WO2022028557A1 - 18f-labeled biphenyl compound, intermediate thereof, preparation method therefor, pharmaceutical composition thereof, and application thereof - Google Patents

Abstract

A ¹⁸F-labeled biphenyl compound, an intermediate thereof, a preparation method therefor, a pharmaceutical composition thereof, and application thereof. The biphenyl compound has a significant suppression effect on PD-1 and/or PD-L1, can effectively alleviate or treat related diseases such as cancer, and can be used in PET tumor imaging technology.

Description

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

This application claims the priority of Chinese patent application 2020107872853 with the filing date of 2020/8/7 and 2021108598282 with the filing date of 2021/7/28. This application cites the full text of the above Chinese patent application.

technical field

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

Background technique

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 cloned 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 with PD-L1, it can lead to Tyr phosphorylation of the immunoreceptor tyrosine-based switch motif (ITSM) domain in the cytoplasmic region of T cells, and then Phosphorylated Tyr recruits the phosphatases protein tyrosinase 2 and protein tyrosinase 1, which block not only the activation of extracellular signal-regulated kinases, but also 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, the secretion of cytokines interleukin 2 (IL2), interferon gamma and IL-10 is also reduced (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 with 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 and transmits 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 development. WO2015044900) has just entered clinical phase I, and the 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 a series of small molecule PD-1 / PD-L1 inhibitor (WO2017070089, WO2017087777, WO2017106634, WO2017112730, WO2017192961, WO2017205464, WO2017222976, WO2018013789, WO2018044783, WO2018119221, WO2018119224, WO2018119263, WO2018219266, WO2018119286) still in preclinical studies . Compared with biological macromolecules, small molecular 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 in various aspects such as production process, dosage form design and administration method.

At present, there are no reports that ¹⁸ F-labeled biphenyl compounds have been successfully marketed as small-molecule PD-1/PD-L1 inhibitors and can be used in PET tumor imaging technology in the prior art, and this situation needs to be resolved urgently.

SUMMARY OF THE INVENTION

The purpose of the present disclosure is to provide an ¹⁸ F-labeled biphenyl compound, its intermediates, preparation methods, pharmaceutical compositions and applications which are completely different from the prior art. The ¹⁸ F-labeled biphenyl compounds of the present disclosure have a significant inhibitory effect on PD-1 and/or PD-L1, and can effectively alleviate or treat related diseases such as cancer.

The present disclosure provides an ¹⁸ F-labeled biphenyl compound represented by general formula I, a pharmaceutically acceptable salt, tautomer, meso, racemate, stereoisomer or pharmaceutically acceptable salt thereof. Prodrugs:

in,

Ring A and Ring B are independently aromatic or heteroaromatic;

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 heterocycle alkyl, 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 heterocycle alkyl, substituted or unsubstituted aryl, substituted or 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 ¹ and R ² are independently H, deuterium, ¹⁸ F, F, Cl, Br, I, cyano or substituted or unsubstituted alkyl;

Each R ³ and each R ⁴ is independently hydrogen, deuterium, hydroxy, -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 group refers to C ₆ -C ₁₄ aryl, C ₆ -C substituted One or more of ₁₄ aryl, C ₁ -C ₁₀ heteroaryl and substituted C ₁ -C ₁₀ heteroaryl;

C ₆-C ₁₄芳基、取代的C ₆-C ₁₄芳基、C ₁-C ₁₀杂芳基、取代的C ₁-C ₁₀杂芳基、C ₁-C ₄烷氧基、C ₁-C ₄羧基、C ₁-C ₄酯基和C ₁-C ₄酰胺基中的一个或多个；

中，R ¹⁷和R ¹⁸独立地为氢、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环烷基、或取代或未取代的C ₁-C ₄烷氧基；或者R ¹⁷、R ¹⁸和与它们相连接的氮原子一起形成一个取代或未取代的5-7元碳杂环；所述碳杂环中，杂原子为N，或N和O，杂原子数为1-4个；每个R ¹⁷和每个R ¹⁸相同或不同； The substituted cycloalkyl group described in L ¹ and L ² , the substituted heterocycloalkyl group described in, the substituted aryl group described in, the substituted heteroaryl group described in, R ¹ and R ² described in ^The substituents in the substituted alkyl group, ^the substituted alkyl group described in each ^R3 and each R4, or the substituted alkoxy group described are selected from F, F, Cl, Br, I, cyano base, 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 amide 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;

C ₁-C ₄烷氧基、C ₁-C ₄羧基、C ₁-C ₄酯基和C ₁-C ₄酰胺基中的一个或多个； The substituted C ₁ -C ₄ alkyl groups described in R ¹⁷ and R ¹⁸ , the substituted C ₆ -C ₁₄ aryl groups, the substituted C ₃ -C ₆ cycloalkyl groups, the substituted C 6 -C 6 cycloalkyl groups, and the Substituents in C ₁ -C ₄ alkoxy and said substituted 5-7 membered carbon heterocycle 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 amide group;

C ₁-C ₄烷氧基、C ₁-C ₄羧基、C ₁-C ₄酯基和C ₁-C ₄酰胺基中的一个或多个；

中，R ^a1和R ^b1独立地为氢、C ₁-C ₄的烷基或

R ^a11为C ₁-C ₄的烷基； In R ¹⁷ and R ¹⁸ , when said substituted C ₁ -C ₄ alkyl group, said substituted C ₆ -C ₁₄ aryl group, said substituted C ₃ -C ₆ cycloalkyl group, said substituted C 3 -C 6 cycloalkyl group, said When the substituents in the substituted C ₁ -C ₄ alkoxy and the substituted 5-7-membered carboheterocycle are substituted C ₁ -C ₄ alkyl groups, among the substituents, the substituted C ₁ Substituents in -C ₄ alkyl are selected 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, hydroxyl,

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 amide group;

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

R ^a11 is C ₁ -C ₄ alkyl;

All the above C ₁ -C ₁₀ heteroaryl groups refer to C ₁ -C ₁₀ heteroaryl groups with heteroatoms selected from N, O and S, and the number of heteroatoms is 1-4;

Substituents in all of the above substituted C ₆ -C ₁₄ aryl groups and substituted C ₁ -C ₁₀ heteroaryl groups are selected from cyano, ¹⁸ F, F, Cl, Br, I, hydroxyl, C ₁ -C ₄ alkanes one or more of C ₁ -C ₄ alkoxy groups;

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;

The condition is: 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) ) ^18F ;

不存在。 or

does not exist.

