Highly efficient myeloperoxidase-activating contrast agents

Abstract

Provided herein are compounds useful as imaging agents. Representative compounds provided herein are useful as eloperoxidase imaging agents using magnetic resonance or nuclear imaging techniques. Methods for preparing the compounds provided herein and diagnostic methods using the compounds are also provided.

Description

[Technical Field]

[0001] Federal government-sponsored research or development This invention was made with government support under grant numbers NS103998 and HL150305, awarded by the National Institutes of Health. The government has certain rights in this invention.

[0002] Cross-reference of related applications This application claims the interests of U.S. Provisional Patent Application No. 62 / 949,336, filed on 17 December 2019, the disclosure of which is incorporated herein by reference in its entirety.

[0003] The present invention relates to compounds useful as contrast agents, and more specifically, to compounds useful as myeloperoxidase contrast agents. [Background technology]

[0004] Myeloperoxidase (MPO) is a pro-inflammatory enzyme expressed in neutrophils and M1-type microglia and macrophages, but not in anti-inflammatory M2-type microglia and macrophages (see, for example, Swirski et al, J. Clin. Invest., 2010, 120:2627-2634; Bradley et al, Blood, 1982, 60:618-622; and Scholz et al. Exp. Hematol., 2004, 32:270-276). MPO is a component of innate immunity, but when secreted abnormally, it can potentially damage tissues. [Overview of the project]

[0005] This application relates, in particular, to compounds of formula I: [ka] or provide a pharmaceutically acceptable salt thereof, in the formula: Ring A is C 6~10selected from the group consisting of aryl, 4- to 16-membered heterocycloalkyl, and 5- to 16-membered heteroaryl; Ring B is C 6~10 selected from the group consisting of aryl, 4- to 16-membered heterocycloalkyl, and 5- to 16-membered heteroaryl; L 1 is NHC(O)L 2 、NHC(O)-L 2 -C(O)NH、L 2 -NHC(O)-L 2 、L 2 -NHC(O)-L 2 -NHC(O)、and L 2 -NHC(O)-L 2 -NHC(O)-L 2 -selected from the group consisting of;<​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ Selected from the group consisting of, During the ceremony, [ka] are ring A and L 1 This shows a connection between [the two].

[0007] In some embodiments, m is 1 or 2. In some embodiments, m is 1.

[0008] In some embodiments, each R 2 R is independently selected from the group consisting of OH, OCH3, C(O)CH3, and OC(O)CH3. In some embodiments, each R 2 It is OH.

[0009] In some embodiments, ring A is: [ka] Selected from the group consisting of, During the ceremony, [ka] are ring A and L 1 This shows a connection between [the two].

[0010] In some embodiments, ring A is: [ka] Selected from the group consisting of, During the ceremony, [ka] are ring A and L 1 This shows a connection between [the two].

[0011] In some embodiments, ring B is selected from the group consisting of phenyl, bicyclic 8-16 member heterocycloalkyl, tricyclic 8-16 member heterocycloalkyl, bicyclic 8-16 member heteroaryl, and tricyclic 8-16 member heteroaryl. In some embodiments, ring B is: [ka] Selected from the group consisting of, During the ceremony, [ka] are ring B and L 1 This shows a connection between [the two].

[0012] In some embodiments, n is 1 or 2. In some embodiments, n is 1.

[0013] In some embodiments, each R 3 R is independently selected from the group consisting of OH, OCH3, C(O)CH3, and OC(O)CH3. In some embodiments, each R 3 It is OH.

[0014] In some embodiments, ring B is: [ka] Selected from the group consisting of, During the ceremony, [ka]

[0015] are ring B and L 1 This shows a connection between [the two].

[0016] In some embodiments, ring B is: [ka] Selected from the group consisting of, During the ceremony, [ka] are ring B and L 1 This shows a connection between [the two].

[0017] In some embodiments, rings A and B are the same. In some embodiments, rings A and B are different.

[0018] In some embodiments, ring A and ring B are, respectively [ka] That is the case.

[0019] In some embodiments, L 1 L 2 -NHC(O)-L 2 -NHC(O)-L 2 - and each L 2 C is selected independently 1~4 It is alkylene.

[0020] In some embodiments, L 1 teeth: [ka]

[0021] And, During the ceremony: [ka]

[0022] L 1 It shows the bond between and ring A; [ka]

[0023] L 1 This shows the bond between and ring B; and [ka]

[0024] L 1 and R 1 This shows a connection between [the two].

[0025] In some embodiments, R 1 The metal is Gd 3+ Mn 2+ , 68 Ga, 64 Cu, and 111 Selected from the group consisting of In. In some embodiments, R 1 The metal is Gd 3+ In some embodiments, R 1 The chelating group is: [ka]

[0026] Selected from the group consisting of, In the formula, M is a metal. [ka] R 1 and L 1 This shows a connection between [the two].

[0027] In some embodiments, R 1 teeth: [ka] And, During the ceremony, [ka] R 1 and L 1 This shows a connection between [the two].

[0028] In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is the compound of formula II: [ka] or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is the compound of formula III: [ka] or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is the compound of formula IV: [ka] or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is the compound of formula Vb: [ka] or a pharmaceutically acceptable salt thereof, where M is a metal.

[0032] In some embodiments, the compound of formula I is: [ka] or a pharmaceutically acceptable salt thereof.

[0033] This application further provides a pharmaceutical composition comprising a compound provided herein or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0034] This application further provides a method for imaging a sample of cells or tissue, the method being: i) To administer the compounds provided herein, or pharmaceutically acceptable salts thereof, to the target; ii) Allow sufficient time for the compound to accumulate in the cell or tissue sample; and iii) Imaging a cell or tissue sample using imaging techniques. Includes.

[0035] This application further provides a method for imaging a target liver, the method being: i) To administer the compounds provided herein, or pharmaceutically acceptable salts thereof, to the target; ii) Waiting for a sufficient amount of time for the compound to accumulate in the liver; and iii) Imaging a cell or tissue sample using imaging techniques. Includes.

[0036] In some embodiments, subjects are identified as having non-alcoholic steatohepatitis.

[0037] This application is recommended: i) To administer the compounds provided herein, or pharmaceutically acceptable salts thereof, to the target; ii) Waiting for a sufficient amount of time for the compound to accumulate in the disease-related cell or tissue site; and iii) Imaging cells or tissues using imaging techniques. This invention provides a method for diagnosing diseases or disorders related to abnormal myeloperoxidase activity in a subject, including those mentioned above.

[0038] In some embodiments, the method further includes imaging the subject prior to step i).

[0039] This application further provides a method for imaging myeloperoxidase activity in cells, the method being: i) Contacting cells with the compounds provided herein, or pharmaceutically acceptable salts thereof; and ii) Imaging cells using imaging techniques Includes.

[0040] This application further provides a method for detecting myeloperoxidase activity in a cell or tissue sample, the method being: i) Contacting a cell or tissue sample with a compound provided herein, or a pharmaceutically acceptable salt thereof; and ii) Imaging a cell or tissue sample using imaging techniques. Includes.

[0041] This application further provides a method for detecting myeloperoxidase activity in a subject, the method being: i) administering the compounds provided herein, or pharmaceutically acceptable salts thereof, to the target; and ii) Imaging the subject using imaging technology. Includes.

[0042] This application further provides a method for monitoring the treatment of diseases or disorders related to abnormal myeloperoxidase activity in a subject, the method being: i) To administer the compounds provided herein, or pharmaceutically acceptable salts thereof, to the target; ii) Imaging the subject using imaging techniques; iii) Administering a therapeutically effective dose of a therapeutic compound to the target of a disease or disorder; iv) Imaging cells or tissues in a subject using imaging techniques; and v) Compare the image from step i) with the image from step iv). Includes.

[0043] In some embodiments, the method further includes administering the compound provided herein, or a pharmaceutically acceptable salt thereof, to the subject after the administration in step iii) and before imaging in step iv).

[0044] In some embodiments, the imaging technique is selected from the group consisting of magnetic resonance imaging and nuclear imaging.

[0045] In some embodiments, diseases or disorders associated with abnormal myeloperoxidase activity are selected from the group consisting of non-alcoholic steatohepatitis, cancer, rheumatic diseases, infectious diseases, central nervous system diseases, cardiovascular diseases, autoimmune diseases, and inflammation associated with one or more of cancer, rheumatic diseases, infectious diseases, central nervous system diseases, cardiovascular diseases, and autoimmune diseases.

[0046] In some embodiments, the central nervous system disorder is selected from the group consisting of Alzheimer's disease, stroke, epilepsy, Parkinson's disease, neurodegenerative diseases, and inflammation associated with one or more of Alzheimer's disease, stroke, epilepsy, Parkinson's disease, and neurodegenerative diseases.

[0047] In some embodiments, cardiovascular diseases are selected from the group consisting of atherosclerosis, myocardial infarction, atrial fibrillation, vasculitis, and inflammation associated with one or more of atherosclerosis, myocardial infarction, atrial fibrillation, and vasculitis.

[0048] In some embodiments, the autoimmune disease is selected from the group consisting of multiple sclerosis, meningitis, encephalitis, and inflammation associated with one or more of multiple sclerosis, meningitis, and encephalitis.

[0049] In some embodiments, cancer is selected from the group consisting of bladder cancer, breast cancer, carcinoma, cervical cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, skin cancer, gastric cancer, testicular cancer, leukemia, and thyroid cancer. In some embodiments, cancer is a solid tumor.

[0050] In some embodiments, the rheumatic disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, and inflammatory arthritis.

[0051] In some embodiments, inflammatory arthritis is selected from the group consisting of gout and calcium pyrophosphate crystal deposition disease (CPPD).

[0052] In some embodiments, the infectious disease is selected from the group consisting of fungal diseases and bacterial diseases.

[0053] In some embodiments, a disease or disorder associated with abnormal myeloperoxidase activity is non-alcoholic steatohepatitis (NASH).

[0054] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this invention belongs. Methods and materials for use in this invention are described herein; other suitable methods and materials known in the art may also be used. Materials, methods, and examples are illustrative and not intended to limit the scope. All publications, patent applications, patents, sequences, database entries, and other references referenced herein are incorporated in their entirety by reference. In case of any conflict, this specification, including its definitions, shall prevail. [Brief explanation of the drawing]

[0055] [Figure 1] Figure 1 shows the chemical structures of a representative compound of formula I, mcMPO-Gd, and a previously reported compound, MPO-Gd. [Figure 2] Figure 2A shows the T1 relaxation rates of mcMPO-Gd measured in PBS at 0.47T and 40°C at concentrations of 0.33 mM, 0.5 mM, 0.75 mM, and 1 mM. The relaxation rates were calculated from the 1 / T1 values ​​relative to the mcMPO-Gd concentration data (R2=0.996, n=3). Figure 2B shows the dynamic R1 ratios of mcMPO-Gd and MPO-Gd after activation with MPO. mcMPO-Gd showed faster activation compared to MPO-Gd when incubated with MPO, GOX, and glucose at 40°C for 180 minutes. [Figure 3] Figure 3 shows the results of the MTT assay in RAW264.7 cells. No significant toxicity of mcMPO-Gd was observed up to 5 mM. [Figure 4]Figures 4A–4D show representative images of mcMPO-Gd, DOTA-Gd, and MPO-Gd in wild-type mice, as well as mcMPO-Gd in Mpo- / - mice, before contrast enhancement and at approximately 60 minutes. Figure 4E shows the normalized contrast-to-noise ratio (CNR) of the MR images over a period of approximately 60 minutes. Figure 4F shows the activation ratio of the MR images over a period of approximately 60 minutes, with mcMPO-Gd showing approximately twice the activation ratio compared to MPO-Gd at approximately 60 minutes. Both compounds showed even higher activation ratios than DOTA-Gd and Mpo- / - mice. [Figure 5] Figures 5A to 5C show representative MR images of MPO-Gd and mcMPO-Gd±AZM198 treatment in a tandem stenosis model of atherosclerotic plaque instability. Figure 5D shows the contrast-to-noise ratio (CNR) of unstable plaques for MPO-Gd (0.3 mmol / kg) and mcMPO-Gd (0.1 mmol / kg) (n=3 mice per probe), showing no significant difference even when mcMPO-Gd was used at a dose three times lower than MPO-Gd (p=0.368, ns, no significant difference, determined by Mann-Whitney U test). Figure 5E shows the ΔCNR of unstable and stable plaques (brachiocephalic truncal artery) in control and AZM198-treated TS mice. The signal in unstable plaques of AZM198-treated mice was reduced by approximately 50% compared to the untreated control group (*p=0.039, determined by unpaired t-test). ΔCNR = post-CNR-pre-CNR. [Figure 6] Figure 6 shows the changes in CNR of AZM198-treated mice and control mice over 60 minutes. The signal from control mice increased from 30 to 60 minutes, while the signal from AZM198-treated mice decreased over this period. [Figure 7] Figure 7 shows that the intramolecular hydrogen bond formed between the two amide bonds increases the rigidity of mcMPO-Gd, as illustrated in the molecular docking of mcMPO-Gd to MPO. [Figure 8]Figure 8 shows the binding affinity for mcMPO-Gd (left) and MPO-Gd (right) from the docking experiment described in Example 13. [Figure 9] Figure 9 shows molecular docking depictions of mcMPO-Gd (left) and MPO-Gd (right) bound to the MPO-CN complex using PyMol. Amino acid residues Q91, H95, and R239 (shown as lines), along with the heme (stick-shaped), form the active site of MPO. All other amino acid residues shown (as lines) are within 4A of mcMPO-Gd and MPO-Gd. Hydrogen bonds and electrostatic interactions are shown as dashed lines. [Modes for carrying out the invention]

