NOVEL MACROCYCLIC INHIBITORS OF LRRK2 KINASE

Abstract

Compounds of formula (I): (see Formula) wherein R, X1, X2, X3, Z1, Z2, Z3, A and Ra are as defined in the description.

Description

NOVEL MACROCYCLIC INHIBITORS OF LRRK2 KINASE FIELD OF INVENTION The present invention relates to novel macrocyclic compounds and compositions containing such compounds that act as kinase inhibitors, in particular, as inhibitors of LRRK2 (Leucine-Rich Repeat Kinase 2). Furthermore, the present invention provides processes for preparing the described compounds, pharmaceutical compositions containing them, and methods for using them, for example, as a pharmacological or diagnostic agent, particularly 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, but also cardiac diseases or inflammatory disorders such as Crohn's disease. BACKGROUND OF THE INVENTION 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 over 65 years of age and is characterized by the four classic central motor complications: resting tremor, bradykinesia, postural instability, and rigidity. Patients with Parkinson's disease are also affected by various non-motor symptoms such as constipation, hyposmia, orthostatic hypotension, sleep disturbances including REM sleep behavior disorder, dementia, visual disturbances, depression, anxiety, hallucinations, and mood swings. The standard of care for Parkinson's disease is the symptomatic relief of motor complications using dopamine replacement therapy, such as the dopamine precursor L-dopa, dopamine agonists, or compounds that affect the dopamine half-life, such as MAO-B inhibitors. To date, there is no approved therapy to prevent, cure, or slow the progression of Parkinson's disease. The distinctive pathological features of Parkinson's disease are the loss of dopaminergic neurons in the pars compacta of the substantia nigra, as well as postmortem evidence of protein inclusions, also known as Lewy bodies and Lewy neurites. In postmortem tissue from patients with Parkinson's disease, Lewy bodies and neurites are observed throughout the central nervous system, as well as in peripheral tissues. A major component of the inclusions is the aggregated and misfolded protein asynuclein, phosphorylated at a serine residue at amino acid position 129 (Natura 388, 839-840, 1997; Nat Cell Biol 4, 160-64, 2002).Lewy bodies and neurites also contain proteins implicated in other neurodegenerative diseases, such as hyperphosphorylated tau protein, a 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 in Parkinson's disease is not restricted to the loss of dopaminergic neurons in the basal ganglia system. Different neuronal populations in other brain regions, such as the neocortex, sleep nuclei, and raphe nuclei, are also affected. MA / a / ZUZZ / UI ÓOO I as peripheral organs and tissues such as the heart and gastrointestinal system are also affected by degenerative processes in patients with Parkinson's disease.Leucine-rich repeat kinase 2 (LRRK2) is a 2527-amino-acid protein with a molecular weight 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 Ras domain (Roe), Roe c-terminal domain (COR), map kinase (MAPK), and tryptophan-aspartate repeat domain (WD40). LRRK2 exists primarily as a dimeric protein, either closely associated with membrane structures or localized in the cytoplasm. The protein-protein interaction domains of the armadillo, ankyrin, LRR, and WD40 domains allow LRRK2 to interact with a multitude of different partner proteins, influencing its own subcellular localization as well as that of its partner proteins.The core enzyme of the LRRK2 protein, containing the Roc-COR and MAPK domains, has distinct GTPase and ATPase activities that allow LRRK2 to phosphorylate and control the function of intracellular substrates. Through its enzymatic activity and interactions with substrates, LRRK2 affects various subcellular processes and biological mechanisms important for the trafficking of vesicular structures and intracellular organelles such as lysosomes, endosomes, autophagosomes, the Golgi apparatus, and mitochondria. Structural work, as well as modeling, highlights how natural missense variation in the functional and structural domains of LRRK2 affects enzymatic activity (bioRxiv 2020.01.06.895367). In the inactive (open) conformation of LRRK2, important interactions exist between the GTPase (Roc-COR) and ATPase (MAPK) domains.Furthermore, the last C-terminus preceding the WD40 domain binds along the entire kinase (MAPK) domain. In the active (closed) conformation of LRRK2, the LRR domain positions the Ser1292 autophosphorylation site close to the kinase active site. Phosphorylation of LRRK2 at a cluster of serine residues immediately preceding the LRR domain allows the LRRK2 LRR domain to bind to 14-3-3 proteins. Among these phosphorylation sites are serine residues (Ser) at the following amino acid positions: Ser910, Ser935, Ser955, and Ser973. Pathogenic LRRK2 mutations originating in the GTPase domain have decreased phosphorylation at these sites and, therefore, reduced 14-3-3 binding, resulting in increased microtubule network recruitment.All ATP-competitive LRRK2 inhibitors induce dephosphorylation at the Ser910, Ser935, Ser955, and Ser973 sites, making these sites useful as surrogate target-binding markers (Biochem J 430(3), 405-13, 2010; J Neurochem 120(1), 37-45, 2012). Bona fide 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). 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 the serine at amino acid position 1292 (Sci Trans Med, 4(164), 164ra161, 2012). The estimated worldwide prevalence of the p.G2019S mutation in PD patients is 1-2%; however, in Ashkenazi Jewish and Berber populations... MA / a / ZUZZ / UI ÓOO I North African Arabs, the prevalence of p.G2019S in patients with PD is as high as 30% and 40%, respectively (Lancet Neurol 7, 583-90, 2008; N Engl J Med 354(4), 424-5, 2006; Lancet Neurol 7, 591-4, 2008). The clinical manifestation of Parkinson's disease in patients carrying the p.G2019S mutation is indistinguishable from that of patients with the sporadic form of Parkinson's disease (Ann Neurol 57(5), 762-5, 2005). In addition to p.G2019S, seven additional rare exonic variants of LRRK2 that have nonsynonymous amino acid substitutions in the central enzyme core (p.N1437H; p.R1441C / G / H; p.Y1699C; p.S1761R; p.l2020T) 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, 2012). As with p.In G2019S, the clinical presentations are indistinguishable from idiopathic PD (Neurology 70, 1456-60, 2008). Missense variants of LRRK2 exhibit increased phosphorylation of Ser1292, increased trans-Golgi recruitment by Rab29, and increased phosphorylation of Rab10 at amino acid position 73 (Rab10-Thr73), which can be reversed by LRRK2 inhibition (Sci Trans Med 4(164), 164ra161, 2012; EMBO J 37(1), 1-18, 2018; Proc Nati Acad Sci USA 111, 2626-31, 2014). Variants encoding common proteins in the LRRK2 gene are also associated with Parkinson's disease risk. Variants such as p.A419V, p.M1646T, p.R1628P and p.G2385R increase the risk of Parkinson's disease and have increased kinase activity (bioRxiv 447946, 2018) (Proc Nati Acad Sci USA 116(5), 1579-1584, 2019), while the p. variantN551K is associated with a reduced risk of Parkinson's disease (Lancet Neurol 10(10), 898-908, 2011) and has reduced kinase activity (bioRxiv 447946, 2018). Evidence that LRRK2 also plays a role in sporadic Parkinson's disease comes from genetic studies as well as post-mortem analyses of PD brains. A single nucleotide polymorphism (SNP) at the LRRK2 gene locus is genome-wide associated with Parkinson's disease risk (Nat Genet 46(9), 989-93, 2014). This particular SNP variant is associated with increased LRRK2 expression (Sci Trans Med 9 (421), 2017), which is consistent with the increased LRRK2 kinase activity observed in surviving dopamine neurons from post-mortem brains of patients with sporadic PD (Sci Trans Med 10 (451), 2018). Therefore, LRRK2 kinase activity inhibitors can be used as therapies for patients with sporadic PD, as well as for patients with PD with LRRK2 mutations or Rab29 / Rab7L1 polymorphisms. Risk loci for Parkinson's disease containing several genes encoding proteins involved in endosomal-lysosomal processes, such as GBA, SCARB2, GALC, VPS35, LAMP1, VPS13C, VPS35, TMEM175, ATP6V0A1, and CTSB, have been identified by Genome-Wide Association Studies (GWAS) and linkage studies. LRRK2 also plays a key role in the endosomal-lysosomal system and in processes linked to endosomal function, such as autophagy and mitophagy. LRRK2 interacts with the α subunit of vacuolar H+-ATPase to regulate lysosomal pH, and rotenone-induced endosomal-lysosomal dysfunction, caused by a toxin known to be associated with an increased risk of Parkinson's disease, can be alleviated by LRRK2 inhibition (Neurobiol Dis 134, 104626, 2020). Disease-causing mutations in LRRK2 induce lysosomal stress by enlarging lysosomes (Hum Mol Genet 24(21), 6013-28, 2015).Likewise, a mutation with a change of direction of. MA / a / ZUZZ / UI ÓOO I The aspartate to asparagine mutation in the VPS35 retromer complex protein at amino acid position 620 (VPS35-D620N) causes late-onset autosomal dominant familial Parkinson's disease. In the disease state, the VPS35-D620N missense mutation disrupts cathepsin D trafficking, the protease responsible for the degradation of α-synuclein (Traffic 15(2), 230-44, 2014), and activates LRRK2, resulting in increased autophosphorylation at the Ser1292 site of LRRK2 and increased phosphorylation of Thr73 of Rab10 (Biochem J 475(11), 1861-1883, 2018). In lysosomes, LRRK2 interacts with GBA, which is causally linked to lysosomal storage disorder, Gaucher disease, and a risk gene for Parkinson's disease. Missense mutations in LRRK2 reduce GBA activity, which can be counteracted by LRRK2 inhibition (Nat Commun 10(1), 5570, 2019).Conversely, deficits relevant to GBA disease in lysosomal biology 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 early-onset autosomal recessive Parkinson's disease that is associated with mitochondrial dysfunction (Science 304(5674), 1158-60, 2004; Nature 392(6676), 605-8, 1998). LRRK2-dependent phosphorylation of Rab8a at threonine position 72 is modulated by PINK1 phosphorylation of serine at amino acid position 111 in Rab8a (Biochem J. Mar 30, 2020, doi: 10.1042 / BCJ20190664). Furthermore, this LRRK2 activity disrupts mitophagy, which is normally regulated by the PINK1 / PARKIN pathway. This can be reversed by LRRK2 inhibition (Hum Mol Genet 28(10), 1645-1660, 2019).LRRK2 missense mutations cause mitochondrial DNA damage that can be reversed by gene corrections (Neurobiol Dis 62, 381-6, 2014), as well as with LRRK2 inhibitors (Hum Mol Genet. 26(22), 4340-4351, 2017). This suggests that LRRK2 inhibitors are useful for treating lysosomal storage disorders such as Gaucher disease, Krabbe disease, Niemann-Pick disease, and Fabry disease, disorders with mitochondrial deficiencies including early-onset Parkinson's disease associated with missense mutations of PINK1 and PARKIN, as well as Parkinson's disease in patients with polymorphisms in genes encoding proteins involved in the endosomal-lysosomal system such as GBA, GALO, VPS35, VPS13C, ATP6V0A1, LAMP1, SCARB2, TMEM175, and CTSB. Post-mortem analysis of brains from Parkinson's disease patients carrying LRRK2 mutations shows the presence of α-synuclein pathology (JAMA Neurol. 