18F-labeled biphenyl compounds, intermediates thereof, preparation methods, pharmaceutical compositions and applications

Abstract

The present disclosure provides a 18F-labeled biphenyl compound, its intermediate, preparation method, pharmaceutical composition and application. The biphenyl compound disclosed in the present disclosure has a significant inhibitory effect on PD-1 and / or PD-L1, can effectively alleviate or treat cancer and other related diseases, and can be used in PET tumor imaging technology.

Description

Technical Field

[0001] The present disclosure relates to a 18 F-labeled biphenyl compounds, intermediates thereof, preparation methods, pharmaceutical compositions and applications. Background Art

[0002] PD-1 (programmed death 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. Immune regulation targeting PD-1 is of great significance in anti-tumor, anti-infection, anti-autoimmune disease and organ transplant survival. Its ligand PD-L1 can also be used as a target, and the corresponding antibody can also play the same role.

[0003] PD-1 / PD-L1 plays a negative immunoregulatory role. When PD-1 on the cell surface couples with PD-L1, it can lead to the phosphorylation of Tyr in the immunoreceptor tyrosine-based switch motif (ITSM) domain in the cytoplasm of T cells. Then the phosphorylated Tyr can recruit phosphatases protein tyrosinase 2 and protein tyrosinase 1, which can not only block the activation of extracellular signal-regulated kinase, but also block the activation of phosphatidylinositol 3-kinase (PI3K) and serine-threonine protein kinase (Akt), and finally inhibit T lymphocyte proliferation and the secretion of related cytokines. PD-1 / PD-L1 signaling can inhibit T cell activation and proliferation. At the same time, the secretion of cytokines interleukin 2 (IL2), interferon γ and IL-10 is also reduced (Eur. J. Immunol., 2002, 32 (3), 634-643.). In addition, the PD-1 / PD-L1 signal also has a similar effect on the immune function of B cells as that of T cells. When PD-1 cross-links with the B cell antigen receptor, the PD-1 cytoplasmic region interacts with tyrosinase containing the protein tyrosinase 2 binding site, ultimately blocking the activation of B cells. The role of the immune negative regulatory molecule PD-1 / PD-L1 in tumor immune escape has attracted more and more attention. A large number of studies have confirmed that the PD-L1 on the surface of tumor cells in the tumor microenvironment increases, and at the same time binds to PD-1 on activated T cells, transmitting negative regulatory signals, leading to apoptosis or immune anergy of tumor antigen-specific T cells, thereby inhibiting the immune response and promoting the escape of tumor cells.

[0004] Currently, the PD-1 / PD-L1 antibody inhibitors on the market include Nivolumab from BMS (2014), Lambrolizumab from Merck (2014), and Atezolizumab from Roche (2016). The PD-1 / PD-L1 antibody inhibitors under development include Pidilizumab from Cure Tech, AMP-224 from GSK, and MEDI-4736 from AstraZeneca. All of the above are biological macromolecules, while small molecule PD-1 / PD-L1 inhibitors are still in the early stage of research and development. Curis peptide-based PD-L1 small molecule inhibitor AC-170 (WO2012168944, WO2015033299, WO2015033301, WO2015036927, WO2015044900) has just entered Phase I clinical trials, and BMS benzyl phenyl ether-based small molecule PD-1 / PD-L1 inhibitors (WO2015034820, WO2015160641, WO2017066227, WO2018009505, WO2018044963, WO201 8118848) is still in the preclinical research stage, and Incyte has also made a series of small molecule PD-1 / PD-L1 inhibitors (WO2017070089, WO2017087777, WO2017106634, WO2017112730, WO2017192961, WO2017205464, WO2017222976, WO2018013789, WO2018044783, WO2018119221, WO2018119224, WO2018119263, WO2018219266, WO2018119286) are still in preclinical research. Compared with biological macromolecules, small molecule compounds can pass through the cell membrane and act on intracellular targets, so they have a wide range of applications. Secondly, small molecules often have good bioavailability and compliance after chemical modification, effectively avoiding decomposition and inactivation by enzymes in the digestive tract. Finally, the research on small molecules is also quite mature in many aspects such as production process, dosage form design and administration method.

[0005] There is no existing technology 18 F-labeled biphenyl compounds have been successfully marketed as small molecule PD-1 / PD-L1 inhibitors and have been reported to be useful in PET tumor imaging technology. This situation needs to be addressed urgently. Summary of the invention

[0006] The purpose of this disclosure is to provide a completely different 18 F-labeled biphenyl compounds, intermediates thereof, preparation methods, pharmaceutical compositions and applications. 18F-labeled biphenyl compounds have a significant inhibitory effect on PD-1 and / or PD-L1, and can effectively alleviate or treat cancer and other related diseases.

[0007] The present invention provides a general formula I 18 F-labeled biphenyl compounds, pharmaceutically acceptable salts, tautomers, mesomers, racemates, stereoisomers or prodrugs thereof:

[0008]

[0009] in,

[0010] Ring A and Ring B are independently an aromatic ring or a heteroaromatic ring;

[0011] L 1 For chemical bonds, alkynyl groups, -C(R 5 )=C(R 6 )-or-CR 7 R 8 -CR 9 R 10 -, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0012] L 2 For chemical bonds, alkynyl groups, -C(R 5 )=C(R 6 )-or-CR 7 R 8 -CR 9 R 10 -, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or absent;

[0013] R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently hydrogen, deuterium, 18 F, F, Cl, Br, I, cyano, or substituted or unsubstituted alkyl;

[0014] R 1 and R 2 independently H, deuterium, 18 F, F, Cl, Br, I, cyano, or substituted or unsubstituted alkyl;

[0015] Each R 3 and each R 4 are independently hydrogen, deuterium, hydroxyl, -SR 11、-NR 12 R 13 , 18 F, F, Cl, Br, I, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -CONH 2 、-COR 14 、-COOR 15 or-OCOR 16 ; R 11 , R 12 and R 13 are independently hydrogen, C 1 -C 4 Alkyl, substituted C 1 -C 4 Alkyl or -COR a , R a Hydrogen, hydroxyl, C 1 -C 4 Alkyl or C 1 -C 4 Alkoxy;

[0016] R 14 , R 15 and R 16 are independently hydrogen, C 1 -C 4 Alkyl or substituted C 1 -C 4 alkyl;

[0017] R 11 , R 12 , R 13 , R 14 , R 15 and R 16 wherein the substituted C 1 -C 4 Alkyl substitution refers to the substitution of C 6 -C 14 Aryl, substituted C 6 -C 14 Aryl, C 1 -C 10 Heteroaryl and substituted C 1 -C 10 one or more substitutions in heteroaryl;

[0018] L 1 and L 2 The substituted cycloalkyl, the substituted heterocycloalkyl, the substituted aryl, the substituted heteroaryl, R 1 and R 2 The substituted alkyl group described in 3 and each R 4The substituents in the substituted alkyl or substituted alkoxy are selected from 18 F, F, Cl, Br, I, cyano, C 1 -C 4 Alkyl, hydroxyl, C 6 -C 14 Aryl, substituted C 6 -C 14 Aryl, C 1 -C 10 Heteroaryl, substituted C 1 -C 10 Heteroaryl, C 1 -C 4 Alkoxy, C 1 -C 4 Carboxyl, C 1 -C 4 Ester group and C 1 -C 4 one or more of the amide groups; 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 Cycloalkyl, substituted or unsubstituted C 1 -C 4 Alkoxy; or R 17 , R 18 Together with the nitrogen atom to which they are connected, they form a substituted or unsubstituted 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; each R 17 and each R 18 Same or different;

[0019] R 17 and R 18 The substituted C 1 -C 4 Alkyl, the substituted C 6 -C 14 Aryl, the substituted C 3 -C 6 Cycloalkyl, the substituted C 1 -C 4 The substituents in the alkoxy group and the substituted 5-7 membered carbon heterocycle are selected from 18 F, F, Cl, Br, I, cyano, C 1 -C 4Alkyl, 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, hydroxyl, C 1 -C 4 Alkoxy, C 1 -C 4 Carboxyl, C 1 -C 4 Ester group and C 1 -C 4 one or more of the amide groups;

[0020] R 17 and R 18 In the case where the substituted C 1 -C 4 Alkyl, the substituted C 6 -C 14 Aryl, the substituted C 3 -C 6 Cycloalkyl, the substituted C 1 -C 4 The substituents in the alkoxy and the substituted 5-7 membered carbon heterocycle are substituted C 1 -C 4 When the alkyl group is substituted, the substituted C 1 -C 4 The substituents in the alkyl group 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, C 1 -C 4 Alkoxy, C 1 -C 4 Carboxyl, C 1 -C 4 Ester group and C 1 -C 4 one or more of the amide groups; In, R a1 and R b1 are independently hydrogen, C 1 -C 4 Alkyl or R a11 C 1 -C 4 The alkyl group;

[0021] All of the above C 1 -C 10 Heteroaryl refers to a C 1 -C 10 heteroaryl;

[0022] All of the above substituted C 6 -C 14 Aryl and substituted C 1 -C 10 The substituents in the heteroaryl group are selected from cyano, 18 F, F, Cl, Br, I, hydroxyl, C 1 -C 4 Alkyl and C 1 -C 4 one or more of the alkoxy groups;

[0023] When there are multiple substituents, the substituents are the same or different;

[0024] m and ma are independently 1, 2, 3 or 4;

[0025] n and na are independently 1, 2, 3 or 4;

[0026] The condition is: at least one R 1 , R 2 , L 1 , L 2 , R 3 and R 4 Contains one or more (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10) 18 F;

[0027] or Does not exist.

