Tricyclic cycloheptatrienone derivatives as SYSTEM XC inhibitors

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is useful in the treatment of diseases and / or conditions in which System Xc-functions. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to substituted 7-membered cyclic amide derivatives and their use in therapy.

[0002] In particular, the present invention relates to pharmacologically active substituted 7-membered cyclic amide or urea derivatives and analogs thereof.

[0003] More particularly, the present invention relates to (cyclo)alkylcarbonyl-substituted (hetero)aryl-acetamides of 7-membered cyclic amide derivatives and analogs thereof. The compounds according to the present invention regulate System Xc - Cystine / glutamate antiporter, and therefore as a therapeutic target for System Xc - Agents for diseases in which the cystine / glutamate antiporter plays a role would be beneficial. Background Art

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

[0005] Across many different cancer types, system Xc -Overexpression compared to normal tissue. These include, but are not limited to, gliomas (particularly glioblastomas) (Takeuchi et al., Neurosurgery (2013), 72, 33-41), colon cancer, colorectal cancer (Sugano et al., Anticancer Res (2015), 35, 677-682), non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma) and other lung cancer types (Ji et al., Oncogene (2018), 37, 5007-5019), esophageal cancer, cancer stem cells in triple-negative breast cancer (Conti et al., Cancer Immunol Res (2020), 8, 1039-105) and hepatocellular carcinoma (Kavanaugh et al., Mol Imaging Biol (2016) 18, 924-934). High system Xc - Expression is associated with poor prognosis in several cancers, including but not limited to colon cancer (Lim et al., Proc Natl Acad Sci U SA (2019), 116, 9433-9442), adrenocortical carcinoma, renal cancer (Wang et al., Oncotarget 2016, 7, 29901-29915), hepatocellular carcinoma (Kinoshita et al., Oncolumn Rep (2013), 29, 685-689), mesothelioma, lung cancer (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 cancer), stromal cells rely heavily on cysteine ​​to prevent ferroptotic cell death, and depletion of SLC7A11 in cancer-associated fibroblasts prevents in situ pancreatic tumor formation (Sharbeen et al., Cancer Res (2021); DOI: 10.1158 / 0008-5472.CAN-20-2496). In other cancers, System Xc - SLC7A11 (system Xc -Downregulation of TNF-α (a light chain) reduces cancer cell proliferation, tumor progression and invasion (Badgley et al., Science (2020), 368, 85-89; Ede et al., Haematologica (2018), 103, 1496-1501; Hu et al., J Clin Invest (2020), 130, 1752-1766; Lei et al., Cell Res (2020), 30, 146-162; Lin et al., Am J Cancer Res (2020), 10, 3106-3126).

[0006] High system Xc - Levels also endow cells with increased synthesis of the antioxidant GSH, the ability to defend 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 radioresistance 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, inhibiting or blocking System Xc - Can be used to treat System Xc - Some cancers that play a role.

[0009] Blocking System Xc - It can also work synergistically with other therapies that target tumor growth. For example, System Xc - Inhibition of cancer stem cell metastasis, together with chemotherapy that blocks tumor growth (induced by oncogenes such as HER2, p53, Kras, etc.), results in additional therapeutic effects 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 several cancer cells, inhibition of toxic lipid peroxidation induced by System Xc can have a synergistic effect when combined with conventional cancer therapies, leading to cancer cell death and overcoming resistance to the conventional cancer therapies (Lin et al., Am J Cancer Res (2020), 10, 3106-3126; Zhu et al., Cancer Res (2021) 77(8), 2064-2077).

[0011] Therefore, inhibiting system Xc - The molecules described above can be used alone or in combination with other molecules or treatments that target other mechanisms and pathways involved in cancer biology to help overcome drug resistance in current cancer treatments or enhance the effectiveness of some existing treatments. - Glutamate release resulting from upregulation of glutamate also affects tumorigenesis, and inhibition of glutamate release is associated with decreased proliferation not only in brain tumors but also in non-brain tumors (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 - The induced influx of L-glutamate into the extracellular space can contribute to excitatory signaling and excitotoxicity, leading to seizures, neuronal death, and other brain pathologies by activating postsynaptic glutamate receptors on neurons. - Mice expressing elevated System Xc have reduced brain glutamate receptors and exhibit reduced or delayed epileptogenesis (Leclercq et al., Epilepsia (2019), 60, 1412-1423). - Glioblastoma cells at the level of the nervous system release high levels of glutamate, which activates glutamate receptors on neighboring neurons and induces 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, inhibiting system Xc - Function or expression can prevent glioma-associated epilepsy in patients with high System Xc -Glutamate-induced seizures and neuronal death in other epilepsy syndromes at the same level as glutamate (Arena et al., (2019), Brain Pathol 29, 351-365).

[0014] International patent application WO 2015 / 196086 relates to a system described as System Xc - compounds that are inhibitors of .

[0015] Sulfasalazine is approved for the treatment of conditions including rheumatoid arthritis, ulcerative colitis, and Crohn's disease. It has been shown to be a promising candidate for System Xc - A nonselective inhibitor of the antiporter; however, due to its poor brain exposure, its use is limited to peripheral indications. - Due to its low efficacy, its efficacy in peripheral indications is limited.

[0016] Therefore, it is necessary to design a system that suppresses System Xc - New agents for antiporters that have improved properties and can be used to treat system Xc - Certain cancers or epilepsy syndromes play a role.

[0017] To accelerate the identification of System Xc - Suitable inhibitors of antiporters are also needed to develop pharmacological tools that can be used to develop new biological tests. Summary of the Invention

[0018] In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0019]

[0020] in

[0021] A is connected to the rest of the molecule at the point V 1 and V 2 Together means choose A 1 、A 2 and A 3 An optionally substituted aryl or heteroaryl group

[0022]

[0023] in

[0024] V 1 Indicates C;

[0025] V2 Indicates C or N;

[0026] Z 4 Indicates N or CR 7 ;

[0027] Z 5 Indicates N or CR 8 ;

[0028] Z 6 Indicates N or CR 9 ;

[0029] Z 7 Indicates N or CR 10 ;

[0030] R a represents halogen;

[0031] R 7 、R 8 、R 9 and R 10 independently represents hydrogen or halogen; or C 1-4 Alkyl or C 1-4 Alkoxy, any of which may be optionally substituted with one or more substituents; and

[0032] Z 1 Indicates N or CR 4 ;

[0033] Z 2 Indicates N or CR 5 ;

[0034] Z 3 Indicates N or CR 6 ;

[0035] R 1a and R 1b independently represents hydrogen or C 1-4 Alkyl, any of these groups may be optionally substituted with one or more substituents;

[0036] R 2 Indicates C 1-4 Alkyl or C 3-7 Cycloalkyl, any of these groups may be optionally substituted with one or more substituents;

[0037] R 3 represents hydrogen, halogen or hydroxy; or C 1-4 an alkyl group, which may be optionally substituted with one or more substituents;

[0038] R 2 and R 3Together with the phenyl group to which they are attached, they form a heteroaryl group, which is optionally substituted with one or more substituents;

[0039] R 4 and R 5 independently represents hydrogen, halogen or cyano; or C 1-4 Alkyl or C 1-4 Alkoxy, any of which may be optionally substituted with one or more substituents; and

[0040] R 6 represents hydrogen, halogen or cyano; or C 1-4 Alkyl, C 1-4 Alkoxy, C 3-7 Heterocycloalkyl or C 3-7 Cycloalkyl, any of these groups may be optionally substituted with one or more substituents.

[0041] In a second aspect, the present invention provides a compound of formula (I')

[0042]

[0043] Among them, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 、R 1a 、R 1b 、R 2 and R 3 As defined above.

[0044] In a third aspect, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt thereof,

[0045]

[0046] in

[0047] Z 1 Indicates N or CR 4 ;

[0048] Z 2 Indicates N or CR 5 ;

[0049] Z 3 Indicates N or CR 6 ;

[0050] Z 4 Indicates N or CR 7 ;

[0051] Z5 Indicates N or CR 8 ;

[0052] Z 6 Indicates N or CR 9 ;

[0053] Z 7 Indicates N or CR 10 ;

[0054] R 1a and R 1b independently represents hydrogen or C 1-4 Alkyl, any of these groups may be optionally substituted with one or more substituents;

[0055] R 2 Indicates C 1-4 Alkyl or C 3-7 Cycloalkyl, any of these groups may be optionally substituted with one or more substituents;

[0056] R 3 represents hydrogen, halogen or hydroxy; or C 1-4 an alkyl group, which may be optionally substituted with one or more substituents;

[0057] R 2 and R 3 Together with the phenyl group to which they are attached, they form a heteroaryl group, which is optionally substituted with one or more substituents;

[0058] R 4 and R 5 independently represents 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;

[0059] R 6 represents hydrogen, halogen or cyano; or C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 Heterocycloalkyl, any of which may be optionally substituted with one or more substituents; and

[0060] R 7 、R 8 、R 9 and R 10 independently represents 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.

[0061] In a fourth aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

[0062] In a fifth aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which can be used to treat system Xc - Conditions in which the cystine / glutamate antiporter plays a role.

[0063] In particular, the present invention provides compounds of formula (I), which can be used to treat cancer or wherein system Xc - Epilepsy syndromes that play a role.

[0064] Furthermore, the present invention provides compounds of formula (I), which can be used to overcome resistance to cancer therapy.

[0065] 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.

[0066] 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

[0067] As used herein, the term "C 1-4 "Alkyl" refers to a linear or branched monovalent saturated aliphatic hydrocarbon chain of 1 to 4 carbon atoms. 1-4 Alkyl groups include methyl and ethyl.

[0068] The term "C 1-4 "Alkoxy" means a group of formula -OR wherein R is as described herein "C 1-4 "alkyl", wherein 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.

[0069] As used herein, the term "C 3-7 "Cycloalkyl" refers to a monovalent group of 3 to 7 carbon atoms derived from a saturated monocyclic hydrocarbon. Exemplary C 3-7 Cycloalkyl groups include cyclopropyl.

[0070] As used herein, the term "C 3-7 "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 3-7 Heterocycloalkyl groups include azetidinyl and azaspiro[2.3]hexan-5-yl.

[0071] The terms "halo", "halogen" and "halide" are used indifferently and denote a chlorine, fluorine, bromine or iodine atom. Suitable examples of halogen according to the present invention include chlorine and fluorine.

[0072] As used herein, the term "heteroaryl" refers to an aromatic carbocyclic group of 5 to 14 carbon atoms having at least one aromatic monocyclic ring or multiple fused rings, wherein one or more of the carbon atoms have been replaced by one or more heteroatoms selected from oxygen, sulfur and nitrogen. Examples of heteroaryl groups according to the present invention are optionally substituted benzofuran-3-one or indan-1-one.

[0073] For the avoidance of doubt, when reference is made to compounds of formula (I), this also includes compounds of formula (I') and (IA).

[0074] When any group in the compound of above-mentioned formula (I) is stated as optionally substituted, the group can be unsubstituted, or replaced by one or more substituents. Usually, such group will be unsubstituted, or replaced by one, two or three substituents. In one embodiment, such group is unsubstituted. Each suitable substituent of the group present on the compound of formula (I) is further described hereinafter in this manual.

[0075] Unless otherwise stated or shown, formula (I) and the formulae described hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof.

[0076] Stereoisomers of compounds of formula (I) include cis and trans isomers, optical isomers, diastereomers, geometric isomers, rotational isomers, atropisomers and conformational isomers of compounds of formula (I), including compounds exhibiting more than one type of isomerism; and mixtures thereof (e.g., racemates and diastereomeric pairs).

[0077] The compound of formula (I) and / or their intermediate can have at least one stereoisomerism source center in their structure.This stereoisomerism source center can exist with R or S configuration (being called aR or as for atropisomer), and described R and S (or aR and as) symbol are used in accordance with the rule described in Pure Appl.Chem., 45 (1976) 11-30.Therefore, the present invention further relates to all stereoisomeric forms of the compound of formula (I ') and formula (I), such as enantiomeric form and diastereomeric form or its mixture (comprising all possible mixtures of stereoisomers).About the present invention, unless specifically mentioning specific isomeric form, mentioning one or more compounds is intended to encompass the compound of each and its mixture in its possible isomeric form.

[0078] The carbon-carbon bonds of the compounds of formula (I) are represented herein by solid lines (-), solid wedges (-), and or dotted wedge Depicting. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that only the stereoisomers shown are 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 solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers are intended to be included.

[0079] Some compounds of Formula (I) may exist as a single atropisomer or as a mixture of atropisomers.

[0080] Atropisomers are stereoisomers arising from hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a sufficiently high barrier to rotation to allow separation of the 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).

[0081] Unlike compounds with classical chiral centers that racemize by bond cleavage and formation processes, atropisomers racemize by a dynamic intramolecular process involving only bond rotation. Depending on the rotational barrier, one particular conformer of a compound of formula (I) may be in equilibrium with another conformer, and thus the conformer composition may change over time or conditions to achieve equilibrium. The conformations of a compound of formula (I) can be represented by solid lines (-) and / or solid wedges. Shown below are examples of specific subgroups of compounds having formula (I), whose atropisomers are represented by formula (Ia) and (Ib), respectively.

[0082]

[0083] Use solid wedges on the A and B rings It is intended to indicate the conformation associated with a particular atropisomer (Ia) or (Ib).

[0084] Some of the compounds of formula (I) may exist in tautomeric forms. Such forms, although not explicitly indicated in the above formula, are intended to be included within the scope of the present invention. Examples of tautomers include ketone (CH2C=O) Enol (CH=CHOH) tautomer or (NHC=O) Hydroxyimine (N=COH) tautomers or 2-hydroxypyridine Unless otherwise stated or shown, formula (I) and the formulae described hereinafter are intended to represent all individual tautomers and all possible mixtures thereof.

[0085] It will also be understood that each individual atom present in formula (I) or in the formulae described hereinafter may exist in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred.

[0086] Thus, for example, each individual hydrogen atom present in formula (I) or in the formulae described below may serve as 1 H. 2 H (deuterium) or 3 H (tritium) atoms, preferably 1 H or 2 H is present. Similarly, for example, each individual carbon atom present in Formula (I'), Formula (I), or the formulae described below may be present as 11 C. 12 C. 13 C or 14 C atoms, preferably 12 C exists. Similarly, for example, each individual fluorine atom can be 18 F or 19 F exists.

[0087] Therefore, the present invention also includes within its scope isotopically labeled compounds of formula (I).

[0088] Specific embodiments of the compounds of formula (I) according to the present invention are described below.

[0089] In one embodiment, A represents A 1 In one aspect of this embodiment, V 1 and V 2 In another embodiment, A represents A 2 In one aspect of this embodiment, V 1 and V 2 In another embodiment, A represents A 3 In one aspect of this embodiment, V 1 Indicates C and V 2 Indicates N.

[0090] Usually, R a represents a halogen. In particular, R a Represents fluorine.

[0091] In a first embodiment, R 1a In a second embodiment, R 1a represents an optionally substituted C 1-4 In one aspect of this embodiment, R 1a represents an optionally substituted methyl group.

[0092] In a first embodiment, R 1b In a second embodiment, R 1b represents an optionally substituted C 1-4 In one aspect of this embodiment, R 1b represents an optionally substituted methyl group.

[0093] Suitably, R 1a and R 1b independently represents hydrogen or C 1-4 alkyl.

[0094] For example, R 1a and R 1b independently represents hydrogen or methyl.

[0095] In a specific embodiment according to the present invention, R 1a Indicates C 1-4 Alkyl and R 1b Represents hydrogen.

[0096] In a first embodiment, R 2 represents an optionally substituted C 1-4 In a first aspect of this embodiment, R 2 In a second aspect of this embodiment, R 2 In a second embodiment, R 2 represents an optionally substituted C 3-7 In a first aspect of this embodiment, R 2 represents an optionally substituted cyclopropyl group.

[0097] Suitably, R 2 Indicates C 1-4 Alkyl or C 3-7 Cycloalkyl.

[0098] For example, R 2 represents a methyl or cyclopropyl group.

[0099] In a first embodiment, R 3 In a second embodiment, R 3 In one aspect of this embodiment, R 3In a third embodiment, R 3 In a fourth embodiment, R 3 represents an optionally substituted C 1-4 In one aspect of this embodiment, R 3 represents an optionally substituted methyl group.

[0100] Suitably, R 3 Represents hydrogen.

[0101] In a specific embodiment according to the present invention, R 2 and R 3 Together with the phenyl group to which they are attached they form a heteroaryl group which is optionally substituted benzofuran-3-one or indan-1-one.

[0102] For example, R 2 and R 3 Together with the phenyl group to which they are attached they form benzofuran-3-one.

[0103] In one embodiment, Z 1 represents N. In another embodiment, Z 1 Indicates CR 4 .

[0104] In one embodiment, Z 2 represents N. In another embodiment, Z 2 Indicates CR 5 .

[0105] In one embodiment, Z 3 represents N. In another embodiment, Z 3 Indicates CR 6 .

[0106] In one embodiment, Z 4 represents N. In another embodiment, Z 4 Indicates CR 7 .

[0107] In one embodiment, Z 5 represents N. In another embodiment, Z 5 Indicates CR 8 .

[0108] In one embodiment, Z 6 represents N. In another embodiment, Z 6 Indicates CR 9 .

[0109] In one embodiment, Z 7represents N. In another embodiment, Z 7 Indicates CR 10 .

[0110] In a specific embodiment according to the present invention, Z 1 , Z 2 and Z 3 In one aspect of this particular embodiment, Z 2 Indicates N, Z 1 Indicates CR 4 and Z 3 Indicates CR 6 .

[0111] In a specific embodiment according to the present invention, Z 4 , Z 5 , Z 6 and Z 7 In one aspect of this particular embodiment, Z 7 Indicates N, Z 4 Indicates CR 7 , Z 5 Indicates CR 8 , Z 6 Indicates CR 9 .

[0112] In a first embodiment, R 4 In a second embodiment, R 4 In a first aspect of this embodiment, R 4 In a second aspect of this embodiment, R 4 In a third embodiment, R 4 In a fourth embodiment, R 4 represents an optionally substituted C 1-4 In one aspect of this embodiment, R 4 represents an optionally substituted methyl group.

[0113] In a fifth embodiment, R 4 represents an optionally substituted C 1-4 In a first aspect of this embodiment, R 4 represents an optionally substituted methoxy group.

[0114] Suitably, R 4 Represents hydrogen, halogen, cyano, C 1-4 Alkyl or C 1-4 Alkoxy.

[0115] For example, R 4 represents hydrogen, fluorine, chlorine or methoxy.

[0116] In a first embodiment, R 5 In a second embodiment, R 5 In a first aspect of this embodiment, R 5 In a second aspect of this embodiment, R 5 In a third embodiment, R 5 In a fourth embodiment, R 5 represents an optionally substituted C 1-4 In one aspect of this embodiment, R 5 In a fifth embodiment, R 5 represents an optionally substituted C 1-4 In a first aspect of this embodiment, R 5 represents an optionally substituted methoxy group.

[0117] Suitably, R 5 Represents hydrogen, halogen, cyano, C 1-4 Alkyl or C 1-4 Alkoxy.

[0118] For example, R 5 represents hydrogen, fluorine, chlorine or methoxy.

[0119] In a first embodiment, R 6 In a second embodiment, R 6 In a first aspect of this embodiment, R 6 In a second aspect of this embodiment, R 6 In a third embodiment, R 6 In a fourth embodiment, R 6 represents an optionally substituted C 1-4 In a first aspect of this embodiment, R 6 In a fifth embodiment, R 6 represents an optionally substituted C 1-4 In a first aspect of this embodiment, R 6 In a sixth embodiment, R 6 represents an optionally substituted C 3-7 In a first aspect of this embodiment, R 6 In a second aspect of this embodiment, R 6 represents optionally substituted azaspiro[2.3]hexyl. In a seventh embodiment, R 6represents an optionally substituted C 3-7 In a first aspect of this embodiment, R 6 represents an optionally substituted cyclobutane.

[0120] Suitably, R 6 Represents hydrogen, halogen, cyano, C 1-4 Alkyl or C 1-4 Alkoxy; or optionally substituted C 3-7 Heterocycloalkyl or C 3-7 Cycloalkyl.

[0121] More appropriately, R 6 Represents hydrogen, halogen, cyano, C 1-4 Alkyl or C 1-4 Alkoxy; or optionally substituted C 3-7 Heterocycloalkyl.

[0122] Ideally, R 6 Indicates C 1-4 Alkyl, C 1-4 Alkoxy or optionally substituted C 3-7 Heterocycloalkyl.

[0123] For example, R 6 represents methyl, methoxy, optionally substituted azetidinyl, optionally substituted azaspiro[2.3]hexanyl or optionally substituted cyclobutane.

[0124] 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.

[0125] More specifically, R 6 represents a methyl group, a methoxy group, a 3,3-difluoroazetidin-1-yl group or a 2,2-difluoro-5-azaspiro[2.3]hexan-5-yl group.

[0126] In a first embodiment, R 7 In a second embodiment, R 7 In a first aspect of this embodiment, R 7 In a third embodiment, R 7 represents an optionally substituted C 1-4 In a first aspect of this embodiment, R 7 In a fourth embodiment, R 7represents an optionally substituted C 1-4 In a first aspect of this embodiment, R 7 represents an optionally substituted methoxy group.

[0127] Suitably, R 7 Represents hydrogen, halogen, C 1-4 Alkyl or C 1-4 Alkoxy.

[0128] For example, R 7 Represents hydrogen.

[0129] In a first embodiment, R 8 In a second embodiment, R 8 In a first aspect of this embodiment, R 8 In a third embodiment, R 8 represents an optionally substituted C 1-4 In a first aspect of this embodiment, R 8 In a fourth embodiment, R 8 represents an optionally substituted C 1-4 In a first aspect of this embodiment, R 8 represents an optionally substituted methoxy group.

[0130] Suitably, R 8 Represents hydrogen, halogen, C 1-4 Alkyl or C 1-4 Alkoxy.

[0131] For example, R 8 represents hydrogen, fluorine or methoxy.

[0132] In a first embodiment, R 9 In a second embodiment, R 9 In a first aspect of this embodiment, R 9 In a third embodiment, R 9 represents an optionally substituted C 1-4 In a first aspect of this embodiment, R 9 In a fourth embodiment, R 9 represents an optionally substituted C 1-4 In a first aspect of this embodiment, R 9 represents an optionally substituted methoxy group.

[0133] Suitably, R 9 Represents hydrogen, halogen, C 1-4 Alkyl or C 1-4Alkoxy.

[0134] For example, R 9 Represents hydrogen.

[0135] In a first embodiment, R 10 In a second embodiment, R 10 In a first aspect of this embodiment, R 10 In a third embodiment, R 10 represents an optionally substituted C 1-4 In a first aspect of this embodiment, R 10 In a fourth embodiment, R 10 represents an optionally substituted C 1-4 In a first aspect of this embodiment, R 10 represents an optionally substituted methoxy group.

[0136] Suitably, R 10 Represents hydrogen, halogen, C 1-4 Alkyl or C 1-4 Alkoxy.

[0137] For example, R 10 Represents hydrogen.

[0138] In R 1a 、R 1b 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 and R 10 Suitable optional substituents on are hydroxy, halogen, C 1-4 Alkyl or C 1-4 Alkoxy. In R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 and R 10 Specific examples of optional substituents on are hydroxy, fluoro, methyl and methoxy.

[0139] For example, R 1a 、R 1b 、R 2 、R 3 、R 4 、R 5 、R7 、R 8 、R 9 and R 10 Not replaced.

[0140] In a first particular embodiment, the invention relates to a particular subclass of compounds of formula (I) represented by formula (IA),

[0141]

[0142] Among them, R 1a 、R 2 、R 4 、R 6 and R 8 As defined above.

[0143] In the compound according to formula (IA), suitably:

[0144] R 1a Represents hydrogen or C 1-4 alkyl;

[0145] R 2 Indicates C 1-4 Alkyl or C 3-7 Cycloalkyl;

[0146] R 4 and R 8 independently represents hydrogen, halogen or C 1-4 alkoxy; and

[0147] R 6 Indicates C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 Heterocycloalkyl.

[0148] In the compound according to formula (IA), suitably:

[0149] R 1a represents hydrogen or methyl;

[0150] R 2 represents a methyl or cyclopropyl group;

[0151] R 4 represents hydrogen, chlorine, fluorine or methoxy;

[0152] R 6 represents methyl, methoxy, 2,2-difluoro-azetidin-1-yl, or 2,2-difluoro-5-azaspiro[2.3]hexane-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; and

[0153] R 8 represents hydrogen, fluorine or methoxy.

[0154] In compounds according to formula (IA), typically:

[0155] R 1a Represents hydrogen or C 1-4 alkyl;

[0156] R 2 Indicates C 1-4 Alkyl or C 3-7 Cycloalkyl;

[0157] R 4 and R 8 independently represents hydrogen, halogen or C 1-4 alkoxy; and

[0158] R 6 Indicates C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 Heterocycloalkyl.

[0159] In the compound according to formula (IA), suitably:

[0160] R 1a represents hydrogen or methyl;

[0161] R 2 represents a methyl or cyclopropyl group;

[0162] R 4 represents hydrogen, chlorine, fluorine or methoxy;

[0163] R 6 represents methyl, methoxy, 2,2-difluoro-azetidin-1-yl or 2,2-difluoro-5-azaspiro[2.3]hexan-5-yl; and

[0164] R 8 represents hydrogen, fluorine or methoxy.

[0165] In a particular aspect of the compounds of formula (IA), R 8 Represents fluorine.

[0166] 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.

[0167] In a particular embodiment, the present invention relates to a compound of formula (I) selected from the group consisting of:

[0168] N-(4-acetylphenyl)-2-[3-fluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide;

[0169] N-[4-(cyclopropanecarbonyl)phenyl]-2-[3-fluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide;

[0170] N-(4-acetylphenyl)-2-[3,14-difluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide;

[0171] N-(4-acetylphenyl)-2-[14-fluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide;

[0172] N-(4-acetylphenyl)-2-[(10R)-3-chloro-14-fluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide;

[0173] N-(4-acetylphenyl)-2-[3-chloro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide;

[0174] N-(4-acetylphenyl)-2-[5-(3,3-difluoroazetidin-1-yl)-3-fluoro-10-methyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide;

[0175] N-(4-acetylphenyl)-2-[3-fluoro-5-(3-fluoroazetidin-1-yl)-10-methyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.02,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide;

[0176] N-(4-acetylphenyl)-2-[3-chloro-5-(2,2-difluoro-5-azaspiro[2.3]hexan-5-yl)-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide; and

[0177] N-(4-acetylphenyl)-2-(1-fluoro-3-methyl-6-oxoylidene-7H-pyrido[4,3-d][3]benzazepine-5-yl)acetamide,

[0178] N-(4-acetylphenyl)-2-[3-fluoro-5-methoxy-10-methyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide;

[0179] N-(4-acetylphenyl)-2-[14-methoxy-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide;

[0180] N-(4-acetylphenyl)-2-[3-methoxy-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(15),2(7),3,5,11,13-hexaen-8-yl]acetamide;

[0181] N-(4-acetylphenyl)-2-(3-methoxy-10-methyl-9-oxyylidene)-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide;

[0182] 2-[3-fluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]-N-(4-propionylphenyl)acetamide;

[0183] N-(4-acetyl-3-hydroxy-phenyl)-2-[3-fluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide;

[0184] N-(4-acetylphenyl)-2-(3,14-difluoro-5-methoxy-10-methyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide;

[0185] 2-[3,14-difluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]-N-(3-oxyylidenebenzofuran-6-yl)acetamide;

[0186] N-(4-acetylphenyl)-2-(10-cyano-2-fluoro-5,9-dimethyl-6-oxylidene-5H-pyrido[2,3-d][1]benzazepine-7-yl)acetamide;

[0187] N-(4-acetylphenyl)-2-[(10)-3-fluoro-14-methoxy-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide;

[0188] N-(4-acetylphenyl)-2-[3-fluoro-5-(3-fluoroazetidin-1-yl)-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide;

[0189] N-(4-acetylphenyl)-2-[5-(3,3-difluoroazetidin-1-yl)-3-fluoro-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide;

[0190] N-(4-acetylphenyl)-2-(3,5-difluoro-10-methyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide;

[0191] N-(4-acetyl-3-fluoro-phenyl)-2-[(10)-3-fluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide;

[0192] N-(4-acetylphenyl)-2-[3-fluoro-5-(3-hydroxy-3-methyl-azetidin-1-yl)-10-methyl-9-oxygenylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide;

[0193] N-(4-acetylphenyl)-2-[3-fluoro-5-(3-fluoro-3-methyl-azetidin-1-yl)-10-methyl-9-oxygenylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide;

[0194] N-(4-acetylphenyl)-2-[3-fluoro-5-(3-hydroxy-3-methyl-azetidin-1-yl)-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide;

[0195] N-(4-acetylphenyl)-2-(14-fluoro-7,12-dimethyl-8-oxyylidene-4-thia-5,9,13-triazatricyclo[8.4.0.0 2,6 ]Tetradec-1(10),2,5,11,13-pentaen-9-yl)acetamide;

[0196] N-(4-acetylphenyl)-2-[3-fluoro-5-(1-hydroxycyclobutyl)-10-methyl-9-oxyde-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(15),2,4,6,11,13-hexaen-8-yl]acetamide;

[0197] N-(4-acetylphenyl)-2-[3,14-difluoro-5-(hydroxymethyl)-10-methyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide;

[0198] N-(4-acetylphenyl)-2-(5-cyclobutyl-3-fluoro-10-methyl-9-oxyylidene)-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide;

[0199] N-(4-acetylphenyl)-2-(14-fluoro-5-methoxy-10-methyl-9-oxyylidene)-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide;

[0200] N-(4-acetyl-3-hydroxy-phenyl)-2-(3,14-difluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide;

[0201] N-(4-acetylphenyl)-2-(3,14-difluoro-5,10-dimethyl-9-oxyylidene-4,8,13-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide;

[0202] 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;

[0203] N-(4-acetylphenyl)-2-(14-chloro-4-fluoro-7,12-dimethyl-8-oxyylidene)-5,6,9,13-tetraazatricyclo[8.4.0.0 2,6 ]Tetradec-1(14),2,4,10,12-pentaen-9-yl)acetamide; and its enantiomers.

