Aromatic vinyl compounds, their metal complexes, their preparation methods and applications

Abstract

This invention discloses an aromatic vinyl compound, its metal complex, its preparation method, and its applications. The structure of the aromatic vinyl compound is shown in general formula II. The aromatic vinyl compound and its metal complex of this invention exhibit inhibitory activity against PD-1 / PD-L1 binding, thereby enabling its use in the treatment of tumors and related diseases. Furthermore, the metal complex of this invention can also be used as an imaging agent.

Description

Technical Field

[0001] This application claims priority to PCT patent application PCT / CN2021 / 141330, filed on December 24, 2021, and to Chinese patent application CN202211627117.3, filed on December 16, 2022. The full text of the aforementioned patent applications is incorporated herein by reference.

[0002] This invention relates to an aromatic ethylene compound, its metal complex, its preparation method, and its application. Prior Technology

[0003] Nuclear medicine is an important branch of modern medicine, primarily based on radionuclides and their labeled compounds, applying nuclear technology to the research, diagnosis, and treatment of diseases. Radiopharmaceuticals refer to a special class of drugs containing radionuclides for medical diagnosis and treatment. These are compounds or biological agents labeled with radionuclides used in the body for medical diagnosis or treatment, and are further divided into diagnostic radiopharmaceuticals and therapeutic radiopharmaceuticals. These two classes of drugs include non-metallic radiopharmaceuticals such as 131I and 18F, and metallic radiopharmaceuticals such as 68Ga, 177Lu, and 186Re.

[0004] PD-1 (programmed death 1) is an important immunosuppressive molecule. A member of the CD28 superfamily, it was initially selected from apoptotic mouse T-cell hybridoma 2B4.11. PD-1-targeted immunomodulation plays a significant role in anti-tumor, anti-infection, anti-autoimmune diseases, and organ transplant survival. Its ligand PD-L1 can also be targeted; corresponding antibodies and small molecule drugs can inhibit the binding of PD-1 to PD-L1, thereby activating the immune response to eliminate tumor cells.

[0005] Currently, there are no existing technologies that have successfully marketed aromatic ethylene derivatives containing radioactive metal elements as small molecule radiopharmaceuticals targeting PD-L1, and there are no reports on the use of such compounds in PET tumor imaging and tumor treatment. Summary of the Invention

[0006] The purpose of this invention is to provide a novel aromatic ethylene compound, its metal complex, its preparation method, and its application.

[0007] This invention provides a pharmaceutically acceptable salt of a compound of formula II or a metal complex thereof, or any of the foregoing (i.e., a compound of formula II or a metal complex thereof): X1, X2, X3, X4, and X5 are each independently CH or N; R1 is hydrogen, halogen, cyano, C1-C4 alkyl, or a C1-C4 alkyl group substituted with one or more Ra groups; R2 and R3 are each independently hydrogen or halogen; R4 is hydrogen, halogen, C1-C4 alkyl, or a C1-C4 alkyl substituted with one or more Rb; R5 and R6 are each independently hydrogen, deuterium, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more Rc atoms; or, R5, R6, and the nitrogen atom attached to them together form a 5-7 membered heterocycle or a 5-7 membered heterocycle substituted with one or more Rc atoms; wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3, or 4, and each heteroatom is independently selected from N, O, and S; Each Ra, each Rb, and each Rc is independently deuterium, halogen, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkyl-O-, -COOH, or -C(O)ORg; Each R8 is independently hydrogen, deuterium, halogen, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkyl-S-, C1-C4 alkyl-O-, -C(O)NH2, -C(O)OC1-4 alkyl, -OR8a, -NHR8a, -NR8aR8b, -NH-C(O)-R8d, C1-C4 alkyl substituted with one or more R8c, C1-C4 alkyl-S-substituted with one or more R8c, or C1-C4 alkyl-O-substituted with one or more R8c; Alternatively, two adjacent R8s together with the carbon atoms on the benzene rings they are attached to form a 5-7 membered carbon ring, a 5-7 membered heterocycle, a 5-7 membered carbon ring substituted with one or more C1-4 alkyl groups, or a 5-7 membered heterocycle substituted with one or more C1-4 alkyl groups; wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3, or 4, and each heteroatom is independently selected from N and O; Each R 8a, R 8b, and each R 8c is independently a C1-C4 alkyl-S-, halogen, C1-C4 alkyl, C1-C4 alkyl-O-, -COOH, -(C1-C4 alkylene)-COOH, -C(O)OC1-C4 alkyl, -C(O)NH2, -C(O)NHC1-C4 alkyl, 5-7 membered heterocycle, or -NR 8eR 8f; in the 5-7 membered heterocycle, the type of heteroatom is independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; R8e and R8f are each independently hydrogen, halogen, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more R8g; Each R 8g is independently a halogen, C1-4 alkyl, hydroxyl, -NR 8hR 8k, C1-C4 alkyl-O-, -COOH, -(C1-C4 alkylene)-COOH, -C(O)OC1-C4 alkyl, -C(O)NH2 or -C(O)NHC1-C4 alkyl; R8h and R8k are each independently hydrogen or C1-4 alkyl; Each R 8d is independently a C 6-C 10 aryl group substituted with one or more R 8d-1 groups or a 5-10 heteroaryl group substituted with one or more R 8d-2 groups; wherein the heteroatom in the 5-10 heteroaryl group is independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; Each R 8d-1 and R 8d-2 is independently a C1-C4 alkoxy or a C1-C4 alkyl substituted with one or more R 8d-1-1; Each R 8d-1-1 is independently a 5-7 membered heterocycle substituted with a carboxyl group; in the 5-7 membered heterocycle, the type of heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; q can be 0, 1, 2, or 3; L1 is (i) Single bond or -(CH2)n-; (ii) -(CH₂)m-, wherein 1, 2, 3, 4, or 5 non-adjacent CH₂ groups are independently replaced by -Y₁-, each Y₁ being independently -C(O)-, -C(O)O-, -O-, -NH-, -C(O)NH-, or -NHC(O)NH-; or (iii) -(CH 2) p-, wherein one CH 2 is replaced by -Y 2-, and the other 0, 1, 2, 3 or 4 non-adjacent CH 2 are independently replaced by -Y 3-; each Y 3 is independently -C(O)-, -C(O)O-, -O-, -NH-, -C(O)NH- or -NHC(O)NH-; Y 2 is a 5-7 membered carbon ring or a 5-7 membered heterocycle, wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3 or 4, and each heteroatom is independently selected from N, O and S; L1 is either unsubstituted or L1 contains 1, 2, or 3 H's, each of which is independently substituted by R7; n, m, and p are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14; Each R 7 is independently a C1-C4 alkyl or -L3-R 9; L3 is (i) -(CH 2) j-; or (ii) -(CH 2) k-, wherein 1, 2, 3 or 4 non-adjacent CH 2 are independently replaced by -Y 4-, each Y 4 being independently -C(O)-, -C(O)O-, -O-, -NH-, -C(O)NH- or -NHC(O)NH-; L3 is either unsubstituted or L3 contains 1, 2, or 3 H atoms, each independently substituted by R10; j and k are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14; R9 is hydrogen, a C6-C10 aryl group, or a C6-C10 aryl group substituted with one or more Rd groups; Each R 10 is independently a C1-C4 alkyl group; Each Rd is independently a C1-C4 alkyl or a C1-C4 alkyl substituted with one or more Ree; Each Re is independently a hydroxyl, amino, C1-C4 alkyl, C1-C4 alkyl-O-, -COOH, or -C(O)ORh; Rg and Rh are each independently C1-C4 alkyl or halo-C1-C4 alkyl; L2 is a metal chelating group; The metal complex is a complex formed by the chelation of a compound of general formula II with a metal atom or ion.

[0008] In some implementations, q is 0, 1, or 2; Each R8 is independently a C1-C4 alkyl, -NH-C(O)-R8d, or a C1-C4 alkyl-O- substituted with one or more R8c; Each R 8c is independently a 5-7 membered heterocycle; in the 5-7 membered heterocycle, the type of heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Each R 8d is independently a C 6-C 10 aryl group substituted with one or more R 8d-1 groups or a 5-10 heteroaryl group substituted with one or more R 8d-2 groups; wherein the heteroatom in the 5-10 heteroaryl group is independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; Each R 8d-1 and R 8d-2 is independently a C1-C4 alkoxy or a C1-C4 alkyl substituted with one or more R 8d-1-1; Each R 8d-1-1 is independently a 5-7 membered heterocycle substituted with a carboxyl group; in the 5-7 membered heterocycle, the type of heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0009] In some implementations, q is 0.

[0010] In some embodiments, R1 is cyano or C1-C4 alkyl; X1, X2 and X3 are each independently CH or N.

[0011] In some embodiments, R1 is cyano or C1-C4 alkyl; X1 and X2 are CH, and X3 is N.

[0012] In some implementations, R2 and R3 are hydrogen.

[0013] In some embodiments, R4 is a C1-C4 alkyl or a C1-C4 alkyl substituted with one or more Rb; each Rb is independently a halogen; X4 and X5 are independently CH or N.

[0014] In some embodiments, R4 is a C1-C4 alkyl or a C1-C4 alkyl substituted with one or more Rb; each Rb is independently a halogen; X4 and X5 are independently CH.

[0015] In some embodiments, R5, R6, and the nitrogen atom attached to them together form a 5-7 membered heterocycle substituted with one or more Rc atoms; wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3, or 4, and each heteroatom is independently selected from N, O, and S; Rc is -COOH.

[0016] In some implementations, L1 is (i) -(CH₂)m-, where 1, 2, 3, 4, or 5 non-adjacent CH₂ are independently replaced by -Y₁-, each Y₁ being independently -C(O)O-, -O-, or -C(O)NH-; or (ii) -(CH2)p-, wherein one CH2 is replaced by -Y2-, and the other 1, 2, 3 or 4 non-adjacent CH2s are independently replaced by -Y3-; each Y3 is independently -C(O)-, -O- or -C(O)NH-; Y2 is a 5-7 membered carbon ring or a 5-7 membered heterocycle, wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3 or 4, and each heteroatom is independently selected from N, O and S; L1 is either unsubstituted or each of the one H atoms contained in L1 is independently substituted by R7; m and p are each independently 5, 6, 7, 8, 9, 10, or 11; R 7 is -L 3 -R 9; L3 is -(CH₂)k-, where 1, 2, 3, or 4 non-adjacent CH₂ are independently replaced by -Y₄-, each Y₄ being -C(O)NH₄-; L3 is unsubstituted; k is 7, 8, or 9; R9 is a C6-C10 aryl group substituted with one or more Rd; each Rd is independently a C1-C4 alkyl group.

[0017] In some embodiments, the metal complex is a complex of a compound of general formula II chelated with a metal ion.

[0018] In some implementations, X1, X2, X3, X4, and X5 are each independently CH or N; R1 is a cyano or C1-C4 alkyl group; R2 and R3 are hydrogen; R4 is a C1-C4 alkyl group or a C1-C4 alkyl group substituted with one or more Rb groups; each Rb group is independently a halogen. R5, R6, and the nitrogen atom attached to them together form a 5-7 membered heterocycle substituted with one or more Rc atoms; wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3, or 4, and each heteroatom is independently selected from N, O, and S; Rc is -COOH; q is 0, 1, or 2; Each R8 is independently a C1-C4 alkyl, -NH-C(O)-R8d, or a C1-C4 alkyl-O- substituted with one or more R8c; Each R 8c is independently a 5-7 membered heterocycle; in the 5-7 membered heterocycle, the type of heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Each R 8d is independently a C 6-C 10 aryl group substituted with one or more R 8d-1 groups or a 5-10 heteroaryl group substituted with one or more R 8d-2 groups; wherein the heteroatom in the 5-10 heteroaryl group is independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; Each R 8d-1 and R 8d-2 is independently a C1-C4 alkoxy or a C1-C4 alkyl substituted with one or more R 8d-1-1; Each R 8d-1-1 is independently a 5-7 membered heterocycle substituted with a carboxyl group; in the 5-7 membered heterocycle, the type of heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; L1 is (i) -(CH₂)m-, where 1, 2, 3, 4, or 5 non-adjacent CH₂ are independently replaced by -Y₁-, each Y₁ being independently -C(O)O-, -O-, or -C(O)NH-; or (ii) -(CH2)p-, wherein one CH2 is replaced by -Y2-, and the other 1, 2, 3 or 4 non-adjacent CH2s are independently replaced by -Y3-; each Y3 is independently -C(O)-, -O- or -C(O)NH-; Y2 is a 5-7 membered carbon ring or a 5-7 membered heterocycle, wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3 or 4, and each heteroatom is independently selected from N, O and S; L1 is either unsubstituted or each of the one H atoms contained in L1 is independently substituted by R7; m and p are each independently 5, 6, 7, 8, 9, 10, or 11; R 7 is -L 3 -R 9; L3 is -(CH₂)k-, where 1, 2, 3, or 4 non-adjacent CH₂ are independently replaced by -Y₄-, each Y₄ being -C(O)NH₄-; L3 is unsubstituted; k is 7, 8, or 9; R9 is a C6-C10 aryl group substituted with one or more Rd; each Rd is independently a C1-C4 alkyl group; L2 is a metal chelating group; The metal complex is a complex formed by the chelation of a compound of general formula II with a metal atom or ion.

[0019] In some implementations, X1, X2, X4, and X5 are CH; X 3 is CH or N; R1 is a cyano or C1-C4 alkyl group; R2 and R3 are hydrogen; R4 is a C1-C4 alkyl group or a C1-C4 alkyl group substituted with one or more Rb groups; each Rb group is independently a halogen. R5, R6, and the nitrogen atom attached to them together form a 5-7 membered heterocycle substituted with one or more Rc atoms; wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3, or 4, and each heteroatom is independently selected from N, O, and S; Rc is -COOH; q is 0; L1 is (i) -(CH₂)m-, where 1, 2, 3, 4, or 5 non-adjacent CH₂ are independently replaced by -Y₁-, each Y₁ being independently -C(O)O-, -O-, or -C(O)NH-; or (ii) -(CH2)p-, wherein one CH2 is replaced by -Y2-, and the other 1, 2, 3 or 4 non-adjacent CH2s are independently replaced by -Y3-; each Y3 is independently -C(O)-, -O- or -C(O)NH-; Y2 is a 5-7 membered carbon ring or a 5-7 membered heterocycle, wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3 or 4, and each heteroatom is independently selected from N, O and S; L1 is either unsubstituted or each of the one H atoms contained in L1 is independently substituted by R7; m and p are each independently 5, 6, 7, 8, 9, 10, or 11; R 7 is -L 3 -R 9; L3 is -(CH₂)k-, where 1, 2, 3, or 4 non-adjacent CH₂ are independently replaced by -Y₄-, each Y₄ being -C(O)NH₄-; L3 is unsubstituted; k is 7, 8, or 9; R9 is a C6-C10 aryl group substituted with one or more Rd; each Rd is independently a C1-C4 alkyl group; L2 is a metal chelating group; The metal complex is a complex of a compound represented by general formula II chelated with a metal ion.

[0020] In some embodiments, in R1, the C1-C4 alkyl group is methyl or ethyl.

[0021] In some embodiments, in R4, the C1-C4 alkyl group is methyl or ethyl.

[0022] In some embodiments, in R4, the C1-C4 alkyl group substituted with one or more Rb is methyl or ethyl.

[0023] In some implementations, the halogen in Rb is fluorine or chlorine.

[0024] In some embodiments, in R4, the C1-C4 alkyl group substituted by one or more Rb is trifluoromethyl.

[0025] In some embodiments, the 5-7 membered heterocycle formed by R5, R6, and the nitrogen atom connected to them, which is substituted by one or more Rc, is a 6-membered saturated monocyclic heterocycle.

[0026] In some embodiments, the number of heteroatoms in a 5-7 membered heterocycle formed by R5, R6, and the nitrogen atom connected to them, which is substituted by one or more Rc atoms, is one.

[0027] In some embodiments, the heteroatom is N in the 5-7 membered heterocycle formed by R5, R6 and the nitrogen atom connected to them, which is substituted by one or more Rc atoms.

[0028] In some embodiments, the 5-7 membered heterocycle formed by R5, R6, and the nitrogen atom connected to them, which is substituted by one or more Rc, is a piperidine ring.

[0029] In some embodiments, the 5-7 membered heterocycle formed by R5, R6, and the nitrogen atoms connected to them, and substituted with one or more Rc atoms, is... .

[0030] In some embodiments, the 5-7 membered heterocycle formed by R5, R6, and the nitrogen atoms connected to them, and substituted with one or more Rc atoms, is... (For example or ).

[0031] In some embodiments, the 5-7 membered heterocycle formed by R5, R6, and the nitrogen atoms connected to them, and substituted with one or more Rc atoms, is... .

[0032] In some implementations, L1 is connected to ring A via -Y1-, and Y1 connected to ring A is -O-.

[0033] In some implementations, L1 is connected to L2 via -CH2-.

[0034] In some embodiments, L is -O(CH2)n2-, -O(CH2)n2O(CH2)m2-, -O(CH2)n2O(CH2) m2O(CH2)m3-, -O(CH2)n2OC(O)(CH2)m2-, -O(CH2)n2NHC(O)(CH2) m2-, -O(CH 2) n2NHC(O)-(CH 2) n3-NHC(O)(CH 2) m3-, -O(CH 2) n2-O(CH 2) n3-NHC(O)-(CH 2) n4NHC(O)-(CH 2) m3-, -O(CH 2) n2NHC(O)-Y 2-(CH 2) n3NHC(O)-(CH 2) m3-, -O(CH 2) n2-Y 2-C(O)-(CH 2) m3-, -O(CH 2) n2NHC(O)-Y 2-C(O)-(CH 2) m3- or -O(CH 2) n2NHC(O)-Y 2-(CH 2) n3NHC(O)-(CH 2) n4NHC(O)-(CH 2) m3-; its right end is connected to L 2; Each n2, each n3, each n4, each m2, and each m3 is independently 1, 2, 3, 4, 5, or 6; L1 is either unsubstituted or L1 contains one H that is substituted by R7.

[0035] In some implementations, m2 is 1 or 2.

[0036] In some implementations, m3 is 1 or 2.

[0037] In some implementations, m2 is 2 and m3 is 2.

[0038] In some implementations, m2 is 1.

[0039] In some implementations, m3 is 1.

[0040] In some implementations, when Y2 is a 5-7 member carbon ring, the 5-7 member carbon ring is... ,For example (For example ).

[0041] In some implementations, when Y2 is a 5-7 member heterocyclic ring, the 5-7 member heterocyclic ring is... ,For example .

[0042] In some embodiments, R9 is a phenyl or a phenyl substituted with one or more Rd.

[0043] In some embodiments, in Rd, the C1-C4 alkyl group is methyl or ethyl.

[0044] In some implementations, R7 is .

[0045] In some implementations, L2 is R11 or -L4-(CH2)sR11; s is 1, 2, or 3; L4 is a 5-7 membered carbon ring (e.g., a benzene ring, for example...). The heterocycle may be a 5- or 7-membered heterocycle, wherein the number of heteroatoms is 1, 2, 3 or 4, and each heteroatom is independently selected from N, O and S; R 11 is an 8-20 quinary (e.g., 8, 9, 10, 11, 12, 13, 14, 15, or 16 quinary) saturated monocyclic or bridged ring carbon ring, wherein 3, 4, 5, or 6 non-adjacent CH 2 atoms of the monocyclic or bridged ring carbon ring are independently replaced by -Y 5-, each Y 5 being independently -O-, -NH-, or -N(R 11a)-; Each R 11a is independently a C1-C4 alkyl or a C1-C4 alkyl substituted with one or more -COOH (e.g., -(C1-C4 alkylene)-COOH, e.g., -CH2-COOH).

[0046] In some implementations, when L2 is -L4-(CH2)sR11, the -L4-(CH2)sR11 is... .

[0047] In some implementations, each Y 5 is independently -NH- or -N(R 11a)-.

[0048] In some embodiments, each R 11a is independently a C1-C4 alkyl group substituted with one or more -COOH groups.

[0049] In some implementations, L2 is R11, which is defined as described herein.

[0050] In some implementations, L2 is , , or Each R 11b is independently either H or R 11a, and R 11a is defined as described in this document.

[0051] In some implementations, in each of the structures of L2 above, at least one, two or three R 11b are R 11a, and the definition of R 11a is as described herein.

[0052] In some implementations, L2 is , , or , where the c end is connected to L1.

[0053] In some implementations, L2 is , where the c end is connected to L1.

[0054] In some embodiments, the metal complex has a structure represented by the following general formula I: Where M is a metal atom or ion, and the definitions of other variables are as described in general formula II.

[0055] In some implementations, M is a metal ion.

[0056] In some implementations, the metal ions are defined as described in the remainder of this document.

[0057] In some embodiments, the metal complex has the following structure: The definitions of each variable are as described in this article.

[0058] In some embodiments, the metal complex has a molar ratio of the compound of general formula II to the metal atoms or ions of 1:1.

[0059] In some embodiments, the metal ion is an ion of one of the following metals: Al, Cu, Ga, Y, Zr, Tc, In, Lu, Re, At, Bi, or Tl.

[0060] In some embodiments, the metal ions are ions of the following metals: 27Al, 63Cu, 64Cu, 68Ga, 70Ga, 89Y, 90Y, 89Zr, 91Zr, 99mTc, 111In, 113In, 175Lu, 177Lu, 186Re, 188Re, 211At, 212Bi, 213Bi, 201Tl, or 203Tl.

[0061] In some implementations, the metal ion is in a monovalent, divalent, trivalent, or tetravalent state.

[0062] In some implementations, the metal ion is in a trivalent valence state.

[0063] In some implementations, the metal ion is a radioactive metal ion or a non-radioactive metal ion.

[0064] In some embodiments, the metal ion may further bind a non-metallic nuclide, such as F. The non-metallic nuclide may be a radioactive or non-radioactive non-metallic nuclide. The radioactive non-metallic nuclide may be 18F.

[0065] In some implementations, the metal ions may not bind to non-metal nuclides.

[0066] In some implementations, the metal ions may be radioactive as a whole (e.g., if the metal ions combine with non-metal nuclides, the non-metal nuclides will be radioactive, which also constitutes radioactivity as a whole).

[0067] In some embodiments, the metal ions are [AlF]²⁺, [GaCl]²⁺, [LuCl]²⁺, Ga³⁺, or Lu³⁺.

[0068] In some embodiments, the metal ions are [Al 18F] 2+, [68GaCl] 2+, [177LuCl] 2+, 68Ga 3+, or 177Lu 3+.

[0069] In some implementation schemes, for , , , , , or .

[0070] In some implementations, L1 is , , , , , , , , , , , , , , , , , , or The upper end is connected to ring A, and the lower end is connected to L2.

[0071] In some implementations, L2 is or .

[0072] In some embodiments, the L2 forms any of the following groups with the metal ions: , , , or .

[0073] This invention provides a pharmaceutically acceptable salt of a compound of formula II or a metal complex thereof, or any of the foregoing (i.e., a compound of formula II or a metal complex thereof): X1, X2, X3, X4, and X5 are each independently CH or N; R1 is hydrogen, halogen, cyano, C1-C4 alkyl, or a C1-C4 alkyl group substituted with one or more Ra groups; R2 and R3 are each independently hydrogen or halogen; R4 is hydrogen, halogen, C1-C4 alkyl, or a C1-C4 alkyl substituted with one or more Rb; R5 and R6 are each independently hydrogen, deuterium, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more Rc atoms; or, R5, R6, and the nitrogen atom attached to them together form a 5-7 membered heterocycle or a 5-7 membered heterocycle substituted with one or more Rc atoms; wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3, or 4, and each heteroatom is independently selected from N, O, and S; Each Ra, each Rb, and each Rc is independently deuterium, halogen, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkyl-O-, -COOH, or -C(O)ORg; Each R8 is independently hydrogen, deuterium, halogen, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkyl-S-, C1-C4 alkyl-O-, -C(O)NH2, -C(O)OC1-4 alkyl, -OR8a, -NHR8a, -NR8aR8b, C1-C4 alkyl substituted with one or more R8c, C1-C4 alkyl-S-substituted with one or more R8c, or C1-C4 alkyl-O-substituted with one or more R8c; Alternatively, two adjacent R8s together with the carbon atoms on the benzene rings they are attached to form a 5-7 membered carbon ring, a 5-7 membered heterocycle, a 5-7 membered carbon ring substituted with one or more C1-4 alkyl groups, or a 5-7 membered heterocycle substituted with one or more C1-4 alkyl groups; wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3, or 4, and each heteroatom is independently selected from N and O; Each R 8a, R 8b, and each R 8c is independently C1-C4 alkyl-S-, halogen, C1-C4 alkyl, C1-C4 alkyl-O-, -COOH, -(C1-C4 alkylene)-COOH, -C(O)OC1-C4 alkyl, -C(O)NH2, -C(O)NHC1-C4 alkyl, or -NR8eR8f; R8e and R8f are each independently hydrogen, halogen, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more R8g; Each R 8g is independently a halogen, C1-4 alkyl, hydroxyl, -NR 8hR 8k, C1-C4 alkyl-O-, -COOH, -(C1-C4 alkylene)-COOH, -C(O)OC1-C4 alkyl, -C(O)NH2 or -C(O)NHC1-C4 alkyl; R8h and R8k are each independently hydrogen or C1-4 alkyl; q can be 0, 1, 2, or 3; L1 is (i) Single bond or -(CH2)n-; (ii) -(CH₂)m-, wherein 1, 2, 3, 4, or 5 non-adjacent CH₂ groups are independently replaced by -Y₁-, each Y₁ being independently -C(O)-, -C(O)O-, -O-, -NH-, -C(O)NH-, or -NHC(O)NH-; or (iii) -(CH 2) p-, wherein one CH 2 is replaced by -Y 2-, and the other 0, 1, 2, 3 or 4 non-adjacent CH 2 are independently replaced by -Y 3-; each Y 3 is independently -C(O)-, -C(O)O-, -O-, -NH-, -C(O)NH- or -NHC(O)NH-; Y 2 is a 5-7 membered carbon ring or a 5-7 membered heterocycle, wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3 or 4, and each heteroatom is independently selected from N, O and S; L1 is either unsubstituted or L1 contains 1, 2, or 3 H's, each of which is independently substituted by R7; n, m, and p are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14; Each R 7 is independently a C1-C4 alkyl or -L3-R 9; L3 is (i) -(CH 2) j-; or (ii) -(CH 2) k-, wherein 1, 2, 3 or 4 non-adjacent CH 2 are independently replaced by -Y 4-, each Y 4 being independently -C(O)-, -C(O)O-, -O-, -NH-, -C(O)NH- or -NHC(O)NH-; L3 is either unsubstituted or L3 contains 1, 2, or 3 H atoms, each independently substituted by R10; j and k are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14; R9 is hydrogen, a C6-C10 aryl group, or a C6-C10 aryl group substituted with one or more Rd groups; Each R 10 is independently a C1-C4 alkyl group; Each Rd is independently a C1-C4 alkyl or a C1-C4 alkyl substituted with one or more Ree; Each Re is independently a hydroxyl, amino, C1-C4 alkyl, C1-C4 alkyl-O-, -COOH, or -C(O)ORh; Rg and Rh are each independently C1-C4 alkyl or halo-C1-C4 alkyl; L2 is a metal chelating group; The metal complex is a complex formed by the chelation of a compound of general formula II with a metal atom or ion.