In a preferred embodiment, the ¹⁸ F-labeled biphenyl compound represented by the general formula I, its pharmaceutically acceptable salt, tautomer, meso, racemate, stereoisomer Conform or prodrug:

wherein, R ¹ and R ² are independently deuterium, ¹⁸ F, F, Cl, Br, I, cyano or substituted or unsubstituted alkyl;

存在；

exist;

The definitions of letters and groups are the same as before.

In a preferred embodiment, the ¹⁸ F-labeled biphenyl compound represented by the general formula I, its pharmaceutically acceptable salt, tautomer, meso, racemate, stereoisomer Conform or prodrug:

不存在。 Wherein, R ² is H;

does not exist.

In this disclosure, 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 this disclosure, all terms heteroaromatic ring are meant to denote 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 disclosure, "heteroaromatic ring" preferably refers to a C ₁ -C ₁₀ heteroaromatic ring with a heteroatom selected from O, N and S, and 1, 2, 3 or 4 heteroatoms, and more preferably a heteroatom 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, carbazole, cinnoline, carboline, quinoxaline, 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 this disclosure, 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 disclosure, 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 disclosure, the heteroatom of the heterocycloalkyl group is preferably selected from O, N and S, the heteroatom of C ₂ -C ₈ with 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, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl and N-oxides thereof.

In this disclosure, 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 disclosure, all terms 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, a C ₁ -C ₈ heteroaryl group 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, carbazole base, carboline, cinnoline, furyl, imidazolyl, indoline, indolyl, indazolyl, isobenzofuranyl, isoazindenyl, isoquinolinyl, isothiazolyl , isoxazolyl, naphthyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridine pyridyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thiophene base and triazolyl.

In this disclosure, 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. The alkyl group in the present disclosure is preferably a _C1 - _C4 alkyl group, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

In this disclosure, 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 disclosure, the alkoxy group is preferably a C ₁ -C ₄ alkoxy group, more preferably a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group or a tert-butoxy group.

In this disclosure, all terms 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 disclosure, the 5-7 membered carbon heterocycles include but are 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 groups are preferably one or more of ¹⁸ F, F, Cl, Br, I and hydroxyl groups. R ¹ is preferably an alkyl group substituted by 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 C ₁ -C ₄ substituted by one or more of ¹⁸ F, F, Cl, Br and I alkyl, 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, R1 is located at the ⁵ ' position of the phenyl ring.

位于苯环的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 amide group, when there are multiple substituent groups, the substituent groups 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杂芳基、取代的C ₁-C ₁₀杂芳基、C ₁-C ₄烷氧基和C ₁-C ₄羧基中的一个或多个取代。当取代基为多个时，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杂芳基中的一个或多个取代。当取代基为多个时，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 replaced by ¹⁸ F, F, Cl, Br, I,

One or more of substituted _C6 - _C14 aryl and substituted _C1 - _C10 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

取代的烷基优选被

取代的C ₁-C ₄的烷基。所述的被

取代的C ₁-C ₄的烷基优选

其中，R ¹⁷和R ¹⁸一个为H，另一个为被羟基和/或羧基取代的烷基。在一优选实施方式中，R ¹⁷和R ¹⁸一个为H，另一个为被C ₁-C ₄烷氧基、羟基和羧基中的一个或多个取代的烷基。 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

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 an alkyl group substituted with one or more of C ₁ -C ₄ alkoxy, hydroxy and carboxy.

取代的烷基。所述的被

取代的烷基优选被

取代的C ₁-C ₄的烷基。所述的被

取代的C ₁-C ₄的烷基优选

其中，R ¹⁷、R ¹⁸和与它们相连接的氮原子一起形成一个取代的5-7元碳杂环；所述碳杂环中，杂原子为N，或N和O，杂原子数为1-4个。所述的5-7元碳杂环优选吡咯或哌啶。所述的取代的5-7元碳杂环中的取代基优选取代的C ₁-C ₄烷基、羟基、C ₁-C ₄羧基、C ₁-C ₄酯基和C ₁-C ₄酰胺基中的一个或多个。所述取代的C ₁-C ₄烷基中取代基优选羟基。 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

Wherein, R ¹⁷ , R ¹⁸ and the nitrogen atom 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 amides one or more of the bases. The substituent in the substituted C ₁ -C ₄ alkyl group is preferably a hydroxyl group.

取代的烷基时，所述的被

取代的烷基优选 In a preferred embodiment, when R ³ and R ⁴ are

substituted alkyl, the

Substituted alkyl preferred

In a preferred embodiment, R ³ or R ⁴ is preferably an alkyl substituted with 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)时，R ³位于环A上与L ¹相连的原子的间位或对位。 In a preferred embodiment, when R ³ is substituted or unsubstituted alkyl (by

substituted alkyl), R ³ is located in the meta or para position of the atom on ring A to which L ¹ is attached.