[0204] In a particular aspect, the invention relates to compounds of formula (I) as described in the accompanying Examples 1-36.

[0205] In another specific aspect, the present invention relates to a compound of formula (I) selected from the group consisting of:

[0206] N-(4-acetylphenyl)-2-[(10R)-3-fluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide;

[0207] N-(4-acetylphenyl)-2-[(10R)-3,14-difluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide;

[0208] N-[4-(cyclopropanecarbonyl)phenyl]-2-[(10R)-3-fluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide;

[0209] N-(4-acetylphenyl)-2-[(10R)-3-chloro-14-fluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide;

[0210] N-(4-acetylphenyl)-2-[3-chloro-5-(2,2-difluoro-5-azaspiro[2.3]hexan-5-yl)-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide;

[0211] N-(4-acetylphenyl)-2-(1-fluoro-3-methyl-6-oxo-7H-pyrido[4,3-d][3]benzazepine-5-yl)acetamide;

[0212] 2-[(10R)-3-fluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]-N-(4-propionylphenyl)acetamide;

[0213] N-(4-acetylphenyl)-2-[3-fluoro-5-(3-fluoroazetidin-1-yl)-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide;

[0214] N-(4-acetylphenyl)-2-[5-(3,3-difluoroazetidin-1-yl)-3-fluoro-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide;

[0215] N-(4-acetylphenyl)-2-[3-fluoro-5-(3-hydroxy-3-methyl-azetidin-1-yl)-10-methyl-9-oxygenylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide;

[0216] N-(4-acetylphenyl)-2-[3-fluoro-5-(3-fluoro-3-methyl-azetidin-1-yl)-10-methyl-9-oxygenylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide;

[0217] N-(4-acetylphenyl)-2-[3-fluoro-5-(3-hydroxy-3-methyl-azetidin-1-yl)-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide;

[0218] N-(4-acetylphenyl)-2-(14-fluoro-7,12-dimethyl-8-oxyylidene-4-thia-5,9,13-triazatricyclo[8.4.0.0 2,6 ]Tetradec-1(10),2,5,11,13-pentaen-9-yl)acetamide;

[0219] N-(4-acetylphenyl)-2-[3-fluoro-5-(1-hydroxycyclobutyl)-10-methyl-9-oxyde-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(15),2,4,6,11,13-hexaen-8-yl]acetamide;

[0220] N-(4-acetylphenyl)-2-[3,14-difluoro-5-(hydroxymethyl)-10-methyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide;

[0221] N-(4-acetylphenyl)-2-(3,14-difluoro-5,10-dimethyl-9-oxyylidene-4,8,13-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide; and

[0222] N-(4-acetylphenyl)-2-(14-chloro-4-fluoro-7,12-dimethyl-8-oxyylidene)-5,6,9,13-tetraazatricyclo[8.4.0.0 2,6 ]Tetradec-1(14),2,4,10,12-pentaen-9-yl)acetamide.

[0223] The present invention also provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0224] In particular, the present invention provides compounds of formula (I) as defined above, or pharmaceutically acceptable salts thereof, for use in the treatment of System Xc - The disease and / or condition at play.

[0225] In the following aspects, the compound of formula (I) as defined above may be System Xc - Inhibitors of antiporters.

[0226] In a first aspect, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in treating a disease in which System Xc - Cancers where System Xc - role in epilepsy syndromes, or for resistance to cancer therapy.

[0227] In a first embodiment according to this aspect, the invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease in which System Xc - Cancer that works.

[0228] 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 cancer, colorectal cancer, lung cancer, esophageal cancer, triple-negative breast cancer, hepatocellular carcinoma, adrenocortical carcinoma, renal cancer, mesothelioma, sarcoma, uveal melanoma, gastric cancer, pancreatic cancer or leukemia.

[0229] In a second embodiment of this aspect, the invention provides a compound of formula (I) as defined above for use in the treatment of a disease in which System Xc - Epilepsy syndromes that play a role.

[0230] 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-related epilepsy, focal cortical dysplasia or tuberous sclerosis.

[0231] In a third embodiment, the present invention provides a compound of formula (I) for use in the treatment of cancer therapy resistance.

[0232] In particular, the present invention provides compounds of formula (I) as defined above, or pharmaceutically acceptable salts thereof, for use in the treatment of multidrug resistance in several cancer types.

[0233] In a second aspect, the present invention provides the use of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for the preparation of a method for treating system Xc - Drugs for diseases and / or conditions in which the cystine / glutamate antiporter plays a role.

[0234] In a first embodiment of 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 preparation of a method for treating a disease wherein system Xc - Cancer drugs that work.

[0235] 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 preparation of a medicament useful for treating glioma, colon cancer, colorectal cancer, lung cancer, esophageal cancer, triple-negative breast cancer, hepatocellular carcinoma, adrenocortical carcinoma, renal cancer, mesothelioma, sarcoma, uveal melanoma, gastric cancer, pancreatic cancer or leukemia.

[0236] In a second 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 preparation of a method for treating System Xc - Drugs that work for epilepsy syndromes.

[0237] In particular, the present invention provides a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament useful for treating epileptogenesis, glutamate-induced epileptic seizures, glioma-related epilepsy, focal cortical dysplasia or tuberous sclerosis.

[0238] In a third embodiment according to this aspect, the invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament useful for the treatment of cancer resistance.

[0239] 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 preparation of a medicament useful in the treatment of multidrug resistance in several cancer types. In a third aspect, the present invention provides a method for treating a cancer suitable for administration of System Xc - A method for treating a condition in which an inhibitor of steroids is present, said method comprising 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.

[0240] In a first embodiment according to this aspect, the present invention provides a method for treating a patient wherein System Xc - A method for treating a cancer 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.

[0241] In particular, the present invention provides a method for treating glioma, colon cancer, colorectal cancer, lung cancer, esophageal cancer, triple-negative breast cancer, hepatocellular carcinoma, adrenocortical carcinoma, renal cancer, mesothelioma, sarcoma, uveal melanoma, gastric cancer, pancreatic cancer or leukemia, which method 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.

[0242] In a second embodiment according to this aspect, the invention provides a method for treating a patient wherein System Xc - A method for treating an epileptic syndrome 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.

[0243] In particular, the present invention provides a method for treating epileptogenesis, glutamate-induced epileptic seizures, glioma-related epilepsy, focal cortical dysplasia or tuberous sclerosis, which method 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.

[0244] In a third embodiment according to this aspect, the present invention provides a method for treating resistance to cancer therapy, the method comprising 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 treating multidrug resistance in several cancer types, the method comprising 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.

[0245] As used herein, the term "patient" refers to a patient who has one or more - It will be appreciated that the most preferred patient is a human.

[0246] It will also be appreciated that one skilled in the art can affect a condition by treating a patient currently suffering from the condition or by prophylactically treating a patient suffering from the condition with an effective amount of a compound of formula (I). Thus, the terms "treatment" or "treating" are intended to refer to all processes in which the progression of the conditions described herein can be slowed, interrupted, prevented, controlled, or stopped, and are intended to include the preventative treatment of such conditions, but do not necessarily represent the complete elimination of all symptoms of the condition.

[0247] Activity in any of the above-mentioned therapeutic indications or conditions can of course be determined by conducting appropriate clinical trials for the specific indication and / or in the general design of clinical trials in a manner known to those skilled in the relevant art.

[0248] For use in medicine, the salt of the compound of formula (I) will be a pharmaceutically acceptable salt. However, other salts may be used to prepare the compounds for use in the present invention or their pharmaceutically acceptable salts. The standard principles for the selection and preparation of pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use, ed. PHS Tahl & C.G. Wermuth, Wiley-VCH, 2002. Suitable pharmaceutically acceptable salts of the compound of formula (I') or formula (I) include acid addition salts, which can be formed, for example, by mixing a solution of the compound of formula (I) with a solution of a pharmaceutically acceptable acid.

[0249] The present invention includes within its scope solvates of the compounds of formula (I) above. Such solvates can be formed with common organic solvents or water.

[0250] The present invention also includes within its scope co-crystals of compounds of formula (I) above. The technical term "co-crystal" is used to describe the situation in which neutral molecular components are present in a crystalline compound in a defined stoichiometric ratio. The preparation of pharmaceutical co-crystals enables the modification of the crystalline form of the active pharmaceutical ingredient, which in turn can alter its physicochemical properties without compromising its intended biological activity (see Pharmaceutical Salts and Co-crystals, edited by J. Wouters & L. Quere, RSC Publishing, 2012).

[0251] The compounds according to the present invention may exist in different polymorphic forms. Although not explicitly indicated in the above formula, such forms are intended to be included within the scope of the present invention.

[0252] The present invention also includes within its scope the prodrug forms of the compounds of formula (I) and the various subranges and subgroups / subgroups thereof.

[0253] For the treatment of diseases, the compounds of formula (I) or their pharmaceutically acceptable salts can be used in an effective daily dose and administered in the form of a pharmaceutical composition.

[0254] Therefore, another embodiment of the present invention is directed 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.

[0255] To prepare the pharmaceutical compositions according to the present invention, one or more compounds of formula (I) or pharmaceutically acceptable salts thereof are intimately mixed with a pharmaceutical diluent or carrier according to conventional pharmaceutical formulation techniques known to those skilled in the art.

[0256] Suitable diluents and carriers can take a wide variety of forms depending on the desired route of administration, eg, oral, rectal, parenteral, intranasal or intratumoral.

[0257] The pharmaceutical compositions comprising the compounds according to the invention can be administered, for example, orally, parenterally, ie intravenously, intramuscularly or subcutaneously, intrathecally, by inhalation, intranasally or ophthalmically.

[0258] Pharmaceutical compositions suitable for oral administration may be solid or liquid and may be in the form of, for example, tablets, pills, dragees, gelatin capsules, solutions, syrups, chewing gums and the like.

[0259] To this end, the active ingredient may be mixed with an inert diluent or a nontoxic pharmaceutically acceptable carrier such as starch or lactose. Optionally, these pharmaceutical compositions may also contain a binder such as microcrystalline cellulose, gum tragacanth or gelatin, a disintegrant such as alginic acid, a lubricant such as magnesium stearate, a glidant such as colloidal silicon dioxide, a sweetener such as sucrose or saccharin, or a coloring or flavoring such as peppermint or methyl salicylate.

[0260] The present invention also contemplates compositions that 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, usually contained in ampoules, disposable syringes, glass or plastic vials or infusion containers.

[0261] In addition to the active ingredient, these solutions or suspensions may optionally contain a sterile diluent such as water for injection, physiological saline solution, oil, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediaminetetraacetic acid, buffers such as acetates, citrates or phosphates, and agents for regulating osmotic pressure such as sodium chloride or dextrose.

[0262] These pharmaceutical forms are prepared using methods routinely used by pharmacists.

[0263] The amount of active ingredient in the pharmaceutical composition can fall within a wide concentration range and depends on various factors, such as the patient's sex, age, weight and medical condition, and the method of administration. Therefore, the amount of the compound of formula (I) in the composition for oral administration is at least 0.5 wt % and can be up to 80 wt %, relative to the gross weight of the composition.

[0264] According to the present invention, it has also been found that the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered alone or in combination with other pharmaceutically active ingredients.

[0265] In particular, the compounds of formula (I) according to the present invention may be combined with other active ingredients that increase intracellular reactive oxygen species, regulate amino acid metabolism, or with immunotherapeutic agents.

[0266] In compositions for parenteral administration, the amount of the compound of formula (I) present is at least 0.5% by weight and can be up to 33% by weight relative to the total weight of the composition. For preferred parenteral compositions, the dosage unit is within the range of 0.5 mg to 3000 mg of the compound of formula (I).

[0267] The daily dose may fall within a wide range of dosage units of the compound of formula (I) and will generally be in the range of 0.5 to 3000 mg. However, it will be appreciated that the specific dose may be adapted to the individual requirements of the particular case at the physician's discretion.

[0268] Synthesis scheme

[0269] It will be apparent to those skilled in the art that there are various synthetic pathways that can produce the compounds according to the present invention. The following methods are intended to illustrate some of these synthetic pathways, but should not be interpreted in any way as limiting how the compounds according to the present invention should be obtained.

[0270] During any following synthetic sequence, it may be necessary and / or desirable to protect sensitive or reactive groups on any relevant molecules. This can be achieved by means of conventional protecting groups (PGs), such as those described in Protective Groups in Organic Chemistry, edited by J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rd edition, 1999. Protecting groups can be removed at any convenient subsequent stage using methods known in the art.

[0271] The compounds of formula (I) according to the present invention can be prepared analogously to conventional methods understood by those skilled in the art of synthetic organic chemistry.

[0272] 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 N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate; and "NMI" refers to N-methylimidazole.

[0273] The following description of the synthesis scheme provides a method for preparing the compound of formula (I). However, similar methods can be used to prepare the compound of formula (I). According to one embodiment, wherein A represents A 1The compound of formula (I) can be prepared by reacting a compound of formula (2) with an amide of formula (4) or by reacting a compound of formula (3) with an aromatic amine of formula (5) according to the following equation:

[0274]

[0275] Among them, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 、R 1a 、R 1b and R 2 As defined above for compounds of formula (I) and wherein LG 1 is a halogen atom or a leaving group, such as mesylate or tosylate; and LG 2 is hydroxy, alkoxy or halogen.

[0276] The reaction according to Scheme A can be carried out using a base such as a trialkylamine, an 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.

[0277] Alternatively, compounds of formula (I) can be prepared according to route B by reacting a carboxylic acid or carboxylic acid derivative of formula (3) with an aromatic amine (5) according to procedures known to those skilled in the art for forming amides from carboxylic acids or carboxylic acid derivatives and amines. 2 When LG is a halogen such as chlorine, the reaction according to route B can be carried out using a base such as trialkylamine, inorganic carbonate or pyridine in a suitable solvent such as DCM, DMSO, DMF, sulfolane, acetonitrile or THF. 2 When LG is hydroxyl, 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 The compound of formula (3) wherein LG is a hydroxyl group can be converted to a compound wherein LG is a hydroxyl group by reacting with sulfonyl chloride or thionyl chloride in the presence or absence of catalytic DMF in a suitable solvent such as DCM or THF at room temperature or at a higher temperature such as 70°C. 2 The compound of formula (3) is chlorine.

[0278] Among them LG 2Compounds of formula (3) where LG is an alkoxy group such as OMe, OEt or OtBu can be prepared by reacting intermediate (2) with an α-chloroester or α-bromoester 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. Further basic or acidic ester hydrolysis known to those skilled in the art can be used to form a compound wherein LG 2 The compound of formula (3) wherein is OH.

[0279] Alternatively, the compound of formula (I) may be prepared by 2 The intermediate of formula (3) (hereinafter referred to as (3')) which is NH2 is reacted with a compound of formula (5') in which X is a sulfonate / ester such as a triflate / ester, a halogen such as chlorine or bromine in the presence of a catalytic amount of a palladium catalyst. This reaction, known as the "Buchwald amide coupling", is known to those skilled in the art.

[0280]

[0281] Compounds of formula (5') are commercially available or can be prepared by any method known to those skilled in the art.

[0282] The compound of formula (3') can be prepared by reacting a compound of formula (2) with an α-haloamide 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, the compound of formula (3') can be prepared by reacting a carboxylic acid or a carboxylic acid derivative of formula (3) with ammonia according to procedures known to those skilled in the art for forming amides from carboxylic acids or carboxylic acid derivatives and amines.

[0283] Compounds of formula (2) can be prepared from their precursors of formula (6) by ring condensation, wherein LG 2 has the same definition as above. For example, when LG 2 In the case of alkoxy groups, the reaction involves the presence of a base such as LiHMDS or K2CO3, or can be obtained directly under heating conditions without isolation from the previous step.

[0284]

[0285] Compounds of formula (6) can be prepared from their corresponding precursors of formula (8) and (9) by a cross-coupling reaction, also known to those skilled in the art as the "Suzuki reaction", provided that when (8) carries B*, (9) carries X*, or when (8) carries X*, (9) carries B*. B* can be a boronic acid B(OH)2, or any boronic ester B(OR)2, such as pinacol boronate, or a mixture of the two, and X* is a halogen, such as Cl, Br or I.

[0286] 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.

[0287] Where A represents A 2 or A 3 The compounds of formula (I') can be synthesized as described in the examples.

[0288] In another aspect, the present invention provides a synthetic intermediate of formula (II),

[0289]

[0290] Among them, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 、R 1a 、R 1b As defined above:

[0291] R 15 Represents hydrogen or CH2-CO-R d ;and

[0292] R d Represents hydroxyl, halogen, amino or C 1-4 Alkoxy.

[0293] In a first embodiment, R 15 represents CH2-CO-R d In a second embodiment, R 15 Represents hydrogen.

[0294] 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).

[0295] Experimental part

[0296] I. Abbreviations / Repeated Reagents

[0297] ACN or MeCN Acetonitrile

[0298] CV column volume

[0299] DCM dichloromethane

[0300] EtOAc

[0301] DMF N,N-dimethylformamide

[0302] DMA dimethylacetamide

[0303] DMAP dimethylaminopyridine

[0304] EDC 1-Ethyl-3-carbodiimide hydrochloride

[0305] MeOH methanol

[0306] DCE dichloroethane

[0307] HATU Azabenzotriazole tetramethyluronium hexafluorophosphate

[0308] HBTU Benzotriazole tetramethyluronium hexafluorophosphate

[0309] HOBt Hydroxybenzotriazole

[0310] TCFH N,N,N',N'-Tetramethylchloroformamidine hexafluorophosphate

[0311] NMI N-Methylimidazole

[0312] MTBE or TBME methyl tert-butyl ether

[0313] PTFE polytetrafluoroethylene

[0314] ELSD Evaporative Light Scattering Detector

[0315] DMSO dimethyl sulfoxide

[0316] Brine saturated sodium chloride aqueous solution

[0317] Et2O ether

[0318] h hour

[0319] d day

[0320] THF Tetrahydrofuran

[0321] AcOH acetic acid

[0322] RT Room temperature

[0323] rt retention time

[0324] Rf retention factor

[0325] br width

[0326] M Moore

[0327] MS

[0328] [M+H] + The exact mass of the protonated ions observed by MS

[0329] [MH] - The exact mass of the deprotonated ions observed by MS

[0330] mL milliliters

[0331] HPLC high-performance liquid chromatography

[0332] UPLC ultra-performance liquid chromatography

[0333] LC-MS liquid chromatography-mass spectrometry

[0334] ESI electrospray ionization

[0335] ES + Electrospray positive ionization

[0336] TEA triethylamine

[0337] DIPEA N,N-Diisopropylethylamine

[0338] DEA Diethylamine

[0339] CDI Carbonyldiimidazole

[0340] PCy3 tricyclohexylphosphine

[0341] TMSCN Trimethylsilyl cyanide

[0342] dppf 1,1'-bis(diphenylphosphino)ferrocene

[0343] PEPPSI Pyridine Enhanced Precatalyst Preparation, Stabilization and Initiation

[0344] HMDS bis(trimethylsilyl)amide or hexamethyldisilazane

[0345] PPh3 triphenylphosphine

[0346] AIBN Azobisisobutyronitrile

[0347] TFA trifluoroacetic acid

[0348] bs. Broad single peak

[0349] NBS N-bromosuccinimide

[0350] DME dimethoxyethane

[0351] HMPA Hexamethylphosphoric triamide

[0352] SFC Supercritical Fluid Chromatography

[0353] SCX Strong Cation Exchange HPLC Column

[0354] TLC thin layer chromatography

[0355] Sat. Saturated

[0356] Hexane

[0357] aq. water

[0358] Eq. Equivalent

[0359] min

[0360] mmol millimole

[0361] UV

[0362] Naming conventions:

[0363] The IUPAC names of the chemical reagents, intermediates, and examples have been generated using Biovia Draw 2020 (version 20.1.100.2161 or 20.1.0.2081). Depending on the Kekule structure of the chemical reagent, intermediate, or example, Biovia Draw may generate different chemical names. As an illustration, the Kekule structures K1 and K2 are named 4,8,14-triazatricyclo[9.4.0.0 2,7 ]pentadecan-1(11),2,4,6,12,14-hexaen-9-one and 4,8,14-triazatricyclo[9.4.0.0 2,7 ] Pentadecan-1(15),2,4,6,11,13-hexaen-9-one. Both names can be used in the following description.

[0364]

[0365] II. Analytical and Synthetic Methods

[0366] All reactions involving air or moisture sensitive reagents were carried out under nitrogen or argon atmosphere (inert atmosphere) using dried solvents and glassware. Experiments requiring microwave irradiation were carried out on a BiotageInitiator Sixty microwave oven upgraded with version 2.0 operating software. The experiment was run to reach the desired temperature as quickly as possible (maximum irradiation power: 400W, no external cooling). Commercial solvents and reagents were typically used without further purification, including anhydrous solvents (typically Sure-Seal® from Aldrich Chemical Company) when appropriate. TM or AcroSeal from ACROS Organics TM Typically, the reaction is followed by thin layer chromatography (TLC), high performance liquid chromatography (HPLC), or mass spectrometry (MS) analysis.

[0367] NMR spectra were recorded on a Bruker Advance III HD 500 MHz or 400 MHz spectrometer. Chemical shifts (δ) are reported in parts per million (ppm), and coupling constants (J) are in Hertz (Hz). Spin multiplicities are reported as s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, ddd = doublet of doublets, dt = doublet of triplets, td = doublet of triplets, and m = multiplet.

[0368] Mass spectrometry measurements in LC-MS mode were performed as follows:

[0369] - For acidic elution (methods A1, A1', A1_S, A2 and A2'), analysis was performed using a QDA Waters simple quadrupole mass spectrometer. The spectrometer was equipped with an ESI source and a UPLC Acquity Hclass with a diode array detector (200 to 400 nm). Data were collected in a full MS scan from m / z 70 to 800 in positive mode for acidic elution. Reverse 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 elution and on a Waters Acquity UPLC HSS T3 1.8 μm (2.1 x 100 mm) column for methods A2 and A2'. For methods A1, A1_S, and A2, gradient elution was performed using water / ACN / TFA (95 / 5 / 0.5 mL / L) (solvent A) and ACN (solvent B). For methods A1' and A2', gradient elution was performed using water / acetonitrile / formic acid (95 / 5 / 0.05%) (solvent A) and acetonitrile / formic acid (99.95 / 0.05%) (solvent B). Injection volume: 1 μL. Full flow chart for the MS gradient program:

[0370] Methods A1 and A1'

[0371] Time (min) A(％) B(％) Flow rate (mL / min) 0 99 1 0.4 0.3 99 1 0.4 3.2 5 95 0.4 3.25 5 95 0.5 4 5 95 0.5 4.1 99 1 0.4 5.5 99 1 0.4

[0372] Method A1_S

[0373] Time (min) A(％) B(％) Flow rate (mL / min) 0 99 1 0.8 0.15 99 1 0.8 1.60 5 95 0.8 1.65 5 95 0.8 2 5 95 0.8 2.05 99 1 0.8 2.75 99 1 0.8

[0374] Methods A2 and A2'

[0375]

[0376]

[0377] - For acidic elution (Method A3), analysis was performed using a Xevo Waters Q-TOF mass spectrometer. The spectrometer was equipped with an ESI source and a Waters Acquity H-class UPLC with a diode array detector (210 to 400 nm). Data were collected in positive mode using a full MS scan from m / z 50 to 1200. Reverse-phase separation was performed on an Acquity UPLC HSS T3 C18 column (1.8 μm, 2.1 x 100 mm) at 40°C. Gradient elution was performed with water / ACN / formic acid (95 / 5 / 750 μL / L) (Solvent C) and water / ACN / formic acid (5 / 95 / 500 μL / L) (Solvent D) at pH ~3. 100% flow was in UV, 10% flow was in MS, and 90% flow was in ELSD. Injection volume: 0.5 to 2 μL.

[0378] Gradient program:

[0379] Method A3

[0380] Time (min) C(％) D(％) Flow rate (mL / min) 0 98 2 0.6 0.3 98 2 0.6 5.9 5 95 0.6 9.3 5 95 0.6 9.4 98 2 0.6 14 98 2 0.6

[0381] 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 an ESI source and a Waters Acquity H-class UPLC with a diode array detector (210 to 400 nm). Data were acquired in positive mode using a full MS scan from m / z 50 to 1200. Reversed-phase separation was performed at 40°C on an Acquity UPLC HSS T3 C18 column (1.8 μm, 2.1 x 100 mm). 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) at pH ~3. Full flow was applied to the MS. Injection volume: 0.5 μL.

[0382] Gradient program:

[0383] Methods A4 and A8

[0384] Time (min) C(％) D(％) Flow rate (mL / min) 0 98 2 0.6 0.5 98 2 0.6 5 5 95 0.6 5.1 5 95 0.6 7.3 5 95 0.6 7.5 98 1 0.6 10 98 1 0.6

[0385] - For acidic elution (method A5), LC-MS analysis was performed using a Shimadzu LC-MS 2010EV mass spectrometer. The spectrometer was equipped with an ESI source and an HPLC with a diode array detector (210 to 400 nm). Data were collected in a full MS scan from m / z 80 to 2000 in positive and negative modes. Reversed-phase separation was performed using a Waters X-Select CSH C18 (4.6×150 mm) 3.5 μm column. Column temperature: 50° C. Gradient elution was performed using a mobile phase of 0.1% formic acid in water (phase A) and acetonitrile (phase B). Injection volume: 2 μL.

[0386] Gradient program:

[0387] Method A5

[0388] Time (min) A(％) B(％) Flow rate (mL / min) 0.01 95 5 1 1.0 95 5 1 8.0 0 100 1 12 0 100 1 14 95 5 1 18 95 5 1

[0389] - For acidic elution (method A6), a Shimadzu LC-MS 2010EV mass spectrometer was used for LC-MS analysis. The spectrometer was equipped with an ESI source and an HPLC with a diode array detector (210 to 400 nm). Data were collected in a full MS scan from m / z 80 to 2000 in positive and negative modes. Reversed phase separation was performed using a Waters X-Select CSH C18 (4.6x150) mm 3.5 μm column. Column temperature: 50° C. Gradient elution was performed using a mobile phase of 0.1% TFA in water (phase A) and acetonitrile (phase B). Injection volume: 2 μL.

[0390] Gradient program:

[0391] Method A6

[0392] Time (min) A(％) B(％) Flow rate (mL / min) 0.01 95 5 1.2 1.0 95 5 1.2 8.0 0 100 1.2 12 0 100 1.2 14 95 5 1.2 18 95 5 1.2

[0393] - For acid elution (Method A7), analysis was performed using an Agilent 1200-6120 LC-MS system coupled to UV detection (254 nm) and MS detection: Agilent 6120 mass spectrometer (ES) m / z 100 to 1000. Column: XSelect CSH C18XP 2.5μm, 4.6mm X 30mm (Waters TM Mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile + 0.1% formic acid. Flow rate: 2.5 mL / min.

[0394] Gradient program:

[0395] Method A7

[0396] Time (min) A(％) B(％) Flow rate (mL / min) 0 95 5 2.5 3 5 95 2.5 3.01 5 95 4.5 3.60 5 95 4.5 3.7 95 5 4.5 3.71 95 5 2.5 4 95 5 2.5

[0397] For acid elution (method A9), analysis was performed using a similar apparatus as described above, but with a Waters Cortecs C18 2.7 μm (30 x 2.1 mm) column for reversed-phase separation. Column temperature: 40° C. Elution was performed with a 1.5 min gradient using a mobile phase consisting of 0.1% formic acid in water (phase A) and ACN (phase B).

