Novel macrocyclic LRRK2 kinase inhibitors

Abstract

A compound of formula (I): wherein R, X1, X2, X3, Z1, Z2, Z3, A and Ra are as defined in the specification. Pharmaceuticals.

Description

[Technical Field]

[0001] The present invention relates to novel macrocyclic compounds and compositions comprising said compounds that act as kinase inhibitors, specifically inhibitors of LRRK2 (leucine-rich repeat kinase 2). Additionally, the present invention provides methods for preparing the disclosed compounds, pharmaceutical compositions containing them, and methods for their use, e.g., as drugs or diagnostic agents, specifically for the treatment and / or diagnosis of diseases affected or modulated by LRRK2 kinase activity, such as neurological disorders including Parkinson's disease and Alzheimer's disease, as well as inflammatory disorders such as heart disease or Crohn's disease. [Background technology]

[0002] Parkinson's disease is the most common movement disorder and the second most common neurodegenerative disease after Alzheimer's disease. It affects approximately 1% of the population aged 65 years or older and is characterized by four classic core motor complications: resting tremor, bradykinesia, postural instability, and muscle rigidity. Patients with Parkinson's disease are also affected by many non-motor symptoms, such as constipation, hyposmia, orthostatic hypotension, sleep disorders including REM sleep behavior disorder, dementia, visual impairment, depression, anxiety, hallucinations, and mood swings.

[0003] The standard treatment for Parkinson's disease is symptomatic relief of motor complications using dopamine replacement therapy, such as the dopamine precursor L-dopa, dopamine agonists, or compounds that affect the half-life of dopamine, such as MAO-B inhibitors. Currently, there are no approved treatments to prevent, treat, or slow the progression of Parkinson's disease.

[0004] The pathological hallmarks of Parkinson's disease are the loss of dopaminergic neurons in the substantia nigra pars compacta and postmortem evidence of protein inclusions, also known as Lewy bodies and Lewy neurites. In postmortem tissue from Parkinson's disease patients, Lewy bodies and Lewy neurites are found throughout the central nervous system as well as in peripheral tissues. The major component of these inclusions is aggregated, misfolded α-synuclein protein phosphorylated at serine at amino acid position 129 (Nature 388, 839-840, 1997; Nat Cell Biol 4, 160-64, 2002). Lewy bodies and Lewy neurites also contain proteins involved in other neurodegenerative diseases, such as hyperphosphorylated tau protein, a pathological hallmark of tauopathies such as Alzheimer's disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) (Biochem Soc Trans 26(3), 463-71, 1998; Am J Hum Genet 64(2), 414-21, 1999; J Neuropathol Exp Neurol 62(4), 389-97, 2003). The pathological process of Parkinson's disease is not limited to the loss of dopaminergic neurons in the basal ganglia system. In addition, distinct neuronal populations in other brain regions, such as the neocortex, sleep nuclei, or raphe nuclei, as well as in peripheral organs and tissues, such as the heart and digestive system, are also affected by the degenerative process in Parkinson's disease patients.

[0005] Leucine-rich repeat kinase 2 (LRRK2) is a 2527-amino acid protein with a molecular mass of 286 kDa encoded by the LRRK2 gene. It consists of the following functional and structural protein domains: armadillo (ARM), ankyrin (ANK), leucine-rich repeat (LRR), complex domain Ras (Roc), c-terminal Roc (COR), MAP kinase (MAPK), and tryptophan-aspartate repeat domain (WD40). LRRK2 exists primarily as a dimeric protein, associated with membrane structures or localized in the cytoplasm. The armadillo, ankyrin, LRR, and WD40 protein-protein interaction domains enable LRRK2 to interact with a host of different protein partners, influencing the subcellular localization of itself and its partner proteins. The central enzymatic core of the LRRK2 protein, containing the Roc-COR and MAPK domains, possesses separate GTPase and ATPase enzymatic activities, allowing LRRK2 to phosphorylate and regulate the function of intracellular substrates. Through its enzymatic activity and substrate interactions, LRRK2 influences various intracellular processes and biological mechanisms important for transporting intracellular vesicular structures and organelles, such as lysosomes, endosomes, autophagosomes, the Golgi apparatus, and mitochondria. Structural studies and modeling have highlighted how naturally occurring missense mutations in the functional and structural domains of LRRK2 affect enzymatic activity (bioRxiv 2020.01.06.895367). In the inactive (open) LRRK2 conformation, significant interactions exist between the GTPase (Roc-COR) and ATPase (MAPK) domains of the enzyme. Furthermore, the final C-terminal, proceeding WD40 domain binds along the entire kinase (MAPK) domain. In the active (closed) LRRK2 conformation, the LRR domain positions the autophosphorylation site Ser1292 near the kinase active site. Phosphorylation of LRRK2 at the cluster of serines immediately preceding the LRR domain allows the LRR domain of LRRK2 to bind to 14-3-3 proteins.Among these phosphorylation sites are serine (Ser) at the following amino acid positions: Ser910, Ser935, Ser955, and Ser973.

[0006] Pathogenic LRRK2 mutations occurring in the GTPase domain reduce phosphorylation at these sites, thereby reducing 14-3-3 binding and leading to increased recruitment of the microtubule network. All ATP-competitive LRRK2 inhibitors induce dephosphorylation at Ser910, Ser935, Ser955, and Ser973, making these sites serve as surrogate target engagement markers (Biochem J 430(3), 405-13, 2010; J Neurochem 120(1), 37-45, 2012). Natural LRRK2 substrates consist of a subset of small Rab GTPases, including Rab10 and Rab29. The Golgi-resident protein Rab29, also known as Rab7L1, is a Parkinson's disease susceptibility gene located at the PARK16 locus (Nat Genet 41(12), 1308-12, 2009).

[0007] Rare protein-coding variants in the LRRK2 gene cause Parkinson's disease. The most common pathogenic variant causing autosomal dominant familial Parkinson's disease is the p.G2019S substitution, which changes a glycine to a serine in the activation loop of the LRRK2 kinase domain, making the p.G2019S variant more active than the wild-type LRRK2 protein (Lancet 365(9457), 412-5, 2005). This results in increased autophosphorylation at serine at amino acid position 1292 (Biochem J 430(3), 405-13, 2010; J Neurochem 120(1), 37-45, 2012). The estimated global prevalence of the p.G2019S mutation in patients with PD is 1-2%, but the prevalence of p.G2019S in PD patients is up to 30% and 40%, respectively, among Ashkenazi Jews and North African Arab Berbers (Lancet Neurol 7, 583-90, 2008; N Engl J Med 354(4), 424-5, 2006; Lancet Neurol 7, 591-4, 2008). The clinical signs of Parkinson's disease in patients carrying the p.G2019S variant are indistinguishable from those in patients with sporadic forms of Parkinson's disease (Ann Neurol 57(5), 762-5, 2005). In addition to p.G2019S, seven rare LRRK2 exonic variants (p.N1437H; p.R1441C / G / H; p.Y1699C; p.S1761R; p.I2020T) with nonsynonymous amino acid substitutions in the central enzyme core also cause autosomal dominant Parkinson's disease (Parkinsonism Relat Disord 15(6), 466-7, 2009; Mov Disord 25(14), 2340-5, 2010; Neuron 44(4), 601-7, 2004; Parkinsonism Relat Disord 18(4), 332-8, 2012; Ann Neurol 57(6), 918-21, 2005; Mov Disord 27(1), 146-51, 2013). 2012).Similar to p.G2019S, their clinical manifestations are indistinguishable from idiopathic PD (Neurology 70, 1456-60, 2008). LRRK2 missense variants exhibit increased Ser1292 phosphorylation, increased trans-Golgi recruitment by Rab, and increased phosphorylation at amino acid position 73 of Rab10 (Rab10-Thr73), which can be reversed by LRRK2 inhibition (Sci Transl Med 4(164), 164ra161, 2012; EMBO J 37(1), 1-18, 2018; Proc Natl Acad Sci USA 111, 2626-31, 2014). Common protein-coding mutations in the LRRK2 gene are also associated with risk for Parkinson's disease. Mutations such as p.A419V, p.M1646T, p.R1628P, and p.G2385R increase the risk of Parkinson's disease and have increased kinase activity (Sci Transl Med 4(164), 164ra161, 2012; EMBO J 37(1), 1-18, 2018; Proc Natl Acad Sci USA 111, 2626-31, 2014), whereas the p.N551K variant is associated with a decreased risk of Parkinson's disease (Lancet Neurol 10(10), 898-908, 2011) and has decreased kinase activity (bioRxiv 447946, 2018). Evidence that LRRK2 is also involved in sporadic Parkinson's disease has come from both genetic studies and postmortem analyses of PD brains. A single nucleotide polymorphism (SNP) at the LRRK2 locus has been associated with genome-wide risk for Parkinson's disease (Nat Genet 46(9), 989-93, 2014). This particular SNP variant is associated with increased LRRK2 expression (Sci Transl Med 9 (421), 2017S), consistent with increased LRRK2 kinase activity observed in surviving dopaminergic neurons from postmortem brains of sporadic PD patients (Sci Transl Med 10 (451), 2018).

[0008] Therefore, inhibitors of LRRK2 kinase activity can be used as treatment for both sporadic PD patients as well as PD patients with LRRK2 mutations or Rab29 / Rab7L1 polymorphisms.

[0009] Genome-wide association studies (GWAS) and related studies have identified risk loci for Parkinson's disease, including several genes encoding proteins involved in endosomal-lysosomal processes, such as GBA, SCARB2, GALC, VPS35, LAMP1, VPS13C, VPS35, TMEM175, ATP6V0A1, and CTSB. LRRK2 also plays an important role in the endosomal-lysosomal system and processes related to endosomal function, such as autophagy and mitophagy. LRRK2 interacts with the vacuolar H+-ATPase α subunit to regulate lysosomal pH, and LRRK2 inhibition may alleviate endosomal-lysosomal dysfunction induced by rotenone, a toxin known to be associated with an increased risk of Parkinson's disease (Neurobiol Dis 134, 104626, 2020). Disease-causing LRRK2 mutations induce lysosomal stress by increasing lysosome size (Hum Mol Genet 24(21), 6013-28, 2015). Similarly, an aspartate-to-asparagine missense mutation in the retromer complex protein VPS35 at amino acid position 620 (VPS35-D620N) causes late-onset autosomal dominant familial Parkinson's disease (PD). In this pathology, the VPS35-D620N missense mutation disrupts the trafficking of cathepsin D, a protease involved in the degradation of α-synuclein (Traffic 15(2), 230-44, 2014), and activates LRRK2, resulting in increased autophosphorylation at LRRK2-Ser1292 and increased phosphorylation of Rab10-Thr73 (Biochem J 475(11), 1861-1883, 2018). In lysosomes, LRRK2 interacts with GBA, which is causally associated with the lysosomal storage disorder Gaucher's disease, and with a risk gene for Parkinson's disease. LRRK2 missense mutations reduce GBA activity, which can be counteracted by LRRK2 inhibition (Nat Commun 10(1), 5570, 2019).Conversely, GBA disease-associated defects in lysosomal biological processes in astrocytes can also be alleviated by LRRK2 inhibition (Mov Disord Feb 8, 2020, doi: 10.1002 / mds.27994). Missense mutations in the mitochondrial kinase PINK1 and the E3 ligase PARKIN both cause autosomal recessive, early-onset Parkinson's disease associated with mitochondrial dysfunction (Science 304(5674), 1158-60, 2004; Nature 392(6676), 605-8, 1998). LRRK2-dependent phosphorylation of Rab8a on threonine at amino acid position 72 is regulated by PINK1 phosphorylation of serine at amino acid position 111 of Rab8a (Biochem J. Mar 30, 2020, doi: 10.1042 / BCJ20190664B). Additionally, this LRRK2 activity reduces mitophagy, which is normally regulated by the PINK1 / PARKIN pathway, and this can be reversed by LRRK2 inhibition (Hum Mol Genet 28(10), 1645-1660, 2019). LRRK2 missense mutations cause mitochondrial DNA damage, which can be reversed by gene correction (Neurobiol Dis 62, 381-6, 2014), as well as by the use of LRRK2 inhibitors (Hum Mol Genet. 26(22), 4340-4351, 2017).

[0010] This suggests that LRRK2 inhibitors may be useful for treating lysosomal storage disorders such as Gaucher disease, Krabbe disease, Niemann-Pick disease, and Fabry disease, disorders involving mitochondrial defects such as early-onset Parkinson's disease associated with PINK1 and PARKIN missense mutations, and Parkinson's disease in patients with polymorphisms in genes encoding proteins involved in the endosomal-lysosomal system, such as GBA, GALC, VPS35, VPS13C, ATP6V0A1, LAMP1, SCARB2, TMEM175, and CTSB.

[0011] Postmortem analysis of brains from Parkinson's disease patients with LRRK2 mutations shows the presence of α-synuclein pathology (JAMA Neurol. 72(1), 100-5, 2015). In preclinical Parkinson's disease (PD) models, p.G2019S exacerbates PD-associated pathology that can be reversed by LRRK2 inhibition. LRRK2 has been identified in Lewy bodies in the substantia nigra and brainstem regions (Neuropathol Appl Neurobiol 34(3), 272-83, 2008) and has also been shown to phosphorylate α-synuclein on Ser129 (Biochem Biophys Res Commun 387(1), 149-52, 2009). LRRK2 exonic mutations are associated with the risk of multiple system atrophy (Neurology 83(24), 2256-61, 2014), and LRRK2 missense mutations have also been reported in patients with multiple system atrophy (J Parkinsons Dis;8(1), 93-100, 2018). Single nucleotide polymorphisms in the MAPT (tau) locus are associated with an increased risk of Parkinson's disease and multiple system atrophy (Hum Genet 124(6), 593-605, 2009; ParkinsonIsm Relat Disord 30, 40-5, 2016). Tau pathology is also a prominent feature seen in Parkinson's disease patients with LRRK2 missense mutations (Acta Neuropathol Commun 7(1), 183, 2019). Pathogenic overexpression of LRRK2 in animal models increases tau pathology (Neurobiol Dis 40(3), 503-17, 2010). LRRK2 missense mutations have been reported in patients with tauopathies such as progressive supranuclear palsy and corticobasal degeneration (MoV Disord. 32(1), 115-123, 2017). Common mutations at the LRRK2 locus are associated with survival in the primary tauopathy progressive supranuclear palsy (bioRXiV2020.02.04.932335), and GWAS studies have identified a risk for frontotemporal dementia at the LRRK2 locus.

[0012] This suggests that LRRK2 inhibitors may be useful in treating synucleinopathies and tauopathies, including frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, and Alzheimer's disease.

[0013] LRRK2 mRNA and protein are widely expressed but are particularly enriched in brain tissue and peripheral organs, more specifically, kidney, lung, intestine, and spleen. LRRK2 expression is also highly enriched in immune cells in the brain, as well as peripheral neutrophils, B cells, macrophages, and monocytes. LRRK2 mRNA and protein expression is induced after proinflammatory stimuli or pathogens, thereby increasing LRRK2 kinase activity. In human peripheral blood mononuclear cells, LRRK2 substrates Rab10 and Rab12 are phosphorylated after stimulation with agents mimicking viral infection (Sci Rep 7(1), 10300, 2017). Consistent with a role for LRRK2 biology in responding to inflammatory stimuli, LRRK2 missense variants are associated with risk for Crohn's disease, an inflammatory bowel disease, and a GWAS study identified a single nucleotide polymorphism at the LRRK2 locus associated with a significant genome-wide risk for Crohn's disease (Inflamm Bowel Dis 17(12), 2407-15, 2011). Ashkenazi Jewish populations have a two- to four-fold increased prevalence of Crohn's disease, and in the same population, LRRK2 variants are associated with increased risk for Crohn's disease (PLoS Genet 14(5), e1007329, 2018). LRRK2 exonic variants, such as p.N2081D and p.M2397T, increase the risk for Crohn's disease, and, as observed in Parkinson's disease, the protective haplotype variant p.N551K / p.R1348H decreases the risk for Crohn's disease. In cell-based studies, the p.N2081D mutant increased kinase activity, leading to increased Rab10 phosphorylation (bioRXiV 447946, 2018; Sci Transl Med 10(423), 2018). The biological link between Parkinson's disease and autoimmune disorders is further supported by a study (JAMA Neurol 74(7), 780-92, 2017) that found that common genetic pathways, including LRRK2, are shared between Parkinson's disease and autoimmune disorders such as rheumatoid arthritis, ulcerative colitis, and Crohn's disease.Consistent with this, LRRK2 has also been associated with the risk of lupus (Oncotarget8, 13754-61, 2017; J Transl Med 17(1), 37, 2019) and leprosy (N Engl J Med 361(27), 2609-18, 2009; PLoS One 8(8), e73103, 2013; PLoS Negl Trop DIs 10(2), e0004412, 2016).

[0014] Therefore, LRRK2 inhibitors can be used to treat Crohn's disease and other autoimmune disorders such as, but not limited to, rheumatoid arthritis, ulcerative colitis, lupus, and leprosy.

[0015] LRRK2 plays a role in tumor growth in renal and thyroid cancers by affecting MET signaling, and reduced LRRK2 expression induces growth arrest (Proc Natl Acad Sci USA 108(4), 1439-44, 2011). LRRK2-PD patients have an increased risk of leukemia as well as skin and colon cancer (MoV Disord 34(9), 1392-8, 2019). Carriers of p.G2019S also have an overall increased risk of non-skin cancers, specifically breast cancer and hormone-related cancers in women (JAMA Neurol 72(1), 58-65, 2015). Research has shown that LRRK2 silencing promotes T cell proliferation inhibition and facilitates apoptosis and cell cycle arrest (Int J Oncol 55(1), 21-34, 2019). LRRK2 is also differentially expressed in lung adenocarcinoma and squamous cell carcinoma, as well as non-small cell lung cancer (J Cell Physiol 234(7), 10918-25, 2019; J Cell Physiol 234(12), 22742-52, 2019).

[0016] Therefore, LRRK2 inhibitors have anti-carcinogenic effects and can be used to treat skin cancers as well as non-skin cancers such as renal cancer, colon cancer, adenocarcinoma and squamous lung cancer, non-small cell lung cancer, hormone-related cancers, thyroid cancer, leukemia, and breast cancer.

[0017] Extensive prior art is known in the field of LRRK2 inhibitors. The most recent patent applications filed in this field include oligomeric derivatives such as the compounds disclosed in WO 2020 / 006267, non-macrocyclic or polycyclic structures such as the compounds disclosed in WO 2019 / 222173, WO 2019 / 112269, WO 2019 / 074809, WO 2018 / 217946, WO 2018 / 163066, WO 2018 / 155916, WO 2018 / 137618, WO 2018 / 06931, and also macrocyclic derivatives such as the compounds disclosed in WO 2019 / 012093, WO 2016 / 042089. Despite the vast amount of constructs created over the past few years, there is a continuing need to design new scaffolds with greater potency and selectivity to fulfill unmet medical needs.

[0018] Detailed Description of the Invention The present invention is described below. In the following sections, various aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects not expressly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

[0019] In a first aspect, the present invention provides a method for producing a composition comprising: Formula (I): [ka] [During the ceremony, R represents a hydrogen atom, a halogen atom, or an alkyl group; Z1, Z2, and Z3 each independently represent a carbon or nitrogen atom, and it is understood that the 6-membered ring comprising Z1, Z2, and Z3 can have 0, 1, or 2 nitrogen atoms; -X1- is absent or represents -O-, -S-, or -N(R'a)-, where R'a represents a hydrogen atom or an alkyl group; -X2- represents an alkanediyl group optionally substituted with one or more identical or different substituents selected from a halogen atom, a polyhalogenoalkyl group, an alkoxy group, a hydroxy group, an amino group, an alkylamino group, a dialkylamino group, and a cyano group; It is understood that the alpha carbon atom of -N(Ra), and the alpha carbon atom of -X1- when -X1- represents -O-, -S-, or N(R'a)-, cannot be substituted with an oxygen or nitrogen heteroatom; -X3- represents an alkanediyl group optionally substituted with one or more identical or different substituents selected from a halogen atom, a polyhalogenoalkyl group, an alkoxy group, a hydroxy group, an amino group, an alkylamino group, a dialkylamino group, a cyano group, a cycloalkyl group, and a heterocycloalkyl group; It is understood that the carbon atom alpha to -O-, and the carbon atom alpha to A when A represents a nitrogen atom, cannot be substituted with an oxygen or nitrogen heteroatom; Ra represents a hydrogen atom or an alkyl group; When Ra represents an alkyl group, it is understood that one carbon atom of Ra can be linked to a carbon atom of —X2— or a carbon atom of X3— to form a cyclic moiety containing 5 or 6 ring members; A is a compound of formula (a): [ka] (In the formula, A1 and A4 each independently represent a carbon atom or a nitrogen atom; A2, A3, and A5 each independently represent a carbon atom, an oxygen atom, a sulfur atom, or a nitrogen atom; It is understood that A1, A2, A3, A4 and A5 cannot simultaneously represent heteroatoms. or an aromatic or partially hydrogenated cyclic group of the formula or formula (b): [ka] (In the formula, A'1, A'2, A'3, and A'4 each independently represent a carbon atom or a nitrogen atom.) represents an aromatic or partially hydrogenated cyclic group of the formula: * is understood to mean that the bond is connected to X3. A compound of the formula: The aromatic or partially hydrogenated cyclic group A so defined is optionally substituted by one or more identical or different substituents selected from halogen atoms, alkyl groups, alkoxy groups, hydroxy groups, oxo groups, alkoxyalkyl groups, alkoxyalkoxy groups, polyhalogenoalkyl groups, polyhalogenoalkoxy groups, heterocycloalkyl groups, heterocycloalkylalkyl groups, (alkoxyalkyl)(alkyl)amino groups, amino groups, alkylamino groups, dialkylamino groups, cycloalkyl groups, (heterocycloalkyl)(alkyl)amino groups, dialkylaminoalkyl groups, heterocycloalkylalkoxy groups, cyano groups and cyanoalkyl groups, Here, the heterocycloalkyl and cycloalkyl groups defined as such may be optionally substituted with one or more substituents selected from an alkyl group, a halogen atom, a polyhalogenoalkyl group, a polyhalogenoalkoxy group, an alkoxy group, an alkoxyalkyl group, a hydroxy group, a cyano group, and an oxo group. Provided are compounds, their enantiomers, diastereomers, tautomers, racemates, hydrates, solvates, N-oxides, isotopes, deuterated derivatives and their pharmaceutically acceptable acid or base addition salts.

[0020] When describing the compounds of the present invention, the terms used shall be construed in accordance with the following definitions, unless the context dictates otherwise.

[0021] The term "alkyl" by itself or as part of another substituent refers to a fully saturated monovalent hydrocarbon group, including its corresponding deuterated derivatives. Alkyl groups of the present invention contain from 1 to 6 carbon atoms. Alkyl groups may be linear or branched, may include a spiran structure, and may be optionally substituted as described herein. Examples of alkyl groups are methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g., n-butyl, i-butyl, and t-butyl), pentyl and its isomers, and hexyl and its isomers.

[0022] The term "alkanediyl" means a fully saturated divalent hydrocarbon group having two single bonds for attachment to two other groups, and may be represented as an "-(alkyl)-" group, where alkyl is as defined above. Alkanediyl groups of the present invention contain 1 to 6 carbon atoms, may be linear or branched, may include a spirane structure, and may be substituted as described herein. Non-limiting examples of alkanediyl groups include -CH-, -CH-CH-, -CD-, -CD-CD-, -CH(CH)-, -CH(CH-CH)-, -CH(i-Pr)-, -C(CH)(CH)-, -CH-C(CH)(CH)-, -CH-CH-C(CH)(CH)-, [ka] -CH2-CH(i-Pr)-, -CH(i-Pr)-CH2-, -CH2-CH(i-Bu)-, -CH(i-Bu)-CH2-, -CH(CH3)-CH2-, -CH2-CH(CH3)-, -CH2-CH2-CH2-, -CD2-CD2-CD2-, -CH(CH3)-CH2-CH2-, -CH2-CH2-CH(CH3)-, -CH2-CH(CH3)-CH2-, -CH(CH3)-CH2-CH(CH3)-, -CH2-CH2-CH(CH2-CH3)-, -CH(CH2-CH3)-CH2-CH2-, -CH(CH2-CH3)-CH2-CH2-, -CH(CH2-CH3)-CH2-CH2-, -CH(CH2-CH3)-CH2-CH(CH3)-, -CH(CH3)-CH2-CH2-CH(CH2-CH3)-, -CH(CH3)-CH2-CH2-CH(CH2-CH3)-, and -CH(CH3)-CH2-CH2-CH(CH2-CH3)-, which groups, where indicated, can be further substituted. For example, alkanediyl groups substituted with alkoxy groups include, but are not limited to, -CH(OCH3)-, -CH(OCH3)-CH(CH3)-, -CH2-CH2-CH(OCH3)-, -CH(OCH3)-CH2-CH2-, -CH2-CH2-CH(CH2-OCH3)-, -CH(CH2-OCH3)-CH2-CH2-, -CH(O-CH2-CH3)-CH2-, and -CH2-CH(O-CH2-CH3)-. As another non-limiting example, alkanediyl groups substituted with cycloalkyl groups include -CH2-CH(Cy-Pr)- and -CH(Cy-Pr)-CH2-, where Cy-Pr is cyclopropyl. Examples of alkanediyl groups substituted with one or more halogen atoms include, but are not limited to, -CHF-, -CHF-CH2-, -CF2-, -CF2-CH2-, and -CH2-CF2-. Examples of alkanediyl groups substituted with heterocycloalkyl groups include, but are not limited to, -CH2-CH(tetrahydropyranyl)-, -CH(tetrahydropyranyl)-CH2-, -CH2-CH(oxolanyl)-, and -CH(oxolanyl)-CH2-.

[0023] The term "cycloalkyl" by itself or as part of another substituent is a monovalent, saturated or unsaturated hydrocarbon group having one or two ring structures. Cycloalkyl includes all saturated, partially saturated, or aromatic hydrocarbon groups having one or two ring structures. Cycloalkyl groups contain three or more carbon atoms, and generally, according to the present invention, contain from 3 to 10 carbon atoms.

[0024] Examples of cycloalkyl groups having a single ring structure include, but are not limited to, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Assuming a bicyclic ring structure, the two rings are: - can be fused, meaning that they share a common bond; exemplary cycloalkyl bicyclic fused systems include, but are not limited to, naphthalenyl, bicyclo[1.1.0]butanyl, octahydropentalenyl, decahydronaphthalenyl, octahydro-1H-indenyl; - may be linked via a bond between the two ring structures; exemplary cycloalkyl bicyclic linked systems include, but are not limited to, biphenyl, bicyclopropanyl, bicyclopentenyl, bicyclohexanyl, cyclopropylcyclohexanyl, cyclopropylcyclopentanyl; - may be bridged, meaning that the two rings share three or more atoms, with a bridge containing at least one atom separating the two bridgehead atoms; exemplary cycloalkyl bicyclic bridged systems include, but are not limited to, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl; - or may represent a spiro bicyclic ring system in which the two rings are connected through a single atom, exemplary cycloalkyl spiro bicyclic systems include, but are not limited to, spiro[2.2]pentanyl, spiro[2.4]heptanyl, spiro[4.4]nonanyl, spiro[5.5]undecanyl.

[0025] The "cycloalkyl group" defined as such can be optionally substituted with 1 to 3 substituents selected from alkyl groups, halogen atoms, polyhalogenoalkyl groups, polyhalogenoalkoxy groups, alkoxy groups, alkoxyalkyl groups, hydroxy groups, cyano groups, and oxo groups. When a cycloalkyl group is substituted with 2 or 3 substituents, the substituents can be borne on the same atom or different atoms, provided that the valence of each atom is taken into consideration.

[0026] The term "alkoxy" by itself or as part of another substituent refers to an "(alkyl)-O-" group, where "alkyl" is defined above. Non-limiting examples of alkoxy groups include methoxy, ethyloxy, n-propyloxy, i-propyloxy, butyloxy (and its isomers), pentyloxy (and its isomers), and hexyloxy (and its isomers).

[0027] The term "alkoxyalkyl" refers to the group "(alkyl)-O-(alkyl)-", where "alkyl" is as defined above. Non-limiting examples include CH3-O-CH2-, CH3-O-CH2-CH2-.

[0028] The term "alkoxyalkoxy" refers to the group "(alkyl)-O-(alkyl)-O-" where "alkyl" is as defined above, non-limiting examples include CH3-O-CH2-O-, CH3-O-CH2-CH2-O-.

[0029] The term "alkylamino" refers to the group "-NH-(alkyl)" where "alkyl" is as defined above. Non-limiting examples include -NH-CH, -NH-CH-CH, -NH-CH(CH)(CH).

[0030] The term "dialkylamino" refers to an "-N(alkyl)(alkyl)" group, where "alkyl" is as defined above. Non-limiting examples include -N(CH), -N(CH)(CH-CH).

[0031] The term "polyhalogenoalkyl" refers to an alkyl group as defined above, in which one or more hydrogen atoms carried by the same or different carbon atoms are replaced by one or more halogen atoms; non-limiting examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl.

[0032] The term "polyhalogenoalkoxy" refers to a "(polyhalogenoalkyl)-O-" group, where "polyhalogenoalkyl" is as defined above. Non-limiting examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-chloroethoxy.

[0033] The term "heterocycloalkyl" refers to a monovalent, monocyclic or bicyclic, aromatic or non-aromatic carbocyclic group containing 3 to 10 ring members and 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen atoms. The heterocycloalkyl group can be linked by a carbon or nitrogen atom, if possible. A heterocycloalkyl group defined as such can be a monocyclic or bicyclic ring system. Heterocycloalkyl monocyclic ring systems include, but are not limited to, pyridinyl, piperazinyl, piperidinyl, tetrahydropyridinyl, tetrahydropyranyl, pyrrolidinyl, dihydropyrrolyl, oxolanyl, dihydrofuranyl, morpholinyl, pyrazolyl, azetidinyl, and oxetanyl. When a bicyclic ring system is envisioned, the two rings are: - can be fused, meaning they share a common bond; exemplary heterocycloalkyl bicyclic fused systems include, but are not limited to, indolyl, indolinyl, benzopyranyl, benzofuranyl, naphthyridinyl, quinolinyl, pyridopyrazinyl, pyridopyridazinyl, pyridopyrimidinyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydrobenzofuranyl, benzopyranyl, dihydrobenzopyranyl; - may be linked via a bond between the two ring structures; exemplary heterocycloalkyl bicyclic linked systems include, but are not limited to, phenylpyridinyl, bipyridinyl, oxetanylpyridinyl, oxetanylpiperidinyl, oxetanyltetrahydropyridinyl, pyrrolidinylpiperidinyl, morpholinopiperidinyl, pyrrolidinyltetrahydropyridinyl, pyrrolidinylpyridinyl, oxetanylpiperazinyl, pyrrolidinylpiperazinyl; - may be bridged, meaning that the two rings share three or more atoms, with a bridge containing at least one atom separating the two bridgehead atoms; exemplary heterocycloalkyl bicyclic bridged systems include, but are not limited to, azabicyclo[2.2.1]heptanyl, oxazabicyclo[2.2.1]heptanyl; - or may represent a spiro bicyclic ring system in which the two rings are connected through a single atom; exemplary heterocycloalkyl spiro bicyclic systems include, but are not limited to, oxaspirooctane, azaspirooctane, diazaspirooctane, oxazaspirooctane, oxaspirononane, azaspirononane, diazaspirononane, oxazaspirononane.

[0034] A "heterocycloalkyl group" defined as such can be optionally substituted with 1 to 3 substituents selected from an alkyl group, a halogen atom, a polyhalogenoalkyl group, a polyhalogenoalkoxy group, an alkoxy group, an alkoxyalkyl group, a hydroxy group, a cyano group, and an oxo group. When a heterocycloalkyl group is substituted with 2 or 3 substituents, the substituents can be borne on the same atom or on different atoms, provided that the valence of each atom is taken into consideration.

[0035] The term "heterocycloalkylalkyl" refers to a "(heterocycloalkyl)-(alkyl)-" group in which the heterocycloalkyl and alkyl portions are as defined above. Non-limiting examples include morpholinylmethyl, pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl.

[0036] The term "halogen atom" means a fluorine, chlorine, bromine or iodine atom.

[0037] Pharmaceutically acceptable acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid, camphoric acid, and the like.

[0038] Pharmaceutically acceptable bases include, but are not limited to, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, and the like.

[0039] Specific embodiments of the compounds of formula (I) of the present invention are described below, and the features of these specific embodiments may be used alone or in combination to create new specific embodiments.

[0040] In one particular embodiment, the present invention more preferably refers to compounds of formula (I) in which R represents a hydrogen atom.

[0041] In another embodiment, R advantageously represents a halogen atom, and most preferably a fluorine or chlorine atom. When R is an alkyl group, preferably R is a methyl group. When Z2 represents a carbon atom, preferably R is linked to Z2.

[0042] In another specific preferred embodiment of the present invention, Z1, Z2 and Z3 simultaneously represent a carbon atom.

[0043] In another advantageous embodiment, one of Z1, Z2 and Z3 is a nitrogen atom and the other two represent carbon atoms. More specifically, when one of Z1, Z2 and Z3 represents a nitrogen atom, it is preferentially Z1 or Z2.

[0044] Another specific embodiment of the present invention relates to compounds of formula (I) in which -X1- represents -O- or NH-. More preferably, -X1- represents -O-.

[0045] In another specific embodiment of the present invention, -X2- represents a linear or branched alkanediyl group having 2, 3, 4 or 5 carbon atoms, more preferably 3, 4 or 5 carbon atoms. Preferably, -X2- is unsubstituted. When -X2- is substituted, it is preferably a fluoro group or a methoxy group. Advantageously, -X2- is -(CH2)2-, -(CH2)3-, -CH(CH3)-(CH2)2-, -(CH2)2-CH(CH3)-, -CH2-CH(CH3)-CH2-, [ka] It is even more preferred that -X- represents -(CH)-, -CH(CH)-(CH)-, -(CH)-CH(CH)-, -CH-CF-CH ...

[0046] A preferred value for Ra in the compounds of formula (I) is a hydrogen atom.

