Fused benzazepine derivatives for use in the treatment of cancer and epilepsy

Abstract

The present invention is based on the system Xc - Compounds of formula (I) or pharmaceutically acceptable salts thereof are useful in the treatment of diseases and / or disorders in which [Formula 1] JPEG2026505789001043.jpg5648 Regarding.

Description

[Technical Field]

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

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

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

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

[0005] In many different cancer types, system Xc -is overexpressed compared to normal tissues. These cancer types include, but are not limited to, glioma (especially glioblastoma) (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 USA (2019), 116, 9433-9442), adrenocortical carcinoma, renal carcinoma (Wang et al., Oncotarget, 2016, 7, 29901-29915), hepatocellular carcinoma (Kinoshita et al., Oncolumn Rep (2013), 29, 685-689), mesothelioma, lung 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 are highly dependent on cysteine ​​to prevent ferroptotic cell death, and depletion of SLC7A11 in cancer-associated fibroblasts prevents orthotopic pancreatic tumor formation (Sharbeen et al., Cancer Res (2021); DOI: 10.1158 / 0008-5472.CAN-20-2496). In other cancers, the expression of SLC7A11 (System Xc) in cancer cells is crucial. - downregulation of the light chain of the X-linked phosphodiesterase (Xc) reduces cancer cell proliferation, tumor progression, and invasion, -plays an important role in tumorigenesis (Badgley et al., Science (2020), 368, 85-89; Ede et al., Haematologica (2018), 103, 1496-1501; Hu et al., J Clin Invest (2020), 130, 1752-1766; Lei et al., Cell Res (2020), 30, 146-162; Lin et al., Am J Cancer Res (2020), 10, 3106-3126).

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

[0007] Furthermore, SLC7A11, cystine, and cysteine ​​have been described to play a role in radiotherapy resistance and multidrug resistance in several cancer types (Horibe et al., Biochem Biophys Res Commun (2018), 507, 426-432; Koppula et al., Cell Res (2020), 30, 146-162).

[0008] Therefore, the system Xc - Inhibition or blockage of system Xc - may be useful in treating certain cancers in which IL-1 plays a role.

[0009] System Xc - Blockade of system Xc can also synergize with other therapies that target tumor growth, such as preventing cancer stem cell metastasis. - Inhibition of IL-1, in conjunction with chemotherapy treatments that block tumor growth (induced by oncogenes such as HER2, p53, and Kras), provides additional therapeutic benefit in breast, esophageal, and other cancer cell lines and models (Conti et al., Cancer Immunol Res (2020), 8, 1039-53; Liu et al., Nat Commun (2017), 8, 14844).

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

[0011] Therefore, the system Xc - Molecules that inhibit system Xc in cancer cells could be used alone or in combination therapy with molecules or treatments that target other mechanisms and pathways involved in cancer biology, thereby helping to overcome drug resistance in current cancer treatments or enhancing the effectiveness of certain existing treatments. - Glutamate release due to upregulation of glutamate also affects tumorigenesis, and inhibition of glutamate release correlates with decreased proliferation not only in brain tumors but also in non-brain cancers (Savaskan et al., Nature Medicine (2008), 14, 629; Lewerenz et al., Antioxid Redox Signal (2013), 18, 522-555; Corsi et al., Int J Mol Sci (2019), 20).

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

[0013] Therefore, the system Xc - By inhibiting the function or expression of glioma-associated epilepsy and high system Xc - It may be possible to prevent glutamate-induced seizures and neuronal death in other epilepsy syndromes that exhibit elevated levels, such as focal cortical dysplasia and tuberous sclerosis (Arena et al., (2019), Brain Pathol 29, 351-365).

[0014] International Patent Application, Publication No. WO 2015 / 196086, brochure, System Xc - The present invention relates to compounds which are said to be inhibitors of

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

[0016] Therefore, the system Xc has improved properties. - System Xc, which can be used to treat certain cancers or epilepsy syndromes - New drugs that inhibit antiporters need to be designed.

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

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

[0019] (In the formula, Y is NR a or CR 1a R 1b represents; R a is hydrogen or C 1~4 represents alkyl; R 1a and R 1b are independently hydrogen, hydroxy, halogen; or C 1~4 Alkoxy or C 1~4 alkyl (any of these groups may be optionally substituted with one or more substituents); A is the point of attachment to the rest of the molecule, V 3 and V 4 Together with A 1 , A 2 , A 3 , A 4 , A 5 , A 6 and A 7 represents an optionally substituted aryl or heteroaryl selected from the group represented by: [ka]

[0020] V 3 and V 4 independently represent C; Z 1 is N or CR 4 represents; Z 2is N or CR 5 represents; Z 3 is N or CR 6 represents; R e represents hydrogen or halogen; R 4 is hydrogen, halogen, hydroxy, cyano or amino; or C 1~4 Alkyl, C 3~7 Cycloalkyl or C 1~4 alkoxy (any of these groups may be optionally substituted with one or more substituents); R 5 is hydrogen, halogen or cyano; or C 1~4 Alkyl or C 1~4 alkoxy (any of these groups may be optionally substituted with one or more substituents); R 6 is hydrogen, halogen or cyano; or C 1~4 Alkoxy, C 1~4 Alkylamino, C 1~4 Alkyl, C 3~7 Heterocycloalkyl or -O-(C 3~7 heterocycloalkyl) (any of these groups may be optionally substituted with one or more substituents); R 7 is hydrogen; or C 1~4 Alkyl or C 3~7 cycloalkyl (any of these groups may be optionally substituted with one or more substituents); R 8 , R 9 and R 10 are independently hydrogen or halogen; or C 1~4 Alkyl, C 3~7 Cycloalkyl or C 1~4 alkoxy (any of these groups may be optionally substituted with one or more substituents); R 11 Ha-NR c -(CO)-R b represents; Rb and R c independently, C 1~4 represents alkyl; B is the point of attachment to the rest of the molecule, V 1 and V 2 Together with B 1 , B 2 , B 3 , B 4 , B 5 , B 6 , B 7 and B 8 represents an optionally substituted aryl or heteroaryl selected from the group represented by: [ka]

[0021] V 1 is B 1 , B 2 , B 3 , B 4 , B 5 , B 6 and B 7 represents C, and B 8 For N, represent; V 2 is B 1 , B 2 , B 4 , B 6 , B 7 and B 8 represents C, and B 3 and B 5 For N, represent; W, U 1 and U 2 independently represent N or CH; Z 4 is N or CR 13 represents; Z 5 is N or CR 14 represents; Z 6 is N or CR 15 represents; Z 7 is N or CR 16 represents; T is N or CR 17 represents; R 12 represents hydrogen; R 13 , R 14 , R 15 , R 16 are independently hydrogen, halogen, or cyano; or C 1~4 Alkyl or C 1~4 alkoxy (any of these groups may be optionally substituted with one or more substituents); R 17 is hydrogen, halogen or C 1~4 represents alkyl; R 17 ' is hydrogen or C 1~4 represents alkyl; Q is Q 1 and Q 2 represents a ring selected from the group represented by: [ka]

[0022] Z 8 is N or CR 3 represents; Z 9 is CR 18 represents; Z 10 is N or CR 19 represents; Z 11 is CR 20 represents; Z 12 is S, O, NH or CR 21 R 22 represents; Z 13 is N or CR 23 represents; Z 14 is N or CR 24 represents; R 2 is halogen or cyano; or C 1~4 Alkyl, C 3~7 Cycloalkyl or C 1~4alkoxy (any of these groups may be optionally substituted with one or more substituents); R 3 is hydrogen, halogen or cyano; or C 1~4 represents alkyl, which may be optionally substituted with one or more substituents; or R 2 and R 3 taken together with the group to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, which groups are optionally substituted with one or more substituents; R 18 is hydrogen or halogen; or C optionally substituted with one or more substituents 1~4 represents alkyl; R 19 , R 20 , R 21 , R 22 , R 23 and R 24 are independently hydrogen or halogen; or C optionally substituted with one or more substituents. 1~4 (representing alkyl) to provide.

[0023] In a second aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.

[0024] In a third aspect, the present invention provides a system Xc - Provided are compounds of formula (I), or pharmaceutically acceptable salts thereof, that are useful in the treatment of disorders in which the hydroxyl / glutamate antiporter plays a role.

[0025] In particular, the present invention provides a system Xc - The present invention provides compounds of formula (I) which may be useful in the treatment of cancer or epilepsy syndromes in which is a role.

[0026] Additionally, the present invention provides compounds of formula (I) that may be useful in overcoming cancer treatment resistance.

[0027] In a fourth aspect, the present invention provides a pharmaceutical composition comprising, as an active ingredient, a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0028] In a fifth aspect, the present invention provides synthetic intermediates of formula (II) useful in the chemical synthesis of compounds of formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0029] As used herein, "C 1~4 The term "alkyl" refers to a straight or branched monovalent saturated aliphatic hydrocarbon chain of 1 to 4 carbon atoms. 1~4 Alkyl is methyl and ethyl.

[0030] "C 1~4 The term "alkoxy" refers to a group of the formula -OR, where R is a group as defined herein. 1~4 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.

[0031] As used herein, "C 3~7 The term "cycloalkyl" refers to a monovalent group of 3 to 7 carbon atoms derived from a saturated monocyclic hydrocarbon. 3~7 Cycloalkyl groups include cyclopropyl.

[0032] As used herein, "C 3~7 The term "heterocycloalkyl" refers to saturated monocyclic and bicyclic rings containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulfur, and nitrogen. Suitable C 3~7Heterocycloalkyl includes azetidinyl, piperazinyl, morpholino, pyrrolidinyl, azaspirohexanyl, azaspiroheptanyl, azabicyclohexanyl, azabicycloheptanyl, oxa-azaspiroheptanyl, and oxa-azaspirooctanyl.

[0033] In one particular embodiment, where the compound of the invention is a compound of formula (I), "C 3~7 The term "heterocycloalkyl" refers to a saturated monocyclic ring containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulfur, and nitrogen. 3~7 Heterocycloalkyl includes azetidinyl and piperazinyl.

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

[0035] The term "amino" as used herein refers to -NH2 for a primary amine group, -NH for a secondary amine group, or -N- for a tertiary amine group, where the nitrogen is linked to the parent molecule. For example, C 1~4 The "amino" used in the term alkylamino is C 1~4 Refers to an alkyl-substituted NH, where the nitrogen is connected to the parent molecule.

[0036] The term "aryl," as used herein, refers to an unsaturated carbocyclic group of from 6 to 14 carbon atoms having a single ring (eg, phenyl) or multiple condensed rings (eg, naphthyl).

[0037] When the compound of the invention is a compound of formula (I), the term "aryl" as used herein refers to an unsaturated heteroaromatic or carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl).

[0038] In one aspect, where the compound of the invention is a compound of Formula (I), the term "aryl" as used herein refers to an unsaturated carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl).

[0039] For the avoidance of doubt, reference to compounds of formula (I) also includes compounds of formula (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), (ID-a), (IE), (IE-a), (IF), (IG), (IJ), (IK), (IL) and (IM).

[0040] The term "heteroaryl," as used herein, refers to an aromatic carbocyclic group of 5 to 14 carbon atoms having a single ring or multiple fused rings in which one or more of the carbon atoms is replaced by one or more heteroatoms selected from oxygen, sulfur, and nitrogen.

[0041] When any of the groups in the compound of formula (I) above is described as being optionally substituted, this group may be unsubstituted or may be substituted with one or more substituents.Typically, such groups are unsubstituted or substituted with one, two or three substituents.In one embodiment, such groups are unsubstituted.Suitable substituents for each of the groups present in the compound of formula (I) are further described herein below.

[0042] Formula (I) and the formulae depicted below are intended to represent all individual stereoisomers and all possible mixtures thereof unless otherwise stated or shown.

[0043] Stereoisomers of the compounds of formula (I) include cis and trans isomers, optical isomers, diastereomers, geometric isomers, rotamers, atropisomers, and conformational isomers of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures thereof (e.g., racemates and diastereomeric pairs).

[0044] The compounds of formula (I) and / or their intermediates may have at least one stereocenter in their structure. This stereocenter may be present in the R or S configuration (referred to as aR or aS for atropisomers), and the R and S (or aR and aS) designations are used in accordance with the rules set forth in Pure Appl. Chem., 45 (1976) 11-30. The present invention therefore also relates to all stereoisomeric forms, such as enantiomeric and diastereoisomeric forms of the compounds of formula (I), or mixtures thereof (including all possible mixtures of stereoisomers). In the context of the present invention, reference to one or more compounds is intended to encompass each compound in its possible isomeric forms and mixtures thereof, unless a particular isomeric form is specifically mentioned.

[0045] Carbon-carbon bonds in compounds of formula (I) are represented herein by solid lines ( [ka] ), solid wedge ( [ka] ) or dotted wedge ( [ka] ) The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers at that carbon atom (e.g., specific enantiomers, racemic mixtures, etc.) are included. The use of a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is included. It is possible that compounds of formula (I) may contain more than one asymmetric carbon atom. In these compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are included.

[0046] Some compounds of formula (I) may exist as a single atropisomer or as a mixture of atropisomers.

[0047] Atropisomers are stereoisomers that arise because rotation around a single bond is hindered, and energy differences due to steric strain or other causes create a sufficiently high barrier to rotation to allow isolation of individual conformers (see, for example, Bringmann G. et al., Atroposelective Synthesis of Axially Chiral Biaryl Compounds. Angewandte Chemie International Edition. (2005) 44(34):5384-5427).

[0048] Unlike compounds with classical chiral centers, which racemize through a bond breaking and forming process, atropisomers racemize through an intramolecular dynamic process involving only bond rotation. Depending on the rotational barrier, one particular conformer of the compounds of formula (I') and formula (I) may be in equilibrium with another conformer, and therefore the composition of conformers may change with time or conditions under which equilibrium is reached. The conformations of the compounds of formula (I') and formula (I) are represented by the solid line ( [ka] ) and / or solid wedge ( [ka] Examples of particular subgroups of compounds of formula (I) whose atropisomers are represented by formula (IA-aa) and formula (IA-ab), respectively, are shown below: [ka]

[0049] Solid wedges on rings A and B [ka] The use of is meant to indicate the conformation associated with the particular atropisomer (IA-aa) or (IA-ab).

[0050] Some compounds of formula (I) can exist in tautomeric forms. Although not explicitly shown in the formula above, such forms are intended to be included within the scope of the present invention. Examples of tautomers include keto (CHC=O)⇔enol (CH=CHOH) tautomers or amide (NHC=O)⇔hydroxyimine (N=COH) tautomers or 2-hydroxypyridine⇔pyridinone. Formula (I) and the formulae shown below are intended to represent all individual tautomers and all possible mixtures thereof, unless otherwise stated or shown.

[0051] It should also be understood that each individual atom present in Formula (I'), Formula (I), or the formulae set forth below, can in fact exist in the form of any of the naturally occurring isotopes, with one or more of the most abundant isotopes being preferred.

[0052] For example, each individual hydrogen atom present in formula (I'), formula (I), or the formulae shown below may be: 1 H, 2 H (deuterium) or 3 H (tritium) atoms, preferably 1 H or 2 H. Similarly, by way of example, each individual carbon atom present in formula (I'), formula (I), or the formulae shown below may be present as: 11 C. 12 C. 13 C or 14 C atoms, preferably 12 C. Similarly, by way of example, each individual fluorine atom can be present as: 18 F or 19 It can exist as F.

[0053] Accordingly, the present invention also includes within its scope isotopically labeled compounds of formula (I).

[0054] Specific embodiments of the compounds of formula (I) according to the present invention are described below.

[0055] In one embodiment, Y is NR a Preferably, R a represents methyl.

[0056] In another embodiment, Y is CR 1a R 1b Represents.

[0057] In the first embodiment, R 1a represents hydrogen. In a particular aspect of this embodiment, R 1a represents deuterium. In a second embodiment, R 1a represents hydroxyl. In a third embodiment, R 1a represents a halogen. In one aspect of this embodiment, R 1a represents fluoro. In a fourth embodiment, R 1a is an optionally substituted C 1~4 In one aspect of this embodiment, R 1a represents optionally substituted methyl. In another aspect of this embodiment, R 1a represents deuterated methyl. In a fifth embodiment, R 1a is an optionally substituted C 1~4 In one aspect of this embodiment, R 1a represents optionally substituted methoxy.

[0058] In the first embodiment, R 1b represents hydrogen. In a particular aspect of this embodiment, R 1b represents deuterium. In a second embodiment, R 1b represents hydroxyl. In a third embodiment, R 1b represents a halogen. In one aspect of this embodiment, R 1a represents fluoro. In a fourth embodiment, R 1b is an optionally substituted C 1~4 In one aspect of this embodiment, R 1b represents optionally substituted methyl. In another aspect of this embodiment, R1a represents deuterated methyl. In a fifth embodiment, R 1b is an optionally substituted C 1~4 In one aspect of this embodiment, R 1b represents optionally substituted methoxy.

[0059] R 1a and R 1b Typical examples of the above substituents are C 1~4 In one embodiment, R 1a and R 1b Typical examples of the above substituents include C 1~4 In a further embodiment, R 1a and R 1b Typical examples of the above substituents include C 1~4 One substituent selected from alkoxy and hydroxyl is included.

[0060] R 1a and R 1b Particular examples of the above substituents include 1, 2, or 3 substituents independently selected from methoxy and hydroxyl. In one embodiment, R 1a and R 1b Particular examples of the above substituents include one or two substituents independently selected from methoxy and hydroxyl. In a further embodiment, R 1a and R 1b Typical examples of the above substituents include one substituent selected from methoxy and hydroxyl.

[0061] Preferably, R 1a is hydrogen, halogen, C 1~4 Alkyl, hydroxyl substituted C 1~4 Alkyl, C 1~4 Alkoxy-substituted C 1~4 Alkyl, or C 1~4 represents alkoxy.

[0062] Illustratively, R 1a represents hydrogen, deuterium, fluoro, hydroxyl, methyl, deuterated methyl (-CD3), hydroxymethyl, methoxymethyl, or methoxy.

[0063] Preferably, R 1b is hydrogen or C 1~4 Represents alkyl.

[0064] Illustratively, R 1b represents hydrogen or methyl.

[0065] In certain embodiments, R 1a ' is hydrogen, halogen, C 1~4 Alkyl, hydroxyl substituted C 1~4 Alkyl, C 1~4 Alkoxy-substituted C 1~4 Alkyl, or C 1~4 R represents alkoxy; 1b represents hydrogen.

[0066] In the first embodiment, A is A 1 In a second embodiment, A represents A 2 In a third embodiment, A represents A 3 In a fourth embodiment, A represents A 4 In a fifth embodiment, A represents A 5 In a sixth embodiment, A represents A 6 In a seventh embodiment, A represents A 7 Represents.

[0067] In one embodiment, Z 1 represents N. In another embodiment, Z 1 is CR 4 Represents.

[0068] In one embodiment, Z 2 represents N. In another embodiment, Z 2 is CR 5 Represents.

[0069] In one embodiment, Z 3represents N. In another embodiment, Z 3 is CR 6 Represents.

[0070] In one embodiment, Z 1 , Z 2 and Z 3 One of the letters represents N, or Z 1 , Z 2 and Z 3 None of these represent N.

[0071] In certain embodiments, Z 1 represents N, and Z 2 is CR 5 represents Z 3 is CR 6 Represents.

[0072] In another particular embodiment, Z 1 is CR 4 represents Z 2 represents N, and Z 3 is CR 6 '.

[0073] In further particular embodiments, Z 1 is CR 4 represents Z 2 is CR 5 represents Z 3 represents N.

[0074] In still further particular embodiments, Z 1 is CR 4 represents Z 2 is CR 5 represents Z 3 is CR 6 '.

[0075] In the first embodiment, R e represents hydrogen. In a second embodiment, R e represents a halogen. In one aspect of this embodiment, R e represents fluoro.

[0076] Preferably, R erepresents hydrogen or fluoro.

[0077] Typically, R e represents hydrogen.

[0078] In the first embodiment, R 4 represents hydrogen. In a second embodiment, R 4 represents a halogen. In one aspect of this embodiment, R 4 represents chloro. In another aspect of this embodiment, R 4 represents fluoro. In a third embodiment, R 4 represents hydroxyl. In a fourth embodiment, R 4 represents cyano. In a fifth embodiment, R 4 represents amino. In a sixth embodiment, R 4 is an optionally substituted C 1~4 In one aspect of this embodiment, R 4 represents optionally substituted methyl. In another aspect of this embodiment, R 4 represents optionally substituted ethyl. In a seventh embodiment, R 4 is an optionally substituted C 3~7 In one aspect according to this embodiment, R 4 represents an optionally substituted cyclopropyl. In an eighth embodiment, R 4 is an optionally substituted C 1~4 In one aspect according to this embodiment, R 4 represents optionally substituted methoxy. In another aspect according to this embodiment, R 4 represents optionally substituted ethoxy.

[0079] R 4 Typical examples of the above substituents include halogen, hydroxyl, and C 1~4 alkoxy.

[0080] R 4Particular examples of the above substituents include one, two or three groups selected from fluoro, hydroxyl and methoxy.

[0081] Preferably, R 4 is hydrogen, halogen, cyano, amino, C 1~4 Alkyl, C 1~4 Alkoxy, C substituted with one, two or three halogens or hydroxyl 1~4 Alkyl or one, two or three C 1~4 Alkoxy-substituted C 1~4 represents alkoxy.

[0082] Illustratively, R 4 represents hydrogen, chloro, fluoro, cyano, hydroxyl, amino, methyl, ethyl, difluoromethyl, hydroxymethyl, cyclopropyl, methoxy, ethoxy, or (methoxy)ethoxy.

[0083] In the first embodiment, R 5 represents hydrogen. In a second embodiment, R 5 represents a halogen. In one aspect of this embodiment, R 5 represents fluoro. In a third embodiment, R 5 represents cyano. In a fourth embodiment, R 5 is an optionally substituted C 1~4 In one aspect of this embodiment, R 5 represents optionally substituted methyl. In a fifth embodiment, R 5 is an optionally substituted C 1~4 In one aspect according to this embodiment, R 5 represents optionally substituted methoxy.

[0084] Preferably, R 5 is hydrogen, halogen, cyano, C 1~4 Alkyl or C 1~4 represents alkoxy.

[0085] Illustratively, R 5represents hydrogen, fluoro, cyano, methyl or methoxy.

[0086] In the first embodiment, R 6 represents hydrogen. In a second embodiment, R 6 represents a halogen. In one aspect of this embodiment, R 6 represents fluoro. In another aspect of this embodiment, R 6 represents chloro. In a third embodiment, R 6 represents cyano. In a fourth embodiment, R 6 is an optionally substituted C 1~4 In one aspect of this embodiment, R 6 represents optionally substituted methyl. In a fifth embodiment, R 6 is C 1~4 In one aspect according to this embodiment, R 6 represents methoxy. In a sixth embodiment, R 6 is an optionally substituted C 1~4 In one aspect of this embodiment, R 6 represents methylamino. In another aspect of this embodiment, R 6 represents methoxyethyl(methyl)amino. In a further aspect of this embodiment, R 6 represents (dimethylamino)ethyl-methyl-amino. In a seventh embodiment, R 6 is an optionally substituted C 3~7 In one aspect of this embodiment, R 6 represents an optionally substituted azetidinyl. In another aspect of this embodiment, R 6 represents an optionally substituted piperazinyl. In a further aspect of this embodiment, R 6 represents an optionally substituted morpholino. In a still further aspect of this embodiment, R 6 represents an optionally substituted pyrrolidinyl. In a still further aspect of this embodiment, R 6 represents an optionally substituted azaspirohexanyl. In a still further aspect of this embodiment, R 6represents an optionally substituted azaspiroheptanyl. In another aspect of this embodiment, R 6 represents an optionally substituted azabicyclohexanyl. In yet another aspect of this embodiment, R 6 represents an optionally substituted azabicycloheptanyl. In an alternative aspect of this embodiment, R 6 represents an optionally substituted oxa-azaspiroheptanyl. In a further alternative aspect of this embodiment, R 6 represents an optionally substituted oxa-azaspirooctanyl. In an eighth embodiment, R 6 is an optionally substituted -O-(C 3~7 In one aspect of this embodiment, R 6 represents an optionally substituted (azetidinyl)oxy.

[0087] R 6 Typical examples of the above substituents are halogen, hydroxyl, oxo, C 1~4 Alkyl carboxyhydroxy, and C 1~4 Examples of alkyl include:

[0088] R 6 Particular examples of the above substituents include fluoro, chloro, hydroxyl, oxo, (methyl)carboxy and methyl.

[0089] Typically, R 6 is hydrogen, chloro, fluoro, cyano, C 1~4 Alkoxy, C 1~4 Alkylamino, C 1~4 Alkyl, C 1~4 Alkoxy, 1, 2 or 3 C 1~4 C substituted with alkylcarboxy or hydroxy 1~4 Alkyl, oxo, halogen and C 1~4 C substituted with one, two or three substituents selected from alkyl 3~7 Heterocycloalkyl, or O-(C 3~7 Heterocycloalkyl) typically represents C 1~4 Alkyl or C3~7 When heterocycloalkyl are substituted, these groups are substituted with one or two substituents, most typically one substituent.

[0090] Preferably, R 6 represents hydrogen, chloro, fluoro, cyano, methoxy, methylamino, methyl, (hydroxy)methyl, (methylcarboxy)methyl, (oxo)(methyl)piperazinyl, (difluoro)azetidinyl, azaspirohexanyl, azabicycloheptanyl, (difluoro)azaspirohexanyl, morpholino, (hydroxymethyl)azetidinyl, (fluoroazetidinyl), (methyl)(hydroxyl)azetidinyl, (fluoro)pyrrolidinyl, (difluoro)pyrrolidinyl, (hydroxyl)pyrrolidinyl, (difluoro)azaspiroheptanyl, oxa-azaspirooctanyl, oxa-azaspiroheptanyl, (fluoro)(methyl)azetidinyl, (difluoro)azabicyclohexanyl, (difluoro)azabicycloheptanyl, (methyl)azetidinyl or (azetidinyl)oxy.

[0091] In the first embodiment, R 7 represents hydrogen. In a second embodiment, R 7 is an optionally substituted C 1~4 In one aspect of this embodiment, R 7 represents optionally substituted methyl. In another aspect of this embodiment, R 7 represents optionally substituted ethyl. In a third embodiment, R 7 is an optionally substituted C 3~7 In one aspect of this embodiment, R 7 represents an optionally substituted cyclopropyl.

[0092] Preferably, R 7 is hydrogen, C 1~4 Alkyl, or C 3~7 represents cycloalkyl.

[0093] Illustratively, R 7represents hydrogen, methyl, ethyl, or cyclopropyl.

[0094] In one embodiment, R 8 is hydrogen or halogen; or C 1~4 Alkyl or C 1~4 In another embodiment, R represents alkoxy (any of these groups may be optionally substituted with one or more substituents). 9 is hydrogen or halogen; or C 1~4 Alkyl or C 3~7 In a further embodiment, R represents cycloalkyl (any of these groups may be optionally substituted with one or more substituents). 10 is hydrogen or halogen; or C 1~4 It represents alkyl, which may be optionally substituted with one or more substituents.

[0095] In certain embodiments, R 8 is 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); R 9 is hydrogen or halogen; or C 1~4 Alkyl or C 3~7 cycloalkyl (any of these groups may be optionally substituted with one or more substituents); R 10 is hydrogen or halogen; or C 1~4 It represents alkyl, which may be optionally substituted with one or more substituents.

[0096] In the first embodiment, R 8 represents hydrogen. In a second embodiment, R 8 represents a halogen. In a third embodiment, R 8 is an optionally substituted C 1~4 In one aspect of this embodiment, R 8 represents optionally substituted methyl. In a fourth embodiment, R 8 is an optionally substituted C1~4 In one aspect of this embodiment, R 8 represents optionally substituted methoxy.

[0097] Preferably, R 8 is hydrogen, C 1~4 Alkyl or C 1~4 represents alkoxy.

[0098] Illustratively, R 8 represents hydrogen, methyl or methoxy.

[0099] In the first embodiment, R 9 represents hydrogen. In a second embodiment, R 9 represents a halogen. In one aspect according to this embodiment, R 9 represents fluoro. In a third embodiment, R 9 is an optionally substituted C 1~4 In one aspect of this embodiment, R 9 represents optionally substituted methyl. In a fourth embodiment, R 9 is an optionally substituted C 3~7 In one aspect of this embodiment, R 9 represents an optionally substituted cyclopropyl.

[0100] Preferably, R 9 is hydrogen, halogen, C 1~4 Alkyl or C 3~7 represents cycloalkyl.

[0101] Illustratively, R 9 represents hydrogen, fluoro, methyl or cyclopropyl.

[0102] In the first embodiment, R 10 represents hydrogen. In a second embodiment, R 10 represents a halogen. In one aspect according to this embodiment, R 10 represents fluoro. In a third embodiment, R 10 is an optionally substituted C 1~4 Represents alkyl.

[0103] Preferably, R 10 represents hydrogen or halogen.

[0104] Illustratively, R 10 represents hydrogen or fluoro.

[0105] In general, R 11 Ha-NR c -(CO)-R b Represents.

[0106] Preferably, R b is C 1~4 Illustratively, R represents alkyl. b represents methyl.

[0107] Preferably, R c is C 1~4 Illustratively, R represents alkyl. c represents methyl.

[0108] Illustratively, R 11 represents (methylcarbonyl)(methyl)amino.

[0109] In the first embodiment, B is B 1 In a second embodiment, B represents B 2 In a third embodiment, B represents B 3 In a fourth embodiment, B represents B 4 In a fifth embodiment, B represents B 5 In a sixth embodiment, B represents B 6 In a seventh embodiment, B represents B 7 In an eighth embodiment, B represents B 8 Represents.

[0110] In one embodiment, W represents N. In another embodiment, W represents CH.

[0111] In one embodiment, U 1 represents N. In another embodiment, U 1 represents CH.

[0112] In one embodiment, U 2 represents N. In another embodiment, U 2 represents CH.

[0113] In one embodiment, Z 4 represents N. In another embodiment, Z 4 is CR 13 Represents.

[0114] In one embodiment, Z 5 represents N. In another embodiment, Z 5 is CR 14 Represents.

[0115] In one embodiment, Z 6 represents N. In another embodiment, Z 6 is CR 15 Represents.

[0116] In one embodiment, Z 7 represents N. In another embodiment, Z 7 is CR 16 Represents.

[0117] In one embodiment, Z 4 , Z 5 , Z 6 and Z 7 Either none of these represent N or Z 4 , Z 5 , Z 6 and Z 7 One or two of these represent N. Typically, Z 4 , Z 5 , Z 6 and Z 7 none of the above represents N, or Z 4 , Z 5 , Z 6 and Z 7 One of them represents N.

[0118] In certain embodiments, Z 4 represents N, and Z 5 is CR 1 represents Z 6 is CR15 represents Z 7 is CR 16 Represents.

[0119] In another particular embodiment, Z 4 is CR 13 represents Z 5 represents N, and Z 6 is CR 15 represents Z 7 is CR 16 Represents.

[0120] In further particular embodiments, Z 4 is CR 13 represents Z 5 is CR 14 represents Z 6 represents N, and Z 7 is CR 16 Represents.

[0121] In still further particular embodiments, Z 4 is CR 13 represents Z 5 is CR 14 represents Z 6 is CR 15 represents Z 7 represents N.

[0122] In yet another more particular embodiment, Z 4 is CR 1 represents Z 5 is CR 14 represents Z 6 is CR 15 represents Z 7 is CR 16 Represents.

[0123] In an alternative particular embodiment, Z 4 is CR 13 represents Z 5 represents N, and Z 6 is CR 15 represents Z 7 represents N.

[0124] In further alternative specific embodiments, Z4 is CR 13 represents Z 5 is CR 14 represents Z 6 represents N, and Z 7 represents N.

[0125] In the first embodiment, R 13 represents hydrogen. In a second embodiment, R 13 represents a halogen. In one aspect according to this embodiment, R 13 represents fluoro. In another aspect according to this embodiment, R 13 represents chloro.

[0126] Illustratively, R 13 represents hydrogen, fluoro or chloro.

[0127] In the first embodiment, R 14 represents hydrogen. In a second embodiment, R 14 represents a halogen. In one aspect according to this embodiment, R 14 represents fluoro. In another aspect according to this embodiment, R 14 represents chloro. In a third embodiment, R 14 is C 1~4 In one aspect according to this embodiment, R 14 represents methoxy.

[0128] Illustratively, R 14 represents hydrogen, fluoro, chloro or methoxy.

[0129] In the first embodiment, R 15 represents hydrogen. In a second embodiment, R 15 represents a halogen. In one aspect according to this embodiment, R 15 represents fluoro. In another aspect according to this embodiment, R 15 represents chloro. In a third embodiment, R 15 is C 1~4 In one aspect according to this embodiment, R 15 represents methyl.

[0130] Illustratively, R 15 represents hydrogen, fluoro, chloro or methyl.

[0131] In the first embodiment, R 16 represents hydrogen. In a second embodiment, R 16 represents a halogen. In one aspect according to this embodiment, R 16 represents fluoro. In another aspect according to this embodiment, R 16 represents chloro. In a third embodiment, R 16 represents cyano. In a fourth embodiment, R 16 is an optionally substituted C 1~4 In one aspect according to this embodiment, R 16 represents optionally substituted methyl.

[0132] R 16 Typical examples of the above optional substituents include hydroxy.

[0133] Illustratively, R 16 represents hydrogen, fluoro, chloro, cyano or (hydroxy)methyl.

[0134] In one embodiment, T represents N. In another embodiment, T represents CR 17 Represents.

[0135] In the first embodiment, R 17 represents hydrogen. In a second embodiment, R 17 is C 1~4 In one aspect of this embodiment, R 17 represents methyl. In a third embodiment, R 17 represents a halogen. In one aspect of this embodiment, R 17 represents fluoro.

[0136] Illustratively, R 17 represents hydrogen, methyl or fluoro.

[0137] In the first embodiment, R 17In a second embodiment, R 17 ' is C 1~4 In one aspect of this embodiment, R 17 ' represents methyl. Illustratively, R 17 ' represents hydrogen or methyl.

[0138] In a first embodiment, Q is Q 1 In a second embodiment, Q represents Q 2 Represents.

[0139] In one embodiment, Z 8 represents N. In another embodiment, Z 8 is CR 3 Represents.

[0140] In one embodiment, Z 10 represents N. In another embodiment, Z 10 is CR 19 '.

[0141] In one embodiment, Z 8 and Z 10 One of the letters represents N, or Z 8 and Z 10 None of these represent N.

[0142] In certain embodiments, Z 8 is CR 3 represents Z 10 is CR 19 Represents.

[0143] In another particular embodiment, Z 8 represents N, and Z 10 is CR 19 Represents.

[0144] In further particular embodiments, Z 8 is CR 3 represents Z 10 represents N.

[0145] In one embodiment, Z 12 represents S. In another embodiment, Z12 is CR 21 R 22 In a further embodiment, Z 12 represents O. In yet another embodiment, Z 12 represents NH.

[0146] In one embodiment, Z 1 represents N. In another embodiment, Z 13 is CR 23 Represents.

[0147] In one embodiment, Z 14 represents N. In another embodiment, Z 14 ' is CR 24 Represents.

[0148] In a further embodiment, Z 12 represents S, O or NH; Z 13 is CR 23 represents Z 14 is CR 24 Represents.

[0149] In still further embodiments, Z 12 is CR 21 R 22 represents Z 13 represents N; Z 14 is CR 24 Represents.

[0150] In still further embodiments, Z 12 is CR 21 R 22 represents Z 13 is CR 23 represents Z 14 represents N.

[0151] In certain embodiments, Z 12 represents S, and Z 13 is CR 23 represents Z 14 is CR 24 Represents.

[0152] In more particular embodiments, Q is Q 3 , Q4 , Q 5 and Q 6 represents an optionally substituted ring selected from the group represented by: [ka]

[0153] (In the formula, X 1 is N or CR 3 represents; X 2 is N or CR 19 represents; X 3 is CR 19 represents; Two Xs 4 One of them is CR 20 represents the other X 4 represents CH; X 5 represents S; R 3 , R 19 and R 20 is as defined above).

[0154] In the first embodiment, R 2 represents a halogen. In a first aspect of this embodiment, R 2 In a second aspect of this embodiment, R 2 In a third aspect of this embodiment, R represents bromo. 2 represents iodo. In a fourth aspect of this embodiment, R 2 represents fluoro. In a second embodiment, R 2 represents cyano. In a third embodiment, R 2 is an optionally substituted C 1~4 In one aspect of this embodiment, R 2 represents optionally substituted methyl. In another aspect of this embodiment, R 2 represents optionally substituted ethyl. In a further embodiment, R 2 represents optionally substituted propyl. In a fourth embodiment, R 2is an optionally substituted C 3~7 In one aspect of this embodiment, R 2 represents an optionally substituted cyclopropyl. In a fifth embodiment, R 2 is an optionally substituted C 1~4 In one aspect of this embodiment, R 2 represents optionally substituted methoxy.

[0155] R 2 Typical examples of the above substituents include one, two or three halogens.

[0156] R 2 Particular examples of the above substituents include one, two or three fluoro.

[0157] Preferably, R 2 is a halogen, a cyano group optionally substituted with one or more halogens, 1~4 Alkyl, C optionally substituted with one or more halogens 3~7 cycloalkyl or C optionally substituted with one or more halogens 1~4 represents alkoxy.

[0158] In particular, R 2 is halogen, cyano, C optionally substituted with one or more halogens 1~4 Alkyl, C optionally substituted with one or more halogens 3~7 cycloalkyl or C optionally substituted with one or more halogens 1~4 represents alkoxy.

[0159] Illustratively, R 2 represents chloro, bromo, iodo, fluoro, cyano, methyl, difluoromethyl, trifluoromethyl, difluoroethyl, cyclopropyl, difluorocyclopropyl, methoxy, or difluoromethoxy.

[0160] In the first embodiment, R 3represents hydrogen. In a second embodiment, R 3 represents a halogen. In one aspect of this embodiment, R 3 represents chloro. In another aspect of this embodiment, R 3 represents fluoro. In a third embodiment, R 3 represents cyano. In a fourth embodiment, R 3 is an optionally substituted C 1~4 In one aspect of this embodiment, R 3 represents optionally substituted methyl.

[0161] Preferably, R 3 is hydrogen, halogen, cyano or C 1~4 Represents alkyl.

[0162] In particular, R 3 is hydrogen, halogen or C 1~4 Represents alkyl.

