Dibenzoazepinone based compounds as therapeutic agents for cancer treatment

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is useful for the treatment of diseases and / or disorders in which System Xc plays a role.

Description

[0001] DIBENZOAZEPINONE BASED COMPOUNDS AS THERAPEUTIC AGENTS FOR CANCER TREATMENT

[0002] The present invention relates to alkylcarbonyl substituted (hetero)aryl-acetamide of 7- membered cyclic amides derivatives and analogs thereof. The compounds according to the present invention modulate the System Xc cystine / glutamate antiporter and accordingly are of benefit as pharmaceutical agents for the treatment of diseases in which System Xc cystine / glutamate antiporter plays a role.

[0003] BACKGROUND OF THE INVENTION

[0004] System Xc, also known as the cystine / glutamate antiporter, is an amino acid transporter that mediates the extrusion of intracellular L-glutamate and the uptake of extracellular L-cystine, which undergoes intracellular reduction to L-cysteine. The influx of L-cystine serves as a rate-limiting step in providing L-cysteine, which is required for the synthesis of glutathione (GSH), the principal antioxidant in cells. L-Glutamate extruded by System Xc can serve as neurotransmitter. System Xc is a complex formed of two proteins, xCT (coded by the SLC7A11 gene) also called the light chain, and CD98hc (SLC3A2) also called heavy chain or 4F2hc. System Xc is expressed predominantly in the brain, in some glial cells such as astrocytes and microglia, and in non-CNS cells such as endothelial cells, fibroblasts, macrophages and hepatocytes.

[0005] In many different cancer types, system Xc is overexpressed compared to normal tissue. Those include, but are not limited to glioma (particularly glioblastoma) (Takeuchi et al. Neurosurgery (2013), 72, 33-41), colon carcinoma, colorectal carcinoma (Sugano et al. Anticancer Res (2015), 35, 677-682), non-small cell lung carcinoma (adenocarcinomas and squamous cell carcinomas) and other lung cancer types (Ji et al. Oncogene (2018), 37, 5007-5019), esophageal carcinoma, cancer stem cells in triple negative breast cancer (Conti et al., Cancer Immunol Res (2020), 8, 1039-105) and hepatocellular carcinoma (Kavanaugh et al., Mol Imaging Biol (2016) 18, 924-934). High system Xc expression is associated with poor prognosis in several cancers including but not limited to colon carcinoma (Lim et al., Proc Natl Acad Sci U S A (2019), 116, 9433-9442), adrenocortical carcinoma, kidney carcinoma (Wang et al., Oncotarget 2016, 7, 29901-29915), hepatocellular carcinoma (Kinoshita et al., Oncolumn Rep (2013), 29, 685-689), mesothelioma, lung carcinoma (Ji et al. Oncogene (2018), 37, 5007-5019), sarcoma, uveal melanoma and gastric cancer (Luo et al., Oncotarget 8, (2017), 112530-112549). In pancreatic ductal adenocarcinoma, a particular form of pancreatic carcinoma, stroma cells heavily rely on cysteine to prevent ferroptotic cell death and depletion of SLC7A11 in cancer-associated fibroblasts prevents orthotopic pancreatic tumor formation (Sharbeen et al., Cancer Res (2021); DOI: 10.1158 / 0008-5472. CAN- 20-2496). In other cancers, System Xc plays a crucial role in tumorigenesis, because down regulation of SLC7A11 (the light chain of system Xc) in cancer cells decreases cancer cell proliferation, tumor progression and invasion (Badgley et al., Science (2020), 368, 85-89; Ede et al., Haematologica (2018), 103, 1496-1501 ; Hu et al., J Clin Invest (2020), 130, 1752-1766; Lei et al., Cell Res (2020), 30, 146-162; Lin et al., Am J Cancer Res (2020), 10, 3106-3126). High system Xc levels also confer to the cell increased capacity for the anti oxidant GSH synthesis, defense against reactive oxygen species (ROS) and tumor growth (Liu et al., Mol Ther (2020), 28, 2358-2366).

[0006] In addition, SLC7A11 , cystine and cysteine have been described to play a role in radiotherapy resistance and in multidrug resistance in several cancer types (Horibe et al., Biochem Biophys Res Commun (2018), 507, 426-432; Koppula et al., Cell Res (2020), 30, 146-162).

[0007] Thus, inhibiting or blocking System Xc may be useful for the treatment of certain cancers where System Xc plays a role.

[0008] Blocking System Xc can also synergize with other therapies targeting tumor growth. For example, inhibition of System Xc preventing cancer stem cell metastasis, together with chemotherapy treatment blocking tumor growth (induced by oncogenes such as HER2, p53, Kras and others), leads to additional therapeutic effects in breast, esophageal and other cancer cell lines and models (Conti et al., Cancer Immunol Res (2020), 8, 1039-53; Liu et al., Nat Commun (2017), 8, 14844).

[0009] In several cancer cells, toxic lipid peroxidation induced by inhibition of System Xc, when combined to conventional cancer therapy can have a synergistic effect, lead to cancer cell death and overcome resistance to this conventional cancer therapy (Lin et al., Am J Cancer Res (2020), 10, 3106-3126; Zhuet al. Cancer Res (2021) 77(8), 2064-2077).

[0010] Therefore, molecules inhibiting system Xc could be used alone or in combination therapy, with molecules or treatments targeting other mechanisms and pathways involved in cancer biology, and thereby help overcome drug resistance in current cancer treatments or enhance the effect of certain existing treatments. Glutamate release due to upregulation of system Xc in cancer cells also affects tumorigenesis, and inhibition of glutamate release is correlated with a decrease in proliferation not only in brain tumors, but also in non-brain carcinoma ((Savaskan et al., Nature Medicine (2008), 14, 629; Lewerenz et al., Antioxid Redox Signal (2013), 18, 522-555; Corsi et al., Int J Mol Sci (2019), 20).

[0011] System Xc induced efflux of L-Glutamate into the extracellular space can contribute to excitatory signaling and to excitotoxicity, leading to seizures, neuronal death, and other brain pathologies through activation of postsynaptic glutamate receptors on neurons. Conversely, mice lacking system Xc have decreased brain glutamate receptors and demonstrate decreased or delayed epileptogenesis (Leclercq et al., Epilepsia (2019), 60, 1412-1423). Glioblastoma cells expressing elevated System Xc levels release high levels of glutamate, which activates glutamate receptors on neighboring neurons, and induces neuronal hyperactivity and seizures (Marcus et al., J. Neurooncol. (2010), 97, 11-23 ; Robert et al., (2015), Sci Transl Med 7, 289ra286).

[0012] Inhibiting system Xc function or expression could therefore prevent glutamate-induced seizures and neuronal death in glioma-associated epilepsy patients and in other epilepsy syndromes presenting high System Xc levels, such as focal cortical dysplasia and tuberous sclerosis (Arena et al., (2019), Brain Pathol 29, 351-365). International patent application WO 2015 / 196086 relates to compounds that are stated to be inhibitors of System Xc.

[0013] International patent application WO 2024 / 160722 relates to substituted 7-membered cyclic amides derivatives modulate the System Xc cystine / glutamate antiporter.

[0014] Sulfasalazine is approved for the treatment of disorders, including rheumatoid arthritis, ulcerative colitis, and Crohn’s disease. It has been demonstrated to be a non-selective inhibitor of the System Xc antiporter; however, due to its poor brain exposure, its uses are limited to peripheral indications. In addition, due to its low potency on human System X function, its efficacy in peripheral indications is limited.

[0015] There is therefore a need to design new agents that inhibit the System Xc antiporter, which agents have improved properties and can be used for the treatment of certain cancers, or epilepsy syndromes where system Xc plays a role.

[0016] SUMMARY OF THE INVENTION

[0017] In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0018] Wherein

[0019] R1represents C-M alkyl;

[0020] R2represents hydrogen, halogen or C1-4 alkyl;

[0021] R3represents hydrogen or halogen;

[0022] R4represents C1-4 alkyl; or C3-7 cycloalkyl substituted by a halogen;

[0023] X1represents N or CR5;

[0024] X2represents N or CR6; and

[0025] R5and R6represent independently cyano; and

[0026] Wherein when R4represents C1-4 alkyl, R2represents C1-4 alkyl In a second aspect, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.

[0027] In a third aspect, the present invention provides compound of Formula (I), or a pharmaceutically acceptable sale thereof, useful for the treatment of disorders for which system Xc cystine / glutamate antiporter plays a role.

[0028] In particular, the present invention provides compounds of formula (I) which may be useful for the treatment of cancers, or epilepsy syndromes where system Xc plays a role.

[0029] Furthermore, the present invention provides compounds of formula (I) which may be useful to overcome cancer treatment resistance.

[0030] In a fourth aspect, the present invention provides a pharmaceutical composition comprising, as an active ingredient, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0031] DETAILED DESCRIPTION OF THE INVENTION

[0032] The term "C- alkyl" as used herein refers to straight or branched, monovalent, saturated aliphatic hydrocarbon chains of 1 to 4 carbon atoms. Illustrative C1-4 alkyl according to the present invention are methyl and ethyl.

[0033] The term "C3-7 cycloalkyl" as used herein refers to monovalent groups of 3 to 7 carbon atoms derived from a saturated monocyclic hydrocarbon. Illustrative C3-7 cycloalkyl groups include cyclopropyl.

[0034] The terms “Halo,” “halogen,” and “halide” are used indifferently and represent a chloro, fluoro, bromo, or iodo atom. Suitable examples of halogens according to the present invention include chloro and fluoro.

[0035] Where any of the groups in the compounds of formula (I) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one, two or three substituents. In one embodiment, such groups are unsubstituted. Suitable substituents for each of the groups present on compounds of formula (I) are further described here after in the present specification.

[0036] Formula (I) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise.

[0037] Stereoisomers of compounds of formula (I) include cis and trans isomers, optical isomers, diastereomers, geometric isomers, rotational isomers, atropisomers, and conformational isomers of the compounds of formula (I), including compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs).

[0038] Compounds of Formula (I) and / or their intermediates may have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration (referred to as aR or aS for atropisomers), said R and S (or aR and aS) notation is used in correspondence with the rules described in Pure Appl. Chem., 45 (1976) 11-30. The invention thus also relates to all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds of Formula (I’) and Formula (I) or mixtures thereof (including all possible mixtures of stereoisomers). With respect to the present invention reference to a compound or compounds is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof, unless the particular isomeric form is specifically referred to.

[0039] The carbon-carbon bonds of the compounds of formula (I) are depicted herein using a solid line ( —J), a solid wedge ( 3), or a dotted wedge ( The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of formula (I’) and formula (I) may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included.

[0040] Some compounds of formula (I) may exist as single atropisomer or as mixture of atropisomers.

[0041] Atropiomers are stereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers (see for example Bringmann G. et al. Atroposelective Synthesis of Axially Chiral Biaryl Compounds. Angewandte Chemie International Edition. (2005) 44 (34): 5384-5427).

[0042] Unlike compounds with classical chiral centers, which racemize via a bond breaking and making process, atropisomers racemize via an intramolecular dynamic process that only involves bond rotation. Depending on rotation barrier, one particular conformer of compounds formula (I) can be in equilibrium with another conformer and thus the composition of the confomers may change with time or condition to reach an equilibrium. The conformation of the compounds of formula (I) can be represented with solid line ( •—■—]) and / or with solid wedge ( An example is displayed where atropisomers are represented respectively by formula (l-a’) and (l-b’). The use of the solid wedge:=r"“ ! on the phenyl rings is meant to indicate a conformation associated to the specific atropisomer (l-a’) or (l-b’).

[0043] Some of the compounds of formula (I) may exist in tautomeric forms. Such forms although not explicity indicated in the above formula are intended to be included within the scope of the present invention. Examples of tautomers include keto (CH2C=O)«->enol (CH=CHOH) tautomers or amide (NHC=O)«->hydroxyimine (N=COH) tautomers or 2-hydroxypyridine^pyridinone. Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise.

[0044] It is also to be understood that each individual atom present in formula (I), or in the formula depicted hereinafter, may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred.

[0045] Thus, by way of example, each individual hydrogen atom present in formula (I), or in the formula depicted hereinafter, may be present as a1H,2H (deuterium) or3H (tritium) atom, preferably1H or2H. Similarly, by way of example, each individual carbon atom present in formula (I’), formula (I), or in the formulae depicted hereinafter, may be present as a11C,12C,13C or14C atom, preferably12C. Similarly, by way of example, each individual fluorine atom may be present as18F or19F.

[0046] Thus, the present invention, also includes within its scope, isotopically-labelled compounds of Formula (I).

[0047] Specific embodiments of compounds of formula (I) according to the present invention are described hereafter.

[0048] In one embodiment, the present invention provides a compound of formula (I) wherein

[0049] R1represents C-M alkyl;

[0050] R2represents hydrogen, halogen or C1-4 alkyl;

[0051] R3represents hydrogen or halogen;

[0052] R4represents C1-4 alkyl; or C3-7 cycloalkyl substituted by a halogen;

[0053] X1represents N;

[0054] X2represents N or CR6; and

[0055] R6represents cyano, and

[0056] Wherein when R4represents C1-4 alkyl, R2represents C1-4 alkyl

[0057] In one embodiment, R1represents methyl.

[0058] In a first embodiment, R2represents hydrogen. In a second embodiment, R2represents flurorine. In a third embodiment, R2represents methyl.

[0059] Suitably, R2represents hydrogen, flurorine or methyl.

[0060] In a first embodiment, R3represents hydrogen. In a second embodiment, R3represents flurorine.

[0061] Suitably, R3represents hydrogen or fluorine. In a first embodiment, R4represents methyl. In a second embodiment, R4represents a cyclopropyl optionally substituted by a halogen. In a particular aspect of this embodiment, R4represents a cyclopropyl substituted by a fluorine.

[0062] Suitably, R4represents methyl or cyclopropyl substituted by a fluorine.

[0063] In a first embodiment, X1represent N. In a second embodiment, X1represent C(CN).

[0064] Suitably, X1represent N or C(CN).

[0065] Ideally, X1represents N.

[0066] In a first embodiment, X2represents N. In a second embodiment X2represent C(CN).

[0067] Suitably, X2represents N or C(CN).

