WO2023025116A1

WO2023025116A1 - Heterocyclic derivative, preparation method therefor and use thereof in medicine

Info

Publication number: WO2023025116A1
Application number: PCT/CN2022/114084
Authority: WO
Inventors: 陈友喜; 黄贤贵; 龚亮; 李文朋; 毛文涛; 叶成; 钱文建; 陈磊
Original assignee: 浙江海正药业股份有限公司; 上海昂睿医药技术有限公司
Priority date: 2021-08-25
Filing date: 2022-08-23
Publication date: 2023-03-02
Also published as: CN116323625A

Abstract

The present invention relates to a heterocyclic derivative, a preparation method therefor and the use thereof in medicine. Specifically, the present invention relates to a heterocyclic derivative represented by general formula (I), a preparation method therefor and a pharmaceutically acceptable salt thereof, as well as the use thereof as a therapeutic agent, especially as a KRas G12D inhibitor; the definitions of each substituent in general formula (I) are the same as the definitions thereof in the description.

Description

杂环类衍生物、其制备方法及其医药上的用途Heterocyclic derivatives, their preparation methods and their medicinal uses

技术领域technical field

本发明涉及一种杂环类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂特别是作为K-Ras GTP酶抑制剂的用途。The invention relates to a heterocyclic derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as a K-Ras GTPase inhibitor.

背景技术Background technique

RAS代表一组紧密相关的单体球状蛋白质(21kDa分子量)，其具有189个氨基酸且与质膜相连并且结合GDP或GTP。在正常发育或生理条件下，RAS接收生长因子和各种其它细胞外信号而被激活，负责调节细胞生长、存活、迁移和分化等功能。RAS起分子开关作用，RAS蛋白的开/关状态通过核苷酸结合确定，活性信号传导构象结合GTP，非活性构象结合GDP。当RAS包含结合的GDP时，其处于休眠或静止或关闭状态，并且是“非活化的”。当细胞暴露于某些生长促进刺激物进行响应时，RAS被诱导将结合的GDP转换为GTP。随着GTP被结合，RAS是“开启的”，并且能够与其它蛋白相互作用且活化其它蛋白(其“下游靶标”)。RAS蛋白本身具有极低的将GTP水解回到GDP并由此将自身变为关闭状态的固有能力。将RAS转换为关闭需要称作GTP酶激活蛋白(GAPs)的外源性蛋白，其与RAS相互作用并且能大大促进GTP向GDP的转化。任何在RAS中的影响其与GAP相互作用或将GTP转化回到GDP的能力的突变，将会导致所述蛋白的延长的活化，并且因此产生到细胞的延长的信号，该信号告知其继续生长和***。因此这些信号会使得细胞生长和***，过度活化的RAS信号转导可能最终导致癌症。RAS represent a group of closely related monomeric globular proteins (21 kDa molecular weight) of 189 amino acids that are associated with the plasma membrane and bind GDP or GTP. Under normal development or physiological conditions, RAS is activated by receiving growth factors and various other extracellular signals, and is responsible for regulating cell growth, survival, migration and differentiation. RAS functions as a molecular switch, the on/off state of RAS protein is determined by nucleotide binding, the active signaling conformation binds GTP, and the inactive conformation binds GDP. When the RAS contains bound GDP it is dormant or resting or off and is "inactive". When cells are exposed to certain growth-promoting stimuli in response, RAS is induced to convert bound GDP to GTP. With GTP bound, RAS is "on" and is able to interact with and activate other proteins (its "downstream targets"). The RAS proteins themselves have a very low intrinsic ability to hydrolyze GTP back to GDP and thereby turn themselves off. Switching RAS off requires exogenous proteins called GTPase activating proteins (GAPs), which interact with RAS and can greatly facilitate the conversion of GTP to GDP. Any mutation in RAS that affects its ability to interact with GAP or convert GTP back to GDP will result in prolonged activation of the protein and thus a prolonged signal to the cell telling it to continue growing and split. These signals thus allow cells to grow and divide, and overactive RAS signaling may ultimately lead to cancer.

在结构上，RAS蛋白包含负责RAS的酶促活性-----鸟嘌呤核苷酸结合和水解(GTP酶反应)的G结构域。其还包括被称为CAAX盒的C端延伸区，其可被转译后修饰并且使该蛋白靶向膜。G结构域在尺寸上大约为21-25kDa并含有磷酸结合环(P-环)。P-环表示蛋白中结合核苷酸的囊袋，并且这是具有保守氨基酸残基的结构域的刚性部分，所述保守氨基酸残基为核苷酸结合和水解所必需的(甘氨酸12、苏氨酸26和赖氨酸16)。G结构域还含有所谓的开关I区(残基30-40)和开关II区(残基60-76)，其均为蛋白的动态部分，由于该动态部分在静止和负载状态之间进行转换的能力而常常被表示为“弹簧加载”机制。主要相互作用为由苏氨酸-35和甘氨酸-60与GTP的γ-磷酸所形成的氢键，其使开关I区和开关II区分别维持它们的活性构象。在水解GTP和释放磷酸盐之后，此两者松弛成无活性的GDP构象。Structurally, RAS proteins contain a G domain responsible for the enzymatic activity of RAS—guanine nucleotide binding and hydrolysis (GTPase reaction). It also includes a C-terminal extension known as the CAAX box, which can be post-translationally modified and targets the protein to the membrane. The G domain is approximately 21-25 kDa in size and contains a phosphate binding loop (P-loop). The P-loop represents the pocket in the protein that binds nucleotides, and this is the rigid part of the domain with conserved amino acid residues necessary for nucleotide binding and hydrolysis (glycine 12, threo amino acid 26 and lysine 16). The G domain also contains the so-called switch I region (residues 30-40) and switch II region (residues 60-76), both of which are the dynamic part of the protein, since this dynamic part switches between the resting and loaded states This capability is often expressed as a "spring-loaded" mechanism. The main interaction is the hydrogen bond formed by threonine-35 and glycine-60 with the γ-phosphate of GTP, which maintains the switch I and switch II regions in their active conformations, respectively. Following hydrolysis of GTP and release of phosphate, both relax into the inactive GDP conformation.

在RAS家族成员中，致癌突变最常见于KRAS(85％)，而NRAS(12％)和HRAS(3％)则较为少见。KRAS突变在美国三大致命癌症类型中普遍存在：胰腺癌(95％)、结肠直肠癌(45％)和肺癌(25％)，在包括心脏粘液瘤、***癌、肝细胞癌、软骨肉瘤、***瘤、恶性黑色素瘤、肾上腺成神经细胞瘤、骨髓性白血病、急性淋巴细胞白血病或胶质母细胞瘤、多发性骨髓瘤、子宫癌、胆管癌、胃癌、膀胱癌、弥漫性大B细胞淋巴瘤、横纹肌肉瘤、皮肤鳞状细胞癌、***、睾丸生殖细胞癌等在内的其他癌症类型中也发现KRAS突变,而在乳腺癌、卵巢癌和脑癌中很少发现(<2％)。在非小细胞肺癌(NSCLC)中，KRAS G12C是最常见的突变，占所有KRAS突变的近一半，其次是G12V和G12D。在非小细胞肺癌中，特定等位基因突变频率的增加多来自经典的由吸烟诱导的典型突变(G:C至T:A置换)，从而导致了KRAS G12C(GGT至TGT)和G12V(GGT至GTT)突变。Among RAS family members, oncogenic mutations were most commonly found in KRAS (85%), while NRAS (12%) and HRAS (3%) were less common. KRAS mutations are prevalent in the three most deadly cancer types in the United States: pancreatic (95%), colorectal (45%), and lung (25%), including cardiac myxoma, prostate, hepatocellular carcinoma, chondrosarcoma, Seminoma, malignant melanoma, adrenal neuroblastoma, myelogenous leukemia, acute lymphoblastic leukemia or glioblastoma, multiple myeloma, uterine cancer, cholangiocarcinoma, gastric cancer, bladder cancer, diffuse large B KRAS mutations are also found in other cancer types, including lymphoma, rhabdomyosarcoma, squamous cell carcinoma of the skin, cervical cancer, and testicular germ cell carcinoma, but rarely in breast, ovarian, and brain cancers (<2 %). In non-small cell lung cancer (NSCLC), KRAS G12C is the most common mutation, accounting for nearly half of all KRAS mutations, followed by G12V and G12D. In non-small cell lung cancer, the increased mutation frequency of specific alleles is mostly from the classic smoking-induced mutations (G:C to T:A substitutions), resulting in KRAS G12C (GGT to TGT) and G12V (GGT to GTT) mutation.

大型基因组学研究表明，肺癌KRAS突变，包括G12C，与NSCLC中其它已知的驱动致癌突变相互排斥，包括EGFR、ALK、ROS1、RET和BRAF，表明KRAS突变在肺癌中的独特性。而同时，KRAS突变经常与某些共突变同时发生，例如STK11、KEAP1和TP53，它们与突变的RAS合作将细胞转化为高度恶性和侵袭性的肿瘤细胞。Large genomic studies have shown that lung cancer KRAS mutations, including G12C, are mutually exclusive with other known driver oncogenic mutations in NSCLC, including EGFR, ALK, ROS1, RET, and BRAF, suggesting the uniqueness of KRAS mutations in lung cancer. At the same time, KRAS mutations often co-occur with certain co-mutations, such as STK11, KEAP1, and TP53, which cooperate with mutated RAS to transform cells into highly malignant and aggressive tumor cells.

三种RAS癌基因构成了人类癌症中突变最频繁的基因家族。令人失望的是，尽管经过三十多年的研究努力，临床上仍然没有有效的抗RAS疗法，使用小分子靶向该基因是项挑战。因此，本领域迫切需要用于靶向RAS(例如，K-RAS，H-RAS和/或N-RAS)的小分子并且利用其治疗多种疾病，例如癌症。Three RAS oncogenes constitute the most frequently mutated gene family in human cancers. Disappointingly, despite more than three decades of research efforts, there are still no clinically effective anti-RAS therapies, and targeting this gene with small molecules is challenging. Therefore, there is an urgent need in the art for small molecules for targeting RAS (eg, K-RAS, H-RAS and/or N-RAS) and using them to treat various diseases, such as cancer.

目前，国内外对于KRas G12D抑制剂的临床开发竞争激烈，其中Mirati Therapeutics Inc公司研发的KRas G12D抑制剂MRTX-1133已经进入临床前阶段，用于治疗大肠肿瘤、非小细胞肺癌和胰腺癌等疾病。目前公开为数不多的KRas G12D抑制剂专利申请，其中包括Mirati Therapeutics Inc公司的WO2021041671。虽然KRas G12D抑制剂的研究和应用已取得一定的进展，但是提高的空间仍然巨大，仍有必要继续研究和开发新的KRas G12D抑制剂。At present, there is fierce competition for the clinical development of KRas G12D inhibitors at home and abroad. Among them, the KRas G12D inhibitor MRTX-1133 developed by Mirati Therapeutics Inc. has entered the preclinical stage and is used to treat diseases such as colorectal tumors, non-small cell lung cancer and pancreatic cancer. . There are currently a handful of published patent applications for KRas G12D inhibitors, including WO2021041671 by Mirati Therapeutics Inc. Although some progress has been made in the research and application of KRas G12D inhibitors, there is still huge room for improvement, and it is still necessary to continue research and development of new KRas G12D inhibitors.

发明内容Contents of the invention

本发明的目的在于提供一种通式(I)所示的杂环类衍生物，或其立体异构体、互变异构体或其可药用的盐：The object of the present invention is to provide a heterocyclic derivative represented by general formula (I), or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

环A为4～12元的杂环基，其中所述的杂环基内至少含有1个氮原子；Ring A is a 4- to 12-membered heterocyclic group, wherein the heterocyclic group contains at least one nitrogen atom;

环B为芳基、杂芳基、杂环基或环烷基；Ring B is aryl, heteroaryl, heterocyclyl or cycloalkyl;

Q为N或CR ^a； Q is N or CR ^a ;

R ^a为氢原子、卤素、羟基、氨基、烷基、烷氧基或氰基；其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基和烷氧基的取代基所取代； R ^a is a hydrogen atom, halogen, hydroxyl, amino, alkyl, alkoxy or cyano; wherein the alkyl or alkoxy is optionally further replaced by one or more selected from halogen, hydroxyl, cyano, alkane Substituents of radicals and alkoxy groups;

L为键、-O-或-NR ^b； L is a bond, -O- or -NR ^b ;

R ^b为氢原子或烷基； R ^b is a hydrogen atom or an alkyl group;

W为N、CR ^c或-S(＝O)-；W优选为N； W is N, CR ^c or -S(=O)-; W is preferably N;

R ^c为不存在或氢原子； R ^c is absent or a hydrogen atom;

R ¹为-L ¹-环烷基、-L ¹-杂环基、-L ¹-芳基、-L ¹-杂芳基或-L ¹-稠合环，其中所述的环烷基、杂环基、芳基、杂芳基或稠合环任选进一步被一个或多个选自烷基、卤素、卤代烷基、羟烷基、苄基、氰基、环烷基、杂环基、芳基、杂芳基、＝O、-OR ⁵、-C(O)R ⁵、-C(O)OR ⁵、-NHC(O)R ⁵、-NHC(O)OR ⁵、-NR ⁶R ⁷、-C(O)NR ⁶R ⁷、-CH ₂NHC(O)OR ⁵、-CH ₂NR ⁶R ⁷和-S(O) _rR ⁵的取代基所取代； R ¹ is -L ¹ -cycloalkyl, -L ¹ -heterocyclyl, -L ¹ -aryl, -L ¹ -heteroaryl or -L ¹ -fused ring, wherein said cycloalkyl, Heterocyclyl, aryl, heteroaryl or fused ring is optionally further selected from one or more groups selected from alkyl, halogen, haloalkyl, hydroxyalkyl, benzyl, cyano, cycloalkyl, heterocyclyl, Aryl, Heteroaryl, =O, -OR ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -NHC(O)R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ^7. Substituents of -C(O)NR ⁶ R ⁷ , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ and -S(O) _r R ⁵ ;

L ¹各自独立地为键或-C ₁-C ₆亚烷基，其中所述的亚烷基任选进一步被一个或多个R ^A所取代； Each of L ¹ is independently a bond or -C ₁ -C ₆ alkylene, wherein said alkylene is optionally further substituted by one or more R ^A ;

R ^A各自独立地为氢原子、卤素、羟基或羟甲基； ^RA is each independently a hydrogen atom, halogen, hydroxyl or hydroxymethyl;

或者，连接于同一碳原子的两个R ^A，与所连接的碳原子一起形成一个环烷基；优选为环丙基； Alternatively, two ^RAs connected to the same carbon atom form a cycloalkyl group together with the connected carbon atoms; preferably cyclopropyl;

R ²相同或不同，各自独立地为氢原子、卤素、羟基、氰基、烷基或烷氧基，其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基和烷氧基的取代基所取代； R ² are the same or different, each independently a hydrogen atom, halogen, hydroxyl, cyano, alkyl or alkoxy, wherein said alkyl or alkoxy is optionally further selected by one or more selected from halogen, hydroxyl , cyano and alkoxy substituents;

或者，任意的两个R ²与其所连接的原子一起形成一个环烷基或杂环基； Alternatively, any two R ² form a cycloalkyl or heterocyclic group together with the atoms they are connected to;

或者，R ²和R ^a，与其所连接的原子一起形成一个6～8元杂环基；所述的杂环基任选进一步被一个或多个R ^B取代； Alternatively, R ² and R ^a form a 6-8 membered heterocyclic group together with the atoms they are connected to; the heterocyclic group is optionally further substituted by one or more R ^B ;

R ^B为氢原子、卤素、烷基、氘代烷基或烷氧基，其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基和烷氧基的取代基所取代；R ^B优选为氢原子、甲基或氘甲基； R ^B is a hydrogen atom, halogen, alkyl, deuterated alkyl or alkoxy, wherein said alkyl or alkoxy is optionally further replaced by one or more selected from halogen, hydroxyl, cyano, alkyl and Substituents of alkoxy groups are substituted; ^RB is preferably a hydrogen atom, methyl or deuteromethyl;

或者，两个R ^B与其所连接的同一个碳原子一起形成-C(＝O)-； Alternatively, two ^RBs form -C(=O)- together with the same carbon atom to which they are attached;

R ³为-L ²-环烷基、-L ²-杂环基、-L ²-芳基、-L ²-杂芳基、-L ²-OR ⁵、-L ²-NR ⁷R ⁸或＝NR ⁵；其中所述的环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、＝O、-OR ⁵、-C(O)R ⁵、-C(O)OR ⁵、-NHC(O)R ⁵、-NHC(O)OR ⁵、-NR ⁶R ⁷、-C(O)NR ⁶R ⁷、-CH ₂NHC(O)OR ⁵、-CH ₂NR ⁶R ⁷和-S(O) _rR ⁵的取代基所取代； R ³ is -L ² -cycloalkyl, -L ² -heterocyclyl, -L ² -aryl, -L 2 -heteroaryl, -L ² ^-OR ⁵ , -L ² -NR ⁷ R ⁸ or =NR ⁵ ; wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from one or more of alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl , aryl, heteroaryl, =O, -OR ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -NHC(O)R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ Substituents of R ⁷ , -C(O)NR ⁶ R ⁷ , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ and -S(O) _r R ⁵ ;

或者，R ²和R ³，与其所连接的原子一起形成一个杂芳基或杂环基； Alternatively, R ² and R ³ together form a heteroaryl or heterocyclic group with the atoms they are connected to;

