Tricyclic azepinone derivatives as system XC inhibitors

Abstract

The present invention is based on the system Xc - The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, which are useful in the treatment of diseases and / or disorders in which [Formula 1] JPEG2026506359000279.jpg7957

Description

[Technical Field]

[0001] The present invention relates to substituted seven-membered cyclic amide derivatives and their use in therapy.

[0002] In particular, the present invention relates to pharmacologically active substituted seven-membered cyclic amide or urea derivatives and analogs thereof.

[0003] More particularly, the present invention relates to seven-membered cyclic amide derivatives and their analogues, (cyclo)alkylcarbonyl-substituted (hetero)aryl-acetamides. The compounds according to the present invention are represented by the system Xc - Regulates the cystine / glutamate antiporter and thus system Xc - It is useful as a pharmaceutical agent for the treatment of diseases in which the cystine / glutamate antiporter plays a role. [Background technology]

[0004] System Xc, also known as the cystine / glutamate antiporter - System Xc 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. L-cystine influx serves as the rate-limiting step in providing the L-cysteine ​​required for the synthesis of glutathione (GSH), the primary antioxidant in cells. - L-glutamate extruded by the system can act as a neurotransmitter. - System Xc is a complex formed by two proteins: xCT (encoded by the SLC7A11 gene), also known as the light chain, and CD98hc (SLC3A2), also known as the heavy chain or 4F2hc. - is expressed primarily in the brain in some glial cells such as astrocytes and microglia, as well as 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 tissues, including, but not limited to, gliomas (especially glioblastomas) (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 (adenocarcinoma and squamous cell carcinoma) 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). - Expression is associated with poor prognosis in several cancers, including but not limited to colon carcinoma (Lim et al., Proc Natl Acad Sci USA (2019), 116, 9433-9442), adrenocortical carcinoma, renal 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 specific form of pancreatic carcinoma, stromal cells are highly dependent 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). SLC7A11 (System Xc) expression in cancer cells - In other cancers, downregulation of system Xc (light chain of IL-1) reduces cancer cell proliferation, tumor progression, and invasion. -plays an important role in tumorigenesis (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).

[0006] High System Xc - Levels also provide cells with increased capacity for the synthesis of the antioxidant GSH, a defense against reactive oxygen species (ROS) and tumor growth (Liu et al., Mol Ther (2020), 28, 2358-2366).

[0007] Furthermore, SLC7A11, cystine, and cysteine ​​have been described to play a role in radiotherapy resistance and 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).

[0008] Therefore, the system Xc - Inhibiting or blocking the system Xc - These compounds may be useful in treating certain cancers in which IL-1 plays a role.

[0009] System Xc - Blocking system Xc can also synergize with other therapies that target tumor growth. For example, blocking system Xc to prevent cancer stem cell metastasis in combination with chemotherapy treatments that block tumor growth (driven by oncogenes such as HER2, p53, and Kras). -Inhibition of β-glucanase (β-glucanase) provides additional therapeutic benefits in breast cancer, esophageal cancer, 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).

[0010] In some cancer cells, the toxic lipid peroxidation induced by inhibition of system Xc has a synergistic effect when combined with conventional cancer treatment, leading to cancer cell death and overcoming resistance to this conventional cancer treatment (Lin et al., Am J Cancer Res (2020), 10, 3106-3126; Zhu et al. Cancer Res (2021) 77(8), 2064-2077).

[0011] Therefore, the system Xc - Molecules that inhibit System Xc in cancer cells can be used alone or in combination therapy with molecules or treatments that target other mechanisms and pathways involved in cancer biology, thereby helping to overcome drug resistance in current cancer treatments or to enhance the effectiveness of certain existing treatments. - Glutamate release through upregulation of glutamate also affects tumorigenesis, and inhibition of glutamate release correlates with decreased proliferation not only in brain tumors but also in non-brain carcinomas (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).

[0012] System Xc of L-glutamate into the extracellular space - Inducible efflux can contribute to excitatory signaling and excitotoxicity, leading to epileptic seizures, neuronal death, and other brain pathologies via activation of postsynaptic glutamate receptors on neurons. -Mice lacking system Xc have reduced brain glutamate receptors and exhibit reduced or delayed epileptogenesis (Leclercq et al., Epilepsia (2019), 60, 1412-1423). - Glioblastoma cells expressing glutamate release high levels of glutamate, which activates glutamate receptors on neighboring neurons, inducing neuronal hyperactivity and epileptic seizures (Marcus et al., J. Neurooncol. (2010), 97, 11-23; Robert et al., (2015), Sci Transl Med 7, 289ra286).

[0013] Therefore, the system Xc - Inhibiting the function or expression of gliomas may contribute to the development of elevated system Xc expression in patients with glioma-associated epilepsy and in diseases such as focal cortical dysplasia and tuberous sclerosis. - It can prevent glutamate-induced epileptic seizures and neuronal death in other epilepsy syndromes (Arena et al., (2019), Brain Pathol 29, 351-365).

[0014] WO 2015 / 196086 discloses the system Xc - The present invention relates to compounds which are stated to be inhibitors of

[0015] Sulfasalazine is approved for the treatment of disorders including rheumatoid arthritis, ulcerative colitis, and Crohn's disease. - Although it has been demonstrated to be a nonselective inhibitor of antiporters, its use is limited to peripheral indications due to poor brain exposure. - Its effectiveness in peripheral indications is limited due to its low efficacy on function.

[0016] Therefore, it has improved properties and can be used to treat certain cancers, or system Xc - can be used to treat epilepsy syndromes in which system Xc- There is a need to design new drugs that inhibit antiporters.

[0017] System Xc - There is also a need to develop pharmacological tools that can be used in the development of new biological tests to accelerate the identification of suitable inhibitors of antiporters. Summary of the Invention

[0018] In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, A is the point of attachment to the rest of the molecule, V 1 and V 2 Together with A 1 , A 2 and A 3 [ka] represents an optionally substituted aryl or heteroaryl selected from the group represented by During the ceremony, V 1 represents C; V 2 represents C or N; Z 4 is N or CR 7 represents; Z 5 is N or CR 8 represents; Z 6 is N or CR 9 represents; Z 7 is N or CR 10 represents; R a represents a halogen; R 7 , R 8 , R 9 and R10 are independently hydrogen or halogen; or C 1~4 Alkyl or C 1~4 alkoxy (any of these groups may be optionally substituted with one or more substituents); Z 1 is N or CR 4 represents; Z 2 is N or CR 5 represents; Z 3 is N or CR 6 represents; R 1a and R 1b are independently hydrogen or C 1~4 alkyl (each of which groups may be optionally substituted with one or more substituents); R 2 is C 1~4 Alkyl or C 3~7 cycloalkyl, each of which may be optionally substituted with one or more substituents; R 3 is hydrogen, halogen or hydroxyl; or C 1~4 alkyl, which may be optionally substituted by one or more substituents; or R 2 and R 3 taken together with the phenyl group to which they are attached form a heteroaryl, which is optionally substituted with one or more substituents; R 4 and R 5 are independently hydrogen, halogen or cyano; or C 1~4 Alkyl or C 1~4 alkoxy (any of these groups may be optionally substituted with one or more substituents); R 6 is hydrogen, halogen or cyano; or C 1~4 Alkyl, C 1~4 Alkoxy or C 3~7 Heterocycloalkyl, or C 3~7represents cycloalkyl (any of these groups may be optionally substituted by one or more substituents) to provide.

[0019] In a second aspect, the present invention provides a compound of formula (I') [ka] In the formula, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , R 1a , R 1b , R 2 and R 3 is as defined above to provide.

[0020] In a third aspect, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, Z 1 is N or CR 4 represents; Z 2 is N or CR 5 represents; Z 3 is N or CR 6 represents; Z 4 is N or CR 7 represents; Z 5 is N or CR 8 represents; Z 6 is N or CR 9 represents; Z 7 is N or CR 10 represents; R 1a and R 1bare independently hydrogen or C 1~4 alkyl (each of which groups may be optionally substituted with one or more substituents); R 2 is C 1~4 Alkyl or C 3~7 cycloalkyl, each of which may be optionally substituted with one or more substituents; R 3 is hydrogen, halogen or hydroxyl; or C 1~4 alkyl, which may be optionally substituted with one or more substituents; R 2 and R 3 taken together with the phenyl group to which they are attached form a heteroaryl, which is optionally substituted with one or more substituents; R 4 and R 5 are independently hydrogen, halogen or cyano; or C 1~4 Alkyl or C 1~4 alkoxy (any of these groups may be optionally substituted with one or more substituents); R 6 is hydrogen, halogen or cyano; or C 1~4 Alkyl, C 1~4 Alkoxy or C 3~7 heterocycloalkyl (any of which groups may be optionally substituted by one or more substituents); R 7 , R 8 , R 9 and R 10 are independently hydrogen or halogen; or C 1~4 Alkyl or C 1~4 represents alkoxy (any of these groups may be optionally substituted by one or more substituents) to provide.

[0021] In a fourth aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

[0022] In a fifth aspect, the present invention provides a system Xc - The present invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof that are useful in the treatment of disorders in which the cystine / glutamate antiporter plays a role.

[0023] In particular, the present invention provides a system Xc - The present invention provides compounds of formula (I) which may be useful in the treatment of cancer or epilepsy syndromes in which

[0024] Additionally, the present invention provides compounds of formula (I) that may be useful in overcoming cancer treatment resistance.

[0025] In a sixth 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.

[0026] In a sixth aspect, the present invention provides synthetic intermediates of formula (II) useful in the chemical synthesis of compounds of formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0027] As used herein, "C 1~4 The term "alkyl" refers to a straight or branched monovalent saturated aliphatic hydrocarbon chain of 1 to 4 carbon atoms. 1~4 Alkyl is methyl and ethyl.

[0028] "C 1~4 The term "alkoxy" refers to a group of formula -OR, where R is any of the groups defined herein as "C 1~4 alkyl," where the C1-C4 alkoxy group is attached to the parent structure via an oxygen atom. Suitable alkoxy groups according to the present invention include methoxy.

[0029] As used herein, "C 3~7The term "cycloalkyl" refers to a monovalent group of 3 to 7 carbon atoms derived from a saturated monocyclic hydrocarbon. 3~7 Cycloalkyl groups include cyclopropyl.

[0030] As used herein, "C 3~7 The term "heterocycloalkyl" refers to saturated monocyclic and bicyclic rings containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulfur, and nitrogen. Suitable C groups according to the present invention are 3~7 Heterocycloalkyl includes azetidinyl and azaspiro[2.3]hexan-5-yl.

[0031] The terms "halo", "halogen", and "halide" are used interchangeably and represent a chloro, fluoro, bromo, or iodo atom. Suitable examples of halogens according to the present invention include chloro and fluoro.

[0032] The term "heteroaryl" as used herein refers to an aromatic carbocyclic group of 5 to 14 carbon atoms having at least one aromatic ring or multiple condensed rings, wherein one or more of said carbon atoms are replaced by one or more heteroatoms selected from oxygen, sulfur, and nitrogen. Examples of heteroaryls according to the present invention are optionally substituted benzofuran-3-one or indan-1-one.

[0033] For the avoidance of doubt, when reference is made to compounds of formula (I), this also includes compounds of formula (I') and (IA).

[0034] When any of the groups in the compound of formula (I) above is described as being optionally substituted, this group can be unsubstituted or can be substituted by one or more substituents.Typically, such group is unsubstituted or substituted by 1, 2 or 3 substituents.In one embodiment, such group is unsubstituted.Suitable substituents for each of the groups present on the compound of formula (I) will be further described later in this specification.

[0035] Formula (I) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless otherwise stated or indicated.

[0036] Stereoisomers of the compounds of formula (I) include cis and trans isomers, optical isomers, diastereomers, geometric isomers, rotamers, atropisomers and conformational isomers of the compounds of formula (I) and mixtures thereof (such as racemates and diastereomeric pairs), including compounds that exhibit more than one type of isomerism.

[0037] The compounds of formula (I) and / or their intermediates may have at least one asymmetric center in their structure. This asymmetric center may be present in the R or S configuration (designated aR or aS for atropisomers), and the R and S (or aR and aS) designations are used in accordance with the rules set forth in Pure Appl. Chem., 45 (1976) 11-30. Accordingly, the present invention also relates to all stereoisomeric forms, such as enantiomeric and diastereoisomeric forms, or mixtures thereof (including all possible mixtures of stereoisomers) of the compounds of formula (I') and formula (I). In the context of the present invention, a reference to a compound or compounds is intended to encompass the compound in each of its possible isomeric forms and mixtures thereof, unless a specific isomeric form is specifically mentioned.

[0038] Carbon-carbon bonds in compounds of formula (I) are represented herein by solid lines ( [ka] ), solid wedge ( [ka] ) or dotted wedge ( [ka] ) are used. The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers at that carbon atom (e.g., a specific enantiomer, a racemic mixture, etc.) are included. The use of either a solid or dashed wedge to depict bonds to asymmetric carbon atoms is intended 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.

[0039] Some compounds of formula (I) may exist as a single atropisomer or as a mixture of atropisomers.

[0040] Atropiomers are stereoisomers that arise because rotation around a single bond is hindered, and energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow the isolation of individual conformers (see, e.g., Bringmann G. et al. Atroposelective Synthesis of Axially Chiral Biaryl Compounds. Angewandte Chemie International Edition. (2005) 44(34):5384-5427).

[0041] Unlike compounds with classical chiral centers, which racemize through bond breaking and formation processes, atropisomers racemize through an intramolecular dynamic process involving only bond rotation. Depending on the rotational barrier, one particular conformer of compound formula (I) may be in equilibrium with another conformer, and thus the composition of conformers may change with time or conditions to reach equilibrium. The conformations of compounds of formula (I) are represented by solid lines ( [ka] ) and / or solid wedge ( [ka] Examples of particular subgroups of compounds of formula (I) are shown below, where the atropisomers are represented by formulae (Ia) and (Ib), respectively. [ka]

[0042] Solid wedges on the A and B rings [ka] The use of is intended to indicate the conformation associated with the particular atropisomer (Ia) or (Ib).

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

[0044] It is also to be understood that each individual atom present in formula (I) or in the formulae set forth below 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 formulae shown below can be: 1 H,2 H (deuterium) or 3 H (tritium) atoms, preferably 1 H or 2 H. Similarly, by way of example, each individual carbon atom present in formula (I'), formula (I) or the formulae shown below may be present as: 11 C. 12 C. 13 C or 14 C atoms, preferably 12 C. Similarly, by way of example, each individual fluorine atom can be present as: 18 F or 19 It can exist as F.

[0046] Accordingly, the present invention also includes within its scope isotopically labeled compounds of formula (I).

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

[0048] In one embodiment, A is A 1 In one aspect of this embodiment, V 1 and V 2 represents C. In another embodiment, A represents A 2 In one aspect of this embodiment, V 1 and V 2 represents C. In a further embodiment, A represents A 3 In one aspect of this embodiment, V 1 represents C, and V 2 represents N.

[0049] In general, R a represents a halogen. In particular, R a represents fluoro.

[0050] In the first embodiment, R 1a represents hydrogen. In a second embodiment, R 1a is an arbitrarily substituted C 1~4 In one aspect of this embodiment, R 1a represents optionally substituted methyl.

[0051] In the first embodiment, R 1b represents hydrogen. In a second embodiment, R 1b is an arbitrarily substituted C 1~4 In one aspect of this embodiment, R 1b represents optionally substituted methyl.

[0052] Appropriately, R 1a and R 1b are independently hydrogen or C 1~4 Represents alkyl.

[0053] Illustratively, R 1a and R 1b independently represent hydrogen or methyl.

[0054] In certain embodiments according to the present invention, R 1a is C 1~4 represents alkyl, and R 1b represents hydrogen.

[0055] In the first embodiment, R 2 is an arbitrarily substituted C 1~4 In a first aspect of this embodiment, R 2 represents optionally substituted methyl. In a second aspect of this embodiment, R 2 represents optionally substituted ethyl. In a second embodiment, R 2 is an arbitrarily substituted C 3~7 In a first aspect of this embodiment, R 2 represents an optionally substituted cyclopropyl.

[0056] Appropriately, R 2 is C 1~4 Alkyl or C 3~7 represents cycloalkyl.

[0057] Illustratively, R 2 represents methyl or cyclopropyl.

[0058] In the first embodiment, R 3 represents hydrogen. In a second embodiment, R 3 represents a halogen. In one aspect of this embodiment, R 3 represents fluoro. In a third embodiment, R 3 represents hydroxyl. In a fourth embodiment, R 3 is an arbitrarily substituted C 1~4 In one aspect of this embodiment, R 3 represents optionally substituted methyl.

[0059] Appropriately, R 3 represents hydrogen.

[0060] In certain embodiments according to the present invention, R 2 and R 3 taken together with the phenyl group to which they are attached form an optionally substituted benzofuran-3-one or indan-1-one.

[0061] Illustratively, R 2 and R 3 together with the phenyl group to which they are attached to form benzofuran-3-one.

[0062] In one embodiment, Z 1 represents N. In another embodiment, Z 1 is CR 4 Represents.

[0063] In one embodiment, Z 2 represents N. In another embodiment, Z 2 is CR 5 Represents.

[0064] In one embodiment, Z 3 represents N. In another embodiment, Z 3 is CR 6 Represents.

[0065] In one embodiment, Z 4 represents N. In another embodiment, Z 4 is CR7 Represents.

[0066] In one embodiment, Z 5 represents N. In another embodiment, Z 5 is CR 8 Represents.

[0067] In one embodiment, Z 6 represents N. In another embodiment, Z 6 is CR 9 Represents.

[0068] In one embodiment, Z 7 represents N. In another embodiment, Z 7 is CR 10 Represents.

[0069] In a particular embodiment according to the present invention, Z 1 , Z 2 and Z 3 One or none of Z represents N. In one aspect of this particular embodiment, Z 2 represents N, and Z 1 is CR 4 represents Z 3 is CR 6 Represents.

[0070] In a particular embodiment according to the present invention, Z 4 , Z 5 , Z 6 and Z 7 One or none of Z represents N. In one aspect of this particular embodiment, Z 7 represents N, and Z 4 is CR 7 represents Z 5 is CR 8 represents Z 6 is CR 9 Represents.

[0071] In the first embodiment, R 4 represents hydrogen. In a second embodiment, R 4 represents a halogen. In a first aspect of this embodiment, R 4represents fluoro. In a second aspect of this embodiment, R 4 represents chloro. In a third embodiment, R 4 represents cyano. In a fourth embodiment, R 4 is an arbitrarily substituted C 1~4 In one aspect of this embodiment, R 4 represents optionally substituted methyl.

[0072] In the fifth embodiment, R 4 is an arbitrarily substituted C 1~4 In a first aspect of this embodiment, R 4 represents an optionally substituted methoxy.

[0073] Appropriately, R 4 is hydrogen, halogen, cyano, C 1~4 Alkyl or C 1~4 represents alkoxy.

[0074] Illustratively, R 4 represents hydrogen, fluoro, chloro or methoxy.

[0075] In the first embodiment, R 5 represents hydrogen. In a second embodiment, R 5 represents a halogen. In a first aspect of this embodiment, R 5 represents fluoro. In a second aspect of this embodiment, R 5 represents chloro. In a third embodiment, R 5 represents cyano. In a fourth embodiment, R 5 is an arbitrarily substituted C 1~4 In one aspect of this embodiment, R 5 represents optionally substituted methyl. In a fifth embodiment, R 5 is an arbitrarily substituted C 1~4 In a first aspect of this embodiment, R 5 represents an optionally substituted methoxy.

[0076] Appropriately, R 5is hydrogen, halogen, cyano, C 1~4 Alkyl or C 1~4 represents alkoxy.

[0077] Illustratively, R 5 represents hydrogen, fluoro, chloro or methoxy.

[0078] In the first embodiment, R 6 represents hydrogen. In a second embodiment, R 6 represents a halogen. In a first aspect of this embodiment, R 6 represents fluoro. In a second aspect of this embodiment, R 6 represents chloro. In a third embodiment, R 6 represents cyano. In a fourth embodiment, R 6 is an arbitrarily substituted C 1~4 In a first aspect of this embodiment, R 6 represents optionally substituted methyl. In a fifth embodiment, R 6 is an arbitrarily substituted C 1~4 In a first aspect of this embodiment, R 6 represents optionally substituted methoxy. In a sixth embodiment, R 6 is an arbitrarily substituted C 3~7 In a first aspect of this embodiment, R represents heterocycloalkyl. 6 represents an optionally substituted azetidinyl. In a second aspect of this embodiment, R 6 represents an optionally substituted azaspiro[2.3]hexanyl. In a seventh embodiment, R 6 is an arbitrarily substituted C 3~7 In a first aspect of this embodiment, R 6 represents an optionally substituted cyclobutane.

[0079] Appropriately, R 6 is hydrogen, halogen, cyano, C 1~4 Alkyl or C 1~4 alkoxy; or optionally substituted, C 3~7 Heterocycloalkyl or C 3~7represents cycloalkyl.

[0080] More appropriately, R 6 is hydrogen, halogen, cyano, C 1~4 Alkyl or C 1~4 Alkoxy; or optionally substituted C 3~7 represents heterocycloalkyl;

[0081] Ideally, R 6 is C 1~4 Alkyl, C 1~4 Alkoxy or optionally substituted C 3~7 represents heterocycloalkyl;

[0082] Illustratively, R 6 represents methyl, methoxy, optionally substituted azetidinyl, optionally substituted azaspiro[2.3]hexanyl, or optionally substituted cyclobutane.

[0083] In particular, R 6 represents methyl, methoxy, 3,3-difluoroazetidin-1-yl, 2,2-difluoro-5-azaspiro[2.3]hexan-5-yl, 3-fluoro-azetidin-1-yl, 3,3-(hydroxy)(methyl)-azetidin-1-yl, 3,3-(fluoro)(methyl)azetidin-1-yl, cyclobutane or 1-hydroxy-cyclobutane.

[0084] More specifically, R 6 represents methyl, methoxy, 3,3-difluoroazetidin-1-yl, or 2,2-difluoro-5-azaspiro[2.3]hexan-5-yl.

[0085] In the first embodiment, R 7 represents hydrogen. In a second embodiment, R 7 represents a halogen. In a first aspect of this embodiment, R 7 represents fluoro. In a third embodiment, R 7 is an arbitrarily substituted C 1~4 In a first aspect of this embodiment, R7 represents optionally substituted methyl. In a fourth embodiment, R 7 is an arbitrarily substituted C 1~4 In a first aspect of this embodiment, R 7 represents an optionally substituted methoxy.

[0086] Appropriately, R 7 is hydrogen, halogen, C 1~4 Alkyl or C 1~4 represents alkoxy.

[0087] Illustratively, R 7 represents hydrogen.

[0088] In the first embodiment, R 8 represents hydrogen. In a second embodiment, R 8 represents a halogen. In a first aspect of this embodiment, R 8 represents fluoro. In a third embodiment, R 8 is an arbitrarily substituted C 1~4 In a first aspect of this embodiment, R 8 represents optionally substituted methyl. In a fourth embodiment, R 8 is an arbitrarily substituted C 1~4 In a first aspect of this embodiment, R 8 represents an optionally substituted methoxy.

[0089] Appropriately, R 8 is hydrogen, halogen, C 1~4 Alkyl or C 1~4 represents alkoxy.

[0090] Illustratively, R 8 represents hydrogen, fluoro or methoxy.

[0091] In the first embodiment, R 9 represents hydrogen. In a second embodiment, R 9 represents a halogen. In a first aspect of this embodiment, R 9 represents fluoro. In a third embodiment, R9 is an arbitrarily substituted C 1~4 In a first aspect of this embodiment, R 9 represents optionally substituted methyl. In a fourth embodiment, R 9 is an arbitrarily substituted C 1~4 In a first aspect of this embodiment, R 9 represents an optionally substituted methoxy.

[0092] Appropriately, R 9 is hydrogen, halogen, C 1~4 Alkyl or C 1~4 represents alkoxy.

[0093] Illustratively, R 9 represents hydrogen.

[0094] In the first embodiment, R 10 represents hydrogen. In a second embodiment, R 10 represents a halogen. In a first aspect of this embodiment, R 10 represents fluoro. In a third embodiment, R 10 is an arbitrarily substituted C 1~4 In a first aspect of this embodiment, R 10 represents optionally substituted methyl. In a fourth embodiment, R 10 is an arbitrarily substituted C 1~4 In a first aspect of this embodiment, R 10 represents an optionally substituted methoxy.

[0095] Appropriately, R 10 is hydrogen, halogen, C 1~4 Alkyl or C 1~4 represents alkoxy.

[0096] Illustratively, R 10 represents hydrogen.

[0097] R 1a , R 1b , R 2 , R 3 , R4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 Suitable optional substituents on the above include hydroxyl, halogen, C 1~4 Alkyl or C 1~4 Alkoxy. R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 Particular examples of the above optional substituents are hydroxyl, fluoro, methyl and methoxy.

[0098] Illustratively, R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 and R 10 is not substituted.

