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EP-4737445-A1 - NOVEL SATURATED HETEROCYCLE-SUBSTITUTED HETEROARYL-CARBONOHYDRAZONOYL DICYANIDE COMPOUND AND USE THEREOF

EP4737445A1EP 4737445 A1EP4737445 A1EP 4737445A1EP-4737445-A1

Abstract

The present invention relates to a novel saturated heterocycle-substituted heteroaryl-carbonohydrazonoyl dicyanide compound or a pharmaceutically acceptable salt thereof, a preparation method therefor, and a pharmaceutical composition comprising same as an active ingredient for preventing or treating neurological diseases. The saturated heterocycle-substituted heteroaryl-carbonohydrazonoyl dicyanide compound of the present invention inhibits the aggregation or hyperphosphorylation of tau protein and/or TDP-43, and thus can be used for preventing and treating neurological diseases including tauopathy and TDP-43 proteinopathy.

Inventors

  • PAE, AE NIM
  • LUKIANENKO, Nataliia
  • KIM, KYU HYEON
  • ABDILDINOVA, Aizhan
  • KIM, YUN KYUNG
  • LIM, SUNG SU
  • LIM, SANG MIN
  • LEE, HA EUN
  • JEONG, DA YEON
  • LEE, CHANG YONG
  • GOTINA, Lizaveta
  • KANG, DONG MIN

Assignees

  • Korea Institute of Science and Technology

Dates

Publication Date
20260506
Application Date
20231201

Claims (16)

