A dimeric FAP targeting agent comprising a (4-quinoinolyl)glycinyl-2-cyanopyrrolidine scaffold, a 1,3,5-triazine or triazinan linkage, and a therapeutic or diagnostic agent for the diagnosis or treatment of tumors.

Abstract

The present invention relates to formula (I) or (II) (In the formula, Z is an FAP binding moiety containing a (4-quinoinolyl)glycinyl-2-cyanopyrrolidine scaffold, and Q is a therapeutic and / or diagnostic agent for the treatment and / or diagnosis of tumors.) This relates to dimeric FAP targeting agents. An example compound is eFAP-34. JPEG2026534222000075.jpg86170

Description

[Technical Field]

[0001] The present invention relates to compounds for targeting fibroblast-activating proteins (FAPs) in cancer-associated fibroblasts (CAFs), particularly to dimeric FAP targeting agents comprising a (4-quinoinolyl)glycinyl-2-cyanopyrrolidine scaffold. [Background technology]

[0002] Various FAP-targeting agents based on (4-quinolinyl)glycinyl-2-cyanopyrrolidine scaffolds have been developed and studied in prior art for imaging and treating tumors (see Lindner et al., Cancers 2021, 13, 5744). Early FAP-targeting agents were disclosed in Jansen et al., ACS Med. Chem. Lett. 2013, 4, 491-496 and Jansen et al., J. Med. Chem. 2014, 57, 3053-3074, the latter of which describes UAMC-1110, an FAP inhibitor with nanomolar affinity for a fluorinated (4-quinolinoyl)-glycyl-2-cyanopyrrolidine scaffold and FAP.

[0003] For FAP-targeting agents to be clinically meaningful, they must be functionalized with a payload, such as a radioisotope, fluorescent dye, or cytotoxic agent. For this purpose, the quinolinoyl portion of the scaffold is commonly used. The current reference compound in clinical use is FAPI-46 (Loktev et al., Journal of Nuclear Medicine, October 2019, 60(10)1421-1429). FAPI-46 was developed after the development of FAPI-04 (see Lindner et al., J. Nucl. Med. 2018;59:1415-1422) and showed an improved tumor-to-organ ratio compared to FAPI-04.

[0004] Other functionalized FAP-targeted compounds are described in WO2021 / 160825 and Millul et al., PNAS 2021 Vol. 118 No. 16 e2101852118, and are referred to as OncoFAP. These compounds are functionalized on a quinoinoryl using bridging nitrogen extending to a carboxylic acid group that enables connection to the payload. The drawback of this carboxylic acid group is that most metal chelates, prosthetic groups, optical dyes, etc., are not readily available as carboxylic acid-reactive substances. They are usually commercially available as amine-reactive substances. Therefore, in OncoFAP compounds, an additional linker (-NHCH2-CH2-NH-) is used to expose an amine that can react with the payload.

[0005] Other FAP-targeting compounds are described in WO2019 / 083990.

[0006] Dimeric FAP-targeted compounds comprising two (4-quinoinolyl)glycinyl-2-cyanopyrrolidine FAP-binding moieties and a payload have been described by Li et al. (European Journal of Nuclear Medicine and Molecular Imaging, 49, 2705-2715 (2022)), Zhao et al. (Journal of Nuclear Medicine, Vol. 63, No. 6, June 2022, 862-868), Galbiati et al. (Journal of Nuclear Medicine, December 2022, 63(12)1852-1858), Moon et al. (Am J Nucl Med Mol Imaging 2021;11(6):476-491), and Ballal et al. (Pharmaceuticals 2021, 14, 1212).

[0007] Despite recent advantages, the need remains to provide improved platforms and enhanced FAP targeting agents based on the (4-quinoinoryl)glycinyl-2-cyanopyrrolidine scaffold. However, previous research and development has shown that FAP imposes stringent structural requirements on its inhibitors, and that stereochemical or electronic parameters are insufficient to streamline assay data (Jansen et al., J. Med. Chem. 2014, 57, 3053-3074). Therefore, developing new FAP targeting agents is challenging because predicting which substituents and positions on the (4-quinoinoryl)glycinyl-2-cyanopyrrolidine scaffold will yield good inhibitors is difficult, if not impossible.

[0008] An object of the present invention is to provide a platform for polyvalent compounds exhibiting improved FAP binding affinity and / or tumor uptake, including tumor-versus-organ distribution, and such polyvalent compounds. Furthermore, an object of the present invention is to provide a platform that enables access to such compounds. [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] WO2021 / 160825 [Patent Document 2] WO2019 / 083990 [Patent Document 3] PCT / NL2023 / 050491 [Patent Document 4] WO2019 / 154859 [Patent Document 5] US2021 / 0402016A1 [Patent Document 6] WO2021 / 005125A1 [Non-patent literature]

[0010] [Non-Patent Document 1] Lindner et al., Cancer 2021, 13, 5744 [Non-licensed document 2] Jansen et al., ACS Med. Chem. Lett. 2013, 4, 491~496 [Non-licensed document 3] Jansen et al., J. Med. Chem. 2014, 57, 3053~3074

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

[0011] The inventors have found that dimeric FAP targeting agents having a central core containing a 1,3,5-triazine moiety (also referred to herein as triazine) or a 1,3,5-triazinane (also referred to herein as triazinane) yield a variety of FAP targeting agents exhibiting good FAP binding affinity and / or tumor uptake, including good tumor-to-organ distribution. Furthermore, dimeric FAP targeting agents based on triazine or triazinane cores exhibit good solubility and stability, and can be prepared relatively easily in good yields compared to other dimeric compounds such as those based on tetrazine cores.

[0012] Furthermore, the inventors have found that when one or more hydrophilic linkers are used to link the payload and / or FAP binding moiety to (and to each other) the core in a dimeric FAP inhibitor, good FAP binding affinity and / or tumor uptake, including good tumor-to-organ distribution, is achieved.

[0013] The inventors have also surprisingly found that by substituting the 8th position of the (4-quinoinolyl)glycinyl-2-cyanopyrrolidine scaffold with a carbon or oxygen atom, a variety of FAP targeting agents exhibiting good FAP binding affinity and / or tumor uptake, including good tumor-to-organ distribution, can be obtained.

[0014] Therefore, the present invention relates to formula (I) or formula (II)

[0015] [ka]

[0016] (In the formula, L 1 , L 2 and L 3 Each of these individually represents a linker. Q includes the payload, (Each Z represents an FAP junction.) The target is compounds produced by or pharmaceutically acceptable salts thereof.

[0017] Compound (I) is based on a triazinan core, while compound (II) is based on a triazine core. [Brief explanation of the drawing]

[0018] [Figure 1] Intermediate 10 was prepared according to the scheme shown in Figure 1. [Figure 2] As illustrated in Figure 2, 10 (65 mg, 125 μmol) was treated with a DCM / TFA (5 mL, 1:1) solution at room temperature for 30 minutes. All volatiles were removed under a gentle stream of air to obtain a brown crude solid. The crude product was redissolved in DMF (1.5 mL), followed by the addition of N-Fmoc-tranexamic acid (1.1 equivalents, 46.8 mg), HBTU (2 equivalents, 95 mg), DIPEA (100 μL), and DMF (1.5 mL). The reaction mixture was stirred at room temperature for 1 hour, diluted with toluene (15 mL), washed with water (3 × 5 mL), dehydrated with Mg₂SO₄, and concentrated under vacuum to obtain a pale yellow solid. The crude product was treated with a piperidine / DMF (2 mL, 1:5) solution at room temperature for 30 minutes, the solvent was removed under vacuum, and the crude product was purified by preparative HPLC to obtain 8QCP-AMCHA (30 mg, 53.9 μmol, 43%) as an off-yellow powder. ESI-MS: m / z 557.2[M+H]+. [Figure 3] Exemplary synthetic routes for compounds containing linker L3a or L3b are schematically illustrated in Figures 3A and 3B. [Figure 4]As illustrated in Figure 4, 8QCP-SH (5.5 mg, 10.8 μmol) was dissolved in DMF (1 mL), followed by the addition of TADB-N3 (1.3 mg, 3.1 μmol, prepared as described in Van de Langemheen et al., ChemBioChem. 2017;18(4):387~395) and DIPEA (10 μL). After 30 minutes, the solvent was removed under vacuum, and the crude product was purified by preparative HPLC to obtain (8QCP-SH)2-TADB (2.9 mg, 2.2 μmol, 41%) as a grayish-white powder. ESI-MS: m / z 1346.3[M+H]+. The powder was redissolved in ACN / H2O (1 mL, 1:1), followed by the addition of BCN-DOTAGA (1.1 equivalents, 1.7 mg). The reaction mixture was stirred at 37°C for 30 minutes, and the solvent was purified by preparative HPLC to obtain eFAP-34 (1.4 mg, 0.7 μmol, 31%) as a grayish-white powder. ESI-MS: m / z 1956.5[M+H]+. [Figure 5] As illustrated in Figure 5, TADB-N3 (8 mg, 19 μmol) was dissolved in DMF (1 mL), followed by the addition of NH2-PEG2-tBu (3 equivalents, 13 mg) and DIPEA (30 μL). The reaction mixture was stirred at room temperature for 2 hours, diluted with RINKAN (15 mL), washed with water (3 × 5 mL), dehydrated with Mg2SO4, and concentrated under vacuum to obtain a pale white solid. The crude product was treated with a solution of DCM / TFA (3 mL, 1:1) at room temperature for 30 minutes. All volatiles were removed under a gentle stream to obtain a pale white crude solid. The crude product was purified by preparative HPLC to obtain platform 1 (6.3 mg, 10.4 μmol, 55%) as a pale white oil. ESI-MS: m / z 605.2[M+H]+. [Figure 6]As illustrated in Figure 6, 2,4,6-trichloro-1,3,5-triazine (25 mg, 13.5 μmol) was dissolved in DMF (1 mL), followed by the addition of NH2-PEG2-tBu (2.3 equivalents, 72.7 mg) and DIPEA (117 μL). The reaction mixture was stirred at room temperature for 2 hours, diluted with SiO2 (15 mL), washed with water (3 × 5 mL), dehydrated with Mg2SO4, and concentrated under vacuum to obtain a pale white solid. The crude product was redissolved in DMF (1 mL), followed by the addition of 3-azidopropan-1-amine (2.2 equivalents, 29.7 mg). The reaction mixture was stirred at room temperature for 24 hours, diluted with SiO2 (15 mL), washed with water (3 × 5 mL), dehydrated with Mg2SO4, and concentrated under vacuum to obtain a pale white solid. The crude product was treated with a solution of DCM / TFA (3 mL, 1:1) at room temperature for 30 minutes. All volatiles were removed under a gentle stream of air to obtain a pale white crude solid. The crude product was purified by preparative HPLC to obtain platform 2 (3 mg, 8.6 μmol, 64%) as a pale white oil. ESI-MS: m / z 530.2[M+H]+. [Figure 7]As illustrated in Figure 7, 2,4,6-trichloro-1,3,5-triazine (60 mg, 32.5 μmol) was dissolved in DMF (1.5 mL), followed by the addition of NH2-PEG2-tBu (2.2 equivalents, 167.0 mg) and DIPEA (210 μL). The reaction mixture was stirred at room temperature for 2 hours, diluted with SiO2 (15 mL), washed with water (3 × 5 mL), dehydrated with Mg2SO4, and concentrated under vacuum to obtain a pale white solid. The crude product was treated with a solution of DCM / TFA (4 mL, 1:1) at room temperature for 30 minutes. All volatiles were removed under a gentle stream of air to obtain a pale white oil. The oil was redissolved in DMF (1 mL), followed by the addition of N-Boc-1,6-diaminohexane (1.5 equivalents, 9.6 mg) and DIPEA. The reaction mixture was stirred at room temperature for 24 hours, diluted with siRNA (15 mL), washed with water (3 × 5 mL), dehydrated with Mg₂SO₄, and concentrated under vacuum to obtain a pale white solid. The crude product was redissolved in DMF (1 mL), followed by the addition of 8QCP-NH₂ (2.5 equivalents, 25 mg, illustrated in Figure 4 and obtained from intermediate 10 as described for eFAP-36), HBTU (2 equivalents, 14 mg), and DIPEA (30 μL). The reaction mixture was stirred at room temperature for 2 hours, diluted with siRNA (15 mL), washed with water (3 × 5 mL), dehydrated with Mg₂SO₄, and concentrated under vacuum to obtain a pale yellow solid. The crude product was treated with a solution of DCM / TFA (2 mL, 1:1) at room temperature for 30 minutes. All volatiles were removed under a gentle stream to obtain a pale yellow solid. The solid was redissolved in DMF (1 mL), followed by the addition of DOTAGA anhydrous (2,2',2''-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid, 1.2 equivalents, 4.6 mg) and DIPEA (40 μL). After 1 hour, the solvent was removed under vacuum, and the crude product was purified by preparative HPLC to obtain eFAP-50 (5 mg, 2.8 μmol, 33%) as a grayish-white powder. ESI-MS: m / z 1803.5[M+H]+. [Figure 8]As illustrated in Figure 8, 2,4,6-trichloro-1,3,5-triazine (60 mg, 32.5 μmol) was dissolved in DMF (1.5 mL), followed by the addition of NH2-PEG2-tBu (2.2 equivalents, 167.0 mg) and DIPEA (210 μL). The reaction mixture was stirred at room temperature for 2 hours, diluted with SiO2 (15 mL), washed with water (3 × 5 mL), dehydrated with Mg2SO4, and concentrated under vacuum to obtain a pale white solid. The crude product was treated with a solution of DCM / TFA (4 mL, 1:1) at room temperature for 30 minutes. All volatiles were removed under a gentle stream of air to obtain a pale white oil. The oil was redissolved in DMF (1 mL), followed by the addition of N-Boc-1,6-diaminohexane (1.5 equivalents, 9.6 mg) and DIPEA. The reaction mixture was stirred at room temperature for 24 hours, diluted with SiO2 (15 mL), washed with water (3 × 5 mL), dehydrated with Mg2SO4, and concentrated under vacuum to obtain a pale white solid. The crude product was redissolved in DMF (1 mL), followed by the addition of 8QCP-AMCHA (2.5 equivalents, 25 mg), HBTU (2 equivalents, 14 mg), and DIPEA (30 μL). The reaction mixture was stirred at room temperature for 2 hours, diluted with SiO2 (15 mL), washed with water (3 × 5 mL), dehydrated with Mg2SO4, and concentrated under vacuum to obtain a pale yellow solid. The crude product was treated with a solution of DCM / TFA (2 mL, 1:1) at room temperature for 30 minutes. All volatiles were removed under a gentle stream of air to obtain a pale yellow solid. The solid was redissolved in DMF (1 mL), followed by the addition of DOTAGA anhydrous (2.5 equivalents, 25 mg) and DIPEA (40 μL). After 1 hour, the solvent was removed under vacuum, and the crude product was purified by preparative HPLC to obtain eFAP-51 (2 mg, 1.0 μmol, 33%) as a grayish-white powder. ESI-MS: m / z 1041.1[M+2H]2+. [Figure 9] As illustrated in Figure 9, eFAP-52 can be obtained by a procedure similar to that described for eFAP-51 in Example 9. [Figure 10]In vitro stability. Radiolabeled compound (approximately 2 MBq) was mixed with 300 μL of PBS (0.1 M, pH 7.4) or mouse serum at 37°C for 1, 4, and 24 hours. At each time point, the protein in the serum sample was precipitated by adding acetonitrile (300 μL), and the solution was centrifuged at 13,000 rpm for 5 minutes (twice). The supernatant was loaded into a radio-HPLC system for analysis. Samples in PBS were analyzed directly by radio-HPLC without any pretreatment. All experiments were performed in triplicate. The results are shown in Table 1 and Figures 10A to 10L. [Figure 11] Cell uptake / blocking experiment using U87 cells. Cells were seeded in a 6-well plate 24 hours prior to the experiment (7 × 10⁵ cells / well). The following day, adhered cells were incubated in 1 mL of culture medium with 10⁻⁹ M [111In]In-labeled compound at 37°C for 90 minutes. The compound was also evaluated using a 50-fold excess block of the unlabeled compound. Membrane-bound fraction (MF) was collected by incubating cells in acid buffer (50 mM glycine, 100 mM NaCl, pH 2.8) at room temperature for 10 minutes. Internalized fraction (IF) was determined by lysing cells in 1 M NaOH at room temperature for 5 minutes. Both fractions were measured using a gamma counter, and the data were analyzed in GraphPad Prism v9 and expressed as a percentage of the added dose. The results are presented in Figure 11 and Table 4. [Figure 12] Figure 12 shows SPECT / CT images. [Figure 13] Figure 13 shows the results of the in vivo distribution study after 48 hours. The results are expressed as a percentage of the injected dose per gram (%ID / g). [Modes for carrying out the invention]