L ²各自独立地为键或-C ₁-C ₆亚烷基，其中所述的亚烷基任选进一步被一个或多个选自卤素、羟基、氰基和＝O的取代基所取代； L ² are each independently a bond or -C ₁ -C ₆ alkylene, wherein said alkylene is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano and =O;

R ⁴相同或不同，各自独立地为氢原子、卤素、氰基、烷基、环烷基、烷氧基、杂环基、芳基、杂芳基或稠合环，其中所述的烷基、环烷基、烷氧基、杂环基、芳基、杂芳基或稠合环任选进一步被一个或多个R ^C取代； R ⁴ are the same or different, each independently hydrogen atom, halogen, cyano, alkyl, cycloalkyl, alkoxy, heterocyclyl, aryl, heteroaryl or fused ring, wherein the alkyl , cycloalkyl, alkoxy, heterocyclyl, aryl, heteroaryl or fused ring optionally further substituted by one or more R ^C ;

或者，两个R ⁴与其所连接的同一个碳原子一起形成一个稠合环；所述的稠合环任选进一步被一个或多个R ^C取代； Alternatively, two R ⁴ form a fused ring together with the same carbon atom to which they are attached; the fused ring is optionally further substituted by one or more R ^C ;

R ^C相同或不同，各自独立地为氢原子、烷基、卤素、硝基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-OR ⁵、-C(O)R ⁵、-C(O)OR ⁵、-NHC(O)R ⁵、-NHC(O)OR ⁵、-NR ⁶R ⁷、-C(O)NR ⁶R ⁷、-CH ₂NHC(O)OR ⁵、-CH ₂NR ⁶R ⁷或-S(O) _rR ⁵；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、＝O、-OR ⁵、-C(O)R ⁵、-C(O)OR ⁵、-NHC(O)R ⁵、-NHC(O)OR ⁵、-NR ⁶R ⁷、-C(O)NR ⁶R ⁷、-CH ₂NHC(O)OR ⁵、-CH ₂NR ⁶R ⁷和-S(O) _rR ⁵的取代基所取代； R and ^C are the same or different, each independently hydrogen atom, alkyl, halogen, nitro, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁵ , - C(O)R ⁵ , -C(O)OR ⁵ , -NHC(O)R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O) _r R ⁵ ; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl The group is optionally further replaced by one or more groups selected from alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -NHC(O)R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -CH ₂ NHC(O)OR ^5. Substituents of -CH ₂ NR ⁶ R ⁷ and -S(O) _r R ⁵ ;

或者，两个R ^C与其所连接的同一个碳原子一起形成-C(＝O)-； Alternatively, two ^RCs form -C(=O)- together with the same carbon atom to which they are attached;

或者，R ²与R ⁴，与其所连接的原子一起形成一个6～8元杂环基；所述的杂环基任选进一步被一个或多个R ^D取代； Or, R ² and R ⁴ together form a 6-8 membered heterocyclic group; the heterocyclic group is optionally further substituted by one or more R ^D ;

R ^D为氢原子、卤素、烷基或烷氧基，其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基和烷氧基的取代基所取代；R ^D优选为氢原子； R ^D is a hydrogen atom, halogen, alkyl or alkoxy, wherein said alkyl or alkoxy is optionally further substituted by one or more selected from halogen, hydroxyl, cyano, alkyl and alkoxy Substituted by group; R ^D is preferably a hydrogen atom;

或者，两个R ^D与其所连接的同一个碳原子一起形成-C(＝O)-； Alternatively, the two ^RDs together form -C(=O)- with the same carbon atom to which they are attached;

R ⁵各自独立地为氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-C(O)R ⁸、-C(O)OR ⁸、-OC(O)R ⁸、-NR ⁹R ¹⁰、-C(O)NR ⁹R ¹⁰、-SO ₂NR ⁹R ¹⁰和-NR ⁹C(O)R ¹⁰的取代基所取代； ^Each R is independently a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group are optionally Further selected from one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -SO ₂ NR ⁹ R ¹⁰ and -NR ⁹ C (O) R ¹⁰ substituents are substituted;

R ⁶和R ⁷各自独立地为氢原子、羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-C(O)R ⁸、-C(O)OR ⁸、-OC(O)R ⁸、-NR ⁹R ¹⁰、-C(O)NR ⁹R ¹⁰、-SO ₂NR ⁹R ¹⁰和-NR ⁹C(O)R ¹⁰的取代基所取代； R ⁶ and R ⁷ are each independently a hydrogen atom, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, ring Alkyl, heterocyclyl, aryl or heteroaryl are optionally further selected from one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl , heteroaryl, =O, -C(O)R ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -SO ₂ NR ⁹ R ¹⁰ and -NR ⁹ C(O)R ¹⁰ are substituted by substituents;

或者，R ⁶和R ⁷与它们相连接的原子一起形成一个4～8元杂环基，其中所述4～8元杂环基内含有一个或多个N、O或S(O) _r，并且所述的4～8元杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-C(O)R ⁸、-C(O)OR ⁸、-OC(O)R ⁸、-NR ⁹R ¹⁰、-C(O)NR ⁹R ¹⁰、-SO ₂NR ⁹R ¹⁰和-NR ⁹C(O)R ¹⁰的取代基所取代； Alternatively, R ⁶ and R ⁷ form a 4-8 membered heterocyclic group together with the atoms they are connected to, wherein the 4-8 membered heterocyclic group contains one or more N, O or S(O) _r , And the 4-8 membered heterocyclic group is optionally further replaced by one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, hetero Aryl, =O, -C(O)R ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -SO ₂ NR ⁹ R ¹⁰ and -NR ⁹ C (O) R ¹⁰ are replaced by substituents;

R ⁸、R ⁹和R ¹⁰各自独立地为氢原子、烷基、氨基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基和羧酸酯基的取代基所取代； R ⁸ , R ⁹ and R ¹⁰ are each independently a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclyl group, Aryl or heteroaryl is optionally further replaced by one or more selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, Carboxyl and carboxylate substituents are substituted;

m各自独立地为0、1、2、3或4；each m is independently 0, 1, 2, 3 or 4;

k各自独立地为0、1、2、3或4；且each k is independently 0, 1, 2, 3 or 4; and

r各自独立地为0、1或2。r is each independently 0, 1 or 2.

在本发明的一个或多个实施方案中，通式(I)所述的杂环类衍生物或其立体异构体、互变异构体或其可药用的盐，其为通式(II)或(III)所示的化合物或其立体异构体、互变异构体或其可药用的盐：In one or more embodiments of the present invention, the heterocyclic derivatives described in general formula (I) or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof, which are general formula ( The compound shown in II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

其中：in:

环C各自独立地为芳基、杂芳基或稠合环；Ring C is each independently aryl, heteroaryl or fused ring;

R ⁴各自独立地为氢原子、卤素、氰基、烷基、环烷基或烷氧基，其中所述的烷基、环烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基、烷氧基和卤代烷基的取代基所取代；R ⁴优选为卤素，更优选为氟或氯； R ⁴ are each independently a hydrogen atom, halogen, cyano, alkyl, cycloalkyl or alkoxy, wherein the alkyl, cycloalkyl or alkoxy are optionally further selected from one or more halogen , hydroxy, cyano, alkyl, alkoxy and haloalkyl substituents are substituted; R is ^preferably halogen, more preferably fluorine or chlorine;

n各自独立地为0、1、2或3；each n is independently 0, 1, 2 or 3;

环A、W、R ¹～R ³、R ^C、L、Q和m的定义如通式(I)中所述。 Ring A, W, R ¹ to R ³ , R ^C , L, Q and m are defined as described in general formula (I).

在本发明的一个或多个实施方案中，通式(I)所述的杂环类衍生物或其立体异构体、互变异构体或其可药用的盐，其为通式(IV)或(V)所示的化合物或其立体异构体、互变异构体或其可药用的盐：In one or more embodiments of the present invention, the heterocyclic derivatives described in general formula (I) or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof, which are general formula ( Compounds shown in IV) or (V) or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

其中：in:

n各自独立地为0、1、2或3；each n is independently 0, 1, 2 or 3;

在本发明的一个或多个实施方案中，通式(I)所述的杂环类衍生物或其立体异构体、互变异构体或其可药用的盐，其为通式(VI)或(VII)所示的化合物或其立体异构体、互变异构体或其可药用的盐：In one or more embodiments of the present invention, the heterocyclic derivatives described in general formula (I) or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof, which are general formula ( The compound shown in VI) or (VII) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

其中：in:

R ⁴各自独立地为氢原子、卤素、氰基、烷基、环烷基或烷氧基；其中所述的烷基、环烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基、烷氧基和卤代烷基的取代基所取代；R ⁴优选为卤素，更优选为氟或氯； R ⁴ are each independently a hydrogen atom, halogen, cyano, alkyl, cycloalkyl or alkoxy; wherein the alkyl, cycloalkyl or alkoxy are optionally further selected by one or more halogen , hydroxy, cyano, alkyl, alkoxy and haloalkyl substituents are substituted; R is ^preferably halogen, more preferably fluorine or chlorine;

R ^B为氢原子或甲基； ^RB is a hydrogen atom or a methyl group;

n各自独立地为0、1、2或3；each n is independently 0, 1, 2 or 3;

p各自独立地为0、1、2或3；each p is independently 0, 1, 2 or 3;

环A、W、R ¹～R ³、R ^C、L和Q的定义如通式(I)中所述。 Ring A, W, R ¹ to R ³ , R ^C , L and Q are as defined in the general formula (I).

在本发明的一个或多个实施方案中，通式(I)所述的杂环类衍生物或其立体异构体、互变异构体或其可药用的盐，其为通式(VIII)所示的化合物或其立体异构体、互变异构体或其可药用的盐：In one or more embodiments of the present invention, the heterocyclic derivatives described in general formula (I) or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof, which are general formula ( The compound shown in VIII) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

其中：in:

环D为稠合环；Ring D is a fused ring;

n为0、1、2或3；n is 0, 1, 2 or 3;

在本发明的一个或多个实施方案中，通式(I)、(II)、(III)、(IV)、(V)或(VIII)所述的杂环类衍生物或其立体异构体、互变异构体或其可药用的盐，其中：In one or more embodiments of the present invention, the heterocyclic derivatives described in general formula (I), (II), (III), (IV), (V) or (VIII) or their stereoisomers isomers, tautomers or pharmaceutically acceptable salts thereof, wherein:

为以下基团：

for the following groups:

R ⁵为氢原子或烷基；其中所述的烷基优选为甲基； R ⁵ is a hydrogen atom or an alkyl group; wherein the alkyl group is preferably a methyl group;

R ³的定义如通式(I)中所述。 The definition of R ³ is as described in the general formula (I).

在本发明的一个或多个实施方案中，通式(VI)所述的杂环类衍生物或其立体异构体、互变异构体或其可药用的盐，其中:In one or more embodiments of the present invention, the heterocyclic derivatives described in general formula (VI) or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein:

为

for

R ³的定义如通式(VI)中所述。 R ³ is defined as described in general formula (VI).

在本发明的一个或多个实施方案中，通式(VII)所述的杂环类衍生物或其立体异构体、互变异构体或其可药用的盐，其中：In one or more embodiments of the present invention, the heterocyclic derivatives described in general formula (VII) or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein:

为

for

R ³的定义如通式(VII)中所述 R ³ is defined as described in general formula (VII)

在本发明的一个或多个实施方案中，通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的杂环类衍生物或其立体异构体、互变异构体或其可药用的盐，其中：In one or more embodiments of the present invention, the heterocycle described in general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) derivatives or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein:

R ³为环烷基、杂芳基、-C(O)-杂环基、-C(O)-杂芳基、-(CH2)q-杂环基、-(CH ₂)q-OR ⁵或-(CH2)q-NR ⁶R ⁷；其中所述的环烷基、杂芳基或杂环基任选进一步被一个或多个选自烷基、卤素、环烷基和烷氧基的取代基所取代； R ³ is cycloalkyl, heteroaryl, -C(O)-heterocyclyl, -C(O)-heteroaryl, -(CH2)q-heterocyclyl, -(CH ₂ )q-OR ⁵ Or -(CH2)q-NR ⁶ R ⁷ ; wherein the cycloalkyl, heteroaryl or heterocyclic group is optionally further replaced by one or more selected from alkyl, halogen, cycloalkyl and alkoxy Substituents are substituted;

R ⁵为氢原子或烷基；R ⁵优选为氢原子； R ⁵ is a hydrogen atom or an alkyl group; R ⁵ is preferably a hydrogen atom;

R ⁶和R ⁷各自独立地为烷基，优选为甲基； R ⁶ and R ⁷ are each independently an alkyl group, preferably a methyl group;

q为0、1或2。q is 0, 1 or 2.

在本发明的一个或多个实施方案中，通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的杂环类衍生物或其立体异构体、互变异构体或其可药用的盐，其中R ³为以下基团： In one or more embodiments of the present invention, the heterocycle described in general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) Class derivatives or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R ³ is the following groups:

在本发明的一个或多个实施方案中，通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的杂环类衍生物或其立体异构体、互变异构体或其可药用的盐，其中Q为N。In one or more embodiments of the present invention, the heterocycle described in general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) derivatives or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein Q is N.

Q为CR ^a； Q is CR ^a ;

R ^a为氢原子或氰基。 R ^a is a hydrogen atom or a cyano group.

在本发明的一个或多个实施方案中，通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的杂环类衍生物或其立体异构体、互变异构体或其可药用的盐，其中L为-O-。In one or more embodiments of the present invention, the heterocycle described in general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) derivatives or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein L is -O-.

R ¹为-L ¹-杂环基； R ¹ is -L ¹ -heterocyclyl;

其中所述的杂环基任选进一步被一个或多个选自烷基、卤素、烷氧基和＝O的取代基所取代；Wherein the heterocyclic group is optionally further substituted by one or more substituents selected from alkyl, halogen, alkoxy and =O;

其中所述的卤素优选为氟；Wherein said halogen is preferably fluorine;

-L ¹-为亚甲基。 -L ¹ - is methylene.

在本发明的一个或多个实施方案中，通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的杂环类衍生物或其立体异构体、互变异构体或其可药用的盐，其中R ¹为： In one or more embodiments of the present invention, the heterocycle described in general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) Class derivatives or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R ¹ is:

在本发明的一个或多个实施方案中，通式(II)、(III)、(IV)、(V)、(VI)或(VII)所述的杂环类衍生物或其立体异构体、互变异构体或其可药用的盐，其中环C为：In one or more embodiments of the present invention, the heterocyclic derivatives described in general formula (II), (III), (IV), (V), (VI) or (VII) or their stereoisomers Body, tautomer or pharmaceutically acceptable salt thereof, wherein ring C is:

苯基、萘基、吡啶基、喹啉基、异喹啉基、吲哚基、吲唑基、苯并噻唑基、四氢化萘基、Phenyl, naphthyl, pyridyl, quinolinyl, isoquinolyl, indolyl, indazolyl, benzothiazolyl, tetralinyl,

优选为萘基。

Naphthyl is preferred.

在本发明的一个或多个实施方案中，通式(II)、(III)、(IV)、(V)、(VI)或(VII)所述的杂环类衍生物或其立体异构体、互变异构体或其可药用的盐，其中

为： In one or more embodiments of the present invention, the heterocyclic derivatives described in general formula (II), (III), (IV), (V), (VI) or (VII) or their stereoisomers isomers, tautomers or pharmaceutically acceptable salts thereof, wherein

for:

在本发明的一个或多个实施方案中，通式(VIII)所述的杂环类衍生物或其立体异构体、互变异构体或其可药用的盐，其中环D为In one or more embodiments of the present invention, the heterocyclic derivatives described in general formula (VIII) or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein ring D is

在一个或多个实施方式中，所述化合物包括，但不限于：In one or more embodiments, the compounds include, but are not limited to:

或其立体异构体、互变异构体或其可药用的盐。Or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

注：如果在画出的结构和给出的该结构的名称之间有差异，则画出的结构将给予更大的权重。NOTE: If there is a discrepancy between the drawn structure and the given name for that structure, the drawn structure will be given greater weight.

在另一方面，本发明提供一种药物组合物，所述的药物组合物含有有效剂量的通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的化合物或其立体异构体、互变异构体或其可药用的盐，及可药用的载体、赋形剂或它们的组合。In another aspect, the present invention provides a pharmaceutical composition, which contains an effective dose of the general formula (I), (II), (III), (IV), (V), (VI), The compound described in (VII) or (VIII) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or their combination.

在另一方面，本发明提供一种抑制KRas G12D酶方法，其中所述的方法包括，给予病人一种药物组合物，所述的药物组合物含有有效剂量的通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的化合物或其立体异构体、互变异构体或其可药用的盐，及可药用的载体、赋形剂或它们的组合。In another aspect, the present invention provides a method for inhibiting KRas G12D enzyme, wherein said method comprises, administering to a patient a pharmaceutical composition, said pharmaceutical composition containing an effective dose of the general formula (I), (II) , (III), (IV), (V), (VI), (VII) or (VIII) compound or stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and Pharmaceutical carrier, excipient or their combination.