[0099] In a first particular embodiment, the present invention provides a compound of formula (IA) [ka] In the formula, R 1a , R 2 , R 4 , R 6 and R 8 is as defined above This relates to a particular sub-class of compounds of formula (I) represented by:

[0100] In the compound according to formula (IA), suitably R 1a is hydrogen or C 1~4 represents alkyl; R 2 is C 1~4Alkyl or C 3~7 represents cycloalkyl; R 4 and R 8 are independently hydrogen, halogen or C 1~4 represents alkoxy; R 6 is C 1~4 Alkyl, C 1~4 Alkoxy or C 3~7 represents heterocycloalkyl;

[0101] In the compound according to formula (IA), suitably R 1a represents hydrogen or methyl; R 2 represents methyl or cyclopropyl; R 4 represents hydrogen, chloro, fluoro or methoxy; R 6 represents methyl, methoxy, 2,2-difluoro-azetidin-1-yl, or 2,2-difluoro-5-azaspiro[2.3]hexan-5-yl, 3-fluoroazetidin-1-yl, 3,3-(hydroxy)(methyl)-azetidin-1-yl, 3,3-(fluoro)(methyl)azetidin-1-yl, cyclobutane, or 1-hydroxy-cyclobutane; R 8 represents hydrogen, fluoro or methoxy.

[0102] In the compounds according to formula (IA), typically R 1a is hydrogen or C 1~4 represents alkyl; R 2 is C 1~4 Alkyl or C 3~7 represents cycloalkyl; R 4 and R 8 are independently hydrogen, halogen or C 1~4 represents alkoxy; R 6 is C 1~4 Alkyl, C 1~4 Alkoxy or C3~7 represents heterocycloalkyl;

[0103] In the compound according to formula (IA), suitably R 1a represents hydrogen or methyl; R 2 represents methyl or cyclopropyl; R 4 represents hydrogen, chloro, fluoro or methoxy; R 6 represents methyl, methoxy, 2,2-difluoro-azetidin-1-yl, or 2,2-difluoro-5-azaspiro[2.3]hexan-5-yl; R 8 represents hydrogen, fluoro or methoxy.

[0104] In one particular embodiment of the compounds of formula (IA), R 8 represents fluoro.

[0105] Specific novel compounds according to the present invention include each of the compounds whose preparation is described in the accompanying examples, their individual stereoisomers, and pharmaceutically acceptable salts and solvates thereof.

[0106] In certain embodiments, the present invention provides a method for producing a pharmaceutical composition comprising: N-(4-acetylphenyl)-2-[3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-[4-(cyclopropanecarbonyl)phenyl]-2-[3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3,14-difluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[14-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[(10R)-3-chloro-14-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3-chloro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[5-(3,3-difluoroazetidin-1-yl)-3-fluoro-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3-fluoro-5-(3-fluoroazetidin-1-yl)-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3-chloro-5-(2,2-difluoro-5-azaspiro[2.3]hexan-5-yl)-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; and N-(4-acetylphenyl)-2-(1-fluoro-3-methyl-6-oxo-7H-pyrido[4,3-d][3]benzazepin-5-yl)acetamide, N-(4-acetylphenyl)-2-[3-fluoro-5-methoxy-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[14-methoxy-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3-methoxy-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(15),2(7),3,5,11,13-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-(3-methoxy-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide; 2-[3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]-N-(4-propanoylphenyl)acetamide; N-(4-acetyl-3-hydroxy-phenyl)-2-[3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-(3,14-difluoro-5-methoxy-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide; 2-[3,14-difluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]-N-(3-oxobenzofuran-6-yl)acetamide; N-(4-acetylphenyl)-2-(10-cyano-2-fluoro-5,9-dimethyl-6-oxo-5H-pyrido[2,3-d][1]benzazepin-7-yl)acetamide; N-(4-acetylphenyl)-2-[(10)-3-fluoro-14-methoxy-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3-fluoro-5-(3-fluoroazetidin-1-yl)-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[5-(3,3-difluoroazetidin-1-yl)-3-fluoro-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-(3,5-difluoro-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide; N-(4-acetyl-3-fluoro-phenyl)-2-[(10)-3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3-fluoro-5-(3-hydroxy-3-methyl-azetidin-1-yl)-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3-fluoro-5-(3-fluoro-3-methyl-azetidin-1-yl)-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3-fluoro-5-(3-hydroxy-3-methyl-azetidin-1-yl)-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-(14-fluoro-7,12-dimethyl-8-oxo-4-thia-5,9,13-triazatricyclo[8.4.0.0 2,6 ]tetradeca-1(10),2,5,11,13-pentaen-9-yl)acetamide; N-(4-acetylphenyl)-2-[3-fluoro-5-(1-hydroxycyclobutyl)-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(15),2,4,6,11,13-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3,14-difluoro-5-(hydroxymethyl)-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-(5-cyclobutyl-3-fluoro-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide; N-(4-acetylphenyl)-2-(14-fluoro-5-methoxy-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide; N-(4-acetyl-3-hydroxy-phenyl)-2-(3,14-difluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide; N-(4-acetylphenyl)-2-(3,14-difluoro-5,10-dimethyl-9-oxo-4,8,13-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide; N-(4-acetylphenyl)-2-[11-fluoro-9-(3-fluoroazetidin-1-yl)-5-methyl-6-oxo-5H-pyrido[2,3-d][1]benzazepin-7-yl]acetamide; N-(4-acetylphenyl)-2-(14-chloro-4-fluoro-7,12-dimethyl-8-oxo-5,6,9,13-tetrazatricyclo[8.4.0.0 2,6 ]tetradeca-1(14),2,4,10,12-pentaen-9-yl)acetamide; and their enantiomers.

[0107] In certain aspects, the present invention relates to compounds of formula (I) as set out in the accompanying Examples 1-36.

[0108] In a further particular aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: N-(4-acetylphenyl)-2-[(10R)-3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[(10R)-3,14-difluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-[4-(cyclopropanecarbonyl)phenyl]-2-[(10R)-3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[(10R)-3-chloro-14-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3-chloro-5-(2,2-difluoro-5-azaspiro[2.3]hexan-5-yl)-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-(1-fluoro-3-methyl-6-oxo-7H-pyrido[4,3-d][3]benzazepin-5-yl)acetamide; 2-[(10R)-3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]-N-(4-propanoylphenyl)acetamide; N-(4-acetylphenyl)-2-[3-fluoro-5-(3-fluoroazetidin-1-yl)-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[5-(3,3-difluoroazetidin-1-yl)-3-fluoro-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3-fluoro-5-(3-hydroxy-3-methyl-azetidin-1-yl)-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3-fluoro-5-(3-fluoro-3-methyl-azetidin-1-yl)-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3-fluoro-5-(3-hydroxy-3-methyl-azetidin-1-yl)-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-(14-fluoro-7,12-dimethyl-8-oxo-4-thia-5,9,13-triazatricyclo[8.4.0.0 2,6 ]tetradeca-1(10),2,5,11,13-pentaen-9-yl)acetamide; N-(4-acetylphenyl)-2-[3-fluoro-5-(1-hydroxycyclobutyl)-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.02,7 ]pentadeca-1(15),2,4,6,11,13-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3,14-difluoro-5-(hydroxymethyl)-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-(3,14-difluoro-5,10-dimethyl-9-oxo-4,8,13-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide; and N-(4-acetylphenyl)-2-(14-chloro-4-fluoro-7,12-dimethyl-8-oxo-5,6,9,13-tetrazatricyclo[8.4.0.0 2,6 ]tetradeca-1(14),2,4,10,12-pentaen-9-yl)acetamide The present invention relates to a compound of formula (I) selected from the group consisting of:

[0109] The present invention also provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0110] In particular, the present invention provides a system Xc - In accordance with the present invention, there is provided 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

[0111] In the following embodiment, the compound of formula (I) as defined above is represented by the system Xc - It may be an inhibitor of the antiporter.

[0112] In a first aspect, the present invention provides a system Xc - System Xc plays a role in cancer treatment -The present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in epilepsy syndromes in which steroids play a role, or in cancer therapy resistance.

[0113] In a first embodiment according to this aspect, the present invention provides a system Xc - The present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in which is plays a role.

[0114] 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, renal carcinoma, mesothelioma, sarcoma, uveal melanoma, gastric cancer, pancreatic carcinoma or leukemia.

[0115] In a second embodiment according to this aspect, the present invention provides a system Xc - The present invention provides a compound of formula (I) as defined above for use in the treatment of epilepsy syndromes in which

[0116] 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 epileptic seizures, glioma-associated epilepsy, focal cortical dysplasia or tuberous sclerosis.

[0117] In a third embodiment, the present invention provides a compound of formula (I) for use in the treatment of cancer therapy resistance.

[0118] 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 some types of cancer.

[0119] In a second aspect, the present invention provides a system Xc -There is provided the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful in the treatment of diseases and / or disorders in which the cystine / glutamate antiporter plays a role.

[0120] In a first embodiment of this aspect, the invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful in the treatment of cancer in which system Xc- plays a role.

[0121] In particular, the present invention provides 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 glioma, colon carcinoma, colorectal carcinoma, lung cancer, esophageal carcinoma, triple-negative breast cancer, hepatocellular carcinoma, adrenocortical carcinoma, renal carcinoma, mesothelioma, sarcoma, uveal melanoma, gastric cancer, pancreatic carcinoma or leukemia.

[0122] In a second embodiment according to this aspect, the present invention provides a system Xc - The present invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful in the treatment of epilepsy syndromes in which

[0123] 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 epileptic seizures, glioma-associated epilepsy, focal cortical dysplasia or tuberous sclerosis.

[0124] In a third embodiment according to this aspect, the present invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful in the treatment of cancer resistance.

[0125] In particular, the present invention provides 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 some cancer types. -The present invention provides a method for the treatment of disorders in which the administration of an inhibitor of formula (I) is indicated, which method comprises administering to a human / animal patient in need of such treatment an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0126] In a first embodiment according to this aspect, the present invention provides a system Xc - The present invention provides a method for the treatment of cancer in which is plays a role, which method comprises administering to a human / animal patient in need of such treatment an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0127] 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, renal carcinoma, mesothelioma, sarcoma, uveal melanoma, gastric cancer, pancreatic carcinoma or leukemia, which method comprises administering to a human / subject in need of such treatment an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0128] In a second embodiment according to this aspect, the present invention provides a system Xc - The present invention provides a method for the treatment of epilepsy syndromes in which β-glucanase plays a role, which method comprises administering to a human / animal patient in need of such treatment an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0129] In particular, the present invention provides a method for the treatment of epileptogenesis, glutamate-induced epileptic seizures, glioma-associated epilepsy, focal cortical dysplasia or tuberous sclerosis, which method comprises administering to a human / subject in need of such treatment an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0130] In a third embodiment according to this aspect, the present invention provides a method for the treatment of cancer therapy 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 some 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.

[0131] As used herein, the term "patient" refers to a patient in System Xc - The term "subject" refers to a mammal suffering from one or more disorders associated with the function or expression of a gene or gene product. It will be understood that the most preferred subject is a human.

[0132] Those skilled in the art will also recognize that disorders may be affected by treating a patient currently suffering from the disorder or by prophylactically treating a patient suffering from the disorder with an effective amount of a compound of Formula (I). Accordingly, the terms "treatment" and "treating" are intended to refer to any process by which there may be a slowing, halting, arresting, controlling, or stopping of the progression of the disorders described herein, and are intended to include prophylactic treatment of such disorders, but do not necessarily indicate a complete elimination of all disorder symptoms.

[0133] Activity in any of the above therapeutic indications or disorders can, of course, be determined by conducting appropriate clinical trials in a manner known to those skilled in the art relevant to the indication in question and / or in the design of clinical trials in general.

[0134] When used in medicine, the salt of the compound of formula (I) may be a pharmaceutically acceptable salt. However, other salts may be useful in the preparation of the compounds that can be used in the present invention or their pharmaceutically acceptable salts. The standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use, edited by P.H. Stahl & C.G. Wermuth, Wiley-VCH, 2002. Suitable pharmaceutically acceptable salts of the compound of formula (I') or formula (I) include, for example, acid addition salts that can be formed by mixing a solution of the compound of formula (I) with a solution of a pharmaceutically acceptable acid.

[0135] 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 with water.

[0136] The present invention also includes within its scope cocrystals of compounds of formula (I) above. The term "cocrystal" is used to describe a situation in which neutral molecular components are present in a crystalline compound in a defined stoichiometric ratio. The preparation of pharmaceutical cocrystals allows modifications to be made to the crystalline form of an active pharmaceutical ingredient, thereby changing its physicochemical properties without impairing its intended biological activity (see Pharmaceutical Salts and Cocrystals, edited by J. Wouters & L. Quere, RSC Publishing, 2012).

[0137] Compounds according to the present invention may exist in different polymorphic forms. Although not explicitly shown in the above formula, such forms are intended to be included within the scope of the present invention.

[0138] The present invention also includes within its scope prodrug forms of compounds of formula (I) and various subranges and subgroups thereof.

[0139] To treat a disease, the compounds of formula (I) or their pharmaceutically acceptable salts are used in an effective daily dosage and may be administered in the form of a pharmaceutical composition.

[0140] Accordingly, another embodiment of the present invention relates to 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.

[0141] To prepare pharmaceutical compositions according to the present invention, one or more of the compounds of formula (I) or pharmaceutically acceptable salts thereof are intimately admixed with a pharmaceutical diluent or carrier according to conventional pharmaceutical compounding techniques known to those skilled in the art.

[0142] Suitable diluents and carriers can take a wide variety of forms depending on the desired route of administration, for example oral, rectal, parenteral, intranasal, or intratumor.

[0143] Pharmaceutical compositions containing compounds according to the invention can be administered, for example, orally, parenterally, ie intravenously, intramuscularly or subcutaneously, intrathecally, by inhalation, intranasally or by ocular administration.

[0144] Pharmaceutical compositions suitable for oral administration may be solid or liquid and may, for example, be in the form of tablets, pills, dragees, gelatin capsules, solutions, syrups, chewing gum, or the like.

[0145] For this purpose, active ingredient can be mixed with inert diluent or non-toxic pharmaceutically acceptable carrier such as starch or lactose.Optionally, these pharmaceutical compositions can also contain binder such as microcrystalline cellulose, tragacanth gum or gelatin, disintegrating agent such as alginic acid, lubricant such as magnesium stearate, glidant such as colloidal silicon dioxide, sweetener such as sucrose or saccharin, or coloring agent or flavoring agent such as peppermint or methyl salicylate.

[0146] The present invention also contemplates compositions that can release the active substance in a controlled manner. Pharmaceutical compositions that can be used for parenteral administration are in conventional forms such as aqueous or oily solutions or suspensions that are generally contained in ampoules, disposable syringes, glass or plastic vials or injection containers.

[0147] In addition to the active ingredient, these solutions or suspensions may optionally contain a sterile diluent such as water for injection, saline solution, oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediamine-tetraacetic acid, buffers such as acetates, citrates or phosphates, and agents for adjusting osmotic pressure such as sodium chloride or dextrose.

[0148] These pharmaceutical forms are prepared using methods routinely used by pharmacists.

[0149] The amount of active ingredient in a pharmaceutical composition can fall within a wide range of concentrations and depends on various factors such as the sex, age, weight and condition of the patient, as well as the method of administration. Thus, the amount of the compound of formula (I) in a composition for oral administration can be at least 0.5% by weight and up to 80% by weight based on the total weight of the composition.

[0150] It has also been found in accordance with the present invention that the compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered alone or in combination with other pharmaceutically active ingredients.

[0151] In particular, the compounds of formula (I) according to the invention can be combined with other active ingredients that increase intracellular reactive oxygen species, modulate amino acid metabolism, or with immunotherapeutic agents.

[0152] In compositions for parenteral administration, the amount of compound of formula (I) present is at least 0.5% by weight and can be up to 33% by weight, based on the total weight of the composition. For preferred parenteral compositions, dosage units range from 0.5 mg to 3000 mg of compound of formula (I).

[0153] The daily dose can fall within a wide range of dosage units of the compound of formula (I), generally ranging from 0.5 to 3000 mg, although it should be understood that the specific dose can be adapted for a particular case according to the individual needs, at the physician's discretion.

[0154] Synthesis scheme It will be apparent to those skilled in the art that there are a variety of synthetic routes that can lead to compounds according to the invention. The following processes are intended to illustrate some of these synthetic routes, but should in no way be construed as limiting as to how compounds according to the invention should be made.

[0155] During any of the following synthetic sequences it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by protecting groups from cleavage, cleavage, or other reactions as 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, 1983. rd This may be achieved by conventional protecting groups (PG), such as those described in The Journal of Chemistry, Vol. 1, No. 1, pp. 1999. The protecting groups may be removed at any convenient subsequent stage using methods known in the art.

[0156] The compounds of formula (I) according to the present invention can be prepared analogously by conventional methods understood by those skilled in the art of synthetic organic chemistry.

[0157] In the following description of the general synthetic methods, "DCM" means dichloromethane, "DIPEA" refers to N,N-diisopropylethylamine, "DMF" refers to N,N-dimethylformamide, "DMSO" refers to dimethyl sulfoxide, "EDC" refers to 1-ethyl-3-carbodiimide hydrochloride, "TEA" refers to triethylamine, "THF" refers to tetrahydrofuran, "HATU" refers to azabenzotriazole tetramethyluronium hexafluorophosphate, "HBTU" refers to benzotriazole tetramethyluronium hexafluorophosphate, "HOBt" refers to hydroxybenzotriazole, "TCFH" refers to chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, and "NMI" refers to N-methylimidazole.

[0158] The following description of a synthetic scheme provides a means for preparing compounds of formula (I). However, similar methods can be used in the preparation of compounds of formula (I). According to one embodiment, A is A 1 The compound having the general formula (I) formula: [ka] In the formula, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , R 1a , R 1b and R 2 is as defined above for compounds of formula (I), and LG 1 is a halogen atom or a leaving group such as mesylate or tosylate, and LG 2 is hydroxy, alkoxy or halogen by reaction of a compound of formula (2) with an amide of formula (4), or by reaction of a compound of formula (3) with an aromatic amine of formula (5).

[0159] The reaction following Route A can be carried out using a base such as a trialkylamine, inorganic carbonate or pyridine in the presence or absence of an iodide salt such as KI or NaI in a suitable solvent such as DMSO, DMF, sulfolane, acetonitrile or THF.

[0160] Alternatively, compounds of formula (I) can be prepared according to Route B by reaction of a carboxylic acid or carboxylic acid derivative of formula (3) with an aromatic amine (5) according to procedures for forming amides from carboxylic acids or carboxylic acid derivatives and amines known to those skilled in the art. The reaction following Route B leads to the formation of LG 2 When LG is a halogen such as chlorine, the reaction may be carried out using a base such as a trialkylamine, an inorganic carbonate or pyridine in a suitable solvent such as DCM, DMSO, DMF, sulfolane, acetonitrile or THF. 2 When LG is hydroxy, the reaction can be carried out using a similar base 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 those skilled in the art. 2 Compounds of formula (3) where is hydroxy can be converted to LG by reaction with sulfonyl chloride or thionyl chloride in a suitable solvent such as DCM or THF, in the presence or absence of catalytic DMF, at room temperature or at a higher temperature such as 70° C. 2 can be converted to a compound of formula (3) where is chloro.

[0161] LG 2 Compounds of formula (3), where LG is alkoxy, such as OMe, OEt, or OtBu, can be prepared by reaction of intermediate (2) with an α-chloro or α-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 those skilled in the art. 2Further basic or acid ester hydrolysis known to those skilled in the art can be used to form compounds of formula (3) where is OH.

[0162] Alternatively, the compound of formula (I) can be reacted with LG in the presence of a catalytic amount of a palladium catalyst. 2 can be prepared by reacting an intermediate of formula (3), where X is NH, (hereinafter referred to as (3')), with a compound of formula (5'), where X is a sulfonate, such as triflate, or a halogen, such as chloro or bromo. This reaction, the "Buchwald amide coupling," is known to those skilled in the art. [ka]

[0163] Compounds of formula (5') are commercially available or can be prepared by any method known to those skilled in the art.

[0164] Compounds of formula (3') can be prepared by reaction of compounds of formula (2) with an α-halogenoamide, 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 those skilled in the art. Alternatively, compounds of formula (3') can be prepared by reaction of a carboxylic acid or carboxylic acid derivative of formula (3) with ammonia, according to procedures for forming amides from carboxylic acids or carboxylic acid derivatives and amines known to those skilled in the art.

[0165] The compound of formula (2) is LG 2 can be prepared by cyclocondensation from their precursors of formula (6) having the same definition as above. For example, LG 2 When is an alkoxy, the reaction can be carried out in the presence of a base such as LiHMDS or K2CO3, or under heating conditions to obtain directly without isolation from the previous step. [ka]

[0166] Compounds of formula (6) can be prepared from the corresponding precursors of formulas (8) and (9) by a cross-coupling reaction, known to those skilled in the art as the "Suzuki reaction," provided that if (8) has B*, then (9) has X*, or if (8) has X*, then (9) has B*. B* can be a boronic acid, 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.

[0167] Compounds of formula (8) and (9) are commercially available, described in the literature, or can be prepared by functional group transformations known to those skilled in the art.

[0168] A is A 2 or A 3 Compounds of formula (I') representing can be synthesised as described in the examples.

[0169] In another aspect, the present invention provides a compound of formula (II) [ka] In the formula, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , R 1a , R 1b is as defined above, R 15 is hydrogen or CH2-CO-R d represents; and R d is hydroxy, halogen, amino or C 1~4 represents alkoxy.

[0170] In the first embodiment, R 15 is CH2-CO-R d In the second embodiment, R 15 represents hydrogen.

[0171] In yet another aspect, the present invention relates to the use of an intermediate of formula (II) for the synthesis of a compound of formula (I).

[0172] Experimental section I. Abbreviations / Replicate Reagents ACN or MeCN acetonitrile CV column volume DCM dichloromethane EtOAc ethyl acetate DMF N,N-dimethylformamide DMA Dimethylacetamide DMAP dimethylaminopyridine EDC 1-ethyl-3-carbodiimide hydrochloride MeOH Methanol DCE Dichloroethane HATU Azabenzotriazole tetramethyluronium hexafluorophosphate HBTU Benzotriazole Tetramethyluronium Hexafluorophosphate HOBt Hydroxybenzotriazole TCFH Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate NMI N-methylimidazole MTBE or TBME Methyl tert-butyl ether PTFE Polytetrafluoroethylene ELSD Evaporative Light Scattering Detector DMSO dimethyl sulfoxide Salt water Saturated sodium chloride solution Et2O diethyl ether h time d day THF tetrahydrofuran AcOH acetic acid RT room temperature rt retention time Rf retention rate br Broad M molar concentration MS mass spectrometry [M+H] + Accurate mass of protonated ions observed by MS [MH] - Accurate mass of deprotonated ions observed by MS mL milliliter HPLC High-Performance Liquid Chromatography UPLC Ultra High Performance Liquid Chromatography LC-MS Liquid Chromatography Mass Spectrometry ESI electrospray ionization ES + Electrospray positive ionization TEA Triethylamine DIPEA N,N-diisopropylethylamine DEA Diethylamine CDI Carbonyldiimidazole PCy3 Tricyclohexylphosphine TMSCN Trimethylsilyl cyanide dppf 1,1'-bis(diphenylphosphino)ferrocene PEPPSI: Pyridine-Promoted Precatalyst Preparation, Stabilization, and Initiation HMDS bis(trimethylsilyl)amide or hexamethyldisilazane PPh3 Triphenylphosphine AIBN Azobisisobutyronitrile TFA trifluoroacetic acid bs. Broad singlet NBS N-Bromosuccinimide DME Dimethoxyethane HMPA Hexamethylphosphoramide SFC Supercritical Fluid Chromatography SCX Strong Cation Exchange HPLC Column TLC thin layer chromatography sat. saturation Hex aq. Water-based Eq. Equivalent amount min mmol millimole UV ultraviolet light

[0173] Naming convention: IUPAC names of chemical reagents, intermediates, and examples were generated using Biovia Draw 2020 (version 20.1.100.2161 or 20.1.0.2081). Depending on the Kekule structures of the chemical reagents, intermediates, and examples, Biovia Draw may generate different chemical names. As an example, Kekule structures K1 and K2 are 4,8,14-triazatricyclo[4,8,14-triazatria ... 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-9-one and 4,8,14-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(15),2,4,6,11,13-hexaen-9-one. Both names can be found in the following descriptions. [ka]

[0174] II. Analytical and Synthetic Methods All reactions involving air- or moisture-sensitive reagents are performed under a nitrogen or argon atmosphere (inert atmosphere) using dehydrated solvents and glassware. Experiments requiring microwave irradiation are performed in a Biotage Initiator 60 microwave oven upgraded with operating software version 2.0. Experiments are performed to reach the required temperature as quickly as possible (maximum irradiation power: 400 W, no external cooling). Commercially available solvents and reagents are generally used without further purification, including anhydrous solvents where appropriate (typically Sure-Seal™ products from Aldrich Chemical Company or AcroSeal™ from ACROS Organics). Reactions are typically followed by thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), or mass spectrometry (MS) analysis.