[0028] In a preferred embodiment, the general formula I 18 F-labeled biphenyl compounds, pharmaceutically acceptable salts, tautomers, mesomers, racemates, stereoisomers or prodrugs thereof:

[0029] Among them, R 1 and R 2 Independently for deuterium, 18F, F, Cl, Br, I, cyano, or substituted or unsubstituted alkyl;

[0030] exist;

[0031] The definitions of letters and groups are the same as above.

[0032] In a preferred embodiment, the general formula I 18 F-labeled biphenyl compounds, pharmaceutically acceptable salts, tautomers, mesomers, racemates, stereoisomers or prodrugs thereof:

[0033]

[0034] Among them, R 2 is H; Does not exist.

[0035] In this disclosure, all terms aromatic ring refer to any stable monocyclic or bicyclic carbon ring with up to 7 atoms in each ring, wherein at least one ring is aromatic. All terms aromatic ring are preferably C 6 -C 20 Aromatic ring, more preferably C 6 -C 14 Aromatic ring, most preferably C 6 -C 10 Aromatic ring. Examples of aromatic rings include, but are not limited to, benzene, naphthalene, tetralin, indane, biphenyl, phenanthrene, anthracene, or acenaphthene.

[0036] In the present disclosure, all terms heteroaromatic ring are intended to represent a stable monocyclic or bicyclic ring with up to 7 atoms in each ring, wherein at least one ring is aromatic and contains 1-4 heteroatoms selected from O, N, and S. In the present disclosure, "heteroaromatic ring" preferably refers to a C 1 -C 10 The heteroaromatic ring is preferably selected from O, N and S, and the number of heteroatoms is 1, 2, 3 or 4 C 1 -C 8 The heteroaromatic ring is more preferably a heteroatom selected from O, N and S, and the number of heteroatoms is 1, 2, 3 or 4 C 1 -C 6Examples of heteroaromatic rings include, but are not limited to, acridine, carbazole, cinnoline, carboline, quinoxaline, imidazole, pyrazole, pyrrole, indole, dihydroindole, benzotriazole, benzimidazole, furan, thiophene, isothiazole, benzothiophene, dihydrobenzothiophene, benzofuran, isobenzofuran, benzoxazole, benzofurazan, benzopyrazole, quinoline, isoazaindene, isoquinoline, oxazole, oxadiazole, isoxazole, indole, pyrazine, pyridopyridine, tetrazolopyridine, pyridazine, pyridine, naphthyrimidine, pyrimidine, pyrrole, tetrazole, thiadiazole, thiazole, thiophene, triazole, quinazoline, tetrahydroquinoline, dihydrobenzimidazole, dihydrobenzofuran, dihydrobenzoxazole, and dihydroquinoline.

[0037] In this disclosure, all terms cycloalkyl are preferably C 3 -C 20 Cycloalkyl, more preferably C 3 -C 10 Cycloalkyl, most preferably C 3 -C 6 Cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecane and cyclododecyl, and cyclohexenyl.

[0038] In the present disclosure, all terms heterocycloalkyl refer to C 2 -C 10 In the present disclosure, the heterocycloalkyl group preferably has a heteroatom selected from O, N and S, and the number of heteroatoms is 1, 2, 3 or 4 C 2 -C 8 The heterocycloalkyl group is preferably a heterocycloalkyl group having 1, 2, 3 or 4 heteroatoms selected from O, N and S. 2 -C 6 Examples of heterocycloalkyl include, but are not limited to, tetrahydropyranyl, azetidinyl, 1,4-dioxanyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, and N-oxides thereof.

[0039] In this disclosure, all the terms aryl are preferably C 6 -C 20 Aryl, more preferably C 6 -C 14 Aryl, most preferably C 6 -C 10Aryl. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthrenyl, anthracenyl, and acenaphthyl.

[0040] In the present disclosure, all the terms heteroaryl preferably have heteroatoms selected from O, N and S, and the number of heteroatoms is 1, 2, 3 or 4 C 1 -C 10 The heteroaryl group is preferably a heteroaryl group, wherein the heteroatom is selected from O, N and S, and the number of heteroatoms is 1, 2, 3 or 4 C 1 -C 8 The heteroaryl group is more preferably a heteroaryl group with a heteroatom selected from O, N and S, and a C 1 -C 6 Examples of heteroaryl groups include, but are not limited to, benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indazolyl, isobenzofuranyl, isoazaindenyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyrimidinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridinyl, thiadiazolyl, thiazolyl, thienyl, and triazolyl.

[0041] In the present 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 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 various isomers thereof. In the present disclosure, alkyl is preferably C 1 -C 4 The alkyl group is more preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group or a tert-butyl group.

[0042] In the present disclosure, all terms alkoxy refers to a cyclic or non-cyclic alkyl group with the stated number of carbon atoms connected via an oxygen bridge. Thus, alkoxy includes the above definitions of alkyl and cycloalkyl. In the present disclosure, alkoxy is preferably C 1 -C 4 The alkoxy group is more preferably a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group or a tert-butoxy group.

[0043] In the present disclosure, all terms 5-7 membered carbon heterocycle refer to a 5-7 membered carbon heterocycle having a heteroatom selected from O, N and S, a heteroatom number of 1, 2, 3 or 4, and a carbon atom number of 1, 2, 3, 4, 5 or 6. The ring atoms in the 5-7 membered carbon heterocycle are 5, 6 or 7. In the present disclosure, the 5-7 membered carbon heterocycle includes, but is not limited to, azetidinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydroimidazolyl, dihydroindolinyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrotriazolyl and dihydroazetidinyl.

[0044] In a preferred embodiment, ring A is a benzene ring.

[0045] In a preferred embodiment, ring B is a benzene ring or a pyridine ring.

[0046] 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-.

[0047] 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-.

[0048] In a preferred embodiment, L 2 Does not exist.

[0049] In a preferred embodiment, R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently hydrogen or deuterium.

[0050] In a preferred embodiment, R 1 For H.

[0051] In a preferred embodiment, R 1 for 18 F, F, Cl, Br, I.

[0052] In a preferred embodiment, R 1 It is cyano.

[0053] In a preferred embodiment, R 1 is an alkyl group, preferably C 1 -C 4 Alkyl, more preferably methyl.

[0054] In a preferred embodiment, R 1 The substituent in the substituted alkyl is preferably 18 One or more of F, F, Cl, Br, I and hydroxyl. 1 Preferred 18 Alkyl substituted by one or more of F, F, Cl, Br, and I. 18 The alkyl group substituted by one or more of F, F, Cl, Br, I is preferably 18 C substituted by one or more of F, F, Cl, Br and I 1 -C 4 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 2or -CF 3 .

[0055] In a preferred embodiment, R 1 Located at the 5' position of the benzene ring.

[0056] In a preferred embodiment, Located at the 4' position of the benzene ring.

[0057] In a preferred embodiment, R 2 For H.

[0058] In a preferred embodiment, R 2 For deuterium.

[0059] In a preferred embodiment, R 2 for 18 F, F, Cl, Br, I.

[0060] In a preferred embodiment, R 2 It is cyano.

[0061] In a preferred embodiment, R 2 is an alkyl group, preferably C 1 -C 4 The alkyl group is more preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group or a tert-butyl group.

[0062] In a preferred embodiment, R 2 is a substituted alkyl group, preferably a substituted C 1 -C 4 The substituent in the substituted alkyl is preferably 18 F, F, Cl, Br, I, cyano, C 1 -C 4 Alkyl, hydroxyl, C 1 -C 4 Alkoxy, C 1 -C 4 Carboxyl, C 1 -C 4 Ester group and C 1 -C 4 One or more of the amide groups, when there are multiple substituents, the substituents are the same or different. 18 Alkyl substituted with F, F, Cl, Br, I is preferably 18 C substituted by one or more of F, F, Cl, Br and I 1 -C 4 Alkyl, more preferably -CH 2 18 F, -CH 18 F 2 、-CH 18FF, -C 18 F 3 , -C 18 FF 2 , -C 18 F 2 F, -CH 2 F, -CHF 2 or -CF 3 .

[0063] In a preferred embodiment, R 2 At position 1 of the benzene ring.

[0064] In a preferred embodiment, R 3 and R 4 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.

[0065] In a preferred embodiment, R 3 and R 4 Preferably, independently deuterium, 18 F, F, Cl, Br, I, cyano, -SR 11 , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.

[0066] In a preferred embodiment, R 3 and R 4 Preferred-SR 11 , R 11 To replace C 1 -C 4 alkyl.

[0067] In a preferred embodiment, R 3 and R 4 Best 18 F, F, Cl, Br, I.

[0068] In a preferred embodiment, R 3 and R 4 Preferably, the substituents in the substituted alkyl group 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 -C10 Heteroaryl, C 1 -C 4 Alkoxy and C 1 -C 4 One or more substituents in the carboxyl group. When there are multiple substituents, the substituents are the same or different.

[0069] In a preferred embodiment, R 3 and R 4 The substituents in the substituted alkyl are preferably 18 F, F, Cl, Br, I, Substituted C 6 -C 14 Aryl and substituted C 1 -C 10 One or more substituents in the heteroaryl group. When there are multiple substituents, the substituents are the same or different.

