Compounds containing a dialkylaryl moiety and their use

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.

Description

[0001] COMPOUNDS CONTAINING A DIALKYLARYL MOIETY AND THEIR USE

[0002] 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.

[0003] BACKGROUND OF THE INVENTION

[0004] 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.

[0005] 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).

[0006] 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, crossing the blood brain barrier and stability when considering use in in vivo CNS settings. However, there is still a need for compounds having the ability to inhibit IRE1 RNase activity and to sensitize cancer cells, in particular GB cells, to anticancer drugs, in particular alkylating agents, and that may be of therapeutic value in the treatment of cancers that may be treated by alkylating agents. SUMMARY OF THE INVENTION

[0007] The inventors have now 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, more particularly a dimethylphenyl or dimethylpyridinyl moiety. These compounds have the advantage of inhibiting IRE1 RNase activity and sensitizing cancer cells, in particular GB cells, to chemotherapy.

[0008] The invention therefore relates to compounds of general Formula I, their pharmaceutically acceptable salts and solvates as well as methods of use of such compounds or compositions comprising such compounds as sensitizers for chemotherapy of malignant tumors. In a general aspect, the invention provides compounds of general Formula I:

[0009] I, a pharmaceutically acceptable salt or a solvate thereof, wherein

[0010]

[0011] B is -C(0)- or -S(02)-;

[0012] Y is -NH- or -CH2-; R1and R2are independently H or Cl-C4-alkyl, with the proviso that R1and R2are not both H;

[0013] Z is N or C-H; is — C(O)~ and Z is C-H.

[0014] In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound of Formula I as defined above, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant.

[0015] The invention futher relates to compounds of Formula I, or their pharmaceutically acceptable salts and solvates, for use in a therapeutic treatment in humans or animals.

[0016] The invention futher relates to compounds of Formula I, or their pharmaceutically acceptable salts and solvates, in combination with an anticancer agent, in particular an alkylating agent, for use in treating cancer, in particular glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer or pancreatic cancer.

[0017] The invention futher relates to compounds of Formula I, or their pharmaceutically acceptable salts and solvates, for use in increasing the sensitivity of cancer cells to an anticancer agent, in particular an alkylating agent, in a treatment of cancer, in particularly glioblastoma, triplenegative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer or pancreatic cancer. The invention also relates to compounds of Formula I, or their pharmaceutically acceptable salts and solvates, for use in treating cancer, in particular glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer or pancreatic cancer.

[0018] DETAILED DESCRIPTION OF THE INVENTION As detailed above, the invention relates to compounds of Formula I, as well as their pharmaceutically acceptable salts or solvates.

[0019] Particular compounds of Formula I or pharmaceutically acceptable salts or solvates thereof are those wherein one or more of Ar, L, B, Y, R1, R2and Z are defined as follows:

[0020] still more particularly Ar is selected from Meooc-

[0021]

[0022]

[0023] B is — C(0)~ or -S(O2)-; in particular B is -C(O)-;

[0024] Y is -NH- or -CH2-; in particular Y is -NH-;

[0025] R1and R2are independently H or Cl-C4-alkyl, with the proviso that R1and R2are not both H; in particular R1and R2are independently Cl-C4-alkyl; more particularly R1and R2are independently Cl-C3-alkyl; still more particularly R1and R2are independently C1-C2- alkyl; even more particularly R1and R2are methyl; Z is N or C-H; in particular Z is C-H; is — C(O)~ and Z is C-H. Cl-C4-alkyl include butyl, in particular n-butyl, isobutyl, sec-butyl or tert-butyl; propyl, in particular n-propyl or isopropyl; ethyl or methyl.

[0026] In the moiety meant that a N atom may be located at any free position of the 6-member aromatic ring.

[0027] In one embodiment, the compound of formula I may be in racemic or optically active form. In one embodiment, the compound of formula I may be in racemic form.

[0028] In one embodiment, the compound of formula I may be in optically active form.

[0029] In one embodiment, the compounds of Formula I are those wherein Ar is selected from

[0030] more particularly Ar is selected from particular example Ar is selected from

[0031] In one embodiment, the compounds of Formula I are those wherein

[0032] In one embodiment, the compounds of Formula I are those wherein Ar is In one embodiment, the compounds of Formula I are those wherein In one embodiment, the compounds of Formula I are those wherein Ar is

[0033] In one embodiment, the compounds of Formula I are those wherein

[0034] In one embodiment, the compounds of Formula I are those wherein

[0035] In one embodiment, the compounds of Formula I are those wherein

[0036] In one embodiment, the compounds of Formula I are those wherein Ar is the compounds of Formula I are those wherein Ar is In one embodiment, the compounds of Formula I are those wherein Ar is nt, the compounds of Formula I are those wherein Ar is In one embodiment, the compounds of Formula I are those wherein

[0037] In one embodiment, the compounds of Formula I are those wherein

[0038] In one embodiment, the compounds of Formula I are those wherein In one embodiment, the compounds of Formula I are those wherein Ar is In one embodiment, the compounds of Formula I are those wherein

[0039] In one embodiment, the compounds of Formula I are those wherein Ar is

[0040] In one embodiment, the compounds of Formula I are those wherein

[0041] In one embodiment, the compounds of Formula I are those wherein L is selected from

[0042]

[0043] In one embodiment, the compounds of Formula I are those wherein L is

[0044] In one embodiment, the compounds of Formula I are those wherein L is In one embodiment, the compounds of Formula I are those wherein L is

[0045] In one embodiment, the compounds of Formula I are those wherein

[0046] In one embodiment, the compounds of Formula I are those wherein

[0047] In one embodiment, the compounds of Formula I are those wherein In one embodiment, the compounds of Formula I are those wherein

[0048] In one embodiment, the compounds of Formula I are those wherein

[0049] In one embodiment, the compounds of Formula I are those wherein

[0050] In one embodiment, the compounds of Formula I are those wherein B is -C(O)-. In one embodiment, the compounds of Formula I are those wherein B is -S(O2)-.

[0051] In one embodiment, the compounds of Formula I are those wherein Y is -NH-.

[0052] In one embodiment, the compounds of Formula I are those wherein Y is -CH2-.

[0053] In one embodiment, the compounds of Formula I are those wherein Z is C-H.

[0054] In one embodiment, the compounds of Formula I are those wherein Z is N.

[0055] In one embodiment, the compounds of Formula I are those of Formula II: or pharmaceutically acceptable salts or solvates thereof, wherein Ar, B, Y, R1, R2and Z are as defined above with respect to Formula I and any of its embodiments.

[0056] Particular compounds of Formula II or pharmaceutically acceptable salts or solvates thereof are those wherein one or more of Ar, B, Y, R1, R2and Z are defined as follows:

[0057]

[0058] B is -C(0)-;

[0059] Y is -NH-; R1and R2are independently H or Cl-C4-alkyl, with the proviso that R1and R2are not both H; in particular R1and R2are independently Cl-C4-alkyl; more particularly R1and R2are independently Cl-C3-alkyl; still more particularly R1and R2are independently C1-C2- alkyl; even more particularly R1and R2are methyl; Z is N or C-H; in particular Z is C-H.

[0060] In one embodiment, the compounds of Formula I are those of Formula Ila:

[0061] Ila, or pharmaceutically acceptable salts or solvates thereof, wherein

[0062] Ar, Y, R1, R2and Z are as defined above with respect to Formula I and any of its embodiments.

[0063] Particular compounds of Formula Ila or pharmaceutically acceptable salts or solvates thereof are those wherein one or more of Ar, Y, R1, R2and Z are defined as follows:

[0064]

[0065]

[0066] Y is -NH-; R1and R2are independently H or Cl-C4-alkyl, with the proviso that R1and R2are not both H; in particular R1and R2are independently Cl-C4-alkyl; more particularly R1and R2are independently Cl-C3-alkyl; still more particularly R1and R2are independently C1-C2- alkyl; even more particularly R1and R2are methyl;

[0067] Z is N or C-H; in particular Z is C-H. In one embodiment, the compounds of Formula I are those of Formula lib : or pharmaceutically acceptable salts or solvates thereof, wherein

[0068] Ar, R1, R2and Z are as defined above with respect to Formula I and any of its embodiments.

[0069] Particular compounds of Formula lib or pharmaceutically acceptable salts or solvates thereof are those wherein one or more of Ar, R1, R2and Z are defined as follows:

[0070] R1and R2are independently H or Cl-C4-alkyl, with the proviso that R1and R2are not both H; in particular R1and R2are independently Cl-C4-alkyl; more particularly R1and R2are independently Cl-C3-alkyl; still more particularly R1and R2are independently C1-C2- alkyl; even more particularly R1and R2are methyl;

[0071] Z is N or C-H; in particular Z is C-H. In one embodiment, the compounds of Formula I are those of Formula lie: or pharmaceutically acceptable salts or solvates thereof, wherein

[0072] Ar and Z are as defined above with respect to Formula I and any of its embodiments.

[0073] Particular compounds of Formula lie or pharmaceutically acceptable salts or solvates thereof are those wherein one or more of Ar and Z are defined as follows:

[0074]

[0075] Z is N or C-H; in particular Z is C-H.

[0076] In one embodiment, the compounds of Formula I are those of Formula lid: lid, or pharmaceutically acceptable salts or solvates thereof, wherein

[0077] Ar is as defined above with respect to Formula I and any of its embodiments.

[0078] Particular compounds of Formula lid or pharmaceutically acceptable salts or solvates thereof are those wherein Ar is defined as follows:

[0079]

[0080] In one embodiment, the compounds of Formula I are those of Formula III: or pharmaceutically acceptable salts or solvates thereof, wherein

[0081] L, B, Y, R1, R2and Z are as defined above with respect to Formula I and any of its embodiments.

[0082] Particular compounds of Formula III or pharmaceutically acceptable salts or solvates thereof are those wherein one or more of L, B, Y, R1, R2and Z are defined as follows: B is — C(O)~ or -S(O2)-; in particular B is -C(O)-;

[0083] Y is -NH- or -CH2-; in particular Y is -NH-;

[0084] R1and R2are independently H or Cl-C4-alkyl, with the proviso that R1and R2are not both H; in particular R1and R2are independently Cl-C4-alkyl; more particularly R1and R2are independently Cl-C3-alkyl; still more particularly R1and R2are independently C1-C2- alkyl; even more particularly R1and R2are methyl; Z is N or C-H; in particular Z is C-H; is C-H.

[0085] In one embodiment, the compounds of Formula I are those of Formula Illa:

[0086] Illa, or pharmaceutically acceptable salts or solvates thereof, wherein

[0087] L, Y, R1, R2and Z are as defined above with respect to Formula I and any of its embodiments.

[0088] Particular compounds of Formula Illa or pharmaceutically acceptable salts or solvates thereof are those wherein one or more of L, Y, R1, R2and Z are defined as follows:

[0089] Y is -NH- or -CH2-; in particular Y is -NH-;

[0090] R1and R2are independently H or Cl-C4-alkyl, with the proviso that R1and R2are not both H; in particular R1and R2are independently Cl-C4-alkyl; more particularly R1and R2are independently Cl-C3-alkyl; still more particularly R1and R2are independently C1-C2- alkyl; even more particularly R1and R2are methyl; Z is N or C-H; in particular Z is C-H; with the proviso that L is not when Z is C-H.

[0091] In one embodiment, the compounds of Formula I are those of Formula Illb : mb, or pharmaceutically acceptable salts or solvates thereof, wherein L, Y, R1, R2and Z are as defined above with respect to Formula I and any of its embodiments.

[0092] Particular compounds of Formula IIIc or pharmaceutically acceptable salts or solvates thereof are those wherein one or more of L, Y, R1, R2and Z are defined as follows: Y is -NH- or -CH2-; in particular Y is -CH2-;

[0093] R1and R2are independently H or Cl-C4-alkyl, with the proviso that R1and R2are not both H; in particular R1and R2are independently Cl-C4-alkyl; more particularly R1and R2are independently Cl-C3-alkyl; still more particularly R1and R2are independently C1-C2- alkyl; even more particularly R1and R2are methyl;

[0094] Z is N or C-H; in particular Z is C-H;

[0095] In one embodiment, the compounds of Formula I are those of Formula IIIc:

[0096] IIIc, or pharmaceutically acceptable salts or solvates thereof, wherein

[0097] L, R1, R2and Z are as defined above with respect to Formula I and any of its embodiments.

[0098] Particular compounds of Formula IIIc or pharmaceutically acceptable salts or solvates thereof are those wherein one or more of L, R1, R2and Z are defined as follows:

[0099]

[0100] R1and R2are independently H or Cl-C4-alkyl, with the proviso that R1and R2are not both H; in particular R1and R2are independently Cl-C4-alkyl; more particularly R1and R2are independently Cl-C3-alkyl; still more particularly R1and R2are independently C1-C2- alkyl; even more particularly R1and R2are methyl;

[0101] Z is N or C-H; in particular Z is C-H; with the proviso that L is not when Z is C-H. In one embodiment, the compounds of Formula I are those of Formula Hid:

[0102]

[0103] Illd, or pharmaceutically acceptable salts or solvates thereof, wherein L, R1and R2are as defined above with respect to Formula I and any of its embodiments.

[0104] Particular compounds of Formula Illd or pharmaceutically acceptable salts or solvates thereof are those wherein one or more of L, R1and R2are defined as follows: R1and R2are independently H or Cl-C4-alkyl, with the proviso that R1and R2are not both H; in particular R1and R2are independently Cl-C4-alkyl; more particularly R1and R2are independently Cl-C3-alkyl; still more particularly R1and R2are independently C1-C2- alkyl; even more particularly R1and R2are methyl.

[0105] In one embodiment, the compounds of Formula I are those of Formula Ille:

[0106]

[0107] Ille, or pharmaceutically acceptable salts or solvates thereof, wherein L, R1and R2are as defined above with respect to Formula I and any of its embodiments.

