TW202214557A - 18f-labeled biphenyl compound, its intermediate, preparation method, pharmaceutical composition and application - Google Patents

Abstract

The invention relates to a 18F-labeled biphenyl compound, it's intermediate, preparatiom method, pharmaceutical composition and application. The biphenyl compound of the invention has obvious inhibitory effect on PD-1 and/or PD-L1. It may alleviate or treat cancer and other related diseases effectively. Moreover, it may be used in PET tumor imaging technology.

Description

18F-labeled biphenyl compound, its intermediate, preparation method, pharmaceutical composition and application

The present invention claims the priority of Chinese patent application 2020107872853 with an application date of August 7, 2020 and 2021108598282 with an application date of July 28, 2021. The present invention cites the full text of the above Chinese patent application.

The present invention relates to an ¹⁸ F-labeled biphenyl compound, an intermediate thereof, a preparation method, a pharmaceutical composition and an application thereof.

PD-1 (programmed death 1) programmed death receptor 1 is an important immunosuppressive molecule. It is a member of the CD28 superfamily and was originally replicated from the apoptotic mouse T-cell hybridoma 2B4.11. Immunomodulation targeting PD-1 is of great significance in anti-tumor, anti-infection, anti-autoimmune diseases and organ transplantation survival. Its ligand PD-L1 can also be used as a target, and the corresponding antibody can also play the same role.

PD-1/PD-L1 plays a negative immunoregulatory role. When PD-1 on the cell surface is coupled to PD-L1, it can lead to Tyr phosphorylation of the immunoreceptor Tyrosine-based Swith motifs (ITSM) domain in the cytoplasmic region of T cells, and then Phosphorylated Tyr recruits the phosphatases protein tyrosinase 2 and protein tyrosinase 1, which not only block the activation of extracellular signal-regulated kinases, but also block phosphatidylinositol 3-kinase (PI3K) and Activation of serine-threonine protein kinase (Akt) ultimately inhibits T lymphocyte proliferation and the secretion of related cytokines. PD-1/PD-L1 signaling inhibits T cell activation and proliferation, and at the same time, decreases the secretion of cytokines interleukin 2 (IL2), interferon gamma and IL-10 (Eur. J. Immunol., 2002 , 32(3), 634-643.). In addition, PD-1/PD-L1 signaling is also similar to T cells in the immune function of B cells. When PD-1 and B cell antigen receptors are cross-linked, the cytoplasmic region of PD-1 binds to protein tyrosinase 2 The tyrosinase at the site acts to ultimately block the activation of B cells. The role of immunonegative regulator PD-1/PD-L1 in tumor immune escape has attracted more and more attention. A large number of studies have confirmed that PD-L1 on the surface of tumor cells in the tumor microenvironment is increased, and at the same time, it binds to PD-1 on activated T cells to transmit negative regulatory signals, resulting in tumor antigen-specific T cells apoptosis or immune incompetence. This inhibits the immune response, which in turn promotes the escape of tumor cells.

Currently available PD-1/PD-L1 antibody inhibitors include BMS's Nivolumab (2014), Merck's Lambrolizumab (2014) and Roche's Atezolizumab (2016). The PD-1/PD-L1 antibody inhibitors under development include Cure Tech's Pidilizumab, GSK's AMP-224 and AstraZeneca's MEDI-4736. All of the above are biological macromolecules, while small-molecule PD-1/PD-L1 inhibitors are still in the early stage of research and development. WO2015044900) has just entered clinical phase I, small molecule PD-1/PD-L1 inhibitors of BMS benzyl phenyl ethers (WO2015034820, WO2015160641, WO2017066227, WO2018009505, WO2018044963, WO2018118848) are still in preclinical research stage, and Incyte is also doing preclinical research.了一系列的小分子PD-1/PD-L1抑制劑(WO2017070089, WO2017087777, WO2017106634, WO2017112730, WO2017192961, WO2017205464, WO2017222976, WO2018013789, WO2018044783, WO2018119221, WO2018119224, WO2018119263, WO2018219266, WO2018119286)還處在臨床前研究. Compared with biological macromolecules, small molecule compounds can cross the cell membrane and act on intracellular targets, so they have a wide range of applications. Secondly, chemically modified small molecules often have good bioavailability and compliance, effectively avoiding the decomposition and inactivation of enzymes in the digestive tract. Finally, the research on small molecules is also quite mature at various levels such as production process, dosage form design and delivery method.

At present, ¹⁸ F-labeled biphenyl compounds have not been successfully marketed as small-molecule PD-1/PD-L1 inhibitors in the prior art, and can be used in PET tumor imaging technology reports, and this situation needs to be resolved urgently.

The purpose of the present invention is to provide a ¹⁸ F-labeled biphenyl compound, its intermediate, preparation method, pharmaceutical composition and application which are completely different from the prior art. The ¹⁸ F-labeled biphenyl compound of the present invention has obvious inhibitory effect on PD-1 and/or PD-L1, and can effectively alleviate or treat related diseases such as cancer.

其中， 環A和環B獨立地為芳環或雜芳環； L ¹為化學鍵、炔基、-C(R ⁵)=C(R ⁶)-或-CR ⁷R ⁸-CR ⁹R ¹⁰-、取代或未取代的環烷基、取代或未取代的雜環烷基、取代或未取代的芳基或取代或未取代的雜芳基； L ²為化學鍵、炔基、-C(R ⁵)=C(R ⁶)-或-CR ⁷R ⁸-CR ⁹R ¹⁰-、取代或未取代的環烷基、取代或未取代的雜環烷基、取代或未取代的芳基、取代或未取代的雜芳基或不存在； R ⁵、R ⁶、R ⁷、R ⁸、R ⁹和R ¹⁰分別獨立地為氫、氘、 ¹⁸F、F、Cl、Br、I、氰基、或取代或未取代的烷基； R ¹和R ²獨立地為H、氘、 ¹⁸F、F、Cl、Br、I、氰基或取代或未取代的烷基； 每個R ³和每個R ⁴獨立地為氫、氘、羥基、-SR ¹¹、-NR ¹²R ¹³、 ¹⁸F、F、Cl、Br、I、氰基、取代或未取代的烷基、取代或未取代的烷氧基、-CONH ₂、-COR ¹⁴、-COOR ¹⁵或-OCOR ¹⁶； R ¹¹、R ¹²和R ¹³獨立地為氫、C ₁-C ₄烷基、取代的C ₁-C ₄烷基或-COR ^a，R ^a為氫、羥基、C ₁-C ₄烷基或C ₁-C ₄烷氧基； R ¹⁴、R ¹⁵和R ¹⁶獨立地為氫、C ₁-C ₄烷基或取代的C ₁-C ₄烷基； R ¹¹、R ¹²、R ¹³、R ¹⁴、R ¹⁵和R ¹⁶中，所述取代的C ₁-C ₄烷基中的取代是指被C ₆-C ₁₄芳基、取代的C ₆-C ₁₄芳基、C ₁-C ₁₀雜芳基和取代的C ₁-C ₁₀雜芳基中的一個或多個取代； L ¹和L ²中所述的取代的環烷基、所述的取代的雜環烷基、所述的取代的芳基、所述的取代的雜芳基、R ¹和R ²中所述的取代的烷基、每個R ³和每個R ⁴中所述的取代的烷基或所述的取代的烷氧基中的取代基選自 ¹⁸F、F、Cl、Br、I、氰基、C ₁-C ₄烷基、羥基、

、C ₆-C ₁₄芳基、取代的C ₆-C ₁₄芳基、C ₁-C ₁₀雜芳基、取代的C ₁-C ₁₀雜芳基、C ₁-C ₄烷氧基、C ₁-C ₄羧基、C ₁-C ₄酯基和C ₁-C ₄醯胺基中的一個或多個；

中，R ¹⁷和R ¹⁸獨立地為氫、取代或未取代的C ₁-C ₄烷基、取代或未取代的C ₆-C ₁₄芳基、取代或未取代的C ₃-C ₆環烷基、或取代或未取代的C ₁-C ₄烷氧基；或者R ¹⁷、R ¹⁸和與它們相連接的氮原子一起形成一個取代或未取代的5-7元碳雜環；所述碳雜環中，雜原子為N，或N和O，雜原子數為1-4個；每個R ¹⁷和每個R ¹⁸相同或不同； R ¹⁷和R ¹⁸中所述的取代的C ₁-C ₄烷基、所述的取代的C ₆-C ₁₄芳基、所述的取代的C ₃-C ₆環烷基、所述取代的C ₁-C ₄烷氧基和所述的取代的5-7元碳雜環中的取代基選自 ¹⁸F、F、Cl、Br、I、氰基、C ₁-C ₄烷基、取代的C ₁-C ₄烷基、C ₆-C ₁₄芳基、取代的C ₆-C ₁₄芳基、C ₁-C ₁₀雜芳基、取代的C ₁-C ₁₀雜芳基、羥基、

、C ₁-C ₄烷氧基、C ₁-C ₄羧基、C ₁-C ₄酯基和C ₁-C ₄醯胺基中的一個或多個； R ¹⁷和R ¹⁸中，當所述的取代的C ₁-C ₄烷基、所述的取代的C ₆-C ₁₄芳基、所述的取代的C ₃-C ₆環烷基、所述取代的C ₁-C ₄烷氧基和所述的取代的5-7元碳雜環中的取代基為取代的C ₁-C ₄烷基時，取代基中，所述的取代的C ₁-C ₄烷基中的取代基選自 ¹⁸F、F、Cl、Br、I、氰基、C ₁-C ₄烷基、C ₆-C ₁₄芳基、取代的C ₆-C ₁₄芳基、C ₁-C ₁₀雜芳基、取代的C ₁-C ₁₀雜芳基、羥基、

、C ₁-C ₄烷氧基、C ₁-C ₄羧基、C ₁-C ₄酯基和C ₁-C ₄醯胺基中的一個或多個；

中，R ^a1和R ^b1獨立地為氫、C ₁-C ₄的烷基或

，R ^a11為C ₁-C ₄的烷基； 上述所有C ₁-C ₁₀雜芳基是指雜原子選自N、O和S，雜原子數為1-4個的C ₁-C ₁₀雜芳基； 上述所有取代的C ₆-C ₁₄芳基和取代的C ₁-C ₁₀雜芳基中的取代基選自氰基、 ¹⁸F、F、Cl、Br、I、羥基、C ₁-C ₄烷基和C ₁-C ₄烷氧基中的一個或多個； 當取代基為多個時，所述的取代基相同或不同； m和ma獨立地為1、2、3或4； n和na獨立地為1、2、3或4； 條件是：至少一個R ¹、R ²、L ¹、L ²、R ³和R ⁴中含有一個或多個（例如1、2、3、4、5、6、7、8、9和10個） ¹⁸F； 或者

不存在。 The present invention provides a ¹⁸ F-labeled biphenyl compound represented by general formula I, a pharmaceutically acceptable salt, tautomer, meso, racemate, stereoisomer or prodrug thereof body:

Wherein, Ring A and Ring B are independently aromatic rings or heteroaromatic rings; L ¹ is a chemical bond, alkynyl, -C(R ⁵ )=C(R ⁶ )- or -CR ⁷ R ⁸ -CR ⁹ R ¹⁰ - , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; L ² is a chemical bond, alkynyl, -C(R ⁵ )=C(R ⁶ )- or -CR ⁷ R ⁸ -CR ⁹ R ¹⁰ -, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted Unsubstituted heteroaryl or absent; R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently hydrogen, deuterium, ¹⁸ F, F, Cl, Br, I, cyano, or substituted or unsubstituted alkyl ^; R and R are independently H, ^{deuterium, 18 F} , F, Cl, Br, I, cyano, or substituted or unsubstituted alkyl; each ^R and each R ⁴ is independently hydrogen, deuterium, hydroxyl, -SR ¹¹ , -NR ¹² R ¹³ , ¹⁸ F, F, Cl, Br, I, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy , -CONH ₂ , -COR ¹⁴ , -COOR ¹⁵ or -OCOR ¹⁶ ; R ¹¹ , R ¹² and R ¹³ are independently hydrogen, C ₁ -C ₄ alkyl, substituted C ₁ -C ₄ alkyl or -COR ^a , R ^a is hydrogen, hydroxyl, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; R ¹⁴ , R ¹⁵ and R ¹⁶ are independently hydrogen, C ₁ -C ₄ alkyl or substituted C ₁ -C ₄ alkyl; in R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ , the substitution in the substituted C ₁ -C ₄ alkyl refers to the substitution of C ₆ -C ₁₄ aryl , substituted C ₆ -C ₁₄ aryl, C ₁ -C ₁₀ heteroaryl and substituted C ₁ -C ₁₀ heteroaryl substituted one or more; the substituted rings described in L ¹ and L ² Alkyl, said substituted heterocycloalkyl, said substituted aryl, said substituted ^heteroaryl , said substituted alkyl as described in ^R1 and R2, each ^R3 and each The substituents in the substituted alkyl group described in each R ⁴ or the substituted alkoxy group are selected from ¹⁸ F, F, Cl, Br, I, cyano, C ₁ -C ₄ alkyl, hydroxyl,

, C ₆ -C ₁₄ aryl, substituted C ₆ -C ₁₄ aryl, C ₁ -C ₁₀ heteroaryl, substituted C ₁ -C ₁₀ heteroaryl, C ₁ -C ₄ alkoxy, C ₁ One or more of -C ₄ carboxyl group, C ₁ -C ₄ ester group and C ₁ -C ₄ amido group;

wherein R ¹⁷ and R ¹⁸ are independently hydrogen, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₆ -C ₁₄ aryl, substituted or unsubstituted C ₃ -C ₆ cycloalkane or substituted or unsubstituted C ₁ -C ₄ alkoxy; or R ¹⁷ , R ¹⁸ and the nitrogen atom to which they are attached together form a substituted or unsubstituted 5-7 membered carbon heterocycle; the carbon In the heterocyclic ring, the heteroatom is N, or N and O, and the number of heteroatoms is 1-4; each R ¹⁷ and each R ¹⁸ are the same or different; the substituted C ₁ - described in R ¹⁷ and R ¹⁸ C ₄ alkyl, said substituted C ₆ -C ₁₄ aryl, said substituted C ₃ -C ₆ cycloalkyl, said substituted C ₁ -C ₄ alkoxy and said substituted Substituents in the 5-7 membered carboheterocycle are selected from ¹⁸ F, F, Cl, Br, I, cyano, C ₁ -C ₄ alkyl, substituted C ₁ -C ₄ alkyl, C ₆ -C ₁₄ Aryl, substituted C ₆ -C ₁₄ aryl, C ₁ -C ₁₀ heteroaryl, substituted C ₁ -C ₁₀ heteroaryl, hydroxy,

, one or more of C ₁ -C ₄ alkoxy group, C ₁ -C ₄ carboxyl group, C ₁ -C ₄ ester group and C ₁ -C ₄ amido group; in R ¹⁷ and R ¹⁸ , when said The substituted C ₁ -C ₄ alkyl group, the substituted C ₆ -C ₁₄ aryl group, the substituted C ₃ -C ₆ cycloalkyl group, the substituted C ₁ -C ₄ alkoxy group When the substituent in the substituted 5-7-membered carbon heterocycle is a substituted C ₁ -C ₄ alkyl group, in the substituent group, the substituent in the substituted C ₁ -C ₄ alkyl group is selected from: From ¹⁸ F, F, Cl, Br, I, cyano, C ₁ -C ₄ alkyl, C ₆ -C ₁₄ aryl, substituted C ₆ -C ₁₄ aryl, C ₁ -C ₁₀ heteroaryl, Substituted C ₁ -C ₁₀ heteroaryl, hydroxy,

, one or more of C ₁ -C ₄ alkoxy group, C ₁ -C ₄ carboxyl group, C ₁ -C ₄ ester group and C ₁ -C ₄ amido group;

, R ^a1 and R ^b1 are independently hydrogen, C ₁ -C ₄ alkyl or

, R ^a11 is a C ₁ -C ₄ alkyl group; all the above C ₁ -C ₁₀ heteroaryl groups refer to C ₁ -C ₁₀ heteroatoms selected from N, O and S, and the number of hetero atoms is 1-4 Aryl; Substituents in all substituted C ₆ -C ₁₄ aryl groups and substituted C ₁ -C ₁₀ heteroaryl groups above are selected from cyano, ¹⁸ F, F, Cl, Br, I, hydroxyl, C ₁ - One or more of C ₄ alkyl and C ₁ -C ₄ alkoxy; When there are multiple substituents, the substituents are the same or different; m and ma are independently 1, 2, 3 or 4 ; n and na are independently 1, 2, 3 or 4; provided that at least one of R ¹ , R ² , L ¹ , L ² , R ³ and R ⁴ contains one or more (eg 1, 2, 3 , 4, 5, 6, 7, 8, 9 and 10) ¹⁸ F; or

does not exist.

存在； 各字母和基團定義均同前所述。 In a preferred embodiment, the ¹⁸ F-labeled biphenyl compound represented by the general formula I, its pharmaceutically acceptable salt, tautomer, meso, racemate, stereoisomer compound or prodrug: wherein, R ¹ and R ² are independently deuterium, ¹⁸ F, F, Cl, Br, I, cyano or substituted or unsubstituted alkyl;

Exist; each letter and group definition are the same as before.