[0070] In a preferred embodiment, R 3 and R 4 Preferred 18 Alkyl substituted with F, F, Cl, Br, or I. 18 Alkyl substituted with F, F, Cl, Br, I is preferably 18 C substituted by one or more of F, F, Cl, Br and I 1 -C 4 Alkyl, preferably -C 18 F 3 , -C 18 FF 2 , -C 18 F 2 F or -CF 3 .

[0071] In a preferred embodiment, R 3 and R 4 Preferred The substituted alkyl group. The substituted alkyl group is preferably Substituted C 1 -C 4 The alkyl group Substituted C 1 -C 4 The alkyl group is preferably Among them, R 17 and R 18 One is H, and the other is an alkyl group substituted with a hydroxyl group and / or a carboxyl group. 17 and R 18 One is H and the other is C 1 -C4 Alkyl substituted by one or more of alkoxy, hydroxy and carboxyl.

[0072] In a preferred embodiment, R 3 and R 4 Preferred The substituted alkyl group. The substituted alkyl group is preferably Substituted C 1 -C 4 The alkyl group Substituted C 1 -C 4 The alkyl group is preferably Among them, R 17 , R 18 Together with the nitrogen atom to which they are connected, they 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 substituent in the substituted 5-7 membered carbon heterocycle is preferably substituted C 1 -C 4 Alkyl, hydroxyl, C 1 -C 4 Carboxyl, C 1 -C 4 Ester group and C 1 -C 4 One or more of the amide groups. 1 -C 4 The substituent in the alkyl group is preferably a hydroxyl group.

[0073] In a preferred embodiment, when R 3 and R 4 For When the alkyl group is substituted, the The substituted alkyl group is preferably

[0074]

[0075] In a preferred embodiment, R 3 or R 4 Preferably substituted C 6 -C 14 Aryl-substituted alkyl, more preferably

[0076] In a preferred embodiment, R 3 or R 4 Preferably substituted C 1 -C 10 Heteroaryl-substituted alkyl, more preferably

[0077] In a preferred embodiment, when R 3 is a substituted or unsubstituted alkyl group ( substituted alkyl), R 3 Located on ring A and L 1 The meta or para position of connected atoms.

[0078] In a preferred embodiment, when R 4 is a substituted or unsubstituted alkyl group (e.g. substituted alkyl), R 4 Located on ring B and L 2 The meta or para position of connected atoms.

[0079] In a preferred embodiment, when R 3 is a substituted or unsubstituted alkyl group (e.g. When there is one substituent, the substituent is located on the substituted or unsubstituted alkyl (e.g., substituted alkyl) at the para, meta or ortho position.

[0080] In a preferred embodiment, when R 4 is a substituted or unsubstituted alkyl group (e.g. When there is one substituent, the substituent is located on the substituted or unsubstituted alkyl (e.g., substituted alkyl) at the para, meta or ortho position.

[0081] In a preferred embodiment, R 3 and R 4 is a substituted or unsubstituted alkoxy group. The substituent in the substituted alkoxy group is 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 and substituted C 1 -C 10 One or more substituents in the heteroaryl group. When there are multiple substituents, the substituents are the same or different.

[0082] In a preferred embodiment, R 3 and R 4 is a substituted or unsubstituted alkoxy group. The substituent in the substituted alkoxy group is 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 and C 1 -C 4 One or more substituents in the alkoxy group. When there are multiple substituents, the substituents are the same or different.

[0083] In a preferred embodiment, R 3 and R 4 is a substituted alkoxy group, wherein the substituent in the substituted alkoxy group is preferably C 1 -C 10 Heteroaryl and substituted C 1 -C 10 One or more substitutions in the heteroaryl group, when there are multiple substituents, the substituents are the same or different. The substituted alkoxy group is preferably

[0084] In a preferred embodiment, R 3 and R 4 Preferably, the substituted alkoxy group is C 1 -C 4 The substituted alkoxy group is preferably

[0085] In a preferred embodiment, when R 3 When R is a substituted or unsubstituted alkoxy group, 3 Located on ring A and L 1 The adjacent or meta position of the atoms.

[0086] In a preferred embodiment, when R 4 When R is a substituted or unsubstituted alkoxy group, 4 Located on ring B and L 2 The adjacent or meta position of the atoms.

[0087] In a preferred embodiment, na and ma are 1.

[0088] In a preferred embodiment, the group Best More preferred Among them, R 1 and R 2 The definitions are the same as above.

[0089] In a preferred embodiment, the group Best

[0090] In a preferred embodiment, Independently Among them, M 1 and N 1 For Substituted alkyl, or M 1 and N 1 One of them was substituted alkyl, the other is substituted alkoxy; wherein M 1 and N 1 In The definitions of substituted alkyl and substituted alkoxy are the same as those of R 3 or R 4 The corresponding group in R 17 , R 18 , R 3 and R 4 The definitions are the same as above, and n1 and m1 are independently 0, 1 or 2.

[0091] Preferably, M 1 and N 1 for or M 1 and N 1 One of them is The other is C 1 -C 4 Alkoxy, C 1 -C 10 Heteroaryl and substituted C 1 -C 10 One or more substituted alkoxy groups in the heteroaryl group; R 3 and R 4 Preferably hydrogen, 18 F, F, Cl, Br, I, alkyl, 18 F, F, Cl, Br, I substituted alkyl, alkoxy or substituted alkoxy, the substituent in the substituted alkoxy is preferably C 1 -C 4 Alkoxy, C 1 -C 10 Heteroaryl and substituted C 1 -C 10 One or more substitutions in heteroaryl; R 17 and R 18 The definitions are the same as above.

[0092] More preferably, M 1 and N 1 for or M 1 and N 1 One of them is The other is C 1 -C 4 Alkoxy substituted alkoxy; R 3 and R 4 Best 18 F, F, Cl, Br, I, alkyl, 18 Alkyl, alkoxy substituted with F, F, Cl, Br, I or C 1 -C 4 Alkoxy substituted alkoxy; R 17 and R 18 The definitions are the same as above.

[0093] In a preferred embodiment, Best Where N 1 , R 17 and R 18 The definitions are the same as above.

[0094] In a preferred embodiment, Best Among them, M 1 , R 17 and R 18 The definitions are the same as above.

[0095] In a preferred embodiment, Independently selected

[0096]

[0097]

[0098] In a preferred embodiment, Best

[0099] In a preferred embodiment, Best

[0100] In a preferred embodiment, Independently selected

[0101]

[0102] In a preferred embodiment,

[0103] L 1 is alkynyl, -C(R 5 )=C(R 6 )-or-CR 7 R 8 -CR 9 R 10 -,

[0104] L 2 is alkynyl, -C(R 5 )=C(R 6 )-、-CR 7 R 8 -CR 9 R 10 - or does not exist,

[0105] R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently hydrogen or deuterium,

[0106] R 1 for 18 F, F, Cl, Br, I, or substituted or unsubstituted alkyl,

[0107] R 2 for 18 F, F, Cl, Br, I, or substituted or unsubstituted alkyl, and

[0108] R 3 and R 4 Independently for deuterium, 18 F, F, Cl, Br, I, cyano, -SR 11 、-NR 12 R 13 , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.

[0109] In a preferred embodiment,

[0110] L 1 is alkynyl, -C(R 5 )=C(R 6 )-or-CR 7 R 8 -CR 9 R 10 -,

[0111] L 2 is alkynyl, -C(R 5 )=C(R 6 )-、-CR 7 R 8 -CR 9 R 10 - or does not exist,

[0112] R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently hydrogen or deuterium,

[0113] R 1 for 18 F, F, Cl, Br, I, or substituted or unsubstituted alkyl,

[0114] R 2 for 18 F, F, Cl, Br, I, or substituted or unsubstituted alkyl, and

[0115] R 3 and R 4 Independently 18 F, F, Cl, Br, I, -SR 11 , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; R 11 To replace C 1 -C 4 Alkyl; the substituent in the substituted alkyl is 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 -C 4 One or more substitutions in the carboxyl group; the substituents in the substituted alkoxy group are 18 F, F, Cl, Br, I, cyano, hydroxyl, C 6 -C 14 Aryl, substituted C 6 -C 14 Aryl, C 1 -C10 Heteroaryl and substituted C 1 -C 10 One or more substituents in the heteroaryl group; when there are multiple substituents, the substituents are the same or different.

[0116] In a preferred embodiment,

[0117] L 1 is alkynyl, -C(R 5 )=C(R 6 )-or-CR 7 R 8 -CR 9 R 10 -,

[0118] L 2 is alkynyl, -C(R 5 )=C(R 6 )-、-CR 7 R 8 -CR 9 R 10 - or does not exist,

[0119] R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently hydrogen or deuterium;

[0120] R 1 for 18 F, F, Cl, Br, I, substituted or unsubstituted alkyl;

[0121] R 2 for 18 F, F, Cl, Br, I or alkyl,

[0122] R 3 and R 4 Independently 18 F, F, Cl, Br, I, -SR 11 , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; R 11 To replace C 1 -C 4 Alkyl; the substituent in the substituted alkyl is 18 F, F, Cl, Br, I, Substituted C 6 -C 14 Aryl and substituted C 1 -C 10One or more substitutions in the heteroaryl group; the substituents in the substituted alkoxy group are preferably C 1 -C 4 Alkoxy, C 1 -C 10 Heteroaryl and substituted C 1 -C 10 One or more substituents in the heteroaryl group; when there are multiple substituents, the substituents are the same or different.