[0074] In some embodiments, the metal complex is a complex of a compound of general formula II chelated with a metal ion.

[0075] In some embodiments, the metal complex has a molar ratio of the compound of general formula II to the metal atoms or ions of 1:1.

[0076] In some embodiments, the metal complex has a structure represented by the following general formula I: Where M is a metal atom or ion, and the definitions of other variables are as described in general formula II.

[0077] In some implementations, M is a metal ion.

[0078] In some embodiments, the metal is Cu, Ga, Y, Zr, Tc, In, Lu, Re, At, Bi, Tl, or a radioactive or non-radioactive isotope thereof.

[0079] In some embodiments, the metal is Ga, Lu, or a radioactive or non-radioactive isotope thereof.

[0080] In some embodiments, the metal is 63Cu, 64Cu, 68Ga, 70Ga, 89Y, 90Y, 89Zr, 91Zr, 99mTc, 111In, 113In, 175Lu, 177Lu, 186Re, 188Re, 211At, 212Bi, 213Bi, 201Tl, or 203Tl.

[0081] In some embodiments, the valence state of the metal ion can be any valence state of the metal, such as monovalent, divalent, trivalent, or tetravalent. In some embodiments, the valence state of the metal ion is trivalent.

[0082] In some embodiments, the metal ions are Ga³⁺ and Lu³⁺.

[0083] In some implementations, X1 is CH.

[0084] In some implementations, X2 is CH.

[0085] In some implementations, X3 is CH.

[0086] In some implementations, X4 is CH.

[0087] In some implementations, X5 is CH.

[0088] In some implementations, X1, X2, X3, X4 and X5 are CH.

[0089] In some implementations, one, two, three, or four of X1, X2, X3, X4, and X5 are N.

[0090] In some implementations, q is 0.

[0091] In some embodiments, R1 is a cyano or C1-C4 alkyl group.

[0092] In some implementations, R1 is cyano or methyl.

[0093] In some implementations, R2 is hydrogen.

[0094] In some implementations, R3 is hydrogen.

[0095] In some embodiments, R4 is a C1-C4 alkyl or a C1-C4 alkyl substituted with one or more Rb.

[0096] In some implementations, each Rb is independently a halogen, such as fluorine.

[0097] In some implementations, R4 is methyl or trifluoromethyl.

[0098] In some implementations, R5, R6, and the nitrogen atom attached to them together form a 5-7 membered heterocycle or a 5-7 membered heterocycle substituted with one or more Rc atoms.

[0099] In some embodiments, when R5, R6 and the nitrogen atom attached to them together form a 5-7 membered heterocycle or a 5-7 membered heterocycle substituted by one or more Rc atoms, the heteroatom in the 5-7 membered heterocycle is an N atom.

[0100] In some embodiments, when R5, R6, and the nitrogen atom attached to them together form a 5-7 membered heterocycle or a 5-7 membered heterocycle substituted by one or more Rc, the 5-7 membered heterocycle is a saturated 5-7 membered heterocycle, such as piperidine.

[0101] In some implementations, R5, R6, and the nitrogen atoms bonded to them together form .

[0102] In some implementations, each Rc is independently -COOH.

[0103] In some implementations, R5, R6, and the nitrogen atoms bonded to them together form (For example or ).

[0104] In some implementations, R5, R6, and the nitrogen atoms bonded to them together form .

[0105] In some implementations, L1 is connected to ring A via -Y1-, and Y1 connected to ring A is -O-.

[0106] In some implementations, L1 is connected to L2 via -CH2-.

[0107] In some implementations, n, m, and p are each independently 5, 6, 7, 8, 9, 10, 11, or 12.

[0108] In some implementations, L1 satisfies the definition of at least one of the aforementioned schemes, and L1 is a single bond, -(CH2)n1NH(CH2)m1-, -(CH2)n1O(CH2)m1-, -(CH2)n1NHC(O)NH(CH2)m1-, -O(CH2)n1NH-, -O(CH2)n1O-, -O(CH2)n1O(CH2)m1O-, -NH(CH2)n1NH(CH2)m1NH-, -NH(CH2)n1O(CH2)m1O-, -NH(CH2)n1NH(CH2)m1O-, -O(CH2)n1NH(CH2)m1O-, -O(CH2)n1O(CH2)m1NH-, -O(CH2)n1NH(CH2)m1NH-, -O(CH2)n1NH(CH2) m1NH-, -NH(CH 2) n1O(CH 2) m1NH-, -OY 2-(CH 2) n1NH-, -O(CH 2) n2OC(O)(CH 2) m2-, -O(CH 2) n2O(CH 2) m2-, -O(CH 2) n2NHC(O)(CH 2) m2-, -O(CH 2) n2NHC(O)-(CH 2) n3-NHC(O)(CH 2) m3-, -O-(CH 2) n2-Y 2-C(O)-(CH 2) m2-, -O(CH 2) n2NHC(O)-Y 2-(CH 2) n3NHC(O)-(CH 2) m3-, -O(CH 2) n2NHC(O)-Y 2-C(O)-(CH 2) m3-, -O(CH 2) n2-Y 2-C(O)-(CH 2) m3-, -O(CH 2) n2NHC(O)-Y 2-(CH 2) n3NHC(O)-(CH 2) n4NHC(O)-(CH 2) m3, -O(CH 2) n2NHC(O)-(CH 2) n3NHC(O)-(CH 2) m3- or -O(CH 2) n2-O(CH 2) n3-NHC(O)-(CH 2) n4NHC(O)-(CH 2) m3-, each n1, each n2, each n3, n4, each m1, each m2 and each m3 is independently 1, 2, 3, 4, 5 or 6; L1 is unsubstituted or L1 contains 1, 2 or 3 Hs that are independently substituted by R 7.

[0109] In some implementations, m2 is 1.

[0110] In some implementations, m3 is 1.

[0111] In some implementations, when Y2 is a 5-7 member carbon ring, the 5-7 member carbon ring is... ,For example (For example ).

[0112] In some implementations, when Y2 is a 5-7 member heterocyclic ring, the 5-7 member heterocyclic ring is... ,For example .

[0113] In some implementations, L1 is unsubstituted or the H contained in L1 is replaced by R7.

[0114] In some implementations, each R 7 is independently -L 3-R 9.

[0115] In some implementations, each Y4 is independently -C(O)NH-.

[0116] In some implementations, L3 is -(CH2)k-, where one of the CH2 is replaced by -Y4-, and Y4 is -C(O)-, -C(O)O-, -O-, -NH-, -C(O)NH- or -NHC(O)NH-.

[0117] In some implementations, each Y4 is independently -C(O)NH-.

[0118] In some implementations, L3 is not replaced.

[0119] In some implementations, j and k are each independently 7, 8, or 9.

[0120] In some embodiments, R9 is a C6-C10 aryl group or is a C6-C10 aryl group substituted with one or more Rd groups.

[0121] In some embodiments, R9 is a phenyl or a phenyl substituted with one or more Rd.

[0122] In some implementations, each Rd is independently a C1-C4 alkyl group.

[0123] In some implementations, R7 is .

[0124] In some implementations, L1 is not replaced.

[0125] In some implementations, L1 is , , , , , , , , , , , , , , , , , or , where end a is connected to ring A, and end b is connected to L2.

[0126] In some implementations, L1 is , , , , , , , , , , , , , or Where end a is connected to ring A, and end b is connected to L2. Preferably, L1 is... , , , , , , , , or , where end a is connected to ring A, and end b is connected to L2.

[0127] In some implementations, L2 is R11 or -L4-(CH2)sR11; s is 1, 2, or 3; L4 is a 5-7 membered carbon ring (e.g., a benzene ring, for example...). The heterocycle may be a 5- or 7-membered heterocycle, wherein the number of heteroatoms is 1, 2, 3 or 4, and each heteroatom is independently selected from N, O and S; R 11 is an 8-20 quinary (e.g., 8, 9, 10, 11, 12, 13, 14, 15, or 16 quinary) saturated monocyclic or bridged ring carbon ring, wherein 3, 4, 5, or 6 non-adjacent CH 2 atoms of the monocyclic or bridged ring carbon ring are independently replaced by -Y 5-, each Y 5 being independently -O-, -NH-, or -N(R 11a)-; Each R 11a is independently a C1-C4 alkyl or a C1-C4 alkyl substituted with one or more -COOH (e.g., -(C1-C4 alkylene)-COOH, e.g., -CH2-COOH).

[0128] In some implementations, when L2 is -L4-(CH2)sR11, the -L4-(CH2)sR11 is... .

[0129] In some implementations, each Y 5 is independently -NH- or -N(R 11a)-.

[0130] In some embodiments, each R 11a is independently a C1-C4 alkyl group substituted with one or more -COOH groups.

[0131] In some implementations, L2 is R11, which is defined as described herein.

[0132] In some implementations, L2 is , , or Each R 11b is independently either H or R 11a, and R 11a is defined as described herein. In some embodiments, in each structure of L 2 above, at least one, two, or three R 11b are R 11a, and R 11a is defined as described herein.

[0133] In some implementations, L2 is , , or , where the c end is connected to L1.

[0134] In some implementations, L2 is , where the c end is connected to L1.

[0135] In some embodiments, the metal complex has the following structure: The definitions of each variable are as described in this article.

[0136] In some implementations, the general formula The compound shown in [II] has any of the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0137] In some embodiments, the metal complex is a complex formed by any of the following compounds and 177Lu³⁺: , , , , , , , , , , , , , , , , , , , or .

[0138] In some embodiments, the metal complex is a complex formed by any of the following compounds and 68Ga³⁺: , , , , , , , , , , , , , , , , , , , or .

[0139] In some embodiments, the metal complex is a complex formed by any of the following compounds and [Al18F]2+: , , , , , , , , , , or .

[0140] In some embodiments, the metal complex is a complex formed by any of the following compounds and [68GaCl]²⁺: , , , , , , , , , , or .

[0141] In some embodiments, the metal complex is a complex formed by any of the following compounds and [177LuCl]²⁺: , , , , , , , , , , or .

[0142] In some embodiments, the metal complex has any of the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0143] The present invention also provides a method for preparing a compound of general formula I as described above, comprising the following steps: reacting a compound of general formula II with a halide of metal M (e.g., chloride, or [AlF]2+) in a solvent (e.g., water, or a mixture of water and methanol) in the presence or absence of a buffer (e.g., sodium acetate-acetic acid) to obtain the compound of general formula I; The definitions of each variable are as described in this article.

[0144] The present invention also provides a method for preparing the compound represented by general formula II as described above, comprising the following steps: in a solvent (e.g., dichloromethane), removing the Boc protecting group from the compound represented by general formula III in the presence of an acid (e.g., trifluoroacetic acid) to obtain the compound represented by general formula II; In Equation II, L2 is R11 or -L4-(CH2)sR11; In Formula III, L20 is R110 or -L4-(CH2)sR110; s is 1, 2, or 3; L4 is a 5-7 membered carbon ring or a 5-7 membered heterocycle, wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3 or 4, and each heteroatom is independently selected from N, O and S; R 11 is an 8-20 quinary (e.g., 8, 9, 10, 11, 12, 13, 14, 15, or 16 quinary) saturated monocyclic or bridged ring carbon ring, wherein 3, 4, 5, or 6 non-adjacent CH 2 atoms of the monocyclic or bridged ring carbon ring are independently replaced by -Y 5-, each Y 5 being independently -O-, -NH-, or -N(R 11a)-; R 110 is an 8-20 quinary (e.g., 8, 9, 10, 11, 12, 13, 14, 15, or 16 quinary) saturated monocyclic or bridged ring carbon ring, wherein 3, 4, 5, or 6 non-adjacent CH 2 atoms of the monocyclic or bridged ring carbon ring are independently replaced by -Y 6-, each Y 6 being independently -O-, -NH-, or -N(R 12a)-; Each R 11a is independently a C1-C4 alkyl or a C1-C4 alkyl substituted with one or more -COOH groups (e.g., -(C1-C4 alkylene)-COOH, e.g., -CH2-COOH); Each R 12a is independently a C1-C4 alkyl or a C1-C4 alkyl substituted with one or more -COO tBu (e.g., -(C1-C4 alkylene)-COO tBu, e.g., -CH2-COO tBu); In formulas II and III, R5, R6, and the nitrogen atoms bonded to them together form ; The definitions of other variables are as described in this article.

[0145] The present invention also provides a compound represented by general formula III: The definitions of each variable are as described in this article.

[0146] The present invention also provides a compound as shown in any of the following: Compound 2-b, 3-b, 4-b, 9-b, 10-b, 11-b, 16-b, 18-b, 19-b, 21-b, 23-b, 25-b, 30-b, 30-c, 39- b, 40-b, 42-b, 43-b, 49-b, 51-b, 53-b, 55-b, 57-b, 63-b, 16-c, 81-b, 1-a, 2-a, 3-a, 4-a ,9-a,10-a,11-a,16-a,18-a,19-a,21-a,23-a,25-a,30-a,31-a,39-a,40-a,42-a,43 -a, 47-a, 49-a, 51-a, 53-a, 55-a, 57-a, 59-a, 61-a, 63-a, 65-a, 67-a, 69-a, 71-a or 81-a.

[0147] The present invention also provides a pharmaceutical composition comprising a compound of general formula II as described above, or a metal complex thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical adjuvant.

[0148] The present invention also provides the use of a compound of general formula II as described above, or a metal complex thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating tumors.

[0149] In some embodiments, the metal complex is a complex of a compound of general formula II chelated with a radioactive metal ion; the radioactive metal ion is a radioactive metal ion used for treatment.

[0150] In some embodiments, the metal complex is a complex of a compound of general formula II chelated with a radioactive metal ion, wherein the metal ion is [177LuCl]2+ or 177Lu3+.

[0151] The present invention also provides the use of the metal complex or a pharmaceutically acceptable salt thereof as described above in the preparation of radiodiagnostic drugs for tumors.

[0152] In some embodiments, the metal complex is a complex of a compound of general formula II chelated with a radioactive metal ion; the radioactive metal ion is a radioactive metal ion used for diagnosis.

[0153] In some embodiments, the metal complex is a complex of a compound of general formula II chelated with a radioactive metal ion, wherein the metal ion is [Al 18F] 2+, [68GaCl] 2+, or 68Ga 3+.

[0154] The present invention also provides a method for treating tumors, comprising administering to a tumor patient a therapeutically effective amount of a compound of general formula II as described above, or a metal complex thereof, or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments, the metal complex is a complex of a compound of general formula II chelated with a radioactive metal ion; the radioactive metal ion is a radioactive metal ion used for treatment.

[0156] In some embodiments, the metal ion in the metal complex is [177LuCl]2+ or 177Lu3+.

[0157] In some implementations, the tumor is lung cancer, stomach cancer, colorectal cancer, cervical cancer, ovarian cancer, prostate cancer, breast cancer, pancreatic cancer, liver cancer, bladder cancer, kidney cancer, bone cancer, skin cancer, melanoma, glioma, glioblastoma, leukemia, or lymphoma.

[0158] The present invention also provides a method for diagnosing tumors, comprising administering to a tumor patient a therapeutically effective amount of the metal complex as described above or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, the metal complex is a complex of a compound of general formula II chelated with a radioactive metal ion; the radioactive metal ion is a radioactive metal ion used for diagnosis.

[0160] In some embodiments, the metal complex is a complex of a compound of general formula II chelated with a radioactive metal ion, wherein the metal ion is [Al 18F] 2+, [68GaCl] 2+, or 68Ga 3+.

[0161] In some implementations, the tumor is lung cancer, stomach cancer, colorectal cancer, cervical cancer, ovarian cancer, prostate cancer, breast cancer, pancreatic cancer, liver cancer, bladder cancer, kidney cancer, bone cancer, skin cancer, melanoma, glioma, glioblastoma, leukemia, or lymphoma.

[0162] [, Definitions and Explanations , ] [, , ]

[0163] 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 in this document, it is intended to refer to the corresponding product or its active ingredient.

[0164] In this invention, the term "metal chelating group" refers to a group that forms a complex with a metal atom or ion. A metal chelating group can be any metal chelating group known in the art for chelating pharmaceutically useful metal atoms or ions.

[0165] In this invention, the term "substitution" or "substituent" means that a hydrogen atom in a group is replaced by a specified group. When the substitution position is not specified, substitution can occur at any position, but only if a stable or chemically viable chemical is formed is it permitted. Examples are given below: The structure indicates that the hydrogen atoms on the benzene ring are replaced by q R8s. When there are multiple R8s, each R8 may be the same or different.

[0166] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and R has independent options in each case. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0167] When the linking group listed in this invention does not specify its linking direction, the linking direction can be arbitrary, including both left-to-right and right-to-left linking. For example, in -ALB, the linking group L is -CD-. When the linking direction of L is not specified, -ALB includes -ACDB and -ADCB.

[0168] When one of the variables is selected as a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0169] 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, dibutyl, or terbutyl.

[0170] In this invention, the term "alkylene" refers to a saturated straight-chain or branched divalent hydrocarbon group. C1-C4 alkylene refers to an alkylene having 1-4 carbon atoms, specifically methylene, ethylene (e.g., -CH2CH2-, -CH(CH3)-), propylene (e.g., -CH2CH2CH2-, -C(CH3)2-, -CH2CH(CH3)-), and butylene (e.g., -CH2CH2CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)CH2-).

[0171] In this invention, halogen refers to F, Cl, Br or I.

[0172] In this invention, the term "haloalkyl" refers to a group formed by replacing one or more hydrogen atoms in an alkyl group with a halogen, wherein the definition of alkyl is as described above, and each halogen is independently F, Cl, Br, or I. Halogenated C1-C4 alkyl refers to a C1-C4 alkyl group substituted with one or more halogens, such as fluoroC1-C4 alkyl, wherein the definition of C1-C4 alkyl is as described above. Examples of halogenated alkyl groups include, but are not limited to, trifluoromethyl, pentafluoroethyl, and 1-fluoro-2-chloroethyl.

[0173] In this invention, the term "carbocyclic ring" refers to a cyclic group consisting of saturated, partially unsaturated, or aromatic monocyclic or polycyclic (e.g., fused, spirocyclic, or bridged) rings formed from carbon atoms. In a saturated carbocyclic ring, each carbon atom on the ring is saturated; examples of saturated carbocyclic rings include, but are not limited to, those listed below. , , , , , , , , In aromatic carbocyclic rings, each ring is aromatic; examples of aromatic carbocyclic rings include, but are not limited to, those described above. , In a partially unsaturated carbide ring, at least one carbon atom is saturated and at least one carbon atom is unsaturated or aromatic. 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... , , In some implementation schemes, the 5-7 membered carbon ring can specifically be a benzene ring.

[0174] In this invention, the term "heterocycle" refers to a saturated, partially unsaturated, or aromatic 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; examples of saturated heterocycles include, but are not limited to, those listed below. , , , , , , , , , , , In aromatic heterocycles, each ring is aromatic; examples of aromatic heterocycles include, but are not limited to, those mentioned above. , , , , , , , , , , In a partially unsaturated heterocycle, at least one atom on the ring is saturated and at least one atom is unsaturated or aromatic. Examples of partially unsaturated heterocycles include, but are not limited to, those listed below. , , , , 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... , , , , , , , In some implementation schemes, the 5-7 membered carbon ring can specifically be a benzene ring.

[0175] In this invention, the term "aryl" refers to an aromatic carbocyclic group, wherein each ring is aromatic. Specifically, the C6-C10 aryl group can be phenyl or naphthyl. In some embodiments, the C6-C10 aryl group can specifically be phenyl.

[0176] In chemical structures, wedge-shaped solid line bonds are used ( ) and wedge-shaped dashed key ( The absolute configuration of a solid center is represented by a straight solid line key ( ). ) and straight dashed key ( () indicates the relative configuration of the solid center. Key " "No configuration is specified, meaning that if configurational isomerism exists in the chemical structure, the bond..." "can be " "or" ", or both contain " "and" "Two configurations (e.g., " "and" The ratio is 1:1.

[0177] 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 without causing an adverse biological reaction or interacting adversely with any component contained in the composition.

[0178] 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, third amines, and anilines. The third amine organic base is preferably triethylamine and / or N,N-diisopropylethylamine. The aniline organic base is preferably N,N-dimethylaniline. The pyridine organic base is preferably one or more of pyridine, methylpyridine, 4-dimethylaminopyridine, and 2-methyl-5-ethylpyridine. The inorganic base can be any conventional salt-forming inorganic base in the art, preferably one or more of alkali metal hydrides, alkali metal hydroxides, alkali metal alkoxides, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium bicarbonate, and sodium bicarbonate. The alkali metal hydrides are preferably sodium hydride and / or potassium hydride. The alkali metal hydroxides are preferably one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide. The alkali metal alkoxides are preferably one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide, and sodium tert-butoxide.

[0179] In this invention, the term "therapeutic effective dose" refers to a sufficient amount of a non-toxic drug or agent that achieves the desired effect. The determination of the effective dose varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. In individual cases, the appropriate effective dose can be determined by those skilled in the art based on routine testing.

[0180] In this invention, the term "patient" includes any animal, preferably a mammal, and more preferably a human.

[0181] In this invention, the term "one or more" can refer to 1, 2, 3, 4, 5, or 6.

[0182] 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.

[0183] The reagents and raw materials used in this invention are all commercially available.

[0184] The significant advantages of this invention are as follows: It provides a novel aromatic vinyl compound, its metal complex, its preparation method, and its applications. The aromatic vinyl compound and its metal complex of this invention exhibit inhibitory activity against PD-1 / PD-L1 binding, thus enabling their use in the treatment of tumors and related diseases. Furthermore, the metal complex of this invention can also be used as an imaging agent. Simple Explanation of the Diagram

[0185] Other features and effects of the present invention will be clearly presented in the embodiments with reference to the drawings, wherein: Figure 1 shows the inhibitory effect of compound 78 on tumors. Implementation

[0186] 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.

[0187] [Main Experimental Instruments:]

[0188] Radioactivity meter (CRC-55tR type); electronic balance (YP30002); germanium-gallium generator (20mCi); vortex mixer (MX-F); HPLC (1200); TLC (Scan-RAM); gamma radioimmunoassay counter (GC-2016); ultraviolet spectrophotometer (T6 New Century);

[0189] Example 1

[0190] (S, E)-2,2',2''-(10-(2-(2-(2-((2-carboxypiperidin-1-yl)methyl)-5-(2-(2-cyano-[1,1'-biphenyl]-3-yl)vinyl)-4-methylphenoxy)ethoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid( [Compound] [1])

[0191] compound Synthesis of [1-e]

[0192] 3-Bromo-4-methylphenol (3.74 g, 20 mmol), paraformaldehyde (4.41 g, 152 mmol), magnesium chloride (2.86 g, 30 mmol), and triethylamine (7.56 g, 75 mmol) were dissolved in acetonitrile (150 mL). The reaction mixture was heated and stirred at 80 °C for 4 hours. The reaction mixture was cooled to room temperature, diluted with water (500 mL), and the pH was adjusted to 2-3 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (500 mL × 2). The organic phases were combined, washed with saturated brine (200 mL × 1), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1) to give a white solid. [1-e] (2.45 g, yield: 57%).

[0193] compound Synthesis of [1-d]

[0194] Will [1-e] (645 mg, 3.0 mmol), (2-bromoethoxy)(tert-butyl)dimethylsilane (1.08 g, 4.5 mmol), and potassium carbonate (829 mg, 6.0 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction mixture was heated at 60 °C for 16 hours. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was washed successively with water (50 mL × 2) and saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give a white solid. [1-d] (767 mg, yield: 68%).

[0195] compound Synthesis of [1-c]

[0196] compound [1-d] (373 mg, 1.0 mmol), (E)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)vinyl)-[1,1'-biphenyl]-2-carboxynitrile (397 mg, 1.2 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (73 mg, 0.1 mmol), and potassium carbonate (276 mg, 2.0 mmol) were dissolved in 1,4-dioxane (5 mL) and water (0.5 mL). The reaction mixture was heated and stirred at 90 °C for 16 hours. The reaction mixture was cooled to room temperature and diluted with saturated brine (20 mL). The resulting mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a yellow solid. [1-c] (355 mg, yield: 71%).

[0197] LC-MS (ESI): m / z = 498.5(M+H) +.

