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CN-122003409-A - Ligand compound with quinoline structure, and radioactive or non-radioactive marker and application thereof

CN122003409ACN 122003409 ACN122003409 ACN 122003409ACN-122003409-A

Abstract

The present disclosure relates to a class of ligand compounds of quinoline structure and their radioactive or non-radioactive labels and uses, in particular, the disclosure relates to ligand compounds of formula I, non-radioactive labels of formula II and radioactive labels of formula III, and their use in diagnosing or treating diseases in which cells proliferate abnormally.

Inventors

  • TIAN QIANG
  • ZHANG YITAO
  • LIU WANLI
  • GE YONG
  • YUAN XIAOXI
  • SONG HONGMEI
  • GE JUNYOU

Assignees

  • 四川科伦博泰生物医药股份有限公司

Dates

Publication Date
20260508
Application Date
20241227
Priority Date
20231027

Claims (16)

  1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof: In the above-mentioned formula (I), Ring A is selected from 9-20 membered heterocyclyl; Each of X 1 、X 2 and X 3 is independently selected from the group consisting of a single bond, -O-, -S-, -NH-, -N (C 1-6 alkyl) -, C 1-6 alkylene, -C (=O) -, 4-6 membered heterocyclyl, cyclobutene-dione residues For example, is a heterocyclic group selected from the group consisting of single bond, -O-, -S-, -NH-, -N (C 1-6 alkyl) -, C 1-6 alkylene, -C (=O) -, and 4-6 membered; L 1 、L 2 and L 3 are each independently selected from hydrogen, C 1-6 alkyl, carboxyl, sulfonic acid groups, amino acid residues, FAP affinity ligands, albumin binding ligands, or R c ; Wherein the FAP affinity ligand is selected from The albumin binding ligand is selected from the group consisting of Evan blue residues or the following structures R 2 is selected from halogen (e.g., iodine, bromine, chlorine, fluorine), C 1-6 alkyl (e.g., methyl), C 1- 6 alkoxy (e.g., methoxy), hydroxy, amino, nitro, cyano; Y is each independently selected from a single bond, C 1-6 alkylene, -C (=O) -, -S-, -NH-, -O-, and- (CH 2 CH 2 OCH 2 CH 2 ) n -, cyclobutene-dione residues) Piperazinyl, triazole, or amino acid residues; R c is selected from chelators of radionuclides or nonradionuclides, including but not limited to 99mTc (CO) 3 -chelator 、CB-TE2A、CHX-A"-DTPA、DTPA、DATA、DFO、HBED、Crown、DOTA、DOTAGA、DOTAM、FSC、H4octapa、Macropa、HEHA、HOPO、Hynic、PCTA、PSC、NETA、NOTA、NOTA-MPAA、NODAGA、NOTP、NOPO、Pycup、RESCA、Sarcophagine、TETA、THP or TRAP; Each m is independently selected from 1,2,3,4,5,6,7,8,9,10; each n is independently selected from 1,2,3,4,5,6,7,8,9,10.
  2. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein ring a is selected from 9-or 12-membered nitrogen containing heterocyclyl.
  3. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein the compound has a structure represented by formula I-1 or formula I-2:
  4. A compound of any one of claims 1-3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein: Y is selected from a single bond and a C 1-6 alkylene group, preferably a single bond, and/or Rc is selected from the following structures: R 1 is selected from halogen (e.g., iodine, bromine, chlorine, fluorine), C 1-6 alkyl (e.g., methyl), C 1-6 alkoxy (e.g., methoxy), hydroxy, amino, nitro, cyano; Preferably, R c is selected from
  5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein the compound has a structure of formula I-1, wherein L 1 and L 2 are each selected from - (X 1 ) m -and- (X 2 ) m -selected from R' is selected from H or C 1-6 alkyl (e.g., methyl), p is each independently selected from 1-6, and- (X 1 ) m -and- (X 2 ) m -are the same); preferably, - (X 1 ) m -and- (X 2 ) m -are selected from More preferably, - (X 1 ) m -and- (X 2 ) m -are selected from Wherein position 1 is attached to either L 1 or L 2 and position 2 is attached to the A ring.
  6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein the compound has a structure of formula I-2, wherein- (X 1 ) m -、-(X 2 ) m -or- (X 3 ) m -are each independently selected from a single bond, C 1-6 alkylene, R' is selected from H or C 1-6 alkyl (e.g., methyl), p is each independently selected from 1-6; Preferably, - (X 1 ) m -、-(X 2 ) m -or- (X 3 ) m -each independently selected from a single bond, C 1-6 alkylene, R' is selected from H or C 1-6 alkyl (e.g., methyl), p is each independently selected from 1-6; Preferably, the method comprises the steps of, - (X 1 ) m -、-(X 2 ) m -or- (X 3 ) m -each independently selected from a single bond) methylene group, More preferably, the process is carried out, - (X 1 ) m -、-(X 2 ) m -or- (X 3 ) m -each independently selected from a single bond) methylene group, Wherein position 1 is attached to L 1 or L 2 or L 3 and position 2 is attached to the A ring.