[0068] In a particular embodiment, the present invention provides a compound of formula (I) wherein R1represents methyl;

[0069] R2represents hydrogen, fluorine or methyl;

[0070] R3represents hydrogen or fluorine;

[0071] R4represents methyl; or cyclopropyl substituted by a fluorine;

[0072] X1represents N or CR5;

[0073] X2represents N or CR6; and

[0074] R5and R6represent independently cyano.

[0075] In another particular embodiment, the present invention provides a compound of formula (I) wherein

[0076] R1represents methyl;

[0077] R2represents hydrogen, fluorine or methyl;

[0078] R3represents hydrogen or fluorine;

[0079] R4represents methyl; or cyclopropyl substituted by a fluorine;

[0080] X1represents N;

[0081] X2represents N or CR6; and

[0082] R6represents cyano.

[0083] In one aspect the present invention provides for a compound represented by formula (la),

[0084]

[0085] Wherein,

[0086] R2and R3independently represent hydrogen or halogen; and

[0087] Rarepresents halogen.

[0088] In a first embodiment of compound of formula (la), R2represents hydrogen. In a second embodiment of compound of formula (la), R2represents halogen. In one aspect ofthis embodiment, R2represents flurorine.

[0089] In a first embodiment of compound of formula (la), R3represents hydrogen. In a second embodiment of compound of formula (la), R3represents halogen. In one aspect ofthis embodiment, R3represents flurorine.

[0090] In one embodiment of compound of formula (la), Rarepresents fluorine.

[0091] In a particular asect, the present invention provides for a compound of formula (la) wherein

[0092] R2and R3independently represent hydrogen or flurorine; and

[0093] Rarepresents flurorine.

[0094] In a particular aspect, the present invention relates to compounds of formula (I) as provided in the Examples.

[0095] In particular, the present invention relates to compounds which are selected from the group consisting essentially of

[0096] (I OR)-A / -(4-acetylphenyl)-2-[14-fluoro-5-(1 -fluorocyclopropyl)-10-methyl-9-oxo-4,8,12- triazatricyclo[9.4.0.027]pentadeca-1 (11),2(7),3,5,12,14-hexaen-8-yl]acetamide;

[0097] (I OS)-N-(4-acetylphenyl)-2-[14-fluoro-5-(1 -fluorocyclopropyl)-10-methyl-9-oxo-4,8,12- triazatricyclo[9.4.0.027]pentadeca-1 (11),2(7),3,5,12,14-hexaen-8-yl]acetamide;

[0098] A / -(4-acetylphenyl)-2-[3-fluoro-5-(1 -fluorocyclopropyl)-10-methyl-9-oxo-4,8,12- triazatricyclo[9.4.0.027]pentadeca-1 (11),2(7),3,5,12,14-hexaen-8-yl]acetamide;

[0099] (10R)-A / -(4-acetylphenyl)-2-(3-fluoro-5,10,14-trimethyl-9-oxo-4,8,12- triazatricyclo[9.4.0.027]pentadeca-1 (11),2(7),3,5,12,14-hexaen-8-yl)acetamide; (10S)-A / -(4-acetylphenyl)-2-(3-fluoro-5, 10,14-trimethyl-9-oxo-4,8,12- triazatricyclo[9.4.0.027]pentadeca-1 (11),2(7),3,5,12,14-hexaen-8-yl)acetamide

[0100] (I OR)-A / -(4-acetylphenyl)-2-(10-cyano-5,9-dimethyl-6-oxo-5 / 7-pyrido[2,3-d][1]benzazepin-7- yl)acetamide; and

[0101] (I OS)-A / -(4-acetylphenyl)-2-(10-cyano-5,9-dimethyl-6-oxo-5 / 7-pyrido[2,3-d]

[0001] benzazepin-7- yl)acetamide.

[0102] In the following sections, when reference is made to compound of formula (I) it s deemed to encompass specific embodiments thereof, including compound of formula (la).

[0103] The present invention also provides a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, for use in therapy.

[0104] In particular, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases and / or disorders in which System Xc plays a role.

[0105] In the following aspects, the compound of formula (I) as defined above may be an inhibitor of the System Xc anti porter.

[0106] In a first aspect, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancers where System Xc plays a role, in epilepsy syndromes where System Xc plays a role, or in cancer treatment resistance.

[0107] In a first embodiment according to this aspect, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancers where System Xc plays a role.

[0108] In particular, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof for use in the treatment of glioma, colon carcinoma, colorectal carcinoma, lung cancer, esophageal carcinoma, triple negative breast cancer, hepatocellular carcinoma, adrenocortical carcinoma, kidney carcinoma, mesothelioma, sarcoma, uveal melanoma, gastric cancer, pancreatic carcinoma or leukemia.

[0109] In a second embodiment according to this aspect, the present invention provides a compound of formula (I) as defined above for use in the treatment of epilepsy syndromes where System Xc plays a role.

[0110] In particular, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of epileptogenesis, glutamate induced seizures, glioma associated epilepsy, focal cortical dysplasia or tuberous sclerosis.

[0111] In a third embodiment, the present invention provides compounds of formula (I) for use in the treatment of cancer treatment resistance.

[0112] In particular, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of multidrug resistance in several cancer types. In a second aspect, the present invention provides for the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment of diseases and / or disorders in which system Xc cystine / glutamate antiporter plays a role.

[0113] In a first embodiment of this aspect, the present invention provides for the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment of cancers where System Xc- plays a role.

[0114] In particular, the present invention provides for the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful for the treatment glioma, colon carcinoma, colorectal carcinoma, lung cancer, esophageal carcinoma, triple negative breast cancer, hepatocellular carcinoma, adrenocortical carcinoma, kidney carcinoma, mesothelioma, sarcoma, uveal melanoma, gastric cancer, pancreatic carcinoma or leukemia.

[0115] In a second embodiment according to this aspect, the present invention provides for the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment of epilepsy syndromes where System X plays a role.

[0116] In particular, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment of epileptogenesis, glutamate induced seizures, glioma associated epilepsy, focal cortical dysplasia or tuberous sclerosis.

[0117] In a third embodiment according to this aspect, the present invention provides for the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for cancer treatment resistance.

[0118] In particular, the present invention provides for the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment of multidrug resistance in several cancer types. In a third aspect, the present invention provides a method for the treatment of disorders for which the administration of inhibitors of the System Xc is indicated, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0119] In a first embodiment according to this aspect, the present invention provides a method for the treatment of cancers where System X plays a role, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0120] In particular, the present invention provides a method for the treatment of glioma, colon carcinoma, colorectal carcinoma, lung cancer, esophageal carcinoma, triple negative breast cancer, hepatocellular carcinoma, adrenocortical carcinoma, kidney carcinoma, mesothelioma, sarcoma, uveal melanoma, gastric cancer, pancreatic carcinoma or leukemia, which comprises administering to a patient in need of such treatment of an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0121] In a second embodiment according to this aspect, the present invention provides a method for the treatment of epilepsy syndromes where System Xc plays a role, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0122] In particular, the present invention provides a method for the treatment of epileptogenesis, glutamate induced seizures, glioma associated epilepsy, focal cortical dysplasia or tuberous sclerosis, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0123] In a third embodiment according to this aspect, the present invention provides a method for the treatment of cancer treatment resistance, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof. In particular, the present invention provides a method for the treatment of multidrug resistance in several cancer types, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0124] As used herein, the term “patient” refers to a mammal that is afflicted with one or more disorders associated with function or expression of System Xc. It will be understood that the most preferred patient is a human.

[0125] It is also recognized that one skilled in the art may affect the disorders by treating a patient presently afflicted with the disorders, or by prophylactically treating a patient afflicted with the disorders with an effective amount of the compound of Formula (I). Thus, the terms “treatment” and “treating” are intended to refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the disorders described herein, and is intended to include prophylactic treatment of such disorders, but does not necessarily indicate a total elimination of all disorder symptoms.

[0126] Activity in any of the above-mentioned therapeutic indications or disorders can of course be determined by carrying out suitable clinical trials in a manner known to a person skilled in the relevant art for the particular indication and / or in the design of clinical trials in general.

[0127] For use in medicine, the salts of the compounds of formula (I) will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of use in the invention or of their pharmaceutically acceptable salts. Standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use, ed. P.H. Stahl & C.G. Wermuth, Wiley-VCH, 2002. Suitable pharmaceutically acceptable salts of the compound of formula (I’) or formula (I) include acid addition salts which may, for example, be formed by mixing a solution of the compound of formula (I) with a solution of a pharmaceutically acceptable acid. The present invention includes within its scope solvates of the compounds of formula (I) above. Such solvates may be formed with common organic solvents or water.

[0128] The present invention also includes within its scope co-crystals of the compounds of formula (I) above. The technical term “co-crystal” is used to describe the situation where neutral molecular components are present within a crystalline compound in a definite stoichiometric ratio. The preparation of pharmaceutical co-crystals enables modifications to be made to the crystalline form of an active pharmaceutical ingredient, which in turn can alter its physicochemical properties without compromising its intended biological activity (see Pharmaceutical Salts and Co-crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012).

[0129] Compounds according to the present invention may exist in different polymorphic forms. Although not explicitly indicated in the above formula, such forms are intended to be included within the scope of the present invention.

[0130] The invention also includes within its scope pro-drug forms of the compounds of formula (I) and its various sub-scopes and sub-groups.

[0131] For treating diseases, compounds of formula (I) or their pharmaceutically acceptable salts may be employed at an effective daily dosage and administered in the form of a pharmaceutical composition.

[0132] Therefore, another embodiment of the present invention concerns a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier.

[0133] To prepare a pharmaceutical composition according to the invention, one or more of the compounds of formula (I) or a pharmaceutically acceptable salt thereof is intimately admixed with a pharmaceutical diluent or carrier according to conventional pharmaceutical compounding techniques known to the skilled practitioner.

[0134] Suitable diluents and carriers may take a wide variety of forms depending on the desired route of administration, e.g., oral, rectal, parenteral, intranasal, or intratumoral.

[0135] Pharmaceutical compositions comprising compounds according to the invention can, for example, be administered orally, parenterally, i.e. intravenously, intramuscularly or subcutaneously, intrathecally, by inhalation, intranasally or by ophthalmic administration.

[0136] Pharmaceutical compositions suitable for oral administration can be solids or liquids and can, for example, be in the form of tablets, pills, dragees, gelatin capsules, solutions, syrups, chewing- gums and the like.

[0137] To this end the active ingredient may be mixed with an inert diluent or a non-toxic pharmaceutically acceptable carrier such as starch or lactose. Optionally, these pharmaceutical compositions can also contain a binder such as microcrystalline cellulose, gum tragacanth or gelatine, a disintegrant such as alginic acid, a lubricant such as magnesium stearate, a glidant such as colloidal silicon dioxide, a sweetener such as sucrose or saccharin, or colouring agents or a flavouring agent such as peppermint or methyl salicylate. The invention also contemplates compositions which can release the active substance in a controlled manner. Pharmaceutical compositions which can be used for parenteral administration are in conventional form such as aqueous or oily solutions or suspensions generally contained in ampoules, disposable syringes, glass or plastics vials or infusion containers.

[0138] In addition to the active ingredient, these solutions or suspensions can optionally also contain a sterile diluent such as water for injection, a physiological saline solution, oils, polyethylene glycols, glycerine, propylene glycolumn or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulphite, chelating agents such as ethylene diamine-tetra-acetic acid, buffers such as acetates, citrates or phosphates and agents for adjusting the osmolarity, such as sodium chloride or dextrose.

[0139] These pharmaceutical forms are prepared using methods which are routinely used by pharmacists.

[0140] The amount of active ingredient in the pharmaceutical compositions can fall within a wide range of concentrations and depends on a variety of factors such as the patient’s sex, age, weight and medical condition, as well as on the method of administration. Thus, the quantity of compound of formula (I) in compositions for oral administration is at least 0.5 % by weight and can be up to 80 % by weight with respect to the total weight of the composition.

[0141] In accordance with the invention, it has also been found that the compounds of formula (I) or the pharmaceutically acceptable salts thereof can be administered alone or in combination with other pharmaceutically active ingredients.

[0142] In particular, compounds of formula (I) according to the present invention could be combined with other active ingredients that increase intracellular reactive oxygen species, regulate amino acid metabolism or with immunotherapeutic agents.

[0143] In compositions for parenteral administration, the quantity of compound of formula (I) present is at least 0.5 % by weight and can be up to 33 % by weight with respect to the total weight of the composition. For the preferred parenteral compositions, the dosage unit is in the range 0.5 mg to 3000 mg of compounds of formula (I).

[0144] The daily dose can fall within a wide range of dosage units of compound of formula (I) and is generally in the range 0.5 to 3000 mg. However, it should be understood that the specific doses can be adapted to particular cases depending on the individual requirements, at the physician’s discretion.

[0145] SYNTHETIC SCHEMES

[0146] It will be apparent to the person skilled in the art that there are various synthetic pathways that can lead to the compounds according to the invention. The following processes are aimed at illustrating some of these synthetic pathways but should not be construed in any way as a limitation on how the compounds according to the invention should be made.

[0147] During any of the below synthetic sequences, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups (PG), such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rdedition, 1999. The protecting groups may be removed at any convenient subsequent stage utilising methods known from the art.

[0148] The compounds of Formula (I) according to the invention can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry.

[0149] In the following description of general synthetic methods, “DCM” means dichloromethane; “DIPEA” refers to N,N-di-iso-propylethylamine; “DMF” refers to N,N-dimethylformamide; “DMSO” refers to dimethylsulfoxide; “EDC” refers to 1-Ethyl-3-carbodiimide hydrochloride; “; “TEA” refers to triethylamine; “THF” refers to tetra hydrofuran; “HATU” refers to hexafluorophosphate azabenzotriazole tetramethyl uranium; “HBTU” refers to hexafluorophosphate benzotriazole tetramethyl uronium; “HOBt” refers to hydroxybenzotriazole”; “TCFH” refers to chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate; and “NMI” refers to N-methylimidazole.