[0123] In a preferred embodiment,

[0124] L 1 -C(R 5 )=C(R 6 )-(preferably -CH=CH-),

[0125] L 2 -C(R 5 )=C(R 6 )- or absent (preferably -CH=CH-),

[0126] R 5 and R 6 are independently hydrogen or deuterium,

[0127] R 1 for 18 F, F, Cl, Br, I, alkyl (preferably C 1 -C 4 alkyl, more preferably methyl), or 18 Alkyl substituted by one or more of F, F, Cl, Br, I,

[0128] R 2 for 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),

[0129] R 3 and R 4 Independently 18 F, F, Cl, Br, I, -SR 11 , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; R 11 To replace C 1 -C 4 Alkyl; the substituent in the substituted alkyl is preferably 18 F, F, Cl, Br, I, Substituted C 6 -C 14 Aryl and substituted C1 -C 10 One or more substitutions in the heteroaryl group (further R 3 and R 4 The definitions are as follows: (1) R 3 and R 4 Preferred-SR 11 , R 11 To replace C 1 -C 4 Alkyl; (2) R 3 and R 4 Preferred 18 Alkyl substituted by one or more of F, F, Cl, Br, I; 18 The alkyl group substituted by one or more of F, F, Cl, Br, I is preferably 18 C substituted by one or more of F, F, Cl, Br and I 1 -C 4 Alkyl, preferably -C 18 F 3 , -C 18 FF 2 , -C 18 F 2 F or -CF 3 ; (3) R 3 and R 4 Preferred Substituted alkyl; The substituted alkyl group is preferably Substituted C 1 -C 4 The alkyl group Substituted C 1 -C 4 The alkyl group is preferably Among them, R 17 and R 18 One is H and the other is C 1 -C 4 Alkyl substituted with one or more of alkoxy, hydroxy and carboxyl; or R 17 , R 18 Together with the nitrogen atom connected to them, they 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 piperidine; the substituent in the substituted 5-7 membered carbon heterocycle is preferably C 1 -C 4 Carboxyl (when R 3 and R 4 For When the alkyl group is substituted, the The substituted alkyl group is preferably ); (4) R 3 and R 4 Preferably substituted C 6 -C 14 Aryl-substituted alkyl, more preferably (5)R 3 and R 4 Preferably substituted C 1 -C 10 Heteroaryl-substituted alkyl, more preferably (6)R 3 and R 4 Preferably, the substituted alkoxy group is C 1 -C 4 Alkoxy, C 1 -C 10 Heteroaryl and substituted C 1 -C 10 One or more substitutions in the heteroaryl group, the substituted alkoxy group is preferably ).

[0130] In a preferred embodiment,

[0131] R 1 for 18 F, F, Cl, Br, I, alkyl (preferably C 1 -C 4 alkyl, more preferably methyl), or 18 Alkyl substituted with one or more of F, F, Cl, Br, I (preferably 18 C substituted by one or more of F, F, Cl, Br, I 1 -C 4 Alkyl groups, such as -CH 2 18 F);

[0132] R 2 is H;

[0133] L 1 -C(R 5 )=C(R 6 )-(preferably -CH=CH-);

[0134] does not exist;

[0135] R 3 Independently for deuterium, 18 F, F, Cl, Br, I, cyano, -SR 11 、-NR 12 R13 , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy (preferably Substituted alkyl; The substituted alkyl group is preferably Substituted C 1 -C 4 The alkyl group Substituted C 1 -C 4 The alkyl group is preferably Among them, R 17 and R 18 One is H and the other is C 1 -C 4 Alkyl substituted with one or more of alkoxy, hydroxy and carboxyl; or R 17 , R 18 Together with the nitrogen atom connected to them, they 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 piperidine; the substituent in the substituted 5-7 membered carbon heterocycle is preferably C 1 -C 4 carboxyl).

[0136] The general formula I described in the present disclosure is 18 The F-labeled biphenyl compound is preferably selected from any of the following compounds:

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152] In a preferred embodiment, the general formula I shown in 18 The F-labeled biphenyl compound is preferably represented by the general formula IA or II 18 F-labeled biphenyl compounds:

[0153]

[0154] Among them, ring A, ring B, L 1 , L 2 , R 1 , R 2 , R 3 , R 4 、M 1 、N 1 , R 17 , R 18 The definitions of , na and ma are the same as described above, n1 is 0, 1 or 2, and m1 is 0, 1 or 2.

[0155] In a preferred embodiment, the general formula I shown in 18 The F-labeled biphenyl compound is preferably represented by the general formula I-A1 or II-1 18 F-labeled biphenyl compounds:

[0156]

[0157] Among them, 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 The definitions are the same as above, n1 is 0, 1 or 2, and m1 is 0, 1 or 2.

[0158] In the present disclosure, the general formula II 18 In F-labeled biphenyl compounds, the and ring B Can be the same or different.

[0159] In the present disclosure, the general formula I shown in 18The preparation method of F-labeled biphenyl compounds can be prepared by conventional methods in the art, such as stepwise synthesis, addition method, substitution method, isotope exchange method, etc.

[0160] The stepwise synthesis method generally uses simple compounds containing radionuclides to synthesize complex compounds of the present disclosure step by step according to a predetermined synthetic route.

[0161] The addition method generally uses a compound with a double bond or a triple bond as a precursor, and combines the radioactive nuclide or its simple compound with the precursor through an addition reaction to synthesize the compound disclosed in the present invention. The present disclosure also provides a compound shown in the general formula IA or II. 18 Preparation method of F-labeled biphenyl compounds,

[0162] In the compound represented by the general formula IA, when M 1 and N 1 When -NH- or -COOH is contained in the compound, it is prepared by the following method: The method comprises the following steps: subjecting the compound represented by the general formula II-F to a deprotection reaction as shown below to obtain the compound represented by the general formula IA 18 F-labeled biphenyl compounds,

[0163]

[0164] Among them, ring A, ring B, L 1 , L 2 , R 1 , R 2 , R 3 , R 4 、M 1 、N 1 The definitions of na and ma are the same as above, n1 is 0, 1 or 2, m1 is 0, 1 or 2, R IIF M 1 The corresponding group containing an amino or carboxyl protecting group, R IIF1 With N 1 Same; or, R IIF and M 1 Same, R IIF1 N 1 The corresponding group containing an amino or carboxyl protecting group; or R IIF M 1 The corresponding group containing an amino or carboxyl protecting group, R IIF1 N 1 The corresponding groups containing amino or carboxyl protecting groups;

[0165] The general formula II 18 The preparation method of F-labeled biphenyl compounds adopts any of the following methods:

[0166] (1) Method 1 comprises the following steps: reacting the compound represented by the general formula II-A with compound II-A1 as shown below to obtain the compound represented by the general formula II 18 F-labeled biphenyl compounds,

[0167]

[0168] The structure of compound II-A1 is as follows: or its acid salt,

[0169] Ring A, Ring B, L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , R 17 , R 18 , na and ma are defined as above, n1 is 0, 1 or 2, m1 is 0, 1 or 2; in this method, same;

[0170] (2) Method 2 comprises the following steps: reacting the compound represented by the general formula II-B with compound II-B1 as shown below to obtain the compound represented by the general formula II 18 F-labeled biphenyl compounds,

[0171]

[0172] The structure of compound II-B1 is as follows: or its acid salt,

[0173] Ring A, Ring B, L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , R 17 , R 18 , na and ma are defined as above, n1 is 0, 1 or 2, m1 is 0, 1 or 2, and M is halogen; in this method, same;

[0174] (3) Method 3 comprises the following steps: reacting the compound represented by the general formula II-C with compound II-C1 as shown below to obtain the compound represented by the general formula II 18 F-labeled biphenyl compounds,

[0175]

[0176] The structure of compound II-C1 is as follows: or its acid salt,

[0177] Ring A, Ring B, L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , R 17 , R 18 The definitions of na and ma are the same as above, n1 is 0, 1 or 2, m1 is 0, 1 or 2; R IIC and R IIC1 One of them is Another one is In this method, the rings A and B Same or different;

[0178] (4) Method 4 comprises the following steps: reacting the compound represented by the general formula II-D with compound II-D1 as shown below to obtain the compound represented by the general formula II 18 F-labeled biphenyl compounds,

[0179]

[0180] The structure of compound II-D1 is as follows: or its acid salt,

[0181] Ring A, Ring B, L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , R 17 , R 18 The definitions of na and ma are the same as above, n1 is 0, 1 or 2, m1 is 0, 1 or 2, R IID and R IID1 One of them is The other is halogen. In this method, Same or different;

[0182] (5) Method 5 comprises the following steps: subjecting the compound represented by the general formula II-E to a deprotection reaction as shown below to obtain the compound represented by the general formula II-E. 18 F-labeled biphenyl compounds, wherein R 17 or R 18 Contains carboxyl groups;

[0183]

[0184] Among them, ring A, ring B, L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , R 17 , R 18 The definitions of na and ma are the same as above, n1 is 0, 1 or 2, m1 is 0, 1 or 2, R IIE and R IIE1 for Each R 17’ and each R 18’ The same or different, and at least one of them has a carboxyl protecting group, and R without a carboxyl protecting group 17’ and R 18’ Respectively with the corresponding R in formula II 17 and R 18 Same; in this method, the ring A and the ring B Same or different.

