TWI760919B

TWI760919B - A kind of pyrimidocyclic derivative and its application in medicine

Info

Publication number: TWI760919B
Application number: TW109139393A
Authority: TW
Inventors: 張晨; 何平; 魏琦; 王健民; 錢國飛; 葉飛; 唐平明; 李瑤; 嚴龐科
Original assignee: 大陸商四川海思科製藥有限公司
Priority date: 2019-11-15
Filing date: 2020-11-11
Publication date: 2022-04-11
Also published as: TW202128672A; WO2021093758A1; CN114630832A

Abstract

本發明涉及通式(I)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽。本發明還涉及該化合物的中間體和製備方法，以及在製備預防或治療與KRAS G12C活性或表達量相關疾病的藥物中的應用。

The present invention relates to compounds of general formula (I) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof. The present invention also relates to an intermediate and a preparation method of the compound, as well as its application in the preparation of a medicament for preventing or treating diseases related to KRAS G12C activity or expression.

Description

A kind of pyrimidocyclic derivative and its application in medicine

本發明涉及通式(I)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，及其中間體和製備方法，以及在製備預防或治療與KRAS G12C活性或表達量相關疾病的藥物中的應用。The present invention relates to compounds of general formula (I) or their stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts, and intermediates and preparation methods thereof, and Application in the preparation of medicines for preventing or treating diseases related to KRAS G12C activity or expression.

RAS蛋白由RAS基因 (Rat Sarcoma viral oncogene)表達，是細胞內鳥嘌呤核苷酸結合蛋白，屬GTP酶(水解活性較弱)。RAS蛋白存在於兩種不同的狀態：非活性的的GDP結合狀態和活性的GTP結合狀態。激活態的RAS蛋白藉由與不同下游效應器相互作用進行訊號傳導，對細胞的生長、分化、細胞骨架、蛋白質運輸和分泌等都具有影響。RAS訊號傳導的激活受鳥嘌呤核苷酸交換因子(GEF，可導致GDP-GTP交換)或者GTP酶活化蛋白(GAP，可導致RAS蛋白由活化態轉變為失活態)的調節，突變型RAS蛋白可致對GAP的抵抗導致RAS蛋白處於持續激活狀態，引起細胞不受控制的生長，最終發展為癌變組織(Molecular Cancer,2018,17:33)。The RAS protein is expressed by the RAS gene (Rat Sarcoma viral oncogene), which is an intracellular guanine nucleotide binding protein and is a GTPase (with weak hydrolytic activity). RAS proteins exist in two distinct states: an inactive GDP-bound state and an active GTP-bound state. The activated RAS protein conducts signal transduction by interacting with different downstream effectors, and has effects on cell growth, differentiation, cytoskeleton, protein transport and secretion. Activation of RAS signaling is regulated by guanine nucleotide exchange factor (GEF, which results in GDP-GTP exchange) or GTPase activating protein (GAP, which causes RAS protein to switch from an active to an inactive state). Mutant RAS The protein can cause resistance to GAP and lead to the continuous activation of the RAS protein, causing uncontrolled cell growth and eventually the development of cancerous tissue (Molecular Cancer, 2018, 17:33).

RAS基因突變是癌症患者中常見的基因突變類型(Nat. Rev. Drug Discov. 2014,13, 828-851)，例如RAS基因突變在胰腺癌、結直腸癌、多發性骨髓瘤及NSLCL中分別占到了97.7%，52.2%，42.6%及32.2%。KARS基因(Kristen Rat Sarcoma viral oncogene)突變是RAS突變中影響最大的突變，占到所有RAS突變的86%。KRAS基因被激活最常見的方式是點突變，95%的KRAS突變主要發生在2號外顯子的第12號密碼子和13號密碼子上，常見的突變形式有KRAS G12C突變(39%)，KRAS G12V(18-21%)和KRAS G12D(17-18%)突變。RAS gene mutation is a common type of gene mutation in cancer patients (Nat. Rev. Drug Discov. 2014, 13, 828-851). For example, RAS gene mutation accounts for pancreatic cancer, colorectal cancer, multiple myeloma and NSLCL, respectively. to 97.7%, 52.2%, 42.6% and 32.2%. KARS gene (Kristen Rat Sarcoma viral oncogene) mutation is the most influential mutation among RAS mutations, accounting for 86% of all RAS mutations. The most common way for KRAS gene to be activated is point mutation. 95% of KRAS mutations mainly occur in codons 12 and 13 of exon 2. The common mutation form is KRAS G12C mutation (39%), KRAS G12V (18-21%) and KRAS G12D (17-18%) mutations.

自發現癌症中的KRAS突變蛋白並且觀察到抑制這些突變蛋白能抑制腫瘤增殖以來，KRAS突變蛋白抑制劑就受到了廣泛關注。KRAS長期以來被認為是一個“不可成藥靶點”：RAS對GTP / GDP具有很高的親和力(皮摩爾級別)，整個蛋白也缺少其他的“配體結合口袋”(Clin. Cancer Res. 2015, 21, 1810–1818)。在KRAS G12C突變蛋白中，鑒定發現緊鄰GTP/GDP-RAS結合口袋處出現了一個“結合口袋II” (Nature. 2013, 503, 548-551)，可以作為KRAS G12C突變蛋白抑制劑的結合位點。Since the discovery of KRAS mutant proteins in cancer and the observation that inhibiting these mutant proteins inhibits tumor proliferation, KRAS mutant protein inhibitors have received extensive attention. KRAS has long been considered a "non-drugable target": RAS has a high affinity (picomolar scale) for GTP/GDP, and the whole protein also lacks other "ligand-binding pockets" (Clin. Cancer Res. 2015, 21, 1810–1818). In the KRAS G12C mutein, it was identified that a "binding pocket II" appeared next to the GTP/GDP-RAS binding pocket (Nature. 2013, 503, 548-551), which can serve as a binding site for KRAS G12C mutein inhibitors .

本發明的目的之一在於提供一種KRAS G12C蛋白的抑制劑。One of the objects of the present invention is to provide an inhibitor of KRAS G12C protein.

特別地，本發明提供了能夠抑制KRAS G12C蛋白的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽。本發明還提供了該化合物的中間體和製備方法，以及該化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽在製備預防或治療與KRAS G12C活性或表達量相關疾病的藥物中的應用。In particular, the present invention provides compounds capable of inhibiting KRAS G12C protein, or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof. The present invention also provides an intermediate and a preparation method of the compound, as well as the compound or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt in the preparation of prophylactic or therapeutic Use in medicines for diseases related to KRAS G12C activity or expression.

本發明提供通式(I)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中

(I) 在一些實施方案中，R¹ 選自-C(=O)-C(R^1a )=C(R^1b )₂ 、

、-S(=O)₂ -C(R^1a )=C(R^1b )₂ 或

；在一些實施方案中，R¹ 選自-C(=O)-C(R^1a )=C(R^1b )₂ ；在一些實施方案中，R¹ 選自

、

、

、

、

、

、

、

、

、

；在一些實施方案中，R^1a 各自獨立地選自H、F、Cl、Br、I、氰基、CF₃ 、C_1-4 烷基、C_1-4 烷氧基或-NHC(=O)R^1d ，所述的烷基或烷氧基任選進一步被0至4個(例如0、1、2、3或4個)選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代；在一些實施方案中，R^1a 選自H 、F或C_1-4 烷基，所述的烷基任選進一步被0至4個(例如0、1、2、3或4個)選自H、F、Cl、Br、I、氰基、OH、CF₃ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代；在一些實施方案中，R^1a 選自H、F、甲基、乙基、丙基或異丙基，所述的甲基、乙基、丙基或異丙基任選進一步被0至4個(例如0、1、2、3或4個)選自H、F、Cl、Br、I、氰基、OH、CF₃ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代；在一些實施方案中，R^1b 或R^1c 各自獨立地選自H、F、Cl、Br、I、氰基、CF₃ 、C_1-4 烷基、C_1-4 烷氧基、-C(=O)N(R^1d )₂ 、-(CH₂ )_p -N(C_1-4 烷基)₂ 、-(CH₂ )_p NHC(=O)-C_1-4 烷基、-(CH₂ )_p -C_3-10 碳環或-(CH₂ )_p -3至12元雜環，所述的烷基、烷氧基、雜環或碳環任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基、C_1-4 烷氧基、C_3-10 碳環或5至12元雜環的取代基所取代，所述的雜環含有1至4個(例如1、2、3或4個)選自O、S、N的雜原子；在一些實施方案中，R^1b 各自獨立地選自H、C_1-4 烷基或-(CH₂ )_p -3至6元雜環，所述的烷基或雜環任選進一步被0至4個(例如0、1、2、3或4個)選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基、C_1-4 烷氧基、C_3-6 碳環或3至6元雜環的取代基所取代，所述的雜環含有1至4個(例如1、2、3或4)選自O、S、N的雜原子；在一些實施方案中，R^1b 各自獨立地選自H、甲基、乙基、丙基、異丙基、-CH₂ -4元含氮雜環、-CH₂ -5元含氮雜環、-CH₂ -6元含氮雜環、4元含氮雜環、5元含氮雜環或6元含氮雜環，所述的甲基、乙基、丙基、異丙基或含氮雜環任選進一步被0至4個(例如0、1、2、3或4個)選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代；在一些實施方案中，R^1c 選自H、F、Cl、Br、I、氰基、CF₃ 、C_1-4 烷基或C_1-4 烷氧基，所述的烷基或烷氧基任選進一步被0至4個(例如0、1、2、3或4個)選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代；在一些實施方案中，R^1a 與任意一個R^1b 形成C_5-10 碳環或5至12元雜環，所述的碳環或雜環任選進一步被0至4個(例如0、1、2、3或4個)選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-N(C_1-4 烷基)₂ 、C_1-4 烷基、C_1-4 烷氧基、C_3-10 碳環基或5至12元雜環基的取代基所取代，所述的雜環基含有1至4個(例如1、2、3或4)選自O、S、N的雜原子；在一些實施方案中，R^1d 各自獨立地選自H或C_1-4 烷基，所述的烷基任選進一步被0至4個(例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代；在一些實施方案中，環A選自4至12元含氮雜環，所述的含氮雜環選自飽和或部分飽和的如下基團之一：單環、並環、橋環或螺環，所述的含氮雜環、單環、並環、橋環或螺環任選進一步被0至4個(例如0、1、2、3或4個）R^a 取代；在一些實施方案中，環A選自4至9元含氮雜環，所述的含氮雜環選自飽和或部分飽和如下結構之一：單環、並環、橋環或螺環，所述的含氮雜環任選進一步被0至4個(例如0、1、2、3或4個）R^a 取代基所取代；在一些實施方案中，R^a 各自獨立地選自H、oxo、F、Cl、Br、I、氰基、C_1-6 烷基或C_1-6 烷氧基，所述的烷基或烷氧基任選進一步被0至4個(例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代；在一些實施方案中，環A選自未被取代的或者取代的

、

、

、

、

、

、

、

、

或

，當被取代時，任選進一步被0至4個（例如0、1、2、3或4個）R^a 取代基所取代；在一些實施方案中，環A選自取代的或者未取代的如下基團之一：

、、

、

或

，當被取代時，任選被0至4個(例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、氰基、OH、CF₃ 、甲基、乙基、丙基、異丙基或CH₂ CN的取代基所取代；在一些實施方案中，環A選自

、

、

、

、

、

、

、

、

、

、

、

、

或

；在一些實施方案中，環A選自

、

、

或

；The present invention provides a compound of general formula (I) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, wherein

(I) In some embodiments, R ¹ is selected from -C(=O)-C(R ^1a )=C(R ^1b ) ₂ ,

, -S(=O) ₂ -C(R ^1a )=C(R ^1b ) ₂ or

In some embodiments, R ¹ is selected from -C(=O)-C(R ^1a )=C(R ^1b ) ₂ ; In some embodiments, R ¹ is selected from

,

; In some embodiments, each R ^1a is independently selected from H, F, Cl, Br, I, cyano, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy, or -NHC (=O ) R ^1d , the alkyl or alkoxy group is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano , CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents Substituted; In some embodiments, R ^1a is selected from H, F, or C _1-4 alkyl, optionally further selected from 0 to 4 (eg, 0, 1, 2, 3, or 4) Substituents substituted from H, F, Cl, Br, I, cyano, OH, _CF3 , _C1-4alkyl , or _C1-4alkoxy ; in some embodiments, ^R1a is selected from H , F, methyl, ethyl, propyl or isopropyl, said methyl, ethyl, propyl or isopropyl optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4 ) is substituted with a substituent selected from H, F, Cl, Br, I, cyano, OH, CF ₃ , C _1-4 alkyl or C _1-4 alkoxy; in some embodiments, R ^1b or R ^1c are each independently selected from H, F, Cl, Br, I, cyano, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy, -C(=O)N(R ^1d ) ₂ , -(CH ₂ ) _p -N(C _1-4 alkyl) ₂ , -(CH ₂ ) _p NHC(=O)-C _1-4 alkyl, -(CH ₂ ) _p -C _3-10 Carbocycle or -( _CH2 ) _p -3 to 12 membered heterocycle, said alkyl, alkoxy, heterocycle or carbocycle is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ) ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-10 carbocyclic or 5- to 12-membered heterocyclic substituents, and the heterocyclic ring contains 1 to 4 (for example, 1 , 2, 3 or 4) heteroatoms selected from O, S, N; in some embodiments, R ^1b is each independently selected from H, C _1-4 alkyl or -(CH ₂ ) _p -3 to 6-membered heterocycle, said alkyl or heterocycle is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbon ring or 3- to 6-membered heterocyclic substituents, the heterocyclic ring contains 1 to 4 (eg 1, 2, 3 or 4) selected from Heteroatoms of O, S, N; in some embodiments, R ^1b is each independently selected from H, methyl, ethyl, propyl, isopropyl, -CH ₂ -4-membered nitrogen-containing heterocycle, -CH _2-5 -membered nitrogen-containing heterocycle, -CH _2-6 -membered nitrogen-containing heterocycle, 4-membered nitrogen-containing heterocycle, 5-membered nitrogen-containing heterocycle or 6-membered nitrogen-containing heterocycle, the methyl, ethyl, Propyl, isopropyl or nitrogen-containing heterocycles are optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano , CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents Substituted; In some embodiments, R ^1c is selected from H, F, Cl, Br, I, cyano, CF ₃ , C _1-4 alkyl or C _1-4 alkoxy, said alkyl or alkoxy The oxy group is optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, 1, oxo, OH, cyano, _CF3 , COOH, _NH2 , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituent; In some embodiments, R ^1a and any one of R ^1b form a C _5-10 carbocycle or 5- to 12-membered heterocycle optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) Selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-10 carbocyclyl or substituents of 5- to 12-membered heterocyclyl, said heterocyclyl containing 1 to 4 (eg 1, 2, 3 or 4) selected from O, Heteroatoms of S, N; In some embodiments, R ^1d is each independently selected from H or C _1-4 alkyl optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) is selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituent; In some embodiments, ring A is selected from 4- to 12-membered nitrogen-containing heterocycles, and the nitrogen-containing heterocycles are selected from Self-saturated or partially saturated one of the following groups: monocyclic, paracyclic, bridged or spirocyclic, said nitrogen-containing heterocyclic, monocyclic, paracyclic, bridged or spirocyclic optionally further substituted by 0 to 4 (eg, 0, 1, 2, 3, or 4) ^Ra substitutions; In some embodiments, Ring A is selected from a 4- to 9-membered nitrogen-containing heterocycle selected from saturated or partially saturated One of the following structures: monocyclic, paracyclic, bridged or spirocyclic, the nitrogen-containing heterocycle is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^a substituent replace; in some embodiments , R ^a is independently selected from H, oxo, F, Cl, Br, I, cyano, C _1-6 alkyl or C _1-6 alkoxy, the alkyl or alkoxy optionally further is 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, 1, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or Substituents of C _1-4 alkoxy are substituted; In some embodiments, ring A is selected from unsubstituted or substituted

,

or

, when substituted, optionally further substituted with 0 to 4 (eg, 0, 1, 2, 3, or 4) R substituents; in some embodiments, Ring ^A is selected from substituted or unsubstituted One of the following groups:

,,

,

or

, when substituted, optionally by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, 1, oxo, cyano, OH, _CF3 , methyl , ethyl, propyl, isopropyl or CH ₂ CN substituents; In some embodiments, Ring A is selected from

,

or

; In some embodiments, Ring A is selected from

,

or

;

在一些實施方案中，R^a 各自獨立地選自H、oxo、F、Cl、Br、I、氰基、C_1-4 烷基或C_1-4 烷氧基，所述的烷基或烷氧基任選進一步被0至4個(例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代；在一些實施方案中，Q、M和與二者直接相連接的原子一起形成C_3-12 碳環或者3至12元的雜環，所述的碳環或者雜環為單環、並環或者螺環，所述的碳環、雜環、單環、並環或者螺環任選進一步被0至5（例如0、1、2、3、4或5）個R² 取代，所述的雜環含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子；在一些實施方案中，Q、M和與二者直接相連接的原子一起形成

或

，環B選自非芳香4至7元雜環，所述的雜環含有1至4(例如1、2、3或4個)個選自O、S、N的雜原子，X₁ 選自N，環C和環D一起形成C_6-12 碳環並環或5至12元雜環並環，所述的雜環並環含有1至4個(例如1、2、3或4個)選自O、S、N的雜原子，m1選自0、1、2、3或4，m2、m3各自獨立地選自0、1、2、3或4，且m2+m3≤5；在一些實施方案中，Q、M和與二者直接相連接的原子一起形成

或

，環B選自氮雜環丁烷、氮雜環戊烷、呱啶或咪唑烷，環D選自苯環、吡啶、噠嗪或嘧啶；環C選自C_4-6 碳環、4至6元雜環，所述的雜環含有1至3個（例如1、2或3個）選自O、S、N的雜原子；在一些實施方案中，Q、M和與二者直接相連接的原子一起形成

，環B選自呱啶；在一些實施方案中，Q、M和與二者直接相連接的原子一起形成

、

、

、

、

、

或

；在一些實施方案中，Q、M和與二者直接相連接的原子一起形成

，

選自

、

、

、

、

、

、

、

、

或

；在一些實施方案中，

選自

、

、

、

、

、

、

或

、

, G_1- G₂ 選自-CH₂ CH₂ -、-CH=CH-、-C(=O)-NH-、-C(=O)-N(CH₃ )-、 -N(CH₃ )-C(=O)-或者-NH-C(=O)-, m2選自0、1、2或3；在一些實施方案中，Q、M和與二者直接相連接的原子一起形成

、

，R^2c 各自獨立地選自H、F、Cl、Br、I、OH、氰基、CF₃ 、甲基、乙基、甲氧基、乙氧基、環丙基或環丁基，所述的甲基、乙基、甲氧基、乙氧基、環丙基或環丁基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-4 烷基、C_1-4 烷氧基取代基所取代，m2選自0、1、2或3；在一些實施方案中，R² 各自獨立地選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、-C(=O)-C_1-6 烷基、-C(=O)-C_3-6 環烷基、-C(=O)- 3至8元雜環烷基、-C(=O)-C_6-10 芳基、-C(=O)- 5至10元雜芳基、C_1-6 烷基、C_1-6 烷氧基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、烷氧基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、C_1-6 烷基、C_2-6 炔基、C_1-6 烷氧基、羥基取代的C_1-6 烷基、C_3-6 環烷基、3至6元雜環烷基、C_6-10 芳基或5至10元雜芳基的取代基所取代，所述的雜環烷基或雜芳基含有1至4個選自O、S、N的雜原子；在一些實施方案中，R² 各自獨立地選自R^2a 、R^2b 、R^2c 、R^2d ；在一些實施方案中，R^2a 選自H、COOH、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、-C(=O)-C_1-6 烷基、-C(=O)- C_3-6 環烷基、-C(=O)- 3至8元雜環烷基、-C(=O)-C_6-10 芳基、-C(=O)- 5至10元雜芳基、C_1-6 烷基、C_1-6 烷氧基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、烷氧基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、C_1-6 烷基、C_2-6 炔基、C_1-6 烷氧基、羥基取代的C_1-6 烷基、C_3-6 環烷基、3至6元雜環烷基、C_6-10 芳基或5至10元雜芳基的取代基所取代，所述的雜環烷基或雜芳基含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子；在一些實施方案中，R^2a 選自H、COOH、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、-C(=O)-C_1-4 烷基、-C(=O)-苯基、-C(=O)-5至6元雜芳基、C_1-4 烷基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、- C_1-6 烷基、C_2-6 炔基、C_1-6 烷氧基、羥基取代的C_1-6 烷基、C_3-6 環烷基、3至6元雜環烷基、C_6-10 芳基或5至10元雜芳基的取代基所取代，所述的雜環烷基或雜芳基含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子；在一些實施方案中，R^2a 選自H或者取代的或者未被取代的如下基團之一：-C(=O)NH₂ 、-NHC(=O)H、-C(=O)NH-CH₃ 、-NHC(=O)-CH₃ 、-C(=O)NH-CH₂ CH₃ 、-NHC(=O)CH₂ CH₃ 、-C(=O)N(CH₃ )₂ 、-C(=O)N(CH₂ CH₃ )₂ 、-C(=O)-CH₃ 、-C(=O)-CH₂ CH₃ 、-C(=O)-CH₂ CH₂ CH₃ 、-C(=O)-CH(CH₃ )₂ 、-C(=O)NH-苯基、-NHC(=O)-苯基、-C(=O)-苯基、-C(=O)-吡啶、-C(=O)-噻吩、-C(=O)-呋喃、-C(=O)-吡咯、甲基、乙基、異丙基、丙基、環丙基、環丁基、環戊基、環己基、苯基、萘基、噻吩基、呋喃基、吡咯基、噻唑基、異噻唑基、噁唑基、異噁唑基、咪唑基、吡唑基、苯並咪唑基、苯並吡唑基或吡啶基，當被取代時，任選被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、-C(=O)NH₂ 、-NHC(=O)H、-C(=O)NH-CH₃ 、-NHC(=O)-CH₃ 、-C(=O)NH-CH₂ CH₃ 、-NHC(=O)CH₂ CH₃ 、-C(=O)N(CH₃ )₂ 、-C(=O)N(CH₂ CH₃ )₂ 、-C(=O)NH-苯基、-NHC(=O)-苯基、C_1-4 烷基、C_1-4 烷氧基或C_2-4 炔基的取代基所取代；在一些實施方案中，R^2a 選自H或者取代的或者未被取代的如下基團之一：-C(=O)NH₂ 、-NHC(=O)H、-C(=O)NH-CH₃ 、-NHC(=O)-CH₃ 、-C(=O)NH-CH₂ CH₃ 、-NHC(=O)CH₂ CH₃ 、-C(=O)N(CH₃ )₂ 、-C(=O)N(CH₂ CH₃ )₂ 、-C(=O)-CH₃ 、-C(=O)-CH₂ CH₃ 、-C(=O)-CH₂ CH₂ CH₃ 、-C(=O)-CH(CH₃ )₂ 、-C(=O)NH-苯基、-NHC(=O)-苯基、-C(=O)-苯基、-C(=O)-吡啶、-C(=O)-噻吩、-C(=O)-呋喃、-C(=O)-吡咯、甲基、乙基、異丙基、丙基、苯基、萘基、噻吩基、呋喃基、吡咯基或吡啶基，當被取代時，任選被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、-C(=O)NH₂ 、-NHC(=O)H、-C(=O)NH-CH₃ 、-NHC(=O)-CH₃ 、-C(=O)NH-CH₂ CH₃ 、-NHC(=O)CH₂ CH₃ 、-C(=O)N(CH₃ )₂ 、-C(=O)N(CH₂ CH₃ )₂ 、-C(=O)NH-苯基、-NHC(=O)-苯基、甲基或乙基的取代基所取代；在一些實施方案中，R^2a 選自H、C_1-6 烷基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-C_1-6 烷基、C_2-6 炔基、C_1-6 烷氧基、C_3-6 環烷基、3至6元雜環烷基、C_6-10 芳基或5至10元雜芳基的取代基所取代，所述的雜環烷基或雜芳基含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子；在一些實施方案中，R^2a 選自H或者取代的或者未被取代的如下基團之一：甲基、乙基、異丙基、丙基、環丙基、環丁基、苯基、萘基、噻吩基、呋喃基、吡咯基或吡啶基，當被取代時，任選被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、NH₂ 、甲基、乙基、甲氧基、乙氧基、環丙基、環丁基或苯基的取代基所取代；在一些實施方案中，R^2b 各自獨立地選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH或C_1-6 烷基，所述的烷基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-6 烷基、C_2-6 炔基或C_1-6 烷氧基的取代基所取代；在一些實施方案中，R^2b 各自獨立地選自H、F、oxo、OH、氰基、CF₃ 、甲基或乙基，所述的甲基或乙基任選被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代；在一些實施方案中，R^2b 各自獨立地選自H、F、oxo、OH、氰基、CF₃ 、甲基或乙基，所述的甲基或乙基任選被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、甲基或乙基的取代基所取代；在一些實施方案中，R^2c 、R^2d 各自獨立地選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、COOH、-C(=O)-C_1-6 烷基、-C(=O)-C_3-6 環烷基、-C(=O)-C_6-10 芳基、-C(=O)- 5至10元雜芳基、C_1-6 烷基、C_1-6 烷氧基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、烷氧基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、C_1-6 烷基、C_2-6 炔基、C_1-6 烷氧基、羥基取代的C_1-6 烷基、C_3-6 環烷基、3至6元雜環烷基、C_6-10 芳基或5至10元雜芳基的取代基所取代，所述的雜環烷基或雜芳基含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子；在一些實施方案中，R^2c 各自獨立地選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、C_1-4 烷基、C_1-4 烷氧基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、烷氧基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、C_1-6 烷基、C_2-6 炔基、C_1-6 烷氧基、羥基取代的C_1-6 烷基、C_3-6 環烷基、3至6元雜環烷基、C_6-10 芳基或5至10元雜芳基的取代基所取代，所述的雜環烷基或雜芳基含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子；在一些實施方案中，R^2c 各自獨立地選自H、F、Cl、Br、I、OH、氰基、CF₃ 、-C(=O)NH₂ 、-NHC(=O)H、-C(=O)NH-CH₃ 、-NHC(=O)-CH₃ 、-C(=O)NH-CH₂ CH₃ 、-NHC(=O)CH₂ CH₃ 、-C(=O)N(CH₃ )₂ 、- -C(=O)N(CH₂ CH₃ )₂ 、-C(=O)NH-苯基、-NHC(=O)-苯基、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基、乙氧基或苯基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-4 烷基、C_1-4 烷氧基取代基所取代；在一些實施方案中，R^2c 各自獨立地選自H、F、Cl、Br、I、OH、氰基、CF₃ 、-C(=O)NH₂ 、-NHC(=O)H、-C(=O)NH-CH₃ 、-NHC(=O)-CH₃ 、-C(=O)NH-CH₂ CH₃ 、-NHC(=O)CH₂ CH₃ 、-C(=O)N(CH₃ )₂ 、-C(=O)N(CH₂ CH₃ )₂ 、-C(=O)NH-苯基、-NHC(=O)-苯基、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基、乙氧基或苯基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、甲基或乙基的取代基所取代；在一些實施方案中，R^2c 各自獨立地選自H、F、Cl、Br、I、OH、氰基、CF₃ 、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基或乙氧基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、甲基或乙基的取代基所取代；在一些實施方案中，R^2c 各自獨立地選自H、F、Cl、Br、I、OH、氰基、CF₃ 、C_1-6 烷基、C_1-6 烷氧基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、烷氧基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-6 烷基、C_2-6 炔基、C_1-6 烷氧基、羥基取代的C_1-6 烷基、C_3-6 環烷基、3至6元雜環烷基、C_6-10 芳基或5至10元雜芳基的取代基所取代，所述的雜環烷基或雜芳基含有1至4個1、2、3或4個選自O、S、N的雜原子；在一些實施方案中，R^2c 各自獨立地選自H、F、Cl、Br、I、OH、氰基、CF₃ 、甲基、乙基、甲氧基、乙氧基、環丙基或環丁基，所述的甲基、乙基、甲氧基、乙氧基、環丙基或環丁基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-4 烷基、C_1-4 烷氧基取代基所取代；在一些實施方案中，R^2d 各自獨立地選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、C_1-4 烷基或C_1-4 烷氧基，所述的烷基或烷氧基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 或C_1-6 烷基的取代基所取代；在一些實施方案中，R^2d 各自獨立地選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、甲基或乙基，所述的甲基或乙基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代；在一些實施方案中，R^2d 各自獨立地選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、甲基或乙基，所述的甲基或乙基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、甲基或乙基的取代基所取代；在一些實施方案中，R^2A 、R^2B 或R^2C 各自獨立地選自H、C_1-6 烷基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-6 烷基、C_2-6 炔基、C_1-6 烷氧基、羥基取代的C_1-6 烷基、C_3-6 環烷基、3至6元雜環烷基的取代基所取代，所述的雜環烷基含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子；在一些實施方案中，X₃ 選自鍵、O、-OCH₂ -、-CH₂ O-、S或NR^x ；在一些實施方案中，X₃ 選自鍵或O；在一些實施方案中，R^x 選自H、C_1-6 烷基或C_3-6 環烷基，所述的烷基或環烷基任選進一步被0、1、2、3或4個選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代；0至4個（例如0、1、2、3或4個）。In some embodiments, each R is ^{independently} selected from H, oxo, F, Cl, Br, I, cyano, C _1-4 alkyl or C _1-4 alkoxy, said alkyl or alkoxy The oxy group is optionally further selected by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, 1, OH, cyano, _CF3 , COOH, _NH2 , _{C1 -4} alkyl or C _1-4 alkoxy substituents; in some embodiments, Q, M, and the atom to which they are directly attached together form a C _3-12 carbocyclic ring or a 3- to 12-membered Heterocycle, said carbocycle or heterocycle is monocycle, paracycle or spirocycle, said carbocycle, heterocycle, monocycle, paracycle or spirocycle is optionally further substituted by 0 to 5 (eg 0, 1 , 2, 3, 4 or 5) R ² substitutions, the heterocycle contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; in some embodiments , Q, M and the atoms directly connected to them form together

or

, Ring B is selected from non-aromatic 4- to 7-membered heterocycles, the heterocycles contain 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N, X ₁ is selected from N, Ring C and Ring D together form a C _6-12 carbocyclic or 5- to 12-membered heterocyclic ring containing 1 to 4 (eg 1, 2, 3 or 4) A heteroatom selected from O, S, N, m1 is selected from 0, 1, 2, 3 or 4, m2, m3 are each independently selected from 0, 1, 2, 3 or 4, and m2+m3≤5; In some embodiments, Q, M, and the atom directly attached to both form together

or

, ring B is selected from azetidine, azetidine, oxidine or imidazolidine, ring D is selected from benzene ring, pyridine, pyridazine or pyrimidine; ring C is selected from C _4-6 carbocycle, 4 to 6-membered heterocycle containing 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N; in some embodiments, Q, M and connected atoms form together

, Ring B is selected from oxidine; In some embodiments, Q, M and the atom directly attached to the two together form

,

or

; In some embodiments, Q, M, and the atoms directly linked to both form together

,

selected from

,

or

; In some embodiments,

selected from

,

or

,

, G _1- G ₂ is selected from -CH ₂ CH ₂ -, -CH=CH-, -C(=O)-NH-, -C(=O)-N(CH ₃ )-, -N(CH ₃ )-C(=O)- or -NH-C(=O)-, m2 is selected from 0, 1, 2 or 3; In some embodiments, Q, M and the atoms directly connected to both form together

,

, R ^2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, the The methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl are optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) from H, F, Cl , Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy substituents, m2 is selected from 0, 1, 2 or 3; in some In embodiments, each R ² is independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, -C(=O)NR ^2A R ^2B , -NR ^2A C(= O)R ^2C , -C(=O)-C _1-6 alkyl, -C(=O)-C _3-6 cycloalkyl, -C(=O)- 3- to 8-membered heterocycloalkyl, -C(=O)-C _6-10 aryl, -C(=O)- 5- to 10-membered heteroaryl, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkane group, 3- to 8-membered heterocycloalkyl, C _6-10 -membered aryl or 5- to 10-membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) from H, F, Cl, Br, 1, oxo, OH, cyano, _CF3 , COOH, _NH2 , - NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , C _1-6 alkyl , C _2-6 alkynyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C _6-10 aryl or Substituents of 5- to 10-membered heteroaryl groups, the heterocycloalkyl or heteroaryl groups contain 1 to 4 heteroatoms selected from O, S, N; In some embodiments, R ² are each independently is selected from R ^2a , R ^2b , R ^2c , R ^2d ; in some embodiments, R ^2a is selected from H, COOH, -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , -C(=O)-C _1-6 alkyl, -C(=O)-C _3-6 cycloalkyl, -C(=O)- 3- to 8-membered heterocycloalkyl, -C(= O)-C _6-10 aryl, -C(=O)- 5- to 10-membered heteroaryl, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3 to 8-membered heterocycloalkyl, C _6-10 aryl or 5- to 10-membered heteroaryl, the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, 1, oxo, OH, cyano, _CF3 , COOH, _NH2 , -NH( _{C1 -4} alkyl), -N(C _1-4 alkyl) ₂ , -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , C _1-6 alkyl, C _{2- 6} -alkynyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C _6-10 -membered aryl, or 5- to 10-membered Substituted by a heteroaryl substituent, the heterocycloalkyl or heteroaryl contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; in some implementations In the scheme, R ^2a is selected from H, COOH, -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , -C(=O)-C _1-4 alkyl, -C( =O)-phenyl, -C(=O)-5- to 6-membered heteroaryl, C _1-4 alkyl, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _6-10 Aryl or 5- to 10-membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ) ₂ , -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , -C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxyl substituted C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C _6-10 -membered aryl or 5- to 10-membered heteroaryl substituents, the heterocycle The alkyl or heteroaryl group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; in some embodiments, R ^2a is selected from H or substituted or not One of the following substituted groups: -C(=O)NH ₂ , -NHC(=O)H, -C(=O)NH-CH ₃ , -NHC(=O)-CH ₃ , -C(= O)NH-CH ₂ CH ₃ , -NHC(=O)CH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)N(CH ₂ CH ₃ ) ₂ , -C (=O)-CH ₃ , -C(=O)-CH ₂ CH ₃ , -C(=O)-CH ₂ CH ₂ CH ₃ , -C(=O)-CH(CH ₃ ) ₂ , -C (=O)NH-phenyl, -NHC(=O)-phenyl, -C(=O)-phenyl, -C(=O)-pyridine, -C(=O)-thiophene, -C( =O)-furan, -C(=O)-pyrrole, methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, thiophene radical, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, benzimidazolyl, benzopyrazolyl or pyridyl , when substituted, optionally by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , -C (= O)NH ₂ , -NHC(=O)H, -C(=O)NH-CH ₃ , -NHC(=O)-CH ₃ , -C(=O)NH-CH ₂ CH ₃ , -NHC( =O)CH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)N(CH ₂ CH ₃ ) ₂ , -C(=O)NH-phenyl, -NHC( =O)-substituted with substituents of phenyl, C _1-4 alkyl, C _1-4 alkoxy or C _2-4 alkynyl; in some embodiments, R ^2a is selected from H or substituted or unsubstituted One of the following substituted groups: -C(=O)NH ₂ , -NHC(=O)H, -C(=O)NH-CH ₃ , -NHC(=O)-CH ₃ , -C( =O)NH-CH ₂ CH ₃ , -NHC(=O)CH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)N(CH ₂ CH ₃ ) ₂ , - C(=O)-CH ₃ , -C(=O)-CH ₂ CH ₃ , -C(=O)-CH ₂ CH ₂ CH ₃ , -C(=O)-CH(CH ₃ ) ₂ , - C(=O)NH-phenyl, -NHC(=O)-phenyl, -C(=O)-phenyl, -C(=O)-pyridine, -C(=O)-thiophene, -C (=O)-furan, -C(=O)-pyrrole, methyl, ethyl, isopropyl, propyl, phenyl, naphthyl, thienyl, furanyl, pyrrolyl or pyridyl, when substituted , optionally by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, 1, OH, cyano, CF ₃ , -C(=O)NH ₂ , -NHC(=O)H, -C(=O)NH-CH ₃ , -NHC(=O)-CH ₃ , -C(=O)NH-CH ₂ CH ₃ , -NHC(=O)CH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)N(CH ₂ CH ₃ ) ₂ , -C(=O)NH-phenyl, -NHC(=O)- substituted with a phenyl, methyl or ethyl substituent; in some embodiments, R ^2a is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _6-10 aryl group or 5- to 10-membered heteroaryl group, the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group are optionally further replaced by 0 to 4 (for example, 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _{1 -4} alkyl) ₂ , -C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C _6-10 aryl or 5- to 10-membered heteroaryl substituents Substituted, the heterocycloalkyl or heteroaryl group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; In some embodiments, R ^2a is selected from H or substituted or unsubstituted one of the following groups: methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl or pyridyl, when substituted, optionally 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, _CF3 , NH _2. Substituents of methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl or phenyl are substituted; In some embodiments, R ^2b is independently selected from H, F, Cl , Br, I, oxo, OH, cyano, _CF3 , COOH or _C1-6 alkyl optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) Selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , substituted by substituents of C _1-6 alkyl, C _2-6 alkynyl or C _1-6 alkoxy; in some embodiments, R ^2b are each independently selected from H, F, oxo, OH, cyano , CF ₃ , methyl or ethyl, said methyl or ethyl optionally being 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents; In some embodiments, R ^2b is each independently selected from H, F, oxo, OH, cyano, _CF3 , methyl or ethyl optionally 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, substituted by substituents of Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , methyl or ethyl; in some embodiments, R ^2c , R ^2d are each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , COOH, -C(=O)-C _{1- 6} -alkyl, -C(=O)-C _3-6 cycloalkyl, -C(=O)-C _6-10 aryl, -C(=O)- 5- to 10-membered heteroaryl, C _{1 -6} alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _6-10 -membered aryl or 5- to 10-membered heteroaryl, the alkyl , alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) H, F, Cl, Br , I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkyl, C _3-6 cycloalkane , 3- to 6-membered heterocycloalkyl, C _6-10 aryl or 5- to 10-membered heteroaryl substituents, the heterocycloalkyl or heteroaryl contains 1 to 4 (for example, 1 , 2, 3 or 4) heteroatoms selected from O, S, N; In some embodiments, R ^2c is each independently selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 3 to 8 Membered heterocycloalkyl, C _6-10 aryl or 5- to 10-membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, 1, oxo, OH, cyano, _CF3 , COOH, _NH2 , -C(=O) NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkyl, C ₃ -Substituted by substituents of ₆ -cycloalkyl, 3- to 6-membered heterocycloalkyl, C _6-10 aryl or 5- to 10-membered heteroaryl, the heterocycloalkyl or heteroaryl contains 1 to 4 (eg, 1, 2, 3, or 4) heteroatoms selected from O, S, N; in some embodiments, each R ^2c is independently selected from H, F, Cl, Br, I, OH, cyano , CF ₃ , -C(=O)NH ₂ , -NHC(=O)H, -C(=O)NH-CH ₃ , -NHC(=O)-CH ₃ , -C(=O)NH- CH ₂ CH ₃ , -NHC(=O)CH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , - -C(=O)N(CH ₂ CH ₃ ) ₂ , -C(=O) )NH-phenyl, -NHC(=O)-phenyl, methyl, ethyl, methoxy or ethoxy, said methyl, ethyl, methoxy, ethoxy or phenyl is any is further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkanes In some embodiments, R _2c ^is each independently selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , -C(=O )NH ₂ , -NHC(=O)H, -C(=O)NH-CH ₃ , -NHC(=O)-CH ₃ , -C(=O)NH-CH ₂ CH ₃ , -NHC(=O)CH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , - C(=O)N(CH ₂ CH ₃ ) ₂ , -C(=O)NH-phenyl, -NHC(=O)-phenyl, methyl, ethyl, methoxy or ethoxy, so Said methyl, ethyl, methoxy, ethoxy or phenyl is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I , OH, cyano, CF ₃ , COOH, NH ₂ , methyl or ethyl substituent; in some embodiments, R ^2c is each independently selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , methyl, ethyl, methoxy or ethoxy, said methyl, ethyl, methoxy or ethoxy optionally further replaced by 0 to 4 (eg 0, 1, 2, 3 or 4) substituted with a substituent selected from H, F, Cl, Br, I, OH, cyano, _CF3 , COOH, _NH2 , methyl or ethyl; in some embodiments, R ^2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3 to 8 Membered heterocycloalkyl, C _6-10 aryl or 5- to 10-membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, ₁ , oxo, OH, cyano, _CF3 , COOH, _NH2 , -NH(C1- ₄ alkyl), -N(C _1-4 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C _6-10 aryl or 5- to 10-membered heteroaryl substituents, the heterocycloalkyl or heteroaryl contains 1 to 10 4 1, 2, 3, or 4 heteroatoms selected from O, S, N; in some embodiments, R ^2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF _3. Methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, the methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl are optional is further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl , C _1-4 alkoxy substituents; In some embodiments, R ^2d are each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , C _1-4 Alkyl or C _1-4 alkoxy optionally further selected from H, F, Cl, Br by 0 to 4 (eg 0, 1, 2, 3 or 4) , I , oxo, OH, cyano, CF ₃ , COOH, NH ₂ or C _1-6 alkyl substituents; In some embodiments, R ^2d is each independently selected from H, F, Cl, Br, I , oxo, OH, cyano, CF ₃ , methyl or ethyl optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituent; in some embodiments, R ^2d each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, _CF3 , methyl or ethyl, optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) substituted with a substituent selected from H, F, Cl, Br, 1, OH, cyano, _CF3 , COOH, _NH2 , methyl or ethyl; in some embodiments , R ^2A , R ^2B or R ^2C are each independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, 3 to 8 membered heterocycloalkyl, C _6-10 aryl or 5 to 10 Membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) H , F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1- Substituted by substituents of ₆ alkyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl , the heterocycloalkyl group contains 1 to 4 (eg 1, 2, ₃ or 4) heteroatoms selected from O, S, N; In some embodiments, X is selected from bonds, O, - OCH ₂ -, -CH ₂ O-, S or NR ^x ; In some embodiments, X ₃ is selected from a bond or O; In some embodiments, R ^{x is} selected from H, C _1-6 alkyl or C _{3 -6} cycloalkyl, said alkyl or cycloalkyl is optionally further selected by 0, 1, 2, 3 or 4 selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH , NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents; 0 to 4 (eg 0, 1, 2, 3 or 4).

在一些實施方案中，R³ 選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-6 烷基、C_1-6 烷氧基、N(R^3a )₂ 、-(CH₂ )_q -C(=O)C_1-6 烷基、-(CH₂ )_q -C(=O)-3至12元雜環、-(CH₂ )_q -C(=O)-C_3-10 碳環、-(CH₂ )_q -C(=O)-N(R^3a )₂ 、-(CH₂ )_q -N(R^3a )-C(=O)R^3b 、-(CH₂ )_q -3至12元雜環或-(CH₂ )_q -C_3-10 碳環，所述的CH₂ 、烷基、烷氧基、碳環或雜環任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基、-C_1-4 亞烷基-OH、-(CH₂ )_q -C_3-10 碳環、-(CH₂ )_q -3至12元雜環、C_3-6 環烷基、C_1-4 烷氧基、-N(C_1-4 烷基)C(=O)-3至12元雜環或3至12元雜環的取代基所取代，所述的雜環含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子；在一些實施方案中，R³ 選自H或者取代的或者未取代的如下基團之一：甲基、乙基、丙基、異丙基、甲氧基、乙氧基、丙氧基、-N(CH₃ )₂ 、-N(CH₂ CH₃ )₂ 、-(CH₂ )_q -環丙烷、-(CH₂ )_q -環丁烷、-(CH₂ )_q -環戊烷、-(CH₂ )_q -環己烷、-(CH₂ )_q -氮雜環丁烷、-(CH₂ )_q -氧雜環丁烷、-(CH₂ )_q -四氫噻吩、-(CH₂ )_q -四氫呋喃、-(CH₂ )_q -四氫吡咯、-(CH₂ )_q -苯基、-(CH₂ )_q -萘基、-(CH₂ )_q- 吡啶、-(CH₂ )_q -嘧啶、-(CH₂ )_q -吡嗪、-(CH₂ )_q -噻吩、-(CH₂ )_q -呋喃、-(CH₂ )_q -吡咯、-(CH₂ )_q -咪唑、-(CH₂ )_q -咪唑、-(CH₂ )_q -吡唑、-(CH₂ )_q -三氮唑、-(CH₂ )_q -四氮唑、-(CH₂ )_q -呱啶、-(CH₂ )_q -嗎啉、-(CH₂ )_q -四氫吡喃、-(CH₂ )_q -吡咯雙烷、-(CH₂ )_q -1,3-氧氮雜環庚烷、-(CH₂ )_q -2-氧雜-5-氮雜雙環[2.2.1]庚烷、-(CH₂ )_q -呱嗪或-(CH₂ )_q -N(R^3a )-C(=O)R^3b ，當被取代時，任選被0、1、2、3或4個選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基、-C_1-4 亞烷基-OH、-(CH₂ )_q -C_3-6 碳環、-(CH₂ )_q -3至6元雜環、C_3-6 環烷基、C_1-4 烷氧基、-N(C_1-4 烷基)C(=O)-3至12元雜環或3至12元雜環的取代基所取代，所述的雜環含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子；在一些實施方案中，R³ 選自H或者取代的或者未取代的如下基團之一：甲基、乙基、-(CH₂ )_q -四氫吡咯、-(CH₂ )_q -氮雜環丁烷、-N(CH₃ )₂ 或-N(CH₂ CH₃ )₂ ，當被取代時，任選被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基、-C_1-4 亞烷基-OH、-(CH₂ )q -C_3-6 碳環、-(CH₂ )q -3至6元雜環、C_3-6 環烷基或C_1-4 烷氧基，所述的雜環含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子；在一些實施方案中，R^3a 各自獨立地選自H、C_1-4 烷基、-C_1-4 烷基-3至12元雜環，所述的烷基或雜環任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代，所述的雜環含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子；在一些實施方案中，R^3a 選自H、甲基、乙基、丙基或異丙基，所述的甲基、乙基、丙基或異丙基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、氰基、OH、CF₃ 、C_1-4 烷基或C_1-4 烷氧基取代基所取代；在一些實施方案中，兩個R^3a 和與二者直接相連的氮原子一起形成4至8元含氮雜環，所述的含氮雜環任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代，所述的雜環含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子；在一些實施方案中，R^3b 選自H、C_1-6 烷基、C_3-6 環烷基或3至12元雜環，所述的烷基、環烷基或雜環任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代，所述的雜環含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子；在一些實施方案中，R^3b 選自H、甲基、乙基、丙基、異丙基、氮雜環丁烷或氧雜環丁烷，所述的甲基、乙基、丙基、異丙基、氮雜環丁烷或氧雜環丁烷任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、氰基、OH、CF₃ 、C_1-4 烷基或C_1-4 烷氧基取代基所取代；在一些實施方案中，R³ 選自-CH₂ N(CH₃ )₂ 、-CH₂ N(CH₂ CH₃ )₂ 、-N(CH₂ CH₃ )₂ 、-N(CH₃ )₂ 、

、

、

、

、

、

、

、

、

；在一些實施方案中，X₃ -R³ 選自

、

、

、

、

；在一些實施方案中，R⁴ 各自獨立地選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 或C_1-6 烷基，所述的烷基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代；在一些實施方案中，R⁴ 各自獨立地選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 或甲基；在一些實施方案中，n、p、q各自獨立地選自0、1、2、3或4；在一些實施方案中，n選自0；在一些實施方案中，m2選自0、1、2或3。作為本發明的第一種實施方案，上述通式(I)化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中 R¹ 選自-C(=O)-C(R^1a )=C(R^1b )₂ 、

、-S(=O)₂ -C(R^1a )=C(R^1b )₂ 或

； R^1a 各自獨立地選自H、F、Cl、Br、I、氰基、CF₃ 、C_1-4 烷基、C_1-4 烷氧基或-NHC(=O)R^1d ，所述的烷基或烷氧基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代； R^1b 或R^1c 各自獨立地選自H、F、Cl、Br、I、氰基、CF₃ 、C_1-4 烷基、C_1-4 烷氧基、-C(=O)N(R^1d )₂ 、-(CH₂ )_p -N(C_1-4 烷基)₂ 、-(CH₂ )_p NHC(=O)-C_1-4 烷基、-(CH₂ )_p -C_3-10 碳環或-(CH₂ )_p -3至12元雜環，所述的烷基、烷氧基、雜環或碳環任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基、C_1-4 烷氧基、C_3-10 碳環或5至12元雜環的取代基所取代，所述的雜環含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子；作為選擇，R^1a 與任意一個R^1b 形成C_5-10 碳環或5至12元雜環，所述的碳環或雜環任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-N(C_1-4 烷基)₂ 、C_1-4 烷基、C_1-4 烷氧基、C_3-10 碳環基或5至12元雜環基的取代基所取代，所述的雜環基含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子； R^1d 各自獨立地選自H或C_1-4 烷基，所述的烷基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代；環A選自4至12元含氮雜環，所述的含氮雜環選自飽和或部分飽和的如下基團之一：單環、並環、橋環或螺環，所述的含氮雜環、單環、並環、橋環或螺環任選進一步被0至4個（例如0、1、2、3或4個）R^a 取代； R^a 各自獨立地選自H、oxo、F、Cl、Br、I、氰基、C_1-6 烷基或C_1-6 烷氧基，所述的烷基或烷氧基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代； Q、M和與二者直接相連接的原子一起形成C_3-12 碳環或者3至12元的雜環，所述的碳環或者雜環為單環、並環或者螺環，所述的碳環、雜環、單環、並環或者螺環任選進一步被0至5個R² 取代，所述的雜環含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子； R² 各自獨立地選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、-C(=O)-C_1-6 烷基、-C(=O)-C_3-6 環烷基、-C(=O)- 3至8元雜環烷基、-C(=O)-C_6-10 芳基、-C(=O)-5至10元雜芳基、C_1-6 烷基、C_1-6 烷氧基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、烷氧基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-6 烷基、C_2-6 炔基、C_1-6 烷氧基、羥基取代的C_1-6 烷基、C_3-6 環烷基、3至6元雜環烷基、C_6-10 芳基或5至10元雜芳基、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 的取代基所取代，所述的雜環烷基或雜芳基含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子； R^2A 、R^2B 或R^2C 各自獨立地選自H、C_1-6 烷基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-6 烷基、C_2-6 炔基、C_1-6 烷氧基、羥基取代的C_1-6 烷基、C_3-6 環烷基、3至6元雜環烷基的取代基所取代，所述的雜環烷基含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子； X₃ 選自鍵、O、-OCH₂ -、-CH₂ O-、S或NR^x ； R^x 選自H、C_1-6 烷基或C_3-6 環烷基，所述的烷基或環烷基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代； R³ 選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-6 烷基、C_1-6 烷氧基、N(R^3a )₂ 、-(CH₂ )_q -C(=O)C_1-6 烷基、-(CH₂ )_q -C(=O)-3至12元雜環、-(CH₂ )_q -C(=O)-C_3-10 碳環、-(CH₂ )_q -C(=O)-N(R^3a )₂ 、-(CH₂ )_q -N(R^3a )-C(=O)R^3b 、-(CH₂ )_q -3至12元雜環或-(CH₂ )_q -C_3-10 碳環，所述的CH₂ 、烷基、烷氧基、碳環或雜環任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基、-C_1-4 亞烷基-OH、-(CH₂ )_q -C_3-10 碳環、-(CH₂ )_q -3至12元雜環、C_3-6 環烷基、C_1-4 烷氧基、-N(C_1-4 烷基)C(=O)-3至12元雜環或3至12元雜環的取代基所取代，所述的雜環含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子； R^3a 各自獨立地選自H、C_1-4 烷基、-C_1-4 烷基-3至12元雜環，所述的烷基或雜環任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代，所述的雜環含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子；作為選擇，兩個R^3a 和與二者直接相連的氮原子一起形成4至8元含氮雜環，所述的含氮雜環任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代，所述的雜環含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子； R^3b 選自H、C_1-6 烷基、C_3-6 環烷基或3至12元雜環，所述的烷基、環烷基或雜環任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代，所述的雜環含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子； R⁴ 各自獨立地選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 或C_1-6 烷基，所述的烷基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代； n、p、q各自獨立地選自0、1、2、3或4。In some embodiments, R ³ is selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, N( R ^3a ) ₂ , -(CH ₂ ) _q -C(=O)C _1-6 alkyl, -(CH ₂ ) _q -C(=O)-3- to 12-membered heterocycle, -(CH ₂ ) _q -C(=O)-C _3-10 carbocycle, -(CH ₂ ) _q -C(=O)-N(R ^3a ) ₂ , -(CH ₂ ) _q -N(R ^3a )-C(= O)R ^3b , -(CH ₂ ) _q -3- to 12-membered heterocycle or -(CH ₂ ) _q -C _3-10 carbocycle, said CH ₂ , alkyl, alkoxy, carbocycle or heterocycle The ring is optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, _CF3 , COOH, _NH2 , - NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl, -C _1-4 alkylene-OH, -(CH ₂ ) _q -C _{3- 10} carbon ring, -(CH ₂ ) _q -3 to 12 membered heterocycle, C _3-6 cycloalkyl, C _1-4 alkoxy, -N(C _1-4 alkyl)C(=O)- 3- to 12-membered heterocycle or substituents of 3- to 12-membered heterocycle containing 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N ; In some embodiments, R ³ is selected from H or substituted or unsubstituted one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, -N( _CH3 ) ₂ , -N( _CH2CH3 ) ₂ , -( _CH2 ) _q -cyclopropane, -( _CH2 ) _q -cyclobutane, -( _CH2 ₎ _q -cyclopentane, -( _CH2 ) _q -cyclohexane, -( _CH2 ) _q -azetidine, -( _CH2 ) _q -oxetane, -( _CH2 ) _q -tetrahydrothiophene, -( _CH2 ) _q -tetrahydrofuran, -( _CH2 ) _q -tetrahydropyrrole, -( _CH2 ) _q -phenyl, -( _CH2 ) _q -naphthyl, -( _CH2 ) _q- pyridine, -(CH2)q-pyridine ₂ ) _q -pyrimidine, -( _CH2 ) _q -pyrazine, -( _CH2 ) _q -thiophene, -( _CH2 ) _q -furan, -( _CH2 ) _q -pyrrole, -( _CH2 ) _q- Imidazole, -( _CH2 ) _q -imidazole, -( _CH2 ) _q -pyrazole, -( _CH2 ) _q -triazole, -( _CH2 ) _q -tetrazolium, -( _CH2 ) _q- Quaridine, -(CH ₂ ) _q -morpholine, -(CH ₂ ) _q -tetrahydropyran, -( _CH2 ) _q -pyrrolidiidine, -( _CH2 ) _q -1,3-oxazepane, -( _CH2 ) _q -2-oxa- 5-azabicyclo[2.2.1]heptane, -( _CH2 ) _q -oxazine or -( _CH2 ) _q -N( ^R3a )-C(=O) ^R3b , when substituted, either Selected from 0, 1, 2, 3 or 4 selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl, -C _1-4 alkylene-OH, -(CH ₂ ) _q -C _3-6 carbocycle, -(CH ₂ ) _q -3 to 6 membered heterocycle, _C3-6 cycloalkyl, _C1-4 alkoxy, -N( _C1-4 alkyl)C(=O)-3 to 12 membered heterocycle or 3 to 12 membered heterocycle substituted by substituents of a membered heterocyclic ring containing 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; in some embodiments, R ³ is selected From H or substituted or unsubstituted one of the following: methyl, ethyl, -( _CH2 ) _q -tetrahydropyrrole, -( _CH2 ) _q -azetidine, -N( _CH3 ) ₂ or -N(CH ₂ CH ₃ ) ₂ , when substituted, optionally by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl, -C _1-4 alkylene-OH, -(CH ₂ )q-C _3-6 carbocycle, -(CH ₂ )q -3- to 6-membered heterocycle, C _3-6 cycloalkyl or C _1-4 alkoxy, The heterocycle contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; in some embodiments, R ^3a is each independently selected from H, C _{1- 4} alkyl, -C _1-4 alkyl-3- to 12-membered heterocycle, said alkyl or heterocycle is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 Alkyl or C _1-4 alkoxy substituents, the heterocycle contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; in some In an embodiment, R ^3a is selected from H, methyl, ethyl, propyl or isopropyl, and said methyl, ethyl, propyl or isopropyl is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, cyano, OH, CF ₃ , C _1-4 alkyl or C _1-4 alkoxy In some embodiments, the two R ^3a and the nitrogen atom directly attached to the two together form a 4- to 8-membered nitrogen-containing heterocycle optionally further substituted by 0-4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituent, the heterocycle contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; In some embodiments, R ^3b is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl or 3- to 12-membered heterocycle, the The alkyl, cycloalkyl or heterocycle is optionally further selected from 0 to 4 (eg 0, 1, ₂ , 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituent, the Said heterocycle contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; In some embodiments, R ^3b is selected from H, methyl, ethyl, propyl base, isopropyl, azetidine or oxetane, the methyl, ethyl, propyl, isopropyl, azetidine or oxetane is optionally further modified by O to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, cyano, OH, _CF3 , _C1-4alkyl or _C1-4alkoxy Substituents substituted; In some embodiments, R ³ is selected from -CH ₂ N(CH ₃ ) ₂ , -CH ₂ N(CH ₂ CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , -N( CH ₃ ) ₂ ,

,

; In some embodiments, X ₃ -R ³ is selected from

,

; In some embodiments, R ⁴ is each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ or C _1-6 alkyl, which is optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, ₁ , oxo, OH, cyano, _CF3 , COOH, _NH2 , -NH(C1- ₄ alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituent; In some embodiments, R ⁴ are each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF, or methyl; in some embodiments, n, p, q are each independently selected from 0, 1, 2, ₃ , or 4; in In some embodiments, n is selected from 0; in some embodiments, m2 is selected from 0, 1, 2, or 3. As the first embodiment of the present invention, the above-mentioned compound of general formula (I) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein R ¹ is selected Since -C(=O)-C(R ^1a )=C(R ^1b ) ₂ ,

, -S(=O) ₂ -C(R ^1a )=C(R ^1b ) ₂ or

; R ^1a is each independently selected from H, F, Cl, Br, I, cyano, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy or -NHC(=O)R ^1d , the The alkyl or alkoxy group is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, _CF3 , COOH, Substituents of NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy; R ^1b or R ^1c is each independently selected from H, F, Cl, Br, I, cyano, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy, -C(=O)N(R ^1d ) ₂ , -(CH ₂ ) _p -N(C _1-4 alkyl) ₂ , -(CH ₂ ) _p NHC(=O)-C _1-4 alkyl, -(CH ₂ ) _p -C _3-10 carbocycle or -(CH ₂ ) _p -3 to 12 membered heterocycle, said alkyl, alkoxy, heterocycle or carbocycle optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4 ) is selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-10 carbocyclic or 5- to 12-membered heterocycle substituents, the heterocycle contains 1 to 4 (eg 1, 2 , 3 or 4) heteroatoms selected from O, S, N; alternatively, R ^1a and any one R ^1b form a C _5-10 carbocycle or a 5- to 12-membered heterocycle, the carbocycle or heterocycle optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, _CF3 , COOH, _NH2 , -N (C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-10 carbocyclic or 5- to 12-membered heterocyclic substituents, the heterocyclic The cyclic group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; R ^1d is each independently selected from H or C _1-4 alkyl, said alkyl optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, 1, OH, cyano, _CF3 , COOH, _NH2 , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituent; Ring A is selected from 4- to 12-membered nitrogen-containing hetero Ring, the nitrogen-containing heterocycle is selected from one of the following saturated or partially saturated groups: monocyclic, paracyclic, bridged or spirocyclic, the nitrogen-containing heterocycle, monocyclic, paracyclic, bridged or the spiro ring is optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R ^a ; R ^a is independently selected from H, oxo, F, Cl, Br, I, cyano, C _1-6 alkyl or C _1-6 alkoxy, said alkyl or alkoxy optionally further replaced by 0 to 4 (eg 0, 1, 2 , 3 or 4) are substituted with substituents selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy ; Q, M and the atoms directly connected to the two together form a C _3-12 carbocyclic ring or a 3- to 12-membered heterocyclic ring, the carbocyclic or heterocyclic ring is a monocyclic ring, a ring or a spirocyclic ring, the The carbocyclic, heterocyclic, monocyclic, paracyclic or spirocyclic ring is optionally further substituted by 0 to 5 R ² , and the heterocyclic ring contains 1 to 4 (eg 1, 2, 3 or 4) selected from Heteroatoms of O, S, N; R ² is each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, -C(=O)NR ^2A R ^2B , - NR ^2A C(=O)R ^2C , -C(=O)-C _1-6 alkyl, -C(=O)-C _3-6 cycloalkyl, -C(=O)- 3- to 8-membered Heterocycloalkyl, -C(=O)-C _6-10 aryl, -C(=O)-5 to 10-membered heteroaryl, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _6-10 -membered aryl or 5- to 10-membered heteroaryl, the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, Aryl or heteroaryl is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, _CF3 , COOH , NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxyl Substituted C _1-6 alkyl, C _3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C _6-10 aryl or 5 to 10 membered heteroaryl, -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C Substituents are substituted, and the heterocycloalkyl or heteroaryl group contains 1 to 4 (for example, 1, 2, 3 or 4) selected from O, S , a heteroatom of N; R ^2A , R ^2B or R ^2C are each independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _6-10 aryl or a 5- to 10-membered heteroaryl group, the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4 a) is selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl substituted by the substituent, the heterocycloalkyl contains 1 to 4 ( For example 1, 2, ₃ or 4) heteroatoms selected from O, S, N; X is selected from bonds, O, -OCH ₂ -, -CH ₂ O-, S or NR ^x ; R ^{x is} selected from H , C _1-6 alkyl or C _3-6 cycloalkyl, said alkyl or cycloalkyl is optionally further selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituent; R ³ is selected from H, F, Cl , Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, N(R ^3a ) ₂ , -(CH ₂ ) _q -C(= O)C _1-6 alkyl, -(CH ₂ ) _q -C(=O)-3 to 12-membered heterocycle, -(CH ₂ ) _q -C(=O)-C _3-10 carbocycle, - (CH ₂ ) _q -C(=O)-N(R ^3a ) ₂ , -(CH ₂ ) _q -N(R ^3a )-C(=O)R ^3b , -(CH ₂ ) _q -3 to 12 Member heterocycle or -(CH ₂ ) _q -C _3-10 carbocycle, said CH ₂ , alkyl, alkoxy, carbocycle or heterocycle is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _{1 -4} alkyl) ₂ , C _1-4 alkyl, -C _1-4 alkylene-OH, -(CH ₂ ) _q -C _3-10 carbocycle, -(CH ₂ ) _q -3 to 12 membered Substitution of heterocycle, _{C3-6cycloalkyl} , _{C1-4alkoxy, -N(C1-4alkyl} ₎ C(=O)-3- to 12-membered heterocycle or 3- to 12-membered heterocycle is substituted by a base, and the heterocycle contains 1 to 4 (for example, 1, 2, 3 or 4) heteroatoms selected from O, S, N; R ^3a is independently selected from H, C _1-4 alkane base, -C _1-4 alkyl-3- to 12-membered heterocycle, the alkyl or heterocycle is optionally further selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents, the heterocycle contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; alternatively, two The R ^3a and the nitrogen atom directly attached to both form together a 4- to 8-membered nitrogen-containing heterocycle optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4 ) is selected from H, F, Cl, Br, I, OH, cyano, _CF3 , COOH, _NH2 , -N H(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituent, the heterocycle contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; R ^3b is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl or 3 to 12 membered heteroatoms Ring, said alkyl, cycloalkyl or heterocycle optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano Substituents of radical, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituted, the heterocycle contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; R ⁴ are each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, _CF3 or _C1-6 alkyl optionally further selected from H, F by 0 to 4 (eg 0, 1, 2, 3 or 4) , Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkane substituted by a substituent of C 1-4 alkoxy group or C _1-4 alkoxy group; n, p and q are each independently selected from 0, 1, 2, 3 or 4.