本发明还提供了一种通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物在制备用于治疗由KRas G12D突变介导的疾病的药物中的用途，其中所述的由KRas G12D突变介导的疾病优选为癌症，其中所述的癌症优选为心脏粘液瘤、肺癌、胃癌、大肠肿瘤、直肠癌、胰腺癌、***癌、膀胱癌、肝细胞癌、胆管癌、软骨肉瘤、多发性骨髓瘤、子宫癌、***、***瘤、恶性黑色素瘤、皮肤鳞状细胞癌、肾上腺成神经细胞瘤、骨髓性白血病、急性淋巴细胞白血病或胶质母细胞瘤，更优选为胰腺癌、大肠肿瘤、直肠癌和肺癌；其中所述的肺癌选为非小细胞肺癌或小细胞肺癌。The present invention also provides a compound described in general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or its stereoisomer , a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicine for treating a disease mediated by a KRas G12D mutation, wherein the disease mediated by a KRas G12D mutation Cancer is preferred, wherein said cancer is preferably cardiac myxoma, lung cancer, gastric cancer, colorectal tumor, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, cholangiocarcinoma, chondrosarcoma, multiple myeloma, uterine Carcinoma, cervical cancer, seminoma, malignant melanoma, squamous cell carcinoma of the skin, adrenal neuroblastoma, myelogenous leukemia, acute lymphoblastic leukemia or glioblastoma, more preferably pancreatic cancer, colorectal tumor, Rectal cancer and lung cancer; wherein said lung cancer is selected as non-small cell lung cancer or small cell lung cancer.

在另一方面，本发明提供一种通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物在制备KRas G12D抑制剂中的用途。In another aspect, the present invention provides a compound described in general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or its stereo Isomers, tautomers or pharmaceutically acceptable salts thereof, or the use of pharmaceutical compositions thereof in the preparation of KRas G12D inhibitors.

本发明的另一方面涉及一种预防和/或治疗KRas G12D突变介导的疾病的方法，其包括向患者施用治疗有效剂量的通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其可药用盐或包含其的药物组合物。Another aspect of the present invention relates to a method for preventing and/or treating diseases mediated by KRas G12D mutations, comprising administering to patients a therapeutically effective dose of the general formula (I), (II), (III), (IV) , (V), (VI), (VII) or (VIII) described compound or its tautomer, mesoform, racemate, enantiomer, diastereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

本发明还提供了通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的化合物或其立体异构体、互变异构体或其可药用的盐所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物在制备用于治疗癌症的药物中的用途，其中所述的癌症优选为心脏粘液瘤、肺癌、胃癌、大肠肿瘤、直肠癌、胰腺癌、***癌、膀胱癌、肝细胞癌、胆管癌、软骨肉瘤、多发性骨髓瘤、子宫癌、***、***瘤、恶性黑色素瘤、皮肤鳞状细胞癌、肾上腺成神经细胞瘤、骨髓性白血病、急性淋巴细胞白血病或胶质母细胞瘤，更优选为胰腺癌、大肠肿瘤、直肠癌和肺癌；其中所述的肺癌优选为非小细胞肺癌。The present invention also provides the compound described in general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or its stereoisomer, mutual Variant or pharmaceutically acceptable salt thereof The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition in the preparation of drugs for the treatment of cancer purposes, wherein the cancer is preferably cardiac myxoma, lung cancer, gastric cancer, colorectal tumor, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, bile duct cancer, chondrosarcoma, multiple myeloma, uterine cancer, Cervical cancer, seminoma, malignant melanoma, squamous cell carcinoma of the skin, adrenal neuroblastoma, myeloid leukemia, acute lymphoblastic leukemia or glioblastoma, more preferably pancreatic cancer, colorectal tumor, rectal cancer and lung cancer; wherein said lung cancer is preferably non-small cell lung cancer.

本发明还提供通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的化合物或其立体异构体、互变异构体或其可药用的盐所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物，其用作药物。The present invention also provides compounds described in general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or their stereoisomers, interconversion Isomers or pharmaceutically acceptable salts thereof The compound or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, for use as a medicament.

本发明还提供通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的化合物或其立体异构体、互变异构体或其可药用的盐所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物，其用于预防和/或治疗癌症；所述的癌症优选为心脏粘液瘤、肺癌、胃癌、大肠肿瘤、直肠癌、胰腺癌、***癌、膀胱癌、肝细胞癌、胆管癌、软骨肉瘤、多发性骨髓瘤、子宫癌、***、***瘤、恶性黑色素瘤、皮肤鳞状细胞癌、肾上腺成神经细胞瘤、骨髓性白血病、急性淋巴细胞白血病或胶质母细胞瘤，更优选为胰腺癌、大肠肿瘤、直肠癌和肺癌；其中所述的肺癌优选为非小细胞肺癌。The present invention also provides compounds described in general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or their stereoisomers, interconversion Isomers or pharmaceutically acceptable salts thereof The compound or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, which is used for the prevention and/or treatment of cancer; The cancer is preferably cardiac myxoma, lung cancer, gastric cancer, colorectal tumor, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, bile duct cancer, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, Seminoma, malignant melanoma, squamous cell carcinoma of the skin, adrenal neuroblastoma, myelogenous leukemia, acute lymphoblastic leukemia or glioblastoma, more preferably pancreatic cancer, colorectal tumors, rectal cancer and lung cancer; Wherein said lung cancer is preferably non-small cell lung cancer.

本发明还提供通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的化合物或其立体异构体、互变异构体或其可药用的盐所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物，其用作KRas G12D抑制剂。The present invention also provides compounds described in general formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or their stereoisomers, interconversion Isomers or pharmaceutically acceptable salts thereof The compounds or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, are used as KRas G12D inhibitors.

本发明还提供预防和/或治疗癌症的方法，其包括向有需要的对象给予通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的化合物或其立体异构体、互变异构体或其可药用的盐所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物。The present invention also provides a method for preventing and/or treating cancer, which comprises administering the general formula (I), (II), (III), (IV), (V), (VI), (VII) to a subject in need Or the compound described in (VIII) or its stereoisomer, tautomer or its pharmaceutically acceptable salt The described compound or its stereoisomer, tautomer or its pharmaceutically acceptable salt , or a pharmaceutical composition thereof.

本发明还提供抑制对象中KRas G12D的方法，其包括向有需要的对象给予通式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)或(VIII)所述的化合物或其立体异构体、互变异构体或其可药用的盐所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物。The present invention also provides a method for inhibiting KRas G12D in a subject, comprising administering general formula (I), (II), (III), (IV), (V), (VI), (VII) or The compound described in (VIII) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof The compound described above or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition.

本发明的药物制剂可以经局部、口服、经皮、经直肠、经***、非经肠、鼻内、肺内、眼内、静脉内、肌肉内、动脉内、鞘内、囊内、皮内、腹膜内、皮下、角质层下或者通过吸入进行给药。含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。The pharmaceutical formulations of the present invention can be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intrapulmonarily, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intravesically, intradermally , intraperitoneally, subcutaneously, subkeratinally or by inhalation. The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.

本发明的制剂适合以单位计量的形式存在，并且所述制剂可借由在制药技术中所众所周知的任何方法进行制备。能够通过与载体物质进行组合，从而产生单一剂型的活性成分的量可以依据所治疗的宿主及特定给药模式而变化。能够通过与载体物质进行组合从而产生单一剂型的活性成分的量通常指的是能够产生治疗效果的化合物的量。The formulations of the invention are suitably presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form generally refers to that amount of the compound which produces a therapeutic effect.

用于本发明化合物的局部或者透皮给药的剂型可包括粉末、喷雾剂、软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、溶液、贴片及吸入剂。活性化合物可在无菌条件下与药学上可接受的载剂进行混合，并且其可与可能需要的任何防腐剂、缓冲剂或者推进剂进行混合。Dosage forms for the topical or transdermal administration of a compound of this invention may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, in admixture with any preservatives, buffers or propellants which may be required.

当本发明的化合物以药物的形式对人类及动物进行给药时，所述化合物可进行单独提供或者以药物组合物的形式提供，所述药物组合物含有与药学上可接受的载剂进行组合的活性成分，例如0.1％至99.5％(更优选地，0.5％至90％)的活性成分。When the compound of the present invention is administered to humans and animals in the form of medicine, the compound can be provided alone or in the form of a pharmaceutical composition containing Active ingredient, such as 0.1% to 99.5% (more preferably, 0.5% to 90%) active ingredient.

药学上可接受的载剂的实例包括但不限于：(1)糖，例如乳糖、葡萄糖及蔗糖；(2)淀粉，例如玉米淀粉及马铃薯淀粉；(3)纤维素及其衍生物，例如羧甲基纤维素钠、乙基纤维素及乙酸纤维素；(4)粉末状黄蓍胶；(5)麦芽；(6)明胶；(7)滑石；(8)赋形剂，例如可可脂及栓剂蜡；(9)油，例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油；(10)二醇，例如丙二醇；(11)多元醇，例如甘油、山梨糖醇、甘露糖醇及聚乙二醇；(12)酯，例如油酸乙酯及月桂酸乙酯；(13)琼脂；(14)缓冲剂，例如氢氧化镁及氢氧化铝；(15)海藻酸；(16)无热原水；(17)等渗盐水；(18)林格氏溶液(Ringer's solution)；(19)乙醇；(20)磷酸盐缓冲溶液；(21)环糊精，例如连接于纳米粒子的靶向配体，例如AccurinsTM；及(22)用于药物制剂中的其它无毒兼容物质，例如聚合物基组合物。Examples of pharmaceutically acceptable carriers include, but are not limited to: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as carboxy Sodium methylcellulose, ethylcellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and Suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol , mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) seaweed (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffered saline; (21) cyclodextrin, e.g. Targeting ligands for nanoparticles, such as AccurinsTM; and (22) other non-toxic compatible substances for use in pharmaceutical formulations, such as polymer-based compositions.

药学上可接受的抗氧化剂的实例包括但不限于：(1)水溶性抗氧化剂，例如抗坏血酸、半胱胺酸盐酸盐、硫酸氢钠、偏亚硫酸氢钠、亚硫酸钠及其类似物；(2)油溶性抗氧化剂，例如抗坏血酸棕榈酸酯、丁基化羟基苯甲醚(BHA)、丁基化羟基甲苯(BHT)、卵磷脂、五倍子酸丙酯、α-生育酚及其类似物；及(3)金属螯合剂，例如柠檬酸、乙二胺四乙酸(EDTA)、山梨糖醇、酒石酸、磷酸及其类似物。固体剂型(例如胶囊、锭剂丸剂、糖衣锭、粉末、颗粒剂及其类似物)可包括一种或者多种药学上可接受的载剂，例如柠檬酸钠或者磷酸二钙，和/或以下任意其中之一：(1)填充剂或增量剂，例如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇及/或者硅酸；(2)黏合剂，例如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯啶酮、蔗糖和/或***胶；(3)保湿剂，例如甘油；(4)崩解剂，例如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐及碳酸钠；(5)溶解阻滞剂，例如石蜡；(6)吸收加速剂，例如四级铵化合物；(7)湿润剂，例如十六醇及甘油单硬脂酸酯；(8)吸收剂，例如高岭土及膨润土；(9)润滑剂，例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠及其混合物；和(10)着色剂。液体剂型可包括药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆及酏剂。除活性成分之外，液体剂型可含有通常用于本技术领域中的惰性稀释剂，例如水或其它溶剂；增溶剂及乳化剂，例如乙醇、异丙醇、碳酸乙酯、乙酸乙脂、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油、及芝麻油)、甘油、四氢呋喃甲醇、聚乙二醇以及脱水山梨醇的脂肪酸酯、及其混合物。Examples of pharmaceutically acceptable antioxidants include, but are not limited to: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; ( 2) Oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Solid dosage forms (such as capsules, troches pills, dragees, powders, granules, and the like) may include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or the following Any one of: (1) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binders, such as carboxymethylcellulose, alginate, Gelatin, polyvinylpyrrolidone, sucrose, and/or gum arabic; (3) humectants such as glycerin; (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) dissolution retarders, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) absorption (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) colorants. Liquid dosage forms can include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzene Methanol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, THF, polyethylene glycol Fatty acid esters of diols and sorbitan, and mixtures thereof.

除活性化合物之外，悬浮液也可含有悬浮剂，例如乙氧基化异硬脂醇、聚氧化乙烯山梨糖醇及脱水山梨醇酯、微晶纤维素、氢氧化铝氧化物、膨润土、琼脂及黄蓍胶及其混合物。Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide oxide, bentonite, agar and gum tragacanth and mixtures thereof.

除活性化合物之外，软膏剂、糊剂、乳膏剂以及凝胶剂也可含有赋形剂，例如动物脂肪及植物脂肪、油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、聚硅氧、膨润土、硅酸、滑石及氧化锌或者其混合物。Ointments, pastes, creams and gels may contain, in addition to the active compounds, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyesters, etc. Glycol, polysiloxane, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

除活性化合物之外，粉末及喷雾剂也可以含有赋形剂，例如乳糖、滑石、硅酸、氢氧化铝、硅酸钙及聚酰胺粉末或者上述这些物质的混合物。所述喷雾剂可以含有其它的常用推进剂，例如氯氟烃、以及挥发性的未被取代的烃，例如丁烷及丙烷。Powders and sprays can contain, in addition to the active compounds, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. The sprays can contain other customary propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

发明的详细说明Detailed Description of the Invention

除非有相反陈述，否则本发明在说明书和权利要求书中所使用的部分术语定义如下：Unless otherwise stated, some terms used in the present invention in the specification and claims are defined as follows:

“键”是指标示的取代基不存在，该取代基的两端部分直接连接成键。"Bond" means that the indicated substituent does not exist, and the two end portions of the substituent are directly connected to form a bond.

“烷基”当作一基团或一基团的一部分时是指包括C ₁-C ₂₀直链或者带有支链的脂肪烃基团(包含例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20个碳原子)。优选为C ₁-C ₁₀烷基，更优选为C ₁-C ₆烷基。烷基基团的实施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、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代或未取代的。 "Alkyl" when taken as a group or a part of a group means to include C ₁ -C ₂₀ straight chain or branched aliphatic hydrocarbon groups (including for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms). It is preferably C ₁ -C ₁₀ alkyl, more preferably C ₁ -C ₆ alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl wait. Alkyl groups can be substituted or unsubstituted.

“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，代表性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等(包含例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20个碳原子)。烯基可以是任选取代的或未取代的。"Alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples include but are not limited to ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl etc. (including for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms). Alkenyl groups can be optionally substituted or unsubstituted.

“炔基”是指含有一个碳碳三键的脂肪烃基团，可为直链也可以带有支链。优先选择的是C ₂-C ₁₀的炔基，更优选C ₂-C ₆炔基，最优选C ₂-C ₄炔基(包含例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20个碳原子)。炔基基团的实施例包括，但不限于乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。炔基可以是取代或未取代的。 "Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight or branched. Preference is given to C ₂ -C ₁₀ alkynyl, more preferably C ₂ -C ₆ alkynyl, most preferably C ₂ -C ₄ alkynyl (comprising e.g. 1, 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms). Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. Alkynyl groups can be substituted or unsubstituted.

“环烷基”是指饱和或部分饱和的单环、稠环、桥环和螺环的碳环(包含例如3、4、5、6、7、8、9、10、11、12个碳原子)。优选为C ₃-C ₁₂环烷基，更优选为C ₃-C ₈环烷基，最优选为C ₃-C ₆环烷基。单环环烷基的实施例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环己烯基。环烷基可以是任选取代的或未取代的。 "Cycloalkyl" means saturated or partially saturated monocyclic, fused, bridged, and spiro carbocyclic rings (containing, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 carbon atom). It is preferably a C ₃ -C ₁₂ cycloalkyl group, more preferably a C ₃ -C ₈ cycloalkyl group, and most preferably a C ₃ -C ₆ cycloalkyl group. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc., preferably cyclopropyl, cyclohexenyl. Cycloalkyl groups can be optionally substituted or unsubstituted.

“螺环烷基”指5至18元(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18元)，两个或两个以上环状结构，且单环之间彼此共用一个碳原子(称螺原子)的多环基团，环内含有1个或多个双键，但没有一个环具有完全共轭的π电子的芳香***。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺、双螺或多螺环烷基，优选为单螺和双螺环烷基，优选为4元/5元、4元/6元、5元/5元或5元/6元。“螺环烷基”的非限制性实施例包括但不限于：螺[4.5]癸基、螺[4.4]壬基、螺[3.5]壬基、螺[2.4]庚基。"Spirocycloalkyl" means 5 to 18 members (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 members), two or more rings A polycyclic group with a carbon-like structure, and the single rings share a carbon atom (called a spiro atom) with each other. The ring contains one or more double bonds, but none of the rings has an aromatic system with fully conjugated π electrons. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the ring and the ring, the spiro cycloalkyl group is divided into single spiro, double spiro or polyspiro cycloalkyl, preferably single spiro and double spiro cycloalkyl, preferably 4-membered/5-membered, 4-membered Yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

“稠环烷基”指5至18元(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18元)，含有两个或两个以上环状结构彼此共用一对碳原子的全碳多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香***，优选为6至12元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。“稠环烷基”的非限制性实施例包括但不限于：二环[3.1.0]己基、二环[3.2.0]庚-1-烯基、二环[3.2.0]庚基、十氢化萘基或十四氢菲基。"Fused cycloalkyl" means 5 to 18 members (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 members), containing two or more An all-carbon polycyclic group in which the ring structures share a pair of carbon atoms with each other, and one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron aromatic system, preferably 6 to 12 yuan, more preferably 7 to 10 yuan. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetrahydrophenanthrenyl.

“桥环烷基”指5至18元(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18元)，含有两个或两个以上环状结构，彼此共用两个不直接相连接碳原子的全碳多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香***，优选为6至12元，更优选为7至10元。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。“桥环烷基”的非限制性实施例包括但不限于：(1s,4s)-二环[2.2.1]庚基、二环[3.2.1]辛基、(1s,5s)-二环[3.3.1]壬基、二环[2.2.2]辛基、(1r,5r)-二环[3.3.2]癸基。"Bridged cycloalkyl" refers to 5 to 18 members (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 members), containing two or more A ring structure, an all-carbon polycyclic group that shares two carbon atoms that are not directly attached to each other, an aromatic system in which one or more rings may contain one or more double bonds, but none of the rings has fully conjugated π-electrons , preferably 6 to 12 yuan, more preferably 7 to 10 yuan. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bis Cyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl.