[0150] The following description of synthetic schemes provides for means of preparing compounds of formula (I). However, analogous methods known to the person skilled in the art may be used in the preparation of compounds of formula (I). According to one embodiment, compounds having the general Formula (I), wherein A represents A1may be prepared by reaction of a compound of formula (2) with an amide of formula (4) or by reaction of a compounds of formula (3) with an aromatic amine of formula (5) according to the equation: wherein R1, R2, R3, R4, X1, and X2are as defined above for compound of Formula (I) and where LG1is a halogen atom or a leaving group such as a mesylate or tosylate; and LG2is hydroxy, alkoxy, or halogen.

[0151] The reaction following route A may be performed with a base such as trialkyl amines, inorganic carbonates or pyridines, with or without the presence of an iodide salt such as KI or Nal in a suitable solvent such as DMSO, DMF, sulfolane, acetonitrile, or THF. Alternatively, compounds of Formula (I) may be prepared following route B by reaction of a carboxylic acid or carboxylic derivatives of formula (3) with aromatic amines (5) following procedures for the formation of an amide from carboxylic acids or carboxylic derivatives and amines known to the person skilled in the art. The reaction following route B, when LG2is a halogen such as chlorine, may be performed with a base such as trialkyl amines, inorganic carbonates, or pyridines in a suitable solvent such as DCM, DMSO, DMF, sulfolane, acetonitrile, or THF. When LG2is hydroxy, the reaction may be performed with similar bases and in the presence of an amide coupling reagent such as HBTU, HATU, TCFH / NMI, EDC / HOBt, or according to any other method known to the person skilled in the art. Alternatively, compounds of formula (3) in which LG2is hydroxy can be transformed into compounds of formula (3) in which LG2is chloro by reaction with sulfonyl chloride or thionyl chloride in the presence or absence of catalytic DMF, in a suitable solvent such as DCM or THF at room or at higher temperatures such as 70°C.

[0152] Compounds of formula (3) where LG2is an alkoxy such as OMe, OEt, or OtBu may be prepared by reaction of intermediate (2) with an alpha-chloro ester or an alpha-bromo ester such as methyl 2-bromoacetate, ethyl 2-bromoacetate, or tert-butyl 2-bromoacetate in the presence of a base such as potassium carbonate in a polar solvent such as DMF at room temperature or by any method known to the person skilled in the art. Further basic or acid ester hydrolysis known to the person skilled in the art may be used to form compounds of formula (3) in which LG2is OH.

[0153] Alternatively, compounds of Formula (I) may be prepared by reaction of an intermediate of Formula (3) wherein LG2is NH2, hereinafter referred to as (3’), with a compound of formula (5’) wherein X is sulfonate such as a triflate, an halogen such as chloro or bromo in the presence of a catalytic amount of a palladium catalyst. This reaction, the “Buchwald amide coupling”, is known to the person skilled in the art.

[0154] Compounds of Formula (5’) are either commercially available or maybe prepared by any method known to the person skilled in the art.

[0155] Compounds of Formula (3’) may be prepared by reaction of a compound of Formula (2) with an alpha-halogeno amide such as iodoacetamide in the presence of a base such as potassium carbonate in a polar solvent such as DMF at room temperature or by any other method known to the person skilled in the art. Alternatively, compounds of Formula (3’) may be prepared by reaction of a carboxylic acid or carboxylic acid derivatives of formula (3) with ammonia following procedures for the formation of an amide from carboxylic acids or carboxylic derivatives and amines known to the person skilled in the art.

[0156] Compounds of Formula (2) may be prepared by cyclocondensation from their precursors of Formula (6) in which LG2has the same definition as depicted above. For example, when LG2is an alkoxy, the reaction involves the presence of a base such as LiHMDS or K2CO3 or may be directly obtained without isolation from the previous step under heating conditions.

[0157] Compounds of Formula (6) may be prepared by a cross-coupling reaction, the “Suzuki reaction” known by the person skilled in the art, from their corresponding precursors of Formula (8) and (9), with the proviso that when (8) bears B*, (9) bears X* or when (8) bears X*, (9) bears B*. B* may be a boronic acic B(OH)2, or any boronic ester B(OR)2 such as pinacol boronic ester or a mixture of the two, and X* is a halogen such as Cl, Br or I.

[0158] Compounds of Formula (8) and (9) are either commercially available, described in the literature or may be prepared by functional group transformations known to the person skilled in the art.

[0159] For example, compounds of formula (9) may be prepared by bromination or borylation of compounds (11), where PG is hydrogen or a protecting group such as Boc or benzyl group, followed by a deprotection step when needed according to methods known to the person skilled in the art.

[0160] Compounds of formula (11) may be prepared by a cross-coupling reaction from compounds (10), where LG3is a leaving group such as a halogen atom or a sulfonate, with a reagent R4-M where M is a boronic acic B(OH)2, any boronic ester B(OR)2, a trialkyl stannyl group or a group containing a metal such as lithium, zinc or magnesium. Alternatively, compounds of formula (2) wherein PG is is hydrogen can be prepared by a crosscoupling reaction from compounds (13), where LG3is a leaving group such as a halogen atom or a sulfonate and PG is hydrogen, a protecting group or a (2-alkoxy-2-oxo-1-substituted-ethyl) represented by compounds of formula (3), with a reagent R4-M where M is a boronic acic B(OH)2, any boronic ester B(OR)2 ,a trialkyl stannyl group or a group containing a metal such as lithium, zinc or magnesium.

[0161] EXPERIMENTAL SECTION

[0162] I. Abbreviations / recurrent reagents

[0163] ACN or MeCN Acetonitrile

[0164] CV Column Volume

[0165] DCM Dichloromethane

[0166] EtOAc Ethyl acetate

[0167] DMF N,N-Dimethylformamide

[0168] DMA Dimethyl acetamide

[0169] DMAP Dimethylaminopyridine

[0170] EDC 1-Ethyl-3-carbodiimide hydrochloride

[0171] MeOH Methanol

[0172] DCE Dichloroethane

[0173] HATU Hexafluorophosphate Azabenzotriazole Tetramethyl Uranium

[0174] HBTU Hexafluorophosphate Benzotriazole Tetramethyl Uranium

[0175] HOBt Hydroxybenzotriazole

[0176] TCFH Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate

[0177] NMI N-Methylimidazole

[0178] MTBE or TBME Methyl tert-butyl ether

[0179] PTFE polytetrafluoroethylene

[0180] ELSD Evaporative light scattering detector

[0181] DMSO Dimethylsulfoxide

[0182] Brine Saturated aqueous sodium chloride solution

[0183] Et2O Diethyl ether h Hour d Days THF Tetrahydrofuran

[0184] AcOH Acetic acid

[0185] RT Room temperature rt Retention time

[0186] Rf Retention factor br Broad

[0187] M Molar

[0188] MS Mass Spectrometry

[0189] [M+H]+Exact mass of protonated ion observed by MS

[0190] [M-H]- Exact mass of deprotonated ion observed by MS mL Milliliter

[0191] HPLC High Performance Liquid Chromatography

[0192] UPLC Ultra High Performance Liquid Chromatography

[0193] LC-MS Liquid Chromatography Mass Spectrometry

[0194] ESI Electrospray Ionisation

[0195] ES+Electrospray Positive Ionisation

[0196] TEA Triethylamine

[0197] DI PEA N,N-di-iso-propylethylamine

[0198] DEA Diethylamine

[0199] CDI Carbonyl diimidazole

[0200] PCy3 Tricyclohexylphosphine

[0201] TMSCN Trimethylsilyl cyanide dppf 1 ,1 '-Bis(diphenylphosphino)ferrocene

[0202] PEPPSI Pyridine-Enhanced Precatalyst Preparation Stabilization and Initiation

[0203] HMDS bis(trimethylsilyl)amide or Hexamethyldisilazane

[0204] PPhs Triphenylphosphine

[0205] AIBN Azobisisobutyronitrile

[0206] TFA Trifluoroacetic acid bs. Broad singlet

[0207] NBS N-bromosuccinimide

[0208] DME Dimethoxy ethane

[0209] HMPA Hexamethylphosphoramide

[0210] SFC Supercritical Fluid Chromatography

[0211] SCX Strong Cation Exchange HPLC column

[0212] TLC Thin Layer Chromatography

[0213] Sat. Saturated

[0214] Hex Hexane aq. Aqueous

[0215] Eq. Equivalent mm Minute mmol Millimole

[0216] UV Ultraviolet

[0217] Naming convention :

[0218] IUPAC names of chemical reagents, Intermediates and Examples have been generated using Biovia Draw 2020 (version 20.1 .100.2161 or 20.1 .0.2081). Depending on the Kekule structures of chemical reagents, Intermediates and Examples, Bovia Draw may generate different chemical names. As an illustration, the Kekule structures K1 and K2 are named 4,8,14- triazatricyclo[9.4.0.027]pentadeca-1 (11),2,4,6,12,14-hexaen-9-one and 4,8,14- triazatricyclo[9.4.0.027]pentadeca-1 (15),2,4,6,11 ,13-hexaen-9-one, respectively. Both names could be found in the below descriptions.

[0219] Kekule structure K1 Kekule structure K2

[0220] II. Analytical and synthetic methods

[0221] All reactions involving air or moisture-sensitive reagents are performed under a nitrogen or argon atmosphere (inert atmosphere) using dried solvents and glassware. Experiments requiring microwave irradiation are performed on a Biotage Initiator Sixty microwave oven upgraded with version 2.0 of the operating software. Experiments are run to reach the required temperature as quickly as possible (maximum irradiation power: 400 W, no external cooling). Commercial solvents and reagents are generally used without further purification, including anhydrous solvents when appropriate (generally Sure-Seal™ products from Aldrich Chemical Company or AcroSeal™ from ACROS Organics). In general, reactions are followed by thin layer chromatography (TLC), high performance liquid chromatography (HPLC) or mass spectrometry (MS) analyses.

[0222] NMR spectra were recorded on a Bruker Advance III HD 500 MHz or 400 MHz spectrometer. The chemical shifts (6) reported are given in parts per million (ppm), and the coupling constants (J) are in Hertz (Hz). The spin multiplicities are reported as s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublet, ddd = doublet of doublet of doublet, dt = doublet of triplet, td = triplet of doublet, and m = multiplet.

[0223] Mass spectrometric measurements in LC-MS mode are performed as follows:

[0224] - For acidic elution (Method A 1, A 1’, A 1_S, A2 andA2’), analyses are performed using a QDA Waters simple quadrupole mass spectrometer. This spectrometer is equipped with an ESI source and an UPLC Acquity Hclass with diode array detector (200 to 400 nm). Data are acquired in a full MS scan from m / z 70 to 800 in positive mode with an acidic elution. The reverse phase separation is carried out at 45°C on a Waters Acquity UPLC HSS T3 1 .8 pm (2.1 x 50 mm) column for Method

[0225] A1 , A1 ’ and A1_S elution and on a Waters Acquity UPLC HSS T3 1 .8 pm (2.1 x 100mm) column for Method A2 and A2’. Gradient elution is done with water / ACN / TFA (95 / 5 / 0.5 mL / L) (solvent A) and ACN (solvent B) for Method A1 , A1_S and A2 and Water / Acetonitrile / Formic acid (95 / 5 / (0.05%)) (solvent A) Acetonitrile / Formic acid (99.95 / 0.05%) (solvent B) for Method AT and

[0226] A2’. Injection volume: 1 pL. Full flow in MS. Gradient Program:

[0227] Method A 1, A T

[0228] Method A1 S

[0229] Method A2, A2’

[0230] - For acidic elution (Method A3), analysis are performed using a Xevo Waters Q-TOF mass spectrometer. This spectrometer is equipped with an ESI source and a Waters Acquity H-class UPLC with diode array detector (210 to 400 nm). Data are acquired in a full MS scan from m / z 50 to 1200 in positive mode. The reverse phase separation is carried out at 40°C on an Acquity UPLC HSS T3 C18 column (1 .8pm, 2.1 x 100 mm). Gradient elution is done with Water / ACN / Formic acid (95 / 5 / 750pL / L) (Solvent C) and Water / ACN / Formic acid (5 / 95 / 500pL / L) (Solvent D) at pH~3. 100% Flow in UV, 10 % flow in MS-, 90 % flow in ELSD. Injection volume: 0.5 to 2 pL.

[0231] Gradient Program:

[0232] Method A3

[0233] - For acidic elution (Method A4 andA8), analysis is performed using a SYNAPT G2-SI Waters Q-TOF mass spectrometer for Method A4 and on a SQD2 Waters single quadrupole for Method A8. These spectrometers are equipped with an ESI source and a Waters Acquity H-class UPLC with diode array detector (210 to 400 nm). Data are acquired in a full MS scan from m / z 50 to 1200 in positive mode. The reverse phase separation is carried out at 45°C on an Acquity UPLC HSS T3 C18 column (1 .8 pm, 2.1 x 100 mm). Gradient elution is done with Water / ACN / Formic acid (95 / 5 / 750 pL / L) (Solvent C) and Water / ACN / Formic acid (5 / 95 / 500 pL / L) (Solvent D) pH~3. Full flow in MS. injection volume: 0.5 pL.

[0234] Gradient Program:

[0235] Method A4, A8

[0236] - For acidic elution (Method A5), analyses are performed using a Shimadzu LC-MS 201 OEV mass spectrometer for LC-MS analysis. This spectrometer is equipped with an ESI source and HPLC with diode array detector (210 to 400 nm). Data is acquired in a full MS scan from m / z 80 to 2000 in positive mode and negative mode. The reverse phase separation is carried out with Waters X-Select CSH C18 (4.6 x 150 mm), 3.5 pm column. Column temp: 50°C. Gradient elution is done with Mobile phase with 0.1 % Formic acid in water (Phase A) and Acetonitrile (Phase B). Injection volume: 2 pL.

[0237] Gradient Program:

[0238] Method A5

[0239] - For acidic elution (Method A6), analyses are performed using a Shimadzu LC-MS 201 OEV mass spectrometer for LC-MS analysis. This spectrometer is equipped with an ESI source and HPLC with diode array detector (210 to 400 nm). Data is acquired in a full MS scan from m / z 80 to 2000 in positive mode and negative mode. The reverse phase separation is carried out with Waters X-Select CSH C18 (4.6 x 150) mm, 3.5 pm column. Column temp: 50°C. Gradient elution is done with Mobile phase with 0.1 % TFA in water (Phase A) and Acetonitrile (Phase B). Injection volume: 2 pL.