作為本發明的第二種實施方案，下述通式(Ia)或(Ib)化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中

(Ia)，

(Ib) 環B選自非芳香4至7元雜環，所述的雜環含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子； X₁ 選自N； R^2a 選自H、COOH、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、-C(=O)-C_1-6 烷基、-C(=O)- C_3-6 環烷基、-C(=O)- 3至8元雜環烷基、-C(=O)-C_6-10 芳基、-C(=O)- 5至10元雜芳基、C_1-6 烷基、C_1-6 烷氧基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、烷氧基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、C_1-6 烷基、C_2-6 炔基、C_1-6 烷氧基、羥基取代的C_1-6 烷基、C_3-6 環烷基、3至6元雜環烷基、C_6-10 芳基或5至10元雜芳基的取代基所取代，所述的雜環烷基或雜芳基含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子； R^2b 各自獨立地選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH或C_1-6 烷基，所述的烷基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-6 烷基、C_2-6 炔基或C_1-6 烷氧基的取代基所取代；環C和環D一起形成C_6-12 碳環並環或5至12元雜環並環，所述的雜環並環含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子； R^2c 、R^2d 各自獨立地選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、COOH、-C(=O)-C_1-6 烷基、-C(=O)-C_3-6 環烷基、-C(=O)-C_6-10 芳基、-C(=O)- 5至10元雜芳基、C_1-6 烷基、C_1-6 烷氧基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、烷氧基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、C_1-6 烷基、C_2-6 炔基、C_1-6 烷氧基、羥基取代的C_1-6 烷基、C_3-6 環烷基、3至6元雜環烷基、C_6-10 芳基或5至10元雜芳基的取代基所取代，所述的雜環烷基或雜芳基含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子； R^2A 、R^2B 或R^2C 各自獨立地選自H、C_1-6 烷基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-6 烷基、C_2-6 炔基、C_1-6 烷氧基、羥基取代的C_1-6 烷基、C_3-6 環烷基、3至6元雜環烷基的取代基所取代，所述的雜環烷基含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子； m1選自0、1、2、3或4； m2、m3各自獨立地選自0、1、2、3或4，且m2+m3≤5；其餘基團的定義與第一種實施方案相同。作為本發明的第三種實施方案，上述通式(Ia)或(Ib)化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中 R^1c 選自H、F、Cl、Br、I、氰基、CF₃ 、C_1-4 烷基或C_1-4 烷氧基，所述的烷基或烷氧基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代；環A選自4至9元含氮雜環，所述的含氮雜環選自飽和或部分飽和如下結構之一：單環、並環、橋環或螺環，所述的含氮雜環任選進一步被0至4個（例如0、1、2、3或4個）R^a 取代基所取代； R^a 各自獨立地選自H、oxo、F、Cl、Br、I、氰基、C_1-4 烷基或C_1-4 烷氧基，所述的烷基或烷氧基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代；其餘基團的定義與第二種實施方案相同。As a second embodiment of the present invention, a compound of the following general formula (Ia) or (Ib) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof ,in

(Ia),

(Ib) Ring B is selected from non-aromatic 4- to 7-membered heterocycles containing 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; X ₁ is selected from N; R ^2a is selected from H, COOH, -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , -C(=O)-C _1-6 alkyl, -C (=O)-C _3-6 cycloalkyl, -C(=O)- 3- to 8-membered heterocycloalkyl, -C(=O)-C _6-10 aryl, -C(=O)- 5- to 10-membered heteroaryl, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _6-10 aryl, or 5 to 10 A membered heteroaryl group, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4 ) is selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxy substituted C _{1 -6} alkyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C _6-10 aryl or 5- to 10-membered heteroaryl substituent, the heterocycloalkyl or Heteroaryl groups contain 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; each R ^2b is independently selected from H, F, Cl, Br, I, oxo, OH , cyano, CF ₃ , COOH or C _1-6 alkyl optionally further selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkynyl or C _1-6 alkoxy substituent; ring C and ring D together form a C _6-12 carbocyclic ring or a 5- to 12-membered heterocyclic ring, the heterocyclic ring The ring contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; R ^2c , R ^2d are each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , COOH, -C(=O)-C _1-6 alkyl, -C(= O)-C _3-6 cycloalkyl, -C(=O)-C _6-10 aryl, -C(=O)- 5- to 10-membered heteroaryl, C _1-6 alkyl, C _{1- 6} -alkoxy, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _6-10 -membered aryl or 5- to 10-membered heteroaryl, the alkyl, alkoxy, cycloalkyl , heterocycloalkyl, aryl or Heteroaryl is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) H, F, Cl, Br, I, oxo, OH, cyano, _CF3 , COOH, _NH2 , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , C _1-6 Alkyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C _6-10 aryl substituted by substituents of 5- to 10-membered heteroaryl groups, the heterocycloalkyl or heteroaryl groups contain 1 to 4 (eg 1, 2, 3 or 4) selected from O, S, N Heteroatom; R ^2A , R ^2B or R ^2C are each independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _6-10 aryl, or 5 to 10 membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) From H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C Substituents for _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl substituted, the heterocycloalkyl group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; m1 is selected from 0, 1, 2, 3 or 4; m2 and m3 are each independently selected from 0, 1, 2, 3 or 4, and m2+m3≤5; the definitions of the remaining groups are the same as in the first embodiment. As a third embodiment of the present invention, the above-mentioned compound of general formula (Ia) or (Ib) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, wherein R ^1c is selected from H, F, Cl, Br, I, cyano, CF ₃ , C _1-4 alkyl or C _1-4 alkoxy, and the alkyl or alkoxy is optionally further modified by O to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, 1, oxo, OH, cyano, _CF3 , COOH, _NH2 , -NH( _C1-4 Alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents; Ring A is selected from 4- to 9-membered nitrogen-containing heterocycles, the Said nitrogen-containing heterocyclic ring is selected from one of the following saturated or partially saturated structures: monocyclic, parallel, bridged or spirocyclic, and said nitrogen-containing heterocyclic ring is optionally further replaced by 0 to 4 (such as 0, 1, 2, 3 or 4) R ^a substituents are substituted; R ^a is independently selected from H, oxo, F, Cl, Br, I, cyano, C _1-4 alkyl or C _1-4 alkoxy , the alkyl or alkoxy group is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents; the definitions of the remaining groups are the same as in the second embodiment.

作為本發明的第四種實施方案，上述通式(Ia)或(Ib)化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中環A選自未被取代的或者取代的

、

或

，當被取代時，任選進一步被0至4個（例如0、1、2、3或4個）R^a 取代基所取代； R^a 各自獨立地選自H、oxo、F、Cl、Br、I、氰基、C_1-4 烷基或C_1-4 烷氧基，所述的烷基或烷氧基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代；其餘基團的定義與第三種實施方案相同。As a fourth embodiment of the present invention, the above-mentioned compound of general formula (Ia) or (Ib) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, wherein Ring A is selected from unsubstituted or substituted

,

or

, when substituted, optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^a substituent; R ^a is independently selected from H, oxo, F, Cl, Br , I, cyano, C _1-4 alkyl or C _1-4 alkoxy, said alkyl or alkoxy optionally further replaced by 0 to 4 (eg 0, 1, 2, 3 or 4 ) is substituted with a substituent selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy; The definitions are the same as in the third embodiment.

作為本發明的第五種實施方案，上述通式(Ia)或(Ib)化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中環B選自氮雜環丁烷、氮雜環戊烷或呱啶；或者環B選自咪唑烷； R^2a 選自H、COOH、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、-C(=O)-C_1-4 烷基、-C(=O)-苯基、-C(=O)-5至6元雜芳基、C_1-4 烷基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、- C_1-6 烷基、C_2-6 炔基、C_1-6 烷氧基、羥基取代的C_1-6 烷基、C_3-6 環烷基、3至6元雜環烷基、C_6-10 芳基或5至10元雜芳基的取代基所取代，所述的雜環烷基或雜芳基含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子；環D選自苯環、吡啶、噠嗪或嘧啶；環C選自C_4-6 碳環；或者環C選自4至6元雜環，所述的雜環含有1至3個選自O、S、N的雜原子； R^2c 各自獨立地選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、C_1-4 烷基、C_1-4 烷氧基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、烷氧基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、C_1-6 烷基、C_2-6 炔基、C_1-6 烷氧基、羥基取代的C_1-6 烷基、C_3-6 環烷基、3至6元雜環烷基、C_6-10 芳基或5至10元雜芳基的取代基所取代，所述的雜環烷基或雜芳基含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子； R^2A 、R^2B 或R^2C 各自獨立地選自H、C_1-6 烷基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-6 烷基、C_2-6 炔基、C_1-6 烷氧基、羥基取代的C_1-6 烷基、C_3-6 環烷基、3至6元雜環烷基的取代基所取代，所述的雜環烷基含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子； R^2d 各自獨立地選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、C_1-4 烷基或C_1-4 烷氧基，所述的烷基或烷氧基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 或C_1-6 烷基的取代基所取代；其餘基團的定義與第二、三或四種實施方案中任意一種相同。As a fifth embodiment of the present invention, the above-mentioned compound of general formula (Ia) or (Ib) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, wherein ring B is selected from azetidine, azetidine or oxidine; or ring B is selected from imidazolidine; R ^2a is selected from H, COOH, -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , -C(=O)-C _1-4 alkyl, -C(=O)-phenyl, -C(=O)-5- to 6-membered heteroaryl, C _{1- 4} -alkyl, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _6-10 -membered aryl or 5- to 10-membered heteroaryl, the alkyl, cycloalkyl, heterocycloalkyl , aryl or heteroaryl optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, _CF3 , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , - C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C _6-10 aryl or 5- to 10-membered heteroaryl substituent, the heterocycloalkyl or heteroaryl contains 1 to 4 (eg 1, 2, 3 or 4) selected from O , S, N heteroatoms; Ring D is selected from benzene ring, pyridine, pyridazine or pyrimidine; Ring C is selected from C _4-6 carbocycle; Or Ring C is selected from 4-6 membered heterocycle, the heterocycle Contains 1 to 3 heteroatoms selected from O, S, N; R ^2c is each independently selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _{6- 10} -aryl or 5- to 10-membered heteroaryl, the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally further replaced by 0 to 4 (eg 0, 1 , 2, 3 or 4) selected from H, F, Cl, Br, 1, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -C(=O)NR ^2A R ^2B , -NR ^2A C (=O)R ^2C , C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkyl, C _3-6 cycloalkyl, 3 to 6 substituted by substituents of membered heterocycloalkyl, C _6-10 aryl or 5 to 10 membered heteroaryl, said heterocycloalkyl or heteroaryl containing 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; R ^2A , R ^2B or R ^2C are each independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 8-membered Heterocycloalkyl, C _6-10 aryl or 5- to 10-membered heteroaryl, the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally further replaced by 0 to 4 ( For example, 0, 1, 2, 3 or 4) are selected from H, F, Cl, Br, 1, oxo, OH, cyano, _CF3 , COOH, _NH2 , -NH( _C1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkyl, C _3-6 cycloalkane substituted by substituents of 3- to 6-membered heterocycloalkyl groups, the heterocycloalkyl groups contain 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; R ^2d is each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , C _1-4 alkyl or C _1-4 alkoxy, said alkyl or alkoxy The group is optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, 1, oxo, OH, cyano, _CF3 , COOH, _NH2 or C Substituents of _1-6 alkyl groups are substituted; the definitions of the remaining groups are the same as those of any one of the second, third or fourth embodiments.

作為本發明的第六種實施方案，上述通式(Ia)或(Ib)化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中 R¹ 選自-C(=O)-C(R^1a )=C(R^1b )₂ ； R^1a 選自H 、F或C_1-4 烷基，所述的烷基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、氰基、OH、CF₃ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代； R^1b 各自獨立地選自H、C_1-4 烷基或-(CH₂ )_p -3至6元雜環，所述的烷基或雜環任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基、C_1-4 烷氧基、C_3-6 碳環或3至6元雜環的取代基所取代，所述的雜環含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子；其餘基團的定義與第二、三、四或五種實施方案中任意一種相同。As the sixth embodiment of the present invention, the above-mentioned compound of general formula (Ia) or (Ib) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, Wherein R ¹ is selected from -C(=O)-C(R ^1a )=C(R ^1b ) ₂ ; R ^1a is selected from H , F or C _1-4 alkyl, and the alkyl is optionally further modified by O to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, cyano, OH, _CF3 , _C1-4alkyl or _C1-4alkoxy R ^1b is independently selected from H, C _1-4 alkyl or -(CH ₂ ) _p -3 to 6-membered heterocycle, and the alkyl or heterocycle is optionally further substituted by 0 to 6 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, _CF3 , COOH, _NH2 , -NH( _C1-4alkane base), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocyclic or 3- to 6-membered heterocyclic substituents, the Said heterocycle contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; the remaining groups are as defined in any of the second, third, fourth or fifth embodiments kind of the same.

作為本發明的第七種實施方案，上述通式(Ia)或(Ib)化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中 R^1a 選自H、F、甲基、乙基、丙基或異丙基，所述的甲基、乙基、丙基或異丙基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、氰基、OH、CF₃ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代； R^1b 各自獨立地選自H、甲基、乙基、丙基、異丙基、-CH₂ -4元含氮雜環、-CH₂ -5元含氮雜環、-CH₂ -6元含氮雜環、4元含氮雜環、5元含氮雜環或6元含氮雜環，所述的甲基、乙基、丙基、異丙基或含氮雜環任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代； X₃ 選自鍵或O； R^2a 選自H或者取代的或者未被取代的如下基團之一：-C(=O)NH₂ 、-NHC(=O)H、-C(=O)NH-CH₃ 、-NHC(=O)-CH₃ 、-C(=O)NH-CH₂ CH₃ 、-NHC(=O)CH₂ CH₃ 、-C(=O)N(CH₃ )₂ 、-C(=O)N(CH₂ CH₃ )₂ 、-C(=O)-CH₃ 、-C(=O)-CH₂ CH₃ 、-C(=O)-CH₂ CH₂ CH₃ 、-C(=O)-CH(CH₃ )₂ 、-C(=O)NH-苯基、-NHC(=O)-苯基、-C(=O)-苯基、-C(=O)-吡啶、-C(=O)-噻吩、-C(=O)-呋喃、-C(=O)-吡咯、甲基、乙基、異丙基、丙基、環丙基、環丁基、環戊基、環己基、苯基、萘基、噻吩基、呋喃基、吡咯基、噻唑基、異噻唑基、噁唑基、異噁唑基、咪唑基、吡唑基、苯並咪唑基、苯並吡唑基或吡啶基，當被取代時，任選被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、-C(=O)NH₂ 、-NHC(=O)H、-C(=O)NH-CH₃ 、-NHC(=O)-CH₃ 、-C(=O)NH-CH₂ CH₃ 、-NHC(=O)CH₂ CH₃ 、-C(=O)N(CH₃ )₂ 、-C(=O)N(CH₂ CH₃ )₂ 、-C(=O)NH-苯基、-NHC(=O)-苯基、C_1-4 烷基、C_1-4 烷氧基或C_2-4 炔基的取代基所取代； R^2b 各自獨立地選自H、F、oxo、OH、氰基、CF₃ 、甲基或乙基，所述的甲基或乙基任選被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代；環C和環D一起形成的並環選自

或

；或者環C和環D一起形成的並環選自

、

或

； R^2c 各自獨立地選自H、F、Cl、Br、I、OH、氰基、CF₃ 、-C(=O)NH₂ 、-NHC(=O)H、-C(=O)NH-CH₃ 、-NHC(=O)-CH₃ 、-C(=O)NH-CH₂ CH₃ 、-NHC(=O)CH₂ CH₃ 、-C(=O)N(CH₃ )₂ 、- -C(=O)N(CH₂ CH₃ )₂ 、-C(=O)NH-苯基、-NHC(=O)-苯基、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基、乙氧基或苯基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-4 烷基、C_1-4 烷氧基取代基所取代； R^2d 各自獨立地選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、甲基或乙基，所述的甲基或乙基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代； R³ 選自H或者取代的或者未取代的如下基團之一：甲基、乙基、丙基、異丙基、甲氧基、乙氧基、丙氧基、-N(CH₃ )₂ 、-N(CH₂ CH₃ )₂ 、-(CH₂ )_q -環丙烷、-(CH₂ )_q -環丁烷、-(CH₂ )_q -環戊烷、-(CH₂ )_q -環己烷、-(CH₂ )_q -氮雜環丁烷、-(CH₂ )_q -氧雜環丁烷、-(CH₂ )_q -四氫噻吩、-(CH₂ )_q -四氫呋喃、-(CH₂ )_q -四氫吡咯、-(CH₂ )_q -苯基、-(CH₂ )_q -萘基、-(CH₂ )_q- 吡啶、-(CH₂ )_q -嘧啶、-(CH₂ )_q -吡嗪、-(CH₂ )_q -噻吩、-(CH₂ )_q -呋喃、-(CH₂ )_q -吡咯、-(CH₂ )_q -咪唑、-(CH₂ )_q -咪唑、-(CH₂ )_q -吡唑、-(CH₂ )_q -三氮唑、-(CH₂ )_q -四氮唑、-(CH₂ )_q -呱啶、-(CH₂ )_q -嗎啉、-(CH₂ )_q -四氫吡喃、-(CH₂ )_q -吡咯雙烷、-(CH₂ )_q -1,3-氧氮雜環庚烷、-(CH₂ )_q -2-氧雜-5-氮雜雙環[2.2.1]庚烷、-(CH₂ )_q -呱嗪或-(CH₂ )_q -N(R^3a )-C(=O)R^3b ，當被取代時，任選被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基、-C_1-4 亞烷基-OH、-(CH₂ )_q -C_3-6 碳環、-(CH₂ )_q -3至6元雜環、C_3-6 環烷基、C_1-4 烷氧基、-N(C_1-4 烷基)C(=O)-3至12元雜環或3至12元雜環的取代基所取代，所述的雜環含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子； R^3a 選自H、甲基、乙基、丙基或異丙基，所述的甲基、乙基、丙基或異丙基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、氰基、OH、CF₃ 、C_1-4 烷基或C_1-4 烷氧基取代基所取代； R^3b 選自H、甲基、乙基、丙基、異丙基、氮雜環丁烷或氧雜環丁烷，所述的甲基、乙基、丙基、異丙基、氮雜環丁烷或氧雜環丁烷任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、氰基、OH、CF₃ 、C_1-4 烷基或C_1-4 烷氧基取代基所取代； R⁴ 各自獨立地選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 或甲基； q選自0、1、2、3或4；其餘基團的定義與第二、三、四、五或六種實施方案中任意一種相同。As the seventh embodiment of the present invention, the above-mentioned compound of general formula (Ia) or (Ib) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, wherein R ^1a is selected from H, F, methyl, ethyl, propyl or isopropyl, and said methyl, ethyl, propyl or isopropyl is optionally further substituted by 0 to 4 (eg 0, 1 _R _1b _{_} ^_ Each is independently selected from H, methyl, ethyl, propyl, isopropyl, -CH ₂ -4-membered nitrogen-containing heterocycle, -CH ₂ -5-membered nitrogen-containing heterocycle, -CH ₂ -6-membered nitrogen-containing heterocycle Heterocycle, 4-membered nitrogen-containing heterocycle, 5-membered nitrogen-containing heterocycle or 6-membered nitrogen-containing heterocycle, the methyl, ethyl, propyl, isopropyl or nitrogen-containing heterocycle is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) are selected from H, F, Cl, Br, I, oxo, OH, cyano, _CF3 , COOH, _NH2 , -NH( _C1-4alkane base), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituent; X ₃ is selected from bond or O; R ^2a is selected from H or substituted or unsubstituted one of the following groups: -C(=O)NH ₂ , -NHC(=O)H, -C(=O)NH-CH ₃ , -NHC(=O)-CH ₃ , -C(=O)NH-CH ₂ CH ₃ , -NHC(=O)CH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)N(CH ₂ CH ₃ ) ₂ , -C(=O)-CH ₃ , -C(=O)-CH ₂ CH ₃ , -C(=O)-CH ₂ CH ₂ CH ₃ , -C(=O)-CH(CH ₃ ) ₂ , -C(=O)NH-phenyl, -NHC(=O)-phenyl, -C(=O)-phenyl, -C(=O)-pyridine, -C(=O)-thiophene , -C(=O)-furan, -C(=O)-pyrrole, methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, benzimidazolyl, benzopyrazolyl or pyridyl, when When substituted, optionally 0 to 4 (eg 0, 1, 2, 3 or 4) are selected from H, F, Cl, Br, I, OH, cyano, _CF3 , -C(=O) NH ₂ , -NHC(=O)H, -C(=O)NH-CH ₃ , -NHC(=O)-CH ₃ , -C(=O)NH-CH ₂ CH ₃ , -NHC(=O )CH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)N(CH ₂ CH ₃ ) ₂ , -C(=O)NH-phenyl, -NHC(=O)-phenyl, C _1-4 alkyl, C _1-4 alkoxy or C _2-4 alkynyl substituent; R ^2b Each is independently selected from H, F, oxo, OH, cyano, CF ₃ , methyl or ethyl, said methyl or ethyl optionally being separated by 0 to 4 (eg 0, 1, 2, 3 or 4) substituted with substituents selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy; ring C The concatenated ring formed together with ring D is selected from

or

; Or ring C and ring D formed together and the ring is selected from

,

or

; R ^2c is each independently selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , -C(=O)NH ₂ , -NHC(=O)H, -C(=O)NH -CH ₃ , -NHC(=O)-CH ₃ , -C(=O)NH-CH ₂ CH ₃ , -NHC(=O)CH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)N(CH ₂ CH ₃ ) ₂ , -C(=O)NH-phenyl, -NHC(=O)-phenyl, methyl, ethyl, methoxy or ethoxy group, the methyl, ethyl, methoxy, ethoxy or phenyl is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy substituent; R ^2d is independently selected from H, F, Cl, Br , I, oxo, OH, cyano, _CF3 , methyl or ethyl optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituent; R ³ is selected from H or substituted one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, -N(CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , -( _CH2 ) _q -cyclopropane, -( _CH2 ) _q -cyclobutane, -( _CH2 ) _q -cyclopentane, -( _CH2 ) _q -cyclohexane, -(CH2) ₂ ) _q -azetidine, -( _CH2 ) _q -oxetane, -( _CH2 ) _q -tetrahydrothiophene, -( _CH2 ) _q -tetrahydrofuran, -( _CH2 ) _q- Tetrahydropyrrole, -( _CH2 ) _q -phenyl, -( _CH2 ) _q -naphthyl, -( _CH2 ) _q- pyridine, -( _CH2 ) _q -pyrimidine, -( _CH2 ) _q -pyridine oxazine, -( _CH2 ) _q -thiophene, -( _CH2 ) _q -furan, -( _CH2 ) _q -pyrrole, -( _CH2 ) _q -imidazole, -( _CH2 ) _q -imidazole, -(CH2)q-imidazole ₂ ) _q -pyrazole, -(CH ₂ ) _q -triazole, -(CH ₂ ) _q -tetrazolium, -(CH ₂ ) _q -pyridine, -(CH ₂ ) _q -morpholine, - (CH ₂ ) _q -tetrahydropyran, -(CH ₂ ) _q -pyrrolidiidine, -(CH ₂ ) _q -1,3-oxazepane, -(CH ₂ ) _q -2-oxo Hetero-5-azabicyclo[2.2.1]heptane, - ( _CH2 ) _q -oxazine or -( _CH2 ) _q -N( ^R3a )-C(=O) ^R3b , when substituted, optionally by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl, -C _1-4 alkylene-OH, -(CH ₂ ) _q -C _3-6 carbocycle, -(CH ₂ ) _q -3- to 6-membered heterocycle , C _3-6 cycloalkyl, C _1-4 alkoxy, -N(C _1-4 alkyl) C(=O)-3- to 12-membered heterocycle or 3- to 12-membered heterocycle substituents Substituted, the heterocycle contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; R ^3a is selected from H, methyl, ethyl, propyl or iso propyl, said methyl, ethyl, propyl or isopropyl optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) from H, F, Cl, Br, I , cyano, OH, CF ₃ , C _1-4 alkyl or C _1-4 alkoxy substituent; R ^3b is selected from H, methyl, ethyl, propyl, isopropyl, nitrogen heterocycle Butane or oxetane, the methyl, ethyl, propyl, isopropyl, azetidine or oxetane is optionally further separated by 0 to 4 (eg 0, 1, 2, 3 or 4) are selected from H, F, Cl, Br, I, cyano, OH, CF ₃ , C _1-4 alkyl or C _1-4 alkoxy substituents; R ⁴ are each independently q is selected from H, F, Cl, Br, I, oxo, OH, cyano, CF or methyl; q is selected from 0, 1, 2, ₃ or 4; the definitions of the remaining groups are the same as those of the second, third, Any of the four, five or six embodiments are the same.

作為本發明的第八種實施方案，上述通式(Ia)或(Ib)化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中 R¹ 選自

、

；環A選自取代的或者未取代的如下基團之一：

、

或

，當被取代時，任選被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、氰基、OH、CF₃ 、甲基、乙基、丙基、異丙基或CH₂ CN的取代基所取代；環B選自呱啶；或者

選自

、

或

； R^2a 選自H或者取代的或者未被取代的如下基團之一：-C(=O)NH₂ 、-NHC(=O)H、-C(=O)NH-CH₃ 、-NHC(=O)-CH₃ 、-C(=O)NH-CH₂ CH₃ 、-NHC(=O)CH₂ CH₃ 、-C(=O)N(CH₃ )₂ 、-C(=O)N(CH₂ CH₃ )₂ 、-C(=O)-CH₃ 、-C(=O)-CH₂ CH₃ 、-C(=O)-CH₂ CH₂ CH₃ 、-C(=O)-CH(CH₃ )₂ 、-C(=O)NH-苯基、-NHC(=O)-苯基、-C(=O)-苯基、-C(=O)-吡啶、-C(=O)-噻吩、-C(=O)-呋喃、-C(=O)-吡咯、甲基、乙基、異丙基、丙基、苯基、萘基、噻吩基、呋喃基、吡咯基或吡啶基，當被取代時，任選被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、-C(=O)NH₂ 、-NHC(=O)H、-C(=O)NH-CH₃ 、-NHC(=O)-CH₃ 、-C(=O)NH-CH₂ CH₃ 、-NHC(=O)CH₂ CH₃ 、-C(=O)N(CH₃ )₂ 、-C(=O)N(CH₂ CH₃ )₂ 、-C(=O)NH-苯基、-NHC(=O)-苯基、甲基或乙基的取代基所取代； R^2b 各自獨立地選自H、F、oxo、OH、氰基、CF₃ 、甲基或乙基，所述的甲基或乙基任選被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、甲基或乙基的取代基所取代； R^2c 各自獨立地選自H、F、Cl、Br、I、OH、氰基、CF₃ 、-C(=O)NH₂ 、-NHC(=O)H、-C(=O)NH-CH₃ 、-NHC(=O)-CH₃ 、-C(=O)NH-CH₂ CH₃ 、-NHC(=O)CH₂ CH₃ 、-C(=O)N(CH₃ )₂ 、-C(=O)N(CH₂ CH₃ )₂ 、-C(=O)NH-苯基、-NHC(=O)-苯基、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基、乙氧基或苯基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、甲基或乙基的取代基所取代； R^2d 各自獨立地選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、甲基或乙基，所述的甲基或乙基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、甲基或乙基的取代基所取代； R³ 選自H或者取代的或者未取代的如下基團之一：甲基、乙基、-(CH₂ )_q -四氫吡咯、-(CH₂ )_q -氮雜環丁烷、-N(CH₃ )₂ 或-N(CH₂ CH₃ )₂ ，當被取代時，任選被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基、-C_1-4 亞烷基-OH、-(CH₂ )q -C_3-6 碳環、-(CH₂ )q -3至6元雜環、C_3-6 環烷基或C_1-4 烷氧基，所述的雜環含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子；其餘基團的定義與第二、三、四、五、六或七種實施方案中任意一種相同。As an eighth embodiment of the present invention, the above-mentioned compound of general formula (Ia) or (Ib) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, wherein R ¹ is selected from

,

; Ring A is selected from one of the following groups substituted or unsubstituted:

,

or

, when substituted, optionally 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, cyano, OH, _CF3 , methyl , ethyl, propyl, isopropyl or CH ₂ CN substituents; Ring B is selected from oxidine; or

selected from

,

or

; R ^2a is selected from H or substituted or unsubstituted one of the following groups: -C(=O)NH ₂ , -NHC(=O)H, -C(=O)NH-CH ₃ , -NHC (=O)-CH ₃ , -C(=O)NH-CH ₂ CH ₃ , -NHC(=O)CH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O )N(CH ₂ CH ₃ ) ₂ , -C(=O)-CH ₃ , -C(=O)-CH ₂ CH ₃ , -C(=O)-CH ₂ CH ₂ CH ₃ , -C(= O)-CH(CH ₃ ) ₂ , -C(=O)NH-phenyl, -NHC(=O)-phenyl, -C(=O)-phenyl, -C(=O)-pyridine, -C(=O)-thiophene, -C(=O)-furan, -C(=O)-pyrrole, methyl, ethyl, isopropyl, propyl, phenyl, naphthyl, thienyl, furan , pyrrolyl or pyridyl, when substituted, optionally 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , -C(=O)NH ₂ , -NHC(=O)H, -C(=O)NH-CH ₃ , -NHC(=O)-CH ₃ , -C(=O)NH-CH ₂ CH ₃ , -NHC(=O)CH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)N(CH ₂ CH ₃ ) ₂ , -C(=O)NH -phenyl, -NHC(=O)-phenyl, methyl or ethyl substituent; R ^2b are each independently selected from H, F, oxo, OH, cyano, CF ₃ , methyl or ethyl group, the methyl or ethyl group is optionally 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , Substituents of COOH, NH ₂ , methyl or ethyl; R ^2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , -C(=O)NH ₂ , -NHC(=O)H, -C(=O)NH-CH ₃ , -NHC(=O)-CH ₃ , -C(=O)NH-CH ₂ CH ₃ , -NHC(=O)CH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)N(CH ₂ CH ₃ ) ₂ , -C(=O)NH-phenyl, -NHC(=O)-benzene group, methyl, ethyl, methoxy or ethoxy, said methyl, ethyl, methoxy, ethoxy or phenyl optionally further replaced by 0 to 4 (eg 0, 1, 2 , 3 or 4) are substituted with substituents selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , methyl or ethyl; R ^2d are each independently selected from H , F, Cl, Br, I, oxo, OH, cyano, _CF3 , methyl or ethyl optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) Substituted from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , methyl or ethyl substituent; R ³ is selected from H or substituted or unsubstituted following groups One of: methyl, ethyl, -(CH ₂ ) _q -tetrahydropyrrole, -(CH ₂ ) _q -azetidine, -N(CH ₃ ) ₂ or -N(CH ₂ CH ₃ ) ₂ , when substituted, optionally by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, _CF3 , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl, -C _1-4 alkylene-OH, -(CH ₂ )q -C _3-6 carbocycle, -(CH ₂ )q -3- to 6-membered heterocycle, C _3-6 cycloalkyl or C _1-4 alkoxy, the heterocycle contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; the remaining groups are as defined in any of the second, third, fourth, fifth, sixth or seventh embodiments.

作為本發明的第九種實施方案，上述通式(Ia)或(Ib)化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中環A選自

、

或

； X₃ 選自O或鍵； R³ 選自-CH₂ N(CH₃ )₂ 、-CH₂ N(CH₂ CH₃ )₂ 、-N(CH₂ CH₃ )₂ 、-N(CH₃ )₂ 、

、

； n選自0；其餘基團的定義與第二、三、四、五、六、七或八種實施方案中任意一種相同。As the ninth embodiment of the present invention, the above-mentioned compound of general formula (Ia) or (Ib) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, wherein ring A is selected from

,

or

X ₃ is selected from O or a bond; R ³ is selected from -CH ₂ N(CH ₃ ) ₂ , -CH ₂ N(CH ₂ CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , -N(CH ₃ ) ₂ ,

,

; n is selected from 0; the remaining groups are as defined in any of the second, third, fourth, fifth, sixth, seventh or eighth embodiments.

作為本發明的第十種實施方案，上述通式(Ia)或(Ib)化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中環A選自

、

或

； X₃ -R³ 選自

、

； n選自0；其餘基團的定義與第二、三、四、五、六、七、八或九種實施方案中任意一種相同。As a tenth embodiment of the present invention, the above-mentioned compound of general formula (Ia) or (Ib) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, wherein ring A is selected from

,

or

; X ₃ -R ³ is selected from

,

; n is selected from 0; the remaining groups are as defined in any of the second, third, fourth, five, six, seven, eight or nine embodiments.

作為本發明的第十一種實施方案，上述通式(Ia)或(Ib)化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中

選自

、

或

；

選自

、

、

、

、

、

或

； R^2c 各自獨立地選自H、F、Cl、Br、I、OH、氰基、CF₃ 、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基或乙氧基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、甲基或乙基的取代基所取代； n選自0； m2選自0、1、2或3；其餘基團的定義與第二、三、四、五、六、七、八、九或十種實施方案中任意一種相同。As the eleventh embodiment of the present invention, the above-mentioned compound of general formula (Ia) or (Ib) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt ,in

selected from

,

or

;

selected from

,

or

; R ^2c is independently selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , methyl, ethyl, methoxy or ethoxy, the methyl, ethyl, methyl Oxy or ethoxy is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, _CF3 , COOH, NH _2. Substituted by methyl or ethyl substituent; n is selected from 0; m2 is selected from 0, 1, 2 or 3; the definitions of the remaining groups are the same as those of the second, third, fourth, fifth, sixth, seventh, eighth, Any of the nine or ten embodiments is the same.

作為本發明的第十二種實施方案，上述通式(Ia)或(Ib)化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中環A選自

、

或

、

、

； n選自0；其餘基團的定義與第十一種實施方案相同。As the twelfth embodiment of the present invention, the above-mentioned compound of general formula (Ia) or (Ib) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof , where Ring A is selected from

,

or

,

; n is selected from 0; the definitions of the remaining groups are the same as in the eleventh embodiment.

作為本發明的第十三種實施方案，上述通式(Ia)或(Ib)化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中環A選自

、

或

； X₃ -R³ 選自

、

；其餘基團的定義與第十二種實施方案相同。As the thirteenth embodiment of the present invention, the above-mentioned compound of general formula (Ia) or (Ib) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof , where Ring A is selected from

,

or

; X ₃ -R ³ is selected from

,

; The definitions of the remaining groups are the same as in the twelfth embodiment.

作為本發明的第十四種實施方案，下述通式(Ia-1)或(Ib-1)化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中

G_1- G₂ 選自-CH₂ CH₂ -、-CH=CH-、-C(=O)-NH-、-C(=O)-N(CH₃ )-、 -N(CH₃ )-C(=O)-或者-NH-C(=O)-； R^2a 選自H、C_1-6 烷基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-C_1-6 烷基、C_2-6 炔基、C_1-6 烷氧基、C_3-6 環烷基、3至6元雜環烷基、C_6-10 芳基或5至10元雜芳基的取代基所取代，所述的雜環烷基或雜芳基含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子； R^2c 各自獨立地選自H、F、Cl、Br、I、OH、氰基、CF₃ 、C_1-6 烷基、C_1-6 烷氧基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、烷氧基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-6 烷基、C_2-6 炔基、C_1-6 烷氧基、羥基取代的C_1-6 烷基、C_3-6 環烷基、3至6元雜環烷基、C_6-10 芳基或5至10元雜芳基的取代基所取代，所述的雜環烷基或雜芳基含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子； m2選自0、1、2或3；其餘基團的定義與第二、三、四、五、六、七或八種實施方案中任意一種相同。As the fourteenth embodiment of the present invention, the compound of the following general formula (Ia-1) or (Ib-1) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, co-crystal or pharmaceutical an acceptable salt, wherein

G _1- G ₂ is selected from -CH ₂ CH ₂ -, -CH=CH-, -C(=O)-NH-, -C(=O)-N(CH ₃ )-, -N(CH ₃ ) -C(=O)- or -NH-C(=O)-; R ^2a is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _{6 -10} aryl or 5- to 10-membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C _6-10 aryl substituted with 5- to 10-membered heteroaryl substituents, the heterocycloalkyl or heteroaryl contains 1 to 4 (eg 1, 2, 3 or 4) selected from O, S, N Heteroatoms; R ^2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl , 3- to 8-membered heterocycloalkyl, C _6-10 -membered aryl or 5- to 10-membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, 1, oxo, OH, cyano, _CF3 , COOH, _NH2 , -NH (C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxy substituted C _1-6 Substituents of alkyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C _6-10 -membered aryl or 5- to 10-membered heteroaryl groups, the heterocycloalkyl or heteroaryl The group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; m2 is selected from 0, 1, 2 or 3; the definitions of the remaining groups are the same as those of the second, third, Any of the four, five, six, seven or eight embodiments are the same.

作為本發明的第十五種實施方案，上述通式(Ia-1)或(Ib-1)化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中 R¹ 選自

、

； R^2a 選自H或者取代的或者未被取代的如下基團之一：甲基、乙基、異丙基、丙基、環丙基、環丁基、苯基、萘基、噻吩基、呋喃基、吡咯基或吡啶基，當被取代時，任選被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、NH₂ 、甲基、乙基、甲氧基、乙氧基、環丙基、環丁基或苯基的取代基所取代； R^2c 各自獨立地選自H、F、Cl、Br、I、OH、氰基、CF₃ 、甲基、乙基、甲氧基、乙氧基、環丙基或環丁基，所述的甲基、乙基、甲氧基、乙氧基、環丙基或環丁基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-4 烷基、C_1-4 烷氧基取代基所取代；環A選自

、

或

； X₃ -R³ 選自

、

、

； n選自0。As the fifteenth embodiment of the present invention, the above-mentioned compound of general formula (Ia-1) or (Ib-1) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salts, wherein R ¹ is selected from

,

; R ^2a is selected from H or substituted or unsubstituted one of the following groups: methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, phenyl, naphthyl, thienyl, furanyl, pyrrolyl or pyridyl, when substituted, optionally 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano , CF ₃ , NH ₂ , methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl or phenyl substituents; R ^2c is independently selected from H, F, Cl, Br, I, OH, cyano, _CF3 , methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, said methyl, ethyl, methoxy, ethoxy , cyclopropyl or cyclobutyl optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, _CF3 , COOH , NH ₂ , C _1-4 alkyl, C _1-4 alkoxy substituents; Ring A is selected from

,

or

; X ₃ -R ³ is selected from

,

; n is selected from 0.

作為本發明的第十六種實施方案，下述通式(Ic-1)和(Ic-2)化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中

；各個基團的定義與本發明第二、三、四、五、六、七、八、九、十、十一、十二、十三、十四或十五種實施方案中任意一種相同。As the sixteenth embodiment of the present invention, the compounds of the following general formulae (Ic-1) and (Ic-2) or their stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceuticals an acceptable salt, wherein

; The definition of each group is the same as any one of the second, third, fourth, fifth, sixth, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or fifteen embodiments of the present invention.

本發明的一些實施例涉及通式(I)、(Ia) 、(Ib)、(Ia-1) 、(Ib-1)、(Ic-1)或(Ic-2)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中該化合物選自如下結構之一：

。Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) or their A stereoisomer, deuterated compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, wherein the compound is selected from one of the following structures:

.

本發明的一些實施例涉及通式(I)、(Ia) 、(Ib) 、(Ia-1)、(Ib-1) 、(Ic-1)或(Ic-2)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽， R¹ 選自-C(=O)-C(R^1a )=C(R^1b )₂ ； R^1a 選自H 、F或C_1-4 烷基，所述的烷基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、氰基、OH、CF₃ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代； R^1b 各自獨立地選自H或C_1-4 烷基，所述的烷基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代。Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2), or their Stereoisomer, deuterated compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, R ¹ is selected from -C(=O)-C(R ^1a )=C(R ^1b ) ₂ ; R ^1a is selected from H, F or C _1-4 alkyl, and the alkyl is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) from H, F, Cl, Br, I, cyano, OH, CF ₃ , C _1-4 alkyl or C _1-4 alkoxy substituent; R ^1b is independently selected from H or C _1-4 alkyl, the The alkyl group is optionally further selected by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, _CF3 , COOH, _NH2 , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituent.

本發明的一些實施例涉及通式(I)、(Ia) 、(Ib) 、(Ia-1)、(Ib-1) 、(Ic-1)或(Ic-2)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽， R¹ 選自-C(=O)-C(R^1a )=C(R^1b )₂ ； R^1a 選自H 、F或C_1-4 烷基，所述的烷基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、氰基、OH、CF₃ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代； R^1b 各自獨立地選自H、C_1-4 烷基或-(CH₂ )_p -3至6元雜環，所述的烷基或雜環任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基、C_1-4 烷氧基、C_3-6 碳環或3至6元雜環的取代基所取代，所述的雜環含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子。Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2), or their Stereoisomer, deuterated compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, R ¹ is selected from -C(=O)-C(R ^1a )=C(R ^1b ) ₂ ; R ^1a is selected from H, F or C _1-4 alkyl, and the alkyl is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) from H, F, Cl, Br, I, cyano, OH, CF ₃ , C _1-4 alkyl or C _1-4 alkoxy substituent; R ^1b is independently selected from H, C _1-4 alkyl or -( CH ₂ ) _p -3- to 6-membered heterocycle, said alkyl or heterocycle is optionally further selected from H, F, Cl, Br by 0 to 4 (eg 0, 1, 2, 3 or 4) , I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _{1 -4} alkoxy, C _3-6 carbocyclic or 3- to 6-membered heterocycle substituents, the heterocycle contains 1 to 4 (eg 1, 2, 3 or 4) selected from O, S and N heteroatoms.

本發明的一些實施例涉及通式(I)、(Ia) 、(Ib) 、(Ia-1)、(Ib-1) 、(Ic-1)或(Ic-2)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽、(Ic-1)或(Ic-2)或共晶， R¹ 選自-C(=O)-C(R^1a )=C(R^1b )₂ ； R^1a 選自H 、F或C_1-4 烷基，所述的烷基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、氰基、OH、CF₃ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代； R^1b 各自獨立地選自H、C_1-4 烷基或-(CH₂ )_p -4至6元含氮雜環，所述的烷基或含氮雜環任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基、C_1-4 烷氧基、C_3-6 碳環或3至6元雜環的取代基所取代，所述的雜環含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子。Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2), or their Stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, (Ic-1) or (Ic-2) or co-crystal, R ¹ is selected from -C(=O)- C(R ^1a )=C(R ^1b ) ₂ ; R ^1a is selected from H , F or C _1-4 alkyl, which is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) are substituted with substituents selected from H, F, Cl, Br, I, cyano, OH, CF ₃ , C _1-4 alkyl or C _1-4 alkoxy; R ^1b is independently selected From H, C _1-4 alkyl or -(CH ₂ ) _p -4 to 6-membered nitrogen-containing heterocycle, the alkyl or nitrogen-containing heterocycle is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, _CF3 , COOH, _NH2 , -NH( _C1-4 alkyl), -N( _{C1 -4} alkyl) ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocyclic or 3- to 6-membered heterocycle substituents, the heterocycle contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N.

本發明的一些實施例涉及通式(I)、(Ia) 、(Ib) 、(Ic-1)或(Ic-2)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽， R¹ 選自-C(=O)-C(R^1a )=C(R^1b )₂ ； R^1a 選自H、F、甲基、乙基、丙基或異丙基，所述的甲基、乙基、丙基或異丙基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、氰基、OH、CF₃ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代； R^1b 各自獨立地選自H、甲基、乙基、丙基或異丙基，所述的甲基、乙基、丙基或異丙基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代。Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ic-1) or (Ic-2) or stereoisomers, deuterated compounds, solvates, pro- Drugs, metabolites, co-crystals or pharmaceutically acceptable salts, R ¹ is selected from -C(=O)-C(R ^1a )=C(R ^1b ) ₂ ; R ^1a is selected from H, F, methyl, Ethyl, propyl or isopropyl, said methyl, ethyl, propyl or isopropyl optionally further selected from H, F, Cl, Br, I, cyano, OH, CF ₃ , C _1-4 alkyl or C _1-4 alkoxy substituent; R ^1b is independently selected from H, methyl, ethyl , propyl or isopropyl, the methyl, ethyl, propyl or isopropyl optionally further selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents.

本發明的一些實施例涉及通式(I)、(Ia) 、(Ib) 、(Ic-1)或(Ic-2)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽， R¹ 選自-C(=O)-C(R^1a )=C(R^1b )₂ ； R^1a 選自H、F、甲基、乙基、丙基或異丙基，所述的甲基、乙基、丙基或異丙基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、氰基、OH、CF₃ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代； R^1b 各自獨立地選自H、甲基、乙基、丙基、異丙基、-CH₂ -4元含氮雜環、-CH₂ -5元含氮雜環、-CH₂ -6元含氮雜環、4元含氮雜環、5元含氮雜環或6元含氮雜環，所述的甲基、乙基、丙基、異丙基或含氮雜環任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代。Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ic-1) or (Ic-2) or stereoisomers, deuterated compounds, solvates, pro- Drugs, metabolites, co-crystals or pharmaceutically acceptable salts, R ¹ is selected from -C(=O)-C(R ^1a )=C(R ^1b ) ₂ ; R ^1a is selected from H, F, methyl, Ethyl, propyl or isopropyl, said methyl, ethyl, propyl or isopropyl optionally further selected from H, F, Cl, Br, I, cyano, OH, CF ₃ , C _1-4 alkyl or C _1-4 alkoxy substituent; R ^1b is independently selected from H, methyl, ethyl , propyl, isopropyl, -CH ₂ -4-membered nitrogen-containing heterocycle, -CH ₂ -5-membered nitrogen-containing heterocycle, -CH ₂ -6-membered nitrogen-containing heterocycle, 4-membered nitrogen-containing heterocycle, 5-membered A nitrogen-containing heterocycle or a 6-membered nitrogen-containing heterocycle, the methyl, ethyl, propyl, isopropyl or nitrogen-containing heterocycles are optionally further replaced by 0 to 4 (such as 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituent.

本發明的一些實施例涉及通式(I)、(Ia) 、(Ib) 、(Ia-1) 、(Ib-1) 、(Ic-1)或(Ic-2)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽， R¹ 選自

、

。Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) or their Stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts, R ¹ is selected from

,

.

本發明的一些實施例涉及通式(I)、(Ia) 、(Ib) 、(Ia-1) 、(Ib-1) 、(Ic-1)或(Ic-2)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，環A選自取代的或者未取代的如下基團之一：

、

或

，當被取代時，任選被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、氰基、OH、CF₃ 、甲基、乙基、丙基、異丙基或CH₂ CN的取代基所取代。Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) or their Stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts, Ring A is selected from substituted or unsubstituted one of the following groups:

,

or

, when substituted, optionally 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, cyano, OH, _CF3 , methyl , ethyl, propyl, isopropyl or CH ₂ CN substituents.

、

或

,

or

本發明的一些實施例涉及通式(I)、(Ia) 、(Ib) 、(Ia-1) 、(Ib-1)、(Ic-1)或(Ic-2)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，環A選自未被取代的或者取代的如下結構之一：

、

或

，當被取代時，任選進一步被0至4個（例如0、1、2、3或4個）R^a 取取代； R^a 各自獨立地選自H、oxo、F、Cl、Br、I、氰基、C_1-4 烷基或C_1-4 烷氧基，所述的烷基或烷氧基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代。Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) or their Stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts, Ring A is selected from one of the following unsubstituted or substituted structures:

,

or

, when substituted, optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R ^a ; R ^a is independently selected from H, oxo, F, Cl, Br, I , cyano, C _1-4 alkyl or C _1-4 alkoxy, said alkyl or alkoxy optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) Substituted from substituents of H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy.

本發明的一些實施例涉及通式(I)、(Ia) 、(Ib) 、(Ia-1) 、(Ib-1)、(Ic-1)或(Ic-2)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，環A選自

、

或

。Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) or their Stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts, Ring A is selected from

,

or

.

本發明的一些實施例涉及通式(I)、(Ia) 、(Ib) 、(Ia-1) 、(Ib-1) 、(Ic-1)或(Ic-2)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽， R³ 選自取代的或者未取代的如下基團之一：H、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、丙氧基、-N(CH₃ )₂ 、-N(CH₂ CH₃ )₂ 、-(CH₂ )_q -環丙烷、-(CH₂ )_q -環丁烷、-(CH₂ )_q -環戊烷、-(CH₂ )_q -環己烷、-(CH₂ )_q -氮雜環丁烷、-(CH₂ )_q -氧雜環丁烷、-(CH₂ )_q -四氫噻吩、-(CH₂ )_q -四氫呋喃、-(CH₂ )_q -四氫吡咯、-(CH₂ )_q -苯基、-(CH₂ )_q -萘基、-(CH₂ )_q- 吡啶、-(CH₂ )_q -嘧啶、-(CH₂ )_q -吡嗪、-(CH₂ )_q -噻吩、-(CH₂ )_q -呋喃、-(CH₂ )_q -吡咯、-(CH₂ )_q -咪唑、-(CH₂ )_q -咪唑、-(CH₂ )_q -吡唑、-(CH₂ )_q -三氮唑、-(CH₂ )_q -四氮唑、-(CH₂ )_q -呱啶、-(CH₂ )_q -嗎啉、-(CH₂ )_q -四氫吡喃、-(CH₂ )_q -吡咯雙烷、-(CH₂ )_q -1,3-氧氮雜環庚烷、-(CH₂ )_q -2-氧雜-5-氮雜雙環[2.2.1]庚烷、-(CH₂ )_q -呱嗪或-(CH₂ )_q -N(R^3a )-C(=O)R^3b ，當被取代時，任選被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基、-C_1-4 亞烷基-OH、-(CH₂ )_q -C_3-6 碳環、-(CH₂ )_q -3至6元雜環、C_3-6 環烷基、C_1-4 烷氧基、-N(C_1-4 烷基)C(=O)-3至12元雜環或3至12元雜環的取代基所取代，所述的雜環含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子； R^3a 選自H、甲基、乙基、丙基或異丙基，所述的甲基、乙基、丙基或異丙基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、氰基、OH、CF₃ 、C_1-4 烷基或C_1-4 烷氧基取代基所取代； R^3b 選自H、甲基、乙基、丙基、異丙基、氮雜環丁烷或氧雜環丁烷，所述的甲基、乙基、丙基、異丙基、氮雜環丁烷或氧雜環丁烷任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、氰基、OH、CF₃ 、C_1-4 烷基或C_1-4 烷氧基取代基所取代。Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) or their Stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts, R ³ is selected from one of the following substituted or unsubstituted groups: H, methyl, ethyl , propyl, isopropyl, methoxy, ethoxy, propoxy, -N( _CH3 ) ₂ , -N( _CH2CH3 ) ₂ , -( _CH2 ₎ _q -cyclopropane, -( _CH2 ) _q -cyclobutane, -( _CH2 ) _q -cyclopentane, -( _CH2 ) _q -cyclohexane, -( _CH2 ) _q -azetidine, -( _CH2 ) _q -oxetane, -( _CH2 ) _q -tetrahydrothiophene, -( _CH2 ) _q -tetrahydrofuran, -( _CH2 ) _q -tetrahydropyrrole, -( _CH2 ) _q -phenyl, -( _CH2 ) _q -naphthyl, -( _CH2 ) _q- pyridine, -( _CH2 ) _q -pyrimidine, -( _CH2 ) _q -pyrazine, -( _CH2 ) _q -thiophene, -( _CH2 ) _q -furan, -( _CH2 ) _q -pyrrole, -( _CH2 ) _q -imidazole, -( _CH2 ) _q -imidazole, -( _CH2 ) _q -pyrazole, -( _CH2 ) _q -triazol azole, -(CH ₂ ) _q -tetrazolium, -(CH ₂ ) _q -pyridine, -(CH ₂ ) _q -morpholine, -(CH ₂ ) _q -tetrahydropyran, -(CH ₂ ) _q -pyrrolidine, -( _CH2 ) _q -1,3-oxazepine, -( _CH2 ) _q -2-oxa-5-azabicyclo[2.2.1]heptane, - ( _CH2 ) _q -oxazine or -( _CH2 ) _q -N( ^R3a )-C(=O) ^R3b , when substituted, optionally by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl, -C _1-4 alkylene-OH, -(CH ₂ ) _q -C _3-6 carbocycle, -(CH ₂ ) _q -3- to 6-membered heterocycle , C _3-6 cycloalkyl, C _1-4 alkoxy, -N(C _1-4 alkyl) C(=O)-3- to 12-membered heterocycle or 3- to 12-membered heterocycle substituents Substituted, the heterocycle contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; R ^3a is selected from H, methyl, ethyl, propyl or iso propyl, the methyl, ethyl, propyl or isopropyl is optionally further 0 to 4 (eg 0, 1, 2 , 3 or 4) are selected from H, F, Cl, Br, I, cyano, OH, CF ₃ , C _1-4 alkyl or C _1-4 alkoxy substituents; R ^3b is selected from H , methyl, ethyl, propyl, isopropyl, azetidine or oxetane, said methyl, ethyl, propyl, isopropyl, azetidine or oxetane Cyclobutane is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) H, F, Cl, Br, I, cyano, OH, _CF3 , _C1-4 alkyl or C _1-4 alkoxy substituent.