72(1), 100-5, 2015). In preclinical models of Parkinson's disease (PD), p.G2019S exacerbates PD-related pathology that can be reversed by LRRK2 inhibition. LRRK2 has been identified in Lewy bodies in nigral and brainstem regions (Neuropathol Appl Neurobiol 34(3), 272-83, 2008) and has also been shown to phosphorylate α-synuclein at Ser129 (Biochem Biophys Res Commun 387(1), 149-52, 2009). Exonic variation of LRRK2 is associated with 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 at 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 involved. MA / a / ZUZZ / UI ÓOO I is a prominent feature observed in Parkinson's disease patients with LRRK2 missense mutations (Acta Neuropathol Commun 7(1), 183, 2019). Pathogenic LRRK2 overexpression 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 variation in the LRRK2 locus is associated with survival in primary tauopathy, progressive supranuclear palsy (bioRxiv 2020.02.04.932335) and GWAS studies have identified risk of frontotemporal dementia in the LRRK2 locus (PLoS Med 15(1), e1002487, 2018). This suggests that LRRK2 inhibitors are useful for treating synucleinopathies and tauopathies, including frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, and Alzheimer's disease. LRRK2 mRNA and protein are widely expressed, but are particularly enriched in brain tissue, as well as in peripheral organs, specifically the kidney, lung, intestine, and spleen. Furthermore, LRRK2 expression is highly enriched in immune cells in the brain and in neutrophils, B cells, macrophages, and monocytes in the periphery. LRRK2 mRNA and protein expression is induced by pro-inflammatory or pathogenic stimuli, thereby increasing LRRK2 kinase activity. In human peripheral blood mononuclear cells, the LRRK2 substrates Rab10 and Rab2 are phosphorylated after stimulation with reagents that mimic viral infections (Sci Rep 7(1), 10300, 2017).Consistent with the fact that LRRK2 biology plays a role in response to inflammatory stimuli, LRRK2 missense mutations are associated with an increased risk of the inflammatory bowel disorder Crohn's disease, and GWAS studies have identified single nucleotide polymorphisms at the LRRK2 locus associated with a significant genome-wide risk of Crohn's disease (Inflamm Bowel Dis 17(12), 2407-15, 2011). In Ashkenazi Jewish populations, there is a two- to four-fold increased prevalence of Crohn's disease, and in the same population, LRRK2 variants are associated with an increased risk of Crohn's disease (PLoS Genet 14(5), e1007329, 2018). Exonic variants of LRRK2 such as p.N2081D and p.M2397T increase the risk of Crohn's disease, and, as observed for Parkinson's disease, the protective haplotype variant p.N551K / p.R1348H decreases the risk of Crohn's disease.In cell-based studies, the p.N2081D variant has increased kinase activity, leading to increased phosphorylation of Rab10 (bioRxiv 447946, 2018; Sci Trans Med 10(423), 2018). The biological link between Parkinson's disease and autoimmune disorders is further supported by studies that have found shared genetic pathways, including LRRK2, between Parkinson's disease and autoimmune disorders such as rheumatoid arthritis, ulcerative colitis, and Crohn's disease (JAMA Neurol 74(7), 780-92, 2017). Consistent with this, LRRK2 is also associated with risk of lupus (Oncotarget8, 13754-61, 2017; J Transí 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). 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. MA / a / ZUZZ / UI ÓOO I LRRK2 plays a role in tumor growth in renal and thyroid cancers by affecting MET signaling, and decreased LRRK2 expression induces growth arrest (Proc Nati Acad Sel USA 108(4), 1439-44, 2011). LRRK2-PD patients have an increased risk of leukemia, as well as skin and colon cancers (Mov Disord 34(9), 1392-8, 2019). Carriers of p.G2019S also have an increased overall risk of non-skin cancers; in particular, breast cancer and hormone-related cancers in women (JAMA Neurol 72(1), 58-65, 2015). Studies have shown that silencing LRRK2 promotes inhibition of T cell growth and facilitates apoptosis and cell cycle arrest (IntJ Oncol 55(1), 21-34, 2019).LRRK2 is also differentially expressed in lung adenocarcinomas and lung squamous cell carcinomas, as well as non-small cell lung cancer (J Cell Physiol 234(7), 10918-25, 2019; J Cell Physiol 234(12), 22742-52, 2019). Therefore, LRRK2 inhibitors have anticarcinogenic effects and can be used for the treatment of skin cancer and non-skin cancers such as kidney cancer, colon cancer, squamous and adeno-lung cancers, non-small cell lung cancer, hormone-related cancer, thyroid cancer, leukemia, and breast cancer. The extended prior art is known in the field of LRRK2 inhibitors. The most recent patent applications filed in the field cover oligomeric derivatives such as the compounds described in WO2020 / 006267, non-macrocyclic or polycyclic structures such as the compounds described in WO2019 / 222173, WO2019 / 112269, WO2019 / 074809, WO2018 / 217946, WO2018 / 163066, WO2018 / 155916, WO2018 / 137618, WO2018 / 06931, and also macrocyclic derivatives such as the compounds described in WO2019 / 012093, WO2016 / 042089. Despite the large number of structures developed in recent years, there is a continuing need to design new scaffolds that have improved potency and selectivity to meet unmet medical needs. DETAILED DESCRIPTION OF THE INVENTION The present invention is described below. In the following passages, different aspects of the invention are defined in more detail. Each aspect thus defined may be combined with any other aspect or aspects, unless clearly stated otherwise. In particular, any feature stated as preferred or advantageous may be combined with any other feature or features stated as preferred or advantageous. In a first aspect, the present invention provides a compound of Formula (I) ML / a / ZUZZ / U 1 ÓOO I ΜΛ / a / ZUZZ / U 1 ÓOO I where: ♦ R represents a hydrogen atom, a halogen atom, or an alkyl group, ♦ Z1, Z2, Z3 each independently represent a carbon or nitrogen atom, it being understood that the 6-membered ring containing Z1, Z2, and Z3 may 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 alkanedyl group optionally substituted with one or more identical or different substituents selected from halogen atoms, polyhalogenalkyl groups, alkoxy groups, hydroxy groups, amino groups, alkylamino groups, dialkylamino groups, and cyano groups, it being understood that the carbon atom in the alpha position of -N(Ra), and the carbon atom in the alpha 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 substituents,identical or different, selected from halogen atoms, polyhalogenalkyl group, alkoxy group, hydroxy group, amino group, alkylamino group, dialkylamino group, cyano group, cycloalkyl group and heterocycloalkyl group, it being understood that the carbon atom in the alpha position of -O-, and the carbon atom in the alpha 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, it being understood that when Ra represents an alkyl group, a carbon atom of Ra can be bonded to a carbon atom of -X2-, or to a carbon atom of -X3- to form a cyclic residue containing 5 or 6 ring members, ♦ A represents an aromatic or partially hydrogenated cyclic group of formula (a):, * A1—A2 / α\ A5χA3 (a)ϧA4 / where X A1, A4 each independently represents a carbon atom or a nitrogen atom, X A2, A3, A5 each independently represents a carbon atom, an oxygen atom, a sulfur atom or a nitrogen atom, it being understood that A1, A2, A3, A4 and A5 cannot simultaneously represent a heteroatom, or an aromatic or partially hydrogenated cyclic group of formula (b): MA / a / ZUZZ / UI ÓOO I A A'2 (b) \---A'3 wherein A', A'2, A'3, A'4 each independently represents a carbon atom or a nitrogen atom, it being understood that * means that the bond is attached to X3, the aromatic or partially hydrogenated cyclic group A thus defined being optionally substituted with one or more identical or different substituents selected from halogen atoms, alkyl group, alkoxy group, hydroxy group, oxo group, alkoxyalkyl group, alkoxyalkoxy group, polyhalogenalkyl group, polyhalogenalkoxy group, heterocycloalkyl group, heterocycloalkylalkyl group, (alkoxyalkyl)(alkyl)amino group, amino group, alkylamino group, dialkylamino group, cycloalkyl group, (heterocycloalkyl)(alkyl)amino group, dialkylaminoalkyl group, heterocycloalkylalkoxy group, cyano group, and cyanoalkyl group, wherein the group heterocycloalkyl and cycloalkyl as defined may be optionally substituted with one or more alkyl group substituents,halogen atoms, polyhalogenalkyl group, polyhalogenalkoxy group, alkoxy group, alkoxyalkyl group, hydroxy group, cyano group and oxo group, their enantiomers, diastereomers, tautomers, racemic, hydrates, solvates, N-oxide, isotopes, deuterated derivatives and addition salts thereof with a pharmaceutically acceptable acid or base. When describing the compounds of the invention, the terms used should be considered according to the following definitions, unless the context dictates otherwise: The term alkyl, by itself or as part of another substituent, refers to a fully saturated monovalent hydrocarbon radical, including the corresponding deuterated derivatives. The alkyl groups of this invention comprise from 1 to 6 carbon atoms. The alkyl groups may be linear or branched, may include a spiro structure, and may be optionally substituted as indicated 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. The term “alkanedyl” means a fully saturated divalent hydrocarbon radical having two single bonds for attachment to two other groups, and may be represented as the “-(alkyl)-” group, where alkyl is as defined above. The alkanedyl groups of this invention comprise from 1 to 6 carbon atoms, may be linear or branched, may include a spiro structure, and may be substituted as indicated herein. Non-limiting examples of alkanedyl groups include: -CH2-, -CH2-CH2-, -CD2-, -CD2-CD2-, -CH(CH3)-, -CH(CH2-CH3)-, -CH(i-Pr)-, -C(CH3)(CH3)-, -CH2H2C—CH2H2C—CH2H2C—CH2H2C—CH C(CH3)(CH3)-, -CH2-CH2-C(CH3)(CH3)-, -ch2 -CH2-CH(i-Pr)-, -CH(i-Pr)-CH2-, -CH2-CH(i-Bu)-, -CH(¡-Bu)-CH2-, -CH(CH3)-CH2-, -CH2-CH(CH3)-, -CH2-CH2-CH2-, -CD2-CD2CD2-, -CH(CH3)-CH2-CH2-, -CH2-CH2-CH(CH3)-, -CH2-CH(CH3)-CH2-, -CH(CH3)-CH2-CH(CH3)-, -CH2-CH2CH(CH2-CH3)-, -CH(CH2-CH3)-CH2-CH2-, -CH(CH2-CH3)-CH2-CH(CH3)-, -CH(CH3)-CH2-CH(CH2-CH3)-, -CH(CH3)-CH2-CH(CH2-CH3)-, For example, an alkanedyl group substituted with an alkoxy group will include, but not be limited to, -CH(OCH3)-, -CH(OCH3)CH(CH3)-, -CH2-CH2-CH(OCH3)-, -CH(OCH3)-CH2-CH2-, -CH2-CH2-CH(CH2-OCH3)-, -CH(CH2-OCH3)-CH2CH2-, -CH(O-CH2-CH3)-CH2-, -CH2-CH(O-CH2-CH3)-. As another non-limiting example, an alkanedyl group substituted with a cycloalkyl group will include -CH2-CH(Cy-Pr)-, -CH(Cy-Pr)-CH2-, where Cy-Pr stands for cyclopropyl.An alkanedyl group substituted with one or more halogen atoms includes, for example, but is not limited to, -CHF-, -CHF-CH2-, -CF2-, -CF2-CH2-, -CH2-CF2-. An alkanedyl group substituted with a heterocycloalkyl group will include, for example, but is not limited to, -CH2-CH(tetrahydropyranyl)-, -CH(tetrahydropyranyl)-CH2-, -CH2-CH(oxolanyl)-, -CH(oxolanyl)-CH2-. The term “cycloalkyl,” either by itself or as part of another substituent, refers to a monovalent, saturated, or unsaturated hydrocarbon group having one or two cyclic structures. Cycloalkyl includes all saturated, partially saturated, or aromatic hydrocarbon groups having one or two cyclic structures. Cycloalkyl groups comprise three or more carbon atoms and, generally, according to this invention, comprise from three to ten carbon atoms. Examples of cycloalkyl groups that have a cyclic structure include, but are not limited to, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. When considering a bicyclic ring structure, the two rings can be: fused, meaning 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-1 / 7-indenyl; joined by a bond between the two cyclic structures; exemplary cycloalkyl bicyclic linked systems include, but are not limited to, biphenyl, bicyclopropanyl, bicyclopentenyl, bicyclohexanyl, cyclopropylcyclohexanyl, cyclopropylcyclopentanyl; with a bridge, meaning that the two rings share three or more atoms, separating the two MA / a / ZUZZ / UI ÓOO I atoms at the head of the bridge by a bridge containing at least one atom; exemplary cycloalkyl bicyclic bridged systems include, but are not limited to, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl; or represent a spiro bicyclic ring system wherein the two rings are connected through a single atom; exemplary spiro bicyclic ring systems include, but are not limited to, spiro[2.2]pentanyl, spiro[2.4]heptanyl, spiro