“杂环基”、“杂环”或“杂环的”在本申请中可交换使用，都是指非芳香性杂环基，其中一个或多个(例如1个、2个、3个或4个)成环的原子是杂原子，如氧、氮、硫原子等，包括单环、稠环、桥环和螺环。优选具有5至7元单环或7至10元(例如4、5、6、7、8、9、10元)双或三环，其可以包含1、2或3个选自氮、氧和/或硫中的原子。单环或多环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香***，“杂环基”的实例包括但不限于吗啉基，氧杂环丁烷基，硫代吗啉基，四氢吡喃基，1,1-二氧代硫代吗啉基，哌啶基，2-氧代哌啶基，吡咯烷基，二氢吡咯基、二氢噻唑基、二氢异噻唑基、2-氧代吡咯烷基，哌嗪-2-酮，8-氧杂-3-氮杂-双环[3.2.1]辛基和哌嗪基。杂环基可以是取代或未取代的。"Heterocyclyl", "heterocyclic" or "heterocyclic" are used interchangeably in this application and all refer to non-aromatic heterocyclic groups in which one or more (eg 1, 2, 3 or 4) The atoms forming the ring are heteroatoms, such as oxygen, nitrogen, sulfur atoms, etc., including monocyclic rings, condensed rings, bridged rings and spiro rings. Preferably having a 5 to 7 membered monocyclic ring or a 7 to 10 membered (e.g. 4, 5, 6, 7, 8, 9, 10 membered) bi- or tricyclic ring, which may contain 1, 2 or 3 members selected from nitrogen, oxygen and / or atoms in sulfur. A monocyclic or polycyclic ring that may contain one or more double bonds, but none of the rings has a fully conjugated π-electron aromatic system. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl , thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, piperidinyl, 2-oxopiperidinyl, pyrrolidinyl, dihydropyrrolyl, dihydrothiazole Dihydroisothiazolyl, 2-oxopyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl. A heterocyclyl group can be substituted or unsubstituted.

“螺杂环基”指5至18元(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18元)，两个或两个以上环状结构，且单环之间彼此共用一个原子的多环基团，环内含有1个或多个双键，但没有一个环具有完全共轭的π电子的芳香***，其中一个或多个(例如1、2、3、4个)环原子选自氮、氧或S(O) _r(其中r选自0、1或2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。“螺杂环基”的非限制性实施例包括但不限于：1,7-二氧杂螺[4.5]癸基、2-氧杂-7-氮杂螺[4.4]壬基、7-氧杂螺[3.5]壬基和5-氧杂螺[2.4]庚基。 "Spiroheterocyclyl" means 5 to 18 members (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 members), two or more rings Like structure, and the single rings share one atom with each other, the ring contains 1 or more double bonds, but none of the rings has a fully conjugated π-electron aromatic system, one or more ( For example 1, 2, 3, 4) ring atoms are selected from nitrogen, oxygen or heteroatoms of S(O) _r (where r is selected from 0, 1 or 2), and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[4.4]nonyl, Heteraspiro[3.5]nonyl and 5-oxaspiro[2.4]heptyl.

“稠杂环基”指含有两个或两个以上环状结构彼此共用一对原子的多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香***，其中一个或多个(例如1、2、3、4个)环原子选自氮、氧或S(O) _r(其中r选自0、1或2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元(例如6、7、8、9、10、11、12、13、14元)。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。“稠杂环基”的非限制性实施例包括但不限于：八氢吡咯并[3,4-c]吡咯基、八氢-1H-异吲哚基，3-氮杂二环[3.1.0]己基，八氢苯并[b][1,4]二噁英(dioxine)或

"Fused heterocyclic group" refers to a polycyclic group containing two or more ring structures that share a pair of atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has complete conjugation Aromatic system of π electrons in which one or more (for example 1, 2, 3, 4) ring atoms are selected from nitrogen, oxygen or S(O) _r (where r is selected from 0, 1 or 2) heteroatoms , and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 6, 7, 8, 9, 10, 11, 12, 13, 14 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclyl" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1. 0]hexyl, octahydrobenzo[b][1,4]dioxine or

“桥杂环基”指5至14元，5至18元(例如5、6、7、8、9、10、11、12、13、14、15、 16、17、18元)，含有两个或两个以上环状结构，彼此共用两个不直接相连接的原子的多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香***，其中一个或多个(例如1、2、3、4个)环原子选自氮、氧或S(O) _r(其中r选自0、1或2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。“桥杂环基”的非限制性实施例包括但不限于：2-氮杂二环[2.2.1]庚基，2-氮杂二环[2.2.2]辛基和2-氮杂二环[3.3.2]癸基。 "Bridged heterocyclic group" means 5 to 14 members, 5 to 18 members (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 members), containing two A polycyclic group of one or more ring structures sharing two atoms not directly connected to each other, one or more rings may contain one or more double bonds, but none of the rings has fully conjugated π electrons The aromatic system of wherein one or more (eg 1, 2, 3, 4) ring atoms are selected from nitrogen, oxygen or S(O) _r (wherein r is selected from 0, 1 or 2) heteroatoms, and the remaining ring The atom is carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclyl" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-azabicyclo[2.2.2]octyl Cyclo[3.3.2]decyl.

“芳基”是指含有一个或者两个环的碳环芳香***，其中所述环可以以稠合的方式连接在一起。术语“芳基”包括单环或双环的芳基，比如苯基、萘基、四氢萘基的芳香基团。优选芳基为C ₆-C ₁₀芳基，更优选芳基为苯基和萘基，最优选为萘基。芳基可以是取代或未取代的。 "Aryl" means a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion. The term "aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferred aryl groups are C ₆ -C ₁₀ aryl groups, more preferred aryl groups are phenyl and naphthyl, most preferably naphthyl. Aryl groups can be substituted or unsubstituted.

“杂芳基”是指芳香族5至6元单环或8至10元(例如8、9、10元)双环，其可以包含1至4个(例如1、2、3、4个)选自氮、氧和/或硫中的原子。优选为双环杂芳基，“杂芳基”的实施例包括但不限于呋喃基，吡啶基，2-氧代-1,2-二氢吡啶基，哒嗪基，嘧啶基，吡嗪基，噻吩基，异噁唑基，噁唑基，噁二唑基，咪唑基，吡咯基，吡唑基，***基，四氮唑基，噻唑基，异噻唑基，1,2,3-噻二唑基，苯并间二氧杂环戊烯基，苯并噻吩基、苯并咪唑基，吲哚基，异吲哚基，1,3-二氧代-异吲哚基，喹啉基，吲唑基，苯并异噻唑基，苯并噁唑基、苯并异噁唑基、"Heteroaryl" means an aromatic 5 to 6 membered monocyclic ring or 8 to 10 membered (e.g. 8, 9, 10 membered) bicyclic ring, which may contain 1 to 4 (e.g. 1, 2, 3, 4) optional from nitrogen, oxygen and/or sulfur atoms. Bicyclic heteroaryl is preferred. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, Thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiazolyl Adiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl , Indazolyl, Benzisothiazolyl, Benzoxazolyl, Benzisoxazolyl,

杂芳基可以是取代或未取代的。Heteroaryl groups can be substituted or unsubstituted.

“稠合环”是指两个或两个以上环状结构彼此共用一对原子的多环基团，一个或多个环可以含有一个或多个双键，但至少一个环不具有完全共轭的π电子的芳香***，其中环原子选自0个、一个或多个(例如1、2、3、4个)选自氮、氧或S(O) _r(其中r选自0、1或2)的杂原子，其余环原子为碳。稠合环优选包括双环或三环的稠合环，其中双环稠合环优选为芳基或杂芳基与单环杂环基或单环环烷基的稠合环。优选为7至14元(例如7、8、9、10、11、12、13、14元)，更优选为8至10元。“稠合环”的实施例包括但不限于： "Fused ring" refers to a polycyclic group in which two or more ring structures share a pair of atoms with each other, one or more rings may contain one or more double bonds, but at least one ring does not have complete conjugation Aromatic system of π electrons, wherein the ring atoms are selected from 0, one or more (eg 1, 2, 3, 4) selected from nitrogen, oxygen or S(O) _r (where r is selected from 0, 1 or 2), the remaining ring atoms are carbon. The fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. It is preferably 7 to 14 yuan (for example, 7, 8, 9, 10, 11, 12, 13, 14 yuan), more preferably 8 to 10 yuan. Examples of "fused rings" include, but are not limited to:

“烷氧基”是指(烷基-O-)的基团。其中，烷基见本文有关定义。C ₁-C ₆的烷氧基为优先选择。其实例包括，但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。 "Alkoxy" refers to a group of (alkyl-O-). Wherein, alkyl refers to relevant definitions herein. C ₁ -C ₆ alkoxy is preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

“卤代烷基”是指烷基任选进一步被一个或多个卤素所取代的基团，其中烷基见本文有关定义。"Haloalkyl" means an alkyl group optionally further substituted with one or more halogens, wherein alkyl is as defined herein.

“羟烷基”是指烷基任选进一步被一个或多个羟基所取代的基团，其中烷基见本文有关定义。"Hydroxyalkyl" means an alkyl group optionally further substituted with one or more hydroxy groups, wherein alkyl is as defined herein.

“羟甲基”指甲基任选进一步被一个或多个羟基所取代的基团。"Hydroxymethyl" refers to a group in which the methyl group is optionally further substituted with one or more hydroxy groups.

“卤代烷氧基”是指(烷基-O-)的烷基任选进一步被一个或多个卤素所取代的基团，其中烷氧基见本文有关定义。"Haloalkoxy" refers to a group in which the alkyl group of (alkyl-O-) is optionally further substituted by one or more halogens, wherein alkoxy is as defined herein.

“羟基”指-OH基团。"Hydroxy" means an -OH group.

“卤素”是指氟、氯、溴和碘。"Halogen" refers to fluorine, chlorine, bromine and iodine.

“氨基”指-NH ₂。 "Amino" refers to _-NH2 .

“氰基”指-CN。"Cyano" refers to -CN.

“硝基”指-NO ₂。 "Nitro" refers to _-NO2 .

“苄基”指-CH ₂-苯基。 "Benzyl" means _-CH2 -phenyl.

“羧基”指-C(O)OH。"Carboxy" refers to -C(O)OH.

“羧酸酯基”指-C(O)O-烷基或-C(O)O-环烷基，其中烷基、环烷基的定义如上所述。"Carboxylate group" refers to -C(O)O-alkyl or -C(O)O-cycloalkyl, wherein the definitions of alkyl and cycloalkyl are as above.

“DMSO”指二甲基亚砜。"DMSO" means dimethylsulfoxide.

“BOC”指叔丁氧基羰基。"BOC" means t-butoxycarbonyl.

“MOM”指甲氧基甲基。"MOM" methoxymethyl.

“Ts”指对甲苯磺酰基。"Ts" refers to p-toluenesulfonyl.

“T3P”指丙基磷酸酐。"T3P" refers to propylphosphoric anhydride.

“DPPA”指叠氮磷酸二苯酯。"DPPA" refers to diphenylphosphoryl azide.

“DEA”指二乙胺。"DEA" means diethylamine.

“X-PHOS Pd G2”指氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)。"X-PHOS Pd G2" refers to chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino- 1,1'-biphenyl)]palladium(II).

“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.

本说明书所述的“取代”或“取代的”，如无特别指出，均是指基团可被一个或多个选自以下的基团取代：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、疏基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、＝O、-C(O)R ^5’、-C(O)OR ^5’、-NHC(O)R ^5’、-NHC(O)OR ^5’、-NR ^6’R ^7’、-C(O)NR ^6’R ^7’、-CH ₂NHC(O)OR ^5’、-CH ₂NR ^6’R ^7’或-S(O) _rR ^5’的取代基所取代； The "substituted" or "substituted" mentioned in this specification, unless otherwise specified, means that the group can be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy , alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, -C(O)R ^5' , -C(O)OR ^5' , -NHC(O )R ^5' , -NHC(O)OR ^5' , -NR ^6' R ^7' , -C(O)NR ^6' R ^7' , -CH ₂ NHC(O)OR ^5' , -CH ₂ NR ^{6 '} R ^7' or -S(O) _r R ^5' is substituted by a substituent;

其中：in:

R ^5’选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-C(O)R ^8’、-C(O)OR ^8’、-OC(O)R ^8’、-NR ^9’R ^10’、-C(O)NR ^9’R ^10’、-SO ₂NR ^9’R ^10’或-NR ^9’C(O)R ^10’的取代基所取代； R ^5' is selected from hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally further By one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, - C(O)R ^8' , -C(O)OR ^8' , -OC(O)R ^8' , -NR ^9' R ^10' , -C(O)NR ^9' R ^10' , -SO ₂ NR ^9' R ^10' or -NR ^9' C(O)R ^10' is substituted by a substituent;

R ^6’和R ^7’各自独立地选自氢原子、羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-C(O)R ^8’、-C(O)OR ^8’、-OC(O)R ^8’、-NR ^9’R ^10’、-C(O)NR ^9’R ^10’、-SO ₂NR ^9’R ^10’或-NR ^9’C(O)R ^10’的取代基所取代； R ^6' and R ^7' are each independently selected from a hydrogen atom, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkoxy Base, cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally further selected from one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl , aryl, heteroaryl, =O, -C(O)R ^8' , -C(O)OR ^8' , -OC(O)R ^8' , -NR ^9' R ^10' , -C(O ) NR ^9' R ^10' , -SO ₂ NR ^9' R ^10' or -NR ^9' C(O)R ^10' are substituted by substituents;

或者，R ⁶和R ⁷与它们相连接的原子一起形成一个4～8元杂环基，其中4～8元杂环基内含有一个或多个N、O或S(O) _r，并且所述的4～8元杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-C(O)R ^8’、-C(O)OR ^8’、-OC(O)R ^8’、-NR ^9’R ^10’、-C(O)NR ^9’R ^10’、-SO ₂NR ^9’R ^10’或-NR ^9’C(O)R ^10’的取代基所取代； Alternatively, R ⁶ and R ⁷ form a 4-8 membered heterocyclic group together with the atoms they are connected to, wherein the 4-8 membered heterocyclic group contains one or more N, O or S(O) _r , and the The 4-8 membered heterocyclic group is optionally further replaced by one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl , =O, -C(O)R ^8' , -C(O)OR ^8' , -OC(O)R ^8' , -NR ^9' R ^10' , -C(O)NR ^9' R ^10' , -SO ₂ NR ^9' R ^10' or -NR ^9' C(O)R ^10' are substituted by substituents;

R ^8’、R ^9’和R ^10’各自独立地选自氢原子、烷基、氨基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代； R ^8' , R ^9' and R ^10' are each independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, Heterocyclyl, aryl or heteroaryl is optionally further selected from one or more groups selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, Substituents of heteroaryl, carboxyl or carboxylate;

r为0、1或2。r is 0, 1 or 2.

本发明化合物可以含有不对称中心或手性中心，因此以不同的立体异构体形式存在。所预期的是，本发明化合物的所有立体异构体形式，包括但不限于非对映异构体、对映异构体和阻转异构体(atropisomer)和几何(构象)异构体及它们的混合物，如外消旋体混合物，均在本发明的范围内。The compounds of the present invention may contain asymmetric centers or chiral centers and thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention are contemplated, including but not limited to diastereomers, enantiomers and atropisomers (atropisomers) and geometric (conformational) isomers and Mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

除非另外指出，本发明描述的结构还包括此结构的所有异构体(如，非对映异构体、对映异构体和阻转异构体和几何(构象)异构体形式；例如，各不对称中心的R和S构型，(Z)和(E)双键异构体，以及(Z)和(E)构象异构体。因此本发明化合物的单个立体异构体以及对映体混合物、非对映异构体混合物和几何(构象)异构体混合物均在本发明范围内。Unless otherwise indicated, structures depicted herein also include all isomeric (eg, diastereoisomers, enantiomers, and atropisomers) and geometric (conformational) isomeric forms of such structures; e.g. , the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers.Therefore the individual stereoisomers of the compounds of the present invention and the pair Mixtures of enantiomers, diastereoisomers and geometric (conformational) isomers are within the scope of the present invention.

“可药用的盐”是指上述化合物能保持原有生物活性并且适合于医药用途的某些盐类。式(I)所表示的化合物的可药用的盐可以为金属盐、与合适的酸形成的胺盐。"Pharmaceutically acceptable salt" refers to certain salts of the above compounds that can maintain their original biological activity and are suitable for medical use. The pharmaceutically acceptable salt of the compound represented by formula (I) may be a metal salt or an amine salt with a suitable acid.

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

具体实施方式Detailed ways

以下结合实施例用于进一步描述本发明，但这些实施例并非限制着本发明的范围。The following examples are used to further describe the present invention, but these examples do not limit the scope of the present invention.

实施例Example

实施例给出了式(I)所表示的代表性化合物的制备及相关结构鉴定数据。必须说明，下述实施例是用于说明本发明而不是对本发明的限制。 ¹HNMR图谱是用Bruker仪器(400MHz)测定而得，化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。 ¹HNMR的表示方法：s＝单峰，d＝双重峰，t＝三重峰，m＝多重峰，br＝变宽的，dd＝双重峰的双重峰，dt＝三重峰的双重峰。若提供偶合常数时，其单位为Hz。 The examples give the preparation of representative compounds represented by formula (I) and relevant structural identification data. It must be noted that the following examples are used to illustrate the present invention rather than limit the present invention. The ¹ HNMR spectrum is obtained by Bruker instrument (400MHz), and the chemical shift is expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. Notation method of ¹ HNMR: s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet. If the coupling constant is provided, its unit is Hz.