[0175] NMR spectra were recorded on a Bruker Advance III HD 500 MHz or 400 MHz analyzer. Reported chemical shifts (δ) are given in parts per million (ppm), and coupling constants (J) are expressed in hertz (Hz). 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 = triplet doublet, td = doublet of doublet, and m = multiplet.

[0176] Mass spectrometry measurements in LC-MS mode are performed as follows: For acidic elution (methods A1, A1', A1_S, A2, and A2'), analysis was performed using a QDA Waters single quadrupole mass spectrometer. The spectrometer was equipped with a UPLC Acquity H-class with an ESI source and a diode array detector (200-400 nm). Data were acquired using acidic elution in positive mode with a full MS scan from m / z 70 to 800. Reversed-phase separation was performed at 45 °C on a Waters Acquity UPLC HSS T3 1.8 μm (2.1 x 50 mm) column for methods A1, A1', and A1_S, and on a Waters Acquity UPLC HSS T3 1.8 μm (2.1 x 100 mm) column for methods A2 and A2'. Gradient elution is performed using water / ACN / TFA (95 / 5 / 0.5 mL / L) (solvent A) and ACN (solvent B) for methods A1, A1_S and A2, and water / acetonitrile / formic acid (95 / 5 / (0.05%)) (solvent A) and acetonitrile / formic acid (99.95 / 0.05%) (solvent B) for methods A1' and A2'. Injection volume: 1 μL. Full flow rate on MS. Gradient program:

[0177] [Table 1]

[0178] [Table 2]

[0179] [Table 3]

[0180] For acidic elution (Method A3), analysis was performed using a Xevo Waters Q-TOF mass spectrometer. The analyzer was equipped with a Waters Acquity H-class UPLC with an ESI source and a diode array detector (210–400 nm). Data were acquired in positive mode with a full MS scan from m / z 50 to 1200. Reversed-phase separation was performed on an Acquity UPLC HSS T3 C18 column (1.8 μm, 2.1 × 100 mm) at 40 °C. Gradient elution was performed at pH ≈3 using water / ACN / formic acid (95 / 5 / 750 μL / L) (solvent C) and water / ACN / formic acid (5 / 95 / 500 μL / L) (solvent D). Flow rates were 100% for UV, 10% for MS, and 90% for ELSD. Injection volumes were 0.5–2 μL.

[0181] Gradient Program: [Table 4]

[0182] For acidic elution (Methods A4 and A8), analysis was performed using a SYNAPT G2-SI Waters Q-TOF mass spectrometer for Method A4 and an SQD2 Waters single quadrupole for Method A8. These spectrometers were equipped with a Waters Acquity H-class UPLC equipped with an ESI source and a diode array detector (210-400 nm). Data were acquired in positive mode with a full MS scan from m / z 50 to 1200. Reversed-phase separation was performed on an Acquity UPLC HSS T3 C18 column (1.8 μm, 2.1 × 100 mm) at 45°C. Gradient elution was performed using water / ACN / formic acid (95 / 5 / 750 μL / L) (Solvent C) and water / ACN / formic acid (5 / 95 / 500 μL / L) (Solvent D), pH approximately 3. The MS flow rate was full. Injection volume: 0.5 μL.

[0183] Gradient Program: [Table 5]

[0184] For acidic elution (Method A5), analysis is performed using a Shimadzu LC-MS 2010EV mass spectrometer. The analyzer is equipped with an HPLC equipped with an ESI source and a diode array detector (210-400 nm). Data are acquired in positive and negative modes with full MS scans from m / z 80 to 2000. Reversed-phase separation is performed using a Waters X-Select CSH C18 (4.6 x 150 mm), 3.5 μm column. Column temperature: 50 °C. Gradient elution is performed using a mobile phase containing 0.1% formic acid in water (phase A) and acetonitrile (phase B). Injection volume: 2 μL.

[0185] Gradient Program: [Table 6]

[0186] For acidic elution (Method A6), analysis is performed using a Shimadzu LC-MS 2010EV mass spectrometer. The analyzer is equipped with an HPLC equipped with an ESI source and a diode array detector (210-400 nm). Data are acquired in positive and negative modes with full MS scans from m / z 80 to 2000. Reversed-phase separation is performed using a Waters X-Select CSH C18 (4.6 x 150 mm), 3.5 μm column. Column temperature: 50 °C. Gradient elution is performed using a mobile phase containing 0.1% TFA in water (phase A) and acetonitrile (phase B). Injection volume: 2 μL.

[0187] Gradient Program: [Table 7]

[0188] For acid elution (Method A7), the analysis is performed using an Agilent 1200-6120 LC-MS system coupled to an Agilent 6120 mass spectrometer (ES) with UV detection (254 nM) and MS detection: m / z 100-1000. Column: XSelect CSH C18 XP 130 Å, 2.5 μm, 4.6 mm × 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.

[0189] Gradient Program: [Table 8]

[0190] For acid elution (method A9), the analysis is carried out using the same equipment as above, but the reversed-phase separation is carried out using a Waters Cortecs C18 2.7 μm (30 × 2.1 mm) column. Column temperature: 40 °C. A 1.5 min gradient elution is carried out using a mobile phase containing 0.1% formic acid in water (phase A) and ACN (phase B).

[0191] For basic elution (Methods B1, B1_S, and B2), analysis was performed using a QDA Waters Simple Quadrupole Mass Spectrometer. The analyzer was equipped with a UPLC Acquity H-class with an ESI source and a diode array detector (200-400 nm). Data were acquired in positive mode with a full MS scan from m / z 70 to 800. Reversed-phase separation was performed at 45°C on a Waters Acquity UPLC BEHC18 1.7 μm (2.1 x 50 mm) column for Methods B1 and B1_S, and on a Waters Acquity UPLC BEH C18 1.7 μm (2.1 x 100 mm) column for Method B2. Gradient elution was performed using 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 μL. Full flow rate in MS.

[0192] Gradient Program: [Table 9]

[0193] [Table 10]

[0194] [Table 11]

[0195] For basic elution (Method B3), analysis is performed using a Xevo Waters Q-TOF mass spectrometer. The spectrometer is equipped with a Waters Acquity H-class UPLC with an ESI source and a diode array detector (210–400 nm). Data are acquired in positive mode with a full MS scan from m / z 50 to 1200. Reversed-phase separation is performed on an Acquity UPLC BEH C18 column (1.7 μm, 2.1 × 100 mm) at 45 °C. Gradient elution is performed with water / ACN / ammonium formate (95 / 5 / (40 mg / L ammonium bicarbonate + 100 μL / L NH4OH)) (solvent A) and ACN (solvent B) at a pH of approximately 8–9. Flow rates are 100% for UV and 10% for MS, and 90% for ELSD. Injection volume: 0.2–2 μL.

[0196] Gradient Program: [Table 12]

[0197] For basic elution (Methods B4 and B8), analysis was performed using a SYNAPT G2-SI system and a Waters Q-TOF mass spectrometer for Method B4, and an SQD2 Waters single quadrupole for Method B8. These analyzers were equipped with a Waters Acquity H-class UPLC with an ESI source and a diode array detector (210-400 nm). Data were acquired in positive mode with a full MS scan from m / z 50 to 1200. Reversed-phase separation was performed on an Acquity UPLC BEH C18 column (1.7 μm, 2.1 × 100 mm) at 45 °C. Gradient elution was performed at pH approximately 8-9 using water / ACN / ammonium formate (95 / 5 / (63 mg / L + 100 μL / L NH4OH)) (solvent A) and ACN (solvent B). The MS flow rate was full. Injection volume: 0.5 μL.

[0198] Gradient Program: [Table 13]

[0199] For basic elution (methods B5 and B5'), analysis is performed using an Agilent 1200-6120 LC-MS system coupled to an Agilent 6120 mass spectrometer (ES) with UV detection (254 nM) and MS detection m / z 100-1000. Reverse-phase separation is performed on an XBridge BEH C18 XP column, 130 Å, 2.5 μm, 4.6 mm × 30 mm (Waters™), at 45 °C. Column temperature: 40 °C. Flow rate: 2.5 mL / min. Gradient elution is performed using the mobile phases 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'.

[0200] Gradient Program: [Table 14]

[0201] For basic elution (Method B6), analysis is performed using a Shimadzu LC-MS 2010EV mass spectrometer. The spectrometer is equipped with an HPLC equipped with an ESI source and a diode array detector (210-400 nm). Data are acquired with full MS scans from m / z 80 to 2000 in positive and negative modes. Reversed-phase separation is performed using a Waters X-Select CSH C18 (4.6 x 150 mm), 3.5 μm column. Column temperature: 50 °C. Gradient elution is performed using a mobile phase containing 10 mM ammonium bicarbonate in water (phase A) and acetonitrile (phase B). Injection volume: 2 μL.

[0202] Gradient Program: [Table 15]

[0203] For basic elution (Method B7), analysis is performed using a Shimadzu LC-MS 2010EV mass spectrometer. The spectrometer is equipped with an HPLC equipped with an ESI source and a diode array detector (210-400 nm). Data are acquired with full MS scans from m / z 80 to 2000 in positive and negative modes. Reverse-phase separation is performed using a Waters X-Bridge C18 (4.6 x 150 mm), 5 μm column. Column temperature: 50 °C. Gradient elution is performed using the mobile phases 0.1% ammonia in water (phase A) and acetonitrile (phase B). Injection volume: 5 μL.

[0204] Gradient Program: [Table 16]

[0205] For basic elution (Method B9), the analysis is performed using an Agilent 1200 Series LC in tandem with a 6140 Mass Spectrometer. Reversed-phase separation is performed on a Phenomenex Gemini NX-C18 3 μM (2 × 20 mm) column, eluting with a gradient of 5 to 95% 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), at a flow rate of 1.0 mL / min and a column temperature of 40 °C.

[0206] For basic elution (Method B10), the analysis is performed using an Agilent 1290 Infinity II LC in tandem with a 6135 MSD XT mass spectrometer. Reversed-phase separation is performed on an Acquity UPLC BEH C18 2.1 x 50 mm, 1.7 μM column, 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), at a flow rate of 1.5 mL / min and a column temperature of 60 °C.

[0207] All analytical chiral LC-MS was performed on 4.6 × 150 mm columns at 30 °C with a flow rate of 1.5 mL / min, except for the Chiralpak IG-u (Daicel) column, which had dimensions of 3 × 100 mm and a flow rate of 0.425 mL / min. All columns exhibit a particle size distribution of 3 μm, except for the WhelkO-1(R,R) (Regis Technology), which was 3.5 μm, and the Chiralpak IG-u (Daicel), which was less than 2 μm.

[0208] High-resolution mass spectrometry measurements in LC-MS mode are performed as follows: Method HRMS_A1: A SYNAPT G2-SI Waters Q-TOF mass spectrometer was used for QC analysis. The spectrometer was equipped with a Waters Acquity H-class UPLC with an ESI source and a diode array detector (210–400 nm). Data were acquired in positive mode with a full MS scan from m / z 50 to 1200. Reversed-phase separation was performed on an Acquity UPLC BEH C18 column (1.7 μm, 2.1 × 30 mm) at 45 °C. Gradient elution was performed at pH ≈3 using water / ACN / formic acid (95 / 5 / (750 μL / L)) (solvent C) and water / ACN / formic acid (5 / 95 / (500 μL / L)) (solvent D). The MS was run at full flow. Injection volume: 0.5–1 μL.

[0209] Method HRMS_A2: Analyses are performed using a Xevo Waters Q-TOF mass spectrometer. The spectrometer is equipped with a Waters Acquity H-class UPLC with an ESI source and a diode array detector (210–400 nm). Data are acquired as full MS scans from m / z 50 to 1200 in positive mode. Reversed-phase separation is performed on an Acquity UPLC HSS T3 C18 column (1.8 μm, 2.1 × 50 mm) at 40 °C. Gradient elution is performed at pH ≈3 using water / ACN / formic acid (95 / 5 / 750 μL / L) (solvent C) and water / ACN / formic acid (5 / 95 / 500 μL / L) (solvent D). Flow rates are 100% for UV, 10% for MS, and 90% for ELSD. Injection volume: 0.5–1 μL.

[0210] [Table 17]

[0211] [Table 18]

[0212] Preparative HPLC purification is performed using an SQD Waters or QDa Performance single quadrupole mass spectrometer. The spectrometer is equipped with a Waters 2525 binary pump coupled to an ESI source, a 2767 sample manager, and a diode array detector (210–400 nm). Data are acquired in positive and negative modes with full MS scans from m / z 100 to 850. LC parameters: Reversed-phase separation is performed on a Waters XBridge OBD MS C18 column (5 μm, 30 × 50 mm) at room temperature. Typical HPLC flow rates are 35–45 mL / min. Typical example of basic elution: a gradient from solvent A (H2O + 10 mM NH4HCO3 + 50 μL / L NH4OH) to solvent B (100% acetonitrile) [Purification Method P_B]. Typical example of acidic elution: gradient from solvent A (HO / TFA: 99.5% / 0.5%) to solvent B (ACN / TFA: 99.5% / 0.5%) [purification method P_A].

[0213] Some preparative HPLC purifications are performed using a Gilson Modular System equipped with a YMC Triart-500g-10 μm-76, 5 × 200 mm column (333 Pre-Scale HPLC Pump (water), 334 Presp-Scale HPLC Pump (acetonitrile), 334 Presp-Scale HPLC Pump (modifier: a solution of 5 mL of NHOH in 1000 mL of HO for basic elution [Purification Method G_B] or a solution of 20 mL of TFA in 1000 mL of HO [Purification Method G_A]), 171 Diode Array Detector, GX-271 Prep Liquid Handler, PrepFC Fraction Collector). Typical HPLC flow rates are 180 mL / min.

[0214] Where analytical methods are not specified in the following protocols, the methods used were similar to those described above. It will be apparent to those skilled in the art that similar analytical and preparative chromatographic methods exist and can be used for the following procedures.

[0215] III. Intermediate Intermediate C1: N-(4-acetylphenyl)-2-chloro-acetamide [ka] To a solution of 1-(4-aminophenyl)ethanone (2.0 g, 14.6 mmol) and triethylamine (2.5 mL, 18 mmol) in anhydrous DCM (14.6 mL) was added dropwise chloroacetyl chloride (1.4 mL, 18 mmol) at 0° C. The resulting mixture was slowly warmed to room temperature and stirred at room temperature for 18 hours. The reaction mixture was quenched by the addition of water and extracted with DCM. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (using a gradient from 0% EtOAc to 100% EtOAc in heptane as eluent) to give the title compound (2.65 g, yield: 86%) as a beige solid. LC-MS (Method B1_S) m / z: [M+H] + :212.0;rt:0.93min;purity:100%.

number

[0216] Intermediate C2: N-(4-acetyl-3-hydroxy-phenyl)-2-chloro-acetamide [ka] To a solution of 1-(4-amino-2-hydroxyphenyl)ethanone (200 mg, 1.32 mmol) and DIPEA (485 μL, 2.92 mmol) in anhydrous DCM (4.00 mL) under a N atmosphere, chloroacetyl chloride (172 μL, 2.12 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 16 h. Additional chloroacetyl chloride (40 μL, 0.49 mmol) was added, and the reaction mixture was further stirred at room temperature for 4 h. Upon completion, the reaction mixture was diluted with DCM (50 mL) and washed with water (2 × 50 mL). The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (using a gradient from 0% EtOAc to 100% EtOAc in heptane as the eluent) to afford the title compound as a brownish solid (163 mg, yield: 54%). LC-MS (Method A1_S) m / z:[M+H] + :227.9;rt:1.09min;purity:99%.

number

[0217] Intermediate L1: 2-[(10R)-3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetic acid, trifluoroacetate [ka] Step 1: Synthesis of dimethyl 2-(4-amino-3,5-dichloro-6-fluoro-2-pyridyl)propanedioate L1_1 [ka] 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 collected on a sinter, washed with water (2 L), and dried. Trituration with TBME (2 L) and washing with isohexane (1.5 L) afforded the title product (529 g, 84%) as a white crystalline solid.

number

[0218] Step 2: Synthesis of 3,5-dichloro-2-fluoro-6-methyl-pyridin-4-amine L1_2 [ka] To dimethyl 2-(4-amino-3,5-dichloro-6-fluoro-2-pyridyl)propanedioate (Intermediate L1_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 h, analysis by LCMS showed 87% conversion to the monoester. The temperature was increased to 125 °C. After 72 h, 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 collected 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 carbon (30 g) was added, and heating was continued. After 15 minutes, the warm mixture was filtered through Celite. Water (3 L, giving 1:1 ethanol:water) was added to the filtrate. The mixture was then cooled to 5°C for 20 hours. The crystals were collected on a sinter, washed with water (600 mL), and dried (Caution: solids are slightly volatile when dried at approximately 2 mbar and 50°C) to give the title product as an off-white solid (179 g, 77%).

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[0219] Step 3: Preparation of 2-fluoro-6-methyl-pyridin-4-amine L1_3 [ka] 3,5-Dichloro-2-fluoro-6-methyl-pyridin-4-amine (intermediate L1_2, 150 g, 769 mmol) and 5% palladium on carbon (49 g, 23 mmol) were solubilized in methanol (2.6 L) and pyridine (125 mL). The mixture was placed under a hydrogen atmosphere at 1 bar and heated to 50 °C for 18 h. 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 × 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%).

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[0220] Step 4: Synthesis of 2-fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine L1_4 [ka] In a nitrogen-filled glovebox, 2-fluoro-6-methyl-pyridin-4-amine (Intermediate L1_3, 138 mg, 1.04 mmol) was dissolved in anhydrous THF (1 mL) in a 6 mL pressure tube containing a magnetic stir bar. Pinacolborane (211 μL, 1.45 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. (1,5-Cyclooctadiene)(methoxy)iridium(I) 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 a 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 gas evolution ceased, then concentrated in vacuo. The crude brown oil was purified by column chromatography on silica gel (using a gradient of DCM / EtOAc from 100 / 0 to 50 / 50 as eluent) and trituration in hexane to give the title compound as a pale pink solid (200 mg, yield: 72%). LC-MS (Method B1) m / z: [M+H] + :253.0, rt:1.13min, purity:95%.

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[0221] Step 5: Synthesis of methyl 2-[3-(4-amino-2-fluoro-6-methyl-3-pyridyl)-2-pyridyl]propanoate L1_5 [ka] To a solution of 2-fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (Intermediate L1_4, 100 mg, 0.39 mmol) and methyl 2-(3-bromopyridin-2-yl)propanoate (102 mg, 0.40 mmol) in anhydrous toluene (2 mL) was added potassium carbonate (170 mg, 1.22 mmol). Argon was passed through the reaction mixture before the addition of tris(dibenzylideneacetone)dipalladium(0) (36 mg, 0.04 mmol) and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (17 mg, 0.04 mmol). The reaction mixture was then stirred at 100 °C for 4 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (10 mL) and filtered through a PTFE filter. The filtrate was concentrated in vacuo to give the crude title compound as a yellow oil (225 mg), which was used directly in the next step without purification. LC-MS (Method A1) m / z: [M+H] + :290; rt: 0.80, 0.84 and 0.92 min (as a mixture of diastereoisomers).

[0222] Step 6: 3-Fluoro-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one L1_6 [ka] To a solution of crude methyl 2-[3-(4-amino-2-fluoro-6-methyl-3-pyridyl)-2-pyridyl]propanoate (Intermediate L1_5, 115 mg, 0.40 mmol) in anhydrous toluene (2 mL) at 0 °C, a 1.5 M solution of lithium bis(trimethylsilyl)amide in THF (200 μL, 0.30 mmol) was added, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was neutralized by the addition of saturated aqueous NH4Cl at 0 °C and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated in vacuo to give a yellow solid. Purification by trituration in Et2O afforded the title compound as a brown solid (11 mg, yield: 10%). LC-MS (Method A1) m / z: [M+H] + :258.0;rt:0.93min;purity:94%.

[0223] Step 7: tert-Butyl 2-[(10R)-3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 Synthesis of ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetate L1_7 [ka] To a solution of intermediate L1_6 (1.05 g, 3.47 mmol) in anhydrous DMF (17 mL) was added tert-butyl bromoacetate (627 μL, 4.16 mmol), potassium carbonate (970 mg, 6.90 mmol), and potassium iodide (58 mg, 0.35 mmol), and the resulting mixture was stirred at room temperature for 20 h. Water was added, and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The crude orange oil was purified by flash chromatography on silica gel (using a gradient of heptane / EtOAc from 100 / 0 to 0 / 100) to give the title compound (1.22 g, yield: 92%) as a yellow solid. LC-MS (Method-A1) m / z: [M+H] +:372.4, rt:1.33min, purity:97%.

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[0224] The racemate (21.5 g) was separated by chiral SFC (Whelk O-1 (R,R) from Regis Technology, CO2 + iPrOH 20%) to give the title compound (9.22 g, yield: 45%). Chiral purity: 99%; rt = 2.52 min (first-eluting enantiomer). For reference, rt = 3.27 min for the second-eluting enantiomer. Both were determined by HPLC (Whelk O-1 (R,R) from Regis Technology, iPrOH 50% - heptane 50% - DEA 0.1%).

[0225] Step 8: 2-[(10R)-3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetic acid, trifluoroacetate salt L1 [ka] To a solution of intermediate L1_7 (2.28 g, 5.89 mmol) in DCM (18 mL) was added TFA (18 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was concentrated to dryness and co-evaporated with Et2O to give the title compound as a white solid (TFA salt, 2.85 g, yield: 94%). LC-MS (Method A1_S) m / z: [M+H] + :316.1;rt:0.92min;purity:99%.

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[0226] Intermediate L2: 3,14-difluoro-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Step 1: Synthesis of O1-tert-butyl O3-ethyl 2-(3-bromo-5-fluoro-2-pyridyl)propanedioate L2_1 [ka] 3-Bromo-2,5-difluoropyridine (163.3 g, 800 mmol) and dimethyl sulfoxide (3.2 L) were charged into a 5 L process reactor. To the stirred solution, tert-butyl ethyl malonate (300 mL, 1610 mmol) was added, followed by CsCO (652 g, 2000 mmol) at room temperature. The resulting reaction mixture was stirred at 100 °C (internal temperature) for 21 hours, then cooled to room temperature, quenched with ice-cold water (1.7 L), and extracted with tert-butyl methyl ether (4 × 1.5 L). The combined organic extracts were washed with water (2 × 1.5 L), brine (2 × 1.2 L), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product (266 g) as a tan residue, which was then purified by flash chromatography (silica, gradient from 0% ethyl acetate in isohexane to 15% ethyl acetate in isohexane) to give O1-tert-butyl O3-ethyl 2-(3-bromo-5-fluoro-2-pyridyl)propanedioate (120.6 g, 330 mmol, 42% yield) as a white solid that spontaneously precipitated from the chromatographed fractions. The precipitate was filtered off, the filtrate was concentrated, and the resulting yellow residue (67 g) was further purified by chromatography (silica, gradient from 0% ethyl acetate in hexane to 10% ethyl acetate in hexane). The resulting pale yellow solid was slurried with ethyl acetate (20 mL) and isohexane (20 mL) and filtered off. The solid was washed with isohexane (2 × 20 mL) to give O1-tert-butyl O3-ethyl 2-(3-bromo-5-fluoro-2-pyridyl)propanedioate (22.1 g, 61.0 mmol, 7.6% yield). LC-MS (Method B10) m / z: 306.0 / 308.0 (M-tBu+H), 262.0 / 264.0 (M-Boc+H); rt: 2.1 min, purity: 100%.

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[0227] Step 2: Synthesis of ethyl 2-(3-bromo-5-fluoro-2-pyridyl)acetate L2_2 [ka] A 2 L process reactor was charged with dichloromethane (400 mL) and trifluoroacetic acid (300 mL). To the stirred solution was added a freshly prepared solution of O1-tert-butyl O3-ethyl 2-(3-bromo-5-fluoro-2-pyridyl)propanedioate L2_1 (69.3 g, 191 mmol) in dichloromethane (400 mL) at room temperature. The reaction mixture was stirred at room temperature for 5 hours and then quenched by pouring into two stirred beakers of ice water (2 × 1.7 L). The stirred mixture was carefully neutralized to pH 7 with solid K3PO4. The mixture was then partitioned and the organic extracts were combined. The separated aqueous layer was extracted with dichloromethane (2 × 1 L). The combined organic extracts were washed with saturated NaHCO solution (1.5 L), dried over sodium sulfate, and concentrated in vacuo to give ethyl 2-(3-bromo-5-fluoro-2-pyridyl)acetate (53.6 g, 200 mmol, 100% yield) as a yellow oil. LC-MS (Method B10) m / z: 262.0 / 264.0 [M+H] + ;rt: 1.42 minutes, purity: 100%.