  1. A carbonohydrazonoyl dicyanide compound represented by Formula 1 or a pharmaceutically acceptable salt thereof: wherein in Formula 1, n is 0 or 1; R 1 is any one selected from hydrogen, C 1-4 alkyl, or C 1-4 alkylcarbonyl; R 2 is absent or halogen; X is any one selected from O, S or NR 3 ; R 3 is hydrogen, or C 1-4 alkyl; Y 1 and Y 2 are C or N; Z is absent or NH; and Cy is a 5- to 10-membered saturated heterocyclyl which is unsubstituted or substituted with one or more selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylcarbonyl, and C 1-4 alkoxycarbonyl.
  2. The carbonohydrazonoyl dicyanide compound or pharmaceutically acceptable salt thereof of claim 1, wherein R 1 is any one selected from hydrogen, methyl, or acetyl; R 2 is absent, or chlorine; X is any one selected from O, S, or NR 3 ; R 3 is any one selected from hydrogen, methyl, or ethyl; and Cy is a 5- to 10-membered saturated heterocyclyl substituted with one or more selected from the group consisting of fluoro, methyl, isopropyl, methoxy, methylcarbonyl, and tert-butoxycarbonyl.
  3. The carbonohydrazonoyl dicyanide compound or pharmaceutically acceptable salt thereof of claim 1, wherein the carbonohydrazonoyl dicyanide compound represented by Formula 1 is represented by Formula 1-1 or Formula 1-2:
  4. The carbonohydrazonoyl dicyanide compound or pharmaceutically acceptable salt thereof of claim 1, wherein the carbonohydrazonoyl dicyanide compound is 1. (2-morpholinobenzo[d]thiazol-5-yl)carbonohydrazonoyl dicyanide, 2. (2-morpholinobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 3. (2-morpholinobenzo[d]oxazol-5-yl)carbonohydrazonoyl dicyanide, 4. (2-morpholinobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 5. (1-methyl-2-morpholino-1H-benzo[d]imidazol-6-yl)carbonohydrazonoyl dicyanide, 6. (1-methyl-2-morpholino-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 7. (2-morpholino-1H-benzo[d]imidazol-6-yl)carbonohydrazonoyl dicyanide, 8. (2-(4-methylpiperazin-1-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 9. (2-(4-methoxypiperidin-1-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 10. (2-(2,6-dimethylmorpholino)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 11. (2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 12. (2-(2-methylmorpholino)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 13. (2-(3-methylmorpholino)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 14. (2-(4-methylpiperazin-1-yl)benzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 15. (2-(2-methylmorpholino)benzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 16. (2-(3-methylmorpholino)benzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 17. (2-(4-methoxypiperidin-1-yl)benzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 18. (2-(2,6-dimethylmorpholino)benzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 19. (5-chloro-2-morpholinobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 20. (2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 21. tert-butyl 4-(6-(2-(dicyanomethylene)hydrazinyl)benzo[d]oxazol-2-yl)piperazine-1-carboxylate, 22. tert-butyl 4-(6-(2-(dicyanomethylene)hydrazinyl)benzo[d]thiazol-2-yl)piperazine-1-carboxylate, 23. (2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 24. (2-(piperazin-1-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 25. (2-(piperazin-1-yl)benzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 26. (2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)benzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 27. (2-(4-isopropylpiperazin-1-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 28. (2-(4-isopropylpiperazin-1-yl)benzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 29. (2R,6S)-tert-butyl 4-(6-(2-(dicyanomethylene)hydrazinyl)benzo[d]thiazol-2-yl)-2,6-dimethylpiperazine-1-carboxylate, 30. (2-(4-acetylpiperazin-1-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 31. (2-(4-acetylpiperazin-1-yl)benzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 32. (1-ethyl-2-morpholino-1H-benzo[d]imidazol-6-yl)carbonohydrazonoyl dicyanide, 33. (1-ethyl-2-morpholino-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 34. (2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-methyl-1H-benzo[d]imidazol-6-yl)carbonohydrazonoyl dicyanide, 35. (2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 36. (2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazol-6-yl)(methyl)carbonohydrazonoyl dicyanide, 37. acetyl(2-morpholinobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 38. (2-(morpholine-4-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 39. (2-(2,6-dimethylmorpholine-4-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 40. (2-(8-oxa-3-azabicyclo[3.2.1]octane-3-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 41. (R)-(2-(3-fluoropyrrolidin-1-yl)benzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 42. (S)-(2-(3-fluoropiperidin-1-yl)benzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 43. (S)-(2-(3-fluoropyrrolidin-1-yl)benzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 44. (2-(3-fluoropiperidin-1-yl)benzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 45. (2-(pyrrolidin-1-yl)benzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 46. (2-(piperidin-1-yl)benzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 47. (R)-N-(2-(3-fluoropiperidin-1-yl)benzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 48. N-(2-(morpholine-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide, or 49. N-(2-morpholinooxazolo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide.