质谱是用LC/MS仪测定得到，离子化方式可为ESI或APCI。The mass spectrum is measured by LC/MS instrument, and the ionization method can be ESI or APCI.

薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ~0.5mm.

柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

在下列实例中，除非另有指明，所有温度为摄氏温度，除非另有指明，各种起始原料和试剂来自市售或者是根据已知的方法合成，市售原料和试剂均不经进一步纯化直接使用，除非另有指明，市售厂家包括但不限于上海皓鸿生物医药科技有限公司，上海韶远试剂有限公司，上海毕得医药科技有限公司，萨恩化学技术(上海)有限公司和上海凌凯医药科技有限公司等。In the following examples, all temperatures are in degrees Celsius unless otherwise indicated, and unless otherwise indicated, various starting materials and reagents were either commercially available or synthesized according to known methods, and commercially available materials and reagents were not further purified For direct use, unless otherwise specified, commercially available manufacturers include but are not limited to Shanghai Haohong Biomedical Technology Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Shanghai Beide Pharmaceutical Technology Co., Ltd., Sarn Chemical Technology (Shanghai) Co., Ltd. and Shanghai Lingkai Pharmaceutical Technology Co., Ltd., etc.

CD ₃OD：氘代甲醇。 CD ₃ OD: deuterated methanol.

CDCl ₃：氘代氯仿。 CDCl ₃ : deuterated chloroform.

DMSO-d ₆：氘代二甲基亚砜。 DMSO-d ₆ : deuterated dimethylsulfoxide.

实施例中无特殊说明，反应中的溶液是指水溶液。Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

对化合物进行纯化，采用柱层析和薄层色谱法的洗脱剂体系，其中该体系选自：A：石油醚和乙酸乙酯体系；B：二氯甲烷和甲醇体系；C：二氯甲烷和乙酸乙酯体系，D：二氯甲烷和乙醇体系，其中溶剂的体积比根据化合物的极性不同而不同，也可以加入少量的酸性或碱性试剂进行条件，如醋酸或三乙胺等。Purify the compound, using the eluent system of column chromatography and thin layer chromatography, wherein the system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane And ethyl acetate system, D: dichloromethane and ethanol system, wherein the volume ratio of the solvent is different according to the polarity of the compound, and a small amount of acidic or alkaline reagent can also be added to the condition, such as acetic acid or triethylamine.

室温：20℃～30℃。Room temperature: 20℃～30℃.

实施例1Example 1

4-(4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol4-(4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol

4-(4-(5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-氟萘-2-醇4-(4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetra Hydrogen-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol

第一步first step

2,7-dichloro-4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-8-fluoropyrido[4,3-d]pyrimidine2,7-dichloro-4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-8-fluoropyrido[4,3-d]pyrimidine

2,7-二氯-4-(5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基)-8-氟吡啶并[4,3-d]嘧啶2,7-Dichloro-4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-8-fluoropyrido[4,3-d]pyrimidine

将2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶1a(600mg,2.38mmol,根据公开专利WO2020146613制备)加入到二氯甲烷(3.44mL)中，加入N,N-二异丙基乙胺(3.07g,23.77mmol,4.14mL)，降温至-40℃，加入5,6,7,8-四氢咪唑并[1,2-a]吡嗪1b(234.15mg,1.90mmol,根据公开专利US20140336182制备)的二氯甲烷溶液(3mL)，-40℃下继续反应搅拌20分钟。反应液减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：B体系)分离纯化，得到2,7-二氯-4-(5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基)-8-氟吡啶并[4,3-d]嘧啶1c(260mg,766.61μmol)，产率32.26％。MS m/z(ESI)：338.8[M+H] ⁺ 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine 1a (600mg, 2.38mmol, prepared according to published patent WO2020146613) was added to dichloromethane (3.44mL), N, N-Diisopropylethylamine (3.07g, 23.77mmol, 4.14mL), cooled to -40°C, added 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 1b (234.15 mg, 1.90 mmol, prepared according to the published patent US20140336182) in dichloromethane solution (3 mL), and continued to react and stir for 20 minutes at -40°C. The reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: system B) to obtain 2,7-dichloro-4-(5,6-dihydroimidazo[1,2 -a]pyrazin-7(8H)-yl)-8-fluoropyrido[4,3-d]pyrimidine 1c (260 mg, 766.61 μmol), yield 32.26%. MS m/z(ESI): 338.8[M+H] ⁺

第二步second step

7-chloro-4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine7-chloro-4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin -7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

7-氯-4-(5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶7-chloro-4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

将2,7-二氯-4-(5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基)-8-氟吡啶并[4,3-d]嘧啶1c(260.00mg,766.61μmol)，((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇1d(134.25mg,843.27μmol,根据公开专利WO2020146613制备)，分子筛

型(506.45mg,1.15mmol)和N,N-二异丙基乙胺(594.46mg,4.60mmol,825.64μL)依次加入1,4-二氧六环(4.17mL)中，氩气保护，升温至90℃反应过夜。反应液冷却到室温，过滤除去分子筛，滤液减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：B体系)分离纯化，得到7-氯-4-(5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶1e(220mg,476.61μmol)，产率62％。 2,7-dichloro-4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-8-fluoropyrido[4,3-d]pyrimidine 1c (260.00 mg, 766.61 μmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol 1d (134.25 mg, 843.27 μmol, prepared according to published patent WO2020146613), Molecular sieve

(506.45mg, 1.15mmol) and N,N-diisopropylethylamine (594.46mg, 4.60mmol, 825.64μL) were sequentially added to 1,4-dioxane (4.17mL), under the protection of argon, the temperature was raised React overnight at 90°C. The reaction solution was cooled to room temperature, filtered to remove molecular sieves, the filtrate was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: B system) to obtain 7-chloro-4-(5,6-dihydro Imidazo[1,2-a]pyrazin-7(8H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidine 1e (220 mg, 476.61 μmol), yield 62%.

MS m/z(ESI)：462.0[M+H] ⁺ MS m/z(ESI): 462.0[M+H] ⁺

第三步third step

4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

4-(5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基)-8-氟-7-(8-氟-3-(甲氧基甲氧基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶4-(5,6-Dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-8-fluoro-7-(8-fluoro-3-(methoxymethoxy) Naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

将7-氯-4-(5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪- 7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶1e(220mg,476.30μmol)，2-(8-氟-3-甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷1f(221.50mg,666.82μmol,根据公开专利WO2021041671A1制备)，磷酸钾(303.31mg,1.43mmol)和甲磺酰氧基(二金刚烷基-正丁基膦基)-2'-氨基-1,1'-联苯-2-基)钯II(104.21mg,142.89μmol)依次加入到四氢呋喃(8mL)中，氩气保护，升温至60℃反应过夜。反应液降至室温，减压浓缩，所得残余物用乙酸乙酯萃取(100mL×2)，合并有机相，用饱和食盐水洗(100mL×3)，以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：B体系)分离纯化，得到4-(5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基)-8-氟-7-(8-氟-3-(甲氧基甲氧基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶1g(110mg,174.15μmol)，产率36.56％。7-chloro-4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine 1e (220mg, 476.30μmol), 2-(8-fluoro-3-methoxy Methoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborinane 1f (221.50 mg, 666.82 μmol, prepared according to published patent WO2021041671A1), phosphoric acid Potassium (303.31mg, 1.43mmol) and methanesulfonyloxy(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium II (104.21mg, 142.89 μmol) was sequentially added into tetrahydrofuran (8 mL), protected by argon, and heated to 60° C. to react overnight. The reaction solution was lowered to room temperature, concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate (100mL×2), the organic phases were combined, washed with saturated brine (100mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure , the resulting residue was separated and purified by silica gel column chromatography (eluent: B system) to obtain 4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl )-8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine -7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine 1 g (110 mg, 174.15 μmol), yield 36.56%.

MS m/z(ESI)：632.0[M+H] ⁺ MS m/z(ESI): 632.0[M+H] ⁺

第四步the fourth step

将4-(5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基)-8-氟-7-(8-氟-3-(甲氧基甲氧基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶1g(110mg,174.15μmol)溶于乙腈(2mL)中，室温下加入氯化氢的1,4-二氧六环溶液(4M,2mL)，室温下继续搅拌1小时。反应液减压浓缩，得到的残留物通过制备液相分离纯化(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H2O，流动相B：CH3CN)，得到4-(4-(5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-氟萘-2-醇1(10mg,17.02μmol)，产率9.77％。4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-8-fluoro-7-(8-fluoro-3-(methoxymethoxy )naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine 1 g (110 mg, 174.15 μmol) was dissolved in acetonitrile (2 mL), hydrogen chloride in 1,4-dioxane solution (4 M, 2 mL) was added at room temperature, and stirring was continued for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2mm I.D.; 5μm, 20mL/min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) , to give 4-(4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol 1 (10mg, 17.02μmol ), yield 9.77%.

MS m/z(ESI)：587.9[M+H] ⁺ MS m/z(ESI): 587.9[M+H] ⁺

实施例2Example 2

5-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol5-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(8-(2-hydroxyethyl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

5-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(8-(2-羟基乙基)-3,8-二氮杂二环[3.2.1]辛烷-3-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇5-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(8-( 2-Hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol

第一步first step

tert-butyl 8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylatetert-butyl 8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

8-(2-羟基乙基)-3,8-二氮杂二环[3.2.1]辛烷-3-羧酸叔丁酯tert-butyl 8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

在氩气氛围下，将3,8-二氮杂二环[3.2.1]辛烷-3-羧酸叔丁酯2a(882.98mg,7.07mmol)、2-溴乙-1-醇2b(1g,4.71mmol)和三乙胺(953.33mg,9.42mmol)依次加入到1,4-二氧六环(10mL)中，升温至50℃下持续搅拌过夜。反应液降至室温，减压蒸馏除去有机溶剂，以乙酸乙酯(30mL)萃取，分去水层，有机相以无水硫酸钠干燥，过滤，减压浓缩，得到粗品8-(2-羟基乙基)-3,8-二氮杂二环[3.2.1]辛烷-3-羧酸叔丁酯2c(1.2g,4.68mmol)，产率99.38％。Under argon atmosphere, tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate 2a (882.98 mg, 7.07 mmol), 2-bromoethan-1-ol 2b ( 1 g, 4.71 mmol) and triethylamine (953.33 mg, 9.42 mmol) were sequentially added to 1,4-dioxane (10 mL), and the temperature was raised to 50°C and stirring was continued overnight. The reaction solution was lowered to room temperature, the organic solvent was distilled off under reduced pressure, extracted with ethyl acetate (30 mL), the water layer was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product 8-(2-hydroxyl Ethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester 2c (1.2 g, 4.68 mmol), yield 99.38%.

MS m/z(ESI)：257.1[M+H] ⁺ MS m/z(ESI): 257.1[M+H] ⁺

第二步second step

2-(3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-1-ol2-(3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-1-ol

2-(3,8-二氮杂二环[3.2.1]辛烷-8-基)乙-1-醇2-(3,8-Diazabicyclo[3.2.1]octan-8-yl)ethan-1-ol

将粗品8-(2-羟基乙基)-3,8-二氮杂二环[3.2.1]辛烷-3-羧酸叔丁酯2c(600mg,2.34mmol)，加入到二氯甲烷(1mL)中，加入三氟乙酸(1mL)，室温条件下持续搅拌过夜。将反应液减压蒸馏除去有机溶剂，所得残余物中加入饱和碳酸氢钠水溶液直至没有气泡产生，加入乙酸乙酯(30mL)萃取，分液，有机相减压浓缩，水相冻干，所得产物合并干燥，得到2-(3,8-二氮杂二环[3.2.1]辛烷-8-基)乙-1-醇2d(340mg,2.18mmol)，产率92.98％。The crude tert-butyl 8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate 2c (600 mg, 2.34 mmol) was added to dichloromethane ( 1 mL), trifluoroacetic acid (1 mL) was added, and stirring was continued overnight at room temperature. The reaction liquid was distilled off under reduced pressure to remove the organic solvent, and saturated aqueous sodium bicarbonate solution was added to the obtained residue until no bubbles were generated, ethyl acetate (30 mL) was added for extraction, liquid separation, the organic phase was concentrated under reduced pressure, and the aqueous phase was freeze-dried to obtain the product Combined and dried, 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-1-ol 2d (340 mg, 2.18 mmol) was obtained with a yield of 92.98%.

MS m/z(ESI)：157.1[M+H] ⁺ MS m/z(ESI): 157.1[M+H] ⁺

第三步third step

2-(3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-1-ol2-(3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-1-ol

2-(3-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-基)乙-1-醇2-(3-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8 -yl)ethan-1-ol

在氩气氛围下，将2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶1a(387mg,1.54mmol)加入到二氯甲烷(15mL)中，加入N,N-二异丙基乙胺(595.63mg,4.61mmol,802.74μL)，降温至-40℃，加入2-(3,8-二氮杂二环[3.2.1]辛烷-8-基)乙-1-醇2d(240mg,1.54mmol)，-40℃下继续反应20分钟。反应液升至室温，以二氯甲烷萃取(20mL×2)，有机相用饱和食盐水洗(20mL×3)，以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)分离纯化，得到2-(3-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-基)乙-1-醇2e(530mg,1.42mmol)，产率92.69％。Under argon atmosphere, 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine 1a (387mg, 1.54mmol) was added to dichloromethane (15mL), and N,N -Diisopropylethylamine (595.63mg, 4.61mmol, 802.74μL), cooled to -40°C, added 2-(3,8-diazabicyclo[3.2.1]octane-8-yl) ethyl -1-ol 2d (240mg, 1.54mmol), continue to react at -40°C for 20 minutes. The reaction solution was raised to room temperature, extracted with dichloromethane (20mL×2), the organic phase was washed with saturated brine (20mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Analysis method (eluent: A system) separation and purification to obtain 2-(3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8- Diazabicyclo[3.2.1]octan-8-yl)ethan-1-ol 2e (530 mg, 1.42 mmol), yield 92.69%.

MS m/z(ESI)：372.0[M+H] ⁺ MS m/z(ESI): 372.0[M+H] ⁺

第四步the fourth step

2-(3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-1-ol2-(3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin -4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-1-ol

2-(3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-基乙-1-醇2-(3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4 ,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-ylethan-1-ol

将2-(3-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-基)乙-1-醇2e(375mg,1.01mmol)，((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇1d(176.43mg,1.11mmol)，分子筛

型(392.26mg,890.64μmol)和N,N-二异丙基乙胺(781.22mg,6.04mmol,1.05mL)依次加入到1,4-二氧六环(9mL)中，氩气保护，升温至90℃反应过夜。反应液冷却至室温，用乙酸乙酯萃取(100mL×2)，有机相用饱和食盐水洗(100mL×3)，以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：B体系)分离纯化，得到2-(3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-基乙-1-醇2f(360mg,727.33μmol)，产率72.19％。 2-(3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-yl)ethan-1-ol 2e (375mg, 1.01mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol 1d (176.43mg, 1.11mmol ), molecular sieve

(392.26mg, 890.64μmol) and N,N-diisopropylethylamine (781.22mg, 6.04mmol, 1.05mL) were sequentially added to 1,4-dioxane (9mL), under the protection of argon, the temperature was raised React overnight at 90°C. The reaction solution was cooled to room temperature, extracted with ethyl acetate (100mL×2), the organic phase was washed with saturated brine (100mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column Analysis method (eluent: B system) separation and purification to obtain 2-(3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a (5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-ylethyl-1- Alcohol 2f (360 mg, 727.33 μmol), yield 72.19%.

MS m/z(ESI)：495.2[M+H] ⁺ MS m/z(ESI): 495.2[M+H] ⁺

第五步the fifth step

2-(3-(8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-1-ol2-(3-(8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H )-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-1-ol

2-(3-(8-氟-7-(8-氟-3-(甲氧基甲氧基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-基)乙-1-醇2-(3-(8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8 -yl)ethan-1-ol

将2-(3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-基乙-1-醇2f(140mg,282.85μmol)，2-(8-氟-3-甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷1f(131.54mg,395.99μmol)，磷酸钾(180.12mg,848.55μmol)和甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(61.88mg,84.85 μmol)依次加入到四氢呋喃(5mL)中，氩气保护，升温至60℃反应过夜。反应液降至室温，减压蒸馏除去有机溶剂，残余物以乙酸乙酯萃取(100mL×2)，有机相用饱和食盐水洗(100mL×3)，无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：B体系)分离纯化，得到2-(3-(8-氟-7-(8-氟-3-(甲氧基甲氧基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-基)乙-1-醇2g(128mg,192.56μmol)，产率68.08％。2-(3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[ 4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-ylethan-1-ol 2f (140mg, 282.85μmol), 2-(8 -Fluoro-3-methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborin 1f (131.54mg, 395.99μmol) , potassium phosphate (180.12 mg, 848.55 μmol) and [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate ( 61.88 mg, 84.85 μmol) were sequentially added into tetrahydrofuran (5 mL), protected by argon, and heated to 60° C. to react overnight. The reaction solution was lowered to room temperature, and the organic solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate (100 mL×2), the organic phase was washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (eluent: system B) to obtain 2-(3-(8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalene) -1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4 -yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-1-ol 2 g (128 mg, 192.56 μmol), yield 68.08%.