取代的烷基)时，R ⁴位于环B上与L ²相连的原子的间位或对位。 In a preferred embodiment, when R ⁴ is substituted or unsubstituted alkyl (eg, 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)时，环A上还可有0、1或2个取代基。当还可有1个取代基时，该取代基位于取代或未取代的烷基(例如被

取代的烷基)的对位、间位或邻位。 In a preferred embodiment, when R ³ is substituted or unsubstituted alkyl (eg, 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)时，环B上还可有0、1或2个取代基。当还可有1个取代基时，该取代基位于取代或未取代的烷基(例如被

取代的烷基)的对位、间位或邻位。 In a preferred embodiment, when R ⁴ is substituted or unsubstituted alkyl (eg, 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杂芳基和取代的C ₁-C ₁₀杂芳基中的一个或多个取代。当取代基为多个时，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 substituted. 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杂芳基、取代的C ₁-C ₁₀杂芳基和C ₁-C ₄烷氧基中的一个或多个取代。当取代基为多个时，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.

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 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

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.

优选

更优选

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

preferred

more preferred

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

优选

In a preferred embodiment, the group

preferred

独立地为

其中M ¹和N ¹为被

取代的烷基，或者M ¹和N ¹其中一个为被

取代的烷基，另一个为取代的烷氧基；其中M ¹和N ¹中，被

取代的烷基的定义和取代的烷氧基的定义，均同前R ³或R ⁴中相应的基团；R ¹⁷、R ¹⁸、R ³和R ⁴的定义均同前所述，n1和m1独立地为0、1或2。 In a preferred embodiment,

independently for

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 substituted alkyl group and the definition of 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其中一个为

另一个为被C ₁-C ₄烷氧基、C ₁-C ₁₀杂芳基和取代的C ₁-C ₁₀杂芳基中的一个或多个取代的烷氧基；R ³和R ⁴优选氢、 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优选被C ₁-C ₄烷氧基、C ₁-C ₁₀杂芳基和取代的C ₁-C ₁₀杂芳基中的一个或多个取代；R ¹⁷和R ¹⁸的定义均同前所述。 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 are 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 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; the definitions of R ¹⁷ and R ¹⁸ are both Same as before.

或者M ¹和N ¹其中一个为

另一个为被C ₁-C ₄烷氧基取代的烷氧基；R ³和R ⁴优选 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的定义均同前所述。 More preferably, M ¹ and N ¹ are

or one of M ¹ and N ¹ is

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, substituted by ¹⁸ F, F, Cl, Br, I The alkyl group, alkoxy group or alkoxy group substituted by C ₁ -C ₄ alkoxy group; R ¹⁷ and R ¹⁸ are as defined above.

优选

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

preferred

The definitions of N ¹ , R ¹⁷ and R ¹⁸ are as described above.

优选

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

preferred

The definitions of M ¹ , R ¹⁷ and R ¹⁸ are as described above.

独立地优选

In a preferred embodiment,

independently preferred

优选

In a preferred embodiment,

preferred

优选

In a preferred embodiment,

preferred

独立地优选

In a preferred embodiment,

independently preferred

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 are 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.

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

C ₆-C ₁₄芳基、取代的C ₆-C ₁₄芳基、C ₁-C ₁₀杂芳基、取代的C ₁-C ₁₀杂芳基、C ₁-C ₄烷氧基和C ₁-C ₄羧基中的一个或多个取代；所述的取代的烷氧基中的取代基为被 ¹⁸F、F、Cl、Br、I、氰基、羟基、

C ₆-C ₁₄芳基、取代的C ₆-C ₁₄芳基、C ₁-C ₁₀杂芳基和取代的C ₁-C ₁₀杂芳基中的一个或多个取代；当取代基为多个时，所述的取代基相同或不同。 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; 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; In each case, the substituents are the same or different.

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,

取代的C ₆-C ₁₄芳基和取代的C ₁-C ₁₀杂芳基中的一个或多个取代；所述的取代的烷氧基中的取代基优选被C ₁-C ₄烷氧基、C ₁-C ₁₀杂芳基和取代的C ₁-C ₁₀杂芳基中的一个或多个取代；当取代基为多个时，所述的取代基相同或不同。 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 groups; the substituents in the substituted alkyl groups are replaced by ¹⁸ F, F, Cl, Br, I,

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

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 absent (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 by one or more of ¹⁸ F, F, Cl, Br, I substituted alkyl,

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),

取代的C ₆-C ₁₄芳基和取代的C ₁-C ₁₀杂芳基中的一个或多个取代(进一步地R ³和R ⁴定义如下：(1)R ³和R ⁴优选-SR ¹¹，R ¹¹为取代的C ₁-C ₄烷基；(2)R ³和R ⁴优选被 ¹⁸F、F、Cl、Br、I中的一个或多个取代的烷基；所述的被 ¹⁸F、F、Cl、Br、I中的一个或多个取代的烷基优选被 ¹⁸F、F、Cl、Br和I中的一个或多个取代的C ₁-C ₄烷基，优选-C ¹⁸F ₃、-C ¹⁸FF ₂、-C ¹⁸F ₂F或-CF ₃；(3)R ³和R ⁴优选被

取代的烷基；所述的被

取代的烷基优选被

取代的C ₁-C ₄的烷基；所述的被

取代的C ₁-C ₄的烷基优选

其中，R ¹⁷和R ¹⁸一个为H，另一个为被C ₁-C ₄烷氧基、羟基和羧基中的一个或多个取代的烷基；或者R ¹⁷、R ¹⁸和与它们相连接的氮原子一起形成一个取代的5-7元碳杂环；所述碳杂环中，杂原子为N，或N和O，杂原子数为1-4个；所述的5-7元碳杂环优选哌啶；所述的取代的5-7元碳杂环中的取代基优选C ₁-C ₄羧基(当R ³和R ⁴为被

取代的烷基时，所述的 被

取代的烷基优选

)；(4)R ³和R ⁴优选被取代的C ₆-C ₁₄芳基取代的烷基，更优选

(5)R ³和R ⁴优选被取代的C ₁-C ₁₀杂芳基取代的烷基，更优选

(6)R ³和R ⁴优选取代的烷氧基，所述的取代的烷氧基中的取代基优选被C ₁-C ₄烷氧基、C ₁-C ₁₀杂芳基和取代的C ₁-C ₁₀杂芳基中的一个或多个取代，所述的取代的烷氧基优选

