Quinoline compounds and their uses
Quinoline compounds acting as PROTACs degrade TDP-43, addressing the lack of effective protein breakdown treatments for neurodegenerative diseases, offering a therapeutic solution to prevent and treat conditions like Alzheimer's and Parkinson's.
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- IND TECH RES INST
- Filing Date
- 2025-12-22
- Publication Date
- 2026-07-10
AI Technical Summary
Current treatments for neurodegenerative diseases primarily provide symptom relief without effectively addressing the breakdown of harmful proteins, such as TDP-43, which are key contributors to diseases like Alzheimer's, Parkinson's, and Huntington's.
Development of quinoline compounds that act as proteolysis-targeting chimeras (PROTACs) to target and degrade TDP-43 by binding to it and recruiting E3 ubiquitin ligase, leading to ubiquitination and proteasomal degradation.
The quinoline compounds effectively degrade TDP-43, potentially providing a therapeutic approach to treat and prevent neurodegenerative diseases by targeting the underlying pathological mechanism of protein accumulation.
Smart Images
Figure 2026116726000001_ABST
Abstract
Description
[Technical Field]
[0001] This disclosure relates to quinoline compounds and their applications, and more particularly to related applications of proteolysis-targeting chimeras (PROTACs) containing the structure of quinoline compounds. [Background technology]
[0002] Neurodegenerative diseases are a type of disease that primarily affects neurons (the building blocks of the nervous system). A characteristic of this type of disease is the gradual decrease in neurons (nerve cells) in the nervous system, leading to brain atrophy, and ultimately a decline and loss of cognitive, memory, motor, and emotional control abilities.
[0003] Neurodegenerative diseases are closely related to protein abnormalities, primarily caused by protein misfolding and deposition, which disrupt nerve cell function and ultimately lead to cell death. These abnormal protein deposits are a major pathological feature of many neurodegenerative diseases; for example, Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are all associated with abnormal protein deposition.
[0004] Recent studies have shown that transactive response DNA-binding protein 43 (TDP-43) is a major pathogenic factor in various neurodegenerative diseases, with TDP-43 being present in 50% of patients with frontotemporal dementia (FTD) and 90% of patients with amyotrophic lateral sclerosis (ALS), respectively.
[0005] Currently, almost all conventional treatments for neurodegenerative diseases only provide symptom relief, lacking effective approaches that target pathological mechanisms or etiologies. More specifically, existing treatments for neurodegenerative diseases do not yet include therapies to break down harmful proteins. Therefore, there is a strong need for technological solutions that eliminate harmful proteins in relation to neurodegenerative diseases. [Overview of the project] [Problems that the invention aims to solve]
[0006] Currently, almost all conventional treatments for neurodegenerative diseases only provide symptom relief and lack treatment for the breakdown of harmful proteins. The primary objective of this disclosure is to provide a drug that can achieve the goal of treating / preventing disease by breaking down harmful proteins. [Means for solving the problem]
[0007] This disclosure provides quinoline compounds and their applications.
[0008] In other words, this disclosure may include, but is not limited to, the following:
[0009] [1] A compound or a salt thereof, wherein the compound has a structure represented by formula (I), formula (II), or formula (III).
[0010] [ka]
[0011] In the formula, R1 is H, cyano group, NH2, NO2, NHR3, NHR3R4, heterocycle, NHCOR5 or [ka] R2 is NHCOR6 or NH2. A and B are independently N, C, or absent. y and z are independently integers from 1 to 3. R3, R4, R5, and R6 are independently C1-C6 alkyl groups, which are linear or branched alkyl groups and may be substituted with one or more halogen atoms, oxygen atoms, sulfur atoms, or amines as needed. R7 is SCH3 or OCH3. R8 is NHCOR9 or NH2. R9 is a C1-C6 alkyl group. 10 R is H, cyano group, NH2, NO2, NHR3, NHR3R4, heterocycle or NHCOR5. 11 is SCH3, OCH3, or a heterocycle. L1 is a linker having a structure selected from the group of structures shown below.
[0012] [Table 1] JPEG2026116726000005.jpg213149
[0013] L2 and L3 are linkers that independently have a structure selected from the group of structures shown below. [Table 2]
[0014] Of these, X1 is a binding, -NH-, -O-, -CO-, CONH, or -PhNHCO-. X2 is a binding, -NH-, -O-, -NHCOCH2NH-, -NHCOCH2O-, or -alkyne-. X is a heterocycle. n is an integer from 1 to 6. m is an integer from 0 to 8. Also, E is an E3 ubiquitin ligase binding domain, which contains one of the structures shown below.
[0015] [Table 3]
[0016] [2] The compound or its salt according to [1], wherein the compound has a structure represented by the formula (I).
[0017] [3] R1 is H, a cyano group, NO2, N(CH3)2, NHAc or
Chemical formula
[0018] [4] The compound or its salt according to [2], wherein the compound contains one of the compounds shown below.
Table 4
[0019] [5] The compound or its salt according to [1], wherein the compound has a structure represented by the formula (II).
[0020] [6] R7 is SCH3 and R8 is NHAc, the compound or its salt according to [5].