本發明的一些實施例涉及通式(I)、(Ia) 、(Ib) 、(Ia-1) 、(Ib-1) 、(Ic-1)或(Ic-2)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，R³ 選自取代的或者未取代的如下基團之一：H、甲基、乙基、-(CH₂ )_q -四氫吡咯、-(CH₂ )_q -氮雜環丁烷、-N(CH₃ )₂ 或-N(CH₂ CH₃ )₂ ，當被取代時，任選被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-4 烷基、-C_1-4 亞烷基-OH、-(CH₂ )q -C_3-6 碳環、-(CH₂ )q -3至6元雜環、C_3-6 環烷基或C_1-4 烷氧基，所述的雜環含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子。Some embodiments of the present invention relate to compounds of general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) or their Stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts, R ³ is selected from substituted or unsubstituted one of the following groups: H, methyl, ethyl , -( _CH2 ) _q -tetrahydropyrrole, -( _CH2 ) _q -azetidine, -N( _CH3 ) ₂ or -N( _CH2CH3 ₎₂ _, when substituted, optionally 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, 1, oxo, OH, cyano, _CF3 , COOH, _NH2 , -NH( _{C1 -4} alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl, -C _1-4 alkylene-OH, -(CH ₂ )q -C _3-6 carbocycle, -(CH ₂ )q -3- to 6-membered heterocycle, C _3-6 cycloalkyl or C _1-4 alkoxy, said heterocycle containing 1 to 4 (eg 1, 2, 3 or 4 ) is a heteroatom selected from O, S, N.

本發明的一些實施例涉及通式(I)、(Ia) 、(Ib) 、(Ia-1) 、(Ib-1)、(Ic-1)或(Ic-2)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽， R³ 選自-CH₂ N(CH₃ )₂ 、-CH₂ N(CH₂ CH₃ )₂ 、-N(CH₂ CH₃ )₂ 、-N(CH₃ )₂ 、

、

。Some embodiments of the present invention relate to a compound of general formula (I), (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or a compound thereof Stereoisomer, deuterated compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt, R ³ is selected from -CH ₂ N(CH ₃ ) ₂ , -CH ₂ N(CH ₂ CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , -N(CH ₃ ) ₂ ,

,

.

本發明的一些實施例涉及通式 (Ia)、(Ib)、(Ia-1) 、(Ib-1)、(Ic-1)或(Ic-2)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，X₃ -R³ 選自

、

。Some embodiments of the present invention relate to compounds of general formula (Ia), (Ib), (Ia-1), (Ib-1), (Ic-1) or (Ic-2) or stereoisomers thereof , deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts, X ₃ -R ³ is selected from

,

.

本發明的一些實施例涉及通式 (Ia)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，環B選自氮雜環丁烷、氮雜環戊烷或呱啶。Some embodiments of the present invention relate to compounds of general formula (Ia) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof, Ring B is selected from nitrogen tetracyclobutane, azetidine or pyridine.

本發明的一些實施例涉及通式 (Ia)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，環B選自咪唑烷。Some embodiments of the present invention relate to compounds of general formula (Ia) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof, Ring B is selected from imidazolidines.

本發明的一些實施例涉及通式 (Ia) 或(Ia-1)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽， R^2a 選自H、COOH、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、-C(=O)-C_1-4 烷基、-C(=O)- 3至8元雜環烷基、-C(=O)-苯基、-C(=O)-5至6元雜芳基、C_1-4 烷基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、- C_1-6 烷基、C_2-6 炔基、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、C_1-6 烷氧基、羥基取代的C_1-6 烷基、C_3-6 環烷基、3至6元雜環烷基、C_6-10 芳基或5至10元雜芳基的取代基所取代，所述的雜環烷基或雜芳基含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子； R^2A 、R^2B 或R^2C 各自獨立地選自H、C_1-6 烷基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-6 烷基、C_2-6 炔基、C_1-6 烷氧基、羥基取代的C_1-6 烷基、C_3-6 環烷基、3至6元雜環烷基的取代基所取代，所述的雜環烷基含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子。Some embodiments of the present invention relate to compounds of general formula (Ia) or (Ia-1) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof , R ^2a is selected from H, COOH, -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , -C(=O)-C _1-4 alkyl, -C(=O )- 3- to 8-membered heterocycloalkyl, -C(=O)-phenyl, -C(=O)-5 to 6-membered heteroaryl, C _1-4 alkyl, C _3-6 cycloalkyl , 3- to 8-membered heterocycloalkyl, C _6-10 -membered aryl or 5- to 10-membered heteroaryl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, ₁ , oxo, OH, cyano, _CF3 , COOH, _NH2 , -NH(C1- ₄ alkyl), -N(C _1-4 alkyl) ₂ , -C _1-6 alkyl, C _2-6 alkynyl, -C(=O)NR ^2A R ^2B , -NR ^2A C(=O ) R ^2C , C _1-6 alkoxy, hydroxy-substituted C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C _6-10 aryl or 5- to 10-membered Substituted by the substituent of heteroaryl, the heterocycloalkyl or heteroaryl contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N; R ^2A , R ^2B or R ^2C are each independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _6-10 aryl, or 5- to 10-membered heteroaryl , the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl , Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl substituents, the said Heterocycloalkyl groups contain 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N.

本發明的一些實施例涉及通式 (Ia) 或(Ia-1)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽， R^2a 選自取代的或者未被取代的如下基團之一：H、-C(=O)NH₂ 、-NHC(=O)H、-C(=O)NH-CH₃ 、-NHC(=O)-CH₃ 、-C(=O)NH-CH₂ CH₃ 、-NHC(=O)CH₂ CH₃ 、-C(=O)N(CH₃ )₂ 、- -C(=O)N(CH₂ CH₃ )₂ 、-C(=O)-CH₃ 、-C(=O)-CH₂ CH₃ 、-C(=O)-CH₂ CH₂ CH₃ 、-C(=O)-CH(CH₃ )₂ 、-C(=O)NH-苯基、-NHC(=O)-苯基、-C(=O)-苯基、-C(=O)-吡啶、-C(=O)-噻吩、-C(=O)-呋喃、-C(=O)-吡咯、甲基、乙基、異丙基、丙基、環丙基、環丁基、環戊基、環己基、苯基、萘基、噻吩基、呋喃基、吡咯基、噻唑基、異噻唑基、噁唑基、異噁唑基、咪唑基、吡唑基、苯並咪唑基、苯並吡唑基或吡啶基，當被取代時，任選被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、-C(=O)NH₂ 、-NHC(=O)H、-C(=O)NH-CH₃ 、-NHC(=O)-CH₃ 、-C(=O)NH-CH₂ CH₃ 、-NHC(=O)CH₂ CH₃ 、-C(=O)N(CH₃ )₂ 、-C(=O)N(CH₂ CH₃ )₂ 、-C(=O)NH-苯基、-NHC(=O)-苯基、C_1-4 烷基、C_1-4 烷氧基或C_2-4 炔基的取代基所取代。Some embodiments of the present invention relate to compounds of general formula (Ia) or (Ia-1) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof , R ^2a is selected from substituted or unsubstituted one of the following groups: H, -C(=O)NH ₂ , -NHC(=O)H, -C(=O)NH-CH ₃ , -NHC (=O)-CH ₃ , -C(=O)NH-CH ₂ CH ₃ , -NHC(=O)CH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , - -C(= O)N(CH ₂ CH ₃ ) ₂ , -C(=O)-CH ₃ , -C(=O)-CH ₂ CH ₃ , -C(=O)-CH ₂ CH ₂ CH ₃ , -C( =O)-CH(CH ₃ ) ₂ , -C(=O)NH-phenyl, -NHC(=O)-phenyl, -C(=O)-phenyl, -C(=O)-pyridine , -C(=O)-thiophene, -C(=O)-furan, -C(=O)-pyrrole, methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclo Amyl, cyclohexyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, benzimidazolyl, benzene Pyrazolyl or pyridyl, when substituted, optionally 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , -C(=O)NH ₂ , -NHC(=O)H, -C(=O)NH-CH ₃ , -NHC(=O)-CH ₃ , -C(=O)NH-CH ₂ CH ₃ , -NHC(=O)CH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)N(CH ₂ CH ₃ ) ₂ , -C(=O)NH -Phenyl, -NHC(=O)-phenyl, C _1-4 alkyl, C _1-4 alkoxy or C _2-4 alkynyl substituent.

本發明的一些實施例涉及通式 (Ia)或(Ia-1)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽， R^2a 選自取代的或者未被取代的如下基團之一：H、-C(=O)NH₂ 、-NHC(=O)H、-C(=O)NH-CH₃ 、-NHC(=O)-CH₃ 、-C(=O)NH-CH₂ CH₃ 、-NHC(=O)CH₂ CH₃ 、-C(=O)N(CH₃ )₂ 、 -C(=O)N(CH₂ CH₃ )₂ 、-C(=O)-CH₃ 、-C(=O)-CH₂ CH₃ 、-C(=O)-CH₂ CH₂ CH₃ 、-C(=O)-CH(CH₃ )₂ 、-C(=O)NH-苯基、-NHC(=O)-苯基、-C(=O)-苯基、-C(=O)-吡啶、-C(=O)-噻吩、-C(=O)-呋喃、-C(=O)-吡咯、甲基、乙基、異丙基、丙基、苯基、萘基、噻吩基、呋喃基、吡咯基或吡啶基，當被取代時，任選被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、-C(=O)NH₂ 、-NHC(=O)H、-C(=O)NH-CH₃ 、-NHC(=O)-CH₃ 、-C(=O)NH-CH₂ CH₃ 、-NHC(=O)CH₂ CH₃ 、-C(=O)N(CH₃ )₂ 、-C(=O)NH-苯基、-NHC(=O)-苯基、甲基或乙基的取代基所取代。Some embodiments of the present invention relate to compounds of general formula (Ia) or (Ia-1) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof , R ^2a is selected from substituted or unsubstituted one of the following groups: H, -C(=O)NH ₂ , -NHC(=O)H, -C(=O)NH-CH ₃ , -NHC (=O)-CH ₃ , -C(=O)NH-CH ₂ CH ₃ , -NHC(=O)CH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O )N(CH ₂ CH ₃ ) ₂ , -C(=O)-CH ₃ , -C(=O)-CH ₂ CH ₃ , -C(=O)-CH ₂ CH ₂ CH ₃ , -C(= O)-CH(CH ₃ ) ₂ , -C(=O)NH-phenyl, -NHC(=O)-phenyl, -C(=O)-phenyl, -C(=O)-pyridine, -C(=O)-thiophene, -C(=O)-furan, -C(=O)-pyrrole, methyl, ethyl, isopropyl, propyl, phenyl, naphthyl, thienyl, furan , pyrrolyl or pyridyl, when substituted, optionally 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , -C(=O)NH ₂ , -NHC(=O)H, -C(=O)NH-CH ₃ , -NHC(=O)-CH ₃ , -C(=O)NH-CH ₂ CH ₃ , -NHC(=O)CH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)NH-phenyl, -NHC(=O)-phenyl, methyl substituted with ethyl or ethyl substituents.

本發明的一些實施例涉及通式 (Ia)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，

選自

、

或

。Some embodiments of the present invention relate to compounds of general formula (Ia) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof,

selected from

,

or

.

本發明的一些實施例涉及通式 (Ib)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，

選自

、

或

； R^2c 各自獨立地選自H、F、Cl、Br、I、OH、氰基、CF₃ 、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基或乙氧基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、甲基或乙基的取代基所取代； m2選自0、1、2或3。Some embodiments of the present invention relate to compounds of general formula (Ib) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof,

selected from

,

or

; R ^2c is independently selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , methyl, ethyl, methoxy or ethoxy, the methyl, ethyl, methyl Oxy or ethoxy is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, _CF3 , COOH, NH _2. Substituted by methyl or ethyl substituent; m2 is selected from 0, 1, 2 or 3.

本發明的一些實施例涉及通式 (Ia)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽， R^2b 各自獨立地選自H、F、oxo、OH、氰基、CF₃ 、甲基或乙基，所述的甲基或乙基任選被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、甲基或乙基的取代基所取代。Some embodiments of the present invention relate to compounds of formula (Ia) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof, R ^2b independently is selected from H, F, oxo, OH, cyano, _CF3 , methyl or ethyl optionally 0 to 4 (eg 0, 1, 2, 3 or 4) Substituted with substituents selected from H, F, Cl, Br, I, OH, cyano, _CF3 , COOH, _NH2 , methyl or ethyl.

本發明的一些實施例涉及通式 (Ib)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，環D選自苯環、吡啶、噠嗪或嘧啶；環C選自C_4-6 碳環或4至6元雜環, 所述的雜環含有1至3個選自O、S、N的雜原子。Some embodiments of the present invention relate to compounds of general formula (Ib) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof, wherein Ring D is selected from benzene Ring, pyridine, pyridazine or pyrimidine; Ring C is selected from C _4-6 carbocyclic ring or 4- to 6-membered heterocycle, and the heterocycle contains 1 to 3 heteroatoms selected from O, S, N.

本發明的一些實施例涉及通式 (Ib)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，環C和環D一起形成的並環選自

或

。Some embodiments of the present invention relate to compounds of formula (Ib) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof, Ring C and Ring D The concatenated rings formed together are selected from

or

.

、

、

、

、

或

,

or

.

本發明的一些實施例涉及通式 (Ib)或(Ib-1)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽， R^2c 各自獨立地選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、C_1-4 烷基、C_1-4 烷氧基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、烷氧基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-C(=O)NR^2A R^2B 、-NR^2A C(=O)R^2C 、C_1-6 烷基、C_2-6 炔基、C_1-6 烷氧基、羥基取代的C_1-6 烷基、C_3-6 環烷基、3至6元雜環烷基、C_6-10 芳基或5至10元雜芳基的取代基所取代，所述的雜環烷基或雜芳基含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子。Some embodiments of the present invention relate to compounds of general formula (Ib) or (Ib-1) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof , R ^2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _6-10 aryl or 5- to 10-membered heteroaryl, said Alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) H, F, Cl , Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C _6-10 aryl or 5- to Substituents of 10-membered heteroaryl groups, the heterocycloalkyl or heteroaryl groups contain 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N.

本發明的一些實施例涉及通式 (Ib)或(Ib-1)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽， R^2c 各自獨立地選自H、F、Cl、Br、I、OH、氰基、CF₃ 、-C(=O)NH₂ 、-NHC(=O)H、-C(=O)NH-CH₃ 、-NHC(=O)-CH₃ 、-C(=O)NH-CH₂ CH₃ 、-NHC(=O)CH₂ CH₃ 、-C(=O)N(CH₃ )₂ 、-C(=O)N(CH₂ CH₃ )₂ 、-C(=O)NH-苯基、-NHC(=O)-苯基、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基、乙氧基或苯基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-4 烷基、C_1-4 烷氧基取代基所取代。Some embodiments of the present invention relate to compounds of general formula (Ib) or (Ib-1) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof , R ^2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , -C(=O)NH ₂ , -NHC(=O)H, -C(=O)NH -CH ₃ , -NHC(=O)-CH ₃ , -C(=O)NH-CH ₂ CH ₃ , -NHC(=O)CH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)N(CH ₂ CH ₃ ) ₂ , -C(=O)NH-phenyl, -NHC(=O)-phenyl, methyl, ethyl, methoxy or ethoxy , the methyl, ethyl, methoxy, ethoxy or phenyl groups are optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) from H, F, Cl, Br , I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy substituents.

本發明的一些實施例涉及通式 (Ib)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽， R^2d 各自獨立地選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、C_1-4 烷基或C_1-4 烷氧基，所述的烷基或烷氧基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 或C_1-6 烷基的取代基所取代。Some embodiments of the present invention relate to compounds of general formula (Ib) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof, R ^2d independently Selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , C _1-4 alkyl or C _1-4 alkoxy, the alkyl or alkoxy is optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, _CF3 , COOH, _NH2 or _C1-6 alkyl substituted by the substituents.

本發明的一些實施例涉及通式 (Ib)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽， R^2d 各自獨立地選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、甲基或乙基，所述的甲基或乙基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-4 烷基或C_1-4 烷氧基的取代基所取代。Some embodiments of the present invention relate to compounds of general formula (Ib) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof, R ^2d independently is selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , methyl or ethyl, and said methyl or ethyl is optionally further replaced by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from the substituents of H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy replace.

本發明的一些實施例涉及通式 (Ib)或(Ib-1)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽， R^2c 各自獨立地選自H、F、Cl、Br、I、OH、氰基、CF₃ 、-C(=O)NH₂ 、-NHC(=O)H、-C(=O)NH-CH₃ 、-NHC(=O)-CH₃ 、-C(=O)NH-CH₂ CH₃ 、-NHC(=O)CH₂ CH₃ 、-C(=O)N(CH₃ )₂ 、-C(=O)N(CH₂ CH₃ )₂ 、-C(=O)NH-苯基、-NHC(=O)-苯基、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基、乙氧基或苯基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、甲基或乙基的取代基所取代。Some embodiments of the present invention relate to compounds of general formula (Ib) or (Ib-1) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof , R ^2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , -C(=O)NH ₂ , -NHC(=O)H, -C(=O)NH -CH ₃ , -NHC(=O)-CH ₃ , -C(=O)NH-CH ₂ CH ₃ , -NHC(=O)CH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)N(CH ₂ CH ₃ ) ₂ , -C(=O)NH-phenyl, -NHC(=O)-phenyl, methyl, ethyl, methoxy or ethoxy , the methyl, ethyl, methoxy, ethoxy or phenyl groups are optionally further selected from H, F, Cl, Br , I, OH, cyano, _CF3 , COOH, _NH2 , methyl or ethyl substituent.

本發明的一些實施例涉及通式 (Ib)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽， R^2d 各自獨立地選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、甲基或乙基，所述的甲基或乙基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、甲基或乙基的取代基所取代。Some embodiments of the present invention relate to compounds of general formula (Ib) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof, R ^2d independently is selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , methyl or ethyl, and said methyl or ethyl is optionally further replaced by 0 to 4 (eg 0, 1, 2, 3 or 4) is substituted with a substituent selected from H, F, Cl, Br, I, OH, cyano, _CF3 , COOH, _NH2 , methyl or ethyl.

本發明的一些實施例涉及通式 (Ib-1)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，G_1- G₂ 選自-CH₂ CH₂ -、-CH=CH-、-C(=O)-NH-、-C(=O)-N(CH₃ )-、 -N(CH₃ )-C(=O)-或者-NH-C(=O)-。Some embodiments of the present invention relate to compounds of general formula (Ib-1) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof, G _1- G ₂ is selected from -CH ₂ CH ₂ -, -CH=CH-, -C(=O)-NH-, -C(=O)-N(CH ₃ )-, -N(CH ₃ )-C( =O)- or -NH-C(=O)-.

本發明的一些實施例涉及通式 (Ia-1)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽， R^2a 選自H、C_1-6 烷基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、烷氧基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-C_1-6 烷基、C_2-6 炔基、C_1-6 烷氧基、C_3-6 環烷基、3至6元雜環烷基、C_6-10 芳基或5至10元雜芳基的取代基所取代，所述的雜環烷基或雜芳基含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子。Some embodiments of the present invention relate to compounds of general formula (Ia-1) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof, R ^2a is selected from From H, C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _6-10 aryl or 5- to 10-membered heteroaryl, the alkyl, alkoxy radical, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C _6-10 -membered aryl or 5- to 10-membered heteroaryl substituents, the The heterocycloalkyl or heteroaryl group contains 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N.

本發明的一些實施例涉及通式 (Ia-1)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽， R^2a 選自取代的或者未被取代的如下基團之一：H、甲基、乙基、異丙基、丙基、環丙基、環丁基、苯基、萘基、噻吩基、呋喃基、吡咯基或吡啶基，當被取代時，任選被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、甲基、乙基、甲氧基、乙氧基、環丙基、環丁基或苯基的取代基所取代。Some embodiments of the present invention relate to compounds of general formula (Ia-1) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof, R ^2a is selected from Self-substituted or unsubstituted one of the following: H, methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, phenyl, naphthyl, thienyl, furyl, pyrrole or pyridyl, when substituted, optionally 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, _CF3 , Substituents of methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl or phenyl.

本發明的一些實施例涉及通式 (Ib-1) 、(Ic-1)或(Ic-2)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽， R^2c 各自獨立地選自H、F、Cl、Br、I、OH、氰基、CF₃ 、C_1-6 烷基、C_1-6 烷氧基、C_3-6 環烷基、3至8元雜環烷基、C_6-10 芳基或5至10元雜芳基，所述的烷基、烷氧基、環烷基、雜環烷基、芳基或雜芳基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、oxo、OH、氰基、CF₃ 、COOH、NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、C_1-6 烷基、C_2-6 炔基、C_1-6 烷氧基、羥基取代的C_1-6 烷基、C_3-6 環烷基、3至6元雜環烷基、C_6-10 芳基或5至10元雜芳基的取代基所取代，所述的雜環烷基或雜芳基含有1至4個（例如1、2、3或4個）選自O、S、N的雜原子。Some embodiments of the present invention relate to compounds of general formula (Ib-1), (Ic-1) or (Ic-2) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co- crystalline or pharmaceutically acceptable salts, R ^2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _6-10 -membered aryl or 5- to 10-membered heteroaryl, the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, Aryl or heteroaryl is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, oxo, OH, cyano, _CF3 , COOH , NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxyl Substituted by substituents of substituted C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C _6-10 aryl or 5- to 10-membered heteroaryl, the hetero Cycloalkyl or heteroaryl groups contain 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from O, S, N.

本發明的一些實施例涉及通式 (Ib-1)、(Ic-1)或(Ic-2)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽， R^2c 各自獨立地選自H、F、Cl、Br、I、OH、氰基、CF₃ 、甲基、乙基、甲氧基、乙氧基、環丙基或環丁基，所述的甲基、乙基、甲氧基、乙氧基、環丙基或環丁基任選進一步被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-4 烷基、C_1-4 烷氧基取代基所取代。Some embodiments of the present invention relate to compounds of general formula (Ib-1), (Ic-1) or (Ic-2) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co- crystalline or pharmaceutically acceptable salt, each R ^2c is independently selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, said methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4 ) is substituted by H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy substituents.

本發明的一些實施例涉及通式(Ia)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中，環A選自

、

；環B為呱啶；n為0；m1為0； R¹ 選自

、

； R^2a 選自取代的或者未被取代的如下基團之一：-C(=O)-C_1-4 烷基、苯基、萘基、吡啶基，當被取代時，任選被0至4個（例如0、1、2、3或4個）選自H、F、Cl、Br、I、OH、氰基、CF₃ 、甲基、乙基、甲氧基、乙氧基、環丙基、環丁基、苯基或-C(=O)NH-苯基的取代基所取代； R³ 選自

、

；X₃ 為鍵或O。Some embodiments of the present invention relate to compounds of general formula (Ia) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof, wherein Ring A is selected from since

,

; Ring B is pyridine; n is 0; m1 is 0; R ¹ is selected from

,

; R ^2a is selected from one of the following substituted or unsubstituted groups: -C(=O)-C _1-4 alkyl, phenyl, naphthyl, pyridyl, when substituted, optionally by O to 4 (eg 0, 1, 2, 3 or 4) selected from H, F, Cl, Br, I, OH, cyano, _CF3 , methyl, ethyl, methoxy, ethoxy, substituted by substituents of cyclopropyl, cyclobutyl, phenyl or -C(=O)NH-phenyl; ^R is selected from

,

; X ₃ is a bond or O.

、

；環B選自氮雜環丁烷或氮雜環戊烷； n為0；m1為0，1或2； R¹ 選自

、

； R^2a 選自取代的或者未被取代的苯基或萘基，當被取代時，該苯基或萘基任選被0至4個（例如0、1、2、3或4個）選自F、Cl、Br、I、OH、氰基、CF₃ 、甲基、乙基、甲氧基、乙氧基的取代基所取代； R^2b 為oxo； R³ 選自

、

；X₃ 為O。Some embodiments of the present invention relate to compounds of general formula (Ia) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof, wherein Ring A is selected from since

,

; Ring B is selected from azetidine or azetidine; n is 0; m1 is 0, 1 or 2; R ¹ is selected from

,

; R ^2a is selected from substituted or unsubstituted phenyl or naphthyl, when substituted, this phenyl or naphthyl is optionally selected from 0 to 4 (for example 0, 1, 2, 3 or 4) Substituted from substituents of F, Cl, Br, I, OH, cyano, CF ₃ , methyl, ethyl, methoxy and ethoxy; R ^2b is oxo; R ³ is selected from

,

; X ₃ is O.

本發明的一些實施例涉及通式(Ib)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中，環A選自

、

；環C和環D一起形成的並環選自

、

； n為0；m2為1；m3為0； R¹ 選自

、

； R^2c 各自獨立地選自F、Cl、Br、I、OH、氰基、CF₃ 、甲基、乙基、甲氧基或乙氧基； R³ 選自

、

；X₃ 為O。Some embodiments of the present invention relate to compounds of general formula (Ib) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof, wherein Ring A is selected from since

,

; Ring C and Ring D together form a ring selected from

,

; n is 0; m2 is 1; m3 is 0; R ¹ is selected from

,

; R ^2c is each independently selected from F, Cl, Br, I, OH, cyano, CF ₃ , methyl, ethyl, methoxy or ethoxy; R ³ is selected from

,

; X ₃ is O.

本發明的一些實施例涉及通式(Ia-1)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中，環A選自

、

或

；n為0； R^2a 為H或苯基，該苯基任選被1、2、3或4個選自F、Cl、Br、I、OH、氰基、CF₃ 、NH₂ 、甲基、乙基、甲氧基、乙氧基的取代基取代； R³ 選自

、

；X₃ 為O。Some embodiments of the present invention relate to compounds of general formula (Ia-1), or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof, wherein ring A is selected from

,

or

; n is 0; R ^2a is H or phenyl, the phenyl is optionally surrounded by 1, 2, 3 or 4 selected from F, Cl, Br, I, OH, cyano, CF ₃ , NH ₂ , methyl , ethyl, methoxy, ethoxy substituents are substituted; R ³ is selected from

,

; X ₃ is O.

本發明的一些實施例涉及通式(Ic-1)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中，環A選自

、

或

； R¹ 選自

、

； R^2c 各自獨立地選自H、F、Cl、Br、I、OH、氰基、CF₃ 、-C(=O)NH-苯基、甲基、乙基、甲氧基或乙氧基，所述的甲基、乙基、甲氧基、乙氧基或苯基任選進一步被0至4個選自H、F、Cl、Br、I、OH、氰基、CF₃ 、COOH、NH₂ 、C_1-4 烷基、C_1-4 烷氧基取代基所取代；m2選自0、1、2或3； R³ 選自

、

；X₃ 為O。Some embodiments of the present invention relate to a compound of formula (Ic-1) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, co-crystal or pharmaceutically acceptable salt thereof, wherein ring A is selected from

,

or

; R ¹ is selected from

,

; R ^2c is each independently selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , -C(=O)NH-phenyl, methyl, ethyl, methoxy or ethoxy , the methyl group, ethyl group, methoxy group, ethoxy group or phenyl group is optionally further selected from 0 to 4 groups selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, substituted by NH ₂ , C _1-4 alkyl, C _1-4 alkoxy substituent; m2 is selected from 0, 1, 2 or 3; R ³ is selected from

,

; X ₃ is O.

本發明的一些實施例涉及通式(Ib-1)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中，環A選自

、

或

；n為0；m2為0； R³ 選自

、

；X₃ 為O； G₁ -G₂ 為NH-C(=O)-或-C(=O)-NH。Some embodiments of the present invention relate to compounds of general formula (Ib-1) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof, wherein ring A is selected from

,

or

; n is 0; m2 is 0; R ³ is selected from

,

; X ₃ is O; G ₁ -G ₂ are NH-C(=O)- or -C(=O)-NH.

本發明的一些實施例涉及通式(Ic-2)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中，環A選自

、

；m2為0； R³ 選自

、

；X₃ 為O。Some embodiments of the present invention relate to compounds of general formula (Ic-2), or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof, wherein ring A is selected from

,

; m2 is 0; R ³ is selected from

,

; X ₃ is O.

、

或

；n為0；R^2a 為苯基； R³ 選自

、

,

or

; n is 0; R ^2a is phenyl; R ³ is selected from

,

; X ₃ is O.

、

或

；n為0；m2為0； R³ 選自

、

；X₃ 為O； G₁ -G₂ 為NH-C(=O)-。Some embodiments of the present invention relate to compounds of general formula (Ib-1) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts thereof, wherein ring A is selected from

,

or

; n is 0; m2 is 0; R ³ is selected from

,

; X ₃ is O; G ₁ -G ₂ is NH-C(=O)-.

本發明的一些實施例涉及通式(Ic-1)或(Ic-2)所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，其中，環A選自

、

或

；m2為0； R³ 選自

、

；X₃ 為O。Some embodiments of the present invention relate to compounds of general formula (Ic-1) or (Ic-2) or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable compounds thereof of salts, wherein Ring A is selected from

,

or

; m2 is 0; R ³ is selected from

,

; X ₃ is O.

本發明涉及一種藥物組合物，包括本發明所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽，以及藥學上可接受的載體。The present invention relates to a pharmaceutical composition, comprising the compound of the present invention or its stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts, and pharmaceutically acceptable salts thereof. vector.

本發明涉及一種本發明所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽在用於製備預防或治療與KRAS G12C活性或表達量相關疾病的藥物中的應用，較佳用於製備腫瘤藥物中的應用。所述的腫瘤較佳血液學癌症、胰臟癌、MYH相關息肉病、結腸直腸癌、非小細胞肺癌或小細胞肺癌。The present invention relates to a compound of the present invention or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts for the preparation of prophylactic or therapeutic and KRAS G12C activity or The application in the medicine of expression related diseases is preferably used in the preparation of tumor medicine. The tumor is preferably hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, non-small cell lung cancer or small cell lung cancer.

本文所述反應中使用的化合物是根據本領域技術人員已知的有機合成技術製備的，起始於市售化學品和(或)化學文獻中所述的化合物。“市售化學品”是從正規商業來源取得的，供應商包括：泰坦科技、安耐吉化學、上海德默、成都科龍化工、韶遠化學科技、南京藥石、藥明康德和百靈威科技等公司。The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature. "Commercially available chemicals" are obtained from regular commercial sources. Suppliers include: Titan Technology, Annagy Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec and Bailingwei Technology, etc. company.

本領域的參考書和專著，詳細介紹了可用於製備本文所述化合物的反應物的合成，或提供了描述該製備方法的文章以供參考。這些參考書和專著包括：“Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York； S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983； H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972； T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992； J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley‑Interscience, New York, 1992； Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3‑527-29074-5； Hoffman, R.V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5； Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4； March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2； Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1； Patai, S. “Patai’s 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9； Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0； Stowell, J.C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2； “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann’s Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes； “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes； and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes。References and monographs in the art detail the synthesis of reactants useful in the preparation of the compounds described herein, or provide references for articles describing such preparations. These reference books and monographs include: "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; HO House, “Modern Synthetic Reactions”, 2nd Ed., WA Benjamin, Inc. Menlo Park, Calif. 1972; TL Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley‑Interscience, New York, 1992 ; Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3‑527-29074-5; Hoffman, RV “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wi ley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, TWG "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell , JC, "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN : 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

藉由美國化學會化學文摘社製備的已知化學物質的索引，可以選擇性地識別特定和類似的反應物，這些索引可在大多數公共圖書館和大學圖書館以及線上取得。已知但在目錄中不可商購的化學品可選地由定制化學合成工廠製備，其中許多標準化學供應工廠(例如，上面列出的那些)提供定制合成服務。製備和選擇本文所述化合物的藥用鹽的參考文獻是P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002。Specific and similar reactants can be selectively identified by indexes of known chemicals prepared by the Chemical Abstracts Service of the American Chemical Society, available in most public and university libraries and online. Chemicals that are known but not commercially available in the catalog are optionally prepared by custom chemical synthesis facilities, many of which standard chemical supply facilities (eg, those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutically acceptable salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

R1、R2a、R2b、R2c、R2d、R3、R4、環A、環B、環C、環D、X1、X3或m1、m2、m3、n的定義與上述通式(Ia)和(Ib)化合物相同； R5選自C1-6烷基； R6選自離去基團，較佳F、Cl、Br、I、三氟甲磺酸酯基、甲磺酸酯基、對甲苯磺酸酯基或苯磺酸酯基；PG和R7選自氨基保護基；合成方法一：

R1, R2a, R2b, R2c, R2d, R3, R4, Ring A, Ring B, Ring C, Ring D, X1, X3 or m1, m2, m3, n are as defined in the general formulae (Ia) and (Ib) above The compounds are the same; R5 is selected from C1-6 alkyl; R6 is selected from leaving groups, preferably F, Cl, Br, I, trifluoromethanesulfonate, mesylate, p-toluenesulfonate Or besylate group; PG and R7 are selected from amino protecting group; Synthetic method one:

通式(Ia-1)化合物在鹼的作用下與含有雙離去基團的化合物反應得到通式(Ia-2)化合物；通式(Ia-2)化合物在脫出羰基和乙二醇保護基後得到通式(Ia-3)化合物；通式(Ia-3)化合物在鹼的作用下與碳酸二酯基化合物反應得到通式(Ia-4)化合物；通式(Ia-4)化合物在鹼的作用下與S-甲基異硫脲硫酸鹽反應、或者通式(Ia-4)化合物先與硫脲反應然後在鹼的作用下與甲基化試劑反應得到通式(Ia-5)化合物；通式(Ia-5)化合物在鹼的作用下與三氟甲磺酸酐反應、或者通式(Ib-5)化合物藉由氯代反應得到通式(Ia-6)化合物；通式(Ia-6)化合物藉由取代反應得到通式(Ia-7)化合物；通式(Ia-7)化合物藉由氧化反應得到通式(Ia-8)化合物；通式(Ia-8)化合物藉由取代反應得到通式(Ia-9)化合物；通式(Ia-9)化合物脫出R⁷ 後得到通式(Ia-10)化合物；通式(Ia-10)化合物藉由偶聯、取代或縮合反應通式(Ib-11)化合物；通式(Ia-11)化合物藉由脫掉氨基保護基團得到通式(Ib-12)化合物；通式(Ib-10)化合物藉由取代反應或者縮合反應得通式(Ia)化合物。合成方法二：

The compound of general formula (Ia-1) reacts with a compound containing a double leaving group under the action of a base to obtain a compound of general formula (Ia-2); The compound of the general formula (Ia-3) is obtained after the base; The compound of the general formula (Ia-3) is reacted with the carbonic diester compound under the action of a base to obtain the compound of the general formula (Ia-4); The compound of the general formula (Ia-4) Under the action of a base, react with S-methyl isothiourea sulfate, or the compound of the general formula (Ia-4) is first reacted with thiourea and then reacted with a methylating reagent under the action of a base to obtain the general formula (Ia-5) ) compound; the compound of general formula (Ia-5) reacts with trifluoromethanesulfonic anhydride under the action of a base, or the compound of general formula (Ib-5) is chlorinated to obtain the compound of general formula (Ia-6); Compound (Ia-6) obtains the compound of general formula (Ia-7) through substitution reaction; Compound of general formula (Ia-7) obtains compound of general formula (Ia-8) through oxidation reaction; Compound of general formula (Ia-8) The compound of general formula (Ia-9) is obtained by substitution reaction; The compound of general formula (Ia-9) is obtained by removing R ⁷ to obtain the compound of general formula (Ia-10); The compound of general formula (Ia-10) is obtained by coupling, Substitution or condensation reaction of the compound of general formula (Ib-11); The compound of general formula (Ia-11) is obtained by removing the amino protecting group to obtain the compound of general formula (Ib-12); The compound of general formula (Ib-10) is obtained by substituting The reaction or condensation reaction gives the compound of general formula (Ia). Synthesis method two:

通式(Ib-a)化合物在鹼的作用下與含有雙離去基團的化合物反應得到通式(Ib-2)化合物；通式(Ib-2)化合物在脫出羰基和乙二醇保護基後得到通式(Ib-3)化合物；通式(Ib-3)化合物在鹼的作用下與碳酸二酯基化合物反應得到通式(Ib-4)化合物；通式(Ib-4)化合物在鹼的作用下與S-甲基異硫脲硫酸鹽反應、或者通式(Ib-4)化合物先與硫脲反應然後在鹼的作用下與甲基化試劑反應得到通式(Ib-5)化合物；通式(Ib-5)化合物在鹼的作用下與三氟甲磺酸酐反應、或者通式(Ib-5)化合物藉由氯代反應得到通式(Ib-6)化合物；通式(Ib-6)化合物藉由取代反應得到通式(Ib-7)化合物；通式(Ib-7)化合物藉由氧化反應得到通式(Ib-8)化合物；通式(Ib-8)化合物藉由取代反應得到通式(Ib-9)化合物；通式(Ib-9)化合物藉由脫掉氨基保護基團得到通式(Ib-10)化合物；通式(Ib-10)化合物藉由取代反應或者縮合反應得通式(Ib)化合物。合成方法三：

The compound of general formula (Ib-a) reacts with a compound containing a double leaving group under the action of a base to obtain a compound of general formula (Ib-2); The compound of the general formula (Ib-3) is obtained after the base; The compound of the general formula (Ib-3) is reacted with the carbonic diester compound under the action of a base to obtain the compound of the general formula (Ib-4); The compound of the general formula (Ib-4) Under the action of a base, react with S-methyl isothiourea sulfate, or the compound of the general formula (Ib-4) is first reacted with thiourea and then reacted with a methylating reagent under the action of a base to obtain the general formula (Ib-5) ) compound; the compound of general formula (Ib-5) reacts with trifluoromethanesulfonic anhydride under the action of a base, or the compound of general formula (Ib-5) is chlorinated to obtain the compound of general formula (Ib-6); general formula Compound (Ib-6) is obtained by substitution reaction to obtain compound of general formula (Ib-7); Compound of general formula (Ib-7) is obtained by oxidation reaction to obtain compound of general formula (Ib-8); Compound of general formula (Ib-8) The compound of general formula (Ib-9) is obtained by substitution reaction; The compound of general formula (Ib-9) is obtained by removing the amino protecting group to obtain the compound of general formula (Ib-10); The compound of general formula (Ib-10) is obtained by Substitution reaction or condensation reaction gives the compound of general formula (Ib). Synthesis method three:

通式(Ib-1a)化合物經Danheiser-Stork反應得到通式(Ib-1b)化合物；通式(Ib-1b)化合物在酸催化下脫出甲基得到通式(Ib-1c)化合物；通式(Ib-1c)化合物在有機胺催化下得到通式(Ib-1d)化合物；通式(Ib-1d)化合物在鹼的作用下引入離去基團例如OTf，鹵素等得到通式(Ib-1e)化合物；通式(Ib-1e)化合物在金屬催化劑的作用下加氫得到通式(Ib-1f)化合物。合成方法四：

The compound of general formula (Ib-1a) is subjected to Danheiser-Stork reaction to obtain the compound of general formula (Ib-1b); The compound of general formula (Ib-1b) is demethylated under acid catalysis to obtain the compound of general formula (Ib-1c); The compound of formula (Ib-1c) can obtain the compound of general formula (Ib-1d) under the catalysis of organic amine; The compound of general formula (Ib-1d) can be introduced with a leaving group such as OTf, halogen, etc. under the action of a base to obtain the compound of general formula (Ib -1e) compound; The compound of general formula (Ib-1e) is hydrogenated under the action of a metal catalyst to obtain the compound of general formula (Ib-1f). Synthesis method four:

通式(Ib-1g)化合物經取代反應得到通式(Ib-1h)化合物；通式(Ib-1h)化合物金屬催化劑作用下，加氫得到通式(Ib-1i)化合物；通式(Ib-1i)化合物在酸催化下得到通式(Ib-1f)化合物。合成方法五：

The compound of the general formula (Ib-1g) is subjected to substitution reaction to obtain the compound of the general formula (Ib-1h); The compound of the general formula (Ib-1h) is hydrogenated under the action of a metal catalyst to obtain the compound of the general formula (Ib-1i); The general formula (Ib) -1i) Compounds of general formula (Ib-1f) are obtained under acid catalysis. Synthesis method five:

通式(Ib-1f)化合物在鹼的作用下與碳酸二酯基化合物或者氰基碳酸酯基化合物反應得到通式(Ib-1j)化合物；通式(Ib-1j)化合物與氨作用的得到通式(Ib-1k)化合物；通式(Ib-1k)化合物與苯甲醯異硫氰酸酯反應得到通式(Ib-1l)化合物；通式(Ib-1l)化合物在鹼性條件下關環得到通式(Ib-1m)化合物；或者通式(Ib-1j)化合物與硫脲反應得到通式(Ib-1m)化合物；通式(Ib-1m)化合物在鹼性作用下與甲基化試劑反應得到通式(Ib-1n)化合物；或者通式(Ib-1j)化合物在鹼的作用下與S-甲基異硫脲硫酸鹽反應得到通式(Ib-1n)化合物；通式(Ib-1n)化合物在鹼的作用下與三氟甲磺酸酐反應、或者通式(Ib-1n)化合物藉由氯代反應得到通式(Ib-1o)化合物；通式(Ib-1o)化合物藉由取代反應得到通式(Ib-1p)化合物；通式(Ib-1p)化合物藉由氧化反應得到通式(Ib-1q)化合物(q = 1 或2)；通式(Ib-1q)化合物藉由取代反應得到通式(Ib-1r)化合物；通式(Ib-1r)化合物藉由脫掉氨基保護基團得到通式(Ib-1s)化合物；通式(Ib-1s)化合物藉由取代反應或者縮合反應得通式(Ib-1)化合物。除非有相反的陳述，在說明書和申請專利範圍中使用的術語具有下述含義。The compound of general formula (Ib-1f) is reacted with a carbonic diester compound or a cyanocarbonate compound under the action of a base to obtain a compound of general formula (Ib-1j); The compound of general formula (Ib-1j) is reacted with ammonia to obtain the compound of general formula (Ib-1k); The compound of general formula (Ib-1k) is reacted with benzyl isothiocyanate to obtain the compound of general formula (Ib-11); The compound of general formula (Ib-1l) is ring-closed under basic conditions to obtain the compound of general formula (Ib-1m); or the compound of general formula (Ib-1j) is reacted with thiourea to obtain the compound of general formula (Ib-1m); The compound of general formula (Ib-1m) reacts with a methylating reagent under the action of alkali to obtain the compound of general formula (Ib-1n); or the compound of general formula (Ib-1j) reacts with S-methylisosulfide under the action of alkali Urea sulfate reacts to obtain the compound of general formula (Ib-1n); The compound of general formula (Ib-1n) is reacted with trifluoromethanesulfonic anhydride under the action of a base, or the compound of general formula (Ib-1n) is obtained by chlorination to obtain the compound of general formula (Ib-1o); The compound of general formula (Ib-1o) is obtained by substitution reaction to obtain the compound of general formula (Ib-1p); The compound of general formula (Ib-1p) is obtained by oxidation reaction to obtain the compound of general formula (Ib-1q) (q = 1 or 2); The compound of general formula (Ib-1q) is obtained by substitution reaction to obtain the compound of general formula (Ib-1r); The compound of general formula (Ib-1r) is obtained by removing the amino protecting group to obtain the compound of general formula (Ib-1s); The compound of the general formula (Ib-1s) can be obtained by a substitution reaction or a condensation reaction to obtain the compound of the general formula (Ib-1). Unless stated to the contrary, terms used in the specification and claims have the following meanings.

本發明所述基團和化合物中所涉及的碳、氫、氧、硫、氮或F、Cl、Br、I均包括它們的同位素情況，及本發明所述基團和化合物中所涉及的碳、氫、氧、硫或氮任選進一步被一個或複數它們對應的同位素所替代，其中碳的同位素包括¹² C、¹³ C和¹⁴ C，氫的同位素包括氕 (H)、氘(D，又叫重氫)、氚(T，又叫超重氫)，氧的同位素包括¹⁶ O、¹⁷ O和¹⁸ O，硫的同位素包括³² S、³³ S、³⁴ S和³⁶ S，氮的同位素包括¹⁴ N和¹⁵ N，氟的同位素包括¹⁷ F和¹⁹ F，氯的同位素包括³⁵ Cl和³⁷ Cl，溴的同位素包括⁷⁹ Br和⁸¹ Br。The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention all include their isotopic conditions, and the carbons involved in the groups and compounds of the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include ¹² C, ¹³ C and ¹⁴ C, hydrogen isotopes include protium (H), deuterium (D, and called heavy hydrogen), tritium (T, also known as super-heavy hydrogen), the isotopes of oxygen include ¹⁶ O, ¹⁷ O and ¹⁸ O, the isotopes of sulfur include ³² S, ³³ S, ³⁴ S and ³⁶ S, and the isotopes of nitrogen include ¹⁴ N and ¹⁵ N, isotopes of fluorine include ¹⁷ F and ¹⁹ F, isotopes of chlorine include ³⁵ Cl and ³⁷ Cl, and isotopes of bromine include ⁷⁹ Br and ⁸¹ Br.

“烷基”是指1至20個碳原子的直鏈或支鏈飽和脂肪族烴基，較佳為1至8個碳原子的烷基，更佳為1至6個碳原子的烷基，進一步較佳為1至4個碳原子的烷基。非限制性實施例包括甲基、乙基、正丙基、異丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、異戊基、新戊基、正己基及其各種支鏈異構體；所述的烷基可以任選進一步被0至6個選自F、Cl、Br、I、羥基、巰基、硝基、氰基、氨基、烷基氨基、醯胺基、烯基、炔基、C_1-6 烷基、C_1-6 羥基烷基、C_1-6 烷氧基、3至8元碳環基、3至8元雜環基、3至8元碳環基氧基、3至8元雜環基氧基、羧基或者羧酸酯基的取代基所取代，本文中出現的烷基，其定義與本定義一致。"Alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, further Preferred is an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and its various branched chain isomers; the alkyl group can be optionally further selected from 0 to 6 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, acyl Amine, alkenyl, alkynyl, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, 3- to 8-membered carbocyclyl, 3- to 8-membered heterocyclyl, 3 to 8-membered Substituents substituted by 8-membered carbocyclyloxy, 3- to 8-membered heterocyclyloxy, carboxyl or carboxylate groups, and alkyl groups appearing herein, have the same definition as this definition.

“亞烷基”是指直鏈和支鏈的二價飽和烴基，包括-(CH₂ )_v -(v為1至10的整數)，亞烷基實施例包括但不限於亞甲基、亞乙基、亞丙基和亞丁基等；所述的亞烷基可以任選進一步被0至5個選自F、Cl、Br、I、羥基、巰基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羥基烷基、烷氧基、碳環基、雜環基、碳環基氧基、雜環基氧基、羧基或者羧酸酯基的取代基所取代。本文中出現的亞烷基，其定義與本定義一致。"Alkylene" refers to linear and branched divalent saturated hydrocarbon groups, including -(CH ₂ ) _v - (v is an integer from 1 to 10). Examples of alkylene include but are not limited to methylene, methylene Ethyl, propylene and butylene, etc.; the alkylene group can be optionally further selected from 0 to 5 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkyl Substituted by substituents of amino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate . Alkylene groups appearing herein are defined in accordance with this definition.

“環烷基”是指一價飽和的碳環烴基，通常有3至10個碳原子，非限制性實施例包括環丙基、環丁基、環戊基、環己基或環庚基等。所述的環烷基可以任選進一步被0至5個選自F、Cl、Br、I、羥基、巰基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羥基烷基、烷氧基、碳環基、雜環基、碳環基氧基、雜環基氧基、羧基或者羧酸酯基的取代基所取代。本文中出現的環烷基，其定義如上所述。"Cycloalkyl" refers to a monovalent saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms, non-limiting examples including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and the like. The cycloalkyl group can be optionally further selected from 0 to 5 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, Substituents of hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate. Cycloalkyl groups appearing herein are as defined above.

“炔基”是指直鏈和支鏈的一價不飽和烴基，其具有至少1個，通常有1、2或3個碳碳三鍵，主鏈包括2至10個碳原子，進一步較佳2至6個碳原子，更佳在主鏈上有2至4個碳原子，炔基實施例包括但不限於乙炔基、炔丙基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-甲基-1-丁炔基、2-甲基-1-丁炔基、2-甲基-3-丁炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基、1-甲基-1-戊炔基、2-甲基-1-戊炔基、1-庚炔基、2-庚炔基、3-庚炔基、4-庚炔基、1-辛炔基、3-辛炔基、1-壬炔基、3-壬炔基、1-癸炔基、4-癸炔基、1,3-丁二炔、1,3-戊二炔、1,4-戊二炔和1,4-己二炔等；所述的炔基可以任選進一步被0至5個選自F、Cl、Br、I、羥基、巰基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羥基烷基、烷氧基、碳環基、雜環基、碳環基氧基、雜環基氧基、羧基或者羧酸酯基的取代基所取代。本文中出現的炔基，其定義與本定義一致。"Alkynyl" refers to linear and branched monovalent unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, and the main chain includes 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain, examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1- Butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl , 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl Alkynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1 -Octynyl, 3-Octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, 1,3-butadiyne, 1,3-pentadiyne , 1,4-pentadiyne and 1,4-hexadiyne, etc.; the alkynyl group can be optionally further selected from 0 to 5 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano group, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate substituted by the substituents of the base. Alkynyl groups appearing herein are defined in accordance with this definition.

“烷氧基”是指-O-烷基。非限制性實施例包括甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、環丙氧基和環丁氧基。所述的烷氧基可以任選進一步被0至5個選自F、Cl、Br、I、羥基、巰基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羥基烷基、烷氧基、碳環基、雜環基、碳環基氧基、雜環基氧基、羧基或者羧酸酯基的取代基所取代。本文中出現的烷氧基，其定義與本定義一致。"Alkoxy" refers to -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyl oxy and cyclobutoxy. The alkoxy group can be optionally further selected from 0 to 5 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, Substituents of hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate. Alkoxy groups appearing herein are defined in accordance with this definition.

“碳環基”或“碳環”是指取代的或未取代的飽和或不飽和的芳香環或者非芳香環，芳香環或者非芳香環可以是3至8元的單環、4至12元雙環或者10至15元三環體系，芳香環或者非芳香環任選為單環、橋環或者螺環。非限制性實施例包括環丙烷、環丁烷、環戊烷、環己烷、環庚烷、1-環戊基-1-烯基、1-環戊基-2-烯基、1-環戊基-3-烯基、環己基、1-環己基-2-烯基、1-環己基-3-烯基、環己烯基、苯環或萘環。所述的碳環可以任選進一步被0至5個選自F、Cl、Br、I、=O、羥基、巰基、硝基、氰基、氨基、烷基氨基、醯胺基、烯基、炔基、烷基、羥基烷基、烷氧基、碳環基、雜環基、碳環基氧基、雜環基氧基、羧基或者羧酸酯基的取代基所取代。本文中出現的碳環或碳環基，其定義與本定義一致。"Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which may be a 3- to 8-membered monocyclic, 4- to 12-membered A bicyclic or 10 to 15 membered tricyclic ring system, the aromatic or non-aromatic ring is optionally monocyclic, bridged or spirocyclic. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring or naphthalene ring. Said carbocycle can optionally be further selected from 0 to 5 groups selected from F, Cl, Br, I, =O, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, Substituents of alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate. Where carbocycle or carbocyclyl occurs herein, the definition is consistent with this definition.

“雜環基”或“雜環”是指包含1至3個選自N、O或S的雜原子的、取代的或未取代的飽和或不飽和的芳香環或者非芳香環，芳香環或者非芳香環可以是3至8元的單環、4至12元雙環或者10至15元三環體系，較佳3至8元雜環基，雜環基的環中選擇性取代的N、S可被氧化成各種氧化態。雜環基可以連接在雜原子或者碳原子上，雜環基可以連接有橋環或者螺環，非限制性實施例包括環氧乙基、氮雜環丙基、氧雜環丁基、氮雜環丁基、1,3-二氧戊環基、1,4-二氧戊環基、1,3-二氧六環基、氮雜環庚基、吡啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、噠嗪基、咪唑基、呱啶基、呱叮基、嗎啉基、硫代嗎啉基、1,3-二噻基、二氫呋喃基、二氫吡喃基、二噻戊環基、四氫呋喃基、四氫吡咯基、四氫咪唑基、四氫噻唑基、四氫吡喃基、苯並咪唑基、苯並吡啶基、吡咯並吡啶基、苯並二氫呋喃基、氮雜二環[3.2.1]辛烷基、氮雜二環[5.2.0]壬烷基、氧雜三環[5.3.1.1]十二烷基、氮雜金剛烷基和氧雜螺[3.3]庚烷基。所述的雜環基可以任選進一步被0至5個選自F、Cl、Br、I、=O、羥基、巰基、硝基、氰基、氨基、烷基氨基、醯胺基、烯基、炔基、烷基、羥基烷基、烷氧基、碳環基、雜環基、碳環基氧基、雜環基氧基、羧基或者羧酸酯基的取代基所取代。本文中出現的雜環基，其定義與本定義一致。"Heterocyclyl" or "heterocycle" means a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring containing 1 to 3 heteroatoms selected from N, O or S, an aromatic ring or The non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring or a 10- to 15-membered tricyclic ring system, preferably a 3- to 8-membered heterocyclic group, the N, S optionally substituted in the ring of the heterocyclic group Can be oxidized into various oxidation states. The heterocyclyl group can be attached to a heteroatom or a carbon atom, and the heterocyclyl group can be attached to a bridged ring or a spiro ring, non-limiting examples include oxirane, azetidinyl, oxetanyl, aza Cyclobutyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, pyridyl, furyl, thienyl, pyridine Alkyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyridyl, cyanidyl, morpholinyl, thiomorpholinyl, 1,3-dithiyl, Dihydrofuranyl, dihydropyranyl, dithiopenanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl , pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl Alkyl, azaadamantyl and oxaspiro[3.3]heptyl. The heterocyclic group can be optionally further selected from 0 to 5 groups selected from F, Cl, Br, I, =O, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl , alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate substituents. Heterocyclyl groups appearing herein are defined in accordance with this definition.

“螺環”是指取代的或未取代的單環之間共用一個碳原子(稱螺原子)的5至20元多環基團，其可以包含0至5個雙鍵，且可以含有0至5個選自N、O或S(=O)n的雜原子。較佳為6至14元，進一步較佳為6至12元，更佳6至10元，其非限定性實例包括：

、

、

、

或

，當被取代時，取代基可以為1至5個選自F、Cl、Br、I、烷基、環烷基、烷氧基、鹵代烷基、硫醇、羥基、硝基、巰基、氨基、氰基、異氰基、芳基、雜芳基、雜環基、橋環基、螺環基、並環基、羥基烷基、=O、羰基、醛、羧酸、甲酸酯、-(CH₂ )_m -C(=O)-Ra、-O-(CH₂ )_m -C(=O)-Ra、-(CH₂ )_m -C(=O)-NRbRc、-(CH₂ )_m S(=O)nRa、-(CH₂ )_m -烯基-Ra、ORd或-(CH₂ )_m -炔基-Ra (其中m、n為0、1或2)、芳基硫基、硫代羰基、矽烷基或-NRbRc等基團，其中Rb與Rc獨立選自包括H、羥基、氨基、羰基、烷基、烷氧基、環烷基、雜環基、芳基、雜芳基、磺醯基、三氟甲磺醯基，作為選擇，Rb與Rc可形成五或六元環烷基或雜環基。Ra與Rd各自獨立選自芳基、雜芳基、烷基、烷氧基、環烷基、雜環基、羰基、酯基、橋環基、螺環基或並環基。本文中出現的螺環，其定義與本定義一致。"Spirocyclic" refers to a 5- to 20-membered polycyclic group of substituted or unsubstituted monocyclic rings sharing one carbon atom (called a spiro atom), which may contain 0 to 5 double bonds, and may contain 0 to 5 5 heteroatoms selected from N, O or S(=O)n. Preferably it is 6 to 14 yuan, more preferably 6 to 12 yuan, more preferably 6 to 10 yuan, and non-limiting examples thereof include:

,

or

, when substituted, the substituent may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, paracyclyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -( CH ₂ ) _m -C(=O)-Ra, -O-(CH ₂ ) _m -C(=O)-Ra, -(CH ₂ ) _m -C(=O)-NRbRc, -(CH ₂ ) mS(=O)nRa, -( _CH2 ) _m -alkenyl-Ra, ORd or -( _CH2 ) _m -alkynyl-Ra (where _m , n are 0, 1 or 2), arylthio , thiocarbonyl, silyl or -NRbRc and other groups, wherein Rb and Rc are independently selected from the group consisting of H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl sulfonyl, sulfonyl, trifluoromethanesulfonyl, and alternatively, Rb and Rc may form a five- or six-membered cycloalkyl or heterocyclyl group. Ra and Rd are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or cyclo. The spiro rings appearing herein are defined in accordance with this definition.

“並環”是指系統中的每個環與體系中的其他環共享毗鄰的一對碳原子的多環基團，其中一個或複數環可以含有0個或複數雙鍵，且可以是取代的或未取代，並環體系中的各個環可以含0至5個選自Ｎ、S(=O)n或O的雜原子。較佳為5至20元，進一步較佳為5至14元，更有選5至12元，再進一步較佳5至10元。非限定性實例包括：

、

、

、

"Paracyclic" refers to a polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain zero or more double bonds and may be substituted Or unsubstituted, each ring in the ring system may contain 0 to 5 heteroatoms selected from N, S(=O)n or O. It is preferably 5 to 20 yuan, more preferably 5 to 14 yuan, more preferably 5 to 12 yuan, and still more preferably 5 to 10 yuan. Non-limiting examples include:

,

當被取代時，取代基可以為1至5個選自F、Cl、Br、I、烷基、環烷基、烷氧基、鹵代烷基、硫醇、羥基、硝基、巰基、氨基、氰基、異氰基、芳基、雜芳基、雜環基、橋環基、螺環基、並環基、羥基烷基、=O、羰基、醛、羧酸、甲酸酯、-(CH₂ )_m -C(=O)-Ra、-O-(CH₂ )_m -C(=O)-Ra、-(CH₂ )_m -C(=O)-NRbRc、-(CH₂ )_m S(=O)nRa、-(CH₂ )_m -烯基-Ra、ORd或-(CH₂ )_m -炔基-Ra (其中m、n為0、1或2)、芳基硫基、硫代羰基、矽烷基或-NRbRc等基團，其中Rb與Rc獨立選自包括H、羥基、氨基、羰基、烷基、烷氧基、環烷基、雜環基、芳基、雜芳基、磺醯基、三氟甲磺醯基，作為選擇，Rb與Rc可形成五或六元環烷基或雜環基。Ra與Rd各自獨立選自芳基、雜芳基、烷基、烷氧基、環烷基、雜環基、羰基、酯基、橋環基、螺環基或並環基。本文中出現的並環，其定義與本定義一致。When substituted, the substituents may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano radical, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, cyclo, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH ₂ ) _m -C(=O)-Ra, -O-(CH ₂ ) _m -C(=O)-Ra, -(CH ₂ ) _m -C(=O)-NRbRc, -(CH ₂ ) _m S(=O)nRa, -( _CH2 ) _m -alkenyl-Ra, ORd or -( _CH2 ) _m -alkynyl-Ra (where m, n are 0, 1 or 2), arylthio, Thiocarbonyl, silyl or -NRbRc and other groups, wherein Rb and Rc are independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , sulfonyl, trifluoromethanesulfonyl, alternatively, Rb and Rc may form a five- or six-membered cycloalkyl or heterocyclyl group. Ra and Rd are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or cyclo. Conjunctions appearing in this document are defined in accordance with this definition.