)。 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; the substituents in the substituted alkyl are preferably replaced by ¹⁸ F, F, Cl, Br, I,

One or more of the substituted C ₆ -C ₁₄ aryl and substituted C ₁ -C ₁₀ heteroaryl groups (further R ³ and R ⁴ are defined as follows: (1) R ³ and R ⁴ are preferably -SR ¹¹ , R ¹¹ is a 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; the ¹⁸ One or more of F, F, Cl, Br, I substituted alkyl preferably C ¹ -C ₄ alkyl substituted with _one or more of 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

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 the The nitrogen atoms 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 The ring is preferably piperidine; the substituents in the substituted 5-7-membered carbon heterocycle are preferably C ₁ -C ₄ carboxyl groups (when R ³ and R ⁴ are

substituted alkyl, the

Substituted alkyl preferred

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

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

).

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 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, I, eg -CH ₂ ¹⁸ F);

R ² is H;

L ¹ is -C(R ⁵ )=C(R ⁶ )- (preferably -CH=CH-);

不存在；

does not exist;

取代的烷基；所述的被

取代的烷基优选被

取代的C ₁-C ₄的烷基；所述的被

取代的C ₁-C ₄的烷基优选

其中，R ¹⁷和R ¹⁸一个为H，另一个为被C ₁-C ₄烷氧基、羟基和羧基中的一个或多个取代的烷基；或者R ¹⁷、R ¹⁸和与它们相连接的氮原子一起形成一个取代的5-7元碳杂环；所述碳杂环中，杂原子为N，或N和O，杂原子数为1-4个；所述的5-7元碳杂环优选哌啶；所述的取代的5-7元碳杂环中的取代基优选C ₁-C ₄羧基)。 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 (preferably quilt

Substituted alkyl; described by

Substituted alkyl groups are preferably

Substituted C ₁ -C ₄ alkyl;

Substituted C ₁ -C ₄ alkyl groups are preferred

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 the The nitrogen atoms 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 The ring is preferably piperidine; the substituents in the substituted 5-7-membered carbon heterocycle are preferably C ₁ -C ₄ carboxyl).

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

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:

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.

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:

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.

和环B中的

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

and in ring B

Can be the same or can be different.

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

The step-by-step synthesis method generally uses simple radionuclide-containing compounds to synthesize complex compounds of the present disclosure 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 radionuclide or a simple compound thereof to the precursor through an addition reaction to synthesize the compound of the present disclosure. The present disclosure also provides a preparation method of the ¹⁸ F-labeled biphenyl compound 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 -COOH, it is prepared by the following method: the method comprises the following steps: the compound represented by the general formula II-F is carried out as follows The deprotection reaction is shown to prepare the ¹⁸ F-labeled biphenyl compound shown in the general formula IA,

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 amino or carboxyl protecting group, R ^IIF1 is the same as N ¹ ; or, R ^IIF and M ¹ are the same, R ^IIF1 is a corresponding amino group containing N ¹ or a carboxyl protecting group; or R ^IIF is ^a corresponding amino or carboxyl protecting group for M , and R ^IIF is ^a N corresponding amino or carboxyl protecting group;

The preparation method of the ¹⁸ F-labeled biphenyl compound represented by the general formula II adopts any of the following methods:

(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 reaction shown below to obtain the ¹⁸ F-labeled biphenyl compound represented by the general formula II ,

或其酸式盐， The structure of compound II-A1 is as follows:

or its acid salt,

相同； 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, n1 is 0, 1 or 2, m1 is 0, 1, or 2; in this method, in Ring A and Ring B

same;

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

或其酸式盐， The structure of compound II-B1 is as follows:

or its acid salt,

相同； 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, n1 is 0, 1 or 2, m1 is 0, 1 or 2, and M is halogen; in this method, the

same;

(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 ,

或其酸式盐， The structure of compound II-C1 is as follows:

or its acid salt,

另一个为

在此方法中，环A和环B中的

相同或不同； 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, n1 is 0, 1 or 2, m1 is 0, 1, or 2; one of R ^IIC and R ^IIC1 is

another for

In this method, ring A and ring B

same or different;

(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 ,

或其酸式盐， The structure of compound II-D1 is as follows:

or its acid salt,

另一个为卤素，在此方法中，环A和环B中的

相同或不同； 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, n1 is 0, 1 or 2, m1 is 0, 1, or 2, and one of R ^IID and R ^IID1 is

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

same or different;

(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;

每个R ^17’和每个R ^18’相同或不同，且至少有一个有羧基保护基，不含羧基保护基的R ^17’和R ^18’分别与通式II中对应的R ¹⁷和R ¹⁸相同；此方法中，环A和环B中的

相同或不同。 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 corresponding R ¹⁷ and R ¹⁸ in the general formula II The same; in this method, in Ring A and Ring B

same or different.

In a preferred embodiment, the synthetic method of the compound of the present disclosure is as follows:

The present disclosure also provides compounds of general formula II-A, II-B, II-C, II-D, II-E, and II-F:

另一个为

R ^IID和R ^IID1其中一个为

另一个为卤素，R ^IIE和R ^IIE1为

每个R ^17’和每个R ^18’相同或不同，且至少有一个有羧基保护基，不含羧基保护基的R ^17’和R ^18’分别与通式II中对应的R ¹⁷和R ¹⁸相同；R ^IIF为M ¹对应的含有氨基或羧基保护基的基团，R ^IIF1与N ¹相同；或者，R ^IIF和M ¹相同，R ^IIF1为N ¹对应的含有氨基或羧基保护基的基团；或者R ^IIF为M ¹对应的含有氨基或羧基保护基的基团，R ^IIF1为N ¹对应的含有氨基或羧基保护基的基团。 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, m1 is 0, 1 or 2; M is halogen, one of R ^IIC and R ^IIC1 is

another for

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 corresponding R ¹⁷ and R ¹⁸ in the general formula II The same; R ^IIF is the 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 the group corresponding to N ¹ containing an amino or carboxyl protecting group or R ^IIF is a group corresponding to M ¹ containing an amino or carboxyl protecting group, and R ^IIF1 is a group corresponding to N ¹ containing an amino or 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 deprotection reaction shown below;