[0198] compound Synthesis of [1-b]

[0199] compound [1-c] (75 mg, 0.15 mmol) and (S)-piperidine-2-carboxylic acid (39 mg, 0.30 mmol) were dissolved in methanol (1 mL) and tetrahydrofuran (1 mL), and sodium cyanoborohydride (38 mg, 0.60 mmol) was added. The reaction mixture was stirred at 60 °C for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and tetrahydrofuran (1 mL), water (0.2 mL), and trifluoroacetic acid (0.5 mL) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by pre-HPLC to obtain a white solid. [1-b](48.3 mg, yield: 53%).

[0200] LC-MS (ESI): m / z = 497.5 (M+H) +.

[0201] 1H-NMR (400 MHz, DMSO) δ:8.05 (d, J= 8.0 Hz, 1H), 7.79 (t, J= 7.9 Hz, 1H), 7.67 (d, J= 16.0 Hz, 1H), 7.63–7.47 (m, 6H), 7.40 (d, J= 16.0 Hz, 1H), 7.27 (s, 2H), 7.07 (s, 1H), 4.13–3.90 (m, 5H), 3.75 (t, J= 4.6 Hz, 2H), 3.28–3.21 (m, 1H), 3.08–3.00 (m, 1H), 2.38 (s, 3H), 1.97–1.86 (m, 1H), 1.78–1.66 (m, 1H), 1.63–1.48 (m, 3H), 1.45–1.31 (m, 1H).

[0202] compound Synthesis of [1-a]

[0203] compound [1-b] (40 mg, 0.08 mmol) and triethylamine (65 mg, 0.64 mmol) were dissolved in dichloromethane (1 mL). The reaction mixture was cooled to 0 °C, and 2-bromoacetyl bromide (19 mg, dissolved in 1 mL dichloromethane) and 2,2',2''-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid tributyl ester (206 mg, 0.40 mmol) were added sequentially. The reaction mixture was brought to room temperature and stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by reverse-phase preparative chromatography (column: xBridge C18, 19 * 150 mm * 5 μm; mobile phase: water (0.1% trifluoroacetic acid), methanol; gradient: 65%–80% (initial mobile phase: 35% water / 65% methanol, final mobile phase: 20% water / 80% methanol, where % refers to volume percentage); 13 min; flow rate: 15 mL / min) to obtain a white solid. [1-a](22 mg, yield: 26%).

[0204] LC-MS (ESI): m / z = 1051.87(M+H) +.

[0205] compound Synthesis of [1]

[0206] compound [1-a] (22 mg, 0.021 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was separated by reverse-phase preparative chromatography (column xBridge C18, 19 * 150 mm * 5 μm; mobile phase: water (0.1% trifluoroacetic acid), methanol; gradient: 65%–80% (initial mobile phase was 35% water / 65% methanol, final mobile phase was 20% water / 80% methanol, where % refers to volume percentage); 13 min; flow rate 15 mL / min) to obtain a white solid. [1] (7 mg, yield: 38%).

[0207] LC-MS (ESI): m / z = 883.8(M+H) +.

[0208] 1H-NMR (400 MHz, DMSO) δ:8.05 (d, J= 8.2 Hz, 1H), 7.79 (t, J= 7.9 Hz, 1H), 7.66 (d, J= 16.1 Hz,1H), 7.62-7.47 (m, 6H), 7.39 (d, J= 16.0 Hz, 1H), 7.28 (d, J= 6.1 Hz, 2H), 4.56-4.41 (m, 1H), 4.39-4.21 (m, 3H), 4.08-3.96 (m, 1H), 3.82-3.40 (m, 15H), 3.11-2.73 (m, 16H), 2.38 (s, 3H), 2.36-2.28 (m,1H), 1.94-1.62 (m, 3H), 1.59-1.33 (m, 3H).

[0209] Example 2

[0210] (2S)-1-({4-[(1E)-2-(2-methyl-3-phenylphenyl)vinyl]-5-(trifluoromethyl)-2-{[2-({2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]ethyl}oxy)ethyl]oxy}phenyl}methyl)hexahydropyridine-2-carboxylic acid( [Compound] [2])

[0211] compound Synthesis of [2-e]

[0212] (2S)-hexahydropyridine-2-carboxylic acid (20 g, 154.847 mmol) was dissolved in 2-methylpropyl-2-yl acetate (313.727 mL, 2322.701 mmol), and perchloric acid (18.630 mL, 309.693 mmol) was added. The reaction mixture was stirred overnight at room temperature. The solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (50 mL), adjusted to pH 9-10 with saturated sodium carbonate solution, and washed successively with water (50 mL × 2) and saturated brine (50 mL × 1). The organic phase was dried and concentrated under reduced pressure to obtain... [2-e] (23.24 g, yield: 81.00%).

[0213] compound Synthesis of [2-d]

[0214] 3-Bromo-4-(trifluoromethyl)phenol (10.96 g, 45.475 mmol) was dissolved in toluene (200 mL), and the following was added to the reaction solution: [2-e] (12.64 g, 68.213 mmol) and paraformaldehyde (2.73 g, 90.951 mmol) were reacted at 110 °C with stirring for 6 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed successively with water (50 mL × 2) and saturated brine (50 mL × 1). The organic phase was dried and concentrated under reduced pressure to obtain... [2-d] (15.26 g, yield: 76.57%).

[0215] compound Synthesis of [2-c]

[0216] 4,4,5,5-Tetramethyl-2-[(1E)-2-(2-methyl-3-phenylphenyl)vinyl]-1,3,2-dioxoborane (9.00 g, 28.092 mmol) was dissolved in dioxane (160 mL) and water (4 mL), and the compound was added to the reaction solution. [2-d] (10.26 g, 23.410 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (2.02 g, 2.341 mmol), and sodium carbonate (6.20 g, 58.524 mmol) were used. The reaction mixture was heated and stirred at 80 °C for 12 hours. The reaction mixture was then cooled to room temperature and diluted with ethyl acetate (50 mL). The solution was washed successively with water (50 mL × 2) and saturated brine (50 mL × 1). The organic phase was dried and concentrated to obtain... [2-c] (10.78 g, yield: 83.50%).

[0217] compound Synthesis of [2-b]

[0218] compound [2-c] (551.65 mg, 1.0 mmol) and 1-bromo-2-[(2-bromoethyl)oxy]ethane (695.73 mg, 3.000 mmol) were dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (276.42 mg, 2.000 mmol) was added. The reaction mixture was stirred at 70 °C for 3 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 mL), and washed successively with water (20 mL × 2) and saturated brine (20 mL × 2). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to give the product. [2-b](548 mg, yield: 77.99%).

[0219] compound Synthesis of [2-a]

[0220] compound [2-b] (400 mg, 0.569 mmol) and tert-butyl 2,2',2''-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (292.87 mg, 0.569 mmol) were dissolved in acetonitrile (4 mL), and potassium carbonate (78.68 mg, 0.569 mmol) was added. The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and subjected to silica gel column chromatography (acetic acid / methanol:dichloromethane = 1:10) to obtain... [2-a](450 mg, yield: 69.56%).

[0221] compound [2] Synthesis

[0222] compound [2-a] was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (4 mL, 0.510 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain... [2](153 mg, yield: 42.37%).

[0223] 1H-NMR(400MHz, MeOD) δ:7.89 (s, 1H), 7.66 (d, J= 15.8Hz, 1H), 7.59 (s, 1H), 7.54 (d, J= 7.5Hz, 1H), 7.46–7.39 (m, 2H), 7.38–7.24 (m, 5H), 7.18 (d, J= 6.9Hz, 1H), 4.61 (d, J= 13.0Hz, 1H), 4.50–4.37 (m, 3H), 4.00–3.83 (m, 4H), 3.77–3.56 (m, 7H), 3.53–3.26 (m, 9H), 3.25–2.98 (m, 11H), 2.35–2.29 (m, 3H), 2.25 (d, J= 15.2Hz, 1H), 2.02–1.51 (m, 5H).

[0224] Example 3

[0225] (2S)-1-({4-[(1E)-2-(2-methyl-3-phenylphenyl)vinyl]-5-(trifluoromethyl)-2-{[2-({2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]acetyl}amino)ethyl]oxy}phenyl}methyl)hexahydropyridine-2-carboxylic acid( [Compound] [3])

[0226] compound Synthesis of [3-c]

[0227] compound [2-c] (22.53 mg, 0.05 mmol), 2-(2-bromoethyl)isoindole-1,3-dione (508.16 mg, 2.000 mmol), and potassium carbonate (276.40 mg, 2.000 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction mixture was heated and stirred at 60 °C for 16 hours. After cooling to room temperature, the reaction mixture was directly subjected to C18 reversed-phase column chromatography to obtain a mixture of product and starting material. [3-c](450 mg) was directly added to the next reaction step.

[0228] compound Synthesis of [3-b]

[0229] compound [3-c] (450 mg, 0.174 mmol) and hydrazine hydrate (10.89 mg, 0.174 mmol) were dissolved in methanol (5 mL). The reaction solution was heated and stirred at 65 °C for 2 hours. After cooling to room temperature, the product was obtained directly from the reaction solution by prep-HPLC. [3-b](35 mg, yield: 33.82%).

[0230] compound Synthesis of [3-a]

[0231] compound [3-b] (35 mg, 0.059 mmol), (10-{1-[(methylpropyl-2-yl)oxy]-1-oxoethyl-2-yl}-4,7-bis{2-[(2-methylpropyl-2-yl)oxy]-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (40.45 mg, 0.071 mmol) and HBTU reagent O-(IH-benzotriazol-1-yl)-N,N,N',N'-tetramethylisourea phosphorus hexafluoride (33.48 mg, 0.088 mmol) were dissolved in N,N-dimethylformamide (1 mL), and N,N-diisopropylethylamine (0.019 mL, 0.118 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was directly separated by reverse-phase preparative chromatography to obtain [3-a](76 mg, 0.051 mmol, yield: 86.36%).

[0232] compound [3] Synthesis

[0233] compound [3-a] (76 mg, 0.051 mmol) was dissolved in dichloromethane (1.0 mL), and trifluoroacetic acid (1.0 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. The solution was concentrated under reduced pressure, and the residue was separated by reverse-phase preparative chromatography (column xBridge C18, 19 * 150 mm * 5 μm; mobile phase: water (0.1% trifluoroacetic acid), methanol; gradient: 65%-80% (initial mobile phase 35% water / 65% methanol, final mobile phase 20% water / 80% methanol, where % refers to volume percentage); 13 min; flow rate 15 mL / min) to obtain the desired product. [3](37 mg, yield: 57.26%).

[0234] LC-MS (ESI): m / z = 925.72(M+H) +.

[0235] 1H-NMR (400 MHz, D 2O) δ:7.45 (s, 1H), 7.27–6.18 (m, 11H), 4.3–2.25 (m, 32H), 2.22–0.60 (m, 10H).

[0236] Example 4

[0237] (2S)-1-({4-[(1E)-2-(2-methyl-3-phenylphenyl)vinyl]-5-(trifluoromethyl)-2-{[4-({2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]acetyl}amino)butyl]oxy}phenyl}methyl)hexahydropyridine-2-carboxylic acid( [Compound] [4])

[0238] compound Synthesis of [4-c]

[0239] compound [2-c] (275.82 mg, 0.5 mmol) and 1,4-diiodobutane (619.84 mg, 2.000 mmol) were dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (138.21 mg, 1.00 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL) and washed successively with water (20 mL × 2) and saturated brine (20 mL × 1). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether:ethyl acetate = 20:1) to give the product. [4-c] (310 mg, yield: 84.51%).

[0240] compound Synthesis of [4-b]

[0241] compound [4-c] (410 mg, 0.559 mmol) was dissolved in ammonia-methanol solution (7 M, 11.975 mL), sealed in a microwave tube, and the reaction solution was stirred at 50 °C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in dichloromethane (20 mL) and methanol (2 mL), and washed with 10% potassium carbonate solution (5 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and a yellow oil was obtained. [4-b] (280 mg, yield: 80.45%), can be used directly in the next step without purification.

[0242] compound Synthesis of [4-a]

[0243] compound [4-b] (180 mg, 0.289 mmol), 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetate (198.65 mg, 0.347 mmol), and HBTU reagent O-(IH-benzotriazol-1-yl)-N,N,N',N'-tetramethylisourea phosphorus hexafluoride (164.42 mg, 0.434 mmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (0.096 mL, 0.578 mmol) was added. The reaction solution was stirred at room temperature for 0.5 hours, followed by direct reversed-phase preparative chromatography (column: xBridge C18, 19 * 150 mm * 5 μm; mobile phase: water (0.1% trifluoroacetic acid), methanol; gradient: 65%–80% (initial mobile phase: 35% water / 65% methanol, final mobile phase: 20% water / 80% methanol, where % refers to volume percentage); 13 min; flow rate: 15 mL / min). [4-a](268 mg, 0.176 mmol, yield: 61.03%).

[0244] LC-MS (ESI): m / z = 1178.18(M+H) +.

[0245] compound [4] and synthesis

[0246] compound [4-a] (268 mg, 0.176 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. The solution was concentrated under reduced pressure, and the residue was separated by reverse-phase preparative chromatography (column xBridge C18, 19 * 150 mm * 5 μm; mobile phase: water (0.1% trifluoroacetic acid), methanol; gradient: 65%–80% (initial mobile phase: 35% water / 65% methanol, final mobile phase: 20% water / 80% methanol, where % refers to volume percentage); 13 min; flow rate: 15 mL / min). [4](156 mg, yield: 68.44%).

[0247] LC-MS (ESI): m / z = 953.64(M+H) +.

[0248] 1H-NMR (400 MHz, D 2O) δ: 7.48 (s, 1H), 7.19–6.19 (m, 11H), 4.41–2.32 (m, 33H), 2.19–0.83 (m, 13H).

[0249] Example 5

[0250] compound [4] (56 mg, 0.043 mmol) and chalamine trichloride (60.82 mg, 0.216 mmol) were dissolved in sodium acetate-acetic acid buffer (pH=4.5) (2.0 mL). The reaction solution was stirred at 90 °C for 0.5 hours. The reaction solution was cooled to room temperature and purified by pre-HPLC to obtain [5](33 mg, yield: 52.03%).

[0251] LC-MS (ESI): m / z = 1125.95(M+H) +.

[0252] Example 6

[0253] compound [2] (182.40 mg, 0.2 mmol) and chalamine trichloride (56.26 mg, 0.200 mmol) were dissolved in sodium acetate-acetic acid buffer (pH=4.5) (2.0 mL), and the reaction solution was stirred at room temperature for 1 hour. The solution was then purified by pre-HPLC to obtain... [6](80 mg, 0.074 mmol, yield: 36.90%).

[0254] LC-MS (ESI): m / z = 1084.68(M+H) +.

[0255] 1H-NMR (400 MHz, MeOD) δ:7.85 (s, 1H), 7.62 (d, J= 16.0 Hz, 1H), 7.58–7.46 (m, 2H), 7.46–7.38 (m, 2H), 7.38–7.21 (m, 5H), 7.17 (d, J= 7.4 Hz, 1H), 4.66–1.40 (m, 44H).

[0256] Example 7

[0257] compound [2] Gallium trichloride (3.52 mg, 0.020 mmol) was dissolved in water (0.2 mL), and the reaction solution was stirred at 90 °C for 5 minutes. Direct prep-HPLC purification (column XT C18, 19 * 150 mm * 5 μm; mobile phase: water (0.1% FA), acetonitrile; gradient: 25%-95% (initial mobile phase was 75% water / 25% acetonitrile, and the final mobile phase was 5% water / 95% acetonitrile, where % refers to volume percentage); 10 min; flow rate 15 mL / min) yielded a white solid. [7] (9.7 mg, yield: 99.08%).

[0258] LC-MS (ESI): m / z =978.61 (M+H) +.

[0259] 1H-NMR (400 MHz, MeOD) δ:7.88 (s, 1H), 7.63 (d, J= 15.9 Hz, 1H), 7.58–7.51 (m, 2H), 7.47–7.39 (m, 2H), 7.38–7.24 (m, 5H), 7.18 (d, J = 7.5 Hz, 1H), 4.62 (d, J= 13.0 Hz, 1H), 4.50–4.42 (m, 2H), 4.40 (d, J= 13.1 Hz, 1H), 4.06–3.86 (m, 6H), 3.85–3.45 (m, 10H), 3.44–3.32 (m, 9H), 3.26–3.10 (m, 5H), 3.09–2.97 (m, 1H), 2.30 (s, 3H), 2.28–2.17 (m, 1H), 2.05–1.68 (m, 4H), 1.66–1.52 (m, 1H).

[0260] Example 8

[0261] compound [4] 12.95 mg (0.010 mmol), gallium trichloride (3.52 mg, 0.020 mmol), and sodium acetate (0.150 mL, 0.030 mmol) were dissolved in water (0.5 mL). The reaction solution was stirred at 90 °C for 10 minutes. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. [8] (8.76 mg, yield: 85.90%).

[0262] LC-MS (ESI): m / z =1019.65 (M+H) +.

[0263] 1H-NMR (400 MHz, MeOD) δ:7.91 (s, 1H), 7.62 (d, J= 15.9 Hz, 1H), 7.57–7.49 (m, 2H), 7.46–7.38 (m, 2H), 7.38–7.23 (m, 5H), 7.18 (d, J= 6.8 Hz, 1H), 4.52 (dd, J= 34.7, 12.7 Hz, 2H), 4.37–4.22 (m, 2H), 3.89–3.46 (m, 13H), 3.45–2.96 (m, 16H), 2.30 (s, 3H), 2.28–2.19 (m, 1H), 2.05–1.90 (m, 3H), 1.89–1.67 (m, 5H), 1.66–1.50 (m, 1H).

[0264] Example 9

[0265] compound Synthesis of [9-d]

[0266] 2-Methylpropyl-2-yl(2S)-1-[(2-{[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)ethyl]oxy}-4-[(1E)-2-(2-methyl-3-phenylphenyl)vinyl]-5-(trifluoromethyl)phenyl)methyl]hexahydropyridine-2-carboxylic acid ester (610 mg, 0.842 mmol) and hydrazine hydrate (0.511 mL, 8.416 mmol) were dissolved in methanol (6 mL). The reaction mixture was stirred at 60 °C for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was washed with dichloromethane (6 mL), filtered, and the filtrate was concentrated under reduced pressure to obtain... [9-d] (498 mg, yield: 99.50%).

[0267] LC-MS (ESI): m / z = 595.53(M+H)+.

[0268] compound Synthesis of [9-c]

[0269] N,N-diisopropylethylamine (0.020 mL, 0.120 mmol), compound [9-d] (59.47 mg, 0.1 mmol), (1r,4r)-4-(((((9H-fluorene-9-yl)methoxy)carbonyl)amino)methyl)cyclohexane-1-carboxylic acid (37.95 mg, 0.100 mmol), and benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (45.51 mg, 0.120 mmol) were dissolved in N,N-dimethylformamide (0.5 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (20 mL) and washed successively with water (20 mL × 2) and saturated brine (10 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate:ethanol = 20:10:1) to obtain... [9-c] (72 mg, yield: 75.30%).

[0270] compound Synthesis of [9-b]

[0271] Piperidine (0.021 mL, 0.226 mmol) and compound [9-c] (72 mg, 0.075 mmol) was dissolved in acetonitrile (1 mL). The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane:methanol:ammoniamethanol = 400:100:1) to obtain... [9-b](49 mg, yield: 88.66%).

[0272] compound Synthesis of [9-a]

[0273] N,N-diisopropylethylamine (0.017 mL, 0.100 mmol), compound [9-b] (49 mg, 0.067 mmol), (10-{1-[(2-methylprop-2-yl)oxy]-1-oxoethyl-2-yl}-4,7-bis{2-[(2-methylprop-2-yl)oxy]-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (42.06 mg, 0.073 mmol), and benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (32.92 mg, 0.087 mmol) were dissolved in N,N-dimethylformamide (0.5 mL). The reaction solution was stirred at room temperature for 1 hour. The residue was then prepared by Prep-HPLC. [9-a] (72 mg, yield: 83.39%).

[0274] compound [9] Synthesis

[0275] Trifluoroacetic acid (2.0 mL), compound [9-a] (72 mg, 0.056 mmol) was dissolved in dichloromethane (2.0 mL), and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was prepared by Prep-HPLC. [9](59.46 mg, yield: 67.27%).

[0276] LC-MS (ESI): m / z =1065.21 (M+H) +.

[0277] Example 10

[0278] compound Synthesis of [10-d]

[0279] 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (191.70 mg, 1.000 mmol), 4-(4-methylphenyl)butyric acid (178.23 mg, 1.00 mmol), and 1-hydroxytetrahydro-1H-pyrrole-2,5-dione (115.09 mg, 1.000 mmol) were dissolved in dimethyl sulfoxide (2 mL). The reaction mixture was stirred at room temperature for 48 hours. (2S)-6-amino-2-({[(9H-fluorene-9-ylmethyl)oxy]carbonyl}amino)hexanoic acid (368.43 mg, 1.000 mmol) was added, and the reaction mixture was stirred at room temperature for another 1 hour. The reaction mixture was directly prepared by Prep-HPLC. [10-d] (400 mg, yield: 75.66%).

[0280] compound Synthesis of [10-c]

[0281] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (188.56 mg, 0.984 mmol), compound [10-d] and 1-hydroxytetrahydro-1H-pyrrole-2,5-dione (95.79 mg, 0.832 mmol) were dissolved in dimethyl sulfoxide (2 mL). The reaction solution was stirred at room temperature for 2 hours. The reaction solution was then directly prepared by Prep-HPLC to obtain... [10-c] (400 mg, yield: 84.49%).

[0282] compound Synthesis of [10-b]

[0283] compound [9-d] (59.47 mg, 0.1 mmol) and compounds [10-c] (75.09 mg, 0.120 mmol) was dissolved in acetonitrile (1 mL). The reaction mixture was stirred at room temperature for 1 hour. Piperidine (0.037 mL, 0.400 mmol) was added, and the reaction mixture was stirred at room temperature for another 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 5:1, 6 CV, then dichloromethane:methanol = 10:1, 8 CV, CV is column volume) to obtain... [10-b] (78 mg, yield: 88.32%).

[0284] compound Synthesis of [10-a]

[0285] N,N-diisopropylethylamine (0.029 mL, 0.177 mmol), compound [10-b] (78 mg, 0.088 mmol), (10-{1-[(2-methylprop-2-yl)oxy]-1-oxoethyl-2-yl}-4,7-bis{2-[(2-methylprop-2-yl)oxy]-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (55.65 mg, 0.097 mmol), and benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (43.54 mg, 0.115 mmol) were dissolved in N,N-dimethylformamide (1.0 mL). The reaction solution was stirred at room temperature for 1 hour, and the solution was directly prepared by Prep-HPLC. [10-a](108 mg, yield: 85.04%).

[0286] compound

[10] Synthesis

[0287] Trifluoroacetic acid (2.0 mL), compound [10-a] (72 mg, 0.056 mmol) was dissolved in dichloromethane (2.0 mL), and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was prepared by Prep-HPLC.

[10] (50 mg, yield: 54.86%).

[0288] LC-MS (ESI): m / z =1214.47 (M+H) +.

[0289] Example 11

[0290] compound Synthesis of [11-b]

[0291] compound [4-b] (124.55 mg, 0.20 mmol) and compounds [10-c] (150.17 mg, 0.240 mmol) was dissolved in acetonitrile (5.0 mL). The reaction mixture was stirred at room temperature for 1 hour, and then dichloromethane (2.0 mL) was added and stirred for another 1 hour. Piperidine (0.073 mL, 0.800 mmol) was added, and stirring was continued at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain... [11-b](177 mg, yield: 97.13%).

[0292] compound Synthesis of [11-a]

[0293] N,N-diisopropylethylamine (0.064 mL, 0.389 mmol), [11-b] (78 mg, 0.088 mmol), (10-{1-[(2-methylprop-2-yl)oxy]-1-oxoethyl-2-yl}-4,7-bis{2-[(2-methylprop-2-yl)oxy]-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (122.39 mg, 0.214 mmol), and benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (95.77 mg, 0.253 mmol) were dissolved in N,N-dimethylformamide (2.0 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate, 6 CV, then dichloromethane:methanol = 10:1, 8 CV, CV is column volume) to obtain [11-a] (284 mg, yield: 99.73%).

[0294] compound

[11] Synthesis

[0295] compound [11-a] (284 mg, 0.194 mmol) was dissolved in dichloromethane (3 mL). The reaction solution was cooled to 0 °C, and trifluoroacetic acid (3 mL) was added. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by reverse-phase preparative chromatography to obtain...

[11] (150 mg, 0.121 mmol, yield: 62.37%).

[0296] 1H-NMR (400 MHz, MeOD) δ:8.00 (s, 0H), 7.80 (s, 1H), 7.52 (d, J= 15.8 Hz, 1H), 7.47–7.40 (m, 2H), 7.36–7.29 (m, 2H), 7.28–7.15 (m, 5H), 7.08 (d, J= 7.0 Hz, 1H), 6.94 (s, 4H), 4.48 (d, J= 12.7 Hz, 1H), 4.33 (d, J= 12.9 Hz, 1H), 4.23–4.13 (m, 3H), 3.75–3.59 (m, 5H), 3.56–3.26 (m, 11H), 3.10–2.87 (m, 11H), 2.50–2.41 (m, 2H), 2.20 (s, 3H), 2.16 (s, 3H), 2.11–2.05 (m, 2H), 1.96–1.16 (m, 22H).

[0297] Example 12

[0298] compound

[12] Synthesis

[0299] compound

[11] (30 mg, 0.024 mmol) and chalamine trichloride (13.60 mg, 0.048 mmol) were dissolved in methanol (1.0 mL) and sodium acetate-acetic acid buffer (pH=4.5) (0.5 mL). The reaction solution was stirred at room temperature for 20 minutes, then stirred at 90 °C for 5 minutes, and cooled to room temperature. The reaction solution was directly prepared by reverse-phase Pre-HPLC.

[12] (14 mg, yield: 48.08%).

[0300] LC-MS (ESI): m / z =1414.3 (M+H) +.