[0021] [7] The compound or its salt according to [5], wherein the compound contains one of the compounds shown below. [Table 5] JPEG2026116726000022.jpg60149
[0022] [8] The compound according to [1] or a salt thereof, wherein the compound has a structure represented by formula (III).
[0023] [9]R 10 NO2, CN or [ka] And R 11 The compound or salt thereof described in [8], wherein is OCH3, SCH3, morpholine, n-methylpiperazine, pyrrolidin-3-amine, 4-aminopiperidine, or 4-(N-Boc-amino)piperidine.
[0024]
[10] The compound includes one of the following compounds: the compound described in [8] or a salt thereof. [Table 6] JPEG2026116726000025.jpg225149JPEG2026116726000026.jpg225149JPEG2026116726000027.jpg54149
[0025]
[11] Pharmaceutical composition, [1] The compound or a salt thereof, A pharmaceutically acceptable carrier or salt, A pharmaceutical composition containing the following:
[0026]
[12] A reagent for degrading and / or inhibiting the activity of transactive response DNA binding protein 43 (TDP-43), comprising the compound or a salt thereof described in [1].
[0027] A reagent for degrading and / or inhibiting the activity of the transactive response DNA-binding protein-43 described in
[13]
[12] , wherein the transactive response DNA-binding protein-43 is the full-length transactive response DNA-binding protein-43 or the C-terminal domain of an independent transactive response DNA-binding protein-43.
[0028]
[14] A pharmaceutical composition for use in treating and / or preventing diseases associated with the accumulation of transactive response DNA-binding protein-43, comprising the compound described in [1] or a salt thereof.
[0029] A pharmaceutical composition for use in treating and / or preventing diseases associated with the accumulation of transactive response DNA-binding protein-43 as described in
[15]
[14] , wherein the diseases associated with the accumulation of transactive response DNA-binding protein-43 include neurodegenerative diseases.
[0030] Preferred embodiments are described below in detail, with reference to the accompanying drawings, so that the above-mentioned and other purposes, features, and advantages of this disclosure may be made clearer and easier to understand. [Brief explanation of the drawing]
[0031] [Figure 1]One embodiment of this disclosure shows the expression vector pcDNA3.1-Myc-NanoLuc-LinkerTDP43 (abbreviated as NanoLuc-TDP-43(WT)) used in an experiment to analyze the activity of a test compound in degrading transactive response DNA binding protein 43 (TDP-43) using a NanoLuc-TDP-43 fusion protein analysis system. WT: wild type. [Figure 2] One embodiment of this disclosure shows the expression vector pcDNA3.1-Myc-NanoLuc-LinkerTDP43CTD (abbreviated as NanoLuc-TDP-43(CTD)) used in an experiment to analyze the activity of a test compound in degrading the transactive response DNA-binding protein-43 (TDP-43) using a NanoLuc-TDP-43 fusion protein analysis system. CTD: C-terminal domain. [Modes for carrying out the invention]
[0032] Transactive response DNA binding protein 43 (TDP-43) is a protein encoded by the human TARDBP gene.
[0033] Transactive response DNA-binding protein-43 has 414 amino acid residues and consists of one N-terminal domain (NTD), two highly conserved, folded RNA recognition motifs, and one unstructured C-terminal domain (CTD). The N-terminal domain spans amino acid residues 1–76, has a clear folded structure, and has been shown to be dimerizable or oligomeric. The two highly conserved, folded RNA recognition motifs span amino acid residues 106–176 (RRM1) and 191–259 (RRM2), respectively, and are essential for binding to target RNA and DNA. The unstructured C-terminal domain spans amino acid residues 274–414, contains one glycine-rich region, participates in protein-protein interactions, and most mutations in familial amyotrophic lateral sclerosis (ALS) are concentrated here.
[0034] Transactive response DNA-binding protein-43 is a highly conserved nuclear RNA / DNA-binding protein involved in the control of RNA processing. However, its abnormal localization and aggregation in the cytoplasm serve as markers for several neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Therefore, it is hoped that removing this harmful protein could be one of the treatments that fundamentally resolves neurodegenerative diseases.
[0035] A proteolysis-targeting chimera (PROTAC) is a small molecule drug with two different functional ligands: one that binds to a protein of interest (POI), and the other that attracts E3 ubiquitin ligase. When the proteolysis-targeting chimera binds to the target protein, the E3 ubiquitin ligase approaches the protein and can label it with ubiquitin. The ubiquitin-labeled target protein is then recognized by the proteasome, cleaved, and broken down into small peptide fragments. This allows the proteolysis-targeting chimera to dissociate from the target protein and be recycled within the cell.