[0019] The present invention particularly relates to formula (I) or formula (II)

[0020] [ka]

[0021] [In the formula, L 1 , L 2 and L 3 each independently represent a linker, Q comprises a payload, preferably a therapeutic agent, a diagnostic agent, or a combination thereof, each Z independently represents a moiety of formula (Z)

[0022] [Chemical Formula]

[0023] (In the formula, X represents NH, CH2 or O, R 1 represents H, Me, CH(CH3)C2H5, CH2CH(CH3)2, CH(CH3)2, CH2OH, CH2SH, CH(OH)CH3, CH2C(O)NH2, CH2CH2C(O)NH2, (CH2) m CO2H, (CH2) m NH2, wherein m is 1 to 4, R 2 and R 3 each independently represent H or F) which is a FAP-binding moiety comprising a scaffold represented by The present invention is directed to a compound represented by or a pharmaceutically acceptable salt thereof.

[0024] Here, the wavy line symbol (

[0025] [Chemical Formula]

[0026] ) indicates the position at which the specified moiety is bonded to the rest of the compound. Therefore, for example, with respect to Z, the wavy line symbol indicates that X is bonded to linker L 1 or L 2 .

[0027] FAP joint part Z The basic structure of the FAP bond is described below, with the numbering of carbon atoms in the quinoinoryl moiety indicated. The X portion, and thus the rest of the compound, is also preferably located at the 5th, 6th, 7th, or 8th carbon atom of the quinoinoryl moiety.

[0028] [ka]

[0029] However, in preferred embodiments, the compounds of the present invention include a (4-quinoinol)glycinyl-2-cyanopyrrolidine scaffold (also referred to herein as a scaffold) in which the 8-position of the quinoinolyl moiety is substituted with a bridging carbon or oxygen atom. The bridging carbon or oxygen atom is the linker L 1 or L 2 and are connected to or enable connection to the payload via a triazinane or triazine core. It can be understood that this scaffold may include further substituents such as fluoride and others, as known for FAP inhibitors based on (4-quinoinolyl)glycinyl-2-cyanopyrrolidine scaffolds. As detailed in concurrently pending application PCT / NL2023 / 050491 incorporated herein by reference, this results in specific FAP binding affinity and / or tumor uptake, including good tumor-versus-organ distribution.

[0030] Therefore, in a preferred embodiment, each Z in formula (I) and / or (II) independently represents an FAP bond portion according to formula (Za) (wherein X represents CH2 or O, preferably O).

[0031] [ka]

[0032] Among the (4-quinoinolyl)glycinyl-2-cyanopyrrolidine scaffolds of the present invention, preferably R 2 and R 3At least one of them is F, and more preferably at least R 2 is F and (R 2 and R 3 Most preferably, R 2 and R 3 Both are F.

[0033] R 1 The substituent is preferably hydrogen (H).

[0034] In a preferred embodiment, the FAP bond portion is given by formula (Zb)

[0035] [ka]

[0036] (In the formula, R 4 (This represents a spacer, preferably an aliphatic spacer.) As illustrated, at least spacer R 4 It is conjugated into the compound via [a certain mechanism].

[0037] R 4 The spacer represented by formula (Zc) (wherein R 4' This includes a nitrogen atom, as exemplified by (representing optionally substituted hydrocarbylene or optionally substituted alkylene ether, preferably alkylene, more preferably C1-C8 alkylene), which can be used to connect (4-quinoinol)glycinyl-2-cyanopyrrolidine scaffolds.

[0038] [ka]

[0039] Spacer (R 4 and R 4') can be substituted or interrupted by one or more heteroatoms, such as OH, NH2, SO2, and one or more halogens such as F, Cl, Br, and I. 4 and R 4' The spacers represented by are preferably based on aliphatic C1-C8 amino-terminus spacers. Such spacers have been found to result in particularly good FAP binding affinity and tumor uptake. Therefore, in particularly preferred embodiments of the compounds of the present invention, each Z independently has a structure according to formula (Zd) (wherein n is 1-6, preferably 1).

[0040] [ka]

[0041] In other embodiments, the compound is given by formula (Z') or (Z'').

[0042] [ka]

[0043] Linker L 1 , L 2 and L 3 Linker L 1 , L 2 and L 3The linker plays a role in linking one or more payloads and FAP binding sites. The linker can assist in the solubility of the compound. For example, 4-amino-3-hydroxybutanoic acid (GABOB) and (oligo)ethylene glycol can be used to aid in water solubility and lower lipophilicity (observed by logP value). The linker can be cleavable or incleavable (see, e.g., Kovtun et al., Cancer Letters 255 (2007) 232-240, Beck et al., Nature Reviews Drug Discovery 16 (2017) 315-337 and WO2021 / 160825) or a combination of both (i.e., one or more cleavable parts linking one or more payloads, and one or more other incleavable parts linking one or more other payloads or scaffolds). In general, the linker L 1 and L 2 It is impossible to cut, L 3 It may be optional to disconnect it.

[0044] In a particular embodiment, L 1 , L 2 and L 3 These are, independently, linear or branched amino acids, more preferably glycine, alanine, β-alanine, 3-aminopropionic acid, 4-aminobutyric acid, 4-amino-3-hydroxybutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 7-aminoheptanoic acid, 8-aminooctanoic acid, 9-aminononanoic acid, 10-aminodecanoic acid, 2-aminooctanoic acid, etc., peptide spacer (Xaa) 1~4 Based in part or entirely on the above, where each Xaa is independently an L-amino acid, a D-amino acid (proteinogenic amino acid), and a N-amino acid. ε ,N ε ,N ε-Trimethyllysine, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), ornithine (Orn), homoarginine (hArg), 2-amino-4-guanidinobutyric acid (Agb), 2-amino-3-guanidinopropionic acid (Agp), β-alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 7-aminoheptanoic acid, 8-aminooctanoic acid, 9-aminononanoic acid, 10-aminodecanoic acid, 2- Aminooctanoic acid, 2-aminoadipic acid (2-Aad), 3-aminoadipic acid (3-Aad), 4-(aminomethyl)cyclohexane-1-carbonylic acid (Amcha), 4-amino-1-carboxymethyl-piperidine (Pip), 2-(piperazine-1-yl)acetic acid (Pipa), 2-(4-(2-aminoethyl)piperazine-1-yl)acetic acid, cysteic acid, diglycolic acid (DGA), and NH2(CH2)2[O(CH2)2] q It is a proteinogenic or non-proteinogenic amino acid residue selected from the group consisting of C(O)OH (wherein q = 1 to 36). Most preferably, L 1 and L 2 Both are NH2(CH2)2[O(CH2)2] q C(O)OH (where q = 1 to 36), more preferably NH2(CH2)2[O(CH2)2] q This represents C(O)OH (where q = 2 to 6). The amino acid NH2(CH2)2[O(CH2)2] q Compounds containing a C(O)OH-based linker provided good FAP binding affinity.

[0045] The term "~based" can be understood herein to mean that the linker is described in its unreacted, free form, but the linker in the compound is bonded to the triazinan and / or triazine core and FAP bond site via amine and carboxylic acid groups. Typically, these listed linkers L 1 and L 2 It is bonded to the triazinane and / or triazine core of the compound via its amine group, and to the FAP bond portion via its carboxylic acid group.

[0046] In one embodiment, linker L 1 , L 2 and / or L 3 It includes a part having a structure shown in any of the formulas La to Lp. In particular L 1 and / or L 2 Lo and / or Lp are preferred.

[0047] [ka]

[0048] (In the formula, further, Y 1 It is selected from the group consisting of C and N, preferably N for formulas La, Lg and Lh, and C for formula Ld. Y 2 is selected from the group consisting of C, N, and O, preferably N and C, and more preferably C. q is in the range of 1 to 36, preferably 1 to 6).

[0049] In a further preferred embodiment, linker L 1 , L 2 and / or L 3 This includes a portion having a structure according to one of the formulas Laa, Lfa, Lfb, Lfc, Lga, Lha, Lhb, Lhc, and Lma, which are specific versions of the formulas La, Lf, Lg, Lh, and Lm, respectively. For Lfb, Lfc, Lhb, and Lhc, q can be in the range of 1 to 36, preferably 1 to 6.

[0050] [ka]

[0051] Unless the stereochemistry of an atom is described in detail herein, the stereochemistry of the atom is undefined, which can be understood as indicating that the structure represents all possible stereoisomers of the atom. For example, structure Lfa represents at least two diastereoisomers: trans and cis isomers. However, preferably, the linker represented by this formula has a trans configuration, as shown by formula Lfa' below.

