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EP-4739659-A1 - COMPOUNDS CONTAINING A DIALKYLARYL MOIETY AND THEIR USE

EP4739659A1EP 4739659 A1EP4739659 A1EP 4739659A1EP-4739659-A1

Abstract

The inventors have succeeded in developing urea, amide or sulfonamide compounds, in particular urea compounds, bearing two side groups, one of which carries a dialkylaryl moiety, in particular a dialkylphenyl or dialkylpyridinyl moiety. These compounds have the advantage of inhibiting IRE1 RNase activity and sensitizing cancer cells, in particular GB cells, to chemotherapy. The present invention relates to urea, amide or sulfonamide compounds, in particular urea compounds, bearing two side groups, one of which carries a dialkylaryl moiety, in particular a dialkylphenyl or dialkylpyridinyl moiety, including their pharmaceutically acceptable salts and solvates which are useful as sensitizers for chemotherapy of cancer cells, particularly in glioblastoma, and are useful as therapeutic compounds, particularly in the treatment of cancers that may be treated by alkylating agents, such as temozolomide.

Inventors

  • CHEVET, ERIC
  • PORÉE, François-Hugues
  • ERIKSSON, Leif Axel
  • SUERON, Sébastien
  • LANGLAIS, Timothy
  • GUILLORY, Xavier
  • PELIZZARI-RAYMUNDO, Diana

Assignees

  • Institut National de la Santé et de la Recherche Médicale
  • Université de Rennes
  • Centre National de la Recherche Scientifique

Dates

Publication Date
20260513
Application Date
20240705

Claims (15)

  1. 1. A compound of Formula I: I, a pharmaceutically acceptable salt or a solvate thereof, wherein Bis-C(O)- or-S(O 2 )-; Y is -NH- or -CH 2 -; R 1 and R 2 are independently H or Cl-C4-alkyl, with the proviso that R 1 and R 2 are not both H; Z is N or C-H;
  2. 2. The compound according to claim 1, wherein
  3. 3. The compound according to claim 1 or 2, wherein B is -C(O)-.
  4. 4. The compound according to any one of claims 1 to 3, wherein Y is -NH-.
  5. 5. The compound according to claim 1, having the formula II: II, a pharmaceutically acceptable salt or a solvate thereof, wherein Ar, B, Y, R 1 , R 2 and Z are as defined in claim 1.
  6. 6. The compound according to claim 1, having the formula III: III, a pharmaceutically acceptable salt or a solvate thereof, wherein L, B, Y, R 1 , R 2 and Z are as defined in claim 1.
  7. 7. The compound according to claim 1, selected from the group consisting of: methyl 4-(3-(3-(2,5-dimethyl-phenyl)ureido)but-l-yn-l-yl)benzoate; 1 -(4-(3 -acetylphenyl)but-3 -yn-2-yl)-3 -(2,5 -dimethylphenyl)urea; 1 -(2, 5 -dimethylphenyl)-3 -(4-( 1 -oxo- 1 ,2,3 ,4-tetrahy droi soquinolin-6-yl)but-3 -yn-2- yl)urea; l-(2,5-dimethylphenyl)-3-(4-(2-oxo-l,2,3,4-tetrahydroquinolin-6-yl)but-3-yn-2-yl)urea; l-(2,5-dimethylphenyl)-3-(4-(2-oxo-l,2,3,4-tetrahydroquinolin-5-yl)but-3-yn-2-yl)urea; 1 -(2, 5 -dimethylphenyl)-3 -(4-( 1 -oxo- 1 ,2-dihy droi soquinolin-6-yl)but-3 -yn-2-yl)urea; 1 -(4-( 1 H-indazol-5 -yl)but-3 -yn-2-yl)-3 -(2,5 -dimethylphenyl)urea; l-(2,5-dimethylphenyl)-3-(4-(3-methyl-lH-indazol-5-yl)but-3-yn-2-yl)urea; l-(4-(lH-pyrazolo[4,3-c]pyridin-4-yl)but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea; l-(4-(2H-indazol-5-yl)but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea; l-(4-(lH-pyrrolo[2,3-b]pyridin-4-yl)but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea; l-(4-(lH-indazol-6-yl)but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea; 1 -(2, 5 -dimethylphenyl)-3 -( 1 -(4-hy droxyphenyl)- 1 H-indazol-3 -yl)urea; l-(2,5-dimethylpyridin-3-yl)-3-(l-(4-hydroxyphenyl)-lH-indol-3-yl)urea; and l-(2,5-dimethylphenyl)-N-(4-(4-hydroxyphenyl)butan-2-yl)methanesulfonamide.
  8. 8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.
  9. 9. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, for use in a therapeutic treatment in humans or animals.
  10. 10. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, in combination with an anticancer agent, for use in treating cancer.
  11. 11. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, for use in increasing the sensitivity of cancer cells to an anticancer agent in a treatment of cancer.
  12. 12. The compound for use according to claim 10 or 11, wherein the anticancer agent is an alkylating agent.
  13. 13. The compound for use according to claim 12, wherein the alkylating agent is temozolomide.
  14. 14. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, for use in treating cancer.
  15. 15. The compound for use according to any one of claims 10 to 14, wherein the cancer is selected from glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer.