[0163] Illustratively, R 3 represents hydrogen, chloro, fluoro or methyl.

[0164] In certain embodiments, R 2 and R 3 taken together with the group to which they are attached form an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl. In one aspect according to this embodiment, R 2 and R 3 together with the group to which they are attached form an optionally substituted benzotriazolyl. In another aspect according to this embodiment, R 2 and R 3 together with the group to which they are attached form an optionally substituted indazolyl. In a further aspect according to this embodiment, R 2 and R 3 together with the group to which they are attached form an optionally substituted indanyl. In still a further aspect according to this embodiment, R 2 and R 3together with the group to which they are attached form an optionally substituted benzodioxolyl. In yet a further aspect according to this embodiment, R 2 and R 3 taken together with the group to which they are attached form an optionally substituted isoquinolyl.

[0165] Typical optional substituents on the cycloalkyl, heterocyclyl, aryl or heteroaryl include halogen and C optionally substituted with 1, 2 or 3 halogens. 1~4 Examples of alkyl include:

[0166] Suitable optional substituents on cycloalkyl, heterocyclyl, aryl, or heteroaryl include fluoro, chloro, and methyl optionally substituted with 1, 2, or 3 halogens.

[0167] Illustrative examples of optional substituents on cycloalkyl, heterocyclyl, aryl or heteroaryl include fluoro, chloro, methyl and difluoromethyl.

[0168] Preferably, R 2 and R 3 taken together with the group to which they are attached form (methyl)indazolyl, (difluoromethyl)indazolyl, (methyl)triazolyl, (difluoro)indanyl, (difluoro)benzodioxolyl, (fluoro)isoquinolyl or (chloro)isoquinolyl.

[0169] In the first embodiment, R 18 represents hydrogen. In a second embodiment, R 18 represents a halogen. In one aspect of this embodiment, R 18 represents fluoro. In a third embodiment, R 18 is C 1~4 In one aspect of this embodiment, R 18 represents methyl.

[0170] Preferably, R18 represents hydrogen or fluoro.

[0171] In the first embodiment, R 19 represents hydrogen. In a second embodiment, R 19 represents a halogen. In one aspect of this embodiment, R 19 represents fluoro. In a third embodiment, R 19 is C 1~4 In one aspect of this embodiment, R 19 represents methyl.

[0172] Preferably, R 19 represents hydrogen or fluoro.

[0173] In the first embodiment, R 20 represents hydrogen. In a second embodiment, R 20 represents a halogen. In one aspect of this embodiment, R 20 represents chloro. In another aspect of this embodiment, R 20 represents fluoro. In a third embodiment, R 20 is an optionally substituted C 1~4 In one aspect of this embodiment, R 20 represents optionally substituted methyl.

[0174] Preferably, R 20 is hydrogen, halogen, or C 1~4 Represents alkyl.

[0175] In particular, R 20 represents hydrogen or halogen.

[0176] Illustratively, R 20 represents hydrogen or fluoro.

[0177] In the first embodiment, R 21 represents hydrogen. In a second embodiment, R 21 represents a halogen. In one aspect of this embodiment, R 21 represents fluoro. In a third embodiment, R 21 is C1~4 In one aspect of this embodiment, R 21 represents methyl.

[0178] Preferably, R 21 represents hydrogen or fluoro.

[0179] In the first embodiment, R 22 represents hydrogen. In a second embodiment, R 22 represents a halogen. In one aspect of this embodiment, R 22 represents fluoro. In a third embodiment, R 22 is C 1~4 In one aspect of this embodiment, R 22 represents methyl.

[0180] Preferably, R 22 represents hydrogen or fluoro.

[0181] In the first embodiment, R 23 represents hydrogen. In a second embodiment, R 23 represents a halogen. In one aspect of this embodiment, R 23 represents fluoro. In a third embodiment, R 23 is C 1~4 In one aspect of this embodiment, R 23 represents methyl.

[0182] Preferably, R 23 represents hydrogen or fluoro.

[0183] In the first embodiment, R 24 represents hydrogen. In a second embodiment, R 24 represents a halogen. In one aspect of this embodiment, R 24 represents fluoro. In a third embodiment, R 24 is C 1~4 In one aspect of this embodiment, R 24 represents methyl.

[0184] Preferably, R 24 represents hydrogen or fluoro.

[0185] In a first particular embodiment, Y is NR a or CR 1a R 1b represents;R a represents methyl; R 1a is hydrogen, halogen, C 1~4 Alkyl, hydroxyl substituted C 1~4 Alkyl, C 1~4 Alkoxy-substituted C 1~4 Alkyl, or C 1~4 R represents alkoxy; 1b is hydrogen or C 1~4 represents alkyl; A is the point of attachment to the rest of the molecule, V 3 and V 4 Together with A 1 , A 2 , A 3 , A 4 , A 5 , A 6 and A 7 Z represents an optionally substituted aryl or heteroaryl selected from the group represented by 1 is N or CR 4 represents Z 2 is N or CR 5 represents Z 3 is N or CR 6 represents Z 1 , Z 2 and Z 3 One of the letters represents N, or Z 1 , Z 2 and Z 3 None of the above represents N; R e represents hydrogen or fluoro; R 4 is hydrogen, halogen, cyano, amino, C 1~4 Alkyl, C 1~4 Alkoxy, C substituted with one, two or three halogens or hydroxyl 1~4 Alkyl or one, two or three C 1~4 Alkoxy-substituted C 1~4 R represents alkoxy; 5 is hydrogen, halogen, cyano, C 1~4Alkyl or C 1~4 R represents alkoxy; 6 is hydrogen, chloro, cyano, C 1~4 Alkoxy, C 1~4 Alkylamino, C 1~4 Alkyl, C 1~4 Alkoxy, 1, 2 or 3 C 1~4 C substituted with alkylcarboxy or hydroxy 1~4 Alkyl, oxo, halogen and C 1~4 C substituted with one, two or three substituents selected from alkyl 3~7 Heterocycloalkyl, or O-(C 3~7 heterocycloalkyl); R 7 is hydrogen, C 1~4 Alkyl, or C 3~7 R represents cycloalkyl; 8 is hydrogen, C 1~4 Alkyl or C 1~4 R represents alkoxy; 9 is hydrogen, halogen, C 1~4 Alkyl or C 3~7 R represents cycloalkyl; 10 represents hydrogen or halogen; R 11 Ha-NR c -(CO)-R b represents;R b is C 1~4 R represents alkyl; c is C 1~4 represents alkyl; B is the point of attachment to the rest of the molecule, V 1 and V 2 Together with B 1 , B 2 , B 3 , B 4 , B 5 , B 6 , B 7 and B 8 represents an optionally substituted aryl or heteroaryl selected from the group represented by 1 is B 1 , B 2 , B 3 , B 4 , B 5 , B 6 and B7 represents C, and B 8 For N, represent V 2 is B 1 , B 2 , B 4 , B 6 , B 7 and B 8 represents C, and B 3 and B 5 For N, W, U 1 and U 2 each independently represents N or CH; Z 4 is N or CR 13 represents Z 5 is N or CR 14 represents Z 6 is N or CR 15 represents Z 7 is N or CR 16 represents Z 4 , Z 5 , Z 6 and Z 7 none of the above represents N, or Z 4 , Z 5 , Z 6 and Z 7 one of the groups represents N; T is N or CR 17 represents;R 12 represents hydrogen; R 13 represents hydrogen or halogen; R 14 is hydrogen, halogen or C 1~4 R represents alkoxy; 15 is hydrogen, halogen or C 1~4 R represents alkyl; 16 is hydrogen, halogen, cyano or optionally substituted C 1~4 R represents alkyl; 17 is hydrogen, halogen or C 1~4 R represents alkyl; 17 ' is hydrogen or C 1~4 represents alkyl; Q represents Q 1 and Q 2 represents a ring selected from the group represented by 8 is N or CR 3 represents Z 9 is CR 18 represents Z10 is N or CR 19 represents Z 11 is CR 20 represents Z 8 and Z 10 One of the letters represents N, or Z 8 and Z 10 None of these represent N; Z 12 represents S, and Z 13 is CR 23 represents Z 14 is CR 24 represents;R 2 is a halogen, a cyano group optionally substituted with one or more halogens, 1~4 Alkyl, C optionally substituted with one or more halogens 3~7 cycloalkyl or C optionally substituted with one or more halogens 1~4 R represents alkoxy; 3 is hydrogen, halogen, cyano or C 1~4 represents alkyl; or R 2 and R 3 together with the groups to which they are attached form indazolyl, indazolyl, triazolyl, indanyl, benzodioxolyl, isoquinolyl or isoquinolyl; R 18 represents hydrogen or fluoro; R 19 represents hydrogen or fluoro; R 20 represents hydrogen or halogen; R 23 represents hydrogen or fluoro; R 24 represents hydrogen or fluoro.

[0186] In more particular embodiments, Y is NR a or CR 1a R 1b represents;R a represents methyl; R 1a represents hydrogen, deuterium, fluoro, hydroxyl, methyl, deuterated methyl (-CD3), hydroxymethyl, methoxymethyl, or methoxy; R 1b represents hydrogen or methyl; A is the point of attachment to the rest of the molecule, V 3 and V 4 Together with A1 , A 2 , A 3 , A 4 , A 5 , A 6 and A 7 Z represents an optionally substituted aryl or heteroaryl selected from the group represented by 1 is N or CR 4 represents Z 2 is N or CR 5 ' and Z 3 is N or CR 6 represents Z 1 , Z 2 and Z 3 One of the letters represents N, or Z 1 , Z 2 and Z 3 None of the above represents N; R e represents hydrogen or fluoro; R 4 represents hydrogen, chloro, fluoro, cyano, hydroxyl, amino, methyl, ethyl, difluoromethyl, hydroxymethyl, cyclopropyl, methoxy, ethoxy, or (methoxy)ethoxy; R 5 represents hydrogen, fluoro, cyano, methyl, or methoxy; R 6 represents hydrogen, chloro, fluoro, cyano, methoxy, methylamino, methyl, (hydroxy)methyl, (methylcarboxy)methyl, (oxo)(methyl)piperazinyl, (difluoro)azetidinyl, azaspirohexanyl, azabicycloheptanyl, (difluoro)azaspirohexanyl, morpholino, (hydroxymethyl)azetidinyl, (fluoroazetidinyl), (methyl)(hydroxyl)azetidinyl, (fluoro)pyrrolidinyl, (difluoro)pyrrolidinyl, (hydroxyl)pyrrolidinyl, (difluoro)azaspiroheptanyl, oxa-azaspirooctanyl, oxa-azaspiroheptanyl, (fluoro)(methyl)azetidinyl, (difluoro)azabicyclohexanyl, (difluoro)azabicycloheptanyl, (methyl)azetidinyl, or (azetidinyl)oxy; R 7 represents hydrogen, methyl, ethyl, or cyclopropyl; R 8 represents hydrogen, methyl or methoxy; R9 represents hydrogen, fluoro, methyl or cyclopropyl; R 10 represents hydrogen or fluoro; R 11 Ha-NR c -(CO)-R b represents;R b represents methyl; R c represents methyl; B is the point of attachment to the rest of the molecule, V 1 and V 2 Together with B 1 , B 2 , B 3 , B 4 , B 5 , B 6 , B 7 and B 8 represents an optionally substituted aryl or heteroaryl selected from the group represented by 1 is B 1 , B 2 , B 3 , B 4 , B 5 , B 6 and B 7 represents C, and B 8 For N, represent V 2 is B 1 , B 2 , B 4 , B 6 , B 7 and B 8 represents C, and B 3 and B 5 For N, W, U 1 and U 2 each independently represents N or CH; Z 4 is N or CR 13 represents Z 5 is N or CR 14 represents Z 6 is N or CR 15 represents Z 7 is N or CR 16 represents Z 4 , Z 5 , Z 6 and Z 7 Either none of these represent N or Z 4 , Z 5 , Z6 and Z 7 one or two of the groups represent N; T represents N or CR 17 represents;R 12 represents hydrogen; R 13 represents hydrogen, fluoro or chloro; R 14 represents hydrogen, fluoro, chloro or methoxy; R 15 represents hydrogen, fluoro, chloro or methyl; R 16 represents hydrogen, fluoro, chloro, cyano or (hydroxy)methyl; R 17 represents hydrogen, methyl or fluoro; R 17 ' represents hydrogen or methyl; Q represents Q 3 , Q 4 , Q 5 and Q 6 represents an optionally substituted ring selected from the group represented by 1 is N or CR 3 represents ;X 2 is N or CR 19 represents ;X 3 is CR 19 Two X's 4 One of them is CR 20 represents the other X 4 represents CH; X 5 represents S; R 2 represents chloro, bromo, iodo, fluoro, cyano, methyl, difluoromethyl, trifluoromethyl, difluoroethyl, cyclopropyl, difluorocyclopropyl, methoxy, or difluoromethoxy; R 3 represents hydrogen, chloro, fluoro, or methyl; or R 2 and R 3 together with the groups to which they are attached form (methyl)indazolyl, (difluoromethyl)indazolyl, (methyl)triazolyl, (difluoro)indanyl, (difluoro)benzodioxolyl, (fluoro)isoquinolyl and (chloro)isoquinolyl; R 19 represents hydrogen or fluoro; R 20 represents hydrogen or fluoro.

[0187] In a first particular embodiment, the present invention relates to a particular subclass of compounds of formula (I) represented by formula (IA): [ka]

[0188] (In the formula, Q, Y, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 is as defined above). In a particular aspect of this embodiment, the present invention relates to a particular subclass of compounds of formula (IA) represented by formula (IA-a): [ka]

[0189] (In the formula, X, Y, R 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 is as defined above).

[0190] In a second particular embodiment, the present invention relates to a particular subclass of compounds of formula (I) represented by formula (IB): [ka]

[0191] (In the formula, Q, Y, Z 4 , Z 5 , Z 6 , Z 7 , R 7 and R 8 is as defined above).

[0192] In a particular aspect of this embodiment, the present invention relates to a particular subclass of compounds of formula (IB) represented by formula (IB-a): [ka]

[0193] (In the formula, X 1 , Y, Z 4 , Z 5 , Z 6 , Z 7 , R 2 , R 7 and R 8 is as defined above).

[0194] In a third particular embodiment, the present invention relates to a particular subclass of compounds of formula (I) represented by formula (IC): [ka]

[0195] (In the formula, Q, Y, Z 4 , Z 5 , Z 6 , Z 7 , R 7 and R 9 is as defined above).

[0196] In a particular aspect of this embodiment, the present invention relates to a particular subclass of compounds of formula (IC) represented by formula (IC-a): [ka]

[0197] (In the formula, X, Y, Z 4 , Z 5 , Z 6 , Z 7 , R 2 , R 7 and R 9 is as defined above).

[0198] In a fourth particular embodiment, the present invention relates to a particular subclass of compounds of formula (I) represented by formula (ID): [ka]

[0199] (In the formula, Q, Y, Z 1 , Z 2 , Z 3 , and T is as defined above).

[0200] In a particular aspect of this embodiment, the present invention relates to a particular subclass of compounds of formula (ID) represented by formula (ID-a): [ka]

[0201] (In the formula, X, Y, R 2 , Z 1 , Z 2 , Z 3 , and T is as defined above).

[0202] In a fifth particular embodiment, the present invention relates to a particular subclass of compounds of formula (I) represented by formula (IE): [ka]

[0203] (In the formula, Q, Y, Z 1 , Z 2 , Z 3 , and W is as defined above).

[0204] In a particular aspect of this embodiment, the present invention relates to a particular subclass of compounds of formula (IE) represented by formula (IE-a): [ka]

[0205] (In the formula, X, Y, R 2 , Z 1 , Z 2 , Z 3 , and W is as defined above).

[0206] 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.

[0207] Thus, in certain aspects, the present invention relates to compounds of formula (I) as set out in the accompanying Examples 1-424.

[0208] In a most particular embodiment, the present invention relates to a subclass of compounds of formula (I) represented by formula (IF): [ka]

[0209] (In the formula, R 1a , R 2 ' R 4 , R 6 and R 17 is as defined above). In compounds of formula (IF), typically: R 1a is methyl or hydroxyl; R 2 is difluoromethyl or difluoroethyl; R 4 is hydrogen, chloro or fluoro; R 6 is methyl; R 17 is hydrogen or fluoro.

[0210] In a further most particular embodiment, the present invention relates to a subclass of compounds of formula (I) represented by formula (IG): [ka]

[0211] (In the formula, R 1a , R 2 , R 4 R 6 and R 14 is as defined above). In compounds of formula (IG), typically: R 1a is methyl or hydroxyl; R 2 is difluoromethyl or difluoroethyl; R 4 is hydrogen, chloro or fluoro; R 6 is methyl; R 14 is hydrogen or fluoro.

[0212] In a still further most particular embodiment, the present invention relates to a subclass of compounds of formula (I) represented by formula (IH): [ka]

[0213] (In the formula, R 1a , R 2 , R 4 , R 6 and R 14 is as defined above). In compounds of formula (IH), typically: R 1a is methyl or hydroxyl; R 2 is difluoromethyl or difluoroethyl; R 4 is hydrogen, chloro or fluoro; R 6 is methyl; R 14 is hydrogen or fluoro.

[0214] In a still further most particular embodiment, the present invention relates to a subclass of compounds of formula (I) represented by formula (IJ): [ka]

[0215] (In the formula, R 1a , R 2 , R 5 R 6 and R 14 is as defined above). In compounds of formula (IJ), typically: R 1a is methyl or hydroxyl; R 2 is difluoromethyl or difluoroethyl; R 5 is cyano; R 6 is methyl; R 14 is hydrogen or fluoro.

[0216] In another most particular embodiment, the present invention relates to a subclass of compounds of formula (I) represented by formula (IK): [ka]

[0217] (In the formula, R 2 , R 4 and R 6 is as defined above). In compounds of formula (IK'), typically: R 2 is difluoromethyl or difluoroethyl; R 4 is hydrogen, chloro or fluoro; R 6 is 2,2-difluoro-5-azaspiro[2.3]hexan-5-yl.

[0218] In yet another most particular embodiment, the present invention relates to a subclass of compounds of formula (I) represented by formula (IL): [ka]

[0219] (In the formula, R 1a , R 2 , R 7 and R 6 is as defined above). In compounds of formula (IL), typically: R 1a is methyl or hydroxyl; R 2 is difluoromethyl or trifluoromethyl; R 7 is hydrogen or methyl; R 6 is methyl.

[0220] In yet another most particular embodiment, the present invention relates to a subclass of compounds of formula (I) represented by formula (IM): [ka]

[0221] (In the formula, R 1a , R 2 , R 7 and R 9 is as defined above). In compounds of formula (IM), typically: R 1a is methyl or hydroxyl; R 2 is difluoromethyl or trifluoromethyl; R 7 is hydrogen or methyl; R 9 is methyl.

[0222] The compound is represented by formula (IF), formula (IG), formula (IH), formula (IJ), formula (IK), formula (IL), or formula (IM), and R 2 In one aspect of the most particular embodiment, R is difluoroethyl. 2 is specifically -CF2CH3.

[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 a system Xc - The present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases and / or disorders in which β-actin plays a role.

[0225] In the following embodiment, the compound of formula (I) as defined above is represented by the system Xc - It may be an inhibitor of the antiporter.

[0226] In a first aspect, the present invention provides a system Xc - System Xc plays a role in cancer treatment - The present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in epilepsy syndromes in which steroids play a role, or in cancer therapy resistance.

[0227] In a first embodiment according to this aspect, the present invention provides a system Xc - The present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in which is plays a role.

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

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

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

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

[0233] In a second aspect, the present invention provides a system Xc - There is provided the use of a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment of diseases and / or disorders 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 manufacture of a medicament useful in the treatment of cancer in which system Xc- plays a role.

[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 manufacture of a medicament useful for 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.

[0236] In a second embodiment according to this aspect, the present invention provides a system Xc - The present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, for the manufacture of a medicament useful in the treatment of epilepsy syndromes in which β-glucanase plays a role.

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

[0238] In a third embodiment according to this aspect, the present invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in treating cancer therapy 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 manufacture of a medicament useful for the treatment of multidrug resistance in some cancer types. - The present invention provides a method for treating a disorder in which administration of an inhibitor of the formula (I) is indicated, which method comprises the step of 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 system Xc - The present invention provides a method for treating cancer in which is plays a role, which method comprises the step of 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 carcinoma, 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 present invention provides a system Xc - The present invention provides a method for treating epilepsy syndromes in which steroid hormone plays a role, which method comprises the step of 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 seizures, glioma-associated 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 cancer therapy resistance, 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 some cancer types, 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. As used herein, the term "patient" refers to a patient in need of such treatment. - The term "subject" refers to a mammal suffering from one or more disorders associated with the function or expression of a gene or gene product. It will be understood that the most preferred subject is a human.

[0245] It is also recognized that one skilled in the art can affect a disorder by treating a patient currently suffering from the disorder or by prophylactically treating a patient suffering from the disorder with an effective amount of a compound of Formula (I). Accordingly, the terms "treatment" and "treating" are intended to refer to any process by which there may be a slowing, interrupting, suppressing, controlling, or halting the progression of the disorders described herein, and are intended to include prophylactic treatment of such disorders, but do not necessarily indicate a complete elimination of all disorder symptoms.

[0246] Activity in any of the above therapeutic indications or disorders can, of course, be determined by conducting appropriate clinical trials for the particular indication and / or in a manner known to those skilled in the art in clinical trial design in general.

[0247] For use in medicine, the salts of the compounds of formula (I) are pharmaceutically acceptable salts. However, other salts may be useful in the preparation of the compounds used in the present invention or their pharmaceutically acceptable salts. Standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use, editors P.H. Stahl & C.G. Wermuth, Wiley-VCH, 2002. Suitable pharmaceutically acceptable salts of the compounds of formula (I) include, for example, acid addition salts that can be formed by mixing a solution of the compound of formula (I) with a solution of a pharmaceutically acceptable acid.

[0248] The present invention includes within its scope solvates of the compounds of formula (I) above. Such solvates may be formed using common organic solvents or water.

[0249] The present invention also includes within its scope co-crystals of compounds of formula (I) above. The term "co-crystal" is used to describe a situation in which neutral molecular components are present in a crystalline compound in a well-defined stoichiometric ratio. The preparation of pharmaceutical co-crystals allows for modifications to the crystalline form of an active pharmaceutical ingredient, altering its physicochemical properties without impairing its intended biological activity (see Pharmaceutical Salts and Co-crystals, editors J. Wouters & L. Quere, RSC Publishing, 2012).

[0250] Compounds according to the present invention may exist in different polymorphic forms, and although not explicitly indicated in the above formula, such forms are intended to be included within the scope of the present invention.

[0251] The present invention also includes within its scope prodrug forms of compounds of formula (I) and various subranges and subgroups thereof.

[0252] To treat a disease, the compounds of formula (I) or their pharmaceutically acceptable salts are used in an effective daily dosage and may be administered in the form of a pharmaceutical composition.

[0253] Therefore, another embodiment of the present invention relates to a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier.

[0254] To prepare pharmaceutical compositions according to the present invention, one or more of the compounds of formula (I) or pharmaceutically acceptable salts thereof are intimately admixed with a pharmaceutical diluent or carrier according to conventional pharmaceutical compounding techniques known to those skilled in the art.

[0255] Suitable diluents and carriers can take a wide variety of forms depending on the desired route of administration, for example oral, rectal, parenteral, intranasal, or intratumor.

[0256] Pharmaceutical compositions containing compounds according to the invention can be administered, for example, orally, parenterally, ie, intravenously, intramuscularly or subcutaneously, intrathecally, by inhalation, intranasally or ocular administration.

[0257] Pharmaceutical compositions suitable for oral administration may be solid or liquid and may, for example, be in the form of tablets, pills, dragees, gelatin capsules, liquids, syrups, chewing gum, or the like.

[0258] For this purpose, the active ingredient may be mixed with an inert diluent or a non-toxic pharmaceutically acceptable carrier such as starch or lactose.Optionally, these pharmaceutical compositions may also contain a binder such as microcrystalline cellulose, tragacanth gum or gelatin, a disintegrating agent 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 agent, or a flavoring agent such as peppermint or methyl salicylate.

[0259] The present invention also contemplates compositions that can release the active substance in a controlled manner. Pharmaceutical compositions that can be used for parenteral administration are in conventional forms such as aqueous or oily solutions or suspensions, which are generally contained in ampoules, disposable syringes, glass or plastic vials or infusion containers.

[0260] In addition to the active ingredient, these solutions or suspensions may optionally contain a sterile diluent such as water for injection, saline, oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediaminetetraacetic acid, buffers such as acetates, citrates or phosphates, and agents for adjusting the osmotic pressure such as sodium chloride or dextrose.

[0261] These pharmaceutical forms are prepared using methods routinely used by pharmacists.

[0262] The amount of active ingredient in a pharmaceutical composition can fall within a wide range of concentrations and depends on various factors such as the patient's sex, age, weight and condition, as well as the method of administration. Thus, the amount of the compound of formula (I) in a composition for oral administration is at least 0.5% by weight and can be up to 80% by weight based on the total weight of the composition.

[0263] It has also been found in accordance with the present invention that the compounds of formula (I') or formula (I), or pharmaceutically acceptable salts thereof, can be administered alone or in combination with other active pharmaceutical ingredients.

[0264] In particular, the compounds of formula (I) according to the invention can be combined with other active ingredients that increase intracellular reactive oxygen species and modulate amino acid metabolism, or with immunotherapeutic agents.

[0265] In compositions for parenteral administration, the amount of compound of formula (I) present is at least 0.5% by weight and can be up to 33% by weight, based on the total weight of the composition. For preferred parenteral compositions, dosage units range from 0.5 mg to 3000 mg of compound of formula (I).

[0266] The daily dose can fall within a wide range of dosage units of the compound of formula (I), generally ranging from 0.5 to 3000 mg. However, it should be understood that the specific dose can be adapted to a particular case according to the individual requirements at the discretion of the physician.

[0267] Synthesis scheme It will be apparent to those skilled in the art that there are a variety of synthetic routes that can lead to compounds according to the invention. The following processes are intended to illustrate some of these synthetic routes, but should in no way be construed as a limitation on how compounds according to the invention should be prepared.

[0268] During any of the following synthetic sequences it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by conventional protecting groups (PG), such as those described in Protective Groups in Organic Chemistry, J.F.W. McOmie (ed.), Plenum Press, 1973; and T.W. Greene & P. ​​G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rd Edition, 1999. The protecting groups may be removed at any convenient later stage using methods known in the art.

[0269] The compounds of formula (I) according to the present invention can be prepared analogously by conventional methods understood by those skilled in the art of synthetic organic chemistry.

[0270] 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 hexafluorophosphate azabenzotriazole tetramethyluronium; "HBTU" refers to hexafluorophosphate benzotriazole tetramethyluronium; "HOBt" refers to hydroxybenzotriazole; "TCFH" refers to chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate; and "NMI" refers to N-methylimidazole.

[0271] The compounds of formula (I) according to the present invention can be prepared by analogous methods as would be understood by one skilled in the art of synthetic organic chemistry. The following description of a synthetic scheme provides a means for preparing compounds of formula (I). However, analogous methods may also be used to prepare compounds of formula (I'). According to one embodiment, Q is Q 3 can be obtained 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) to give a compound of formula: [ka] (In the formula, A, B, V 1 , V 2 , V 3 , V 4 , Y, X 1 and R 2 is as defined above for compounds of formula (I), and LG 1 is a halogen atom or a leaving group, such as mesylate or tosylate; LG 2 is hydroxy, alkoxy or halogen) It can be prepared according to

[0272] The reaction according to Route 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.

[0273] Alternatively, compounds of formula (I) can be prepared according to Route B by reaction of a carboxylic acid or carboxylic acid derivative of formula (3) with an aromatic amine (5) according to procedures for forming an amide from a carboxylic acid or carboxylic acid derivative and an amine known to those skilled in the art. The reaction according to Route B can be carried out by the reaction of LG 2 When LG is a halogen such as chlorine, this can be carried out using a base such as a trialkylamine, an inorganic carbonate or pyridine in a suitable solvent such as DCM, DMSO, DMF, sulfolane, acetonitrile or THF. 2 When LG is hydroxy, the reaction can be carried out using a similar base in the presence of an amide coupling reagent such as HBTU, HATU, TCFH / NMI, EDC / HOBt, or according to any other method known to those skilled in the art. 2 Compounds of formula (3) wherein is hydroxy can be converted to LG by reaction with sulfonyl chloride or thionyl chloride in a suitable solvent such as DCM or THF in the presence or absence of catalytic DMF at room temperature or higher temperature, for example 70°C. 2 can be converted to a compound of formula (3) where is chloro.

[0274] LG 2 Compounds of formula (3), where is alkoxy such as OMe, OEt, or OtBu, can be prepared by reaction of 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 acid ester hydrolysis known to those skilled in the art can be used to obtain LG. 2 Compounds of formula (3) can be formed where is OH.

[0275] Or, Q is Q 3 The compound of formula (I) represented by 2 can be prepared by reacting an intermediate of formula (3) (hereinafter referred to as (3')), where X is NH, with a compound of formula (5'), where X is a sulfonate such as triflate, or a halogen such as chloro or bromo. This reaction, the "Buchwald amide coupling," is known to those skilled in the art. [ka]

[0276] Compounds of formula (5') are commercially available or can be prepared by any method known to those skilled in the art.

[0277] Compounds of formula (3') can be prepared by the reaction of compounds of formula (2) with an α-halogenoamide, such as iodoacetamide, in the presence of a base, such as potassium carbonate, in a polar solvent, such as DMF, at room temperature, or by any other method known to those skilled in the art. Alternatively, compounds of formula (3') can be prepared by the reaction of a carboxylic acid or carboxylic acid derivative of formula (3) with ammonia, following procedures for forming an amide from a carboxylic acid or carboxylic acid derivative and an amine, known to those skilled in the art.

[0278] V 1 The compound of formula (2) (hereinafter referred to as (2')) where =C is 2 can be prepared by cyclocondensation from their precursors of formula (6) having the same definition as above. For example, LG 2 When is an alkoxy, the reaction can be carried out in the presence of a base such as LiHMDS or K2CO3 or under heating conditions to obtain directly without isolation from the previous step. [ka]

[0279] Compounds of formula (6) can be prepared from the corresponding precursors of formulas (8) and (9) by a cross-coupling reaction, known to those skilled in the art as the "Suzuki reaction," provided that if (8) has B*, then (9) has X*, or if (8) has X*, then (9) has B*. B* can be a boronic acid B(OH)2, or any boronic ester B(OR)2, such as pinacol boronic ester, or a mixture of the two, and X* is a halogen such as Cl, Br, or I.

[0280] Or V 1 = C and V 2 The compound of formula (2) in which =N (hereinafter referred to as the compound of formula (2')) is 1 can be prepared by cyclization from their precursors of formula (6') where 1 When is Cl or Br, the reaction involves the presence of a base such as NaH, NaOH, DIEPA or TEA.

[0281] Compounds of formula (2') can also be obtained directly without isolation from the previous step after subsequent cyclization under Suzuki reaction conditions after heating at elevated temperature, for example 100°C. [ka]

[0282] Compounds of formula (6') can be prepared by reacting the corresponding acyl halide with a base and their precursor (7'), with the protecting group PG being removed in situ during the reaction. For example, precursor (7') can be reacted with NaH, DIPEA, or TEA and chloroacetyl chloride, methyl bromoacetate, or bromopropionyl chloride. Alternatively, an additional step of deprotection can be used to remove PG. For example, if PG is tetrahydropyran, deprotection can involve the use of HCl in dioxane.

[0283] The compound of formula (7') can be prepared from the corresponding precursors of formula (8') and (9') by a cross-coupling reaction, known to those skilled in the art as the so-called "Suzuki reaction", provided that when (8') has B*, (9') has X*, or when (8') has X*, (9') has B*. B* and R* have the same definitions as previously described.

[0284] Compounds of formula (8), (8'), (9) and (9') are commercially available, described in the literature, or can be prepared by functional group transformations known to those skilled in the art.

[0285] Q is Q 4 , Q 5 , or Q 6 It will be apparent to one skilled in the art that methods similar to those described above can be used for compounds of formula (I) representing:

[0286] In another aspect, the present invention provides a synthetic intermediate of formula (II): [ka]

[0287] (In the formula, A, B, Y, V 1 , V 2 , V 3 and V 4 is as defined above; R 25 is hydrogen or CH2-CO-R d represents; R d is hydroxy, halogen, amino or C 1~4 (representing alkoxy).

[0288] In the first embodiment, R 25 is CH2-CO-R d In the second embodiment, R 25 represents hydrogen.

[0289] In the first embodiment, A is A 1In a second embodiment, A represents A 2 In a third embodiment, A represents A 3 In a fourth embodiment, A represents A 4 In a fifth embodiment, A represents A 5 In a sixth embodiment, A represents A 6 In a seventh embodiment, A represents A 7 Represents.

[0290] In the first embodiment, B is B 1 In a second embodiment, B represents B 2 In a third embodiment, B represents B 3 In a fourth embodiment, B represents B 4 In a fifth embodiment, B represents B 5 In a sixth embodiment, B represents B 6 In a seventh embodiment, B represents B 7 In an eighth embodiment, B represents B 8 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). [Example]

[0291] Experimental Section I. Abbreviations / Reproduced Reagents ACN or MeCN acetonitrile DCM dichloromethane EtOAc ethyl acetate DMF N,N-dimethylformamide DMA Dimethylacetamide DMAP dimethylaminopyridine EDC 1-ethyl-3-carbodiimide hydrochloride MeOH Methanol DCE Dichloroethane HATU Hexafluorophosphate Azabenzotriazole Tetramethyluronium HBTU Hexafluorophosphate Benzotriazole Tetramethyluronium HOBt Hydroxybenzotriazole TCFH Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate NMI N-methylimidazole MTBE or TBME Methyl tert-butyl ether PTFE Polytetrafluoroethylene ELSD Evaporative Light Scattering Detector DMSO dimethyl sulfoxide Brine Saturated sodium chloride solution Et2O diethyl ether h time d day THF tetrahydrofuran AcOH acetic acid RT room temperature rt retention time Rf retention factor br Broad M molar concentration MS mass spectrometry [M+H] + Accurate mass of protonated ions observed by MS [MH] - Accurate mass of deprotonated ions observed by MS mL milliliter HPLC High Performance Liquid Chromatography UPLC Ultra High Performance Liquid Chromatography LC-MS Liquid Chromatography Mass Spectrometry ESI electrospray ionization ES + Electrospray positive ionization TEA Triethylamine DIPEA N,N-di-iso-propylethylamine DEA Diethylamine CDI Carbonyldiimidazole PCy3 Tricyclohexylphosphine TMSCN Trimethylsilyl cyanide dppf 1,1'-bis(diphenylphosphino)ferrocene Preparation, stabilization, and initiation of PEPPSI pyridine-enhanced precatalysts HMDS bis(trimethylsilyl)amide or hexamethyldisilazane PPh3 Triphenylphosphine AIBN Azobisisobutyronitrile TFA trifluoroacetic acid bs. Broad singlet NBS N-Bromosuccinimide DME Dimethoxyethane HMPA Hexamethylphosphoramide SFC Supercritical Fluid Chromatography SCX Strong Cation Exchange HPLC Column TLC thin layer chromatography Sat.Saturation Hex aq.water-based Eq.Equivalent min mmol millimole UV ultraviolet light

[0292] Naming convention: IUPAC names for chemical reagents, intermediates, and examples were generated using Biovia Draw 2020 (version 20.1.100.2161 or 20.1.0.2081). Depending on the Kekulé structures of the chemical reagents, intermediates, and examples, Biovia Draw may generate different chemical names. For example, Kekulé structures K1 and K2 are 4,8,14-triazatricyclo[9.4.0.0], respectively. 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-9-one and 4,8,14-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(15),2,4,6,11,13-hexaen-9-one. Both names can be found in the description below. [ka]

[0293] II. Analytical and Synthetic Methods All reactions involving air- or moisture-sensitive reagents are carried out under a nitrogen or argon atmosphere (inert atmosphere) using dry solvents and glassware. Experiments requiring microwave irradiation are performed in a Biotage Initiator Sixty microwave oven upgraded with operating software version 2.0. Experiments are run to reach the required temperature as quickly as possible (maximum irradiation power: 400 W, no external cooling). Commercially available solvents and reagents are generally used without further purification and include anhydrous solvents where appropriate (typically Sure-Seal™ products from Aldrich Chemical Company or AcroSeal™ from ACROS Organics). Reactions are typically followed by thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), or mass spectrometry (MS).

[0294] NMR spectra were recorded on a Bruker Advance III HD 500 MHz or 400 MHz spectrometer. Reported chemical shifts (δ) are given in parts per million (ppm) and coupling constants (J) are given in hertz (Hz). Spin multiplicities are reported as s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, dd = doublet doublet, ddd = doublet doublet doublet, dt = triplet doublet, td = doublet triplet, and m = multiplet.

[0295] Mass spectrometry measurements in LC-MS mode are carried out as follows: For acidic elution (methods A1, A1', A2, and A2'), analysis was performed using a QDA Waters single quadrupole mass spectrometer. The mass spectrometer was equipped with a UPLC Acquity Hclass with an ESI source and a diode array detector (200-400 nm). Data were acquired in positive mode for acidic elution with a full MS scan from m / z 70 to 800. Reversed-phase separation was performed at 45 °C on a Waters Acquity UPLC HSS T3 1.8 μm (2.1 × 50 mm) column for methods A1 and A1', and on a Waters Acquity UPLC HSS T3 1.8 μm (2.1 × 100 mm) column for methods A2 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, and water / acetonitrile / formic acid (95 / 5 / (0.05%)) (solvent A) and acetonitrile / formic acid (99.95 / 0.05%) (solvent B) for methods A1' and A2'. Injection volume: 1 μL. Full flow rate on MS. Gradient program:

[0296] [Table 1]

[0297] [Table 2]

[0298] For acidic elution (Method A3), analysis was performed using a Xevo Waters Q-TOF mass spectrometer. The mass spectrometer was equipped with a Waters Acquity H-class UPLC equipped with an ESI source and a diode array detector (210–400 nm). Data were acquired as a full MS scan from m / z 50–1200 in positive mode. Reversed-phase separation was performed on an Acquity UPLC HSS T3 C18 column (1.8 μm, 2.1 × 100 mm) at 40 °C. Gradient elution was performed at pH ≈3 using water / ACN / formic acid (95 / 5 / 750 μL / L) (solvent C) and water / ACN / formic acid (5 / 95 / 500 μL / L) (solvent D). Flow rates were 100% for UV, 10% for MS, and 90% for ELSD. Injection volumes were 0.5–2 μL.