其中，R ²為H；

不存在。 In a preferred embodiment, the ¹⁸ F-labeled biphenyl compound represented by the general formula I, its pharmaceutically acceptable salt, tautomer, meso, racemate, stereoisomer Substances or prodrugs:

Wherein, R ² is H;

does not exist.

In the present invention, all terms aromatic ring refer to any stable monocyclic or bicyclic carbocyclic ring of up to 7 atoms in each ring, at least one of which is aromatic. All terms aromatic rings are preferably _C6 - _C20 aromatic rings, more preferably _C6 - _C14 aromatic rings, most preferably _C6 - _C10 aromatic rings. Examples of aromatic rings include, but are not limited to, benzene, naphthalene, tetrahydronaphthalene, 2,3-indene, biphenyl, phenanthrene, anthracene, or acenaphthene.

In the present invention, all terms heteroaromatic ring refer to stable monocyclic or bicyclic rings of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains 1-4 atoms selected from O, N, and S heteroatoms. In the present invention, "heteroaromatic ring" preferably refers to a C ₁ -C ₁₀ heteroaromatic ring with heteroatoms selected from O, N and S, and the number of heteroatoms is 1, 2, 3 or 4. More preferably, heteroatoms are selected from _C1 -C8 heteroaromatic ring selected from O, N and S, the number of heteroatoms is 1, ₂ , 3 or 4, more preferably the heteroatom is selected from O, N and S, the number of heteroatoms is 1, 2, 3 or 4 _C1 - _C6 heteroaromatic rings. Examples of heteroaromatic rings include, but are not limited to: acridine, oxazole, cinnoline, oxoline, quinoline, imidazole, pyrazole, pyrrole, indole, indoline, benzotriazole, benzimidazole, furan, thiophene, isothiazole, benzothiophene, dihydrobenzothiophene, benzofuran, isobenzofuran, benzoxazole, benzofurazan, benzopyrazole, quinoline, isoazindene, iso Quinoline, oxazole, oxadiazole, isoxazole, indole, pyrazine, pyridopyridine, tetrazolopyridine, pyridazine, pyridine, naphthyridine, pyrimidine, pyrrole, tetrazole, thiadiazole, thiazole, Thiophene, triazole, quinazoline, tetrahydroquinoline, dihydrobenzimidazole, dihydrobenzofuran, dihydrobenzoxazole and dihydroquinoline.

In the present invention, all terms cycloalkyl are preferably C3 _{- C20} cycloalkyl, more preferably C3 _{- C10} cycloalkyl, most preferably C3 _{- C6} cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecane and cyclododecyl, and cyclohexenyl.

In the present invention, all terms heterocycloalkyl refer to a C2 _{- C10} non-aromatic ring with heteroatoms selected from O, N and S and 1, 2, 3 or 4 heteroatoms. In the present invention, the heteroatom of the heterocycloalkyl group is preferably selected from O, N and S, the heterocycloalkyl group of C ₂ -C ₈ having 1, 2, 3 or 4 heteroatoms, more preferably, the heteroatom is selected from O , N and S, a C ₂ -C ₆ heterocycloalkyl having 1, 2, 3 or 4 heteroatoms. Examples of heterocycloalkyl include, but are not limited to: tetrahydropyranyl, azetidinyl, 1,4-dioxanyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, sulfur morpholinyl, dihydrofuranyl, dihydroimidazolyl, indoline, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyridine Azinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydro Thienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzyl, tetrahydrofuranyl, tetrahydrothienyl and N-oxides thereof.

In the present invention, all terms aryl are preferably _C6 - _C20 aryl, more preferably _C6 - _C14 aryl, most preferably _C6 - _C10 aryl. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, 2,3-indenyl, biphenyl, phenanthrenyl, anthracenyl, and acenaphthyl.

In the present invention, all terms of heteroaryl are preferably heteroatoms selected from O, N and S, _C1 - _C10 heteroaryls with 1, 2, 3 or 4 heteroatoms, more preferably heteroatoms are selected from O, N and S, C ₁ -C ₈ heteroaryl groups with 1, 2, 3 or 4 heteroatoms, more preferably the heteroatoms are selected from O, N and S, and the number of heteroatoms is 1, 2 , 3 or 4 C ₁ -C ₆ heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, halazole base, quinolinyl, cinnoline, furyl, imidazolyl, indoline, indolyl, indazolyl, isobenzofuranyl, isoazindenyl, isoquinolinyl, isothiazolyl , isoxazolyl, naphthyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxobutyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridine pyridyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxolinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thiophene base and triazolyl.

In the present invention, all terms alkyl include branched and straight chain saturated aliphatic hydrocarbon groups of 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl , 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and their various isomers. In the present invention, the alkyl group is preferably a C ₁ -C ₄ alkyl group, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

In the present invention, all terms alkoxy represent a cyclic or acyclic alkyl group having the stated number of carbon atoms attached through an oxygen bridge. Thus, alkoxy includes the above definitions of alkyl and cycloalkyl. In the present invention, the alkoxy group is preferably a C ₁ -C ₄ alkoxy group, more preferably a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group or a tert-butoxy group.

In the present invention, all terms of 5-7 membered carbon heterocycle refer to heteroatoms selected from O, N and S, the number of heteroatoms is 1, 2, 3 or 4, and the number of carbon atoms is 1, 2, 3, 4, 5 or 6 5-7 membered carbon heterocycles. The number of ring atoms in the 5-7 membered carbon heterocycle is 5, 6 or 7. In the present invention, the 5-7 membered carbon heterocycle includes but is not limited to: azetidinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydro Imidazolyl, Indoline, Dihydroisoxazolyl, Dihydroisothiazolyl, Dihydrooxadiazolyl, Dihydrooxazolyl, Dihydropyrazinyl, Dihydropyrazolyl, Dihydropyridine dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrotriazolyl and dihydroazetidinyl .

In a preferred embodiment, Ring A is a benzene ring.

In a preferred embodiment, Ring B is a benzene ring or a pyridine ring.

In a preferred embodiment, L ¹ is alkynyl, -C(R ⁵ )=C(R ⁶ )-, -CR ⁷ R ⁸ -CR ⁹ R ¹⁰ -, substituted or unsubstituted cycloalkyl, substituted or Unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, preferably alkynyl, -C(R ⁵ )=C(R ⁶ )- or -CR ⁷ R ⁸ - CR ⁹ R ¹⁰ -, more preferably -C(R ⁵ )=C(R ⁶ )-, most preferably -CH=CH-.

In a preferred embodiment, L ² is alkynyl, -C(R ⁵ )=C(R ⁶ )-, -CR ⁷ R ⁸ -CR ⁹ R ¹⁰ -, substituted or unsubstituted cycloalkyl, substituted or Unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, preferably alkynyl, -C(R ⁵ )=C(R ⁶ )- or -CR ⁷ R ⁸ - CR ⁹ R ¹⁰ -, more preferably -C(R ⁵ )=C(R ⁶ )-, most preferably -CH=CH-.

^In a preferred embodiment, L2 is absent.

In a preferred embodiment, R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently hydrogen or deuterium.

In ^a preferred embodiment, R1 is H.

In a preferred embodiment, R ¹ is ¹⁸ F, F, Cl, Br, I.

In a preferred embodiment, R ¹ is cyano.

In a preferred embodiment, R ¹ is alkyl, preferably C ₁ -C ₄ alkyl, more preferably methyl.

In ^a preferred embodiment, R1 is substituted alkyl. The substituents in the substituted alkyl group are preferably one or more of ¹⁸ F, F, Cl, Br, I and hydroxyl groups. R ¹ is preferably an alkyl group substituted with one or more of ¹⁸ F, F, Cl, Br, I. Said alkyl substituted by one or more of ¹⁸ F, F, Cl, Br, I is preferably a C ₁ -C ₄ alkane substituted by one or more of ¹⁸ F, F, Cl, Br and I group, more preferably -CH ₂ ¹⁸ F, -CH ¹⁸ F ₂ , -CH ¹⁸ FF, -C ¹⁸ F ₃ , -C ¹⁸ FF ₂ , -C ¹⁸ F ₂ F, -CH ₂ F, -CHF ₂ or - _CF3 .

In a preferred embodiment, R1 is located at the ⁵ ' position of the phenyl ring.

位於苯環的4’位。 In a preferred embodiment,

Located at the 4' position of the benzene ring.

^In a preferred embodiment, R2 is H.

In a preferred embodiment, R ² is deuterium.

In a preferred embodiment, R ² is ¹⁸ F, F, Cl, Br, I.

In a preferred embodiment, R ² is cyano.

In a preferred embodiment, R ² is alkyl, preferably C ₁ -C ₄ alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

In a preferred embodiment, R ² is substituted alkyl, preferably substituted C ₁ -C ₄ alkyl. The substituents in the substituted alkyl are preferably ¹⁸ F, F, Cl, Br, I, cyano, C ₁ -C ₄ alkyl, hydroxyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ One or more of the carboxyl group, the C ₁ -C ₄ ester group and the C ₁ -C ₄ amido group, when there are multiple substituents, the substituents are the same or different. The alkyl substituted by ¹⁸ F, F, Cl, Br, I is preferably a C ₁ -C ₄ alkyl substituted by one or more of ¹⁸ F, F, Cl, Br and I, more preferably -CH ₂ ¹⁸ F, -CH ¹⁸ F ₂ , -CH ¹⁸ FF, -C ¹⁸ F ₃ , -C ¹⁸ FF ₂ , -C ¹⁸ F ₂ F, -CH ₂ F, -CHF ₂ or -CF ₃ .

In a preferred embodiment, R2 is in the ¹ -position of the phenyl ring.

In a preferred embodiment, R ³ and R ⁴ are preferably independently deuterium, ¹⁸ F, F, Cl, Br, I, cyano, -SR ¹¹ , -NR ¹² R ¹³ , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.

In a preferred embodiment, R ³ and R ⁴ are preferably independently deuterium, ¹⁸ F, F, Cl, Br, I, cyano, -SR ¹¹ , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.

In a preferred embodiment, R ³ and R ⁴ are preferably -SR ¹¹ , and R ¹¹ is substituted C ₁ -C ₄ alkyl.

In a preferred embodiment, R ³ and R ⁴ are preferably ¹⁸ F, F, Cl, Br, I.

、C ₆-C ₁₄芳基、取代的C ₆-C ₁₄芳基、C ₁-C ₁₀雜芳基、取代的C ₁-C ₁₀雜芳基、C ₁-C ₄烷氧基和C ₁-C ₄羧基中的一個或多個取代。當取代基為多個時，所述的取代基相同或不同。 ^In a preferred embodiment, ^R3 and R4 are preferably substituted or unsubstituted alkyl groups. The substituents in the substituted alkyl are preferably ¹⁸ F, F, Cl, Br, I, cyano, hydroxyl,

, C ₆ -C ₁₄ aryl, substituted C ₆ -C ₁₄ aryl, C ₁ -C ₁₀ heteroaryl, substituted C ₁ -C ₁₀ heteroaryl, C ₁ -C ₄ alkoxy and C ₁ - One or more substitutions in the C ₄ carboxyl group. When there are multiple substituents, the substituents are the same or different.

、取代的C ₆-C ₁₄芳基和取代的C ₁-C ₁₀雜芳基中的一個或多個取代。當取代基為多個時，所述的取代基相同或不同。 ^In a preferred embodiment, ^R3 and R4 are preferably substituted alkyl groups. The substituents in the substituted alkyl are preferably ¹⁸ F, F, Cl, Br, I,

One or more of substituted C ₆ -C ₁₄ aryl and substituted C ₁ -C ₁₀ heteroaryl. When there are multiple substituents, the substituents are the same or different.

In a preferred embodiment, R ³ and R ⁴ are preferably alkyl substituted with ¹⁸ F, F, Cl, Br, I. The alkyl substituted by ¹⁸ F, F, Cl, Br, I is preferably a C ₁ -C ₄ alkyl substituted by one or more of ¹⁸ F, F, Cl, Br and I, preferably -C ¹⁸ F ₃ , -C ¹⁸ FF ₂ , -C ¹⁸ F ₂ F or -CF ₃ .

取代的烷基。所述的被

取代的烷基優選被

取代的C ₁-C ₄的烷基。所述的被

取代的C ₁-C ₄的烷基優選

或

，其中，R ¹⁷和R ¹⁸一個為H，另一個為被羥基和/或羧基取代的烷基。在一優選實施方式中，R ¹⁷和R ¹⁸一個為H，另一個為被C ₁-C ₄烷氧基、羥基和羧基中的一個或多個取代的烷基。 In a preferred embodiment, R ³ and R ⁴ are preferably

Substituted alkyl. said to be

Substituted alkyl groups are preferably

Substituted _C1 - _C4 alkyl. said to be

Substituted C ₁ -C ₄ alkyl groups are preferred

or

, wherein one of R ¹⁷ and R ¹⁸ is H, and the other is an alkyl group substituted by a hydroxyl group and/or a carboxyl group. In a preferred embodiment, one of R ¹⁷ and R ¹⁸ is H and the other is alkyl substituted with one or more of C ₁ -C ₄ alkoxy, hydroxy and carboxy.

取代的烷基。所述的被

取代的烷基優選被

取代的C ₁-C ₄的烷基。所述的被

取代的C ₁-C ₄的烷基優選

或

，其中，R ¹⁷、R ¹⁸和與它們相連接的氮原子一起形成一個取代的5-7元碳雜環；所述碳雜環中，雜原子為N，或N和O，雜原子數為1-4個。所述的5-7元碳雜環優選吡咯或哌啶。所述的取代的5-7元碳雜環中的取代基優選取代的C ₁-C ₄烷基、羥基、C ₁-C ₄羧基、C ₁-C ₄酯基和C ₁-C ₄醯胺基中的一個或多個。所述取代的C ₁-C ₄烷基中取代基優選羥基。 In a preferred embodiment, R ³ and R ⁴ are preferably

Substituted alkyl. said to be

Substituted alkyl groups are preferably

Substituted _C1 - _C4 alkyl. said to be

Substituted C ₁ -C ₄ alkyl groups are preferred

or

, wherein, R ¹⁷ , R ¹⁸ and the nitrogen atoms connected to them together form a substituted 5-7 membered carbon heterocycle; in the carbon heterocycle, the heteroatom is N, or N and O, and the number of heteroatoms is 1-4. The 5-7 membered carbon heterocycle is preferably pyrrole or piperidine. The substituents in the substituted 5-7-membered carbon heterocycle are preferably substituted C ₁ -C ₄ alkyl groups, hydroxyl groups, C ₁ -C ₄ carboxyl groups, C ₁ -C ₄ ester groups and C ₁ -C ₄ acyl groups one or more of the amine groups. The substituent in the substituted C ₁ -C ₄ alkyl group is preferably a hydroxyl group.

取代的烷基時，所述的被

取代的烷基優選

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、

或

。 In a preferred embodiment, when R ³ and R ⁴ are

substituted alkyl, the

Substituted alkyl preferred

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

.

。 In a preferred embodiment, R ³ or R ⁴ is preferably an alkyl substituted by a substituted C ₆ -C ₁₄ aryl group, more preferably

.

。 In a preferred embodiment, R ³ or R ⁴ is preferably an alkyl substituted with a substituted C ₁ -C ₁₀ heteroaryl group, more preferably

.

取代的烷基）時，R ³位於環A上與L ¹相連的原子的間位或對位。 In a preferred embodiment, when R ³ is substituted or unsubstituted alkyl (by

substituted alkyl), ^R3 is in the meta or para position to the atom on ring ^A to which L1 is attached.

取代的烷基）時，R ⁴位於環B上與L ²相連的原子的間位或對位。 In a preferred embodiment, when R ⁴ is substituted or unsubstituted alkyl (for example, by

substituted alkyl ⁾ , R4 is in the meta or para position to the atom ^on ring B to which L2 is attached.

取代的烷基）時，環A上還可有0、1或2個取代基。當還可有1個取代基時，該取代基位於取代或未取代的烷基（例如被

取代的烷基）的對位、間位或鄰位。 In a preferred embodiment, when R ³ is substituted or unsubstituted alkyl (for example, by

substituted alkyl), ring A may also have 0, 1 or 2 substituents. When there is also 1 substituent, the substituent is located in a substituted or unsubstituted alkyl group (for example, by

substituted alkyl) in the para, meta or ortho position.

取代的烷基）時，環B上還可有0、1或2個取代基。當還可有1個取代基時，該取代基位於取代或未取代的烷基（例如被

取代的烷基）的對位、間位或鄰位。 In a preferred embodiment, when R ⁴ is substituted or unsubstituted alkyl (for example, by

substituted alkyl), ring B may also have 0, 1 or 2 substituents. When there is also 1 substituent, the substituent is located in a substituted or unsubstituted alkyl group (for example, by

substituted alkyl) in the para, meta or ortho position.