[0240] Gradient Program:

[0241] Method A6

[0242] - For acid elution (Method A7), analyses are performed using an Agilent 1200-6120 LC-MS system coupled to UV detection (254 nM) and MS Detection: Agilent 6120 Mass Spectrometer (ES) m / z 100 to 1000. Column: XSelect CSH C18 XP 130A, 2.5 pm, 4.6 mm X 30 mm (Waters™). Mobile Phase A: 0.1% Formic acid in water, Mobile Phase B: Acetonitrile + 0.1 % Formic acid. Flow rate: 2.5 mL / min.

[0243] Gradient Program:

[0244] Method A7

[0245] - For acid elution (Method A9), analyses are performed using similar equipments as above, but the reverse phase separation is carried out with a Waters Cortecs C18 2.7 pm (30 x 2.1 mm) column. Column temp: 40°C. 1 .5 min gradient elution is done with Mobile phase with 0.1 % formic acid in water (Phase A) and ACN (Phase B).

[0246] - For basic elution (Method B1, B1_S and B2), analyses are performed using a QDA Waters simple quadrupole mass spectrometer. This spectrometer is equipped with an ESI source and a UPLC Acquity Hclass with diode array detector (200 to 400 nm). Data are acquired in a full MS scan from m / z 70 to 800 in positive mode. The reverse phase separation is carried out at 45°C on a Waters Acquity UPLC BEHC18 1 .7 pm (2.1 x 50 mm) column for Method B1 and B1_S and on a Waters Acquity UPLC BEH C18 1 .7pm (2.1x100 mm) column basic elution for Method B2. Gradient elution is performed with water / ACN / ammonium formate (95 / 5 / 63 mg / L) (solvent A) and ACN / water / ammonium formate (95 / 5 / 63 mg / L) (solvent B). Injection volume: 1 pL. Full flow in MS. Gradient Program:

[0247] Method B1_S

[0248] Method B2

[0249] - For Basic elution (Method B3) analysis are performed using a Xevo Waters Q-TOF mass spectrometer. This spectrometer is equipped with an ESI source and a Waters Acquity H-class UPLC with diode array detector (210 to 400 nm). Data are acquired in a full MS scan from m / z 50 to 1200 in positive mode. The reverse phase separation is carried out at 45°C on an Acquity UPLC BEH C18 column (1.7pm, 2.1 x 100 mm). Gradient elution is done with Water / ACN / Ammonium formate (95 / 5 / (40mg / L ammonium bicarbonate + 1 OOpL / L NH4OH)) (Solvent A) and ACN (Solvent B) pH~8-9. 100% Flow in UV,10 % flow in MS. 90 % Flow in ELSD injection volume: 0.2 to 2 pL.

[0250] Gradient Program:

[0251] Method B3

[0252] - For basic elution (Method B4 and B8) analysis are performed using a SYNAPT G2-SI system and Waters Q-TOF mass spectrometer for Method A4 and on a SQD2 Waters single quadrupole for Method B8. These spectrometer is equipped with an ESI source and a Waters Acquity H-class UPLC with diode array detector (210 to 400 nm). Data are acquired in a full MS scan from m / z 50 to 1200 in positive mode. The reverse phase separation is carried out at 45°C on an Acquity UPLC BEH C18 column (1.7pm, 2.1 x 100 mm). Gradient elution is done with water / ACN / ammonium formate (95 / 5 / (63 mg / L+ 100pL / L NH4OH)) (solvent A) and ACN (solvent B), at pH- 8-9. Full flow in MS. injection volume: 0.5 pL.

[0253] Gradient Program:

[0254] Method B4, B8

[0255] - For basic elution (Method B5 and B5”), analyses are performed using an Agilent 1200-6120 LC-MS system coupled to UV detection (254 nM) and a MS Detection Agilent 6120 Mass Spectrometer (ES) m / z 100 to 1000. The reverse phase separation is carried out at 45°C on a XBridge BEH C18 XP Column, 130A, 2.5 pm, 4.6 mm X 30 mm (Waters™). Column temp: 40°C. Flow rate: 2.5 mL / min. Gradient elution is done with Mobile phase Acetonitrile / 10 mM aqueous ammonium bicarbonate (Phase A) and Acetonitrile (Phase B) for method B5 and Mobile Phase A: 0.1 % Ammonia in water, Mobile Phase B: Acetonitrile for method B5’.

[0256] Gradient Program:

[0257] Method B5, B5’

[0258] - For Basic elution (Method B6), analyses are performed using a Shimadzu LC-MS 201 OEV mass spectrometer. This spectrometer is equipped with an ESI source and HPLC with diode array detector (210 to 400 nm). Data is acquired in a full MS scan from m / z 80 to 2000 in positive mode and negative mode. The reverse phase separation is carried out with Waters X-Select CSH C18 (4.6 x 150) mm, 3.5 pm column. Column temp: 50°C. Gradient elution is done with Mobile phase: 10 mM ammonium bicarbonate in Water (Phase A) and acetonitrile (Phase B). Injection volume: 2 pL.

[0259] Gradient Program:

[0260] Method B6

[0261] - For Basic elution (Method B7), analyses are performed using a Shimadzu LC-MS 201 OEV mass spectrometer. This spectrometer is equipped with an ESI source and HPLC with diode array detector (210 to 400 nm). Data is acquired in a full MS scan from m / z 80 to 2000 in positive mode and negative mode. The reverse phase separation is carried out with Waters X-Bridge C18 (4.6 x 150) mm, 5 pm column. Column temp: 50°C. Gradient elution is done with Mobile phase 0.1 % Ammonia in Water (Phase A) and Acetonitrile (Phase B). Injection volume: 5 pL. Gradient Program:

[0262] Method B7

[0263] - For Basic elution (Method B9), analyses are performed using an Agilent 1200 series LC in tandem with a 6140 mass spectrometer. The reverse phase separation is carried out with a Phenomenex Gemini NX-C18 3 pM (2 x 20 mm), flow rate 1 .0 mL / min, column temperature 40°C, eluting with a 5-95% gradient over 6.0 minutes (solvent A: 10 mM ammonium formate in water + 0.1 % ammonia solution, solvent B: ACN + 5% water + 0.1 % ammonia solution).

[0264] - For Basic elution (Method B1O), analyses are performed using an Agilent 1290 Infinity II LC in tandem with a 6135 MSD XT mass spectrometer. The reverse phase separation is carried out with an Acquity UPLC BEH C18 2.1 x 50 mm, 1.7 pM, flow rate 1.5 mL / min , 60°C column temperature, eluting with a 5-95% gradient over 4.5 minutes (solvent A - 10 mM ammonium formate in water + 0.1 % Ammonia solution, solvent B - ACN + 5% water + 0.1 % ammonia solution).

[0265] Analytical chiral LC-MS were all performed at 30°C on 4.6 x 150 mm columns with a flow rate of 1.5mL / min except for Chiralpak IG-u (Daicel) column which dimension is 3 x 100 mm and the flow rate is 0.425 mL / min. All columns display a granulometry of 3 pm except for WhelkO-1 (R,R) (Regis Technology) which is 3.5 pm and Chiralpak IG-u (Daicel) which is sub-2 pm.

[0266] High Resolution Mass spectrometric measurements in LC-MS mode are performed as follows:

[0267] Method HRMS_A1 : A SYNAPT G2-SI Waters Q-TOF mass spectrometer is used for QC analysis. This spectrometer is equipped with an ESI source and a Waters Acquity H-class UPLC with diode array detector (210 to 400 nm). Data are acquired in a full MS scan from m / z 50 to 1200 in positive mode. The reverse phase separation is carried out at 45°C on an Acquity UPLC BEH C18 column (1.7 pm, 2.1 x 30 mm). Gradient elution is done with Water / ACN / Formic acid (95 / 5 / (750 pL / L)) (Solvent C) and Water / ACN / Formic acid (5 / 95 / (500 pL / L)) (Solvent D) at pH ~ 3. Full flow in MS. injection volume: 0.5 to 1 pL.

[0268] Method HRMS_A2: analysis are performed using a Xevo Waters Q-TOF mass spectrometer. This spectrometer is equipped with an ESI source and a Waters Acquity H-class UPLC with diode array detector (210 to 400 nm). Data are acquired in a full MS scan from m / z 50 to 1200 in positive mode. The reverse phase separation is carried out at 40°C on an Acquity UPLC HSS T3 C18 column (1.8|jm, 2.1 x 50 mm). Gradient elution is done with Water / ACN / Formic acid (95 / 5 / 750pL / L) (Solvent C) and Water / ACN / Formic acid (5 / 95 / 500pL / L) (Solvent D) at pH~3. 100% Flow in UV, 10 % flow in MS-, 90 % flow in ELSD. Injection volume: 0.5 to 1 pL.

[0269] Method HRMS_A1

[0270] Method HRMS_A2

[0271] Preparative HPLC purifications are performed using SQD Waters or QDa Performance single quadrupole mass spectrometer. This spectrometer is equipped with an ESI source, Waters 2525 binary pump coupled with 2767 sample Manager and with diode array detector (210 to 400 nm). Data are acquired in a full MS scan from m / z 100 to 850 in positive and negative modes. LC parameters: The reverse phase separation is carried out at room temperature on a Waters XBridge OBD MS C18 column (5 pm, 30 x 50 mm). Typical HPLC flow rate from 35 mL / min to 45 mL / min. Typical example of basic elution: gradient from solvent A (H2O + 10mM NH4HCO3 + 50 pL / L NH4OH) and solvent B (100% acetonitrile) [Purification Method P_B]. Typical example of acidic elution: gradient from solvent A (H2O / TFA: 99.5% / 0.5%) and solvent B (ACN / TFA: 99.5% / 0.5%) [Purification Method P_A],

[0272] Some preparative HPLC purifications are performed using a Gilson Modular System (333 Prep- Scale HPLC Pump (Water), 334 Presp-Scale HPLC Pump (Acetonitrile), 334 Presp-Scale HPLC Pump (Modifier: a solution of 5 mL NH4OH in 1000 mL of H2O for basic elution [Purification Method G_B]. or a solution of 20 mL TFA in 1000 mL H2O [Purification Method G_A]), 171 Diode Array Detector, GX-271 Prep Liquid Handler, PrepFC Fraction Collector) equipped with a YMC Triart - 500g -10pm - 76,5 x 200mm column. Typical HPLC flow rate is 180 mL / min. When analytical methods are not specified in the below protocols, the methods used were similar to the ones described above. It will be apparent to the person skilled in the art that there are analytical and preparative chromatographic methods analogues to the ones described above can be use for the below procedures.

[0273] III. INTERMEDIATES Intermediate 1 : 2-fluoro-6-(1 -fluorocvclopropyl)-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- vhpyridin-4 -amine

[0274] Step 1: Synthesis of 2-bromo-6-fluoro-pyridin-4-amine 11_ 1

[0275] Cesium fluoride (3.65 g, 23.8 mmol) was added to a solution of 2,6-dibromopyridin-4-amine (2.00 g, 7.78 mmol) in dry DMSO (30 mL) at room temperature. The reaction mixture was stirred for 18 h at 140 °C. After completion, the reaction mixture was cooled down with ice (100 g) and diluted with water (250 mL) then extracted three times with ethyl acetate (100 mL). The combined organic layers were washed two times with brine (100 mL), dried over Na2SO4, filtered, and concentrated to dryness to afford a brown solid. The solution was concentrated under vacuum and the residue was purified by column chromatography on silica gel (using a gradient of 0 to 25% MeOH in DCM) to afford the title compound (773 mg, yield: 28%) as a white solid. LC-MS (Method B4) m / z: [M+H]+: 191 / 193; rt: 0.92 min; purity: 100%.1H NMR (400 MHz, DMSO-cfe) 5 6.78 (s, 2H), 6.61 (t, J = 1.6 Hz, 1 H), 6.08 (d, J = 1 .6 Hz, 1 H).19F NMR (376 MHz, DMSO-cfe) 5 -71 .05.

[0276] Step 2: Synthesis of tert-butyl N-(2-bromo-6-fluoro-4-pyridyl)-N-tert-butoxycarbonyl-carbamate

[0277] 11 2 i Boc

[0278] To a solution of Intermediate I1_1 (700 mg, 3.40 mmol) and di-tert-butyl decarbonate (2.30 g, 10 mmol) in THF (30 mL) was added 4-dimethylaminopyridine (43 mg, 0,35 mmol). The resulting mixture was stirred at room temperature for 16 h. After completion, water was added, and the reaction mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness afford an orange oil. The residue was purified by column chromatography on silica gel (using a gradient of 0 to 20% EtOAc in heptane over 10 CV) to afford the title compound (1.13 g, yield: 78%) as a white solid.

[0279] LC-MS (Method A1_S) m / z: [M+H]+: 391 / 393; rt: 1 .70 min; purity: 98%.1H NMR (400 MHz, DMSO- d6) 6 7.72 (s, 1 H), 7.38 (s, 1 H), 1 .42 (s, 18H).

[0280] Step 3: Synthesis of tert-butyl N-tert-butoxycarbonyl-N-[2-fluoro-6-( 1-fluorocyclopropyl)-4- pyridyl]carbamate I1_3

[0281] F

[0282] To a 30 mL screw capped vial, equipped with a stir bar, tert-butyl N-(2-bromo-6-fluoro-4-pyridyl)- N-tert-butoxycarbonyl-carbamate I1_2 (1.30 g, 3.32 mmol), tetrakis(triphenylphosphine)palladium(0) (390 mg, 0.33 mmol) and cesium fluoride (2.53 g, 16.6 mmol) were added. The vial was evacuated and backfilled with Ar (3x) while heating with a heat gun. Dry copper(l) chloride (680 mg, 6.66 mmol) was added and the mixture was again evacuated and backfilled with Ar (3x). Finally, a solution of tributyl-(1-fluorocyclopropyl)stannane (Adv. Synth. Catal. 2024, doi.org / 10.1002 / adsc.202400401, 1 .21 g, 3.32 mmol) in dry, degassed THF (16 mL) was added quickly. The resulting mixture was stirred at 60 °C for 15 h. The mixture was filtered over silica, washing with DCM. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (using a gradient of 1 to 15% EtOAc in heptane as eluent) to give the title compound (652 mg, yield: 53%) as a yellow oil. LC-MS (Method A1_S) m / z: [M+H]+: 371.2; rt: 1.73 min; purity: 93.1 %.1H NMR (500 MHz, CDCI3) 5 7.29 (s, 1 H), 6.63 (s, 1 H), 1.49 (s, 18H), 1.47 - 1.41 (m, 4H).19F NMR (471 MHz, CDCh) 6 -67.30 (d, J = 4.4 Hz, 1 F), -193.91

[0283] - -194.12 (m, 1 F).