[0108] Particular compounds of Formula Ille or pharmaceutically acceptable salts or solvates thereof are those wherein one or more of L, R1and R2are defined as follows: R1and R2are independently H or Cl-C4-alkyl, with the proviso that R1and R2are not both H; in particular R1and R2are independently Cl-C4-alkyl; more particularly R1and R2are independently Cl-C3-alkyl; still more particularly R1and R2are independently C1-C2- alkyl; even more particularly R1and R2are methyl. Particularly preferred compounds of the invention are those listed in Table 1 hereafter:

[0109] Table 1

[0110] The compounds of the invention can be prepared by different ways with reactions known by the person skilled in the art. Typical routes of synthesis are described thereafter

[0111] The compounds of the invention (i.e. the compounds of Formula I and its subformulae as described above) are indeed capable of inhibiting IRE RNase activity and sensitizing cancer cells to anticancer drugs. They further have the advantage of sensitizing cancer cells, in particular GGM cells to anticancer drugs, in particular alkylating agents. The invention thus also provides the use of the compounds of the invention, or pharmaceutically acceptable salts or solvates thereof, as sensitizers for chemotherapy of cancer cells.

[0112] Accordingly, the invention relates to the use of compounds of the invention, or pharmaceutically acceptable salts or solvates thereof, for the treatment of cancer, particularly as sensitizers for chemotherapy of cancer cells.

[0113] APPLICATIONS

[0114] Unexpectedly, the inventors have discovered that the compounds of the invention may be used as inhibitors of IRE1 RNase activity and have the potentential of increasing the sensitivity of cancer cells to an anticancer agent in a treatment of cancer.

[0115] In fact, and without wanting to be tied to any theory whatsoever, the inventors think the specific structure of the compounds of the invention allow them to interact with the ATP kinase binding pocket of IRE1.

[0116] The compounds of the invention, i.e. the compounds of Formula I and any of its embodiments, or any of its subformulae as defined above, are able to inhibit IRE1 RNase activity and to increase the sensitivity of cancer cells to an anticancer agent in a treatment of cancer, in particular glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer.

[0117] The compounds of the invention as defined above, can thus be used for treating cancer, particularly as sensitizers for chemotherapy of cancer cells, aiming at improving the chemotherapy effect of the cancer treatment, preventing tolerance and decreasing toxicity and adverse effects.

[0118] The invention thus relates to a compound of Formula I, or any of its embodiments, or any of its subformulae as defined above, or a pharmaceutically acceptable salt or solvate thereof, in combination with an anticancer agent, for use in treating cancer.

[0119] The invention also relates to the compounds of the invention as described above, 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.

[0120] The invention thus relates to a compound of Formula I, or any of its embodiments or subformulae as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in treating cancer.

[0121] Treatment of cancer, in particular chemotherapy, is a type of treatment that uses one or more anti cancer agents. Anticancer agents, or cytotoxic agents, within the meaning of the present invention include, but are not limited to, alkylating agents, anti -microtubule agents, anti metabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti angiogenic agents. Preferably, the anticancer agent is an alkylating agent. Preferred alkylating agent is temozolamide.

[0122] The compounds of the invention are therefore useful in the treatment of cancers, and particularly cancers that may be treated by anticancer agents selected from alkylating agents, anti-microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly cancers that may be treated by alkylating agents.

[0123] Cancers that may be treated by anticancer agents selected from alkylating agents, antimicrotubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, within the meaning of the present invention include, but are not limited to, glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer. A preferred cancer that may be treated by alkylating agents is glioblastoma.

[0124] Thus, in one embodiment, there is provided a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, in combination with an anticancer agent, for use in treating cancer.

[0125] The invention thus also relates to a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, in combination with an anticancer agent, in particular an anticancer agent selected from alkylating agents, anti -microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly an alkylating agent, even more particularity temozolamide, for use in treating cancer, preferably cancers that may be treated by anticancer agents selected from alkylating agents, anti-microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly a cancer selected from glioblastoma (GB), triplenegative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, even more particularly cancers that may be treated by alkylating agents, still more preferably glioblastoma.

[0126] In other terms, the invention also relates to a method of treating cancer, in particular cancers that may be treated by anticancer agents selected from alkylating agents, anti -microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly a cancer selected from glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, even more particularly cancers that may be treated by alkylating agents, still more particularly glioblastoma, comprising the administration of a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, in combination with an anticancer agent, in particular an anticancer agent selected from alkylating agents, anti -microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly an alkylating agent, even more particularly temozolamide, to a patient in need of such treatment. Preferably the patient is a warm-blooded animal, more preferably a human. The cancers that may be treated by an alkylating agent are preferably those defined above.

[0127] The invention further provides the use of a compound of the present invention, or a pharmaceutically acceptable salt or solvates thereof, in combination with an anticancer agent, in particular an anticancer agent selected from alkylating agents, anti -microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti angiogenic agents, more particularly an alkylating agent, even more particularly temozolamide, for the manufacture of a medicament for use in treating cancer, in particular cancers that may be treated by anticancer agents selected from alkylating agents, anti -microtubule agents, anti metabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti angiogenic agents, more particularly a cancer selected from glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, even more particularly cancers that may be treated by an alkylating agent, still more particularly glioblastoma. Preferably the patient is a warm-blooded animal, more preferably a human. The cancers that may be treated by an alkylating agent are preferably those defined above.

[0128] By “in combination”, it is meant a combined preparation wherein the active ingredients are physically together in the same preparation or physically separated for use in a combined therapy by simultaneous administration or sequential administration to the patient.

[0129] Hence, according to the present invention, a compound of the invention or a pharmaceutically acceptable salt or solvate thereof and the anticancer agent are administered to the patient in the same preparation or in a separate form, either simultaneously or sequentially, for the treatment of cancer.

[0130] According to a further feature of the present invention, there is provided a compound of the present invention, 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.

[0131] The invention thus relates to a compound of the present invention, i.e. a compound of Formula I or any of its embodiments, or any of its subformulae as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in increasing the sensitivity of cancer cells to an anticancer agent, in particular an anticancer agent selected from alkylating agents, anti -microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti angiogenic agents, more particularly an alkylating agent, still more particularly temozolamide, in a treatment of cancer, in particular cancers that may be treated by anticancer agents selected from alkylating agents, anti -microtubule agents, anti metabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti angiogenic agents, more particularly a cancer selected from glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, even more particularly cancer that may be treated by an alkylating agent, still more particularly glioblastoma.

[0132] In other terms, the invention also relates to a method for increasing the sensitivity of cancer cells to an anticancer agent, in particular an anticancer agent selected from alkylating agents, anti-microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly an alkylating agent, even more particularly temozolomide, in a treatment of cancer, in particular cancers that may be treated by anti cancer agents selected from alkylating agents, anti -microtubule agents, anti metabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly a cancer selected from glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, even more particularly cancers that may be treated by alkylating agents, still more particularly glioblastoma, comprising the administration of a therapeutically effective amount of a compound of the present invention, i.e. a compound of Formula I or any of its embodiments, or any of its subformulae as defined above, or a pharmaceutically acceptable salt or solvate thereof, in combination with an anticancer agent, in particular an anticancer agent selected from alkylating agents, anti -microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly an alkylating agent, even more particularly temozolamide, to a patient in need thereof. Preferably the patient is a warm-blooded animal, more preferably a human.

[0133] The invention further provides the use of a compound of the present invention, i.e. a compound of Formula I or any of its embodiments, or any of its subformulae as defined above, or a pharmaceutically acceptable salt or solvates thereof, for the manufacture of a medicament for use in sensitizing cancer cells to an anticancer agent, in particular an anticancer agent selected from alkylating agents, anti -microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti angiogenic agents, more particularly an alkylating agent, even more particularly temozolomide, in a treatment of cancer, in particular cancers that may be treated by anticancer agents selected from alkylating agents, anti-microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti angiogenic agents, more particularly a cancer selected from glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, even more particularly cancers that may be treated by alkylating agents, still more particularly glioblastoma.

[0134] According to a further feature of the present invention, there is provided the use of a compound of the present invention, i.e. a compound of Formula I and any of its embodiments, or any of its subformulae as defined above, or a pharmaceutically acceptable salt or solvate thereof, for inhibiting IRE1 RNase activity, in a patient in need of such treatment, comprising administering to said patient an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof. In other terms, the invention also provides a method for inhibiting IRE1 RNase activity, in a patient in need of such treatment, which comprises the step of administering to said patient an effective amount of a compound of the present invention, i.e. a compound of Formula I and any of its embodiments, or any of its subformulae as defined above, or a pharmaceutically acceptable salt or solvate thereof. Preferably, the patient is a warm blooded animal, and even more preferably a human.

[0135] The invention also relates to a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, for use in treating cancer, preferably cancers that may be treated by anticancer agents selected from alkylating agents, anti -microtubule agents, anti metabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti angiogenic agents, more particularly a cancer selected from glioblastoma (GB), triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, even more particularly cancers that may be treated by alkylating agents, still more preferably glioblastoma. In other terms, the invention also relates to a method of treating cancer, in particular cancers that may be treated by anticancer agents selected from alkylating agents, anti -microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti angiogenic agents, more particularly a cancer selected from glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, even more particularly cancers that may be treated by alkylating agents, still more particularly glioblastoma, comprising the administration of a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, to a patient in need of such treatment. Preferably the patient is a warm-blooded animal, more preferably a human. The cancers that may be treated by an alkylating agent are preferably those defined above.

[0136] The invention further provides the use of a compound of the present invention, or a pharmaceutically acceptable salt or solvates thereof, for the manufacture of a medicament for use in treating cancer, in particular cancers that may be treated by anticancer agents selected from alkylating agents, anti -microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly a cancer selected from glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, even more particularly cancers that may be treated by an alkylating agent, still more particularly glioblastoma. Preferably the patient is a warm-blooded animal, more preferably a human. The cancers that may be treated by an alkylating agent are preferably those defined above.

[0137] According to the present invention, the compound of the invention or the compound for use according to the invention may be administered as a pharmaceutical formulation in a therapeutically effective amount by any of the accepted modes of administration, preferably by intravenous or oral route.

[0138] Therapeutically effective amount ranges are typically from 0.1 to 50 000 pg / kg of body weight daily, preferably from 1 000 to 40 000 pg / kg of body weight daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound, the route and the form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able in reliance upon personal knowledge, to ascertain a therapeutically effective amount of the anti cancer agent of the present invention for a given cancer.

[0139] According to one embodiment, the compounds of the invention, their pharmaceutical acceptable salts or solvates may be administered as part of a combination therapy. Thus, are included within the scope of the present invention embodiments comprising coadministration of, and compositions and medicaments which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt or solvate thereof as active ingredient, additional therapeutic agents and / or active ingredients. Such multiple drug regimens, often referred to as combination therapy, may be used in the treatment of cancer, particularly those defined above.

[0140] Thus, the methods of treatment and pharmaceutical compositions of the present invention may employ the compounds of the invention or their pharmaceutical acceptable salts or solvates thereof in the form of monotherapy, but said methods and compositions may also be used in the form of multiple therapy in which one or more compounds of the invention or their pharmaceutically acceptable salts or solvates are co-administered in combination with one or more other therapeutic agents. Such additional therapeutic agents include, but are not limited to, alkylating agents, and preferably temozolomide.

[0141] In one embodiment, the methods of treatment and pharmaceutical compositions of the present invention may employ the compounds of the present invention, or their pharmaceutical acceptable salts or solvates thereof, in combination with radiation therapy. According to this embodiment, the compounds of the invention, their pharmaceutical acceptable salts or solvates may be administered in combination with radiation therapy. Thus, there is provided a compound of Formula I and any of its embodiments, or any of its subformulae as defined above, or a hydrophenyl compound of Table 2b, for use in the treatment of cancers as defined above in combination with radiation therapy. Such radiation therapies include, but are not limited to, external beam radiation therapy, brachytherapy and systemic radioisotope therapy.

[0142] The invention also provides a pharmaceutical composition comprising a compound of the present invention, i.e. a compound of Formula I or any of its embodiments, or any of its subformulae as defined above, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant.

[0143] As indicated above, the invention also covers pharmaceutical compositions which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt or solvate thereof as active ingredient, additional therapeutic agents and / or active ingredients, in particular an anticancer agent.

[0144] The invention also provides a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, for use in a therapeutic treatment in humans or animals.

[0145] Another object of this invention is a medicament comprising at least one compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, as active ingredient.

[0146] Generally, for pharmaceutical use, the compounds of the invention may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant, and optionally one or more further pharmaceutically active compounds.

[0147] By means of non-limiting examples, such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), cerebral administration, for administration by inhalation, by a skin patch, by an implant, by a suppository, etc. Such suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is made to the latest edition of Remington’s Pharmaceutical Sciences.

[0148] For example, the compound of the invention or a pharmaceutical composition comprising a compound of the invention can be administered orally in the form of tablets, coated tablets, pills, capsules, soft gelatin capsules, oral powders, granules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications. The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, a disintegrant such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, a binder such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia, a lubricant such as magnesium stearate, stearic acid, glyceryl behenate. Solid compositions of a similar type may also be employed as fillers in hard gelatin capsules. Preferred excipients in this regard include lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. Hard gelatin capsules may contain granules of the compound of the invention.

[0149] Soft gelatin capsules may be prepared with capsules containing the compound of the invention, vegetable oil, waxes, fat, or other suitable vehicle for soft gelatin capsules. As an example, the acceptable vehicle can be an oleaginous vehicle, such as a long chain triglyceride vegetable oil (e.g. corn oil).