“橋環”是指任意兩個環共用2個不直接連接的原子的多環基團，可以含有0個或複數雙鍵，且可以是取代的或未取代的，橋環體系中的任意環可以含0至5個選自N、S(=O)n或O雜原子或基團(其中n為1、1、2)。環原子包含5至20個原子，較佳為5至14個原子，進一步較佳5至12個，再進一步較佳5至10個。非限定性實例包括

、

、

、

、

和金剛烷。當被取代時，取代基可以為1至5個選自F、Cl、Br、I、烷基、環烷基、烷氧基、鹵代烷基、硫醇、羥基、硝基、巰基、氨基、氰基、異氰基、芳基、雜芳基、雜環基、橋環基、螺環基、並環基、羥基烷基、=O、羰基、醛、羧酸、甲酸酯、-(CH₂ )_m -C(=O)-Ra、-O-(CH₂ )_m -C(=O)-Ra、-(CH₂ )_m -C(=O)-NRbRc、-(CH₂ )_m S(=O)nRa、-(CH₂ )_m -烯基-Ra、ORd或-(CH₂ )_m -炔基-Ra (其中m、n為0、1或2)、芳基硫基、硫代羰基、矽烷基或-NRbRc等基團，其中Rb與Rc獨立選自包括H、羥基、氨基、羰基、烷基、烷氧基、環烷基、雜環基、芳基、雜芳基、磺醯基、三氟甲磺醯基，作為選擇，Rb與Rc可形成五或六元環烷基或雜環基。Ra與Rd各自獨立選自芳基、雜芳基、烷基、烷氧基、環烷基、雜環基、羰基、酯基、橋環基、螺環基或並環基。本文中出現的橋環，其定義與本定義一致。"Bridged ring" refers to a polycyclic group in which any two rings share 2 atoms that are not directly connected, may contain 0 or more double bonds, and may be substituted or unsubstituted, any ring in the bridged ring system May contain 0 to 5 heteroatoms or groups selected from N, S(=O)n or O (wherein n is 1, 1, 2). The ring atoms contain 5 to 20 atoms, preferably 5 to 14 atoms, more preferably 5 to 12 atoms, still more preferably 5 to 10 atoms. Non-limiting examples include

,

and adamantane. When substituted, the substituents may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano radical, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, cyclo, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH ₂ ) _m -C(=O)-Ra, -O-(CH ₂ ) _m -C(=O)-Ra, -(CH ₂ ) _m -C(=O)-NRbRc, -(CH ₂ ) _m S(=O)nRa, -( _CH2 ) _m -alkenyl-Ra, ORd or -( _CH2 ) _m -alkynyl-Ra (where m, n are 0, 1 or 2), arylthio, Thiocarbonyl, silyl or -NRbRc and other groups, wherein Rb and Rc are independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , sulfonyl, trifluoromethanesulfonyl, alternatively, Rb and Rc may form a five- or six-membered cycloalkyl or heterocyclyl group. Ra and Rd are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or cyclo. Bridged rings appearing in this document are defined in accordance with this definition.

“雜單環”是指單環體系的“雜環基”或“雜環”，本文中出現的雜單環，其定義與本定義一致。"Heteromonocycle" refers to a "heterocyclyl" or "heterocycle" of a monocyclic ring system, and heteromonocycles appearing herein are as defined herein.

“雜並環”是指含有雜原子的“並環”。本文中出現的雜並環，其定義與本定義一致。"Heterocyclic" refers to a "heterocyclic" containing a heteroatom. Heterocycles appearing herein are defined in accordance with this definition.

“雜螺環”是指含有雜原子的“螺環”。本文中出現的雜螺環，其定義與本定義一致。"Heterospirocycle" refers to a "spirocycle" containing a heteroatom. Heterospirocycles appearing herein are defined in accordance with this definition.

“雜橋環”是指含有雜原子的“橋環”。本文中出現的雜橋環，其定義與本定義一致。"Heterobridged ring" refers to a "bridged ring" containing a heteroatom. Heterobridged rings appearing herein are defined in accordance with this definition.

“芳基”或“芳環”是指具有單環或稠合環的一價芳香族烴基，通常有6至10個碳原子，且可以是取代的或未取代的。當被取代時，取代基可以為1至5個選自F、Cl、Br、I、烷基、環烷基、烷氧基、鹵代烷基、硫醇、羥基、硝基、巰基、氨基、氰基、異氰基、芳基、雜芳基、雜環基、橋環基、螺環基、並環基、羥基烷基、=O、羰基、醛、羧酸、甲酸酯、-(CH₂ )_m -C(=O)-Ra、-O-(CH₂ )_m -C(=O)-Ra、-(CH₂ )_m -C(=O)-NRbRc、-(CH₂ )_m S(=O)nRa、-(CH₂ )_m -烯基-Ra、ORd或-(CH₂ )_m -炔基-Ra (其中m、n為0、1或2)、芳基硫基、硫代羰基、矽烷基或-NRbRc等基團，其中Rb與Rc獨立選自包括H、羥基、氨基、羰基、烷基、烷氧基、環烷基、雜環基、芳基、雜芳基、磺醯基、三氟甲磺醯基，作為選擇，Rb與Rc可形成五或六元環烷基或雜環基。Ra與Rd各自獨立選自芳基、雜芳基、烷基、烷氧基、環烷基、雜環基、羰基、酯基、橋環基、螺環基或並環基。本文中出現的芳基或芳環，其定義與本定義一致。"Aryl" or "aromatic ring" refers to a monovalent aromatic hydrocarbon group having a single or fused ring, usually 6 to 10 carbon atoms, and may be substituted or unsubstituted. When substituted, the substituents may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano radical, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, cyclo, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH ₂ ) _m -C(=O)-Ra, -O-(CH ₂ ) _m -C(=O)-Ra, -(CH ₂ ) _m -C(=O)-NRbRc, -(CH ₂ ) _m S(=O)nRa, -( _CH2 ) _m -alkenyl-Ra, ORd or -( _CH2 ) _m -alkynyl-Ra (where m, n are 0, 1 or 2), arylthio, Thiocarbonyl, silyl or -NRbRc and other groups, wherein Rb and Rc are independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , sulfonyl, trifluoromethanesulfonyl, alternatively, Rb and Rc may form a five- or six-membered cycloalkyl or heterocyclyl group. Ra and Rd are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or cyclo. Aryl groups or aromatic rings appearing herein are defined in accordance with this definition.

“雜芳基”是指取代或未取代的5至15元芳香環，且含有1至5個選自N、O或S(=O)n雜原子或基團，較佳5至10元雜芳香環，進一步較佳5至6元。雜芳基的非限制性實施例包括但不限於吡啶基、呋喃基、噻吩基、吡啶基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、噠嗪基、咪唑基、呱啶基、嗎啉、硫代嗎啉、1,3-二噻烷、苯並吡唑、呱叮基、苯並咪唑、苯並吡啶、吡咯並吡啶等。該雜芳基環可以稠合於芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為雜芳基環，非限制性實施例包含

和

。"Heteroaryl" refers to a substituted or unsubstituted 5- to 15-membered aromatic ring containing 1 to 5 heteroatoms or groups selected from N, O or S(=O)n, preferably a 5- to 10-membered heteroatom Aromatic ring, more preferably 5 to 6 members. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Quaridinyl, morpholine, thiomorpholine, 1,3-dithiane, benzopyrazole, quaternyl, benzimidazole, benzopyridine, pyrrolopyridine and the like. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples include

and

.

當被取代時，取代基可以為1至5個選自F、Cl、Br、I、烷基、環烷基、烷氧基、鹵代烷基、硫醇、羥基、硝基、巰基、氨基、氰基、異氰基、芳基、雜芳基、雜環基、橋環基、螺環基、並環基、羥基烷基、=O、羰基、醛、羧酸、甲酸酯、-(CH₂ )_m -C(=O)-Ra、-O-(CH₂ )_m -C(=O)-Ra、-(CH₂ )_m -C(=O)-NRbRc、-(CH₂ )_m S(=O)nRa、-(CH₂ )_m -烯基-Ra、ORd或-(CH₂ )_m -炔基-Ra (其中m、n為0、1或2)、芳基硫基、硫代羰基、矽烷基或-NRbRc等基團，其中Rb與Rc獨立選自包括H、羥基、氨基、羰基、烷基、烷氧基、環烷基、雜環基、芳基、雜芳基、磺醯基、三氟甲磺醯基，作為選擇，Rb與Rc可形成五或六元環烷基或雜環基。Ra與Rd各自獨立選自芳基、雜芳基、烷基、烷氧基、環烷基、雜環基、羰基、酯基、橋環基、螺環基或並環基。本文中出現的雜芳基，其定義與本定義一致。When substituted, the substituents may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano radical, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, cyclo, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH ₂ ) _m -C(=O)-Ra, -O-(CH ₂ ) _m -C(=O)-Ra, -(CH ₂ ) _m -C(=O)-NRbRc, -(CH ₂ ) _m S(=O)nRa, -( _CH2 ) _m -alkenyl-Ra, ORd or -( _CH2 ) _m -alkynyl-Ra (where m, n are 0, 1 or 2), arylthio, Thiocarbonyl, silyl or -NRbRc and other groups, wherein Rb and Rc are independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , sulfonyl, trifluoromethanesulfonyl, alternatively, Rb and Rc may form a five- or six-membered cycloalkyl or heterocyclyl group. Ra and Rd are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro, or cyclo. Heteroaryl groups appearing herein are defined in accordance with this definition.

“含有1至4個選自O、S、N的雜原子”是指含有1、2、3或4個選自O、S、N的雜原子。本文中，“所述的雜環含有1至4個選自O、S、N的雜原子”意指所述表述所位於的段落中的所有雜環各自獨立地含有1、2、3或4個選自O、S、N的雜原子。"Containing 1 to 4 heteroatoms selected from O, S, N" means containing 1, 2, 3 or 4 heteroatoms selected from O, S, N. Herein, "the said heterocycle contains 1 to 4 heteroatoms selected from O, S, N" means that all heterocycles in the paragraph in which the said expression is placed each independently contain 1, 2, 3 or 4 a heteroatom selected from O, S, N.

“0至X個取代基所取代”是指被0、1、2、3…X個取代基所取代，X選自1至10之間的任意整數。如“0至4個取代基所取代”是指被0、1、2、3或4個取代基所取代。如“0至5個取代基所取代”是指被0、1、2、3、4或5個取代基所取代。如“雜橋環任選進一步被0至4個選自H或F的取代基所取代”是指雜橋環任選進一步被0、1、2、3或4個選自H或F的取代基所取代。"Substituted with 0 to X substituents" means substituted with 0, 1, 2, 3 . . . X substituents, and X is selected from any integer between 1 and 10. As in "substituted with 0 to 4 substituents" means substituted with 0, 1, 2, 3 or 4 substituents. As in "substituted with 0 to 5 substituents" means substituted with 0, 1, 2, 3, 4 or 5 substituents. Such as "heterobridged ring is optionally further substituted with 0 to 4 substituents selected from H or F" means that the heterobridged ring is optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H or F base substituted.

X-Y元的環（X選自小於Y大於等於3的整數，Y選自4至12之間的任意整數）包括了X+1、X+2、X+3、X+4….Y元的環。環包括了雜環、碳環、芳環、芳基、雜芳基、環烷基、雜單環、雜並環、雜螺環或雜橋環。如“4-7元雜單環”是指4元、5元、6元或7元的雜單環，“5-10元雜並環” 是指5元、6元、7元、8元、9元或10元的雜並環。“4至9元含氮雜環”是指4元、5元、6元、7元、8元或9元的含氮雜環。The ring of X-Y members (X is selected from an integer less than Y and greater than or equal to 3, and Y is selected from any integer between 4 and 12) includes X+1, X+2, X+3, X+4....Y-membered rings ring. Rings include heterocycles, carbocycles, aromatic rings, aryl, heteroaryl, cycloalkyl, heteromonocycles, heterocycles, heterospirocycles, or heterobridged rings. For example, "4-7 membered heteromonocycle" refers to a 4-membered, 5-membered, 6-membered or 7-membered heteromonocycle, and "5-10 membered heterocyclic ring" refers to 5-membered, 6-membered, 7-membered, 8-membered , 9- or 10-membered heterocyclic ring. "4- to 9-membered nitrogen-containing heterocycle" refers to a 4-, 5-, 6-, 7-, 8-, or 9-membered nitrogen-containing heterocycle.

“藥學上可接受的鹽”或者“其藥學上可接受的鹽”是指本發明化合物保持游離酸或者游離鹼的生物有效性和特性，且所述的游離酸藉由與無毒的無機鹼或者有機鹼，所述的游離鹼藉由與無毒的無機酸或者有機酸反應取得的鹽。"Pharmaceutically acceptable salt" or "a pharmaceutically acceptable salt thereof" means that a compound of the present invention retains the biological effectiveness and properties of a free acid or a free base that is treated with a nontoxic inorganic base or Organic bases, said free bases are salts obtained by reaction with non-toxic inorganic or organic acids.

“藥物組合物”是指一種或多種本發明所述或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、共晶或藥學上可接受的鹽和其它化學組分形成的混合物，其中，“其它化學組分”是指藥學上可接受的載體。“載體”是指不會對生物體產生明顯刺激且不會消除所給予化合物的生物活性和特性的材料。"Pharmaceutical composition" means a mixture of one or more of the present invention or its stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, co-crystals or pharmaceutically acceptable salts and other chemical components , where "other chemical components" refers to a pharmaceutically acceptable carrier. "Carrier" refers to a material that is not appreciably irritating to the organism and that does not abrogate the biological activity and properties of the administered compound.

“前藥”是指可經體內代謝轉化為具有生物活性的本發明化合物。本發明的前藥藉由修飾本發明化合物中的氨基或者羧基來製備，該修飾可以藉由常規的操作或者在體內被除去，而得到母體化合物。當本發明的前藥被施予哺乳動物個體時，前藥可被割裂形成游離的氨基或者羧基。A "prodrug" refers to a compound of the present invention that can be metabolized in vivo into a biologically active compound. The prodrugs of the present invention are prepared by modifying the amino or carboxyl groups in the compounds of the present invention, and the modification can be removed by conventional manipulations or in vivo to obtain the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs can be cleaved to form free amino or carboxyl groups.

“共晶”是指活性藥物成分(API)和共晶形成物(CCF)在氫鍵或其他非共價鍵的作用下結合而成的晶體，其中API和CCF的純態在室溫下均為固體，並且各組分間存在固定的化學計量比。共晶是一種多組分晶體，既包含兩種中性固體之間形成的二元共晶，也包含中性固體與鹽或溶劑化物形成的多元共晶。"Co-crystal" refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein the pure states of API and CCF are both at room temperature is a solid, and there is a fixed stoichiometric ratio between the components. A co-crystal is a multicomponent crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between neutral solids and salts or solvates.

“動物”是指包括哺乳動物，例如人、陪伴動物、動物園動物和家畜，較佳人、馬或者犬。"Animal" is meant to include mammals such as humans, companion animals, zoo animals and domestic animals, preferably humans, horses or dogs.

“立體異構體”是指由分子中原子在空間上排列方式不同所產生的異構體，包括順反異構體、對映異構體和構象異構體。"Stereoisomers" refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.

“任選”或“任選地”或“選擇性的”或“選擇性地”是指隨後所述的事件或狀況可以但未必發生，該描述包括其中發生該事件或狀況的情況及其中未發生的情況。例如，“選擇性地被烷基取代的雜環基”是指該烷基可以但未必存在，該描述包括其中雜環基被烷基取代的情況，及其中雜環基未被烷基取代的情況。"Optional" or "optionally" or "selective" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not occur what happened. For example, "heterocyclyl optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes instances where the heterocyclyl group is substituted with an alkyl group, as well as where the heterocyclyl group is not substituted with an alkyl group Condition.

以下實施例詳細說明本發明的技術方案，但本發明的保護範圍包括但是不限於此。The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited thereto.

化合物的結構是藉由核磁共振 (NMR) 或 (和) 質譜 (MS) 來確定的。NMR 位移 (δ) 以10-6 (ppm) 的單位給出。NMR的測定是用 (Bruker Avance III 400和Bruker Avance 300) 核磁儀，測定溶劑為氘代二甲基亞碸 (DMSO-d6)，氘代氯仿 (CDCl3)，氘代甲醇 (CD3OD)，內標為四甲基矽烷(TMS)； MS的測定用(Agilent 6120B(ESI) 和Agilent 6120B(APCI))； HPLC的測定使用Agilent 1260DAD高壓液相色譜儀 (Zorbax SB-C18 100 × 4.6 mm,3.5 μM)；薄層層析矽膠板使用煙臺黃海HSGF254 或青島GF254 矽膠板，薄層色譜法 (TLC) 使用的矽膠板採用的規格是0.15 mm-0.20 mm，薄層層析分離純化產品採用的規格是0.4 mm - 0.5 mm；柱層析一般使用煙臺黃海矽膠200-300目矽膠為載體； Boc：叔丁氧基羰基；Ts：對甲苯磺醯基；Cbz：苄氧羰基；TMS：三甲基矽基；實施例 1 2-[(S)-1-丙烯醯基-4-[2'-[[(S)-1-甲基吡咯烷-2-基]甲氧基]-1,3,5',8'-四氫-6'H-螺[茚-2,7'-喹唑啉]-4'-基] 呱嗪-2-基] 乙腈；2,2,2-三氟乙酸鹽(化合物 1 )； 2-[(S)-1-acryloyl-4-[2'-[[(S)-1-methylpyrrolidin-2-yl]methoxy]-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl]piperazin-2-yl]acetonitrile；2,2,2-trifluoroacetic acid.

The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), internal standard For tetramethylsilane (TMS); for MS determination (Agilent 6120B (ESI) and Agilent 6120B (APCI)); for HPLC determination using Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM ); TLC silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15 mm-0.20 mm, and the specification used for TLC separation and purification products is 0.4 mm - 0.5 mm; Yantai Huanghai silica gel 200-300 mesh is generally used as a carrier for column chromatography; Boc: tert-butoxycarbonyl; Ts: p-toluenesulfonyl; Cbz: benzyloxycarbonyl; TMS: trimethylsilicon base; Example 1 2-[(S)-1-propenyl-4-[2'-[[(S)-1-methylpyrrolidin-2-yl]methoxy]-1,3, 5',8'-Tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl]oxazin-2-yl]acetonitrile; 2,2,2-trifluoroacetic acid Salt ( Compound 1 ); 2-[(S)-1-acryloyl-4-[2'-[[(S)-1-methylpyrrolidin-2-yl]methoxy]-1,3,5',8'- tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl]piperazin-2-yl]acetonitrile; 2,2,2-trifluoroacetic acid.

第一步：1,3-二氫二螺[茚-2,3'-環己烷-1',2''-[1,3]二氧戊環]-4'-酮(1a)； 1,3-dihydrodispiro[indene-2,3'-cyclohexane-1',2''-[1,3]dioxolan]-4'-one.

將1,4-環己二酮單乙二醇縮酮(8 g，51.3 mmol)溶於乾燥的叔丁醇(130 mL)中，氮氣保護，加入叔丁醇鉀固體(12.8 g，113.7 mmol)。室溫下攪拌30 min後加入1，2-二(溴甲基)苯(13.5 g，51.2 mmol)，加畢，保持室溫反應過夜。TLC監控反應完全後，加入100 mL冰水淬滅反應，用100 mL二氯甲烷萃取三次，合併有機相，無水硫酸鈉乾燥，減壓濃縮。柱層析後得到目標產物1a，無色黏稠狀液體(3 g，收率：22.7%)。 MS m/z (ESI): 259.3 [M+H]⁺ The first step: 1,3-dihydrodispiro[indene-2,3'-cyclohexane-1',2''-[1,3]dioxolane]-4'-one (1a); 1,3-dihydrodispiro[indene-2,3'-cyclohexane-1',2''-[1,3]dioxolan]-4'-one.

1,4-Cyclohexanedione monoethylene glycol ketal (8 g, 51.3 mmol) was dissolved in dry tert-butanol (130 mL) under nitrogen, and potassium tert-butoxide solid (12.8 g, 113.7 mmol) was added. ). After stirring at room temperature for 30 min, 1,2-bis(bromomethyl)benzene (13.5 g, 51.2 mmol) was added, the addition was completed, and the reaction was kept at room temperature overnight. After monitoring the completion of the reaction by TLC, 100 mL of ice water was added to quench the reaction, extracted three times with 100 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target product 1a was obtained as a colorless viscous liquid (3 g, yield: 22.7%). MS m/z (ESI): 259.3 [M+H] ⁺

第二步：1,3-二氫二螺[茚-2,1'-環己烷-3',2''-[1,3] 二氧戊烷](1b)； 1,3-dihydrodispiro[indene-2,1'-cyclohexane-3',2''-[1,3]dioxolane].

將化合物1a(1 g，3.87 mmol)溶於10 mL一縮二乙二醇中，加入2 mL水合肼，體系升至80^o C反應1h，後用微波加熱至200^o C反應30 min。TLC監控反應結束，加入15 mL水稀釋，用20 mL二氯甲烷萃取三次，合併有機相，無水硫酸鈉乾燥，減壓濃縮。柱層析後得到目標產物1b，無色黏稠狀液體(0.7 g，收率：77%)。 MS m/z (ESI): 245.3 [M+H]⁺ Step 2: 1,3-Dihydrodispiro[indene-2,1'-cyclohexane-3',2''-[1,3]dioxolane](1b); 1,3-dihydrodispiro [indene-2,1'-cyclohexane-3',2''-[1,3]dioxolane].

Compound 1a (1 g, 3.87 mmol) was dissolved in 10 mL of diethylene glycol, 2 mL of hydrazine hydrate was added, the system was heated to 80 ^o C for 1 h, and then heated to 200 ^o C by microwave for 30 min. TLC monitored the end of the reaction, added 15 mL of water to dilute, extracted three times with 20 mL of dichloromethane, combined the organic phases, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target product 1b was obtained as a colorless viscous liquid (0.7 g, yield: 77%). MS m/z (ESI): 245.3 [M+H] ⁺

第三步：1',3'-二氫螺[環己烷-1,2'-茚]-3-酮(1c)； 1',3'-dihydrospiro[cyclohexane-1,2'-inden]-3-one.

將化合物1b(2.5 g，10.23 mmol)溶於10 mL四氫呋喃溶液中，於室溫下滴加6N鹽酸20 mL，滴加完全後，室溫下反應4h。TLC監控反應完全後，加入15 mL水稀釋，用20 mL二氯甲烷萃取三次，合併有機相，用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到目標產物1c，白色固體(1.8 g，收率：87.8%)。 MS m/z (ESI): 201.3 [M+H]⁺ The third step: 1',3'-dihydrospiro[cyclohexane-1,2'-inden]-3-one (1c); 1',3'-dihydrospiro[cyclohexane-1,2'-inden] -3-one.

Compound 1b (2.5 g, 10.23 mmol) was dissolved in 10 mL of tetrahydrofuran solution, and 20 mL of 6N hydrochloric acid was added dropwise at room temperature. After the dropwise addition was complete, the reaction was carried out at room temperature for 4 h. After monitoring the completion of the reaction by TLC, add 15 mL of water to dilute, extract three times with 20 mL of dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. After column chromatography, the target product 1c was obtained as a white solid (1.8 g, yield: 87.8%). MS m/z (ESI): 201.3 [M+H] ⁺

第四步：3-氧代-1'，3'-二氫螺[環己烷-1,2'-茚] -4-羧酸甲酯(1d)； methyl 3-oxo-1',3'-dihydrospiro[cyclohexane-1,2'-indene]-4-carboxylate.

將氫化鈉(0.4 g，10.0 mmol)懸浮於15 mL乾燥的四氫呋喃中，氮氣保護，加入碳酸二甲酯(2.1 mL，25.0 mmol)，加畢，體系加熱至80^o C攪拌30 min。然後滴加化合物1c(1.0 g，5.0 mmol)的四氫呋喃溶液(8 mL)，滴加完後保持80^o C繼續反應2h。TLC監控反應完成後，冷卻至室溫，墊矽藻土過濾，濾液加入20 mL冰水稀釋，用30 mL二氯甲烷萃取三次，合併有機相，用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到目標產物1d，白色固體(0.8 g，收率：62%)。 MS m/z (ESI): 259.1 [M+H]⁺ The fourth step: methyl 3-oxo-1',3'-dihydrospiro[cyclohexane-1,2'-indene]-4-carboxylate (1d); methyl 3-oxo-1',3 '-dihydrospiro[cyclohexane-1,2'-indene]-4-carboxylate.

Sodium hydride (0.4 g, 10.0 mmol) was suspended in 15 mL of dry tetrahydrofuran, under nitrogen protection, dimethyl carbonate (2.1 mL, 25.0 mmol) was added, and the system was heated to 80 ^o C and stirred for 30 min. Then, a solution of compound 1c (1.0 g, 5.0 mmol) in tetrahydrofuran (8 mL) was added dropwise, and the reaction was continued at 80 ^° C for 2 h after the dropwise addition. After monitoring the reaction by TLC, it was cooled to room temperature, filtered through celite, the filtrate was diluted with 20 mL of ice water, extracted three times with 30 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target product 1d was obtained as a white solid (0.8 g, yield: 62%). MS m/z (ESI): 259.1 [M+H] ⁺

第五步：2'-(甲硫基)-1,3,5'，8'-四氫-6'H-螺[茚-2,7'-喹唑啉] -4'-醇(1e)； 2'-(methylthio)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-ol.

將化合物1d(0.2 g，0.78 mmol)溶於1 mL四氫呋喃中，加入S-甲基異硫脲硫酸鹽(335 mg，1.17 mmol)，後於室溫下滴加氫氧化鉀(359 mg，6.4 mmoL)的水溶液(2 mL)。滴加完畢後保持室溫反應過夜。待反應完成後，加入10 mL水稀釋，用1N鹽酸調節pH至9-10左右，然後用20 mL二氯甲烷萃取三次，合併有機相，用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到目標產物1e，白色固體(34 mg，收率：14.6%)。 Ms m/z (ESI): 299.4 [M+H]⁺ The fifth step: 2'-(methylthio)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazoline]-4'-ol (1e ); 2'-(methylthio)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-ol.

Compound 1d (0.2 g, 0.78 mmol) was dissolved in 1 mL of tetrahydrofuran, S-methylisothiourea sulfate (335 mg, 1.17 mmol) was added, and potassium hydroxide (359 mg, 6.4 mmol) was added dropwise at room temperature mmol) in water (2 mL). After the dropwise addition, the reaction was kept at room temperature overnight. After the reaction is completed, add 10 mL of water to dilute, adjust the pH to about 9-10 with 1N hydrochloric acid, then extract three times with 20 mL of dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. After column chromatography, the target product 1e was obtained as a white solid (34 mg, yield: 14.6%). Ms m/z (ESI): 299.4 [M+H] ⁺

第六步：2'-(甲硫基)-1,3,5'，8'-四氫-6'H-螺[茚-2,7'-喹唑啉] -4'-三氟甲磺酸酯(1f)； 2'-(methylthio)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl trifluoromethanesulfonate

The sixth step: 2'-(methylthio)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazoline]-4'-trifluoromethane Sulfonate (1f); 2'-(methylthio)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl trifluoromethanesulfonate

將化合物1e(34 mg，0.114 mmol)溶於5 mL二氯甲烷中，加入N,N-二異丙基乙胺(0.08 mL，0.456 mmol)，冰浴下加入三氟甲磺酸酐(64.3 mg，0.228 mmol)，冰浴下攪拌1 h。待反應完全後加入15 mL二氯甲烷稀釋，後用10 mL水洗滌反應液，再用10 mL飽和碳酸氫鈉水溶液洗滌反應液，有機層用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到目標產物1f，白色固體(30 mg，收率：61%)。 MS m/z (ESI): 431.5 [M+H]⁺ Compound 1e (34 mg, 0.114 mmol) was dissolved in 5 mL of dichloromethane, N,N-diisopropylethylamine (0.08 mL, 0.456 mmol) was added, and trifluoromethanesulfonic anhydride (64.3 mg) was added under ice bath. , 0.228 mmol), and stirred under ice bath for 1 h. After the reaction was completed, 15 mL of dichloromethane was added to dilute, and then the reaction solution was washed with 10 mL of water, and then washed with 10 mL of saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After column chromatography, the target product 1f was obtained as a white solid (30 mg, yield: 61%). MS m/z (ESI): 431.5 [M+H] ⁺

第七步：(S)-2-(氰甲基)-4-(2'-(甲硫基)-1,3,5'，8'-四氫-6'H-螺[茚-2,7'-喹唑啉] -4'-基)呱嗪-1-甲酸叔丁酯(1g)； tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylthio)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl)piperazine-1-carboxylate

將化合物1f(30 mg，0.07 mmol)溶於3 mL N,N-二甲基乙醯胺中，加入(S)-2-(呱嗪-2-基)乙腈(9.6 mg，0.08 mmol)和二異丙基乙胺(54 mg，0.42 mmol)，室溫攪拌3 h。TLC監控反應完全後，向體系中加入二碳酸二叔丁酯(46 mg，0.21 mmol)，加畢，反應室溫過夜。加入20 mL乙酸乙酯稀釋，用10 mL水洗有機相三次，有機相用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到目標產物1g，白色固體(40 mg，收率：100%)。 MS m/z (ESI): 506.7 [M+H]⁺ The seventh step: (S)-2-(cyanomethyl)-4-(2'-(methylthio)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2 ,7'-Quinazoline]-4'-yl)oxazine-1-carboxylate tert-butyl ester (1g); tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylthio)- 1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl)piperazine-1-carboxylate

Compound 1f (30 mg, 0.07 mmol) was dissolved in 3 mL of N,N-dimethylacetamide, (S)-2-(oxazin-2-yl)acetonitrile (9.6 mg, 0.08 mmol) and Diisopropylethylamine (54 mg, 0.42 mmol) was stirred at room temperature for 3 h. After monitoring the completion of the reaction by TLC, di-tert-butyl dicarbonate (46 mg, 0.21 mmol) was added to the system, the addition was completed, and the reaction was carried out at room temperature overnight. 20 mL of ethyl acetate was added to dilute, and the organic phase was washed three times with 10 mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After column chromatography, 1 g of the target product was obtained as a white solid (40 mg, yield: 100%). MS m/z (ESI): 506.7 [M+H] ⁺

第八步：(S)-2-(氰甲基)-4-(2'-(甲基磺醯基)-1,3,5'，8'-四氫-6'H-螺[茚-2,7'-喹唑啉] -4'-基)呱嗪-1-甲酸叔丁酯(1h)； tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl)piperazine-1-carboxylate

將化合物1g(40 mg，0.079 mmol)溶於2 mL四氫呋喃中，室溫下加入間氯過氧苯甲酸(27 mg，0.16 mmol)，室溫攪拌2 h。加入5 mL飽和硫代硫酸鈉水溶液，攪拌20 min，加入15 mL乙酸乙酯萃取，有機層用10 mL飽和碳酸氫鈉水溶液洗滌，減壓濃縮，得到目標化合物1h粗品，黃色固體48 mg，直接用於下一步。 MS m/z (ESI): 538.7 [M+H]⁺ The eighth step: (S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-1,3,5',8'-tetrahydro-6'H-spiro[indene -2,7'-Quinazoline]-4'-yl)oxazine-1-carboxylate tert-butyl ester (1h); tert-butyl(S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl) )-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl)piperazine-1-carboxylate

Compound 1 g (40 mg, 0.079 mmol) was dissolved in 2 mL of tetrahydrofuran, m-chloroperoxybenzoic acid (27 mg, 0.16 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 h. Add 5 mL of saturated aqueous sodium thiosulfate solution, stir for 20 min, add 15 mL of ethyl acetate for extraction, wash the organic layer with 10 mL of saturated aqueous sodium bicarbonate solution, and concentrate under reduced pressure to obtain the target compound 1h crude product, 48 mg of yellow solid, directly for the next step. MS m/z (ESI): 538.7 [M+H] ⁺

第九步：(S)-2-(氰基甲基)-4-(2'-((((S)-1-甲基吡咯烷-2-基)甲氧基)-1,3,5'，8'-四氫-6' H-螺[茚-2,7'-喹唑啉] -4'-基)呱嗪-1-甲酸叔丁酯(1i)； tert-butyl (S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy) -1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl)piperazine-1-carboxylate

將化合物1h粗品(48 mg，0.089 mmol)和(S)- (1-甲基吡咯烷-2-基)甲醇(22 mg，0.19 mmol)溶於2 mL甲苯中，冰浴下加入叔丁醇鈉(14 mg，0.14 mmol)，冰浴下攪拌1 h。加入5 mL水淬滅反應，加入10 mL乙酸乙酯萃取三次，合併有機相，用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到目標產物1i，白色固體(46 mg，收率：95%)。 MS m/z (ESI): 573.6 [M+H]⁺ The ninth step: (S)-2-(cyanomethyl)-4-(2'-((((S)-1-methylpyrrolidin-2-yl)methoxy)-1,3, 5',8'-Tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl)oxazine-1-carboxylate tert-butyl ester (1i); tert-butyl (S )-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,3,5',8'-tetrahydro-6'H-spiro[indene -2,7'-quinazolin]-4'-yl)piperazine-1-carboxylate

The crude compound 1h (48 mg, 0.089 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (22 mg, 0.19 mmol) were dissolved in 2 mL of toluene, and tert-butanol was added under ice bath Sodium (14 mg, 0.14 mmol) was stirred under ice bath for 1 h. 5 mL of water was added to quench the reaction, 10 mL of ethyl acetate was added to extract three times, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target product 1i was obtained as a white solid (46 mg, yield: 95%). MS m/z (ESI): 573.6 [M+H] ⁺

第十步：2-((S)-4-(2'-((((S)-1-甲基吡咯烷-2-基]甲氧基])-1,3,5'，8'-四氫-6'H-螺[ 2,7'-喹唑啉] -4'-基)呱嗪-2-基)乙腈(1j)； 2-((S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile

將化合物1i(46 mg，0.08 mmol)溶於3 mL二氯甲烷中，加入0.5 mL三氟乙酸，於室溫下攪拌2 h。待反應完成後，加入5 mL水稀釋，然後用10 mL二氯甲烷萃取三次，合併有機相，用無水硫酸鈉乾燥，減壓濃縮，得到目標化合物1j粗品，黃色固體40 mg，直接用於下一步。 MS m/z (ESI): 473.6 [M+H]⁺ Step 10: 2-((S)-4-(2'-((((S)-1-methylpyrrolidin-2-yl]methoxy])-1,3,5',8'-Tetrahydro-6'H-spiro[2,7'-quinazolin]-4'-yl)oxazin-2-yl)acetonitrile(1j);2-((S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl) piperazin-2-yl)acetonitrile

Compound 1i (46 mg, 0.08 mmol) was dissolved in 3 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, 5 mL of water was added to dilute, and then extracted three times with 10 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target compound 1j crude product, 40 mg of yellow solid, which was directly used in the next step. step. MS m/z (ESI): 473.6 [M+H] ⁺

第十一步：2-[(S)-1-丙烯醯基-4-[2'-[[(S)-1-甲基吡咯烷-2-基]甲氧基]-1,3,5',8'-四氫-6'H-螺[茚-2,7'-喹唑啉]-4'-基] 呱嗪-2-基] 乙腈；2,2,2-三氟乙酸鹽(化合物1) ； 2-[(S)-1-acryloyl-4-[2'-[[(S)-1-methylpyrrolidin-2-yl]methoxy]-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl]piperazin-2-yl]acetonitrile； 2,2,2-trifluoroacetic acid.

將化合物1j粗品(46 mg，0.097 mmol)溶於5 mL二氯甲烷中，加入三乙胺(49 mg，0.49 mmol)，冰浴下計入烯丙醯氯(8 mg，0.092 mmol)，冰浴下攪拌30 min。加入5 mL冰水淬滅反應，然後用10 mL二氯甲烷萃取三次，合併有機相，用無水硫酸鈉乾燥，減壓濃縮，送液相酸性製備(流動相體系：乙腈/0.1%TFA水)得到目標化合物1，白色固體(23 mg，收率：45%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.21 – 7.08 (m, 4H), 6.90 – 6.70 (m, 1H), 6.29 (d, 1H), 5.84 (d, 1H), 4.69 (dd, 1H), 4.60 (d, 1H), 4.41 (d, 1H), 4.20 – 4.03 (m, 1H), 3.96 – 3.83 (m, 1H), 3.78 – 3.41 (m, 4H), 3.26 – 3.14 (m, 1H), 3.06 – 2.93 (m, 6H), 2.89 – 2.81 (m, 3H), 2.80 (d, 1H), 2.75 (s, 2H), 2.44 – 2.32 (m, 1H), 2.22 – 1.97 (m, 4H), 1.94 – 1.85 (m, 2H), 1.35 – 1.25 (m, 2H). Ms m/z (ESI): 527.6 [M+H]⁺ 實施例 2 2-[((2S)-4- [2-[[((2S)-1-甲基吡咯烷-2-基]甲氧基] -2'-氧-螺環[6,8-二氫-5H-喹唑啉-7,3' -二氫吲哚] -4-基]呱嗪-2-基]乙腈；2,2,2-三氟乙酸(化合物 2 ) ； 2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl]piperazin-2-yl]acetonitrile；2,2,2-trifluoroacetic acid

The eleventh step: 2-[(S)-1-propenyl-4-[2'-[[(S)-1-methylpyrrolidin-2-yl]methoxy]-1,3, 5',8'-Tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl]oxazin-2-yl]acetonitrile; 2,2,2-trifluoroacetic acid Salt (Compound 1); 2-[(S)-1-acryloyl-4-[2'-[[(S)-1-methylpyrrolidin-2-yl]methoxy]-1,3,5',8'- tetrahydro-6'H-spiro[indene-2,7'-quinazolin]-4'-yl]piperazin-2-yl]acetonitrile; 2,2,2-trifluoroacetic acid.

The crude compound 1j (46 mg, 0.097 mmol) was dissolved in 5 mL of dichloromethane, triethylamine (49 mg, 0.49 mmol) was added, allyl chloride (8 mg, 0.092 mmol) was added under an ice bath, and the ice Stir under the bath for 30 min. The reaction was quenched by adding 5 mL of ice water, and then extracted three times with 10 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and sent to the liquid phase for acid preparation (mobile phase system: acetonitrile/0.1% TFA water) The target compound 1 was obtained as a white solid (23 mg, yield: 45%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.21 – 7.08 (m, 4H), 6.90 – 6.70 (m, 1H), 6.29 (d, 1H), 5.84 (d, 1H), 4.69 (dd, 1H) , 4.60 (d, 1H), 4.41 (d, 1H), 4.20 – 4.03 (m, 1H), 3.96 – 3.83 (m, 1H), 3.78 – 3.41 (m, 4H), 3.26 – 3.14 (m, 1H) , 3.06 – 2.93 (m, 6H), 2.89 – 2.81 (m, 3H), 2.80 (d, 1H), 2.75 (s, 2H), 2.44 – 2.32 (m, 1H), 2.22 – 1.97 (m, 4H) , 1.94 – 1.85 (m, 2H), 1.35 – 1.25 (m, 2H). Ms m/z (ESI): 527.6 [M+H] ⁺ Example 2 2-[((2S)-4-[2- [[((2S)-1-Methylpyrrolidin-2-yl]methoxy]-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3'-di Indoline]-4-yl]oxazin-2-yl]acetonitrile; 2,2,2-trifluoroacetic acid ( compound 2 ); 2-[(2S)-4-[2-[[(2S)- 1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl]piperazin-2-yl]acetonitrile;2, 2,2-trifluoroacetic acid

第一步：3-(2-氨基苯基)環己-2-烯-1-酮(2a) 3-(2-aminophenyl)cyclohex-2-en-1-one

將2-碘苯胺(44 g,200.9 mmol)，三(鄰甲基苯基)磷(6.11 g,20.09 mmol), 醋酸鈀(2.26 g,10.04 mmol)，環己烯酮(21.24 g,221.0 mmol)和三乙胺(40.66 g,401.8 mmol)溶於1220 mL 乙腈，氮氣氛圍下加熱至85℃回流反應40小時。TLC監測反應完全後，將反應液冷至室溫，減壓濃縮除去乙腈，加入800 mL 乙酸乙酯稀釋，加入300 mL 水洗滌，攪拌靜置分層，水相用乙酸乙酯 400 mL x 2萃取，合併有機相，用500 mL飽和食鹽水洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得粗品，粗品柱層析純化得目標產物 2a,黃褐色固體(11.2 g,收率：29.8%)。 MS m/z (ESI): 188.1 [M+H]⁺ The first step: 3-(2-aminophenyl)cyclohex-2-en-1-one (2a) 3-(2-aminophenyl)cyclohex-2-en-1-one

Combine 2-iodoaniline (44 g, 200.9 mmol), tris(o-methylphenyl)phosphorus (6.11 g, 20.09 mmol), palladium acetate (2.26 g, 10.04 mmol), cyclohexenone (21.24 g, 221.0 mmol) ) and triethylamine (40.66 g, 401.8 mmol) were dissolved in 1220 mL of acetonitrile, heated to 85° C. for reflux reaction under nitrogen atmosphere for 40 hours. After monitoring the completion of the reaction by TLC, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove acetonitrile, diluted with 800 mL of ethyl acetate, washed with 300 mL of water, stirred and left to stand for layers. Extracted, combined the organic phases, washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product 2a, a tan solid (11.2 g, yield: 29.8%) . MS m/z (ESI): 188.1 [M+H] ⁺

第二步：螺[環己烷-3,3'-二氫吲哚] -1,2'-二酮(2b) spiro[cyclohexane-3,3'-indoline]-1,2'-dione

將三光氣(9.51 g, 32.0 mmol) 用二氯甲烷(200 mL)溶解於500 mL 單口圓底燒瓶中，將化合物2a(3 g,16.0 mmol)用二氯甲烷 (100 mL) 溶解後滴加入到反應中，滴加完畢後將二氯甲烷(100 mL)稀釋的三乙胺(9.73 g,96.1 mmol)溶液滴加入到反應中，室溫攪拌3小時。減壓濃縮除去二氯甲烷，殘餘物加入200 mL乙醚攪拌10分鐘，抽濾，濾餅用100 mL 乙醚洗滌。將濾液減壓濃縮後得到的殘餘物用100 mL 四氫呋喃溶解於1L容量的三口圓底燒瓶中，加入叔丁醇(1.19 g, 16.0 mmol)，氮氣氛圍下降溫至-78℃攪拌十分鐘。將無水氯化鋰(5.43 g, 128.2 mmol) 與二碘化釤-四氫呋喃溶液(40 mmol, 400 mL,0.1M)的混合溶液於室溫攪拌10分鐘後滴加入到反應中，保持-78℃攪拌半小時。 TLC顯示原料消耗完全，加入200 mL 飽和氯化銨水溶液淬滅，升溫至室溫，加入乙酸乙酯(3 x 300 mL)萃取，合併有機相，飽和食鹽水洗滌,無水硫酸鈉乾燥有機相，過濾，減壓濃縮得到的殘留物矽膠柱層析純化得2b,棕色固體(2.34 g,收率：67.8%)。 MS m/z (ESI): 216.2 [M+H]⁺ Step 2: Spiro[cyclohexane-3,3'-indoline]-1,2'-dione (2b) spiro[cyclohexane-3,3'-indoline]-1,2'-dione

Triphosgene (9.51 g, 32.0 mmol) was dissolved in dichloromethane (200 mL) in a 500 mL single-neck round-bottomed flask, compound 2a (3 g, 16.0 mmol) was dissolved in dichloromethane (100 mL) and added dropwise To the reaction, after the dropwise addition was completed, a solution of triethylamine (9.73 g, 96.1 mmol) diluted with dichloromethane (100 mL) was added dropwise to the reaction, and the mixture was stirred at room temperature for 3 hours. Concentrate under reduced pressure to remove dichloromethane, add 200 mL of diethyl ether to the residue and stir for 10 minutes, filter with suction, and wash the filter cake with 100 mL of diethyl ether. The residue obtained after the filtrate was concentrated under reduced pressure was dissolved in a 1L three-necked round-bottomed flask with 100 mL of tetrahydrofuran, tert-butanol (1.19 g, 16.0 mmol) was added, and the temperature was lowered to -78 °C under a nitrogen atmosphere and stirred for ten minutes. The mixed solution of anhydrous lithium chloride (5.43 g, 128.2 mmol) and samarium diiodide-tetrahydrofuran solution (40 mmol, 400 mL, 0.1 M) was stirred at room temperature for 10 minutes and added dropwise to the reaction, maintaining -78 ° C Stir for half an hour. TLC showed that the raw material was completely consumed, quenched by adding 200 mL saturated aqueous ammonium chloride solution, warming to room temperature, adding ethyl acetate (3 x 300 mL) for extraction, combining the organic phases, washing with saturated brine, drying the organic phase over anhydrous sodium sulfate, Filtration, concentration under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 2b as a brown solid (2.34 g, yield: 67.8%). MS m/z (ESI): 216.2 [M+H] ⁺

第三步：2,2'-二氧雜螺[環己烷-4,3'-二氫吲哚] -1-羧酸乙酯(2c) ethyl 2,2'-dioxospiro[cyclohexane-4,3'-indoline]-1-carboxylate

將化合物2b(2.34 g,10.9 mmol)用四氫呋喃(200 mL)溶解於500 mL 三口圓底燒瓶中，氮氣氛圍下冷卻至-78℃，量取LiHMDS(22 mL，1M in THF)滴加入到反應瓶中，攪拌十分鐘，將3 mL 四氫呋喃稀釋的氰基甲酸乙酯(1.4 g, 14.1 mmol)緩慢滴加入到反應中，-78℃反應半小時後升溫至室溫反應2小時。加入50 mL 飽和氯化銨水溶液淬滅反應，加入100 mL水，加入乙酸乙酯(3 x 80 mL)萃取，合併有機相，用飽和食鹽水洗滌,無水硫酸鈉乾燥，過濾，減壓濃縮得粗品，粗品柱層析純化得2c,淡黃色固體(1.22 g, 收率：38.4%)。 MS m/z (ESI): 288.2 [M+H]⁺ The third step: 2,2'-dioxospiro[cyclohexane-4,3'-indoline]-1-carboxylate ethyl ester (2c) ethyl 2,2'-dioxospiro[cyclohexane-4, 3'-indoline]-1-carboxylate

Compound 2b (2.34 g, 10.9 mmol) was dissolved in tetrahydrofuran (200 mL) in a 500 mL three-necked round-bottomed flask, cooled to -78°C under nitrogen atmosphere, and LiHMDS (22 mL, 1M in THF) was added dropwise to the reaction The flask was stirred for ten minutes, and 3 mL of ethyl cyanoformate diluted in tetrahydrofuran (1.4 g, 14.1 mmol) was slowly added dropwise to the reaction, and the reaction was carried out at -78 °C for half an hour and then heated to room temperature for 2 hours. 50 mL of saturated aqueous ammonium chloride solution was added to quench the reaction, 100 mL of water was added, ethyl acetate (3 x 80 mL) was added for extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The crude product was purified by column chromatography to obtain 2c as a pale yellow solid (1.22 g, yield: 38.4%). MS m/z (ESI): 288.2 [M+H] ⁺

第四步：4-羥基-2-硫烷基-螺[6,8-二氫-5H-喹唑啉-7,3'-二氫吲哚] -2'-酮(2d)； 4-hydroxy-2-sulfanyl-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-2'-one

將化合物2c (1.22 g,4.25 mmol) 用甲醇 (25 mL)溶解於單口圓底燒瓶中，依次稱取甲醇鈉 (1.38 g, 25.48 mmol) 和硫脲 (970 mg, 12.74 mmol)並加入到反應瓶中。加熱至60℃反應5小時， LC-MS顯示原料消耗完全。減壓濃縮大部分甲醇，殘餘物加入35 mL 水溶解，加入25 mL甲基叔丁基醚洗滌，水相加入2N 稀鹽酸調節pH=3-4，大量固體析出，抽濾，濾餅加入水洗滌。濾餅加入 8 mL 乙醇打漿過夜，抽濾，濾餅乾燥得2d,白色固體(0.358 g,收率：28.2%)。 MS m/z (ESI): 298.1 [M-H]^- The fourth step: 4-hydroxy-2-sulfanyl-spiro[6,8-dihydro-5H-quinazolin-7,3'-indoline]-2'-one (2d); 4- hydroxy-2-sulfanyl-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-2'-one

Compound 2c (1.22 g, 4.25 mmol) was dissolved in a single-necked round-bottomed flask with methanol (25 mL), and sodium methoxide (1.38 g, 25.48 mmol) and thiourea (970 mg, 12.74 mmol) were weighed in turn and added to the reaction bottle. The reaction was heated to 60°C for 5 hours, LC-MS showed complete consumption of starting material. Most of the methanol was concentrated under reduced pressure, the residue was dissolved in 35 mL of water, washed with 25 mL of methyl tert-butyl ether, the aqueous phase was adjusted to pH=3-4 by adding 2N dilute hydrochloric acid, a large amount of solid was precipitated, suction filtered, and water was added to the filter cake washing. The filter cake was added with 8 mL of ethanol to make slurry overnight, suction filtered, and the filter cake was dried to obtain 2d, a white solid (0.358 g, yield: 28.2%). MS m/z (ESI): 298.1 [MH] ^-

第五步：4-羥基-2-甲基硫烷基-螺[6,8-二氫-5H-喹唑啉-7,3'-二氫吲哚] -2'-酮(2e)； 4-hydroxy-2-methylsulfanyl-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-2'-one.

將化合物2d (0.1 g,0.334 mmol) 用甲醇 (15 mL)溶解於單口圓底燒瓶中，加入碳酸鉀(0.185 g, 1.34 mmol)攪拌半小時，加入碘甲烷(0.05 g, 0.334 mmol)攪拌1小時， LC-MS顯示原料未消耗完全，繼續加入碘甲烷(0.05 g,0.334 mmol)攪拌1小時， LC-MS顯示原料幾乎消耗完全。減壓濃縮除去甲醇，加入 20 mL 水溶解，加入 2 N 稀鹽酸調節 pH=3-4，有白色固體析出，加入 3 x 80 mL 混合溶劑(二氯甲烷/甲醇(v/v)=10/1)萃取，合併有機相，用無水硫酸鈉乾燥，過濾，減壓濃縮得2e，黃白色固體(120 mg, 收率：100%)。 Ms m/z (ESI): 314.1 [M+H]⁺ The fifth step: 4-hydroxy-2-methylsulfanyl-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-2'-one (2e); 4-hydroxy-2-methylsulfanyl-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-2'-one.

Compound 2d (0.1 g, 0.334 mmol) was dissolved in a single-necked round-bottomed flask with methanol (15 mL), potassium carbonate (0.185 g, 1.34 mmol) was added and stirred for half an hour, and iodomethane (0.05 g, 0.334 mmol) was added and stirred for 1 After 1 hour, LC-MS showed that the starting material was not completely consumed, continued adding iodomethane (0.05 g, 0.334 mmol) and stirring for 1 hour, LC-MS showed that the starting material was almost completely consumed. Concentrate under reduced pressure to remove methanol, add 20 mL of water to dissolve, add 2 N dilute hydrochloric acid to adjust pH=3-4, a white solid is precipitated, add 3 x 80 mL of mixed solvent (dichloromethane/methanol (v/v)=10/ 1) Extract, combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 2e as a yellow-white solid (120 mg, yield: 100%). Ms m/z (ESI): 314.1 [M+H] ⁺

第六步：(2-甲基硫烷基-2'-氧-螺[6,8-二氫-5H-喹唑啉-7,3'-二氫吲哚] -4-基)三氟甲磺酸酯(2f)； (2-methylsulfanyl-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl) trifluoromethanesulfonate

將化合物2e(0.12 g,0.383 mmol)用二氯甲烷 (20 mL)溶解於單口圓底燒瓶中，加入三乙胺(0.117 g,1.15 mmol)，氮氣氛圍下用冰水浴降溫，內溫降至 5 - 10℃，用2 mL 二氯甲烷稀釋的三氟甲磺酸酐 (0.162 g，0.574 mmol)加入反應中，反應十分鐘，TLC監測原料未消耗完全，補加三氟甲磺酸酐(0.05 g,0.191 mmol)，繼續反應十分鐘，TLC監測原料消耗完全。加入 20 mL 飽和碳酸氫鈉水溶液淬滅，攪拌靜置分層，水相用二氯甲烷 (20 mL x 2)萃取,合併有機相，用飽和食鹽水 30 mL 洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得2f, 棕黑色固體(170 mg,收率：100%)。粗品直接用於下一步。 MS m/z (ESI): 446.1 [M+H]⁺ The sixth step: (2-methylsulfanyl-2'-oxygen-spiro[6,8-dihydro-5H-quinazolin-7,3'-indoline]-4-yl)trifluoro Mesylate (2f); (2-methylsulfanyl-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl)trifluoromethanesulfonate

Compound 2e (0.12 g, 0.383 mmol) was dissolved in a single-necked round-bottomed flask with dichloromethane (20 mL), triethylamine (0.117 g, 1.15 mmol) was added, and the temperature was lowered to an ice-water bath under nitrogen atmosphere. 5 - 10°C, trifluoromethanesulfonic anhydride (0.162 g, 0.574 mmol) diluted with 2 mL of dichloromethane was added to the reaction, and the reaction was carried out for ten minutes. , 0.191 mmol), continue to react for ten minutes, TLC monitoring raw material consumption is complete. Add 20 mL of saturated aqueous sodium bicarbonate solution to quench, stir and stand to separate the layers, the aqueous phase was extracted with dichloromethane (20 mL x 2), the organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, Concentration under reduced pressure gave 2f as a brown-black solid (170 mg, yield: 100%). The crude product was used directly in the next step. MS m/z (ESI): 446.1 [M+H] ⁺

第七步：(2S)-2-(氰甲基)-4-(2-甲基硫烷基-2'-氧代螺基[6,8-二氫-5H-喹唑啉-7,3'-二氫吲哚] -4-基)呱嗪 -1-甲酸叔丁酯(2g)； tert-butyl (2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl)piperazine-1-carboxylate

將化合物2f(0.17 g,0.383 mmol)用N,N-二甲基乙醯胺(15 mL)溶解於單口圓底燒瓶中，加入N,N-二異丙基乙胺(0.21 g, 1.62 mmol)和 (S)-2-(呱嗪-2-基)乙腈鹽酸鹽(0.152 g,0.81 mmol),室溫反應半小時，TLC監測原料消耗完全，加入碳酸二叔丁酯(240 mg,1.08 mmol),室溫攪拌16 h。加入 45 mL 水淬滅，加入二氯甲烷(30 mL x 4)萃取，合併有機相，飽和食鹽水洗滌有機相，無水硫酸鈉乾燥，過濾，減壓濃縮得粗品，粗品矽膠柱層析純化得2g,棕色固體(0.13 g,收率：65%) MS m/z (ESI): 521.3 [M+H]⁺ The seventh step: (2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-2'-oxospiro[6,8-dihydro-5H-quinazoline-7, 3'-Indoline]-4-yl)oxazine-1-carboxylate tert-butyl ester (2g); tert-butyl (2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-2'-oxo -spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl)piperazine-1-carboxylate

Compound 2f (0.17 g, 0.383 mmol) was dissolved in a single-neck round bottom flask with N,N-dimethylacetamide (15 mL), and N,N-diisopropylethylamine (0.21 g, 1.62 mmol) was added. ) and (S)-2-(oxazin-2-yl)acetonitrile hydrochloride (0.152 g, 0.81 mmol), reacted at room temperature for half an hour, TLC monitoring the raw material consumption was complete, adding di-tert-butyl carbonate (240 mg, 1.08 mmol) and stirred at room temperature for 16 h. Add 45 mL of water to quench, add dichloromethane (30 mL x 4) for extraction, combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product, which is purified by silica gel column chromatography to obtain 2g, brown solid (0.13 g, yield: 65%) MS m/z (ESI): 521.3 [M+H] ⁺

第八步：(2S)-2-(氰甲基)-4-(2-甲基亞磺醯基-2'-氧代螺基[6,8-二氫-5H-喹唑啉-7,3'-二氫吲哚] -4-基)呱嗪-1-甲酸叔丁基酯(2h)； tert-butyl (2S)-2-(cyanomethyl)-4-(2-methylsulfinyl-2'-oxo-spiro[6,8-dihydro- 5H-quinazoline-7,3'-indoline]-4-yl)piperazine-1-carboxylate

將化合物2g (0.13 g, 0.250 mmol)用 20 mL 四氫呋喃溶解於單口圓底燒瓶中，稱取間氯過氧苯甲酸(87 mg,0.499 mmol)加入到反應瓶中，室溫攪拌1小時，取樣TLC顯示原料消耗完全。可以後處理。加入 20 mL 飽和硫代硫酸鈉水溶液淬滅反應，攪拌半小時，加入乙酸乙酯 (20 mL x 3)萃取，合併有機相，用飽和碳酸氫鈉水溶液( 30 mL x 3)洗滌，飽和食鹽水洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得2f粗品，淡黃色固體(0.134 g ,收率：100%)，粗品直接用於下一步。 MS m/z (ESI): 537.3 [M+H]⁺ The eighth step: (2S)-2-(cyanomethyl)-4-(2-methylsulfinyl-2'-oxospiro[6,8-dihydro-5H-quinazoline-7 ,3'-Indoline]-4-yl)oxazine-1-carboxylate tert-butyl ester (2h); tert-butyl (2S)-2-(cyanomethyl)-4-(2-methylsulfinyl-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl)piperazine-1-carboxylate

Compound 2g (0.13 g, 0.250 mmol) was dissolved in a single-necked round-bottomed flask with 20 mL of tetrahydrofuran, and m-chloroperoxybenzoic acid (87 mg, 0.499 mmol) was weighed into the reaction flask, stirred at room temperature for 1 hour, and sampled. TLC showed complete consumption of starting material. can be post-processed. Add 20 mL of saturated aqueous sodium thiosulfate solution to quench the reaction, stir for half an hour, add ethyl acetate (20 mL x 3) for extraction, combine the organic phases, wash with saturated aqueous sodium bicarbonate solution (30 mL x 3), saturated brine Washed, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude 2f as a pale yellow solid (0.134 g, yield: 100%), which was directly used in the next step. MS m/z (ESI): 537.3 [M+H] ⁺

第九步：(2S)-2-(氰甲基)-4- [2-[[((2S)-1-甲基吡咯烷-2-基]甲氧基] -2`-氧代螺[6,8-二氫-5H- 喹唑啉-7,3`-二氫吲哚] -4-基]呱嗪-1-甲酸叔丁酯(2i)； tert-butyl (2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2`-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3`-indoline]-4-yl]piperazine-1-carboxylate

將化合物2h(0.134 g，0.250 mmoL)用乾燥四氫呋喃(15 mL)溶解於單口圓底燒瓶中，加入 N-甲基-L-脯氨醇(87 mg, 0.749 mmol)，氮氣氛圍下，用冰水浴降溫，內溫降至 5-10 ℃，加入叔丁醇鈉(48 mg, 0.499 mmol)，在此溫度反應十分鐘，TLC顯示原料消耗完全。加入 10 mL 飽和碳酸氫鈉水溶液淬滅，用 20 mL x 3 混合溶劑(二氯甲烷/甲醇(v/v)=10/1)，合併有機相，無水硫酸鈉乾燥，過濾，減壓濃縮得粗品，粗品矽膠柱層析純化得2h,淡黃色固體(108 mg,收率：73.6%)。 MS m/z (ESI): 588.3 [M+H]⁺ The ninth step: (2S)-2-(cyanomethyl)-4-[2-[[((2S)-1-methylpyrrolidin-2-yl]methoxy]-2`-oxospiro [6,8-Dihydro-5H-quinazoline-7,3`-indoline]-4-yl]oxazine-1-carboxylate tert-butyl ester (2i); tert-butyl (2S)-2 -(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2`-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3`-indoline ]-4-yl]piperazine-1-carboxylate

Compound 2h (0.134 g, 0.250 mmol) was dissolved in a single-neck round-bottomed flask with dry tetrahydrofuran (15 mL), N-methyl-L-prolinol (87 mg, 0.749 mmol) was added, and the mixture was heated with ice under a nitrogen atmosphere. The temperature was lowered to 5-10 °C in a water bath, sodium tert-butoxide (48 mg, 0.499 mmol) was added, and the reaction was carried out at this temperature for ten minutes. TLC showed that the starting material was completely consumed. Add 10 mL saturated aqueous sodium bicarbonate solution to quench, use 20 mL x 3 mixed solvent (dichloromethane/methanol (v/v)=10/1), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain The crude product was purified by silica gel column chromatography for 2 h to obtain a pale yellow solid (108 mg, yield: 73.6%). MS m/z (ESI): 588.3 [M+H] ⁺

第十步：2-[((2S)-4- [2-[[((2S)-1-甲基吡咯烷-2-基]甲氧基] -2'-氧-螺環[6,8-二氫-5H-喹唑啉-7,3' -二氫吲哚] -4-基]呱嗪-2-基]乙腈 (2i)； 2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl]piperazin-2-yl]acetonitrile

將化合物2h (0.108 g,0.184 mmol)用二氯甲烷(5 mL)溶解於單口圓底燒瓶中，加入 2.5 mL 三氟醋酸，室溫攪拌一小時，取樣，TLC和LC-MS。MS顯示有產品生成，TLC顯示原料消耗完全。減壓濃縮得2i粗品，黃色固體(89 mg，收率：99%)，粗品直接用於下一步。 MS m/z (ESI): 488.3[M+H]⁺ Step 10: 2-[((2S)-4-[2-[[((2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-spiro[6, 8-Dihydro-5H-quinazolin-7,3'-indoline]-4-yl]oxazin-2-yl]acetonitrile (2i); 2-[(2S)-4-[2- [[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3'-indoline]-4-yl]piperazin-2- yl]acetonitrile

Compound 2h (0.108 g, 0.184 mmol) was dissolved in a single-neck round-bottom flask with dichloromethane (5 mL), 2.5 mL of trifluoroacetic acid was added, stirred at room temperature for one hour, sampled, TLC and LC-MS. MS showed product formation and TLC showed complete consumption of starting material. Concentration under reduced pressure gave crude 2i as a yellow solid (89 mg, yield: 99%), which was directly used in the next step. MS m/z (ESI): 488.3[M+H] ⁺

第十一步：2-[((2S)-4- [2-[[((2S)-1-甲基吡咯烷-2-基]甲氧基] -2'-氧-螺環[6,8-二氫-5H-喹唑啉-7,3' -二氫吲哚] -4-基]呱嗪-2-基]乙腈；2,2,2-三氟乙酸 (化合物 2 )； 2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2`-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3`-indoline]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile； 2,2,2-trifluoroacetic acid

將化合物2i(0.089 g,0.182 mmol)用 30 mL 二氯甲烷溶解於單口圓底燒瓶中，加入N,N-二異丙基乙胺(0.2 g,1.46 mmol),氮氣氛圍下，用冰水浴降溫，內溫降至5-10℃，將2 mL 二氯甲烷稀釋的烯丙醯氯(0.016 g,0.182 mmol),注射加入到反應中，在此溫度反應10分鐘，TLC監測原料反應完全。加入 15 mL 飽和碳酸氫鈉水溶液淬滅，攪拌靜置分層，用二氯甲烷 (20 mL x 2)萃取，合併有機相，飽和食鹽水洗滌有機相，無水硫酸鈉乾燥，過濾，減壓濃縮得粗品，粗品送製備液相(酸性製備，流動相體系：乙腈/0.1%TFA水)得到目標化合物2，白色固體(25 mg，收率：26%)。¹ H NMR (400 MHz, CD₃ OD) δ 7.27 (t, 1H), 7.22 – 7.13 (m, 1H), 7.07 – 6.94 (m, 2H), 6.90 – 6.70 (m, 1H), 6.30 (d, 1H), 5.84 (d, 1H), 5.10 – 4.78 (m, 2H), 4.73 – 4.62 (m, 1H), 4.60 – 4.46 (m, 1H), 4.40 – 4.04 (m, 2H), 4.01 – 3.35 (m, 5H), 3.30-3.19 (m, 1H), 3.17 – 2.84 (m, 9H), 2.49 – 2.34 (m, 1H), 2.28 – 1.85 (m, 5H). Ms m/z (ESI): 542.3 [M-CF₃ COOH+H]⁺ 實施例 3 2-[(2S)-4-[2-[[(2S)-1-甲基吡咯烷-2-基]甲氧基] -2'-氧代-1'-苯基-螺[6,8-二氫-5H-喹唑啉] -7,4'-吡咯烷] -4-基] -1-丙-2-烯醯基-呱嗪-2-基]乙腈(化合物3)； 2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.