[0398] -For alkaline elution (methods B1, B1_S and B2), analysis was performed using a QDA Waters simple quadrupole mass spectrometer. The spectrometer was equipped with an ESI source and a UPLC Acquity Hclass with a diode array detector (200 to 400 nm). Data were collected in a full MS scan from m / z 70 to 800 in positive mode. For methods B1 and B1_S, alkaline elution was performed on a Waters Acquity UPLC BEHC18 1.7 μm (2.1 x 50 mm) column and for method B2, on a Waters Acquity UPLC BEHC18 1.7 μm (2.1 x 100 mm) column at 45°C for reverse phase separation. Gradient elution was performed with water / ACN / ammonium formate (95 / 5 / 63 mg / L) (solvent A) and ACN / water / ammonium formate (95 / 5 / 63 mg / L) (solvent B). Injection volume: 1 μL. Full flow in MS.

[0399] Gradient program:

[0400] Method B1

[0401] Time (min) A(％) B(％) Flow rate (mL / min) 0 99 1 0.4 0.3 99 1 0.4 3.2 0 100 0.4 3.25 0 100 0.5 4 0 100 0.5 4.1 99 1 0.4 4.8 90 1 0.4

[0402] Method B1_S

[0403]

[0404]

[0405] Method B2

[0406] Time (min) A(％) B(％) Flow rate (mL / min) 0 99 1 0.4 0.8 99 1 0.4 5.30 0 100 0.4 5.35 0 100 0.5 7.30 0 100 0.5 7.35 99 1 0.4 9 90 1 0.4

[0407] For alkaline elution (Method B3), analysis was performed using a Xevo Waters Q-TOF mass spectrometer. The spectrometer was equipped with an ESI source and a Waters Acquity H-class UPLC with a diode array detector (210 to 400 nm). Data were acquired in positive mode using a full MS scan from m / z 50 to 1200. Reverse-phase separation was performed on an Acquity UPLC BEH C18 column (1.7 μm, 2.1 x 100 mm) at 45°C. Gradient elution was performed with water / ACN / ammonium formate (95 / 5 / (40 mg / L ammonium bicarbonate + 100 μL / L NH4OH)) (Solvent A) and ACN (Solvent B) at pH ~8-9. 100% flow rate was in the UV, 10% flow rate was in the MS, and 90% flow rate was in the ELSD. Injection volume: 0.2 to 2 μL.

[0408] Gradient program:

[0409] Method B3

[0410] Time (min) A(％) B(％) Flow rate (mL / min) 0 98 2 0.6 0.3 98 2 0.6 5.9 5 95 0.6 9.3 5 95 0.6 9.4 98 2 0.6 14 98 2 0.6

[0411] -For alkaline elution (methods B4 and B8), analysis was performed using a SYNAPT G2-SI system and a Waters Q-TOF mass spectrometer for method A4, and an SQD2 Waters single quadrupole for method B8. These spectrometers were equipped with an ESI source and a Waters Acquity H-class UPLC with a diode array detector (210 to 400 nm). Data were collected in a full MS scan from m / z 50 to 1200 in positive mode. Reverse phase separation was performed on an Acquity UPLC BEH C18 column (1.7 μm, 2.1 x 100 mm) at 45°C. Gradient elution was performed with water / ACN / ammonium formate (95 / 5 / (63 mg / L+100 μL / L NH4OH)) (solvent A) and ACN (solvent B) at pH ~8-9. Full flow was in the MS. Injection volume: 0.5 μL.

[0412] Gradient program:

[0413] Methods B4 and B8

[0414] Time (min) A(％) B(％) Flow rate (mL / min) 0 98 2 0.6 0.5 98 2 0.6 5 5 95 0.6 5.5 5 95 0.7 7.3 5 95 0.7 7.5 98 1 0.6 10 98 1 0.6

[0415] - For basic elution (methods B5 and B5'), analysis was performed using an Agilent 1200-6120 LC-MS system coupled to UV detection (254 nM) and an Agilent 6120 mass spectrometer (ES) with MS detection from m / z 100 to 1000. HPLC was performed at 45°C on an XBridge BEH C18 XP column. 2.5μm, 4.6mm X 30mm (Waters TM ) were used for reverse-phase separation. Column temperature: 40°C. Flow rate: 2.5 mL / min. For Method B5, gradient elution was performed using the mobile phases acetonitrile / 10 mM aqueous ammonium bicarbonate (Phase A) and acetonitrile (Phase B). For Method B5', mobile phase A: 0.1% ammonia in water, mobile phase B: acetonitrile.

[0416] Gradient program:

[0417] Methods B5 and B5'

[0418]

[0419]

[0420] -For alkaline elution (method B6), a Shimadzu LC-MS2010EV mass spectrometer was used for analysis. The spectrometer was equipped with an ESI source and an HPLC with a diode array detector (210 to 400 nm). Data were collected in a full MS scan from m / z 80 to 2000 in positive and negative modes. Reverse phase separation was performed using a Waters X-Select CSH C18 (4.6x150) mm, 3.5 μm column. Column temperature: 50°C. Gradient elution was performed using the mobile phase: 10 mM ammonium bicarbonate in water (phase A) and acetonitrile (phase B). Injection volume: 2 μL.

[0421] Gradient program:

[0422] Method B6

[0423] Time (min) A(％) B(％) Flow rate (mL / min) 0.01 95 5 1 1.0 95 5 1 8.0 0 100 1 12 0 100 1 14 95 5 1 18 95 5 1

[0424] -For alkaline elution (method B7), a Shimadzu LC-MS2010EV mass spectrometer was used for analysis. The spectrometer was equipped with an ESI source and an HPLC with a diode array detector (210 to 400 nm). Data were collected in a full MS scan from m / z 80 to 2000 in positive and negative modes. Reverse phase separation was performed using a Waters X-Bridge C18 (4.6x150) mm, 5 μm column. Column temperature: 50°C. Gradient elution was performed using a mobile phase of 0.1% ammonia in water (phase A) and acetonitrile (phase B). Injection volume: 5 μL.

[0425] Gradient program:

[0426] Method B7

[0427] Time (min) A(％) B(％) Flow rate (mL / min) 0.01 98 2 1.2 6 85 15 1.2 8 85 15 1.2 9 0 100 1.2 12 0 100 1.2 14 98 2 1.2 18 98 2 1.2

[0428] For basic elution (Method B9), analysis was performed using an Agilent 1200 Series LC coupled to a 6140 mass spectrometer. Reverse-phase separation was performed using a Phenomenex Gemini NX-C18 3 μM (2 x 20 mm) column at a flow rate of 1.0 mL / min and a column temperature of 40°C, with a 5-95% gradient elution 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).

[0429] For basic elution (method B10), analysis was performed using an Agilent 1290 Infinity II LC coupled to a 6135MSD XT mass spectrometer. Reverse phase separation was performed using an Acquity UPLC BEH C18 2.1 x 50 mm, 1.7 μM column, with a flow rate of 1.5 mL / min and a column temperature of 60°C. Elution was performed using a 5-95% gradient over 4.5 minutes (solvent A: 10 mM ammonium formate in water + 0.1% ammonia solution, solvent BACN + 5% water + 0.1% ammonia solution).

[0430] Analytical chiral LC-MS were all performed at 30° C. on 4.6×150 mm columns at a flow rate of 1.5 mL / min, with the exception of the Chiralpak IG-u (Daicel) column, which was 3×100 mm in size, and a flow rate of 0.425 mL / min. The particle size analysis was 3 μm for all columns, 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.

[0431] High-resolution mass spectrometry measurements in LC-MS mode were performed as follows:

[0432] Method HRMS_A1: QC analysis was performed on a SYNAPT G2-SI Waters Q-TOF mass spectrometer. The spectrometer was equipped with an ESI source and a Waters Acquity H-class UPLC with a diode array detector (210 to 400 nm). Data were acquired in positive mode with a full MS scan from m / z 50 to 1200. Reverse-phase separation was performed on an Acquity UPLC BEH C18 column (1.7 μm, 2.1 x 30 mm) at 45°C. Gradient elution was performed with water / ACN / formic acid (95 / 5 / (750 μL / L)) (Solvent C) and water / ACN / formic acid (5 / 95 / (500 μL / L)) (Solvent D) at pH ~3. Full flow was applied to the MS. Injection volume: 0.5 to 1 μL.

[0433] Method HRMS_A2: QC analysis was performed using a Xevo Waters Q-TOF mass spectrometer. The spectrometer was equipped with an ESI source and a Waters Acquity H-class UPLC with a diode array detector (210 to 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 x 50 mm) at 40°C. Gradient elution was performed with water / ACN / formic acid (95 / 5 / 750 μL / L) (Solvent C) and water / ACN / formic acid (5 / 95 / 500 μL / L) (Solvent D) at pH ~3. 100% flow rate was in the UV, 10% flow rate was in the MS, and 90% flow rate was in the ELSD. Injection volume: 0.5 to 1 μL.

[0434] Method HRMS_A1

[0435] Time (min) C(％) D(％) Flow rate (mL / min) 0 95 5 0.8 1.8 5 95 0.8 2.4 5 95 0.8 2.5 95 5 0.8 3.1 95 5 0.8

[0436] Method HRMS_A2

[0437] Time (min) C(％) D(％) Flow rate (ml / min) 0 98 2 0.8 0.3 98 2 0.8 3 5 95 0.8 4 5 95 0.8 4.1 98 2 0.8 5.1 98 2 0.8

[0438] Preparative HPLC purification was performed using an SQD Waters or QDa Performance single quadrupole mass spectrometer. The spectrometer was equipped with an ESI source, a Waters 2525 binary pump coupled to a 2767 sample manager, and a diode array detector (210 to 400 nm). Data were collected in a full MS scan from m / z 100 to 850 in positive and negative modes. LC parameters: reverse phase separation was performed on a Waters XBridge OBD MS C18 column (5 μm, 30x50 mm) at room temperature. Typical HPLC flow rates were 35 mL / min to 45 mL / min. A typical example of alkaline elution was a gradient from solvent A (H2O+10 mM NH4HCO3+50 μL / L NH4OH) and solvent B (100% acetonitrile) [Purification Method P_B]. Typical example of acidic elution: Gradient from solvent A (H2O / TFA: 99.5% / 0.5%) and solvent B (ACN / TFA: 99.5% / 0.5%) [Purification method P_A].

[0439] Some preparative HPLC purifications were performed using a Gilson modular system equipped with a YMC Triart-500g-10μm-76, 5x200mm column (333 Prep HPLC Pump (water), 334 Presp HPLC Pump (acetonitrile), 334 Presp HPLC Pump (Modifier: 5 mL NH4OH in 1000 mL of HO for basic elution [Purification Method G_B] or 20 mL TFA in 1000 mL of HO [Purification Method G_A]), 171 Diode Array Detector, GX-271 Preparative Processor, PrepFC Fraction Collector). Typical HPLC flow rate was 180 mL / min.

[0440] When no analytical method is specified in the following schemes, the methods used are similar to those described above. It will be apparent to those skilled in the art that there are analytical and preparative chromatographic methods similar to those described above that can be used for the following procedures.

[0441] III. Intermediates

[0442] Intermediate C1: N-(4-acetylphenyl)-2-chloro-acetamide

[0443]

[0444] At 0 ° C, chloroacetyl chloride (1.4 mL, 18 mmol) was added dropwise to a solution of 1- (4- aminophenyl) ethanone (2.0 g, 14.6 mmol) and triethylamine (2.5 mL, 18 mmol) in dry DCM (14.6 mL). The resulting mixture was slowly warmed to room temperature and stirred at room temperature for 18 h. The reaction mixture was quenched with water and extracted with DCM. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (using a gradient of 0 to 100% EtOAc in heptane as eluent) to provide the title compound (2.65 g, yield: 86%) in the form of a beige solid. LC-MS (Method B1-S) m / z: [M+H] + :212.0; rt:0.93min; purity: 100%. 1 H NMR (400MHz, DMSO-d6) δ10.61(s,1H),7.95(d,J=8.8Hz,2H),7.72(d,J=8.8Hz,2H),4.30(s,2H),2.53(s,3H).

[0445] Intermediate C2: N-(4-acetyl-3-hydroxy-phenyl)-2-chloro-acetamide

[0446]

[0447] Under N2 atmosphere, chloroacetyl chloride (172 μ L, 2.12 mmol) was added dropwise to a solution of 1- (4- amino -2- hydroxyphenyl) ethanone (200 mg, 1.32 mmol) and DIPEA (485 μ L, 2.92 mmol) in dry DCM (4.00 mL). The resulting mixture was stirred at room temperature for 16 h. Additional chloroacetyl chloride (40 μ L, 0.49 mmol) was added and the reaction mixture was stirred for another 4 h at room temperature. After completion, the reaction mixture was diluted with DCM (50 mL) and washed with water (2x50 mL). The organic layer was dried over MgSO4, filtered and concentrated under vacuum. The residue was purified on silica gel by flash chromatography (using EtOAc as eluent with a gradient of 0 to 100% in heptane) to provide the title compound (163 mg, yield: 54%) with a brown solid form. LC-MS (method A1-S) m / z: [M+H] + :227.9; rt:1.09min; purity: 99%. 1 H NMR(400MHz,DMSO-d6)δ12.27(s,1H),10.61(s,1H),7.88(d,J=8.7Hz,1H),7 .34(d,J=2.0Hz,1H),7.08(dd,J=8.7,2.0Hz,1H),4.30(s,2H),2.58(s,3H).

[0448] Intermediate L1: 2-[(10R)-3-fluoro-5,10-dimethyl-9-oxyde-4,8,12-triazatricyclic] [9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetic acid, trifluoroacetate

[0449]

[0450] Step 1: Synthesis of dimethyl 2-(4-amino-3,5-dichloro-6-fluoro-2-pyridyl)malonate L1_1

[0451]

[0452] To a mixture of 4-amino-3,5-dichloro-2,6-difluoropyridine (402.2 g, 2021 mmol), dimethyl malonate (470 mL, 4030 mmol) and N,N-dimethylformamide (2.4 L) (colorless solution) was added potassium carbonate (830 g, 6005 mmol) (white suspension). The mixture was heated to 65 ° C (internal temperature) for 19 hours. The mixture was cooled to ambient temperature and poured into mechanically stirred water (6 L). The solid was recovered on the sinter, washed with water (2 L) and dried. Triturated with TBME (2 L) and washed with isohexane (1.5 L) to obtain the title product (529 g, 84%) as a white crystalline solid. 1H NMR (300MHz, DMSO) δ7.24(s,2H),5.20(s,1H),3.71(s,6H). 19 FNMR (282 MHz, DMSO) δ-75.10. LC / MS (method B9) m / z (ES): 310.8, 312.8, 314.8 (M+H).

[0453] Step 2: Synthesis of 3,5-dichloro-2-fluoro-6-methyl-pyridin-4-amine L1_2

[0454]

[0455] 1-Methyl-2-pyrrolidone (1.5L) is added to 2-(4-amino-3,5-dichloro-6-fluoro-2-pyridyl) dimethyl malonate (intermediate L1-1, 370g, 1190mmol) and calcium chloride hexahydrate (780g, 3560mmol). The suspension is heated to 100°C to obtain a solution. After 20 hours, 87% conversion to monoesters was shown by LCMS analysis. The temperature was raised to 125°C. After 72 hours, complete conversion was shown by LCMS analysis. The mixture was cooled to 25°C and mechanically stirred water (2.5L) was poured into it. The precipitate was recovered on the sinter, washed with water (1L) and partially dried. The wet solid was suspended in ethanol (3L) and heated to 65°C to obtain a turbid solution. Activated carbon (30g) was added and heating was continued. After 15 minutes, the warm mixture was filtered through Celite. Water (3 L, to obtain 1:1 ethanol: water) was added to the filtrate. The mixture was then cooled to 5°C for 20 hours. The crystals were recovered on a sinter, washed with water (600 mL) and dried (note: if dried at 50°C at 2 mbar, the solid is slightly volatile) to obtain the title product (179 g, 77%) in the form of an off-white solid. 1 H NMR (300MHz, DMSO) δ6.94 (s, 2H), 2.35 (d, J = 0.6Hz, 3H). 19 F NMR (282 MHz, DMSO) δ -76.01. LC / MS (Method B9) m / z (ES): 194.8, 196.8, 198.8 (M+H), rt: 1.38 min, 100% purity.

[0456] Step 3: Preparation of 2-fluoro-6-methyl-pyridin-4-amine L1_3

[0457]

[0458] By 3,5-dichloro-2-fluoro-6-methyl-pyridine-4-amine (intermediate L1-2, 150g, 769mmol) and 5% palladium on carbon (49g, 23mmol) in methanol (2.6L) and pyridine (125mL) dissolve.Mixture is placed under 1 bar hydrogen atmosphere and is heated to 50 DEG C 18 hours.Then the mixture is cooled, filtered through Celite and concentrated under reduced pressure.Water (750mL) is added to residue and solution is extracted with ethyl acetate (3x750mL).Organic matter is washed with salt water (500mL), through MgSO4 drying, filtered and concentrated under reduced pressure, to obtain the title product (93g, 91%) as white solid. 1 H NMR (400MHz, DMSO) δ6.30 (s, 2H), 6.24 (s, 1H), 5.85 (s, 1H), 2.17 (t, J = 1.5Hz, 3H). 19 F NMR (376 MHz, DMSO) δ -71.85. LC / MS (Method B2) m / z (ES): 127.0 (M+H), rt: 2.1 min, 98.6% purity.

[0459] 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

[0460]

[0461] In a nitrogen-filled glove box, 2-fluoro-6-methyl-pyridine-4-amine (intermediate L1_3, 138mg, 1.04mmol) was dissolved in dry THF (1mL) in a 6mL pressure tube containing a magnetic stirring bar. Pinacol borane (211 μL, 1.45mmol) was added and the reaction mixture was stirred at room temperature for 1h. (1,5-cyclooctadiene) (methoxy) iridium (I) dimer (10mg, 0.015mmol), 4,4'-di-tert-butyl-2,2'-bipyridyl (9mg, 0.033mmol) and bis(pinacol) diboron (158mg, 0.62mmol) were added, the tube was sealed under a nitrogen atmosphere and the reaction mixture was heated at 80°C for 16h. After cooling to room temperature, methanol (3mL) was added and the reaction mixture was stirred for 10min until gas evolution stopped, then concentrated under vacuum. 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 by trituration in hexanes to provide the title compound as a light pink solid (200 mg, yield: 72%). LC-MS (Method B1) m / z: [M+H] +:253.0,rt:1.13min, purity: 95%. 1 H NMR (400MHz, DMSO-d6) δ6.58 (s, 2H), 6.29 (d, J = 1.9Hz, 1H), 2.16 (s, 3H), 1.28 (s, 12H).

[0462] Step 5: Synthesis of methyl 2-[3-(4-amino-2-fluoro-6-methyl-3-pyridyl)-2-pyridyl]propionate L1_5

[0463]

[0464] To the fluoro- 6- methyl -3- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) pyridine -4- amine (intermediate L1-4, 100mg, 0.39mmol) and 2- (3- bromopyridine -2- bases) methyl propionate (102mg, 0.40mmol) in dry toluene (2mL) solution of potassium carbonate (170mg, 1.22mmol). Make argon pass through reaction mixture, then add tris (dibenzylideneacetone) dipalladium (0) (36mg, 0.04mmol) and 2- dicyclohexylphosphino -2,6- dimethoxybiphenyl (17mg, 0.04mmol).Then reaction mixture is stirred at 100 DEG C for 4h.After cooling to room temperature, reaction mixture is diluted with EtOAc (10mL) and filtered through PTFE filter. The filtrate was concentrated under vacuum to provide the crude title compound (225 mg) as a yellow oil, 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. (in the form of a mixture of diastereomers).

[0465] Step 6: Synthesis of 3-fluoro-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadecan-1(11),2(7),3,5,12,14-hexaen-9-one L1_6

[0466]

[0467] At 0 ° C, to a solution of crude 2- [3- (4-amino-2-fluoro-6-methyl-3-pyridyl) -2-pyridyl] methyl propanoate (intermediate L1-5, 115 mg, 0.40 mmol) in dry toluene (2 mL) was added 1.5 M solution of lithium bis (trimethylsilyl) amide in THF (200 μL, 0.30 mmol) and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was neutralized at 0 ° C by adding saturated NH4Cl aqueous solution and extracted with EtOAc (3x20 mL). The combined organic layer was washed with brine (20 mL), dried over MgSO4, filtered off and concentrated under vacuum to obtain a yellow solid. Purified by grinding in Et2O to provide the title compound (11 mg, yield: 10%) in the form of a brown solid. LC-MS (method A1) m / z: [M+H] + :258.0; rt:0.93min; purity: 94%.

[0468] Step 7: Synthesis of 2-[(10R)-3-fluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl] tert-butyl acetate L1_7

[0469]

[0470] To a solution of intermediate L1-6 (1.05 g, 3.47 mmol) in dry 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 mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered off 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 provide 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%. 1H NMR (400MHz, DMSO-d6) δ8.66(dd,J=4.8,1.6Hz,1H),8.11(ddd,J=7.9,4.8,1.6Hz,1H),7.48(dd,J=7.9,4.8Hz ,1H),7.29(s,1H),4.65-4.30(m,2H),3.74(d,J=6.6Hz,1H),2.52(s,3H),1.49(d,J=6.6Hz,3H),1.24(s,9H).

[0471] The racemate (21.5 g) was separated by chiral SFC (Whelk O-1 (R, R), from Regis Technology, CO2 + iPrOH 20%) to provide the title compound (9.22 g, yield: 45%). Chiral purity: 99%; rt = 2.52 min (first eluting enantiomer). For reference, the second eluting enantiomer rt = 3.27 min. Both were measured by HPLC (Whelk O-1 (R, R), from Regis Technology, iPrOH 50%-heptane 50%-DEA 0.1%).

[0472] Step 8: 2-[(10R)-3-fluoro-5,10-dimethyl-9-oxyylidene-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 L1

[0473]

[0474] 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 h. Upon completion, the reaction mixture was concentrated to dryness and co-evaporated with Et2O to provide 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%. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (dd, J = 4.8, 1.6 Hz, 1H), 8.13-8.06 (m, 1H), 7.48 (dd, J = 7.9, 4.8 Hz, 1H), 7.31 (s, 1H), 4.44 (s, 2H), 3.76 (q, J = 6.6 Hz, 1H), 1.49 (d, J = 6.6 Hz, 3H). No COOH protons were observed. CH3 protons are below the DMSO signal. 19 F NMR (376 MHz, DMSO-d6) δ -70.82 (d, J = 4.7 Hz). Chiral purity: 100%; rt = 1.80 min (first eluting enantiomer). For reference, rt = 2.91 min for the second eluting enantiomer. Both were measured by HPLC (Chiralpak AD from Daicel, EtOH 30%-heptane 70%-DEA 0.1%).

[0475] Intermediate L2: 3,14-difluoro-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]15-carbon-1 (11),2(7),3,5,12,14-Hexaen-9-one

[0476]

[0477] Step 1: Synthesis of O1-tert-butyl O3-ethyl 2-(3-bromo-5-fluoro-2-pyridyl)malonate L2_1

[0478]

[0479] 3-Bromo-2,5-difluoropyridine (163.3 g, 800 mmol) and dimethyl sulfoxide (3.2 L) were loaded into a 5 L process reactor. Tert-butyl ethyl malonate (300 mL, 1610 mmol) was then added to the stirred solution at room temperature followed by Cs CO (652 g, 2000 mmol). 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 x 1.5 L). The combined organic extracts were washed with water (2 x 1.5 L), brine (2 x 1.2 L), dried over sodium sulfate, filtered and concentrated under vacuum to give the crude product (266 g) as a tan residue, which was then purified by flash chromatography (silica, 0 to 15% ethyl acetate gradient in isohexane) to provide O1-tert-butyl O3-ethyl 2-(3-bromo-5-fluoro-2-pyridyl)propanediol (120.6 g, 330 mmol, 42% yield) as a white solid that spontaneously precipitated from the chromatographic fractions. The precipitate was filtered off and the filtrate was concentrated, and the resulting yellow residue (67 g) was further purified by chromatography (silica, 0 to 10% ethyl acetate gradient in hexane). The resulting pale yellow solid was slurried in ethyl acetate (20 mL) and isohexane (20 mL) and filtered off. The solid was washed with isohexane (2 x 20 mL) to afford 01-tert-butyl 03-ethyl 2-(3-bromo-5-fluoro-2-pyridyl)propanediol (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%. 1 H NMR (300MHz, CDCl3) δ8.41(d,J=2.6Hz,1H),7.66(dd,J=7.5,2.6Hz,1H),5.10(s,1H),4.29(qd,J=7.2,4.5Hz,2H),1.49(s,9H),1.29(t,J=7.1Hz,3H). 19 F NMR (282MHz, CDCl3) δ-125.48 (d, J=7.4Hz). 13 C NMR (101MHz, CDCl3) δ166.98, 165.57, 157.80 (d, J = 263.2Hz), 149.25 (d, J = 4.0Hz), 136.19 (d ,J=23.1Hz),127.43(d,J=20.8Hz),121.16(d,J=3.5Hz),82.90,61.97,60.01,27.88,14.06.

[0480] Step 2: Synthesis of ethyl 2-(3-bromo-5-fluoro-2-pyridyl)acetate L2_2

[0481]

[0482] To 2L process reactor, add methylene dichloride (400mL) and trifluoroacetic acid (300mL).In room temperature, add the new solution of O 1-tert-butyl O 3-ethyl 2-(3-bromo-5-fluoro-2-pyridyl) propylene glycol L2-1 (69.3g, 191mmol) in methylene dichloride (400mL) to the solution that stirs.Reactant mixture was stirred at room temperature 5 hours, then quenched by pouring into two ice water beakers (2x1.7L) that stir.The mixture that stirs is carefully used solid K 3 PO 4 neutralize to pH 7.Then the mixture is distributed and merged organic extract.The water layer that separates is extracted with methylene dichloride (2x1L). The combined organic extracts were washed with saturated NaHCO3 solution (1.5 L), dried over sodium sulfate and concentrated under vacuum 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:1.42min, purity: 100%. 1 H NMR (300MHz, CDCl3) δ8.39(d,J=2.6Hz,1H),7.66(dd,J=7.5,2.6Hz,1H),4.20(q,J=7.1Hz,2H),4.02(s,2H),1.27(t,J=7.1Hz,3H). 19 F NMR (282MHz, CDCl3) δ-126.48 (d, J=7.6Hz). 13 C NMR (101MHz, CDCl3) δ169.43, 157.64 (d, J = 262.2Hz), 149.91, 136.18 (d, J = 22.6Hz), 127.39 (d, J = 20.6Hz), 121.11, 61.27, 43.00, 14.16.

[0483] Step 3: Synthesis of ethyl 2-(3-bromo-5-fluoro-2-pyridyl)propionate L2_3

[0484]

[0485] Under nitrogen at -74 DEG C to the stirring solution of lithium diisopropylamide (2.0M in THF / heptane / ethylbenzene, 56mL, 110mmol) in anhydrous tetrahydrofuran (340mL) via the dropping funnel maintaining the internal temperature below -70 DEG C, add dropwise a solution of 2- (3- bromo -5- fluoro -2- pyridyl) ethyl acetate L2-2 (28.3g, 100mmol) in anhydrous tetrahydrofuran (100mL). The gained dark brown mixture was stirred at -72 DEG C for 30 minutes, then iodomethane (9.6mL, 150mmol) was added dropwise. Stirring was continued at -72 DEG C for 30 minutes, then the cooling bath was removed and the reaction mixture was warmed to room temperature. After 16 hours, the reaction mixture was quenched with saturated NH4Cl solution (450mL) and extracted with ethyl acetate (2x450mL). The combined organic extracts were washed with water (450 mL) and brine (300 mL), dried over sodium sulfate and concentrated under vacuum. Purification by chromatography (silica, gradient of 0 to 5% ethyl acetate in isohexane) provided 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:1.74min, purity: 100%. 1 H NMR (300MHz, CDCl3) δ8.40 (d, J=2.6Hz, 1H), 7.64 (dd, J=7.6, 2.6Hz, 1H), 4.33 (q, J=7.1Hz,1H),4.16(q,J=7.1Hz,2H),1.53(d,J=7.1Hz,3H),1.20(t,J=7.1Hz,3H). 19 F NMR (282MHz, CDCl3) δ-126.94 (d, J=7.6Hz).

[0486] Step 4: Synthesis of 3,14-difluoro-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadecan-1(11),2(7),3,5,12,14-hexaen-9-one L2

[0487] Under argon atmosphere, to 2-(3-bromo-5-fluoro-2-pyridyl)ethyl propionate (intermediate L2-3, 2.00g, 7.24mmol), 2-fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-4-amine (intermediate L1-4, 2.19g, 8.69mmol) and K3PO4(3.17g, 14.5mmol) mixture in dry toluene (36mL) is added tris(dibenzylideneacetone)dipalladium(0)(663mg, 0.72mmol) at room temperature, then 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (303mg, 0.72mmol) is added. Gained mixture is stirred at 100 DEG C for 2h. After completion, reaction mixture is diluted with EtOAc (100mL) and filtered through diatomaceous earth (Celite). The filtrate is concentrated to dryness. The residue is dissolved in dry toluene (36mL), and LiHMDS (1.5M in THF, 9.70mL, 14.5mmol) is then added at room temperature. The resulting mixture is stirred at room temperature for 1h. After complete conversion, the reaction mixture is quenched with water (80mL) and extracted with EtOAc (4x20mL). The combined organic extracts are washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The residue is purified on silica gel by flash chromatography (using EtOAc as eluent with a gradient of 20 to 100% in heptane), then ground in Et2O (20mL), filtered and dried in vacuo to provide the title compound (634mg, yield: 32%) in the form of a beige solid. LC-MS (Method A1-S) m / z:[M+H] + :276.0; rt:1.09min; purity: 100%. 19 FNMR(376MHz, DMSO-d6)δ-70.19(d,J=4.1Hz),-130.44(d,J=9.8Hz).