MS m/z(ESI)：665.0[M+H] ⁺ MS m/z(ESI): 665.0[M+H] ⁺

第六步step six

将2-(3-(8-氟-7-(8-氟-3-(甲氧基甲氧基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-基)乙-1-醇2g(128mg,192.56μmol)，加入到氯化氢的1,4-二氧六环溶液(4M,1mL)中，室温条件下持续搅拌0.5小时。将反应液中加入饱和碳酸氢钠水溶液直到没有气泡产生，以乙酸乙酯(5mL)萃取，有机相减压浓缩，所得的残余物通过制备液相分离纯化(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H2O，流动相B：CH3CN)，得到5-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(8-(2-羟基乙基)-3,8-二氮杂二环[3.2.1]辛烷-3-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-醇1(1.9mg,2.43μmol)，产率1.26％。2-(3-(8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro -1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-yl)ethan-1-ol 2g (128 mg, 192.56 μmol) was added to a solution of hydrogen chloride in 1,4-dioxane (4M, 1 mL), and stirring was continued for 0.5 hours at room temperature. Add saturated aqueous sodium bicarbonate solution to the reaction solution until no bubbles are generated, extract with ethyl acetate (5 mL), and concentrate the organic phase under reduced pressure. The resulting residue is separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; I.D.; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 5-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane- 3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol 1 (1.9 mg, 2.43 μmol), yield 1.26%.

MS m/z(ESI)：620.9[M+H] ⁺ MS m/z(ESI): 620.9[M+H] ⁺

实施例3Example 3

4-(8-(D-prolyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine4-(8-(D-prolyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

4-(8-(D-脯氨酰基)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-7-(8-氟-3-羟基萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶4-(8-(D-prolyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7-(8-fluoro-3-hydroxynaphthalene -1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

第一步first step

tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylatetert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

3-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯3-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

在氩气氛围下，将2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶1a(2g,7.92mmol)加入到二氯甲烷(10mL)中，加入N,N-二异丙基乙胺(3.07g,23.77mmol,4.14mL)，降温至-40℃，加入3,8-二氮杂二环[3.2.1]辛烷-3-羧酸叔丁酯2a(1.35g,6.34mmol)，-40℃下继续反应15分钟。反应液升至室温，以二氯甲烷萃取(20mL×2)，有机相用饱和食盐水洗(20mL×3)，以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)分离纯化，得到3-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯3a(560mg,1.31mmol)，产率16.51％。Under argon atmosphere, 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine 1a (2 g, 7.92 mmol) was added to dichloromethane (10 mL), N,N -Diisopropylethylamine (3.07g, 23.77mmol, 4.14mL), cooled to -40°C, added tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate 2a (1.35g, 6.34mmol), the reaction was continued at -40°C for 15 minutes. The reaction solution was raised to room temperature, extracted with dichloromethane (20mL×2), the organic phase was washed with saturated brine (20mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Analysis method (eluent: A system) separation and purification to obtain 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazepine tert-butyl bicyclo[3.2.1]octane-8-carboxylate 3a (560 mg, 1.31 mmol), yield 16.51%.

MS m/z(ESI)：428.1[M+H] ⁺ MS m/z(ESI): 428.1[M+H] ⁺

第二步second step

tert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylatetert-butyl 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin -4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯3-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

在氩气氛围下，将3-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯3a(1.10g,2.57mmol)，((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇1d(449.77mg,2.83mmol)，分子筛

型(1g,2.27mmol)和N,N-二异丙基乙胺(1.99g,15.41mmol,2.68mL)依次加入到1,4-二氧六环(10mL)中，升温至90℃反应过夜。反应液降至室温，以乙酸乙酯萃取(100mL×2)，有机相用饱和食盐水洗(100mL×3)，无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：B体系)分离纯化，得到3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯3b(1.1g,2.00mmol)，产率77.73％。 Under argon atmosphere, 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] Octane-8-carboxylate tert-butyl ester 3a (1.10g, 2.57mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol 1d (449.77mg, 2.83mmol), molecular sieve

(1g, 2.27mmol) and N,N-diisopropylethylamine (1.99g, 15.41mmol, 2.68mL) were sequentially added to 1,4-dioxane (10mL), heated to 90°C and reacted overnight . The reaction solution was lowered to room temperature, extracted with ethyl acetate (100mL×2), the organic phase was washed with saturated brine (100mL×3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography method (eluent: system B) to separate and purify 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)- Base)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 3b (1.1g , 2.00mmol), the yield was 77.73%.

MS m/z(ESI)：551.2[M+H] ⁺ MS m/z(ESI): 551.2[M+H] ⁺

第三步third step

tert-butyl 3-(8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylatetert-butyl 3-(8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H )-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

3-(8-氟-7-(8-氟-3-(甲氧基甲氧基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯3-(8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole Azin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

将3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯3b(400mg,725.92μmol)，2-(8-氟-3-甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷1f(337.58mg,1.02mmol)，磷酸钾(462.27mg,2.18mmol)和甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(158.82mg,217.78μmol)加入到四氢呋喃(8mL)中，氩气保护，升温至60℃反应过夜。反应液减压蒸馏除去有机溶剂，乙酸乙酯萃取(100mL×2)，有机相用饱和食盐水洗(100mL×3)，无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：B体系)分离纯化，得到3-(8-氟-7-(8-氟-3-(甲氧基甲氧基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯3c(490mg,679.82μmol)，产率93.65％。3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3 -d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 3b (400mg, 725.92μmol), 2-(8-fluoro-3 -Methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborin 1f (337.58mg, 1.02mmol), potassium phosphate ( 462.27mg, 2.18mmol) and [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (158.82mg, 217.78 μmol) was added into tetrahydrofuran (8 mL), under the protection of argon, the temperature was raised to 60° C. to react overnight. The reaction liquid was distilled off under reduced pressure to remove the organic solvent, extracted with ethyl acetate (100mL×2), the organic phase was washed with saturated brine (100mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column Chromatography (eluent: B system) separation and purification to obtain 3-(8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-2-(( (2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazepine Heterobicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 3c (490 mg, 679.82 μmol), yield 93.65%.

MS m/z(ESI)：721.3[M+H] ⁺ MS m/z(ESI): 721.3[M+H] ⁺

第四步the fourth step

4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol

4-(4-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-氟萘-2-醇4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol

将3-(8-氟-7-(8-氟-3-(甲氧基甲氧基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯3c(170mg,235.86μmol)，加入到氯化氢的乙酸乙酯溶液(4M,1mL)中，室温条件下搅拌0.5小时。反应液减压蒸馏除去有机溶剂，所得的残余物通过制备液相分离纯化(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H2O，流动相B：CH3CN)，得到4-(4-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-氟萘-2-醇3d(63.36mg,86.24μmol)，产率18.28％。3-(8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxy Acid tert-butyl ester 3c (170 mg, 235.86 μmol) was added to hydrogen chloride in ethyl acetate solution (4M, 1 mL), and stirred at room temperature for 0.5 hours. The reaction solution was distilled off under reduced pressure to remove the organic solvent, and the resulting residue was separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2mm I.D.; 5 μm, 20mL/min; mobile phase A: 0.05% TFA+H O, mobile phase B : CH3CN), to obtain 4-(4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol 3d (63.36mg, 86.24μmol ), yield 18.28%.

MS m/z(ESI)：577.0[M+H] ⁺ MS m/z(ESI): 577.0[M+H] ⁺

第五步the fifth step

tert-butyl(2R)-2-(3-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidine-1-carboxylatetert-butyl(2R)-2-(3-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin -7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)pyrrolidine-1-carboxylate

(2R)-2-(3-(8-氟-7-(8-氟-3-羟基萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羰基)吡咯烷-1-羧酸叔丁酯(2R)-2-(3-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole Azin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl) Pyrrolidine-1-carboxylate tert-butyl ester

将4-(4-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-氟萘-2-醇3d(100mg,173.43μmol)，(叔丁氧羰基)-D-脯氨酸3e(111.99mg,520.28μmol)，N,N-二异丙基乙胺(67.24mg,520.28μmol)和(2-肟基-氰基乙酸乙酯)-N,N-二甲基-吗啉基脲六氟磷酸酯(74.27mg,173.43μmol)加入到N,N-二甲基甲酰胺中，氩气保护，升温至60℃反应过夜。反应液降至室温，以乙酸乙酯萃取(10mL×2)，有机相用饱和食盐水洗(10mL×3)，无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：B体系)分离纯化，得到(2R)-2-(3-(8-氟-7-(8-氟-3-羟基萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羰基)吡咯烷-1-羧酸叔丁酯3f(120mg,155.07μmol)，产率89.42％。4-(4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H -pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol 3d (100 mg, 173.43 μmol), (tert-butyl Oxycarbonyl)-D-proline 3e (111.99 mg, 520.28 μmol), N,N-diisopropylethylamine (67.24 mg, 520.28 μmol) and (2-oximino-cyanoacetic acid ethyl ester)-N , N-dimethyl-morpholinourea hexafluorophosphate (74.27mg, 173.43μmol) was added to N,N-dimethylformamide, protected by argon, and heated to 60°C for overnight reaction. The reaction solution was lowered to room temperature, extracted with ethyl acetate (10mL×2), the organic phase was washed with saturated brine (10mL×3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography method (eluent: B system) to separate and purify (2R)-2-(3-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalene-1-yl)-2-(((2R ,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabis Cyclo[3.2.1]octane-8-carbonyl)pyrrolidine-1-carboxylate tert-butyl ester 3f (120 mg, 155.07 μmol), yield 89.42%.

MS m/z(ESI)：774.0[M+H] ⁺ MS m/z(ESI): 774.0[M+H] ⁺

第六步step six

将(2R)-2-(3-(8-氟-7-(8-氟-3-羟基萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羰基)吡咯烷-1-羧酸叔丁酯3f(120mg,155.07μmol)，加入到氯化氢的1,4-二氧六环溶液(4M,1mL)中，室温条件下持续搅拌0.5小时。反应液减压蒸馏除去有机溶剂，残余物加入饱和碳酸氢钠水溶液直到没有气泡产生，将体系以乙酸乙酯(5mL)萃取，有机相减压浓缩，所得的残余物通过制备液相分离纯化(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H2O，流动相B：CH3CN)，得到4-(8-(D-脯氨酰基)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-7-(8-氟-3-羟基萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶3(3mg,3.39μmol)，产率2.19％。(2R)-2-(3-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl ) tert-butyl pyrrolidine-1-carboxylate 3f (120 mg, 155.07 μmol) was added to a solution of hydrogen chloride in 1,4-dioxane (4M, 1 mL), and stirring was continued at room temperature for 0.5 hours. The reaction liquid was distilled off under reduced pressure to remove the organic solvent, and the residue was added to saturated aqueous sodium bicarbonate until no bubbles were generated. The system was extracted with ethyl acetate (5 mL), the organic phase was concentrated under reduced pressure, and the obtained residue was separated and purified by preparative liquid phase separation ( Separation column AKZONOBEL Kromasil; 250×21.2mm I.D.; 5μm, 20mL/min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN), to obtain 4-(8-(D-prolyl)-3, 8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS) -2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine 3 (3 mg, 3.39 μmol), yield 2.19%.

MS m/z(ESI)：673.9[M+H] ⁺ MS m/z(ESI): 673.9[M+H] ⁺

实施例4Example 4

4-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ ⁶-thiomorpholine 1-oxide 4-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) pyrido[4,3-d]pyrimidin-4-yl)-1-imino- ^1λ6 -thiomorpholine 1-oxide

4-(8-氟-7-(8-氟-3-羟基萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-1-亚氨基-1λ ⁶-硫代吗啉1-氧化物 4-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)- Base)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ ⁶ -thiomorpholine 1-oxide

第一步first step

4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ ⁶-thiomorpholine 1-oxide 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ ⁶ -thiomorpholine 1-oxide

4-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-1-亚氨基-1λ ⁶-硫代吗啉1-氧化物 4-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ ⁶ -thiomorpholine 1-oxide

将1-亚氨基-1λ ⁶-硫代吗啉1-氧化物4a(286mg,2.13mmol,根据公开专利WO2021169958制备)加入二氯甲烷(5mL)中，加入N,N-二异丙基乙胺(688.58mg,5.33mmol,880.53μL)，降温至-40℃，加入2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶1a(448.36mg,1.78mmol)，升至室温继续反应3小时。反应液减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)分离纯化，得到4-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-1-亚氨基-1λ ⁶-硫代吗啉1-氧化物4b(130mg,371.22μmol)，产率20.90％。 Add 1-imino- ^1λ6 -thiomorpholine 1-oxide 4a (286mg, 2.13mmol, prepared according to published patent WO2021169958) into dichloromethane (5mL), add N,N-diisopropylethylamine (688.58mg, 5.33mmol, 880.53μL), cooled to -40°C, added 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine 1a (448.36mg, 1.78mmol), liter The reaction was continued for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: system A) to obtain 4-(2,7-dichloro-8-fluoropyrido[4,3-d] Pyrimidin-4-yl)-1-imino-1λ ⁶ -thiomorpholine 1-oxide 4b (130 mg, 371.22 μmol), yield 20.90%.

MS m/z(ESI)：350.0[M+H] ⁺ MS m/z(ESI): 350.0[M+H] ⁺

第二步second step

4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ ⁶-thiomorpholine 1-oxide 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-1-imino-1λ ⁶ -thiomorpholine 1-oxide

4-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-1- 亚氨基-1λ ⁶-硫代吗啉1-氧化物 4-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3- d] pyrimidin-4-yl)-1-imino-1λ ⁶ -thiomorpholine 1-oxide

将4-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-1-亚氨基-1λ ⁶-硫代吗啉1-氧化物4b(130mg,371.22μmol)、((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇1d(76.83mg,482.58μmol)、分子筛

型(144.53mg,328.17μmol)和N,N-二异丙基乙胺(287.86mg,2.23mmol,387.95μL)依次加入到1,4-二氧六环(8mL)中，氩气保护，升温至90℃反应过夜。反应液降至室温，减压浓缩，所得的残余物通过制备液相分离纯化(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H2O，流动相B：CH3CN)，得到4-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-1-亚氨基-1λ ⁶-硫代吗啉1-氧化物4c(30mg,61.43μmol)，产率17％。 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ ⁶ -thiomorpholine 1-oxide 4b (130mg, 371.22 μmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol 1d (76.83mg, 482.58μmol), molecular sieves

(144.53mg, 328.17μmol) and N,N-diisopropylethylamine (287.86mg, 2.23mmol, 387.95μL) were sequentially added to 1,4-dioxane (8mL), under the protection of argon, the temperature was raised React overnight at 90°C. The reaction solution was lowered to room temperature, concentrated under reduced pressure, and the resulting residue was separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H O, mobile phase B: CH3CN) to give 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine And[4,3-d]pyrimidin-4-yl)-1-imino-1λ ⁶ -thiomorpholine 1-oxide 4c (30 mg, 61.43 μmol), the yield was 17%.

MS m/z(ESI)：473.1[M+H] ⁺ MS m/z(ESI): 473.1[M+H] ⁺

第三步third step

4-(8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ ⁶-thiomorpholine 1-oxide 4-(8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl )methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ ⁶ -thiomorpholine 1-oxide

4-(8-氟-7-(8-氟-3-(甲氧基甲氧基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-1-亚氨基-1λ ⁶-硫代吗啉1-氧化物 4-(8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole Azin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ ⁶ -thiomorpholine 1-oxide

将2-(8-氟-3-甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷1f(25.28mg,76.12μmol)、4-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-1-亚氨基-1λ ⁶-硫代吗啉1-氧化物4c(30mg,63.43μmol)、碳酸钠(20.17mg,190.30μmol)和四三苯基膦钯(7.33mg,6.34μmol)依次加入1,4-二氧六环(5mL)和水(1mL)的混合溶剂中，氩气保护，升温至90℃反应3小时。反应液降至室温，减压浓缩，所得的残余物通过制备液相分离纯化(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H2O，流动相B：CH3CN)，得到4-(8-氟-7-(8-氟-3-(甲氧基甲氧基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-1-亚氨基-1λ ⁶-硫代吗啉1-氧化物4d(10mg,15.56μmol)，产率24.53％。 2-(8-fluoro-3-methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborin 1f (25.28 mg, 76.12μmol), 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine And[4,3-d]pyrimidin-4-yl)-1-imino-1λ ⁶ -thiomorpholine 1-oxide 4c (30mg, 63.43μmol), sodium carbonate (20.17mg, 190.30μmol) and four Triphenylphosphine palladium (7.33mg, 6.34μmol) was sequentially added to a mixed solvent of 1,4-dioxane (5mL) and water (1mL), protected by argon, and heated to 90°C for 3 hours. The reaction solution was lowered to room temperature, concentrated under reduced pressure, and the resulting residue was separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H O, mobile phase B: CHCN), to give 4-(8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino- ^1λ6 -thiomorpholine 1-oxidation Compound 4d (10 mg, 15.56 μmol), yield 24.53%.