[0056] MPO is associated with atherosclerosis (see, e.g., Teng et al, Redox.Rep. 2017, 22:51-73), vasculitis (see, e.g., Su et al, Radiology, 2012, 262:181-190), stroke (see, e.g., Forghani et al, J.Cereb.Blood Flow Metab. 2015, 35:485-493), Parkinson's disease (see, e.g., Choi et al, J.Neurosci. 2005, 25:6594-6600), and Alzheimer's disease (see, e.g., Maki et al, J.Biol.Chem. 2009, 284:3158-3169; and Tzikas et al, J.Alzheimers). This enzyme is a factor in many diseases, including Dis.2014,39:557-564, and multiple sclerosis (see, e.g., Gray et al, Neurosci.Lett.2008,444:195-198), and has emerged as a target for diagnosis and treatment (see, e.g., Ruggeri et al,J.Med.Chem.2015,58:8513-8528; Jucaite et al,Brain,2015,138:2687-2700;Malle et al,Br.J.Pharmacol.2007,152:838-854;and Rashid et al,Eur.Heart J.2018,39:3301-3310).Previous reports have described the activatable MPO-specific gadolinium-based MRI agent, bis-5-HT-Gd-DTPA (i.e., MPO-Gd; structure shown in Figure 1) (see, e.g., Rodriguez et al, J.Am.Chem.Soc. 2010, 132:168-177), and MPO-Gd imaging has been shown to be effective in experimental models of autoimmune encephalomyelitis (EAE) (see, e.g., Chen et al, Brain, 2008, 131:1123-1133), atherosclerosis (see, e.g., Rashid et al, Eur.Heart J. 2018, 39:3301-3310; and Ronald et al, Circulation, 2009, 120:592-599), and stroke (see, e.g., Breckwoldt et al. We demonstrated that the method could detect myocardial infarction (see, for example, Nahrendorf et al, Circulation, 2008, 117:1153-1160), and vasculitis (see, for example, Su et al, Radiology, 2012, 262:181-190).MPO-Gd images also show signs of stroke (see, e.g., Forghani et al, J Cereb. Blood Flow Metab. 2015, 35:485-493), unstable atherosclerotic plaque (see, e.g., Rashid et al, Eur. Heart J. 2018, 39:3301-3310; and Ronald et al, Circulation, 2009, 120:592-599), myocardial infarction (see, e.g., Nahrendorf et al, Circulation, 2008, 117:1153-1160; and Ali et al, JACC: Basic to Translational Science, 2016, 1:633-643) and EAE (see, e.g., Forghani et al. The effects of the treatment could also be tracked in a mouse model of steatohepatitis (see, e.g., Pulli et al, Radiology, 2012, 263:451-460), and it was possible to distinguish between steatohepatitis and nonalcoholic fatty steatohepatitis (NASH) (see, e.g., Pulli et al, Radiology, 2017, 284:390-400).

[0057] However, the literature has reported concerns about gadolinium deposition in magnetic resonance (MR) imaging using gadolinium-based contrast agents (GBCAs), particularly linear GBCAs, based on the association between the administration of GBCAs and the development of nephrogenic systemic fibrosis in patients with renal failure (see, e.g., Grobner, T. Nephrol. Dial. Transplant. 2006, 21:1104-1108; and Marckmann et al, J. Am. Soc. Nephrol. 2006, 17:2359-2362). Representative cases of gadolinium accumulation in nephrogenic systemic fibrosis and nerve tissue have been associated with the use of gadodiamide (Omniscan), gadopentetate dimeglumine (Gd-DTPA or Magnevist), and linear GBCAs such as OptiMARK. Recent studies have reported that gadolinium deposition after administration of linear GBCA has been observed in the nerve tissue of patients and animals with normal renal function (see, for example, McDonald et al, Radiology, 2015, 275:772-782; Kanda et al, Radiology, 2015, 276:228-232; and Robert et al, Invest.Radiol. 2015, 50:473-480).

[0058] Compared to linear GBCAs, macrocyclic GBCAs bind gadolinium more strongly, thus reducing the likelihood of gadolinium ions dissociating from the chelate molecule. Consistent with this, administration of macrocyclic GBCAs such as gadoterate meglumine (Dotarem) (see, e.g., Robert et al, Invest.Radiol. 2015, 50:473-480; and Radbruch et al, Radiology, 2015, 275:783-791) and gadoteridol (Prohance) (see, e.g., Kanda et al, Radiology, 2015, 275:803-809) results in little to no observed tissue deposition of gadolinium. Therefore, there is a need for novel contrast agents to improve the safety and benefits of MR imaging while minimizing risks. Accordingly, this application provides a macrocyclic activatable MRI contrast agent for the detection of MPO activity.

[0059] compound This application concerns the compound of formula I: [ka] or provide a pharmaceutically acceptable salt thereof, in the formula: Ring A is C 6~10 Selected from the group consisting of aryls, 4- to 16-membered heterocycloalkyls, and 5- to 16-membered heteroaryls; Ring B is C 6~10 Selected from the group consisting of aryls, 4- to 16-membered heterocycloalkyls, and 5- to 16-membered heteroaryls; L 1 NHC(O)L 2 NHC(O)-L 2 -C(O)NH, L 2 -NHC(O)-L 2 , L 2 -NHC(O)-L 2 -NHC(O), and L 2 -NHC(O)-L 2 -NHC(O)-L 2-Selected from the group consisting of; Each L 2 C 1~4 Alkylene, C 1~4 Alkylene, C 1~4 Alkylene oxy, and C 1~4 Independently selected from the group consisting of alkenylenes; R 1 (i) a chelating group; or (ii) a chelating group and a metal; R 2 and R 3 is OR a , C(O)R a , and OC(O)R a Each is independently selected from the group consisting of; Each R a H and C 1~4 Independently selected from the group consisting of alkyl groups; m is 0, 1, 2, 3, or 4; and n is 0, 1, 2, 3, or 4.

[0060] In some embodiments, ring A is C 6~10 The group is selected from aryl, bicyclic 8-16 member heterocycloalkyl, tricyclic 8-16 member heterocycloalkyl, bicyclic 8-16 member heteroaryl, and tricyclic 8-16 member heteroaryl. In some embodiments, ring A is selected from the group consisting of phenyl, bicyclic 8-16 member heterocycloalkyl, tricyclic 8-16 member heterocycloalkyl, bicyclic 8-16 member heteroaryl, and tricyclic 8-16 member heteroaryl. In some embodiments, ring A is phenyl. In some embodiments, ring A is a bicyclic 8-16 member heterocycloalkyl. In some embodiments, ring A is a tricyclic 8-16 member heterocycloalkyl. In some embodiments, ring A is a bicyclic 8-16 member heteroaryl. In some embodiments, ring A is a tricyclic 8-16 member heteroaryl.

[0061] In some embodiments, ring A is: [Chemical formula] selected from the group consisting of wherein [Chemical formula] represents the bond between ring A and L 1 and.

[0062] In some embodiments, ring A is [Chemical formula] .

[0063] In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0064] In some embodiments, ring A is: [Chemical formula] selected from the group consisting of wherein [Chemical formula] represents the bond between ring A and L 1 and.

[0065] In some embodiments, ring A is [Chemical formula] is.

[0066] In some embodiments, each R 2 is OR a , C(O)R a , and OC(O)R a is independently selected from the group consisting of, and each R a is independently selected from the group consisting of H and CH3. In some embodiments, each R 2 is independently selected from the group consisting of OH, OCH3, C(O)CH3, and OC(O)CH3. In some embodiments, each R 2 is OH. In some embodiments, each R 2 is OCH3. In some embodiments, each R 2 is C(O)CH3. In some embodiments, each R 2 is OC(O)CH3.

[0067] In some embodiments, ring A is: [Chemical formula] <000093S>is selected from the group consisting of, [Chemical formula] represents the bond between ring A and L 1 .

[0068] In some embodiments, ring B is C 6~10It is selected from the group consisting of aryl, bicyclic 8-16 member heterocycloalkyl, tricyclic 8-16 member heterocycloalkyl, bicyclic 8-16 member heteroaryl, and tricyclic 8-16 member heteroaryl. In some embodiments, ring B is selected from the group consisting of phenyl, bicyclic 8-16 member heterocycloalkyl, tricyclic 8-16 member heterocycloalkyl, bicyclic 8-16 member heteroaryl, and tricyclic 8-16 member heteroaryl. In some embodiments, ring B is phenyl. In some embodiments, ring B is bicyclic 8-16 member heterocycloalkyl. In some embodiments, ring B is tricyclic 8-16 member heterocycloalkyl. In some embodiments, ring B is bicyclic 8-16 member heteroaryl. In some embodiments, ring B is tricyclic 8-16 member heteroaryl.

[0069] In some embodiments, ring B is:

Chemical formula

Chemical formula

[0070] In some embodiments, ring B is [[ID=J4]]

Chemical formula

[0071] In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0072] In some embodiments, ring B is: [ka] Selected from the group consisting of, During the ceremony, [ka] are ring B and L 1 This shows a connection between [the two].

[0073] In some embodiments, ring B is [ka] That is the case.

[0074] In some embodiments, each R 3 is OR a , C(O)R a , and OC(O)R a Independently selected from the group consisting of, each R a R is independently selected from the group consisting of H and CH3. In some embodiments, each R 3 R is independently selected from the group consisting of OH, OCH3, C(O)CH3, and OC(O)CH3. In some embodiments, each R 3 is OH. In some embodiments, each R 3 This is OCH3. In some embodiments, each R 3is C(O)CH3. In some embodiments, each R 3 It is OC(O)CH3.

[0075] In some embodiments, ring B is: [ka] Selected from the group consisting of, During the ceremony, [ka] are ring B and L 1 This shows a connection between [the two].

[0076] In some embodiments, ring B is [ka] That is the case.

[0077] In some embodiments, rings A and B are the same. In some embodiments, rings A and B are different. In some embodiments, rings A and B are, respectively [ka] That is the case.

[0078] In some embodiments, L 1 NHC(O)L 2 In some embodiments, L 1 is NHC(O)-L 2 -C(O)NH. In some embodiments, L 1 L 2 -NHC(O)-L2 In some embodiments, L 1 L 2 -NHC(O)-L 2 -NHC(O). In some embodiments, L 1 L 2 -NHC(O)-L 2 -NHC(O)-L 2 - is

[0079] In some embodiments, each L 2 C 1~4 Alkylene and C 1~4 Independently selected from the group consisting of alkenylenes. In some embodiments, each L 2 C is selected independently 1~4 It is an alkylene. In some embodiments, each L 2 C is selected independently 1~4 It is an alkylene oxy. In some embodiments, each L 2 C is selected independently 1~4 It is alkenylene.