The eleventh step: 2-[((2S)-4-[2-[[((2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-spiro[6 ,8-Dihydro-5H-quinazolin-7,3'-indoline]-4-yl]oxazin-2-yl]acetonitrile; 2,2,2-trifluoroacetic acid ( compound 2 ); 2-[4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2`-oxo-spiro[6,8-dihydro-5H-quinazoline-7,3`-indoline]- 4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile; 2,2,2-trifluoroacetic acid

Compound 2i (0.089 g, 0.182 mmol) was dissolved in a single-necked round-bottomed flask with 30 mL of dichloromethane, N,N-diisopropylethylamine (0.2 g, 1.46 mmol) was added, and an ice-water bath was added under a nitrogen atmosphere. Cool down, the inner temperature is reduced to 5-10 ℃, and the allyl chloride (0.016 g, 0.182 mmol) diluted with 2 mL of dichloromethane is injected into the reaction, and the reaction is performed at this temperature for 10 minutes, and the TLC monitoring of the raw materials is completed. Add 15 mL of saturated aqueous sodium bicarbonate solution to quench, stir and stand for layers, extract with dichloromethane (20 mL x 2), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure The crude product was obtained, and the crude product was sent to the preparative liquid phase (acidic preparation, mobile phase system: acetonitrile/0.1% TFA water) to obtain the target compound 2 as a white solid (25 mg, yield: 26%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.27 (t, 1H), 7.22 – 7.13 (m, 1H), 7.07 – 6.94 (m, 2H), 6.90 – 6.70 (m, 1H), 6.30 (d, 1H), 5.84 (d, 1H), 5.10 – 4.78 (m, 2H), 4.73 – 4.62 (m, 1H), 4.60 – 4.46 (m, 1H), 4.40 – 4.04 (m, 2H), 4.01 – 3.35 ( m, 5H), 3.30-3.19 (m, 1H), 3.17 – 2.84 (m, 9H), 2.49 – 2.34 (m, 1H), 2.28 – 1.85 (m, 5H). Ms m/z (ESI): 542.3 [M-CF ₃ COOH+H] ⁺ Example 3 2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'- Oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline]-7,4'-pyrrolidin]-4-yl]-1-prop-2-enyl-guaiac Azin-2-yl]acetonitrile (compound 3); 2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-1'-phenyl -spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.

第一步：3- [叔丁基(二甲基)甲矽烷基]氧基環己醇(3a)； 3-[tert-butyl(dimethyl)silyl]oxycyclohexanol.

將化合物1,3-環己二醇(5 g, 43.04 mmol)溶於30 mL N,N-二甲基甲醯胺中，依次加入咪唑(4.40 g, 64.50 mmol)和叔丁基二甲基氯矽烷(6.49 g, 43.04 mmol)，室溫攪拌4 h。加入50 mL 甲基叔丁基醚和50 mL水，萃取分液，有機層用飽和食鹽水洗滌(40 mL x 3)，有機層減壓濃縮後矽膠柱層析純化(流動相：乙酸乙酯/石油醚(v/v)=1/10-1/3)得化合物3a，淡黃色油狀物(4 g，收率：40%)。 Ms m/z (ESI): 231.3 [M+H]⁺ The first step: 3-[tert-butyl(dimethyl)silyl]oxycyclohexanol (3a); 3-[tert-butyl(dimethyl)silyl]oxycyclohexanol.

Compound 1,3-cyclohexanediol (5 g, 43.04 mmol) was dissolved in 30 mL of N,N-dimethylformamide, followed by adding imidazole (4.40 g, 64.50 mmol) and tert-butyldimethylformamide Chlorosilane (6.49 g, 43.04 mmol) was stirred at room temperature for 4 h. Add 50 mL of methyl tert-butyl ether and 50 mL of water, extract and separate, the organic layer was washed with saturated brine (40 mL x 3), the organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (mobile phase: ethyl acetate) /Petroleum ether (v/v)=1/10-1/3) to obtain compound 3a as a pale yellow oil (4 g, yield: 40%). Ms m/z (ESI): 231.3 [M+H] ⁺

第二步：3- [叔丁基(二甲基)甲矽烷基]氧基環己酮(3b)； 3-[tert-butyl(dimethyl)silyl]oxycyclohexanone.

將化合物3a (2.7 g, 11.74 mmol)溶於20 mL 二氯甲烷中，加入戴斯馬丁氧化劑 (5 g, 11.79 mmol)，室溫下攪拌反應1 h。加入20 mL飽和硫代硫酸鈉和20 mL飽和碳酸氫鈉水溶液，室溫攪拌20 min，分液，有機層減壓濃縮後，矽膠柱層析純化(流動相：乙酸乙酯/石油醚(v/v)=1/10-1/3)得化合物3b，淺黃色油狀物(2 g，收率：75%)。¹ HNMR (400 MHz, CDCl₃ ) δ 4.21-4.10 (m, 1H), 2.56-2.48 (m, 1H), 2.42-2.34 (m, 1H), 2.34-2.22 (m, 2H), 2.12-2.00 (m, 1H), 1.93-1.85 (m, 1H), 1.78-1.62 (m, 2H), 0.87 (s, 9H), 0.05 (s, 6H). Ms m/z (ESI): 229.3 [M+H]⁺ The second step: 3-[tert-butyl(dimethyl)silyl]oxycyclohexanone (3b); 3-[tert-butyl(dimethyl)silyl]oxycyclohexanone.

Compound 3a (2.7 g, 11.74 mmol) was dissolved in 20 mL of dichloromethane, Dess Martin oxidant (5 g, 11.79 mmol) was added, and the reaction was stirred at room temperature for 1 h. Add 20 mL of saturated sodium thiosulfate and 20 mL of saturated aqueous sodium bicarbonate solution, stir at room temperature for 20 min, and separate the layers. After the organic layer is concentrated under reduced pressure, it is purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v /v)=1/10-1/3) to obtain compound 3b as light yellow oil (2 g, yield: 75%). ¹ HNMR (400 MHz, CDCl ₃ ) δ 4.21-4.10 (m, 1H), 2.56-2.48 (m, 1H), 2.42-2.34 (m, 1H), 2.34-2.22 (m, 2H), 2.12-2.00 ( m, 1H), 1.93-1.85 (m, 1H), 1.78-1.62 (m, 2H), 0.87 (s, 9H), 0.05 (s, 6H). Ms m/z (ESI): 229.3 [M+H ] ⁺

第三步：2- [3- [3- [叔丁基(二甲基)甲矽烷基]氧基環己叉]乙酸乙酯(3c)； ethyl 2-[3-[tert-butyl(dimethyl)silyl]oxycyclohexylidene]acetate.

將氫化鈉 (2.05 g, 85.38 mmol)加入到100 mL 的四氫呋喃中，冰浴下緩慢滴入磷醯基乙酸三乙酯 (21.69 g, 96.76 mmol)，滴畢，冰浴下攪拌30 min後加入3b (13 g, 56.92 mmol)，冰浴下攪拌30 min。加入30 mL飽和氯化銨水溶液和100 mL水淬滅，加入100 mL 甲基叔丁基醚萃取，有機層用100 mL飽和食鹽水洗滌，減壓乾燥後，矽膠柱層析純化(流動相：乙酸乙酯/石油醚(v/v)=1/20-1/6)得化合物3c，淡黃色油狀物(13 g，收率：76%)。 Ms m/z (ESI): 299.3 [M+H]⁺ The third step: ethyl 2-[3-[3-[tert-butyl(dimethyl)silyl]oxycyclohexylidene]ethyl acetate (3c); ethyl 2-[3-[tert-butyl(dimethyl )silyl]oxycyclohexylidene]acetate.

Sodium hydride (2.05 g, 85.38 mmol) was added to 100 mL of tetrahydrofuran, and triethyl phosphonoacetate (21.69 g, 96.76 mmol) was slowly added dropwise under ice bath. 3b (13 g, 56.92 mmol) was stirred under ice bath for 30 min. Add 30 mL of saturated ammonium chloride aqueous solution and 100 mL of water to quench, add 100 mL of methyl tert-butyl ether for extraction, the organic layer was washed with 100 mL of saturated brine, dried under reduced pressure, and purified by silica gel column chromatography (mobile phase: Ethyl acetate/petroleum ether (v/v)=1/20-1/6) to obtain compound 3c as a pale yellow oil (13 g, yield: 76%). Ms m/z (ESI): 299.3 [M+H] ⁺

第四步：2- [3-羥基-1-(硝基甲基)環己基]乙酸乙酯(3d) ； ethyl 2-[3-hydroxy-1-(nitromethyl)cyclohexyl]acetate.

將化合物3c (0.5 g, 1.7 mmol) 溶於10 mL 四氫呋喃中，依次加入硝基甲烷(0.31 g, 5.0 mmol) 和四丁基氟化銨 (1.1 g, 4.2 mmol)，升溫回流攪拌過夜。加入20 mL水和20 mL 甲基叔丁基醚萃取，有機層減壓濃縮後，殘留物矽膠柱層析純化(流動相：乙酸乙酯/石油醚(v/v)=1/10-1/2)得化合物3d，淡黃色油狀物(0.35 g，收率：85%)。 Ms m/z (ESI): 246.3 [M+H]⁺ The fourth step: ethyl 2-[3-hydroxy-1-(nitromethyl)cyclohexyl]acetate (3d); ethyl 2-[3-hydroxy-1-(nitromethyl)cyclohexyl]acetate.

Compound 3c (0.5 g, 1.7 mmol) was dissolved in 10 mL of tetrahydrofuran, nitromethane (0.31 g, 5.0 mmol) and tetrabutylammonium fluoride (1.1 g, 4.2 mmol) were successively added, and the mixture was heated under reflux and stirred overnight. Add 20 mL of water and 20 mL of methyl tert-butyl ether for extraction, after the organic layer was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/v)=1/10-1 /2) Compound 3d was obtained as pale yellow oil (0.35 g, yield: 85%). Ms m/z (ESI): 246.3 [M+H] ⁺

第五步：7-羥基-2-氮雜螺[4.5]癸烷-3-酮(3e) ； 7-hydroxy-2-azaspiro[4.5]decan-3-one.

將化合物3d (0.35 g, 1.4 mmol) 溶於10 mL甲醇中，加入雷尼鎳(0.1 g, ≤50μm,分散在水中)和碳酸鉀(19 mg, 0.14 mmol)，於氫氣(1atm)下攪拌過夜。過濾，濾液減壓濃縮，殘留物矽膠柱層析純化(流動相：二氯甲烷/甲醇(v/v)=100/1-10/1)得化合物3e，白色固體(0.16 g，收率：66%)。¹ H NMR (400 MHz, CD₃ OD) δ 3.68-3.58 (m, 1H), 3.21-3.14 (m, 2H), 2.26-2.13 (m, 2H), 1.94-1.84 (m, 2H), 1.78-1.68 (m, 1H), 1.65-1.56 (m, 1H), 1.48-1.20 (m, 4H). Ms m/z (ESI): 170.2 [M+H]⁺ The fifth step: 7-hydroxy-2-azaspiro[4.5]decan-3-one (3e); 7-hydroxy-2-azaspiro[4.5]decan-3-one.

Compound 3d (0.35 g, 1.4 mmol) was dissolved in 10 mL of methanol, Raney nickel (0.1 g, ≤50 μm, dispersed in water) and potassium carbonate (19 mg, 0.14 mmol) were added, and stirred under hydrogen (1 atm) overnight. The filtrate was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol (v/v)=100/1-10/1) to obtain compound 3e as a white solid (0.16 g, yield: 66%). ¹ H NMR (400 MHz, CD ₃ OD) δ 3.68-3.58 (m, 1H), 3.21-3.14 (m, 2H), 2.26-2.13 (m, 2H), 1.94-1.84 (m, 2H), 1.78- 1.68 (m, 1H), 1.65-1.56 (m, 1H), 1.48-1.20 (m, 4H). Ms m/z (ESI): 170.2 [M+H] ⁺

第六步：7-[叔丁基 (二甲基)甲矽烷基]氧基-2-氮雜螺[4.5]癸烷-3-酮(3f) ； 7-[tert-butyl(dimethyl)silyl]oxy-2-azaspiro[4.5]decan-3-one.

將化合物3e (0.16 g, 0.95 mmol)溶於10 mL 二氯甲烷中，依次加入咪唑(0.13 g, 1.90 mmol)和叔丁基二甲基氯矽烷(0.17 g, 1.10 mmol)，室溫攪拌3 h。加入10 mL 的水溶液洗滌有機層，有機層減壓濃縮，殘留物矽膠柱層析純化(流動相：乙酸乙酯/石油醚(v/v)=1/5-1/0)得化合物3f，白色固體(0.17 g，收率：63%)。 Ms m/z (ESI): 284.3 [M+H]⁺ The sixth step: 7-[tert-butyl(dimethyl)silyl]oxy-2-azaspiro[4.5]decane-3-one (3f); 7-[tert-butyl(dimethyl)silyl ]oxy-2-azaspiro[4.5]decan-3-one.

Compound 3e (0.16 g, 0.95 mmol) was dissolved in 10 mL of dichloromethane, followed by adding imidazole (0.13 g, 1.90 mmol) and tert-butyldimethylchlorosilane (0.17 g, 1.10 mmol), stirring at room temperature for 3 h. 10 mL of aqueous solution was added to wash the organic layer, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/v)=1/5-1/0) to obtain compound 3f, White solid (0.17 g, yield: 63%). Ms m/z (ESI): 284.3 [M+H] ⁺

第七步：7-[叔丁基 (二甲基)甲矽烷基]氧基-2-苯基-2-氮雜螺[4.5]癸烷-3-酮(3g) ； 7-[tert-butyl(dimethyl)silyl]oxy-2-phenyl-2-azaspiro[4.5]decan-3-one.

將化合物3f (0.13 g, 0.46 mmol)和碘苯 (0.14 g, 0.69 mmol)溶於10 mL 甲苯中，依次加入碳酸銫 (0.30 g, 0.92 mmol)、反式1,2-環己二胺 (5.2 mg, 0.046mmol)和碘化亞銅 (4.4 mg, 0.023 mmol)，氮氣保護下升溫至110℃攪拌過夜。冷卻至室溫，加入10 mL乙酸乙酯和20 mL 氨水萃取，有機層用無水硫酸鈉乾燥後，殘留物矽膠柱層析純化(流動相：乙酸乙酯/石油醚(v/v)=1/20-1/5)得化合物3g，白色固體(0.1 g，收率：61%)。¹ HNMR (400 MHz, CDCl₃ ) δ 7.59 (d, 2H), 7.38-7.32 (m, 2H), 7.16-7.10 (m, 1H), 3.93-3.85 (m, 1H), 3.83-3.64 (m, 2H), 2.51-2.36(m, 2H), 1.82-1.74 (m, 2H), 1.70-1.40 (m, 6H), 0.90 (s, 9H), 0.06 (d, 6H). Ms m/z (ESI): 360.3 [M+H]⁺ The seventh step: 7-[tert-butyl(dimethyl)silyl]oxy-2-phenyl-2-azaspiro[4.5]decane-3-one (3g); 7-[tert- butyl(dimethyl)silyl]oxy-2-phenyl-2-azaspiro[4.5]decan-3-one.

Compound 3f (0.13 g, 0.46 mmol) and iodobenzene (0.14 g, 0.69 mmol) were dissolved in 10 mL of toluene, followed by adding cesium carbonate (0.30 g, 0.92 mmol), trans-1,2-cyclohexanediamine ( 5.2 mg, 0.046 mmol) and cuprous iodide (4.4 mg, 0.023 mmol), warmed to 110 °C and stirred overnight under nitrogen protection. Cooled to room temperature, added 10 mL of ethyl acetate and 20 mL of ammonia water for extraction, the organic layer was dried with anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/v)=1 /20-1/5) to obtain compound 3g as a white solid (0.1 g, yield: 61%). ¹ HNMR (400 MHz, CDCl ₃ ) δ 7.59 (d, 2H), 7.38-7.32 (m, 2H), 7.16-7.10 (m, 1H), 3.93-3.85 (m, 1H), 3.83-3.64 (m, 2H), 2.51-2.36(m, 2H), 1.82-1.74 (m, 2H), 1.70-1.40 (m, 6H), 0.90 (s, 9H), 0.06 (d, 6H). Ms m/z (ESI) ): 360.3 [M+H] ⁺

第八步：7-羥基-2-苯基-2-氮雜螺[4.5]癸烷-3-酮(3h)； 7-hydroxy-2-phenyl-2-azaspiro[4.5]decan-3-one.

將化合物3g (1 g, 2.78 mmol)溶於10 mL 的四氫呋喃中，加入四丁基氟化銨 (1.45 g, 5.56 mmol)，升溫至60℃攪拌2 h。加入20 mL水和20 mL乙酸乙酯萃取，有機層減壓濃縮後直接用於下一步。 Ms m/z (ESI): 246.2 [M+H]⁺ Step 8: 7-hydroxy-2-phenyl-2-azaspiro[4.5]decan-3-one (3h); 7-hydroxy-2-phenyl-2-azaspiro[4.5]decan-3-one .

Compound 3g (1 g, 2.78 mmol) was dissolved in 10 mL of tetrahydrofuran, tetrabutylammonium fluoride (1.45 g, 5.56 mmol) was added, the temperature was raised to 60 °C and stirred for 2 h. 20 mL of water and 20 mL of ethyl acetate were added for extraction, and the organic layer was concentrated under reduced pressure and used directly in the next step. Ms m/z (ESI): 246.2 [M+H] ⁺

第九步：2-苯基-2-氮雜螺[4.5]癸烷-3,7-二酮(3i)； 2-phenyl-2-azaspiro[4.5]decane-3,7-dione.

將化合物3h (0.7 g, 2.85 mmol) 溶於20 mL 二氯甲烷中，加入戴斯馬丁氧化劑 (1.21 g, 2.85 mmol)，室溫下攪拌反應1 h。加入20 mL飽和硫代硫酸鈉和20 mL飽和碳酸氫鈉水溶液，室溫攪拌20 min，分液，有機層減壓濃縮後，殘留物矽膠柱層析純化(流動相：乙酸乙酯/石油醚(v/v)=1/10-1/1)得化合物3i，白色固體(0.6 g，收率：86%)。 Ms m/z (ESI): 244.2 [M+H]⁺ The ninth step: 2-phenyl-2-azaspiro[4.5]decane-3,7-dione (3i); 2-phenyl-2-azaspiro[4.5]decane-3,7-dione.

Compound 3h (0.7 g, 2.85 mmol) was dissolved in 20 mL of dichloromethane, Dess Martin oxidant (1.21 g, 2.85 mmol) was added, and the reaction was stirred at room temperature for 1 h. Add 20 mL of saturated sodium thiosulfate and 20 mL of saturated aqueous sodium bicarbonate solution, stir at room temperature for 20 min, and separate the layers. After the organic layer is concentrated under reduced pressure, the residue is purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether). (v/v)=1/10-1/1) to obtain compound 3i as a white solid (0.6 g, yield: 86%). Ms m/z (ESI): 244.2 [M+H] ⁺

第十步：3,7-二氧代-2-苯基-2-氮雜螺[4.5]癸烷-8-羧酸乙酯(3k)； ethyl 3,7-dioxo-2-phenyl-2-azaspiro[4.5]decane-8-carboxylate.

將化合物3i (0.4 g, 1.64 mmol)，碳酸(2,3,4,5,6-五氟苯基)乙酯 (3j, 合成參考Org. Lett. 2013, 15, 2, 370-373) (0.42 g, 1.64 mmol)，二異丙基乙胺 (0.64 g, 4.95 mmol)和4-二甲氨基吡啶 (0.06 g, 0.493 mmol)混合在一50 mL的單口瓶中，加入20 mL二氯甲烷，氮氣保護下加入溴化鎂乙醚絡合物 (1.06 g, 4.11 mmol)，於氮氣保護下室溫攪拌3 h。加入20 mL 5%的鹽酸水溶液和20 mL二氯甲烷溶液萃取，有機層用無水硫酸鈉乾燥後，減壓濃縮，殘留物矽膠柱層析純化(流動相：乙酸乙酯/石油醚(v/v)=1/5-1/1)得化合物3k，淺黃色油狀物(0.4 g，收率：77%)。 Ms m/z (ESI): 316.2 [M+H]⁺ Step 10: Ethyl 3,7-dioxo-2-phenyl-2-azaspiro[4.5]decane-8-carboxylate (3k); ethyl 3,7-dioxo-2-phenyl-2 -azaspiro[4.5]decane-8-carboxylate.

Compound 3i (0.4 g, 1.64 mmol), (2,3,4,5,6-pentafluorophenyl) ethyl carbonate (3j, synthetic reference Org. Lett. 2013, 15, 2, 370-373) ( 0.42 g, 1.64 mmol), diisopropylethylamine (0.64 g, 4.95 mmol) and 4-dimethylaminopyridine (0.06 g, 0.493 mmol) were mixed in a 50 mL single-neck flask, and 20 mL of dichloromethane was added , magnesium bromide ether complex (1.06 g, 4.11 mmol) was added under nitrogen protection, and the mixture was stirred at room temperature for 3 h under nitrogen protection. Add 20 mL of 5% hydrochloric acid aqueous solution and 20 mL of dichloromethane solution for extraction, the organic layer was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/ v)=1/5-1/1) to obtain compound 3k as a pale yellow oil (0.4 g, yield: 77%). Ms m/z (ESI): 316.2 [M+H] ⁺

第十一步：2-甲基硫烷基-1'-苯基-螺基[3,5,6,8-四氫喹唑啉-7,4'-吡咯烷] -2',4-二酮(3l)； 2-methylsulfanyl-1'-phenyl-spiro[3,5,6,8-tetrahydroquinazoline-7,4'-pyrrolidine]-2',4-dione.

將化合物3k (0.36 g, 1.14 mmol)和S-甲基異硫脲硫酸鹽 (0.32 g, 1.71 mmol)溶於5 mL的乙腈中，加入5 mL水和碳酸鉀 (0.32 g, 2.30 mmol)，升溫至60℃攪拌3 h。用0.5 N的稀鹽酸調節pH = 5~6,過濾，濾餅用20 mL 50%的乙腈水溶液和20 mL 水依次洗滌。濾餅減壓乾燥後，得化合物3l，白色固體(0.18 g，收率：46%)，直接用於下一步。 Ms m/z (ESI): 342.2 [M+H]⁺ Step 11: 2-Methylsulfanyl-1'-phenyl-spiro[3,5,6,8-tetrahydroquinazoline-7,4'-pyrrolidine]-2',4- Dione (3l); 2-methylsulfanyl-1'-phenyl-spiro[3,5,6,8-tetrahydroquinazoline-7,4'-pyrrolidine]-2',4-dione.

Compound 3k (0.36 g, 1.14 mmol) and S-methylisothiourea sulfate (0.32 g, 1.71 mmol) were dissolved in 5 mL of acetonitrile, 5 mL of water and potassium carbonate (0.32 g, 2.30 mmol) were added, The temperature was raised to 60 °C and stirred for 3 h. Adjust pH=5~6 with 0.5 N dilute hydrochloric acid, filter, and wash the filter cake successively with 20 mL of 50% acetonitrile aqueous solution and 20 mL of water. After the filter cake was dried under reduced pressure, compound 31 was obtained as a white solid (0.18 g, yield: 46%), which was directly used in the next step. Ms m/z (ESI): 342.2 [M+H] ⁺

第十二步：(2-甲基硫烷基-2'-氧代-1'-苯基-螺[6,8-二氫-5H-喹唑啉-7,4'-吡咯烷] -4-基)三氟甲磺酸酯(3m)； (2-methylsulfanyl-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl) trifluoromethanesulfonate. 將化合物3l (0.17 g, 0.50 mmol)溶於10 mL二氯甲烷中，加入三乙胺(0.10 g, 1.0 mmol)，冰浴下加入三氟甲磺酸酐 (0.21 g, 0.75 mmol)，冰浴下攪拌1 h。用10 mL水洗滌反應液，再用10 mL飽和碳酸氫鈉水溶液洗滌反應液，有機層減壓濃縮後，殘留物矽膠柱層析純化(流動相：乙酸乙酯/石油醚(v/v)=1/20-1/5)得化合物3m，黃色固體(0.17 g，收率：72%)。 Ms m/z (ESI): 474.1 [M+H]⁺ The twelfth step: (2-methylsulfanyl-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]- 4-yl)trifluoromethanesulfonate (3m); (2-methylsulfanyl-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4 -yl) trifluoromethanesulfonate. Compound 3l (0.17 g, 0.50 mmol) was dissolved in 10 mL of dichloromethane, triethylamine (0.10 g, 1.0 mmol) was added, and trifluoromethanesulfonic anhydride (0.21 g, 0.75 mmol), and stirred under ice bath for 1 h. The reaction solution was washed with 10 mL of water, and then washed with 10 mL of saturated aqueous sodium bicarbonate solution. After the organic layer was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/v) =1/20-1/5) to obtain compound 3m as a yellow solid (0.17 g, yield: 72%). Ms m/z (ESI): 474.1 [M+H] ⁺

第十三步：叔丁基(2S)-2-(氰甲基)-4-(2-甲基硫烷基-2'-氧代-1'-苯基-螺[6,8-二氫-5H-喹唑啉-7,4'-吡咯烷]- 4-基)呱嗪-1-羧酸酯(3n)； tert-butyl (2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl)piperazine-1-carboxylate.

將化合物3m (0.17 g, 0.36 mmol)溶於10 mL N,N-二甲基甲醯胺中，加入二異丙基乙胺 (0.28 g, 2.17 mmol)和2-[(2S)-呱嗪-2-基]乙腈二鹽酸鹽 (0.071 g, 0.36 mmol)，室溫攪拌1 h後加入二碳酸二叔丁酯 (0.24 g, 1.10 mmol)，繼續攪拌5 h。加入20 mL水和20 mL乙酸乙酯萃取，有機層減壓濃縮後，殘留物矽膠柱層析純化(流動相：乙酸乙酯/石油醚(v/v)=1/10-1/2)得化合物3n，白色固體(0.14 g，收率：71%)。 Ms m/z (ESI): 549.3 [M+H]⁺ The thirteenth step: tert-butyl (2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-2'-oxo-1'-phenyl-spiro[6,8-di] Hydrogen-5H-quinazolin-7,4'-pyrrolidin]-4-yl)oxazine-1-carboxylate (3n); tert-butyl (2S)-2-(cyanomethyl)-4-(2 -methylsulfanyl-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl)piperazine-1-carboxylate.

Compound 3m (0.17 g, 0.36 mmol) was dissolved in 10 mL N,N-dimethylformamide, diisopropylethylamine (0.28 g, 2.17 mmol) and 2-[(2S)-oxazine were added -2-yl]acetonitrile dihydrochloride (0.071 g, 0.36 mmol), stirred at room temperature for 1 h, then added di-tert-butyl dicarbonate (0.24 g, 1.10 mmol), and continued stirring for 5 h. Add 20 mL of water and 20 mL of ethyl acetate for extraction. After the organic layer was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (v/v)=1/10-1/2) Compound 3n was obtained as a white solid (0.14 g, yield: 71%). Ms m/z (ESI): 549.3 [M+H] ⁺

第十四步：叔丁基(2S)-2-(氰甲基)-4-(2-甲基亞磺醯基-2'-氧代-1'-苯基-螺[6,8-二氫-5H-喹唑啉-7,4'-吡咯烷]- 4-基)呱嗪-1-羧酸酯(3o)； tert-butyl (2S)-2-(cyanomethyl)-4-(2-methylsulfinyl-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl)piperazine-1-carboxylate.

將化合物3n (0.13 g, 0.24 mmol)溶於10 mL四氫呋喃中，加入間氯過氧苯甲酸 (0.082 g, 0.47 mmol)，室溫攪拌2 h。加入10 mL飽和硫代硫酸鈉水溶液，攪拌20 min，加入20 mL乙酸乙酯萃取，有機層用10 mL飽和碳酸氫鈉水溶液洗滌，減壓濃縮得化合物3o，直接用於下一步。 Ms m/z (ESI): 565.3 [M+H]⁺ The fourteenth step: tert-butyl (2S)-2-(cyanomethyl)-4-(2-methylsulfinyl-2'-oxo-1'-phenyl-spiro[6,8- Dihydro-5H-quinazolin-7,4'-pyrrolidin]-4-yl)oxazine-1-carboxylate (3o); tert-butyl (2S)-2-(cyanomethyl)-4-( 2-methylsulfinyl-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl)piperazine-1-carboxylate.

Compound 3n (0.13 g, 0.24 mmol) was dissolved in 10 mL of tetrahydrofuran, m-chloroperoxybenzoic acid (0.082 g, 0.47 mmol) was added, and the mixture was stirred at room temperature for 2 h. Add 10 mL of saturated aqueous sodium thiosulfate solution, stir for 20 min, add 20 mL of ethyl acetate for extraction, wash the organic layer with 10 mL of saturated aqueous sodium bicarbonate solution, and concentrate under reduced pressure to obtain compound 3o, which is directly used in the next step. Ms m/z (ESI): 565.3 [M+H] ⁺

第十五步：叔丁基(2S)-2-(氰甲基)-4- [2-[[(2S)-1-甲基吡咯烷-2-基]甲氧基] -2'-氧代-1'-苯基-螺[6,8 -二氫-5H-喹唑啉-7,4'-吡咯烷] -4-基]呱嗪-1-甲酸酯(3p)； tert-butyl (2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl]piperazine-1-carboxylate.

將化合物3o (0.15 g, 0.27 mmol)和(S)-(1-甲基吡咯烷-2-基)甲醇 (0.092 g, 0.80 mmol)溶於10 mL 四氫呋喃中，冰浴下加入叔丁醇鈉 (0.051 g, 0.53 mmol)，冰浴下攪拌1 h。加入10 mL水淬滅反應，加入20 mL乙酸乙酯萃取，有機層減壓濃縮，殘留物矽膠柱層析純化(流動相：二氯甲烷/甲醇(v/v)=50/1-10/1)得化合物3p，白色固體(0.11 g，收率：67%)。 Ms m/z (ESI): 616.3 [M+H]⁺ The fifteenth step: tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'- Oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidin]-4-yl]oxazine-1-carboxylate (3p); tert -butyl (2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-1'-phenyl-spiro[6,8- dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl]piperazine-1-carboxylate.

Compound 3o (0.15 g, 0.27 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (0.092 g, 0.80 mmol) were dissolved in 10 mL of tetrahydrofuran, and sodium tert-butoxide was added under ice bath (0.051 g, 0.53 mmol), and stirred for 1 h under an ice bath. 10 mL of water was added to quench the reaction, 20 mL of ethyl acetate was added for extraction, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol (v/v)=50/1-10/ 1) Compound 3p was obtained as a white solid (0.11 g, yield: 67%). Ms m/z (ESI): 616.3 [M+H] ⁺

第十六步：2-[(2S)-4- [2-[[(2S)-1-甲基吡咯烷-2-基]甲氧基] -2'-氧代-1'-苯基-螺[6,8-二氫-5H-喹唑啉] -7,4'-吡咯烷] -4-基]呱嗪-2-基]乙腈； 2,2,2-三氟乙酸鹽(3q)； 2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl]piperazin-2-yl]acetonitrile；2,2,2-trifluoroacetic acid.

將化合物3p (0.11 g, 0.18 mmol) 溶於4 mL二氯甲烷中，加入4 mL 三氟乙酸，室溫攪拌2 h。減壓除去溶劑得到化合物3q，直接用於下一步。 Ms m/z (ESI): 516.4 [M+H]⁺ Step Sixteen: 2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-1'-phenyl - Spiro[6,8-dihydro-5H-quinazoline]-7,4'-pyrrolidin]-4-yl]oxazin-2-yl]acetonitrile; 2,2,2-trifluoroacetate ( 3q); 2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-1'-phenyl-spiro[6,8-dihydro- 5H-quinazoline-7,4'-pyrrolidine]-4-yl]piperazin-2-yl]acetonitrile; 2,2,2-trifluoroacetic acid.

Compound 3p (0.11 g, 0.18 mmol) was dissolved in 4 mL of dichloromethane, 4 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give compound 3q, which was used directly in the next step. Ms m/z (ESI): 516.4 [M+H] ⁺

第十七步：2-[(2S)-4-[2-[[(2S)-1-甲基吡咯烷-2-基]甲氧基] -2'-氧代-1'-苯基-螺[6,8-二氫-5H-喹唑啉] -7,4'-吡咯烷] -4-基] -1-丙-2-烯醯基-呱嗪-2-基]乙腈(化合物3)； 2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-1'-phenyl-spiro[6,8-dihydro-5H-quinazoline-7,4'-pyrrolidine]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.

將化合物3p (0.13 g, 0.17 mmol)溶於5 mL二氯甲烷中，加入三乙胺 (0.053 g, 0.52 mmol)，冰浴下加入烯丙醯氯 (16 mg, 0.17 mmol)，冰浴下攪拌30 min。加入10 mL飽和碳酸氫鈉水溶液淬滅，有機層減壓濃縮後，殘留物矽膠柱層析純化(流動相：二氯甲烷/甲醇(v/v)=30/1-8/1)得化合物3，白色固體(0.06 g，收率：60%)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.59 (t, 2H), 7.40-7.32 (m, 2H), 7.19-7.10 (m, 1H), 6.65-6.50 (m, 1H), 6.43-6.33 (m, 1H), 5.86-5.77 (m, 1H), 5.16-4.33 (m, 2H), 4.25-3.94 (m, 3H), 3.93 -3.45 (m, 4H), 3.42-3.26 (m, 1H), 3.24-3.11 (m, 1H), 3.11-2.98 (m, 1H), 2.98-2.87 (m, 2H), 2.85-2.59 (m, 6H), 2.58-2.45 (m, 4H), 2.41-2.29 (m, 1H), 2.13-1.93 (m, 2H), 1.92-1.70 (m, 4H). Ms m/z (ESI): 570.4 [M+H]⁺ 實施例 4 2-[(2S)-4-[2-[[(2S)-1-甲基吡咯烷-2-基] 亞甲氧基]雜環[6,8-二氫-5H-喹唑啉-7,1'-茚滿]-4-基]-1-丙基-2-烯醯-呱嗪-2-基]乙腈 (化合物4)； 2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

Step 17: 2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-1'-phenyl - Spiro[6,8-dihydro-5H-quinazoline]-7,4'-pyrrolidin]-4-yl]-1-prop-2-enyl-oxazin-2-yl]acetonitrile ( Compound 3); 2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-2'-oxo-1'-phenyl-spiro[6,8-dihydro -5H-quinazoline-7,4'-pyrrolidine]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.

Compound 3p (0.13 g, 0.17 mmol) was dissolved in 5 mL of dichloromethane, triethylamine (0.053 g, 0.52 mmol) was added, allyl chloride (16 mg, 0.17 mmol) was added under ice bath, and under ice bath Stir for 30 min. 10 mL of saturated aqueous sodium bicarbonate solution was added to quench, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane/methanol (v/v)=30/1-8/1) to obtain the compound 3. White solid (0.06 g, yield: 60%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 (t, 2H), 7.40-7.32 (m, 2H), 7.19-7.10 (m, 1H), 6.65-6.50 (m, 1H), 6.43-6.33 (m , 1H), 5.86-5.77 (m, 1H), 5.16-4.33 (m, 2H), 4.25-3.94 (m, 3H), 3.93 -3.45 (m, 4H), 3.42-3.26 (m, 1H), 3.24 -3.11 (m, 1H), 3.11-2.98 (m, 1H), 2.98-2.87 (m, 2H), 2.85-2.59 (m, 6H), 2.58-2.45 (m, 4H), 2.41-2.29 (m, 1H), 2.13-1.93 (m, 2H), 1.92-1.70 (m, 4H). Ms m/z (ESI): 570.4 [M+H] ⁺ Example 4 2-[(2S)-4-[2 -[[(2S)-1-Methylpyrrolidin-2-yl]methyleneoxy]heterocycle[6,8-dihydro-5H-quinazoline-7,1'-indan]-4- 2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

第一步：2-(3,5-二甲氧基苯基)乙-1-醇(4a)； 2-(3,5-dimethoxyphenyl)ethan-1-ol.

將(3，5-二甲氧基苯基)乙酸(1.07 g，5.48 mmol)的THF(10 mL)溶液，於室溫下滴加到四氫鋁鋰(312 mg，8.22 mmol)在THF(35mL)中的懸浮液中。保持室溫反應一小時，待原料反應完全後，將反應冷卻至0℃，並藉由緩慢加入1 mL水將過量的四氫鋁鋰淬滅。然後將混合物倒入1N HCl水溶液中，用乙酸乙酯(50 mL)萃取3次，合併有機相，有機相用飽和食鹽水洗滌，經無水硫酸鎂乾燥，並減壓濃縮，得到無色液體粗產品(4a)直接用於下一步(0.9 g，收率：90%)。The first step: 2-(3,5-dimethoxyphenyl)ethan-1-ol (4a); 2-(3,5-dimethoxyphenyl)ethan-1-ol.

A solution of (3,5-dimethoxyphenyl)acetic acid (1.07 g, 5.48 mmol) in THF (10 mL) was added dropwise at room temperature to lithium tetrahydroaluminum (312 mg, 8.22 mmol) in THF ( 35mL) in the suspension. The reaction was held at room temperature for one hour, and after the reaction of the starting materials was complete, the reaction was cooled to 0° C. and the excess lithium aluminum tetrahydride was quenched by slowly adding 1 mL of water. Then the mixture was poured into 1 N aqueous HCl solution, extracted three times with ethyl acetate (50 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude colorless liquid. The product (4a) was used directly in the next step (0.9 g, yield: 90%).

第二步：1-(2-溴乙基)-3,5-二甲氧基苯(4b)； 1-(2-bromoethyl)-3,5-dimethoxybenzene.

將化合物4a溶於二氯甲烷(11 mL)中，並加入CBr₄ (2.00 g，6.03 mmol)。然後將體系冷卻至0℃，並緩慢添加Ph₃ P(1.58 g，6.03 mmol)。體系自動升至室溫並攪拌30分鐘，待原料反應完全後，將溶液倒入20 mL水中，用乙酸乙酯50 mL萃取3次，合併有機相，有機相用飽和食鹽水洗滌，並用無水硫酸鎂乾燥，再減壓濃縮。將濃縮後的混合物置於-20^o C條件下析出白色固體，用混合溶劑(冷正己烷：乙醚=7:1)溶解混合物後，過濾，繼續用混合溶劑(冷正己烷：乙醚=7:1)洗滌濾餅兩次，濾液旋乾，柱層析得到澄清油狀物化合物4b(1.18 g，收率：88%)。 MS m/z (ESI): 245.1 [M+H]⁺ The second step: 1-(2-bromoethyl)-3,5-dimethoxybenzene (4b); 1-(2-bromoethyl)-3,5-dimethoxybenzene.

Compound 4a was dissolved in dichloromethane (11 mL) and _CBr4 (2.00 g, 6.03 mmol) was added. _The system was then cooled to 0°C and Ph3P (1.58 g, 6.03 mmol) was added slowly. The system was automatically raised to room temperature and stirred for 30 minutes. After the reaction of the raw materials was completed, the solution was poured into 20 mL of water, extracted three times with 50 mL of ethyl acetate, the organic phases were combined, and the organic phases were washed with saturated brine and anhydrous sulfuric acid. It was dried over magnesium and concentrated under reduced pressure. The concentrated mixture was placed at -20 ^o C to separate out a white solid. After dissolving the mixture with a mixed solvent (cold n-hexane: diethyl ether=7:1), the mixture was filtered, and continued to use a mixed solvent (cold n-hexane: diethyl ether=7:1) to dissolve the mixture. 1) The filter cake was washed twice, the filtrate was spin-dried, and a clear oily compound 4b (1.18 g, yield: 88%) was obtained by column chromatography. MS m/z (ESI): 245.1 [M+H] ⁺

第三步：3-(3,5-二甲氧基苯乙基)環己-2-烯-1-酮 (4c)； 3-(3,5-dimethoxyphenethyl)cyclohex-2-en-1-one.

在乾燥氮氣保護下，將鎂屑(228 mg，8.65 mmol)置於50 mL的三口燒瓶中，緩慢滴加約1/4的化合物4b(424 mg，1.73 mmol)的THF(0.5 mL)溶液。加入一粒碘，並對燒瓶加熱使得碘單質的顏色褪去，繼續緩慢滴加化合物4b的THF溶液，使得反應體系保持微沸。滴加完畢後，體系於室溫下繼續反應1h。並在0^o C下滴加到3-乙氧基-2-環己烯酮(107 mg，0.763 mmol)的THF(1.5 mL)溶液中。體系於室溫下攪拌2 h，並在0^o C下加入1N HCl水溶液(10 mL)淬滅反應。然後在室溫下再攪拌30分鐘後，將混合物用EA(20 mL×3)萃取。將合併的萃取液乾燥並在減壓下濃縮。經柱層析純化(EtOAc /己烷，1∶4)，得到無色油狀化合物4c(89 mg，收率：45%)。 MS m/z (ESI): 261.1 [M+H]⁺ The third step: 3-(3,5-dimethoxyphenethyl)cyclohex-2-en-1-one (4c); 3-(3,5-dimethoxyphenethyl)cyclohex-2-en-1- one.

Under the protection of dry nitrogen, magnesium turnings (228 mg, 8.65 mmol) were placed in a 50 mL three-necked flask, and about 1/4 of compound 4b (424 mg, 1.73 mmol) in THF (0.5 mL) was slowly added dropwise. One grain of iodine was added, and the flask was heated so that the color of the iodine element faded, and the THF solution of compound 4b was slowly added dropwise to keep the reaction system slightly boiling. After the dropwise addition, the system continued to react for 1 h at room temperature. And added dropwise to a solution of 3-ethoxy-2-cyclohexenone (107 mg, 0.763 mmol) in THF (1.5 mL) at 0 ^o C. The system was stirred at room temperature for 2 h, and the reaction was quenched by the addition of 1 N aqueous HCl (10 mL) at 0 ^° C. Then after stirring for another 30 minutes at room temperature, the mixture was extracted with EA (20 mL x 3). The combined extracts were dried and concentrated under reduced pressure. Purification by column chromatography (EtOAc/hexane, 1:4) gave compound 4c (89 mg, yield: 45%) as a colorless oil. MS m/z (ESI): 261.1 [M+H] ⁺

第四步：3-(3,5-二羥基苯乙基)環己-2-烯-1-酮(4d)； 3-(3,5-dihydroxyphenethyl)cyclohex-2-en-1-one.

將4c (2.5 g，9.6 mmol)溶於DCM(100 mL)中，冷卻至-78^o C。然後緩慢滴加BBr₃ (1N 的CH₂ Cl₂ 溶液，24 mL，24 mmol)。滴加完畢後，體系自動升至室溫反應6 h。待反應完成後，體系於-78^o C下，加入冰水淬滅反應，後用EA(100 mL)萃取3次。合併有機相，有機相用飽和食鹽水洗滌，並用無水硫酸鎂乾燥，再減壓濃縮。藉由柱層析得到白色固體4d(1.3 g，收率：58%)。 MS m/z (ESI): 233.1 [M+H]⁺ The fourth step: 3-(3,5-dihydroxyphenethyl)cyclohex-2-en-1-one (4d); 3-(3,5-dihydroxyphenethyl)cyclohex-2-en-1-one.

4c (2.5 g, 9.6 mmol) was dissolved in DCM (100 mL) and cooled to -78 ^° C. Then _BBr3 ( ₁ N in _CH2Cl2 , 24 mL, 24 mmol) was slowly added dropwise. After the dropwise addition, the system was automatically warmed to room temperature for 6 h. After the reaction was completed, the system was at -78 ^o C, ice water was added to quench the reaction, and then extracted with EA (100 mL) for 3 times. The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 4d (1.3 g, yield: 58%) was obtained as a white solid by column chromatography. MS m/z (ESI): 233.1 [M+H] ⁺

第五步：5',7'-二羥基-2',3'-二氫螺[環己烷-1,1'-茚基] -3-酮(4e)； 5',7'-dihydroxy-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-one.

向攪拌的4d(19.4 mg，83.5 µmol)的苯(0.8 mL)溶液中加入催化劑cat. (A:B=1:1, 24.4 mg，83.5 µmol)，對溴苯酚(14.4 mg，83.5 µmol)和H₂ O(1.5 µL，83 µmol)。在65^o C下攪拌10 h後，將混合物用1N HCl水溶液(3 mL)淬滅，並用EtOAc(5 mL×3)萃取。將合併的萃取液乾燥並在減壓下濃縮。藉由柱色譜法純化，得到白色固體4e(15 mg，收率：77%)。 MS m/z (ESI): 233.1 [M+H]⁺ The fifth step: 5',7'-dihydroxy-2',3'-dihydrospiro[cyclohexane-1,1'-indenyl]-3-one (4e); 5',7'-dihydroxy -2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-one.

To a stirred solution of 4d (19.4 mg, 83.5 µmol) in benzene (0.8 mL) was added catalyst cat. (A:B=1:1, 24.4 mg, 83.5 µmol), p-bromophenol (14.4 mg, 83.5 µmol) and _H2O (1.5 µL, 83 µmol). After stirring at 65 ^o C for 10 h, the mixture was quenched with 1 N aqueous HCl (3 mL) and extracted with EtOAc (5 mL x 3). The combined extracts were dried and concentrated under reduced pressure. Purification by column chromatography gave 4e as a white solid (15 mg, yield: 77%). MS m/z (ESI): 233.1 [M+H] ⁺

第六步：3-氧代-2',3'-二氫螺[環己烷-1,1'-茚] -5',7'-二基雙(三氟甲磺酸酯)(4f)； 3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-5',7'-diyl bis(trifluoromethanesulfonate).

將化合物4e(0.35 g，1.51 mmol)溶於15 mL二氯甲烷中，加入N,N-二異丙基乙胺(1.5 mL，9.05 mmol)，冰浴下加入三氟甲磺酸酐(0.76 mL，4.53 mmol)，冰浴下攪拌1 h。待反應完全後加入15 mL二氯甲烷稀釋，加入5 mL水洗滌淬滅反應，再用10 mL飽和碳酸氫鈉水溶液洗滌反應液，有機層用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到目標產物4f，無色液體(0.37 g，收率：50%)。 MS m/z (ESI): 497.0 [M+H]⁺ Step 6: 3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-5',7'-diylbis(triflate) (4f ); 3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-5',7'-diyl bis(trifluoromethanesulfonate).

Compound 4e (0.35 g, 1.51 mmol) was dissolved in 15 mL of dichloromethane, N,N-diisopropylethylamine (1.5 mL, 9.05 mmol) was added, and trifluoromethanesulfonic anhydride (0.76 mL) was added under ice bath. , 4.53 mmol), and stirred under ice bath for 1 h. After the reaction was completed, 15 mL of dichloromethane was added to dilute, 5 mL of water was added to wash and quench the reaction, and the reaction solution was washed with 10 mL of saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After column chromatography, the target product 4f was obtained as a colorless liquid (0.37 g, yield: 50%). MS m/z (ESI): 497.0 [M+H] ⁺

第七步：2’,3'-二氫螺[環己烷-1,1'-茚] -3-酮(4g)； (2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-one.

將4f(0.1 g，0.2 mmol)溶於DMF(5 mL)中，於冰浴下依次加入Pd(OAc)₂ (4.4 mg，0.02 mmol)，dppe(1,2-雙(二苯基膦)乙烷，cas:1663-45-2 ，16.4 mg，0.04 mmol)，Et₃ N(110 µL，0.8 mmol)和甲酸(30 µL，0.8 mmol)。氮氣置換氣三次後加熱至60^o C下攪拌1小時，後用飽和NH₄ Cl水溶液(30 mL)淬滅，並用EtOAc(10 mL×3)萃取。合併有機相，有機相用飽和食鹽水洗滌，並用無水硫酸鎂乾燥，再減壓濃縮。藉由柱層析得到白色固體4g(22 mg，收率：55 %)。 MS m/z (ESI): 201.3 [M+H]⁺ Step 7: 2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-one (4g); (2',3'-dihydrospiro[cyclohexane-1,1'-inden] ]-3-one.

4f (0.1 g, 0.2 mmol) was dissolved in DMF (5 mL), Pd(OAc) ₂ (4.4 mg, 0.02 mmol), dppe (1,2-bis(diphenylphosphine)) were added successively under ice bath Ethane, cas: 1663-45-2, 16.4 mg, 0.04 mmol), _Et3N (110 µL, 0.8 mmol) and formic acid (30 µL, 0.8 mmol). After three nitrogen purges, the mixture was heated to 60 ^° C and stirred for 1 hour, then quenched with saturated aqueous _NH4Cl (30 mL) and extracted with EtOAc (10 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A white solid 4 g (22 mg, yield: 55%) was obtained by column chromatography. MS m/z (ESI): 201.3 [M+H] ⁺

第八步：3-氧代-2',3'-二氫螺[環己烷-1,1'-茚] -4-羧酸甲酯(4h)； methyl-3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylate.

將氫化鈉(0.1 g，4.0 mmol)懸浮於10 mL乾燥的四氫呋喃中，氮氣保護，加入碳酸二甲酯(0.9 g，10.0 mmol)，加畢，體系加熱至80^o C攪拌30 min。然後滴加化合物4g(0.4 g，2.0 mmol)的四氫呋喃溶液(8 mL)，滴加完後保持80^o C繼續反應2h。TLC監控反應完成後，冷卻至室溫，墊矽藻土過濾，濾液加入20 mL冰水稀釋，用30 mL二氯甲烷萃取三次，合併有機相，用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到產物4h，黏稠液體(0.4 g，收率：80%)。 MS m/z (ESI): 259.1 [M+H]⁺ The eighth step: methyl 3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylate (4h); methyl-3-oxo-2', 3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylate.

Sodium hydride (0.1 g, 4.0 mmol) was suspended in 10 mL of dry tetrahydrofuran, under nitrogen protection, dimethyl carbonate (0.9 g, 10.0 mmol) was added, and the system was heated to 80 ^o C and stirred for 30 min. Then, a solution of compound 4g (0.4 g, 2.0 mmol) in tetrahydrofuran (8 mL) was added dropwise, and the reaction was continued at 80 ^° C after the dropwise addition for 2 h. After monitoring the reaction by TLC, it was cooled to room temperature, filtered through celite, the filtrate was diluted with 20 mL of ice water, extracted three times with 30 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was obtained after column chromatography for 4 h as a viscous liquid (0.4 g, yield: 80%). MS m/z (ESI): 259.1 [M+H] ⁺

第九步：2'-(甲硫基)-2,3,5',8'-四氫-6'H-螺[茚-1,7'-喹唑啉] -4'-醇(4i)； 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.

將化合物4h(0.4 g，2.0 mmol)溶於1 mL四氫呋喃中，加入S-甲基異硫脲硫酸鹽(858 mg，3.0 mmol)，後於室溫下滴加氫氧化鉀(897 mg，16 mmol)的水溶液(5 mL)。滴加完畢後保持室溫反應過夜。待反應完成後，加入10 mL水稀釋，用1N 鹽酸調節pH至9-10左右，然後用20 mL二氯甲烷萃取三次，合併有機相，用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到目標產物4i，白色固體(0.1 g，收率：20%)。 Ms m/z (ESI): 299.4 [M+H]⁺ The ninth step: 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-ol (4i ); 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.

Compound 4h (0.4 g, 2.0 mmol) was dissolved in 1 mL of tetrahydrofuran, S-methylisothiourea sulfate (858 mg, 3.0 mmol) was added, and potassium hydroxide (897 mg, 16 mmol) was added dropwise at room temperature. mmol) in water (5 mL). After the dropwise addition, the reaction was kept at room temperature overnight. After the reaction was completed, 10 mL of water was added to dilute, and the pH was adjusted to about 9-10 with 1 N hydrochloric acid, and then extracted three times with 20 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target product 4i was obtained as a white solid (0.1 g, yield: 20%). Ms m/z (ESI): 299.4 [M+H] ⁺

第十步：2'-(甲硫基)-2,3,5',8'-四氫-6'H-螺[茚-1,7'-喹唑啉] -4'-三氟甲磺酸酯(4j)； 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate.

將化合物4i(100 mg，0.3 mmol)溶於5 mL二氯甲烷中，加入N,N-二異丙基乙胺(0.5 g，1.2 mmol)，冰浴下加入三氟甲磺酸酐(169.2 mg，0.6 mmol)，冰浴下攪拌1 h。待反應完全後加入15 mL二氯甲烷稀釋，加入5mL水洗滌淬滅反應，再用10 mL飽和碳酸氫鈉水溶液洗滌反應液，有機層用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到產物4j，白色固體(80 mg，收率：61%)。 MS m/z (ESI): 431.5 [M+H]⁺ Step 10: 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-trifluoromethane Sulfonate (4j); 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate.