MS m/z(ESI)：644.3[M+H] ⁺ MS m/z(ESI): 644.3[M+H] ⁺

第四步the fourth step

将4-(8-氟-7-(8-氟-3-(甲氧基甲氧基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-1-亚氨基-1λ ⁶-硫代吗啉1-氧化物4d(10mg,15.56μmol)加入乙腈(5mL)中，加入氯化氢的乙酸乙酯溶液(4M,0.5mL)，室温反应1小时。反应液加入饱和碳酸钠水溶液调节Ph至碱性，用乙酸乙酯萃取(100mL)，有机相用饱和食盐水洗(100mL×3)，无水硫酸钠干燥，过滤，减压浓缩，所得的残余物通过制备液相分离纯化(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H2O，流动相B：CH3CN)，得到4-(8-氟-7-(8-氟-3-羟基萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-1-亚氨基-1λ ⁶-硫代吗啉1-氧化物4(1mg,1.64μmol)，产率10.52％。 4-(8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ ⁶ -thiomorpholine 1-oxide 4d (10mg, 15.56 μmol) was added to acetonitrile (5 mL), hydrogen chloride in ethyl acetate (4M, 0.5 mL) was added, and reacted at room temperature for 1 hour. Add saturated aqueous sodium carbonate solution to the reaction solution to adjust Ph to alkaline, extract with ethyl acetate (100 mL), wash the organic phase with saturated brine (100 mL×3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue Separation and purification by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5 μm, 20mL/min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 4-(8-fluoro-7 -(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)-1-imino-1λ ⁶ -thiomorpholine 1-oxide 4 (1 mg, 1.64 μmol), yield 10.52%.

MS m/z(ESI)：600.2[M+H] ⁺ MS m/z(ESI): 600.2[M+H] ⁺

生物学评价biological evaluation

测试例1.本发明化合物对AGS(人胃腺癌)细胞中p-ERK1/2抑制活性的测定Test example 1. The compound of the present invention is to the determination of p-ERK1/2 inhibitory activity in AGS (human gastric adenocarcinoma) cell

以下方法用于测定本发明化合物对AGS细胞中p-ERK1/2抑制活性。本方法使用Cisbio公司的Advanced phospho-ERK1/2(Thr202/tyr204)试剂盒(货号64AERPEH)，详细实验操作可参考试剂盒说明书。AGS细胞(含有KRAS G12D突变)购于中国科学院上海生命科学研究院细胞资源中心。The following method is used to determine the inhibitory activity of the compounds of the present invention on p-ERK1/2 in AGS cells. This method uses the Advanced phospho-ERK1/2 (Thr202/tyr204) kit (Cat. No. 64AERPEH) from Cisbio, and the detailed experimental operation can refer to the kit instruction manual. AGS cells (containing the KRAS G12D mutation) were purchased from the Cell Resource Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.

将实验流程简述如下：AGS细胞培养于含10％胎牛血清、100U青霉素和100μg/mL链霉素的F12K完全培养基中。AGS细胞按每孔40000个铺于96孔板中，培养基为完全培养基，在37℃，5％CO2培养箱内培养过夜。将受试化合物溶解于DMSO中制备为10mM贮存液，随后使用F12K完全培养基进行稀释，每孔加入100uL含对应浓度受试化合物的F12K完全培养基，受试化合物在反应体系中的终浓度范围为1000nM-0.015nM，置于细胞培养箱培养3小时后，弃去细胞上清，使用冰浴的PBS清洗细胞，之后每孔加入50μl的1×cell phospho/total protein lysis buffer(Advanced phospho-ERK1/2试剂盒组分)进行裂解，96孔板置于冰上裂解半小时，随后参照Advanced phospho-ERK1/2(Thr202/tyr204)试剂盒说明书检测裂解液。最后在酶标仪以TF-FRET模式上测定在304nM的激发波长下，各孔发射波长为620nM和665nM的荧光强度，并计算各孔665/620的荧光强度比值。通过与对照组(0.1％DMSO)的荧光强度比值进行比较，计算受试化合物在各浓度下的百分比抑制率，并通过GraphPad Prism 5软件以受试化合物浓度对数值-抑制率进行非线性回归分析，获得化合物的IC50值。The experimental procedure is briefly described as follows: AGS cells were cultured in F12K complete medium containing 10% fetal bovine serum, 100 U penicillin and 100 μg/mL streptomycin. AGS cells were plated in 96-well plates at 40,000 per well, and the medium was complete medium, and cultured overnight at 37° C. in a 5% CO2 incubator. The test compound was dissolved in DMSO to prepare a 10mM stock solution, and then diluted with F12K complete medium, and 100uL of F12K complete medium containing the corresponding concentration of the test compound was added to each well. The final concentration range of the test compound in the reaction system 1000nM-0.015nM, placed in a cell culture incubator for 3 hours, discarded the cell supernatant, washed the cells with ice-bathed PBS, and then added 50μl of 1×cell phospho/total protein lysis buffer (Advanced phospho-ERK1 /2 kit components) were lysed, and the 96-well plate was lysed on ice for half an hour, and then the lysate was detected according to the instructions of the Advanced phospho-ERK1/2 (Thr202/tyr204) kit. Finally, the fluorescence intensity of each well with emission wavelengths of 620nM and 665nM was measured on a microplate reader in TF-FRET mode at an excitation wavelength of 304nM, and the ratio of the fluorescence intensity of each well at 665/620 was calculated. By comparing with the fluorescence intensity ratio of the control group (0.1% DMSO), the percentage inhibition rate of the test compound at each concentration was calculated, and the non-linear regression analysis was carried out with the concentration of the test compound on the value-inhibition rate by GraphPad Prism 5 software , to obtain the IC50 value of the compound.

本发明优选化合物对AGS细胞中p-ERK1/2活性具有明显的抑制作用，优选化合物的IC50<500nM，更优化合物的IC50<200nM。The preferred compound of the present invention has obvious inhibitory effect on the activity of p-ERK1/2 in AGS cells, the IC50 of the preferred compound is <500nM, and the IC50 of the more optimal compound is <200nM.

测试例2.本发明化合物对AsPC-1细胞增殖抑制测定Test example 2. The compounds of the present invention inhibit the proliferation of AsPC-1 cells

以下方法用于测定本发明化合物对AsPC-1(人转移胰腺腺癌)细胞增殖的影响。AsPC-1细胞(含有KRAS G12D突变)购于中国科学院上海生命科学研究院细胞资源中心，培养于含10％胎牛血清、100U青霉素，100μg/mL链霉素和1mM Sodium Pyruvate的RPMI 1640培养基中。细胞活力通过

Luminescent Cell Viability Assay试剂盒(Promega，货号G7573)进行测定。 The following method was used to determine the effect of the compounds of the present invention on the proliferation of AsPC-1 (human metastatic pancreatic adenocarcinoma) cells. AsPC-1 cells (containing KRAS G12D mutation) were purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100U penicillin, 100μg/mL streptomycin and 1mM Sodium Pyruvate middle. cell viability through

Luminescent Cell Viability Assay Kit (Promega, Cat. No. G7573) was used for determination.

实验方法按照试剂盒说明书的步骤操作，简述如下：受试化合物首先溶解于DMSO中制备为10mM贮存液，随后以培养基进行稀释，配制成测试样品，化合物的终浓度范围在1000nM-0.015nM。将处于对数生长期的细胞以800个细胞每孔的密度接种至96孔细胞培养板中，在37℃，5％CO2培养箱中培养过夜，随后加入受试化合物后继续培养120小时。培养结束后，向每孔加入50uL体积的CellTiter-Glo检测液，震荡5分钟后静置10分钟，随后在酶标仪上使用Luminescence模式读取样品各孔发光值。通过与对照组(0.3％DMSO)的数值进行比较计算化合物在各浓度点的百分比抑制率，之后在GraphPad Prism 5软件中以化合物浓度对数-抑制率进行非线性回归分析，获得化合物抑制细胞增殖的IC50值。The experimental method is operated according to the steps of the kit manual, which is briefly described as follows: the test compound is first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with medium to prepare a test sample. The final concentration of the compound ranges from 1000nM to 0.015nM . Cells in the logarithmic growth phase were inoculated into 96-well cell culture plates at a density of 800 cells per well, cultivated overnight at 37°C in a 5% CO2 incubator, and then continued to cultivate for 120 hours after adding the test compound. After the incubation, add 50uL of CellTiter-Glo detection solution to each well, shake for 5 minutes and let it stand for 10 minutes, then use the Luminescence mode on the microplate reader to read the luminescence value of each well of the sample. By comparing with the value of the control group (0.3% DMSO), the percentage inhibition rate of the compound at each concentration point is calculated, and then the compound concentration logarithm-inhibition rate is used for nonlinear regression analysis in the GraphPad Prism 5 software, and the compound inhibits cell proliferation IC50 value.

本发明优选化合物对AsPC-1细胞增殖具有明显的抑制作用，优选化合物的IC50<500nM，更优化合物的IC50<200nM。The preferred compound of the present invention has obvious inhibitory effect on the proliferation of AsPC-1 cells, the IC50 of the preferred compound is <500nM, and the IC50 of the more optimal compound is <200nM.

测试例3.本发明化合物对KRAS G12D：RAF1蛋白相互作用的抑制能力测定Test example 3. Determination of the inhibitory ability of the compound of the present invention to KRAS G12D:RAF1 protein interaction

以下方法用于测定本发明化合物在体外条件下阻断KRAS G12D：RAF1蛋白相互作用的能力。本方法使用Cisbio公司的KRAS-G12C/SOS1BINDING ASSAY KITS试剂盒(63ADK000CB21PEG)，详细实验操作可参考试剂盒说明书。The following method is used to determine the ability of the compound of the present invention to block KRAS G12D:RAF1 protein interaction in vitro. This method uses the KRAS-G12C/SOS1BINDING ASSAY KITS kit (63ADK000CB21PEG) from Cisbio. For detailed experimental operations, please refer to the kit instruction manual.

将实验流程简述如下：使用diluent buffer(货号62DLBDDF)配置Tag1-RAF1和Tag2-KRAS-G12D蛋白为5X的工作液浓度备用。受试化合物溶解于DMSO中制备为10mM贮存液，随后使用diluent buffer进行稀释备用。首先向孔中加入2uL受试化合物(反应体系终浓度为10000nM-0.1nM)，随后加入4uL Tag1-RAF1 5X的工作液和4uL Tag2-KRAS-G12D 5X的工作液，离心并混匀，静置15分钟；随后加入10uL预混匀的anti-Tag1-Eu ³⁺和anti-Tag2-XL665，室温下孵育4小时；最后使用酶标仪以TF-FRET模式上测定在304nM的激发波长下，各孔发射波长为620nM和665nM的荧光强度，并计算各孔665/620的荧光强度比值。通过与对照组(0.1％DMSO)的荧光强度比值进行比较，计算受试化合物在各浓度下的百分比抑制率，并通过GraphPad Prism 5软件以受试化合物浓度对数值-抑制率进行非线性回归分析，获得化合物的IC ₅₀值，本发明化合物的IC ₅₀值，结果见表1。 The experimental procedure is briefly described as follows: use diluent buffer (Product No. 62DLBDDF) to prepare Tag1-RAF1 and Tag2-KRAS-G12D proteins at a working solution concentration of 5X for later use. The test compound was dissolved in DMSO to prepare a 10 mM stock solution, and then diluted with diluent buffer for use. First, add 2uL of the test compound to the well (the final concentration of the reaction system is 10000nM-0.1nM), then add 4uL of Tag1-RAF1 5X working solution and 4uL of Tag2-KRAS-G12D 5X working solution, centrifuge and mix, let stand 15 minutes; then add 10uL pre-mixed anti-Tag1-Eu ³⁺ and anti-Tag2-XL665, and incubate at room temperature for 4 hours; finally use a microplate reader to measure in TF-FRET mode at an excitation wavelength of 304nM, each The wells emit fluorescence intensities at wavelengths of 620 nM and 665 nM, and the ratio of the fluorescence intensity of 665/620 for each well is calculated. By comparing with the fluorescence intensity ratio of the control group (0.1% DMSO), the percentage inhibition rate of the test compound at each concentration was calculated, and the nonlinear regression analysis was carried out with the concentration of the test compound on the value-inhibition rate by GraphPad Prism 5 software , to obtain the IC ₅₀ value of the compound, the IC ₅₀ value of the compound of the present invention, the results are shown in Table 1.

表1 本发明化合物对KRAS G12D：RAF1蛋白相互作用的抑制活性Table 1 The inhibitory activity of the compounds of the present invention on KRAS G12D:RAF1 protein interaction

实施例编号Example number	IC50(nM)IC50(nM)
22	189189
33	114114

结论：本发明化合物对KRAS G12D：RAF1蛋白相互作用的抑制活性的具有较好抑制作用。Conclusion: The compound of the present invention has a good inhibitory effect on the inhibitory activity of KRAS G12D: RAF1 protein interaction.

Claims

一种通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐A compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof

其中：in:

环A为4～12元的杂环基，其中所述的杂环基内至少含有1个氮原子；Ring A is a 4- to 12-membered heterocyclic group, wherein the heterocyclic group contains at least one nitrogen atom;

环B为芳基、杂芳基、杂环基或环烷基；Ring B is aryl, heteroaryl, heterocyclyl or cycloalkyl;

Q为N或CR ^a； Q is N or CR ^a ;

R ^a为氢原子、卤素、羟基、氨基、烷基、烷氧基或氰基；其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基和烷氧基的取代基所取代； R ^a is a hydrogen atom, halogen, hydroxyl, amino, alkyl, alkoxy or cyano; wherein the alkyl or alkoxy is optionally further replaced by one or more selected from halogen, hydroxyl, cyano, alkane Substituents of radicals and alkoxy groups;

L为键、-O-或-NR ^b； L is a bond, -O- or -NR ^b ;

R ^b为氢原子或烷基； R ^b is a hydrogen atom or an alkyl group;

W为N、CR ^c或-S(＝O)-；W优选为N； W is N, CR ^c or -S(=O)-; W is preferably N;

R ^c为不存在或氢原子； R ^c is absent or a hydrogen atom;

R ¹为-L ¹-环烷基、-L ¹-杂环基、-L ¹-芳基、-L ¹-杂芳基或-L ¹-稠合环，其中所述的环烷基、杂环基、芳基、杂芳基或稠合环任选进一步被一个或多个选自烷基、卤素、卤代烷基、羟烷基、苄基、氰基、环烷基、杂环基、芳基、杂芳基、＝O、-OR ⁵、-C(O)R ⁵、-C(O)OR ⁵、-NHC(O)R ⁵、-NHC(O)OR ⁵、-NR ⁶R ⁷、-C(O)NR ⁶R ⁷、-CH ₂NHC(O)OR ⁵、-CH ₂NR ⁶R ⁷和-S(O) _rR ⁵的取代基所取代； R ¹ is -L ¹ -cycloalkyl, -L ¹ -heterocyclyl, -L ¹ -aryl, -L ¹ -heteroaryl or -L ¹ -fused ring, wherein said cycloalkyl, Heterocyclyl, aryl, heteroaryl or fused ring is optionally further selected from one or more groups selected from alkyl, halogen, haloalkyl, hydroxyalkyl, benzyl, cyano, cycloalkyl, heterocyclyl, Aryl, Heteroaryl, =O, -OR ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -NHC(O)R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ^7. Substituents of -C(O)NR ⁶ R ⁷ , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ and -S(O) _r R ⁵ ;

L ¹各自独立地为键或-C ₁-C ₆亚烷基，其中所述的亚烷基任选进一步被一个或多个R ^A所取代； Each of L ¹ is independently a bond or -C ₁ -C ₆ alkylene, wherein said alkylene is optionally further substituted by one or more R ^A ;

R ^A各自独立地为氢原子、卤素、羟基或羟甲基； ^RA is each independently a hydrogen atom, halogen, hydroxyl or hydroxymethyl;

或者，连接于同一碳原子的两个R ^A，与所连接的碳原子一起形成一个环烷基；优选为环丙基； Alternatively, two ^RAs connected to the same carbon atom form a cycloalkyl group together with the connected carbon atoms; preferably cyclopropyl;

R ²相同或不同，各自独立地为氢原子、卤素、羟基、氰基、烷基或烷氧基，其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基和烷氧基的取代基所取代； R ² are the same or different, each independently a hydrogen atom, halogen, hydroxyl, cyano, alkyl or alkoxy, wherein said alkyl or alkoxy is optionally further selected by one or more selected from halogen, hydroxyl , cyano and alkoxy substituents;

或者，任意的两个R ²与其所连接的原子一起形成一个环烷基或杂环基； Alternatively, any two R ² form a cycloalkyl or heterocyclic group together with the atoms they are connected to;

或者，R ²和R ^a，与其所连接的原子一起形成一个6～8元杂环基；所述的杂环基任选进一步被一个或多个R ^B取代； Alternatively, R ² and R ^a form a 6-8 membered heterocyclic group together with the atoms they are connected to; the heterocyclic group is optionally further substituted by one or more R ^B ;

R ^B为氢原子、卤素、烷基、氘代烷基或烷氧基，其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基和烷氧基的取代基所取代；R ^B优选为氢原子、甲基或氘甲基； R ^B is a hydrogen atom, halogen, alkyl, deuterated alkyl or alkoxy, wherein said alkyl or alkoxy is optionally further replaced by one or more selected from halogen, hydroxyl, cyano, alkyl and Substituents of alkoxy groups are substituted; ^RB is preferably a hydrogen atom, methyl or deuteromethyl;

或者，两个R ^B与其所连接的同一个碳原子一起形成-C(＝O)-； Alternatively, two ^RBs form -C(=O)- together with the same carbon atom to which they are attached;