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 the above, and M ¹ and N ¹ are as defined above. 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 amino 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 the same, and R ^IIF 1 is a group corresponding to N ¹ containing at least one of an amino 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 an amino protecting group, a hydroxyl protecting group and a carboxyl protecting group, and R ^IIF 1 is a corresponding N ¹ containing amino protecting group, a hydroxyl protecting group and a carboxyl protecting group 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 group corresponding to M ¹ containing an amino protecting group and a hydroxyl protecting group, and R ^IIF1 is a group corresponding to N ¹ containing an amino protecting group and a 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, M1 and N1 contain at least ^{one of} -NH- and -OH, for example, M1 and N1 contain -NH- and -OH, another 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 C ₁ -C ₄ substituted by one or more of ¹⁸ F, F, Cl, Br and I alkyl, 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, 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. groups 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 compounds shown in the general formula IA, when R ^IIF and R ^IIF1 have an amino protecting group, the amino protecting group can be a conventional amino protecting group in the art. group, such as di-tert-butylmethyl dicarbonate ( _-Boc2O ), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc) or trimethylsilylethoxycarbonyl (Teoc), another example _-Boc2O .

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

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 the 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 the 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 can 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 its mixture. Mixed, another example is 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.

In one embodiment, the preparation method of the compound of general formula I-A 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 I-A, the definitions of letters and groups are the same as those described above. The conditions of the substitution reaction and the deprotection reaction are the same as described above.

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 may 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.

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 can 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 can 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.

The application also provides compound II-F2, II-F3 or II-F4:

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

The present disclosure also provides compounds shown below:

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

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

The present disclosure also provides the ¹⁸ F-labeled biphenyl compounds represented by the general formula I, their pharmaceutically acceptable salts, tautomers, mesomers, racemates, and stereoisomers The use of one or more of a precursor, a metabolite, a metabolic precursor and a drug precursor 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 disclosure also provides a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of the 18F-labeled biphenyl compound represented by general formula I, a pharmaceutically acceptable salt thereof, and a tautomer body, meso, racemate, stereoisomer, metabolite, metabolic precursor or prodrug, and a pharmaceutically acceptable carrier and/or diluent.

The compound of the present disclosure is injected into an animal (such as a mammal, which can be a mouse, a dog, a pig or a human), and an annihilation effect can occur in the process of participating in the metabolism of the human body, generating 2 energies substantially emitted in the 180° direction 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 disclosure 1) can be used for the diagnosis of tumors (such as malignant tumors), the identification of benign tumor lesions and the detection 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 tumor primary and metastases.

Therefore, the present disclosure also provides the ¹⁸ F-labeled biphenyl compounds represented by the general formula I, their pharmaceutically acceptable salts, tautomers, mesomers, racemates, stereoisomers Use of one or more of isomers, metabolites, metabolic precursors, and prodrugs in PET tumor imaging techniques.

In the present invention, tumor and cancer have the same definition, for example, tumor 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 .

In the present disclosure, according to the therapeutic purpose, 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 suspension) and the like, 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, ordinary 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, carbonic acid Calcium, 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 promoters, such as quaternary amine 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.

In order 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 glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides and the like .

In order to prepare a pharmaceutical composition in the form of an 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. For example, 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 of the following terms appearing in this disclosure and the 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, a _C2-12 alkenyl group refers to an alkenyl group having 2-12 carbon atoms. C _2-6 alkenyl refers to an alkenyl group having 2 to 6 carbon atoms, including vinyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The straight chain, branched or cyclic portion of an 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 alkynyl groups having 2-6 carbon atoms, including ethynyl, propynyl, butynyl, 3-methylbutynyl, and the like.

All terms hydroxyl represent

All terms amino means

All terms cyano represent -CN.

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

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. Although 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 those skilled in the art.

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 subjects use, preferably a mammalian subject, more preferably a human subject.

All terms pharmaceutically acceptable salts refer to pharmaceutically acceptable organic or inorganic salts of the compounds of the present disclosure. Exemplary salts include, but are not limited to: sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinic acid Salt, Lactate, Salicylate, Acid Citrate, Tartrate, Oleate, Tannin, Pantothenate, Bitartrate, Ascorbate, Succinate, Maleate, Dragon gentisinate, fumarate, gluconate, glucuronate, gluconate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate salt, 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 Ureas.

The compounds of the present disclosure 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 the embodiments of the present disclosure. 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 physiological, 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 disclosure 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 disclosure.

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

The positive progress effect of the present disclosure is that the ¹⁸ F-labeled biphenyl compounds of the present disclosure have a significant inhibitory effect on PD-1 and PD-L1, can effectively alleviate or treat cancer and other related diseases, and can be used in PET tumor imaging technology middle.

detailed description

In the following examples, abbreviations are explained:

Ci (curie) is the unit of radioactive intensity of a substance. 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 ; 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 warmed 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, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to obtain compound 1-h (730 mg, yield: 81%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.65 (s, 1H), 7.95 (t, J=8.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 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 crude product compound 1-g, which was directly used in the next reaction.

Synthesis of compound 1-f

1-g of the crude product obtained above 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=18.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 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=16.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 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=8.0 Hz, 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 it by ultrasonic for later use.

3) Prepare mobile phase 10mM tetrabutylammonium bromide+0.2% triethylamine solution (pH2.5±0.05): Weigh 6.45g tetrabutylammonium bromide and dissolve 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, and prepare for immediate use.