Compound 4i (100 mg, 0.3 mmol) was dissolved in 5 mL of dichloromethane, N,N-diisopropylethylamine (0.5 g, 1.2 mmol) was added, and trifluoromethanesulfonic anhydride (169.2 mg) was added under ice bath. , 0.6 mmol), and stirred under ice bath for 1 h. After the reaction was completed, 15 mL of dichloromethane was added to dilute, 5 mL of water was added to wash and quench the reaction, and then the reaction solution was washed with 10 mL of saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product 4j was obtained after column chromatography as a white solid (80 mg, yield: 61%). MS m/z (ESI): 431.5 [M+H] ⁺

第十一步：(S)-2-(氰甲基)-4-(2'-(甲硫基)-2,3,5',8'-四氫-6'H-螺[茚-1,7 '-喹唑啉] -4'-基)呱嗪-1-甲酸叔丁酯(4k)； tert-butyl (S)-2-(cyanomethyl)-4-(2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

將化合物4j (80 mg，0.18 mmol)溶於3 mL N,N-二甲基乙醯胺中，加入(S)-2-(呱嗪-2-基)乙腈(40 mg，0.2 mmol)和二異丙基乙胺(139 mg，1.08 mmol)，室溫攪拌1 h。TLC監控反應完全後，向體系中加入二碳酸二叔丁酯(118 mg，0.54 mmol)，加畢，反應室溫過夜。加入20 mL乙酸乙酯稀釋，用10 mL水洗有機相三次，有機相用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到產物4k，白色固體(90 mg，收率：100%)。 MS m/z (ESI): 506.7 [M+H]⁺ The eleventh step: (S)-2-(cyanomethyl)-4-(2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene- 1,7'-Quinazoline]-4'-yl)oxazine-1-carboxylate tert-butyl ester (4k); tert-butyl (S)-2-(cyanomethyl)-4-(2'-(methylthio) -2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

Compound 4j (80 mg, 0.18 mmol) was dissolved in 3 mL of N,N-dimethylacetamide, (S)-2-(oxazin-2-yl)acetonitrile (40 mg, 0.2 mmol) and Diisopropylethylamine (139 mg, 1.08 mmol) was stirred at room temperature for 1 h. After monitoring the completion of the reaction by TLC, di-tert-butyl dicarbonate (118 mg, 0.54 mmol) was added to the system, the addition was completed, and the reaction was carried out at room temperature overnight. 20 mL of ethyl acetate was added to dilute, and the organic phase was washed three times with 10 mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product 4k was obtained after column chromatography as a white solid (90 mg, yield: 100%). MS m/z (ESI): 506.7 [M+H] ⁺

第十二步：(S)-2-(氰甲基)-4-(2'-(甲基磺醯基)-2,3,5',8'-四氫-6'H-螺[茚-1,7 '-喹唑啉] -4'-基)呱嗪-1-甲酸叔丁酯(4l)； tert-butyl (S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

將化合物4k(90 mg，0.178 mmol)溶於2 mL四氫呋喃中，室溫下加入間氯過氧苯甲酸(61 mg，0.356 mmol)，室溫攪拌2 h。加入5 mL飽和硫代硫酸鈉水溶液，攪拌20 min，加入15 mL乙酸乙酯萃取，有機層用10 mL飽和碳酸氫鈉水溶液洗滌3次，有機相乾燥，減壓濃縮，得到化合物4l粗品，黃色固體90 mg，直接用於下一步。 MS m/z (ESI): 538.7 [M+H]⁺ The twelfth step: (S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-2,3,5',8'-tetrahydro-6'H-spiro[ Indene-1,7'-quinazoline]-4'-yl) oxazine-1-carboxylate tert-butyl ester (4l); tert-butyl (S)-2-(cyanomethyl)-4-(2'-( methylsulfonyl)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

Compound 4k (90 mg, 0.178 mmol) was dissolved in 2 mL of tetrahydrofuran, m-chloroperoxybenzoic acid (61 mg, 0.356 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 h. Add 5 mL of saturated aqueous sodium thiosulfate solution, stir for 20 min, add 15 mL of ethyl acetate for extraction, wash the organic layer with 10 mL of saturated aqueous sodium bicarbonate solution for 3 times, dry the organic phase, and concentrate under reduced pressure to obtain compound 41 crude product, yellow The solid 90 mg was used directly in the next step. MS m/z (ESI): 538.7 [M+H] ⁺

第十三步：(S)-2-(氰甲基)-4-(2'-((((S)-1-甲基吡咯烷-2-基)甲氧基)-2,3,5',8'- 四氫-6'H-螺[茚-1,7'-喹唑啉] -4'-基)呱嗪-1-甲酸叔丁酯(4m)； tert-butyl (S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

將化合物4l粗品(90 mg，0.167 mmol)和(S)-(1-甲基吡咯烷-2-基)甲醇(38 mg，0.335 mmol)溶於2 mL甲苯中，冰浴下加入叔丁醇鈉(14 mg，0.14 mmol)，冰浴下攪拌1 h。加入5 mL水淬滅反應，加入10 mL乙酸乙酯萃取三次，合併有機相，用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到產物4m，白色固體(78 mg，收率：80%)。 MS m/z (ESI): 573.6 [M+H]⁺ The thirteenth step: (S)-2-(cyanomethyl)-4-(2'-((((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3, 5',8'-Tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)oxazine-1-carboxylic acid tert-butyl ester (4m); tert-butyl (S )-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene -1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

The crude compound 41 (90 mg, 0.167 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (38 mg, 0.335 mmol) were dissolved in 2 mL of toluene, and tert-butanol was added under ice bath Sodium (14 mg, 0.14 mmol) was stirred under ice bath for 1 h. 5 mL of water was added to quench the reaction, 10 mL of ethyl acetate was added to extract three times, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product 4m was obtained after column chromatography as a white solid (78 mg, yield: 80%). MS m/z (ESI): 573.6 [M+H] ⁺

第十四步：2-[(2S)-4-[2-[[(2S)-1-甲基吡咯烷-2-基]亞甲氧基]雜環[6,8-二氫-5H-喹唑啉-7,1'-茚滿]-4-基]-呱嗪-2-基]乙腈(4n)； 2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.

將化合物4m (78 mg，0.136 mmol)溶於3 mL二氯甲烷中，加入0.5 mL三氟乙酸，於室溫下攪拌2 h。待反應完成後，加入5 mL水稀釋，滴加飽和碳酸氫鈉調節pH到鹼性，然後用10 mL二氯甲烷萃取三次，合併有機相，用無水硫酸鈉乾燥，減壓濃縮，得到化合物4n粗品，黃色固體63 mg，直接用於下一步。 MS m/z (ESI): 473.6 [M+H]⁺ Step Fourteen: 2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methyleneoxy]heterocyclo[6,8-dihydro-5H -Quinazolin-7,1'-indan]-4-yl]-oxazin-2-yl]acetonitrile (4n); 2-[(2S)-4-[2-[[(2S)-1 -methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.

Compound 4m (78 mg, 0.136 mmol) was dissolved in 3 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, 5 mL of water was added to dilute, and saturated sodium bicarbonate was added dropwise to adjust the pH to alkaline, and then extracted three times with 10 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 4n. Crude product, yellow solid 63 mg, used directly in the next step. MS m/z (ESI): 473.6 [M+H] ⁺

第十五步： 2-[(2S)-4-[2-[[(2S)-1-甲基吡咯烷-2-基] 亞甲氧基]雜環[6,8-二氫-5H-喹唑啉-7,1'-茚滿]-4-基]-1-丙基-2-烯醯-呱嗪-2-基]乙腈 (化合物4) 2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile

將化合物4n粗品(63 mg，0.133 mmol)溶於5 mL二氯甲烷中，加入三乙胺(40 mg，0.4 mmol)，冰浴下計入烯丙醯氯(12 mg，0.13 mmol)，冰浴下攪拌30 min。加入5 mL冰水淬滅反應，然後用10 mL二氯甲烷萃取三次，合併有機相，用無水硫酸鈉乾燥，減壓濃縮，經製備TLC純化得到化合物4 (8 mg，收率：10%)。手性HPLC積分面積_{T 8.2 min} : 積分面積_{T 11.6 min} (63:37) Ms m/z (ESI): 527.6 [M+H]⁺ 手性HPLC分析方法：樣品溶於正己烷/異丙醇(90:10)中，儀器：Shimadzu LC-20AT；手性柱：CHIRALPAK AD-H，4.6 × 250 mm, 5 μm 流動相：正己烷(含0.1% 二乙胺)-異丙醇(80:20)；流速：1 mL/min 柱溫：35 ℃；檢測波長：210 nm；進樣量：20 μL實施例 4-1 和 4-2 ： 2-((2S)-1-丙烯醯基-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-2,3,5',8'-四氫- 6'H-螺[茚-1,7'-喹唑啉] -4'-基)呱嗪-2-基)乙腈–異構體4-1和異構體4-2 2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile – isomer 4-1 and isomer 4-2.

The fifteenth step: 2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methyleneoxy]heterocycle[6,8-dihydro-5H -Quinazolin-7,1'-indan]-4-yl]-1-propyl-2-enyl-oxazin-2-yl]acetonitrile (compound 4) 2-[(2S)-4- [2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]-1-prop-2- enoyl-piperazin-2-yl]acetonitrile

The crude compound 4n (63 mg, 0.133 mmol) was dissolved in 5 mL of dichloromethane, triethylamine (40 mg, 0.4 mmol) was added, allyl chloride (12 mg, 0.13 mmol) was added under ice bath, ice Stir under the bath for 30 min. The reaction was quenched by adding 5 mL of ice water, and then extracted three times with 10 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative TLC to obtain compound 4 (8 mg, yield: 10%) . Chiral HPLC integrated area _{T 8.2 min} : Integrated area _{T 11.6 min} (63:37) Ms m/z (ESI): 527.6 [M+H] ⁺ Chiral HPLC analytical method: The sample was dissolved in n-hexane/isopropanol ( 90:10), instrument: Shimadzu LC-20AT; chiral column: CHIRALPAK AD-H, 4.6 × 250 mm, 5 μm Mobile phase: n-hexane (containing 0.1% diethylamine)-isopropanol (80:20 ); Flow rate: 1 mL/min Column temperature: 35 °C; Detection wavelength: 210 nm; Injection volume: 20 μL Examples 4-1 and 4-2 : 2-((2S)-1-propenyl-4 -(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1, 7'-Quinazolin]-4'-yl)oxazin-2-yl)acetonitrile – Isomer 4-1 and Isomer 4-2 2-((2S)-1-acryloyl-4-(2 '-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'- yl)piperazin-2-yl)acetonitrile - isomer 4-1 and isomer 4-2.

第一步：3-氧代-2',3'-二氫螺[環己烷-1,1'-茚] -4-羧酸乙酯(4o)； ethyl 3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylate.

-78^o C氮氣保護下，將化合物4g (0.37 g，1.84 mmol, 參照化合物4合成路線中間體4g的合成)懸浮於30 mL乾燥的四氫呋喃中，緩慢滴加LiHMDS的四氫呋喃溶液(2.77 mL, 1 mol/L，2.77 mmol)，保持-78^o C攪拌30 min後，將氰基甲酸乙酯(0.3 g，2.77 mmol)的四氫呋喃溶液(8 mL)緩慢滴入反應液中，滴加完後反應液緩慢升至室溫反應4h。TLC監控反應完成後，冷卻至0^o C，滴加100 mL冰水淬滅反應。乙酸乙酯100 mL萃取三次，合併有機相，用無水硫酸鈉乾燥，減壓濃縮得到化合物4o，黃色黏稠液體(0.54 g粗品)。無需純化直接用於下一步反應。 MS m/z (ESI): 273.1 [M+H]⁺ The first step: 3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylic acid ethyl ester (4o); ethyl 3-oxo-2',3 '-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylate.

Under -78 ^o C nitrogen protection, compound 4g (0.37 g, 1.84 mmol, refer to the synthesis of compound 4 synthetic route intermediate 4g) was suspended in 30 mL of dry tetrahydrofuran, and a solution of LiHMDS in tetrahydrofuran (2.77 mL, 1 mol/L, 2.77 mmol), after stirring at -78 ^o C for 30 min, the tetrahydrofuran solution (8 mL) of ethyl cyanoformate (0.3 g, 2.77 mmol) was slowly added dropwise to the reaction solution, and the reaction was completed after the dropwise addition. The solution was slowly raised to room temperature for 4 h. After monitoring the reaction by TLC, it was cooled to ^{0 ℃} , and 100 mL of ice water was added dropwise to quench the reaction. Extracted with 100 mL of ethyl acetate three times, combined the organic phases, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 4o as a yellow viscous liquid (0.54 g crude product). It was used directly in the next reaction without purification. MS m/z (ESI): 273.1 [M+H] ⁺

第二步：3-氨基-2',3'-二氫螺[環己烷-1,1'-茚] -3-烯-4-羧酸乙酯(4p)； ethyl 3-amino-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate.

將粗品化合物4o溶於20 mL乙醇中，加入醋酸銨(0.7 g，9.2 mmol)室溫反應12 h，TLC監控反應完成後，減壓旋乾溶劑，加入100 mL乙酸乙酯稀釋，然後用10 mL水洗三次，有機相用無水硫酸鈉乾燥，減壓濃縮得到化合物4p，黃色黏稠液體(0.49 g粗品)，無需純化直接用於下一步反應。 MS m/z (ESI): 272.2 [M+H]⁺ The second step: 3-amino-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-3-ene-4-carboxylic acid ethyl ester (4p); ethyl 3-amino-2 ',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate.

The crude compound 4o was dissolved in 20 mL of ethanol, and ammonium acetate (0.7 g, 9.2 mmol) was added to react at room temperature for 12 h. After the reaction was monitored by TLC, the solvent was spin-dried under reduced pressure, diluted with 100 mL of ethyl acetate, and then diluted with 10 mL water was washed three times, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 4p as a yellow viscous liquid (0.49 g crude product), which was directly used in the next reaction without purification. MS m/z (ESI): 272.2 [M+H] ⁺

第三步：3-(3-苯甲醯基硫脲基)-2',3'-二氫螺[環己烷-1,1'-茚] -3-烯-4-羧酸乙酯(4q)； ethyl 3-(3-benzoylthioureido)-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate.

將粗品化合物4p溶於50 mL丙酮中，加入苯甲醯基異硫氰酸酯氫化鈉(0.37 mL，2.76 mmol)，氮氣保護下加熱至80^o C，反應1 h。TLC監控反應完成後，冷卻至室溫，減壓濃縮。柱層析(PE：EA=3:1)後得到目標產物4q，黃色黏稠液體(0.43 g，三步收率：53%)。 MS m/z (ESI): 435.2 [M+H]⁺ The third step: 3-(3-benzylthioureido)-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-3-ene-4-carboxylic acid ethyl ester (4q); ethyl 3-(3-benzoylthioureido)-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate.

The crude compound 4p was dissolved in 50 mL of acetone, sodium benzyl isothiocyanate hydride (0.37 mL, 2.76 mmol) was added, heated to 80 ^o C under nitrogen protection, and reacted for 1 h. After completion of the reaction monitored by TLC, it was cooled to room temperature and concentrated under reduced pressure. After column chromatography (PE:EA=3:1), the target product 4q was obtained as a yellow viscous liquid (0.43 g, three-step yield: 53%). MS m/z (ESI): 435.2 [M+H] ⁺

第四步：2'-巰基-2,3,5',8'-四氫-6'H-螺[茚-1,7'-喹唑啉] -4'-醇(4r)； 2'-mercapto-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.

將化合物4q (0.43 g，0.99 mmol)溶於15 mL乙醇中，加入氫氧化鉀(0.17 g，3.0 mmol)，體系加熱至80^o C攪拌1 h。TLC監控反應完成後，冷卻至室溫，減壓濃縮除去溶劑至2 mL左右。滴加1N 稀鹽酸至不再有白色固體析出(pH = 2)，過濾，濾餅用水洗兩次，收集濾餅得到目標產物4r，白色固體(0.28 g，收率：99%)。 MS m/z (ESI): 285.4 [M+H]⁺ The fourth step: 2'-mercapto-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-ol (4r); 2'-mercapto-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.

Compound 4q (0.43 g, 0.99 mmol) was dissolved in 15 mL of ethanol, potassium hydroxide (0.17 g, 3.0 mmol) was added, and the system was heated to 80 ^o C and stirred for 1 h. After monitoring by TLC, the reaction was completed, cooled to room temperature, and concentrated under reduced pressure to remove the solvent to about 2 mL. 1 N dilute hydrochloric acid was added dropwise until no white solid was precipitated (pH = 2), filtered, the filter cake was washed twice with water, and the filter cake was collected to obtain the target product 4r as a white solid (0.28 g, yield: 99%). MS m/z (ESI): 285.4 [M+H] ⁺

第五步：2'-(甲硫基)-2,3,5',8'-四氫-6'H-螺[茚-1,7'-喹唑啉] -4'-醇(4i)； 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.

將化合物4r(0.28 g，0.99 mmol)溶於氫氧化鉀(0.17 g，3.0 mmoL)的水溶液中，再加入2 mL甲醇使不溶物溶解。於室溫下滴加碘甲烷(184 mg，1.3 mmoL)，保持室溫反應2 h。TLC監控反應完成後，滴加1N 稀鹽酸至不再有白色固體析出(pH = 2)，過濾，濾餅用水洗兩次，收集濾餅得到目標產物4i，白色固體(0.2 g，收率：68%)。 Ms m/z (ESI): 299.4 [M+H]⁺ The fifth step: 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-ol (4i ); 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.

Compound 4r (0.28 g, 0.99 mmol) was dissolved in an aqueous solution of potassium hydroxide (0.17 g, 3.0 mmol), and 2 mL of methanol was added to dissolve the insolubles. Iodomethane (184 mg, 1.3 mmol) was added dropwise at room temperature, and the reaction was kept at room temperature for 2 h. After the completion of the TLC monitoring reaction, 1 N dilute hydrochloric acid was added dropwise until no more white solid was precipitated (pH=2), filtered, and the filter cake was washed twice with water, and the filter cake was collected to obtain the target product 4i, a white solid (0.2 g, yield : 68%). Ms m/z (ESI): 299.4 [M+H] ⁺

第六步：2'-(甲硫基)-2,3,5',8'-四氫-6'H-螺[茚-1,7'-喹唑啉] -4'-三氟甲磺酸酯(4j)； 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate.

將化合物4i(200 mg，0.67 mmol)溶於5 mL二氯甲烷中，加入N,N-二異丙基乙胺(1.0 g，1.2 mmol)，冰浴下加入三氟甲磺酸酐(378 mg，1.35 mmol)，冰浴下攪拌1 h。待反應完全後加入30 mL二氯甲烷稀釋，加入5 mL水洗滌淬滅反應，再用10 mL飽和碳酸氫鈉水溶液洗滌反應液，有機層用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到目標產物4j，白色固體(256 mg，收率：89%)。 MS m/z (ESI): 431.5 [M+H]⁺ The sixth step: 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-trifluoromethane Sulfonate (4j); 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate.

Compound 4i (200 mg, 0.67 mmol) was dissolved in 5 mL of dichloromethane, N,N-diisopropylethylamine (1.0 g, 1.2 mmol) was added, and trifluoromethanesulfonic anhydride (378 mg) was added under ice bath. , 1.35 mmol), and stirred under ice bath for 1 h. After the reaction was completed, 30 mL of dichloromethane was added to dilute, 5 mL of water was added to wash and quench the reaction, and the reaction solution was washed with 10 mL of saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After column chromatography, the target product 4j was obtained as a white solid (256 mg, yield: 89%). MS m/z (ESI): 431.5 [M+H] ⁺

第七步：(S)-2-(氰甲基)-4-(2'-(甲硫基)-2,3,5',8'-四氫-6'H-螺[茚-1,7 '-喹唑啉] -4'-基)呱嗪-1-甲酸叔丁酯(4k)； tert-butyl (S)-2-(cyanomethyl)-4-(2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

將化合物4j(256 mg，0.6 mmol)溶於3 mL N, N-二甲基乙醯胺中，加入(S)-2-(氰基甲基)呱嗪-1-羧酸叔丁酯(202 mg，0.9 mmol)和二異丙基乙胺(0.4 mL，2.4 mmol)，室溫攪拌12 h。TLC監控反應完全後，加入50 mL乙酸乙酯稀釋，用10 mL水洗有機相三次，有機相用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到目標產物4k，白色固體(330 mg，收率：99%)。 MS m/z (ESI): 506.7 [M+H]⁺ The seventh step: (S)-2-(cyanomethyl)-4-(2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1 ,7 '-Quinazoline]-4'-yl)oxazine-1-carboxylate tert-butyl ester (4k); tert-butyl (S)-2-(cyanomethyl)-4-(2'-(methylthio)- 2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

Compound 4j (256 mg, 0.6 mmol) was dissolved in 3 mL of N,N-dimethylacetamide, and (S)-tert-butyl 2-(cyanomethyl)oxazine-1-carboxylate ( 202 mg, 0.9 mmol) and diisopropylethylamine (0.4 mL, 2.4 mmol), stirred at room temperature for 12 h. After monitoring the completion of the reaction by TLC, 50 mL of ethyl acetate was added to dilute, and the organic phase was washed three times with 10 mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After column chromatography, the target product 4k was obtained as a white solid (330 mg, yield: 99%). MS m/z (ESI): 506.7 [M+H] ⁺

第八步：(S)-2-(氰甲基)-4-(2'-(甲基磺醯基)-2,3,5',8'-四氫-6'H-螺[茚-1,7 '-喹唑啉] -4'-基)呱嗪-1-甲酸叔丁酯(4l)； tert-butyl (S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

將化合物4k(330 mg，0.65mmol)溶於15 mL四氫呋喃中，室溫下加入間氯過氧苯甲酸(449 mg，2.6 mmol)，室溫攪拌2 h。加入10 mL飽和硫代硫酸鈉水溶液，攪拌20 min，加入50 mL乙酸乙酯萃取，有機層用10 mL飽和碳酸氫鈉水溶液洗滌3次，有機相乾燥，減壓濃縮，柱層析後得到目標產物4l，白色固體(300 mg，收率：93%)。 MS m/z (ESI): 538.7 [M+H]⁺ The eighth step: (S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-2,3,5',8'-tetrahydro-6'H-spiro[indene -1,7'-Quinazoline]-4'-yl)oxazine-1-carboxylate tert-butyl ester (4l); tert-butyl (S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl) )-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

Compound 4k (330 mg, 0.65 mmol) was dissolved in 15 mL of tetrahydrofuran, m-chloroperoxybenzoic acid (449 mg, 2.6 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 h. Add 10 mL saturated aqueous sodium thiosulfate solution, stir for 20 min, add 50 mL ethyl acetate for extraction, wash the organic layer with 10 mL saturated aqueous sodium bicarbonate solution 3 times, dry the organic phase, concentrate under reduced pressure, and obtain the target after column chromatography Product 41, white solid (300 mg, yield: 93%). MS m/z (ESI): 538.7 [M+H] ⁺

第九步：(S)-2-(氰甲基)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-2,3,5',8'- 四氫-6'H-螺[茚-1,7'-喹唑啉] -4'-基)呱嗪-1-甲酸叔丁酯(4m)； tert-butyl (S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

將化合物4l(300 mg，0.56 mmol)和(S)-(1-甲基吡咯烷-2-基)甲醇(128 mg，1.1 mmol)溶於10 mL甲苯中，冰浴下加入叔丁醇鈉(81 mg，0.84 mmol)，冰浴下攪拌1 h。加入5 mL水淬滅反應，加入50 mL乙酸乙酯萃取三次，合併有機相，用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到目標產物4m，白色固體(292 mg，收率：91%)。 MS m/z (ESI): 573.6 [M+H]⁺ The ninth step: (S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-Tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)oxazine-1-carboxylate tert-butyl ester (4m); tert-butyl (S)- 2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1 ,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

Compound 4l (300 mg, 0.56 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (128 mg, 1.1 mmol) were dissolved in 10 mL of toluene, and sodium tert-butoxide was added under ice bath (81 mg, 0.84 mmol), and stirred under ice bath for 1 h. 5 mL of water was added to quench the reaction, 50 mL of ethyl acetate was added for extraction three times, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target product 4m was obtained as a white solid (292 mg, yield: 91%). MS m/z (ESI): 573.6 [M+H] ⁺

第十步：2-((2S)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-2,3,5',8'-四氫-6'H- 螺[茚-1,7'-喹唑啉] -4'-基)呱嗪-2-基)乙腈(化合物4n)； 2-((2S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile

將化合物4m(292 mg，0.51 mmol)溶於15 mL二氯甲烷中，加入5 mL三氟乙酸，於室溫下攪拌2 h。待反應完成後，加入5 mL水稀釋，滴加飽和碳酸氫鈉調節pH到鹼性，然後用30 mL二氯甲烷萃取三次，合併有機相，用無水硫酸鈉乾燥，減壓濃縮，得到目標化合物4n粗品，黃色固體350 mg，直接用於下一步。 MS m/z (ESI): 473.6 [M+H]⁺ Step 10: 2-((2S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetra Hydro-6'H-spiro[inden-1,7'-quinazolin]-4'-yl)oxazin-2-yl)acetonitrile (compound 4n); 2-((2S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl )piperazin-2-yl)acetonitrile

Compound 4m (292 mg, 0.51 mmol) was dissolved in 15 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. After the reaction is completed, add 5 mL of water to dilute, add saturated sodium bicarbonate dropwise to adjust the pH to basic, then extract with 30 mL of dichloromethane three times, combine the organic phases, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the target compound 4n crude product, yellow solid 350 mg, used directly in the next step. MS m/z (ESI): 473.6 [M+H] ⁺

第十一步：2-((2S)-1-丙烯醯基-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-2,3,5',8'-四氫- 6'H-螺[茚-1,7'-喹唑啉] -4'-基)呱嗪-2-基)乙腈-異構體4-1和異構體4-2 2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile – isomer 4-1 and isomer 4-2.

將化合物4n粗品(350 mg)溶於20 mL二氯甲烷中，加入三乙胺(258 mg，2.55 mmol)，冰浴下滴加入烯丙醯氯(46 mg，0.51 mmol)，冰浴下攪拌30 min。加入5 mL冰水淬滅反應，然後用30 mL二氯甲烷萃取三次，合併有機相，用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到目標化合物4 (216 mg，收率：81%，手性HPLC積分面積_{T 8.2 min} ：積分面積_{T 11.6 min} = 65 ：35，分析方法參照實施例4)。化合物4經SFC製備分離純化後得到4-1(60 mg, SFC製備保留時間為4.5 min；手性HPLC保留時間為8.2 min)和4-2 (31 mg，SFC製備保留時間為3.9 min，手性HPLC保留時間為11.6 min). SFC製備分離條件：儀器: «Instrument__Prep» 柱子: «Column_3»流動相: A 為CO₂ ，B 為乙醇(含0.1%氨水)，30%B洗脫。流速: 60«Flow_Rate» mL /min；柱溫: 38 ℃；檢測波長: «Wavelength» 經製備分離後，合併相同保留時間的組分，減壓濃縮得化合物4-1和4-2。化合物4-1: LCMS: m/z (ESI): 527.3 [M+H]⁺ ¹ H NMR (400 MHz, CD₃ COOD) δ 7.30 – 7.11 (m, 4H), 6.91 – 6.67 (m, 1H), 6.37 (d, 1H), 5.87 (d, 1H), 5.16 – 5.02 (m, 1H), 4.97 – 4.80 (m, 2H), 4.72 – 4.57 (m, 1H), 4.56 – 4.43 (m, 1H), 4.24 – 4.07 (m, 1H), 4.06 – 3.53 (m, 5H), 3.51 – 3.16 (m, 2H), 3.13 – 2.77 (m, 10H), 2.48 – 2.34 (m, 1H), 2.26 – 2.05 (m, 6H), 1.91 – 1.79 (m, 1H). 化合物4-2: LCMS: m/z (ESI): 527.3 [M+H]⁺ ¹ H NMR (400 MHz, CD₃ OD) δ 7.27 – 7.19 (m, 1H), 7.19 – 7.08 (m, 2H), 7.08 – 7.01 (m, 1H), 6.94 – 6.72 (m, 1H), 6.28 (d, 1H), 5.82 (d, 1H), 5.15 – 5.00 (m, 1H), 4.63 – 4.46 (m, 1H), 4.43 – 4.28 (m, 2H), 4.18 – 3.92 (m, 3H), 3.68 – 3.49 (m, 1H), 3.26 – 3.19 (m, 1H), 3.16 – 2.73 (m, 9H), 2.72 – 2.60 (m, 1H), 2.54 (s, 3H), 2.47 – 2.37 (m, 1H), 2.17 – 1.94 (m, 4H), 1.89 – 1.66 (m, 4H). 2'，3'-二氫螺環[環己烷-1,1'-茚]-3-酮(中間體1 )

The eleventh step: 2-((2S)-1-propenyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3, 5',8'-Tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)oxazin-2-yl)acetonitrile-isomer 4-1 and isomeric Body 4-2 2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro- 6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile – isomer 4-1 and isomer 4-2.

The crude compound 4n (350 mg) was dissolved in 20 mL of dichloromethane, triethylamine (258 mg, 2.55 mmol) was added, allyl chloride (46 mg, 0.51 mmol) was added dropwise under an ice bath, and the mixture was stirred under an ice bath. 30 minutes. The reaction was quenched by adding 5 mL of ice water, and then extracted three times with 30 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target compound 4 was obtained (216 mg, yield: 81%, chiral HPLC integrated area _{T 8.2 min} : integrated area _{T 11.6 min} = 65:35, the analytical method refers to Example 4). Compound 4 was isolated and purified by SFC to obtain 4-1 (60 mg, retention time of SFC preparation was 4.5 min; chiral HPLC retention time was 8.2 min) and 4-2 (31 mg, retention time of SFC preparation was 3.9 min, manual The retention time of HPLC is 11.6 min). SFC preparation and separation conditions: Instrument: «Instrument__Prep» Column: «Column_3» Mobile phase: A is CO ₂ , B is ethanol (containing 0.1% ammonia water), 30% B elution. Flow rate: 60«Flow_Rate» mL/min; Column temperature: 38 ℃; Detection wavelength: «Wavelength» After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compounds 4-1 and 4-2. Compound 4-1: LCMS: m/z (ESI): 527.3 [M+H] ⁺ ¹ H NMR (400 MHz, CD ₃ COOD) δ 7.30 – 7.11 (m, 4H), 6.91 – 6.67 (m, 1H) , 6.37 (d, 1H), 5.87 (d, 1H), 5.16 – 5.02 (m, 1H), 4.97 – 4.80 (m, 2H), 4.72 – 4.57 (m, 1H), 4.56 – 4.43 (m, 1H) , 4.24 – 4.07 (m, 1H), 4.06 – 3.53 (m, 5H), 3.51 – 3.16 (m, 2H), 3.13 – 2.77 (m, 10H), 2.48 – 2.34 (m, 1H), 2.26 – 2.05 ( m, 6H), 1.91 – 1.79 (m, 1H). Compound 4-2: LCMS: m/z (ESI): 527.3 [M+H] ⁺ ¹ H NMR (400 MHz, CD ₃ OD) δ 7.27 – 7.19 (m, 1H), 7.19 – 7.08 (m, 2H), 7.08 – 7.01 (m, 1H), 6.94 – 6.72 (m, 1H), 6.28 (d, 1H), 5.82 (d, 1H), 5.15 – 5.00 (m, 1H), 4.63 – 4.46 (m, 1H), 4.43 – 4.28 (m, 2H), 4.18 – 3.92 (m, 3H), 3.68 – 3.49 (m, 1H), 3.26 – 3.19 (m, 1H) , 3.16 – 2.73 (m, 9H), 2.72 – 2.60 (m, 1H), 2.54 (s, 3H), 2.47 – 2.37 (m, 1H), 2.17 – 1.94 (m, 4H), 1.89 – 1.66 (m, 4H). 2',3'-Dihydrospiro[cyclohexane-1,1'-indene]-3-one (Intermediate 1 )

第一步：2-溴-1-環丙烯-1-酮 (中間體 1B ) 2-bromo-1-cyclopropylethan-1-one

將原料甲基環丙酮(8.4 g, 0.1 mol) 溶解在60 mL 甲醇中，置於0 °C攪拌溶解，再向體系中緩慢滴加溴素 (5.0 mL，90 mmol)，溴素滴加完畢後，繼續在此溫度下攪拌直至反應體系變為無色透明。反應結束後，向反應中加入三乙胺直至體系PH為中性，再將反應液甲醇減壓蒸餾除去，得到三乙胺氫溴酸鹽固體以及油狀產物的混合物，該混合物用石油醚洗滌過濾，將液體部分旋蒸抽乾後得到無色油狀產物 (中間體 1B )(16.0 g，產率97%)。The first step: 2-bromo-1-cyclopropen-1-one ( Intermediate 1B ) 2-bromo-1-cyclopropylethan-1-one

The raw material methylcycloacetone (8.4 g, 0.1 mol) was dissolved in 60 mL of methanol, placed at 0 °C with stirring to dissolve, and then slowly added bromine (5.0 mL, 90 mmol) dropwise to the system, and the dropwise addition of bromine was completed. Then, continue to stir at this temperature until the reaction system becomes colorless and transparent. After the reaction finishes, add triethylamine to the reaction until the system PH is neutral, then the reaction solution methanol is distilled off under reduced pressure to obtain the mixture of triethylamine hydrobromide solid and oily product, and the mixture is washed with petroleum ether After filtration, the liquid part was rotary evaporated to dryness to obtain a colorless oily product ( Intermediate 1B ) (16.0 g, yield 97%).

第二步：1,5-二溴戊烷-2-酮 (中間體 1C ) 1,5-dibromopentan-2-one

將底物中間體 1B (16.0 g, 98 mmol)加入到50 mL氫溴酸水溶液(v/v = 48%)中，再將反應液置於50 °C攪拌2小時，反應結束後，向反應液中加入200 mL石油醚，再加入適量的冰塊，直至白色固體析出，過濾乾燥得到白色固體產物 (中間體 1C )(18 g， 75%)。The second step: 1,5-dibromopentan-2-one ( intermediate 1C ) 1,5-dibromopentan-2-one

Substrate Intermediate 1B (16.0 g, 98 mmol) was added to 50 mL of aqueous hydrobromic acid (v/v=48%), the reaction solution was then placed at 50 °C and stirred for 2 hours. 200 mL of petroleum ether was added to the liquid, and then an appropriate amount of ice cubes was added until a white solid was precipitated, which was filtered and dried to obtain a white solid product ( Intermediate 1C ) (18 g, 75%).

第三步：2-(溴甲基)-2-(3-溴丙基)-1,3-二氧環烷 (中間體 1D ) 2-(bromomethyl)-2-(3-bromopropyl)-1,3-dioxolane

將底物中間體 1C (14.0 g, 57.6 mmol )與乙二醇 (21.4 g, 0.35 mol)以及對甲苯磺酸 (1.1 g, 5.8 mmol)加入到150 mL的甲苯中，再將體系置於120 °C加熱回流分水。反應至分水器中沒有新增水，且甲苯清澈時，反應即結束，冷卻至室溫，減壓濃縮，殘餘物經矽膠色譜分離得到黃色油狀物中間體 1 D (11.7 g，產率70%)。¹ H NMR (400 MHz, CDCl₃ ) δ 4.09 – 4.04 (m, 2H), 4.03 – 3.98 (m, 2H), 3.43 (t, 2H), 3.37 (s, 2H), 2.02 – 1.96 (m, 4H).The third step: 2-(bromomethyl)-2-(3-bromopropyl)-1,3-dioxane ( Intermediate 1D ) 2-(bromomethyl)-2-(3-bromopropyl)-1 ,3-dioxolane

The substrate intermediate 1C (14.0 g, 57.6 mmol) and ethylene glycol (21.4 g, 0.35 mol) and p-toluenesulfonic acid (1.1 g, 5.8 mmol) were added to 150 mL of toluene, and the system was placed at 120 °C heating under reflux to separate water. The reaction was completed until no new water was added in the water separator and the toluene was clear, cooled to room temperature, concentrated under reduced pressure, and the residue was separated by silica gel chromatography to obtain a yellow oily intermediate 1 D (11.7 g, yield 70%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.09 – 4.04 (m, 2H), 4.03 – 3.98 (m, 2H), 3.43 (t, 2H), 3.37 (s, 2H), 2.02 – 1.96 (m, 4H) ).

第四步：雙螺環[茚-1,1'-環己烷-3',2'-[1,3]二氧環烷] (中間體 1E ) dispiro[indene-1,1'-cyclohexane-3',2''-[1,3]dioxolane]

將茚 (4.87 g, 42.0 mmol )加入到80 mL的THF中，置於0 °C攪拌溶解後，向體系中緩慢滴加LiHMDS (42 mL, 42.0 mmol, 1M in hexane), 滴加完畢後，反應置於此溫度下繼續攪拌30 min。在0 °C下，將此反應液用轉移針頭緩慢滴加到中間體 1D (10.0 g, 35.0 mmol) 的THF(80 mL)的溶液中，滴加完畢後，反應置於0 °C攪拌1小時。再向體系中緩慢滴加LiHMDS(42 mL, 42.0 mmol, 1M in hexane),滴加完畢後，將反應溫度緩慢上升至室溫並攪拌過夜。反應即結束，冷卻至0 °C，將反應液加入到NH₄ Cl的飽和水溶液中淬滅，用乙酸乙酯萃取，有機相乾燥過濾後直接旋乾，矽膠色譜分離得到白色固體中間體 1E (4.1 g，產率48%)。The fourth step: double spiro[indene-1,1'-cyclohexane-3',2'-[1,3]dioxane] ( Intermediate 1E ) dispiro[indene-1,1'-cyclohexane] -3',2''-[1,3]dioxolane]

Indene (4.87 g, 42.0 mmol) was added to 80 mL of THF, placed at 0 °C and stirred to dissolve, then LiHMDS (42 mL, 42.0 mmol, 1M in hexane) was slowly added dropwise to the system. After the dropwise addition was completed, The reaction was left to stir at this temperature for 30 min. At 0 °C, the reaction solution was slowly added dropwise to the solution of Intermediate 1D (10.0 g, 35.0 mmol) in THF (80 mL) with a transfer needle. After the dropwise addition, the reaction was placed at 0 °C and stirred for 1 Hour. Then LiHMDS (42 mL, 42.0 mmol, 1M in hexane) was slowly added dropwise to the system. After the dropwise addition, the reaction temperature was slowly raised to room temperature and stirred overnight. The reaction was completed, cooled to 0 °C, the reaction solution was added to a saturated aqueous solution of NH ₄ Cl to quench, extracted with ethyl acetate, the organic phase was dried and filtered, and directly spin-dried, and silica gel chromatography was used to obtain a white solid intermediate 1E ( 4.1 g, 48% yield).

第五步：2,3-二氫雙螺環[茚-1,1'-環己烷-3',2'-[1,3]二氧環烷] (中間體 1F ) 2,3-dihydrodispiro[indene-1,1'-cyclohexane-3',2''-[1,3]dioxolane]

將中間體 1E (4.0 g, 16.5 mmol )溶解到50 mL甲醇中，加入400 mg Pd/C (10%_wt )反應用氫氣球保護，置於室溫攪拌3小時。反應即結束，用矽藻土過濾，濾液旋乾再使用矽膠色譜柱分離得到無色油狀物產物中間體 1F (3.7 g，產率92%)。The fifth step: 2,3-dihydrobispiro[indene-1,1'-cyclohexane-3',2'-[1,3]dioxane] ( Intermediate 1F ) 2,3- dihydrodispiro[indene-1,1'-cyclohexane-3',2''-[1,3]dioxolane]

Intermediate 1E (4.0 g, 16.5 mmol) was dissolved in 50 mL of methanol, 400 mg of Pd/C (10% _wt ) was added, and the reaction was protected with a hydrogen balloon, and stirred at room temperature for 3 hours. The reaction was completed, filtered with celite, the filtrate was spin-dried and separated by silica gel chromatography to obtain the intermediate 1F (3.7 g, yield 92%) as a colorless oily product.

第六步：2'，3'-二氫螺環[環己烷-1,1'-茚]-3-酮(中間體 1 ) 2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-one

將中間體 1F (3.7 g, 15.1 mmol )溶解到10 mL的THF中，再向體系中加入6N 的鹽酸甲醇溶液(20 mL)，反應置於室溫攪拌1小時。反應結束後，減壓濃縮，殘餘物加水50 mL，乙酸乙酯萃取(50 mL×3)，飽和NaHCO₃ 水溶液洗滌，有機相乾燥過濾後直接旋乾經矽膠色譜柱分離得到白色固體中間體 1 (2.8 g，產率94%)。 LCMS: m/z (ESI): 201.2 [M+H]⁺ ¹ H NMR (400 MHz, CDCl₃ ) δ 7.24 – 7.02 (m, 4H), 2.96 – 2.76 (m, 2H), 2.55 – 2.24 (m, 4H), 2.11 – 1.64 (m, 4H).實施例 5 2-[(2S)-4- [2-[[((2S，4R)-4-氟-1-甲基-吡咯烷-2-基]甲氧基]螺[6,8-二氫-5H-喹唑啉-7, 1'-茚滿] -4-基] -1-丙-2-烯醯基-呱嗪-2-基]乙腈(化合物5)； 2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.

The sixth step: 2',3'-dihydrospiro[cyclohexane-1,1'-indene]-3-one ( Intermediate 1 ) 2',3'-dihydrospiro[cyclohexane-1,1'- inden]-3-one

Intermediate 1F (3.7 g, 15.1 mmol) was dissolved in 10 mL of THF, 6 N methanolic hydrochloric acid solution (20 mL) was added to the system, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, concentrated under reduced pressure, added 50 mL of water to the residue, extracted with ethyl acetate (50 mL×3), washed with saturated aqueous NaHCO ₃ solution, dried and filtered the organic phase, directly spin-dried, and separated by silica gel column to obtain intermediate 1 as a white solid (2.8 g, 94% yield). LCMS: m/z (ESI): 201.2 [M+H] ⁺ ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.24 – 7.02 (m, 4H), 2.96 – 2.76 (m, 2H), 2.55 – 2.24 (m , 4H), 2.11 - 1.64 (m, 4H). Example 5 2-[(2S)-4-[2-[[((2S,4R)-4-fluoro-1-methyl-pyrrolidine-2 -yl]methoxy]spiro[6,8-dihydro-5H-quinazolin-7,1'-indan]-4-yl]-1-prop-2-enyl-oxazine-2 -yl]acetonitrile (compound 5); 2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8 -dihydro-5H-quinazoline-7,1'-indane]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.

第一步：3-氧代-2',3'-二氫螺[環己烷-1,1'-茚] -4-羧酸乙酯(5b)； ethyl 3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylate.

將中間體1 (8.0 g，40 mmol)懸浮於150 mL乾燥的四氫呋喃中，氮氣保護降溫至-78^o C，緩慢滴加LiHMDS的四氫呋喃溶液(60 mL, 1 mol/L，60 mmol)，加畢，體系保持-78^o C攪拌30 min。然後滴加氰基甲酸乙酯(5.9 g，60 mmol)的四氫呋喃溶液(20 mL)，滴加完後體系自動升至室溫反應。TLC監控反應完成後，冷卻至0^o C，滴加100 mL冰水淬滅反應。然後用乙酸乙酯150 mL萃取三次，合併有機相，用無水硫酸鈉乾燥，減壓濃縮得到化合物5b，黃色黏稠液體(11.5 g粗品)，無需純化直接用於下一步反應。 MS m/z (ESI): 273.1 [M+H]⁺ The first step: 3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylic acid ethyl ester (5b); ethyl 3-oxo-2',3 '-dihydrospiro[cyclohexane-1,1'-indene]-4-carboxylate.

Intermediate 1 (8.0 g, 40 mmol) was suspended in 150 mL of dry tetrahydrofuran, cooled to -78 ^o C under nitrogen protection, slowly added dropwise a solution of LiHMDS in tetrahydrofuran (60 mL, 1 mol/L, 60 mmol), added After completion, the system was kept at -78 ^o C and stirred for 30 min. Then, a solution of ethyl cyanoformate (5.9 g, 60 mmol) in tetrahydrofuran (20 mL) was added dropwise. After the dropwise addition, the system was automatically warmed to room temperature for reaction. After monitoring the reaction by TLC, it was cooled to 0 ^o C, and 100 mL of ice water was added dropwise to quench the reaction. Then it was extracted three times with 150 mL of ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 5b as a yellow viscous liquid (11.5 g crude product), which was directly used in the next reaction without purification. MS m/z (ESI): 273.1 [M+H] ⁺

第二步：3-氨基-2',3'-二氫螺[環己烷-1,1'-茚] -3-烯-4-羧酸乙酯(5c)； ethyl 3-amino-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate.

將粗品化合物5b溶於200 mL乙醇中，加入醋酸銨(23.1 g，300 mmol)室溫反應12 h，TLC監控反應完成後，減壓旋乾溶劑，加入100 mL乙酸乙酯稀釋，然後用30 mL水洗三次，有機相用無水硫酸鈉乾燥，減壓濃縮得到化合物5c，黃色黏稠液體(10.7 g粗品)，無需純化直接用於下一步反應。 MS m/z (ESI): 272.2 [M+H]⁺ The second step: 3-amino-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-3-ene-4-carboxylic acid ethyl ester (5c); ethyl 3-amino-2 ',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate.

The crude compound 5b was dissolved in 200 mL of ethanol, and ammonium acetate (23.1 g, 300 mmol) was added to react at room temperature for 12 h. After the reaction was monitored by TLC, the solvent was spin-dried under reduced pressure, diluted with 100 mL of ethyl acetate, and then diluted with 30 mL water was washed three times, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 5c as a yellow viscous liquid (10.7 g crude product), which was directly used in the next reaction without purification. MS m/z (ESI): 272.2 [M+H] ⁺

第三步：3-(3-苯甲醯基硫脲基)-2',3'-二氫螺[環己烷-1,1'-茚] -3-烯-4-羧酸乙酯(5d)； ethyl 3-(3-benzoylthioureido)-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate.

將粗品化合物5c溶於100 mL丙酮中，加入苯甲醯基異硫氰酸酯(12.1 mL，90 mmol)，氮氣保護下加熱至80^o C，反應1 h。TLC監控反應完成後，冷卻至室溫，減壓濃縮。柱層析(PE：EA=3:1)後得到目標產物5d，黃色黏稠液體(12 g，三步收率：69%)。 MS m/z (ESI): 435.2 [M+H]⁺ The third step: 3-(3-benzylthioureido)-2',3'-dihydrospiro[cyclohexane-1,1'-indene]-3-ene-4-carboxylic acid ethyl ester (5d); ethyl 3-(3-benzoylthioureido)-2',3'-dihydrospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate.

The crude compound 5c was dissolved in 100 mL of acetone, benzyl isothiocyanate (12.1 mL, 90 mmol) was added, heated to 80 ^o C under nitrogen protection, and reacted for 1 h. After completion of the reaction monitored by TLC, it was cooled to room temperature and concentrated under reduced pressure. After column chromatography (PE:EA=3:1), the target product 5d was obtained as a yellow viscous liquid (12 g, three-step yield: 69%). MS m/z (ESI): 435.2 [M+H] ⁺

第四步：2'-巰基-2,3,5',8'-四氫-6'H-螺[茚-1,7'-喹唑啉] -4'-醇(5e)； 2'-mercapto-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.

將化合物5d (12 g，27.6 mmol)溶於150 mL乙醇中，加入氫氧化鉀(4.6 g，82.8 mmol)，體系加熱至80^o C攪拌1 h。TLC監控反應完成後，冷卻至室溫，減壓濃縮除去溶劑至20 mL左右。滴加1N HCl水溶液至不再有白色固體析出(PH = 2)，過濾，濾餅用水洗兩次，收集濾餅得到目標產物5e，白色固體(6.0 g，收率：70.5%)。 MS m/z (ESI): 285.4 [M+H]⁺ The fourth step: 2'-mercapto-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-ol (5e); 2'-mercapto-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.

Compound 5d (12 g, 27.6 mmol) was dissolved in 150 mL of ethanol, potassium hydroxide (4.6 g, 82.8 mmol) was added, and the system was heated to 80 ^o C and stirred for 1 h. After monitoring the reaction by TLC, it was cooled to room temperature, and concentrated under reduced pressure to remove the solvent to about 20 mL. 1 N HCl aqueous solution was added dropwise until no white solid was precipitated (PH = 2), filtered, the filter cake was washed twice with water, and the filter cake was collected to obtain the target product 5e as a white solid (6.0 g, yield: 70.5%). MS m/z (ESI): 285.4 [M+H] ⁺

第五步：2'-(甲硫基)-2,3,5',8'-四氫-6'H-螺[茚-1,7'-喹唑啉] -4'-醇(5f)； 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.

將化合物5e (6.0 g，21.1 mmol)溶於氫氧化鉀(3.6 g，63.4 mmoL)的水(100 mL)溶液中，再加入2 mL甲醇使不溶物溶解。於室溫下滴加碘甲烷(3.9 g，27.4 mmoL)，保持室溫反應2 h。TLC監控反應完成後，滴加1N HCl至不再有白色固體析出(PH = 2)，過濾，濾餅用水洗兩次，收集濾餅得到目標產物5f，白色固體(4.1 g，收率：65%)。 MS m/z (ESI): 299.4 [M+H]⁺ The fifth step: 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-ol (5f ); 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol.

Compound 5e (6.0 g, 21.1 mmol) was dissolved in a solution of potassium hydroxide (3.6 g, 63.4 mmol) in water (100 mL), and 2 mL of methanol was added to dissolve the insolubles. Iodomethane (3.9 g, 27.4 mmol) was added dropwise at room temperature, and the reaction was kept at room temperature for 2 h. After the completion of the TLC monitoring reaction, 1 N HCl was added dropwise until no more white solid was precipitated (PH=2), filtered, and the filter cake was washed twice with water, and the filter cake was collected to obtain the target product 5f, a white solid (4.1 g, yield: 65%). MS m/z (ESI): 299.4 [M+H] ⁺

第六步：2'-(甲硫基)-2,3,5',8'-四氫-6'H-螺[茚-1,7'-喹唑啉] -4'-三氟甲磺酸酯(5g)； 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate.

將化合物5f(1.7 g，5.7 mmol)溶於300 mL二氯甲烷中，加入N,N-二異丙基乙胺(4.4 g，34.2 mmol)，冰浴下加入三氟甲磺酸酐(4.83 g，17.1 mmol)，冰浴下攪拌1 h。待反應完全後，加入30 mL水洗滌淬滅反應，再用20 mL飽和碳酸氫鈉水溶液洗滌反應液，有機層用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到目標產物5g，白色固體(2.42 g，收率：99%)。 MS m/z (ESI): 431.5 [M+H]⁺ The sixth step: 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-trifluoromethane Sulfonate (5g); 2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate.

Compound 5f (1.7 g, 5.7 mmol) was dissolved in 300 mL of dichloromethane, N,N-diisopropylethylamine (4.4 g, 34.2 mmol) was added, and trifluoromethanesulfonic anhydride (4.83 g) was added under ice bath. , 17.1 mmol), and stirred under ice bath for 1 h. After the reaction was completed, 30 mL of water was added to wash to quench the reaction, and then the reaction solution was washed with 20 mL of saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After column chromatography, 5 g of the target product was obtained as a white solid (2.42 g, yield: 99%). MS m/z (ESI): 431.5 [M+H] ⁺

第七步：(S)-2-(氰甲基)-4-(2'-(甲硫基)-2,3,5',8'-四氫-6'H-螺[茚-1,7 '-喹唑啉] -4'-基)呱嗪-1-甲酸叔丁酯(5h)； tert-butyl (S)-2-(cyanomethyl)-4-(2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

將化合物5g(2.42 g，5.6 mmol)溶於30 mL N,N-二甲基乙醯胺中，加入(S)-2-(氰基甲基)呱嗪-1-羧酸叔丁酯(1.9 g，8.4 mmol)和二異丙基乙胺(3.67 mL，22.4 mmol)，室溫攪拌12 h。TLC監控反應完全後，加入150 mL乙酸乙酯稀釋，用30 mL水洗有機相三次，有機相用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到目標產物5h，白色固體(2.73 g，收率：96%)。 MS m/z (ESI): 506.7 [M+H]⁺ The seventh step: (S)-2-(cyanomethyl)-4-(2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1 ,7 '-Quinazoline]-4'-yl)oxazine-1-carboxylate tert-butyl ester (5h); tert-butyl (S)-2-(cyanomethyl)-4-(2'-(methylthio)- 2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

Compound 5g (2.42 g, 5.6 mmol) was dissolved in 30 mL of N,N-dimethylacetamide, and (S)-2-(cyanomethyl)oxazine-1-carboxylate tert-butyl ester ( 1.9 g, 8.4 mmol) and diisopropylethylamine (3.67 mL, 22.4 mmol), stirred at room temperature for 12 h. After monitoring the completion of the reaction by TLC, 150 mL of ethyl acetate was added to dilute, and the organic phase was washed three times with 30 mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The target product was obtained after column chromatography for 5 h as a white solid (2.73 g, yield: 96%). MS m/z (ESI): 506.7 [M+H] ⁺

第八步：(S)-2-(氰甲基)-4-(2'-(甲基磺醯基)-2,3,5',8'-四氫-6'H-螺[茚-1,7 '-喹唑啉] -4'-基)呱嗪-1-甲酸叔丁酯(5i)； tert-butyl (S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

將化合物5h(2.73 g，5.4 mmol)溶於100 mL四氫呋喃中，室溫下加入間氯過氧苯甲酸(2.8 g，16.2 mmol)，室溫攪拌2 h。加入20 mL飽和硫代硫酸鈉水溶液，攪拌20 min，減壓除去大部分溶劑後，加入100 mL乙酸乙酯稀釋，有機層用30 mL飽和碳酸氫鈉水溶液洗滌3次，有機相乾燥，減壓濃縮，柱層析後得到目標產物5i，白色固體(2.54 g，收率：87%)。 MS m/z (ESI): 538.7 [M+H]⁺ The eighth step: (S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl)-2,3,5',8'-tetrahydro-6'H-spiro[indene -1,7'-Quinazoline]-4'-yl)oxazine-1-carboxylate tert-butyl ester (5i); tert-butyl (S)-2-(cyanomethyl)-4-(2'-(methylsulfonyl) )-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

Compound 5h (2.73 g, 5.4 mmol) was dissolved in 100 mL of tetrahydrofuran, m-chloroperoxybenzoic acid (2.8 g, 16.2 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 h. Add 20 mL of saturated aqueous sodium thiosulfate solution, stir for 20 min, remove most of the solvent under reduced pressure, add 100 mL of ethyl acetate to dilute, wash the organic layer with 30 mL of saturated aqueous sodium bicarbonate solution 3 times, dry the organic phase, and reduce the pressure Concentration and column chromatography gave the target product 5i as a white solid (2.54 g, yield: 87%). MS m/z (ESI): 538.7 [M+H] ⁺

第九步：(2S)-2-(氰基甲基)-4- [2-[[((2S,4R)-4-氟-1-甲基-吡咯烷基-2-基]甲氧基]螺[6,8-二氫- 5H-喹唑啉-7,1'-茚滿] -4-基]呱嗪-1-甲酸叔丁酯(5j)； tert-butyl(2S)-2-(cyanomethyl)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy] spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazine-1-carboxylate.

將化合物5i(950 mg，1.77 mmol)和(1-甲基-4-氟代吡咯烷-2-基)甲醇(471 mg，3.54 mmol)溶於40 mL甲苯中，冰浴下加入叔丁醇鈉(255 mg，2.66 mmol)，冰浴下攪拌1 h。加入15 mL水淬滅反應，加入100 mL乙酸乙酯萃取三次，合併有機相，用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到目標產物5j，白色固體(1.0 g，收率：96%)。 MS m/z (ESI): 591.3 [M+H]⁺ Step 9: (2S)-2-(cyanomethyl)-4-[2-[[((2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy yl]spiro[6,8-dihydro-5H-quinazoline-7,1'-indan]-4-yl]oxazine-1-carboxylate tert-butyl ester (5j); tert-butyl(2S)- 2-(cyanomethyl)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1 '-indane]-4-yl]piperazine-1-carboxylate.

Compound 5i (950 mg, 1.77 mmol) and (1-methyl-4-fluoropyrrolidin-2-yl)methanol (471 mg, 3.54 mmol) were dissolved in 40 mL of toluene, and tert-butanol was added under ice bath Sodium (255 mg, 2.66 mmol), stirred under ice bath for 1 h. 15 mL of water was added to quench the reaction, 100 mL of ethyl acetate was added to extract three times, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target product 5j was obtained as a white solid (1.0 g, yield: 96%). MS m/z (ESI): 591.3 [M+H] ⁺

第十步：2-[(2S)-4- [2-[[((2S,4R)-4-氟-1-甲基-吡咯烷-2-基]甲氧基]螺[6,8-二氫-5H-喹唑啉-7， 1'-茚滿] -4-基]呱嗪-2-基]乙腈(5k)； 2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.

將化合物5j(1.0 g，1.7 mmol)溶於20 mL二氯甲烷中，加入5 mL三氟乙酸，於室溫下攪拌2 h。待反應完成後，減壓旋乾溶劑，再加入100 mL二氯甲烷稀釋，滴加飽和碳酸氫鈉調節PH到鹼性，然後用100 mL二氯甲烷萃取三次，合併有機相，用無水硫酸鈉乾燥，減壓濃縮，得到目標化合物5k粗品，黃色固體1.2 g，直接用於下一步。 MS m/z (ESI): 491.3 [M+H]⁺ Step 10: 2-[(2S)-4-[2-[[((2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8 -Dihydro-5H-quinazolin-7,1'-indan]-4-yl]oxazin-2-yl]acetonitrile (5k); 2-[(2S)-4-[2-[[( 2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl ]acetonitrile.

Compound 5j (1.0 g, 1.7 mmol) was dissolved in 20 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. After the reaction is completed, spin dry the solvent under reduced pressure, add 100 mL of dichloromethane to dilute, add dropwise saturated sodium bicarbonate to adjust the pH to basic, then extract three times with 100 mL of dichloromethane, combine the organic phases, and use anhydrous sodium sulfate. Dry and concentrate under reduced pressure to obtain the target compound 5k as a crude product, 1.2 g of a yellow solid, which is directly used in the next step. MS m/z (ESI): 491.3 [M+H] ⁺

第十一步：2-[(2S)-4- [2-[[((2S,4R)-4-氟-1-甲基-吡咯烷-2-基]甲氧基]螺[6,8-二氫-5H-喹唑啉-7, 1'-茚滿] -4-基] -1-丙-2-烯醯基-呱嗪-2-基]乙腈(化合物5)； 2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.

