Folate receptor-targeting compounds and uses thereof

Abstract

This invention discloses a folic acid receptor-targeting compound and its uses, belonging to the field of pharmaceutical technology. The folic acid receptor-targeting compound is a compound of formula (I), its stereoisomer, its crystalline hydrate, its deuterated derivative, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof: [target]-(L x ) s -R x (I), where [target] is a folic acid receptor-binding ligand; R x The chelating group is Ch or the prosthetic group is PG; s is an integer from 1 to 10; L x It contains at least one L 3 and with AA, L 1 L 2 or L 3 Arbitrary combinations are possible. The folic acid receptor-targeting compounds of this invention have low KD values ​​and strong affinity between the ligands and receptors, and can be used as folic acid receptor-targeted radiotherapy agents for imaging, diagnosis, and treatment of folic acid receptor (FR)-expressing tumors or cells.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a folic acid receptor-targeting compound and its uses. Specifically, it relates to a folic acid receptor-targeting compound that can be used as a folic acid receptor-targeted radiotherapy agent for imaging, diagnosis, and treatment of folic acid receptor (FR)-expressing tumors or cells. Furthermore, this invention also covers pharmaceutical compositions of the said folic acid receptor-targeting compound, its preparation method, and its usage. Background Technology

[0002] In recent years, with the development of molecular biology and targeted therapy, radionuclide therapy has made significant progress in the field of tumor treatment. For example, 177 Lu-labeled radiopharmaceuticals have shown promise in the treatment of neuroendocrine tumors and other malignancies due to their good therapeutic effects and high tumor uptake rates. Furthermore, clinical research on radionuclide therapy is continuously progressing, including the exploration of new drugs and the optimization of existing treatment methods.

[0003] Despite these advances, radionuclide therapy still faces several technical challenges. First, improving drug tumor specificity and minimizing damage to normal tissues remains a significant challenge. Furthermore, dosage assessment and individualized treatment planning are current research hotspots, as accurate dosage assessment is crucial for optimizing treatment efficacy and reducing side effects. Therefore, improving drug targeting and enhancing therapeutic efficacy are key technical issues that need to be addressed in the field of radionuclide therapy.

[0004] Folate receptors (FRs) are overexpressed in various cancers, such as ovarian cancer, lung cancer, breast cancer, and brain cancer. Folate (FA), as a high-affinity ligand for FRs, can specifically recognize and bind to them. FR-based targeting technologies have been successfully applied to the diagnosis and treatment of folate receptor-positive tumors, significantly enhancing the specificity and selectivity for cancer cells. Therefore, FR-based targeting strategies hold promise for improving the safety and efficacy of related anticancer drugs in clinical practice.

[0005] Therefore, researching novel folic acid receptor-targeting compounds remains of great significance in improving targeting and therapeutic efficacy. Summary of the Invention

[0006] The purpose of this invention is to provide a folic acid receptor-targeting compound and its uses. The folic acid receptor-targeting compound has good targeting properties and can be used for imaging, diagnosis and treatment of folic acid receptor (FR)-expressing tumors or cells.

[0007] To achieve the above-mentioned objectives, the technical solution of this invention is as follows:

[0008] In a first aspect, the present invention provides a folic acid receptor-targeting compound, which is a compound of formula (I), its stereoisomer, its crystalline hydrate, its deuterated derivative, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof:

[0009] [Target Head]-(L x ) s -R x (I),

[0010] in,

[0011] [Target] is a folic acid receptor binding ligand;

[0012] R x It is a chelating group Ch or a prosthetic group PG;

[0013] s is an integer from 1 to 10;

[0014] L x It contains at least one L 3 and with AA, L 1 L 2 or L 3 Any combination,

[0015] in,

[0016] AA is independently selected from amino acid residues;

[0017] L 1 Compounds independently selected from the following structures:

[0018]

[0019] in,

[0020] R 16 Independently selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, -C(O)R 19 -C(O)OR 19 and -C(O)NR 19 R 19’ ;

[0021] Wherein, the substituents of the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl groups are independently selected from halogens, C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, and -OR groups. 20 -OC(O)R 20 -OC(O)NR 20 R 20’ -OS(O)R 20 -OS(O)2R 20 -SR20 -S(O)R 20 -S(O)2R 20 -S(O)NR 20 R 20’ -S(O)NR 20 R 20’ -OS(O)NR 20 R 20’ -OS(O)2NR 20 R 20’ -NR 20 R 20’ -NR 20 C(O)R 21 -NR 20 C(O)OR 21 -NR 20 C(O)NR 21 R 21’ -NR 20 S(O)R 21 -NR 20 S(O)2R 21 -NR 20 S(O)NR 21 R 21’ -NR 20 S(O)2NR 21 R 21’ -C(O)R 20 -C(O)OR 20 or -C(O)NR 20 R 20 ;

[0022] R 17 and R 17’ Independently selected from the group consisting of: H, halogens, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 7-membered heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5 to 7-membered heteroaryl, -OR 22 -OC(O)R 22 -OC(O)NR 22 R 22’ -OS(O)R 22 -OS(O)2R 22 -SR 22 -S(O)R 22 -S(O)2R 22 -S(O)NR 22 R 22’-S(O)NR 22 R 22’ -OS(O)NR 22 R 22’ -OS(O)2NR 22 R 22’ -NR 22 R 22’ -NR 22 C(O)R 23 -NR 22 C(O)OR 23 -NR 22 C(O)NR 23 R 23’ -NR 22 S(O)R 23 -NR 22 S(O)2R 23 -NR 22 S(O)NR 23 R 23’ -NR 22 S(O)2NR 23 R 23’ -C(O)R 22 -C(O)OR 22 or -C(O)NR 22 R 22 ';

[0023] Among them, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 The substituents of the aryl and 5- to 7-membered heteroaryl groups are independently selected from halogens, C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, and -OR groups. 24 -OC(O)R 24 -OC(O)NR 24 R 24’ -OS(O)R 24 -OS(O)2R 24 -SR 24 -S(O)R 24 -S(O)2R 24 -S(O)NR 24 R 24’ -S(O)NR 24 R 24’ -OS(O)NR 24 R 24’ -OS(O)2NR 24 R 24’ -NR 24 R 24’ -NR24 C(O)R 25 -NR 24 C(O)OR 25 -NR 24 C(O)NR 25 R 25’ -NR 24 S(O)R 25 -NR 24 S(O)2R 25 -NR 24 S(O)NR 25 R 25’ -NR 24 S(O)2NR 25 R 25’ -C(O)R 24 -C(O)OR 24 or -C(O)NR 24 R 24’ ;

[0024] R 18 Individually selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 7-membered heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5 to 7-membered heteroaryl, -OR 26 -OC(O)R 26 -OC(O)NR 26 R 26’ -OS(O)R 26 -OS(O)2R 26 -SR 26 -S(O)R 26 -S(O)2R 26 -S(O)NR 26 R 26’ -S(O)NR 26 R 26’ -OS(O)NR 26 R 26’ -OS(O)2NR 26 R 26’ -NR 26 R 26’ -NR 26 C(O)R 27 -NR 26 C(O)OR 27 -NR 26 C(O)NR 27 R27’ -NR 26 S(O)R 27 -NR 26 S(O)2R 27 -NR 26 S(O)NR 27 R 27’ -NR 26 S(O)2NR 27 R 27’ -C(O)R 26 -C(O)OR 26 or -C(O)NR 26 R 26’ ;

[0025] Among them, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 The substituents of the aryl and 5- to 7-membered heteroaryl groups are independently selected from halogens, C1-C6 alkyl groups, C2-C6 alkenyl groups, and -(CH2). p OR 28 -(CH2) p (OCH2) q OR 28 -(CH2) p (OCH2CH2) q OR 28 -OR 29 -OC(O)R 29 -OC(O)NR 29 R 29’ -OS(O)R 29 -OS(O)2R 29 -(CH2) p OS(O)2OR 29 -OS(O)2OR 29 -SR 29 -S(O)R 29 -S(O)2R 29 -S(O)NR 29 R 29’ -S(O)NR 29 R 29’ -OS(O)NR 29 R 29’ -OS(O)2NR 29 R 29’ -NR 29 R 29’ -NR 29 C(O)R 30 -NR 29C(O)OR 30 -NR 29 C(O)NR 30 R 30’ -NR 29 S(O)R 30 -NR 29 S(O)2R 30 -NR 29 S(O)NR 30 R 30’ -NR 29 S(O)2NR 30 R 30’ -C(O)R 29 -C(O)OR 29 or -C(O)NR 29 R 29’ .

[0026] R 19 R I9’ R 20 R 20’ R 21 R 21’ R 22 R 22 '、R 23 R 23’ R 24 R 24’ R 25 R 25’ R 26 R 26’ R 26” R 29 R 29’ R 30 and R 30’ Independently selected from the group consisting of: H, substituted or unsubstituted C1-C7 alkyl, substituted or unsubstituted C2-C7 alkenyl, substituted or unsubstituted C2-C7 ynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 7-membered heterocyclic alkyl, substituted or unsubstituted C6- to C10 aryl and substituted or unsubstituted 5- to 7-membered heteroaryl;

[0027] Among them, the C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 The substituents of the aryl or 5- to 7-membered heteroaryl groups are independently selected from halogens, -OH, -SH, -NH, or -COOH.

[0028] R 27 and R 27’Each is independently selected from the following groups: H, C1-C9 alkyl, C2-C9 alkenyl, C2-C9 ynyl, C3-C6 cycloalkyl, -(CH2). p (sugar), -(CH2) p (ОCH2CH2) q- (sugar) and -(CH2) p (ОCH2CH2CH2) q (sugar).

[0029] R 28 Independently selected from H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl or sugar.

[0030] w is an integer between 1 and 5, p is an integer between 1 and 5, and q is an integer between 1 and 5.

[0031] L 2 Independently selected from the following compounds:

[0032]

[0033] in,

[0034] R 31 and R 31’ Independently selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl and substituted or unsubstituted C3-C6 cycloalkyl;

[0035] Wherein, the substituents of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl and C3-C6 cycloalkyl are independently selected from halogens, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3 to 7 membered heterocyclic alkyl, C6-C 10 aryl, 5- to 7-membered heteroaryl, -OR 32 -OC(O)R 32 -OC(O)NR 32 R 32’ -OS(O)R 32 -OS(O)2R 32 -SR 32 -S(O)R 32 -S(O)2R 32 -S(O)NR 32 R 32’ -S(O)NR 32 R 32’ -OS(O)NR32 R 32’ -OS(O)2NR 32 R 32’ -NR 32 R 32’ -NR 32 C(O)R 33 -NR 32 C(O)OR 33 -NR 32 C(O)NR 33 R 33’ -NR 32 S(O)R 33 -NR 32 S(O)2R 33 -NR 32 S(O)NR 33 R 33’ -NR 32 S(O)2NR 33 R 33’ -C(O)R 32 -C(O)OR 32 or -C(O)NR 32 R 32 ;

[0036] X 6 Independently selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C6-C 10 Aryl;

[0037] Wherein, the C1-C6 alkyl and C6-C 10 The substituents of the aryl group are independently selected from halogens, C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 ynyl groups, C3-C6 cycloalkyl groups, 3- to 7-membered heterocyclic alkyl groups, and C6-C6 alkyl groups. 10 Aryl, 5- to 7-membered heteroaryl, -OR 34 -OC(O)R 34 -OC(O)NR 34 R 34’ -OS(O)R 34 -OS(O)2R 34 -SR 34 -S(O)R 34 -S(O)2R 34 -S(O)NR 34 R 34’ -S(O)NR 34 R 34’ -OS(O)NR 34 R 34’ -OS(O)2NR 34 R34’ -NR 34 R 34’ -NR 34 C(O)R 35 -NR 34 C(O)OR 35 -NR 34 C(O)NR 35 R 35’ -NR 34 S(O)R 35 -NR 34 S(O)2R 35 -NR 34 S(O)NR 35 R 35’ -NR 34 S(O)2NR 35 R 35’ -C(O)R 34 -C(O)OR 34 or -C(O)NR 34 R 34 ;

[0038] R 32 R 32 '、R 33 R 33’ R 34 R 34’ R 35 or R 35 'Independently selected from the group consisting of: H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl and 5- to 7-membered heteroaryl groups;

[0039] R 36 Independently selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl and substituted or unsubstituted C3-C6 cycloalkyl;

[0040] Wherein, the substituents of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl and C3-C6 cycloalkyl are independently selected from halogens, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3 to 7 membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 37 -OC(O)R 37 -OC(O)NR 37 R 37’ -OS(O)R 37-OS(O)2R 37 -SR 37 -S(O)R 37 -S(O)2R 37 -S(O)NR 37 R 37’ -S(O)NR 37 R 37’ -OS(O)NR 37 R 37’ -OS(O)2NR 37 R 37’ -NR 37 R 37’ -NR 37 C(O)R 38 -NR 37 C(O)OR 38 -NR 37 C(O)NR 38 R 38’ -NR 37 S(O)R 38 -NR 37 S(O)2R 38 -NR 37 S(O)NR 38 R 38’ -NR 37 S(O)2NR 38 R 38’ -C(O)R 37 -C(O)OR 37 or -C(O)NR 37 R 37 ;

[0041] R 37 R 37’ R 38 and R 38 Each is independently selected from the group consisting of: H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl and 5 to 7-membered heteroaryl groups.