5) Preparation of standard solution: Take a bottle of 1 mg standard solution, add 1 mL of acetonitrile to dissolve it, and then 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 12 mM hydrochloric acid solution: measure 200 mL of ultrapure water with a graduated cylinder, add 200 μL of hydrochloric acid, and mix well for later use.

8) Prepare 12 mM hydrochloric acid ethanol solution: take 20 mL of ethanol, add 20 μL of hydrochloric acid, mix well and then 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 experiment

(1) Clean the CFN synthesis module, replace the ferrule, 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 rinse 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.

2) Compound 18F labeling 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 flask.

(2) Before passing the target, click "Recovery from TG", and the fluorine [18F] 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 [18F] ion water to QMA for adsorption, and then rinse the QMA column with 0.6 mL of TBAHCO ₃ , and the fluorine [18F] 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 crude reaction product was diluted with 10 mL of 12 mM hydrochloric acid solution and adsorbed on the C18 small column, then washed with 10 mL of ultrapure water, and washed 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 was diluted with 10 mL of 12 mM hydrochloric acid solution and passed through the C18 column, then used 10 mL of 12 mM hydrochloric acid solution to clean the C18 column, and finally washed 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. 5mci crude product is prepared by high performance liquid phase to obtain 20μCi compound 1 (yield: 0.4%).

A fluorinated compound with the same structure but no radioactivity was added to the 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 method, such as the document "Radionuclide Therapeutics", is a book published by the People's Medical Publishing House in 2006, and the author is Pan Zhongyun. "Handbook of Radiopharmaceuticals" [Kuwait] Weinwani et al; translated by Xia Zhenmin et al.

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

1. Preparation of 18F marker: 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) In this experiment, the dosage setting of non-18F-labeled substances is about 30 mg/kg. At the same time, according to the requirements of radiation safety and instrumental testing, the radioactive dose of 18F-labeled compound 1 is set to be about 200 μCi per animal. The actual radioactive dose of the injected drug is calculated according to the body weight of each animal and the specific activity of the labeled drug. The route of administration is intravenous injection. .

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

After intravenous administration, the tumor-bearing mice were subjected to 1h PET dynamic scan, and 3h, 5h, 7h and 9h static scans at four time points, keeping the animal stationary, and completing CT before/after the small animal PET scan scanning. Before scanning, the animals were anesthetized by 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 minutes, scanning energy window: 350-650Kev, and the scanning time was recorded.

4. Data collection and calculation results:

After the small animal PET/CT scan is completed, image reconstruction is performed, and 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 to obtain the radioactivity of the region of interest concentration (i.e., the value of 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 (abbreviated as %ID/g value) of each organ per gram of tissue was calculated, and the tumor target ratio was provided; Microsoft Office Excel was used to calculate the average value and standard deviation and other data.

5. Experimental results:

After administration of 18F-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.

Claims (15)

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

in, Ring A and Ring B are independently aromatic or heteroaromatic; 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 heterocycle alkyl, 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 heterocycle alkyl, substituted or unsubstituted aryl, substituted or 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 ¹ and R ² are independently H, deuterium, ¹⁸ F, F, Cl, Br, I, cyano or substituted or unsubstituted alkyl; Each R ³ and each R ⁴ is independently hydrogen, deuterium, hydroxy, -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 group refers to C ₆ -C ₁₄ aryl, C ₆ -C substituted One or more of ₁₄ aryl, C ₁ -C ₁₀ heteroaryl and substituted C ₁ -C ₁₀ heteroaryl; The substituted cycloalkyl group described in L ¹ and L ² , the substituted heterocycloalkyl group described in, the substituted aryl group described in, the substituted heteroaryl group described in, R ¹ and R ² described in ^The substituents in the substituted alkyl group, ^the substituted alkyl group described in each ^R3 and each R4, or the substituted alkoxy group described are selected from F, F, Cl, Br, I, cyano base, 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 amide 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 -C ₄ alkyl groups described in R ¹⁷ and R ¹⁸ , the substituted C ₆ -C ₁₄ aryl groups, the substituted C ₃ -C ₆ cycloalkyl groups, the substituted C 6 -C 6 cycloalkyl groups, and the Substituents in C ₁ -C ₄ alkoxy and said substituted 5-7 membered carbon heterocycle 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 amide group; In R ¹⁷ and R ¹⁸ , when said substituted C ₁ -C ₄ alkyl group, said substituted C ₆ -C ₁₄ aryl group, said substituted C ₃ -C ₆ cycloalkyl group, said substituted C 3 -C 6 cycloalkyl group, said When the substituents in the substituted C ₁ -C ₄ alkoxy and the substituted 5-7-membered carboheterocycle are substituted C ₁ -C ₄ alkyl groups, among the substituents, the substituted C ₁ Substituents in -C ₄ alkyl are selected 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, hydroxyl,

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 amide group;

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

R ^a11 is C ₁ -C ₄ alkyl; All the above C ₁ -C ₁₀ heteroaryl groups refer to C ₁ -C ₁₀ heteroaryl groups with heteroatoms selected from N, O and S, and the number of heteroatoms is 1-4; 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 -C ₄ alkanes one or more of radicals and C ₁ -C ₄ alkoxy groups; 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 compounds represented by the general formula I according to claim 1, their pharmaceutically acceptable salts, tautomers, mesomers, racemates, stereoisomers or a prodrug characterized by,

Ring A and Ring B are independently aromatic or heteroaromatic; 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 heterocycle alkyl, 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 heterocycle alkyl, substituted or unsubstituted aryl, substituted or 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 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 is independently hydrogen, deuterium, hydroxy, -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 group refers to C ₆ -C ₁₄ aryl, C ₆ -C substituted One or more of ₁₄ aryl, C ₁ -C ₁₀ heteroaryl and substituted C ₁ -C ₁₀ heteroaryl; The substituted cycloalkyl group described in L ¹ and L ² , the substituted heterocycloalkyl group described in, the substituted aryl group described in, the substituted heteroaryl group described in, R ¹ and R ² described in ^The substituents in the substituted alkyl group, ^the substituted alkyl group described in each ^R3 and each R4, or the substituted alkoxy group described are selected from F, F, Cl, Br, I, cyano base, 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 amide group;