[0080] In some embodiments, L 1 L 2 -NHC(O)-L 2 -NHC(O)-L 2 - and each L 2 C is selected independently 1~4 It is alkylene.

[0081] In some embodiments, L 1 teeth: [ka] And, During the ceremony: [ka] L1 It shows the bond between and ring A; [ka] L 1 This shows the bond between and ring B; and [ka] L 1 and R 1 This shows a connection between [the two].

[0082] In some embodiments, R 1 It contains a chelating group. In some embodiments, R 1 It contains a chelate group and a metal. In some embodiments, R 1 It comprises a chelate group and a metal suitable for imaging using imaging techniques (e.g., magnetic resonance imaging, nuclear imaging, etc.). In some embodiments, R 1 It contains chelate groups and metals suitable for magnetic resonance imaging. In some embodiments, R 1 It contains chelating groups and metals suitable for nuclear imaging.

[0083] In some embodiments, R 1 The metal is Gd 3+ Mn 2+ , 68 Ga, 64 Cu, and 111 Selected from the group consisting of In. In some embodiments, R 1 The metal is Gd 3+ That is the case.

[0084] In some embodiments, R 1The chelating group is selected from the group consisting of 1,4,7-triazacyclononane triacetic acid (NOTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA), and ethylenediaminetetraacetic acid (EDTA).

[0085] In some embodiments, R 1 teeth: [ka] Selected from the group consisting of, In the formula, M is a metal. [ka] R 1 and L 1 This shows a connection between [the two].

[0086] In some embodiments, R 1 teeth: [ka] Selected from the group consisting of, In the formula, M is Gd 3+ Mn 2+ , 68 Ga, 64 Cu, and 111 A metal selected from the group consisting of In [ka] R 1 and L 1 This shows a connection between [the two].

[0087] In some embodiments, R 1 teeth: [ka] And, In the formula, M is a metal. [ka] R 1 and L 1 This shows a connection between [the two].

[0088] In some embodiments, R 1 teeth: [ka] And, In the formula, M is Gd 3+ Mn 2+ , 68 Ga, 64 Cu, and 111 A metal selected from the group consisting of In [ka] R 1 and L 1 This shows a connection between [the two].

[0089] In some embodiments, R 1 teeth: [ka] And in the formula, [ka] R 1 and L 1 This shows a connection between [the two].

[0090] In some embodiments: Ring A is selected from the group consisting of phenyl, bicyclic 8-16 member heterocycloalkyl, tricyclic 8-16 member heterocycloalkyl, bicyclic 8-16 member heteroaryl, and tricyclic 8-16 member heteroaryl; Ring B is selected from the group consisting of phenyl, bicyclic 8-16 member heterocycloalkyl, tricyclic 8-16 member heterocycloalkyl, bicyclic 8-16 member heteroaryl, and tricyclic 8-16 member heteroaryl; L 1 L 2 -NHC(O)-L 2 -NHC(O)-L 2 -and; Each L 2 C is selected independently 1~4 It is alkylene; R 1 It contains a chelate group and a metal; R 2 and R 3 is OR a , C(O)R a , and OC(O)R a Each is independently selected from the group consisting of; Each R a H and C 1~4 Independently selected from the group consisting of alkyl groups; m is 0, 1, or 2; and n is 0, 1, or 2.

[0091] In some embodiments: Ring A is: [ka] Selected from the group consisting of; Ring B is: [ka] Selected from the group consisting of; L 1 L 2 -NHC(O)-L 2 -NHC(O)-L 2 -and; Each L 2 C is selected independently 1~4 It is alkylene; R 1 It contains a chelate group and a metal; R 2 and R 3 These are OR a and; Each R a H and C 1~4 Independently selected from the group consisting of alkyl groups; m is 0, 1, or 2; and n is 0, 1, or 2.

[0092] In some embodiments: Ring A is: [ka] Selected from the group consisting of; Ring B is: [ka]

[0093] Selected from the group consisting of; L 1 L 2 -NHC(O)-L 2 -NHC(O)-L 2 -and; Each L 2 C is selected independently1~4 It is alkylene; R 1 It contains a chelate group and a metal; R 2 and R 3 These are OR a and; Each R a H and C 1~4 Independently selected from the group consisting of alkyl groups; m is 0, 1, or 2; and n is 0, 1, or 2.

[0094] In some embodiments: Rings A and B are: [ka] Each is independently selected from the group consisting of; L 1 L 2 -NHC(O)-L 2 -NHC(O)-L 2 -and; Each L 2 C is selected independently 1~4 It is alkylene; and R 1 teeth: [ka] Selected from the group consisting of; In the formula, M is Gd 3+ Mn 2+ , 68 Ga, 64 Cu, and 111 It is a metal selected from the group consisting of In.

[0095] In some embodiments: Ring A and Ring B are, respectively [ka] And, L 1 L 2 -NHC(O)-L 2 -NHC(O)-L 2 -and; Each L 2 C is selected independently 1~4 It is alkylene; and R 1 teeth, [ka] And in the formula, M is Gd 3+ Mn 2+ , 68 Ga, 64 Cu, and 111 It is a metal selected from the group consisting of In.

[0096] In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is the compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, variable R 1 , R 2 , R 3 m and n are defined according to the definitions provided herein for compounds of formula I.

[0097] In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is the compound of formula III: [ka] or a pharmaceutically acceptable salt thereof, variable R1 , R 2 , and R 3 This is defined according to the definition provided herein for compounds of formula I.

[0098] In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is the compound of formula IV: [ka] or a pharmaceutically acceptable salt thereof, variable R 1 This is defined according to the definition provided herein for compounds of formula I.

[0099] In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is the compound of formula V: [ka] or a pharmaceutically acceptable salt thereof, where M is a metal, defined according to the definition provided herein for the compound of formula I.

[0100] In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is the compound of formula Va: [ka] or a pharmaceutically acceptable salt thereof, where M is a metal, defined according to the definition provided herein for the compound of formula I.

[0101] In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is the compound of formula Vb: [ka] or a pharmaceutically acceptable salt thereof, where M is a metal, defined according to the definition provided herein for the compound of formula I.

[0102] In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is the compound of formula Vc: [ka] or a pharmaceutically acceptable salt thereof, where M is a metal, defined according to the definition provided herein for the compound of formula I.

[0103] In some embodiments, the compound of formula I is: [ka] or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the compound of formula I is: [ka] or a pharmaceutically acceptable salt thereof.

[0105] synthesis The synthesis of a representative compound of formula I, mcMPO-Gd, using the following general reaction conditions: (a) NaNO2, NaBr, 0.75M HBr, -15℃; (b) MgSO4, H2SO4, t-BuOH, rt, 45% in 2 steps; (c) Boc2O, K2CO3, THF / H2O(1 / 4), rt; (d) EDC.HCl, HOBt, DMF, rt, 82% in 2 steps; (e) TFA / DCM(1 / 2), 63%; f) K2CO3, CH3CN, reflux, 78%; g) TFA / DCM, rt; h) GdCl3, pH 5.5, rt, then overnight at 50℃; i) EDC.HCl, HOBt, NEt3, DMSO, 25%, is shown in schemes 1A to 1B. [ka] [ka]

[0106] Compound 1 was synthesized in two steps according to the published procedure (see, for example, International Patent Application No. WO2005 / 122682; and Moumne et al, J. Org. Chem., 2006, 71:3332-3334). Intermediate 4 was synthesized in three steps, starting with Boc protection of 5-hydroxytryptophan, followed by coupling with 5-hydroxyindoleacetic acid using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) to give compound 3, which was then deprotected with Boc to provide intermediate 4. The synthesis of intermediate 8 began with macrocyclic compound 5 and compound 1 under basic conditions to give compound 6. Compound 6 was hydrolyzed under acidic conditions and subsequently chelated with GdCl3 (see, for example, Kielar et al, J. Am. Chem. Soc. 2010, 132:7836-7837) to provide intermediate 8. Intermediate 8 was then coupled with intermediate 4 using EDC hydrochloride and hydroxybenzotriazole (HOBt) to provide the final product mcMPO-Gd. The structure of mcMPO-Gd was confirmed by high-resolution mass spectrometry.

[0107] DOTA was selected as the representative chelating group due to its thermodynamic and kinetic stability compared to linear chelates and other macrocyclic chelates (see, e.g., Port et al, Biometals, 2008, 21:469-490). Two 5-hydroxyindole units were selected as MPO-activatable moieties to enhance retention, as previously reported (see, e.g., Rodriguez et al, J.Am.Chem.Soc. 2010, 132:168-177). As shown in Figure 1, mcMPO-Gd differs from the previously reported compound "MPO-Gd" in that the two 5-hydroxyindole moieties (5-hydroxytryptophan and 5-hydroxyindoleacetic acid) are offset and separated from the chelate via a short linker to the side rather than the opposite side of the chelate. The two amide bonds formed via the linker in mcMPO-Gd increased the stiffness of the drug compared to MPO-Gd. Without being constrained by theory, it was hypothesized that the rigid structure of mcMPO-Gd would result in a more effective agent compared to MPO-Gd by 1) reducing segmental movement to increase relaxation and 2) creating better protein binding efficiency to improve sensitivity to MPO activity.

[0108] The reactions for preparing the compounds and salts described herein can be carried out in suitable solvents readily selectable by those skilled in the art of organic synthesis. Suitable solvents may be substantially inactive with the starting materials (reactants), intermediates, or products at the temperature in which the reaction is carried out (e.g., a temperature that may range from the freezing temperature to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, a solvent suitable for that particular reaction step can be selected by those skilled in the art.

[0109] The preparation of the compounds and salts described herein may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in TW Greene and PGMWuts, Protecting Groups in Organic Synthesis, 3rd Edition, Willie & Sons, New York (1999).

[0110] The reaction can be monitored by any suitable method known to those skilled in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) The compounds can be monitored by spectroscopic means such as infrared spectroscopy, spectrophotometric methods (e.g., UV-Vis), and mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin-layer chromatography (TLC). The compounds can be purified by those skilled in the art by various methods, including high-performance liquid chromatography (HPLC) and normal-phase silica chromatography.

[0111] Divalent bond substituents are described in various places in this specification. Each divalent bond substituent is particularly intended to include both forward and reverse forms of the bond substituent. For example, -NR(CR'CR'') n - is -NR(CR'R'') n -and-(CR'R'') n Includes both NR- and NHC(O)L 2 is -NHC(O)L 2 -and -L 2 It includes both C(O)NH-. When a structure clearly requires a binding group, the Markush variable listed for that group is understood to be a binding group.

[0112] The term "n-membered," where n is an integer, typically describes ring-forming atoms in a part of a ring where the number of ring-forming atoms is n. For example, phenyl is an example of a 6-membered aryl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, and pyridyl is an example of a 6-membered heteroaryl ring.

[0113] Throughout the definition, the term "C n~m " refers to the range including the endpoint, where n and m are integers and refer to the number of carbon atoms. For example, C 1~4 , C 1~6 This includes, among others.

[0114] As used herein, the term "C n~m "Alkyl" refers to a saturated hydrocarbon group that may be linear or branched, having n to m carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, and sec-butyl. In some embodiments, alkyl groups may contain 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0115] As used herein, the term "C n~m "Alkylene" refers to a divalent alkyl bond group having n to m carbon atoms (e.g., -CH2-, ethane-1,2-diyl, propane-1,3-diyl, etc.). In some embodiments, the alkylene portion contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

[0116] As used herein, the term "C n~m "Alkenylene" refers to a divalent alkene bond group having n to m carbon atoms. In some embodiments, the alkylene portion contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0117] As used herein, the term "C n~m "Alkylene oxy" is a divalent alkoxy bond group having n to m carbon atoms (i.e., "-OC"). n~m This refers to alkylene-). In some embodiments, the alkylene oxy portion contains 1 to 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

[0118] As used herein, the term "aryl" refers to an aromatic hydrocarbon group that may be monocyclic or polycyclic (e.g., having two, three, or four fused rings). n~m The term "aryl" refers to an aryl group having n to m ring carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthracenyl, phenantrenyl, indanyl, and indenyl. In some embodiments, the aryl group has 6 to about 20 carbon atoms, 6 to about 15 carbon atoms, or 6 to about 10 carbon atoms. In some embodiments, the aryl group is phenyl.