[0052] [ka]

[0053] In a particular embodiment, linker L 3 The linker section may include a cleavable linker section containing a portion that can be cleaved in vivo. Such a linker section is particularly preferred when the payload contains a drug that benefits from delivery and release from a scaffold near or within a target site (see, for example, Kovtun et al., Cancer Letters 255(2007)232-240, Beck et al., Nature Reviews Drug Discovery 16(2017)315-337, and WO2021 / 160825).

[0054] Therefore, an enzyme-sensitive cleavable linker section is a preferred linker section, and most preferably, a cleavable section that is sensitive to an enzyme overexpressed in the tumor, such as glutathione.

[0055] Examples of cleavable moieties that can be included in the cleavable linker section include amides, esters, carbamates, hydrazones, thiazolidinedions, methylene alkoxycarbamates, and disulfides. The cleavable moieties may include one or more such moieties, for example, peptides, oligosaccharides, or other oligomeric sequences that can be selectively cleaved in vivo.

[0056] In a preferred embodiment, the cleavable portion includes a disulfide moiety or terminal thiol that enables disulfide linkage to a payload (e.g., meltansine or DM1) that also contains a terminal thiol.

[0057] In one embodiment, the cleavable linker section is based on or contains linear or branched mercaptocarboxylic acids, such as thioglycolic acid, thiolactic acid (also known as 2-mercaptopropionic acid), 3-mercaptopropionic acid (3-MPA), 4-mercaptobutanoic acid (SPDB), 4-mercaptopentanoic acid (SPP), 4-mercapto-2-sulfobutanoic acid (sulfo-SPDB), etc. The cleavable linker section may also contain a self-immolative moiety, which, through a reaction cascade, can release an unfunctionalized payload after activation (see, e.g., RV Gonzaga et al., Journal of Pharmaceutical Sciences 109(2020) 3262-3281). Examples of suitable self-destructing moieties include those in which p-aminobenzylcarbamate (PAB) is coupled to valine-citrulline (Val-Cit-PAB), glycine-proline (Gly-Pro-PAB), ala-Ala-Asn-PAB, DGA-Lys-PAB, or β-glucuronide, and those based on glob fragmentation (referred to herein as glob fragmentable moiety; see, for example, Ferhati et al., Org. Lett. 2021, 23, 21, 8580-8584).

[0058] Linker L 3 Linker L binds the payload to the triazinan and / or triazine core. 3 Connect the payload and linker L 1 and L 2 Multiple synthetic strategies can be used to achieve selectivity when connecting to the FAP bond. One method for obtaining selectivity may be through the use of orthogonal protecting groups. In such embodiments, linker L1 and L 2 For example, it can be connected to the FAP bonding portion, while L 3 It still has a protecting group. Next, as the next step, L 3 The linker L may be deprotected and coupled to the payload. Suitable protecting group strategies are well known and, for example, described in *Protecting Groups in Organic Synthesis*, TW Greene and PGMWuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference in its entirety. Another strategy is, for example, linker L via a click reaction. 3 L enables orthogonal coupling reactions. 1 and L 2 The method involves using a linker L. In such embodiments, for example, linker L 1 and L 2 For example, L can be linked to the FAP bond portion via an amide bond. 3 It has an azide that can react orthogonally with an alkyne or another part that enables a click reaction.

[0059] In a preferred embodiment, linker L 3 is, equation (L 3 a), (L 3 b), (L 3 c) and (L 3 d) The structure is one of the following (wherein (Q) indicates the relative position of the payload Q, r is in the range of 1 to 6, preferably 1 to 3, more preferably 3, and p is in the range of 1 to 6, preferably 1 to 3, more preferably 2).

[0060] [ka]

[0061] Linker L 3The structure of is preferably the reaction product of an orthogonal reaction (also referred to in the art as a click reaction) between a triazinan and / or triazine core bearing an azide functional group and a payload bearing an alkyne functional group, via, for example, a copper-catalyzed alkyne-azide Huisgen cycloaddition or a copper-free reaction between an azide and bicyclo[6.1.0]non-4-yne, BCN, or dibenzocyclooctyne, DBCO.

[0062] Linker (L 3 b) and (L 3 d) are preferably used for the triazinan core, while linker (L 3 a) and (L 3 c) are preferably used for the triazine core.

[0063] Linker L 3 may also be based on a moiety having a structure according to any one of formulae (L 3 e), (L 3 f), (L 3 g), (L 3 h), (L 3 i), (L 3 j), (L 3 k), (L 3 l), (L 3 m) and (L 3 n), wherein (Q) indicates the relative position of payload Q, and r is in the range of 1 to 6.

[0064] [Chemical Formula]

[0065] Linker (L 3 e) and (L 3 f) can be used, for example, to link a carboxylic acid-terminated payload, while linker (L 3 g), (L 3 h), (L 3 m) and (L 3n) can similarly be used to enable disulfide linking to a payload containing terminal thiols (e.g., meltansine or DM1). Linker (L 3 k) and (L 3 l) can be used, for example, to link amine-terminated payloads. Linker (L) 3 i) and (L 3 j) can be used, for example, to concatenate the alkyne terminal payload.

[0066] Therefore, compounds of formula (Ia), (Ib), (Ic), (IIa), (IIb), or (IIc) are particularly preferred. Here, r is in the range of 1 to 6, preferably 1 to 3, more preferably 3, and p is in the range of 1 to 6, preferably 1 to 3, more preferably 2.

[0067] [ka]

[0068] Even more preferable is the linker L, as illustrated below. 1 and L 2 is the amino acid NH2(CH2)2[O(CH2)2] q These are compounds of the formula (Iaa), (IIaa), (Iba), (IIba), (Ibb), (IIbb), (Ibc), (IIbc), (Ica), or (IIca), based on C(O)OH and optionally combined with Pipa (see, e.g., (Ibc) and (IIbc)) or Amcha (see, e.g., (Ibb) and (IIbc)). The amino acid NH2(CH2)2[O(CH2)2] q The combination of C(O)OH linker and Amcha or Pipa yields particularly good results, and therefore such compounds are even more preferable. Linker L of these compounds 1 and L 2This includes a portion having a structure with Lfb and Lhb, and therefore these are particularly preferred. Compounds of structures (Iaa), (IIaa), (Iba), (IIba), (Ica), and (IIca), although not separately illustrated below, may also contain such linkers, that is, the ethylene oxide portion (formula Lp) can be used in combination with Pipa (formula Lha) or Amcha (formula Lfa).

[0069] [ka]

[0070] [ka]

[0071] [ka]

[0072] [ka]

[0073] Payload Q The present invention is not particularly limited to specific payloads, diagnostics, and therapeutic agents. Advantageously, the present invention enables the use of a wide variety of payloads in combination with scaffolds without impairing the FAP affinity and / or tumor uptake of the compounds. It can be understood that appropriate payloads and agents can be selected based on desired uses such as diagnosis and treatment.

[0074] For example, known payloads for previously developed FAP targeting agents disclosed in WO2019 / 154859 and WO2021 / 160825 can also be suitably used in conjunction with the present invention.

[0075] In certain embodiments, the payload includes a radioisotope that forms a complex with the chelating agent. The radioisotope can be any suitable radioisotope. See, for example, Tornesello et al., Molecules 2017, 22(8), 1282, US2021 / 0402016A1, WO2021 / 005125A1 and Price and Orvig, Chem. Soc. Rev., 2014, 43, 260-290 and the references cited therein. The radioisotope can be an α or β particle emitter, an Auger emitter, a positron emitter and / or a γ particle emitter. α particle emitters and β particle emitters, for example 90 Y, 212 Pb, 177 Lu, 188 Re, 186 Re, 67 Cu, 64 Cu, 195m Pt, 212 Bi, 213 Bi, 211 At, 225 Ac, 131 I, etc., can be used in therapy. Suitable gamma-releasing bodies, for example 99m Tc, 67 Ga, 111 While materials like In can be used for SPECT imaging, positron emitters, for example, 68 Ga, 64 Cu, 18 F, etc., are useful for PET imaging. Therefore, the radioactive isotope M of the present invention is preferably, 18 F, 123 I, 124 I, 125 I, 131 I, 76 Br, 77 Br, 212 Pb, 203 Pb, 64 Cu, 67 Cu, 212 Bi, 68 Ga, 213 Bi, 225 Ac, 243 Am, 211 At, 217 At, 154 Dy, 148 Gd,146 Sm, 147 Sm, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 165 Er, 72 As, 77 As, 47 Sc, 188 Re, 186 Re, 105 Rh, 109 Pd, 199 Au, 175 Yb, 142 Pr, 114m In, 94m Tc, 99m Tc, 227 Th, 229 Th, 59 Fe, 60 Cu, 61 Cu, 62 Cu, 67 Ga, 44 Sc, 89 Zr, 90 Nb, 86 Y, 90 Y, 111 In, 177 Lu, 117m Sn, 153 Gd, 153 Sm, and 166 From the group consisting of Ho, preferably 18 F, 64 Cu, 67 Ga, 68 Ga, 90 Y, 111 In, 177 Lu, 212 Pb and 225 From the group consisting of Ac, most preferably 18 F, 68 Ga, 111 In, 212 Pb, 225 American and 177 Selected from the group consisting of Lu.

[0076] In this field, various chelating agents are known to bind to radioisotopes. The chelating agent of the present invention is a pharmaceutically acceptable chelating agent. Since not all chelating agents are equally suitable for all radioisotopes, the chelating agent is typically selected based on the radioisotope desired for diagnosis or treatment. Typically, radioisotope chelating agents include cyclic or branched polyaminopolycarboxylic acid moieties or their amide derivatives. See, for example, Tornesello et al., Molecules 2017, 22(8), 1282, US2021 / 0402016A1, WO2021 / 005125A1 and Price and Orvig, Chem. Soc. Rev., 2014, 43, 260-290 and the references cited therein.

[0077] In a preferred embodiment of the present invention, the radioisotope chelating agent is - Derivatives such as DOTA (1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid, also known as tetraxetan) and p-SCN-Bn-DOTA (2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid); - PSC(1,4,7,10-tetraazacyclododecane-7-acetamido-1,4,10-triacetic acid); - DO3A(1,4,7,10-tetraazacyclododecane-N,N',N''-triacetic acid); - DOTAGA(1,4,7,10-tetraazacyclododecane-1-(glutaric acid)-4,7,10-triacetic acid); - DO3AM(2,2',2''-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetamide); - Derivatives such as DOTAM (2-[4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododeca-1-yl]acetamide) and p-SCN-Bn-TCMC (2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane); - NOTA(1,4,7-triazacyclononane-N,N',N''-triacetic acid); - NODAGA(1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane); - NODASA(1,4,7-Triazacyclononane-1-succinate-4,7-diacetic acid); - CB-DO2A(4,10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane); - 3p-C-DEPA(2-[(carboxymethyl)][5-(4-nitrophenyl-1-[4,7,10-tris-(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]pentan-2-yl)-amino]acetic acid); - TCMC(1,4,7,10-tetrakis(carbamoylmethyl)1,4,7,10-tetraazacyclododecane); - DTPA (diethylenetriaminepentaacetic acid) and DTPA derivatives such as CHX-A''-DTPA (2-(p-isothiocyanatobenzyl)cyclohexyldiethylenetriaminepentaacetic acid) and 1B4M-DTPA; - TETA(1,4,8,11-tetraazacyclotetradecane 1,4,8,11-tetraacetic acid) and analogs and derivatives such as C-NETA; - Derivatives such as NE3TA (7-[2-[(carboxymethyl)amino]ethyl]-1,4,7-triazacyclononane-1,4-diacetic acid) and C-NE3TA; - CB-TE2A(4,11-bis(carboxymethyl)-1,4,8,11tetraazabicyclo[6.6.2]hexadecane); - NETA ({4-[2-(bis-carboxymethylamino)-ethyl]7-carboxymethyl-[1,4,7]triazonan-1-yl}acetic acid); and NETA derivatives such as 3p-C-NETA (see Sun et al., ACS Omega 2020, 5, 44, 28615~28620) - H2azapa(N,N'-[1-benzyl-1,2,3-triazole-4-yl]methyl-N,N'-[6-(carboxy)pyridine-2-yl]-1,2-diaminoethane) and H2dedpa(1,2-[[6-(carboxy)-pyridine-2-yl]methylamino]ethane), H4octapa(N,N'-bis(6-carboxy-2-pyridylmethyl) - Ethylenediamine-N,N'-diacetic acid), H4Py4pa, H4Pypa, H6phospha, H4CHXoctapa, H5decapa(N,N''-[[6-(carboxy)pyridine-2-yl]methyl] - Diethylenetriamine-N,N',N''-triacetic acid), and other picolinic acid derivatives such as H4neunpa-p-Bn-NO2; - SHBED(N,N'-bis(2-hydroxy-5-sulfobenzyl)ethylenediamine-N,N'-diacetic acid); - HBED(N,N'-bis(2-hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid); - H2-MACROPA(N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6); - PCTA(3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid); - Me-3,2-HOPO (See Ramdahl, Bioorganic & Medicinal Chemistry Letters 26(2016)17, 4318-4321); - CB-TE1A1P(1,4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8-(methanecarboxylic acid)); - CB-TE2P(1,4,8,11-tetraazacyclotetradecane-1,8-di(methanephosphonic acid)); - MM-TE2A(N-monomethyl 1,8-N,N'-bis-(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane); - DM-TE2A(N,N'-dimethyl1,8-N,N'-bis-(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane); - Sarcofazine and sarcofadin derivatives such as SarAr(1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexazabicyclo[6.6.6]-eicosan-1,8-diamine), diamSar, AmBaSar, and BaBaSar; - Analogues such as TRAP(1,4,7-trizacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid]) and NOPO(1,4,7-trizacyclononane-1,4-bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid]); - AAZTA(1,4-bis(hydroxycarbonylmethyl)-6-[bis(hydroxylcarbonylmethyl)]amino-6-methylperhydro-1,4-diazepine); - DATA and DATA derivatives; - CP256(4-acetamide-N1,N7-bis-[(3-hydroxy-1,6-dimethyl-4-methylene-1,4-dihydropyridine-2-yl)methyl]-4-(3-[(3-hydroxy-1,6-dimethyl-4-methylene-1,4-dihydropyridine-2-yl)methylamino]-3-oxopropyl)heptanediamide) and its derivative YM103(4-(3-[3-(2,5-di Oxo-2,5-dihydro-1H-pyrrole-1-yl)propanamide]propanamide)-N1,N7-bis[(3-hydroxy-1,6-dimethyl-4-methylene-1,4-dihydropyridine-2-yl)methyl]-4-(3-[(3-hydroxy-1,6-dimethyl-4-methylene-1,4-dihydropyridine-2-yl)methylamino]-3-oxopropyl)heptanediamide); - PCTA(6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid); - BCPA (See Price and Orvig, Chem. Soc. Rev., 2014, 43, 260-290); - DFO (desferrioxamine) and DFO derivatives; - Trithiol chelate; - Mercaptoacetyl; - Hydrazinonicotinamide; - Dimercaptosuccinate; - 1,2-ethylenediylbis-L-cysteinediethyl ester; - Methylenediphosphonate; - Hexamethylpropyleneamineoxime; - Hexakis(methoxyisobutylisonitrile); The compound is based on a compound selected from the group consisting of the compound and its analogues.