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[0228] Step 3: Synthesis of ethyl 2-(3-bromo-5-fluoro-2-pyridyl)propanoate L2_3 [ka] To a stirred solution of lithium diisopropylamide (2.0 M in THF / heptane / ethylbenzene, 56 mL, 110 mmol) in anhydrous tetrahydrofuran (340 mL) at −74 °C under nitrogen, a solution of ethyl 2-(3-bromo-5-fluoro-2-pyridyl)acetate L2_2 (28.3 g, 100 mmol) in anhydrous tetrahydrofuran (100 mL) was added dropwise via an addition funnel, maintaining the internal temperature below −70 °C. The resulting dark brown mixture was stirred at −72 °C for 30 min, after which iodomethane (9.6 mL, 150 mmol) was added dropwise. Stirring at −72 °C was continued for 30 min, after which the cooling bath was removed and the reaction mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was quenched with saturated NH4Cl solution (450 mL) and extracted with ethyl acetate (2 × 450 mL). The combined organic extracts were washed with water (450 mL) and brine (300 mL), dried over sodium sulfate, and concentrated in vacuo. Purification by chromatography (silica, gradient from 0% to 5% ethyl acetate in isohexane) afforded ethyl 2-(3-bromo-5-fluoro-2-pyridyl)propanoate (25.64 g, 92.86 mmol, 91% yield) as a yellow oil. LC-MS (Method B10) m / z: 276.0 / 278.0 [M+H] + ;rt: 1.74 minutes, purity: 100%.

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[0229] Step 4: 3,14-difluoro-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one L2 To a mixture of ethyl 2-(3-bromo-5-fluoro-2-pyridyl)propanoate (Intermediate L2, 2.00 g, 7.24 mmol), 2-fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (Intermediate L1, 2.19 g, 8.69 mmol), and KPO (3.17 g, 14.5 mmol) in anhydrous toluene (36 mL) under an argon atmosphere at room temperature, tris(dibenzylideneacetone)dipalladium(0) (663 mg, 0.72 mmol) was added, followed by 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (303 mg, 0.72 mmol). The resulting mixture was stirred at 100 °C for 2 h. After completion, the reaction mixture was diluted with EtOAc (100 mL) and filtered through Celite. The filtrate was concentrated to dryness. The residue was dissolved in anhydrous toluene (36 mL), followed by the addition of LiHMDS (1.5 M in THF, 9.70 mL, 14.5 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. After complete conversion, the reaction mixture was quenched with water (80 mL) and extracted with EtOAc (4 x 20 mL). The combined organic extracts were washed with brine, dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (using a gradient from 20% EtOAc to 100% EtOAc in heptane as eluent), then triturated in EtO (20 mL), filtered, and dried in vacuo to afford the title compound as a beige solid (634 mg, yield: 32%). LC-MS (Method A1_S) m / z: [M+H] + :276.0;rt:1.09min;purity:100%.

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[0230] Racemic intermediate L2 (74.8 g) was separated by Chiral SFC (Chiralpak IG from Daicel, CO2 + MeOH 35%). The desired enantiomer (first eluting product) was triturated in iPrOH (300 mL) at 45 °C, filtered, rinsed with iPrOH (30 mL), and dried under high vacuum at 50 °C for 2 h to give the title compound (34.3 g, yield: 46%) as a white solid. LC-MS (Method A2) m / z: [M+H] + :275.9;rt:3.71min;purity:100%. LC-MS (Method B2) m / z:[M+H] + :275.9 rt:3.61 min; Purity: 100%.

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[0231] Intermediate L3: 14-Fluoro-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2,4,6,12,14-hexaen-9-one [ka] To a solution of ethyl 2-(3-bromo-5-fluoro-2-pyridyl)propanoate (Intermediate L2_3, 1 g, 3.62 mmol) in 1,4-dioxane (14.5 mL) at room temperature in a 60 mL vial, 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (CAS: 1668475-78-2, 3.56 g, 5.43 mmol, 1.5 equiv.), potassium carbonate (1.52 g, 10.9 mmol, 3.01 equiv.), and water (3.6 mL) were added. The mixture was evacuated and backfilled with N (3x), followed by the addition of X-PHOS Pd G3 (161 mg, 0.18 mmol, 0.05 equiv.) and X-PHOS (88 mg, 0.18 mmol, 0.05 equiv.). The resulting mixture was evacuated and backfilled with N2 (3x) and then stirred at 100 °C for 3 h. The reaction mixture was diluted with EtOAc and water, filtered through a pad of Celite, and rinsed with EtOAc. The phases were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness to give the crude mixture as an orange solid, which was used in the next step without further purification. The residue (1.1 g) was dissolved in anhydrous THF (18 mL), and then LiHMDS (1.5 M in THF, 4.8 mL, 7.2 mmol) was added at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After complete conversion, the reaction mixture was diluted with methanol (5 mL), Celite was added, and the residue was concentrated to dryness and purified by flash chromatography on silica gel (using a gradient from 0% MeOH to 10% MeOH in DCM as the eluent) to give the title compound as a pale yellow solid (842 mg, yield: 90%). LC-MS (Method A1_S) m / z:[M+H] + :258;rt:0.70min;purity:100%.

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[0232] Intermediate L4: (10R)-3-chloro-14-fluoro-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Step 1: Synthesis of 3-bromo-2-chloro-6-methyl-pyridin-4-amine L4_1 [ka] A solution of 2-chloro-6-methyl-pyridin-4-amine (10.0 g, 66.6 mmol) in anhydrous acetonitrile (300 mL) was cooled to 0° C., then N-bromosuccinimide (11.3 g, 63.3 mmol) was added over 1 h, and the reaction mixture was stirred at 0° C. for 3 h, then allowed to warm to room temperature and stirred for a further 18 h. The reaction mixture was then concentrated in vacuo and purified by column chromatography on silica gel (using a gradient from 0% EtOAc to 50% EtOAc in isohexane as eluent) to afford the title compound (7.05 g, yield: 47%) as a yellow solid.

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[0233] Step 2: Synthesis of ethyl 2-[5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]propanoate L4_2 [ka] To a nitrogen-sparged suspension of ethyl 2-(3-bromo-5-fluoro-2-pyridyl)propanoate L2_3 (86% pure, 1.50 g, 4.67 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.4 g, 5.61 mmol), and CH3COOK (1.8 g, 18.7 mmol) in 1,4-dioxane (13 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) DCM complex (172 mg, 0.21 mmol) was added, and the reaction mixture was sparged with nitrogen for an additional 10 minutes. The suspension was heated at reflux for 4 hours. The reaction mixture was allowed to cool to room temperature and then filtered through Celite, washing with EtOAc (100 mL). The filtrate was concentrated under reduced pressure and then purified by column chromatography on silica gel (using a gradient from 0% EtOAc to 100% EtOAc in isohexane as eluent) to give the title compound as a clear, colorless oil (950 mg, yield: 35%) that partially crystallized on standing. LC-MS (Method A9) m / z [M+H] + :324.4;rt:1.27min, purity:55%.

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[0234] Step 3: (10R)-3-chloro-14-fluoro-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one L4 To a solution of 3-bromo-2-chloro-6-methyl-pyridin-4-amine (Intermediate L4_1, 860 mg, 3.87 mmol) and ethyl 2-[5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]propanoate (Intermediate L4_2, 2.09 g, 4.46 mmol) in 1,4-dioxane (31 mL), CsF (5 M in water, 1.94 mL, 9.70 mmol) was added, followed by bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (140 mg, 0.19 mmol). The resulting mixture was stirred at 85 °C for 16 h. After completion, the reaction mixture was filtered through a pad of Celite and rinsed with EtOAc. The filtrate was concentrated to dryness. The residue was dissolved in anhydrous toluene (20 mL), and then LiHMDS (1.5 M in THF, 7.70 mL, 11.6 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was concentrated under vacuum. The residue was purified twice by flash chromatography on silica gel (first, by using a gradient of 0% MeOH to 5% MeOH in DCM as eluent, and second, by using a gradient of 0% EtOAc to 70% EtOAc in heptane as eluent) to give the title compound as a white solid (333 mg, yield: 30%). LC-MS (Method A1_S) m / z: [M+H] + :292;rt:1.16min;purity:100%.

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[0235] Intermediate L5: 3-chloro-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2,4,6,12,14-hexaen-9-one enantiomer (10R) or (10S) [ka] or [ka] Step 1: Synthesis of ethyl 2-(3-bromo-2-pyridyl)acetate L5_1 [ka] To a solution of 3-bromo-2-methyl-pyridine (5.00 g, 29.1 mmol) in anhydrous THF (100 mL) at -78 °C, LiHMDS (1 M solution in THF, 58 mL, 58.0 mmol) was added, 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 HO (200 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were dried over anhydrous NaSO 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%.

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[0236] Step 2: Synthesis of ethyl 2-(3-bromo-2-pyridyl)propanoate L5_2 [ka] Ethyl 2-(3-bromo-2-pyridyl)acetate (Intermediate L5_1, 30.0 g, 117 mmol) was dissolved in anhydrous 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. Iodomethane (21.5 g, 152 mmol) was added and the reaction mixture was stirred for an additional 1 h at 0 °C. The solution was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (using a gradient from 0% MTBE to 60% MTBE in isohexane as eluent) to give the title compound (29.5 g, yield: 96%) as a pale yellow oil. LC-MS (Method A7) m / z: [M+H] + :258 / 260;rt:1.93min;purity:99%.

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[0237] Step 3: Synthesis of ethyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]propanoate L5_3 [ka] Ethyl 2-(3-bromo-2-pyridyl)propanoate (Intermediate L5_2, 30.0 g, 116 mmol), bis(pinacolato)diboron (35.4 g, 139 mmol), and potassium acetate (45.6 g, 465 mmol) were suspended in anhydrous 1,4-dioxane (500 mL), and the reaction mixture was degassed with nitrogen for 10 minutes. Pd(dppf)Cl2 (5.95 g, 8.14 mmol) was added, and the reaction mixture was stirred at 80 °C for 24 hours. The reaction mixture was cooled to room temperature and filtered through a small pad of Celite®. The filter cake was rinsed with EtOAc (200 mL), and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with a gradient from 0% MTBE to 100% MTBE in isohexane) to give the title compound (32.3 g, 45% yield) as a yellow oil.

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[0238] Step 4: 3-chloro-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Synthesis of the enantiomer (10R) or (10S) of pentadeca-1(11),2,4,6,12,14-hexaen-9-one L5 A mixture of 3-bromo-2-chloro-6-methyl-pyridin-4-amine (Intermediate L4_1, 400 mg, 1.81 mmol), ethyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]propanoate (Intermediate L5_3, 1.10 g, 2.53 mmol), cesium fluoride (768 mg, 5.06 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (64 mg, 0.090 mmol) in 1,4-dioxane (34 mL) and water (1.7 mL) was purged with nitrogen and then heated at reflux for 18 hours. The reaction was allowed to cool to room temperature and then filtered through a bed of Celite®, washing with EtOAc (100 mL). The filtrate was concentrated in vacuo and then taken up in absolute EtOH (16 mL), to which potassium carbonate (499 mg, 3.61 mmol) was added and the reaction mixture was heated at 65° C. for 4 hours. The reaction mixture was concentrated in vacuo, then water (75 mL) was added and the reaction mixture was extracted with EtOAc (3×75 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (using a gradient from 0% EtOAc to 100% EtOAc in isohexane as eluent) to give the title compound (178 mg, yield: 35%) as an off-white solid. LC-MS (Method A7) m / z: [M+H] + :274;rt:1.45min;purity:99%.

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[0239] The racemate was separated by chiral chromatography (SFC, Chiralpak AS from Daicel, CO2 + isopropanol 20%). Chiral purity 98.6%; rt = 1.79 min (second-eluting enantiomer, L5). For reference, first-eluting enantiomer: rt = 1.62 min. Both were determined by HPLC, Chiralpak AS from Daicel, solvent: heptane 50% - ethanol 50% - DEA 0.1%.

[0240] Intermediate L6: N-(4-acetylphenyl)-2-(3,5-difluoro-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl)acetamide [ka] Step 1: Synthesis of 2,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine L6_1 [ka] In a 60 mL vial, a suspension of 4,4'-di-tert-butyl-2,2'-dipyridyl (63 mg, 0.23 mmol, 0.03 equiv.) and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (76 mg, 0.115 mmol, 0.015 equiv.) in anhydrous THF (1.2 mL) was added to a solution of 2,6-difluoropyridin-4-amine (1.0 g, 7.740 mmol) and bis(pinacolato)diboron (3.9 g, 15 mmol, 2.0 equiv.) in anhydrous THF (5.8 mL) under a N atmosphere. The reaction mixture was sparged with N and stirred at 80 °C for 20 h. The reaction mixture was slowly poured into MeOH (50 mL) and then concentrated to dryness. The brown residue was purified by column chromatography on silica gel (eluent: 0% EtOAc to 30% EtOAc in DCM) to give the title intermediate as a white solid (1.73 g, yield: 71%). LC-MS (Method B1) m / z: [M+H] + :257.3, rt:1.15min, purity:81%.

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[0241] Step 2: 3,5-difluoro-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one L6_2 [ka] To 2,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (Intermediate L6_1, 48.2 g, 0.19 mmol), an aqueous solution of potassium phosphate (2 M, 190 mL) was added, followed by a solution of ethyl 2-(3-bromo-2-pyridyl)propanoate (Intermediate L5_2, 44.0 g, 170 mmol) in dioxane (380 mL). Under a nitrogen atmosphere, 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (8.1 g, 19.0 mmol) and tris(dibenzylideneacetone)dipalladium(0) (8.7 g, 9.4 mmol) were added, and the resulting mixture was heated to 80 °C (internal temperature) and stirred for 1.5 hours. The reaction mixture was cooled to 20°C (internal temperature), filtered through a pad of Celite, washed with ethyl acetate (2 x 500 mL), and the filtrate was concentrated in vacuo. The resulting mixture was diluted with ethyl acetate (800 mL), washed with water (2 x 500 mL), saturated sodium bicarbonate (500 mL), brine (500 mL), dried over sodium sulfate, and concentrated to dryness to give the crude product (95.5 g) as a dark brown residue. Purification by column chromatography on silica gel (eluent: 0% ethyl acetate in isohexane, gradient from 100% ethyl acetate) gave ethyl 2-[3-(4-amino-2,6-difluoro-3-pyridyl)-2-pyridyl]propanoate (34.6 g, 90 mmol, yield: 48%) as a tan oil. LC-MS (Method B9) m / z: [M+H] + :=308.2, purity >99%, rt: 1.30 and 1.41 min as a mixture of diastereoisomers.

[0242] Under a nitrogen atmosphere, a 1 M solution of lithium bis(trimethylsilyl)amide in THF (130 mL, 130 mmol) was added via a dropping funnel to a solution of ethyl 2-[3-(4-amino-2,6-difluoro-3-pyridyl)-2-pyridyl]propanoate (42.8 g, 110 mmol) in anhydrous THF (450 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour, then allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralized with saturated ammonium chloride solution (500 mL) and water (250 mL). Ethyl acetate (500 mL) was then added and stirred at room temperature for 15 minutes. The separated aqueous layer was extracted with ethyl acetate (500 mL), and the combined organic extracts were washed with water (2 × 500 mL), brine (500 mL), dried over sodium sulfate, and evaporated in vacuo. The crude solid was slurried in ethyl acetate (100 mL), isohexane (100 mL) was added, and the solid was collected by filtration, washed with isohexane (50 mL x 2), and dried under vacuum to give the title intermediate L6_2 (22.33 g, yield: 77%) as an off-white solid. LC-MS (Method B9) m / z: [M+H] + :262.0, rt:1.13 min, purity >99%.

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[0243] Step 3: N-(4-acetylphenyl)-2-(3,5-difluoro-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 Synthesis of pentadeca-1(11),2,4,6,12,14-hexaen-8-yl)acetamide L6 3,5-Difluoro-10-methyl-4,8,12-triazatricyclo[9.4.0.0] in DMF (15 mL) 2,7To a solution of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one L6_2 (646 mg, 2.5 mmol) and N-(4-acetylphenyl)-2-chloro-acetamide (Intermediate C1, 520 mg, 2.5 mmol), K2CO3 (1030 mg, 7.4 mmol) and KI (422 mg, 2.5 mmol) were added. The reaction mixture was then stirred overnight at room temperature. The reaction mixture was poured into 50 mL of AcOEt. The organic layer was washed with 100 mL of water, 100 mL of NaCl solution, and 100 mL of water. The organic layer was dried over MgSO4, filtered, and the solvent was removed under high vacuum to give the crude product (94% yield). LC-MS (Method A1_S) m / z: [M+H] + : 437.1, rt: 1.25 min, purity 92%. The crude product was used as is in the next step.

[0244] Intermediate L7: 3-chloro-5-(2,2-difluoro-5-azaspiro[2.3]hexan-5-yl)-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2,4,6,12,14-hexaen-9-one [ka] Step 1: Synthesis of tert-butyl N-[2-chloro-6-(2,2-difluoro-5-azaspiro[2.3]hexan-5-yl)-4-pyridyl]carbamate L7_1 [ka] To a solution of tert-butyl(2,6-dichloropyridin-4-yl)carbamate (300 mg, 1.08 mmol) and 1,1-difluoro-5-azaspiro[2.3]hexane hydrochloride (177 mg, 1.08 mmol) in anhydrous toluene (3.2 mL) at room temperature under a N atmosphere, Pd2dba3 (51 mg, 0.05 mmol), BINAP (70 mg, 0.11 mmol), and potassium tert-butoxide (273 mg, 2 0.38 mmol) was added. The reaction mixture was stirred at 90° C. for 16 hours. After completion, the reaction mixture was filtered through Celite, rinsed with EtOAc, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (using a gradient from 0% EtOAc to 100% EtOAc in heptane as eluent) to afford the title compound as a white solid (247 mg, yield: 66%). LC-MS (Method A1_S) m / z: [M+H] + :346.1;rt:1.59min;purity:99%.

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[0245] Step 2: Synthesis of 2-chloro-6-(2,2-difluoro-5-azaspiro[2.3]hexan-5-yl)pyridin-4-amine, trifluoroacetate salt L7_2 [ka] To a solution of intermediate L7_1 (247 mg, 0.71 mmol) in DCM (2.9 mL) at room temperature, trifluoroacetic acid (2.7 mL, 35.7 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was used as the TFA salt in the next step without further purification. LC-MS (Method A1_S) m / z: [M+H]+: 246.0; rt: 0.89 min; purity: 88%.

[0246] Step 3: Synthesis of 2-chloro-6-(2,2-difluoro-5-azaspiro[2.3]hexan-5-yl)-3-iodo-pyridin-4-amine L7_3 [ka] To a solution of intermediate L7_2 (1.00 mmol) in MeCN (2 mL) was added a solution of N-iodosuccinimide (213 mg, 0.90 mmol) in MeCN (2 mL). The resulting mixture was stirred at room temperature for 2 h. Additional N-iodosuccinimide (70 mg, 0.30 mmol) was added, and the reaction mixture was further stirred at room temperature for 1 h. After completion, the reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (using a gradient from 0% EtOAc to 25% EtOAc in heptane as eluent) to afford the title compound as a brownish solid (240 mg, yield: 64%). LC-MS (Method A1_S) m / z: [M+H] + :371.9;rt:1.39min;purity:100%.

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[0247] Step 4: Synthesis of ethyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]acetate L7_4 [ka] Under an inert atmosphere, to a suspension of ethyl 2-(3-bromo-2-pyridyl)acetate (Intermediate L5_1, 5.00 g, 20.5 mmol), bis(pinacolato)diboron (CAS 73183-34-3, 6.24 g, 24.6 mmol), potassium acetate (8.0 g, 81.9 mmol), and 3 Å molecular sieves (3 g) in 1,4-dioxane (200 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (749 mg, 1.02 mmol). The suspension was heated at reflux overnight and then cooled to room temperature. It was filtered through a pad of Celite® and washed with ethyl acetate (400 mL). The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (eluent: 0-100% tert-butyl methyl ether in cyclohexane) to give the title compound as a brown oil (2.35 g, yield: 37%). LC-MS (Method B5) m / z: [M+H] + :292.2;rt:2.08 minutes, purity:95%.

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[0248] Step 5: 3-chloro-5-(2,2-difluoro-5-azaspiro[2.3]hexan-5-yl)-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2,4,6,12,14-hexaen-9-one L7 The reaction was divided into three batches. Under a N atmosphere, to a solution of intermediate L7_3 (60 mg, 0.16 mmol) and ethyl 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetate L7_4 (73 mg, 0.24 mmol) in anhydrous toluene (0.81 mL) was added K3PO4 (105 mg, 0.48 mmol), CataCXium A (6 mg, 0.02 mmol), followed by Pd2dba3 (15 mg, 0.02 mmol). The resulting mixture was stirred at 100 °C for 16 h. Upon completion, the reaction mixture was filtered through Celite, rinsed with EtOAc, and concentrated in vacuo. The residue was dissolved in anhydrous THF (0.8 mL), followed by the addition of LiHMDS (1 M in THF, 480 μL, 0.48 mmol). The resulting mixture was stirred at room temperature for 1 hour. After complete conversion, the reaction mixture was quenched with water and extracted with EtOAc (3x). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (using a gradient from 0% EtOAc to 100% EtOAc in heptane as eluent) to give the title compound as a brown solid (16 mg, yield: 23%). LC-MS (Method A1_S) m / z: [M+H] + :363.0;rt:1.13min;purity:85%.

[0249] Intermediate L8: 2-(1-fluoro-3-methyl-6-oxo-7H-pyrido[4,3-d][3]benzazepin-5-yl)acetic acid, hydrochloride [ka] Step 1: Synthesis of 1-fluoro-3-methyl-5,7-dihydropyrido[4,3-d][3]benzazepin-6-one L8_1 [ka] Under an argon atmosphere, a suspension of 2-fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (Intermediate L1_4, 3.00 g, 11.9 mmol), methyl 2-(2-bromophenyl)acetate (1.92 mL, 11.9 mmol), K2CO3 (4.98 g, 35.7 mmol), and Pd(dppf)Cl2 (436 mg, 0.60 mmol) in 1,4-dioxane (40 mL) and water (2.4 mL) was stirred at 100 °C for 18 h. Upon completion, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water (2x), brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated in DCM, filtered, rinsed with DCM and dried in vacuo to give the title compound as a beige solid (944 mg, yield: 33%). LC-MS (Method B1_S) m / z: [M+H] + :243.1;rt:1.10min;purity:100%.

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[0250] Step 2: Synthesis of tert-butyl 2-(1-fluoro-3-methyl-6-oxo-7H-pyrido[4,3-d][3]benzazepin-5-yl)acetate L8_2 [ka] To a suspension of intermediate L8_1 (892 mg, 3.68 mmol), K2CO3 (1.03 g, 7.36 mmol), and potassium iodide (62 mg, 0.37 mmol) in DMF (15 mL) was added tert-butyl bromoacetate (666 μL, 4.42 mmol). The resulting mixture was stirred at room temperature for 18 hours. Upon completion, water was added. The resulting precipitate was collected by filtration, rinsed with water, Et2O, and dried in vacuo to give the title compound as a white solid (1.29 g, yield: 95%). LC-MS (Method B1_S) m / z: [M+H] + :357.2;rt:1.48min;purity:99%.

[0251] Step 3: Synthesis of 2-(1-fluoro-3-methyl-6-oxo-7H-pyrido[4,3-d][3]benzazepin-5-yl)acetic acid, hydrochloride L8 To a solution of intermediate L8_2 (1.24 g, 3.47 mmol) in DCM (17 mL) at room temperature was added HCl (4.0 M in 1,4-dioxane, 8.67 mL, 34.7 mmol). The resulting mixture was stirred at room temperature for 18 hours. After completion, the precipitate was collected by filtration, rinsed with DCM (3×), and dried in vacuo to give the title compound as the HCl salt (1.07 g, yield: 86%). LC-MS (Method B1_S) m / z: [M+H] + :301.0;rt:0.77min;purity:100%.

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[0252] Intermediate L9: 2-[3-fluoro-5-methoxy-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetic acid, hydrochloride enantiomer (10R) or (10S) [ka] or [ka] Step 1: Synthesis of 2-fluoro-6-methoxy-pyridin-4-amine L9_1 [ka] A solution of 2,6-difluoropyridin-4-amine (760 mg, 5.84 mmol) and sodium methoxide (5.4 M solution in methanol, 2.4 mL, 12.9 mmol) in anhydrous THF (29 mL) was heated at reflux for 4 h. The reaction mixture was diluted with water (30 mL) and then extracted with EtOAc (3 × 30 mL). The combined extracts were washed with brine (60 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (using a gradient from 0% EtOAc to 60% EtOAc in isohexane as eluent) to give the title compound (725 mg, yield: 78%) as a yellow oil. LC-MS (Method A7) m / z: [M+H] + :143;rt:0.96min;purity:55%.

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[0253] Step 2: Synthesis of 2-fluoro-6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine L9_2 [ka] A solution of 2-fluoro-6-methoxy-pyridin-4-amine (Intermediate L9_1, 211 mg, 1.34 mmol) in anhydrous THF (6.4 mL) was degassed with nitrogen for 5 minutes, and then 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.20 mL, 1.43 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes, and then bis(pinacolato)diboron (CAS 73183-34-3, 376 mg, 1.48 mmol), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (36 mg, 0.134 mmol), and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (45 mg, 0.07 mmol) were added. The resulting mixture was degassed with nitrogen for 5 minutes, and then stirred at 80 °C overnight. The reaction mixture was filtered through a pad of Celite, washed with EtOAc (10 mL), and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: 0% EtOAc to 100% EtOAc in isohexane) to give the title compound (265 mg, yield: 59%) as a white solid. LC-MS (Method A7) m / z: [M+H] + :269;rt:2.02min;purity:70%.