[0284] Step 4: Synthesis of 2-fluoro-6-( 1-fluorocyclopropyl)pyndin-4-amine 11_4

[0285] To a solution of tert-butyl N-tert-butoxycarbonyl-N-[2-fluoro-6-(1-fluorocyclopropyl)-4- pyridyl]carbamate 11_3 (635 mg, 1 .71 mmol) in THF (2 mL) was added phosphoric acid (85% w / w in water, 1.20 mL, 18.0 mmol). The mixture was stirred at room temperature for 17 h and then sonicated at room temperature for 5 h. The reaction mixture was diluted with water and neutralized to pH 7-8 with 1 M aqueous NaOH solution. The aqueous layer was extracted three times with EtOAc. The combined organic phases were washed with water (2x), brine (1x), and dried over

[0286] Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (using a gradient of 0 to 100% EtOAc in heptane as eluent) to give the title compound (253 mg, yield: 87%) as a white solid. LC-MS (Method A1_S) m / z: [M+H]+: 171.1 ; rt: 1.06 min; purity: 94.8%.1H NMR (500 MHz, CDCh) 6 6.74 (q, J = 1.8 Hz, 1 H), 5.94 (d, J = 1.8 Hz, 1 H), 4.37 (s, 2H), 1 .43 - 1 .39 (m, 2H), 1 .38 (s, 2H).19F NMR (471 MHz, CDCh) 6 -70.28 (d, J = 4.5 Hz, 1 F), -192.69 - -193.15 (m, 1 F).

[0287] Step 5: Synthesis of 2-fluoro-6-(1-fluorocyclopropyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridin-4-amine 11

[0288] A 30 mL screw cap reaction tube, evacuated and backfilled with argon (3x), was charged with 2- fluoro-6-(1-fluorocyclopropyl)pyridin-4-amine I1_4 (251 mg, 1.48 mmol) and bis(pinacolato)diboron (750 mg, 2.92 mmol) in THF (15 mL) at room temperature. The mixture was stirred at room temperature for 30 min then sparged with argon for 5 min. 4,4'-di-tert-butyl-2,2'-dipyridyl (40 mg, 0.15 mmol) followed by (1 ,5-cyclooctadiene)(methoxy)iridium(l) dimer (49 mg, 0.07 mmol) were added and the reaction tube was sealed with a screw cap. The mixture was heated to 80 °C for 5 h. After completion, the reaction mixture was allowed to return to room temperature and was carefully poured in methanol (10 mL) at -45 °C. The obtained solution was concentrated in vacuo. The residue was filtered over a silica plug, washing with a 1 :1 Heptane / EtOAc solution. The resulting filtrate was concentrated in vacuo to + / -5 mL of volume. The product crystallized from the solution. After cooling overnight in the fridge (3 °C), the supernatant was decanted off. The solid was washed with 3 mL of heptane (at 3 °C) and dried in the vacuum drying oven (at 45 °C) to give the title compound (431 mg, yield: 83%, purity: 84% w / w) as an off-white solid. LC-MS (Method A2) m / z: mixture of expected product [M+H]+: 297.3; rt: 4.89 min and corresponding boronic acid [M+H]+: 215.1 ; rt: 3.13 min; global purity: 80.6%. LC-MS (Method B2) m / z: mixture of expected product [M+H]+: 297.4; rt: 4.60 min and corresponding boronic acid [M+H]+: 215.1 ; rt: 2.94 min; global purity: 94.0%.1H NMR (500 MHz, CDCh) 6 6.63 (t, J = 1 .8 Hz, 1 H), 5.62 (s, 2H), 1 .43 - 1 .37 (m, 4H), 1.36 (s, 12H).19F NMR (471 MHz, CDCh) 6 -57.58 (s, 1 F), -192.91 - -193.67 (m, 1 F).

[0289] Intermediate I2: 2-(1-fluorocvclopropyl)pyridin-4-amine

[0290] Step 1 : Synthesis of 1 -fluorocyclopropanecarbonyl chloride I2_ 1

[0291] Oxalyl chloride (3.86 mL, 45.0 mmol) was added to a solution of 1 -fluorocyclopropanecarboxylic acid (4.68 g, 45.0 mmol) and DMF (0.100 mL, 1 .30 mmol) in DCM (100 mL) at 0 °C and the reaction mixture was stirred at RT for 3 h. The solution was concentrated under reduced pressure to afford the title compound as a colourless oil (6.14 g). The product was used in the next step without further purification.

[0292] Step 2: Synthesis of (1Z,4E)-1-(1-fluorocyclopropyl)-1-hydroxy-5-methoxy-penta-1,4-dien-3-one I2_2

[0293] To a solution of (E)-4-methoxybut-3-en-2-one (10.0 g, 90.2 mmol) in THF (120 mL) at -70°C was added dropwise a solution of LiHMDS 1 M in THF (90.2 mL, 90.2 mmol). The resulting red solution was stirred at -70 °C for 20 min then a solution of 1 -fluorocyclopropanecarbonyl chloride I2_1 (6.14 g, 45.1 mmol) in THF (80 mL) was added over 20 min. The resulting solution was stirred at -70 °C for 1 h then let warmed at RT overnight. A saturated aqueous solution of NH4CI (250 mL) was added and was extracted with EtOAc (3x200 mL). The combined organic extracts were washed with brine (250 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound as a red oil (11.5 g, yield: quant.). LC-MS m / z [M+H]+: 187.1 ; purity: 73%.

[0294] Step 3: Synthesis of 2-( 1-fluorocyclopropyl)pyran-4-one I2_3

[0295] .o ' JFo

[0296] TFA (10.3 g, 90.2 mmol) was added to a solution of (1Z,4E)-1-(1-fluorocyclopropyl)-1-hydroxy-5- methoxy-penta-1 ,4-dien-3-one I2_2 (73%, 11.5 g, 45 mmol) in DCM (60 mL). The solution was stirred at RT for 2 h then concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (using a gradient of 0-100% EtOAc in isohexane as eluent) to afford the title compound as a red solid (2.44 g, yield: 32%). LC-MS m / z [M+H]+: 155.0; purity: 98%.1H NMR (400 MHz, DMSO-cfe) 6 8.10 (d, J = 5.8 Hz, 1 H), 6.39 (dd, J = 2.6, 1.5 Hz, 1 H), 6.29 (dd, J = 5.8, 2.5 Hz, 1 H), 1 .60 - 1 .50 (m, 2H), 1 .40 - 1 .32 (m, 2H); purity: 90%.

[0297] Step 4: Synthesis of 2-(1-fluorocyclopropyl)-1 H-pyridin-4-one I2_4

[0298] A solution of 2-(1-fluorocyclopropyl)pyran-4-one I2_3 (2.44 g, 14.2 mmol) and aqueous NH4OH (35%, 27 mL, 243 mmol) was heated at 50 °C for 1 h then concentrated under reduced pressure to afford the title compound as a red gum (2.35 g, yield: 100%). LC-MS m / z [M+H]+: 154.2; purity: 98%.

[0299] Step 5: Synthesis of 4-bromo-2-(1-fluorocyclopropyl)pyndine I2_5

[0300] A mixture of 2-(1-fluorocyclopropyl)pyridin-4-ol I2_4 (2.35 g, 14.3 mmol) and POBrs (4.5 g, 15.7 mmol) was heated at 120 °C for 1 h then cooled to RT. A saturated aqueous solution of NaHCOs (200 mL) was added and was extracted with EtOAc (3x100 mL). The combined organic extracts were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (using a gradient of 0- 100% EtOAc in isohexane as eluent) to afford the title compound as a pale beige solid (1.97 g, yield: 64%).1H NMR (400 MHz, DMSO-cfc) 5 8.40 (dd, J = 5.3, 1.2 Hz, 1 H), 7.77 (t, J = 1.8 Hz, 1 H), 7.59 (dd, J = 5.3, 1 .9 Hz, 1 H), 1 .60 - 1 .54 (m, 1 H), 1 .54 - 1 .49 (m, 1 H), 1 .38 - 1 .35 (m, 1 H), 1 .35 - 1.31 (m, 1 H); purity: 100%.

[0301] Step 6: Synthesis of tert-butyl N-[2-(1-fluorocyclopropyl)-4-pyridyl]carbamate I2_6

[0302] A suspension of 4-bromo-2-(1-fluorocyclopropyl)pyridine I2_5 (1.86 g, 8.61 mmol), tert-butyl carbamate (2.02 g, 17.2 mmol), CS2CO3 (5.61 g, 17.2 mmol) and XPhos Pd(crotyl)CI (290 mg, 0.430 mmol) in 1 ,4-dioxane (79 mL) was refluxed under N2 overnight then cooled to rt. More tertbutyl carbamate (500 mg), CS2CO3 (1 .80 g) and XPhos Pd(crotyl)CI (100 mg) were added and the reaction mixture was again refluxed overnight then cooled to RT. The suspension was filtered on a pad of celite and washed with EtOAc (150 mL). The filtrate was concentrated under reduced pressure, and the crude was purified by column chromatography on silica gel (using a gradient of 0-50% EtOAc in isohexane as eluent) to afford the title compound as an orange solid (2.07 g, yield: 65%). LC-MS m / z [M+H]+: 253.2; purity: 98%.1H NMR (400 MHz, DMSO-cfc) 6 9.91 (s, 1 H), 8.25 (dd, J = 5.6, 1 .2 Hz, 1 H), 7.74 (t, J = 2.0 Hz, 1 H), 7.30 (dd, J = 5.6, 2.1 Hz, 1 H), 1 .49 (s, 9H), 1 .47 - 1 .44 (m, 1 H), 1 .42 (q, J = 5.0 Hz, 1 H), 1 .32 - 1 .29 (m, 1 H), 1 .29 - 1 .25 (m, 1 H); purity: 68%.

[0303] Step 7: Synthesis of 2-( 1-fluorocyclopropyl)pyridin-4-amine 12

[0304] A suspension of tert-butyl N-[2-(1-fluorocyclopropyl)-4-pyridyl]carbamate I2_6 (68%, 2.07 g, 5.58 mmol) in 4 M HCI in 1 ,4-dioxane (27.9 mL, 112 mmol) and 1 ,4-dioxane (27.7 mL) was stirred at RT overnight. The resulting suspension was filtered, and the precipitate was washed with TBME (100 mL) then dried under reduced pressure. The resulting solid was dissolved in MeOH (15 mL) and loaded on a SCX column (20 g). The column was eluted first with MeOH (100 mL) which was discarded then with 0.7 M NH3 in MeOH (100 mL). The filtrate was concentrated to afford the title compound as a pale beige solid (730 mg, yield: 85%). LC-MS m / z [M+H]+: 153.2; purity: 99%.1H NMR (400 MHz, DMSO-cfc) 6 7.87 (d, J = 5.6 Hz, 1 H), 6.72 (t, J = 2.2 Hz, 1 H), 6.32 (ddd, J = 5.5, 2.3, 0.9 Hz, 1 H), 6.11 (s, 2H), 1 .39 - 1 .34 (m, 1 H), 1 .34 - 1 .29 (m, 1 H), 1 .28 - 1 .18 (m, 2H).

[0305] Intermediate I3: N-(4-acetylphenyl)-2-chloro-acetamide

[0306] To a solution of 1-(4-aminophenyl)ethanone (2.0 g, 14.6 mmol) and triethylamine (2.5 mL, 18 mmol) in dry DCM (14.6 mL) was added dropwise at 0 °C chloroacetyl chloride (1.4 mL, 18 mmol). The resulting mixture was slowly warmed to room temperature and stirred at room temperature for 18 h. The reaction mixture was quenched by addition of water and extracted with DCM The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (using a gradient of 0 to 100% EtOAc in Heptane as eluent) to afford the title compound (2.65 g, yield: 86%) as a beige solid. LC-MS (Method B1_S) m / z: [M+H]+: 212.0; rt: 0.93 min; purity: 100%.1H NMR (400 MHz, DMSO-d6) 6 10.61 (s, 1 H), 7.95 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 4.30 (s, 2H), 2.53 (s, 3H). Intermediate 14: ethyl 2-(3-bromo-2-pyridyl)propanoate

[0307] Step 1: Synthesis of ethyl 2-(3-bromo-2-pyridyl)acetate I4_ 1

[0308] At -78 °C, to a solution of 3-bromo-2-methyl-pyridine (5.00 g, 29.1 mmol) in dry THF (100 mL) was added LiHMDS (1 M solution in THF, 58 mL, 58.0 mmol) and the reaction mixture was stirred at 0 °C for 1 h. Diethyl carbonate (5.15 g, 43.6 mmol) was added at 0 °C and the reaction mixture was stirred at room temperature for 15 min. The reaction mixture was treated with H2O (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. Purification by column chromatography on silica gel (using DCM as eluent) afforded the title compound (5.00 g, yield: 71 %) as a brown oil. LC-MS (Method B6): [M+H]+m / z: 243.8, rt: 1.71 min, purity: 94%.1H NMR (400 MHz, DMSO-cfc) 5 1.18 (t, J = 6.8 Hz, 3H), 3.98 (s, 2H), 4.11 (q, J = 6.8 Hz, 2H), 7.27-7.30 (m, 1 H), 8.08 (d, J = 8.4 Hz, 1 H), 8.50 (d, J = 4.4 Hz, 1 H).

