Biphenyl compound and use thereof

Abstract

Disclosed in the present invention are a biphenyl compound and the use thereof. The present invention provides a biphenyl compound represented by formula I or formula II, a pharmaceutically acceptable salt and solvate thereof or a solvate of the pharmaceutically acceptable salt thereof. The biphenyl compound has an inhibitory effect on PD-1 / PD-L1 binding, and thus can be used for treating or diagnosing related diseases such as tumors.

Description

Biphenyl compounds and their applications

[0001] This application claims priority to Chinese patent application 2024115517739, filed on November 1, 2024. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to a biphenyl compound and its applications. Background Technology

[0003] Radioactive drug conjugates (RDCs) are a class of special drugs containing radioactive isotopes for medical diagnosis and treatment. They typically consist of a radioactive isotope paired with a molecular reagent specifically designed to target particular organs and tissues. The molecular reagent delivers the radioactive isotope to the specific organ, tissue, or cell. After patients take the radiopharmaceutical or injectable, PET or SPECT scans are used to detect the radiation emitted by the radioactive isotope in the drug, which is used for the diagnosis and treatment of specific diseases. Radiopharmaceuticals can utilize the biological characteristics of their labeled carriers to reflect the state of disease genes, molecules, metabolism, and function, enabling earlier and more specific insights into the molecular level of diseases. Furthermore, the radiation energy of the radionuclide can accurately kill tumors.

[0004] In recent years, with the successful launch of Novartis' two blockbuster therapeutic radiopharmaceuticals, Lutathera and Pluvicto, and the increasing number of biopharmaceutical giants acquiring or merging with radiopharmaceutical companies or product pipelines, radiopharmaceutical research has received increasing attention from domestic and international companies. Radionuclide conjugates are classified into diagnostic radiopharmaceuticals and therapeutic radiopharmaceuticals according to their clinical uses. Currently, among radiopharmaceuticals in clinical research and market launch stages, the main research targets are concentrated on PSMA, SSTR, FAP, and CAIX.

[0005] Currently, there are no commercially available small-molecule radionuclide conjugates based on PD-1 / PD-L1 targets. Therefore, developing a highly targeted radiopharmaceutical for treatment, diagnosis, or integrated diagnosis and treatment would be of great significance in providing more new treatment options for more patients. Summary of the Invention

[0006] This invention provides a novel biphenyl compound and its application. This type of biphenyl compound has an inhibitory effect on PD-1 / PD-L1 binding and can be used to treat or diagnose tumors and other related diseases.

[0007] The present invention provides a biphenyl compound as shown in Formula I or Formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof;

[0008] R 1 It is hydrogen, halogen, C1-C4 alkyl, or formed by one or more R a Substituted C1-C4 alkyl groups;

[0009] Each R a Each can be independently deuterium, halogen, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkyl-O- or -COOH-;

[0010] L 1 for

[0011] (i) Single bond or -(CH2) n -;

[0012] (ii)-(CH2) m - where 1, 2, 3, 4, or 5 non-adjacent CH2 groups are independently replaced by -Y1-, each Y1 being independently -O-, C(O)-, -C(O)O-, -NH-, -C(O)NH-, or -NHC(O)NH-; or

[0013] (iii)-(CH2) p - where one CH2 is replaced by -Y2-, and the other 0, 1, 2, 3 or 4 non-adjacent CH2s are independently replaced by -Y3-; each Y3 is independently -O-, C(O)-, -C(O)O-, -NH-, -C(O)NH- or -NHC(O)NH-; Y2 is a 5-7 membered carbon ring or a 5-12 membered heterocycle, wherein the number of heteroatoms in the 5-12 membered heterocycle is 1, 2, 3 or 4, and each heteroatom is independently selected from N, O and S;

[0014] L 1 Is it unreplaced or L 1 The 1, 2, or 3 Hs contained therein are each independently controlled by R. 2 replace;

[0015] n, m and p are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14;

[0016] Each R 2 Each is independently a C1-C4 alkyl or -L 3 -R 3 ;

[0017] L 3 for

[0018] (i)-(CH2) j -;or

[0019] (ii)-(CH2) k - where 1, 2, 3 or 4 non-adjacent CH2 are independently replaced by -Y4-, each Y4 being independently -O-, -C(O)-, -C(O)O-, -NH-, -C(O)NH- or -NHC(O)NH-;

[0020] L 3 Is it unreplaced or L 3 The 1, 2, or 3 Hs contained therein are each independently controlled by R. 4 replace;

[0021] j and k are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14;

[0022] R 3 Hydrogen, C6-C 10 aryl or aryl with one or more R b Replacement C6-C 10 Aryl;

[0023] Each R 4 Each is independently a C1-C4 alkyl group;

[0024] Each R b Independently C1-C4 alkyl or containing one or more R c Substituted C1-C4 alkyl groups;

[0025] Each R c Independently, it can be deuterium, halogen, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkyl-O- or -COOH-;

[0026] L 2 It is a group containing a radioactive nuclide.

[0027] In some implementation schemes, R 1 It is a C1-C4 alkyl group or is composed of one or more R groups. a Substituted C1-C4 alkyl groups; each R a Each is an independent halogen.

[0028] In some implementation schemes, R 1 R a and R c In this context, the halogen is F, Cl, Br, or I.

[0029] In some implementation schemes, R 1 R a R 2 R 4 R b and R cIn the context, the C1-C4 alkyl group, with one or more R a Substituted C1-C4 alkyl groups and those with one or more R c The C1-C4 alkyl groups in the substituted C1-C4 alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0030] In some implementations, L 1 for

[0031] (ii)-(CH2) m - where 1, 2, 3, 4, or 5 non-adjacent CH2 groups are independently replaced by -Y1-, each Y1 being independently -O-, C(O)-, -C(O)O-, -NH-, -C(O)NH-, or -NHC(O)NH-; or

[0032] (iii)-(CH2) p - where one CH2 is replaced by -Y2-, and the other 0, 1, 2, 3 or 4 non-adjacent CH2s are independently replaced by -Y3-; each Y3 is independently -O-, C(O)-, -C(O)O-, -NH-, -C(O)NH- or -NHC(O)NH-; Y2 is a 5-7 membered carbon ring or a 5-12 membered heterocycle, wherein the number of heteroatoms in the 5-12 membered heterocycle is 1, 2, 3 or 4, and each heteroatom is independently selected from N, O and S;

[0033] L 1 Is it unreplaced or L 1 One of the H included is R 2 replace;

[0034] m and p are each independently 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14;

[0035] R 2 -L 3 -R 3 ;

[0036] L 3 -(CH2) k - where 1, 2, 3 or 4 non-adjacent CH2 are independently replaced by -Y4-, each Y4 being independently -C(O)NH-;

[0037] L 3 It is unreplaced;

[0038] k is 7, 8, or 9;

[0039] R 3 For one or more R b Replacement C6-C10 Aryl; each R b It is independently a C1-C4 alkyl group.

[0040] In some implementations, L 1 The benzene ring is connected to the benzene ring via -Y1-, and the Y1 connected to the benzene ring is -O-.

[0041] In some implementations, L 1 -O(CH2) n1 -、-O(CH2) n1 NH-, -O(CH2) n1 O(CH2) m1 -、-O(CH2) n1 NH(CH2) n2 O(CH2) m1 -O(CH2) n1 NHC(O)(CH2) m1 -O(CH2) n1 O(CH2) m1 NH-, -O(CH2) n1 O(CH2) n2 O(CH2) m1 NH-, -O(CH2) n1 O(CH2) n2 O(CH2) m1 -、-O(CH2) n1 OC(O)(CH2) m1 -、-O(CH2)n1Y2-C(O)-(CH2) m1 -、-O(CH2) n1 Y2-, -O(CH2) n1 O(CH2) n2 -NHC(O)-(CH2) n3 -NHC(O)-(CH2) m1 -、-O(CH2) n1 O(CH2) n2 -NHC(O)-(CH2) m1 NH-, -O(CH2) n1 -NHC(O)-Y2-(CH2) n2 -NHC(O)-(CH2) m1 NH- or -O(CH2) n1 -NHC(O)-Y2-(CH2) n2 -NH-C(O)-(CH2) n3 -NHC(O)-(CH2) m1 -; where the oxygen atom is connected to the benzene ring at its end;

[0042] Preferably, L 1 -O(CH2) n1 -、-O(CH2) n1 NH-, -O(CH2) n1 O(CH2) m1 -、-O(CH2) n1 O(CH2) m1 NH-, O(CH2) n1 O(CH2) n2 O(CH2) m1 NH-, -O(CH2) n1 O(CH2) n2 O(CH2) m1 -、-O(CH2)n1Y2-C(O)-(CH2) m1 -、-O(CH2) n1 Y2-, -O(CH2) n1 O(CH2) n2 -NHC(O)-(CH2) n3 -NHC(O)-(CH2) m1 -、-O(CH2) n1 O(CH2) n2 -NHC(O)-(CH2) m1 NH-, -O(CH2) n1 -NHC(O)-Y2-(CH2) n2 -NHC(O)-(CH2) m1 NH- or -O(CH2) n1 -NHC(O)-Y2-(CH2) n2 -NH-C(O)-(CH2) n3 -NHC(O)-(CH2) m1 -; where the oxygen atom is connected to the benzene ring at its end;

[0043] More preferably, L 1 -O(CH2) n1 O(CH2) m1 -、-O(CH2)n1Y2-C(O)-(CH2) m1 -、-O(CH2) n1 -NHC(O)-Y2-(CH2) n2 -NH-C(O)-(CH2) n3 -NHC(O)-(CH2) m1 -、-O(CH2) n1 O(CH2) n2 -NHC(O)-(CH2) n3-NHC(O)-(CH2) m1 -、-O(CH2) n1 O(CH2) n2 O(CH2) m1 -or -O(CH2) n1 -;

[0044] Each n1, each n2, each n3, and each m1 is independently 1, 2, 3, 4, 5, or 6;

[0045] L 1 Is it unreplaced or L 1 One of the H's was R 2 replace.

