Compounds and their uses

Abstract

The present invention relates generally to the field of diagnostic and therapeutic compounds. More specifically, the present invention relates to certain radiolabeled compounds, their precursors, and their respective uses. The radiolabeled compounds specifically bind to ALDH and emit radiation for the detection or treatment of ALDH-mediated diseases by molecular imaging.

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS]

[0002] This application claims priority to and the benefit of UK Application No. 2216665.6, filed November 9, 2022, the entire contents of which are incorporated herein by reference. [Technical field]

[0003] The present invention relates generally to the field of diagnostic and therapeutic compounds. More specifically, the present invention relates to certain radiolabeled PQM-H compounds and their precursors (referred to herein as "PQM-H compounds" and "PQM-P compounds," respectively). The PQM-H compounds specifically bind to ALDH, more specifically ALDH1A1, and emit radiation for detection by molecular imaging or for the treatment of diseases involving ALDH.

[0004] The present invention also relates to pharmaceutical compositions containing such PQM-H compounds, and to the following uses of the compounds and compositions: - Use both in vitro and in vivo, for example to bind and inhibit ALDH, in particular for example to bind and inhibit ALDH1A1; - Use for molecular imaging, for example by molecular imaging modalities (positron emission tomography (PET), single photon emission computed tomography (SPECT) and scintigraphy), in particular for PET and / or SPECT imaging of cancer; drug-resistant cancer; diseases associated with ALDH1A1 overexpression; and - Use to treat diseases, including cancer and drug-resistant cancer.

[0005] The invention also relates to the use of the PQM-P compounds in the preparation of PQM-H compounds; processes for preparing PQM-H compounds from PQM-P compounds; and kits containing the PQM-P compounds. [Background technology]

[0006] In order to more fully describe and disclose the present invention and the state of the art to which it pertains, numerous publications are cited herein, and each of these publications is herein incorporated by reference in its entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

[0007] Throughout this specification, including the claims which follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" will be understood to imply the inclusion of a stated integer or step or group of integers or steps, but not the exclusion of other integers or steps or groups of integers or steps.

[0008] It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, reference to a "pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.

[0009] Ranges are often expressed herein as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment.

[0010] This disclosure contains information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art. <Aldehyde dehydrogenase (ALDH)>

[0011] Aldehyde dehydrogenase (ALDH) converts NAD(P) + ALDHs are a family of enzymes that catalyze the oxidative oxidation of various aldehydes to their corresponding carboxylic acids (Singh et al., 2013). Currently, there are 20 known functional human ALDHs (Black et al., 2009), which mediate the metabolism of aldehydes generated during oxidative stress (Vassilou et al., 2000; Hartley et al., 1995), amino acid and bioactive amine metabolism (Ambroziak et al., 1991), retinoic acid biosynthesis (Duester et al., 2003), and ethanol metabolism (Vassilou et al., 2000). ALDHs regulate the detoxification of exogenous reactive aldehydes and therapeutic drugs, such as cyclophosphamide (Sladek, 2003).

[0012] Abnormal expression of ALDH has been associated with many diseases, including cancer, and increased ALDH expression and activity have been shown to be predictive of metastatic potential and reduced overall survival (Marcato et al., 2011). In particular, the ALDH1A1 isoenzyme is a well-characterized marker of cancer stem cells, which are known for their tumor-initiating properties and resistance to conventional therapies (Nakahata et al., 2015; Raha et al., 2014; Liu et al., 2013).

[0013] Studies have shown that chemotherapy resistance and poor prognosis are associated with high ALDH1A1 activity in breast cancer (Liu et al., 2014), ovarian cancer (Landen et al., 2010), prostate cancer (Li et al., 2010), colorectal cancer (Kahlert et al., 2012), and lung cancer (Huang et al., 2013). Consequently, ALDH1A1 is considered a target for anticancer therapy, and ALDH inhibitors have been shown to reverse chemotherapy resistance in various preclinical tumor models (Abdullah, 2013).

[0014] Given the causal relationship between ALDH1A1 expression and chemotherapy resistance in some cancers, identifying high ALDH1A1-expressing tumors represents a clinical challenge that, if resolved, could significantly improve patient outcomes.

[0015] Imaging these tumors using ALDH1A1 expression as a marker of chemotherapy resistance may inform therapeutic intervention and provide an opportunity to tailor treatment to patients ( Greenwood et al., 2021 ).

[0016] Imaging strategies for assessing ALDH activity have largely been limited to fluorescence-based assays in isolated cells ( Anorma et al., 2018 ; Maity et al., 2017 ; Minn et al., 2014 ; Ucar et al., 2009 ). However, the poor tissue penetration of the fluorescent signal and the need for direct injection into tumors currently limit their usefulness in vivo.

[0017] Other methods for detecting cancer treatment resistance are disadvantageous because they are invasive, requiring tumor biopsies ( Woolston et al., 2021 ), or require extensive data analysis ( Shen et al., 2021 ; Volm et al., 2015 ).

[0018] To circumvent these limitations, PET has been proposed as an alternative to fluorescence-based imaging ( Pereira et al., 2019 ; Vaidyanathan et al., 2009 ). <Known compounds>

[0019] To date, imaging strategies focused on radiotracers for ALDH1A1 have used a substrate-based approach, i.e., designing chemical probes with: a) aldehydes that can function as substrates for ALDH1A1; b) Radioisotope atoms that allow detection by gamma ray counting / PET imaging; c) an appropriate hydrophobic-hydrophilic balance that allows passive diffusion across the cell membrane; and d) the corresponding oxidation product is sufficiently polar to be retained intracellularly (i.e., cannot passively diffuse out of the cell).

[0020] Such substrate-based radiotracers have been reported to offer advantages such as improved sensitivity over radiolabeled inhibitors, as the substrate-based drug may be trapped within target cells after conversion from an aldehyde to a carboxylic acid ( Pereira et al., 2019 ).

[0021] Vaidyanathan et al., 2009, described two iodinated ALDH1A1 substrates: [ka] and [ka]

[0022] WO 2011 / 087823 A1 describes certain fluorine- and iodine-containing aldehydes of the following structural formula as ALDH substrates for use as diagnostic imaging or therapeutic agents: A-Ar-NH-C n -CH=O

[0023] WO 2013 / 048811 A1 describes certain detectably labeled ALDH substrates of the following structural formula, which are said to be useful for in vivo imaging and cancer therapy: [ka]

[0024] WO 2014 / 145493 A1 describes a specific radiodetectable substrate for ALDH of the following structural formula, which is said to be useful for selecting ALDH-positive cells: [ka]

[0025] Pereira et al., 2019, described the development of specific fluorinated ALDH1A1-selective chemical probes, including the following compounds: [ka]

[0026] Pereira et al., 2022, describes the development of the following acylal prodrugs of the compounds described in Pereira et al. 2019 and shown above: [ka]

[0027] Substrate-based imaging agents have shown promise in vitro; however, in vivo, substrate-based imaging agents have been found to have short blood half-lives ( Pereira et al., 2019 ).

[0028] Aldehyde substrates were found to be rapidly oxidized to carboxylic acids before reaching target cells, thereby preventing their diffusion across the cell membrane and retention in ALDH-expressing cells, even when protected by prodrug strategies. No radiolabeled ALDH substrate has yet been shown to be able to distinguish between drug-sensitive and drug-resistant tumors in vivo (Pereira et al., 2022).

[0029] Fluorescent compounds have been considered as an alternative to radiolabeled compounds for detecting ALDH activity (Minn et al. 2013; Yuen et al., 2016; Maity et al., 2017; Anorma et al., 2018; Yagishita et al., 2021; Okamoto et al., 2022).

[0030] Such fluorescent compounds have limited usefulness because scattering of emitted light by body tissues reduces the situations in which fluorescence is a viable means of imaging. For example, such compounds can be used in vitro, at external body surfaces, or in combination with invasive techniques to image deeper tissues.

[0031] In contrast, radiotracer-focused imaging strategies have the great advantage of enabling clinical imaging of the whole body. <Efficacy / selectivity>

[0032] The PQM-H compounds described herein are highly potent ALDH1A1 binders, eg, inhibitors, that also have high selectivity for ALDH1A1 compared to, eg, ALDH2. Summary of the Invention

[0033] One aspect of the present invention relates to certain radiolabeled compounds according to formula (I) described herein (referred to herein as PQM-H compounds).

[0034] Another aspect of the present invention relates to certain precursor compounds of PQM-H compounds (herein referred to as PQM-P compounds) according to formula (Ia) described herein.

[0035] Another aspect of the present invention relates to the use of PQM-P compounds in the preparation of PQM-H compounds.

[0036] Another aspect of the present invention relates to a process for preparing PQM-H compounds from the PQM-P compounds described herein.

[0037] Another aspect of the invention relates to a kit comprising a PQM-P compound and instructions for preparing a PQM-H compound.

[0038] Another aspect of the present invention relates to a pharmaceutical composition comprising a PQM-H compound and a pharmaceutically acceptable carrier, diluent, or excipient.

[0039] Another aspect of the invention relates to PQM-H compounds or pharmaceutical compositions comprising PQM-H compounds for use in diagnosis or therapy.

[0040] Another aspect of the present invention relates to a PQM-H compound or a pharmaceutical composition comprising a PQM-H compound for use in the diagnosis or treatment of cancer.

[0041] In one embodiment, the diagnosis or treatment is the diagnosis or treatment of drug-resistant cancer.

[0042] Another aspect of the present invention relates to a medical imaging method comprising the steps of: 1) administering to a subject a PQM-H compound or a pharmaceutical composition containing a PQM-H compound; and 2) Imaging the subject by PET, SPECT or scintigraphy.

[0043] As will be appreciated by those skilled in the art, features and preferred embodiments of one aspect of the invention also relate to other aspects of the invention. [Brief explanation of the drawings]

[0044] [Figure 1a] Graph showing cisplatin-induced growth inhibition in SKOV3-ip1 cells (open circles) and SKOV3 TRip2 cells (closed squares) after 72 hours of treatment using the MTT assay (n = 3-5). [Figure 1b] Bar graph showing relative ALDH1A1 mRNA expression in SKOV3-ip1 and SKOV3 TRip2 cells (n = 2). [Figure 1c] Images of Western blot analysis of ALDH1A1 protein expression in SKOV3-ip1 and SKOV3 TRip2 cells. [Figure 1d] Graph showing ALDH-specific retention of Aldefluor reagent in the presence and absence of the ALDH inhibitor N,N-diethylaminobenzaldehyde (DEAB). [Figure 1e] Bar graph showing the ratio of Aldefluor median fluorescence intensity (MFI) in DEAB- and vehicle-treated SKOV3-ip1 and SKOV3-TRip2 cells (n = 3). **, P < 0.01. Data represent mean ± SD. [Figure 2a] Graph showing inhibition of ALDH1A1 activity in the presence of PQM-C-001 (squares, IC50 = 0.015 μM) and in the presence of DEAB (circles, IC50 = 0.298 μM). [Figure 2b] Graph showing inhibition of ALDH2 activity in the presence of PQM-C-001 (squares, IC50 > 100 μM) and in the presence of DEAB (circles, IC50 = 1.19 μM). [Figure 2c] Bar graph showing the uptake of PQM-H-001, denoted as [18F]PQM-H-001, by drug-resistant SKOV3-TRip2 cells (filled squares / open bars on the right) and cisplatin-sensitive SKOV3-ip1 cells (open circles / filled bars on the left) at 20, 40, and 60 min. [Figure 2d] Bar graph showing the uptake of PQM-H-002, denoted as [125I]PQM-H-002, by drug-resistant SKOV3-TRip2 cells (filled squares / open bars on the right) and cisplatin-sensitive SKOV3 ip1 cells (open circles / filled bars on the left) at 20, 40, and 60 min. [Figure 3a] Representative time-lapse axial PET / CT images of PQM-H-001 in BALB / c-nu / nu mice bearing SKOV3-ip1 (top row) and SKOV3-TRip2 (bottom row) tumors. Tumors are indicated by dotted circles. [Figure 3b] Representative PET / CT maximum intensity projections of PQM-H-001 in BALB / c-nu / nu mice bearing SKOV3-ip1 (left) and SKOV3-TRip2 (right) tumors. Tumors are indicated by dotted circles. [Figure 4]Graph showing time versus radioactivity curves of PQM-H-001 injected into BALB / c-nu / nu mice bearing SKOV3-ip1 (circles) and SKOV3-TRip2 (squares) tumors, normalized to the percentage of injected activity. Data are expressed as mean ± standard deviation. n = 3-4 mice per group. [Figure 5] Bar graph showing the ex vivo biodistribution of PQM-H-001, designated [18F]PQM-H-001, in organs of interest in BALB / c-nu / nu mice bearing SKOV3-ip1 (left open bar of each pair) and SKOV3 TRip2 (right closed bar of each pair) ovarian cancer tumors. Data are expressed as mean ± standard deviation. n = 3-4 animals per group. [Figure 6] HPLC coelution chromatogram trace of PQM-H-001 (denoted as [F]PQM-H-001) and the non-radioactive reference compound (denoted as PQM-C-001); the taller peak in gray corresponds to PQM-H-001; the smaller peak in black corresponds to the reference compound PQM-C-001. [Figure 7] HPLC coelution chromatogram trace of PQM-H-002 (denoted as [I]PQM-H-002) and the non-radioactive reference compound (denoted as PQM-C-002); the taller peak in gray corresponds to PQM-H-002; the smaller peak in black corresponds to the reference compound PQM-C-002. [Figure 8] HPLC co-elution chromatogram trace of PQM-H-007 (denoted as [I]PQM-H-007) and non-radioactive reference compound PQM-C-007; the higher peak corresponds to PQM-H-007; the smaller peak corresponds to reference compound PQM-C-007. [Figure 9] HPLC co-elution chromatogram trace of PQM-H-017 (denoted as [I]PQM-H-017) and non-radioactive reference compound PQM-C-017; the higher peak corresponds to PQM-H-017; the smaller peak corresponds to reference compound PQM-C-017. [Figure 10a]Graph showing the uptake of PQM-H-002 by A549-WT (ALDH1A1 positive) (filled circles) and A549-KO-ALDH1A1 (ALDH1A1 negative) (open circles) human lung cancer cells at 20, 40, 60, and 120 minutes. [Figure 10b] Graph showing uptake of PQM-H-002 by HEK293-WT (ALDH1A1 negative) (black circles) and HEK293-ALDH1A1 (ALDH1A1 positive) (gray circles) human embryonic kidney cells at 20, 40, 60, and 120 minutes. [Figure 11a] Graph showing the uptake of PQM-H-007 by A549-WT (ALDH1A1 positive) (filled circles) and A549-KO-ALDH1A1 (ALDH1A1 negative) (open circles) human lung cancer cells at 20, 40, 60, and 120 minutes. [Figure 11b] Graph showing uptake of PQM-H-007 by HEK293-WT (ALDH1A1 negative) (black circles) and HEK293-ALDH1A1 (ALDH1A1 positive) (gray circles) human embryonic kidney cells at 20, 40, 60, and 120 minutes. [Figure 12a] Graph showing the uptake of PQM-H-017 by A549-WT (ALDH1A1 positive) (filled circles) and A549-KO-ALDH1A1 (ALDH1A1 negative) (open circles) human lung cancer cells at 20, 40, 60, and 120 minutes. [Figure 12b] Graph showing uptake of PQM-H-017 by HEK293-WT (ALDH1A1 negative) (black circles) and HEK293-ALDH1A1 (ALDH1A1 positive) (gray circles) human embryonic kidney cells at 20, 40, 60, and 120 minutes. [Figure 13] Graph showing the uptake of PQM-H-022 by A549-WT (ALDH1A1 positive) (filled circles) and A549-KO-ALDH1A1 (ALDH1A1 negative) (open circles) human lung cancer cells at 20, 40, 60, and 120 minutes. DETAILED DESCRIPTION OF THE INVENTION

[0045] <Compound>

[0046] One aspect of the present invention relates to certain compounds related to quinoline: [ka]

[0047] More specifically, this compound is related to piperazin-1-yl(3-quinolyl)methanone ("PQM"): [ka]

[0048] Additionally, the compounds described herein have the following: (a) a substituent at the 4-position (referred to herein as -R 4 or -R 14 (denoted as ); (b) The substituent of the secondary amine of the piperazine of the PQM (herein -L 1 -R L or -L 11 -R 1L (denoted as ); (c) one or two substituents (referred to herein as -R 6 , -R 7 , and -R 8 ; or -R 16 , -R 17 , and -R 18 (Written as follows). Accordingly, one aspect of the present invention is a compound of the following formula: or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: -R 4 , -L 1 -, -R L , -R 6 , -R 7 and -R 8 is as defined herein (for convenience, collectively referred to herein as "PQM-H compounds"): [ka]

[0049] The PQM-H compounds described herein are radiolabeled compounds, i.e., the PQM-H compounds are enriched with a radioactive isotope at one substituent position.

[0050] For the avoidance of doubt, in the population of PQM-H compounds, a substituent that is a radioisotope contains said radioisotope in an amount greater than the natural abundance of the radioisotope.

[0051] Some embodiments include: <Radiolabeled compound>

[0052] (1) A radiolabeled compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof: [ka] (I) During the ceremony, -R 4 teeth, [ka] or [ka] is; -R 4A and -R 4B along with the carbon atoms to which they are attached, C 3-5 Forms a cycloalkyl; or -R 4A and -R 4B are each independently C 1-3 is alkyl; -R 4C -H, -F, or -R X4C is; -R 4D is phenyl optionally substituted with: a) One -R X4D groups; and / or b) one or more -F; -L 1- is independently selected from -S(O)2- and -C(O)2; -R L is C 1-6 independently selected from alkyl and cyclopropyl; -R 6 -H, -F, -I, -R X6 and -NO2; -R 7 -H, -F, -I, -R X7 and -NO2; -R 8 -H, -F, -I, -R X8 and -NO2; -R X4C teeth, 18 F, 123 I, 124 I, 125 I, 131 I, and 211 is a radioisotope selected from At; -R X4D teeth, 18 F, 123 I, 124 I, 125 I, 131 I, and 211 is a radioisotope selected from At; -R X6 teeth, 18 F, 123 I, 124 I, 125 I, 131 I, and 211 is a radioisotope selected from At; -R X7 teeth, 18 F, 123 I, 124 I, 125 I, 131 I, and 211 At is a radioisotope selected from At; and -R X8 teeth, 18 F, 123 I, 124 I, 125 I, 131 I, and 211is a radioisotope selected from At; wherein the compound is -R X4C , -R X4D , R X6 , -R X7 , and -R X8 and contains only one group selected from -R 6 , -R 7 , and -R 8 At least one of is -H. (2) The compound according to (1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound is a radiolabeled compound of formula (I): [ka] (I) During the ceremony, -R 4 teeth, [ka] or [ka] is; -R 4A and -R 4B along with the carbon atoms to which they are attached, C 3-5 Forms a cycloalkyl; or -R 4A and -R 4B are each independently C 1-3 is alkyl; -R 4C is -H or -F; -R 4D is phenyl optionally substituted with one or more -F; -L 1 - is independently selected from -S(O)2- and -C(O)2; -R L is C 1-6 independently selected from alkyl and cyclopropyl; -R 6are independently selected from -H, -F, -I, a radioisotope, and -NO2; -R 7 are independently selected from -H, -F, -I, a radioisotope, and -NO2; -R 8 are independently selected from -H, -F, -I, a radioisotope, and -NO2; where -R 6 , -R 7 , and -R 8 One of the isotopes is -R 6 , -R 7 , and -R 8 The others are not radioisotopes; and -R 6 , -R 7 , and -R 8 at least one of is -H; Here, the radioisotope is 18 F, 123 I, 124 I, 125 I, 131 I, and 211 At is selected. <-R 4 Base>

[0053] (3)-R 4 but, [ka] The compound according to (1) or (2), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein (4)-R 4 but, [ka] The compound according to any one of (1) to (3), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: (5)-R 4 but, [ka] The compound according to (1) or (2), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein <-R 4A Groups and -R 4B Base>

[0054] (6)-R 4A and -R 4B together with the carbon atoms to which they are attached, C 3-5 The compound according to any one of (1) to (4), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, which forms a cycloalkyl. (7)-R 4A and -R 4B together with the carbon atom to which they are attached form cyclopropyl, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (8)-R 4A and -R 4B However, each independently C 1-3 The compound according to any one of (1) to (4), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R is alkyl. (9)-R 4A and -R 4B and R are each methyl, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0055] <-R 4C Base>

[0056] (10)-R 4C But -H or -R X4C or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: (11)-R 4C The compound according to any one of (1) to (4) and (6) to (9), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein is -H or -F. (12)-R 4CThe compound according to any one of (1) to (4) and (6) to (9), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein is —H. (13)-R 4C The compound according to any one of (1) to (4) and (6) to (9), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein is -F. (14)-R 4C But -R X4C or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: <-R X4C Base>

[0057] (15)-R X4C But if it exists, 18 F, 123 I, 124 I, 125 I, and 131 The compound according to any one of (1) to (14), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the radioisotope is selected from I. (16)-R X4C But if it exists, 18 The compound according to any one of (1) to (14), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein F is a radioactive isotope. (17)-R X4C But if it exists, 123 I, 124 I, 125 I, and 131 The compound according to any one of (1) to (14), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the radioisotope is selected from I. (18)-R X4C But if it exists, 125 I and 131 The compound according to any one of (1) to (14), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the radioisotope is selected from I. (19)-R X4C But if it exists,125 The compound according to any one of (1) to (14), wherein the radioisotope is I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. <-R 4D Base>

[0058] (20)-R 4D is phenyl optionally substituted with one or more -F, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (21)-R 4D The compound according to any one of (1), (2) and (5), or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein is phenyl. (22)-R 4D The compound according to any one of (1), (2) and (5), or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein is phenyl substituted with -F. (23)-R 4D But one -R X4D or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (24)-R 4D But one -R X4D or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (25)-R 4D but, [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof. <-R X4D Base>

[0059] (26)-R X4D But if it exists, 18 F, 123 I, 124 I, 125I, and 131 The compound according to any one of (1) to (25), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the radioisotope is selected from I. (27)-R X4D But if it exists, 18 The compound according to any one of (1) to (25), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein F is a radioactive isotope. (28)-R X4D But if it exists, 123 I, 124 I, 125 I, and 131 The compound according to any one of (1) to (25), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the radioisotope is selected from I. (29)-R X4D But if it exists, 125 I and 131 The compound according to any one of (1) to (25), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the radioisotope is selected from I. (30)-R X4D But if it exists, 125 The compound according to any one of (1) to (25), wherein the radioisotope is I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. <-L 1 -base>

[0060] (31)-L 1 The compound according to any one of (1) to (30), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein - is -S(O)2-. (32)-L 1 The compound according to any one of (1) to (30), wherein - is -C(O)-, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. <-R L Base>

[0061] (33)-R L -But C 1-6The compound according to any one of (1) to (32), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R is alkyl. (34)-R L -But C 1-3 The compound according to any one of (1) to (32), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R is alkyl. (35)-R L The compound according to any one of (1) to (32), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein - is methyl. (36)-R L The compound according to any one of (1) to (32), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein - is cyclopropyl. <Radioisotope>

[0062] When the atomic mass of a particular atom is defined, for example, for a radioisotope, the structural formula does not assume isotopic substitution at that position. 18 If the fluorine atom is defined as F, 19 It is not expected to be replaced by other isotopes such as F.

[0063] In this context, as used herein, when a substituent position is defined to be a "radioisotope", the substituent at that position may be, for example, 18 F, 123 I, 124 I, 125 I, 131 I, or 211 Enriched in a radioisotope, such as At, means that the amount of the compound contains the radioisotope in an amount greater than the natural abundance of the radioisotope.