將化合物5k粗品(0.6 g，1.23 mmol)溶於50 mL二氯甲烷中，加入三乙胺(0.85 mL，6.1 mmol)，冰浴下計入烯丙醯氯(111 mg，1.23 mmol)，冰浴下攪拌30 min。加入5 mL冰水淬滅反應，然後用50 mL二氯甲烷萃取三次，合併有機相，用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到目標化合物5，白色固體(254 mg，兩步收率：55%)。化合物5經SFC製備分離純化後得到異構體5-1(95 mg, SFC製備保留時間為1.23 min；手性HPLC保留時間為12.78 min)和異構體5-2 (100 mg，SFC製備保留時間為1.47 min，手性HPLC保留時間為18.30 min)。手性HPLC分析方法：樣品溶於正己烷/異丙醇(90:10)中，儀器：Shimadzu LC-20AT；手性柱：CHIRALPAK AD-H，4.6 × 250 mm, 5 μm 流動相：正己烷(含0.1% 二乙胺)-異丙醇(80:20)；流速：1 mL/min 柱溫：35 ℃；檢測波長：210 nm；進樣量：50 μL SFC製備分離條件：儀器: «Instrument__Prep»柱子: «Column_3» 流動相: A 為CO₂ ，B 為乙醇(含0.1%氨水)，30%B洗脫。流速: 70«Flow_Rate» mL /min；柱溫: 38 ℃；檢測波長: «Wavelength» 經製備分離後，合併相同保留時間的組分，減壓濃縮得化合物5-1和5-2。異構體5-1¹ H NMR (400 MHz, CD₃ OD) δ 7.30 – 7.03 (m, 4H), 6.93 – 6.71 (m, 1H), 6.27 (d, 1H), 5.82 (d, 1H), 5.26 – 4.99 (m, 2H), 4.43 – 4.30 (m, 2H), 4.21 – 3.96 (m, 3H), 3.76 – 3.58 (m, 1H), 3.57 – 3.42 (m, 2H), 3.42 – 3.36 (m, 1H), 3.18 – 3.03 (m, 2H), 3.02 – 2.90 (m, 3H), 2.90 – 2.77 (m, 3H), 2.77 – 2.48 (m, 5H), 2.33 – 2.18 (m, 1H), 2.13 – 1.86 (m, 4H), 1.85 – 1.75 (m, 1H).¹⁹ F NMR (376 MHz, CD₃ OD) δ -169.68. Ms m/z (ESI): 545.3 [M+H]⁺ 異構體5-2¹ H NMR (400 MHz, CD₃ OD) δ 7.26 – 7.19 (m, 1H), 7.19 – 7.09 (m, 2H), 7.09 – 7.02 (m, 1H), 6.94 – 6.72 (m, 1H), 6.28 (d, 1H), 5.82 (d, 1H), 5.28 – 5.00 (m, 2H), 4.44 – 4.31 (m, 2H), 4.21 – 3.93 (m, 3H), 3.67 – 3.43 (m, 2H), 3.28 – 3.20 (m, 1H), 3.19 – 3.08 (m, 2H), 3.07 – 2.86 (m, 4H), 2.85 – 2.62 (m, 5H), 2.55 (s, 3H), 2.35 – 2.21 (m, 1H), 2.10 – 1.88 (m, 4H), 1.82 – 1.72 (m, 1H).¹⁹ F NMR (376 MHz, CD₃ OD) δ -169.73. Ms m/z (ESI): 545.3 [M+H]⁺ 實施例 6 2-[(2S)-4- [2-[[((2S，4R)-4-氟-1-甲基-吡咯烷-2-基]甲氧基]螺[6,8-二氫-5H-喹唑啉-7， 1'-茚滿] -4-基] -1-(2-氟丙-2-烯醯基)呱嗪-2-基]乙腈(化合物 6 )； 2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.

The eleventh step: 2-[(2S)-4-[2-[[((2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6, 8-Dihydro-5H-quinazolin-7,1'-indan]-4-yl]-1-prop-2-enyl-oxazin-2-yl]acetonitrile (compound 5); 2- [(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1' -indane]-4-yl]-1-prop-2-enoyl-piperazin-2-yl]acetonitrile.

The crude compound 5k (0.6 g, 1.23 mmol) was dissolved in 50 mL of dichloromethane, triethylamine (0.85 mL, 6.1 mmol) was added, allyl chloride (111 mg, 1.23 mmol) was added under ice bath, ice Stir under the bath for 30 min. The reaction was quenched by adding 5 mL of ice water, then extracted three times with 50 mL of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target compound 5 was obtained as a white solid (254 mg, two-step yield: 55%). Compound 5 was separated and purified by SFC to obtain isomer 5-1 (95 mg, retention time of SFC preparation was 1.23 min; chiral HPLC retention time was 12.78 min) and isomer 5-2 (100 mg, retention time of SFC preparation was 12.78 min) The time was 1.47 min, and the chiral HPLC retention time was 18.30 min). Chiral HPLC analysis method: The sample was dissolved in n-hexane/isopropanol (90:10), instrument: Shimadzu LC-20AT; chiral column: CHIRALPAK AD-H, 4.6 × 250 mm, 5 μm Mobile phase: n-hexane (containing 0.1% diethylamine)-isopropanol (80:20); flow rate: 1 mL/min column temperature: 35 ℃; detection wavelength: 210 nm; injection volume: 50 μL SFC preparation separation conditions: instrument: « Instrument__Prep»Column: «Column_3» Mobile phase: A is CO ₂ , B is ethanol (containing 0.1% ammonia water), eluted with 30% B. Flow rate: 70«Flow_Rate» mL/min; Column temperature: 38 ℃; Detection wavelength: «Wavelength» After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compounds 5-1 and 5-2. Isomer 5-1 ¹ H NMR (400 MHz, CD ₃ OD) δ 7.30 – 7.03 (m, 4H), 6.93 – 6.71 (m, 1H), 6.27 (d, 1H), 5.82 (d, 1H), 5.26 – 4.99 (m, 2H), 4.43 – 4.30 (m, 2H), 4.21 – 3.96 (m, 3H), 3.76 – 3.58 (m, 1H), 3.57 – 3.42 (m, 2H), 3.42 – 3.36 (m , 1H), 3.18 – 3.03 (m, 2H), 3.02 – 2.90 (m, 3H), 2.90 – 2.77 (m, 3H), 2.77 – 2.48 (m, 5H), 2.33 – 2.18 (m, 1H), 2.13 – 1.86 (m, 4H), 1.85 – 1.75 (m, 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -169.68. Ms m/z (ESI): 545.3 [M+H] ⁺ isomer 5-2 ¹ H NMR (400 MHz, CD ₃ OD) δ 7.26 – 7.19 (m, 1H), 7.19 – 7.09 (m, 2H), 7.09 – 7.02 (m, 1H), 6.94 – 6.72 (m, 1H) , 6.28 (d, 1H), 5.82 (d, 1H), 5.28 – 5.00 (m, 2H), 4.44 – 4.31 (m, 2H), 4.21 – 3.93 (m, 3H), 3.67 – 3.43 (m, 2H) , 3.28 – 3.20 (m, 1H), 3.19 – 3.08 (m, 2H), 3.07 – 2.86 (m, 4H), 2.85 – 2.62 (m, 5H), 2.55 (s, 3H), 2.35 – 2.21 (m, 1H), 2.10 – 1.88 (m, 4H), 1.82 – 1.72 (m, 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -169.73. Ms m/z (ESI): 545.3 [M+H] ⁺ Example 6 2-[(2S)-4-[2-[[((2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]spiro[6,8 -Dihydro-5H-quinazoline-7,1'-indan]-4-yl]-1-(2-fluoroprop-2-enylidene base) oxazin-2-yl]acetonitrile ( compound 6 ); 2-[(2S)-4-[2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy ]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.

將化合物5k粗品(0.6 g，1.23 mmol)和2-氟丙烯酸(166 mg，1.85 mmol)溶於30 mL N,N-二甲基甲醯胺中，加入二異丙基乙胺(793 mg，6.15 mmol)，室溫下加入O-(7-氮雜苯並三唑-1-基)-N,N,N'；-四甲基脲六氟磷酸鹽 (701 mg，1.85 mmol)，反應3 h。待原料反應完全後加入100 mL乙酸乙酯稀釋反應，然後用30 mL水洗有機相三次，有機相用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到目標化合物6，白色固體(334 mg，收率：two steps 70%)。化合物6經SFC製備分離純化後得到異構體6-1(100 mg, SFC製備保留時間為1.07 min；手性HPLC保留時間為11.46 min)和異構體6-2 (150 mg，SFC製備保留時間為1.29 min，手性HPLC保留時間為19.75 min). 手性HPLC分析方法：樣品溶於正己烷/異丙醇(90:10)中，儀器：Shimadzu LC-20AT；手性柱：CHIRALPAK AD-H，4.6 × 250 mm, 5 μm 流動相：正己烷(含0.1% 二乙胺)-異丙醇(80:20)；流速：1 mL/min 柱溫：35 ℃；檢測波長：210 nm；進樣量：50 μL SFC製備分離條件：儀器: «Instrument__Prep»柱子: «Column_3» 流動相: A 為CO₂ ，B 為乙醇(含0.1%氨水)，30%B洗脫。流速: 70«Flow_Rate» mL /min；柱溫: 38 ℃；檢測波長: «Wavelength» 經製備分離後，合併相同保留時間的組分，減壓濃縮得化合物6-1和6-2。異構體6-1¹ H NMR (400 MHz, CD₃ OD) δ7.06 – 7.02 (m, 4H), 5.42 – 5.04 (m, 3H), 5.02 – 4.85 (m, 1H), 4.44 – 4.30 (m, 2H), 4.20 – 3.98 (m, 3H), 3.75 – 3.57 (m, 1H), 3.56 – 3.42 (m, 1H), 3.42 – 3.34 (m, 1H), 3.17 – 2.76 (m, 9H), 2.76 – 2.64 (m, 2H), 2.52 (s, 3H), 2.33 – 2.18 (m, 1H), 2.12 – 1.85 (m, 4H), 1.85 – 1.74 (m, 1H).¹⁹ F NMR (376 MHz, CD₃ OD) δ -105.10, -169.66. Ms m/z (ESI): 563.3 [M+H]⁺ 異構體6-2¹ H NMR (400 MHz, CD₃ OD) δ 7.26 – 7.20 (m, 1H), 7.19 – 7.09 (m, 2H), 7.09 – 7.02 (m, 1H), 5.42 – 5.05 (m, 3H), 4.99 – 4.84 (m, 1H), 4.43 – 4.31 (m, 2H), 4.22 – 3.93 (m, 3H), 3.63 – 3.42 (m, 2H), 3.28 – 3.11 (m, 3H), 3.10 – 3.01 (m, 2H), 3.01 – 2.85 (m, 2H), 2.85 – 2.72 (m, 3H), 2.71 – 2.57 (m, 2H), 2.53 (s, 3H), 2.34 – 2.16 (m, 1H), 2.11 – 1.85 (m, 4H), 1.85 – 1.71 (m, 1H).¹⁹ F NMR (376 MHz, CD₃ OD) δ -105.06, -169.64. Ms m/z (ESI): 563.3 [M+H]⁺ 實施例 7 2-[(2S)-1-(2-氟丙-2-烯醯基)-4- [2-[[((2S)-1-甲基吡咯烷-2-基]甲氧基]螺[6,8-二氫-5H- 喹唑啉-7,1'-茚滿] -4-基]呱嗪-2-基]乙腈(化合物 7 )； 2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.

Crude compound 5k (0.6 g, 1.23 mmol) and 2-fluoroacrylic acid (166 mg, 1.85 mmol) were dissolved in 30 mL of N,N-dimethylformamide, and diisopropylethylamine (793 mg, 6.15 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N';-tetramethylurea hexafluorophosphate (701 mg, 1.85 mmol) was added at room temperature to react 3 hours. After the reaction of the raw materials was completed, 100 mL of ethyl acetate was added to dilute the reaction, and then the organic phase was washed three times with 30 mL of water, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target compound 6 was obtained as a white solid (334 mg, yield: two steps 70%). Compound 6 was separated and purified by SFC to obtain isomer 6-1 (100 mg, retention time of SFC preparation was 1.07 min; chiral HPLC retention time was 11.46 min) and isomer 6-2 (150 mg, retention time of SFC preparation was 11.46 min) The time was 1.29 min, and the retention time of chiral HPLC was 19.75 min). Chiral HPLC analysis method: The sample was dissolved in n-hexane/isopropanol (90:10), instrument: Shimadzu LC-20AT; chiral column: CHIRALPAK AD -H, 4.6 × 250 mm, 5 μm Mobile phase: n-hexane (containing 0.1% diethylamine)-isopropanol (80:20); Flow rate: 1 mL/min Column temperature: 35 ℃; Detection wavelength: 210 nm ; Injection volume: 50 μL SFC preparation Separation conditions: Instrument: «Instrument__Prep» Column: «Column_3» Mobile phase: A is CO ₂ , B is ethanol (containing 0.1% ammonia water), 30% B elution. Flow rate: 70«Flow_Rate» mL/min; Column temperature: 38 ℃; Detection wavelength: «Wavelength» After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compounds 6-1 and 6-2. Isomer 6-1 ¹ H NMR (400 MHz, CD ₃ OD) δ7.06 – 7.02 (m, 4H), 5.42 – 5.04 (m, 3H), 5.02 – 4.85 (m, 1H), 4.44 – 4.30 ( m, 2H), 4.20 – 3.98 (m, 3H), 3.75 – 3.57 (m, 1H), 3.56 – 3.42 (m, 1H), 3.42 – 3.34 (m, 1H), 3.17 – 2.76 (m, 9H), 2.76 – 2.64 (m, 2H), 2.52 (s, 3H), 2.33 – 2.18 (m, 1H), 2.12 – 1.85 (m, 4H), 1.85 – 1.74 (m, 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -105.10, -169.66. Ms m/z (ESI): 563.3 [M+H] ⁺ isomer 6-2 ¹ H NMR (400 MHz, CD ₃ OD) δ 7.26 – 7.20 (m, 1H), 7.19 – 7.09 (m, 2H), 7.09 – 7.02 (m, 1H), 5.42 – 5.05 (m, 3H), 4.99 – 4.84 (m, 1H), 4.43 – 4.31 (m, 2H), 4.22 – 3.93 (m, 3H), 3.63 – 3.42 (m, 2H), 3.28 – 3.11 (m, 3H), 3.10 – 3.01 (m, 2H), 3.01 – 2.85 (m, 2H), 2.85 – 2.72 (m, 3H) ), 2.71 – 2.57 (m, 2H), 2.53 (s, 3H), 2.34 – 2.16 (m, 1H), 2.11 – 1.85 (m, 4H), 1.85 – 1.71 (m, 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -105.06, -169.64. Ms m/z (ESI): 563.3 [M+H] ⁺ Example 7 2-[(2S)-1-(2-fluoroprop-2-ene amide yl)-4-[2-[[((2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'- Indan]-4-yl]oxazin-2-yl]acetonitrile ( compound 7 ); 2-[(2S)-1-(2-fluoroprop-2-enoyl)-4- [2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile .

第一步：(S)-2-(氰甲基)-4-(2'-((((S)-1-甲基吡咯烷-2-基)甲氧基)-2,3,5'，8'- 四氫-6'H-螺[茚-1,7'-喹唑啉] -4'-基)呱嗪-1-甲酸叔丁酯(7a)； tert-butyl(S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

將化合物5i(1.6 g，3.0 mmol)和(1-甲基吡咯烷-2-基)甲醇(686 mg，6.0 mmol)溶於60 mL甲苯中，冰浴下加入叔丁醇鈉(432 mg，4.5 mmol)，冰浴下攪拌1 h。加入20 mL水淬滅反應，加入1000 mL乙酸乙酯萃取三次，合併有機相，用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到目標產物7a，白色固體(1.54 g，收率：90%)。 MS m/z (ESI): 573.6 [M+H]⁺ The first step: (S)-2-(cyanomethyl)-4-(2'-((((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5 ',8'-Tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)oxazine-1-carboxylate tert-butyl ester (7a); tert-butyl(S) -2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene- 1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate.

Compound 5i (1.6 g, 3.0 mmol) and (1-methylpyrrolidin-2-yl)methanol (686 mg, 6.0 mmol) were dissolved in 60 mL of toluene, and sodium tert-butoxide (432 mg, 6.0 mmol) was added under ice bath. 4.5 mmol), and stirred under ice bath for 1 h. 20 mL of water was added to quench the reaction, 1000 mL of ethyl acetate was added for extraction three times, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target product 7a was obtained as a white solid (1.54 g, yield: 90%). MS m/z (ESI): 573.6 [M+H] ⁺

第二步：2-((S)-4-(2'-(((S)-1-甲基吡咯烷-2-基)甲氧基)-2,3,5'，8'-四氫-6'H- 螺[茚-1,7'-喹唑啉] -4'-基)呱嗪-2-基)乙腈(7b)； 2-[(2S)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.

將化合物7a(1.54 g，2.7 mmol)溶於25 mL二氯甲烷中，加入5 mL三氟乙酸，於室溫下攪拌2 h。待反應完成後，減壓旋乾溶劑，再加入100 mL二氯甲烷稀釋，滴加飽和碳酸氫鈉調節PH到鹼性，然後用100 mL二氯甲烷萃取三次，合併有機相，用無水硫酸鈉乾燥，減壓濃縮，得到目標化合物7b粗品，黃色固體1.5 g，直接用於下一步。 MS m/z (ESI): 473.6 [M+H]⁺ Step 2: 2-((S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetra Hydro-6'H-spiro[inden-1,7'-quinazolin]-4'-yl)oxazin-2-yl)acetonitrile (7b); 2-[(2S)-4-[2-[ [(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.

Compound 7a (1.54 g, 2.7 mmol) was dissolved in 25 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. After the reaction is completed, spin dry the solvent under reduced pressure, add 100 mL of dichloromethane to dilute, add dropwise saturated sodium bicarbonate to adjust the pH to basic, then extract three times with 100 mL of dichloromethane, combine the organic phases, and use anhydrous sodium sulfate. Dry and concentrate under reduced pressure to obtain the target compound 7b as a crude product as a yellow solid, 1.5 g, which is directly used in the next step. MS m/z (ESI): 473.6 [M+H] ⁺

第三步：2-[(2S)-1-(2-氟丙-2-烯醯基)-4- [2-[[((2S)-1-甲基吡咯烷-2-基]甲氧基]螺[6,8-二氫-5H- 喹唑啉-7,1'-茚滿] -4-基]呱嗪-2-基]乙腈(化合物 7 )； 2-[(2S)-1-(2-fluoroprop-2-enoyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.

將化合物7b粗品(0.46 g，0.97 mmol)和2-氟丙烯酸(132 mg，1.46 mmol)溶於30 mL N,N-二甲基甲醯胺中，加入二異丙基乙胺(626 mg，4.85 mmol)，室溫下加入O-(7-氮雜苯並三唑-1-基)-N,N,N'；-四甲基脲六氟磷酸鹽 (555 mg，1.46 mmol)，反應3 h。待原料反應完全後加入100 mL乙酸乙酯稀釋反應，然後用30 mL水洗有機相三次，有機相用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到目標化合物7，白色固體(330 mg，兩步收率：72%)。化合物7經SFC製備分離純化後得到異構體7-1(95 mg, SFC製備保留時間為1.07 min；手性HPLC保留時間為7.69 min)和異構體7-2 (60 mg，SFC製備保留時間為1.26 min，手性HPLC保留時間為13.65 min). 手性HPLC分析方法：樣品溶於正己烷/異丙醇(90:10)中，儀器：Shimadzu LC-20AT；手性柱：CHIRALPAK AD-H，4.6 × 250 mm, 5 μm 流動相：正己烷(含0.1% 二乙胺)-異丙醇(80:20)；流速：1 mL/min 柱溫：35 ℃；檢測波長：210 nm；進樣量：50 μL SFC製備分離條件：儀器: «Instrument__Prep»柱子: «Column_3»；流動相: A 為CO₂ ，B 為乙醇(含0.1%氨水)，30%B洗脫。流速: 70«Flow_Rate» mL /min；柱溫: 38 ℃；檢測波長: «Wavelength» 經製備分離後，合併相同保留時間的組分，減壓濃縮得化合物7-1和7-2。異構體7-1¹ H NMR (400 MHz, CD₃ OD) δ 7.26 – 7.06 (m, 4H), 5.41 – 5.22 (m, 2H), 5.02 – 4.84 (m, 1H), 4.43 – 4.25 (m, 2H), 4.21 – 3.99 (m, 3H), 3.75 – 3.52 (m, 1H), 3.44 – 3.33 (m, 1H), 3.17 – 3.00 (m, 3H), 2.99 – 2.90 (m, 3H), 2.89 – 2.65 (m, 5H), 2.51 (s, 3H), 2.37 (dd, 1H), 2.16 – 1.96 (m, 4H), 1.88 – 1.76 (m, 3H), 1.76 – 1.64(m, 1H).¹⁹ F NMR (376 MHz, CD₃ OD) δ -105.11. Ms m/z (ESI): 545.3 [M+H]⁺ 異構體7-2¹ H NMR (400 MHz, CD₃ OD) δ 7.26 – 7.19 (m, 1H), 7.19 – 7.08 (m, 2H), 7.09 – 7.01 (m, 1H), 5.42 – 5.19 (m, 2H), 5.01 – 4.84 (m, 1H), 4.42 – 4.25 (m, 2H), 4.23 – 3.91 (m, 3H), 3.67 – 3.38 (m, 1H), 3.27 – 3.01 (m, 5H), 3.01 – 2.85 (m, 2H), 2.85 – 2.60 (m, 5H), 2.50 (s, 3H), 2.36 (dd, 1H), 2.15 – 1.94 (m, 4H), 1.89 – 1.64 (m, 4H).¹⁹ F NMR (376 MHz, CD₃ OD) δ -105.06. Ms m/z (ESI): 545.3 [M+H]⁺ 實施例 8 2-[((2S)-1-[(E)-4-(二甲基氨基)丁-2-烯醯基] -4- [2-[[((2S)-1-甲基吡咯烷-2-基]甲氧基]螺] [6 ，8-二氫-5H-喹唑啉-7,1'-茚滿] -4-基]呱嗪-2-基]乙腈(化合物 8 )； 2-[(2S)-1-[(E)-4-(dimethylamino)but-2-enoyl]-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.

The third step: 2-[(2S)-1-(2-fluoroprop-2-enyl)-4-[2-[[((2S)-1-methylpyrrolidin-2-yl]methane Oxy]spiro[6,8-dihydro-5H-quinazolin-7,1'-indan]-4-yl]oxazin-2-yl]acetonitrile ( compound 7 ); 2-[(2S) -1-(2-fluoroprop-2-enoyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1' -indane]-4-yl]piperazin-2-yl]acetonitrile.

Crude compound 7b (0.46 g, 0.97 mmol) and 2-fluoroacrylic acid (132 mg, 1.46 mmol) were dissolved in 30 mL of N,N-dimethylformamide, and diisopropylethylamine (626 mg, 4.85 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N';-tetramethylurea hexafluorophosphate (555 mg, 1.46 mmol) was added at room temperature, and the reaction 3 hours. After the reaction of the raw materials was completed, 100 mL of ethyl acetate was added to dilute the reaction, and then the organic phase was washed three times with 30 mL of water, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target compound 7 was obtained as a white solid (330 mg, two-step yield: 72%). Compound 7 was separated and purified by SFC to obtain isomer 7-1 (95 mg, retention time of SFC preparation was 1.07 min; chiral HPLC retention time was 7.69 min) and isomer 7-2 (60 mg, retention time of SFC preparation was 7.69 min) The time was 1.26 min, and the retention time of chiral HPLC was 13.65 min). Chiral HPLC analysis method: The sample was dissolved in n-hexane/isopropanol (90:10), instrument: Shimadzu LC-20AT; chiral column: CHIRALPAK AD -H, 4.6 × 250 mm, 5 μm Mobile phase: n-hexane (containing 0.1% diethylamine)-isopropanol (80:20); Flow rate: 1 mL/min Column temperature: 35 ℃; Detection wavelength: 210 nm ; Injection volume: 50 μL SFC preparation Separation conditions: Instrument: «Instrument__Prep» Column: «Column_3»; Mobile phase: A is CO ₂ , B is ethanol (containing 0.1% ammonia water), 30% B elution. Flow rate: 70«Flow_Rate» mL/min; Column temperature: 38 ℃; Detection wavelength: «Wavelength» After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compounds 7-1 and 7-2. Isomer 7-1 ¹ H NMR (400 MHz, CD ₃ OD) δ 7.26 – 7.06 (m, 4H), 5.41 – 5.22 (m, 2H), 5.02 – 4.84 (m, 1H), 4.43 – 4.25 (m , 2H), 4.21 – 3.99 (m, 3H), 3.75 – 3.52 (m, 1H), 3.44 – 3.33 (m, 1H), 3.17 – 3.00 (m, 3H), 2.99 – 2.90 (m, 3H), 2.89 – 2.65 (m, 5H), 2.51 (s, 3H), 2.37 (dd, 1H), 2.16 – 1.96 (m, 4H), 1.88 – 1.76 (m, 3H), 1.76 – 1.64(m, 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -105.11. Ms m/z (ESI): 545.3 [M+H] ⁺ isomer 7-2 ¹ H NMR (400 MHz, CD ₃ OD) δ 7.26 – 7.19 (m, 1H), 7.19 – 7.08 (m, 2H), 7.09 – 7.01 (m, 1H), 5.42 – 5.19 (m, 2H), 5.01 – 4.84 (m, 1H), 4.42 – 4.25 (m, 2H) , 4.23 – 3.91 (m, 3H), 3.67 – 3.38 (m, 1H), 3.27 – 3.01 (m, 5H), 3.01 – 2.85 (m, 2H), 2.85 – 2.60 (m, 5H), 2.50 (s, 3H), 2.36 (dd, 1H), 2.15 – 1.94 (m, 4H), 1.89 – 1.64 (m, 4H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -105.06. Ms m/z (ESI) : 545.3 [M+H] ⁺ Example 8 2-[((2S)-1-[(E)-4-(dimethylamino)but-2-enyl]-4-[2-[[ ((2S)-1-Methylpyrrolidin-2-yl]methoxy]spiro][6,8-dihydro-5H-quinazolin-7,1'-indan]-4-yl]quay oxazin-2-yl]acetonitrile ( compound 8 ); 2-[(2S)-1-[(E)-4-(dimethylamino)but-2-enoyl]-4-[2-[[(2S)-1 -methylpyrroli din-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1'-indane]-4-yl]piperazin-2-yl]acetonitrile.

將化合物7b粗品(0.4 g，0.85 mmol)和反式-4-二甲基胺基巴豆酸鹽酸鹽(211 mg，1.28 mmol)溶於30 mL N,N-二甲基甲醯胺中，加入二異丙基乙胺(548 mg，4.25 mmol)，室溫下加入O-(7-氮雜苯並三唑-1-基)-N,N,N'；-四甲基脲六氟磷酸鹽 (486 mg，1.28 mmol)，反應3 h。待原料反應完全後加入100 mL乙酸乙酯稀釋反應，然後用30 mL水洗有機相三次，有機相用無水硫酸鈉乾燥，減壓濃縮。柱層析後得到目標化合物8，白色固體(100 mg，收率：23%)。化合物8經SFC製備分離純化後得到異構體8-1(36 mg, SFC製備保留時間為5.57 min；手性HPLC保留時間為11.6 min)和異構體8-2(25 mg，SFC製備保留時間為6.08 min，手性HPLC保留時間為14.9 min)。手性HPLC分析方法：樣品溶於正己烷/異丙醇(90:10)中，儀器：Shimadzu LC-20AT；手性柱：CHIRALPAK AD-H，4.6 × 250 mm, 5 μm 流動相：正己烷(含0.1% 二乙胺)-乙醇(80:20)；流速：1 mL/min 柱溫：35 ℃；檢測波長：210 nm；進樣量：50 μL SFC製備分離條件：儀器: «Instrument__Prep»；柱子: «Column_3» 流動相: A 為CO₂ ，B 為乙醇(含0.1%氨水)，30%B洗脫。流速: 70«Flow_Rate» mL /min；柱溫: 38 ℃；檢測波長: «Wavelength»Crude compound 7b (0.4 g, 0.85 mmol) and trans-4-dimethylaminocrotonate hydrochloride (211 mg, 1.28 mmol) were dissolved in 30 mL of N,N-dimethylformamide, Diisopropylethylamine (548 mg, 4.25 mmol) was added, and O-(7-azabenzotriazol-1-yl)-N,N,N';-tetramethylureahexafluoro was added at room temperature Phosphate (486 mg, 1.28 mmol), reacted for 3 h. After the reaction of the raw materials was completed, 100 mL of ethyl acetate was added to dilute the reaction, and then the organic phase was washed three times with 30 mL of water, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, the target compound 8 was obtained as a white solid (100 mg, yield: 23%). Compound 8 was isolated and purified by SFC to obtain isomer 8-1 (36 mg, retention time of SFC preparation: 5.57 min; retention time of chiral HPLC: 11.6 min) and isomer 8-2 (25 mg, retention time of SFC preparation) The time was 6.08 min, and the chiral HPLC retention time was 14.9 min). Chiral HPLC analysis method: The sample was dissolved in n-hexane/isopropanol (90:10), instrument: Shimadzu LC-20AT; chiral column: CHIRALPAK AD-H, 4.6 × 250 mm, 5 μm Mobile phase: n-hexane (containing 0.1% diethylamine)-ethanol (80:20); flow rate: 1 mL/min column temperature: 35 ℃; detection wavelength: 210 nm; injection volume: 50 μL SFC preparation separation conditions: instrument: «Instrument__Prep» ; Column: «Column_3» Mobile phase: A is CO ₂ , B is ethanol (containing 0.1% ammonia water), 30% B elution. Flow rate: 70«Flow_Rate» mL/min; Column temperature: 38 ℃; Detection wavelength: «Wavelength»

經製備分離後，合併相同保留時間的組分，減壓濃縮得化合物8-1和8-2。異構體8-1¹ H NMR (400 MHz, CD₃ OD) δ 7.26 – 7.19 (m, 1H), 7.19 – 7.05 (m, 3H), 6.91 – 6.59 (m, 2H), 5.12 – 4.97 (m, 1H), 4.60 – 4.46 (m, 1H), 4.43 – 4.28 (m, 2H), 4.19 – 3.99 (m, 3H), 3.76 – 3.60 (m, 1H), 3.44 – 3.35 (m, 1H), 3.23 – 3.16 (m, 2H), 3.16 – 3.06 (m, 2H), 3.00 – 2.76 (m, 7H), 2.76 – 2.67 (m, 1H), 2.53 (s, 3H), 2.48 – 2.34 (m, 1H), 2.30 (s, 6H), 2.16 – 1.97 (m, 4H), 1.90 – 1.65 (m, 4H). Ms m/z (ESI): 584.3 [M+H]⁺ 異構體8-2¹ H NMR (400 MHz, CD₃ OD) δ 7.27 – 7.19 (m, 1H), 7.19 – 7.08 (m, 2H), 7.08 – 7.01 (m, 1H), 6.89 – 6.79 (m, 1H), 6.79 – 6.58 (m, 1H), 5.16 – 4.98 (m, 1H), 4.61 – 4.45 (m, 1H), 4.42 – 4.26 (m, 2H), 4.19 – 3.92 (m, 3H), 3.66 – 3.50 (m, 1H), 3.26 – 3.06 (m, 5H), 3.06 – 2.86 (m, 4H), 2.85 – 2.74 (m, 3H), 2.71 – 2.61 (m, 1H), 2.51 (s, 3H), 2.42 – 2.33 (m, 1H), 2.29 (s, 6H), 2.15 – 1.95 (m, 4H), 1.87 – 1.65 (m, 4H). Ms m/z (ESI): 584.3 [M+H]⁺ 實施例 9 ： 2-（（2S）-1-丙烯醯-4-（2'-（（（S）-1-甲基吡咯烷-2-基）甲氧基）-5',8'-二氫-6'H-螺環[茚-1,7'-喹唑啉]-4'-基）呱嗪-2-基）乙腈的光學純異構體(化合物 9-1 和化合物 9-2 ) 2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile； isomer 9-1 and isomer 9-2

After separation by preparation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compounds 8-1 and 8-2. Isomer 8-1 ¹ H NMR (400 MHz, CD ₃ OD) δ 7.26 – 7.19 (m, 1H), 7.19 – 7.05 (m, 3H), 6.91 – 6.59 (m, 2H), 5.12 – 4.97 (m , 1H), 4.60 – 4.46 (m, 1H), 4.43 – 4.28 (m, 2H), 4.19 – 3.99 (m, 3H), 3.76 – 3.60 (m, 1H), 3.44 – 3.35 (m, 1H), 3.23 – 3.16 (m, 2H), 3.16 – 3.06 (m, 2H), 3.00 – 2.76 (m, 7H), 2.76 – 2.67 (m, 1H), 2.53 (s, 3H), 2.48 – 2.34 (m, 1H) , 2.30 (s, 6H), 2.16 – 1.97 (m, 4H), 1.90 – 1.65 (m, 4H). Ms m/z (ESI): 584.3 [M+H] ⁺ isomer 8-2 ¹ H NMR (400 MHz, CD ₃ OD) δ 7.27 – 7.19 (m, 1H), 7.19 – 7.08 (m, 2H), 7.08 – 7.01 (m, 1H), 6.89 – 6.79 (m, 1H), 6.79 – 6.58 (m , 1H), 5.16 – 4.98 (m, 1H), 4.61 – 4.45 (m, 1H), 4.42 – 4.26 (m, 2H), 4.19 – 3.92 (m, 3H), 3.66 – 3.50 (m, 1H), 3.26 – 3.06 (m, 5H), 3.06 – 2.86 (m, 4H), 2.85 – 2.74 (m, 3H), 2.71 – 2.61 (m, 1H), 2.51 (s, 3H), 2.42 – 2.33 (m, 1H) , 2.29 (s, 6H), 2.15 – 1.95 (m, 4H), 1.87 – 1.65 (m, 4H). Ms m/z (ESI): 584.3 [M+H] ⁺ Example 9 : 2-((2S )-1-propenyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6'H-spiro Optically pure isomers of [indene-1,7'-quinazolin]-4'-yl)oxazin-2-yl)acetonitrile ( compound 9-1 and compound 9-2 ) 2-((2S) -1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin ]-4'-yl)piperazin-2-yl)acetonitrile; isomer 9-1 and isomer 9-2

第一步：螺環[環己烷-1,1'-茚]-3-酮 (9F ) spiro[cyclohexane-1,1'-inden]-3-one

將中間體 1 E (3.0 g, 12.4 mmol )溶解到THF (10.0 mL)中，再向體系中加入6 N 的鹽酸 (20.0 mL)，反應置於室溫攪拌1 h。反應結束後，將反應液直接旋乾，再用乙酸乙酯萃取，飽和NaHCO₃ 水溶液洗滌，有機相乾燥過濾後直接旋乾經矽膠色譜柱分離得到產物9F ，無油狀物 (2.5 g，產率98%)。The first step: spiro[cyclohexane-1,1'-inden]-3-one (9 F ) spiro[cyclohexane-1,1'-inden]-3-one

Intermediate 1 E (3.0 g, 12.4 mmol) was dissolved in THF (10.0 mL), 6 N hydrochloric acid (20.0 mL) was added to the system, and the reaction was stirred at room temperature for 1 h. After the reaction, the reaction solution was directly spin-dried, then extracted with ethyl acetate, washed with saturated aqueous NaHCO ₃ , the organic phase was dried and filtered, directly spin-dried, and separated by a silica gel chromatographic column to obtain the product 9F , without oil (2.5 g, 98% yield).

第二步：3-羥基螺環[環己烷-1,1'-茚]-3-烯-4-羧酸乙酯 (9G ) ethyl 3-hydroxyspiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate

將螺環[環己烷-1,1'-茚]-3-酮 (9F ) (2.3 g, 11.6 mmol )溶解到THF (80.0 mL)中，-70 °C下攪拌降溫，再向體系中緩慢滴加LiHMDS (14 mL, 14.0 mmol)，反應置於此溫度下繼續攪拌1 h後, 向反應中緩慢滴加氰基甲酸乙酯(1.38 g, 14.0 mmol)，滴加完畢後，反應緩慢升溫至室溫後再攪拌30m in。反應結束後，將反應液降溫到0 °C，用飽和氯化銨水溶液淬滅反應，再用乙酸乙酯萃取，有機相乾燥過濾後直接旋乾，經矽膠色譜柱分離得到產物9G ，無油狀物 (2.3 g，產率73%)。Step 2: Ethyl 3-hydroxyspiro[cyclohexane-1,1'-indene]-3-ene-4-carboxylate (9 G ) ethyl 3-hydroxyspiro[cyclohexane-1,1'-inden] -3-ene-4-carboxylate

Spiro[cyclohexane-1,1'-indene]-3-one ( 9F ) (2.3 g, 11.6 mmol) was dissolved in THF (80.0 mL), stirred at -70 °C to cool down, and then added to the system LiHMDS (14 mL, 14.0 mmol) was slowly added dropwise to the reaction, and the reaction was kept stirring for 1 h at this temperature, and ethyl cyanoformate (1.38 g, 14.0 mmol) was slowly added dropwise to the reaction. The temperature was slowly raised to room temperature and then stirred for 30 min. After the reaction was completed, the reaction solution was cooled to 0 °C, the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was dried and filtered, and it was directly spin-dried, and the product 9G was obtained through silica gel chromatographic column separation . Oil (2.3 g, 73% yield).

第三步：3-氨基螺[1,1'-茚]-3-烯-4-羧酸乙酯 (9H ) ethyl 3-aminospiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate

將3-羥基螺環[環己烷-1,1'-茚]-3-烯-4-羧酸乙酯 (9G ) (2.3 g, 8.4 mmol )和乙酸銨(2.2 g, 29 mmol)溶解到乙醇(80.0 mL)中，置於90 °C攪拌回流2小時。反應結束後，將反應液直接旋乾，經矽膠色譜柱分離得到產物9H ，無油狀物 (2.15 g，產率95%)。Step 3: Ethyl 3-aminospiro[1,1'-inden]-3-ene-4-carboxylate (9 H ) ethyl 3-aminospiro[cyclohexane-1,1'-inden]-3-ene- 4-carboxylate

Combine 3-hydroxyspiro[cyclohexane-1,1'-indene]-3-ene-4-carboxylic acid ethyl ester (9G) (2.3 g , 8.4 mmol) and ammonium acetate (2.2 g, 29 mmol) Dissolved in ethanol (80.0 mL), placed at 90 °C with stirring and refluxing for 2 hours. After the reaction, the reaction solution was directly rotated to dryness, and the product 9H was obtained by silica gel chromatography column separation without oil (2.15 g, yield 95%).

第四步：3-（3-苯甲醯硫脲基）螺環[環己烷-1,1'-茚]-3-烯-4-羧酸乙酯 (9I ) ethyl 3-(3-benzoylthioureido)spiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate

將3-氨基螺[1,1'-茚]-3-烯-4-羧酸乙酯 (9H ) (2.1 g, 8.0 mmol ), 苯甲醯基異硫氰酸酯(1.9 g, 12.0 mmol)加入到丙酮(50.0 mL)中攪拌均勻，再置於60 °C攪拌回流1 h. 反應結束後，將反應液冷卻至室溫，反應液直接減壓旋蒸，經矽膠柱純化得到產物9I ，白色固體(2.8 g, 產率81%)。The fourth step: 3-(3-benzylthioureido) spiro[cyclohexane-1,1'-indene]-3-ene-4-carboxylic acid ethyl ester (9 I ) ethyl 3-(3 -benzoylthioureido)spiro[cyclohexane-1,1'-inden]-3-ene-4-carboxylate

3-Aminospiro[1,1'-indene]-3-ene-4-carboxylic acid ethyl ester (9H) (2.1 g, 8.0 mmol), benzyl isothiocyanate (1.9 g, 12.0 mmol) was added to acetone (50.0 mL) and stirred evenly, and then placed at 60 °C and stirred for 1 h under reflux. After the reaction, the reaction solution was cooled to room temperature, the reaction solution was directly evaporated under reduced pressure, and purified by silica gel column to obtain the product 9I , white solid (2.8 g, 81% yield).

第五步：2'-巰基-5'，8'-二氫-6'H-螺環[茚-1,7'-喹唑啉]-4'-醇 (9J ) 2'-mercapto-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol

將3-（3-苯甲醯硫脲基）螺環[環己烷-1,1'-茚]-3-烯-4-羧酸乙酯 (9I ) (2.8 g, 6.5 mmol )和KOH (1.1 g, 19.5 mmol)溶解到乙醇(50.0 mL)中，置於90 °C攪拌回流30 min。反應結束後，將反應液冷卻至室溫，再用2N鹽酸中和至大量白色固體析出，將固體過濾，得到濾餅減壓乾燥得到產物9J 。白色固體 (1.3 g，產率74%)。The fifth step: 2'-mercapto-5', 8'-dihydro-6'H-spiro[indene-1,7'-quinazoline]-4'-ol (9 J ) 2'-mercapto- 5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol

3-(3-Benzylthioureido)spiro[cyclohexane-1,1'-indene]-3-ene-4-carboxylic acid ethyl ester ( 9I ) (2.8 g, 6.5 mmol) and KOH (1.1 g, 19.5 mmol) was dissolved in ethanol (50.0 mL) and placed at 90 °C with stirring and refluxing for 30 min. After the reaction, the reaction solution was cooled to room temperature, and then neutralized with 2N hydrochloric acid until a large amount of white solid was precipitated, and the solid was filtered to obtain the filter cake and dried under reduced pressure to obtain the product 9 J . White solid (1.3 g, 74% yield).

第六步：2'-（甲硫基）-5',8'-二氫-6'H-螺環[茚-1,7'-喹唑啉]-4'-醇 (9K ) 2'-(methylthio)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol

將2'-巰基-5',8'-二氫-6'H-螺環[茚-1,7'-喹唑啉]-4'-醇 (9J ) (1.3 g, 4.6 mmol )和KOH (1.0 g, 18 mmol)溶解到THF(10 mL)-H₂ O(40.0 mL)的混合溶劑中，置於室溫攪拌均勻後，再置於冰浴中，向反應液中滴加MeI (930 mg, 6.4mmol)，滴加完畢後，繼續在該溫度下攪拌1h。反應結束後，向反應液加2N鹽酸中和至pH=7，再贏乙酸乙酯萃取，有機相用無水硫酸鈉乾燥後過濾，旋乾，再用矽膠柱純化得到產物9K ，白色固體 (1.3 g，產率95%)。The sixth step: 2'-(methylthio)-5',8'-dihydro-6'H-spiro[indene- 1,7' -quinazoline]-4'-ol (9K) 2 '-(methylthio)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol

2'-Mercapto-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol (9 J ) (1.3 g, 4.6 mmol) and KOH (1.0 g, 18 mmol) was dissolved in a mixed solvent of THF (10 mL)-H ₂ O (40.0 mL), stirred at room temperature, then placed in an ice bath, and MeI was added dropwise to the reaction solution (930 mg, 6.4 mmol), after the dropwise addition was completed, stirring was continued at this temperature for 1 h. After the reaction, 2N hydrochloric acid was added to the reaction solution to neutralize to pH=7, then extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered, spin-dried, and purified with silica gel column to obtain product 9K , a white solid ( 1.3 g, 95% yield).

第七步：2'-（甲硫基）-5',8'-二氫-6'H-螺環[茚-1,7'-喹唑啉]-4'-三氟甲基磺酸酯 (9L ) 2'-(methylthio)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate

將2'-（甲硫基）-5'，8'-二氫-6'H-螺環[茚-1,7'-喹唑啉]-4'-醇 (9K ) (1.3 g, 4.5 mmol )和DIPEA (1.5 g, 11.6 mmol)溶解到DCM (50.0 mL)中，置於- 20 °C攪拌10 min, 再向反應中緩慢滴加Tf₂ O(1.9 g, 6.7 mmol),反應繼續在該溫度下攪拌10 min。反應結束後，用碳酸氫鈉水溶液淬滅反應，再用DCM萃取，有機相用無水硫酸鈉乾燥後過濾，旋乾，再用矽膠柱純化得到產物9L ，無色油狀物 (1.7 g，產率88%)。Step 7: 2'-(methylthio)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazoline]-4'-trifluoromethanesulfonic acid Ester (9 L ) 2'-(methylthio)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate

2'-(Methylthio)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-ol (9 K ) (1.3 g, 4.5 mmol) and DIPEA (1.5 g, 11.6 mmol) were dissolved in DCM (50.0 mL), placed at -20 °C and stirred for 10 min, then Tf ₂ O (1.9 g, 6.7 mmol) was slowly added dropwise to the reaction, and the reaction was carried out. Continue stirring at this temperature for 10 min. After the reaction was completed, the reaction was quenched with aqueous sodium bicarbonate solution, extracted with DCM, the organic phase was dried with anhydrous sodium sulfate, filtered, spin-dried, and purified with silica gel column to obtain 9 L of the product, a colorless oil (1.7 g, the product rate 88%).

第八步：叔丁基（2S）-2-（氰基甲基）-4-（2'-（甲硫醇）-5',8'-二氫-6'H-螺環[茚-1,7'-喹唑啉]-4'-基）呱嗪-1-羧酸酯的光學純異構體 (9M-1 和 9M-2 ) tert-butyl (2S)-2-(cyanomethyl)-4-(2'-(methylthio)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate； isomer 9M-1 and isomer 9M-2

將2'-（甲硫基）-5'，8'-二氫-6'H-螺環[茚-1,7'-喹唑啉]-4'-三氟甲基磺酸酯 (9L ) (1.7 g, 4.0 mmol )和DIPEA (1.3 g, 10.0 mmol)，以及叔丁基（S）-2-（氰基甲基）呱嗪-1-羧酸酯(1.1 g, 4.8 mmol)溶解到DMA(20.0 mL)中，置於室溫攪拌1h。反應結束後，將反應液直接旋乾，經矽膠柱純化得到叔丁基（2S）-2-（氰基甲基）-4-（2'-（甲硫醇）-5'，8'-二氫-6'H-螺環[茚-1,7'-喹唑啉]-4'-基）呱嗪-1-羧酸酯（9M 消旋體） 白色固體 (1.7 g，產率88%)。 9M 消旋體 經手性拆分(Preparative separation method : Instrument: «Instrument__Prep», Column: «Column_3», Mobile phase: A for CO₂ and B for «Mobile_phase_Analysis», Gradient: B 40%, Flow rate: 50«Flow_Rate» mL /min, Back pressure: 100 bar, Column temperature: 38℃, Wavelength: «Wavelength», Cycle time: ~4.2 min)後得到光學純的異構體9M-1 (860 mg)和異構體9M-2 (820 mg)。The eighth step: tert-butyl (2S)-2-(cyanomethyl)-4-(2'-(methylthiol)-5',8'-dihydro-6'H-spiro[indene- Optically pure isomers of 1,7'-quinazolin]-4'-yl)oxazine-1-carboxylate (9M- 1 and 9M-2 ) tert-butyl (2S)-2-(cyanomethyl) )-4-(2'-(methylthio)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate; isomer 9M- 1 and isomer 9M-2

2'-(Methylthio)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazoline]-4'-trifluoromethanesulfonate (9 L ) (1.7 g, 4.0 mmol) and DIPEA (1.3 g, 10.0 mmol), and tert-butyl(S)-2-(cyanomethyl)oxazine-1-carboxylate (1.1 g, 4.8 mmol) It was dissolved in DMA (20.0 mL) and stirred at room temperature for 1 h. After the reaction, the reaction solution was directly rotated to dryness, and purified by silica gel column to obtain tert-butyl (2S)-2-(cyanomethyl)-4-(2'-(methylthiol)-5',8'- Dihydro-6'H-spiro[inden-1,7'-quinazolin]-4'-yl)oxazine-1-carboxylate (9 M racemate) as white solid (1.7 g, yield 88%). 9 M racemate is separated by chirality ( Preparative separation method : Instrument: «Instrument__Prep», Column: «Column_3», Mobile phase: A for CO ₂ and B for «Mobile_phase_Analysis», Gradient: B 40%, Flow rate: 50 «Flow_Rate» mL/min, Back pressure: 100 bar, Column temperature: 38°C, Wavelength: «Wavelength», Cycle time: ~4.2 min), optically pure isomers 9 M-1 (860 mg) and isoforms were obtained. Conform 9 M-2 (820 mg).

第九步：叔丁基（2S）-2-（氰基甲基）-4-（2'-（甲基亞磺醯基）-5',8'-二氫-6'H-螺環[茚-1,7'-喹唑啉]-4'-基）呱嗪-1-羧酸酯的其中一個光學純異構體 (9N-1 ) tert-butyl (2S)-2-(cyanomethyl)-4-(2'-(methylsulfinyl)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate； isomer 9N-1

將9M-1 (150 mg, 0.3 mmol )溶解到DCM (6.0 mL)中，置於0 °C攪拌10 min, 再向體系中加入間氯過氧苯甲酸(62 mg, 0.36 mmol),反應置於室溫攪拌1h。反應結束後，向反應液中添加硫代硫酸鈉水溶液淬滅反應，再用DCM 萃取，有機相用無水硫酸鈉乾燥後旋乾，經矽膠柱純化得到產物9N-1 。白色固體 (140 mg，產率90%)。The ninth step: tert-butyl (2S)-2-(cyanomethyl)-4-(2'-(methylsulfinyl)-5',8'-dihydro-6'H-spiro One of the optically pure isomers of [indene-1,7'-quinazolin]-4'-yl)oxazine-1-carboxylate (9 N-1 )tert-butyl (2S)-2-( cyanomethyl)-4-(2'-(methylsulfinyl)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate; isomer 9N -1

9 M-1 (150 mg, 0.3 mmol) was dissolved in DCM (6.0 mL), placed at 0 °C and stirred for 10 min, then m-chloroperoxybenzoic acid (62 mg, 0.36 mmol) was added to the system, and the reaction Stir at room temperature for 1 h. After the reaction, an aqueous solution of sodium thiosulfate was added to the reaction solution to quench the reaction, and then extracted with DCM. The organic phase was dried with anhydrous sodium sulfate, spin-dried, and purified by silica gel column to obtain product 9 N-1 . White solid (140 mg, 90% yield).

第十步：叔丁基（2S）-2-（氰甲基）-4-（2'-（（（S）-1-甲基吡咯烷-2-基）甲氧基）-5',8'-二氫-6'H-螺環[茚-1,7'-喹唑啉]-4'-基）呱嗪-1-羧酸酯的其中一個光學純異構體 (9O-1 ) tert-butyl (2S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate； isomer 9O-1

將底物9N-1 (140 mg, 0.27 mmol )和N-甲基-L-脯氨醇 (46 mg, 0.4 mmol)溶解到甲苯(6.0 mL)中，置於0 °C攪拌10 min後，再向體系中添加叔丁醇鈉(39 mg, 0.4 mmol), 繼續在該溫度下攪拌30 min。反應結束後，向反應液中加入氯化銨水溶液淬滅，DCM萃取，有機相用無水硫酸鈉乾燥後過濾，旋乾，經矽膠柱純化得到產物9O-1 。白色固體 (140 mg，產率91%)。The tenth step: tert-butyl (2S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5', One of the optically pure isomers (9 O- 1 ) tert-butyl (2S)-2-(cyanomethyl)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6'H- spiro[indene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate; isomer 9O-1

Substrate 9N-1 (140 mg, 0.27 mmol) and N-methyl-L-prolinol (46 mg, 0.4 mmol) were dissolved in toluene (6.0 mL), placed at 0 °C and stirred for 10 min, Sodium tert-butoxide (39 mg, 0.4 mmol) was added to the system, and stirring was continued at this temperature for 30 min. After the reaction, an aqueous ammonium chloride solution was added to the reaction solution to quench, and the mixture was extracted with DCM. The organic phase was dried with anhydrous sodium sulfate, filtered, and spin-dried, and purified by silica gel column to obtain the product 9 O-1 . White solid (140 mg, 91% yield).

第十一步：2-（（2S）-4-（2'-（（（S）-1-甲基吡咯烷-2-基）甲氧基）-5',8'-二氫-6'H-螺環[茚-1,7'-喹唑啉]-4'-基）呱嗪-2-基）乙腈的其中一個光學純異構體 (9P-1 ) 2-((2S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile； isomer 9P-1

將底物9O-1 (140 mg, 0.24 mmol )溶解到DCM (6.0 mL)中，再緩慢滴加三氟乙酸(1.0 mL)置於室溫攪拌30 min。反應結束後，用碳酸鈉水溶液淬滅反應並用DCM萃取，有機相用無水硫酸鈉乾燥後，過濾旋乾得到產物9P-1 。白色固體 (120 mg，產率106%)。Step 11: 2-((2S)-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6 One of the optically pure isomers of 'H-spiro[inden-1,7'-quinazolin]-4'-yl)oxazin-2-yl)acetonitrile (9 P-1 ) 2-((2S )-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4 '-yl)piperazin-2-yl)acetonitrile; isomer 9P-1

The substrate 9O-1 (140 mg, 0.24 mmol) was dissolved in DCM (6.0 mL), and then trifluoroacetic acid (1.0 mL) was slowly added dropwise and stirred at room temperature for 30 min. After the reaction was completed, the reaction was quenched with an aqueous sodium carbonate solution and extracted with DCM. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried to obtain the product 9 P-1 . White solid (120 mg, 106% yield).