[0046] In some implementations, n1 is 1, 2, or 5.

[0047] In some implementations, n2 is 1 or 2.

[0048] In some implementations, n3 is 1 or 2.

[0049] In some implementations, m1 is 1 or 2.

[0050] In some implementations, when Y2 is a 5-7 member carbon ring, the 5-7 member carbon ring is a 5-7 member saturated carbon ring, preferably. For example (For example ).

[0051] In some implementations, when Y2 is a 5-12 member heterocyclic ring, the 5-12 member heterocyclic ring is a single ring or a double ring, and the double ring is a fused ring, a helical ring or a bridged ring, preferably a helical ring.

[0052] In some implementations, when Y2 is a 5-12 member heterocycle, the 5-12 member heterocycle is a 5-7 member heterocycle or an 8-12 member heterocycle.

[0053] In some implementations, when Y2 is a 5-12 member heterocycle, and when the 5-12 member heterocycle is a 5-7 member heterocycle, the 5-7 member heterocycle is... For example

[0054] In some implementations, when Y2 is a 5-12 member heterocyclic ring, and the 5-12 member heterocyclic ring is an 8-12 member heterocyclic ring, the 8-12 member heterocyclic ring is a bicyclic ring, preferably a helical ring, for example...

[0055] In some embodiments, Y2 is a 5-7 membered saturated carbide ring, a 5-7 membered monocyclic heterocyclic alkyl group, or an 8-12 membered bicyclic heterocyclic alkyl group (the bicyclic ring is preferably a spirocyclic ring), for example...

[0056] In some implementation schemes, R 3 It is a phenyl group or is composed of one or more R groups. b Substituted phenyl groups.

[0057] In some implementation schemes, R b In this context, the C1-C4 alkyl group is methyl or ethyl.

[0058] In some implementation schemes, R 2 for

[0059] In some implementations, L 1 for The b-end is connected to the benzene ring.

[0060] In some implementations, L 1 for The b-end is connected to the benzene ring.

[0061] In some implementations, L 2 It consists of ions containing radioactive nuclides and chelating groups.

[0062] In some embodiments, the radionuclide is a radionuclide capable of emitting alpha rays, beta rays, or gamma rays, preferably a radionuclide capable of emitting alpha rays.

[0063] In some embodiments, the radionuclide is Mn, At, Ac, Pb, Th, Tb, Ra, Bi, F, K, Sc, Ti, Cr, Co, Fe, Ni, Ge, As, Se, Br, Rb, Ru, Pd, Rh, Ag, Sb, Sn, Pr, Pm, Eu, Gr, Dy, Ho, Yb, Os, Pt, Ir, Hg, Au, Lu, Y, I, Re, Ce, Sm, La, Cu, Zr, Sr, In, Tl, Ga, Nb, Mo, Tc, Te, Er, Gd, Hf, Ta, Po, Rn, Pa, U, Np, Pu, Am, Cm, Bk, Cf, Es, Fm, Md, No, Lr, Rf, Sg, Hs, Mt, Rg, or Nh, preferably. Mn, At, Ac, Pb, Th, Tb, Ra, Bi, F, K, Sc, Ti, Cr, Co, Fe, Ni, Ge, As, Se, Br, Rb, Ru, Pd, Rh, Ag, Sb, Sn, Pr, Pm, Eu, Gr, Dy, Ho, Yb, Os, Pt, Ir, Hg, Au, Y, I, Re, Ce, Sm, La, Cu, Zr, Sr, In, Tl, Ga, Nb, Mo, Tc, Te, Er, Gd, Hf, Ta, Po, Rn, Pa, U, Np, Pu, Am, Cm, Bk, Cf, Es, Fm, Md, No, Lr, Rf, Sg, Hs, Mt, Rg or Nh, more preferably Ac, Pb or Ra, and even more preferably Ac or Pb.

[0064] In some implementations, the radionuclide is 51 Mn, 52 Mn, 43 K, 43 Sc、 44 Sc、 46 Sc、 47 Sc、 48 Sc、 49 Sc、 44 Ti、 51 Ti、 51 Cr 57 Co、 58 Co、 59 Fe、 61 Fe、 63 Ni、 65 Ni、 66 Ni、 64 Cu、 67 Cu、 67 Ga、 68 Ga、 71 Ge 72 As、 72 Se、 75 Br、76 Br、 77 As、 77 Br、 81 Rb、 86 Y、 88 Y、 90 Y、 89 Zr、 89 Sr、 94m Tc、 99m Tc、 97 Ru、 100 Pd、 101m Rh、 105 Rh、 103 Pd、 109 Pd、 111 Ag、 111 In、 113 In、 119 Sb、 121 Sn、 142 Pr、 143 Pr、 149 Pm、 149 Tb、 152 Tb、 155 Tb、 161 Tb、 151 Eu、 153 Eu、 169 Eu、 159 Gr、 165 Dy、 166 Ho、 175 Yb、 186 Re, 188 Re, 189 Re, 191 Horse、 193 Pt、 194 Is、 197 Hg、 198 I、 199 I、 211 Assets, 203 Pb、 212 Pb、 225 Ac、 226 Th、 227 Th、 223 Ra、 224 Ra、 212 Wind、 213 Wind、 18 F、 177 Lu、 134 What、 153 Sm、 132 The、 135 The、 139 The、 140La, 124 I, 125 I, 123 I, 131 I, 201 Tl, 95 Nb, 99 Mo, 132 Te, 182 Hf, 210 Po, preferably 51 Mn, 52 Mn, 43 K, 43 Sc, 44 Sc, 46 Sc, 47 Sc, 48 Sc, 49 Sc, 44 Ti, 51 Ti, 51 Cr, 57 Co, 58 Co, 59 Fe, 61 Fe, 63 Ni, 65 Ni, 66 Ni, 64 Cu, 67 Cu, 71 Ge, 72 As, 72 Se,[[ID=,69]] 75 Br, 76 Br, 77 As, 77 Br, 81 Rb, 86 Y, 88 Y, 90 Y, 89 Zr, 89 Sr, 94m Tc, 99m Tc, 97 Ru, 100 Pd, 101m Rh, 105 Rh, 103 Pd, 109 Pd, 111 Ag, 111 In, 113 In, 119 Sb, 121 Sn, 142 Pr, 143 Pr, 149 Pm, 149 Tb, 152 Tb, 155Tb, 161 Tb, 151 Eu、 153 Eu、 169 Eu、 159 Gr、 165 Dy、 166 Ho、 175 Yb、 186 Re、 188 Re、 189 Re、 191 Os、 193 Pt, 194 Ir、 197 Hg, 198 Au、 199 Au、 211 At、 203 Pb, 212 Pb, 225 Ac、 226 Th、 227 Th、 223 Ra、 224 Ra、 212 Bi、 213 Bi、 18 F, 134 Ce、 153 Sm、 132 La、 135 La、 139 La、 140 La、 124 I, 125 I, 123 I, 131 I, 201 Tl、 95 Nb, 99 Mo、 132 Te、 182 Hf, 210 Po, more preferably 225 Ac、 203 Pb, 212 Pb, 223 Ra or 224 Ra, further preferred 225 Ac、 203 Pb or 212 Pb.

[0065] In some embodiments, the valence state of the radionuclide ion is monovalent, divalent, trivalent, or tetravalent, for example, divalent, trivalent, or tetravalent.

[0066] In some embodiments, the ions of the radionuclide are radioactive metal ions or radioactive nonmetal ions, preferably radioactive metal ions.