、C ₆-C ₁₄芳基、取代的C ₆-C ₁₄芳基、C ₁-C ₁₀雜芳基和取代的C ₁-C ₁₀雜芳基中的一個或多個取代。當取代基為多個時，所述的取代基相同或不同。 ^In a preferred embodiment, ^R3 and R4 are substituted or unsubstituted alkoxy. The substituents in the substituted alkoxy are preferably ¹⁸ F, F, Cl, Br, I, cyano, hydroxyl,

One or more of , C ₆ -C ₁₄ aryl, substituted C ₆ -C ₁₄ aryl, C ₁ -C ₁₀ heteroaryl and substituted C ₁ -C ₁₀ heteroaryl. When there are multiple substituents, the substituents are the same or different.

、C ₆-C ₁₄芳基、取代的C ₆-C ₁₄芳基、C ₁-C ₁₀雜芳基、取代的C ₁-C ₁₀雜芳基和C ₁-C ₄烷氧基中的一個或多個取代。當取代基為多個時，所述的取代基相同或不同。 ^In a preferred embodiment, ^R3 and R4 are substituted or unsubstituted alkoxy. The substituents in the substituted alkoxy are preferably ¹⁸ F, F, Cl, Br, I, cyano, hydroxyl,

one of , C ₆ -C ₁₄ aryl, substituted C ₆ -C ₁₄ aryl, C ₁ -C ₁₀ heteroaryl, substituted C ₁ -C ₁₀ heteroaryl and C ₁ -C ₄ alkoxy or multiple substitutions. When there are multiple substituents, the substituents are the same or different.

或

。 In a preferred embodiment, R ³ and R ⁴ are substituted alkoxy groups, and the substituents in the substituted alkoxy groups are preferably C ₁ -C ₁₀ heteroaryl groups and substituted C ₁ -C ₁₀ heteroaryl groups. One or more substitutions in the aryl group, and when there are multiple substituents, the substituents are the same or different. The substituted alkoxy group is preferably

or

.

。 In a preferred embodiment, R ³ and R ⁴ are preferably substituted alkoxy groups, and the substituents in said substituted alkoxy groups are preferably substituted with C ₁ -C ₄ alkoxy groups. The substituted alkoxy group is preferably

.

In a preferred embodiment, when ^R3 is a substituted or unsubstituted alkoxy group, ^R3 is located in the ortho or meta position on the ring ^A to the atom to which L1 is attached.

^In a preferred embodiment, when R4 is a substituted or unsubstituted alkoxy group, R4 is located in the ortho or meta position ^on the ring B to the atom to which ^L2 is attached.

In a preferred embodiment, na and ma are one.

優選

，更優選

，其中，R ¹和R ²的定義均同前所述。 In a preferred embodiment, the group

preferred

, more preferably

, wherein, the definitions of R ¹ and R ² are the same as above.

優選

、

、

、

、

、

或

。 In a preferred embodiment, the group

preferred

,

,

,

,

,

or

.

和

獨立地為

和

，其中M ¹和N ¹為被

取代的烷基，或者M ¹和N ¹其中一個為被

取代的烷基，另一個為取代的烷氧基；其中M ¹和N ¹中，被

取代的烷基的定義和取代的烷氧基的定義，均同前R ³或R ⁴中相應的基團；R ¹⁷、R ¹⁸、R ³和R ⁴的定義均同前所述，n1和m1獨立地為0、1或2。 In a preferred embodiment,

and

independently for

and

, where M ¹ and N ¹ are the

substituted alkyl, or one of M ¹ and N ¹ is

Substituted alkyl, the other is substituted alkoxy; wherein M ¹ and N ¹ , by

^The definition of the substituted alkyl group and the definition of the substituted ^alkoxy group are the same as the corresponding groups in ^the previous R ³ or R ^{4 ;} m1 is independently 0, 1 or 2.

，或者M ¹和N ¹其中一個為

，另一個為被C ₁-C ₄烷氧基、C ₁-C ₁₀雜芳基和取代的C ₁-C ₁₀雜芳基中的一個或多個取代的烷氧基；R ³和R ⁴優選氫、 ¹⁸F、F、Cl、Br、I、烷基、被 ¹⁸F、F、Cl、Br、I取代的烷基、烷氧基或取代的烷氧基，所述的取代的烷氧基中的取代基優選被C ₁-C ₄烷氧基、C ₁-C ₁₀雜芳基和取代的C ₁-C ₁₀雜芳基中的一個或多個取代；R ¹⁷和R ¹⁸的定義均同前所述。 Preferably, M ¹ and N ¹ are

, or one of M ¹ and N ¹ is

, the other is alkoxy substituted by one or more of C ₁ -C ₄ alkoxy, C ₁ -C ₁₀ heteroaryl and substituted C ₁ -C ₁₀ heteroaryl; R ³ and R ⁴ Preferably hydrogen, ¹⁸ F, F, Cl, Br, I, alkyl, alkyl substituted by ¹⁸ F, F, Cl, Br, I, alkoxy or substituted alkoxy, said substituted alkoxy The substituents in the base are preferably substituted by one or more of C ₁ -C ₄ alkoxy, C ₁ -C ₁₀ heteroaryl and substituted C ₁ -C ₁₀ heteroaryl; definitions of R ¹⁷ and R ¹⁸ All the same as before.

，或者M ¹和N ¹其中一個為

，另一個為被C ₁-C ₄烷氧基取代的烷氧基；R ³和R ⁴優選 ¹⁸F、F、Cl、Br、I、烷基、被 ¹⁸F、F、Cl、Br、I取代的烷基、烷氧基或被C ₁-C ₄烷氧基取代的烷氧基；R ¹⁷和R ¹⁸的定義均同前所述。 More preferably, M ¹ and N ¹ are

, or one of M ¹ and N ¹ is

, and the other is alkoxy substituted by C ₁ -C ₄ alkoxy; R ³ and R ⁴ are preferably ¹⁸ F, F, Cl, Br, I, alkyl, ¹⁸ F, F, Cl, Br, I Substituted alkyl, alkoxy or alkoxy substituted by C ₁ -C ₄ alkoxy; R ¹⁷ and R ¹⁸ are as defined above.

優選

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、

或

，其中N ¹、R ¹⁷和R ¹⁸的定義均同前所述。 In a preferred embodiment,

preferred

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

, wherein N ¹ , R ¹⁷ and R ¹⁸ are defined as previously described.

優選

、

、

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、

、

、

、

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、

、

、

或

，其中M ¹、R ¹⁷和R ¹⁸的定義均同前所述。 In a preferred embodiment,

preferred

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

, wherein M ¹ , R ¹⁷ and R ¹⁸ are defined as previously described.

和

獨立地優選

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或

。 In a preferred embodiment,

and

independently preferred

,

,

,

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or

.

優選

、

、

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、

、

、

、

或

。 In a preferred embodiment,

preferred

,

,

,

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,

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,

or

.

優選

、

、

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、

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、

、

、

或

。 In a preferred embodiment,

preferred

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

.

和

獨立地優選

、

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、

或

。 In a preferred embodiment,

and

independently preferred

,

,

,

,

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,

or

.

In a preferred embodiment, L ¹ is alkynyl, -C(R ⁵ )=C(R ⁶ )- or -CR ⁷ R ⁸ -CR ⁹ R ¹⁰ -, L ² is alkynyl, -C(R ⁵ )=C(R ⁶ )-, -CR ⁷ R ⁸ -CR ⁹ R ¹⁰ - or absent, R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently hydrogen or deuterium, R ¹ is ¹⁸ F, F, Cl, Br, I, or substituted or unsubstituted alkyl, R ² is ¹⁸ F, F, Cl, Br, I, or substituted or unsubstituted alkyl, and R ³ and R ⁴ is independently deuterium, ¹⁸ F, F, Cl, Br, I, cyano, -SR ¹¹ , -NR ¹² R ¹³ , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.

、C ₆-C ₁₄芳基、取代的C ₆-C ₁₄芳基、C ₁-C ₁₀雜芳基、取代的C ₁-C ₁₀雜芳基、C ₁-C ₄烷氧基和C ₁-C ₄羧基中的一個或多個取代；所述的取代的烷氧基中的取代基為被 ¹⁸F、F、Cl、Br、I、氰基、羥基、

、C ₆-C ₁₄芳基、取代的C ₆-C ₁₄芳基、C ₁-C ₁₀雜芳基和取代的C ₁-C ₁₀雜芳基中的一個或多個取代；當取代基為多個時，所述的取代基相同或不同。 In a preferred embodiment, L ¹ is alkynyl, -C(R ⁵ )=C(R ⁶ )- or -CR ⁷ R ⁸ -CR ⁹ R ¹⁰ -, L ² is alkynyl, -C(R ⁵ )=C(R ⁶ )-, -CR ⁷ R ⁸ -CR ⁹ R ¹⁰ - or absent, R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently hydrogen or deuterium, R ¹ is ¹⁸ F, F, Cl, Br, I, or substituted or unsubstituted alkyl, R ² is ¹⁸ F, F, Cl, Br, I, or substituted or unsubstituted alkyl, and R ³ and R ⁴ is independently ¹⁸ F, F, Cl, Br, I, -SR ¹¹ , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; R ¹¹ is substituted C ₁ -C ₄ alkyl; The substituents in the substituted alkyl are ¹⁸ F, F, Cl, Br, I, cyano, hydroxyl,

, C ₆ -C ₁₄ aryl, substituted C ₆ -C ₁₄ aryl, C ₁ -C ₁₀ heteroaryl, substituted C ₁ -C ₁₀ heteroaryl, C ₁ -C ₄ alkoxy and C ₁ One or more substitutions in -C ₄ carboxyl groups; the substituents in the substituted alkoxy groups are replaced by ¹⁸ F, F, Cl, Br, I, cyano, hydroxyl,

One or more of , C ₆ -C ₁₄ aryl, substituted C ₆ -C ₁₄ aryl, C ₁ -C ₁₀ heteroaryl and substituted C ₁ -C ₁₀ heteroaryl; when the substituent is When there are more than one, the substituents are the same or different.

、取代的C ₆-C ₁₄芳基和取代的C ₁-C ₁₀雜芳基中的一個或多個取代；所述的取代的烷氧基中的取代基優選被C ₁-C ₄烷氧基、C ₁-C ₁₀雜芳基和取代的C ₁-C ₁₀雜芳基中的一個或多個取代；當取代基為多個時，所述的取代基相同或不同。 In a preferred embodiment, L ¹ is alkynyl, -C(R ⁵ )=C(R ⁶ )- or -CR ⁷ R ⁸ -CR ⁹ R ¹⁰ -, L ² is alkynyl, -C(R ⁵ )=C(R ⁶ )-, -CR ⁷ R ⁸ -CR ⁹ R ¹⁰ - or absent, R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently hydrogen or deuterium; R ¹ is ¹⁸ F, F, Cl, Br, I, substituted or unsubstituted alkyl; R ² is ¹⁸ F, F, Cl, Br, I or alkyl, R ³ and R ⁴ are independently ¹⁸ F, F , Cl, Br, I, -SR ¹¹ , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; R ¹¹ is substituted C ₁ -C ₄ alkyl; in the substituted alkyl The substituents are replaced by ¹⁸ F, F, Cl, Br, I,

One or more of substituted C ₆ -C ₁₄ aryl and substituted C ₁ -C ₁₀ heteroaryl groups; the substituents in the substituted alkoxy groups are preferably C ₁ -C ₄ alkoxy groups One or more of substituted C 1 -C 10 heteroaryl, C ₁ -C ₁₀ heteroaryl and substituted C ₁ -C ₁₀ heteroaryl; when there are multiple substituents, the substituents are the same or different.

、取代的C ₆-C ₁₄芳基和取代的C ₁-C ₁₀雜芳基中的一個或多個取代（進一步地R ³和R ⁴定義如下：(1)R ³和R ⁴優選-SR ¹¹，R ¹¹為取代的C ₁-C ₄烷基；(2)R ³和R ⁴優選被 ¹⁸F、F、Cl、Br、I中的一個或多個取代的烷基；所述的被 ¹⁸F、F、Cl、Br、I中的一個或多個取代的烷基優選被 ¹⁸F、F、Cl、Br和I中的一個或多個取代的C ₁-C ₄烷基，優選-C ¹⁸F ₃、-C ¹⁸FF ₂、-C ¹⁸F ₂F或-CF ₃；(3)R ³和R ⁴優選被

取代的烷基；所述的被

取代的烷基優選被

取代的C ₁-C ₄的烷基；所述的被

取代的C ₁-C ₄的烷基優選

或

，其中，R ¹⁷和R ¹⁸一個為H，另一個為被C ₁-C ₄烷氧基、羥基和羧基中的一個或多個取代的烷基；或者R ¹⁷、R ¹⁸和與它們相連接的氮原子一起形成一個取代的5-7元碳雜環；所述碳雜環中，雜原子為N，或N和O，雜原子數為1-4個；所述的5-7元碳雜環優選哌啶；所述的取代的5-7元碳雜環中的取代基優選C ₁-C ₄羧基（當R ³和R ⁴為被

取代的烷基時，所述的被

取代的烷基優選

、

、

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或

）；(4)R ³和R ⁴優選被取代的C ₆-C ₁₄芳基取代的烷基，更優選

；(5)R ³和R ⁴優選被取代的C ₁-C ₁₀雜芳基取代的烷基，更優選

；(6)R ³和R ⁴優選取代的烷氧基，所述的取代的烷氧基中的取代基優選被C ₁-C ₄烷氧基、C ₁-C ₁₀雜芳基和取代的C ₁-C ₁₀雜芳基中的一個或多個取代，所述的取代的烷氧基優選

、

或

。）。 In a preferred embodiment, L ¹ is -C(R ⁵ )=C(R ⁶ )- (preferably -CH=CH-), L ² is -C(R ⁵ )=C(R ⁶ )- or not present (preferably -CH=CH-), R ⁵ and R ⁶ are independently hydrogen or deuterium, R ¹ is ¹⁸ F, F, Cl, Br, I, alkyl (preferably C ₁ -C ₄ alkyl, more preferably methyl), or alkyl substituted by one or more of ¹⁸ F, F, Cl, Br, I, R ² is ¹⁸ F, F, Cl, Br, I or alkyl (preferably C ₁ -C ₄ alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl), R ³ and R ⁴ are independently ¹⁸ F, F, Cl, Br, I , -SR ¹¹ , a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkoxy group; R ¹¹ is a substituted C ₁ -C ₄ alkyl group; the substituents in the substituted alkyl group are preferably replaced by ¹⁸ F, F, Cl, Br, I,

, substituted C ₆ -C ₁₄ aryl and substituted C ₁ -C ₁₀ heteroaryl in one or more substitutions (further R ³ and R ⁴ are defined as follows: (1) R ³ and R ⁴ preferably -SR ¹¹ , R ¹¹ is substituted C ₁ -C ₄ alkyl; (2) R ³ and R ⁴ are preferably alkyl substituted by one or more of ¹⁸ F, F, Cl, Br, and I; One or more of ¹⁸ F, F, Cl, Br, I substituted alkyl preferably C ₁ -C ₄ alkyl substituted with one or more of ¹⁸ F, F, Cl, Br and I, preferably - C ¹⁸ F ₃ , -C ¹⁸ FF ₂ , -C ¹⁸ F ₂ F or -CF ₃ ; (3) R ³ and R ⁴ are preferably

Substituted alkyl; described by

Substituted alkyl groups are preferably

Substituted C ₁ -C ₄ alkyl;

Substituted C ₁ -C ₄ alkyl groups are preferred

or

, wherein, one of R ¹⁷ and R ¹⁸ is H, and the other is an alkyl group substituted by one or more of C ₁ -C ₄ alkoxy, hydroxyl and carboxyl; or R ¹⁷ , R ¹⁸ and their connection The nitrogen atoms form a substituted 5-7 membered carbon heterocycle; in the carbon heterocycle, the heteroatom is N, or N and O, and the number of heteroatoms is 1-4; the 5-7 membered carbon The heterocycle is preferably piperidine; the substituents in the substituted 5-7-membered carbon heterocycle are preferably C ₁ -C ₄ carboxyl (when R ³ and R ⁴ are

substituted alkyl, the

Substituted alkyl preferred

,

,

,

,

,

,

,

,

,

,

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,

or

); (4) R ³ and R ⁴ are preferably substituted C ₆ -C ₁₄ aryl substituted alkyl groups, more preferably

(5) R ³ and R ⁴ are preferably substituted C ₁ -C ₁₀ heteroaryl substituted alkyl groups, more preferably

(6) R ³ and R ⁴ are preferably substituted alkoxy groups, and the substituents in the substituted alkoxy groups are preferably C ₁ -C ₄ alkoxy groups, C ₁ -C ₁₀ heteroaryl groups and substituted One or more substitutions in the C ₁ -C ₁₀ heteroaryl group, the substituted alkoxy group is preferably

,

or

. ).