  7. The compound of any one of claims 1-4 or 6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein the compound has a structure of formula I-2, wherein L 1 、L 2 and L 3 are each independently selected from hydrogen, C 1-6 alkyl, carboxyl, rc, Preferably, L 1 、L 2 and L 3 are each independently selected from hydrogen, carboxyl,
  8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, selected from the group consisting of:
  9. A class of compounds having the structure of formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof: In the above formula (II), Ring Z is a chelating structure for Rc and a non-radionuclide Rn as defined in any one of claims 1 to 8, and rings A, X 1 、X 2 、X 3 、L 1 、L 2 、L 3 , Y, rc, m and n are as defined in any one of claims 1 to 8; Rn is selected from 69 Ga and 175 Lu.
  10. The compound of claim 9, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein the compound is selected from the group consisting of:
  11. A class of compounds having the structure of formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof: in the above formula (III), Ring Z 'is a chelate structure of Rc with a radionuclide R' n as defined in any of claims 1 to 8, and rings A, X 1 、X 2 、X 3 、L 1 、L 2 、L 3 , Y, rc, m and n are as defined in any of claims 1 to 8; R' n is selected from 43 Sc、 44 Sc、 47 Sc、 55 Co、 62 Cu、 64 Cu、 67 Cu、 66 Ga、 67 Ga、 68 Ga、 86 Y、 89 Zr、 90 Y、 90 Nb、 99m Tc、 111 In、 135 Sm、 140 Pr、 149 Tb、 159 Gd、 160 Tb、 161 Tb、 165 Er、 166 Dy、 166 Ho、 175 Yb、 177 Lu、 186 Re、 188 Re、 211 At、 212 Pb、 213 Bi、 225 Ac or 232 Th.
  12. The compound of claim 11, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein the compound is selected from the group consisting of:
  13. A pharmaceutical composition comprising a diagnostically or therapeutically effective amount of a compound of any one of claims 1-12, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers.
  14. Use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite or prodrug thereof, or a pharmaceutical composition according to claim 13, for the manufacture of a medicament for the diagnosis or treatment of a disease in which cell proliferation is abnormal (e.g. a solid tumor, such as a advanced solid tumor).
  15. A compound, or a salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, or metabolite thereof, as shown below: wherein the rings X 1 、X 2 、X 3 、L 1 , Y, m and n are as defined in any of claims 1 to 8; L 2 ' is L 2 or L 2 protected with a protecting group (e.g., a carboxyl protecting group); L 3 ' is L 3 or L 3 protected with a protecting group (e.g., a carboxyl protecting group); Rc' is Rc or Rc protected by a protecting group (e.g., a carboxyl protecting group); l 2 、L 3 , rc are as defined in any one of claims 1 to 8; The carboxyl protecting group is preferably selected from the group consisting of C 1-6 alkyl, allyl, benzyl, 2, 4-dimethoxybenzyl, p-methoxybenzyl, methoxyethoxymethyl, pentafluorophenyl, 4-p-methylbenzoxybenzyl; PG 1 、PG 2 、PG 3 、PG 4 is each independently H or an amino protecting group, preferably selected from alkoxycarbonyl amino protecting groups such as carbobenzoxy (Cbz), t-butoxycarbonyl (Boc), methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxy (or ethoxy) oxycarbonyl, acyl amino protecting groups such as phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o (p) nitrobenzenesulfonyl (Ns), pivaloyl, benzoyl, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, trifluoroacetyl, methoxycarbonyl, or ethoxycarbonyl, alkyl amino protecting groups such as trityl (Trt), 2, 4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB), benzyl (Bn).
  16. A compound, or a salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, or metabolite thereof, as shown below: Wherein PG 1 、PG 2 、PG 3 、PG 4 is as defined in claim 15; R 2 is as defined in any one of claims 1 to 8; PG 5 is each independently H or a carboxyl protecting group, preferably selected from C 1-6 alkyl, allyl, benzyl, 2, 4-dimethoxybenzyl, p-methoxybenzyl, methoxyethoxymethyl, pentafluorophenyl, 4-p-methylbenzoxybenzyl.