[44] nonanyl, spiro[5.5]undecanyl. The “cycloalkyl group” thus defined, may be optionally substituted with 1 to 3 substituents chosen from alkyl groups, halogen atoms, polyhalogenalkyl groups, polyhalogenalkoxy groups, alkoxy groups, alkoxy groups, alkoxyalkyl groups, hydroxy groups, cyano groups, and oxo groups. When the cycloalkyl group is substituted with 2 or 3 substituents, the substituents may be present on the same atom or on different atoms, provided that the valency of each atom is respected. The term “alkoxy,” either by itself or as part of another substituent, refers to an “(alkyl)-O-” group, where “alkyl” is as 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). The term “alkoxyalkyl” refers to a “(alkyl)-O-(alkyl)-” group, where “alkyl” is as defined above. Non-limiting examples include CH3-O-CH2- and CH3-O-CH2-CH2-. The term “alkoxyalkoxy” refers to a “(alkyl)-O-(alkyl)-O-” group where “alkyl” is as defined above. Non-limiting examples include CH3-O-CH2-O-, CH3-O-CH2-CH2-O-. The term “alkylamino” refers to a “-NH-(alkyl)” group, where “alkyl” is as defined above. Non-limiting examples include -NH-CH3, -NH-CH2-CH3, and -NH-CH(CH3)(CH3). The term “dialkylamino” refers to an “-N(alkyl)(alkyl)” group, where “alkyl” is as defined above. Non-limiting examples include -N(CH3)2 and -N(CH3)(CH2-CH3). The term “polyhalogenalkyl” refers to an alkyl group as defined above in which one or more hydrogen atoms, borne on the same or different carbon atoms, are replaced by one or more halogen atoms. Non-limiting examples include fluoromethyl, difluoromethyl, trifluoromethyl, and 2-chloroethyl. The term “polyhalogenalkoxy” refers to a “(polyhalogenalkyl)-O-” group, where “polyhalogenalkyl” is as defined above. Non-limiting examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2-chloroethoxy. The term “heterocycloalkyl” means a monocyclic or bicyclic, aromatic or non-aromatic, monovalent carbocyclic group containing 3 to 10 ring members and 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen atoms. The heterocycloalkyl group may be attached by a carbon or nitrogen atom when possible. The heterocycloalkyl group thus defined may be a monocyclic or bicyclic ring system. Monocyclic heterocycloalkyl ring systems include, but are not limited to, pyridinyl, piperazinyl, piperidinyl, tetrahydropyridinyl, tetrahydropyranyl, pyrrolidinyl, dihydropyrrolyl, oxolanyl, dihydrofuranyl, morpholinyl, pyrazolyl, azetidinyl, and oxethanyl. When considering a bicyclic ring system, the two rings may be: fused, meaning they share a common link; bicyclic fused systems MA / a / ZUZZ / UI ÓOO I heterocycloalkyl examples include, but are not limited to, indolyl, indolinyl, benzopyranyl, benzofuranyl, naftiridinyl, quinolinyl, pyridopyrazinyl, pyridopyridazinyl, pyridopyrimidinyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydrobenzofuranyl, benzopyranyl, dihydrobenzopyranyl; joined by a bond between the two cyclic structures; exemplary heterocycloalkyl bicyclic linked systems include, but are not limited to, phenylpyridinyl, bipyridinyl, oxetanylpyridinyl, oxetanylpiperidinyl, oxetanyltetrahydropyridinyl, pyrrolidinylpiperidinyl, morpholinopiperidinyl, pyrrolidinyltetrahydropyridinyl, pyrrolidinylpyridinyl, oxetanylpiperazinyl, pyrrolidinylpiperazinyl; bridged, meaning that the two rings share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom; exemplary heterocycloalkyl bicyclic bridged systems include, but are not limited to, azabicyclo[2.2.1]heptanyl, oxaazabicyclo[2.2.1]heptanyl; or represent a spiro bicyclic ring system in which the two rings are connected through a single atom; exemplary spiro heterocycloalkyl bicyclic systems include, but are not limited to, oxaspirooctane, azaspirooctane, diazaspirooctane, oxaazaspirooctane, oxaspirononane, azaspirononane, diazaspirononane, oxaazaspirononane. The “heterocycloalkyl group” thus defined may be optionally substituted with 1 to 3 substituents chosen from alkyl groups, halogen atoms, polyhalogenalkyl groups, polyhalogenalkoxy groups, alkoxy groups, alkoxy groups, alkoxyalkyl groups, hydroxy groups, cyano groups, and oxo groups. When the heterocycloalkyl group is substituted with 2 or 3 substituents, the substituents may be present on the same atom or on different atoms, provided that the valency of each atom is respected. The term “heterocycloalkylalkyl” refers to a “(heterocycloalkyl)-(alkyl)-” group where the heterocycloalkyl and alkyl groups are as defined above. Non-limiting examples include morpholinylmethyl, pyrrolidinylmethyl, piperazinylmethyl, and piperidinylmethyl. The term “halogen atoms” means an atom of fluorine, chlorine, bromine, or iodine. Among the pharmaceutically acceptable acids, without implying any limitation, the following can be mentioned: 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, etc. Among the pharmaceutically acceptable bases, without implying any limitation, one can mention sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc. Specific embodiments of compounds of formula (I) of the invention are described below. The characteristics of these specific embodiments may be taken individually or in combination to generate new specific embodiments. In one specific embodiment, the invention most preferably relates to compounds of formula (I) where R represents a hydrogen atom. In another embodiment, R advantageously represents a halogen atom, and most preferably a fluorine or chlorine atom. When R is an alkyl group, it is preferably a methyl group. R is preferably attached to Z2 when Z2 represents a carbon atom. MA / a / ZUZZ / UI ÓOO I In another preferred specific embodiment of the invention, Z1, Z2 and Z3 simultaneously represent a carbon atom. In an advantageous alternative embodiment, one of Z1, Z2, and Z3 is a nitrogen atom, while the other two represent a carbon atom. More specifically, when one of Z1, Z2, and Z3 represents a nitrogen atom, it is preferably Z1 or Z2. Another specific embodiment of the invention relates to compounds of formula (I) wherein -X1 represents -O- or -NH-. More preferably, -X1- represents -O-. In another specific embodiment of the invention, -X2- represents a linear or branched alkanedyl group having 2, 3, 4, or 5 carbon atoms, and more preferably 3, 4, or 5 carbon atoms. -X2- is preferably unsubstituted. When -X2- is substituted, a fluorine or methoxy group is preferred. Advantageously, -X2 represents -(CH2)2-, -(CH2)3-, -CH(CH3)-(CH2)2-, -(CH2)2-CH(CH3)-, -CH2-CH(CH3)-CH2-, H2C—ch22, -CH2-CHF-CH2-, -CH2-CF2-CH2-, -(CH2)2-CH(CH2-CH3)- or -CH(CH2-CH3)-(CH2)2-. Even more preferably, -X2- represents -(CH2)3-, -CH(CH3)-(CH2)2-, -(CH2)2-CH(CH3)-, -CH2-CF2-CH2- or -CH2-CHF-CH2-, The preferred value for Ra in compounds of formula (I) is hydrogen atom. In another specific embodiment of the invention, -X3- represents a linear or branched alkanedyl group having 1, 2, 3, 4, or 5 carbon atoms, and more preferably 1 or 2 carbon atoms. -X3 is preferably 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)-, -CH(CyPr)-CH2-. Even more preferably, -X3- represents -(CH2)2-, -CH2-, or -CH(CH3)-. Another specific embodiment of the present invention is represented by the compounds of formula (I) for which A represents a group of formula (b): MA / a / ZUZZ / UI ÓOO I The preferred values ​​for (ΑΊ, A'2, A'3, A'4) are: four carbon atoms, or three carbon atoms and one nitrogen atom, more preferably with the nitrogen atom in A'4, or two carbon atoms and two nitrogen atoms. A'3 is advantageously a carbon atom. As a particular modality of the invention, A represents the following supports, being represented in this specification without any substitution: The most preferred form for A in formula (b) is a phenyl or pyridinyl group. An alternative MA / a / ZUZZ / UI ÓOO I advantageous for A is a pyrazinyl group. An advantageous alternative to A is represented by the group of formula (a): The most preferred support of formula (a) contains one, two, or three heteroatoms, one of which is a nitrogen atom. The representative preferred supports of formula (a) are as follows, represented herein without substitution: The most preferred form for A of formula (a) is a triazolyl or pyrazolyl group. Preferably, group A of the compounds of formula (I) is not substituted. When group A of the compounds of formula (I) is substituted, the substitution can occur at any carbon or nitrogen atom of the A supports that has at least one free valency. The most preferred substitutions include halogen atoms, cyano groups, cyanoalkyl groups, oxo groups, alkoxy groups, alkyl groups, cycloalkyl groups, and heterocycloalkyl groups. In particular, preferred substitutions include fluorine, bromine, or chlorine atoms, methyl, ethyl, cyclopropyl, methoxy, isopropyloxy, cyano, cyanomethyl, and oxo groups. The most preferred heterocycloalkyl groups include pyrrolidinyl group, piperazinyl group, morpholinyl group, azetidinyl group, piperidinyl, tetrahydropyridinyl, tetrahydrofuranyl, dihydrofuranyl, oxetanyl, pyrazolidinyl. The most preferred substitutions in group A are fluorine or bromine atom, methoxy group, methyl group, ethyl group, unsubstituted or substituted pyrrolidinyl group, unsubstituted or substituted piperazinyl group. Another specific embodiment of the invention is represented by the compounds of formula (la): ML / a / ZUZZ / U 1 ÓOO I where X1, X2, X3, Ra and A are as defined for formula (I). In another preferred embodiment, the invention relates to compounds of the formula (lb): where X2, X3, Ra, and A are as defined for formula (I). The most preferred compounds of formula (lb) are those for which -X2- represents -(O-)2)3-, -CH(CH3)-(CH2)2-, -CH2-CHF-CH2-, -CH2CF2-CH2-, or -(CH2)2-CH(CH3)-. Other most preferred compounds of formula (lb) are those for which X3- represents -CH2- or -(CH)(CH3)-. Another specific embodiment of the invention relates to compounds of formula (I) for 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)2NH-C(O)O-CH2-, -O-CH2-CHF-CH2-NHC(O)O-CH2-, -O-CH2-CF2-CH2-NHC(O)O-CH2-, -O-CH(CH3)-(CH2)2NHC(O)O-(CH2)2- or -O-CH(CH3)-(CH2)2-NH-C(O)O-CH(CH3)-. Preferably, compounds of the invention are compounds of the formula (lc) or (l-c'): ΜΛ / a / ZUZZ / U 1 ÓOO I where X1, X2, X3, Ra, ΑΊ, A'2 and A'4 are as defined for formula (I). Another specific modality is related to compounds of the formula (ld) or (l-d'): where X2, X3, Ra, A'2, and A'4 are as defined for formula (I). The most preferred compounds of formula (ld) or (l-d') are those for which -X2- represents -(O-)2)3-, -CH(CH3)-(CH2)2-, CH2-CHF-CH2-, -CH2-CF2-CH2-, or -(CH2)2-CH(CH3)-. Other most preferred compounds of formula (ld) or (Id') are those for which -X3- represents -CH2- or -(O-)2)2-. Other preferred compounds of the invention are the compounds of formula (le): where X1, X2, X3, Ra, A1, A2 and A5 are as defined for