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EP-4739692-A1 - SUBSTITUTED HEXAHYDRO-2H-PYRAZINO[1,2-A]PYRAZIN-1(6H)-ONE DERIVATIVES AS ACTIVATORS OF HUMAN CASEINOLYTIC PROTEASE P (HSCLPP)

EP4739692A1EP 4739692 A1EP4739692 A1EP 4739692A1EP-4739692-A1

Abstract

Substituted hexahydro-2H-pyrazino[1,2-a]pyrazin-1(6H)-one derivatives of formula (I) that activate human caseinolytic protease P (HsClpP), and pharmaceutical compositions comprising such compounds, are disclosed. Additionally, methods of treating or alleviating conditions such as cancer, through the modulation of HsClpP, are also disclosed.

Inventors

  • MCNAUGHTON-SMITH, GRANT
  • Ayra Plasencia, Jessel
  • Velázquez García, Silvia Ascensión
  • Estévez Silva, Héctor Martín
  • ABREU GARCÍA, Andrea
  • CHICO CAMPOS, María Atteneri
  • MACHÍN CONCEPCIÓN, Felix Manuel

Assignees

  • Centro Atlantico del Medicamento S.A (Ceamed, S.A)
  • Fundación Canaria Instituto de Investigación Sanitaria de Canarias

Dates

Publication Date
20260513
Application Date
20240703

Claims (15)

  1. 1 . A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof: (I), wherein; A is independently selected from the group consisting of: Ci-Ce alkyl or is absent; X and Y are independently selected from the group consisting of Ci-Ce haloalkyl, aromatic carbocyclic 6-membered ring, or an aromatic heterocyclic 5- or 6-membered ring comprising one or more heteroatoms selected from the group consisting of O, N and S, wherein said aromatic carbocyclic ring, or said aromatic heterocyclic ring, is unsubstituted or substituted at one or more atoms of C, with a R 7 substituent; R 7 substituent is independently selected from the group consisting of: H, halogen, Ci-Ce haloalkyl, -O-Ci-Ce alkyl, -O-C1-C3 haloalkyl, cyano, Ci-Ce alkyl and -C(O)OR 8 ; R 8 is independently selected from the group consisting of: Ci-Ce alkyl, C3-C6 cycloalkyl or Ci-Ce aminoalkyl.
  2. 2. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to claim 1 , wherein: A is independently selected from the group consisting of: Ci-Ce alkyl or is absent; X and Y are independently selected from the group consisting of Ci-Ce haloalkyl, aromatic carbocyclic 6-membered ring, or an aromatic heterocyclic 5- or 6-membered ring comprising one or more heteroatoms selected from the group consisting of O, N and S, wherein said aromatic carbocyclic ring, or said aromatic heterocyclic ring, is unsubstituted or substituted at one or more atoms of C, with a R 7 substituent; wherein R 7 substituent is independently selected from the group consisting of: H, halogen, Ci-Ce haloalkyl, -O-Ci-Ce alkyl, -O-C1-C2 haloalkyl, cyano and Ci-Ce alkyl.
  3. 3. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to claims 1 or 2, wherein: A is independently selected from the group consisting of: C1-C3 alkyl or is absent; X and Y are independently selected from the group consisting of C1-C3 haloalkyl, aromatic carbocyclic 6-membered ring, or an aromatic heterocyclic 5-membered ring comprising one or more heteroatoms selected from the group consisting of O, N and S, wherein said aromatic carbocyclic ring, or said aromatic heterocyclic ring, is unsubstituted or substituted at one or more atoms of C, with a R 7 substituent; wherein R 7 substituent is independently selected from the group consisting of: H, F, Cl, Br, C1-C3 haloalkyl, -O-Ci-Ce alkyl, -O-CF3, cyano and Ci-Ce alkyl.
  4. 4. A compound according to claim 1 or 2, having formula (II), or a pharmaceutically acceptable salt or solvate thereof: wherein; R 1 and R 2 substituents are independently selected from the group consisting of: H, halogen and CF3; R 3 and R 4 substituents are independently selected from halogen or CF3.
  5. 5. A compound or pharmaceutical acceptable salt or solvate thereof according to any one of claims 1 to 4, wherein the compound is selected from:
  6. 6. A compound of formula (I) or formula (II), or pharmaceutical acceptable salt or solvate thereof, according to any one of claims 1 to 5, wherein the compound, the salt, or the solvate comprise stereoisomers, polymorphs, isotopes, or in the form of complexes with antibodies.
  7. 7. A pharmaceutical composition comprising at least one compound of formula (I) or formula (II), according to any one of claims 1 to 6, and at least one pharmaceutically acceptable excipient or carrier.
  8. 8. A pharmaceutical composition according to claim 7, further comprising at least one additional active compound or agent selected from the group consisting of a chemotherapeutic, a cell therapy, an immunotherapeutic or an antibiotic.
  9. 9. A compound of formula (I) or formula (II), according to any one of claims 1 to 6, or a pharmaceutical composition according to claim 7 or 8, for use as a medicament.
  10. 10. A compound of formula (I) or formula (II), according to any one of claims 1 to 6, or a pharmaceutical composition according to any of claims 7 or 8 for use in the prevention and/or treatment of cancer.
  11. 11. A compound or pharmaceutical composition for use according to claim 10, wherein the cancer is selected from the group consisting of: sarcoma, breast cancer, prostate cancer, head and neck cancer, brain tumour, colorectal cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, gastric cancer, renal cell carcinoma, melanoma, endometrial cancer, hepatocellular carcinoma, chronic myelogenous leukaemia, acute myelogenous leukaemia, cutaneous T-cell lymphoma, Hodgkin's disease, anaplastic large-cell lymphoma and Burkitt's lymphoma.
  12. 12. A compound or pharmaceutical composition for use according to claim 10 or 11 , wherein said compound is administered together, prior to, or subsequently to radiotherapy, immunotherapy or chemotherapy.
  13. 13. A compound of formula (II), according to claim 4, for use in the prevention and/or treatment of a bacterial infection.
  14. 14. A pharmaceutical composition comprising at least a compound of formula (II), according to any one of claims 4 to 6, and at least one pharmaceutically acceptable excipient or carrier, for use in the prevention and/or treatment of a bacterial infection.
  15. 15. A compound for use according to claim 13 or a pharmaceutical composition for use according to claim 14, wherein the bacterial infection is caused by Staphylococcus aureus.