[0042] L 3 Independently selected from the following compounds:

[0043]

[0044] Each rp is an independent integer between 1 and 80;

[0045] Each asterisk (*) represents a covalent bond.

[0046] In some embodiments, the [target] contains a pteroyl group or a derivative thereof.

[0047] Preferably, the [target] comprises an amino acid residue covalently attached to a pteroyl group or a derivative thereof.

[0048] In some embodiments, the [target] is a compound having the following structure:

[0049]

[0050] in,

[0051] AA is independently selected from amino acid residues;

[0052] R 1 and R 2 Independently selected from the group consisting of: H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, -OR 7 -SR 7 and -NR 7 R 7’ The substituents of the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl groups are independently selected from halogens, -OR 8 -SR 8 -NR 8 R 8’ -C(O)R 8 -C(O)OR 8 or -C(O)NR 8 R 8’ ;

[0053] R 3 R 4 R 5 and R 6 Independently selected from the group consisting of: H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, -CN, -NO2, -NCO, -OR 9 -SR 9 -NR 9 R 9’ 、-CO)R 9 -C(O)OR 9 and -C(O)NR 9 R 9’ The substituents of the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl groups are independently selected from halogens, -OR 10 -SR 10 -NR10 R 10’ 、-CO)R 10 -C(O)OR 10 or -C(O)NR 10 R 10’ ;

[0054] R 7 R 7’ R 8 R 8’ R 9 R 9’ R 10 R and R' are independently selected from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 ynyl;

[0055] X 1 Selected from -N(R) 11 -, =N-, -N=, -C(R1)= or =C(R 11 )-;

[0056] X 2 Selected from -N(R) 11’ )- or = N-;

[0057] X 3 Selected from -N(R) 11” -, -N = or -C(R) 11’ = ;

[0058] X 4 Selected from -N= or -C=;

[0059] X 5 Selected from -N(R) 12 - or -C(R) 12 (R) 12 )-;

[0060] R 1’ R 2’ R 11 R 11’ R 11” R 12 R 12’ R 13 R 14 and R 14’ Independently selected from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, -C(O)R 15 -C(O)OR 15 and C(O)NR 15 R 15’ ;

[0061] R 15and R 15 Independently selected from H or C1-C6 alkyl groups;

[0062] m is an integer from 1 to 4, and n is 0 or 1.

[0063] In some implementations, when the X 1 -N = or -C(R) 11 When ) =, the Y 1 Selected from H, -OR 13 or -SR 13 .

[0064] In some implementations, when the X 1 For -NR 11 -、=N- or =C(R) 11 When )-, the Y 1 =O.

[0065] In some implementations, when the X 4 When -C=, the Y 2 Selected from H, C1-C6 alkyl, C2-C6 alkenyl, -C(O)R 14 -C(O)OR 14 or -C(O)NR 14 R 14’ .

[0066] In some implementations, when the X 4 When -N=, Y 2 It does not exist.

[0067] In some implementations, m is 1.

[0068] In some implementations, the X 1 For -NR 11 -

[0069] In some implementations, the X 2 =N-.

[0070] In some implementations, the Y 1 =O.

[0071] In some implementations, the X 1 For -NR 11 Wherein R 11 For H.

[0072] In some implementations, the X 3 -C(R) 11’ = ).

[0073] In some implementations, the X 3-C(R) 11’ ) =, where R 11’ For H.

[0074] In some implementations, the X 4 For -C=.

[0075] In some implementations, the Y 2 For H.

[0076] In some implementations, the X 3 For -N=.

[0077] In some implementations, the X 4 For -N=.

[0078] In some implementations, the X 5 For -NR 12 .

[0079] In some implementations, the R 12 For H.

[0080] In some implementations, the R 1’ and R 2’ For H.

[0081] In some implementations, the R 1 and R 2 For H.

[0082] In some implementations, the R 3 R 4 R 5 and R 6 For H.

[0083] In some implementations, n is 1.

[0084] In some embodiments, the [target] is a compound having the following structure:

[0085]

[0086] Where n is 0 or 1, and AA represents amino acid residues.

[0087] In some embodiments, the pteroyl group or a derivative thereof is covalently bonded to at least one of the following compounds:

[0088]

[0089] In some implementations, the [target] is:

[0090]

[0091] In some embodiments, the chelating group Ch comprises a metal, a radioactive element, or Si- 18 F, B- 18 F or Al- 18 One or more of F; the prosthetic group PG is a radiolabeled prosthetic group PG.

[0092] Preferably, the chelating group Ch comprises a radioactive element selected from the group consisting of: 111 In、 99m Tc, 94m Tc, 66 Ga、 67 Ga、 68 Ga、 52 Fe、 169 Er、 72 As、 97 Ru、 203 pb, 62 Cu、 64 Cu、 67 Cu、 186 Re、 18 Re、 86 Y、 90 Y、 51 Cr 52m Mn, 177 Lu、 161 Tb, 169 Yb、 175 Yb、 105 Rh、 166 Dy、 166 Ho、 153 Sm、 149 Pm, 151 Pm, 172 Tm、 121 Sn、 117m Sn、 213 Bi、 142 Pr、 143 Pr、 198 Au、 199 Au、 123 I, 124 I, 125 I, 18 F, 149 Tb, 152 Tb, 155 Tb, 47 Sc、 44 Sc、 43 Sc、 225 Ac、 212 Pb, 211 At、 223 Ra、227 Th、 131 I, 82 Rb、 76 As、 89 Zr、 111 Ag、 165 Er、 227 Ac、and 61 Cu;

[0093] More preferably, the chelating group Ch comprises a radioactive element selected from the group consisting of: 66 Ga、 67 Ga、 68 Ga、 177 Lu and 225 Ac.

[0094] In some embodiments, the chelating group Ch is selected from the group consisting of:

[0095]

[0096] Preferably, the prosthetic group PG is labeled with a radioactive halogen selected from the group consisting of: 18 F, 75 Br、 76 Br、 77 Br、 80 Br、 80m Br、 82 Br、 123 I, 124 I, 125 I, 131 I and 211 At.

[0097] In some implementations, the R 17 and R 17’ These can be combined to form substituted or unsubstituted C4-C6 cycloalkyl groups, substituted or unsubstituted 4- to 6-membered heterocycles, wherein the substituents of the C4-C6 cycloalkyl groups and the 4- to 6-membered heterocycles are independently selected from halogens, C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 ynyl groups, C3-C6 cycloalkyl groups, 3- to 7-membered heterocyclic alkyl groups, and C6-C6 heterocyclic alkyl groups. 10 Aryl, 5- to 7-membered heteroaryl, -OR 24 -OC(O)R 24 -OC(O)NR 24 R 24’ -OS(O)R 24 -OS(O)2R 24 -SR 24 -S(O)R 24 -S(O)2R 24 -S(O)NR24 R 24’ -S(O)NR 24 R 24’ -OS(O)NR 24 R 24’ -OS(O)2NR 24 R 24’ -NR 24 R 24’ -NR 24 C(O)R 25 -NR 24 C(O)OR 25 -NR 24 C(O)NR 25 R 25’ -NR 24 S(O)R 25 -NR 24 S(O)2R 25 -NR 24 S(O)NR 25 R 25’ -NR 24 S(O)2NR 25 R 25’ -C(O)R 24 -C(O)OR 24 or -C(O)NR 24 R 24’ .

[0098] In some implementations, the L 1 Independently selected from the following compounds:

[0099]

[0100] in,

[0101] R 16 It's H.

[0102] R 17 and R 17’ Independently selected from H, C1-C6 alkyl groups or -C(O)OH,

[0103] R 18 Independently selected from H, substituted or unsubstituted C6-C 10 Aryl, -OH-SH, -NHC(=NH')NH2 or -C(O)OH,

[0104] Among them, the C6-C 10 The substituents of the aryl group are halogens.

[0105] In some implementations, the L 2Independently selected from the following compounds:

[0106]

[0107] in,

[0108] R 31 and R 31’ For H,

[0109] R 36 For H.

[0110] In some implementations, the -(L x ) s - Includes a (II-x) group, where x is an integer between 1 and 9;

[0111] The (II-x) group is selected from any of the following:

[0112]

[0113] In some embodiments, when s > 3, at least two L atoms are present in the compound of formula I. x Independently selected from the following compounds:

[0114]

[0115] Wherein, rp is independently selected from integers between 1 and 80; and the prerequisite is that the compound of formula (I) is not any of the following:

[0116]

[0117]

[0118] In some embodiments, when s > 4, the compound of formula (I) contains at least 3 L atoms. x Independently selected from the following compounds:

[0119]

[0120]

[0121] rp is independently selected from integers between 1 and 80.

[0122] Preferably, the compound of formula (I) contains at least 3 L... x Independently selected from the following compounds:

[0123]

[0124]

[0125] Here, rp is independently selected from integers between 1 and 80.

[0126] In some embodiments, at least one L in the compound of formula (I) x Selected from the following compounds:

[0127]

[0128] Preferably, at least one L in the compound of formula (I) x Selected from the following compounds:

[0129]

[0130] More preferably, at least one L in the compound of formula (I) x for

[0131] In some embodiments, the compound of formula (1), one, two or three L x Independently selected from L 1 ,

[0132] Where w is independently selected from 1 or 2,

[0133] R 18 Independently selected from substituted C6-C 10 Aryl, the C6-C 10 The substituents of the aryl group are independently selected from halogens or C1-C6 alkyl groups;

[0134] Preferably, the L x for

[0135] In some embodiments, the compound of formula (I) is: [target]-(L x ) s -Ch.

[0136] Preferably, [target head]-(L x ) s -Ch can be any of the following structures:

[0137] [Target Head]-L 3 -Ch、[Target Head]-L 1 -L 3 -Ch、[Target Head]-L 3 -L 3 -L 1 -L 1 -L 1 -L 3 -Ch、[Target Head]-L 3 -L 1-Ch、[Target Head]-L 3 -L 3 L 3 -Ch、[Target Head]-L 3 -L 3 -L 1 -L 3 -L 3 -Ch、[Target Head]-L 3 -L 1 -L 3 -Ch、[Target Head]-L 3 -L 3 -AA-L 1 -L 2 -L 3 -Ch、[Target Head]-L 3 -L 3 -L 1 -L 1 -L 1 -L 2 -Ch、[Target Head]-L 3 -L 3 -L 3 -L 1 -AA-Ch、[Target Head]-L 3 -L 3 -AA-Ch、[Target Head]-L 3 -L 3 -Ch、[Target Head]-L 3 -L 1 -AA-Ch、[Target Head]-L 3 -L 3 -L 3 -L 1 -Ch、[Target Head]-L 3 -L 3 -L 3 -L 1 -L 1 -Ch、[Target Head]-L 3 -L 1 -L 1 -L 1 -L 1 -AA-AA-AA-AA-Ch、[Target Head]-L 3 -AA-Ch、[Target Head]-L 3 -L 1 -L 1 -L 1 -AA-AA-AA-AA-Ch、[Target Head]-L 3 -L 3 -L 3 -AA-Ch, or [target]-L 3 -L3 -L 3 -L 3 -C h, where AA is independently selected from amino acid residues.