[0301] Example 13

[0302] compound

[13] Synthesis

[0303] compound

[10] (12.13 mg, 0.01 mmol) and chalamine trichloride (5.63 mg, 0.020 mmol) were dissolved in sodium acetate-acetic acid buffer (pH=4.5) (1.0 mL). The reaction solution was stirred at room temperature for 20 minutes, then stirred at 90 °C for 5 minutes, and cooled to room temperature. The reaction solution was directly prepared by reverse-phase Pre-HPLC.

[13] (10 mg, yield: 72.20%).

[0304] LC-MS (ESI): m / z =1386.7 (M+H) +.

[0305] Example 14

[0306] compound

[14] Synthesis

[0307] compound [9] (10.64 mg, 0.01 mmol) and chalamine trichloride (5.63 mg, 0.020 mmol) were dissolved in sodium acetate-acetic acid buffer (pH=4.5) (1.0 mL). The reaction solution was stirred at room temperature for 20 minutes, stirred at 90 °C for 5 minutes, and cooled to room temperature. The reaction solution was directly prepared by reverse-phase Pre-HPLC.

[14] (6 mg, yield: 48.54%).

[0308] LC-MS (ESI): m / z =1237.3 (M+H) +.

[0309] Example 15

[0310] compound

[15] Synthesis

[0311] compound [1] (15 mg, 0.017 mmol) and chalamine trichloride (23.89 mg, 0.085 mmol) were dissolved in sodium acetate-acetic acid buffer (pH=4.5) (1.0 mL), and the reaction solution was stirred at room temperature for 1 hour. The solution was prepared directly by prep-HPLC.

[15] (8.6 mg, yield: 36%).

[0312] LC-MS (ESI): m / z = 1055.79(M+H) +.

[0313] 1H-NMR (400 MHz, D 2O)δ:7.20 (s, 1H), 7.15-6.87 (m, 6H), 6.81 (s, 1H), 6.75-6.22 (m, 4H), 4.50-3.82 (m, 3H), 3.78-2.89 (m, 17H), 2.86-2.18 (m, 13H), 2.08-0.96 (m, 9H).

[0314] Example 16

[0315] compound Synthesis of [16-c]

[0316] compound [2-c] (500 mg, 0.910 mmol) was dissolved in N,N-dimethylformamide (15 mL), and 1,5-diiodopentane (294.66 mg, 0.910 mmol) and potassium carbonate (314.30 mg, 2.274 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed successively with water (20 mL × 2) and saturated brine (20 mL × 1). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography to obtain... [16-c](171 mg, yield: 25.20%).

[0317] compound Synthesis of [16-b]

[0318] compound [16-c] (171 mg, 0.229 mmol) was dissolved in tetrahydrofuran (2 mL), and ammonia-methanol solution (7 M, 10 mL) was added. The reaction mixture was stirred at 50 °C for 12 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), and washed successively with water (2 mL × 2) and saturated brine (2 mL × 1). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain... [16-b] (145 mg, yield: 99.61%).

[0319] compound Synthesis of [16-a]

[0320] compound [16-b] (145 mg, 0.228 mmol) was dissolved in N,N-dimethylformamide (5 mL), and [4,7,10-tris(4,4-dimethyl-2-oxopentyl)-1,4,7,10-tetraazacyclododecane-1-yl]acetic acid (155.36 mg, 0.274 mmol), benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (129.70 mg, 0.342 mmol) and N,N-diisopropylethylamine (0.075 mL, 0.456 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (5 mL) and washed successively with water (2 mL × 2) and saturated brine (2 mL × 1). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain... [16-a] (243 mg, yield: 98.10%).

[0321] compound

[16] Synthesis

[0322] compound [16-a] (243 mg, 0.224 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (10 mL) was added. The reaction mixture was stirred at room temperature for 18 hours, then concentrated under reduced pressure. The residue was directly prepared by prep-HPLC.

[16] (104.77 mg, yield: 48.35%).

[0323] LC-MS (ESI): m / z =968.4 (M+H) +.

[0324] Example 17

[0325] compound

[17] Synthesis

[0326] compound [16, [49 mg, 0.051 mmol] was dissolved in sodium acetate-acetic acid buffer (pH=4.5) (10 mL), and chalamine trichloride (28.69 mg, 0.102 mmol) was added. The reaction solution was stirred at room temperature for 10 minutes, and the solution was directly prepared by prep-HPLC.

[17] (29.67 mg, yield: 51.41%).

[0327] LC-MS (ESI): m / z =1140.7 (M+H) +.

[0328] Example 18

[0329] compound Synthesis of [18-c]

[0330] 1-{[(9H-fluorene-9-ylmethyl)oxy]carbonyl}hexahydropyridine-4-carboxylic acid (702.80 mg, 2.00 mmol), 1-hydroxytetrahydro-1H-pyrrole-2,5-dione (230.18 mg, 2.000 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (383.40 mg, 2.000 mmol) were dissolved in acetonitrile (7.0 mL) and dichloromethane (7.0 mL). The reaction mixture was stirred at room temperature for 5 hours, and the product was prepared directly by reverse phase reaction. [18-c] (800 mg, yield: 89.19%).

[0331] compound Synthesis of [18-b]

[0332] compound [9-d] (59.47 mg, 0.100 mmol) and compounds [18-c] (57.41 mg, 0.128 mmol) was dissolved in acetonitrile (1.0 mL). The reaction solution was stirred at room temperature for 16 hours. Piperidine (85.15 mg, 1.000 mmol) was added, and stirring was continued for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was directly purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1, 6 CV; dichloromethane:methanol = 7:3, 6 CV, CV being column volume). [18-b] ​​(50 mg, yield: 70.83%).

[0333] compound Synthesis of [18-a]

[0334] N,N-diisopropylethylamine (0.023 mL, 0.142 mmol), compound [18-b] ​​(50 mg, 0.071 mmol), (10-{1-[(2-methylprop-2-yl)oxy]-1-oxoethyl-2-yl}-4,7-bis{2-[(2-methylprop-2-yl)oxy]-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (44.63 mg, 0.078 mmol) and O-benzotriazole-tetramethylurea hexafluorophosphate (34.92 mg, 0.092 mmol) were dissolved in N,N-dimethylformamide (1.0 mL). The reaction solution was stirred at room temperature for 1 hour and then purified directly by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1, 6 CV, dichloromethane:methanol = 10:1, 6 CV, CV is column volume) to obtain [18-a] (80 mg, yield: 89.59%).

[0335] compound

[18] Synthesis

[0336] compound [18-a] (80 mg, 0.063 mmol) was dissolved in dichloromethane (2.0 mL), and trifluoroacetic acid (2.0 mL) was added. The reaction mixture was stirred at room temperature for 24 hours, and then concentrated under reduced pressure to obtain the compound.

[18] (30 mg, yield: 45.62%).

[0337] LC-MS (ESI): m / z =1037.3 (M+H) +.

[0338] Example 19

[0339] compound Synthesis of [19-c]

[0340] compound [2-c] (500 mg, 0.906 mmol) and 2-methylpropyl-2-yl-4-(iodomethyl)hexahydropyridine-1-carboxylic acid ester (1473.11 mg, 4.530 mmol) were dissolved in N,N-dimethylformamide (3.0 mL), and potassium carbonate (180 mg, 1.302 mmol) was added. The reaction mixture was stirred at 80 °C for 60 hours and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (40 mL) and washed successively with water (20 mL × 2) and saturated brine (20 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give [19-c] (620 mg, yield: 91.34%).

[0341] compound Synthesis of [19-b]

[0342] compound [19-c] (284 mg, 0.379 mmol) was dissolved in tetrahydrofuran (2 mL), and 1,4-dioxane hydrochloride (1.5 mL) was added. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with potassium carbonate aqueous solution (20% aqueous solution, 5 mL). The mixture was extracted with dichloromethane (20 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain... [19-b] (246 mg, yield: 99.99%) can be directly used for the next reaction without purification.

[0343] compound Synthesis of [19-a]

[0344] compound [19-b] (246 mg, 0.379 mmol), (10-{1-[(2-methylprop-2-yl)oxy]-1-oxoethyl-2-yl}-4,7-bis{2-[(2-methylprop-2-yl)oxy]-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (238.87 mg, 0.417 mmol), and benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (186.93 mg, 0.493 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), and N,N-diisopropylethylamine (0.125 mL, 0.758 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate:ethanol = 10:20:1) to obtain... [19-a](360 mg, yield: 78.89%).

[0345] compound

[19] Synthesis

[0346] compound [19-a] (360 mg, 0.299 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at room temperature for 16 hours, and then concentrated under reduced pressure. The residue was directly prepared by pre-HPLC.

[19] (194 mg, yield: 66.24%).

[0347] LC-MS (ESI): m / z =980.7 (M+H) +.

[0348] Example 20

[0349] compound Synthesis of

[20]

[0350] compound [19 (]23.50 mg, 0.024 mmol) and chrysene trichloride (13.50 mg, 0.048 mmol) were dissolved in sodium acetate-acetic acid buffer (pH=4.5) (1 mL). The reaction solution was stirred at 90 °C for 5 minutes, cooled to room temperature, and then prepared by pre-HPLC.

[20] (23 mg, yield: 83.24%).

[0351] LC-MS (ESI): m / z =1152.1 (M+H) +.

[0352] Example 21

[0353] compound Synthesis of [21-f]

[0354] 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (383.40 mg, 2.000 mmol), 4-(4-methylphenyl)butyric acid (356.46 mg, 2.00 mmol), and 1-hydroxytetrahydro-1H-pyrrole-2,5-dione (230.18 mg, 2.000 mmol) were added to dimethyl sulfoxide (4 mL). The reaction was stirred at room temperature for 48 hours. (2S)-6-amino-2-({[(9H-fluorene-9-ylmethyl)oxy]carbonyl}amino)hexanoic acid (736.86 mg, 2.00 mmol) was added, and stirring was continued at room temperature for 1 hour. The reaction solution was directly reversed to prepare (120 g of C18, water (0.1% formic acid), 0-95% acetonitrile, 6 CV, CV is column volume) to give [21-f](860 mg, yield: 81.34%).

[0355] compound Synthesis of [21-e]

[0356] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (498.97 mg, 2.603 mmol), compound [21-f] (860 mg, 1.627 mmol) and 1-hydroxytetrahydro-1H-pyrrole-2,5-dione (252.76 mg, 2.196 mmol) were added to dimethyl sulfoxide (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then directly reverse-phase prepared (120 g of C18, water (0.1% formic acid), 0-95% acetonitrile, 6 CV, CV being column volume) to obtain [21-e] (900 mg, yield: 88.42%).

[0357] compound Synthesis of [21-d]

[0358] N,N-diisopropylethylamine (0.040 mL, 0.240 mmol), compound [9-d] (118.94 mg, 0.20 mmol), (1r,4r)-4-(((((9H-fluorene-9-yl)methoxy)carbonyl)amino)methyl)cyclohexane-1-carboxylic acid (75.89 mg, 0.200 mmol), and benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (91.02 mg, 0.240 mmol) were dissolved in N,N-dimethylformamide (1.0 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (20 mL) and washed successively with water (20 mL × 2) and saturated brine (10 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate:ethanol = 20:10:1) to obtain [21-d] (164 mg, yield: 85.76%).

[0359] compound Synthesis of [21-c]

[0360] Piperidine (0.047 mL, 0.515 mmol) and compound [21-d] (164 mg, 0.172 mmol) was dissolved in acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was column chromatography (dichloromethane:methanol:ammoniamethanol (7 M in MeOH) = 400:100:1) to obtain... [21-c](110 mg, yield: 87.38%).

[0361] compound Synthesis of [21-b]

[0362] compound [21-c] (110 mg, 0.150 mmol) and compounds [21-e] (112.63 mg, 0.180 mmol) was dissolved in acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 1 hour, and dichloromethane (2.0 mL) was added, followed by stirring for another hour. Piperidine (0.069 mL, 0.749 mmol) was added, and the reaction mixture was stirred at room temperature for another 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5:1, then dichloromethane: methanol: ammonia-methanol (7 M in MeOH) = 100:10:2) to obtain... [21-b](127 mg, yield: 82.82%).

[0363] compound Synthesis of [21-a]

[0364] compound [21-b] (127 mg, 0.124 mmol), (4,7,10-tris{2-[(2-methylprop-2-yl)oxy]-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (92.33 mg, 0.161 mmol) and O-benzotriazole-tetramethylurea hexafluorophosphate (70.54 mg, 0.186 mmol) were dissolved in N,N-dimethylformamide (1.0 mL), and N,N-diisopropylethylamine (0.041 mL, 0.248 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The residue was column chromatography (petroleum ether:ethyl acetate = 4:1, 6 CV, then 100% PE, 5 CV, then dichloromethane:methanol = 10:1, 8 CV, CV is column volume) to obtain [21-a] (195 mg, yield: 99.54%).

[0365] compound

[21] Synthesis

[0366] compound [21-b] (195 mg, 0.124 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The reaction solution was stirred at room temperature for 16 hours, and then concentrated under reduced pressure. The solution was then directly prepared by pre-HPLC.

[21] (100 mg, yield: 59.79%).

[0367] LC-MS (ESI): m / z =1353.61 (M+H) +.

[0368] Example 22

[0369] compound

[22] Synthesis

[0370] Compound

[21] (13.53 mg, 0.01 mmol) was dissolved in sodium acetate-acetic acid buffer (pH=4.5) (1 mL), and chalamine trichloride (5.63 mg, 0.020 mmol) was added. The reaction solution was heated and stirred at 90 °C for 10 minutes. The solution was prepared directly by prep-HPLC.

[22] (10 mg, yield: 65.59%).

[0371] LC-MS (ESI): m / z =1525.55 (M+H) +.

[0372] Example 23

[0373] compound Synthesis of [23-c]

[0374] compound [2-c] (500 mg, 0.910 mmol) was dissolved in N,N-dimethylformamide (15 mL), and 1,6-diiodohexane (307.55 mg, 0.910 mmol) and potassium carbonate (314.43 mg, 2.275 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed successively with water (20 mL × 2) and saturated brine (20 mL × 1). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography to obtain... [23-c](462 mg, yield: 66.82%).

[0375] compound Synthesis of [23-b]

[0376] compound [23-c] (462 mg, 0.608 mmol) was dissolved in tetrahydrofuran (2 mL) and ammonia-methanol solution (7 M, 15 mL) was added. The reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), and washed successively with water (2 mL × 2) and saturated brine (2 mL × 1). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. [23-b](483 mg, yield: 122.41%) can be directly proceeded to the next step of the reaction without purification.

[0377] compound Synthesis of [23-a]

[0378] compound [23-b] (145 mg, 0.228 mmol) was dissolved in N,N-dimethylformamide (5 mL), and [4,7,10-tris(4,4-dimethyl-2-oxopentyl)-1,4,7,10-tetraazacyclododecane-1-yl]acetic acid (104.83 mg, 0.185 mmol), benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (87.67 mg, 0.231 mmol) and N,N-diisopropylethylamine (0.051 mL, 0.308 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (5 mL) and washed successively with water (2 mL × 2) and saturated brine (2 mL × 1). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain... [23-a] (91 mg, yield: 49.10%).

[0379] compound

[23] Synthesis

[0380] compound [23-a] (91 mg, 0.076 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (10 mL) was added. The reaction mixture was stirred at room temperature for 18 hours, then concentrated under reduced pressure. The residue was directly prepared by prep-HPLC.

[23] (55.42 mg, yield: 74.34%).

[0381] LC-MS (ESI): m / z =982.12 (M+H) +.

[0382] Example 24

[0383] compound

[24] Synthesis

[0384] compound

[23] (30 mg, 0.031 mmol) was dissolved in sodium acetate-acetic acid buffer (pH=4.5) (10 mL), and chalamine trichloride (17.20 mg, 0.061 mmol) was added. The reaction solution was stirred at room temperature for 10 minutes, and the solution was directly prepared by prep-HPLC.

[24] (28.12 mg, yield: 78.67%).

[0385] LC-MS (ESI): m / z =1154.3 (M+H) +.

[0386] Example 25

[0387] compound Synthesis of [25-b]

[0388] compound [23-b] (200 mg, 0.308 mmol) was dissolved in acetonitrile (5 mL) and dichloromethane (5 mL). 9H-fluorene-9-ylmethyl{[(2S)-125-b-[(2,5-dioxotetrahydro-1H-pyrrolo-1-yl)oxy]-6-{[4-(4-methylphenyl)-1-oxobutyl]amino}-1-oxohexyl-2-yl]amino}carbamate (231.44 mg, 0.370 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. Piperidine (0.102 mL, 0.616 mmol) was added, and stirring continued for 1 hour. The reaction mixture was diluted with ethyl acetate (5 mL) and washed successively with water (2 mL × 2) and saturated brine (2 mL × 1). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain... [25-b](184 mg, yield: 63.69%).

[0389] compound Synthesis of [25-a]

[0390] compound [25-b] (184 mg, 0.196 mmol) was dissolved in N,N-dimethylformamide (5 mL), and (4,7,10-tris{2-[(2-methylprop-2-yl)oxy]-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (112.44 mg, 0.196 mmol), benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (111.68 mg, 0.294 mmol) and N,N-diisopropylethylamine (0.065 mL, 0.393 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (5 mL) and washed successively with water (2 mL × 2) and saturated brine (2 mL × 1). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain... [25-a] (158.85 mg, yield: 54.16%).

[0391] compound

[25] Synthesis

[0392] compound [25-a] (158.85 mg, 0.106 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (10 mL) was added. The reaction mixture was stirred at room temperature for 18 hours, then concentrated under reduced pressure. The residue was directly prepared by prep-HPLC.

[25] (84.5 mg, yield: 62.60%).

[0393] LC-MS (ESI): m / z =1270.5 (M+H) +.

[0394] Example 26

[0395] compound

[26] Synthesis

[0396] compound

[25] (20 mg, 0.016 mmol) was dissolved in sodium acetate-acetic acid buffer (pH=4.5) (3 mL), and chalamine trichloride (8.86 mg, 0.032 mmol) was added. The reaction solution was stirred at room temperature for 10 minutes, and the solution was directly prepared by prep-HPLC.

[26] (19.02 mg, yield: 83.75%).

[0397] LC-MS (ESI): m / z =1142.46(M+H) +.

[0398] Example 27

[0399] compound

[27] Synthesis

[0400] compound

[25] (20 mg, 0.016 mmol) was added to water (2 mL), and gallium trichloride (0.640 mL, 0.032 mmol) was added. The reaction solution was stirred at 90 °C for 10 minutes, cooled to room temperature, and directly prepared by prep-HPLC.

[27] (17.37 mg, yield: 81.24%).

[0401] LC-MS (ESI): m / z =1337.21(M+H) +.

[0402] Example 28

[0403] compound

[28] Synthesis

[0404] compound

[23] (8 mg, 0.008 mmol) was added to water (2 mL), sodium acetate (0.164 mL, 0.024 mmol) was added, the reaction solution was stirred for 1 minute, gallium trichloride (0.319 mL, 0.016 mmol) was added, the reaction solution was stirred at 90 °C for 10 minutes, the reaction solution was cooled to room temperature, and the product was directly prepared by prep-HPLC.

[28] (4.92 mg, yield: 57.61%).

[0405] LC-MS (ESI): m / z =1048.82(M+H) +.

[0406] Example 29

[0407] compound

[29] Synthesis

[0408] compound

[16] (20 mg, 0.021 mmol) was added to water (2 mL), and gallium trichloride (0.809 mL, 0.041 mmol) was added. The reaction solution was stirred at 90 °C for 10 minutes, cooled to room temperature, and directly prepared by prep-HPLC.

[29] (19.64 mg, yield: 90.47%).

[0409] LC-MS (ESI): m / z =1334.8(M+H) +.

[0410] Example 30

[0411] compound Synthesis of [30-d]

[0412] compound [2-c] (551.65 mg, 1.00 mmol), 2-methylpropyl-2-yl({2-[(2-bromoethyl)oxy]ethyl}amino)carbamate (321.78 mg, 1.200 mmol) and potassium carbonate (179.66 mg, 1.300 mmol) were dissolved in N,N-dimethylformamide (3.0 mL). The reaction mixture was stirred at 80 °C for 60 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (40 mL), and washed successively with water (20 mL × 2) and saturated brine (20 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 10:3) to obtain... [30-d] (438 mg, yield: 59.28%).

[0413] compound Synthesis of [30-c]

[0414] compound [30-d] (438 mg, 0.593 mmol) was dissolved in tetrahydrofuran (4 mL), and 1,4-dioxane hydrochloride (4 M) (4 mL) was added. The reaction solution was stirred at room temperature for 1 hour, and then concentrated under reduced pressure to obtain... [30-c] (260 mg, yield: 68.64%).

[0415] compound Synthesis of [30-b]

[0416] compound [30-c](127.75 mg, 0.2 mmol), compound [21-e] (150.17 mg, 0.240 mmol) was dissolved in acetonitrile (2.0 mL) and dichloromethane (2.0 mL). The reaction mixture was stirred at room temperature for 1 hour, then piperidine (0.183 mL, 2.00 mmol) was added, and the mixture was stirred at room temperature for another 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was passed through a silica gel column (petroleum ether:ethyl acetate = 5:1, 6 CV, then dichloromethane:methanol:ammoniamethanol (7 M in MeOH) = 100:10:2, 8 CV, CV is column volume) to obtain [30-b](160 mg, yield: 86.29%).

[0417] compound Synthesis of [30-a]

[0418] N,N-diisopropylethylamine (0.057 mL, 0.346 mmol), compound [30-b] (160 mg, 0.173 mmol), (4,7,10-tris{2-[(2-methylprop-2-yl)oxy]-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (118.61 mg, 0.207 mmol) and benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (85.29 mg, 0.225 mmol) were dissolved in N,N-dimethylformamide (2.0 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was subjected to column chromatography (petroleum ether:ethyl acetate = 4:1, 6 CV, then 100% PE, 5 CV, then dichloromethane:methanol = 10:1, 8 CV, CV is column volume) to give [30-a](255 mg, 0.172 mmol, yield: 99.71%).

[0419] compound

[30] Synthesis

[0420] Trifluoroacetic acid (3 mL) and compound [30-a] (255 mg, 0.172 mmol) was dissolved in dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was prepared by Pre-HPLC.

[30] (121 mg, yield: 55.92%).

[0421] LC-MS (ESI): m / z =1258.46(M+H) +.

[0422] Example 31

[0423] compound Synthesis of [31-a]

[0424] N,N-diisopropylethylamine (0.033 mL, 0.200 mmol), compound [30-c] (63.88 mg, 0.1 mmol), (4,7,10-tris{2-[(2-methylprop-2-yl)oxy]-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (68.73 mg, 0.120 mmol), and benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (49.30 mg, 0.130 mmol) were dissolved in acetonitrile (1.0 mL), and the reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether:ethyl acetate = 5:1, then dichloromethane:methanol:ammoniamethanol (7 M in MeOH) = 200:20:1) to give [31-a](119 mg, yield: 99.71%).

[0425] compound

[31] Synthesis

[0426] Trifluoroacetic acid (2.0 mL) and compound [31-a] (119 mg, 0.100 mmol) was dissolved in dichloromethane (2.0 mL). The reaction solution was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and obtained by Pre-HPLC.

[31] (47 mg, yield: 48.64%).

[0427] LC-MS (ESI): m / z =970.13(M+H) +.

[0428] Example 32

[0429] compound

[32] Synthesis

[0430] compound

[30] (12.57 mg, 0.01 mmol) and chalamine trichloride (5.63 mg, 0.020 mmol) were added to sodium acetate-acetic acid buffer (pH=4.5) (1.0 mL), and the reaction solution was stirred at 90 °C for 10 minutes. The reaction solution was cooled to room temperature and directly reversed to prepare the product.

[32] (7.2 mg, yield: 50.38%).

[0431] LC-MS (ESI): m / z =1430.4(M+H) +.

[0432] Example 33

[0433] compound

[33] Synthesis

[0434] Lumium trichloride (5.63 mg, 0.020 mmol) and compound

[31] (9.69 mg, 0.01 mmol) was added to sodium acetate-acetic acid buffer (pH=4.5) (1.0 mL), and the reaction solution was stirred at 90 °C for 5 minutes. The reaction solution was then cooled to room temperature. The solution was prepared directly by Pre-HPLC.

[33] (8.7 mg, yield: 76.25%).

[0435] LC-MS (ESI): m / z =1142.01(M+H) +.

[0436] Example 34

[0437] compound

[34] Synthesis

[0438] compound

[31] 4.85 mg (0.005 mmol) and gallium trichloride (1.76 mg, 0.010 mmol) were added to water (0.2 mL), and the reaction solution was heated and stirred at 90 °C for 5 minutes. The reaction solution was cooled to room temperature, and the reaction solution was directly prepared by Pre-HPLC.

[34] (3.5 mg, yield: 67.57%).

[0439] LC-MS (ESI): m / z =1036.77(M+H) +.

[0440] Example 35

[0441] compound

[35] Synthesis

[0442] compound [9] (5.32 mg, 0.005 mmol) and gallium trichloride (1.76 mg, 0.010 mmol) were added to water (0.2 mL), the reaction solution was heated and stirred at 90 °C for 10 minutes, the reaction solution was cooled to room temperature, and the product was directly prepared by Pre-HPLC.

[35] (2.3 mg, yield: 40.71%).

[0443] LC-MS (ESI): m / z =1131.91(M+H) +.

[0444] Example 36

[0445] compound

[36] Synthesis

[0446] compound

[18] (5.18 mg, 0.005 mmol) and gallium trichloride (1.76 mg, 0.010 mmol) were added to water (0.2 mL), the reaction solution was stirred at 90 °C for 10 minutes, the reaction solution was cooled to room temperature, and the product was directly prepared by Pre-HPLC.

[36] (2.7 mg, yield: 49.00%).

[0447] LC-MS (ESI): m / z =1103.86(M+H) +.