[0185] In a preferred embodiment, the synthesis method of the compound disclosed herein is as follows:

[0186]

[0187]

[0188] The present disclosure also provides compounds represented by the general formula II-A, II-B, II-C, II-D, II-E and II-F:

[0189]

[0190]

[0191] Ring A, Ring B, L 1 , L 2 , R 1 , R 2 , R 3 , R 4 、M 1 、N 1 , R 17 , R 18 The definitions of na and ma are the same as above, n1 is 0, 1 or 2, m1 is 0, 1 or 2; M is halogen, R IIC and R IIC1 One of them is Another one is R IID and R IID1 One of them is The other is a halogen, R IIE and RIIE1 for Each R 17’ and each R 18’ The same or different, and at least one of them has a carboxyl protecting group, and R without a carboxyl protecting group 17’ and R 18’ Respectively with the corresponding R in formula II 17 and R 18 Same; R IIF M 1 The corresponding group containing an amino or carboxyl protecting group, R IIF1 With N 1 Same; or, R IIF and M 1 Same, R IIF1 N 1 The corresponding group containing an amino or carboxyl protecting group; or R IIF M 1 The corresponding group containing an amino or carboxyl protecting group, R IIF1 N 1 The corresponding groups containing amino or carboxyl protecting groups.

[0192] The present invention provides a general formula IA 18 The preparation method of F-labeled biphenyl compounds comprises the following steps: subjecting compound II-F to a deprotection reaction as shown below;

[0193]

[0194] Among them, ring A, ring B, L 1 , L 2 , R 1 , R 2 , R 3 , R 4 、M 1 、N 1 The definitions of , na and ma are the same as above, and M 1 and N 1 contains at least one of -NH-, -OH and -COOH, n1 is 0, 1 or 2, m1 is 0, 1 or 2,

[0195] R IIF , R IIF1 、M 1 and N 1 Meet any of the following conditions:

[0196] (1)R IIF M 1 The corresponding group containing at least one of an amino protecting group, a hydroxyl protecting group and a carboxyl protecting group, and R IIF1 With N1 same;

[0197] (2)R IIF and M 1 The same, and R IIF1 N 1 A corresponding group containing at least one of an amino protecting group, a hydroxy protecting group and a carboxyl protecting group;

[0198] (3)R IIF M 1 The corresponding group containing at least one of an amino protecting group, a hydroxyl protecting group and a carboxyl protecting group, R IIF1 N 1 The corresponding group contains at least one of an amino protecting group, a hydroxyl protecting group and a carboxyl protecting group.

[0199] In a preferred embodiment, the general formula IA is 18 In F-labeled biphenyl compounds, R IIF , R IIF1 、M 1 and N 1 The following conditions are met:

[0200] R IIF M 1 The corresponding group containing an amino protecting group and a hydroxyl protecting group, R IIF1 N 1 The corresponding groups containing amino protecting groups and hydroxyl protecting groups.

[0201] In a preferred embodiment, the general formula IA is 18 In the biphenyl compound labeled with F, ring A and ring B are independently benzene rings; 1 , L 2 are independently -C(R 5 )=C(R 6 )-, for example -CH=CH-; R 3 and R 4 is a substituted or unsubstituted alkyl group, and the substituents in the substituted alkyl group are as defined above. 3 and R 4 Preferred 18 Alkyl substituted with F, F, Cl, Br, or I. 18 Alkyl substituted with F, F, Cl, Br, I is preferably 18 C substituted by one or more of F, F, Cl, Br and I 1 -C 4 Alkyl, preferably -C 18 F 3 , -C 18 FF 2 , -C18 F 2 F or -CF 3 .

[0202] In a preferred embodiment, the general formula IA is 18 Among the F-labeled biphenyl compounds, M 1 and N 1 Contains at least one of -NH- and -OH, for example, M 1 and N 1 Contains -NH- and -OH, for example,

[0203] In a preferred embodiment, the general formula IA is 18 In F-labeled biphenyl compounds, R 1 for 18 F, F, Cl, Br, I, alkyl (preferably C 1 -C 4 alkyl, more preferably methyl), or 18 Alkyl substituted by one or more of F, F, Cl, Br, and I. 18 The alkyl group substituted by one or more of F, F, Cl, Br, I is preferably 18 C substituted by one or more of F, F, Cl, Br and I 1 -C 4 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 .

[0204] In a preferred embodiment, the general formula IA is 18 In F-labeled biphenyl compounds, R 2 for 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).

[0205] In a preferred embodiment, the general formula IA is 18 In F-labeled biphenyl compounds, when RIIF , R IIF1 When there is a hydroxyl protecting group, the hydroxyl protecting group can be a conventional hydroxyl protecting group in the art, such as di(p-methoxyphenyl)phenylmethyl (-DMTr), tetramethylsilane (-TMS), tert-butyldiphenylsilyl (-TBDPS) or triisopropylsilyl (-TIPS), for example -DMTr.

[0206] In a preferred embodiment, the general formula IA is 18 In F-labeled biphenyl compounds, when R IIF , R IIF1 When there is an amino protecting group, the amino protecting group may be a conventional amino protecting group in the art, such as di-tert-butyl methyl dicarbonate (-Boc 2 O), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc) or trimethylsilylethoxycarbonyl (Teoc), for example -Boc 2 O.

[0207] In a preferred embodiment, the general formula IA is 18 In F-labeled biphenyl compounds, when R IIF , R IIF1 When there is a carboxyl protecting group, the carboxyl protecting group can be a conventional carboxyl protecting group in the art.

[0208] The general formula IA is shown in 18 The method for preparing a F-labeled biphenyl compound may further include the following step: subjecting the compound II-F to a deprotection reaction in a solvent under the action of a deprotection reagent.

[0209] The deprotecting agent may be a conventional acid in the art. The acid may be an inorganic acid, such as hydrochloric acid. The amount of the deprotecting agent may not be specifically limited, as long as the protecting group to be removed can be removed.

[0210] The deprotecting agent can be added to the reaction in the form of a mixture with an organic solvent, such as a mixture of an acid and an alcohol solvent, or a mixture of an acid and an ether solvent, such as a hydrochloric acid-methanol solution, a hydrochloric acid-ethyl acetate solution, or a hydrochloric acid-1,4-dioxane solution. When the deprotecting agent is added to the reaction in the form of a solution, the concentration of the deprotecting agent can be 1.5 to 2.5 M, such as 2 M.

[0211] 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 also such as methanol.

[0212] The temperature of the deprotection reaction can be a conventional temperature for such reactions in the art, such as 50-70° C. (eg, 60° C.).

[0213] The progress of the deprotection reaction can be monitored by conventional detection methods in the art, such as TLC, HPLC, GC or NMR.

[0214] The post-treatment step of the deprotection reaction can be a conventional post-treatment step for this type of reaction in the art, for example: HPLC.

[0215] The general formula IA is shown in 18 The preparation method of the biphenyl compound labeled with F may further include the following steps: in a solvent, subjecting the compound II-F2 to a substitution reaction with a halogenating agent to obtain the compound II-F;

[0216]

[0217] Wherein, in compounds II-F and II-F2, the definitions of the letters and groups are the same as above, and R 1 and R 2 At least one alkyl group is substituted with halogen, preferably 18 F substituted alkyl; R 11 and R 12 At least one of them is an alkyl-R L , R L It is a group which can be substituted by halogen.

[0218] In a preferred embodiment, the R 11 and R 12 At least one of them can be alkyl-OTs, alkyl-OMs or alkyl-OTf, such as TsO-alkyl. L Can be -OTs or -OMs.

[0219] In a preferred embodiment, R 1 For 18 Alkyl substituted by one or more of F, F, Cl, Br, I, in which case R 11 Alkyl-R L , R L It is a group which can be substituted by halogen.

[0220] In a preferred embodiment, R 2 is an alkyl group (preferably C 1 -C 4 alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl), in which case R 2 and R 12 same.

[0221] In the substitution reaction, the halogenating agent may be a conventional halogenating agent in the art, such as KX, wherein X is 18F, F, Cl, Br or I; for example, K 18 F.

[0222] In the substitution reaction, when the halogenating agent is a 18 When the halogenation reagent of F is used, the halogenation reagent can be prepared by reacting KF with fluorine [ 18 F] Ionized water was enriched by an anion exchange column (QMA).

[0223] In the substitution reaction, when QMA is used to enrich the halogenated reagent, the QMA column is used with TBAHCO 3 Rinse.

[0224] In the substitution reaction, the molar ratio of the halogenating agent to the compound II-F may be above 1:1, for example, 1:1-10:1.

[0225] In the substitution reaction, the organic solvent may be a chlorinated hydrocarbon solvent, a nitrile solvent, an ether solvent, an amide solvent or a mixture thereof, such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, DMF or a mixture thereof, and also such as acetonitrile.

[0226] In the substitution reaction, the temperature of the substitution reaction can be a conventional temperature for such reactions in the art, such as 50-70° C. (such as 60° C.).

[0227] In the substitution reaction, the time of the substitution reaction is based on the complete reaction of the above reactants, for example, 1 to 4 hours.

[0228] The progress of the substitution reaction can be monitored by conventional detection methods in the art, such as TLC, HPLC, GC or NMR.

[0229] In one embodiment, the method for preparing the compound of the general formula IA may include the following steps: subjecting compound II-F2 to the substitution reaction, and then subjecting the compound II-F2 to the deprotection reaction;

[0230]

[0231] Wherein, in compounds II-F2 and IA, the definitions of each letter and group are the same as described above. The conditions of the substitution reaction and the deprotection reaction are the same as described above.

[0232] The general formula IA is shown in 18 The preparation method of the biphenyl compound labeled with F may also include the following steps: in a solvent, compound II-F3 and a compound containing R L The reagent is subjected to the substitution reaction shown below to obtain the compound II-F2;

[0233]

[0234] In compounds II-F3 and II-F2, the definitions of the letters and groups are the same as above, and R 11 and R 12 At least one of them is an alkyl-R L , R L is a group that can be substituted by halogen; R 11a and R 12a R 11 and R 12 Correspondingly, the condition is R 11 and R 12 R L Replace with R L groups, such as -OH.