[0150] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water may contain the active ingredient in a mixture with dispersing agents, wetting agents, and suspending agents and one or more preservatives. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

[0151] Liquid dosage forms for oral administration may include pharmaceutically acceptable, solutions, emulsions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water or an oleaginous vehicle. Liquid dosage form may be presented as a dry product for constitution with water or other suitable vehicle before use. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, complexing agents such as 2-hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta-cylodextrin, and sweetening, flavouring, perfuming agents, colouring matter or dyes with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof. These compositions may be preserved by the addition of an antioxidant such as butylated hydroxyanisol or alpha-tocopherol. Finely divided powder of the compound of the invention may be prepared for example by micronisation or by processes known in the art. The compound of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types.

[0152] If the compound of the present invention is administered parenterally, then examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously administering the agent; and / or by using infusion techniques.

[0153] The compound of the invention can be administered via the parenteral route with a readily available or a depot-type formulation.

[0154] The pharmaceutical compositions for the parenteral administration of a readily available formulation may be in the form of a sterile injectable aqueous or oleagenous solution or suspension in a non-toxic parenterally-acceptable diluent or solvent and may contain formulatory agents such as suspending, stabilising dispersing, wetting and / or complexing agents such as cyclodextrin e.g. 2-hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta- cylodextrin.

[0155] The depot-type formulation for the parenteral administration may be prepared by conventional techniques with pharmaceutically acceptable excipient including without being limited to, biocompatible and biodegradable polymers (e.g. poly(P-caprolactone), polyethylene oxide), poly(gly colic acid), poly [(lactic acid)-co-(gly colic acid)...)], poly(lactic acid)...), non-biodegradable polymers (e.g. ethylene vinylacetate copolymer, polyurethane, polyester(amide), polyvinyl chloride...) aqueous and non-aqueous vehicles (e.g. water, sesame oil, cottonseed oil, soybean oil, castor oil, almond oil, oily esters, ethyl alcohol or fractionated vegetable oils, propylene glycol, DMSO, THF, 2-pyrrolidone, N- methylpyrrolidinone, N-vinylpyrrolidinone... ).

[0156] Alternatively, the active ingredient may be in dry form such as a powder, crystalline or freeze-dried solid for constitution with a suitable vehicle. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0157] As indicated, the compound of the present invention can be administered intranasally or by inhalation and is conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebuliser with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, di chlorotetrafluoroethane, (for example from Ineos Fluor), carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray or nebuliser may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch. For compositions suitable and / or adapted for inhaled administration, it is preferred that the compound or salt of the invention is in a particle-size-reduced form, and more preferably the size-reduced form is obtained or obtainable by micronisation. The preferable particle size of the size-reduced (e.g. micronised) compound or salt or solvate is defined by a D50 value of about 0.5 to about 50 microns (for example as measured using laser diffraction).

[0158] Alternatively, the compound of the present invention can be administered in the form of a suppository or pessary, or it may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compound of the present invention may also be dermally or transdermally administered, for example, by the use of a skin patch. They may also be administered by the pulmonary or rectal routes. It may also be administered by the ocular route. For ophthalmic use, the compound can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, it may be formulated in an ointment such as petrolatum.

[0159] For topical application to the skin, the agent of the present invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, it can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0160] DEFINITIONS

[0161] The definitions and explanations below are for the terms as used throughout the entire application, including both the specification and the claims.

[0162] Unless otherwise stated, any reference to compounds of the invention herein, means the compounds as such as well as their pharmaceutically acceptable salts and solvates.

[0163] When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless indicated otherwise.

[0164] The term “unsubstituted” as used herein means that a radical, a group or a residue carries no substituents. The term “substituted” means that a radical, a group or a residue carries one or more substituents.

[0165] The term “halo” or “halogen” refers to the atoms of the group 17 of the periodic table (halogens) and includes in particular fluorine, chlorine, bromine and iodine atom. Preferred halo groups in the context of the invention are fluoro and iodo, fluoro being particularly preferred.

[0166] The term “alkyl” by itself or as part of another substituent refers to a hydrocarbyl group of Formula CnEhn+i wherein n is a number greater than or equal to 1. Alkyl groups may thus comprise 1 or more carbon atoms and generally, according to this invention comprise from 1 to 12, more preferably from 1 to 8 carbon atoms, and still more preferably from 1 to 6 carbon atoms. Alkyl groups within the meaning of the invention may be linear or branched. Examples of alkyl groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopenyl, isopentyl, sec-pentyl, tert-pentyl, n-hexyl, neohexyl, isohexyl, sec-hexyl and tert-hexyl. Particular examples of alkyl groups in the context of the invention include methyl, ethyl, isopropyl and tert-butyl. The term “haloalkyl” alone or in combination, refers to an alkyl group having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above. Non -limiting examples of such haloalkyl groups include chloromethyl, 1- bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1 -trifluoroethyl and the like.

[0167] The term “cycloalkyl” as used herein is a monovalent, saturated, or unsaturated monocyclic or bicyclic hydrocarbyl group. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 10, more preferably from 3 to 8 carbon atoms, and still more preferably from 3 to 6 carbon atoms. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0168] The term “heteroatom” as used herein refers to any atom that is not carbon or hydrogen. Non-limiting examples of such heteroatoms include nitrogen, oxygen, sulfur, and phosphorus. Preferred heteroatoms according to the invention are nitrogen, oxygen and sulfur.

[0169] The terms “heterocyclyl”, “heterocycloalkyl” or “heterocyclo” as used herein by itself or as part of another group refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and / or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. Examples of heterocyclyl groups include but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, piperazinyl, morpholinyl.

[0170] The term “aryl” as used herein refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (e.g. phenyl) or multiple aromatic rings fused together (e.g. naphthyl), typically containing 5 to 12 atoms; preferably 6 to 10, wherein at least one ring is aromatic. Examples of aryl groups include but are not limited to phenyl, biphenyl, 1 -naphthyl (or naphthal ene-l-yl), 2-naphthyl (or naphthalene-2-yl), anthracenyl, indanyl, indenyl, 1, 2,3,4- tetrahydronaphthyl .

[0171] The term “heteroaryl” as used herein by itself or as part of another group refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 2 rings which are fused together, each ring typically containing 5 to 6 atoms; at least one of which is aromatic, in which one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and / or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quatemized. Examples of heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, furanyl, benzofuranyl, pyrrolyl, indolyl, thiophenyl, benzothiophenyl, imidazolyl, benzimidazolyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, thiazolyl, and benzothiazolyl, triazolyl, oxadi azolyl, thiadi azolyl, di oxazolyl, di thiazolyl and tetrazolyl.

[0172] The compounds of the invention containing a basic functional group may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of the invention containing one or more basic functional groups include in particular the acid addition salts thereof. Suitable acid addition salts are formed from acids which form nontoxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bi sulphate / sulphate, borate, camsylate, cinnamate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

[0173] Pharmaceutically acceptable salts of compounds of Formula I and subformulae, or a hydrophenyl compounds of Table 2b, may for example be prepared as follows:

[0174] (i) reacting the compound of Formula I or any of its subformulae, or a hydrophenyl compounds of Table 2b, with the desired acid; or (ii) converting one salt of the compound of Formula I or any of its subformulae, or a hydrophenyl compounds of Table 2b, to another by reaction with an appropriate acid or by means of a suitable ion exchange column.

[0175] All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.

[0176] The term “solvate” is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term “hydrate” is employed when said solvent is water.

[0177] The compounds of the invention include compounds of the invention as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically-labeled compounds of the invention.

[0178] In addition, although generally, with respect to the salts of the compounds of the invention, pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also includes non-pharmaceutically acceptable salts, which may for example be used in the isolation and / or purification of the compounds of the invention. For example, salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of the invention.

[0179] The term “patient” refers to a warm-blooded animal, more preferably a human, who / which is awaiting or receiving medical care or is or will be the object of a medical procedure.

[0180] The term “human” refers to subjects of both genders and at any stage of development (i.e. neonate, infant, juvenile, adolescent, adult). In one embodiment, the human is an adolescent or adult, preferably an adult.

[0181] The terms “treat”, “treating” and “treatment”, as used herein, are meant to include alleviating or abrogating a condition or disease and / or its attendant symptoms. The term “therapeutically effective amount” (or more simply an “effective amount”) as used herein means the amount of active agent or active ingredient which is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered.

[0182] The term “administration”, or a variant thereof (e.g., “administering”), means providing the active agent or active ingredient, alone or as part of a pharmaceutically acceptable composition, to the patient in whom / which the condition, symptom, or disease is to be treated.

[0183] By “pharmaceutically acceptable” is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the patient thereof.

[0184] The term “excipient” as used herein means a substance formulated alongside the active agent or active ingredient in a pharmaceutical composition or medicament. Acceptable excipients for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington’s Pharmaceutical Sciences, 21stEdition 2011. The choice of excipient can be selected with regard to the intended route of administration and standard pharmaceutical practice. The excipient must be acceptable in the sense of being not deleterious to the recipient thereof. The at least one pharmaceutically acceptable excipient may be for example, a binder, a diluent, a carrier, a lubricant, a disintegrator, a wetting agent, a dispersing agent, a suspending agent, and the like.

[0185] The term “pharmaceutical vehicle” as used herein means a carrier or inert medium used as solvent or diluent in which the pharmaceutically active agent is formulated and / or administered. Non-limiting examples of pharmaceutical vehicles include creams, gels, lotions, solutions, and liposomes.

[0186] The term “cancer” as used herein refers to the physiological condition in subjects that is characterized by unregulated or dysregulated cell growth with the potential to invade or spread to other parts of the body. The term “cancer” includes solid tumors and blood born tumors, whether malignant or benign.

[0187] Examples of cancer include, but are not limited to: Acinar adenocarcinoma, acinar carcinoma, acral-lentiginous melanoma, actinic keratosis, adenocarcinoma, adenocystic carcinoma, adenosquamous carcinoma, adnexal carcinoma, adrenal rest tumor, adrenocortical carcinoma, aldosterone secreting carcinoma, alveolar soft part sarcoma, amelanotic melanoma, ameloblastic thyroid carcinoma, angiosarcoma, apocrine carcinoma, Askin’s tumor, astrocytoma, basal cell carcinoma, basaloid carcinoma, basosquamous cell carcinoma, biliary cancer, bone cancer, bone marrow cancer, botryoid sarcoma, brain cancer, breast cancer, bronchioalveolar carcinoma, bronchogenic adenocarcinoma, bronchogenic carcinoma, carcinoma ex pleomorphic adenoma, cervical cancer, chloroma, cholangiocellular carcinoma, chondrosarcoma, choriocarcinoma, choroid plexus carcinoma, clear cell adenocarcinoma, colon cancer, colorectal cancer, comedocarcinoma, corti sol -producing carcinoma, cylindrical cell carcinoma, dedifferentiated liposarcoma, ductal adenocarcinoma of the prostate, ductal carcinoma, ductal carcinoma in situ, duodenal cancer, eccrine carcinoma, embryonal carcinoma, endometrial carcinoma, endometrial stromal carcinoma, epithelioid sarcoma, esophageal cancer, Ewing’s sarcoma, exophytic carcinoma, fibroblastic sarcoma, fibrocarcinoma, fibrolamellar carcinoma, fibrosarcoma, follicular thyroid carcinoma, gallbladder cancer, gastric adenocarcinoma, giant cell carcinoma, giant cell sarcoma, giant cell tumor of bone, glioma, glioblastoma or glioblastoma multiforme, granulose cell carcinoma, head & neck cancer, hemangioma, hemangiosarcoma, hepatoblastoma, hepatocellular carcinoma, Hurthle cell carcinoma, ileal cancer, infiltrating lobular carcinoma, inflammatory carcinoma of the breast, intraductal carcinoma, intraepidermal carcinoma, jejuna cancer, Kaposi’s sarcoma, Krukenberg’s tumor, Kulchitsky cell carcinoma, Kupffer cell sarcoma, large cell carcinoma, larynx cancer, lentigo maligna melanoma, liposarcoma, liver cancer, lobular carcinoma, lobular carcinoma in situ, lung cancer, lymphoepithelioma, lymphoepithelioma, lymphosarcoma, malignant melanoma, medullary carcinoma, medullary thyroid carcinoma, medulloblastoma, meningeal carcinoma, Merkel cell carcinoma, micropapillary carcinoma, mixed cell sarcoma, mucinous carcinoma, mucoepidermoid carcinoma, mucosal melanoma, myxoid liposarcoma, myxosarcoma, nasopharyngeal carcinoma, nephroblastoma, neuroblastoma, nodular melanoma, non-clear cell renal cancer, non-small cell lung cancer, oat cell carcinoma, ocular melanoma, oral cancer, osteoid carcinoma, osteosarcoma, ovarian cancer, Paget’ s carcinoma, pancreatic cancer, pancreatoblastoma, papillary adenocarcinoma, papillary carcinoma, papillary thyroid carcinoma, pelvic cancer, periampullary carcinoma, phyllodes tumor, pituitary cancer, pleomorphic liposarcoma, pleuropulmonary blastoma, primary intraosseous carcinoma, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, round cell liposarcoma, scar cancer, schistosomal bladder cancer, Schneiderian carcinoma, sebaceous carcinoma, signet-ring cell carcinoma, skin cancer, small cell lung cancer, small cell osteosarcoma, soft tissue sarcoma, splindle cell carcinoma, spindle cell sarcoma, squamous cell carcinoma, stomach cancer, superficial spreading melanoma, synovial sarcoma, telangiectatic sarcoma, terminal duct carcinoma, testicular cancer, thyroid cancer, transitional cell carcinoma, tubular carcinoma, tumorigenic melanoma, undifferentiated carcinoma, urachal adenocarcinoma, urinary bladder cancer, uterine cancer, uterine corpus carcinoma, uveal melanoma, aginal cancer, cerrucous carcinoma, villous carcinoma, well-differentiated liposarcoma, Wilm’s tubor or yolk sac tumor. Preferred cancers according to the invention are glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, more preferred cancer is glioblastoma.