In, 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 -C ₄ alkyl groups described in R ¹⁷ and R ¹⁸ , the substituted C ₆ -C ₁₄ aryl groups, the substituted C ₃ -C ₆ cycloalkyl groups, the substituted C 6 -C 6 cycloalkyl groups, and the Substituents in C ₁ -C ₄ alkoxy and said substituted 5-7 membered carbon heterocycle 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 amide group; In R ¹⁷ and R ¹⁸ , when said substituted C ₁ -C ₄ alkyl group, said substituted C ₆ -C ₁₄ aryl group, said substituted C ₃ -C ₆ cycloalkyl group, said substituted C 3 -C 6 cycloalkyl group, said When the substituents in the substituted C ₁ -C ₄ alkoxy and the substituted 5-7-membered carboheterocycle are substituted C ₁ -C ₄ alkyl groups, among the substituents, the substituted C ₁ Substituents in -C ₄ alkyl are selected 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, hydroxyl,

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 amide group;

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

R ^a11 is C ₁ -C ₄ alkyl; All the above C ₁ -C ₁₀ heteroaryl groups refer to C ₁ -C ₁₀ heteroaryl groups with heteroatoms selected from N, O and S, and the number of heteroatoms is 1-4; 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 -C ₄ alkanes one or more of radicals and C ₁ -C ₄ alkoxy groups; 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 compounds represented by the general formula I according to claim 1, their pharmaceutically acceptable salts, tautomers, mesomers, racemates, stereoisomers or a prodrug wherein R 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 Constructs or prodrugs characterized by, 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 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, preferably the 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 C ₁ -C ₆ heteroaromatic rings, most preferably acridine, carbazole, cinnoline, carboline, quinoxaline, imidazole, pyrazole, pyrrole, indole, indoline, benzotriazole, benzimidazole, furan, thiophene, isothiazole, benzothiophene, dihydrobenzothiophene, benzofuran, isobenzofuran, benzoxazole, benzofurazan, benzopyrazole, Quinoline, isoazindene, isoquinoline, oxazole, oxadiazole, isoxazole, indole, pyrazine, pyridopyridine, tetrazolopyridine, pyridazine, pyridine, naphthyridine, pyrimidine, pyrrole, tetrazole, thiadiazole, thiazole, thiophene, triazole, quinazoline, tetrahydroquinoline, dihydrobenzimidazole, dihydrobenzofuran, 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 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 C ₂ -C ₈ heterocycloalkyl with 1, 2, 3 or 4 heteroatoms selected from O, N and S, 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, pyrrole Alkyl, morpholinyl, thiomorpholinyl, dihydrofuranyl, dihydroimidazolyl, indoline, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydroisothiazolyl Hydroxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl , dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidine, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl or its N-oxide; And/or, the 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, phenanthryl, anthracenyl or acenaphthyl, And/or, the heteroaryl group refers to a C ₁ -C ₁₀ heteroaryl group with heteroatoms selected from O, N and S, and the number of heteroatoms is 1, 2, 3 or 4, more preferably heteroatoms C ₁ -C ₈ heteroaryl group 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 C ₁ -C ₆ heteroaryl groups, most preferably benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzoyl thienyl, benzoxazolyl, carbazolyl, carboline, cinnoline, furyl, imidazolyl, indoline, indolyl, indazolyl, isobenzofuranyl, isoazepine Indenyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthymidyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazine base, pyrazolyl, pyridazinyl, pyridopyridyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, tetrazolopyridine base, thiadiazolyl, thiazolyl, thienyl or triazolyl; And/or, the alkyl group refers to a branched and straight chain saturated aliphatic hydrocarbon group comprising 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, most preferably methyl yl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, 4,4-dimethylpentyl base, 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 a methoxy group, an ethoxy group group, 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, 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, preferably azetidinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydroimidazolyl, dihydroimidazolyl Indoline, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydro Pyrimidyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrotriazolyl or dihydroazetidinyl. The ¹⁸ F-labeled biphenyl compound represented by general formula I according to any one of claims 1 to 4, its pharmaceutically acceptable salt, tautomer, meso, and racemate , a stereoisomer or a prodrug characterized in that, 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( ^R5 )=C( ^R6 ) ^- , ^-CR7R8 -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 each independently hydrogen or deuterium; And/or, R ¹ is ¹⁸ F, F, Cl, Br, I, cyano, substituted or unsubstituted alkyl, and the alkyl is preferably C ₁ -C ₄ alkyl, more preferably methyl; the 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, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, the substituents in the substituted alkyl are preferably ¹⁸ F, F, Cl, Br, I, cyano, C One or more of ₁ - _C4 alkyl group, hydroxyl group, _C1 - _C4 alkoxy group, _C1 - _C4 carboxyl group, _C1 - _C4 ester group and _C1 - _C4 amide group; 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 Substituted alkoxy; 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 of R ¹ , R 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 or 2, its pharmaceutically acceptable salt, tautomer, meso, racemate, stereoisomer Constructs or prodrugs characterized by, R ¹ and R ² are independently ¹⁸ F, F, Cl, Br, I, alkyl or alkyl substituted with one or more of ¹⁸ F, F, Cl, Br, I; Alternatively, R ³ and R ⁴ are independently ¹⁸ F, F, Cl, Br, I; Alternatively, R ³ and R ⁴ are substituted or unsubstituted alkyl groups, and the substituents in the substituted alkyl groups are replaced 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 of the C ₄ carboxyl groups are substituted, preferably by ¹⁸ F, F, Cl, Br, I,

