm for 30 seconds, shake and mix, and stop the kinase reaction. Use Caliper EZ Reader to read the conversion rate.

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，得到该化合物的IC ₅₀值。 GraphPad Prism 5 software log (inhibitor) vs. response-Variable slope was used to fit the dose-response curve to obtain the IC ₅₀ value of the compound.

抑制率计算公式：

其中： Inhibition rate calculation formula:

among them:

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

Conversion％_min：阴性对照孔均值，代表没有酶活孔的转化率读数；Conversion%_min: Mean value of negative control wells, representing the conversion rate readings of wells without enzyme activity;

Conversion％_max：阳性对照孔均值，代表没有化合物抑制孔的转化率读数。Conversion%_max: The mean value of the positive control wells, representing the conversion rate readings of the wells without 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 IC ₅₀数据 Table 1. AXL IC ₅₀ data

生物活性测试2 本发明化合物对MV-4-11细胞增殖抑制实验Biological activity test 2 The compound of the present invention inhibits the proliferation of MV-4-11 cells

1.实验流程1. Experimental procedure

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)购自南京科佰生物科技有限公司，置于37℃,5％CO ₂的培养箱中培养。取对数生长期的细胞以8000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 myeloid monocytic leukemia cell line, culture medium: IMDM+10% fetal bovine serum) was purchased from Nanjing Kebai Biotechnology Co., Ltd. and placed in an incubator at _{37°C and 5% CO 2} bring up. The cells in the logarithmic growth phase were plated in a 96-well plate at a cell density of 8000 cells/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200μM，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(二甲基亚砜终浓度为0.5％,v/v)，每个浓度设置两个复孔。加药处理72h后，每孔加入50μl的

(购自Promega)，按照说明书的操作流程在Envision(PerkinElmer)上测定荧光信号，使用GraphPad Prism 5软件log(inhibitor)vs.response-Variable slope拟合量效曲线，得到化合物对细胞增殖抑制的IC ₅₀值。抑制率计算公式： The test compound and the positive drug were dissolved in dimethyl sulfoxide to prepare a 10 mM stock solution, and stored in a refrigerator at -80°C for a long time. After the cells were plated for 24 hours, the 10 mM compound stock solution was diluted with dimethyl sulfoxide to obtain a 200-fold concentration of the working solution (the highest concentration was 200 μM, a 3-fold gradient, a total of 10 concentrations), and 3 μL of each concentration was added to 197 μL of complete Dilute in the culture medium to obtain a 3-fold concentration of the working solution, and then add 50 μL to 100 μL of cell culture medium (final concentration of dimethyl sulfoxide is 0.5%, v/v), and two replicate holes are set for each concentration. After 72 hours of dosing, add 50μl of

(Purchased from Promega). Measure the fluorescence signal on Envision (PerkinElmer) according to the operating procedure of the instruction. Use GraphPad Prism 5 software log (inhibitor) vs. response-Variable slope to fit the dose-response curve to obtain the IC of the compound's inhibition of cell proliferation. ₅₀ value. Inhibition rate calculation formula:

其中：among them:

受试物信号值：细胞+培养基+化合物组荧光信号均值；The signal value of the test substance: the average value of the fluorescence signal of the cell + medium + compound group;

空白组信号值：培养基组(含0.5％DMSO)荧光信号均值；Signal value of blank group: mean value of fluorescence signal of medium group (containing 0.5% DMSO);

阴性对照组信号值：细胞+培养基组(含0.5％DMSO)荧光信号均值。Signal value of the negative control group: the mean value of the fluorescence signal of the cell + medium group (containing 0.5% DMSO).

2.实验结果2. Experimental results

实验结果如表2所示：The experimental results are shown in Table 2:

表2 MV4-11细胞IC50数据Table 2 IC50 data of MV4-11 cells

生物活性测试3 体内药效实验Biological Activity Test 3 In vivo efficacy test

(1)小鼠模型的构建：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。 (1) Construction of mouse model: Collect logarithmic growth phase MV-4-11 cells, resuspend the cells after counting, adjust the cell concentration to 7.0×10 ⁷ cells/mL; inject into the right axillary subcutaneously before nude mice, Each animal was inoculated with 200 μL (14×10 ⁶ cells/animal) to establish a MV-4-11 transplanted tumor model. When the tumor volume reaches 100-300mm ³ , select tumor-bearing mice with good health and similar tumor volume.