[0188] The terms “anticancer agent”, “anticancer drug”, “chemotherapeutic agent” or “cytotoxic agent”, as used herein, refer to a chemical agent used to treat cancer, administered in regimens of one or more cycles, alone or combined with one or more agents over a period of days to weeks. Such agents are toxic to cells with high proliferative rates, such as cancer cells.

[0189] Examples of anticancer agents include, but are not limited to: alkylating agents, such as for example cyclophosphamide, mechlorethamine, chlorambucil, melphalan, dacarbazine, dacarbazine, nitrosoureas or temozolomide; anti metabolites, including antifolates, such as for example methotrexate, pemetrexed, pralatrexate or trimetrexate; pyrimidine analogues, such as for example azacitidine, capecitabine, cytarabine, decitabine, floxurinine, fluorouracil, gemcitabine or trifluridine; and purine analogues such as for example azathioprine, cladribine, fludarabine, mercaptopurine or tioguanine (formerly thioguanine); anti -microtubule agents, including taxanes, such as for example paclitaxel, docetaxel, abraxane or taxotere; and vinca alkaloids, such as for example vinblastine, vincristine, vindesine or vinorelbine; cytotoxic antibiotics, including anthracyclines, such as for example daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone or valrubicin; and peptide antibiotics, such as for example bleomycin or actinomycin;

[0190] - topoisomerase inhibitors, including inhibitors of topoisomerase I, such as for example irinotecan or topotecan; and inhibitors of topoisomerase II, such as for example etoposide, teniposide or tafluposide; epothilones; histone deacetylase inhibitors, such as for example vorinostat, romidepsin, panobinostat or quisinostat; kinase inhibitors, such as for example afatinib, avitinib, bortezomib, carfilzomib, dabrafenib, erlotinib, gefitinib, imatinib, osimertinib, vemurafenib or vismodegib; platinum-based agents, such as for example carboplatin, cisplatin or oxaliplatin; proteasome inhibitors, such as for example bortezomib, carfilzomib or ixazomib; retinoids, such as tretinoin, alitretinoin or bexarotene.

[0191] Preferred anticancer agents according to the invention are alkylating agents. Preferred anti cancer agent according to the invention is temozolomide.

[0192] The present invention will be better understood with reference to the following examples and figures. These examples are intended to be representative of specific embodiments of the invention, and are not intended as limiting the scope of the invention.

[0193] EXAMPLES

[0194] ABBREVIATIONS anh.: anhydrous;

[0195] DCM: dichloromethane;

[0196] DiPE: diisopropylethylether;

[0197] DIPEA: diisopropylethylamine;

[0198] DMF : N,N-dimethylformamide; DMSO: dimethyl suf oxide;

[0199] DPPA: diphenylphosphoryl azide;

[0200] DTT: dithiothreitol;

[0201] EGTA: ethylene glycol-bis(P-aminoethyl ether)-A, N, N', N' -tetraacetic acid eq. or equiv. : equivalent;

[0202] ESI: electrospray ionization;

[0203] HPLC: high-performance liquid chromatography;

[0204] HRMS: high-resolution mass spectrometry;

[0205] MS: mass spectrometry;

[0206] NMR: nuclear magnetic resonance;

[0207] PE: petroleum ether; ppm: parts per million; r.t. or rt: room temperature;

[0208] SCC: Silica-gel column chromatography;

[0209] TFA: trifluoroacetic acid;

[0210] THF : tetrahydrofurane;

[0211] TLC: thin-layer chromatography.

[0212] SYNTHESIS

[0213] General information - Commercially available reagents and solvents were purchased from Enamine, Fluorochem, Sigma-Aldrich, Alfa Aesar, Acros and were used as received. All reactions under inert atmosphere were performed under an argon atmosphere. Petroleum ether (PE) refers to petroleum ether with 40-60°C. Thin-layer chromatography (TLC) was performed on TLC silica gel 60 F254 aluminum plates. Compounds were visualized by exposure to UV light (254 nm) or by dipping the plates into potassium permanganate or phosphomolybdic acid solution followed by heating. Silica-gel column chromatography (SCC) was carried out using silica gel (particle size 40-63 pm) with isocratic or step gradient elution as indicated. Automated flash column chromatography was carried out on an Interchim PuriFlash 450 using FlashPure Ecoflex silica cartridges (irregular particle size 50 pm). NMR spectra were acquired on 300 / 400 / 500 MHz spectrometers and were referenced to the residual solvent. All chemical shifts are reported in parts per million (ppm). Abbreviations used in the description of resonances are s (singlet), d (doublet), t (triplet), q (quartet), sept (septet), a (apparent), bs (broad singlet), and m (multiplet). Coupling constants (J) are quoted to the nearest 0.1 Hz. HPLC-MS analyses were performed on a Shimadzu Prominence system couple to an Advion ESI mass spectrometer using a Thermoscientific Hypersil Gold aQ column chromatography (5p, 250 x 4.6 mm) [method: binary gradient, solvent A = H2O + 0.1% TFA, solvent B = MeCN + 0.1% TFA, flow = 1 mL / min, 20 to 100% A / B],

[0214] Typical procedure 1 (TP1) - Reduction of triple bond into simple bond

[0215] To a round-bottom flask equipped with a magnetic stirrer was added the alkyne substrate (1.0 eq.) and the Pd catalyst (1 / 5 of alkyne substrate’s mass). Then, MeOH or EtOH (10 mL / mmol) was added. The flask was purged three times with argon and vacuumed. Then, the flask was put under H2 atmosphere (1 bar). The mixture was stirred at room temperature overnight, the flask was purged with argon and the solvent was removed under reduced pressure. The crude product was filtered through a Celite pad and the catalyst was rinsed three times using the reaction’ s solvent. The filtrate was concentrated under reduced pressure to obtain the final product.

[0216] Typical procedure 1 bis (TP1 bis) - Reduction of triple bond into simple bond at P > 1 bar.

[0217] To a dry autoclave equipped with a magnetic stirring bar was added alkyne substrate (1.0 eq.) and the Pd catalyst (1 / 5 of alkyne substrate’s mass) The autoclave was purged with argon and MeOH or EtOH (10 mL / mmol) was added. Then, the autoclave was vacuumed and put under EE atmosphere (3 to 5 bars). The mixture was stirred at room temperature. After 16h to 60h of reaction, the flask was purged with argon and the solvent was removed under reduced pressure. The crude product was filtered through a Celite pad and the catalyst was rinsed three times using the reaction’s solvent. The filtrate was concentrated under reduced pressure to obtain the final product.

[0218] Typical procedure 2 (TP2) - Chan-Lam coupling.

[0219] In a round-bottom flask equipped with a magnetic stirring bar were successively added the V-heterocycle (1.0 eq.), (4-methoxyphenyl)boronic acid (2 eq.), Cu(OAc)2.H2O (1.5 eq.) and EtsN (2.0 eq.) in DCM (15 mL / mmol). The mixture was stirred at room temperature as much as necessary. After completion (monitored by TLC), the mixture was filtered through a pad of Celite. The filtrate was washed with a 14% aqueous solution of ammonia (2 times) and the organic layer was dried using MgSCh. Then, the solution was filtered and concentrated under vacuo to afford the desired product.

[0220] Typical procedure 2 Bis (TP2 Bis)- Sonogashira’s Reaction.

[0221] To a dry flask, under argon, equipped with a magnetic stirring bar were successively added Alkyne derivative (1 equiv.), Cui (5 mol%), PdfPPhs^CE (3 mol%), degassed DMF or THF and degassed triethylamine (2: 1 / v:v, 6 mL / 0.5 mmol). Halogenated derivative (1.2 equiv.) was added and the resulting mixture was heated at 80°C (DMF) or 50°C (THF) (Monitored by TLC). After consumption of starting materials, H2O was added at room temperature (Volume = DMF + triethylamine) and EtOAc (Volume = DMF + tri ethylamine + H2O). Most of the time, a precipitate appears at the interface of aqueous and organic phase. Both organic phase and precipitate were taken and the resulting mixture was evaporated under reduced pressure. The resulting solid was purified using trituration and filtration or preparative TLC or semi -preparative HPLC.

[0222] Typical procedure 3 (TP3) - Saponification of ester group with a 4M aqueous solution of NaOH. To a solution of ester compound (1.0 eq.) in EtOH (2.5 mL / 1 mmol) in a round-bottom flask equipped with a magnetic stirring bar was added NaOH (4M) in H2O (2.5 mL / 1 mmol). The reaction was stirred until completion (monitored by TLC) at 60°C. The reaction mixture was then diluted with H2O and washed with EtOAc. The aqueous layer was acidified with a solution of HC1 (IM). The aqueous layer is then extracted with EtOAc (2 times). The combined organic layers were dried over MgSO4 and concentrated to afford desired product without purification.

[0223] Typical procedure 4 (TP4) - Acylazide formation, Curtins rearrangement and urea formation without isolation of intermediates.

[0224] The carboxylic acid (1.0 eq.) was added in a round-bottom dry flask equipped with a magnetic stirring bar under argon. Toluene was then added (6 mL / mmol) followed by EtsN (1.05 eq.). The mixture was stirred under argon at room temperature during 10 min and DPPA (1.05 eq.) was added. The mixture was stirred at room temperature overnight. Then, 2,5-dimethylaniline (1.1 eq.) was added and the mixture was stirred under argon at reflux during few hours. After completion, the mixture is concentrated under vacuo to obtain the crude product. The product obtained was then purified via silica column chromatography to afford the desired product.

[0225] Typical procedure 5 (TP5) - Deprotection of methoxy group using BBr3.

[0226] To a dry flask, under argon, equipped with a magnetic stirring bar was dissolved aromatic compound (1.0 eq.) in DCM (2 mL / 0.1 mmol). The solution was cooled at -78°C and BBn (IM in DCM, 4.0 eq.) was added dropwise. The mixture was stirred with slow return to room temperature until complete consumption of the starting material (monitored by TLC). The mixture was quenched by adding ice (around 2 g / 0.1 mmol), followed by extraction with DCM and EtOAc. The solvent was removed under reduced pressure and crude mixture was purified via preparative TLC to afford the final product with sufficient purity for characterization and biological assays.

[0227] Preparation of synthetic intermediates

[0228] Synthesis of l-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3. STEP 1 Synthesis of but-3-yn-2-yl methanesulfonate Al

[0229] Triethylamine (21.40 mmol, 1.5 equiv., 2.98 mL) was added in a solution of but-3-yn-2-ol (14.27 mmol, 1.0 equiv., 1.129 mL, 1.0 g) in DCM (10 mL). The resulting solution was cooled to 0°C and mesyl chloride (17.12 mmol, 1.2 equiv., 1.33 mL, 1.96 g) was added dropwise. The mixture was allowed to reach ambient temperature and stirred for 4h. DCM (10 mL) and H2O (10 mL) were added and the organic layer was separated, washed with brine (10 mL), dried and concentrated to afford crude but-3-yn-2-yl methanesulfonate Al, 2.17 g, yield: 68%. The product was used in next step without purification.

[0230] 'll NMR (300MHz, Chloroform-^, 20°C), 8 (ppm): 5 29 (qd, J= 6.7, 2.2 Hz, 1H), 3 12 (s, 3H), 2.70 (d, J= 2.2 Hz, 1H), 1.66 (d, J= 6.7 Hz, 3H).

[0231] 13C NMR (75MHz, Chloroform-^, 20°C), 8 (ppm): 80 3, 76 4, 67 6, 39 3, 22 6

[0232] STEP 2: Synthesis of but-3-yn-2-amine hydrochloride A2

[0233] But-3-yn-2-yl methanesulfonate Al (14.62 mmol, 1.0 equiv., 2.16 g) was stirred for 18h with aqueous NH3 (5.3 ml) at 25 / 30°C. The resulting mixture was diluted with DCM (10 mL) and H2O (10 mL), the organic layer was separated and dried over MgSCh. The organic layer was set up to reflux for 2h30, until the vapour above the double condenser no longer gave a positive alkali test. After the addition of 4N HC1 in Dioxane, the solution was stirred 24h, filtered and washed with cold Et2O to give but-3-yn-2-amine hydrochloride A2, 445 mg, yield: 29%, as an impure white solid.

[0234] ’H-NMR (300MHz, DMSO-J6, 20°C), 8 (ppm): 8.63 (s, 3H), 4.24 (s, 1H), 3.66 (d, 1H, J = 2.1 Hz), 1.42 (d, 3H, J = 6.9 Hz).