[0488] The racemic intermediate L2 (74.8 g) was separated by chiral SFC (Chiralpak IG from Daicel, CO2 + MeOH 35%). The desired enantiomer (the 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 provide 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] +:275.9rt:3.61min; Purity: 100%. 1 H NMR (500 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.69 (s, 1H), 8.07 (d, J = 9.5 Hz, 1H), 7.01 (s, 1H), 3.64 (t, J = 6.5 Hz, 1H), 2.46 (s, 3H), 1.48 (d, J = 6.5 Hz, 3H). Chiral purity: 100%; rt = 1.87 min (first eluting enantiomer). For reference, rt = 2.52 min for the second eluting enantiomer. Both were measured by HPLC (Chiralpak IG from Daicel, MeOH 100%-DEA 0.1%).

[0489] Intermediate L3: 14-fluoro-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadecan-1(11), 2,4,6,12,14-Hexaen-9-one

[0490]

[0491] 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 eq.), potassium carbonate (1.52 g, 10.9 mmol, 3.01 eq.) and water (3.6 mL) were added to a solution of ethyl 2-(3-bromo-5-fluoro-2-pyridinyl)propanoate (Intermediate L2-3, 1 g, 3.62 mmol) in 1,4-dioxane (14.5 mL) at room temperature. The mixture was evacuated and backfilled with N (3x), followed by the addition of XPHOS Pd G (161 mg, 0.18 mmol, 0.05 eq.) and X-PHOS (88 mg, 0.18 mmol, 0.05 eq.). The obtained mixture is evacuated, backfilled with N2(3x), then stirred at 100 DEG C for 3h.The reaction mixture is diluted with EtOAc and water, filtered through a diatomaceous earth pad and rinsed with EtOAc.Phase separation and aqueous layer are extracted twice with EtOAc.The combined organic layer is washed with salt water, through Na2SO4 drying, filtered and concentrated to dryness, providing the crude mixture in the form of an orange solid, which is used for the next step without further purification.Residue (1.1g) is dissolved in dry THF (18mL), then LiHMDS (1.5M in THF, 4.8mL, 7.2mmol) is added at 0 DEG C.The obtained mixture is stirred at room temperature for 1h.After complete conversion, the reaction mixture is diluted with methanol (5mL), diatomaceous earth is added and residue is concentrated to dryness, and purified on silica gel by flash chromatography (using 0 to 10% MeOH in DCM as eluent) to provide the title compound (842mg, yield: 90%) in the form of a light yellow solid. LC-MS (Method A1_S) m / z: [M+H] + :258; rt:0.70min; purity: 100%. 1 H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.76 (s, 1H), 8.67 (d, J = 2.8 Hz, 1H), 8.12 (dd, J = 9.7, 2.8 Hz, 1H), 7.03 (s, 1H), 3.51 (q, J = 6.6 Hz, 1H), 1.48 (d, J = 6.6 Hz, 3H). The CH3 protons are below the DMSO signal.

[0492] Intermediate L4: (10R)-3-chloro-14-fluoro-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]ten Pentacarbon-1(11),2(7),3,5,12,14-hexaen-9-one

[0493]

[0494] Step 1: Synthesis of 3-bromo-2-chloro-6-methyl-pyridin-4-amine L4_1

[0495]

[0496] A solution of 2-chloro-6-methyl-pyridin-4-amine (10.0 g, 66.6 mmol) in dry 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 warmed 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 of 0 to 50% EtOAc in isohexane as eluent) to afford the title compound (7.05 g, 47% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ6.53 (s, 2H), 6.47 (d, J = 0.7Hz, 1H), 2.20 (s, 3H).

[0497] 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

[0498]

[0499] To a nitrogen-purged suspension of ethyl 2-(3-bromo-5-fluoro-2-pyridyl)propanoate L2-3 (86% purity, 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-dioxaborolan (1.4 g, 5.61 mmol) and CHCOOK (1.8 g, 18.7 mmol) in 1,4-dioxane (13 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride DCM complex (172 mg, 0.21 mmol), and the reaction mixture was purged with nitrogen for an additional 10 min. The suspension was heated at reflux for 4 h. The reaction mixture was allowed to cool to room temperature, then filtered through celite and washed thoroughly with EtOAc (100 mL). The filtrate was concentrated under reduced pressure and then purified by column chromatography on silica gel (using a gradient of 0-100% EtOAc in isohexane as eluent) to provide the title compound as a clear, colorless oil that partially crystallized upon standing (950 mg, yield: 35%). LC-MS (Method A9) m / z [M+H] + :324.4; rt:1.27min, purity: 55%. 1H NMR (400MHz, CDCl3) δ8.42 (d, J=3.1Hz, 1H), 7.77 (dd, J=8.8, 3.1Hz, 1H), 4.67 (q, J=7.0 Hz,1H),4.17-4.09(m,2H),1.50(d,J=7.1Hz,3H),1.35(s,12H),1.18(t,J=7.2Hz,3H).

[0500] Step 3: Synthesis of (10R)-3-chloro-14-fluoro-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadecan-1(11),2(7),3,5,12,14-hexaen-9-one L4

[0501] 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-pyridinyl]propanoate (intermediate L4-2, 2.09 g, 4.46 mmol) in 1,4-dioxane (31 mL) was added CsF (5 M in water, 1.94 mL, 9.70 mmol) followed by bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (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 is dissolved in dry toluene (20 mL), and LiHMDS (1.5 M in THF, 7.70 mL, 11.6 mmol) is then added at room temperature. The resulting mixture is stirred at room temperature for 2 h. After completion, the reaction mixture is concentrated under vacuum. The residue is purified twice by flash chromatography on silica gel (first by using a 0 to 5% MeOH gradient in DCM, secondly by using a gradient of 0 to 70% EtOAc in heptane as eluent) to provide the title compound (333 mg, yield: 30%) as a white solid. LC-MS (Method A1-S) m / z: [M+H] + :292; rt:1.16min; purity: 100%. 1 HNMR (400MHz, DMSO-d6) δ10.74(s,1H),8.68(d,J=2.8Hz,1H),8.19(dd,J=9.9,2. 8Hz,1H),7.06(s,1H),3.67(q,J=6.6Hz,1H),2.49(s,3H),1.46(d,J=6.6Hz,3H). 19F NMR (376 MHz, DMSO) δ -130.63 (d, J = 9.9 Hz). The racemate was separated by chiral chromatography (SFC Lux cellulose 2, from Phenomenex, CO2 + 20% isopropanol). Chiral purity 100%; rt = 2.46 min. (second-eluting enantiomer). For reference, the first-eluting enantiomer had a rt = 2.03 min. Both were measured by HPLC on a LuxCell 2, solvent: 50% heptane-50% ethanol-0.1% DEA.

[0502] Intermediate L5: 3-chloro-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadecan-1(11),2, Enantiomer (10R) or (10S) of 4,6,12,14-hexaen-9-one

[0503]

[0504] Step 1: Synthesis of ethyl 2-(3-bromo-2-pyridyl)acetate L5_1

[0505]

[0506] To a solution of 3-bromo-2-methyl-pyridine (5.00 g, 29.1 mmol) in dry THF (100 mL) was added LiHMDS (1 M solution in THF, 58 mL, 58.0 mmol) at -78 ° C. The reaction mixture was stirred at 0 ° C for 1 h. Diethyl carbonate (5.15 g, 43.6 mmol) was added at 0 ° C. The reaction mixture was stirred at room temperature for 15 min. The reaction mixture was treated with H2O (200 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. Purified by column chromatography on silica gel (using DCM as eluent) to provide 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%. 1 HNMR (400MHz, DMSO-d6) δ1.18(t,J=6.8Hz,3H),3.98(s,2H),4.11(q,J=6.8Hz,2H),7.27-7.30(m,1H),8.08(d,J=8.4Hz,1H),8.50(d,J=4.4Hz,1H).

[0507] Step 2: Synthesis of ethyl 2-(3-bromo-2-pyridyl)propionate L5_2

[0508]

[0509] Ethyl 2-(3-bromo-2-pyridyl)acetate (intermediate L5_1, 30.0 g, 117 mmol) was dissolved in dry THF (400 mL) and cooled to 0 ° C. A 1 M solution of lithium bis(trimethylsilyl)amide in THF (134 mL, 134 mmol) was added dropwise and stirred for 30 min. Iodomethane (21.5 g, 152 mmol) was added and the reaction mixture was stirred at 0 ° C for another 1 h. The solution was concentrated under vacuum and the residue was purified by flash chromatography on silica gel (using a gradient of 0 to 60% MTBE in isohexane as eluent) to provide the title compound (29.5 g, yield: 96%) as a light yellow oil. LC-MS (method A7) m / z: [M+H] + :258 / 260; rt:1.93min; purity: 99%. 1 H NMR (400MHz, CDCl3) δ8.51 (dd, J=4.6, 1.5Hz, 1H), 7.85 (dd, J=8.0, 1.5Hz, 1H), 7.06 (dd, J=8.0, 4.6 Hz,1H),4.36(q,J=7.1Hz,1H),4.17(q,J=7.1Hz,2H),1.55(d,J=7.1Hz,3H),1.20(t,J=7.1Hz,3H).

[0510] Step 3: Synthesis of ethyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]propionate L5_3

[0511]

[0512] 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 dry 1,4-dioxane (500 mL) and the reaction mixture was degassed with nitrogen for 10 min. Pd(dppf)Cl2 (5.95 g, 8.14 mmol) was added and the reaction mixture was stirred at 80°C for 24 h. The reaction mixture was cooled to room temperature and stirred by The mixture was filtered through a small pad. The filter cake was rinsed with EtOAc (200 mL) and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (using a gradient of 0 to 100% MTBE in isohexane as eluent) to provide the title compound (32.3 g, yield: 45%) as a yellow oil. 1H NMR (400MHz, CDCl3) δ8.60(dd,J=4.8,2.0Hz,1H),8.10(d,J=7.4Hz,1H),7.17(d,J=6.6Hz,1H),4. 71(d,J=7.1Hz,1H),4.14(q,J=7.2Hz,2H),1.55-1.51(m,3H),1.34(s,12H),1.18(d,J=6.9Hz,3H).

[0513] Step 4: Synthesis of 3-chloro-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ] enantiomers (10R) or (10S) L5 of pentadecan-1(11),2,4,6,12,14-hexaen-9-one

[0514] 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-pyridinyl]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)palladium(II) chloride (64 mg, 0.090 mmol) in 1,4-dioxane (34 mL) and water (1.7 mL) was purged with nitrogen and then heated under reflux for 18 h. The reaction was allowed to cool to room temperature and then filtered. The bed was filtered and washed with EtOAc (100mL). The filtrate was concentrated under vacuum, then extracted in absolute EtOH (16mL), potassium carbonate (499mg, 3.61mmol) was added thereto and the reaction mixture was heated at 65°C for 4h. The reaction mixture was concentrated under vacuum, water (75mL) was added and the reaction mixture was extracted with EtOAc (3x75mL). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (using a gradient of 0 to 100% EtOAc in isohexane as eluent) to provide the title compound (178mg, yield: 35%) in the form of an off-white solid. LC-MS (method A7) m / z:[M+H] + :274; rt:1.45min; purity: 99%. 1H NMR (400MHz, DMSO-d6) δ10.69(s,1H),8.64(dd,J=4.7,1.7Hz,1H),8.18(dd,J=7.9,1.7Hz,1H),7. 44(dd,J=7.9,4.7Hz,1H),7.05(s,1H),3.64(q,J=6.6Hz,1H),2.48(s,3H),1.47(d,J=6.6Hz,3H).

[0515] The racemates were separated by chiral chromatography (SFC Chiralpak AS from Daicel, CO2 + isopropanol 20%). The purity of the longevity star was 98.6%; rt = 1.79 min. (second-eluting enantiomer, L5). For reference, the first-eluting enantiomer had an rt = 1.62 min. Both were measured by HPLC, Chiralpak AS from Daicel, solvent: heptane 50%-ethanol 50%-DEA 0.1%.

[0516] Intermediate L6: N-(4-acetylphenyl)-2-(3,5-difluoro-10-methyl-9-oxydeoxy-4,8,12-triaza Three Rings [9.4.0.0 2,7 ]pentadecan-1(11),2,4,6,12,14-hexaen-8-yl)acetamide

[0517]

[0518] Step 1: Synthesis of 2,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine L6_1

[0519]

[0520] In a 60mL vial, under N2 atmosphere, to a suspension of 4,4'-di-tert-butyl-2,2'-bipyridyl (63mg, 0.23mmol, 0.03eq.) and (1,5-cyclooctadiene) (methoxy) iridium (I) dimer (76mg, 0.115mmol, 0.015eq.) in dry THF (1.2mL) was added 2,6-difluoropyridine-4-amine (1.0g, 7.740mmol) and bis(pinacolato) diboron (3.9g, 15mmol, 2.0eq.) in dry THF (5.8mL). The reaction mixture was purged with N2 and stirred at 80°C for 20h. The reaction mixture was slowly poured into MeOH (50mL) and then concentrated to dryness. The brown residue was purified by column chromatography on silica gel (using a gradient of 0% to 30% EtOAc in DCM as eluent) to afford 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%.1 H NMR (400MHz, DMSO-d6) δ1.29(s,12H),6.10(s,1H),6.87(bs,2H).

[0521] Step 2: Synthesis of 3,5-difluoro-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadecan-1(11),2(7),3,5,12,14-hexaen-9-one L6_2

[0522]

[0523] 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) was added an aqueous solution of potassium phosphate (2 M, 190 mL) 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 at 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 (2x500mL) and the filtrate was concentrated under vacuum. The resulting mixture was diluted with ethyl acetate (800mL) and washed with water (2x500mL), saturated sodium bicarbonate (500mL), brine (500mL), dried over sodium sulfate and concentrated to dryness to give a crude product (95.5g) in the form of a dark brown residue. Purified on silica gel by column chromatography (using a gradient of 0% to 100% ethyl acetate in isohexane as eluent) to provide ethyl 2-[3-(4-amino-2,6-difluoro-3-pyridyl)-2-pyridyl] propanoate (34.6g, 90mmol, yield: 48%) in the form of a tan oil. LC-MS (method B9) m / z:[M+H] + :=308.2, purity>99%, rt: 1.30 and 1.41 min, in the form of a mixture of diastereomers.

[0524] Under nitrogen atmosphere, at 0 ℃, to a solution of 2- [3- (4-amino -2,6- difluoro -3- pyridyl) -2- pyridyl] ethyl propionate (42.8g, 110mmol) in anhydrous THF (450mL) via a dropping funnel, a 1M solution of lithium bis (trimethylsilyl) amide in THF (130mL, 130mmol) was added. The resulting mixture was stirred at 0 ℃ 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 (500mL) and water (250mL). Ethyl acetate (500mL) was then added and stirred at room temperature for 15 minutes. The separated aqueous layer was extracted with ethyl acetate (500mL) and the combined organic extracts were washed with water (2x500mL), brine (500mL), dried over sodium sulfate and evaporated under vacuum. 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 afford 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%. 1H NMR (300 MHz, DMSO-d6) δ11.04 (s, 1H), 8.68 (dd, J=4.7, 1.7 Hz, 1H), 8.11 (ddd, J=7.9, 4.6, 1.7 Hz, 1H), 7.47 (ddd, J=7.9, 4.8, 0.5 Hz, 1H), 6.87 (d, J=1.1 Hz, 1H), 3.72 (q, J=6.6 Hz, 1H), 1.49 (d, J=6.6 Hz, 3H).

[0525] Step 3: Synthesis of N-(4-acetylphenyl)-2-(3,5-difluoro-10-methyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadecan-1(11),2,4,6,12,14-hexaen-8-yl)acetamide L6

[0526] To 3,5-difluoro-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7] A solution of 15-carbon-1(11),2(7),3,5,12,14-hexaene-9-one L6_2 (646 mg, 2.5 mmol) and N-(4-acetylphenyl)-2-chloro-acetamide (intermediate C1, 520 mg, 2.5 mmol) in DMF (15 mL) was added K2CO3 (1030 mg, 7.4 mmol) and KI (422 mg, 2.5 mmol). The reaction mixture was then stirred at room temperature overnight. 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 (yield 94%). LC-MS (Method A1_S) m / z: [M+H] + : 437.1, rt: 1.25 min, purity 92%. The crude product was used as it is in the next step.

[0527] 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 ]pentadecan-1(11),2,4,6,12,14-hexaen-9-one

[0528]

[0529] Step 1: Synthesis of tert-butyl N-[2-chloro-6-(2,2-difluoro-5-azaspiro[2.3]hexane-5-yl)-4-pyridinyl]carbamate L7_1

[0530]

[0531] Under N2 atmosphere, in room temperature, to (2,6-dichloropyridine-4-yl) tert-butyl carbamate (300mg, 1.08mmol) and 1,1-difluoro-5-azaspiro [2.3] hexane hydrochloride (177mg, 1.08mmol) in dry toluene (3.2mL) solution add Pd2dba3 (51mg, 0.05mmol), BINAP (70mg, 0.11mmol) and potassium tert-butoxide (273mg, 2.38mmol).Reactant mixture is stirred at 90 DEG C for 16h.After completion, reactant mixture is filtered through diatomite, rinsed with EtOAc and concentrated under vacuum.Residue is purified on silica gel (using the gradient in heptane to be 0 to 100% EtOAc as eluent) by flash chromatography, to provide the title compound (247mg, yield: 66%) as white solid. LC-MS (Method A1_S) m / z: [M+H] + :346.1; rt:1.59min; purity: 99%. 1H NMR (400MHz, DMSO-d6) δ9.80(s,1H),6.77(d,J=1.5Hz,1H),6.53(d,J=1.5Hz,1H),4.05(s,4H),1.74(t,J=8.9Hz,2H),1.47(s,9H). 19 FNMR(376MHz,DMSO-d6)δ-137.58(t,J=8.9Hz).

[0532] Step 2: Synthesis of 2-chloro-6-(2,2-difluoro-5-azaspiro[2.3]hexan-5-yl)pyridin-4-amine, trifluoroacetate L7_2

[0533]

[0534] To a solution of intermediate L7_1 (247 mg, 0.71 mmol) in DCM (2.9 mL) was added trifluoroacetic acid (2.7 mL, 35.7 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h and then concentrated under vacuum. The residue was used in the next step as a TFA salt without further purification. LC-MS (Method A1_S) m / z: [M+H] +: 246.0; rt: 0.89 min; purity: 88%.

[0535] Step 3: Synthesis of 2-chloro-6-(2,2-difluoro-5-azaspiro[2.3]hexane-5-yl)-3-iodo-pyridin-4-amine L7_3

[0536]

[0537] To a solution of intermediate L7_2 (1.00mmol) in MeCN (2mL) was added a solution of N-iodosuccinimide (213mg, 0.90mmol) in MeCN (2mL). The resulting mixture was stirred at room temperature for 2h. Additional N-iodosuccinimide (70mg, 0.30mmol) was added and the reaction mixture was stirred for another 1h at room temperature. After completion, the reaction mixture was concentrated under vacuum. The residue was purified on silica gel by flash chromatography (using a gradient of 0 to 25% EtOAc in heptane as eluent) to provide the title compound (240mg, yield: 64%) with a brown solid form. LC-MS (method A1_S) m / z:[M+H] + :371.9; rt:1.39min; purity: 100%. 1 H NMR (400MHz, DMSO-d6) δ6.17 (s, 2H), 5.61 (s, 1H), 3.99-3.91 (m, 4H), 1.73 (t, J = 8.9Hz, 2H).19 F NMR (376MHz, DMSO-d6) δ-137.57 (t, J=8.9Hz).

[0538] Step 4: Synthesis of ethyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]acetate L7_4

[0539]

[0540] Under inert atmosphere, 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), To a suspension of 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 under reflux overnight and then cooled to room temperature. The mixture was filtered over a pad of 4% paraffin and washed with ethyl acetate (400 mL). The filtrate was concentrated under vacuum and the residue was purified by flash chromatography on silica gel (using 0 to 100% tert-butyl methyl ether in cyclohexane as eluent) to give the title compound (2.35 g, yield: 37%) as a brown oil. LC-MS (Method B5) m / z: [M+H] + :292.2; rt:2.08min, purity: 95%. 1 H NMR (400MHz, CDCl3) δ8.60 (dd, J=4.9, 1.9Hz, 1H), 8.14 (dd, J=7.6, 1.9Hz, 1H), 7.23 (dd, J=7.6,4.9Hz,1H),4.22(s,2H),4.18(q,J=7.1Hz,2H),1.35(s,12H),1.28-1.24(m,3H).

[0541] Step 5: Synthesis of 3-chloro-5-(2,2-difluoro-5-azaspiro[2.3]hexan-5-yl)-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadecan-1(11),2,4,6,12,14-hexaen-9-one L7

[0542] The reaction was divided into 3 batches. Under N2 atmosphere, to a solution of intermediate L7_3 (60 mg, 0.16 mmol) and 2- (3- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) pyridin-2-yl) ethyl acetate L7_4 (73 mg, 0.24 mmol) in dry toluene (0.81 mL) was added K3PO4 (105 mg, 0.48 mmol), CataCXium A (6 mg, 0.02 mmol), followed by addition of Pd2dba3 (15 mg, 0.02 mmol). The resulting mixture was stirred at 100 ° C for 16 h. After completion, the reaction mixture was filtered through diatomaceous earth, rinsed with EtOAc and concentrated under vacuum. The residue was dissolved in dry THF (0.8 mL), followed by addition of LiHMDS (1 M in THF, 480 μL, 0.48 mmol). The resulting mixture was stirred at room temperature for 1 h. After complete conversion, the reaction mixture was quenched with water and washed with EtOAc (3x). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (using a gradient of 0 to 100% EtOAc in heptane as eluent) to provide the title compound (16 mg, yield: 23%) in the form of a brown solid. LC-MS (Method A1-S) m / z: [M+H] + :363.0; rt:1.13min; purity: 85%.

[0543] Intermediate L8: 2-(1-fluoro-3-methyl-6-oxyylidene-7H-pyrido[4,3-d][3]benzazepine- 5-amino)acetic acid, hydrochloride

[0544]

[0545] Step 1: Synthesis of 1-fluoro-3-methyl-5,7-dihydropyrido[4,3-d][3]benzazepine-6-one L8_1

[0546]

[0547] Under argon atmosphere, 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), 2-(2-bromophenyl)acetic acid methyl ester (1.92 mL, 11.9 mmol), KCO (4.98 g, 35.7 mmol) and a suspension of Pd(dppf)Cl (436 mg, 0.60 mmol) in 1,4-dioxane (40 mL) and water (2.4 mL) were stirred at 100 ° C for 18 h. After completion, the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water (2x), with brine, dried over MgSO, filtered and concentrated under vacuum. The residue was triturated in DCM, filtered, rinsed with DCM and dried in vacuo to afford 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%. 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),7.64(t,J=6.3Hz,1H),7.50-7.37(m,3H),6.96(s,1H),3.49(s,2H),2.43(s,3H).

[0548] Step 2: Synthesis of tert-butyl 2-(1-fluoro-3-methyl-6-oxyylidene-7H-pyrido[4,3-d][3]benzazepine-5-yl)acetate L8_2

[0549]

[0550] To a suspension of intermediate L8_1 (892 mg, 3.68 mmol), K2CO3 (1.03 g, 7.36 mmol), potassium iodide (62 mg, 0.37 mmol) in DMF (15 mL) was added tert-butyl bromoacetate (666 μL, 4.42 mmol) at room temperature. The resulting mixture was stirred at room temperature for 18 h. Water was added after completion. The resulting precipitate was collected by filtration, rinsed with water, Et2O and dried in vacuo to provide the title compound (1.29 g, yield: 95%) as a white solid. LC-MS (Method B1_S) m / z: [M+H] + :357.2; rt:1.48min; purity: 99%.

[0551] Step 3: Synthesis of 2-(1-fluoro-3-methyl-6-oxyylidene-7H-pyrido[4,3-d][3]benzazepine-5-yl)acetic acid, hydrochloride L8

[0552] To a solution of intermediate L8_2 (1.24 g, 3.47 mmol) in DCM (17 mL) was added HCl (4.0 M in 1,4-dioxane, 8.67 mL, 34.7 mmol) at room temperature. The resulting mixture was stirred at room temperature for 18 h. Upon completion, the precipitate was collected by filtration, rinsed with DCM (3x) and dried under vacuum to provide the title compound (1.07 g, yield: 86%) in the form of an HCl salt. LC-MS (Method B1_S) m / z: [M+H] + :301.0; rt:0.77min; purity: 100%. 1 HNMR (400 MHz, DMSO-d6) δ 7.66 (dd, J = 7.2, 5.4 Hz, 1H), 7.49-7.39 (m, 3H), 7.23 (s, 1H), 4.46-4.31 (m, 2H), 3.64-3.49 (m, 2H), 2.48 (s, 3H). The proton of COOH was not observed.

[0553] Intermediate L9: 2-[3-fluoro-5-methoxy-10-methyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2 ,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetic acid, enantiomer (10R) or (10S) of the hydrochloride salt

[0554]

[0555] Step 1: Synthesis of 2-fluoro-6-methoxy-pyridin-4-amine L9_1

[0556]

[0557] A solution of 2,6-difluoropyridine-4-amine (760 mg, 5.84 mmol) and sodium methoxide (5.4 M solution in methanol, 2.4 mL, 12.9 mmol) in dry THF (29 mL) was heated under reflux for 4 h. The reaction mixture was diluted with water (30 mL) and then extracted with EtOAc (3x30 mL). The combined extracts were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (using a gradient of 0 to 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%. 1 H NMR (400MHz, CDCl3) δ5.82 (dd, J=1.6, 1.0Hz, 1H), 5.78 (d, J=1.6Hz, 1H), 4.25 (s, 2H), 3.87 (s, 3H).

[0558] 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

[0559]

[0560] A solution of 2-fluoro-6-methoxy-pyridine-4-amine (intermediate L9_1, 211 mg, 1.34 mmol) in dry THF (6.4 mL) was degassed with nitrogen for 5 min, followed by the addition of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.20 mL, 1.43 mmol). The resulting mixture was stirred at room temperature for 30 min, followed by the addition of 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). The resulting mixture was degassed with nitrogen for 5 min, 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 under vacuum. The residue was purified by flash chromatography on silica gel (using a gradient of 0 to 100% EtOAc in isohexane as eluent) 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%. 1 H NMR (400MHz, DMSO-d6) δ6.57 (s, 2H), 6.29 (t, J = 1.3Hz, 1H), 2.16 (s, 3H), 1.28 (s, 12H).

[0561] Step 3: Synthesis of ethyl 2-[3-(4-amino-2-fluoro-6-methoxy-3-pyridyl)-2-pyridyl]propionate L9_3

[0562]

[0563] 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 min, and then PEPPSI was added. TM -IPr(CAS 905459-27-0, 748mg,

[0564] 1.10 mmol). The reaction mixture was purged with nitrogen for another 5 min and heated at 80°C for 16 h. The reaction mixture was cooled to room temperature and The mixture was filtered through a pad of 4% paraffin wax and washed with EtOAc (50 mL). The filtrate was concentrated under vacuum and the residue was purified by flash chromatography on silica gel (using a gradient of 0 to 5% MeOH in DCM as eluent) to provide the title compound (1.73 g, yield: 42%) as a yellow solid. LC-MS (Method A7) m / z [M+H] + :320.2; rt:1.71min; purity: 87%.

[0565] Step 4: Synthesis of 3-fluoro-5-methoxy-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ] enantiomers (10S) or (10R) of 15-carbon-1(11),2(7),3,5,12,14-hexaen-9-one

[0566]

[0567] To a solution of 2-[3-(4-amino-2-fluoro-6-methoxy-3-pyridyl)-2-pyridyl]ethyl propionate (intermediate L9-3, 1.96 g, 5.52 mmol) in dry THF (50.0 mL) was added dropwise a 1M 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 h. The reaction mixture was treated with ice water (10 mL) and extracted with EtOAc (3x20 mL) and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (1.59 g, quantitative yield) in the form of a light brown powder. LC-MS (method A7) m / z[M+H] + :274.1; rt:1.59min; purity: 96%. 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.62 (dd, J = 4.7, 1.7 Hz, 1H), 8.04 (ddd, J = 7.9, 4.7, 1.7 Hz, 1H), 7.44 (dd, J = 7.9, 4.7 Hz, 1H), 6.54 (s, 1H), 3.89 (s, 3H), 3.72-3.66 (m, 1H), 1.47 (d, J = 6.6 Hz, 3H). The racemate was separated by chiral chromatography (SFC, Chiralpak IG from Daicel, CO2 + methanol 20%). Chiral purity 100%. Rt = 1.78 min (first eluting enantiomer). (For reference, the second eluting enantiomer: rt = 2.24 min. Both were measured by HPLC, Chiralpak IG from Daicel, solvent: ACN 100%-DEA 0.1%).