[0448] Example 37

[0449] compound

[37] Synthesis

[0450] compound

[19] (9.79 mg, 0.01 mmol) and gallium trichloride (3.52 mg, 0.020 mmol) were added to water (0.5 mL), and the reaction solution was heated and stirred at 90 °C for 10 minutes. The reaction solution was then cooled to room temperature. The reaction solution was directly prepared by Pre-HPLC.

[37] (8.5 mg, yield: 81.26%).

[0451] LC-MS (ESI): m / z =1146.81(M+H) +.

[0452] Example 38

[0453] compound

[38] Synthesis

[0454] compound

[18] 15.54 mg (0.015 mmol) and chalamine trichloride (8.44 mg, 0.030 mmol) were added to sodium acetate-acetic acid buffer (pH=4.5) (1.0 mL), and the reaction solution was stirred at room temperature for 10 minutes. The solution was then directly prepared by Pre-HPLC.

[38] (8 mg, yield: 44.15%).

[0455] LC-MS (ESI): m / z =1209.1(M+H) +.

[0456] Example 39

[0457] compound Synthesis of [39-b]

[0458] compound [2-c] (441.32 mg, 0.80 mmol) and 1,8-dibromo-3,6-dioxooctane (242.85 mg, 0.880 mmol) were dissolved in N,N-dimethylformamide (3.0 mL), and potassium carbonate (143.73 mg, 1.040 mmol) was added. The reaction mixture was stirred at 80 °C for 60 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (40 mL), and washed successively with water (20 mL × 2) and saturated brine (20 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give... [39-b](240 mg, yield: 40.18%).

[0459] compound Synthesis of [39-a]

[0460] compound [39-b] (140 mg, 0.187 mmol) and 2-methylpropane-2-yl(4,7-bis{2-[(2-methylpropane-2-yl)oxy]-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1-yl)acetate (96.50 mg, 0.187 mmol) were dissolved in acetonitrile (2 mL), and potassium carbonate (25.91 mg, 0.187 mmol) was added. The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by Pre-HPLC to obtain... [39-a](240 mg, yield: 84.29%).

[0461] compound

[39] Synthesis

[0462] compound [39-a] (240 mg, 0.158 mmol) and trifluoroacetic acid (3.0 mL) were dissolved in dichloromethane (3.0 mL), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated under reduced pressure. The residue was purified by Pre-HPLC to obtain...

[39] (78 mg, yield: 51.76%).

[0463] LC-MS (ESI): m / z = 956.24 (M+H) +.

[0464] Example 40

[0465] compound Synthesis of [40-f]

[0466] 3-Bromo-1-chloro-2-toluene (3082.20 mg, 15.00 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborane (2772.36 mg, 18.000 mmol), and triethylamine (20.850 mL, 150.000 mmol) were dissolved in toluene (30 mL). Di(tris-tert-butylphosphine)palladium (383.29 mg, 0.750 mmol) was added. The reaction mixture was purged with nitrogen three times and heated at 80 °C for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain... [40-f](1000 mg, yield: 23.93%).

[0467] compound Synthesis of [40-e]

[0468] compound [2-d] (1200 mg, 2.738 mmol) and compounds [40-f] (991.60 mg, 3.559 mmol) was dissolved in dioxane (10.0 mL) and water (2.0 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (100.17 mg, 0.137 mmol) and potassium carbonate (756.83 mg, 5.476 mmol) were added. The reaction mixture was heated and stirred at 80 °C for 16 hours under nitrogen protection. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with dichloromethane (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (petroleum ether: ethyl acetate = 20:1) to give [40-e] (220 mg, yield: 15.76%).

[0469] LC-MS (ESI): m / z =510.39 (M+H) +.

[0470] compound Synthesis of [40-d]

[0471] compound [40-e] (220 mg, 0.431 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentanane (219.09 mg, 0.863 mmol) was dissolved in toluene (3 mL), and palladium acetate (9.68 mg, 0.043 mmol), 2-biscyclohexylphosphine-2',4',6'-triisopropylbiphenyl (41.13 mg, 0.086 mmol) and potassium acetate (84.60 mg, 0.862 mmol) were added. The reaction mixture was heated at 100 °C for 16 hours under nitrogen protection. The reaction mixture was cooled to room temperature, diluted with dichloromethane (40 mL), and washed with water (10 mL × 1). The organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain... [40-d] (220 mg, yield: 84.86%).

[0472] compound Synthesis of [40-c]

[0473] compound [40-d] (220 mg, 0.366 mmol) and 4-{3-[(3-bromo-2-methylphenyl)oxy]propyl}-1,4-oxazine (137.91 mg, 0.439 mmol) were dissolved in dioxane (2.0 mL) and water (0.4 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (26.76 mg, 0.037 mmol) and potassium carbonate (101.10 mg, 0.731 mmol) were added. The reaction mixture was heated and stirred at 90 °C for 16 hours under nitrogen protection. The reaction mixture was cooled to room temperature and diluted with water (10 mL). The resulting mixture was extracted with dichloromethane (40 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (100% ethyl acetate) to obtain... [40-c] (195 mg, yield: 75.21%).

[0474] compound Synthesis of [40-b]

[0475] compound [40-c] (195 mg, 0.275 mmol), 1-bromo-2-[(2-bromoethyl)oxy]ethane (191.39 mg, 0.825 mmol) was dissolved in N,N-dimethylformamide (2.0 mL), and potassium carbonate (76.02 mg, 0.550 mmol) was added. The reaction mixture was heated and stirred at 70 °C for 20 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to column chromatography (ethyl acetate:ethanol = 20:1) to obtain... [40-b] (150 mg, yield: 63.44%).

[0476] compound Synthesis of [40-a]

[0477] compound [40-b] (150 mg, 0.174 mmol), 2-methylpropyl-2-yl(4,7-bis{2-[(2-methylpropyl-2-yl)oxy]-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1-yl)acetate (134.68 mg, 0.262 mmol) was dissolved in acetonitrile (2.0 mL), and potassium carbonate (36.17 mg, 0.262 mmol) was added. The reaction mixture was heated and stirred at 60 °C for 16 hours, and the remaining 13% was... [40-b], continue heating and stirring for 8 hours. The reaction solution was evaporated to dryness, and the residue was subjected to column chromatography (methanol:ammonia-methanol (7 M) = 5:1) to obtain... [40-a] (170 mg, yield: 75.33%).

[0478] compound Synthesis of

[40]

[0479] compound [40-a] (170 mg, 0.131 mmol) was dissolved in dichloromethane (5.0 mL), and trifluoroacetic acid (5.0 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was prepared by Pre-HPLC.

[40] (40 mg, yield: 21.64%).

[0480] Example 41

[0481] compound

[41] Synthesis

[0482] compound

[39] (11.2 mg, 0.012 mmol) and chrysene trichloride (7.25 mg, 0.026 mmol) were dissolved in sodium acetate-acetic acid buffer (pH=4.5) (0.5 mL), and the reaction solution was heated at 90 °C for 20 minutes. The reaction solution was cooled to room temperature and purified directly by Pre-HPLC.

[41] (11 mg, yield: 83.27%).

[0483] Example 42

[0484] compound Synthesis of [42-e]

[0485] 2-Chloro-4-phenylpyridine-3-carbamate (4293.20 mg, 20.00 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborane (7701.00 mg, 50.00 mmol) were dissolved in dioxane (50.0 mL) and water (10.0 mL). Potassium carbonate (8292.60 mg, 60.00 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1463.40 mg, 2.00 mmol) were added and mixed in a microwave-safe tube. The tube was purged with nitrogen for 1 minute and then sealed. The reaction mixture was heated and stirred at 100 °C for 16 hours, and then cooled to room temperature. The reaction mixture was diluted directly with water (50 mL) and extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether:ethyl acetate = 85:15) to obtain... [42-e] (3150 mg, yield: 76.36%).

[0486] LC-MS (ESI): m / z = 207.29(M+H) +.

[0487] compound Synthesis of [42-d]

[0488] compound [42-e](412.50 mg, 2.0 mmol), compound [2-d] (876.56 mg, 2.00 mmol) was dissolved in N,N-dimethylacetamide (6.0 mL), and palladium acetate (44.90 mg, 0.20 mmol), tris(o-methylphenyl)phosphine (121.75 mg, 0.40 mmol), and triethylamine (2.0 mL, 14.389 mmol) were added. The mixture was microwave-heated at 160 °C for 0.5 h under nitrogen protection. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain... [42-d] (550 mg, yield: 48.79%).

[0489] compound Synthesis of [42-c]

[0490] compound [42-d] (225.45 mg, 0.4 mmol) and 2-methylpropyl-2-yl-4-(iodomethyl)hexahydropyridine-1-carboxylate (650.38 mg, 2.00 mmol) were dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (276.42 mg, 2.00 mmol) was added. The reaction mixture was heated and stirred at 80 °C for 60 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (40 mL), and washed successively with water (20 mL × 2) and saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give [42-c](248 mg, yield: 81.48%).

[0491] compound Synthesis of [42-b]

[0492] compound [42-c] (248 mg, 0.326 mmol) was dissolved in tetrahydrofuran (3 mL), and dioxane hydrochloride solution (1 mL) was added. The reaction mixture was stirred at room temperature for 6 hours. 1 M K₂CO₃ solution (10 mL) was added. The mixture was extracted with dichloromethane (30 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain... [42-b](215 mg, yield: 99.83%). No purification is required; it can be used directly in the next reaction.

[0493] compound Synthesis of [42-a]

[0494] compound [42-b] (100 mg, 0.151 mmol), (10-{1-[(2-methylpropyl-2-yl)oxy]-1-oxoethyl-2-yl}-4,7-bis{2-[(2-methylpropyl-2-yloxy)-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (104.01 mg, 0.182 mmol), and O-benzotriazole-tetramethylurea hexafluorophosphate (74.61 mg, 0.197 mmol) were dissolved in N,N-dimethylformamide (1.0 mL). Diisopropylethylamine (0.050 mL, 0.303 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate:ethanol = 10:20:1) to obtain... [42-a](360 mg, yield: 78.89%).

[0495] compound

[42] Synthesis

[0496] compound [42-a] (150 mg, 0.096 mmol) was dissolved in dichloromethane (2.0 mL), and trifluoroacetic acid (2.0 mL) was added. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was prepared by Pre-HPLC.

[42] (63 mg, yield: 66.01%).

[0497] Example 43

[0498] compound Synthesis of [43-c]

[0499] compound [42-d] (112.72 mg, 0.2 mmol) and 1,4-diiodobutane (247.94 mg, 0.80 mmol) were dissolved in N,N-dimethylformamide (1.0 mL), and potassium carbonate (55.28 mg, 0.40 mmol) was added. The reaction mixture was stirred at 50 °C for 1 hour. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 mL), and washed successively with water (20 mL × 2) and saturated brine (20 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain... [43-c](124 mg, yield: 83.15%).

[0500] compound Synthesis of [43-b]

[0501] compound [43-c] (124 mg, 0.166 mmol) was dissolved in tetrahydrofuran (3 mL), and ammonia-methanol solution (10 mL, 70.00 mmol) was added. The reaction mixture was heated and stirred at 50 °C for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in dichloromethane (30 mL) and washed with 1 M K₂CO₃ solution (10 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain... [43-b] (105 mg, yield: 99.47%), without purification, can be used directly in the next reaction.

[0502] compound Synthesis of [43-a]

[0503] compound [43-b] (105 mg, 0.165 mmol), (4,7,10-tris{2-[(2-methylpropyl-2-yl)oxy]-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (113.69 mg, 0.199 mmol) and O-benzotriazole-tetramethylurea hexafluorophosphate (81.56 mg, 0.215 mmol) were dissolved in acetonitrile (1.0 mL), and diisopropylethylamine (0.055 mL, 0.331 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography (dichloromethane:methanol = 94:6) to obtain... [43-a](196 mg, yield: 99.61%).

[0504] compound

[43] Synthesis

[0505] compound [43-a] (196 mg, 0.165 mmol) was dissolved in dichloromethane (3.0 mL). Trifluoroacetic acid (3.0 mL) was added. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was used to prepare the compound by Pre-HPLC.

[43] (80 mg, yield: 50.31%).

[0506] LC-MS (ESI): m / z = 965.45 (M+H) +.

[0507] Example 44

[0508] compound

[44] Synthesis

[0509] compound

[42] (9.91 mg, 0.01 mmol) was dissolved in sodium acetate-acetic acid buffer (pH=4.5) (0.5 mL), and chalamine trichloride (5.63 mg, 0.020 mmol) was added. The reaction solution was stirred at 90 °C for 10 minutes. The reaction solution was cooled to room temperature and 44 (10.6 mg, yield: 91.14%) was prepared directly by Pre-HPLC.

[0510] LC-MS (ESI): m / z = 1163.12 (M+H) +.

[0511] Example 45

[0512] compound

[45] Synthesis

[0513] compound

[43] (11 mg, 0.011 mmol) and chrysene trichloride (9.28 mg, 0.033 mmol) were dissolved in sodium acetate-acetic acid buffer (pH=4.5) (0.5 mL), and the reaction solution was stirred at 90 °C for 10 minutes. The reaction solution was directly prepared by Pre-HPLC.

[45] (9 mg, yield: 71.94%).

[0514] LC-MS (ESI): m / z = 1137.80 (M+H) +.

[0515] Example 46

[0516] Synthesis of Compound 46

[0517] Compound 40 (15 mg, 0.011 mmol) was dissolved in sodium acetate-acetic acid buffer (pH=4.5) (0.5 mL), and chalamine trichloride (5.98 mg, 0.021 mmol) was added. The reaction mixture was heated and stirred at 90 °C for 10 min. The reaction mixture was cooled to room temperature and directly purified by pre-HPLC to give 46 (5.5 mg, yield: 41.70%).

[0518] Example 47

[0519] compound Synthesis of [47-b]

[0520] At 0 °C, 2-methylpropyl-2-bromoacetate (3019.14 mg, 15.478 mmol) was dissolved in acetonitrile (40 mL). This solution was then added dropwise to a solution of 1,4,7-triazine (1000 mg, 7.739 mmol) dissolved in acetonitrile (10 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 24 hours. The mixture was then concentrated under reduced pressure and diluted with pure water (5 mL). The pH of the mixture was adjusted to 3 using 1 M hydrochloric acid. The mixture was extracted with methyl tributyl ether (15 mL × 3). The pH of the mixture was adjusted to 8 using 1 M sodium hydroxide solution, and then extracted with dichloromethane (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain... [47-b](1200 mg, yield: 43.37%).

[0521] compound Synthesis of [47-a]

[0522] compound [2-b] (140.53 mg, 0.20 mmol) and compounds [47-b] was dissolved in acetonitrile (1.0 mL), and potassium carbonate (55.28 mg, 0.400 mmol) was added. The reaction mixture was stirred overnight at 60 °C. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to column chromatography (dichloromethane:methanol = 5:1) to obtain... [47-a](153 mg, yield: 78.12%).

[0523] compound

[47] Synthesis

[0524] compound [47-a] (153 mg, 0.156 mmol) was dissolved in dichloromethane (2.5 mL), and trifluoroacetic acid (2.5 mL) was added. The reaction mixture was stirred overnight at room temperature. The solution was concentrated under reduced pressure and prepared by Pre-HPLC.

[47] (75 mg, yield: 59.19%).

[0525] Example 48

[0526] compound

[48] ​​Synthesis

[0527] Aluminum chloride (0.80 mg, 0.006 mmol) was dissolved in 0.60 mL of 0.2 M sodium acetate-acetic acid buffer (pH=4.5), and sodium fluoride (0.25 mg, 0.006 mmol) was added. The reaction solution was stirred at room temperature for 5 minutes. [The compound was then added.]

[47] (4.05 mg, 0.005 mmol), heated at 100 °C for 15 min, cooled to room temperature, and the reaction solution was directly purified by Pre-HPLC to obtain

[48] ​​(3.0 mg, yield: 70.26%).

[0528] Example 49

[0529] compound Synthesis of [49-d]

[0530] 4,4,5,5-Tetramethyl-2-[(1E)-2-(2-methyl-3-phenylphenyl)vinyl]-1,3,2-dioxoborane (960.7 mg, 3.0 mmol) and 4-bromo-2-hydroxy-5-methylbenzene-1-carboxaldehyde (645.1 mg, 3.00 mmol) were dissolved in dioxane (100.0 mL) and water (20.0 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (219.3 mg, 0.3 mmol) and potassium carbonate (1243.8 mg, 9.00 mmol) were added. The reaction mixture was heated and stirred at 90 °C for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain... [49-d] (950 mg, yield: 86.78%).

[0531] LC-MS (ESI): m / z = 329.1(M+Na) +.

[0532] compound Synthesis of [49-c]

[0533] compound [49-d] (620 mg, 2.89 mmol) and 1-bromo-2-[(2-bromoethyl)oxy]ethane (875.6 mg, 3.77 mmol) were dissolved in N,N-dimethylformamide (50 mL), and potassium carbonate (782.7 mg, 5.66 mmol) was added. The reaction mixture was stirred at 70 °C for 12 hours, cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in dichloromethane (100 mL). The residue was washed successively with water (50 mL × 2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain... [49-c](220mg, yield: 23.09%).

[0534] compound Synthesis of [49-b]

[0535] compound [49-c] (280.0 mg, 0.58 mmol) and compounds [2-e] (216.41 mg, 1.16 mmol) was dissolved in methanol (40 mL), and sodium cyanoborohydride (110.39 mg, 1.752 mmol) and acetic acid (35.0 mg, 0.584 mmol) were added. The reaction mixture was stirred at 60 °C for 6 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the concentrate was subjected to column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain... [49-b](280mg, yield: 70.21%).

[0536] LC-MS (ESI): m / z = 648.3(M+H) +.

[0537] compound Synthesis of [49-a]

[0538] compound [49-b] (380 mg, 0.586 mmol) and compounds [47-b] (418.8 mg, 1.172 mmol) was dissolved in acetonitrile (30.0 mL), and potassium carbonate (323.36 mg, 2.343 mmol) was added. The reaction mixture was stirred at 60 °C for 12 hours, cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in dichloromethane (100 mL). The residue was washed successively with water (50 mL × 2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain... [49-a] (320 mg, yield: 56.09%)

[0539] compound

[49] Synthesis

[0540] compound [49-a] (320 mg, 0.346 mmol) was dissolved in dichloromethane (20.0 mL), and trifluoroacetic acid (20 mL) was added. The reaction mixture was stirred at room temperature for 12 hours, concentrated under reduced pressure, and the residue was directly prepared by pre-HPLC.

[49] (52 mg, yield: 19.86%).

[0541] LC-MS (ESI): m / z = 757.5(M+H) +.

[0542] Example 50

[0543] compound

[50] Synthesis

[0544] Preparation of [AlF]2+ solution

[0545] Dissolve 100 mg of AlCl3 in 50 mL of 0.2 M AcONa / AcoH buffer and mix well. Add 50 mg of NaF and 40 mL of 0.2 M AcONa / AcoH buffer to a capped plastic centrifuge tube and mix well. Add 10.0 mL of the above AlCl3 solution to the plastic centrifuge tube, then add 5.0 mL of NaF solution and shake for 2 minutes.

[0546] compound

[49] (1.0 mg, 0.13 mmol) was dissolved in anhydrous ethanol (0.6 mL), and the [AlF]2+ solution prepared above (0.016 mmol, 1.6 mL) was added. The reaction solution was stirred at 100 °C for 30 minutes, cooled to room temperature, concentrated under reduced pressure, and the residue was directly prepared by pre-HPLC.

[50] (6.2 mg, yield: 58.6%).

[0547] LC-MS (ESI): m / z = 801.2 (M+H) +.

[0548] Example 51

[0549] compound Synthesis of [51-d]

[0550] Butane-1,4-diol (901.2 mg, 10.0 mmol) was dissolved in dichloromethane (50.0 mL), and pyridine (3160.0 mg, 40.0 mmol) was added. The reaction solution was cooled to 0 °C, and 4-methylbenzenesulfonyl chloride (5719.5 mg, 30.00 mmol) was added. The reaction solution was stirred overnight at room temperature, concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL), washed with water (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain... [51-d] (670 mg, yield: 16.8%).

[0551] LC-MS (ESI): m / z = 329.1(M+Na) +.

[0552] compound Synthesis of [51-c]

[0553] compound [49-d] (656.8 mg, 2.0 mmol) and compounds [51-d] (1594.0 mg, 4.0 mmol) was dissolved in N,N-dimethylformamide (50.0 mL), and potassium carbonate (1382.0 mg, 10.0 mmol) was added. The reaction mixture was heated and stirred at 50 °C for 6 hours, and then cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (100 mL), washed successively with water (50 mL × 2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain... [51-c] (610 mg, yield: 54.98%).

[0554] LC-MS (ESI): m / z = 555.2 (M+H) +.

[0555] compound Synthesis of [51-b]

[0556] compound [51-c] (554.7 mg, 1.0 mmol) and compounds [2-e] (555.8 mg, 3.0 mmol) was dissolved in methanol (40 mL), and sodium cyanoborohydride (126.0 mg, 2.0 mmol) and acetic acid (120.0 mg, 2.0 mmol) were added. The reaction mixture was heated and stirred at 60 °C for 6 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain... [51-b](370 mg, yield: 51.1%).

[0557] LC-MS (ESI): m / z = 724.6 (M+H) +.

[0558] compound Synthesis of [51-a]

[0559] compound [57-b] (370 mg, 0.511 mmol) and compounds [47-b] (365.4 mg, 1.02 mmol) was dissolved in acetonitrile (30.0 mL), and potassium carbonate (282.1 mg, 2.04 mmol) was added. The reaction solution was heated and stirred at 60 °C for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in dichloromethane (100 mL). The residue was washed successively with water (50 mL × 2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 10:1) to obtain... [51-a] (350 mg, yield: 75.32%).

[0560] LC-MS (ESI): m / z = 926.2 (M+H) +.

[0561] compound

[51] Synthesis

[0562] compound [51-a] (350 mg, 0.385 mmol) was dissolved in dichloromethane (20.0 mL), and trifluoroacetic acid (20 mL) was added. The reaction solution was stirred at room temperature for 12 hours, concentrated under reduced pressure, and the residue was directly prepared by pre-HPLC.

[51] (158 mg, yield: 55.4%).

[0563] LC-MS (ESI): m / z = 741.5 (M+H) +.

[0564] Example 52

[0565] compound

[52] Synthesis

[0566] compound

[51] (20 mmol, 0.027 mg) was dissolved in anhydrous ethanol (0.5 mL), and the [AlF]2+ solution (0.016 mmol, 1.6 mL) prepared in Example 50 was added. The reaction solution was stirred at 100 °C for 30 minutes, and then cooled to room temperature. The solution was then directly prepared by pre-HPLC.

[52] (15 mg, yield: 70.79%).

[0567] LC-MS (ESI): m / z = 785.2 (M+H) +.

[0568] Example 53

[0569] compound Synthesis of [53-c]

[0570] compound [49-d] (328.4 mg, 1.0 mmol) and 1,5-diiodopentane (647.8 mg, 2.0 mmol) were dissolved in N,N-dimethylformamide (20.0 mL), and potassium carbonate (414.6 mg, 3.0 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours, and water (60 mL) was added. The mixture was extracted with dichloromethane (150 mL), and the organic phases were combined and washed successively with water (50 mL × 2) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain... [53-c] (55 mg, yield: 9.96%).

[0571] LC-MS (ESI): m / z = 525.2(M+H) +.

[0572] compound Synthesis of [53-b]

[0573] compound [53-c] (340 mg, 0.648 mmol) and compounds [2-e] (240.23 mg, 1.297 mmol) was dissolved in methanol (40 mL), and sodium cyanoborohydride (81.69 mg, 1.29 mmol) and acetic acid (77.8 mg, 1.29 mmol) were added. The reaction mixture was heated and stirred at 60 °C for 5 hours, then cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain... [53-b](158 mg, yield: 55.4%).

[0574] LC-MS (ESI): m / z =694.8 (M+H) +.

[0575] compound Synthesis of [53-a]

[0576] compound [53-b] (230 mg, 0.332 mmol) and compounds [47-b] (237.0 mg, 0.663 mmol) was dissolved in acetonitrile (30.0 mL), and potassium carbonate (137.2 mg, 0.995 mol) was added. The reaction solution was heated and stirred at 65 °C for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in dichloromethane (100 mL). The residue was washed successively with water (50 mL × 2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain... [53-a] (230 mg, yield: 75.13%).

[0577] LC-MS (ESI): m / z =923.7 (M+H) +.

[0578] compound

[53] Synthesis

[0579] compound [53-a] (230 mg, 0.249 mmol) was dissolved in dichloromethane (20.0 mL), and trifluoroacetic acid (10.0 mL) was added. The reaction mixture was stirred at room temperature for 18 hours, and then concentrated under reduced pressure. The residue was directly prepared by pre-HPLC.

[53] (110.3 mg, yield: 58.65%).

[0580] LC-MS (ESI): m / z =755.7 (M+H) +.

[0581] Example 54

[0582] compound

[54] Synthesis

[0583] compound

[53] (0.033 mmol, 25.0 mg) was dissolved in anhydrous ethanol (0.5 mL), and the [AlF]2+ solution (0.016 mmol, 1.6 mL) prepared in Example 50 was added. The reaction solution was heated and stirred at 100 °C for 30 minutes. The reaction solution was then cooled to room temperature and directly prepared by pre-HPLC.

[54] (14.1 mg, yield: 53.29%).

[0584] LC-MS (ESI): m / z =800.6 (M+H) +.

[0585] Example 55

[0586] compound Synthesis of [55-c]

[0587] compound [49-d] (328.41 mg, 1.0 mmol) and 1,6-diiodohexane (675.94 mg, 2.0 mmol) were dissolved in N,N-dimethylformamide (30.0 mL), and potassium carbonate (414.60 mg, 3.0 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours, concentrated under reduced pressure, and the residue was dissolved in dichloromethane (100 mL). The residue was washed successively with water (50 mL × 2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 10, 1) to obtain... [55-c] (380 mg, yield: 67.04%).