[0299] Gradient Program: [Table 3]

[0300] For acidic elution (Method A4), analysis was performed using a SYNAPT G2-SI Waters Q-TOF mass spectrometer. The mass spectrometer was equipped with a Waters Acquity H-class UPLC equipped with an ESI source and a diode array detector (210-400 nm). Data were acquired in positive mode with a full MS scan from m / z 50 to 1200. Reversed-phase separation was performed on an Acquity UPLC HSS T3 C18 column (1.8 μm, 2.1 × 100 mm) at 45 °C. Gradient elution was performed using water / ACN / formic acid (95 / 5 / 750 μL / L) (solvent C) and water / ACN / formic acid (5 / 95 / 500 μL / L) (solvent D) at pH ∼3. Total flow rate was measured on the MS. Injection volume: 0.5 μL.

[0301] Gradient Program: [Table 4]

[0302] For acidic elution (Method A5), analysis was performed using a Shimadzu LC-MS 2010EV mass spectrometer. The mass spectrometer was equipped with an HPLC equipped with an ESI source and a diode array detector (210-400 nm). Data were acquired in positive and negative modes with full MS scans from m / z 80 to 2000. Reversed-phase separation was performed using a Waters X-Select CSH C18 (4.6 x 150) mm, 3.5 μm column. Column temperature: 50 °C. Gradient elution was performed using a mobile phase containing 0.1% formic acid in water (phase A) and acetonitrile (phase B). Injection volume: 2 μL.

[0303] Gradient Program: [Table 5]

[0304] For acidic elution (Method A6), analysis was performed using a Shimadzu LC-MS 2010EV mass spectrometer for LC-MS analysis. The mass spectrometer was equipped with an HPLC equipped with an ESI source and a diode array detector (210-400 nm). Data were acquired in positive and negative modes with full MS scans from m / z 80 to 2000. Reversed-phase separation was performed using a Waters X-Select CSH C18 (4.6 x 150) mm, 3.5 μm column. Column temperature: 50 °C. Gradient elution was performed using a mobile phase containing 0.1% TFA in water (phase A) and acetonitrile (phase B). Injection volume: 2 μL.

[0305] Gradient Program: [Table 6]

[0306] For acidic elution (Method A7), the analysis was performed using an Agilent 1200-6120 LC-MS system connected to an Agilent 6120 mass spectrometer (ES) with UV detection (254 nm) and MS detection: m / z 100-1000. Column: XSelect CSH C18 XP 130 Å, 2.5 μm, 4.6 mm × 30 mm (Waters™). Mobile phase A: 0.1% formic acid in water, Mobile phase B: acetonitrile + 0.1% formic acid. Flow rate: 2.5 mL / min.

[0307] Gradient Program: [Table 7]

[0308] For acidic elution (Method A9), the analysis is performed using the same equipment as above, but with a Waters Cortecs C18 2.7 μm (30 × 2.1 mm) column for reversed-phase separation. Column temperature: 40 °C. A 1.5-minute gradient elution is performed with a mobile phase containing 0.1% formic acid in water (phase A) and ACN (phase B).

[0309] For basic elution (Methods B1 and B2), analysis was performed using a QDA Waters single quadrupole mass spectrometer. The mass spectrometer was equipped with a UPLC Acquity H-class with an ESI source and a diode array detector (200-400 nm). Data were acquired in positive mode with a full MS scan from m / z 70 to 800. Reversed-phase separations were performed at 45 °C with basic elution on a Waters Acquity UPLC BEHC18 1.7 μm (2.1 x 50 mm) column for Method B1 and a Waters Acquity UPLC BEH C18 1.7 μm (2.1 x 100 mm) column for Method B2. Gradient elution was performed using water / ACN / ammonium formate (95 / 5 / 63 mg / L) (solvent A) and ACN / water / ammonium formate (95 / 5 / 63 mg / L) (solvent B). Injection volume: 1 μL. Full flow rate on MS.

[0310] Gradient Program: [Table 8]

[0311] [Table 9]

[0312] For basic elution (Method B3), analysis was performed using a Xevo Waters Q-TOF mass spectrometer. The mass spectrometer was equipped with a Waters Acquity H-class UPLC equipped with an ESI source and a diode array detector (210–400 nm). Data were acquired as a full MS scan from m / z 50–1200 in positive mode. Reversed-phase separation was performed on an Acquity UPLC BEH C18 column (1.7 μm, 2.1 × 100 mm) at 45 °C. Gradient elution was performed at pH approximately 8–9 using water / ACN / ammonium formate (95 / 5 / (40 mg / L ammonium bicarbonate + 100 μL / L NH4OH)) (solvent A) and ACN (solvent B). Flow rates were 100% for UV, 10% for MS, and 90% for ELSD. Injection volume: 0.2–2 μL.

[0313] Gradient Program: [Table 10]

[0314] For basic elution (Method B4), analysis was performed using a SYNAPT G2-SI system and a Waters Q-TOF mass spectrometer. The mass spectrometer was equipped with a Waters Acquity H-class UPLC equipped with an ESI source and a diode array detector (210-400 nm). Data were acquired as a full MS scan from m / z 50 to 1200 in positive mode. Reversed-phase separation was performed on an Acquity UPLC BEH C18 column (1.7 μm, 2.1 × 100 mm) at 45 °C. Gradient elution was performed using water / ACN / ammonium formate (95 / 5 / (63 mg / L + 100 μL / L NH4OH)) (solvent A) and ACN (solvent B) at pH approximately 8-9. Total flow rate was measured on the MS. Injection volume: 0.5 μL.

[0315] Gradient Program: [Table 11]

[0316] For basic elution (Methods B5 and B5'), analysis was performed using an Agilent 1200-6120 LC-MS system connected to an Agilent 6120 mass spectrometer (ES) with UV detection (254 nm) and MS detection (m / z 100-1000). Reversed-phase separation was performed on an XBridge BEH C18 XP column, 130 Å, 2.5 μm, 4.6 mm × 30 mm (Waters™), at 45°C. Column temperature: 40°C. Flow rate: 2.5 mL / min. Gradient elution was performed using the mobile phases acetonitrile / 10 mM aqueous ammonium bicarbonate (phase A) and acetonitrile (phase B) for Method B5, and mobile phase A: 0.1% ammonia in water, mobile phase B: acetonitrile for Method B5'.

[0317] Gradient Program: [Table 12]

[0318] For basic elution (Method B6), analysis was performed using a Shimadzu LC-MS 2010EV mass spectrometer. The mass spectrometer was equipped with an HPLC equipped with an ESI source and a diode array detector (210-400 nm). Data were acquired in positive and negative modes with full MS scans from m / z 80 to 2000. Reverse-phase separation was performed using a Waters X-Select CSH C18 (4.6 x 150) mm, 3.5 μm column. Column temperature: 50 °C. Mobile phase: Gradient elution with 10 mM ammonium bicarbonate in water (phase A) and acetonitrile (phase B). Injection volume: 2 μL.

[0319] Gradient Program: [Table 13]

[0320] For basic elution (Method B7), analysis was performed using a Shimadzu LC-MS 2010EV mass spectrometer. The mass spectrometer was equipped with an HPLC equipped with an ESI source and a diode array detector (210-400 nm). Data were acquired in positive and negative modes with full MS scans from m / z 80 to 2000. Reverse-phase separation was performed using a Waters X-Bridge C18 (4.6 x 150) mm, 5 μm column. Column temperature: 50 °C. Mobile phase: 0.1% ammonia in water (phase A) and acetonitrile (phase B) with gradient elution. Injection volume: 5 μL.

[0321] Gradient Program: [Table 14]

[0322] For basic elution (Method B9), analysis is performed using an Agilent 1200 Series LC in tandem with a 6140 mass spectrometer. Reversed-phase separation is performed using a Phenomenex Gemini NX-C18 3 μM (2 × 20 mm) column at a flow rate of 1.0 mL / min, a column temperature of 40 °C, and a 5 to 95% gradient over 6.0 min (Solvent A: 10 mM ammonium formate in water + 0.1% ammonia solution; Solvent B: ACN + 5% water + 0.1% ammonia solution).

[0323] For basic elution (Method B10), analysis is performed using an Agilent 1290 Infinity II LC in tandem with a 6135 MSD XT mass spectrometer. Reversed-phase separation is performed on an Acquity UPLC BEH C18 2.1x50 mm, 1.7 μM column, with a flow rate of 1.5 mL / min, a column temperature of 60 °C, and a 5-95% gradient over 4.5 min (Solvent A - 10 mM ammonium formate in water + 0.1% ammonia solution, Solvent B - ACN + 5% water + 0.1% ammonia solution).

[0324] All analytical chiral LC-MS runs were performed at 30°C on 4.6 x 150 mm columns with dimensions of 3 x 100 mm and a flow rate of 1.5 mL / min, except for the Chiralpak IG-u (Daicel) column, which had a flow rate of 0.425 mL / min. All columns exhibit a particle size distribution of 3 μm, except for the WhelkO-1(R,R) (Regis Technology) which was 3.5 μm and the Chiralpak IG-u (Daicel) which was sub-2 μm.

[0325] High resolution mass spectrometry measurements in LC-MS mode are carried out as follows: A SYNAPT G2-SI Waters Q-TOF mass spectrometer was used for QC analysis. The mass spectrometer was equipped with a Waters Acquity H-class UPLC equipped with an ESI source and a diode array detector (210–400 nm). Data were acquired in positive mode with full MS scans from m / z 50–1200. Reversed-phase separation was performed on an Acquity UPLC BEH C18 column (1.7 μm, 2.1 × 30 mm) at 45 °C. Gradient elution was performed 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. The flow rate was controlled by the MS. Injection volume: 0.5–1 μL.

[0326] Gradient Program: [Table 15]

[0327] Preparative HPLC purification is performed using an SQD Waters or QDa Performance single quadrupole mass spectrometer. The mass spectrometer is equipped with a Waters 2525 binary pump connected to an ESI source, a 2767 sample manager, and a diode array detector (210-400 nm). Data are acquired as full MS scans from m / z 100 to 850 in both positive and negative modes. LC parameters: Reversed-phase separation is performed at room temperature on a Waters XBridge OBD MS C18 column (5 μm, 30 x 50 mm). Typical HPLC flow rates are 35 mL / min to 45 mL / min. Typical example of basic elution: a gradient of 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 of solvent A (HO / TFA: 99.5% / 0.5%) and solvent B (ACN / TFA: 99.5% / 0.5%) [purification method P_A].

[0328] Several preparative HPLC purifications are performed using a Gilson Modular System equipped with a YMC Triart-500g-10µm-76.5 x 200mm column (333 preparative-scale HPLC pump (water), 334 preparative-scale HPLC pump (acetonitrile), 334 preparative-scale HPLC pump (modifier: for basic elution, 5 mL of NHOH in 1000 mL of HO [Purification Method G_B] or 20 mL of TFA in 1000 mL of HO [Purification Method G_A]), 171 diode array detector, GX-271 preparative liquid handler, and preparative FC fraction collector. The typical HPLC flow rate is 180 mL / min.

[0329] If an analytical method is not specified in the following protocol, the method used was similar to that 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 in the following procedures.

[0330] The photochemical reactions are carried out using photoreactors M1 or M2 (manufactured by Penn PHD), referred to as Pennoc in the following experimental protocols.

[0331] III. Intermediates Intermediate N1: 9,10-dimethyl-5,7-dihydropyrido[3,2-d][1]benzazepin-6-one [ka] Step 1: Synthesis of 1-bromo-4,5-dimethyl-2-nitrobenzene N1_1 [ka] A stirred solution of 4,5-dimethyl-2-nitroaniline (5.00 g, 30.1 mmol) in 47% aqueous HBr (60 mL) was heated at 70 °C for 1.5 h. The reaction mixture was cooled to 0 °C, followed by the dropwise addition of a solution of NaNO (16.0 g, 232 mmol) in water (60 mL) over 20 min, and the reaction mixture was stirred at 0 °C for 30 min. At 0 °C, a solution of CuBr (51.8 g, 361 mmol) in 47% aqueous HBr (150 mL) was added slowly over 15 min, and the reaction mixture was allowed to warm to room temperature and then heated at 70 °C for 30 min. After cooling to room temperature, the reaction mixture was extracted with DCM (3 × 150 mL). The organic layer was separated, washed with 2 N aqueous NaOH (250 mL), dried over anhydrous NaSO, and concentrated in vacuo to give the title compound (5.20 g, 75% yield) as a brown solid. This compound was taken to the next step without purification. 1 H NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H), 2.30 (s, 3H), 7.71 (s, 1H), 7.86 (s, 1H).

[0332] Step 2: Synthesis of 2-(4,5-dimethyl-2-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane N1_2 [ka] To a solution of 1-bromo-4,5-dimethyl-2-nitrobenzene (Intermediate N1_1, 3.00 g, 13.0 mmol) in dioxane (30 mL), bispinacolatodiboron (4.97 g, 19.6 mmol) and potassium acetate (3.33 g, 33.9 mmol) were added, and the reaction mixture was purged with argon at room temperature for 20 minutes. PdCl(dppf) (0.48 g, 0.65 mmol) was added, and the reaction mixture was heated at 80 °C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo, and the crude product was purified by silica gel column chromatography (DCM as eluent) to give the title compound (1.80 g, 50% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.32 (s, 12H), 2.33 (s, 6H), 7.36 (s, 1H), 7.98 (s, 1H).

[0333] Step 3: Synthesis of 4,5-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline N1_3 [ka] To a suspension of 10% Pd / C (50% wet, 0.20 g) in MeOH (30 mL) was added 2-(4,5-dimethyl-2-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate N1_2, 1.00 g, 3.61 mmol), and the reaction mixture was stirred under a hydrogen atmosphere (P = 1 atm) at room temperature for 5 h. Upon completion, the reaction mixture was filtered through a Celite® pad, washed with MeOH (100 mL), and the filtrate was concentrated in vacuo to give the title compound (0.515 g, 58% yield) as an off-white solid. This compound was carried forward without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 1.26 (s, 12H), 2.03 (s, 3H), 2.08 (s, 3H), 5.18 (s, 2H), 6.38 (s, 1H), 7.10 (s, 1H).

[0334] Step 4: Synthesis of 3-(bromomethyl)-2-chloropyridine N1_4 [ka] Under a nitrogen atmosphere, to a solution of 2-chloro-3-methyl-pyridine (8.6 mL, 78.4 mmol) in DCE (200 mL) were added NBS (16.7 g, 94.1 mmol) and AIBN (1.29 g, 7.84 mmol), and the reaction mixture was heated at 70 °C for 16 h. After cooling to room temperature, the reaction mixture was treated with water (50 mL) and extracted with DCM (2 × 100 mL). The organic layer was separated, washed with brine (60 mL), dried over anhydrous NaSO, and concentrated in vacuo. Purification by silica gel column chromatography (using 3% EtOAc in hexane as the eluent) afforded the title compound (8.0 g, yield: 49%) as a colorless oil. LC-MS (Method B6): [M+H] + m / z: 207, rt: 1.74 min, purity: 87%. 1 H NMR (400 MHz, DMSO-d6) δ 4.78 (s, 2H), 7.46-7.49 (m, 1H), 8.17 (d, J = 7.6 Hz, 1H), 8.41 (d, J = 4.4 Hz, 1H).

[0335] Step 5: Synthesis of 2-(2-chloropyridin-3-yl)acetonitrile N1_5 [ka] To a solution of 3-(bromomethyl)-2-chloropyridine (Intermediate N1_4, 8.00 g, 38.7 mmol) in CHCN (100 mL) at 0 °C, a 1 M solution of tetrabutylammonium fluoride in THF (50.4 mL, 50.4 mmol) and TMSCN (14.5 mL, 116 mmol) were added, and the reaction mixture was stirred at room temperature for 3 h. After completion, the reaction mixture was treated with saturated aqueous NaHCO (70 mL) and extracted with DCM (3 × 100 mL). The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. Purification by silica gel column chromatography (using 10% EtOAc in hexane as the eluent) afforded the title compound (3.10 g, yield: 52%) as a white solid. LC-MS (Method A5): [M+H] +m / z: 152.9, rt: 1.48 min, purity: 96%. 1 H NMR (400 MHz, DMSO-d6) δ 4.14 (s, 2H), 7.48-7.51 (m, 1H), 7.99 (d, J = 7.6 Hz, 1H), 8.41 (d, J = 5.2 Hz, 1H).

[0336] Step 6: Synthesis of 2-(2-chloropyridin-3-yl)acetic acid N1_6 [ka] A suspension of 2-(2-chloropyridin-3-yl)acetonitrile (Intermediate N1_5, 3.10 g, 20.3 mmol) in 15% aqueous NaOH (51.7 mL, 194 mmol) was heated at 90 °C for 5 h. After cooling to room temperature, the reaction mixture was acidified with concentrated aqueous HCl (80 mL) to pH = 1 and left at room temperature for 1 h. The resulting precipitate was collected by filtration and washed with pentane (3 x 60 mL) to give the title compound (2.60 g, yield: 75%) as a white solid. This compound was carried on to the next reaction without purification. LC-MS (Method B6): [M+H] + m / z: 171.7, rt: 0.69 min, purity: 98%. 1 H NMR (400 MHz, DMSO-d6) δ 3.76 (s, 2H), 7.39-7.42 (m, 1H), 7.85 (d, J = 7.2 Hz, 1H), 8.27 (d, J = 4.8 Hz, 1H), 12.61 (s, 1H).

[0337] Step 7: Synthesis of ethyl 2-(2-chloropyridin-3-yl)acetate N1_7 [ka] To a solution of 2-(2-chloropyridin-3-yl)acetic acid (Intermediate N1_6, 2.60 g, 15.2 mmol) in absolute ethanol (50 mL) at room temperature, concentrated sulfuric acid (6.1 mL, 114 mmol) was added, and the reaction mixture was heated at 70° C. for 16 h. After cooling to room temperature, the reaction mixture was basified with saturated NaHCO solution (80 mL) to pH=9, and the solvent was removed under vacuum. The aqueous layer was extracted with DCM (2×100 mL). The organic layer was separated, dried over anhydrous NaSO, and concentrated under vacuum. Purification by silica gel column chromatography (using 5% EtOAc in hexane as the eluent) afforded the title compound (2.80 g, yield: 93%) as a pale yellow oil. LC-MS (Method A5): [M+H] + m / z: 199.8, rt: 1.74 min, purity: 98%. 1 H NMR (400 MHz, CDCl3) δ 1.25-1.28 (m, 3H), 3.82 (s, 2H), 4.16-4.24 (m, 2H), 7.22-7.30 (m, 1H), 7.64 (d, J = 7.2 Hz, 1H), 8.38 (d, J = 4.8 Hz, 1H).

[0338] Step 8: Synthesis of 9,10-dimethyl-5,7-dihydropyrido[3,2-d][1]benzazepin-6-one N1 A suspension of 4,5-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (Intermediate N1_3, 0.87 g, 3.51 mmol), ethyl 2-(2-chloropyridin-3-yl)acetate (Intermediate N1_7, 0.70 g, 3.51 mmol), and K2CO3 (0.97 g, 7.01 mmol) in dioxane (16 mL) and HO (4 mL) was purged with argon at room temperature for 30 minutes. Pd(PPh3)4 (0.20 g, 0.18 mmol) was added, and the reaction mixture was heated at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was treated with water (25 mL), and the resulting precipitate was collected by filtration and dried under vacuum. Purification by silica gel column chromatography (using 3% MeOH in DCM as eluent) afforded the title compound (0.335 g, yield: 40%) as an off-white solid. LC-MS (Method B7): [M+H] + m / z: 239.0, rt: 2.01 min, purity: 98%. 1 H NMR (400 MHz, DMSO-d6) δ 2.27 (s, 3H), 2.38 (s, 3H), 3.32 (s, 2H), 6.96 (s, 1H), 7.39-7.42 (m, 1H), 7.75 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 8.63 (d, J = 4.4 Hz, 1H), 10.02 (s, 1H).

[0339] Intermediate N2: 9,10-dimethyl-5,7-dihydropyrido[4,3-d][1]benzazepin-6-one [ka] Step 1: Synthesis of (E)-3-bromo-4-(2-(methylsulfinyl)-2-(methylthio)vinyl)pyridine N2_1 [ka] To a solution of 3-bromopyridine-4-carbaldehyde (10.0 g, 53.8 mmol) in a 1:1 mixture of THF and MeOH (120 mL) was added methylsulfanyl(methylsulfinyl)methane (11.1 mL, 108 mmol), and the reaction mixture was stirred at room temperature for 10 min. A 40% solution of benzyltrimethylammonium hydroxide in methanol (45 mL, 108 mmol) was added dropwise, and the reaction mixture was heated at 70 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated in vacuo, and the residue was partitioned between DCM (500 mL) and water (500 mL). The organic layer was separated, washed with water (500 mL), dried over anhydrous NaSO, and concentrated in vacuo. Purification by silica gel column chromatography (using 20% ​​EtOAc in hexane as the eluent) afforded the title compound (7.50 g, 48% yield) as a pale yellow oil. 1 H NMR (400 MHz, CDCl) δ 3.30 (s, 3H), 3.34 (s, 3H), 7.70 (d, J = 4.9 Hz, 1H), 8.47 (d, J = 4.4 Hz, 1H), 8.72 (s, 1H). One H is fused to the solvent peak.

[0340] Step 2: Synthesis of methyl 2-(3-bromopyridin-4-yl)acetate N2_2 [ka] To a solution of (E)-3-bromo-4-(2-(methylsulfinyl)-2-(methylthio)vinyl)pyridine (Intermediate N2_1, 5.00 g, 17.1 mmol) in MeOH (50 mL) was added a 4 M solution of HCl in MeOH (50 mL), and the reaction mixture was heated at 70 °C for 16 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo, and the residue was treated with HO (50 mL) and diluted with DCM (150 mL). The organic layer was separated, washed with HO (50 mL), dried over anhydrous NaSO, and concentrated in vacuo. Purification by silica gel column chromatography (using 5% MeOH in DCM as the eluent) afforded the title compound (2.90 g, yield: 74%) as a brown oil. LC-MS (Method B6): [M+H] + m / z: 231.8, rt: 1.58 min, purity: 78%. 1 H NMR (400 MHz, DMSO-d6) δ 3.64 (s, 3H), 3.94 (s, 2H), 7.49 (d, J = 4.4 Hz, 1H), 8.56 (d, J = 4.9 Hz, 1H), 8.77 (s, 1H).

[0341] Step 3: Synthesis of methyl 2-(3-(4,5-dimethyl-2-nitrophenyl)pyridin-4-yl)acetate N2_3 [ka] To a solution of methyl 2-(3-bromopyridin-4-yl)acetate (Intermediate N2_2, 2.00 g, 8.69 mmol) in anhydrous toluene (50 mL), 2-(4,5-dimethyl-2-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate N1_2, 2.41 g, 8.69 mmol), K2CO3 (1.80 g, 13.0 mmol), TEA (2.23 mL, 17.4 mmol), and PPh3 (0.23 g, 0.87 mmol) were added, and the reaction mixture was purged with nitrogen for 30 minutes. Pd(OAc)2 (0.10 g, 0.44 mmol) was added, and the reaction mixture was again purged with nitrogen for 10 minutes before heating at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was treated with H2O (100 mL) and diluted with EtOAc (100 mL). The organic layer was separated, washed with H2O (100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. Purification by silica gel column chromatography (using 10% EtOAc in hexane as eluent) afforded the title compound (0.752 g, yield: 29%) as an off-white solid. LC-MS (Method A5): [M+H] + m / z: 301.0, rt: 1.95 min, purity: 90%. 1 H NMR (400 MHz, CDCl3) δ 2.38 (s, 3H), 2.43 (s, 3H), 3.37-3.44 (m, 1H), 3.47-3.54 (m, 1H), 3.62 (s, 3H), 7.09 (s, 1H), 7.37 (d, J = 4.9 Hz, 1H), 7.97 (s, 1H), 8.37 (s, 1H), 8.61 (d, J = 4.4 Hz, 1H).

[0342] Step 4: Synthesis of methyl 2-(3-(2-amino-4,5-dimethylphenyl)pyridin-4-yl)acetate and 9,10-dimethyl-5,7-dihydro-6H-benzo[b]pyrido[3,4-d]azepin-6-one N2_4 [ka] To a solution of methyl 2-(3-(4,5-dimethyl-2-nitrophenyl)pyridin-4-yl)acetate (Intermediate N2_3, 0.72 g, 2.40 mmol) in MeOH (30 mL) was added 20% Pd / C (0.20 g), and the reaction mixture was stirred under a hydrogen atmosphere (P=1 atm) at room temperature for 3 h. Upon completion, the reaction mixture was filtered through a Celite® pad, washed with MeOH (50 mL), and the filtrate was concentrated in vacuo to give a mixture of methyl 2-(3-(2-amino-4,5-dimethylphenyl)pyridin-4-yl)acetate and 9,10-dimethyl-5,7-dihydro-6H-benzo[b]pyrido[3,4-d]azepin-6-one (0.60 g) as an off-white solid. This mixture was carried on to the next reaction without further purification. LC-MS (Method A5): [M+H] + m / z: 238.9, rt: 1.71 min, purity: 91%. LC-MS (Method A5): [M+H] + m / z: 271.1, rt: 1.84 min, purity: 4%.

[0343] Step 5: Synthesis of 9,10-dimethyl-5,7-dihydropyrido[4,3-d][1]benzazepin-6-one N2 A suspension of a mixture of methyl 2-(3-(2-amino-4,5-dimethylphenyl)pyridin-4-yl)acetate and 9,10-dimethyl-5,7-dihydro-6H-benzo[b]pyrido[3,4-d]azepin-6-one (Intermediate N2_4, 0.60 g, 2.22 mmol) and K2CO3 (0.92 g, 6.66 mmol) in EtOH (25 mL) was heated at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was treated with HO (100 mL) and diluted with DCM (150 mL). The organic layer was separated, washed with HO (150 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. Purification by trituration with Et2O (25 mL) afforded the title compound (0.48 g, 80% yield) as an off-white solid. LC-MS (Method A5): [M+H] + m / z: 238.9, rt: 1.64 min, purity: 98%. 1H NMR (400 MHz, DMSO-d6) δ 2.27 (s, 3H), 2.29 (s, 3H), 3.41 (s, 2H), 7.00 (s, 1H), 7.43 (d, J = 4.5 Hz, 1H), 7.51 (s, 1H), 8.55 (d, J = 5.0 Hz, 1H), 8.77 (s, 1H), 10.06 (s, 1H).

[0344] Intermediate N3: 9,10-dimethyl-5,7-dihydropyrido[2,3-d][1]benzazepin-6-one [ka] Step 1: Synthesis of ethyl 2-(3-bromo-2-pyridyl)acetate N3_1 [ka] To a solution of 3-bromo-2-methyl-pyridine (5.00 g, 29.1 mmol) in dry THF (100 mL) at -78 °C, LiHMDS (1 M solution in THF, 58 mL, 58.0 mmol) was added, and the reaction mixture was stirred at 0 °C for 1 h. Diethyl carbonate (5.15 g, 43.6 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 15 min. The reaction mixture was treated with HO (200 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under vacuum. Purification by silica gel column chromatography (using DCM as the eluent) afforded the title compound (5.00 g, yield: 71%) as a brown oil. LC-MS (Method B6): [M+H] + m / z: 243.8, rt: 1.71 min, purity: 94%. 1 H NMR (400 MHz, DMSO-d6) δ 1.18 (t, J = 6.8 Hz, 3H), 3.98 (s, 2H), 4.11 (q, J = 6.8 Hz, 2H), 7.27-7.30 (m, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.50 (d, J = 4.4 Hz, 1H).

[0345] Step 2: Synthesis of ethyl 2-(3-(4,5-dimethyl-2-nitrophenyl)pyridin-2-yl)acetate N3_2 [ka] To a solution of ethyl 2-(3-bromo-2-pyridyl)acetate (Intermediate N3_1, 2.00 g, 8.19 mmol) in dioxane (40 mL), 2-(4,5-dimethyl-2-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate N1_2, 2.73 g, 9.83 mmol) and K3PO4 (3.48 g, 16.4 mmol) were added, and the reaction mixture was purged with argon for 20 minutes. PdCl2(dppf) (0.30 g, 0.41 mmol) was added, and the reaction mixture was heated at 80 °C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. Purification by silica gel column chromatography (using 15% EtOAc in hexane as the eluent) afforded the title compound (1.20 g, 47% yield) as an off-white solid. LC-MS (Method B6): [M+H] + m / z: 315.1, rt: 1.97 min, purity: 99%. 1 H NMR (400 MHz, DMSO-d6) δ 1.04 (t, J = 6.8 Hz, 3H), 2.31 (s, 3H), 2.36 (s, 3H), 3.46-3.59 (m, 2H), 3.91 (q, J = 6.8 Hz, 2H), 7.18 (s, 1H), 7.34-7.37 (m, 1H), 7.58 (d, J = 7.6 Hz, 1H), 8.00 (s, 1H) 8.52 (d, J = 5.2 Hz, 1H).

[0346] Step 3: Synthesis of ethyl 2-(3-(2-amino-4,5-dimethylphenyl)pyridin-2-yl)acetate N3_3 [ka] To a solution of ethyl 2-(3-(4,5-dimethyl-2-nitrophenyl)pyridin-2-yl)acetate (Intermediate N3_2, 1.10 g, 3.50 mmol) in MeOH (25 mL) was added 10% Pd / C (0.20 g), and the reaction mixture was stirred under a hydrogen atmosphere (P=1 atm) at room temperature for 4 hours. After completion, the reaction mixture was filtered through a Celite® pad, washed with MeOH (50 mL), and the filtrate was concentrated in vacuo to give the title compound (0.81 g, yield: 81%) as a colorless oil. This compound was carried on to the next reaction without purification. LC-MS (Method A5): [M+H] + m / z: 285.0, rt: 1.93 min, purity: 31%. 1 H NMR (400 MHz, DMSO-d6) δ 1.07 (t, J = 7.4 Hz, 3H), 2.06 (s, 3H), 2.12 (s, 3H), 3.62 (s, 2H), 3.94 (q, J = 7.4 Hz, 2H), 4.34 (s, 2H), 6.56 (s, 1H), 6.60 (s, 1H), 7.33-7.36 (m, 1H), 7.53 (d, J = 7.6 Hz, 1H), 8.48 (d, J = 5.2 Hz, 1H).

[0347] Step 4: Synthesis of 9,10-dimethyl-5,7-dihydropyrido[2,3-d][1]benzazepin-6-one N3 A suspension of ethyl 2-(3-(2-amino-4,5-dimethylphenyl)pyridin-2-yl)acetate (Intermediate N3_3, 0.80 g, 2.81 mmol) and K2CO3 (1.17 g, 8.44 mmol) in anhydrous EtOH (30 mL) was stirred at room temperature for 16 h. After completion, the reaction mixture was treated with HO (50 mL), and the resulting precipitate was collected by filtration, washed with Et2O (50 mL) and n-pentane (50 mL), and dried under vacuum to give the title compound (0.44 g, yield: 66%) as an off-white solid. LC-MS (Method B7): [M+H] + m / z: 239.0, rt: 2.10 min, purity: 99%. 1H NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H), 2.28 (s, 3H), 3.55 (s, 2H), 7.00 (s, 1H), 7.44-7.48 (m, 2H), 8.01 (d, J = 8.0 Hz, 1H), 8.53 (d, J = 4.8 Hz, 1H), 10.09 (bs, 1H).

[0348] Intermediate N4: 3,9,10-trimethyl-5,7-dihydropyrido[2,3-d][1]benzazepin-6-one [ka] Step 1: Synthesis of 2-(3-bromo-6-methylpyridin-2-yl)acetonitrile N4_1 [ka] To a solution of 3-bromo-2-fluoro-6-methyl-pyridine (4.3 mL, 26.3 mmol) in anhydrous CHCN (5.50 mL, 105 mmol) and anhydrous toluene (50 mL) at 0 °C, KHMDS (1 M solution in THF, 31.5 mL, 31.5 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 min and then allowed to reach room temperature for 16 h. The reaction mixture was diluted with EtOAc (100 mL), washed with 2 N aqueous HCl (2 × 40 mL), brine (2 × 40 mL), dried over anhydrous NaSO, and concentrated under vacuum. Purification by silica gel column chromatography (using 5% EtOAc in hexane as the eluent) afforded the title compound (3.20 g, yield: 58%) as a yellow solid. LC-MS (Method A5): [M+H] + m / z: 210.8, rt: 1.70 min, purity: 53%. 1 H NMR (400 MHz, CDCl3) δ 2.53 (s, 3H), 4.02 (s, 2H), 7.02 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H).

[0349] Step 2: Synthesis of methyl 2-(3-bromo-6-methylpyridin-2-yl)acetate N4_2 [ka] Under a nitrogen atmosphere, a solution of 2-(3-bromo-6-methylpyridin-2-yl)acetonitrile (Intermediate N4_1, 2.00 g, 9.48 mmol) in 4 M HCl solution in MeOH (30 mL) was heated at 70 °C for 16 h. After cooling to room temperature, the reaction mixture was basified with saturated aqueous NaHCO (80 mL) to pH = 9, and MeOH was removed under vacuum. The aqueous layer was extracted with DCM (2 × 100 mL). The organic layer was separated, dried over anhydrous NaSO, and concentrated under vacuum. Purification by silica gel column chromatography (using 5% EtOAc in hexane as the eluent) afforded the title compound (1.20 g, yield: 52%) as a pale yellow oil. LC-MS (Method A6): [M+H] + m / z: 244.1, rt: 1.14 min, purity: 65%. 1 H NMR (400 MHz, DMSO-d6) δ 2.41 (s, 3H), 3.63 (s, 3H), 3.94 (s, 2H), 7.14 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H).

[0350] Step 3: Synthesis of 3,9,10-trimethyl-5,7-dihydropyrido[2,3-d][1]benzazepin-6-one N4 A stirred solution of 2-(3-bromo-6-methylpyridin-2-yl)acetate (Intermediate N4_2, 0.60 g, 2.43 mmol), 4,5-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (Intermediate N1_3, 0.60 g, 2.43 mmol), and K2CO3 (0.68 g, 4.92 mmol) in dioxane (16 mL) and HO (4 mL) was purged with argon at room temperature for 30 minutes. Pd(PPh3)4 (0.14 g, 0.12 mmol) was added, and the reaction mixture was heated in a sealed tube at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was treated with HO (25 mL), and the resulting precipitate was collected by filtration, washed with pentane (2 × 15 mL), and dried by suction. Purification by silica gel column chromatography (using 2% MeOH in DCM as eluent) afforded the title compound (0.28 g, yield: 45%) as an off-white solid. LC-MS (Method B7): [M+H] + m / z: 253.0, rt: 2.28 min, purity: 99%. 1 H NMR (400 MHz, DMSO-d6) δ 2.25 (s, 3H), 2.27 (s, 3H), 3.49 (s, 2H), 6.98 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 10.04 (s, 1H). Three H protons are fused with the solvent peak.

[0351] Intermediate N5: 8,9-dimethyl-4,6-dihydropyrazolo[1,5-a][1,5]benzodiazepin-5-one [ka] Step 1: Synthesis of 3-(benzyloxy)propanoic acid N5_1 [ka] To a solution of 3-benzyloxypropan-1-ol (5.00 g, 30.1 mmol) in acetone (50 mL) at 0 °C, Jones reagent (2.5 M solution in HO, 16.2 mL, 40.6 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 30 min. After completion, the reaction mixture was filtered through a Celite® pad, and the filtrate was concentrated in vacuo. The residue was diluted with HO (100 mL) and extracted with EtOAc (2 × 100 mL). The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. Purification by silica gel column chromatography (using 2-3% MeOH in DCM as the eluent) afforded the title compound (3.00 g, yield: 55%) as a colorless oil. 1 H NMR (400 MHz, CDCl) δ 2.68 (t, J = 6.3 Hz, 2H), 3.76 (t, J = 6.3 Hz, 2H), 4.56 (s, 2H), 7.29–7.37 (m, 5H). One H proton is fused to the solvent peak.

[0352] Step 2: Synthesis of 3-(benzyloxy)-N-methoxy-N-methylpropanamide N5_2 [ka] To a solution of 3-(benzyloxy)propanoic acid (Intermediate N5_1, 3.00 g, 16.6 mmol) in anhydrous CH3CN (60 mL), O,N-dimethylhydroxylamine hydrochloride (1.95 g, 20.0 mmol), NMI (2.7 mL, 33.3 mmol), and TCFH (7.00 g, 25.0 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was treated with HO (100 mL) and extracted with EtOAc (2 × 200 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification by silica gel column chromatography (using 3-5% MeOH in DCM as the eluent) afforded the title compound (3.20 g, 86% yield) as a colorless oil. LC-MS (Method A5): [M+H] +m / z: 224.0, rt: 0.78 min, purity: 98%. 1 H NMR (400 MHz, CDCl3) δ 2.76-2.81 (m, 2H), 3.21 (s, 3H), 3.70 (s, 3H), 3.82 (t, J = 6.4 Hz, 2H), 4.56 (s, 2H) 7.34-7.36 (m, 5H).

[0353] Step 3: Synthesis of (E)-5-(benzyloxy)-1-(methoxy(methyl)amino)pent-1-en-3-one N5_3 [ka] A solution of 3-(benzyloxy)-N-methoxy-N-methylpropanamide (Intermediate N5_2, 3.20 g, 14.3 mmol) and acetylene magnesium chloride (0.50 M solution in THF, 36 mL, 17.9 mmol) in anhydrous THF (65 mL) was heated at 50 °C for 40 min. The reaction mixture was cooled at 30 °C, followed by the addition of saturated aqueous NH4Cl (35 mL) and heating at 50 °C for 40 min. After cooling to room temperature, the reaction mixture was treated with HO (100 mL) and extracted with EtOAc (2 × 100 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification by silica gel column chromatography (using 2–3% MeOH in DCM as the eluent) afforded the title compound (2.70 g, 76% yield) as a yellow oil. LC-MS (Method A5): [M+H] + m / z: 250.0, rt: 1.76 min, purity: 84%. 1 H NMR (400 MHz, CDCl3) δ 2.73 (t, J = 6.7 Hz, 2H), 3.14 (s, 3H), 3.67 (s, 3H), 3.81 (t, J = 6.7 Hz, 2H), 4.55 (s, 2H), 5.48 (d, J = 12.6 Hz, 1H), 7.29-7.37 (m, 5H), 7.41 (d, J = 12.6 Hz, 1H).