[0568] Step 5: Synthesis of 2-(3-fluoro-5-methoxy-10-methyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ] enantiomers (10R) or (10S) of 15-pentadecan-1(11),2(7),3,5,12,14-hexaen-8-yl)acetic acid tert-butyl ester

[0569]

[0570] To 3-fluoro-5-methoxy-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 To the enantiomer (10S) or (10R) (intermediate L9-4, 1.00 g, 3.66 mmol) of 15-carbon-1 (11), 2 (7), 3, 5, 12, 14-hexaene-9-one) KI (305 mg, 1.82 mmol) and KCO (1.02 g, 7.31 mmol) in DMF (18 mL) was added tert-butyl bromoacetate (660 μ L, 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 (3x80 mL). The combined organic extracts were washed with salt water (2x200 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (using a gradient of 0 to 40% EtOAc in heptane as eluent) to provide the title compound as a white solid (1.37 g, yield: 94%). 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%. 1 H NMR (400MHz, DMSO-d6) δ8.63(dd,J=4.8,1.7Hz,1H),8.08(ddd,J=7.9,4.5,1.7Hz,1H),7.47(dd,J=7.9,4.8Hz ,1H),6.80(s,1H),4.52-4.39(m,2H),3.93(s,3H),3.81(q,J=6.6Hz,1H),1.48(d,J=6.6Hz,3H),1.25(s,9H). 19 F NMR (376 MHz, DMSO-d6) δ -71.73 (d, J = 4.5 Hz). Chiral purity: 100%; rt = 4.22 min (second-eluting enantiomer). For reference, rt = 3.22 min for the first-eluting enantiomer. Both were measured by HPLC (Chiralpak IG-u from Daicel, EtOH 50%-heptane 50%-DEA 0.1%).

[0571] Step 6: Synthesis of 2-[3-fluoro-5-methoxy-10-methyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetic acid, enantiomer (10R) or (10S) L9, hydrochloride

[0572] To 2-(3-fluoro-5-methoxy-10-methyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ] A solution of the enantiomer (10S) or (10R) of 15-hexadecane-1 (11), 2 (7), 3, 5, 12, 14-hexaen-8-yl) tert-butyl acetate (intermediate L9-5, 1.36 g, 3.42 mmol) in DCM (34 mL) was added with HCl (4 M in 1,4-dioxane, 8.55 mL, 34.2 mmol). The resulting mixture was stirred at room temperature for 5 h. Additional HCl (4 M in 1,4-dioxane, 1.71 mL, 6.84 mmol) was added and the reaction mixture was stirred for another 17 h at room temperature. The reaction mixture was concentrated under vacuum to provide 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%. 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (dd, J = 4.8, 1.7 Hz, 1H), 8.08 (ddd, J = 7.9, 4.5, 1.7 Hz, 1H), 7.48 (dd, J = 7.9, 4.8 Hz, 1H), 6.82 (s, 1H), 4.45 (s, 2H), 3.92 (s, 3H), 3.84 (q, J = 6.6 Hz, 1H), 1.48 (d, J = 6.6 Hz, 3H). No COOH proton was observed. 19 F NMR (376 MHz, DMSO-d6) δ -71.90 (d, J = 4.5 Hz). Chiral purity: 100%; rt = 2.74 min (first eluting enantiomer). For reference, rt = 3.72 min for the second eluting enantiomer. Both were measured by HPLC (Lux Cellulose-2, from Phenomenex, EtOH 50%-heptane 50%-DEA 0.1%).

[0573] Intermediate L10: 3-fluoro-14-methoxy-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]fifteen Carbon-1(11),2(7),3,5,12,14-hexaen-9-one

[0574]

[0575] The mixture of intermediate L1_4 (415mg, 1.65mmol), intermediate L11_1 (395mg, 1.37mmol) and tripotassium phosphate (594mg, 2.74mmol) in toluene (11mL) was degassed with nitrogen for 10min, followed by addition of tris(dibenzylideneacetone)dipalladium (0) (128mg, 0.14mmol) and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (57mg, 0.14mmol). The reaction mixture was heated at 90°C for 3h. After completion, the reaction mixture was filtered through diatomaceous earth with EtOAc and the filtrate wax was concentrated under vacuum to obtain a yellow oil.

[0576] At room temperature under N2 atmosphere, the crude oil was dissolved in toluene (13.7 mL) and bis(trimethylsilyl)lithium amide (1.5 M in THF, 2.7 mL) was added. 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 obtain a beige solid. The residue was ground with Et2O / DCM (75 / 25), and the solid was filtered to provide the title compound (203 mg, yield: 52%). LC-MS (Method B1-S) m / z: [M+H]+: 288; rt: 1.05 min; purity: 89%.

[0577] Intermediate L11: 14-methoxy-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]15-carbon-1 (11),2(7),3,5,12,14-Hexaen-9-one

[0578]

[0579] Step 1: Synthesis of ethyl 2-(3-bromo-5-methoxy-2-pyridyl)propionate L11_1

[0580]

[0581] To a solution of ethyl 2-(3-bromo-5-fluoro-2-pyridyl)propanoate (L2_3, 1.0 g, 3.62 mmol) in dry DMF (18 mL) cooled at 0° C. was added a 25% solution of sodium methoxide in methanol (1.5 mL, 6.52 mmol) and the reaction mixture was allowed to reach room temperature within 1 hour. The reaction mixture was treated with water and extracted twice with EtOAc. The combined organic extracts were dried over brine, dried over MgSO , filtered off and concentrated to dryness to obtain 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:1.40min. 1 H NMR (400MHz, CDCl3) δ8.28(d,J=2.6Hz,1H),7.36(d,J=2.6Hz,1H),4.28(q,J=7.2Hz, 1H), 4.20 (q, J = 7.2Hz, 2H), 3.77 (s, 3H), 1.51 (d, J = 7.2Hz, 3H), 1.20 (t, J = 7.2Hz, 3H).

[0582] Step 2: Synthesis of 14-methoxy-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadecan-1(11),2(7),3,5,12,14-hexaen-9-one L11

[0583] By 2- methyl -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- bases) pyridine -4- amine (CAS: 1668475-78-2, 1.04g, 1.64mmol), 2- (3- bromo -5- methoxy -2- pyridyl) propionic acid ethyl ester (L11_1, 395mg, 1.37mmol) and potassium phosphate (594mg, 2.74mmol) in dry toluene (11mL) suspension degassed with argon. Add tris (dibenzylideneacetone acetone) dipalladium (0) (128mg, 0.18mmol) and 2- dicyclohexylphosphino -2,6- dimethoxybenzyl (57mg, 0.14mmol). The bottle is sealed under an argon atmosphere and the reaction mixture is heated at 90 DEG C for 3h. After cooling to room temperature, the reaction mixture is filtered through a celite pad and rinsed with EtOAc. The filtrate is concentrated under vacuum to obtain a crude oil which is dissolved in dry toluene (14 mL). A 1.5 M solution of bis(trimethylsilyl)lithium amide in THF (2.7 mL) is added to the solution and the reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is treated with water and extracted twice with EtOAc. The combined organic extracts are washed with brine, then dried over MgSO , filtered off and concentrated to dryness to obtain a brown solid. Grinding and ultrasonication in a 75 / 25 mixture of Et o: DCM provide the title product (258 mg, yield: 70%) as a white solid. LC-MS (method B2) m / z[M+H] + :270.1; purity: 97%, rt:0.89min. 1 H NMR (400MHz, DMSO-d6) δ8.62(s,1H),8.31(d,J=2.7Hz,1H),7.59(d,J=2.9Hz,1H),6 .81(s,1H),3.89(s,3H),3.59(q,J=7.0Hz,1H),2.44(s,4H),1.43(d,J=6.7Hz,3H).

[0584] Intermediate L12: 3-methoxy-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]15-carbon-1 (11),2,4,6,12,14-hexaen-9-one

[0585]

[0586] Step 1: Synthesis of 3-bromo-2-methoxy-6-methyl-pyridin-4-amine L12_1

[0587]

[0588] At 0 ° C, a suspension of NBS (618 mg, 3.47 mmol) in DCM (10 mL) was added to a solution of 2-methoxy-6-methyl-pyridin-4-amine (505 mg, 3.47 mmol) in DCM (25 mL) 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 (2x30 mL). The combined organic extracts were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (using 0 to 4% MeOH (0.7N in NH3) in DCM as eluent) to obtain the title compound (653 mg, yield: 86%) as a colorless oil. LC-MS (method B5) m / z: [M+H] + :217.1 / 219.1; rt:1.57min; purity>99%. 1 H NMR (400MHz, CDCl3) δ6.16 (d, J = 0.7Hz, 1H), 4.47 (s, 2H), 3.97 (s, 3H), 2.31 (s, 3H).

[0589] Step 2: Synthesis of ethyl 2-(4'-amino-2'-methoxy-6'-methyl-[3,3'-bipyridyl]-2-yl)propionate L12_2

[0590]

[0591] To the bromo-2-methoxy-6-methylpyridine-4-amine (intermediate L12_1) (1.60g, 7.37mmol), 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl] ethyl propionate (intermediate L5_3,3.29g, 8.85mmol) and K cO 1.5M aqueous solution (14.5mL, 22.0mmol) in the stirring of dry 1,4-dioxane (100mL) mixture adds bis-(di-tert-butyl-(4-dimethylaminophenyl)-phosphine) palladium chloride (II) (522mg, 0.737mmol) and reactant mixture is stirred at 90 DEG C for 2h.Reactant mixture is cooled to room temperature and filtered through a small pad of diatomaceous earth.Filter cake is rinsed with EtOAc (150mL) and filtrate is concentrated under vacuum. The residue was purified by flash chromatography on silica gel using a gradient of 0 to 100% (0.7 M NH 3 / MeOH) in DCM as eluent to afford the title compound as a brown oil (3.24 g, yield: 73%). LC-MS (Method A7) m / z [M+H] + :316.2; rt:0.90min; purity: 53%. 1HNMR (400MHz, CDCl3) δ8.61 (dd, J=4.8, 1.8Hz, 1H), 7.50 (dd, J=7.7, 1.8Hz, 1H), 7.25-7.22 (m, 1H), 6.21 (s,1H),4.17-4.02(m,2H),3.86-3.75(m,6H),2.38(d,J=2.1Hz,3H),1.42(m,3H),1.16(t,J=7.2Hz,3H).

[0592] Step 3: Synthesis of 3-methoxy-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadecan-1(11),2(7),3,5,12,14-hexaen-9-one L12_3

[0593] Ethyl 2-[3-(4-amino-2-methoxy-6-methyl-3-pyridinyl)-2-pyridinyl]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 h. The reaction mixture was concentrated under vacuum and the residue was dissolved in water (30 mL) and extracted with EtOAc (4x50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under vacuum to provide the title compound (1.99 g, yield: 92%) as a white solid. The product was carried to the next step without further purification. LC-MS (Method A7) m / z[M+H] + :270.2; rt:1.50min; purity: 68%. 1 H NMR (400MHz, DMSO-d6) δ10.45(s,1H),8.56(dd,J=4.7,1.7Hz,1H),8.11(dd,J=8.0,1.7Hz,1H),7.37(dd,J= 7.9,4.7Hz,1H),6.74-6.64(m,1H),3.89(s,3H),3.46(d,J=6.6Hz,1H),2.41(s,3H),1.46(d,J=6.6Hz,3H).

[0594] Intermediate L13: 3,14-difluoro-5,10-dimethyl-4,8,13-triazatricyclo[9.4.0.0 2,7 ]15-carbon-1 (11),2(7),3,5,12,14-Hexaen-9-one

[0595]

[0596] Step 1: Synthesis of (E) and (Z) 4-bromo-2-fluoro-5-(2-methoxyvinyl)pyridine L13_1

[0597]

[0598] At 0 DEG C, under N2 atmosphere, to the solution of (methoxymethyl) triphenylphosphonium chloride (184mg, 0.54mmol) in dry THF (2.40mL), bis(trimethylsilyl) sodium amide (750 μ L, 0.75mmol, 1M in THF) is added. The gained mixture is stirred at 0 DEG C for 30min, then a solution of 4-bromo-6-fluoropyridinecarboxaldehyde (100mg, 0.47mmol) in dry THF (2.40mL) is added dropwise. The gained mixture is stirred at 0 DEG C for 30min, then stirred at room temperature for 30min. After complete conversion, the reaction mixture is quenched with water (30mL) and extracted with EtOAc (3x30mL). The organic layer merged is dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (using a gradient of 0 to 10% EtOAc in heptane as eluent) to provide a mixture of E and Z isomers 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:1.37min&1.40min; purity: 100%. Isomer E: 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.59 (d, J = 2.9 Hz, 1H), 7.32 (d, J = 12.8 Hz, 1H), 5.82 (d, J = 12.8 Hz, 1H), 3.70 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -73.14 (d, J = 2.9 Hz). Isomer Z: 1 H NMR (400MHz, DMSO-d6) δ8.69(s,1H),7.61(d,J=2.9Hz,1H),6.62(d,J=7.0Hz,1H),5.38(d,J=7.0Hz,1H),3.81(s,3H). 19 F NMR (376MHz, DMSO-d6) δ-72.24 (d, J = 2.9Hz).

[0599] Step 2: Synthesis of 2-(4-bromo-6-fluoro-3-pyridyl)acetaldehyde L13_2

[0600]

[0601] A solution of hydrochloric acid diluted in water (300 μL) (12 M in water; 300 μL, 3.49 mmol) 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 h. After completion, the reaction mixture was concentrated under vacuum to provide the title compound in the form of a brown solid, which was used directly in the next step without purification (42.9 mg, yield: 86%). 1 H NMR (400MHz, DMSO-d6) δ9.73 (s, 1H), 8.19 (s, 1H), 7.68 (d, J = 2.7Hz, 1H), 4.02 (s, 2H). 19 F NMR(376MHz,DMSO-d6)δ-70.54.

[0602] Step 3: Synthesis of 2-(4-bromo-6-fluoro-3-pyridyl)acetic acid L13_3

[0603]

[0604] To the solution of intermediate L13_2 (42.9mg, 0.20mmol) and 2-methyl-2-butene (210 μ L, 1.96mmol) in the tert-butanol (2mL) was added a solution of sodium dihydrogen phosphate (118mg, 0.98mmol) in water (0.8mL), then sodium chlorite (27mg, 0.24mmol) was added in batches. The resulting mixture was stirred at room temperature for 1h. After completion, the reaction mixture was quenched with water (20mL) and the 4MHCl aqueous solution (5mL), then extracted with DCM (3x30mL). The organic layer merged was dried over MgSO4, filtered and concentrated under vacuum to provide the thick title compound of yellow oil form, which was directly used in the next step without purification. LC-MS (method A1_S) m / z:[M+H] + :233.9 / 235.9; rt:0.91min; purity: 70%.

[0605] Step 4: Synthesis of 2-(4-bromo-6-fluoro-3-pyridyl)propionic acid L13_4

[0606]

[0607] To a solution of crude intermediate L13_3 (41.0 mg, 0.18 mmol) in dry THF (1.7 mL) was added dropwise bis(trimethylsilyl)lithium amide (1 M in THF, 350 μL, 0.35 mmol) at -78 ° C under N2 atmosphere. The reaction mixture was stirred at -78 ° C for 30 min. Iodomethane (12.1 μL, 0.19 mmol) was then added dropwise and the reaction mixture was stirred at room temperature for 2 h. After completion, the reaction mixture was quenched by adding water (10 mL) and then adding 4M HCl aqueous solution (10 mL). The mixture was extracted with DCM (2x20 mL) and then with CHCl3 / iPrOH (4:1 v / v, 3x20 mL). The combined organic layer was dried over MgSO4, filtered and concentrated under vacuum to provide the crude title compound in the form of a brown oil, which was directly used in the next step without purification. LC-MS (method A1_S) m / z:[M+H] + :247.9 / 249.9; rt:1.04min; purity: 60%.

[0608] Step 5: Synthesis of methyl 2-(4-bromo-6-fluoro-3-pyridyl)propionate L13_5

[0609]

[0610] To a solution of crude intermediate L13_4 (39.4 mg, 0.16 mmol) in dry acetonitrile (0.80 mL) was added potassium carbonate (66.5 mg, 0.47 mmol) and then iodomethane (12.5 μL, 0.21 mmol). The reaction mixture was stirred at room temperature for 16 h. Additional iodomethane (12.5 μL, 0.21 mmol) was added and the reaction mixture was stirred at room temperature for 5 h. After completion, the reaction mixture was quenched with water (15 mL) and extracted with EtOAc (3x20 mL). The combined organic layer was dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (using a gradient of 0 to 20% EtOAc as eluent in heptane) to provide the title compound (12.5 mg, yield: 22% over 3 steps) in the form of a yellow oil. LC-MS (method A1_S) m / z:[M+H] + :261.9 / 263.9; rt:1.29min; purity: 91%. 1H NMR (500MHz, CDCl3) δ8.14(s,1H),7.20(d,J=3.0Hz,1H),4.12(q,J=7.3Hz,1H),3.71(s,3H),1.57(d,J=7.3Hz,3H).19F NMR (471MHz, CDCl3) δ-69.81 (d, J=3.0Hz).

[0611] Step 6: Synthesis of 3,14-difluoro-5,10-dimethyl-4,8,13-triazatricyclo[9.4.0.0 2,7 ]pentadecan-1(11),2(7),3,5,12,14-hexaen-9-one L13

[0612] To a solution of intermediate L13_5 (12.5 mg, 0.04 mmol) and intermediate L1_4 (16.4 mg, 0.06 mmol) in dry toluene (0.22 mL) was added potassium phosphate (28.1 mg, 0.13 mmol), 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (2 mg, 0.005 mmol) under N2 atmosphere, followed by addition of tris(dibenzylideneacetone)dipalladium (0) (4 mg, 0.004 mmol). 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 (3x10 mL). The combined organic layer was dried over MgSO4, filtered and concentrated under vacuum. The residue was dissolved in dry toluene (220 μL), then bis(trimethylsilyl)lithium amide (1 M in THF, 130 μL, 0.13 mmol) was added under N2 atmosphere. The resulting mixture was stirred at room temperature for 2 h. After completion, the reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC (Purification Method P_B) to provide the title compound (1.7 mg, yield: 14%) as a white solid. LC-MS (Method A4) m / z: [M+H] + :276.1; rt:3.37min; purity: 100%.

[0613] Intermediate L14: 3-methoxy-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadecan-1(11),2 (7),3,5,12,14-hexaen-9-one

[0614]

[0615] Step 1: Synthesis of 3-fluoro-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadecan-1(11),2(7),3,5,12,14-hexaen-9-one L14_1

[0616]

[0617] To 4-amino-3-bromo-2-fluoropyridine (75mg, 0.37mmol) and 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl] ethyl propionate (intermediate L5-3, 244mg, 0.74mmol) in 1,4-dioxane (1.9mL) solution is added KCO(104mg, 0.74mmol) and water (82 μ L).Reactant mixture is degassed with nitrogen for 5min, then Pd[(Amphos)Cl](CAS 887919-35-9,14mg, 0.02mmol) and reactant mixture is stirred at 100 DEG C for 20h.After being cooled to RT, water is added, and reactant mixture is extracted with EtOAc(3x).By the organic layer washed with salt water, through MgSO4 drying, filter and be concentrated to dryness. The residue was then dissolved in dry toluene (2.4 mL) and cooled to 0 ° C., and then 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 h. A saturated aqueous NH4Cl solution was added and the reaction mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The residue was ground in Et2O, filtered and dried in vacuo to provide the title compound (45 mg, yield: 50%) in the form of an off-white solid. LC-MS (Method B1) m / z[M+H] + :244.1; rt:0.89min; purity: 96%. 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),8.68(dd,J=4.7,1.7Hz,1H),8.18(d,J=5.5Hz,1H),8.12(ddd,J=7.9,4. 6,1.7Hz,1H),7.48(dd,J=7.9,4.7Hz,1H),7.18(d,J=5.5Hz,1H),3.63(q,J=6.6Hz,1H),1.50(d,J=6.6Hz,3H).

[0618] Step 2: Synthesis of 3-methoxy-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadecan-1(11),2(7),3,5,12,14-hexaen-9-one

[0619] 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 (4x10 mL). The combined organic layers were washed with brine (40 mL), dried over MgSO4, filtered and concentrated under vacuum to provide the title compound (303 mg, yield: 58%) as a white solid. 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%. 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),8.59(dd,J=4.7,1.7Hz,1H),8.15(dd,J=7.9,1.7Hz,1H),8.11(d,J=5.6Hz ,1H),7.39(dd,J=7.9,4.7Hz,1H),6.86(d,J=5.6Hz,1H),3.91(s,3H),3.53-3.44(m,1H),1.47(d,J=6.7Hz,3H).

[0620] Intermediate L15: 3-fluoro-5-methoxy-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadecan-1(11),2 (7),3,5,12,14-hexaen-9-one

[0621]

[0622] The title compound was prepared according to 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 with Pd2dba3, Sphos and K3PO4 in toluene at 100°C. The second step was carried out using LiHMDS in THF at RT, 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%.

[0623] 1 H NMR (400MHz, DMSO-d6) δ10.77 (s, 1H), 8.65 (d, J = 2.8Hz, 1H), 8.06-8.02 (m, 1H), 6.54 (s, 1H), 3.90 (s, 3H), 3.70 (q, J = 6.7Hz, 1H), 1.47 (d, J = 6.7Hz, 3H).

[0624] Intermediate L16: 2-(3,14-difluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclic [9.4.0.0 2,7 ]pentadecan-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide

[0625]

[0626] To a solution of intermediate L2 (300 mg, 1.09 mmol) in DMF (5.5 mL) was added iodoacetamide (224 mg, 1.20 mmol) and potassium carbonate (183 mg, 1.31 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After completion, water (15 mL) was added and the reaction mixture was stirred at room temperature for 30 min. The precipitate was filtered on a glass frit, rinsed with water and dried in vacuo to provide the title compound (328 mg, yield: 91%) as a white solid. LC-MS (Method A1-S) m / z: [M+H] + :333.1; rt:0.97min; purity: 97%. 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 2.8 Hz, 1H), 8.09 (ddd, J = 9.6, 4.1, 2.8 Hz, 1H), 7.58 (s, 1H), 7.28 (s, 1H), 7.13 (s, 1H), 4.38 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.75 (q, J = 6.6 Hz, 1H), 1.47 (d, J = 6.6 Hz, 3H). The CH3 protons are below the DMSO signal.

[0627] Intermediate L17: (3-Oxylidenebenzofuran-6-yl) trifluoromethanesulfonate

[0628]

[0629] Pyridine (0.82mL, 10.0mmol) is added to a suspension of 6-hydroxy-2H-benzofuran-3-one (500mg, 3.33mmol) in dry DCM (10mL) at room temperature. The mixture is cooled to 0°C, trifluoromethanesulfonic anhydride (1M in DCM, 5.33mL, 5.33mmol) is then added. The reaction mixture is stirred at 0°C for 2h. After completion, water (15mL) is added and the reaction mixture is extracted with DCM (3x15mL). The combined organic layer is washed with 1M citric acid aqueous solution (2x20mL), then with saturated NaHCO3 aqueous solution (20mL), brine (20mL), washed with Na2SO4, dried, filtered and concentrated under vacuum. The residue is purified on silica gel by flash chromatography (using the gradient in heptane being 0 to 30% EtOAc as eluent) to provide the title compound (601mg, yield: 61%) in the form of a yellow solid. LC-MS (Method A1_S) m / z: no mass response; rt: 1.35 min; purity: 96%. 1 H NMR (400MHz, DMSO-d6) δ7.85(d,J=8.5Hz,1H),7.64(d,J=2.1Hz,1H),7.25(dd,J=8.5,2.1Hz,1H),4.93(s,2H).

[0630]

[0631] Step 1: Synthesis of 4-bromo-3-(bromomethyl)isothiazole L18_1

[0632]

[0633] 2,2'-azobis(2-methylpropionitrile) (88 mg, 0.54 mmol) was added to a vial filled with 4-bromo-3-methylisothiazole (500 mg, 2.68 mmol), N-bromosuccinimide (712 mg, 4.00 mmol) and 1,2-dichloroethane (20 mL). The vial was sealed and the reaction mixture was stirred and heated at 80 ° C for 16 h to obtain 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 material was purified by column chromatography on silica gel (using 0 to 10% EtOAc in heptane as eluent over 10 CV) to provide the title compound (660 mg, yield: 96%) as a light yellow oil. LC-MS (Method A1_S) m / z: [M+H] + :257; rt:1.29min; purity: 62%.

[0634] Step 2: Synthesis of 2-(4-bromoisothiazol-3-yl)acetonitrile L18_2

[0635]

[0636] To a solution of intermediate L18_1 (660 mg, 2.5686 mmol) in dry acetonitrile (12 mL) was added trimethylsilyl cyanide (1.0 mL, 7.6 mmol), followed by addition of tetrabutylammonium fluoride (1 mol / L in THF, 3.8 mL) at 0 ° C. 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 obtained crude material was purified by column chromatography on silica gel (using 0 to 50% EtOAc in heptane as eluent over 13 CV) to provide the title compound (200 mg, yield: 38%) as a colorless oil. LC-MS (Method A1_S) m / z: no mass response; rt: 0.99 min; purity: 100%.

[0637] 1 H NMR (400MHz, DMSO-d6) δ9.26 (s, 1H), 4.30 (s, 2H).

[0638] Step 3: Synthesis of methyl 2-(4-bromoisothiazol-3-yl)acetate L18_3

[0639]

[0640] To a solution of intermediate L18_2 (200 mg, 0.98 mmol) in dry methanol (4 mL) was added hydrochloric acid solution (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 crude material obtained was purified by column chromatography on silica gel (using 5 to 40% EtOAc in heptane as eluent over 7 CV) to obtain the title compound (137 mg, yield: 59%) as a colorless oil. LC-MS (Method A1_S) m / z: [M+H] + :237 / 239; rt:1.10min; purity: 96%.

[0641] Step 4: Synthesis of methyl 2-(4-bromoisothiazol-3-yl)propionate L18_4

[0642]

[0643] In a dry vial under an argon atmosphere, a solution of diisopropylamine (100 μL, 0.70 mmol) in dry THF (0.2 mL) was cooled at 0°C and then n-butyl lithium (1.4 mol / L in THF, 0.5 mL) was added dropwise. The reaction mixture was then cooled at -78°C and stirred for 10 min. A solution of intermediate L18_3 (137 mg, 0.58 mmol) in dry THF (0.3 mL) was added dropwise at -78°C and the reaction mixture was stirred for 10 min at -78°C.

[0644] To 4-nitro-1-oxo-2-oxo-2-oxo-4-oxo-6-piperidin-2-yl)-2-nitro-1-oxo-2-oxo-4-oxo-6-piperidin-2-yl)-4-nitro-1-oxo-2-oxo-4-piperidin-2-yl)-2 ...

[0645] LC-MS (Method A1_S) m / z: [M+H] + :252; rt:1.24min; purity:80%.

[0646] Step 5: Synthesis of 14-fluoro-7,12-dimethyl-4-thia-5,9,13-triazatricyclo[8.4.0.0 2,6 ]Tetradeca-1(10),2,5,11,13-pentaen-8-one L18

[0647] 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 min, followed by the addition of XPHOS PD G3 (18 mg, 0.02 mmol). The reaction mixture was heated at 80 ° C for 4 h. After completion, the reaction mixture was distributed between a saturated aqueous solution of NH4Cl and EtOAc. The resulting mixture was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered off and concentrated under vacuum to obtain a yellow oil. The crude material was dissolved in dry THF (2 mL) and bis(trimethylsilyl)lithium amide (1.5 M in THF, 80 μL) was added at room temperature under an N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h, 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 MgSO4, filtered, and concentrated to dryness to give a white solid. The residue was triturated with Et2O and the solid was filtered to provide the title compound (30 mg, yield: 32%). LC-MS (Method A1_S) m / z: [M+H] + :264; rt:1.06min; purity: 100%.

[0648] Intermediate L19: 3-fluoro-5-(1-hydroxycyclobutyl)-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ] Pentadecan-1(15),2,4,6,11,13-hexaen-9-one

[0649]

[0650] Step 1: Synthesis of 2-bromo-6-fluoro-pyridin-4-amine L19_1

[0651]

[0652] Cesium fluoride (3.65g, 23.8mmol) is added to a solution of 2,6-dibromopyridin-4-amine (2.00g, 7.78mmol) in dry DMSO (30mL) at room temperature. The reaction mixture is stirred at 140 ° C for 18h. After completion, the reaction mixture is cooled with ice (100g) and diluted with water (250mL), then extracted three times with ethyl acetate (100mL). The combined organic layer is washed twice with brine (100mL), dried over Na2SO4, filtered, and concentrated to dryness to provide a brown solid. The solution is concentrated under vacuum and the residue is purified by column chromatography on silica gel (using a gradient of 0 to 25% MeOH in DCM) to provide the title compound (773mg, yield: 28%) as a white solid. LC-MS (method B4) m / z:[M+H] +:191 / 193; rt:0.92min; purity: 100%. 1 H NMR (400MHz, DMSO-d6) δ6.78 (s, 2H), 6.61 (t, J = 1.6Hz, 1H), 6.08 (d, J = 1.6Hz, 1H). 19 F NMR(376MHz,DMSO-d6)δ-71.05.