第十二步：2-（（2S）-1-丙烯醯-4-（2'-（（（S）-1-甲基吡咯烷-2-基）甲氧基）-5',8'-二氫-6'H-螺環[茚-1,7'-喹唑啉]-4'-基）呱嗪-2-基）乙腈的光學純異構體(化合物 9-1 和化合物 9-2 ) 2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile

將底物9P-1 (70 mg, 0.15 mmol )以及三乙胺(46 mg, 0.45 mmol)溶解到DCM (10.0 mL)中，置於0 °C攪拌10 min, 再緩慢滴加丙烯醯氯(20 mg, 0.23 mmol)，置於該溫度下攪拌30 min。反應結束後，用碳酸鈉水溶液淬滅反應並用DCM萃取，有機相用無水硫酸鈉乾燥後，過濾旋乾後送HPLC製備純化（製備條件：儀器及製備柱：採用WATERS 2767製備液相，製備柱型號Xbridge C18, 5μm, 內徑×長度= 19 mm × 250 mm。流動相體系：乙腈/(含0.05%三氟乙酸)水。梯度洗脫：乙腈含量30%-75%，洗脫時間15min。）得到化合物 9-1 。白色固體 (33 mg，產率42%)。 LCMS m/z =525.3 [M+1]⁺ ¹ H NMR (400 MHz, CD₃ OD) δ 7.34 (d, 1H), 7.29 (d, 1H), 7.25 (dt, 1H), 7.17 (dt, 1H), 6.84 (s, 1H), 6.80 (d, 1H), 6.58 (d, 1H), 6.28 (d, 1H), 5.83 (d, 1H), 5.10 (s, 1H), 4.70 – 4.36 (m, 3H), 4.23 (d, 1H), 4.19 – 4.09 (s, 1H), 4.06 (d, 1H), 3.58 (s, 1H), 3.37 – 3.31 (m, 1H), 3.27 – 3.12 (m, 3H), 3.09 – 3.01 (m, 2H), 2.94 (t, 2H), 2.72 (s, 3H), 2.68 (t, 2H), 2.25 – 2.15 (m, 1H), 2.04 – 1.93 (m, 2H), 1.93 – 1.89 (m, 1H), 1.88 – 1.80 (m, 1H), 1.80 – 1.71 (m, 1H).9M-2 (150 mg, 0.3 mmol )經過與9M-1 到化合物 9-1 相同的合成路線方法得到化合物 9-2 。白色固體 (28 mg)。 LCMS m/z =525.3 [M+1]⁺ ¹ H NMR (400 MHz, CD₃ OD) δ 7.33 (t, 2H), 7.24 (dt, 1H), 7.19 (dt, 1H), 6.81 (d, 2H), 6.69 (d, 1H), 6.28 (d, 1H), 5.83 (d, 1H), 5.05 (s, 1H), 4.50 – 4.38 (m, 2H), 4.16 (d, 2H), 4.09 (s, 1H), 3.72 (s, 1H), 3.47 (s, 1H), 3.29 – 3.24 (m, 1H), 3.21 – 3.05 (m, 3H), 3.02 – 2.86 (m, 4H), 2.67 (s, 3H), 2.65 – 2.60 (t, 1H), 2.54 (d, 1H), 2.24 – 2.04 (m, 2H), 1.96 – 1.93 (m, 1H), 1.92 – 1.88 (m, 1H), 1.85 – 1.75 (m, 1H), 1.70 – 1.61 (m, 1H).實施例 10 1-（7-（2'-（（（（2S，4R）-4-氟-1-甲基吡咯烷-2-基）甲氧基）-2,3,6'，8'-四氫-5'H-螺[ 茚-1,7'-喹唑啉] -4'-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮（化合物 10 ） 1-(7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro -5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonan-2-yl) prop-2-en-1-one

Step 12: 2-((2S)-1-propenyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8' - Optically pure isomers of dihydro-6'H-spiro[inden-1,7'-quinazolin]-4'-yl)oxazin-2-yl)acetonitrile ( compound 9-1 and compound 9 -2 ) 2-((2S)-1-acryloyl-4-(2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-6'H-spiro [indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile

Substrate 9P-1 (70 mg, 0.15 mmol) and triethylamine (46 mg, 0.45 mmol) were dissolved in DCM (10.0 mL), placed at 0 °C and stirred for 10 min, and then slowly added acrylonitrile chloride ( 20 mg, 0.23 mmol) and stirred at this temperature for 30 min. After the reaction was completed, the reaction was quenched with an aqueous sodium carbonate solution and extracted with DCM. The organic phase was dried with anhydrous sodium sulfate, filtered and spin-dried, and then sent to HPLC for preparation and purification (preparation conditions: instrument and preparative column: using WATERS 2767 to prepare liquid phase, preparative column Model Xbridge C18, 5μm, inner diameter × length = 19 mm × 250 mm. Mobile phase system: acetonitrile/(containing 0.05% trifluoroacetic acid) water. Gradient elution: acetonitrile content 30%-75%, elution time 15min. ) to obtain compound 9-1 . White solid (33 mg, 42% yield). LCMS m/z =525.3 [M+1] ⁺ ¹ H NMR (400 MHz, CD ₃ OD) δ 7.34 (d, 1H), 7.29 (d, 1H), 7.25 (dt, 1H), 7.17 (dt, 1H) ), 6.84 (s, 1H), 6.80 (d, 1H), 6.58 (d, 1H), 6.28 (d, 1H), 5.83 (d, 1H), 5.10 (s, 1H), 4.70 – 4.36 (m, 3H), 4.23 (d, 1H), 4.19 – 4.09 (s, 1H), 4.06 (d, 1H), 3.58 (s, 1H), 3.37 – 3.31 (m, 1H), 3.27 – 3.12 (m, 3H) , 3.09 – 3.01 (m, 2H), 2.94 (t, 2H), 2.72 (s, 3H), 2.68 (t, 2H), 2.25 – 2.15 (m, 1H), 2.04 – 1.93 (m, 2H), 1.93 – 1.89 (m, 1H), 1.88 – 1.80 (m, 1H), 1.80 – 1.71 (m, 1H). 9M-2 (150 mg, 0.3 mmol) was synthesized in the same way as 9 M-1 to compound 9-1 The route method affords compound 9-2 . White solid (28 mg). LCMS m/z =525.3 [M+1] ⁺ ¹ H NMR (400 MHz, CD ₃ OD) δ 7.33 (t, 2H), 7.24 (dt, 1H), 7.19 (dt, 1H), 6.81 (d, 2H) ), 6.69 (d, 1H), 6.28 (d, 1H), 5.83 (d, 1H), 5.05 (s, 1H), 4.50 – 4.38 (m, 2H), 4.16 (d, 2H), 4.09 (s, 1H), 3.72 (s, 1H), 3.47 (s, 1H), 3.29 – 3.24 (m, 1H), 3.21 – 3.05 (m, 3H), 3.02 – 2.86 (m, 4H), 2.67 (s, 3H) , 2.65 – 2.60 (t, 1H), 2.54 (d, 1H), 2.24 – 2.04 (m, 2H), 1.96 – 1.93 (m, 1H), 1.92 – 1.88 (m, 1H), 1.85 – 1.75 (m, 1H), 1.70 - 1.61 (m, 1H). Example 10 1-(7-(2'-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy base)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5 ]Nonyl-2-yl)prop-2-en-1-one ( Compound 10 ) 1-(7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl) methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonan-2-yl ) prop-2-en-1-one

第一步: 叔丁基7-（2'-（甲硫基）-2,3,6'，8'-四氫-5'H-螺[茚-1,7'-喹唑啉] -4'-基）-2,7 二氮雜螺[3.5]壬烷-2-羧酸酯（10a ） tert-butyl 7-(2'-(methylthio)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

向化合物5f（2.1 g, 7.04 mmol）中依次加入15mL DMF和二異丙基乙胺（2.73g, 21.12 mmol），攪拌下加入1H-苯並三唑-1-基氧三吡咯烷基六氟磷酸鹽（4.4 g, 8.45 mmol）。加畢，待反應液澄清，加入2-叔丁氧羰基-2,7-二氮雜螺[3.5]壬烷（1.91 g, 8.45 mmol），升溫至80℃攪拌2 h。加入50 mL乙酸乙酯稀釋，用30 mL水洗有機相三次，有機相用無水硫酸鈉乾燥，減壓濃縮。矽膠柱層析得到目標產物叔丁基7-（2'-（甲硫基）-2,3,6'，8'-四氫-5'H-螺[茚-1,7'-喹唑啉] -4'-基）-2,7 二氮雜螺[3.5]壬烷-2-羧酸酯（10a ），白色固體(2.7 g，收率：75%)。 LCMS m/z =507.2 [M+H]⁺ The first step: tert-butyl 7-(2'-(methylthio)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazoline]- 4'-yl)-2,7diazaspiro[3.5]nonane-2-carboxylate ( 10a ) tert-butyl 7-(2'-(methylthio)-2,3,6',8'- tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

To compound 5f (2.1 g, 7.04 mmol), 15 mL of DMF and diisopropylethylamine (2.73 g, 21.12 mmol) were sequentially added, and 1H-benzotriazol-1-yloxytripyrrolidinylhexafluoro was added with stirring Phosphate (4.4 g, 8.45 mmol). After the addition was completed, when the reaction solution was clear, 2-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonane (1.91 g, 8.45 mmol) was added, and the temperature was raised to 80 °C and stirred for 2 h. Add 50 mL of ethyl acetate to dilute, wash the organic phase with 30 mL of water three times, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. The target product tert-butyl 7-(2'-(methylthio)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazole] was obtained by silica gel column chromatography lino]-4'-yl)-2,7diazaspiro[3.5]nonane-2-carboxylate ( 10a ), white solid (2.7 g, yield: 75%). LCMS m/z =507.2 [M+H] ⁺

第二步：叔丁基7-（2'-（甲基磺醯基）-2,3,6'，8'-四氫-5'H-螺[茚-1,7'-喹唑啉] -4'-基）-2,7 二氮雜螺[3.5]壬烷-2-羧酸酯（10b ） tert-butyl 7-(2'-(methylsulfonyl)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin] -4'-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

將化合物10a (2.7 g，5.33 mmol)溶於20 mL甲苯中，冰浴下加入間氯過氧苯甲酸(1.84 g，10.66 mmol)，升溫至室溫攪拌1 h。加入20 mL飽和硫代硫酸鈉水溶液，攪拌40 min，加入50 mL乙酸乙酯，混合液用30 mL飽和碳酸氫鈉水溶液洗滌3次，有機相乾燥，減壓濃縮，得到目標產物叔丁基7-（2'-（甲基磺醯基）-2,3,6'，8'-四氫-5'H-螺[茚-1,7'-喹唑啉] -4'-基）-2,7 二氮雜螺[3.5]壬烷-2-羧酸酯（10b ）粗品 (2.9 g)，直接用於下一步。 LCMS m/z =539.2 [M+H]⁺ The second step: tert-butyl 7-(2'-(methylsulfonyl)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazoline ]-4'-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate ( 10b ) tert-butyl 7-(2'-(methylsulfonyl)-2,3,6',8 '-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

Compound 10a (2.7 g, 5.33 mmol) was dissolved in 20 mL of toluene, m-chloroperoxybenzoic acid (1.84 g, 10.66 mmol) was added under ice bath, and the temperature was raised to room temperature and stirred for 1 h. 20 mL of saturated aqueous sodium thiosulfate solution was added, stirred for 40 min, 50 mL of ethyl acetate was added, the mixture was washed 3 times with 30 mL of saturated aqueous sodium bicarbonate solution, the organic phase was dried, and concentrated under reduced pressure to obtain the target product tert-butyl 7 -(2'-(Methylsulfonyl)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazoline]-4'-yl)- Crude 2,7 diazaspiro[3.5]nonane-2-carboxylate ( 10b ) (2.9 g) was used directly in the next step. LCMS m/z =539.2 [M+H] ⁺

第三步：叔丁基7-（2'-（（（（2S，4R）-4-氟-1-甲基吡咯烷-2-基）甲氧基）-2,3,6',8'-四氫-5'H-螺[ 茚-1,7'-喹唑啉] -4'-基）-2,7-二氮雜螺[3.5]壬烷-2-羧酸酯（10c ） tert-butyl 7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

將化合物10b (2.7 g)和((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇 (2.67 g，20.04 mmol)溶於20 mL甲苯中，冰浴下加入叔丁醇鈉(1.44 g，15.03 mmol)，冰浴下攪拌1 h。加入15 mL水淬滅反應，加入20 mL乙酸乙酯萃取，有機相用無水硫酸鈉乾燥，減壓濃縮。矽膠柱層析後得到目標產物叔丁基7-（2'-（（（（2S，4R）-4-氟-1-甲基吡咯烷-2-基）甲氧基）-2,3,6',8'-四氫-5'H-螺[ 茚-1,7'-喹唑啉] -4'-基）-2,7-二氮雜螺[3.5]壬烷-2-羧酸酯（10c ），白色固體(2.0 g，兩步收率：67%)。 LCMS m/z =592.3 [M+H]⁺ The third step: tert-butyl 7-(2'-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8 '-Tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate ( 10c ) tert-butyl 7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro [indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

Compound 10b (2.7 g) and ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (2.67 g, 20.04 mmol) were dissolved in 20 mL of toluene, and tert. Sodium butoxide (1.44 g, 15.03 mmol) was stirred under ice bath for 1 h. 15 mL of water was added to quench the reaction, 20 mL of ethyl acetate was added for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After silica gel column chromatography, the target product tert-butyl 7-(2'-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3, 6',8'-Tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonane-2-carboxy acid ester ( 10c ), white solid (2.0 g, 67% over two steps). LCMS m/z =592.3 [M+H] ⁺

第四步：2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-（基）甲氧基）-4'-（2,7-二氮雜螺[3.5]壬基-7-基）-2,3,6',8'-四氫-5'H-螺[茚-1,7'-喹唑啉]（10d） 2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4'-(2,7-diazaspiro[3.5]nonan-7-yl)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazoline]

將底物10d (2 g, 3.38 mmol )溶解到DCM (10 mL)中，再緩慢滴加三氟乙酸(5 mL)置於室溫攪拌30 min。反應結束後，減壓濃縮，殘留物用10 mL飽和碳酸氫鈉水溶液鹼化，並用DCM（20 mL x 2）萃取，合併有機相，用無水硫酸鈉乾燥後，過濾，減壓濃縮得到產物2'-(((2S,4R)-4-氟-1-甲基吡咯烷-2-（基）甲氧基）-4'-（2,7-二氮雜螺[3.5]壬基-7-基）-2,3,6',8'-四氫-5'H-螺[茚-1,7'-喹唑啉]（10d）粗品 (2 g)，直接用於下一步。The fourth step: 2'-(((2S,4R)-4-fluoro-1-methylpyrrolidine-2-(yl)methoxy)-4'-(2,7-diazaspiro[3.5 ]nonyl-7-yl)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazoline](10d) 2'-((((2S, 4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4'-(2,7-diazaspiro[3.5]nonan-7-yl)-2,3,6',8'-tetrahydro-5 'H-spiro[indene-1,7'-quinazoline]

Substrate 10d (2 g, 3.38 mmol) was dissolved in DCM (10 mL), and then trifluoroacetic acid (5 mL) was slowly added dropwise and stirred at room temperature for 30 min. After the reaction was completed, concentrated under reduced pressure, the residue was basified with 10 mL of saturated aqueous sodium bicarbonate solution, and extracted with DCM (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain product 2 '-(((2S,4R)-4-Fluoro-1-methylpyrrolidine-2-(yl)methoxy)-4'-(2,7-diazaspiro[3.5]nonyl-7 -yl)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazoline] (10d) crude (2 g) was used directly in the next step.

第五步：1-（7-（2'-（（（（2S,4R）-4-氟-1-甲基吡咯烷-2-基）甲氧基）-2,3,6',8'-四氫-5'H-螺[ 茚-1,7'-喹唑啉] -4'-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮（化合物 10 ） 1-(7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one

將底物9d (800 mg, 1.63 mmol )以及二異丙基乙胺(0.63 g, 4.89 mmol)溶解到DCM (10.0 mL)中，置於0℃攪拌10 min, 再緩慢滴加丙烯醯氯(150 mg, 1.63 mmol)，置於該溫度下攪拌30 min。反應結束後，用20mL碳酸氫鈉水溶液淬滅反應並用20 mL DCM萃取，有機相用無水硫酸鈉乾燥後，減壓濃縮，殘留物矽膠柱層析得到1-（7-（2'-（（（（2S，4R）-4-氟-1-甲基吡咯烷-2-基）甲氧基）-2,3,6'，8'-四氫-5'H-螺[ 茚-1,7'-喹唑啉] -4'-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮（化合物 10 ），白色固體（450 mg, 兩步收率：61%）。 LCMS m/z =546.2[M+H]⁺ 實施例 11 2-氟-1-（7-（2'-（（（（2S，4R）-4-氟-1-甲基吡咯烷-2-基）甲氧基）-2,3,6'，8'-四氫-5' H-螺[吲哚-1,7'-喹唑啉] -4'-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮（化合物 11 ） 2-fluoro-1-(7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonan-2-yl) prop-2-en-1-one

Step 5: 1-(7-(2'-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8 '-Tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)propan-2 -En-1-one ( Compound 10 ) 1-(7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8 '-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one

Substrate 9d (800 mg, 1.63 mmol) and diisopropylethylamine (0.63 g, 4.89 mmol) were dissolved in DCM (10.0 mL), placed at 0 °C and stirred for 10 min, and then slowly added acrylonitrile chloride ( 150 mg, 1.63 mmol) and stirred at this temperature for 30 min. After the reaction was completed, the reaction was quenched with 20 mL of aqueous sodium bicarbonate solution and extracted with 20 mL of DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1-(7-(2'-(( ((2S,4R)-4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1, 7'-Quinazolin-4'-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one ( Compound 10 ), white solid (450 mg, two-step yield: 61%).LCMS m/z=546.2[M+H] ⁺ Example 11 2-Fluoro-1-(7-(2'-((((2S,4R)-4- Fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[indole-1,7'-quinazoline]- 4'-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one (compound 11 ) 2-fluoro-1-(7-(2'- (((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin] -4'-yl)-2,7-diazaspiro[3.5]nonan-2-yl) prop-2-en-1-one

第一步：2-氟-1-（7-（2'-（（（（2S,4R）-4-氟-1-甲基吡咯烷-2-基）甲氧基）-2,3,6',8'-四氫-5' H-螺[吲哚-1,7'-喹唑啉] -4'-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮（化合物 11 ） 2-fluoro-1-(7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonan-2-yl) prop-2-en-1-one

將化合物10d (0.65 g，1.32 mmol)和2-氟丙烯酸 (140 mg，1.58 mmol)溶於10 mL N,N-二甲基甲醯胺中，加入二異丙基乙胺(510 mg，3.96 mmol)，室溫下加入1H-苯並三唑-1-基氧三吡咯烷基六氟磷酸鹽 (0.82 g，1.58 mmol)，反應1 h。加入20 mL水，析出大量固體，過濾，濾餅減壓乾燥，矽膠柱層析純化得到2-氟-1-（7-（2'-（（（（2S,4R）-4-氟-1-甲基吡咯烷-2-基）甲氧基）-2,3,6',8'-四氫-5' H-螺[吲哚-1,7'-喹唑啉] -4'-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮（化合物 11 ），白色固體 (200 mg, 兩步收率：32%)。 LCMS m/z =564.3[M+H]⁺ The first step: 2-fluoro-1-(7-(2'-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3, 6',8'-Tetrahydro-5'H-spiro[indole-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonyl-2- yl)prop-2-en-1-one (Compound 11 ) 2-fluoro-1-(7-(2'-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy) -2,3,6',8'-tetrahydro-5'H-spiro[indene-1,7'-quinazolin]-4'-yl)-2,7-diazaspiro[3.5]nonan-2-yl) prop -2-en-1-one

Compound 10d (0.65 g, 1.32 mmol) and 2-fluoroacrylic acid (140 mg, 1.58 mmol) were dissolved in 10 mL of N,N-dimethylformamide, and diisopropylethylamine (510 mg, 3.96 mmol), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (0.82 g, 1.58 mmol) was added at room temperature, and the reaction was carried out for 1 h. 20 mL of water was added, a large amount of solid was precipitated, filtered, the filter cake was dried under reduced pressure, and purified by silica gel column chromatography to obtain 2-fluoro-1-(7-(2'-((((2S,4R)-4-fluoro-1 -Methylpyrrolidin-2-yl)methoxy)-2,3,6',8'-tetrahydro-5'H-spiro[indole-1,7'-quinazoline]-4'- yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one (compound 11 ), white solid (200 mg, two-step yield: 32%). LCMS m/z =564.3[M+H] ⁺

參考實施例3的方法，選取相應的原料/中間體，製備得到化合物如下表格A中的化合物 12、13、14、15、16、17、18。With reference to the method of Example 3, the corresponding raw materials/intermediates were selected to prepare the compounds 12, 13, 14, 15, 16, 17, 18 in the following Table A.

參考實施例1的方法，選取相應的原料/中間體，製備得到化合物如下表格A中的化合物20、21、22、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41。Referring to the method of Example 1, select the corresponding raw materials/intermediates to prepare the compounds 20, 21, 22, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41.

參考實施例4至11的方法，選取相應的原料/中間體，製備得到化合物如下表格A中的化合物42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、121、122、123、124、125、126。表A: 化合物12-化合物126結構化合物編號結構化合物編號結構 12

13

14

15

16

17

18

19

20

21

22

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

生物測試例 With reference to the methods of Examples 4 to 11, the corresponding raw materials/intermediates were selected to prepare compounds 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126. Table A: Compound 12-Compound 126 Structure

Compound number structure Compound number structure 12

13

14

15

16

17

18

19

20

twenty one

twenty two

twenty four

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

Biological test case

方法1: NCI-H358細胞（人非小細胞肺癌細胞）購自於ATCC，培養於RPMI1640，10%FBS，37 ºC, 5% CO2。第一天，收集處於指數生長期的NCI-H358細胞，用Vi-Cell XR細胞計數儀(Beckman Coulter，TACEL0030)進行活細胞計數。用培養基將細胞懸液調整到5000個/90 µL。每孔加90 µL 細胞懸液於96-孔細胞培養板。第二天，化合物孵育。受試化合物起始濃度10 µM，3倍稀釋，9個濃度，每孔DMSO終濃度為0.1%。於37 ºC，5% CO₂ 孵箱中培養72小時。藥物處理72小時後，每孔加入50 µL(1/2培養體積)預先融化並平衡到室溫的CTG溶液(promega，G7572)，用微孔板震盪器混勻2分鐘，於室溫放置10分鐘後用Envision2104讀板儀測定螢光訊號值。Method 1: NCI-H358 cells (human non-small cell lung cancer cells) were purchased from ATCC and cultured in RPMI1640, 10% FBS, 37 ºC, 5% CO2. On the first day, NCI-H358 cells in exponential growth phase were collected and viable cell counts were performed using a Vi-Cell XR cytometer (Beckman Coulter, TACEL0030). Adjust the cell suspension to 5000 cells/90 µL with medium. Add 90 µL of cell suspension to each well of a 96-well cell culture plate. The next day, compounds were incubated. The initial concentration of the test compound was 10 µM, 3-fold dilution, 9 concentrations, and the final concentration of DMSO in each well was 0.1%. Incubate for 72 hours in a 37 ºC, 5% CO ₂ incubator. After 72 hours of drug treatment, 50 µL (1/2 culture volume) of CTG solution (promega, G7572) pre-thawed and equilibrated to room temperature was added to each well, mixed with a microplate shaker for 2 minutes, and placed at room temperature for 10 minutes. Fluorescence signal values were measured with an Envision2104 plate reader after minutes.

細胞存活率用公式(1)計算。其中V_sample 為藥物處理組的讀數，V_{vehicle control} 為溶劑對照組的平均值。應用GraphPad Prism 5.0 軟體，使用非線性回歸模型繪製S型劑量-存活率曲線並計算IC₅₀ 值。細胞最大抑制率(Max inh.%) 化合物在某一濃度下，對細胞的最大抑制作用，用公式(2)計算 V_sample /V_{vehicle control} x100% 公式(1) 1-V_sample /V_{vehicle control} x100% 公式(2)Cell viability was calculated using formula (1). where V _sample is the reading of the drug treatment group, and V _{vehicle control} is the average value of the solvent control group. Using GraphPad Prism 5.0 software, a nonlinear regression model was used to draw sigmoid dose-survival curves and _IC50 values were calculated. Maximum inhibition rate of cells (Max inh.%) The maximum inhibitory effect of a compound on cells at a certain concentration is calculated by formula (2) V _sample /V _{vehicle control} x100% formula (1) 1-V _sample /V _{vehicle control} x100% formula (2)

方法2: NCI-H358細胞購自於ATCC，培養基為RPMI1640+10%FBS，於37 ºC， 5% CO₂ 孵箱中培養。第一天，收集處於指數生長期的NCI-H358細胞，用自動細胞分析儀(countstar)進行活細胞計數。用培養基將細胞懸液調整後鋪板96孔細胞培養板，每孔1500個細胞。第二天，吸去培養基，每孔加入90 µL新鮮培養基和10 µL不同濃度化合物，每孔DMSO終濃度為0.1%。於37 ºC，5% CO₂ 孵箱中培養72小時。藥物處理72小時後，每孔加入50 µL預先融化並平衡到室溫的CTG溶液(promega，G7572)，用微孔板震盪器混勻2分鐘，於室溫放置10分鐘後用酶標儀(PHERAstar FSX)測定螢光訊號值。Method 2: NCI-H358 cells were purchased from ATCC, and the medium was RPMI1640+10% FBS, cultured in a 37 ºC, 5% CO ₂ incubator. On the first day, NCI-H358 cells in exponential growth phase were collected and viable cell counts were performed using an automated cell analyzer (countstar). The cell suspension was adjusted with culture medium and plated in 96-well cell culture plates at 1500 cells per well. The next day, the medium was aspirated and 90 µL of fresh medium and 10 µL of compounds of various concentrations were added to each well, with a final concentration of 0.1% DMSO per well. Incubate for 72 hours in a 37 ºC, 5% CO ₂ incubator. After 72 hours of drug treatment, 50 µL of CTG solution (promega, G7572) pre-thawed and equilibrated to room temperature was added to each well, mixed with a microplate shaker for 2 minutes, and placed at room temperature for 10 minutes with a microplate reader ( PHERAstar FSX) to measure the fluorescence signal value.

細胞存活率用公式V_sample /V_{vehicle control} x100%計算。其中V_sample 為藥物處理組的讀數，V_{vehicle control} 為溶劑對照組的平均值。應用origen9.2軟體, 使用非線性回歸模型繪製S型劑量-存活率曲線並計算IC₅₀ 值。表 1 抑制 NCI-H358 細胞增殖的 IC₅₀ 值序號測試方法化合物編號 IC₅₀ (μM) 1 方法1 化合物1 0.279 2 方法2 化合物4 0.035 3 方法2 化合物4-1 0.024 4 方法2 化合物4-2 1.231 5 方法2 化合物5 0.117 6 方法2 化合物5-1 0.044 7 方法2 化合物5-2 0.968 8 方法2 化合物6-1 0.467 9 方法2 化合物6-2 4.244 10 方法2 化合物7-1 1.133 11 方法2 化合物8-1 0.375 12 方法2 化合物8-2 4.702 13 方法2 化合物9-1 0.605 14 方法2 化合物9-2 0.055 Cell viability was calculated using the formula V _sample /V _{vehicle control} x100%. where V _sample is the reading of the drug treatment group, and V _{vehicle control} is the average value of the solvent control group. Using origen9.2 software, a nonlinear regression model was used to draw the sigmoid dose-survival curve and calculate the IC ₅₀ value. Table 1 _IC50 value of inhibiting NCI-H358 cell proliferation serial number testing method Compound number _IC50 (μM) 1 method 1 Compound 1 0.279 2 Method 2 Compound 4 0.035 3 Method 2 Compound 4-1 0.024 4 Method 2 Compound 4-2 1.231 5 Method 2 Compound 5 0.117 6 Method 2 Compound 5-1 0.044 7 Method 2 Compound 5-2 0.968 8 Method 2 Compound 6-1 0.467 9 Method 2 Compound 6-2 4.244 10 Method 2 Compound 7-1 1.133 11 Method 2 Compound 8-1 0.375 12 Method 2 Compound 8-2 4.702 13 Method 2 Compound 9-1 0.605 14 Method 2 Compound 9-2 0.055

結論：本發明實施例化合物具有良好的抑制NCI-H358細胞增殖作用，化合物1、4、4-1、4-2、5、5-1、5-2、6-1、6-2、7-1、8-1、8-2、9-1、9-2、10的IC₅₀ 小於5μM、化合物10的IC₅₀ 小於3μM。部分化合物的具體IC₅₀ 值見表1。測試例 2 ： KRAS G12C 激酶抑制活性測試 Conclusion: The compounds of the examples of the present invention have a good inhibitory effect on the proliferation of NCI-H358 cells, compounds 1, 4, 4-1, 4-2, 5, 5-1, 5-2, 6-1, 6-2, 7 The _IC50 of -1, 8-1, 8-2, 9-1, 9-2, 10 is less than 5 μM, and the _IC50 of compound 10 is less than 3 μM. The specific _IC50 values of some compounds are shown in Table 1. Test Example 2 : KRAS G12C Kinase Inhibitory Activity Test

激酶KRAS G12C（Sino , Cat.No 12259-H07E2）配製成2.5× 的激酶溶液，底物及抗體混合液配製成2×的溶液（c-RAF：Pharmaron；SOS1：Pharmaron；GTP：Sigma，Cat.No G8877-25MG；MAb Anti 6HIS-d2：Cisbio，Cat.No 61HISDLB；MAb Anti GST-Eu：Cisbio，Cat.No 61GSTKLB）。在384孔板中加入1 µL不同濃度的化合物，加入4 µL 2.5× 的激酶溶液，室溫孵育60分鐘。加入5 µL 2× 的底物及抗體混合液，室溫孵育120分鐘後，使用BioTek（Synergy 4）多功能酶標儀設置激發光為320 nM，發射光為615 nM和665 nM，讀615 nm (Eu)和665 nm (d2)的螢光訊號。計算每孔的比值Ratio=（665/615）×10000。運用Prism GraphPad 7.0軟體計算IC₅₀ 值。抑制率計算公式見式1，其中

: 10個陽性對照孔比值的平均值（10 μM AMG510），

: 10個陰性對照孔比值的平均值（0.5% DMSO）。

×100 式1表 2 抑制 KRAC G12C 激酶的 IC₅₀ 值

序號化合物編號 IC₅₀ (μM) 1 化合物4-1 0.041 2 化合物5-1 0.008 3 化合物6-1 0.050 4 化合物8-1 0.027 5 化合物9-2 0.010

Kinase KRAS G12C (Sino, Cat.No 12259-H07E2) was prepared as 2.5× kinase solution, and the substrate and antibody mixture was prepared as 2× solution (c-RAF: Pharmaron; SOS1: Pharmaron; GTP: Sigma, Cat. No G8877-25MG; MAb Anti 6HIS-d2: Cisbio, Cat. No 61HISDLB; MAb Anti GST-Eu: Cisbio, Cat. No 61GSTKLB). Add 1 µL of various concentrations of compounds to a 384-well plate, add 4 µL of 2.5× kinase solution, and incubate for 60 minutes at room temperature. Add 5 µL of 2× substrate and antibody mixture, incubate at room temperature for 120 minutes, use a BioTek (Synergy 4) multifunctional microplate reader to set excitation light to 320 nM, emission light to be 615 nM and 665 nM, read 615 nm (Eu) and fluorescence signals at 665 nm (d2). Calculate the ratio of each well Ratio=(665/615)×10000. _IC50 values were calculated using Prism GraphPad 7.0 software. The formula for calculating the inhibition rate is shown in Equation 1, where

: the mean of the ratios of 10 positive control wells (10 μM AMG510),

: Average of the ratios of 10 negative control wells (0.5% DMSO).

×100 Formula 1 Table 2 IC ₅₀ value for inhibition of KRAC G12C kinase

serial number Compound number _IC50 (μM) 1 Compound 4-1 0.041 2 Compound 5-1 0.008 3 Compound 6-1 0.050 4 Compound 8-1 0.027 5 Compound 9-2 0.010

結論：本發明實施例化合物具有良好的抑制KRAC G12C激酶活性作用。測試例 3 ：人肝微粒 CYP 酶抑制測試 Conclusion: The compounds of the examples of the present invention have a good inhibitory effect on KRAC G12C kinase activity. Test Example 3 : Human Liver Microparticles CYP Enzyme Inhibition Test

孵育體系為200µL。先取20µL底物溶液於樣品孔中，20µL空白磷酸鹽緩衝液於空白對照孔中，隨後加入2 µL系列濃度的待測化合物工作液和陽性對照至相應樣品孔中，於陰性對照和空白對照孔中加入2 µL空白溶劑替代；於所有樣品孔中加入158µL人肝微粒體工作液後置37℃水浴中預孵10min，之後加入20µL NADPH再生系統啟動反應，在37℃水浴中繼續孵育10min後，加入400µL含200ng/mL甲苯磺丁脲和拉貝洛爾的冰乙腈溶液終止反應並沉澱蛋白，樣品於4000 rpm，4℃離心20min，取上清液200 µL，加入100 µL超純水，渦漩混勻10min後，LC-MS/MS進樣分析。表 3 抑制人肝微粒 CYP 酶的 IC₅₀ 值化合物編號 IC₅₀ (μM) CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4-M 化合物4-1 ＞50 35.0 ＞50 37.5 18.9 MRTX849 ＞50 1.24 18.9 14.1 7.78 The incubation system is 200 µL. First take 20 µL of substrate solution into sample wells, 20 µL of blank phosphate buffer solution into blank control wells, and then add 2 µL of the test compound working solution and positive control to the corresponding sample wells, then add 2 µL of serial concentrations of the working solution of the test compound and positive control to the corresponding sample wells, and add 20 µL of blank phosphate buffer to the negative control and blank control wells. 2 µL of blank solvent was added to replace it; 158 µL of human liver microsome working solution was added to all sample wells, then pre-incubated in a 37°C water bath for 10 minutes, then 20 µL of NADPH regeneration system was added to start the reaction, and after further incubation in a 37°C water bath for 10 minutes, Add 400 µL of ice acetonitrile solution containing 200 ng/mL tolbutamide and labetalol to stop the reaction and precipitate the protein. Centrifuge the sample at 4000 rpm and 4°C for 20 min. Take 200 µL of the supernatant, add 100 µL of ultrapure water, and vortex. After swirl mixing for 10 min, LC-MS/MS injection analysis. Table 3 _IC50 values for inhibition of human liver microparticles CYP enzymes Compound number _IC50 (μM) CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4-M Compound 4-1 >50 35.0 >50 37.5 18.9 MRTX849 >50 1.24 18.9 14.1 7.78

J. Med. Chem. 2020, 63, 13, 6679–6693公開報導MRTX849結構為

。 J. Med. Chem. 2020, 63, 13, 6679-6693 publicly reported that the structure of MRTX849 is

.

結論：本發明實施例化合物對人肝微粒主要代謝酶亞型無明顯抑制（IC₅₀ 大於10 μM），且與MRTX849相比，對CYP2C9、CYP2C19、CYP2D6和CYP3A4-M亞型代謝酶的抑制作用明顯降低。測試例 4 ： hERG 抑制測試 Conclusion: The compounds in the examples of the present invention have no significant inhibitory effect on the main metabolic enzyme subtypes of human liver microparticles (IC ₅₀ is greater than 10 μM), and compared with MRTX849, they have inhibitory effects on the metabolic enzymes of CYP2C9, CYP2C19, CYP2D6 and CYP3A4-M subtypes Obvious reduction. Test Example 4 : hERG Inhibition Test

細胞外液配方(mM)：140 NaCl, 5 KCl, 1 CaCl₂ , 1.25 MgCl₂ , 10 HEPES and 10 Glucose，用NaOH調節pH至7.4。細胞內液配方(mM)：140 KCl, 1 MgCl2, 1 CaCl2, 10 EGTA and 10 HEPES，用KOH調節pH 至7.2。Extracellular fluid formulation (mM): 140 NaCl, 5 KCl, 1 CaCl ₂ , 1.25 MgCl ₂ , 10 HEPES and 10 Glucose, adjusted to pH 7.4 with NaOH. Intracellular fluid formulation (mM): 140 KCl, 1 MgCl2, 1 CaCl2, 10 EGTA and 10 HEPES, pH adjusted to 7.2 with KOH.

穩定表達hERG的CHO細胞培養於直徑35mm的細胞培養皿中，置於37℃，5% CO₂ 的培養箱培養，每48小時按1:5比例進行傳代，培養基配方：90%F12 (Invitrogen)，10%胎牛血清(Gibco)，100μg/mL G418 (Invitrogen)和100μg/mL Hygromycin B(Invitrogen)。試驗當天，吸走細胞培養液，用細胞外液淋洗一遍後加入0.25% Trypsin-EDTA (Invitrogen)溶液，在室溫下消化3-5分鐘。吸走消化液，用細胞外液重懸後將細胞轉移到用於電生理記錄的實驗皿中備用。CHO cells stably expressing hERG were cultured in a cell culture dish with a diameter of 35 mm, placed in an incubator at 37 °C, 5% CO ₂ , and passaged at a ratio of 1:5 every 48 hours. Medium formula: 90% F12 (Invitrogen ), 10% fetal bovine serum (Gibco), 100 μg/mL G418 (Invitrogen) and 100 μg/mL Hygromycin B (Invitrogen). On the day of the experiment, the cell culture medium was aspirated, rinsed with extracellular fluid, and then 0.25% Trypsin-EDTA (Invitrogen) solution was added, and the cells were digested at room temperature for 3-5 minutes. Aspirate the digestion solution, resuspend the cells with extracellular fluid, and transfer the cells to the experimental dish for electrophysiological recording.

測試當天，將化合物DMSO母液用100% DMSO進行稀釋，即取10μL的化合物母液加入到20μL DMSO 中，3 倍稀連續釋成中間濃度。然後再取10μL的化合物中間濃度加入到4990μL 細胞外液中，500倍稀釋得到需要測試的最終濃度：最高測試濃度為40μM，一次分別為40、13.33、4.44、1.48、0.49、0.16μM 。陽性對照化合物cisapride準備：取150μM的cisapride DMSO母液10μL，加入到4990μL細胞外液中，500倍稀釋得到需要測試的最終濃度300nM。最終測試濃度中的DMSO含量不超過0.2%，此濃度的DMSO對hERG鉀通道沒有影響。On the test day, the compound DMSO stock solution was diluted with 100% DMSO, that is, 10 μL of the compound stock solution was added to 20 μL DMSO, and the 3-fold dilution was serially diluted to an intermediate concentration. Then 10 μL of the intermediate concentration of the compound was added to 4990 μL of extracellular fluid, and the final concentration to be tested was obtained by 500-fold dilution: the highest test concentration was 40 μM, and one time was 40, 13.33, 4.44, 1.48, 0.49, 0.16 μM respectively. Preparation of positive control compound cisapride: Take 10 μL of 150 μM cisapride DMSO stock solution, add it to 4990 μL of extracellular fluid, and dilute 500 times to obtain the final concentration to be tested, 300 nM. The DMSO content in the final test concentration did not exceed 0.2%, and this concentration of DMSO had no effect on the hERG potassium channel.

穩定表達hERG 鉀通道的CHO (Chinese Hamster Ovary) 細胞，在室溫下用全細胞膜片鉗技術記錄hERG鉀通道電流。數據分析處理採用pClamp 10，GraphPad Prism 5和Excel 軟體。不同化合物濃度對hERG 鉀電流 (-50 mV 時誘發的hERG尾電流峰值) 的抑制程度用以下公式計算： Inhibition % = [1 – (I /I ο)]×100% 其中，Inhibition %代表化合物對hERG 鉀電流的抑制百分率，I 和I ο分別表示在加藥後和加藥前hERG 鉀電流的幅度。In CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels, hERG potassium channel currents were recorded by whole-cell patch-clamp technique at room temperature. Data analysis was performed using pClamp 10, GraphPad Prism 5 and Excel software. The degree of inhibition of hERG potassium current (peak hERG tail current evoked at -50 mV) by different compound concentrations was calculated by the following formula: Inhibition % = [1 – ( I / I ο)]×100% where Inhibition % represents the Percent inhibition of hERG potassium current, I and Io represent the magnitude of hERG potassium current after and before dosing, respectively.

化合物IC₅₀ 使用GraphPad Prism 5 軟體藉由以下方程擬合計算得出： Y=Bottom + (Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)) 其中，X為供試品檢測濃度的Log值，Y為對應濃度下抑制百分率，Bottom和Top分別為最小和最大抑制百分率。表 4 化合物對 hERG 鉀通道電流抑制的 IC₅₀ 值化合物編號 IC₅₀ (μM) 化合物4-1 4.51 MRTX849 1.60 Compound _IC50 was calculated using GraphPad Prism 5 software by fitting the following equation: Y=Bottom + (Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)) where X is the test product The Log value of the detection concentration, Y is the inhibition percentage at the corresponding concentration, Bottom and Top are the minimum and maximum inhibition percentages, respectively. Table 4 _IC50 values of compounds for inhibition of hERG potassium channel currents Compound number _IC50 (μM) Compound 4-1 4.51 MRTX849 1.60

結論：與MRTX849相比，本發明實施例化合物對hERG鉀通道電流抑制作用明顯降低。Conclusion: Compared with MRTX849, the compounds in the examples of the present invention have a significantly lower inhibitory effect on hERG potassium channel current.

Claims

A compound of general formula (I) or a stereoisomer, deuterated substance or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from -C(=O)-C(R ^1a )=C(R ^1b ) ₂ ,

, -S(=O) ₂ -C(R ^1a )=C(R ^1b ) ₂ or

R ^1a is each independently selected from H, F, Cl, Br, I, cyano, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy, said alkyl or alkoxy optionally further by 0 to 4 selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl ) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituent; R ^1b or R ^1c are independently selected from H, F, Cl, Br, I, cyano, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy, -(CH ₂ ) _p -N(C _1-4 alkyl) ₂ , -(CH ₂ ) _p NHC(=O)-C _1-4 alkyl , -(CH ₂ ) _p -C _3-10 carbocycle or -(CH ₂ ) _p -3 to 12-membered heterocycle, the alkyl, alkoxy, heterocycle or carbocycle is optionally further substituted by 0 to 12 4 selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-10 carbocyclic or 5 to 12-membered heterocyclic substituents, the heterocyclic contains 1 to 4 selected from O, Heteroatoms of S and N; Ring A is selected from 4- to 12-membered nitrogen-containing heterocycles, and the nitrogen-containing heterocycles are selected from one of the following saturated or partially saturated groups: monocyclic, paracyclic, bridged or spiro ring, the nitrogen-containing heterocyclic ring, monocyclic ring, paracyclic ring, bridged ring or spirocyclic ring is optionally further substituted by 0 to 4 R ^a ; R ^a is independently selected from H, oxo, F, Cl, Br, I, cyano group, C _1-6 alkyl group or C _1-6 alkoxy group, said alkyl group or alkoxy group is optionally further selected from 0 to 4 groups selected from H, F, Cl, Br, I, OH , cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents; Q, M and the atoms directly connected to them form together

or

Ring B is selected from non-aromatic 4- to 7-membered heterocycles containing 1 to 4 heteroatoms selected from O, S, N, X ₁ is selected from N, and ring C and ring D together form C _{6- 12} -carbocycle or 5- to 12-membered heterocycle, the heterocycle contains 1 to 4 heteroatoms selected from O, S, N, and m1 is selected from 0, 1, 2, 3 or 4 , m2, m3 are independently selected from 0, 1, 2, 3 or 4, and m2+m3

5; R ^2a is selected from H, COOH, -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , -C(=O)-C _1-6 alkyl, -C(= O)-C _3-6 cycloalkyl, -C(=O)-3 to 8-membered heterocycloalkyl, -C(=O)-C _6-10 aryl, -C(=O)-5 to 10-membered heteroaryl, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _6-10 -membered aryl, or 5- to 10-membered hetero Aryl, the alkyl group, alkoxy group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group is optionally further selected from 0 to 4 groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkyl, C _3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl, C _6-10 aryl or 5- to 10-membered heteroaryl substituent, the heterocycloalkyl or heteroaryl contains 1 to 4 selected from O, S, N heteroatom; R ^2b is each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH or C _1-6 alkyl, the alkyl is optionally further O to 4 selected from H, F, Cl, Br, I, oxo, OH, cyano, _CF3 , COOH, _NH2 , -NH( _C1-4alkyl ), -N( _C1-4alkyl ) ) ₂ , C _1-6 alkyl, C _2-6 alkynyl or C _1-6 alkoxy substituent; R ^2c and R ^2d are independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , COOH, -C(=O)-C _1-6 alkyl, -C (=O)-C _3-6 cycloalkyl, -C(=O)-C _6-10 aryl, -C(=O)-5 to 10-membered heteroaryl, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _6-10 -membered aryl or 5- to 10-membered heteroaryl, the alkyl, alkoxy, ring Alkyl, heterocycloalkyl, aryl or heteroaryl optionally further selected from 0 to 4 groups selected from H, F, Cl, Br, I, oxo, OH, cyano, _CF3 , COOH, _NH2 , - NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , C _1-6 alkyl , C _2-6 alkynyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C _6-10 aryl or 5- to 10-membered heteroaryl substituent, the heterocycloalkyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S, N; R ^2A , R ^2B or R ^2C are each independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _6-10 -membered aryl, or 5- to 10-membered heteroaryl , the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group are optionally further selected from 0 to 4 groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy C 1-6 alkyl, hydroxy-substituted C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl substituents, and the heterocycloalkyl contains 1 to 4 selected from O, heteroatom of S, N; X ₃ is selected from bond, O, -OCH ₂ -, -CH ₂ O- or S; R ³ is selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, N(R ^3a ) ₂ , -(CH ₂ ) _q -C(=O)C _1-6 alkyl, -(CH ₂ ) _q -C(=O)-3 to 12-membered heterocycle, -(CH ₂ ) _q -C(=O)-C _3-10 carbocycle, -(CH ₂ ) _q -C(=O)-N (R ^3a ) ₂ , -(CH ₂ ) _q -N(R ^3a )-C(=O)R ^3b , -(CH ₂ ) _q -3- to 12-membered heterocycle or -(CH ₂ ) _q -C _{3 -10} carbocycle, said _CH2 , alkyl, alkoxy, carbocycle or heterocycle is optionally further 0 to 4 selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl, -C _1-4 alkylene-OH, - (CH ₂ ) _q -C _3-10 carbocycle, -(CH ₂ ) _q -3- to 12-membered heterocycle, C _3-6 cycloalkyl, C _1-4 alkoxy, -N(C _1-4 Alkyl) C(=O)-3- to 12-membered heterocycle or 3- to 12-membered heterocycle substituent, the heterocycle contains 1 to 4 heteroatoms selected from O, S, N; R ^3a are each independently selected from H, C _1-4 alkyl, -C _1-4 alkyl-3 to 12-membered heterocycle, and the alkyl or heterocycle is optionally further selected from 0 to 4 H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents, the heterocycle contains 1 to 4 heteroatoms selected from O, S, N ; Alternatively, the two R ^3a and the nitrogen atoms directly connected to the two together form a 4- to 8-membered nitrogen-containing heterocycle, and the nitrogen-containing heterocycle is optionally further 0 to 4 selected from H, F, Cl , Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl or C _{1 -4} alkoxy substituents, the heterocycle contains 1 to 4 heteroatoms selected from O, S, N; R ^3b is selected from H, C _1-6 alkyl, C _3-6 ring Alkyl or 3- to 12-membered heterocycle, said alkyl, cycloalkyl or heterocycle is optionally further selected from 0 to 4 groups selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituent, said The heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, N; R ⁴ is each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ or C _1-6 Alkyl, which is optionally further selected from 0 to 4 groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituent; n, p, q are independently selected from 0, 1, 2, 3 or 4.

The compound according to claim 1 or its stereoisomer, deuterated product or pharmaceutically acceptable salt, wherein, the compound is represented by general formula (Ia) or (Ib),

R ¹ , R ^2a , R ^2b , R ^2c , R ^2d , R ⁴ , R ³ , X ₁ , X ₃ , ring A, ring B, ring C, ring D, m1 in formulas (Ia) and (Ib) The definitions of , m2, m3 and n are consistent with request item 1.

The compound according to claim 2, or a stereoisomer, deuterated compound or pharmaceutically acceptable salt thereof, wherein R ^1c is selected from H, F, Cl, Br, I, cyano, CF ₃ , C _1-4 Alkyl or C _1-4 alkoxy, said alkyl or alkoxy optionally further selected from 0 to 4 groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , Substituents of COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy; Ring A Selected from 4 to 9-membered nitrogen-containing heterocycles, the nitrogen-containing heterocycles are selected from one of the following saturated or partially saturated structures: monocyclic, paracyclic, bridged or spirocyclic, and the nitrogen-containing heterocycles are optional is further substituted by 0 to 4 R ^a substituents; R ^a is each independently selected from H, oxo, F, Cl, Br, I, cyano, C _1-4 alkyl or C _1-4 alkoxy, The alkyl or alkoxy group is optionally further selected from 0 to 4 groups selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituents are substituted.

The compound according to claim 3 or a stereoisomer, deuterated product or a pharmaceutically acceptable salt thereof, Ring A is selected from unsubstituted or substituted

or

, when substituted, optionally further substituted by 0 to 4 R ^a substituent; R ^a is independently selected from H, oxo, F, Cl, Br, I, cyano, C _1-4 alkyl or C _1-4 alkoxy, said alkyl or alkoxy is optionally further selected from 0 to 4 groups selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , Substituents of C _1-4 alkyl or C _1-4 alkoxy.

The compound according to claim 4, or its stereoisomer, deuterated compound or pharmaceutically acceptable salt, wherein ring B is selected from azetidine, azetidine or oxidine; or ring B is selected from imidazole Alkane; R ^2a is selected from H, COOH, -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , -C(=O)-C _1-4 alkyl, -C(= O)-phenyl, -C(=O)-5- to 6-membered heteroaryl, C _1-4 alkyl, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _6-10 aryl or a 5- to 10-membered heteroaryl group, the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group are optionally further 0 to 4 selected from H, F, Cl, Br, I , oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , -C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkyl, C _3-6 cycloalkane base, 3- to 6-membered heterocycloalkyl, C _6-10 -membered aryl or 5- to 10-membered heteroaryl substituent, the heterocycloalkyl or heteroaryl contains 1 to 4 selected from O , S, N heteroatoms; ring D is selected from benzene ring, pyridine, pyridazine or pyrimidine; ring C is selected from C _4-6 carbocycle; or ring C is selected from 4-6 membered heterocycle, the heterocycle Contains 1 to 3 heteroatoms selected from O, S, N; R ^2c is each independently selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _{6- 10} -aryl or 5- to 10-membered heteroaryl, the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally further 0 to 4 selected from H, F , Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -C(=O)NR ^2A R ^2B , -NR ^2A C(=O)R ^2C , C _1-6 alkyl , C _2-6 alkynyl, C _1-6 alkoxy, hydroxy-substituted C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C _6-10 aryl or Substituted with 5- to 10-membered heteroaryl substituents, the heterocycloalkyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S, N; R ^2A , R ^2B or R ^2C are each independently is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _6-10 aryl or 5- to 10-membered heteroaryl, the alkyl, Cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally further selected from 0 to 4 groups selected from H, F, Cl, Br, I, oxo, OH, cyano, _CF3 , COOH, _NH2 , -N H(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, hydroxy substituted C _1- _R _{_} ^2d are each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , C _1-4 alkyl or C _1-4 alkoxy, said alkyl or alkoxy Optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, oxo, OH, cyano, _CF3 , COOH, _NH2 or _C1-6 alkyl.

The compound of claim 5, or a stereoisomer, deuterated product or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from -C(=O)-C(R ^1a )=C(R ^1b ) ₂ ; R ^1a is selected from H, F or C _1-4 alkyl, and said alkyl is optionally further selected from 0 to 4 groups selected from H, F, Cl, Br, I, cyano, OH, CF ₃ , C _{1 -4} alkyl or C _1-4 alkoxy substituents; R ^1b are each independently selected from H, C _1-4 alkyl or -(CH ₂ ) _p -3- to 6-membered heterocycle, the The alkyl or heterocycle is optionally further selected from 0 to 4 groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl ), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocyclic or 3- to 6-membered heterocyclic substituents, the The heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, N.

The compound according to claim 6 or its stereoisomer, deuterated product or pharmaceutically acceptable salt, wherein R ^1a is selected from H, F, methyl, ethyl, propyl or isopropyl, the Methyl, ethyl, propyl or isopropyl are optionally further 0 to 4 selected from H, F, Cl, Br, I, cyano, OH, CF ₃ , C _1-4 alkyl or C _{1- 4} alkoxy substituents; R ^1b are independently selected from H, methyl, ethyl, propyl, isopropyl, -CH ₂ -4-membered nitrogen-containing heterocycle, -CH ₂ -5-membered containing Nitrogen heterocycle, -CH ₂ -6-membered nitrogen-containing heterocycle, 4-membered nitrogen-containing heterocycle, 5-membered nitrogen-containing heterocycle or 6-membered nitrogen-containing heterocycle, the methyl, ethyl, propyl, isopropyl The radical or nitrogen-containing heterocycle is optionally further selected from 0 to 4 groups selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl ), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl or C _1-4 alkoxy substituent; X ₃ is selected from bond or O; R ^2a is selected from H or substituted Or one of the following unsubstituted groups: -C(=O)NH ₂ , -NHC(=O)H, -C(=O)NH-CH ₃ , -NHC(=O)-CH ₃ , - C(=O)NH-CH ₂ CH ₃ , -NHC(=O)CH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)N(CH ₂ CH ₃ ) ₂ , -C(=O)-CH ₃ , -C(=O)-CH ₂ CH ₃ , -C(=O)-CH ₂ CH ₂ CH ₃ , -C(=O)-CH(CH ₃ ) ₂ , -C(=O)NH-phenyl, -NHC(=O)-phenyl, -C(=O)-phenyl, -C(=O)-pyridine, -C(=O)-thiophene, -C(=O)-furan, -C(=O)-pyrrole, methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthalene radical, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, benzimidazolyl, benzopyrazolyl or pyridyl, when When substituted, optionally by 0 to 4 selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , -C(=O)NH ₂ , -NHC(=O)H, -C( =O)NH-CH ₃ , -NHC(=O)-CH ₃ , -C(=O)NH-CH ₂ CH ₃ , -NHC(=O)CH ₂ CH ₃ , -C(=O)N( CH ₃ ) ₂ , -C(=O)N(CH ₂ CH ₃ ) ₂ , -C(=O)NH-phenyl, -NHC(=O)-phenyl, C _1-4 alkyl, C _{1 -4} alkoxy or C _2-4 alkynyl substituent; R ^2b are each independently selected from H, F, oxo, OH, cyano group, CF ₃ , methyl or ethyl, said methyl or ethyl optionally being selected from 0 to 4 groups selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl or C _1-4 alkoxy substituent; ring C and ring D together form a ring selected from

or

or ring C and ring D together form a ring selected from

Each R ^2c is independently selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , -C(=O)NH ₂ , -NHC(=O)H, -C(=O)NH- CH ₃ , -NHC(=O)-CH ₃ , -C(=O)NH-CH ₂ CH ₃ , -NHC(=O)CH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , - -C(=O)N(CH ₂ CH ₃ ) ₂ , -C(=O)NH-phenyl, -NHC(=O)-phenyl, methyl, ethyl, methoxy or ethoxy , the methyl group, ethyl group, methoxy group, ethoxy group or phenyl group is optionally further selected from 0 to 4 groups selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy substituents; R ^2d are each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , methyl group or ethyl group, the methyl or ethyl group is optionally further selected from 0 to 4 groups selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 Substituted by alkyl or C _1-4 alkoxy substituent; R ³ is selected from H or substituted or unsubstituted one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy , ethoxy, propoxy, -N( _CH3 ) ₂ , -N( _CH2CH3 ) ₂ , -( _CH2 ) _q -cyclopropane, -( _CH2 ₎ _q -cyclobutane, -( _CH2 ) _q -cyclopentane, -( _CH2 ) _q -cyclohexane, -( _CH2 ) _q -azetidine, -( _CH2 ) _q -oxetane, -( _CH2 ) _q -tetrahydrothiophene, -( _CH2 ) _q -tetrahydrofuran, -( _CH2 ) _q -tetrahydropyrrole, -( _CH2 ) _q -phenyl, -( _CH2 ) _q -naphthyl, -(CH2) ₂ ) _q -pyridine, -( _CH2 ) _q -pyrimidine, -( _CH2 ) _q -pyrazine, -( _CH2 ) _q -thiophene, -( _CH2 ) _q -furan, -( _CH2 ) _q- Pyrrole, -( _CH2 ) _q -imidazole, -( _CH2 ) _q -imidazole, -( _CH2 ) _q -pyrazole, -( _CH2 ) _q -triazole, -( _CH2 ) _q -tetrazolium oxazole, -(CH ₂ ) _q -pyridine, -(CH ₂ ) _q -morpholine, -(CH ₂ ) _q -tetrahydropyran, -(CH ₂ ) _q -pyrrolidiidine, -(CH ₂ ) _q -1,3-oxazepane, -( _CH2 ) _q -2-oxa-5-azabicyclo[2.2.1]heptane, -( _CH2 ) _q -oxazine or -( CH ₂ ) _q -N(R ^3a )-C(=O)R ^3b , when substituted, optionally by 0 to 4 selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl, -C _1-4 alkylene-OH, -(CH ₂ ) _q -C _{3 -6} carbocycle, -(CH ₂ ) _q -3 to 6 membered heterocycle, C _3-6 cycloalkyl, C _1-4 alkoxy, -N(C _1-4 alkyl)C(=O) -3- to 12-membered heterocycle or 3- to 12-membered heterocycle substituents, the heterocycle contains 1 to 4 heteroatoms selected from O, S, N; R ^3a is selected from H, methyl, Ethyl, propyl or isopropyl, the methyl, ethyl, propyl or isopropyl is optionally further selected from 0 to 4 groups selected from H, F, Cl, Br, I, cyano, OH, Substituted by CF ₃ , C _1-4 alkyl or C _1-4 alkoxy substituent; R ^3b is selected from H, methyl, ethyl, propyl, isopropyl, azetidine or oxetane Butane, the methyl, ethyl, propyl, isopropyl, azetidine or oxetane is optionally further selected from 0 to 4 H, F, Cl, Br, I, substituted by cyano, OH, CF ₃ , C _1-4 alkyl or C _1-4 alkoxy substituent; R ⁴ are each independently selected from H, F, Cl, Br, I, oxo, OH, cyano , CF ₃ or methyl; q is selected from 0, 1, 2, 3 or 4.

The compound as claimed in claim 7 or a stereoisomer, deuterated product or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from

Ring A is selected from one of the following groups, substituted or unsubstituted:

or

When substituted, optionally 0 to 4 selected from H, F, Cl, Br, I, oxo, cyano, OH, _CF3 , methyl, ethyl, propyl, isopropyl or _CH2CN Replaced by the substituent of ; Ring B is selected from pyridine; Or

selected from

R ^2a is selected from H or substituted or unsubstituted one of the following groups: -C(=O)NH ₂ , -NHC(=O)H, -C(=O)NH-CH ₃ , -NHC ( =O)-CH ₃ , -C(=O)NH-CH ₂ CH ₃ , -NHC(=O)CH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O) N(CH ₂ CH ₃ ) ₂ , -C(=O)-CH ₃ , -C(=O)-CH ₂ CH ₃ , -C(=O)-CH ₂ CH ₂ CH ₃ , -C(=O )-CH(CH ₃ ) ₂ , -C(=O)NH-phenyl, -NHC(=O)-phenyl, -C(=O)-phenyl, -C(=O)-pyridine, - C(=O)-thiophene, -C(=O)-furan, -C(=O)-pyrrole, methyl, ethyl, isopropyl, propyl, phenyl, naphthyl, thienyl, furyl , pyrrolyl or pyridyl, when substituted, optionally by 0 to 4 selected from H, F, Cl, Br, I, OH, cyano, _CF3 , -C(=O) _NH2 , -NHC (=O)H, -C(=O)NH- _CH3 , -NHC(=O) _-CH3 , -C(=O)NH _- _CH2CH3 , -NHC( ₌ O) _CH2CH3 , -C(=O)N(CH ₃ ) ₂ , -C(=O)N(CH ₂ CH ₃ ) ₂ , -C(=O)NH-phenyl, -NHC(=O)-phenyl, Substituents of methyl or ethyl; R ^2b are each independently selected from H, F, oxo, OH, cyano, CF ₃ , methyl or ethyl, and the methyl or ethyl is optionally 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , methyl or ethyl; R ^2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , -C(=O)NH ₂ , -NHC(=O)H, -C(=O)NH-CH ₃ , -NHC(=O)-CH ₃ , -C(=O)NH-CH ₂ CH ₃ , -NHC(=O)CH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)N(CH ₂ CH ₃ ) ₂ , -C(=O)NH-phenyl, -NHC(=O)-phenyl, methyl, ethyl, methoxy or ethoxy, the methyl, ethyl, methoxy group, ethoxy or phenyl is optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, _CF3 , COOH, _NH2 , methyl or ethyl Substituted; R ^2d is each independently selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , methyl or ethyl optionally further 0 to 4 choice Substituted from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , methyl or ethyl substituent; R ³ is selected from H or substituted or unsubstituted following groups One of: methyl, ethyl, -(CH ₂ ) _q -tetrahydropyrrole, -(CH ₂ ) _q -azetidine, -N(CH ₃ ) ₂ or -N(CH ₂ CH ₃ ) ₂ , when substituted, optionally by 0 to 4 selected from H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl) , -N(C _1-4 alkyl) ₂ , C _1-4 alkyl, -C _1-4 alkylene-OH, -(CH ₂ )qC _3-6 carbocycle, -(CH ₂ )q- 3- to 6-membered heterocycle, C _3-6 cycloalkyl or C _1-4 alkoxy, said heterocycle contains 1 to 4 heteroatoms selected from O, S, N.

The compound as claimed in claim 8, or a stereoisomer, deuterated product or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from

n is selected from zero.

The compound as claimed in claim 9, or a stereoisomer, deuterated compound or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from

or

X ₃ -R ³ is selected from

n is selected from zero.

The compound as claimed in claim 8 or a stereoisomer, deuterated product or a pharmaceutically acceptable salt thereof, wherein,

selected from

selected from

R ^2c is each independently selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , methyl, ethyl, methoxy or ethoxy, said methyl, ethyl, methoxy or ethoxy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, cyano, _CF3 , COOH, _NH2 , methyl or ethyl; n is selected from 0; m2 is selected from 0, 1, 2 or 3.

The compound of claim 11 or a stereoisomer, deuterated compound or pharmaceutically acceptable salt thereof, wherein Ring A is selected from

n is selected from zero.

The compound of claim 12 or a stereoisomer, deuterated compound or pharmaceutically acceptable salt thereof, wherein Ring A is selected from

or

X ₃ -R ³ is selected from

The compound according to claim 2 or a stereoisomer, deuterated compound or a pharmaceutically acceptable salt thereof, the compound is selected from the compounds represented by the general formula (Ia-1) or (Ib-1),

G _1- G ₂ is selected from -CH ₂ CH ₂ -, -CH=CH-, -C(=O)-NH-, -C(=O)-N(CH ₃ )-, -N(CH ₃ ) -C(=O)- or -NH-C(=O)-; R ^2a is selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _{6 -10} aryl or 5 to 10 membered heteroaryl, the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further selected from 0 to 4 groups of H, F, Cl, Br, I, oxo, OH, cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C _6-10 aryl or 5- to 10-membered heteroaryl substituents Substituted, the heterocycloalkyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S, N; R ^2c is independently selected from H, F, Cl, Br, I, OH, cyano , CF ₃ , C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3- to 8-membered heterocycloalkyl, C _6-10 -membered aryl or 5- to 10-membered heteroaryl , the alkyl group, alkoxy group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group are optionally further selected from 0 to 4 groups selected from H, F, Cl, Br, I, oxo, OH, Cyano, CF ₃ , COOH, NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkynyl, C ₁ Substituents for _-6 alkoxy, hydroxy-substituted C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C _6-10 aryl or 5- to 10-membered heteroaryl substituted, the heterocycloalkyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S, N; m2 is selected from 0, 1, 2 or 3.

The compound as claimed in claim 14 or its stereoisomer, deuterated product or pharmaceutically acceptable salt, R ¹ is selected from

R ^2a is selected from H or substituted or unsubstituted one of the following groups: methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, phenyl, naphthyl, thienyl, furan group, pyrrolyl or pyridyl, when substituted, optionally by 0 to 4 selected from H, F, Cl, Br, I, OH, cyano, _CF3 , _NH2 , methyl, ethyl, methyl Substituents of oxy, ethoxy, cyclopropyl, cyclobutyl or phenyl; R ^2c are each independently selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , methyl , ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl, said methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl are optionally further 4 substituents selected from H, F, Cl, Br, I, OH, cyano, CF ₃ , COOH, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy substituents; Ring A is selected from

or

X ₃ -R ³ is selected from

n is selected from zero.

The compound according to claim 15 or a stereoisomer, deuterated compound or a pharmaceutically acceptable salt thereof, the compound is selected from the compounds represented by the general formulae (Ic-1) and (Ic-2),

The compound as claimed in claim 1 or a stereoisomer, deuterated product or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

.

A pharmaceutical composition comprising the compound according to any one of claim 1 to claim 17, or a stereoisomer, deuterated substance or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

A compound as described in any one of claim 1 to claim 17 or the application of its stereoisomer, deuterated substance or pharmaceutically acceptable salt, for preparation and treatment of diseases related to KRAS G12C activity or expression level Drug.

The use according to claim 19, wherein the disease is selected from a tumor.

The use according to claim 20, wherein the tumor is selected from hematological cancer, pancreatic cancer, MYH-related polyposis, colorectal cancer, non-small cell lung cancer or small cell lung cancer.