[0067] In some embodiments, the radioactive metal ions are 44 Ti 4+ , 51 Cr 3+ , 59 Fe 2+ , 63 Ni 2+ , 177 Lu 3+ , 68 Ga 3+ , 47 Sc 3+ , 57 Co 2+ , 58 Co 2+ , 71 Ge 4+ , 81 Rb + , 90 Y 4+ , 225 Ac 3+ , 212 Pb 2+ , 203 Pb 2+ , 223 Ra 3+ , 224 Ra 3+ , 67 Cu 2+ , 161 Tb 3+ , 213 Bi 3+ , 212 Bi 3+ , 89 Zr 4+ , 99 Mo 3+ , 111 In 3+ , 113 In 3+ , 153 Eu 3+ , 186 Re 3+ , 188 Re 3+ , 153 Sm 3+ , 134 Ce 3+ , 132 La 3+ , 135 La 3+ , 139 La 3+, 140 La 3+ , 99m Tc 4+ , 201 Tl 3+ , 226 Th 4+ or 227 Th 4+ , preferably 44 Ti 4+ , 51 Cr 3+ , 59 Fe 2+ , 63 Ni 2+ , 47 Sc 3+ , 57 Co 2+ , 58 Co 2+ , 71 Ge 4+ , 81 Rb + , <00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​La 3+ , 139 La 3+ , 140 La 3+ , 99m Tc 4+ , 201 Tl 3+ , 226 Th 4+ or 227 Th 4+ More preferably 225 Ac 3+ , 212 Pb 2+ , 203 Pb 2+ , 223 Ra 3+ or 224 Ra 3+ Further optimized 225 Ac 3+ , 212 Pb 2+ or 203 Pb 2+ .

[0068] In some implementations, the radioactive nonmetallic ion is [Al]. 18 F] 2+ .

[0069] In some embodiments, the chelating group is (HBED) (NOTAGA) (DOTAGA) (DEDPA) (HEHA) (PEPA) (HBED-CC) (TCMC) (p-SCN-Bn-TCMC) (PSC) (Crown) (Macropa) (p-SCN-Bn-NOTA) or (DTPA), where the a end is connected to the L end. 1 Connection; preferably, the chelating group is (TCMC) More preferably

[0070] In some implementations, L 2 for ( 225 Ac-DOTAGA), ( 225 Ac-PEPA or Preferably, L 2 for

[0071] In some implementations, L 2 It is composed of ions containing radioactive nuclides and chelating groups; the radioactive nuclide is... 225 Ac、 203 Pb or 212 Pb;

[0072] The chelating group is (TCMC)

[0073] In some embodiments, the biphenyl compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof;

[0074] R 1 It is a C1-C4 alkyl group or is composed of one or more R groups. a Substituted C1-C4 alkyl groups; each R a Each is an independent halogen;

[0075] L 1 -O(CH2) n1 O(CH2) m1 -、-O(CH2) n1 -NHC(O)-Y2-(CH2) n2 -NH-C(O)-(CH2) n3 -NHC(O)-(CH2) m1 -or -O(CH2) n1 -NHC(O)-Y2-(CH2) n2 -NHC(O)-(CH2) m1 NH-; Y2 is a 5-7 member saturated carbon ring; each n1, each n2, each n3 and each m1 is independently 1 or 2;

[0076] Preferably, L 1 for The b-end is connected to the benzene ring;

[0077] L 2 It is composed of ions containing radioactive nuclides and chelating groups; the radioactive nuclide is... 225 Ac;

[0078] The chelating group is

[0079] In some embodiments, the biphenyl compound represented by Formula II, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof;

[0080] L 1 The expression is -O(CH2)n1Y2-C(O)-(CH2). m1 -or -O(CH2) n1 Y2-; Y2 is a 5-7 membered heterocyclic alkyl group; each n1 and each m1 is independently 1 or 2;

[0081] Preferably, L 1 for The b-end is connected to the benzene ring;

[0082] L 2 It is composed of ions containing radioactive nuclides and chelating groups; the radioactive nuclide is... 225 Ac;

[0083] The chelating group is

[0084] In some embodiments, the biphenyl compound represented by Formula I is selected from any of the following structures:

[0085] In some embodiments, the compound of formula II is selected from any of the following structures:

[0086] This invention provides a biphenyl compound as shown in Formula III or Formula IV, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0087] Among them, L 4 R is a group containing a non-radioactive nuclide. 1 and L 1 The definition is as described above.

[0088] In some implementations, L 4 It consists of ions containing non-radioactive nuclides and chelating groups.

[0089] In some embodiments, the non-radioactive nuclide is Mn, At, Ac, Pb, Th, Tb, Ra, Bi, F, K, Sc, Ti, Cr, Co, Fe, Ni, Ge, As, Se, Br, Rb, Ru, Pd, Rh, Ag, Sb, Sn, Pr, Pm, Eu, Gr, Dy, Ho, Yb, Os, Pt, Ir, Hg, Au, Lu, Y, I, Re, Ce, Sm, La, Cu, Zr, Sr, In, Tl, Ga, Nb, Mo, Tc, Te, Er, Gd, Hf, Ta, Po, Rn, Pa, U, Np, Pu, Am, Cm, Bk, Cf, Es, Fm, Md, No, Lr, Rf, Sg, Hs, Mt, Rg, or Nh, preferably. The materials selected are Mn, At, Ac, Pb, Th, Tb, Ra, Bi, F, K, Sc, Ti, Cr, Co, Fe, Ni, Ge, As, Se, Br, Rb, Ru, Pd, Rh, Ag, Sb, Sn, Pr, Pm, Eu, Gr, Dy, Ho, Yb, Os, Pt, Ir, Hg, Au, Y, I, Re, Ce, Sm, La, Cu, Zr, Sr, In, Tl, Nb, Mo, Tc, Te, Er, Gd, Hf, Ta, Po, Rn, Pa, U, Np, Pu, Am, Cm, Bk, Cf, Es, Fm, Md, No, Lr, Rf, Sg, Hs, Mt, Rg, or Nh, more preferably Ac, Pb, or Ra, and even more preferably Ac or Pb.

[0090] In some embodiments, the ion of the non-radioactive nuclide is Ti. 4+ Cr 3+ Fe 2+ Ni 2+ Lu 3+ Ga 3+ ,Sc 3+ Co 2+ 、Ge 4+ 、Rb + Y 4+ Ac 3+ Pb 2+ Ra 3+ Cu 2+ 、Tb 3+ Bi 3+ Zr4+ Mo 3+ In 3+ Eu 3+ , 1 Re 3+ 、Sm 3+ Ce 3+ La 3+ 、Tc 4+ 、Tl 3+ or Th 4+ Ti is preferred. 4+ Cr 3+ Fe 2+ Ni 2+ ,Sc 3+ Co 2+ 、Ge 4+ 、Rb + Y 4+ Ac 3+ Pb 2+ Ra 3+ Cu 2+ 、Tb 3+ Bi 3+ Zr 4+ Mo 3+ In 3+ Eu 3+ , 1 Re 3+ 、Sm 3+ Ce 3+ La 3+ 、Tc 4+ 、Tl 3+ or Th 4+ Ac is preferred. 3+ Pb 2+ or Ra 3+ Ac is further preferred. 3+ or Pb 2+ .

[0091] In some implementations, L 4 In this context, the chelating group is as described above.

[0092] In some implementations, L 4 for (Ac-DOTAGA) (Ac-PEPA) or

[0093] In some embodiments, the biphenyl compounds represented by Formula III or Formula IV are selected from any of the following structures:

[0094] The present invention provides a pharmaceutical composition comprising substance A and pharmaceutical excipients, wherein substance A is substance B, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and substance B is a biphenyl compound represented by formula I, II, III, or IV as described above.

[0095] This invention provides the use of biphenyl compounds as shown in Formula I or Formula II, pharmaceutically acceptable salts thereof, solvates thereof, or solvates of pharmaceutically acceptable salts thereof, in the preparation of medicaments for treating tumors.

[0096] In some embodiments, the radionuclide in the biphenyl compound represented by Formula I or Formula II is a radionuclide ion used for treatment.

[0097] The present invention provides the use of biphenyl compounds as shown in Formula I or Formula II, pharmaceutically acceptable salts thereof, solvates thereof, or solvates of pharmaceutically acceptable salts thereof in the preparation of medicaments for diagnosing tumors.

[0098] In some embodiments, the radionuclide in the biphenyl compounds represented by Formula I or Formula II is a radionuclide ion used for diagnosis.

[0099] The present invention provides the use of biphenyl compounds as shown in Formula III or Formula IV, pharmaceutically acceptable salts thereof, solvates thereof, or solvates of pharmaceutically acceptable salts thereof in the preparation of medicaments for treating and / or preventing tumors.

[0100] In the above-described applications, the tumors are PD-1 / PD-L1 related or mediated tumors, such as colorectal cancer, prostate cancer, lung cancer, gastric cancer, cervical cancer, ovarian cancer, breast cancer, pancreatic cancer, liver cancer, bladder cancer, kidney cancer, bone cancer, melanoma, glioma, glioblastoma, or leukemia; for example, colorectal cancer, lung cancer, or prostate cancer.

[0101] The present invention also provides a method for treating tumors, comprising administering to a tumor patient a therapeutically effective amount of a biphenyl compound as described above, such as Formula I or Formula II.

[0102] In some embodiments, the radionuclide in the biphenyl compound represented by Formula I or Formula II is a radionuclide ion used for treatment; for example... 225 Ac 3+ , 212Pb 2+ , 203 Pb 2+ or 224 Ra 3+ .

[0103] In some implementations, the tumor is a PD-1 / PD-L1-related or mediated tumor, such as colorectal cancer, prostate cancer, lung cancer, gastric cancer, cervical cancer, ovarian cancer, breast cancer, pancreatic cancer, liver cancer, bladder cancer, kidney cancer, bone cancer, melanoma, glioma, glioblastoma, or leukemia; for example, colorectal cancer, lung cancer, or prostate cancer.