[0036] Based on the foregoing, this disclosure provides compounds or salts thereof. The compounds or salts thereof of this disclosure can be used, but are not limited to, in the preparation of reagents, drugs, or pharmaceutical compositions. The reagents may be reagents used to degrade and / or inhibit the activity of transactive response DNA-binding protein-43. The drugs or pharmaceutical compositions may be drugs or pharmaceutical compositions used to treat and / or prevent diseases associated with transactive response DNA-binding protein-43 accumulation, or drugs or pharmaceutical compositions used to treat and / or prevent diseases that can be mitigated and / or cured by degrading and / or inhibiting the activity of transactive response DNA-binding protein-43. Alternatively, the compounds or salts thereof of the present disclosure may be used directly for the treatment and / or prevention of a disease, which may be, but is not limited to, a disease associated with the accumulation of transactive response DNA-binding protein-43, or a disease that can be mitigated and / or cured by inhibiting the activity of transactive response DNA-binding protein-43 and / or degrading transactive response DNA-binding protein-43.
[0037] In one embodiment, the compounds or salts thereof of the disclosed herein may be in the form of proteolytic chimeric molecules.
[0038] The compounds of this disclosure may have, but are not limited to, a structure represented by formula (I), formula (II), or formula (III).
[0039] [ka]
[0040] In the formula, R1 is H, cyano group, NH2, NO2, NHR3, NHR3R4, heterocycle, NHCOR5, [ka] The alkyl groups may be, but are not limited to, NHCOR6, NH2, etc. R2 may be, but is not limited to, NHCOR6, NH2, etc. R3, R4, R5, and R6 may each be independently C1-C6 alkyl groups. The alkyl groups may be linear or branched alkyl groups and may be substituted with one or more halogen atoms, oxygen atoms, sulfur atoms, or amines as needed. The halogen atoms may be, but are not limited to, F, Cl, or Br.
[0041] A and B may be N and C independently, or they may not exist at all.
[0042] y and z can each be independent integers between 1 and 3.
[0043] R7 may be SCH3 or OCH3. R8 may be NHCOR9 or NH2. R9 is a C1-C6 alkyl group.
[0044] R 10 R3, R4, and R5 may be, but are not limited to, H, a cyano group, NH2, NO2, NHR3, NHR3R4, a heterocycle, or NHCOR5. The definitions of R3, R4, and R5 are the same as those described above.
[0045] R 11 This can be SCH3, OCH3, or a heteroalgebra, but is not limited to these.
[0046] L1 may be, but is not limited to, a linker having one of the structures shown in Table 1 below.
[0047] [Table 7] JPEG2026116726000031.jpg213149
[0048] L2 and L3 may, but are not limited to, linkers having one of the structures shown in Table 2 below.
[0049] [Table 8] JPEG2026116726000033.jpg32149
[0050] In Tables 1 and 2, the definitions of X1, X2, X, n, and m may be as follows:
[0051] X1 may be a bond, -NH-, -O-, -CO-, CONH, or -PhNHCO-, but is not limited to these. X2 may be a bond, -NH-, -O-, -NHCOCH2NH-, -NHCOCH2O-, or -alkyne-, but is not limited to these.
[0052] X may be a complex algebra, but is not limited to it.
[0053] n can be an integer between 1 and 6, and m can be an integer between 0 and 8.
[0054] Furthermore, E may be an E3 ubiquitin ligase binding domain, which may include, but is not limited to, one of the structures shown in Table 3 below.
[0055] [Table 9]
[0056] In one embodiment, the compound of the present disclosure may have the structure represented by formula (I).
[0057] In a particular embodiment of the above embodiment, in which the compound of the present disclosure may have a structure represented by formula (I), R1 is H, a cyano group, NO2, N(CH3)2, NHAc or [ka] This may be the case, but is not limited thereto. In another specific embodiment of the embodiments in which the compound of the present disclosure may have the structure represented by formula (I), R2 in the structure represented by formula (I) may be NHAc, but is not limited thereto.
[0058] Furthermore, in certain embodiments, the compounds of the present disclosure may have a structure represented by formula (I), and the compounds of the present disclosure may include, but are not limited to, one of the compounds shown in Table 4 below.
[0059] [Table 10] JPEG2026116726000037.jpg225149JPEG2026116726000038.jpg225149JPEG2026116726000039.j pg225149JPEG2026116726000040.jpg225149JPEG2026116726000041.jpg215149JPEG20261167260 00042.jpg192149JPEG2026116726000043.jpg197149JPEG2026116726000044.jpg225149JPEG202 6116726000045.jpg225149JPEG2026116726000046.jpg198149JPEG2026116726000047.jpg151149
[0060] In another embodiment, the compound of the present disclosure may have the structure represented by formula (II).
[0061] In a particular embodiment of the above embodiment in which the compound of the present disclosure may have a structure represented by formula (II), R7 in the structure represented by formula (II) may be SCH3, but is not limited thereto. Furthermore, in another particular embodiment of the above embodiment in which the compound of the present disclosure may have a structure represented by formula (II), R8 in the structure represented by formula (II) may be NHAc, but is not limited thereto.
[0062] Furthermore, in certain embodiments, the compounds of the present disclosure may have a structure represented by formula (II), and the compounds of the present disclosure may include, but are not limited to, one of the compounds shown in Table 5 below.
[0063] [Table 11] JPEG2026116726000049.jpg60149
[0064] In another embodiment, the compound of the present disclosure may have the structure represented by formula (III).