Description

COMPOUNDS CONTAINING A DIALKYLARYL MOIETY AND THEIR USE The present invention relates to urea, amide or sulfonamide compounds, in particular urea compounds, bearing two side groups, one of which carries a dialkylaryl moiety, in particular a dialkylphenyl or dialkylpyridinyl moiety, including their pharmaceutically acceptable salts and solvates which are useful as sensitizers for chemotherapy of cancer cells, particularly in glioblastoma, and are useful as therapeutic compounds, particularly in the treatment of cancers that may be treated by alkylating agents, such as temozolomide. BACKGROUND OF THE INVENTION Glioblastoma (GB) is the most common primary central nervous system (CNS) tumour, displaying high levels of aggressiveness, recurrence and heterogeneity; traits that contribute to a dismal prognosis of an average of 1.5 year survival post diagnosis. The standard of care comprises maximal safe resection of the tumour followed by a combination of irradiation and chemotherapy with the alkylating agent temozolomide; however, all patients succumb to the disease (R. Stupp et al., N. Engl. J. Med., 2005, 352, 987-996). GB cells, as with most solid tumours, survives in a hostile environment which includes hypoxia, nutrient shortage, necrosis and immune infiltration, as well as having to cope with a high metabolic turnover and protein synthesis demand (D. Doultsinos et al., SLAS Discov. Adv. Life Sci. R&D, 2017, 22, 787-800). As such, the Unfolded Protein Response (UPR) is inextricably linked to GB pathophysiology (J. Obacz et al., Sci. Signal., 2017, 10, eaal2323). It has been shown that in particular Inositol Requiring Enzyme 1 (IREl), a major Unfolded Protein Response (UPR) transducer, plays a decisive role in tumorigenesis and aggressiveness as through XBPls signalling it is promoting tumour infiltration by immune cells, angiogenesis and invasion. GB tumours displaying high levels of IRE1/XBP1 activity have a worse prognosis than those with low activity (S. Lhomond et al., EMBO Mol. Med., 2018, 10, 139-308). This pertains to the possibility that attenuating IREl activity could lead to sensitization of tumours to current therapies as GB cells would exhibit reduced capacity to cope with the hostile environment. Indeed, such studies have been performed in Triple Negative Breast Cancer (TNBC) showing that inhibition of IREl RNase activity with salicylaldehyde MKC8866 increased paclitaxel -dependent attenuation of TNBC development in mouse xenograft models (S.E. Logue et al., Nat. Commun., 2018, 9, 3267). Further to this, MKC8866 treatment greatly enhanced the efficacy of docetaxel in regressing MYC-overexpressing tumours in breast cancer PDX models (N. Zhao et al., J. Clin. Invest., 2018, 128, 1283-1299). This inhibitor is currently tested on other types of cancers. IRE1 activity inhibition can be mediated by compounds targeting either the ATP -binding kinase domain or the RNase domain. Direct RNase pharmacological inhibitors include 4p8c, STF-083010, toyocamycin and a series of MKC compounds, all relying on a hydroxy-aryl aldehyde (HAA) motif, whilst kinase pharmacological inhibitors that in turn inhibit the RNase include amongst others l-(4-(8-amino-3-isopropylimidazo[l,5-a]pyrazin-l- yl)naphthalen-l-yl)-3-(3-(trifhioro-methyl)phenyl)urea (CAS# 1414938-21-8), l-(4-(8- amino-3-(tert-butyl)imidazo[l,5-a]pyrazin-l-yl)naphthalen-l-yl)-3-(3- (trifluoromethyl)phenyl)urea (CAS# 1589527-65-0), l-(4-(8-amino-3-(l- methylcy clopropyl)imi dazo[ 1 , 5 -a]pyrazin- 1 -yl)naphthalen- 1 -y 1 )- 3 -(3 -fluorophenyl)urea (CAS# 1937235-76-1), 6-chloro-3-(6-fhioro-2-(phenylamino)-lH-benzo[d]imidazol-5-yl)- N-((l -methylpiperidin-4-yl)methyl)imidazo[ 1 ,2-b]pyridazin-8-amine (CAS# 2328097 -41- 0), 2-(3,4-dichlorobenzyl)-N-(4-methylbenzyl)-2-azaspiro[4.5]decane-8-carboxamide (CAS# 2121989-91-9), 2-chloro-N-(6-methyl-5-((3-(2-(piperidin-3-ylamino)pyrimidin-4- yl)pyridin-2-yl)oxy)naphthalen-l-yl)benzenesulfonamide (CAS# 1630086-20-2) (T. Langlais, Biochem. J., 2021, 478, 2953-2975; D. Pelizzari-Raymundo et al., Trends in Cancer, 2020, 6, 1018-1030) and, although unclear as to its effect on IRE1 activity, sunitinib (C. Hetz et al., Nat. Rev. Drug Discov., 2013, 12, 703-719). The description of an allosteric IRE1 RNase inhibitory mechanism by ATP competitive ligands was provided through the discovery of Kinase inhibiting RNase attenuators (KIRAs) showing that inhibition of the kinase site may have an inhibitory effect on the RNase activity (L. Wang et al., Nat. Chem. Biol., 2012, 8, 982-989; H.C. Feldman et al., CS Chem. Biol., 2016, 11, 219-2205). Other studies indicated that large (18-50 amino acid long) peptides derived from the cytosolic domain of IRE1 could affect its oligomerisation and subsequent RNase activity (M. Bouchecareilh et al., FASEB J., 2011, 25, 3115-3129). However, such peptides, even in their reduced 18 amino acid form, presented a plethora of issues such as bioavailability, proteasomal degradation, sheer size, cr