[0119] As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has one, two, three, or four heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N in the heteroaryl moiety may be an N-oxide. In some embodiments, the heteroaryl has 5 to 20 ring atoms and one, two, three, or four heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl has 5 to 16 ring atoms and one, two, three, or four heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a bicyclic heteroaryl (e.g., a fused bicyclic heteroaryl) having 5 to 16 ring atoms and 1, 2, 3, or 4 heteroatom members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a tricyclic heteroaryl (e.g., a fused tricyclic heteroaryl) having 5 to 16 ring atoms and 1, 2, 3, or 4 heteroatom members independently selected from nitrogen, sulfur, and oxygen.

[0120] As used herein, “heterocycloalkyl” refers to a non-aromatic monocyclic or polycyclic heterocycle having one or more ring-forming heteroatoms selected from O, N, or S. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may optionally be substituted with oxo or sulfide (e.g., C(O), S(O), C(S), or S(O)2). The heterocycloalkyl group may be attached through the ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds or 0 to 2 double bonds. The heterocycloalkyl group containing a condensed aromatic ring may be attached through any ring-forming atoms, including the ring-forming atoms of the condensed aromatic ring. In some embodiments, the heterocycloalkyl group has 4 to 20, 4 to 16, 8 to 20, or 8 to 16 ring atoms, each having one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, and optionally one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a bicyclic heterocycloalkyl (e.g., a condensed bicyclic heterocycloalkyl) having 4 to 16 ring atoms and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen, and optionally having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a tricyclic heterocycloalkyl (e.g., a condensed tricyclic heterocycloalkyl) having 4 to 16 ring atoms and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen, and optionally having one or more oxidized ring members.

[0121] In certain contexts, definitions or embodiments refer to specific rings (e.g., azetidine rings, pyridine rings, etc.). Unless otherwise specified, these rings may be attached to any ring member, provided that the valence of the atoms does not exceed the limit. For example, a pyridinyl ring may be attached at any position on the ring, while a pyridine-3-yl ring is attached at position 3.

[0122] As used herein, the term “compound” includes all stereoisomers, geometric isomers, tautomers, and isotopes of the structure depicted. A compound defined herein by name or structure as one specific tautomer is intended to include other tautomers unless otherwise specified.

[0123] The compounds provided herein also include tautomers. Tautomers arise from the exchange of a single bond with an adjacent double bond, along with the simultaneous transfer of protons. Tautomers include prototropic tautomers, which are the protonated states of isomers having the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imoid acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in a heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomers may be in equilibrium or sterically fixed to one form by appropriate substitution.

[0124] Unless otherwise defined, the compounds provided herein may also contain all isotopes of the atoms that result in the intermediate or final compound. An isotope is an atom that has the same atomic number but a different mass number. Unless otherwise specified, when an atom is designated as an isotope or radioisotope, it is understood that the atom contains that isotope or radioisotope in amounts greater than its natural abundance. For example, when an atom is designated as "D" or "deuterium," its position is understood to contain at least 3000 times more deuterium than its natural abundance of 0.015% (i.e., at least 45% of deuterium).

[0125] All compounds and their pharmaceutically acceptable salts can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or isolated.

[0126] In some embodiments, the preparation of the compound may involve the addition of an acid or base to affect, for example, the catalytic action of a desired reaction or the catalysis of the formation of a salt form, such as an acid addition salt.

[0127] Examples of acids may be inorganic or organic acids, and include, but are not limited to, strong and weak acids. Some examples of acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, 4-nitrobenzoic acid, methanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, and nitric acid. Some weak acids include, but are not limited to, acetic acid, propionic acid, butyric acid, benzoic acid, tartaric acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, and decanoic acid.

[0128] Examples of bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, and sodium bicarbonate. Some examples of strong bases include, but are not limited to, hydroxides, alkoxides, metal amides, metal hydrides, metal dialkylamides, and arylamines. Alkoxides include lithium, sodium, and potassium salts of methyl oxide, ethyl oxide, and t-butyl oxide; metal amides include sodium amide, potassium amide, and lithium amide; metal hydrides include sodium hydride, potassium hydride, and lithium hydride; and metal dialkylamides include lithium, sodium, and potassium salts of methyl-substituted amides, ethyl-substituted amides, n-propyl-substituted amides, isopropyl-substituted amides, n-butyl-substituted amides, tert-butyl-substituted amides, trimethylsilyl-substituted amides, and cyclohexyl-substituted amides.

[0129] In some embodiments, the compounds provided herein, or salts thereof, are substantially isolated. “Substantially isolated” means that the compounds are at least partially or substantially separated from the environment in which they were formed or detected. Partial isolation may include, for example, a composition in which the compounds provided herein are concentrated. Substantial isolation may include a composition containing at least about 50%, at least about 60%, at least about 70%, at least 80%, at least 90%, at least 95%, at least 97%, or at least about 99% by weight of the compounds provided herein, or salts thereof. Methods for isolating compounds and salts thereof are common in the art.

[0130] As used herein, the terms “room temperature” or “rt” are understood in the art to generally refer to the temperature that is approximately the same as the temperature of the room in which the reaction is carried out, for example, a temperature of about 20°C to about 30°C, e.g., the reaction temperature.

[0131] The phrase "pharmaceutically acceptable" is used to refer to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with human or animal tissues within the bounds of sound medical judgment, without excessive toxicity, irritation, allergic reactions, or other problems or complications, and in proportion to a reasonable benefit / risk ratio.

[0132] This application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salt” refers to a derivative of a disclosed compound in which the parent compound is modified by converting the present acidic or basic moiety to the form of its salt. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts of this application include, for example, conventional non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of this application can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic or free base form of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent, or in a mixture of two generally non-aqueous media, preferably ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (MeCN). A list of suitable salts can be found in Remington Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977). Conventional methods for preparing salt forms are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, 2002.

[0133] How to use This application further provides a method for imaging a sample of cells or tissue. As used herein, the term “subject” refers to any animal, including mammals. For example, mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human.

[0134] In some embodiments, the method is: i) To administer the compounds provided herein (e.g., any of the compounds of formulas I to Vc, or pharmaceutically acceptable salts thereof) to the target; ii) Allow sufficient time for the compound to accumulate in the cell or tissue sample; and iii) Imaging a cell or tissue sample using imaging techniques. This includes. In some embodiments, the method further includes imaging a cell or tissue sample prior to step i). In some embodiments, the method is an in vitro method. In some embodiments, the method is an in vivo method.

[0135] This application further provides a method for diagnosing diseases or disorders associated with abnormal myeloperoxidase (MPO) activity in a subject. In some embodiments, the method is: i) To administer the compounds provided herein (e.g., any of the compounds of formulas I to Vc, or pharmaceutically acceptable salts thereof) to the target; ii) Waiting for a sufficient amount of time for the compound to accumulate in the disease-related cell or tissue site; and iii) Imaging a cell or tissue sample using imaging techniques. This includes. In some embodiments, the method further includes imaging the subject before step i). In some embodiments, the method is an in vitro method. In some embodiments, the method is an in vivo method.

[0136] In some embodiments, a sufficient time is approximately 5 minutes to 6 hours, for example, approximately 5 minutes to 6 hours, approximately 5 minutes to 4 hours, approximately 5 minutes to 2 hours, approximately 5 minutes to 1 hour, approximately 5 minutes to 30 minutes, approximately 30 minutes to 6 hours, approximately 30 minutes to 4 hours, approximately 30 minutes to 2 hours, approximately 30 minutes to 1 hour, approximately 1 hour to 6 hours, approximately 1 hour to 4 hours, approximately 1 hour to 2 hours, approximately 2 hours to 6 hours, approximately 2 hours to 4 hours, or approximately 4 hours to 6 hours.

[0137] This application further provides a method for imaging myeloperoxidase (MPO) activity in cells. In some embodiments, the method is: i) Contacting cells with the compounds provided herein (e.g., any of the compounds of formulas I to Vc, or pharmaceutically acceptable salts thereof); and ii) Imaging cells using imaging techniques Includes.

[0138] This application further provides a method for imaging myeloperoxidase (MPO) activity in tissue samples. In some embodiments, the method is: i) Contacting a tissue sample with a compound provided herein (e.g., any compound of formulas I to Vc, or a pharmaceutically acceptable salt thereof); and ii) Imaging cells using imaging techniques Includes.

[0139] This application further provides a method for detecting myeloperoxidase (MPO) activity in a cell or tissue sample. In some embodiments, the method is: i) Contacting a cell or tissue sample with a compound provided herein (e.g., any compound of formulas I to Vc, or a pharmaceutically acceptable salt thereof); and ii) Imaging a cell or tissue sample using imaging techniques. Includes.

[0140] This application further provides a method for detecting myeloperoxidase activity in a subject. In some embodiments, the method is: i) administering the compounds provided herein (e.g., any of the compounds of formulas I to Vc, or pharmaceutically acceptable salts thereof) to the subject; and ii) Imaging the subject using imaging technology. Includes.

[0141] This application further provides a method for monitoring the treatment of diseases or disorders related to abnormal myeloperoxidase (MPO) activity in a subject, the method being: i) To administer the compounds provided herein (e.g., any of the compounds of formulas I to Vc, or pharmaceutically acceptable salts thereof) to the target; ii) Imaging the subject using imaging techniques; iii) Administering a therapeutically effective dose of a therapeutic compound to treat a disease or disorder; iv) Imaging the target cells or tissues using imaging techniques; and v) Compare the image from step i) with the image from step iv). Includes.

[0142] In some embodiments, the method further comprises administering a compound provided herein (e.g., any compound of formulas I to Vc, or a pharmaceutically acceptable salt thereof) after the administration in step iii) and before imaging in step iv). In some embodiments, the therapeutic compound is useful in treating diseases or disorders associated with abnormal myeloperoxidase (MPO) activity. In some embodiments, the therapeutic compound is a therapeutic compound provided herein.

[0143] In some embodiments, the imaging technique is selected from the group consisting of magnetic resonance imaging and nuclear imaging. In some embodiments, the imaging technique is magnetic resonance imaging. In some embodiments, the imaging technique is nuclear imaging.

[0144] In some embodiments, the compound of formula I is: [ka] or a pharmaceutically acceptable salt thereof, and the imaging technique is selected from the group consisting of magnetic resonance imaging and nuclear imaging. In some embodiments, the imaging technique is magnetic resonance imaging. In some embodiments, the imaging technique is nuclear imaging.

[0145] In some embodiments, diseases or disorders associated with abnormal myeloperoxidase activity are selected from the group consisting of non-alcoholic steatohepatitis (NASH), cancer, rheumatic diseases, inflammatory diseases, central nervous system diseases, cardiovascular diseases, autoimmune diseases, and inflammation associated with one or more of cancer, rheumatic diseases, infectious diseases, central nervous system diseases, cardiovascular diseases, and autoimmune diseases. In some embodiments, diseases or disorders associated with abnormal myeloperoxidase activity are selected from the group consisting of cancer, rheumatic diseases, inflammatory diseases, central nervous system diseases, cardiovascular diseases, and autoimmune diseases. In some embodiments, diseases or disorders associated with abnormal myeloperoxidase activity are selected from the group consisting of inflammation associated with one or more of cancer, rheumatic diseases, infectious diseases, central nervous system diseases, cardiovascular diseases, and autoimmune diseases.

[0146] In some embodiments, a disease or disorder associated with abnormal myeloperoxidase activity is non-alcoholic steatohepatitis (NASH).

[0147] In some embodiments, the disease or disorder associated with abnormal myeloperoxidase activity is cancer. In some embodiments, cancer includes solid tumors. In some embodiments, cancer is a solid tumor. In some embodiments, cancer is selected from the group consisting of bladder cancer, breast cancer, carcinoma, cervical cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, skin cancer, gastric cancer, testicular cancer, leukemia, and thyroid cancer. In some embodiments, cancer is a solid tumor associated with one or more of bladder cancer, breast cancer, carcinoma, cervical cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, skin cancer, gastric cancer, testicular cancer, thyroid cancer, or any combination thereof. In some embodiments, the disease or disorder associated with abnormal myeloperoxidase activity is inflammation associated with one or more cancers selected from the group consisting of bladder cancer, breast cancer, carcinoma, cervical cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, skin cancer, gastric cancer, testicular cancer, thyroid cancer, leukemia, or any combination thereof.