[0065] In a particular embodiment of the above embodiment, in which the compound of the present disclosure may have a structure represented by formula (III), among the structures represented by formula (III), R 10 is NO2, CN or [ka] It may be, but is not limited thereto. Furthermore, in another specific embodiment of the embodiment in which the compound of the present disclosure may have the structure represented by formula (III), among the structures represented by formula (III), R 11This may be, but is not limited to, OCH3, SCH3, morpholine, n-methylpiperazine, pyrrolidin-3-amine, 4-aminopiperidine, or 4-(N-Boc-amino)piperidine.
[0066] Furthermore, in certain embodiments, the compounds of the present disclosure may have a structure represented by formula (III), and the compounds of the present disclosure may, but are not limited to, include one of the compounds shown in Table 6 below.
[0067] [Table 12] JPEG2026116726000052.jpg225149JPEG2026116726000053.jpg225149JPEG2026116726000054.jpg54149
[0068] As can be seen from the structures of the compounds of the present disclosure shown above, the compounds of the present disclosure or salts thereof may be proteolytic chimeric molecules for transactive response DNA-binding protein-43, which can effectively bind to transactive response DNA-binding protein-43, thereby enabling transactive response DNA-binding protein-43 to be recognized by the proteasome, cleaved, and degraded. The transactive response DNA-binding protein-43 may be the full-length transactive response DNA-binding protein-43, or it may be only the C-terminal region of an independent transactive response DNA-binding protein-43, and is not particularly limited. Specifically, the compounds of the present disclosure or salts thereof can bind to the full-length transactive response DNA-binding protein-43, or they may bind only the C-terminal region of an independent transactive response DNA-binding protein-43, and is not particularly limited.
[0069] Based on the foregoing, the Disclosure may also provide pharmaceutical compositions which may comprise, but are not limited to, any of the compounds of the Disclosure described herein or their salts, and pharmaceutically acceptable carriers or salts.
[0070] The pharmaceutical compositions of this disclosure may be drugs or pharmaceutical compositions used to treat and / or prevent diseases associated with the accumulation of transactive response DNA-binding protein-43, or drugs or pharmaceutical compositions used to treat and / or prevent diseases that can be mitigated and / or cured by inhibiting the activity of transactive response DNA-binding protein-43 and / or degrading transactive response DNA-binding protein-43, but are not limited thereto. Alternatively, the pharmaceutical compositions of this disclosure may be used to treat and / or prevent diseases, which may be diseases associated with the accumulation of transactive response DNA-binding protein-43, or diseases that can be mitigated and / or cured by inhibiting the activity of transactive response DNA-binding protein-43 and / or degrading transactive response DNA-binding protein-43, but are not limited thereto. In one embodiment, such diseases may include, but are not limited to, neurodegenerative diseases. Examples of neurodegenerative diseases may include, but are not limited to, Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), frontotemporal dementia (FTD), and Huntington's disease (HD).
[0071] The pharmaceutically acceptable carriers described above may include, but are not limited to, solvents, dispersion media, coatings, antimicrobial and antifungal reagents, and isotonic and absorption-delaying reagents, as well as other pharmaceutically applicable materials. Depending on the different dosing methods, the pharmaceutical compositions can be prepared into dosage forms using general methods.
[0072] Furthermore, the pharmaceutically acceptable salts mentioned above may include, but are not limited to, inorganic cations, such as alkali metal salts, e.g., sodium, potassium, or ammonium salts; alkaline earth metal salts, e.g., magnesium or calcium salts; and salts containing divalent or tetravalent cations, e.g., zinc, aluminum, or zirconium salts. Organic salts, e.g., dicyclohexylamine salts, methyl-D-glucosamine, and amino acid salts, e.g., arginine, lysine, histidine, and glutamine, may also be included.
[0073] Furthermore, the pharmaceutical compositions of this disclosure may, but are not limited to, be administered to individuals requiring such a pharmaceutical composition. The routes of administration of the pharmaceutical compositions of this disclosure may, but are not limited to, parenteral, oral, inhalation spray, or implanted reservoir methods. Parenteral administration may, but are not limited to, subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional injection and infusion techniques.
[0074] The individuals requiring administration of the aforementioned pharmaceutical composition may include, but are not limited to, vertebrates. These vertebrates may include, but are not limited to, fish, amphibians, reptiles, birds, or mammals. Examples of mammals may include, but are not limited to, humans, orangutans, monkeys, horses, donkeys, dogs, cats, rabbits, guinea pigs, rats, and mice. In one embodiment, the individual may be a human.
[0075] Furthermore, based on the foregoing, the present disclosure can also provide applications for preparing reagents to degrade and / or inhibit the activity of any of the above-described compounds or salts thereof, or any of the above-described pharmaceutical compositions of the present disclosure. The transactive response DNA-binding protein-43 may be the full-length transactive response DNA-binding protein-43, or only the C-terminal region of an independent transactive response DNA-binding protein-43, and is not particularly limited. In other words, a reagent used to degrade and / or inhibit the activity of the transactive response DNA-binding protein-43 may degrade the full-length transactive response DNA-binding protein-43, or it may degrade the C-terminal region of an independent transactive response DNA-binding protein-43, and is not particularly limited.