[0064] As noted above, the PQM-H compounds are radioisotopically enriched at one substituent. That is, the PQM-H compounds described herein are radioisotopically enriched at one (and not more than one) substituent. More specifically, the PQM-H compounds are -R X4C , -RX4D , -R X6 , -R X7 , and -R X8 (each defined as a radioisotope). That is, in the PQM-H compounds described herein, -R X4C , -R X4D , -R X6 , -R X7 , and -R X8 There is one of -R X4C , -R X4D , -R X6 , -R X7 , and -R X8 In other words, the compound has -R X4C , -R X4D , -R 6 , -R 7 , and -R 8 It contains a radioactive isotope at one position.

[0065] (37) A radioisotope is 18 F, 123 I, 124 I, 125 I, and 131 The compound according to any one of (1) to (36), selected from I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (38) A radioisotope is 18 The compound according to any one of (1) to (36), wherein F is F, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (39) A radioisotope is 123 I, 124 I, 125 I, and 131 The compound according to any one of (1) to (36), selected from I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (40) A radioisotope is 125 I and 131 The compound according to any one of (1) to (36), selected from I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (41) A radioisotope is 125The compound according to any one of (1) to (36), wherein I is I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (42) A radioisotope is 131 The compound according to any one of (1) to (36), wherein I is I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (43) A radioisotope is 124 The compound according to any one of (1) to (36), wherein I is I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (44) A radioisotope is 123 The compound according to any one of (1) to (36), wherein I is I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (45) A radioisotope is 211 The compound according to any one of (1) to (36), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein At is At. (46)-R 6 , -R 7 , or -R 8 One of the isotopes is a radioisotope, e.g., -R 6 Ga-R X6 -R 7 Ga-R X7 or -R 8 Ga-R X8 The compound according to any one of (1) to (45) (if applicable), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: (47)-R 6 or -R 7 is a radioisotope, e.g., -R 6 Ga-R X6 or -R 7 Ga-R X7 The compound according to any one of (1) to (45) (if applicable), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: (48)-R 6 or -R 8 is a radioisotope, e.g., -R 6 Ga-R X6 or -R 8 Ga-RX8 The compound according to any one of (1) to (45) (if applicable), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: <-R 6 Base>

[0066] (49)-R 6 is selected from -H, -F, -I, a radioactive isotope, and -NO2, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (50)-R 6 But, -H, -R X6 A compound according to any one of (1) to (48) (if applicable), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, selected from -NO2, and -NO2. (51)-R 6 But -H and -R X6 A compound according to any one of (1) to (48) (if applicable), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, selected from: (52)-R 6 is not a radioisotope and is selected from -H, -F, -I, and -NO2, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (53)-R 6 is not a radioisotope and is selected from -H and -NO2, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (54)-R 6 is not a radioisotope and is selected from -H, -F, and -I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (55)-R 6 is not a radioisotope and is selected from -H and -F, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, according to any one of (1) to (48). (56)-R 6The compound according to any one of (1) to (48), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein is not a radioactive isotope and is —H. (57)-R 6 is a radioisotope, e.g., -R 6 Ga-R X6 The compound according to any one of (1) to (48) (if applicable), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: <-R 7 Base>

[0067] (58)-R 7 is selected from -H, -F, -I, a radioactive isotope, and -NO2, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (59)-R 7 But, -H, -R X7 A compound according to any one of (1) to (57) (if applicable), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, selected from -NO2, and -NO2. (60)-R 7 But -H and -R X7 A compound according to any one of (1) to (57) (if applicable), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, selected from: (61)-R 7 is not a radioisotope and is selected from -H, -F, -I, and -NO2, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (62)-R 7 is not a radioisotope and is selected from -H and -NO2, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (63)-R 7 is not a radioisotope and is selected from -H, -F, and -I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (64)-R7 is not a radioisotope and is selected from -H and -F, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, according to any one of (1) to (57). (65)-R 7 The compound according to any one of (1) to (57), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein is not a radioactive isotope and is —H. (66)-R 7 is a radioisotope, e.g., -R 7 Ga-R X7 The compound according to any one of (1) to (57) (if applicable), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: <-R 8 Base>

[0068] (67)-R 8 is selected from -H, -F, -I, a radioisotope, and -NO2, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (68)-R 8 But, -H, -R X8 A compound according to any one of (1) to (66) (if applicable), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, selected from -NO2, and -NO2. (69)-R 8 But -H and -R X8 A compound according to any one of (1) to (66) (if applicable), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, selected from: (70)-R 8 is not a radioisotope and is selected from -H, -F, -I, and -NO2, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (71)-R 8 is not a radioisotope and is selected from -H and -NO2, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (72)-R8 is not a radioisotope and is selected from -H, -F, and -I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (73)-R 8 is not a radioisotope and is selected from -H and -F, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (74)-R 8 The compound according to any one of (1) to (66), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein is not a radioactive isotope and is —H. (75)-R 8 is a radioisotope, e.g., -R 8 Ga-R X8 The compound according to any one of (1) to (66) (if applicable), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

[0069] <-R X6 Base> (76)-R X6 But if it exists, 18 F, 123 I, 124 I, 125 I, and 131 The compound according to any one of (1) to (77), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the radioisotope is selected from I. (77)-R X6 But if it exists, 18 The compound according to any one of (1) to (77), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein F is a radioactive isotope. (78)-R X6 But if it exists, 123 I, 124 I, 125 I, and 131 The compound according to any one of (1) to (77), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the radioisotope is selected from I. (79)-RX6 But if it exists, 125 I and 131 The compound according to any one of (1) to (77), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the radioisotope is selected from I. (80)-R X6 But if it exists, 125 The compound according to any one of (1) to (77), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein I is a radioactive isotope. <-R X7 Base>

[0070] (81)-R X7 But if it exists, 18 F, 123 I, 124 I, 125 I, and 131 The compound according to any one of (1) to (80), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the radioisotope is selected from I. (82)-R X7 But if it exists, 18 The compound according to any one of (1) to (80), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein F is a radioactive isotope. (83)-R X7 But if it exists, 123 I, 124 I, 125 I, and 131 The compound according to any one of (1) to (80), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the radioisotope is selected from I. (84)-R X7 But if it exists, 125 I and 131 The compound according to any one of (1) to (80), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the radioisotope is selected from I. (85)-R X7 But if it exists, 125The compound according to any one of (1) to (80), wherein the radioisotope is I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. <-R X8 Base>

[0071] (86)-R X8 But if it exists, 18 F, 123 I, 124 I, 125 I, and 131 The compound according to any one of (1) to (85), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the radioisotope is selected from I. (87)-R X8 But if it exists, 18 The compound according to any one of (1) to (85), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein F is a radioactive isotope. (88)-R X8 But if it exists, 123 I, 124 I, 125 I, and 131 The compound according to any one of (1) to (85), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the radioisotope is selected from I. (89)-R X8 But if it exists, 125 I and 131 The compound according to any one of (1) to (85), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the radioisotope is selected from I. (90)-R X8 But if it exists, 125 The compound according to any one of (1) to (85), wherein the radioisotope is I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. <Some preferred combinations>

[0072] (91) -R X4C But if it exists, 18 F is a radioactive isotope; -R X4D But if it exists, 18 F is a radioactive isotope; -R X6 But if it exists, 18 F, 123 I, 124 I, 125 I, and 131 I is a radioisotope selected from; -R X7 But if it exists, 18 F, 123 I, 124 I, 125 I, and 131 I; and -R X8 But if it exists, 18 F, 123 I, 124 I, 125 I, and 131 I, The compound according to any one of (1) to (90), or a pharmaceutically acceptable salt or solvate thereof. (92) -R 6 is a radioisotope, e.g., -R 6 Ga-R X6 is; -R 7 is -H; and -R 8 is -H or -NO2; The compound according to any one of (1) to (36), or a pharmaceutically acceptable salt or solvate thereof. (93) -R 6 is a radioisotope, e.g., -R 6 Ga-R X6 is; -R 7 is -H;-R 8 is -H or -NO2; and Radioactive isotopes 18 F, The compound according to any one of (1) to (36), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (94) -R 6 is a radioisotope, e.g., -R 6 Ga-R X6 is; -R 7 is -H;-R 8 is -H or -NO2; and Radioactive isotopes 123 I, 124 I, 125 I, 131 I and 211 At, selected from The compound according to any one of (1) to (36), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (95) -R 6 is a radioisotope, e.g., -R 6 Ga-R X6 is; -R 7 is -H;-R 8 is -H or -NO2; and Radioactive isotopes 123 I, 124 I, 125 I, and 131 I is selected from The compound according to any one of (1) to (36), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (96) -R 6 is a radioisotope, e.g., -R 6 Ga-R X6 is; -R 7 is -H;-R 8 is -H or -NO2; and Radioactive isotopes 125 I am, The compound according to any one of (1) to (36), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (97) -R 7 is a radioisotope, e.g., -R 7 Ga-R X7 is; and -R6 is -H;-R 8 is -H, The compound according to any one of (1) to (36), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (98) -R 7 is a radioisotope, e.g., -R 7 Ga-R X7 is; -R 6 is -H;-R 8 is -H; and Radioactive isotopes 18 F, The compound according to any one of (1) to (36), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (99) -R 7 is a radioisotope, e.g., -R 7 Ga-R X7 is; -R 6 is -H;-R 8 is -H; and Radioactive isotopes 123 I, 124 I, 125 I, 131 I and 211 At, selected from The compound according to any one of (1) to (36), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (100) -R 7 is a radioisotope, e.g., -R 7 Ga-R X7 is; -R 6 is -H;-R 8 is -H; and Radioactive isotopes 123 I, 124 I, 125 I, and 131 I is selected from The compound according to any one of (1) to (36), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (101) -R 7 is a radioisotope, e.g., -R 7 Ga-R X7 is; -R 6 is -H;-R 8 is -H; and Radioactive isotopes 125 I am, The compound according to any one of (1) to (36), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (102) -R 6 is -H or -NO2; -R 7 is -H; and -R 8 is a radioisotope, e.g., -R 8 Ga-R X8 That is, The compound according to any one of (1) to (36), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (103) -R 6 is -H or -NO2; -R 7 is -H; -R 8 is a radioisotope, e.g., -R 8 Ga-R X8 is; and Radioactive isotopes 18 F, The compound according to any one of (1) to (36), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (104) -R 6 is -H or -NO2; -R 7 is -H; -R 8 is a radioisotope, e.g., -R 8 Ga-R X8 is; and Radioactive isotopes 123 I, 124 I, 125 I, 131 I and 211 At, selected from The compound according to any one of (1) to (36), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (105) -R 6 is -H or -NO2; -R 7 is -H; -R 8 is a radioisotope, e.g., -R 8 Ga-R X8 is; and Radioactive isotopes 123 I, 124 I, 125 I, and 131 I is selected from The compound according to any one of (1) to (36), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (106) -R 6 is -H or -NO2; -R 7 is -H; -R 8 is a radioisotope, e.g., -R 8 Ga-R X8 is; and Radioactive isotopes 125 I am, The compound according to any one of (1) to (36), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (107) -R 4C If present, -H, -F, or -R X4C is; -R 4D If present, one -R X4D phenyl optionally substituted with a group; -R 6 is independently selected from -H, -F, -I, and -NO2; -R 7 is independently selected from -H, -F, -I, and -NO2; and -R 8 are independently selected from -H, -F, -I, and -NO2; A compound according to any one of (1) to (36) (if applicable) or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (108) -R 4C If present, -H, -F, or -R X4C is; -R 4D If present, one -R X4D phenyl optionally substituted with a group; -R 6 is independently selected from -H, -F, -I, and -NO2; -R 7 is independently selected from -H, -F, -I, and -NO2; -R 8 is independently selected from -H, -F, -I, and -NO2; -R X4C but, 18 F, 123 I, 124 I, 125 I, and 131 I; and -R X4D but, 18 F, 123 I, 124 I, 125 I, and 131 The compound according to any one of (1) to (36) (if applicable), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the radioisotope is selected from I. (109) -R 4C If present, -H, -F, or -R X4C is; -R 4D If present, one -R X4D phenyl optionally substituted with a group; -R 6 is independently selected from -H, -F, -I, and -NO2; -R 7 is independently selected from -H, -F, -I, and -NO2; -R 8is independently selected from -H, -F, -I, and -NO2; -R X4C but, 18 is a radioactive isotope that is F; and -R X4D but, 18 F is a radioactive isotope, A compound according to any one of (1) to (36) (if applicable) or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (110) -R 4 but, [ka] is; and -R 4D But one -R X4D phenyl substituted with a group; (1) The compound according to (1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (111) -R 4 but, [ka] is; -R 4D But one -R X4D phenyl substituted with a group; -R 6 is -H;-R 7 is -H; and -R 8 is -H, (1) The compound according to (1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (112) -R 4 but, [ka] is; R 4D But one -R X4D phenyl substituted with a group; -L 1 - is -S(O)2-; -RL C 1-6 alkyl; and -R 6 is -H;-R 7 is -H; and -R 8 is -H, (1) The compound according to (1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (113) -R 4 but, [ka] is; -R 4D But one -R X4D phenyl substituted with a group; -L 1 - is -S(O)2-; -R L C 1-6 alkyl; and -R 6 is -H;-R 7 is -H;-R 8 is -H; and -R X4D but 18 F, 123 I, 124 I, 125 I, and 131 I is selected from (1) The compound according to (1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (114) -R 4 but, [ka] is; and -R 6 is a radioisotope, e.g., -R 6 Ga-R X6 That is, (1) The compound according to (1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (115) -R 4 but, [ka] is; -R 4A and -R 4B together with the carbon atoms to which they are attached, C 3-5 Forming a cycloalkyl; -R 4C is -H; and -R 6 is a radioisotope, e.g., -R 6 Ga-R X6 That is, (1) The compound according to (1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (116) -R 4 but, [ka] is; -R 4A and -R 4B together with the carbon atoms to which they are attached, C 3-5 Forming a cycloalkyl; -R 4C is -H; -L 1 - is -S(O)2-; -R L C 1-6 alkyl; and -R 6 is a radioisotope, e.g., -R 6 Ga-R X6 That is, (1) The compound according to (1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (117) -R 4 but, [ka] is; -R 4A and -R 4B together with the carbon atoms to which they are attached, C 3-5 Forming a cycloalkyl; -R 4C is -H; -L 1 - is -S(O)2-; -R L C 1-6 selected from alkyl; -R 7 is -H;-R 8 is -H; and -R 6 is a radioisotope, e.g., -R 6 Ga-R X6 That is, (1) The compound according to (1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (118) -R 4 but, [ka] is; -R 4A and -R 4B together with the carbon atoms to which they are attached, C 3-5 Forming a cycloalkyl; -R 4C is -H; -L 1 - is -S(O)2-; -R L C 1-6 selected from alkyl; -R 7 is -H;-R 8 is -H;-R 6 is a radioisotope, e.g., -R 6 Ga-R X6 is; and Radioactive isotopes 18 F, 123 I, 124 I, 125 I, and 131 I is selected from (1) The compound according to (1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (119) -R 4 but, [ka] is; -R 4A and -R 4B together with the carbon atoms to which they are attached, C 3-5 Forming a cycloalkyl; -R 4C is -H; -L 1 - is -S(O)2-; -R L C 1-6 selected from alkyl; -R 7 is -H;-R 8 is -H;-R 6 is a radioisotope, e.g., -R 6 Ga-R X6 is; and Radioactive isotopes 18 F and 125 I is selected from (1) The compound according to (1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. <Specific compound>

[0073] (120) The compound according to (1), selected from the compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] (121) The compound according to (1), selected from the compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] (122) The compound according to (1), selected from compounds of the following formulae, and pharmaceutically acceptable salts, hydrates, and solvates thereof: [Table 3-1] [Table 3-2] (123)1-(4-(6-(fluoro- 18 F)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile (PQM-H-001), or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to (1). (124)1-(4-(6-(iodo- 125 The compound according to (1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is I)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile (PQM-H-002). (125)1-(4-(6-(fluoro- 18 F)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)-8-nitroquinolin-4-yl)phenyl)cyclopropane-1-carbonitrile (PQM-H-006), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (126)1-(4-(6-(iodine- 125 The compound according to (1), which is I)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)-8-nitroquinolin-4-yl)phenyl)cyclopropane-1-carbonitrile (PQM-H-007), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (127)1-(4-(8-(fluoro- 18 F)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile (PQM-H-016), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (128)1-(4-(8-(fluoro- 125 The compound according to (1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is I)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile (PQM-H-017). (129)4-(4-(fluoro- 18 F) The compound according to (1), which is (phenyl)-1-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)piperidine-4-carbonitrile (PQM-H-026), or a pharmaceutically acceptable salt, hydrate, or solvate thereof. <Radiolabeled compound precursor>

[0074] The radiolabeled (PQM-H) compounds described herein undergo radioactive decay. As a result, PQM-H compounds cannot be stored for extended periods of time without a decrease in the radioactivity of the sample. Furthermore, storage and transportation of PQM-H compounds poses a safety risk to those handling these compounds due to exposure to radioactive decay.

[0075] Therefore, it is convenient to store and transport PQM-H compounds as synthetic precursors (i.e., PQM-P compounds). PQM-H compounds can be produced by a short synthetic transformation from an appropriate PQM-P compound when and where needed for use. In this way, exposure of third parties to radioactivity generated by the PQM-H compounds is minimized, maximizing the amount of radiolabeled compound available to subjects in need. In fact, the PQM-P compounds are crucial to the anticipated use of PQM-H compounds.

[0076] Thus, another aspect of the present invention relates to certain compounds that are synthetic precursors to PQM-H compounds in which a radioisotope has been replaced with a leaving group (eg, a -BPin group).

[0077] Thus, another aspect of the present invention is a compound of the following formula: or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: 14 , -L 11 -, -R 1L , -R 16 , -R 17 and -R 18 (wherein PQM P is defined herein). For convenience, they are collectively referred to herein as "PQM P" compounds. [ka] (130) A compound of formula (Ia) or a salt, hydrate, or solvate thereof: [ka] (Ia) During the ceremony, -R 14 teeth, [ka] or [ka] is; -R 14Aand -R 14B along with the carbon atoms to which they are attached, C 3-5 Forms a cycloalkyl; or -R 14A and -R 14B are each independently C 1-3 is alkyl; -R 14C -H, -F, or -R X14C is; -R 14D is phenyl optionally substituted with: a) One -R X14D groups; and / or b) one or more -F; -L 11 - is independently selected from -S(O)2- and -C(O)2; -R 1L is C 1-6 independently selected from alkyl and cyclopropyl; -R 16 -H, -F, -I, -R X16 and NO2; -R 17 -H, -F, -I, -R X17 and NO2; -R 18 -H, -F, -I, -R X18 and NO2; -R X14C , -R X14D , -R X16 , -R X17 , and -R X18 each of which is independently a leaving group; The compound is -R X14C , -R X14D , -R X16 , -R X17 , and -R X18 and -R 16 , -R 17 , and -R 18 At least one of is -H.

[0078] (131) A compound according to (130), or a salt, hydrate, or solvate thereof, which is a compound of formula (Ia): [ka] (Ia) During the ceremony, -R 14 teeth, [ka] or [ka] is; -R 14A and -R 14B along with the carbon atoms to which they are attached, C 3-5 Forms a cycloalkyl; or -R 14A and -R 14B are each independently C 1-3 is alkyl; -R 14C is -H or -F; -R 14D is phenyl optionally substituted with one or more -F; -L 11 - is independently selected from -S(O)2- and -C(O)2; -R 1L is C 1-6 independently selected from alkyl and cyclopropyl; -R 16 is independently selected from -H, -F, -I, a leaving group, and -NO2; -R 17 is independently selected from -H, -F, -I, a leaving group, and -NO2; -R 18 is independently selected from -H, -F, -I, a leaving group, and -NO2; where -R 16 , -R 17 , and -R 18 One of the groups is a leaving group, -R 16 , -R 17 , and -R18 is not a leaving group; and -R 16 , -R 17 , and -R 18 At least one of is -H. <-R 14 Base>

[0079] (132)-R 14 but, [ka] The compound according to (130) or (131), or a salt, hydrate, or solvate thereof, wherein (133)-R 14 but, [ka] The compound according to (130) or (131), or a salt, hydrate, or solvate thereof, wherein (134)-R 14 but, [ka] The compound according to (130) or (131), or a salt, hydrate, or solvate thereof, wherein <-R 14A Groups and -R 14B Base>

[0080] (135)-R 14A and -R 14B together with the carbon atoms to which they are attached, C 3-5 The compound according to any one of (130) to (133), or a salt, hydrate, or solvate thereof, which forms a cycloalkyl. (136)-R 14A and -R 14B and (132) form a cyclopropyl group together with the carbon atom to which they are attached, or a salt, hydrate, or solvate thereof. (137)-R 14A and -R 14B However, each independently C1-3 The compound according to any one of (130) to (133), or a salt, hydrate, or solvate thereof, wherein R is alkyl. (138)-R 14A and -R 14B and (133) are each methyl, or a salt, hydrate, or solvate thereof. <-R 14C Base>

[0081] (139)-R 14C But -H or -R X14C The compound according to any one of (130) to (133) and (135) to (138), where applicable, or a salt, hydrate, or solvate thereof, wherein (140)-R 14C The compound according to any one of (130) to (133) and (135) to (138), or a salt, hydrate, or solvate thereof, wherein is —H or —F. (141)-R 14C The compound according to any one of (130) to (133) and (135) to (138), or a salt, hydrate, or solvate thereof, wherein is —H. (142)-R 14C The compound according to any one of (130) to (133) and (135) to (138), or a salt, hydrate, or solvate thereof, wherein is —F. (143)-R 14C But -R X14C The compound according to any one of (130) to (133) and (135) to (138), where applicable, or a salt, hydrate, or solvate thereof, wherein <-R 14D Base>

[0082] (144)-R 14D is phenyl optionally substituted with one or more -F, or a salt, hydrate, or solvate thereof. (145)-R 14DThe compound according to any one of (130), (131) or (134), or a salt, hydrate or solvate thereof, wherein is phenyl. (146)-R 14D The compound according to any one of (130), (131) or (134), or a salt, hydrate or solvate thereof, wherein is phenyl substituted with -F. (147)-R 14D But one -R X14D The compound according to (130) or (134), wherein R is phenyl optionally substituted with R, or a salt, hydrate, or solvate thereof. (148)-R 14D But one -R X14D The compound according to (130) or (134), wherein R is phenyl substituted with R, or a salt, hydrate, or solvate thereof. (149)-R 14D but, [ka] The compound according to (130) or (134), or a salt, hydrate, or solvate thereof, wherein <-L 11 -base>

[0083] (150)-L 11 The compound according to any one of (130) to (149), or a salt, hydrate, or solvate thereof, wherein - is -S(O)2-. (151)-L 11 The compound according to any one of (130) to (149), wherein - is -C(O)-, or a salt, hydrate, or solvate thereof. <-R 1L Base>

[0084] (152)-R 1L - is C 1-6 The compound according to any one of (130) to (151), or a salt, hydrate, or solvate thereof, wherein R is alkyl. (153)-R 1L - is C 1-3The compound according to any one of (130) to (151), or a salt, hydrate, or solvate thereof, wherein R is alkyl. (154)-R 1L The compound according to any one of (130) to (151), or a salt, hydrate, or solvate thereof, wherein - is methyl. (155)-R 1L The compound according to any one of (130) to (151), or a salt, hydrate, or solvate thereof, wherein - is cyclopropyl. <-R 16 Base>