[0148] In some embodiments, the disease or disorder associated with abnormal myeloperoxidase activity is a central nervous system disorder. In some embodiments, the central nervous system disorder is selected from the group consisting of Alzheimer's disease, stroke, epilepsy, Parkinson's disease, and inflammation associated with Alzheimer's disease, stroke, epilepsy, and Parkinson's disease. In some embodiments, the central nervous system disorder is selected from the group consisting of Alzheimer's disease, stroke, epilepsy, and Parkinson's disease. In some embodiments, the central nervous system disorder is Alzheimer's disease and inflammation associated with one or more of stroke, epilepsy, and Parkinson's disease.

[0149] In some embodiments, the disease or disorder associated with abnormal myeloperoxidase activity is a cardiovascular disease. In some embodiments, the cardiovascular disease is selected from the group consisting of atherosclerosis, myocardial infarction, atrial fibrillation, vasculitis, and inflammation associated with one or more of atherosclerosis, myocardial infarction, atrial fibrillation, and vasculitis. In some embodiments, the cardiovascular disease is selected from the group consisting of atherosclerosis, myocardial infarction, atrial fibrillation, and vasculitis. In some embodiments, the cardiovascular disease is inflammation associated with one or more of atherosclerosis, myocardial infarction, atrial fibrillation, and vasculitis.

[0150] In some embodiments, the disease or disorder associated with abnormal myeloperoxidase activity is an autoimmune disease. In some embodiments, the autoimmune disease is selected from the group consisting of multiple sclerosis, meningitis, encephalitis, and inflammation associated with one or more of multiple sclerosis, meningitis, and encephalitis. In some embodiments, the autoimmune disease is inflammation associated with one or more of multiple sclerosis, meningitis, and encephalitis.

[0151] In some embodiments, the disease or disorder associated with abnormal myeloperoxidase activity is a rheumatic disease. In some embodiments, the rheumatic disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, and inflammatory arthritis. In some embodiments, the rheumatic disease is inflammatory arthritis. In some embodiments, the inflammatory arthritis is selected from the group consisting of gout and calcium pyrophosphate crystal deposition disease (CPPD). In some embodiments, the disease or disorder associated with abnormal myeloperoxidase activity is inflammation associated with one or more of rheumatoid arthritis, osteoarthritis, and inflammatory arthritis.

[0152] In some embodiments, the disease or disorder associated with abnormal myeloperoxidase activity is an infectious disease. In some embodiments, the infectious disease is a fungal disease and a bacterial disease. In some embodiments, the fungal disease is a disease associated with C. albicans. In some embodiments, the infectious disease includes a yeast infection. In some embodiments, the yeast infection is an infection associated with C. tropicalis. In some embodiments, the disease or disorder associated with abnormal myeloperoxidase activity is inflammation associated with an infectious disease or a bacterial disease.

[0153] As used herein, the phrase “therapeutic effective dose” refers to the amount of an active compound or pharmaceutical product that elicits a biological or medical response in a tissue, system, animal, individual, or human, as sought by a researcher, veterinarian, physician, or other clinician. In some embodiments, the dose of the compound, or a pharmaceutically acceptable salt thereof, administered to a subject or individual is about 1 mg to about 2 g, about 1 mg to about 1000 mg, about 1 mg to about 500 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, or about 50 mg to about 500 mg.

[0154] As used herein, the term “to treat” or “treatment” means one or more of the following: (1) inhibiting a disease; for example, inhibiting a disease, condition or disorder in an individual experiencing or presenting the pathology or symptomatology of a disease, condition or disorder (i.e., preventing further development of the pathology and / or symptomatology); and (2) improving a disease; for example, improving a disease, condition or disorder in an individual experiencing or presenting the pathology or symptomatology of a disease, condition or disorder (i.e., reversing the pathology and / or symptomatology) in order to reduce the severity of the disease or reduce or alleviate one or more symptoms of the disease.

[0155] Combination therapy For example, one or more additional therapeutic agents, such as anti-inflammatory agents, steroids, immunosuppressants, chemotherapeutic agents, or other drugs such as therapeutic antibodies, may be used in combination with the compounds and salts of this application for the treatment of diseases provided herein.

[0156] Examples of antibodies for use in combination therapy include, but are not limited to, trastuzumab (e.g., anti-HER2), ranibizumab (e.g., anti-VEGF-A), bevacizumab (e.g., anti-VEGF), panitumumab (e.g., anti-EGFR), cetuximab (e.g., anti-EGFR), rituxan (anti-CD20), and antibodies directed towards c-MET.

[0157] Examples of steroids include corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone.

[0158] Examples of anti-inflammatory compounds include aspirin, choline salicylate, celecoxib, diclofenac potassium, diclofenac sodium, diclofenac sodium with misoprostol, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, sodium meclofenamate, mefenamic acid, nabumetone, naproxen, sodium naproxen, oxaprozin, piroxicam, rofecoxib, salsalate, sodium salicylate, sulindac, tolmetin sodium, and valdecoxib.

[0159] Examples of immunosuppressants include azathioprine, chlorambucil, cyclophosphamide, cyclosporine, daclizumab, infliximab, methotrexate, and tacrolimus.

[0160] One or more of the following drugs may be used in combination with the compounds provided herein and are presented as a non-limiting list: cell proliferation inhibitors, cisplatin, doxorubicin, taxol, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epotilon, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, tipifarnib, gefitinib, erlotinib hydrochloride, antibodies against EGFR, imatinib mesylate, gemcitabine, uracil mustard, chlormethine, ifosf Amid, melphalan, chlorambucil, pipobromane, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, folinic acid, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mito Ramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide, 17α-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianicene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene Goserelin, Carboplatin, Hydroxyurea, Amsacrin, Procarbazine, Mitotane, Mitoxantrone, Levamizole, Vinorelbine, Anastrozole, Letrozole, Capecitabine, Reloxafine, Hexamethylmelamine, Bevacizumab, Bexal, Velcade, Zevalin, Trisenox, Xeloda, Porfimer, Erbitux, Thiotepa, Altretamine, Trastuzumab, Fulvestrant, Exemestane, Rituximab, Alemtuzumab, Clofarabine, Cladribine, Aphydicolin,Sunitinib, dasatinib, tezacitabine, triapine, zidox, trimidox, amidox, bendamustine, ofatumumab, and idelalisib.

[0161] In some embodiments, additional therapeutic agents are useful for treating multiple sclerosis. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon beta-1a, interferon beta-1b, pegylated interferon beta-1a, glatiramer acetate, teriflunomide, fingolimod, mitoxantrone, dimethyl fumarate, natalizumab, ozanimod, laquinimod, alemtuzumab, daclizumab, rituximab, ocrelizumab, and ofatumumab.

[0162] Pharmaceutical preparations When used as pharmaceuticals, the compounds and salts provided herein can be administered in the form of pharmaceutical compositions. These compositions can be prepared as described herein or elsewhere and can be administered by various routes depending on whether topical or systemic treatment is desired and the area to be treated. Administration may be topical (including transdermal, epidermal, ocular, and mucosal delivery including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or inhalation of powder or aerosol, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration may include intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracranial (e.g., subarachnoid or intraventricular) administration. Parenteral administration may be in the form of a single bolus dose, or, for example, by a continuous perfusion pump. In some embodiments, the compounds provided herein are suitable for parenteral administration. In some embodiments, the compounds provided herein are suitable for intravenous administration. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powdered, or oily bases, thickeners, etc., may be required or desirable. In some embodiments, the pharmaceutical compositions provided herein are suitable for parenteral administration. In some embodiments, the compositions provided herein are suitable for intravenous administration.

[0163] Also provided are pharmaceutical compositions containing, in combination with one or more pharmaceutically acceptable carriers (excipients), the compounds provided herein (e.g., any of the compounds of formulas I to Vc, or pharmaceutically acceptable salts thereof) as an active ingredient. When preparing the compositions provided herein, the active ingredient is typically mixed with the excipient, diluted by the excipient, or encapsulated in such carriers in the form of capsules, sachets, paper, or other containers. If the excipient functions as a diluent, it may be a solid, semi-solid, or liquid material that functions as a medium, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), ointments, soft gelatin capsules and hard gelatin capsules, suppositories, sterile injections, and sterile packaged powders.

[0164] Some examples of suitable excipients, but not limited to, include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginic acid, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulation may also contain, but not limited to, lubricants such as talc, magnesium stearate, and mineral oil; humectants; emulsifiers and suspending agents; preservatives such as methylbenzoic acid and propyl hydroxybenzoic acid; sweeteners; flavorings, or combinations thereof.

[0165] Active compounds may be effective across a wide range of doses and are generally administered in pharmaceutically effective doses. However, it should be understood that the actual amount of compound administered is usually determined by a physician, depending on relevant circumstances, including the chosen route of administration, the compound actually administered, age, weight, and the individual patient's response and the severity of the patient's symptoms.

[0166] Examples The present invention will be described in more detail as specific embodiments. The following embodiments are provided for illustrative purposes only and are not intended to limit the invention in any way.

[0167] General methods and materials Unless otherwise specified, all chemicals were obtained from Sigma Chemical Corporation. 5-hydroxy-L-tryptophan was obtained from ChemImpex International (Wooddale, IL). DO3A-tert-butyl ester was purchased from Macrocyclic Corporation (Plano, TX), and serotonin was purchased from TCI America (Portland, OR). Glucose oxidase was obtained from Affymetrix (Santa Clara, CA). Complete Freudian adjuvant was purchased from Sigma-Aldrich. Myeloperoxidase was obtained from Lee Biosolutions (St. Louis, MO). High-resolution mass spectrometry was performed using ThermoScientific® Q-Exactive Plus Ultimate 3000 HPLC flow injection analysis. 1 H-NMR and 13 13C NMR was performed using a Bruker Ascend® 400. Liquid chromatography-mass spectrometry was performed using a Waters 2545 binary gradient module with a 2777 sample manager.

[0168] All numerical data were first analyzed for normality using the Shapiro-Wilk normality test, followed by significance determination using appropriate parametric or nonparametric tests. TS Apoe - / - and Mpo - / - Apoe - / - During, or TS Apoe - / -Differences in ΔCNR between feeding WD ± AZM198 were evaluated using the Kruskal-Wallis test, followed by Dunn's multiple comparison test, Mann-Whitney rank-sum test, or, where appropriate, unpaired t-tests. All statistical analyses were performed using GraphPad Prism version 8.01 for Mac (GraphPad Software, La Jolla, California, USA), and individual data are presented mean ± SEM. A p-value < 0.05 was considered statistically significant.

[0169] Example 1. Synthesis of (S)-2-bromopentanediate di-tert-butyl (compound 1) [ka] Compound 1 was prepared according to a previously reported procedure (see, for example, International Patent Application No. WO2005 / 122682; and Moumne et al, J.Org.Chem.2006, 71:3332-3334).

[0170] Step 1. (S)-2-bromopentanioic acid [ka] A solution of NaNO2 (0.9 g, 13 mmol) in water (5 mL) was added dropwise over 30 minutes at -15°C to a mixture of L-glutamic acid (1.47 g, 10 mmol) and NaBr (3.8 g, 37 mmol) in 0.75 M HBr (30 mL). The reaction was stirred at the same temperature for a further 2 hours, after which concentrated H2SO4 (1 mL) was gradually added to the solution, followed by extraction with Et2O (30 mL x 3). The assembled organic phase was washed with brine, dried over Na2SO4, and evaporated to give (S)-2-bromopentanedioic acid, which was used in the next step without further purification.

[0171] Step 2. (S)-2-bromopentanediate di-tert-butyl (compound 1) [ka]

[0172] A mixture of MgSO4 (5 g) and concentrated H2SO4 (0.5 mL) in DCM (5 mL) was stirred at room temperature for 2 hours. Then, the above compound and t-BuOH (3 g, 40 mmol) were added, and the mixture was stirred for a further 20 hours. The reaction product was filtered to remove the salts and extracted with DCM (20 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, evaporated, and subjected to flash chromatography (hexane:ethyl acetate 5:1) to give compound 1 as a yellow oil (45% in 2 steps). 1 H NMR(500MHz,CDCl3)δ4.23(dd,1H),2.51(m,2H),2.29(m,2H),1.48(s,9H),1.43(s,9H); 13 ¹³C NMR (125 MHz, CDCl3): δ 172.7, 168.4, 82.8, 82.6, 46.8, 32.9, 30.0, 28.1, 27.9. m / z (ES+): 325.3 (M+H) confirmed by LC-MS.