[0076] Furthermore, based on the same basis as above, the Disclosure may also provide applications for producing pharmaceuticals to treat and / or prevent diseases associated with the accumulation of transactive response DNA-binding protein-43, using any of the compounds or salts thereof described above in the Disclosure, or any of the pharmaceutical compositions described above in the Disclosure.
[0077] In one embodiment, diseases associated with the accumulation of the above-described transactive response DNA-binding protein-43 may include, but are not limited to, neurodegenerative diseases. Examples of neurodegenerative diseases may include, but are not limited to, Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), frontotemporal dementia (FTD), Huntington's disease (HD), and others.
[0078] Similarly, based on the foregoing, the Disclosure may also provide reagents for use in degrading and / or inhibiting the activity of the transactive response DNA-binding protein-43. These reagents for use in degrading and / or inhibiting the activity of the transactive response DNA-binding protein-43 may include, but are not limited to, any of the compounds or salts thereof described herein, or any of the pharmaceutical compositions described herein.
[0079] Furthermore, the Disclosure may also provide a method for degrading and / or inhibiting the activity of transactive response DNA-binding protein-43 in the body, which may, but is not limited to, administering any of the compounds or salts thereof described herein, or any of the pharmaceutical compositions described herein, to an individual in need thereof.
[0080] Alternatively, the Disclosure may provide a method for degrading and / or inhibiting the activity of transactive response DNA-binding protein-43 in vitro, which may, but is not limited to, contacting and / or reacting any of the compounds or salts thereof described herein, or any of the pharmaceutical compositions described herein, with transactive response DNA-binding protein-43 and E3 ubiquitin ligase in vitro.
[0081] Furthermore, based on the foregoing, the Disclosure may also provide a pharmaceutical composition for use in treating and / or preventing diseases relating to the accumulation of transactive response DNA-binding protein-43. This pharmaceutical composition for use in treating and / or preventing diseases relating to the accumulation of transactive response DNA-binding protein-43 may, but is not limited to, any of the compounds or salts thereof described herein, or any of the pharmaceutical compositions described herein.
[0082] The disclosure may also provide a method for treating and / or preventing diseases relating to the accumulation of transactive response DNA-binding protein-43, the method which may include, but is not limited to, administering any of the compounds or salts thereof described herein, or any of the pharmaceutical compositions described herein, to an individual in need thereof.
[0083] The disease-related explanations regarding the accumulation of the transactive response DNA-binding protein-43 described here are as stated above and will not be repeated here.
[0084] Descriptions of any individual requiring any of the compounds or salts thereof described above in this disclosure, or any individual requiring any of the pharmaceutical compositions described above in this disclosure, are not repeated here, as they can be found in the descriptions of individuals given above with respect to the pharmaceutical compositions of this disclosure. [Examples]
[0085] A. Preparation of compounds
[0086] A-1. Abbreviations of compounds EtOH: Ethanol (ethanol) DCM: Dichloromethane DIPEA: Diisopropylethylamine (N,N-diisopropylethylamine) DMF: Dimethylformamide DMSO: Dimethyl sulfoxide T3P: 1-propanephosphonic acid cyclic anhydride Et3N: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofuran
[0087] A-2. Preparation of Category I Compounds
[0088] The Category I compounds have a structure in which an E3 ubiquitin ligase-binding domain is linked to the 6-position of the quinoline skeleton via a linker.
[0089] (1) Method A
[0090] [ka]
[0091] Ra' is NO2, H, CN, N(CH3)2 or [ka] The LEs are as shown in the table below.
[0092] [Table 13] JPEG2026116726000058.jpg72149
[0093] Example 1
[0094] [ka]
[0095] Preparation of compound D101
[0096] 64 mg of int-1, i.e., N-(5-nitro-6-(piperazin-1-yl)quinolin-8-yl)acetamide, was dissolved in 1 mL of DMF. Then, 1 eq of pomalidomide-PEG1-C2-COOH, 3 eq of Et3N, and 1.5 eq of T3P were added, and the reaction was allowed to proceed with stirring at room temperature for 3 hours. After the reaction was complete, the reaction product was placed in water and extracted by DCM. The DCM layer was then removed, dried, concentrated, and purified by column chromatography to obtain 93 mg of compound D101 (yield 67.7%).
[0097] (2) Method B
[0098] [ka]
[0099] Example 2
[0100] [ka]
[0101] Preparation of compound D102
[0102] 53 mg of compound D101 was dissolved in EtOH / THF. Then, 3 eq of Fe and 1.5 eq of NH4Cl were added, and the reaction was allowed to proceed by stirring at 85°C for 16 hours. After the reaction was complete, the reaction product was filtered. The resulting filtrate was concentrated, evaporated, and extracted with DCM / H2O. The DCM layer was then removed, dried, concentrated, and purified by column chromatography to obtain 36 mg of compound D102 (yield 70.1%).
[0103] (3) Method C
[0104] [ka]
[0105] Rb' is either NO2 or NHAc, and LE is as shown in the table below.