[0235] In the preparation method of compound II-F2, the R L The reagent can be Ts 2 O、Ts 2 N.Ms. 2 O or Tf 2 O, such as Ts 2 O.

[0236] In the preparation method of compound II-F2, the organic solvent can be a chlorinated hydrocarbon solvent, a nitrile solvent, an ether solvent, an amide solvent or a mixture thereof, such as a chlorinated hydrocarbon solvent. Further, the organic solvent can be dichloromethane, chloroform, acetonitrile, tetrahydrofuran, DMF or a mixture thereof, such as dichloromethane.

[0237] In the preparation method of compound II-F2, the amount of the organic solvent is not specifically limited, as long as it does not affect the reaction. L The molar ratio of the reagent to the compound II-F3 may be above 1:1, for example, 1:1-10:1.

[0238] In the preparation method of compound II-F2, the temperature of the substitution reaction can be -10 to 10°C, for example, 0°C.

[0239] In the preparation method of compound II-F2, the progress of the substitution reaction can be monitored by conventional detection methods in the art, such as TLC, HPLC, GC or NMR.

[0240] The general formula IA is shown in 18 The preparation method of the biphenyl compound labeled with F may also include the following steps: in a solvent, compound II-F4 is subjected to a reduction reaction as shown below with a reducing agent to obtain the compound II-F3;

[0241]

[0242] In compounds II-F4 and II-F3, the definitions of the letters and groups are the same as above, and R 11a and R 12a The definition of R is the same as above. 11b and R 12b R 11a and R 12a Correspondingly, the condition is R 11a and R 12a Can be combined with R L The group is replaced by a group that can be reduced by a reducing agent to bind to R L The group.

[0243] In the reduction reaction, the reducing agent may be a conventional reducing agent in the art, such as sodium borohydride.

[0244] 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 may also be dichloromethane, chloroform, acetonitrile, tetrahydrofuran, ethanol, DMF or a mixture thereof, such as dichloromethane.

[0245] 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 for such reactions in the art, such as 40 to 50 mL / g.

[0246] In the reduction reaction, the molar ratio of the reducing agent to the compound II-F4 can be a conventional molar ratio for such reactions in the art, such as 6:1 to 8:1.

[0247] In the reduction reaction, the temperature of the reduction reaction can be a conventional temperature for such reactions in the art, such as -10-10°C.

[0248] The progress of the reduction reaction can be monitored by conventional detection methods in the art, such as TLC, HPLC, GC or NMR.

[0249] The present application also provides compounds II-F2, II-F3 or II-F4:

[0250]

[0251]

[0252] The definitions of the letters and groups are the same as described above.

[0253] The present disclosure also provides compounds as shown below:

[0254]

[0255] The general formula I shown in the present disclosure 18 IC values ​​of F-labeled biphenyl compounds for PD-1 / PD-L1 binding 50 The values ​​are basically below 10 μM, for example below 5 μM, most compounds are below 1 μM, some preferred compounds are below 0.5 μM, some particularly preferred compounds are below 0.01 μM, and some most preferred compounds are below 0.005 μM.

[0256] In the present disclosure, the general formula I shown in the present disclosure 18 IC values ​​of F-labeled biphenyl compounds for PD-1 / PD-L1 binding 50 The method for determining the value can be a conventional method in the art.

[0257] The present disclosure also provides the general formula I 18 Use of F-labeled biphenyl compounds, pharmaceutically acceptable salts, tautomers, mesomers, racemates, stereoisomers or drug precursors thereof in the preparation of PD-1 inhibitors and / or PD-L1 inhibitors.

[0258] The present disclosure also provides the general formula I 18 Use of one or more of a F-labeled biphenyl compound, its pharmaceutically acceptable salt, tautomer, mesomer, racemate, stereoisomer, metabolite, metabolic precursor and drug precursor in the preparation of a drug for preventing, alleviating or treating cancer, infection, autoimmune disease or diseases related thereto.

[0259] 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.

[0260] The present disclosure also provides a pharmaceutical composition, which comprises a therapeutically and / or preventively effective amount of the 18F-labeled biphenyl compound represented by the general formula I, a pharmaceutically acceptable salt, tautomer, mesomer, racemate, stereoisomer, metabolite, metabolic precursor or drug precursor thereof, and a pharmaceutically acceptable carrier and / or diluent.

[0261] The compounds of the present disclosure are injected into animals (e.g., mammals, which may be mice, dogs, pigs, or humans), and an annihilation effect may occur during the human body's metabolic process, generating two gamma-ray photons with an energy of 0.511 MeV that are emitted in a direction of 180° and move in opposite directions. The compounds of the present disclosure can accumulate at the tumor site in the animal body, and thus can be applied to PET tumor imaging technology. For example, the compounds of the present disclosure can be used for 1) diagnosis of tumors (such as malignant tumors), identification of benign tumor lesions, and detection of systemic metastases; 2) tumor staging and restaging; 3) identification of postoperative tumor recurrence and scars; 4) identification of recurrence after radiotherapy and radiation necrosis; 5) efficacy detection of tumor treatment (radiotherapy, chemotherapy, etc.); and 6) search for primary and metastatic tumors.

[0262] Therefore, the present disclosure also provides the general formula I shown in 18 Application of one or more of F-labeled biphenyl compounds, their pharmaceutically acceptable salts, tautomers, mesomers, racemates, stereoisomers, metabolites, metabolic precursors and drug precursors in PET tumor imaging technology.

[0263] In the present invention, the definitions of tumor and cancer are the same. For example, the 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.

[0264] In the present disclosure, the pharmaceutical composition can be prepared into various types of dosage unit forms according to the therapeutic purpose, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions), etc., preferably liquids, suspensions, emulsions, suppositories and injections (solutions and suspensions), etc.

[0265] In order to shape the pharmaceutical composition in tablet form, any excipient 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, polyvinyl pyrrolidone, etc.; disintegrants such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, calcium carbonate, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceride of stearic acid, starch and lactose, etc.; disintegration inhibitors such as white sugar, tristearate, coconut oil and hydrogenated oil; adsorption promoters such as quaternary ammonium base and sodium lauryl sulfate, etc.; wetting agents such as glycerol and starch, etc.; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, etc.; and lubricants such as purified talc, stearate, boric acid powder and polyethylene glycol, etc. Ordinary coating materials can be selected as needed to make sugar-coated tablets, gelatin-film-coated tablets, enteric-coated tablets, film-coated tablets, double-layer film tablets and multi-layer tablets.

[0266] In order to shape the pharmaceutical composition in the form of pills, any excipient known and widely used in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, etc.; disintegrants such as agar and kelp powder, etc.

[0267] In order to shape the pharmaceutical composition in the form of a suppository, any excipient known and widely used in the art may be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides and the like.

[0268] In order to prepare the pharmaceutical composition in the form of injection, the solution or suspension can be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerol, etc.) to prepare an injection with an osmotic pressure equal to that of blood. When preparing the injection, any commonly used carrier 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, etc. In addition, common solvents, buffers and analgesics, etc. can also be added.

[0269] In the pharmaceutical composition, the diluent may be a conventional diluent in the art.

[0270] The pharmaceutical composition can be in the form of oral administration or in the form of a sterile injection aqueous solution. The oral or injection composition can be prepared according to any method known in the art for preparing pharmaceutical compositions.

[0271] Unless otherwise stated, all of the following terms appearing in this disclosure and claims have the following meanings:

[0272] All terms cycloalkyl (including when used alone or 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.

[0273] All terms alkoxy represent cyclic or acyclic alkyl groups with the stated number of carbon atoms attached via an oxygen bridge. Thus, alkoxy encompasses the above definitions of alkyl and cycloalkyl.

[0274] 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 there is one carbon-carbon double bond, and up to four non-aromatic carbon-carbon double bonds may be present. Alkenyl is preferably C 2-12 Alkenyl, more preferably C 2-6 Thus, C 2-12 Alkenyl refers to an alkenyl group having 2 to 12 carbon atoms. 2-6 Alkenyl refers to alkenyl groups having 2 to 6 carbon atoms, including ethenyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The straight chain, branched chain or cyclic portion of the alkenyl group may contain double bonds and may be substituted if indicated as a substituted alkenyl group.

[0275] All terms alkynyl refer to straight chain, branched or cyclic hydrocarbon groups containing the specified number of carbon atoms and at least one carbon-carbon triple bond. Up to three carbon-carbon triple bonds may be present. Alkynyl is preferably C 2-12 Alkynyl, more preferably C 2-6 Thus, C 2-12 Alkynyl refers to an alkynyl group having 2 to 12 carbon atoms. 2-6 The alkynyl group refers to an alkynyl group having 2 to 6 carbon atoms, including ethynyl, propynyl, butynyl, 3-methylbutynyl and the like.

[0276] All the terms hydroxyl represent

[0277] All amino terms mean

[0278] All terms cyano refer to -CN.

[0279] All terms carboxyl refer to -COOH, where C 1 -C 4 Carboxyl refers to -(CH 2 ) n COOH, n is 0, 1, 2 or 3. All terms C 1 -C 4 Carboxyl group is preferred

[0280] All terms ester group means -COO-, where C 1 -C 4 Ester group refers to -COOR x , R x C 1 -C 4 alkyl.