(2)化合物的配制：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柠檬酸缓冲液，涡旋振荡，使液体混合均匀，得到浓度为0.1、0.5、1mg·mL ^-1的给药制剂。 (2) Preparation of the compound: The compound and the positive drug are vortexed with a suitable solvent and then ultrasonicated to completely dissolve the compound. Then, an appropriate volume of citric acid buffer is slowly added, and the liquid is vortexed to make the liquid mixed uniformly to obtain a concentration of 0.1, ^{0.5, 1} mg·mL -1 dosage formulation.

溶剂对照组：PEG400&柠檬酸缓冲液(20:80，v:v)。Solvent control group: PEG400 & citrate buffer (20:80, v:v).

(3)动物分组及给药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。 (3) Animal grouping and administration The modeled mice were randomly grouped (n=6), and the relevant compounds and positive drugs were given on the day of grouping. After 21 days or the tumor volume of the solvent control group reached 2000mm ³ , the experiment was ended (first reaching The index shall prevail), and the administration volume is 10mL·kg ^-1 . Both the compound and the positive drug were administered by gavage, 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.

(4)数据分析：肿瘤体积(TV)计算公式为：肿瘤体积(mm ³)＝l×w ²/2， (4) Data analysis: Tumor volume (TV) calculation formula is: tumor volume (mm ³ ) = l×w ² /2,

其中，l表示肿瘤长径(mm)；w表示肿瘤短径(mm)。Among them, l represents the long diameter of the tumor (mm); w represents the short diameter of the tumor (mm).

相对肿瘤体积(RTV)的计算公式为：RTV＝TV _t/TV _initial The calculation formula of relative tumor volume (RTV) is: RTV=TV _t /TV _initial

其中，TV _initial为分组给药时测量到的肿瘤体积；TV _t为给药期间每一次测量时的肿瘤体积。 Among them, TV _initial is the tumor volume _{measured during group administration; TV t} is the tumor volume at each measurement during the administration period.

肿瘤生长抑制率TGI(％)的计算公式为：The calculation formula of tumor growth inhibition rate TGI (%) is:

TGI＝100％×[1－(TV _t(T)－TV _initial(T))/(TV _t(C)－TV _initial(C))] TGI=100%×[1－(TV _t(T) －TV _initial(T) )/(TV _t(C) －TV _initial(C) )]

其中，TV _t(T)表示治疗组每次测量的肿瘤体积；TV _initial(T)表示分组给药时治疗组的肿瘤体积；TV _t(C)表示溶剂对照组每次测量的肿瘤体积；TV _initial(C)表示分组给药时溶剂对照组的肿瘤体积。 Among them, TV _t(T) represents the tumor volume measured each time in the treatment group; TV _initial(T) represents the tumor volume of the treatment group when the group is administered; TV _t(C) represents the tumor volume measured each time in the solvent control group; TV _{initial (C)} represents the tumor volume of the solvent control group when administered in groups.

相对肿瘤增殖率(％T/C)的计算公式为：％T/C＝100％×(RTV _T/RTV _C) The calculation formula of the relative tumor proliferation rate (%T/C) is: %T/C=100%×(RTV _T /RTV _C )

其中，RTV _T表示治疗组RTV；RTV _C表示溶剂对照组RTV。 Among them, RTV _T represents the RTV of the treatment group; RTV _C represents the RTV of the solvent control group.

试验数据用Microsoft Office Excel 2007软件进行计算和相关统计学处理。The test data was calculated and related statistical processing with Microsoft Office Excel 2007 software.

(5)实验结果：实验结果详见表3，(5) Experimental results: The experimental results are detailed in Table 3.

表3：化合物的MV4-11体内药效Table 3: In vivo efficacy of MV4-11 compounds

备注：表中的实验数据为实验结束(实验结束定义为：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))时获得的相关数据。 Remarks: The experimental data in the table are related data obtained at the end of the experiment (the end of the experiment is defined as: the end of the experiment after 21 days or the tumor volume of the solvent control group reaches 2000mm ³ (whichever comes first)).