[0078] The most preferred chelating agents are DOTA, NOTA, and DO3AM, because these chelating agents are 18 F, 68 Ga, 111 In, 177 Lu, 225 American and 212 This is because it is particularly well compatible with Pb.

[0079] Preferably, the chelating agent is bonded to the linker via one of its carboxylic acid groups, resulting in an amide bond. However, this bond may also be formed via one of its carbon atoms. For bonding to carbon atoms, the chelating agent may appropriately comprise an isothiocyanate functional group, such as isothiocyanatobenzyl. Examples of chelating agents comprising such a group include pSCN-Bn-DOTA and p-SCN-Bn-TCMC. The chelating agent may also contain a BCN or DBCO group for click reactions; see, for example, the examples for eFAP-37 and eFAP-38 below.

[0080] In a preferred embodiment, the linker is bonded to one of the carboxylic acid groups of the chelating agent.

[0081] In some embodiments, Q is any of formulas Qa to Qh, preferably Qa, Qg, or Qh, more preferably Qa or Qg, and most preferably Qg

[0082] [ka]

[0083] (In the formula, m is 0 to 6, preferably 1 or 2, A 1 ~A 4 is independently selected from the group consisting of H, alkyl, aliphatic acids, carboxylic acids such as CH2CO2H and CO2H, and their amides and esters, preferably A 1 ~A 3 It is CH2CO2H, and A 4 It is CO2H, A 5 This refers to a fluoride-18-containing group or precursor, for example, 1,4-butanesulton-1-yl(1,2λ 6 -Oxatian-2,2-dione-3-yl or 2,2-dioxide-1,2-oxatian-3-yl), CH(SO3H)(CH2)3F and / or N(CH3)2)CH2BF3, (M) represents a radioactive isotope. (L 3 ) is Linker L 3 (Indicates the relative position) It has a structure based on the following.

[0084] In the structure represented by any of formulas Qa to Qh, A1 to A4 are preferably H, (C1 to C6)-alkyl, (C1 to C6)-alkylene-(CO2A 6 ), (C1~C6)-alkylene-(C(O)NA 6 A 7 Independently selected from the group consisting of ), where A 6 and A 7 is independently selected from the group consisting of H and (C1-C6)-alkyl, and is preferably H. Most preferably, A 1 ~A 3It is CH2CO2H, and A 4 A is CO2H to aid in the water solubility of the compound. In a further preferred embodiment, A 1 ~A 4 These are all the same and are selected from the group consisting of -CH2CO2H and -CH2C(O)NH2.

[0085] In certain embodiments, the chelating agent is A 5 As exemplified by formula (Qh) representing CH(SO3H)(CH2)3F and / or N(CH3)2)CH2BF3, it may be combined with fluoride labeling. This fluoride is suitable for imaging such as PET imaging. 18 It can be the F isotope. The compound can also be A 5 1,4-butanesultone (1,2λ 6 As illustrated by formula (Qh) representing -oxathian-2,2-dione, the preparation of such compounds may include precursors.

[0086] The payload is 1,4-butanesulton-1-yl(1,2λ 6 These may be fluoride-18-containing groups or precursors thereof, such as (-oxatian-2,2-dione-3-yl or 2,2-dioxide-1,2-oxatian-3-yl), CH(SO3H)(CH2)3F, and / or N(CH3)2)CH2BF3. Such payloads can be applied in PET imaging directly or, in the case of precursors, after conversion.

[0087] The payload may be a dye, preferably a fluorescent dye, selected from the group consisting of cyanine, phthalocyanine, rhodamine, fluorescein, xanthene, coumarin, styryl, porfin, fluorescent organometallic complexes, oxanine, perylene, acridine, boron-dipyromethene, etc.

[0088] Particularly preferred fluorescent dyes include cyanines and / or phthalocyanines. Preferred dyes are CY5 dyes, especially sulfo-CY5, FNIR-Tag, CyTE-777, CyTE-807, IRDye 800CW, and ZW800-1.

[0089] Preferably, the dye is bonded to the linker via one of its carboxylic acid groups, resulting in an amide bond. However, this bond may also be via one of its carbon atoms. For linking to carbon atoms, the dye may appropriately comprise an isothiocyanate functional group, such as isothiocyanatobenzyl. In a preferred embodiment, the linker is bonded to one of the carboxylic acid groups of the dye.

[0090] In some embodiments, Q is given by equation (Qi) ~ (Qm) (wherein L 3 ) is Linker L 3 It has a structure that indicates the relative position of the elements.

[0091] [ka]

[0092] [ka]

[0093] (In the formula,

[0094] [ka]

[0095] teeth,

[0096] [ka]

[0097] And, Here, Z 1 teeth,

[0098] [ka]

[0099] (That is.)

[0100] The payload may be a drug, preferably a cytotoxic or cytostatic agent. Examples include some of the radioisotopes described above herein, and molecular drugs. Suitable drugs are also those described in WO2021 / 160825, which are incorporated herein in their entirety. Specific suitable drugs include Hsp90 inhibitors, e.g., geldanamycin analogs, radicicol analogs, zelavespib (PU-H71), onarespib (AT13387), SNX-0723, HSP990, YC-72-AB85, luminesspib (AUY922), VER-49009, NMS-E973, meltansine (DM1), and N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytan. The drug comprises meltansine (DM4), doxorubicin, idarubicin, PNU, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), exatecan, exatecan derivative DXD, SN-38 (active metabolite of irinotecan), pyrrolo[2,1-c][1,4]benzodiazepine (PBD), SG3199 (PDB dimer), duocalmycin, bortezomib, AVA2727D, tubulisin A, and calicheamicin. Most preferably, the drug comprises meltansine (DM1), DM4, MMAE, exatecan, SN38, bortezomib, and doxorubicin.

[0101] The drugs can be prepared to be suitably bonded to the linker, as is well known to those skilled in the art. For example, if the drug contains a thiol, as in the case of DM1 and DM4, this thiol can be suitably used.

[0102] In multiple embodiments, Q is given by equation (Qn)~(Qt) (wherein L 3 ) is Linker L3 indicating the relative position of) has a structure according to any one of the above.

[0103]

Chemical Formula

[0104]

Chemical Formula

[0105]

Chemical Formula

[0106] Exemplary Compounds In a particularly preferred embodiment, the pharmaceutical compound or a pharmaceutically acceptable salt thereof has a structure according to any one of the following formulas eFAP-34, eFAP-35, eFAP-36, and eFAP-37. These compounds preferably contain a radioisotope, more preferably 111 In, 68 Ga, 177 Lu, 212 Pb or 225 Ac radioisotope. Compounds eFAP-34 to eFAP-38 are particularly suitable for use in radioisotope-based tumor therapy and / or radionuclide-based tumor imaging, inter alia, in view of their advantageous tumor retention properties.

[0107]

Chemical Formula

[0108]

Chemical Formula

[0109]

Chemical Formula

[0110]

Chem.

[0111]

Chem.

[0112]

Chem.

[0113]

Chem.

[0114]

Chem.

[0115]

Chem.

[0116]

Chem.

[0117]

Chem.

[0118]

Chem.

[0119] Preparation The compounds of the present invention can be prepared by orthogonally conjugating the FAP binding moiety to the core in one reaction (typically forming linker L 1 and L 2 ), and conjugating the payload to the core in another reaction (typically forming linker L3 Linker L can be suitably prepared by forming a linker L. 3 a or L 3 An exemplary synthetic route for a compound containing b is schematically illustrated in Figures 3A and 3B. In the first step, the FAP bond is linked to linker L via amide bond formation. 1 and L 2 The payload is attached (terminated with a carboxylic acid or activated ester). In the next step, the payload is conjugated to the core via a copper-free click reaction using the payload-BCN (bicyclo[6.1.0]nonine) reagent. Further details are presented in the Examples section below.

[0120] Therefore, a particular aspect of the present invention is an intermediate compound suitable for the preparation of the compounds described herein. The intermediate compound is of formula (IIIa), (IVa), (IIIb), (IVb), (IIIaa), (IVaa), (IIIab) and (IVab) (wherein L 1 , L 2 The structure includes one of the following (where Z, q, and r are as defined for the compound).

[0121] [ka]

[0122] [ka]

[0123] medical use More than 90% of solid tumors contain cancer-associated fibroblasts that overexpress FAP. Therefore, the compounds of the present invention can be used for the diagnosis and treatment of a wide variety of tumors, including sarcomas, cancers of the breast, lung, ovary, head and neck, prostate, and colorectal cancers, as well as rare or difficult-to-treat cancers such as pancreatic and / or brain cancers.

[0124] The compound or its pharmaceutically acceptable salts may be for medicinal use. More specifically, for use in the medical treatment or diagnosis (including imaging) of tumors. Whether it can be used in treatment or diagnosis largely depends on the payload used as described herein.

[0125] Accordingly, further aspects of the present invention relate to methods for treating or diagnosing tumors, particularly tumors that overexpress FAP. The methods include administering a compound or a pharmaceutically acceptable salt thereof to a patient in a pharmaceutically acceptable dose.

[0126] Any portion of this specification that may be optionally replaced or interrupted may also be understood to be optional, not replaced or interrupted.

[0127] Furthermore, where a compound is described herein, unless otherwise specified, its salts, prodrugs, metabolites, etc., are also referred to.

[0128] When the stereochemistry of atoms in a structure is undefined (for example, CR 1 ), and its structure refers to each of the stereoisomers of the aforementioned atom individually.

[0129] As used herein, the singular forms “a,” “an,” and “the” are intended to also include the plural forms unless explicitly indicated otherwise in the context. The terms “and / or” include any combination of one or more of the enumerated items relating to them. The terms “comprises” and / or “comprising” should be understood to identify the presence of the described feature but not to exclude the presence or addition of one or more other features.

[0130] For the purposes of clarity and concise description, features are described herein as part of the same or distinct embodiments, but it will be understood that the scope of the invention may include embodiments having all or some combinations of the described features.

[0131] The present invention can be illustrated by the following non-limiting examples and embodiments.