[0281] All the terms amide group refer to "-CONR x1 R x2 " or "-NR x3 COR x4 ”, R x1 , R x2 , R x3 and R x4 are independently H or C 1 -C 4 alkyl.

[0282] All terms heteroaromatic ring should also be understood to include the N-oxide derivatives 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 heteroatoms, it is understood that attachment is through the aromatic ring or through the heteroatoms containing the ring, respectively.

[0283] All terms therapeutically effective amount refer to an amount of a compound that is sufficient to effectively treat a disease or condition described herein when administered to a subject. Although the amount of a 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.

[0284] When referring to a particular salt, pharmaceutical composition, composition, excipient, etc. as "pharmaceutically acceptable", it is meant that the salt, pharmaceutical composition, composition, excipient, etc. is generally non-toxic, safe, and suitable for use in subjects, preferably mammalian subjects, and more preferably human subjects.

[0285] All terms pharmaceutically acceptable salt refer to pharmaceutically acceptable organic or inorganic salts of the disclosed compounds. Exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbates, succinates, maleates, gentisinates, fumarates, gluconates, glucuronates, sugarates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and pamoates (i.e., 1-1-methylene-bis(2-hydroxy-3-naphthoate)).

[0286] All terms prodrug refers to a derivative of a compound containing a bioreactive functional group, such that under biological conditions (in vitro or in vivo), the bioreactive functional group can be cleaved from the compound or otherwise reacted to provide the compound. Typically, the prodrug is inactive, or at least less active than the compound itself, so that its activity can only be exerted after the compound is cleaved from the bioreactive functional group. The bioreactive functional group can be hydrolyzed or oxidized under biological conditions to provide the compound. For example, a prodrug may contain a biohydrolyzable group. Examples of biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, biohydrolyzable carbamates, and biohydrolyzable ureides.

[0287] 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 methods (e.g., separation, crystallization, thin layer chromatography, column chromatography, gas chromatography, high performance liquid chromatography). These stereoisomers can also be derived from the diastereomers of a mixture of enantiomers or racemates reacted with an appropriate chiral compound, and then obtained by crystallization or any other suitable conventional method.

[0288] All terms "subject" refer to any animal that is about to or has been administered the compound or pharmaceutical composition according to the embodiments of the present disclosure, preferably a mammal, and most preferably a human. As used herein, all terms "mammal" include any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.

[0289] In certain embodiments, treatment or treating refers to the improvement, prevention, or reversal of a disease or condition or at least one discernible symptom thereof. In other embodiments, treatment or treating refers to the improvement, prevention, or reversal of at least one measurable physical parameter of the disease or condition being treated, which disease or condition may not be identified in a mammal. In yet another embodiment, treatment or treating refers to slowing the progression of a disease or condition, either physically, such as stabilization of discernible symptoms, or physiologically, such as stabilization of a physical parameter, or both. In other embodiments, treatment or treating refers to delaying the onset of a disease or condition.

[0290] In certain embodiments, the compounds of the present disclosure may be administered as a preventive measure. As used herein, "prevention" or "preventing" refers to reducing the risk of acquiring a given disease or condition. In a preferred mode of the embodiments, a given compound is administered as a preventive measure to a subject, such as a subject with a family history or predisposition to cancer or an autoimmune disease.

[0291] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present disclosure.

[0292] The reagents and raw materials used in the present disclosure are commercially available.

[0293] The positive improvement effect of the present disclosure is: 18 F-labeled biphenyl compounds 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. DETAILED DESCRIPTION

[0294] In the following embodiments, the abbreviations are explained:

[0295] Ci (Curie) is the unit of radioactivity of a substance. One Curie is defined as the radioactivity intensity of one gram of radium decaying into radon, and its symbol is Ci.

[0296] Synthesis module, model: CFN200, produced by Sumitomo Heavy Industries, Japan; semi-preparative high performance liquid chromatograph, model: 2100 series, produced by Alltech, USA; analytical high performance liquid chromatograph, model: E2695, produced by Waters, USA; online radioactivity detector, model: Mini-scan, produced by Eckert & Ziegler, Germany; pipette, model: Finnpipette, produced by Thermo Fisher, USA.

[0297] Example 1 Synthesis of labeled compounds

[0298]

[0299]

[0300] Synthesis of compound 1-j

[0301] 6-Bromo-2-hydroxybenzaldehyde (804 mg, 4.0 mmol), biboronic acid pinacol ester (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) were added to a 100 ml reaction bottle. The mixture was stirred at 80 ° C and reacted for 16 hours under nitrogen protection. 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%).

[0302] LC-MS (ESI): m / z = 247 [M-1] - .

[0303] Synthesis of compound 1-i

[0304] [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (154 mg, 0.21 mmol), potassium phosphate (1.27 g, 6.0 mmol), cesium fluoride (900 mg, 6.0 mmol) were added 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), and stirred at 80°C for 16 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6: 1) to obtain compound 1-i (431 mg, yield: 63%).

[0305] LC-MS (ESI): m / z = 227 [MH] - .

[0306] Synthesis of compound 1-h

[0307] Trifluoromethanesulfonic anhydride (1.69 g, 6.0 mmol) was slowly added dropwise to a solution of compound 1-i (417 mg, 1.83 mmol) and triethylamine (1.01 g, 10.0 mmol) in dichloromethane (20 mL) at -78°C. After the addition, 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 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain compound 1-h (730 mg, yield: 81%).

[0308] 1 H NMR (400 MHz, DMSO-d 6): δ9.65(s,1H),7.95(t,J=8.0Hz,1H),7.69(d,J=8.0Hz,1H),7.51~7.59(m,3H),7.40(dd,J=2.0Hz,8.0Hz,1H),2.04(s,3H)ppm

[0309] Synthesis of compound 1-g

[0310] To a solution of 3-bromo-4-(trifluoromethyl)benzaldehyde (4.00g, 15.8mmol) in dichloromethane (40mL), add ethanolamine (1.93g, 31.6mmol) and a few drops of acetic acid. Stir at room temperature for 1 hour, then add methanol (40mL) and sodium cyanoborohydride (995mg, 15.8mmol), and stir at room temperature for 16 hours. The reaction solution is concentrated under reduced pressure, the residue is diluted with water (100mL), and extracted with ethyl acetate (40mL×3). The organic phases are combined, washed with water (100mL), washed with saturated brine (100mL), and dried over anhydrous sodium sulfate. Concentrated under reduced pressure to obtain a crude product compound 1-g, which is directly used in the next step reaction.

[0311] Synthesis of compound 1-f

[0312] The crude product 1-g obtained above was dissolved in ethanol (100 mL), di-tert-butyl dicarbonate (4.44 g, 20.5 mmol) was added, and the mixture was reacted at 40°C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was diluted with 100 mL of water and extracted with ethyl acetate (40 mL×3). The organic phases were combined and washed with water (100 mL) and saturated brine (100 mL) in sequence. The mixture 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%).

[0313] LC-MS (ESI): m / z = 398 [M+H] + .

[0314] Synthesis of compound 1-e

[0315] Triethylenediamine (840 mg, 7.5 mmol) was added to a solution of compound 1-f (2.00 g, 5.0 mmol) in dry dichloromethane (40 mL), and then a solution of 4,4'-bismethoxytrityl chloride (2.03 g, 6.0 mmol) dissolved in dichloromethane (12 mL) was added dropwise to the mixture at 0°C. After the addition, 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 and washed with water (40 mL) and saturated brine (40 mL) in turn. The mixture 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%).

[0316] Synthesis of compound 1-d

[0317] 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), bis(tri-tert-butylphosphine) palladium (180 mg, 0.36 mmol) and diisopropylethylamine (2.76 g, 21.4 mmol) were added. The mixture was stirred at 80 ° C for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. 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%).

[0318] 1 H NMR (400 MHz, CDCl 3 ): δ7.73(d,J=18.0Hz,1H),7.55(d,J=8.0Hz,1H),7.49~7.51(m,1H),7.39(d,J=8.0Hz,2H),7.16~7.29(m,8H),6.81(d,J=8.0 Hz,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

[0319] Synthesis of compound 1-c

[0320] A mixture of 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(diphenylphosphino)ferrocene]palladium dichloride (30 mg, 0.04 mmol) and toluene (15 mL) was stirred at 90°C for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 1-c (96 mg, yield: 65%).

[0321] 1 H NMR (400 MHz, CDCl 3 ): δ9.92(s,1H),8.02(d,J=16.0Hz,1H),7.74(d,J=8.0Hz,1H),7.70~7. 72(m,1H),7.58~7.65(m,6H),7.38~7.41(m,7H),7.24~7.32(m,12H),7. 17~7.19(m,6H),6.78~6.81(m,8H),4.65(s,2H),4.64(s,2H),3.74(s,1 2H),3.38~3.47(m,4H),3.20~3.26(m,4H),2.15(s,3H)1.42(s,18H)ppm

[0322] Synthesis of compound 1-b

[0323] 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 under an ice-water bath, and after the addition, the mixture was reacted at 0°C for 20 minutes. The reaction solution was warmed to room temperature and concentrated under reduced pressure. Water (20 mL) was added to the residue, and ethyl acetate (30 mL×3) was extracted. The organic phases were combined and washed with water (20 mL) and saturated brine (20 mL) in turn. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound 1-b (160 mg, yield: 76%).