[0173] Example 2. Synthesis of (S)-2-amino-3-(5-hydroxy-1H-indole-3-yl)-N-(2-(5-hydroxy-1H-indole-3-yl)ethyl)propanamide (intermediate 4) [ka]

[0174] Step 1. (S)-2-((tert-butoxycarbonyl)amino)-3-(5-hydroxy-1H-indole-3-yl)propionic acid (Compound 2) [ka]

[0175] A solution of di-t-butyl dicarbonate (784 mg, 3.6 mmol) in THF (4 mL) was added to a solution of L-5-hydroxytryptophan (5-HTP, 660 mg, 3.0 mmol) and K2CO3 (880 mg, 6.4 mmol) in water (8 mL). The reaction mixture was stirred at room temperature for 2 hours, and then neutralized to pH 2-3 by adding 1 M HCl. After removing the THF by evaporation, the solution was extracted with ethyl acetate (20 mL x 3), the organic phase was washed with brine (10 mL x 3), dried over anhydrous Na2CO3, and evaporated to give compound 2, which was used in the next step without further purification.

[0176] Step 2. tert-butyl(S)-(3-(5-hydroxy-1H-indole-3-yl)-1-((2-(5-hydroxy-1H-indole-3-yl)ethyl)amino)-1-oxopropan-2-yl)carbamate (compound 3) [ka]

[0177] To a solution of compound 2 (385 mg, 1.2 mmol) in DMF (5 mL), EDC.HCl (280 mg, 1.4 mmol) was added, followed by HOBt (216 mg, 1.4 mmol), and the resulting mixture was stirred for 10 minutes. Next, a solution of free base serotonin (220 mg, 1.0 mmol), prepared beforehand in DMF (4 mL), was added to the reaction mixture. The resulting mixture was then stirred for a further 2 hours. The reaction mixture was extracted with ethyl acetate (10 mL x 3), the organic phase was washed with brine (10 mL x 3), dried over anhydrous Na2CO3, and evaporated. The residue was purified by flash chromatography (ethyl acetate as eluate) to give compound 3 as a white solid (390 mg) in 82% yield. 1H NMR(500MHz,DMSO)δ10.45(s,2H),8.56(s,1H),8.54(s,1H),7.89(t,1H),7.10(d,1H),7.09(d,1H),7.0(m,2H),6.88(d,1H) ),6.83(d,1H),6.67(d,1H),6.57(m,2H),4.12(m,1H),3.26(m,2H),2.96(dd,1H),2.79(dd,1H),2.66(m,2H),1.32(s,9H); 13 ¹³C NMR (125MHz, DMSO) δ 171.8, 155.1, 150.15, 150.13, 130.8, 130.6, 128.1, 127.8, 123.9, 123.0, 111.6, 111.4, 111.2, 111.1, 110.7, 109.3, 102.5, 102.2, 77.9, 55.0, 40.1, 28.2, 28.0, 25.2; m / z confirmed by LCMS: 479.4 (M+H).

[0178] Step 3. (S)-2-amino-3-(5-hydroxy-1H-indole-3-yl)-N-(2-(5-hydroxy-1H-indole-3-yl)ethyl)propanamide (Intermediate 4) [ka]

[0179] Compound 3 (300 mg) was added to a solution of 10% trifluoroacetic acid (TFA) in dichloromethane (DCM; 4 mL), and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was then evaporated under reduced pressure to remove the solvent, and subjected to preparative HPLC to give the desired intermediate 4 (63% yield). 1 H NMR(500MHz,DMSO)δ10.70(d,1H),10.50(d,1H),8.57(m,3H),8.05(m,2H),7.14(dd,2H),7.09(d,1H),6.9 8(dd,2H),6.81(d,1H),6.62(dd,2H),3.87(dt,1H),3.34(m,2H),3.10(dd,1H),2.98(dd,1H),2.68(m,2H); 13¹³C NMR (125MHz, DMSO): δ 168.3, 150.4, 150.2, 130.9, 130.8, 127.8, 127.7, 125.2, 123.2, 111.7, 111.5, 111.2, 110.4, 106.0, 102.6, 102.1, 94.8, 52.8, 39.9, 27.6, 25.0. m / z confirmed by LCMS: 379.5 (M+H).

[0180] Example 3. Synthesis of (R)-2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)pentanedioate di-tert-butyl (compound 6) [ka]

[0181] Potassium carbonate (210 mg, 1.5 mmol) was added to a solution of 2,2',2”-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)tri-tert-butyl (DO3A-tBu-ester; compound 5; 770 mg, 1.5 mmol) and compound 1 (480 mg, 1.5 mmol) in acetonitrile (5 mL). The reaction mixture was heated under reflux for 24 hours. After removing the solvent under reduced pressure, the residue was dissolved in DCM and filtered. Flash chromatography using a gradient elution of DCM into 5% MeOH in DMF yielded compound 6 as a pale yellow solid in 78% yield. 1 H NMR(500MHz,DMSO)δ3.48-1.90(m,27H),1.40(s,45H) 13 ¹³C NMR (125MHz, DMSO): 174.8, 173.1, 173.0, 172.3, 82.5, 82.0, 81.9, 80.6, 60.0, 55.9(2), 55.6, 52.7, 52.5, 48.6, 48.1, 47.3, 44.3, 32.8, 28.2, 28.0, 27.9. m / z confirmed by δLCMS: 757.7 (M+H), 779.6 (M-H+Na).

[0182] Example 4. Synthesis of Compound 8 [ka]

[0183] Compound 8 was prepared according to a previously reported procedure (see, for example, Kielar et al, J.Am.Chem.Soc.2010,132:7836-7837), as described below.

[0184] Step 1. (R)-2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)pentanedioic acid (compound 7) [ka]

[0185] A solution of compound 6 (250 mg, 0.33 mmol) in TFA / DMF (4 mL / 2 mL) was stirred for 18 hours. The solvent was removed under reduced pressure, and the above process was repeated until deprotection was complete to obtain compound 7 (monitored by LC-MS, m / z(ES+): 477.4(M+H)), which was used in the next step without further purification.

[0186] Step 2. Synthesis of Compound 8 GdCl3·6H2O (135 mg, 0.36 mmol) was added to the solution of compound 7 in water (10 mL). The pH of the solution was adjusted to 5.5-6.0 by adding 1 M NaOH solution until the pH stabilized. The reaction mixture was heated overnight at 50°C. After cooling, the reaction mixture was adjusted to approximately 10.9 pH by adding 1 M HCl, stirred for 40 minutes, and then centrifuged. The supernatant was adjusted to pH 6.5 and freeze-dried to give compound 8 as a white solid. The m / z (ES-) confirmed by LC-MS was 630.2 (M), 652.1 (M-H+Na).

[0187] Example 5. Synthesis of mcMPO-Gd [ka]

[0188] To a solution of compound 8 (125 mg, 0.2 mmol) and triethylamine (56 μL, 0.4 mmol) in DMSO (3 mL), EDC.HCl (57 mg, 0.3 mmol) and HOBt (40 mg, 0.3 mmol) were added. After 20 minutes, a solution of intermediate 4 (76 mg, 0.2 mmol) in DMSO was added to the above reaction. The reaction mixture was stirred at room temperature for 1 hour, and then subjected to preparative HPLC to give the desired mcMPO-Gd (25%) as a white powder. The m / z (ES+): 992.5 (M+H); HRMS: 992.2795 (M+H, cal.C) confirmed by LC-MS. 40 H 49 GdN8O 12 ,992.2793)

[0189] Example 6. Stability of mcMPO-Gd: Zn 2+ Metal exchange reaction using Zn 2+ Zn is the main competing ion for gadolinium and is present in high concentrations in the blood. 2+ The kinetic stability of mcMPO-Gd in the presence of was compared to the kinetic stability of other drugs (see, for example, Rodriguez et al, J.Am.Chem.Soc., 2010, 132:168-177; and Laurent et al, Invest.Radiol., 2001, 36:115-122).

[0190] mcMPO-Gd or MPO-Gd (1 mM) was incubated with ZnCl2 (2.5 mM) in PBS at 40°C, and the relaxation rate (R1) was measured for 95 hours at 40°C at 0.47 T (20 MHz) using a Bruker Minispec (Bruker Analytics, Northvillerica, MA) with a reverse recovery pulse sequence. The stability of mcMPO-Gd was determined by the kinetic index (R1). (t) / R1( t=0 )=0.8) and thermodynamic index (R1 (72時間) / R1 (t=0)The results were evaluated using the following method and compared with MPO-Gd (see, for example, Rodriguez et al, J.Am.Chem.Soc., 2010, 132:168-177) and BMA-Gd-DTPA (see, for example, Moumne et al, J.Org.Chem., 2006, 71:3332-3334).

[0191] Zn 2+ and Gd 3+ The metal exchange reaction between these two points in time would result in a change in relaxation due to the formation of a GdPO4 precipitate. The T1 relaxation time was measured at different time points as previously described (see, for example, Rodriguez et al, J.Am.Chem.Soc., 2010, 132:168-177). As shown in Table 1, there was no change in T1 over 95 hours for mcMPO-Gd, and R1 (t) / R1 (t=0) The long-term index, defined as t=72 to 95 hours, was >0.97, and the ratio index was >5,000 minutes. This long-term index is substantially higher than that of MPO-Gd (0.76) and BMA-Gd-DTPA (0.09) (see, e.g., Laurent et al, Invest.Radiol., 2001, 36:115-122), and is consistent with previous reports on the kinetic stability of macrocyclic GBCAs (see, e.g., Laurent et al, Contrast Media Mol.Imaging 2006, 1:128-137), suggesting the high stability of mcMPO-Gd. [Table 1]

[0192] Example 7. Relaxation rate of mcMPO-Gd The relaxation rate (r1) of an MRI contrast agent reflects the sensitivity of the drug. The relaxation rates of mcMPO-Gd in PBS were measured at 40°C at concentrations of 0.33 mM, 0.5 mM, 0.75 mM, and 1 mM. The 1 / T1 values ​​were plotted against mcMPO-Gd concentration and fitted using linear regression. The slope of the linear function is defined as the relaxation rate of mcMPO-Gd (see, e.g., Rohrer et al, Invest.Radiol. 2005, 40:715-724). The relaxation rate of mcMPO-Gd was 5.4 mM at 0.47T (PBS, 40°C), as shown in Figure 2A. -1 seconds -1 This is the same as the 4.3 mM previously measured for MPO-Gd under the same conditions. -1 seconds -1 It was slightly higher than (see, for example, Querol et al, Org. Lett. 2005, 7: 1719-1722).

[0193] Example 8. In vitro activity of mcMPO-Gd after activation with MPO. To compare the reactivity of mcMPO-Gd and MPO-Gd with that of MPO, a solution of mcMPO-Gd or MPO-Gd in PBS (0.5 mM, 150 μL total) was incubated at 40°C with glucose (as an H2O2 donor; 6 μL, 1 M), glucose oxidase (GOX; 4 μL, 1 mg / mL), and MPO (10 μL, 2 mg / mL). The reaction was stopped by adding sodium azide (1 μL, 250 mg / mL), and the T1 relaxation time was measured at 40°C at 0 (before MPO addition), 1 minute, 2 minutes, 5 minutes, 10 minutes, 30 minutes, 60 minutes, 120 minutes, and 180 minutes as described above. The R1 ratio was measured (R1 (t) -R1 (t=0) ) / R1 (t=0) It was expressed as follows.

[0194] As shown in Figure 2B, the T1 change of mcMPO-Gd was more than three times greater than that of MPO-Gd over 3 hours, suggesting more significant activation of mcMPO-Gd compared to MPO-Gd.