[0132] General Chemicals and solvents were purchased from commercial suppliers and used without further purification. The reaction mixture was magnetically stirred and monitored by thin-layer chromatography (TLC) on a Merck aluminum-backed pre-coated plate (silica gel 60 F254). The melting point was determined using a Stuart SMP20. Liquid chromatography-mass spectrometry (LC-MS) was performed on an Agilent 1260 Infinity II electrospray ionization (ESI) LC-MS system equipped with an Agilent® InfinityLab Poroshell 120 EC-C18 column (2.7 μm, 3.0 × 100 mm). The product was eluted for 8 minutes at a flow rate of 0.5 mL / min using a gradient of acetonitrile (ACN; 5-100%) in H2O containing 0.1% formic acid (FA), and monitored at 220 nm, 254 nm, and 280 nm using a UV detector. Nuclear magnetic resonance (NMR) spectra were recorded at room temperature using a Bruker AVANCE 400 or Nanalysis 60 Pro in deuterated dimethyl sulfoxide (DMSO-d6) and chloroform-d (CDCl3). Chemical shifts are expressed as δ values ​​in ppm, and coupling constants J are expressed in Hz. Splitting patterns are reported as s (singular), d (double), t (tripular), q (quadular), qt (quintular), m (multiline), and br (broad signal). Raw NMR data were processed using a MestreNova 13. Compound purification was performed over 10 minutes at a flow rate of 10 mL / min using a preparative HPLC 1260 Infinity II system with a preparative column (50 × 21.2 mm, 5 μm) and gradient elution of ACN (10% to 95% in H2O containing 0.1% FA).

[0133] Instant thin-layer chromatography (iTLC-SG) plates on silica gel-impregnated glass fiber sheets were eluted with sodium citrate (0.1 M, pH 5). The plates were analyzed using a Brightspec bSCAN radiochromatography scanner equipped with a sodium iodide detector. LogD 7.4Radioactive samples used for determination, in vitro assays, and in vivo studies were counted using a Wizard 2480 gamma counter. Radioactivity measurements were performed using a VDC-405 dose calibrator. Quality control and stability analysis of radiolabeled compounds were performed using a Waters Acquity Arc ultrahigh-performance liquid chromatography (UHPLC) system equipped with a diode array detector, a Canberra radiation detector, and an analytical C18 Gemini® column (250.0 × 4.6 mm, 5 μm), by elution at a flow rate of 1 mL / min over 30 minutes using a gradient of ACN (5 to 95% in H2O containing 0.1% trifluoroacetic acid TFA).

[0134] Preparation of (S)-1-tert-butyl2-methyl4,4-difluoropyrrolidine-1,2-dicarboxylate

[0135] [ka]

[0136] Step 1: (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (2) 1,3,5-Trichloro-1,3,5-triazinan-2,4,6-trione (0.95 g, 4.07 mmol) was added to a chilled (0°C) solution of (S)-1-tert-butyl2-methyl4-oxopyrrolidine-1,2-dicarboxylate (0.95 g, 3.88 mmol) in DCM (10 ml), followed by the addition of catalyst TEMPO (6 mg, 0.04 mmol). After 5 minutes, the mixture was allowed to reach room temperature, stirred for a further 30 minutes, and filtered through Celite. The organic layer was washed with 10 mL of saturated potassium carbonate solution, sodium thiosulfate, and brine, dehydrated with anhydrous sodium sulfate, filtered, and evaporated. Crude compound 2 (0.65 g, 70%) was used without further purification. 1H NMR (400 M Hz, CDCl3): δ 4.77 (dd, 1H, J = 36.8, 8 Hz), 3.88 (br s, 2H), 3.75 (s, 3H), 2.90 (s, 1H), 2.57 (dd, 1H, J = 18.8, 2.4 Hz), 1.46 (s, 9H). ESI-MS: m / z 376.2 [M + MeOH + H] + .

[0137] Step 2: (S)-1-tert-butyl2-methyl4,4-difluoropyrrolidine-1,2-dicarboxylate (3) A solution of 2 (0.23 g, 0.946 mmol) in DCM (3 mL) was treated with a solution of diethylaminosulfur trifluoride (DAST, 0.197 mL, 1.607 mmol) in DCM (2 mL) at room temperature. Ethanol (0.011 mL, 0.189 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The solution was poured into saturated sodium bicarbonate, extracted with DCM (3 × 15 mL), dehydrated (Na₂SO₄), filtered, and evaporated under vacuum. The product was obtained as a yellowish oily substance (0.150 g, 61%) by chromatography on silica gel (100% DCM). 1 H NMR (400 MHz, CDCl3): δ 4.55-4.45 (m, 1H), 3.90-3.60 (m, 2H), 3.75 (s, 3H), 2.81-2.61 (m, 1H), 2.45 (dq, 1H, J = 13.6, 5.2 Hz,), 1.44 (br s, 9H). ESI-MS: m / z 266.1 [M + H] + .

[0138] Preparation of intermediate 10 Intermediate 10 was prepared according to the scheme shown in Figure 1.

[0139] Step 1: (S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid (4) 3 (2.06 g, 7.78 mmol) was dissolved in MeOH (10 mL), and a solution of NaOH (0.67 g, 17.18 mmol) in MeOH (15 mL) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes. Immediately after completion, the reaction mixture was acidified to pH 2 using 1N HCl, and the aqueous layer was extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine, dehydrated with MgSO4, and concentrated under vacuum. This yielded a grayish-white solid product (1.62 g, 6.44 mmol, 86%). 1 H NMR (60 MHz, DMSO-d6): δ 4.33 (dd, 1H, J = 9.3, 4.4 Hz), 3.68 (t, 2H, J = 13.2 Hz), 2.76-2.12 (m, 2H), 1.34 (s, 9H). Melting point: 118-119℃. ESI-MS: m / z 152.1 [M + H - Boc] + .

[0140] Step 2: tert-butyl(S)-2-carbamoyl-4,4-difluoropyrrolidine-1-carboxylate(5) Dissolve 4 (1.55 g, 6.15 mmol) in DCM (dry, 30 mL), add HONSu (0.88 g, 7.65 mmol), and stir at room temperature until completely dissolved. Add DCC (1.55 g, 7.52 mmol) and stir at room temperature for 30 minutes to allow insoluble matter to slowly form in the reaction mixture. Add NH3 (14 mL, 4 M in MeOH) dropwise, and stir the reaction mixture at room temperature for 3 hours. Immediately after completion, add RINKAN (50 mL), wash the organic layer with saturated NaHCO3 aqueous solution (5 × 25 mL) and brine (25 mL), dehydrate with MgSO4, and concentrate under vacuum. The product was obtained as a grayish-white solid (1.53 g, 6.02 mmol, 97%). 1H NMR (60 MHz, CDCl3): δ 6.50 (br, s, 1H), 5.60 (br, s, 1H), 4.48 (dd, 1H, J = 8.6, 5.8 Hz), 3.76 (td, 2H, J = 12.4, 5.2 Hz), 2.74 (td, 2H, J = 13.6, 4.6 Hz), 1.46 (s, 9H). Melting point: 127-128℃. ESI-MS: m / z 151.1 [M + H - Boc] + .

[0141] Step 3: (S)-4,4-difluoropyrrolidine-2-carboxamide (6) 5 (1.19 g, 4.69 mmol) was dissolved in DCM (10 mL) and TFA (5 mL). The reaction mixture was stirred at room temperature for 2.5 hours. Immediately after completion, all volatiles were removed. Cold ether was added, and 6 was recovered as a white solid (0.98 g, 3.66 mmol, 78%). 1 H NMR (60 MHz, DMSO-d6): δ 7.82 (s, 1H), 7.70 (s, 1H), 4.55-4.17 (t, 1H, J = 7.8 Hz), 3.54 (d, 2H, J = 12.0 Hz), 2.45 (m, 2H). Melting point: > 130℃. ESI-MS: m / z 151.0 [M + H] + .

[0142] Step 4: tert-butyl(S)-(2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamate(7) 6 (0.93 g, 3.47 mmol) was dissolved in DMF (30 mL). Boc-Gly-OH (0.81 g, 4.62 mmol), HBTU (1.64 g, 4.32 mmol), and DIPEA (3.0 mL, 2.3 g, 17.6 mmol) were added, and the reaction mixture was stirred overnight. HCl (50 mL) was added, the organic layer was washed with brine (5 × 25 mL), dehydrated with MgSO4, and concentrated under vacuum. The crude reaction mixture was redissolved in THF (30 mL) and cooled to -15°C. Pyridine (1.00 mL, 12.4 mmol) and TFAA (1.00 mL, 7.19 mmol) were added, and the reaction mixture was stirred for 5 hours to reach room temperature. HCl (50 mL) and H2O (50 mL) were added. The layers were separated, and the aqueous layer was extracted with HCl (3 × 25 mL). The combined organic layers were washed with water and brine, dehydrated with MgSO4, and concentrated under vacuum. The product was purified by flash chromatography (silica gel, hexane / EtOac 1:1). Compound 7 was obtained as a yellow solid (200 mg, 0.69 mmol, 25%). 1 H NMR (60 MHz, CDCl3): δ 5.48 (s, 1H), 4.94 (t, 1H, J = 6.3 Hz), 3.70-4.15 (m, 4H), 2.42-2.94 (m, 2H), 1.40 (s, 9H). Melting point: 128-129℃. ESI-MS: m / z 190.1 [M + H - Boc] + .

[0143] Step 5: 8-(3-((Tert-butoxycarbonyl)amino)propoxy)quinoline-4-carboxylic acid (9) 8 (0.25 g, 1.32 mmol) was dissolved in DMF (25 mL). 3-(Boc-amino)-propyl bromide (0.94 g, 4.0 mmol) and Cs2CO3 (1.31 g, 4.0 mmol) were added. The reaction mixture was stirred at room temperature for 2.5 hours. Immediately after completion, Depositphotos (50 mL) was added, the organic layer was washed with brine (5 × 25 mL), dehydrated with MgSO4, and concentrated under vacuum. The residue was redissolved in MeOH (10 mL) and NaOH (78 mg, 2.0 mmol) was added. The reaction mixture was stirred at room temperature for 35 minutes. The reaction mixture was concentrated under vacuum, and the product was purified using preparative HPLC. 9 was obtained as a pale yellow solid (0.26 g, 0.75 mmol, 57%). 1 H NMR (60 MHz, DMSO-d6): δ 8.94 (d, 1H, J = 4.2 Hz), 8.16 (d, 1H, J = 8.3 Hz), 7.88 (d, 1H, J = 4.3 Hz), 7.55 (t, 1H, J = 8.1 Hz), 7.18 (d, Melting point: > 130℃. ESI-MS: m / z 346.7 [M + H] + .

[0144] Step 6: tert-butyl(S)-(3-((4-((2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)oxy)propyl)carbamate(10) 7 (0.18 g, 0.61 mmol) was dissolved in DCM (3 mL) and TFA (3 mL). The reaction mixture was stirred at room temperature for 45 minutes. Immediately after completion, all volatiles were removed under a gentle stream of air. 9 (0.2 g, 0.58 mmol), HBTU (0.34 g, 0.87 mmol), and DIPEA (0.35 mL) were added to the residue redissolved in DMF (5 mL). The reaction mixture was stirred overnight at room temperature. Depositphotos (50 mL) was added, the organic layer was washed with brine (5 × 25 mL), dehydrated with MgSO4, and concentrated under vacuum. The product was purified using flash chromatography (silica gel, hexane / EtOac 1:1) to obtain 10 as a pale yellow viscous oil (0.23 g, 0.44 mmol, 72%). 1 H NMR (60 MHz, CDCl3): δ 8.69 (d, 1H, J = 4.2 Hz), 7.64 (m, 2H), 7.45-7.02 (m, 2H), 6.86 (d, 1H, J = 7.3 Hz), 6.30 (s, 1H), 4.82 (s, 1H), 4.02 (m, 4H), 3.22 (m, 2H), 2.55 (m, 4H), 2.04 (m, 2H), 1.35 (s, 9H). ESI-MS: m / z 618.0 [M + H] + .