[0106] [Table 14] JPEG2026116726000064.jpg78149
[0107] Example 3
[0108] [ka]
[0109] Preparation of compound D105
[0110] 27 mg of int-2, i.e., 8-acetylamino-6-chloro-5-nitroquinoline, was dissolved in 2 mL of DMF. Then, 1.5 eq of LE-013, i.e., 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(piperidin-4-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione) and 4.5 eq of K2CO3 were added, and the reaction was allowed to proceed by stirring at 85°C for 16 hours. After the reaction was complete, the reaction mixture was placed in water, stirred, and filtered. After filtration, the solid was collected and extracted with DCM / H2O. Next, the DCM layer was removed, dried, concentrated, and then purified by column chromatography to obtain 56 mg of compound D105 (yield 82.0%).
[0111] (4) Method D
[0112] [ka]
[0113] The LE values are as shown in the table below.
[0114] [Table 15]
[0115] Example 4
[0116] [ka]
[0117] Preparation of compound D111
[0118] 72 mg of int-3, i.e., 1-(8-acetamido-5-nitroquinoline-6-yl)piperidine-4-carboxylic acid, was dissolved in 1 mL of DMF. Then, 1 eq of thalidomide-NH-PEG1-NH2, 3 eq of Et3N, and 1.5 eq of T3P were added, and the reaction was allowed to proceed with stirring at room temperature for 3 hours. After the reaction was complete, the reaction product was added to water and extracted by DCM. The DCM layer was then removed, dried, concentrated, and purified by column chromatography to obtain 66 mg of compound D111 (yield 47.1%).
[0119] (5) Method E
[0120] [ka]
[0121] Rc' is NO2, and LE is as shown in the table below.
[0122] [Table 16]
[0123] Example 5
[0124] [ka]
[0125] Preparation of compound D123
[0126] 88 mg of int-4, i.e., N-(6-(4-aminophenyl)-5-nitroquinolin-8-yl)acetamide, was dissolved in 1 mL of DMF. Then, 1 eq of thalidomide-NH-CH2-COOH, 3 eq of Et3N, and 1.5 eq of T3P were added, and the reaction was allowed to proceed with stirring at room temperature for 3 hours. After the reaction was complete, the reaction product was added to water and extracted by DCM. The DCM layer was then removed, dried, concentrated, and purified by column chromatography to obtain 64 mg of compound D123 (yield 50.3%).
[0127] (6) Method F
[0128] [ka]
[0129] Rd' is CN, N(CH3)2, H or [ka] Therefore, X is either F or Br.
[0130] Example 6
[0131] [ka]
[0132] Preparation of compound D134
[0133] 60 mg of int-5, i.e., N-(5-cyano-6-(piperazin-1-yl)quinolin-8-yl)acetamide, was dissolved in 2 mL of DMSO. Then, 1.0 eq of thalidomide 4-fluoride and 3.0 eq of DIPEA were added, and the reaction was allowed to proceed by stirring at 130°C for 3 hours. After the reaction was complete, the reaction mixture was placed in water, stirred, and filtered. After filtration, the solid was removed and extracted with DCM and H2O. The DCM layer was then removed, dried, concentrated, and purified by column chromatography to obtain 32 mg of compound D134 (yield 31.7%).
[0134] In this example, compound D151 was prepared from compound D101. The structures of compound D151 from compound D101 are shown in Table 8 below. The methods used to prepare compound D151 from compound D101, as well as the results of proton nuclear magnetic resonance (HNMR) analysis and liquid chromatography-mass spectrometry (LCMS) analysis of compound D101 and compound D151, are shown in Table 9.
[0135] [Table 17] JPEG2026116726000076.jpg225149JPEG2026116726000077.jpg225149JPEG2026116726000078.j pg225149JPEG2026116726000079.jpg225149JPEG2026116726000080.jpg215149JPEG20261167260 00081.jpg192149JPEG2026116726000082.jpg197149JPEG2026116726000083.jpg225149JPEG202 6116726000084.jpg225149JPEG2026116726000085.jpg198149JPEG2026116726000086.jpg151149
[0136] [Table 18] JPEG2026116726000088.jpg214149JPEG2026116726000089.jpg178149JPEG20261167260 00090.jpg209149JPEG2026116726000091.jpg209149JPEG2026116726000092.jpg204149 JPEG2026116726000093.jpg198149JPEG2026116726000094.jpg198149JPEG20261167260 00095.jpg219149JPEG2026116726000096.jpg183149JPEG2026116726000097.jpg183149
[0137] A-3. Preparation of Class II Compounds
[0138] The Category II compounds have a structure in which an E3 ubiquitin ligase-binding domain is linked to the 5-position of the quinoline skeleton via a linker.