Description

Ligand compound with quinoline structure, and radioactive or non-radioactive marker and application thereof Cross reference The present disclosure is based on and claims priority from chinese application number 202311414691.5, application number 2023, 10, 27 and chinese application number 202410268912.0, application number 2024, 3, 08, the disclosure of which is incorporated herein by reference in its entirety. Technical Field The present disclosure relates to ligand compounds of quinoline structure and radioactive or non-radioactive labels and uses thereof. Background The tumor microenvironment (Tumor microenvironment, TME) is a dynamic, complex local environment, closely related to tumor growth, metastasis, immune escape, and drug resistance. Although traditional diagnostic and therapeutic approaches to cancer have focused mainly on tumor cells, tumor stroma, a key component of the tumor microenvironment, plays a critical role in the development and progression of cancer, and has received extensive attention from researchers. Tumor-associated fibroblasts (Cancer associated fibroblasts, CAFs) are the major cell type in the tumor microenvironment, and are present in almost all solid tumors, accounting for about 50% of the total tumor tissue cells. Fibroblast activation protein (Fibroblast activation protein, FAP) is a key tool for CAFs carcinomatous action, a serine protease that can promote the recruitment, differentiation and proliferation of CAFs, which is mainly present on the surfaces of tumor-associated fibroblasts, mesenchymal cells and tumor cells, is a member of the type II transmembrane serine protease family, and has dipeptidase and collagenase activities. FAP is selectively upregulated on the stromal fibroblast surface of more than 90% of epithelial malignancies, including breast, colorectal, skin, prostate and pancreatic cancers, and the like. While the expression in normal tissues is very low, and besides tumors, the expression is only carried out in some inflammatory parts, such as wound healing, scar tissues, rheumatoid arthritis, osteoarthritis, myocarditis, liver fibrosis, lung fibrosis, liver cirrhosis and the like. Furthermore, high expression of FAP is closely related to invasion, metastasis and poor prognosis of malignant tumors, so FAP is considered as a potential target for treatment and diagnosis of tumors, termed the "next billion dollar nuclear therapeutic target". In recent years, radiopharmaceuticals targeting FAP have been the focus of attention of researchers, including radionuclide-labeled antibodies, cyclic peptides (e.g., FAP-2286), and small molecule inhibitors (e.g., FAPI-74, FAPI-46, FAPI-04, oncofAP, PNT-6555, EB-FAPI, SA. FAPI, etc.). Although FAP antibodies have been developed in 1988, only a few anti-FAP diagnostic and therapeutic agents have been reported for (Eur J Nucl Med Mol Imaging.2023,10.1007/s00259-023-06300-6.;Clin Cancer Res.2012,18(22):6208-6218.;J Nucl Med.2015,56(5):778-783.;J Clin Oncol.1994,12(6):1193-1203.;Clin Cancer Res.2020,26(18):4882-4891.;Molecules.2020,25(16):3672.;Clin Cancer Res.2020,26(18):4882-4891). radionuclide-labeled antibodies as molecular imaging agents, which have hampered further development due to slow clearance of blood and non-target tissues, non-specific tissue uptake, and other pharmacokinetic limitations. The FAP targeting radioactive diagnosis and treatment agent with low molecular weight has been widely reported and proved to have clinical value because of the characteristics of strong tissue penetrating power, high specificity, easy structure transformation and modification so as to facilitate radiolabeling, and the like. The university of Heidelberg team found a range of quinoline-based FAP inhibitors (WO 2019154886A 1), of which FAPI-02, FAPI-04, FAPI-46 and FAPI-74 have proven useful in PET imaging for high contrast tumor imaging of various cancers, exhibiting rapid tumor accumulation and good tumor background ratios (J Nucl Med.2018,59 (9): 1423-1429.; J Nucl Med.2018,59 (9): 1415-22;J Nucl Med.2019,60 (10): 1421-9). Preclinical studies have shown that radiolabeled FAPI-04 inhibits tumor growth in glioma (131I), pancreatic cancer (225 Ac) xenograft models (Mol pharm.2021,18 (11): 4179-87;J Nucl Med.2020,61 (4): 563-9). Similarly, 177Lu-FAPI-46 and 225Ac-FAPI-46 showed tumor growth inhibition in the pancreatic cancer mouse model, however tumor retention was only 0.3% ID/g after 3 hours of injection and only 0.1% ID/g after 24 hours (Eur J Nucl Med Mol imaging.2022,49 (3): 871-880). Although FAPI-46 have been modified at the linker moiety to extend tumor retention time, radionuclide labeled FAPI-46 has limited therapeutic efficacy on tumors due to rapid clearance of blood and tumor tissue. The university of taffeta reports in patent WO 2021195198A1 the development of a class of FAP targeting ligands with pyrrole boronic acid fragments, in which clinical transformations of PNT6555 are underway with no clinical data releas