[0195] Example 9. Binding to protein The ability of mcMPO-Gd and MPO-Gd to bind to bovine serum albumin (BSA) after activation by MPO was evaluated. A 150 μL solution of mcMPO-Gd / MPO-Gd (0.5 mM) in PBS was incubated with glucose (6 μL, 1 M), GOX (4 μL, 1 mg / mL), and MPO (10 μL, 2 mg / mL) at 40°C for 1 hour, with and without BSA. Relaxation rates were measured as described above.

[0196] As shown in Table 2, MPO-Gd showed a slight 22% improvement (from 32% to 54%) in T1 shortening in the presence of BSA. However, mcMPO-Gd showed a 41% improvement (80-121%) with BSA. Overall, MPO-mediated activation of mcMPO-Gd showed 2.2 times higher binding efficacy in the presence of BSA compared to MPO-Gd. These data suggest that mcMPO-Gd is more responsive to MPO activation than MPO-Gd. [Table 2]

[0197] Example 10. Cytotoxic MTT assay The cytotoxicity of mcMPO-Gd was evaluated using RAW264.7 cells and measured using the 3-(4,5-dimethylthiazole-2-yl)2,5-diphenyl-tetrazolium bromide (MTT) reduction assay, as previously described (see, e.g., Rodriguez et al, J.Am.Chem.Soc., 2010, 132:168-177). Approximately 1.5 × 10⁶ cells per well in a 96-well plate. 4Cells were incubated at 37°C for 16 hours in a solution of mcMPO-Gd in DMEM containing 10% FBS and 5% DMSO at 0 mM, 0.1 mM, 0.5 mM, 1 mM, 2 mM, and 5 mM concentrations. After incubation, cells were treated at 37°C for 2 hours with 100 μL of 0.5 mg / mL MTT before adding 100 μL of DMSO to each well. Plates were incubated overnight at 37°C, and optical density was measured at 570 nm using a microplate reader (Tecan Safire 2, Tecan, Mönnedorff, Switzerland). No significant cytotoxicity was observed up to 5 mM, as shown in Figure 3, which is well above the expected in vivo concentration.

[0198] Example 11. Magnetic resonance (MR) imaging of complete Freund's adjuvant (CFA) inflammation The efficacy of mcMPO-Gd was investigated in a well-established mouse model of subcutaneous inflammation induced by complete Freund's adjuvant (CFA). Female C57BL / 6J mice (Jackson Laboratory, Bar Harbor, ME) aged 6 to 10 weeks and MPO-deficient mice were used for this experiment. Under isoflurane anesthesia, the mice were subcutaneously injected with a 1:1 (v:v) emulsion of CFA:PBS (total volume 40 μL) into one forearm, and PBS (40 μL) was injected into the other side as a control. 24 hours later, gadolinium agents (mcMPO-Gd in PBS containing 10% DMSO and 20% N,N-dimethylacetamide, or MPO-Gd in PBS containing 5% DMSO, or Dotarem in PBS) were administered by tail vein injection, and mice were imaged at 0, 15, 30, 45, and 60 minutes using serial T1-weighted imaging (TR: 900 ms, TE: 13.59 ms, 0.156 × 0.156 × 0.5 mm voxels) with chemolipid suppression and respiratory gating on a 4.7T small animal MR scanner (Bruker, Cambridge, MA) equipped with a 3 cm orthogonal volume coil (Rapid MR International, Germany). The region of interest (ROI) was manually drawn by a person whose identity as the mouse or contrast agent was concealed, and the contrast-to-noise ratio (CNR) was calculated as CNR = (SI 病変 -SI骨格筋 ) / SD バックグラウンド It was calculated as follows.

[0199] 24 hours after injecting CFA emulsion into the shoulder of mice, a contrast agent (0.3 mol / kg) was injected via the tail vein, and the animals were imaged. Figures 4A to 4D show the results for mcMPO-Gd, Dotarem, and MPO-Gd in wild-type mice, as well as for MPO gene deficiency (Mpo - / - The images obtained in mice for mcMPO-Gd before contrast enhancement and 60 minutes after contrast agent administration are shown. In wild-type mice, the contrast-to-noise ratio (CNR) observed with mcMPO-Gd increased over 60 minutes, while the CNR observed with Dotarem decreased rapidly over time, as shown in Figure 4E, indicating that mcMPO-Gd, not Dotarem, was retained in the inflammatory tissue, likely resulting from the activation of the former by inflammation-related MPO activity and subsequent binding to protein tyrosine residues. In contrast, Mpo using mcMPO-Gd... - / - Mouse MR images, as shown in Figures 4C and 4E, showed little increase in signal, indicating the specificity of the signal observed with mcMPO-Gd to MPO in this model. mcMPO-Gd showed a >4-fold increase in the activation ratio (AR = CNR (post-contrast) / CNR (post-initial contrast)) compared to the 2-fold increase seen with MPO-Gd, as shown in Figure 4F (see, e.g., Breckwoldt et al, Proc. Natl. Acad. Sci. USA 2008, 105:18584-18589), suggesting higher sensitivity of mcMPO-Gd to MPO activity compared to MPO-Gd.

[0200] Example 12. MR imaging of tandem stenosis (TS) and intervention with AZM198 MPO activity has been reported to be elevated in unstable plaques compared to stable plaques in tandem stenosis (TS) mouse models, as assessed by both MPO-Gd MRI and LC-MS / MS measurements of the conversion of hydroethidine to 2-chloroethidine (see, e.g., Rashid et al, Eur. Heart J., 2018, 39:3301-3310).

[0201] Male apolipoprotein E gene deficiency (Apoe - / - Six-week-old mice were fed a Western diet (WD) containing 22% fat and 0.15% cholesterol (SF00-219, Specialty Feeds, Western Australia) for a total of 13 weeks. Six weeks after the start of the WD, tandem stenosis (TS) was introduced into the mice as previously described (see, for example, Rashid et al, Eur. Heart J., 2018, 39:3301-3310). Male Apoe - / -Mice were anesthetized with 4% isoflurane. The right common carotid artery was resected from the surrounding connective tissue. Two stenoses were positioned by tying 6-0 blue braided polyester fiber sutures (Tyklon 0.7 metric) around the exposed artery, with the distal stenosis 1 mm from the carotid bifurcation and the proximal stenosis 3 mm from the distal stenosis. Blood flow was measured before and after the addition of each ligament using a perivascular flow module (Transonic, TS420) and a 0.7 mm perivascular flow probe (Transonic MA0.7PSB). Each ligament in the TS was defined as 70% of the baseline flow after the addition of the distal ligament and 20% of the baseline flow after the addition of the proximal ligament. Changes in the flow lead to the development of atherosclerotic plaque in the right carotid artery with an unstable phenotype in the proximal segment of the proximal suture, characterized by consistent thinning of the fibrous capsule, abundant inflammatory cells, irregular neovascularization, capsular rupture and intraplaque hemorrhage, and luminal thrombus with fibrin and platelet deposition (see, e., Chen et al, Circ. Res. 2013, 113:252-265). By comparison, atheroma in the brachiocephalic artery includes a thick capsule and abundant collagen, characteristic of a stable plaque phenotype (see, e., Rashid et al, Eur. Heart J., 2018, 39:3301-3310).

[0202] Isoflurane-anesthetized mice were imaged in the prone position before surgery and at 1, 2, 4, and 7 weeks post-TS surgery using a 9.4T Bruker Biospec 94 / 20 Avance III system (Bruker, Ettlingen, Germany) equipped with a 35mm orthogonal radiofrequency coil and respiratory gating imaging acquisition, as previously described, before and after intravenous administration of 0.3 mmol / kg MPO-Gd via tail vein catheter. T1-weighted high-speed spin echo (TurboRARE, T1-TSE) was acquired using the following parameters: TR 1500 ms, TE 8.5 ms, ETL 8, slice thickness 1 mm, FOV 20 × 20 mm, matrix size 192 × 192, and intra-plane resolution 104 × 104 μm. This T1-TSE protocol was then repeated with scan sequences covering a period of 1 hour post-contrast injection to evaluate contrast agent inflow and retention. OsiriX (version 10.0.2, Pixmeo, Switzerland) was used for image analysis. In T1-TSE images, separate regions of interest were assigned to the blood vessel wall, skeletal muscle (reference), and background (air). The contrast-to-noise ratio (CNR) was calculated as follows: CNR = (SI 血管壁 -SI 骨格筋 ) / SD バックグラウンド The mean CNR was calculated for 1-2 consecutive slices in the brachiocephalic artery (stable plaque), 3 consecutive slices in plaque with an unstable phenotype, and the corresponding segment (plaque-free) of the left carotid artery. Strengthening of the segment due to MPO was defined as ΔCNR = CNR. 造影後 -CNR 造影前 The evaluation was performed by calculating [the value].

[0203] For pharmacological inhibition of MPO, AZM198 (AstraZeneca, Sweden) was administered by incorporating it into the WD at a daily dose of 500 μmol / kg body weight based on an average daily food intake of approximately 3.7 g per mouse, as previously described (see, for example, Rashid et al, Eur. Heart J., 2018, 39:3301-3310). Treatment with AZM198 was initiated one week after TS surgery and continued for 6 weeks until MRI seven weeks after TS surgery, before and after intravenous administration of 0.1 mmol / kg mcMPO-Gd according to the protocol described above.

[0204] Imaging was performed 7 weeks after TS surgery, with administration of 0.3 mmol / kg MPO-Gd or 0.1 mmol / kg mcMPO-Gd via the tail vein. As shown in Figures 5A, 5B, and 5D, signal enhancement of unstable plaques (arrows) was comparable for mcMPO-Gd and MPO-Gd (ΔCNR 17.8 vs. 15.0, P=0.368), although the dose of mcMPO-Gd was three times lower.

[0205] To confirm that MR images of mcMPO-Gd can reflect MPO activity, TS mice were treated with the MPO inhibitor AZM198 one week after TS surgery, and then subjected to MRI after a further 6-week treatment period (a total of 7 weeks post-TS). After administration of mcMPO-Gd, the CNR for stable and unstable plaques increased 30 minutes after contrast agent administration, but then decreased in AZM198-treated mice after 60 minutes, as shown in Figure 6, but not in control animals. As a result, the ΔCNR in the region corresponding to unstable plaques was reduced by approximately 50% in AZM198-treated mice compared to control mice, as shown in Figures 5C and 5E, suggesting effective inhibition of MPO activity by AZM198.

[0206] The results described in the examples demonstrate that mcMPO-Gd exhibits superior sensitivity and efficacy compared to MPO-Gd both in vitro and in vivo. Not bound by theory, given the similarity of the activated sites, this difference may be a result of the closer proximity and rigidity of the two activated sites. In MPO-Gd, each activated site is ligated to one side of DTPA, which can lead to binding to two proteins or itself after MPO oxidation. However, in mcMPO-Gd, the proximity of the two activated sites prevents self-binding and likely forces the drug to bind to the same protein. This improves the efficiency of protein binding (as shown in Figure 2) and further reduces segmental motility from binding multiple proteins to the drug. Due to its improved stability and ability to image harmful inflammation, mcMPO-Gd is thought to be capable of detecting and mapping harmful inflammation at low concentrations in many diseases, including but not limited to multiple sclerosis, nonalcoholic fatty steatohepatitis (NASH), rheumatoid arthritis, and atherosclerosis. These data suggest that mcMPO-Gd is a candidate molecular contrast agent for technology transfer to human use.

[0207] Example 13. Molecular docking experiment To investigate why mcMPO-Gd was found to be more effective than MPO-Gd in detecting MPO activity, molecular docking studies were performed using AutoDock Vina (see, e.g., Trott et al, J.Comput.Chem. 2010, 31(2), 455-61) and visualized with PyMol. Since the gadolinium (Gd) parameter is not included in AutoDock Vina, Gd was replaced with iron (Fe) for the docking experiments (see, e.g., Wu et al, J.Mol.Model 2016, 22(7), 161). Gd and Fe have the same positive charge; and without being bound by theory, it was assumed that replacing Gd with Fe should not affect the docking results, as Gd "embedded" within the drug's chelate portion without direct interaction with the docking protein.