Description

Substituted hexahydro-2H-pyrazino[1,2-a]pyrazin-1(6H)-one derivatives as activators of Human Caseinolytic Protease P (HsCIpP) FIELD OF THE INVENTION The present invention discloses compounds of formula (I), and pharmaceutical compositions containing formula (I), and their application as pharmaceuticals for the treatment of diseases. In particular, the invention discloses compounds of formula (I), their preparation and their use in treatments of a disease or condition responsive to activation of human caseinolytic protease P (HsCIpP), or a bacterial caseinolytic protease P, such as SaCIpP expressed in Staphylococcus aureus. BACKGROUND OF THE INVENTION Proteolysis is an essential mechanism for eukaryotic cells. It allows them to maintain protein homeostasis, or modify protein levels, in order to adapt to their changing environment. This proteolysis is carried out by a group of specialized enzymes called proteases, among which is the caseinolytic protease P (CIpP). This protease CIpP, along with chaperone proteins, form a serine protease complex. Seven monomer CIpP units initially co-assemble to form a donut shaped entity. Two of these entities stack one upon the other to form a barrel shape with a central pore. The chaperones bind to one, or both, ends of this tetradecameric structure, to complete the CIpP-CIpPATPase protease system. The role of the chaperones is to bind damaged or misfolded proteins and feed them into the tetradecameric barrel shaped CIpP complex, which degrades them. In human cells, human CIpP (HsCIpP) forms a complex with CIpXP chaperones, and the complex is located in the mitochondrial matrix. This complex participates in the maintenance of the mitochondrial proteome through the degradation of misfolded or dysfunctional proteins (1). This guarantees the proper functioning of the mitochondria, which regulates the bioenergetic activity of a cell (1). Cancer cells need to generate higher quantities of proteins to support their prolonged growth/proliferation phases. To remove damaged or badly constructed proteins, that would be detrimental to these cells, they require elevated quantities of proteases to remove them. HsCIpP expression levels have been reported to be considerably higher in several cancer cells compared to normal cells (2). Dysregulation of these well controlled proteolytic processes, by either inhibition or activation of their function, is detrimental to the well-being of these cells, and therefore maybe useful mechanism of action against cancer (3). A few naturally occurring, and synthetic, compounds have been identified as activators of HsCIpP (4-6). Activators of HsCIpP induce significant conformational changes in the tetrameric structure, which lead to the loss of binding of the chaperones, and the stabilization of the axial pore in an open and active position. These combined events allow the HsCIpP system to act independently of the chaperones, and to degrade a greater range of proteins. In human cells with elevated HsCIpP levels, these agonists promote ClpP-mediated degradation of respiratory chain complexes, activating the JNK/c-Jun pathway and inducing an endoplasmic reticulum (ER) stress response. This response consequently leads to the activation of apoptopic pathways and causes growth arrest. Known activators of HsCIpP, such as the acyldepsipeptides (ADEPs), TR-57, ZG-111 , ONC-201 and ONC-206 have been reported to reduce cell viability in several human derived cancer cells including pancreatic, AML, glioma, glioblastoma, colorectal, ovarian and breast cancers Furthermore, several of these compounds have been reported to reduce tumour growth in in vivo models of cancers. Currently, the small molecules ONC-201 and ONC-206, are being studied in human clinical trials against several type of cancers. Bacteria also possess significant levels of proteases including CIpP. Although bacteria do not possess mitochondria, bacteria versions of CIpP, such as Staphylococcus aureus (SaCIpP), Bacillus subtilis (BsCIpP), Escherichia coli (EsCIpP), A. baumannii (AbCIpP), K. pneumoniae (KpCIpP) and P. aeruginosa (PaCIpP) perform the same functions as HsCIpP and maintain protein homeostasis. Genetic studies have established that the cIpp gene, and genes encoding the AAA+ partners, are essential for virulence of several bacteria such as S. aureus, Listeria monocytogenes and S.pnuemoniae. Dysregulation of these well controlled proteolytic processes, by either inhibition or activation of their function, is detrimental to the well-being of these cells, and activators of bacterial versions of CIpP have been shown to have antibacterial properties. Recently the work reported by Wei, B., et al. (7) has demonstrated that small molecules that can selective activate SaCIpP, over HsCIpP, can possess promising antibacterial properties against wild-type, antibiotic resistant and clinical strains of S. aureus both in vitro and in vivo. CIpP is also present in mycobacterium, such as M. tuberculosis (