[0235] STEP 3 : Synthesis of l-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 Impure but-3-yn-2-amine hydrochloride A2 (0.947 mmol, 1.0 equiv., 100 mg) was added in dry DCM (5 mL). Dry triethylamine (0.974 mmol, 1.0 equiv., 0.133 µL) was added and the resulting solution was filtered under argon using syringe and filter adapter to remove non- soluble powder. According to TP5, 2-isocyanato-1,4-dimethylbenzene (0.947 mmol, 1.0 equiv., 139 mg) in dry DCM (2 mL) was added. The resulting precipitate was filtered to afford 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3, 105 mg, yield: 51%, as a pale white solid. Mp: 200°C.1H-NMR (300MHz, DMSO-d6, 20°C), δ (ppm): 7.67 (d, J = 1.8 Hz, 1H), 7.55 (s, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.69 (dd, J = 7.6, 1.8 Hz, 1H), 4.55-4.39 (dtd, J = 7.9, 6.9, 2.3 Hz, 1H), 3.22 (d, J = 2.3 Hz, 1H), 2.21 (s, 3H), 2.11 (s, 3H), 1.33 (d, J = 6.9 Hz, 3H).13C NMR (75MHz, DMSO-d6, 20°C), δ (ppm): 154.2, 137.7, 135.0, 129.9, 123.4, 122.7, 120.8, 85.8, 72.3, 36.5, 22.5, 21.0, 17.5. EXAMPLE 1: methyl 4-(3-(3-(2,5-dimethylphenyl)ureido)but-1-yn-1-yl)benzoate 1 According to TP2 Bis with 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 (0.231 mmol, 1.0 equiv., 50 mg) and methyl 4-iodobenzoate (0.277 mmol, 1.2 equiv., 73 mg), THF (2 mL) as solvent and the resulting solution was heated at 50°C overnight. The organic phase was evaporated and triturated with DiPE, filtered and dried to afford methyl 4-(3-(3-(2,5- dimethylphenyl)ureido)but-1-yn-1-yl)benzoate 1, 72 mg, yield: 74%. A fraction (10 - 20 mg) of the crude mixture was purified by semi-preparative HPLC to afford sufficient quantity of pure compound, as a yellowish solid, for characterization and biological assays (0.54 mg).1H NMR (300MHz, DMSO-d6, 20°C), δ (ppm): 7.99-7.89 (m, 2H, CH 18), 7.68 (d, J = 1.8 Hz, 1H, CH 8), 7.58 (s, 1H, NH 9), 7.59-7.51 (m, 2H, CH 17), 7.07 (d, J = 7.9 Hz, 1H, NH 11), 6.99 (d, J = 7.6 Hz, 1H, CH 4), 6.70 (dd, J = 7.6, 1.8 Hz, 1H, CH 3), 4.78 (dq, J = 7.6, 6.9 Hz, 1H, CH 12), 3.85 (s, 3H, CH321), 2.22 (s, 3H, CH31), 2.13 (s, 3H, CH36), 1.45 (d, J = 6.9 Hz, 3H, CH313).13C NMR (75MHz, DMSO-d6, 20°C), δ (ppm): 165.6 (C 20), 154.3 (C 10), 137.6 (C 7), 135.0 (C 2), 131.7 (CH 17), 129.9 (CH 4), 129.4 (CH 18), 129.2 (C 16), 127.1 (C 19), 123.6 (C 5), 122.8 (CH 3), 121.0 (CH 8), 95.0 (CC 14), 80.22 (CC 15), 52.3 (CH321), 37.3 (CH 12), 22.3 (CH313), 20.9 (CH31), 17.4 (CH36). HRMS (ESI+): m / z calcd for C21H22N2O3Na+(M+Na)+373.15226; found 373.15190. HPLC purity @ ^=254 nm: 97% (General conditions, Rt = 20.60 min). MS (ESI+): m / z (%) 349.1 (100) [M+H+]. EXAMPLE 2: 1-(4-(3-acetylphenyl)but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea 2 According to TP2 Bis with 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 (0.231 mmol, 1.0 equiv., 50 mg) and 1-(3-iodophenyl)ethanone (0.277 mmol, 1.2 equiv., 68 mg), THF (2 mL) as solvent and the resulting solution was heated at 50°C overnight. The organic phase was evaporated and triturated with DiPE, filtered and dried to afford 1-(4-(3- acetylphenyl)but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea 2, 63 mg, yield: 68%. A fraction (10 - 20 mg) of the crude mixture was purified by semi-preparative HPLC to afford sufficient quantity of pure compound, as a whitish solid, for characterization and biological assays (3.62 mg).1H NMR (300MHz, Acetone-d6, 20°C), δ (ppm): 7.99 (t, J = 0.7 Hz, 1H, CH 21), 7.95 (dt, J = 7.7, 1.4 Hz, 1H, CH 19), 7.83-7.77 (d, J = 2.1 Hz, 1H, CH 8), 7.64 (dt, J = 7.7, 1.4 Hz, 1H, CH 17), 7.51 (td, J = 7.7, 0.7 Hz, 1H, CH 18), 7.22 (s, 1H, NH 9), 6.99 (d, J = 7.6 Hz, 1H, CH 4), 6.73 (dd, J = 7.6, 2.1 Hz, 1H, CH 3), 6.49 (d, J = 8.1 Hz, 1H, NH 11), 4.95 (dq, J = 8.1, 6.9 Hz, 1H, CH 12), 2.60 (s, 3H, CH323), 2.26 (s, 3H, CH31), 2.18 (s, 3H, CH36), 1.50 (d, J = 6.9 Hz, 3H, CH313).13C NMR (75MHz, Acetone-d6, 20°C), δ (ppm): 197.4 (C 22), 155.2 (C 10), 138.7 (C 7), 138.4 (C 20), 136.4 (C 2), 136.4 (CH 17), 131.0 (CH 21), 130.8 (CH 4), 129.8 (CH 18), 128.7 (CH 19), 125.0 (C 16), 124.4 (C 5), 124.1 (CH 3), 122.6 (CH 8), 92.9 (CC 14), 81.2 (CC 15), 38.6 (CH 12), 26.8 (CH323), 23.1 (CH31), 21.3 (CH36), 17.6 (CH313). HRMS (ESI+): m / z calcd for C21H22N2O2Na+(M+Na)+357.15735; found 357.15790. HPLC purity @ ^=254 nm: 99% (General conditions, Rt= 19.13 min). MS (ESI+): m / z (%) 335.3 (100) [M+H+]. EXAMPLE 3: 1-(2,5-dimethylphenyl)-3-(4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6- yl)but-3-yn-2-yl)urea 3 According to TP2 Bis with 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 (0.231 mmol, 1.0 equiv., 50 mg) and 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (0.277 mmol, 1.2 equiv., 52 mg), DMF (2 mL) as solvent and the resulting solution was heated at 90°C for 2 hours. The organic phase was evaporated and triturated with acetone twice, filtered and dried to afford 1-(2,5-dimethylphenyl)-3-(4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)but-3-yn-2- yl)urea 3, to afford sufficient quantity of pure compound for characterization and biological assays (1.21 mg). HRMS (ESI+): m / z calcd for C22H23N3O2Na+(M+Na)+384.16825; found 384.16860. HPLC purity @ ^=254 nm: 94% (General conditions, Rt = 19.22 min). MS (ESI+): m / z (%) 362.4 (100) [M+H+]. EXAMPLE 4: 1-(2,5-dimethylphenyl)-3-(4-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)but- 3-yn-2-yl)urea 4 According to TP2 Bis with 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 (0.231 mmol, 1.0 equiv., 50 mg) and 6-bromo-3,4-dihydro-1H-quinolin-2-one (0.277 mmol, 1.2 equiv., 52 mg), DMF (2 mL) as solvent and the resulting solution was heated at 90°C for 2 hours. The organic phase was evaporated and triturated with acetone twice, filtered and dried to afford 1-(2,5-dimethylphenyl)-3-(4-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)but-3-yn-2-yl)urea 4 in sufficient quantity of pure compound for characterization and biological assays (0.78 mg).1H NMR (500MHz, DMSO-d6, 20°C), δ (ppm): 10.24 (s, 1H, NH 22), 7.89 (s, 1H, NH 9), 7.68 (d, J = 2.0 Hz, 1H, CH 8), 7.36 (d, J = 8.0 Hz, 1H, NH 11), 7.24 (s, 1H, CH 21), 7.20 (d, J = 8.3 Hz, 1H, CH 17), 6.98 (d, J = 7.6 Hz, 1H, CH 4), 6.84 (d, J = 8.1 Hz, 1H, CH 18), 6.69 (dd, J = 7.6, 2.0 Hz, 1H, CH 3), 4.72 (p, J = 7.8 Hz, 1H, CH 12), 2.86 (t, J = 7.6 Hz, 2H, CH225), 2.43 (t, J = 7.5 Hz, 2H, CH224), 2.22 (s, 3H, CH31), 2.15 (s, 3H, CH36), 1.41 (d, J = 6.9 Hz, 3H, CH313).13C NMR (126MHz, DMSO-d6, 20°C), δ (ppm): 170.6 (CO 23), 154.9 (CO 10), 138.9 (C 19), 138.3 (C 7), 135.3 (C 2), 131.3 (CH 21), 130.8 (CH 17), 130.3 (CH 4), 124.4 (C 20), 124.1 (C 5), 123.0 (CH 3), 121.3 (CH 8), 115.9 (C 16), 115.6 (CH 18), 90.8 (CC 14), 81.5 (CC 15), 37.6 (CH 12), 30.6 (CH224), 24.9 (CH225), 23.2 (CH313), 21.4 (CH31), 18.1 (CH36). HRMS (ESI+): m / z calcd for C22H23N3O2Na+(M+Na)+384.16825; found 384.16860. HPLC purity @ ^=254 nm: 95% (General conditions, Rt= 19.42 min). MS (ESI+): m / z (%) 362.4 (100) [M+H+]. EXAMPLE 5: 1-(2,5-dimethylphenyl)-3-(4-(2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)but- 3-yn-2-yl)urea 5 According to TP2 Bis with 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 (0.231 mmol, 1.0 equiv., 50 mg) and 5-Bromo-3,4-dihydroquinolin-2(1H)-one (0.277 mmol, 1.2 equiv., 52 mg), DMF (2 mL) as solvent and the resulting solution was heated at 90°C for 2 hours. The organic phase was evaporated and triturated with acetone twice, filtered and dried to afford 1-(2,5-dimethylphenyl)-3-(4-(2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)but-3-yn-2- yl)urea 5 in sufficient quantity of pure compound for characterization and biological assays (0.96 mg).1H NMR (300MHz, DMSO-d6, 20°C), δ (ppm): 10.17 (s, 1H, NH 22), 7.93 (s, 1H, NH 9), 7.66 (d, J = 1.9 Hz, 1H, CH 8), 7.42 (d, J = 7.9 Hz, 1H, NH 11), 7.13 (t, J = 7.8 Hz, 1H, CH 18), 6.99 (dd, 1H, J = 7.8, 1.3 Hz, CH 17), 6.97 (d, J = 7.6 Hz, 1H, CH 4), 6.87 (dd, J = 7.8, 1.3 Hz, 1H, CH 19), 6.69 (dd, J = 7.6, 1.9 Hz, 1H, CH 3), 4.76 (p, J = 7.0 Hz, 1H, CH 12), 3.00 (t, J = 7.6 Hz, 2H, CH224), 2.45 (t, J = 7.6 Hz, 2H, CH225), 2.21 (s, 3H, CH31), 2.15 (s, 3H, CH36), 1.44 (d, J = 6.9 Hz, 3H, CH313).13C NMR (75MHz, DMSO-d6, 20°C), δ (ppm): 170.0 (CO 23), 154.5 (CO 10), 138.6 (C 16), 137.8 (C 7), 134.8 (C 2), 129.9 (CH 4), 127.1 (CH 18), 125.2 (C 20), 125.1 (CH 17), 123.8 (C 5), 122.6 (CH 3), 121.2 (C 21), 121.0 (CH 8), 115.3 (CH 19), 96.0 (CC 14), 78.9 (CC 15), 37.3 (CH 12), 29.9 (CH225), 23.2 (CH224), 22.6 (CH313), 21.0 (CH31), 17.7 (CH36). HRMS (ESI+): m / z calcd for C22H23N3O2Na+(M+Na)+384.16825; found 384.16850. HPLC purity @ ^=254 nm: 94% (General conditions, Rt = 19.47 min). MS (ESI+): m / z (%) 362.4 (100) [M+H+]. EXAMPLE 6: 1-(2,5-dimethylphenyl)-3-(4-(1-oxo-1,2-dihydroisoquinolin-6-yl)but-3- yn-2-yl) urea 6 According to TP2 Bis with 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 (0.231 mmol, 1.0 equiv., 50 mg) and 6-Bromoisoquinolin-1(2H)-one (0.277 mmol, 1.2 equiv., 52 mg), DMF (2 mL) as solvent and the resulting solution was heated at 90°C for 2 hours. The organic phase was evaporated and triturated with acetone twice, filtered and dried to afford 1-(2,5-dimethylphenyl)-3-(4-(1-oxo-1,2-dihydroisoquinolin-6-yl)but-3-yn-2-yl)urea 6 in sufficient quantity of pure compound for characterization and biological assays (1.36 mg).1H NMR (300MHz, DMSO-d6, 20°C), δ (ppm): 11.36 (s, 1H, NH 23), 8.13 (d, J = 8.3 Hz, 1H, CH 18), 8.00 (s, 1H, NH 9), 7.74 (d, J = 1.6 Hz, 1H, CH 21), 7.68 (d, J = 1.8 Hz, 1H, CH 8), 7.56 (d, J = 7.8 Hz, 1H, NH 11), 7.45 (dd, J = 8.3, 1.7 Hz, 1H, CH 17), 7.19 (d, J = 7.2 Hz, 1H, CH 24), 6.98 (d, J = 7.6 Hz, 1H, CH 4), 6.68 (dd, J = 7.6, 1.8 Hz, 1H, CH 3), 6.53 (d, J = 7.2 Hz, 1H, CH 25), 4.79 (p, J = 7.0 Hz, 1H, CH 12), 2.21 (s, 3H, CH31), 2.16 (s, 3H, CH36), 1.46 (d, J = 6.9 Hz, 3H, CH313).13C NMR (75MHz, DMSO-d6, 20°C), δ (ppm): 161.36 (CO 22), 154.51 (CO 10), 137.98 (C 7), 137.86 (C 19), 134.85 (C 2), 129.91 (C 16), 129.87 (CH 4), 129.08 (CH 21), 128.71 (CH 17), 127.08 (CH 18), 126.14 (C 20), 125.36 (CH 24), 123.76 (C 5), 122.59 (CH 3), 120.94 (CH 8), 104.10 (CH 25), 94.36 (CC 14), 80.31 (CC 15), 37.19 (CH 12), 22.33 (CH313), 20.98 (CH31), 17.76 (CH36). HRMS (ESI+): m / z calcd for C22H23N3O2Na+(M+Na)+382.1526; found 382.1527. HPLC purity @ ^=254 nm: 95% (General conditions, Rt= 19.34 min). MS (ESI+): m / z (%) 360.7 (100) [M+H+]. EXAMPLE 7: 1-(4-(1H-indazol-5-yl)but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea 7 According to TP2 Bis with 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 (0.231 mmol, 1.0 equiv., 50 mg) and 5-bromo-1H-indazole (0.277 mmol, 1.2 equiv., 45 mg), DMF (2 mL) as solvent and the resulting solution was heated at 90°C for 2 hours. The organic phase was evaporated and triturated with acetone twice, filtered and dried to afford 1-(4-(1H-indazol- 5-yl)but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea 7. HRMS (ESI+): m / z calcd for C20H20N4ONa+(M+Na)+: 355.15293 ; found 355.1527. HPLC purity @ ^=254 nm: 80% (General conditions, Rt = 19.73 min). MS (ESI+): m / z (%) 333.2 (100) [M+H+]. EXAMPLE 8: 1-(2,5-dimethylphenyl)-3-(4-(3-methyl-1H-indazol-5-yl)but-3-yn-2- yl)urea 8 According to TP2 Bis with 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 (0.231 mmol, 1.0 equiv., 50 mg) and 5-bromo-3-methyl-1H-indazole (0.277 mmol, 1.2 equiv., 49 mg), DMF (2 mL) as solvent and the resulting solution was heated at 90°C for 2 hours. The organic phase was evaporated and triturated with acetone twice, filtered and dried to afford 1-(2,5-dimethylphenyl)-3-(4-(3-methyl-1H-indazol-5-yl)but-3-yn-2-yl)urea 8. HRMS (ESI+): m / z calcd for C21H22N4ONa+(M+Na)+: 369.16858 ; found 369.1686. HPLC purity @ ^=254 nm: 83% (General conditions, Rt= 20.41 min). MS (ESI+): m / z (%) 347.4 (100) [M+H+]. EXAMPLE 9: 1-(4-(1H-pyrazolo[4,3-c]pyridin-4-yl)but-3-yn-2-yl)-3-(2,5- dimethylphenyl)urea 9 According to TP2 Bis with 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 (0.231 mmol, 1.0 equiv., 50 mg) and 4-bromo-1H-pyrazolo[4,3-c]pyridine (0.277 mmol, 1.2 equiv., 46 mg), DMF (2 mL) as solvent and the resulting solution was heated at 90°C for 2 hours. The organic phase was evaporated and triturated with acetone twice, filtered and dried to afford 1-(4-(1H-pyrazolo[4,3-c]pyridin-4-yl)but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea 9. HRMS (ESI+): m / z calcd for C19H19N5ONa+(M+Na)+356.14818; found 356.14850. HPLC purity @ ^=254 nm: 70% (General conditions, Rt= 14.51 min). MS (ESI+): m / z (%) 334.5 (100) [M+H+]. EXAMPLE 10: 1-(4-(2H-indazol-5-yl)but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea 10 According to TP2 Bis with 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 (0.231 mmol, 1.0 equiv., 50 mg) and 5-bromo-2H-indazole (0.277 mmol, 1.2 equiv., 46 mg), DMF (2 mL) as solvent and the resulting solution was heated at 90°C for 2 hours. The organic phase was evaporated and triturated with acetone twice, filtered and dried to afford 1-(4-(2H-indazol- 5-yl)but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea 10. HRMS (ESI+): m / z calcd for C20H21N4O+(M+H)+: 333.17099 ; found 333.1709. MS (ESI+): m / z (%) 333.4 (100) [M+H+]. EXAMPLE 11: 1-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)but-3-yn-2-yl)-3-(2,5- dimethylphenyl)urea 11