[0138] Preferably, the [target head]-(L x ) s -Ch can be any of the following structures:

[0139] [Target Head]-L 3 -Ch、[Target Head]-L 1 -L 1 -L 1 -L 3 -Ch、[Target Head]-L 3 -Ch、[Target Head]-L 3 -L 3 -Ch、[Target Head]-L 1 -L 3 -L 3 -Ch、[Target Head]-L 1 -L 3 -Ch、[Target Head]-L 3 -L 3 -AA-L 1 -L 2 -L 3 -Ch、[Target Head]-L 1 -L 1 -L 1 -L 2 -Ch、[Target Head]-L 3 -L 3 -L 1 -AA-Ch、[Target Head]-L 3 -AA-Ch、[Target Head]-L 1 -AA-Ch、[Target Head]-L 3 -L 3 -L 1 -Ch、[Target Head]-L 3 -L 1 -Ch、[Target Head]-L 3 -L 3 -L 1 -L 1 -Ch、[Target Head]-L 3 -L 1 -L 1 -Ch or [target]-L 1 -L 1 -L 1 -L 1 -L 2 -L 3 -L 1 -L1 -Ch, where AA is independently selected from amino acid residues.

[0140] In some embodiments, the compound of formula (1) is any one of the following compounds:

[0141]

[0142]

[0143] Wherein, BL stands for [target].

[0144] Preferably, any L in the compound of formula (1) x A group is affected by different L x Alternatives, wherein one of the groups is an AA group, and the different L x For a corresponding group, different AA groups, wherein the different AA groups are conserved amino acid substitutions of the AA group.

[0145] In some embodiments, the compound of formula (1) is any one of the following compounds:

[0146]

[0147]

[0148]

[0149]

[0150]

[0151] The chelating group Ch contains radioactive elements, Si- 18 F, B- 18 F, or Al- 18 F.

[0152] In some embodiments, the compound of formula (I) is:

[0153]

[0154] Wherein, M is a bound radioactive element, and M is... 177 Lu or 225 Ac.

[0155] In some embodiments, the compound of formula (I) comprises the following groups:

[0156]

[0157] In this context, ** represents the carboxyl group at the α, β, γ, δ, ε, or ζ position of the carbonyl group.

[0158] In a second aspect, the present invention provides a pharmaceutical composition comprising the aforementioned folic acid receptor-targeting compound and a pharmaceutically acceptable carrier.

[0159] Preferably, the pharmaceutical composition is a tablet, pill, cream, emulsion, ointment, suspension, lyophilized agent, capsule, sustained-release agent, granule, powder, injectable agent, or spray.

[0160] Thirdly, the present invention provides the use of the aforementioned folic acid receptor-targeting compounds or the aforementioned pharmaceutical compositions in the preparation of a medicament for treating proliferative diseases.

[0161] Preferably, the proliferative disease is cancer.

[0162] Fourthly, the present invention provides the use of the aforementioned folic acid receptor-targeting compounds or the aforementioned pharmaceutical compositions in the preparation of medicaments for treating cancer.

[0163] Preferably, the cancer is selected from the group consisting of: lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, melanoma of the skin or eye, ovarian cancer, rectal cancer, anal cancer, gastric cancer, colon cancer, breast cancer, triple-negative breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancers, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system vegetations (CNS), primary CNS lymphoma, spinal axis tumors, brainstem gliomas, or pituitary adenomas.

[0164] Fifthly, the present invention provides the use of the aforementioned folic acid receptor-targeting compounds or pharmaceutical compositions in the preparation of folic acid receptor-targeting radiotherapy agents.

[0165] In a sixth aspect, the present invention provides a method for treating FR-expressing tumors or cells, comprising contacting one or more FR-expressing tumors or cells with an effective amount of the aforementioned folic acid receptor-targeting compound or the aforementioned pharmaceutical composition.

[0166] Preferably, the folic acid receptor-targeting compound contains a chelating group that chelates radioactive elements.

[0167] Preferably, the FR-expressing tumor or cells are expressed in vitro, in vivo, or ex vivo.

[0168] In a seventh aspect, the present invention provides a method for imaging FR-expressing cells in a subject, comprising administering an effective amount of the aforementioned folic acid receptor-targeting compound or the aforementioned pharmaceutical composition to the subject.

[0169] Preferably, the folic acid receptor-targeting compound contains a metal, a radioactive element, or a radioactive halogen.

[0170] Eighthly, the present invention provides a method for treating proliferative diseases in a subject in need, comprising administering to the subject a therapeutically effective amount of the aforementioned folic acid receptor-targeting compound or the aforementioned pharmaceutical composition; wherein the folic acid receptor-targeting compound comprises a chelating group that chelates a radioactive element.

[0171] Preferably, the proliferative disease is cancer; more preferably, the cancer is selected from the group consisting of: lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, melanoma of the skin or eye, ovarian cancer, rectal cancer, anal cancer, gastric cancer, colon cancer, breast cancer, triple-negative breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancers, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system vegetations (CNS), primary CNS lymphoma, spinal axis tumors, brainstem gliomas, or pituitary adenomas.

[0172] Preferably, the method further includes administering an effective amount of folic acid to the subject.

[0173] Preferably, the method further includes administering an effective amount of an anti-folic acid agent to the subject.

[0174] Preferably, the method further includes administering an effective amount of a radiosensitizer to the subject.

[0175] The beneficial effects of this invention are:

[0176] The compounds provided by this invention can specifically target folate receptor (FR)-positive tumors or cells, especially those cancer types that express or overexpress folate receptors. The folate receptor-targeting compounds of this invention have low KD values ​​and strong affinity between the ligand and receptor, and can be used as folate receptor-targeted radiotherapy agents for imaging, diagnosis, and treatment of folate receptor (FR)-expressing tumors or cells. Attached Figure Description

[0177] Figure 1 The biodistribution of the compound in Hela tumor-bearing mice was shown at 0.5 hours (left) and 1 hour (right) after injection of the positive control compound.

[0178] Figure 2 The results showed that in Hela tumor-bearing mice, after injection 68 Biodistribution of Ga-BL-6 compound in vivo at 0.5 hours (left) and 1 hour (right);

[0179] Figure 3 The biodistribution of the compound in KB tumor-bearing mice was shown at 0.5 hours (left) and 1 hour (right) after injection of the positive control compound.

[0180] Figure 4 The image shows the effect of injection in KB tumor-bearing mice. 68 Biodistribution of Ga-BL-7 compound in vivo at 0.5 hours (left) and 1 hour (right);

[0181] Figure 5 The results showed that in Hela tumor-bearing mice, after injection of the positive control compound and 68 In vivo biodistribution analysis results of Ga-BL-6 compound 1 hour after administration, specific percentage injection dose / g (%ID / g);

[0182] Figure 6 The results showed that in Hela tumor-bearing mice, after injection 68 The results of the biodistribution analysis of Ga-BL-6 compound 1 hour after administration are plotted as the ratio of tumor to kidney, tumor to liver, and tumor to muscle.

[0183] Figure 7 The results showed that in KB tumor-bearing mice, after injection of the positive control compound and 68 In vivo biodistribution analysis results of Ga-BL-7 compound 1 hour after administration, specific percentage injection dose / g (%ID / g);

[0184] Figure 8 The results showed that in KB tumor-bearing mice, after injection of the positive control compound and 68 The results of the biodistribution analysis of Ga-BL-7 compound 1 hour after administration are plotted as the ratio of tumor to kidney, tumor to liver, and tumor to muscle. Detailed Implementation

[0185] Unless otherwise stated, the following terms and phrases used in this invention have the following meanings:

[0186] In this invention, the terms "comprising," "having," "including," and "containing," and their grammatical variations, are interpreted inclusively or openly, not excluding the presence of other elements and / or method steps not explicitly listed. When these terms are associated with a composition, use, or method, "consistently composed of..." indicates the possible presence of other elements and / or steps, but these additions do not materially affect the effectiveness of the listed composition, method, or use; while "composed of..." excludes the presence of other elements and / or steps. Compositions, uses, or methods comprising certain elements and / or steps described in this invention may consist substantially of these elements and / or steps in some embodiments, and entirely of these elements and / or steps in other embodiments, regardless of whether these embodiments are specifically mentioned.

[0187] The use of the indefinite article "a" to refer to an element does not preclude the possibility of multiple instances of that element, unless the context explicitly requires the presence of only one element. Unless otherwise explicitly indicated, the singular forms "a," "an," and "the" also include plural referents. When used with "comprising," "a" or "an" can refer to "a," but the same applies to the meanings of "one or more," "at least one," and "one or more."

[0188] The terms “some implementations,” “certain implementations,” “one implementation,” and similar terms include one or more specific features described for the implementation, either alone or in combination with any other one or more implementations described herein, whether or not directly or indirectly referencing the other implementations, and whether or not the features or implementations are described in the context of methods, products, uses, compositions, compounds, etc.

[0189] Folic acid receptor-targeting compounds

[0190] "Stereoisomers" are compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and hindered isomers.

[0191] Compounds of Formula I in this invention may have a chiral center, such as a chiral carbon. The compounds therefore comprise racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and transisomers. Additionally, the compounds of this invention comprise optical isomers enriched or resolved at any or all asymmetric chiral atoms. In other words, the chiral center, similar to that described, is provided in the form of chiral isomers or racemic mixtures. Mixtures of racemic and diastereomers, as well as isolated or synthesized individual optical isomers substantially free of their enantiomers or diastereomer conjugates, are all within the scope of this invention. Racemic mixtures are isolated into their individual, substantially optically pure isomers using known techniques, such as isolating salts of diastereomers formed with optically active auxiliaries (e.g., acids or bases) and then converting them back to the optically active substance. In most cases, the desired optical isomer is synthesized from a suitable stereoisomer of the desired starting material through a stereospecific reaction.

[0192] "Hydrate" refers to an assemblage formed when the solvent molecules are water.

[0193] "Deuteration" refers to the substitution of one or more hydrogen atoms in a compound or group by deuterium. Deuteration can be monosubstituted, disubstituted, polysubstituted, or total substituted.

[0194] "Solvate" refers to an association formed by one or more solvent molecules with the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.

[0195] The term "prodrug" is used in its broadest sense and includes those derivatives that are converted into the compounds of this invention in vivo. These derivatives are readily apparent to those skilled in the art. In prodrug design, the most common form is the structural modification of drugs containing carboxyl, hydroxyl, or amino groups to produce prodrugs of the types of esters, carboxylic acid esters, amino acid esters, amides, and phosphate esters. In addition, azo prodrugs, nitric oxide prodrugs, and prodrugs with novel structures such as open-ring and closed-ring prodrugs can also be produced.

[0196] Preferred prodrugs are those that, relative to the parent substance, improve the bioavailability of the compounds of the invention when used on a patient (e.g., by making orally administered compounds more readily absorbed into the bloodstream) or enhance the delivery of the parent compound to biological compartments (brain or lymphatic system).

[0197] The compounds of this invention may be in crystalline form as a beneficial compound or as a solvator, both of which are included within the scope of this invention. Methods of solvation are well known in the art. Suitable solvators are pharmaceutical solvators.

[0198] "Pharmaceutically acceptable salts" include salts derived from suitable bases, such as alkali metals or alkaline earth metals (e.g., Na₂O₃). + Li + K + Ca +2 and Mg +2 ) and ammonium. Physiologically acceptable salts of nitrogen atoms or amino groups include: (a) acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc.; (b) salts formed with organic acids, such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, ethanesulfonic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalene. Sulfonic acids, methanesulfonic acids, p-toluenesulfonic acids, benzenesulfonic acids, naphthalenedisulfonic acids, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthylcarboxylate, dihydroxynaphthylcarboxylate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine, etc.; and (c) salts formed with elemental anions, such as chlorine, bromine, and iodine. Physiologically acceptable salts of hydroxyl compounds include salts formed with anions of the compounds such as Na+. + and NR4 + A suitable combination of cations.