不存在； R ³獨立地為氘、 ¹⁸F、F、Cl、Br、I、氰基、-SR ¹¹、-NR ¹²R ¹³、取代或未取代的烷基、或取代或未取代的烷氧基（優選被

取代的烷基；所述的被

取代的烷基優選被

取代的C ₁-C ₄的烷基；所述的被

取代的C ₁-C ₄的烷基優選

或

，其中，R ¹⁷和R ¹⁸一個為H，另一個為被C ₁-C ₄烷氧基、羥基和羧基中的一個或多個取代的烷基；或者R ¹⁷、R ¹⁸和與它們相連接的氮原子一起形成一個取代的5-7元碳雜環；所述碳雜環中，雜原子為N，或N和O，雜原子數為1-4個；所述的5-7元碳雜環優選哌啶；所述的取代的5-7元碳雜環中的取代基優選C ₁-C ₄羧基）。 In a preferred embodiment, R ¹ is ¹⁸ F, F, Cl, Br, I, alkyl (preferably C ₁ -C ₄ alkyl, more preferably methyl), or by ¹⁸ F, F, Cl, Br, One or more substituted alkyl groups of I (preferably C ₁ -C ₄ alkyl substituted with one or more of ¹⁸ F, F, Cl, Br, I, eg -CH ₂ ¹⁸ F); R ² is H; L ¹ is -C(R ⁵ )=C(R ⁶ )- (preferably -CH=CH-);

Absent; R ³ is independently deuterium, ¹⁸ F, F, Cl, Br, I, cyano, -SR ¹¹ , -NR ¹² R ¹³ , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy base (preferably

Substituted alkyl; described by

Substituted alkyl groups are preferably

Substituted C ₁ -C ₄ alkyl;

Substituted C ₁ -C ₄ alkyl groups are preferred

or

, wherein, one of R ¹⁷ and R ¹⁸ is H, and the other is an alkyl group substituted by one or more of C ₁ -C ₄ alkoxy, hydroxyl and carboxyl; or R ¹⁷ , R ¹⁸ and their connection The nitrogen atoms form a substituted 5-7 membered carbon heterocycle; in the carbon heterocycle, the heteroatom is N, or N and O, and the number of heteroatoms is 1-4; the 5-7 membered carbon The heterocycle is preferably piperidine; the substituents in the substituted 5-7-membered carbon heterocycle are preferably C ₁ -C ₄ carboxyl).

和

。 The ¹⁸ F-labeled biphenyl compound represented by the general formula I described in the present invention is preferably selected from any of the following compounds:

and

.

或

其中，環A、環B、L ¹、L ²、R ¹、R ²、R ³、R ⁴、M ¹、N ¹、R ¹⁷、R ¹⁸、na和ma的定義均同前所述，n1為0、1或2，m1為0、1或2。 In a preferred embodiment, the ¹⁸ F-labeled biphenyl compound represented by the general formula I is preferably the ¹⁸ F-labeled biphenyl compound represented by the general formula IA or II:

or

Wherein, the definitions of ring A, ring B, L ¹ , L ² , R ¹ , R ² , R ³ , R ⁴ , M ¹ , N ¹ , R ¹⁷ , R ¹⁸ , na and ma are the same as above, and n1 is 0, 1 or 2, and m1 is 0, 1 or 2.

或

其中，環A、環B、L ¹、L ²、R ¹、R ²、R ³、R ⁴、M ¹、N ¹、R ¹⁷和R ¹⁸的定義均同前所述，n1為0、1或2，m1為0、1或2。 In a preferred embodiment, the ¹⁸ F-labeled biphenyl compound represented by the general formula I is preferably the ¹⁸ F-labeled biphenyl compound represented by the general formula I-A1 or II-1:

or

Wherein, the definitions of ring A, ring B, L ¹ , L ² , R ¹ , R ² , R ³ , R ⁴ , M ¹ , N ¹ , R ¹⁷ and R ¹⁸ are the same as above, and n1 is 0, 1 or 2, m1 is 0, 1 or 2.

和環B中的

可相同或也可不同。 In the present invention, in the ¹⁸ F-labeled biphenyl compound represented by the general formula II, the

and in ring B

Can be the same or can be different.

In the present invention, the preparation method of the ¹⁸ F-labeled biphenyl compound represented by the general formula I can be prepared by conventional methods in the art, such as step-by-step synthesis method, addition method, substitution method, isotope exchange method, etc. .

The step-by-step synthesis method generally uses simple radioisotope-containing compounds to synthesize complex compounds of the present invention step by step according to a predetermined synthetic route.

The addition method generally uses a compound with a double bond or a triple bond as a precursor, and combines a radioisotope or a simple compound thereof to the precursor through an addition reaction to synthesize the compound of the present invention. The present invention also provides a method for preparing the ¹⁸ F-labeled biphenyl compounds represented by the general formula IA or II. In the compound represented by the general formula IA, when M ¹ and N ¹ contain -NH- or In the case of -COOH, it is prepared by the following method: the method comprises the following steps: subjecting the compound represented by the general formula II-F to the deprotection reaction shown below to obtain the ¹⁸ F-labeled compound represented by the general formula IA biphenyl compounds,

wherein Ring A, Ring B, L ¹ , L ² , R ¹ , R ² , R ³ , R ⁴ , M ¹ , N ¹ , na and ma are as defined above, and n1 is 0, 1 or 2, m1 is 0, 1 or 2, R ^IIF is a group corresponding to M ¹ containing an amine group or a carboxyl protecting group, and R ^IIF1 is the same as N ¹ ; or, R ^IIF is the same as M ¹ , and R ^IIF1 is ^a group corresponding to N An amino or carboxyl protecting group; or R ^IIF is a group corresponding to M ¹ containing an amine or carboxyl protecting group, and R ^IIF1 is ^a N corresponding group containing an amine or carboxyl protecting group; general formula II The preparation method of the shown ¹⁸ F-labeled biphenyl compounds adopts any of the following methods:

其中化合物II-A1結構如下：

或其酸式鹽，環A、環B、L ¹、L ²、R ¹、R ²、R ³、R ⁴、R ¹⁷、R ¹⁸、na和ma的定義均同前所述，n1為0、1或2，m1為0、1或2；在此方法中，環A和環B中的

相同； (1) Method 1 includes the following steps: the compound represented by the general formula II-A and the compound II-A1 are subjected to the following reaction to obtain the ¹⁸ F-labeled biphenyl compound represented by the general formula II ,

The structure of compound II-A1 is as follows:

or its acid salt, ring A, ring B, L ¹ , L ² , R ¹ , R ² , R ³ , R ⁴ , R ¹⁷ , R ¹⁸ , na and ma are as defined above, and n1 is 0 , 1 or 2, m1 is 0, 1 or 2; in this method, the

same;

其中化合物II-B1結構如下：

或其酸式鹽，環A、環B、L ¹、L ²、R ¹、R ²、R ³、R ⁴、R ¹⁷、R ¹⁸、na和ma的定義均同前所述，n1為0、1或2，m1為0、1或2，M為鹵素；在此方法中，環A和環B中的

相同； (2) Method 2 includes the following steps: performing the following reaction with the compound represented by the general formula II-B and the compound II-B1 to obtain the ¹⁸ F-labeled biphenyl compound represented by the general formula II ,

The structure of compound II-B1 is as follows:

or its acid salt, ring A, ring B, L ¹ , L ² , R ¹ , R ² , R ³ , R ⁴ , R ¹⁷ , R ¹⁸ , na and ma are as defined above, and n1 is 0 , 1 or 2, m1 is 0, 1 or 2, M is halogen; in this method, the

same;

其中化合物II-C1結構如下：

或其酸式鹽，環A、環B、L ¹、L ²、R ¹、R ²、R ³、R ⁴、R ¹⁷、R ¹⁸、na和ma的定義均同前所述，n1為0、1或2，m1為0、1或2；R ^IIC和R ^IIC1其中一個為

，另一個為

，在此方法中，環A和環B中的

相同或不同； (3) Method 3 includes the following steps: the compound represented by the general formula II-C and the compound II-C1 are subjected to the following reaction to obtain the ¹⁸ F-labeled biphenyl compound represented by the general formula II ,

The structure of compound II-C1 is as follows:

or its acid salt, ring A, ring B, L ¹ , L ² , R ¹ , R ² , R ³ , R ⁴ , R ¹⁷ , R ¹⁸ , na and ma are as defined above, and n1 is 0 , 1 or 2, m1 is 0, 1 or 2; one of R ^IIC and R ^IIC1 is

, the other is

, in this method, in ring A and ring B

same or different;

其中化合物II-D1結構如下：

或其酸式鹽，環A、環B、L ¹、L ²、R ¹、R ²、R ³、R ⁴、R ¹⁷、R ¹⁸、na和ma的定義均同前所述，n1為0、1或2，m1為0、1或2，R ^IID和R ^IID1其中一個為

，另一個為鹵素，在此方法中，環A和環B中的

相同或不同； (4) Method 4 includes the following steps: the compound represented by the general formula II-D and the compound II-D1 are subjected to the following reaction to obtain the ¹⁸ F-labeled biphenyl compound represented by the general formula II ,

The structure of compound II-D1 is as follows:

or its acid salt, ring A, ring B, L ¹ , L ² , R ¹ , R ² , R ³ , R ⁴ , R ¹⁷ , R ¹⁸ , na and ma are as defined above, and n1 is 0 , 1 or 2, m1 is 0, 1 or 2, one of R ^IID and R ^IID1 is

, the other is halogen, in this method, the ring A and ring B

same or different;

其中環A、環B、L ¹、L ²、R ¹、R ²、R ³、R ⁴、R ¹⁷、R ¹⁸、na和ma的定義均同前所述，n1為0、1或2，m1為0、1或2，R ^IIE和R ^IIE1為

，每個R ^17’和每個R ^18’相同或不同，且至少有一個有羧基保護基，不含羧基保護基的R ^17’和R ^18’分別與通式II中對應的R ¹⁷和R ¹⁸相同；此方法中，環A和環B中的

相同或不同。 (5) Method 5 includes the following steps: subjecting the compound represented by the general formula II-E to a deprotection reaction as shown below to obtain the ¹⁸ F-labeled biphenyl compound represented by the general formula II, the general formula II In the compound shown, R ¹⁷ or R ¹⁸ contains a carboxyl group;

wherein Ring A, Ring B, L ¹ , L ² , R ¹ , R ² , R ³ , R ⁴ , R ¹⁷ , R ¹⁸ , na and ma are as defined above, and n1 is 0, 1 or 2, m1 is 0, 1, or 2, and R ^IIE and R ^IIE1 are

, each R ^17' and each R ^18' are the same or different, and at least one has a carboxyl protecting group, and R ^17' and R ^18' without a carboxyl protecting group are respectively the same as the corresponding R ¹⁷ and R in the general formula II ¹⁸ is the same; in this method, in ring A and ring B

same or different.

。 In a preferred embodiment, the compounds of the present invention are synthesized as follows

.

The present invention also provides compounds represented by general formula II-A, II-B, II-C, II-D, II-E and II-F:

，另一個為

，R ^IID和R ^IID1其中一個為

，另一個為鹵素，R ^IIE和R ^IIE1為

，每個R ^17’和每個R ^18’相同或不同，且至少有一個有羧基保護基，不含羧基保護基的R ^17’和R ^18’分別與通式II中對應的R ¹⁷和R ¹⁸相同；R ^IIF為M ¹對應的含有胺基或羧基保護基的基團，R ^IIF1與N ¹相同；或者，R ^IIF和M ¹相同，R ^IIF1為N ¹對應的含有胺基或羧基保護基的基團；或者R ^IIF為M ¹對應的含有胺基或羧基保護基的基團，R ^IIF1為N ¹對應的含有胺基或羧基保護基的基團。 Ring A, ring B, L ¹ , L ² , R ¹ , R ² , R ³ , R ⁴ , M ¹ , N ¹ , R ¹⁷ , R ¹⁸ , na and ma are as defined above, and n1 is 0 , 1 or 2, m1 is 0, 1 or 2; M is halogen, one of R ^IIC and R ^IIC1 is

, the other is

, one of R ^IID and R ^IID1 is

, the other is halogen, R ^IIE and R ^IIE1 are

, each R ^17' and each R ^18' are the same or different, and at least one has a carboxyl protecting group, and R ^17' and R ^18' without a carboxyl protecting group are respectively the same as the corresponding R ¹⁷ and R in the general formula II ¹⁸ is the same; R ^IIF is a group corresponding to M ¹ containing an amino or carboxyl protecting group, and R ^IIF1 is the same as N ¹ ; or, R ^IIF is the same as M ¹ , and R ^IIF1 is a corresponding N ¹ containing an amino or carboxyl protecting group or R ^IIF is a group corresponding to M ¹ containing an amine group or a carboxyl protecting group, and R ^IIF1 is a group corresponding to N ¹ containing an amine group or a carboxyl protecting group.

The present invention provides a method for preparing a ¹⁸ F-labeled biphenyl compound represented by general formula IA, which comprises the following steps: subjecting compound II-F to the following deprotection reaction;

Wherein, the definitions of ring A, ring B, L ¹ , L ² , R ¹ , R ² , R ³ , R ⁴ , M ¹ , N ¹ , na and ma are the same as those described above, and in M ¹ and N ¹ Contains at least one of -NH-, -OH and -COOH, n1 is 0, 1 or 2, m1 is 0, 1 or 2,

R ^IIF , R ^IIF1 , M ¹ and N ¹ satisfy any of the following conditions:

(1) R ^IIF is a group corresponding to M ¹ containing at least one of an amine protecting group, a hydroxyl protecting group and a carboxyl protecting group, and R ^IIF 1 is the same as N ¹ ;

(2) R ^IIF and M ¹ are identical, and R ^IIF 1 is a group corresponding to N ¹ containing at least one of an amine protecting group, a hydroxyl protecting group and a carboxyl protecting group;

(3) R ^IIF is a group corresponding to M ¹ containing at least ^one of amino protecting group, hydroxyl protecting group and carboxyl protecting group, and R ^IIF1 is N corresponding containing amino protecting group, hydroxyl protecting group and carboxyl protecting at least one of the groups.

In a preferred embodiment, in the ¹⁸ F-labeled biphenyl compound represented by the general formula IA, R ^IIF , R ^IIF1 , M ¹ and N ¹ satisfy the following conditions: R ^IIF is a corresponding amine group protected by M ¹ group of amine group and hydroxyl protecting group, R ^IIF1 is the group corresponding to N ¹ containing amine protecting group and hydroxyl protecting group.

In a preferred embodiment, in the ¹⁸ F-labeled biphenyl compound represented by the general formula IA, ring A and ring B are independently benzene rings; L ₁ and L ₂ are independently -C(R ⁵ )= C(R ⁶ )-, such as -CH=CH-; R ³ and R ⁴ are substituted or unsubstituted alkyl groups, and the definitions of the substituents in the substituted alkyl groups are as described above. R ³ and R ⁴ are preferably alkyl substituted with ¹⁸ F, F, Cl, Br, I. The alkyl substituted by ¹⁸ F, F, Cl, Br, I is preferably a C ₁ -C ₄ alkyl substituted by one or more of ¹⁸ F, F, Cl, Br and I, preferably -C ¹⁸ F ₃ , -C ¹⁸ FF ₂ , -C ¹⁸ F ₂ F or -CF ₃ .

。 In a preferred embodiment, in the ¹⁸ F-labeled biphenyl compound represented by the general formula IA, M ¹ and N ¹ contain at least one of -NH- and -OH, for example, M ¹ and N ¹ Contains -NH- and -OH, and for example,

.

In a preferred embodiment, in the ¹⁸ F-labeled biphenyl compound represented by the general formula IA, R ¹ is ¹⁸ F, F, Cl, Br, I, alkyl (preferably C ₁ -C ₄ alkyl, More preferably methyl), or alkyl substituted with one or more ^of18F , F, Cl, Br, I. Said alkyl substituted by one or more of ¹⁸ F, F, Cl, Br, I is preferably a C ₁ -C ₄ alkane substituted by one or more of ¹⁸ F, F, Cl, Br and I group, more preferably -CH ₂ ¹⁸ F, -CH ¹⁸ F ₂ , -CH ¹⁸ FF, -C ¹⁸ F ₃ , -C ¹⁸ FF ₂ , -C ¹⁸ F ₂ F, -CH ₂ F, -CHF ₂ or - _CF3 .

In a preferred embodiment, in the ¹⁸ F-labeled biphenyl compound represented by the general formula IA, R ² is ¹⁸ F, F, Cl, Br, I or an alkyl group (preferably a C ₁ -C ₄ alkyl group, More preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl).

In a preferred version, in the ¹⁸ F-labeled biphenyl compound shown in the general formula IA, when R ^IIF and R ^IIF1 have a hydroxyl protecting group, the hydroxyl protecting group can be a conventional hydroxyl protecting group in the art. radicals such as bis(p-methoxyphenyl)phenylmethyl (-DMTr), tetramethylsilane (-TMS), tert-butyldiphenylsilyl (-TBDPS) or triisopropylsilyl (-TIPS) , another example - DMTr.