[0354] Step 4: Synthesis of (4,5-dimethyl-2-nitrophenyl)hydrazine, hydrochloride N5_4 [ka] At 10° C., a solution of sodium nitrite (2.08 g, 30.1 mmol) in HO (20 mL) was added dropwise to a solution of 4,5-dimethyl-2-nitroaniline (5.00 g, 30.1 mmol) in concentrated aqueous HCl (38 mL). The reaction mixture was poured into a solution of tin chloride monohydrate (13.6 g, 60.2 mmol) in concentrated aqueous HCl (15 mL) at 0° C., and the reaction mixture was stirred at room temperature for 1 hour. After completion, the resulting precipitate was collected by filtration and dried under vacuum to give the title compound (5.00 g, crude product) as a yellow solid. LC-MS (Method A6): [M+H] + m / z: 182.0, rt: 1.59 min, purity: 92%. 1 H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.30 (s, 3H), 7.18 (s, 1H), 7.95 (s, 1H), 9.10 (brs, 1H). Two H protons are fused to the solvent peak.

[0355] Step 5: Synthesis of 5-(2-(benzyloxy)ethyl)-1-(4,5-dimethyl-2-nitrophenyl)-1H-pyrazole N5_5 [ka] A solution of (E)-5-(benzyloxy)-1-(methoxy(methyl)amino)pent-1-en-3-one (Intermediate N5_3, 2.60 g, 10.4 mmol), (4,5-dimethyl-2-nitrophenyl)hydrazine, hydrochloride (Intermediate N5_4, 2.84 g, 13.0 mmol), and Na2CO3 (2.21 g, 20.9 mmol) in MeOH (40 mL) and water (6.5 mL) was heated at reflux for 2 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with EtOAc (2 × 100 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification by silica gel column chromatography (using 2–3% MeOH in DCM as the eluent) afforded the title compound (1.75 g, yield: 48%) as a yellow solid. 1 H NMR (400 MHz, CDCl) δ 2.31 (s, 3H), 2.39 (s, 3H), 2.83 (t, J = 7.0 Hz, 2H), 3.62-3.70 (m, 2H), 4.47 (s, 2H), 6.28 (d, J = 1.5 Hz, 1H), 7.23 (s, 1H), 7.29-7.36 (m, 3H), 7.61 (d, J = 1.5 Hz, 1H), 7.82 (s, 1H). Two Hs are fused to the solvent peak.

[0356] Step 6: Synthesis of 2-(1-(2-amino-4,5-dimethylphenyl)-1H-pyrazol-5-yl)ethan-1-ol N5_6 [ka] To a solution of 5-(2-(benzyloxy)ethyl)-1-(4,5-dimethyl-2-nitrophenyl)-1H-pyrazole (Intermediate N5_5, 1.70 g, 4.84 mmol) in dry THF (25 mL) was added 20% Pd(OH)2 / C (0.34 g, 0.48 mmol), and the reaction mixture was stirred under a hydrogen atmosphere (P=1 atm) at room temperature for 16 hours. After completion, the reaction mixture was filtered through a Celite® pad, washed with MeOH (25 mL), and the filtrate was concentrated in vacuo to give the title compound (1.00 g, 89% yield) as a yellow sticky solid. LC-MS (Method A5): [M+H] + m / z: 231.9, rt: 1.56 min, purity: 92%. 1 H NMR (400 MHz, DMSO-d6) δ 2.10 (s, 3H), 2.15 (s, 3H), 2.58 (t, J = 7.3 Hz, 2H), 3.47-3.55 (m, 2H), 4.47 (s, 2H), 4.68 (t, J = 5.4 Hz, 1H), 6.26 (s, 1H), 6.65 (s, 1H), 6.79 (s, 1H), 7.54 (s, 1H).

[0357] Step 7: Synthesis of 8,9-dimethyl-4,6-dihydropyrazolo[1,5-a][1,5]benzodiazepin-5-one N5 A suspension of 2-(1-(2-amino-4,5-dimethylphenyl)-1H-pyrazol-5-yl)ethan-1-ol (0.50 g, 2.16 mmol) and K2CO3 (0.03 g, 0.22 mmol) in acetone (25 mL) in a steel bomb was purged with argon for 30 min. Pentamethylcyclopentadienylrhodium dichloride dimer (0.07 g, 0.11 mmol) was added, and the reaction mixture was heated at 140 °C for 16 h. After cooling to room temperature, the reaction mixture was filtered through a Celite® pad, washed with MeOH (10 mL), and the filtrate was concentrated in vacuo. Purification by silica gel column chromatography (using 2-3% MeOH in DCM as the eluent) afforded the title compound (0.29 g, 59% yield) as an off-white solid. LC-MS (Method B7): [M+H]+ m / z: 228.0, rt: 1.99 min, purity: 99%. 1 H NMR (400 MHz, DMSO-d6) δ 2.24 (s, 3H), 2.27 (s, 3H), 3.58 (s, 2H), 6.37 (s, 1H), 7.00 (s, 1H), 7.57 (s, 1H), 7.72 (s, 1H), 10.11 (s, 1H).

[0358] Intermediate N6: 13-chloro-3,10,14-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(15),2,4,6,11,13-hexaen-9-one [ka] Step 1: Synthesis of 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine N6_1 [ka] A suspension of 4-amino-5-bromo-2-chloropyridine (4.40 g, 21.2 mmol), bispinacolatodiboron (5.92 g, 23.3 mmol), and KOAc (5.20 g, 53.0 mmol) in dioxane (60 mL) was purged with argon for 20 minutes at room temperature. PdCl(dppf) (0.78 g, 1.06 mmol) was added, and the reaction mixture was heated at 90 °C for 16 hours. After cooling to room temperature, the reaction mixture was filtered through a Celite® pad, washed with EtOAc (100 mL), and the filtrate was concentrated in vacuo to give the title compound (6.00 g, crude) as a brown solid. This compound was carried on to the next reaction without further purification. LC-MS (Method A5): [M+H] + m / z: 255.0, rt: 1.96 min, purity: 37%.

[0359] Step 2: 13-chloro-3,10,14-triazatricyclo[9.4.0.0 2,7]Synthesis of pentadeca-1(15),2,4,6,11,13-hexaen-9-one N6 A solution of ethyl 2-(2-chloropyridin-3-yl)acetate (2.00 g, 10.0 mmol), K2CO3 (3.46 g, 25.0 mmol), and 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (Intermediate N6_1, 5.10 g, 20.0 mmol) in dioxane (40 mL) and HO (6 mL) was purged with argon for 20 minutes. PdCl2(dppf) (0.37 g, 0.50 mmol) was added, and the reaction mixture was heated at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. Purification by silica gel column chromatography (using 3% MeOH in DCM as the eluent) afforded the title compound (0.55 g, 22% yield) as an off-white solid. LC-MS (Method B7): [M+H] + m / z: 246.0, rt: 1.55 min, purity: 99%. 1 H NMR (400 MHz, DMSO-d6) δ 3.62 (s, 2H), 7.22 (s, 1H), 7.51-7.54 (m, 1H), 7.92 (d, J = 8.3 Hz, 1H), 8.70 (d, J = 8.3 Hz, 1H), 8.93 (s, 1H), 10.76 (s, 1H).

[0360] Intermediate N7: 8,9-dimethyl-4,6-dihydroimidazo[2,1-d][1,5]benzodiazepin-5-one [ka] Step 1: Synthesis of ethyl 3-(dimethylamino)-3-oxopropanoate N7_1 [ka] To a solution of dimethylamine (2 M solution in THF, 20 mL, 39.9 mmol) and TEA (9 mL, 66.4 mmol) in DCM (100 mL) at 0 °C, ethyl malonyl chloride (5.00 g, 33.2 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 12 h. After completion, the reaction mixture was treated with HO (200 mL) and extracted with DCM (2 × 100 mL). The organic layer was separated, washed with HO (200 mL), dried over anhydrous NaSO, and concentrated under vacuum. Purification by silica gel column chromatography (using 5% MeOH in DCM as the eluent) afforded the title compound (3.00 g, yield: 57%) as a colorless oil. LC-MS (Method A6): [M+H] + m / z: 159.8, rt: 1.10 min, purity: 99%. 1 H NMR (400 MHz, DMSO-d6) δ 1.18 (t, J = 7.1 Hz, 3H), 2.82 (s, 3H), 2.94 (s, 3H), 3.48 (s, 2H), 4.08 (q, J = 7.1 Hz, 2H).

[0361] Step 2: Synthesis of 4-(dimethylamino)-7,8-dimethyl-1,3-dihydro-2H-benzo[b][1,4]diazepin-2-one N7_2 [ka] To a mixture of ethyl 3-(dimethylamino)-3-oxopropanoate (Intermediate N7_1, 4.21 g, 26.4 mmol) and 4,5-dimethyl-1,2-phenylenediamine (1.80 g, 13.2 mmol) was added POCl3 (1.24 mL, 13.2 mmol) at 0 °C, and the reaction mixture was heated at 100 °C for 4 h. After cooling to room temperature, the reaction mixture was treated with HO (100 mL) and heated at 70 °C for 1 h. The reaction mixture was cooled to room temperature and diluted with DCM (100 mL). The aqueous layer was separated, acidified with 2 N aqueous HCl (100 mL), treated with aqueous ammonia (20 mL), and extracted with DCM (250 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was dissolved in dioxane (50 mL), followed by the addition of 4 M HCl in dioxane (25 mL). The reaction mixture was concentrated in vacuo, and the residue was triturated with EtO (55 mL). The resulting solid was dissolved in H0 (100 mL), basified with 10% aqueous NaCO (50 mL), and extracted with DCM (250 mL). The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. The crude solid was purified by preparative HPLC (basic elution) to give the title compound (0.61 g, yield: 20%) as a yellow solid. LC-MS (Method B7): [M+H] + m / z: 232.0, rt: 1.98 min, purity: 95%. 1 H NMR (400 MHz, DMSO-d6) δ 2.13 (s, 6H), 3.06 (s, 6H), 3.11 (brs, 2H), 6.75 (s, 1H), 6.81 (s, 1H), 10.0 (s, 1H).

[0362] Step 3: Synthesis of 4-((2,2-dimethoxyethyl)amino)-7,8-dimethyl-1,3-dihydro-2H-benzo[b][1,4]diazepin-2-one N7_3 [ka] A suspension of 4-(dimethylamino)-7,8-dimethyl-1,3-dihydro-2H-benzo[b][1,4]diazepin-2-one (Intermediate N7_2, 0.40 g, 1.73 mmol), aminoacetaldehyde dimethyl acetal (0.30 mL, 3.46 mmol), and para-toluenesulfonic acid monohydrate (0.09 g, 0.52 mmol) in Dowtherm® (10 mL) was heated at 160 °C for 2 h. After cooling to room temperature, the reaction mixture was treated with HO (50 mL) and extracted with EtOAc (2 × 100 mL). The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. Purification by silica gel column chromatography (using 3% MeOH in DCM as the eluent) afforded the title compound (0.15 g, 29% yield) as an off-white solid. LC-MS (Method A5): [M+H] + m / z: 292.0, rt: 1.65 min, purity: 96%. 1 H NMR (400 MHz, DMSO-d6) δ 2.13 (s, 6H), 2.95 (s, 2H), 3.38 (s, 6H), 4.52-4.55 (m, 1H), 6.74 (s, 1H), 6.81 (s, 1H), 7.32-7.36 (m, 1H), 9.89 (s, 1H). Two H protons are fused to the solvent peak.

[0363] Step 4: Synthesis of 8,9-dimethyl-4,6-dihydroimidazo[2,1-d][1,5]benzodiazepin-5-one N7 A solution of 4-((2,2-dimethoxyethyl)amino)-7,8-dimethyl-1,3-dihydro-2H-benzo[b][1,4]diazepin-2-one (Intermediate N7_3, 0.30 g, 1.03 mmol) in formic acid (10 mL) was heated at 100 °C for 5 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was treated with saturated aqueous NaHCO (50 mL) and extracted with EtOAc (2 × 100 mL). The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. Purification by silica gel column chromatography (using 3% MeOH in DCM as eluent) afforded the title compound (0.15 g, yield: 62%) as an off-white solid. LC-MS (Method B7): [M+H] + m / z: 228.0, rt: 1.85 min, purity: 97%. 1 H NMR (400 MHz, DMSO-d6) δ 2.24 (s, 3H), 2.26 (s, 3H), 3.55 (s, 2H), 7.03 (s, 2H), 7.40 (s, 1H), 7.64 (s, 1H), 10.16 (s, 1H).

[0364] Intermediate N8: 9,10-dimethyl-5,7-dihydropyrimido[5,4-d][1]benzazepin-6-one [ka] A mixture of ethyl 2-(4-chloropyrimidin-5-yl)acetate (0.60 g, 2.99 mmol), KCO (1.24 g, 8.97 mmol), and 4,5-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (Intermediate N1_3, 0.88 g, 3.59 mmol) in dioxane (12 mL) and HO (4 mL) was purged with argon at room temperature for 30 minutes. Pd(PPh) (0.35 g, 0.30 mmol) was added, and the reaction mixture was heated at 90 °C for 16 hours. After cooling to room temperature, the reaction mixture was filtered through a Celite pad, and the filtrate was partitioned between EtOAc (100 mL) and HO (50 mL). The organic layer was separated, washed with brine (100 mL), dried over anhydrous NaSO, and concentrated in vacuo. Purification by silica gel column chromatography (using 2-3% MeOH in DCM as eluent) afforded the title compound (0.22 g, 31% yield) as an off-white solid. LC-MS (Method B7): [M+H] + m / z: 240.0, rt: 1.76 min, purity: 98%. 1 H NMR (400 MHz, DMSO-d6) δ 2.29 (s, 3H), 2.30 (s, 3H), 3.47 (s, 2H), 7.02 (s, 1H), 7.82 (s, 1H), 8.82 (s, 1H), 9.20 (s, 1H), 10.22 (s, 1H).

[0365] Intermediate N9: 2-chloro-9,10-dimethyl-5,7-dihydropyrido[3,2-d][1]benzazepin-6-one [ka] Step 1: Synthesis of 3-(bromomethyl)-2,6-dichloropyridine N9_1 [ka] To a solution of 2,6-dichloro-3-methylpyridine (5.00 g, 30.9 mmol) in DCE (50 mL) was added NBS (6.04 g, 33.9 mmol) and AIBN (0.51 g, 3.09 mmol), and the reaction mixture was heated at 90 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was treated with HO (50 mL) and extracted with DCM (100 mL). The organic layer was separated, washed with HO (100 mL), dried over anhydrous NaSO, and concentrated in vacuo. Purification by silica gel column chromatography (using 8% EtOAc in hexane as the eluent) afforded the title compound (3.50 g, 47% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 4.74 (s, 2H), 7.63 (d, J = 7.9 Hz, 1H), 8.15 (d, J = 7.9 Hz, 1H).

[0366] Step 2: Synthesis of 2-(2,6-dichloropyridin-3-yl)acetonitrile N9_2 [ka] To a solution of 3-(bromomethyl)-2,6-dichloropyridine (Intermediate N9_1, 3.50 g, 14.5 mmol) in CHCN (20 mL) at 0 °C, TMSCN (3.64 mL, 29.1 mmol) was added, and the reaction mixture was stirred at the same temperature for 15 min. TBAF (1 M solution in THF, 29 mL, 29.0 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 6 h. After completion, the reaction mixture was treated with HO (50 mL) and extracted with EtOAc (2 × 100 mL). The organic layer was separated, washed with HO (100 mL), dried over anhydrous NaSO, and concentrated in vacuo. Purification by silica gel column chromatography (using 15% EtOAc in hexane as the eluent) afforded the title compound (1.75 g, yield: 64%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 4.15 (s, 2H), 7.66 (d, J = 7.9 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H).

[0367] Step 3: Synthesis of methyl 2-(2,6-dichloropyridin-3-yl)acetate N9_3 [ka] A solution of 2-(2,6-dichloropyridin-3-yl)acetonitrile (Intermediate N9_2, 1.60 g, 8.55 mmol) in a 2N solution of HCl in methanol (8 mL) was heated at 70° C. for 16 h under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was treated with saturated aqueous NaHCO (80 mL) and extracted with EtOAc (100 mL). The organic layer was separated, washed with brine (100 mL), dried over Na SO and concentrated in vacuo. Purification by silica gel column chromatography (using 35% EtOAc in hexane as the eluent) afforded the title compound (1.60 g, yield: 87%) as an off-white solid. LC-MS (Method A5): [M+H] + m / z: 219.7, rt: 1.82 min, purity: 94%. 1 H NMR (400 MHz, DMSO-d6) δ 3.65 (s, 3H), 3.88 (s, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H).

[0368] Step 4: Synthesis of 2-chloro-9,10-dimethyl-5,7-dihydropyrido[3,2-d][1]benzazepin-6-one N9 A mixture of methyl 2-(2,6-dichloropyridin-3-yl)acetate (Intermediate N9_3, 0.70 g, 3.18 mmol), K2CO3 (1.32 g, 9.54 mmol), and 4,5-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (Intermediate N1_3, 0.79 g, 3.18 mmol) in dioxane (5 mL) and HO (1 mL) was purged with argon at room temperature for 15 minutes. Pd(PPh3)4 (0.18 g, 0.16 mmol) was added, and the reaction mixture was heated at 90 °C under a nitrogen atmosphere for 16 hours. After cooling to room temperature, the reaction mixture was partitioned between EtOAc (100 mL) and HO (50 mL). The organic layer was separated, washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. Purification by silica gel column chromatography (using 5% MeOH in DCM as eluent) afforded the title compound (0.065 g, yield: 7%) as an off-white solid. LC-MS (Method A5): [M+H] + m / z: 273.0, rt: 2.50 min, purity: 98%. 1 H NMR (400 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.29 (s, 3H), 3.42 (s, 2H), 6.98 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 10.11 (s, 1H).

[0369] Intermediate N10: 5-chloro-4,8,14-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(15),2,4,6,11,13-hexaen-9-one [ka] The title compound was prepared according to the procedure of Intermediate N12, starting from methyl 2-(3-bromopyridin-4-yl)acetate in Step 2. Purification by silica gel column chromatography (using 3% MeOH in DCM as eluent) afforded the title product (0.40 g, yield: 25%) as an off-white solid. LC-MS (Method B7): [M+H] + m / z: 246.0, rt: 1.22 min, purity: 94%. 1 H NMR (400 MHz, DMSO-d6) δ 3.64 (s, 2H), 7.25 (s, 1H), 7.52 (d, J = 5.2 Hz, 1H) 8.66 (d, J= 5.2 Hz, 1H) 8.78 (s, 1H) 8.88 (s, 1H) 10.8 (s, 1H).

[0370] Intermediate N11: 3-chloro-5,7-dihydropyrido[4,3-d][3]benzazepin-6-one [ka] The title compound was prepared according to the procedure of Intermediate N12 using 2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate in Step 2. Purification by trituration in DCM afforded the title product (30 mg, yield: 52%) as a beige solid, which was carried on to the next step without further purification. LC-MS (Method B1): [MH] - m / z: 243.0, rt: 2.00 min, purity: 87%.

[0371] Intermediate N12: 5-chloro-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexan-9-one [ka] Step 1: Synthesis of 2-[3-(4,6-dichloro-3-pyridyl)-2-pyridyl]acetonitrile N12_1 [ka] Under an inert atmosphere, to a solution of 2-(3-bromopyridin-2-yl)acetonitrile (302 mg, 1.50 mmol) and 4,6-dichloropyridine-3-boronic acid (587 mg, 3.00 mmol) in dioxane (12 mL) was added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (112 mg, 0.15 mmol), followed by 2 M aqueous NaCO solution (3 mL). The reaction mixture was sonicated for a few seconds and then heated at 80 °C for 3 h. After cooling to room temperature, water was added, and the reaction mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated in vacuo. The crude solid was purified by silica gel flash column chromatography (using a gradient of heptane / EtOAc 100:0 to 50:50 as eluent) to give the title compound as an orange oil (200 mg, yield: 47%). LC-MS (Method B1) m / z: [M+H] + :265.9, rt:1.15 min, purity: 93%. 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 4.9 Hz, 1H), 8.46 (s, 1H), 8.04 (s, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.55 (dd, J = 7.7, 4.9 Hz, 1H), 4.13 - 3.90 (m, 2H).

[0372] Step 2: Synthesis of 2-[3-(4,6-dichloro-3-pyridyl)-2-pyridyl]acetamide N12_2 [ka] A suspension of 2-[3-(4,6-dichloro-3-pyridyl)-2-pyridyl]acetonitrile (Intermediate N12_1, 200 mg, 0.70 mmol) in concentrated sulfuric acid (1 mL) was heated at 60 °C for 2 h. After cooling to 0 °C, the reaction mixture was slowly neutralized by the addition of saturated aqueous NaHCO3 and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over MgSO4, filtered off, and concentrated in vacuo to give the title compound as a yellow solid (175 mg, yield: 80%). LC-MS (Method B1) m / z: [M+H] + :282.0, rt:0.94min, purity:91%. 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 4.9 Hz, 1H), 8.39 (s, 1H), 7.98 (s, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.42 (dd, J = 7.7, 4.9 Hz, 1H), 7.32 (s, 1H), 6.85 (s, 1H), 3.55 (d, J = 15.2 Hz, 1H), 3.36 (d, J = 15.2 Hz, 1H).

[0373] Step 3: 5-chloro-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexan-9-one N12 At 0°C, sodium hydride (60% suspension in oil, 240 mg, 6.0 mmol) was slowly added to a solution of 2-[3-(4,6-dichloro-3-pyridyl)-2-pyridyl]acetamide (Intermediate N12_2, 876 mg, 2.98 mmol) in dry DMF (15 mL), and the resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into cold water and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a brown solid. Trituration in DCM afforded the title compound as a light brown solid (402 mg, yield: 55%). LC-MS (Method B1) m / z: [M+H] + :246.0, rt:0.82 min, purity >99%. 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.72 (s, 1H), 8.64 (dd, J = 4.8, 1.6 Hz, 1H), 8.16 (dd, J = 7.8, 1.6 Hz, 1H), 7.54 (dd, J = 7.8, 4.8 Hz, 1H), 7.26 (s, 1H), 3.76 (s, 2H).

[0374] Intermediate N13: 12-chloro-5-thia-9,13-diazatricyclo[8.4.0.0 2,6 ]Tetradeca-1(10),2(6),3,11,13-pentaen-8-one [ka] Step 1: Synthesis of ethyl 2-(3-bromothiophen-2-yl)acetate N13_1 [ka] To a solution of 3-bromothiophene-2-carbaldehyde (6.00 g, 31.4 mmol) in anhydrous THF (150 mL) were added methylsulfanyl(methylsulfinyl)methane (10 mL, 97.4 mmol) and a 40% solution of benzyltrimethylammonium hydroxide in methanol (8.5 mL, 18.8 mmol), and the reaction mixture was heated at 60° C. under nitrogen for 4 h. After cooling to room temperature, the reaction mixture was poured into 0.5 N HCl solution and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was dissolved in a 0.5 N solution of HCl in EtOH (50 mL), and the reaction mixture was heated at reflux for 2 h. The solvent was removed in vacuo, and the crude mixture was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (100 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with a gradient of 10-15% EtOAc in hexanes) to afford the title product (2.50 g, 29% yield) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 5.4 Hz, 1H), 6.96 (d, J = 5.4 Hz, 1H), 4.21 (q, J = 7.3 Hz, 2H), 3.83 (s, 2H), 1.30 (t, J = 7.3 Hz, 3H).

[0375] Step 2: Synthesis of ethyl 2-(3-(4-amino-6-chloropyridin-3-yl)thiophen-2-yl)acetate N13_2 [ka] To a solution of ethyl 2-(3-bromothiophen-2-yl)acetate (Intermediate N13_1, 0.35 g, 1.40 mmol) in dioxane (5 mL) and water (1 mL) was added K2CO3 (0.58 g, 4.21 mmol) and 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (Intermediate N6_1, 1.07 g, 4.21 mmol), and the reaction mixture was purged with argon for 30 minutes. PdCl2(dppf) (0.05 g, 0.07 mmol) was added, and the reaction mixture was heated at 80 °C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo, and the residue was directly purified by silica gel column chromatography (using a gradient of 3-5% MeOH in DCM as eluent) to give ethyl 2-(3-(4-amino-6-chloropyridin-3-yl)thiophen-2-yl)acetate (0.07 g, yield: 17%) as an off-white solid and 3-chloro-5,7-dihydro-6H-pyrido[4,3-b]thieno[3,2-d]azepin-6-one (0.05 g, yield: 14%) as an off-white solid. LC-MS (Method A5) m / z: [M+H] + :296.7, rt:1.80min, purity:73%.

[0376] Step 3: 12-chloro-5-thia-9,13-diazatricyclo[8.4.0.0 2,6 ]Synthesis of tetradeca-1(10),2(6),3,11,13-pentaen-8-one N13 To a solution of ethyl 2-(3-(4-amino-6-chloropyridin-3-yl)thiophen-2-yl)acetate (Intermediate N13_2, 0.07 g, 0.24 mmol) in anhydrous DMF (2 mL) at 0 °C, NaH (60% dispersion in oil, 0.01 g, 0.35 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography (using a gradient of 3–5% MeOH in DCM as the eluent) to give the title product (0.03 g, yield: 51%) as an off-white solid. LC-MS (Method A5) m / z: [M+H] + :251.0, rt:1.94min, purity:98%. 1 H NMR (400 MHz, DMSO-d6) δ 10.67 (bs, 1H), 8.69 (s, 1H), 7.58 (d, J = 5.4 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.20 (s, 1H), 3.69 (s, 2H).

[0377] Intermediate N14: 1,3-dimethyl-5,7-dihydropyrido[4,3-d][3]benzazepin-6-one [ka] Step 1: Synthesis of methyl 2-[2-(4-amino-2,6-dimethyl-3-pyridyl)phenyl]acetate N14_1 [ka] Under an inert atmosphere, a mixture of 4-amino-3-bromo-2,6-dimethylpyridine (50 mg, 0.24 mmol), cesium carbonate (59 mg, 0.18 mmol), methyl 2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (31 mg, 0.11 mmol), and Pd(PPh) (11 mg, 0.01 mmol) in 1,2-dimethoxyethane (1 mL) was heated at 120 °C for 4 h. After cooling to room temperature, the reaction mixture was filtered through a Celite pad with EtOAc, and the filtrate was concentrated in vacuo to give the title compound (62 mg, 94% yield) as a yellow solid, which was carried on crude to the next step. LC-MS (Method B1): [M+H] + m / z: 271.0, rt: 2.12 min.

[0378] Step 2: Synthesis of 1,3-dimethyl-5,7-dihydropyrido[4,3-d][3]benzazepin-6-one N14 To a solution of methyl 2-[2-(4-amino-2,6-dimethyl-3-pyridyl)phenyl]acetate (Intermediate N14_1, 62 mg, 0.23 mmol) in dry toluene (2.3 mL) at room temperature, a 1 M solution of lithium bis(trimethylsilyl)amide in THF (690 μL, 0.69 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was treated with saturated aqueous NH4Cl and extracted twice with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by silica gel preparative TLC (using 10% MeOH in DCM as the eluent) afforded the title compound (8 mg, yield: 15%) as an off-white solid. LC-MS (Method B1): [M+H] + m / z:239.0, rt:1.81 min, purity >90%.

[0379] Intermediate N15: 12-chloro-5,6,9,13-tetraazatricyclo[8.4.0.0 2,6 ]Tetradeca-1(10),2,4,11,13-pentaen-8-one [ka] Step 1: Synthesis of 2-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-4-amine N15_1 [ka] To a solution of 4-amino-5-bromo-2-chloropyridine (1.20 g, 5.78 mmol) in dioxane (20 mL) was added KCO (2.00 g, 14.5 mmol) and 1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (3.22 g, 11.6 mmol), and the reaction mixture was purged with argon for 30 min. SPhos Pd G (0.23 g, 0.31 mmol) and Pd(dba) (0.27 g, 0.29 mmol) were added at room temperature, and the reaction mixture was heated at 80 °C for 16 h. After completion, the reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (using 3-5% MeOH in DCM as eluent) to give the title product (1.00 g, yield: 62%) as a yellow sticky solid. LC-MS (Method A5): [M+H] + m / z: 279.0, rt: 1.69 min, purity: 86%. 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.64 (d, J = 1.0 Hz, 1H), 6.71 (s, 1H), 6.40 (d, J = 1.0 Hz, 1H), 6.19 (bs, 2H), 5.01 (dd, J = 9.8, 2.0 Hz, 1H), 3.39-3.49 (m, 2H), 2.28-2.38 (m, 2H), 1.80-1.98 (m, 2H), 1.46-1.60 (m, 2H).

[0380] Step 2: Synthesis of 2-chloro-N-(2-chloro-5-(1H-pyrazol-5-yl)pyridin-4-yl)acetamide N15_2 [ka] To a solution of 2-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-4-amine (Intermediate N15_1, 0.50 g, 1.79 mmol) in THF (10 mL) at 0 °C, NaH (60% dispersion in oil, 0.11 g, 2.69 mmol) was added and the reaction mixture was stirred at room temperature for 10 min. 2-Chloroacetyl chloride (0.3 mL, 3.59 mmol) was added at 0 °C and the reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with HO (25 mL), neutralized with saturated aqueous NaHCO (25 mL), and extracted with EtOAc (2 × 50 mL). The organic layer was separated, dried over anhydrous NaSO, filtered off, and concentrated in vacuo. Purification by silica gel column chromatography (using 3-5% MeOH in DCM as eluent) afforded the title product (0.20 g, yield: 41%) as an off-white solid. LC-MS (Method A5): [M+H] + m / z: 270.9, rt: 1.84 min, purity: 82%. 1 H NMR (400 MHz, DMSO-d6) δ 13.56 (bs, 1H), 12.57 (bs, 1H), 8.88 (s, 1H), 8.54 (s, 1H), 8.00 (d, J = 1.9 Hz, 1H), 7.07 (d, J = 1.9 Hz, 1H), 4.53 (s, 2H). Step 3: 12-chloro-5,6,9,13-tetraazatricyclo[8.4.0.0 2,6 ]Synthesis of tetradeca-1(10),2,4,11,13-pentaen-8-one N15

[0381] To a solution of 2-chloro-N-(2-chloro-5-(1H-pyrazol-5-yl)pyridin-4-yl)acetamide (Intermediate N15_2, 0.40 g, 1.48 mmol) in dry DMF (10 mL) was added NaH (60% dispersion in oil, 0.09 g, 2.21 mmol), and the reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with HO (25 mL) and extracted with EtOAc (2 × 50 mL). The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. Purification by silica gel column chromatography (using 3-5% MeOH in DCM as the eluent) afforded the title product (0.165 g, 48% yield) as an off-white solid. LC-MS (Method B7): [M+H] + m / z: 235.0, rt: 1.84 min, purity: 99%. 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (bs, 1H), 8.70 (d, J = 1.9 Hz, 1H), 7.63 (s, 1H), 7.26 (d, J = 1.9 Hz, 1H), 6.86 (s, 1H), 4.98 (s, 2H).

[0382] Intermediate N16: 15-Fluoro-13-methyl-3,10,14-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Step 1: Synthesis of 2-fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine N16_1 [ka] In a nitrogen-filled glovebox, 2-fluoro-6-methyl-pyridin-4-amine (Intermediate NN445, 138 mg, 1.04 mmol) was dissolved in anhydrous THF (1 mL) in a 6 mL pressure tube containing a magnetic stir bar. Pinacolborane (211 μL, 1.45 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. (1,5-Cyclooctadiene)(methoxy)iridium(I) dimer (10 mg, 0.015 mmol), 4,4'-di-tert-butyl-2,2'-dipyridyl (9 mg, 0.033 mmol), and bis(pinacolato)diboron (158 mg, 0.62 mmol) were added, the tube was sealed under a nitrogen atmosphere, and the reaction mixture was heated at 80 °C for 16 h. After cooling to room temperature, methanol (3 mL) was added, and the reaction mixture was stirred for 10 min until gas evolution ceased, then concentrated in vacuo. The crude brown oil was purified by silica gel column chromatography (using a gradient of 100 / 0 to 50 / 50 DCM / EtOAc as eluent) and trituration in hexane to give the title compound as a pale pink solid (200 mg, yield: 72%). LC-MS (Method B1) m / z: [M+H] + :253.0, rt:1.13min, purity:95%. 1 H NMR (400 MHz, DMSO-d6) δ 6.58 (s, 2H), 6.29 (d, J = 1.9 Hz, 1H), 2.16 (s, 3H), 1.28 (s, 12H).

[0383] Step 2: 15-Fluoro-13-methyl-3,10,14-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one N16 To a solution of 2-fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (Intermediate N16_1, 237 mg, 0.94 mmol) and methyl 2-(2-chloro-3-pyridyl)acetate (175 mg, 0.94 mmol) in dioxane (4.7 mL) was added K2CO3 (394 mg, 2.82 mmol) and water (0.3 mL). The resulting mixture was degassed and filled with N2, and then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (39 mg, 0.047 mmol) was added. The reaction mixture was heated at 100 °C for 16 h. After cooling to room temperature, the reaction mixture was treated with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over NaSO, filtered and concentrated in vacuo. The crude brown oil was triturated in EtO to give the title compound as a brown solid (70 mg, yield: 28%). LC-MS (Method A1) m / z: [M+H] + :244.0, rt:0.67min, purity:92%. 1 H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.64 (d, J = 4.7 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.47 (dd, J = 7.8, 4.7 Hz, 1H), 6.96 (s, 1H), 3.61 (d, J = 12.8 Hz, 1H), 3.54 (d, J = 12.8 Hz, 1H).

[0384] Intermediate N17: 9-chloro-3-methyl-5,7-dihydropyrido[4,3-d][3]benzazepin-6-one [ka] A suspension of 4-amino-5-bromo-2-methylpyridine (200 mg, 1.05 mmol), methyl 2-(5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (514 mg, 1.56 mmol), and cesium carbonate (684 mg, 2.1 mmol) in 1,2-dimethoxyethane (10 mL) was purged with argon for 20 minutes. 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (86 mg, 0.10 mmol) was added, and the reaction mixture was heated at 140°C for 6 hours. After cooling to room temperature, water was added, and the reaction mixture was extracted three times with EtOAc. The combined organic layers were washed with water, brine, dried over NaSO, filtered, and concentrated in vacuo. The crude brown oil was purified by trituration in diethyl ether to give the title compound as a beige solid (84 mg, yield: 31%). LC-MS (Method B1) m / z: [M+H] + :259.0;rt:1.98min;purity:85%.

[0385] Intermediate N18: 12-Methyl-5,6,9,13-tetraazatricyclo[8.4.0.0 2,6 ]Tetradeca-1(10),2,4,11,13-pentaen-8-one [ka] Under an inert atmosphere, a 2M solution of methylzinc chloride in THF (0.42 mL, 0.84 mmol) was added dropwise to a suspension of Intermediate N15 (50 mg, 0.21 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (17 mg, 0.02 mmol), and cuprous iodide (4 mg, 0.02 mmol) in anhydrous THF (2 mL), and the reaction mixture was heated at 70 °C for 16 h. After cooling to room temperature, the reaction mixture was filtered through a Celite pad with DMF, and the filtrate was purified by reverse-phase chromatography to give the title compound (23 mg, 44% yield) as a white solid. LC-MS (Method B1): [M+H] +m / z:215.1, rt:0.73 min, purity >99%.

[0386] Intermediate N19: 1-chloro-3-methyl-5,7-dihydropyrido[4,3-d][3]benzazepin-6-one [ka] Step 1: Synthesis of 2-chloro-3-iodo-6-methyl-pyridin-4-amine N19_1 [ka] To a solution of 2-chloro-6-methylpyridin-4-amine (2.0 g, 13.3 mmol) in anhydrous acetonitrile (67 mL) was added N-iodosuccinimide (3.15 g, 14.0 mmol), and the reaction mixture was heated at 80 °C for 22 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between EtOAc and saturated aqueous NaSO. The phases were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The crude yellow solid was purified by silica gel column chromatography (using a gradient of 100 / 0 to 50 / 50 heptane / EtOAc as eluent) to give the title product as a gray solid (1.69 g, yield: 47%). LC-MS (Method A1) m / z: [M+H] + :269.0, rt: 0.72 min, purity: >99%. 1 H NMR (400 MHz, DMSO-d6) δ 6.41 (s, 2H), 6.39 (s, 1H), 2.19 (s, 3H).

[0387] Step 2: Synthesis of methyl 2-[2-(4-amino-2-chloro-6-methyl-3-pyridyl)phenyl]acetate N19_2 [ka] Under an inert atmosphere, to a solution of 2-chloro-3-iodo-6-methyl-pyridin-4-amine (Intermediate N19_1, 1.35 g, 5.03 mmol) in 1,4-dioxane (40 mL) was added methyl 2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1.9 g, 6.50 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (356 mg, 0.50 mmol), KCO (2.11 g, 15.1 mmol), and water (10 mL). The reaction mixture was sonicated for a few seconds and heated at 100 °C for 3 h. After cooling to room temperature, water was added, and the mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO4, filtered off and concentrated in vacuo to give the title compound as a brown oil (2.46 g, yield: 79%), which was carried on crude to the next step. LC-MS (Method B1) m / z: [M+H] + :290.9, rt:1.09min, purity:74%. 1 H NMR (400 MHz, DMSO-d6) δ 7.47 - 7.33 (m, 4H), 6.49 (s, 1H), 5.46 (s, 2H), 3.47 (s, 3H), 3.44 (s, 2H), 2.26 (s, 3H).

[0388] Step 3: Synthesis of 1-chloro-3-methyl-5,7-dihydropyrido[4,3-d][3]benzazepin-6-one N19 Starting from methyl 2-[2-(4-amino-2-chloro-6-methyl-3-pyridyl)phenyl]acetate (Intermediate N19_2, 185 mg, 0.64 mmol), the title product was prepared according to the same procedure as Step 2 of Intermediate N14. Purification by trituration in Et2O afforded the title compound (70 mg, yield: 41%) as a beige solid. LC-MS (Method B1): [M+H] + m / z:258.9, rt:1.09 min, purity >99%. 1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 7.85 - 7.61 (m, 2H), 7.53 - 7.26 (m, 3H), 3.63 - 3.39 (m, 2H), 2.46 (s, 3H).