[0085] (156)-R 16 is selected from -H, -F, -I, a leaving group, and -NO2, or a salt, hydrate, or solvate thereof, according to any one of (130) to (155) (if applicable). (157)-R 16 -H, R X16 A compound according to any one of (130) to (155) (if applicable), or a salt, hydrate, or solvate thereof, selected from -NO2, and -NO2. (158)-R 16 -H and R X16 A compound according to any one of (130) to (155) (if applicable), or a salt, hydrate, or solvate thereof, selected from: (159)-R 16 is not a leaving group and is selected from -H, -F, -I, and -NO2, or a salt, hydrate, or solvate thereof, according to any one of (130) to (155). (160)-R 16 is not a leaving group and is selected from -H and -NO2, or a salt, hydrate, or solvate thereof, according to any one of (130) to (155). (161)-R 16 The compound according to any one of (130) to (155), or a salt, hydrate, or solvate thereof, wherein is not a leaving group and is selected from -H, -F, and -I. (162)-R 16The compound according to any one of (130) to (155), or a salt, hydrate, or solvate thereof, wherein is not a leaving group and is selected from -H and -F. (163)-R 16 The compound according to any one of (130) to (155), or a salt, hydrate, or solvate thereof, wherein is not a leaving group and is —H. (164)-R 16 is a leaving group, e.g., -R 16 Ga-R X16 The compound according to any one of (130) to (155), or a salt, hydrate, or solvate thereof, wherein <-R 17 Base>

[0086] (165)-R 17 is selected from -H, -F, -I, a leaving group, and -NO2, or a salt, hydrate, or solvate thereof, according to any one of (130) to (164) (if applicable). (166)-R 17 -H, R X17 A compound according to any one of (130) to (164) (if applicable), or a salt, hydrate, or solvate thereof, wherein the compound is selected from -NO2 and -NO2. (167)-R 17 -H and R X17 A compound according to any one of (130) to (164) (if applicable), or a salt, hydrate, or solvate thereof, selected from: (168)-R 17 is not a leaving group and is selected from -H, -F, -I, and -NO2, or a salt, hydrate, or solvate thereof. (169)-R 17 is not a leaving group and is selected from -H and -NO2, or a salt, hydrate, or solvate thereof, according to any one of (130) to (164). (170)-R 17The compound according to any one of (130) to (164), or a salt, hydrate, or solvate thereof, wherein is not a leaving group and is selected from -H, -F, and -I. (171)-R 17 is not a leaving group and is selected from -H and -F, or a salt, hydrate, or solvate thereof, according to any one of (130) to (164). (172)-R 17 The compound according to any one of (130) to (164), or a salt, hydrate, or solvate thereof, wherein is not a leaving group and is —H. (173)-R 17 is a leaving group, e.g., -R 17 Ga-R X17 The compound according to any one of (130) to (164) (if applicable), or a salt, hydrate, or solvate thereof, wherein <-R 18 Base>

[0087] (174)-R 18 is selected from -H, -F, -I, a leaving group, and -NO2, or a salt, hydrate, or solvate thereof, according to any one of (130) to (173) (if applicable). (175)-R 18 -H, R X18 A compound according to any one of (130) to (173) (if applicable), or a salt, hydrate, or solvate thereof, selected from -NO2, and -NO2. (176)-R 18 -H and R X18 A compound according to any one of (130) to (173) (if applicable), or a salt, hydrate, or solvate thereof, selected from: (177)-R 18 is not a leaving group and is selected from -H, -F, -I, and -NO2, or a salt, hydrate, or solvate thereof. (178)-R 18is not a leaving group and is selected from -H and -NO2, or a salt, hydrate, or solvate thereof, according to any one of (130) to (173). (179)-R 18 The compound according to any one of (130) to (173), or a salt, hydrate, or solvate thereof, wherein is not a leaving group and is selected from -H, -F, and -I. (180)-R 18 The compound according to any one of (130) to (173), or a salt, hydrate, or solvate thereof, wherein is not a leaving group and is selected from -H and -F. (181)-R 18 The compound according to any one of (130) to (173), or a salt, hydrate, or solvate thereof, wherein is not a leaving group and is —H. (182)-R 18 is a leaving group, e.g., -R 18 Ga-R X18 The compound according to any one of (130) to (173) (if applicable), or a salt, hydrate, or solvate thereof, wherein: <Leaving group>

[0088] As used herein, the term "leaving group" refers to one of the halogen radioisotopes described herein (e.g., 18 F, 123 I, 124 I, 125 I, 131 I, and 211

[0023] The term "leaving group" represents a group suitable for functioning as a leaving group in a halogenation reaction of an aryl ring with At. For example, the leaving groups described herein are suitable for use in nucleophilic halogenation reactions, such as copper-catalyzed nucleophilic halogenation reactions (including copper-catalyzed fluorination and copper-catalyzed iodination). The term "leaving group" is defined in: IUPAC. Glossary of Chemical Terms ("Gold Book"), 2nd Edition; edited by A.D. McNaught and A. Wilkinson; Blackwell Scientific Publications, Oxford (1997); Online Edition (2019-) compiled by S.J. Chalk; ISBN 0-9678550-9-8; https: / / doi.org / 10.1351 / goldbook. Suitable leaving groups for the PQM-P compounds described herein include boronic esters, boronic acids, alkylsulfonates, haloalkylsulfonates, arylsulfonates, trialkylamines, organotin compounds, aryl iodonium salts, and arylsulfonium salts. In some embodiments, the leaving group is a nucleophilic leaving group. In some embodiments, compounds substituted with a leaving group described herein have a higher relative reactivity in a given nucleophilic substitution reaction compared to the same compound in which the leaving group has been replaced with iodide.

[0089] Just as PQM-H compounds contain only one radioisotope, PQM-P compounds also contain only one leaving group. That is, the PQM-P compounds described herein contain a leaving group at one (and not more than one) substituent position. More specifically, PQM-P compounds contain a -R X14C , -R X14D , -R X16 , -R X17 , and -R X18 (each of which is defined as a leaving group). That is, in the PQM-P compounds described herein, -R X14C , -R X14D , -R X16 , -R X17 , and -R X18 There is one of -R X14C , -R X14D , -RX16 , -R X17 , and -R X18 There is no other.

[0090] (183) The compound according to any one of (130) to (182), or a salt, hydrate, or solvate thereof, wherein the leaving group is selected from boronic acid esters, boronic acids, alkylsulfonates, haloalkylsulfonates, arylsulfonates, trialkylamines, organotin compounds, aryl iodonium salts, and arylsulfonium salts. (184) The compound according to any one of (130) to (182), or a salt, hydrate, or solvate thereof, wherein the leaving group is selected from boronic acid esters, boronic acids, trialkylamines, organotin compounds, aryl iodonium salts, and aryl sulfonium salts. (185) The compound according to any one of (130) to (182), or a salt, hydrate, or solvate thereof, wherein the leaving group is selected from boronic acid esters, boronic acids, aryl iodonium salts, and aryl sulfonium salts. (186) The compound according to any one of (130) to (182), or a salt, hydrate, or solvate thereof, wherein the leaving group is selected from boronic acid esters and boronic acids. (187) The compound according to any one of (130) to (182), or a salt, hydrate, or solvate thereof, wherein the leaving group is selected from boronic acid esters. (188) The compound according to any one of (183) to (187), or a salt, hydrate, or solvate thereof, wherein the boronic acid ester is selected from boronic acid pinacol ester (-BPin), boronic acid neopentyl glycol ester (-Bneop), boronic acid MIDA ester (-BMIDA), boronic acid catechol ester (-BCat), boronic acid hexylene glycol ester (-Bhex), and boronic acid 1,3-propanediol ester (-Bprop). (189) The compound according to any one of (183) to (187), or a salt, hydrate, or solvate thereof, wherein the boronic acid ester is selected from boronic acid pinacol ester (-BPin) and boronic acid catechol ester (-BCat). (190) The compound according to any one of (183) to (187), or a salt, hydrate, or solvate thereof, wherein the boronic acid ester is boronic acid pinacol ester (-BPin). (191) The compound according to (183), or a salt, hydrate, or solvate thereof, wherein the alkyl sulfonate is mesylate. (192) The compound according to (183), or a salt, hydrate, or solvate thereof, wherein the haloalkylsulfonate is triflate or perfluorobutylsulfonate. (193) The compound according to (183), or a salt, hydrate, or solvate thereof, wherein the haloalkylsulfonate is triflate. (194) The compound according to (183), or a salt, hydrate, or solvate thereof, wherein the arylsulfonate is tosylate. (195) Trialkylamine is -N + (C 1-6 The compound according to (183) or (184), or a salt, hydrate, or solvate thereof, wherein R is 1 or 2; (196) Trialkylamine is -N + The compound according to (183) or (184), or a salt, hydrate, or solvate thereof, wherein Me3. (197) Organotin compounds are -Sn(C 1-6 The compound according to (183) or (184), or a salt, hydrate, or solvate thereof, wherein R is 1 or 2; (198) The compound according to (183) or (184), or a salt, hydrate, or solvate thereof, wherein the organotin compound is —SnMe3. (199) Aryliodonium salts are -[PhI] + BF4 - The compound according to any one of (183) to (185), or a salt, hydrate, or solvate thereof, wherein (200) Aryl sulfonium salts are -[PhS] + TfO - The compound according to any one of (183) to (185), or a salt, hydrate, or solvate thereof, wherein (201) The leaving groups are -BPin, -B(OH)2, and -[PhI] + BF4 - , -[Ph2S] + TfO - , -SnMe3, and -N + The compound according to any one of (130) to (182), or a salt, hydrate, or solvate thereof, wherein the compound is selected from Me3. (202) The compound according to any one of (130) to (182), or a salt, hydrate, or solvate thereof, wherein the leaving group is selected from -BPin and -B(OH)2. (203) The compound according to any one of (130) to (182), or a salt, hydrate, or solvate thereof, wherein the leaving group is -BPin. (204) The compound according to any one of (130) to (182), or a salt, hydrate, or solvate thereof, wherein the leaving group is -B(OH)2. (205)-R 16 , -R 17 , or -R 18 is a leaving group, e.g., -R 16 Ga-R X16 -R 17 Ga-R X17 or -R 18 Ga-R X18 The compound according to any one of (130) to (204) (if applicable), or a salt, hydrate, or solvate thereof, wherein (206)-R 16 or -R 17 is a leaving group, e.g., -R 16 Ga-R X16 or -R 17 Ga-R X17 The compound according to any one of (130) to (204) (if applicable), or a salt, hydrate, or solvate thereof, wherein (207)-R16 or -R 18 is a leaving group, e.g., -R 16 Ga-R X16 or -R 18 Ga-R X18 The compound according to any one of (130) to (204) (if applicable), or a salt, hydrate, or solvate thereof, wherein

[0091] For the avoidance of doubt, as used herein, the term "-BPin" refers to a boronic acid pinacol ester group that can function as a leaving group, i.e., the group: [ka]

[0092] For the avoidance of doubt, as used herein, "-[PhI] + BF4 - " refers to a phenyliodonium tetrafluoroborate group that can function as a leaving group, i.e., the group: [ka]

[0093] For the avoidance of doubt, as used herein, "-[Ph2S] + TfO - The term " refers to a diarylsulfonium triflate group that can function as a leaving group, i.e., the group: [ka]

[0094] For the avoidance of doubt, -R X14C , -R X14D , -R X16 , -R X17 , and -R X18 can be individually and independently defined. Thus, each embodiment of "leaving group" described above can be defined as -RX14C , -R X14D , -R X16 , -R X17 , and -R X18 can be applied separately and independently. In one embodiment, -R X14C is a leaving group selected from boronic esters such as -BPin. X14D is a leaving group selected from boronic esters such as -BPin. X16 is a leaving group selected from boronic esters such as -BPin. X17 is a leaving group selected from boronic esters such as -BPin. X18 is a leaving group that is a boronic acid (i.e., -B(OH)2). <Some preferred combinations>

[0095] (208) -R 16 is a leaving group, e.g., -R 16 Ga-R X16 is; and -R 17 is -H, The compound according to any one of (130) to (155), or a salt or solvate thereof. (209) -R 16 is a leaving group, e.g., -R 16 Ga-R X16 is; -R 17 is -H; and -R 18 is -H or NO2; The compound according to any one of (130) to (155), or a salt, hydrate, or solvate thereof. (210) -R 16 is a leaving group, e.g., -R 16 Ga-R X16 is; -R 17 is -H;-R 18 is -H or NO2; and The leaving group is -BPin. The compound according to any one of (130) to (155), or a salt, hydrate, or solvate thereof. (211) -R 17 is a leaving group, e.g., -R 17 Ga-R X17 is; and -R 16 is -H;-R 18 is -H, The compound according to any one of (130) to (155), or a salt, hydrate, or solvate thereof. (212) -R 17 is a leaving group, e.g., -R 17 Ga-R X17 is; -R 16 is -H;-R 18 is -H; and The leaving group is -BPin. The compound according to any one of (130) to (155), or a salt, hydrate, or solvate thereof. (213) -R 16 is -H or -NO2; -R 17 is -H; and -R 18 is a leaving group, e.g., -R 18 Ga-R X18 That is, The compound according to any one of (130) to (155), or a salt, hydrate, or solvate thereof. (214) -R 16 is -H or -NO2; -R 17 is -H; -R 18 is a leaving group, e.g., -R 18 Ga-R X18 is; and The leaving group is -BPin. The compound according to any one of (130) to (155), or a salt, hydrate, or solvate thereof. (215) -R 14C If present, -H, -F, or -R X14C is; -R 14D If present, one -R X14D phenyl optionally substituted with a group; -R 16 is independently selected from -H, -F, -I, and -NO2; -R 17 is independently selected from -H, -F, -I, and -NO2; and -R 18 are independently selected from -H, -F, -I, and -NO2; The compound according to any one of (130) to (155), or a salt, hydrate, or solvate thereof. (216) -R 14C If present, -H, -F, or -R X14C is; -R 14D If present, one -R X14D phenyl optionally substituted with a group; -R 14 is independently selected from -H, -F, -I, and -NO2; -R 14 is independently selected from -H, -F, -I, and -NO2; -R 14 is independently selected from -H, -F, -I, and -NO2; -R X14C is a leaving group selected from boronic esters, boronic acids, trialkylamines, organotin compounds, aryl iodonium salts, and aryl sulfonium salts; and -R X14D is a leaving group selected from boronic esters, boronic acids, trialkylamines, organotin compounds, aryl iodonium salts, and aryl sulfonium salts; The compound according to any one of (130) to (155), or a salt, hydrate, or solvate thereof. (217) -R14C If present, -H, -F, or -R X14C is; -R 14D If present, one -R X14D phenyl optionally substituted with a group; -R 16 is independently selected from -H, -F, -I, and -NO2; -R 17 is independently selected from -H, -F, -I, and -NO2; -R 18 is independently selected from -H, -F, -I, and -NO2; -R X14C is a leaving group selected from -BPin and -B(OH)2; and -R X14D is a leaving group selected from -BPin and -B(OH)2; The compound according to any one of (130) to (155), or a salt, hydrate, or solvate thereof. (218) -R 14 but, [ka] is; and -R 14D There is one -R X14D phenyl substituted with a group; (130) A compound according to (130), or a salt, hydrate, or solvate thereof. (219) -R 14 but, [ka] is; -R 14D There is one -R X14D phenyl substituted with a group; (130) A compound according to (130), or a salt, hydrate, or solvate thereof; (220) -R 14 but, [ka] is; -R 14D There is one -R X14D phenyl substituted with a group; -R 16 is -H;-R 17 is -H; and -R 18 is -H, (130) A compound according to (130), or a salt, hydrate, or solvate thereof. (221) -R 14 but, [ka] is; -R 14D There is one -R X14D phenyl substituted with a group; -L 11 - is -S(O)2-; -R 1L C 1-6 alkyl; and -R 16 is -H;-R 17 is -H; and -R 18 is -H, (130) A compound according to (130), or a salt, hydrate, or solvate thereof. (222) -R 14 but, [ka] is; -R 14D There is one -R X14D phenyl substituted with a group; -L 11 - is -S(O)2-; -R 1L C 1-6 alkyl; and -R 16 is -H;-R 17 is -H;-R 18 is -H; and -R X14Dis a leaving group selected from boronic esters and boronic acids; (130) A compound according to (130), or a salt, hydrate, or solvate thereof. (223) -R 14 but, [ka] is; and -R 16 is a leaving group, e.g., -R 16 Ga-R X16 That is, (130) A compound according to (130), or a salt, hydrate, or solvate thereof. (224) -R 14 but, [ka] is; -R 14A and -R 14B together with the carbon atoms to which they are attached, C 3-5 Forming a cycloalkyl; -R 14C is -H; and -R 16 is a leaving group, e.g., -R 16 Ga-R X16 That is, (130) A compound according to (130), or a salt, hydrate, or solvate thereof. (225) -R 14 but, [ka] is; -R 14A and -R 14B together with the carbon atoms to which they are attached, C 3-5 Forming a cycloalkyl; -R 14C is -H; -L 11 - is -S(O)2-; -R 1L C 1-6alkyl; and -R 16 is a leaving group, e.g., -R 16 Ga-R X16 That is, (130) A compound according to (130), or a salt, hydrate, or solvate thereof. (226) -R 14 but, [ka] is; -R 14A and -R 14B together with the carbon atoms to which they are attached, C 3-5 Forming a cycloalkyl; -R 14C is -H; -L 11 - is -S(O)2-; -R 1L C 1-6 selected from alkyl; -R 17 is -H;-R 18 is -H; and -R 16 is a leaving group, e.g., -R 16 Ga-R X16 That is, (130) A compound according to (130), or a salt, hydrate, or solvate thereof. (227) -R 14 but, [ka] is; -R 14A and -R 14B together with the carbon atoms to which they are attached, C 3-5 Forming a cycloalkyl; -R 14C is -H;-L 11 - is -S(O)2-; -R 1L C 1-6 selected from alkyl; -R 17 is -H;-R18 is -H; -R 16 is a leaving group, e.g., -R 16 Ga-R X16 is; and the leaving group is selected from boronic esters, boronic acids, trialkylamines, organotin compounds, aryl iodonium salts, and aryl sulfonium salts; (130) A compound according to (130), or a salt, hydrate, or solvate thereof. (228) -R 14 but, [ka] is; -R 14A and -R 14B together with the carbon atoms to which they are attached, C 3-5 Forming a cycloalkyl; -R 14C is -H; -L 11 - is -S(O)2-; -R 1L C 1-6 selected from alkyl; -R 17 is -H;-R 18 is -H; -R 16 is a leaving group, e.g., -R 16 Ga-R X16 is; and The leaving groups are -BPin, -B(OH)2, and -[PhI] + BF4 - , -[Ph2S] + TfO - , -SnMe3, and -N + Me3, or a salt, hydrate, or solvate thereof. <Specific compound>

[0096] (229) The compound according to (130), selected from compounds of the following formulae, and salts, hydrates, and solvates thereof: [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] (230) The compound according to (130), selected from compounds of the following formulae, and salts, hydrates, and solvates thereof: [Table 5-1] [Table 5-2] [Table 5-3] (231) The compound according to (130) below: [Table 6] (232) The compound according to (130), which is 1-[4-[3-(4-methylsulfonylpiperazine-1-carbonyl)-8-nitro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-quinolyl]phenyl]cyclopropanecarbonitrile (PQM-P-007). (233) The compound according to (130), which is [4-[4-(1-cyanocyclopropyl)phenyl]-3-(4-methylsulfonylpiperazine-1-carbonyl)-8-quinolyl]boronic acid (PQM-P-020). (234) The compound according to (130), which is 1-[3-(4-methylsulfonylpiperazine-1-carbonyl)-4-quinolyl]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-4-carbonitrile (PQM-P-031). For the avoidance of doubt:

[0097] "C 9-10 Heteroaryl, C 3-7 Index "C" in terms such as "heterocyclyl" x-y " refers to the number of ring atoms, which may be carbon atoms or heteroatoms (e.g., optionally N, O, S). For example, pyridyl is an example of a C6 heteroaryl group, and piperidino is an example of a C6 heterocyclyl group.

[0098] Unless otherwise indicated, when a compound is shown or described as having one or more chiral centers and thus capable of two or more stereoisomers, all such stereoisomers are disclosed and encompassed, individually (e.g., isolated from other stereoisomers) and in admixture (e.g., equimolar or non-equimolar mixtures of two or more stereoisomers). For example, unless otherwise indicated, if a compound has one chiral center, each of the (R) and (S) enantiomers is disclosed and encompassed, individually (e.g., isolated from other enantiomers) and in admixture (e.g., equimolar or non-equimolar mixtures of the two enantiomers). For example, the first carbon atom of the side chain sec-butyl group, —CH(CH3)CH2CH3, is typically chiral and therefore, when it is the only chiral center, gives rise to stereoisomers such as the (R) and (S) enantiomers, each of which is disclosed and encompassed.

[0099] In certain cases, a later embodiment may refer to an earlier embodiment and describe a feature that is not permitted in the earlier embodiment. In such cases, the term "if present" may be used after the feature described in the later embodiment to indicate that the definition of the later embodiment applies only to the earlier embodiment in which the feature is permitted (i.e., only to the earlier embodiment in which the same feature is present in the definition). For example, if an embodiment is -R 4 -R 4A , -R 4B , and -R 4C When defined as a phenyl variant containing -R 4D piperidinyl-R 4 Variants do not exist in this embodiment. 4D (Piperidinyl variant - R 4 (existing only in -R 4 to the phenyl variant (-R 4D A later embodiment that references a prior embodiment in which a compound is defined as "is not present" uses the term "if present" to indicate that the feature of the later embodiment is applicable only to the prior embodiment in which that same feature is permitted (i.e., present in the definition of the compound).

[0100] Similarly, a particular definition set forth in an embodiment may refer to a feature present in a prior embodiment, but defines that feature in a manner that is not applicable in light of the prior embodiment (e.g., broader or different than the definition used in the prior embodiment). For example, in some embodiments, -R 4C The group can be -H or -F, and in other embodiments, -R 4C is furthermore a radioactive isotope -R X4C -R X4C This latter contains -R 4C The definition of -R 4C This is different from the previous embodiment, which allows for -R to be only -H or -F. In such cases, the phrase "where applicable" means that the definition set forth in that embodiment applies to the definition of that feature (e.g., -R 4C is used to indicate that the definition of applies only to the preceding embodiment. <Combination>

[0101] It will be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. 4 , -L 1 -, -R 6 All combinations of embodiments relating to chemical groups represented by formulas such as (a), (b), (c), (d), (e), (e), (f), (g), (h), (i), (i), (j ... Substantially Purified Form

[0102] One aspect of the present invention pertains to the PQM-H or PQM-P compounds described herein in substantially purified and / or substantially contaminant-free form.

[0103] In one embodiment, the substantially purified form contains at least 50% by weight, such as at least 60% by weight, such as at least 70% by weight, such as at least 80% by weight, such as at least 90% by weight, such as at least 95% by weight, such as at least 97% by weight, such as at least 98% by weight, for example at least 99% by weight of the desired compound relative to other components.

[0104] Unless otherwise specified, a substantially purified form refers to a desired compound in any stereoisomeric or enantiomeric form. For example, in one embodiment, a substantially purified form refers to a mixture of stereoisomers, i.e., purified relative to other compounds. In one embodiment, a substantially purified form refers to a single stereoisomer, e.g., an optically pure stereoisomer. In one embodiment, a substantially purified form refers to a mixture of enantiomers. In one embodiment, a substantially purified form refers to an equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, a substantially purified form refers to a single enantiomer, e.g., an optically pure enantiomer. In one embodiment, a substantially purified form refers to a compound containing a particular isotope, e.g., a compound containing a given radioisotope at a given position as opposed to other atoms (e.g., non-radioactive isotopes or products of radioactive decay).

[0105] In one embodiment, the contaminants do not exceed 50% by weight, such as not exceeding 40% by weight, for example not exceeding 30% by weight, such as not exceeding 20% ​​by weight, for example not exceeding 10% by weight, such as not exceeding 5% by weight, for example not exceeding 3% by weight, such as not exceeding 2% by weight, for example not exceeding 1% by weight.