Claims

式I所示的喹唑啉类化合物或其药学上可接受的盐，The quinazoline compound represented by formula I or a pharmaceutically acceptable salt thereof,

其中，X为CH或N；Among them, X is CH or N;

Y ¹为CH或N； Y ¹ is CH or N;

Y ²为CHR ¹、O或NR ²； Y ² is CHR ¹ , O or NR ² ;

选自
优选为

Selected from
Preferably

R ¹为氢、C1-C6烷基、卤素、硝基、氨基或羟基； R ¹ is hydrogen, C1-C6 alkyl, halogen, nitro, amino or hydroxyl;

R ²为氢或C1-C6烷基； R ² is hydrogen or C1-C6 alkyl;

Q为NH；Q is NH;

m选自0或1；m is selected from 0 or 1;

n选自1、2或3；n is selected from 1, 2 or 3;

R ³选自苯基、5-6元杂芳基、9-12元苯并杂环基或9-12元苯并氧代杂环基，其中所述基团任选地被一个或多个R ⁵取代；优选地，R ³选自苯基、5-6元杂芳基或9-12元苯并杂环基，其中所述基团任选地被一个或多个R ⁵取代； R ^{3 is} selected from phenyl, 5-6 membered heteroaryl, 9-12 membered benzoheterocyclyl or 9-12 membered benzooxoheterocyclyl, wherein the group is optionally substituted by one or more R ^{5 is} substituted; preferably, R ^{3 is} selected from phenyl, 5-6 membered heteroaryl or 9-12 membered benzoheterocyclyl, wherein the group is optionally substituted ^{by one or more R 5;}

R ⁵选自卤素、C1-C4烷基、

R ^{5 is} selected from halogen, C1-C4 alkyl,

R ⁴选自苯基、5-6元杂芳基或9-12元苯并杂环基,其中所述基团任选地被一个或多个R ⁶取代；优选地，R ⁴为任选地被一个或多个R ⁶取代的苯基； R ^{4 is} selected from phenyl, 5-6 membered heteroaryl or 9-12 membered benzoheterocyclyl, wherein the group is optionally ^{substituted by one or more R 6} ; preferably, R ⁴ is optional Phenyl substituted by one or more R ^6;

R ⁶选自卤素、C1-C4烷基、

优选地，R ⁶选自
更优选优选地，R ⁶为
R ^{6 is} selected from halogen, C1-C4 alkyl,

Preferably, R ^{6 is} selected from
More preferably preferably, R ⁶ is

R ^a为氢、C1-C4烷基或3-6元环烷基； R ^a is hydrogen, C1-C4 alkyl or 3-6 membered cycloalkyl;

R ^b为氢或C1-C4烷基； R ^b is hydrogen or C1-C4 alkyl;

或R ^a、R ^b与和它们相连接的N共同构成5-7元单环饱和杂环，所述基团可任选地被一个或多个卤素或C1-C3烷基取代； Or R ^a, R ^b and the N to which they are attached together form a 5-7 membered monocyclic saturated heterocyclic ring, the group may be optionally substituted with one or more halogen or C1-C3 alkyl substituent;

R ^c为C1-C4烷基或任选地被卤素或C1-C3烷基取代的苯基；优选地，R ^c为甲基、异丙基或任选地被一个甲基取代的苯基； R ^c is C1-C4 alkyl or phenyl optionally substituted by halogen or C1-C3 alkyl; preferably, R ^c is methyl, isopropyl or phenyl optionally substituted by one methyl;

优选地，所述化合物具有式II所示的结构，Preferably, the compound has a structure shown in formula II,

优选地，所述化合物具有如式V所示的结构，Preferably, the compound has a structure as shown in formula V,

优选地，所述化合物具有如式VI所示的结构，Preferably, the compound has a structure as shown in formula VI,