[0588] LC-MS (ESI): m / z =539.2 (M+H) +.

[0589] compound Synthesis of [55-b]

[0590] compound [55-c] (340 mg, 0.631 mmol) and compounds [2-e] (240.0 mg, 1.263 mmol) was dissolved in methanol (40 mL), and sodium cyanoborohydride (79.56 mg, 1.26 mmol) and acetic acid (75.8 mg, 1.26 mmol) were added. The reaction mixture was heated and stirred at 60 °C for 5 hours, cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain... [55-b] (230 mg, yield: 51.47%).

[0591] LC-MS (ESI): m / z =709.8 (M+H) +.

[0592] compound Synthesis of [55-a]

[0593] compound [55-b] (380 mg, 0.586 mmol) and compounds [47-b] (418.8 mg, 1.172 mmol) was dissolved in acetonitrile (30.0 mL), and potassium carbonate (323.36 mg, 2.343 mmol) was added. The reaction solution was heated and stirred at 60 °C for 12 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), washed successively with water (50 mL × 2) and saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain... [55-a] (180 mg, yield: 61.78%).

[0594] LC-MS (ESI): m / z =926.2 (M+H) +.

[0595] compound

[55] Synthesis

[0596] compound [55-a] (220 mg, 0.235 mmol) was dissolved in dichloromethane (20.0 mL), and trifluoroacetic acid (10.0 mL) was added. The reaction solution was stirred at room temperature for 12 hours, concentrated under reduced pressure, and the residue was directly prepared by pre-HPLC.

[55] (160 mg, yield: 88.65%).

[0597] LC-MS (ESI): m / z =769.6 (M+H) +.

[0598] Example 56

[0599] compound

[56] Synthesis

[0600] compound

[55] (0.039 mmol, 6.0 mg) was dissolved in anhydrous ethanol (1.0 mL), and the [AlF]2+ solution (0.05 mmol, 5.0 mL) prepared in Example 50 was added. The reaction solution was heated and stirred at 100 °C for 30 minutes, and then cooled to room temperature. The solution was then directly prepared by pre-HPLC.

[56] (6 mg, yield: 18.92%).

[0601] LC-MS (ESI): m / z =814.6 (M+H) +.

[0602] Example 57

[0603] compound Synthesis of [57-b]

[0604] compound [42-d] (195 mg, 0.346 mmol) and 1,5-diiodopentane (224.15 mg, 0.692 mmol) were dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (239.09 mg, 1.730 mmol) was added. The reaction mixture was stirred at 60 °C for 1 hour, cooled to room temperature, and extracted with ethyl acetate (10 mL). The mixture was washed successively with water (10 mL × 3) and saturated brine (10 mL × 1). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain... [57-b](211 mg, yield: 80.49%).

[0605] compound Synthesis of [57-a]

[0606] compound [57-b] (211 mg, 0.278 mmol) and compounds [47-b] was dissolved in acetonitrile (10 mL), and potassium carbonate (76.98 mg, 0.557 mmol) was added. The reaction mixture was stirred overnight at 60 °C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL), washed successively with water (10 mL × 3) and saturated brine (10 mL × 1), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain... [57-a] (242 mg, yield: 87.85%).

[0607] compound

[57] Synthesis

[0608] compound [57-a] (242 mg, 0.245 mmol) was dissolved in dichloromethane (9 mL), and trifluoroacetic acid (9 mL, 1.223 mmol) was added. The reaction solution was stirred at room temperature for 30 minutes, and then concentrated under reduced pressure. The residue was prepared by prep-HPLC.

[57] (93.61 mg, yield: 46.61%).

[0609] Example 58

[0610] compound

[58] Synthesis

[0611] compound

[57] (20 mg, 0.024 mmol) was dissolved in ethanol (0.50 mL), and 0.2 M sodium acetate-acetic acid buffer (pH=4.6) (1.0 mL), aluminum chloride (2 mg, 0.029 mmol) and sodium fluoride (1 mg, 0.029 mmol) were added. The reaction solution was stirred at 100 °C for 30 minutes, cooled to room temperature, concentrated under reduced pressure, and the residue was prepared by prep-HPLC.

[58] (11.68 mg, yield: 55.43%).

[0612] Example 59

[0613] compound Synthesis of [59-b]

[0614] compound [47-b] (715.00 mg, 2.0 mmol) and potassium carbonate (552.84 mg, 4.00 mmol) were dissolved in methanol (10 mL) and water (10 mL), and bromoacetic acid (383.48 mg, 2.76 mmol) was added. The reaction mixture was stirred overnight at room temperature, and the pH was adjusted to 6 with hydrochloric acid (1 mol / L). The reaction mixture was extracted with dichloromethane (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain... [59-b](610 mg, yield: 73.40%).

[0615] compound Synthesis of [59-a]

[0616] compound [42-b] (115 mg, 0.174 mmol) was dissolved in N,N-dimethylformamide (5 mL) and added... [59-b] (86.78 mg, 0.209 mmol), O-benzotriazole-tetramethylurea hexafluorophosphate (85.80 mg, 0.226 mmol), and diisopropylethylamine (0.058 mL, 0.348 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate (10 mL), washed successively with water (10 mL × 3) and saturated brine (10 mL × 1), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain... [59-a](45.66 mg, yield: 24.79%).

[0617] compound

[59] Synthesis

[0618] compound [59-a] (45.66 mg, 0.043 mmol) was dissolved in dichloromethane (9 mL), and trifluoroacetic acid (9 mL, 1.223 mmol) was added. The reaction solution was stirred at room temperature for 30 minutes, and then concentrated under reduced pressure. The solution was directly prepared by prep-HPLC.

[59] (22.57 mg, yield: 58.78%).

[0619] LC-MS (ESI): m / z =890 (M+H) +.

[0620] Example 60

[0621] compound Synthesis of

[60]

[0622] compound

[59] (5 mg, 0.006 mmol) was dissolved in 0.2 M sodium acetate-acetic acid buffer (pH=4.6) (1.0 mL), and aluminum chloride AlCl3 (0.6 mL, 0.002 mmol) and sodium fluoride (0.3 mL, 0.002 mmol) were added. The reaction solution was stirred at 100 °C for 30 minutes. The reaction solution was cooled to room temperature and directly prepared by prep-HPLC.

[60] (1.96 mg, yield: 37.33%) [。]

[0623] LC-MS (ESI): m / z =934 (M+H) +.

[0624] Example 61

[0625] compound Synthesis of [61-a]

[0626] compound [4-b] (124.5 mg, 0.20 mmol) and compounds [59-b] (108.0 mg, 0.26 mmol) was dissolved in N,N-dimethylformamide (15.0 mL), and O-benzotriazole-tetramethylurea hexafluorophosphate (113.7 mg, 0.30 mmol) and diisopropylethylamine (77.4 mg, 0.60 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours, diluted with dichloromethane (100 mL), washed successively with water (50 mL × 3) and saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 10:1) to obtain... [61-a] (60 mg, yield: 29.81%) [。]

[0627] LC-MS (ESI): m / z =1020.7 (M+H) +.

[0628] compound

[61] Synthesis

[0629] compound [61-a] (60 mg, 0.059 mmol) was dissolved in dichloromethane (12.0 mL), and trifluoroacetic acid (6.0 mL) was added. The reaction solution was stirred at room temperature for 6 hours, concentrated under reduced pressure, and the residue was directly prepared by pre-HPLC.

[61] (15 mg, yield: 29.94%) [。]

[0630] LC-MS (ESI): m / z =852.8 (M+H) +.

[0631] Example 62

[0632] compound

[62] Synthesis

[0633] compound

[61] (0.008 mmol, 7.0 mg) was dissolved in anhydrous ethanol (1.0 mL), and the [AlF]2+ solution (0.016 mmol, 1.6 mL) prepared in Example 50 was added. The reaction solution was heated and stirred at 100 °C for 2 hours. The reaction solution was then cooled to room temperature and directly prepared by pre-HPLC.

[62] (1.6 mg, yield: 21.74%) [。]

[0634] LC-MS (ESI): m / z =897.4 (M+H) +.

[0635] Example 63

[0636] compound Synthesis of [63-c]

[0637] compound [2-c] (551.65 mg, 1.0 mmol) and 1,3-dibromopropane (0.305 mL, 3.00 mmol) were dissolved in DMF (5.0 mL), and potassium carbonate (276.42 mg, 2.00 mmol) was added. The reaction mixture was heated and stirred at 50 °C for 7 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed successively with water (20 mL × 2) and saturated brine (20 mL × 1). The combined phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain... [63-c] (461 mg, yield: 68.54%).

[0638] compound Synthesis of [63-b]

[0639] compound [63-c] (461 mg, 0.807 mmol) and ammonia-methanol solution (7 M) (23 mL) were sealed in a microwave tube. The reaction solution was heated and stirred at 50 °C for 60 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and washed with 10% K₂CO₃ solution (10 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain... [63-b] (409 mg, yield: 99.89%) can be used directly in the next reaction without purification.

[0640] compound Synthesis of [63-a]

[0641] compound [63-b] (121.7 mg, 0.20 mmol) and compounds [59-b] (108.0 mg, 0.26 mmol) was dissolved in N,N-dimethylformamide (15.0 mL), and O-benzotriazole-tetramethylurea hexafluorophosphate (113.7 mg, 0.30 mmol) and diisopropylethylamine (77.4 mg, 0.60 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours, diluted with dichloromethane (100 mL), washed successively with water (50 mL × 3) and saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (dichloromethane:methanol = 10:1) to obtain... [63-a] (90 mg, yield: 44.72%).

[0642] LC-MS (ESI): m / z =1006.7 (M+H) +.

[0643] compound

[63] Synthesis

[0644] compound [63-a] (90 mg, 0.089 mmol) was dissolved in dichloromethane (20.0 mL), and trifluoroacetic acid (10.0 mL) was added. The reaction mixture was stirred at room temperature for 12 hours, concentrated under reduced pressure, and the residue was directly prepared by pre-HPLC.

[63] (25 mg, yield: 33.36%).

[0645] LC-MS (ESI): m / z =838.4 (M+H) +.

[0646] Example 64

[0647] compound

[64] Synthesis

[0648] compound

[63] (0.008 mmol, 7.0 mg) was dissolved in anhydrous ethanol (1.0 mL), and the [AlF]2+ solution prepared in Example 50 (0.016 mmol, 1.6 mL) was added. The reaction solution was heated and stirred at 100 °C for 2 hours. The reaction solution was then cooled to room temperature and directly prepared by pre-HPLC.

[64] (6.67 mg, yield: 70.42%).

[0649] LC-MS (ESI): m / z =883.4 (M+H) +.

[0650] Example 65

[0651] compound Synthesis of [65-a]

[0652] compound [16-c] (252 mg, 0.337 mmol) and compounds [47-b] (156.64 mg, 0.438 mmol) was dissolved in acetonitrile (3.0 mL), and potassium carbonate (72 mg, 0.521 mmol) was added. The reaction solution was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain... [65-a] (190 mg, yield: 57.68%).

[0653] compound

[65] Synthesis

[0654] compound [65-a] (190 mg, 0.194 mmol) was dissolved in dichloromethane (3.0 mL), and trifluoroacetic acid (3.0 mL) was added. The reaction solution was stirred overnight at room temperature, and then concentrated under reduced pressure. The solution was then directly prepared by Pre-HPLC.

[65] (74 mg, yield: 47.05%).

[0655] LC-MS (ESI): m / z =809.5(M+H) +.

[0656] 1H NMR (400 MHz, MeOD) δ 7.90 (s, 1H), 7.62 (d, J= 15.9 Hz, 1H), 7.57 – 7.49 (m, 2H), 7.46 – 7.38 (m, 2H), 7.38 – 7.23 (m, 5H), 7.18 (d, J= 7.5 Hz, 1H), 4.59 (d, J= 13.0 Hz, 1H), 4.42 (d, J= 13.0 Hz, 1H), 4.32 (t, J= 6.3 Hz, 2H), 3.59 (dd, J= 9.9, 3.6 Hz, 1H), 3.56 – 3.35 (m, 5H), 3.24 – 2.78 (m, 15H), 2.30 (s, 3H), 2.28 – 2.16 (m, 1H), 2.06 – 1.67 (m, 8H), 1.67 – 1.51 (m, 3H).

[0657] Example 66

[0658] compound Synthesis of

[66]

[0659] Aluminum chloride (1.60 mg, 0.012 mmol) was dissolved in 0.2 M sodium acetate-acetic acid buffer (pH=4.6) (0.8 mL), and sodium fluoride (0.50 mg, 0.012 mmol) was added. The reaction solution was stirred at room temperature for 5 minutes. Ethanol (0.60 mL) and the compound were then added.

[65] (8.09 mg, 0.01 mmol), the reaction solution was heated at 100 °C for 30 minutes, cooled to room temperature, and directly purified by Pre-HPLC to obtain

[66] (4.6 mg, yield: 53.93%).

[0660] Example 67

[0661] compound Synthesis of [67-a]

[0662] compound [19-b] (64.88 mg, 0.1 mmol), compound [59-b] (54.02 mg, 0.130 mmol) and O-benzotriazole-tetramethylurea hexafluorophosphate (75.85 mg, 0.200 mmol) were dissolved in N,N-dimethylformamide (1.0 mL), and diisopropylethylamine (0.050 mL, 0.30 mmol) was added. The reaction solution was stirred at room temperature for 1 hour, and the reaction solution was directly purified by Pre-HPLC to obtain... [67-a] (58 mg, yield: 55.43%).

[0663] compound

[67] Synthesis

[0664] compound [67-a] (58 mg, 0.055 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The reaction solution was stirred at room temperature for 24 hours. The reaction solution was then directly purified by Pre-HPLC to obtain...

[67] (25 mg, yield: 41.10%).

[0665] 1H NMR (400 MHz, MeOD) δ:7.94 (s, 1H), 7.62 (d, J= 15.8Hz, 1H), 7.54 (t, J= 3.4 Hz, 2H), 7.47–7.39 (m, 2H), 7.39–7.23 (m, 5H), 7.18 (d, J= 7.5 Hz, 1H), 4.63–4.49 (m, 2H), 4.40 (d, J= 13.3 Hz, 1H), 4.16 (d, J= 6.3 Hz, 2H), 3.95 (d, J= 12.7 Hz, 1H), 3.84–3.53 (m, 7H), 3.44–3.33 (m, 1H), 3.26–2.61 (m, 15H), 2.30 (s, 3H), 2.29–2.17 (m, 2H), 2.06–1.49 (m, 7H), 1.49–1.23 (m, 2H).

[0666] Example 68

[0667] compound

[68] Synthesis

[0668] Aluminum chloride (1.60 mg, 0.012 mmol) was dissolved in 0.2 M sodium acetate-acetic acid buffer (pH=4.6) (0.8 mL), and sodium fluoride (0.50 mg, 0.012 mmol) was added. The reaction solution was stirred at room temperature for 5 minutes. Ethanol (0.60 mL) and the compound were then added.

[67] (8.78 mg, 0.01 mmol), the reaction solution was heated at 100 °C for 30 minutes, cooled to room temperature, and directly purified by Pre-HPLC to obtain

[68] (4.74 mg, yield: 51.41%).

[0669] Example 69

[0670] compound Synthesis of [69-a]

[0671] 2-Methylpropyl-2-yl(2R)-1-{[2-({2-[(2-bromoethyl)oxy]ethyl}oxy)-4-[(1E)-2-(2-methyl-3-phenylphenyl)vinyl]-5-(trifluoromethyl)phenyl]methyl}hexahydropyridine-2-carboxylate (140.53 mg, 0.2 mmol) and compound 2,2',2''-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate tributyl ester (154.41 mg, 0.300 mmol) were dissolved in acetonitrile (5.0 mL), and potassium carbonate (55.28 mg, 0.400 mmol) was added. The reaction mixture was heated and stirred at 60 °C for 16 hours. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain... [69-a] (226 mg, yield: 99.43%) can be used directly in the next reaction without purification.

[0672] compound

[69] Synthesis

[0673] compound [69-a] (226 mg, 0.199 mmol) was dissolved in dichloromethane (3.0 mL), and trifluoroacetic acid (3.0 mL) was added. The reaction mixture was stirred overnight at room temperature, and the solution was directly prepared by Pre-HPLC.

[69] (127 mg, yield: 70.02%).

[0674] Example 70

[0675] compound

[70] Synthesis

[0676] compound

[69] (13.68 mg, 0.015 mmol) and chrysene trichloride (8.44 mg, 0.030 mmol) were dissolved in 0.2 M AcONa / AcOH pH 4.5 buffer (1.0 mL), and the reaction solution was stirred at room temperature for 1 h. The solution was then directly purified by prep-HPLC to obtain...

[70] (9.77 mg, yield: 60.09%).

[0677] LC-MS (ESI): m / z =1084.68(M+H) +.

[0678] Example 71

[0679] compound Synthesis of [71-a]

[0680] compound [53-b] (180 mg, 0.259 mmol) and tert-butyl 2,2',2''-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (237.0 mg, 0.519 mmol) were dissolved in acetonitrile (30.0 mL), and potassium carbonate (35.81 mg, 0.259 mmol) was added. The reaction mixture was heated and stirred at 60 °C for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in dichloromethane (100 mL). The residue was washed successively with water (50 mL × 2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain... [71-a](230 mg, yield: 75.13%).

[0681] LC-MS (ESI): m / z =1080.5 (M+H) +.

[0682] compound

[71] Synthesis

[0683] compound [71-a] (170 mg, 0.157 mmol) was dissolved in dichloromethane (15.0 mL), and trifluoroacetic acid (15.0 mL) was added. The reaction mixture was stirred at room temperature for 16 hours, concentrated under reduced pressure, and the residue was directly prepared by pre-HPLC.

[71] (85.7 mg, yield: 63.6%).

[0684] LC-MS (ESI): m / z = 856.0(M+H) +.

[0685] Example 72

[0686] compound

[71] (13.68 mg, 0.015 mmol) and chalamine trichloride (8.44 mg, 0.030 mmol) were dissolved in 0.2 M AcONa / AcOH pH 4.5 buffer (1.0 mL), and the reaction solution was stirred at room temperature for 1 h. The solution was then purified directly by prep-HPLC.

[72] (9.60 mg, yield: 53.3%).

[0687] LC-MS (ESI): m / z =1028.02(M+H) +.

[0688] Example 73

[0689] compound

[71] 11.0 mg (0.013 mmol) and gallium trichloride (1.76 mg, 0.010 mmol) were added to water (0.2 mL), and the reaction solution was heated and stirred at 90 °C for 5 minutes. The reaction solution was cooled to room temperature, and the reaction solution was directly prepared by Pre-HPLC.

[73] (11.1 mg, yield: 92.5%).

[0690] LC-MS (ESI): m / z =922.77(M+H) +.

[0691] Example 74

[0692] compound

[74] Synthesis

[0693] compound [4] Dissolve the compound in DMSO to a concentration of 10 mg / mL. Take a portion of the solution and dilute it to 0.1 mg / mL with metal-free sodium acetate buffer (pH 5.5). Rinse the germanium-gallium generator in fractions with 5 mL of 0.1 M HCl. Take the fraction with the highest activity (0.5 mL), add 0.5 mL of sodium acetate buffer, and then add 20 equivalents of the compound. [4] (0.1 mg / mL), vortex for 10 s, heat and shake at 95℃ and 800 rpm for 30 min. After activation with ethanol, the C18 column was rinsed with pure water and dried. The solution after the reaction was completed was passed through the C18 column, rinsed with pure water and dried, and then rinsed with ethanol. The purity was determined by TLC using 1% EDTA as the developing solvent. The radiochemical purity of compound 4 labeled with 68Ga was 99.67% by TLC scanning.

[0694] Appropriate amounts of 68Ga-labeled compounds 4 and 8 were characterized by HPLC under the following conditions: Mobile phase A: 0.1% TFA-H₂O; Mobile phase B: ACN; Chromatographic column: Waters XBridge, 19 * 150 mm, 5 μm; Flow rate: 1 mL / min; Method and time: 0 min 25% B, 10 min 95% B.

[0695] HPLC characterization showed that the UV peak time of compound 8 and the emitting peak time of 68Ga-labeled compound 4 were both around 7:07 (mm:ss), indicating that 68Ga successfully labeled compound 4 (i.e., compound 74), which is consistent with the TLC scan results.

[0696] Example 75

[0697] compound

[75] Synthesis

[0698] compound [2] Dissolve the compound in DMSO to a concentration of 10 mg / mL. Take a portion of the solution and dilute it to 0.1 mg / mL with metal-free sodium acetate buffer (pH 5.5). Rinse the germanium-gallium generator in fractions with 5 mL of 0.1 M HCl. Take the fraction with the highest activity (0.5 mL), add 0.5 mL of sodium acetate buffer, and then add 20 equivalents of the compound. [2] (0.1 mg / mL), vortex for 10 s, heat and shake at 95℃ and 800 rpm for 30 min. The C18 column was activated with ethanol, rinsed thoroughly with pure water and dried. The solution after the reaction was completed was passed through the C18 column, rinsed with pure water and dried, and then washed with ethanol. Compounds labeled with 68Ga [2] Its radiochemical purity was 99.74% as determined by TLC scanning.

[0699] Appropriate amounts of 68Ga-labeled compounds 2 and 7 were characterized by HPLC under the following conditions: Mobile phase A: 0.1% TFA-H₂O; Mobile phase B: ACN; Chromatographic column: Waters XBridge, 19 * 150 mm, 5 μm; Flow rate: 1 mL / min; Method and time: 0 min 25% B, 10 min 95% B.

[0700] HPLC characterization showed that the UV peak time of compound 7 and the ELECTRIC peak time of 68Ga-labeled compound 2 were both around 7:03 (mm:ss), indicating that 68Ga successfully labeled compound 2 (i.e., compound 75), which is consistent with the TLC scan results.

[0701] Example 76

[0702] compound

[76] Synthesis

[0703] compound [1] Dissolve the compound in DMSO to a concentration of 10 mg / mL. Take a portion of the solution and dilute it to 0.1 mg / mL with metal-free sodium acetate buffer at pH 5.5. Open the metal bath reactor and preheat it to 25°C. Take 1 mCi (approximately 50 pmol) of 177LuCl3 solution and add 20 equivalents of the compound. [1] Solution, add sodium acetate buffer to 50 μL, react at 25℃, 800 rpm for 120 min. TLC purity was determined using 1% EDTA as the developing solvent. Compound labeled with 177Lu [1] Its radiochemical purity reached 96.90% as detected by TLC scanning.

[0704] Appropriate amounts of compound 15 and 177Lu-labeled compound 1 were characterized by HPLC under the following conditions: Mobile phase A: 0.1% TFA-water; Mobile phase B: Acetonitrile; Method: 25% B-95% B, 10 min, UV 214 nm; Flow rate: 1 mL / min; Column: Velch Xtimate C18, 4.6 * 150 mm, 5 μm.

[0705] Compound 1 labeled with 175Lu was characterized by HPLC, and its elution time was confirmed to be 5.731 min.

[0706] The amount of 177Lu-labeled compound 1 was so low that it could not be detected by ultraviolet light. Therefore, one tube of mobile phase was collected every 0.5 min for a total of 20 tubes. The radioactivity count of each tube of mobile phase was detected, and a radioactivity count-time curve was plotted and compared with the HPLC of compound 15. It was found that the elution time of 177Lu-labeled compound 1 was consistent with that of compound 15, indicating that 177Lu-labeled compound 1 (i.e., compound 76) was successfully prepared. Time / min 0-0.5 0.5-1 1-1.5 1.5-2 2-2.5 0.5-3 3-3.5 3.5-4 4-4.5 4.5-5 Radioactivity count 80 123 253 199 156 177 85 101 139 192 Time / min 5-5.5 5.5-6 6-6.5 6.5-7 7-7.5 7.5-8 8-8.5 8.5-9 9-9.5 9.5-10 Radioactivity count 2091 33721 3054 868 879 407 349 413 421 123

[0707] Example 77

[0708] Synthesis of Compound 77

[0709] compound [2] Dissolve the compound in DMSO to a concentration of 10 mg / mL. Take a portion of the solution and dilute it to 0.1 mg / mL with metal-free sodium acetate buffer at pH 5.5. Open the metal bath reactor and preheat it to 95°C. Take 1 mCi (approximately 50 pmol) of 177LuCl3 solution and add 20 equivalents of the compound. [2] Solution, add sodium acetate buffer to 50 μL, react at 95℃ and 800 rpm for 30 min. TLC purity was determined using 1% EDTA as the developing solvent. The 177Lu-labeled compound... [2] The radiochemical purity was 100% as detected by TLC scanning, which meets the requirements for animal administration and does not require further purification.

[0710] Take appropriate amounts of compound 6 and compound 2 labeled with 177Lu, and characterize them by HPLC under the following conditions: Mobile phase A: 0.1% TFA-water; Mobile phase B: Acetonitrile; Method: 25% B-95% B, 10 min, UV 214 nm; Flow rate: 1 mL / min; Column: Velch Xtimate C18, 4.6 * 150 mm, 5 μm.

[0711] Compound 2 labeled with 175Lu was characterized by HPLC, and its elution time was confirmed to be 6.457 min.