In a preferred version, in the ¹⁸ F-labeled biphenyl compound shown in the general formula IA, when R ^IIF and R ^IIF1 have an amine protecting group, the amine protecting group can be conventional in the art. Amine protecting groups, such as di-tert-butyl methyl dicarbonate (-Boc ₂ O), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), or trimethylsilylethoxycarbonyl (Teoc), such as -Boc ₂ O.

In a preferred version, in the ¹⁸ F-labeled biphenyl compounds shown in the general formula IA, when R ^IIF and R ^IIF1 have a carboxyl protecting group, the carboxyl protecting group can be a conventional carboxyl protecting group in this area. base.

The preparation method of the ¹⁸ F-labeled biphenyl compound represented by the general formula IA may further comprise the following steps: in a solvent, under the action of a deprotection reagent, the compound II-F is subjected to a deprotection reaction .

The deprotection reagent can be a conventional acid in the art. The acid may be a mineral acid, such as hydrochloric acid. The amount of the deprotection reagent is not particularly limited, as long as the protecting group to be removed can be removed.

The deprotection reagent can participate in the reaction in the form of a mixed solution with an organic solvent, such as a mixed solution of an acid and an alcohol solvent, or a mixed solution of an acid and an ether solvent, such as hydrochloric acid-methanol solution, hydrochloric acid-ethyl acetate solution. Or hydrochloric acid-1,4-dioxane solution. When the deprotection reagent participates in the reaction in the form of a solution, the concentration of the deprotection reagent may be 1.5-2.5M, for example, 2M.

In the deprotection reaction, the solvent can be an alcohol solvent, an ether solvent or a mixture thereof, such as methanol, 1,4-dioxane or a mixture thereof, and another example is methanol.

The temperature of the deprotection reaction can be a conventional temperature for this type of reaction in the art, for example, 50-70°C (eg, 60°C).

The progress of the deprotection reaction can be monitored by conventional detection methods in the art, such as TLC, HPLC, GC or NMR.

The post-processing steps of the deprotection reaction can be conventional post-processing steps of this type of reaction in the art, such as: HPLC.

其中，化合物II-F和化合物II-F2中，各字母和基團的定義同前所述，且R ¹和R ²至少有一個為鹵素取代的烷基，優選 ¹⁸F取代的烷基；R ¹¹和R ¹²至少有一個為烷基-R ^L，R ^L為能被鹵素取代的基團。 The preparation method of the ¹⁸ F-labeled biphenyl compound represented by the general formula IA may further include the following steps: in a solvent, the compound II-F2 is subjected to a substitution reaction with a halogenated reagent to obtain the compound II -F;

Wherein, in compound II-F and compound II-F2, the definition of each letter and group is the same as above, and at least one of R ¹ and R ² is a halogen-substituted alkyl group, preferably ¹⁸ F-substituted alkyl group; R At least one of ¹¹ and R ¹² is an alkyl group-R ^L , and R ^L is a group which can be substituted by halogen.

In a preferred embodiment, at least one of said R ¹¹ and R ¹² can be alkyl-OTs, alkyl-OMs or alkyl-OTf, such as TsO-alkyl. Therefore, in one embodiment of the present invention, ^RL can be -OTs or -OMs.

In a preferred embodiment, R ¹ is an alkyl group substituted by one or more of ¹⁸ F, F, Cl, Br, and I, at this time R ¹¹ is an alkyl group-R ^L , and R ^L can be substituted by halogen. group.

In a preferred embodiment, R ² is alkyl (preferably C ₁ -C ₄ alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl), In this case, R ² and R ¹² are the same.

In the substitution reaction, the halogenated reagent can be a conventional halogenated reagent in the art, such as KX, wherein X is ¹⁸ F, F, Cl, Br or I; another example is K ¹⁸ F.

In the substitution reaction, when the halogenated reagent is a halogenated reagent containing ¹⁸ F, the halogenated reagent can be enriched by KF and fluorine [ ¹⁸ F] ion water through an anion exchange column (QMA) .

In the described substitution reaction, when using QMA to enrich the halogenated reagent, the QMA column was rinsed with TBAHCO ₃ .

In the substitution reaction, the molar ratio of the halogenated reagent to the compound II-F can be above 1:1, for example, 1:1-10:1.

In the substitution reaction, the organic solvent may be a chlorinated hydrocarbon solvent, a nitrile solvent, an ether solvent, an amide solvent or a mixture thereof, such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, DMF or A mixture thereof, for example acetonitrile.

In the substitution reaction, the temperature of the substitution reaction may be a conventional temperature for this type of reaction in the art, for example, 50-70° C. (eg, 60° C.).

In the substitution reaction, the time for the substitution reaction is based on the complete reaction of the above reactants, for example, 1 to 4 hours.

The progress of the substitution reaction can be monitored by detection methods conventional in the art, such as TLC, HPLC, GC or NMR.

其中，化合物II-F2、I-A中，各字母、基團的定義同前所述。所述的取代反應和所述的脫保護反應的條件同前所述。 In one embodiment, the preparation method of the compound of general formula IA may include the following steps: subjecting compound II-F2 to the substitution reaction, and then to the deprotection reaction;

Among them, in compounds II-F2 and IA, the definitions of each letter and group are the same as those described above. The conditions for the substitution reaction and the deprotection reaction are the same as described above.

化合物II-F3和化合物II-F2中，各字母和基團的定義同前所述，且R ¹¹和R ¹²至少有一個為烷基-R ^L，R ^L為能被鹵素取代的基團；R ^11a和R ^12a分別與R ¹¹和R ¹²對應，條件是R ¹¹和R ¹²中的R ^L替換為可結合R ^L的基團，例如-OH。 The preparation method of the ¹⁸ F-labeled biphenyl compound represented by the general formula IA may further include the following steps: in a solvent, the compound II-F3 is subjected to the following substitution reaction with a reagent containing R ^L to obtain The compound II-F2;

In compound II-F3 and compound II-F2, the definition of each letter and group is the same as above, and at least one of R ¹¹ and R ¹² is alkyl-R ^L , and R ^L is a group that can be substituted by halogen; R ^11a and R ^12a correspond to R ¹¹ and R ¹² , respectively, with the proviso that ^RL in R ¹¹ and R ¹² is replaced by a group that can bind to ^RL , such as -OH.

In the preparation method of compound II-F2, the ^RL -containing reagent can be Ts ₂ O, Ts ₂ N, Ms ₂ O or Tf ₂ O, such as Ts ₂ O.

In the preparation method of compound II-F2, the organic solvent can be a chlorinated hydrocarbon solvent, a nitrile solvent, an ether solvent, an amide solvent or a mixture thereof, such as a chlorinated hydrocarbon solvent. Further, the organic solvent can be dichloromethane, chloroform, acetonitrile, tetrahydrofuran, DMF or a mixture thereof, such as dichloromethane.

In the preparation method of compound II-F2, the amount of the organic solvent may not be specifically limited, as long as it does not affect the reaction. In the preparation method of compound II-F2, the molar ratio of the ^RL -containing reagent to the compound II-F3 can be above 1:1, for example, 1:1-10:1.

In the preparation method of compound II-F2, the temperature of the substitution reaction may be -10 to 10°C, for example, 0°C.

In the preparation method of compound II-F2, the progress of the substitution reaction can be monitored by a conventional detection method in the art, such as TLC, HPLC, GC or NMR.

化合物II-F4和化合物II-F3中，各字母和基團的定義同前所述，R ^11a和R ^12a的定義同前所述，R ^11b和R ^12b分別與R ^11a和R ^12a對應，條件是R ^11a和R ^12a中可結合R ^L的基團替換為可被還原試劑還原為可結合R ^L的基團。 The preparation method of the ¹⁸ F-labeled biphenyl compound represented by the general formula IA may further include the following steps: in a solvent, the compound II-F4 is subjected to the reduction reaction shown below with a reducing reagent to obtain the Compound II-F3;

In compound II-F4 and compound II-F3, the definitions of letters and groups are the same as those described above, the definitions of R ^11a and R ^12a are the same as those described above, and R ^11b and R ^12b correspond to R ^11a and R ^12a , respectively. It is R ^11a and R ^12a that the group that can bind to ^RL is replaced by a group that can be reduced by a reducing agent to a group that can bind to ^RL .

In the reduction reaction, the reducing agent can be a conventional reducing agent in the art, such as sodium borohydride.

In the reduction reaction, the organic solvent may be a chlorinated hydrocarbon solvent, a nitrile solvent, an ether solvent, an alcohol solvent, an amide solvent or a mixture thereof, such as a chlorinated hydrocarbon solvent. The organic solvent can also be dichloromethane, chloroform, acetonitrile, tetrahydrofuran, ethanol, DMF or a mixture thereof, such as dichloromethane.

In the reduction reaction, the volume-to-mass ratio of the organic solvent to the compound II-F4 can be a conventional volume-to-mass ratio of this type of reaction in the art, for example, 40-50 mL/g.

In the reduction reaction, the molar ratio of the reducing agent to the compound II-F4 may be a conventional molar ratio of this type of reaction in the art, for example, 6:1 to 8:1.

In the reduction reaction, the temperature of the reduction reaction may be a conventional temperature for this type of reaction in the art, for example, -10-10°C.

The progress of the reduction reaction can be monitored by detection methods conventional in the art, such as TLC, HPLC, GC or NMR.

或

其中各字母和基團的定義均同前所述。 The present invention also provides compound II-F2, II-F3 or II-F4:

or

The definitions of the letters and groups are the same as those described above.

The present invention also provides the compounds shown below:

The ¹⁸ F-labeled biphenyl compounds represented by the general formula I of the present invention have an IC ₅₀ value for PD-1/PD-L1 binding basically below 10 μM, for example, below 5 μM, and most compounds are below 1 μM, Some of the preferred compounds are below 0.5 μM, some particularly preferred compounds are below 0.01 μM, and some of the most preferred compounds are below 0.005 μM.

In the present invention, the method for measuring the IC ₅₀ value of the ¹⁸ F-labeled biphenyl compound represented by the general formula I of the present invention for binding to PD-1/PD-L1 can be a conventional method in the art.

The present invention also provides the ¹⁸ F-labeled biphenyl compounds represented by the general formula I, pharmaceutically acceptable salts, tautomers, mesomers, racemates and stereoisomers thereof Or the application of prodrug in the preparation of PD-1 inhibitor and/or PD-L1 inhibitor.

The present invention also provides the ¹⁸ F-labeled biphenyl compounds represented by the general formula I, pharmaceutically acceptable salts, tautomers, mesomers, racemates and stereoisomers thereof Use of one or more of , metabolites, metabolic precursors and prodrugs in the preparation of a medicament for preventing, alleviating or treating cancer, infection, autoimmune disease or related diseases.

The cancer is preferably one or more of lung cancer, esophageal cancer, gastric cancer, colorectal cancer, liver cancer, nasopharyngeal cancer, brain tumor, breast cancer, cervical cancer, blood cancer and bone cancer.

The present invention also provides a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of the ¹⁸ F-labeled biphenyl compound represented by general formula I, its pharmaceutically acceptable salts, and tautomers , meso, racemate, stereoisomer, metabolite, metabolic precursor or prodrug, and a pharmaceutically acceptable carrier and/or diluent.

The compounds of the present invention are injected into animals (such as mammals, which can be mice, dogs, pigs or humans), and can have an annihilation effect in the process of participating in human metabolism, generating 2 energies emitted substantially in the 180° direction with a value of 0.511 MeV gamma-ray photons that move opposite to each other. The compounds of the present invention can accumulate in tumor sites in animals, so they can be applied to PET tumor imaging technology. For example, the compounds of the present invention 1) can be used for the diagnosis of tumors (such as malignant tumors), the identification of benign tumor lesions and the exploration of systemic metastases; 2) the staging and restaging of tumors; 3) the identification of postoperative recurrence and scarring of tumors; 4) Identification of recurrence and radiation necrosis after radiotherapy; 5) Efficacy detection of tumor treatment (radiotherapy, chemotherapy, etc.); and 6) Search for primary tumor and metastases.

Therefore, the present invention also provides the ¹⁸ F-labeled biphenyl compounds represented by the general formula I, their pharmaceutically acceptable salts, tautomers, mesoforms, racemates, stereoisomers The application of one or more of the structure, metabolite, metabolic precursor and prodrug in PET tumor imaging technology.

In the present invention, tumor and cancer have the same definition, for example, tumor is preferably one or more of lung cancer, esophagus cancer, gastric cancer, colorectal cancer, liver cancer, nasopharyngeal cancer, brain tumor, breast cancer, cervical cancer, blood cancer and bone cancer.

In the present invention, according to the purpose of treatment, the pharmaceutical composition can be made into various types of administration unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions) liquid), etc., preferably liquid, suspension, emulsion, suppository and injection (solution and suspension) and the like.

In order to shape the pharmaceutical composition in tablet form, any of the excipients known and widely used in the art can be used. For example, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, etc.; binders such as water, ethanol, propanol, common syrup, glucose solution, starch solution , gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.; disintegrating agents, such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, Calcium carbonate, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceryl stearate, starch and lactose, etc.; disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil and Hydrogenated oils; adsorption accelerators, such as quaternary ammonium bases and sodium lauryl sulfate, etc.; wetting agents, such as glycerol, starch, etc.; adsorbents, such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, etc.; and lubricants , such as pure talc, stearate, boric acid powder and polyethylene glycol. The usual coating materials can also be used to make sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-layered film tablets and multi-layered tablets as required.

In order to shape the pharmaceutical composition in pill form, any excipient known and widely used in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oils, kaolin and talc, etc.; binders, Such as gum arabic powder, tragacanth powder, gelatin and ethanol, etc.; disintegrating agents, such as agar and kelp powder.

To shape the pharmaceutical composition in the form of a suppository, any excipient known and widely used in the art can be used, for example, polyethylene glycols, coconut oil, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides Wait.

In order to prepare the pharmaceutical composition in the form of injection, the solution or suspension can be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerol, etc.) to prepare an injection of isotonic pressure with blood. In the preparation of injections, any carrier commonly used in the art can also be used. Examples include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol and fatty acid esters of polyethylene sorbitan, and the like. In addition, usual solubilizers, buffers, pain relievers and the like may be added.

In the pharmaceutical composition, the diluent can be a conventional diluent in the art.

The pharmaceutical composition can be in the form of oral administration or in the form of sterile injectable aqueous solution, and the oral or injectable composition can be prepared according to any method known in the art for preparing pharmaceutical compositions.

Unless otherwise specified, all the following terms appearing in the description of the present invention and the scope of claims have the following meanings:

All terms cycloalkyl (including when used alone and when included in other groups) include saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including Monocycloalkyl, bicycloalkyl and tricycloalkyl.

All terms alkoxy represent a cyclic or acyclic alkyl group having the stated number of carbon atoms attached through an oxygen bridge. Thus, alkoxy includes the above definitions of alkyl and cycloalkyl.

All terms alkenyl refer to straight chain, branched chain or cyclic non-aromatic hydrocarbon groups containing the specified number of carbon atoms and at least one carbon-carbon double bond. Preferably one carbon-carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present. The alkenyl group is preferably a C _2-12 alkenyl group, more preferably a C _2-6 alkenyl group. Thus, _C2-12 alkenyl refers to an alkenyl group having 2-12 carbon atoms. C _2-6 alkenyl refers to alkenyl groups having 2 to 6 carbon atoms, including vinyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The straight, branched or cyclic portion of the alkenyl group may contain double bonds and, if indicated as a substituted alkenyl group, may be substituted.

All terms alkynyl refer to straight chain, branched chain or cyclic hydrocarbon groups containing the specified number of carbon atoms and at least one carbon-carbon triple bond. There may be up to three carbon-carbon triple bonds in it. The alkynyl group is preferably a C _2-12 alkynyl group, more preferably a C _2-6 alkynyl group. Thus, C2-12alkynyl refers to an alkynyl group having _2-12 carbon atoms. C _2-6 alkynyl refers to an alkynyl group having 2-6 carbon atoms, including ethynyl, propynyl, butynyl, 3-methylbutynyl, and the like.

。 All terms hydroxyl represent

.

。 All terms amine represent

.

All terms cyano represent -CN.

、

、

、

、

、

或

。 All terms carboxyl refer to -COOH, wherein _C1 - _C4 carboxyl refers to -( _CH2 )nCOOH and _n is 0, 1, 2 or 3. All terms C ₁ -C ₄ carboxyl are preferred

,

,

,

,

,

or

.

All terms ester refer to -COO-, wherein C ₁ -C ₄ ester refers to -COOR ^x and R ^x is C ₁ -C ₄ alkyl.

All terms ^amido mean " ^-CONRx1Rx2 " or " ^-NRx3CORx4 ", where ^Rx1 , ^Rx2 , ^Rx3 and ^{Rx4 are} independently H or _C1 - _C4 alkyl.

All terms heteroaromatic ring should also be understood to include the N-oxide derivative of any nitrogen-containing heteroaromatic ring. In the case where the heteroaryl substituent is a bicyclic substituent and one ring is non-aromatic or does not contain a heteroatom, it is understood that the attachment is through the aromatic ring or through the heteroatom containing the ring, respectively.