[0653] Step 2: Synthesis of 2-bromo-6-fluoro-N-trityl-pyridin-4-amine L19_2

[0654]

[0655] To a solution of intermediate L19_1 (773 mg, 4.18 mmol) and triphenylmethane (1.25 g, 4.35 mmol) in dichloromethane (8 mL) was added N, N-dipropylethylamine (765 μL, 4.61 mmol). The reaction mixture was stirred at 40 ° C for 48 h. The reaction mixture was concentrated to dryness to provide a yellow foam, which was purified on silica gel by column chromatography (using a gradient of 0 to 25% EtOAc in heptane) to provide 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%.

[0656] 1 H NMR (500MHz, CDCl3) δ7.36-7.21(m,15H),6.44(s,1H),5.73(s,1H),5.59(s,1H). 19 F NMR (376 MHz, CDCl3) δ-68.05.

[0657] Step 3: Synthesis of 1-[6-fluoro-4-(tritylamino)-2-pyridyl]cyclobutanol L19_3

[0658]

[0659] To a solution of intermediate L19_2 (500 mg, 1.15 mmol) in THF (12 mL) was added n-butyl lithium (1.5 mol / L in hexane, 2.89 mL) at -78 ° C and the reaction mixture was stirred for 1 h at -78 ° C. After 1 h, cyclobutanone (195 μL, 2.55 mmol) was added at -78 ° C and the reaction mixture was slowly brought to room temperature. After 18 h, EtOAc (30 mL) and water (30 mL) were added and 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 obtain a yellow oil. The residue was purified by column chromatography on silica gel (using 0 to 60% EtOAc in heptane) to provide 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%. 1 H NMR (500MHz, CDCl3) δ7.35-7.23(m,15H),6.32(s,1H),5.74(s,1H),5.69(d,J=10.8H z,1H),4.21(s,1H),2.29(m,2H),2.16-2.07(m,2H),1.69-1.52(m,1H),1.79(m,1H).

[0660] Step 4: Synthesis of 1-(4-amino-6-fluoro-2-pyridyl)cyclobutanol L19_4

[0661]

[0662] To a solution of intermediate L19_3 (206 mg, 0.39 mmol) in 1,4-dioxane (4 mL) was added hydrochloric acid (4 mol / L in 1,4-dioxane, 924 μL) and the reaction mixture was stirred at 60° C. After 6 h, the reaction mixture was concentrated under vacuum to provide the title compound (98 mg, yield: 89%) as a brown oil.

[0663] LC-MS (Method A1_S) m / z: [M+H] + :183; rt:0.67min; purity: 90%.

[0664] 1H NMR(500MHz, CDCl3)δ6.63(t,J=1.8Hz,1H),5.99(d,J=1.8Hz,1H),4.39(s, 2H),4.03(s,1H),2.50-2.37(m,4H),2.04-1.97(m,1H),1.80-1.75(m,1H).

[0665] 19 F NMR (376 MHz, CDCl3) δ-70.50.

[0666] Step 5: Synthesis of 1-(4-amino-5-bromo-6-fluoro-2-pyridyl)cyclobutanol L19_5

[0667]

[0668] To a solution of intermediate L19_4 (98 mg, 0.20 mmol) in acetonitrile (0.2 mL) was slowly added N-bromosuccinimide (40 mg, 0.23 mmol) at 0°C. The resulting mixture was stirred at 0°C for 30 min. The resulting mixture was concentrated under vacuum to provide an orange oil, and the residue was purified by preparative HPLC (Purification Method P_A) to provide 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%.

[0669] 1 H NMR (400MHz, CDCl3) δ6.73(s,1H),4.89(s,2H),3.79-3.53(m,1H),2.51-2.44(m,2H),2.44-2.32(m,2H),2.07-1.96(m,1H),1.86-1.75(m,1H). 19 F NMR (376 MHz, CDCl3) δ-69.68.

[0670] Step 6: Synthesis of 3-fluoro-5-(1-hydroxycyclobutyl)-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadecan-1(15),2,4,6,11,13-hexaen-9-one L19

[0671] By intermediate L5_3 (152mg, 0.50mmol), intermediate L19_5 (108mg, 0.41mmol), potassium phosphate (179mg, 0.83mmol) and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (17mg, 0.04mmol) in 1,4-dioxane (2mL) and water (124 μ L) degassed with nitrogen for 10min, then add tris (dibenzylideneacetone) dipalladium (0) (38mg, 0.04mmol). The reaction mixture is heated at 100 DEG C for 16h. EtOAc (5mL) and water (5mL) are added to the reaction mixture. The water layer is extracted three times with EtOAc. The organic layer merged is washed with salt water, dried over MgSO4, filtered, and concentrated to dryness, to provide a black oil. The crude material was dissolved in dry THF (0.8 mL) and bis(trimethylsilyl)lithium amide (1.5 M in THF, 34 μL) was added at room temperature under N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. Water and ethyl acetate were added after 2 h, 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 obtain a yellow oil. The residue was purified by column chromatography on silica gel (using a gradient of 0 to 100% EtOAc in heptane), to provide the title compound (32 mg, yield: 95%). LC-MS (Method B1-S) m / z: [M+H] + :314; rt:1.06min; purity: 96.5%. 1 H NMR (500MHz, CDCl3) δ8.72(dd,J=4.7,1.7Hz,1H),8.18(s,1H),8.04(ddd,J=7.9,4.7,1.7Hz,1H),7.37(dd,J=7.9,4.7Hz,1H),7.21(s,1H ),5.30(s,1H),3.57(q,J=6.5Hz,1H),2.70-2.58(m,2H),2.50-2.39(m,2H),2.19-2.05(m,1H),2.02-1.89(m,1H),1.73(d,J=6.5Hz,3H). 19 F NMR (471MHz, CDCl3) δ-68.50 (d, J=4.8Hz).

[0672] Intermediate L20: 3,14-difluoro-5-(hydroxymethyl)-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ] Pentadecan-1(11),2,4,6,12,14-hexaen-9-one

[0673]

[0674] Step 1: Synthesis of tert-butyl N-(2-bromo-6-fluoro-4-pyridyl)-N-tert-butoxycarbonylcarbamate L20_1

[0675]

[0676] To the solution of intermediate L19_1 (700mg, 3.40mmol) and di-tert-butyl dicarbonate (2.30g, 10mmol) in THF (30mL) add 4-dimethylaminopyridine (43mg, 0.35mmol). The gained mixture is stirred at room temperature for 16h. After completion, water is added, and the reaction mixture is extracted three times with EtOAc. The organic layer washed with salt water combined, through Na2SO4 drying, filtered, and concentrated into dryness, there is provided orange oil. Residue is purified on silica gel by column chromatography (using the gradient of 0 to 20% EtOAc in heptane through 10 CV), to provide the title compound (1.13g, yield: 78%) as a white solid.

[0677] LC-MS (Method A1_S) m / z: [M+H] + :391 / 393; rt:1.70min; purity: 98%. 1 H NMR (400MHz, DMSO-d6) δ7.72(s,1H),7.38(s,1H),1.42(s,18H).

[0678] Step 2: Synthesis of tert-butyl N-[2-fluoro-6-(hydroxymethyl)-4-pyridyl]carbamate L20_2

[0679]

[0680] To intermediate L20_1 (781mg, 2.00mmol), six (μ-acetic acid) three palladium (II) (269mg, 0.40mmol) and butyl two-1-adamantyl phosphine (301mg, 0.80mmol) in N, N-dimethylformamide (3.3mL) solution add N, N, N ', N '-tetramethylethylenediamine (466mg, 4.00mmol).Reactant mixture is placed at 100 DEG C for 16h under 5 bar synthesis gas.After completion, reactant mixture is filtered through diatomite.Filtrate is extracted with EtOAc and washed three times with salt water, through MgSO4 drying, filter, and concentrate under vacuum, to obtain black oil.Residue is dissolved in methanol (18mL) at 0 DEG C, then sodium borohydride (132mg, 3.31mmol) is added.Reactant mixture is stirred at room temperature for 4h.After completion, reactant mixture is quenched with water and extracted three times with EtOAc. The resulting mixture was dried over MgSO 4 , filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (Purification Method P_A) to provide the title compound (163 mg, yield: 37%) as a white solid. LC-MS (Method A1_S) m / z: [M+H-Boc] + :143; rt:1.24min; purity: 98%. 1 H NMR (500MHz, DMSO-d6) δ10.14(s,1H),7.45(s,1H),7.00(d,J=1.6Hz,1H),5.48(s,1H),4.38(s,2H),1.48(s,9H).

[0681] Step 3: Synthesis of (4-amino-6-fluoro-2-pyridyl)methanol L20_3

[0682]

[0683] 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 under vacuum. The residue was dissolved in water and DCM, extracted three times with DCM, dried over MgSO4, filtered, and concentrated under vacuum to provide 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%.

[0684] Step 4: Synthesis of (4-amino-5-bromo-6-fluoro-2-pyridyl)methanol L20_4

[0685]

[0686] To a solution of intermediate L20_3 (56 mg, 0.27 mmol) in acetonitrile (0.2 mL) was slowly added N-bromosuccinimide (20 mg, 0.11 mmol) at 0 ° C. The resulting mixture was stirred at room temperature for 15 min. The resulting mixture was concentrated under vacuum to provide a brown oil. The residue was dissolved in DCM and water, extracted with DCM, dried over MgSO4, filtered, and concentrated under vacuum to provide the title compound (45 mg, yield: 67%) as a white solid.

[0687] LC-MS (Method A1_S) m / z: [M+H] + :222 / 224; rt:0.81min; purity: 98%. 1 H NMR (500MHz, CDCl3) δ6.53(s,1H),4.84(s,2H),4.55(s,2H),2.78(s,1H).

[0688] Step 5: Synthesis of 3,14-difluoro-5-(hydroxymethyl)-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadecan-1(11),2,4,6,12,14-hexaen-9-one L20

[0689] To intermediate L20_4 (35mg, 0.16mmol), intermediate L4_2 (176mg, 0.19mmol) in 1,4-dioxane (0.8mL) and water (48 μ l) solution add 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (7mg, 0.02mmol) and tripotassium phosphate (69mg, 0.32mmol). Reactant mixture is degassed with nitrogen for 10min, then tris (dibenzylideneacetone) dipalladium (0) (15mg, 0.02mmol) is added. Reactant mixture is heated at 100 DEG C for 18h. After completion, EtOAc (5mL) and water (5mL) are added in reactant mixture. Water layer is extracted three times with EtOAc, the organic layer washed with salt water for merging, through MgSO4 drying, filter, and be concentrated to dryness, to provide brown oil. The crude oil was dissolved in dry THF (0.7 mL) and lithium bis(trimethylsilyl)amide (1.5 M in THF, 25 μL) was added under N2 atmosphere. The reaction mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel (using a gradient of 0 to 100% EtOAc in heptane) to provide 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%.

[0690] Intermediate L21: 5-cyclobutyl-3-fluoro-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]15-carbon-1 (15),2,4,6,11,13-hexaen-9-one

[0691]

[0692] Step 1: Synthesis of 2-cyclobutyl-6-fluoro-pyridin-4-amine L21_1

[0693]

[0694] Under an argon atmosphere, to a mixture of intermediate L19_1 (650 mg, 3.40 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (II) (524 mg, 0.68 mmol) and cuprous iodide (129 mg, 0.68 mmol) in 1,4-dioxane (34 mL) was added cyclobutylzinc bromide (20 mL, 0.5 M in THF) at room temperature. 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 and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness to provide a black oil. The residue was purified by column chromatography on silica gel (using a gradient of 0 to 15% EtOAc in heptane) to provide 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%. 1 H NMR (400MHz, CDCl3) δ6.26 (d, J = 1.9Hz, 1H), 5.91 (s, 1H), 4.27 (s, 2H), 3.45 (p,J=8.7Hz,1H),2.32-2.19(m,4H),2.06-1.91(m,1H),1.90-1.77(m,1H). 19 F NMR (376 MHz, CDCl3) δ-69.87.

[0695] Step 3: Synthesis of 3-bromo-6-cyclobutyl-2-fluoro-pyridin-4-amine L21_2

[0696]

[0697] To a solution of intermediate L21_1 (860 mg, 4.14 mmol) in acetonitrile (20 mL) was slowly added N-bromosuccinimide (736 mg, 4.14 mmol) at 0°C. The resulting mixture was stirred at 0°C for 10 min. The reaction mixture was treated with a saturated aqueous solution of NaHCO3 and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated under vacuum to provide a black oil. The residue was purified by column chromatography on silica gel (using a gradient of 0 to 20% EtOAc in heptane) to provide the title compound (459 mg, yield: 43%) as a white solid. LC-MS (Method A1_S) m / z: [M+H]+: 245 / 247; rt: 1.38 min; purity: 96.3%. 1 H NMR (500MHz, DMSO-d6) δ6.59(s,2H),6.41(s,1H),3.46-3.25(m,1H),2.22-2.05(m,4H),1.98-1.86(m,1H),1.82-1.71(m,1H).

[0698] Step 4: 5-cyclobutyl-3-fluoro-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadecan-1(15),2,4,6,11,13-hexaen-9-one L21

[0699] 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)palladium(II) chloride (90 mg, 0.13 mmol) in 1,4-dioxane (15 mL) and water (1.3 mL) was degassed with nitrogen for 10 min. The reaction mixture was heated at 80 ° C for 16 h. 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 provide a brown oil. The crude material was dissolved in dry THF (10 mL) and bis(trimethylsilyl)lithium amide (1.5 M in THF, 2.5 mL) was added at room temperature under an N2 atmosphere. The reaction mixture was stirred at room temperature for 1 h. After 1 h, 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 of 0 to 13% MeOH in DCM) to provide the title compound (260 mg, yield: 41%). LC-MS (Method A1_S) m / z: [M+H]+: 298; rt: 1.31 min; purity: 83.9%.

[0700] Intermediate L22: 2-Fluoro-5,9-dimethyl-6-oxyylidene-6,7-dihydro-5H-benzo[b]pyrido[3,2-d]cyclopentadiene Heptatriene-10-carbonitrile

[0701]

[0702] Step 1: Synthesis of 4-amino-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile L22_1

[0703]

[0704] 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. (1,5-cyclooctadiene) (methoxy) iridium (i) dimer (243 mg, 0.37 mmol) and 2-[4-(dimethylamino)-2-pyridyl]-N, N-dimethyl-pyridine-4-amine (178 mg, 0.73 mmol) were then added successively and the resulting mixture was purged with nitrogen for 5 min and stirred at 80 ° C for 18 h. The reaction mixture was filtered through a Celite pad and washed with EtOAc (150 mL). The filtrate was concentrated and the resulting residue was purified by column chromatography on silica gel (using a gradient of 0-70% EtOAc / isohexane as eluent) to afford the title compound as a white solid (892 mg, yield: 47%). LC-MS (Method B5) m / z [M+H] + :259.2; rt:2.02min; purity: 100%. 1 H NMR (400MHz, DMSO-d6) δ7.56 (s, 1H), 6.56 (d, J = 1.0Hz, 1H), 6.28 (s, 2H), 2.29 (s, 3H), 1.29 (s, 12H).

[0705] Step 2: Synthesis of 2-fluoro-5,9-dimethyl-6-oxyylidene-5,7-dihydropyrido[2,3-d][1]benzazepine-10-carbonitrile L22

[0706] 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) was added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (54 mg, 0.08 mmol). The reaction mixture was stirred at 90 ° C for 18 h and then concentrated under vacuum. The residue was purified by column chromatography on silica gel (using a gradient of 10% MeOH (0.7 M NH 3 ) / DCM as eluent) to provide 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%. 1H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.67(d,J=2.7Hz,1H),8.22(s,1H),8.12(dd,J=9 .7,2.8Hz,1H),7.24(s,1H),3.49(q,J=6.5Hz,1H),2.53(s,3H),1.47(d,J=6.5Hz,3H). 19 F NMR (376 MHz, DMSO-d6) δ -130.12. Purity: 90%.

[0707] Intermediate L23: 3,5-difluoro-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadecan-1(11),2,4,6,12, 14-Hexaen-9-one

[0708]

[0709] The title compound was prepared by the same reaction sequence as described for intermediate L6_2, starting from intermediate L6_1 and intermediate L5_1. The first step (Suzuki reaction) was carried out using CsF, PEPPSI-Ipent in H2O / toluene with heating at 80°C. The second step was carried out using LiHMDS (3 eq.) in toluene at RT (17% yield over two steps). Both steps were similar to those described for intermediate L6_2. LC-MS (Method A7) m / z [M+H] + :248.1;rt:1.32min. 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H),8.62(dd,J=4.8,1.7Hz,1H),8.13(ddd,J=8.0,4.8,1.7Hz ,1H),7.50(dd,J=8.0,4.8Hz,1H),6.88(s,1H),3.92(d,J=12.7Hz,1H),3.67(d,J=12.7Hz,1H).

[0710] Intermediate L24: 3-fluoro-5-methoxy-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadecan-1(11),2 (7),3,5,12,14-hexaen-9-one

[0711]

[0712] Step 1: Synthesis of 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolidone Pyridin-4-amine L24_1

[0713]

[0714] To a flame-dried 100mL three-necked 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'-bipyridyl (90 mg, 0.32 mmol). The flask was evacuated and backfilled three times with nitrogen, and then anhydrous 1,4-dioxane (20 mL) was added. The reaction mixture was stirred at 75°C (internal temperature) for 17 hours, and then cooled to RT. The solution mixture was used cautiously as is for the next step (gas evolution in the next step).

[0715] Step 2: 3-Fluoro-5-methoxy-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadecan-1(11),2(7),3,5,12,14-hexaen-9-one L24

[0716] The title compound was prepared by the same reaction sequence as described for intermediate L3, starting from intermediate L24_1 and intermediate L2_3. The first step (Suzuki reaction) was carried out with Pd2dba3, Sphos and K3PO4 in toluene at 100°C. The second step was carried out using LiHMDS in methylTHF at RT. Both steps were similar to those described for intermediate L3. LC-MS (Method B1_S) m / z [M+H] + :274; rt:1.04min. 1 H NMR(500MHz,DMSO-d6)δ10.61(s,1H),8.63(d,J=2.8Hz,1H),8.54(s,1H),8.07(dd,J=9 .7,2.8Hz,1H),6.57(s,1H),3.92(s,3H),3.57(q,J=6.6Hz,1H),1.46(d,J=6.6Hz,3H).

[0717] Intermediate L25: 11-fluoro-9-(3-fluoroazetidin-1-yl)-5-methyl-5,7-dihydropyrido[2,3-d] [1]Benzazepine-6-one

[0718]

[0719] Step 1: Synthesis of 5-chloro-3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene Amine L25_1

[0720]

[0721] Under nitrogen, 250mL flame-dried three-necked round-bottom flasks were charged with bis(pinacol)diboron (15g, 58mmol), (1,5-cyclooctadiene) (methoxy)iridium (I) dimer (190mg, 0.28mmol) and 4,4'-di-tert-butyl-2,2'-bipyridyl (160mg, 0.58mmol). The flask was evacuated and backfilled three times with nitrogen, and then a solution of 3-chloro-5-fluoroaniline (4.3g, 29mmol) in anhydrous tetrahydrofuran (60mL) was added under nitrogen. The stirred mixture was heated at 65°C (internal temperature) for 19 hours, and then cooled to RT. Methanol (30mL) was carefully added to the reaction mixture of cooling and the resulting solution was stirred at room temperature for 30 minutes, then concentrated under vacuum. Purification by flash chromatography (Biotage Selekt, Sfar Silica HCD, 100 g, 0-20% ethyl acetate in hexanes) provided 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%. 1 H NMR (300MHz, DMSO-d6) δ6.53-6.44(m,1H),6.28(dd,J=9.7,1.9Hz,1H),6.11(s,2H),1.28(s,12H).

[0722] Step 2: Synthesis of 9-chloro-11-fluoro-5-methyl-5,7-dihydropyrido[2,3-d][1]benzazepine-6-one L25_2

[0723]

[0724] The title compound was prepared (45% yield) according to the same reaction sequence as described for intermediate L3, starting from intermediate L25_1, methyl 2-(3-bromopyridin-2-yl)propanoate, CsF, bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride heated in dioxane / water at 80°C, followed by cyclization with LiHMDS in THF at 0°C. LC-MS m / z: 277.0 / 279.0 [M+H] + ; Purity: 100%. 1H NMR (300MHz, DMSO-d6) δ10.47(s,1H),8.66(dd,J=4.8,1.7Hz,1H),8.04(ddd,J=7.9,4.6,1.7Hz,1H ),7.52-7.38(m,2H),7.16(dd,J=2.1,1.5Hz,1H),3.58(q,J=6.6Hz,1H),1.47(d,J=6.7Hz,3H).19F NMR (282MHz, DMSO-d6) δ-112.89 (ddd, J=10.5, 4.6, 1.5Hz.

[0725] Step 3: Synthesis of 11-fluoro-9-(3-fluoroazetidin-1-yl)-5-methyl-5,7-dihydropyrido[2,3-d][1]benzazepine-6-one

[0726] To the mixture of intermediate L25_2 (100mg, 0.36mmol) and 3-fluoroazetidine hydrochloride (60mg, 0.51mmol) in 1,4-dioxane (3mL) add (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] methanesulfonic acid palladium (II) (30mg, 0.04mmol), then add 2-dicyclohexylphosphino-2', 6'-diisopropoxy-biphenyl (17mg, 0.04mmol). The bottle is sonicated and purged under nitrogen, then sodium tert-butoxide (105mg, 1.09mmol) is added. The bottle is sealed and the reaction mixture is heated at 90 DEG C for 4h. After completion, water and EtOAc are added. The combined organic layer is washed with salt water, separated, dried over MgSO4, filtered, and concentrated under vacuum. The residue was triturated with DCM to afford the title compound as a white solid (68 mg, yield: 60%). LC-MS (Method A1_S) m / z: [M+H]+: 316.1; rt: 1.09 min; purity: 90%.

[0727] Intermediate L26: 14-chloro-4-fluoro-7,12-dimethyl-5,6,9,13-tetraazatricyclo[8.4.0.0 2,6 ]fourteen Carbon-1(14),2,4,10,12-pentaen-8-one

[0728]

[0729] 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

[0730] 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) was added dropwise a solution of n-BuLi in hexane (2.5 M, 12.7 mL, 31.9 mmol) at -70 ° C. The reaction mixture was stirred for 1 h at -70 ° C. Triisopropyl borate (7.4 mL, 31.9 mmol) was added at -78 ° C. The reaction mixture was stirred for 30 minutes at this temperature, then allowed to warm to RT and stirred for 1 h. Pinacol (3.76 g, 31.9 mmol) and AcOH (3.1 mL, 54.5 mmol) were added and the reaction mixture was stirred at RT overnight. Water (100 mL) was added and aqueous phase was extracted with EtOAc (3x75 mL). The combined organic matter was washed with salt water (100 mL), dried over Na SO , filtered, and concentrated under vacuum. The crude material was purified by column chromatography on silica gel using a gradient of 0-100% TBME in isohexane as eluent to afford the title compound as an off-white solid (7.3 g, 84% yield). LC-MS m / z [M-166+H] + :131.2; purity: 98% (215nm). 1 H NMR (400MHz, CDCl3) δ6.22(d,J=6.0Hz,1H),5.70(dt,J=10.0,2.6Hz,1H),4.08-4.01(m,1H),3.64(td,J=11.3,2.8Hz,1H),2.40- 2.25(m,1H),2.08(d,J=14.5Hz,1H),1.91(dd,J=13.5,3.5Hz,1H),1.68(qt,J=11.8,7.9Hz,2H),1.62-1.49(m,1H),1.34(s,12H).

[0731] Step 2: Synthesis of 2-chloro-3-(5-fluoro-2-tetrahydropyran-2-yl-pyrazol-3-yl)-6-methyl-pyridin-4-amine L26_2

[0732] Nitrogen is purged through the fluoro-1-tetrahydropyran-2-base of 3---5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazole L26-1 (1.0g, 3.1mmol), the chloro-6-methyl-pyridine-4-amine L4-1 (1.0g of the bromo-2-of 3-, 4.7mmol), CsF (951mg, 6.26mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) palladium chloride (II) (332mg, 0.470mmol) in 1,4-dioxane (35mL) and water (7mL).Reactant mixture is heated under reflux overnight, is then cooled to RT.Solution is filtered through diatomaceous earth pad and thoroughly washed with EtOAc (150mL).Filtrate is concentrated under vacuum. The crude material was purified by column chromatography on silica gel (using a gradient of 0-100% EtOAc in hexanes as eluent) to provide 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 (in the form of a mixture of diastereomers); purity: 96%.

[0733] Step 3: Synthesis of 2-chloro-N-[2-chloro-3-(5-fluoro-2-tetrahydropyran-2-yl-pyrazol-3-yl)-6-methyl-4-pyridyl]acrylamide L26_3

[0734] To the solution of 2-chloro-3-(5-fluoro-2-tetrahydropyran-2-yl-pyrazole-3-yl)-6-methyl-pyridine-4-amine L26-2 (1.05g, 2.0mmol) in DMF (18mL) was added NaH (60% purity, 97.3mg, 2.4mmol) at 0°C. The solution was stirred for 30 minutes, then 2-chloropropionyl chloride (0.28mL, 2.84mmol) was added dropwise. The reaction mixture was stirred for 1h at 0°C, then allowed to RT and stirred for 1h. Water (50mL) was added and aqueous phase was extracted with EtOAc (3x50mL). The organic extracts merged were washed with salt water (100mL), through Na2SO4 drying, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (using a gradient of 0-100% EtOAc in isohexane as eluent) to afford the title compound as a yellow oil (183 mg, yield: 21%). LC-MS m / z [M+H] + : 401.0, 403.0; rt: 1.16 and 2.00 min (in the form of a mixture of diastereomers); purity: 94%.

[0735] Step 4: Synthesis of 13-chloro-7-(1-chloroethyl)-4-fluoro-11-methyl-5,6,8,12-tetraazatricyclo[7.4.0.0 2,6 ]Tridecyl-1(13),2,4,7,9,11-hexaene L26_4

[0736] A solution of 2-chloro-N-[2-chloro-3-(5-fluoro-2-tetrahydropyran-2-yl-pyrazol-3-yl)-6-methyl-4-pyridinyl]propanamide #389_3 (288 mg, 0.703 mmol) and HCl (4 M in 1,4-dioxane, 2.0 mL, 8.0 mmol) was stirred overnight at RT. The reaction mixture was evaporated to dryness to provide the title compound as an off-white solid (155 mg, yield: 64%). LC-MS m / z [M+H] + :299.1,301.1; Purity: 96%. 1 H NMR (400MHz, DMSO-d6) δ7.82 (s, 1H), 7.48 (d, J = 5.2Hz, 1H), 5.93 (q, J = 6.7Hz, 1H), 2.64 (s, 3H), 1.97 (d, J = 6.7Hz, 3H).

[0737] Step 5: Synthesis of 14-chloro-4-fluoro-7,12-dimethyl-5,6,9,13-tetraazatricyclo[8.4.0.0 2,6 ]Tetradec-1(14),2,4,10,12-pentaen-8-one L26

[0738] To 13-chloro-7-(1-chloroethyl)-4-fluoro-11-methyl-5,6,8,12-tetraazatricyclo[7.4.0.0 2,6 ] A suspension of tridecane-1(13),2,4,7,9,11-hexaene L26_4 (155 mg, 0.508 mmol) in DMSO (2.00 mL) was added with an aqueous NaOH solution (2 M, 0.51 mL, 1.0 mmol). The resulting orange solution was stirred at RT for 1 h, 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 provide the title compound (120 mg, yield: 83%) as an off-white solid. LC-MS m / z [M+H] + :281.1,283.1; Purity: 100%. 1 HNMR (400MHz, DMSO-d6) δ11.06(s,1H),7.06(s,1H),6.58(d,J=5.8Hz,1H),4.87(d,J=8.1Hz,1H),2.54(s,3H),1.58(s,3H).

[0739] IV. Examples

[0740] Example No. 1: N-(4-acetylphenyl)-2-[(10R)-3-fluoro-5,10-dimethyl-9-oxygenylidene-4,8, 12-Triazatricyclic[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide

[0741]

[0742] To a solution of intermediate L1 (20 mg, 0.055 mmol) and HATU (27 mg, 0.071 mmol) in dry 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 provide the title compound (13.4 mg, yield: 56%) as a white solid. LC-MS m / z: [M+H] + :433.2; Purity: 95%. High Resolution Mass Spectrometry (method HRMS_A2) m / z (+H); Observed mass: 433.168; Expected mass: 433.1676 (for C 24 H 21 FN4O3); (rt: 1.87 min, purity: 96.3%).