[0712] The amount of 177Lu-labeled compound 2 was so low that it could not be detected by ultraviolet light. Therefore, one tube of mobile phase was collected every 0.5 min for a total of 20 tubes. The radioactivity count of each tube of mobile phase was detected, and a radioactivity count-time curve was plotted and compared with the HPLC of 175Lu-labeled compound 2. It was found that the elution time of 177Lu-labeled compound 2 was consistent with that of compound 6, indicating that 177Lu-labeled compound 2 (i.e., compound 77) was successfully prepared. Time / min 0-0.5 0.5-1 1-1.5 1.5-2 2-2.5 0.5-3 3-3.5 3.5-4 4-4.5 4.5-5 Radioactivity count 67 70 55 177 82 65 106 58 58 51 Time / min 5-5.5 5.5-6 6-6.5 6.5-7 7-7.5 7.5-8 8-8.5 8.5-9 9-9.5 9.5-10 Radioactivity count 92 134 25596 22183 1146 63 55 60 116 105

[0713] Example 78

[0714] Synthesis of Compound 78

[0715] compound [4] Dissolve the compound in DMSO to a concentration of 10 mg / mL. Take a portion of the solution and dilute it to 0.1 mg / mL with metal-free sodium acetate buffer at pH 5.5. Open the metal bath reactor and preheat it to 95°C. Take 1 mCi (approximately 50 pmol) of 177LuCl3 solution and add 20 equivalents of the compound. [4], add sodium acetate buffer to 50 μL, react at 95℃ and 800 rpm for 30 min. TLC purity was determined using 1% EDTA as the developing solvent. The 177Lu-labeled compound... [4] The radiochemical purity was 100% as detected by TLC scanning, which meets the requirements for animal administration and does not require further purification.

[0716] Take appropriate amounts of compound 5 and 177Lu-labeled compound 4, and perform HPLC characterization under the following conditions: Mobile phase A: 0.1% TFA-water; Mobile phase B: Acetonitrile; Method: 25% B-95% B, 10 min, UV 214 nm; Flow rate: 1 mL / min; Column: Velch Xtimate C18, 4.6 * 150 mm, 5 μm.

[0717] Compound 4, labeled with 175Lu, was characterized by HPLC, and its elution time was confirmed to be 6.690 min.

[0718] The amount of 177Lu-labeled compound 4 was so low that it could not be detected by ultraviolet light. Therefore, one tube of mobile phase was collected every 0.5 min for a total of 20 tubes. The radioactivity count of each tube of mobile phase was detected, and a radioactivity count-time curve was plotted and compared with the HPLC of compound 5. It was found that the elution time of 177Lu-labeled compound 4 was consistent with that of compound 5, indicating that 177Lu-labeled compound 4 (i.e., compound 78) was successfully prepared. Time / min 0-0.5 0.5-1 1-1.5 1.5-2 2-2.5 0.5-3 3-3.5 3.5-4 4-4.5 4.5-5 Radioactivity count 70 46 59 74 80 203 92 95 296 240 Time / min 5-5.5 5.5-6 6-6.5 6.5-7 7-7.5 7.5-8 8-8.5 8.5-9 9-9.5 9.5-10 Radioactivity count 199 479 1399 27203 5134 129 115 109 86 96

[0719] Example 79

[0720] Buffer system: Sodium acetate-acetic acid buffer solution (freshly prepared) with a pH of around 4.0 and a concentration of 0.5 M.

[0721] QMA column activation: 5 mL water, 5 mL freshly prepared sodium acetate-acetic acid buffer solution with a pH of approximately 4.0 and a concentration of 0.5 M.

[0722] F-18 ion purification: Target water was passed through a QMA column and washed sequentially with 0.3 mL of buffer.

[0723] Precursor solution: 100 μL buffer, 6 μL 10 mM AlCl3 buffer solution, 300 μL acetonitrile (reaction-promoting solvent), 20 μL precursor solution (3 mg / mL).

[0724] Mix the precursor solution thoroughly and allow it to stand for 5 minutes to equilibrate.

[0725] Add 300 μL of QMA column eluent containing F-18 to the reaction solution.

[0726] Seal the plastic centrifuge tubes and heat them for 15 minutes at a temperature of 100°C.

[0727] C18 Light column purification: Dilute the reaction solution with 5 mL of water, then load the sample onto a C18 Light column and elute the product with 1 mL of 50% (v / v) ethanol-water solution. Analyze the eluent using HPLC.

[0728] Chromatographic conditions are as follows chromatographic column Phenomenex, Luna 5 μm C18(2) 110 Å, 150 x 4.60 mm Detection wavelength 300 nm Flow rate 1 mL / min mobile phase Time / min Acetonitrile 0.1% TFA aqueous solution 0 40 60 3 70 30 10 70 30 12 40 60 15 40 60

[0729] Quality control analysis of compound 79

[0730] The radiochemical purity of compound 79 is 95.28%.

[0731] Example 80

[0732] Buffer system: Sodium acetate-acetic acid buffer solution (freshly prepared) with a pH of around 4.0 and a concentration of 0.5 M.

[0733] Compound 67 was dissolved in a buffer solution, and 300 μL of 68Ga 3+ solution was added. The plastic centrifuge tube was sealed and heated for 15 min at 100 °C.

[0734] C18 Light column purification: The reaction solution was diluted with 5 mL of water and then loaded onto a C18 Light column. The product was eluted with 1 mL of 50% (v / v) ethanol-water solution to obtain compound 80.

[0735] Example 81

[0736] compound Synthesis of [81-h]

[0737] Methyl 4-methoxypyridinecarboxylate (5000 mg, 29.94 mmol) was added to concentrated sulfuric acid (100 mL). N-bromosuccinimide (7993.98 mg, 44.91 mmol) was added in portions at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The mixture was then cooled to 0°C and slowly added to ice water (1.0 L). The pH was adjusted to 7-9 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (1.0 L), and the organic phase was collected. The organic phase was washed successively with water (500 mL × 3) and saturated brine (500 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain... [81-h](7 g, yield: 95.04%).

[0738] LC-MS (ESI): m / z =248.3(M+H) +.

[0739] compound Synthesis of [81-g]

[0740] compound [81-h] (7.0 g, 28.448 mmol) and potassium trifluoro(vinyl)borate (5675.45 mg, 42.673 mmol) were dissolved in dioxane (60.0 mL) and water (6.0 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (2081.57 mg, 2.845 mmol) and potassium carbonate (11795.5 mg, 85.3 mmol) were added. The reaction mixture was heated and stirred at 90 °C for 16 hours. The mixture was then cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain... [81-g] (3.4 g, yield: 61.86%).

[0741] LC-MS (ESI): m / z =194.22(M+H) +.

[0742] compound Synthesis of [81-f]

[0743] compound [81-g] (966.0 mg, 5.0 mmol) and 3-bromo-2-methylphenyl-1-amine (1023.2 mg, 5.50 mmol) were dissolved in tetrahydrofuran (30 mL). The reaction solution was cooled to 0 °C, and sodium di(trimethylsilyl)amino (6.5 mL, 1.0 M) was added dropwise to the reaction solution. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour. The reaction was quenched by slowly adding ammonium chloride aqueous solution (100 mL). The mixture was extracted with ethyl acetate (150 mL), and the organic phase was collected. The organic phase was washed successively with water (100 mL × 3) and saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain... [81-f](1.4 g, yield: 80.64%).

[0744] LC-MS (ESI): m / z =349.3(M+H) +.

[0745] compound Synthesis of [81-e]

[0746] compound [81-f] (850 mg, 2.448 mmol) and potassium osmium tetroxide (90.09 mg, 0.245 mmol) were dissolved in dioxane (60 mL) and water (20 mL). Sodium periodate (1570.86 mg, 7.344 mmol) was added in portions. After the addition was complete, the reaction solution was stirred at room temperature for 6 hours. The reaction solution was filtered, and the filter cake was washed with dioxane (50 mL). The filter cake was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain... [81-e](360 mg, yield: 42.11%).

[0747] LC-MS (ESI): m / z =351.2(M+H) +.

[0748] compound Synthesis of [81-d]

[0749] compound [81-e] (360 mg, 1.03 mmol) and compounds [2-e] (382.02 mg, 2.06 mmol) was dissolved in methanol (60.0 mL), and sodium cyanoborohydride (129.91 mg, 2.06 mmol) and acetic acid (129.90 mg, 2.16 mmol) were added. The reaction mixture was heated and stirred at 60 °C for 6 hours. The reaction mixture was then cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain... [81-d] (280 mg, yield: 52.38%).

[0750] LC-MS (ESI): m / z =520.3(M+H) +.

[0751] compound Synthesis of [81-c]

[0752] compound [81-d] (280.0 mg, 0.54 mmol) and compounds [40-d] (487.2 mg, 0.81 mmol) was dissolved in dioxane (50.0 mL) and water (5.0 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (39.52 mg, 0.054 mmol) and potassium carbonate (223.9 mg, 1.62 mmol) were added. The reaction mixture was heated and stirred at 110 °C for 12 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain... [81-c](210 mg, yield: 38.46%).

[0753] LC-MS (ESI): m / z =913.53 (M+H) +.

[0754] compound Synthesis of [81-b]

[0755] compound [81-c] (198 mg, 0.217 mmol) and 1-bromo-2-[(2-bromoethyl)oxy]ethane (150.8 mg, 0.651 mmol) were dissolved in N,N-dimethylformamide (50.0 mL), and potassium carbonate (89.77 mg, 0.651 mmol) was added. The reaction mixture was heated and stirred at 80 °C for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dioxane (60 mL), washed successively with water (40 mL × 3) and saturated brine (40 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain... [81-b](70 mg, yield: 28.6%).

[0756] LC-MS (ESI): m / z =1065.14(M+H) +.

[0757] compound Synthesis of [81-a]

[0758] compound [81-b] (70 mg, 0.066 mmol) and compounds [47-b] (47.07 mg, 0.132 mmol) was dissolved in acetonitrile (10.0 mL), and potassium carbonate (36.37 mg, 0.263 mmol) was added. The reaction solution was heated and stirred at 60 °C for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to column chromatography (dichloromethane:methanol = 10:1) to obtain... [81-a] (80 mg, yield: 90.7%).

[0759] LC-MS (ESI): m / z =1341.0(M+H) +.

[0760] compound

[81] Synthesis

[0761] compound [81-a] (80 mg, 0.060 mmol) was dissolved in dichloromethane (10.0 mL), and trifluoroacetic acid (5.0 mL) was added. The reaction solution was stirred at room temperature for 6 hours, concentrated under reduced pressure, and the residue was directly prepared by pre-HPLC.

[81] (28 mg, yield: 42.04%).

[0762] LC-MS (ESI): m / z =1116.64(M+H) +.

[0763] Example 82

[0764] compound

[82] Synthesis

[0765] compound

[81] (8.0 mg, 0.007 mmol) was dissolved in ethanol (0.5 mL), and [AlF]2+ solution (0.016 mmol, 1.6 mL) was added. The reaction solution was stirred at 100 °C for 1 hour, and then cooled to room temperature. The solution was directly prepared by pre-HPLC.

[82] (4 mg, yield: 48.08%).

[0766] LC-MS (ESI): m / z =1160.8(M+H) +.

[0767] [, Effect Example , ] [, 1 , ] [, : , ] [, , ]

[0768] Homogeneous time-resolved fluorescence (HTRF) binding assays were used to detect the binding ability of the compounds of the present invention to PD-1 / PD-L1.

[0769] The purchased kit (CisBio, #64CUS000C-1) contains reagents required for the experiment, including PD-1, PD-L1, anti-tag1-Eu, Anti-tag2-XL665, Dilute Buffer, and Detection Buffer.

[0770] [Experimental Procedure] 1. Prepare 10 concentrations of the compound with a concentration gradient of 3 times using 100% DMSO. 2. Add the DMSO solution of the compound to the dilution buffer, mix well, and then transfer to a 96-well pan. 3. Dilute PD-L1 with dilute buffer and then add it to the 96-well disk mentioned above. 4. Dilute PD-1 with dilution buffer, then add it to the 96-well plate and incubate at room temperature for 30 minutes. 5. Add one part anti-tag1-Eu and one part Anti-tag2-XL665 to the detection buffer solution, mix well, and then transfer to the 96-well disk mentioned above. 6. Incubate the mixture in this 96-well dish at room temperature for 1 to 24 hours. 7. Use Envision to read the HTRF value.

[0771] [Experimental Results]

[0772] The biological activity of the compounds of this invention was determined by the above experiments, and the results are as follows (Table 1):

[0773] Table 1. IC50 values ​​of some compounds in this application for binding to PD-1 / PD-L1. compound IC 50(nM) compound IC 50(nM) 2 1.29 29 0.5711 3 3.16 30 9.217 4 0.8881 31 0.6027 6 2.658 32 12.37 7 0.9691 33 0.6012 8 0.5216 34 0.4048 9 1.072 35 0.7659 10 169.3 36 0.5214 11 32.57 37 0.7292 12 32.52 38 1.134 13 299.5 48 0.8853 14 0.95 50 3.316 15 5.33 52 4.377 16 1.422 54 7.365 17 1.191 56 11.46 18 0.9012 57 4.834 19 0.869 59 5.471 20 1.012 62 0.5288 twenty one 3.741 64 0.7003 twenty two 5.029 66 1.08 twenty three 0.8334 68 1.249 twenty four 0.7852 69 24.85 25 16.17 70 47.7 26 33.21 71 13.24 27 13.61 72 112.5 28 0.5616

[0774] [, Effect Example , ] [, 2 , ] [, : , ] [, , ]

[0775] 1. The inhibitory effect of compound 78 on tumors.

[0776] 1.1 Experimental animal information: tumor-bearing C57 / BL6 mice; SPF grade; weight range: 17-20 g; Shanghai Qishang Biomedical Technology Co., Ltd.

[0777] 1.2 Experimental Procedure

[0778] Ten tumor-bearing mice with tumor volumes ranging from 10 to 100 mm³ were systematically and randomly divided into two groups of five mice each, corresponding to PBS and compound 78, respectively. After anesthetizing the mice with isoflurane, compound 78 was administered via tail vein injection at a dose of 45 MBq (approximately 1.2 mCi) per mouse, in a volume of 0.2 mL. Tumor size and body weight were measured periodically after administration, and tumor growth curves were plotted to assess the drug's inhibitory effect on tumors.

[0779] 1.3 Experimental Results

[0780] The experimental results showed that, compared with the control group, compound 78 had a very good therapeutic effect on inhibiting tumor growth (see Figure 1).

[0781] Following the experimental procedures described above, the results showed that injections of compounds 5, 6, 12, 13, 14, 15, 17, 20, 22, 24, 26, 32, 33, 38, 41, 44, 45, 46, 70, 72, 76, and 77, respectively, also exhibited very good therapeutic effects in inhibiting tumor growth.

[0782] [, Effect Example , ] [, 3 , ] [, : , ] [, , ]

[0783] Micro-PET / CT Scan Tumor Targeting Study of Compound 79

[0784] 1. Experimental animal information: C57BL / 6J mice, SPF grade; 15-21 g; Model mouse construction: bilateral tumors.

[0785] [Construction of a bilateral tumor model mouse]

[0786] Cell culture

[0787] Human PD-L1 gene knocked into MC-38 cells (MC-38-hPD-Ll cells) was cultured in vitro in adherent form under the following conditions: DMEM medium supplemented with 10% heat-deactivated fetal bovine serum and hygromycin B (final concentration 100 μL / mL), cultured at 37°C in 5% CO2. Cells were passaged 2-3 times per week. When the cells reached the exponential growth phase, they were harvested, counted, and subcutaneously inoculated onto the left side of mice.

[0788] Mouse-derived MC-38 cells were cultured in vitro in adherent medium at 37°C with 10% heat-deactivated fetal bovine serum in DMEM medium, using 5% CO2. Cells were passaged 2-3 times per week. When the cells reached the exponential growth phase, they were harvested, counted, and subcutaneously inoculated onto the right side of mice.

[0789] Tumor cell inoculation

[0790] 100 µL of 1×10⁶ MC-38-hPD-Ll cell suspension was subcutaneously injected into the left dorsal side of C57BL / 6J mice. The following day, 100 µL of 1×10⁶ MC-38 cell suspension was subcutaneously injected into the right dorsal side of the same mouse. Mice were fed normally after inoculation, and after a certain number of days, tumor-bearing mice with bilateral xenograft tumor volumes ranging from 150 mm³ to 350 mm³ were selected for the experiment.

[0791] Experimental process

[0792] After quality control, compound 79 was diluted with 10% ethanol saline, the drug was extracted, and injected into each animal via the tail vein. The administration volume was 100 μL / animal, and the dosage was 100-200 μCi / animal. Micro-PET / CT imaging studies were performed at 0.5 h, 1.5 h, 2.5 h, and 3.5 h after injection of compound 79.

[0793] Experimental results

[0794] Experimental results showed that in mice with bilateral tumors scanned by compound 79, the left side was MC38-PDL1 and the right side was MC38. The results showed that the tumor uptake value on the left side was significantly higher than that on the right side (see Table 2).

[0795] Table 2 Tumor target uptake values ​​(unit: ID% / g) time Compound 79 Bilateral tumor model MC-38 MC38-PDL1 30min 0.75 1.3 90min 0.3 0.65 150min 0.07 0.54 210min 0.06 0.66

[0796] Following the above experimental procedure, the results showed that when compounds 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68 and 82 were injected and subjected to Micro-PET / CT imaging, the uptake value of the left tumor (MC38-PDL1) in mice was significantly higher than that of the right tumor (MC38) in mice.

[0797] [, Effect Example , ] [, 4 , ] [, : , ] [, , ]

[0798] Micro-PET / CT Scan Tumor Targeting Study of Compound 80

[0799] Laboratory animal information: C57BL / 6J mice, SPF grade; 15-21g.

[0800] [Construction of a bilateral tumor model mouse]

[0801] Cell culture

[0802] Human PD-L1 gene knocked into MC-38 cells (MC-38-hPD-Ll cells) was cultured in vitro in adherent form under the following conditions: DMEM medium supplemented with 10% heat-deactivated fetal bovine serum and hygromycin B (final concentration 100 μL / mL), cultured at 37°C in 5% CO2. Cells were passaged 2-3 times per week. When the cells reached the exponential growth phase, they were harvested, counted, and subcutaneously inoculated onto the left side of mice.

[0803] Mouse-derived MC-38 cells were cultured in vitro in adherent medium at 37°C with 10% heat-deactivated fetal bovine serum in DMEM medium, using 5% CO2. Cells were passaged 2-3 times per week. When the cells reached the exponential growth phase, they were harvested, counted, and subcutaneously inoculated onto the right side of mice.

[0804] Tumor cell inoculation

[0805] 100 µL of 1×10⁶ MC-38-hPD-Ll cell suspension was subcutaneously injected into the left dorsal side of C57BL / 6J mice. The following day, 100 µL of 1×10⁶ MC-38 cell suspension was subcutaneously injected into the right dorsal side of the same mouse. Mice were fed normally after inoculation, and after a certain number of days, tumor-bearing mice with bilateral xenograft tumor volumes ranging from 150 mm³ to 350 mm³ were selected for the experiment.

[0806] Experimental process

[0807] After quality control, compound 80 was diluted with 10% ethanol saline, the drug was extracted, and injected into each animal via the tail vein. The administration volume was 100 μL / animal, and the dosage was 100-200 μCi / animal. Micro-PET / CT imaging studies were performed at 0.5 h, 1.5 h, 2.5 h, and 3.5 h after injection of compound 80.

[0808] Experimental results

[0809] The experimental results showed that the uptake value of compound 80 in the left tumor (MC38-PDL1) of the scanning model mouse was significantly higher than that in the right tumor (MC-38), as shown in Table 3.

[0810] Table 3. Tumor target uptake values ​​(unit: ID% / g) time Compound 80 Bilateral tumor model MC-38 MC38-PDL1 30min 0.98 2.6 90min 1.2 2.8 150min 0.74 2.2 210min 0.46 2.3

[0811] Following the above experimental procedure, the results showed that when compounds 7, 8, 27, 28, 29, 34, 35, 36, 37, 73, 74 and 75 were injected and Micro-PET / CT imaging was performed, the uptake value of the left tumor (MC38-PDL1) in mice was significantly higher than that of the right tumor (MC38) in mice.

[0812] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound of general formula II or its metal complex, or a pharmaceutically acceptable salt thereof: X1, X2, X3, X4 and X5 are each independently CH or N; R1 is hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 alkyl substituted with one or more Ra; R2 and R3 are each independently hydrogen or halogen; R4 is hydrogen, halogen, C1-C4 alkyl or C1-C4 alkyl substituted with one or more Rb; R5 and R6 are each independently hydrogen, deuterium, C1-C4 alkyl or C1-C4 alkyl substituted with one or more Rc; or, R5, R6 and the nitrogen atom attached to them together form a 5-7 membered heterocycle or a 5-7 membered heterocycle substituted with one or more Rc; wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3 or 4, and each heteroatom is independently selected from N, O and S; Each Ra, each Rb, and each Rc is independently deuterium, halogen, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkyl-O-, -COOH, or -C(O)ORg; each R8 is independently hydrogen, deuterium, halogen, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkyl-S-, C1-C4 alkyl-O-, -C(O)NH2, -C(O)OC1-4 alkyl, -OR8a, -NHR8a, -NR8aR8b, -NH-C(O)-R8d, C1-C4 alkyl substituted with one or more R8c, C1-C4 alkyl-S-substituted with one or more R8c, or C1-C4 alkyl-O-substituted with one or more R8c; Alternatively, two adjacent R8s together with the carbon atoms on the benzene rings they are attached to form a 5-7 membered carbon ring, a 5-7 membered heterocycle, a 5-7 membered carbon ring substituted with one or more C1-4 alkyl groups, or a 5-7 membered heterocycle substituted with one or more C1-4 alkyl groups; wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3, or 4, and each heteroatom is independently selected from N and O; Each R8a, R8b, and each R8c is independently C1-C4 alkyl-S-, halogen, C1-C4 alkyl, C1-C4 alkyl-O-, -COOH, -(C1-C4 alkylene)-COOH, -C(O)OC1-C4 alkyl, -C(O)NH2, -C(O)NHC1-C4 alkyl, 5-7 membered heterocycle, or -NR8eR8f; in the 5-7 membered heterocycle, the type of heteroatom is independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; R8e and R8f are each independently hydrogen, halogen, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more R8g; Each R8g is independently a halogen, C1-4 alkyl, hydroxyl, -NR8hR8k, C1-C4 alkyl-O-, -COOH, -(C1-C4 alkylene)-COOH, -C(O)OC1-C4 alkyl, -C(O)NH2 or -C(O)NHC1-C4 alkyl;R8h and R8k are each independently hydrogen or C1-4 alkyl; each R8d is independently a C6-C10 aryl group substituted with one or more R8d-1 groups or a 5-10 heteroaryl group substituted with one or more R8d-2 groups; in the 5-10 heteroaryl group, the type of heteroatom is independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; each R8d-1 and R8d-2 are each independently C1-C4 alkoxy groups or C1-C4 alkyl groups substituted with one or more R8d-1-1 groups; each R8d-1-1 is independently a 5-7 heterocycle substituted with a carboxyl group; in the 5-7 heterocycle, the type of heteroatom is independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; q is 0, 1, 2, or 3; L1 is (i). (ii) -(CH2)m-, wherein 1, 2, 3, 4 or 5 non-adjacent CH2 bonds are independently replaced by -Y1-, each Y1 being independently -C(O)-, -C(O)O-, -O-, -NH-, -C(O)NH- or -NHC(O)NH-; or (iii) -(CH2)p-, wherein 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 -C(O)-, -C(O)O-, -O-, -NH-, -C(O)NH-, or -NHC(O)NH-; Y2 is a 5-7 membered carbon ring or a 5-7 membered heterocycle, wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3, or 4, and each heteroatom is independently selected from N, O, and S; L1 is unsubstituted or L1 contains 1, 2, or 3 H atoms, each independently replaced by R7; n, m, and p are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14; each R7 is independently C1-C4 alkyl or -L3-R9; L3 is (i) -(CH2)j-; or (ii) -(CH2)k-, wherein 1, 2, 3, or 4 non-adjacent CH2 groups are independently replaced by -Y4-, each Y4 being independently -C(O)-, -C(O)O-, -O-, -NH-, -C(O)NH-, or -NHC(O)NH-; L3 is unsubstituted or L3 contains 1, 2, or 3 H groups, each independently replaced by R10; j and k are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14; R9 is hydrogen, C6-C10 aryl, or C6-C10 aryl substituted with one or more Rds; each R10 is independently C1-C4 alkyl; each Rd is independently C1-C4 alkyl or C1-C4 alkyl substituted with one or more Res;Each Re group is independently a hydroxyl, amino, C1-C4 alkyl, C1-C4 alkyl-O-, -COOH, or -C(O)ORh group; Rg and Rh are each independently a C1-C4 alkyl or halo-C1-C4 alkyl group; L2 is a metal chelating group; the metal complex is a complex of a compound of general formula II chelated with a metal atom or ion.

2. A compound of formula II as claimed in claim 1, or a metal complex thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, It satisfies one or more of the following conditions: q is 0, 1, or 2; each R8 is independently a C1-C4 alkyl, -NH-C(O)-R8d, or a C1-C4 alkyl-O- substituted with one or more R8c; each R8c is independently a 5-7 membered heterocycle; in the 5-7 membered heterocycle, the type of heteroatom is independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; each R8d is independently a C6-C10 aryl substituted with one or more R8d-1 or a 5-10 membered heteroaryl substituted with one or more R8d-2; in the 5-10 membered heteroaryl, the type of heteroatom is independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3. Each R8d-1 and R8d-2 is independently a C1-C4 alkoxy or a C1-C4 alkyl group substituted with one or more R8d-1-1 groups; each R8d-1-1 is independently a 5-7 membered heterocycle substituted with a carboxyl group; in the 5-7 membered heterocycle, the type of heteroatom is independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; R1 is cyano or a C1-C4 alkyl group; X1, X2, and X3 are independently CH or N; R2 and R3 are hydrogen; R4 is a C1-C4 alkyl or a C1-C4 alkyl group substituted with one or more Rb groups; each Rb is independently a halogen; X4 and X5 are independently CH or N. R5, R6, and the nitrogen atom attached to them together form a 5-7 membered heterocycle substituted with one or more Rc atoms; wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3, or 4, and each heteroatom is independently selected from N, O, and S; Rc is -COOH; L1 is (i) -(CH2)m-, wherein 1, 2, 3, 4, or 5 non-adjacent CH2 atoms are independently replaced by -Y1-, each Y1 being independently -C(O)O-, -O-, or -C(O)NH-; or (ii) -(CH2)p-, wherein one CH2 is replaced by -Y2-, and the other 1, 2, 3, or 4 non-adjacent CH2s are independently replaced by -Y3-; each Y3 is independently -C(O)-, -O-, or -C(O)NH-; Y2 is a 5-7 membered carbon ring or a 5-7 membered heterocycle, wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3, or 4, and each heteroatom is independently selected from N, O, and S; L1 is unsubstituted or L1 contains one H that is independently replaced by R7; m and p are independently 5, 6, 7, 8, 9, 10, or 11; R7 is -L3-R9; L3 is -(CH2)k-, wherein one, 2, 3, or 4 non-adjacent CH2s are independently replaced by -Y4-, each Y4 being -C(O)NH-; L3 is unsubstituted; k is 7, 8, or 9;R9 is a C6-C10 aryl group substituted with one or more Rd groups; each Rd group is independently a C1-C4 alkyl group; the metal complex is a complex of a compound of general formula II chelated with a metal ion; the metal ion does not bind a non-metallic nuclide.