[0199] The term "acceptable" as used in this invention refers to salts that are physiologically acceptable, meaning they are salts derived from physiologically acceptable acids or bases. However, salts that are not physiologically acceptable acids or bases may also be used, for example, to prepare or purify physiologically acceptable compounds. All salts, whether or not derived from physiologically acceptable acids or bases, are within the scope of this invention.

[0200] Compounds of Formula I or their pharmaceutically acceptable salts can exist as different polymorphs or pseudopolymorphs. Crystal polymorphism, as used in this invention, refers to the ability of a crystalline compound to exist in different crystal structures. Crystal polymorphism can originate from differences in crystal packing (packing polymorphism) or differences in packing between different conformational isomers of the same molecule (conformational polymorphism). Pseudopolymorphism, as used in this invention, refers to the ability of a compound's hydrates or solvates to exist in different crystal structures. Pseudopolymorphs of this invention can exist due to differences in crystal packing (packing pseudopolymorphism) or due to differences in packing between different conformational isomers of the same molecule (conformational pseudopolymorphism). This invention encompasses all polymorphs and pseudopolymorphs of compounds of Formula I and their pharmaceutically acceptable salts.

[0201] Compounds of Formula I or their pharmaceutically acceptable salts can also exist as amorphous solids. The amorphous solids used in this invention are solids in which the positions of atoms do not exhibit long-range order. This definition also applies when the crystal size is 2 nanometers or less. Additives, including solvents, can be used to establish the amorphous forms of this invention. This invention encompasses all amorphous forms of compounds of Formula I and their pharmaceutically acceptable salts.

[0202] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg, "Advanced Organic Chemistry 4th Edition," Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise stated, conventional methods within the scope of the art, such as mass spectrometry, NMR, IR, UV / Vis spectroscopy, and pharmacological methods, are employed. Unless specifically defined, the terminology used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry is known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, reactions and purifications can be carried out using the manufacturer's instructions for use of kits, or in accordance with methods known in the art or the description of this invention. The techniques and methods described above can generally be carried out according to conventional methods well known in the art, based on the descriptions in the various summary and more specific references cited and discussed in this specification. In this invention, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0203] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2.

[0204] Unless otherwise stated, the commonly used chemical terms, such as, but not limited to, “alkyl,” “alkenyl,” “ynyl,” “cycloalkyl,” “heterocycloalkyl,” “aryl,” and “heteroaryl,” are equivalent to their optionally substituted forms. For example, “alkyl” as used in this invention includes optionally substituted alkyl groups.

[0205] In this invention, "unsubstituted" means not substituted by a substituent, and "substituted" means substituted by a substituent. Specifically, one or more hydrogen atoms on a particular atom are replaced by a specified group. If the normal valence of the specified atom is not exceeded under existing conditions, then the result of the substitution is a stable compound.

[0206] C1-C used in this invention n Including C1-C2, C1-C3, ..., C1-Cn For example, the term "C1-C4" group refers to a group having 1-4 carbon atoms, meaning the group contains 1, 2, 3, or 4 carbon atoms. Therefore, "C1-C4 alkyl" refers to an alkyl group having 1-4 carbon atoms, where the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Numerical ranges in this invention, such as "1-6," refer to integers within a given range; for example, "1-6 carbon atoms" means the group can have 1, 2, 3, 4, 5, or 6 carbon atoms.

[0207] The term "alkyl" as used alone or in combination in this invention refers to a saturated aliphatic hydrocarbon that is optionally substituted with a straight chain or optionally substituted with a branched chain. Examples of alkyl compounds in this invention include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl.

[0208] When the group defined in this invention, such as "alkyl", appears in a numerical range, for example, "C1-C6 alkyl" or "C 1-6 "Alkyl" refers to an alkyl group that can be composed of 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl groups of this invention also include those for which no numerical range is specified.

[0209] In this invention, "alkyl" refers to an alkyl group linked with other groups, such as alkyl in alkoxy, alkyl in alkylthio, hydroxyalkyl, haloalkyl, cyanalkyl, monoalkylamino, dialkylamino, etc.

[0210] The term "alkenyl" as used alone or in combination herein refers to a monovalent hydrocarbon group of optional substituted straight or optional substituted branched form having at least one C=C double bond. The alkenyl group has, but is not limited to, 2 to about 6 carbon atoms, for example, 2 to about 4 carbon atoms or 2 to about 6 carbon atoms. The double bond in these groups can be in cis or trans conformation and should be understood to include both isomers. Examples include, but are not limited to, vinyl (CH=CH2), 1-propenyl (CH2CH=CH2), isopropenyl (C(CH3)=CH2), etc. When alkenyl groups as defined herein appear in numerical ranges, for example, "C2-C6 alkenyl" or "C 2-6 "Alkenyl" refers to an alkenyl group that can be composed of 2, 3, 4, 5, or 6 carbon atoms. The alkenyl groups in this invention also cover cases where no numerical range is specified.

[0211] The term "alkynyl" as used alone or in combination in this invention refers to an optionally substituted straight-chain or branched monovalent hydrocarbon group having at least one C≡C triple bond. The alkynyl group has, but is not limited to, 2 to about 6 carbon atoms, for example, having 2 to about 6 carbon atoms, or 2 to about 4 carbon atoms. Examples of alkynyl groups in this invention include, but are not limited to, acetylenyl, 2-propynyl, etc. When the alkynyl group defined in this invention has a numerical range, for example, "C2-C6 alkynyl" or "C 2-6 "Alkyne" refers to an alkynyl group that can be composed of 2, 3, 4, 5, or 6 carbon atoms. The alkynyl groups in this invention also cover cases where no numerical range is specified.

[0212] The term "aryl" as used alone or in combination in this invention refers to an optionally substituted aromatic hydrocarbon group having 6 to about 10, such as 6 to 8 or 6 to 10 cyclic carbon atoms, which may be monocyclic aryl, bicyclic aryl or more cyclic aryl.

[0213] The term "heteroaryl" as used alone or in combination in this invention refers to an arbitrarily substituted heteroaryl group comprising about 5 to about 7 skeletal cyclic atoms, wherein at least one (e.g., 1-4, 1-3, 1-2) of the cyclic atoms is a heteroatom, which is independently selected from, but not limited to, heteroatoms of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin. Heteroaryls include monocyclic heteroaryls (having one ring), bicyclic heteroaryls (having two rings), or polycyclic heteroaryls (having two or more rings). In embodiments where two or more heteroatoms appear in the ring, the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other. Bicyclic or more cyclic heteroaryls may be a monocyclic heteroaryl group fused with other independent rings, such as alicyclic, heterocyclic, aromatic, or aromatic-heterocyclic rings (collectively referred to as fused cyclic heteroaryls). Non-limiting examples of monocyclic heteroaryl groups include monocyclic heteroaryl groups with 5 to about 7 or 6 skeletal cyclic atoms, such as including but not limited to: pyridine, pyrimidine, pyrazine, pyridazine, triazine, furan, thiophene, imidazole, triazole, tetrazolium, thiazole, isothiazole, 1,2,4-thiadiazole, pyrrole, pyrazole, oxazole, isoxazole, oxadiazole, benzofuran, benzothiophene, benzothiazole, indole, indazole, quinoline, isoquinoline, purine, carbazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine, pyrazolopyridine, pyrazolopyrimidine, etc.; acridinel, phenazinyl, benzoxazolyl, benzothiadiazolel, benzoxazolyl, etc. The group includes azole, benzotriazolyl, isoquinolinyl, indolizinyl, isothiazolyl, isoindolyl, oxadiazolyl, purinyl, phthalazinyl, pteridinyl, quinazolinyl, quinoxalinyl, triazinyl, and thiadiazolyl, among others.

[0214] The term "heterocycle," used alone or in combination in this invention, refers to a non-aromatic heterocycle, including saturated heterocycles or unsaturated heterocycles (containing unsaturated bonds). One or more of the cyclic atoms (e.g., 1-4, 1-3, 1-2) are heteroatoms, such as oxygen, nitrogen, or sulfur atoms. Heterocycles can include monocyclic (having one ring), bicyclic (having two bridging rings), or polycyclic (having more than two bridging rings); spirocyclics are also included. The heterocyclic group can have 3 to about 7, such as 4-7, 5-6, 3-4, or 4-5 cyclic atoms.

[0215] The "cycloalkyl" used alone or in combination in this invention can have 3 to 6 carbon atoms, for example, 3 to about 4 cyclic carbon atoms, 4 to about 5 cyclic carbon atoms, or 5 to 6 cyclic carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0216] In this invention, "halogen" refers to fluorine, chlorine, bromine, and iodine. A cyano group is "-CN"; a hydroxyl group is "-OH"; a mercapto group is "-SH"; and an amino group is "-NH2".

[0217] In this invention, "*" represents a covalent bond, "**" represents a carboxyl group at the β, γ, δ, ε, or ζ position of the carbonyl group, "(R)" and "(r)" have the same meaning, representing the R configuration, and "S" represents the S configuration.

[0218] All ranges listed in this invention are inclusive. For example, "n is an integer between 0 and 5" means that n can be 0, 1, 2, 3, 4, or 5, and n can be replaced by letters such as w, p, q, rp, etc.

[0219] Pharmaceutical Composition

[0220] The pharmaceutical compositions described in this invention comprise the aforementioned folic acid receptor-targeting compounds and pharmaceutically acceptable excipients. In some embodiments, the folic acid receptor-targeting compounds described in this invention are provided in the pharmaceutical composition in an effective amount (e.g., a therapeutically effective amount).

[0221] The pharmaceutical compositions of this invention are formulated with conventional carriers and excipients, which will be selected according to conventional practice. Although the active ingredients can be administered alone, it is preferred to formulate them into pharmaceutical preparations. The preparations of this invention, whether for animal or human use, comprise at least one active ingredient as defined above and one or more acceptable carriers therefor, and optionally include other therapeutic ingredients, particularly those disclosed herein. The carrier must be "acceptable," meaning compatible with other components in the preparation and physiologically harmless to its recipient.

[0222] The pharmaceutical compositions described in this invention can be prepared by any method known in pharmaceutical science. Generally, these preparation methods involve associating the folic acid receptor-targeting compound (i.e., the “active ingredient”) with a carrier or excipient and / or one or more other auxiliary ingredients, and then, if desired and / or expected, shaping and / or packaging the product into desired single-dose or multi-dose units.

[0223] The pharmaceutical compositions of the present invention can be prepared according to known methods, such as those described in the General Rules for Preparation of Pharmaceuticals in the Chinese Pharmacopoeia, the 16th edition of the Japanese Pharmacopoeia, the United States Pharmacopoeia, and the 9th edition of the European Pharmacopoeia. Depending on the dosage form, the pharmaceutical compositions of the present invention can be appropriately administered to patients.

[0224] Pharmaceutical compositions may be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as multiple single unit doses. A “unit dose” is a discrete amount of a pharmaceutical composition containing a predetermined amount of the active ingredient. The amount of the active ingredient is typically equal to the dose of the active ingredient administered to a subject and / or a convenient fraction of that dose (e.g., one-half or one-third of the dose).

[0225] The active ingredient and pharmaceutically acceptable excipients in the pharmaceutical compositions described in this invention will vary depending on the identity, body type, and / or condition of the treated subject and further on the route of administration of the composition. The pharmaceutical composition may contain between 0.1% and 100% (w / w) of the active ingredient.

[0226] Pharmaceutically acceptable excipients used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersants and / or granulators, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants and / or oils. The pharmaceutical compositions may also contain excipients (e.g., cocoa butter and suppository waxes), colorants, coating agents, sweeteners, flavoring agents, and aroma agents.

[0227] In this invention, terms such as “treat,” “treatment,” and “therapeutic” include alleviating symptoms, slowing disease progression, improving prognosis, and reducing recurrence (e.g., reducing cancer recurrence).