formula (I). Other preferred compounds of the invention are the compounds of formula (lf): ML / a / ZUZZ / U 1 ÓOO I where X2, X3, Ra, A1, A2 and A5 are as defined for formula (I). The most preferred compounds of formula (lf) are those for which -X2- represents -(CH2)3-, -CH(CH3)-(CH2)2-, -CH2-CHFCH2-, -CH2-CF2-CH2- or -(CH2)2-CH(CH3)-. Other most preferred compounds of formula (lf) are those for which -X3- represents -CH2- or -(CH2)2-. In another specific embodiment, the preferred compounds of the invention are: 8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.12'6.018'21]tricose-1 (20),2,4,6(23), 15,17,21heptaen-9-one; 10-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2,4,6(23), 15,17,21 -heptaen-9-one; 4-fluoro-8,14-dioxa-10,19,20-triazatetracyl[13.5.2.12'6.01821]tricosa-1(20),2,4,6(23),15,17,21heptaen-9-one; 8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.12'6.01821]tricose-1 (20),2,4,6(23), 15,17,21heptaen-9-one; 8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.01821]tricosa-1 (20),2,4,6(23),15,17,21 -heptaen-9one; 10-(propan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.12'6.018'21]tricosa1(20),2,4,6(23),15,17,21-heptaen-9-one; 8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.12'6.018'21]tricosa-1(20),2,4,6(23), 15,17,21heptaen-9-one; 4-methoxy-8,14-dioxa-10,19,20-triazatetrac¡clo[13.5.2.126.018'21]tr¡cosa-1(20),2,4,6(23),15,17,21heptaen-9-one; 4-bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricosa-1 (20),2,4,6(23), 15,17,21heptaen-9-one; 5-fluoro-8,14-d¡oxa-10,19,20-tr¡azatetraciclo[13.5.2.12'6.018'21]tr¡cosa-1(20),2,4,6(23),15,17,21heptaen-9-one; 5-methi I-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricosa-1 (20),2,4,6(23), 15,17,21heptaen-9-one; 4-(pyrrolidine-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12-6.018'21]tricosa1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[4-(propan-2-yl)p¡perazin-1-¡l]-8,14-dioxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,11-hep-one; 4-{2-oxa-6-azaespiro[3.4]octane-6-¡l}-8,14-d¡oxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23,5,17-19-hepta; 4-[4-(oxetan-3-yl)piperaz¡n-1-¡l]-8,14-d¡oxa-10,19,20-triazetetracyclo[13.5.2.126.018'21]tricose1 (20) ,2,4,6(23), 15,17, 219-hep-one; 4-(morphol¡n-4-¡l)-8,14-d¡oxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,12-heptaene; 4-[(2R,6S)-2,6-d¡meth¡lmorphol¡n-4-¡l]-8,14-dioxa-10,19,20-tr¡azatetrac ¡chlo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018-21]tricose-1 (20),2,4,6(23), 15,17,21heptaene-9-one; 5-methoxy¡-8,14-d¡oxa-10,19,20-triazatetrac¡chlo[13.5.2.126.018'21]tr¡cosa-1(20),2,4,6(23),15,17,21heptaen-9-one; 4-(4,4-d¡fluoropipend¡n-1-yl)-8,14-d¡oxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-hep-one; 4-(3,3-difluoropyrrol¡d¡n-1-¡l)-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-hepone; 7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose-1 (20),2,4,6(23), 15,17,21heptaene-9-one; 4-[4-(2-methox¡et¡l)p¡per¡d¡n-1-¡l]-8,14-d¡oxa-10,19,20-tr¡azatetrac¡ clo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,21-heptaen-9-ona; 9,14-dioxa-11,19,20-triazatetracyclo[13.5.2.126.018'21]tr¡cosa-1 (20),2,4,6(23),15,17,21 -heptaene-10one; 4-[(3R)-3-hydrox¡p¡rrol¡d¡n-1-yl]-8,14-d¡oxa-10,19,20-triazatetracyclo[13.5.2.126.018'21]tricose1 (20) ,2,4,6(23,217), -heptane-9-one; 4-[(2-methox¡ethyl)(meth¡l)am¡no]-8,14-d¡oxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),17,2-9-hepta; 4-chloro-8,14-dioxa-10,19,20-triazatetrac¡chlo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21heptaene-9-one; 4-fluoro-5-methyl-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tr¡cosa1 (20) ,2,4,6(23), 15,17,21 -heptaen-9-one; 4,5-difluoro-8,14-d¡oxa-10,19,20-triazatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa-1(20),2,4,6(23),15,17,21heptaen-9-one; 5-bromo-8,14-d¡oxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21 ΜΛ / a / ZUZZ / U 1 ÓOO I heptaen-9-one; 4-(4-methylpiperazin-1-yl)-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1 (20) ,2,4,6(23), 15,17,21 -heptane-9-one; 4-(3-methoxy¡azet¡d¡n-1-yl)-8,14-dioxa-10,19,20-triazatetrac¡clo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,17-hep-one; -{9-OXO-8,14-dioxa-10,19,20-triazatetrac¡chlo[13.5.2.126.018'21]tricose-1 (20),2,4,6(23), 15,17,21heptaene-4-¡l}piper¡d¡d¡4-tr¡lo; 4-[4-(pyrrolidin-1 -yl)piperidin-1-yl]-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018 21]tricose1(20),2,4,6(23),15,17,21-heptaene-9-one; 4-(azet¡d¡n-1-¡l)-8,14-d¡oxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,2-heptaene; 4-(p¡per¡d¡n-1-¡l)-8,14-dioxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(2,5-dihydrofuran-3-¡l)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[4-(morphol¡n-4-¡l)p¡per¡d¡n-1-¡l]-8,14-d¡oxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.018'21]tr¡cosa1 (2,2,2,2),(2) 15,17,21 -heptaene-9-one; 4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20triazatetracido[13.5.2.12'6.018'21]tricose-1 (20),2,4,6(23),15,17,2 -hepone; 4-[(2S,5S)-2,5-dimethylmorpholin-4-yl]-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-hepone; 4-[(morphol¡n-4-¡l)met¡l]-8,14-d¡oxa-10,19,20-tr¡azatetracyclo[13.5.2.12íi.018'21]tricose1 (20) ,2,4,6(23), 15,17, 219-hephona; 4-[(p¡rrol¡n-1-¡l)meth¡l]-8,14-d¡oxa-10,19,20-tr¡azatetrac¡chlo[ 13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(p¡rrol¡n-1-¡l)met¡l]-8,14-d¡oxa-10,19,20-tr¡azatetracyclo[13.5.2.126.018'21]tr¡cosa1(20),2,4,6(23,2,17-17-hep; 4-[(4-methylpiperaz¡n-1-yl)methyl]-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one; 5-(morphol¡n-4-¡l)-8,14-dioxa-10,19,20-triazatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[4-(2-methoxyet¡l)p¡perazine-1-¡l]-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,17-hep-one; 4-(d ieti lam ino)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricosa1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-c¡cloprop¡l-8,14-d¡oxa-10,19,20-tr¡azatetracyclo[13.5.2.12601821]tricose-1(20),2,4,6(23),15,17,21heptaene-9-one; 5-(4-meth¡lp¡peraz¡n-1-yl)-8,14-d¡oxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,17-hep-one; ΜΛ / a / ZUZZ / U 1 ÓOO I 13-methyl-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.126.01821]tricose-1(20),2,4,6(23),15,17,21heptaen-9-one; 8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.12'5.018,21]tr¡cosa1 (20),2(23),3,15(22), 16,18(21 )-hexaen-9-one; 4-[met¡l(oxetane-3-¡l)amino]-8,14-d¡oxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,2-heptaene; 4-[(d¡met¡lam¡no)meth¡l]-8,14-d¡oxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,17-hep-one; 4,10-d¡met¡l-8,14-d¡oxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21heptaen-9-one; 4-(propan-2-lox¡)-8,14-d¡oxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa1(20),24,6(23),15,17,21-hep-one; 4-fluoro-7-methyl-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1(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-10,19,20tr¡aza tetrac¡chlo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(3-met¡lp¡perid¡n-1-¡l)-8,14-d¡oxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23,2,5,17-1-hepta; 4-[(3S)-3-hydrox¡p¡rrol¡din-1-yl]-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,2-19-hepta; 4-fluoro-8,14-dioxa-10,19,20-triazapentacyclo[13.5.2.126.17'1°.018'21]tetracosa1 (20),2(24),3,5,15(22), 16,18(21 )-heptaen-9-one; 4-(oxolan-3-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one; (13S)-13-methyl-8,14-d¡oxa-10,19,20-triazatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa1 (20),2(23),3,5,15(22), 16,18(21 )-taen-9-hepone; (13R)-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-heptane-9-one; 4-(1-met¡l-1H-p¡razol-3-¡l)-8,14-d¡oxa-10,19,20-tnazatetrac¡chlo[13.5.2.126.018'21]tr¡cosa1(20),2(23),3,5,15(2,16),(21) )-heptane-9-one; (7S)-7-methyl-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-heptane-9-one; 4¿2-(morphol¡n-4-¡l)ethoxy¡]-8,14-d¡oxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.018'21]tr¡cosa1 (20),2(23),3,5,15(2,16),(21) )-heptane-9-one; 4-(2-methoxyethyl)-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1(20),2(23),3,5,15(22),16,18(21 )-heptane-9-one; (7R)-7-methyl-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-heptane-9-one; 5-cyclopropyl-8,14-d¡oxa-10,19,20-triazatetrac¡clo[13.5.2.12'6.018'21]tr¡cosa-1(20),2,4,6(23),15,17,21ΜΛ / a / ZUZZ-U-O-9 Heptanic Ione; 4-(2-methoxyethoxy)-8,14-d¡oxa-10,19,20-triazatetracyclo[13.5.2.12'6.01821]tricose1 (20) ,2,4,6(23), 15,17,21 -heptaen-9-one; 4-fluoro-13-met¡l-8,14-d¡oxa-10,19,20-triazatetrac¡chlo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one; 11-met¡l-8,14-d¡oxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.018'21]tr¡cosa-1(20),2,4,6(23),15,17,21heptaene-9-one; 4-(3-oxomorpholin-4-¡l)-8,14-d¡oxa-10,19,20-triazetetracyclo[13.5.2.12'6.01821]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-hepone; 4-(2-oxop¡rrol¡d¡n-1-¡l)-8,14-d¡oxa-10,19,20-tr¡azatetracyclo[13.5.2.12B.018'21]tr¡cosa1(20),2(23),3,5,15(2,18),18(2) )-heptane-9-one; 5-(2-oxop¡rrol¡d¡n-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tr¡cosa1 (20),2(23),3,5,15(22), 16-hep-one; 4-(2-methylpyrrole¡d¡n-1-yl)-8,14-dioxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21-9)-one; 2-{9-oxo-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1(20),2(23),3,5,15(22), 16,18(21 )-heptaen-4-yl}acetone; (11 R)-11-met¡l-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'2Jtricose1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one; (11 S)-11-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-heptane-9-one; 4-ethynyl-8,14-d¡oxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1(20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one; 4-(piperazin-1-yl)-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-heptane-9-one; 4-(1,2,3,6-tetrah¡drop¡r¡din-4-¡l)-8,14-d¡oxa-10,19,20-tr¡azatetracyclo[13.5.2.126.01821]tricose1 (20),2(23),3,5,15(2),(16),(2) )-heptane-9-one; 11-(methoxymethyl)-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-heptane-9-one; 8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.12'5.018'21]tricose1 (20),2(23),3,15(22), 16,18(21 )-hexaen-9-one; -methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.12'5.018'21]tricose1 (20),2(23),3,15(22), 16,18(21 )-hexaen-9-one; 12-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one; 11-et¡l-8,14-d¡oxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.018'21]tricose1(20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one; 4-fluoro-5,7-d¡meth¡l-8,14-dioxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(2)-hep-one; ΜΛ / a / ZUZZ / U 1 ÓOO I 4-fluoro-5-methoxy-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one; 5-fluoro-4,7-d¡met¡l-8,14-d¡oxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12i6.01821]tr¡cosa1(20),2(23),3,5,15(22),16,21(9)-hepone; 8,14-d¡oxa40,19,204riazapentac¡chlo[13.5.2.12'6.17'1°.018'21]tetracosa1 (20),2(24),3,5,15(22), 16,18(21 )-heptane-9-one; 13-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-heptane-9-one; 12-methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.12'5.018'21]tricose1 (20),2(23),3,15(22), 16,18(21 )-hexaen-9-one; 7-methyl-8,14-d¡oxa-4,5,10,19,20-pentaazatetrac¡chlo[13.5.2.12'5.018'21]tr¡cosa1 (20),2(23),3,15(22), 16,18(21 )-hexaenone; 5-fluoro4-methoxy-7-methyl-8,14-d¡oxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tr¡cosa1 (20),2(23),3,5,15(22), 16,18(21)-hep-9-one; (7R,13R)-7,13-dimet¡l-8,14-dioxa-10,19,20-triazatetrac¡chlo[13.5.2.12'6.018'21]tricose1(20),2(23),3,5,15(22), 16,18(21)-hep-one; (13R)-13-methyl-8,14-dioxa-4,5,10,19,20-pentaazetetracyclo[13.5.2.12,5 Qis,2i^r¡cosa_ (20),2(23),3,15,17,21 -hexaen-9-one; 8,15-dioxa4,10,20,21-tetraazapentacyclo[14.5.2.12'6.11°'13.019'22]pentacos1 (21 ),2(25),3,5,16(23), 