[0047] In another specific embodiment of the present invention, -X3- represents a linear or branched alkanediyl group having 1, 2, 3, 4 or 5 carbon atoms, more preferably 1 or 2 carbon atoms. Preferably, -X3- is unsubstituted. Advantageously, -X3- represents -CH2-, -CH(CH3)-, -(CH2)2-, -(CH2)3-, -CH(CH2-CH3)-, -CH(CH3)-CH2-, -CH2-CH(CH3)-, -CH2-CH(i-Pr)-, -CH(i-Pr)-CH2-, -CH2-CH(Cy-Pr)-, or -CH(Cy-Pr)-CH2-. Even more preferably, -X3- represents -(CH2)2-, -CH2-, or -CH(CH3)-.

[0048] Another specific embodiment of the present invention is where A is of formula (b): [ka] The compound of formula (I) is represented by a group Preferred useful ones of (A'1, A'2, A'3, A'4) are: -4 carbon atoms, or - 3 carbon atoms and 1 nitrogen atom (more preferably, the nitrogen atom is in A'4), -or two carbon atoms and two nitrogen atoms is. A'3 is advantageously a carbon atom.

[0049] In a particular embodiment of the invention, A is: [ka] and is represented herein without substitution. The most preferred embodiment for A in formula (b) is a phenyl or pyridinyl group. Another advantageous embodiment for A is a pyrazinyl group.

[0050] An advantageous alternative for A is formula (a): [ka] is represented by the group:

[0051] The most preferred skeletons of formula (a) contain one, two, or three heteroatoms, one of which is a nitrogen atom. Representative preferred skeletons of formula (a) are: [ka] and is represented herein without substitution.

[0052] The most preferred embodiment for A in formula (a) is a triazolyl or pyrazolyl group.

[0053] Preferably, the group A in the compounds of formula (I) is unsubstituted.

[0054] When the group A of the compound of formula (I) is substituted, the substitution can occur on any carbon or nitrogen atom of the A backbone that has at least one free valence. Most preferred substituents include halogen atoms, cyano groups, cyanoalkyl groups, oxo groups, alkoxy groups, alkyl groups, cycloalkyl groups, and heterocycloalkyl groups. Specifically, preferred substituents include fluorine, bromine, or chlorine atoms, methyl, ethyl, cyclopropyl, methoxy, isopropyloxy, cyano, cyanomethyl, and oxo groups.

[0055] Most preferred heterocycloalkyl groups include pyrrolidinyl, piperazinyl, morpholinyl, azetidinyl, piperidinyl, tetrahydropyridinyl, tetrahydrofuranyl, dihydrofuranyl, oxetanyl, and pyrazolidinyl.

[0056] The most preferred substituents for group A are a fluorine or bromine atom, a methoxy group, a methyl group, an ethyl group, an unsubstituted or substituted pyrrolidinyl group, and an unsubstituted or substituted piperazinyl group.

[0057] Another specific embodiment of the present invention is a compound of formula (Ia): [ka] (In the formula, X1, X2, X3, Ra, and A are as defined in formula (I).) The compound is represented by:

[0058] In another preferred embodiment, the present invention provides a compound of formula (Ib): [ka] (Wherein, X2, X3, Ra, and A are as de?ned in formula (I). Most preferred compounds of formula (Ib) are those Wherein -X2- represents -(CH2)3-, -CH(CH3)-(CH2)2-, -CH2-CHF-CH2-, -CH2-CF2-CH2-, or -(CH2)2-CH(CH3)-. Another most preferred compound of formula (Ib) is those Wherein -X3- represents -CH2- or -(CH)(CH3)-.) The present invention relates to the compound

[0059] Another particular embodiment of the invention relates to compounds of formula (I) in which the chain -X1-X2-N(Ra)-C(O)O-X3- preferably represents -O-(CH2)3-NH-C(O)O-CH2-, -O-CH(CH3)-(CH2)2-NH-C(O)O-CH2-, -O-CH2-CHF-CH2-NHC(O)O-CH2-, -O-CH2-CF2-CH2-NHC(O)O-CH2-, -O-CH(CH3)-(CH2)2-NHC(O)O-(CH2)2- or -O-CH(CH3)-(CH2)2-NH-C(O)O-CH(CH3)-.

[0060] Preferably, the compound of the present invention has formula (Ic) or (I-c'): [ka] (In the formula, X1, X2, X3, Ra, A'1, A'2 and A'4 are as defined in formula (I).) is a compound of

[0061] Another specific embodiment is a compound of formula (Id) or (I-d'): [ka] (In the formula, X2, X3, Ra, A'1, A'2 and A'4 are as defined in formula (I).) The most preferred compounds of formula (Id) or (I-d') are those in which -X2- represents -(CH2)3-, -CH(CH3)-(CH2)2-, -CH2-CHF-CH2-, -CH2-CF2-CH2-, or -(CH2)2-CH(CH3)-. Another most preferred compound of formula (Id) or (I-d') is those in which -X3- represents -CH2- or -(CH2)2-.

[0062] Another preferred compound of the present invention has formula (Ie): [ka] (In the formula, X1, X2, X3, Ra, A1, A, and A5 are as defined in formula (I).) is a compound of

[0063] Another preferred compound of the present invention has the formula (If): [ka] (wherein X2, X3, Ra, A1, A2 and A5 are as defined in formula (I). Most preferred compounds of formula (If) are those where -X2- represents -(CH2)3-, -CH(CH3)-(CH2)2-, -CH2-CHF-CH2-, -CH2-CF2-CH2- or -(CH2)2-CH(CH3)-. Another most preferred compound of formula (If) is those where -X3- represents -CH2- or -(CH2)2-.

[0064] In another specific embodiment, preferred compounds of the invention are the following compounds: 8,14-Dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 10-Methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .018,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 8,14-Dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 8,14-Dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 10-(propan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 8,14-Dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Methoxy-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 5-Fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 5-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(pyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[4-(propan-2-yl)-piperazin-1-yl]8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-{2-oxa-6-azaspiro[3.4]octan-6-yl}-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[4-(oxetan-3-yl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(morpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 5-Methoxy-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(4,4-Difluoropiperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(3,3-Difluoropyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 7-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[4-(2-methoxyethyl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 9,14-Dioxa-11,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-10-one; 4-[(3R)-3-hydroxypyrrolidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(2-methoxyethyl(methyl)amino)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Chloro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Fluoro-5-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4,5-Difluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 5-Bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(4-methylpiperazin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(3-Methoxyazetidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 1-{9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptan-4-yl}piperidine-4-carbonitrile; 4-[4-pyrrolidin-1-yl]piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(azetidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(Piperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(2,5-Dihydrofuran-3-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[4-(morpholin-4-yl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(2S,5S)-2,5-dimethylmorpholin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(morpholin-4-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(pyrrolodin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(pyrrolodin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(4-methylpiperazin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 5-(morpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[4-(2-methoxyethyl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(Diethylamino)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Cyclopropyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 5-(4-Methylpiperazin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 13-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 8,14-Dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; 4-[methyl(oxetan-3-yl)amino]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(Dimethylamino)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4,10-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(propan-2-yloxy)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,2 1]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(3-methylpiperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(3S)-3-Hydroxypyrrolidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Fluoro-8,14-dioxa-10,19,20-triazapentacyclo[13.5.2.1 2,6 .1 7,10 .0 18,21 ]tetracosa-1(20),2(24),3,5,15(22),16,18(21)-heptaen-9-one; 4-(oxolan-3-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13S)-13-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13R)-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-(1-methyl-1H-pyrazol-3-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (7S)-7-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-[2-(morpholin-4-yl)ethoxy]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-(2-Methoxyethyl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (7R)-7-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 5-Cyclopropyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(2-Methoxyethoxy)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 11-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(3-oxomorpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-(2-oxopyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 5-(2-oxopyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-(2-methylpyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 2-{9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-4-yl}acetonitrile; (11R)-11-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (11S)-11-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-Ethynyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-(piperazin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-(1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 11-(Methoxymethyl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 8,14-Dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; 11-Methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; 12-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 11-Ethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-Fluoro-5,7-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-Fluoro-5-methoxy-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 5-Fluoro-4,7-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 8,14-Dioxa-10,19,20-triazapentacyclo[13.5.2.1 2,6 .1 7,10 .0 18,21 ]tetracosa-1(20),2(24),3,5,15(22),16,18(21)-heptaen-9-one; 13-Methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 12-Methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; 7-Methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; 5-Fluoro-4-methoxy-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (7R,13R)-7,13-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13R)-13-Methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),3,15,17,21-hexaen-9-one; 8,15-Dioxa-4,10,20,21-tetraazapentacyclo[14.5.2.1 2,6 .1 10,13 .0 19,22 ]pentacosa-1(21),2(25),3,5,16(23),17,19(22)-heptaen-9-one; 8,14-Dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; (13S)-4-Fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13R)-4-Fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13R)-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 6-Cyclopropyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; 7-Ethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13-Ethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (7R,13R)-4-Fluoro-7,13-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 7-Methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (7R)-4-Fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (7S)-4-Fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 6-Methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),3,15,17,21-hexaen-9-one; 7-Methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 6-(propan-2-yl)-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; (13R)-7,13-dimethyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; (13R)-13-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (7R)-7-Ethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (7S)-7-Ethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13-methyl-8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 6-(oxan-4-yl)-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),3,15,17,21-hexaen-9-one; 4-Ethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),15,17,21-pentaen-9-one; (13R)-23-Fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 9,14-Dioxa-4,5,11,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),3,15,17,21-hexaen-10-one; 4-Ethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),3,15,17,21-hexaen-9-one; 3,9,15-trioxa-4,11,20,21-tetraazatetracyclo[14.5.2.1 2,5 .0 19,22 ]tetracosa-1(21),2(24),4,16,18,22-hexaen-10-one; (13R)-16-Fluoro-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-4-chloro-13-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 8,14-Dioxa-2,4,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),3,5(23),15(22),16,18(21)-hexaen-9-one; (13R)-4-Methoxy-13-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13-Methyl-9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaene-5-carbonitrile; (13R)-13-methyl-4-(pyrrolidin-1-yl)-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (7S,13R)-7,13-dimethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (7R,13R)-7,13-dimethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-16-Fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13-methyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 8,14-Dioxa-4-thia-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2,5(23),15,17,21-hexaen-9-one; 8,14-Dioxa-3-thia-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),4,15,17,21-hexaen-9-one; (7R,13R)-7,13-dimethyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-4-[(3R)-3-methylpyrrolidin-1-yl]-13-methyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-16-chloro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13,16-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13-methyl-8,14-dioxa-3,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 8-Oxa-10,14,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one hydrochloride; 8-Oxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13R)-5-Methoxy-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,6(23),15,17,21-hexaene-5,9-dione; 4-Methyl-8,14-dioxa-3,4,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2,5(23),15(22),16,18(21)-hexaen-9-one; (13R)-16-Fluoro-13-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 7,13-Dioxa-4-thia-9,18,19,22-tetraazatetracyclo[12.5.2.1 2,5 .0 17,20 ]docosa-1(19),2,5(22),14(21),15,17(20)-hexaen-8-one; (13R)-4,13-dimethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 8,14-Dioxa-23-thia-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2,4,15(22),16,18(21)-hexaen-9-one; (7S,13R)-7,13-dimethyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13R)-13-methyl-9-oxo-8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaene-4-carbonitrile; 12,12-Difluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2. 12,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13R)-17-Fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (7S,13R)-7,13-dimethyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (7R,13R)-7,13-dimethyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13S)-13-Methyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13R)-13-methyl-8,14-dioxa-10,19,20,22-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15,17,21-heptaen-9-one; (12R)-4,12-dimethyl-7,13-dioxa-4,9,18,19,22-pentaazatetracyclo[12.5.2.1 2,5 .0 17,20 ]docosa-1(19),2,5(22),14(21),15,17(20)-hexaen-8-one; (13R)-13-Methyl-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),3,15,17,21-hexaen-9-one; (13R)-13-methyl-8,14-dioxa-23-thia-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2,4,15,17,21-hexaen-9-one; (13R)-4,13-dimethyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2,5(23),15(22),16,18(21)-hexaen-9-one; (13R)-13-methyl-8,14-dioxa-10,16,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 14-Methyl-8-oxa-10,14,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21]tricosa-1(20),2(23),3,5,15,17,21-heptaen-9-one; (13R)-13-Methyl-8,14-dioxa-4,10,19,20,22-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15,17,21-heptaen-9-one; (13R)-13-methyl-8,14-dioxa-10,17,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 8,14-Dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; 12,12-Difluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; (12R)-12-Fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (12S)-12-Fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 12,12-Difluoro-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (12S)-12-Fluoro-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15,17,21-heptaen-9-one; (12R)-12-Fluoro-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15,17,21-heptaen-9-one; (12S)-12-Fluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),3,15,17,21-hexaen-9-one; (12R)-12-Fluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),3,15,17,21-hexaen-9-one; 8',14'-Dioxa-10',19',20'-triazaspiro[cyclopropane-1,13'-tetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosane]-1'(20'),2'(23'),3',5',15'(22'),16',18'(21')-heptaen-9'-one.

[0065] The present invention also relates to a general method for preparing a compound of formula (I), which comprises using as a starting material a compound of formula (I-1): [ka] (wherein R, X1, Z1, Z2 and Z3 are as defined in formula (I)). to which a compound PG1-LG1 is first condensed, and then a compound PG2-LG2 is condensed, or a compound PG2-LG2 is first condensed, and then a compound PG1-LG1 is condensed (wherein PG1 is a protecting group, or when X1 is a single bond, PG1 represents a halogen, and PG2 is a protecting group, and LG1 and LG2 are leaving groups), to obtain a compound of formula (I-2): [ka] wherein R, X1, Z1, Z2, Z3, PG1 and PG2 are as defined above, To the compound of formula (I-2): - condensation of a leaving group LG3 to give a compound of formula (I-3): [ka] wherein R, X1, Z1, Z2, Z3, PG1, PG2 and LG3 are as defined above, To this compound of formula (I-3): After deprotection of X1, the compound LG4-X2-NPG3 (wherein LG4 is a leaving group, PG3 is a protecting group, and X2 is as defined in formula (I)) is condensed to give a compound of formula (I-4): [ka] wherein R, X1, X2, Z1, Z2, Z3, PG2, PG3 and LG3 are as defined above, The compound of formula (I-4) may be treated with a compound of formula (I-5): [ka] wherein A and X3 are as defined in formula (I), or an organometallic derivative of a compound of formula (I-5), such as a boronate, to give a compound of formula (I-6): [ka] wherein R, X1, X2, X3, A, Z1, Z2, Z3, PG2 and PG3 are as defined above, The compound of formula (I-6) is subjected to deprotection of -X2-NPG3 and then subjected to a cyclization reaction to obtain a compound of formula (I-7): [ka] wherein R, X1, X2, X3, A, Z1, Z2, Z3 and PG2 are as defined above, This compound of formula (I-7) can be optionally alkylated on the carbamate functionality and / or optionally substituted on the A ring, followed by deprotection of -N(PG2)- to give a compound of formula (I), or or a compound of formula (I-3) with a compound of formula (I-8): [ka] wherein Ra, X2, X3, and A are as defined above, and LG4 is a leaving group, or an organometallic derivative of a compound of formula (I-8), such as a boronate, to give a compound of formula (I-9): [ka] wherein R, Ra, X1, X2, X3, A, Z1, Z2, Z3, PG1, PG2 and LG4 are as defined above, Compounds of formula (I-9), after deprotection of X1, are subjected to a cyclization reaction to produce compounds of formula (I-7) as defined above, which, after deprotection of -N(PG2)- and / or optional substitution on the A ring, give compounds of formula (I); or by condensing a compound of formula (I-3), after deprotection of X1, with a compound LG5-X2-NRaCOOBn (wherein X2 and Ra are as defined in formula (I) and LG5 is a leaving group), to give a compound of formula (I-10): [ka] wherein R, Ra, X1, X2, Z1, Z2, Z3, PG2 and LG3 are as defined above, The compound of formula (I-10) may be treated with a compound of formula (I-5): [ka] wherein X3 and A are as defined above, or an organometallic derivative of a compound of formula (I-5), such as a boronate, to give a compound of formula (I-11): [ka] wherein R, Ra, X1, X2, X3, Z1, Z2, Z3, A and PG2 are as defined above, This compound of formula (I-11) is subjected to a cyclization reaction to produce a compound of formula (I-7) as defined above, which, after deprotection of -N(PG2)- and / or optional substitution on the A ring, gives a compound of formula (I); or to a compound of formula (I-2), after deprotection of X1, a compound of formula (I-12): [ka] wherein A, X3 and X2 are as defined above, and LG6 and LG7 are leaving groups, to form a compound of formula (I-13): [ka] wherein R, X1, X2, X3, A, Z1, Z2, Z3, PG2 and LG6 are as defined above, This compound of formula (I-13) is cyclized to give a compound of formula (I-7), which is optionally alkylated on the carbamate functionality and then subjected to deprotection of -N(PG2) and / or optionally substituted on the A ring to give a compound of formula (I); or a compound of formula (I-2) with a compound of formula (I-14): [ka] wherein R, X1, Z1, Z2, Z3, PG1 and PG2 are as defined above, R' represents a hydrogen atom or an alkyl group, and it is understood that two R' alkyl groups can be linked to form a cyclic structure, The compound of formula (I-14) is reacted with the compound of formula (I-15): [ka] wherein A is as defined above, X4 is a carboxylic acid or ester or carbonyl derivative of X3, and LG8 is a leaving group, to give a compound of formula (I-16): [ka] wherein R, X1, Z1, Z2, Z3, X4, PG1 and PG2 are as defined above, This compound of formula (I-16), after deprotection of X1, is condensed with the compound LG5-X2-NRaCOOBn defined above to give the compound of formula (I-17): [ka] wherein R, Ra, X1, X2, Z1, Z2, Z3, X4 and PG2 are as defined above, This is subjected to a reduction reaction to produce a compound of formula (I-11), which is then converted to the compound of formula (I) above, or or the compound of formula (I-14) with a compound of formula (I-18): [ka] wherein A, X2, X3 and Ra are as defined above, and LG9 is a leaving group, to obtain a compound of formula (I-19): [ka] wherein R, Ra, A, X1, X2, X3, Z1, Z2, Z3, PG1 and PG2 are as defined above, a leaving group is introduced into the compound of formula (I-19) to produce a compound of formula (I-9) as defined above, which is then converted into a compound of formula (I) as defined above; or to this compound of formula (I-2), after deprotection of X1, condensation with the compound LG5-X2-NRaCOOBn as defined above to give the compound of formula (I-20): [ka] wherein R, Ra, X1, X2, Z1, Z2, Z3 and PG2 are as defined above, The compound of formula (I-20) can be reacted with a compound of formula (I-21): [ka] wherein R, Ra, X1, X2, Z1, Z2, Z3, PG2 and R' are as defined above, The compound of formula (I-21) is reacted with a compound of formula (I-22): [ka] (wherein X3 and A are as defined above, and LG10 is a leaving group). to produce a compound of formula (I-11), which is converted to a compound of formula (I) above, or or by condensing this compound of formula (I-21) with a compound of formula (I-15) as defined above to produce a compound of formula (I-17), which is then converted into a compound of formula (I) as defined above, The compound of formula (I) may then be purified according to conventional separation techniques and, if necessary, converted into its addition salt with a pharmaceutically acceptable acid or base, which may then optionally be separated into its isomers according to conventional separation techniques. It is characterized by the fact that It is understood that at any point deemed appropriate during the course of the above processes, some groups on the starting reagents or synthetic intermediates may be protected and subsequently deprotected and functionalized as required by the synthesis.

[0066] Compounds of formulae (I-5), (I-8), (I-12), (I-15), (I-18) and (I-22) are either commercially available or can be obtained by those skilled in the art using conventional chemical reactions described in the literature.

[0067] Pharmacological studies of compounds of formula (I) of the present invention demonstrate inhibitory activity against LRRK2 kinase, including LRRK2 mutant kinases such as the mutant p.G2019S. Kinase activity can be measured using a kinase assay, typically using a kinase substrate and a phosphate donor such as ATP (or a derivative thereof). Exemplary kinase assays are described in the pharmacological studies.

[0068] The compounds of formula (I) of the present invention, or pharmaceutically acceptable salts thereof, are believed to be inhibitors of LRRK2 kinase activity and therefore may be used in the treatment or prevention of diseases associated with or characterized by LRRK2 kinase activity, such as neurological diseases, endosomal-lysosomal disorders, inflammatory diseases, bacterial, viral and parasitic infections, cardiovascular diseases, autoimmune diseases, and cancer.

[0069] In particular, the compounds of the present invention are useful for treating neurological disorders including, but not limited to, Parkinson's disease (including patients with sporadic Parkinson's disease and patients with LRRK2 mutations such as p.G2019S or Rab29 / Rab7L1 polymorphisms), Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dementia (including dementia with Lewy bodies, vascular dementia, and HIV-induced dementia), diabetic neuropathy, age-related memory impairment, mild cognitive impairment, argyrophilic grain dementia, Pick's disease, epilepsy, tauopathies such as progressive supranuclear palsy and corticobasal degeneration, other synucleinopathies such as multiple system atrophy, frontotemporal dementia, hereditary frontotemporal dementia, and parkinsonism linked to chromosome 17 (FTDP-17), withdrawal / relapse associated with drug addiction, L-dopa-induced dyskinesia, ischemic stroke, traumatic brain injury, spinal cord injury, and multiple sclerosis.

[0070] Other diseases that may be treatable by inhibition of LRRK2 activity are endosomal-lysosomal diseases, including but not limited to Niemann-Pick disease types A, B, or C, Gaucher disease, Krabbe disease, Fabry disease, and disorders involving mitochondrial defects; inflammatory diseases, including but not limited to vasculitis, lung diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, inflammatory myopathy, ankylosing spondylitis; autoimmune diseases, including but not limited to Crohn's disease, inflammatory bowel disease, rheumatoid arthritis, ulcerative colitis, lupus, autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura, type 1 diabetes, obesity, Evans syndrome, bullous skin disorders, Sjogren's syndrome, Devic's disease, and leprosy. The compounds of the present invention also have anti-carcinogenic activity and may be useful in the treatment of cancers including, but not limited to, thyroid cancer, renal cancer (including papillary renal), breast cancer, hormone-related cancers, adenocarcinoma and squamous cell lung cancer, non-small cell lung cancer, colon cancer, prostate cancer, skin cancer, leukemia (including acute myeloid leukemia), and lymphoma.

[0071] Compounds of the invention may also be useful in the treatment of cardiovascular disease, including but not limited to stroke.

[0072] Other diseases that may be treatable by the compounds of the present invention are bacterial infections, such as, but not limited to, leprosy and tuberculosis; viral infections, such as, but not limited to, coronaviruses, such as SARS-CoV, MERS-CoV, and SARS-CoV-2, HIV, West Nile virus, and Chikungunya virus.

[0073] Another aspect of the present invention relates to pharmaceutical compositions comprising at least one compound of formula (I) in combination with one or more pharmaceutically acceptable excipients. Specifically, these pharmaceutical compositions are of use in the treatment or prevention of diseases associated with or characterized by LRRK2 kinase activity, such as, but not limited to, neurological diseases, endosomal-lysosomal disorders, inflammatory diseases, bacterial, viral and parasitic infections, cardiovascular diseases, autoimmune diseases, and cancer. In a specific embodiment, the pharmaceutical compositions of the present invention are useful for treating Parkinson's disease (including sporadic Parkinson's disease patients and patients with LRRK2 mutations or Rab29 / Rab7L1 polymorphisms), Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dementia (including dementia with Lewy bodies, vascular dementia, and HIV-induced dementia), diabetic neuropathy, age-related memory impairment, mild cognitive impairment, argyrophilic grain dementia, Pick's disease, epilepsy, tauopathies such as progressive supranuclear palsy and corticobasal degeneration, other synucleinopathies such as multiple system atrophy, frontotemporal dementia, hereditary frontotemporal dementia, and parkinsonism associated with chromosome 17 (FTDP-17), withdrawal / relapse associated with drug addiction, L-dopa-induced dyskinesia, ischemic stroke, traumatic brain injury, spinal cord injury. , multiple sclerosis, Niemann-Pick disease types A, B or C, Gaucher disease, Krabbe disease, Fabry disease, disorders involving mitochondrial defects, Crohn's disease, inflammatory bowel disease, rheumatoid arthritis, ulcerative colitis, lupus, autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura, type 1 diabetes, obesity, Evans syndrome, bullous skin disorders, Sjogren's syndrome, Devic's disease, leprosy, thyroid cancer, kidney cancer (including papillary kidney), breast cancer, hormone-related cancers, adenocarcinoma and squamous cell lung cancer, non-small cell lung cancer, colon cancer, prostate cancer, skin cancer, leukemia (including acute myeloid leukemia), lymphoma, stroke, leprosy, tuberculosis, and SARS-CoV, MERS-CoV, SARS-CoV-2, HIV, West Nile virus and chikungunya virus infections.

[0074] Among the pharmaceutical compositions according to the invention, mention may be made more particularly of those suitable for oral, parenteral, nasal, transdermal, rectal, lingual, ocular or respiratory administration, in particular tablets or dragees, sublingual tablets, sachets, packets, capsules, glossettes, pastilles, suppositories, creams, ointments, skin gels and drinkable or injectable ampoules.

[0075] The pharmaceutical composition according to the present invention comprises one or more excipients or carriers selected from diluents, lubricants, binders, disintegrants, stabilizers, preservatives, absorbents, colorants, sweeteners, flavoring agents, and the like.

[0076] Non-limiting examples include: Diluents include lactose, glucose, sucrose, mannitol, sorbitol, cellulose, glycerol, Lubricants include silica, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol, Binders include magnesium aluminum silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone, As disintegrants: agar, alginic acid and its sodium salt, effervescent mixture.

[0077] The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication or any associated treatment, and is between 0.01 mg and 1 g per 24 hours in single or multiple administrations.

[0078] The following preparations and examples illustrate the present invention but do not limit it in any way.

[0079] The compounds of the present invention can be prepared by any standard synthetic method commonly used by one of ordinary skill in the art of organic chemistry. The compounds are generally prepared from starting materials that are commercially available or prepared by standard means apparent to one skilled in the art.

[0080] General scheme As indicated above, the present invention provides a compound of formula (I): [ka] (wherein R, Z1, Z2, Z3, X1, X2, X3, Ra and A are as defined in formula (I). The present invention provides a compound according to the present invention.

[0081] With regard to general reaction schemes suitable for preparing the above compounds, these compounds are represented by formula (I), the general reaction scheme for which can be shown below.

[0082] In the following general scheme, R, Z1, Z2, Z3, X1, X2, X3, Ra and A have the same meaning as defined in formula (I).

[0083] Hereinafter, the fused pyrazolo bicyclic ring system containing Z1, Z2, Z3 and R will be referred to as a fused pyrazolo system.

[0084] In the following general scheme, Lg1 and Lg2 each independently represent a suitable leaving group. Pg1 and Pg3 each independently represent a suitable protecting group that can be used to protect X1 and / or X2. Pg2 represents a protecting group suitable for protecting the NH of the fused pyrazolo structure.

[0085] Rb in the scheme below can be either H, alkyl or cyclic alkyl.

[0086] In compounds where a transcarbamylation reaction is used, the CbzX2Lg2 moiety can be generated either via reaction with Cbz chloride from the corresponding bromoalkylamine or via reaction of a hydroxyalkylamine with Cbz chloride followed by mesylation or tosylation.

[0087] In all of the following general schemes, prior to deprotection of the NH of the fused pyrazolo structure, the carbamate can optionally be displaced by an alkylation reaction to give a compound of formula (XIIIa), which can then be deprotected at the NH of the fused pyrazolo structure to give the final compound of formula (I).

[0088] Alternatively, in all of the following general schemes, an optional cross-coupling reaction such as a Buchwald, Suzuki, Sonogashira reaction, or O-alkylation or nucleophilic aromatic substitution can be carried out on a (hetero)aromatic ring containing a leaving group such as a halide before deprotection of the NH of the fused pyrazolo structure to form a compound of formula (XIIIa). After a cross-coupling reaction such as a Buchwald, Suzuki, Sonogashira reaction, or another O-alkylation or nucleophilic aromatic substitution, the NH of the fused pyrazolo structure can be deprotected to provide the final compound of formula (I).

[0089] Compounds of formula (I) can be prepared as shown in general scheme A below, where a compound of formula (II) is converted to a protected compound of formula (III). This compound of formula (III) can be converted to a compound of formula (IV) containing a leaving group on the fused pyrazolo structure, which can then be converted to a nitrogen-protected compound of formula (V). The compound of formula (V) can be converted to a selectively protected fused pyrazolo structure of formula (VI), which is then alkylated with an intermediate of formula (XIII) containing a leaving group to provide a compound of formula (IX). Compounds of formula (VIII) can be prepared from compounds of formula (VII) via nucleophilic substitution. Compounds of formula (IX) can be coupled with (hetero)aryls of formula (X) or (Xa) via organometallic cross-coupling, such as Suzuki or Ullmann coupling, to form compounds of formula (XI). Compounds of formula (XI) can then be selectively deprotected to compounds of formula (XII), which can then be cyclized to form compounds of formula (XIII). Final deprotection of the nitrogen of the fused pyrazolo structure, following either or both alkylation of the carbamate moiety and / or substitution of the A ring, provides compounds of formula (I). [ka]

[0090] In Reaction Scheme A above, the reaction between compounds of formula (VI) and formula (VIII) can be accomplished in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate.

[0091] In the above reaction between a compound of formula (IX) and a compound of formula (X), the leaving group Lg1 is advantageously a halogen atom such as chlorine, bromine or iodine. Such a halogen substitution reaction can be carried out under cross-coupling conditions such as Suzuki conditions using a palladium catalyst, for example tetrakis(triphenylphosphine)palladium(0), with or without 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos), in a solvent mixture, for example 1,4-dioxane / water, in the presence of potassium phosphate tribasic, at an elevated temperature, for example 90°C, either under microwave or non-microwave conditions.

[0092] Alternatively, the halogen substitution reaction can be carried out under Ullmann's conditions using copper iodide in the presence of potassium carbonate and 8-hydroxyquinoline in a solvent such as dimethylsulfoxide at an elevated temperature such as 70°C.

[0093] Suitable compounds of formula (X) or formula (Xa) may be obtained either commercially or through a variety of selective protection and deprotection steps known to those skilled in the art. The synthesis of compounds of formula (Xa) may require a boronation step.

[0094] Deprotection of Pg3 yields compounds of formula (XII).

[0095] Cyclization of compounds of formula (XII) to give compounds of formula (XIII) can be accomplished by a method known to those skilled in the art as carbamylation, for example by treatment with 1,1'-carbonyldiimidazole and N,N-diisopropylethylamine or sodium hydride in a solvent such as N,N-dimethylacetamide at, for example, 90° C. Final deprotection of the NH of the fused pyrazolo structure under acidic conditions, followed by either or both alkylation of the carbamate and / or substitution of the A ring, yields the final compound of formula (I).

[0096] Alternatively, compounds of formula (I) can be prepared as shown in general scheme B below, in which a fused pyrazolo structure of formula (II) is converted to a protected compound of formula (III). The NH of the fused pyrazolo structure can be protected to give a compound of formula (XIV). This compound of formula (XIV) can be converted to a boronic acid (or boronic ester) of formula (XV). The compound of formula (XV) can be coupled with a (hetero)aryl of formula (XVI) via an organometallic cross-coupling reaction, such as Suzuki coupling, to form a compound of formula (XVII). The compound of formula (XVII) can be alkylated using an intermediate of formula (XIX) containing a carbamate ester, such as benzyl carbamate, to give a compound of formula (XX). The compound of formula (XIX) can be commercially obtained or prepared from a compound of formula (XVIII) via reaction with CbzCl or via introduction of a leaving group Lg2 into a compound of formula (XVIIIa). The X4 moiety of compound (XX) can be converted to X3-OH, typically by reduction of a carboxylic acid or carboxylic acid ester, or a (cyclo)alkylcarbonyl or heterocycloalkylcarbonyl. Compounds of formula (XXI) can then be cyclized by a transcarbamylation reaction to form compounds of formula (XIII). Final deprotection of the nitrogen of the fused pyrazolo structure, following either or both alkylation of the carbamate ester and / or substitution of the A ring, provides compounds of formula (I). [ka]

[0097] In Reaction Scheme B above, boronation of the fused pyrazolo structure of a compound of formula (XV) to a compound of formula (XVI) can be achieved using an iridium catalyst and bis(pinacolato)diboron in a solvent such as TBME.

[0098] In the above reaction between compounds of formula (XV) and (XVI), the leaving group Lg1 is advantageously a halogen atom such as chlorine, bromine or iodine. Such a halogen substitution reaction can be carried out under cross-coupling conditions such as Suzuki conditions using a palladium catalyst, for example tetrakis(triphenylphosphine)palladium(0), with or without 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos), in a solvent mixture such as 1,4-dioxane / water, in the presence of potassium phosphate tribasic, at an elevated temperature, for example 110°C, either under microwave or non-microwave conditions.

[0099] In the above reaction scheme, the alkylation between a compound of formula (XVII) and a compound of formula (XIX) can be achieved in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 120°C. The appropriate compound of formula (XIX) can either be obtained commercially or via the reaction of a compound of formula (XVIII) with CbzCl and sodium hydroxide in water as the solvent. Alternatively, a compound of formula (XIX) can be prepared by introducing Lg2 into a compound of formula (XVIIIa).

[0100] X4 in compounds of formula (XX) can be a (cyclo)alkyl-carbonyl, heterocycloalkyl-carbonyl or carboxylic acid derivative (carboxylic acid or ester), which can be reduced to the corresponding alcohol using sodium borohydride or lithium aluminum hydride in a solvent such as THF at an elevated temperature such as 120°C.

[0101] The transcarbamylation of a compound of formula (XXI) to a macrocycle of formula (XIII) can be carried out using potassium carbonate or cesium carbonate or potassium hydroxide in a solvent such as acetonitrile at temperatures ranging from room temperature to reflux, or using sodium hydride in a dry solvent such as toluene at temperatures ranging from 0° C. to reflux, either under microwave or non-microwave conditions.

[0102] Final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, following either or both alkylation of the carbamate and / or substitution of the A ring, yields the final compound of formula (I).