[0324] 1 H NMR (400 MHz, CDCl 3): δ7.69(d,J=8.0Hz,1H),7.58~7.64(m,6H),7.44~7.48(m,1H),7.38~7.4 1(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

[0325] Synthesis of compound 1-a

[0326] 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. Ice water (20 mL) was added to quench the reaction, and dichloromethane was extracted (20 mL×2). The organic phases were combined, washed with water (20 mL), saturated brine (20 mL), and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 1-a (20 mg, yield: 17%).

[0327] Synthesis of compound 1

[0328] 1. Solution Preparation

[0329] 1) Prepare 10 mg / mL KF solution: weigh 10 mg potassium fluoride and dissolve it in 1 mL ultrapure water. Sonicate and dissolve for later use.

[0330] 2) Prepare 0.5 M sodium bicarbonate buffer: weigh 4.20 g of sodium bicarbonate and dissolve it in 100 mL of ultrapure water. Sonicate and dissolve for later use.

[0331] 3) Prepare the mobile phase of 10 mM tetrabutylammonium bromide + 0.2% triethylamine solution (pH 2.5 ± 0.05): weigh 6.45 g tetrabutylammonium bromide and dissolve it in 2 L ultrapure water. After ultrasonic dissolution, add 4 mL triethylamine and mix well. Add phosphoric acid and adjust the pH value to 2.5 under pH meter measurement. Filter through 0.45 μm microporous filter membrane for use.

[0332] 4) Prepare compound 1-a solution: Take a bottle of 2 mg of compound 1-a, add 0.5 mL of ultra-dry acetonitrile to dissolve it and prepare it for immediate use.

[0333] 5) Prepare standard solution: Take a bottle of 1 mg standard, add 1 mL of acetonitrile to dissolve and set aside.

[0334] 6) Prepare 2M hydrochloric acid-methanol solution: Use a pipette to take 5 mL of methanol and 1 mL of hydrochloric acid, mix and set aside.

[0335] 7) Prepare 12 mM hydrochloric acid solution: Use a measuring cylinder to measure 200 mL of ultrapure water, add 200 μL of hydrochloric acid, mix well and set aside.

[0336] 8) Prepare 12 mM hydrochloric acid ethanol solution: Take 20 mL of ethanol, add 20 μL of hydrochloric acid, mix well and set aside.

[0337] 9) Prepare 20% acetonitrile dilution: Take 8 mL of 10 mM tetrabutylammonium bromide + 0.2% triethylamine solution (pH 2.5 ± 0.05) as the mobile phase, and then transfer 2 mL of acetonitrile to mix and set aside.

[0338] 2. Labeling the Experimental Process

[0339] 1) Preparation before the experiment

[0340] (1) Clean the CFN synthesis module, replace the ferrule, and check the status of each system.

[0341] (2) Equilibrate the semi-preparative HPLC and complete the injection of standard samples as a control.

[0342] (3) After the semi-preparative injection is completed, use 20% acetonitrile to rinse the quantitative loop, clean the injection needle, and continue to balance the system.

[0343] (4) Use 10 mL of ethanol solution to activate the C18 column, then rinse with 20 mL of ultrapure water, blow dry and set aside. Prepare 3 more columns in the same way. Use 10 mL of 0.5 M NaHCO 3 The solution was used to activate the QMA column, which was then rinsed with 20 mL of ultrapure water and dried for later use. One column was prepared.

[0344] (5) Prepare TBAHCO 3 0.6 mL of solution, 1 mL of anhydrous acetonitrile, 0.5 mL of compound 1-a solution, and 0.5 mL of 2M hydrochloric acid methanol solution were respectively placed in vials of corresponding specifications.

[0345] 2) Synthesis of compound 18F labeling

[0346] (1) After the synthesis module is checked, TBAHCO 3 , anhydrous acetonitrile, compound 1-a solution and hydrochloric acid methanol vials were installed to the corresponding positions of the module, and 20 μL of KF solution was pre-loaded in the reaction bottle.

[0347] (2) Before target transfer, click “Recovery from TG” and the fluorine [18F] ions produced by the accelerator will be transferred to the fluorine ion recovery bottle of the synthesis module through the target transfer pipeline.

[0348] (3) Transfer fluoride [18F] ion water to QMA for adsorption, and then use 0.6 mL TBAHCO 3 The QMA column is eluted and the fluoride [18F] ion solution flows into the reaction bottle.

[0349] (4) Heat to 110°C to remove solvent for 5 min, cool. Add 1 mL of anhydrous acetonitrile, heat to 110°C to remove water for the second time for 5 min, and cool.

[0350] (5) Add the precursor solution, transfer the reaction solution to a constant temperature mixer and heat it to 60°C for 2 h, then cool it down after the reaction is complete. Add hydrochloric acid and methanol, and perform deprotection and oscillation reaction at 60°C for 30 min, then cool it down after the reaction is complete.

[0351] (6) The crude reaction product was diluted with 10 mL of 12 mM hydrochloric acid solution and adsorbed on a C18 column. The column was then washed with 10 mL of ultrapure water and eluted with 1.5 mL of 12 mM hydrochloric acid ethanol to obtain a crude purified reaction stock solution.

[0352] (7) Transferring the crude purified reaction stock solution to semi-preparative high performance liquid chromatography for preparative purification to collect the radioactive peak at the corresponding retention time.

[0353] (8) After purification, the obtained product was diluted with 10 mL of 12 mM hydrochloric acid solution and passed through a C18 column. The C18 column was then cleaned with 10 mL of 12 mM hydrochloric acid solution, and finally the product was eluted with 1.5 mL of 12 mM hydrochloric acid ethanol into the final product bottle.

[0354] (9) A solvent removal device was used to remove part of the ethanol in the final product to meet the dosing requirements and obtain the final product. 5 mci of the crude product was prepared by high performance liquid chromatography to obtain 20 μCi of compound 1 (yield: 0.4%).

[0355] A fluorinated compound with the same structure but without radioactivity was added to the above-synthesized compound 1, so that the specific activity of the drug was between 0.56 GBq / μmol and 1.37 GBq / μmol, which met the requirements for drug administration in animal experiments.

[0356] The above-mentioned drug specific activity test method is described in the literature "Radionuclide Therapy", a book published by People's Medical Publishing House in 2006, authored by Pan Zhongyun, and "Radiopharmaceutical Handbook" [Kuwait] Wen Wani et al., translated by Xia Zhenmin et al.

[0357] Example 2: Imaging of 18F-labeled Compound 1 in MC38 tumor-bearing mice

[0358] 1. Preparation of 18F marker: The solvent of compound 1 is ethanol, and the diluent for administration is physiological saline.

[0359] 2. Experimental methods:

[0360] 1) Prepare 4 MC38 tumor-bearing mice, half male and half female, 3 to 9 weeks old and weighing 12 to 25 g when purchased. Select animals with tumor volume ≥ 100 mm3 before the experiment, and prepare enough spare animals.

[0361] 2) In this experiment, the dosage of non-18F labeled substances was set at about 30 mg / kg. At the same time, according to the requirements of radiation safety and instrument detection, the radioactive dosage of 18F labeled compound 1 was set at about 200 μCi / animal. The actual radioactive dosage of the injected drug was calculated according to the weight of each animal and the specific activity of the labeled drug, and the administration route was intravenous injection.

[0362] 3. PET / CT scanning method of tumor-bearing mice:

[0363] After intravenous administration, tumor-bearing mice were subjected to 1-hour PET dynamic scanning and static scanning at four time points: 3h, 5h, 7h and 9h. The animals were kept immobile and CT scanning was completed before / after the small animal PET scanning. Before the scan, the animals were anesthetized by breathing with isoflurane through an anesthesia machine. The animals that had completed anesthesia induction were placed on the small animal PET / CT bed. During the scan, the animals continued to inhale isoflurane to maintain the anesthetic effect. Each bed was statically scanned for 10 to 30 minutes, with a scanning energy window of 350 to 650 Kev, and the scanning time was recorded.

[0364] 4. Data collection and calculation results:

[0365] After the small animal PET / CT scan is completed, image reconstruction is performed, and PMOD software is used to process images and data. The heart, liver, spleen, lungs, kidneys, stomach, tumors and other organs are delineated as regions of interest, and the radioactivity concentration of the region of interest (i.e., the radioactivity value per unit volume) is obtained, and then the activity at each time point is decay corrected. The percentage injection dose rate per gram of tissue of each organ (abbreviated as %ID / g value) is calculated according to the administration dose, and the target-to-body ratio of the tumor is provided; Microsoft Office Excel is used to calculate the mean value and standard deviation and other data.

[0366] 5. Experimental results:

[0367] After the mouse tail vein was administered with 18F labeled compound 1, the radioactivity was mainly distributed in the liver, followed by tissues with rich blood flow (spleen, lung, kidney, heart), and a small amount in bones and joints. The remaining tissues were comparable to muscles. The tumor-heart ratio gradually increased over time, reaching the highest value at 7 hours, and then decreased. The average tumor-muscle ratio was slightly higher than 1.

Claims

1. 18 F-labeled biphenyl compound or a pharmaceutically acceptable salt thereof, It is characterized in that The 18 F-labeled biphenyl compounds are 2. A 18 use of an F-labeled biphenyl compound or a pharmaceutically acceptable salt thereof in the preparation of a cancer imaging molecular probe.

3. The method according to claim 2 18 Application of F-labeled biphenyl compounds or pharmaceutically acceptable salts thereof in the preparation of cancer imaging molecular probes, It is characterized in that The cancer is 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.

4. A pharmaceutical composition comprising a therapeutically and / or prophylactically effective amount of the 18 F-labeled biphenyl compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and / or diluent.

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