All terms therapeutically effective amount refer to an amount of a compound that, when administered to a subject, is sufficient to effectively treat the disease or disorder described herein. While the amount of compound that constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the subject to be treated, it can be determined in a routine manner by one of ordinary skill in the art to which this invention pertains.

When referring to specific salts, pharmaceutical compositions, compositions, excipients, etc. as "pharmaceutically acceptable", it means that the salts, pharmaceutical compositions, compositions, excipients, etc. are generally non-toxic, safe, and suitable for use by subjects , preferably mammalian subjects, more preferably human subjects.

All terms pharmaceutically acceptable salts refer to pharmaceutically acceptable organic or inorganic salts of the compounds of the present invention. Exemplary salts include, but are not limited to: sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate , lactate, salicylate, acid citrate, tartrate, oleate, tannin, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisic acid Salt (gentisinate), fumarate, gluconate, glucuronate, sugar salt, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, Benzenesulfonate, p-toluenesulfonate and pamoate (ie 1-1-methylene-bis(2-hydroxy-3-naphthoate)).

All terms prodrug refer to derivatives of compounds that contain biologically reactive functional groups such that under biological conditions (in vitro or in vivo), the biologically reactive functional groups can be cleaved or otherwise reacted from the compound to provide the compound. Typically, prodrugs are inactive, or at least less active than the compound itself, such that the compound cannot exert its activity until the compound is cleaved from the biologically reactive functional group. Bioreactive functional groups can be hydrolyzed or oxidized under biological conditions to provide the compounds. For example, a prodrug may contain biohydrolyzable groups. Examples of biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, biohydrolyzable carbamates, and biohydrolyzable Hydrolyzed urea.

The compounds of the present invention may contain one or more asymmetric centers ("stereoisomers"). As used herein, all terms "stereoisomers" refer to cis- and trans-isomers, R- and S-enantiomers, and diastereomers. These stereoisomers can be prepared by asymmetric synthesis or chiral separation (eg, separation, crystallization, thin layer chromatography, column chromatography, gas chromatography, high performance liquid chromatography). These stereoisomers can also be derived from diastereomers by reacting mixtures of enantiomers or racemates with the appropriate chiral compound, followed by crystallization or any other suitable conventional method.

All terms subject refer to any animal, preferably a mammal, and most preferably a human, to which the compound or pharmaceutical composition is to be or has been administered according to embodiments of the present invention. All terms "mammal" as used herein include any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.

In certain embodiments, treating or being treated refers to amelioration, prevention or reversal of a disease or disorder or at least one identifiable symptom thereof. In other embodiments, treating or being treated refers to the improvement, prevention or reversal of at least one measurable physical parameter of the disease or condition being treated, which may not have been identified in the mammal. In yet another embodiment, treating or being treated refers to slowing the progression of a disease or condition, either physically, such as stabilization of discernible symptoms, or physiologically, such as stabilization of physical parameters, or both both. In other embodiments, treating or being treated refers to delaying the onset of a disease or disorder.

In certain embodiments, the compounds of the present invention may be administered as a preventive measure. As used herein, "preventing" or "preventing" refers to reducing the risk of acquiring a given disease or disorder. In a preferred mode of embodiment, the indicated compound is administered as a preventive measure to a subject, eg, a subject with a family history or predisposition to cancer or autoimmune disease.

On the basis of not violating common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

The positive improvement effect of the present invention is that the ¹⁸ F-labeled biphenyl compounds of the present invention have obvious inhibitory effect on PD-1 and PD-L1, can effectively alleviate or treat related diseases such as cancer, and can be used for PET tumor imaging technology middle.

In the following examples, the abbreviations are explained: Ci (curie) is the unit of radioactive intensity of a substance, and one Curie is defined by the radioactive intensity of one gram of radium decaying into radon, and its symbol is Ci.

Synthesis module, model: CFN200, produced by Sumitomo Heavy Industries, Japan; semi-preparative high performance liquid chromatograph, model: 2100 series, produced by Alltech Company of the United States; analytical high performance liquid chromatograph, model: E2695, produced by Waters Company of the United States Production; online radioactivity detector, model: Mini-scan, produced by Eckert & Ziegler, Germany; pipette, model: Finnpipette, produced by American Thermo Fisher.

Example 1 Synthesis of labeled compounds

Synthesis of Compound 1-j

Into a 100 mL reaction flask was added 6-bromo-2-hydroxybenzaldehyde (804 mg, 4.0 mmol), pinacol diboronate (1.52 g, 6.0 mmol), potassium acetate (980 mg, 10.0 mmol), [1,1 - bis(diphenylphosphino)ferrocene]palladium dichloride (234 mg, 0.32 mmol) and toluene (30 mL). The mixture was reacted for 16 hours at 80°C with stirring under nitrogen protection. It was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=8:1) to obtain compound 1-j (670 mg, yield: 68%).

LC-MS (ESI): m/z=247 [M-1] ^- .

Synthesis of Compound 1-i

To a mixture of compound 1-j (744 mg, 3.0 mmol), 3-bromo-2-methylphenol (561 mg, 3.0 mmol) and toluene (30 mL) was added [1,1'-bis(diphenylphosphonium)bis Ferrocene]palladium dichloride (154 mg, 0.21 mmol), potassium phosphate (1.27 g, 6.0 mmol), cesium fluoride (900 mg, 6.0 mmol), stirred at 80°C for 16 hours under nitrogen atmosphere. It was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=6:1) to obtain compound 1-i (431 mg, yield: 63%).

LC-MS (ESI): m/z = 227 [MH] ⁻ .

Synthesis of compound 1-h

To a solution of compound 1-i (417 mg, 1.83 mmol) and triethylamine (1.01 g, 10.0 mmol) in dichloromethane (20 mL) was slowly added dropwise trifluoromethanesulfonic anhydride (1.69 g) at -78°C. , 6.0 mmol). After the addition was completed, stirring was continued for 30 minutes, the reaction solution was raised to room temperature, and water (20 mL) was added to quench the reaction. The aqueous phase was extracted with dichloromethane (30 mL×2). The organic phases were combined and concentrated under reduced pressure. The residue was passed through a silica gel column layer. Analytical purification (petroleum ether:ethyl acetate=5:1) gave compound 1-h (730 mg, yield: 81%).

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.65 (s, 1H), 7.95 (t, J =8.0Hz, 1H), 7.69 (d, J =8.0Hz, 1H), 7.51～7.59 (m , 3H), 7.40 (dd, J =2.0Hz, 8.0Hz, 1H), 2.04 (s, 3H) ppm.

Synthesis of compound 1-g

To a solution of 3-bromo-4-(trifluoromethyl)benzaldehyde (4.00 g, 15.8 mmol) in dichloromethane (40 mL) was added ethanolamine (1.93 g, 31.6 mmol) and a few drops of acetic acid. After stirring at room temperature for 1 hour, methanol (40 mL) was added and sodium cyanoborohydride (995 mg, 15.8 mmol) was added, and the addition was completed, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, the residue was diluted with water (100 mL), and extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed with water (100 mL) and saturated brine (100 mL) successively, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the initial product compound 1-g, which was directly used in the next reaction.

Synthesis of compound 1-f

1-g of the above-obtained initial product was dissolved in ethanol (100 mL), di-tert-butyl dicarbonate (4.44 g, 20.5 mmol) was added, and the reaction was carried out at 40° C. for 3 hours. Concentrated under reduced pressure, the residue was diluted with 100 mL of water, and extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed with water (100 mL) and saturated brine (100 mL) successively. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to obtain compound 1-f (3.64 g, two-step yield: 58%).

LC-MS (ESI): m/z=398 [M+H] ⁺ .

Synthesis of Compound 1-e

To a solution of compound 1-f (2.00 g, 5.0 mmol) in dry dichloromethane (40 mL) was added triethylenediamine (840 mg, 7.5 mmol), and then 4,4'- A solution of bismethoxytrityl chloride (2.03 g, 6.0 mmol) in dichloromethane (12 mL). After the addition was completed, stirring was continued at 0°C for 2 hours. Water (40 mL) was added to quench the reaction, the organic layer was separated, and the aqueous layer was extracted with dichloromethane (40 mL×2). The organic phases were combined, washed with water (40 mL) and saturated brine (40 mL) successively. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=6:1) to obtain compound 1-e (2.54 g, yield: 72%).

Synthesis of Compound 1-d

To a mixture of compound 1-e (2.50 g, 3.57 mmol), vinylboronic acid pinacol ester (803 mg, 5.35 mmol) and toluene (80 mL) was added bis(tri-tert-butylphosphine)palladium (180 mg, 0.36 mmol) , diisopropylethylamine (2.76 g, 21.4 mmol). Under nitrogen atmosphere, it was stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=6:1) to obtain compound 1-d (1.23 g, yield: 44%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.73 (d, J =18.0Hz, 1H), 7.55 (d, J =8.0Hz, 1H), 7.49～7.51 (m, 1H), 7.39 (d, J =8.0Hz, 2H), 7.16～7.29 (m, 8H), 6.81 (d, J =8.0Hz, 4H), 6.11 (d, J =18.0Hz, 1H), 4.59 (s, 2H), 3.78 (s , 6H), 3.35～3.45 (m, 2H), 3.17～3.25 (m, 2H), 1.41 (s, 9H), 1.31 (s, 12H) ppm.

Synthesis of Compound 1-c

Compound 1-d (200 mg, 0.26 mmol), compound 1-h (50 mg, 0.10 mmol), potassium phosphate (106 mg, 0.50 mmol), cesium fluoride (75 mg, 0.50 mmol), [1,1'-bis( A mixture of diphenylphosphorus)ferrocene]palladium dichloride (30 mg, 0.04 mmol) and toluene (15 mL) was stirred at 90°C for 16 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to obtain compound 1-c (96 mg, yield: 65%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 9.92 (s, 1H), 8.02 (d, J =16.0Hz, 1H), 7.74 (d, J =8.0Hz, 1H), 7.70～7.72 (m, 1H) ), 7.58～7.65 (m, 6H), 7.38～7.41 (m, 7H), 7.24～7.32 (m, 12H), 7.17～7.19 (m, 6H), 6.78～6.81 (m, 8H), 4.65 (s , 2H), 4.64 (s, 2H), 3.74 (s, 12H), 3.38～3.47 (m, 4H), 3.20～3.26 (m, 4H), 2.15 (s, 3H) 1.42 (s, 18H) ppm.

Synthesis of compound 1-b

Compound 1-c (210 mg, 0.14 mmol) was dissolved in tetrahydrofuran (10 mL), ethanol (10 mL) was added to the solution, sodium borohydride (38 mg, 1.0 mmol) was added to the mixture in an ice-water bath, the addition was completed, and the reaction was carried out at 0°C for 20 minute. The reaction solution was warmed to room temperature, concentrated under reduced pressure, the residue was added with water (20 mL), and extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with water (20 mL) and saturated brine (20 mL) successively. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=4:1) to obtain compound 1-b (160 mg, yield: 76%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.69 (d, J =8.0Hz, 1H), 7.58～7.64 (m, 6H), 7.44～7.48 (m, 1H), 7.38～7.41 (m, 6H) , 7.29～7.32 (m, 1H), 7.23～7.28 (m, 13H), 7.13～7.20 (m, 6H), 6.78～7.80 (m, 8H), 4.62～4.64 (m, 4H), 4.58～4.61 ( m, 1H), 4.45～4.48 (m, 1H), 3.74 (s, 12H), 3.38～3.47 (m, 4H), 3.19～3.26 (m, 4H), 2.12 (s, 3H) 1.42 (s, 18H) ) ppm.

Synthesis of Compound 1-a

To a solution of compound 1-b (110 mg, 0.074 mmol) and triethylenediamine (22 mg, 0.2 mmol) in dry dichloromethane (10 mL) was added p-toluenesulfonic anhydride (33 mg, 0.10 mmol) at 0°C . The mixture was stirred at 0°C for 30 minutes. The reaction was quenched by adding ice water (20 mL) and extracted with dichloromethane (20 mL×2). The organic phases were combined, washed with water (20 mL) and saturated brine (20 mL) successively, and dried over anhydrous sodium sulfate. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to obtain compound 1-a (20 mg, yield: 17%).

Synthesis of Compound 1

1. Solution Preparation

1) Prepare 10mg/mL KF solution: weigh 10mg potassium fluoride and dissolve it in 1mL ultrapure water, dissolve it by ultrasonic for later use.

2) Preparation of 0.5M sodium bicarbonate buffer: Weigh 4.20g of sodium bicarbonate and dissolve it in 100mL of ultrapure water. Dissolve by ultrasonic for later use.

3) Prepare mobile phase 10mM tetrabutylammonium bromide + 0.2% triethylamine solution (pH 2.5±0.05): weigh 6.45g tetrabutylammonium bromide and dissolve it in 2L ultrapure water, add 4mL after ultrasonic dissolving Mix triethylamine, add phosphoric acid, adjust the pH value to 2.5 under pH meter measurement, and filter through a 0.45 μm microporous membrane for use.

4) Preparation of compound 1-a solution: Take a 2 mg bottle of compound 1-a, add 0.5 mL of ultra-dry acetonitrile to dissolve it, and prepare it for immediate use.

5) Prepare standard solution: Take a bottle of 1 mg standard solution, add 1 mL of acetonitrile to dissolve it, and use it for later use.

6) Prepare 2M hydrochloric acid methanol solution: use a pipette to take 5 mL of methanol, and then take 1 mL of hydrochloric acid, and mix them for later use.

7) Preparation of 12mM hydrochloric acid solution: Measure 200mL of ultrapure water in a graduated cylinder, add 200μL of hydrochloric acid, mix well and use it for later use.

8) Prepare 12mM hydrochloric acid ethanol solution: take 20 mL of ethanol, add 20 μL of hydrochloric acid, mix well and use it for later use.

9) Prepare 20% acetonitrile diluent: take 8 mL of mobile phase 10 mM tetrabutylammonium bromide + 0.2% triethylamine solution (pH 2.5±0.05), and then pipette 2 mL of acetonitrile and mix it for later use.

2. Labeling the experimental procedure

1) Preparation before the experiment

(1) Clean the CFN synthesis module, replace the card sleeve, and check the status of each system.

(2) Equilibrium semi-preparative high performance liquid chromatography, complete standard sample injection, as a control.

(3) After the semi-preparative injection is completed, use 20% acetonitrile to flush the quantitative loop, clean the injection needle, and the system continues to equilibrate.

(4) Use 10 mL of ethanol solution to activate the C18 cartridge, rinse with 20 mL of ultrapure water, and blow dry for use. Prepare 3 cartridges in the same way. Use 10 mL of 0.5M NaHCO ₃ solution to activate the QMA cartridge, rinse with 20 mL of ultrapure water, dry it for later use, and prepare one.

(5) Prepare 0.6 mL of TBAHCO ₃ solution, 1 mL of anhydrous acetonitrile, 0.5 mL of compound 1-a solution, and 0.5 mL of 2M hydrochloric acid methanol solution, and put them in vials of corresponding specifications respectively.

2) Compound ¹⁸ F-labeled synthesis

(1) After the synthesis module inspection is completed, install the vial containing TBAHCO ₃ , anhydrous acetonitrile, compound 1-a solution and hydrochloric acid methanol to the corresponding position of the module, and pre-fill 20 μL of KF solution in the reaction bottle.

(2) Before passing the target, click "Recovery from TG", the fluorine [ ¹⁸ F] ions produced by the accelerator are transferred to the fluoride ion recovery bottle of the synthesis module through the target passing pipeline.

(3) Transfer the fluorine [ ¹⁸ F] ion water to QMA for adsorption, and then rinse the QMA column with 0.6 mL of TBAHCO ₃ , and the fluorine [ ¹⁸ F] ion solution flows into the reaction flask.

(4) The temperature was raised to 110° C. to remove the solvent for 5 min, and then cooled. Then 1 mL of anhydrous acetonitrile was added, and the temperature was raised to 110° C. for the second dewatering for 5 min, and then cooled.

(5) The precursor solution was added, and the reaction solution was transferred to a constant temperature mixer and heated to 60° C. for oscillating reaction for 2 hours. After the reaction was completed, the temperature was lowered. Hydrochloric acid methanol was added, and the reaction was deprotected and shaken at 60°C for 30 min. After the reaction was completed, the temperature was lowered.

(6) The initial reaction product was diluted with 10 mL of 12 mM hydrochloric acid solution, adsorbed on a C18 column, washed with 10 mL of ultrapure water, and rinsed with 1.5 mL of 12 mM hydrochloric acid and ethanol on the C18 small column to obtain a crudely purified reaction stock solution.

(7) Transfer the crudely purified reaction stock solution to semi-preparative high performance liquid chromatography, and carry out preparative purification to collect radiation peaks with corresponding retention times.

(8) The product obtained after purification is diluted with 10 mL of 12 mM hydrochloric acid solution and passed through the C18 column, and then uses 10 mL of 12 mM hydrochloric acid solution to clean the C18 column, and finally rinses the product with 1.5 mL of 12 mM hydrochloric acid ethanol to the final product bottle.