[0106] Unless specified, contaminants refer to other compounds, i.e., other than stereoisomers or enantiomers. In one embodiment, contaminants refer to other compounds and other stereoisomers. In one embodiment, contaminants refer to other compounds and other enantiomers. In one embodiment, contaminants refer to non-radioactive isotopes, decay products, or compounds containing unwanted radioactive isotopes.

[0107] In one embodiment, the substantially purified form is at least 60% optically pure (i.e., on a molar basis, 60% of the compound is the desired stereoisomer or enantiomer and 40% is the undesired stereoisomer or enantiomer), for example, at least 70% optically pure, for example, at least 80% optically pure, for example, at least 90% optically pure, for example, at least 95% optically pure, for example, at least 97% optically pure, for example, at least 98% optically pure, for example, at least 99% optically pure. <Isomers>

[0108] Certain compounds may exist in one or more specific geometric isomers, optical isomers, enantiomers, diastereomeric isomers, epimeric isomers, atropisomers, stereoisomers, tautomeric isomers, conformational isomers, or anomeric isomers, including, but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r-forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+)- and (-)-forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; α- and β-forms; axial- and equatorial-forms; boat-, chair-, twist-, envelope-, and half-chair-forms; and combinations thereof (collectively referred to herein as "isomers" (or "isomeric forms")).

[0109] Reference to a structural class may include structural isomeric forms contained within that class (e.g., C 1-7 Alkyl includes n-propyl and isopropyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl). However, reference to a particular group or substitution pattern is not intended to include other structural (or constitutional) isomers that differ with respect to the bonding between atoms, rather than spatial position. For example, a reference to a methoxy group, -OCH3, should not be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a specific reference to ortho-chlorophenyl should not be construed as a reference to its structural isomer, meta-chlorophenyl.

[0110] The above exclusion does not apply to tautomeric forms, such as keto, enol, and enolate. For example, there are the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, N-nitroso / hydroxyazo, and nitro / acinitro. Reference herein to one tautomer is intended to encompass both tautomers. [ka]

[0111] For example, 1H-pyridin-2-one-5-yl and 2-hydroxy-pyridin-5-yl (shown below) are tautomers of each other, and reference to one herein is intended to encompass both.

[0112] [ka]

[0113] It should be noted that specifically included in the term "isomer" are compounds with one or more isotopic substitutions where the atomic mass of a particular atom has not yet been given. For example, -H is 1 H, 2 H(D), and 3 H can be in any isotopic form, including T; C can be in any isotopic form, including T; 12 C. 13 C, and 14It can be any isotopic form, including C; O is 16 O and 18 It should be noted, however, that when the atomic mass of a particular atom is defined, such as in the case of a radioisotope, the structural formula does not assume isotopic substitution at that position. For example, if a position is 18 If the fluorine atom is defined as F, 19 It is not expected to be replaced by other isotopes such as F.

[0114] In this context, as used herein, when a substituent position is defined to be a "radioisotope", the substituent at that position may be, for example, 18 F, 123 I, 124 I, 125 I, 131 I, or 211 Enriched in a radioisotope, such as At, means that the amount of the compound contains the radioisotope in an amount greater than the natural abundance of the radioisotope.

[0115] Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including mixtures thereof (e.g., racemic mixtures). Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallization and chromatographic means) of such isomeric forms are either already known in the art or are readily obtained by the adaptation of known methods in known manners. <Salt>

[0116] It may be convenient or desirable to prepare, purify, and / or handle the corresponding salt of a compound, e.g., a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts are described in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19.

[0117] For example, if the compound is anionic, or if a functional group that can be anionic (e.g., -COOH can be replaced with -COO In the case of a compound having a cation, it can be salted with a suitable cation. Examples of suitable inorganic cations include Na + and K. + Alkali metal ions such as Ca 2+ and Mg 2+ alkaline earth cations such as Al 3+ Other cations such as ammonium ions (i.e., NH4 + Examples of suitable organic cations include, but are not limited to, substituted ammonium ions (e.g., NHR + , NH2R2 + , NHR3 + , NR4 + ) For example, each R is independently a linear or branched saturated C 1-18 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl-C 1-6 Alkyl and phenyl-C 1-6 Examples of suitable substituted ammonium ions include, but are not limited to, ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as those derived from amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4. + is.

[0118] If the compound is cationic, or if it has a functional group that can be made cationic by protonation (e.g., -NH2 becomes -NH3 + When the compound has a structure such as

[0119] For example, if the parent structure is a cationic group (e.g., -NMe2 +), or functional groups that can be protonated to become cationic (e.g., -NH2 to -NH3 + In the case of quaternary ammonium compounds, a counter anion is generally always present to neutralize the positive charge. + , -NH3 + If, in addition to the aryl group, the compound contains a group that can form an anion (e.g., —COOH), an internal salt (also known as a zwitterion) can be formed.

[0120] Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, and phosphorous acid.

[0121] Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyloxybenzoic acid, acetic acid, trifluoroacetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, edetic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthalenecarboxylic acid, isethionic acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, methanesulfonic acid, mucoic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, pantothenic acid, phenylacetic acid, phenylsulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, toluenesulfonic acid, and valeric acid. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

[0122] Quaternary ammonium compounds (e.g., -NMe2 +Examples of suitable counterions, particularly suitable for amines (those containing a -COOH group), include 1-adamantanesulfonate, benzenesulfonate, bisulfate, bromide, chloride, iodide, methanesulfonate, methylsulfate, 1,5-naphthalene-bis-sulfonate, 4-nitrobenzenesulfonate, formate, tartrate, tosylate, trifluoroacetate, trifluoromethylsulfonate, and sulfate. Again, if the compound contains a group capable of forming an anion (e.g., -COOH), an internal salt may be formed.

[0123] Unless otherwise specified, a reference to a particular compound also includes its salt forms. <Solvates and hydrates>

[0124] It may be convenient or desirable to prepare, purify, and / or handle a corresponding solvate of a compound. The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. When the solvent is water, the solvate may be conveniently referred to as a hydrate, e.g., a monohydrate, a dihydrate, a trihydrate, etc.

[0125] Unless otherwise specified, a reference to a particular compound also includes solvated and hydrated forms thereof.

[0126] <Chemically protected form>

[0127] It may be convenient or desirable to prepare, purify, and / or handle a compound in a chemically protected form. The term "chemically protected form" is used herein in its conventional chemical sense to refer to a compound in which one or more reactive functional groups are protected from undesired chemical reactions under certain conditions (e.g., pH, temperature, radiation, solvent, etc.). In practice, well-known chemical methods are used to reversibly render functional groups that would otherwise be reactive under certain conditions unreactive. In a chemically protected form, one or more reactive functional groups are in the form of protected or protective groups (or masked or blocked groups). Protecting a reactive functional group allows reactions involving other unprotected reactive functional groups to occur without affecting the protected groups; protecting groups can usually be removed or masked groups converted in a subsequent step without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2006).

[0128] Various such "protecting," "blocking," or "masking" methods are widely used and well known in organic synthesis. For example, a compound having two unequal reactive functional groups that are reactive under certain conditions can be derivatized to "protect" one of the functional groups, thereby rendering it unreactive under the specified conditions; thus protected, the compound can be used as a reactant having essentially only one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group can be "deprotected" to restore its original functionality.

[0129] For example, a hydroxy group can be protected as an ether (-OR) or ester (-OC(=O)R), e.g., as a t-butyl ether; as a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; as a trimethylsilyl or t-butyldimethylsilyl ether; or as an acetyl ester (-OC(=O)CH3, -OAc).

[0130] For example, aldehyde or ketone groups can be protected as acetals (R-CH(OR)2) or ketals (RC(OR)2), respectively. In this case, the carbonyl group (>C=O) is converted to a 1,1-diether (>C(OR)2), for example, by reaction with a primary alcohol in the presence of acid. The aldehyde or ketone group is readily regenerated, for example, by hydrolysis with water in the presence of acid.

[0131] For example, amino groups can be represented, for example, as amides (-NRCO-R) or urethanes (-NRCO-OR), for example, as acetamides (-NHCO-CH3); benzyloxyamides (-NHCO-OCH2C6H5, -NH-Cbz); t-butoxyamides (-NHCO-OC(CH3)3, -NH-Boc); 2-biphenyl-2-propoxyamides (-NHCO-OC(CH3)2C6H4C6H5, -NH-Bpoc); 9-fluorenylmethoxyamides (-N H-Fmoc), as 6-nitroveratryloxyamide (-NH-Nvoc), as 2-trimethylsilylethyloxyamide (-NH-Teoc), as 2,2,2-trichloroethyloxyamide (-NH-Troc), as allyloxyamide (-NH-Alloc), as 2(-phenylsulfonyl)ethyloxyamide (-NH-Psec); or, where appropriate (e.g., cyclic amines), as the nitroxide radical (>NO·).

[0132] For example, a carboxylic acid group can be protected as an ester, e.g., as follows: 1-7As alkyl esters (e.g., methyl esters; t-butyl esters); C 1-7 As haloalkyl esters (e.g., 2,2,2-trihaloethyl esters); 2-tri(C 1-7 alkyl)silyl-ethyl ester; or C 5-20 Aryl-C 1-7 It can be protected as an alkyl ester (eg, benzyl ester; nitrobenzyl ester), or as an amide or hydrazide, for example, as acetamide or N,N,N'-trimethylhydrazide.

[0133] For example, thiol groups can be protected as thioethers (-SR), e.g., as benzyl thioethers; as acetamidomethyl ethers (-S-CH2NHC(=O)CH3). <Prodrug>

[0134] It may be convenient or desirable to prepare, purify, and / or handle compounds in the form of a prodrug. As used herein, the term "prodrug" refers to a compound that yields the desired active compound in vivo. Typically, prodrugs are inactive or less active than the desired active compound, but may offer advantageous handling, administration, or metabolic properties.

[0135] For example, some prodrugs are esters of active compounds (e.g., physiologically acceptable metabolically labile esters). During metabolism, the ester group (-C(=O)OR) is cleaved to yield the active drug. Such esters can be formed, for example, by esterifying any carboxylic acid group (-C(=O)OH) in the parent compound, optionally after first protecting and optionally deprotecting any other reactive groups present in the parent compound.

[0136] Additionally, some prodrugs are enzymatically activated to yield the active compound, or to yield a compound that, upon further chemical reaction, yields the active compound (e.g., antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT), lipid-directed enzyme prodrug therapy (LIDEPT), etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative. <Composition>

[0137] One aspect of the present invention pertains to compositions (eg, pharmaceutical compositions) comprising a PQM-H compound described herein and a pharmaceutically acceptable carrier, diluent, or excipient.

[0138] Another aspect of the present invention relates to a method for preparing a composition (e.g., a pharmaceutical composition) comprising mixing a PQM-H compound described herein and a pharmaceutically acceptable carrier, diluent, or excipient. <Application>

[0139] The PQM-H compounds described herein are useful in molecular imaging methods, such as molecular medical imaging methods, of cells expressing ALDH1A1. In particular, the PQM-H compounds are suitable for imaging of cells expressing ALDH1A1 by PET, SPECT, and / or scintigraphy.

[0140] The PQM-H compounds described herein are useful, for example, in the treatment of cancer (as "anti-cancer agents," particularly for radiation therapy).

[0141] The PQM-P compounds described herein are useful in methods for making PQM-H compounds. <Medical imaging method>

[0142] Another aspect of the present invention relates to a method of medical imaging (e.g., a method of imaging a cell population expressing ALDH1A1) comprising administering (i.e., delivering) a PQM-H compound described herein to a subject and then imaging the subject by PET, SPECT, or scintigraphy.

[0143] The medical imaging methods described herein are molecular imaging methods.

[0144] In one embodiment, the subject is imaged by PET. In one embodiment, the subject is imaged by SPECT. In one embodiment, the subject is imaged by scintigraphy.

[0145] PET, SPECT, and scintigraphy each rely on the detection and counting of gamma photons. Without being bound by theory, in some embodiments, the PQM-H compounds described herein, after administration to a subject, accumulate at a target site, for example, a cell population expressing ALDH1A1 (such as a cancer cell population), causing the emission of gamma photons from the site (e.g., by annihilation after positron emission, by gamma decay, as a result of electron capture, or through the subsequent decay of a daughter isotope). The target cell population expressing ALDH1A1 in which the PQM-H compound has accumulated can be detected by collecting the emitted gamma photons, for example, through imaging of the subject by PET, SPECT, or scintigraphy.

[0146] In one embodiment, the medical imaging method further comprises the step of incorporating a radioisotope into the PQM-H compound, for example by suitable reaction with the corresponding PQM-P compound. <Use in diagnostic methods>

[0147] Another aspect of the present invention relates to PQM-H compounds as described herein for use in methods for diagnosing disorders (e.g., diseases) of the human or animal body, e.g., for use in methods for diagnosing disorders (e.g., diseases) as described herein. <Diagnostic method>

[0148] Another aspect of the present invention relates to a method of diagnosis, e.g., a method of diagnosing a disorder (e.g., a disease) described herein, comprising administering to a subject an effective amount of a PQM-H compound described herein, preferably in the form of a pharmaceutical composition.

[0149] In one embodiment, the diagnostic method comprises performing a medical imaging method described herein on a subject.

[0150] In one embodiment, the subject is imaged by PET. In one embodiment, the subject is imaged by SPECT. In one embodiment, the subject is imaged by scintigraphy.

[0151] In one embodiment, the diagnostic method further comprises examining images produced by the medical imaging method to identify locations where the PQM-H compound has accumulated.

[0152] In one embodiment, the diagnostic method further comprises processing the image and comparing it with a standard value to determine the level of accumulation of the PQM-H compound at the identified location.

[0153] In one embodiment, the method further comprises attributing the difference in the accumulation level of the PQM-H compound to a disease (e.g., a condition described herein). In one embodiment, increased accumulation of the PQM-H compound at a location is attributable to a cancer cell population.

[0154] In one embodiment, the cancer cell population is therapy-resistant cancer cells. <Use in treatment methods>

[0155] Another aspect of the present invention relates to the use of the PQM-H compounds described herein, for example, for use in a method of treating a human or animal body by therapy, such as in a method of treating a disease (e.g., disorder) described herein. <Use in the manufacture of a pharmaceutical>

[0156] Another aspect of the present invention relates to the use of the PQM-H compounds described herein in the manufacture of a pharmaceutical, for example, for use in a method of treatment, such as in a method of treating a disease (e.g., disorder) described herein.

[0157] In one embodiment, the pharmaceutical comprises a PQM-H compound. <Method of treatment>

[0158] Another aspect of the present invention relates to a method of treatment, for example, of a disease (e.g., disorder) described herein, comprising administering to a subject in need of treatment a therapeutically effective amount of the PQM-H compound described herein, preferably in the form of a pharmaceutical composition. <Diseases related to ALDH>

[0159] In one embodiment (e.g., use in a diagnostic method, method of diagnosis, use in a method of treatment, use in the manufacture of a pharmaceutical, method of treatment), the disease is a disease (e.g., disorder) related to ALDH, particularly a disease (e.g., disorder) related to ALDH1A1; a disease (e.g., disorder) resulting from inappropriate activity of ALDH, particularly a disease (e.g., disorder) resulting from inappropriate activity of ALDH1A1; a disease (e.g., disorder) related to an ALDH mutation, particularly a disease (e.g., disorder) related to an ALDH1A1 mutation; a disease (e.g., disorder) related to overexpression of ALDH, particularly a disease (e.g., disorder) related to overexpression of ALDH1A1; a disease (e.g., disorder) improved by inhibition (e.g., selective inhibition) of ALDH, particularly a disease (e.g., disorder) improved by inhibition (e.g., selective inhibition) of ALDH1A1.

[0160] In one embodiment (e.g., use in diagnostic methods, methods of diagnosis, use in therapeutic methods, use in the manufacture of pharmaceuticals, methods of treatment), the disease is an ALDH-associated disease (e.g., a disorder), particularly an ALDH1A1-associated disease (e.g., a disorder).

[0161] In one embodiment, the disorder is a disorder (eg, a disease) caused by inappropriate activity of ALDH, particularly a disorder (eg, a disease) caused by inappropriate activity of ALDH1A1.

[0162] In one embodiment, the disease is a disease (e.g., a disease) associated with an ALDH mutation, particularly a disease (e.g., a disease) associated with an ALDH1A1 mutation; a disease (e.g., a disease) associated with ALDH overexpression, particularly a disease (e.g., a disease) associated with ALDH1A1 overexpression (e.g., compared to a corresponding normal cell; e.g., overexpression is 1.5-fold, 2-fold, 3-fold, 5-fold, 10-fold, 20-fold, or 50-fold); or a disease (e.g., a disease) associated with activation of the upstream pathway of ALDH, particularly a disease (e.g., a disease) associated with activation of the upstream pathway of ALDH1A1.

[0163] In some embodiments, the disease is a disorder (eg, a disease) associated with ALDH overexpression regulated through epigenetic regulation, particularly ALDH1A1 overexpression regulated through epigenetic regulation.

[0164] In one embodiment, the disease is a disease (e.g., a disorder) that is ameliorated by the inhibition (e.g., selective inhibition) of ALDH, particularly a disease (e.g., a disorder) that is ameliorated by the inhibition (e.g., selective inhibition) of ALDH1A1. <Specific diseases>

[0165] In one embodiment (eg, use in diagnostic methods, methods of diagnosis, use in therapeutic methods, use in the manufacture of medicaments, methods of treatment), the disease is cancer, eg, treatment-resistant cancer.

[0166] In one embodiment (eg, use in diagnostic methods, methods of diagnosis, use in therapeutic methods, use in the manufacture of medicaments, methods of treatment), the condition is a treatment-resistant condition (eg, a disease).

[0167] In one embodiment, a treatment-resistant disease is a disease (eg, illness) in a patient who has previously received therapeutic treatment but derives little or no clinical benefit from those treatments.

[0168] This includes, for example, patients who have been previously treated therapeutically with standard of care.

[0169] In one embodiment, the treatment-resistant disease is treatment-resistant cancer. In one embodiment, a treatment-resistant cancer is a cancer that does not respond (e.g., decrease in size, slow down in replication, go into remission, etc.) to a clinically approved treatment. In one embodiment, the clinically approved treatment is the standard of care. In one embodiment, the standard of care is chemotherapy. In one embodiment, the standard of care is radiation therapy. In one embodiment, the standard of care is a targeted therapy. In one embodiment, chemotherapy includes treatment with an agent selected from cyclophosphamide, platinum-based therapy, gemcitabine, paclitaxel, etoposide, doxorubicin, 5-fluorouracil, or a combination thereof. In one embodiment, the chemotherapy includes treatment with cyclophosphamide, a drug that is directly detoxified by ALDH1A1. In one embodiment, the targeted therapy is selected from a PARP inhibitor, a CDK inhibitor, and / or a HER2-directed therapy. In one embodiment (eg, use in diagnostic methods, methods of diagnosis, use in therapeutic methods, use in the manufacture of medicaments, methods of treatment), the disease is cancer. In one embodiment, the cancer is a treatment-resistant cancer. In one embodiment, the cancer is cancer metastasis.

[0170] Cancers include: (1) Epithelial cancer, including tumors arising from stratified squamous epithelium (squamous cell carcinoma) and tumors arising within organs or glands (adenocarcinoma). Examples include breast, colon, lung, prostate, and ovary. (2) Sarcomas, including osteosarcoma and osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (skeletal muscle); mesosarcoma and mesothelioma (membranous lining of body cavities); fibrosarcoma (fibrous tissue); angiosarcoma and hemangioendothelioma (blood vessels); liposarcoma (fatty tissue); glioma and astrocytoma (neurogenic connective tissue in the brain); myxosarcoma (primitive embryonic connective tissue); mesenchymal tumor and mixed mesodermal tumor (mixed connective tissue). (3) Myeloma. (4) Myeloid and granulocytic leukemias (malignant tumors of the myeloid and granulocytic leukemia lineages), e.g., chronic myeloid leukemia (CML), acute myeloid leukemia (AML); lymphoid, lymphocytic, and lymphoblastic leukemias (malignant tumors of lymphocytes and lymphocytic blood cells), e.g., acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL); hematopoietic tumors, including polycythemia vera (malignant tumors of various blood cell products, but with a predominance of red blood cells). (5) Lymphoma, including Hodgkin's lymphoma and non-Hodgkin's lymphoma. (6) Mixed types, including, for example, adenosquamous carcinoma; mixed mesodermal tumor; carcinosarcoma; and teratocarcinoma.

[0171] For example, in one embodiment, the disease is breast cancer, ovarian cancer, prostate cancer, colon cancer, lung cancer, pancreatic cancer, lymphoma, and / or head and neck cancer.

[0172] In one embodiment, the disease is breast cancer. In one embodiment, the disease is ovarian cancer. In one embodiment, the disease is prostate cancer. In one embodiment, the disease is colon cancer. In one embodiment, the disease is lung cancer. In one embodiment, the disease is pancreatic cancer. In one embodiment, the disease is lymphoma. In one embodiment, the disease is head and neck cancer. In one embodiment, the cancer is associated with ALDH, particularly ALDH1A1. In one embodiment, the cancer is characterized or further characterized by inappropriate activity of ALDH, particularly inappropriate activity of ALDH1A1. In one embodiment, the cancer is characterized or further characterized by overexpression of ALDH, particularly overexpression of ALDH1A1. In one embodiment, the cancer is characterized or further characterized by amplification of the ALDH1A1 gene.

[0173] With respect to treatment, anti-cancer effects may occur through one or more mechanisms, including, but not limited to, radiotherapeutic effects (e.g., damage to cellular DNA due to the release of ionizing radiation), inhibition of mechanisms of therapeutic resistance (i.e., enhancing the effects of concomitantly administered anti-cancer drugs), control of cell proliferation, inhibition of cell cycle progression, inhibition of angiogenesis (the formation of new blood vessels), inhibition of metastasis (the spread of tumors from their source), inhibition of cell migration (the spread of cancer cells to other parts of the body), inhibition of invasion (the spread of tumor cells into surrounding normal structures), promotion of apoptosis (programmed cell death), induction of necrotic death, or autophagic death. The compounds described herein can be used in the treatment of cancers described herein regardless of the mechanisms described herein.

[0174] As one of skill in the art will appreciate, certain PQM-H compounds may be applicable to a variety of diseases for imaging use, as opposed to therapeutic use. <Measures>

[0175] As used herein, the term "treatment" in the context of treating a disease generally relates to the treatment of a human or animal (e.g., in veterinary applications) to achieve some desired therapeutic effect, e.g., inhibition of disease progression, including reducing the rate of disease progression, halting the rate of disease progression, alleviating symptoms of disease, ameliorating the disease, and curing the disease. Treatment as a preventative measure (i.e., prophylaxis) is also included. For example, use in patients who have not yet developed the disease but are at risk of developing the disease is encompassed by the term "treatment."

[0176] For example, treatment includes preventing cancer, reducing the incidence of cancer, alleviating the symptoms of cancer, and the like.

[0177] The term "therapeutically effective amount," as used herein, relates to an amount of a compound, or a substance, composition, or dosage form containing a compound, that is effective to produce some desired therapeutic effect when administered in accordance with a desired treatment regimen, commensurate with a reasonable benefit / risk ratio. <Combination therapy>

[0178] The term "treatment" includes combination treatments and therapies, in which two or more treatments or therapies are combined, e.g., sequentially or simultaneously. For example, the compounds described herein can be used in combination therapy, e.g., in combination with other agents. Examples of treatments and therapies include chemotherapy (e.g., including administration of active agents, including drugs, antibodies (e.g., as in immunotherapy); prodrugs (e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.)); surgery; radiation therapy; photodynamic therapy; gene therapy; and controlled diets.

[0179] One aspect of the present invention pertains to compounds described herein in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents, as described below. The particular combination is left to the discretion of the physician, who will select the dosages using his or her general knowledge and dosing regimens known to skilled physicians.