R ³为-L ²-环烷基、-L ²-杂环基、-L ²-芳基、-L ²-杂芳基、-L ²-OR ⁵、-L ²-NR ⁷R ⁸或＝NR ⁵；其中所述的环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、＝O、-OR ⁵、-C(O)R ⁵、-C(O)OR ⁵、-NHC(O)R ⁵、-NHC(O)OR ⁵、-NR ⁶R ⁷、-C(O)NR ⁶R ⁷、-CH ₂NHC(O)OR ⁵、-CH ₂NR ⁶R ⁷和-S(O) _rR ⁵的取代基所取代； R ³ is -L ² -cycloalkyl, -L ² -heterocyclyl, -L ² -aryl, -L 2 -heteroaryl, -L ² ^-OR ⁵ , -L ² -NR ⁷ R ⁸ or =NR ⁵ ; wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from one or more of alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl , aryl, heteroaryl, =O, -OR ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -NHC(O)R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ Substituents of R ⁷ , -C(O)NR ⁶ R ⁷ , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ and -S(O) _r R ⁵ ;

或者，R ²和R ³，与其所连接的原子一起形成一个杂芳基或杂环基； Alternatively, R ² and R ³ together form a heteroaryl or heterocyclic group with the atoms they are connected to;

L ²各自独立地为键或-C ₁-C ₆亚烷基，其中所述的亚烷基任选进一步被一个或多个选自卤素、羟基、氰基和＝O的取代基所取代； L ² are each independently a bond or -C ₁ -C ₆ alkylene, wherein said alkylene is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano and =O;

R ⁴相同或不同，各自独立地为氢原子、卤素、氰基、烷基、环烷基、烷氧基、杂环基、芳基、杂芳基或稠合环，其中所述的烷基、环烷基、烷氧基、杂环基、芳基、杂芳基或稠合环任选进一步被一个或多个R ^C取代； R ⁴ are the same or different, each independently hydrogen atom, halogen, cyano, alkyl, cycloalkyl, alkoxy, heterocyclyl, aryl, heteroaryl or fused ring, wherein the alkyl , cycloalkyl, alkoxy, heterocyclyl, aryl, heteroaryl or fused ring optionally further substituted by one or more R ^C ;

或者，两个R ⁴与其所连接的同一个碳原子一起形成一个稠合环；所述的稠合环任选进一步被一个或多个R ^C取代； Alternatively, two R ⁴ form a fused ring together with the same carbon atom to which they are attached; the fused ring is optionally further substituted by one or more R ^C ;

R ^C相同或不同，各自独立地为氢原子、烷基、卤素、硝基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-OR ⁵、-C(O)R ⁵、-C(O)OR ⁵、-NHC(O)R ⁵、-NHC(O)OR ⁵、-NR ⁶R ⁷、-C(O)NR ⁶R ⁷、-CH ₂NHC(O)OR ⁵、-CH ₂NR ⁶R ⁷或-S(O) _rR ⁵；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、＝O、-OR ⁵、-C(O)R ⁵、-C(O)OR ⁵、-NHC(O)R ⁵、-NHC(O)OR ⁵、-NR ⁶R ⁷、-C(O)NR ⁶R ⁷、-CH ₂NHC(O)OR ⁵、-CH ₂NR ⁶R ⁷和-S(O) _rR ⁵的取代基所取代； R and ^C are the same or different, each independently hydrogen atom, alkyl, halogen, nitro, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁵ , - C(O)R ⁵ , -C(O)OR ⁵ , -NHC(O)R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O) _r R ⁵ ; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl The group is optionally further replaced by one or more groups selected from alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -NHC(O)R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -CH ₂ NHC(O)OR ^5. Substituents of -CH ₂ NR ⁶ R ⁷ and -S(O) _r R ⁵ ;

或者，两个R ^C与其所连接的同一个碳原子一起形成-C(＝O)-； Alternatively, two ^RCs form -C(=O)- together with the same carbon atom to which they are attached;

或者，R ²与R ⁴，与其所连接的原子一起形成一个6～8元杂环基；所述的杂环基任选进一步被一个或多个R ^D取代； Or, R ² and R ⁴ together form a 6-8 membered heterocyclic group; the heterocyclic group is optionally further substituted by one or more R ^D ;

R ^D为氢原子、卤素、烷基或烷氧基，其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基和烷氧基的取代基所取代；R ^D优选为氢原子； R ^D is a hydrogen atom, halogen, alkyl or alkoxy, wherein said alkyl or alkoxy is optionally further substituted by one or more selected from halogen, hydroxyl, cyano, alkyl and alkoxy Substituted by group; R ^D is preferably a hydrogen atom;

或者，两个R ^D与其所连接的同一个碳原子一起形成-C(＝O)-； Alternatively, the two ^RDs together form -C(=O)- with the same carbon atom to which they are attached;

R ⁵各自独立地为氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-C(O)R ⁸、-C(O)OR ⁸、-OC(O)R ⁸、-NR ⁹R ¹⁰、-C(O)NR ⁹R ¹⁰、-SO ₂NR ⁹R ¹⁰和-NR ⁹C(O)R ¹⁰的取代基所取代； ^Each R is independently a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group are optionally Further selected from one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -SO ₂ NR ⁹ R ¹⁰ and -NR ⁹ C (O) R ¹⁰ substituents are substituted;

R ⁶和R ⁷各自独立地为氢原子、羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-C(O)R ⁸、-C(O)OR ⁸、-OC(O)R ⁸、-NR ⁹R ¹⁰、-C(O)NR ⁹R ¹⁰、-SO ₂NR ⁹R ¹⁰和-NR ⁹C(O)R ¹⁰的取代基所取代； R ⁶ and R ⁷ are each independently a hydrogen atom, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, ring Alkyl, heterocyclyl, aryl or heteroaryl are optionally further selected from one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl , Heteroaryl, =O, -C(O)R ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -SO ₂ NR ⁹ R ¹⁰ and -NR ⁹ C(O)R ¹⁰ are substituted by substituents;

或者，R ⁶和R ⁷与它们相连接的原子一起形成一个4～8元杂环基，其中所述4～8元杂环基内含有一个或多个N、O或S(O) _r，并且所述的4～8元杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-C(O)R ⁸、-C(O)OR ⁸、-OC(O)R ⁸、-NR ⁹R ¹⁰、-C(O)NR ⁹R ¹⁰、-SO ₂NR ⁹R ¹⁰和-NR ⁹C(O)R ¹⁰的取代基所取代； Alternatively, R ⁶ and R ⁷ form a 4-8 membered heterocyclic group together with the atoms they are connected to, wherein the 4-8 membered heterocyclic group contains one or more N, O or S(O) _r , And the 4-8 membered heterocyclic group is optionally further replaced by one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, hetero Aryl, =O, -C(O)R ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -SO ₂ NR ⁹ R ¹⁰ and -NR ⁹ C (O) R ¹⁰ are replaced by substituents;

R ⁸、R ⁹和R ¹⁰各自独立地为氢原子、烷基、氨基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基和羧酸酯基的取代基所取代； R ⁸ , R ⁹ and R ¹⁰ are each independently a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclyl group, Aryl or heteroaryl is optionally further replaced by one or more selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, Carboxyl and carboxylate substituents are substituted;

m各自独立地为0、1、2、3或4；each m is independently 0, 1, 2, 3 or 4;

k各自独立地为0、1、2、3或4；且each k is independently 0, 1, 2, 3 or 4; and

r各自独立地为0、1或2。r is each independently 0, 1 or 2.
根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐，其为通式(II)或(III)所示的化合物或其立体异构体、互变异构体或其可药用的盐：The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound represented by general formula (II) or (III) or its stereoisomer, Tautomers or their pharmaceutically acceptable salts:

其中：in:

环C为芳基、杂芳基或稠合环；Ring C is aryl, heteroaryl or fused ring;

R ⁴各自独立地为氢原子、卤素、氰基、烷基、环烷基或烷氧基，其中所述的烷基、环烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基、烷氧基和卤代烷基的取代基所取代；R ⁴优选为卤素，更优选为氟或氯； R ⁴ are each independently a hydrogen atom, halogen, cyano, alkyl, cycloalkyl or alkoxy, wherein the alkyl, cycloalkyl or alkoxy are optionally further selected from one or more halogen , hydroxy, cyano, alkyl, alkoxy and haloalkyl substituents are substituted; R is ^preferably halogen, more preferably fluorine or chlorine;

n各自独立地为0、1、2或3；each n is independently 0, 1, 2 or 3;

环A、W、R ¹～R ³、R ^C、L、Q和m的定义如权利要求1中所述。 Ring A, W, R ¹ -R ³ , R ^C , L, Q and m are as defined in claim 1.
根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐，其为通式(IV)或(V)所示的化合物或其立体异构体、互变异构体或其可药用的盐：The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IV) or (V) or its stereoisomer, Tautomers or their pharmaceutically acceptable salts:

其中：in:

环C为芳基、杂芳基或稠合环；Ring C is aryl, heteroaryl or fused ring;

n各自独立地为0、1、2或3；each n is independently 0, 1, 2 or 3;

环A、W、R ¹～R ³、R ^C、L、Q和m的定义如权利要求1中所述。 Ring A, W, R ¹ -R ³ , R ^C , L, Q and m are as defined in claim 1.
根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐，其为通式(VI)或(VII)所示的化合物或其立体异构体、互变异构体或其可药用的盐：The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound represented by general formula (VI) or (VII) or its stereoisomer, Tautomers or their pharmaceutically acceptable salts:

其中：in:

环C各自独立地为芳基、杂芳基或稠合环；Ring C is each independently aryl, heteroaryl or fused ring;

R ⁴各自独立地为氢原子、卤素、氰基、烷基、环烷基或烷氧基；其中所述的烷基、环烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基、烷氧基和卤代烷基的取代基所取代；R ⁴优选为卤素，更优选为氟或氯； R ⁴ are each independently a hydrogen atom, halogen, cyano, alkyl, cycloalkyl or alkoxy; wherein the alkyl, cycloalkyl or alkoxy are optionally further selected by one or more halogen , hydroxy, cyano, alkyl, alkoxy and haloalkyl substituents are substituted; R is ^preferably halogen, more preferably fluorine or chlorine;

R ^B为氢原子或甲基； ^RB is a hydrogen atom or a methyl group;

n各自独立地为0、1、2或3；each n is independently 0, 1, 2 or 3;

p各自独立地为0、1、2或3；each p is independently 0, 1, 2 or 3;

环A、W、R ¹～R ³、R ^C、L和Q的定义如权利要求1中所述。 Ring A, W, R ¹ -R ³ , R ^C , L and Q are as defined in claim 1.
根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐，其为通式(VIII)所示的化合物或其立体异构体、互变异构体或其可药用的盐：The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound represented by general formula (VIII) or its stereoisomer, tautomer body or its pharmaceutically acceptable salts:

其中：in:

环D为稠合环；Ring D is a fused ring;

n为0、1、2或3；n is 0, 1, 2 or 3;

环A、W、R ¹～R ³、R ^C、L、Q和m的定义如权利要求1中所述。 Ring A, W, R ¹ -R ³ , R ^C , L, Q and m are as defined in claim 1.
根据权利要求1、2、3或5中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 3 or 5, wherein:

为以下基团：
for the following groups:

R ⁵为氢原子或烷基；其中所述的烷基优选为甲基； R ⁵ is a hydrogen atom or an alkyl group; wherein the alkyl group is preferably a methyl group;

R ³的定义如权利要求1中所述。 R ³ is as defined in claim 1.
根据权利要求4中所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：
为
The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to claim 4, wherein:
for

R ³的定义如权利要求4中所述。 R ³ is as defined in claim 4.
根据权利要求4中所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中
为
According to the compound described in claim 4 or its stereoisomer, tautomer or its pharmaceutically acceptable salt, wherein
for

R ³的定义如权利要求4中所述。 R ³ is as defined in claim 4.
根据权利要求1～8中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein:

R ³为环烷基、杂芳基、-C(O)-杂环基、-C(O)-杂芳基、-(CH ₂)q-杂环基、-(CH ₂)q-OR ⁵或-(CH ₂)q-NR ⁶R ⁷；其中所述的环烷基、杂芳基或杂环基任选进一步被一个或多个选自烷基、卤素、环烷基和烷氧基的取代基所取代； R ³ is cycloalkyl, heteroaryl, -C(O)-heterocyclyl, -C(O)-heteroaryl, -(CH ₂ )q-heterocyclyl, -(CH ₂ )q-OR ⁵ or -(CH ₂ )q-NR ⁶ R ⁷ ; wherein the cycloalkyl, heteroaryl or heterocyclic group is optionally further replaced by one or more selected from the group consisting of alkyl, halogen, cycloalkyl and alkoxy The substituent of the group is substituted;

R ⁵为氢原子或烷基；R ⁵优选为氢原子； R ⁵ is a hydrogen atom or an alkyl group; R ⁵ is preferably a hydrogen atom;

R ⁶和R ⁷各自独立地为烷基，优选为甲基； R ⁶ and R ⁷ are each independently an alkyl group, preferably a methyl group;

q为0、1或2。q is 0, 1 or 2.
根据权利要求9所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中R ³为以下基团： The compound according to claim 9 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ³ is the following groups:
根据权利要求1～5任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中Q为N。The compound according to any one of claims 1-5, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein Q is N.
根据权利要求1～5任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein:

Q为CR ^a； Q is CR ^a ;

R ^a为氢原子或氰基。 R ^a is a hydrogen atom or a cyano group.
根据权利要求1～5任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中L为-O-。The compound according to any one of claims 1-5, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein L is -O-.
根据权利要求1～5任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein:

R ¹为-L ¹-杂环基； R ¹ is -L ¹ -heterocyclyl;

其中所述的杂环基任选进一步被一个或多个选自烷基、卤素、烷氧基和＝O的取代基所取代；Wherein the heterocyclic group is optionally further substituted by one or more substituents selected from alkyl, halogen, alkoxy and =O;

其中所述的卤素优选为氟；Wherein said halogen is preferably fluorine;

-L ¹-为亚甲基。 -L ¹ - is methylene.
根据权利要求14所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中R ¹为： The compound according to claim 14 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ^R is:
根据权利要求2～4任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中环C为：The compound according to any one of claims 2-4 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring C is:

苯基、萘基、吡啶基、喹啉基、异喹啉基、吲哚基、吲唑基、苯并噻唑基、四氢化萘基、Phenyl, naphthyl, pyridyl, quinolinyl, isoquinolyl, indolyl, indazolyl, benzothiazolyl, tetralinyl,

优选为萘基。
Naphthyl is preferred.
根据权利要求2～4任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中
为： The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 2 to 4, wherein
for:
根据权利要求5所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中环D为The compound according to claim 5 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring D is
根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中所述的化合物为：The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein said compound is:
一种药物组合物，所述的药物组合物含有有效剂量的权利要求1～19中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，及可药用的载体、赋形剂或它们的组合。A pharmaceutical composition containing an effective dose of the compound according to any one of claims 1 to 19 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and Pharmaceutically acceptable carrier, excipient or their combination.
权利要求1～19中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，或权利要求20所述的药物组合物在制备KRas G12D抑制剂中的用途。The compound described in any one of claims 1 to 19 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in claim 20 in the preparation of KRas G12D inhibitor the use of.
权利要求1～19中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，或权利要求20所述的药物组合物在制备用于治疗由KRas G12D突变介导的疾病的药物中的用途，其中所述的由KRas G12D突变介导的疾病优选为癌症，其中所述的癌症优选为心脏粘液瘤、肺癌、胃癌、大肠肿瘤、直肠癌、胰腺癌、***癌、膀胱癌、肝细胞癌、胆管癌、软骨肉瘤、多发性骨髓瘤、子宫癌、***、***瘤、恶性黑色素瘤、皮肤鳞状细胞癌、肾上腺成神经细胞瘤、骨髓性白血病、急性淋巴细胞白血病或胶质母细胞瘤；更优选为胰腺癌、大肠肿瘤、直肠癌和肺癌。The compound described in any one of claims 1 to 19 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in claim 20 is used for the treatment of KRas Use in medicine for diseases mediated by G12D mutation, wherein the disease mediated by KRas G12D mutation is preferably cancer, wherein the cancer is preferably cardiac myxoma, lung cancer, gastric cancer, colorectal tumor, rectal cancer, pancreatic cancer carcinoma, prostate cancer, bladder cancer, hepatocellular carcinoma, cholangiocarcinoma, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, squamous cell carcinoma of the skin, adrenal neuroblastoma, Myelogenous leukemia, acute lymphoblastic leukemia or glioblastoma; more preferably pancreatic cancer, colorectal tumor, rectal cancer and lung cancer.
权利要求1～19中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，或权利要求20所述的药物组合物在制备用于治疗癌症的药物中的用途，其中所述的癌症优选为心脏粘液瘤、肺癌、胃癌、大肠肿瘤、直肠癌、胰腺癌、***癌、膀胱癌、肝细胞癌、胆管癌、软骨肉瘤、多发性骨髓瘤、子宫癌、***、***瘤、恶性黑色素瘤、皮肤鳞状细胞癌、肾上腺成神经细胞瘤、骨髓性白血病、急性淋巴细胞白血病或胶质母细胞瘤；更优选为胰腺癌、大肠肿瘤、直肠癌或肺癌。The compound described in any one of claims 1 to 19 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in claim 20 is used in the preparation of Use in medicine, wherein the cancer is preferably cardiac myxoma, lung cancer, gastric cancer, colorectal tumor, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, cholangiocarcinoma, chondrosarcoma, multiple myeloma, Uterine cancer, cervical cancer, seminoma, malignant melanoma, squamous cell carcinoma of the skin, adrenal neuroblastoma, myelogenous leukemia, acute lymphoblastic leukemia or glioblastoma; more preferably pancreatic cancer, colorectal tumor , rectal or lung cancer.
根据权利要求22或23所述的用途，其中所述的肺癌为非小细胞肺癌或小细胞肺癌。The use according to claim 22 or 23, wherein said lung cancer is non-small cell lung cancer or small cell lung cancer.