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[0254] Step 3: Synthesis of ethyl 2-[3-(4-amino-2-fluoro-6-methoxy-3-pyridyl)-2-pyridyl]propanoate L9_3 [ka] A suspension of ethyl 2-(3-bromo-2-pyridyl)propanoate (Intermediate L5_2, 2.90 g, 11.0 mmol), 2-fluoro-6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (Intermediate L9_2, 4.56 g, 13.8 mmol), and CsF (5.85 g, 38.5 mmol) was poured into a mixture of toluene (12.0 mL), EtOH (6.0 mL), and water (6.0 mL). The mixture was purged with nitrogen for 10 minutes, and then PEPPSI™-IPr (CAS 905459-27-0, 748 mg, 1.10 mmol) was added. The reaction mixture was purged with nitrogen for an additional 5 minutes and heated at 80 °C for 16 hours. The reaction mixture was cooled to room temperature and filtered through a pad of Celite®, washing with EtOAc (50 mL). The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (using a gradient from 0% MeOH to 5% MeOH in DCM as eluent) to give the title compound as a yellow solid (1.73 g, yield: 42%). LC-MS (Method A7) m / z [M+H] + :320.2;rt:1.71min;purity:87%.

[0255] Step 4: 3-Fluoro-5-methoxy-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 Synthesis of the enantiomer (10S) or (10R) of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one L9_4 [ka] or [ka] To a solution of ethyl 2-[3-(4-amino-2-fluoro-6-methoxy-3-pyridyl)-2-pyridyl]propanoate (Intermediate L9_3, 1.96 g, 5.52 mmol) in anhydrous THF (50.0 mL) was added dropwise a 1 M solution of lithium bis(trimethylsilyl)amide in THF (11.0 mL, 11.0 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was treated with ice water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to give the title compound as a light brown powder (1.59 g, quantitative yield). LC-MS (Method A7) m / z [M+H] + :274.1;rt:1.59min;purity:96%.

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[0256] Step 5: tert-Butyl 2-(3-fluoro-5-methoxy-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 Synthesis of the enantiomer (10R) or (10S) of pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetate L9_5 [ka] or [ka] 3-Fluoro-5-methoxy-10-methyl-4,8,12-triazatricyclo[9.4.0.0] in DMF (18 mL) 2,7 To a solution of the enantiomer (10S) or (10R) of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one (intermediate L9_4, 1.00 g, 3.66 mmol), KI (305 mg, 1.82 mmol), and KCO (1.02 g, 7.31 mmol) was added tert-butyl bromoacetate (660 μL, 4.38 mmol). The resulting mixture was stirred at room temperature for 2 h. After complete conversion, water (80 mL) was added, and the reaction mixture was extracted with EtOAc (3 × 80 mL). The combined organic extracts were washed with brine (2 × 200 mL), dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: 0% EtOAc to 40% EtOAc in heptane gradient) to give the title compound (1.37 g, yield: 94%) as a white solid. LC-MS (Method A2) m / z: [M+H] + :388.2;rt:4.68min;purity:98%. LC-MS (Method B2) m / z:[M+H] + :388.1;rt:4.59min;purity:97%.

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[0257] Step 6: 2-[3-fluoro-5-methoxy-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 Synthesis of the enantiomers (10R) or (10S) of ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetic acid, hydrochloride L9 tert-Butyl 2-(3-fluoro-5-methoxy-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0]) in DCM (34 mL) 2,7 To a solution of the enantiomer (10S) or (10R) of pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetate (Intermediate L9_5, 1.36 g, 3.42 mmol) was added HCl (4 M in 1,4-dioxane, 8.55 mL, 34.2 mmol). The resulting mixture was stirred at room temperature for 5 hours. Additional HCl (4 M in 1,4-dioxane, 1.71 mL, 6.84 mmol) was added, and the reaction mixture was further stirred at room temperature for 17 hours. The reaction mixture was concentrated in vacuo to give the title compound (HCl salt, 1.41 g, quantitative yield) as a white solid. LC-MS (Method A2) m / z: [M+H] + :332.1;rt:3.43min;purity:89%. LC-MS (Method B2) m / z:[M+H] + :332.0;rt:2.45min;purity:94%.

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[0258] Intermediate L10: 3-Fluoro-14-methoxy-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] A mixture of intermediate L1_4 (415 mg, 1.65 mmol), intermediate L11_1 (395 mg, 1.37 mmol), and potassium phosphate tripotassium (594 mg, 2.74 mmol) in toluene (11 mL) was degassed with nitrogen for 10 minutes, after which tris(dibenzylideneacetone)dipalladium(0) (128 mg, 0.14 mmol) and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (57 mg, 0.14 mmol) were added. The reaction mixture was heated at 90 °C for 3 hours. Upon completion, the reaction mixture was filtered through Celite and washed with EtOAc. The filtered wax was concentrated in vacuo to give a yellow oil.

[0259] The crude oil was dissolved in toluene (13.7 mL) and lithium bis(trimethylsilyl)amide (1.5 M in THF, 2.7 mL) was added at room temperature under a N2 atmosphere. The reaction mixture was stirred at room temperature. After 1 h, the reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to dryness to give a beige solid. The residue was triturated with Et2O / DCM (75 / 25), and the solid was filtered to give the title compound (203 mg, yield: 52%). LC-MS (Method B1_S) m / z: [M+H]+: 288; rt: 1.05 min; purity: 89%.

[0260] Intermediate L11: 14-Methoxy-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Step 1: Synthesis of ethyl 2-(3-bromo-5-methoxy-2-pyridyl)propanoate L11_1 [ka] To a solution of ethyl 2-(3-bromo-5-fluoro-2-pyridyl)propanoate (L2_3, 1.0 g, 3.62 mmol) in anhydrous DMF (18 mL) cooled to 0 °C, a 25% solution of sodium methoxide in methanol (1.5 mL, 6.52 mmol) was added, and the reaction mixture was allowed to reach room temperature over 1 h. The reaction mixture was treated with water and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated to dryness to give the title intermediate L11_1 (848 mg, yield: 81%) as a crude yellow oil, which was used in the next step without purification. LC-MS (Method A2) m / z [M+H] + :270.1;rt:1.40 minutes.

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[0261] Step 2: 14-Methoxy-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one L11 A suspension of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (CAS: 1668475-78-2, 1.04 g, 1.64 mmol), ethyl 2-(3-bromo-5-methoxy-2-pyridyl)propanoate (L11_1, 395 mg, 1.37 mmol), and potassium phosphate (594 mg, 2.74 mmol) in anhydrous toluene (11 mL) was degassed with argon. Tris(dibenzylideneacetone)dipalladium(0) (128 mg, 0.18 mmol) and 2-dicyclohexylphosphino-2,6-dimethoxybenzyl (57 mg, 0.14 mmol) were added. The vial was sealed under an argon atmosphere, and the reaction mixture was heated at 90 °C for 3 h. After cooling to room temperature, the reaction mixture was filtered through a pad of Celite and rinsed with EtOAc. The filtrate was concentrated in vacuo to give a crude oil, which was redissolved in anhydrous toluene (14 mL). To this solution was added a 1.5 M solution of lithium bis(trimethylsilyl)amide in THF (2.7 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was treated with water and extracted twice with EtOAc. The combined organic extracts were washed with brine, then dried over MgSO, filtered, and concentrated to dryness to give a brown solid. Trituration in a 75 / 25 mixture of EtO:DCM and sonication afforded the title product (258 mg, yield: 70%) as a white solid. LC-MS (Method B2) m / z [M+H] + :270.1; Purity: 97%, rt: 0.89 min.

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[0262] Intermediate L12: 3-Methoxy-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2,4,6,12,14-hexaen-9-one [ka] Step 1: Synthesis of 3-bromo-2-methoxy-6-methyl-pyridin-4-amine L12_1 [ka] To a solution of 2-methoxy-6-methyl-pyridin-4-amine (505 mg, 3.47 mmol) in DCM (25 mL) at 0 °C, a suspension of NBS (618 mg, 3.47 mmol) in DCM (10 mL) was added, and the reaction mixture was stirred at 0 °C for 1 h. Water (40 mL) was added, and the aqueous layer was extracted with DCM (2 × 30 mL). The combined organic extracts were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (using 0-4% MeOH (0.7 N in NH3) in DCM as eluent) to give the title compound as a colorless oil (653 mg, yield: 86%). LC-MS (Method B5) m / z: [M+H] + :217.1 / 219.1;rt:1.57min;Purity>99%.

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[0263] Step 2: Synthesis of ethyl 2-(4'-amino-2'-methoxy-6'-methyl-[3,3'-bipyridin]-2-yl)propanoate L12_2 [ka] To a stirred mixture of 3-bromo-2-methoxy-6-methylpyridin-4-amine (Intermediate L12_1) (1.60 g, 7.37 mmol), ethyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]propanoate (Intermediate L5_3, 3.29 g, 8.85 mmol), and 1.5M KCO aqueous solution (14.5 mL, 22.0 mmol) in anhydrous 1,4-dioxane (100 mL), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (522 mg, 0.737 mmol) was added, and the reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was cooled to room temperature and filtered through a small pad of Celite. The filter cake was rinsed with EtOAc (150 mL), and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient from 0% (0.7M NH3 / MeOH) to 100% (0.7M NH3 / MeOH) in DCM as eluent to give the title compound (3.24 g, yield: 73%) as a brown oil. LC-MS (Method A7) m / z [M+H] + :316.2;rt:0.90min;purity:53%.

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[0264] Step 3: 3-Methoxy-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one L12_3 Ethyl 2-[3-(4-amino-2-methoxy-6-methyl-3-pyridyl)-2-pyridyl]propanoate (Intermediate L12_2, 3.24 g, 5.45 mmol) was dissolved in EtOH (70 mL) and potassium carbonate (1.50 g, 10.9 mmol) was added. The reaction mixture was stirred at 90° C. for 16 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in water (30 mL) and extracted with EtOAc (4×50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (1.99 g, yield: 92%) as a white solid. The product was carried on to the next step without further purification. LC-MS (Method A7) m / z [M+H] + :270.2;rt:1.50min;purity:68%.

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[0265] Intermediate L13: 3,14-difluoro-5,10-dimethyl-4,8,13-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Step 1: Synthesis of (E) and (Z) 4-bromo-2-fluoro-5-(2-methoxyvinyl)pyridine L13_1 [ka] To a solution of (methoxymethyl)triphenylphosphonium chloride (184 mg, 0.54 mmol) in anhydrous THF (2.40 mL) was added sodium bis(trimethylsilyl)amide (750 μL, 0.75 mmol, 1 M in THF) under a N atmosphere at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes, and then a solution of 4-bromo-6-fluoronicotinaldehyde (100 mg, 0.47 mmol) in anhydrous THF (2.40 mL) was added dropwise. The resulting mixture was stirred at 0° C. for 30 minutes and then at room temperature for 30 minutes. After complete conversion, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: 0% EtOAc to 10% EtOAc in heptane gradient) to give a mixture of isomers E and Z of the title compound as a colorless oil (66.9 mg, yield: 62%). LC-MS (Method A1_S) m / z: [M+H] + : 232.0 / 234.0; mixture of E / Z isomers, rt: 1.37 min and 1.40 min; purity: 100%. Isomer E:

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[0266] Step 2: Synthesis of 2-(4-bromo-6-fluoro-3-pyridyl)acetaldehyde L13_2 [ka] A solution of hydrochloric acid (12 M in water, 300 μL, 3.49 mmol) diluted with water (300 μL) was added dropwise to a solution of intermediate L13_1 (53 mg, 0.23 mmol) in acetone (5.7 mL). The resulting mixture was stirred at 50° C. for 3 hours. After completion, the reaction mixture was concentrated in vacuo to give the title compound as a brown solid, which was used directly in the next step without purification (42.9 mg, yield: 86%).

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[0267] Step 3: Synthesis of 2-(4-bromo-6-fluoro-3-pyridyl)acetic acid L13_3 [ka] To a solution of intermediate L13_2 (42.9 mg, 0.20 mmol) and 2-methyl-2-butene (210 μL, 1.96 mmol) in tert-butyl alcohol (2 mL) was added a solution of sodium dihydrogen phosphate (118 mg, 0.98 mmol) in water (0.8 mL), followed by the portionwise addition of sodium chlorite (27 mg, 0.24 mmol). The resulting mixture was stirred at room temperature for 1 h. After completion, the reaction mixture was quenched with water (20 mL) and 4 M aqueous HCl (5 mL), followed by extraction with DCM (3 × 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford the crude title compound as a yellow oil, which was used directly in the next step without purification. LC-MS (Method A1_S) m / z: [M+H] + :233.9 / 235.9;rt:0.91min;purity:70%.

[0268] Step 4: Synthesis of 2-(4-bromo-6-fluoro-3-pyridyl)propanoic acid L13_4 [ka] To a solution of crude intermediate L13_3 (41.0 mg, 0.18 mmol) in anhydrous THF (1.7 mL) at −78° C. under a N atmosphere, lithium bis(trimethylsilyl)amide (1 M in THF, 350 μL, 0.35 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 30 minutes. Iodomethane (12.1 μL, 0.19 mmol) was then added dropwise, and the reaction mixture was stirred at room temperature for 2 hours. Upon completion, the reaction mixture was quenched by the addition of water (10 mL), followed by 4 M aqueous HCl (10 mL). The mixture was extracted with DCM (2×20 mL) and then with CHCl / iPrOH (4:1 v / v, 3×20 mL). The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo to afford the crude title compound as a brown oil, which was used directly in the next step without purification. LC-MS (Method A1_S) m / z:[M+H] + :247.9 / 249.9;rt:1.04min;purity:60%.

[0269] Step 5: Synthesis of methyl 2-(4-bromo-6-fluoro-3-pyridyl)propanoate L13_5 [ka] To a solution of crude intermediate L13_4 (39.4 mg, 0.16 mmol) in anhydrous acetonitrile (0.80 mL) was added potassium carbonate (66.5 mg, 0.47 mmol), followed by iodomethane (12.5 μL, 0.21 mmol). The reaction mixture was stirred at room temperature for 16 hours. Additional iodomethane (12.5 μL, 0.21 mmol) was added, and the reaction mixture was stirred at room temperature for 5 hours. Upon completion, the reaction mixture was quenched with water (15 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (using a gradient from 0% EtOAc to 20% EtOAc in heptane as the eluent) to afford the title compound as a yellow oil (12.5 mg, yield: 22% over three steps). LC-MS (Method A1_S) m / z: [M+H] +:261.9 / 263.9;rt:1.29min;purity:91%.

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[0270] Step 6: 3,14-difluoro-5,10-dimethyl-4,8,13-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one L13 To a solution of intermediate L13_5 (12.5 mg, 0.04 mmol) and intermediate L1_4 (16.4 mg, 0.06 mmol) in anhydrous toluene (0.22 mL) under a N atmosphere, potassium phosphate tripotassium (28.1 mg, 0.13 mmol), 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (2 mg, 0.005 mmol), followed by tris(dibenzylideneacetone)dipalladium(0) (4 mg, 0.004 mmol) were added. The resulting mixture was stirred at 100 °C for 3 h. After completion, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The residue was dissolved in anhydrous toluene (220 μL), and then lithium bis(trimethylsilyl)amide (1 M in THF, 130 μL, 0.13 mmol) was added under a N atmosphere. The resulting mixture was stirred at room temperature for 2 hours. Upon completion, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (purification method P_B) to give the title compound as a white solid (1.7 mg, yield: 14%). LC-MS (method A4) m / z: [M+H] + :276.1;rt:3.37min;purity:100%.

[0271] Intermediate L14: 3-Methoxy-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Step 1: 3-Fluoro-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one L14_1 [ka] To a solution of 4-amino-3-bromo-2-fluoropyridine (75 mg, 0.37 mmol) and ethyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]propanoate (Intermediate L5_3, 244 mg, 0.74 mmol) in 1,4-dioxane (1.9 mL) was added KCO (104 mg, 0.74 mmol) and water (82 μL). After degassing the reaction mixture with nitrogen for 5 minutes, Pd[(Amphos)Cl] (CAS 887919-35-9, 14 mg, 0.02 mmol) was added, and the reaction mixture was stirred at 100 °C for 20 h. After cooling to room temperature, water was added, and the reaction mixture was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated to dryness. The residue was then dissolved in anhydrous toluene (2.4 mL) and cooled to 0° C., after which a 1.5 M solution of LiHMDS in THF (0.37 mL, 0.56 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 1.5 hours. Saturated aqueous NH4Cl was added, and the reaction mixture was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was triturated in Et2O, filtered, and dried in vacuo to give the title compound as an off-white solid (45 mg, yield: 50%). LC-MS (Method B1) m / z [M+H] + :244.1;rt:0.89min;purity:96%.

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[0272] Step 2: 3-Methoxy-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one A suspension of intermediate L14_1 (461 mg, 1.90 mmol) and potassium carbonate (794 mg, 5.69 mmol) in methanol (6.3 mL) was stirred at 70° C. for 4 days. After completion, the reaction mixture was quenched with water (40 mL) and extracted with EtOAc (4×10 mL). The combined organic layers were washed with brine (40 mL), dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a white solid (303 mg, yield: 58%). LC-MS (Method A1_S) m / z: [M+H] + :256.1;rt:0.87min;purity:92%. LC-MS (Method B1_S) m / z:[M+H] + :256.1;rt:0.94min;purity:94%.

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[0273] Intermediate L15: 3-Fluoro-5-methoxy-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] The title compound was prepared by following the same reaction sequence as described for intermediate L9_4, but starting from intermediate L9_2 and intermediate L2_3. The first step (Suzuki reaction) was carried out using Pd2dba3, SPhos, and K3PO4 in toluene at 100 °C. The second step was carried out using LiHMDS in THF at room temperature, both steps being similar to those described for intermediate L9_4. LC-MS (Method B1_S) m / z: [M+H] + :292;rt:1.23min;purity:90%.

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[0274] Intermediate L16: 2-(3,14-difluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide [ka] To a solution of intermediate L2 (300 mg, 1.09 mmol) in DMF (5.5 mL) at room temperature was added iodoacetamide (224 mg, 1.20 mmol) and potassium carbonate (183 mg, 1.31 mmol). The resulting mixture was stirred at room temperature for 16 hours. After completion, water (15 mL) was added and the reaction mixture was stirred at room temperature for 30 minutes. The precipitate was filtered through a glass frit, rinsed with water, and dried in vacuo to give the title compound as a white solid (328 mg, yield: 91%). LC-MS (Method A1_S) m / z: [M+H] + :333.1;rt:0.97min;purity:97%.

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[0275] Intermediate L17: (3-oxobenzofuran-6-yl)trifluoromethanesulfonate [ka] To a suspension of 6-hydroxy-2H-benzofuran-3-one (500 mg, 3.33 mmol) in anhydrous DCM (10 mL) at room temperature, pyridine (0.82 mL, 10.0 mmol) was added. The mixture was cooled to 0 °C, and then trifluoromethanesulfonic anhydride (1 M in DCM, 5.33 mL, 5.33 mmol) was added. The reaction mixture was stirred at 0 °C for 2 h. Upon completion, water (15 mL) was added, and the reaction mixture was extracted with DCM (3 × 15 mL). The combined organic layers were washed with 1 M aqueous citric acid solution (2 × 20 mL), then saturated aqueous NaHCO (20 mL), brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (using a gradient from 0% EtOAc to 30% EtOAc in heptane as the eluent) to afford the title compound as a yellow solid (601 mg, yield: 61%). LC-MS (Method A1_S) m / z: no mass response; rt: 1.35 min; purity: 96%.

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[0276] Step 1: Synthesis of 4-bromo-3-(bromomethyl)isothiazole L18_1 [ka] To a vial charged with 4-bromo-3-methylisothiazole (500 mg, 2.68 mmol), N-bromosuccinimide (712 mg, 4.00 mmol), and 1,2-dichloroethane (20 mL) was added 2,2'-azobis(2-methylpropionitrile) (88 mg, 0.54 mmol). The vial was sealed, and the reaction mixture was stirred and heated at 80 °C for 16 h to give a yellow solution. The reaction mixture was quenched with water (30 mL) and extracted twice with EtOAc (2 × 50 mL). The combined organic layers were separated, dried over anhydrous MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: 0% to 10% EtOAc in heptane over 10 CV) to give the title compound as a pale yellow oil (660 mg, yield: 96%). LC-MS (Method A1_S) m / z:[M+H] + :257;rt:1.29min;purity:62%.

[0277] Step 2: Synthesis of 2-(4-bromoisothiazol-3-yl)acetonitrile L18_2 [ka] To a solution of intermediate L18_1 (660 mg, 2.5686 mmol) in anhydrous acetonitrile (12 mL) was added trimethylsilyl cyanide (1.0 mL, 7.6 mmol) followed by tetrabutylammonium fluoride (1 mol / L in THF, 3.8 mL) at 0 °C, and the reaction was stirred at room temperature for 16 h. The reaction mixture was quenched with water (100 mL) and extracted twice with EtOAc (2 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo to give a brown oil. The resulting crude product was purified by column chromatography on silica gel (using 0% to 50% EtOAc in heptane over 13 CV as the eluent) to give the title compound as a colorless oil (200 mg, yield: 38%). LC-MS (Method A1_S) m / z: no mass response; rt: 0.99 min; purity: 100%.

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[0278] Step 3: Synthesis of methyl 2-(4-bromoisothiazol-3-yl)acetate L18_3 [ka] To a solution of intermediate L18_2 (200 mg, 0.98 mmol) in anhydrous methanol (4 mL) was added a solution of hydrochloric acid (4 mol / L in 1,4-dioxane, 1.2 mL) at room temperature, and the reaction mixture was heated at 70 °C for 4 days. After completion, methanol was removed under vacuum, and the reaction mixture was quenched with a saturated aqueous solution of NaHCO3 (10 mL) and extracted three times with EtOAc. The combined organic layers were separated, dried over MgSO4, and concentrated under vacuum. The resulting crude product was purified by column chromatography on silica gel (using 5% to 40% EtOAc in heptane over 7 CV as the eluent) to afford the title compound as a colorless oil (137 mg, yield: 59%). LC-MS (Method A1_S) m / z: [M+H] + :237 / 239;rt:1.10min;purity:96%.

[0279] Step 4: Synthesis of methyl 2-(4-bromoisothiazol-3-yl)propanoate L18_4 [ka] In a dry vial under an argon atmosphere, a solution of diisopropylamine (100 μL, 0.70 mmol) in anhydrous THF (0.2 mL) was cooled at 0 °C, and then n-butyllithium (1.4 mol / L in THF, 0.5 mL) was added dropwise. The reaction mixture was then cooled to -78 °C and stirred for 10 min. A solution of intermediate L18_3 (137 mg, 0.58 mmol) in anhydrous THF (0.3 mL) was added dropwise at -78 °C, and the reaction mixture was stirred at -78 °C for 10 min.

[0280] Iodomethane (55 μL, 0.87 mmol) was added and the reaction mixture was allowed to reach room temperature over 30 min. Upon completion, the reaction mixture was quenched with a saturated solution of NH4Cl and water at 0 °C and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude product was purified by column chromatography on silica gel (using 0% to 15% EtOAc in heptane over 10 CV as eluent) to afford the title compound as a colorless oil (93 mg, yield: 51%). LC-MS (Method A1_S) m / z: [M+H] + :252;rt:1.24min;purity:80%.

[0281] Step 5: 14-Fluoro-7,12-dimethyl-4-thia-5,9,13-triazatricyclo[8.4.0.0 2,6 ]Synthesis of tetradeca-1(10),2,5,11,13-pentaen-8-one L18 A mixture of intermediate L1_4 (50 mg, 0.20 mmol), intermediate L18_4 (50 mg, 0.20 mmol), and potassium carbonate (84 mg, 0.60 mmol) in 1,4-dioxane (2 mL) was degassed with nitrogen for 10 minutes, followed by the addition of XPHOS PD G3 (18 mg, 0.02 mmol). The reaction mixture was heated at 80 °C for 4 hours. Upon completion, the reaction mixture was partitioned between water and a saturated aqueous solution of NH4Cl and EtOAc. The resulting mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a yellow oil. The crude product was dissolved in anhydrous THF (2 mL), and lithium bis(trimethylsilyl)amide (1.5 M in THF, 80 μL) was added at room temperature under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 hours and then poured into a saturated aqueous solution of water and NH4Cl. The resulting mixture was extracted twice with EtOAc, and the combined organic layers were washed with brine. The resulting solution was dried over MgSO, filtered, and concentrated to dryness to give a white solid. The residue was triturated with EtO, and the solid was filtered to give the title compound (30 mg, yield: 32%). LC-MS (Method A1_S) m / z: [M+H] +:264;rt:1.06min;purity:100%.