[0180] The agents (i.e., a compound described herein and one or more other agents) can be administered simultaneously or sequentially, and can be administered via individually varying dosing schedules and various routes. For example, when administered sequentially, the agents can be administered closely spaced (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1, 2, 3, 4 hours or more apart, or even longer periods apart if necessary), with the exact dosing regimen commensurate with the properties of the therapeutic agents.

[0181] The agents (i.e., a compound described herein and one or more other agents) may be formulated together in a single dosage form, or the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use.

[0182] Examples of additional drugs / therapies that can be administered / combined with treatment with the PQM-H compounds described herein include: aromatase inhibitors, such as exemestane (also known as Aromasin), letrozole (also known as Femara), and anastrozole (also known as Arimidex); Antiestrogens, such as Faslodex (also known as Fulvestrant and ICI182780), Tamoxifen (also known as Nolvadex), Hydroxytamoxifen, etc.; antiandrogens, for example, antiandrogens used in the treatment of prostate cancer, such as flutamide, enzalutamide, apalutamide, bicalutamide, nilutamide, etc.; Her2 blockers, such as Herceptin, pertuzumab, and lapatinib; Cytotoxic chemotherapeutic agents, such as taxanes (e.g., paclitaxel, also known as taxol; docetaxel, also known as taxotere), cyclophosphamide, antimetabolites (e.g., carboplatin, capecitabine, gemcitabine, doxorubicin, epirubicin, 5-fluorouracil, etc.); Agents that stimulate the immune system, such as Toll-like receptor (TLR1-13) agonists, stimulator of interferon genes (STING) agonists, etc.; Checkpoint inhibitors, such as inhibitors of PD1, PD1L, and CTLA4, for example, pembrolizumab, atezolizumab, and ipilimumab; DNA repair inhibitors, for example, PARP inhibitors, such as olaparib, niraparib, etc.

[0183] Thus, in one embodiment, the treatment further comprises treatment with another active agent (e.g., simultaneous or sequential treatment), such as, for example, an aromatase inhibitor, an anti-estrogen, an anti-androgen, a Her2 blocker, a cytotoxic chemotherapeutic agent, an immune system stimulating agent, a checkpoint inhibitor, a DNA repair inhibitor, etc.

[0184] In one embodiment, two or more different PQM-H compounds may be administered simultaneously or sequentially.

[0185] In one embodiment, a radioisotope that decays by positron emission or gamma decay (e.g., 18 F, 125 A first PQM-H compound containing a radioisotope (e.g., I) that decays by alpha or beta particle emission is then administered to the subject; 131 I, 211 A second PQM-H compound containing ALDH, e.g., At, can be administered to the subject. In this way, the state of the disease (including the presence of ALDH, e.g., the presence of ALDH1A1) can be determined, for example, by the medical imaging methods described herein after administration of the first PQM-H compound; the disease can then be treated by radiation therapy via administration of the second PQM-H compound.

[0186] Optionally, after administration of the second PQM-H compound, an additional dose of the first PQM-H compound is administered to the subject. In this manner, the effectiveness of the treatment can be actively monitored via the second administration of the first PQM-H compound, for example, by the medical imaging methods described herein.

[0187] The subject can be subjected to an additional cycle of treatment with a second PQM-H compound and monitoring of the treatment effect with a first PQM-H compound. In these cycles, the first and second PQM-H compounds can be administered simultaneously or sequentially.

[0188] In one embodiment, a second PQM-H compound containing a radioisotope that decays by alpha particle emission or beta particle emission (e.g., 131 I, 211 At, etc.) can be administered (simultaneously or sequentially) in combination with a first PQM-H compound containing a radioisotope that decays by positron emission or gamma decay (e.g., 18 F, 125 I, etc.). In this way, the second PQM-H compound can treat the disease by radiotherapy, and the effect of the treatment can be actively monitored via the first PQM-H compound, for example, by the medical imaging methods described herein. <Process for Preparing PQM-H Compound from PQM-P Compound>

[0189] Another aspect of the present invention relates to a process for preparing a PQM-H compound from a PQM-P compound.

[0190] [[ID=​​​​​​​​​​​​​​124 I, 125 I, 131 I, or 211 It is a source of At. In one embodiment, the radioisotope source is 18 F, 123 I, 124 I, 125 I, or 131 It is a source of I. In one embodiment, the radioisotope source is 18 F or 125 It is a source of I. In one embodiment, the radioisotope source is 125 It is a source of I. In one embodiment, the radioisotope source is 18 It is a source of F. In one embodiment, the reaction is carried out in the presence of a catalyst. In one embodiment, the reaction is carried out in the presence of a copper catalyst. In one embodiment, the catalyst is tetrakis(pyridine)copper(II) bis(trifluoromethanesulfonate). In one embodiment, the catalyst is Cu(OCOCF3)2. In one embodiment, the reaction is heated to a temperature between about 20°C and about 150°C. In one embodiment, the reaction is heated to a temperature between about 40°C and about 140°C. In one embodiment, the reaction is heated to a temperature between about 50°C and about 130°C. In one embodiment, the reaction is heated to a temperature between about 60°C and about 120°C. In one embodiment, the reaction is heated to a temperature between about 80°C and about 110°C. In one embodiment, the reaction is heated to a temperature of about 80°C. In one embodiment, the reaction is heated to a temperature of about 110°C. In one embodiment, the reaction is heated at room temperature (eg, about 25° C.). In one embodiment, the reaction is carried out in less than 6 hours. In one embodiment, the reaction is carried out in less than 5 hours. In one embodiment, the reaction is carried out in less than 4 hours. In one embodiment, the reaction is carried out in less than 3 hours. In one embodiment, the reaction is carried out in less than 2 hours. In one embodiment, the reaction is carried out in less than 1 hour. In one embodiment, the reaction is carried out in less than 45 minutes. In one embodiment, the reaction is carried out in less than 30 minutes. In one embodiment, the reaction is carried out in about 20 minutes. In one embodiment, the reaction is stirred for about 1 minute to about 3 hours. In one embodiment, the reaction is stirred for about 5 minutes to about 1 hour. In one embodiment, the reaction is stirred for about 10 minutes to about 30 minutes. In one embodiment, the reaction is stirred for about 20 minutes. <Other uses>

[0192] The PQM-H compounds described herein can also be used as cell culture additives to inhibit ALDH (eg, ALDH1A1).

[0193] The PQM-H compounds described herein can also be used as part of an in vitro assay, for example, to determine whether a candidate host is likely to benefit from treatment with the compound in question.

[0194] The PQM-H compounds described herein can also be used, for example, as standards in assays to identify other active compounds, other ALDH1A1 inhibitors, etc. For example, the PQM-H compounds described herein can be useful as standards in competitive binding assays. <Kit>

[0195] One aspect of the present invention relates to a kit that includes: (a) a PQM-H compound described herein, or a composition comprising a PQM-H compound described herein (e.g., preferably provided in a suitable container and / or with suitable packaging); and (b) instructions for use, e.g., instructions on how to administer the compound or composition.

[0196] The instructions may also include a list of indications for which the active ingredient is an appropriate treatment.

[0197] Another aspect of the present invention relates to a kit comprising: (a) a PQM-P compound described herein, or a composition comprising a PQM-P compound described herein (e.g., preferably provided in a suitable container and / or with suitable packaging); and (b) instructions for use, e.g., instructions on how to produce a PQM-H compound from the PQM-P compound. <Administration route>

[0198] The PQM-H compound or a pharmaceutical composition containing the PQM-H compound can be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (i.e., at the desired site of action).

[0199] Examples of routes of administration include oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patches, plasters); transmucosal (including, e.g., by patches, plasters); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., via aerosol, e.g., through the mouth or nose, e.g., by inhalation therapy or insufflation therapy); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrasternal; and by implantation of a depot or reservoir, e.g., subcutaneously or intramuscularly. <Subject / Patient>

[0200] The subject / patient may be a chordate, vertebrate, mammal, placental mammal, marsupial (e.g., kangaroo, wombat), rodent (e.g., guinea pig, hamster, rat, mouse), murine (e.g., mouse), lagomorph (e.g., rabbit), avian (e.g., bird), canine (e.g., dog), feline (e.g., cat), equine (e.g., horse), porcine (e.g., pig), ovine (e.g., sheep), bovine (e.g., cow), primate, primate (e.g., monkey or ape), monkey (e.g., marmoset, baboon), ape (e.g., gorilla, chimpanzee, orangutan, gibbon), or human.

[0201] Furthermore, the subject / patient may be in any form of development, for example, a fetus.

[0202] In a preferred embodiment, the subject / patient is a human. <Formulation>

[0203] While it is possible for the PQM-H compounds to be administered alone, they are preferably present as pharmaceutical formulations (e.g., compositions, preparations, medicaments) containing at least one PQM-H compound described herein along with one or more other pharmaceutically acceptable components known to those of skill in the art, including pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, colorants, flavoring agents, and sweetening agents. The formulation may further include other active agents, e.g., other therapeutic or prophylactic agents.

[0204] Thus, the present invention further provides a pharmaceutical composition as defined above, and a method for preparing a pharmaceutical composition comprising mixing at least one PQM-H compound described herein with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, such as carriers, diluents, excipients, etc. When formulated as discrete units (e.g., vials, ampoules, etc.), each unit contains a predetermined amount (dose) of the compound.

[0205] The term "pharmaceutically acceptable," as used herein, refers to compounds, ingredients, substances, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject (e.g., human) in question, without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, diluent, excipient, etc. must be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0206] Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts, e.g., Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 5th edition, 2005.

[0207] Preparation can be prepared by any method known in the pharmaceutical field.Such method includes the step of combining compound with carrier, which constitutes one or more accessory ingredients.Generally, preparation is prepared by uniformly and intimately combining compound with carrier (for example, liquid carrier, finely divided solid carrier, etc.), and then shaping product as needed.

[0208] The formulation is preferably in the form of a liquid, solution (e.g., aqueous, non-aqueous), suspension (e.g., aqueous, non-aqueous), emulsion (e.g., water-in-oil, oil-in-water), elixir, syrup, electuary, mouthwash, drops, tablet (e.g., including coated tablets), granules, powder, troche, paste, capsule (e.g., including hard and soft gelatin capsules), cachet, pill, ampoule, bolus, suppository, pessary, tincture, gel, paste, ointment, cream, lotion, oil, foam, spray, mist, or aerosol.

[0209] Formulations may suitably be presented as patches, adhesive plasters, bandages, dressings, etc. impregnated with one or more compounds and, optionally, one or more other pharmaceutically acceptable ingredients (including, for example, penetration, permeation, and absorption enhancers). Formulations may also suitably be presented in the form of a depot or reservoir.

[0210] The compound may be dissolved, suspended, or mixed in one or more other pharmaceutically acceptable components. The compound may be present, for example, in a liposome or other microparticle designed to target blood components or one or more organs.

[0211] Formulations suitable for oral administration (e.g., by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, lozenges, tablets, granules, powders, capsules, cachets, pills, ampoules, and boluses.

[0212] The formulation suitable for buccal administration includes mouthwash, lozenges, paste, and patch, adhesive plaster, depot and reservoir.Lozens typically contain the compound in a flavored base, usually sucrose and acacia or tragacanth.Paste typically contain the compound in an inert base, such as gelatin and glycerin, or sucrose and acacia.Mouthwash typically contain the compound in a suitable liquid carrier.

[0213] Formulations suitable for sublingual administration include tablets, troches, pastes, capsules, and pills.

[0214] Formulations suitable for oral mucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., water-in-oil, oil-in-water), mouthwashes, lozenges, pastes, as well as patches, adhesive plasters, depots, and reservoirs.

[0215] Formulations suitable for parenteral mucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., water-in-oil, oil-in-water), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.

[0216] Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.

[0217] Tablets can be produced by conventional methods, such as compression or molding, and are optionally produced with one or more accessory ingredients.Compressed tablets are produced by compressing the compound in a free form, for example, in powder or granular form, in a suitable machine, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethylcellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose); surfactants or dispersants or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid); flavors, flavor enhancers, and sweeteners.Tablets can be produced by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and may be formulated to provide slow or controlled release of the compound therein, for example using various percentages of hydroxypropyl methylcellulose to provide a desired release profile. The tablets may optionally be coated, for example enteric coated, to affect release, for example to provide release in parts of the digestive tract other than the stomach.

[0218] Ointments are typically prepared from the compound and a paraffinic or a water-miscible ointment base.

[0219] Creams are typically prepared from a compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base can contain, for example, at least about 30% by weight of a polyhydric alcohol, i.e., an alcohol having two or more hydroxy groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol, and mixtures thereof. Topical formulations can desirably contain a compound that enhances the absorption or penetration of the compound through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

[0220] Emulsions are typically prepared from a compound and an oil phase. This oil phase may optionally contain only an emulsifier (also known as an emulgent), or may contain a mixture of at least one emulsifier with a fat or oil, or both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. The emulsifier, together with or without a stabilizer, constitutes the so-called emulsifying wax, which, together with the oil and / or fat, constitutes the so-called emulsifying ointment base that forms the oily dispersed phase of a cream formulation.

[0221] Suitable emulsifiers and emulsion stabilizers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. The selection of an appropriate oil or fat for a formulation is based on achieving the desired cosmetic properties, since the solubility of compounds in most oils likely to be used in pharmaceutical emulsion formulations can be very low. Therefore, creams should preferably be non-greasy, non-staining, and washable products with a viscosity suitable to avoid leakage from tubes or other containers. Linear or branched mono- or dibasic alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or the mixture of branched esters known as Crodamol CAP can be used, with the last three being preferred. These can be used alone or in combination, depending on the desired properties. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.

[0222] Formulations suitable for intranasal administration (wherein the carrier is a liquid) include, for example, nasal spray, including aqueous or oily solutions of the compound, nasal drops, or by aerosol administration by nebulizer.

[0223] Formulations suitable for intranasal administration (wherein the carrier is a solid) include, for example, those presented as a coarse powder having a particle size in the range of from about 20 to about 500 microns, which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage while holding a container of the powder close to the nose.

[0224] Formulations suitable for pulmonary administration (e.g., by inhalation or insufflation therapy) include those presented as an aerosol spray from pressurized packs using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.

[0225] Formulations suitable for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.

[0226] Formulations suitable for rectal administration may be presented as a suppository with a suitable base such as, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or salicylates, or as solutions or suspensions for treatment by enema.

[0227] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing, in addition to the compound, such carriers as are known in the art to be appropriate.

[0228] Formulations suitable for parenteral administration (e.g., by injection) include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions) in which the compound is dissolved, suspended, or otherwise provided (e.g., in liposomes or other microparticles). Such liquids may further contain other pharmaceutically acceptable ingredients, such as antioxidants, buffers, preservatives, stabilizers, bacteriostats, suspending agents, thickening agents, and solutes that render the formulation isotonic with the blood (or other relevant bodily fluids) of the intended recipient. Examples of additives include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of isotonic carriers suitable for use in such formulations include sodium chloride injection, Ringer's solution, or lactated Ringer's injection. Typically, the concentration of the compound in the liquid is from about 1 ng / mL to about 10 μg / mL, e.g., from about 10 ng / mL to about 1 μg / mL. The formulations may be presented in unit-dose or multi-dose hermetically sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. <Dose>

[0229] Those skilled in the art will understand that appropriate doses of PQM-H compounds and compositions containing PQM-H compounds may vary from patient to patient. Determining the optimal dose typically involves balancing the level of therapeutic benefit against any risk or adverse side effects. A dose for therapeutic effect may differ from the dose required for diagnostic effect. The selected dose level will depend on various factors, including the activity of the particular PQM-H compound, the route of administration, the time of administration, the rate of excretion of the PQM-H compound, the duration of treatment, other drugs, compounds, and / or materials used in combination, the severity of the disease, and the patient's species, sex, age, weight, condition, general health, and medical history. The amount and route of administration of the PQM-H compound are ultimately at the discretion of the physician, veterinarian, or clinician, but generally, the dose will be selected to achieve a local concentration at the site of action that achieves the desired effect without causing substantial adverse or deleterious side effects.

[0230] Administration can be carried out in one dose, continuously, or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage are well known to those skilled in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.

[0231] In the case of use of the PQM-H compounds for imaging, the dose is sufficient to provide a signal for medical imaging.

[0232] In the case of therapeutic use of a PQM-H compound, the dose is sufficient to provide a sufficient concentration of the PQM-H compound to provide a therapeutic benefit, e.g., in the case of targeted radiation therapy, the dose of the PQM-H compound is an amount that provides a sufficient level of ionizing radiation at the desired site.

[0233] As radioactive compounds, the dose of a PQM-H compound is typically measured as a dose of radioactivity, e.g., as measured in curies (Ci) or becquerels (Bq). The radioactive dose also varies depending on the radioisotopes present in the PQM-H compound.

[0234] <Example> <Chemical synthesis> <abbreviation>

[0235] aq: aqueous; br: broad; ca.: approx. Cu(OCOCF3)2: Copper(II) trifluoroacetate hydrate; d: doublet; DCM: dichloromethane; DEEM: diethyl ethoxymethylene malonate; dioxane: 1,4-dioxane; DIPEA: diisopropylethylamine; DMA: N,N-dimethylacetamide; DMF: N,N-dimethylformamide; Eq: equivalent; Et3N: triethylamine; EtOAc: ethyl acetate; EtOH: ethanol; h: time; HATU: N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; HCl: Hydrochloric acid; HPLC: high performance liquid chromatography; K2CO3: Potassium carbonate; KOAc: potassium acetate; KOH: potassium hydroxide; Kryptofix 222:4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane; LCMS: liquid chromatography-mass spectrometry; LiCl: lithium chloride; m: multiplet; M: mole, molecular ion; MBq: megabecquerel; MeCN: acetonitrile; MeOH: methanol; MgSO4: magnesium sulfate; min:minutes; mmol: millimolar; MS: mass spectrometry; NaHCO3: sodium bicarbonate; NaI: sodium iodide; NaOH: sodium hydroxide; Na2SO4: sodium sulfate; NMR: nuclear magnetic resonance; PBS: phosphate-buffered saline; Pd2dba3: tris(dibenzylideneacetone)dipalladium(0); PdCl2(dppf)·DCM: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex; PdCl2(dtbpf): [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); PE: petroleum ether; q: quartet; RCY: Radiochemical yield; rotovap: rotary evaporator; RT: Room temperature (approx. 20℃); R T :holding time; brs: broad singlet; s: singlet, solid; sat.: saturation; t: triplet; THF: tetrahydrofuran; TLC: thin layer chromatography; XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0236] Other abbreviations are intended to convey their generally accepted meaning.

[0237] Structure naming was performed using the "Structure to Name" conversion in ChemDraw™ Professional 17 (PerkinElmer). <General synthesis method>

[0238] Methods for the chemical synthesis of PQM-P and PQM-H compounds are described herein. These methods, and / or other known methods, can be modified and / or adapted in known ways to provide alternative or improved methods for the synthesis of PQM compounds.

[0239] In the first method, the synthesis begins with the quinoline derivative I-1. Suzuki coupling (a) affords the corresponding 4-substituted quinoline I-2. Hydrolysis of the aryl ester affords intermediate I-3, which is then used in an amide coupling reaction with an appropriately substituted piperazine to afford the chloroquinoline intermediate I-4. Miyaura borylation affords the boron pinacol ester I-5 (PQM-P compound). Final copper-catalyzed nucleophilic radiohalogenation of the arylboronic ester affords compound I-6 (PQM-H compound).

[0240] This method is illustrated in the chemical scheme below.

[0241] <Scheme 1> [ka] Scheme 1: General synthesis method for PQM-P and PQM-H compounds. Representative reaction conditions for the above scheme are as follows: (a) R 4 -BPin, PdCl2(dtbpf), K2CO3, DMF, 90℃; (b) NaOH, THF / MeOH, 50℃; (c) R L -L 1-piperazine, DIPEA, HATU, DMF, RT; (d) bis(pinacolato)diborane, KOAc, Pd(cat), THF / DMF, 110°C; (e) Cu(cat), Na / KX (X = radiohalogen), solvent. <Example of chemical synthesis>

[0242] The following examples are provided solely to illustrate the invention and are not intended to limit the scope of the invention described herein. <General experimental conditions>

[0243] All starting materials and solvents were obtained commercially or prepared according to literature references. 18 [F] fluoride was supplied by Alliance Medical Radiopharmacy Ltd (London, UK) or St Thomas' Hospital (London, UK) in approximately 3 mL of concentrated [ 18 [O]H2O targets were produced at the GE PETrace cyclotron by irradiating them with 16 MeV. 18 [F] fluoride was used without further purification. 125 [I]NaI was purchased from PerkinElmer (product number NEZ033A) as a carrier-free 10 M NaOH solution (pH 8–11). Radioactivity was measured with a CRC-25R dose calibrator (Capintec, Inc.). Reaction mixtures were magnetically stirred unless otherwise indicated.

[0244] Column chromatography was performed on an automated flash chromatography system, Biotage Isolera One, using Biotage™ Sfaer or Biotage™ Sfaer Bio C18 Duo prepacked silica (60 μm, 20 μm) cartridges unless otherwise indicated.

[0245] 1 H NMR and 13C NMR spectra were recorded using a Bruker Avance III 400 MHz spectrometer. Chemical shifts are expressed in parts per million relative to the central peak of the residual protic solvent or to an internal standard of tetramethylsilane. Spectra were recorded at room temperature unless otherwise indicated.

[0246] Analytical and semi-preparative RP-HPLC were performed on an Agilent 1200 HPLC system equipped with a 1200 series diode array detector and a Raytest GABI Star NaI(Tl) scintillation detector (energy window 400-700 keV). The isolated radiochemical yield (RCY) was calculated by dividing the radioactivity of the pure tracer isolated after HPLC by the amount of the tracer used for labeling [ 18 O] in H2O 18 F] in fluoride or NaOH solution 125 Radiochemical purity refers to the percentage of total radioactivity in a sample that is present as the desired radiotracer as determined by radio-HPLC. <Analysis method>

[0247] Method 1 - LCMS 15 minute method: Column: ZORBAX Eclipse, XDB-C18, 80Å, 1.8μm, 4.6×50mm Detection: UV (254 nm) MS ionization: electrospray Solvent A: Water Solvent B: MeCN Flow rate: 1.0mL / min [Table 7] Method 2 - LCMS 15 minute method: Column: ZORBAX Eclipse, XDB-C18, 80Å, 1.8 μm, 4.6 x 50 mm Detection: UV (254 nm) MS ionization: electrospray Solvent A: Water Solvent B: MeCN Flow rate: 1.0mL / min [Table 8] Method 3 - LCMS 25 minute method for radioactive chemicals: Column: Zorbax™ HPLC column C18 (octadecyl), 5 μm, 25 cm × 4.6 mm or Detection: UV (254 nm) Solvent A: Water Solvent B: MeOH Flow rate: 3.0 ml / min [Table 9] <Synthesis 1 - Synthesis of precursor compound (PQM-P compound)>

[0248] PQM-P-001, PQM-H-001, and PQM-H-002 were synthesized by the following synthetic route (Scheme 2): [ka] Scheme 2: Synthesis of precursor compound PQM-P-001, and radiolabeled compounds PQM-H-001 and PQM-H-002 from intermediate compound PQM-I-003 via PQM-I-010. <Synthesis 1a - Synthesis of 1-[4-[3-(4-methylsulfonylpiperazine-1-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-quinolyl]phenyl]cyclopropanecarbonitrile> (PQM-P-001) [ka]

[0249] Step 1 – Diethyl 2-(((4-chlorophenyl)amino)methylene)malonate (PQM-I-003) [ka] A 100 mL round-bottom flask was charged with 4-chloroaniline (4.13 g, 1 equiv., 32.4 mmol) and diethyl 2-(ethoxymethylene)malonate (7.00 g, 1 equiv., 32.4 mmol). The mixture was then stirred at 130 °C for 2 h. After the starting compound was consumed (TLC monitoring), the reaction was cooled to room temperature, and the crude product was purified by silica gel column chromatography eluting with 0–10% EtOAc / PE. Diethyl 2-(((4-chlorophenyl)amino)methylene)malonate was obtained as a white solid (94% yield). 1 H NMR (400MHz, CDCl3): δ[ppm]=1.33(t, J=7.1Hz, 3H, CH3CH2), 1.38(t, J=7.1Hz, 3H, CH3CH2), 4.25(q, J=7.1Hz, 2H, CH3CH2), 4.30(q, J= 7.1Hz, 2H, CH3CH2), 7.07(d, J=8.8Hz, 2H, Ar-H), 7.34(d, J=8.8Hz, 2H, Ar-H), 8.45(d, J=13.6Hz, 1H, CH), 11.00(d, J=13.5Hz, 1H, NH). 13 C NMR (100MHz, CDCl3): δ[ppm]=14.4, 14.5, 60.3, 60.6, 94.4, 118.4, 130.1, 130.2, 138.1, 151.7, 165.7, 169.1

[0250] Step 2 – Ethyl 6-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylate (PQM-I-004) [ka] A 250 mL round-bottom flask was charged with diethyl 2-(((4-chlorophenyl)amino)methylene)malonate (4.00 g, 1 equivalent, 13.4 mmol) and diphenyl ether (15 mL). The mixture was then stirred at 260 °C for 2 h. After the starting compound was consumed (TLC monitoring), the reaction was cooled to room temperature and diluted with 100 mL of hexane. The resulting precipitate was collected by filtration through a glass filter and dried under high vacuum to give ethyl 6-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylate as a white solid (70%). This was used in the next step without further purification.