[0139] (1) Method G
[0140] [ka]
[0141] The LE values are as shown in the table below. [Table 19]
[0142] Example of production
[0143] [ka]
[0144] Preparation of compound D204
[0145] 32 mg of int-6, i.e., N-(8-acetamido-6-(methylthio)quinolin-5-yl)-2-chloroacetamide, was dissolved in 2 mL of DMF. Then, 1.5 eq of LE-023 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(piperidin-4-yl)ethyl)piperazin-1-yl)isoindoline-1,3-dione and 4.5 eq of K2CO3 were added, and the reaction was allowed to proceed by stirring at 100°C for 16 hours. After the reaction was complete, the reaction mixture was placed in water, stirred, and filtered. After filtration, the solid was collected and extracted with DCM and H2O. The DCM layer was then removed, dried, concentrated, and purified by column chromatography to obtain 36 mg of compound D204 (yield 48.6%).
[0146] In this embodiment, compounds D201 to D204 were prepared. The structures of compounds D201 to D204 are as shown in Table 10 below, the methods respectively used to prepare compounds D201 to D204, as well as the respective proton nuclear magnetic resonance analysis results and liquid chromatography / mass spectrometry analysis results of compounds D201 to D204 are as shown in Table 11.
[0147] [Table 20] JPEG2026116726000102.jpg52149
[0148] [Table 21]
[0149] A-4. Preparation of Class III Compounds
[0150] The Class III compounds have a structure in which an E3 ubiquitin ligase binding domain is linked by a linker to the 8-position of the quinoline skeleton.
[0151] (1) Method H
[0152] [Chemical formula]
[0153] R x is NO2, CN or [Chemical formula] is. R yThese are OCH3, SCH3, morpholine, n-methylpiperazine, pyrrolidine-3-amine, 4-aminopiperidine, or 4-(N-Boc-amino)piperidine. The LEs are as shown in the table below.
[0154] [Table 22]
[0155] Example of production
[0156] [ka]
[0157] Preparation of compound D301
[0158] 36 mg of int-7, i.e., 2-chloro-N-(6-methoxy-5-nitroquinolin-8-yl)acetamide, was dissolved in 2 mL of DMF. Then, 1.5 eq of 2-(2,6-dioxopiperidin-3-yl)-4-(piperidin-4-yl)isoindole-1,3-dione and 4.5 eq of K2CO3 were added, and the mixture was stirred at 100°C for 16 hours to allow the reaction to proceed. After the reaction was complete, the reaction product was placed in water, stirred, and filtered. After filtration, the solid was collected and extracted with DCM / H2O. Next, the DCM layer was removed, dried, concentrated, and then purified by column chromatography to obtain 36 mg of compound D301 (yield 48.5%).
[0159] In this embodiment, compound D316 was prepared from compound D301. The structures of compound D316 from compound D301 are shown in Table 12 below, and the methods used to prepare compound D316 from compound D301, as well as the results of proton nuclear magnetic resonance analysis and liquid chromatography / mass spectroscopy analysis of compound D301 and compound D316, are shown in Table 13.
[0160] [Table 23] JPEG2026116726000109.jpg214149JPEG2026116726000110.jpg214149JPEG2026116726000111.jpg47149
[0161] [Table 24] JPEG2026116726000113.jpg198149JPEG2026116726000114.jpg198149JPEG2026116726000115.jpg93149
[0162] B. Analysis of the compound's degradation ability against transactive response DNA binding protein 43 (TDP-43).
[0163] In this experiment, the activity of compounds in degrading TDP-43 was analyzed using the NanoLuc-TDP-43 fusion protein analysis system.
[0164] In this experiment, 293-H cells (cat. no. 11631017) purchased from Thermo Fisher Scientific were used as the target cells for transfection. The cells were cultured in DMEM medium (Corning Incorporated; cat. no. 10-013-CM) containing 10% fetal bovine serum (FBS) (Thermo Fisher Scientific; cat. no. 10437028). Subsequently, the cells were inoculated into 24-well plates at a cell density of 100,000 / well and cultured for 2 days before transfection.
[0165] Transfection was performed using the transfection reagent (ViaFect® Transfection Reagent, Promega; cat. no. E4982) according to the manufacturer's instructions. 500 ng of expression vector and 1.5 μL of transfection reagent were added to each well of the aforementioned 24-well plate, and cells were transfected. The expression vectors used were pcDNA3.1-Myc-NanoLuc-LinkerTDP43 (abbreviated as NanoLuc-TDP-43(WT); its shape is shown in Figure 1) and pcDNA3.1-Myc-NanoLuc-LinkerTDP43CTD (abbreviated as NanoLuc-TDP-43(CTD); its shape is shown in Figure 2).
[0166] Three hours after transfection, the test compound was added to each well, and after overnight incubation, the NanoLuc luminescence activity of each well was analyzed. Total protein was extracted from the cells in each well using 100 μL of CelLytic® M cell lysate (Merck KGaA; cat.no.C2978-250ML), and coelenterazine-H (Regis Technologies; cat.no.50909-86-9) was used as the substrate for NanoLuc. Luminescence analysis was performed using a multimode microplate reader (Thermo Varioskan LUX) to confirm the luminescence intensity of each well and to confirm the NanoLuc activity of the wells.
[0167] The activity of NanoLuc was measured by setting the luminescence intensity of the untreated group to 100%, and calculating the relative suppression rate for each group treated with each compound. This allowed us to determine the degradation ability of each compound against transactive response DNA binding protein 43 (TDP-43).