[0103] Alternatively, compounds of formula (I) can be prepared as shown in general scheme C below, in which a fused pyrazolo structure of formula (II) is converted to a protected compound of formula (III). This compound of formula (III) can be converted to a compound of formula (IV) containing a leaving group on the fused pyrazolo structure, which can then be converted to a nitrogen-protected compound of formula (V). Compounds of formula (V) can be converted to a selectively protected fused pyrazolo structure of formula (VI), which is then alkylated with an intermediate of formula (XIX) containing a leaving group to provide compounds of formula (XXII). Compounds of formula (XIX) can be obtained commercially or prepared from compounds of formula (XVIII) via reaction with CbzCl or via introduction of a leaving group Lg2 into compounds of formula (XVIIIa). Compounds of formula (XXII) can be coupled with (hetero)aryls of formula (X) via organometallic cross-coupling reactions, such as Suzuki coupling, to form compounds of formula (XXI). Compounds of formula (XXI) can then be cyclized via a transcarbamylation reaction to form compounds of formula (XIII). Final deprotection of the nitrogen of the fused pyrazolo structure, following either or both of alkylation of the carbamate ester and / or substitution of the A ring, leads to compounds of formula (I). [ka]

[0104] In Reaction Scheme C above, the alkylation between a compound of formula (VI) and a compound of formula (XIX) can be achieved in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 120°C.

[0105] Suitable compounds of formula (XIX) may either be obtained commercially or via reaction of compounds of formula (XVIII) with CbzCl and sodium hydroxide in water as solvent. Alternatively, compounds of formula (XIX) can be prepared by introduction of Lg2 into compounds of formula (XVIIIa).

[0106] In the above reaction between a compound of formula (XXII) and a compound of formula (X), the leaving group Lg1 is advantageously a halogen atom such as chlorine, bromine or iodine. Such a halogen substitution reaction can be carried out under organometallic coupling conditions such as Suzuki conditions using a palladium catalyst, for example tetrakis(triphenylphosphine)palladium(0), with or without 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos), in a solvent mixture, for example 1,4-dioxane / water, in the presence of potassium phosphate tribasic, at an elevated temperature, for example 110°C, either under microwave or non-microwave conditions.

[0107] Suitable compounds of formula (X) may be either commercially obtained or obtained through a variety of selective protection and deprotection steps known to those skilled in the art. A boronation step may be required to obtain compounds of formula (X).

[0108] Transcarbamylation of compounds of formula (XXI) to macrocycles of formula (XIII) can be carried out using potassium carbonate or cesium carbonate or potassium hydroxide in solvents such as acetonitrile at temperatures ranging from room temperature to reflux, or using sodium hydride in dry solvents such as toluene at temperatures ranging from 0° C. to reflux, either under microwave or non-microwave conditions.

[0109] Final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, following either or both alkylation of the carbamate ester and / or substitution of the A ring, provides the final compound of formula (I).

[0110] Alternatively, compounds of formula (I) can be prepared as shown in general scheme D below, in which a fused pyrazolo structure of formula (II) is converted to a protected compound of formula (III) and then converted to a nitrogen-protected compound of formula (XIV). Compounds of formula (XIV) can be converted to a selectively protected fused pyrazolo structure of formula (XXIII), which is then alkylated with a Cbz group-containing intermediate compound of formula (XIX) to provide compounds of formula (XXIV). Compounds of formula (XIX) can be prepared from compounds of formula (XVIII) via reaction with CbzCl or via introduction of a leaving group Lg2 into compounds of formula (XVIIIa). Compounds of formula (XXIV) can be borated to compounds of formula (XXV). The borated compounds of formula (XXV) can be reacted with a (hetero)aryl of formula (XXVI) in a cross-coupling reaction, such as a Suzuki coupling, to form compounds of formula (XXI). Compounds of formula (XXI) can then be cyclized via a transcarbamylation reaction to form compounds of formula (XIII). Final deprotection of the nitrogen of the fused pyrazolo structure, following either or both of alkylation of the carbamate ester and / or substitution of the A ring, leads to compounds of formula (I). [ka]

[0111] In Reaction Scheme D above, the reaction between a compound of formula (XXIII) and a compound of formula (XIX) can be accomplished in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate.

[0112] Suitable compounds of formula (XIX) may either be obtained commercially or via reaction of compounds of formula (XVIII) with CbzCl and sodium hydroxide in water as solvent. Alternatively, compounds of formula (XIX) can be prepared by introduction of Lg2 into compounds of formula (XVIIIa).

[0113] In the above reaction scheme, boronation of the fused pyrazolo structure of a compound of formula (XXIV) to a compound of formula (XXV) can be achieved using an iridium catalyst and bis(pinacolato)diboron in a solvent such as TBME.

[0114] In the above reaction between compounds of formula (XXV) and (XXVI), the leaving group Lg1 is advantageously a halogen atom such as chlorine, bromine or iodine. Such a halogen substitution reaction can be carried out under organometallic cross-coupling conditions such as Suzuki conditions using a palladium catalyst, for example tetrakis(triphenylphosphine)palladium(0), with or without 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos), in a solvent mixture, for example 1,4-dioxane / water, in the presence of potassium phosphate tribasic, at an elevated temperature, for example 90°C, either under microwave or non-microwave conditions.

[0115] Suitable compounds of formula (XXVI) may either be obtained commercially or may be obtained via a variety of reactions involving selective protection and deprotection steps known to those skilled in the art.

[0116] The transcarbamylation of a compound of formula (XXI) to a macrocycle of formula (XIII) can be carried out using potassium carbonate or cesium carbonate or potassium hydroxide in a solvent such as acetonitrile at temperatures ranging from room temperature to reflux, or using sodium hydride in a dry solvent such as toluene at temperatures ranging from 0° C. to reflux, either under microwave or non-microwave conditions.

[0117] Final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, following either or both alkylation of the carbamate and / or substitution of the A ring, yields the final compound of formula (I).

[0118] Alternatively, compounds of formula (I) can be prepared as shown in general scheme E below, in which a fused pyrazolo structure of formula (II) is converted to a protected compound of formula (III). This compound of formula (III) can be converted to a compound of formula (IV) containing a leaving group on the fused pyrazolo structure, which can then be converted to a nitrogen-protected compound of formula (V). The compound of formula (V) can be converted to a selectively protected fused pyrazolo structure of formula (VI), which is then coupled with a (hetero)aryl of formula (XXVII) in a cross-coupling reaction, such as a Suzuki coupling, to form a compound of formula (XXVIII). The X4 moiety of compound of formula (XXVII) contains a carbonyl precursor, such as a (cyclo)alkyl-carbonyl, heterocycloalkyl-carbonyl, carboxylic acid, or ester, which can be reduced to a compound of formula (XXIX). The compound of formula (XXIX) can then be alkylated with an intermediate of formula (XIX) containing a leaving group to provide a compound of formula (XXI). Compounds of formula (XIX) can be obtained commercially or prepared from compounds of formula (XVIII) via reaction with CbzCl or via introduction of a leaving group Lg2 into compounds of formula (XVIIIa). Compounds of formula (XXI) can then be cyclized via a transcarbamylation reaction to form compounds of formula (XIII). Final deprotection of the nitrogen-fused pyrazolo structure, following either or both alkylation of the carbamate ester and / or substitution of the A ring, provides compounds of formula (I). [ka]

[0119] In the above scheme E, in the reaction between compounds of formula (VI), the leaving group Lg1 is advantageously a halogen atom such as chlorine, bromine or iodine. Such halogen substitution reactions can be carried out under organometallic cross-coupling conditions such as Suzuki conditions using a palladium catalyst, for example, tetrakis(triphenylphosphine)palladium(0), with or without 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos), in a solvent mixture, for example, 1,4-dioxane / water, in the presence of potassium phosphate tribasic, at elevated temperatures, for example, 110°C, either under microwave or non-microwave conditions.

[0120] Suitable compounds of formula (XXVII) contain a precursor moiety of an alcohol, such as an ester or a carboxylic acid. Compounds of formula (XXVII) can be obtained commercially or through various reactions involving selective protection and deprotection steps known to those skilled in the art. Compounds of formula (XXVII) may require a boronation step.

[0121] Reduction of the X4 carbonyl in a compound of formula (XXVIII) gives a compound of formula (XXIX).

[0122] In the above reaction scheme, the alkylation between compounds of formula (XXIX) and (XIX) can be achieved in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 120°C.

[0123] Suitable compounds of formula (XIX) may either be commercially obtained or obtained via reaction of compounds of formula (XVIII) with CbzCl and sodium hydroxide in water as solvent. Alternatively, compounds of formula (XIX) can be prepared by introducing Lg2 into compounds of formula (XVIIIa).

[0124] Transcarbamylation of compounds of formula (XXI) to macrocycles of formula (XIII) can be carried out using potassium carbonate or cesium carbonate or potassium hydroxide in a solvent such as acetonitrile at temperatures ranging from room temperature to reflux, or using sodium hydride in a dry solvent such as toluene at temperatures ranging from 0° C. to reflux, either under microwave or non-microwave conditions.

[0125] Final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, followed by either or both alkylation of the carbamate and / or substitution of the A ring, yields the final compound of formula (I).

[0126] Alternatively, compounds of formula (I) can be prepared as shown in general scheme F below, in which a fused pyrazolo structure of formula (II) is converted to a protected compound of formula (III). This compound of formula (III) can be converted to a compound of formula (IV) containing a leaving group on the fused pyrazolo structure, and then converted to a nitrogen-protected compound of formula (V). Compounds of formula (V) can be converted to a selectively protected fused pyrazolo structure of formula (VI), which is then alkylated with an intermediate of formula (XIX) containing a leaving group to provide compounds of formula (XXII). Compounds of formula (XIX) can be obtained commercially or prepared from compounds of formula (XVIII) via reaction with CbzCl or via introduction of a leaving group Lg2 into compounds of formula (XVIIIa). Compounds of formula (XXII) can be coupled with (hetero)aryls of formula (XXVII) via organometallic cross-coupling reactions, such as Suzuki coupling, to form compounds of formula (XX). The X4 moiety of compounds of formula (XX) contains a carbonyl precursor, such as a (cyclo)alkyl-carbonyl, heterocycloalkyl-carbonyl, carboxylic acid, or ester, which can be reduced to compounds of formula (XXI). Compounds of formula (XXI) can then be cyclized by a transcarbamylation reaction to form compounds of formula (XIII). Final deprotection of the nitrogen of the fused pyrazolo structure, after either or both alkylation of the carbamate ester and / or substitution of the A ring, provides compounds of formula (I). [ka]

[0127] In Reaction Scheme F above, the alkylation between a compound of formula (VI) and a compound of formula (XIX) can be achieved in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 120°C.

[0128] Suitable compounds of formula (XIX) may either be obtained commercially or via reaction of compounds of formula (XVIII) with CbzCl and sodium hydroxide in water as solvent. Alternatively, compounds of formula (XIX) can be prepared by introduction of Lg2 into compounds of formula (XVIIIa).

[0129] In the above reaction between a compound of formula (XXII) and a compound of formula (XXVII), the leaving group Lg1 is advantageously a halogen atom such as chlorine, bromine or iodine. Such a halogen substitution reaction can be carried out under cross-coupling conditions such as Suzuki conditions using a palladium catalyst, for example tetrakis(triphenylphosphine)palladium(0), with or without 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos), in a solvent mixture, for example 1,4-dioxane / water, in the presence of potassium phosphate tribasic, at an elevated temperature, for example 110°C, either under microwave or non-microwave conditions.

[0130] Suitable compounds of formula (XXVII) may be either commercially obtained or obtained via a variety of reactions involving selective protection and deprotection steps known to those skilled in the art. For compounds of formula (XXVII), a boronation step may be required.

[0131] Reduction of the X4 carbonyl in a compound of formula (XX) gives a compound of formula (XXI).

[0132] Transcarbamylation of compounds of formula (XXI) to macrocycles of formula (XIII) can be achieved using sodium hydride in dry toluene at elevated temperatures, such as in the range of 130° C. or 150° C. Alternatively, transcarbamylation can be carried out using potassium carbonate or KOH in a solvent such as acetonitrile at elevated temperatures, such as 140° C. Final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, after either or both of alkylation of the carbamate and / or substitution of the A ring, yields the final compound of formula (I).

[0133] Alternatively, compounds of formula (I) can be prepared as shown in general scheme G below, in which a fused pyrazolo structure of formula (II) is converted to a protected compound of formula (III) and then converted to a nitrogen-protected compound of formula (XIV). Compounds of formula (XIV) can be converted to a selectively protected fused pyrazolo structure of formula (XXIII), which is then alkylated with an intermediate compound of formula (XIX) containing a Cbz group to provide compounds of formula (XXIV). Compounds of formula (XIX) can be prepared from compounds of formula (XVIII) via reaction with CbzCl or via introduction of a leaving group Lg2 into compounds of formula (XVIIIa). Compounds of formula (XXIV) can be boronated to compounds of formula (XXV). The boronated compound of formula (XXV) can be reacted with a (hetero)aryl of formula (XVI) in a cross-coupling, such as a Suzuki coupling, to form compounds of formula (XX). The X4 moiety of compounds of formula (XX) contains a carbonyl precursor, such as a (cyclo)alkyl-carbonyl, heterocycloalkyl-carbonyl, carboxylic acid, or ester, which can be reduced to compounds of formula (XXI). Compounds of formula (XXI) can then be cyclized by a transcarbamylation reaction to form compounds of formula (XIII). Final deprotection of the nitrogen of the fused pyrazolo structure, after either or both alkylation of the carbamate ester and / or substitution of the A ring, provides compounds of formula (I). [ka]

[0134] In Reaction Scheme G above, the reaction between a compound of formula (XXIII) and a compound of formula (XIX) can be accomplished in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate.

[0135] Suitable compounds of formula (XIX) may either be obtained commercially or via reaction of compounds of formula (XVIII) with CbzCl and sodium hydroxide in water as solvent. Alternatively, compounds of formula (XIX) may be prepared by introduction of Lg2 into compounds of formula (XVIIIa).

[0136] In the above reaction scheme, boronation of the fused pyrazolo structure of a compound of formula (XXIV) to a compound of formula (XXV) can be achieved using an iridium catalyst and bis(pinacolato)diboron in a solvent such as BME.

[0137] In the above reaction between compound of formula (XXV) and compound of formula (XVI), the leaving group Lg1 is advantageously a halogen atom such as chlorine, bromine or iodine. Such a halogen substitution reaction can be carried out under cross-coupling conditions such as Suzuki conditions using a palladium catalyst, for example tetrakis(triphenylphosphine)palladium(0), with or without 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos), in the presence of potassium phosphate tribasic in a solvent mixture such as 1,4-dioxane / water, at an elevated temperature, for example 90°C, either under microwave or non-microwave conditions.

[0138] Suitable compounds of formula (XVI) may either be obtained commercially or may be obtained via a variety of reactions involving selective protection and deprotection steps known to those skilled in the art.

[0139] The carbonyl moiety of X4 in compounds of formula (XX) can be reduced to the corresponding alcohol using, for example, sodium borohydride or lithium aluminum hydride in a solvent such as THF at elevated temperatures such as 120°C.

[0140] The transcarbamylation of a compound of formula (XXI) to a macrocycle of formula (XIII) can be carried out using potassium carbonate or cesium carbonate or potassium hydroxide in a solvent such as acetonitrile at temperatures ranging from room temperature to reflux, or using sodium hydride in a dry solvent such as toluene at temperatures ranging from 0° C. to reflux, either under microwave or non-microwave conditions.

[0141] Final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, followed by either or both alkylation of the carbamate and / or substitution of the A ring, yields the final compound of formula (I).

[0142] Alternatively, compounds of formula (I) can be prepared as shown in general scheme H below, in which a fused pyrazolo structure of formula (II) is converted to a protected compound of formula (III) and then converted to a nitrogen-protected compound of formula (XIV). Compounds of formula (XIV) can be converted to a selectively protected fused pyrazolo structure of formula (XXIII), which is then alkylated with an intermediate compound (XXX) containing a (hetero)aromatic group to yield compounds of formula (XXXI). Compounds of formula (XXX) can be prepared using various reaction steps known to those skilled in the art and are described in detail for exemplary compounds. Compounds of formula (XXXI) can be macrocyclized via a C-H activation reaction. Final deprotection of the nitrogen of the fused pyrazolo structure, following either or both alkylation of the carbamate ester and / or substitution of the A ring, yields compounds of formula (I). [ka]

[0143] In Reaction Scheme H above, the alkylation between a compound of formula (XXIII) and a compound of formula (XXX) can be achieved in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 80° C.

[0144] Suitable compounds of formula (XXX) may be either commercially available or obtained via synthetic routes available in the literature. In the above reaction between compounds of formula (XXX) and compounds of formula (XXIII), the leaving group Lg2 is advantageously a mesylate group.

[0145] C-H activation of compounds of formula (XXXI) to macrocycles of formula (XIII) can be achieved using CataCXIum, palladium acetate, and potassium acetate in dry toluene under microwave conditions at elevated temperatures, such as 140°C. The leaving group Lg1 is advantageously a halogen atom, such as chlorine, bromine, or iodine. Final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, after either or both of alkylation of the carbamate and / or substitution of the A ring, generates the final compounds of formula (I).

[0146] Alternatively, compounds of formula (I), particularly those in which X is NR', can be prepared as shown in general scheme I below, where a fused pyrazolo structure of formula (XXXII), where X is, for example, a nitro group, is converted to a protected compound of formula (XXXIII) and then converted to a nitrogen-protected compound of formula (XXXIV). The compound of formula (XXXIV) can be converted to a selectively protected fused pyrazolo structure of formula (VI), which is then alkylated with a compound of formula (VIII) containing a protecting group Pg. After alkylation, deprotection of X yields a compound of formula (XXXVI), which is then coupled in a cross-coupling reaction, such as a Suzuki reaction, with a compound of formula (X). The resulting compound of formula (XII) can be macrocyclized to give a compound of formula (XIII). Final deprotection of the nitrogen of the fused pyrazolo structure, following either or both of alkylation of the carbamate and / or substitution of the A ring, yields a compound of formula (I). [ka]

[0147] In the above Reaction Scheme I, X5 is a nitro group, and X1 is NR'a in this particular scheme. Halogenation of the fused pyrazolo structure can be accomplished, for example, using iodine and potassium hydroxide in a solvent such as N,N-dimethylformamide at an elevated temperature such as 60°C.

[0148] Reduction of the nitro group can be achieved using iron in the presence of ammonia chloride in a mixture of solvents such as EtOH, THF and water at elevated temperatures such as 80° C. to yield compounds of formula (VI).

[0149] Alkylation between compounds of formula (VI) and (VIII) can be achieved in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at elevated temperatures such as 80° C. or 90° C. Compounds of formula (VIII) contain a protecting group Pg3, which can be a phthalimide group.

[0150] Deprotection of X2-NPg3 in compounds of formula (IX) can be achieved using a reagent such as hydrazine in a solvent such as EtOH at an elevated temperature such as 60°C.

[0151] Organometallic cross-coupling, such as Suzuki coupling, of compounds of formula (XXXVI) with compounds of formula (X) can be carried out using a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), with or without 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos), in the presence of potassium phosphate tribasic, in a solvent mixture, such as 1,4-dioxane / water, at an elevated temperature, such as 120°C, either under microwave or non-microwave conditions.

[0152] Cyclization of compounds of formula (XII) to give compounds of formula (XIII) can be carried out by methods known to those skilled in the art as carbamylation reactions, for example by treatment with 1,1'-carbonyldiimidazole and N,N-diisopropylethylamine in a solvent such as N,N-dimethylacetamide at, for example, 90° C. Final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, after either or both of alkylation of the carbamate and / or substitution of the A ring, generates the final compounds of formula (I).

[0153] Alternatively, compounds of formula (I) can be prepared as shown in general scheme J below, where a fused pyrazolo structure of formula (II) is converted to a protected compound of formula (III). This compound of formula (III) can be converted to a compound of formula (IV) containing a leaving group on the fused pyrazolo structure, which can then be converted to a nitrogen-protected compound of formula (V). The compound of formula (V) can be converted to a selectively protected fused pyrazolo structure of formula (VI), where X1 is then protected to form a compound of formula (XXXVII). The compound of formula (XXXVII) can be coupled with a (hetero)aryl of formula (XXXVIII) via an organometallic cross-coupling, such as a Suzuki coupling, to form a compound of formula (XXXIX). Alkylation of the (hetero)aromatic ring provides a compound of formula (XL). Deprotection of X1, followed by alkylation with a compound of formula (XIX), provides a compound of formula (XLII). Compounds of formula (XIX) can be obtained commercially or prepared from compounds of formula (XVIII) via reaction with CbzCl or via introduction of a leaving group Lg2 into compounds of formula (XVIIIa). Deprotection of X3 provides compounds of formula (XXI). Compounds of formula (XXI) can then be cyclized via a transcarbamylation reaction to form compounds of formula (XIII). Final deprotection of the nitrogen of the fused pyrazolo structure, following either or both alkylation of the carbamate ester and / or substitution of the A ring, provides compounds of formula (I). [ka]

[0154] In Reaction Scheme J above, protection of X1 in compounds of formula (VI) can be achieved using benzyl chloride in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at room temperature or elevated temperature.

[0155] In the above reaction between compounds of formula (XXXVII) and (XXXVIII), the leaving group Lg1 is advantageously a halogen atom such as chlorine, bromine or iodine. Such a halogen substitution reaction can be carried out via organometallic cross-coupling conditions such as Suzuki conditions using a palladium catalyst, for example tetrakis(triphenylphosphine)palladium(0), with or without 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos), in a solvent mixture such as 1,4-dioxane / water, in the presence of potassium phosphate tribasic, at an elevated temperature, for example 110°C, with or without microwave conditions.

[0156] Suitable compounds of formula (XXXVIII) may either be obtained commercially or via a variety of reactions involving selective protection and deprotection steps known to those skilled in the art. For compounds of formula (XXXVIII), a boronation step may be required.

[0157] In the above reaction scheme, alkylation of a compound of formula (XXXIX) can be achieved using (2-bromoethoxy)(tert-butyl)dimethylsilane in a solvent such as N,N-dimethylformamide and a base such as sodium hydride at 0° C. or room temperature.

[0158] Deprotection of X1 in compounds of formula (XL) can be achieved using hydrogen gas in the presence of Pd / C in a solvent such as EtOH at room temperature.

[0159] The alkylation between compounds of formula (XLI) and compounds of formula (XIX) can be achieved in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 120°C.

[0160] Suitable compounds of formula (XIX) may either be obtained commercially or via reaction of compounds of formula (XVIII) with CbzCl and sodium hydroxide in water as solvent. Alternatively, compounds of formula (XIX) can be prepared by introduction of Lg2 into compounds of formula (XVIIIa).

[0161] Deprotection of X3-OPg4 in compounds of formula (XLII) can be carried out using TBAF in a solvent such as THF at room temperature.

[0162] The transcarbamylation of a compound of formula (XXI) to a macrocycle of formula (XIII) can be carried out using potassium carbonate or cesium carbonate or potassium hydroxide in a solvent such as acetonitrile at temperatures ranging from room temperature to reflux, or using sodium hydride in a dry solvent such as toluene at temperatures ranging from 0° C. to reflux, either under microwave or non-microwave conditions.

[0163] Final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, following either or both alkylation of the carbamate and / or substitution of the A ring, yields the final compound of formula (I).

[0164] Alternatively, compounds of formula (I) can be prepared as shown in general scheme K, where a fused pyrazolo structure of formula (II) is converted to a protected compound of formula (III). The NH of the fused pyrazolo structure can be protected to give a compound of formula (XIV). This compound of formula (XIV) can be converted to a boronic acid (or boronic ester) of formula (XV). The compound of formula (XV) can be coupled with a (hetero)aryl of formula (XLIII) or formula (XXVI) via an organometallic cross-coupling, such as Suzuki coupling, to form a compound of formula (XLIV) or a compound of formula (XLIVa). Deprotection of X1 gives a compound of formula (XLV) or a compound of formula (XLVa). The compound of formula (XLV) or a compound of formula (XLVa) can be alkylated with a carbamate-containing intermediate of formula (XIX) to give a compound of formula (XLVI) or a compound of formula (XXI). Deprotection of X3-OPg4 in a compound of formula (XLVI) provides a compound of formula (XXI). Compounds of formula (XXI) can then be cyclized by a transcarbamylation reaction to form compounds of formula (XIII). Final deprotection of the nitrogen of the fused pyrazolo structure, after either or both of alkylation of the carbamate ester and / or substitution of the A ring, provides compounds of formula (I). [ka]

[0165] In Reaction Scheme K above, boronation of the fused pyrazolo moiety of a compound of formula (XIV) to a compound of formula (XV) can be achieved using an iridium catalyst and bis(pinacolato)diboron in a solvent such as TBME.

[0166] In the above reaction between a compound of formula (XV) and a compound of formula (XLIII) or a compound of formula (XXVI), the leaving group Lg1 is advantageously a halogen atom such as chlorine, bromine or iodine. Such a halogen substitution reaction can be carried out under cross-coupling conditions such as Suzuki conditions using a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), in combination with 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos), in a solvent mixture such as 1,4-dioxane / water, in the presence of potassium phosphate tribasic, at an elevated temperature, such as 90°C, either under microwave or non-microwave conditions.

[0167] Deprotection of X1 in a compound of formula (XLIV) or a compound of formula (XLIVa) can be achieved using a reagent such as TBAF in a solvent such as THF at room temperature.

[0168] In the above reaction scheme, the alkylation between a compound of formula (XLV) or a compound of formula (XLVa) and a compound of formula (XIX) can be achieved in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 50°C. The appropriate compound of formula (XIX) can either be obtained commercially or via the reaction of a compound of formula (XVIII) with CbzCl and sodium hydroxide salt in water as the solvent. Alternatively, a compound of formula (XIX) can be prepared by the introduction of Lg2 into a compound of formula (XVIIIa).

[0169] Deprotection of X3-OPg4 in compounds of formula (XLVI) can be achieved using conditions such as potassium carbonate in a solvent such as MeOH at room temperature.

[0170] The transcarbamylation of a compound of formula (XXI) to a macrocycle of formula (XIII) can be carried out using potassium carbonate or cesium carbonate or potassium hydroxide in a solvent such as acetonitrile at temperatures ranging from room temperature to reflux, or using sodium hydride in a dry solvent such as toluene at temperatures ranging from 0° C. to reflux, either under microwave or non-microwave conditions.

[0171] Final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, followed by either or both alkylation of the carbamate and / or substitution of the A ring, yields the final compound of formula (I).

[0172] Alternatively, compounds of formula (I) can be prepared as shown in general scheme L below, where a fused pyrazolo structure of formula (II) is converted to a protected compound of formula (III). The NH of the fused pyrazolo structure can be protected to give a compound of formula (XIV). This compound of formula (XIV) can be converted to a boronic acid (or boronic ester) of formula (XV). The compound of formula (XV) can be coupled with a (hetero)aryl of formula (XLVIII) in a cross-coupling reaction, such as a Suzuki coupling, to form a compound of formula (XLIX). Introduction of a leaving group at X2 gives a compound of formula (L). Deprotection of X1 gives a compound of formula (LI). The compound of formula (LI) can then be cyclized by nucleophilic substitution to form a compound of formula (XIII). Final deprotection of the nitrogen of the fused pyrazolo structure, after either or both of alkylation of the carbamate ester and / or substitution of the A ring, gives a compound of formula (I). [ka]

[0173] In Reaction Scheme L above, boronation of the fused pyrazolo structure of a compound of formula (XIV) to a compound of formula (XV) can be achieved using an iridium catalyst and bis(pinacolato)diboron in a solvent such as TBME.

[0174] In the above reaction between a compound of formula (XV) and a compound of formula (XLVIII), the leaving group Lg1 is advantageously a halogen atom such as chlorine, bromine or iodine. Such a halogen substitution reaction can be carried out under organometallic cross-coupling conditions such as Suzuki conditions using a palladium catalyst, for example tetrakis(triphenylphosphine)palladium(0), with or without 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos), in a solvent mixture such as 1,4-dioxane / water, in the presence of potassium phosphate tribasic, at an elevated temperature, for example 90°C, either under microwave or non-microwave conditions.

[0175] Compounds of formula (XLVIII) can be prepared from the reaction of an alcohol of formula (XXVI), a chloroformate such as nitrophenyl chloroformate and an amine of formula (XLVII).

[0176] Introduction of a leaving group on X2, such as mesylate, into compounds of formula (XLIX) can be achieved using mesyl chloride in the presence of a base such as trimethylamine in a solvent such as DCM at room temperature to afford compounds of formula (L).

[0177] Deprotection of X1 to compounds of formula (LI) can be achieved using a reagent such as TBAF in a solvent such as THF at room temperature.

[0178] Macrocyclization of compounds of formula (LI) by nucleophilic substitution can be carried out using cesium carbonate in a solvent such as N,N-dimethylformamide at elevated temperatures such as 80°C to give compounds of formula (XIII).

[0179] Final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, following either or both alkylation of the carbamate and / or substitution of the A ring, yields the final compound of formula (I).

[0180] Alternatively, compounds of formula (I) can be prepared as shown in general scheme M below, in which a fused pyrazolo structure of formula (II) is converted to a protected compound of formula (III). This compound of formula (III) can be converted to a compound of formula (IV) containing a leaving group on the fused pyrazolo structure, and then converted to a nitrogen-protected compound of formula (V). Compounds of formula (V) can be converted to a selectively protected fused pyrazolo structure of formula (VI), which is then alkylated with an intermediate of formula (XIX) containing a leaving group to provide compounds of formula (XXII). Compounds of formula (XIX) can be obtained commercially or prepared from compounds of formula (XVIII) via reaction with CbzCl or via introduction of a leaving group Lg2 into compounds of formula (XVIIIa). Compounds of formula (XXII) can be coupled with a protected alkyne (LII) in a copper-mediated coupling to form compounds of formula (LIII).

[0181] Deprotection of the alkyne leads to a compound of formula (LIV). A (hetero)aromatic ring can be formed from the alkyne to give a compound of formula (XLII). Deprotection of X3-OPg4 leads to a compound of formula (XXI). Compounds of formula (XXI) can then be cyclized by a transcarbamylation reaction to form compounds of formula (XIII). Final deprotection of the nitrogen of the fused pyrazolo structure, after either or both alkylation of the carbamate ester and / or substitution of the A ring, leads to compounds of formula (I). [ka]

[0182] In Scheme M above, A is a 5-membered aromatic cyclic group defined by formula (a), A4 is a carbon atom, and A5 represents an optionally substituted carbon atom.

[0183] In the above reaction scheme, the alkylation between compounds of formula (VI) and formula (XIX) can be achieved in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 120°C.

[0184] Suitable compounds of formula (XIX) may either be obtained commercially or via reaction of compounds of formula (XVIII) with CbzCl and sodium hydroxide in water as solvent. Alternatively, compounds of formula (XIX) can be prepared by introduction of Lg2 into compounds of formula (XVIIIa).

[0185] In the above reaction of a compound of formula (XXII) with a compound of formula (LII), the leaving group Lg1 is advantageously a halogen atom such as chlorine, bromine or iodine. Such a halogen substitution reaction can be carried out in the presence of triethylamine, in a solvent such as THF, at an elevated temperature such as 80° C., using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) with or without CuI.

[0186] Deprotection of the alkyne can be achieved using TBAF in a solvent such as THF at room temperature to give a compound of formula (LIV).

[0187] Heteroaromatic ring formation on compounds of formula (XLII) can be carried out via reaction with a reagent such as tert-butyl-(3-nitropropoxy)-diphenyl-silane in the presence of PhNCO and trimethylamine in a solvent such as THF at an elevated temperature such as 80°C.

[0188] Deprotection of X3-OPg4 in compound (XLII) can be carried out using TBAF in a solvent such as THF at room temperature to give a compound of formula (XXI).

[0189] The transcarbamylation of a compound of formula (XXI) to a macrocycle of formula (XIII) can be carried out using potassium carbonate or cesium carbonate or potassium hydroxide in a solvent such as acetonitrile at temperatures ranging from room temperature to reflux, or using sodium hydride in a dry solvent such as toluene at temperatures ranging from 0° C. to reflux, either under microwave or non-microwave conditions.

[0190] Final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, followed by either or both alkylation of the carbamate and / or substitution of the A ring, yields the final compound of formula (I).

[0191] Alternatively, compounds of formula (I) can be prepared as shown in general scheme N below, where a fused pyrazolo structure of formula (II) is converted to a protected compound of formula (III). This compound of formula (III) can be converted to a compound of formula (IV) containing a leaving group on the fused pyrazolo structure, which can then be converted to a nitrogen-protected compound of formula (V). The compound of formula (V) can be converted to a selectively protected fused pyrazolo structure of formula (VI). The compound of formula (VI) is alkylated with a compound of formula (VIIIa) to form a compound of formula (LV).

[0192] Deprotection of X2-N(Ra)Pg3 provides a compound of formula (LVI). The compound of formula (LVI) can be coupled to a (hetero)aromatic compound of formula (LVII) via reaction with CDI. The compound of formula (LVIII) can then be cyclized via a CH activation reaction to form a compound of formula (XIII). Final deprotection of the nitrogen of the fused pyrazolo structure, after either or both of alkylation of the carbamate ester and / or substitution of the A ring, provides a compound of formula (I). [ka]

[0193] In Reaction Scheme N above, the alkylation between a compound of formula (VI) and a compound of formula (VIIIa) can be accomplished at room temperature or elevated temperature in a solvent such as N,N-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate. The appropriate compound of formula (VIIIa) can be either commercially obtained or obtained through various selective protection and deprotection steps known to those skilled in the art.

[0194] Deprotection of compounds of formula (LV) can be carried out using palladium on carbon on charcoal and hydrogen gas in a solvent such as MeOH at room temperature.

[0195] Coupling of the (hetero)aromatic moiety on formula (LVI) can be achieved using 1,1'-carbonyldiimidazole and a base such as cesium carbonate in a solvent such as N,N-dimethylacetamide at room temperature.

[0196] Ring closure of compounds of formula (LVIII) to macrocycles of formula (XIII) via CH activation can be achieved using cataCXIum, palladium acetate and potassium acetate in dry toluene under microwave conditions at elevated temperatures such as 150°C.

[0197] Final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, followed by either or both alkylation of the carbamate and / or substitution of the A ring, yields the final compound of formula (I).