[0145] Preparation of (S)-8-(3-(4-(aminomethyl)cyclohexane-1-carboxamide)propoxy)-N-(2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)quinoline-4-carboxamide (8-QCP-Amcha) As illustrated in Figure 2, 10 (65 mg, 125 μmol) was treated with a DCM / TFA (5 mL, 1:1) solution at room temperature for 30 minutes. All volatiles were removed under a gentle stream of air to obtain a brown crude solid. The crude product was redissolved in DMF (1.5 mL), followed by the addition of N-Fmoc-tranexamic acid (1.1 equivalents, 46.8 mg), HBTU (2 equivalents, 95 mg), DIPEA (100 μL), and DMF (1.5 mL). The reaction mixture was stirred at room temperature for 1 hour, diluted with toluene (15 mL), washed with water (3 × 5 mL), dehydrated with Mg₂SO₄, and concentrated under vacuum to obtain a pale yellow solid. The crude product was treated with a piperidine / DMF (2 mL, 1:5) solution at room temperature for 30 minutes, the solvent was removed under vacuum, and the crude product was purified by preparative HPLC to obtain 8QCP-AMCHA (30 mg, 53.9 μmol, 43%) as an off-yellow powder. ESI-MS: m / z 557.2 [M+H] + . [Examples]

[0146] 2,2',2''-(10-(4-((2-(((((5aR,6S,6aS)-1-(2-(3,5-bis(2-((3-((3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)oxy)propyl)amino)-3-oxopropyl)thio)acetyl)-1,3,5-triazinan- Preparation of 1-yl)-2-oxoethyl)-1,4,5,5a,6,6a,7,8-octahydrocyclopropa[5,6]cycloocta[1,2-d][1,2,3]triazole-6-yl)methoxy)carbonyl)amino)ethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (eFAP-34) As illustrated in Figure 4, 8QCP-SH (5.5 mg, 10.8 μmol) was dissolved in DMF (1 mL), followed by the addition of TADB-N3 (1.3 mg, 3.1 μmol, Van de Langemheen et al., prepared as described in ChemBioChem. 2017;18(4):387~395) and DIPEA (10 μL). After 30 minutes, the solvent was removed under vacuum, and the crude product was purified by preparative HPLC to obtain (8QCP-SH)2-TADB (2.9 mg, 2.2 μmol, 41%) as a grayish-white powder. ESI-MS: m / z 1346.3 [M+H] + The powder was redissolved in ACN / H2O (1 mL, 1:1), and then BCN-DOTAGA (1.1 equivalents, 1.7 mg) was added. The reaction mixture was stirred at 37°C for 30 minutes, and the solvent was purified by preparative HPLC to obtain eFAP-34 (1.4 mg, 0.7 μmol, 31%) as a grayish-white powder. ESI-MS: m / z 1956.5 [M+H] + . [Examples]

[0147] 2,2',2''-(10-(4-((2-(((((5aS,6R,6aR)-1-(2-(3,5-bis(2-((6-((3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)oxy)propyl)amino)-6-oxohexyl)thio)acetyl)-1,3,5-triazinan- Preparation of 1-yl)-2-oxoethyl)-1,4,5,5a,6,6a,7,8-octahydrocyclopropa[5,6]cycloocta[1,2-d][1,2,3]triazole-6-yl)methoxy)carbonyl)amino)ethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (eFAP-35) 8QCP-SH (4.1 mg, 7.5 μmol) was dissolved in DMF (1 mL), followed by the addition of TADB-N3 (1 mg, 2.4 μmol) and DIPEA (10 μL). After 30 minutes, the solvent was removed under vacuum, and the crude product was purified by preparative HPLC to obtain (8QCP-SH)2-TADB (2.2 mg, 1.6 μmol, 44%) as a grayish-white powder. ESI-MS: m / z 1346.3 [M+H] + The powder was redissolved in ACN / H2O (1 mL, 1:1), and then BCN-DOTAGA (1.1 equivalents, 1.3 mg) was added. The reaction mixture was stirred at 37°C for 30 minutes, and the solvent was purified by preparative HPLC to obtain eFAP-35 (1.8 mg, 0.9 μmol, 54%) as a grayish-white powder. ESI-MS: m / z 2040.8 [M+H] + . [Examples]

[0148] Preparation of 3,3'-(((((((5-(2-azidoacetyl)-1,3,5-triazino-1,3-diyl)bis(2-oxoethane-2,1-diyl))bis(azandiyl))bis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(oxy))dipropionic acid (PEG2-TADB-PEG2, platform 1) As illustrated in Figure 5, TADB-N3 (8 mg, 19 μmol) was dissolved in DMF (1 mL), followed by the addition of NH2-PEG2-tBu (3 equivalents, 13 mg) and DIPEA (30 μL). The reaction mixture was stirred at room temperature for 2 hours, diluted with RINKAN (15 mL), washed with water (3 × 5 mL), dehydrated with Mg2SO4, and concentrated under vacuum to obtain a pale white solid. The crude product was treated with a solution of DCM / TFA (3 mL, 1:1) at room temperature for 30 minutes. All volatiles were removed under a gentle stream to obtain a pale white crude solid. The crude product was purified by preparative HPLC to obtain platform 1 (6.3 mg, 10.4 μmol, 55%) as a pale white oil. ESI-MS: m / z 605.2 [M+H] + . [Examples]

[0149] 2,2',2''-(10-(4-((2-(((((5aR,6S,6aS)-1-(2-(3,5-bis(16-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)oxy)-12-oxo-6,9-dioxa-3,13-diazahexadecanoyl)-1,3,5-triazinan-1 Preparation of (-yl)-2-oxoethyl)-1,4,5,5a,6,6a,7,8-octahydrocyclopropa[5,6]cycloocta[1,2-d][1,2,3]triazole-6-yl)methoxy)carbonyl)amino)ethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (eFAP-36) 10 (15 mg, 29 μmol) was treated with a solution of DCM / TFA (3 mL, 1:1) at room temperature for 30 minutes, and all volatiles were removed under a gentle stream to obtain a brown crude solid (8QCP-NH2). The crude product was redissolved in DMF (1 mL), and subsequently PEG2-TADB-PEG2 (1.5 equivalents, 26 mg), HBTU (2 equivalents, 23.6 mg), DIPEA (30 μL), and DMF (1.5 mL) were added. The reaction mixture was stirred at room temperature for 1 hour, diluted with SiO (15 mL), washed with water (3 × 5 mL), dehydrated with MgSO4, and concentrated under vacuum to obtain a grayish-white solid. The crude product was redissolved in ACN / H2O (1 mL, 1:1), and subsequently BCN-DOTAGA (1.1 equivalents, 2.6 mg) was added. The reaction mixture was stirred at 37°C for 30 minutes, and the solvent was purified by preparative HPLC to obtain eFAP-36 (2.7 mg, 1.2 μmol, 34%) as a grayish-white powder. ESI-MS: m / z 2099.2 [M+H] + . [Examples]

[0150] Preparation of 3,3'-((((((6-((3-azidopropyl)amino)-1,3,5-triazine-2,4-diyl)bis(azandiyl))bis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(oxy))dipropionic acid (Platform 2, PEG2-triazine-PEG2). As illustrated in Figure 6, 2,4,6-trichloro-1,3,5-triazine (25 mg, 13.5 μmol) was dissolved in DMF (1 mL), followed by the addition of NH2-PEG2-tBu (2.3 equivalents, 72.7 mg) and DIPEA (117 μL). The reaction mixture was stirred at room temperature for 2 hours, diluted with SiO2 (15 mL), washed with water (3 × 5 mL), dehydrated with Mg2SO4, and concentrated under vacuum to obtain a pale white solid. The crude product was redissolved in DMF (1 mL), followed by the addition of 3-azidopropan-1-amine (2.2 equivalents, 29.7 mg). The reaction mixture was stirred at room temperature for 24 hours, diluted with SiO2 (15 mL), washed with water (3 × 5 mL), dehydrated with Mg2SO4, and concentrated under vacuum to obtain a pale white solid. The crude product was treated with a solution of DCM / TFA (3 mL, 1:1) at room temperature for 30 minutes. All volatiles were removed under a gentle stream of air to obtain a pale white crude solid. The crude product was purified by preparative HPLC to obtain platform 2 (3 mg, 8.6 μmol, 64%) as a pale white oil. ESI-MS: m / z 530.2 [M+H] + . [Examples]

[0151] 2,2',2''-(10-(4-((2-(((((5aR,6S,6aS)-1-(3-((4,6-bis((2-(2-(3-((3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)oxy)propyl)amino)-3-oxopropoxy)ethoxy)ethyl)amino)-1,3,5-to Preparation of liazin-2-yl)amino)propyl)-1,4,5,5a,6,6a,7,8-octahydrocyclopropa[5,6]cycloocta[1,2-d][1,2,3]triazole-6-yl)methoxy)carbonyl)amino)ethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (eFAP-37) 10 (15 mg, 29 μmol) was treated with a solution of DCM / TFA (3 mL, 1:1) at room temperature for 30 minutes, and all volatiles were removed under a gentle stream to obtain a brown crude solid. The crude product was redissolved in DMF (1 mL), and subsequently PEG2-triazine-PEG2 (1.5 equivalents, 23 mg), HBTU (2 equivalents, 23.6 mg), DIPEA (30 μL), and DMF (1.5 mL) were added. The reaction mixture was stirred at room temperature for 1 hour, diluted with SiO (15 mL), washed with water (3 × 5 mL), dehydrated with Na2SO4, and concentrated under vacuum to obtain a pale white solid. The crude product was redissolved in ACN / H2O (1 mL, 1:1), and subsequently BCN-DOTAGA (1.1 equivalents, 2.6 mg) was added. The reaction mixture was stirred at 37°C for 30 minutes, and the solvent was purified by preparative HPLC to obtain eFAP-37 (3 mg, 1.5 μmol, 39%) as a grayish-white powder. ESI-MS: m / z 2024.1[M+H] + . [Examples]

[0152] Preparation of 2,2',2''-(10-(4-((3-(1-(2-(3,5-bis(2-((3-((3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)oxy)propyl)amino)-3-oxopropyl)thio)acetyl)-1,3,5-triazinan-1-yl)-2-oxoethyl)-1,9-dihydro-8H-dibenzo[b,f][1,2,3]triazolo[4,5-d]azosin-8-yl)-3-oxopropyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (eFAP-38) (8QCP-SH)2-TADB (0.8 equivalents, 1 mg) was dissolved in ACN / H2O (1 mL, 1:1), followed by the addition of DBCO-DOTAGA (1.1 equivalents, 0.6 mg). The reaction mixture was stirred at 37°C for 30 minutes, and the solvent was purified by preparative HPLC to obtain eFAP-38 (0.5 mg, 0.25 μmol, 31%) as a grayish-white powder. ESI-MS: m / z 1996.7[M+H] + . [Examples]

[0153] Preparation of 2,2',2''-(10-(4-((6-((4,6-bis((2-(2-((3-((3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)oxy)propyl)amino)-3-oxopropoxy)ethoxy)ethyl)amino)-1,3,5-triazine-2-yl)amino)hexyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (eFAP-50) As illustrated in Figure 7, 2,4,6-trichloro-1,3,5-triazine (60 mg, 32.5 μmol) was dissolved in DMF (1.5 mL), followed by the addition of NH2-PEG2-tBu (2.2 equivalents, 167.0 mg) and DIPEA (210 μL). The reaction mixture was stirred at room temperature for 2 hours, diluted with SiO2 (15 mL), washed with water (3 × 5 mL), dehydrated with Mg2SO4, and concentrated under vacuum to obtain a pale white solid. The crude product was treated with a solution of DCM / TFA (4 mL, 1:1) at room temperature for 30 minutes. All volatiles were removed under a gentle stream of air to obtain a pale white oil. The oil was redissolved in DMF (1 mL), followed by the addition of N-Boc-1,6-diaminohexane (1.5 equivalents, 9.6 mg) and DIPEA. The reaction mixture was stirred at room temperature for 24 hours, diluted with siRNA (15 mL), washed with water (3 × 5 mL), dehydrated with Mg₂SO₄, and concentrated under vacuum to obtain a pale white solid. The crude product was redissolved in DMF (1 mL), followed by the addition of 8QCP-NH₂ (2.5 equivalents, 25 mg, illustrated in Figure 4 and obtained from intermediate 10 as described for eFAP-36), HBTU (2 equivalents, 14 mg), and DIPEA (30 μL). The reaction mixture was stirred at room temperature for 2 hours, diluted with siRNA (15 mL), washed with water (3 × 5 mL), dehydrated with Mg₂SO₄, and concentrated under vacuum to obtain a pale yellow solid. The crude product was treated with a solution of DCM / TFA (2 mL, 1:1) at room temperature for 30 minutes. All volatiles were removed under a gentle stream to obtain a pale yellow solid. The solid was redissolved in DMF (1 mL), followed by the addition of DOTAGA anhydrous (2,2',2''-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid, 1.2 equivalents, 4.6 mg) and DIPEA (40 μL). After 1 hour, the solvent was removed under vacuum, and the crude product was purified by preparative HPLC to obtain eFAP-50 (5 mg, 2.8 μmol, 33%) as a grayish-white powder. ESI-MS: m / z 1803.5 [M+H] + . [Examples]