[0743] Example No. 2: N-[4-(cyclopropanecarbonyl)phenyl]-2-[(10R)-3-fluoro-5,10-dimethyl-9-oxo- 4,8,12-triazatricyclic [9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide

[0744]

[0745] The title compound was prepared according to the same procedure as in Example 1 from intermediate L1 (30 mg, 0.08 mmol) and (4-aminophenyl)-cyclopropyl-methanone hydrochloride (32 mg, 0.16 mmol). 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, CO 2 + EtOH 15%) to provide 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%. 1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.67 (dd, J = 4.7, 1.7 Hz, 1H), 8.13 (ddd, J = 7.9, 4.7, 1.7 Hz, 1H), 8.03 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.50 (dd, J = 7.9, 4.7 Hz, 1H), 7.38 (s, 1H), 4.68-4.53 (m, 2H), 3.79 (q, J = 6.6 Hz, 1H), 2.85 (p, J = 6.1 Hz, 1H), 1.49 (d, J = 6.6 Hz, 3H), 1.04-0.97 (m, 4H). The CH3 protons are below the DMSO signal. High resolution mass spectrometry (method HRMS_A2) m / z (+H); observed mass: 459.183; expected mass: 459.1832 (for C 26 H 23 FN4O3); (rt: 2.06 min, purity: 100%).

[0746] Example No. 3: N-(4-acetylphenyl)-2-[(10R)-3,14-difluoro-5,10-dimethyl-9-oxyylidene- 4,8,12-Triazatricyclic[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide

[0747]

[0748] To the suspension of the split intermediate L2 (1.50 g, 5.45 mmol) in MeCN (22 mL) was added intermediate C1 (1.15 g, 5.45 mmol) at room temperature. In an Easymax reactor, the resulting mixture was cooled to 15 ° C under vigorous stirring, and then K CO (1.52 g, 10.9 mmol) was added. The reaction mixture was stirred at 15 ° C for 3 days. At room temperature, water (40 mL) was added dropwise to the reaction mixture. After stirring at room temperature for 30 min, the mixture was filtered on a glass frit. The solid was washed with water (3x20 mL) until pH = 6. The solid was dried at 40 ° C for 4 days under high vacuum, then purified on silica gel by flash chromatography (using a gradient of 0 to 100% EtOAc in heptane as eluent). The product was triturated in Et2O (15 mL), filtered on a glass frit, rinsed with Et2O (5 mL) and dried under high vacuum at 40°C for 16 h to provide 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%. 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.70 (d, J = 2.7 Hz, 1H), 8.14 (dt, J = 9.6, 3.4 Hz, 1H), 7.93 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.39 (s, 1H), 4.61 (s, 2H), 3.81 (q, J = 6.5 Hz, 1H), 2.52 (s, 3H), 1.49 (d, J = 6.5 Hz, 3H). The CH3 protons are below the DMSO signal. 19 F NMR (471 MHz, DMSO-d6) δ -70.59 (d, J = 3.4 Hz), -130.19 (d, J = 9.6 Hz). Chiral purity: 100%; rt = 3.07 min (first eluting enantiomer). For reference, rt = 4.07 min for the second eluting enantiomer. Both were measured by HPLC (Reprosil Chiral NR-R, from Dr Maisch, EtOH 50%-heptane 50%-DEA 0.1%). High-resolution mass spectrometry (method HRMS_A2) m / z (+H); observed mass: 451.1586; expected mass: 451.1582 (for C 24 H 20 F2N4O3); (rt: 2.05 min, purity: 100%).

[0749] Example No. 4: N-(4-acetylphenyl)-2-[14-fluoro-5,10-dimethyl-9-oxygenylidene-4,8,12-trifluoromethyl]- Azatricyclic [9.4.0.0 2,7 Enantiomers of pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide (10R) or (10S)

[0750]

[0751] The title compound was prepared from intermediate L3 (600 mg, 2.33 mmol) and intermediate C1 (543 mg, 2.57 mmol) according to a similar procedure to Example 3, but without potassium iodide. After completion, the reaction mixture was poured into water. The resulting precipitate was filtered off and washed with water (3x20 mL). The solid was ground in water, filtered off and washed with water (3x20 mL). The corresponding racemate was separated by chiral SFC (Chiralpak IA, from Daicel, CO2 + MeOH 20%). The enantiomer eluted for the second time was then purified by column chromatography on silica gel (using 0-100% EtOAc in heptane, then a gradient of 0-15% MeOH in EtOAc as eluent) to provide the title compound (193 mg, yield: 19%) as a white solid. 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%. 1 H NMR (500MHz, DMSO-d6) δ10.60(s,1H),8.77(s,1H),8.70(d,J=2.8Hz,1H),8.21(dd,J=9.5,2.8Hz,1H),7.99-7.88(m,2H), 7.74-7.68(m,2H),7.41(s,1H),4.70-4.53(m,2H),3.67(q,J=6.6Hz,1H),2.58(s,3H),2.54(s,3H),1.50(d,J=6.6Hz,3H). 19 F NMR (471 MHz, DMSO-d6) δ -129.71 (d, J = 9.5 Hz). Chiral purity: 100%; rt = 3.54 min (second eluting enantiomer). For reference, the first eluting enantiomer rt = 1.87 min. Both were measured by HPLC (Chiralpak IA from Daicel, EtOH 50%-heptane 50%-DEA 0.1%). High-resolution mass spectrometry (method HRMS_A2) m / z (+H); observed mass: 433.1679; expected mass: 433.1676 (for C 24 H 21 FN4O3); (rt: 1.58 min, purity: 100%).

[0752] Example No. 5: N-(4-acetylphenyl)-2-[(10R)-3-chloro-14-fluoro-5,10-dimethyl-9-oxo- 4,8,12-triazatricyclic [9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide

[0753]

[0754] Example 5 was prepared from intermediate L4 (600 mg, 2.06 mmol) and intermediate C1 (435 mg, 1 equivalent) according to a procedure similar to that for Example 3. 50 mg of the crude material 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%. 1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.69 (d, J = 2.8 Hz, 1H), 8.23 ​​(dd, J = 9.7, 2.8 Hz, 1H), 7.92 (m, J = 8.9 Hz, 2H), 7.68 (d, J = 8.9 Hz, 2H), 7.47 (s, 1H), 4.61 (d, J = 16.8 Hz, 1H), 4.54 (d, J = 16.8 Hz, 1H), 3.83 (q, J = 6.6 Hz, 1H), 2.54 (s, 3H), 2.52 (s, 3H), 1.48 (d, J = 6.6 Hz, 3H). High-resolution mass spectrum (method HRMS_A2) m / z (+H); observed mass: 467.1288; expected mass: 467.1286 (for C 24 H 20 ClFN4O3); (rt: 2.09 min, purity: 100%).

[0755] Example No. 6: N-(4-acetylphenyl)-2-[3-chloro-5,10-dimethyl-9-oxyde-4,8,12-triazine Heterotricyclic [9.4.0.0 2,7 ] enantiomer (10R) of pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide or (10S)

[0756]

[0757] Example 6 was prepared from intermediate L5 (252 mg, 0.92 mmol) and intermediate C1 (195 mg, 1 equivalent) according to a similar procedure to that for Example 3. It was purified by trituration in isopropanol (1 mL) and isopropyl ether (6 mL) to give a white solid (321 mg, yield: 76%). 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%. 1H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.66(dd,J=4.8,1.6Hz,1H),8.23(dd,J=7.9,1.7Hz,1 H),7.93(d,J=8.5Hz,2H),7.68(d,J=8.5Hz,2H),7.48(dd,J=7.9,4.8Hz,1H),7.45(s,1H),4. 60 (d, J = 16.8 Hz, 1H), 4.54 (d, J = 16.8 Hz, 1H), 3.81 (q, J = 6.6 Hz, 1H), 2.53 (s, 3H), 2.52 (s, 3H), 1.49 (d, J = 6.6 Hz, 3H). High resolution mass spectrum (method HRMS_A2) m / z (+H); observed mass: 449.1386; expected mass: 449.138 (for C 24 H 21 ClN4O3); (rt: 1.9 min, purity: 100%).

[0758] Example No. 7: N-(4-acetylphenyl)-2-[5-(3,3-difluoroazetidin-1-yl)-3-fluoro-10- Methyl-9-oxydeoxy-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl] Enantiomer (10R) or (10S) of acetamide

[0759]

[0760] To intermediate L6 (300mg, 0.63mmol) and 3,3-difluoroazetidine hydrochloride (190mg, 1.40mmol) solution in acetonitrile (6mL) in room temperature add N, N-diisopropylethylamine (0.42mL, 2.5mmol) and stir the mixture overnight.In room temperature, the mixture is stirred for other 5 days and after daily analysis, N, N-diisopropylethylamine (0.42mL) is added three times again.Reactant mixture is evaporated, then diluted with dichloromethane (10mL) and washed with water (20mL). The organic layer was dried over MgSO 4 , filtered and concentrated under vacuum to provide 360 ​​mg of a crude solid, which was purified by SFC (GreenSep-Nitro column, 80 mL / min, CO 2 + 35% MeOH) to provide racemic N-(4-acetylphenyl)-2-[5-(3,3-difluoroazetidin-1-yl)-3-fluoro-10-methyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0] 2,7

[0366] pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide (171 mg, major regioisomer, second eluting isomer) and minor regioisomer (45 mg, first eluting isomer) were purified by chiral HPLC (Reprosil NR-R, from Dr Maisch, EtOH 50%-heptane 50%, 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) measured by UHPLC (Reprosil Chiral NR-R, from Dr Maisch, EtOH 50%-heptane 50%-DEA 0.1%). High-resolution mass spectrometry (method HRMS_A2) m / z (+H); observed mass: 510.1765; expected mass: 510.1753 (for C 26 H 22 F3N5O3); (rt: 2.15 min, purity: 100%).

[0761] Example No. 8: N-(4-acetylphenyl)-2-[3-fluoro-5-(3-fluoroazetidin-1-yl)-10-methyl- 9-Oxylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetyl Amine enantiomer (10R) or (10S)

[0762]

[0763] Example No. 8 was prepared from intermediate L6 (310 mg, 0.65 mmol) and 3-fluoroazetidine hydrochloride (98 mg, 0.83 mmol) according to a procedure similar to that for Example No. 7. The crude mixture (374 mg) was purified by SFC (2-EP column from Kromasil, 80 mL / min, CO2 + 5 to 50% MeOH gradient) to provide 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 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), measured by UHPLC (column (R,R) Whelk-O1, EtOH 100%-DEA 0.1%). High-resolution mass spectrometry (method HRMS_A2) m / z (+H); observed mass: 492.1859; expected mass: 492.1847 (for C 26 H 23 F2N5O3); (rt: 2.01 min, purity: 98.5%).

[0764] Example No. 9: N-(4-acetylphenyl)-2-[3-chloro-5-(2,2-difluoro-5-azaspiro[2.3]hexane-5- yl)-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl] Acetamide

[0765]

[0766] The title compound was prepared from intermediate L7 (8.0 mg, 0.019 mmol) and intermediate C1 (5.4 mg, 0.024 mmol) 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 provide 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%. 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.53(dd,J=4.8,1.7Hz,1H),8.15(dd,J=7 .9,1.7Hz,1H),7.95-7.88(m,2H),7.69-7.63(m,2H),7.46(dd,J=7.9,4.8Hz,1H) ,6.56(s,1H),4.62(d,J=16.7Hz,1H),4.50(d,J=16.7Hz,1H),4.27-4.11(m,4H) ,3.90(d,J=12.5Hz,1H),3.62(d,J=12.5Hz,1H),2.52(s,3H),1.86-1.73(m,2H). 19 F NMR (376 MHz, DMSO-d6) δ -137.56 (t, J = 8.7 Hz). High-resolution mass spectrometry (method HRMS_A2) m / z (+H); observed mass: 538.1469; expected mass: 538.1458 (for C 27 H 22 ClF2N5O3); (rt: 2.14 min, purity: 100%).

[0767] Example No. 10: N-(4-acetylphenyl)-2-(1-fluoro-3-methyl-6-oxygenylidene)-7H-pyrido[4,3- d][3]benzoazepine-5-yl)acetamide

[0768]

[0769] The title compound was prepared from intermediate L8 (15 mg, 0.04 mmol) and 1-(4-aminophenyl)ethanone (12.2 mg, 0.09 mmol) according to the same procedure as for Example 1. After complete conversion, the reaction mixture was purified by preparative HPLC (Purification Method P_B) to provide the title compound (10.2 mg, yield: 55%). LC-MS m / z: [M+H]+ :418.2; Purity: 96%. High Resolution Mass Spectrometry (method HRMS_A2) m / z (+H); Observed mass: 418.1558; Expected mass: 418.1567 (for C 24 H 20 FN3O3); (rt: 2.02 min, purity: 94.54%).

[0770] Example No. 11: N-(4-acetylphenyl)-2-[3-fluoro-5-methoxy-10-methyl-9-oxygen-4,8, 12-Triazatricyclic[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide Conformation (10R) or (10S)

[0771]

[0772] 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 h. After completion, water was added and the reaction mixture was extracted with DCM (3x, separated through a phase separator). The combined organic layers were concentrated under vacuum. The residue was purified by preparative HPLC (purification method P_B) to provide the title compound (26.4 mg, yield: 79%) as a white solid. 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:3.50min; purity: 97%; chiral purity>99%. 1 H NMR(400MHz, DMSO-d6)δ10.56(s,1H),8.64(dd,J=4.8,1.6Hz,1H),8.13-8.05(m,1H),7.96-7.89(m,2H),7.71-7.64(m,2H),7 .48(dd,J=7.9,4.8Hz,1H),6.90(s,1H),4.61(s,2H),3.92(s,3H),3.85(q,J=6.6Hz,1H),2.52(s,3H),1.49(d,J=6.6Hz,3H). 19 F NMR (376 MHz, DMSO-d6) δ -72.04 (d, J = 4.6 Hz). High-resolution mass spectrometry (method HRMS_A2) m / z (+H); observed mass: 449.1635; expected mass: 449.1625 (for C 24 H 21FN4O4); (rt: 2.04 min, purity: 98.43%).

[0773] Example No. 12: N-(4-acetylphenyl)-2-[14-methoxy-5,10-dimethyl-9-oxygen-4,8, 12-Triazatricyclic[9.4.0.0 2,7 Enantiomers of pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide (10R) or (10S)

[0774]

[0775] Example 12 was prepared from intermediate L11 (90 mg, 0.33 mmol) and intermediate C1 (71 mg, 1 equivalent) according to 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 with solvent A (H 2 O 95%-ACN 5% + NH 4 HCO 3 50 mM + 200 μL / L NH 4 OH) and solvent B (100% ACN) (pH 8.5), flow rate: 35 to 45 mL / min) and the enantiomers were purified by chiral HPLC (Chiralpak IB from Daicel, EtOH 100%) 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), measured by HPLC (Chiralpak IB, EtOH 100%-DEA 0.1%). 1 H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.79 (s, 1H), 8.39 (d, J = 3.0 Hz, 1H), 7.93 (d, J = 8.7 Hz, 2H), 7.76-7.67 (m, 3H), 7.37 (s, 1H), 4.64 (d, J = 16.8 Hz, 1H), 4.53 (d, J = 16.8 Hz, 1H), 3.93 (s, 3H), 3.54 (q, J = 6.8 Hz, 1H), 2.56 (s, 3H), 2.53 (s, 3H), 1.47 (d, J = 6.8 Hz, 3H). High-resolution mass spectrum (method HRMS_A2) m / z (+H); observed mass: 445.1882; expected mass: 445.1876 (for C 25 H 24N4O4); (rt: 1.5 min, purity: 95.81%).

[0776] Example No. 13: N-(4-acetylphenyl)-2-[3-methoxy-5,10-dimethyl-9-oxygen-4,8, 12-Triazatricyclic[9.4.0.0 2,7 ]pentadeca-1(15),2(7),3,5,11,13-hexaen-8-yl]acetamide Conformation (10R) or (10S)

[0777]

[0778] The title compound was prepared from intermediate L12 (141 mg, 0.52 mmol) and intermediate C1 (137 mg, 0.63 mmol) according to a procedure similar to that 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 provide 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%. 1 H NMR (500 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.58 (dd, J = 4.7, 1.7 Hz, 1H), 8.15 (dd, J = 7.9, 1.7 Hz, 1H), 7.99-7.87 (m, 2H), 7.75-7.62 (m, 2H), 7.42 (dd, J = 7.9, 4.7 Hz, 1H), 7.03 (s, 1H), 4.56-4.47 (m, 2H), 3.90 (s, 3H), 3.64 (q, J = 6.7 Hz, 1H), 2.53 (s, 3H), 2.46 (s, 3H), 1.47 (d, J = 6.7 Hz, 3H). Chiral purity: 100%; rt = 3.15 min (first eluting enantiomer). For reference, the second eluting enantiomer had a rt = 4.85 min. Both were measured by HPLC (Reprosil NR-R, from Dr Maisch, EtOH 50% - heptane 50% - DEA 0.1%). High resolution mass spectrometry (method HRMS_A2) m / z (+H); observed mass: 445.1879; expected mass: 445.1876 (for C 25 H 24 N4O4); (rt: 2.03 min, purity: 100%).

[0779] Example No. 14: N-(4-acetylphenyl)-2-(3-methoxy-10-methyl-9-oxygen-4,8,12-tri Azatricyclic [9.4.0.0 2,7 ] Enantiomers of pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide (10R) or (10S)

[0780]

[0781] The title compound was prepared from intermediate L14 (140 mg, 0.50 mmol) and intermediate C1 (147 mg, 0.61 mmol) according to a procedure similar to that 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 provide 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%. 1 H NMR (400MHz, DMSO-d6) δ10.56(s,1H),8.61(dd,J=4.7,1.7Hz,1H),8.23(d,J=5.8Hz,1 H),8.19(dd,J=7.9,1.7Hz,1H),7.93(d,J=8.8Hz,2H),7.68(d,J=8.8Hz,2H),7.44(dd, 4.7 Hz, 1H), 7.16 (d, J = 5.8 Hz, 1H), 4.63-4.46 (m, 2H), 3.92 (s, 3H), 3.66 (q, J = 6.6 Hz, 1H), 2.52 (s, 3H), 1.49 (d, J = 6.6 Hz, 3H). Chiral purity: 100%; rt = 2.16 min (first eluting enantiomer). For reference, rt = 2.54 min for the second eluting enantiomer. Both were measured by HPLC (WhelkO-1 (R,R), from Regis Technology, EtOH 100%-DEA 0.1%).

[0782] Example No. 15: 2-[(10R)-3-fluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclic] [9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]-N-(4-propionylphenyl)acetamide

[0783]

[0784] The title compound was prepared from intermediate L1 (53 mg, 0.11 mmol) and 4'-aminopropiophenone (15 mg, 0.10 mmol) according to a procedure similar to that for Example 1. The crude mixture was purified by preparative HPLC (Purification Method P-B) to provide 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%. 1 H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.67 (dd, J = 4.8, 1.6 Hz, 1H), 8.17-8.09 (m, 1H), 7.94 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H), 7.50 (dd, J = 7.9, 4.8 Hz, 1H), 7.38 (s, 1H), 4.60 (s, 2H), 3.79 (q, J = 6.6 Hz, 1H), 2.99 (q, J = 7.2 Hz, 2H), 1.49 (d, J = 6.6 Hz, 3H), 1.07 (t, J = 7.2 Hz, 3H). The CH3 protons are below the DMSO signal. 19 F NMR (376MHz, DMSO-d6) δ-70.96 (d, J=5.1Hz).

[0785] Example No. 16: N-(4-acetyl-3-hydroxy-phenyl)-2-(3-fluoro-5,10-dimethyl-9-oxygen-4, 8,12-Triazatricyclic[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)

[0786] Enantiomer (10R) or (10S) of acetamide

[0787]

[0788] The title compound was prepared from intermediate L1-6 (50 mg, 0.19 mmol) and intermediate C2 (49 mg, 0.21 mmol) according to a procedure similar to that 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 provide 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%. 1 H NMR (500 MHz, DMSO-d6) δ 12.29 (s, 1H), 10.59 (s, 1H), 8.67 (dd, J = 4.7, 1.8 Hz, 1H), 8.13 (ddd, J = 7.9, 4.7, 1.8 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.50 (dd, J = 7.9, 4.7 Hz, 1H), 7.36 (s, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.05 (dd, J = 8.7, 2.1 Hz, 1H), 4.58 (s, 2H), 3.79 (q, J = 6.6 Hz, 1H), 2.57 (s, 3H), 1.49 (d, J = 6.6 Hz, 3H). The CH3 protons are below the DMSO signal. 19 F NMR (471 MHz, DMSO-d6) δ -70.97 (d, J = 4.7 Hz). Chiral purity: 100%; rt = 2.23 min (first eluting enantiomer). For reference, rt = 2.77 min for the second eluting enantiomer. Both were measured by HPLC (Reprosil NR-R, from Dr. Maisch, EtOH 100%-DEA 0.1%).

[0789] Example No. 17: N-(4-acetylphenyl)-2-(3,14-difluoro-5-methoxy-10-methyl-9-oxyylidene- 4,8,12-Triazatricyclic[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)

[0790] Enantiomer (10R) or (10S) of acetamide

[0791]

[0792] The title compound was prepared from intermediate L15 (333 mg, 0.64 mmol) and intermediate C1 (187 mg, 0.77 mmol) according to a procedure similar to that for Example 3. After purification by reverse phase chromatography (alkaline elution), the corresponding racemate was separated by chiral SFC (Chiralpak IB from Daicel, CO2 + EtOH 20%) to provide 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%. 1H NMR (500MHz, DMSO-d6) δ10.59(s,1H),8.67(d,J=2.9Hz,1H),8.11(dt,J=9.5,3.4Hz,1H),7.93(d,J=8.8Hz,2H),7.6 8(d,J=8.8Hz,2H),6.92(s,1H),4.62(s,2H),3.92(s,3H),3.87(q,J=6.6Hz,1H),2.52(s,3H),1.47(d,J=6.6Hz,3H). 19 F NMR (471 MHz, DMSO-d6) δ -71.56 (t, J = 3.4 Hz), -130.18 (d, J = 9.5 Hz). Chiral purity: 100%; rt = 2.42 min (second-eluting enantiomer). For reference, rt = 1.94 min for the first-eluting enantiomer. Both were measured by HPLC (Chiralpak IB from Daicel, MeOH 100%-DEA 0.1%).

[0793] Example No. 18: 2-[3,14-difluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclic] [9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]-N-(3-oxyylidenebenzofuran-6-yl)ethyl Enantiomer (10R) or (10S) of amide

[0794]

[0795] To a mixture of intermediate L16 (297 mg, 0.89 mmol) and intermediate L17 (394 mg, 1.34 mmol) in dry 1,4-dioxane (9 mL) was added cesium carbonate (882 mg, 2.68 mmol) at room temperature. The resulting mixture was purged with N2, 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. After completion, the reaction was diluted with EtOAc (10 mL), filtered through a celite pad and rinsed with EtOAc. The filtrate was concentrated under vacuum. After purification by flash chromatography on silica gel (using a gradient of 0 to 100% EtOAc in heptane as eluent), the corresponding racemate was separated by chiral HPLC (Chiralpak IB from Daicel, MeOH 100%) to afford the title compound (17.9 mg, yield: 4%) as a yellow solid. 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%. 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.71 (d, J = 2.8 Hz, 1H), 8.15 (dt, J = 9.7, 3.6 Hz, 1H), 7.63 (d, J = 1.7 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.38 (s, 1H), 7.17 (dd, J = 8.4, 1.7 Hz, 1H), 4.77 (s, 2H), 4.62 (s, 2H), 3.82 (q, J = 6.5 Hz, 1H), 1.48 (d, J = 6.5 Hz, 3H). The CH3 protons are below the DMSO signal. 19 F NMR (471 MHz, DMSO) δ -70.60 (d, J = 3.6 Hz), -130.15 (d, J = 9.7 Hz). Chiral purity: 98%; rt = 2.41 min (second-eluting enantiomer). For reference, rt = 1.91 min for the first-eluting enantiomer. Both were measured by HPLC (Chiralpak IB from Daicel, EtOH 100%-DEA 0.1%).

[0796] Example No. 19: N-(4-acetylphenyl)-2-(10-cyano-2-fluoro-5,9-dimethyl-6-oxydeoxy-5H- The enantiomer (10R) or (10S) of pyrido[2,3-d][1]benzazepine-7-yl)acetamide

[0797]

[0798] 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 h. 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 under vacuum. The residue was purified by preparative HPLC (purification method P_B) to provide the corresponding racemic compound (12 mg, yield: 48%) in the form of a white solid. 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%. The racemate was purified by chiral SFC (column Lux A1, from Phenomenex, CO2 + MeOH:MeCN (1:1) 60%) to give the title product. Chiral purity >95%; rt:3.26 min (second-eluting enantiomer). For reference, rt:1.55 min for the first-eluting enantiomer). Both were measured by SFC (column Lux A1, from Phenomenex, CO2 + MeOH 50% + NH3 0.1%).

[0799] Example No. 20: N-(4-acetylphenyl)-2-[(10)-3-fluoro-14-methoxy-5,10-dimethyl-9-oxo- Subunit-4,8,12-triazatricyclic [9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide enantiomer (10R) or (10S)

[0800]

[0801] To a solution of intermediate L10 (100 mg, 0.35 mmol) in N,N-dimethylformamide (1.7 mL) was added potassium carbonate (146 mg, 1.05 mmol) and intermediate C1 (74 mg, 0.35 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. 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 under vacuum. The residue was purified by preparative HPLC (Purification Method P-B) to provide the corresponding racemate (75.0 mg, yield: 47%) as a white solid. The product was purified by chiral HPLC (Reprosil Chiral NR-R, from Dr Maisch, EtOH 50%-heptane 50%+DEA The racemate was separated by HPLC (Reprosil Chiral NR-R, from Dr. Maisch, EtOH 50%-heptane 50% + DEA 0.1%) to give the title product (24.5 mg, 15% yield). Chiral purity >99%; rt: 3.97 min (first eluting enantiomer). For reference, rt: 5.43 min for the second eluting enantiomer). Both were measured 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%. 1H NMR (400MHz, DMSO-d6) δ10.55(s,1H),8.40(d,J=2.8Hz,1H),7.96-7.89(m,2H),7.73-7.66(m,3H),7.36(s,1H),4.61(d,J =16.9Hz,1H),4.54(d,J=16.9Hz,1H),3.88(s,3H),3.68(q,J=6.6Hz,1H),2.52(s,3H),2.50(s,3H),1.47(d,J=6.6Hz,3H).

[0802] Example No. 21: N-(4-acetylphenyl)-2-[3-fluoro-5-(3-fluoroazetidin-1-yl)-9-oxo- 4,8,12-triazatricyclic [9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide

[0803]

[0804] Step 1: Synthesis of N-(4-acetylphenyl)-2-(3,5-difluoro-9-oxyylidene)-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadecan-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide

[0805]

[0806] 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 h. 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 under vacuum to provide the title compound (1.27 g, yield: 96%). LC-MS (Method A1_S) m / z: [M+H] + :423.0; rt:1.14min; purity: 96%. 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),8.64(dd,J=4.9,1.7Hz,1H),8.19(ddd,J=8.0,4.7,1.7Hz,1H),7.97-7.90(m,2H),7.74-7.66(m,2H),7. 54(dd,J=8.0,4.9Hz,1H),7.34(s,1H),4.69(d,J=17.0Hz,1H),4.64(d,J=17.0Hz,1H),4.06-3.98(m,1H),3.75(d,J=12.7Hz,1H),2.53(s,3H).

[0807] Step 2: Synthesis of N-(4-acetylphenyl)-2-[3-fluoro-5-(3-fluoroazetidin-1-yl)-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide Example No. 21

[0808] At room temperature, N-(4-acetylphenyl)-2-(3,5-difluoro-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ] To a solution of 15-carbon-1(11), 2(7), 3,5,12,14-hexaen-8-yl)acetamide (Example No. 21 Step 1, 280 mg, 0.61 mmol) and 3-fluoroazetidine hydrochloride (85 mg, 0.76 mmol) in acetonitrile (5 mL) was added N, N-diisopropylethylamine (0.3 mL, 2 mmol). 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 under vacuum. The residue was purified by SFC chromatography (P4VPDCpak, from Daicel, CO2+MeOH 20%) to provide 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%. 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),8.50(dd,J=4.8,1.6Hz,1H),8.00(ddd,J=7.9,4.8,1 .6Hz,1H),7.95-7.87(m,2H),7.70-7.62(m,2H),7.44(dd,J=7.9,4.8Hz,1H),6.38(s,1H), 5.50(dtd,J=60.4,6.0,3.1Hz,1H),4.61(d,J=16.6Hz,1H),4.54(d,J=16.6Hz,1H),4.44-4 .24(m,2H),4.18-3.97(m,2H),3.86(d,J=12.4Hz,1H),3.65(d,J=12.4Hz,1H),2.50(s,3H).