优选地，所述化合物具有如式VII所示的结构，Preferably, the compound has a structure as shown in formula VII,
根据权利要求1所述的化合物或其药学上可接受的盐，其中，Y ²为CHR ¹或O，R ¹为氢、C1-C6烷基、卤素、硝基、氨基或羟基；优选地，Y ²为CHR ¹，且R ¹为氢、甲基、乙基、异丙基、氟、氯、溴、羟基或氨基；更优选地，Y ²为CH ₂。 The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Y ² is CHR ¹ or O, and R ¹ is hydrogen, C1-C6 alkyl, halogen, nitro, amino or hydroxyl; preferably, Y ² is CHR ¹ , and R ¹ is hydrogen, methyl, ethyl, isopropyl, fluorine, chlorine, bromine, hydroxyl, or amino; more preferably, Y ² is CH ₂ .
根据权利要求1所述的化合物或其药学上可接受的盐，X为CH，Y ¹为N且Y ²为CH ₂。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, X is CH, Y ¹ is N and Y ² is CH ₂ .
根据权利要求1所述的化合物或其药学上可接受的盐，其中，m为0，且n为1，或者m为0，且n为2，或者m和n均为1。The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein m is 0 and n is 1, or m is 0 and n is 2, or both m and n are 1.
根据权利要求1所述的化合物或其药学上可接受的盐，其中，R ³选自苯基、吡啶基、噻吩基、呋喃基、1H-吡唑基、1,2,3-***基、1,2,4-***基、吡嗪基、

其中所述基团任选地被一个或多个R ⁵取代；优选地，R ³选自苯基、吡啶基、噻吩基、呋喃基、1H-吡唑基、1,2,3-***基、1,2,4-***基、吡嗪基、

其中所述基团任选地被一个或多个R ⁵取代；优选地，R ³选自苯基、吡啶基、

其中所述基团任选地被一个或多个R ⁵取代；优选地，R ³选自苯基、吡啶基、

其中所述基团任选地被一个或多个R ⁵取代；。 The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ^{3 is} selected from phenyl, pyridyl, thienyl, furyl, 1H-pyrazolyl, 1,2,3-triazolyl , 1,2,4-triazolyl, pyrazinyl,

Wherein said group is optionally ^{substituted by one or more R 5} ; preferably, R ^{3 is} selected from phenyl, pyridyl, thienyl, furyl, 1H-pyrazolyl, 1,2,3-triazole Group, 1,2,4-triazolyl, pyrazinyl,

Wherein the group is optionally ^{substituted by one or more R 5} ; preferably, R ^{3 is} selected from phenyl, pyridyl,

Wherein the group is optionally ^{substituted by one or more R 5} ; preferably, R ^{3 is} selected from phenyl, pyridyl,

Wherein the group is optionally substituted with one or more R ⁵ ;.
根据权利要求1所述的化合物或其药学上可接受的盐，其中，R ⁵选自氟、氯、溴、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、

优选地，R ⁵选自氟、氯、甲基、

The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ^{5 is} selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl ,

Preferably, R ^{5 is} selected from fluorine, chlorine, methyl,
根据权利要求1所述的化合物或其药学上可接受的盐，R ^a为氢、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环丙基或环戊基；R ^b为氢、甲基、乙基、正丙基或异丙基；或R ^a、R ^b与和它们相连接的N共同构成吗啉环基、吡咯烷基、哌嗪基或高哌嗪基，其中所述基团任选地被一个或多个氟、氯、溴、甲基或乙基取代；优选地，R ^a为甲基，且R ^b为氢或甲基；或R ^a、R ^b与和它们相连接的N共同构成吗啉环基、吡咯烷基、哌嗪基或高哌嗪基，其中所述基团任选地被一个甲基取代；更优选地，R ^a为甲基，且R ^b为氢或甲基；或R ^a、R ^b与和它们相连接的N共同构成

The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein ^Ra is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl or cyclopentyl group; R ^b is hydrogen, methyl, ethyl, n-propyl or isopropyl group; or R ^a, R ^b and the N to which they are attached together form a morpholine ring, pyrrolidinyl, piperazinyl or higher piperazinyl, wherein the group is optionally substituted by one or more fluorine, chlorine, bromine, methyl or ethyl; preferably, R ^a is methyl, and R ^b is hydrogen or methyl; or R ^a , R ^b and the N to which they are connected together constitute a morpholinyl ring group, a pyrrolidinyl group, a piperazinyl group or a homopiperazinyl group, wherein the group is optionally substituted by a methyl group; more preferably, R ^a is ^a methyl group, and R ^b is hydrogen or methyl; or R ^a, R ^b and the N to which they are attached together form
根据权利要求1所述的化合物或其药学上可接受的盐，R ⁵选自氟、氯、甲基、

更优选地，R ⁵选自氟、氯、甲基、

最优选地，R ⁵选自氟、氯、甲基、

The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ^{5 is} selected from fluorine, chlorine, methyl,