3. A compound of formula II as claimed in claim 2, or a metal complex thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, It satisfies one or more of the following conditions: q is 0; R1 is cyano or C1-C4 alkyl; X1 and X2 are CH, X3 is N; R4 is C1-C4 alkyl or C1-C4 alkyl substituted by one or more Rb; each Rb is independently halogen; X4 and X5 are independently CH.

4. A compound of formula II as claimed in claim 1, or a metal complex thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, Its definition is as described in any of the following schemes: Scheme 1: X1, X2, X3, X4, and X5 are each independently CH or N; R1 is cyano or C1-C4 alkyl; R2 and R3 are hydrogen; R4 is C1-C4 alkyl or C1-C4 alkyl substituted with one or more Rb; each Rb is independently a halogen; R5, R6, and the nitrogen atom attached to them together form a 5-7 membered heterocycle substituted with one or more Rc; the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3, or 4, and each heteroatom is independently selected from N, O, and S; Rc is -COOH; q is 0, 1, or 2; each R8 is independently a C1-C4 alkyl, -NH-C(O)-R8d, or a C1-C4 alkyl-O- substituted with one or more R8c; Each R8c is independently a 5-7 membered heterocycle; in the 5-7 membered heterocycle, the type of heteroatom is independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; each R8d is independently a C6-C10 aryl group substituted with one or more R8d-1 groups or a 5-10 membered heteroaryl group substituted with one or more R8d-2 groups; in the 5-10 membered heteroaryl group, the type of heteroatom is independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; each R8d-1 and R8d-2 is independently a C1-C4 alkoxy group or a C1-C4 alkyl group substituted with one or more R8d-1-1 groups; Each R8d-1-1 is independently a 5-7 membered heterocycle substituted with a carboxyl group; in the 5-7 membered heterocycle, the type of heteroatom is independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3; L1 is (i) -(CH2)m-, where 1, 2, 3, 4, or 5 non-adjacent CH2 groups are independently replaced by -Y1-, each Y1 being independently -C(O)O-, -O-, or -C(O)NH-; or (ii) -(CH2)p-, wherein one CH2 is replaced by -Y2-, and the other 1, 2, 3, or 4 non-adjacent CH2s are independently replaced by -Y3-; each Y3 is independently -C(O)-, -O-, or -C(O)NH-; Y2 is a 5-7 membered carbon ring or a 5-7 membered heterocycle, wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3, or 4, and each heteroatom is independently selected from N, O, and S; L1 is unsubstituted or L1 contains one H that is independently replaced by R7; m and p are independently 5, 6, 7, 8, 9, 10, or 11; R7 is -L3-R9; L3 is -(CH2)k-, wherein one, 2, 3, or 4 non-adjacent CH2s are independently replaced by -Y4-, each Y4 being -C(O)NH-; L3 is unsubstituted; k is 7, 8, or 9; R9 is a C6-C10 aryl group substituted with one or more Rd groups;Each Rd is independently a C1-C4 alkyl group; L2 is a metal chelating group; the metal complex is a complex of a compound of general formula II chelated with a metal atom or ion; Scheme 2: X1, X2, X4 and X5 are CH; X3 is CH or N; R1 is cyano or C1-C4 alkyl; R2 and R3 are hydrogen; R4 is a C1-C4 alkyl or a C1-C4 alkyl substituted with one or more Rb; each Rb is independently a halogen; R5, R6 and the nitrogen atom attached to them together form a 5-7 membered heterocycle substituted with one or more Rc; the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3 or 4, and each heteroatom is independently selected from N, O and S; Rc is -COOH; q is 0; L1 is (i) -(CH2)m-, wherein 1, 2, 3, 4, or 5 non-adjacent CH2 atoms are independently replaced by -Y1-, each Y1 being independently -C(O)O-, -O-, or -C(O)NH-; or (ii) -(CH2)p-, wherein 1 CH2 atom is replaced by -Y2-, and the other 1, 2, 3, or 4 non-adjacent CH2 atoms are independently replaced by -Y3-; each Y3 being independently -C(O)-, -O-, or -C(O)NH-; Y2 is a 5-7 membered carbon ring or a 5-7 membered heterocycle, wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3, or 4, each heteroatom being independently selected from N, O, and S; L1 is unsubstituted or L1 contains 1 H atom each independently replaced by R7; m and p are each independently 5, 6, 7, 8, 9, 10, or 11; R7 is -L3-R9; L3 is -(CH2)k-, wherein 1, 2, 3, or 4 non-adjacent CH2 groups are independently replaced by -Y4-, each Y4 being -C(O)NH-; L3 is unsubstituted; k is 7, 8, or 9; R9 is a C6-C10 aryl group substituted with one or more Rd groups; each Rd is independently a C1-C4 alkyl group; L2 is a metal chelating group; the metal complex is a complex of the compound of general formula II chelated with a metal ion.

5. A compound of formula II as claimed in claim 1, or a metal complex thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, It satisfies one or more of the following conditions: The metal complex has a structure represented by the following general formula I: Wherein, M is the metal atom or ion; In R1, the C1-C4 alkyl group is methyl or ethyl; In R4, the C1-C4 alkyl group is methyl or ethyl; In R4, the C1-C4 alkyl group substituted by one or more Rb is methyl or ethyl; In Rb, the halogen is fluorine or chlorine; In the 5-7 membered heterocycles formed by R5, R6 and the nitrogen atom connected to them, which are substituted by one or more Rc, the 5-7 membered heterocycles are 6-membered saturated monocyclic heterocycles; In the 5-7 membered heterocycles formed by R5, R6 and the nitrogen atom connected to them, which are substituted by one or more Rc, the number of heteroatoms is 1; In the 5-7 membered heterocycles formed by R5, R6 and the nitrogen atom connected to them, which are substituted by one or more Rc, the heteroatom is N; L1 is connected to ring A through -Y1-, and the Y1 connected to ring A is -O-. L1 is connected to L2 via -CH2-; L1 is -O(CH2)n2-, -O(CH2)n2O(CH2)m2-, -O(CH2)n2O(CH2)m2O(CH2)m3-, -O(CH2)n2OC(O)(CH2)m2-, -O(CH2)n2NHC(O)(CH2)m2-, -O(CH2)n2NHC(O)-(CH2)n3-NHC(O)(CH2)m3-, -O(CH2)n2-O(CH2)n3-NHC(O)-(CH2)n4NHC(O)-(CH2)m3-, -O(CH2)n2NHC(O)-Y2 -(CH2)n3NHC(O)-(CH2)m3-, -O(CH2)n2-Y2-C(O)-(CH2)m3-, -O(CH2)n2NHC(O)-Y2-C(O)-(CH2)m3- or -O(CH2)n2NHC(O)-Y2-(CH2)n3NHC(O)-(CH2)n4NHC(O)-(CH2)m3-; its right end is connected to L2; each n2, each n3, each n4, each m2 and each m3 is independently 1, 2, 3, 4, 5 or 6; L1 is unsubstituted or L1 contains one H that is substituted by R7; When Y2 is a 5-7 membered carbon ring, the 5-7 membered carbon ring is: ; When Y2 is a 5-7 membered heterocycle, the 5-7 membered heterocycle is: ; R9 is a phenyl or a phenyl substituted with one or more Rd; In Rd, the C1-C4 alkyl group is methyl or ethyl; L2 is R11 or -L4-(CH2)s-R11; s is 1, 2, or 3; L4 is a 5-7 membered carbon ring or a 5-7 membered heterocycle, wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3, or 4, and each heteroatom is independently selected from N, O, and S;R11 is an 8-20 saturated monocyclic or bridged carbon ring, wherein 3, 4, 5, or 6 non-adjacent CH2 atoms of the monocyclic or bridged carbon ring are independently replaced by -Y5-, each Y5 being independently -O-, -NH-, or -N(R11a)-; each R11a is independently a C1-C4 alkyl group or a C1-C4 alkyl group substituted with one or more -COOH atoms; when L2 is -L4-(CH2)s-R11, the -L4-(CH2)s-R11 is: each Y5 being independently -NH- or -N(R11a)-; each R11a being independently a C1-C4 alkyl group substituted with one or more -COOH atoms; in the metal complex, the molar ratio of the compound represented by general formula II to the metal atom or ion is 1:1; the metal ion is an ion of the following metals: Al, Cu, Ga, Y, Zr, Tc, In, Lu, Re, At, Bi, or Tl; The metal ion has a monovalent, divalent, trivalent, or tetravalent valence; the metal ion is either a radioactive or non-radioactive metal ion; the metal ion further binds to a non-metallic nuclide; and the metal ion as a whole is radioactive.

6. A compound of formula II as claimed in claim 5, or a metal complex thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, It satisfies one or more of the following conditions: The metal complex has the structure shown in general formula I: Wherein, M is the metal ion; In R4, the C1-C4 alkyl group substituted by one or more Rb is trifluoromethyl; In the 5-7 membered heterocycle formed by R5, R6 and the nitrogen atom connected thereto, which is substituted by one or more Rc, the 5-7 membered heterocycle is a piperidine ring; m2 is 1 or 2; m3 is 1 or 2; When Y2 is a 5-7 membered carbon ring, the 5-7 membered carbon ring is; When Y2 is a 5-7 membered heterocycle, the 5-7 membered heterocycle is; R7 is; L2 is R11; In L4, the 5-7 membered carbon ring is; In R11, the 8-20 members are 8, 9, 10, 11, 12, 13, 14, 15 or 16 members; In R11a, the C1-C4 alkyl group substituted by one or more -COOH is -CH2-COOH; The metal ions are ions of the following metals: 27Al, 63Cu, 64Cu, 68Ga, 70Ga, 89Y, 90Y, 89Zr, 91Zr, 99mTc, 111In, 113In, 175Lu, 177Lu, 186Re, 188Re, 211At, 212Bi, 213Bi, 201Tl, or 203Tl; the valence state of the metal ions is trivalent; the non-metallic nuclides are radioactive or non-radioactive, and the radioactive non-metallic nuclide is 18F.

7. A compound of formula II as claimed in claim 6, or a metal complex thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, It satisfies one or more of the following conditions: A 5-7 membered heterocycle formed by R5, R6, and the nitrogen atom connected to them, substituted with one or more Rc atoms, is ; When Y2 is a 5-7 membered carbon ring, the 5-7 membered carbon ring is ; L2 is , , or , where the c-terminus is connected to L1; The metal ion is [Al18F]2+, [68GaCl]2+, [177LuCl]2+, 68Ga3+, or 177Lu3+.

8. A compound of formula II as claimed in claim 1, or a metal complex thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, It satisfies one or more of the following conditions: is , , , , , or; L1 is , , , , , , , , , , , , , , , , or; wherein the upper end is connected to ring A and the lower end is connected to L2; L2 is or; the L2 forms any of the following groups with the metal ion: , , , or.

9. A compound of formula II as claimed in claim 1, or a metal complex thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X1, X2, X3, X4, and X5 are each independently CH or N; R1 is hydrogen, halogen, cyano, C1-C4 alkyl, or a C1-C4 alkyl substituted with one or more Ra; R2 and R3 are each independently hydrogen or halogen; R4 is hydrogen, halogen, C1-C4 alkyl, or a C1-C4 alkyl substituted with one or more Rb; R5 and R6 are each independently hydrogen, deuterium, C1-C4 alkyl, or a C1-C4 alkyl substituted with one or more Rc; or, R5, R6, and the nitrogen atom attached to them together form a 5-7 membered heterocycle or a 5-7 membered heterocycle substituted with one or more Rc; wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3, or 4, and each heteroatom is independently selected from N, O, and S; Each Ra, each Rb, and each Rc is independently deuterium, halogen, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkyl-O-, -COOH, or -C(O)ORg; each R8 is independently hydrogen, deuterium, halogen, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkyl-S-, C1-C4 alkyl-O-, -C(O)ONH2, -C(O)OC1-4 alkyl, -OR8a, -NHR8a, -NR8aR8b, C1-C4 alkyl substituted with one or more R8c, C1-C4 alkyl-S-substituted with one or more R8c, or C1-C4 alkyl-O-substituted with one or more R8c; Alternatively, two adjacent R8s together with the carbon atoms on the benzene rings they are attached to form a 5-7 membered carbon ring, a 5-7 membered heterocycle, a 5-7 membered carbon ring substituted with one or more C1-4 alkyl groups, or a 5-7 membered heterocycle substituted with one or more C1-4 alkyl groups; wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3, or 4, and each heteroatom is independently selected from N and O; each R8a, R8b, and each R8c is independently C1-C4 alkyl-S-, halogen, C1-C4 alkyl, C1-C4 alkyl-O-, -COOH, -(C1-C4 alkylene)-COOH, -C(O)OC1-C4 alkyl, -C(O)NH2, -C(O)NHC1-C4 alkyl, or -NR8eR8f; R8e and R8f are independently hydrogen, halogen, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more R8gs; Each R8g is independently a halogen, C1-4 alkyl, hydroxyl, -NR8hR8k, C1-C4 alkyl-O-, -COOH, -(C1-C4 alkylene)-COOH, -C(O)OC1-C4 alkyl, -C(O)NH2 or -C(O)NHC1-C4 alkyl; R8h and R8k are each independently hydrogen or C1-4 alkyl; q is 0, 1, 2 or 3; L1 is (i) a single bond or -(CH2)n-;(ii) -(CH2)m-, wherein 1, 2, 3, 4 or 5 non-adjacent CH2 atoms are independently replaced by -Y1-, each Y1 being independently -C(O)-, -C(O)O-, -O-, -NH-, -C(O)NH- or -NHC(O)NH-; or (iii) -(CH2)p-, wherein 1 CH2 atom is replaced by -Y2-, and the other 0, 1, 2, 3 or 4 non-adjacent CH2 atoms are independently replaced by -Y3-; each Y3 being independently -C(O)-, -C(O)O-, -O-, -NH-, -C(O)NH- or -NHC(O)NH-; Y2 is a 5-7 membered carbon ring or a 5-7 membered heterocycle, wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3 or 4, and each heteroatom is independently selected from N, O and S; L1 is unsubstituted or L1 contains 1, 2, or 3 H atoms, each independently substituted by R7; n, m, and p are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14; each R7 is independently C1-C4 alkyl or -L3-R9; L3 is (i) -(CH2)j-; or (ii) -(CH2)k-, wherein 1, 2, 3, or 4 non-adjacent CH2 atoms are independently substituted by -Y4-, each Y4 being independently -C(O)-, -C(O)O-, -O-, -NH-, -C(O)NH-, or -NHC(O)NH-; L3 is unsubstituted or L3 contains 1, 2, or 3 H atoms, each independently substituted by R10; j and k are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14; R9 is hydrogen, a C6-C10 aryl group, or a C6-C10 aryl group substituted with one or more Rd groups; each R10 is independently C1-C4 alkyl; each Rd is independently C1-C4 alkyl or a C1-C4 alkyl group substituted with one or more Re groups; each Re group is independently hydroxyl, amino, C1-C4 alkyl, C1-C4 alkyl-O-, -COOH, or -C(O)ORh; Rg and Rh are each independently C1-C4 alkyl or halo-C1-C4 alkyl; L2 is a metal chelating group; the metal complex is a complex of a compound of general formula II chelated with a metal atom or ion.

10. A compound of formula II as claimed in claim 1 or 9, or a metal complex thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, The metal is Cu, Ga, Y, Zr, Tc, In, Lu, Re, At, Bi, Tl, or a radioactive or non-radioactive isotope thereof; and / or, the metal ion is monovalent, divalent, trivalent, or tetravalent; and / or, X1 is CH; and / or, X2 is CH; and / or, X3 is CH; and / or, X4 is CH; and / or, X5 is CH; and / or, q is 0; and / or, R1 is cyano or C1-C4 alkyl; and / or, R2 is hydrogen; and / or, R3 is hydrogen; and / or, R4 is C1-C4 alkyl or a C1-C4 alkyl substituted with one or more Rb; and / or, each Rb is independently a halogen; And / or, when R5, R6 and the nitrogen atom connected to them together form a 5-7 membered heterocycle or a 5-7 membered heterocycle substituted by one or more Rc, the 5-7 membered heterocycle is piperidine; and / or, n, m and p are each independently 5, 6, 7, 8, 9, 10, 11 or 12.And / or, L1 is a single bond, -(CH2)n1NH(CH2)m1-, -(CH2)n1O(CH2)m1-, -(CH2)n1NHC(O)NH(CH2)m1-, -O(CH2)n1NH-, -O(CH2)n1O-, -O(CH2)n1O(CH2)m1O-, -NH(CH2)n1NH(CH2)m1NH-, -NH(CH2)n1O(CH2)m1O-, -NH(CH2)n1NH(CH2)m1O-, -O( CH2)n1NH(CH2)m1O-, -O(CH2)n1O(CH2)m1NH-, -O(CH2)n1NH(CH2)m1NH-, -NH(CH2)n1O(CH2)m1NH-, -O-Y2-(CH2 )n1NH-, -O(CH2)n2OC(O)(CH2)m2-, -O(CH2)n2O(CH2)m2-, -O(CH2)n2NHC(O)(CH2)m2-, -O(CH2)n2NHC(O)-(CH2 )n3-NHC(O)(CH2)m3-, -O-(CH2)n2-Y2-C(O)-(CH2)m2-, -O(CH2)n2NHC(O)-Y2-(CH2)n3NHC(O)-(CH2)m3-, -O(C H2)n2NHC(O)-Y2-C(O)-(CH2)m3-, -O(CH2)n2-Y2-C(O)-(CH2)m3-, -O(CH2)n2NHC(O)-Y2-(CH2)n3NHC(O)-(CH2 -O(CH2)n4NHC(O)-(CH2)m3, -O(CH2)n2NHC(O)-(CH2)n3NHC(O)-(CH2)m3- or -O(CH2)n2-O(CH2)n3-NHC(O)-(CH2)n4NHC(O)-(CH2)m3-, where each n1, each n2, each n3, n4, each m1, each m2, and each m3 is independently 1, 2, 3, 4, 5, or 6; L1 is unsubstituted or L1 contains 1, 2, or 3 H atoms, each of which is independently substituted by R7; And / or, when Y2 is a 5-7 membered carbon ring, the 5-7 membered carbon ring is; and / or, when Y2 is a 5-7 membered heterocycle, the 5-7 membered heterocycle is; and / or, L2 is R11 or -L4-(CH2)s-R11; s is 1, 2 or 3; L4 is a 5-7 membered carbon ring or a 5-7 membered heterocycle, wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3 or 4, and each heteroatom is independently selected from N, O and S; R11 is an 8-20 membered saturated monocyclic or bridged ring carbon ring, wherein 3, 4, 5 or 6 non-adjacent CH2 atoms of the monocyclic or bridged ring carbon ring are independently replaced by -Y5-, and each Y5 is independently -O-, -NH- or -N(R11a)-;Each R11a is independently a C1-C4 alkyl group or a C1-C4 alkyl group substituted with one or more -COOH groups; and / or, each R7 is independently -L3-R9; and / or, each Y4 is independently -C(O)NH-; and / or, L3 is -(CH2)k-, wherein one CH2 group is replaced by -Y4-; L3 is unsubstituted or L3 contains one, two, or three H groups, each independently substituted with R10; and / or, j and k are independently 7, 8, or 9; and / or, each Y4 is independently -C(O)NH-; and / or, R9 is a phenyl group or a phenyl group substituted with one or more Rd groups; and / or, each Rd is independently a C1-C4 alkyl group.

11. A compound of formula II as claimed in claim 1 or 9, or a metal complex thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, The metal is 63Cu, 64Cu, 68Ga, 70Ga, 89Y, 90Y, 89Zr, 91Zr, 99mTc, 111In, 113In, 175Lu, 177Lu, 186Re, 188Re, 211At, 212Bi, 213Bi, 201Tl, or 203Tl; and / or, X1, X2, X3, X4, and X5 are CH; and / or, R1 is cyano or methyl; and / or, R4 is methyl or trifluoromethyl; and / or, R5, R6, and the nitrogen atom attached to them are formed together; and / or, each Rc is independently -COOH; and / or, L1 is connected to ring A via -Y1-, and the Y1 connected to ring A is -O-; and / or, L1 is connected to L2 via -CH2-. And / or, L1 is unsubstituted or L1 contains one H that is substituted by R7; and / or, R7 is; and / or, when Y2 is a 5-7 membered carbon ring, the 5-7 membered carbon ring is; and / or, when Y2 is a 5-7 membered heterocycle, the 5-7 membered heterocycle is; and / or, L2 is, or, each R11b is independently H or R11a; each R11a is independently C1-C4 alkyl or a C1-C4 alkyl substituted with one or more -COOH groups.

12. A compound of formula II as claimed in claim 1 or 9, or a metal complex thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, The metal complex is a complex of a compound of general formula II chelated with a metal ion; and / or, the metal is Ga, Lu or a radioactive or non-radioactive isotope thereof; and / or, R5, R6 and the nitrogen atom connected to them are formed together; and / or, when Y2 is a 5-7 membered carbon ring, the 5-7 membered carbon ring is; and / or, L1 is , ...

13. A compound of formula II as claimed in claim 1 or 9, or a metal complex thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, The metal ions are Ga3+ and Lu3+; and / or, L1 is , ...

14. A compound of formula II as claimed in claim 1 or 9, or a metal complex thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, The metal complex has the following structure: M is a trivalent metal ion.

15. A compound of formula II as claimed in claim 1 or 9, or a metal complex thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, The C1-C4 alkyl group, when present in any position, is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, dibutyl, or tributyl; and / or, the "one or more" group, when present in any position, is independently 1, 2, 3, 4, 5, or 6; and / or, the C6-C10 aryl group, when present in any position, is independently phenyl or naphthyl; and / or, the 5-7 membered carbon ring, when present in any position, is independently a 5, 6, or 7 membered saturated monocyclic carbon ring; and / or, the 5-7 membered heterocycle, when present in any position, is independently a 5, 6, or 7 membered saturated monocyclic heterocycle; and / or, the halogen, when present in any position, is independently F, Cl, Br, or I.

16. A compound of formula II as claimed in claim 1 or 9, or a metal complex thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, The compound represented by general formula II has any of the following structures: , ...

17. A compound of formula II as claimed in claim 1 or 9, or a metal complex thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, The metal complex has any of the following structures: , ...

18. A method for preparing a compound of general formula I, comprising the steps of: reacting a compound of general formula II with a halide of metal M in a solvent, with or without a buffer, to obtain the compound of general formula I; wherein the variables are defined as described in any one of claims 1 to 17.

19. A method for preparing a compound of formula II as claimed in any one of claims 1 to 17, comprising the steps of: removing the Boc protecting group from a compound of formula III in the presence of an acid in a solvent to obtain the compound of formula II; wherein in formula II, L2 is R11 or -L4-(CH2)s-R11; in formula III, L20 is R110 or -L4-(CH2)s-R110; s is 1, 2 or 3; L4 is a 5-7 membered carbon ring or a 5-7 membered heterocycle, wherein the number of heteroatoms in the 5-7 membered heterocycle is 1, 2, 3 or 4, and each heteroatom is independently selected from N, O and S; R11 is an 8-20 saturated monocyclic or bridged carbon ring, wherein 3, 4, 5, or 6 non-adjacent CH2 atoms of the monocyclic or bridged carbon ring are independently replaced by -Y5-, each Y5 being independently -O-, -NH-, or -N(R11a)-; R110 is an 8-20 saturated monocyclic or bridged carbon ring, wherein 3, 4, 5, or 6 non-adjacent CH2 atoms of the monocyclic or bridged carbon ring are independently replaced by -Y6-, each Y6 being independently -O-, -NH-, or -N(R12a)-; each R11a is independently a C1-C4 alkyl group or a C1-C4 alkyl group substituted with one or more -COOH atoms; each R12a is independently a C1-C4 alkyl group or a C1-C4 alkyl group substituted with one or more -COOtBu atoms; in Formulas II and III, R5, R6, and the nitrogen atoms attached to them are formed together; The definitions of other variables are as described in any of the requests 1 through 17.

20. A compound represented by general formula III: The variables are defined as described in claim 19.

21. A compound represented by any of the following: , ...

22. A pharmaceutical composition comprising a compound of formula II as claimed in any one of claims 1 to 17, or a metal complex thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical adjuvant.

23. Use of a compound of general formula II as claimed in any one of claims 1 to 17, or a metal complex thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating tumors or a radiodiagnostic medicament for tumors.

24. The application as described in claim 23, wherein, The tumors mentioned are lung cancer, stomach cancer, colorectal cancer, cervical cancer, ovarian cancer, prostate cancer, breast cancer, pancreatic cancer, liver cancer, bladder cancer, kidney cancer, bone cancer, skin cancer, melanoma, glioma, glioblastoma, leukemia, or lymphoma.

25. The application as described in claim 23, wherein, The metal complex is a complex of a compound of general formula II chelated with a radioactive metal ion; the radioactive metal ion is a radioactive metal ion used for treatment or for diagnosis.

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