[0228] In this invention, "diagnostic agent" includes "imaging agent". Therefore, "diagnosing radioactive metals" includes radioactive metals suitable for use in imaging agents, and "diagnosing radioactive isotopes" includes radioactive isotopes suitable for use in imaging agents.

[0229] In this invention, "subject" refers to an animal, including mammals and non-mammals. Subjects can be humans or non-human primates, laboratory mammals (e.g., mice, rats, rabbits, hamsters, etc.), agricultural animals (e.g., horses, sheep, cattle, pigs, camels, etc.) or domesticated animals (e.g., dogs, cats, etc.).

[0230] Application route

[0231] The folic acid receptor-targeting compounds or pharmaceutical compositions of the present invention may be administered via any route suitable for the condition being treated. Suitable routes include oral, rectal, nasal, pulmonary, local (including oral and sublingual), and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It should be understood that preferred routes may vary depending on, for example, the recipient's condition. The advantage of the folic acid receptor-targeting compounds or pharmaceutical compositions of the present invention is that they are orally bioavailable and can be administered orally.

[0232] It should also be noted that the specific dosage and method of administration of the folic acid receptor-targeting compounds for different patients are determined by many factors, including the patient's age, weight, sex, natural health condition, nutritional status, drug activity, timing of administration, metabolic rate, severity of condition, and the subjective judgment of the treating physician. The effective dosage of the active ingredient depends at least on the nature of the condition to be treated, its toxicity (regardless of whether the compound is used prophylactically or against an active viral infection), the method of delivery, and the pharmaceutical formulation, and will be determined through clinicians using routine dose escalation studies. Expected dosages are approximately 0.0001 to approximately 100 mg / kg body weight per day; typically, approximately 0.01 to approximately 10 mg / kg body weight per day; more typically, approximately 0.01 to approximately 5 mg / kg body weight per day; and most typically, approximately 0.05 to approximately 0.5 mg / kg body weight per day. For example, for an adult weighing approximately 70 kg, the candidate daily dose would be in the range of 1 mg to 1000 mg, preferably 5 mg to 500 mg, and could be administered in single or multiple doses.

[0233] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0234] It is worth noting that the present invention provides a method for preparing intermediate compounds of related compounds, and the raw materials used in each step can be commercially available or obtained by conventional organic synthesis methods.

[0235] [Intermediate compounds]

[0236] In this embodiment This indicates a resin (Wang's resin or dichloro resin) suitable for solid-phase peptide synthesis.

[0237] Example 1 Intermediate 2a

[0238] The synthesis method is as follows:

[0239]

[0240] 1a (1 mmol) and 1b (1.2 mmol) were added to a reaction flask, dissolved in 10 mL of LMF, and then cesium carbonate (2 mmol) was added. The mixture was reacted at room temperature for 12 hours. The reaction solution was purified by preparative column HPLC to obtain the target product 2a. LCMS (ESI): [M+H] + =For C 18 H 20 The calculated value of N6O3 is 368.40; the measured value is 368.39.

[0241] Example 2 Intermediate 2a-1

[0242] The synthesis method is as follows:

[0243]

[0244] 2a was dissolved in trifluoroacetic acid (TFA), reacted at room temperature for 3 hours, and the solvent was removed by rotary evaporation under vacuum to obtain the target product 2a-1. LCMS (ESI): [M+H] + =For C 16 H 11 The calculated value of F3N6O4 is 408.30; the measured value is 408.29.

[0245] Example 3 Intermediate 3a

[0246] The synthesis method is as follows:

[0247]

[0248] 1a (1 mmol) and 1b (1.2 mmol) were added to a reaction flask, dissolved in 10 mL of LDM, and then a condensation aid (2 mmol) and a base (2.4 mmol) were added. The mixture was reacted at room temperature for 6 hours. The reaction solution was purified by preparative column HPLC to obtain the target product 3a. LCMS (ESI): [M+H] + =For C 37 H 33 The calculated value of F3N8O7 is 758.72; the measured value is 773.68.

[0249] Example 4 Intermediate A1

[0250] The synthesis method is as follows:

[0251]

[0252] The intermediate A1 is obtained by attaching 3a to the resin using conventional methods.

[0253] Example 5 Intermediate A2

[0254] The synthesis method is as follows:

[0255]

[0256]

[0257] First, remove the Fmoc protection at the A1 end using standard methods, then use standard methods to combine it with L. 3 -1 is coupled to obtain intermediate A2.

[0258] Example 6 Intermediate A3

[0259] The synthesis method is as follows:

[0260]

[0261] First, the Fmoc protection at the end of A2 is removed using a general method, and then it is coupled with L-1 using a general method to obtain intermediate A3.

[0262] Example 7 Intermediate A4

[0263] The synthesis method is as follows:

[0264]

[0265] First, the Fmoc protection at the end of A3 is removed using a general method, and then the intermediate A4 is obtained by coupling it with DOTA using a general method.

[0266] Example 8 Intermediate A5

[0267] The synthesis method is as follows:

[0268]

[0269] Resin was removed from intermediate A4 to obtain intermediate A5. LCMS (ESI): [M+H] + =For C 63 H 75 F3N 14 O 14 The calculated value is 1309.37; the measured value is 1309.51.

[0270] Example 9 Compound BL-1

[0271] The synthesis method is as follows:

[0272]

[0273] X on intermediate A5 5 De-trifluoroacetyl group at position 1 yields the final compound BL-1. LCMS (ESI): [M+H] + =For C 61 H 76N 14 O 13 The calculated value is 1213.36; the measured value is 1309.51.

[0274] Example 10 Compound BL-2

[0275] The synthesis method is as follows: Using the same method as in Example 8, L... 3 -1 is replaced with L 3 -2, yielding compound BL-2. LCMS(ESI): [M+H] + =For C 61 H 76 N 14 O 13 The calculated value is 1213.36; the measured value is 1309.51.

[0276]

[0277] Example 11 Intermediate A6

[0278] The synthesis method is as follows:

[0279]

[0280] First, the Fmoc protection at the end of A3 is removed using a general method, and then the intermediate A6 is obtained by coupling it with a DOTA derivative using a general method.

[0281] Example 12 Compound BL-3

[0282] The synthesis method is as follows:

[0283]

[0284] Using the same method as BL-1, A6 underwent resin removal and then deprotection of the trifluoroacetyl group to finally obtain compound BL-3. LCMS(ESI): [M+H] + =For C 64 H 80 N 14 O 15 The calculated value is 1285.43; the measured value is 1309.51.

[0285] Example 13 Compound BL-4

[0286] The synthesis method is as follows:

[0287]

[0288] Using the same method as BL-3, L 3 -1 is replaced with L 3-2 yields compound BL-4. LCMS (ESI): [M+H] + =For C 64 H 80 N 14 O 15 The calculated value is 1285.43; the measured value is 1309.51.

[0289] Example 14 Intermediate B1

[0290] The synthesis method is as follows:

[0291]

[0292] First, remove the Fmoc protection at the A1 end using standard methods, then react with Fmoc-Asp-O using standard methods. t Bu is coupled to obtain intermediate B1.

[0293] Example 15 Intermediate B2

[0294] The synthesis method is as follows:

[0295]

[0296] First, remove the B1-terminal Fmoc protection using standard methods, then use standard methods to combine it with L... 3 -1 is coupled to obtain intermediate B2.

[0297] Example 16 Intermediate B3

[0298] The synthesis method is as follows:

[0299]

[0300] First, the Fmoc protection at the end of B2 is removed by conventional methods, and then intermediate B3 is obtained by coupling with Fmoc-Gly-OH by conventional methods.

[0301] Example 17 Intermediate B4

[0302] The synthesis method is as follows:

[0303]

[0304] First, the Fmoc protection at the end of B3 is removed using a conventional method, and then it is coupled with a DOTA derivative using a conventional method to obtain intermediate B4.

[0305] Example 18 Compound BL-5

[0306] The synthesis method is as follows:

[0307]

[0308] Using the same method as BL-1, B4 underwent resin removal, followed by removal of trifluoroacetyl and tert-butyl protection, ultimately yielding compound BL-5. LCMS (ESI): [M+H] + =For C 59 H 71 N 15 O 16 The calculated value is 1246.31; the measured value is 1246.52.

[0309] Example 19 Compound BL-6

[0310] The synthesis method is as follows:

[0311]

[0312] Using the same method as BL-5, L 3 -1 is replaced with L 3 -2 yields compound BL-6. LCMS (ESI): [M+H] + =For C 59 H 71 N 15 O 16 The calculated value is 1246.31; the measured value is 1246.52.

[0313] Example 20 Intermediate C1

[0314] The synthesis method is as follows:

[0315]

[0316] First, the Fmoc protection at the A2 end is removed using a general method, and then the intermediate C1 is obtained by coupling with Fmoc-Gly-OH using a general method.

[0317] Example 21 Intermediate C2

[0318] The synthesis method is as follows:

[0319]

[0320]

[0321] First, the Fmoc protection at the end of C1 is removed using a general method, and then the intermediate C2 is obtained by coupling it with a DOTA derivative using a general method.

[0322] Example 22 Compound BL-7

[0323] The synthesis method is as follows:

[0324]

[0325] Using the same method as BL-1, C2 underwent resin removal and then deprotection of the trifluoroacetyl group to finally obtain compound BL-7. LCMS(ESI): [M+H] + =For C 55 H 66 N 14 O 13 The calculated value is 1131.22; the measured value is 1131.31.

[0326] Example 23 Compound BL-8

[0327] The synthesis method is as follows:

[0328]

[0329] Using the same method as BL-7, L 3 -1 is replaced with L 3 -2 yields compound BL-8. LCMS (ESI): [M+H] + =For C 55 H 66 N 14 O 13 The calculated value is 1131.22; the measured value is 1131.31.

[0330] Example 24 Intermediate B5

[0331] The synthesis method is as follows:

[0332]

[0333] First, the Fmoc protection at the B2 end is removed using a conventional method, and then the intermediate B5 is obtained by coupling it with a DOTA derivative using a conventional method.

[0334] Example 25 Compound BL-9

[0335] The synthesis method is as follows:

[0336]

[0337] Using the same method as BL-5, C2 underwent resin removal, followed by removal of trifluoroacetyl and tert-butyl protection, ultimately yielding compound BL-9. LCMS (ESI): [M+H] + =For C 57 H 68 N 14 O 15 The calculated value is 1189.25; the measured value is 1189.20.

[0338] Example 26 Compound BL-10

[0339] The synthesis method is as follows:

[0340]

[0341] Using the same method as BL-7, L 3 -1 is replaced with L 3 -2 yields compound BL-10. LCMS (ESI): [M+H] + =For C 57 H 68 N 14 O 15 The calculated value is 1189.25; the measured value is 1189.20.

[0342] Example 27 Intermediate B6

[0343] The synthesis method is as follows:

[0344]

[0345] First, the Fmoc protection at the B1 terminal is removed using a conventional method, and then the intermediate B6 is obtained by coupling with Fmoc-2-Nal-OH using a conventional method.

[0346] Example 28 Intermediate B7

[0347] The synthesis method is as follows:

[0348]

[0349] First, remove the B1-terminal Fmoc protection using standard methods, then use standard methods to combine it with L... 3 -1 is coupled to obtain intermediate B7.

[0350] Example 29 Intermediate B8

[0351] The synthesis method is as follows:

[0352]

[0353]

[0354] First, the Fmoc protection at the end of B6 was removed using a conventional method, and then the intermediate B8 was obtained by coupling it with a DOTA derivative using a conventional method.

[0355] Example 30 Compound BL-11

[0356] The synthesis method is as follows:

[0357]

[0358] Using the same method as BL-5, B6 underwent resin removal, followed by removal of trifluoroacetyl and tert-butyl protection, ultimately yielding compound BL-11. LCMS (ESI): [M+H] + =For C 70 H 79 N 15 O 16 The calculated value is 1386.49; the measured value is 1386.73.