More preferably, R ^{5 is} selected from fluorine, chlorine, methyl,

Most preferably, R ^{5 is} selected from fluorine, chlorine, methyl,
式III所示结构的化合物或其药学上可接受的盐，The compound of the structure represented by formula III or a pharmaceutically acceptable salt thereof,

其中，R ³如式I化合物中所定义；优选地，R ³选自苯基、

其中所述基团任选地被一个或两个R ⁵取代；更优选地，R ³选自苯基、

其中所述基团任选地被一个或两个R ⁵取代；其中R ⁵选自氟、氯、甲基、

Wherein, R ^{3 is} as defined in the compound of formula I; preferably, R ^{3 is} selected from phenyl,

Wherein the group is optionally ^{substituted by one or two R 5} ; more preferably, R ^{3 is} selected from phenyl,

Wherein the group is optionally ^{substituted by one or two R 5} ; wherein R ^{5 is} selected from fluorine, chlorine, methyl,
根据权利要求9所述的化合物或其药学上可接受的盐，R ³选自苯基、

其中所述基团任选地被一个R ⁵取代；优选地，R ³选自苯基、

其中所述基团任选地被一个R ⁵取代；所述R ⁵选自氟、甲基、

优选地，R ³选自

更优选地，R ³选自
The compound according to claim 9 or a pharmaceutically acceptable salt thereof, R ^{3 is} selected from phenyl,

Wherein the group is optionally ^{substituted with one R 5} ; preferably, R ^{3 is} selected from phenyl,

Wherein said group is optionally ^{substituted by one R 5} ; said R ^{5 is} selected from fluorine, methyl,

Preferably, R ^{3 is} selected from

More preferably, R ^{3 is} selected from
式IV所示的化合物或其药学上可接受的盐，The compound represented by formula IV or a pharmaceutically acceptable salt thereof,

R ³的定义如式I化合物中所定义的；优选地，R ³为任选地被一个或多个R ⁵取代的苯基，其中R ⁵选自
更优选地，R ³为被一个R ⁵取代的苯基，其中R ⁵为
R ³ is defined as in the compound of formula I; preferably, R ³ is phenyl optionally substituted with one or more R ⁵ , wherein R ^{5 is} selected from
More preferably, R ³ is phenyl substituted with one R ⁵ ^{, wherein R 5} is
式VIII所示化合物或其药学上可接受的盐，The compound represented by formula VIII or a pharmaceutically acceptable salt thereof,

其中，R ³的定义如式I化合物中所定义的；优选地，R ³选自苯基，所述苯基任选被R ⁵取代，其中R ⁵选自
R ^a、R ^b和R ^c的定义同式I化合物；优选地，R ^a为氢或C1-C4烷基；优选地，R ^a为氢或C1-C4烷基，且R ^b为氢；优选地，R ^a为C1-C4烷基，且R ^b为氢；更优选地，R ^c为C1-C4烷基；更优选地，R ^c为甲基、乙基、正丙基、异丙基、正丁基或叔丁基。 Wherein, R ³ is defined as defined in the compound of formula I; preferably, R ^{3 is} selected from phenyl, which is optionally ^{substituted by R 5} , wherein R ^{5 is} selected from
Compound R ^a, R ^b and R ^c are defined for formula I; preferably, R ^a is hydrogen or C1-C4 alkyl; preferably, R ^a is hydrogen or C1-C4 alkyl, and R ^b is hydrogen; preferably Preferably, R ^a is C1-C4 alkyl, and R ^b is hydrogen; more preferably, R ^c is C1-C4 alkyl; more preferably, R ^c is methyl, ethyl, n-propyl, isopropyl , N-butyl or tert-butyl.
下列化合物或其药学上可接受的盐，The following compounds or their pharmaceutically acceptable salts,
一种药物组合物，其包含治疗有效量的式I、II、III、IV、V、VI、VII或VIII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, V, VI, VII or VIII or a pharmaceutically acceptable salt thereof.
权1-13所述的化合物或其药学上可接受的盐或权14所述的组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。Use of the compound described in claims 1-13 or a pharmaceutically acceptable salt thereof or the composition described in claim 14 in the preparation of a medicament for preventing and/or treating diseases or disease states mediated by AXL protein kinase.