[0198] Alternatively, compounds of formula (I) can be prepared as shown in general scheme O below, in which a fused pyrazolo structure of formula (II) is converted to a protected compound of formula (III). The NH of the fused pyrazolo structure can be protected to give a compound of formula (XIV). This compound of formula (XIV) can be converted to a boronic acid (or boronic ester) of formula (XV). The compound of formula (XV) can be coupled with a (hetero)aryl of formula (XLIII) or formula (XXVI) via an organometallic cross-coupling, such as Suzuki coupling, to form a compound of formula (XLIV) or a compound of formula (XLIVa), which can then be alkylated with a compound of formula (XIX) and cyclized by a transcarbamylation reaction in a one-pot reaction to form a compound of formula (XIII). Alternatively, the compound of formula (XLIVa) can first be deprotected to a compound of formula (XLIVb) prior to the one-pot alkylation and cyclization. Final deprotection of the nitrogen of the fused pyrazolo structure, following either or both alkylation of the carbamate and / or substitution of the A ring, provides compounds of formula (I). [ka]

[0199] In Reaction Scheme O above, boronation of the fused pyrazolo structure of a compound of formula (XIV) to a compound of formula (XV) can be achieved using an iridium catalyst and bis(pinacolato)diboron in a solvent such as TBME.

[0200] In the reaction between the compound of formula (XV) and the compound of formula (XLIII) or the compound of formula (XXVI) above, the leaving group Lg1 is advantageously a halogen atom such as chlorine, bromine or iodine. Such a halogen substitution reaction can be carried out under cross-coupling conditions such as Suzuki conditions using a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), in combination with 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos), in a solvent mixture such as 1,4-dioxane / water, in the presence of potassium phosphate tribasic, at an elevated temperature, such as 90°C, either under microwave or non-microwave conditions.

[0201] Possible deprotection of X1 can be accomplished using TBAF in a solvent such as THF at a temperature such as room temperature.

[0202] A possible one-pot alkylation with compounds of formula (XIX) and transcarbamylation to macrocycles of formula (XIII) can be carried out using cesium carbonate in a solvent such as acetonitrile at temperatures ranging from room temperature to 80°C.

[0203] Final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, followed by either or both alkylation of the carbamate and / or substitution of the A ring, yields the final compound of formula (I).

[0204] Alternatively, compounds of formula (I) can be prepared as shown in general scheme P below, in which a fused pyrazolo structure of formula (II) is converted to a protected compound of formula (III). The NH of the fused pyrazolo structure can be protected to give a compound of formula (XIV). This compound of formula (XIV) can be converted to a boronic acid (or boronic ester) of formula (XV). The compound of formula (XV) can be coupled with a (hetero)aryl of formula (XXVI) via an organometallic cross-coupling, such as a Suzuki coupling, to form a compound of formula (XLIVa), which can then be alkylated with a compound of formula (XLVI) and cyclized via a carbamylation reaction to form a compound of formula (XLVIII). Final deprotection of the nitrogen of the fused pyrazolo structure after either or both of alkylation of the carbamate ester and / or substitution of the A ring provides a compound of formula (I). [ka]

[0205] In Reaction Scheme P above, boronation of the fused pyrazolo structure of a compound of formula (XIV) to a compound of formula (XV) can be achieved using an iridium catalyst and bis(pinacolato)diboron in a solvent such as TBME.

[0206] In the above reaction between a compound of formula (XV) and a compound of formula (XXVI), the leaving group Lg1 is advantageously a halogen atom such as chlorine, bromine or iodine. Such a halogen substitution reaction can be carried out under cross-coupling conditions such as Suzuki conditions using a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), in combination with 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos), in a solvent mixture such as 1,4-dioxane / water, in the presence of potassium phosphate tribasic, at an elevated temperature such as 90°C, either under microwave or non-microwave conditions.

[0207] Alkylation of a compound of formula (XLV) with a compound of formula (XLVI) can be carried out using cesium carbonate in a solvent such as acetonitrile at a temperature ranging from room temperature to 80°C.

[0208] Carbamylation of compounds of formula (XLVIII) can be achieved using reagents such as CDI, COCl 2 , CO 2 or CO.

[0209] Final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, followed by either or both alkylation of the carbamate and / or substitution of the A ring, yields the final compound of formula (I). [Example]

[0210] The IUPAC names of the compounds of the present invention were generated using the following software: Product version: MarVInSketch18.3.0 Manufacturing date:2018-01-26 Internal manufacturing ID:18.3.0-7913 Operating System: amd64 Windows 10.10.0 Character code: Windows-1252 JaVa:JeroenFrIjtersJaVa1.8.0 Memory: 43, total 8M, 10, 0M free space Environment:Application .NET version: V2.0.50727 IKVM version: 8.10.1.2 JChem: NET API assembly version: 18.3.07913 JChem:NET API file version: 18.3.0.7913 Marvin:NET version:18.3.0.137 Process Type: X64 http: / / www.chemaXon.com

[0211] In the event of a discrepancy between the depicted chemical structure and the corresponding chemical name, the depicted chemical structure is considered to be the true structure.

[0212] To prepare the compounds described in the examples, the following experimental procedures were followed unless otherwise indicated.

[0213] Unless otherwise noted, reaction mixtures were magnetically stirred at room temperature. When organic solutions were "dried," they were generally dried over a desiccant such as sodium sulfate or magnesium sulfate. When mixtures, solutions, and extracts were "concentrated," they were typically concentrated on a rotary evaporator under reduced pressure.

[0214] All intermediates and final exemplified compounds were analyzed by high performance liquid chromatography (HPLC) according to one of the methods described below.

[0215] LCMS method A Analyses were performed on a Thermo Scientific Accucore C18 (50 mm length x 2.1 mm internal diameter, 2.6 μm particle size) at 35 °C with a flow rate of 1.50 mL / min. Gradient elution was performed from 95% (water + 0.1% formic acid) / 5% acetonitrile to 5% (water + 0.1% formic acid) / 95% acetonitrile in 1.30 min; the resulting composition was held for 0.5 min; then the final mobile phase composition was changed from 5% (water + 0.1% formic acid) / 95% acetonitrile to 90% (water + 0.1% formic acid) / 10% acetonitrile in 0.10 min. The injection volume was 1 μL. The MS acquisition range and UV detector were set to 100–1000 m / z and 190–400 nm, respectively.

[0216] LCMS method B Analyses were performed on a Phenomenex Kinetex 00B-4475-AN C18 column (50 mm length × 2.1 mm internal diameter, 1.7 μm particle size) at 60 °C and a flow rate of 1.5 mL / min. Gradient elution was performed from 90% (water + 0.1% formic acid) / 10% acetonitrile to 10% (water + 0.1% formic acid) / 90% acetonitrile in 1.50 min; the resulting composition was held for 0.40 min; then the final mobile phase composition was 10% (water + 0.1% formic acid) / 90% acetonitrile to 90% (water + 0.1% formic acid) / 10% acetonitrile in 0.10 min. Injection volumes were 2 μL using an Agilent autosampler injector or 5 μL using an Agilent autosampler injector. The MS acquisition range and DAD detector were set at 100-800 m / z and 190-400 nm, respectively.

[0217] LCMS method C The analysis was performed on a YMC pack ODS-AQ C18 column (50 mm length × 4.6 mm internal diameter, 3 μm particle size) at 35 °C with a flow rate of 2.6 mL / min. Gradient elution was performed from 95% (water + 0.1% formic acid) / 5% acetonitrile to 5% (water + 0.1% formic acid) / 95% acetonitrile in 4.8 min; the resulting composition was held for 1.0 min; and from 5% (water + 0.1% formic acid) / 95% acetonitrile to 95% (water + 0.1% formic acid) / 5% acetonitrile in 0.2 min. The standard injection volume was 2 μL. The acquisition range was set to 190–400 nm with a UV-PDA detector and 100–1400 m / z with a TOF-LCMS detector. The total run time was 6.2 min.

[0218] LCMS method D The analysis was performed on a Phenomenex Kinetex C18 column (50 mm length × 2.1 mm internal diameter, 2.6 μm particle size) at 35 °C with a flow rate of 0.7 mL / min. Gradient elution was performed from 95% (water + 50 mM ammonium acetate) / 5% acetonitrile to 5% (water + 50 mM ammonium acetate) / 95% acetonitrile in 4.8 min; the resulting composition was held for 1.0 min; and from 5% (water + 50 mM ammonium acetate) / 95% acetonitrile to 95% (water + 50 mM ammonium acetate) / 5% acetonitrile in 0.2 min. The standard injection volume was 2 μL. The acquisition range was set to 190–400 nm with a UV-PDA detector and 100–1400 m / z with a MS detector. The total run time was 6.2 min.

[0219] LCMS method E The analysis was performed on a YMC pack ODS-AQ C18 column (50 mm length × 4.6 mm internal diameter, 3 μm particle size) at 35 °C with a flow rate of 2.6 mL / min. Gradient elution was performed from 95% (water + 0.1% formic acid) / 5% acetonitrile to 5% (water + 0.1% formic acid) / 95% acetonitrile in 4.8 min; the resulting composition was held for 1.0 min; and from 5% (water + 0.1% formic acid) / 95% acetonitrile to 95% (water + 0.1% formic acid) / 5% acetonitrile in 0.2 min. The standard injection volume was 2 μL. The acquisition range was set to 190–400 nm with a UV-PDA detector and 100–1400 m / z with a mass spectrometer.

[0220] LCMS method F Analytical HPLC was performed on an X-Select CSH C18 XP column (2.5 μm, 30 × 4.6 mm i.d.) using 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B) with the following elution gradient: 5% to 100% B for 0–3 min, 100% B for 3–4 min, at 40°C and a flow rate of 1.8 mL / min. Mass spectra (MS) were obtained using electrospray positive ionization [ES+, [M+H]] at a cone voltage of 20 V. +to give the molecular ion] or electrospray negative ionization [ES-[MH] - The data were recorded on a Waters ZQ mass spectrometer (scan 200–900 uma) using the [give molecular ion] mode.

[0221] LCMS method G Analytical HPLC was performed on an X-Select CSH C18 XP column (2.5 μm, 30 × 4.6 mm i.d.) using 2 g / L aqueous (NH4)2CO3 in water (solvent A) and 2 g / L (NH4)2CO3 in acetonitrile (solvent B) with the following elution gradient: 0–3 min, 5% to 100% B, 3–4 min, 100% B, at 40 °C and a flow rate of 1.8 mL / min. Mass spectra (MS) were acquired using electrospray positive ionization (ES) at 20 V cone voltage [ES+ is [M+H]]. + to give the molecular ion] or electrospray negative ionization [ES-[MH] - The data were recorded on a Waters ZQ mass spectrometer (scan 200–900 uma) using the [give molecular ion] mode.

[0222] LCMS method H Analytical HPLC was performed on an X-Select CSHC18X column (2.5 μm, 30 × 4.6 mm i.d.) using 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B) with the following elution gradient: 0% to 50% B in 0–4 min, at 40 °C and a flow rate of 1.8 mL / min. Mass spectra (MS) were obtained using electrospray positive ionization [ES+ is [M+H]] at a cone voltage of 20 V. + to give the molecular ion] or electrospray negative ionization [ES-[MH] - The data were recorded on a Waters ZQ mass spectrometer (scan 200–900 uma) using the [give molecular ion] mode.

[0223] LCMS Method I Analytical HPLC was performed on an X-Select CSHC18XP column (2.5 μm, 30 × 4.6 mm i.d.) using 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B) with the following elution gradient: 0–4 min: 40% to 100% B, 4–5 min: 100% B, at 40 °C and a flow rate of 1.8 mL / min. Mass spectra (MS) were acquired using electrospray positive ionization [ES+ is [M+H]] at a cone voltage of 20 V. + to give the molecular ion] or electrospray negative ionization [ES-[MH] - The data were recorded on a Waters ZQ mass spectrometer (scan 200–900 uma) using the [give molecular ion] mode.

[0224] LCMS method J Analytical HPLC was performed on an X-Select CSHC18XP column (2.5 μm, 30 × 4.6 mm i.d.) using 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B) with the following elution gradient: 5% to 100% B in 0–6 min, 100% B in 6–7 min, at 40 °C and a flow rate of 1.8 mL / min. Mass spectra (MS) were acquired using electrospray positive ionization [ES+ is [M+H]] at a cone voltage of 20 V. + to give the molecular ion] or electrospray negative ionization [ES-[MH] - The data were recorded on a Waters ZQ mass spectrometer (scan 200–900 uma) using the [give molecular ion] mode.

[0225] Chiral analytical SFC was performed on a WhelkO1(R,R) column (1.8 μm, 100 × 4.6 mm i.d.) and eluted with CO2 / methanol (70 / 30) at 35 °C and a flow rate of 2.5 mL / min.

[0226] Finally, all exemplified compounds were analyzed by proton NMR. H NMR spectra were recorded on a Bruker AVance 400 MHz spectrometer in either CDCl, d-DMSO, or CDOD, or on a Bruker Ultrashield AV 300 MHz spectrometer using a Bruker 5 mm BBI H / D-BB Z-GRD probe with a BACS-60 sample changer and registered with Bruker TopspIn 2.1 software. Chemical shifts are reported in parts per million (ppm) relative to the residual protonated solvent (7.26 ppm for CDCl, 2.50 ppm for d-DMSO, and 3.31 ppm for CDOD). 1 For H NMR spectra, the multiplicity, coupling constant in Hertz, and number of protons are given in parentheses. Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, brs = broad singlet.

[0227] or, 1 H-NMR measurements were carried out on a Bruker AVanceIII 500 MHz spectrometer using DMSO-d6 (hexadeutero-dimethyl sulfoxide) or CDCl3 (deuterochloroform) as the solvent. 1 H-NMR data are in the form of delta values ​​given in ppm using the residual peak of the solvent (2.50 ppm for DMSO-d6, 7.26 ppm for CDCl3) as internal standard. Splitting patterns are designated as follows: s (singlet), 2s (2 x singlets), d (doublet), 2d (2 x doublet), t (triplet), 2t (2 x triplet), q (quartet), 2q (2 x quartet), quint (quintet), sept (septet), m (multiplet), 2m (2 x multiplet), brs (broad singlet), brd (broad doublet), brt (broad triplet), brq (broad quartet), brm (broad multiplet), Vbrs (very broad singlet), dd (double of doublets), td (triple of doublets), dt (double of triplets), dq (double of quartet), ddd (double of doublet doublet), dm (double of multiplets), tm (triple of multiplets), qm (quartet of multiplets).

[0228] Abbreviation: The following abbreviations are used herein: Ph = phenyl Ac = acetate Bn = benzyl t-Bu = tert-butyl n-Bu = normal butyl Me = methyl Et = ethyl Pr = Propyl iPr = isopropyl Bu = butyl TMS = trimethylsilyl TBS = tert-butyldimethylsilyl TFA = trifluoroacetic acid i-Pr2NEt or DIPEA = N,N-diisopropylethylamine TEA = triethylamine DMAP = 4-dimethylaminopyridine Pd / C = palladium supported on carbon KOH = potassium hydroxide NaOH = Sodium hydroxide LiOH = lithium hydroxide Ar = argon N2 = nitrogen H2 = Hydrogen LAH = lithium aluminum hydride Boc = tert-butoxycarbonyl Cbz = carboxybenzyl LDA = lithium diisopropylamide NBS = N-bromosuccinimide NIS = N-iodosuccinimide ACN = acetonitrile PTSA = p-toluenesulfonic acid THF = tetrahydrofuran DCM = dichloromethane DMF = N,N-dimethylformamide AA = acetic acid TBME = methyl tert-butyl ether Hept = heptane EtOAc = ethyl acetate DHP = 3,4-dihydro-2H-pyran THP = tetrahydropyran TBAF = tetrabutylammonium fluoride cataCXium = Di(1-adamantyl)-n-butylphosphine XPhos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl dppf = 1,1'-bis(diphenylphosphino)ferrocene wt%=weight% ee = enantiomeric excess min=minute(s) h or hr = time (s) L = liters (s) mL = milliliter(s) μL = microliter(s) g = grams (s) mg = milligram(s) mol = mole mmol = millimoles (s) RT=room temperature t R = retention time sat=saturated aq. = aqueous TLC = thin layer chromatography HPLC = High-Performance Liquid Chromatography LC / MS = high performance liquid chromatography / mass spectrometry MS or Mass Spec=mass spectrometry NMR=nuclear magnetic resonance ppm=parts per million

[0229] Example 1 : 8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 1 is prepared according to the synthetic route described in general Scheme A.

[0230] Preparation of Intermediate 1 : 5-((tert-butyldimethylsilyl)oxy)-1H-indazole [ka] 1H-Indazol-5-ol (19 g, 141.643 mmol) was dissolved in DCM (425 mL). Then, imidazole (11.572 g, 169.972 mmol) and tert-butylchlorodimethylsilane (23.485 g, 155.807 mmol) were added, and the mixture was stirred at room temperature for 16 h. Saturated NaHCO solution was added, and the reaction mixture was extracted with DCM (2×). The combined organic layers were dried over MgSO, filtered, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel using Hept / EtOAc (100:0 to 70:30). The desired fractions were combined and concentrated under reduced pressure to yield 5-((tert-butyldimethylsilyl)oxy)-1H-indazole 1 as a salmon-colored solid. LCMS method A: [M+H] + =249.0, retention time=0.997 minutes

[0231] Preparation of intermediate 2 : 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1H-indazole [ka] 5-((tert-Butyldimethylsilyl)oxy)-3-iodo-1H-indazole 1 (20 g, 80.515 mmol) was dissolved in DCM (240 mL), N-iodosuccinimide (19.021 g, 84.541 mmol) was added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM, and saturated NaHCO solution was added. The two layers were separated, and the aqueous layer was extracted with DCM (2×). The combined organic layers were dried over MgSO, filtered, and the solvent was removed under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel using Hept / EtOAc (100:0 to 80:20) as eluent. The desired fractions were combined, and the solvent was removed under reduced pressure to yield 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1H-indazole 2 as a light brown solid. LCMS method A: [M+H] + =374.9, retention time=1.156 minutes

[0232] Preparation of intermediate 3 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole [ka] To a solution of 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1H-indazole 2 (27.960 g, 74.699 mmol) in DCM (224 mL) was added 4-methylbenzenesulfonic acid monohydrate (1.421 g, 7.470 mmol) and 3,4-dihydro-2H-pyran (20.490 mL, 224.097 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM, and saturated NaHCO3 solution was added. The two layers were separated, and the aqueous layer was extracted with DCM (2x). The combined organic layers were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The concentrate was purified by flash chromatography (silica; heptane / EtOAc 100:0 to 95:5). The desired fractions were combined and the solvent removed under reduced pressure to give 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 3 as a pale orange oil. LCMS method A: [M+H] + =458.9, retention time=1.377 minutes

[0233] Preparation of Intermediate 4: 3-Iodo-1-(tetrahydro-pyran-2-yl)-1H-indazol-5-ol [ka] 5-((tert-Butyldimethylsilyl)oxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 3 (10.000 g, 21.814 mmol) was dissolved in THF (62 mL). TBAF [1 M] in THF (32.8 mL, 32.800 mmol) was added at 0 °C. The reaction was stirred at room temperature for 16 h. Saturated NaHCO solution was added and the two layers were separated. The aqueous layer was extracted with DCM (2x). The combined organic layers were dried over MgSO, filtered, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (silica; heptane / EtOAc 100:0 to 60:40). Fractions containing the desired product were combined and the solvent evaporated under reduced pressure to yield 3-iodo-1-(tetrahydro-pyran-2-yl)-1H-indazol-5-ol 4 as a cream solid. LCMS method B: [M+H] + =345.0, retention time=0.767 minutes

[0234] Preparation of Intermediate 5 : 3-(dibenzylamino)propan-1-ol [ka] To a solution of 3-aminopropan-1-ol (5 g, 66.569 mmol) in EtOH (200 mL), potassium carbonate (18.861 g, 136.466 mmol) and benzyl bromide (17.395 mL, 146.452 mmol) were carefully added, and the resulting mixture was stirred under reflux at 70 °C for 4 h. The mixture was filtered, and the filtrate was washed with water. The aqueous layer was extracted with EtOAc (2x), and the combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel using Hept / EtOAc (100:0 to 80:20) as eluent. The desired fractions were combined, and the solvent was removed under reduced pressure to yield 3-(dibenzylamino)propan-1-ol 5 as a yellowish oil. LCMS Method B: m / z not detected, retention time = 0.248 min

[0235] Preparation of Intermediate 6 : 3-(dibenzylamino)propyl methanesulfonate [ka] 3-(Dibenzylamino)propan-1-ol 5 (5.000 g, 19.580 mmol) was dissolved in DCM (60 mL) and triethylamine (8.187 mL, 58.740 mmol) was added. The mixture was cooled to 0 °C, and methanesulfonyl chloride (1.970 mL, 25.454 mmol) was added. The mixture was stirred at room temperature for 16 h. DCM and saturated NaHCO3 solution were added. The two layers were separated, and the mixture was extracted with DCM (x2). The combined organic layers were dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure to yield 3-(dibenzylamino)propyl methanesulfonate 6 as a yellow oil, which was used in the next step without purification. LCMS Method B: m / z not detected, retention time = 0.380 min

[0236] Preparation of Intermediate 7 N,N-Dibenzyl-3-((3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)oxy)propan-1-amine [ka] 3-(Dibenzylamino)propyl methanesulfonate 6 (crude, 6.298 g, 18.888 mmol) dissolved in N,N-dimethylformamide (10 mL) was added to a stirred mixture of 3-iodo-1-(tetrahydro-pyran-2-yl)-1H-indazol-5-ol 4 (5.000 g, 14.529 mmol) and cesium carbonate (7.101 g, 21.794 mmol) in N,N-dimethylformamide (40 mL). The reaction was stirred at room temperature for 30 min and then heated at 85 °C for 2 h. The mixture was diluted with EtOAc, and water was added. The two layers were separated, and the aqueous layer was extracted with DCM (×2). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using Hept / EtOAc (100:0 to 80:20). Fractions containing the desired compound were combined and the solvent was removed under reduced pressure to yield N,N-dibenzyl-3-((3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)oxy)propan-1-amine 7 as a yellowish oil. LCMS method B: [M+H] + =582.2, retention time=0.890 minutes

[0237] Preparation of Intermediate 8 : (5-(hydroxymethyl)pyridin-3-yl)boronic acid [ka] (5-Bromopyridin-3-yl)methanol (3.000 g, 15.956 mmol), bis(pinacolato)diboron (4.862 g, 19.147 mmol), and potassium acetate (4.698 g, 47.868 mmol) were dissolved in 1,4-dioxane (50 mL). After degassing with N for 5 min, Pd(dppf)Cl·DCM (1.303 g, 1.596 mmol) was added, and the reaction mixture was stirred at 110 °C for 4 h. The mixture was diluted with EtOAc and filtered through a Celite pad. The solvent was evaporated under reduced pressure to yield (5-(hydroxymethyl)pyridin-3-yl)boronic acid 8 as a dark brown solid. The crude product was used in the next step without purification. LCMS method B: [M+H] + =154.1, retention time=0.107 minutes

[0238] Preparation of Intermediate 9 : {5-[5-(3-dibenzylamino-propoxy)-1-(tetrahydro-pyran-2-yl)-1H-indazol-3-yl]-pyridin-3-yl}-methanol [ka] Tetrakis(triphenylphosphine)palladium(0) (1.411 g, 1.221 mmol) and XPhos (0.291 g, 0.611 mmol) were added to a mixture of N,N-dibenzyl-3-((3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)oxy)propan-1-amine 7 (7.100 g, 12.210 mmol), (5-(hydroxymethyl)pyridin-3-yl)boronic acid 8 (crude, 8.84 g, 15.873 mmol), and potassium phosphate tribasic (7.77 g, 36.63 mmol) in 1,4-dioxane / HO (3:1) (122.00 mL). The mixture was degassed with N for 5 min and stirred at 90 °C for 16 h. The mixture was diluted with EtOAc, and water was added. The two layers were separated, and the aqueous layer was extracted with DCM (×2). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using DCM:MeOH (100:0 to 98:2). The desired fractions were combined, and the solvent was removed under reduced pressure to give {5-[5-(3-dibenzylamino-propoxy)-1-(tetrahydro-pyran-2-yl)-1H-indazol-3-yl]-pyridin-3-yl}-methanol 9 as a yellow oil. LCMS method B: [M+H] + =563.3, retention time=0.749 minutes

[0239] Preparation of Intermediate 10 : {5-[5-(3-amino-propoxy)-1-(tetrahydro-pyran-2-yl)-1H-indazol-3-yl]-pyridin-3-yl}-methanol [ka] {5-[5-(3-Dibenzylamino-propoxy)-1-(tetrahydro-pyran-2-yl)-1H-indazol-3-yl]-pyridin-3-yl}-methanol 9 (6.000 g, 10.662 mmol) was dissolved in 106 mL of EtOAc and degassed with N. Pd / C 10% w / w (6.000 g) was added, and the reaction mixture was stirred under a H atmosphere with a balloon at room temperature for 66 h. The reaction mixture was filtered through a pad of Celite and washed with a mixture of DCM:MeOH:DMA (9:1:1). The filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (silica gel, DCM / MeOH / MeOH(NH) (100:0:0 to 90:9:1). The desired fractions were combined and the solvent was removed under reduced pressure to yield {5-[5-(3-amino-propoxy)-1-(tetrahydro-pyran-2-yl)-1H-indazol-3-yl]-pyridin-3-yl}-methanol 10 as a cream-colored solid. LCMS method B: [M+H] + =383.3, retention time=0.316 minutes

[0240] Preparation of intermediate 11 : 19-(oxan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetra-cyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] CDI (0.103 g, 0.633 mmol) was added to a solution of (5-(5-(3-aminopropoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridin-3-yl)methanol 10 (0.220 g, 0.575 mmol) in DMA (133 mL). The mixture was stirred at room temperature for 2 h and at 90 °C for 72 h. The reaction was diluted with EtOAc, cooled to 0 °C, and saturated NaHCO solution was added. The two layers were separated, and the aqueous layer was extracted with EtOAc (×2). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The product was purified by flash chromatography (silica gel, DCM:MeOH 100:0 to 97.5:2.5). The desired fractions were combined and the solvent removed under reduced pressure to give 19-(oxan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 11 as a colorless foam. LCMS method B: [M+H] + =409.1, retention time=0.753 minutes

[0241] Preparation of Example 1 : 8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] 19-(oxan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1] in HCl [4N] in 1,4-dioxane (33 mL) 2,6 .0 18,21A mixture of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 11 (0.135 g, 0.331 mmol) was stirred at room temperature for 2 h. The mixture was cooled to 0 °C, diluted with DCM, and carefully quenched with saturated NaHCO solution. The two layers were separated, and the aqueous layer was extracted with DCM (×2). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The product was purified by flash chromatography on silica gel (DCM:MeOH, 100:0 to 94:6). The desired fractions were combined, and the solvent was removed under reduced pressure to give 8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 1 was produced as a white solid. LCMS method C: [M+H] + =325.05, retention time=2.020 minutes LCMS method D: [M+H] + =325.1, retention time=3.945 minutes 1 H NMR (300 MHz, DMSO) δ13.32 (s, 1H), 9.03 (s, 1H), 8.53 (s, 1H), 8.15 (s, 1H), 7.99 (t, J=5.9 Hz, 1H), 7.54 (d, J=9.0 Hz, 1H), 7.21 (s, 1H), 7.01 (d, J=8.9 Hz, 1H), 5.28 (brs, 2H), 4.29 (t, J=8.3 Hz, 2H), 3.17 (d, J=4.6 Hz, 2H), 1.97 (brs, 2H) ppm.

[0242] Example 2 : 10-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 2 is prepared according to the synthetic route described in general Scheme A.

[0243] Preparation of intermediate 12: 10-Methyl-19-(oxan-2-yl)-8,14-dioxa-4,10,19,20-tetraaza-tetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] To a solution of Intermediate 11 (0.05 g, 0.12 mmol) in dry N,N-dimethylformamide (5 mL) under a nitrogen atmosphere at 0°C was added 60% sodium hydride in mineral oil (0.007 g, 0.15 mmol). The mixture was stirred at 0°C for 15 minutes, then iodomethane (0.02 mL, 0.33 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. The mixture was cooled to 0°C, diluted with EtOAc, and carefully quenched with water. The two layers were separated, and the aqueous layer was extracted with EtOAc (×2). The combined organic layers were washed with brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The product was purified by flash chromatography on silica gel (DCM:MeOH 100:0 to 97.5:2.5). The desired fractions were combined and the solvent removed under reduced pressure to give 10-methyl-19-(oxan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 12 as a yellow oil. LCMS method B: [M+H] + =423.1, retention time=0.897 minutes

[0244] Preparation of Example 2 : 10-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .018,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] 10-Methyl-19-(oxan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1] in HCl [4N] in 1,4-dioxane (5.0 mL) 2,6 .0 18,21 A mixture of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 12 (0.042 g, 0.099 mmol) was stirred at room temperature for 2 h. The mixture was cooled to 0 °C, diluted with DCM, and carefully quenched with saturated NaHCO3 solution. The two layers were separated, and the aqueous layer was extracted with DCM (×2). The combined organic layers were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The product was purified by flash chromatography on silica gel (DCM:MeOH, 100:0 to 94:6). The desired fractions were combined, and the solvent was removed under reduced pressure to give 10-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 2 as a white solid. LCMS method E: [M+H] + =339.1, retention time=2.298 minutes LCMS method D: [M+H] + =339.1, retention time=3.425 minutes 1H NMR (300 MHz, 100℃, d6-DMSO) δ 13.00 (s, 1H), 9.03 (s, 1H), 8.55 (s, 1H), 8.28 (s, 1H), 7.52 (d, J=9.0 Hz, 1H), 7.20 (s, 1H), 7.02 (dd.

[0245] Example 3 : 4-Fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 3 is prepared according to the synthetic route described in general Scheme A.

[0246] Preparation of intermediate 13: 2-[3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]isoindoline-1,3-dione [ka] A suspension of 3-iodo-1-tetrahydropyran-2-yl-indazol-5-ol 4 (4 g, 11.63 mmol), cesium carbonate (7.560 g, 23.26 mmol), and N-(3-bromopropyl)phthalimide (4.679 g, 17.45 mmol) in N,N-dimethylformamide (48 mL) was heated at 60° C. for 16 h. The reaction mixture was concentrated under reduced pressure. The resulting white solid was triturated with ethyl acetate and collected. The collected filtrate was washed with water. The aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with water, then brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give a cream-colored solid. Both the white and cream solids were collected to give 2-[3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]isoindoline-1,3-dione 13 as a cream solid. LCMS method F: [M+H] + =532, retention time=3.12 minutes

[0247] Preparation of intermediate 14 : 3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropan-1-amine [ka] A mixture of 2-[3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]isoindoline-1,3-dione 13 (6.176 g, 11.63 mmol) and hydrazine monohydrate (2.04 mL, 58.15 mmol) in EtOH (40 mL) was heated to 50° C. for 16 h. The reaction mixture was evaporated under reduced pressure, and EtOH was added to the white solid. The solid was filtered and washed with EtOH (3×), and the filtrate was evaporated under reduced pressure to give 3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropan-1-amine 14 as a slightly brown oil. LCMS method F: [M+H] + =402, retention time=1.65 minutes

[0248] Preparation of Intermediate 15 : [3-[5-(3-aminopropoxy)-1-tetrahydropyran-2-yl-indazol-3-yl]-5-fluoro-phenyl]methanol [ka] To a degassed solution of 3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropan-1-amine 14 (200 mg, 0.500 mmol), 3-fluoro-5-(hydroxymethyl)phenylboronic acid (127 mg, 0.750 mmol), tripotassium phosphate (318 mg, 1.500 mmol), and xPhos (24 mg, 0.050 mmol) in 1,4-dioxane (3.2 mL) and water (1.4 mL) was added tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol). The reaction mixture was irradiated in a microwave (Biotage initiator+) at 120 °C for 1 h (high absorption level). The reaction mixture was filtered through a Celite bed, and the Celite was then washed with ethyl acetate. The filtrate was diluted with water and extracted with ethyl acetate (3x). The organic layer was washed with water, then brine, dried over sodium sulfate, and concentrated under reduced pressure to give [3-[5-(3-aminopropoxy)-1-tetrahydropyran-2-yl-indazol-3-yl]-5-fluoro-phenyl]methanol 15 as a pale yellow oil. LCMS method F: [M+H] + =400, retention time=1.76 minutes

[0249] Preparation of Intermediate 16 : 4-Fluoro-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one [ka] To a solution of [3-[5-(3-aminopropoxy)-1-tetrahydropyran-2-yl-indazol-3-yl]-5-fluoro-phenyl]methanol 15 (199 mg, 0.499 mmol) in DMA (150 mL) was added 1,1′-carbonyldiimidazole (89 mg, 0.549 mmol). The reaction mixture was stirred at room temperature for 2 h and then heated to 90° C. for 48 h. The reaction was concentrated under reduced pressure, followed by the addition of ethyl acetate and saturated aqueous NaHCO3. The mixture was extracted with ethyl acetate (2×). The combined organic layers were washed with water, then brine, dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography eluting with cyclohexane / EtOAc / EtOH (3-1):100 / 0-70 / 30 to give 4-fluoro-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one 16 as a white solid. LCMS method F: [M+H] + =426, retention time=2.84 minutes

[0250] Preparation of Example 3 : 4-Fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] 4-Fluoro-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21To a solution of tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one 16 (92 mg, 0.217 mmol) was added 4 M HCl in 1,4-dioxane (0.54 mL, 2.17 mmol), and the reaction was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was heated to 50 °C for 60 hours. The solvent was removed under reduced pressure, and the cream-colored solid was recrystallized from acetonitrile to give 4-fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 3 as a white solid. LCMS method F: [M+H] + =342, retention time=2.16 minutes LCMS method G: [M+H] + =342, retention time=2.24 minutes 1 H NMR (400 MHz, d6-DMSO) δ 13.06 (1H, s), 7.74 (2H, m), 7.62 - 7.58 (1H, m), 7.52 - 7.49 (1H, m), 7.35 (1H, m), 7.14 - 7.11 (1H, m), 7.00 (1H, m), 5.29 (2H, s), 4.33 (2H, t), 3.22 - 3.18 (2H, m), 2.06 - 2.05 (2H, m) ppm.

[0251] Example 4 : 8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 4 is prepared according to the synthetic route described in general Scheme B.