[0359] Example 31 Intermediate B9

[0360] The synthesis method is as follows:

[0361]

[0362] First, the Fmoc protection at the B2 terminal was removed using a conventional method, and then the intermediate B9 was obtained by coupling with Fmoc-2-Nal-OH using a conventional method.

[0363] Example 32 Intermediate B10

[0364] The synthesis method is as follows:

[0365]

[0366] First, the Fmoc protection at the B9 terminal was removed using a conventional method, and then the intermediate B10 was obtained by coupling it with a DOTA derivative using a conventional method.

[0367] Example 33 Compound BL-12

[0368] The synthesis method is as follows:

[0369]

[0370] Using the same method as BL-7, B10 underwent resin removal, followed by removal of trifluoroacetyl and tert-butyl protection, ultimately yielding compound BL-12. LCMS (ESI): [M+H] + =For C 70 H 79 N 15 O 16 The calculated value is 1386.49; the measured value is 1386.73.

[0371] Example 34 Compound BL-13

[0372] The synthesis method is as follows:

[0373]

[0374] Replace Fmoc-2-Nal-OH with L using the same method as BL-12. 3 -1 yields compound BL-13. LCMS (ESI): [M+H] + =For C 74 H 81 N 15 O 16 The calculated value is 1436.55; the measured value is 1435.67.

[0375] Example 35 Compound BL-14

[0376] The synthesis method is as follows:

[0377]

[0378] Using the same method as BL-11, L 3 -1 is replaced with L 3 -2 yields compound BL-14. LCMS (ESI): [M+H] + =For C 70 H 79 N 15 O 16 The calculated value is 1386.49; the measured value is 1386.73.

[0379] Example 36 Compound BL-15

[0380] The synthesis method is as follows:

[0381]

[0382] Using the same method as BL-12, L 3 -1 is replaced with L 3 -2 yields compound BL-15. LCMS (ESI): [M+H] + =For C 74 H 81 N 15 O 16 The calculated value is 1436.55; the measured value is 1435.67.

[0383] Example 37 Intermediate D1

[0384] The synthesis method is as follows:

[0385]

[0386] First, remove the B1-terminal Fmoc protection using standard methods, then use standard methods to combine it with L... 3 -2 is coupled to obtain intermediate D1.

[0387] Example 38 Intermediate D2

[0388] The synthesis method is as follows:

[0389]

[0390] First, the Fmoc protection at the end of D1 is removed by conventional methods, and then the intermediate D2 is obtained by coupling with Fmoc-2-Nal-OH by conventional methods.

[0391] Example 39 Intermediate D3

[0392] The synthesis method is as follows:

[0393]

[0394] First, the Fmoc protection at the end of D2 is removed using a general method, and then the intermediate D3 is obtained by coupling it with a DOTA derivative using a general method.

[0395] Example 40 Compound BL-16

[0396] The synthesis method is as follows:

[0397]

[0398] Using the same method as BL-7, D3 underwent resin removal, followed by removal of trifluoroacetyl and tert-butyl protection, ultimately yielding compound BL-16. LCMS (ESI): [M+H] + =For C 70 H 79 N 15 O 16 The calculated value is 1386.49; the measured value is 1386.73.

[0399] Example 41 Compound BL-17

[0400] The synthesis method is as follows:

[0401]

[0402] Replace Fmoc-2-Nal-OH with L using the same method as BL-16. 3 -1 yields compound BL-17. LCMS (ESI): [M+H] + =For C 74 H 81 N 15 O 16 The calculated value is 1436.55; the measured value is 1435.67.

[0403] Example 42 Compound BL-18

[0404] The synthesis method is as follows:

[0405]

[0406] Using the same method as BL-16, L 3 -1 is replaced with L 3 -2, and the compound BL-18 can be obtained.

[0407] LCMS(ESI): [M+H] + =For C 74 H 81 N 15 O 16 The calculated value is 1436.55; the measured value is 1435.67.

[0408] [Marking Method]

[0409] In this invention, small molecule nuclide probes can be prepared by radiolabeling small molecule nuclide ligands. Specifically, the ligands are dissolved in a radiolabeling buffer solution, and then different radionuclides are added to react and obtain the corresponding molecular probes.

[0410] According to the present invention, the radionuclide may be a diagnostic radionuclide or a therapeutic radionuclide.

[0411] According to some preferred embodiments of the present invention, the diagnostic radionuclide is 68 Ga、 64 Cu、 18 F, 86 Y、 90 Y、 89 Zr、 111 In、 99m Tc, 11 C 123 I, 125 I and 124 At least one of I.

[0412] According to some preferred embodiments of the present invention, the therapeutic radionuclide is 177 Lu、 125 I, 131 I, 211 At、 111 In、 153 Sm、 186 Re、 188 Re、 67 Cu、 212 Pb, 225 Ac、 213At least one of Bi, 212Bi and 212Pb.

[0413] Example 43 Compound 68 Ga-BL-6 preparation

[0414]

[0415] Marking operation process

[0416] Within 1 to 2 minutes, all the 0.05M hydrochloric acid solution in the syringe is pushed into the germanium-gallium generator, and the rinsing solution flowing out of the germanium-gallium generator (the part with the strongest radioactivity) is directly put into the reaction bottle.

[0417] Replace the rubber stopper on the reaction flask and gently shake for about 10 seconds to mix the reaction solution. Place the reaction flask in a heater and incubate at 40°C for 30 minutes. After incubation, spot the mixture onto a TLC slide and measure the Rf ratio and purity.

[0418] Purification procedure steps

[0419] Extract the reaction solution and attach it to a C18 light column. Elute slowly, and the eluent flows into a waste bottle. Elute the C18 light column with 5 mL of ddH2O, and the eluent flows into a waste bottle.

[0420] The C18 light column was rinsed with 0.6 mL of 80% ethanol, and the eluent was filtered through a 0.22 μm sterile filter membrane into the product vial.

[0421] Preparation of tumor-bearing mice

[0422] NPG mice were purchased from the supplier, and the experimental mice had unlimited access to special mouse food. Throughout the experiment, the experimental mice had unlimited access to drinking water that had been treated internally by Pengli. The treatment method was to filter the local municipal water supply into pure water or high-pressure sterilized water through an RO water purifier and adjust the pH of the water to 2-3 with hydrochloric acid.

[0423] Within the foreseeable future, the levels of known contaminants in animal food and drinking water will not affect the purpose or procedures of the experiments in this invention.

[0424] HeLa cell preparation

[0425] The HeLa cell line used in this experiment was cultured in DMEM medium supplemented with 10% FBS in a 37°C incubator containing 5% CO2.

[0426] Tumor inoculation

[0427] Before the cells are cultured for ten generations, approximately 1×10 7After mixing 100 μL of PBS with an equal volume of Matrigel, HeLa cells were subcutaneously inoculated into the right back of each mouse near the axilla, with an inoculation volume of approximately 200 μL. Mice were anesthetized with 3-4% isoflurane prior to inoculation.

[0428] When the tumor grows to an average size of approximately 250 mm 3 The above steps complete the preparation of tumor-bearing mice.

[0429] [SPR Detection]

[0430] Surface plasmon resonance (SPR) studies were conducted using Biacore 8K system (GE Healthcare). Polarized light was directed onto a gold-labeled sensor surface, and the lowest intensity of the reflected light was detected. The angle of the reflected light varied with molecular bonding and dissociation. Control software plotted the raw SPR data in resonance units (RUs) into test spectra.

[0431] Using the CM5 sensor chip, the chip was first activated for 600 s with 400 mM EDC and 100 mM NHS at a flow rate of 10 μL / min. Then, the target protein FOLR1 was diluted to 30 μg / mL with 10 mM sodium acetate (pH 4.0) and coupled for 600 s with a flow rate of 5 μL / min. Finally, the chip was blocked with 1 M ethanolamine at a flow rate of 10 μL / min for 600 s to complete the chip preparation.

[0432] Working fluid (Running buffer) preparation

[0433] Use 10 mM HEPES, pH 7.4, 137 mM NaCl, 2.7 mM KCl and 0.05% P20 (Tween 20).

[0434] Analyte preparation

[0435] Dilute the analyte using running buffer, starting at 100 nM and diluting to 0.78 nM at a ratio of 1:2.

[0436] Each concentration of the analyte working solution constitutes one cycle, with a flow rate of 30 μL / min for 180 s for binding and 180 s for dissociation.

[0437] When analyzing the results, at least five effective concentrations were selected and kinetics fitting analysis was performed using a 1:1 model.

[0438] The KD values ​​of the compounds of this invention obtained by SPR testing are shown in Tables 1 and 2. Among these, the values ​​for affinity A are in the range of 10. -10 -10 -9 Between nM, the affinity value of B is 10.-9 -10 -8 Between nM, the affinity C value is 10. -8 -10 -7 Between nM.

[0439] Table 1. Affinity Level Measured by SPR

[0440]

[0441]

[0442]

[0443] Table 2. Measurements using SPR 68 Affinity level of Ga-labeled compounds

[0444]

[0445]

[0446]

[0447]

[0448] [In vivo effect verification]

[0449] Using HeLa tumor-bearing mice as the research subjects, the biodistribution of the compound in the mice was investigated 1 hour after injection via tail vein injection, simulating the clinical administration route. The administration frequency was a single dose; the dosage was 200 μCi / mouse; and the administration volume was 150 μL / mouse.

[0450] The results are as follows Figure 1 , Figure 2 , Figure 5 , Figure 6 As shown in Table 3.

[0451] Table 3. Injection of [[] in HeLa tumor-bearing mice 68 Biodistribution analysis data (%ID / g) 1 hour after Ga-labeled drug administration.

[0452]

[0453]

[0454] The results show: 68 Ga-BL-6 has tumor targeting properties and a good tumor-to-organ ratio.

[0455] Using KB tumor-bearing mice as the research subjects, the biodistribution of the compound in the mice was investigated 1 hour after injection via tail vein injection, simulating the clinical administration route. The administration frequency was a single dose; the dosage was 200 μCi / mouse; and the administration volume was 150 μL / mouse.

[0456] The results are as follows Figure 3 , Figure 4 , Figure 7 , Figure 8 As shown in Table 4.

[0457] Table 4. Injection of [ ] in KB tumor-bearing mice 68 Biodistribution analysis data (%ID / g) 1 hour after Ga-labeled drug administration.

[0458]

[0459]

[0460] The results show: 68 Ga-BL-7 has tumor targeting properties and a good tumor-to-organ ratio.

[0461] The present invention is not limited to the technical means disclosed above, but also includes technical solutions composed of any combination of the above technical features. The above descriptions are specific embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications are also considered within the scope of protection of the present invention.