[0104] The present invention also provides a method for diagnosing tumors, comprising administering to a tumor patient a therapeutically effective amount of a biphenyl compound as described above, such as Formula I or Formula II.

[0105] In some embodiments, the radionuclide in the biphenyl compound represented by Formula I or Formula II is a radionuclide ion used for diagnostic purposes; for example... 64 Cu、 89 Zr、 99m Tc or 111 In.

[0106] In some implementations, the tumor is a PD-1 / PD-L1-related or mediated tumor, such as colorectal cancer, prostate cancer, lung cancer, gastric cancer, cervical cancer, ovarian cancer, breast cancer, pancreatic cancer, liver cancer, bladder cancer, kidney cancer, bone cancer, melanoma, glioma, glioblastoma, leukemia; or, for example, colorectal cancer, lung cancer, or prostate cancer.

[0107] Definitions and Explanations

[0108] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0109] In this invention, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group. C1-C4 alkyl refers to an alkyl group having 1-4 carbon atoms, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0110] In this invention, halogen refers to F, Cl, Br or I.

[0111] In this invention, "carbon ring" refers to a cyclic group consisting of a saturated or partially unsaturated monocyclic or polycyclic (e.g., fused, spirocyclic, or bridged) ring formed from carbon atoms. In a saturated carbon ring, each carbon atom on the ring is saturated; examples of saturated carbon rings include, but are not limited to, those listed below. In a partially unsaturated carbide ring, at least one carbon atom is saturated and at least one carbon atom is unsaturated. Examples of partially unsaturated carbide rings include, but are not limited to, those mentioned above. The 5-7 membered carbon ring can specifically be a 5, 6, or 7 membered carbon ring. In some embodiments, the 5-7 membered carbon ring can specifically be a 5, 6, or 7 membered saturated carbon ring. In some embodiments, the 5-7 membered carbon ring can specifically be a 5, 6, or 7 membered saturated monocyclic carbon ring, including...

[0112] In this invention, the term "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic (e.g., fused, spirocyclic, or bridged) cyclic group formed by a carbon atom and at least one heteroatom, wherein the heteroatom is independently selected from N, O, and S. In a saturated heterocycle, both the carbon atom and the heteroatom on the ring are saturated, and examples of saturated heterocycles include, but are not limited to, those shown below. In a partially unsaturated heterocycle, at least one atom on the ring is saturated and at least one atom is unsaturated. Examples of partially unsaturated heterocycles include, but are not limited to, those mentioned above. The 5-7 membered heterocycle can specifically be a 5-, 6-, or 7-membered heterocycle. In some embodiments, the 5-7 membered heterocycle can specifically be a 5-, 6-, or 7-membered saturated heterocycle. In some embodiments, the 5-7 membered heterocycle can specifically be a 5-, 6-, or 7-membered saturated monocyclic heterocycle, including...

[0113] In this invention, the term "aryl" refers to an aromatic carbocyclic group, wherein each ring is aromatic. In some embodiments, C6-C 10 The aryl group can specifically be phenyl.

[0114] In this invention, the term "pharmaceutically acceptable" means a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of this invention and is relatively non-toxic, i.e., the substance can be administered to an individual and cause an adverse biological response or interact adversely with any component contained in the composition.

[0115] In this invention, the term "pharmaceutically acceptable salt" refers to a salt formed from a suitable non-toxic organic acid, inorganic acid, organic base, or inorganic base with a compound, which retains the biological activity of the compound. The organic acid may be one or more of the conventional salt-forming organic acids in the art, preferably methanesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, lactic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, hydroxyethylsulfonic acid, naphthalenesulfonic acid, and salicylic acid. The inorganic acid may be one or more of the conventional salt-forming inorganic acids in the art, preferably hydrochloric acid, sulfuric acid, and phosphoric acid. The organic base may be one or more of the conventional salt-forming organic bases in the art, preferably pyridines, imidazoles, pyrazines, indoles, purines, tertiary amines, and anilines.

[0116] In this invention, the term "solvent" refers to a substance formed by a compound or its salt with a suitable solvent.

[0117] In this invention, the term "solvent of a pharmaceutically acceptable salt" refers to a substance formed by combining a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base, or a solvent (including but not limited to: water, methanol, ethanol, etc.), wherein the pharmaceutically acceptable salt has the same meaning as the term "pharmaceuticalally acceptable salt" mentioned above, and the solvent is stoichiometric or non-stoichiometric.

[0118] In this invention, the term "therapeutic effective amount" refers to the amount of compound administered to a patient that is sufficient to effectively treat the disease. The therapeutic effective amount will vary depending on the compound, the type of disease, the severity of the disease, the patient's age, etc., but may be adjusted as appropriate by those skilled in the art.

[0119] In this invention, the term "pharmaceutical excipients" refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions; it includes all substances contained in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009) for details.

[0120] In this invention, the term "patient" includes any animal, preferably a mammal, and more preferably a human.

[0121] In this invention, the term "one or more" can be 1, 2, 3, 4, 5 or 6.

[0122] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0123] The reagents and raw materials used in this invention are all commercially available.

[0124] The significant advantages of this invention are: it provides a biphenyl compound containing a radionuclide and its applications. The radionuclide-containing biphenyl compound of this invention has excellent effects on the treatment and / or diagnosis of tumors. Attached Figure Description

[0125] Figure 1 shows the tumor volume growth curves of mice in each group in Example 1.

[0126] Figure 2 is a graph showing the tumor inhibition rate of each group of mice in Example 1.

[0127] Figure 3 shows the tumor volume growth curve of mice in the relevant group in Example 2.

[0128] Figure 4 is a graph showing the tumor inhibition rate of mice in the relevant groups in Example 2.

[0129] Figure 5 is a curve showing the tumor inhibition rate of mice in the relevant group in Example 2.

[0130] Figure 6 shows the tumor volume growth curves of each group of mice in Example 3.

[0131] Figure 7 is a graph showing the tumor inhibition rate of each group of mice in Example 3. Detailed Implementation

[0132] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0133] Implementation 1 225 Synthesis of Ac-compound 1

[0134] 225 Ac-compound 1:

[0135] Step 1. Preparation of 0.1M sodium acetate buffer: Weigh 0.4104 (0.41±0.0015) g sodium acetate, dissolve it in 45 mL of ultrapure water, adjust the pH to 5.0 with glacial acetic acid, and filter it through a 0.22 μm sterile filter;

[0136] Step 2. Preparation of labeled precursor compound 1: Weigh 0.9 mg of labeled precursor compound 1 using a balance, and then add 90 μL of dimethyl sulfoxide to obtain a solution of labeled precursor compound 1 with a concentration of 10 mg / mL.

[0137] Labeled precursor compound 1: The synthesis can be carried out with reference to Example 2 in WO2023116856A1.

[0138] Step 3. Dilution of labeled precursor compound 1: Take 10 μL of the 10 mg / mL labeled precursor compound 1 solution prepared in Step 2 and add it to 90 μL of the 0.1 M pH 5.0 sodium acetate buffer prepared in Step 1.

[0139] Step 4. 225 Preparation of Ac solution: 225 Ac solid dissolved in 0.1 M hydrochloric acid solution yielded a radioactivity of 1.7 μCi / μL;

[0140] Step 5. Turn on the thermostatic mixer and preheat it to 85°C;

[0141] according to 225 Ac: Labeling with precursor compound 1 = 2:1 (μCi / nmol): Take 77 μL of 0.1 M pH 5.0 sodium acetate buffer prepared in step 1 (the volume of the buffer is the total reaction system of 120 μL minus the amount of the labeled precursor). 225 The amount of Ac was determined, and then 19 μL of the labeled precursor compound 1 prepared in step 3 (the amount of precursor calculated according to the labeling ratio) was added to it. Finally, the amount of Ac prepared in step 4 was added. 225 24 μL of Ac solution (calculated according to the labeled ratio) 225 (Amount of Ac), to obtain the reaction solution;

[0142] Step 6. Place the reaction solution prepared in Step 5 into a preheated constant temperature mixer and react for 20 minutes. Detect the reaction solution using TLC scanning to obtain the desired result. 225 The Ac-labeled compound 1 has a radiochemical purity of 100%, which meets the requirements for animal experiments, and no further purification is needed.

[0143] Example 2 225 Synthesis of Ac-compound 2 225 Synthesis of Ac-compound 3 225 Synthesis of Ac-compound 4 225 Synthesis of Ac-compound 5 225 Synthesis of Ac-compound 6 225 Synthesis of Ac-compound 7

[0144] Following the operating steps of Example 1 above, the following preparations were obtained respectively. 225 Ac-compound 2 was detected by TLC scanning. 225 The Ac-labeled compound 2 achieved a radiochemical purity of 100%; the prepared compound... 225 Ac-compound 3 was detected by TLC scanning. 225 The Ac-labeled compound 3 achieved an radiochemical purity of 96.86%; the prepared compound... 225 Ac-compound 4 was detected by TLC scanning.225 The radiochemical purity of the Ac-labeled compound 4 reached 88.73%; the prepared 225 Ac-compound 5 was detected by TLC scanning. 225 The radiochemical purity of the Ac-labeled compound 5 reached 100%; the prepared 225 Ac-compound 6 was detected by TLC scanning. 225 The radiochemical purity of the Ac-labeled compound 6 reached 100%; the prepared 225 Ac-compound 7 was detected by TLC scanning. 225 The radiochemical purity of the Ac-labeled compound 7 reached 100%.