[0251] Step 3 - Ethyl 4-bromo-6-chloroquinoline-3-carboxylate (PQM-I-005) [ka] A 100 mL round-bottom flask was charged with ethyl 6-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylate (2.1 g, 1 equivalent, 8.3 mmol) and phosphoryl tribromide (12 g, 5 equivalents, 42 mmol). The mixture was then stirred at 125 °C for 3 h. After consumption of the starting compound (TLC monitoring), the reaction was cooled to 0 °C, quenched with ice slush and NaHCO₃, and extracted with EtOAc (3 × 20 mL). The organic layers were combined, washed with brine (3 × 20 mL), dried over Na₂SO₄, and filtered. After filtration, the solvent was removed in vacuo to give the title compound as a white solid (84% yield). 1 H NMR (400MHz, CDCl3): δ[ppm]=1.47(t, J=7.2Hz, 3H, CH3CH2), 4.51(q, J=7.2Hz, 2H, CH3CH2), 7.75(dd, J=9.0, 2.3Hz, 1H, Ar-H), 8.06(d, J=9.0Hz, 1H, Ar-H), 8.39(d, J=2.3Hz, 1H, Ar-H), 9.05(s, 1H, Ar-H). 13C NMR (100MHz, CDCl3, 298K): δ[ppm]=14.4, 62.6, 127.3, 127.4, 128.6, 131.7, 132.8, 133.6, 135.1, 147.7, 149.9, 165.0.

[0252] Step 4 - 1-(4-Bromophenyl)cyclopropane-1-carbonitrile (PQM-I-006) [ka] A 100 mL round-bottom flask was charged with 2-(4-bromophenyl)acetonitrile (5.00 g, 1 equiv., 25.5 mmol), 1-bromo-2-chloroethane (7.31 g, 2 equiv., 51.0 mmol), tetrabutylammonium bromide (1.64 g, 0.2 equiv., 5.10 mmol), potassium hydroxide (7.16 g, 5 equiv., 128 mmol), and toluene / saturated KOH (aq.) (20:12). The mixture was then stirred at 50 °C overnight. After the starting compound was consumed (TLC monitoring), the reaction was cooled to room temperature, quenched with water, and extracted with DCM (3 × 20 mL). The organic layers were combined, washed with brine (3 × 20 mL), dried over NaSO, and filtered. After that, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluting with 5–20% EtOAc / n-heptane to give the title compound as a white solid (67% yield). 1 H NMR (400MHz, CDCl3): δ[ppm]=1.38(m, 2H, CH2), 1.73(m, 2H, CH2), 7.16(d, J=8.6Hz, 2H, Ar-H), 7.47(d, J=8.6Hz, 2H, Ar-H). 13 C NMR (100MHz, CDCl3): δ[ppm]=13.6, 18.4, 121.7, 122.2, 127.6, 132.1, 135.3

[0253] Step 5 – 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carbonitrile (PQM-I-007) [ka] A 100 mL round-bottom flask was charged with 1-(4-bromophenyl)cyclopropane-1-carbonitrile (4.30 g, 1 equiv., 19.36 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (14.75 g, 3.0 equiv., 58.08 mmol), XPhos (461.5 mg, 0.05 equiv.), Pd2dba3 (443.2 mg, 0.025 equiv.), KOAc (5.7 g, 3 equiv.), and 1,4-dioxane (60 mL). The reaction mixture was stirred at 110 °C for 1 h. After the starting compound was consumed (TLC monitoring), the reaction mixture was cooled to room temperature, diluted with ethyl acetate (25 mL), and filtered through Celite. The solvent was removed under reduced pressure and the resulting oily residue was purified by flash chromatography eluting with 5-10% EtOAc / n-hexane to give the title compound as a white solid (4.3 g, 91%). 1 H NMR (400MHz, CDCl3) δ1.28(s, 12H, CH3), 1.37(m, 2H, CH2), 1.69(m, 2H, CH2), 7.23(d, J=2H, Ar-H), 7.72(d, J=7.8Hz, 2H, Ar-H). 13 C NMR (100MHz, CDCl3) δ14.1, 18.9, 25.0, 83.6, 84.1, 122.5, 124.8, 135.5, 139.2.

[0254] Step 6 – Ethyl 6-chloro-4-(4-(1-cyanocyclopropyl)phenyl)quinoline-3-carboxylate (PQM-I-008) [ka] A 50 mL round-bottom flask was charged with ethyl 4-bromo-6-chloroquinoline-3-carboxylate (1.5 g, 1 equiv., 4.8 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carbonitrile (1.7 g, 1.3 equiv., 6.2 mmol), PdCl(dtbpf) (310 mg, 0.1 equiv.), potassium carbonate (2.0 g, 3 equiv., 14 mmol), and 20 mL of dry DMF. The reaction mixture was then stirred at 90 °C for 3 h. After the starting compound was consumed (TLC monitoring), the reaction mixture was cooled to room temperature, and the DMF was removed under reduced pressure. The residue was diluted with ethyl acetate (50 mL) and washed with LiCl (sat. aq.) (3 × 15 mL), water (3 × 20 mL), the organic layer was washed with brine (3 × 10 mL), dried over NaSO, filtered, and then the solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluting with 20% EtOAc / n-hexane to give the title compound as a white solid (yield 56%). 1 H NMR (400MHz, CDCl3): δ[ppm]=1.05(t, J=7.1Hz, 3H, CH3CH2), 1.55(m, 2H, CH2), 1.84(m, 2H, CH2), 4.15(q, J=7.2Hz, 2H, CH3CH2), 7.28(d, J=8.2Hz, 2H , Ar-H), 7.45(d, J=8.2Hz, 2H, Ar-H), 7.49(d, J=2.3Hz, 1H, Ar-H), 7.73(dd, J=9.0, 2.3Hz, 1H, Ar-H), 8.14(d, J=9.0Hz, 1H, Ar-H), 9.33(s, 1H, Ar-H). 13 C NMR (100MHz, CDCl3): δ[ppm]=13.86, 13.99, 18.83, 61.7, 122.4, 124.1, 125.7, 126 .0, 127.9, 129.5, 131.3, 132.3, 133.8, 135.3, 136.7, 147.5, 148.3, 150.3, 166.0.

[0255] Step 7 - 6-chloro-4-(4-(1-cyanocyclopropyl)phenyl)quinoline-3-carboxylic acid (PQM-I-009) [ka] A 25 mL flask was charged with ethyl 6-chloro-4-(4-(1-cyanocyclopropyl)phenyl)quinoline-3-carboxylate (0.9 g, 1 equivalent, 2 mmol) and THF / MeOH (2:8, 10 mL). Then, sodium hydroxide (0.3 g, 3 equivalents, 7 mmol) in 1 mL of water was added dropwise to the reaction mixture, which was stirred at 50°C for 3 h. After the starting compound was consumed (TLC monitoring), the reaction mixture was cooled to 0°C and the pH was adjusted to 5 by adding cold 1 M HCl (aq.) solution to form a heavy precipitate. The precipitate was collected by filtration, washed with water (3 × 10 mL), and dried under vacuum to give the title compound as a white solid (69% yield). 1 H NMR (400MHz, DMSO-d6): δ[ppm]=1.65(m, 2H, CH2), 1.85(m, 2H, CH2), 7.38(m, 3H, Ar-H), 7.48(d, J=8.4Hz, 2H, Ar-H), 7. 90(d, J=8.9Hz, 1H, Ar-H), 8.17(d, J=8.9, 1H, Ar-H), 8.14(d, J=9.0Hz, 1H, Ar-H), 9.2(s, 1H, Ar-H), 13.3(brs, 1H, OH).

[0256] Step 8 - 1-(4-(6-chloro-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile (PQM-I-010) [ka] A 10 mL round-bottom flask was charged with 6-chloro-4-(4-(1-cyanocyclopropyl)phenyl)quinoline-3-carboxylic acid (0.80 g, 1 equiv., 2.3 mmol), HATU (0.96 g, 1.1 equiv.), DIPEA (1.5 g, 5 equiv., 11 mmol), and 10 mL of DMF and stirred at room temperature for 5 min. Next, 1-(methylsulfonyl)piperazine (0.56 g, 1.5 equiv., 3.4 mmol) was added, and the reaction mixture was stirred at room temperature for 4 h. After consumption of the starting compound (TLC monitoring), the reaction was quenched with 1 M HCl (aq.) solution at 0 °C and extracted with EtOAc (3 × 10 mL). The organic layers were combined, washed with brine (3 × 10 mL), dried over NaSO, and filtered. After that, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluting with 2–8% MeOH / DCM to give the title compound as a white solid (40% yield). 1 H NMR (400MHz, CDCl3): δ[ppm]=1.55(m, 2H, CH2), 1.85(m, 2H, CH2), 2.37(m, 1H), 2.70( s, 3H, CH3), 2.82(m, 1H), 2.97(m, 2H), 3.21(m, 2H), 3.69(m, 2H), 7.39(d, J=8.1Hz, 1H , Ar-H), 7.45(d, J=8.1Hz, 1H, Ar-H), 7.54(brs, 2H, Ar-H), 7.68(d, J=2.2Hz, 1H, Ar-H ), 7.72 (dd, J=9.0, 2.3Hz, 1H, Ar-H), 8.13 (d, J=9.0Hz, 1H, Ar-H), 8.85 (s, 1H, Ar-H). 13 C NMR (100MHz, CDCl3): δ[ppm]=13.9, 18.8, 35.1, 41.2, 45.4, 45.6, 46.4, 122.1, 124.9, 126.1, 12 6.6, 126.7, 128.6, 130.1, 131.2, 131.6, 131.7, 133.6, 134.2, 138.1, 142.4, 147.1, 147.9, 167.1

[0257] Step 9 - 1-[4-[3-(4-methylsulfonylpiperazine-1-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-quinolyl]phenyl]cyclopropanecarbonitrile (PQM-P-001) [ka] An 8 mL borax tube was charged with 1-(4-(6-chloro-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile (0.150 g, 1 equiv., 303 μmol), bis(pinacolato)diborane (154 mg, 2 equiv., 606 μmol), potassium acetate (89.2 mg, 56.8 μL, 3 equiv., 909 μmol), methanesulfonate(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II) dichloromethane adduct (12.1 mg, 0.05 equiv., 15.2 μmol), and 4 mL of THF / DMF (2.5 / 1.5). The reaction mixture was heated in a closed system using a microwave synthesizer (CEM Discovery SP) at 110 °C for 20 min. The vessel was then cooled using an air jet. All solvents were then removed under vacuum, and the residue was purified by C-18 reverse-phase flash column chromatography eluting with 0-100% water / MeCN to afford the title compound as a white solid (39% yield). 1 H NMR (400MHz, CDCl3): δ[ppm]=1.25(s, 12H, CH3), 1.55(m, 2H, CH2), 1.86(m, 2H, CH2), 2.36(m, 1H), 2.71(s, 3H, CH3), 2.84( m, 1H), 2.97(m, 2H), 3.22(m, 2H), 3.69(brs, 2H), 7.39(d, J=8.1Hz, 1H, Ar-H), 7.45(d, J=8.1Hz, 1H, Ar-H), 7.55(brs, 2H, Ar H), 7.69(m, 1H, Ar-H), 7.73(m, 1H, Ar-H), 8.14(d, J=8.9Hz, 1H, Ar-H), 8.85(s, 1H, Ar-H). 13 C NMR (100MHz, CDCl3): δ[ppm]=13.9, 18.8, 24.7, 25.2, 35.2, 41.3, 45.4, 45.7, 46.4, 83.6, 122.1, 124. 9, 126.1, 126.6, 126.8, 128.6, 130.1, 131.2, 131.6, 133.6, 134.3, 138.1, 142.6, 147.0, 147.9, 167.0. <Synthesis 1b - Synthesis of 1-[4-[3-(4-methylsulfonylpiperazine-1-carbonyl)-8-nitro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-quinolyl]phenyl]cyclopropanecarbonitrile> (PQM-P-007) [ka]

[0258] Following the procedure of PQM-P-001, 4-chloro-2-nitroaniline (1 equiv.) and DEEM (1.2 equiv.) were used as starting reagents, and the resulting residue was purified by C-18 reverse-phase flash column chromatography eluting with 0-100% water / MeCN to afford the title compound as a white solid. 1 H NMR (400MHz, CDCl3): δ1.34(s, 12H), 1.57(m, 2H), 1.88(t, 2H), 2.49(m, 1H), 2.72(s, 3H), 2.89(m, 3H), 3.17(b rs, 1H), 3.52(brs, 1H), 3.81(brs, 1H), 7.40(m, 2H), 7.55(d, J=7.2, 2H), 8.39(d, J=24.9Hz, 2H), 8.98(s, 1H). 13 C NMR (100MHz, CDCl3): δ13.8, 19.1, 24.8, 35.1, 41.1, 45.2, 45.4, 46.1, 77.2, 85.0, 121.8, 126. 0, 126.1, 128.8, 129.5, 130.2, 131.1, 132.9, 136.8, 138.3, 141.2, 143.9, 148.3, 150.4, 166.3. <Synthesis 1c - Synthesis of 1-[4-[3-(4-methylsulfonylpiperazine-1-carbonyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-quinolyl]phenyl]cyclopropanecarbonitrile> (PQM-P-013) [ka]

[0259] Following the procedure of PQM-P-001, 3-chloroaniline (1 equiv.) and DEEM (1.2 equiv.) were used as starting reagents, and the resulting residue was purified by C-18 reverse-phase flash column chromatography eluting with 0-100% water / MeCN to give the title compound as a white solid. 1 H NMR (400MHz, CDCl3): δ1.39(s, 12H), 1.53(m, 2H), 1.84(t, 2H), 2.35(m, 1H), 2.70(s, 3H), 2.83(m, 1H), 2.95(m, 2H), 3.20(t, J=7.1Hz, 2H), 3.68(m, 2H), 7.40(m, 2H), 7.55(dd, J=8.1, 18.6Hz, 2H), 7.68(d, J=22.6Hz, 1H), 7.87(d, J=8.4Hz, 1H), 8.65(s, 1H), 8.87(s, 1H). 13 C NMR (100MHz, CDCl3): δ13.8, 18.7, 24.9, 34.9, 41.0, 45.3, 45.5, 46.2, 84.4, 122.1, 124.9, 125. 7, 126.1, 127.3, 128.1, 130.2, 131.0, 132.4, 134.1, 137.5, 137.7, 142.7, 147.6, 148.0, 167.3. <Synthesis 1d - Synthesis of [4-[4-(1-cyanocyclopropyl)phenyl]-3-(4-methylsulfonylpiperazine-1-carbonyl)-8-quinolyl]boronic acid> (PQM-P-020) [ka]

[0260] Following the procedure of PQM-P-001, 2-chloroaniline (1 equiv.) and DEEM (1.2 equiv.) were used as starting reagents, and the resulting residue was purified by C-18 reverse-phase flash column chromatography eluting with 0-100% water / MeCN to afford the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6): δ1.64(m, 2H), 1.84(m, 2H), 2.18(brs, 1H), 2.56(m, 1H), 2.79(s, 3H), 3.02(m, 2H), 3.21(m, 2H), 3.43(m, 1H), 3.60(brs, 1H), 7.51(m, 4H), 7.69(d, J=7.5Hz, 1H), 7.77(d, J=8.1Hz, 1H), 8.34(d, J=5.8Hz, 1H), 8.97(s, 1H), 9.48(s, 1H). 13 C NMR (100MHz, DMSO-d6): δ13.8, 19.2, 34.3, 41.0, 45.5, 45.7, 46.1, 119.4, 122.7, 125.8, 12 5.9, 128.2, 128.6, 129.1, 130.6, 130.9, 133.6, 137.7, 138.5, 144.9, 147.1, 151.8, 166.2. <Synthesis 1e - Synthesis of 1-[4-[3-(4-methylsulfonylpiperazine-1-carbonyl)-4-quinolyl]-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarbonitrile> (PQM-P-025) [ka]

[0261] Step 1 – 1-(2-bromo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carbonitrile (PQM-I-011) [ka] Following the procedure of Steps 4 and 5 of PQM-I-007 in Synthesis 1a, replacing 2-(4-bromophenyl)acetonitrile in Step 4 with 2-(2-bromo-4-iodophenyl)acetonitrile as the starting reagent, the resulting residue was purified by flash chromatography eluting with 5–10% EtOAc / n-hexane to give the title compound as a white solid.

[0262] Step 2 - 1-[4-[3-(4-methylsulfonylpiperazine-1-carbonyl)-4-quinolyl]-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarbonitrile (PQM-P-025) [ka] Following the procedure for steps 1–9 of PQM-P-001 in Synthesis 1a, replacing 4-chloroaniline with aniline in step 1 and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carbonitrile with 1-(2-bromo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carbonitrile in step 6, the resulting residue was purified by C18 reverse-phase flash column chromatography eluting with 0–100% water / MeCN to give the title compound as a white solid. 1 H NMR (400 MHz,DMSO-d6): δ 1.38 (s,12H),1.45 (m,1H),1.65 (brs,1H),1.74 (m,2H),2.13 (m,1H),2.41 (m,1H),2.71 (s,3H),3.17 (m,4H),3.43 (d,J = 11.2 Hz,1H),4.13 (d,J = 13.2 Hz,1H), 7.56 (m,2H),7.62 (d,J = 8.0 Hz,1H),7.69 (d,J = 8.2 Hz,1H),7.78 (m,2H),8.99 (d,J = 8.2 Hz,1H),8.85 (s,1H). 13 C NMR (100 MHz,DMSO-d6): δ 14.7,16.5,17.7,24.9,25.0,35.1,41.1,45.4,45.6,46.4,84.7,123.4,125.9,126.1,12 7.8,128.0,129.9,130.4,130.5,133.0,134.5,136.9,142.6,143.3,147.3,148.5,167.4. <Synthesis 1f - Synthesis of 1-[3-(4-methylsulfonylpiperazine-1-carbonyl)-4-quinolyl]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-4-carbonitrile> (PQM-P-031) [ka]

[0263] Step 1 - tert-Butyl 4-(4-bromophenyl)-4-cyanopiperidine-1-carboxylate (PQM-I-012) [ka] A 100 mL round-bottom flask was charged with 2-(4-bromophenyl)acetonitrile (500 mg, 1 equiv., 2.55 mmol), tert-butyl bis(2-chloroethyl)carbamate (741 mg, 1.2 equiv., 3.06 mmol), NaH (245 mg, 4 equiv., 10.2 mmol), and 20 mL DMF at 0 °C. The mixture was then stirred at 60 °C overnight. After the starting compound was consumed (TLC monitoring), the reaction was cooled to 0 °C and quenched with slush. This was followed by extraction with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over NaSO, and filtered. The solvent was removed under vacuum to give a residue. This was purified by silica gel column chromatography (eluting with 5-50% EtOAc / n-hexane) to give the title compound as a white solid in 52% yield.

[0264] Step 2 - 4-(4-Bromophenyl)piperidine-4-carbonitrile (PQM-I-013) [ka] A 100 mL round-bottom flask was charged with tert-butyl 4-(4-bromophenyl)-4-cyanopiperidine-1-carboxylate (200 mg, 1 equiv., 548 μmol), TFA (312 mg, 211 μL, 5 equiv., 2.74 mmol), and 20 mL DCM. The mixture was then stirred at room temperature for 3 h. After the starting compound was consumed (TLC monitoring), the solvent was removed under vacuum, and the crude product was diluted with a 1 M solution of hydrochloric acid in diethyl ether. The heavy precipitate was filtered and washed with cold diethyl ether (3 × 20 mL) to give the title compound as a white solid in 69% yield, which was used directly in the next step.

[0265] Step 3 - Ethyl 4-(4-(4-bromophenyl)-4-cyanopiperidin-1-yl)quinoline-3-carboxylate (PQM-I-014) [ka] A 100 mL round-bottom flask was charged with 4-(4-bromophenyl)piperidine-4-carbonitrile (330 mg, 1 equiv., 1.24 mmol), commercially available ethyl 4-bromoquinoline-3-carboxylate (349 mg, 1 equiv., 1.24 mmol), DIPEA (804 mg, 1.08 mL, 5 equiv., 6.22 mmol), and 20 mL EtOH. The mixture was then refluxed for 3 h. After the starting compound was consumed (TLC monitoring), the solvent was removed under vacuum. The resulting residue was diluted with ethyl acetate (20 mL) and washed with water (3 × 20 mL). The organic layer was subsequently washed with brine (3 × 10 mL), dried over Na2SO4, filtered, and the solvent was removed under vacuum to give a residue. This was purified by silica gel column chromatography (eluted with 5–60% EtOAc / n-hexane) to give the corresponding compound as a white solid in 72% yield, which was used directly in the next step.