[0282] Intermediate L19: 3-Fluoro-5-(1-hydroxycyclobutyl)-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(15),2,4,6,11,13-hexaen-9-one [ka] Step 1: Synthesis of 2-bromo-6-fluoro-pyridin-4-amine L19_1 [ka] 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 anhydrous DMSO (30 mL) at room temperature. The reaction mixture was stirred at 140° C. for 18 hours. After completion, the reaction mixture was cooled with ice (100 g), diluted with water (250 mL), and then extracted three times with ethyl acetate (100 mL). The combined organic layers were washed twice with brine (100 mL), dried over Na2SO4, filtered, and concentrated to dryness to give a brown solid. The solution was concentrated under vacuum, and the residue was purified by column chromatography on silica gel (using a gradient from 0% MeOH to 25% MeOH in DCM) to give the title compound (773 mg, yield: 28%) as a white solid. LC-MS (Method B4) m / z: [M+H] + :191 / 193;rt:0.92min;purity:100%.

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[0283] Step 2: Synthesis of 2-bromo-6-fluoro-N-trityl-pyridin-4-amine L19_2 [ka] To a solution of intermediate L19_1 (773 mg, 4.18 mmol) and triphenylmethyl chloride (1.25 g, 4.35 mmol) in dichloromethane (8 mL) was added N,N-diisopropylethylamine (765 μL, 4.61 mmol). The reaction mixture was stirred at 40° C. for 48 h. The reaction mixture was concentrated to dryness to give a yellow foam, which was purified by column chromatography on silica gel (using a gradient from 0% EtOAc to 25% EtOAc in heptane) to give the title compound (1.18 g, yield: 59%) as a white solid. LC-MS (Method A1_S) m / z: [M+H] + :435 / 437;rt:1.76min;purity:97%.

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[0284] Step 3: Synthesis of 1-[6-fluoro-4-(tritylamino)-2-pyridyl]cyclobutanol L19_3 [ka] To a solution of intermediate L19_2 (500 mg, 1.15 mmol) in THF (12 mL) at −78° C., n-butyllithium (1.5 mol / L in hexane, 2.89 mL) was added, and the reaction mixture was stirred at −78° C. for 1 h. After 1 h, cyclobutanone (195 μL, 2.55 mmol) was added at −78° C., and the reaction mixture was allowed to slowly reach room temperature. After 18 h, EtOAc (30 mL) and water (30 mL) were added, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed three times with water and brine. The resulting solution was dried over MgSO4, filtered, and concentrated to dryness to give a yellow oil. The residue was purified by column chromatography on silica gel (using a gradient from 0% EtOAc to 60% EtOAc in heptane) to give the title compound (206 mg, yield: 34%) as a white solid. LC-MS (Method A1_S) m / z: [M+H] + :425;rt:1.76min;purity:85%.

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[0285] Step 4: Synthesis of 1-(4-amino-6-fluoro-2-pyridyl)cyclobutanol L19_4 [ka] To a solution of intermediate L19_3 (206 mg, 0.39 mmol) in 1,4-dioxane (4 mL), hydrochloric acid (4 mol / L in 1,4-dioxane, 924 μL) was added and the reaction mixture was stirred at 60° C. After 6 h, the reaction mixture was concentrated in vacuo to give the title compound (98 mg, yield: 89%) as a brown oil. LC-MS (Method A1_S) m / z:[M+H] + :183;rt:0.67min;purity:90%.

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[0286] Step 5: Synthesis of 1-(4-amino-5-bromo-6-fluoro-2-pyridyl)cyclobutanol L19_5 [ka] To a solution of intermediate L19_4 (98 mg, 0.20 mmol) in acetonitrile (0.2 mL) at 0° C., N-bromosuccinimide (40 mg, 0.23 mmol) was added slowly. The resulting mixture was stirred at 0° C. for 30 minutes. The resulting mixture was concentrated in vacuo to give an orange oil. The residue was purified by preparative HPLC (purification method P_A) to give the title compound (108 mg, yield: 98%) as a white solid. LC-MS (method B4) m / z: [M+H] + :243 / 245;rt:3.14min;purity:100%.

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[0287] Step 6: 3-fluoro-5-(1-hydroxycyclobutyl)-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(15),2,4,6,11,13-hexaen-9-one L19 A mixture of intermediate L5_3 (152 mg, 0.50 mmol), intermediate L19_5 (108 mg, 0.41 mmol), tripotassium phosphate (179 mg, 0.83 mmol), and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (17 mg, 0.04 mmol) in 1,4-dioxane (2 mL) and water (124 μL) was degassed with nitrogen for 10 minutes, and then tris(dibenzylideneacetone)dipalladium(0) (38 mg, 0.04 mmol) was added. The reaction mixture was heated at 100 °C for 16 hours. EtOAc (5 mL) and water (5 mL) were added to the reaction mixture. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to dryness to give a black oil. The crude product was dissolved in anhydrous THF (0.8 mL), and lithium bis(trimethylsilyl)amide (1.5 M in THF, 34 μL) was added at room temperature under a N atmosphere. The reaction mixture was stirred at room temperature for 2 hours. After 2 hours, water and ethyl acetate were added, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed three times with water and brine. The resulting solution was dried over MgSO, filtered, and concentrated to dryness to give a yellow oil. The residue was purified by column chromatography on silica gel (using a gradient from 0% EtOAc to 100% EtOAc in heptane) to give the title compound (32 mg, yield: 95%). LC-MS (Method B1_S) m / z: [M+H] + :314;rt:1.06min;purity:96.5%.

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[0288] Intermediate L20: 3,14-difluoro-5-(hydroxymethyl)-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7]Pentadeca-1(11),2,4,6,12,14-hexaen-9-one [ka] Step 1: Synthesis of tert-butyl N-(2-bromo-6-fluoro-4-pyridyl)-N-tert-butoxycarbonyl-carbamate L20_1 [ka] To a solution of intermediate L19_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 to give an orange oil. The residue was purified by column chromatography on silica gel (using a gradient from 0% EtOAc to 20% EtOAc in heptane over 10 CV) to give the title compound (1.13 g, yield: 78%) as a white solid. LC-MS (Method A1_S) m / z:[M+H] + :391 / 393;rt:1.70min;purity:98%.

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[0289] Step 2: Synthesis of tert-butyl N-[2-fluoro-6-(hydroxymethyl)-4-pyridyl]carbamate L20_2 [ka] To a solution of intermediate L20_1 (781 mg, 2.00 mmol), hexakis(μ-acetato)tripalladium(II) (269 mg, 0.40 mmol), and butyldi-1-adamantylphosphine (301 mg, 0.80 mmol) in N,N-dimethylformamide (3.3 mL) was added N,N,N',N'-tetramethylethylenediamine (466 mg, 4.00 mmol). The reaction mixture was placed under 5 bar of synthesis gas at 100 °C for 16 h. Upon completion, the reaction mixture was filtered through Celite. The filtrate was extracted with EtOAc, washed three times with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a black oil. The residue was dissolved in methanol (18 mL) at 0 °C, followed by the addition of sodium borohydride (132 mg, 3.31 mmol). The reaction mixture was stirred at room temperature for 4 h. After completion, the reaction mixture was quenched with water and extracted three times with EtOAc. The resulting mixture was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (purification method P_A) to give the title compound as a white solid (163 mg, yield: 37%). LC-MS (method A1_S) m / z: [M+H-Boc] + :143;rt:1.24min;purity:98%.

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[0290] Step 3: Synthesis of (4-amino-6-fluoro-2-pyridyl)methanol L20_3 [ka] To a solution of intermediate L20_2 (163 mg, 0.65 mmol) in dichloromethane (6.5 mL) was added trifluoroacetic acid (490 μL, 6.53 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. After completion, the reaction mixture was concentrated in vacuo. The residue was dissolved in water and DCM, extracted three times with DCM, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (56 mg, yield: 48%) as a brown oil. LC-MS (Method A1_S) m / z: [M+H] +:143;rt:0.35min;purity:94%.

[0291] Step 4: Synthesis of (4-amino-5-bromo-6-fluoro-2-pyridyl)methanol L20_4 [ka] To a solution of intermediate L20_3 (56 mg, 0.27 mmol) in acetonitrile (0.2 mL) at 0 °C, N-bromosuccinimide (20 mg, 0.11 mmol) was added slowly. The resulting mixture was stirred at room temperature for 15 minutes. The resulting mixture was concentrated in vacuo to give a brown oil. The residue was dissolved in DCM and water, extracted with DCM, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a white solid (45 mg, yield: 67%). LC-MS (Method A1_S) m / z:[M+H] + :222 / 224;rt:0.81min;purity:98%.

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[0292] Step 5: 3,14-difluoro-5-(hydroxymethyl)-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2,4,6,12,14-hexaen-9-one L20 To a solution of intermediate L20_4 (35 mg, 0.16 mmol), intermediate L4_2 (176 mg, 0.19 mmol) in 1,4-dioxane (0.8 mL) and water (48 μL) was added 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (7 mg, 0.02 mmol) and potassium phosphate tripotassium (69 mg, 0.32 mmol). The reaction mixture was degassed with nitrogen for 10 minutes, and then tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.02 mmol) was added. The reaction mixture was heated at 100° C. for 18 hours. After completion, EtOAc (5 mL) and water (5 mL) were added to the reaction mixture. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to dryness to give a brown oil. The crude oil was dissolved in anhydrous THF (0.7 mL) and lithium bis(trimethylsilyl)amide (1.5 M in THF, 25 μL) was added under N atmosphere. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (using a gradient from 0% EtOAc to 100% EtOAc in heptane) to give the title compound (19 mg, yield: 92%) as a yellow oil. LC-MS-Acid (Method A1_S) m / z: [M+H] + :290;rt:0.92min;purity:94%.

[0293] Intermediate L21: 5-cyclobutyl-3-fluoro-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(15),2,4,6,11,13-hexaen-9-one [ka] Step 1: Synthesis of 2-cyclobutyl-6-fluoro-pyridin-4-amine L21_1 [ka] To a mixture of intermediate L19_1 (650 mg, 3.40 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (524 mg, 0.68 mmol), and cuprous iodide (129 mg, 0.68 mmol) in 1,4-dioxane (34 mL) at room temperature under an argon atmosphere, cyclobutylzinc bromide (20 mL, 0.5 M in THF) was added. The reaction mixture was then stirred at 80 °C. After 1 h, the reaction mixture was quenched with ice and a saturated aqueous solution of NH4Cl, then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness to give a black oil. The residue was purified by column chromatography on silica gel (using a gradient from 0% EtOAc to 15% EtOAc in heptane) to give the title compound (630 mg, yield: 100%) as a red oil. LC-MS (Method A1_S) m / z:[M+H] + :167;rt:0.91min;purity:90.1%.

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[0294] Step 3: Synthesis of 3-bromo-6-cyclobutyl-2-fluoro-pyridin-4-amine L21_2 [ka] To a solution of intermediate L21_1 (860 mg, 4.14 mmol) in acetonitrile (20 mL) at 0 °C, N-bromosuccinimide (736 mg, 4.14 mmol) was added slowly. The resulting mixture was stirred at 0 °C for 10 min. The reaction mixture was treated with a saturated aqueous solution of NaHCO and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over NaSO, filtered, and concentrated in vacuo to give a black oil. The residue was purified by column chromatography on silica gel (using a gradient from 0% EtOAc to 20% EtOAc in heptane) to give the title compound (459 mg, yield: 43%) as a white solid. LC-MS (Method A1_S) m / z: [M+H] +:245 / 247;rt:1.38min;purity:96.3%.

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[0295] Step 4: 5-Cyclobutyl-3-fluoro-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(15),2,4,6,11,13-hexaen-9-one L21 A mixture of intermediate L5_3 (800 mg, 2.62 mmol), intermediate L21_2 (460 mg, 1.79 mmol), cesium fluoride (800 mg, 5.26 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (90 mg, 0.13 mmol) in 1,4-dioxane (15 mL) and water (1.3 mL) was degassed with nitrogen for 10 minutes. The reaction mixture was heated at 80 °C for 16 hours. The reaction mixture was diluted with a saturated aqueous solution of NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give a brown oil. The crude product was dissolved in anhydrous THF (10 mL), and lithium bis(trimethylsilyl)amide (1.5 M in THF, 2.5 mL) was added at room temperature under a N2 atmosphere. The reaction mixture was stirred at room temperature for 1 hour. After 1 hour, water and ethyl acetate were added and the layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed three times with water and brine. The resulting solution was dried over MgSO4, filtered, and concentrated to dryness to give a brown solid. The residue was purified by column chromatography on silica gel (using a gradient from 0% MeOH to 13% MeOH in DCM) to give the title compound (260 mg, yield: 41%). LC-MS (Method A1_S) m / z: [M+H]+: 298; rt: 1.31 min; purity: 83.9%.

[0296] Intermediate L22: 2-Fluoro-5,9-dimethyl-6-oxo-6,7-dihydro-5H-benzo[b]pyrido[3,2-d]azepine-10-carbonitrile [ka] Step 1: Synthesis of 4-amino-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile L22_1 [ka] 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, and the Celite pad was washed with EtOAc (150 mL). The filtrate was concentrated and the resulting residue was purified by column chromatography on silica gel (eluent: 0-70% EtOAc / iso-hexane gradient) to give the title compound as a white solid (892 mg, yield: 47%). LC-MS (Method B5) m / z [M+H] + :259.2;rt:2.02min;purity:100%.

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[0297] Step 2: Synthesis of 2-fluoro-5,9-dimethyl-6-oxo-5,7-dihydropyrido[2,3-d][1]benzazepine-10-carbonitrile L22 To a mixture of intermediate L22_1 (531 mg, 2.06 mmol), intermediate L2_3 (500 mg, 1.53 mmol), and CsF (464 mg, 3.05 mmol) in 1,4-dioxane (25 mL) and water (1.5 mL), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (54 mg, 0.08 mmol) was added. The reaction mixture was stirred at 90° C. for 18 hours and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (using a gradient of 10% MeOH (0.7 M NH) / DCM as eluent) to give the title compound (250 mg, yield: 52%) as an off-white solid. LC-MS (Method B5) m / z [M+H] + :282.0;rt:1.22min;purity:82%.

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[0298] Intermediate L23: 3,5-difluoro-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2,4,6,12,14-hexaen-9-one [ka] Starting from intermediate L6_1 and intermediate L5_1, the title compound was prepared according to the same reaction sequence as that described for intermediate L6_2. The first step (Suzuki reaction) was carried out using CsF, PEPPSI-Ipent, heated in H2O / toluene at 80 °C. The second step was carried out at room temperature using LiHMDS (3 equivalents) in toluene (17% yield over two steps), both steps being similar to those described for intermediate L6_2. LC-MS (Method A7) m / z [M+H] + :248.1;rt:1.32 minutes.

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[0299] Intermediate L24: 3-Fluoro-5-methoxy-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Step 1: Synthesis of 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine L24_1 [ka] To a flame-dried 100 mL three-neck round-bottom flask under nitrogen was added 4-amino-2-methoxypyridine (1.0 g, 7.8 mmol), bis(pinacolato)diboron (4.0 g, 16 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (100 mg, 0.15 mmol), and 4,4'-di-tert-butyl-2,2'-dipyridyl (90 mg, 0.32 mmol). The flask was evacuated and backfilled with nitrogen three times before the addition of anhydrous 1,4-dioxane (20 mL). The reaction mixture was stirred at 75 °C (internal temperature) for 17 h and then cooled to room temperature. Careful attention was paid to the solution mixture, which was used directly in the next step (gas evolution in the next step).

[0300] Step 2: 3-Fluoro-5-methoxy-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one L24 Starting from intermediate L24_1 and intermediate L2_3, the title compound was prepared according to the same reaction sequence as that described for intermediate L3. The first step (Suzuki reaction) was carried out using Pd2dba3, SPhos, and K3PO4 in toluene at 100 °C. The second step was carried out using LiHMDS in THF at room temperature, both steps being similar to those described for intermediate L3. LC-MS (Method B1_S) m / z [M+H] + :274;rt:1.04 minutes.

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[0301] Intermediate L25: 11-fluoro-9-(3-fluoroazetidin-1-yl)-5-methyl-5,7-dihydropyrido[2,3-d][1]benzazepin-6-one [ka] Step 1: Synthesis of 5-chloro-3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline L25_1 [ka] A flame-dried 250 mL, three-necked round-bottom flask under nitrogen was charged with bis(pinacolato)diboron (15 g, 58 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (190 mg, 0.28 mmol), and 4,4'-di-tert-butyl-2,2'-bipyridyl (160 mg, 0.58 mmol). The flask was evacuated and backfilled with nitrogen three times before adding a solution of 3-chloro-5-fluoroaniline (4.3 g, 29 mmol) in anhydrous tetrahydrofuran (60 mL) under nitrogen. The stirred mixture was heated at 65 °C (internal temperature) for 19 h and then cooled to room temperature. Methanol (30 mL) was carefully added to the cooled reaction mixture, and the resulting solution was stirred at room temperature for 30 min and then concentrated in vacuo. Purification by flash chromatography (Biotage Selekt, Sfar Silica HCD, 100 g, 0-20% ethyl acetate in hexanes) afforded 5-chloro-3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (6.60 g, 23 mmol, 80% yield) as an off-white solid. LC-MS m / z: 272.0 [M+H] + ;Purity: 96%.

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[0302] Step 2: Synthesis of 9-chloro-11-fluoro-5-methyl-5,7-dihydropyrido[2,3-d][1]benzazepin-6-one L25_2 [ka] Starting from intermediate L25_1, methyl 2-(3-bromopyridin-2-yl)propanoate, CsF, bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) in dioxane / water heated at 80 ° C., followed by cyclization with LiHMDS in THF at 0 ° C., the title compound was prepared following the same reaction sequence as described for intermediate L3 (45% yield). LC-MS m / z: 277.0 / 279.0 [M+H]+ ;Purity: 100%.

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[0303] Step 3: Synthesis of 11-fluoro-9-(3-fluoroazetidin-1-yl)-5-methyl-5,7-dihydropyrido[2,3-d][1]benzazepin-6-one To a mixture of intermediate L25_2 (100 mg, 0.36 mmol) and 3-fluoroazetidine hydrochloride (60 mg, 0.51 mmol) in 1,4-dioxane (3 mL), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (30 mg, 0.04 mmol) was added, followed by 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (17 mg, 0.04 mmol). The vial was sonicated and purged under argon, after which sodium tert-butoxide (105 mg, 1.09 mmol) was added. The vial was sealed, and the reaction mixture was heated at 90 °C for 4 h. Upon completion, water and EtOAc were added. The combined organic layers were washed with brine, separated, dried over MgSO, filtered, and concentrated in vacuo. The residue was triturated with DCM to give the title compound (68 mg, yield: 60%) as a white solid. LC-MS (Method A1_S) m / z: [M+H]: 316.1; rt: 1.09 min; purity: 90%.

[0304] Intermediate L26: 14-chloro-4-fluoro-7,12-dimethyl-5,6,9,13-tetrazatricyclo[8.4.0.0 2,6 ]Tetradeca-1(14),2,4,10,12-pentaen-8-one [ka] Step 1: Synthesis of 3-fluoro-1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole L26_1 To a solution of 3-fluoro-1-tetrahydropyran-2-yl-pyrazole (4.61 g, 26.5 mmol) (CAS 2200261-28-3) in THF (100 mL) at -70 °C, a solution of n-BuLi in hexane (2.5 M, 12.7 mL, 31.9 mmol) was added dropwise. The reaction mixture was stirred at -70 °C for 1 hour. Triisopropyl borate (7.4 mL, 31.9 mmol) was added at -78 °C, and the reaction mixture was stirred at this temperature for 30 minutes, then allowed to warm to room temperature and stirred for 1 hour. Pinacol (3.76 g, 31.9 mmol) and AcOH (3.1 mL, 54.5 mmol) were added, and the reaction mixture was stirred at room temperature overnight. Water (100 mL) was added, and the aqueous phase was extracted with EtOAc (3 × 75 mL). The combined organics were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: 0% TBME to 100% TBME in isohexane) to give the title compound as an off-white solid (7.3 g, yield: 84%). LC-MS m / z [M-166+H] + :131.2; Purity: 98% (215nm).

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[0305] Step 2: Synthesis of 2-chloro-3-(5-fluoro-2-tetrahydropyran-2-yl-pyrazol-3-yl)-6-methyl-pyridin-4-amine L26_2 A solution of 3-fluoro-1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole L26_1 (1.0 g, 3.1 mmol), 3-bromo-2-chloro-6-methyl-pyridin-4-amine L4_1 (1.0 g, 4.7 mmol), CsF (951 mg, 6.26 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (332 mg, 0.470 mmol) in 1,4-dioxane (35 mL) and water (7 mL) was sparged with nitrogen. The reaction mixture was heated at reflux overnight and then cooled to room temperature. The solution was filtered through a pad of Celite and washed with EtOAc (150 mL). The filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: 0% EtOAc to 100% EtOAc in isohexane) to give the title compound as a yellow wax (950 mg, yield: 59%). LC-MS m / z [M+H] + : 311.2, 313.2; rt: 0.79 and 0.92 min (as a mixture of diastereoisomers); purity: 96%.

[0306] Step 3: Synthesis of 2-chloro-N-[2-chloro-3-(5-fluoro-2-tetrahydropyran-2-yl-pyrazol-3-yl)-6-methyl-4-pyridyl]propenamide L26_3 To a solution of 2-chloro-3-(5-fluoro-2-tetrahydropyran-2-yl-pyrazol-3-yl)-6-methyl-pyridin-4-amine L26_2 (1.05 g, 2.0 mmol) in DMF (18 mL) was added NaH (60% pure, 97.3 mg, 2.4 mmol) at 0 °C. The solution was stirred for 30 min, and then 2-chloropropanoyl chloride (0.28 mL, 2.84 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h, then allowed to reach room temperature and stirred for 1 h. Water (50 mL) was added, and the aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with brine (100 mL), dried over Na SO , filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent: 0% EtOAc to 100% EtOAc in isohexane) to give the title compound as a yellow oil (183 mg, yield: 21%). LC-MS m / z [M+H] + : 401.0, 403.0; rt: 1.16 and 2.00 min (as a mixture of diastereoisomers); purity: 94%.

[0307] Step 4: 13-chloro-7-(1-chloroethyl)-4-fluoro-11-methyl-5,6,8,12-tetrazatricyclo[7.4.0.0 2,6 Synthesis of ]trideca-1(13),2,4,7,9,11-hexaene L26_4 A solution of 2-chloro-N-[2-chloro-3-(5-fluoro-2-tetrahydropyran-2-yl-pyrazol-3-yl)-6-methyl-4-pyridyl]propanamide #389_3 (288 mg, 0.703 mmol) and HCl (4 M in 1,4-dioxane, 2.0 mL, 8.0 mmol) was stirred at room temperature overnight. The reaction mixture was evaporated to dryness to give the title compound as an off-white solid (155 mg, yield: 64%). LC-MS m / z [M+H] + :299.1, 301.1; Purity: 96%.

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[0308] Step 5: 14-chloro-4-fluoro-7,12-dimethyl-5,6,9,13-tetrazatricyclo[8.4.0.0 2,6 ]Synthesis of tetradeca-1(14),2,4,10,12-pentaen-8-one L26 13-chloro-7-(1-chloroethyl)-4-fluoro-11-methyl-5,6,8,12-tetrazatricyclo[7.4.0.0] in DMSO (2.00 mL) 2,6 To a suspension of ]trideca-1(13),2,4,7,9,11-hexaene L26_4 (155 mg, 0.508 mmol) was added aqueous NaOH (2 M, 0.51 mL, 1.0 mmol). The resulting orange solution was stirred at room temperature for 1 hour, and then water (20 mL) was added, followed by AcOH (0.5 mL). The resulting suspension was filtered, and the solid was washed with water and dried under vacuum to give the title compound as an off-white solid (120 mg, 83% yield). LC-MS m / z [M+H] + :281.1, 283.1; Purity: 100%.

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[0309] IV. Examples Example #1: N-(4-acetylphenyl)-2-[(10R)-3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide [ka] To a solution of intermediate L1 (20 mg, 0.055 mmol) and HATU (27 mg, 0.071 mmol) in anhydrous DMF (0.275 mL) was added 1-(4-aminophenyl)ethanone (15 mg, 0.11 mmol) followed by diisopropylethylamine (47 μL, 0.285 mmol), and the reaction mixture was stirred at room temperature for 3 h. After complete conversion, the reaction mixture was purified by preparative HPLC (purification method P_B) to give the title compound as a white solid (13.4 mg, yield: 56%). LC-MS m / z: [M+H] + :433.2;Purity:95%. High-resolution mass (method HRMS_A2) m / z(+H); Observed mass: 433.168; Expected mass: 433.1676(C 24 H 21 for FN4O3); (rt: 1.87 min, purity: 96.3%).