[0236] According to TP2 Bis with 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 (0.231 mmol, 1.0 equiv., 50 mg) and 4-iodo-7-azaindole (0.277 mmol, 1.2 equiv., 56 mg), DMF (2 mL) as solvent and the resulting solution was heated at 90°C for 2 hours. The organic phase was evaporated and triturated with acetone twice, filtered and dried to afford 1-(4-(1H- pyrrolo[2,3-b]pyridin-4-yl)but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea 11. HRMS (ESI+): m / z calcd for C20H20N4ONa+(M+Na)+355.15293; found 355.15340. HPLC purity @ ^=254 nm: 79% (General conditions, Rt= 18.94 min). MS (ESI+): m / z (%) 333.5 (100) [M+H+]. EXAMPLE 12: 1-(4-(1H-indazol-6-yl)but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea 12 According to TP2 Bis with 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea A3 (0.231 mmol, 1.0 equiv., 50 mg) and 6-bromo-1H-indazole (0.277 mmol, 1.2 equiv., 45 mg), DMF (2 mL) as solvent and the resulting solution was heated at 90°C for 2 hours. The organic phase was evaporated and triturated with acetone twice, filtered and dried to afford 1-(4-(1H-indazol- 6-yl)but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea 12. HRMS (ESI+): m / z calcd for C20H21N4OH+(M+H)+: 333.17099; found 333.1713. HPLC purity @ ^=254 nm: 75% (General conditions, Rt= 20.11 min). MS (ESI+): m / z (%) 333.3 (100) [M+H+]. EXAMPLE 13: 1-(2,5-dimethylphenyl)-3-(1-(4-hydroxyphenyl)-1H-indazol-3-yl)urea 13 STEP 1: Synthesis of compound B1 According to TP2, methyl 1H-indazole-3-carboxylate (400 mg, 2.27 mmol, 1.0 eq.), 4- methoxyphenylboronic acid (690 mg, 4.54 mmol, 2 eq.) and CuOAc2.H2O (681 mg, 3.41 mmol, 1.5 eq.) were dissolved in DCM (40 mL). Et3N (0.61 mL, 4.54 mmol, 2.0 eq.) was added and the mixture was stirred at room temperature during 2h. The crude product was treated as mentioned in TP2 and compound B1 was obtained without further purification as an orange solid (119 mg, 19%). Rf (EP / EtOAc, 70 / 30) = 0.6.1H NMR (300MHz, CDCl3, 293K), δ(ppm) = 8.32 (dt, J = 8.0, 1.1 Hz, 1H), 7.68-7.57 (m, 3H), 7.55 – 7.30 (m, 2H), 7.06 (d, J = 9.0 Hz, 2H), 4.07 (s, 3H), 3.89 (s, 3H).13C NMR (300MHz, CDCl3, 293K), δ(ppm) = 159.4, 140.5, 132.3, 127.6, 125.6, 124.3, 123.7, 122.3, 114.8, 114.7, 110.9, 55.7, 52.2. STEP 2: Synthesis of compound B2 According to TP3, compound B1 (200 mg, 0.71 mmol, 1.0 eq.) was dissolved in EtOH (1.8 mL) and a NaOH (4M) aqueous solution was added (1.8 mL). The mixture was stirred at 60°C during 1h. The crude product was treated as mentioned in TP3 and 1-(4- methoxyphenyl)-1H-indazole-3-carboxylic acid B2 was obtained as a beige solid (175 mg, 92%). Rf (EP / EtOAC, 70 / 30) = 0.1.1H NMR (300MHz, acetone-d6, 293K), δ(ppm) = 8.29 (d, J = 8.3 Hz, 1H), 7.80 – 7.67 (m, 3H), 7.54 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.17 (d, J = 4.8 Hz, 2H), 3.89 (s, 3H).13C NMR (300MHz, acetone-d6, 293K), δ(ppm) = 160.2, 133.4, 128.4, 128.3, 127.3, 125.9, 124.3, 120.3, 119.0, 116.5, 115.6, 115.4, 114.2, 56.0. STEP 3: Synthesis of compound B3 According to TP4, 1-(4-methoxyphenyl)-1H-indazole-3-carboxylic acid B2 (590 mg, 0.34 mmol, 1.0 eq.) was dissolved in dry toluene (2 mL) in a round bottom dry flask under argon. Et3N (48 μL, 0.36 mmol, 1.05 eq.) was added and the solution was stirred 10 minutes and DPPA (77 μL, 0.36 mmol, 1.05 eq.) was added too. After 16h of stirring at room temperature (monitored by TLC), the mixture was heated to reflux and the 2,5-dimethylaniline (46 µL, 0.37 mmol, 1.1 eq.) was added. After 6h, the mixture was concentrated under reduced pressure and the crude product was purified via silica column chromatography with a mixture of EP / EtOAc (90 / 10 to 80 / 20) as eluent. Compound B3 (16 mg, 12%) was obtained as a light-yellow solid. Rf (EP / EtOAc, 70 / 30) = 0.8.1H NMR (300MHz, acetone-d6, 293K), δ(ppm) = 9.22 (bs, 1H), 8.45 (dt, J = 8.1, 1.1 Hz, 1H), 7.94 (d, J = 1.8 Hz, 1H), 7.86 – 7.72 (m, 3H), 7.55 (ddd, J = 8.5, 6.9, 1.2 Hz, 1H), 7.48 – 7.25 (m, 2H), 7.24 – 7.16 (m, 2H), 7.14 (d, J = 7.7 Hz, 1H), 6.92 (dd, J = 7.5, 1.8 Hz, 1H), 3.92 (s, 3H), 2.36 (s, 3H), 2.34 (s, 3H).13C NMR (300MHz, acetone-d6, 293K), δ(ppm) = 160.8, 160.2, 141.6, 139.8, 137.0, 136.7, 133.3, 131.1, 131.0, 130.9, 128.6, 127.1, 126.1, 125.9, 124.4, 124.2, 124.1, 123.4, 121.0, 120.9, 115.7, 111.8, 56.0, 21.2, 17.4. STEP 4: Synthesis of compound 13 According to TP5, compound B3 (34 mg, 88 μmol, 1.0 eq.) was used as methoxy-protected urea in DCM (2 mL). BBr3 (1M in DCM, 0.35 mL, 0.35 mmol, 4.0 eq.) was added at -78°C and the mixture was stirred during 4h. The crude product was purified via preparative plate using DCM / MeOH (90 / 10) as eluent. Compound 13 was obtained as a light-yellow solid (14 mg, yield: 42%). Rf (DCM / MeOH, 90 / 10) = 0.5.1H NMR (300MHz, acetone-d6, 293K), δ(ppm) = 9.21 (bs, 1H, H1), 8.94 (bs, 1H, H15), 8.44 (dt, JH11-H12= JH11-H10= 8.1 Hz, JH11-H9= 1.1 Hz, 1H, H11), 7.95 (d, JH18-H19= 6.6 Hz, 1H, H18), 7.77 (dd, JH9-H10 = 8.5 Hz, JH9-H11 = JH9-H12 = 0.9 Hz, 1H, H9), 7.73 – 7.65 (m, 2H, H3), 7.55 (ddd, JH12-H11 = 8.5 Hz, JH12-H10 = 6.9 Hz, JH12-H9 = 1.2 Hz, 1H, H12), 7.40 (ddd, JH10-H11= 7.9 Hz, JH10-H12= 6.9, JH10-H9= 0.9 Hz, 1H, H10), 7.18 – 7.07 (m, 3H, H4 and H21), 6.96 – 6.88 (m, 1H, H19), 2.36 (s, 3H, H22), 2.34 (s, 3H, H23).13C NMR (75MHz, acetone-d6, 293K), δ(ppm) = 160.9 (C6), 158.2 (C2), 141.6 (C8), 137.1 (C16), 136.7 (C5), 131.0 (C3), 128.5 (C18), 126.1 (C19), 127.1 (C21), 124.1 (C10), 123.9 (C9), 123.4 (C12), 117.0 (C4), 111.8 (C11), 21.2 (C22), 17.5 (C23). The numbered carbons 14, 17 and 20 could not be observed and surely assigned due to low resolution in 13C NMR and 2D analyses (HSQC / HMBC). LC / MS : RT = 21.27 min ; [M+H+] = 420.9 Da. EXAMPLE 14: 1-(2,5-dimethylpyridin-3-yl)-3-(1-(4-hydroxyphenyl)-1H-indol-3- yl)urea 14 STEP 1: Synthesis of compound C1 In a round-bottom dry flask, under argon, were successively added methyl 1H-indole-3- carboxylate (300 mg, 1.71 mmol, 1.0 eq.), 4-iodoanisole (521 mg, 2.23 mmol, 1.3 eq.), CuI (33 mg, 10 mol%) K3PO4(693 mg, 3.423 mmol, 2.0 eq.) and trans-1,2-diaminocyclohexane (20 μL, 10 mol%) in 1,4-dioxane (4 mL). The mixture was stirred at reflux overnight. After completion (monitored by TLC), the mixture was allowed to return at room temperature. The mixture was quenched with H2O (5 mL) and extracted with EtOAc (2 × 5 mL). The organic layer was filtered through Celite and concentrated under vacuo. The obtained residue was triturated with Et2O and filtered to the desired product C1 as a green solid (410 mg, 85%).1H NMR (400MHz, MeOD, 293K), δ (ppm) = 8.23-8.13 (m, 1H), 8.09 (s, 1H), 7.54-7.45 (m, 2H), 7.46-7.40 (m, 1H), 7.35-7.24 (m, 2H), 7.21-7.13 (m, 2H), 3.95 (s, 3H), 3.92 (s, 3H).13C NMR (101MHz, MeOD, 293K), δ (ppm) = 167.3, 160.9, 138.6, 135.9, 132.5, 128.0, 127.5, 124.5, 123.3, 122.4, 116.1, 112.0, 109.2, 56.1, 51.6. STEP 2: Synthesis of compound C2 To a solution of compound C1 (100 mg, 0.35 mmol, 1.0 eq.) in THF (1 mL) and MeOH (0.5 mL) at room temperature was added 1N aqueous NaOH solution (0.9 mL, 0.9 mmol, 2.5 eq.). The solution was stirred to 50°C overnight. After completion (monitored by TLC), the mixture was allowed to return at room temperature and was acidified using 1N aqueous HCl. The aqueous layer was extracted with EtOAc (3 × 3 mL), and the combined organic layers were dried over MgSO4, filtered and evaporated under reduced pressure to afford 1-(4- methoxyphenyl)-1H-indole-3-carboxylic acid C2 as a light brown solid (95 mg, 99%). Rf (Cyclohexane / EtOAc, 70 / 30) = 0.2.1H NMR (400MHz, CDCl3, 293K), δ (ppm) = 8.34-8.27 (m, 1H), 8.07 (s, 1H), 7.47-7.39 (m, 3H), 7.39-7.25 (m, 2H), 7.11-7.03 (m, 2H), 3.90 (s, 3H).13C NMR (101MHz, CDCl3, 293K), δ (ppm) = 170.0, 159.5, 137.5, 135.8, 131.4, 127.1, 126.5, 123.6, 122.8, 122.0, 115.1, 111.2, 108.0, 55.8. STEP 3: Synthesis of compound C3 In a round-bottom dry flask under argon, was added 1-(4-methoxyphenyl)-1H-indole-3- carboxylic acid C2 (100 mg, 0.37 mmol, 1.0 eq.) in dry toluene (2 mL) at room temperature. Et3N (52 μL, 0.39 mmol, 1.05 eq.) was added and the solution was stirred 15 minutes and DPPA (84 μL, 0.39 mmol, 1.05 eq.) was added too. After 5h of stirring at room temperature (monitored by TLC), the solvent was removed and the mixture was purified via silica column chromatography with a mixture of cyclohexane / EtOAc (100 / 0 to 90 / 10) to compound C3 as a green solid (95 mg, 87%). Rf (Cyclohexane / EtOAc, 70 / 30) = 0.6.1H NMR (300MHz, CDCl3, 293K), δ (ppm) = 8.34 – 8.28 (m, 1H), 7.97 (s, 1H), 7.43 – 7.38 (m, 2H), 7.36 – 7.29 (m, 2H), 7.26 (s, 1H), 7.09 – 7.03 (m, 2H), 3.90 (s, 3H).13C NMR (75MHz, CDCl3, 293K), δ (ppm) = 168.3, 159.6, 137.8, 135.7, 131.0, 126.6, 126.5, 124.1, 123.3, 122.0, 115.1, 111.3, 110.2, 55.8. STEP 4: Synthesis of compound C4 In a round-bottom dry flask under argon, was added the isolated acylazide C3 (109 mg, 0.37 mmol, 1.0 eq.) in dry toluene (2 mL) and the solution was heated at reflux overnight to form the isocyanate compound by Curtius rearrangement (not isolated). The mixture was allowed to return at room temperature and 2,5-dimethylaniline (50 mg, 0.37 mmol, 1.0 eq.) was added and stirred 3 hours. The mixture was filtered and the precipitate was washed with cold toluene to afford an orange solid. The crude product was purified via silica column chromatography with a mixture of DCM / MeOH (100 / 0 to 95 / 5) to obtain the desired urea C4 as a light-yellow solid (54 mg, 41%). Rf (DCM / MeOH, 95 / 5) = 0.3.1H NMR (300MHz, DMSO-d6, 293K), δ(ppm) = 9.16 (s, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.12 (s, 1H), 7.95 (bs, 1H), 7.75 (s, 1H), 7.71 – 7.64 (m, 1H), 7.52 – 7.43 (m, 3H), 7.27 – 7.09 (m, 4H), 3.83 (s, 3H), 2.46 (s, 3H), 2.25 (s, 3H).13C NMR (300MHz, DMSO-d6, 293K), δ(ppm) = 157.47, 152.61, 144.29, 142.43, 133.62, 133.10, 132.17, 130.43, 127.02, 125.11, 122.87, 121.69, 119.39, 117.58, 116.95, 116.47, 114.98, 110.26, 55.44, 40.35, 40.07, 39.80, 39.52, 39.24, 38.96, 38.68, 20.69, 17.73. STEP 5: Synthesis of compound 14 According to TP5, compound C4 (34 mg 88 μmol, 1.0 eq.) was used as methoxy-protected urea in DCM (2 mL). BBr3 (1M in DCM, 0.35 mL, 0.35 mmol, 4.0 eq.) was added at -78°C and the mixture was stirred during 4h. The crude product was purified via preparative plate using DCM / MeOH (90 / 10) as eluent. Compound 14 was obtained as a light-yellow solid (14 mg, 42%). Rf (DCM / MeOH, 90 / 10) = 0.5.1H NMR (300MHz, MeOD, 293K), δ(ppm) = 8.10 (s, 1H, H19), 7.97 (s, 1H, H21), 7.68 (d, 1H,3JH10-H11 = 8.1Hz, H10), 7.62 (s, 1H, H6), 7.40 (d, 1H,3JH13-H12 = 8.1Hz, H13), 7.33 (d, 2H,3JH4-H3 = 9.0Hz, H4), 7.20 ( dt, 1H,3JH12-H11 = 8.0Hz,4JH12-H10 = 1.4Hz, H12), 7.12 (dt, 1H, H11), 6.95 (d, 2H, H3), 2.50 (s, 3H, H22), 2.32 (s, 3H, H23).13C NMR (300MHz, MeOD, 293K), δ(ppm) = 156.1 (C2), 142.7 (C21), 133.8 (C5), 131.8 (C19), 131.5 (C18), 125.5 (C4), 122.4 (C12), 119.2 (C11), 117.1 (C10), 115.8 (C3), 109.9 (C13), 18.6 (C22), 16.6 (C23). The numbered carbons 5 to 9, 15, 17 and 20 could not be observed and surely assigned due to low resolution in13C NMR and 2D analyses (HSQC / HMBC). EXAMPLE 15: 1-(2,5-dimethylphenyl)-N-(4-(4-hydroxyphenyl)butan-2- yl)methanesulfonamide STEP 1: Synthesis of (2,5-dimethylphenyl)methanesulfonyl chloride D1 In an oven dry