[0389] Intermediate N20: 3,5-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] A suspension of 3-bromo-2,6-dimethylpyridin-4-amine (200 mg, 0.97 mmol), methyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]acetate (Intermediate N25_2, 341 mg, 1.69 mmol), and potassium phosphate tribasic (640 mg, 2.92 mmol) in toluene (4.9 mL) was purged with argon for 20 minutes. Tris(dibenzylideneacetone)dipalladium(0) (92 mg, 0.10 mmol) and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (82 mg, 0.96 mmol) were added, and the reaction mixture was heated at 120 °C for 20 hours. After cooling to room temperature, water was added, and the reaction mixture was extracted three times with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo to give an orange solid. Purification by trituration in diethyl ether gave the title compound as a beige solid (114 mg, yield: 49%). LC-MS (Method B1) m / z: [M+H] + :240.0;rt:0.74min;purity:98%.

[0390] Intermediate N21: 9-chloro-1,3-dimethyl-5,7-dihydropyrido[4,3-d][3]benzazepin-6-one [ka] Step 1: Synthesis of methyl 2-[2-(4-amino-2,6-dimethyl-3-pyridyl)-5-chloro-phenyl]acetate N21_1 [ka] Under an inert atmosphere, a mixture of 4-amino-3-bromo-2,6-dimethyl-pyridine (100 mg, 0.49 mmol), KCO (204 mg, 1.46 mmol), methyl 2-(5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (191 mg, 0.58 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (35 mg, 0.05 mmol) in dioxane (3.9 mL) and water (1.0 mL) was heated at 100° C. for 3.5 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water and extracted twice with EtOAc. The combined organic extracts were dried with brine and over MgSO4, filtered off and concentrated in vacuo to give the title compound (155 mg, quantitative yield) as a yellow oil, which was carried on crude to the next step. LC-MS (Method B1): [M+H] + m / z: 305.0, rt: 1.22 min.

[0391] Step 2: Synthesis of 9-chloro-1,3-dimethyl-5,7-dihydropyrido[4,3-d][3]benzazepin-6-one N21 Starting from methyl 2-[2-(4-amino-2,6-dimethyl-3-pyridyl)-5-chloro-phenyl]acetate (Intermediate N21_2, 149 mg, 0.49 mmol), the title product was prepared according to the same procedure as Step 2 of Intermediate N14. Purification by trituration in Et2O afforded the title compound (107 mg, yield: 80%) as a beige solid. LC-MS (Method B1): [M+H] + m / z: 273.0, rt: 1.12 min, purity: 95%.

[0392] Intermediate N22: 3-Fluoro-10-hydroxy-5-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Step 1: Synthesis of ethyl 2-acetoxy-2-(3-bromo-2-pyridyl)acetate N22_1 [ka] To a solution of ethyl 2-(3-bromo-2-pyridyl)acetate (Intermediate N3_1, 3.9 g, 15.6 mmol) in DCM (60 mL) was added iodobenzene diacetate (5.6 g, 17.0 mmol), and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was treated with 50 mL of water, the DCM phase was separated using a Phase Separator Syringe, and the organic layer was concentrated under vacuum. Purification by silica gel column chromatography (using 20% ​​EtOAc in hexane as the eluent) afforded the title compound as a pale yellow solid (3.5 g, yield: 75%). LC-MS (Method B1) m / z: [M+H] + :302.0;rt:1.22min;Purity.

[0393] Step 2: Synthesis of ethyl 2-acetoxy-2-[3-(4-amino-2-fluoro-6-methyl-3-pyridyl)-2-pyridyl]acetate N22_2 [ka] To a solution of 2-fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (Intermediate N16_1, 200 mg, 0.71 mmol) and ethyl 2-acetoxy-2-(3-bromo-2-pyridyl)acetate (Intermediate N22_1, 216 mg, 0.71 mmol) in anhydrous toluene (4 mL) was added potassium phosphate tribasic (312 mg, 1.42 mmol). After argon was passed through the reaction mixture, tris(dibenzylideneacetone)dipalladium(0) (65 mg, 0.07 mmol) and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (30 mg, 0.07 mmol) were added. The reaction mixture was then stirred at 100 °C for 5 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered through a PTFE filter, and the filtrate was concentrated to dryness to give the crude title compound as a brown foam, which was carried on to the next step without purification. LC-MS (Method A1) m / z: [M+H] + :348; rt: 0.94 min and 1.08 min as a mixture of diastereoisomers; purity 32%.

[0394] Step 3: 3-Fluoro-10-hydroxy-5-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one N22 At 0° C., to a solution of ethyl 2-acetoxy-2-[3-(4-amino-2-fluoro-6-methyl-3-pyridyl)-2-pyridyl]acetate (Intermediate N22_2, 248 mg, 0.71 mmol) in anhydrous toluene (4 mL) was added a 1.5 M solution of lithium bis(trimethylsilyl)amide in THF (1.4 mL, 2.10 mmol), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized by adding saturated aqueous NH4Cl and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by trituration in Et2O to give the title compound as a beige solid (135 mg, yield: 65%). LC-MS (Method A1) m / z: [M+H]+ RT: 260.0; rt: 0.69 min; Purity: 95%. Major diastereoisomer (7:3) 1 H NMR (400 MHz, DMSO-d6)δ 10.92 (bs, 1H), 8.70 (d, J = 4.7 Hz, 1H), 8.14 (ddd, J = 8.0, 4.7, 1.6 Hz, 1H), 7.54 (dd, J = 8.0, 4.7 Hz, 1H), 7.01 (s, 1H), 5.59 (d, J = 8.2 Hz, 1H), 5.01 (d, J = 8.2 Hz, 1H), 2.46 (s, 3H). 1 H NMR (400 MHz, DMSO-d6): δ 10.92 (bs, 1H), 8.62 (d, J = 4.7 Hz, 1H), 8.18 (ddd, J = 8.0, 4.7, 1.6 Hz, 1H), 7.56 (dd, J = 8.0, 4.7 Hz, 1H), 6.96 (s, 1H), 6.26 (d, J = 3.1 Hz, 1H), 5.28 (d, J = 3.1 Hz, 1H), 2.43 (s, 3H).

[0395] Intermediate N23: 3-Fluoro-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Step 1: Synthesis of methyl 2-[3-(4-amino-2-fluoro-6-methyl-3-pyridyl)-2-pyridyl]propanoate N23_1 [ka] To a solution of 2-fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (Intermediate N16_1, 100 mg, 0.39 mmol) and methyl 2-(3-bromopyridin-2-yl)propanoate (102 mg, 0.40 mmol) in anhydrous toluene (2 mL) was added potassium carbonate (170 mg, 1.22 mmol). After argon was passed through the reaction mixture, tris(dibenzylideneacetone)dipalladium(0) (36 mg, 0.04 mmol) and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (17 mg, 0.04 mmol) were added. The reaction mixture was then stirred at 100 °C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (10 mL) and filtered through a PTFE filter. The filtrate was concentrated in vacuo to give the crude title compound as a yellow oil (225 mg), which was used directly in the next step without purification. LC-MS (Method A1) m / z: [M+H] + :290; rt: 0.80 min, 0.84 min and 0.92 min.

[0396] Step 2: 3-Fluoro-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one N23 At 0° C., a solution of crude methyl 2-[3-(4-amino-2-fluoro-6-methyl-3-pyridyl)-2-pyridyl]propanoate (Intermediate N23_1, 115 mg, 0.40 mmol) in dry toluene (2 mL) was added with a 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 minutes. The reaction mixture was neutralized at 0° C. by the addition of saturated aqueous NH4Cl and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated in vacuo to give a yellow solid. Purification by trituration in Et2O afforded the title compound as a brown solid (11 mg, yield: 10%). LC-MS (Method A1) m / z: [M+H] +:258.0;rt:0.93min;purity:94%.

[0397] Intermediate N24: 14-Methoxy-12-methyl-4,5,6,9,13-pentaazatricyclo[8.4.0.0 2,6 ]Tetradeca-1(10),2,4,11,13-pentaen-8-one [ka] Step 1: Synthesis of 3-iodo-2-methoxy-6-methyl-pyridin-4-amine N24_1 [ka] 2-Methoxy-6-methyl-pyridin-4-amine (2.5 g, 18.1 mmol) was dissolved in anhydrous THF (100 mL), and N-iodosuccinimide (3.66 g, 16.3 mmol) was added portionwise over 45 min at −78° C. The reaction mixture was stirred at −78° C. for 3 h and then allowed to warm gradually to room temperature. The resulting suspension was diluted with water (50 mL), extracted with ethyl acetate (3×50 mL), and the combined organic extracts were washed with brine (2×50 mL). The organic phase was filtered through a hydrophobic frit and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (using 0–30% ethyl acetate in cyclohexane as eluent) to give the title compound (4.59 g, 93% yield) as a pale orange solid. LC-MS (Method B5) m / z: [M+H] + :265.0;rt:1.69min;purity:99%. 1 H NMR (400 MHz, CDCl3) δ 6.14 (d, J = 0.7 Hz, 1H), 4.54 (s, 2H), 3.95 (s, 3H), 2.32 (d, J = 0.7 Hz, 3H).

[0398] Step 2: Synthesis of 2-methoxy-6-methyl-3-(2-trimethylsilylethynyl)pyridin-4-amine N24_2 [ka] A mixture of 3-iodo-2-methoxy-6-methyl-pyridin-4-amine (Intermediate N24_1, 5.00 g, 18.9 mmol), trimethylsilylacetylene (11.16 g, 114 mmol), cuprous iodide (361 mg, 1.89 mmol), bis(triphenylphosphine)palladium(II) chloride (1.33 g, 1.89 mmol), and triethylamine (18.5 mL, 133 mmol) in anhydrous dioxane (70 mL) was heated at 80 °C for 2 h. The reaction mixture was cooled to room temperature and filtered through a small plug of Celite®. The filter cake was rinsed with ethyl acetate (70 mL), and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (0–30% ethyl acetate in cyclohexane as eluent) to give the title compound (2.80 g, 57% yield) as an orange oil. 1 H NMR (400 MHz, CDCl3) δ 6.13 (d, J = 0.7 Hz, 1H), 4.63 (s, 2H), 3.98 (s, 3H), 2.33 (s, 3H), 0.29 (s, 9H).

[0399] Step 3: Synthesis of 3-ethynyl-2-methoxy-6-methyl-pyridin-4-amine N24_3 [ka] 2-Methoxy-6-methyl-3-(2-trimethylsilylethynyl)pyridin-4-amine (Intermediate N24_2, 2.50 g, 10.1 mmol) was dissolved in MeOH (50 mL) and potassium carbonate (1.68 g, 12.2 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes and at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were filtered through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel flash chromatography (using 0-100% ethyl acetate in isohexane as eluent) to give the title compound (1.35 g, 80% yield) as a yellow oil. LC-MS (Method B5) m / z: [M+H] + :163.0;rt:1.35min;purity:97%. 1 H NMR (400 MHz, CDCl3) δ 6.13 (s, 1H), 4.64 (s, 2H), 3.99 (s, 3H), 3.63 (s, 1H), 2.34 (s, 3H).

[0400] Step 4: Synthesis of 2-chloro-N-(3-ethynyl-2-methoxy-6-methyl-4-pyridyl)acetamide N24_4 [ka] 3-Ethynyl-2-methoxy-6-methyl-pyridin-4-amine (Intermediate N24_3, 1.25 g, 7.40 mmol) and triethylamine (973 mg, 9.62 mmol) were dissolved in dry DCM (25 mL) and 2-chloroacetyl chloride (1.67 g, 14.8 mmol) was added slowly at 0 °C. The reaction mixture was allowed to warm gradually to room temperature and stirred for 20 h. The reaction mixture was diluted with DCM (25 mL) and washed with saturated aqueous NaHCO3 (2 × 20 mL). The organic phase was filtered through a hydrophobic frit and concentrated in vacuo to give the title compound (1.90 g, 97% yield) as a brown solid. The product was carried on to the next step without further purification or analysis.

[0401] Step 5: Synthesis of 2-azido-N-(3-ethynyl-2-methoxy-6-methyl-4-pyridyl)acetamide N24_5 [ka] 2-Chloro-N-(3-ethynyl-2-methoxy-6-methyl-4-pyridyl)acetamide (Intermediate N24_4, 1.90 g, 7.16 mmol) was dissolved in anhydrous DMF (20 mL) and sodium azide (699 mg, 10.7 mmol) was added. The reaction mixture was stirred at room temperature for 3 h, then diluted with water (40 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic extracts were filtered through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel flash chromatography (using 0–50% ethyl acetate in isohexane as eluent) to give the title compound (1.64 g, 87% yield) as a pale orange solid. LC-MS (Method B5) m / z: [M+H] + :246.0;rt:1.93 minutes, purity:93%. 1 H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 7.88 (s, 1H), 4.20 (s, 2H), 4.04 (s, 3H), 3.82 (s, 1H), 2.48 (s, 3H).

[0402] Step 6: 14-Methoxy-12-methyl-4,5,6,9,13-pentaazatricyclo[8.4.0.0 2,6 ]Synthesis of tetradeca-1(10),2,4,11,13-pentaen-8-one N24 2-Azido-N-(3-ethynyl-2-methoxy-6-methyl-4-pyridyl)acetamide (Intermediate N24_5, 1.64 g, 6.22 mmol) was dissolved in anhydrous DMF (120 mL) and stirred at 150 °C for 18 h. The reaction mixture was cooled to room temperature and diluted with water (150 mL). The aqueous phase was extracted with ethyl acetate (3 × 150 mL) and the combined organic layers were washed with brine (2 × 100 mL). The organic phase was filtered through a hydrophobic frit and concentrated in vacuo. The residue was triturated in MeOH (50 mL) and filtered. The filtrate was concentrated in vacuo and triturated in tert-butyl methyl ether (50 mL). The solid thus formed was collected by filtration and dissolved in MeOH (50 mL) to form a suspension. The suspension was filtered and the filtrate was concentrated in vacuo to give the title compound (1.51 g, yield: 69%) as a beige solid. LC-MS (Method B5) m / z:[M+H] + :246.0;rt:1.20 minutes, purity:80%. 1 H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.06 (s, 1H), 6.77 (s, 1H), 5.20 (s, 2H), 3.96 (s, 3H), 2.42 (s, 3H).

[0403] Intermediate N25: 3-Methoxy-5-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Step 1: Synthesis of 3-bromo-2-methoxy-6-methyl-pyridin-4-amine N25_1 [ka] To a solution of 2-methoxy-6-methyl-pyridin-4-amine (505 mg, 3.47 mmol) in DCM (25 mL) at 0 °C, a suspension of NBS (618 mg, 3.47 mmol) in DCM (10 mL) was added, and the reaction mixture was stirred at 0 °C for 1 h. Water (40 mL) was added, and the aqueous layer was extracted with DCM (2 × 30 mL). The combined organic extracts were washed with brine (80 mL), dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (using 0-4% MeOH (0.7 N in NH ) in DCM as eluent) to give the title compound as a colorless oil (653 mg, yield: 86%). LC-MS (Method B5) m / z: [M+H] + :217.1 / 219.1;rt:1.57min;Purity over 99%. 1 H NMR (400 MHz, CDCl3) δ 6.16 (d, J = 0.7 Hz, 1H), 4.47 (s, 2H), 3.97 (s, 3H), 2.31 (s, 3H).

[0404] Step 2: Synthesis of ethyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]acetate N25_2 [ka] Under an inert atmosphere, ethyl 2-(3-bromo-2-pyridyl)acetate (Intermediate N3_1, 5.00 g, 20.5 mmol), bis(pinacolato)diboron To a suspension of 1,4-dioxane (CAS 73183-34-3, 6.24 g, 24.6 mmol), potassium acetate (8.0 g, 81.9 mmol), and 3 Å molecular sieves (3 g) in 1,4-dioxane (200 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (749 mg, 1.02 mmol). The suspension was heated at reflux overnight and then cooled to room temperature. It was filtered through a Celite® pad and washed with ethyl acetate (400 mL). The filtrate was concentrated in vacuo, and the residue was purified by silica gel flash chromatography (0–100% tert-butyl methyl ether in cyclohexane as eluent) to give the title compound as a brown oil (2.35 g, 37% yield). LC-MS (Method B5) m / z: [M+H] + :292.2;rt:2.08 minutes, purity:95%. 1 H NMR (400 MHz, CDCl3) δ 8.60 (dd, J = 4.9, 1.9 Hz, 1H), 8.14 (dd, J = 7.6, 1.9 Hz, 1H), 7.23 (dd, J = 7.6, 4.9 Hz, 1H), 4.22 (s, 2H), 4.18 (q, J = 7.1 Hz, 2H), 1.35 (s, 12H), 1.28 - 1.24 (m, 3H).

[0405] Step 3: 3-Methoxy-5-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one N25 Under an inert atmosphere, palladium(II) acetate (28.2 mg, 0.125 mmol) was added to a suspension of 3-bromo-2-methoxy-6-methyl-pyridin-4-amine (Intermediate N25_1, 550 mg, 2.51 mmol), ethyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]acetate (Intermediate N25_2, 1.25 g, 3.51 mmol), SPhos (103 mg, 0.251 mmol), and CsF (1.07 g, 7.02 mmol) in 1,4-dioxane (22.8 mL) and water (1.1 mL). The solution was heated at reflux overnight. It was cooled to room temperature, filtered through a Celite® pad, washed with ethyl acetate (150 mL), and the filtrate was concentrated in vacuo. The residue was dissolved in EtOH (22.8 mL) and potassium carbonate (693 mg, 5.02 mmol) was added. The reaction mixture was heated at reflux overnight, and the EtOH was removed in vacuo. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (3 × 70 mL). The combined organic extracts were washed with brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (using 0–10% MeOH (0.7 N NH) in DCM as eluent). Evaporation of the fractions and trituration of the resulting solid with tert-butyl methyl ether afforded the title compound as an off-white solid (378 mg, yield: 59%). LC-MS (Method B5) m / z: [M+H] + :256.2;rt:1.45 minutes, purity over 99%. 1 H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.51 (dd, J = 4.7, 1.7 Hz, 1H), 8.14 (dd, J = 8.0, 1.7 Hz, 1H), 7.40 (dd, J = 8.0, 4.7 Hz, 1H), 6.70 (s, 1H), 3.89 (s, 3H), 3.65 (d, J = 12.4 Hz, 1H), 3.59 (d, J = 12.4 Hz, 1H), 2.41 (s, 3H).

[0406] Intermediate N26: 15-Methoxy-13-methyl-4,6,10,14-tetraazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Step 1: Synthesis of ethyl 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-4-yl]acetate N26_1 To a solution of ethyl 2-(5-bromopyrimidin-4-yl)acetate (Intermediate N36_2, 0.10 g, 0.408 mmol) in dioxane (2 mL) was added potassium acetate (120 mg, 1.22 mmol) and bis(pinacolato)diboron (155 mg, 0.612 mmol). The reaction mixture was purged with nitrogen for 5 minutes, and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (33 mg, 0.041 mmol) was added. The reaction mixture was heated at 80°C for 18 hours. The reaction mixture was cooled to room temperature and filtered through a small pad of Celite®. The filter cake was rinsed with ethyl acetate (20 mL), and the filtrate was concentrated in vacuo to give the crude title compound as a tan solid, which was carried on to the next step without purification.

[0407] Step 2: 15-Methoxy-13-methyl-4,6,10,14-tetraazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one N26 To a solution of 3-bromo-2-methoxy-6-methyl-pyridin-4-amine (Intermediate N25_1, 80 mg, 0.365 mmol) in dioxane (2 mL) and water (0.1 mL) was added ethyl 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-4-yl]acetate (107 mg, 0.365 mmol) and CsF (166 mg, 1.09 mmol). The reaction mixture was purged with nitrogen for 5 minutes, and S-Phos (15 mg, 0.036 mmol) and palladium(II) acetate (8 mg, 0.036 mmol) were added. The reaction mixture was again purged with nitrogen for 5 minutes and heated at 90 °C for 18 hours. The reaction mixture was cooled to room temperature and filtered through a small pad of Celite®. The filter cake was rinsed with ethyl acetate (20 mL), and the filtrate was concentrated in vacuo. The residue was dissolved in ethanol (2 mL), potassium carbonate (101 mg, 0.73 mmol) was added, and the reaction mixture was heated at 70° C. for 4 h. After cooling to room temperature, the reaction mixture was filtered through Celite®, washed with ethyl acetate (15 mL), and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (using 0-10% MeOH in DCM as eluent) to afford the title compound (25 mg, yield: 23%) as a pale yellow solid. LC-MS (Method B5) m / z: [M+H] + :257.2;rt:1.30min;purity 86%. 1 H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 9.16 (s, 1H), 9.09 (s, 1H), 6.73 (s, 1H), 3.92 (s, 3H), 3.81 (d, J = 12.5 Hz, 1H), 3.55 (d, J = 12.5 Hz, 1H), 2.43 (s, 3H).

[0408] Intermediate N27: 14-Methoxy-12-methyl-5,6,9,13-tetraazatricyclo[8.4.0.0 2,6 ]Tetradeca-1(10),2,4,11,13-pentaen-8-one [ka] Step 1: Synthesis of 2-methoxy-6-methyl-3-(2-tetrahydropyran-2-ylpyrazol-3-yl)pyridin-4-amine N27_1 [ka] A mixture of 3-bromo-2-methoxy-6-methyl-pyridin-4-amine (Intermediate N25_1, 2.00 g, 9.21 mmol), 1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (3.07 g, 11.1 mmol), bis(dibenzylideneacetone)palladium (265 mg, 0.461 mmol), S-Phos (189 mg, 0.461 mmol), and potassium carbonate (3.82 g, 27.6 mmol) in anhydrous dioxane (45 mL) was heated at 90 °C for 3 h. The reaction mixture was cooled to room temperature and filtered through a small pad of Celite®. The filter cake was rinsed with ethyl acetate (45 mL), and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (0-100% ethyl acetate in isohexane) to give the title compound (1.10 g, 38% yield) as a sticky orange solid. LC-MS (Method B5) m / z: [M+H] + :289.0;rt:1.59min;purity 91%. 1 H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J = 1.9 Hz, 1H), 6.23 (d, J = 12.9 Hz, 1H), 6.18 (dd, J = 18.0, 1.7 Hz, 1H), 5.46 (d, J = 25.7 Hz, 2H), 4.94 - 4.80 (m, 1H), 3.89 - 3.80 (m, 1H), 3.67 (m, 3H), 3.39 - 3.33 (m, 1H), 2.34 - 2.20 (m, 4H), 1.98 - 1.91 (m, 1H), 1.82 - 1.72 (m, 1H), 1.63 - 1.42 (m, 3H). Split peak due to atropisomerism.

[0409] Step 2: Synthesis of 2-chloro-N-[2-methoxy-6-methyl-3-(1H-pyrazol-5-yl)-4-pyridyl]acetamide N27_2 [ka] At 0° C., 2-methoxy-6-methyl-3-(2-tetrahydropyran-2-ylpyrazol-3-yl)pyridin-4-amine (Intermediate N27_1, 1.05 g, 3.46 mmol) was dissolved in anhydrous THF (25 mL) and sodium hydride (60% dispersion in oil, 208 mg, 5.19 mmol) was added. The resulting suspension was stirred at room temperature for 15 minutes, and then 2-chloroacetyl chloride (0.55 mL, 6.92 mmol) was added slowly at 0° C. The reaction mixture was allowed to gradually warm to room temperature and stirred overnight. The reaction mixture was diluted with water (30 mL) and saturated aqueous NaHCO3 (30 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic extracts were filtered through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluting with 0-100% ethyl acetate in isohexane) to give the title compound (427 mg, 36% yield) as a yellow solid. LC-MS (Method B5) m / z: [M+H] + :281.0 / 283.0;rt:1.77min;purity 83%.

[0410] Step 3: 14-Methoxy-12-methyl-5,6,9,13-tetraazatricyclo[8.4.0.0 2,6 ]Synthesis of tetradeca-1(10),2,4,11,13-pentaen-8-one N27 2-Chloro-N-[2-methoxy-6-methyl-3-(1H-pyrazol-5-yl)-4-pyridyl]acetamide (Intermediate N27_2, 427 mg, 1.26 mmol) was dissolved in anhydrous DMF (15 mL) and sodium hydride (60% dispersion in oil, 76 mg, 1.89 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Water (35 mL) was added and the mixture was extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were washed with brine (2 × 20 mL), filtered through a hydrophobic frit, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (using 0–10% MeOH in DCM as eluent) to afford the title compound (245 mg, 71% yield) as a pale yellow solid. LC-MS (Method B5) m / z: [M+H] + :245.0;rt:1.39min;purity 89%. 1 H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 7.56 (d, J = 2.0 Hz, 1H), 6.68 (s, 1H), 6.67 (d, J = 2.0 Hz, 1H), 4.85 (s, 2H), 3.93 (s, 3H), 2.40 (s, 3H).

[0411] Intermediate N28: 3,10-difluoro-5-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Step 1: Synthesis of ethyl 2-(3-bromo-2-pyridyl)-2-fluoro-acetate N28_1 [ka] A solution of ethyl 2-(3-bromo-2-pyridyl)acetate (Intermediate N3_1, 100 mg, 0.40 mmol) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor®, 165 mg, 0.44 mmol) in acetonitrile (0.9 mL) and water (0.9 mL) was stirred at room temperature for 16 hours. The reaction mixture was extracted twice with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title product as a colorless oil (88 mg, yield: 84%). LC-MS (Method A1) m / z: [M+H] + :264.0;rt:1.25 minutes, purity:99%. 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (dd, J = 4.6, 1.4 Hz, 1H), 8.24 (dt, J = 8.1, 1.4 Hz, 1H), 7.48 (ddd, J = 8.1, 4.6, 1.4 Hz, 1H), 6.43 (d, J = 46.7 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H).

[0412] Step 2: Synthesis of ethyl 2-[3-(4-amino-2-fluoro-6-methyl-3-pyridyl)-2-pyridyl]-2-fluoro-acetate N28_2 [ka] The title compound was prepared according to the same procedure as in Step 2 of Intermediate N22, starting from 2-fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (Intermediate N16_1, 100 mg, 0.36 mmol) and ethyl 2-(3-bromo-2-pyridyl)-2-fluoroacetate (Intermediate N28_1, 97 mg, 0.36 mmol). The reaction mixture was diluted with EtOAc and filtered through Celite®. The filtrate was concentrated to dryness and carried on to the next step as crude product (109 mg, yield: 99%). LC-MS (Method B1) m / z: [M+H] + :309.0, rt:1.12 minutes.

[0413] Step 3: 3,10-difluoro-5-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one N28 The title compound was prepared according to the same procedure as in Step 3 of Intermediate N22, starting from ethyl 2-[3-(4-amino-2-fluoro-6-methyl-3-pyridyl)-2-pyridyl]-2-fluoroacetate (Intermediate N28_2, 109 mg, 0.35 mmol). Purification by trituration in diethyl ether afforded the title compound (52 mg, yield: 47%). LC-MS (Method B1) m / z: [M+H] + :262.0, rt:0.83min, purity:84%.

[0414] Intermediate N29: 3-Fluoro-5-methyl-4,8,11-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(15),2(7),3,5,13-pentaene-9,12-dione [ka] Step 1: Synthesis of methyl 2-(2-bromo-6-oxo-1-pyridyl)acetate N29_1 [ka] To a solution of 6-bromopyridin-2(1H)-one (100 mg, 0.55 mmol) in anhydrous 1,2-dimethoxyethane (1 mL) and anhydrous DMF (0.3 mL) at 0°C, sodium hydride (60% dispersion in oil, 24 mg, 0.65 mmol) was added, and the reaction mixture was stirred for 10 minutes. Lithium bromide (104 mg, 1.20 mmol) was then added in one portion, and the resulting mixture was stirred at room temperature for 15 minutes. Methyl bromoacetate (78 μL, 0.82 mmol) was added, and the reaction mixture was heated at 60°C for 16 hours. The reaction mixture was poured into cold water and extracted with DCM (3 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give a crude colorless oil. Purification by silica gel column chromatography (using a gradient of 100:0 to 50:50 heptane / EtOAc as eluent) afforded the title compound as a colorless oil (60 mg, yield: 45%). LC-MS (Method A1) m / z: [M+H] + :246.0, rt:0.87min, purity:99%. 1 H NMR (400 MHz, DMSO-d6) δ 7.38 (dd, J = 9.2, 7.2 Hz, 1H), 6.69 (dd, J = 7.2, 1.2 Hz, 1H), 6.47 (dd, J = 9.2, 1.2 Hz, 1H), 4.99 (s, 2H), 3.71 (s, 3H).

[0415] Step 2: 3-Fluoro-5-methyl-4,8,11-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(15),2(7),3,5,13-pentaene-9,12-dione N29 To a solution of 2-fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (Intermediate N16_1, 100 mg, 0.40 mmol) and methyl 2-(2-bromo-6-oxo-1-pyridyl)acetate (98 mg, 0.40 mmol) in anhydrous toluene (2 mL) was added KPO (260 mg, 1.20 mmol). After argon was passed through the reaction mixture, both tris(dibenzylideneacetone)dipalladium(0) (36 mg, 0.04 mmol) and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (17 mg, 0.04 mmol) were added. The reaction mixture was then stirred at 100 °C for 10 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and filtered through Celite®. The filtrate was concentrated in vacuo. Purification by trituration with Et2O afforded the title compound as a dark green solid (58 mg, yield: 46%). LC-MS (Method B1) m / z: [M+H] + :259.9, rt:0.79min, purity:81%.

[0416] Intermediate N30: ​​14-chloro-4,12-dimethyl-5,6,9,13-tetraazatricyclo[8.4.0.0 2,6 ]Tetradeca-1(14),2,4,10,12-pentaen-8-one [ka] Step 1: Synthesis of 3-bromo-2-chloro-6-methyl-pyridin-4-amine N30_1 [ka] A solution of 2-chloro-6-methyl-pyridin-4-amine (10.0 g, 66.6 mmol) in anhydrous acetonitrile (300 mL) was cooled to 0° C., then N-bromosuccinimide (11.3 g, 63.3 mmol) was added over 1 h, and the reaction mixture was stirred at 0° C. for 3 h, then warmed to room temperature and stirred for a further 18 h. The reaction mixture was then concentrated in vacuo and purified by silica gel column chromatography (using a gradient of 0-50% EtOAc in isohexane as eluent) to afford the title compound (7.05 g, yield: 47%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 6.53 (s, 2H), 6.47 (d, J = 0.7 Hz, 1H), 2.20 (s, 3H).

[0417] Step 2: Synthesis of 3-methyl-1-tetrahydropyran-2-yl-pyrazole N30_2 [ka] A stirred solution of 3-methyl-1H-pyrazole (10.0 g, 122 mmol), 2,3-dihydro-4H-pyran (13.3 mL, 146 mmol), and TFA (0.45 mL, 6.09 mmol) in anhydrous toluene (70 mL) was heated at 110 °C for 24 h. The reaction mixture was cooled to room temperature and diluted with brine (100 mL) and saturated aqueous NaHCO (100 mL). The aqueous layer was extracted with EtOAc (3 × 100 mL), and the combined organic layers were filtered through a hydrophobic frit and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (using a gradient of 0–50% MTBE in isohexane as eluent) to afford the title compound (20.3 g, 92% yield) as a colorless oil. LC-MS (Method B5') m / z: [M+H] + :167.0;rt:1.23min;purity:99%.

[0418] Step 3: Synthesis of 3-methyl-1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole N30_3 [ka] 3-Methyl-1-tetrahydropyran-2-yl-pyrazole (Intermediate N30_2, 9.50 g, 57.2 mmol) was dissolved in anhydrous THF (70 mL), and then n-butyllithium (2.50 M in hexane, 25 mL, 62.9 mmol) was slowly added at −78° C. The reaction mixture was stirred at −78° C. for 1.5 hours. Triisopropylborate (11.8 g, 62.9 mmol) was then slowly added at −78° C., and the reaction mixture was stirred at −78° C. for an additional 15 minutes. The reaction mixture was allowed to warm gradually to room temperature and then stirred for an additional 1.5 hours. Pinacol (7.43 g, 62.9 mmol) and acetic acid (6.54 mL, 114 mmol) were added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the residue was partitioned between water (150 mL) and EtOAc (150 mL). The layers were separated and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with brine (2 x 50 mL), filtered through a hydrophobic frit, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: 0-50% MTBE in isohexane) to afford the title compound (11.20 g, 64% yield) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 6.54 (s, 1H), 5.79 (dd, J = 10.5, 2.3 Hz, 1H), 4.11 - 4.05 (m, 1H), 3.74 - 3.61 (m, 1H), 2.55 - 2.40 (m, 1H), 2.32 (s, 3H), 2.13 - 2.06 (m, 1H), 1.98 - 1.92 (m, 1H), 1.73 (ddt, J = 25.6, 12.7, 3.9 Hz, 2H), 1.59 - 1.50 (m, 1H), 1.35 (s, 12H).

[0419] Step 4: Synthesis of 2-chloro-6-methyl-3-(5-methyl-2-tetrahydropyran-2-yl-pyrazol-3-yl)pyridin-4-amine N30_4 [ka] A stirred mixture of 3-bromo-2-chloro-6-methyl-pyridin-4-amine (Intermediate N30_1, 0.40 g, 1.81 mmol), 3-methyl-1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (Intermediate N30_3, 1.06 g, 3.61 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)-phosphine)-dichloro-palladium(II) (128 mg, 0.181 mmol) and aqueous potassium carbonate (1.50 M, 3.6 mL, 5.42 mmol) in 1,4-dioxane (40 mL) was heated at 90° C. for 1.5 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (40 mL). The resulting suspension was filtered through a small pad of Celite® and the filter cake was rinsed with EtOAc (30 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel flash chromatography (using a gradient of 0-100% EtOAc in isohexane as eluent) to afford the title compound (405 mg, yield: 68%) as a yellow foam. The product was obtained as a mixture of diastereomers. LC-MS (Method B5') m / z: [M+H] + :307 / 309;rt:1.25 / 1.47min;purity:94%. 1 H NMR (400 MHz, CDCl3) δ 6.45 (t, J = 1.2 Hz, 1H), 6.12 - 6.07 (m, 1H), 4.89 (dd, J = 10.6, 2.4 Hz, 1H), 4.42 (s, 2H), 4.08 - 3.96 (m, 1H), 3.57 - 3.40 (m, 1H), 2.59 - 2.44 (m, 4H), 2.39 - 2.34 (m, 3H), 2.04 - 1.92 (m, 2H), 1.81 - 1.46 (m, 3H).

[0420] Step 5: Synthesis of 2-chloro-N-[2-chloro-6-methyl-3-(5-methyl-2-tetrahydropyran-2-yl-pyrazol-3-yl)-4-pyridyl]acetamide N30_5 [ka] 2-Chloro-6-methyl-3-(5-methyl-2-tetrahydropyran-2-yl-pyrazol-3-yl)pyridin-4-amine (Intermediate N30_4, 400 mg, 1.21 mmol) was dissolved in anhydrous DCM (15 mL) and N,N-diisopropylethylamine (940 mg, 7.28 mmol) was added. 2-Chloroacetyl chloride (0.24 mL, 3.03 mmol) was added dropwise slowly at 0 °C, and the reaction mixture was allowed to gradually warm to room temperature and stirred overnight. The reaction mixture was diluted with DCM (25 mL) and then washed with water (2 × 25 mL). The organic phase was filtered through a hydrophobic frit and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (using a gradient of 0–100% EtOAc in isohexane as eluent) to afford the title compound (122 mg, 23% yield) as an orange oil. 1 H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 8.16 (d, J = 18.2 Hz, 1H), 6.16 (d, J = 12.0 Hz, 1H), 4.81 (dd, J = 10.2, 2.5 Hz, 1H), 4.04 (d, J = 8.4 Hz, 2H), 3.98 - 3.90 (m, 1H), 3.34 (m, 1H), 2.64 (d, J = 1.2 Hz, 3H), 2.61 - 2.48 (m, 1H), 2.38 (d, J = 9.8 Hz, 3H), 2.05 - 1.92 (m, 2H), 1.76 - 1.43 (m, 3H).

[0421] Step 6: 13-chloro-7-(chloromethyl)-4,11-dimethyl-5,6,8,12-tetraazatricyclo[7.4.0.02,6 Synthesis of ]trideca-1(13),2,4,7,9,11-hexaene hydrochloride N30_6 [ka] 2-Chloro-N-[2-chloro-6-methyl-3-(5-methyl-2-tetrahydropyran-2-yl-pyrazol-3-yl)-4-pyridyl]acetamide (Intermediate N30_5, 122 mg, 0.28 mmol) was dissolved in a 4 M solution of HCl in 1,4-dioxane (2.0 mL) and stirred at room temperature for 30 minutes. Evaporation of the volatiles afforded the title compound (90 mg, yield: 92%) as a beige solid. The product was used in the next step without further purification. LC-MS (Method A7) m / z: [M+H] + :281 / 283;rt:2.22min;purity:91%.

[0422] Step 7: 14-chloro-4,12-dimethyl-5,6,9,13-tetraazatricyclo[8.4.0.0 2,6 ]Synthesis of tetradeca-1(14),2,4,10,12-pentaen-8-one N30 13-chloro-7-(chloromethyl)-4,11-dimethyl-5,6,8,12-tetraazatricyclo[7.4.0.0 2,6 ]Trideca-1(13),2,4,7,9,11-hexaene hydrochloride (Intermediate N30_6, 90.0 mg, 0.258 mmol) was dissolved in 1,4-dioxane (5 mL) and water (2 mL), and aqueous NaOH (2 M, 0.26 mL, 0.516 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 h, then diluted with water (10 mL) and acidified to pH 3-5 with aqueous HCl (1 M, 1 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL), and the combined organic extracts were filtered through a hydrophobic frit and concentrated in vacuo. The residue was triturated with MTBE (5 mL) to give the title compound (38 mg, 53% yield) as a beige solid. The product was used in the next step without further purification. LC-MS (Method B5') m / z: [M+H] +:263 / 265;rt:1.15min;purity:98%. 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 7.05 (s, 1H), 6.63 (s, 1H), 4.83 (s, 2H), 2.47 (s, 3H), 2.23 (s, 3H).