[0154] Preparation of 2,2',2''-(10-(4-((6-((4,6-bis((2-(2-((3-(((4-((3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)oxy)propyl)carbamoyl)cyclohexyl)methyl)amino)-3-oxopropoxy)ethoxy)ethyl)amino)-1,3,5-triazine-2-yl)amino)hexyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (eFAP-51) As illustrated in Figure 8, 2,4,6-trichloro-1,3,5-triazine (60 mg, 32.5 μmol) was dissolved in DMF (1.5 mL), followed by the addition of NH2-PEG2-tBu (2.2 equivalents, 167.0 mg) and DIPEA (210 μL). The reaction mixture was stirred at room temperature for 2 hours, diluted with SiO2 (15 mL), washed with water (3 × 5 mL), dehydrated with Mg2SO4, and concentrated under vacuum to obtain a pale white solid. The crude product was treated with a solution of DCM / TFA (4 mL, 1:1) at room temperature for 30 minutes. All volatiles were removed under a gentle stream of air to obtain a pale white oil. The oil was redissolved in DMF (1 mL), followed by the addition of N-Boc-1,6-diaminohexane (1.5 equivalents, 9.6 mg) and DIPEA. The reaction mixture was stirred at room temperature for 24 hours, diluted with SiO2 (15 mL), washed with water (3 × 5 mL), dehydrated with Mg2SO4, and concentrated under vacuum to obtain a pale white solid. The crude product was redissolved in DMF (1 mL), followed by the addition of 8QCP-AMCHA (2.5 equivalents, 25 mg), HBTU (2 equivalents, 14 mg), and DIPEA (30 μL). The reaction mixture was stirred at room temperature for 2 hours, diluted with SiO2 (15 mL), washed with water (3 × 5 mL), dehydrated with Mg2SO4, and concentrated under vacuum to obtain a pale yellow solid. The crude product was treated with a solution of DCM / TFA (2 mL, 1:1) at room temperature for 30 minutes. All volatiles were removed under a gentle stream of air to obtain a pale yellow solid. The solid was redissolved in DMF (1 mL), followed by the addition of DOTAGA anhydrous (2.5 equivalents, 25 mg) and DIPEA (40 μL). After 1 hour, the solvent was removed under vacuum, and the crude product was purified by preparative HPLC to obtain eFAP-51 (2 mg, 1.0 μmol, 33%) as a grayish-white powder. ESI-MS: m / z 1041.1 [M+2H] 2+ . [Examples]

[0155] Preparation of 2,2',2''-(10-(4-((6-((4,6-bis((2-(2-(3-(4-((2-((3-((4-(((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)oxy)propyl)amino)-2-oxoethyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-1,3,5-triazine-2-yl)amino)hexyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (eFAP-52) As illustrated in Figure 9, eFAP-52 can be obtained by a procedure similar to that described for eFAP-51 in Example 9.

[0156] Radioactive labeling, analysis, and results [ 111 Radioactive labeling with [In]InCl3 The precursor (1 nmol) is used, 111 In]InCl3 (20 MBq), ascorbic acid / gentisic acid (10 μL, 50 mM), sodium acetate (2.5 M, 1 μL, pH 8), and water containing kolliphor (2.0 mg / mL, 58.6 μL) were added. The labeling mixture (pH 4.5) was incubated at 90°C for 15 minutes. It was then cooled for 5 minutes, and the radiochemical yield (RCY) was determined by iTLC on a silica gel-impregnated glass fiber sheet. Diethylenetriaminepentaacetic acid (4 mM, 5 μL) was added to indium-111 without the complex. 111 The radiochemical purity (RCP) of the In-labeled peptide was measured by radio-HPLC. The results are shown in Table 1.

[0157] in vitro stability Radiolabeled compounds (approximately 2 MBq) were mixed with 300 μL of PBS (0.1 M, pH 7.4) or mouse serum at 37°C for 1, 4, and 24 hours. At each time point, proteins in the serum samples were precipitated by adding acetonitrile (300 μL), and the solutions were centrifuged at 13,000 rpm for 5 minutes (twice). The supernatant was loaded into a radio-HPLC system for analysis. Samples in PBS were analyzed directly by radio-HPLC without any pretreatment. All experiments were performed in triplicate. The results are shown in Table 1 and Figures 10A to 10L.

[0158] LogD 7.4 The partition coefficients of the compounds were determined by the shaking flask method. The experiment was performed in three series for each compound. A radiolabeled compound (approximately 0.3 MBq) was added to a mixture of phosphate-buffered saline (PBS) / n-octanol (1 mL, v / v=1:1) in an Eppendorf vial. The Eppendorf vial was vigorously vortexed and centrifuged at 10,000 rpm for 3 minutes. n-octanol was separated from the PBS and poured into a new vial. Samples (10 μL) from each phase were poured into glass tubes and measured with a gamma counter. LogD 7.4 The value is given by the following expression: logD 7.4 The calculation was performed using =log10([count in organic phase] / [count in aqueous phase]). The results are shown in Table 1.

[0159] [Table 1]

[0160] In vitro inhibition assays for human and mouse FAP The enzymatic activity of human FAP (hFAP) and mouse FAP (mFAP) against the Z-GP-AMC substrate was measured at room temperature using a Hidex microplate reader by monitoring fluorescence at an excitation wavelength of 360 nm and an emission wavelength of 465 nm. The reaction mixture consisted of 20 μM substrate, 20 nM FAP, assay buffer (50 mM Tris, 100 mM NaCl, 1 mM EDTA, pH 7.4), and the test compound (10 -6 from 10 -12 It contained (sequential dilutions up to a certain point) in a total volume of 50 μL. 50 The value is defined as the concentration of the inhibitor required to reduce enzyme activity by 50% after substrate addition.

[0161] All eFAP compounds tested showed an IC50 ratio of less than 2 nM relative to human FAP. 50 The values ​​are shown. For comparison, the results for FAPI-46 obtained in the same assay are included.

[0162] [Table 2]

[0163] In vitro inhibition assay for DPP4 The DPP4 enzyme assay uses the substrate H-Gly-Pro-AMC (100 μM), DPP4 (0.5 nM), assay buffer (50 mM Tris, 100 mM NaCl, pH=8 (1 v / v DMSO)), and 10 -4 M to 10 -10 The target inhibitor was serially diluted up to M, and the total volume was 50 μL. Sitagliptin (10 -4M) and assay buffer 1 v / v% DMSO were used as positive and negative controls, respectively. H-Gly-Pro-AMC (100 μM) in assay buffer 1 v / v% DMSO was used as a baseline control. Plates were incubated in the dark at 37°C for 30 minutes, followed by measurement by monitoring fluorescence at an excitation wavelength of 360 nm and an emission wavelength of 465 nm using a Hidex microplate reader. All experiments were performed in triplicate and repeated three times. Data obtained from the enzyme assays were logarithmically transformed and normalized for positive (0%) and negative (100%) controls, and fitted using Y = 100 / (1 + 10^((LogIC50-X) * slope (HillSlope))), where the value represents the concentration of the inhibitor required to reduce enzyme activity by 50% after substrate addition.

[0164] The results are shown in Table 3.

[0165] [Table 3]

[0166] Cell uptake / blocking experiment using U87 cells. Cells were seeded in a 6-well plate 24 hours before the experiment (7 × 10⁶). 5 (10 cells / well). The next day, the adhered cells were placed in 1 mL of culture medium for 10 minutes. -9 M's 111 Cells were incubated with an In]In-labeled compound at 37°C for 90 minutes. The compound was also evaluated using a 50-fold excess block of the unlabeled compound. The membrane-bound fraction (MF) was collected by incubating the cells with acid buffer (50 mM glycine, 100 mM NaCl, pH 2.8) at room temperature for 10 minutes. The internalized fraction (IF) was determined by lysing the cells with 1 M NaOH at room temperature for 5 minutes. Both fractions were measured using a gamma counter, and the data were analyzed using GraphPad Prism v9 and expressed as a percentage of the added dose. The results are presented in Figure 11 and Table 4.

[0167] [Table 4]

[0168] in vivo studies Five-week-old male NMRI-Foxn1 nu / nu mice (Janvier; Le Genest-Saint-Isle, France) were housed in individually ventilated cages, with a maximum of three mice per cage. After one week of acclimatization, the mice were subcutaneously inoculated with HT1080-huFAP in the right shoulder and HT1080-WT in the left shoulder. 200 μL of [ 111 In]In-eFAP-51 (n=4 per group) or [ 111 In]In-FAPI-46 (n=4 per group) (20 MBq / 1 nmol) was administered intravenously via tail vein, and SPECT / CT imaging was performed at 1, 4, 24, and 48 hours. A biodistribution study was conducted at 48 hours. Blood was collected by orbital puncture under isoflurane / O2 anesthesia, followed immediately by cervical dislocation. Subsequently, two tumor xenografts, pancreas, liver, gastrointestinal tract (stomach, small intestine, cecum, colon), kidneys (left and right), lungs, heart, muscle, and bone (femur) were collected, weighed, and measured using a gamma counter (PerkinElmer) along with 10 μL of injected radioactivity as a standard.

[0169] Figure 12 shows SPECT / CT images. Figure 13 shows the results of the in vivo distribution study after 48 hours. The results are expressed as a percentage of the injected dose per gram (%ID / g).

Claims

1. Equation (I) or Equation (II) 【Chemistry 1】 [In the formula, L 1 , L 2 and L 3 Each of these individually represents a linker. Q represents the payload, preferably a therapeutic agent, a diagnostic agent, or a combination thereof. Each Z is independent of equation (Z) 【Chemistry 2】 (In the formula, X is NH, CH 2 Or it represents O, R 1 is H, Me, CH(CH 3 )C 2 H 5 , CH 2 CH(CH 3 ) 2 , CH(CH 3 ) 2 , CH 2 OH, CH 2 SH, CH(OH)CH 3 , CH 2 C(O)NH 2 , CH 2 CH 2 C(O)NH 2 , (CH 2 ) m CO 2 H, (CH 2 ) m NH 2 wherein m is 1 to 4, R 2 and R 3 (Each of these independently represents either H or F) [Represents the FAP connection section including the scaffolding.] Compounds or pharmaceutically acceptable salts thereof.

2. Each Z independently gives equation (Za) 【Transformation 3】 (In the formula, X is CH 2 Or O, preferably O, R 1 , R 2 and R 3 (This is as defined in claim 1.) A compound according to claim 1 or a pharmaceutically acceptable salt thereof, representing the FAP binding portion by .

3. Each Z is independent of equation (Zb) 【Chemistry 4】 (In the formula, R 4 represents a spacer, preferably an aliphatic spacer, and X, R 1 , R 2 and R 3 (This is as set forth in claim 1 or 2.) A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, representing the FAP binding portion by .

4. Each Z is independent of equation (Zc) 【Transformation 5】 (In the formula, R 4' This is an optionally substituted hydrocarbylene or an optionally substituted alkylene ether, preferably alkylene, more preferably C 1 ~C 8 X represents alkylene, R 1 , R 2 and R 3 (This is as set forth in any one of claims 1 to 3.) A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, representing the FAP binding portion by .

5. Each Z independently gives equation (Zd) 【Transformation 6】 (In the formula, n is 1 to 6, preferably 1, X, R) 1 , R 2 and R 3 (This is as provided for in any one of claims 1 to 4.) A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, representing the FAP binding portion by .

6. L 1 , L 2 and / or L 3 However, independently, linear or branched amino acids, preferably glycine, alanine, β-alanine, 3-aminopropionic acid, 4-aminobutyric acid, 4-amino-3-hydroxybutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 7-aminoheptanoic acid, 8-aminooctanoic acid, 9-aminononanoic acid, 10-aminodecanoic acid, 2-aminooctanoic acid, etc., peptide spacer (Xaa) 1～4 Based at least partially on this, where each Xaa is independently a D-amino acid of a proteinogenic amino acid, N ε ,N ε ,N ε -Trimethyllysine, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), ornithine (Orn), homoarginine (hArg), 2-amino-4-guanidinobutyric acid (Agb), 2-amino-3-guanidinopropionic acid (Agp), β-alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 7-aminoheptanoic acid, 8-aminooctanoic acid, 9-aminononanoic acid, 10- Aminodecanoic acid, 2-aminooctanoic acid, 2-aminoadipic acid (2-Aad), 3-aminoadipic acid (3-Aad), 4-(aminomethyl)cyclohexane-1-carbonyl (Amcha), 4-amino-1-carboxymethyl-piperidinyl (Pip), 2-(piperazine-1-yl)acetic acid (Pipa), 2-(4-(2-aminoethyl)piperazine-1-yl)acetic acid, cysteic acid, diglycolic acid, and NH 2 (CH 2 ) 2 [O(CH 2 ) 2 ] q A proteinogenic or non-proteinogenic amino acid residue selected from the group consisting of C(O)OH (wherein q=1 to 36), preferably L 1 and L 2 Both are NH 2 (CH 2 ) 2 [O(CH 2 ) 2 ] q C(O)OH (where q = 1 to 36), more preferably NH 2 (CH 2 ) 2 [O(CH 2 ) 2 ] q A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, representing C(O)OH (wherein q = 2 to 6).