[0168] The results are shown in Tables 14 to 16.
[0169] [Table 25] JPEG2026116726000117.jpg110149
[0170] [Table 26]
[0171] [Table 27]
[0172] From Tables 14 to 16 above, it can be seen that all the compounds prepared in the examples exhibit inhibitory activity against both NanoLuc-TDP43(WT) fusion protein and NanoLuc-TDP43(CTD) fusion protein.
[0173] In other words, all the compounds prepared in the examples had the ability to degrade the transactive response DNA-binding protein-43. That is, all the proteolysis-targeting chimeras (PROTACs) prepared in the examples against the transactive response DNA-binding protein-43 can effectively degrade the transactive response DNA-binding protein-43, and thus can be used for the treatment and / or prevention of diseases related to the accumulation of the transactive response DNA-binding protein-43.
[0174] While preferred embodiments have been disclosed above, this disclosure is not limited thereto, and those skilled in the art can make some modifications and changes without departing from the spirit and scope of this disclosure. Therefore, the scope of protection of this disclosure shall be as defined in the appended claims.
Claims
1. Formula (I), Formula (II), or Formula (III): 【Chemistry 1】 A compound or salt thereof having a structure represented by, During the ceremony, R １ H, cyano group, NH ２ NO ２ NHR ３ NHR ３ R ４ heterocycle, NHCOR ５ or 【Chemistry 2】 And, R ２ is NHCOR ６ or NH ２ and A and B are independently N and C, or do not exist. y and z are each independent integers between 1 and 3. R ３ , R ４ , R ５ and R ６ Each is independently C １ -C ６ It is an alkyl group, which is a linear or branched alkyl group, and may be substituted with one or more halogen atoms, oxygen atoms, sulfur atoms, or amines as needed. R ７ is SCH ３ or OCH ３ And, R ８ NHCOR ９ or NH ２ And, R ９ is C １ -C ６ It is an alkyl group, R １０ H, cyano group, NH ２ NO ２ NHR ３ NHR ３ R ４ , heterogeneous ring or NHCOR ５ And, R １１ is SCH ３ , OCH ３ or it is a complex algebra, L １ The structure is as shown below: Table 1 【change】 A linker having a structure selected from the group consisting of the following: L ２ and L ３ Each of these independently has the structure shown below: Table 2 A linker having a structure selected from the group consisting of the following: During the ceremony, X １ These are bonds, -NH-, -O-, -CO-, CONH, or -PhNHCO-, X ２ The bonds are -NH-, -O-, and -NHCOCH. ２ NH-, -NHCOCH ２ It is O- or -alkyne-, X is a complex algebra, n is an integer from 1 to 6. m is an integer from 0 to 8. Furthermore, E is the E3 ubiquitin ligase binding domain, which has the structure shown below: Table 3 A compound or a salt thereof containing one of the following.
2. The compound according to claim 1 or a salt thereof, wherein the compound has a structure represented by formula (I).
3. R １ H, cyano group, NO ２ , N (CH ３ ) ２ , NHAc or 【Transformation 3】 And R ２ The compound or a salt thereof according to claim 2, wherein the compound is NHAc.
4. The compound according to claim 2, wherein the compound comprises one of the following compounds, or a salt thereof. Table 4
5. The compound according to claim 1 or a salt thereof, wherein the compound has a structure represented by formula (II).
6. R ７ SCH ３ And R ８ The compound or salt thereof according to claim 5, wherein is NHAc.
7. The compound according to claim 5, wherein the compound comprises one of the following compounds, or a salt thereof. Table 5
8. The compound according to claim 1 or a salt thereof, wherein the compound has a structure represented by formula (III).
9. R １０ NO ２ , CN or 【Chemistry 4】 And R １１ ga OCH ３ SCH ３ The compound or salt thereof according to claim 8, wherein the compound is morpholine, n-methylpiperazine, pyrrolidin-3-amine, 4-aminopiperidine, or 4-(N-Boc-amino)piperidine.
10. The compound according to claim 8, wherein the compound comprises one of the following compounds, or a salt thereof. Table 6
11. A pharmaceutical composition, The compound or a salt thereof according to claim 1, A pharmaceutically acceptable carrier or salt, A pharmaceutical composition containing the following:
12. A reagent used to degrade and / or suppress the activity of transactive response DNA binding protein 43 (TDP-43), A reagent comprising the compound or a salt thereof as described in claim 1.
13. A reagent for degrading and / or inhibiting the activity of the transactive response DNA-binding protein-43 according to claim 12, wherein the transactive response DNA-binding protein-43 is a full-length transactive response DNA-binding protein-43 or the C-terminal region of an independent transactive response DNA-binding protein-43.
14. A pharmaceutical composition for use in treating and / or preventing diseases related to the accumulation of transactive response DNA-binding protein-43, A pharmaceutical composition comprising the compound or a salt thereof as described in claim 1.
15. A pharmaceutical composition for treating and / or preventing a disease relating to the accumulation of the transactive response DNA-binding protein-43, according to claim 14, wherein the disease relating to the accumulation of the transactive response DNA-binding protein-43 includes neurodegenerative diseases.