  5. A method of preparing a compound represented by Formula 1, comprising a first step of forming an imine bond by reacting a compound represented by Formula 2, which includes a reactive amine group at one terminal, with sodium nitrite and malononitrile in the presence of an acid; and optionally, when R 1 is a substituent other than hydrogen, further comprising a second step of introducing an R 1 substituent into a product obtained from the first step: wherein in Formulas 1 and 2, n is 0 or 1; R 1 is any one selected from hydrogen, C 1-4 alkyl, or C 1-4 alkylcarbonyl; R 2 is absent or halogen; X is any one selected from O, S or NR 3 ; R 3 is hydrogen, or C 1-4 alkyl; Y 1 and Y 2 are C or N; Z is absent or NH; and Cy is a 5- to 10-membered saturated heterocyclyl which is unsubstituted or substituted with one or more selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylcarbonyl, and C 1-4 alkoxycarbonyl.
  6. The method of claim 5, wherein the second step is performed by: i) when R 1 is C 1-6 alkyl, reacting with a halogenated alkane in the presence of potassium tert-butoxide or sodium hydride in an organic solvent, and ii) when R 1 is C 1-4 alkylcarbonyl, reacting with a halogenated alkylcarbonyl in the presence of a base and triethylamine.
  7. The method of claim 5, wherein the compound represented by Formula 2 is obtained by: i) when n is 0 and X is S or NR 3 , reacting Cy-H with a compound represented by Formula 3-a under microwave irradiation, ii) when n is 0 and X is O, reacting Cy-H with a compound represented by Formula 3-b in the presence of triethylamine, iii) when n is 1, reacting Cy-H with a compound represented by Formula 3-c, and when R N is nitro, further reducing the reaction product, and iv) when Y2 is N, n is 1, and Z is NH, reacting with a compound represented by Formula 3-d: wherein in Formulas 3-a to 3-d, X 1 is halogen, R N is nitro or amino; R 5 is any one selected from t-butoxycarbonyl, hydrogen, or benzyloxycarbonyl; and Cy is a 5- to 10-membered saturated heterocyclyl which is unsubstituted or substituted with one or more selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylcarbonyl, and C 1-4 alkoxycarbonyl.
  8. The method of claim 7, wherein in the compound represented by Formula 3-a, when X is NR 3 and R 3 is C 1-4 alkyl, the compound is prepared by preparing a compound in which R 3 is hydrogen according to step i) and reacting the compound with halogenated R 3 in the presence of DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene).
  9. The method of claim 7, wherein the compound represented by Formula 3-b is prepared by reacting a compound represented by Formula 4 with potassium ethyl xanthogenate:
  10. The method of claim 7, wherein the compound represented by Formula 3-c is prepared by reacting a compound represented by Formula 5 with phenyl chloroformate in the presence of triethylamine:
  11. A pharmaceutical composition for preventing or treating a disease caused by aggregation or hyperphosphorylation of tau protein or TDP-43 protein, comprising the compound of claim 1 as an active ingredient.
  12. The pharmaceutical composition of claim 11, wherein the disease caused by aggregation or hyperphosphorylation of tau protein is selected from the group consisting of Alzheimer's disease, Parkinson's disease, vascular dementia, acute stroke, trauma, cerebrovascular disease, brain cord trauma, spinal cord trauma, peripheral neuropathy, retinopathy, glaucoma, and tauopathies.
  13. The pharmaceutical composition of claim 12, wherein the tauopathy is selected from the group consisting of chronic traumatic encephalopathy (CTE), primary age-related tauopathy, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, argyrophilic grain disease (AGD), frontotemporal dementia (FTD), Parkinsonism linked to chromosome 17, Lytico-Bodig disease (Parkinson-dementia complex of Guam), ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Pantothenate kinase-associated neurodegeneration, lipofuscinosis, posttraumatic stress disorder, and traumatic brain injury.
  14. The pharmaceutical composition of claim 11, wherein the disease caused by aggregation or hyperphosphorylation of TDP-43 protein is selected from the group consisting of amyotrophic lateral sclerosis (ALS), Familial ALS-SOD1, sporadic amyotrophic lateral sclerosis, superoxide dismutase 1 (SOD1), frontotemporal lobar degeneration (FTLD), ALS-FTLD, Multiple system proteinopathy (MSP), limbic-predominant age-related TDP-43 encephalopathy (LATE)/CART (cerebral age-related TDP-43 with sclerosis), Perry disease, facial onset sensory and motor neuronopathy (FOSMN), and sporadic inclusion body myositis (sIBM).
  15. The pharmaceutical composition of claim 11, characterized by inhibiting aggregation of tau protein or TDP-43 protein.
  16. The pharmaceutical composition of claim 11, characterized by inhibiting hyperphosphorylation of tau protein or TDP-43 protein.