17,19(22)-heptane-9-one; - 8,14-dioxa-5,10,19,20-tetrazatetracyclo[13.5.2.12'5.018'21]tricose-1(20),2(23),3,15(22),16,18(21)hexaen-9-one; (13S)4-fluoiO-13-methyl-8,14-d¡oxa-10,19,20-triazatetrac¡chlo[13.5.2.12'6.018'21]tricose1(20),2(23),3,5,15(22),16,18(21)-hepone; (13R)-4-fluoro-13-met¡l-8,14-d¡oxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tr¡cosa1 (20),2(23),3,5,15(22), 16,18(21)-hep-one; (13R)-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-heptane-9one; 6-c¡cloprop¡l-8,14-d¡oxa-4,5,10,19,20-pentaazatetrac¡chlo[13.5.2.12'5.01821]tr¡cosa1 (20),2(23),3,15(22), 16,18(19)-hexa-one; 7-ethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose-1 (20),2,4,6(23), 15,17,21 heptaene-9-one; (13R)-13-et¡l-8,14-d¡oxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,21-heptaen-9-one; (7R,13R)-4-fluoro-7,13-dimethyl-8,14-d¡oxa-10,19,20-triazetetracyclo[13.5.2.12'6.01821]tricose1 (20) ,2,4,6(23), 15,17,219 -hepone; 7-methyl-8,14-dioxa-4,10,19,20-tetraazatetrac¡chlo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21heptaene-9-one; (7R)4-fluoro-7-met¡l-8,14-dioxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.018'21]tricoseΜΛ / a / ZUZZ / U 1 ÓOO I 1(20),2,4,6(23),15,17,21-heptaen-9-one; (7S)-4-fluoro-7-methyl-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1 (20) ,2,4,6(23), 15,17,21 -heptane-9-one; 6-methyl-8,14-dioxa-4,5,10,19,20-pentaazatetrac¡clo[13.5.2.12i5.018'21]tncosa1 (20),2(23),3,15,17,21 -hexaen-9-one; 7-methyl-8,14-d¡oxa-10,19,20,23-tetraazatetrac¡chlo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one; 6-(propan-24l)-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.12'5.018'21]tricose1 (20),2(23),3,15(22), 16,18(21 )-hexaen-9; (13R)-7,13-dimet¡l-8,14-d¡oxa-4,5,10,19,20-pentaazatetrac¡chlo[13.5.2.12'5.018'21]tr¡cosa1 (20),2(23),3,15(22), 26-hexane(19); (13R)-13-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaene-9-one; (7R)-7-ethyl-8,14-dioxa-10,19,20-triazatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa-1(20),2,4,6(23),15,17,21heptaen-9-one; (7S)-7-et¡l-8,14-d¡oxa-10,19,20-triazatetrac¡chlo[13.5.2.12'6.018i21]tricose-1(20),2,4,6(23),15,17,21heptaen-9-one; (13R)-13-methyl-8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaene-9-one; 6-(oxan-44l)-8,14-dioxa-4,5,10,19,20-pentaazatetrac¡chlo[13.5.2.12'5.018'21]tricosa1 (20),2(23),3,15,17,21 -hexaen-9-one; 4-ethyl-8,14-dioxa-5,10,19,20,23-pentaazetetracyclo[13.5.2.12'5.018'21]tricose-1 (20),2(23), 15,17,21pentane-9-one; (13R)-23-fluoro-13-met¡l-8,14-d¡oxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,2-hep-one; 9,14-dioxa-4,5,11,19,20-pentaazatetracyclo[13.5.2.12'5.018 21]tricose-1 (20),2(23),3,15,17,21hexaen-10-one; 4-ethyl-8,14-dioxa-5,10,19,20,23-pentaazetetracyclo[13.5.2.12'5.018'21]tricose-1 (20),2(23),3,15,17,21 hexaen-9-one; 3,9,15-tr¡oxa-4,11,20,21-tetraazatetracyclo[14.5.2.12'5.019'22]tetracosa-1(21),2(24),4,16,18,22hexaen-10-one; (13R)-16-fluoro-13-methyl-8,14-d¡oxa-4,10,19,20-tetraazatetracyclo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,21-hepone; (13R)-4-chloro-13-methyl-8,14-dioxa-10,19,20,23-tetrazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21)-hep-9; 8,14-dioxa-2,4,10,19,20-pentaazatetracyclo[13.5.2.12'5.018'21]tr¡cosa1 (20),3,5(23), 15(22), 16,18(21 )-hexaen-9-one; (13R)-4-methoxy¡-13-methyl-8,14-d¡oxa-10,19,20,23-tetraazatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,27-heptaene; ΜΛ / a / ZUZZ / U 1 ÓOO I (13R)-13-methyl-9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaene-5-carbonitrile; (13R)-13-methyl-4-(p¡rrol¡din-1-¡l)-8,14-d¡oxa-5,10,19,20,23pentaazatetra cyclo[13.5.2.12'6.018'21]tr¡cosa-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-pentaazetetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptane-9-one; (7R,13R)-7,13-dimeth¡l-8,14-d¡oxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,27-hepta-en; (13R)-16-fluoro-13-met¡l-8,14-d¡oxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.018'21]tr¡cosa1 (20) ,2,4,6(23), 15,17, -heptaene; (13R)-13-methyl-8,14-dioxa-4,10,19,20,23-pentaazetetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptane-9-one; 8,14-dioxa-4-thia-10,19,20,23-tetraazatetracyclo[13.5.2.12'5.018'21]tricose-1 (20),2,5(23), 15,17,21hexaen-9-one; 8,14-dioxa-3-thia-10,19,20,23-tetraazatetrac¡chlo[13.5.2.12i5.018'21]tricose-1(20),2(23),4,15,17,21hexaen-9-one; (7R,13R)-7,13-dimeth¡l-8,14-d¡oxa-10,19,20,23-tetraazatetracyclo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,17-hep-one; (13R)-4-[(3R)-3-methoxypyrrolide¡n-1-¡l]-13-met¡l-8,14-dioxa-5,10,19,20,23pentaa zatetracyclo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-16-chloro-13-met¡l-8,14-dioxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.018'21]tricose-1(20),2, 4,6(23),15,17,21-heptaen-one; (13R)-13,16-d imethyl-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.126.018'21]tr¡cosa-1 (20),2,4, 6(23), 15,17,21 -heptaen-9-one; (13R)-13-methyl-8,14-dioxa-3,10,19,20,23-pentaazetetracyclo[13.5.2.12'6.018'21]tricose-1 (20),2,4, 6(23), 15,17,21 -heptane-9-one; hydrochloride of 8-oxa-10,14,19,20-tetraazatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa1 (20),2(23),3,5,15(22), 16,18(21 )-heptane-9-one; 8-oxa-10,19,20-triazatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen9-one; (13R)-5-methoxy-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.12'6.018'21]trichose1(20),2,4,6(23),15,17,21-heptaen-9-one; (13 R)-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,6(23), 15,17,21-hexaen-5,9-dione; 4-methyl-8,14-dioxa-3,4,10,19,20-pentaazatetracyclo[13.5.2.12i5.018'21]tricose1(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[13.5.2.12'6.01821]trichose1(20),2,4,6(23),15,17,21-heptaen-9-one; 7,13-dioxa-4-thia-9,18,19,22-tetraazatetracyclo[12.5.2.12'5.017'20]docosaΜΛ / a / ZUZZ / U 1 ÓOO I (19),2,5(22), 14(21), 15,17(20)-hexaen-8-one; (13R)-4,13-dimethyl-8,14-dioxa-5,10,19,20,23-pentaazetetracyclo[13.5.2.12'6.018'21]tricose1(20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one; 8,14-dioxa-23-tia-4,10,19,20-tetraazatetrac¡clo[13.5.2.125.01821]tr¡cosa-1(20),2,4,15(22),16,18(21)hexaen-9-one; (7C, 13R)-7,13-dimethyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22),16,18(21)-hep-9; (13R)-13-methyl-9-oxo-8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.12'5.018'21]tricose1 (20),2(23),3,15(22), 16,18(21 )-hexaentrile-4; 12,12-difluoro-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22),16,18(21 )-heptane-9-one; (13R)-17-fluoro-13-methyl-8,14-d¡oxa-10,19,20-triazatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa1 (20),2(23),3,5,15(22),16,18(21)-hepone; (7S, 13R)-7,13-dimethyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22),16,18(21)-hep-one; (7R,13R)-7,13-dimethyl-8,14-d¡oxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22),16,18(9)-hep; (13S)-13-methyl-8,14-dioxa-4,10,19,20,23-pentaazetetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22),16,18(21 )-heptanone-9-9; (13 R)-13-methyl-8,14-dioxa-10,19,20,22-tetraazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15,17,21 -heptaene-9-one; (12R)-4,12-dimethyl-7,13-dioxa-4,9,18,19,22-pentaazatetrac¡clo[12.5.2.12'5.017'20]docosa1 (19),2,5(22), 14(21), 15,17(20)-hexaene; (13R)-13-methyl-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.12'5.018'21]tricose1(20),2(23),3,15,17,21-hexaen-9-one; (13R)-13-met¡l-8,14-dioxa-23-t¡a-4,10,19,20-tetraazatetrac¡chlo[13.5.2.12'5.018'21]tr¡cosa1(20),2,4,15,17,21-hexaen-one; (13R)-4,13-dimethyl-8,14-dioxa A 10,19,20,23-pentaazatetracyclo[13.5.2.12'5.018'21]tricose1 (20),2,5(23),15(22), 16,18(21 )-hexaene; (13R)-13-met¡l-8,14-dioxa-10,16,19,20-tetraazatetrac¡chlo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22),16,18(21 )-taen-9-hepone; 14-met¡l-8-oxa-10,14,19,20-tetraazatetracyclo[13.5.2.12'6.018'21]tricose-1(20),2(23),3,5,15,17,21heptaen-9-one; (13R)-13-methyl-8,14-dioxa-4,10,19,20,22-pentaazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15,17,21 -heptane-9-one; (13R)-13-met¡l-8,14-dioxa-10,17,19,20-tetraazatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa1 (20),2(23),3,5,15(22),16,18(21)-hep-9-taen; 8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.12'5.018'21]tricose1 (20),2(23),3,15(22), 16,18(21 )-hexaen-9-one; ΜΛ / a / ZUZZ / U 1 ÓOO I 12,12-difluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.12'5.018'21]tricose1 (20),2(23),3,15(22), 16,18(21 )-hexaenone); (12R)-12-fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22),16,18(21 )-heptane-9-one; (12S)-12-fluoro-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-heptane-9-one; 12,12-difluoro-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.12'6.018'21]tricosa1 (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[13.5.2.12'6.01821]tricosa1(20),2(23),3,5,15,17,21-heptaen-9-one; (12R)-12-fluoro-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.12'6.018'21]tricosa1 (20),2(23),3,5,15,17,21 -heptaen-9-one; (12S)-12-fluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetraciclo[13.5.2.12'5.018'21]tr¡cosa1 (20),2(23),3,15,17,21 -hexaen-9-one; (12R)-12-fluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetraciclo[13.5.2.12'5.018'21]tricosa1 (20),2(23),3,15,17,21 -hexaen-9-one; 8',14'-d¡oxa-10',19',20'-tr¡azaesp¡ro[c¡clopropano-1,13'-tetrac¡clo[13.5.2.12'6.018'21]tr¡cosan]1 '(20'),2'(23'),3',5', 15'(22'), 16',18'(21')-heptaen-9'-one. The invention also relates to an overall process for preparing the compounds of formula (I), a process characterized in that the compound of formula (I1) is used as a starting material: ML / a / ZUZZ / U 1 ÓOO I where R, X1, Z1, Z2 and Z3 are as defined for formula (I), on which a compound PG1-LG1 is condensed first, then a compound PG2-LG2, or first a compound PG2-LG2 then a compound PG1-LG1, wherein PG1 is a protecting group or, when -X1- is a bond, PG1 represents a halogen, and PG2 is a protecting group and LG1 and LG2 are leaving groups, to yield the compound of formula (I-2): PG1 where R, X1, Z1, Z2, Z3, PG1 and PG2 are as defined above in this document, composed of formula (I-2) on which: A leaving group LG3 is condensed to yield the compound of formula (I-3): ML / a / ZUZZ / U 1 ÓOO I where R, X1, Z1, Z2, Z3, PG1, PG2 and LG3 are as previously defined in this document, composed of formula (I-3): • on which, after deprotection of X1, a compound LG4-X2-NPG3 is condensed, wherein LG4 is a leaving group, PG3 is a protecting group, and X2 is as defined for formula (I) to yield the compound of formula (I-4): NPG3 where R, X1, X2, Z1, Z2, Z3, PG2, PG3 and LG3 are as previously defined in this document, a compound of formula (I-4) on which a compound of formula (I-5) is condensed: HO—X3 CD(μ5) where A and X3 are as defined in formula (I), or an organometallic derivative of the compound of formula (I-5) such as a boronate, to yield the compound of formula (I-6): ML / a / ZUZZ / U 1 ÓOO I where R, X1, X2, X3, A, Z1, Z2, Z3, PG2 and PG3 are as previously defined in this memory, compound of formula (I-6) which is subjected to deprotection of -X2-NPG3, then to cyclization to provide the compound of formula (I-7): wherein R, X1, X2, X3, A, Z1, Z2, Z3 and PG2 are as defined above in this specification, a compound of formula (I-7) that is optionally alkylated at the carbamate function, and / or optionally substituted at ring A, then subjected to deprotection of -N(PG2)- to provide the compound of formula (I), • or a compound of formula (I-3) on which a compound of formula (I-8) is condensed: ML / a / ZUZZ / U 1 ÓOO I wherein Ra, X2, X3, and A are as defined above in this memory and LG4 is a leaving group, or an organometallic derivative of the compound of formula (I-8) such as a boronate, to yield the compound of formula (I-9): wherein