[0145] Effect Example 1 225 Ac-compound 1, 225 Ac-compound 2, 225 Ac-compound 5, 225 Ac-compound 6, 225 In vivo pharmacodynamic study of Ac-compound 1, Ac-compound 2, Ac-compound 5, Ac-compound 6, and Ac-compound 7 on the mouse colon cancer cell MC-38 hPD-L1 model

[0146] 1. Experimental animal information: C57 / BL6 mice, female, 120 mice, 6 - 8 weeks old, body weight 18 - 20 g, Shanghai Jihui Experimental Animal Breeding Co., Ltd., animal quality certificate number: SCXK(Shanghai)2022 - 0009, 20220009024783.

[0147] 2. Experimental methods and procedures:

[0148] 2.1 Cell culture

[0149] Human PD-L1 gene knock-in murine MC-38 cells (MC-38-hPD-L1 cells) were cultured adherently in vitro. The culture conditions were adding 10% heat-inactivated fetal bovine serum to the DEME medium and adding hygromycin B (final concentration 50 μL / mL), and culturing at 37°C with 5% CO2. Subculture was performed 2 - 3 times a week, and when the cells were in the exponential growth phase, the cells were harvested, counted, and inoculated subcutaneously on the right dorsal side of the mice.

[0150] 2.2 Tumor cell inoculation and grouped administration

[0151] 100 μL of 1×10 6 MC-38-hPD-Ll cell suspension was inoculated subcutaneously on the right dorsal side of C57 / BL6 mice. Tumors with a volume of 40 mm 3- 120 mm 3Thirty tumor-bearing mice were randomly divided into six groups of five mice each, according to the experimental protocol. The mice were given medication starting on day 5 after inoculation.

[0152] Table 1. Grouping and Dosing Regimens of Animals in In Vivo Efficacy Experiments

[0153] 2.3 Experimental Indicators

[0154] The experimental indicators examine whether tumor growth can be inhibited, delayed, or cured. Tumor volume was measured three times a week using digital calipers. The formula for calculating tumor volume is: V = 0.5a × b 2 a and b represent the long and short diameters of the tumor, respectively. The antitumor efficacy of the compound is measured by TGI, TGI(%) = [1 - (TV...] i -TV0) / (TV Vi -TV V0 )]×100% (TV0 is the average volume on day 0 of the treatment group, TV V0 This is the average volume of the control group on day 0; TV i TV is the average volume on day i in the treatment group. Vi (This is the average volume of the control group on day i).

[0155] 2.4 End of Experiment

[0156] If the animal's health condition continues to deteriorate, or the tumor size exceeds 2,000 mm 3 In cases where the animal has a serious illness or is in pain, euthanasia may be necessary. In the following situations, notify a veterinarian for euthanasia:

[0157] (1) Significant emaciation, with a weight loss of more than 20%;

[0158] (2) They cannot freely obtain food and water;

[0159] (3) The average tumor volume in the control group reached 2000 mm. 3 The experiment was terminated.

[0160] 2.5 Data Analysis

[0161] GraphPad Prism 8.0 software was used for plotting. Changes in mouse tumor volume were analyzed using two-way ANOVA and compared with the solvent control group according to Dunnett's method. P < 0.05 was considered to be statistically significant.

[0162] 3. Experimental Results:

[0163] 3.1 Tumor volume

[0164] In the in vivo pharmacodynamic experiment of the test drug on the mouse colorectal cancer MC-38 hPD-L1 model, the tumor volumes, tumor inhibition effects, and statistical analysis results of each treatment group are shown in Table 2, Figure 1, and Figure 2.

[0165] Table 2 Tumor volume (mm 3 )(Mean)

[0166] The experimental results show that compared with the control group, 225Ac-compound 1 (Group 2), 225Ac-compound 2 (Group 3), 225Ac-compound 5 (Group 4), 225Ac-compound 7 (Group 5), and 225Ac-compound 6 (Group 6) had tumor growth inhibition rates (TGI) of 77.06% (Group 2), 74.39% (Group 3), 48.28% (Group 4), 60.03% (Group 5), and 99.21% (Group 6) on the 16th day after intravenous administration. These compounds can all inhibit tumor growth well, especially 225Ac-compound 1 (Group 2), 225Ac-compound 2 (Group 3), and 225Ac-compound 6 (Group 6) with tumor growth inhibition rates reaching over 70%.

[0167] Effect Example 2 225 Ac-compound 1, 225 Ac-compound 5, <9999999>Ac-compound 6, 225 Ac-compound 2, 225 Ac-compound 3 and 225 In vivo pharmacodynamic study of Ac-compound 4 on the human lung cancer cell NCI-H441 model

[0168] 1. Experimental animal information: BALB / c nude mice, female, 65 mice, 6 - 8 weeks old, body weight 18 - 20 g, Shanghai Jihui Experimental Animal Breeding Co., Ltd., animal quality certificate number: SCXK (Shanghai) 2022 - 0009, 20220009026110.

[0169] 2. Experimental methods and procedures:

[0170] 2.1 Cell culture

[0171] Human lung cancer cell NCI-H441 was cultured adherently in vitro. The culture conditions were RPMI-1640 medium supplemented with 10% heat-inactivated fetal bovine serum and 1% Pen Strep, and cultured at 37°C with 5% CO2. Passage was carried out 1 - 2 times a week. When the cells were in the exponential growth phase, the cells were harvested, counted, and subcutaneously inoculated on the right dorsal side of the mice.

[0172] 2.2 Tumor cell inoculation and grouping

[0173] Will contain 5×10 6 One hundred and ten milliliters of NCI-H441 cell suspension were thoroughly mixed with one hundred and ten milliliters of Matrigle matrix gel and subcutaneously seeded on the right dorsal side of BALB / c nude mice. Tumors with a volume of 80 mm² were selected. 3 -150mm 3 The 21 tumor-bearing mice were randomly divided into 7 groups of 3 mice each, according to the experimental protocol. The mice were given medication on the same day they were grouped.

[0174] Table 3 Grouping and Dosing Regimens of Animals in In Vivo Efficacy Experiments

[0175] 2.3 Experimental Indicators

[0176] The experimental indicators examine whether tumor growth can be inhibited, delayed, or cured. Tumor volume was measured three times a week using digital calipers. The formula for calculating tumor volume is: V = 0.5a × b 2 a and b represent the long and short diameters of the tumor, respectively. The antitumor efficacy of the compound is measured by TGI, TGI(%) = [1 - (TV...] i -TV0) / (TV Vi -TV V0 )]×100% (TV0 is the average volume on day 0 of the treatment group, TV V0 This is the average volume of the control group on day 0; TV i TV is the average volume on day i in the treatment group. Vi (This is the average volume of the control group on day i).

[0177] 2.4 End of Experiment

[0178] If the animal's health condition continues to deteriorate, or the tumor size exceeds 2,000 mm 3 In cases where the animal has a serious illness or is in pain, euthanasia may be necessary. In the following situations, notify a veterinarian for euthanasia:

[0179] (1) Significant emaciation, with a weight loss of more than 20%;

[0180] (2) They cannot freely obtain food and water;

[0181] (3) The average tumor volume in the control group reached 2000 mm. 3 The experiment was terminated.

[0182] 2.5 Data Analysis

[0183] GraphPad Prism 8.0 software was used for graphing. The changes in mouse tumor volume were analyzed by Two-way ANOVA and compared with the vehicle control group according to the Dunnett method. A P value < 0.05 was considered statistically significant.

[0184] 3. Experimental Results

[0185] 3.1 Tumor Volume

[0186] The tumor volume, tumor inhibition effect, and statistical analysis results of each treatment group in the in vivo pharmacodynamic experiment of the test drug on the human lung cancer cell NCI-H441 model are shown in Table 4, Figures 3, 4, and 5.

[0187] Table 4 Tumor Volume (mm 3 )(Mean)

[0188] The experimental results showed that: when the administration dose was 1 μCi, compared with the control group, the tumor growth inhibition rates (TGI) of 225Ac-compound 1 (Group 2), 225Ac-compound 5 (Group 3), 225Ac-compound 6 (Group 4), and 225Ac-compound 3 (Group 6) on the 28th day after administration were 92.05% (Group 2), 53.78% (Group 3), 93.65% (Group 4), and 90.34% (Group 6), respectively. These compounds could all inhibit tumor growth well, especially 225Ac-compound 1 (Group 2), 225Ac-compound 6 (Group 4), and 225Ac-compound 3 (Group 6) with a tumor growth inhibition rate of over 90%. <00​​​​​​​​​​​​​​​​​​​​​​​

[0193] Human prostate cancer cells PC-3 were cultured in vitro in adherent form under the following conditions: F-12K medium supplemented with 10% heat-inactivated fetal bovine serum and 1% Pen Strep, at 37°C and 5% CO2. Cells were passaged 1-2 times per week. When the cells reached the exponential growth phase, they were harvested, counted, and subcutaneously inoculated onto the right dorsal side of mice.