[0266] Step 4 - 1-[3-(4-methylsulfonylpiperazine-1-carbonyl)-4-quinolyl]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-4-carbonitrile (PQM-P-031) [ka] Following the procedure of steps 7–9 of synthesis 1a of PQM-P-001, substituting PQM-I-014 for PQM-I-008 in step 7, the resulting residue was purified by C-18 reverse-phase flash column chromatography (eluted with 0–100% water / MeCN) to afford the title compound as a white solid in 45% yield. 1 H NMR (400 MHz,DMSO-d6): δ 1.31 (s,12H),2.33 (m,3H),2.93 (s,3H),3.17 (m,2H),3.30 (m,2H),3.34 (m,3H),3.44 (m,1H),3.53 (m,1H), 3.65 (d,J = 12.6 Hz,1H),3.75 (m,1H),3.93 (m,1H),7.65 (d,J = 7.3 Hz,1H),7.70 (d,J = 8.3 Hz,2H),7.79 (m,3H),8.01 (d,J = 8.0 Hz,1H),8.22 (d,J = 8.0 Hz,1H), 8.60 (s,1H). 13 C NMR (100 MHz,DMSO-d6): δ 25.1,34.9,36.1,36.4,41.4,42.9,45.6,45.7,47.1,48.6,50.3,84.3,121.6,12 2.1,124.6,125.1,125.8,127.1,129.9,130.5,135.6,143.6,149.5,153.1,167.6 <Synthesis 2 - Synthesis of "cold" reference compound (PQM-C compound)> General Procedure A - Fluorination of PQM-P Compounds

[0267] A 10 mL round-bottom flask was charged with sodium hydroxide (1.2 equiv.), the corresponding quinolineboronic acid or quinolineboronic ester (PQM-P compound) (0.170 μM, 1 equiv.), and 5 mL of MeOH. After stirring at room temperature for 15 min, the reaction mixture was cooled to 0 °C, and silver(I) trifluoromethanesulfonate (3 equiv.) was added. After stirring at 0 °C for 30 min, the solvent was removed under reduced pressure at 0 °C, and the remaining MeOH was completely removed by azeotropy with acetone (2.5 mL × 2). To the residue was added acetone (5.0 mL), MS3Å (250 mg), and 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate (1 equiv.). The reaction mixture was stirred for 1 h and concentrated in vacuo. The residue was dissolved in DCM and filtered through Celite. After removing DCM, the residue was diluted with ethyl acetate (20 mL), washed with water (3 × 20 mL), and the organic layer was washed with brine (3 × 10 mL), dried over NaSO, filtered, and the solvent removed in vacuo to give a residue that was purified by C-18 reverse-phase flash column chromatography (eluted with 0-100% water / MeCN) to give the corresponding compound as a white solid. General Procedure B - Iodination of PQM-P Compounds

[0268] A 0.5 mL Borax tube was charged with the corresponding quinolineboronic ester or quinolineboronic acid (150 μM, 1 equiv.) (PQM-P compound), cuprous iodide (0.05 equiv.), N-iodosuccinimide (1.3 equiv.), iodine (1 equiv.), and 0.2 mL ACN. The reaction mixture was heated to 80 °C for 10 min in a closed system using a microwave synthesizer (CEM Discovery SP). Upon completion, the vessel was cooled with air jet cooling. All solvent was removed in vacuo to give a residue. This was purified by C-18 reverse-phase flash column chromatography (eluting with 0-100% water / ACN) to give the corresponding compound as a white solid.

[0269] <Synthesis 2a - Synthesis of 1-(4-(6-fluoro-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile> (PQM-C-001) [ka] Scheme 3: Synthesis of cold reference compound PQM-C-001 via intermediate compounds PQM-I-001 and PQM-I-002

[0270] Step 1 – Ethyl 4-(4-(1-cyanocyclopropyl)phenyl)-6-fluoroquinoline-3-carboxylate (PQM-I-001) [ka] An oven-dried round-bottom flask (25 mL) was charged with ethyl 4-chloro-6-fluoroquinoline-3-carboxylate, 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carbonitrile, PdCl(dppf) DCM, and KCO. The flask was evacuated and backfilled with nitrogen (×3), then charged with DMF and stirred at 110 °C for 1.5 h. The reaction was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water (40 mL × 2) and brine (40 mL), and dried over MgSO. The organic solvent was removed under reduced pressure to give a dark brown solid. Purification by flash chromatography [silica gel (24 g), ethyl acetate / petroleum ether (20:80) to (50:50)] gave ethyl 4-(4-(1-cyanocyclopropyl)phenyl)-6-fluoroquinoline-3-carboxylate as a white solid (0.44 g, 66%). 1H NMR (400 MHz,CDCl3): δ[ppm] = 1.05 (t,J = 7.1 Hz,3H,CH3),1.55 (m,2H,CH2),1.84 (m,2H,CH2),4.15 (q,J = 7.2 Hz,2H,CH2),7.28 (d,J = 8.2 Hz,2H,Ar-H),7.45 (d,J = 8.2 Hz,2H,Ar-H),7.49 (d,J =2.3 Hz,1H,Ar-H),7.73 (dd J = 9.0,2.3 Hz,1H,Ar-H) 8.14 (d,J = 9.0 Hz,1H,Ar-H),9.33 (s,1H,Ar-H). 13 C NMR (100 MHz, CDCl3): δ[ppm] = 13.86,13.99,18.83,61.7,122.4,124.1,125.7,126.0,127.9,129.5,131.3,132.3,133.8,135.3,136.7,147.5,148.3,150.3,166.0.

[0271] Step 2 – 4-(4-(1-cyanocyclopropyl)phenyl)-6-fluoroquinoline-3-carboxylic acid (PQM-I-002) [ka] A round-bottom flask (25 mL) was charged with ethyl 4-chloro-6-fluoroquinoline-3-carboxylate, NaOH (1N, aq.), THF, and MeOH and stirred vigorously at 50° C. for 4 hours. The reaction mixture was then cooled to 0° C., and the pH was adjusted to approximately 4-5 with HCl (1N, aq.). The solvent was removed under reduced pressure to give a yellow solid, which was triturated with a small amount of water to give 4-(4-(1-cyanocyclopropyl)phenyl)-6-fluoroquinoline-3-carboxylic acid as a white solid (0.32 g, 87%).

[0272] Step 3 - 1-(4-(6-fluoro-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile (PQM-C-001) [ka] A round-bottom flask (25 mL) was charged with 4-(4-(1-cyanocyclopropyl)phenyl)-6-fluoroquinoline-3-carboxylic acid, HATU, DIPEA, and DMF. After stirring at room temperature for 15 minutes, 1-(methylsulfonyl)piperazine was added and the reaction was stirred at room temperature overnight. The volatile solvents were removed under reduced pressure (rotary evaporator), and the resulting liquid was then diluted with ethyl acetate (75 mL) and washed with water (30 mL x 2) and brine (30 mL). The ethyl acetate phase was dried over MgSO4, and the volatiles were removed under reduced pressure to give an orange oil. This was purified by flash chromatography [Buchi-silica gel (24 g), wet-loaded with DCM, methylene chloride (0.5% EtN) / ethyl acetate (0.5% EtN) (80:20) to (20:80)] to give 1-(4-(6-fluoro-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile as a pale yellow solid (0.401 g, 46% yield). 1 H NMR (400 MHz,CDCl3) δ 1.53 (m,2H,CH2),1.85 (m,2H,CH2),2.37 (m,1H),2.71 (s,3H,CH3),2.81 (m,1H),2.98 (m,2H),3.22 (m,2H),3.70 (s,2H),7.34 (d,J = 8.0 Hz,1H,Ar-H),7.41 (m,2H,Ar-H) 7.57 (m,3H,Ar-H),8.20 (m,1H,Ar-H),8.84 (s,1H,Ar-H).

[0273] <Synthesis 2b - Synthesis of 1-(4-(6-fluoro-3-(4-(methylsulfonyl)piperazine-1-carbonyl)-8-nitroquinolin-4-yl)phenyl)cyclopropane-1-carbonitrile> (PQM-C-006) [ka] Following general procedure A, PQM-P-007 was used as the starting material, and the resulting residue was purified by C-18 reverse-phase flash column chromatography (eluting with 0-100% water / MeCN) to afford the title compound as a white solid. 1 H NMR (400 MHz,DMSO-d6): δ 1.54 (m,2H),1.85 (m,2H),2.37 (m,1H),2.71 (s,3H),2.82 (m,1H),2.97 (m,2H),3.22 (m,2H),3.69 (t,J = 4.8 Hz 2H),7.39 (d,J = 8.0 Hz,1H),7.45 (d,J = 7.9 Hz,1H) 7.55 (brs,2H),7.69 (d,J = 1.9 Hz),7.74 (dd,J = 9.0,2.3 Hz,1H),8.13 (d,J = 9.0 Hz,1H),8.85 (s,1H). 13 C NMR (100 MHz,DMSO-d6):13.9,18.8,35.2,41.3,45.5,45.7,46.4,122.1,124.8,126.5,126 .6,128.5,131.1,131.5,131.7,133.5,134.1,137.9,142.5,147.0,147.9,166.9. 19 F NMR (376 MHz,DMSO-d6): δ -114.4.

[0274] <Synthesis 2c - Synthesis of 1-(4-(6-iodo-3-(4-(methylsulfonyl)piperazine-1-carbonyl)-8-nitroquinolin-4-yl)phenyl)cyclopropane-1-carbonitrile> (PQM-C-007) [ka]

[0275] Following general procedure B, PQM-P-007 was used as the starting material, and the resulting residue was purified by C-18 reverse-phase flash column chromatography (eluting with 0-100% water / MeCN) to afford the title compound as a white solid. 1 H NMR (400 MHz,DMSO-d6): δ 1.68 (m,2H),1.85 (m,2H),2.15 (t,J = 8.9,1H),2.56 (t,J = 9.9,1H), 2.79 (s,3H),3.04 (m,2H),3.18 (m,2H),3.45 (m,1H),3.60 (m,1H),7.53 (m,4H),8.16 (s,1H),8.73 (s,1H),9.03 (s,1H). 13 C NMR (100 MHz,DMSO-d6):13.8,19.4,34.4,45.5,45.7,46.0,92.6,122.6,126.0,128.8, 130.8,131.0,131.5,132.3,137.9,138.1,138.4,142.7,148.9,150.6,165.5.

[0276] <Synthesis 2d - Synthesis of 1-(4-(7-fluoro-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile> (PQM-C-011) [ka]

[0277] Following general procedure A, PQM-P-013 was used as the starting material, and the resulting residue was purified by C-18 reverse-phase flash column chromatography (eluting with 0-100% water / MeCN) to afford the title compound as a white solid. 1H NMR (400 MHz,DMSO-d6): δ 1.63 (m,2H),1.83 (m,2H),2.15 (m,1H),2.57 (m,1H),2.78 (s,3H),3.02 (m,2H),3.21 (m,2H),3.45 (brs,1H),3.60 (brs,1H),7.40 (d,J = 7.6 Hz,1H),7.49 (d,J = 7.6 Hz,1H),7.58 (m,3H),7.74 (dd,J = 6.1,9.1 Hz,1H),7.90 (dd,J = 2.6,10.1 Hz,1H),8.91 (s,1H). 19 F NMR (376 MHz,DMSO-d6): δ -109.4.

[0278] <Synthesis 2e - Synthesis of 1-(4-(7-iodo-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile> (PQM-C-012) [ka]

[0279] Following general procedure B, PQM-P-013 was used as the starting material, and the resulting residue was purified by C-18 reverse-phase flash column chromatography (eluting with 0-100% water / MeCN) to afford the title compound as a white solid. 1 H NMR (400 MHz,DMSO-d6): δ 1.64 (m,2H),1.83 (m,2H),2.12 (m,1H),2.55 (m,1H),2.78 (s,3H),2.99 (m,2H),3.21 (brs,2H),3.43 (m,1H),3.60 (brs,1H),7.43 (d,J = 8.8 Hz,1H),7.53 (m,3H),7.74 (d,J = 8.9 Hz,1H),8.56 (s,1H),8.88 (s,1H). 13C NMR (100 MHz,DMSO-d6): δ 13.8,19.2,34.3,45.5,45.7,46.1,61.2,97.9,122.7,125.3,125.9,128.1,1 29.2,130.7,130.9,133.3,136.7,137.8,138.1,143.5,148.9,149.2,166.4. <Synthesis 2f - Synthesis of 1-(4-(8-fluoro-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile> (PQM-C-016) [ka]

[0280] Following the procedure of steps 1-8 of PQM-I-010 in Synthesis 1a, replacing 4-chloroaniline with 2-fluoroaniline (1 equivalent) and DEEM (1.2 equivalents) as starting reagents in step 1, the resulting residue was purified by C-18 reverse-phase flash column chromatography (eluted with 0-100% water / MeCN) to give the title compound as a white solid. 1 H NMR (400 MHz,DMSO-d6): δ 1.63 (m,2H),1.83 (m,2H),2.17 (t,J = 8.3 Hz,1H),2.57 (t,J = 8.2 Hz,1H),2.79 (s,3H),3.01 (m,1H),3.05 (m,1H),3.21 (m,2H),3.47 (brs,1H),3.59 (brs,1H),7.41 (d,J = 7.6 Hz,1H),7.48 (d,J = 8.5 Hz,1H), 7.59 (m,3H),7.71 (m,1H),8.94 (s,1H). 13C NMR (100 MHz,DMSO-d6): δ 13.8,19.2,34.3,40.9,45.5,45.7,46.1,114.8,122.6,125.8,128.0,128 .2,129.7,130.6,133.4,137.8,138.3,143.2,148.0,148.5,156.6,166.2. 19 F NMR (376 MHz,DMSO-d6): δ -124.8.

[0281] <Synthesis 2g - Synthesis of 1-(4-(8-iodo-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile> (PQM-C-017) [ka]

[0282] Following general procedure B, PQM-P-020 was used as the starting material, and the resulting residue was purified by C-18 reverse-phase flash column chromatography (eluting with 0-100% water / MeCN) to afford the title compound as a white solid. 1 H NMR (400 MHz,DMSO-d6): δ 1.63 (m,2H),1.83 (m,2H),2.21 (m,1H),2.57 (m,1H),2.79 (s,3H),3.01 (m,2H),3.22 (m,2H),3.49 (m,1H),3.58 (m,1H),7.38 (m,2H),7.50 (m,2H),7.57 (m,1H), 7.67 (d,J = 8.0 Hz,1H),8.49 (d,J = 7.3 Hz,1H),8.95 (s,1H). 13C NMR (100 MHz,DMSO-d6): δ 13.8,19.2,34.3,41.0,45.5,45.8,46.1,104.8,122.7,125.8,127.1,127.4, 129.6,129.7,130.7,130.9,133.3,137.7,141.1,144.2,146.7,149.2,166.2.

[0283] <Synthesis 2h - Synthesis of 1-(4-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carbonitrile> (PQM-C-021) [ka]

[0284] Following general procedure A, PQM-P-025 was used as the starting material, and the resulting residue was purified by C-18 reverse-phase flash column chromatography (eluting with 0-100% water / MeCN) to afford the title compound as a white solid. 1 H NMR (400 MHz,DMSO-d6): δ 1.57 (m,2H),1.77 (m,2H),2.44 (m,1H),2.66 (m,1H),2.82 (s,3H),3.04 (m,2H),3.20 (brs,2H),3.52 (brs,1H),4.13 (d,J = 13.2 Hz,1H), 7.31 (m,1H),7.53 (m,1H), 7.66 (m,3H),7.86 (m,1H),8.16 (d,J = 8.5 Hz,1H),8.91 (s,1H). 19 F NMR (376 MHz,DMSO-d6): δ -108.8

[0285] <Synthesis 2i - Synthesis of 1-(2-iodo-4-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile> (PQM-C-022) [ka]

[0286] Following general procedure B, PQM-P-025 was used as the starting material, and the resulting residue was purified by C-18 reverse-phase flash column chromatography (eluting with 0-100% water / MeCN) to afford the title compound as a yellow solid. 1 H NMR (400 MHz,DMSO-d6): δ 1.57 (m,2H),1.77 (m,2H),2.44 (m,1H),2.66 (m,1H),2.82 (s,3H),3.04 (m,2H),3.20 (brs,2H),3.52 (brs,1H),4.13 (d,J = 13.2 Hz,1H), 7.31 (m,1H),7.53 (m,1H), 7.66 (m,3H),7.86 (m,1H),8.16 (d,J = 8.5 Hz,1H),8.91 (s,1H). 13 C NMR (100 MHz,DMSO-d6): δ 14.7,16.5,17.7,24.9,25.0,35.1,41.1,45.4,45.6,46.4,84.7,123.4,125.9,126.1,12 7.8,128.0,129.9,130.4,130.5,133.0,134.5,136.9,142.6,143.3,147.3,148.5,167.4 <Synthesis 2j - Synthesis of 4-(4-fluorophenyl)-1-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)piperidine-4-carbonitrile> (PQM-C-026) [ka]

[0287] Following general procedure A, PQM-P-031 was used as the starting material, and the resulting residue was purified by C-18 reverse-phase flash column chromatography (eluting with 0-100% water / MeCN) to afford the title compound as a white solid. 1 H NMR (400 MHz,DMSO-d6): δ 2.24 (m,4H),2.41 (m,2H),2.921 (s,3H),3.14 (m,3H),3.49 (m,6H),3.77 (m,2H), 3.89 (m,1H),6.85 (d,J = 8.7 Hz,2H),7.45 (d,J = 8.7 Hz,2H),7.67 (t,J = 8.0 Hz,1H),7.84 (t,J = 8.0 Hz,1H),8.01 (d,J = 8.3 Hz,1H),8.21 (d,J = 8.6 Hz,1H),8.66 (s,1H). 19 F NMR (376 MHz,DMSO-d6): δ -148.2

[0288] <Synthesis 2k - Synthesis of 4-(4-iodophenyl)-1-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)piperidine-4-carbonitrile> (PQM-C-027) [ka]

[0289] Following general procedure B, PQM-P-031 was used as the starting material, and the resulting residue was purified by C-18 reverse-phase flash column chromatography (eluting with 0-100% water / MeCN) to afford the title compound as a white solid. 1H NMR (400 MHz,DMSO-d6): δ 2.24 (m,4H),2.41 (m,2H),2.921 (s,3H),3.14 (m,3H),3.49 (m,6H),3.77 (m,2H), 3.89 (m,1H),6.85 (d,J = 8.7 Hz,2H),7.45 (d,J = 8.7 Hz,2H),7.67 (t,J = 8.0 Hz,1H),7.84 (t,J = 8.0 Hz,1H),8.01 (d,J = 8.3 Hz,1H),8.21 (d,J = 8.6 Hz,1H),8.66 (s,1H).

[0290] <Synthesis 3 - Synthesis of PET / SPECT radiotracer (PQM-H compound)> Synthesis 3a - 1-(4-(6-(fluoro- 18 F) Synthesis of -3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile (Scheme 2, Step 10A) (PQM-H-001) [ka]

[0291] 18 Underwater 18[F]fluoride (900 MBq) was captured on a Sep-Pak™ QMA cartridge and eluted with a solution of Kryptofix 222 (0.65 mL) and potassium carbonate solution into a V-Wheaton vial. After removing the solvent by heating at 110 °C under a stream of nitrogen in the presence of dry acetonitrile (3 × 0.1 mL), 300 μL of a DMA solution containing 1-[4-[3-(4-methylsulfonylpiperazine-1-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-quinolyl]phenyl]cyclopropanecarbonitrile (PQM-P-001) (11.7 mg, 1 equiv., 0.0200 mmol) and tetrakis(pyridine)copper(II) bis(trifluoromethanesulfonate) (33.9 mg, 2.5 equiv., 50.0 μmol) was added to the vial. The reaction was mixed at 110 °C for 20 min. The reaction was then quenched with 100 μL of water, and the crude mixture was diluted with 15 mL of demineralized water and passed through a pre-treated (5 mL EtOH, 10 mL water) Sep-Pak™ HLB cartridge. The captured labeled compound was eluted from the cartridge with EtOH and purified by semi-preparative HPLC method 3 (Rt = approximately 11 min). The isolated fraction was diluted and passed through a Sep-Pak™ HLB cartridge, after which the pure labeled compound was eluted with ethanol (4 mL). The ethanol was removed under a stream of nitrogen, and the residue was reconstituted in PBS buffer and sterile filtered into a sealed sterile vial. The decay-corrected isolated RCY was calculated to be 10% at the end of HPLC purification, and the radiochemical purity was >99%. The radiochemical product was confirmed by coelution with a non-radioactive analog (Figure 6).

[0292] <Synthesis 3b - 1-(4-(6-(iodo- 125 I) Synthesis of -3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile (Scheme 2, Step 10B) (PQM-H-002) [ka]

[0293] In a V-vial, 1-[4-[3-(4-methylsulfonylpiperazine-1-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-quinolyl]phenyl]cyclopropanecarbonitrile (PQM-P-001) (2.9 mg, 1 equivalent, 0.005 mmol), [ 123 [I]NaI (approximately 7.5 KBq, approximately 2 μL MeOH), and Cu(OCOCF) (0.25 equiv.) were added, along with 1,10-phenanthroline (0.25 μmol) in MeOH:HO (4:1, 200 μL). The reaction vial was heated at 80 °C for 20 min. The reaction was then diluted with HO (10 mL) and passed through a Sep-Pak™ HLB cartridge. The captured labeled compound was eluted from the cartridge with EtOH and purified by semi-preparative HPLC method 3 (R T = approximately 12 min). The isolated fraction was diluted and passed through a Sep-Pak™ HLB cartridge, after which the pure labeled compound was eluted with ethanol (4 mL). The ethanol was removed under a stream of nitrogen, and the residue was reconstituted in PBS buffer and sterile filtered into a sealed sterile vial. The RCY was calculated to be 40% at the end of HPLC purification, and the radiochemical purity was >99%. The radiochemical product was confirmed by coelution with the non-radioactive analog (Figure 7). <Synthesis 3c - 1-(4-(6-(iodo- 125 Synthesis of I)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)-8-nitroquinolin-4-yl)phenyl)cyclopropane-1-carbonitrile (PQM-H-007) [ka]

[0294] Following the procedure for PQM-H-002, PQM-P-007 was used as the starting material. The resulting residue was reconstituted in PBS buffer and sterile filtered into a sealed sterile vial. The RCY was calculated to be 30% at the end of HPLC purification, and the radiochemical purity was >99%. The radiochemical product was confirmed by coelution with the non-radioactive analog (Figure 8). <Synthetic 3d - 1-(4-(8-(iodo- 125 I) Synthesis of -3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile> (PQM-H-017) [ka]

[0295] Following the procedure for PQM-H-002, PQM-P-020 was used as the starting material. The resulting residue was reconstituted in PBS buffer and sterile filtered into a sealed sterile vial. The RCY was calculated to be 35% at the end of HPLC purification, and the radiochemical purity was >99%. The radiochemical product was confirmed by coelution with the non-radioactive analog (Figure 9). <Synthetic 3d - 1-(2-(iodo- 125 Synthesis of I)-4-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile> (PQM-H-022) [ka]

[0296] Following the procedure for PQM-H-002, PQM-P-025 was used as the starting material. The resulting residue was reconstituted in PBS buffer and sterile filtered into a sealed sterile vial. The RCY was calculated to be 10% at the end of HPLC purification, and the radiochemical purity was >99%. The radiochemical product was confirmed by coelution with the non-radioactive analog. Biological Examples Target characterization

[0297] Human SKOV3 ovarian cancer cells were used as a tumor model. This cell line contains two variants: one with low ALDH1A1 activity that is sensitive to treatment (SKOV3-ip1) and one with high ALDH1A1 activity that is resistant to treatment (SKOV-TRip2) (Figures 1a–1e).

[0298] The SKOV3-TRip2 cell line was generated by graded exposure to paclitaxel (Duan et al., 1999), whereas the SKOV3-ip1 cell line was left untreated. Similar to previous findings with paclitaxel (Landen et al., 2010), cisplatin resistance in SKOV3-TRip2 cells was increased by more than three orders of magnitude compared to SKOV3-ip1 (EC50: 0.88 nM vs. 2.6 μM, respectively; n = 3–5; Figure 1a). ALDH1A1 mRNA (Figure 1b) and protein expression (Figure 1c) were substantially increased in SKOV3-TRip2 cells compared to SKOV3-ip1 cells. ALDH activity, measured by the Aldefluor assay (Pereira, R., et al., 2022), was also significantly increased in SKOV3-TRip2 cells compared to SKOV3-ip1 (n = 3, P < 0.01, Figures 1d and 1e). <Aldeflourアッセイ>

[0299] ALDH activity was measured by flow cytometry using the ALDEFLUOR kit (STEMCELL Technologies 01700) according to the manufacturer's instructions. 5 × 10 cells were cultured. 5Cells were stained with ALDEFLUOR at a concentration of cells / mL for 45 minutes at 37 °C in the presence or absence of 60 μM DEAB. The cell suspension was passed through a 35 μM filter and placed on ice before analysis. Flow cytometry was performed using BD FACSMelody (488 nm laser and 527 / 32 bandpass filter) with FACS Chorus software and then analyzed with FlowJo. At least 10,000 events were collected for each sample. The data were gated after acquisition to include only single-cell events and exclude cell debris based on forward scatter (FS) and side scatter (SS) profiles. <mRNA expression>

[0300] RNA was extracted from SKOV3-ip1 cells and SKOV3-TRip2 cells using the RNeasy kit (Qiagen, UK), and cDNA was synthesized using the Quantitect Reverse Transcription kit (Qiagen, UK) according to the manufacturer's instructions. Quantitect Primer Assay (Qiagen, UK) for human ACTB and ALDH1A1 was used to prepare Rotor-Gene SYBR Green (Qiagen, UK) master mix according to the manufacturer's instructions. Ct values were obtained using Rotor-Gene Q software. Expression changes were measured using the DDCt method and represented as relative expression to the experimental control or internal universal reference. <Western blotting (protein expression)>

[0301] Western blot analysis was performed using the iBind Flex system (ThermoFisher Scientific) for primary and secondary antibody immunoblotting according to a previously reported method (Greenwood et al., 2022).