[0252] Preparation of intermediate 17: tert-Butyl-dimethyl-(1-tetrahydropyran-2-ylindazol-5-yl)oxy-silane [ka] To a solution of tert-butyl-(1H-indazol-5-yloxy)-dimethyl-silane 1 (15.95 g, 64.28 mmol) in DCM (200 mL) and THF (100 mL) was added methanesulfonic acid (0.834 mL, 12.86 mmol) and DHP (17.59 mL, 192.84 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature overnight. The residue was diluted with saturated sodium bicarbonate solution and extracted twice with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (120 g silica Biotage) chromatography (cyclohexane-ethyl acetate, 1:0 to 90 / 10). The desired fractions were combined, and the solvent was removed under reduced pressure to give tert-butyl-dimethyl-(1-tetrahydropyran-2-ylindazol-5-yl)oxy-silane 17 as white crystals. LCMS method F: [M+H] + =333.2, retention time=3.53 minutes

[0253] Preparation of intermediate 18 [5-[tert-butyl(dimethyl)silyl]oxy-1-tetrahydropyran-2-yl-indazol-3-yl]boronic acid and 5-[(tert-butyldimethylsilyl)oxy]-1-(oxan-2-yl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole [ka] In a sealed tube, tert-butyl-dimethyl-(1-tetrahydropyran-2-ylindazol-5-yl)oxy-silane 17 (3 g; 9.03 mmol), TBME (15 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.3 g; 9.03 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (145 mg; 0.54 mmol), and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (119 mg; 0.18 mmol) were added. The reaction was degassed with argon for 10 minutes and then allowed to react at 80 °C overnight. The solvent was removed under reduced pressure, and the oil was dissolved in ethyl acetate and water. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, and the solvent was removed under reduced pressure to give a mixture of [5-[tert-butyl(dimethyl)silyl]oxy-1-tetrahydropyran-2-yl-indazol-3-yl]boronic acid and 5-[(tert-butyldimethylsilyl)oxy]-1-(oxan-2-yl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 18 as a brown oil. The product was used in the next step without further purification. LCMS method F: [M+H] + =459, retention time=3.80 minutes LCMS method G: [M+H] + =377.2, retention time=3.15 minutes

[0254] Preparation of intermediate 19 : 2-(5-hydroxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyridine-4-carboxylate [ka] To a solution of [5-[tert-butyl(dimethyl)silyl]oxy-1-tetrahydropyran-2-yl-indazol-3-yl]boronic acid and 5-[(tert-butyldimethylsilyl)oxy]-1-(oxan-2-yl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 18 (1.5 g, 3.99 mmol) in N,N-dimethylformamide (5 mL) was added methyl 6-bromopyridine-2-carboxylate (1.030 g, 4.78 mmol), cesium carbonate (3.8 g, 11.96 mmol), and PdCl2dppf.DCM (163 mg, 0.2 mmol) at room temperature. The resulting reaction mixture was stirred at 110 °C overnight. The solvent was removed under reduced pressure, and the oil was dissolved in EtOAc and water. The two layers were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (30 g silica BIOTAGE) chromatography (cyclohexane-ethyl acetate, 100 / 0 to 50 / 50) to give methyl 2-(5-hydroxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyridine-4-carboxylate 19 as a yellow powder. LCMS method F: [M+H] + =354.1, retention time=2.59 minutes

[0255] Preparation of Intermediate 20 : Benzyl N-(3-bromopropyl)carbamate [ka] To a solution of 3-bromopropylamine hydrochloride (6 g, 27 mmol) in 10% aqueous NaOH (40 mL) at 0 °C, CbzCl (4.3 mL, 30 mmol) and 10% NaOH (40 mL) were slowly added. After 12 h, the reaction mixture was diluted with DCM. The aqueous layer was extracted twice with DCM (100 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Macherey Nagel, 80 g) with gradient elution: cyclohexane / EtOAc 0–20% to give benzyl N-(3-bromopropyl)carbamate 20 as a clear oil. LCMS method F: [M+H] + =274, retention time=2.41 minutes

[0256] Preparation of intermediate 21 : Methyl 6-[5-(3-{[(benzyloxy)carbonyl]amino}propoxy)-1-(oxan-2-yl)-1H-indazol-3-yl]pyridine-2-carboxylate [ka] To a solution of methyl 6-[5-hydroxy-1-(oxan-2-yl)-1H-indazol-3-yl]pyridine-2-carboxylate 19 (1 g, 2.82 mmol) in N,N-dimethylformamide (100 mL) was added cesium carbonate (1.83 g, 5.6 mmol) and benzyl N-(3-bromopropyl)carbamate 20 (0.765 g, 2.82 mmol). The reaction was stirred at 120 °C for 16 h. The mixture was concentrated under reduced pressure. Water (200 mL) was added, and the resulting mixture was extracted with EtOAc (4 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure to give a brown / orange oil. The residue was purified by flash chromatography on silica gel (Macherey Nagel, 120 g) with gradient elution: cyclohexane / EtOAc 0–70% to give methyl 6-[5-(3-{[(benzyloxy)carbonyl]amino}propoxy)-1-(oxan-2-yl)-1H-indazol-3-yl]pyridine-2-carboxylate 21 as a white solid. LCMS method F: [M+H] + =545.2, retention time=3.21 minutes

[0257] Preparation of intermediate 22 : Benzyl N-[3-({3-[6-(hydroxymethyl)pyridin-2-yl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamate [ka] To methyl 6-[5-(3-{[(benzyloxy)carbonyl]amino}propoxy)-1-(oxan-2-yl)-1H-indazol-3-yl]pyridine-2-carboxylate 21 (1.2 g, 2.2 mmol) in THF (50 mL) was added 1 M lithium aluminum tetrahydride solution (4.4 mL, 4.2 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. EtOAc (10 mL) was added to the reaction mixture at 0 °C, and 10% Rochelle's salt solution (100 mL) and EtOAc (100 mL) were poured into it. The mixture was stirred at room temperature for 2 h. After separation, the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give a brown / orange oil. The residue was purified by flash chromatography on silica gel (Macherey Nagel, 120 g) with gradient elution: cyclohexane / EtOAc 0–100% to give benzyl N-[3-({3-[6-(hydroxymethyl)pyridin-2-yl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamate 22 as a yellow oil. LCMS method F: [M+H] + =517.3, retention time=2.76 minutes

[0258] Preparation of intermediate 23 : 19-(oxan-2-yl)-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] A solution of benzyl N-[3-({3-[6-(hydroxymethyl)pyridin-2-yl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamate 22 (0.4 g; 0.775 mmol) in toluene (100 mL) was added over 30 min to a solution of sodium hydride solution (60% suspension in paraffin oil) (310 mg, 7.75 mmol) in toluene (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 5 min and then at 130 °C for 1 h. The reaction was allowed to cool, then EtOH (10 mL) was carefully added. Water (100 mL) was added. After separation, the aqueous layer was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give an orange oil. Purification by column chromatography (DCM / MeOH 0–10%) afforded pure 19-(oxan-2-yl)-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 23 as a whitish solid. LCMS method F: [M+H] + =409.2, retention time=2.53 minutes

[0259] Preparation of Example 4 : 8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4, 6(23),15,17,21-heptaen-9-one [ka] 19-(oxan-2-yl)-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21To a solution of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 23 (0.2 g; 0.489 mmol) was added trifluoroacetic acid (0.38 mL, 4.89 mmol) at room temperature. The mixture was stirred at 50° C. for 24 hours. The reaction was allowed to cool. Toluene (50 mL) was added to the solution, and the reaction mixture was concentrated under reduced pressure to give an orange oil. Water (25 mL), DCM (25 mL), and 25 wt% aqueous ammonia solution (1.5 mL) were added. After separation, the aqueous layer was extracted with DCM (2×20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give an orange oil. Purification by column chromatography (DCM / MeOH 0–5%) afforded pure 8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 4 as a whitish solid. LCMS method F: [M+H] + =325.2, retention time=1.93 minutes LCMS method G: [M+H] + =325.2, retention time=1.94 minutes 1 H NMR (400 MHz, d6-DMSO) δ 13.2 (1H, m), 8.08 (1H, d, J=9.7 Hz), 7.90 (1H, d, J=3.5 Hz), 7.83 (1H, t, J=8.3 Hz), 7.75 (1H, t, J=5.9 Hz), 7.47 (1H, d, J=8.3 Hz), 7.26 (1H, d, J=8.3 Hz), 6.97 (1H, dd, J=2.5, 9.1 Hz), 5.31 (2H, m), 4.31 (2H, dd, J=7.7, 8.6 Hz), 3.11 - 3.09 (2H, m), 1.97- 2.03 (2H, m) ppm.

[0260] Example 5 : 8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6.0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 5 is prepared according to the synthetic route described in general Scheme A.

[0261] Preparation of intermediate 24 : [3-[5-(3-aminopropoxy)-1-tetrahydropyran-2-yl-indazol-3-yl]phenyl]methanol [ka] To a degassed solution of 3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropan-1-amine 14 (400 mg, 0.998 mmol), 3-(hydroxymethyl)phenylboronic acid (227 mg, 1.497 mmol), potassium phosphate tripotassium (636 mg, 2.994 mmol), and xPhos (48 mg, 0.100 mmol) in dioxane (6.4 mL) and water (2.8 mL) was added tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.050 mmol). The reaction mixture was heated at 120 °C under microwave conditions (Biotage initiator+) for 1 h. The reaction mixture was filtered through a Celite bed, and the Celite was washed with ethyl acetate. The filtrate was then diluted with water and extracted with ethyl acetate (3x). The organic layer was washed with water, then brine, dried over sodium sulfate, and concentrated under reduced pressure to give [3-[5-(3-aminopropoxy)-1-tetrahydropyran-2-yl-indazol-3-yl]phenyl]methanol 24 as a pale yellow oil. LCMS method F: [M+H] + =382, retention time=1.64 minutes

[0262] Preparation of Intermediate 25 : 19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6.0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] To a solution of [3-[5-(3-aminopropoxy)-1-tetrahydropyran-2-yl-indazol-3-yl]phenyl]methanol 24 (380 mg, 0.998 mmol) in DMA (300 mL) was added 1,1′-carbonyldiimidazole (178 mg, 1.100 mmol). The reaction mixture was stirred at room temperature for 2 h and then at 90° C. for 64 h. The reaction was concentrated under reduced pressure, and then ethyl acetate and saturated aqueous NaHCO3 were added. The mixture was extracted with ethyl acetate (2×). The combined organic layers were washed with water, then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with cyclohexane / ethyl acetate-EtOH (3 to 1):100 / 0 to 70 / 30 to give a white solid. The solid was recrystallized from acetonitrile to give 19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 25 as a white solid. LCMS method F: [M+H] + =408, retention time=2.76 minutes

[0263] Preparation of Example 5 : 8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] 19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12,6 .0 18,21 To a solution of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 25 (81 mg, 0.199 mmol) was added 4 M HCl in dioxane (0.75 mL, 2.985 mmol), and the reaction was heated to 50 °C for 24 h. The reaction mixture was cooled to room temperature, and the solid was filtered, then rinsed with diisopropyl ether (3x) to give 8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 5 as a white solid. LCMS method F: [M+H] + =324, retention time=2.02 minutes LCMS method G: [M+H] + =324, retention time=2.10 minutes 1 H NMR (400 MHz, d6-DMSO) δ 7.93 - 7.87 (2H, m), 7.69 - 7.66 (1H, m), 7.50 - 7.44 (2H, m), 7.36 (1H, d, J=2.3 Hz), 7.28 - 7.25 (1H, m), 6.98 (1H, dd, J=2.3, 8.9 Hz), 5.33 - 5.29 (3H, m), 4.32 (2H, m), 3.18 (2H, m), 2.04 (2H, m) ppm.

[0264] Example 6 : 10-(propan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 6 is prepared according to the synthetic route described in general Scheme A.

[0265] Example 6 is prepared using conditions similar to those of Example 2. 2-Iodopropane is used in the carabamate alkylation step to give 10-(propan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .01 8,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 6 was produced. LCMS method E: [M+H] + =367.2, retention time=2.829 minutes LCMS method D: [M+H] + =367.2, retention time=3.832 minutes 1 H NMR (300 MHz, 100℃, d6-DMSO) δ 12.96 (s, 1H), 9.01 (s, 1H), 8.54 (s, 1H), 8.39 (t, J=2.1 Hz, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.23 (s, 1H), 6.99 (dd, J=9.0, 2.3 Hz, 1H), 5.36 (brs, 2H), 4.28 (t, J=8.6 Hz, 2H), 4.20 - 4.04 (m, 1H), 3.32 (brt, J=7.3 Hz, 2H), 2.19 (brs, 2H), 1.18 (s, 3H), 1.15 (s, 3H) ppm.

[0266] Example 7 : 8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 7 is prepared according to the synthetic route described in general Scheme B.

[0267] Example 7 is made using similar conditions as for Example 4. Methyl 4-bromopyridine-2-carboxylate is used in the Suzuki reaction to give 8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 7 was given. LCMS method F: [M+H] + =325.1, retention time=1.58 minutes LCMS method G: [M+H] + =325.2, retention time=1.83 minutes 1 H NMR (400 MHz, d6-DMSO) δ 13.28 (1H, s), 8.59 - 8.57 (1H, m), 7.86 (2H, m), 7.83 (1H, dd, J=2.1, 5.5 Hz), 7.55 (1H, d, J=9.0 Hz), 7.44 (1H, d, J=2.1 Hz), 7.03 (1H, dd, J=2.1, 9.0 Hz), 5.32 - 5.31 (2H, m), 4.37 (2H, dd, J=8.3, 8.6 Hz), 3.19 - 3.18 (2H, m), 2.10 - 2.05 (2H, m) ppm.

[0268] Example 8 : 4-Methoxy-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 8 is prepared according to the synthetic route described in general Scheme C.

[0269] Preparation of Intermediate 26: Benzyl N-[3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]carbamate [ka] A suspension of 3-iodo-1-tetrahydropyran-2-yl-indazol-5-ol 4 (17.012 g, 49.453 mmol), cesium carbonate (32.144 g, 98.906 mmol), and benzyl N-(3-bromopropyl)carbamate 20 (10.6 mL, 54.398 mmol) in N,N-dimethylformamide (250 mL) was heated at 60 °C for 20 h. The reaction mixture was filtered and rinsed with acetonitrile. The filtrate crystallized, and it was filtered to give a white solid, which was rinsed with water (3x). The filtrate was collected and evaporated under reduced pressure to give a pink solid. It was solubilized with DCM, and water was added. It was extracted with DCM (2x), and the combined organic layers were then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a slightly pink solid. The solid was recrystallized from acetonitrile to give benzyl N-[3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]carbamate 26 as a white solid. LCMS method F: [M+H] + =536.0, retention time=3.11 minutes

[0270] Preparation of intermediate 27 : Benzyl N-[3-[3-[3-(hydroxymethyl)-5-methoxy-phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate [ka] To a degassed solution of benzyl N-[3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]carbamate 26 (600 mg, 1.12 mmol), [3-methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (444 mg, 1.68 mmol), potassium phosphate tripotassium (713 mg, 3.36 mmol), and xPhos (53 mg, 0.112 mmol) in 1,4-dioxane (7 mL) and water (4.8 mL) was added tetrakis(triphenylphosphine)palladium(0) (65 mg, 0.056 mmol). The reaction mixture was irradiated in a microwave oven (Biotage initiator+) at 120 °C for 1 h (high absorption level). The reaction mixture was filtered through a Celite bed, and the Celite was then washed with ethyl acetate. The filtrate was then diluted with water and extracted with ethyl acetate (3x). The organic layer was washed with water, then brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with DCM / ethyl acetate, 100 / 0 to 70 / 30, to give benzyl N-[3-[3-[3-(hydroxymethyl)-5-methoxy-phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate 27 as a colorless oil. LCMS method F: [M+H] + =546, retention time=2.89 minutes

[0271] Preparation of intermediate 28 : 4-Methoxy-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] To a suspension of potassium carbonate (80 mg, 0.582 mmol) in acetonitrile (12 mL) was added a solution of benzyl N-[3-[3-[3-(hydroxymethyl)-5-methoxy-phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate 27 (53 mg, 0.097 mmol) in acetonitrile (7 mL) at room temperature. The reaction mixture was heated at 140 °C for 6 h under microwave conditions. The reaction mixture was filtered and directly purified by column chromatography eluting with DCM / ethyl acetate, 100 / 0 to 80 / 20, to give 4-methoxy-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1]. 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 28 as a colorless oil. LCMS method F: [M+H] + =438, retention time=2.76 minutes

[0272] Preparation of Example 8 : 4-Methoxy-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] 4-Methoxy-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 To a solution of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 28 (23 mg, 0.053 mmol) was added trifluoroacetic acid (80 μL, 1.06 mmol) at room temperature. The reaction mixture was irradiated in a microwave oven (Biotage initiator+) at a high absorption level for 1 h 30 min at 80 °C.

[0273] The crude reaction mixture was purified by flash column chromatography eluting with DCM / ethyl acetate: 100 / 0 to 80 / 20 to give 4-methoxy-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 8 as a white solid. LCMS method F: [M+H] + =354, retention time=2.07 minutes LCMS method G: [M+H] + =354, retention time=2.09 minutes 1 H NMR (400 MHz, d6-DMSO) δ 12.89 (1H, s), 7.67 (1H, m), 7.52 - 7.47 (2H, m), 7.42 - 7.34 (2H, m), 6.99 - 6.96 (1H, m), 6.88 (1H, m), 5.25 (2H, m), 4.31 (2H, t), 3.86 (3H, s), 3.17 (2H, m), 2.03 (2H, m) ppm.

[0274] Example 9 : 4-Bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 9 can be prepared according to the synthetic routes described in general schemes A, C and D.

[0275] Preparation of intermediate 29 : 1-Tetrahydropyran-2-ylindazol-5-ol [ka] To a solution of tert-butyl-dimethyl-(1-tetrahydropyran-2-ylindazol-5-yl)oxy-silane 17 (12.58 g, 37.8 mmol) in tetrahydrofuran (100 mL) was added 1.0 M tetra-n-butylammonium fluoride (47.58 mL, 47.58 mmol) in THF in small portions at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ice-water (300 mL) and stirred for 1 h. The aqueous phase was extracted with ethyl acetate (2 × 150 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification on a silica column (RS SiOH 80 g) using cyclohexane / ethyl acetate 90 / 10 to 80 / 20 as eluent gave 1-tetrahydropyran-2-ylindazol-5-ol 29 as a colorless oil. LCMS method F: [M+H] + =219, retention time=1.81 minutes

[0276] Preparation of Intermediate 30 : Benzyl N-[3-(1-tetrahydropyran-2-ylindazol-5-yl)oxypropyl]carbamate [ka] To a solution of 1-tetrahydropyran-2-ylindazol-5-ol 29 (7.06 g, 32.3 mmol) in N,N-dimethylformamide (110 mL) was added cesium carbonate (21.0 g, 64.6 mmol) and benzyl N-(3-bromopropyl)carbamate 20 (10.14 g, 37.3 mmol) at room temperature. The mixture was stirred at 80 °C overnight. The reaction mixture was concentrated under reduced pressure. Water (100 mL) and ethyl acetate (200 mL) were added to the residue. After separation, the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure.

[0277] Purification on a silica column (RS SiOH 200 g) using cyclohexane / ethyl acetate 80 / 20 to 60 / 40 as eluent gave benzyl N-[3-(1-tetrahydropyran-2-ylindazol-5-yl)oxypropyl]carbamate 30 as a beige solid. LCMS method F: [M+H] + =410.2, holding time=2.77 minutes (current 20V)

[0278] Preparation of intermediate 31 : Benzyl N-[3-[1-tetrahydropyran-2-yl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-5-yl]oxypropyl]carbamate [ka] To a solution of benzyl N-[3-(1-tetrahydropyran-2-ylindazol-5-yl)oxypropyl]carbamate 30 (11.42 g, 27.9 mmol) in TBME / THF (500 / 100 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (7.79 g, 30.69 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (450 mg, 1.67 mmol). The reaction mixture was degassed by bubbling nitrogen through for 15 minutes, and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (370 mg, 0.56 mmol) was added. The reaction mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The solvent was removed under reduced pressure, and the oil was then dissolved in ethyl acetate and water. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, and the solvent was removed under reduced pressure to give benzyl N-[3-[1-tetrahydropyran-2-yl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-5-yl]oxypropyl]carbamate 31 as a brown oil. The product was used in the next step without further purification. LCMS method F: [M+H]+ =536.2, holding time=3.18 minutes (current 20V)

[0279] Preparation of intermediate 32 :(3-Bromo-5-iodo-phenyl)methanol [ka] To a solution of 3-bromo-5-iodobenzoic acid (10.0 g, 30.6 mmol) in THF (450 mL) was added solid sodium borohydride (3.47 g, 91.8 mmol) slowly at 0 °C. After gas evolution had ceased (i.e., 5 min), boron trifluoride dimethyl etherate (11.3 mL, 91.8 mmol) was added dropwise at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred overnight at room temperature. The reaction mixture was cooled to 0 °C, and 1 M aqueous sodium hydroxide solution (100 mL) was added slowly. The reaction mixture was filtered through a Celite pad and eluted with ethyl acetate. The solution was washed with water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give pure (3-bromo-5-iodophenyl)methanol 32 as a beige solid. LCMS method F: [M+H] + = Not detected, retention time = 2.54 min (current 20 V)

[0280] Preparation of intermediate 33 : Benzyl N-[3-[3-[3-bromo-5-(hydroxymethyl)phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate [ka] To a solution of benzyl N-[3-[1-tetrahydropyran-2-yl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-5-yl]oxypropyl]carbamate 32 (1.870 g, 3.50 mmol) in N,N-dimethylformamide (15 mL) was added (3-bromo-5-iodo-phenyl)methanol 31 (1.314 g, 4.20 mmol) and CsCO (3.421 g, 10.50 mmol) at room temperature. The reaction mixture was degassed by bubbling nitrogen through it for 15 min, and PdCldppf (0.128 g, 0.18 mmol) was added. The resulting mixture was stirred at 110 °C for 50 min under microwave irradiation. The reaction mixture was filtered through Celite and washed with ethyl acetate. The solvent was removed under reduced pressure, and the oil was dissolved in EtOAc and water. The two layers were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography (40 g RS SiOH) (cyclohexane-ethyl acetate, 100 / 0 to 50 / 50) gave benzyl N-[3-[3-[3-bromo-5-(hydroxymethyl)phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate 33 as an orange oil. LCMS method F: [M+H] + =596.1, holding time=3.07 minutes (current 20V)

[0281] Preparation of intermediate 34 : 4-Bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] To a solution of benzyl N-[3-[3-[3-bromo-5-(hydroxymethyl)phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate 33 (288 mg, 0.48 mmol) in dry toluene (300 mL) was added 60% sodium hydride in oil (480 mg, 12 mmol) at room temperature. The reaction mixture was stirred at 130 °C for 1 h. The reaction was then stirred overnight at room temperature, and 60% sodium hydride in oil (192 mg, 4.8 mmol) was added. The reaction mixture was stirred at 130 °C for 3 h. An additional 60% sodium hydride in oil (192 mg, 4.8 mmol) was added, and the reaction mixture was stirred at 140 °C overnight. An additional 60% sodium hydride in oil (192 mg, 4.8 mmol) was added, and the reaction mixture was stirred at 140 °C for 5 h. Again, 60% sodium hydride in oil (192 mg, 4.8 mmol) was added, and the reaction mixture was stirred at 140° C. for 1 hour until the reaction was complete. The reaction mixture was brought to room temperature and cooled in an ice bath. EtOH (50 mL) was added slowly. The reaction mixture was diluted with ethyl acetate (200 mL), and water was added (200 mL). After separation, the aqueous layer was extracted with ethyl acetate (×3 50 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered, and evaporated to dryness to give an orange oil.

[0282] Purification on a silica column (RS SiOH 80 g) using cyclohexane / ethyl acetate 100 / 0 to 0 / 100 and DCM / MeOH 90 / 10 as eluents gave 60 mg of the desired product. Impure fractions were pooled and the solvent was removed under reduced pressure. The residue was purified on a silica column (RS SiOH 40 g) using cyclohexane / ethyl acetate 100 / 0 to 50 / 50 as eluent to give 4-bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1]. 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 34 as a white solid. LCMS method F: [M+H] + =487.7, retention time=3.05 minutes

[0283] Preparation of Example 9 : 4-Bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] 4-Bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 To a solution of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 34 (30 mg, 0.062 mmol) was added trifluoroacetic acid (95 μL, 1.24 mmol). The reaction mixture was stirred at 80° C. for 2 h under microwave irradiation. The reaction mixture was diluted with DCM (20 mL). Water (50 mL) and 25% by weight aqueous ammonium hydroxide solution (3 mL) were added. After separation, the aqueous layer was extracted with DCM (×3 10 mL). The combined organic layers were washed with saturated aqueous sodium carbonate solution (30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to give a beige solid. DCM was added to the solid. The precipitate was filtered, and the filtrate was purified by preparative TLC using cyclohexane / ethyl acetate; 50 / 50 as eluent. The resulting product was purified once again by preparative TLC using cyclohexane / ethyl acetate; 50 / 50 as eluent to give 4-bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 9 as a beige solid. LCMS method F: [M+H] + =403, retention time=2.40 minutes LCMS method G: [M+H] + =403, retention time=2.38 minutes 1 H NMR (400 MHz, d6-DMSO) δ 13.07 (1H, s), 8.02 (1H, s), 7.87 (1H, s), 7.74 (1H, s), 7.51 (2H, q, J=2.8 Hz), 7.32 (1H, d, J=2.7 Hz), 7.00 (1H, dd, J=2.3, 8.9 Hz), 5.29 (2H, m), 4.32 (2H, m), 3.18 (2H, m, J=8.1 Hz), 2.03 (2H, m) ppm.

[0284] Example 10 : 5-Fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 10 is prepared according to the synthetic route described in general Scheme E.

[0285] Preparation of intermediate 35 : 2-Fluoro-5-[5-hydroxy-1-(oxan-2-yl)-1H-indazol-3-yl]benzoic acid [ka] To a solution of 3-iodo-1-(oxan-2-yl)-1H-indazol-5-ol 4 (1 g, 2.90 mmol), 2-fluoro-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.925 g, 2.52 mmol) in dioxane / water (70 / 30) (12 mL) was added potassium phosphate tribasic (1.84 g, 8.7 mmol). The mixture was degassed by bubbling nitrogen through for 15 minutes. Xphos (0.138 g, 0.29 mmol) and palladium-tetrakis(triphenylphosphine) (0.167 g, 0.145 mmol) were added. The mixture was heated at 120 °C under microwave irradiation for 2 hours (BIOTAGE). The reaction mixture was filtered through a Celite pad and eluted with ethyl acetate. The solution was washed with water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to give a brown oil. Purification on a Biotage silica column using cyclohexane / ethyl acetate 100 / 0 to 20 / 80 as eluent gave 2-fluoro-5-[5-hydroxy-1-(oxan-2-yl)-1H-indazol-3-yl]benzoic acid 35 as a white powder. LCMS method F: [M+H] + =357.1, retention time=2.34 minutes

[0286] Preparation of intermediate 36 : 3-[4-fluoro-3-(hydroxymethyl)phenyl]-1-(oxan-2-yl)-1H-indazol-5-ol [ka] To a solution of 2-fluoro-5-[5-hydroxy-1-(oxan-2-yl)-1H-indazol-3-yl]benzoic acid 35 (0.2 g, 0.56 mmol) in THF (25 mL) was added solid sodium borohydride (0.062 g, 1.68 mmol) at room temperature. After gas evolution had ceased (i.e., 5 min), the reaction mixture was cooled to 0 °C, and neat boron trifluoride dimethyl etherate (0.163 mL, 1.68 mmol) was added dropwise over 1 h. The reaction mixture was allowed to warm to room temperature and stirred at 65 °C for 2 h. The reaction mixture was cooled to 0 °C, and 1 M aqueous sodium hydroxide solution (50 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction mixture was filtered through Celite and eluted with ethyl acetate. The solution was washed with water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to give a brown oil. Purification on a silica column (Biotage) using cyclohexane / ethyl acetate 100 / 00 to 50 / 50 as eluent gave 3-[4-fluoro-3-(hydroxymethyl)phenyl]-1-(oxan-2-yl)-1H-indazol-5-ol 36 as a white powder. LCMS method F: [M+H] + =343.1, retention time=2.27 minutes

[0287] Preparation of intermediate 37 : Benzyl N-[3-({3-[4-fluoro-3-(hydroxymethyl)phenyl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamate [ka] To a solution of 3-[4-fluoro-3-(hydroxymethyl)phenyl]-1-(oxan-2-yl)-1H-indazol-5-ol 36 (0.18 g, 0.52 mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (0.338 g, 1.04 mmol) and tert-butyl 3-[(methanesulfonyloxy)methyl]pyrrolidine-1-carboxylate 20 (0.169 g, 0.624 mmol). The reaction was stirred at 80 °C for 16 h. The mixture was concentrated under reduced pressure. Water (50 mL) was added, and the resulting mixture was extracted with EtOAc (4 × 100 mL). The combined organic layers were washed with saturated brine (2 × 50 mL). The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure to give a brown / orange oil. The residue was purified by flash chromatography on silica gel (Macherey Nagel, 12 g) with gradient elution: cyclohexane / EtOAc 0–70% to give benzyl N-[3-({3-[4-fluoro-3-(hydroxymethyl)phenyl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamate 37 as a white solid. LCMS method F: [M+H] + =534.2, retention time=2.90 minutes

[0288] Preparation of intermediate 38 : 5-Fluoro-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] A solution of benzyl N-[3-({3-[4-fluoro-3-(hydroxymethyl)phenyl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamate 37 (0.153 g; 0.28 mmol) in toluene (50 mL) was added to a solution of sodium hydride (60% suspension in paraffin oil) (114 mg, 24 mmol) in toluene (50 mL) at room temperature. The reaction mixture was stirred at room temperature for 5 minutes and then at 130° C. for 1 hour. The reaction was allowed to cool, then EtOH (10 mL) was carefully added. Water (100 mL) was added. After separation, the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to give an orange oil. Purification by column chromatography (DCM / MeOH 0–10%) afforded pure 5-fluoro-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 38 as an off-white solid. LCMS method F: [M+H] + =426.2, retention time=2.78 minutes

[0289] Preparation of Example 10 : 5-Fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] 5-Fluoro-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21To a solution of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 38 (35 mg, 0.082 mmol) was added trifluoroacetic acid (63 μL, 0.82 mmol). The reaction mixture was stirred at room temperature for 6 h and at 30 °C overnight. Further trifluoroacetic acid (32 μL, 0.41 mmol) was added, and the reaction mixture was stirred at 50 °C for 5 h. Again, further trifluoroacetic acid (32 μL, 0.41 mmol) was added, and the reaction mixture was stirred at 50 °C for an additional 2 h. The reaction mixture was evaporated to dryness and coevaporated with toluene. DCM (40 mL), water (125 mL), and 25 wt% aqueous ammonium hydroxide solution (3 mL) were added. After separation, the aqueous layer was extracted with DCM (3 × 20 mL). The combined organic layers were washed with saturated sodium carbonate solution (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give a beige solid.

[0290] Trituration of the residue once with acetonitrile, five times with DCM and twice with EtOH gave 5-fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 10 was obtained as a white powder. LCMS method F: [M+H] + =342.1, retention time=2.18 minutes LCMS method G: [M+H] + =342.1, retention time=2.36 minutes 1 H NMR (400 MHz, d6-DMSO) δ 12.95 (1H, s), 7.93 (2H, m), 7.81 (1H, s), 7.89 (1H, d, J=9.0 Hz), 7.33 (2H, m), 6.99 (1H, dd, J=9.1 Hz), 5.35 (2H, s), 4.33 (2H, m), 3.19 (2H, m), 2.03 (2H, m) ppm.

[0291] Example 11: 5-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 11 is prepared according to the synthetic route described in general Scheme F.

[0292] Preparation of intermediate 39 : Methyl 5-[5-[3-(benzyloxycarbonylamino)propoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-methyl-benzoate [ka] A solution of benzyl N-[3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]carbamate 26 (1.2 g, 2.2 mmol assumed), (3-methoxycarbonyl-4-methyl-phenyl)boronic acid (467 mg, 2.42 mmol), tribasic potassium phosphate (1.4 g, 6.6 mmol), and triethylamine (1.4 mL, 9.9 mmol) in THF / HO (6.5 / 3.2 mL) was degassed for 15 min. Pd(dppf)Cl.DCM (179 mg, 0.22 mmol) was added, and the reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 17 h. The reaction mixture was filtered through Celite and washed with EtOAc. The filtrate was diluted with water (100 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by column (Macherey Nagel, 40 g) chromatography using cyclohexane / EtOAc (100 / 0 to 80 / 20) as eluent. The desired fractions were collected, and the solvent was removed under reduced pressure to give methyl 5-[5-[3-(benzyloxycarbonylamino)propoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-methyl-benzoate 39 (1.04 g, 1.87 mmol) as a white solid. LCMS method F: [M+H] + =558, retention time=3.33 minutes

[0293] Preparation of intermediate 40 : Benzyl N-[3-[3-[3-(hydroxymethyl)-4-methyl-phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate [ka] To a solution of methyl 5-[5-[3-(benzyloxycarbonylamino)propoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-methyl-benzoate 39 (1 g, 1.8 mmol) in THF (6 mL) was added 1 M LAH in THF (2.2 mL, 2.2 mmol) at 0 °C under N. The reaction was stirred at 0 °C for 2 h 30 min. The mixture was quenched with water (1 mL), NaOH 10% (0.2 mL), and water (0.5 mL). The mixture was filtered and washed with EtOAc. The filtrate was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by silica pad using cyclohexane / EtOAc (60 / 40) as eluent to give benzyl N-[3-[3-[3-(hydroxymethyl)-4-methyl-phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate 40 as a white oil. LCMS method F: [M+H] + =530, retention time=2.90 minutes

[0294] Preparation of intermediate 41 : 5-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] To a solution of benzyl N-[3-[3-[3-(hydroxymethyl)-4-methyl-phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate 40 (120 mg, 0.23 mmol) in acetonitrile (40 mL) was added potassium carbonate (190 mg, 1.38 mmol). The mixture was divided into two vials and then heated in a microwave at 140° C. for 4 h 30 min. The two vials were again heated in a microwave at 140° C. for 4 h. The mixture was filtered to remove potassium carbonate, and the solvent was evaporated under reduced pressure to give 5-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 41 as a white powder. The crude product was used in the next step without further purification. LCMS method F: [M+H] + =422, retention time=2.87 minutes

[0295] Preparation of Example 11 : 5-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] 5-Methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21To a solution of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 41 (84 mg, 0.2 mmol) was added trifluoroacetic acid (306 μL, 4 mmol). The mixture was heated in a microwave at 80 °C for 1 h. The solvent was removed under reduced pressure to give an oily residue, which was dissolved in DCM (20 mL). A precipitate formed and was filtered. The solid was dissolved in DCM / MeOH (15 mL), and then saturated NaHCO3 was added (15 mL). After separation, the aqueous layer was extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give 5-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 11 as a white solid. LCMS method F: [M+H] + =338, retention time=2.32 minutes LCMS method G: [M+H] + =338, retention time=2.35 minutes 1 H NMR (400 MHz, d6-DMSO) δ 12.86 - 12.79 (1H, m), 7.84 (1H, m), 7.82 (1H, m), 7.74 (1H, s), 7.46 (1 H, d, J=8.9 Hz), 7.42 (1H, m), 7.28 (1H, dd, J=0.6, 8.3 Hz), 6.98 (1H, dd, J=2.4, 9.0 Hz), 5.28 (2H, s), 4.34 (2H, dd, J=8.2, 8.5 Hz), 3.2 (2H, m), 2.32 (3H, s), 2.04 - 1.99 (2H, m) ppm.