[0423] Intermediate N31: 3-chloro-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2,4,6,12,14-hexaen-9-one [ka] Step 1: Synthesis of ethyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]propanoate N31_1 [ka] Ethyl 2-(3-bromo-2-pyridyl)propanoate (Intermediate N68_2, 30.0 g, 116 mmol), bis(pinacolato)diboron (35.4 g, 139 mmol), and potassium acetate (45.6 g, 465 mmol) were suspended in anhydrous 1,4-dioxane (500 mL), and the reaction mixture was degassed with nitrogen for 10 minutes. Pd(dppf)Cl2 (5.95 g, 8.14 mmol) was added, and the reaction mixture was stirred at 80 °C for 24 hours. The reaction mixture was cooled to room temperature and filtered through a small pad of Celite®. The filter cake was rinsed with EtOAc (200 mL), and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluting with a gradient of 0–100% MTBE in isohexane) to give the title compound (32.3 g, 45% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.60 (dd, J = 4.8, 2.0 Hz, 1H), 8.10 (d, J = 7.4 Hz, 1H), 7.17 (d, J = 6.6 Hz, 1H), 4.71 (d, J = 7.1 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 1.55 - 1.51 (m, 3H), 1.34 (s, 12H), 1.18 (d, J = 6.9 Hz, 3H).

[0424] Step 2: 3-chloro-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2,4,6,12,14-hexaen-9-one N31 [ka] A mixture of 3-bromo-2-chloro-6-methyl-pyridin-4-amine (Intermediate N30_1, 400 mg, 1.81 mmol), ethyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]propanoate (Intermediate N31_1, 1.10 g, 2.53 mmol), cesium fluoride (768 mg, 5.06 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (64 mg, 0.090 mmol) in 1,4-dioxane (34 mL) and water (1.7 mL) was purged with nitrogen and then heated at reflux for 18 hours. The reaction was allowed to cool to room temperature and then filtered through a Celite® bed, washing with EtOAc (100 mL). The filtrate was concentrated in vacuo and then dissolved in absolute EtOH (16 mL), to which potassium carbonate (499 mg, 3.61 mmol) was added, and the reaction mixture was heated at 65° C. for 4 hours. The reaction mixture was concentrated in vacuo, then water (75 mL) was added, and the reaction mixture was extracted with EtOAc (3×75 mL). The combined organic layers were dried, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (using a gradient of 0-100% EtOAc in isohexane as eluent) to afford the title compound (178 mg, yield: 35%) as an off-white solid. LC-MS (Method A7) m / z: [M+H] + :274;rt:1.45min;purity:99%. 1 H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.64 (dd, J = 4.7, 1.7 Hz, 1H), 8.18 (dd, J = 7.9, 1.7 Hz, 1H), 7.44 (dd, J = 7.9, 4.7 Hz, 1H), 7.05 (s, 1H), 3.64 (q, J = 6.6 Hz, 1H), 2.48 (s, 3H), 1.47 (d, J = 6.6 Hz, 3H).

[0425] The racemate was separated by chiral chromatography (Daicel SFC Chiralpak AS, CO₂ + isopropanol 20%). Chiral purity 98.6%; rt = 1.79 min (second eluting enantiomer, N31_A). For reference, first eluting enantiomer N31_B rt = 1.615 min. Both were determined by HPLC, Daicel Chiralpak AS, solvent: heptane 50% - ethanol 50% - DEA 0.1%.

[0426] Intermediate N32: 1-chloro-7-methoxy-3-methyl-5,7-dihydropyrido[3,4-a][3]benzazepin-6-one [ka] Step 1: Synthesis of methyl 2-bromo-2-(2-bromophenyl)acetate N32_1 [ka] A mixture of methyl 2-(2-bromophenyl)acetate (4.71 g, 20.6 mmol), 2,2'-azobis(2-methylpropionitrile) (338 mg, 2.06 mmol), and N-bromosuccinimide (3.66 g, 20.6 mmol) in chloroform (50 mL) was heated under reflux for 4 h. The reaction mixture was cooled to room temperature and washed with brine (2 × 50 mL), and the organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (6.20 g, 88% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.80 (dd, J = 7.9, 1.7 Hz, 1H), 7.61 - 7.58 (m, 1H), 7.39 (td, J = 7.6, 1.3 Hz, 1H), 7.25 - 7.20 (m, 1H), 5.93 (s, 1H), 3.83 (s, 3H).

[0427] Step 2: Synthesis of methyl 2-(2-bromophenyl)-2-methoxy-acetate N32_2 [ka] To a solution of sodium methoxide prepared from sodium metal (542 mg, 23.6 mmol) and methanol (90 mL), methyl 2-bromo-2-(2-bromophenyl)acetate (Intermediate N32_1, 6.20 g, 18.1 mmol) was added, and the reaction mixture was heated at reflux for 30 min. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was dissolved in EtOAc (30 mL), washed with brine (20 mL), and the organic phase was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The product was purified by flash chromatography on silica gel (using a gradient of 0–10% EtOAc in isohexane as the eluent) to afford the title compound (2.10 g, 44% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.64 - 7.57 (m, 1H), 7.51 (dt, J = 8.3, 2.4 Hz, 1H), 7.41 - 7.33 (m, 1H), 7.28 - 7.19 (m, 1H), 5.30 (d, J = 2.5 Hz, 1H), 3.76 (d, J = 1.5 Hz, 3H), 3.45 (d, J = 2.3 Hz, 3H).

[0428] Step 3: Synthesis of methyl 2-methoxy-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate N32_3 [ka] To a suspension of methyl 2-(2-bromophenyl)-2-methoxyacetate (Intermediate N32_2, 1.00 g, 3.78 mmol), bis(pinacolato)diboron (1.15 g, 4.54 mmol), and potassium acetate (1.48 g, 15.1 mmol) in anhydrous 1,4-dioxane (40 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (138 mg, 0.189 mmol) under an inert atmosphere, and the suspension was heated at reflux for 8 h. The reaction mixture was filtered through a Celite® pad, which was washed with EtOAc (50 mL). The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (eluting with a gradient of 0–30% MTBE in isohexane) to give the title compound (270 mg, 18% yield). LC-MS (Method B5') m / z:[M+H] + :307;rt:2.03min;purity:80%.

[0429] Step 4: Synthesis of methyl 2-[2-(4-amino-2-chloro-6-methyl-3-pyridyl)phenyl]-2-methoxy-acetate N32_4 [ka] A mixture of 3-bromo-2-chloro-6-methyl-pyridin-4-amine (Intermediate N30_1, 350 mg, 1.50 mmol), methyl 2-methoxy-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (Intermediate N32_3, 469 mg, 1.50 mmol), and cesium fluoride (684 mg, 4.50 mmol) in anhydrous 1,4-dioxane (30.0 mL) was degassed for 10 minutes. SPhos Pd(crotyl)Cl (Pd-172, CAS: 1798781-99-3, 91 mg, 0.15 mmol) was added, and the reaction mixture was heated at 90 °C for 8 hours. The reaction mixture was cooled to room temperature and poured onto water (100 mL). The crude product was extracted with EtOAc (2 x 50 mL), and the organic layers were combined and dried over sodium sulfate. The crude product was purified by silica gel flash chromatography (using a gradient of 0-100% EtOAc in isohexane as eluent) to give a mixture of the title compound (123 mg, yield: 5%) and 1-chloro-7-methoxy-3-methyl-5,7-dihydropyrido[4,3-d][3]benzazepin-6-one (123 mg, yield: 22%). The product was used in the next step without further purification. LC-MS (Method A7) m / z: [M+H] + : 321 / 323; rt: 1.01 min; purity 20% and m / z: [M+H] + :281 / 291;rt:1.66min;purity 80%.

[0430] Step 5: Synthesis of 1-chloro-7-methoxy-3-methyl-5,7-dihydropyrido[3,4-a][3]benzazepin-6-one N32 A mixture of methyl 2-[2-(4-amino-2-chloro-6-methyl-3-pyridyl)phenyl]-2-methoxyacetate (Intermediate N32_4, 125 mg, 0.078 mmol) and potassium carbonate (32 mg, 0.234 mmol) in ethanol (5.0 mL) was heated under reflux for 2 h. The reaction mixture was evaporated to dryness, and water (10 mL) was added to the residue. The reaction mixture was adjusted to pH = 5 by adding a few drops of glacial acetic acid. The resulting precipitate was collected by filtration, washed with water (5 mL), and dried under vacuum to give the title compound (89 mg, yield: 97%) as a white solid. LC-MS (Method A7) m / z: [M+H] + :289 / 291;rt:1.66min;purity:98%.

[0431] Intermediate N33: 3,5-dimethoxy-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Step 1: Synthesis of 3-bromo-2,6-dimethoxy-pyridin-4-amine N33_1 [ka] To a solution of 2,6-dimethoxypyridin-4-amine (300 mg, 1.85 mmol) in DCM (18 mL) was added N-bromosuccinimide (329 mg, 1.85 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 h and then at room temperature overnight. Water (20 mL) was then added and the phases were separated. The aqueous layer was extracted with DCM (2 x 20 mL). The organic layers were combined, washed with brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (using a gradient of 0-100% EtOAc in isohexane as eluent) to afford the title compound (360 mg, yield: 83%) as a white solid. LC-MS (Method A7) m / z: [M+H] +:233 / 235;rt:1.78min;purity:99%. 1 H NMR (400 MHz, DMSO-d6) δ 6.10 (s, 2H), 5.75 (s, 1H), 3.82 (s, 3H), 3.75 (s, 3H).

[0432] Step 2: Synthesis of ethyl 2-[3-(4-amino-2,6-dimethoxy-3-pyridyl)-2-pyridyl]acetate N33_2 [ka] A suspension of 3-bromo-2,6-dimethoxy-pyridin-4-amine (Intermediate N33_1, 145 mg, 0.616 mmol), ethyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]acetate (Intermediate N25_2, 280 mg, 0.863 mmol), SPhos (CAS 657408-07-6, 51 mg, 0.012 mmol), and cesium fluoride (294 mg, 1.85 mmol) in 1,4-dioxane (5.3 mL) and water (0.3 mL) was purged with nitrogen for 5 min. Palladium(II) acetate (11 mg, 0.048 mmol) was then added. The reaction mixture was heated at reflux overnight, then cooled to room temperature and filtered through a Celite® pad, washing with EtOAc (60 mL). The filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (using a gradient of 0-10% MeOH in DCM as eluent) to afford the title compound (332 mg, yield: 61%) as a brown oil. LC-MS (Method A7) m / z: [M+H] + :318.2;rt:1.36min;purity:36%.

[0433] Step 3: 3,5-Dimethoxy-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one N33 A suspension of ethyl 2-[3-(4-amino-2,6-dimethoxy-3-pyridyl)-2-pyridyl]acetate (Intermediate N33_2, 332 mg, 0.377 mmol), 3 Å molecular sieves (1.00 g), and anhydrous potassium carbonate (156 mg, 1.13 mmol) in anhydrous EtOH (5.0 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature and filtered through a Celite® pad, which was then washed with a 1:1 mixture of DCM / MeOH (75 mL). The filtrate was concentrated in vacuo, and the residue was purified by silica gel flash chromatography (using a gradient of 0–8% MeOH in DCM as the eluent) followed by trituration in MTBE (10 mL) to afford the title compound (60 mg, 59% yield) as an off-white solid. LC-MS (Method A7) m / z: [M+H] + :272;rt:1.38min;Purity over 99%. 1 H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.48 (dd, J = 4.8, 1.7 Hz, 1H), 8.11 (dd, J = 8.0, 1.7 Hz, 1H), 7.39 (dd, J = 8.0, 4.8 Hz, 1H), 6.24 (s, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.69 (d, J = 12.4 Hz, 1H), 3.57 (d, J = 12.4 Hz, 1H).

[0434] Intermediate N34: 3-Fluoro-5-methyl-4,8,12,13-tetraazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2,4,6,12,14-hexaen-9-one [ka] Step 1: Synthesis of 3,4-dichloropyridazine N34_1 [ka] To a solution of 5-chloro-1H-pyridazin-6-one (3.0 g, 23.0 mmol) in dry acetonitrile (25 mL) was added phosphorus oxychloride (5.3 mL, 57.5 mmol) at room temperature, and the reaction mixture was heated at 80° C. overnight. The reaction mixture was allowed to cool to room temperature and then poured onto ice / water. The reaction mixture was diluted with saturated aqueous NaHCO (50 mL) and then extracted with DCM (2×50 mL). The organic layers were combined, dried over NaSO, filtered, and concentrated in vacuo to give the title compound (3.39 g, yield: 92%) as a brown solid, which was used in the next step without further purification. LCMS (Method A7) m / z: [M+H] + :149;rt:1.04min;purity 98%.

[0435] Step 2: Synthesis of 4-(benzyloxy)-3-chloropyridazine N34_2 [ka] At 0 °C, a solution of benzyl alcohol (1.49 g, 13.7 mmol) in anhydrous THF (10 mL) was added dropwise to a suspension of NaH (60.0% dispersion in oil, 599 mg, 15.0 mmol) in anhydrous THF (20 mL). The reaction mixture was stirred at 0 °C for 30 min and then allowed to warm to room temperature. A solution of 3,4-dichloropyridazine (Intermediate N34_1, 2.0 g, 12.5 mmol) in THF (10 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was treated with water and extracted with EtOAc (2 × 30 mL). The combined organic extracts were dried over Na SO , filtered, and concentrated in vacuo. The residue was then purified by silica gel flash chromatography (using a gradient of 0–10% MeOH in DCM as the eluent) to afford the title compound (2.21 g, 77% yield) as a brown oil. LCMS (Method A7) m / z:[M+H] + :221;rt:1.77min;purity 97%.

[0436] Step 3: Synthesis of ethyl 2-(4-(benzyloxy)pyridazin-3-yl)acetate N34_3 [ka] A degassed solution of 4-benzyloxy-3-chloro-pyridazine (Intermediate N34_2, 200 mg, 0.880 mmol), bromo-(2-ethoxy-2-oxo-ethyl)zinc (0.48 M solution in THF, 3.7 mL, 1.76 mmol), tris(dibenzylideneacetone)dipalladium(0) (25 mg, 0.044 mmol), and X-Phos (CAS 564483-18-7, 19 mg, 0.044 mmol) in anhydrous THF (5.0 mL) was stirred at 65 °C for 4 h. The reaction mixture was concentrated in vacuo, then treated with saturated aqueous NH4Cl (20 mL) and extracted with DCM (2 × 25 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (using a gradient of 0-10% MeOH in DCM as eluent) to give the title compound as a yellow oil. LCMS (Method A7) m / z: [M+H] + :273;rt:1.59min;purity 77%.

[0437] Step 4: Synthesis of ethyl 2-(4-hydroxypyridazin-3-yl)acetate N34_4 [ka] To a solution of ethyl 2-(4-benzyloxypyridazin-3-yl)acetate (Intermediate N34_3, 195 mg, 0.573 mmol) in ethanol (8 mL) was added 10% Pd / C (31 mg, 0.028 mmol), and the reaction mixture was stirred under a hydrogen atmosphere (P=5 bar) for 3 hours. The reaction mixture was filtered through Celite®, and the filtrate was concentrated in vacuo to give the title compound (135 mg, yield: 75%) as an orange solid. The product was used in the next step without further purification. LCMS (Method A7) m / z: [M+H] + :183;rt:0.57min;purity 58%.

[0438] Step 5: Synthesis of ethyl 2-(4-chloropyridazin-3-yl)acetate N34_5 [ka] To a solution of ethyl 2-(4-hydroxypyridazin-3-yl)acetate (Intermediate N34_4, 200 mg, 0.56 mmol) in anhydrous acetonitrile (4 mL) was added phosphorus oxychloride (0.13 mL, 1.41 mmol) at room temperature, and the reaction mixture was heated at 80 °C for 1 h. The reaction mixture was allowed to cool to room temperature and then poured onto ice / water. Saturated aqueous NaHCO (15 mL) was added, and the aqueous phase was then extracted with DCM (2 × 15 mL). The organic layers were combined, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (using a gradient of 0-100% EtOAc in isohexane as eluent) to afford the title compound (33 mg, yield: 28%) as a yellow solid. LC-MS (Method A7) m / z: [M+H] + :201 / 203;rt:1.23min;purity:97%.

[0439] Step 6: 3-Fluoro-5-methyl-4,8,12,13-tetraazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2,4,6,12,14-hexaen-9-one N34 A mixture of ethyl 2-(4-chloropyridazin-3-yl)acetate (Intermediate N34_5, 44 mg, 0.196 mmol), 2-fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (Intermediate N16_1, 137 mg, 0.49 mmol), SPhos Pd(crotyl)Cl (CAS: 1798781-99-3, 12 mg, 0.020 mmol), aqueous potassium carbonate (1.50 M, 0.4 mL, 0.59 mmol), and cesium fluoride (89 mg, 0.588 mmol) in 1,4-dioxane (6 mL) was stirred overnight at 90 °C under an inert atmosphere. The reaction mixture was cooled to room temperature and filtered through a small pad of Celite. The filter cake was rinsed with EtOAc (10 mL) and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (using a gradient of 0-10% MeOH in DCM as eluent) to afford the title compound (19 mg, yield: 35%) as an off-white solid. LC-MS (Method A7) m / z: [M+H] + :245;rt:0.88min;purity:88%. 1 H NMR (400 MHz, CD3OD) δ 9.28 (d, J = 5.4 Hz, 1H), 8.07 (dd, J = 5.4, 4.3 Hz, 1H), 7.05 (s, 1H), 4.31 - 3.97 (m, 2H), 2.55 (s, 3H). No NH protons were observed.

[0440] Intermediate N35: 14-Fluoro-7,12-dimethyl-5,6,9,13-tetraazatricyclo[8.4.0.0 2,6 ]Tetradeca-1(10),2,4,11,13-pentaen-8-one [ka] Step 1: Synthesis of 2-fluoro-6-methyl-3-(2-tetrahydropyran-2-ylpyrazol-3-yl)pyridin-4-amine N35_1 [ka] To a solution of 4-amino-3-bromo-2-fluoro-6-methylpyridine (400 mg, 1.95 mmol) and 1-(2-tetrahydropyranyl)-1H-pyrazole-5-boronic acid pinacol ester (657 mg, 2.34 mmol) in anhydrous toluene (10 mL) was added KPO (1.28 g, 5.85 mmol). The white suspension was degassed with argon for 5 minutes, and then tris(dibenzylideneacetone)dipalladium(0) (184 mg, 0.19 mmol) and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (163 mg, 0.39 mmol) were added. The reaction mixture was stirred in a sealed reactor at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered through a celite pad, rinsed with EtOAc, and the filtrate was concentrated in vacuo. The residue was triturated with Et2O and collected by filtration to give the title product (455 mg, yield: 45%) as an orange solid. LC-MS (Method B1) m / z: [M+H] + :277.0, rt: 0.98 min, purity: 53%.

[0441] Step 2: 14-Fluoro-7,12-dimethyl-5,6,9,13-tetraazatricyclo[8.4.0.0 2,6 ]Synthesis of tetradeca-1(10),2,4,11,13-pentaen-8-one N35 To a solution of 2-fluoro-6-methyl-5-(2-tetrahydropyran-2-ylpyrazol-3-yl)pyridin-4-amine (Intermediate N35_1, 100 mg, 0.36 mmol) in anhydrous DMF (5 mL), 2-bromopropionyl chloride (107 μL, 0.87 mmol) and diisopropylethylamine (180 μL, 1.1 mmol) were added dropwise, and the reaction mixture was stirred at room temperature for 3 hours. 2-Bromopropionyl chloride (107 μL, 0.87 mmol) and diisopropylethylamine (180 μL, 1.1 mmol) were added again, and the reaction mixture was stirred at 130 °C for 1 hour. After cooling to room temperature, EtOAc was added, and the organic phase was washed three times with water. The organic layer was dried over MgSO , filtered, and concentrated in vacuo. Purification by silica gel preparative TLC (using 5% EtOH in dichloromethane as eluent) afforded the title product (24 mg, yield: 21%) as an orange oil. LC-MS (Method B1) m / z: [M+H] + :247.05, rt:0.94min, purity:80%.

[0442] Intermediate N36: 15-Fluoro-8,13 dimethyl-4,6,10,14-tetraazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(15),2(7),3,5,11,13-hexaen-9-one [ka] Step 1: Synthesis of 1-(tert-butyl) 3-ethyl 2-(5-bromopyrimidin-4-yl)malonate N36_1 [ka] To a suspension of NaH (60% dispersion in oil, 12.4 g, 310 mmol) in anhydrous DMF (400 mL) at 0° C., tert-butyl ethyl malonate (53.5 g, 284 mmol) in anhydrous DMF (50 mL) was added over 45 minutes, and the reaction mixture was stirred at 0° C. for an additional 45 minutes. A solution of 5-bromo-4-chloro-pyrimidine (50.0 g, 258 mmol) in anhydrous DMF (50 mL) was added, and the reaction mixture was stirred at 0° C. for 30 minutes, then allowed to reach room temperature and stirred for an additional 20 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride solution (1 L) and extracted with EtOAc (3×350 mL). The organic layers were combined, washed with brine (3×500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent: 0-50% EtOAc in isohexane gradient) to give the title compound (38.9 g, 41% yield) as a yellow oil. LC-MS (Method A7) m / z: [M-C4H8+H] + :289 / 291;rt:2.16min;Purity:>99%. 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 9.08 (s, 1H), 5.14 (s, 1H), 4.30 - 4.14 (m, 2H), 1.43 (s, 9H), 1.21 (t, J = 7.1 Hz, 3H).

[0443] Step 2: Synthesis of ethyl 2-(5-bromopyrimidin-4-yl)acetate N36_2 [ka] To an ice-bath cooled solution of 1-(tert-butyl) 3-ethyl 2-(5-bromopyrimidin-4-yl)malonate (Intermediate N36_1, 38.9 g, 107 mmol) in DCM (300 mL) was added TFA (100 mL), and the reaction mixture was warmed to room temperature and stirred for 18 h. The volatiles were removed in vacuo and azeotroped with toluene (100 mL). The residue was purified by silica gel flash chromatography (using a gradient of 0-50% EtOAc in isohexane as eluent) to afford the title compound (29.5 g, quantitative yield) as a yellow oil. LC-MS (Method A7) m / z: [M+H] + :245 / 247;rt:1.42min;purity:90%. 1 H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 9.02 (s, 1H), 4.13 (q, J = 7.1 Hz, 2H), 4.02 (s, 2H), 1.19 (t, J = 7.1 Hz, 3H).

[0444] Step 3: Synthesis of ethyl 2-(5-bromopyrimidin-4-yl)propanoate N36_3 [ka] To an ice-bath cooled solution of ethyl 2-(5-bromopyrimidin-4-yl)acetate (Intermediate N36_2, 29.8 g, 108 mmol) in anhydrous THF (400 mL) was added lithium bis(trimethylsilyl)amide (1 M solution in THF, 130 mL, 130 mmol) over 20 minutes, and the reaction mixture was stirred at 0° C. for 1 hour. Iodomethane (23.0 g, 162 mmol) was added dropwise, and the reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for an additional 16 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride solution (600 mL) and extracted with EtOAc (3×400 mL). The organic layers were combined, washed with saturated aqueous ammonium chloride solution (500 mL), brine (300 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: 0-50% EtOAc in isohexane) to give the title compound (12.6 g, 43% yield) as a yellow oil. LC-MS (Method A7) m / z: [M+H] + :259 / 261;rt:1.7 min;purity over 99%. 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 9.01 (s, 1H), 4.29 (q, J = 7.1 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 1.44 (d, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H).

[0445] Step 4: 15-Fluoro-8,13-dimethyl-4,6,10,14-tetraazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(15),2(7),3,5,11,13-hexaen-9-one N36 A stirred mixture of ethyl 2-(5-bromopyrimidin-4-yl)propanoate (Intermediate N36_3, 90 mg, 0.347 mmol), 2-fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (Intermediate N16_1, 138 mg, 0.521 mmol), and aqueous potassium carbonate (1.5 M, 0.7 mL, 1.04 mmol) in 1,4-dioxane (5 mL) was degassed with nitrogen for 5 minutes. Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloropalladium(II) (25 mg, 0.035 mmol) was added, and the reaction mixture was degassed with nitrogen for an additional 5 minutes. The reaction mixture was heated at 90 °C for 3 hours and then cooled to room temperature. The reaction mixture was diluted with EtOAc (20 mL) and filtered through a small pad of Celite. The filter cake was rinsed with EtOAc (10 mL) and the filtrate was concentrated in vacuo. The residue was dissolved in EtOH (5 mL), potassium carbonate (96 mg, 0.695 mmol) was added and the reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was cooled to room temperature and filtered through a small pad of Celite. The filter cake was rinsed with EtOH (10 mL) and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (using a gradient of 0-10% MeOH in DCM as eluent) to afford the title compound (28 mg, yield: 30%) as a pink solid. LC-MS (Method A7) m / z: [M+H] + :259;rt:1.25min;purity:98%. 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.24 (s, 1H), 9.09 (d, J = 4.7 Hz, 1H), 7.03 (s, 1H), 3.74 (d, J = 6.6 Hz, 1H), 2.47 (s, 3H), 1.49 (d, J = 6.6 Hz, 3H).

[0446] Intermediate N37: 5-Fluoro-3-methoxy-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Step 1: Synthesis of 2-fluoro-6-methoxy-pyridin-4-amine N37_1 [ka] A solution of 2,6-difluoropyridin-4-amine (760 mg, 5.84 mmol) and sodium methoxide (5.4 M solution in methanol, 2.4 mL, 12.9 mmol) in anhydrous THF (29 mL) was heated at reflux for 4 h. The reaction mixture was diluted with water (30 mL) and then extracted with EtOAc (3 × 30 mL). The combined extracts were washed with brine (60 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (using a gradient of 0–60% EtOAc in isohexane as eluent) to afford the title compound (725 mg, 78% yield) as a yellow oil. LC-MS (Method A7) m / z: [M+H] + :143;rt:0.96min;purity:55%. 1 H NMR (400 MHz, CDCl3) δ 5.82 (dd, J = 1.6, 1.0 Hz, 1H), 5.78 (d, J = 1.6 Hz, 1H), 4.25 (s, 2H), 3.87 (s, 3H).

[0447] Step 2: Synthesis of 3-bromo-6-fluoro-2-methoxy-pyridin-4-amine N37_2 [ka] To a solution of 2-fluoro-6-methoxy-pyridin-4-amine (intermediate N37_1, 160 mg, 1.01 mmol) in DCM (10.0 mL) was added a suspension of N-bromosuccinimide (198 mg, 1.11 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 3 hours. A second portion of N-bromosuccinimide (20 mg, 0.11 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then heated at reflux overnight. A third portion of N-bromosuccinimide (40 mg, 0.22 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. Water (10 mL) was added, and the phases were separated. The aqueous layer was extracted with DCM (2 × 10 mL). The combined extracts were washed with brine (40 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent: 0-50% EtOAc in isohexane gradient) to give the title compound (203 mg, 91% yield) as a white solid. LC-MS (Method A7) m / z: [M+H] + :221 / 223;rt:1.69min;Purity over 99%. 1 H NMR (400 MHz, DMSO-d6) δ 6.59 (s, 2H), 5.99 (s, 1H), 3.80 (s, 3H).

[0448] Step 3: Synthesis of ethyl 2-[3-(4-amino-6-fluoro-2-methoxy-3-pyridyl)-2-pyridyl]acetate N37_3 [ka] Under an inert atmosphere, palladium(II) acetate (11 mg, 0.049 mmol) was added to a suspension of 3-bromo-6-fluoro-2-methoxy-pyridin-4-amine (Intermediate N37_2, 108 mg, 0.488 mmol), ethyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]acetate (Intermediate N25_2, 222 mg, 0.684 mmol), SPhos (40 mg, 0.098 mmol), and cesium fluoride (223 mg, 1.44 mmol) in 1,4-dioxane (5.2 mL) and water (0.3 mL). The reaction mixture was heated at reflux overnight, then cooled to room temperature, filtered through a Celite® pad, and washed with EtOAc (50 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel flash chromatography (using a gradient of 0-6% MeOH in DCM as eluent) to give the title compound (259 mg, quantitative yield) as a brown oil. LC-MS (Method A7) m / z: [M+H] + :306;rt:1.35min;purity:60%.

[0449] Step 4: 5-Fluoro-3-methoxy-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one N37 A suspension of ethyl 2-[3-(4-amino-6-fluoro-2-methoxy-3-pyridyl)-2-pyridyl]acetate (Intermediate N37_3, 259 mg, 0.488 mmol), potassium carbonate (300 mg, 2.17 mmol), and 3 Å molecular sieves (1.50 g) in EtOH (5.0 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature, filtered through a Celite® pad, and washed with a 2:1 solution of DCM / MeOH (50 mL). The filtrate was concentrated in vacuo, and the resulting residue was purified by silica gel flash chromatography (using a gradient of 0–8% MeOH in DCM as eluent) and triturated in MTBE (10 mL) to afford the title compound (35 mg, 25% yield) as an off-white solid. LC-MS (Method A7) m / z: [M+H] +:260;rt:1.34min;purity:89%. 1 H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.54 (dd, J = 4.7, 1.7 Hz, 1H), 8.17 (dd, J = 8.0, 1.7 Hz, 1H), 7.43 (dd, J = 8.0, 4.7 Hz, 1H), 6.53 (d, J = 1.2 Hz, 1H), 3.91 (s, 3H), 3.76 (d, J = 12.5 Hz, 1H), 3.63 (d, J = 12.5 Hz, 1H).

[0450] Intermediate N39: 1-chloro-7-(methoxymethyl)-3-methyl-5,7-dihydropyrido[4,3-d][3]benzazepin-6-one [ka] Step 1: Synthesis of methyl 2-(2-bromophenyl)-3-methoxy-propanoate N39_1 [ka] To a stirred solution of methyl 2-(2-bromophenyl)acetate (7.20 g, 31.4 mmol) in anhydrous THF (100 mL) at −60° C., lithium diisopropylamide (2 M solution in THF / ethylbenzene / heptane, 17 mL, 34.6 mmol) was added over 20 min while maintaining the temperature at −60° C. After the addition was complete, the reaction mixture was stirred at this temperature for an additional 20 min, followed by the dropwise addition of chloromethyl methyl ether (3.1 mL, 34.6 mmol). The reaction mixture was warmed to room temperature and then treated with water (200 mL) and extracted with EtOAc (2 × 100 mL). The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (using a gradient of 0–10% MTBE in isohexane as eluent) to afford the title compound (6.0 g, 69% yield) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.61 (dd, J = 8.0, 1.3 Hz, 1H), 7.43 (dd, J = 7.8, 1.7 Hz, 1H), 7.31 (td, J = 7.6, 1.3 Hz, 1H), 7.16 (ddd, J = 8.0, 7.4, 1.7 Hz, 1H), 4.50 (dd, J = 8.6, 5.2 Hz, 1H), 3.95 - 3.91 (m, 1H), 3.74 (s, 3H), 3.65 (dd, J = 9.5, 5.2 Hz, 1H), 3.41 (s, 3H).

[0451] Step 2: Synthesis of methyl 3-methoxy-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate N39_2 [ka] Under a nitrogen atmosphere, to a suspension of methyl 2-(2-bromophenyl)-3-methoxypropanoate (Intermediate N39_1, 1.66 g, 5.96 mmol) in 1,4-dioxane (30 mL) was added [1,1'-[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (218 mg, 0.298 mmol), bis(pinacolato)diboron (1.81 g, 7.15 mmol), and potassium acetate (2.34 mg, 23.8 mmol). The suspension was heated at 90 °C for 18 h. After cooling to room temperature, the reaction mixture was filtered through a Celite® pad, which was washed with EtOAc (50 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel flash chromatography (using a gradient of 0-50% MTBE in isohexane as eluent) to afford the title compound (1.32 g, yield: 55%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.87 - 7.83 (m, 1H), 7.41 (dd, J = 6.5, 1.7 Hz, 2H), 7.28 (td, J = 6.9, 6.3, 2.2 Hz, 1H), 4.97 (dd, J = 9.2, 4.8 Hz, 1H), 4.01 (t, J = 9.4 Hz, 1H), 3.70 (s, 3H), 3.57 (dd, J = 9.5, 4.9 Hz, 1H), 3.40 (s, 3H), 1.38 (d, J = 3.3 Hz, 12H).

[0452] Step 3: Synthesis of methyl 2-[2-(4-amino-2-chloro-6-methyl-3-pyridyl)phenyl]-3-methoxy-propanoate N39_3 [ka] A mixture of 3-bromo-2-chloro-6-methyl-pyridin-4-amine (Intermediate N30_1, 25 mg, 0.112 mmol), methyl 3-methoxy-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (Intermediate N39_2, 30 mg, 0.094 mmol), aqueous potassium carbonate (1.5 M, 0.08 mL, 0.120 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (7 mg, 0.009 mmol) in anhydrous 1,4-dioxane (2.0 mL) was heated at 90 °C for 4 h. The reaction mixture was cooled to room temperature, diluted with water (5 mL), and extracted with DCM (5 mL). The organic extract was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: 0-100% EtOAc in isohexane gradient) to give the title compound (22 mg, 69% yield) as a pale yellow gum. LC-MS (Method A7) m / z: [M+H] + : 335 / 337; rt: 1.21 min and 1.78 min; purity: 98%.

[0453] Step 4: Synthesis of 1-chloro-7-(methoxymethyl)-3-methyl-5,7-dihydropyrido[4,3-d][3]benzazepin-6-one N39 To a solution of methyl 2-[2-(4-amino-2-chloro-6-methyl-3-pyridyl)phenyl]-3-methoxypropanoate (Intermediate N39_3, 200 mg, 0.597 mmol) in anhydrous THF (10.0 mL) was added dropwise a 1 M solution of lithium bis(trimethylsilyl)amide in MTBE (0.66 mL, 0.66 mmol) at room temperature, and the reaction mixture was stirred for 1 hour. An additional aliquot of the solution of lithium bis(trimethylsilyl)amide in MTBE (0.33 mL, 0.330 mmol) was added, and the reaction mixture was stirred for an additional hour. The reaction mixture was cooled in an ice / water bath, treated with water (10 mL), and extracted with EtOAc (2 × 10 mL). The combined organic extracts were washed with water (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Trituration in cold MTBE (2 mL) afforded the title compound (122 mg, yield: 66%) as a pale yellow solid. LC-MS (Method A7) m / z: [M+H] + :303 / 305;rt:1.74min;purity:98%. 1 H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 7.74 (dd, J = 7.9, 1.4 Hz, 1H), 7.49 (td, J = 7.6, 1.4 Hz, 1H), 7.39 (td, J = 7.6, 1.3 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.02 (s, 1H), 4.08 (d, J = 7.1 Hz, 2H), 3.49 (s, 1H), 3.31 (s, 3H), 2.48 (s, 3H).

[0454] Intermediate N40: 3-Fluoro-5-methoxy-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Step 1: Synthesis of 2-fluoro-6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine N40_1 [ka] A solution of 2-fluoro-6-methoxy-pyridin-4-amine (Intermediate N37_1, 211 mg, 1.34 mmol) in anhydrous THF (6.4 mL) was degassed with nitrogen for 5 minutes, and then 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.20 mL, 1.43 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes, and then bis(pinacolato)diboron (CAS 73183-34-3, 376 mg, 1.48 mmol), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (36 mg, 0.134 mmol), and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (45 mg, 0.07 mmol) were added. The resulting mixture was degassed with nitrogen for 5 minutes and then stirred at 80 °C overnight. The reaction mixture was filtered through a Celite pad, washed with EtOAc (10 mL), and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluting with a gradient of 0-100% EtOAc in isohexane) to afford the title compound (265 mg, 59% yield) as a white solid. LC-MS (Method A7) m / z: [M+H] + :269;rt:2.02min;purity:70%. 1 H NMR (400 MHz, DMSO-d6) δ 6.57 (s, 2H), 6.29 (t, J = 1.3 Hz, 1H), 2.16 (s, 3H), 1.28 (s, 12H).

[0455] Step 2: Synthesis of ethyl 2-[3-(4-amino-2-fluoro-6-methoxy-3-pyridyl)-2-pyridyl]acetate N40_2 [ka] Nitrogen was passed through a suspension of ethyl 2-(3-bromo-2-pyridyl)acetate (Intermediate N3_1, 82 mg, 0.336 mmol), 2-fluoro-6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (Intermediate N40_1, 141 mg, 0.420 mmol) and cesium fluoride (179 mg, 1.18 mmol) in anhydrous toluene (1.2 mL), EtOH (0.6 mL) and water (0.6 mL) for 5 minutes. PEPPSI™-IPent (dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (CAS 1158652-41-5, 27 mg, 0.034 mmol) was then added. The reaction mixture was heated at 80° C. overnight, then cooled to room temperature, filtered through a Celite pad, washed with EtOAc (50 mL), and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (using a gradient of 0-7% MeOH in DCM as eluent) to afford the title compound (158 mg, quantitative yield) as a yellow oil. LC-MS (Method A7) m / z: [M+H] + :306;rt:1.39min;purity:80%.

[0456] Step 3: 3-Fluoro-5-methoxy-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one N40 A suspension of ethyl 2-[3-(4-amino-2-fluoro-6-methoxy-3-pyridyl)-2-pyridyl]acetate (Intermediate N40_2, 158 mg, 0.34 mmol), potassium carbonate (207 mg, 1.50 mmol), and 3 Å molecular sieves (1.0 g) in anhydrous EtOH (5.0 mL) was heated at reflux overnight. After cooling to room temperature, the reaction mixture was filtered through a Celite® pad and washed with a 2:1 solution of DCM / MeOH (50 mL). The filtrate was concentrated in vacuo, and the residue was purified by silica gel flash chromatography (using a gradient of 0–8% MeOH / DCM as eluent) and triturated in MTBE (10 mL) to give the title compound (33 mg, 30% yield) as a white solid. LC-MS (Method A7) m / z: [M+H] + :260;rt:1.37min;purity:88%. 1 H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.57 (dd, J = 4.8, 1.6 Hz, 1H), 8.07 (ddd, J = 8.0, 4.8, 1.6 Hz, 1H), 7.47 (dd, J = 8.0, 4.8 Hz, 1H), 6.56 (s, 1H), 3.90 (s, 3H), 3.87 (d, J = 12.6 Hz, 1H), 3.62 (d, J = 12.6 Hz, 1H).

[0457] Intermediate N40A: 3-Fluoro-5-methoxy-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Starting from intermediate N40_1 and methyl 2-(3-bromo-5-fluoro-2-pyridyl)propanoate, the title compound was prepared according to the same reaction sequence as described for intermediate N40. Methyl 2-(3-bromo-5-fluoro-2-pyridyl)propanoate was prepared by methylation of methyl 2-(3-bromo-5-fluoro-2-pyridyl)acetate (CAS: 1804408-40-9) according to the same procedure as described, for example, in NN213. The first step (Suzuki reaction) was carried out at 100 °C using Pd2dba3, SPhos, and K3PO4 in toluene. The second step was carried out at RT using LiHMDS in THF, and both steps were similar to those described for intermediate NN142.