round bottom flask, under argon, were added 2-(chloromethyl)-1,4- dimethylbenzene (3.23 mmol, 1.0 equiv., 0.48 mL) and thiourea (3.23 mmol, 1.0 equiv., 0.25 g) in absolute EtOH (5 mL) and refluxed at 80°C. After 3 h, the reaction was taken out and concentrated under reduced pressure. The obtained solid salt was suspended in acetonitrile (7 mL) and 2M HCl (1.5 mL) was added. The mixture was stirred at 0°C for 10 min, then, N-chlorosuccinimide (12.93 mmol, 4.0 equiv., 1.73 g) was added in portion to the suspension in order to obtain a clear solution. The solution was stirred for another 30 min at room temperature and the resulting mixture was concentrated under reduced pressure to remove ACN. The remaining aqueous portion was extracted with EtOAc (2 × 8 mL), the combined organic layers were dried over MgSO4and the crude mixture was evaporated. Purification using SCC (Cyclohexane / EtOAc – 100:0 to 95:5), afforded (2,5- dimethylphenyl)methanesulfonyl chloride D1, 363 mg, yield: 51%, as a white solid. Rf(Cyclohexane / EtOAc – 90:10): 0.45.1H NMR (300MHz, Chloroform-d1, 20°C), δ (ppm): 7.25 (s, 1H), 7.17 (s, 1H), 7.16 (s, 1H), 4.94 (s, 2H), 2.43 (s, 3H), 2.35 (s, 3H). STEP 2: Synthesis of 4-(4-acetoxyphenyl)butan-2-aminium chloride D2 To a solution of DCM (8 mL) and TFA (8 mL) was added acetic anhydride (7.93 mmol, 4.0 equiv., 810 mg) and 4-(4-hydroxyphenyl)butan-2-aminium chloride (obtained from reductive amination of frambinone without basification, 1.98 mmol, 1.0 equiv., 400 mg) at room temperature. The resulting mixture was stirred (Monitored by TLC, around 4h), and stopped upon complete consumption. The solution was concentrated and was purified using SCC (DCM / MeOH – 100:0 to 95:5) to obtain 4-(4-acetoxyphenyl)butan-2-aminium chloride D2, 388 mg, yield: 80%. Rf(DCM / MeOH – 95:5): 0.3.1H NMR (300MHz, Chloroform-d1, 20°C), δ (ppm): 7.85-7.66 (br s, 3H), 7.18-7.09 (m, 2H), 6.99-6.92 (m, 2H), 3.25-3.11 (m, 1H), 2.73-2.52 (m, 2H), 2.28 (s, 3H), 1.98 (m, 1H), 1.78 (m, 1H), 1.27 (d, J = 6.3 Hz, 3H).13C NMR (75MHz, Acetone-d6, 20°C), δ (ppm): 172.8, 169.8, 150.3, 139.4, 130.1, 122.6, 55.5, 48.3, 37.1, 32.0, 20.9, 20.6. STEP 3: Synthesis of 4-(3-((2,5-dimethylphenyl)methylsulfonamido)butyl)phenyl acetate D3 To a stirred solution of 4-(4-acetoxyphenyl)butan-2-aminium chloride D2 (0.85 mmol, 1.1 equiv., 200 mg) in dry THF (8 mL) was added DiPEA (2.31 mmol, 3.0 equiv., 0.4 mL) under argon, then, (2,5-dimethylphenyl)methanesulfonyl chloride D1 (0.77 mmol, 1.0 equiv., 168 mg) was added. The resulting mixture was stirred at room temperature for 2h. The solution was diluted with EtOAc (12 mL), washed with 1M HCl (15 mL) and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were concentrated under reduced pressure and purified using SCC (Cyclohexane / EtOAc – 100:0 to 80:20) to afford 4-(3-((2,5-dimethylphenyl)methylsulfonamido)butyl)phenyl acetate D3, 129 mg, yield: 45%, as a yellowish oil. Rf (Cyclohexane / EtOAc – 70:30): 0.4.1H NMR (300MHz, Chloroform-d1, 20°C), δ (ppm): 7.15 (d, J =1.9 Hz, 1H), 7.18-7.11 (m, 2H), 7.07 (d, J =7.7 Hz, 1H), 7.04 (dd, J =7.7, 1.9 Hz, 1H), 7.01-6.95 (m, 2H), 4.26 (s, 1H), 4.25 (s, 1H), 4.14 (d, J = 8.2 Hz, 1H), 3.42 (dq, J = 8.2, 6.6 Hz, 1H), 2.62 (t, J = 8.1 Hz, 2H), 2.39 (s, 3H), 2.30 (s, 3H), 2.28 (s, 3H), 1.86-1.63 (m, 2H), 1.21 (d, J = 6.6 Hz, 3H).13C NMR (75MHz, Chloroform-d1, 20°C), δ (ppm): 169.8, 149.0, 138.9, 135.7, 135.2, 132.4, 130.9, 129.7, 129.4, 127.6, 121.6, 57.8, 50.5, 39.7, 31.5, 22.2, 21.3, 21.1, 19.5. STEP 4: Synthesis of 1-(2,5-dimethylphenyl)-N-(4-(4-hydroxyphenyl)butan-2- yl)methanesulfonamide 15 To a solution of 4-(3-((2,5-dimethylphenyl)methylsulfonamido)butyl)phenyl acetate D3 (0.171 mmol, 1.0 equiv., 65 mg) in THF (4 mL) was added LiOH (0.683 mmol, 4.0 equiv., 16 mg) in H2O (2 mL). The reaction was stirred at room temperature (Monitored by TLC) and quenched by H2O after 1 hour. The biphasic solution was extracted by EtOAc (3 × 3 mL) and the combined organic layers were dried over MgSO4, filtered and concentrated to afford 58 mg of crude. Purification was performed on 12 mg by preparative TLC (Cyclohexane / Acetone – 70:30, Rf: 0.25) to give the pure 1-(2,5-dimethylphenyl)-N-(4-(4- hydroxyphenyl)butan-2-yl)methanesulfonamide 15 as a yellowish oil (10 mg).1H NMR (300MHz, Acetone-d6, 20°C), δ (ppm): 8.10 (s, 1H, OH 19), 7.18 (d, J = 2.1 Hz, 1H, CH 8), 7.13-6.99 (m, 2+1+1H, CH 16 & 3 & 4), 6.80-6.69 (m, 2H, CH 17), 6.00 (d, J = 8.0 Hz, 1H, NH 10), 4.30 (d, J = 1.0 Hz, 2H, CH29), 3.46 (dsext, J = 8.1, 6.5 Hz, 1H, CH 11), 2.65-2.57 (m, 2H, CH214), 2.37 (s, 3H, CH36), 2.27 (s, 3H, CH31), 1.94 – 1.65 (m, 2H, CH213), 1.26 (d, J = 6.5 Hz, 3H, CH312).13C NMR (75MHz, Acetone-d6, 20°C), δ (ppm): 156.4 (COH 18) , 136.0 (C 5), 135.8 (C 2), 133.5 (C 15), 133.5 (CH 8), 131.1 (CH 4), 130.1 (CH 3 & 7), 129.7(CH 16), 116.0 (CH 17), 57.7 (CH29), 50.7 (CH 11), 40.7 (CH213), 32.0 (CH214), 22.5 (CH312), 20.9 (CH31), 19.4 (CH36). HRMS (ESI+): m / z calcd for C19H25NO3SNa+(M+Na)+370.14474; found 370.14430. HPLC purity @ ^=254 nm: 95% (General conditions, Rt = 20.81 min). MS (ESI+): m / z (%) 348.3 (15) [M+H+]. EXAMPLE 16: 1-(2,5-dimethylphenyl)-3-(1-(4-hydroxyphenyl)-1H-indol-4-yl)urea tert-butyl(4-iodophenoxy)dimethylsilane (0.922 g, 2.76 mmol, 1.2 eq.), 4-nitro-indole (373 mg, 2.30 mmol, 1.0 eq.), CuI (0.044 g, 0.23 mmol, 0.1 eq.), K3PO4 (1.025 g, 4.83 mmol, 2.1 eq.) and trans-1,2-diaminocyclohexane (0.056 mL, 0.46 mmol, 0.1 eq.) were dissolved in toluene (2.3 mL) in a sealed Schlenk. The flask was flushed with argon and the mixture was stirred at reflux overnight. The solution was allowed to return to room temperature, then the reaction mixture is quenched with H2O (5 mL), diluted with brine (30 mL) and extracted with EtOAc (2x30 mL). The organic layers were dried with MgSO4, filtered and concentrated under reduced pressure. The crude product was purified via silica column chromatography with a mixture of cyclohexane / EtOAc (7 / 3 to 5 / 5) as eluent to afford the desired product as an orange solid (313 mg, 37%). Rf (cyclohexane / EtOAc, 7 / 3) = 0.651H NMR (300MHz, CDCl3, 293K), δ(ppm): 8.15 (dd, J = 8.0, 0.8 Hz, 1H), 7.71 (dt, J = 8.2, 0.9 Hz, 1H), 7.50 (d, J = 3.2 Hz, 1H), 7.38 (dd, J = 3.2, 0.9 Hz, 1H), 7.31 (d, J = 8.8 Hz, 2H), 7.25 (t, J = 8.1 Hz, 1H), 7.01 (d, J = 8.7 Hz, 2H), 1.04 (s, 10H), 0.28 (s, 6H).13C NMR (75MHz, CDCl3, 293K), δ(ppm): 155.54, 140.56, 138.72, 132.81, 131.97, 126.54, 123.06, 121.23, 121.09, 118.08, 117.43, 103.27, 25.76, 18.34, -4.27. STEP 2: Synthesis of 1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1H-indol-4-amine 1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-4-nitro-1H-indole (0.768 g, 2,08 mmol, 1.0 eq.) and Pd / C (80 mg, 10 mol%) were dissolved in EtOH (20 mL) in a two-necked round-bottom flask. The mixture was purged with argon (5 min) and stirred at 0°C. Then, hydrazine monohydrate (80% in water, 1.69 mL, 13 eq.) was added and the mixture was stirred at reflux under argon flow during 4h. The mixture was then filtrated through a pad of celite with EtOAc. The yellow / orange liquid obtained was purified via silica column chromatography (Puriflash) with a gradient from PE to PE / EtOAc (8 / 2) to afford the desired product as a light pink solid (508 mg, 72%). Rf (PE / EtOAc, 8 / 2) = 0.51H NMR (300MHz, CDCl3, 293K), δ(ppm): 7.50 – 7.31 (m, 2H), 7.21 (d, J = 3.3 Hz, 1H), 7.12 – 6.99 (m, 1H), 6.99 – 6.91 (m, 3H), 6.59 (dd, J = 3.3, 0.9 Hz, 1H), 6.47 (dd, J = 7.3, 0.9 Hz, 1H), 3.99 (s, 2H), 1.04 (s, 9H), 0.27 (s, 6H). STEP 3: Synthesis of 1-(1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1H-indol-4-yl)-3-(2,5- dimethylphenyl)urea 1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1H-indol-4-amine (50 mg, 0.148 mmol, 1.0 eq.) was dissolved in DCM (2 mL) under argon and 2-isocyanato-1,4-dimethylbenzene (21 µL, 0.148 mmol, 1.0 eq.) was added dropwise. The mixture was stirred during 1h at room temperature under argon and concentrated under reduced pressure to afford the desired product as a brown solid (64 mg, 89%). Rf (PE / EtOAc, 8 / 2) = 0.51H NMR (300MHz, CDCl3, 293K), δ(ppm): 7.53 (d, J = 1.5 Hz, 1H), 7.41 (d, J = 7.4 Hz, 1H), 7.35 – 7.15 (m, 6H), 7.08 (d, J = 7.7 Hz, 1H), 7.00 – 6.88 (m, 3H), 6.70 (s, 1H), 6.53 (dd, J = 3.3, 0.8 Hz, 1H), 6.50 (s, 1H), 2.34 (s, 3H), 2.12 (s, 3H), 1.02 (s, 6H), 0.26 (s, 4H).13C NMR (75MHz, CDCl3, 293K), δ(ppm): 154.68, 137.31, 136.69, 136.00, 133.16, 130.50, 128.05, 127.81, 126.00, 125.95, 124.80, 123.04, 122.85, 120.98, 113.33, 107.43, 99.77, 25.79, 21.13, 18.35, 17.48, -4.26. STEP 4: Synthesis of 1-(2,5-dimethylphenyl)-3-(1-(4-hydroxyphenyl)-1H-indol-4-yl)urea 1-(2,5-dimethylphenyl)-3-(1-(4-hydroxyphenyl)-1H-indol-4-yl)urea (30 mg, 0.062 mmol, 1.0 eq.) was dissolved in dry THF (0.63 mL) at 0°C under argon. Then, a solution of TBAF in THF (1M, 0.37 mL, 6 eq.) was added dropwise and the mixture was stirred at room temperature during 1h. Then, the mixture was diluted with EtOAc (10 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure to obtain a crude purple solid (28 mg) that was purified with a preparative TLC using a mixture of cyclohexane / Et2O (8 / 2) as eluant. A beige solid was obtained (10 mg, 44%). Rf (cyclohexane / Et2O, 8 / 2) = 0.51H NMR (300MHz, acetone-d6, 293K), δ(ppm): 8.72 (s, 1H), 8.39 (s, 1H), 7.89 (dd, J = 6.2, 2.3 Hz, 1H), 7.82 (d, J = 1.8 Hz, 1H), 7.69 (s, 1H), 7.40 – 7.32 (m, 3H), 7.13 – 7.10 (m, 2H), 7.06 – 6.99 (m, 3H), 6.79 (ddd, J = 7.7, 1.9, 0.9 Hz, 1H), 6.73 (dd, J = 3.3, 0.6 Hz, 1H), 2.28 (s, 3H), 2.24 (s, 3H).13C NMR (75MHz, acetone-d6, 293K), δ(ppm): 157.25, 153.77, 138.39, 137.91, 136.46, 133.24, 132.51, 130.87, 128.11, 126.84, 125.84, 124.59, 123.53, 123.36, 121.35, 117.00, 110.58, 105.77, 100.00, 21.31, 17.77. EXAMPLE 17: 1-(2,5-dimethylphenyl)-N-(1-(4-hydroxyphenyl)-1H-indol-4- yl)methanesulfonamide STEP 1: Synthesis of N-(1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1H-indol-4-yl)-1-(2,5- dimethylphenyl)methanesulfonamide 1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1H-indol-4-amine (200 mg, 0.59 mmol, 1.0 eq.) was dissolved in pyridine (3 mL) and (2,5-dimethylphenyl)methanesulfonyl chloride (128 µL, 0.59 mmol, 1.0 eq.) was added dropwise. After 2h of stirring at room temperature, the mixture was diluted with EtOAc (30 mL) and washed with a brine solution (20 mL). The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The crude product was purified via silica column chromatography with a mixture of petroleum ether / EtOAc (10 / 0 to 9 / 1) as eluent to afford the desired product as a beige solid (223 mg, 73 %). Rf (PE / EtOAc, 9 / 1) = 0.51H NMR (300MHz, CDCl3, 293K), δ(ppm): 7.42 (dd, J = 7.5, 1.0 Hz, 1H), 7.40 – 7.34 (m, 2H), 7.34 – 7.29 (m, 2H), 7.23 (dd, J = 8.3, 7.5 Hz, 1H), 7.13 – 7.02 (m, 2H), 7.03 (s, 1H), 6.80 (s, 1H), 6.58 (s, 1H), 6.48 (dd, J = 3.3, 0.9 Hz, 1H), 4.45 (s, 2H), 2.33 (s, 3H), 2.17 – 2.06 (m, 3H), 1.05 (s, 9H), 0.29 (s, 6H).13C NMR (75MHz, CDCl3, 293K), δ(ppm): 154.98, 137.43, 135.75, 135.60, 132.94, 132.47, 130.94, 129.88, 129.56, 128.48, 127.07, 126.16, 123.26, 121.14, 110.14, 107.78, 98.92.54.74, 25.81, 20.79, 19.32, 18.39, -4.23. STEP 2: Synthesis of 1-(2,5-dimethylphenyl)-N-(1-(4-hydroxyphenyl)-1H-indol-4- yl)methanesulfonamide