R, Ra, X1, X2, X3, A, Z1, Z2, Z3, PG1, PG2 and LG4 are as defined above in this document, a compound of formula (I-9) which, after deprotection of X1, undergoes cyclization to yield the compound of formula (I-7) as defined above, which, after deprotection of N(PG2)-, and / or optional substitution on ring A, provides the compound of formula (I), • or a compound of formula (I-3) on which, after deprotection of X1, an LG5-X2-NRaCOOBn compound is condensed, wherein X2 and Ra are as defined in formula (I) and LG5 is a leaving group, to yield the compound of formula (1-10): NRaCOOBn (1-10) wherein R, Ra, X1, X2, Z1, Z2, Z3, PG2 and LG3 are as previously defined in this memory, compound of formula (1-10) on which a compound of formula (I-5) is condensed: MA / a / ZUZZ / UI ÓOO I wherein X3 and A are as defined above in this specification, or an organometallic derivative of the compound of formula (I-5) such as a boronate, to yield the compound of formula (1-11): wherein R, Ra, X1, X2, X3, Z1, Z2, Z3, A and PG2 are as defined above in this specification, compound of formula (1-11) that undergoes cyclization to yield the compound of formula (I-7) as defined above, which, after deprotection of -N(PG2)-, and / or optional substitution on ring A, provides the compound of formula (I), or compound of formula (I-2) on which, after deprotection of X1, a compound of Formula (1-12) is condensed: where A, X3 and X2 are as defined above in this memory and LG6 and LG7 are leaving groups, to yield a compound of formula (1-13): ML / a / ZUZZ / U 1 ÓOO I wherein R, X1, X2, X3, A, Z1, Z2, Z3, PG2 and LG6 are as defined above in this memory, compound of formula (1-13) cyclizing to yield compound of formula (I-7) optionally alkylating at the carbamate function, then subjecting -N(PG2) to deprotection, and / or optionally substituting at ring A, to provide compound of formula (I), or compound of formula (I-2) transforming into a boronic derivative of formula (1-14): wherein R, X1, Z1, Z2, Z3, PG1 and PG2 are as defined above in this document, and R' represents a hydrogen atom or an alkyl group, it being understood that the two alkyl groups R' can join together to form a cyclic structure, • compound of formula (1-14) on which a compound of formula (1-15) is condensed: X4 LG8 where A is as defined above in this memory, X4 is a carboxylic acid or an ester or a carbonyl derivative of X3, and LG8 is a leaving group, to yield the compound of formula (1-16): MA / a / ZUZZ / UI ÓOO I X4 wherein R, X1, Z1, Z2, Z3, X4, PG1 and PG2 are, as defined above in this document, a compound of formula (1-16) on which, after deprotection of X1, an LG5-X2-NRaCOOBn compound, as defined above in this document, is condensed to yield the compound of formula (1-17): wherein R, Ra, X1, X2, Z1, Z2, Z3, X4 and PG2 are as defined above in this memory, which is subjected to a reduction to yield the compound of formula (1-11) which is converted into a compound of formula (I) as described above in this memory, • or a compound of formula (1-14) on which a compound of formula (1-18) is condensed: (1-18) ML / a / ZUZZ / U 1 ÓOO I where A, X2, X3 and Ra are as defined above in this memory, and LG9 is a leaving group, to yield the compound of formula (1-19): wherein R, Ra, A, X1, X2, X3, Z1, Z2, Z3, PG1 and PG2 are as defined above in this specification, compound of formula (1-19) in which a leaving group is introduced to yield the compound of formula (I-9) as defined above, which is converted into compound of formula (I) as described above, or compound of formula (I-2) on which, after deprotection of X1, an LG5-X2-NRaCOOBn compound as defined above in this specification is condensed to yield a compound of Formula (I-20): (1-20) MA / a / ZUZZ / UI ÓOO I where R, Ra, X1, X2, Z1, Z2, Z3 and PG2 are as previously defined in this memory, compound of formula (I-20) which transforms into a boronic derivative of formula (1-21): NRaCOOBn X2 where R, Ra, X1, X2, Z1, Z2, Z3, PG2 and R' are as defined above in this memory, • compound of formula (1-21) on which a compound of formula (I-22) is condensed: wherein X3 and A are as defined above in this specification, and LG10 is a leaving group, to yield the compound of formula (1-11) which is converted into a compound of formula (I) as described above in this specification, or a compound of formula (1-21) on which a compound of formula (1-15) as defined above in this specification is condensed to yield the compound of formula (1-17) which is converted into a compound of formula (I) as described above in this specification, the compound of formula (I) may then be purified according to a conventional separation technique, and is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and is optionally separated into its isomers according to a conventional separation technique, it being understood that at any time deemed appropriate during the course of the process described above,Some groups of starting reagents or synthesis intermediates can be protected, subsequently deprotected and functionalized, as required by the synthesis. The compounds of formulas (I-5), (I-8), (1-12), (1-15), (1-18) and (I-22) are readily available commercially or can be obtained by the skilled worker using conventional chemical reactions described in the literature. Pharmacological studies of the compounds of the invention in formula (I) show inhibitory activity against LRRK2 kinase, including mutated LRRK2 kinase, such as mutated p.G2019S. Kinase activity can be determined using a kinase assay, which typically employs a kinase substrate and a phosphate group donor such as ATP (or a derivative thereof). An exemplary kinase assay is described in the Pharmacological Study. The compounds of formula (I) of the invention or pharmaceutically acceptable salts thereof are inhibitors of LRRK2 kinase activity and are therefore believed to have potential use in the treatment of 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 cancers. In particular, the compounds of the invention are useful in the treatment of neurological diseases including, but not limited to, Parkinson's disease (including patients with sporadic Parkinson's disease, as well as patients with LRRK2 mutations such as p.G2019S or Rab29 / Rab7L1 polymorphisms), Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dementia (including Lewy body dementia and vascular dementia, HIV-induced dementia), diabetic neuropathy, age-related memory dysfunction, mild cognitive impairment, argyrophilic granular disease, 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 chromosome 17-linked parkinsonism (FTDP-17), withdrawal / relapse symptoms associated with drug addiction, L-dopa-induced dyskinesia, ischemic stroke, traumatic brain injury, spinal cord injury, and multiple sclerosis. Other diseases potentially treatable by inhibiting LRRK2 activity include endosomal-lysosomal diseases, including but not limited to Niemann-Pick disease Type A, B, or C, Gaucher disease, Krabbe disease, Fabry disease, and disorders with mitochondrial deficiencies; inflammatory diseases including but not limited to vasculitis; and pulmonary diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and myopathies. ML / a / ZUZZ / U 1 ÓOO I inflammatory diseases, 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 I diabetes mellitus, obesity, Evans syndrome, bullous skin disorders, Sjogren's syndrome, Devic's disease, and leprosy. The compounds of the invention also have anticarcinogenic effects and are potentially useful in the treatment of cancers including, but not limited to, thyroid cancer, renal cancer (including papillary renal cancer), breast cancer, hormone-related cancer, adeno- and squamous cell lung cancer, non-small cell lung cancer, colon cancer, prostate cancers, skin cancers, leukemias (including acute myeloid leukemia), and lymphomas. The compounds of the invention are also potentially useful in the treatment of cardiovascular diseases including, but not limited to, stroke. Other diseases potentially treatable with the compounds of the 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. Another aspect of the invention relates to pharmaceutical compositions comprising at least one compound of formula (I) in combination with one or more pharmaceutically acceptable excipients. In particular, these pharmaceutical compositions are of interest for 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 cancers. In one specific embodiment, the pharmaceutical compositions of the invention are useful for the treatment or prevention of Parkinson's disease (including patients with sporadic Parkinson's disease, as well as patients with LRRK2 mutations or Rab29 / Rab7L1 polymorphisms), Alzheimer's disease, and amyotrophic lateral sclerosis (ALS).Dementia (including Lewy body dementia and vascular dementia, HIV-induced dementia), diabetic neuropathy, age-related memory impairment, mild cognitive impairment, argyrophilic granulosa disease, 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 chromosome 17-linked parkinsonism (FTDP-17), withdrawal / relapse symptoms associated with drug addiction, L-dopa-induced dyskinesia, ischemic stroke, traumatic brain injury, spinal cord injury, multiple sclerosis, Niemann-Pick disease Type A, B or C, Gaucher disease, Krabbe disease, Fabry disease, disorders with mitochondrial deficiencies, Crohn's disease, inflammatory bowel disease, arthritis rheumatoid arthritis, ulcerative colitis, lupus, autoimmune hemolytic anemia,pure red cell aplasia, idiopathic thrombocytopenic purpura, type I diabetes mellitus, obesity, Evans syndrome, bullous skin disorders, Sjögren's syndrome, Devic's disease, leprosy, thyroid cancer, kidney cancer (including papillary renal cancer), breast cancer, hormone-related cancer, adeno- and squamous cell lung cancer, non-small cell lung cancer, colon cancer, prostate cancers, skin cancers, leukemias (including, MA / a / ZUZZ / UI ÓOO I acute myelogenous leukemia), lymphomas, stroke, leprosy, tuberculosis, and viral infections due to SARS-CoV, MERSCoV, SARS-CoV-2, HIV, West Nile virus and chikungunya virus. Among the pharmaceutical compositions according to the invention, we can mention more specifically those suitable for oral, parenteral, nasal, per or transcutaneous, rectal, perlingual, ocular or respiratory administration, especially tablets or dragees, sublingual tablets, sachets, packets, capsules, sublingual lozenges, suppositories, creams, ointments, dermal gels, and drinkable or injectable ampoules. The pharmaceutical compositions according to the invention comprise one or more excipients or vehicles selected from diluents, lubricants, binders, disintegrating agents, stabilizers, preservatives, absorbents, colorants, sweeteners, flavor enhancers, etc. Non-limiting examples include: ♦ as diluents: lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerol, ♦ as lubricants: silica, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol, ♦ as binders: magnesium and aluminum silicate, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone, ♦ as disintegrants: agar, alginic acid and its sodium salt, effervescent mixtures. The dosage varies according to the patient's sex, age and weight, the route of administration, the nature of the therapeutic indication, or any associated treatment, and ranges from 0.01 mg to 1 g every 24 hours in one or more administrations. The following Preparations and Examples illustrate the invention, but do not limit it in any way. The compounds of this invention can be prepared by any of several standard synthetic processes commonly used by those skilled in the art of organic chemistry. The compounds are generally prepared from