One or more substitutions in the substituted C ₆ -C ₁₄ aryl group and the substituted C ₁ -C ₁₀ heteroaryl group, when there are multiple substituent groups, the substituent groups are the same or different, Alternatively, R ³ and R ⁴ are substituted or unsubstituted alkoxy groups, and the substituents in the substituted alkoxy groups 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 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 Constructs or prodrugs characterized by, R ¹ and R ² are independently ¹⁸ F, F, Cl, Br, I, C ₁ -C ₄ alkyl or C ₁ -C substituted with one or more of ¹⁸ F, F, Cl, Br and I ₄ ^alkyl ( _eg ^-CH218F , _-CH18F2 , _{-CH18FF ,} ^-C18F3 , ^-C18FF2 _, ^-C18F2F , _{-CH2F ,} ^-CHF2 or -CF ₃ ); or, R ³ and R ⁴ are alkyl substituted by ¹⁸ F, F, Cl, Br, I, and the alkyl substituted by ¹⁸ F, F, Cl, Br, I is preferably ¹⁸ One or more of F, F, Cl, Br and I substituted C ₁ -C ₄ alkyl, preferably -C ¹⁸ F ₃ , -C ¹⁸ FF ₂ , -C ¹⁸ F ₂ F or -CF ₃ , Alternatively, ^R3 and ^R4 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

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 the The nitrogen atoms 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 The ring 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 group and one or more of C ₁ -C ₄ amide groups; the substituents in the substituted C ₁ -C ₄ alkyl groups are preferably hydroxyl groups; when R ³ and R ⁴ are

substituted alkyl, the

Substituted alkyl preferred

Alternatively, R ³ and R ⁴ are alkyl substituted by substituted C ₆ -C ₁₄ aryl, preferably

Alternatively, R ³ and R ⁴ are alkyl substituted with substituted C ₁ -C ₁₀ heteroaryl, preferably

Alternatively, when R ³ is a substituted or unsubstituted alkyl group, R ³ is located in the meta or para position of the atom on ring A to which L ¹ is attached; Alternatively, when R ⁴ is a substituted or unsubstituted alkyl group, R ⁴ is located in the meta or para position of the atom on ring B to which L ² is attached; Alternatively, when R ³ is a substituted or unsubstituted alkyl group, there may be 0, 1 or 2 substituents on the ring A, and when there may be 1 substituent, the substituent is located in the substituted or unsubstituted alkyl group the para, meta or ortho position of the base; Alternatively, when R ⁴ is a substituted or unsubstituted alkyl group, there may be 0, 1 or 2 substituents on the ring B, and when there may be 1 substituent, the substituent is located in the substituted or unsubstituted alkyl group the para, meta or ortho position of the base; Alternatively, R ³ and R ⁴ are substituted or unsubstituted alkoxy groups, and the substituents in the substituted alkoxy groups 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 ₁ One or more substitutions in -C ₁₀ heteroaryl and C ₁ -C ₄ alkoxy, when there are multiple substituents, the substituents are the same or different; the substituted alkoxy is preferably

Alternatively, when R ³ is a substituted or unsubstituted alkoxy group, R ³ is located in the ortho or meta position of the atom on ring A to which L ¹ is attached; Alternatively, 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 ^. The ¹⁸ F-labeled biphenyl compound represented by the general formula I according to any one of claims 1-7, its pharmaceutically acceptable salt, tautomer, meso, and racemate , a stereoisomer or a prodrug characterized in that, group

for

preferably

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

more preferably

or,

independently for

where M ¹ and N ¹ are the

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

substituted alkyl, and the other is substituted alkoxy; wherein R ¹⁷ , R ¹⁸ , R ³ and R ⁴ are defined as described in any one of claims 1-5, 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

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 are 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, said 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 claims 1-5; More preferably, M ¹ and N ¹ are

or one of M ¹ and N ¹ is

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, among ¹⁸ F, F, Cl, Br, I One or more 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 1-5. The ¹⁸ F-labeled biphenyl compounds represented by the general formula I according to claim 8, their pharmaceutically acceptable salts, tautomers, mesomers, racemates, stereoisomers or a prodrug characterized by,

for

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

for

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

independently for

and / or,

independently for

The ¹⁸ F-labeled biphenyl compounds represented by the general formula I as claimed in any one of claims 1-10, their pharmaceutically acceptable salts, tautomers, mesomers, and racemates , a stereoisomer or a prodrug, wherein the ¹⁸ F-labeled biphenyl compound shown in the general formula I is selected from any of the following compounds:

The ¹⁸ F-labeled biphenyl compound represented by the general formula I according to any one of claims 1-11, its pharmaceutically acceptable salt, tautomer, meso, and racemate , a stereoisomer or a prodrug, 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:

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 claims 1-11 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 shown in general formula I as claimed in any one of claims 1-11, its pharmaceutically acceptable salt, tautomer, meso, racem The application of cyclomer, stereoisomer or prodrug in the preparation of PD-1 inhibitor and/or PD-L1 inhibitor. A ¹⁸ F-labeled biphenyl compound shown in general formula I as claimed in any one of claims 1-11, its pharmaceutically acceptable salt, tautomer, meso, racem Use of one or more of spinomers, stereoisomers, metabolites, metabolic precursors, and prodrugs as molecular probes for cancer imaging or in preparation for the prevention, mitigation or treatment of cancer, infection, autoimmunity The application in the medicine of sexual diseases or related diseases, the cancer is preferably one or one of lung cancer, esophageal cancer, gastric cancer, colorectal cancer, liver cancer, nasopharyngeal cancer, brain tumor, breast cancer, cervical cancer, blood cancer and bone cancer. variety. A pharmaceutical composition comprising the ¹⁸ F-labeled biphenyl compound of the general formula I shown in any one of claims 1-11, and a pharmaceutically acceptable salt thereof of an effective dose for treatment and/or prevention , tautomer, meso, racemate, stereoisomer, metabolite, metabolic precursor or prodrug, and a pharmaceutically acceptable carrier and/or diluent.