[0458] Intermediate N40B: 3-Fluoro-5-methoxy-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Starting from intermediate NN232 and methyl 2-(3-bromo-5-fluoro-2-pyridyl)propanoate, the title compound was prepared according to the same reaction sequence as described for intermediate N40A. Methyl 2-(3-bromo-5-fluoro-2-pyridyl)propanoate was prepared by methylation of methyl 2-(3-bromo-5-fluoro-2-pyridyl)acetate (CAS: 1804408-40-9) according to the same procedure as described, for example, for NN213. The first step (Suzuki reaction) was carried out at 100 °C using Pd2dba3, SPhos, and K3PO4 in toluene. The second step was carried out at RT using LiHMDS in THF, both steps being similar to those described for intermediate NN142.

[0459] Intermediate N41: 4-Ethyl-5-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7]Pentadeca-1(11),2(7),5,12,14-pentaene-3,9-dione [ka] Step 1: Synthesis of 4-(benzylamino)-1-ethyl-6-methylpyridin-2(1H)-one N41_1 [ka] A solution of 1-ethyl-4-hydroxy-6-methyl-pyridin-2-one (250 mg, 1.63 mmol) in benzylamine (1.75 g, 16.3 mmol) was heated at 170° C. for 18 hours. The resulting light brown precipitate was collected by filtration, washed with MTBE, and then dried under vacuum to give the title compound (102 mg, 25% yield) as an off-white solid. LC-MS (Method A7) m / z: [M+H] + :243;rt:1.53min;purity:99%. 1 H NMR (400 MHz, DMSO-d6) δ 7.31 (m, 4H), 7.26 - 7.21 (m, 1H), 6.90 (t, J = 6.0 Hz, 1H), 5.63 (d, J = 2.5 Hz, 1H), 5.02 (d, J = 2.5 Hz, 1H), 4.20 (d, J = 5.9 Hz, 2H), 3.79 (q, J = 7.0 Hz, 2H), 2.22 (s, 3H), 1.05 (t, J = 7.0 Hz, 3H).

[0460] Step 2: Synthesis of 4-amino-1-ethyl-6-methylpyridin-2(1H)-one N41_2 [ka] To a solution of 4-(benzylamino)-1-ethyl-6-methyl-pyridin-2-one (Intermediate N41_1, 100 mg, 0.413 mmol) in glacial acetic acid (10.0 mL) was added 10% Pd / C (439 mg, 0.413 mmol). The reaction mixture was purged with nitrogen followed by hydrogen gas (3×) and then stirred under a hydrogen atmosphere (P=2 bar) at room temperature for 18 hours. The reaction mixture was filtered through a Celite® bed, washed with toluene (5 mL), and the filtrate was evaporated. This was further co-evaporated with toluene (3×5 mL) to give a gummy light brown solid, which was triturated with MTBE (5 mL). The resulting gray solid was collected by filtration and then purified using a 2 g SCX (preconditioned) column eluting with neat methanol followed by 0.7 M ammonia-methanol to give the title compound (50 mg, 79% yield) as an off-white waxy solid. LC-MS (Method A7) m / z:[M+H] + :153;rt:0.61min;purity:99%. 1 H NMR (400 MHz, DMSO-d6) δ 5.78 (s, 2H), 5.51 - 5.49 (m, 1H), 5.14 (d, J = 2.4 Hz, 1H), 3.81 (q, J = 7.0 Hz, 2H), 2.21 (s, 3H), 1.07 (t, J = 7.0 Hz, 3H).

[0461] Step 3: Synthesis of 4-amino-3-bromo-1-ethyl-6-methyl-pyridin-2-one N41_3 [ka] To a suspension of 4-amino-1-ethyl-6-methylpyridin-2(1H)-one (Intermediate N41_2, 42 mg, 0.273 mmol) in anhydrous acetonitrile (1.0 mL) was added N-bromosuccinimide (49 mg, 0.273 mmol), and the reaction mixture was stirred at room temperature for 21 h. The volatiles were removed in vacuo, and the residue was purified by silica gel flash chromatography (using a gradient of 0-10% (1% NH3)MeOH in DCM) to give the title compound (42 mg, 59% yield) as an off-white solid. LC-MS (Method A7) m / z: [M+H] + :231 / 233;rt:0.97min;Purity over 99%. 1 H NMR (400 MHz, DMSO-d6) δ 6.13 (s, 2H), 5.72 (d, J = 1.0 Hz, 1H), 3.89 (q, J = 7.0 Hz, 2H), 2.24 (d, J = 0.8 Hz, 3H), 1.10 (t, J = 7.0 Hz, 3H).

[0462] Step 4: Synthesis of ethyl 2-[3-(4-amino-1-ethyl-6-methyl-2-oxo-3-pyridyl)-2-pyridyl]acetate N41_4 [ka] A solution of 4-amino-3-bromo-1-ethyl-6-methyl-pyridin-2-one (Intermediate N41_3, 42 mg, 0.162 mmol), ethyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]acetate (Intermediate N25_2, 94 mg, 0.324 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (12 mg, 0.016 mmol), and aqueous potassium carbonate (1.5 M, 0.11 mL, 0.162 mmol) in 1,4-dioxane (5 mL) was heated at 80° C. for 18 hours under an inert atmosphere. The reaction mixture was then heated at 90° C. for 18 hours. The reaction mixture was cooled to room temperature and then diluted with EtOAc (20 mL). The resulting suspension was filtered through a small pad of Celite® and the filter cake was rinsed with EtOAc (10 mL). The filtrate was concentrated in vacuo and purified by silica gel flash chromatography (using a gradient of 0-10% (NH3 / MeOH) in DCM as eluent) to afford the title compound (2 mg, yield: 1%) as a brown oil. LC-MS (Method A7) m / z: [M+H] + :316;rt:0.81min;purity:35%.

[0463] Step 5: 4-Ethyl-5-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2(7),5,12,14-pentaene-3,9-dione N41 To a solution of ethyl 2-[3-(4-amino-1-ethyl-6-methyl-2-oxo-3-pyridyl)-2-pyridyl]acetate (Intermediate N41_4, 2 mg, 0.006 mmol) in ethanol (1.00 mL) was added potassium carbonate (2 mg, 0.013 mmol), and the reaction mixture was heated at reflux for 18 h. The volatiles were removed in vacuo and coevaporated with toluene (2 mL). The resulting solid was taken on to the next step without purification or analysis.

[0464] Intermediate N42: 3-chloro-5,10-dimethyl-4,8,10,12-tetraazatricyclo[9.4.0.02,7 ]Pentadeca-1(11),2,4,6,12,14-hexaen-9-one [ka] Step 1: Synthesis of N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine N42_1 [ka] To a solution of 3-bromo-N-methyl-pyridin-2-amine (1.50 g, 8.02 mmol) in anhydrous 1,4-dioxane (20.0 mL) was added bis(pinacolato)diboron (CAS 73183-34-3, 2.44 g, 9.62 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (293 mg, 0.401 mmol), and potassium acetate (3.15 g, 32.1 mmol). The reaction mixture was heated at reflux for 16 hours. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated in vacuo to give the title compound as a brown oil, which was used in the next step without further purification. LC-MS (Method B5') m / z: [M+H] + :235;rt:0.44min;purity:60%.

[0465] Step 2: Synthesis of 2-chloro-6-methyl-3-[2-(methylamino)-3-pyridyl]pyridin-4-amine N42_2 [ka] To a solution of N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (Intermediate N42_1, 634 mg, 2.71 mmol) in 1,4-dioxane (8.0 mL) and water (2.0 mL), 3-bromo-2-chloro-6-methyl-pyridin-4-amine (Intermediate N30_1, 500 mg, 2.26 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (160 mg, 0.226 mmol), and KCO (936 mg, 6.77 mmol) were added, and the reaction mixture was heated at reflux for 2 hours. After cooling to room temperature, the reaction mixture was filtered through Celite® and concentrated in vacuo. Purification by silica gel column chromatography (using a gradient of 0-5% MeOH in DCM as eluent) afforded the title compound (220 mg, yield: 75%) as a yellow solid. LC-MS (Method A7) m / z: [M+H] + :249 / 251;rt:1.24min;purity:75%.

[0466] Step 3: 3-chloro-5,10-dimethyl-4,8,10,12-tetraazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2,4,6,12,14-hexaen-9-one N42 To a solution of 2-chloro-6-methyl-3-[2-(methylamino)-3-pyridyl]pyridin-4-amine (Intermediate N42_2, 220 mg, 0.885 mmol) in anhydrous DMF (5.0 mL) was added 1,1'-carbonyldiimidazole (158 mg, 0.973 mmol) and triethylamine (0.22 mL, 1.59 mmol) at room temperature, and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the reaction mixture was treated with water (10.0 mL) and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine (2 × 20 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (using a gradient of 0–2% MeOH in DCM as the eluent) afforded the title compound (150 mg, 46% yield) as a yellow solid. LC-MS (Method A7) m / z:[M+H]+ :275 / 277;rt:1.56min;purity:75%.

[0467] Intermediate N43: 15-Methoxy-8,13-dimethyl-4,6,10,14-tetraazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(15),2(7),3,5,11,13-hexaen-9-one [ka] Step 1: Synthesis of 2-methoxy-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine N43_1 [ka] To a mixture of 3-bromo-2-methoxy-6-methylpyridin-4-amine (Intermediate N64_3, 2.33 g, 9.83 mmol), bis(pinacolato)diboron (7.49 g, 29.5 mmol), PCy3Pd G2 (chloro[(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II), CAS 1353658-81-7, 581 mg, 0.983 mmol), and potassium acetate (3.86 g, 39.3 mmol), 1,4-dioxane (20.0 mL) was added, and the reaction mixture was stirred at 90° C. for 20 hours. After cooling to room temperature, the reaction mixture was filtered through Celite® eluting with EtOAc (100 mL), and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (using a gradient of 0-100% EtOAc in isohexane as eluent) to give the title product, which was used directly in the next step without further purification or analysis.

[0468] Step 2: 15-Methoxy-8,13-dimethyl-4,6,10,14-tetraazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(15),2(7),3,5,11,13-hexaen-9-one N43 A suspension of ethyl 2-(5-bromopyrimidin-4-yl)propanoate (Intermediate N36_3, 1.20 g, 4.40 mmol), 2-methoxy-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (Intermediate N43_2, 1.11 g, 0.127 mmol), SPhos Pd(crotyl)Cl (CAS: 1798781-99-3, 41 mg, 0.067 mmol), and cesium fluoride (1.82 g, 12.0 mmol) in anhydrous 1,4-dioxane (15 mL) was heated at 90° C. for 4 hours. The reaction mixture was cooled to room temperature and then filtered through Celite® eluting with EtOAc (100 mL) and concentrated in vacuo. The residue was dissolved in ethanol (15 mL) and potassium carbonate (1.32 g, 9.54 mmol) was added. The reaction mixture was stirred at 80° C. for 18 h. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (using a gradient of 0-10% MeOH in DCM as eluent) to give the title compound (464 mg, yield: 5%). LC-MS (Method A7) m / z: [M+H] + :271;rt:1.48min;purity:20%.

[0469] Intermediate N44: 1-chloro-10-methoxy-3,7-dimethyl-5,7-dihydropyrido[4,3-d][3]benzazepin-6-one [ka] Step 1: Synthesis of ethyl 2-[4-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate N44_1 [ka] To a suspension of ethyl 2-(2-bromo-4-methoxyphenyl)propanoate (511 mg, 1.78 mmol), bis(pinacolato)diboron (542 mg, 2.14 mmol), potassium acetate (699 mg, 7.12 mmol), and 3 Å molecular sieves (0.5 g) in anhydrous 1,4-dioxane (10 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (65 mg, 0.089 mmol) under an inert atmosphere, and the reaction mixture was heated at 100° C. for 18 h. After cooling to room temperature, the reaction mixture was filtered through a small pad of Celite. The filter cake was rinsed with EtOAc (20 mL), and the filtrate was concentrated in vacuo to give the title compound (910 mg, 99% yield), which was used in the next step without further purification or analysis.

[0470] Step 2: Synthesis of ethyl 2-[2-(4-amino-2-chloro-6-methyl-3-pyridyl)-4-methoxy-phenyl]propanoate N44_2 [ka] To a solution of 3-bromo-2-chloro-6-methyl-pyridin-4-amine (Intermediate N30_1, 100 mg, 0.429 mmol) in 1,4-dioxane (10 mL), ethyl 2-[4-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (Intermediate N44_1, 307 mg, 0.643 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (30 mg, 0.043 mmol), and aqueous KCO (1.5 M, 2.0 mL, 3.00 mmol) were added. The reaction mixture was purged with nitrogen for 5 minutes and then heated at 90 °C for 3 hours. The reaction mixture was cooled to room temperature and filtered through a small pad of Celite®, and the filtrate was concentrated in vacuo. Saturated aqueous NH4Cl (5 mL) was added, and the mixture was extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (using a gradient of 0-100% EtOAc in isohexane as eluent) to afford the title compound (234 mg, quantitative yield) as a mixture of two diastereoisomers, which was used directly in the next step without further purification. LC-MS (Method A7) m / z [M+H] + :349 / 351;rt:1.89 / 1.98min;purity:65%.

[0471] Step 3: Synthesis of 1-chloro-10-methoxy-3,7-dimethyl-5,7-dihydropyrido[4,3-d][3]benzazepin-6-one N44 At 0°C, a 1M solution of lithium bis(trimethylsilyl)amide in THF (1.30 mL, 1.29 mmol) was added to a solution of ethyl 2-[2-(4-amino-2-chloro-6-methyl-3-pyridyl)-4-methoxy-phenyl]propanoate (Intermediate N44_2, 150 mg, 0.430 mmol) in anhydrous toluene (4 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized by the addition of saturated aqueous NH4Cl solution and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (66 mg, yield: 45%). LC-MS (Method A7) m / z: [M+H] + :303 / 305;rt:1.79min;purity:90%.

[0472] Intermediate N45: 1-Fluoro-8-(hydroxymethyl)-3-methyl-5,7-dihydropyrido[3,4-a][3]benzazepin-6-one [ka] Step 1: Synthesis of ethyl 3-bromo-2-methylbenzoate N45_1 [ka] To a stirred solution of 3-bromo-2-methylbenzoic acid (2.0 g, 9.30 mmol) in EtOH (15.0 mL) was added concentrated H2SO4 (547 mg, 5.58 mmol), and the resulting solution was stirred at 90 °C for 18 h. The volatiles were evaporated under reduced pressure, and the residue was dissolved in EtOAc (40 mL) and washed with saturated aqueous NaHCO3 (2 x 50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (2.1 g, yield: 91%) as a pale orange oil. LC-MS (Method A7) m / z: [M+H] + :243 / 245;rt:2.50min;purity:98%. 1H NMR (400 MHz, CDCl3) δ 7.96 - 7.58 (m, 2H), 7.19 - 6.91 (m, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.63 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H).

[0473] Step 2: Synthesis of ethyl 3-bromo-2-(bromomethyl)benzoate N45_2 [ka] To a stirred solution of ethyl 3-bromo-2-methylbenzoate (Intermediate N45_1, 1.0 g, 4.11 mmol) in chloroform (15.0 mL) was added N-bromosuccinimide (879 mg, 4.94 mmol) and benzoyl peroxide (50 mg, 0.206 mmol), and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was collected, diluted with chloroform (15 mL), and then washed with aqueous NaOH (2 M, 40 mL), water (30 mL), and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (900 mg, 61% yield) as a brown oil. 1 H NMR (400 MHz, CDCl3) δ 7.87 (dd, J = 7.8, 1.3 Hz, 1H), 7.75 (dd, J = 8.0, 1.4 Hz, 1H), 7.24 (d, J = 12.6 Hz, 1H), 5.12 (s, 2H), 4.42 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H).

[0474] Step 3: Synthesis of ethyl 3-bromo-2-(cyanomethyl)benzoate N45_3 [ka] To a stirred solution of ethyl 3-bromo-2-(bromomethyl)benzoate (Intermediate N45_2, 900 mg, 2.52 mmol) in DMSO (10.0 mL) was added sodium cyanide (185 mg, 3.77 mmol), and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (90 mL) and extracted with EtOAc (2 × 20 mL). The organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated in vacuo to afford the crude title compound (790 mg, 98% yield) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 7.99 (dd, J = 7.9, 1.4 Hz, 1H), 7.81 (dd, J = 8.0, 1.4 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 4.37 (s, 2H), 1.43 (t, J = 7.1 Hz, 3H).

[0475] Step 4: Synthesis of ethyl 3-bromo-2-(2-ethoxy-2-oxoethyl)benzoate N45_4 [ka] A solution of ethyl 3-bromo-2-(cyanomethyl)benzoate (Intermediate N45_3, 790 mg, 2.48 mmol) in ethanol (6.0 mL) and a 4 M solution of HCl in 1,4-dioxane (6.0 mL) was heated at 90 °C for 16 h. The volatiles were removed in vacuo, and the residue was dissolved in EtOAc (30 mL). The organic phase was washed with saturated aqueous NaHCO3 (2 × 40 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (using a gradient of 0 to 100% EtOAc in isohexane as the eluent) to afford the title compound (270 mg, yield: 33%) as a colorless oil. LC-MS (Method B5') m / z: [M+H] + :315 / 317;rt:2.36min;purity:96%. 1H NMR (400 MHz, CDCl3) δ 7.92 (dd, J = 7.8, 1.4 Hz, 1H), 7.76 (dd, J = 8.0, 1.4 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 4.29 (s, 2H), 4.18 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H).

[0476] Step 5: Synthesis of ethyl 3-(4-amino-2-fluoro-6-methyl-3-pyridyl)-2-(2-ethoxy-2-oxo-ethyl)benzoate N45_5 [ka] To a stirred solution of ethyl 3-bromo-2-(2-ethoxy-2-oxo-ethyl)benzoate (Intermediate N45_4, 160 mg, 0.487 mmol) in 1,4-dioxane (7.0 mL) and water (0.5 mL) was added 2-fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (Intermediate N16_1, 164 mg, 0.585 mmol), SPhos Pd(crotyl)Cl (CAS: 1798781-99-3, 30 mg, 0.049 mmol) and cesium fluoride (222 mg, 1.46 mmol) and the reaction mixture was heated at 90 °C overnight. After cooling to room temperature, the reaction mixture was concentrated in vacuo and directly purified by silica gel flash chromatography (using a gradient of 0-100% EtOAc in isohexane as eluent) to afford the title compound (210 mg, yield: 92%) as a light brown oil. LC-MS (Method B5') m / z: [M+H] + :361;rt:1.93min;purity:77%.

[0477] Step 6: Synthesis of ethyl 1-fluoro-3-methyl-6-oxo-5,7-dihydropyrido[4,3-d][3]benzazepine-8-carboxylate N45_6 [ka] To a stirred solution of ethyl 3-(4-amino-2-fluoro-6-methyl-3-pyridyl)-2-(2-ethoxy-2-oxo-ethyl)benzoate (Intermediate N45_5, 210 mg, 0.449 mmol) in EtOH (10.0 mL) was added K2CO3 (186 mg, 1.35 mmol), and the reaction mixture was stirred at 80 °C for 18 h. The volatiles were removed under reduced pressure, and the residue was treated with water (30 mL) and extracted with EtOAc (2 × 20). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title compound (140 mg, yield: 92%) as a pale yellow solid. LC-MS (Method B5') m / z: [M+H] + :315;rt:1.81min;purity:93%. 1 H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 7.88 (dd, J = 7.8, 1.3 Hz, 1H), 7.86 - 7.78 (m, 1H), 7.51 (t, J = 7.8 Hz, 1H), 6.96 (s, 1H), 4.48 - 4.28 (m, 3H), 3.34 (d, J = 12.8 Hz, 1H), 2.44 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H).

[0478] Step 7: Synthesis of 1-fluoro-8-(hydroxymethyl)-3-methyl-5,7-dihydropyrido[3,4-a][3]benzazepin-6-one N45 At 0 °C, a 4 M solution of LiBH in THF (33 μL, 0.134 mmol) was added dropwise to a stirred solution of ethyl 1-fluoro-3-methyl-6-oxo-5,7-dihydropyrido[4,3-d][3]benzazepine-8-carboxylate (Intermediate N45_6, 50.0 mg, 0.134 mmol) in anhydrous THF (5.0 mL), and the reaction mixture was allowed to reach room temperature overnight. At 0 °C, additional LiBH (4 M solution in THF, 33 μL, 0.134 mmol) was added, and the reaction mixture was stirred at 0 °C for 5 h, then diluted with water (30 mL) and extracted with EtOAc (2 × 15 mL). The combined organic layers were dried over anhydrous Na SO , filtered, and concentrated in vacuo to give the title compound (58 mg, yield: 88%) as a pale yellow solid. LC-MS (Method A7) m / z: [M+Na] + :295;rt:1.30min;purity:86%. 1 H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 7.54 - 7.48 (m, 2H), 7.36 (t, J = 7.7 Hz, 1H), 6.94 (s, 1H), 5.30 (dd, J = 5.9, 4.7 Hz, 1H), 4.77 (dd, J = 13.3, 5.9 Hz, 1H), 4.59 (dd, J = 13.3, 4.6 Hz, 1H), 3.79 (d, J = 12.9 Hz, 1H), 3.20 (d, J = 12.9 Hz, 1H), 2.43 (s, 3H).

[0479] Intermediate N46: (4-amino-3-bromo-6-methyl-2-pyridyl)methyl acetate [ka] Step 1 Synthesis of tert-butyl N-(5-bromo-2-methyl-4-pyridyl)-N-tert-butoxycarbonyl-carbamate N46_1 [ka] To a solution of 4-amino-5-bromo-2-methylpyridine (717 mg, 3.75 mmol, 1 equiv.) in THF (37 mL) at room temperature, DMAP (46 mg, 0.38 mmol, 0.1 equiv.) and di-tert-butyl dicarbonate (2.53 g, 11.3, 3 equiv.) were added, and the reaction mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated to dryness to give a brown oil (1.77 g). The residue was purified by silica gel column chromatography (using a gradient of 0% to 30% EtOAc in heptane as the eluent) to give the title compound as a white solid (1.36 g, yield: 89%). TLC (ethyl acetate / heptane 2 / 8) Rf: 0.26. LC-MS (Method A1) m / z [M+H] + 389.1, rt: 4.52 minutes, purity: 99%.

[0480] Step 2: Synthesis of (4-amino-3-bromo-6-methyl-2-pyridyl)methyl acetate Under an inert atmosphere, a solution of tert-butyl N-(5-bromo-2-methyl-4-pyridyl)-N-tert-butoxycarbonylcarbamate (Intermediate N46_1, 100 mg, 0.258 mmol), [bis(trifluoroacetoxy)iodo]benzene (133 mg, 0.309 mmol), (4,4'-di-t-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridium(III) hexafluorophosphate (3 mg, 0.003 mmol), and acetoxyacetic acid (74 mg, 0.627 mmol) in anhydrous dichloromethane (1.3 mL) was placed in a Pennoc reactor (450 nm; fan speed = 4000; stirring speed = 400; LED power = 100%) for 3 h. The reaction mixture was concentrated in vacuo and diluted again with dry dichloromethane (0.5 mL). Trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 40 minutes. The reaction was concentrated in vacuo and purified by reverse phase chromatography (basic elution) to give the title compound N46 (26 mg, yield: 39%) as a white solid. LC-MS (Method B1') m / z [M+H] + :260.9;rt:1.68min;purity:90%.

[0481] Intermediate N47: 4-Bromo-6-methoxy-5-methyl-pyridin-3-amine [ka] Step 1: Synthesis of 4-bromo-2-methoxy-3-methyl-5-nitro-pyridine N47_1 Nitric acid (633 μL, 9.50 mmol) was added dropwise to a solution of 4-bromo-2-methoxy-3-methylpyridine (200 mg, 0.95 mmol) in concentrated sulfuric acid (2.4 mL, 43 mmol) at 0° C. The reaction mixture was stirred at room temperature for 10 minutes and then heated at 100° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into ice and water, and the resulting precipitate was collected by filtration and rinsed with cold water. The filter cake was dissolved in dichloromethane, dried over MgSO4, filtered off, and concentrated in vacuo to give the title compound (140 mg, yield: 60%) as an off-white solid. LC-MS (Method A1) m / z: [M+H] + :249.2, rt:1.46 min, purity >99%.

[0482] Step 2: Synthesis of 4-bromo-6-methoxy-5-methyl-pyridin-3-amine N47 To a solution of 4-bromo-2-methoxy-3-methyl-5-nitropyridine (130 mg, 0.526 mmol) in absolute ethanol (1 mL) was added concentrated hydrochloric acid (368 μL, 4.40 mmol) and iron powder (104 mg, 1.84 mmol), and the reaction mixture was heated at 80° C. for 30 min. After cooling to room temperature, the reaction mixture was dissolved in saturated NaHCO solution and extracted twice with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo to give the crude title product (120 mg, quantitative yield) as an orange oil, which was carried on to the next step without purification. LC-MS (Method A1) m / z: [M+H] + :217.1, rt:1.06 minutes.

[0483] Intermediate N48: Methyl 2-(2-bromo-6-cyano-phenyl)acetate [ka] Step 1: Synthesis of 2-(2-bromo-6-cyano-phenyl)acetic acid N48_1 [ka] To a solution of LDA (19.5 mL, 39.3 mmol) in dry THF (100 mL) was added HMPA (6.2 mL, 35.7 mmol) and 3-cyano-2-methylbromobenzene (7 g, 35.7 mmol) at −78° C., and the reaction mixture was stirred at the same temperature for 2 h. A CO gas balloon was purged into the reaction mixture for 20 min. The reaction mixture was acidified to pH = 2 with 1 N aqueous HCl. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using 5% ethyl acetate in hexane as the eluent) to give the title compound (4.2 g, yield: 47%). 1 H NMR (400 MHz, DMSO-d6) δ 12.93 (bs, 1H) 8.00 (d, J=7.9 Hz, 1H), 7.90 (d, J=7.9 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 3.96 (s, 2H).

[0484] Step 2: Synthesis of methyl 2-(2-bromo-6-cyano-phenyl)acetate N48 To a solution of 2-(2-bromo-6-cyano-phenyl)acetic acid (1.0 g, 4.16 mmol) in anhydrous methanol (21 mL) was added thionyl chloride (610 μL, 8.38 mmol) dropwise, and the reaction mixture was heated at 40° C. for 4 h. The reaction mixture was concentrated to dryness, and the residue was dissolved in saturated NaHCO and extracted twice with EtOAc. The combined organic extracts were dried over MgSO, filtered, and concentrated in vacuo to give the title compound (1.05 g, yield: 99%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 4.07 (s, 2H), 3.68 (s, 3H).LC-MS (Method B4) m / z[MH] - :467.0;rt:4.27min;purity:96%.

[0485] Intermediate N49: Methyl 2-(3-bromo-2-pyridyl)-2-fluoro-propanoate [ka] At −78° C., a solution of methyl 2-(3-bromopyridin-2-yl)propanoate (170 mg, 0.66 mmol) in anhydrous THF (3.3 mL) was added dropwise to a 2 M solution of LDA in THF (0.36 mL, 0.72 mmol), and the reaction mixture was stirred at −78° C. for another 10 minutes and then at 0° C. for 30 minutes. Again at −78° C., a solution of n-fluorobenzenesulfonimide (280 mg, 0.86 mmol) in anhydrous THF (3.3 mL) was added dropwise, and the reaction mixture was allowed to reach room temperature over 1 hour. The reaction mixture was neutralized by the addition of saturated NH4Cl and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to dryness. Purification by silica gel flash chromatography (using a gradient of 100:0 to 90:10 DCM / MeOH as eluent) afforded the title product (123 mg, yield: 69%) as a colorless oil. LC-MS (Method A1) m / z: [M+H] + :263.9, rt: 1.20 min, purity: 98%. 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 4.6 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.46 (dd, J = 8.0, 4.6 Hz, 1H), 3.74 (s, 3H), 1.96 (d, J = 22.6 Hz, 3H).LC-MS (Method B2) m / z[MH] -:477.0;rt:4.60min;purity:95%.

[0486] Intermediate N50: Ethyl 2-(3-bromo-2-pyridyl)-3,3,3-trideuterio-propanoate [ka] To a 2 M solution of LDA in THF (1 mL, 2.10 mmol), further diluted with anhydrous THF (8 mL), was added a solution of ethyl 2-(3-bromo-2-pyridyl)acetate (Intermediate N3_1, 500 mg, 2.0 mmol) in anhydrous THF (2 mL) at −78° C. The resulting mixture was stirred at −78° C. for 10 minutes, after which iodomethane-d (190 μL, 3.02 mmol) was added. The reaction mixture was allowed to reach room temperature over 30 minutes, then neutralized by the addition of saturated NH4Cl (5 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to dryness. Purification by silica gel flash chromatography (using a gradient of 100:0 to 50:50 heptane / EtOAc as eluent) afforded the title compound (533 mg, quantitative yield) as a yellow oil. LC-MS (Method A1) m / z: [M+H] + :263.2, rt: 1.30 min, purity: 97%. 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 4.6, 1.5 Hz, 1H), 8.08 (dd, J = 8.0, 1.5 Hz, 1H), 7.27 (dd, J = 8.0, 4.6 Hz, 1H), 4.28 (s, 1H), 4.07 (q, J = 7.1 Hz, 2H), 1.11 (t, J = 7.1 Hz, 3H).LC-MS (Method B2) m / z[M+H] + :462.4;rt:4.49min;purity:97%.

[0487] Intermediate N51: Methyl 2-(3-bromo-6-methyl-2-pyridyl)propanoate [ka] Step 1: Synthesis of 2-(3-bromo-6-methylpyridin-2-yl)acetonitrile N51_1 To a solution of 3-bromo-2-fluoro-6-methylpyridine (5.00 g, 26.3 mmol) and acetonitrile (5.50 mL, 106 mmol) in anhydrous toluene (100 mL) was added a 1 M solution of KHMDS in THF (32 mL, 31.6 mmol) at 0 °C. The reaction mixture was stirred at the same temperature for 1 h and then at room temperature for 16 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated NH4Cl (2 × 40 mL) and brine (2 × 40 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification by silica gel column chromatography (using 5% EtOAc in hexane as the eluent) afforded the title compound (3.50 g, yield: 63%) as an off-white solid. LC-MS (Method A5) m / z: [M+H] + :212.7, rt:1.72min, purity:84%. 1 H NMR (400 MHz, DMSO-d6) δ 2.46 (s, 3H), 4.27 (s, 2H), 7.22 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H).

[0488] Step 2: Synthesis of methyl 2-(3-bromo-6-methylpyridin-2-yl)acetate N51_2 A stirred solution of 2-(3-bromo-6-methylpyridin-2-yl)acetonitrile (2.25 g, 10.7 mmol) in a 3 M solution of HCl in MeOH (40 mL) was heated at 50 °C for 16 h. The solvent was removed in vacuo. The reaction mixture was diluted with DCM (50 mL) and basified with saturated NaHCO3 solution (40 mL) to pH = 9. The aqueous layer was separated and extracted with DCM (2 x 50 mL). The organic layer was separated, washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (using a gradient of 0-5% EtOAc in hexane as the eluent) afforded the title compound (0.95 g, yield: 37%) as a pale yellow oil. LC-MS (Method A5) m / z: [M+H] + :244.0, rt:2.44min, purity:97%. 1 H NMR (400 MHz, DMSO-d6) δ 2.41 (s, 3H), 3.63 (s, 3H), 3.94 (s, 2H), 7.14 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H).

[0489] Step 3: Synthesis of methyl 2-(3-bromo-6-methyl-2-pyridyl)propanoate N_51 To a solution of methyl 2-(3-bromo-6-methyl-2-pyridyl)acetate (300 mg, 1.23 mmol) in dry THF (6 mL) at −78° C., a 2 M solution of LDA in THF (0.65 mL, 1.3 mmol) was added, and the resulting mixture was stirred at −78° C. for 20 minutes, followed by the addition of iodomethane (116 μL, 1.84 mmol). The reaction mixture was allowed to reach room temperature over 30 minutes, then neutralized by the addition of saturated NH4Cl (10 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to dryness to give the title product (326 mg, yield: 94%) as a light brown oil. LC-MS (Method A1) m / z: [M+H] + :260.1, rt:1.32 min, purity: 92%. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 8.2 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 4.27 (q, J = 7.2 Hz, 1H), 3.58 (s, 3H), 2.40 (s, 3H), 1.39 (d, J = 7.2 Hz, 3H).LC-MS (Method B2) m / z[M+H] + :473.1;rt:4.90min;Purity 97%.

[0490] Intermediate N52: 4-Amino-3-bromo-6-methyl-pyridine-2-carbonitrile [ka] Step 1: Synthesis of tert-butyl N-(5-bromo-2-methyl-4-pyridyl)-N-tert-butoxycarbonyl-carbamate N52_1 [ka] To a solution of 4-amino-5-bromo-2-methylpyridine (2.0 g, 10.0 mmol) in anhydrous THF (105 mL) was added 4-dimethylaminopyridine (129 mg, 1.05 mmol) and di-tert-butyl dicarbonate (7 g, 31.1 mmol), and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (using a gradient of 0% to 30% EtOAc in heptane as the eluent) to give the title product (2.3 g, 54% yield) as a white solid. LC-MS (Method B4) m / z [M+H] + :389.0;rt:4.49min;purity:98%.

[0491] Step 2: Synthesis of tert-butyl N-(5-bromo-2-methyl-1-oxide-pyridin-1-ium-4-yl)-N-tert-butoxycarbonyl-carbamate N52_2 [ka] To a solution of tert-butyl N-(5-bromo-2-methyl-4-pyridyl)-N-tert-butoxycarbonylcarbamate (Intermediate N52_1, 3.78 g, 8.78 mmol) in anhydrous dichloromethane (90 mL) at 0 °C, 3-chloroperbenzoic acid (3.3 g, 13.0 mmol) was added, and the reaction mixture was stirred at room temperature for 20 h. Water and dichloromethane were added to the reaction mixture, the layers were separated, and the organic layer was concentrated to dryness. The crude solid was purified by silica gel flash chromatography (using a gradient of 80 / 20 to 20 / 80 heptane / EtOAc as the eluent) to give the title product (3.1 g, 82% yield) as a white solid. LC-MS (Method A1) m / z: [M+H] + :403.3;rt:1.27min;purity:94%.

[0492] Step 3: Synthesis of tert-butyl N-(3-bromo-2-cyano-6-methyl-4-pyridyl)-N-tert-butoxycarbonyl-carbamate N52_3 [ka] To a solution of tert-butyl N-(5-bromo-2-methyl-1-oxide-pyridin-1-ium-4-yl)-N-tert-butoxycarbonyl-carbamate (Intermediate N52_2, 3.0 g, 6.9 mmol) in anhydrous acetonitrile (70 mL) at room temperature, trimethylsilyl cyanide (3.6 mL, 27.0 mmol) and triethylamine (2.4 mL, 17.0 mmol) were added, and the reaction mixture was stirred at 90 °C for 2.5 hours. Triethylamine (2.4 mL, 17.0 mmol) and trimethylsilyl cyanide (3.6 mL, 27.0 mmol) were added again, and the reaction mixture was again heated at 90 °C for 18 hours. After cooling to room temperature, the reaction mixture was partitioned between saturated aqueous NaHCO and EtOAc, and the two layers were separated. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. Purification by silica gel flash chromatography (using a gradient of 100 / 0 to 50 / 50 heptane / EtOAc as eluent) afforded the title product (2.15 g, yield: 66%) as a white solid. LC-MS (Method A1) m / z: [M+H] + :414.3;rt:1.61min;purity:87%.

[0493] Step 4: Synthesis of 4-amino-3-bromo-6-methyl-pyridine-2-carbonitrile N52 To a solution of tert-butyl N-(3-bromo-2-cyano-6-methyl-4-pyridyl)-N-tert-butoxycarbonylcarbamate (Intermediate N52_3, 2.2 g, 5.3 mmol) in dichloromethane (45 mL) was added a 4 M solution of hydrochloric acid in 1,4-dioxane (22 mL), and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated to dryness to give a crude yellow solid, which was dissolved in water and saturated aqueous Na2CO3. The aqueous layer was extracted with EtOAc (3x), and the combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. Purification by silica gel flash chromatography (using a gradient of 100 / 0 to 50 / 50 DCM / EtOAc as eluent) afforded the title compound (1.1 g, yield: 97%) as an off-white solid. LC-MS (Method A1) m / z [M+H] +:212.1;rt:0.87min;Purity over 99%. 1 H NMR (400 MHz, DMSO-d6) δ 6.76 (bs, 2H), 6.69 (s, 1H), 2.27 (s, 3H).

[0494] Intermediate N53: 3-Methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaene-5-carbonitrile [ka] Step 1: Synthesis of 4-amino-6-methyl-pyridine-2-carbonitrile N53_1 [ka] To a stirred solution of 6-methyl-4-nitro-pyridine-2-carbonitrile (1.00 g, 6.13 mmol) in AcOH (16 mL) was added iron powder (856 mg, 15.3 mmol), and the reaction mixture was stirred at room temperature for 5 h. Water (15 mL) was added, and the mixture was basified to pH 8 with aqueous NaOH (6 M). The aqueous phase was then extracted with EtOAc (3 × 100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dry-loaded onto silica and purified by silica gel flash chromatography (using a gradient of 0–10% MeOH in DCM as eluent) to afford the title compound (549 mg, 67% yield) as a pale beige solid. LC-MS (Method A7) m / z: [M+H] + :134.2;rt:0.16min;Purity over 99%. 1 H NMR (400 MHz, DMSO-d6) δ 6.80 (d, J = 2.1 Hz, 1H), 6.55 - 6.52 (m, 1H), 6.47 (s, 2H), 2.26 (s, 3H).

[0495] Step 2: Synthesis of 4-amino-5-bromo-6-methyl-pyridine-2-carbonitrile N53_2 [ka] A solution of 4-amino-6-methyl-pyridine-2-carbonitrile (Intermediate N53_1, 549 mg, 4.13 mmol) in AcOH (5 mL) was treated dropwise with a solution of bromine (0.21 mL, 4.13 mmol) in AcOH (1 mL) at room temperature. After 1 h, the resulting slurry was treated with 40 mL of 20% NaOH solution and extracted with EtOAc (3 × 100 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (using a gradient of 0–5% MeOH in DCM as eluent). The resulting solid was then slurried in a 1:1 solution of EtOAc / isohexane, and the insoluble material was filtered off. The filtrate was concentrated in vacuo to give the title compound (155 mg, 17% yield) as a pale beige solid. LC-MS (Method A7) m / z: [M+H] + :212.0 / 214.0;rt:1.35min;Purity:>99%. 1 H NMR (400 MHz, DMSO-d6) δ 7.00 (s, 1H), 6.79 (s, 2H), 2.46 (s, 3H).