[0296] Example 12 : 4-(pyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 12 is prepared according to the synthetic route described in general Scheme C. Pyrrolidine is used in a Buchwald reaction with bromide intermediate 34.

[0297] Preparation of intermediate 42 : 19-(oxan-2-yl)-4-(pyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] To a degassed solution of 4-bromo-10-methyl-19-(oxan-2-yl)-7-oxa-10,13,19,20-tetraazatetracyclo[13.5.2.12,6.018,21]tricosa-1(20),2,4,6(23),15(22),16,18(21)-heptaen-14-one Example 9 (100 mg, 0.206 mmol), pyrrolidine (19 μL, 0.227 mmol), tBuONa (40 mg, 0.412 mmol) and SPhos (3 mg, 0.008 mmol) in dioxane (2.5 mL) was added Pd2dba 3(To the reaction mixture, 19-(oxan-2-yl)-4-(pyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1] was added at room temperature. The reaction mixture was stirred at 60°C under microwave irradiation for 45 minutes. Additional pyrrolidine (2 μL; 0.021 mmol) was added, and the reaction was stirred at 60°C under microwave irradiation for 20 minutes. After cooling to room temperature, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column (5 g SiO2) chromatography (cyclohexane / ethyl acetate, 1:0 to 50 / 50) to give 19-(oxan-2-yl)-4-(pyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1]. 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 42 as a white powder. LCMS method F: [M+H] + =477.2, retention time=3.00 minutes

[0298] Preparation of Example 12 : 4-(pyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] 19-(oxan-2-yl)-4-(pyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21To a mixture of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 42 (60 mg; 0.126 mmol) was added TFA (48 μL; 0.630 mmol). The reaction mixture was stirred at 80 °C for 30 min under microwave irradiation. The solvent was removed under reduced pressure, the mixture was dissolved in EtOAc, and washed with 1N NaOH (pH = 7) and then with water. The organic layer was concentrated under reduced pressure, and the product was purified by chromatography on a 4 g SiO column eluted with DCM / MeOH 100 / 0 to 90 / 10. The desired fractions were combined to give 4-(pyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1]. 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 12 was obtained as a yellow powder. LCMS method F: [M+H] + =393.1, holding time=2.39 minutes (current 20V) LCMS method G: [M+H] + =393.1, retention time=2.47 minutes (pH10 current 20V) 1 H NMR (400 MHz, d6-DMSO) δ 7.61 (1H, m), 7.47 - 7.44 (1H, m), 7.36 (1H, d, J=2.7 Hz), 7.20 (1H, s), 7.04 (1H, t, J=1.9 Hz), 6.95 (1H, dd, J=2.4, 9.0 Hz), 6.50 (1H, s), 5.22 - 5.20 (2H, m), 4.30 (2H, d, J=16.9 Hz),3.32 (4H, m), 3.17 - 3.15 (2H, m), 2.03 - 1.99 (6H, m), 1.07 (1H, d, J=6.1 Hz) ppm.

[0299] Example 13 : 4-[4-(propan-2-yl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 13 is prepared following the synthetic route described in General Scheme C and procedures similar to those used to obtain Example 12. 1-(propan-2-yl)piperazine is used in a Buchwald reaction with bromide intermediate 34 to give 4-[4-(propan-2-yl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 13 was given. LCMS method F: [M+H] + =450.2, retention time=1.54 minutes LCMS method G: [M+H] + =450.2, retention time=2.26 minutes 1 H NMR (400 MHz, d6-DMSO, 80℃) δ 12.80 (1H, s), 7.68 - 7.57 (1H, m), 7.46 (1H, d, J=9.3 Hz), 7.37 - 7.34 (3H, m), 6.96 (1H, dd, J=2.4, 8.8 Hz), 6.87 (1H, s), 5.23 (2H, s), 4.28 (2H, s), 3.25 - 3.22 (4H, m), 3.17 (2H, s), 2.76 - 2.67 (1H, m), 2.66 - 2.61 (4H, m), 2.02 (2H, s), 1.05 (6H, d, J=6.5 Hz) ppm.

[0300] Example 14 : 4-{2-oxa-6-azaspiro[3.4]octan-6-yl}-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 14 is prepared according to the synthetic route described in General Scheme C and procedures similar to those used to obtain Example 12. 2-Oxa-6-azaspiro[3.4]octan-6-yl}-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1] is used in a Buchwald reaction with bromide intermediate 34 to give 4-{2-oxa-6-azaspiro[3.4]octan-6-yl}-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1]. 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 14 was given. LCMS method F: [M+H] + =435, retention time=2.16 minutes LCMS method G: [M+H] + =435, retention time=2.20 minutes 1 H NMR (400 MHz, d6-DMSO, 80℃) δ 12.77 (1H, s), 7.61 (1H, m), 7.46 (1H, d, J=9.2 Hz), 7.36 (1H, m), 7.22 (1H, m), 7.04 (1H, m), 6.96 (1H, m), 6.51 (1H, m), 5.22 (2H, m), 4.64 - 4.56 (4H, m), 4.30 (2H, m), 3.60 (2H, s), 3.35 (2H, t), 3.16 (2H, m), 2.31 (2H, m), 2.02 (2H, m) ppm.

[0301] Example 15 : 4-[4-(oxetan-3-yl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 15 is prepared following the synthetic route described in General Scheme C and procedures similar to those used to obtain Example 12. 1-(oxetan-3-yl)piperazine is used in a Buchwald reaction with bromide intermediate 34 to give 4-[4-(oxetan-3-yl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 15 was given. LCMS method F: [M+H] + =464.2, retention time=1.47 minutes LCMS method G: [M+H] + =464.2, retention time=2.00 minutes 1 H NMR (400 MHz, d6-DMSO, 80℃) δ 12.81 (1H, s), 7.64 (1H, s), 7.48 - 7.45 (1H, d, J=9.0 Hz), 7.39 - 7.34 (3H, m), 6.96 (1H, dd, J=2.2, 8.8 Hz), 6.89 (1H, m), 5.23 (2H, s), 4.62 - 4.57 (2H, t, J=6.5 Hz), 4.55 - 4.51 (2H, m), 4.33 - 4.27 (2H, t, J=8.6 Hz), 3.58 - 3.51 (1H, q, J=6.2 Hz), 3.30 - 3.26 (4H, m), 3.17 - 3.11 (2H, m), 2.10 - 1.99 (2H, m) ppm. Four protons are located under the DMSO peak and are not reported here.

[0302] Example 16 : 4-(morpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 16 is prepared according to the synthetic route described in General Scheme C and procedures similar to those used to obtain Example 12. Morpholine is used in a Buchwald reaction with bromide intermediate 34 to give 4-(morpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 16 was given. LCMS method F: [M+H] + =409.2, retention time=2.13 minutes LCMS method G: [M+H] + =409.2, retention time=2.15 minutes 1 H NMR (400 MHz, d6-DMSO, 80℃) δ 12.82 (1H, s), 7.63 (1H, m), 7.48 - 7.45 (1H, d, J=9.0 Hz ), 7.40 (2H, m), 7.34 (1H, m), 6.97 (1H, dd, J=2.3, 8.9 Hz), 6.89 (1H, s), 5.23 (2H, s), 4.33 - 4.28 (2H, t, J=8.32), 3.82 - 3.76 (4H, t, J=4.8 Hz), 3.23 - 3.20 (4H, t, J=4.9 Hz), 3.17 (2H, s), 2.02 (2H, s) ppm.

[0303] Example 17 : 4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 17 is prepared according to the synthetic route described in General Scheme C and procedures similar to those used to obtain Example 12. 4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1] is prepared using cis-2,6-dimethylmorpholine in a Buchwald reaction with bromide intermediate 34 to give 4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1]. 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 17 was given. LCMS method F: [M+H] + =437.1, retention time=2.30 minutes LCMS method G: [M+H] + =437.2, retention time=2.36 minutes 1 H NMR (400 MHz, d6-DMSO, 80℃) δ 12.81 (1H, s), 7.63 (1H, s), 7.48 - 7.45 (1H, m), 7.39 - 7.34 (3H, m), 6.98 - 6.90 (2H, m), 5.23 (2H, s), 4.30 (2H, m), 3.80 - 3.73 (2H, m), 3.64 (2H, dd, J=1.5, 12.1 Hz), 3.17 (2H, s), 2.41 - 2.35 (2H, m), 2.06 - 2.05 (2H, m), 1.21 (6H, d, J=6.3 Hz) ppm.

[0304] Example 18 : 4-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 18 is prepared following the synthetic route described in General Scheme F and procedures similar to those used to obtain Example 11. Suzuki coupling with intermediate 26 using (3-methoxycarbonyl-5-methyl-phenyl)boronic acid affords 4-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 18 was given. LCMS method F: [M+H] + =338, retention time=2.25 minutes LCMS method G: [M+H] + =338, retention time=2.30 minutes 1 H NMR (400 MHz, d6-DMSO) δ 7.73–7.65 (3H, m), 7.49–7.45 (1H, m), 7.34 (1H, d, J=2.1 Hz), 7.10–7.07 (1H, m), 6.97 (1H, dd, J=2.2, 9.0 Hz), 5.26–5.25 (2H, m), 4.34–4.28 (2H, m), 3.17 (2H, m), 2.41 (3H, s), 2.04–2.01 (2H, m) ppm. The indazole NH protons were not visible in this solvent.

[0305] Example 19 : 5-Methoxy-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 19 is prepared according to the synthetic route described in General Scheme F and procedures similar to those used to obtain Example 11. Suzuki coupling with intermediate 26 uses (4-methoxy-3-methoxycarbonyl-phenyl)boronic acid to give 5-methoxy-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 19 was given. LCMS method F: [M+H] + =354, retention time=2.19 minutes LCMS method G: [M+H] + =354, retention time=2.17 minutes 1 H NMR (400 MHz, d6-DMSO) δ 12.75 (1H, s), 7.91 (1H, dd, J=2.2, 8.6 Hz), 7.83 (1H, m), 7.72 (1H, m), 7.45 (1H, d, J=8.9 Hz), 7.37 (1H, d, J=2.2 Hz), 7.15 (1H, d, J=8.5 Hz), 6.97 (1H, dd, J=2.4, 9.0 Hz), 5.26 (2H, s), 4.33 (2H, m), 3.90 (3H, s), 3.18 (2H, m), 2.02 (2H, m) ppm.

[0306] Example 20 : 4-(4,4-difluoropiperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 20 is prepared according to the synthetic route described in General Scheme C and procedures similar to those used to obtain Example 12. 4,4-Difluoropiperidine is used in a Buchwald reaction with bromide intermediate 34 to give 4-(4,4-difluoropiperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 20 was given. LCMS method F: [M+H] + =443.1, retention time=2.46 minutes LCMS method G: [M+H] + =443.1, retention time=2.49 minutes 1 H NMR (400 MHz, d6-DMSO, 80℃) δ 12.83 (1H, s), 7.64 (1H, s), 7.49 - 7.43 (2H, m), 7.39 (1H, s), 7.36 - 7.33 (1H, m), 5.24 (2H, s), 4.36 - 4.27 (2H, m), 3.46 - 3.42 (4H, m), 3.17 (4H, s), 2.17 - 1.98 (6H, m) ppm.

[0307] Example 21 : 4-(3,3-difluoropyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 21 is prepared following the synthetic route described in General Scheme C and procedures similar to those used to obtain Example 12. 3,3-Difluoropyrrolidine is used in a Buchwald reaction with bromide intermediate 34 to give 4-(3,3-difluoropyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 21 was given. LCMS method F: [M+H] + =429.1, retention time=2.46 minutes LCMS method G: [M+H] + =429.1, retention time=2.48 minutes 1 H NMR (400 MHz, d6-DMSO, 80℃) δ 12.82 (1H, s), 7.63 (1H, s,), 7.47 (1H, d, J=8.9 Hz), 7.36 - 7.31 (2H, m), 7.10 - 7.08 (1H, m), 6.96 (1H, dd, J=2.4, 9.0 Hz), 6.59 - 6.58 (1H, m), 5.23 (2H, s), 4.33 - 4.27 (2H, m), 3.37 (2H, t, J=13.7 Hz), 3.58 (2H, t, J=7.2 Hz), 3.16 (2H, s), 2.63 - 2.53 (2H, m) 2.02 (2H, m) ppm.

[0308] Example 22 : 7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 22 is prepared according to the synthetic route described in General Scheme C and procedures similar to those used to obtain Example 8. Suzuki coupling is carried out using (3-(1-hydroxyethyl)phenyl)boronic acid to afford 7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 22 was given. LCMS method F: [M+H] + =338, retention time=2.22 minutes LCMS method G: [M+H] + =338, retention time=2.25 minutes 1 H NMR (400 MHz, d6-DMSO) δ 13.12 (1H, s), 7.95 - 7.92 (1H, m), 7.86 - 7.83 (2H, m), 7.50 - 7.46 (2H, m), 7.35 (1H, m), 7.31 - 7.29 (1H, m), 7.00 - 6.97 (1H, m), 5.95 - 5.90 (1H, m), 4.37 - 4.25 (2H, m), 3.56 - 3.49 (1H, m), 2.77 - 2.68 (1H, m), 2.24 - 2.15 (1H, m), 1.77 - 1.69 (1H, m), 1.59 (3H, d, J=6.7 Hz) ppm.

[0309] Example 23 : 4-[4-(2-methoxyethyl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 23 is prepared according to the synthetic route described in General Scheme C and procedures similar to those used to obtain Example 12. 4-(2-Methoxyethyl)piperidine is used in a Buchwald reaction with bromide intermediate 34 to give 4-[4-(2-methoxyethyl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 23 was given. LCMS method F: [M+H] + =465.2, retention time=1.81 minutes LCMS method G: [M+H] + =465.2, retention time=2.53 minutes 1 H NMR (400 MHz, d6-DMSO, 80℃) δ 12.79 (1H, br. s), 7.63 - 7.59 (1H, m), 7.46 (1H, d, J=9.2 Hz), 7.37 (1H, d, J=2.0 Hz), 7.34 (1H, d, J=2.0 Hz), 7.32 (1H, s), 6.96 (1H, dd, J=2.3, 8.9 Hz), 6.86 (1H, s), 5.22 - 5.19 (2H, m), 4.33 - 4.28 (2H, m), 3.77 - 3.73 (2H, m), 3.43 (2H, t, J=8.0 Hz), 3.21 - 3.16 (2H, m), 3.09 - 3.06 (3H, br. s), 2.78 (2H, dt, J=4.0, 11.2 Hz), 2.05 - 2.01 (2H, m), 1.82 - 1.77 (2H, m), 1.58 - 1.49 (3H, m), 1.38 - 1.27 (2H, m) ppm.

[0310] Example 24 : 9,14-dioxa-11,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-10-one [ka] Example 24 is prepared according to the synthetic route described in General Scheme C and procedures similar to those used to obtain Example 8. 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethan-1-ol is used in a Suzuki coupling to afford 9,14-dioxa-11,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-10-one gave Example 24. LCMS method F: [M+H] + =324.1, retention time=2.14 minutes LCMS method G: [M+H] + =324.1, retention time=2.19 minutes 1 H NMR (400 MHz, d6-DMSO) δ 13.05 - 13.03 (1H, m), 7.99 (1H, t, J=5.9 Hz), 7.82 (1H, s), 7.68 (1H, d, J=7.6 Hz), 7.58 (1H, d, J=1.9 Hz), 7.46 - 7.41 (2H, m), 7.28 - 7.25 (1H, m), 7.04 (1H, dd, J=2.2, 9.0 Hz), 4.33 - 4.21 (4H, m), 3.40 - 3.3 (2H, m), 3.01 (2H, t, J=5.0 Hz) ppm.

[0311] Example 25 : 4-[(3R)-3-hydroxypyrrolidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 25 is prepared according to the synthetic route described in General Scheme C and procedures similar to those used to obtain Example 12. (3R)-Pyrrolidin-3-ol is used in a Buchwald reaction with bromide intermediate 34 to give 4-[(3R)-3-hydroxypyrrolidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 25 was given. LCMS method F: [M+H] + =409.1, retention time=1.96 minutes LCMS method G: [M+H] + =409.2, retention time=2.04 minutes 1 H NMR (400 MHz, d6-DMSO) δ 7.65- 7.56 (1H, m), 7.48 - 7.45 (1H, m), 7.36 (1H, d, J=2.5 Hz), 7.19 (1H, s), 7.01 (1H, s), 6.93 (1H, dd, J=2.3, 9.1 Hz), 6.46 (1H, s), 5.22 (2H, s), 4.48 - 4.43 (1H, m), 4.32 - 4.27 (2H, m), 3.53 - 3.32 (3H, m), 3.18- 3.13 (2H, m), 3.11- 2.99 (2H, m), 2.15 - 2.07 (1H, m), 2.07 -1.97 (2H, m), 1.97 - 1.92 (1H, m) ppm. The indazole NH protons were not visible in this solvent.

[0312] Example 26 : 4-[(2-methoxyethyl)(methyl)amino]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 26 is prepared according to the synthetic route described in General Scheme C and procedures similar to those used to obtain Example 12. 2-Methoxy-N-methyl-ethanamine is used in a Buchwald reaction with bromide intermediate 34 to give 4-[(2-methoxyethyl)(methyl)amino]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 26 was given. LCMS method F: [M+H] + =411.2, retention time=2.07 minutes LCMS method G: [M+H] + =411.2, retention time=2.32 minutes 1 H NMR (400 MHz, d6-DMSO) δ 12.74 (1H, s), 7.48 - 7.45 (1H, m), 7.36 (1H, d, J=2.3 Hz), 7.23 - 7.19 (2H, m), 6.96 (1H, dd, J=2.4, 9.0 Hz), 6.67 (1H, dd, J=1.3, 2.5 Hz), 5.22 (1H, t, J=9.7 Hz), 4.30 (2H, d, J=16.7 Hz), 3.31 - 3.31 (3H, m), 3.11 - 3.04 (8H, s), 3.01 (3H, s), 2.01 - 2.02 (2H, m) ppm.

[0313] Example 27 : 4-chloro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 27 is prepared following the synthetic route described in General Scheme F and procedures similar to those used to obtain Example 11. Suzuki coupling with intermediate 26 uses (3-chloro-5-methoxycarbonyl-phenyl)boronic acid to give 4-chloro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 27 was given. LCMS method F: [M+H] + =358.0, retention time=2.38 minutes LCMS method G: [M+H] + =358.1, retention time=2.52 minutes 1 H NMR (400 MHz, d6-DMSO, 80℃) δ 13.08 (1H, s), 7.85 (2H, d, J=15.0 Hz), 7.77 - 7.75 (1H, m), 7.50 (1H, d, J=8.0 Hz), 7.36 (1H, s), 7.32 (1H, d, J=2.4 Hz), 7.00 (1H, dd, J=2.3, 8.9 Hz), 5.29 - 5.25 (2H, m), 4.35 - 4.30 (2H, m), 3.23 - 3.12 (2H, m), 2.06 - 2.00 (2H, m) ppm.

[0314] Example 28 : 4-Fluoro-5-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 28 is prepared according to the synthetic route described in general Scheme G.

[0315] Preparation of intermediate 43 : Methyl 5-[5-(3-{[(benzyloxy)carbonyl]amino}propoxy)-1-(oxan-2-yl)-1H-indazol-3-yl]-3-fluoro-2-methylbenzoate [ka] To a solution of benzyl N-(3-{[1-(oxan-2-yl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl]oxy}propyl)carbamate 31 (0.6 g, 1.12 mmol) in N,N-dimethylformamide (15 mL) was added (methyl 5-Bromo-3-fluoro-2-methylbenzoate (0.332 g, 1.35 mmol), Cs2CO3 (1.096 g, 3.36 mmol), and PdCl2(dppf)·DCM (0.041 g, 0.06 mmol) were added at room temperature. The resulting mixture was degassed by bubbling nitrogen through for 10 minutes and stirred at 110 °C for 50 minutes under microwave irradiation. The solvent was removed under reduced pressure, and the oil was dissolved in EtOAc and water. The two layers were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (25 g silica BIOTAGE) chromatography (cyclohexane-ethyl acetate, 100 / 0 to 50 / 50) to give methyl ... 5-[5-(3-{[(benzyloxy)carbonyl]amino}propoxy)-1-(oxan-2-yl)-1H-indazol-3-yl]-3-fluoro-2-methylbenzoate 43 was obtained as a yellow powder. LCMS method F: [M+H] + =576.2, retention time=3.48 minutes

[0316] Preparation of intermediate 44 : Benzyl N-[3-({3-[3-fluoro-5-(hydroxymethyl)-4-methylphenyl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamate [ka] To methyl 5-[5-(3-{[(benzyloxy)carbonyl]amino}propoxy)-1-(oxan-2-yl)-1H-indazol-3-yl]-3-fluoro-2-methylbenzoate 43 (0.225 g, 0.39 mmol) in THF (50 mL) was added 1 M lithium aluminum tetrahydride solution (0.78 mL, 0.78 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. To the reaction mixture was added EtOAc (10 mL) at 0 °C and poured into a 10% solution of Rochelle's salt (100 mL) and EtOAc (100 mL). The mixture was stirred at room temperature for 2 h. After separation, the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to give a brown / orange oil. The residue was purified by flash chromatography on silica gel (Macherey Nagel, 25 g) with gradient elution: cyclohexane / EtOAc 0–100% to give benzyl N-[3-({3-[3-fluoro-5-(hydroxymethyl)-4-methylphenyl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamate 44 as a yellow oil. LCMS method F: [M+H] + =548.2, retention time=3.10 minutes

[0317] Preparation of intermediate 45 : 4-Fluoro-5-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] To a solution of benzyl-N-[3-({3-[3-fluoro-5-(hydroxymethyl)-4-methylphenyl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamate 44 (0.125 g, 0.23 mmol) in anhydrous acetonitrile (33 mL) was added cesium carbonate (0.447 g, 1.37 mmol) at room temperature. The resulting reaction mixture was stirred at 90 °C for 1 h 30 min. The reaction mixture was filtered, the solvent removed under reduced pressure, and the residue purified by flash column (15 g silica Macherey Nagel) chromatography (DCM-ethyl acetate, 1:0 to 8:2) to give 4-fluoro-5-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1]. 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 45 as a white foam. LCMS method F: [M+H] + =440.2, retention time=3.03 minutes

[0318] Preparation of Example 28 : 4-Fluoro-5-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] 4-Fluoro-5-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21To a solution of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 45 (0.066 g, 0.15 mmol) was added TFA (0.143 mL, 1.92 mmol) at room temperature. The resulting reaction mixture was stirred at 80 °C for 1 h 30 min under microwave irradiation. The reaction mixture was concentrated under reduced pressure, diluted with saturated sodium bicarbonate solution, and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by flash column (5 g silica Macherey Nagel) chromatography (DCM-ethyl acetate, 1:0 to 4:6) to give a solid, which was triturated with acetonitrile, filtered, and purified to give 4-fluoro-5-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 28 as a white solid. LCMS method F: [M+H] + =356.2, retention time=2.36 minutes LCMS method G: [M+H] + =356.2, retention time=2.39 minutes 1 H NMR (400 MHz, d6-DMSO) δ 7.80 (1H, s), 7.67 (1H, s), 7.63 (1H, d, J=11.2 Hz), 7.48 (1H, dd, J=0.6, 9.1 Hz), 7.40 (1H, d, J=2.4 Hz), 6.96 (1H, dd, J=2.3, 8.9 Hz), 5.29 (2H, s), 4.35 (2H, t, J=8.1 Hz), 3.24 - 3.17 (2H, m), 2.22 (3H, d, J=1.7 Hz), 2.06 - 2.05 (2H, m) ppm. The indazole NH protons were not visible in this solvent.

[0319] Example 29 : 4,5-Difluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6.0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 29 is prepared according to the synthetic route described in General Scheme F and procedures similar to those used to obtain Example 11. Suzuki coupling with intermediate 26 using methyl 2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate affords 4,5-difluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1]. 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one gave Example 29. LCMS method F: [M+H] + =360, retention time=2.47 minutes LCMS method G: [M+H] + =360, retention time=2.52 minutes 1 H NMR (400 MHz, d6-DMSO, 80℃) δ 13.06 (1H, s), 7.84 - 7.78 (2H, m), 7.71 - 7.69 (1H, m), 7.51 (1H, d, J=9.1 Hz), 7.31 (1H, d, J=2.1 Hz), 7.01 (1H, dd, J=2.4, 9.0 Hz), 5.38 (2H, m), 4.34 (2H, dd, J=8.1, 8.8 Hz), 3.18 (2H, m), 2.03 (2H, m) ppm.

[0320] Example 30 : 5-Bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka]

[0321] Example 30 is prepared following the synthetic route described in general Scheme C and procedures analogous to those used to obtain Example 8.

[0322] Preparation of intermediate 46 : [3-Bromo-5-(hydroxymethyl)phenyl]boronic acid [ka] A solution of borane tetrahydrofuran complex (1.0 M in THF, 8.2 mL, 8.2 mmol) was slowly added to a solution of 3-borono-6-bromobenzoic acid (500 mg, 2.05 mmol) in THF (30 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction was quenched by the addition of MeOH (25 mL) at 0 °C until gas evolution ceased. The solvent was evaporated, and the residue was partitioned between ethyl acetate (50 mL) and water (50 mL). After separation, the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium magnesium sulfate, filtered, and concentrated under reduced pressure to give [3-bromo-5-(hydroxymethyl)phenyl]boronic acid 46 as a white solid. LCMS Method F: m / z not detected, retention time = 1.58 min

[0323] Preparation of intermediate 47 : Benzyl N-[3-[3-[4-bromo-3-(hydroxymethyl)phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate [ka] To a solution of benzyl-N-[3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]carbamate 26 (692 mg, 1.29 mmol), [4-bromo-3-(hydroxymethyl)phenyl]boronic acid 46 (357 mg, 1.55 mmol), and 1 M Na2CO3 solution (3.9 mL, 3.87 mmol) in DME (13 mL) was added palladium-tetrakis(triphenylphosphine) (75 mg, 0.065 mmol, 5 mol%). The reaction mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted twice with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid. The crude product was purified by flash chromatography (CyH / EtOAc 0 to 100% EtOAc) using a 24 g Redisep to give benzyl N-[3-[3-[4-bromo-3-(hydroxymethyl)phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate 47 as a white solid. LCMS method F: [M+H] + =594, retention time=3.12 minutes

[0324] Preparation of intermediate 48 : 5-Bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] A suspension of benzyl N-[3-[3-[4-bromo-5-(hydroxymethyl)phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate 47 (590 mg, 0.99 mmol) and cesium carbonate (1.94 g, 5.96 mmol) in acetonitrile (200 mL) was heated to 90 °C for 2 h. The reaction mixture was cooled to room temperature, then filtered and concentrated under reduced pressure. The resulting solid was triturated with acetonitrile to give 5-bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1]. 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 48 as a white solid. LCMS method F: [M+H] + =486 / 488, retention time=3.25 minutes

[0325] Preparation of Example 30 : 5-Bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] 5-Bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21To a solution of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 48 (50 mg, 0.10 mmol) was added trifluoroacetic acid (157 μL, 2.05 mmol). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with DCM (20 mL). Water (20 mL) and 25 wt% aqueous ammonium hydroxide (3 mL) were added. A white precipitate was present in the organic layer and was not soluble in DCM. The solid was filtered and dried under reduced pressure to give 5-bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 30 as a white solid. LCMS method F: [M+H] + =403, retention time=2.58 minutes LCMS method G: [M+H] + =403, retention time=2.48 minutes 1 H NMR (400 MHz, d6-DMSO) δ 13.05 (1H, s), 7.91 - 7.87 (3H, m), 7.73 - 7.69 (1H, m), 7.52 - 7.49 (1H, m), 7.37 (1H, d, J=1.7 Hz), 7.01 (1H, dd, J=2.3, 8.9 Hz), 5.27 (2H, s), 4.37 - 4.33 (2H, m), 3.19 (2H, m), 2.02 - 1.99 (2H, m) ppm.

[0326] Example 31 : 4-(4-methylpiperazin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 31 is prepared according to the synthetic route described in General Scheme C and procedures similar to those used to obtain Example 12. 1-Methylpiperazine is used in a Buchwald reaction with bromide intermediate 34 to give 4-(4-methylpiperazin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 31 was given. LCMS method F: [M+H] + =422, retention time=1.44 minutes LCMS method G: [M+H] + =422, retention time=2.02 minutes 1 H NMR (400 MHz, d6-DMSO) δ 12.80 (1H, s), 7.62 (1H, m), 7.46 (1H, d, J=9.2 Hz), 7.38 (1H, m), 7.35 (2H, m), 6.98 - 6.95 (1H, m), 6.88 (1H, m), 5.23 (2H, m), 4.32 - 4.28 (2H, m), 3.25 (4H, m), 3.16 (2H, m), 2.53 (4H, m), 2.28 (3H, s), 2.04 (2H, m) ppm.

[0327] Example 32 : 4-(3-methoxyazetidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 32 is prepared according to the synthetic route described in General Scheme C and procedures similar to those used to obtain Example 12. 3-Methoxyazetidine hydrochloride is used in a Buchwald reaction with bromide intermediate 34 to give 4-(3-methoxyazetidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 32 was given. LCMS method F: [M+H] + =409.2, retention time=2.15 minutes LCMS method G: [M+H] + =409.1, retention time=2.13 minutes 1 H NMR (400 MHz, d6-DMSO, 80℃) δ 12.85 (1H, br s), 7.61 (1H, br s), 7.48 - 7.45 (1H, m), 7.36 - 7.34 (1H, m), 7.27 (1H, s), 6.95 (1H, dd, J=2.4, 9.2 Hz), 6.90 (1H, t, J=2.0 Hz), 6.37 (1H, dd, J=1.5, 2.1 Hz), 5.20 (2H, s), 4.40 - 4.27 (3H, m), 4.15 - 4.11 (2H, m), 3.69 (2H, dd, J=4.3, 8.6 Hz), 3.30 (3H, s), 3.22 - 3.12 (2H, m), 2.09 - 1.96 (2H, m) ppm.

[0328] Example 33 : 1-{9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-4-yl}piperidine-4-carbonitrile [ka] Example 33 is prepared according to the synthetic route described in General Scheme C and procedures similar to those used to obtain Example 12. Piperidine-4-carbonitrile is used in a Buchwald reaction with bromide intermediate 34 to give 1-{9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-4-yl}piperidine-4-carbonitrile to give Example 33. LCMS method F: [M+H] + =432, retention time=2.15 minutes LCMS method G: [M+H] + =432, retention time=2.21 minutes 1 H NMR (400 MHz, d6-DMSO) δ 12.82 (1H, s), 7.63 (1H, m), 7.48 - 7.46 (1H, m), 7.40 - 7.35 (3H, m), 7.98 - 7.95 (1H, m), 7.90 (1H, m), 5.23 (2H, m), 4.30 (2H, m), 3.50 - 3.44 (2H, m), 3.22 - 3.15 (4H, m), 2.08 - 2.00 (4H, m), 1.92 - 1.84 (2H, m), 1.07 (1H, d, J=5.9 Hz) ppm.

[0329] Example 34 : 4-[4-(pyrrolidin-1-yl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 34 is prepared according to the synthetic route described in General Scheme C and procedures similar to those used to obtain Example 12. 4-Pyrrolidin-1-ylpiperidine is used in a Buchwald reaction with bromide intermediate 34 to give 4-[4-(pyrrolidin-1-yl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one gave Example 34.

[0330] LCMS method F: [M+H] + =476, retention time=1.59 minutes LCMS method G: [M+H] + =476, retention time=1.51 minutes 1 H NMR (400 MHz, DMSO) δ 12.85 (1H, m), 7.47 (1H, d, J=8.7 Hz), 7.37 (3H, t, J=13.0 Hz), 6.98–6.92 (2H, m), 5.28 (2H, m), 4.30 (2H, s), 3.85 (2H, m), 3.42 (1H, q, J=7.0 Hz), 3.18 (3H, s), 2.88–2.82 (2H, m), 2.14 (2H, s), 2.04 (10H, m) ppm. Two protons are located under the DMSO peak and are not reported here.

[0331] Example 35 : 4-(azetidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 35 is prepared following the synthetic route described in General Scheme C and procedures similar to those used to obtain Example 12. Azetidine is used in a Buchwald reaction with bromide intermediate 34 to give 4-(azetidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one gave Example 35. LCMS method F: [M+H] + =379, retention time=2.08 minutes LCMS method G: [M+H] + =379, retention time=2.23 minutes 1 H NMR (400 MHz, d6-DMSO) δ 12.78 (1H, m), 7.59 (1H, m), 7.48 - 7.44 (1H, m), 7.35 (1H, s), 7.25 (1H, s), 6.98 - 6.94 (1H, m), 6.88 - 6.87 (1H, m), 6.34 (1H, s), 5.20 (2H, s), 4.32 - 4.27 (2H, m), 3.90 (3H, t, J=7.2 Hz), 3.15 (3H, m), 2.39 - 2.32 (2H, m), 2.06 (2H, s) ppm.

[0332] Example 36 : 4-(piperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 36 is prepared according to the synthetic route described in General Scheme A. A Buchwald reaction with bromide intermediate 34 using piperidine affords 4-(piperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one gave Example 36. LCMS method F: [M+H] + =407.2, retention time=1.65 minutes LCMS method G: [M+H] + =407.2, retention time=2.48 minutes 1 H NMR (400 MHz, d6-DMSO, 80℃) δ 12.79 (1H, s), 7.64 - 7.62 (1H, m), 7.48 - 7.44 (1H, d, J=8.4 Hz), 7.38 - 7.32 (3H, m), 6.96 (1H, dd, J=2.3, 9.1 Hz), 6.87 - 6.86 (1H, m), 5.22 (2H, s), 4.30 (2H, dd, J=7.6, 10.0 Hz), 3.27 - 3.21 (4H, m), 3.20 - 3.11 (2H, m), 2.06 - 1.97 (2H, m), 1.71 -1.64 (4H, m), 1.63 - 1.58 (2H, m) ppm.