[0809] Example No. 22: N-(4-acetylphenyl)-2-[5-(3,3-difluoroazetidin-1-yl)-3-fluoro-9- Oxylidene-4,8,12-triazatricyclic [9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetyl amine

[0810]

[0811] At room temperature, N-(4-acetylphenyl)-2-(3,5-difluoro-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ] Pentadecan-1 (11), 2 (7), 3,5,12,14-hexaene-8-yl) acetamide (Example No. 21 Step 1, 280 mg, 0.61 mmol) and 3,3-difluoroazetidine hydrochloride (95 mg, 0.73 mmol) in acetonitrile (5 mL) were added N, N-diisopropylethylamine (0.3 mL, 2 mmol). 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 under vacuum. The residue was purified by SFC chromatography (P4VPDCpak, from Daicel, CO2 + MeOH 15%). The residue was washed with water and extracted with DCM to provide the title compound (77 mg, yield: 25%).

[0812] LC-MS (Method A1_S) m / z: [M+H] + :496.0; rt:1.19min; purity: 97%. 1 H NMR (400MHz, DMSO-d6) δ10.56(s,1H),8.55(dd,J=4.9,1.7Hz,1H),8.05(ddd,J=8.0,4.7,1.7Hz,1H),7.97-7.90(m,2H),7.74-7 .64(m,2H),7.48(dd,J=8.0,4.9Hz,1H),6.54(s,1H),4.71-4.40(m,6H),3.90(d,J=12.5Hz,1H),3.77-3.66(m,1H),2.53(s,3H).

[0813] Example No. 23: N-(4-acetylphenyl)-2-(3,5-difluoro-10-methyl-9-oxygenylidene-4,8,12-trifluoromethyl)- Azatricyclic [9.4.0.0 2,7 ] Enantiomers of pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)-acetamide (10R) or (10S)

[0814]

[0815] The racemic intermediate L6 was separated by chiral HPLC (Reprosil Chiral NR-R, from Dr. Maisch, EtOH 50%-heptane 50% + DEA 0.1%) to give the title product (31.4 mg, yield: 27%). Chiral purity >99%; rt: 2.89 min (first eluting enantiomer). For reference, the second eluting enantiomer rt: 3.85 min. Both were measured 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%.

[0816] Example No. 24: N-(4-acetyl-3-fluoro-phenyl)-2-[(10)-3-fluoro-5,10-dimethyl-9-oxo- 4,8,12-triazatricyclic [9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide Enantiomer (10R) or (10S)

[0817]

[0818] Step 1: Synthesis of N-(4-bromo-3-fluoro-phenyl)-2-(3-fluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadecan-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide

[0819]

[0820] 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), 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 h. 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 h. 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 MgSO 4 , filtered, and concentrated under vacuum. The residue was ground with 10 mL of iPr 2 O and 2 mL of iPrOH to provide 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%.

[0821] Step 2: Synthesis of N-[4-(1-ethoxyvinyl)-3-fluoro-phenyl]-2-(3-fluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadecan-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide

[0822]

[0823] At room temperature, N-(4-bromo-3-fluoro-phenyl)-2-[3,14-difluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadecan-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide (Example No. 24 Step 1, 1.53 g, 3.15 mmol) was added to a solution of tributyl(1-ethoxyvinyl)tin (1.31 mL, 3.76 mmol) and tetrakis(triphenylphosphine)palladium(0) (190 mg, 0.16 mmol) in toluene (15 mL). The reaction mixture was then heated at 110° C. for 20 h. After completion, water and ethyl acetate were added and the reaction mixture was filtered through a celite pad. The resulting mixture was extracted with ethyl acetate. The combined organic layers were dried over MgSO 4 , filtered, and concentrated under vacuum to provide the title compound (3.20 g, quantitative yield). LC-MS (Method B1_S) m / z:[M+H] + :479.0; rt:1.55min; purity: 47%.

[0824] Step 3: Synthesis of N-(4-acetyl-3-fluoro-phenyl)-2-(3-fluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ] Enantiomer (10R) or (10S) of 15-pentadecan-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide Example No. 24

[0825] To N-[4-(1-ethoxyvinyl)-3-fluoro-phenyl]-2-(3-fluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7] To a solution of pentadecan-1(11), 2(7), 3,5,12,14-hexaen-8-yl)acetamide (Example 24 Step 2, 3.20 g, 6.02 mmol) in THF (100 mL) was added hydrochloric acid (1 mol / L in water, 20 mL) and the reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was quenched with a 1 M solution of NaOH in water. The organic layer was extracted three times with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (using a gradient of 0 to 100% EtOAc in heptane as eluent over 20 CV) to provide the corresponding racemate (1.20 g, yield: 85%). 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 (355 mg, yield: 36%). Chiral purity >99%; rt: 2.66 min (first eluting enantiomer). For reference, the second eluting enantiomer rt: 3.42 min. Both were measured by HPLC (Reprosil Chiral NR-R, from Dr. Maisch, EtOH 50%-heptane 50% + DEA 0.1%). LC-MS basicity (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%. 1 H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.68 (dd, J = 4.8, 1.7 Hz, 1H), 8.13 (ddd, J = 8.0, 4.6, 2.0 Hz, 1H), 7.83 (t, J = 8.7 Hz, 1H), 7.67 (dd, J = 14.0, 2.0 Hz, 1H), 7.51 (dd, J = 8.0, 4.6 Hz, 1H), 7.39-7.34 (m, 2H), 4.60 (s, 2H), 3.79 (q, J = 6.6 Hz, 1H), 2.54 (d, J = 4.4 Hz, 3H), 1.49 (d, J = 6.6 Hz, 3H). The CH3 protons are below the DMSO signal.

[0826] Example No. 25: N-(4-acetylphenyl)-2-[3-fluoro-5-(3-hydroxy-3-methyl-azetidine-1- yl)-10-methyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadecan-1(11),2(7),3,5,12,14- Hexaen-8-yl]acetamide

[0827]

[0828] The title compound was prepared according to a similar procedure to that for Example 7 and 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 (P4VPDCpak from Daicel, CO2 + MeOH 25%) to provide 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%.

[0829] Example No. 26: N-(4-acetylphenyl)-2-[3-fluoro-5-(3-fluoro-3-methyl-azetidine-1- yl)-10-methyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadecan-1(11),2(7),3,5,12,14- Hexaen-8-yl]acetamide

[0830]

[0831] The title compound was prepared according to a similar procedure to Example 7 and 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) and then by SFC chromatography (GreenSep Nitro, CO2 + MeOH 30%) to provide 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%.

[0832] Example No. 27: N-(4-acetylphenyl)-2-[3-fluoro-5-(3-hydroxy-3-methyl-azetidine-1- yl)-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaene-8- methyl]acetamide

[0833]

[0834] According to a similar procedure as for Example No. 7 and from N-(4-acetylphenyl)-2-(3,5-difluoro-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7] Pentadecan-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide (Example No. 21 Step 1, 102 mg, 0.24 mmol) and 3-fluoro-3-methylazetidine hydrochloride (45 mg, 0,36 mmol) were used to prepare the title compound. The residue was purified by SFC chromatography (P4VP DCpak from Daicel, CO2+MeOH 25%) to provide 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%.

[0835] Example No. 28: N-(4-acetylphenyl)-2-(14-fluoro-7,12-dimethyl-8-oxyylidene-4-thia-5, 9,13-Triazatricyclic[8.4.0.0 2,6 ]Tetradec-1(10),2,5,11,13-pentaen-9-yl)acetamide

[0836]

[0837] To a solution of intermediate L18 (38 mg, 0.14 mmol) in dry 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 h. After 18 h, the reaction mixture was diluted with EtOAc and water. The combined organic layers were washed with brine, dried over MgSO 4 , filtered, and concentrated to dryness to provide a brown oil. The residue was purified by preparative HPLC (purification method P_B) to provide the title compound (11 mg, yield: 17%) as a white solid. 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%. 1 H NMR (500 MHz, DMSO-d6) δ 10.60 (s, 1H), 9.40 (d, J = 3.6 Hz, 1H), 7.96-7.90 (m, 2H), 7.75-7.67 (m, 2H), 7.36 (s, 1H), 4.62 (d, J = 16.9 Hz, 1H), 4.53 (d, J = 16.9 Hz, 1H), 3.89 (q, J = 6.6 Hz, 1H), 2.48 (s, 3H), 1.52 (d, J = 6.6 Hz, 3H). The CH3 protons are below the DMSO signal.

[0838] Example No. 29: N-(4-acetylphenyl)-2-[3-fluoro-5-(1-hydroxycyclobutyl)-10-methyl-9-oxo- 4,8,12-triazatricyclic [9.4.0.0 2,7 ]pentadeca-1(15),2,4,6,11,13-hexaen-8-yl]acetamide

[0839]

[0840] To a solution of intermediate L19 (32 mg, 0.10 mmol) in dry N, N-dimethylformamide (0.5 mL) was added intermediate C1 (28 mg, 0.12 mmol), potassium iodide (1.6 mg, 0.01 mmol), and then potassium carbonate (34 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 18 h. 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 provide a brown oil. The residue was purified by preparative HPLC (purification method P_B) to provide 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%. 1 H NMR (500MHz, DMSO) δ10.61 (s, 1H), 8.69 (dd, J = 4.8, 1.7Hz, 1H), 8.20-8.16 (m, 1H), 7. 96-7.90(m,2H),7.73-7.67(m,2H),7.60(s,1H),7.52(dd,J=8.0,4.8Hz,1H),5.99(s ,1H),4.63(d,J=17.1Hz,1H),4.50(d,J=17.1Hz,1H),3.81(q,J=6.7Hz,1H),2.60-2. 55(m,2H),2.53(s,3H),2.28-2.19(m,2H),2.02-1.82(m,2H),1.50(d,J=6.7Hz,3H).

[0841] Example No. 30: N-(4-acetylphenyl)-2-[3,14-difluoro-5-(hydroxymethyl)-10-methyl-9-oxo- Subunit-4,8,12-triazatricyclic [9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]acetamide

[0842]

[0843] To a solution of intermediate L20 (19 mg, 0.06 mmol) in dry N, N-dimethylformamide (0.3 mL) was added intermediate C1 (18 mg, 0.12 mmol), potassium iodide (1 mg, 0.01 mmol), and then potassium carbonate (21 mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 3 h. 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 provide a brown oil. The residue was purified by preparative HPLC (purification method P_B) to provide the title compound (3.8 mg, yield: 12%). 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%. 1 HNMR (500 MHz, DMSO-d6) δ10.62 (s, 1H), 8.72 (d, J = 2.7 Hz, 1H), 8.21-8.15 (m, 1H), 7.96-7.92 (m, 2H), 7.72-7.69 (m, 2H), 7.53 (s, 1H), 5.69 (t, J = 5.8 Hz, 1H), 4.68-4.52 (m, 4H), 3.82 (q, J = 6.6 Hz, 1H), 1.50 (d, J = 6.6 Hz, 3H). The CH3 protons are below the DMSO signal.

[0844] Example No. 31: N-(4-acetylphenyl)-2-(5-cyclobutyl-3-fluoro-10-methyl-9-oxygenylidene-4,8, 12-Triazatricyclic[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide Conformation (10R) or (10S)

[0845]

[0846] To intermediate L21 (220mg, 0.63mmol) in dry N, N-dimethylformamide (10mL) solution add intermediate C1 (188mg, 0.89mmol), potassium iodide (12mg, 0.07mmol), subsequently add potassium carbonate (206mg, 1.48mmol).Reactant mixture is stirred at room temperature for 20h.After completion, by reaction mixture NH4Cl saturated aqueous solution cancellation and extract with ethyl acetate.Organic layer is washed with salt water, through Na2SO4 drying, filter, and concentrate, to provide brown solid.Residue passes through column chromatography on silica gel (using 0 to 9%MeOH gradient in DCM), then passes through SFC chromatography (SFC-5-Diol, from Kromasil, CO2+MeOH 5 to 50%) purifying, to provide corresponding racemic compound (189mg, 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, rt: 1.87 min for the first-eluting enantiomer). Both were measured 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%. 1 H NMR (500MHz, DMSO-d6) δ10.58(s,1H),8.67(dd,J=4.8,1.7Hz,1H),8.15(ddd,J=7. 9,4.8,1.7Hz,1H),7.96-7.90(m,2H),7.72-7.65(m,2H),7.50(dd,J=7.9,4.8Hz,1H ),7.33(s,1H),4.62(s,2H),3.79(q,J=6.6Hz,1H),3.68(p,J=8.6Hz,1H),2.52(s,3 H),2.36-2.23(m,4H),2.07-1.94(m,1H),1.91-1.80(m,1H),1.48(d,J=6.6Hz,3H).

[0847] 19 F NMR (471MHz, DMSO-d6) δ-70.10 (d, J = 4.8Hz).

[0848] Example No. 32: N-(4-acetylphenyl)-2-(14-fluoro-5-methoxy-10-methyl-9-oxygen-4,8, 12-Triazatricyclic[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide Conformation (10R) or (10S)

[0849]

[0850] To intermediate L24 (100mg, 0.37mmol) and intermediate C1 (107mg, 0.44mmol) in DMF (1.8mL) solution of potassium carbonate (128mg, 0.92mmol) and potassium iodide (6mg, 0.04mmol) was added in room temperature. The gained mixture was stirred at room temperature for 18h. After completion, water and ethyl acetate were added and the reaction mixture was extracted with ethyl acetate three times. The organic layer merged was dried over MgSO4, filtered, and concentrated under vacuum to provide a brown solid. The residue was triturated with a mixture of water and acetonitrile (3 / 7) to afford 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. 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 (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. Both were measured 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%. 1H NMR (500MHz, DMSO-d6) δ10.58(s,1H),8.66(d,J=2.8Hz,1H),8.53(s,1H),8.15(dd,J=9.5,2.8Hz,1H),7.96-7.90(m,2H),7.71-7.65(m, 2H),6.93(s,1H),4.66(d,J=16.9Hz,1H),4.60(d,J=16.9Hz,1H),3.95(s,3H),3.72(q,J=6.7Hz,1H),2.53(s,3H),1.48(d,J=6.7Hz,3H). 19 F NMR (471MHz, DMSO-d6) δ-129.80 (d, J=9.5Hz).

[0851] Example No. 33: N-(4-acetyl-3-hydroxy-phenyl)-2-(3,14-difluoro-5,10-dimethyl-9-oxo- 4,8,12-triazatricyclic [9.4.0.0 2,7 ]pentadecan-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide Enantiomer (10R) or (10S)

[0852]

[0853] At room temperature, 2-(3,14-difluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2 ,7 ] 15-carbon-1 (11), 2 (7), 3, 5, 12, 14-hexaene-8-yl) acetamide, intermediate L16 (100 mg, 0.30 mmol) in dry 1,4-dioxane (3 mL) was added 1- (4-bromo-2-hydroxyphenyl) ethanone (82 mg, 0.36 mmol). 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. After completion, the reaction was diluted with EtOAc (10 mL), filtered through a celite pad and rinsed with EtOAc. The filtrate was concentrated under vacuum to provide racemic N-(4-acetyl-3-hydroxy-phenyl)-2-(3,14-difluoro-5,10-dimethyl-9-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7] Pentadecan-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide. After purification by reverse chromatography (alkaline elution), the racemate was separated by chiral HPLC (Chiralpak IG, from Daicel, EtOH 50%-heptane 50%) to provide the title compound (18 mg, yield: 13%) as a white solid. Chiral purity: 98.3%; rt: 4.97 min (second eluting enantiomer). For reference, the first eluting enantiomer rt: 2.69 min. Both were measured 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%. 1 HNMR (400 MHz, DMSO) δ 12.28 (s, 1H), 10.57 (s, 1H), 8.71 (d, J = 2.7 Hz, 1H), 8.21-8.09 (m, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.38 (s, 1H), 7.31 (s, 1H), 7.04 (d, J = 8.7 Hz, 1H), 4.59 (s, 2H), 3.81 (q, J = 6.6 Hz, 1H), 2.57 (s, 3H), 1.48 (d, J = 6.6 Hz, 3H). The CH3 protons are below the DMSO signal. 19 F NMR (376MHz, DMSO) δ -70.59 (d, J = 3.6Hz), -130.19 (d, J = 9.6Hz).

[0854] Example No. 34: N-(4-acetylphenyl)-2-(3,14-difluoro-5,10-dimethyl-9-oxydeoxy-4,8, 13-Triazatricyclic[9.4.0.0 2,7 ]pentadecan-1(11),2(7),3,5,12,14-hexaen-8-yl)acetamide

[0855]

[0856] Example No. 34 was prepared from Intermediate L13 (1.7 mg, 0.006 mmol) and Intermediate C1 (1.4 mg, 0.007 mmol) according to a similar procedure to Example No. 3. After completion, the reaction mixture was purified by preparative HPLC (Purification Method P_B) to provide the title compound (1.68 mg, yield: 59%) as a white solid. 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%. 1 H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.28 (s, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H), 7.55 (dd, J = 4.3, 1.7 Hz, 1H), 7.39 (s, 1H), 4.60 (s, 2H), 3.72 (q, J = 6.8 Hz, 1H), 2.52 (s, 3H), 1.54 (d, J = 6.8 Hz, 3H). The CH3 protons are below the DMSO signal. 19 FNMR(376MHz,DMSO-d6)δ-70.02(d,J=4.3Hz),-71.65.

[0857] Example No. 35: N-(4-acetylphenyl)-2-[11-fluoro-9-(3-fluoroazetidin-1-yl)-5-methyl]- enantiomer (5R) or (5S)

[0858]

[0859] 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 layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (purification method P_B) to provide the corresponding racemate (56 mg, yield: 54%) as a white solid. The racemate was separated by chiral HPLC (Whelk O-1 (R, R), from Regis Technology, EtOH 100%) to obtain the title product (17.6 mg, yield: 17%). Chiral purity>99%; rt: 2.38 min (enantiomer of the first elution). For reference, the enantiomer of the second elution rt: 2.92 min). Both were measured 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%.

[0860] Example No. 36: N-(4-acetylphenyl)-2-(14-chloro-4-fluoro-7,12-dimethyl-8-oxygenylidene-5,6, 9,13-Tetraazatricyclic[8.4.0.0 2,6 ]Tetradec-1(14),2,4,10,12-pentaen-9-yl)acetamide

[0861]

[0862] Example 36 was prepared according to a procedure similar to 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 / isohexane as eluent) to provide the title compound as a white solid (62 mg, yield: 69%). LC-MS (Method B5) m / z [M+H]+: 456.1 / 458.1; rt: 1.39 min; purity: 98%. 1HNMR(400MHz,DMSO-d6)δ10.60(s,1H),7.99-7.89(m,2H),7.74-7.65(m,2H),7.48(s,1H),6.64(d,J= 5.8Hz,1H),5.05-4.96(m,1H),4.69-4.55(m,2H),2.53(s,3H),2.52(s,3H),1.60(d,J=6.7Hz,3H).19F NMR(376MHz,DMSO-d6)δ-131.08.

[0863] V. Biological Assays

[0864] The compounds of formula (I) were tested in two independent cell-based assays for their effects on system Xc - Functional effects: (i) measurement of cystine-induced glutamate release; and (ii) measurement of [ 14 C] L-cystine uptake.

[0865] As described above, System Xc - Also known as the cystine / glutamate antiporter, it is an amino acid transporter that mediates the excretion of intracellular L-glutamate and the uptake of extracellular L-cystine into the cell.

[0866] By measuring the concentrations of extracellularly released glutamate and intracellularly taken-up L-cystine, respectively, as the concentration of the compound of formula (I) according to the present invention increases, the inhibition of the compound on System Xc can be evaluated. - Functional efficacy.

[0867] Compounds inhibit system Xc - The efficacy is measured by IC50 To indicate that IC 50 Corresponds to the concentration of compound required to inhibit 50% of the signal from two control groups; DMSO 1% and Erastin 50 μM in the respective assays. pIC 50 Values ​​correspond to IC in moles 50 -log.

[0868] IC 50 The lower the value (pIC 50 The higher the value), the less compound is needed to perform the same amount of inhibition, and thus the inhibitory efficacy is higher.

[0869] Typically, cystine-induced glutamate release and [ 14 C] L-cystine uptake assay in each of the system Xc - Functional inhibitors will each display an IC of 500 nM or lower. 50 value.

[0870] When cystine-induced glutamate release and [ 14 C] The compounds of formula (I) according to the present invention showed pIC values ​​of 50 The value is typically greater than or equal to about 6.3, suitably greater than about 7.0, ideally greater than about 7.4, and appropriately greater than about 7.8.

[0871] V.1. Cystine-induced glutamate release assay

[0872] Measurements of cystine-induced glutamate release indicate that glutamate levels (extracellular) depend on system Xc - Antiporter function. When L-cystine is added to H4 cells, intracellular glutamate is antiported and exported in the supernatant.

[0873] In this assay, the medium does not contain sodium to prevent the transport of glutamate by the sodium-dependent excitatory amino acid transporter (EAAT). H4 cells were plated at 1x10 4Cells / well were plated in 384-well culture plates in Dulbecco's modified Eagle's medium (DMEM) with L-glutamine, penicillin / streptomycin and 10% fetal bovine serum (all from ThermoFisher Scientific) and incubated at 37°C in a humidified CO2 incubator. After 2 days, cells were washed 4 times with preheated sodium-free HEPES buffer (content in mM: 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) and a test compound of formula (I) at a final DMSO concentration of 1%. After incubation for 2 hours in the incubator, the supernatant was transferred to a low-binding polypropylene 384-well plate for use with Amplex TM L-glutamate concentration was determined using the Red Glutamate Assay Kit (ThermoFisher Scientific). Briefly, 10 μL of Amplex TM The ELISA Red working solution was added to 10 μL of the supernatant, and the mixture was incubated for 30 min at 37° C. The fluorescence intensity was measured using an EnVision microplate reader (PerkinElmer).

[0874] When tested, the compounds of formula (I) according to the present invention exhibit a pIC of about 6.3 or higher in a cystine-induced glutamate release assay. 50 .

[0875] V.2.[ 14 C] L-cystine uptake assay

[0876] In this assay, the medium does not contain sodium to prevent the transport of glutamate by sodium-dependent excitatory amino acid transporters (EAATs). H4 cells were plated at 5×10 4 Cells / well were plated on 96-well CytoStar-T scintillation microplates (PerkinElmer). After 1 day, cells were washed once with sodium-free HEPES buffer and pre-incubated with the test compound of formula (I) (1% final DMSO) for 15 min. 14 C] cystine (0.02 mCi / mL, PerkinElmer, Waltham, US) and 4.5 μM L-cystine (Sigma-Aldrich) were used to initiate the uptake. After 1 hour at 37°C, the cells were incubated in a MicroBeta 2 Plates were counted in a microplate counter (PerkinElmer).

[0877] Table I shows the results of the cystine-induced glutamate release assay and / or [ 14 C] The pIC values ​​of the compounds of formula (I) according to the present invention when tested in an L-cystine uptake assay are 50 range.

[0878] Category A: about 6.3 < pIC 50 ≤ approximately 7.00; Category B: approximately 7.00 <pIC 50 ≤ about 7.40; Category C: about 7.40 <pIC 50 ≤ approximately 7.80; Category D: pIC 50 > about 7.80. nt: not tested.

[0879]

[0880]

[0881] As shown in this Table I, the compound of formula (I) according to the present invention is System Xc - Effective inhibitors of function.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in, A is connected to the rest of the molecule at the point V 1 and V 2 Together means choose A 1 、A 2 and A 3 An optionally substituted aryl or heteroaryl group in, V 1 Indicates C; V 2 Indicates C or N; Z 4 Indicates N or CR 7 ; Z 5 Indicates N or CR 8 ; Z 6 Indicates N or CR 9 ; Z 7 Indicates N or CR 10 ; R a represents halogen; R 7 、R 8 、R 9 and R 10 independently represents hydrogen or halogen; or C 1-4 Alkyl or C 1-4 Alkoxy, any of which may be optionally substituted with one or more substituents; and Z 1 Indicates N or CR 4 ; Z 2 Indicates N or CR 5 ; Z 3 Indicates N or CR 6 ; Z 4 Indicates N or CR 7 ; R 1a and R 1b independently represents hydrogen; or C 1-4 an alkyl group, which may be optionally substituted with one or more substituents; R 2 Indicates C 1-4 Alkyl or C 3-7 Cycloalkyl, any of these groups may be optionally substituted with one or more substituents; R 3 represents hydrogen, halogen or hydroxy; or C 1-4 an alkyl group, which may be optionally substituted with one or more substituents; or R 2 and R 3 Together with the phenyl group to which they are attached, they form a heteroaryl group, which is optionally substituted with one or more substituents; and R 4 and R 5 independently represents hydrogen, halogen or cyano; or C 1-4 Alkyl or C 1-4 Alkoxy, any of which may be optionally substituted with one or more substituents; and R 6 represents hydrogen, halogen or cyano; or C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 Heterocycloalkyl or C 3-7 Cycloalkyl, any of these groups may be optionally substituted with one or more substituents.

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

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

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

5. The compound of formula (I) according to claim 1, wherein Z 2 Indicates N, Z 1 Indicates CR 4 And Z 3 Indicates CR 6 .

6. The compound of formula (I) according to claim 1, wherein Z 7 Indicates N, Z 4 Indicates CR 7 , Z 5 Indicates CR 8 , Z 6 Indicates CR 9 .

7. The compound of formula (I) according to claim 1, wherein R 1a 、R 1b 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 and R 10 Optionally hydroxy, halogen, C 1-4 Alkyl or C 1-4 Alkoxy substitution.

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

9. The compound of formula (I) according to claim 1, wherein R 1a Indicates C 1-4 Alkyl and R 1b represents hydrogen; R 2 Indicates C 1-4 Alkyl or C 3-7 Cycloalkyl; R 3 represents hydrogen; R 4 、R 7 、R 8 and R 9 independently represents hydrogen, halogen or C 1-4 alkoxy; and R 6 Indicates C 1-4 Alkyl, C 1-4 Alkoxy or optionally substituted C 3-7 Cycloalkyl or C 3-7 Heterocycloalkyl.

10. The compound of formula (I) according to claim 1, which is represented by formula (IA), in R 1a Indicates C 1-4 alkyl; R 2 Indicates C 1-4 Alkyl or C 3-7 Cycloalkyl; R 4 and R 8 independently represents hydrogen, halogen or C 1-4 alkoxy; and R 6 Indicates C 1-4 Alkyl, C 1-4 Alkoxy or C 3-7 Heterocycloalkyl.

11. A compound of formula (I) according to any one of the preceding claims, wherein R 1a C 1-4 alkyl.

12. A compound of formula (I) according to any one of the preceding claims, wherein R 2 C 1-4 alkyl.

13. A compound of formula (I) according to any one of the preceding claims, wherein R 4 It is a halogen.

14. A compound of formula (I) according to any one of the preceding claims, wherein R 8 It is a halogen.

15. The compound of formula (I) according to claim 1, which is selected from the group consisting of: N-(4-acetylphenyl)-2-[3-fluoro-5,10-dimethyl-9-oxyylidene-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-oxyylidene-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-oxyylidene-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-oxyylidene-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-oxyylidene-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-oxyylidene-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-oxyylidene-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-oxyylidene-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-oxyylidene-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-oxyylidene-7H-pyrido[4,3-d][3]benzazepine-5-yl)acetamide, N-(4-acetylphenyl)-2-[3-fluoro-5-methoxy-10-methyl-9-oxyylidene-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-oxyylidene-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-oxyylidene-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-oxyylidene)-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-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-8-yl]-N-(4-propionylphenyl)acetamide; N-(4-acetyl-3-hydroxy-phenyl)-2-[3-fluoro-5,10-dimethyl-9-oxyylidene-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-oxyylidene)-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-oxyylidene-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]-N-(3-oxyylidenebenzofuran-6-yl)acetamide; N-(4-acetylphenyl)-2-(10-cyano-2-fluoro-5,9-dimethyl-6-oxylidene-5H-pyrido[2,3-d][1]benzazepine-7-yl)acetamide; N-(4-acetylphenyl)-2-[(10)-3-fluoro-14-methoxy-5,10-dimethyl-9-oxyylidene-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-oxyylidene-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-oxyylidene-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-oxyylidene-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-oxyylidene-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-oxygenylidene-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-oxygenylidene-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-oxyylidene-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-oxyylidene-4-thia-5,9,13-triazatricyclo[8.4.0.0 2,6 ]Tetradec-1(10),2,5,11,13-pentaen-9-yl)acetamide; N-(4-acetylphenyl)-2-[3-fluoro-5-(1-hydroxycyclobutyl)-10-methyl-9-oxyde-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-oxyylidene-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-oxyylidene)-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-oxyylidene)-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-oxyylidene-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-oxyylidene-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-oxyylidene)-5,6,9,13-tetraazatricyclo[8.4.0.0 2,6 ]Tetradec-1(14),2,4,10,12-pentaen-9-yl)acetamide; and its enantiomers.

16. A compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof for use in treating System Xc - Cancers where System Xc - Role in epilepsy syndromes or for cancer therapy resistance.

17. A method for treating a System Xc-active cancer or epilepsy syndrome, or cancer therapy resistance, comprising administering to a patient in need of such treatment an effective amount of a compound of formula (I) according to any one of claims 1 to 15.

18. Use of a compound of formula (I) according to any one of claims 1 to 15 for the preparation of a medicament for the treatment of cancer or epilepsy syndromes in which System Xc is involved, or cancer therapy resistance.

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