[0309] Step 2: Synthesis of ethyl 2-(3-bromo-2-pyridyl)propanoate 14

[0310] Ethyl 2-(3-bromo-2-pyridyl)acetate (Intermediate I4_1 , 30.0 g, 117 mmol) was dissolved in dry THF (400 mL) and cooled to 0 °C. A 1 M solution of lithium bis(trimethylsilyl)amide in THF (134 mL, 134 mmol) was added dropwise and stirred for 30 min. lodomethane (21.5 g, 152 mmol) was added and the reaction mixture was stirred for a further 1 h at 0 °C. The solution was concentrated under vacuum and the residue was purified by flash chromatography on silica gel (using a gradient of 0 to 60% MTBE in iso-hexane as eluent) to afford the title compound (29.5 g, yield: 96%) as a lightyellow oil. LC-MS (Method A7) m / z: [M+H]+: 258 / 260; rt: 1 .93 min; purity: 99%.1H NMR (400 MHz, CDCh) 5 8.51 (dd, J = 4.6, 1.5 Hz, 1 H), 7.85 (dd, J = 8.0, 1.5 Hz, 1 H), 7.06 (dd, J = 8.0, 4.6 Hz, 1 H), 4.36 (q, J = 7.1 Hz, 1 H), 4.17 (q, J = 7.1 Hz, 2H), 1 .55 (d, J = 7.1 Hz, 3H), 1 .20 (t, J = 7.1 Hz, 3H) Intermediate I5: 3-fluoro-5, 10,14-trimethyl-4, 8,12-triazatricvclof9.4.0.027lpentadeca-

[0311] 1 (11 ), 2(7), 3, 5,12,14-hexaen-9-one

[0312] Step 1: Synthesis of 01 -tert-butyl 03-ethyl 2-(3-bromo-5-methyl-2-pyridyl)propanedioate I5_1

[0313] To a solution of 3-bromo-2-fluoro-5-methylpyridine (2.00 g, 10.3 mmol) and tert-butyl ethyl malonate (3.91 mL, 20.6 mmol) in dry DMSO (20 mL) was added at room temperature cesium carbonate (6.79 g, 20.6 mmol). The resulting mixture was stirred at 100 °C for 18 h. Water was added and the reaction mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (using a gradient of 0 to 50% EtOAc in heptane as eluent) to give the title compound (1 .14 g, yield: 29%) as a yellow oil. LC-MS (Method A1_S) m / z: [M+H]+: 358.1 / 360.1 ; rt: 1.58 min; purity: 95.0%.1H NMR (500 MHz, DMSO-cfe) 6 8.39 - 8.36 (m, 1 H), 8.00 - 7.97 (m, 1 H), 4.98 (s, 1 H), 4.22 - 4.14 (m, 2H), 2.31 (s, 3H), 1.42 (s, 9H), 1.19 (t, J = 7.1 Hz, 3H).

[0314] Step 2: Synthesis of ethyl 2-(3-bromo-5-methyl-2-pyridyl)acetate I5_2

[0315] To a solution of 01 -tert-butyl 03-ethyl 2-(3-bromo-5-methyl-2-pyridyl)propanedioate I5_1 (1.14 g, 3.02 mmol) in dry DCM (12.1 mL) was added at room temperature trifluoroacetic acid (4.63 mL, 60.4 mmol). The resulting mixture was stirred at room temperature for 5 h. After completion, the reaction was quenched with ice water, carefully neutralized to pH 7 with saturated aqueous NaHCOs solution and extracted with DCM (3x, using a phase separator). The combined organic layers were concentrated under vacuum to give the title compound (610 mg, yield: 78%) as a yellow oil. LC-MS (Method A1_S) m / z: [M+H]+: 258.0 / 260.0; rt: 1 .28 min; purity: 98.1 %.1H NMR (400 MHz, DMSO-cfe) 5 8.36 - 8.33 (m, 1 H), 7.94 - 7.92 (m, 1 H), 4.10 (q, J = 7.1 Hz, 2H), 3.93 (s, 2H), 2.29 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H). Step 3: Synthesis of ethyl 2-(3-bromo-5-methyl-2-pyridyl)propanoate I5_3

[0316] Under N2 atmosphere, to a solution of lithium diisopropylamide (1 M in THF / Hexanes, 2.72 mL, 2.72 mmol) in dry THF (9.5 mL) at -78 °C was added a solution of ethyl 2-(3-bromo-5-methyl-2- pyridyl)acetate I5_2 (610 mg, 2.36 mmol) in dry THF (2.4 mL). The resulting mixture was stirred at -78 °C for 30 min before addition of iodomethane (223 pL, 3.55 mmol). The resulting mixture was stirred at room temperature for 17 h. After completion, the reaction was quenched with saturated aqueous NH4CI solution and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (using a gradient of 0 to 40% EtOAc in heptane as eluent) to give the title compound (410 mg, yield: 64%) as a yellow oil. LC-MS (Method A1_S) m / z: [M+H]+: 272.1 / 274.0; it 1 .40 min; purity: 100%.1H NMR (500 MHz, DMSO) 5 8.35 (d, J = 1 .5 Hz, 1 H), 7.93 (d, J = 1.5 Hz, 1 H), 4.24 (q, J = 7.1 Hz, 1 H), 4.06 (qt, J = 7.1 , 3.7 Hz, 2H), 2.28 (s, 3H), 1.38 (d, J = 7.1 Hz, 3H), 1 .11 (t, J = 7.1 Hz, 3H).

[0317] Step 4: Synthesis of 3-fluoro-5, 10, 14-trimethyl-4,8, 12-triazatricyclo[9.4.0.027]pentadeca- 1(11), 2(7), 3, 5, 12, 14-hexaen-9-one 15

[0318] BrettPhos Pd G3 (94 mg, 0.10 mmol) and BrettPhos (112 mg, 0.20 mmol) were added to a degassed solution of 2-fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-4- amine I6 (129 mg, 0.51 mmol), ethyl 2-(3-bromo-5-methyl-2-pyridyl)propanoate I5_3 (139 mg, 0.51 mmol), potassium carbonate (143 mg, 1.02 mmol) in acetonitrile (5 mL) and water (0.1 mL). The reaction mixture was then heated at 80 °C under Argon for 5 h. After completion, the reaction mixture was diluted in ethyl acetate (100 mL) and acetonitrile (100 mL), dried over Na2SO4 and filtered through Celite. The filtrate was concentrated under vacuum. The residue was dissolved in THF (5 mL) and lithium bis(trimethylsilyl)amide (1.5 M in THF, 0.34 mL, 0.51 mmol) was added at 0 °C. The reaction mixture was slowly allowed to warm to room temperature and stirred at room temperature for 4 h. After completion, the reaction was quenched with saturated aqueous NH4CI solution (10 mL) and diluted in ethyl acetate (50 mL) and water (50 mL). The aqueous phase was extracted with ethyl acetate (3x40 mL) and the combined organics were washed with water (50 mL) and brine (50 mL). The combined extracts were dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (using a gradient of 0 to 100% EtOAc in heptane as eluent) to give the title compound (30 mg, yield: 16%) as a white solid. LC-MS (Method A1_S) m / z: [M+H]+: 272.1 ; it 0.98 min; purity: 73%.1H NMR (500 MHz, DMSO-cfe) 6 10.84 (s, 1 H), 8.56 (d, J = 2.4 Hz, 1 H), 7.98 - 7.93 (m, 1 H), 7.05 (s, 1 H), 3.62 (q, J = 6.7 Hz, 1 H), 2.52 (s, 3H), 2.42 (s, 3H), 1.53 (d, J = 6.7 Hz, 3H).19F NMR (471 MHz, DMSO-cfe) 6 - 70.36.

[0319] Intermediate 16: 2-fluoro-6-methyl-3-(4,4.5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-4- amine

[0320] Step 1: Synthesis of dimethyl 2-(4-amino-3,5-dichloro-6-fluoro-2-pyridyl)propanedioate I6_1

[0321] To a mixture of 4-amino-3,5-dichloro-2,6-difluoropyridine (402.2 g, 2021 mmol), dimethyl malonate (470 mL, 4030 mmol) and N,N-dimethylformamide (2.4 L) (colorless solution) was added potassium carbonate (830 g, 6005 mmol) (white suspension). The mixture was heated to 65 °C (internal temperature) for 19 hours. The mixture was cooled to ambient temperature and poured into mechanically stirred water (6 L). The solid was recovered on a sinter, washed with water (2 L) and dried. Trituration with TBME (2 L) and washing with isohexane (1.5 L) gave the title product (529 g, 84 %) as a white crystalline solid.1H NMR (300 MHz, DMSO) 5 7.24 (s, 2H), 5.20 (s, 1 H), 3.71 (s, 6H).19F NMR (282 MHz, DMSO) 5 -75.10. LC / MS (method B9) m / z (ES): 310.8, 312.8, 314.8 (M+H).

[0322] Step 2: Synthesis of 3,5-dichloro-2-fluoro-6-methyl-pyridin-4-amine I6_2

[0323] To dimethyl 2-(4-amino-3,5-dichloro-6-fluoro-2-pyridyl)propanedioate (Intermediate I6_1 , 370 g, 1190 mmol) and calcium chloride hexahydrate (780 g, 3560 mmol) was added 1-methyl-2- pyrrolidinone (1.5 L). The suspension was heated to 100 °C to give a solution. After 20 hours, analysis by LCMS showed 87% conversion to mono-ester. The temperature was increased to 125 °C. After 72 hours, analysis by LCMS showed complete conversion. The mixture was cooled to 25 °C and poured into mechanically stirred water (2.5 L). The precipitate was recovered on a sinter, washed with water (1 L) and partially dried. The wet solid was suspended in ethanol (3 L) and heated to 65 °C to give a cloudy solution. Activated charcoal (30 g) was added and heating continued. After 15 minutes, the warm mixture was filtered through Celite. To the filtrate was added water (3 L, to give 1 :1 ethanol :water). The mixture was then cooled to 5 °C for 20 hours. The crystals were recovered on a sinter, washed with water (600 mL) and dried (Note: solid is slightly volatile if dried at 50 °C at ~2 mbar) to give the title product as an off-white solid (179 g, 77%).1H NMR (300 MHz, DMSO) 5 6.94 (s, 2H), 2.35 (d, J = 0.6 Hz, 3H).19F NMR (282 MHz, DMSO) 5 - 76.01. LC / MS (method B9) m / z (ES): 194.8, 196.8, 198.8 (M+H), rt: 1.38 min, 100% purity.

[0324] Step 3: Preparation of 2-fluoro-6-methyl-pyridin-4-amine I6_3

[0325] 3,5-dichloro-2-fluoro-6-methyl-pyridin-4-amine (Intermediate I6_2, 150 g, 769 mmol) and 5% palladium on charcoal (49 g, 23 mmol) were solubilized in methanol (2.6 L) and pyridine (125 mL). The mixture was placed under a 1 bar hydrogen atmosphere and heated to 50 °C for 18 hours. The mixture was then cooled, filtered through Celite and concentrated under reduced pressure. Water (750 mL) was added to the residue and the solution was extracted with ethyl acetate (3 x 750 mL). The organics were washed with brine (500 mL), dried over MgSO4 filtered and concentrated under reduced pressure to give the title product as a white solid (93 g, 91 %).1H NMR (400 MHz, DMSO) 5 6.30 (s, 2H), 6.24 (s, 1 H), 5.85 (s, 1 H), 2.17 (t, J = 1 .5 Hz, 3H).19F NMR (376 MHz, DMSO) 5 - 71.85. LC / MS (method B2) m / z (ES): 127.0 (M+H), rt: 2.1 min, 98.6% purity.

[0326] Step 4: Synthesis of 2-fluoro-6-methyl-3-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)pyridin-4- amine 16

[0327] In a nitrogen filled glovebox, 2-fluoro-6-methyl-pyridin-4-amine (Intermediate I6_3, 138 mg, 1.04 mmol) was dissolved in dry THF (1 mL) in a 6 mL pressure tube containing a magnetic stir bar. Pinacolborane (211 pL, 1.45 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. (1 ,5-Cyclooctadiene)(methoxy)iridium(l) dimer (10 mg, 0.015 mmol), 4,4'-di- tert-butyl-2,2'-dipyridyl (9 mg, 0.033 mmol) and bis(pinacolato)diboron (158 mg, 0.62 mmol) were added, the tube was sealed under nitrogen atmosphere and the reaction mixture was heated at 80 °C for 16 h. After cooling to room temperature, methanol (3 mL) was added and the reaction mixture was stirred for 10 min until the gas evolution has ceased, before being concentrated under vacuum. The crude brown oil was purified by column chromatography on silica gel (using a gradient DCM / EtOAc from 100 / 0 to 50 / 50 as eluent) and by trituration in hexane to afford the title compound as light pink solid (200 mg, yield: 72 %). LC-MS (Method B1) m / z: [M+H]+: 253.0, rt: 1 .13 min, purity: 95 %.1H NMR (400 MHz, DMSO-cfe) 5 6.58 (s, 2H), 6.29 (d, J = 1 .9 Hz, 1 H), 2.16 (s, 3H), 1 .28 (s, 12H).

[0328] Intermediate I7: 4-amino-2-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- vDbenzonitrile

[0329] To a solution of 4-amino-2-methyl-benzonitrile (97.0 %, 1.00 g, 7.34 mmol) in THF (60 mL) was added 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (2.1 mL, 14.7 mmol) and the resulting solution was stirred for 30 min. Then, (1 ,5-cyclooctadiene)(methoxy)iridium(i) dimer (243 mg, 0.37 mmol) and 2- [4-(dimethylamino)-2-pyridyl]-N,N-dimethyl-pyridin-4-amine (178 mg, 0.73 mmol) were added sequentially and the resulting mixture was purged with nitrogen gas for 5 min and stirred at 80 °C for 18 h. The reaction mixture was filtered through a pad of Celite, which was washed with EtOAc (150 mL). The filtrate was concentrated, and the resulting residue was purified by column chromatography on silica gel (using a gradient of 0-70% EtOAc / iso-hexane as eluent) to afford the title compound as a white solid (892 mg, yield: 47%). LC-MS (Method B5) m / z [M+H]+: 259.2; rt: 2.02 min; purity: 100%.1H NMR (400 MHz, DMSO-cfe) 5 7.56 (s, 1 H), 6.56 (d, J = 1.0 Hz, 1 H), 6.28 (s, 2H), 2.29 (s, 3H), 1.29 (s, 12H).