[0333] Example 37 : 4-(2,5-dihydrofuran-3-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 37 is prepared according to the synthetic route described in General Scheme A. 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane is used in a Suzuki reaction with bromide intermediate 34 to give 4-(2,5-dihydrofuran-3-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1]. 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one gave Example 37. LCMS method F: [M+H] + =392.2, retention time=2.19 minutes LCMS method G: [M+H] + =392.2, retention time=2.19 minutes 1 H NMR (400 MHz, d6-DMSO, 80℃) δ 12.94 (1H, s), 7.85 (2H, d, J=6.3 Hz), 7.69 (1H, s), 7.50 (1H, d, J=9.6 Hz), 7.37 (1H, s), 7.33 (1H, d, J=2.0 Hz), 6.99 (1H, dd, J=2.3, 8.9 Hz), 6.55 - 6.52 (1H, m), 5.33 - 5.30 (2H, m), 5.00 - 4.96 (2H, m), 4.80 - 4.77 (2H, m), 4.35 - 4.29 (2H, m), 3.19 - 3.17 (2H, m), 1.99 (2H, s) ppm.

[0334] Example 38 : 4-[4-(morpholin-4-yl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 38 is prepared according to the synthetic route described in General Scheme C and procedures similar to those used to obtain Example 12. 4-(4-piperidyl)morpholine is used in a Buchwald reaction with bromide intermediate 34 to give 4-[4-(morpholin-4-yl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one gave Example 38. LCMS method F: [M+H] + =492.2, retention time=1.48 minutes LCMS method G: [M+H] + =492.2, retention time=2.07 minutes 1 H NMR (400 MHz, d6-DMSO) δ 12.79 (1H, s), 7.61 (1H, s), 7.47 (1H, d, J=5.8 Hz),7.39- 7.29 (3H, m), 6.97 (1H, dd, J=2.2, 9.1 Hz), 6.89 (1H, s), 5.22 (2H, s), 4.36 - 4.26 (2H, m), 3.87 - 3.75 (2H, m), 3.64 - 3.54 (4H, m), 3.23- 3.12 (2H, m), 2.88- 2.76 (2H, m), 2.57- 2.52 (4H, m), 2.41 - 2.29 (1H, m), 2.09 -1.88 (4H, m), 1.63 - 1.5 (2H, m) ppm.

[0335] Example 39 : 4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 39 is prepared according to the synthetic route described in General Scheme A. 4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1] is prepared using bromide intermediate 34 in a Suzuki reaction with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine to give 4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1]. 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one gave Example 39. LCMS method F: [M+H] + =419.2, retention time=1.49 minutes LCMS method G: [M+H] + =419.2, retention time=2.16 minutes 1 H NMR (400 MHz, d6-DMSO, 80℃) δ 12.95 (1H, s), 7.97 (1H, s), 7.87 (1H, s), 7.71 - 7.69 (1H, m), 7.50 (1H, d, J=8.0 Hz), 7.40 (1H, s), 7.34 (1H, d, J=1.5 Hz), 7.00 (1H, dd, J=2.3, 8.9 Hz), 6.28 - 6.25 (1H, m), 5.35 - 5.32 (2H, m), 4.32 (2H, dd, J=8.1, 9.0 Hz), 3.94 - 3.91 (2H, m), 3.55 - 3.41 (2H, m), 3.25 - 3.17 (2H, m), 2.92 (3H, s), 2.90 - 2.84 (2H, m), 2.10 - 1.99 (2H, m) ppm.

[0336] Example 40 : 4-[(2S,5S)-2,5-dimethylmorpholin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 40 is prepared according to the synthetic route described in General Scheme C and procedures similar to those used to obtain Example 12. A Buchwald reaction with bromide intermediate 34 employs (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride to give 4-[(2S,5S)-2,5-dimethylmorpholin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1]heptane hydrochloride. 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 40 was given. LCMS method F: [M+H] + =421.1, retention time=2.06 minutes LCMS method G: [M+H] + =421.2, retention time=2.06 minutes 1 H NMR (400 MHz, d6-DMSO) δ 12.78 (1H, s), 7.62 (1H, m), 7.46 (1H, d, J=9.1 Hz), 7.36 (1H, s), 7.23 (1H, s), 7.06 (1H, s), 6.97 - 6.95 (1H, m), 6.58 (1H, s), 5.21 (2H, m), 4.63 (2H, d, J=17.5 Hz), 4.32 - 4.28 (2H, m), 3.82 (1H, m), 3.76 (1H, m), 3.58 - 3.56 (1H, m), 3.16 (2H, m), 3.10 (1H, m), 2.03 (2H, m), 1.98 - 1.95 (1H, m), 1.90 - 1.88 (1H, m) ppm.

[0337] Example 41 : 4-[(morpholin-4-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 41 is prepared according to the synthetic route described in general Scheme C.

[0338] Preparation of intermediate 49 : 4-[(morpholin-4-yl)methyl]-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] To a solution of 4-bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20 triazatetracyclo[13.5.2.12,6.018,21]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one Example 12 (100 mg, 0.21 mmol) in THF / HO 9 / 1 (4 mL) in a sealed tube was added potassium 1-trifluoroboratomethylmorpholine (87 mg, 0.42 mmol) and cesium carbonate (205 mg, 0.63 mmol) at room temperature. The reaction mixture was degassed by bubbling nitrogen gas through the solution for 15 minutes, then palladium acetate (2 mg, 0.01 mmol) and Xphos (10 mg, 0.02 mmol) were added, and the reaction mixture was stirred at 100° C. for 18 hours. The reaction mixture was allowed to cool to room temperature, and the solvent was removed under reduced pressure. EtOAc (50 mL) was added to the residue, and the suspension was filtered through Celite. The filtrate was extracted with EtOAc (2×20 mL), washed with brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to give a yellow oil. The oil was triturated with acetonitrile and diethyl ether to give 4-[(morpholin-4-yl)methyl]-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 49 as a beige powder. LCMS method F: [M+H] + =507, retention time=1.74 minutes

[0339] Preparation of Example 41 : 4-[(morpholin-4-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] 4-[(morpholin-4-yl)methyl]-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 A solution of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 49 (60 mg, 0.13 mmol) was stirred at room temperature for 6 hours. The reaction mixture was evaporated under reduced pressure to give a brown oil. dDCM (20 mL) and saturated bicarbonate solution (10 mL) were added to the residue, and after separation, the organic layer was extracted with DCM (2 × 10 mL), washed with brine, dried over sodium sulfate, and evaporated under reduced pressure to give a yellow oil. Some acetonitrile and dimethyl ether were added to the oil, and the formed precipitate was filtered to give 4-[(morpholin-4-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 41 as a beige solid. LCMS method F: [M+H] + =423, retention time=1.42 minutes LCMS method G: [M+H] + =423, retention time=2.03 minutes 1 H NMR (400 MHz, DMSO) δ 12.89 (1H, s), 7.81 (2H, d, J=11.8 Hz), 7.66 (1H, s), 7.50 - 7.47 (1H, m), 7.35 (1H, d, J=1.9 Hz), 7.22 (1H, s), 6.98 (1H, dd, J=2.4, 9.0 Hz), 5.29 - 5.26 (2H, m), 4.34 - 4.28 (2H, m), 3.63 (4H, m), 3.56 (2H, s), 3.18 (2H, s), 2.46 (4H, m), 2.06 - 2.03 (2H, m) ppm.

[0340] Example 42 : 4-[(pyrrolidin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 42 is prepared according to the synthetic route described in General Scheme C and procedures similar to those used to obtain Example 41. Suzuki coupling with bromide intermediate 34 using potassium trifluoro[(pyrrolidin-1-yl)methyl]borate affords 4-[(pyrrolidin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one gave Example 42. LCMS method F: [M+H] + =407, retention time=1.44 minutes LCMS method G: [M+H] + =407, retention time=2.12 minutes 1 H NMR (400 MHz, d6-DMSO) δ 12.88 (1H, s), 7.84 (1H, s), 7.79 (1H, s), 7.66 (1H, m), 7.48 (1H, d, J=8.8 Hz), 7.35 (1H, d, J=1.7 Hz), 7.22 (1H, s), 6.98 (1H, dd, J=2.3, 8.9 Hz), 5.28 (2H, s), 4.32 (2H, dd, J=8.1, 8.6 Hz), 3.69 (2H, s), 3.17 (2H, m), 2.54 (4H, m), 2.03 (2H, m), 1.75 (4H, m) ppm.

[0341] Example 43: 4-[(pyrrolidin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 43 is prepared according to the synthetic route described in General Scheme C and procedures similar to those used to obtain Example 41. Suzuki coupling with bromide intermediate 34 using potassium trifluoro[(piperidin-1-yl)methyl]borate affords 4-[(pyrrolidin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one gave Example 43. LCMS method F: [M+H] + =421, retention time=1.49 minutes LCMS method G: [M+H] + =421, retention time=2.33 minutes 1 H NMR (400 MHz, d6-DMSO, 80 °C) δ 12.86 (1H, s), 7.86 (2H, m), 7.59 (1H, m), 7.48 (1H, d, J=8.4 Hz), 7.37 (1H, d, J=2.1 Hz), 7.25 (1H, m), 6.99 (1H, dd, J=2.3, 8.9 Hz), 5.30 (2H, s), 4.32 (2H, m), 3.19 (2H, m), 2.05 (2H, m), 1.62 (4H, m), 1.48 (2H, m) ppm. Some protons were not visible due to differential information. Structure confirmed by COSY.

[0342] Example 44: 4-[(4-methylpiperazin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 44 is prepared according to the synthetic route described in General Scheme C and procedures similar to those used to obtain Example 41. Suzuki coupling with bromide intermediate 34 uses potassium trifluoro[(4-methylpiperazin-1-yl)methyl]borate to give 4-[(4-methylpiperazin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one gave Example 44. LCMS method F: [M+H] + =436, holding time=1.36 minutes (current 20V) LCMS method G: [M+H] + =436, retention time = 1.95 minutes (pH10 current 20V) 1 H NMR (400 MHz, d6-DMSO, 80℃) δ 12.89 (1H, s), 7.81 (1H, s), 7.79 (1H, s), 7.66 (1H, m), 7.48 (1H, d, J=8.8 Hz), 7.35 (1H, m), 7.20 (1H, m), 6.98 (1H, dd, J=2.3, 9.1 Hz), 5.28 (2H, s), 4.31 (2H, m), 3.55 (2H, s), 3.17 (2H, m), 2.46 - 2.37 (8H, m), 2.20 (3H, s), 2.04 (2H, m) ppm.

[0343] Example 45: 5-(morpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 45 is prepared according to the synthetic route described in General Scheme C. Morpholine is used in a Buchwald coupling of bromide intermediate 48 to afford 5-(morpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one gave Example 45. LCMS method F: [M+H] + =409, retention time=2.17 minutes LCMS method G: [M+H] + =409, retention time=2.16 minutes 1 H NMR (400 MHz, d6-DMSO) δ 12.80 (1H, s), 7.89 - 7.86 (2H, m), 7.68 (1H, s), 7.49 - 7.45 (1H, m), 7.35 (1H, d, J=1.3 Hz), 7.29 - 7.25 (1H, m), 6.97 (1H, dd, J=2.3, 8.9 Hz), 5.37 (2H, s), 4.31 (2H, dd, J=8.3, 8.6 Hz), 3.78 (4H, m), 3.17 (2H, s), 2.91 (4H, m), 2.05 (2H, s) ppm.

[0344] Example 46 : 4-[4-(2-methoxyethyl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 46 is prepared according to the synthetic route described in General Scheme A. 1-(2-Methoxyethyl)piperazine is used in a Buchwald reaction with bromide intermediate 34 to give 4-[4-(2-methoxyethyl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one gave Example 46. LCMS method F: [M+H] + =466.2, retention time=1.48 minutes LCMS method G: [M+H] + =466.2, retention time=2.06 minutes 1 H NMR (400 MHz, d6-DMSO, 80℃) δ 12.83 (1H, s), 7.64 (1H, s), 7.49 - 7.46 (1H, m), 7.40 (2H, s), 7.34 (1H, s), 6.99 - 6.91 (2H, m), 5.24 (2H, s), 4.33 - 4.27 (2H, m), 3.67 - 3.63 (2H, m), 3.17 - 3.08 (15H, m), 2.10 - 1.99 (2H, m) ppm.

[0345] Example 47 : 4-(diethylamino)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 47 is prepared according to the synthetic route described in General Scheme A. Diethylamine is used in a Buchwald reaction with bromide intermediate 34 to give 4-(diethylamino)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one gave Example 47. LCMS method F: [M+H] + =395.2, retention time=1.57 minutes LCMS method G: [M+H] + =395.2, retention time=2.48 minutes 1 H NMR (400 MHz, d6-DMSO, 80℃) δ 12.73 (1H, br s), 7.59 (1H, br s), 7.46 (1H, d, J=9.3 Hz), 7.36 (1H, d, J=2.1 Hz), 7.18 - 7.16 (2H, m), 6.95 (1H, dd, J=2.4, 8.8 Hz), 6.63 (1H, s), 5.21 - 5.20 (2H, m), 4.32 - 4.27 (2H, m), 3.42 (4H, q, J=7.0 Hz), 3.21 - 3.10 (2H, m), 2.08 - 1.96 (2H, m), 1.17 (6H, t, J=6.9 Hz) ppm.

[0346] Example 48 : 4-Cyclopropyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 48 is prepared according to the synthetic route described in General Scheme C. Suzuki coupling with bromide intermediate 34 uses potassium trifluoro[cyclopropyl]borate to give 4-cyclopropyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one gave Example 48. LCMS method F: [M+H] + =364, retention time=2.40 minutes LCMS method G: [M+H] + =364, retention time=2.39 minutes 1 H NMR (400 MHz, d6-DMSO, 80℃) δ 12.87 (1H, s), 7.68 (1H, s), 7.64 (1H, m), 7.60 (1H, s), 7.47 (1H, d, J=9.1 Hz), 7.33 (1H, d, J=2.1 Hz), 6.99 (1H, s), 6.97 (1H, dd, J=9.0, 2.3 Hz), 5.24 (2H, m), 4.30 (2H, m), 3.17 (2H, m), 2.03 (3H, m), 1.00 (2H, m), 0.74 (2H, m) ppm.

[0347] Example 49 : 5-(4-methylpiperazin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 49 is prepared according to the synthetic route described in General Scheme C. 4-Methylpiperazine is used in a Buchwald coupling with bromide intermediate 48 to give 5-(4-methylpiperazin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one gave Example 49. LCMS method F: [M+H] + =422, retention time=1.44 minutes LCMS method G: [M+H] + =422, retention time=2.13 minutes 1 H NMR (400 MHz, CD3OD) δ 8.01 - 7.99 (1H, m), 7.92 (1H, dd, J=2.1, 8.4 Hz), 7.79 (1H, t, J=6.1 Hz), 7.49 - 7.34 (4H, m), 7.04 (1H, dd, J=2.3, 9.1 Hz), 5.51 - 5.47 (2H, m), 4.36 (2H, m), 3.74 - 3.63 (2H, m), 3.42 (4H, m), 3.21 (4H, m), 3.03 (3H, s), 2.12 (2H, m) ppm.

[0348] Example 50 : 13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 50 is prepared following the synthetic route described in general Scheme C and procedures analogous to those used to obtain Example 8.

[0349] 13-Methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 To a solution of tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one (330 mg, 0.78 mmol), trifluoroacetic acid (1.19 mL, 15.65 mmol) was added at room temperature. The solution was then irradiated in a microwave oven for 2 hours (Biotage initiator+). The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in EtOAc. The organic phase was washed with saturated aqueous sodium bicarbonate, brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting solid was triturated with diisopropyl ether and dried to give the expected compound 13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 50 as a pale yellow solid. LCMS method F: [M+H] + =338, retention time=2.25 minutes LCMS method G: [M+H] + =338, retention time=2.24 minutes 1 H NMR (400 MHz, d6-DMSO) δ 13.12 (1H, s), 7.93 - 7.84 (3H, m), 7.47 (2H, dd, J=8.5, 15.8 Hz), 7.27 (2H, d, J=7.0 Hz), 6.97 (1H, dd, J=2.1, 8.9 Hz), 5.75 (1H, d, J=12.1 Hz), 4.81 (1H, d, J=12.5 Hz), 4.57 (1H, dd, J=6.0, 9.2 Hz), 3.59 - 3.54 (1H, m), 2.93 - 2.86 (1H, m), 2.47-2.33 (1H, m), 1.41 - 1.38 (4H, m) ppm.

[0350] Example 51 : 8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one [ka] Example 51 is prepared according to the synthetic route described in general Scheme C.

[0351] Preparation of Intermediate 50 : Benzyl N-[3-({3-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamate [ka] To a solution of benzyl-N-(3-{[3-iodo-1-(oxan-2-yl)-1H-indazol-5-yl]oxy}propyl)carbamate 26 (0.535 g, 1.0 mmol) in dioxane (3 mL) and water (1 mL), 1-(2-hydroxyethyl)-1H-pyrazole-4-boronic acid pinacol ester (0.286 g, 1.2 mmol), KPO (0.637 g, 3.0 mmol), XPhos (0.048 g, 0.1 mmol), and Pd(PPh) (0.058 g, 0.05 mmol) were added at room temperature. The resulting reaction mixture was stirred at 120 °C under microwave irradiation for 1 h. The residue was diluted with saturated sodium chloride solution and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by flash column (25 g silica Macherey Nagel) chromatography (cyclohexane-ethyl acetate 3 / EtOH 1, 1:0 to 1:1) to give benzyl N-[3-({3-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamate 50 as a yellow oil. LCMS method F: [M+H] + =520.2, retention time=2.56 minutes

[0352] Preparation of intermediate 51 : [ka] To a solution of benzyl N-[3-({3-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamate 50 (0.380 g, 0.73 mmol) in anhydrous acetonitrile (146 mL) was added cesium carbonate (1.430 g, 4.39 mmol) at room temperature. The resulting reaction mixture was stirred at 90 °C for 36 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column (15 g silica Macherey Nagel) chromatography (cyclohexane-ethyl acetate 3 / EtOH 1, 1:0 to 3:7) to give 19-(oxan-2-yl)-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1]. 2,5 .0 18,21 ] to give tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one 51 as a white solid. LCMS method F: [M+H] + =412.2, retention time=2.20 minutes

[0353] Preparation of Example 51 : 8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one [ka] 19-(oxan-2-yl)-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21To a solution of tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one 51 (0.155 g, 0.38 mmol) was added TFA (0.561 mL, 7.53 mmol) at room temperature. The resulting reaction mixture was stirred at 80 °C for 1 h 30 min under microwave irradiation. The reaction mixture was concentrated under reduced pressure, diluted with saturated sodium bicarbonate solution, and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column (15 g silica Macherey Nagel) chromatography (cyclohexane-ethyl acetate 3 / EtOH 1, 9:1 to 0:1) to give a solid (70 mg), which was triturated with diisopropyl ether, filtered, and purified to give 8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 2,5 .0 18,21 ] to give tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one Example 51 as a white solid. LCMS method F: [M+H] + =328.1, retention time=1.68 minutes LCMS method G: [M+H] + =328.1, retention time=1.68 minutes 1 H NMR (400 MHz, d6-DMSO) δ 12.82 (1H, s), 8.09 (1H, s), 7.86 (1H, t, J=6.1 Hz), 7.77 (1H, d, J=0.6 Hz), 7.44 - 7.41 (1H, m), 7.07 (1H, ppm.

[0354] Example 52 : 4-[methyl(oxetan-3-yl)amino]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 52 is prepared according to the synthetic route described in General Scheme C. N-methyloxetan-3-amine is used in a Buchwald reaction with bromide intermediate 34 to give 4-[methyl(oxetan-3-yl)amino]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one gave Example 52. LCMS method F: [M+H] + =409, retention time=2.04 minutes LCMS method G: [M+H] + =409, retention time=2.06 minutes 1 H NMR (400 MHz, d6-DMSO) δ 12.81 (1H, s), 7.62 (1H, s), 7.46 (1H, d), 7.34 (2H, s), 7.13 (1H, s), 6.98 - 6.95 (1H, m), 6.64 (1H, s), 5.22 (2H, m), 4.84 - 4.81 (2H, m), 4.77 - 4.74 (1H, m), 4.65 - 4.64 (2H, m), 4.32 - 4.28 (2H, m), 3.16 (2H, m), 2.96 (3H, s), 2.03 (2H, m) ppm.

[0355] Example 53 : 4-[(dimethylamino)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 53 is prepared according to the synthetic route described in General Scheme C. Suzuki coupling with bromide intermediate 34 uses potassium (dimethylamino)methyltrifluoroborate to give 4-[(dimethylamino)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one gave Example 53. LCMS method F: [M+H] + =381, retention time=1.39 minutes LCMS method G: [M+H] + =381, retention time=2.03 minutes 1 H NMR (400 MHz, d6-DMSO) δ 12.93 (1H, s), 7.87 (2H, m), 7.70 - 7.66 (1H, m), 7.51 - 7.47 (1H, m), 7.36 (1H, d, J=2.1 Hz), 7.25 (1H, s), 6.99 (1H, dd, J=2.3, 9.1 Hz), 5.30 - 5.26 (2H, m), 4.34 - 4.30 (2H, m), 3.73 (2H, m), 3.17 (2H, s), 2.40 - 2.33 (6H, m), 2.06 (2H, s) ppm.

[0356] Example 54 : 4,10-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 54 is prepared according to the synthetic route described in general Scheme F.

[0357] Preparation of intermediate 52: 4,10-dimethyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] 4-Methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 To a mixture of tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one Example 18 (115 mg, 0.273 mmol) was added 60% NaH oil dispersion (8 mg, 0.328 mmol) and MeI (20 μL, 0.328 mmol). The reaction mixture was stirred overnight at room temperature. Additional 60% NaH oil dispersion (8 mg, 0.328 mmol) and MeI (20 μL, 0.328 mmol) were added. The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and EtOAc and water were added. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and the solvent removed under reduced pressure to give 4,10-dimethyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 52 as a colorless oil. LCMS method F: [M+H] + =436.2, retention time=3.15 minutes

[0358] Preparation of Example 54 : 4,10-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] 4,10-Dimethyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 To a mixture of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 52 (150 mg; 0.345 mmol) was added TFA (132 μL, 1.723 mmol). The reaction mixture was stirred at 80 °C for 60 min under microwave conditions. The solvent was removed under reduced pressure, and the mixture was dissolved in EtOAc and washed with saturated 1N NaHCO solution (pH = 7) and then with water. The organic layer was concentrated under reduced pressure, and the oil was purified by chromatography on a 10 g SiO column eluted with DCM / MeOH 100 / 0 to 95 / 5. The desired fractions were combined, but the product was not sufficiently pure, so it was repurified by chromatography on a 10 g SiO column eluted with cyclohexane / ethyl acetate 70 / 30 to 50 / 50. The desired fractions were combined, the solvent was removed under reduced pressure, and the oil was then triturated with pentane. The solid was filtered, boiled in hot water, filtered, and dried under high vacuum to give 4,10-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 54 was obtained as a white powder. LCMS method F: [M+H] + =352.2, retention time=2.49 minutes LCMS method G: [M+H] + =352.2, retention time=2.49 minutes 1 1 H NMR analysis showed the presence of rotamers. 1H NMR (400 MHz, d6-DMSO) δ 13.11 - 13.05 (1H, m), 7.68 (2H, d, J=13.7 Hz), 7.51 - 7.47 (1H, m), 7.20 - 7.12 (2H, m), 6.99 (1H, dd, J=2.2, 9.0 Hz), 5.82 (0.75H, d, J=13.3 Hz), 5.15 (0.25H, s), 4.78 (0.75H, d, J=13.5 Hz), 4.43 - 4.35 (0.75H, m), 4.28 - 4.12 (1.25H, m), 3.94 - 3.84 (0.75H, m), 3.47 - 3.39 (0.25H, m), 3.04 - 3.03 (3H, m), 2.91 - 2.82 (1.25H, m), 2.41 - 2.39 (4H, m), 2.27 - 2.16 (0.25H, m), 1.77 - 1.70 (0.75H, m) ppm.

[0359] Example 55 : 4-(propan-2-yloxy)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 54 is prepared according to the synthetic route described in general Scheme F.

[0360] Preparation of intermediate 53 : Methyl 3-[5-[3-(benzyloxycarbonylamino)propoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-5-hydroxy-benzoate [ka] Benzyl N-[3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]carbamate 26 (2.876 g, 5.372 mmol), methyl 3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.988 g, 10.473 mmol), XPhos (256 mg, 0.537 mmol), and KPO in dioxane (40.0 mL) and water (10.0 mL). 4( To a degassed solution of Pd(PPh3)4 (3.421 g, 16.116 mmol) was added Pd(PPh3)4 (311 mg, 0.269 mmol). The resulting cloudy brown solution was degassed with nitrogen gas for 5 minutes, separated into three batches, sealed, and heated to 120 °C for 1 hour each under microwave irradiation. The mixture was poured into water (50 mL), EtOAc (100 mL) was added, and the phases were separated. The aqueous layer was extracted with EtOAc (3 × 100 mL), and the combined organic extracts were washed with saturated aqueous NaCl (1 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material (brown oil, 4.1 g) was purified by column chromatography (220 g Macherey Nagel SiO, 100 mL / min, CyH / EtOAc 100:0 to 60:40) to give methyl 3-[5-[3-(benzyloxycarbonylamino)propoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-5-hydroxy-benzoate 53 as a brown oil. LCMS method F: [M+H] + =560.1, retention time=2.97 minutes

[0361] Preparation of intermediate 54 : Methyl 3-[5-[3-(benzyloxycarbonylamino)propoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-5-isopropoxy-benzoate [ka] To a solution of methyl 3-[5-[3-(benzyloxycarbonylamino)propoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-5-hydroxybenzoate 53 (2.800 g, 5.004 mmol) and K2CO3 (1.729 g, 12.510 mmol) in N,N-dimethylformamide (25.0 mL) was added 2-bromopropane (940 μL, 1.231 mg, 10.008 mmol). The resulting cloudy brown solution was heated to 70 °C for 2 h. The reaction was quenched with water (20 mL), EtOAc (50 mL) was added, and the phases were separated. The aqueous layer was extracted with EtOAc (3 × 50 mL), and the combined organic extracts were washed with saturated aqueous NaCl (1 × 20 mL), dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure. The resulting crude material (brown solid, 3.5 g) was purified by column chromatography (120 g Macherey Nagel SiO, CyH / EtOAc 100:0-70:30) to give methyl 3-[5-[3-(benzyloxycarbonylamino)propoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-5-isopropoxy-benzoate 54 as a brown solid. LCMS method F: [M+H] + =602.3, retention time=3.48 minutes

[0362] Preparation of intermediate 55 : Benzyl N-[3-[3-[3-(hydroxymethyl)-5-isopropoxy-phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate [ka] To a solution of methyl 3-[5-[3-(benzyloxycarbonylamino)propoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-5-isopropoxy-benzoate 54 (3.000 g, 4.986 mmol) in THF (50.0 mL) at 0 °C, LiAlH (1.0 M in THF, 9.97 mL, 9.972 mmol) was added dropwise. The resulting brown solution was stirred at 0 °C for 15 min and then at room temperature for 1 h. The reaction was carefully quenched with saturated aqueous Rochelle's salt (20 mL), EtOAc (50 mL) was added, and the phases were separated. The aqueous layer was extracted with EtOAc (3 × 50 mL) and the combined organic extracts were washed with saturated aqueous NaCl (1 × 50 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure to give crude benzyl N-[3-[3-[3-(hydroxymethyl)-5-isopropoxy-phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate 55 as a brown oil, which was used in the next step without further purification. LCMS method F: [M+H] + =574.2, retention time=3.06 minutes

[0363] Preparation of intermediate 56 : 19-(oxan-2-yl)-4-(propan-2-yloxy)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] To a solution of benzyl N-[3-[3-[3-(hydroxymethyl)-5-isopropoxy-phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate 55 (100 mg, 0.174 mmol) in MeCN (18.0 mL) was added CsCO (341 mg, 1.046 mmol). The resulting cloudy yellow mixture was heated under reflux for 5 h. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting crude material (yellow oil, 100 mg) was purified by column chromatography (4 g Macherey Nagel SiO, 15 mL / min, CHCl / MeOH 100:0 to 98:2) to give 19-(oxan-2-yl)-4-(propan-2-yloxy)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 56 as a clear oil. LCMS method F: [M+H] + =466.2, retention time=3.03 minutes

[0364] Preparation of Example 55 : 4-(propan-2-yloxy)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] 19-(oxan-2-yl)-4-(propan-2-yloxy)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21To a solution of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 56 (54 mg, 0.116 mmol) was added TFA (300 μL, 447 mg, 3.920 mmol). The vial containing the resulting clear yellow solution was sealed and heated to 50 °C under microwave irradiation for 3 h. Saturated aqueous NaHCO (1 mL) was added and the phases were separated. The aqueous layer was extracted with CHCl (3 × 5 mL), and the combined organic extracts were washed with water (1 × 5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude material (slightly yellow oil, 49 mg) was triturated with iPrO to give 4-(propan-2-yloxy)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 55 as a white amorphous solid. LCMS method F: [M+H] + =382.1, retention time=2.41 minutes LCMS method G: [M+H] + =382.2, retention time=2.40 minutes 1 H NMR (400 MHz, d6-DMSO, 80 °C) δ 7.66 (brs, 1H), 7.49–7.46 (m, 2H), 7.39–7.34 (m, 2H), 6.98 (dd, J=2.4, 9.0 Hz, 1H), 6.85 (brs, 1H), 5.24 (brs, 1H), 4.72–4.63 (sept, J=5.9 Hz, 1H), 4.33–4.29 (m, 2H), 3.19–3.15 (m, 2H), 2.04–2.02 (m, 2H), 1.35–1.33 (m, 6H) ppm. The two labile protons were not visible in this solvent.

[0365] Example 56 : 4-Fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 56 is prepared according to the synthetic route described in general Scheme A.

[0366] Preparation of intermediate 57 : 1-(3-bromo-5-fluoro-phenyl)ethanol [ka] To a cooled solution of 3-bromo-5-fluorobenzaldehyde (1.5 g, 7.389 mmol) in dry tetrahydrofuran (19 mL) at 0 °C was added dropwise a 3 M solution of methylmagnesium bromide in diethyl ether (4.93 mL, 14.778 mmol). The reaction mixture was stirred at 0 °C for 20 min and then at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl and then extracted with ethyl acetate (2x). The combined organic layers were washed with water, then brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography eluting with cyclohexane / ethyl acetate-EtOH (3-1):100 / 0 to 80 / 20 to give 1-(3-bromo-5-fluorophenyl)ethanol 57 as a colorless oil. LCMS method F: [M+H] + = Mass not detected, retention time = 2.32 min

[0367] Preparation of intermediate 58 : 1-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanol [ka] To a degassed solution of 1-(3-bromo-5-fluorophenyl)ethanol 57 (1.196 g, 5.461 mmol), bis(pinacolato)diboron (2.080 g, 8.192 mmol), and potassium acetate (2.144 g, 21.844 mmol) in dioxane (17 mL) in a sealed tube, PdCl(dppf) CHCl (0.446 g, 0.546 mmol) was added. The reaction mixture was heated at 90 °C for 24 h. The reaction mixture was filtered through Whatman Celite and rinsed with ethyl acetate. The reaction mixture was diluted with water and extracted with ethyl acetate (3x). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanol 58 as a black oil. LCMS Method F: m / z not detected, retention time = 2.65 min.

[0368] Preparation of intermediate 59 : Benzyl N-[3-[3-[3-fluoro-5-(1-hydroxyethyl)phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate [ka] To a degassed solution of benzyl N-[3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]carbamate 26 (1.462 g, 2.734 mmol), 1-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanol 58 (1.453 g, 5.466 mmol), potassium phosphate tripotassium (1.742 g, 8.202 mmol), and xPhos (0.130 g, 0.274 mmol) in dioxane (14.6 mL) and water (8.8 mL), tetrakis(triphenylphosphine)palladium(0) (0.158 g, 0.137 mmol) was added. The reaction mixture was irradiated in a microwave oven (Biotage initiator+) at 120 °C for 1 h. The reaction mixture was filtered through Celite, and the Celite was washed with ethyl acetate. The filtrate was then diluted with water and extracted with ethyl acetate (3x). The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure.

[0369] The crude product was purified by column chromatography eluting with DCM / ethyl acetate, 100 / 0 to 80 / 20 to give benzyl N-[3-[3-[3-fluoro-5-(1-hydroxyethyl)phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate 59 as a cream-colored solid. Yield: 780 mg of intermediate 59 (50%) LCMS method F: [M+H] + =548, retention time=3.07 minutes

[0370] Preparation of Intermediate 60 1-[3-[5-(3-aminopropoxy)-1-tetrahydropyran-2-yl-indazol-3-yl]-5-fluoro-phenyl]ethanol and 4-fluoro-7-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one [ka] A suspension of benzyl N-[3-[3-[3-fluoro-5-(1-hydroxyethyl)phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate 59 (0.780 g, 1.426 mmol) and cesium carbonate (2.781 g, 8.556 mmol) in acetonitrile (300 mL) was heated to 90 °C for 16 h. LCMS analysis indicated the formation of the desired product, but starting material remained, and formation of 1-[3-[5-(3-aminopropoxy)-1-tetrahydropyran-2-yl-indazol-3-yl]-5-fluoro-phenyl]ethanol was observed. The reaction mixture was heated to 90 °C for 16 h. The reaction mixture was cooled to room temperature, then filtered and concentrated under reduced pressure to give 1-[3-[5-(3-aminopropoxy)-1-tetrahydropyran-2-yl-indazol-3-yl]-5-fluoro-phenyl]ethanol (66%) and 4-fluoro-7-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give a mixture of tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one (26%) (0.667 g, 1.426 mmol (assumed)) as an orange oil. The crude product was not purified and was used in the next step without further purification.