Claims

1. A folic acid receptor-targeting compound, characterized in that, The compounds of formula (I), their stereoisomers, their crystalline hydrates, their deuterated derivatives, their solvates, their prodrugs, or their pharmaceutically acceptable salts: [Target head] - (L x ) s -R x (I), in, [Target] is a folic acid receptor binding ligand; R x is a chelator group Ch or a prosthetic group PG; s is an integer from 1 to 10; L x at least one L 3 and any combination of AA, L 1 , L 2 or L 3 ​ in, AA is independently selected from amino acid residues. L 1 Compounds independently selected from the following structures: in, R 16 Independently selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, -C(O)R 19 -C(O)OR 19 and -C(O)NR 19 R 19’ The substituents of the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl groups are independently selected from halogens, C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, and -OR groups. 20 -OC(O)R 20 -OC(O)NR 20 R 20’ -OS(O)R 20 -OS(O)2R 20 -SR 20 -S(O)R 20 -S(O)2R 20 -S(O)NR 20 R 20’ -S(O)NR 20 R 20’ -OS(O)NR 20 R 20’ -OS(O)2NR 20 R 20’ -NR 20 R 20’ -NR 20 C(O)R 21 -NR 20 C(O)OR 21 -NR 20 C(O)NR 21 R 21’ -NR 20 S(O)R 21 -NR 20 S(O)2R 21 -NR 20 S(O)NR 21 R 21’ -NR 20 S(O)2NR 21 R 21’ -C(O)R 20 -C(O)OR 20 or -C(O)NR 20 R 20 , R 17 and R 17’ Independently selected from the group consisting of: H, halogens, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 7-membered heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5 to 7-membered heteroaryl, -OR 22 -OC(O)R 22 -OC(O)NR 22 R 22’ -OS(O)R 22 -OS(O)2R 22 -SR 22 -S(O)R 22 -S(O)2R 22 -S(O)NR 22 R 22’ -S(O)NR 22 R 22’ -OS(O)NR 22 R 22’ -OS(O)2NR 22 R 22’ -NR 22 R 22’ -NR 22 C(O)R 23 -NR 22 C(O)OR 23 -NR 22 C(O)NR 23 R 23’ -NR 22 S(O)R 23 -NR 22 S(O)2R 23 -NR 22 S(O)NR 23 R 23’ -NR 22 S(O)2NR 23 R 23’ -C(O)R 22 -C(O)OR 22 or -C(O)NR 22 R 22 ', wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 The substituents of the aryl and 5- to 7-membered heteroaryl groups are independently selected from halogens, C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, and -OR groups. 24 、 -OC(O)R 24 、 -OC(O)NR 24 R 24’ 、 -OS(O)R 24 、 -OS(O)2R 24 、 -SR 24 、 -S(O)R 24 、 -S(O)2R 24 、 -S(O)NR 24 R 24’ 、 -S(O)NR 24 R 24’ 、 -OS(O)NR 24 R 24’ 、 -OS(O)2NR 24 R 24’ 、 -NR 24 R 24’ 、 -NR 24 C(O)R 25 、 -NR 24 C(O)OR 25 、 -NR 24 C(O)NR 25 R 25’ 、 -NR 24 S(O)R 25 、 -NR 24 S(O)2R 25 、 -NR 24 S(O)NR 25 R 25’ 、 -NR 24 S(O)2NR 25 R 25’ 、 -C(O)R 24 、 -C(O)OR 24 or -C(O)NR 24 R 24’ , R 18 Individually selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 7-membered heterocyclic alkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5 to 7-membered heteroaryl, -OR 26 -OC(O)R 26 -OC(O)NR 26 R 26’ -OS(O)R 26 -OS(O)2R 26 -SR 26 -S(O)R 26 -S(O)2R 26 -S(O)NR 26 R 26’ -S(O)NR 26 R 26’ -OS(O)NR 26 R 26’ -OS(O)2NR 26 R 26’ -NR 26 R 26’ -NR 26 C(O)R 27 -NR 26 C(O)OR 27 -NR 26 C(O)NR 27 R 27’ -NR 26 S(O)R 27 -NR 26 S(O)2R 27 -NR 26 S(O)NR 27 R 27’ -NR 26 S(O)2NR 27 R 27’ -C(O)R 26 -C(O)OR 26 or -C(O)NR 26 R 26’ The C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 The substituents of the aryl and 5- to 7-membered heteroaryl groups are independently selected from halogens, C1-C6 alkyl groups, C2-C6 alkenyl groups, and -(CH2). p OR 28 、 -(CH2) p (OCH2) q OR 28 、 -(CH2) p (OCH2CH2) q OR 28 、 -OR 29 、 -OC(O)R 29 、 -OC(O)NR 29 R 29’ 、 -OS(O)R 29 、 -OS(O)2R 29 、 -(CH2) p OS(O)2OR 29 、 -OS(O)2OR 29 、 -SR 29 、 -S(O)R 29 、 -S(O)2R 29 、 -S(O)NR 29 R 29’ 、 -S(O)NR 29 R 29’ 、 -OS(O)NR 29 R 29’ 、 -OS(O)2NR 29 R 29’ 、 -NR 29 R 29’ 、 -NR 29 C(O)R 30 、 -NR 29 C(O)OR 30 、 -NR 29 C(O)NR 30 R 30’ 、 -NR 29 S(O)R 30 、 -NR 29 S(O)2R 30 丶 -NR 29 S(O)NR 30 R 30’ 、 -NR 29 S(O)2NR 30 R 30’ 、 -C(O)R 29 、 -C(O)OR 29 or -C(O)NR 29 R 29’ , R 19 R I9’ R 20 R 20’ R 21 R 21’ R 22 R 22 '、R 23 R 23’ R 24 R 24’ R 25 R 25’ R 26 R 26’ R 26” R 29 R 29’ R 30 and R 30’ Independently selected from the group consisting of: H, substituted or unsubstituted C1-C7 alkyl, substituted or unsubstituted C2-C7 alkenyl, substituted or unsubstituted C2-C7 ynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 7-membered heterocyclic alkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5- to 7-membered heteroaryl, wherein the C1-C7 alkyl, C2-C7 alkenyl, C2-C7 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 The substituents of the aryl or 5- to 7-membered heteroaryl groups are independently selected from halogens, -OH, -SH, -NH, or -COOH. R 27 and R 27’ Each is independently selected from the group consisting of: H, C1-C9 alkyl, C2-C9 alkenyl, C2-C9 ynyl, and C3-C6 cycloalkyl. R 28 Independently selected from H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl or 5- to 7-membered heteroaryl, w is an integer between 1 and 5. p is an integer between 1 and 5. q is an integer between 1 and 5; L 2 Independently selected from the following compounds: in, R 31 and R 31’ The substituent is independently selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, and substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituents of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, and C3-C6 cycloalkyl are independently selected from halogens, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C6 cycloalkyl, C3-C6 cycloalkyl, C4 ... 10 Aryl, 5- to 7-membered heteroaryl, -OR 32 -OC(O)R 32 -OC(O)NR 32 R 32’ -OS(O)R 32 -OS(O)2R 32 -SR 32 -S(O)R 32 -S(O)2R 32 -S(O)NR 32 R 32’ -S(O)NR 32 R 32’ -OS(O)NR 32 R 32’ -OS(O)2NR 32 R 32’ -NR 32 R 32’ -NR 32 C(O)R 33 -NR 32 C(O)OR 33 -NR 32 C(O)NR 33 R 33’ -NR 32 S(O)R 33 -NR 32 S(O)2R 33 -NR 32 S(O)NR 33 R 33’ -NR 32 S(O)2NR 33 R 33’ -C(O)R 32 -C(O)OR 32 or -C(O)NR 32 R 32 ; X 6 Independently selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C6-C 10 aryl, wherein the C1-C6 alkyl and C6-C 10 The substituents of the aryl group are independently selected from halogens, C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 ynyl groups, C3-C6 cycloalkyl groups, 3- to 7-membered heterocyclic alkyl groups, and C6-C6 alkyl groups. 10 Aryl, 5- to 7-membered heteroaryl, -OR 34 -OC(O)R 34 -OC(O)NR 34 R 34’ -OS(O)R 34 -OS(O)2R 34 -SR 34 -S(O)R 34 -S(O)2R 34 -S(O)NR 34 R 34’ -S(O)NR 34 R 34’ -OS(O)NR 34 R 34’ -OS(O)2NR 34 R 34’ -NR 34 R 34’ -NR 34 C(O)R 35 -NR 34 C(O)OR 35 -NR 34 C(O)NR 35 R 35’ -NR 34 S(O)R 35 -NR 34 S(O)2R 35 -NR 34 S(O)NR 35 R 35’ -NR 34 S(O)2NR 35 R 35’ -C(O)R 34 -C(O)OR 34 or -C(O)NR 34 R 34 ; R 32 R 32 '、R 33 R 33’ R 34 R 34’ R 35 or R 35 'Independently selected from the group consisting of: H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl and 5- to 7-membered heteroaryl, R 36 The substituent is independently selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, and substituted or unsubstituted C3-C6 cycloalkyl, wherein the substituents of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, and C3-C6 cycloalkyl are independently selected from halogens, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C6 cycloalkyl, C3-C6 cycloalkyl, C4 ... 10 Aryl, 5- to 7-membered heteroaryl, -OR 37 -OC(O)R 37 -OC(O)NR 37 R 37’ -OS(O)R 37 -OS(O)2R 37 -SR 37 -S(O)R 37 -S(O)2R 37 -S(O)NR 37 R 37’ -S(O)NR 37 R 37’ -OS(O)NR 37 R 37’ -OS(O)2NR 37 R 37’ -NR 37 R 37’ -NR 37 C(O)R 38 -NR 37 C(O)OR 38 -NR 37 C(O)NR 38 R 38’ -NR 37 S(O)R 38 -NR 37 S(O)2R 38 -NR 37 S(O)NR 38 R 38’ -NR 37 S(O)2NR 38 R 38’ -C(O)R 37 -C(O)OR 37 or -C(O)NR 37 R 37 , R 37 R 37’ R 38 and R 38 Each is independently selected from the group consisting of: H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic alkyl, C6-C 10 Aryl and 5- to 7-membered heteroaryl groups; L 3 Independently selected from the following compounds:

2. The folic acid receptor-targeting compound according to claim 1, characterized in that, The target contains a pteroyl group or a derivative thereof; preferably, the target contains an amino acid residue covalently attached to the pteroyl group or a derivative thereof.

3. The folic acid receptor-targeting compound according to claim 2, characterized in that, The [target] is a compound having the following structure: in, AA is independently selected from amino acid residues; R 1 and R 2 Independently selected from the group consisting of: H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, -OR 7 -SR 7 and -NR 7 R 7’ The substituents of the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl groups are independently selected from halogens, -OR 8 -SR 8 -NR 8 R 8’ -C(O)R 8 -C(O)OR 8 or -C(O)NR 8 R 8’ ; R 3 R 4 R 5 and R 6 Independently selected from the group consisting of: H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, -CN, -NO2, -NCO, -OR 9 -SR 9 -NR 9 R 9’ 、-CO)R 9 -C(O)OR 9 and -C(O)NR 9 R 9’ The substituents of the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl groups are independently selected from halogens, -OR 10 -SR 10 -NR 10 R 10’ 、-CO)R 10 -C(O)OR 10 or -C(O)NR 10 R 10’ ; R 7 R 7’ R 8 R 8’ R 9 R 9’ R 10 and R ’ It is independently selected from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 ynyl; X 1 Selected from -N(R) 11 -, =N-, -N=, -C(R1)= or =C(R 11 )-; X 2 Selected from -N(R) 11’ )- or = N-; X 3 Selected from -N(R) 11” -, -N = or -C(R) 11’ = ; X 4 Selected from -N= or -C=; X 5 Selected from -N(R) 12 - or -C(R) 12 (R) 12 )-; R 1’ R 2’ R 11 R 11’ R 11” R 12 R 12’ R 13 R 14 and R 14’ Independently selected from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, -C(O)R 15 -C(O)OR 15 and C(O)NR 15 R 15’ ; R 15 and R 15 Independently selected from H or C1-C6 alkyl groups; m is an integer from 1 to 4, and n is 0 or 1.

4. The folic acid receptor-targeting compound according to claim 3, characterized in that, When the X 1 -N = or -C(R) 11 When ) =, the Y 1 Selected from H, -OR 13 or -SR 13 .

5. The folic acid receptor-targeting compound according to claim 3, characterized in that, When the X 1 For -NR 11 -、=N- or =C(R) 11 When )-, the Y 1 =O.

6. The folic acid receptor-targeting compound according to claim 3, characterized in that, When the X 4 When -C=, the Y 2 Selected from H, C1-C6 alkyl, C2-C6 alkenyl, -C(O)R 14 -C(O)OR 14 or -C(O)NR 14 R 14’ .

7. The folic acid receptor-targeting compound according to claim 3, characterized in that, When the X 4 When -N=, Y 2 It does not exist.

8. The folic acid receptor-targeting compound according to claim 3, characterized in that, The value of m is 1.

9. The folic acid receptor-targeting compound according to claim 5, characterized in that, The X 1 For -NR 11 - 10. The folic acid receptor-targeting compound according to claim 8, characterized in that, The X 1 For -NR 11 Wherein R 11 For H.

11. The folic acid receptor-targeting compound according to claim 3, characterized in that, The X 2 =N-.

12. The folic acid receptor-targeting compound according to claim 3, characterized in that, The Y 1 =O.

13. The folic acid receptor-targeting compound according to claim 3, characterized in that, The X 3 -C(R) 11’ = ).

14. The folic acid receptor-targeting compound according to claim 12, characterized in that, The X 3 -C(R) 11’ ) =, where R 11’ For H.