[0330] Intermediate I8: 5,9-dimethyl-6-oxo-5,7-dihvdropyrido[2,3-d][1lbenzazepine-10-carbonitrile

[0331] Tris(dibenzylideneacetone)dipalladium(0) (263 mg, 0.28 mmol) and BrettPhos (152 mg, 0.28 mmol) were added at room temperature to a solution of 4-amino-2-methyl-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzonitrile I7 (1.00 g, 2.78 mmol), ethyl 2-(3-bromo-2-pyridyl)propanoate I4 (718 mg, 2.78 mmol) and potassium carbonate (1.16 g, 8.31 mmol) in dry and degassed acetonitrile (13.9 mL) and water (0.75 mL) under inert atmosphere. The resulting mixture was stirred at 80 °C for 20 h. After completion, the mixture was diluted with EtOAc (10 mL), filtered through a plug of celite and washed with EtOAc (30 mL). The filtrate was concentrated under vacuum. To the residue dissolved in dry THF (27.8 mL), was added dropwise at 0 °C lithium bis(trimethylsilyl)amide (1.5 M in THF, 5.60 mL, 8.40 mmol). The resulting mixture was stirred at room temperature for 17 h. After completion, water was added and the mixture was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was triturated in Et2<D (15 mL). The solid was filtered, washed with Et2<D (2x10 mL) and vacuum-dried to give the title compound (110 mg, yield: 15%) as a light brown solid. LC-MS (Method A1_S) m / z: [M+H]+: 264.2; it 1.02 min; purity: 100%.1H NMR (400 MHz, DMSO-cfe) 6 10.61 (s, 1 H), 8.66 (dd, J = 4.8, 1 .5 Hz, 1 H), 8.17 (s, 1 H), 8.10 (dd, J = 7.7, 1 .5 Hz, 1 H), 7.66 (s, 1 H), 7.48 (dd, J = 7.7, 4.8 Hz, 1 H), 3.48 (q, J = 6.7 Hz, 1 H), 2.43 (s, 3H), 1 .48 (d, J = 6.7 Hz, 3H).

[0332] Intermediate I9: methyl 2-(3-chloro-5-fluoro-2-pyridyl)propanoate

[0333] Step 1: Synthesis of dimethyl 2-(3-chloro-5-fluoro-2-pyridyl)-2-methyl-propanedioate I9_1

[0334] Under nitrogen atmosphere, a suspension of potassium carbonate (2744 g, 19.88 mol, 3 eq.), dimethyl malonate (1770 g, 13.39 mol, 2 eq.) and 3-chloro-2,5-difluoropyridine (1000 g, 6.68 mol) in dry DMSO (5.0 L) was heated at 100°C for 20 h. After cooling to room temperature, a solution of methyliodide (1084 g, 7.63 mol, 1.1 eq.) in dry DMSO (4.0 L) was slowly added and the reaction mixture was left overnight at room temperature. The reaction mixture was treated with water (35.0 L) and extracted with EtOAc (15.0 L). The organic layer was washed with a 10% aqueous solution of NaCI (3.0 L) and filtered on a pad of 200 g SiO2 and 400 g MgSO4. The organic layer was concentrated under vacuum to give a yellow sticky suspension. 11 .0 L of methanol was added to give an orange solution. The product crystallized out after slow addition of water (up to 10.0 L) and heating at 60 °C. At room temperature, the white crystals were collected by filtration, rinsed with water, and dried to afford the title product (1438 g, purity: 87.4%, yield: 68%).1H NMR (400 MHz, DMSO-cfe) 6 8.53 (d, J = 2.6 Hz, 1 H), 8.18 (dd, J = 8.4, 2.6 Hz, 1 H), 3.72 (s, 6H), 1.81 (s, 3H).

[0335] Step 2: Synthesis of 2-(3-chloro-5-fluoro-2-pyndyl)propanoic acid I9_2

[0336] To a solution of sodium hydroxide pellets (503 g, 12.57 mol) in water (12.57 L) was added dimethyl 2-(3-chloro-5-fluoro-2-pyridyl)-2-methyl-propanedioate (Intermediate I9_1 , 1438 g, 4.56 mol, not fully dry, contains approx 13%w water: theoric quantity is 1257g) and the reaction mixture was heated at 40 °C over the week-end. After cooling to room temperature, the mixture was acidified by addition of aqueous HCI (6 M, ~2.0 L) to pH = 1 . After addition of 1 .5 L seeds were added to initiate the crystallization. The white solid was collected by filtration, rinsed with water and dried in vacuum oven to give the title product (1040 g, purity: 73%, yield: 81 %).1H NMR (400 MHz, DMSO- cfe) 5 8.57 (d, J = 2.6 Hz, 1 H), 8.09 (dd, J = 8.5, 2.6 Hz, 1 H), 4.21 (q, J = 7.1 Hz, 1 H), 1.41 (d, J = 7.1 Hz, 3H). proton for COOH not observed.

[0337] Step 3: Synthesis of methyl 2-(3-chloro-5-fluoro-2-pyridyl)propanoate 19

[0338] To a solution of 2-(3-chloro-5-fluoro-2-pyridyl)propanoic acid (Intermediate I9_2, 1040 g, 5.11 mol) in methanol (5.0 L) was added a 37% aqueous HCI solution (460 mL) by portions with Tmax=22°C and the reaction mixture was left at room temperature overnight. The reaction mixture was partitioned between isopropyl acetate (8.0 L) and water (8.0 L). After separation, the organic phase was washed with aqueous NaHCOs (5%, 4.0 L), dried and concentrated under vacuum to give the title product (932 g, quantitative yield). LC-MS (Method A1_S) m / z: [M+H]+: 218.1 / 220.0; rt: 1.26 min; purity: 100%.1H NMR (400 MHz, CDCh) 6 8.37 (d, J = 2.6 Hz, 1 H), 7.48 (dd, J = 7.8, 2.6 Hz, 1 H), 4.33 (q, J = 7.1 Hz, 1 H), 3.70 (s, 3H), 1 .55 (d, J = 7.1 Hz, 3H). IV. EXAMPLES

[0339] Example 1 : enantiomer (1 OR) or (10S) of M-(4-acetylphenyl)-2-[14-fluoro-5-(1- fluorocvclopropyl)-10-methyl-9-oxo-4,8,12-triazatricvclof9.4.0.02’7lpentadeca- 1(11 ), 2(7), 3, 5,12,14-hexaen-8-yllacetamide

[0340] Step 1: Synthesis of 14-fluoro-5-(1-fluorocyclopropyl)-10-methyl-4,8, 12- triazatricyclo[9.4.0.027]pentadeca- 1(11), 2(7), 3, 5, 12, 14-hexaen-9-one

[0341] To a solution of 2-(1-fluorocyclopropyl)pyridin-4-amine I2 (500 mg, 3.29 mmol) and bis(pinacolato)diboron (1 .69 g, 6.57 mmol) in dry and degassed THF (3.28 mL) was added at room temperature 4,4'-di-tert-butyl-2,2'-dipyridyl (90.0 mg, 0.33 mmol) under argon atmosphere. The mixture was added into another vial containing (1 ,5-cyclooctadiene)(methoxy)iridium(l) dimer (109 mg, 0.16 mmol). The resulting mixture was stirred at 70 °C for 19 h. The reaction mixture was then cooled down to 0 °C and quenched by pouring carefully into MeOH (1.6 mL) at 0 °C. After the quench, the mixture was diluted with 10 mL of ethyl acetate and filtered through a plug of silica gel. The plug was washed with 10 mL of ethyl acetate and the combined filtrate was concentrated under vacuum. To the residue in solution in degassed acetonitrile (25.9 mL) and water (3.25 mL) were added at room temperature methyl 2-(3-chloro-5-fluoro-2-pyridyl)propanoate (Intermediate I9, 704 mg, 3.24 mmol) and potassium carbonate (1.36 g, 9.71 mmol) followed by BrettPhos Pd G3 (299 mg, 0.32 mmol) and BrettPhos (177 mg, 0.32 mmol). The resulting mixture was stirred at 80 °C for 21 h. After completion, the mixture was diluted with 10 mL of ethyl acetate and filtered through a plug of celite. The plug was washed with 30 mL of ethyl acetate and the filtrate was concentrated under vacuum. The residue was triturated in Et2<D (15 mL). The solid was filtered, washed with Et2<D (2x10 mL) and vacuum-dried to give the title compound (646 mg, yield: 66%) as a brown solid. LC- MS (Method A1_S) m / z: [M+H]+: 302.2; rt: 1.21 min; purity: 98.8%. Step 2: Synthesis of enantiomer (10R) or (10S) of N-(4-acetylphenyl)-2-[14-fluoro-5-(1- fluorocyclopropyl)- 10-methyl-9-oxo-4, 8, 12-triazatricyclo[9.4.0.027]pentadeca-1( 11), 2(7), 3, 5, 12, 14- hexaen-8-yl]acetamide

[0342] To a solution of 14-fluoro-5-(1-fluorocyclopropyl)-10-methyl-4,8,12- triazatricyclo[9.4.0.027]pentadeca-1 (11),2(7),3,5,12,14-hexaen-9-one (322 mg, 1.07 mmol) and N- (4-acetylphenyl)-2-chloro-acetamide I3 (226 mg, 1.07 mmol) in dry N,N-di methylformamide (2.70 mL) was added at room temperature potassium carbonate (298 mg, 2.14 mmol). The resulting mixture was stirred at room temperature for 23 h. After completion, water was added to the reaction mixture. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with water (3x), with brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (using a gradient of O to 100% EtOAc in heptane as eluent) to give the racemate title compound (192 mg, yield: 38%) as a white solid. LC-MS (Method A1) m / z: [M+H]+: 477.2; rt: 2.69 min; purity: 100%. LC-MS (Method B1) m / z: [M+H]+: 477.2; rt: 2.44 min; purity: 100%.1H NMR (400 MHz, DMSO-cfe) 5 10.64 (s, 1 H), 8.83 (s, 1 H), 8.72 (d, J = 2.8 Hz, 1 H), 8.23 (dd, J = 9.5, 2.8 Hz, 1 H), 7.98 - 7.91 (m, 2H), 7.73 - 7.68 (m, 3H), 4.76 - 4.61 (m, 2H), 3.72 (q, J = 6.6 Hz, 1 H), 2.53 (s, 3H), 1 .68 - 1 .53 (m, 2H), 1 .50 (d, J = 6.6 Hz, 3H), 1.48 - 1.39 (m, 2H). The racemate was separated by chiral chromatography (SFC Reprosil NR-R from Dr Maisch, CO2 + MeOH 30%). First eluting enantiomer: chiral purity 100%; rt = 3.74 min (first eluting enantiomer). For information, second eluting enantiomer: chiral purity 100%; rt = 5.19 min. (both measured by chiral HPLC (Whelk O-1 (R,R) from Regis Technology, Solvent: Heptane 50% - Ethanol 50% - DEA 0.1 %)). LC-MS (Method A2’) m / z: [M+H]+: 477.2; rt: 4.54 min; purity: 99.2%. LC-MS (Method B2) m / z: [M+H]+: 477.1 ; rt: 4.33 min; purity: 96.3%.

[0343] Example 2: M-(4-acetylphenyl)-2-[3-fluoro-5-(1 -fluorocvclopropyl)-10-methyl-9-oxo-4,8,12- triazatricvclof9.4.0.027lpentadeca-1(11),2(7),3,5,12,14-hexaen-8-yllacetamide

[0344] A vial charged with RuPhos Pd G3 (47.0 mg, 0.06 mmol), RuPhos (26.0 mg, 0.06 mmol), K3PO4 (360 mg, 1.65 mmol) and 2-fluoro-6-(1-fluorocyclopropyl)-3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-4-amine (Intermediate 11 , 192 mg, 0.54 mmol) was evacuated and backfilled with Ar (3x). Ethyl 2-(3-bromo-2-pyridyl)propanoate 14 (140 mg, 0.54 mmol) was then added followed by dry degassed MeCN (2.5 mL). The reaction mixture was heated to 80 °C for 15 h. Water and saturated aqueous NH4CI solution were added, and the reaction mixture was extracted three times with EtOAc. The combined organic phases were washed with water (2x), brine (1x), dried over Na2SO4 and concentrated in vacuo. To a solution of the residue in dry THF (6 mL) was added dropwise at 0 °C lithium bis(trimethylsilyl)amide (1 .5 M in THF, 3.60 mL, 5.45 mmol). The resulting mixture was stirred at room temperature for 1 h. Water and saturated aqueous NH4CI solution were added, and the reaction mixture was extracted three times with EtOAc. The combined organic phases were washed with water (2x), brine (1x), dried over Na2SO4 and concentrated in vacuo. To a solution of the residue in N,N-dimethylformamide (7.5 mL) was added at room temperature potassium carbonate (210 mg, 1.50 mmol) and N-(4-acetylphenyl)-2-chloro- acetamide (160 mg, 0.76 mmol). The resulting mixture was stirred at room temperature for 18 h. After completion, the reaction mixture was diluted in ethyl acetate (30 mL) and water (30 mL). The aqueous phase was extracted with ethyl acetate (3x30 mL). The combined organics were washed with water (30 mL), with brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (using a gradient of 0 to 80% EtOAc in heptane as eluent) followed by preparative HPLC (Purification Method P_A) to give the title compound (15.7 mg, yield: 6%) as a white solid. LC-MS (Method A8) m / z: [M+H]+: 477.5; rt: 4.38 min; purity: 99.0%. LC-MS (Method B8) m / z: [M+H]+: 477.5; rt: 4.00 min; purity: 98.8%.1H NMR (500 MHz, DMSO-cfe) 5 10.66 (s, 1 H), 8.69 (dd, J = 4.8, 1.7 Hz, 1 H), 8.16 (ddd, J = 7.9, 4.6, 1.7 Hz, 1 H), 7.94 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H), 7.64 (s, 1 H), 7.52 (dd, J = 7.9, 4.8 Hz, 1 H), 4.67 (s, 2H), 3.86 (q, J = 6.6 Hz, 1 H), 2.53 (s, 3H), 1.68 - 1.57 (m, 2H), 1.50 (d, J = 6.6 Hz, 3H), 1.45 - 1.36 (m, 2H).19F NMR (471 MHz, DMSO-cfe) 5 -69.70 (t, J = 4.6 Hz, 1 F), -192.01 - - 192.30 (m, 1 F).