[0310] Example #2: N-[4-(cyclopropanecarbonyl)phenyl]-2-[(10R)-3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide [ka] Starting from intermediate L1 (30 mg, 0.08 mmol) and (4-aminophenyl)-cyclopropyl-methanone hydrochloride (32 mg, 0.16 mmol), the title compound was prepared according to the same procedure as in Example #1. After complete conversion, the reaction mixture was purified by preparative HPLC (purification method P_B) and then by SFC (Phenomenex Luna 5 μm silica (2) 100A, CO2 + EtOH 15%) to give the title compound as a white solid (7.4 mg, yield: 19%). LC-MS (method A2') m / z [M+H] + :459;rt:4.24min;purity:97%. LC-MS (Method B2) m / z[M+H] + :459;rt:4.03min;purity:99%.

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[0311] Example #3: N-(4-acetylphenyl)-2-[(10R)-3,14-difluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide [ka] To a suspension of resolved intermediate L2 (1.50 g, 5.45 mmol) in MeCN (22 mL) at room temperature, intermediate C1 (1.15 g, 5.45 mmol) was added. The resulting mixture was cooled to 15 °C with vigorous stirring in an Easymax reactor, and then K2CO3 (1.52 g, 10.9 mmol) was added. The reaction mixture was stirred at 15 °C for 3 days. Water (40 mL) was added dropwise to the reaction mixture at room temperature. After stirring at room temperature for 30 minutes, the mixture was filtered through a glass frit. The solid was washed with water (3 × 20 mL) until pH = 6. The solid was dried under high vacuum at 40 °C for 4 days and then purified by flash chromatography on silica gel using a gradient of 0% EtOAc to 100% EtOAc in heptane as the eluent. The product was triturated in EtO (15 mL), filtered on a glass frit, rinsed with EtO (5 mL), and dried under high vacuum at 40 °C for 16 h to give the title compound as a white solid (1.84 g, yield: 75%). LC-MS (Method A4) m / z [M+H] + :451.3;rt:3.88min;purity:99%. LC-MS (Method B4) m / z[M+H] + :451.3;rt:3.50min;purity:99%.

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[0312] Example #4: N-(4-acetylphenyl)-2-[14-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide enantiomer (10R) or (10S) [ka] or [ka] The title compound was prepared following a procedure similar to that described for Example #3, starting from intermediate L3 (600 mg, 2.33 mmol) and intermediate C1 (543 mg, 2.57 mmol), without using potassium iodide. After completion, the reaction mixture was poured into water. The resulting precipitate was filtered off and washed with water (3 × 20 mL). The solid was triturated in water, filtered off, and washed with water (3 × 20 mL). The corresponding racemate was separated by Chiral SFC (Chiralpak IA from Daicel, CO2 + MeOH 20%). The second-eluting enantiomer was then purified by column chromatography on silica gel (using a gradient from 0% EtOAc to 100% EtOAc in heptane, then from 0% MeOH to 15% MeOH in EtOAc as the eluent) to afford the title compound as a white solid (193 mg, yield: 19%). LC-MS (Method A2') m / z:[M+H] + :433.1;rt:3.34min;purity:100%. LC-MS (Method B2) m / z:[M+H] + :433.1;rt:3.79min;purity:100%.

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[0313] Example #5: N-(4-acetylphenyl)-2-[(10R)-3-chloro-14-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide [ka] Example #5 was prepared following a similar procedure as for Example #3, starting from Intermediate L4 (600 mg, 2.06 mmol) and Intermediate C1 (435 mg, 1 eq). 50 mg of the crude product was purified by reverse phase chromatography (basic elution) to give a white solid (30 mg). LC-MS (Method A8) m / z [M+H] + :467.3;rt:4.12min;purity:98%. LC-MS (Method B8) m / z[M+H] + :467.3;rt:3.69min;purity:98%.

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[0314] Example #6: N-(4-acetylphenyl)-2-[3-chloro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide enantiomer (10R) or (10S) [ka] or [ka] Example #6 was prepared following a similar procedure as for Example #3, starting from Intermediate L5 (252 mg, 0.92 mmol) and Intermediate C1 (195 mg, 1 eq.). It was purified by trituration in isopropanol (1 mL) and diisopropyl ether (6 mL) to give a white solid (321 mg, 76% yield). LC-MS (Method A2) m / z [M+H] + :449.0;rt:3.88min;Purity>99%. LC-MS (Method B2) m / z[M+H] + :449.1;rt:3.67min;Purity>99%.

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[0315] Example #7: N-(4-acetylphenyl)-2-[5-(3,3-difluoroazetidin-1-yl)-3-fluoro-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide enantiomer (10R) or (10S) [ka] or [ka] To a solution of intermediate L6 (300 mg, 0.63 mmol) and 3,3-difluoroazetidine hydrochloride (190 mg, 1.40 mmol) in acetonitrile (6 mL), N,N-diisopropylethylamine (0.42 mL, 2.5 mmol) was added at room temperature, and the mixture was stirred overnight. The mixture was stirred at room temperature for another 5 days, and N,N-diisopropylethylamine (0.42 mL) was added again three times after daily analysis. The reaction mixture was evaporated, then diluted with dichloromethane (10 mL), and washed with water (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give 360 ​​mg of crude solid, which was purified by SFC (GreenSep-Nitro column, 80 mL / min, CO2 + 35% MeOH) to give racemic N-(4-acetylphenyl)-2-[5-(3,3-difluoroazetidin-1-yl)-3-fluoro-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0]. 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide (171 mg, major regioisomer, second-eluting isomer) and the minor regioisomer (45 mg, first-eluting isomer) were obtained. The racemate was separated by chiral HPLC (Reprosil NR-R from Dr. Maisch, 50% EtOH-50% heptane, 30 mL / min) to give the title product as a white solid (78 mg, yield: 24%). LC-MS (Method B2) m / z [M+H] + :510.0;rt:4.53min;purity:99%. LC-MS (Method A2) m / z[M+H] + : 510.0; rt: 4.40 min; purity >99%. Chiral purity >99%; rt: 3.39 min (first eluting enantiomer, second eluting enantiomer rt: 5.22 min), determined by UHPLC (Reprosil Chiral NR-R from Dr. Maisch, EtOH 50% - Heptane 50% - DEA 0.1%). High resolution mass (method HRMS_A2) m / z (+H); observed mass: 510.1765; expected mass: 510.1753 (C 26 H 22 for F3N5O3); (rt: 2.15 min, purity: 100%).

[0316] Example #8: N-(4-acetylphenyl)-2-[3-fluoro-5-(3-fluoroazetidin-1-yl)-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide enantiomer (10R) or (10S) [ka] or [ka] Example #8 was prepared following a similar procedure as for Example #7, starting from intermediate L6 (310 mg, 0.65 mmol) and 3-fluoroazetidine hydrochloride (98 mg, 0.83 mmol). Purification of the crude mixture (374 mg) by SFC (2-EP column from Kromasil, 80 mL / min, CO2 + 5-50% MeOH gradient) gave racemic N-(4-acetylphenyl)-2-[3-fluoro-5-(3-fluoroazetidin-1-yl)-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.02,7]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide (110 mg, major regioisomer, second-eluting isomer) and the minor regioisomer (35 mg, first-eluting isomer). The racemate was separated by chiral HPLC ((R,R)Whelk-O 1 from Regis Technologies, EtOH 100%) to give the title product as a white solid (54 mg, yield: 17%). LC-MS (Method B2) m / z [M+H] + :492.0;rt:4.42min;purity:99%. LC-MS (Method A2) m / z[M+H] +: 492.0; rt: 4.17 min; purity: 99%. Chiral purity >99%; rt: 2.46 min (first eluting enantiomer, second eluting enantiomer rt: 2.92 min), determined by UHPLC (column (R,R) Whelk-O1, EtOH 100% - DEA 0.1%). High-resolution mass (method HRMS_A2) m / z (+H); observed mass: 492.1859; expected mass: 492.1847 (C 26 H 23 for F2N5O3); (rt: 2.01 min, purity: 98.5%).

[0317] Example #9: N-(4-acetylphenyl)-2-[3-chloro-5-(2,2-difluoro-5-azaspiro[2.3]hexan-5-yl)-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide [ka] Starting from intermediate L7 (8.0 mg, 0.019 mmol) and intermediate C1 (5.4 mg, 0.024 mmol), the title compound was prepared according to a procedure similar to that for Example #3. After completion, the reaction mixture was poured into water. The resulting precipitate was filtered off and washed with water. The residue was purified by preparative HPLC (purification method P_B) to give the title compound as a white solid (2.4 mg, yield: 24%). LC-MS (method A4) m / z: [M+H] + :538.2;rt:4.25min;purity:99%. LC-MS (Method B4) m / z:[M+H] + :538.2;rt:3.89min;purity:99%.

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[0318] Example #10: N-(4-acetylphenyl)-2-(1-fluoro-3-methyl-6-oxo-7H-pyrido[4,3-d][3]benzazepin-5-yl)acetamide [ka] Starting from intermediate L8 (15 mg, 0.04 mmol) and 1-(4-aminophenyl)ethanone (12.2 mg, 0.09 mmol), the title compound was prepared according to the same procedure as in Example #1. After complete conversion, the reaction mixture was purified by preparative HPLC (purification method P_B) to give the title compound (10.2 mg, yield: 55%). LC-MS m / z: [M+H] + :418.2;Purity:96%. High-resolution mass (method HRMS_A2) m / z(+H); Observed mass: 418.1558; Expected mass: 418.1567(C 24 H 20 for FN3O3); (rt: 2.02 min, purity: 94.54%).

[0319] Example #11: N-(4-acetylphenyl)-2-[3-fluoro-5-methoxy-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide enantiomer (10R) or (10S) [ka] or [ka] To a solution of intermediate L9 (30 mg, 0.07 mmol) in MeCN (0.73 mL) was added 1-(4-aminophenyl)ethanone (20 mg, 0.15 mmol), TCFH (42 mg, 0.15 mmol), and NMI (23 μL, 0.29 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. After completion, water was added and the reaction mixture was extracted with DCM (3×, separated on a phase separator). The combined organic layers were concentrated under vacuum. The residue was purified by preparative HPLC (purification method P_B) to give the title compound as a white solid (26.4 mg, yield: 79%). LC-MS (Method A4) m / z: [M+H] + :449.4;rt:3.86min;purity:97%. LC-MS (Method B4) m / z:[M+H] + : 449.3; rt: 3.50 min; purity: 97%; chiral purity >99%.

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[0320] Example #12: N-(4-acetylphenyl)-2-[14-methoxy-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide enantiomer (10R) or (10S) [ka] or [ka] Example #12 was prepared starting from intermediate L11 (90 mg, 0.33 mmol) and intermediate C1 (71 mg, 1 equiv.) following a procedure similar to that for Example #3. It was purified by reverse-phase chromatography (Waters XBridge OBD MS C18 column (5 μm, 30×50 mm). Gradient elution was performed using solvent A (95% HO - 5% ACN + 50 mM NHHCO + 200 μL / L NHOH) and solvent B (100% ACN) (pH 8.5, flow rate: 35-45 mL / min). The enantiomers were separated by Chiral HPLC (Chiralpak IB from Daicel, 100% EtOH) to give the title product as a white solid (28 mg, yield: 19%). LC-MS (Method B2) m / z [M+H] + :445.0;rt:3.76min;purity:95%. LC-MS (Method A2) m / z[M+H] + : 445.0; rt: 3.37 min; purity: 96%. Chiral purity: 99%; rt: 2.52 min (second eluting enantiomer, first eluting enantiomer rt: 1.86 min) determined by HPLC (Chiralpak IB, EtOH 100% - DEA 0.1%).

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[0321] Example #13: N-(4-acetylphenyl)-2-[3-methoxy-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(15),2(7),3,5,11,13-hexaen-8-yl]acetamide enantiomer (10R) or (10S) [ka] or [ka] Starting from intermediate L12 (141 mg, 0.52 mmol) and intermediate C1 (137 mg, 0.63 mmol), the title compound was prepared according to a procedure similar to that described for Example #3. After purification by preparative HPLC (purification method P_B), the corresponding racemate was separated by Chiral HPLC (Reprosil NR-R from Dr. Maisch, EtOH 50%-Heptane 50%) to give the title compound as a white solid (59.0 mg, yield: 25%). LC-MS (method A2) m / z: [M+H] + :445.1;rt:4.06min;purity:99%. LC-MS (Method B2) m / z:[M+H] + :445.1;rt:4.24min;purity:99%.

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[0322] Example #14: N-(4-acetylphenyl)-2-(3-methoxy-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide enantiomer (10R) or (10S) [ka] Starting from intermediate L14 (140 mg, 0.50 mmol) and intermediate C1 (147 mg, 0.61 mmol), the title compound was prepared according to a procedure similar to that described for Example #3. After purification by preparative HPLC (purification method P_B), the corresponding racemate was separated by Chiral HPLC (Whelk O-1 (R,R) from Regis Technology, EtOH 100%) to give the title compound as a white solid (55.6 mg, yield: 25%). LC-MS (method A2') m / z: [M+H] + :431.1;rt:3.92min;purity:99%. LC-MS (Method B2) m / z:[M+H] + :431.1;rt:4.36min;purity:99%.

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[0323] Example #15: 2-[(10R)-3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]-N-(4-propanoylphenyl)acetamide [ka] Starting from intermediate L1 (53 mg, 0.11 mmol) and 4'-aminopropiophenone (15 mg, 0.10 mmol), the title compound was prepared according to a procedure similar to that for Example #1. The crude mixture was purified by preparative HPLC (purification method P_B) to give the title compound as a white solid (21 mg, yield: 47%). LC-MS (method A4) m / z: [M+H] +:447.2;rt:4.10min;purity:96%. LC-MS (Method B4) m / z:[M+H] + :447.3;rt:3.53min;purity:96%.

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[0324] Example #16: N-(4-acetyl-3-hydroxy-phenyl)-2-(3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide enantiomer (10R) or (10S) [ka] Starting from intermediate L1_6 (50 mg, 0.19 mmol) and intermediate C2 (49 mg, 0.21 mmol), the title compound was prepared according to a procedure similar to that described for Example #3. After purification by preparative HPLC (purification method P_B), the corresponding racemate was separated by Chiral HPLC (Reprosil NR-R from Dr. Maisch, EtOH 100%) to give the title compound as a white solid (9.9 mg, yield: 11%). LC-MS (method A2) m / z: [M+H] + :449.2;rt:4.05min;purity:99%. LC-MS (Method B2) m / z:[M+H] + :449.1;rt:3.88min;purity:99%.

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[0325] Example #17: N-(4-acetylphenyl)-2-(3,14-difluoro-5-methoxy-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide enantiomer (10R) or (10S) [ka] Starting from intermediate L15 (333 mg, 0.64 mmol) and intermediate C1 (187 mg, 0.77 mmol), the title compound was prepared according to a procedure similar to that described for Example #3. After purification by reversed-phase chromatography (basic elution), the corresponding racemate was separated by Chiral SFC (Chiralpak IB from Daicel, CO2 + EtOH 20%) to give the title compound as a white solid (94 mg, yield: 32%). LC-MS (Method A2') m / z: [M+H] + :467.1;rt:4.51min;purity:99%. LC-MS (Method B2) m / z:[M+H] + :467.1;rt:4.36min;purity:98%.

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[0326] Example #18: 2-[3,14-difluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]-N-(3-oxobenzofuran-6-yl)acetamide enantiomer (10R) or (10S) [ka] To a mixture of intermediate L16 (297 mg, 0.89 mmol) and intermediate L17 (394 mg, 1.34 mmol) in anhydrous 1,4-dioxane (9 mL) was added cesium carbonate (882 mg, 2.68 mmol) at room temperature. The resulting mixture was purged with N, and then BrettPhos Pd G3 (81 mg, 0.09 mmol) and BrettPhos (48 mg, 0.09 mmol) were added. The reaction mixture was then stirred at 110 °C for 2 h. Upon completion, the reaction was diluted with EtOAc (10 mL) and filtered through a pad of Celite, rinsing with EtOAc. The filtrate was concentrated in vacuo. After purification by flash chromatography on silica gel (using a gradient from 0% EtOAc to 100% EtOAc in heptane as eluent), the corresponding racemate was separated by Chiral HPLC (Chiralpak IB from Daicel, MeOH 100%) to give the title compound as a yellow solid (17.9 mg, yield: 4%). LC-MS (Method A2') m / z: [M+H] + :465.1;rt:4.15min;purity:96%. LC-MS (Method B2) m / z:[M+H] + :465.0;rt:3.94min;purity:99%.

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[0327] Example #19: Enantiomer (10R) or (10S) of N-(4-acetylphenyl)-2-(10-cyano-2-fluoro-5,9-dimethyl-6-oxo-5H-pyrido[2,3-d][1]benzazepin-7-yl)acetamide [ka] To a solution of intermediate L22 (15 mg, 0.05 mmol) and intermediate C1 (13 mg, 0.05 mmol) in N,N-dimethylformamide (1 mL) was added potassium carbonate (15 mg, 0.11 mmol). The reaction mixture was stirred at room temperature for 20 hours. After completion, water and ethyl acetate were added, and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (purification method P_B) to give the corresponding racemic compound as a white solid (12 mg, yield: 48%). LC-MS (method B5) m / z: [M+H] + :457;rt:3.37min;purity:97.8%. LC-MS (Method A8) m / z:[M+H] + : 457; rt: 3.75 min; purity: 99.4%. Purification of the racemate by chiral SFC (column Lux A1 from Phenomenex, CO2 + MeOH:MeCN (1:1) 60%) gave the title product. Chiral purity >95%; rt: 3.26 min (second-eluting enantiomer). For reference, first-eluting enantiomer rt: 1.55 min). Both determined by SFC (column Lux A1 from Phenomenex, CO2 + MeOH 50% + NH3 0.1%).

[0328] Example #20: N-(4-acetylphenyl)-2-[(10)-3-fluoro-14-methoxy-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide enantiomer (10R) or (10S) [ka] To a solution of intermediate L10 (100 mg, 0.35 mmol) in N,N-dimethylformamide (1.7 mL) at room temperature, potassium carbonate (146 mg, 1.05 mmol) and intermediate C1 (74 mg, 0.35 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour. After completion, water and ethyl acetate were added, and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (purification method P_B) to give the corresponding racemate as a white solid (75.0 mg, yield: 47%). The racemate was separated by chiral HPLC (Reprosil Chiral NR-R from Dr. Maisch, EtOH 50%-Heptane 50%+DEA 0.1%) to give the title product (24.5 mg, yield: 15%). Chiral purity >99%; rt: 3.97 min (first eluting enantiomer). For reference, rt: 5.43 min for the second eluting enantiomer). Both determined by HPLC (Reprosil Chiral NR-R from Dr. Maisch, EtOH 50% - Heptane 50% + DEA 0.1%). LC-MS (Method A2') m / z: [M+H] + :463.0;rt:4.14min;purity:99%. LC-MS (Method B2) m / z:[M+H] + :463.0;rt:4.24min;purity:98%.

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[0329] Example #21: N-(4-acetylphenyl)-2-[3-fluoro-5-(3-fluoroazetidin-1-yl)-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide [ka] Step 1: N-(4-acetylphenyl)-2-(3,5-difluoro-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide [ka] To a solution of intermediate L23 (776 mg, 3.08 mmol) and intermediate C1 (748 mg, 3.08 mmol) in N,N-dimethylformamide (9 mL) was added potassium carbonate (860 mg, 6.16 mmol) at room temperature. The resulting mixture was stirred at room temperature for 20 hours. After completion, water and ethyl acetate were added, and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (1.27 g, yield: 96%). LC-MS (Method A1_S) m / z: [M+H] + :423.0;rt:1.14min;purity:96%.

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[0330] Step 2: N-(4-acetylphenyl)-2-[3-fluoro-5-(3-fluoroazetidin-1-yl)-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 Synthesis of ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide Example #21 N-(4-acetylphenyl)-2-(3,5-difluoro-9-oxo-4,8,12-triazatricyclo[9.4.0.0] in acetonitrile (5 mL) 2,7 To a solution of pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide (Example #21 Step 1, 280 mg, 0.61 mmol) and 3-fluoroazetidine hydrochloride (85 mg, 0.76 mmol) was added N,N-diisopropylethylamine (0.3 mL, 2 mmol) at room temperature. The resulting mixture was stirred at room temperature for 14 days. After completion, water and DCM were added. The combined organic layers were separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by SFC chromatography (P4VP DCpak from Daicel, CO2 + MeOH 20%) to give the title compound (51 mg, yield: 17%). LC-MS (Method A2') m / z: [M+H] + :478.1;rt:3.89min;purity:100%. LC-MS (Method B2) m / z:[M+H] + :478.0;rt:4.07min;Purity:100%.

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[0331] Example #22: N-(4-acetylphenyl)-2-[5-(3,3-difluoroazetidin-1-yl)-3-fluoro-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide [ka] N-(4-acetylphenyl)-2-(3,5-difluoro-9-oxo-4,8,12-triazatricyclo[9.4.0.0] in acetonitrile (5 mL) 2,7To a solution of pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide (Example #21 Step 1, 280 mg, 0.61 mmol) and 3,3-difluoroazetidine hydrochloride (95 mg, 0.73 mmol) was added N,N-diisopropylethylamine (0.3 mL, 2 mmol) at room temperature. The resulting mixture was stirred at room temperature for 14 days. After completion, water and DCM were added. The combined organic layers were separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by SFC chromatography (P4VP DCpak from Daicel, CO2 + MeOH 15%). The residue was washed with water and extracted with DCM to give the title compound (77 mg, yield: 25%). LC-MS (Method A1_S) m / z:[M+H] + :496.0;rt:1.19min;purity:97%.

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[0332] Example #23: N-(4-acetylphenyl)-2-(3,5-difluoro-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide enantiomer (10R) or (10S) [ka] Separation of the racemic intermediate L6 by chiral HPLC (Reprosil Chiral NR-R from Dr. Maisch, EtOH 50%-Heptane 50%+DEA 0.1%) gave the title product (31.4 mg, yield: 27%). Chiral purity >99%; rt: 2.89 min (first eluting enantiomer). For reference, rt: 3.85 min for the second eluting enantiomer. Both were determined by HPLC (Reprosil Chiral NR-R from Dr. Maisch, EtOH 50%-Heptane 50%+DEA 0.1%). LC-MS (Method A2') m / z: [M+H] + :437.0;rt:4.19min;purity:100%.

[0333] Example #24: N-(4-acetyl-3-fluoro-phenyl)-2-[(10)-3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide enantiomer (10R) or (10S) [ka] Step 1: N-(4-bromo-3-fluoro-phenyl)-2-(3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide [ka] To a solution of intermediate L1_6 (1.00 g, 3.89 mmol), N-(4-bromo-3-fluoro-phenyl)-2-chloro-acetamide (1.04 g, 3.89 mmol), and N,N-dimethylformamide (15 mL) was added potassium carbonate (1.09 g, 7.77 mmol), and the reaction mixture was stirred at room temperature for 20 hours. After completion, N-(4-bromo-3-fluoro-phenyl)-2-chloro-acetamide (1.04 g, 3.89 mmol) and potassium carbonate (1.09 g, 7.77 mmol) were added again, and the reaction mixture was stirred and heated at 80 °C for 5 hours. After completion, water and ethyl acetate were added, and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with 10 mL of iPrO and 2 mL of iPrOH to give a solid (1.53 g, yield: 75%). LC-MS (Method A1_S) m / z: [M+H] + :487.0 / 489.0;rt:1.39min;purity:93%.

[0334] Step 2: N-[4-(1-ethoxyvinyl)-3-fluoro-phenyl]-2-(3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide [ka] N-(4-bromo-3-fluoro-phenyl)-2-[3,14-difluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0] in toluene (15 mL) 2,7To a solution of ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide (Example #24 Step 1, 1.53 g, 3.15 mmol) was added tributyl(1-ethoxyvinyl)tin (1.31 mL, 3.76 mmol) and tetrakis(triphenylphosphine)palladium(0) (190 mg, 0.16 mmol) at room temperature. The reaction mixture was then heated at 110° C. for 20 hours. Upon completion, water and ethyl acetate were added, and the reaction mixture was filtered through a plug of Celite. The resulting mixture was extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (3.20 g, quantitative yield). LC-MS (Method B1_S) m / z: [M+H] + :479.0;rt:1.55min;purity:47%.

[0335] Step 3: N-(4-acetyl-3-fluoro-phenyl)-2-(3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 Synthesis of the enantiomer (10R) or (10S) of pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide Example #24 N-[4-(1-ethoxyvinyl)-3-fluoro-phenyl]-2-(3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0]) in THF (100 mL) 2,7To a solution of pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide (Example 24, Step 2, 3.20 g, 6.02 mmol), hydrochloric acid (1 mol / L in water, 20 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was quenched with 1 M aqueous NaOH. The organic layer was extracted three times with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (using a gradient of 0% EtOAc to 100% EtOAc in heptane over 20 CV as the eluent) to give the corresponding racemate (1.20 g, yield: 85%). The racemate was separated by chiral HPLC (Reprosil Chiral NR-R from Dr. Maisch, 50% EtOH-50% heptane + 0.1% DEA) to give the title product (355 mg, yield: 36%). Chiral purity >99%; rt: 2.66 min (first eluting enantiomer). For reference, rt: 3.42 min for the second eluting enantiomer. Both were determined by HPLC (Reprosil Chiral NR-R from Dr. Maisch, EtOH 50% - Heptane 50% + DEA 0.1%). LC-MS basic (Method B2) m / z: [M+H] + :451.0;rt:4.32min;purity:99%. LC-MS acid (method A2') m / z:[M+H] + :451.0;rt:4.21min;purity:100%.