15. The folic acid receptor-targeting compound according to claim 3, characterized in that, The X 4 For -C=.

16. The folic acid receptor-targeting compound according to claim 3, characterized in that, The Y 2 For H.

17. The folic acid receptor-targeting compound according to claim 3, characterized in that, The X 3 For -N=.

18. The folic acid receptor-targeting compound according to claim 3, characterized in that, The X 4 For -N=.

19. The folic acid receptor-targeting compound according to claim 3, characterized in that, The X 5 For -NR 12 .

20. The folic acid receptor-targeting compound according to claim 3, characterized in that, The R 12 For H.

21. The folic acid receptor-targeting compound according to claim 3, characterized in that, The R 1’ and R 2’ For H.

22. The folic acid receptor-targeting compound according to claim 3, characterized in that, The R 1 and R 2 For H.

23. The folic acid receptor-targeting compound according to claim 3, characterized in that, The R 3 R 4 R 5 and R 6 For H.

24. The folic acid receptor-targeting compound according to claim 3, characterized in that, The value of n is 1.

25. The folic acid receptor-targeting compound according to any one of claims 1-23, characterized in that, The [target] is a compound having the following structure: Where n is 0 or 1, and AA represents amino acid residues.

26. The folic acid receptor-targeting compound according to any one of claims 2-23, characterized in that, The pteroyl group or its derivative thereof is covalently bonded to at least one of the following compounds:

27. The folic acid receptor-targeting compound according to claim 25, characterized in that, The [target head] is:

28. The folic acid receptor-targeting compound according to claim 1, characterized in that, The chelating group Ch contains metals, radioactive elements, and Si- 18 F, B- 18 F or Al- 18 One or more of F; the prosthetic group PG is a radioactively labeled prosthetic group PG; Preferably, the chelating group Ch comprises a radioactive element selected from the group consisting of: 111 In、 99m Tc, 94m Tc, 66 Ga、 67 Ga、 68 Ga、 52 Fe、 169 Er、 72 As、 97 Ru、 203 pb, 62 Cu、 64 Cu、 67 Cu、 186 Re、 18 Re、 86 Y、 90 Y、 51 Cr 52m Mn, 177 Lu、 161 Tb, 169 Yb、 175 Yb、 105 Rh、 166 Dy、 166 Ho、 153 Sm、 149 Pm, 151 Pm, 172 Tm、 121 Sn、 117m Sn、 213 Bi、 142 Pr、 143 Pr、 198 Au、 199 Au、 123 I, 124 I, 125 I, 18 F, 149 Tb, 152 Tb, 155 Tb, 47 Sc、 44 Sc、 43 Sc、 225 Ac、 212 Pb, 211 At、 223 Ra、 227 Th、 131 I, 82 Rb、 76 As、 89 Zr、 111 Ag、 165 Er、 227 Ac、and 61 Cu; preferably 66 Ga、 67 Ga、 68 Ga、 177 Lu and 225 Ac; Preferably, the prosthetic group PG is labeled with a radioactive halogen selected from the group consisting of: 18 F, 75 Br、 76 Br、 77 Br、 80 Br、 80m Br、 82 Br、 123 I, 124 I, 125 I, 131 I and 211 At.

29. The folic acid receptor-targeting compound according to claim 1, characterized in that, The chelating group Ch is selected from the group consisting of:

30. The folic acid receptor-targeting compound according to claim 1, characterized in that, The R 17 and R 17’ They can combine to form substituted or unsubstituted C4-C6 cycloalkyl groups, and substituted or unsubstituted 4- to 6-membered heterocycles, wherein... The C4-C6 cycloalkyl and 4- to 6-membered heterocyclic substituents are independently selected from halogens, C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 ynyl groups, C3-C6 cycloalkyl groups, 3- to 7-membered heterocyclic alkyl groups, and C6-C6 cycloalkyl groups. 10 Aryl, 5- to 7-membered heteroaryl, -OR 24 -OC(O)R 24 -OC(O)NR 24 R 24’ -OS(O)R 24 -OS(O)2R 24 -SR 24 -S(O)R 24 -S(O)2R 24 -S(O)NR 24 R 24’ -S(O)NR 24 R 24’ -OS(O)NR 24 R 24’ -OS(O)2NR 24 R 24’ -NR 24 R 24’ -NR 24 C(O)R 25 -NR 24 C(O)OR 25 -NR 24 C(O)NR 25 R 25’ -NR 24 S(O)R 25 -NR 24 S(O)2R 25 -NR 24 S(O)NR 25 R 25’ -NR 24 S(O)2NR 25 R 25’ -C(O)R 24 -C(O)OR 24 or -C(O)NR 24 R 24’ .

31. The folic acid receptor-targeting compound according to claim 1 or 30, characterized in that, The L 1 Independently selected from the following compounds: in, R 16 It's H. R 17 and R 17’ Independently selected from H, C1-C6 alkyl groups or -C(O)OH, R 18 Independently selected from H, substituted or unsubstituted C6-C 10 Aryl, -OH-SH, -NHC(=NH')NH2 or -C(O)OH, wherein the C6-C 10 The substituents of the aryl group are halogens.

32. The folic acid receptor-targeting compound according to claim 1 or 30, characterized in that, The L 2 Independently selected from the following compounds: in, R 31 and R 31’ For H, R 36 For H.

33. The folic acid receptor-targeting compound according to claim 1 or 30, characterized in that, The -(L) x ) s - Includes a (II-x) group, where x is an integer between 1 and 9; The (II-x) group is selected from any of the following:

34. The folic acid receptor-targeting compound according to claim 1 or 30, characterized in that, When s > 3, at least two L atoms are present in the compound of formula I. x Independently selected from the following compounds: Wherein, rp is independently selected from integers between 1 and 80; and the prerequisite is that the compound of formula (I) is not any of the following:

35. The folic acid receptor-targeting compound according to claim 1 or 30, characterized in that, When s > 4, the compound of formula (I) contains at least 3 L atoms. x Independently selected from the following compounds: Here, rp is independently selected from integers between 1 and 80.

36. The folic acid receptor-targeting compound according to claim 1 or 30, characterized in that, The compound of formula (I) contains at least 3 L x Independently selected from the following compounds: Here, rp is independently selected from integers between 1 and 80.

37. The folic acid receptor-targeting compound according to claim 1 or 30, characterized in that, At least one L in the compound of formula (I) x Selected from the following compounds: Preferred options are: Further preferred options are:

38. The folic acid receptor-targeting compound according to claim 1 or 30, characterized in that, The compound of formula (1), wherein one, two or three L x Independently selected from L 1 , Where w is independently selected from 1 or 2, R 18 Independently selected from substituted C6-C 10 Aryl, the C6-C 10 The substituents of the aryl group are independently selected from halogens or C1-C6 alkyl groups.

39. The folic acid receptor-targeting compound according to claim 1 or 30, characterized in that, The L x for 40. The folic acid receptor-targeting compound according to claim 1 or 30, characterized in that, The compound of formula (I) is: [target]-(L x ) s -Ch.

41. The folic acid receptor-targeting compound according to claim 40, characterized in that, The [target head]-(L) x ) s -Ch can be any of the following structures: [Target Head]-L 3 -Ch、[Target Head]-L 1 -L 3 -Ch、[Target Head]-L 3 -L 3 -L 1 -L 1 -L 1 -L 3 -Ch、[Target Head]-L 3 -L 1 -Ch、[Target Head]-L 3 -L 3 L 3 -Ch、[Target Head]-L 3 -L 3 -L 1 -L 3 -L 3 -Ch、[Target Head]-L 3 -L 1 -L 3 -Ch、[Target Head]-L 3 -L 3 -AA-L 1 -L 2 -L 3 -Ch、[Target Head]-L 3 -L 3 -L 1 -L 1 -L 1 -L 2 -Ch、[Target Head]-L 3 -L 3 -L 3 -L 1 -AA-Ch、[Target Head]-L 3 -L 3 -AA-Ch、[Target Head]-L 3 -L 3 -Ch、[Target Head]-L 3 -L 1 -AA-Ch、[Target Head]-L 3 -L 3 -L 3 -L 1 -Ch、[Target Head]-L 3 -L 3 -L 3 -L 1 -L 1 -Ch、[Target Head]-L 3 -L 1 -L 1 -L 1 -L 1 -AA-AA-AA-AA-Ch、[Target Head]-L 3 -AA-Ch、[Target Head]-L 3 -L 1 -L 1 -L 1 -AA-AA-AA-AA-Ch、[Target Head]-L 3 -L 3 -L 3 -AA-Ch, or [target]-L 3 -L 3 -L 3 -L 3 -Ch, where AA is independently selected from amino acid residues; Or the [target head]-(L x ) s -Ch can be any of the following structures: [Target Head]-L 3 -Ch、[Target Head]-L 1 -L 1 -L 1 -L 3 -Ch、[Target Head]-L 3 -Ch、[Target Head]-L 3 -L 3 -Ch、[Target Head]-L 1 -L 3 -L 3 -Ch、[Target Head]-L 1 -L 3 -Ch、[Target Head]-L 3 -L 3 -AA-L 1 -L 2 -L 3 -Ch、[Target Head]-L 1 -L 1 -L 1 -L 2 -Ch、[Target Head]-L 3 -L 3 -L 1 -AA-Ch、[Target Head]-L 3 -AA-Ch、[Target Head]-L 1 -AA-Ch、[Target Head]-L 3 -L 3 -L 1 -Ch、[Target Head]-L 3 -L 1 -Ch、[Target Head]-L 3 -L 3 -L 1 -L 1 -Ch、[Target Head]-L 3 -L 1 -L 1 -Ch or [target]-L 1 -L 1 -L 1 -L 1 -L 2 -L 3 -L 1 -L 1 -Ch, where AA is independently selected from amino acid residues.

42. The folic acid receptor-targeting compound according to claim 1 or 30, characterized in that, The compound of formula (1) is selected from any of the following compounds: Wherein, BL stands for [target].

43. The folic acid receptor-targeting compound according to claim 42, characterized in that, Any L in the compound of formula (1) x A group is affected by different L x Substitute; Wherein, one of the groups is an AA group, and the different L x For the purposes of this discussion, "different AA groups" refers to different AA groups, where the different AA groups are conserved amino acid substitutions of the AA group.

44. The folic acid receptor-targeting compound according to claim 1 or 30, characterized in that, The compound of formula (1) is selected from any of the following compounds: The chelating group Ch contains radioactive elements, Si- 18 F, B- 18 F, or Al- 18 F.

45. The folic acid receptor-targeting compound according to claim 44, characterized in that, The compound of formula (I) is:

46. ​​The folic acid receptor-targeting compound according to claim 44, characterized in that, The compound of formula (I) is: Wherein, M is a bound radioactive element, and M is... 177 Lu or 225 Ac.

47. The folic acid receptor-targeting compound according to claim 46, characterized in that, The compound of formula (I) contains the following groups: In this context, ** represents the carboxyl group at the α, β, γ, δ, ε, or ζ position of the carbonyl group.

48. A pharmaceutical composition, characterized in that, Includes the folic acid receptor-targeting compound as described in any one of claims 1-47 and a pharmaceutically acceptable carrier.

49. Use of the folic acid receptor-targeting compound of any one of claims 1-47 or the pharmaceutical composition of claim 48 in the preparation of a medicament for treating proliferative diseases, preferably, the proliferative disease being cancer.

50. Use of the folic acid receptor-targeting compound of any one of claims 1-47 or the pharmaceutical composition of claim 48 in the preparation of a medicament for treating cancer; preferably, the cancer is selected from the group consisting of: lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, melanoma of the skin or eye, ovarian cancer, rectal cancer, anal cancer, gastric cancer, colon cancer, breast cancer, triple-negative breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancers, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system vegetations, primary CNS lymphoma, spinal axis tumors, brainstem gliomas, or pituitary adenomas.

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