(9) Use a solvent removal device to remove part of ethanol in the final product to meet the administration requirements to obtain the final product. The 5 mci initial product was prepared by high performance liquid phase to obtain 20 μCi of compound 1 (yield: 0.4%).

A fluorinated compound with the same structure but no radioactivity was added to compound 1 synthesized above, so that the specific activity of the drug was between 0.56GBq/μmol-1.37GBq/μmol, which met the requirements of animal experiment administration.

The above-mentioned drug specific activity testing methods such as the document "Radioisotope Therapeutics" is a book published by the People's Medical Publishing House in 2006, and the author is Pan Zhongyun. "Handbook of Radiopharmaceuticals" [Kuwait] Winwani et al.; Xia Zhenmin et al.

Example 2: Imaging of ¹⁸ F-labeled compound 1 in MC38 tumor-bearing mice

1. Preparation of ¹⁸ F label: Compound 1 solvent is ethanol, and the diluent during administration is normal saline.

2. Experimental method:

1) Prepare a total of 4 MC38 tumor-bearing mice, half male and half, 3 to 9 weeks old at the time of purchase, weighing 12 to 25 g. Before the test, select animals with a tumor volume ≥ 100 ^mm3 into the group, and prepare enough spare animals .

2) The dosage setting of non- ^18F -labeled substances in this experiment is about 30 mg/kg. At the same time, according to the requirements of radiation safety and instrument detection, the radioactive administration dose of ¹⁸ F-labeled compound 1 was set to be about 200 μCi per animal. The actual radioactive dose of the injected drug was calculated according to the body weight of each animal and the specific activity of the labeled drug. The route of administration was as follows. Intravenous injection.

3. PET/CT scanning method of tumor-bearing mice:

After intravenous administration, the tumor-bearing mice were subjected to 1h PET dynamic scanning, and 3h, 5h, 7h and 9h static scanning at four time points, keeping the animal stationary, and completing the CT scan before/after the small animal PET scan. Before scanning, the animals were subjected to respiratory anesthesia with isoflurane through an anesthesia machine, and the animals after anesthesia induction were placed on the small animal PET/CT bed. During the scanning process, the animals would continue to inhale isoflurane to maintain the anesthesia effect. Each bed was scanned statically for 10-30 min, scanning energy window: 350-650 Kev, and the scanning time was recorded.

4. Data acquisition and calculation results:

After the small animal PET/CT scan is completed, image reconstruction is performed, and the PMOD software is used to process the image and data, delineate the heart, liver, spleen, lung, kidney, stomach, tumor and other organs as the region of interest, and obtain the radioactive activity of the region of interest. The radioactivity concentration (i.e., the value of the radioactivity per unit volume), and then decay-corrected for the activity at each time point. According to the administered dose, the percentage injection dose rate per gram of tissue in each organ (referred to as %ID/g value) was calculated, and the tumor target ratio was provided; Microsoft Office Excel was used to calculate the mean and standard deviation.

5. Experimental results:

After administration of ¹⁸ F-labeled compound 1 to the tail vein of mice, the radioactivity was mainly distributed in the liver, followed by the blood-rich tissues (spleen, lung, kidney, heart), and a small amount in the bones and joints, and the rest of the tissues were comparable to the muscles. The tumor-to-cardiac ratio gradually increased with time, reached the highest at 7h, and then decreased. The tumor-muscle ratio was slightly higher than the mean of 1.

none

Claims (15)

A ¹⁸ F-labeled biphenyl compound represented by general formula I, a pharmaceutically acceptable salt, tautomer, meso, racemate, stereoisomer or prodrug thereof:

Wherein, Ring A and Ring B are independently aromatic rings or heteroaromatic rings; L ¹ is a chemical bond, alkynyl, -C(R ⁵ )=C(R ⁶ )- or -CR ⁷ R ⁸ -CR ⁹ R ¹⁰ - , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; L ² is a chemical bond, alkynyl, -C(R ⁵ )=C(R ⁶ )- or -CR ⁷ R ⁸ -CR ⁹ R ¹⁰ -, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted Unsubstituted heteroaryl or absent; R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently hydrogen, deuterium, ¹⁸ F, F, Cl, Br, I, cyano, or substituted or unsubstituted alkyl ^; R and R are independently H, ^{deuterium, 18 F} , F, Cl, Br, I, cyano, or substituted or unsubstituted alkyl; each ^R and each R ⁴ is independently hydrogen, deuterium, hydroxyl, -SR ¹¹ , -NR ¹² R ¹³ , ¹⁸ F, F, Cl, Br, I, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy , -CONH ₂ , -COR ¹⁴ , -COOR ¹⁵ or -OCOR ¹⁶ ; R ¹¹ , R ¹² and R ¹³ are independently hydrogen, C ₁ -C ₄ alkyl, substituted C ₁ -C ₄ alkyl or -COR ^a , R ^a is hydrogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; R ¹⁴ , R ¹⁵ and R ¹⁶ are independently hydrogen, C ₁ -C ₄ alkyl or substituted C ₁ -C ₄ alkyl; in R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ , the substitution in the substituted C ₁ -C ₄ alkyl refers to the substitution of C ₆ -C ₁₄ aryl , substituted C ₆ -C ₁₄ aryl, C ₁ -C ₁₀ heteroaryl and substituted C ₁ -C ₁₀ heteroaryl substituted one or more; the substituted rings described in L ¹ and L ² Alkyl, said substituted heterocycloalkyl, said substituted aryl, said substituted heteroaryl, said substituted alkyl as described in R ¹ and R ² , each R ³ and each The substituents in the substituted alkyl group described in each R ⁴ or the substituted alkoxy group are selected from ¹⁸ F, F, Cl, Br, I, cyano, C ₁ -C ₄ alkyl, hydroxyl,

, C ₆ -C ₁₄ aryl, substituted C ₆ -C ₁₄ aryl, C ₁ -C ₁₀ heteroaryl, substituted C ₁ -C ₁₀ heteroaryl, C ₁ -C ₄ alkoxy, C ₁ One or more of -C ₄ carboxyl group, C ₁ -C ₄ ester group and C ₁ -C ₄ amido group;

wherein R ¹⁷ and R ¹⁸ are independently hydrogen, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₆ -C ₁₄ aryl, substituted or unsubstituted C ₃ -C ₆ cycloalkane or substituted or unsubstituted C ₁ -C ₄ alkoxy; or R ¹⁷ , R ¹⁸ and the nitrogen atom to which they are attached together form a substituted or unsubstituted 5-7 membered carbon heterocycle; the carbon In the heterocyclic ring, the heteroatom is N, or N and O, and the number of heteroatoms is 1-4; each R ¹⁷ and each R ¹⁸ are the same or different; the substituted C ₁ - described in R ¹⁷ and R ¹⁸ C ₄ alkyl, said substituted C ₆ -C ₁₄ aryl, said substituted C ₃ -C ₆ cycloalkyl, said substituted C ₁ -C ₄ alkoxy and said substituted Substituents in the 5-7 membered carboheterocycle are selected from ¹⁸ F, F, Cl, Br, I, cyano, C ₁ -C ₄ alkyl, substituted C ₁ -C ₄ alkyl, C ₆ -C ₁₄ Aryl, substituted C ₆ -C ₁₄ aryl, C ₁ -C ₁₀ heteroaryl, substituted C ₁ -C ₁₀ heteroaryl, hydroxy,

, C ₁ -C ₄ alkoxy group, C ₁ -C ₄ carboxyl group, C ₁ -C ₄ ester group and C ₁ -C ₄ amide group in one or more; R ¹⁷ and R ¹⁸ , when the The substituted C ₁ -C ₄ alkyl group, the substituted C ₆ -C ₁₄ aryl group, the substituted C ₃ -C ₆ cycloalkyl group, the substituted C ₁ -C ₄ alkoxy group When the substituent in the substituted 5-7-membered carbon heterocycle is a substituted C ₁ -C ₄ alkyl group, in the substituent group, the substituent in the substituted C ₁ -C ₄ alkyl group is selected from: From ¹⁸ F, F, Cl, Br, I, cyano, C ₁ -C ₄ alkyl, C ₆ -C ₁₄ aryl, substituted C ₆ -C ₁₄ aryl, C ₁ -C ₁₀ heteroaryl, Substituted C ₁ -C ₁₀ heteroaryl, hydroxy,

, one or more of C ₁ -C ₄ alkoxy group, C ₁ -C ₄ carboxyl group, C ₁ -C ₄ ester group and C ₁ -C ₄ amido group;

, R ^a1 and R ^b1 are independently hydrogen, C ₁ -C ₄ alkyl or

, R ^a11 is a C ₁ -C ₄ alkyl group; all the above C ₁ -C ₁₀ heteroaryl groups refer to C ₁ -C ₁₀ heteroatoms selected from N, O and S, and the number of hetero atoms is 1-4 Aryl; Substituents in all substituted C ₆ -C ₁₄ aryl groups and substituted C ₁ -C ₁₀ heteroaryl groups above are selected from cyano, ¹⁸ F, F, Cl, Br, I, hydroxyl, C ₁ - One or more of C ₄ alkyl and C ₁ -C ₄ alkoxy; When there are multiple substituents, the substituents are the same or different; m and ma are independently 1, 2, 3 or 4 n and na are independently 1, 2, 3 or 4; provided that: at least one of R ¹ , R ² , L ¹ , L ² , R ³ and R ⁴ contains one or more ¹⁸ F; or

does not exist. The ¹⁸ F-labeled biphenyl compound represented by the general formula I according to claim 1, its pharmaceutically acceptable salt, tautomer, meso, racemate, stereoisomer or prodrugs, wherein,

Ring A and Ring B are independently aromatic or heteroaromatic rings; L ¹ is a chemical bond, alkynyl, -C(R ⁵ )=C(R ⁶ )- or -CR ⁷ R ⁸ -CR ⁹ R ¹⁰ -, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; L ² is chemical bond, alkynyl, -C(R ⁵ )= C(R ⁶ )- or -CR ⁷ R ⁸ -CR ⁹ R ¹⁰ -, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted of heteroaryl or absent; R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently hydrogen, deuterium, ¹⁸ F, F, Cl, Br, I, cyano, or substituted or unsubstituted alkyl; R ¹ and R ² are independently deuterium, ¹⁸ F, F, Cl, Br, I, cyano, or substituted or unsubstituted alkyl; each R ³ and each R ⁴ are independently Hydrogen, deuterium, hydroxyl, -SR ¹¹ , -NR ¹² R ¹³ , ¹⁸ F, F, Cl, Br, I, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -CONH ₂ , -COR ¹⁴ , -COOR ¹⁵ or -OCOR ¹⁶ ; R ¹¹ , R ¹² and R ¹³ are independently hydrogen, C ₁ -C ₄ alkyl, substituted C ₁ -C ₄ alkyl or -COR ^a , R ^a is hydrogen, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; R ¹⁴ , R ¹⁵ and R ¹⁶ are independently hydrogen, C ₁ -C ₄ alkyl or substituted C ₁ -C ₄ Alkyl; in R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ , the substitution in the substituted C ₁ -C ₄ alkyl refers to C ₆ -C ₁₄ aryl, substituted C One or more of ₆ -C ₁₄ aryl, C ₁ -C ₁₀ heteroaryl and substituted C ₁ ^-C ₁₀ heteroaryl ^; substituted heterocycloalkyl as described, substituted aryl as described, substituted heteroaryl as described, substituted alkyl as described in R ¹ and R ² , in each of R ³ and each of R ⁴ The substituents in the substituted alkyl or the substituted alkoxy are selected from ¹⁸ F, F, Cl, Br, I, cyano, C ₁ -C ₄ alkyl, hydroxyl,

, C ₆ -C ₁₄ aryl, substituted C ₆ -C ₁₄ aryl, C ₁ -C ₁₀ heteroaryl, substituted C ₁ -C ₁₀ heteroaryl, C ₁ -C ₄ alkoxy, C ₁ One or more of -C ₄ carboxyl group, C ₁ -C ₄ ester group and C ₁ -C ₄ amido group;

wherein R ¹⁷ and R ¹⁸ are independently hydrogen, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₆ -C ₁₄ aryl, substituted or unsubstituted C ₃ -C ₆ cycloalkane or substituted or unsubstituted C ₁ -C ₄ alkoxy; or R ¹⁷ , R ¹⁸ and the nitrogen atom to which they are attached together form a substituted or unsubstituted 5-7 membered carbon heterocycle; the carbon In the heterocyclic ring, the heteroatom is N, or N and O, and the number of heteroatoms is 1-4; each R ¹⁷ and each R ¹⁸ are the same or different; the substituted C ₁ - described in R ¹⁷ and R ¹⁸ C ₄ alkyl, said substituted C ₆ -C ₁₄ aryl, said substituted C ₃ -C ₆ cycloalkyl, said substituted C ₁ -C ₄ alkoxy and said substituted Substituents in the 5-7 membered carboheterocycle are selected from ¹⁸ F, F, Cl, Br, I, cyano, C ₁ -C ₄ alkyl, substituted C ₁ -C ₄ alkyl, C ₆ -C ₁₄ Aryl, substituted C ₆ -C ₁₄ aryl, C ₁ -C ₁₀ heteroaryl, substituted C ₁ -C ₁₀ heteroaryl, hydroxy,

, C ₁ -C ₄ alkoxy group, C ₁ -C ₄ carboxyl group, C ₁ -C ₄ ester group and C ₁ -C ₄ amide group in one or more; R ¹⁷ and R ¹⁸ , when the The substituted C ₁ -C ₄ alkyl group, the substituted C ₆ -C ₁₄ aryl group, the substituted C ₃ -C ₆ cycloalkyl group, the substituted C ₁ -C ₄ alkoxy group When the substituent in the substituted 5-7-membered carbon heterocycle is a substituted C ₁ -C ₄ alkyl group, in the substituent group, the substituent in the substituted C ₁ -C ₄ alkyl group is selected from: From ¹⁸ F, F, Cl, Br, I, cyano, C ₁ -C ₄ alkyl, C ₆ -C ₁₄ aryl, substituted C ₆ -C ₁₄ aryl, C ₁ -C ₁₀ heteroaryl, Substituted C ₁ -C ₁₀ heteroaryl, hydroxy,

, one or more of C ₁ -C ₄ alkoxy group, C ₁ -C ₄ carboxyl group, C ₁ -C ₄ ester group and C ₁ -C ₄ amido group;

, R ^a1 and R ^b1 are independently hydrogen, C ₁ -C ₄ alkyl or

, R ^a11 is a C ₁ -C ₄ alkyl group; all the above C ₁ -C ₁₀ heteroaryl groups refer to C ₁ -C ₁₀ heteroatoms selected from N, O and S, and the number of hetero atoms is 1-4 Aryl; Substituents in all substituted C ₆ -C ₁₄ aryl groups and substituted C ₁ -C ₁₀ heteroaryl groups above are selected from cyano, ¹⁸ F, F, Cl, Br, I, hydroxyl, C ₁ - One or more of C ₄ alkyl and C ₁ -C ₄ alkoxy; When there are multiple substituents, the substituents are the same or different; m and ma are independently 1, 2, 3 or 4 ; n and na are independently 1, 2, 3 or 4; provided that at least one of R ¹ , R ² , L ¹ , L ² , R ³ and R ⁴ contains one or more ¹⁸ F. The ¹⁸ F-labeled biphenyl compound represented by the general formula I according to claim 1, its pharmaceutically acceptable salt, tautomer, meso, racemate, stereoisomer or a prodrug, wherein R ² is H; and