[0496] Step 3: 3-Methyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaene-5-carbonitrile N53 A mixture of 4-amino-5-bromo-6-methyl-pyridine-2-carbonitrile (Intermediate N53_2, 155 mg, 0.729 mmol), ethyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]acetate (Intermediate N25_2, 304 mg, 1.02 mmol), and CsF (310 mg, 2.04 mmol) in anhydrous 1,4-dioxane (14 mL) was degassed by bubbling nitrogen through it for 10 minutes. Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (26 mg, 0.037 mmol) was added, nitrogen was bubbled through for an additional 5 minutes, and the reaction mixture was then stirred at reflux overnight. The reaction mixture was allowed to cool to room temperature and then filtered through a bed of Celite®, washing with EtOAc (100 mL). The filtrate was concentrated in vacuo, and the residue was dry-loaded onto silica and purified by silica gel flash chromatography (using a gradient of 0-100% EtOAc in isohexane as eluent) to give the title compound (28 mg, yield: 9%) as a yellow gum. LC-MS (Method A7) m / z: [M+H] + :251.1;rt:1.13min;purity:60%.

[0497] Intermediate N54: 3,5-dichloro-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Step 1: Synthesis of 2,6-dichloro-3-iodo-pyridin-4-amine N54_1 [ka] 2,6-Dichloropyridin-4-amine (1.00 g, 5.83 mmol) was dissolved in acetonitrile (40 mL) and N-iodosuccinimide (1.14 g, 6.41 mmol) was added at 0° C. The ice bath was removed after 10 min and the reaction mixture was stirred at 80° C. for 24 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel flash chromatography (using a gradient of 0 to 50% EtOAc in isohexane as eluent) to afford the title compound (1.25 g, yield: 72%) as a beige solid. 1 H NMR (400 MHz, CDCl3) δ 6.53 (s, 1H), 5.00 (s, 2H).LC-MS (Method A7) m / z[M+H] + :288.9 / 290.9;rt:1.85min, purity:99%.

[0498] Step 2: Synthesis of ethyl 2-[3-(4-amino-2,6-dichloro-3-pyridyl)-2-pyridyl]acetate N54_2 [ka] A mixture of 2,6-dichloro-3-iodo-pyridin-4-amine (Intermediate N54_1, 233 mg, 0.807 mmol), ethyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]acetate (Intermediate N25_2, 580 mg, 1.21 mmol), CsF (343 mg, 2.26 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (29 mg, 0.040 mmol) in anhydrous 1,4-dioxane (28 mL) and water (1.4 mL) was purged with nitrogen for 15 minutes and then stirred at reflux overnight. The reaction was cooled to room temperature, filtered through a Celite® bed, and washed with EtOAc (50 mL). The filtrate was concentrated in vacuo to give the title compound as a brown oil. The product was carried on crude to the next step without purification. LC-MS (Method B5') m / z [M+H] + :326.1 / 328.1;rt:1.60min, purity:42%.

[0499] Step 3: 3,5-Dichloro-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one N54 Ethyl 2-[3-(4-amino-2,6-dichloro-3-pyridyl)-2-pyridyl]acetate (Intermediate N54_2, 263 mg, 0.806 mmol) was dissolved in EtOH (3.9 mL) and K2CO3 (223 mg, 1.61 mmol) was added. The reaction mixture was heated at 80 °C for 1 h, then cooled to room temperature, and water (50 mL) was added. The aqueous phase was extracted with EtOAc (3 × 50 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (using a gradient of 0-10% MeOH in DCM as eluent) to give the title compound (64 mg, 28% yield) as an off-white solid. LC-MS (Method A7) m / z [M+H] + :280.0;rt:1.48 minutes, purity over 99%. 1 H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.63 (dd, J = 4.8, 1.7 Hz, 1H), 8.25 (dd, J = 8.0, 1.7 Hz, 1H), 7.49 (dd, J = 8.0, 4.8 Hz, 1H), 7.30 (s, 1H), 3.94 (d, J = 12.7 Hz, 1H), 3.61 (d, J = 12.7 Hz, 1H).

[0500] Intermediate N55: 3,12-Difluoro-5,10-dimethyl-4,8,14-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Step 1: Synthesis of ethyl 2-(3-bromo-5-fluoro-4-pyridyl)propanoate N55_1 [ka] Ethyl 2-(3-bromo-5-fluoro-4-pyridyl)acetate (Intermediate N65_1, 1.00 g, 3.62 mmol) was dissolved in THF (10 mL) and cooled to 0 °C. A 1 M solution of lithium bis(trimethylsilyl)amide in THF (4.17 mL, 4.17 mmol) was added dropwise, and the reaction mixture was stirred at 0 °C for 30 min. Iodomethane (669 mg, 4.71 mmol) was added, and the reaction mixture was stirred at 0 °C for an additional 1 h. The solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography (using a gradient of 0-60% MTBE in isohexane as eluent) to give the title compound (1.0 g, yield: 98%) as a colorless oil. LC-MS (Method A7) m / z [M+H] + :276.1 / 278.1;rt:1.99min;purity:98%. 1 H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.38 - 8.33 (m, 1H), 4.28 - 4.08 (m, 3H), 1.51 (dd, J = 7.3, 0.7 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H).

[0501] Step 2: Synthesis of ethyl 2-[3-(4-amino-2-fluoro-6-methyl-3-pyridyl)-5-fluoro-4-pyridyl]propanoate N55_2 [ka] A mixture of ethyl 2-(3-bromo-5-fluoro-4-pyridyl)propanoate (Intermediate N55_1, 75 mg, 0.272 mmol), 2-fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (Intermediate N16_1, 77 mg, 0.299 mmol), and CsF (124 mg, 0.815 mmol) in 1,4-dioxane (7.5 mL) and water (1.0 mL) was degassed with nitrogen for 10 minutes, and then bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (19 mg, 0.027 mmol) was added. The reaction mixture was heated at 90 °C for 3 hours. The reaction mixture was evaporated to dryness and the residue was purified by flash chromatography on silica gel (using a gradient of 0-100% EtOAc in isohexane as eluent) to give the title compound (72 mg, yield: 58%). LC-MS (Method A7) m / z [M+H] + : 322.2; rt: 1.60 min and 1.70 min; purity: 98%.

[0502] Step 3: 3,12-difluoro-5,10-dimethyl-4,8,14-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2,4,6,12,14-hexaen-9-one N55 A suspension of ethyl 2-[3-(4-amino-2-fluoro-6-methyl-3-pyridyl)-5-fluoro-4-pyridyl]propanoate (Intermediate N55_2, 70 mg, 0.213 mmol) and K2CO3 (88 mg, 0.640 mmol) in EtOH (10 mL) was stirred at 80 °C for 2 h. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. Water (10 mL) was added to the residue, and the pH was adjusted to 4-5 by the addition of acetic acid. The resulting precipitate was collected by filtration, washed with water (approximately 2 mL), and dried under vacuum to give the title compound (57 mg, yield: 95%) as a white solid. LC-MS (Method A7) m / z [M+H] + :276.2;rt:1.47min;purity:98%.

[0503] Intermediate N56: 3-Fluoro-5,10-dimethyl-4,8,12,13-tetraazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Step 1: Synthesis of ethyl 2-(4-benzyloxypyridazin-3-yl)propanoate N56_1 [ka] Ethyl 2-(4-(benzyloxy)pyridazin-3-yl)acetate (Intermediate N34_3, 1.0 g, 3.67 mmol) was dissolved in anhydrous THF (20 mL) and cooled to 0 °C. A 1 M solution of lithium bis(trimethylsilyl)amide in THF (4.0 mL, 4.0 mmol) was added dropwise, and the reaction mixture was stirred at 0 °C for 30 min. Iodomethane (680 mg, 4.78 mmol) was added, and the reaction mixture was stirred at 0 °C for an additional 1 h. The reaction mixture was concentrated in vacuo and purified by silica gel flash chromatography (neat EtOAc as eluent) to give the title compound (1.0 g, yield: 79%) as a pale yellow oil. LC-MS (Method B5') m / z [M+H] + :287.2;rt:1.65min;purity:90%. 1 H NMR (400 MHz, DMSO-d6) δ 8.97 (d, J = 5.9 Hz, 1H), 7.43 - 7.37 (m, 5H), 7.34 (d, J = 5.9 Hz, 1H), 5.26 (d, J = 3.4 Hz, 2H), 4.23 (q, J = 7.2 Hz, 1H), 3.99 (qd, J = 7.1, 2.4 Hz, 2H), 1.48 (d, J = 7.1 Hz, 3H), 1.03 (t, J = 7.1 Hz, 3H).

[0504] Step 2: Synthesis of ethyl 2-(4-hydroxypyridazin-3-yl)propanoate N56_2 [ka] To a solution of ethyl 2-(4-benzyloxypyridazin-3-yl)propanoate (Intermediate N56_1, 1.0 g, 3.42 mmol) in EtOH (60 mL), 10% Pd / C (182 mg) was added, and the reaction mixture was stirred under a hydrogen atmosphere (P = 5 bar) for 12 h. The catalyst was removed by filtration, and the filtrate was evaporated to dryness and purified by silica gel flash chromatography (using a gradient of 0-5% MeOH in DCM as eluent) to give the title compound (472 mg, yield: 59%) as a colorless solid. LC-MS (Method B5') m / z [M+H] + :197.2;rt:0.89min;purity:90%. 1 H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 8.18 (d, J = 7.4 Hz, 1H), 6.25 (d, J = 7.4 Hz, 1H), 4.06 - 4.00 (m, 2H), 3.88 (q, J = 7.2 Hz, 1H), 1.31 (d, J = 7.2 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H).

[0505] Step 3: Synthesis of ethyl 2-(4-chloropyridazin-3-yl)propanoate N56_3 [ka] To a solution of ethyl 2-(4-hydroxypyridazin-3-yl)propanoate (Intermediate N56_2, 566 mg, 2.83 mmol) in acetonitrile (25 mL) was added phosphorus oxychloride (0.65 mL, 7.07 mmol), and the reaction was heated at 80 °C for 1 h. The reaction mixture was allowed to cool to room temperature, poured onto saturated aqueous sodium bicarbonate (30 mL), and extracted with EtOAc (2 × 20 mL). The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (using a gradient of 0–60% EtOAc in isohexane as eluent) to afford the title compound (457 mg, 72% yield) as an orange oil. LC-MS (Method A7) m / z [M+H] + :215.1 / 217.1;rt:1.44min;purity:98%. 1 H NMR (400 MHz, CDCl3) δ 9.01 (d, J = 5.5 Hz, 1H), 7.51 (d, J = 5.5 Hz, 1H), 4.42 (q, J = 7.2 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 1.71 (d, J = 7.2 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H).

[0506] Step 4: Synthesis of ethyl 2-[4-(4-amino-2-fluoro-6-methyl-3-pyridyl)pyridazin-3-yl]propanoate N56_4 [ka] A mixture of ethyl 2-(4-chloropyridazin-3-yl)propanoate (Intermediate N56_3, 400 mg, 1.66 mmol), 2-fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (Intermediate N16_1, 559 mg, 2.00 mmol), and aqueous KCO solution (3.5 mL, 4.99 mmol) in 1,4-dioxane (50 mL) was purged with nitrogen for 10 minutes, and then SPhos Pd(crotyl)Cl (CAS: 1798781-99-3, 101 mg, 0.166 mmol) was added. The reaction mixture was heated at 90 °C for 1 hour. The reaction mixture was cooled to room temperature, poured onto water (150 mL), and extracted with EtOAc (2 × 100 mL). The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent: 0-100% EtOAc in isohexane gradient) to give the title compound (402 mg, 69% yield) as a pale yellow solid. LC-MS (Method B5') m / z [M+H] + :305.2;rt:1.34min;purity:95%.

[0507] Step 5: 3-Fluoro-5,10-dimethyl-4,8,12,13-tetraazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one N56 A suspension of ethyl 2-[4-(4-amino-2-fluoro-6-methyl-3-pyridyl)pyridazin-3-yl]propanoate (Intermediate N56_4, 400 mg, 1.25 mmol) and K2CO3 (518 mg, 3.75 mmol) in EtOH (20.0 mL) was stirred at 80 °C for 2 h. The reaction mixture was evaporated to dryness, and the residue was dissolved in water (20 mL). The pH was adjusted to 5 by adding AcOH (ca. 3 mL), and the mixture was extracted with EtOAc (2 × 50 mL). The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (272 mg, yield: 76%) as a light tan solid. LC-MS (Method A7) m / z [M+H] +:259.1;rt:1.14min;purity:90%. 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.31 (d, J = 5.3 Hz, 1H), 7.97 (dd, J = 5.3, 4.2 Hz, 1H), 7.02 (s, 1H), 3.91 (q, J = 6.6 Hz, 1H), 2.47 (s, 3H), 1.63 (d, J = 6.6 Hz, 3H).

[0508] Intermediate N57: 3-Fluoro-5,10-dimethyl-4,8,14-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Step 1: Synthesis of methyl 2-(3-bromo-4-pyridyl)acetate N57_1 [ka] A solution of 3-bromo-4-methylpyridine (3.2 mL, 29.0 mmol) in anhydrous THF (60 mL) was added dropwise to a 1 M solution of lithium bis(trimethylsilyl)amide in THF (87 mL, 87.0 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, and dimethyl carbonate (3.9 mL, 46.5 mmol) was added. The reaction mixture was stirred at room temperature for 15 hours and then concentrated in vacuo. The residue was partitioned between EtOAc (100 mL) and water (50 mL), and the aqueous phase was extracted with EtOAc (2 × 40 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (using a gradient of 0–100% EtOAc in isohexane as the eluent) to give the title compound (3.92 g, 58% yield) as a pale yellow oil. LC-MS (Method A7) m / z [M+H] + :230.0 / 232.0;rt:1.22min;purity:99%. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.58 - 8.45 (m, 1H), 7.51 - 7.44 (m, 1H), 3.89 (s, 2H), 3.65 (s, 3H).

[0509] Step 2: Synthesis of methyl 2-(3-bromo-4-pyridyl)propanoate N57_2 [ka] To a solution of methyl 2-(3-bromo-4-pyridyl)acetate (Intermediate N57_1, 3.92 g, 16.9 mmol) in dry THF (50 mL) cooled to −78° C. was added a 1 M solution of LiHMDS in THF (20.2 mL, 20.2 mmol). The reaction mixture was stirred at −78° C. for 10 minutes, and then iodomethane (1.4 mL, 21.9 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 1 hour, then allowed to warm to 0° C. and stirred for 1 hour. The reaction mixture was treated with 1 M aqueous NH4Cl (10 mL), followed by brine (10 mL), and extracted with EtOAc (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: 0-100% EtOAc in isohexane gradient) to give the title compound (3.60 g, 92% yield) as a yellow / orange liquid. LC-MS (Method A7) m / z [M+H] + :244.1 / 246.1;rt:1.53min;purity:99%. 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.55 - 8.49 (m, 1H), 7.43 - 7.38 (m, 1H), 4.12 (q, J = 7.2 Hz, 1H), 3.63 (s, 3H), 1.44 (d, J = 7.2Hz, 3H).

[0510] Step 3: 3-Fluoro-5,10-dimethyl-4,8,14-triazatricyclo[9.4.0.0 2,7]Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one N57 A stirred mixture of 2-fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (Intermediate N16_1, 200 mg, 0.682 mmol), methyl 2-(3-bromo-4-pyridyl)propanoate (Intermediate N57_2, 290 mg, 1.09 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (48 mg, 0.068 mmol), and CsF (311 mg, 2.05 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was degassed with nitrogen for 5 minutes and then heated at 90 °C for 2 hours. The reaction mixture was cooled to room temperature, filtered through a pad of celite, rinsed with EtOAc (40 mL), and the filtrate was concentrated in vacuo. The residue was dissolved in EtOH (10 mL) and potassium carbonate (189 mg, 1.36 mmol) was added. The reaction mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature and filtered off. The filtrate was concentrated in vacuo and purified by silica gel flash chromatography (using a gradient of 0-10% MeOH in DCM as eluent) to give the title compound (183 mg, yield: 80%) as a yellow gum. LC-MS (Method A7) m / z [M+H] + :258.2;rt:1.01min;purity:77%.

[0511] Intermediate N58: 3-Fluoro-5-methoxy-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Step 1: Synthesis of ethyl 2-[3-(4-amino-2-fluoro-6-methoxy-3-pyridyl)-2-pyridyl]propanoate N58_1 [ka] A suspension of ethyl 2-(3-bromo-2-pyridyl)propanoate (Intermediate N68_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 N40_1, 4.56 g, 13.8 mmol), and CsF (5.85 g, 38.5 mmol) in anhydrous toluene (12.0 mL), EtOH (6.0 mL), and water (6.0 mL) was purged with nitrogen for 10 minutes, followed by the addition of PEPPSI™-IPr (CAS 905459-27-0, 748 mg, 1.10 mmol). The reaction mixture was purged with nitrogen for an additional 5 minutes and heated at 80 °C for 16 hours. The reaction mixture was cooled to room temperature and filtered through a Celite® pad, washing with EtOAc (50 mL). The filtrate was concentrated in vacuo, and the residue was purified by silica gel flash chromatography (using a gradient of 0-5% MeOH in DCM as eluent) to give the title compound as a yellow solid (1.73 g, yield: 42%). LC-MS (Method A7) m / z [M+H] + :320.2;rt:1.71min;purity:87%.

[0512] Step 2: 3-Fluoro-5-methoxy-10-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one N58 To a solution of ethyl 2-[3-(4-amino-2-fluoro-6-methoxy-3-pyridyl)-2-pyridyl]propanoate (Intermediate N58_1, 1.96 g, 5.52 mmol) in anhydrous THF (50.0 mL) was added dropwise a 1 M solution of lithium bis(trimethylsilyl)amide in THF (11.0 mL, 11.0 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was treated with ice water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to give the title compound as a light brown powder (1.59 g, quantitative yield). LC-MS (Method A7) m / z [M+H] +:274.1;rt:1.59min;purity:96%. 1 H 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, Daicel Chiralpak IG, CO2 + methanol 20%). Chiral purity 100%. Rt = 1.78 min (first eluting enantiomer N58_A). For reference, the second eluting enantiomer N58_B rt=2.24 min. Both were measured by HPLC, Daicel Chiralpak IG, solvent: ACN 100%-DEA 0.1%.

[0513] Intermediates N59a and N59b: 3-fluoro-4-methoxy-10-methyl-5,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2,4,6,12,14-hexaen-9-one N59a and 5-fluoro-4-methoxy-10-methyl-3,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2,4,6,12,14-hexaen-9-one N59b [ka] To a solution of 3-amino-5-fluoro-6-methoxypyridine (500 mg, 3.52 mmol) and bispinacolatodiboron (1.79 g, 7.04 mmol) in dry THF (2.5 mL) was added a suspension of 4,4'-di-tert-butyl-2,2'-dipyridyl (29 mg, 0.11 mmol) and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (CAS 12148-71-9, 35 mg, 0.05 mmol) in dry THF (1 mL) at room temperature, and the reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was then cooled to room temperature and slowly added to a solution of ethyl 2-(3-bromo-2-pyridyl)propanoate (Intermediate N68_2, 908 mg, 3.52 mmol) and K2CO3 (1.47 g, 10.6 mmol) in 1,4-dioxane (17.0 mL) and water (1.0 mL). The solution was degassed with nitrogen for 5 minutes, after which Pd[(Amphos)2Cl]2 (CAS 887919-35-9, 125 mg, 0.18 mmol) was added. The reaction mixture was then stirred at 100 °C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100 mL), filtered through a Celite® pad, and the filtrate was concentrated to dryness. The residue was then dissolved in anhydrous toluene (18 mL), and a 1.5 M solution of LiHMDS in THF (7.0 mL, 10.6 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 1 hour. Water was added, and the reaction mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The crude solid was purified by silica gel column chromatography (using a gradient of 0% to 50% EtOAc in DCM as eluent) to afford two separate title products: 3-fluoro-4-methoxy-10-methyl-5,8,12-triazatricyclo[9.4.0.0] as a beige solid (289 mg, yield: 29%). 2,7 ]Pentadeca-1(11),2,4,6,12,14-hexaen-9-one N59a. LC-MS (Method B1) m / z [M+H] + :274;rt:1.05min;purity:99%. 1 H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.71 (dd, J = 4.8, 1.7 Hz, 1H), 8.15 (ddd, J = 7.9, 4.0, 1.7 Hz, 1H), 7.97 (s, 1H), 7.50 (dd, J = 7.9, 4.8 Hz, 1H), 4.00 (s, 3H), 3.65 (q, J= 6.6 Hz, 1H), 1.46 (d, J = 6.6 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -145.23 (d, J = 4.0 Hz). 5-Fluoro-4-methoxy-10-methyl-3,8,12-triazatricyclo[9.4.0.0] was obtained as a beige solid (272 mg, yield: 25%). 2,7 ]Pentadeca-1(11),2,4,6,12,14-hexaen-9-one N59b. LC-MS (Method B1) m / z [M+H] + :274;rt:1.12min;purity:98%. 1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.69 (dd, J= 4.7, 1.8 Hz, 1H), 8.29 (dd, J = 7.8, 1.8 Hz, 1H), 7.57 - 7.44 (m, 2H), 4.05 (s, 3H), 3.49 (q, J = 6.6 Hz, 1H), 1.49 (d, J= 6.6 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -139.08 (d, J = 10.8 Hz).

[0514] Intermediate N60: 3-chloro-10-fluoro-5-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Step 1: Synthesis of ethyl 2-[3-(4-amino-2-chloro-6-methyl-3-pyridyl)-2-pyridyl]acetate N60_1 [ka] A suspension of 2-chloro-3-iodo-6-methyl-pyridin-4-amine (N19_1) (2.0 g, 7.2 mmol), ethyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]acetate (Intermediate N25_2, 4.2 g, 14.4 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (530 mg, 0.71 mmol), and KPO (3.0 g, 21 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was degassed with argon for 5 minutes. The reaction mixture was then heated at 80 °C for 3 hours. After cooling to room temperature, EtOAc (20 mL) and water (10 mL) were added, and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The black residue was purified by silica gel column chromatography (using a gradient of 20% to 100% EtOAc in heptane as eluent) to give the title compound as an orange oil (1.5 g, yield: 42%). LC-MS (Method A1) m / z [M+H] + :306.0, rt:0.69min, purity:96%. 1 H NMR (400 MHz, CDCl3) δ 8.67 (dd, J = 4.8, 1.8 Hz, 1H), 7.55 (dd, J = 7.7, 1.8 Hz, 1H), 7.38 - 7.32 (m, 1H), 6.45 (s, 1H), 4.14 - 4.04 (m, 2H), 3.75 (q, J = 7.2 Hz, 2H), 2.43 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H).

[0515] Step 2: Synthesis of ethyl 2-[3-(4-amino-2-chloro-6-methyl-3-pyridyl)-2-pyridyl]-2-fluoro-acetate N60_2 [ka] To a solution of ethyl 2-[3-(4-amino-2-chloro-6-methyl-3-pyridyl)-2-pyridyl]acetate (Intermediate N60_1, 415 mg, 0.81 mmol) in ACN (2.0 mL) and water (2.0 mL) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (560 mg, 1.5 mmol), and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated in vacuo, and the residue was treated with cold water and extracted with DCM (3 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title product (250 mg, 75% yield) as a crude brown oil. The product was carried on to the next step without purification. LC-MS (Method A1) m / z [M+H] + : 324.0, rt: 0.76 min and 0.78 min, purity: 75%.

[0516] Step 3: 3-chloro-10-fluoro-5-methyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one N60 A suspension of ethyl 2-[3-(4-amino-2-chloro-6-methyl-3-pyridyl)-2-pyridyl]-2-fluoroacetate (Intermediate N60_2, 100 mg, 0.30 mmol) and K2CO3 (86 mg, 0.60 mmol) in EtOH (1 mL) was stirred at room temperature for 20 h. The resulting white precipitate was collected by filtration to give the title product (105 mg, yield: 41%) as a white solid. LC-MS (Method A1) m / z [M+H] + :278.1, rt:0.87min, purity:96%. 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (td, J = 4.6, 1.6 Hz, 1H), 8.14 (dt, J = 7.9, 1.6 Hz, 1H), 7.32 (dd, J = 7.9, 4.7 Hz, 1H), 6.56 (d, J = 0.7 Hz, 1H), 5.37 - 5.09 (d, J = 127, 1H), 2.30 (s, 3H).

[0517] Intermediate N61: (10R)-3-Fluoro-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one [ka] Step 1: Synthesis of ethyl (2R)-2-(3-bromo-2-pyridyl)propanoate N61_1 [ka] Ethyl 2-(3-bromo-2-pyridyl)propanoate was purified by chiral HPLC SFC (column Daicel chiralpak IC) using EtOH:CO (98:2). Chiral purity >99%; tr = 4.04 min (measured by HPLC, Daicel chiralpak IC, i-PrOH 10% - heptane 90% - DEA 0.1%, temperature: 30 °C). Second eluting isomer.

[0518] Step 2: (10R)-3-Fluoro-5,10-dimethyl-4,8,12-triazatricyclo[9.4.0.0 2,7 ]Synthesis of pentadeca-1(11),2(7),3,5,12,14-hexaen-9-one N61 Starting from (2R)-2-(3-bromo-2-pyridyl)propanoate N61_1, the title product was synthesized according to the same procedure as intermediate N23. Chiral purity: 98%; rt=1.99 min (determined by HPLC, Daicel chiralpak IG-u, EtOH 50%-heptane 50%-DEA 0.1%, temperature: 30°C). First eluting peak. LC-MS (Method A1) m / z [M+H] + :258.0;rt:0.93min;purity:94%. 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.66 (dd, J= 4.8, 1.8 Hz, 1H), 8.08 (ddt, J = 6.3, 4.8, 1.8 Hz, 1H), 7.46 (dd, J = 7.9, 4.8 Hz, 1H), 7.00 (s, 1H), 3.61 (q, J= 6.5 Hz, 1H), 2.45 (s, 3H), 1.49 (d, J= 6.5 Hz, 3H).

[0519] Intermediate N62: 2-[(10R)-3-fluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 2,7 ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetic acid [ka] Starting from intermediate N61, the title product was synthesized according to the same procedure as in Example No. 128 (Steps 1 and 2). Chiral purity: >99%; rt=1.59 min (determined by ...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof 【Chemistry 1】 (In the formula, Y is N-R ａ or CR １ａ R １ｂ represents; R ａ is hydrogen or C １～４ represents alkyl; R １ａ and R １ｂ are independently hydrogen, hydroxy, halogen; or C １～４ Alkoxy or C １～４ alkyl (any of these groups may be optionally substituted with one or more substituents); A is the point of attachment to the rest of the molecule, V ３ and V ４ Together with A １ , A ２ , A ３ , A ４ , A ５ , A ６ and A ７ represents an optionally substituted aryl or heteroaryl selected from the group represented by: 【Chemistry 2】 V ３ and V ４ independently represent C; Z １ is N or C-R ４ represents; Z ２ is N or C-R ５ represents; Z ３ is N or C-R ６ represents; R ｅ represents hydrogen or halogen; R ４ is hydrogen, halogen, hydroxy, cyano or amino; or C １～４ Alkyl, C ３～７ Cycloalkyl or C １～４ alkoxy (any of these groups may be optionally substituted with one or more substituents); R ５ is hydrogen, halogen or cyano; or C １～４ Alkyl or C １～４ alkoxy (any of these groups may be optionally substituted with one or more substituents); R ６ is hydrogen, halogen or cyano; or C １～４ Alkoxy, C １～４ Alkylamino, C １～４ Alkyl, C ３～７ Heterocycloalkyl or —O—(C ３～７ heterocycloalkyl), any of which groups may be optionally substituted with one or more substituents; R ７ is hydrogen; or C １～４ Alkyl or C ３～７ cycloalkyl (any of these groups may be optionally substituted with one or more substituents); R ８ , R ９ and R １０ are independently hydrogen or halogen; or C １～４ Alkyl, C ３～７ Cycloalkyl or C １～４ alkoxy (any of these groups may be optionally substituted with one or more substituents); R １１ Ha-NR ｃ -(CO)-R ｂ represents; R ｂ and R ｃ is independent, C １～４ represents alkyl; B is the point of attachment to the rest of the molecule, V １ and V ２ Together with B １ , B ２ , B ３ , B ４ , B ５ , B ６ , B ７ and B ８ represents an optionally substituted aryl or heteroaryl selected from the group represented by: 【Transformation 3】 V １ Is B １ , B ２ , B ３ , B ４ , B ５ , B ６ and B ７ represents C, and B ８ For represents N; V ２ Is B １ , B ２ , B ４ , B ６ , B ７ and B ８ represents C, and B ３ and B ５ For represents N; W, U １ and U ２ independently represent N or C—H; Z ４ is N or C-R １３ represents; Z ５ is N or C-R １４ represents; Z ６ is N or C-R １５ represents; Z ７ is N or C-R １６ represents; T is N or C-R １７ represents; R １２ represents hydrogen; R １３ , R １４ , R １５ , R １６ are independently hydrogen, halogen or cyano; or C １～４ Alkyl or C １～４ alkoxy (any of these groups may be optionally substituted with one or more substituents); R １７ is hydrogen, halogen or C １～４ represents alkyl; R １７ ' is hydrogen or C １～４ represents alkyl; Q is Q １ and Q ２ represents a ring selected from the group represented by: 【Chemistry 4】 Z ８ is N or C-R ３ represents; Z ９ is C-R １８ represents; Z １０ is N or C-R １９ represents; Z １１ is C-R ２０ represents; Z １２ is S, O, N—H or CR ２１ R ２２ represents; Z １３ is N or C-R ２３ represents; Z １４ is N or C-R ２４ represents; R ２ is halogen or cyano; or C １～４ Alkyl, C ３～７ Cycloalkyl or C １～４ alkoxy (any of these groups may be optionally substituted with one or more substituents); R ３ is hydrogen, halogen or cyano; or C １～４ alkyl, which may be optionally substituted with one or more substituents; or R ２ and R ３ taken together with the group to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, which groups are optionally substituted with one or more substituents; R １８ is hydrogen or halogen; or C optionally substituted with one or more substituents １～４ represents alkyl; and R １９ , R ２０ , R ２１ , R ２２ , R ２３ and R ２４ are independently hydrogen or halogen; or C optionally substituted with one or more substituents. １～４ represents alkyl).

2. Q is, Q ３ , Q ４ , Q ５ and Q ６ : 【Transformation 5】 (In the formula, X １ is N or C-R ３ represents; X ２ is N or C-R １９ represents; X ３ is C-R １９ represents; Two Xs ４ One of them is C-R ２０ and the other X ４ represents C—H; X ５ represents S; and R ３ , R １９ and R ２０ is as defined in claim 1) 2. The compound of claim 1, wherein the optionally substituted ring is selected from the group represented by:

3. Formula (IA) 【Transformation 6】 (In the formula, Q, Y, Z １ , Z ２ , Z ３ , Z ４ , Z ５ , Z ６ and Z ７ is as defined in claim 1) 2. The compound of formula (I) according to claim 1, represented by: or a pharmaceutically acceptable salt thereof.

4. Formula (IB) 【Transformation 7】 (In the formula, Q, Y, Z ４ , Z ５ , Z ６ , Z ７ , R ７ and R ８ is as defined in claim 1) 3. The compound of formula (I) according to claim 1 or 2, represented by: or a pharmaceutically acceptable salt thereof.

5. Formula (IC) 【Transformation 8】 (In the formula, Q, Y, Z ４ , Z ５ , Z ６ , Z ７ , R ７ and R ９ is as defined in claim 1) 2. The compound of formula (I) according to claim 1, represented by: or a pharmaceutically acceptable salt thereof.

6. Formula (ID) 【Chemistry 9】 (In the formula, Q, Y, Z １ , Z ２ , Z ３ and T is as defined in claim 1.

2. The compound of formula (I) according to claim 1, represented by: or a pharmaceutically acceptable salt thereof.

7. Formula (IE) 【Chemistry 10】 (In the formula, Q, Y, Z １ , Z ２ , Z ３ and W is as defined in claim 1.

2. The compound of formula (I) according to claim 1, represented by: or a pharmaceutically acceptable salt thereof.

8. Y is N-R ａ or CR １ａ R １ｂ represents; R ａ represents methyl; R １ａ is hydrogen, deuterium, fluoro, hydroxyl, methyl, deuterated methyl (-CD ３ ), hydroxymethyl, methoxymethyl, or methoxy; R １ｂ represents hydrogen or methyl; A is the point of attachment to the rest of the molecule, V ３ and V ４ Together with A １ , A ２ , A ３ , A ４ , A ５ , A ６ and A ７ represents an optionally substituted aryl or heteroaryl selected from the group represented by Z １ is N or C-R ４ represents Z ２ is N or C-R ５ ' and Z ３ is N or C-R ６ represents Z １ , Z ２ and Z ３ represents N, or Z １ , Z ２ and Z ３ none of the represents N; R ｅ represents hydrogen or fluoro; R ４ represents hydrogen, chloro, fluoro, cyano, hydroxyl, amino, methyl, ethyl, difluoromethyl, hydroxymethyl, cyclopropyl, methoxy, ethoxy, or (methoxy)ethoxy; R ５ represents hydrogen, fluoro, cyano, methyl, or methoxy; R ６ represents hydrogen, chloro, fluoro, cyano, methoxy, methylamino, methyl, (hydroxy)methyl, (methylcarboxy)methyl, (oxo)(methyl)piperazinyl, (difluoro)azetidinyl, azaspirohexanyl, azabicycloheptanyl, (difluoro)azaspirohexanyl, morpholino, (hydroxymethyl)azetidinyl, (fluoroazetidinyl), (methyl)(hydroxyl)azetidinyl, (fluoro)pyrrolidinyl, (difluoro)pyrrolidinyl, (hydroxyl)pyrrolidinyl, (difluoro)azaspiroheptanyl, oxa-azaspirooctanyl, oxa-azaspiroheptanyl, (fluoro)(methyl)azetidinyl, (difluoro)azabicyclohexanyl, (difluoro)azabicycloheptanyl, (methyl)azetidinyl, or (azetidinyl)oxy; R ７ represents hydrogen, methyl, ethyl, or cyclopropyl; R ８ represents hydrogen, methyl or methoxy; R ９ represents hydrogen, fluoro, methyl or cyclopropyl; R １０ represents hydrogen or fluoro; R １１ Ga-NR ｃ -(CO)-R ｂ represents; R ｂ represents methyl; R ｃ represents methyl; B is the point of attachment to the rest of the molecule, V １ and V ２ Together with B １ , B ２ , B ３ , B ４ , B ５ , B ６ , B ７ and B ８ represents an optionally substituted aryl or heteroaryl selected from the group represented by V １ But B １ , B ２ , B ３ , B ４ , B ５ , B ６ and B ７ represents C, and B ８ For represents N; V ２ But B １ , B ２ , B ４ , B ６ , B ７ and B ８ represents C, and B ３ and B ５ For represents N; W, U １ and U ２ independently represent N or C—H; Z ４ is N or C-R １３ represents Z ５ is N or C-R １４ represents Z ６ is N or C-R １５ and Z ７ is N or C-R １６ represents Z ４ , Z ５ , Z ６ and Z ７ Either none of these represents N or Z ４ , Z ５ , Z ６ and Z ７ one or two of represent N; T is N or C-R １７ represents; R １２ represents hydrogen; R １３ represents hydrogen, fluoro or chloro; R １４ represents hydrogen, fluoro, chloro or methoxy; R １５ represents hydrogen, fluoro, chloro or methyl; R １６ represents hydrogen, fluoro, chloro, cyano or (hydroxy)methyl; R １７ represents hydrogen, methyl or fluoro; R １７ ' represents hydrogen or methyl; Q is Q ３ , Q ４ , Q ５ and Q ６ represents an optionally substituted ring selected from the group represented by X １ is N or C-R ３ represents X ２ is N or C-R １９ represents X ３ is C-R １９ represents; Two Xs ４ One of them is C-R ２０ and the other X ４ represents C—H; X ５ represents S; R ２ represents chloro, bromo, iodo, fluoro, cyano, methyl, difluoromethyl, trifluoromethyl, difluoroethyl, cyclopropyl, difluorocyclopropyl, methoxy, or difluoromethoxy; R ３ represents hydrogen, chloro, fluoro or methyl; Or R ２ and R ３ together with the groups to which they are attached form (methyl)indazolyl, (difluoromethyl)indazolyl, (methyl)triazolyl, (difluoro)indanyl, (difluoro)benzodioxolyl, (fluoro)isoquinolyl and (chloro)isoquinolyl; R １９ represents hydrogen or fluoro; and R ２０ represents hydrogen or fluoro; A compound of formula (I) according to claim 1.

9. Q is Q ３ 9. The compound according to claim 1, wherein

10. Y is CR １ａ R １ｂ 10. The compound according to any one of claims 1 to 9, wherein

11. Z １ is C-R ４ represents Z ２ represents N, and Z ３ is C-R ６ 11. The compound according to any one of claims 1 to 3 and 6 to 10, wherein

12. Z ４ is C-R １３ represents Z ５ is C-R １４ represents Z ６ represents N, and Z ７ is C-R １６ 11. The compound according to any one of claims 1 to 5 and 9 to 10, wherein

13. Compound of formula (IG) 【Chemistry 11】 (In the formula, R １ａ is methyl or hydroxyl; R ２ is difluoromethyl or difluoroethyl; R ４ is hydrogen, chloro or fluoro; R ６ is methyl; and R １４ is hydrogen or fluoro) 2. The compound of formula (I) according to claim 1, represented by:

14. 10. The compound of claim 1, specifically disclosed herein in Examples 1-424.

15. N-[4-(difluoromethyl)phenyl]-2-[3,14-difluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(11),2(7),3,5,12,14-hexaen-8-yl]acetamide; or 2-[3,14-difluoro-5,10-dimethyl-9-oxo-4,8,12-triazatricyclo[9.4.0.0 ２，７ ]pentadeca-1(15),2,4,6,11,13-hexaen-8-yl]-N-[4-(1,1-difluoroethyl)phenyl]acetamide; The compound of claim 1.

16. System Xc － System Xc plays a role in cancer treatment － 20. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for use in epilepsy syndromes in which is a role, or in cancer therapy resistance.

Images