[0194] 2.2 Tumor cell inoculation and grouping

[0195] Will contain 5×10 6 100 μL of PC-3 cell suspension was subcutaneously injected into the right dorsal side of BALB / c Nude mice. Tumors with a volume of 60 mm² were selected. 3 -160mm 3 The 48 tumor-bearing mice were randomly divided into 7 groups of 3 mice each, according to the experimental protocol. The mice were given medication on the same day they were grouped.

[0196] Table 5. Grouping and Dosing Regimens of Animals in In Vivo Efficacy Experiments

[0197] 2.3 Experimental Indicators

[0198] The experimental indicators examine whether tumor growth can be inhibited, delayed, or cured. Tumor volume was measured three times a week using digital calipers. The formula for calculating tumor volume is: V = 0.5a × b 2 a and b represent the long and short diameters of the tumor, respectively. The antitumor efficacy of the compound is measured by TGI, TGI(%) = [1 - (TV...] i -TV0) / (TV Vi -TV V0 )]×100% (TV0 is the average volume on day 0 of the treatment group, TV V0 This is the average volume of the control group on day 0; TV i TV is the average volume on day i in the treatment group. Vi (This is the average volume of the control group on day i).

[0199] 2.4 End of Experiment

[0200] If the animal's health condition continues to deteriorate, or the tumor size exceeds 2,000 mm 3 In cases where the animal has a serious illness or is in pain, euthanasia may be necessary. In the following situations, notify a veterinarian for euthanasia:

[0201] (1) Significant emaciation, with a weight loss of more than 20%;

[0202] (2) They cannot freely obtain food and water;

[0203] (3) The average tumor volume in the control group reached 2000 mm. 3 The experiment was terminated.

[0204] 2.5 Data Analysis

[0205] GraphPad Prism 8.0 software was used for plotting. Changes in mouse tumor volume were analyzed using two-way ANOVA and compared with the solvent control group according to Dunnett's method. P < 0.05 was considered to be statistically significant.

[0206] 3. Experimental Results

[0207] 3.1 Tumor volume

[0208] The tumor volume, tumor inhibition effect, and statistical analysis results of each treatment group in the in vivo pharmacodynamic experiment of the test drug on the human prostate cancer cell PC-3 model are shown in Table 5, Figure 6, and Figure 7.

[0209] Table 5 Tumor volume (mm) 3 (Mean)

[0210] The experimental results showed that, compared with the control group, the tumor growth inhibition rates (TGI) of 225Ac-compound 1 (Group 2), 225Ac-compound 5 (Group 3), 225Ac-compound 6 (Group 4), 225Ac-compound 3 (Group 6), and 225Ac-compound 4 (Group 7) on day 28 after administration were 81.96% (Group 2), 71.12% (Group 3), 96.17% (Group 4), 91.33% (Group 6), and 46.75% (Group 7), respectively. All four compounds (225Ac-compound 1, 225Ac-compound 5, 225Ac-compound 6, 225Ac-compound 3, and 225Ac-compound 4) effectively inhibited tumor growth, especially 225Ac-compound 1 (Group 2), 225Ac-compound 6 (Group 4), and 225Ac-compound 3 (Group 6), which showed inhibition rates exceeding 80%.

Claims

1. A biphenyl compound as shown in Formula I or Formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; R 1 It is hydrogen, halogen, C1-C4 alkyl, or formed by one or more R a Substituted C1-C4 alkyl groups; Each R a Each can be independently deuterium, halogen, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkyl-O- or -COOH-; L 1 for (i) Single bond or -(CH2) n -; (ii)-(CH2) m - where 1, 2, 3, 4, or 5 non-adjacent CH2 groups are independently replaced by -Y1-, each Y1 being independently -O-, C(O)-, -C(O)O-, -NH-, -C(O)NH-, or -NHC(O)NH-; or (iii)-(CH2) p - where one CH2 is replaced by -Y2-, and the other 0, 1, 2, 3 or 4 non-adjacent CH2s are independently replaced by -Y3-; each Y3 is independently -O-, C(O)-, -C(O)O-, -NH-, -C(O)NH- or -NHC(O)NH-; Y2 is a 5-7 membered carbon ring or a 5-12 membered heterocycle, wherein the number of heteroatoms in the 5-12 membered heterocycle is 1, 2, 3 or 4, and each heteroatom is independently selected from N, O and S; L 1 Is it unreplaced or L 1 The 1, 2, or 3 Hs contained therein are each independently controlled by R. 2 replace; n, m and p are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14; Each R 2 Each is independently a C1-C4 alkyl or -L 3 -R 3 ; L 3 for (i)-(CH2) j -;or (ii)-(CH2) k - where 1, 2, 3 or 4 non-adjacent CH2 are independently replaced by -Y4-, each Y4 being independently -O-, -C(O)-, -C(O)O-, -NH-, -C(O)NH- or -NHC(O)NH-; L 3 Is it unreplaced or L 3 The 1, 2, or 3 Hs contained therein are each independently controlled by R. 4 replace; j and k are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14; R 3 Hydrogen, C6-C 10 aryl or aryl with one or more R b Replacement C6-C 10 Aryl; Each R 4 Each is independently a C1-C4 alkyl group; Each R b Independently C1-C4 alkyl or composed of one or more R c Substituted C1-C4 alkyl groups; Each R c Independently, it can be deuterium, halogen, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkyl-O- or -COOH-; L 2 It is a group containing a radioactive nuclide.

2. The biphenyl compound of formula I or II as described in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The biphenyl compounds represented by Formula I or Formula II satisfy one or more of the following conditions: (1)R 1 R a and R c In this context, the halogen is F, Cl, Br, or I; (2)R 1 R a R 2 R 4 R b and R c In the context, the C1-C4 alkyl group, with one or more R a Substituted C1-C4 alkyl groups and those with one or more R c The C1-C4 alkyl groups in the substituted C1-C4 alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (3) When Y2 is a 5-7 member carbon ring, the 5-7 member carbon ring is a 5-7 member saturated carbon ring, preferably. For example For example (4) When Y2 is a 5-12 member heterocyclic ring, the 5-12 member heterocyclic ring is a single ring or a double ring, and the double ring is a parallel ring, a spiral ring or a bridge ring, preferably a spiral ring; (5) When Y2 is a 5-12 member heterocyclic ring, the 5-12 member heterocyclic ring is a 5-7 member heterocyclic ring or an 8-12 member heterocyclic ring; (6) When Y2 is a 5-12 member heterocyclic ring, and the 5-12 member heterocyclic ring is a 5-7 member heterocyclic ring, the 5-7 member heterocyclic ring is... For example (7) When Y2 is a 5-12 member heterocyclic ring, and the 5-12 member heterocyclic ring is an 8-12 member heterocyclic ring, the 8-12 member heterocyclic ring is a bicyclic ring, preferably a helical ring, for example...