[0208] Unlike MPO inhibitors that block the active site, the 5-hydroxyindole moiety of mcMPO-Gd undergoes one electron transfer with compound type I MPO during the MPO catalytic cycle and is not retained at the active site, making it an MPO substrate (see, for example, Rodriguez et al., J.Am.Chem.Soc.2010,132(1),168-77). The MPO-cyanide (MPO-CN) complex has been proposed as a useful substitute for studying compound I, as both compound I and the MPO-CN complex contain a 6-coordinate low-spin s=1 iron center, making them short-lived; therefore, the cocrystal structure of the MPO-CN complex from human MPO-cyanide-thiocyanate (MPO-CN-SCN, PDB database: 1DNW) was selected as a model for performing docking experiments (see, e.g., Malle et al, Br.J.Pharmacol. 2007, 152(6), 838-54; Blair-Johnson et al, Biochemistry 2001, 40(46), 13990-7; Hallingback et al, Biochemistry 2006, 45(9), 2940-50).

[0209] In this study, 20 docking structures were generated for each drug. As shown in Figure 7, the optimal structure of mcMPO-Gd bound to MPO revealed the formation of a hydrogen bond between the two amide bonds, which suppresses the rotation of mcMPO-Gd by forming a five-membered ring and increases the rigidity of the drug. As shown in Figure 8, the binding affinity generated from the 20 modes of mcMPO-Gd to MPO from docking simulations was found to be generally lower than that of MPO-Gd (11.7–9.5 kcal / mol vs. 9.9–7.9 kcal / mol). Without being constrained by theory, these effects could explain the higher efficacy of mcMPO-Gd when activated by MPO.

[0210] Visualizations of MPO-Gd and mcMPO-Gd bound to MPO showed that, for both drugs, one of the 5-hydroxyindole moieties was parallel to the MPO heme, forming a π-π stacking interaction, consistent with previous docking studies of serotonin and MPO (see, e.g., Hallingback et al, Biochemistry 2006, 45(9), 2940-50). However, in mcMPO-Gd, the hydroxyl group pointing to the heme center formed a hydrogen bond with the cyanide (purple and blue), and the imine group electrostatically interacted with the carbonyl group from hemepropionic acid (NH). ··· O=C, 3.7A). The other 5-hydroxyindole moieties are perpendicular to the heme, and the imines are, respectively, Pro 101 and Thr 100 This formed two hydrogen bonds (see Figure 9, left).

[0211] In contrast, as shown in Figure 9 (right), for MPO-Gd, one of the 5-hydroxyindole moieties interacts with MPO heme without electrostatic interaction, while the other 5-hydroxyindole moiety interacts with Phe 147It formed only one hydrogen bond. These differences resulted in improved binding affinity of mcMPO-Gd compared to MPO-Gd. Therefore, the mechanism for the improvement observed in mcMPO-Gd compared to MPO-Gd was also identified through molecular docking experiments.

[0212] Detecting and differentiating harmful inflammation from beneficial inflammation is challenging, but useful considering the different roles they play in the pathogenesis of disease. MPO is recognized as an important marker for harmful inflammation, and the examples provided herein describe an activatable macrocyclic gadolinium-based MPO-specific agent, mcMPO-Gd, which is significantly more stable than linear MPO-Gd agents and up to three times more responsive to MPO activity compared to previous MPO-detecting MRI agents.

[0213] Other Embodiments The present invention is described in conjunction with its detailed description, but it should be understood that the foregoing description is intended to illustrate, and not to limit, the scope of the invention as defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. The inventions described in the original claims of this application are listed below. [Invention 1] Formula I: [ka] [In formula: Ring A is C 6~10 Selected from the group consisting of aryls, 4- to 16-membered heterocycloalkyls, and 5- to 16-membered heteroaryls; Ring B is C 6~10 Selected from the group consisting of aryls, 4- to 16-membered heterocycloalkyls, and 5- to 16-membered heteroaryls; L 1 However, NHC(O)L 2 NHC(O)-L 2 -C(O)NH, L 2 -NHC(O)-L 2、L 2 -NHC(O)-L 2 -NHC(O), and L 2 -NHC(O)-L 2 -NHC(O)-L 2 - Selected from the group consisting of, Each L 2 However, C 1~4 Alkylene, C 1~4 Alkylene oxy, and C 1~4 Independently selected from the group consisting of alkenylenes; R 1 However, it contains chelate groups and metals; R 2 and R 3 However, OR a , C(O)R a , and OC(O)R a Each is independently selected from the group consisting of; Each R a However, H and C 1~4 Independently selected from the group consisting of alkyl groups; m is 0, 1, 2, 3, or 4; and n is 0, 1, 2, 3, or 4. A compound of or a pharmaceutically acceptable salt thereof. [Invention 2] The compound according to Invention 1, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of phenyl, bicyclic 8-16 member heterocycloalkyl, tricyclic 8-16 member heterocycloalkyl, bicyclic 8-16 member heteroaryl, and tricyclic 8-16 member heteroaryl. [Invention 3] Ring A is:

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Claims

1. Formula I: 【Chemistry 1】 [In the formula: L １ but, 【Chemistry 2】 And in the formula: Each L ２ However, C １～４ It is alkylene, Each 【Transformation 3】 However, L １ and ring A, ring B and R １ This shows a connection between; R １ but, 【Chemistry 4】 A chelate group selected from the group consisting of the following, in formula: M is a metal, 【Transformation 5】 However, R １ and L １ This shows a connection between; Ring A is 【Transformation 6】 And in the formula: 【Transformation 7】 represents the bond between ring A and L １ and; Ring B is 【Transformation 8】 And in the formula: 【Chemistry 9】 However, ring B and L １ This shows a connection between; R ２ and R ３ However, OR ａ , C(O)R ａ , and OC(O)R ａ Each is independently selected from the group consisting of; Each R ａ However, H and C １～４ Independently selected from the group consisting of alkyls; m is 1 or 2; and n is either 1 or 2. A compound of or a pharmaceutically acceptable salt thereof.

2. Each R ２ However, OH, OCH ３ C(O)CH ３ , and OC(O)CH ３ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of the above.

3. Ring A is 【Chemistry 10】 And in the formula: 【Chemistry 11】 However, ring A and L １ This shows a connection between the two. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. Ring A is 【Chemistry 12】 And in the formula: 【Chemistry 13】 However, ring A and L １ This shows a connection between the two. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

5. Ring B is 【Chemistry 14】 And in the formula: 【Chemistry 15】 However, ring B and L １ This shows a bond between and where n is 1 or 2. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. Each R ３ However, OH, OCH ３ C(O)CH ３ , and OC(O)CH ３ A compound according to any one of claims 1 to 5, independently selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

7. Ring B is 【Chemistry 16】 And in the formula: 【Chemistry 17】 However, ring B and L １ This shows a connection between the two. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

8. Ring B is [Chemistry 18] And in the formula: 【Chemistry 19】 However, ring B and L １ This shows a connection between the two. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

9. A compound according to any one of claims 1 to 8, wherein ring A and ring B are the same, or ring A and ring B are different, or a pharmaceutically acceptable salt thereof.

10. L １ but, 【Chemistry 20】 And in the formula: 【Chemistry 21】 However, L １ This shows the bond between and ring A; 【Chemistry 22】 However, L １ This shows the bond between and ring B; and 【Chemistry 23】 However, L １ and Ring R １ This shows a connection between the two. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. The aforementioned R １ The metal is Gd ３＋ Mn ２＋ , ６８ Ga, ６４ Cu, and １１１ A compound according to any one of claims 1 to 10, selected from the group consisting of In, or a pharmaceutically acceptable salt thereof.

12. R １ but, 【Chemistry 24】 And in the formula: 【Chemistry 25】 However, R １ and L １ This shows a connection between the two. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

13. The compound of formula I is the compound of formula II: 【Chemistry 26】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

14. The compound of formula I is the compound of formula Vb: 【Chemistry 27】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein M is a metal in the formula.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

16. The pharmaceutical composition according to claim 15, for use in diagnosing diseases or disorders related to abnormal myeloperoxidase activity in a subject.

17. The pharmaceutical composition according to claim 15, for use in detecting myeloperoxidase activity in a target.

18. The pharmaceutical composition according to claim 15, for use in monitoring the treatment of diseases or disorders related to abnormal myeloperoxidase activity in a subject.

19. The aforementioned disease or disorder related to abnormal myeloperoxidase activity, Non-alcoholic steatohepatitis, A solid tumor, or a cancer selected from the group consisting of bladder cancer, breast cancer, carcinoma, cervical cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, skin cancer, gastric cancer, testicular cancer, leukemia, and thyroid cancer. Rheumatic diseases selected from the group consisting of rheumatoid arthritis, osteoarthritis, and inflammatory arthritis (wherein inflammatory arthritis is selected from the group consisting of gout and calcium pyrophosphate crystal deposition disease (CPPD)), Infectious diseases selected from the group consisting of fungal diseases and bacterial diseases. Disorders of the central nervous system selected from the group consisting of Alzheimer's disease, stroke, epilepsy, Parkinson's disease, neurodegenerative diseases, and inflammation associated with one or more of Alzheimer's disease, stroke, epilepsy, Parkinson's disease, and neurodegenerative diseases. Cardiovascular diseases selected from the group consisting of atherosclerosis, myocardial infarction, atrial fibrillation, vasculitis, and inflammation associated with one or more of atherosclerosis, myocardial infarction, atrial fibrillation, and vasculitis. Autoimmune diseases selected from the group consisting of multiple sclerosis, meningitis, encephalitis, and inflammation associated with one or more of multiple sclerosis, meningitis, and encephalitis, and Inflammation associated with one or more of the following: cancer, rheumatic diseases, infectious diseases, central nervous system disorders, cardiovascular diseases, and autoimmune diseases. A pharmaceutical composition according to claim 16 or 18, selected from the group consisting of the following.

20. The use of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, in the manufacture of a drug for diagnosing a disease or disorder related to abnormal myeloperoxidase activity in a subject, The method described above is i) Administering the compound, or a pharmaceutically acceptable salt thereof, to the subject; ii) Waiting for a sufficient amount of time for the compound to accumulate in the cells or tissues associated with the disease; and iii) Imaging the cells or tissue using imaging technology. The aforementioned use, including.

21. The use of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, in the manufacture of a drug for detecting myeloperoxidase activity in a subject, The method described above is i) administering the compound, or a pharmaceutically acceptable salt thereof, to the subject; and ii) To image the subject using imaging technology. The aforementioned use, including.

22. The use of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, in the manufacture of a drug for monitoring the treatment of a disease or disorder associated with abnormal myeloperoxidase activity in a subject, The method described above is i) Administering the compound, or a pharmaceutically acceptable salt thereof, to the subject; ii) Imaging the subject using imaging technology; iii) Administering a therapeutically effective amount of a therapeutic compound for treating the disease or disorder to the subject; iv) imaging a sample of cells or tissue in the subject using imaging techniques; and v) Compare the image from step ii) with the image from step iv). The aforementioned use, including.

23. The aforementioned disease or disorder related to abnormal myeloperoxidase activity, Non-alcoholic steatohepatitis, A solid tumor, or a cancer selected from the group consisting of bladder cancer, breast cancer, carcinoma, cervical cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, skin cancer, gastric cancer, testicular cancer, leukemia, and thyroid cancer. Rheumatic diseases selected from the group consisting of rheumatoid arthritis, osteoarthritis, and inflammatory arthritis (wherein inflammatory arthritis is selected from the group consisting of gout and calcium pyrophosphate crystal deposition disease (CPPD)), Infectious diseases selected from the group consisting of fungal diseases and bacterial diseases. Disorders of the central nervous system selected from the group consisting of Alzheimer's disease, stroke, epilepsy, Parkinson's disease, neurodegenerative diseases, and inflammation associated with one or more of Alzheimer's disease, stroke, epilepsy, Parkinson's disease, and neurodegenerative diseases. Cardiovascular diseases selected from the group consisting of atherosclerosis, myocardial infarction, atrial fibrillation, vasculitis, and inflammation associated with one or more of atherosclerosis, myocardial infarction, atrial fibrillation, and vasculitis. Autoimmune diseases selected from the group consisting of multiple sclerosis, meningitis, encephalitis, and inflammation associated with one or more of multiple sclerosis, meningitis, and encephalitis, and Inflammation associated with one or more of the following: cancer, rheumatic diseases, infectious diseases, central nervous system disorders, cardiovascular diseases, and autoimmune diseases. The use according to claim 20 or 22, selected from the group consisting of the following.

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