7. L 1 , L 2 and / or L 3 Preferably at least L 1 and L 2 However, independently, any of the formulas La to Lp, preferably Lo and / or Lp; 【Transformation 7】 (In the formula, further, Y 1 It is selected from the group consisting of C and N, preferably N for formulas La, Lg and Lh, and C for formula Ld. Y 2 is selected from the group consisting of C, N, and O, preferably N and C, and more preferably C. (q is in the range of 1 to 36, preferably 2 to 6) Includes a portion having the structure shown, More preferably, Linker L 1 , L 2 and / or L 3 However, the formulas Laa, Lfa, Lfb, Lfc, Lga, Lha, Lhb, Lhc, and Lma 【Transformation 8】 (In the formula, q is in the range of 1 to 36, preferably 1 to 6.) A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, comprising a portion having a structure due to any of the above.

8. L 3 is, formula (L 3 a), (L 3 b), (L 3 c), (L 3 d), (L 3 e), (L 3 f), (L 3 g), (L 3 h), (L 3 i), (L 3 j), (L 3 k), (L 3 l), (L 3 m) and (L 3 n) 【Chemistry 9】 (In the formula, (Q) indicates the relative position of payload Q, r is in the range of 1 to 6, preferably 1 to 3, more preferably 3. p is in the range of 1 to 6, preferably 1 to 3, more preferably 2. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, having a structure according to any one of the above.

9. Formulas (Ia), (Ib), (Ic), (Id), (IIa), (IIb), (IIc), or (IId), preferably formulas (Iaa), (IIaa), (Iba), (IIba), (Ibb), (IIbb), (Ibc), (IIbc), (Ica), (IIca), (Ida), or (IIda) 【Chemical Engineering 10A】 【Chemistry 10B】 [Chemical 10C] 【10D】 [Transform 10E] (In the formula, q is 0 or greater, preferably in the range of 1 to 6, more preferably 2.) r is in the range of 1 to 6, preferably 1 to 3, more preferably 1 or 3. p is in the range of 0 to 6, preferably 1 to 3, more preferably 2. Z, Q, L 1 and L 2 (This is as set forth in any one of claims 1 to 8.) A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, having the structure of the compound.

10. L 3 However, it includes a cleavable linker section containing a portion that can be cleaved in vivo, or forms a portion that can be cleaved in vivo together with the payload, preferably in The compound according to any one of claims 1 to 9, wherein the vivo cleavable portion comprises one or more amides, esters, carbamates, hydrazones, thiazolidinedions, methylene alkoxycarbamates, and disulfides, and more preferably the cleavable linker section comprises one or more linear or branched mercaptocarboxylic acids, such as thioglycolic acid, thiolactic acid (also known as 2-mercaptopropionic acid), 3-mercaptopropionic acid (3-MPA), 4-mercaptobutanoic acid (SPDB), 4-mercaptopentanoic acid (SPP), 4-mercapto-2-sulfobutanoic acid (sulfo-SPDB), p-aminobenzylcarbamate (PAB), valine-citrulline (Val-Cit-PAB), glycine-proline (Gly-Pro-PAB), Ala-Ala-Asn-PAB, DGA-Lys-PAB, β-glucuronide, and Grob fragmentationable portions.

11. The compound according to any one of claims 1 to 10, wherein Q comprises one or more radioisotopes, fluorescent dyes, drugs, or combinations thereof, preferably one or more radioisotopes, fluorescent dyes, and drugs such as cytotoxic or cell proliferation inhibitors that form a complex with a chelating agent.

12. The compound according to any one of claims 1 to 11, wherein Q comprises a radioactive isotope that forms a complex with a chelating agent, preferably the radioactive isotope is an α or β particle emitter, an Auger emitter, a positron emitter and / or a γ emitter, and the chelating agent preferably comprises a cyclic or branched polyaminopolycarboxylic acid moiety or an amide derivative thereof.

13. The compound according to any one of claims 1 to 12, wherein Q comprises a dye selected from the group consisting of dyes, preferably fluorescent dyes, more preferably cyanine, phthalocyanine, rhodamine, fluorescein, xanthene, coumarin, styryl, porfin, fluorescent organometallic complexes, oxanine, perylene, acridine, boron-dipyrromethene, and combinations thereof; even more preferably from cyanine and / or phthalocyanine; even more preferably from the group consisting of CY5 dyes, most preferably from the group consisting of sulfo-CY5, FNIR-Tag, CyTE-777, CyTE-807, IRDye 800CW, ZW800-1, and combinations thereof.

14. Q is a drug, preferably an Hsp90 inhibitor, such as a geldanamycin analog, a radicicol analog, zeravespive (PU-H71), onarespive (AT13387), SNX-0723, HSP990, YC-72-AB85, luminesspive (AUY922), VER-49009, NMS-E973, meltansine (DM1), N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-meitansine (DM4), doxorubicin, idarubicin, PNU, monomethyl auristatin E (MMAE), monomethyl auris The compound according to any one of claims 1 to 13, comprising tatin F (MMAF), exatecan, exatecan derivative for ADC (DXD), SN-38 (active metabolite of irinotecan), pyrrolo[2,1-c][1,4]benzodiazepine (PBD), SG3199 (PDB dimer), duocalmycin, bortezomib, doxorubicin, AVA2727D, tubricin A, and calicheamicin, most preferably the drug comprising meltansine (DM1), DM4, MMAE, exatecan, SN38, bortezomib, and doxorubicin.

15. Q is any of formulas Qa to Qh, preferably Qa, Qg, or Qh, more preferably Qa or Qg 【Chemical Engineering 11A】 【Chemical 11B】 【Chemical 11C】 (In the formula, 【Chemistry 12】 teeth, 【Chemistry 13】 And, Here, Z 1 teeth, 【Chemistry 14】 (is) 【Chemical Engineering 15A】 【Chemical 15B】 [Chemical 15C] (In the formula, m is 0 to 6, preferably 1, A 1 ~A 4 These are H, alkyl, aliphatic acids, for example, CH 2 CO 2 H and CO 2 Carboxylic acids such as H, and their amides and esters, preferably CH 2 CO 2 H and / or CO 2 Independently selected from the group consisting of H, A 5 is 1,4-butanesulton-1-yl(1,2λ 6 -Oxatian-2,2-dione-3-yl or 2,2-dioxide-1,2-oxatian-3-yl), CH(SO 3 H)(CH 2 ) 3 F and / or N(CH) 3 ) 2 )CH 2 BF 3 This represents fluoride-containing groups or their precursors, (M) represents a radioactive isotope. (L 3 ) is Linker L 3 (Indicates the relative position) A compound according to any one of claims 1 to 14, having the structure of the above.

16. X represents O, R 1 However, H represents, and / or R 2 and R 3 At least one of them represents F, preferably R 2 and R 3 A compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein both of the terms represent F.

17. - 2,2',2''-(10-(4-((2-(((((5aR,6S,6aS)-1-(2-(3,5-bis(2-((3-((3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)oxy)propyl)amino)-3-oxopropyl)thio)acetyl)-1,3,5-triazinan (-1-yl)-2-oxoethyl)-1,4,5,5a,6,6a,7,8-octahydrocyclopropa[5,6]cycloocta[1,2-d][1,2,3]triazole-6-yl)methoxy)carbonyl)amino)ethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate(eFAP-34); - 2,2',2''-(10-(4-((2-(((((5aS,6R,6aR)-1-(2-(3,5-bis(2-((6-((3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)oxy)propyl)amino)-6-oxohexyl)thio)acetyl)-1,3,5-triazinan -1-yl)-2-oxoethyl)-1,4,5,5a,6,6a,7,8-octahydrocyclopropa[5,6]cycloocta[1,2-d][1,2,3]triazole-6-yl)methoxy)carbonyl)amino)ethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate(eFAP-35); - 2,2',2''-(10-(4-((2-(((((5aR,6S,6aS)-1-(2-(3,5-bis(16-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)oxy)-12-oxo-6,9-dioxa-3,13-diazahexadecanoyl)-1,3,5-triazinan- 1-yl)-2-oxoethyl)-1,4,5,5a,6,6a,7,8-octahydrocyclopropa[5,6]cycloocta[1,2-d][1,2,3]triazole-6-yl)methoxy)carbonyl)amino)ethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate(eFAP-36); - 2,2',2''-(10-(4-((2-(((((5aR,6S,6aS)-1-(3-((4,6-bis((2-(2-(3-((3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)oxy)propyl)amino)-3-oxopropoxy)ethoxy)ethyl)amino)-1,3,5- Triazin-2-yl)amino)propyl)-1,4,5,5a,6,6a,7,8-octahydrocyclopropa[5,6]cycloocta[1,2-d][1,2,3]triazole-6-yl)methoxy)carbonyl)amino)ethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate(eFAP-37); - 2,2',2''-(10-(4-((3-(1-(2-(3,5-bis(2-((3-((3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)oxy)propyl)amino)-3-oxopropyl)thio)acetyl)-1,3,5-triazinane-1-yl)-2-oxoethyl)-1,9-dihydro-8H-dibenzo[b,f][1,2,3]triazolo[4,5-d]azosin-8-yl)-3-oxopropyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (eFAP-38); - 2-((E)-2-((E)-3-(2-((E)-1-(6-((6-((4,6-bis((2-(2-((3-((3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)oxy)propyl)amino)-3-oxopropoxy)ethoxy)ethyl)amino)-1,3,5- Triazine-2-yl)amino)hexyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfonatoindoline-2-ylidene)ethylidene)-2-(4-sulfonatophenoxy)cyclohexa-1-en-1-yl)vinyl)-3,3-dimethyl-1-(4-sulfonatobutyl)-3H-indole-1-ium-5-sulfonate (eFAP-44); - (1 4 S,1 6 S,3 2 S,3 3 S, 2R, 4S, 10E, 12E, 14R)-8 6 -Chloro-1 4 -Hydroxy-8 5 ,14-dimethoxy-3 3 ,2,7,10-tetramethyl-1 2 ,6-Dioxo-7-Aza-1(6,4)-Oxadinana-3(2,3)-Oxirana-8(1,3)-Benzenacyclotetradecafan-10,12-Dien-4-yl N-(3-((3-((6-((4,6-Bis((2-(2-(3-((3-((4-((2-((S)-2-Cyanol-4,4-Difluoropyrrolidine-1-yl)-2-Oxoethyl)Carbamoyl)Quinoline-8-yl)Oxy)Propyl)Amino)-3-Oxopropoxy)Ethoxy)Ethyl)Amino)-1,3,5-Triadin-2-yl)Amino)Hexyl)Amino)-3-Oxopropyl)Disulfane)Propanoyl)N-Methyl-L-Alaninate (eFAP-45); - 8,8'-((((3,3'-((((((6-((2-(2-(2-(4-((2,2-dioxide-1,2-oxatian-3-yl)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)ethyl)amino)-1,3,5-triazine-2,4-diyl)bis(azandiyl))bis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(propanoyl))bis(azandiyl))bis(propane-3,1-diyl))bis(oxy))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)quinoline-4-carboxamide)(eFAP-46); - 1-(1-(2-(2-(2-((4,6-bis((2-(2-(3-((3-((4-(((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)oxy)propyl)amino)-3-oxopropoxy)ethoxy)ethyl)amino)-1,3,5-triazine-2-yl)amino)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazole-4-yl)-5-fluoropentan-2-sulfonate (eFAP-47); - 2,2',2''-(10-(4-((6-((4,6-bis((2-(2-((3-((3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)oxy)propyl)amino)-3-oxopropoxy)ethoxy)ethyl)amino)-1,3,5-triazine-2-yl)amino)hexyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (eFAP-50); - 2,2',2''-(10-(4-((6-((4,6-bis((2-(2-((3-(((4-((3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)oxy)propyl)carbamoyl)cyclohexyl)methyl)amino)-3-oxopropoxy)ethoxy)ethyl)amino)-1,3,5-triazine-2-yl)amino)hexyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (eFAP-51); - 2,2',2''-(10-(4-((6-((4,6-bis((2-(2-((3-(4-((3-((4-(((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)oxy)propyl)amino)-2-oxoethyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-1,3,5-triazine-2-yl)amino)hexyl)amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (eFAP-52); and - Labeled with a radioactive isotope, preferably 111 In, 68 Ga, 177 Lu, 225 Ac, 212 eFAP-34, eFAP-35, eFAP-36, eFAP-37, eFAP-38, eFAP-50, eFAP-51, and eFAP-52, labeled with Pb radioisotopes. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

18. A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, for medical use, preferably for use in the diagnosis and / or treatment of tumors.

19. An intermediate compound for preparing a compound according to any one of claims 1 to 18, wherein the compound is any of formulas (IIIa), (IVa), (IIIb), (IVb), (IIIaa), (IVaa), (IIIab), and (IVab), preferably any of formulas (IIIaa), (IVaa), (IIIab), and (IVab). 【Chemical Engineering 16A】 【Chemical 16B】 (In the formula, L 1 , L 2 (where Z, q, and r are as defined in any one of claims 1 to 18) An intermediate compound containing a structure due to [the following].

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