commercially available starting materials or by standard means obvious to those skilled in the art. GENERAL SCHEMES As indicated above in this specification, the present invention provides compounds according to formula (I): ML / a / ZUZZ / U 1 ÓOO I R where R, Z1, Z2, Z3, X1, X2, X3, Ra and A are as defined for formula (I). With reference to the general reaction schemes suitable for preparing such compounds, these compounds may be represented by formula (I), for which general reaction schemes can be found below in this document. In the schemes below, R, Z1, Z2, Z3, X1, X2, X3, Ra, and A shall have the same meaning as defined for formula (I). The fused bicyclic pyrazolo structure containing Z1, Z2, Z3 and R will be referred to as the fused pyrazolo structure in what follows. In the general schemes below, Lgi and Lg2 each independently represent suitable leaving groups. Pgi and Pga each independently represent a suitable protecting group that can be used to protect X1 and / or X2. Pg2 represents a suitable protecting group to protect the NH from the fused pyrazolone structure. Rb in the schemes below can be either H, alkyl or cyclic alkyl. For those compounds for which a transcarbamylation reaction is used, the CbzX2Lg2 moiety can be prepared either by reaction from the corresponding bromoalkylamino via reaction with Cbz chloride or by reaction between the hydroxyalkylamino via reaction with Cbz chloride followed by mesylation or tosylation. In all the general schemes below, prior to the deprotection of the NH of the fused pyrazolo structure, the carbamate can optionally be substituted by an alkylation reaction to provide a compound of formula (Xlla), after which the NH of the fused pyrazolo structure can be deprotected to give the final compound of formula (I). Alternatively, in all the general schemes below, prior to deprotection of the NH group of the fused pyrazolone structure, an optional cross-coupling reaction such as a Buchwald, Suzuki, or Sonogashira reaction, or alternatively, an O-alkylation or nucleophilic aromatic substitution on the (hetero-)aromatic ring containing a leaving group such as a halide, can be carried out to form a compound of formula (Xlla). After the optional cross-coupling reaction such as a Buchwald, Suzuki, or Sonogashira reaction, or alternatively, an O-alkylation or nucleophilic aromatic substitution, the NH group of the fused pyrazolone structure can be deprotected to give the final compound of formula (I). Compounds of formula (I) can be prepared as shown in General Scheme A below, wherein the compound of formula (II) is converted into a protected compound of formula (III). This compound of formula (III) can be converted into a compound of formula (IV) containing a leaving group in the fused pyrazolone structure and then into a nitrogen-protected compound of formula (V). The compound of formula (V) can be converted into a selectively protected fused pyrazolone structure of formula (VI), which is then alkylated with a leaving-group intermediate of formula (VIII) to give a compound of formula (IX). The compound of formula (VIII) can be prepared from a compound of formula (VII) via nucleophilic substitution.The compound of formula (IX) can be coupled via organometallic cross-coupling such as Suzuki or Ullmann coupling with a (hetero-)aryl of formula (X) or (Xa) to form a compound of formula (XI). The compound of formula (XI) can then be selectively deprotected. MA / a / ZUZZ / UI ÓOO I to a compound of formula (XII) before cyclizing to form a compound of formula (XIII). The final deprotection of the nitrogen of the fused pyrazolone structure, either after or after alkylation of the carbamate moiety and / or substitution of ring A, gives rise to the compound of formula (I). ML / a / ZUZZ / U 1 ÓOO I Scheme A Vulnerability X1 ivn In the above reaction Scheme A, the reaction between a compound of formula (VI) and a compound of formula (VIII) can be achieved in a solvent such as Λ / , / V-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate. In the above reaction between the compound of formula (IX) and the compound of formula (X), the leaving group Lgi is advantageously a halogen atom such as chlorine, bromine, or iodine. This halogen displacement reaction can be carried out under cross-coupling conditions such as Suzuki conditions using palladium catalysts such as, for example, tetrakis(triphenylphosphine) palladium(O) combined or not with 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (Xphos) in the presence of tribasic potassium phosphate in a solvent mixture such as, for example, 1,4-dioxane / water at an elevated temperature such as, for example, 90°C, either under microwave conditions or not. Alternatively, the halogen displacement reaction can be carried out under Ullmann conditions using copper iodide in the presence of potassium carbonate and 8-hydroxyquinoline in a solvent such as, for example, dimethyl sulfoxide at an elevated temperature such as, for example, 70°C. Suitable compounds of formula (X) or formula (Xa) may be commercially available or obtained through various selective protection and deprotection steps known to those skilled in the art. A borylation step may be required for the synthesis of compounds of formula (Xa). The deprotection of Pg.3 results in a compound of formula (XII). The cyclization of the compound of formula (XII) to provide a compound of formula (XIII) can be carried out by a method known to the skilled worker as a carbamylation reaction, for example, by treatment with 1,T-carbonyldiimidazole and A / ,A / -diisopropylethylamine or sodium hydride in a solvent such as V,A / -dimethylacetamide at, for example, 90°C. The final deprotection of the NH group from the fused pyrazolone structure under acidic conditions, either after or without alkylation of the carbamate and / or substitution of ring A, yields the final compound of formula (I). Alternatively, the compounds of formula (I) can be prepared as shown in General Scheme B below, wherein the fused pyrazolo structure of formula (II) is converted into a protected compound of formula (III). The NH group of the fused pyrazolo structure can be protected to a compound of formula (XIV). This compound of formula (XIV) can be converted into a boronic acid (or boronate ester) of formula (XV). The compound of formula (XV) can be coupled via an organometallic cross-coupling reaction such as Suzuki coupling with a (hetero-)aryl group of formula (XVI) to form a compound of formula (XVII). The compound of formula (XVII) can be alkylated with an intermediate of formula (XIX) containing a carbamate such as a benzyl carbamate, giving a compound of formula (XX).The compound of formula (XIX) can be commercially available or prepared from a compound of formula (XVIII) by reaction with CbzCl or by introduction of a leaving group Lg2 into the compound of formula (XVIIIa). The X4 moiety of compound (XX) can be transformed into X3-OH, usually by reduction of a carboxylic acid or carboxylic ester, or a (cyclo)alkyl carbonyl group, or a heterocycloalkyl carbonyl group. The compound of formula (XXI) can then be cyclized by a transcarbamylation reaction to form a compound of formula (XIII). Final deprotection of the nitrogen from the fused pyrazolone structure, either after or after alkylation of the carbamate and / or substitution of ring A, yields the compound of formula (I). ML / a / ZUZZ / U 1 ÓOO I O. Scheme B :ir txvic ROC Protection | 19XX. Protection Borilation Cross coupling unprotected X1 ML / a / ZUZZ / U 1 ÓOO I : xjv: :xy :xvc transcarbamylation Cyclization IXVIII] CBZ connector IN- 1H ¡XVIIlat Introduction of Lg2?2Akquilation Reduction -c pg :xix: :xx: :xxi! II M. Optional carbamate alkylation and / or A-ring substitution Cesprotection In the above reaction Scheme B, the borylation of the fused pyrazolo structure of a compound of formula (XV) to the compound of formula (XVI) can be achieved using an iridium and bis(pinacolato)diboron catalyst in a solvent such as TBME. In the above reaction between the compound of formula (XV) and the compound of formula (XVI), the leaving group Il is advantageously a halogen atom such as chlorine, bromine, or iodine. This halogen displacement reaction can be carried out under cross-coupling conditions such as Suzuki conditions using palladium catalysts such as, for example, tetrakis(triphenylphosphine) palladium(O) combined or not with 2-dicyclohexylphosphine-2,4',6'-triisopropylphenyl(Xphos) in the presence of tribasic potassium phosphate in a solvent mixture such as, for example, 1,4-dioxane / water at an elevated temperature such as, for example, 110°C, either under microwave conditions or not. In the reaction scheme above, alkylation between a compound of formula (XVII) and a compound of formula (XIX) can be achieved in a solvent such as A / ,A / -dimethylformamide or acetanitrile and a base such as potassium carbonate or potassium carbonate at an elevated temperature such as 120°C. Suitable compounds of formula (XIX) can be either purchased commercially or obtained by reaction with CbzCl and sodium hydroxide of a compound of formula (XVIII) in water as solvent. Alternatively, the compound of formula (XIX) can be prepared by introducing Lg2 into the compound of formula (XVIIIa). X4 in the compound of formula (XX) can be a (cyclo)alkyl-carbonyl, heterocycloalkyl-carbonyl or carboxylic derivative (carboxylic acid or ester) that 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. The transcarbamylation of the compound of formula (XXI) to the macrocycle of formula (XIII) can be done using potassium carbonate or cesium carbonate or potassium hydroxide in a solvent such as acetonitrile at a temperature ranging from RT to solvent reflux, or using sodium hydride in a dry solvent such as toluene at a temperature ranging from 0°C to solvent reflux, either under microwave conditions or not. The final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, either after or not the alkylation of the carbamate and / or substitution of ring A, yields the final compound of formula (I). Alternatively, the compounds of formula (I) can be prepared as shown in General Scheme C below, wherein the fused pyrazolo structure of formula (II) is converted into a protected compound of formula (III). This compound of formula (III) can be converted into a compound of formula (IV) containing a leaving group in the fused pyrazolo structure and then into a nitrogen-protected compound of formula (V). The compound of formula (V) can be converted into a selectively protected fused pyrazolo structure of formula (VI) which is then alkylated with a leaving-group intermediate of formula (XIX) to give a compound of formula (XXII).The compound of formula (XIX) can be commercially available or prepared from a compound of formula (XVIII) by reaction with CbzCl or by introduction of a leaving group Lg2 into the compound of formula (XVIIIa). The compound of formula (XXII) can be coupled via an organometallic cross-coupling reaction, such as Suzuki coupling, with a (hetero-)aryl of formula (X) to form a compound of formula (XXI). The compound of formula (XXI) can then be cyclized by a transcarbamylation reaction to form a compound of formula (XIII). Final deprotection of the nitrogen from the fused pyrazolone structure, either after or after alkylation of the carbamate and / or substitution of ring A, yields the compound of formula (I). ML / a / ZUZZ / U 1 ÓOO I Scheme C PglPU' Protection i V. .. x, zi Halogenation ..Z1. .J Protection L / 1J ~ X ΓN' A LtJn~Kr· -i > τh :ir :m:¡rv: PP1 xtΖ1λ31Unprotection :v: ινΐΛ / a / zuzz / ui óoo i X2 M-N'' -Ly / ¡xvm: Connector I Cbz Lpf ♦+O. -N R >y2 X2 CLzIih·' OH ; XVIIIa) I Introduction I of Lg2lq?Iquilation hc-x: Coupling . crossed ftbU-b----* CRD :xix: HC R3 h / Z3 R ^g2 XI zi 'ranscarnilation 'x Cycle cionZ2.