does not exist. The ¹⁸ F-labeled biphenyl compound represented by the general formula I according to claim 1 or 2, its pharmaceutically acceptable salt, tautomer, meso, racemate, stereoisomer or prodrug, wherein, the aromatic ring is a C ₆ -C ₂₀ aromatic ring, preferably a C ₆ -C ₁₄ aromatic ring, more preferably a C ₆ -C ₁₀ aromatic ring, most preferably benzene, naphthalene, tetrahydronaphthalene, 2,3-indane, biphenyl, phenanthrene, anthracene or acenaphthene; and/or, the heteroaromatic ring means that the heteroatom is selected from O, N and S, and the number of heteroatoms is 1, 2, 3 or 4 C ₁ -C ₁₀ heteroaromatic rings, preferably the heteroatom is selected from O, N and S, the number of hetero atoms is 1, 2, 3 or 4 C ₁ -C ₈ heteroaromatic rings, more preferably Heteroatoms are selected from O, N and S, C ₁ -C ₆ heteroaromatic rings with 1, 2, 3 or 4 heteroatoms, most preferably acridine, oxazole, cinnoline, oxoline, quinoline Line, imidazole, pyrazole, pyrrole, indole, indoline, benzotriazole, benzimidazole, furan, thiophene, isothiazole, benzothiophene, dihydrobenzothiophene, benzofuran, isobenzo Furans, benzoxazoles, benzofurazans, benzopyrazoles, quinolines, isoazindenes, isoquinolines, oxazoles, oxadiazoles, isoxazoles, indole, pyrazine, pyridopyridine, Tetrazolopyridine, pyridazine, pyridine, naphthyridine, pyrimidine, pyrrole, tetrazole, thiadiazole, thiazole, thiophene, triazole, quinazoline, tetrahydroquinoline, dihydrobenzimidazole, dihydrobenzone furan, dihydrobenzoxazole or dihydroquinoline; and/or, the cycloalkyl is C ₃ -C ₂₀ cycloalkyl, preferably C ₃ -C ₁₀ cycloalkyl, more preferably C ₃ -C ₆ cycloalkyl, most preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecane and cyclododecyl or cyclohexenyl; and/or, the Said heterocycloalkyl refers to the heteroatom selected from O, N and S, the number of heteroatoms is 1, 2, 3 or 4 C ₂ -C ₁₀ non-aromatic ring, preferably the heteroatom is selected from O, N and S, a C ₂ -C ₈ heterocycloalkyl group with 1, 2, 3 or 4 heteroatoms, further preferably the heteroatoms are selected from O, N and S, and the number of heteroatoms is 1, 2, 3 or 4 C ₂ -C ₆ heterocycloalkyl, most preferably tetrahydropyranyl, azetidinyl, 1,4-dioxanyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholine base, thiomorpholinyl, dihydrofuranyl, dihydroimidazolyl, indoline, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, Dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl , dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzyl, tetrahydrofuranyl, tetrahydrothienyl or N-oxides thereof; and/or, Described aryl group is C ₆ -C ₂₀ aryl group, preferably C ₆ -C ₁₄ aryl group, more preferably C ₆ -C ₁₀ aryl group, most preferably phenyl, naphthyl, tetrahydronaphthyl, 2,3- Indenyl, biphenyl, phenanthrene and/or, the heteroaryl group refers to a C ₁ -C ₁₀ heteroatom selected from O, N and S, and the number of heteroatoms is 1, 2, 3 or 4. Heteroaryl, more preferably heteroatom selected from O, N and S, C1-C8 heteroaryl with ₁ , 2, 3 or ₄ heteroatoms, more preferably heteroatom selected from O, N and S, C ₁ -C ₆ heteroaryl with 1, 2, 3 or 4 heteroatoms, most preferably benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, quinazolyl, quinolinyl, cinnoline, furyl, imidazolyl, indoline, indolyl, indazolyl, iso benzofuranyl, isoazindenyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthymidyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetane base, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoline, Tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl or triazolyl; and/or, the alkyl group refers to branched and straight chain containing 1-20 carbon atoms Saturated aliphatic hydrocarbon group, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, most preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and Their various isomers; and/or, the alkoxy group represents a cyclic or acyclic alkyl group with the stated number of carbon atoms connected through an oxygen bridge, preferably a C ₁ -C ₄ alkoxy group, more Preferably, methoxy, ethoxy, n-propoxy, isopropoxy or tert-butoxy; and/or, the 5-7 membered carbon heterocycle means that the heteroatom is selected from O, N and S, 5-7-membered carbon heterocycle with 1, 2, 3 or 4 heteroatoms and 1, 2, 3, 4, 5 or 6 carbon atoms, preferably azetidinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydroimidazolyl, indoline, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydroisothiazolyl Hydroxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl , dihydrothiazolyl, dihydrotriazolyl or dihydroazetidinyl. The ¹⁸ F-labeled biphenyl compound represented by the general formula I according to any one of claims 1 to 4, its pharmaceutically acceptable salt, tautomer, meso, racemate, Stereoisomer or prodrug, wherein Ring A is a benzene ring; and/or Ring B is a benzene ring or a pyridine ring; L ¹ is alkynyl, -C(R ⁵ )=C(R ⁶ )-, -CR ⁷ R ⁸ -CR ⁹ R ¹⁰ -, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, preferably Alkynyl, -C(R ⁵ )=C(R ⁶ )- or -CR ⁷ R ⁸ -CR ⁹ R ¹⁰ -, more preferably -C(R ⁵ )=C(R ⁶ )-, most preferably -CH= CH-; and/or, L ² is alkynyl, -C(R ⁵ )=C(R ⁶ )-, -CR ⁷ R ⁸ -CR ⁹ R ¹⁰ -, substituted or unsubstituted cycloalkyl, substituted or Unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or absent, preferably alkynyl, -C(R ⁵ )=C(R ⁶ )-, -CR ⁷ R ⁸ -CR ⁹ R ¹⁰ - or absent, more preferably -C(R ⁵ )=C(R ⁶ )- or absent, most preferably -CH=CH- or absent; and/or, R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently hydrogen or deuterium; and/or R ¹ is ¹⁸ F, F, Cl, Br, I, cyano, substituted or unsubstituted alkyl, and The alkyl group is preferably a C ₁ -C ₄ alkyl group, more preferably a methyl group; the substituents in the substituted alkyl group are preferably one or more of ¹⁸ F, F, Cl, Br, I and hydroxyl; and /or, R ² is deuterium, ¹⁸ F, F, Cl, Br, I, cyano, substituted or unsubstituted alkyl, and the alkyl is preferably C ₁ -C ₄ alkyl, more preferably methyl, ethyl base, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, the substituent in the substituted alkyl group is preferably ¹⁸ F, F, Cl, Br, I, cyano, C ₁ one or more of -C ₄ alkyl, hydroxyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ carboxy, C ₁ -C ₄ ester and C ₁ -C ₄ amido; and/or , R ³ and R ⁴ are independently deuterium, ¹⁸ F, F, Cl, Br, I, cyano, -SR ¹¹ , -NR ¹² R ¹³ , substituted or unsubstituted alkyl, or substituted or unsubstituted alkane oxy; preferably independently deuterium, ¹⁸ F, F, Cl, Br, I, cyano, -SR ¹¹ , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; and/or, at least One or more of ¹⁸ F is contained in one of R ¹ , R ² , R ³ and R ⁴ . The ¹⁸ F-labeled biphenyl compound represented by the general formula I according to claim 1 or 2, its pharmaceutically acceptable salt, tautomer, meso, racemate, stereoisomer drug or prodrug, wherein R ¹ and R ² are independently ¹⁸ F, F, Cl, Br, I, alkyl or alkane substituted by one or more of ¹⁸ F, F, Cl, Br, I Or, R ³ and R ⁴ are independently ¹⁸ F, F, Cl, Br, I; Or, R ³ and R ⁴ are substituted or unsubstituted alkyl groups, and the substituents in the substituted alkyl groups For by ¹⁸ F, F, Cl, Br, I, cyano, hydroxyl,

, C ₆ -C ₁₄ aryl, substituted C ₆ -C ₁₄ aryl, C ₁ -C ₁₀ heteroaryl, substituted C ₁ -C ₁₀ heteroaryl, C ₁ -C ₄ alkoxy and C ₁ One or more substitutions in -C ₄ carboxyl groups, preferably by ¹⁸ F, F, Cl, Br, I,

, substituted C ₆ -C ₁₄ aryl group and substituted C ₁ -C ₁₀ heteroaryl group, one or more substitutions, when there are multiple substituents, the substituents are the same or different; Or, R ³ and R ⁴ is a substituted or unsubstituted alkoxy group, and the substituents in the substituted alkoxy group are replaced by ¹⁸ F, F, Cl, Br, I, cyano, hydroxyl,

one of , C ₆ -C ₁₄ aryl, substituted C ₆ -C ₁₄ aryl, C ₁ -C ₁₀ heteroaryl, substituted C ₁ -C ₁₀ heteroaryl and C ₁ -C ₄ alkoxy or more substituted, preferably by one or more of C ₁ -C ₁₀ heteroaryl, substituted C ₁ -C ₁₀ heteroaryl and C ₁ -C ₄ alkoxy, most preferably by C ₁ -C ₄ Alkoxy substitution; when there are multiple substituents, the substituents are the same or different. The ¹⁸ F-labeled biphenyl compound represented by the general formula I according to claim 1 or 2, its pharmaceutically acceptable salt, tautomer, meso, racemate, stereoisomer or prodrug, wherein R ¹ and R ² are independently ¹⁸ F, F, Cl, Br, I, C ₁ -C ₄ alkyl or by one of ¹⁸ F, F, Cl, Br and I or Multiple substituted C ₁ -C ₄ alkyl (eg -CH ₂ ¹⁸ F, -CH ¹⁸ F ₂ , -CH ¹⁸ FF, -C ¹⁸ F ₃ , -C ¹⁸ FF ₂ , -C ¹⁸ F ₂ F, - CH ₂ F, -CHF ₂ or -CF ₃ ); or, R ³ and R ⁴ are alkyl substituted by ¹⁸ F, F, Cl, Br, I, said ¹⁸ F, F, Cl, Br, I-substituted alkyl is preferably C ₁ -C ₄ alkyl substituted by one or more of ¹⁸ F, F, Cl, Br and I, preferably -C ¹⁸ F ₃ , -C ¹⁸ FF ₂ , -C ¹⁸ F ₂ F or -CF ₃ , or, R ³ and R ⁴ are

substituted alkyl, the

Substituted alkyl groups are preferably

Substituted C ₁ -C ₄ alkyl, said by

Substituted C ₁ -C ₄ alkyl groups are preferred

or

, wherein, one of R ¹⁷ and R ¹⁸ is H, and the other is an alkyl group substituted by one or more of C ₁ -C ₄ alkoxy, hydroxyl and carboxyl; or R ¹⁷ , R ¹⁸ and their connection The nitrogen atoms form a substituted 5-7 membered carbon heterocycle; in the carbon heterocycle, the heteroatom is N, or N and O, and the number of heteroatoms is 1-4; the 5-7 membered carbon The heterocycle is preferably pyrrole or piperidine; the substituents in the substituted 5-7-membered carbon heterocycle are preferably substituted C ₁ -C ₄ alkyl, hydroxyl, C ₁ -C ₄ carboxyl, C ₁ -C ₄ ester one or more of the C 1 -C 4 amide group and the C ₁ -C ₄ amide group; the substituent in the substituted C ₁ -C ₄ alkyl group is preferably a hydroxyl group; when R ³ and R ⁴ are

substituted alkyl, the

Substituted alkyl preferred

,

,

,

,

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,

or

; Or, R ³ and R ⁴ are substituted C ₆ -C ₁₄ aryl substituted alkyl groups, preferably

; Or, R ³ and R ⁴ are substituted C ₁ -C ₁₀ heteroaryl substituted alkyl groups, preferably

; Or, when R ³ is a substituted or unsubstituted alkyl group, R ³ is located in the meta or para position of the atom connected to L ¹ on ring A; Or, when R ⁴ is a substituted or unsubstituted alkyl group, R ⁴ is located in the meta or para position of the atom connected to L ² on the ring B; or, when R ³ is a substituted or unsubstituted alkyl group, there may also be 0, 1 or 2 substituents on the ring A, when When there is still one substituent, the substituent is located at the para, meta or ortho position of the substituted or unsubstituted alkyl group; or, when R ⁴ is a substituted or unsubstituted alkyl group, ring B can also There are 0, 1 or 2 substituents, and when there is also 1 substituent, the substituent is located in the para, meta or ortho position of the substituted or unsubstituted alkyl; or, R ³ and R ⁴ are substituted Or unsubstituted alkoxy, the substituents in the substituted alkoxy are ¹⁸ F, F, Cl, Br, I, cyano, hydroxyl,

one of , C ₆ -C ₁₄ aryl, substituted C ₆ -C ₁₄ aryl, C ₁ -C ₁₀ heteroaryl, substituted C ₁ -C ₁₀ heteroaryl and C ₁ -C ₄ alkoxy or multiple substitutions; preferably, R ³ and R ⁴ are substituted or unsubstituted alkoxy groups, and the substituents in the substituted alkoxy groups are C ₁ -C ₁₀ heteroaryl, substituted C One or more substitutions in the ₁ -C ₁₀ heteroaryl group and the C ₁ -C ₄ alkoxy group, when there are multiple substituent groups, the substituent groups are the same or different; the substituted alkoxy groups are preferably

,

or

; Or, when R ³ is a substituted or unsubstituted alkoxy group, R ³ is located in the ortho or meta position of the atom connected to L ¹ on ring A; Or, when R ⁴ is a substituted or unsubstituted alkoxy group , R ⁴ is located in the ortho or meta position of the atom connected to L ² on ring B. The ¹⁸ F-labeled biphenyl compound represented by the general formula I according to any one of claims 1 to 7, its pharmaceutically acceptable salt, tautomer, meso, racemate, Stereoisomers or prodrugs, wherein the group

for

, preferably

, wherein, the definitions of R ¹ and R ² are as described in claim 1 or 2; the group

more preferably

,

,

,

,

,

or

; or,

and

independently for

and

, where M ¹ and N ¹ are the

substituted alkyl, or one of M ¹ and N ¹ is

Substituted alkyl, the other is substituted alkoxy; wherein R ¹⁷ , R ¹⁸ , R ³ and R ⁴ are defined as described in any one of claims 1 to 5, and n1 and m1 are independently 0, 1 or 2; preferably, M ¹ and N ¹ are

, or one of M ¹ and N ¹ is

, and the other is alkoxy substituted by one or more of C ₁ -C ₄ alkoxy, C ₁ -C ₁₀ heteroaryl and substituted C ₁ -C ₁₀ heteroaryl; R ³ and R ⁴ is hydrogen, ¹⁸ F, F, Cl, Br, I, alkyl, alkyl substituted with one or more of ¹⁸ F, F, Cl, Br, I, alkoxy or substituted alkoxy, so The substituents in the substituted alkoxy groups are preferably substituted by one or more of C ₁ -C ₄ alkoxy groups, C ₁ -C ₁₀ heteroaryl groups and substituted C ₁ -C ₁₀ heteroaryl groups; R ¹⁷ and R ¹⁸ are defined as described in any one of claim 1 to 5; More preferably, M ¹ and N ¹ are

, or one of M ¹ and N ¹ is

, and the other is alkoxy substituted by C ₁ -C ₄ alkoxy; R ³ and R ⁴ are preferably ¹⁸ F, F, Cl, Br, I, alkyl, ¹⁸ F, F, Cl, Br, I One or more of substituted alkyl groups, alkoxy groups or alkoxy groups substituted by C ₁ -C ₄ alkoxy groups; the definitions of R ¹⁷ and R ¹⁸ are the same as those described in any one of claims 1 to 5. The ¹⁸ F-labeled biphenyl compound represented by the general formula I according to claim 8, its pharmaceutically acceptable salt, tautomer, meso, racemate, stereoisomer or prodrugs, wherein,

for

,

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,

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or

, wherein N ¹ , R ¹⁷ and R ¹⁸ are as described in claim 8; or,

for

,

,

,

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,

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,

,

,

,

,

,

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,

,

or

, wherein M ¹ , R ¹⁷ and R ¹⁸ are defined as described in claim 6 . The ¹⁸ F-labeled biphenyl compound represented by the general formula I according to any one of claims 1 to 9, its pharmaceutically acceptable salt, tautomer, meso, racemate, Stereoisomers or prodrugs, wherein,

and

independently for

,

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or

; and / or,

and

independently for

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or

. The ¹⁸ F-labeled biphenyl compound represented by the general formula I according to any one of claims 1 to 10, its pharmaceutically acceptable salt, tautomer, meso, racemate, Stereoisomers or prodrugs, wherein the ¹⁸ F-labeled biphenyl compound represented by the general formula I is selected from any of the following compounds:

and

. The ¹⁸ F-labeled biphenyl compound represented by the general formula I according to any one of claims 1 to 11, its pharmaceutically acceptable salt, tautomer, meso, racemate, Stereoisomers or prodrugs, wherein the ¹⁸ F-labeled biphenyl compound shown in the general formula I is the ¹⁸ F-labeled biphenyl compound shown in the general formula IA or II:

or

Wherein, the definitions of ring A, ring B, L ¹ , L ² , R ¹ , R ² , R ³ , R ⁴ , M ¹ , N ¹ , R ¹⁷ , R ¹⁸ , na and ma are the same as in claim 1 to 11 In any one of the above, n1 is 0, 1 or 2, and m1 is 0, 1 or 2. A ¹⁸ F-labeled biphenyl compound represented by general formula I as described in any one of claims 1 to 11, its pharmaceutically acceptable salt, tautomer, meso, and racemate , application of stereoisomers or prodrugs in the preparation of PD-1 inhibitors and/or PD-L1 inhibitors. A ¹⁸ F-labeled biphenyl compound represented by general formula I as described in any one of claims 1 to 11, its pharmaceutically acceptable salt, tautomer, meso, and racemate Use of one or more of , stereoisomers, metabolites, metabolic precursors and prodrugs as molecular probes for cancer imaging or in preparation for the prevention, mitigation or treatment of cancer, infection, autoimmune disease or its For use in medicines for related diseases, the cancer is preferably one or more of lung cancer, esophageal cancer, gastric cancer, colorectal cancer, liver cancer, nasopharyngeal cancer, brain tumor, breast cancer, cervical cancer, blood cancer and bone cancer. A pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a ¹⁸ F-labeled biphenyl compound of the general formula I as described in any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, A tautomer, meso, racemate, stereoisomer, metabolite, metabolic precursor or prodrug, and a pharmaceutically acceptable carrier and/or diluent.