[0371] Preparation of Intermediate 61 : 4-Fluoro-7-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] 1-[3-[5-(3-aminopropoxy)-1-tetrahydropyran-2-yl-indazol-3-yl]-5-fluoro-phenyl]ethanol and 4-fluoro-7-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 To a solution of tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one 60 (0.567 g, 1.373 mmol) was added 1,1'-carbonyldiimidazole (0.245 g, 1.510 mmol). The reaction mixture was stirred at room temperature for 2 h and then at 90 °C for 22 h. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and saturated aqueous NaHCO3 were added. The mixture was extracted with ethyl acetate (2x). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.

[0372] The crude product was purified by column chromatography eluting with cyclohexane / ethyl acetate-EtOH (3-1): 100 / 0 to 70 / 30 to give a cream-colored solid. The solid was triturated from diisopropyl ether to give 4-fluoro-7-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1]. 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 61 as a white solid. Yield: 100 mg of intermediate 61 (14%) LCMS method F: [M+H] + =440, retention time=2.96 minutes

[0373] Preparation of Example 56 : 4-Fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] 4-Fluoro-7-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 To a solution of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 61 (100 mg, 0.228 mmol) was added trifluoroacetic acid (350 μL, 4.560 mmol) at room temperature. The reaction mixture was irradiated under microwave conditions (Biotage initiator). The solid was triturated from diisopropyl ether to give 4-fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 56 as a cream-colored solid. LCMS method F: [M+H] + =356, retention time=2.33 minutes LCMS method G: [M+H] + =356, retention time=2.32 minutes 1 H NMR (400 MHz, d6-DMSO) δ 13.26 (1H, s), 8.01 - 7.98 (1H, m), 7.69 (1H, s), 7.59 - 7.56 (1H, m), 7.53 - 7.50 (1H, m), 7.33 (1H, m), 7.22 - 7.18 (1H, m), 7.02 - 6.99 (1H, m), 5.91 - 5.86 (1H, m), 4.35 - 4.28 (2H, m), 3.56 - 3.49 (1H, m), 2.79 - 2.72 (1H, m), 2.21 - 2.16 (1H, m), 1.77 - 1.71 (1H, m), 1.61 - 1.58 (3H, d) ppm.

[0374] Example 57: 4-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 57 is prepared according to the synthetic route described in general Scheme C.

[0375] Preparation of Intermediate 62 : 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine [ka] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (370 mg, 1.77 mmol) in DCM (9 mL) was added triethylamine (245 μL, 1.77 mmol) and 3-bromooxetane (750 mg, 5.5 mmol). The resulting mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated under reduced pressure to give 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine 62 (500 mg, 1.77 mmol) as an orange oil. The compound was used in the next step without further purification.

[0376] Preparation of intermediate 63 : 19-(oxan-2-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] 4-Bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 To a solution of tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one intermediate 34 (260 mg, 0.53 mmol), 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine 62 (300 mg, 1.06 mmol assumed) and KPO (337 mg, 1.59 mmol) were added. The mixture was degassed for 10 min, and then Pd(dppf)Cl.DCM (17 mg, 0.021 mmol) was added. The mixture was heated at 90 °C for 20 h. LCMS analysis showed the expected product without the oxetane. The reaction mixture was cooled to room temperature, and then additional 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (200 mg, 0.71 mmol assumed) and KPO (168 mg, 0.79 mmol) were added. The mixture was degassed for 10 min, and more Pd(dppf)Cl.DCM (8 mg, 0.0098 mmol) was added. The mixture was heated at 90 °C for 1 day. The reaction mixture was filtered through Celite and diluted with EtOAc (50 mL) and water (50 mL). After separation, the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column (Macherey Nagel, 25 g) chromatography using DCM / (MeOH / NH) (100 / 0 to 90 / 10). The desired fractions were collected, combined and evaporated to give 19-(oxan-2-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .018,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 63 as an orange solid. LCMS method F: [M+H] + =489, retention time=1.81 minutes

[0377] Preparation of intermediate 64 : 19-(oxan-2-yl)-4-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] 19-(oxan-2-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21To a solution of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 63 (289 mg, 0.59 mmol) was added oxetan-3-one (212 mg, 2.95 mmol). The mixture was cooled to 0 °C, and then sodium tris(acetoxy)borohydride (248 mg, 1.18 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with 1 M NaCO (ca. 7 mL, pH = 8), and then the mixture was diluted with EtOAc (50 mL). After separation, the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column (Macherey Nagel, 15 g) flash chromatography using DCM / MeOH (100 / 0 to 97 / 3) as eluent to give 19-(oxan-2-yl)-4-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ] to give tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 64 as white crystals. LCMS method F: [M+H] + =545, retention time=1.84 minutes

[0378] Preparation of Example 57 : 4-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] 19-(oxan-2-yl)-4-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 To a solution of tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 64 (82 mg, 0.15 mmol) was added trifluoroacetic acid (107 μL, 1.4 mmol). The mixture was stirred at room temperature for 24 h. The reaction mixture was then heated at 40°C for 4 h. Further trifluoroacetic acid (26 μL, 0.35 mmol) was added, and the reaction mixture was heated at 40°C for 3 h and at room temperature overnight. The reaction mixture was diluted with DCM (25 mL) and saturated NaHCO3 solution (25 mL). After separation, the aqueous layer was extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was triturated with acetonitrile, filtered, and the solid was washed several times with acetonitrile to give 4-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ] Tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 57 was obtained as a cream-colored powder. LCMS method F: [M+H] + =461, retention time=1.49 minutes LCMS method G: [M+H] + =461, retention time=2.19 minutes 1H NMR (400 MHz, d6-DMSO, 80℃) δ 12.89 (1H, m), 7.90 (1H, s), 7.80 (1H, s), 7.67 (1H, m), 7.48 (1H, d, J=9.5 Hz), 7.35 (2H, m), 6.98 (1H, dd. J=6.1 Hz), 3.18 (2H, m), 3.09 (2H, m), 2.61 (2H, m), 2.57 (2H, m), 2.04 (2H, m) ppm.

[0379] Example 58 : 4-(3-methylpiperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 58 is prepared according to the synthetic route described in General Scheme C. A Buchwald reaction with bromide intermediate 34 using 3-methylpiperidine affords 4-(3-methylpiperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one gave Example 58. LCMS method F: [M+H] + =421.2, retention time=1.88 minutes LCMS method G: [M+H] + =421.2, retention time=2.66 minutes 1H NMR (400 MHz, d6-DMSO) δ 7.69 - 7.56 (1H , m), 7.48 - 7.45 (1H, m), 7.38 - 7.31 (3H, m), 6.95 (1H, dd, J=2.4, 9.0 Hz), 6.87 - 6.86 (1H, 1.83 - 1.74 (3H, m), 1.7 - 1.55 (1H, m), 1.19 - 1.05 (1H, m) ppm. The indazole NH protons were not visible in this solvent.

[0380] Example 59 : 4-[(3S)-3-hydroxypyrrolidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one [ka] Example 59 is prepared according to the synthetic route described in General Scheme C. (3S)-Pyrrolidin-3-ol is used in a Buchwald reaction with bromide intermediate 34 to give 4-[(3S)-3-hydroxypyrrolidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 2,6 .0 18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one gave Example 59. LCMS method F: [M+H] + =409.2, retention time=1.98 minutes LCMS method G: [M+H] + =409.2, retention time=1.96 minutes 1H NMR (400 MHz, d6-DMSO) δ 12.84 (1H, m), 7.61 - 7.60 (1H, m), 7.48 - 7.45 (1H, m), 7.36 (1H, d, J=2.1 Hz), 7.21 - 6.93 (3H, m), 6.47 (1H, s), 5.25 - 5.21 (2H, m), 4.88 - 4.66 (1H, m) 4.48 - 4.45 (1H, m), 4.32 - 4.27 (2H, m), 3.53 - 3.32 (3H, m), 3.20 - 3.16 (3H, m), 2.16 - 2.07 (1H, m), 2.02 - 1.94 (3H, m) ppm.

[0381] Example 60 : 4-Fluoro-8,14-dioxa-10,19,20-triazapentacyclo[13.5.2.1 2,6 .1 7,10 .0 18,21 ]Tetracosa-1(20),2(24),3,5,15(22),16,18(21)-heptaen-9-one [ka] Example 60 is prepared according to the synthetic route described below.

[0382] Preparation of intermediate 65 : 1-(3-bromo-5-fluorophenyl)-2-nitroethan-1-ol [ka] To a stirred solution of 3-bromo-5-fluorobenzaldehyde (2 g, 10 mmol) in THF (20 mL) was added nitromethane (0.536 mL, 10 mmol) dropwise at 0° C., followed by 1N sodium hydroxide solution (10 mL, 10 mmol). The solution was stirred at 0° C. for 15 minutes. The solution was quenched with acetic acid solution (12 mL). To the resulting mixture was added water (25 mL). The aqueous layer was extracted with EtOAc (4×50 mL). The combined organic layers were washed with saturated brine (2×50 mL). The organic layer was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure to give a brown / orange oil. The residue was purified by flash chromatography on silica gel (Macherey Nagel, 120 g) using gradient elution: cyclohexane / EtOAc 0-30% to give 1-(3-bromo-5-fluorophenyl)-2-nitroethan-1-ol 65 as a white solid. LCMS method F: [MH] - =262.2, retention time=2.28 minutes

[0383] Preparation of Intermediate 66 : 2-amino-1-(3-bromo-5-fluorophenyl)ethan-1-ol [ka] To a solution of 1-(3-bromo-5-fluorophenyl)-2-nitroethan-1-ol 65 (6.2 g, 15.2 mmol) in EtOH (100 mL) was added Raney®-Nickel (2 g) and acetic acid (0.5 mL). Dihydrogen was bubbled through the mixture for 5 minutes. The reaction mixture was stirred under a dihydrogen atmosphere for 16 hours. The reaction mixture was filtered through Celite, and the solvent of the filtrate was removed under reduced pressure to give to give 2-amino-1-(3-bromo-5-fluorophenyl)ethan-1-ol 66, This was used in the next step without further purification. LCMS method F: [M+H] + =236, retention time=1.12 minutes

[0384] Preparation of intermediate 67 : 5-(3-bromo-5-fluorophenyl)-1,3-oxazolidin-2-one [ka] To a solution of 2-amino-1-(3-bromo-5-fluorophenyl)ethan-1-ol 66 (1.75 g, 1.75 mmol) in THF (100 mL) was added 1,1′-carbonyldiimidazole (1.34 g, 8.25 mmol) and imidazole (0.561 g, 8.25 mmol). The reaction mixture was stirred at room temperature for 16 h. Saturated aqueous NH4Cl (100 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Biotage column chromatography eluting with cyclohexane / ethyl acetate (3:1):100 / 0 to 70 / 30 to give 5-(3-bromo-5-fluorophenyl)-1,3-oxazolidin-2-one 67 as a white solid. LCMS method F: [M+H] + =262.0, retention time=2.07 minutes

[0385] Preparation of intermediate 68 5-(3-bromo-5-fluorophenyl)-3-{3-[(tert-butyldimethylsilyl)oxy]propyl}-1,3-oxazolidin-2-one [ka] To a stirred solution of 5-(3-bromo-5-fluorophenyl)-1,3-oxazolidin-2-one 67 (1.6 g, 6.1 mmol) in THF (10 mL) was added sodium hydride (0.366 g, 9.1 mmol) at 0 °C. The solution was stirred at 0 °C for 10 min. Then, a solution of (3-bromopropoxy)(tert-butyl)dimethylsilane (1.5 g, 6.1 mmol) in THF (10 mL) was added to the mixture. The mixture was stirred at room temperature for 16 h. The solution was quenched with a solution of saturated ammonium chloride (25 mL). The resulting mixture was extracted with EtOAc (4 × 100 mL). The combined organic layers were washed with saturated brine (2 × 50 mL). The organic layers were dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure to give a brown / orange oil. The residue was purified by flash chromatography on silica gel (Macherey Nagel, 24 g) with gradient elution: cyclohexane / EtOAc 0–50% to give 5-(3-bromo-5-fluorophenyl)-3-{3-[(tert-butyldimethylsilyl)oxy]propyl}-1,3-oxazolidin-2-one 68 as a yellow oil. LCMS method F: [M+H] + =434.0, retention time=3.42 minutes

[0386] Preparation of intermediate 69 : 5-(3-bromo-5-fluorophenyl)-3-(3-hydroxypropyl)-1,3-oxazolidin-2-one [ka] To a solution of 5-(3-bromo-5-fluorophenyl)-3-{3-[(tert-butyldimethylsilyl)oxy]propyl}-1,3-oxazolidin-2-one 68 (0.8 g, 1.85 mmol assumed) in tetrahydrofuran (50 mL) was added 1.0 M tetra-n-butylammonium fluoride (1.85 mL, 1.85 mmol) in THF in small portions at room temperature. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into ice-water (100 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (24 g silica BIOTAGE) chromatography (cyclohexane-ethyl acetate, 100 / 0 to 50 / 50) to give 5-(3-bromo-5-fluorophenyl)-3-(3-hydroxypropyl)-1,3-oxazolidin-2-one 69 as a beige powder. LCMS method F: [M+H] + =320.0, retention time=2.02 minutes

[0387] Preparation of Intermediate 70 : 3-[5-(3-bromo-5-fluorophenyl)-2-oxo-1,3-oxazolidin-3-yl]propyl methanesulfonate [ka] To a solution of 5-(3-bromo-5-fluorophenyl)-3-(3-hydroxypropyl)-1,3-oxazolidin-2-one 69 (0.5 g, 1.57 mmol) and diisopropylethylamine (0.545 mL, 3.14 mmol) in dichloromethane (50 mL) at 0 °C, methanesulfonyl chloride (0.145 mL, 1.88 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution, and brine, filtered, and the solvent was removed under reduced pressure to give 3-[5-(3-bromo-5-fluorophenyl)-2-oxo-1,3-oxazolidin-3-yl]propyl methanesulfonate 70 as a colorless oil. LCMS method F: [M+H] + =397.9, retention time=2.36 minutes

[0388] Preparation of intermediate 71 5-(3-bromo-5-fluorophenyl)-3-(3-{[1-(oxan-2-yl)-1H-indazol-5-yl]oxy}propyl)-1,3-oxazolidin-2-one [ka] To a solution of 3-[5-(3-bromo-5-fluorophenyl)-2-oxo-1,3-oxazolidin-3-yl]propyl methanesulfonate 70 (0.618 g, 1.57 mmol) in N,N-dimethylformamide (100 mL) was added cesium carbonate (1.02 g, 3.14 mmol) and 1-(oxan-2-yl)-1H-indazol-5-ol 29 (0.343 g, 1.57 mmol). The reaction was stirred at 80 °C for 16 h. The mixture was concentrated under reduced pressure. Water (200 mL) was added, and the resulting mixture was extracted with EtOAc (4 × 100 mL). The combined organ...

Claims

1. Formula (I): 【Chemistry 645】 [During the ceremony, R represents a hydrogen atom, a halogen atom, or an alkyl group; Z1, Z2, and Z3 each independently represent a carbon or nitrogen atom, and the 6-membered ring containing Z1, Z2, and Z3 can have 0, 1, or 2 nitrogen atoms; -X1- is absent or represents -O-, -S-, or -N(R'a)-, where R'a represents a hydrogen atom or an alkyl group; -X2- represents an alkanediyl group optionally substituted with one or more identical or different substituents selected from a halogen atom, a polyhalogenoalkyl group, an alkoxy group, a hydroxy group, an amino group, an alkylamino group, a dialkylamino group, and a cyano group; wherein the carbon atom at the α-position of —N(Ra) and the carbon atom at the α-position of —X1- when —X1- represents —O—, —S—, or N(R′a)— cannot be substituted with an oxygen or nitrogen heteroatom; -X3- represents an alkanediyl group optionally substituted with one or more identical or different substituents selected from a halogen atom, a polyhalogenoalkyl group, an alkoxy group, a hydroxy group, an amino group, an alkylamino group, a dialkylamino group, a cyano group, a cycloalkyl group, and a heterocycloalkyl group; wherein the carbon atom at the α-position of —O— and the carbon atom at the α-position of A1 when A1 represents a nitrogen atom cannot be substituted with an oxygen or nitrogen heteroatom; Ra represents a hydrogen atom or an alkyl group; wherein when Ra represents an alkyl group, one carbon atom of Ra can be linked to a carbon atom of —X2— or a carbon atom of —X3— to form a cyclic moiety containing 5 or 6 ring members; A is a compound of formula (a): 【Chemical 646】 (In the formula, A1 and A4 each independently represent a carbon atom or a nitrogen atom; A2, A3, and A5 each independently represent a carbon atom, an oxygen atom, a sulfur atom, or a nitrogen atom; Here, A1, A2, A3, A4, and A5 cannot simultaneously represent heteroatoms. or an aromatic or partially hydrogenated cyclic group of the formula Or formula (b): 【Transformation 647】 (In the formula, A'1, A'2, A'3, and A'4 each independently represent a carbon atom or a nitrogen atom.) represents an aromatic or partially hydrogenated cyclic group of the formula: where * means that the bond is connected to X3. A compound of the formula The aromatic or partially hydrogenated cyclic group A so defined is optionally substituted with one or more identical or different substituents selected from halogen atoms, alkyl groups, alkoxy groups, hydroxy groups, oxo groups, alkoxyalkyl groups, alkoxyalkoxy groups, polyhalogenoalkyl groups, polyhalogenoalkoxy groups, heterocycloalkyl groups, heterocycloalkylalkyl groups, (alkoxyalkyl)(alkyl)amino groups, amino groups, alkylamino groups, dialkylamino groups, cycloalkyl groups, (heterocycloalkyl)(alkyl)amino groups, dialkylaminoalkyl groups, heterocycloalkylalkoxy groups, cyano groups and cyanoalkyl groups, Here, the heterocycloalkyl group and cycloalkyl group defined as such may be optionally substituted with one or more substituents selected from an alkyl group, a halogen atom, a polyhalogenoalkyl group, a polyhalogenoalkoxy group, an alkoxy group, an alkoxyalkyl group, a hydroxy group, a cyano group, and an oxo group. The compounds, their enantiomers, diastereomers, tautomers, racemates, hydrates, solvates, N-oxides, isotopes, deuterated derivatives and their addition salts with pharmaceutically acceptable acids or bases.

2. 2. The compound of claim 1, wherein R represents a hydrogen atom.

3. 2. The compound of claim 1, wherein R represents a halogen atom.

4. 4. The compound according to claim 1, wherein Z1, Z2 and Z3 simultaneously represent a carbon atom.

5. 4. A compound according to any one of claims 1 to 3, wherein one of Z1 or Z2 represents a nitrogen atom and Z3 represents a carbon atom.

6. 6. The compound according to claim 1, wherein -X1- represents -O-.

7. 7. The compound according to claim 1, wherein -X2- represents a linear or branched alkanediyl group having 2, 3, 4 or 5 carbon atoms.

8. -X2- is -(CH ２ ) ３ -, -CH(CH ３ )-(CH ２ ) ２ -, -CH ２ -CHF-CH ２ -, -CH ２ -CF ２ -CH ２ - or (CH ２ ) ２ -CH(CH ３ 8. The compound according to claim 7, wherein:

9. The compound according to any one of claims 1 to 8, wherein Ra is a hydrogen atom.

10. 10. The compound according to any one of claims 1 to 9, wherein -X3- represents a linear or branched alkanediyl group having 1, 2, 3, 4 or 5 carbon atoms.

11. -X3- is -(CH ２ ) ２ -, -CH ２ - or -CH(CH ３ 11. The compound according to claim 10, wherein:

12. A is a compound of formula (b): 【Chemical Formula 648】 (wherein A'1, A'2, A'3, A'4 and * are as defined in claim 1).

12. A compound according to any one of claims 1 to 11, wherein the compound represents a group of

13. A is, 【Chemical 649】 represents The A group so defined is unsubstituted or optionally substituted; The compound of claim 12.

14. 13. The compound of claim 12, wherein A represents a phenyl group.

15. 13. The compound of claim 12, wherein A represents a pyridinyl group.

16. 13. The compound of claim 12, wherein A represents a pyrazinyl group.

17. A is a compound of formula (a): 【Chemical 650】 (wherein A1, A2, A3, A4, A5 and * are as defined in claim 1) 12. A compound according to claim 1, wherein the compound represents a group of formula:

18. A is, 【Chemical 651】 wherein the A group so defined is unsubstituted or optionally substituted; 18. The compound of claim 17.

19. 18. The compound of claim 17, wherein A represents a triazolyl group.

20. 18. The compound of claim 17, wherein A represents a pyrazolyl group.

21. 21. The compound of claims 12-20, wherein A is unsubstituted.

22. 21. The compound according to claim 12, wherein A is substituted with one or more groups selected from a halogen atom, a cyano group, a cyanoalkyl group, an oxo group, an alkoxy group, an alkyl group, a cycloalkyl group, and a heterocycloalkyl group.

23. Formula (I-a): 【Chemical 652】 (wherein X1, X2, X3, Ra and A are as defined in claim 1).

2. The compound of claim 1, which is a compound of formula:

24. Formula (Ib): 【Chemical 653】 (wherein X2, X3, Ra and A are as defined in claim 1).

24. The compound of claim 23, which is a compound of:

25. Formula (I-c) or (I-c'): 【Chemical 654】 (wherein X1, X2, X3, Ra, A'1, A'2 and A'4 are as defined in claim 1).

24. The compound of claim 23, which is a compound of formula:

26. Formula (I-d) or (I-d'): 【Chemical Formula 655】 (wherein X2, X3, Ra, A'1, A'2 and A'4 are as defined in formula (I)).

26. The compound of claim 23 or 25, which is a compound of the formula:

27. Formula (I-e): 【Chemical 656】 (wherein X1, X2, X3, Ra, A1, A2 and A5 are as defined in formula (I)).

24. The compound of claim 23, which is a compound of formula:

28. Formula (If): 【Chemical Formula 657】 (Wherein, X2, X3, Ra, A1, A2 and A5 are as de?ned in formula (I)).

28. The compound of claim 23 or 27,

29. The -X1-X2-N(Ra)-C(O)O-X3- chain is -O-(CH ２ ) ３ -NHC(O)O-CH ２ -, -O-CH(CH ３ )-(CH ２ ) ２ -NHC(O)O-CH ２ --, --O-CH ２ -CHF-CH ２ -NHC(O)O-CH ２ --, --O-CH ２ -CF ２ -CH ２ -NHC(O)O-CH ２ -, -O-CH(CH ３ )-(CH ２ ) ２ -NHC(O)O-(CH ２ ) ２ - or -O-CH(CH ３ )-(CH ２ ) ２ -NH-C(O)O-CH(CH ３ 28. The compound according to claim 23, 25 or 27, wherein 。

30. 8,14-Dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 10-Methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 8,14-Dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 8,14-Dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 10-(propan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 8,14-Dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Methoxy-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 5-Fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 5-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(pyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[4-(propan-2-yl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-{2-oxa-6-azaspiro[3.4]octan-6-yl}-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[4-(oxetan-3-yl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(morpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 5-Methoxy-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(4,4-difluoropiperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(3,3-Difluoropyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[4-(2-methoxyethyl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 9,14-Dioxa-11,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-10-one; 4-[(3R)-hydroxypyrrolidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(2-methoxyethyl(methyl)amino)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]) tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-chloro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Fluoro-5-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4,5-Difluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 5-Bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(4-methylpiperazin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(3-Methoxyazetidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 1-{9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptan-4-yl}piperidine-4-carbonitrile; 4-[4-pyrrolidin-1-yl]piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(azetidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(piperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(2,5-dihydrofuran-3-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[4-(morpholin-4-yl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(2S,5S)-2,5-dimethylmorpholin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(morpholin-4-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(pyrrolodin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(pyrrolodin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(4-methylpiperazin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 5-(morpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[4-(2-methoxyethyl)piperazin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(diethylamino)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Cyclopropyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 5-(4-methylpiperazin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 13-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 8,14-Dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; 4-[methyl(oxetan-3-yl)amino]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(dimethylamino)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4,10-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(propan-2-yloxy)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(3-methylpiperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(3S)-3-Hydroxypyrrolidin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Fluoro-8,14-dioxa-10,19,20-triazapentacyclo[13.5.2.1 ２，６ .1 ７，１０ .0 １８，２１ ]tetracosa-1(20),2(24),3,5,15(22),16,18(21)-heptaen-9-one; 4-(oxolan-3-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13S)-13-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13R)-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-(1-methyl-1H-pyrazol-3-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (7S)-7-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-[2-(morpholin-4-yl)ethoxy]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-(2-Methoxyethyl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (7R)-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 5-Cyclopropyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(2-Methoxyethoxy)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-Fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 11-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(3-oxomorpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-(2-oxopyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 5-(2-oxopyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-(2-methylpyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 2-{9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-4-yl}acetonitrile; (11R)-11-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (11S)-11-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-ethynyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-(piperazin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-(1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 11-(methoxymethyl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 8,14-Dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; 11-methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; 12-Methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 11-Ethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-Fluoro-5,7-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 4-Fluoro-5-methoxy-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 5-Fluoro-4,7-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 8,14-Dioxa-10,19,20-triazapentacyclo[13.5.2.1 ２，６ .1 ７，１０ .0 １８，２１ ]tetracosa-1(20),2(24),3,5,15(22),16,18(21)-heptaen-9-one; 13-Methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 12-Methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; 7-Methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; 5-Fluoro-4-methoxy-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (7R,13R)-7,13-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13R)-13-methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2(23),3,15,17,21-hexaen-9-one; 8,15-dioxa-4,10,20,21-tetraazapentacyclo[14.5.2.1 ２，６ .1 １０，１３ .0 １９，２２ ]pentacosa-1(21),2(25),3,5,16(23),17,19(22)-heptaen-9-one; 8,14-Dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; (13S)-4-Fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13R)-4-fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13R)-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 6-Cyclopropyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; 7-Ethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13-ethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (7R,13R)-4-fluoro-7,13-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 7-Methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (7R)-4-Fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (7S)-4-Fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 6-methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2(23),3,15,17,21-hexaen-9-one; 7-Methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 6-(propan-2-yl)-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; (13R)-7,13-dimethyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; (13R)-13-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (7R)-7-Ethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (7S)-7-Ethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13-methyl-8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 6-(oxan-4-yl)-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2(23),3,15,17,21-hexaen-9-one; 4-Ethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2(23),15,17,21-pentaen-9-one; (13R)-23-fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 9,14-Dioxa-4,5,11,19,20-pentaazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2(23),3,15,17,21-hexaen-10-one; 4-Ethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2(23),3,15,17,21-hexaen-9-one; 3,9,15-trioxa-4,11,20,21-tetraazatetracyclo[14.5.2.1 ２，５ .0 １９，２２ ]tetracosa-1(21),2(24),4,16,18,22-hexaen-10-one; (13R)-16-fluoro-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-4-chloro-13-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 8,14-Dioxa-2,4,10,19,20-pentaazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),3,5(23),15(22),16,18(21)-hexaen-9-one; (13R)-4-Methoxy-13-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13-methyl-9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaene-5-carbonitrile; (13R)-13-methyl-4-(pyrrolidin-1-yl)-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (7S,13R)-7,13-dimethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (7R,13R)-7,13-dimethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-16-fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13-methyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 8,14-Dioxa-4-thia-10,19,20,23-tetraazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2,5(23),15,17,21-hexaen-9-one; 8,14-Dioxa-3-thia-10,19,20,23-tetraazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2(23),4,15,17,21-hexaen-9-one; (7R,13R)-7,13-dimethyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-4-[(3R)-3-methoxypyrrolidin-1-yl]-13-methyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-16-chloro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13,16-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13-methyl-8,14-dioxa-3,10,19,20,23-pentaazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 8-oxa-10,14,19,20-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one hydrochloride; 8-oxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13R)-5-methoxy-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,6(23),15,17,21-hexaene-5,9-dione; 4-Methyl-8,14-dioxa-3,4,10,19,20-pentaazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2,5(23),15(22),16,18(21)-hexaen-9-one; (13R)-16-fluoro-13-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 7,13-Dioxa-4-thia-9,18,19,22-tetraazatetracyclo[12.5.2.1 ２，５ .0 １７，２０ ]docosa-1(19),2,5(22),14(21),15,17(20)-hexaen-8-one; (13R)-4,13-dimethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 8,14-Dioxa-23-thia-4,10,19,20-tetraazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2,4,15(22),16,18(21)-hexaen-9-one; (7S,13R)-7,13-dimethyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13R)-13-methyl-9-oxo-8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaene-4-carbonitrile; 12,12-Difluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.

2. １２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13R)-17-fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (7S,13R)-7,13-dimethyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (7R,13R)-7,13-dimethyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13S)-13-Methyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (13R)-13-methyl-8,14-dioxa-10,19,20,22-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15,17,21-heptaen-9-one; (12R)-4,12-dimethyl-7,13-dioxa-4,9,18,19,22-pentaazatetracyclo[12.5.2.1 ２，５ .0 １７，２０ ]docosa-1(19),2,5(22),14(21),15,17(20)-hexaen-8-one; (13R)-13-methyl-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2(23),3,15,17,21-hexaen-9-one; (13R)-13-methyl-8,14-dioxa-23-thia-4,10,19,20-tetraazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2,4,15,17,21-hexaen-9-one; (13R)-4,13-dimethyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2,5(23),15(22),16,18(21)-hexaen-9-one; (13R)-13-methyl-8,14-dioxa-10,16,19,20-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 14-methyl-8-oxa-10,14,19,20-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15,17,21-heptaen-9-one; (13R)-13-methyl-8,14-dioxa-4,10,19,20,22-pentaazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15,17,21-heptaen-9-one; (13R)-13-methyl-8,14-dioxa-10,17,19,20-tetraazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 8,14-Dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; 12,12-Difluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2(23),3,15(22),16,18(21)-hexaen-9-one; (12R)-12-Fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (12S)-12-Fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; 12,12-Difluoro-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one; (12S)-12-Fluoro-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15,17,21-heptaen-9-one; (12R)-12-Fluoro-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosa-1(20),2(23),3,5,15,17,21-heptaen-9-one; (12S)-12-Fluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2(23),3,15,17,21-hexaen-9-one; (12R)-12-Fluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.1 ２，５ .0 １８，２１ ]tricosa-1(20),2(23),3,15,17,21-hexaen-9-one; or 8',14'-Dioxa-10',19',20'-triazaspiro[cyclopropane-1,13'-tetracyclo[13.5.2.1 ２，６ .0 １８，２１ ]tricosane]-1'(20'),2'(23'),3',5',15'(22'),16',18'(21')-heptaen-9'-one The compound according to claim 1, wherein

31. 31. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 30 or an addition salt thereof with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients.

32. 32. The pharmaceutical composition of claim 31 for use as an inhibitor of LRRK2 kinase activity.

33. 32. The pharmaceutical composition of claim 31 for use in the treatment of neurological disorders, endosomal-lysosomal disorders, inflammatory diseases, bacterial, viral and parasitic infections, cardiovascular diseases, autoimmune diseases, and cancer.

34. 34. The pharmaceutical composition of claim 33, wherein the neurological disease is selected from Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dementia, diabetic neuropathy, age-related memory impairment, mild cognitive impairment, argyrophilic grain dementia, Pick's disease, epilepsy, tauopathies such as progressive supranuclear palsy and corticobasal degeneration, other synucleinopathies such as multiple system atrophy, frontotemporal dementia, hereditary frontotemporal dementia and parkinsonism associated with chromosome 17 (FTDP-17), withdrawal / relapse associated with drug addiction, L-dopa-induced dyskinesia, ischemic stroke, traumatic brain injury, spinal cord injury, and multiple sclerosis.

35. 35. A pharmaceutical composition according to claim 34 for use in the treatment of Parkinson's disease or Alzheimer's disease.

36. 34. The pharmaceutical composition of claim 33, wherein the endosomal-lysosomal disorder is selected from Niemann-Pick disease type A, type B, or type C, Gaucher disease, Krabbe disease, Fabry disease, and disorders involving mitochondrial defects.

37. 34. The pharmaceutical composition of claim 33, wherein the inflammatory disease is selected from vasculitis, pulmonary diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, inflammatory myopathy, and ankylosing spondylitis.

38. 34. The pharmaceutical composition of claim 33, wherein the autoimmune disease is selected from Crohn's disease, inflammatory bowel disease, rheumatoid arthritis, ulcerative colitis, lupus, autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura, type I diabetes, obesity, Evans syndrome, bullous skin disorders, Sjogren's syndrome, Devic's disease, and leprosy.

39. 34. The pharmaceutical composition of claim 33, wherein the cancer is selected from thyroid cancer, renal cancer, breast cancer, hormone-related cancer, adenocarcinoma and squamous cell lung cancer, non-small cell lung cancer, colon cancer, prostate cancer, skin cancer, leukemia, and lymphoma.

40. 34. The pharmaceutical composition of claim 33, wherein the cardiovascular disease is stroke.

41. 34. The pharmaceutical composition of claim 33, wherein the bacterial or viral infection is selected from leprosy, tuberculosis, SARS-CoV, MERS-CoV and SARS-CoV-2, HIV, West Nile virus, and Chikungunya virus.

42. Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dementia, diabetic neuropathy, age-related memory impairment, mild cognitive impairment, argyrophilic grain dementia, Pick's disease, epilepsy, tauopathies such as progressive supranuclear palsy and corticobasal degeneration, other synucleinopathies, frontotemporal dementia, hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), withdrawal / relapse associated with drug addiction, L-dopa-induced dyskinesia, ischemic stroke, traumatic brain injury, spinal cord injury, multiple sclerosis, Niemann-Pick disease types A, B or C, Gaucher disease, Krabbe disease, Fabry disease, disorders associated with mitochondrial defects, Crohn's disease, inflammatory bowel disease, rheumatoid arthritis, ulcerative colitis 31. The compound of formula (I) according to any one of claims 1 to 30, or a pharmaceutically acceptable acid or base addition salt thereof, for use in the treatment of colitis, lupus, autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura, type 1 diabetes, obesity, Evans syndrome, bullous skin disorders, Sjogren's syndrome, Devic's disease, leprosy, thyroid cancer, kidney cancer (including papillary renal carcinoma), breast cancer, hormone-related cancers, adenocarcinoma and squamous cell lung cancer, non-small cell lung cancer, colon cancer, prostate cancer, skin cancer, leukemia (including acute myeloid leukemia), lymphoma, stroke, leprosy, tuberculosis, and SARS-CoV, MERS-CoV, SARS-CoV-2, HIV, West Nile virus and Chikungunya virus infections.

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