[0345] Example 3: enantiomer (1 OR) or (10S) of M-(4-acetylphenyl)-2-(3-fluoro-5,10,14-trimethyl-9- oxo-4, 8,12-triazatricvclo[9.4.0.02’7]pentadeca-1 (11 ), 2(7), 3, 5,12,14-hexaen-8-yl)acetamide

[0346] To a solution of 3-fluoro-5,10,14-trimethyl-4,8,12-triazatricyclo[9.4.0.027]pentadeca-

[0347] 1 (11),2(7),3,5,12,14-hexaen-9-one I5 (20 mg, 0.06 mmol) in N,N-dimethylformamide (0.6 mL) was added potassium carbonate (16 mg, 0.11 mmol) and N-(4-acetylphenyl)-2-chloro-acetamide I3 (13 mg, 0.06 mmol). The resulting mixture was stirred at room temperature for 3.5 h. After completion, the reaction mixture was diluted in ethyl acetate (30 mL) and water (30 mL). The aqueous phase was extracted with ethyl acetate (3x20 mL). The combined organics were washed with water (30 mL), with brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (using a gradient of 0 to 100% EtOAc in heptane as eluent) to give the racemate title compound (18.8 mg, yield: 73%) as a white solid. LC- MS (Method A2) m / z: [M+H]+: 447.2; rt: 4.04 min; purity: 99.1 %. LC-MS (Method B2) m / z: [M+H]+: 447.2; rt: 3.94 min; purity: 98.9%.1H NMR (500 MHz, DMSO-cfe) 5 10.60 (s, 1 H), 8.51 (d, J = 2.2 Hz, 1 H), 7.97 - 7.91 (m, 3H), 7.73 - 7.68 (m, 2H), 7.37 (s, 1 H), 4.64 - 4.52 (m, 2H), 3.72 (q, J = 6.6 Hz, 1 H), 2.53 (s, 3H), 2.38 (s, 3H), 1.47 (d, J = 6.6 Hz, 3H). CH3protons under DMSO signal.19F NMR (471 MHz, DMSO-cfe) 6 -70.78. The racemate was separated by chiral chromatography (SFC Reprosil NR-R from Dr Maisch, CO2 + MeOH 30%). First eluting enantiomer: chiral purity 100%; rt = 4.55 min. For information, the second eluting enantiomer: chiral purity 99.5%; rt = 6.46 min. (both measured by chiral HPLC (Whelk O-1 (R,R) from Regis Technology, Solvent: Heptane 50% - Ethanol 50% - DEA 0.1 %)). LC-MS (Method A8) m / z: [M+H]+: 447.5; rt: 3.94 min; purity: 98.6%. LC-MS (Method B8) m / z: [M+H]+: 447.5; rt: 3.61 min; purity: 98.8%.

[0348] Example 4: enantiomer (10R) or (10S) of M-(4-acetylphenyl)-2-(10-cvano-5,9-dimethyl-6-oxo- 5H-pyridof2.3-dnilbenzazepin-7-yl)acetamide

[0349] To a solution of 5,9-dimethyl-6-oxo-5,7-dihydropyrido[2,3-d][1]benzazepine-10-carbonitrile I8 (110 mg, 0.42 mmol) and A / -(4-acetylphenyl)-2-chloro-acetamide I3 (88.4 mg, 0.42 mmol) in dry N,N- dimethylformamide (1 .05 mL) was added at room temperature potassium carbonate (117 mg, 0.84 mmol). The resulting mixture was stirred at room temperature for 20 h. After completion, water was added to the reaction mixture. The precipitate formed was filtered and washed with Et20 (2x10 mL). The solid was purified by SFC (Phenomenex Luna 5 pm Silica (2) 100A, CO2 + EtOH 10%) to give the racemate title compound (44.3 mg, yield: 24%) as a white solid. LC-MS (Method A2’) m / z: [M+H]+: 439.2; rt: 4.17 min; purity: 98.8%. LC-MS (Method B2) m / z: [M+H]+: 439.2; rt: 3.98 min; purity: 98.5%.1H NMR (400 MHz, CDCh) 6 8.74 (dd, J = 4.8, 1.7 Hz, 1 H), 8.64 (s, 1 H), 7.96 - 7.90 (m, 2H), 7.87 (dd, J = 7.8, 1 .7 Hz, 1 H), 7.82 (s, 1 H), 7.80 (s, 1 H), 7.59 - 7.53 (m, 2H), 7.41 (dd, J = 7.8, 4.8 Hz, 1 H), 4.76 (d, J = 15.0 Hz, 1 H), 4.10 (d, J = 15.0 Hz, 1 H), 3.64 (q, J = 6.7 Hz, 1 H), 2.68 (s, 3H), 2.58 (s, 3H), 1.73 (d, J = 6.7 Hz, 3H). The racemate was separated by chiral chromatography (SFC Reprosil NR-R from Dr Maisch, CO2 + MeOH 35%). First eluting enantiomer; chiral purity 100%; rt = 2.01 min. For information, the second eluting enantiomer: chiral purity 100%; rt = 2.22 min. (both measured by chiral HPLC (Reprosil NR-R from Dr Maisch, Solvent: MeOH 100% - DEA 0.1 %)). LC-MS (Method A2’) m / z: [M+H]+: 439.2; rt: 4.17 min; purity: 100%. LC-MS (Method B2) m / z: [M+H]+: 439.2; rt: 3.97 min; purity: 98.8%.

[0350] V. BIOLOGICAL ASSAYS

[0351] The effect of compounds of Formula (I) on the system Xc functionality was examined in two independent cell assays: (i) measurement of cystine-induced glutamate release; and (ii) measurement of [14C] L-Cystine uptake.

[0352] As described above, System Xc, also known as the cystine / glutamate antiporter, is an amino acid transporter that mediates the extrusion of intracellular L-glutamate outside the cell and the uptake of extracellular L-cystine into the cell.

[0353] By measuring respectively, the concentration of glutamate released outside the cell and the L- cystine uptaken in the cell, with increasing concentrations of compounds of formula (I) according to the present invention, the efficacy of said compounds to inhibit the System Xc function can be evaluated.

[0354] The efficacy of the compounds to inhibit system Xc is represented by measuring the IC50 which corresponds to the concentration of compound necessary to inhibit 50% of the signals from the two control groups; DMSO 1 % and Erastin 50 pM in the respective assays. pICso values correspond to -log of the IC50 in Molar.

[0355] The lower the value of the IC50 (the higher the value of the pICso is), the less compound is needed to perform the same amount of inhibition and therefore the higher is the inhibition potency.

[0356] Generally, inhibitors of system Xc function will display values of IC50 of 500nM or lower respectively in each of the cystine-induced glutamate release and [14C] L-Cystine uptake assays.

[0357] When tested in either or both the cystine-induced glutamate release and -and [14C] L-Cystine uptake assays, compounds of formula (I) according to the present invention display values of pICso generally greater than or equal to about 6.3, suitably greater than about 7.0

[0358] V.1. Cystine-induced glutamate release assay

[0359] Measurement of cystine-induced glutamate release indicates levels of glutamate (outside of the cell) that are dependent on system Xc antiporter function. Upon the addition of L-Cystine to H4 cells, intracellular glutamate is counter-transported and exported in the supernatant.

[0360] In this assay, the medium is devoid of sodium to prevent the transport of glutamate by sodiumdependent excitatory amino acid transporters (EAATs). H4 cells were plated on 384-well culture plate at 1 x 104cells / well in Dulbecco’s Modified Eagle Medium (DMEM) with L-glutamine, penicillin / streptomycin and 10% fetal bovine serum (all from ThermoFisher Scientific) and incubated in a humidified CO2 incubator at 37°C. After 2 days, cells were washed 4 times with prewarmed sodium-free HEPES buffer (contents in mM: HEPES 10, KCI 5.4, CaCh 2.5, MgCh 1 , KH2PO4 0.4, D-Glucose 5, Choline chloride 140), pH 7.4. Glutamate release was induced by addition of 50 pM of L-Cystine (Sigma-Aldrich), together with a test compound of Formula (I) at 1 % final DMSO concentration. After 2 hours of incubation in the culture incubator, supernatants were transferred to a low-binding polypropylene 384-well plate to determine L-glutamate concentration using Amplex™ Red Glutamic Acid Assay Kit (ThermoFisher Scientific). Briefly, 10 pL of Amplex™ Red working solution was added to 10 pL of the supernatant, then the mixture was incubated for 30 min at 37°C. Fluorescence intensity was measured by EnVision microplate reader (PerkinElmer).

[0361] When tested, compounds of formula (I) according to the present invention have displayed a PIC50 of about 6.3 or greater in the cystine-induced glutamate release assay.

[0362] V.2. r4C / L-Cystine uptake assay

[0363] In this assay, the medium is devoid of sodium to prevent the transport of glutamate by sodiumdependent excitatory amino acid transporters (EAATs). H4 cells were plated on a 96-well CytoStar- T scintillating microplate (PerkinElmer) at 5 x 104cells / well in the medium described above. After 1 day, cells were washed one time with the sodium-free HEPES buffer and preincubated with test compounds of Formula (I) (1 % final DMSO) for 15 min. Uptake was initiated by adding 0.5 pM L- [1 ,2, 1 ’,2’-14C] Cystine (0.02 mCi / mL, PerkinElmer, Waltham, US) and 4.5 pM L-Cystine (Sigma- Aldrich). After 1 hour at 37°C, plates were counted in a MicroBeta2microplate counter (PerkinElmer).

[0364] Table I exhibits the ranges of pICso of the compounds of formula (I) according to the present invention when tested in the Cystine-induced glutamate release assay

[0365] Category A: about 6.3 <plC5o s about 7.00; Category B: about 7.00 < pICso s about 7.40; Category C: about 7.40 < pICso s about 7.80; Category D: pICso > about 7.80. n.t.: not tested.

[0366] As shown in this Table I, compounds of formula (I) according to the present invention are potent inhibitors of the System Xc function.

Claims

1. CLAIMS1 . A compound of formula (I) or a pharmaceutically acceptable salt thereof,WhereinR1represents C-M alkyl;R2represents hydrogen, halogen or C1-4 alkyl;R3represents hydrogen or halogen;R4represents C1-4 alkyl; or C3-7 cycloalkyl substituted by a halogen;X1represents N or CR5;X2represents N or CR6; andR5and R6represent independently cyano; andWherein when R4represents C1-4 alkyl, R2represents C1-4 alkyl.

2. The compound of formula (I) according to Claim 1 or a pharmaceutically acceptable salt thereof,WhereinR1represents C1-4 alkyl;R2represents hydrogen, halogen or C1-4 alkyl;R3represents hydrogen or halogen;R4represents C1-4 alkyl; or C3-7 cycloalkyl substituted by a halogen;X1represents N;X2represents N or CR6; andR6represents cyano; andWherein when R4represents C1-4 alkyl, R2represents a C1-4 alkyl.

3. The compound of formula (I) according to Claim 1 wherein C1-4 alkyl is methyl.

4. The compound of formula (I) according to Claim 1 wherein the C3-7 cycloalkyl is cyclopropyl.

5. The compound of formula (I) according to Claim 1 represented by formula (la),Wherein,R2and R3independently represent hydrogen or halogen; andRarepresents halogen.

6. The compound of formula (I) according to any preceding claim wherein the halogen is fluorine.

7. The compound of formula (I) according to Claim 1 which is selected from the group consisting of(I OR)-A / -(4-acetylphenyl)-2-[14-fluoro-5-(1 -fluorocyclopropyl)-10-methyl-9-oxo-4,8,12- triazatricyclo[9.4.0.027]pentadeca-1 (11),2(7),3,5,12,14-hexaen-8-yl]acetamide;(I OS)-N-(4-acetylphenyl)-2-[14-fluoro-5-(1 -fluorocyclopropyl)-10-methyl-9-oxo-4,8,12- triazatricyclo[9.4.0.027]pentadeca-1 (11),2(7),3,5,12,14-hexaen-8-yl]acetamide;A / -(4-acetylphenyl)-2-[3-fluoro-5-(1 -fluorocyclopropyl)-10-methyl-9-oxo-4,8,12- triazatricyclo[9.4.0.027]pentadeca-1 (11),2(7),3,5,12,14-hexaen-8-yl]acetamide;(IOR)-A / -(4-acetylphenyl)-2-(3-fluoro-5,10,14-trimethyl-9-oxo-4,8,12- triazatricyclo[9.4.0.027]pentadeca-1 (11),2(7),3,5,12,14-hexaen-8-yl)acetamide;(I OS)-A / -(4-acetylphenyl)-2-(3-fluoro-5,10,14-trimethyl-9-oxo-4,8,12- triazatricyclo[9.4.0.027]pentadeca-1 (11),2(7),3,5,12,14-hexaen-8-yl)acetamide(I OR)-A / -(4-acetylphenyl)-2-(10-cyano-5,9-dimethyl-6-oxo-5 / 7-pyrido[2,3-d][1]benzazepin-7- yl)acetamide; and(I OS)-A / -(4-acetylphenyl)-2-(10-cyano-5,9-dimethyl-6-oxo-5 / 7-pyrido[2,3-d][1 ]benzazepin-7- yl)acetamide.

8. A pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier.

9. The compound of formula (I) according to any one of Claims 1-7 or the pharmaceutical composition according to Claim 8 for use in therapy.

10. The compound of formula (I) according to any one Claims 1-7 or the pharmaceutical composition according to Claim 8 for use for use in the treatment of cancers where System Xc plays a role, in epilepsy syndromes where System Xc plays a role, or in cancer treatment resistance.

11. Use of a compound of formula (I) according to any one of Claims 1-7 or the pharmaceutical composition according to Claim 8 for the manufacture of a medicament useful for the treatment of cancers where System Xc plays a role, in epilepsy syndromes where System Xc plays a role, or in cancer treatment resistance.

12. A method for the treatment of disorders for which the administration of inhibitors of the System Xc is indicated, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) according to any one of Claims 1-7 or the pharmaceutical composition according to Claim 8.

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