Description

TECHNICAL FIELD The disclosure relates to novel heteroaryl-carbonohydrazonoyl dicyanide compounds substituted with saturated heterocycles and uses thereof. BACKGROUND ART Tau protein is a microtubule-associated protein (MAP) that is mainly expressed in axons of neurons, plays a role in stabilizing microtubules, and exhibits molecular diversity by phosphorylation. In humans, tau generates six isoforms by insertion of 29 or 58 amino acid residues in the N-terminal region and alternative splicing of 3 or 4 repeat structures (referred to as microtubule binding sites) at the C-terminus. In healthy neurons, tau stabilizes microtubules by promoting growth from axons and neuronal polarization. When pathologically hyperphosphorylated, tau separates from microtubules and accumulation and aggregation occur in the cytoplasm. The hyperphosphorylation and/or aggregation of the tau protein causes abnormal accumulation of these tau proteins in neurons, which is pointed to as the cause of various degenerative neurological diseases. Abnormal tau protein aggregation also appears in tauopathies, and although the exact role of tau protein aggregation in the disease exacerbation stage of tauopathy is not known, it appears similar to the aggregation phenomenon that commonly appears in general degenerative brain diseases. TDP-43 (TDP-43) protein is a protein that mainly exists in the nucleus and is known to be involved in gene expression by binding to DNA or RNA to inhibit gene transcription and regulate RNA splicing and translation processes. In a pathological environment, when TDP-43 protein present in the cell nucleus undergoes modification, it migrates to the cytoplasm and forms abnormal aggregates. As such, tau protein and/or TDP-43 protein are known to be hyperphosphorylated and/or aggregated alone or in combination in neurons to cause various degenerative brain diseases including tauopathies such as amyotrophic lateral sclerosis, frontotemporal dementia, and Alzheimer's dementia. In particular, when tau protein and TDP-43 protein are aggregated in combination and tauopathy appears, it has been reported that the progression of tau pathology is accelerated and intensified. However, the specific mechanism by which these tau protein and/or TDP-43 protein-mediated diseases transmit signals and exhibit toxicity has not yet been elucidated, and no clear treatment or therapeutic agent that can treat these diseases has yet been known. Accordingly, the present inventors intend to complete and provide an invention that can be applied to tau protein and/or TDP-43 protein-related proteinopathies. Prior art related to the disclosure includes Mol. Neurodegeneration, 2009, 4: 13, Biophys. J., 2006, 90: 3739-3748, J. Biol. Chem., 1995, 270: 7679-7688, J. Neurol. Neurosurg. Psychiatry, 2021, 92: 86-95., Front. Neuroscience, 2022, 16, 815765, Geroscience 2021, 43, 1627-1634, and Brain 2022, 145, 2769-2784. DISCLOSURE OF THE INVENTION TECHNICAL GOALS A technical goal to be solved by the disclosure is to provide novel heteroaryl-carbonohydrazonoyl dicyanide compounds substituted with saturated heterocycles or pharmaceutically acceptable salts thereof. A technical goal to be solved by the disclosure is to provide a method of preparing the heteroaryl-carbonohydrazonoyl dicyanide compounds or pharmaceutically acceptable salts thereof. In addition, another object of the disclosure is to provide a pharmaceutical composition for preventing or treating diseases caused by aggregation or hyperphosphorylation of tau protein or TDP-43 protein, which includes the heteroaryl-carbonohydrazonoyl dicyanide compound or pharmaceutically acceptable salt thereof as an active ingredient. However, the technical goals to be solved by the disclosure are not limited to the goals mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the description below. TECHNICAL SOLUTIONS To achieve the above goals, the disclosure provides a carbonohydrazonoyl dicyanide compound represented by Formula 1 or a pharmaceutically acceptable salt thereof: wherein in Formula 1, n may be 0 or 1;R1 may be any one selected from hydrogen, C1-4 alkyl, or C1-4 alkylcarbonyl;R2 may be absent or halogen;X may be any one selected from O, S, or NR3;R3 may be hydrogen or C1-4 alkyl;Y1 and Y2 may be C or N;Z may be absent or NH; andCy may be a 5- to 10-membered saturated heterocyclyl that is unsubstituted or substituted with one or more selected from the group consisting of halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylcarbonyl, and C1-4 alkoxycarbonyl.According to an aspect,R1 may be any one selected from hydrogen, methyl, or acetyl;R2 may be absent or chlorine;X may be any one selected from O, S, or NR3;R3 may be any one selected from hydrogen, methyl, or ethyl; andCy may be a 5- to 10-membered saturated heterocyclyl substituted with one or more selected from the group consisting of fluoro, methyl, isopropyl, methoxy, methylcarbonyl, and tert-but