3. The biphenyl compound of formula I or II as described in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The biphenyl compounds represented by Formula I or Formula II satisfy one of the following schemes: Option 1: L 1 for (ii)-(CH2) m - where 1, 2, 3, 4, or 5 non-adjacent CH2 groups are independently replaced by -Y1-, each Y1 being independently -O-, C(O)-, -C(O)O-, -NH-, -C(O)NH-, or -NHC(O)NH-; or (iii)-(CH2) p - where one CH2 is replaced by -Y2-, and the other 0, 1, 2, 3 or 4 non-adjacent CH2s are independently replaced by -Y3-; each Y3 is independently -O-, C(O)-, -C(O)O-, -NH-, -C(O)NH- or -NHC(O)NH-; Y2 is a 5-7 membered carbon ring or a 5-12 membered heterocycle, wherein the number of heteroatoms in the 5-12 membered heterocycle is 1, 2, 3 or 4, and each heteroatom is independently selected from N, O and S; L 1 Is it unreplaced or L 1 One of the H included is R 2 replace; m and p are each independently 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14; R 2 -L 3 -R 3 ; L 3 -(CH2) k - where 1, 2, 3 or 4 non-adjacent CH2 are independently replaced by -Y4-, each Y4 being independently -C(O)NH-; L 3 It is unreplaced; k is 7, 8, or 9; R 3 For one or more R b Replacement C6-C 10 Aryl; each R b Independently, it is a C1-C4 alkyl group; Option 2: L 1 -O(CH2) n1 -、-O(CH2) n1 NH-, -O(CH2) n1 O(CH2) m1 -、-O(CH2) n1 NH(CH2) n2 O(CH2) m1 -O(CH2) n1 NHC(O)(CH2) m1 -O(CH2) n1 O(CH2) m1 NH-, -O(CH2) n1 O(CH2) n2 O(CH2) m1 NH-, -O(CH2) n1 O(CH2) n2 O(CH2) m1 -、-O(CH2) n1 OC(O)(CH2) m1 -、-O(CH2)n1Y2-C(O)-(CH2) m1 -、-O(CH2) n1 Y2-, -O(CH2) n1 O(CH2) n2 -NHC(O)-(CH2) n3 -NHC(O)-(CH2) m1 -、-O(CH2) n1 O(CH2) n2 -NHC(O)-(CH2) m1 NH-, -O(CH2) n1 -NHC(O)-Y2-(CH2) n2 -NHC(O)-(CH2) m1 NH- or -O(CH2) n1 -NHC(O)-Y2-(CH2) n2 -NH-C(O)-(CH2) n3 -NHC(O)-(CH2) m1 -; where the oxygen atom is connected to the benzene ring at its end; Preferably, L 1 -O(CH2) n1 -、-O(CH2) n1 NH-, -O(CH2) n1 O(CH2) m1 -、-O(CH2) n1 O(CH2) m1 NH-, O(CH2) n1 O(CH2) n2 O(CH2) m1 NH-, -O(CH2) n1 O(CH2) n2 O(CH2) m1 -、-O(CH2)n1Y2-C(O)-(CH2) m1 -、-O(CH2) n1 Y2-, -O(CH2) n1 O(CH2) n2 -NHC(O)-(CH2) n3 -NHC(O)-(CH2) m1 -、-O(CH2) n1 O(CH2) n2 -NHC(O)-(CH2) m1 NH-, -O(CH2) n1 -NHC(O)-Y2-(CH2) n2 -NHC(O)-(CH2) m1 NH- or -O(CH2) n1 -NHC(O)-Y2-(CH2) n2 -NH-C(O)-(CH2) n3 -NHC(O)-(CH2) m1 -; where the oxygen atom is connected to the benzene ring at its end; More preferably, L 1 -O(CH2) n1 O(CH2) m1 -、-O(CH2)n1Y2-C(O)-(CH2) m1 -、-O(CH2) n1 -NHC(O)-Y2-(CH2) n2 -NH-C(O)-(CH2) n3 -NHC(O)-(CH2) m1 -、-O(CH2) n1 O(CH2) n2 -NHC(O)-(CH2) n3 -NHC(O)-(CH2) m1 -、-O(CH2) n1 O(CH2) n2 O(CH2) m1 -or -O(CH2) n1 -; Each n1, each n2, each n3, and each m1 is independently 1, 2, 3, 4, 5, or 6; L 1 Is it unreplaced or L 1 One of the H's was R 2 replace; Preferably, n1 is 1, 2 or 5; n2 is 1 or 2; n3 is 1 or 2; m1 is 1 or 2.

4. The biphenyl compound of formula I or II as described in claim 1 or 3, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The biphenyl compounds represented by Formula I or Formula II satisfy one or more of the following conditions: (1)R 1 It is a C1-C4 alkyl group or is composed of one or more R groups. a Substituted C1-C4 alkyl groups; each R a Each is an independent halogen; (2) Y2 is a 5-7 membered saturated carbon ring, a 5-7 membered monocyclic heterocyclic alkyl group, or an 8-12 membered bicyclic heterocyclic alkyl group, for example (3)R 3 It is a phenyl group or is composed of one or more R groups. b Substituted phenyl; (4)R b In this context, the C1-C4 alkyl group is methyl or ethyl; and (5)R 2 for 5. The biphenyl compound of formula I or II as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, L 2 It consists of ions containing radioactive nuclides and chelating groups.

6. The biphenyl compound of formula I or II as described in claim 5, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The biphenyl compounds represented by Formula I or Formula II satisfy one or more of the following conditions: (1) The radioactive nuclide is a radioactive nuclide capable of emitting α rays, β rays or γ rays, preferably a radioactive nuclide capable of emitting α rays; (2) The radionuclides mentioned are Mn, At, Ac, Pb, Th, Tb, Ra, Bi, F, K, Sc, Ti, Cr, Co, Fe, Ni, Ge, As, Se, Br, Rb, Ru, Pd, Rh, Ag, Sb, Sn, Pr, Pm, Eu, Gr, Dy, Ho, Yb, Os, Pt, Ir, Hg, Au, Lu, Y, I, Re, Ce, Sm, La, Cu, Zr, Sr, In, Tl, Ga, Nb, Mo, Tc, Te, Er, Gd, Hf, Ta, Po, Rn, Pa, U, Np, Pu, Am, Cm, Bk, Cf, Es, Fm, Md, No, Lr, Rf, Sg, Hs, Mt, Rg or Nh, preferably Mn, At, Ac, Pb, Th, Tb, Ra, Bi, F, K, Sc, Ti, Cr, Co, Fe, Ni, Ge, As, Se, Br, Rb, Ru, Pd, Rh, Ag, Sb, Sn, Pr, Pm, Eu, Gr, Dy, Ho, Yb, Os, Pt, Ir, Hg, Au, Y, I, Re, Ce, Sm, La, Cu, Zr, Sr, In, Tl, Ga, Nb, Mo, Tc, Te, Er, Gd, Hf, Ta, Po, Rn, Pa, U, Np, Pu, Am, Cm, Bk, Cf, Es, Fm, Md, No, Lr, Rf, Sg, Hs, Mt, Rg or Nh, more preferably Ac, Pb or Ra, and even more preferably Ac or Pb; (3) The radioactive nuclide mentioned is 51 Mn, 52 Mn, 43 K, 43 Sc、 44 Sc、 46 Sc、 47 Sc、 48 Sc、 49 Sc、 44 Ti、 51 Ti、 51 Cr 57 Co、 58 Co、 59 Fe、 61 Fe、 63 Ni、 65 Ni、 66 Ni、 64 Cu、 67 Cu、 67 Ga、 68 Ga、 71 Ge 72 As、 72 Se、 75 Br、 76 Br、 77 As、 77 Br、 81 Rb、 86 Y、 88 Y、 90 Y、 89 Zr、 89 Sr、 94m Tc, 99m Tc, 97 Ru、 100 Pd, 101m Rh、 105 Rh、 103 Pd, 109 Pd, 111 Ag、 111 In、 113 In、 119 Sb、 121 Sn、 142 Pr、 143 Pr、 149 Pm, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 151 Eu、 153 Eu、 169 Eu、 159 Gr、 165 Dy、 166 Ho, 175 Yb, 186 Re, 188 Re, 189 Re, 191 Os, 193 Pt, 194 Ir, 197 Hg, 198 Au, 199 Au, 211 At, 203 Pb, 212 Pb, 225 Ac, 226 Th, 227 Th, 223 Ra, 224 Ra, 212 Bi, 213 Bi, 18 F, 177 Lu, 134 Ce, 153 Sm, 132 La, 135 La, 139 La, 140 La, 124 I, 125 I, 123 I, 131 I, 201 [[ID=, 66]]Tl, 95 Nb, 99 Mo, 132 Te, 182 Hf, 210 Po, preferably 51 Mn, 52 [[ID=, 80]]Mn, 43 K, 43 Sc, 44 Sc, 46 Sc, 47 Sc, 48 Sc, 49 Sc, <00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ 75 Br、 76 Br、 77 As、 77 Br、 81 Rb、 86 Y、 88 Y、 90 Y、 89 Zr、 89 Sr、 94m Tc、 99m Tc、 97 Ru、 100 Pd、 101m Rh、 105 Rh、 103 Pd、 109 Pd、 111 Ag、 111 In、 113 In、 119 Sb、 121 Sn、 142 Pr、 143 Pr、 149 Pm、 149 Tb、 152 Tb、 155 Tb、 161 Tb、 151 Eu、 153 Eu、 169 Eu、 159 Gr、 165 Dy、 166 Ho、 175 Yb、 186 Re, 188 Re, 189 Re, 191 Horse、 193 Pt、 194 Is、 197 Hg、 198 I、 199 I、 211 Assets, 203 Pb、 212 Pb、 225 Ac、 226 Th、 227 Th、 223 Ra、 224 Ra、 212 Wind、 213 Wind、 18 F、 134 What、 153 Sm、 132 The、 135 The、 139 The、 140 La、 124 I, 125 I, 123 I, 131 I, 201 Tl、 95 Nb, 99 Mo、 132 Te、 182 Hf, 210 Po, more preferably 225 Ac、 203 Pb, 212 Pb, 223 Ra or 224 Ra, further preferred 225 Ac、 203 Pb or 212 Pb; (4) The valence state of the ions of the radionuclides is monovalent, divalent, trivalent or tetravalent, for example, divalent, trivalent or tetravalent; (5) The ions of the radioactive nuclide are radioactive metal ions or radioactive non-metal ions, preferably radioactive metal ions. Preferably, the radioactive metal ions are 44 Ti 4+ , 51 Cr 3+ , 59 Fe 2+ , 63 Ni 2+ , 177 Lu 3+ , 68 Ga 3+ , 47 Sc 3+ , 57 Co 2+ , 58 Co 2+ , 71 Ge 4+ , 81 Rb + , 90 Y 4+ , 225 Ac 3+ , 212 Pb 2+ , 203 Pb 2+ , 223 Ra 3+ , 224 Ra 3+ , 67 Cu 2+ , 161 Tb 3+ , 213 Bi 3+ , 212 Bi 3+ , 89 Zr 4+ , 99 Mo 3+ , 111 In 3+ , 113 In 3+ , 153 Eu 3+ , 186 Re 3+ , 188 Re 3+ , 153 Sm 3+ , 134 Ce 3+ , 132 La 3+ , 135 La 3+ , 139 La 3+ , 140 La 3+ , 99m Tc 4+ , 201 Tl 3+ , 226 Th 4+ or 227 Th 4+ , preferably 44 Ti 4+ , 51 Cr 3+ , 59 Fe 2+ , 63 Ni 2+ , 47 Sc 3+ , 57 Co 2+ , 58 Co 2+ , 71 Ge 4+ , 81 Rb + , 90 Y 4+ , 225 Ac 3+ , 212 Pb 2+ , 203 Pb 2+ , 223 Ra 3+ , 224 Ra 3+ , 67 Cu 2+ , 161 Tb<000046​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​La 3+ , 140 La 3+ , 99m Tc 4+ , 201 Tl 3+ , 226 Th 4+ or 227 Th 4+ More preferably 225 Ac 3+ , 212 Pb 2+ , 203 Pb 2+ , 223 Ra 3+ or 224 Ra 3+ Further optimized 225 Ac 3+ , 212 Pb 2+ or 203 Pb 2+ ; Preferably, the radioactive nonmetallic ion is [Al]. 18 F] 2+ ; The chelating group described in (6) is Where end a and L 1 Connection; preferably, the chelating group is More preferably 7. The biphenyl compound of formula I or II as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The biphenyl compounds represented by Formula I or Formula II satisfy one or both of the following conditions: (1)L 1 for The b-end is connected to the benzene ring; Preferably, L 1 for The b-end is connected to the benzene ring; and (2)L 2 for Preferably, L 2 for 8. The biphenyl compound of formula I or II as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The biphenyl compounds represented by Formula I or Formula II satisfy one of the following schemes: Scheme 1, Scheme 2, and Scheme 3. Option 1: L 2 It is composed of ions containing radioactive nuclides and chelating groups; the radioactive nuclide is... 225 Ac、 203 Pb or 212 Pb; The chelating group is Option 2: Biphenyl compounds represented by Formula I, their pharmaceutically acceptable salts, their solvates, or solvates of their pharmaceutically acceptable salts; R 1 It is a C1-C4 alkyl group or is composed of one or more R groups. a Substituted C1-C4 alkyl groups; each R a Each is an independent halogen; L 1 -O(CH2) n1 O(CH2) m1 -、-O(CH2) n1 -NHC(O)-Y2-(CH2) n2 -NH-C(O)-(CH2) n3 -NHC(O)-(CH2) m1 -or -O(CH2) n1 -NHC(O)-Y2-(CH2) n2 -NHC(O)-(CH2) m1 NH-; Y2 is a 5-7 member saturated carbon ring; each n1, each n2, each n3 and each m1 is independently 1 or 2; Preferably, L 1 for The b-end is connected to the benzene ring; L 2 It is composed of ions containing radioactive nuclides and chelating groups; the radioactive nuclide is... 225 Ac; The chelating group is Option 3: Biphenyl compounds represented by Formula II, their pharmaceutically acceptable salts, their solvates, or solvates of their pharmaceutically acceptable salts; L 1 The expression is -O(CH2)n1Y2-C(O)-(CH2). m1 -or -O(CH2) n1 Y2-; Y2 is a 5-7 membered heterocyclic alkyl group; each n1 and each m1 is independently 1 or 2; Preferably, L 1 for The b-end is connected to the benzene ring; L 2 It is composed of ions containing radioactive nuclides and chelating groups; the radioactive nuclide is... 225 Ac; The chelating group is 9. The biphenyl compound of formula I or II as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The biphenyl compounds represented by Formula I are selected from any of the following structures: The compound of formula II is selected from any of the following structures:

10. A biphenyl compound as shown in Formula III or Formula IV, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof. in, L 4 It is a group containing a non-radioactive nuclide; preferably, L 4 It is composed of ions containing non-radioactive nuclides and chelating groups; The chelating group, R 1 and L 1 The definition is as described in any one of claims 1-9.

11. The biphenyl compound of formula III or IV as claimed in claim 10, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The biphenyl compounds represented by Formula III or Formula IV satisfy one or more of the following conditions: (1) The non-radioactive nuclide is Mn, At, Ac, Pb, Th, Tb, Ra, Bi, F, K, Sc, Ti, Cr, Co, Fe, Ni, Ge, As, Se, Br, Rb, Ru, Pd, Rh, Ag, Sb, Sn, Pr, Pm, Eu, Gr, Dy, Ho, Yb, Os, Pt, Ir, Hg, Au, Lu, Y, I, Re, Ce, Sm, La, Cu, Zr, Sr, In, Tl, Ga, Nb, Mo, Tc, Te, Er, Gd, Hf, Ta, Po, Rn, Pa, U, Np, Pu, Am, Cm, Bk, Cf, Es, Fm, Md, No, Lr, Rf, Sg, Hs, Mt, Rg or Nh, preferably Mn. n, At, Ac, Pb, Th, Tb, Ra, Bi, F, K, Sc, Ti, Cr, Co, Fe, Ni, Ge, As, Se, Br, Rb, Ru, Pd, Rh, Ag, Sb, Sn, Pr, Pm, Eu, Gr, Dy, Ho, Yb, Os, Pt, Ir, Hg, Au, Y, I, Re, Ce, Sm, La, Cu, Zr, Sr, In, Tl, Nb, Mo, Tc, Te, Er, Gd, Hf, Ta, Po, Rn, Pa, U, Np, Pu, Am, Cm, Bk, Cf, Es, Fm, Md, No, Lr, Rf, Sg, Hs, Mt, Rg or Nh, more preferably Ac, Pb or Ra, and even more preferably Ac or Pb; (2) The ion of the non-radioactive nuclide mentioned is Ti. 4+ Cr 3+ Fe 2+ Ni 2+ Lu 3+ Ga 3+ ,Sc 3+ Co 2+ 、Ge 4+ 、Rb + Y 4+ Ac 3+ Pb 2+ Ra 3+ Cu 2+ 、Tb 3+ Bi 3+ Zr 4+ Mo 3+ In 3+ Eu 3+ , 1 Re 3+ 、Sm 3+ Ce 3+ La 3+ Tc 4+ 、Tl 3+ or Th 4+ Ti is preferred. 4+ Cr 3+ Fe 2+ Ni 2+ ,Sc 3+ Co 2+ 、Ge 4+ 、Rb + Y 4+ Ac 3+ Pb 2+ Ra 3+ Cu 2+ 、Tb 3+ Bi 3+ Zr 4+ Mo 3+ In 3+ Eu 3+ , 1 Re 3+ 、Sm 3+ Ce 3+ La 3+ Tc 4+ 、Tl 3+ or Th 4+ Ac is preferred. 3+ Pb 2+ or Ra 3+ Ac is further preferred. 3+ or Pb 2+ ; and (3)L 4 for 12. The biphenyl compound of formula III or IV as described in claim 10, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The biphenyl compounds represented by Formula III or Formula IV have any of the following structures:

13. A pharmaceutical composition comprising substance A and a pharmaceutical excipient, wherein substance A is substance B, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein substance B is a biphenyl compound of formula I or II as claimed in any one of claims 1-9, or a biphenyl compound of formula III or IV as claimed in any one of claims 10-12.

14. The use of a biphenyl compound of any one of claims 1-9, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a medicament; The drug is a drug used to treat tumors or a drug used to diagnose tumors; Preferably, when the drug is a drug for treating tumors, the radionuclide in the biphenyl compound as shown in Formula I or Formula II is a radionuclide ion used for treatment, for example... 225 Ac 3+ , 212 Pb 2+ , 203 Pb 2+ or 224 Ra 3+ ; Preferably, when the drug is a drug for diagnosing tumors, the radionuclide in the biphenyl compound as shown in Formula I or Formula II is a radionuclide ion for diagnosis.

15. The use of a biphenyl compound of formula III or IV as described in any one of claims 10-12, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing tumors.

16. The application as described in claim 14 or 15, characterized in that, The tumors mentioned are PD-1 / PD-L1 related or mediated tumors, such as colorectal cancer, prostate cancer, lung cancer, gastric cancer, cervical cancer, ovarian cancer, breast cancer, pancreatic cancer, liver cancer, bladder cancer, kidney cancer, bone cancer, melanoma, glioma, glioblastoma, or leukemia; for example, colorectal cancer, lung cancer, or prostate cancer.

17. A method of treating a tumor, comprising administering to a tumor patient a therapeutically effective amount of a biphenyl compound of formula I or formula II as described in any one of claims 1-9, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; Preferably, the radionuclide in the biphenyl compound represented by Formula I or Formula II is a radionuclide ion used for treatment; for example... 225 Ac 3+ , 212 Pb 2+ , 203 Pb 2+ or 224 Ra 3+ ; Preferably, the tumor is a PD-1 / PD-L1 related or mediated tumor, such as colorectal cancer, prostate cancer, lung cancer, gastric cancer, cervical cancer, ovarian cancer, breast cancer, pancreatic cancer, liver cancer, bladder cancer, kidney cancer, bone cancer, melanoma, glioma, glioblastoma, or leukemia; or, for example, colorectal cancer, lung cancer, or prostate cancer.

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