[0237] N-(1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1H-indol-4-yl)-1-(2,5- dimethylphenyl)methanesulfonamide (223 mg, 0.43 mmol, 1.0 eq.) was dissolved in dry THF (10 mL) at 0°C under argon. Then, a solution of TBAF in THF (1M, 0.47 mL, 1.1 eq.) was added dropwise and the mixture was stirred at room temperature during 2h. Then, the mixture was diluted with EtOAc (30 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure to obtain a beige solid that was purified with a preparative TLC using a mixture of DCM / EtOH (95 / 5) as eluant (12 mg, 7%). Rf (PE / EtOAc, 6 / 4) = 0.41H NMR (300MHz, acetone-d6, 293K), δ(ppm): 8.70 (s, 1H), 8.49 (s, 1H), 7.47 – 7.35 (m, 4H), 7.27 (m, 1H), 7.18 (m, 1H), 7.09 – 6.97 (m, 5H), 6.86 (s, 1H), 4.44 (s, 2H), 2.31 (s, 3H), 2.13 (s, 3H).13C NMR (75MHz, acetone-d6, 293K), δ(ppm): 170.95, 157.45, 138.31, 136.13, 135.96, 133.46, 132.28, 131.60, 131.17, 129.93, 128.99, 126.97, 123.50, 122.79, 117.06, 111.36, 107.83, 101.09, 55.29, 20.74, 19.26. BIOLOGICAL EVALUATION Materials and methods Materials – IRE1 wild-type recombinant protein encoding the cytoplasmic domain (amino acids 465–977) with N-terminal polyhistidine-tag and GST tag was from Sinobiological (Sino Biological Europe GmbH, Eschborn, Germany, #11905-H20B). The fluorescent probe used for the in vitro IRE1 RNase assay was from Eurogentec. Tunicamycin was purchased from Calbiochem (Merck KGaA, Darmstadt, Germany). IRE1-mediated in vitro RNase assay – Inhibitors were diluted in minimal volume of DMSO and subsequently re-diluted in reaction buffer (20 mM HEPES pH 7.5; 1 mM MgOAc; 50 mM KOAc). Maximum volume of DMSO per reaction never exceeded 1%. Reaction volume was 25 μL. Recombinant IRE1 (0.6 μg / reaction) was incubated at room temperature for 10 minutes with varying concentrations (0-100 μM) of inhibitor and reaction buffer. The assay relied on the use of fluorescence resonance energy transfer (FRET)— quenched mini Xbp1 RNA substrate probe, which when cleaved by IRE1 emits fluorescence at 590 nm (cy3) wavelength (F. Prischi et al., Nature Communications, 2014, 5, 3554). Subsequently equal volume of mixture of reaction buffer, 20 mM ATP, 2 mM DTT and 1 μg of fluorescent probe were added to each sample and fluorescence was read in 96 well plates flat bottom, black polystyrene, matrix active group High Bind (Corning®) every minute for 25 minutes, at 37°C, using a Tecan 200 plate reader. Luciferase assays - Cells were seeded in 96-well plate. Cells were treated with increasing concentration of inhibitors. Medium was discarded and the plate was tapped to remove residual medium. 100 µL of lysis buffer (25 mM Tricine pH 7.8; 15 mM Potassium Phosphate pH 7.8; 15 mM MgSO4; 4 mM EGTA; 1% Triton X-100; 1 mM DTT) were added per well and incubated for 20 minutes at RT.50 µL were transferred to a white 96-well plate and 50 µL of substrate buffer (25 mM Tricine pH 7.8; 15 mM Potassium Phosphate pH 7.8; 15 mM MgSO4; 4 mM EGTA; 1% Triton X-100; 1 mM DTT; 1 mM ATP; 0.2 mM luciferin) were added in each well and the luminescence was read. Results IRE1-mediated in vitro RNase assay and Luciferase assay Results of the IRE1-mediated in vitro RNase assay and Luciferase assay for the compounds of the invention are listed in the Table 2 below: Table 2

Claims

CLAIMS1. A compound of Formula I:I, a pharmaceutically acceptable salt or a solvate thereof, whereinBis-C(O)- or-S(O2)-;Y is -NH- or -CH2-;R1and R2are independently H or Cl-C4-alkyl, with the proviso that R1and R2are not both H;Z is N or C-H;2. The compound according to claim 1, wherein3. The compound according to claim 1 or 2, wherein B is -C(O)-.

4. The compound according to any one of claims 1 to 3, wherein Y is -NH-.

5. The compound according to claim 1, having the formula II:II, a pharmaceutically acceptable salt or a solvate thereof, wherein Ar, B, Y, R1, R2and Z are as defined in claim 1.

6. The compound according to claim 1, having the formula III:III, a pharmaceutically acceptable salt or a solvate thereof, wherein L, B, Y, R1, R2and Z are as defined in claim 1.

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. 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. 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. 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. 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. The compound for use according to claim 10 or 11, wherein the anticancer agent is an alkylating agent.

13. The compound for use according to claim 12, wherein the alkylating agent is temozolomide.

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. 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.

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