[0302] For collection of cell lysates, SKOV3-ip1 cells and SKOV3-TRip2 cells were plated in 6-well plates at 1.25×10 5 mL -1and 1.75×10 5 mL -1 were seeded in 2 mL of medium at a density of. The lysates were recovered in RIPA buffer, and the proteins were quantified by Pierce BCA assay. Twenty to 30 mg were electrophoresed at 200 V on a 10% polyacrylamide gel. Rabbit monoclonal primary antibody against -ALDH1A1 (Cell Signaling Technology) was used at a concentration of 1:1000, and anti-rabbit IgG secondary antibody (1:200 dilution, Cell Signaling Technology) was used for the analysis of cell lysates. Actin was used as a loading control in all experiments (1:1000 dilution, Cell Signaling Technology). After incubation with the antibodies, the membranes were washed 5 times with Tris-buffered saline-Tween (TBST), visualized using ECL reagent (GE Healthcare), and images were acquired using an iBright CCD camera (Invitrogen). Images were always acquired within the linear range of the camera to prevent overexposure of the blot. <Generation of an ALDH1A1 knockout cell line (A549-KO-ALDH1A1 cells) using CRISPR>

[0303] A549-KO-ALDH1A1 cells were obtained using an ALDH1A1 human gene knockout kit (Cat# KN400723) according to the manufacturer's instructions (Origene, Rockville, MD, USA). Briefly, 3×10 5Individual A549 cells were seeded in 6-well plates and maintained at 37 °C and 5% CO2 for 24 hours. Lipofectamine 3000 (Cat# L3000, Invitrogen) was mixed in Opti-MEM with 1 μg of the gRNA vector (pCas-guide) and 1 μg of the donor template and added to the cells for 16 hours. The next day, the transfection medium was removed and replaced with fresh medium. 48 hours after transfection, the medium was replaced with fresh medium containing 0.5 μg / mL of puromycin (Cat# A1113803). This caused 100% cell death in non-transfected control cells after 5 days. Puromycin-resistant cells were selected by clone selection using the limiting dilution method. Protein knockout was confirmed by Western blot. <Generation of ALDH1A1-overexpressing (HEK293-ALDH1A1) cell line using lentiviral particles>

[0304] HEK293 cells stably overexpressing ALDH1A1 were obtained by infecting cells with lentiviral particles containing the nucleotide sequence encoding human ALDH1A1 (Origene RC200723L4V LentiORF particles (tagged with mGFP)). Briefly, 4 Individual HEK-293 cells were seeded in 24-well plates and maintained at 37 °C and 5% CO2 for 24 hours. Next, the cells were infected with lentiviral particles using a multiplicity of infection (MOI) of 10 in the presence of hexadimethrine bromide (6 μg / mL) (Sigma-Aldrich, St. Louis, MO, USA). The next day, the medium was removed and replaced with fresh medium. 36 hours after infection, the medium was replaced with complete culture medium containing puromycin (1 μg / mL). This caused 100% cell death in non-introduced control cells after 5 days. Puromycin-resistant cells were selected by clone selection using the limiting dilution method. Overexpression of ALDH1A1 was confirmed by Western blot and real-time PCR. <In Vitro Characterization> <ALDH Activity Assay>

[0305] ALDH substrate kinetics was measured using an ALDH activity colorimetric assay kit (Biovision) according to the manufacturer's instructions. Human recombinant ALDH1A1 (Bio-Techne), ALDH2 (Abcam), or ALDH3A1 (ATGen Co., Ltd.) was used at 1 μg / well. All reagents were pre-warmed to 37°C, and the assay was initiated by addition of enzyme. Plates were read in kinetic mode at 450 nm for 40 minutes at 37°C using a Multiskan FC plate reader (Thermo Scientific). <Cellular uptake / excretion>

[0306] For cellular uptake studies, SKOV3-ip1 and SKOV3-TRip2, A549-WT, A549-KO-ALDH1A1, HEK293-WT, and HEK293-ALDH1A1 cells were seeded into 6-well plates 24 h prior to the assay, as described above (Western blotting). One mL of fresh medium containing 0.37 MBq of PQM-H-001 and 6 KBq of PQM-H-002 was added to each well for the desired incubation period. After 40 min, plates were placed on ice and washed three times with ice-cold PBS to remove exogenous radioactivity. Cells were then lysed in RIPA buffer (500 mL, Fisher Scientific Ltd).

[0307] For cell efflux testing, after 40 min of incubation, exogenous radioactivity was removed from the plates every 20 min, washed with warm PBS, and 1 mL of warm fresh medium was added and incubated for up to 160 min. After each desired incubation time, the plates were placed on ice and washed three times with ice-cold PBS to remove exogenous radioactivity, which was then dissolved in RIPA buffer (500 mL, Fisher Scientific Ltd).

[0308] For all cellular uptake and efflux studies, decay-corrected radioactivity in the lysate was measured in a gamma counter (300 mL of lysate; Wallac 1282 CompuGamma counter). The remaining cell lysate was centrifuged (21,000 × g, 10 min, 4°C), and the supernatant was used to measure protein concentration after radioactive decay by the Pierce BCA assay. To quantify the uptake of the radiotracer in the cells, three standard solutions of radioactivity-containing medium were counted in a gamma counter. Data were expressed as a percentage of the total radioactivity administered to the cells per mg of protein. <Reference compound (PQM-C compound)>

[0309] The in vitro activity of the non-radioactive cold reference compound was compared against two different ALDH isoforms, ALDH1A1 and ALDH2, using an ALDH activity colorimetric assay kit (Biovision). Consistent with previous findings (Yang, S. et al., 2018), compound PQM-C-001 demonstrated nM activity and ALDH1A1 selectivity over the reference inhibitor DEAB (Figures 2a and 2b). [ka] DEAB

[0310] Another reference compound (PQM-C) was compared to ALDH1A1 using an ALDH activity colorimetric assay kit (Biovision). The results are shown in Table 1.

[0311] Table 1: IC of PQM-C reference compounds against ALDH1A1 50 [Table 10] A: ≦10 nM, B: >10 nM to ≦100 nM, C: >100 nM to ≦1 μM, D: >1 μM to ≦ 10 μM, E: >10 μM <Example Compound (PQM-H Compound)>

[0312] Next, the time-dependent uptake of the radiotracers PQM-H-001( 18 F]PQM-H-001) and PQM-H-002( 125 I]PQM-H-002) was profiled in the drug-resistant SKOV3-TRip2 and drug-sensitive SKOV3-ip1 cell lines (Pereira, R., et al. 2019). The retention of the radiotracers was found to be 9-fold (PQM-H-001) and 200-fold (PQM-H-002) higher in drug-resistant cells compared to drug-sensitive cells (Figures 2c and 2d).

[0313] The following compounds were profiled in A549-WT (ALDH1A1-positive) and A549-KO-ALDH1A1 (ALDH1A1-negative) human lung cancer cells, and HEK293-WT (ALDH1A1-negative) and HEK293-ALDH1A1 (ALDH1A1-positive) human fetal kidney cells. The fold difference in radiotracer retention in ALDH1A1-positive cell lines compared to ALDH1A1-negative cell lines for each compound is shown in Table 2.

[0314] Table 2: Radiotracer retention data

Table 11

[0315] Convincing proof-of-concept data were obtained showing that PQM-H-001 can non-invasively identify drug-resistant tumors in vivo (Figures 3a and 3b). The retention was found to be 5-fold higher in treatment-resistant SKOV3-TRip2 subcutaneous tumors compared to SKOV3-ip1 tumors (Figure 4). <00036​In contrast, it has been reported that substrate-based imaging agents cannot distinguish between SKOV3-TRip2 and SKOV3-ip1 tumors that are treatment-resistant in vivo (Pereira et al., 2022).

[0317] It is surprising and unexpected that the inhibitor-based molecular imaging agents described herein have improved sensitivity and selectivity for in vivo tumor characterization compared to substrate-based molecular imaging agents (Pereira et al., 2022). <In Vivo Tumor Model and PET Imaging>

[0318] All animal experiments were conducted in accordance with the UK Home Office Animals (Scientific Procedures) Act 198. Female Balb / c nu / nu mice (Charles River Laboratories) aged 6-9 weeks were subcutaneously injected with 2×10 6 SKOV3-ip1 cells and 4×10 6 SKOV3-TRip2 cells. Tumor size was measured using a digital caliper, and the volume was calculated using the following formula: Volume = ((π / 6) × h × w × l) where h, w, and l represent height, width, and length, respectively. Imaging examinations were performed when the tumor size was approximately 150-250 mm 3It was performed when [the relevant condition] was reached. Mice were anesthetized with isoflurane (2.5% in oxygen) and maintained at 37 °C using an air-heated scanning bed. A tail vein cannula was inserted, and 3.7 MBq of PQM-H-001 in approximately 100 μL of PBS was administered as a bolus. Immediately after administration, PET imaging was performed for 120 minutes using a Mediso nanoScan PET / CT system. CT images were acquired for anatomical visualization and attenuation correction (480 projections; helical imaging; 50 kVp; exposure time of 300 ms). Reconstructed images (Tera-Tomo 3D reconstruction algorithm; 4 iterations; 6 subsets; 400 - 600 keV; 0.4 mm voxel size) were analyzed using VivoQuant software (v.2.5, Invicro Ltd.). Regions of interest (ROIs) were manually drawn on the CT images, and the radioactivity concentration in each ROI was expressed as the percentage of the administered dose per 1 mL of tissue volume (%ID / mL). <Ex vivo property evaluation>

[0319] The distribution of PQM-H-001 was further evaluated ex vivo 90 minutes after the administration of the radiotracer. Retention of the radiotracer was low in most healthy tissues except the liver, and excretion occurred via the urinary and hepatobiliary pathways (Figure 5). Retention of the radiotracer was significantly increased in drug-resistant tumors compared to drug-sensitive tumors, as evidenced by the image data. <Ex vivo biodistribution>

[0320] The ex vivo distribution of PQM-H-001 was performed by sacrificing all mice at 120 minutes after administration following PET imaging (Section: In Vivo Tumor Model and PET Imaging). Blood, tumor, and major organs and tissues were collected, the wet weights were measured, and counting was performed using an automatic gamma counter (Wallac 1282 CompuGamma g counter). The radioactivity concentration in blood, tumor, and organs and tissues was determined as the percentage of the administered dose per 1 gram of total radioactivity (%ID / g).

[0321] The principles, preferred embodiments, and methods of operation of the present invention have been described above. However, the present invention should not be construed as limited to the particular embodiments described. Rather, the above-described embodiments should be considered illustrative rather than restrictive. It should be understood that various modifications to those embodiments may be made by those skilled in the art without departing from the scope of the present invention. <Reference>

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Claims

1. A radiolabeled compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof: 【Chemistry 1】 (I) During the ceremony, -R ４ teeth, 【Chemistry 2】 or 【Transformation 3】 is: -R ４Ａ and -R ４Ｂ together with the carbon atoms to which they are attached, C ３－５ forms a cycloalkyl; or -R ４Ａ and -R ４Ｂ are each independently C １－３ is alkyl; -R ４Ｃ is -H, -F, or -R Ｘ４Ｃ is; -R ４Ｄ is phenyl optionally substituted with: a) One -R Ｘ４Ｄ groups; and / or b) one or more -F; -L １ - is -S(O) ２ - and -C(O) ; -R Ｌ is C １－６ independently selected from alkyl and cyclopropyl; -R ６ -H, -F, -I, -R Ｘ６ , and -NO ２ are independently selected from -R ７ -H, -F, -I, -R Ｘ７ , and -NO ２ are independently selected from -R ８ -H, -F, -I, -R Ｘ８ , and -NO ２ are independently selected from -R Ｘ４Ｃ teeth, １８ F. １２３ I, １２４ I, １２５ I, １３１ I, and ２１１ At is a radioisotope selected from -R Ｘ４Ｄ teeth, １８ F. １２３ I, １２４ I, １２５ I, １３１ I, and ２１１ At is a radioisotope selected from -R Ｘ６ teeth, １８ F. １２３ I, １２４ I, １２５ I, １３１ I, and ２１１ At is a radioisotope selected from -R Ｘ７ teeth, １８ F. １２３ I, １２４ I, １２５ I, １３１ I, and ２１１ At; and -R Ｘ８ teeth, １８ F. １２３ I, １２４ I, １２５ I, １３１ I, and ２１１ At is a radioisotope selected from wherein the compound is —R Ｘ４Ｃ , -R Ｘ４Ｄ , R Ｘ６ , -R Ｘ７ , and -R Ｘ８ and contains only one group selected from -R ６ , -R ７ , and -R ８ At least one of is —H.

2. 2. The radiolabeled compound of claim 1, which is a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof: 【Chemistry 4】 (I) During the ceremony, -R ４ teeth 【Transformation 5】 or 【Transformation 6】 is; -R ４Ａ and -R ４Ｂ together with the carbon atoms to which they are attached, C ３－５ forms a cycloalkyl; or -R ４Ａ and -R ４Ｂ are each independently C １－３ is alkyl; -R ４Ｃ is —H or —F; -R ４Ｄ is phenyl optionally substituted with one or more —F; -L １ - is -S(O) ２ - and -C(O) ; -R Ｌ is C １－６ independently selected from alkyl and cyclopropyl; -R ６ is —H, —F, —I, radioactive isotopes, and —NO ２ are independently selected from -R ７ is —H, —F, —I, radioactive isotopes, and —NO ２ are independently selected from -R ８ is —H, —F, —I, radioactive isotopes, and —NO ２ are independently selected from Here, -R ６ , -R ７ , and -R ８ One of the isotopes is -R ６ , -R ７ , and -R ８ the other of which is not a radioisotope; and -R ６ , -R ７ , and -R ８ at least one of is —H; Here, the radioisotope is １８ F. １２３ I, １２４ I, １２５ I, １３１ I, and ２１１ At.

3. -R ４ but, 【Transformation 7】 3. The compound of claim 1 or 2, wherein:

4. -R ４Ａ and -R ４Ｂ together with the carbon atom to which they are attached form a cyclopropyl, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

5. -R ４Ｃ The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein is -H.

6. -L １ -, -S(O) ２ 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein

7. -R Ｌ The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein is methyl.

8. -R Ｘ４Ｃ If exists, １８ F is a radioactive isotope; -R Ｘ４Ｄ If exists, １８ F is a radioactive isotope; -R Ｘ６ If exists, １８ F. １２３ I, １２４ I, １２５ I, and １３１ I; -R Ｘ７ If exists, １８ F. １２３ I, １２４ I, １２５ I, and １３１ I; and -R Ｘ８ If exists, １８ F. １２３ I, １２４ I, １２５ I, and １３１ I, 8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof.

9. -R ６ is a radioactive isotope; -R ７ is -H or -NO ２ is; -R ８ is -H or -NO ２ and Radioactive isotopes １８ It is F.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

10. -R ６ is a radioactive isotope; -R ７ is -H or -NO ２ is; -R ８ is -H or -NO ２ and Radioactive isotopes １２５ I am 9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

11. -R ８ The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein is -H.

12. 10. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, selected from: 1-(4-(6-(fluoro- １８ F)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(4-(6-(iodo- １２５ I)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(4-(6-(iodo- １３１ I)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(4-(6-(iodo- １２３ I)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(4-(6-(iodo- １２４ I)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(4-(6-(fluoro- １８ F)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)-8-nitroquinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(4-(6-(iodo- １２５ I)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)-8-nitroquinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(4-(6-(iodo- １３１ I)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)-8-nitroquinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(4-(6-(iodo- １２３ I)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)-8-nitroquinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(4-(6-(iodo- １２４ I)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)-8-nitroquinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(4-(7-(fluoro- １８ F)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(4-(7-(iodine- １２５ I)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(4-(7-(iodine- １３１ I)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(4-(7-(iodine- １２３ I)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(4-(7-(iodine- １２４ I)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(4-(8-(fluoro- １８ F)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(4-(8-(fluoro- １２５ I)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(4-(8-(fluoro- １３１ I)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(4-(8-(fluoro- １２３ I)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(4-(8-(fluoro- １２４ I)-3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(2-(fluoro- １８ F)-4-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(2-(fluoro- １２５ I)-4-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(2-(fluoro- １３１ I)-4-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(2-(fluoro- １２３ I)-4-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 1-(2-(fluoro- １２４ I)-4-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)phenyl)cyclopropane-1-carbonitrile; 4-(4-(fluoro- １８ F) phenyl)-1-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)piperidine-4-carbonitrile; 4-(4-(fluoro- １２５ I) phenyl)-1-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)piperidine-4-carbonitrile; 4-(4-(fluoro- １３１ I) phenyl)-1-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)piperidine-4-carbonitrile; 4-(4-(fluoro- １２３ I) phenyl)-1-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)piperidine-4-carbonitrile; and 4-(4-(fluoro- １２４ I) Phenyl)-1-(3-(4-(methylsulfonyl)piperazine-1-carbonyl)quinolin-4-yl)piperidine-4-carbonitrile.

13. 10. The compound of claim 1 selected from compounds of the following formula: or a pharmaceutically acceptable salt, hydrate, or solvate thereof: Table 1-1 Table 1-2

14. A compound of formula (Ia) or a salt, hydrate, or solvate thereof: 【Transformation 8】 (Ia) During the ceremony, -R １４ teeth, 【Chemistry 9】 or 【Chemistry 10】 is; -R １４Ａ and -R １４Ｂ together with the carbon atoms to which they are attached, C ３－５ forms a cycloalkyl; or -R １４Ａ and -R １４Ｂ are each independently C １－３ is alkyl; -R １４Ｃ is -H, -F, or -R Ｘ１４Ｃ is; -R １４Ｄ is phenyl optionally substituted with: a) One -R Ｘ１４Ｄ groups; and / or b) one or more -F; -L １１ - is -S(O) ２ - and -C(O) ; -R １Ｌ is C １－６ independently selected from alkyl and cyclopropyl; -R １６ -H, -F, -I, -R Ｘ１６ , and NO ２ are independently selected from -R １７ -H, -F, -I, -R Ｘ１７ , and NO ２ are independently selected from -R １８ -H, -F, -I, -R Ｘ１８ , and NO ２ are independently selected from -R Ｘ１４Ｃ , -R Ｘ１４Ｄ , -R Ｘ１６ , -R Ｘ１７ , and -R Ｘ１８ each is independently a leaving group; The compound is -R Ｘ１４Ｃ , -R Ｘ１４Ｄ , -R Ｘ１６ , -R Ｘ１７ , and -R Ｘ１８ and -R １６ , -R １７ , and -R １８ At least one of the groups is —H.

15. 15. The compound of claim 14, which is a compound of formula (Ia), or a salt, hydrate, or solvate thereof: 【Chemistry 11】 (Ia) During the ceremony, -R １４ teeth, 【Chemistry 12】 or 【Chemistry 13】 is; -R １４Ａ and -R １４Ｂ together with the carbon atoms to which they are attached, C ３－５ forms a cycloalkyl; or -R １４Ａ and -R １４Ｂ are each independently C １－３ is alkyl; -R １４Ｃ is —H or —F; -R １４Ｄ is phenyl optionally substituted with one or more —F; -L １１ - is -S(O) ２ - and -C(O) ; -R １Ｌ is C １－６ independently selected from alkyl and cyclopropyl; -R １６ represents -H, -F, -I, a leaving group, and -NO ２ are independently selected from -R １７ represents -H, -F, -I, a leaving group, and -NO ２ are independently selected from -R １８ represents -H, -F, -I, a leaving group, and -NO ２ are independently selected from Here, -R １６ , -R １７ , and -R １８ is a leaving group, and -R １６ , -R １７ , and -R １８ is not a leaving group; and -R １６ , -R １７ , and -R １８ At least one of the groups is —H.

16. -R １４ but 【Chemistry 14】 16. The compound of claim 14 or 15, or a salt, hydrate, or solvate thereof, wherein:

17. -R １４Ａ and -R １４Ｂ together with the carbon atom to which they are attached form cyclopropyl, or a salt, hydrate, or solvate thereof.

18. -R １４Ｃ The compound according to any one of claims 14 to 17, or a salt, hydrate, or solvate thereof, wherein is -H.

19. -L １１ -, -S(O) ２ The compound according to any one of claims 14 to 18, or a salt, hydrate, or solvate thereof, wherein

20. -R １Ｌ The compound according to any one of claims 14 to 19, or a salt, hydrate, or solvate thereof, wherein is methyl.

21. -R １６ is the leaving group; -R １７ is -H or NO ２ and -R １８ is -H or NO ２ That is, 21. The compound according to any one of claims 14 to 20, or a salt, hydrate, or solvate thereof.

22. 22. The compound according to any one of claims 14 to 21, or a salt, hydrate, or solvate thereof, wherein the leaving group is selected from boronic esters, boronic acids, alkylsulfonates, haloalkylsulfonates, arylsulfonates, trialkylamines, organotin compounds, aryliodonium salts, and arylsulfonium salts.

23. 10. The compound of claim 1, or a salt, hydrate, or solvate thereof, selected from: 1-[4-[3-(4-methylsulfonylpiperazine-1-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-quinolyl]phenyl]cyclopropanecarbonitrile; 1-[4-[3-(4-methylsulfonylpiperazine-1-carbonyl)-8-nitro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-quinolyl]phenyl]cyclopropanecarbonitrile; 1-[4-[3-(4-methylsulfonylpiperazine-1-carbonyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-quinolyl]phenyl]cyclopropanecarbonitrile; [4-[4-(1-cyanocyclopropyl)phenyl]-3-(4-methylsulfonylpiperazine-1-carbonyl)-8-quinolyl]boronic acid; 1-[4-[3-(4-methylsulfonylpiperazine-1-carbonyl)-4-quinolyl]-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarbonitrile; and 1-[3-(4-methylsulfonylpiperazine-1-carbonyl)-4-quinolyl]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-4-carbonitrile.

24. 15. The compound of claim 14, or a salt, hydrate, or solvate thereof: Table 2

25. For the preparation of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate or solvate thereof, Use of a compound according to any one of claims 14 to 24, or a salt, hydrate or solvate thereof.

26. A process for preparing a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, comprising: A compound, salt, hydrate, or solvate according to any one of claims 14 to 24, under conditions in which a leaving group on the compound, salt, hydrate, or solvate is replaced with a radioisotope from a radioisotope source, A method of preparation comprising the step of contacting a radioisotope source with a compound according to any one of claims 14 to 24, or a salt, hydrate or solvate thereof.

27. A compound according to any one of claims 14 to 24, or a salt, hydrate, or solvate thereof, and A kit comprising instructions for preparing a compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

28. 14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and a pharmaceutically acceptable carrier, diluent, or excipient.

29. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 28, for use in diagnosis or therapy.

30. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 28, for use in the diagnosis or treatment of cancer, such as drug-resistant cancer.

31. 1. A medical imaging method, comprising the steps of: 1) administering to a subject a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition according to claim 28; and 2) Imaging the subject by PET, SPECT or scintigraphy.

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