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[0336] Example #25: N-(4-acetylphenyl)-2-[3-fluoro-5-(3-hydroxy-3-methyl-azetidin-1-yl)-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide [ka] The title compound was prepared according to the same procedure as in Example #7, starting from intermediate L6 (102 mg, 0.23 mmol) and 3-hydroxy-3-methylazetidine hydrochloride (47 mg, 0.38 mmol). The residue was purified by SFC chromatography (P4VP DCpak from Daicel, CO2 + MeOH 25%) to give the title compound (49 mg, yield: 42%). LC-MS (Method A2') m / z: [M+H] + :504.1;rt:3.75min;purity:99.3%. LC-MS (Method B2) m / z:[M+H] + :504.1;rt:3.60min;purity:98.6%.

[0337] Example #26: N-(4-acetylphenyl)-2-[3-fluoro-5-(3-fluoro-3-methyl-azetidin-1-yl)-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide [ka] The title compound was prepared according to the same procedure as in Example #7, starting from intermediate L6 (102 mg, 0.23 mmol) and 3-fluoro-3-methylazetidine hydrochloride (45 mg, 0.36 mmol). The residue was purified by preparative HPLC (purification method P_B) followed by SFC chromatography (GreenSep Nitro, CO2 + MeOH 30%) to give the title compound (34 mg, yield: 29%). LC-MS (method A2') m / z: [M+H] + :506.1;rt:4.41min;purity:99.5%. LC-MS (Method B2) m / z:[M+H] + :506.1;rt:4.25min;purity:99.0%.

[0338] Example #27: N-(4-acetylphenyl)-2-[3-fluoro-5-(3-hydroxy-3-methyl-azetidin-1-yl)-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide [ka] Following a similar procedure to Example #7, N-(4-acetylphenyl)-2-(3,5-difluoro-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 The title compound was prepared starting from pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide (Example #21 Step 1, 102 mg, 0.24 mmol) and 3-fluoro-3-methylazetidine hydrochloride (45 mg, 0.36 mmol). The residue was purified by SFC chromatography (P4VP DCpak from Daicel, CO2 + MeOH 25%) to give the title compound (22 mg, yield: 19%). LC-MS (Method A2') m / z: [M+H] + :490.1;rt:3.47min;purity:98.9%. LC-MS (Method B2) m / z:[M+H] + :490.1;rt:3.35min;purity:98.9%.

[0339] Example #28: N-(4-acetylphenyl)-2-(14-fluoro-7,12-dimethyl-8-oxo-4-thia-5,9,13-triazatricyclo[8.4.0.0 2,6 ]tetradeca-1(10),2,5,11,13-pentaen-9-yl)acetamide [ka] To a solution of intermediate L18 (38 mg, 0.14 mmol) in anhydrous N,N-dimethylformamide (1 mL) was added intermediate C1 (35 mg, 0.17 mmol) and potassium carbonate (40 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 18 hours. After 18 hours, the reaction mixture was diluted with EtOAc and water. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to dryness to give a brown oil. The residue was purified by preparative HPLC (purification method P_B) to give the title compound as a white solid (11 mg, yield: 17%). LC-MS (method A4) m / z: no mass response; rt: 4.03 min; purity: 98%. LC-MS (method B4) m / z: [M+H] + :438;rt:3.68min;purity:98%.

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[0340] Example #29: N-(4-acetylphenyl)-2-[3-fluoro-5-(1-hydroxycyclobutyl)-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(15),2,4,6,11,13-hexaen-8-yl]acetamide [ka] To a solution of intermediate L19 (32 mg, 0.10 mmol) in anhydrous N,N-dimethylformamide (0.5 mL) was added intermediate C1 (28 mg, 0.12 mmol), potassium iodide (1.6 mg, 0.01 mmol), followed by potassium carbonate (34 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc and water. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to dryness to give a brown oil. The residue was purified by preparative HPLC (purification method P_B) to give the title compound (3.8 mg, yield: 8%). LC-MS (method A4) m / z: [M+H] +:489;rt:3.64min;purity:98.7%. LC-MS (Method B4) m / z:[M+H] + :489;rt:3.98min;purity:98.7%.

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[0341] Example #30: N-(4-acetylphenyl)-2-[3,14-difluoro-5-(hydroxymethyl)-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide [ka] To a solution of intermediate L20 (19 mg, 0.06 mmol) in anhydrous N,N-dimethylformamide (0.3 mL) was added intermediate C1 (18 mg, 0.12 mmol), potassium iodide (1 mg, 0.01 mmol), followed by potassium carbonate (21 mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was diluted with EtOAc and water. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to dryness to give a brown oil. The residue was purified by preparative HPLC (purification method P_B) to give the title compound (3.8 mg, 12% yield). LC-MS (method A4) m / z: [M+H] + :467;rt:3.65min;purity:92%. LC-MS (Method B4) m / z:[M+H] + :467;rt:3.35min;purity:93%.

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[0342] Example #31: N-(4-acetylphenyl)-2-(5-cyclobutyl-3-fluoro-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7]Pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide enantiomer (10R) or (10S) [ka] To a solution of intermediate L21 (220 mg, 0.63 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added intermediate C1 (188 mg, 0.89 mmol), potassium iodide (12 mg, 0.07 mmol), followed by potassium carbonate (206 mg, 1.48 mmol). The reaction mixture was stirred at room temperature for 20 h. Upon completion, the reaction mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give a brown solid. The residue was purified by column chromatography on silica gel (using a gradient from 0% MeOH to 9% MeOH in DCM) followed by SFC chromatography (SFC-5-Diol from Kromasil, CO2 + MeOH 5-50%) to give the corresponding racemic compound (189 mg, yield: 44%). The racemate was separated by Chiral SFC (Chiralpak IB from Daicel, CO2 + MeOH 30%) to give the title product (63.7 mg, yield: 21%). Chiral purity >99%; rt = 2.36 min (second-eluting enantiomer). For reference, first-eluting enantiomer rt: 1.87 min). Both were determined by HPLC (Chiralpak IB from Daicel, MeOH 100% + DEA 0.1%). LC-MS (Method A4) m / z: [M+H] + :473.0;rt:5.26min;purity:99.2%. LC-MS (Method B4) m / z:[M+H] + :473.0;rt:4.58min;purity:98.8%.

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[0343] Example #32: N-(4-acetylphenyl)-2-(14-fluoro-5-methoxy-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide enantiomer (10R) or (10S) [ka] To a solution of Intermediate L24 (100 mg, 0.37 mmol) and Intermediate C1 (107 mg, 0.44 mmol) in N,N-dimethylformamide (1.8 mL) at room temperature was added potassium carbonate (128 mg, 0.92 mmol) and potassium iodide (6 mg, 0.04 mmol). The resulting mixture was stirred at room temperature for 18 hours. After completion, water and ethyl acetate were added, and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give a brown solid. Trituration of the residue with a mixture of water and acetonitrile (3 / 7) gave racemic N-(4-acetylphenyl)-2-(14-fluoro-5-methoxy-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.02,7]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide (107 mg, yield: 63%) as a white solid. Separation of the racemate by chiral HPLC (Reprosil Chiral NR-R from Dr. Maisch, 50% EtOH - 50% Heptane + 0.1% DEA) gave the title product (34.4 mg, yield: 20%). Chiral purity >99%; rt: 3.42 min (first-eluting enantiomer). For reference, rt: 4.40 min for the second-eluting enantiomer. All were determined by HPLC (Reprosil Chiral NR-R from Dr. Maisch, EtOH 50% - Heptane 50% + DEA 0.1%). LC-MS (Method A4) m / z: [M+H] + :449;rt:4.25min;purity:99.6%. LC-MS (Method B4) m / z:[M+H] +:449;rt:4.05min;purity:96.29%.

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[0344] Example #33: N-(4-acetyl-3-hydroxy-phenyl)-2-(3,14-difluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide enantiomer (10R) or (10S) [ka] 2-(3,14-difluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0]) in anhydrous 1,4-dioxane (3 mL) 2,7 To a mixture of pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide intermediate L16 (100 mg, 0.30 mmol) was added 1-(4-bromo-2-hydroxyphenyl)ethanone (82 mg, 0.36 mmol) at room temperature. The resulting mixture was purged with N2, and then XPhos Pd G3 (27 mg, 0.03 mmol), XPhos (15 mg, 0.03 mmol), and cesium carbonate (294 mg, 0.90 mmol) were added. The resulting mixture was stirred at 100 °C for 2 h. Upon completion, the reaction was diluted with EtOAc (10 mL), filtered through a pad of Celite, and rinsed with EtOAc. The filtrate was concentrated under vacuum to give racemic N-(4-acetyl-3-hydroxy-phenyl)-2-(3,14-difluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide was obtained. After purification by reversed-phase chromatography (basic elution), the racemate was separated by Chiral HPLC (Chiralpak IG from Daicel, EtOH 50% - heptane 50%) to give the title compound as a white solid (18 mg, yield: 13%). Chiral purity: 98.3%; rt: 4.97 min (second-eluting enantiomer). For reference, the first-eluting enantiomer rt: 2.69 min. Both were determined by HPLC (Chiralpak IG from Daicel, EtOH 50% - heptane 50% - DEA 0.1%). LC-MS (Method A2) m / z: [M+H] + :466.9;rt:4.53min;purity:99.6%. LC-MS (Method B2) m / z:[M+H] + :467.2;rt:4.25min;purity:99.5%.

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[0345] Example #34: N-(4-acetylphenyl)-2-(3,14-difluoro-5,10-dimethyl-9-oxo-4,8,13-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide [ka] Example #34 was prepared following a similar procedure as for Example #3, starting from Intermediate L13 (1.7 mg, 0.006 mmol) and Intermediate C1 (1.4 mg, 0.007 mmol). After completion, the reaction mixture was purified by preparative HPLC (purification method P_B) to give the title compound as a white solid (1.68 mg, yield: 59%). LC-MS (Method A8) m / z: [M+H]+ :451.1;rt:3.47min;purity:98%. LC-MS (Method B8) m / z:[M+H] + :451.1;rt:3.14min;purity:99%.

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[0346] Example #35: Enantiomer (5R) or (5S) of N-(4-acetylphenyl)-2-[11-fluoro-9-(3-fluoroazetidin-1-yl)-5-methyl-6-oxo-5H-pyrido[2,3-d][1]benzazepin-7-yl]acetamide [ka] To a solution of intermediate L25 (65 mg, 0.21 mmol) in DMF (0.7 mL) was added potassium carbonate (60 mg, 0.43 mmol) and intermediate C1 (51 mg, 0.21 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 days. After completion, water and ethyl acetate were added, and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (purification method P_B) to give the corresponding racemate as a white solid (56 mg, yield: 54%). The racemate was separated by chiral HPLC (Whelk O-1 (R,R) from Regis Technology, EtOH 100%) to give the title product (17.6 mg, yield: 17%). Chiral purity >99%; rt: 2.38 min (first-eluting enantiomer). For reference, the second-eluting enantiomer rt: 2.92 min). All were determined by HPLC (Whelk O-1 (R,R) from Regis Technology, EtOH 100% + DEA 0.1%). LC-MS (Method A2') m / z: [M+H] +:491.0;rt:4.36min;purity:97.6%. LC-MS (Method B2) m / z:[M+H] + :491.0;rt:4.53min;purity:99.0%.

[0347] Example #36: N-(4-acetylphenyl)-2-(14-chloro-4-fluoro-7,12-dimethyl-8-oxo-5,6,9,13-tetrazatricyclo[8.4.0.0 2,6 ]tetradeca-1(14),2,4,10,12-pentaen-9-yl)acetamide [ka] Example #36 was prepared following a similar procedure as for Example #3, starting from Intermediate L26 (54 mg, 0.19 mmol) and Intermediate C1 (45 mg, 0.20 mmol). After completion, the reaction mixture was purified by column chromatography on silica gel (using a gradient of 0-60% EtOAc / iso-hexane as eluent) to afford the title compound (62 mg, yield: 69%) as a white solid. LC-MS (Method B5) m / z [M+H]: 456.1 / 458.1; rt: 1.39 min; purity: 98%.

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[0348] V. Biological Assays Two independent cellular assays: (i) measurement of cystine-induced glutamate release; and (ii) [ 14 In measuring [C]L-cystine uptake, system Xc - The effect of compounds of formula (I) on functionality was investigated.

[0349] As mentioned above, system Xc, also known as the cystine / glutamate antiporter, - is an amino acid transporter that mediates the extrusion of intracellular L-glutamate out of cells and the uptake of extracellular L-cystine into cells.

[0350] The concentration of glutamate released outside the cells and the concentration of L-cystine taken up into the cells were measured while increasing the concentration of the compound of formula (I) according to the present invention. - The effectiveness of the compound in inhibiting the function can be assessed.

[0351] System Xc - The efficacy of the compounds in inhibiting Erastin was measured in each assay using IC values, which correspond to the concentration of compound required to inhibit 50% of the signal from two control groups: DMSO 1% and Erastin 50 μM. 50 It is expressed by measuring pIC 50 Values ​​are expressed as molar IC 50 Corresponds to -log.

[0352] I C 50 The lower the value of (pIC 50 The higher the value of ), the less compound is needed to produce the same amount of inhibition, and therefore the greater the inhibitory potency.

[0353] In general, System Xc - Inhibitors of the functions were cystine-induced glutamate release and [ 14 IC of 500 nM or less in each of the [C]L-cystine uptake assays 50 Indicates the value of

[0354] Cystine-induced glutamate release and [ 14 When tested in each of the [C]L-cystine uptake assays, compounds of formula (I) according to the present invention generally have a pIC of greater than or equal to about 6.3, suitably greater than about 7.0, ideally greater than about 7.4, suitably greater than about 7.8. 50 Indicates the value.

[0355] V.1. Cystine-induced glutamate release assay Measurement of cystine-induced glutamate release was performed using System Xc -Figure 1 shows the level of (extracellular) glutamate, which depends on antiporter function. When L-cystine is added to H4 cells, intracellular glutamate is countertransported and excreted into the supernatant.

[0356] In this assay, the medium lacks sodium to prevent transport of glutamate by sodium-dependent excitatory amino acid transporters (EAATs). Cells were cultured at 1 × 10 in Dulbecco's modified Eagle's medium (DMEM) containing L-glutamine, penicillin / streptomycin, and 10% fetal bovine serum (all from ThermoFisher Scientific). 4 H4 cells were plated onto 384-well culture plates at 1 cell / well and incubated at 37°C in a humidified CO2 incubator. After 2 days, the cells were washed four times with prewarmed sodium-free HEPES buffer (mM contents: HEPES 10, KCl 5.4, CaCl2 2.5, MgCl2 1, KH2PO4 0.4, D-glucose 5, choline chloride 140), pH 7.4. Glutamate release was induced by adding 50 μM L-cystine (Sigma-Aldrich) together with the test compound of Formula (I) at a final DMSO concentration of 1%. After 2 hours of incubation in the culture incubator, the supernatant was transferred to a low-binding polypropylene 384-well plate, and the L-glutamate concentration was determined using the Amplex™ Red Glutamic Acid Assay Kit (ThermoFisher Scientific). Briefly, 10 μL of Amplex™ Red standard solution was added to 10 μL of supernatant, and then the mixture was incubated for 30 minutes at 37° C. The fluorescence intensity was measured by an EnVision microplate reader (PerkinElmer).

[0357] When tested, compounds of formula (I) according to the present invention have a pIC of about 6.3 or greater in the cystine-induced glutamate release assay. 50 showed.

[0358] V.2.[ 14 [C]L-cystine uptake assay In this assay, the medium lacks sodium to prevent transport of glutamate by sodium-dependent excitatory amino acid transporters (EAATs). 5 × 10 cells were plated in the above medium onto a 96-well CytoStar-T scintillating microplate (PerkinElmer). 4 H4 cells were plated at 1000 cells / well. After one day, the cells were washed once with sodium-free HEPES buffer and pre-incubated with the test compound of formula (I) (1% final DMSO) for 15 minutes. 0.5 μM L-[1,2,1',2'- 14 Uptake was initiated by adding [C]cystine (0.02 mCi / mL, PerkinElmer, Waltham, USA) and 4.5 μM L-cystine (Sigma-Aldrich). After 1 h at 37 °C, MicroBeta 2 Plates were counted in a microplate counter (PerkinElmer).

[0359] Table I shows the pIC of compounds of formula (I) according to the invention when tested in the cystine-induced glutamate release assay and / or the [C]L-cystine uptake assay. 50 Indicates the range.

[0360] [Table 19]

[0361] As shown in this Table I, the compound of formula (I) according to the present invention can be prepared by the system Xc - It is a potent inhibitor of function.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 where A is the point of attachment to the rest of the molecule, V １ and V ２ Together with A １ , A ２ and A ３ 【Chemistry 2】 represents an optionally substituted aryl or heteroaryl selected from the group represented by During the ceremony, V １ represents C; V ２ represents C or N; Z ４ is N or C-R ７ represents; Z ５ is N or C-R ８ represents; Z ６ is N or C-R ９ represents; Z ７ is N or C-R １０ represents; R ａ represents a halogen; R ７ , R ８ , R ９ and R １０ are independently hydrogen or halogen; or C １～４ Alkyl or C １～４ alkoxy (any of these groups may be optionally substituted with one or more substituents); Z １ is N or C-R ４ represents; Z ２ is N or C-R ５ represents; Z ３ is N or C-R ６ represents; Z ４ is N or C-R ７ represents; R １ａ and R １ｂ are independently hydrogen; or C １～４ represents alkyl, which may be optionally substituted with one or more substituents; R ２ is C １～４ Alkyl or C ３～７ represents cycloalkyl, any of which groups may be optionally substituted by one or more substituents; R ３ is hydrogen, halogen or hydroxyl; or C １～４ alkyl, which may be optionally substituted by one or more substituents; or R ２ and R ３ taken together with the phenyl group to which they are attached form a heteroaryl, which is optionally substituted with one or more substituents; R ４ and R ５ are independently hydrogen, halogen or cyano; or C １～４ Alkyl or C １～４ alkoxy (any of these groups may be optionally substituted with one or more substituents); R ６ is hydrogen, halogen or cyano; or C １～４ Alkyl, C １～４ Alkoxy or C ３～７ heterocycloalkyl, or C ３～７ represents cycloalkyl (any of these groups may be optionally substituted by one or more substituents).

2. A is A １ represents V １ and V ２ A compound of formula (I) according to claim 1, wherein independently represents C.

3. A is A ２ represents V １ and V ２ A compound of formula (I) according to claim 1, wherein independently represents C.

4. A is A ３ represents V １ represents C, and V ２ represents N, and R ａ 2. A compound of formula (I) according to claim 1, wherein represents fluoro.

5. Z ２ represents N, and Z １ is C-R ４ represents Z ３ is C-R ６ 2. A compound of formula (I) according to claim 1, wherein

6. Z ７ represents N, and Z ４ is C-R ７ represents Z ５ is C-R ８ represents Z ６ is C-R ９ 2. A compound of formula (I) according to claim 1, wherein

7. R １ａ , R １ｂ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ and R １０ However, hydroxyl, halogen, C １～４ Alkyl or C １～４ 2. A compound of formula (I) according to claim 1, optionally substituted by alkoxy.

8. R １ａ , R １ｂ , R ２ , R ３ , R ４ , R ５ , R ７ , R ８ , R ９ and R １０ 2. The compound of formula (I) according to claim 1, wherein is unsubstituted.

9. R １ａ But C １～４ represents alkyl, and R １ｂ represents hydrogen; R ２ But C １～４ Alkyl or C ３～７ represents cycloalkyl; R ３ represents hydrogen; R ４ , R ７ , R ８ and R ９ are independently hydrogen, halogen or C １～４ represents alkoxy; R ６ But C １～４ Alkyl, C １～４ Alkoxy or optionally substituted, C ３～７ Cycloalkyl or C ３～７ represents heterocycloalkyl, A compound of formula (I) according to claim 1.

10. Formula (IA) 【Transformation 3】 During the ceremony R １ａ is C １～４ represents alkyl; R ２ is C １～４ Alkyl or C ３～７ represents cycloalkyl; R ４ and R ８ are independently hydrogen, halogen or C １～４ represents alkoxy; R ６ is C １～４ Alkyl, C １～４ Alkoxy or C ３～７ represents heterocycloalkyl 2. The compound of formula (I) according to claim 1, represented by:

11. R １ａ is C １～４ A compound of formula (I) according to any one of claims 1 to 10, which is alkyl.

12. R ２ is C １～４ A compound of formula (I) according to any one of claims 1 to 11, which is alkyl.

13. R ４ A compound of formula (I) according to any one of claims 1 to 12, wherein is halogen.

14. R ８ A compound of formula (I) according to any one of claims 1 to 13, wherein is halogen.

15. N-(4-acetylphenyl)-2-[3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-[4-(cyclopropanecarbonyl)phenyl]-2-[3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3,14-difluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[14-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[(10R)-3-chloro-14-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3-chloro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[5-(3,3-difluoroazetidin-1-yl)-3-fluoro-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3-fluoro-5-(3-fluoroazetidin-1-yl)-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3-chloro-5-(2,2-difluoro-5-azaspiro[2.3]hexan-5-yl)-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; and N-(4-acetylphenyl)-2-(1-fluoro-3-methyl-6-oxo-7H-pyrido[4,3-d][3]benzazepin-5-yl)acetamide, N-(4-acetylphenyl)-2-[3-fluoro-5-methoxy-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[14-methoxy-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3-methoxy-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(15),2(7),3,5,11,13-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-(3-methoxy-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide; 2-[3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]-N-(4-propanoylphenyl)acetamide; N-(4-acetyl-3-hydroxy-phenyl)-2-[3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-(3,14-difluoro-5-methoxy-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide; 2-[3,14-difluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]-N-(3-oxobenzofuran-6-yl)acetamide; N-(4-acetylphenyl)-2-(10-cyano-2-fluoro-5,9-dimethyl-6-oxo-5H-pyrido[2,3-d][1]benzazepin-7-yl)acetamide; N-(4-acetylphenyl)-2-[(10)-3-fluoro-14-methoxy-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3-fluoro-5-(3-fluoroazetidin-1-yl)-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[5-(3,3-difluoroazetidin-1-yl)-3-fluoro-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-(3,5-difluoro-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide; N-(4-acetyl-3-fluoro-phenyl)-2-[(10)-3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3-fluoro-5-(3-hydroxy-3-methyl-azetidin-1-yl)-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3-fluoro-5-(3-fluoro-3-methyl-azetidin-1-yl)-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3-fluoro-5-(3-hydroxy-3-methyl-azetidin-1-yl)-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-(14-fluoro-7,12-dimethyl-8-oxo-4-thia-5,9,13-triazatricyclo[8.4.0.0 ２，６ ]tetradeca-1(10),2,5,11,13-pentaen-9-yl)acetamide; N-(4-acetylphenyl)-2-[3-fluoro-5-(1-hydroxycyclobutyl)-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(15),2,4,6,11,13-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-[3,14-difluoro-5-(hydroxymethyl)-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; N-(4-acetylphenyl)-2-(5-cyclobutyl-3-fluoro-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide; N-(4-acetylphenyl)-2-(14-fluoro-5-methoxy-10-methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide; N-(4-acetyl-3-hydroxy-phenyl)-2-(3,14-difluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide; N-(4-acetylphenyl)-2-(3,14-difluoro-5,10-dimethyl-9-oxo-4,8,13-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide; N-(4-acetylphenyl)-2-[11-fluoro-9-(3-fluoroazetidin-1-yl)-5-methyl-6-oxo-5H-pyrido[2,3-d][1]benzazepin-7-yl]acetamide; N-(4-acetylphenyl)-2-(14-chloro-4-fluoro-7,12-dimethyl-8-oxo-5,6,9,13-tetrazatricyclo[8.4.0.0 ２，６ ]tetradeca-1(14),2,4,10,12-pentaen-9-yl)acetamide; 2. The compound of formula (I) according to claim 1, selected from the group consisting of:

16. System Xc － In the treatment of cancer, where System Xc plays a role － 16. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for use in epilepsy syndromes in which steroids play a role, or in cancer therapy resistance.

17. A method for the treatment of cancer or epilepsy syndromes in which system Xc- plays a role, or cancer therapy resistance, which method comprises administering an effective amount of a compound of formula (I) according to any one of claims 1 to 15 to a human / animal patient in need of such treatment.

18. Use of a compound of formula (I) according to any one of claims 1 to 15 for the manufacture of a medicament useful in the treatment of cancer or epilepsy syndromes in which system Xc- plays a role, or cancer therapy resistance.

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