· ----* / ¿3 Optional carbamate annulation and / or A ring substitution pq; Zl •4 Unprotection you :xxr :xiiu: In the above reaction Scheme C, alkylation between a compound of formula (VI) with a compound of formula (XIX) can be achieved in a solvent such as A / ,A / -dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 120°C. Suitable compounds of formula (XIX) may be commercially available or obtained by reaction with CbzCl and sodium hydroxide of a compound of formula (XVIII) in water as solvent. Alternatively, the compound of formula (XIX) may be prepared by introducing Lg2 into the compound of formula (XVIIIa). In the above reaction between the compound of formula (XXII) and the compound of formula (X), the leaving group Il is advantageously a halogen atom such as chlorine, bromine, or iodine. This halogen displacement reaction can be carried out under organometallic coupling conditions such as Suzuki conditions using palladium catalysts such as, for example, tetrakis(triphenylphosphine)palladium(O) combined or not with 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl(Xphos) in the presence of tribasic potassium phosphate in a solvent mixture such as, for example, 1,4-dioxane / water at an elevated temperature such as, for example, 110°C, either under microwave conditions or not. Suitable compounds of formula (X) may be commercially available or obtained through various selective protection and deprotection steps known to those skilled in the art. A borylation step may be required to obtain the compounds of formula (X). The transcarbamylation of the compound of formula (XXI) to the macrocycle of formula (XIII) can be done using potassium carbonate or cesium carbonate or potassium hydroxide in a solvent such as acetonitrile at a temperature ranging from RT to solvent reflux, or using sodium hydride in a dry solvent such as toluene at a temperature ranging from 0°C to solvent reflux, either under microwave conditions or not. ML / a / ZUZZ / U 1 ÓOO I The final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, either after or not the alkylation of the carbamate and / or substitution of ring A, yields the final compound of formula (I). Alternatively, the compounds of formula (I) can be prepared as shown in the general Scheme D below, wherein the fused pyrazolo structure of formula (II) is converted into a protected compound of formula (III) and then into a nitrogen-protected compound of formula (XIV). The compound of formula (XIV) can be converted into a selectively protected fused pyrazolo structure of formula (XXIII), which is then alkylated with an intermediate compound (XIX) containing a Cbz group to give a compound of formula (XXIV). The compound of formula (XIX) can be prepared from a compound of formula (XVIII) via a reaction with CbzCl or via the introduction of an Lg2 leaving group into the compound of formula (XVIIIa). The compound of formula (XXIV) can be boronated to a compound of formula (XXV).The boronated compounds of formula (XXV) can be reacted in a cross-coupling reaction, such as a Suzuki coupling, with a (hetero-)aryl of formula (XXVI) to form a compound of formula (XXI). The compound of formula (XXI) can then be cyclized by a transcarbamylation reaction to form a compound of formula (XIII). Final deprotection of the nitrogen from the fused pyrazolone structure, either after or after alkylation of the carbamate and / or substitution of ring A, gives rise to the compound of formula (I). Scheme D xviie CBZ connector 18th century! Introduction of Lg2 m; Protection I XI me Protection :xv: lack of protection I X1 ΙΧΧΙΙΓ :xixi Alkylation T T' Borilation ¿vi-,,· * Cross coupling ixxv: ixxv: ixxvr :xxi: 'ranscarbamylation Cycling Optional carbamate alkylation and / or A-ring substitution Lack of protection txiir 1CHIIG In the above reaction Scheme D, the reaction between a compound of formula (XXIII) and a compound of formula (XIX) can be achieved in a solvent such as Λ / , / V-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate. Suitable compounds of formula (XIX) may be commercially available or obtained by reaction with CbzCl and sodium hydroxide of a compound of formula (XVIII) in water as solvent. Alternatively, the compound of formula (XIX) may be prepared by introducing Lg2 into the compound of formula (XVIIIa). In the above reaction scheme, the borylation of the fused pyrazolo structure of a compound of formula (XXIV) to the compound of formula (XXV) can be achieved using an iridium and bis(pinacolato)diboron catalyst in a solvent such as TBME. In the above reaction between the compound of formula (XXV) and the compound of formula (XXVI), the leaving group Il is advantageously a halogen atom such as chlorine, bromine, or iodine. This halogen displacement reaction can be carried out under organometallic cross-coupling conditions such as Suzuki conditions using palladium catalysts such as, for example, tetraquls(triphenylphosphine)palladium(O) combined or not with 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (Xphos) in the presence of tribasic potassium phosphate in a solvent mixture such as, for example, 1,4-dioxane / water at an elevated temperature such as, for example, 90°C, either under microwave conditions or not. Suitable compounds of formula (XXVI) may be either commercially purchased or obtained through various reactions including selective protection and deprotection steps known to the person skilled in the art. The transcarbamylation of the compound of formula (XXI) to the macrocycle of formula (XIII) can be done using potassium carbonate or cesium carbonate or potassium hydroxide in a solvent such as acetonitrile at a temperature ranging from RT to solvent reflux, or using sodium hydride in a dry solvent such as toluene at a temperature ranging from 0°C to solvent reflux, either under microwave conditions or not. The final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, either after or not the alkylation of the carbamate and / or substitution of ring A, yields the final compound of formula (I). Alternatively, compounds of formula (I) can be prepared as shown in General Scheme E below, wherein the fused pyrazolo structure of formula (II) is converted into a protected compound of formula (III). This compound of formula (III) can be converted into a compound of formula (IV) containing a leaving group in the fused pyrazolo structure and then into a nitrogen-protected compound of formula (V). The compound of formula (V) can be converted into a selectively protected fused pyrazolo structure of formula (VI) which then couples in a cross-coupling reaction such as a Suzuki coupling with a (hetero-)aryl of formula (XXVII) to form a compound of formula (XXVIII).The X4 residue in the compound of formula (XXVII) contains a carbonyl precursor such as (cyclo)alkyl-carbonyl, heterocycloalkyl-carbonyl, carboxylic acid, or ester that can be reduced to a compound of formula (XXIX). The compound of the. MA / a / ZUZZ / UI ÓOO I formula (XXIX) is then alkylated with an intermediate of formula (XIX) containing a leaving group, giving a compound of formula (XXI). The compound of formula (XIX) can be commercially available or prepared from a compound of formula (XVIII) by reaction with CbzCl or by introduction of an Lg2 leaving group into the compound of formula (XVIIIa). The compound of formula (XXI) can then be cyclized by a transcarbamylation reaction to form a compound of formula (XIII). Final deprotection of the nitrogen of the fused pyrazolone structure, either after or after alkylation of the carbamate and / or substitution of ring A, gives the compound of formula (I). MA / a / ZUZZ / UI ÓOO I Er*1Iu 1 Scheme Protection | . ,LUJ,z, Cesprotection . ..· . ...x! ·' zi Halogenation or . Protection -.-.- / ,X1l-v - - w --Jn p ·'M·'ζ· μ pMι·«: / Coupling 1 cross-cut”. 7' to Reduction, r - ID ' ” qtir y-.,-- --N IBi* « :xx. । Connector Introduction, from Lg2 “ranscarbamylation 4, [ > Cycling ' / , , --ri ► '•u·· Optional carbamate alkylation and / or A-ring substitution X) zi / Cesprotección 4 xr? - In Scheme E above, the reaction between the compounds of formula (VI) involves the leaving group Lgi, which is advantageously a halogen atom such as chlorine, bromine, or iodine. This halogen displacement reaction can be carried out under organometallic cross-coupling conditions such as Suzuki conditions using palladium catalysts such as, for example, tetrakis(triphenylphosphine)palladium(O) combined or not with 2-dicyclohexylphosphine-2',4',6'-triisopropylphenyl(Xphos) in the presence of tribasic potassium phosphate in a solvent mixture such as, for example, 1,4-dioxane / water at an elevated temperature such as, for example, 110°C, either under microwave conditions or not. Suitable compounds of formula (XXVII) contain an alcohol precursor moiety such as an ester or a carboxylic acid. These compounds may be commercially available or obtained through various reactions, including selective protection and deprotection steps known to those skilled in the art. A borylation step may be required for compounds of formula (XXVII). The reduction of carbonyl X4 in the compound of formula (XXVIII) gives rise to a compound of formula (XXIX). In the above reaction scheme, alkylation between a compound of formula (XXIX) with a compound of formula (XIX) can be achieved in a solvent such as A / ,A / -dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 120°C. Suitable compounds of formula (XIX) may be commercially available or obtained by reaction with CbzCl and sodium hydroxide of a compound of formula (XVIII) in water as solvent. Alternatively, the compound of formula (XIX) may be prepared by introducing Lg2 into the compound of formula (XVIIIa). The transcarbamylation of the compound of formula (XXI) to the macrocycle of formula (XIII) can be done using potassium carbonate or cesium carbonate or potassium hydroxide in a solvent such as acetonitrile at a temperature ranging from RT to solvent reflux, or using sodium hydride in a dry solvent such as toluene at a temperature ranging from 0°C to solvent reflux, either under microwave conditions or not. The final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, either after or not the alkylation of the carbamate and / or substitution of ring A, yields the final compound of formula (I). Alternatively, the compounds of formula (I) can be prepared as shown in the general Scheme F below, wherein the fused pyrazolo structure of formula (II) is converted into a protected compound of formula (III). This compound of formula (III) can be converted into a compound of formula (IV) containing a leaving group in the fused pyrazolo structure and then into a nitrogen-protected compound of formula (V). The compound of formula (V) can be converted into a selectively protected fused pyrazolo structure of formula (VI) which is then alkylated with a leaving-group intermediate of formula (XIX) to give a compound of formula (XXII).The compound of formula (XIX) can be commercially available or prepared from a compound of formula (XVIII) by reaction with CbzCl or by introducing a leaving group Lg2 into the compound of formula (XVIIIa). The compound of formula (XXII) can be coupled via an organometallic cross-coupling reaction, such as a Suzuki coupling, with a (hetero-)aryl of formula (XXVII) to form a compound of formula (XX). The X4 moiety in the compound of formula (XX) 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 (XXI). The compound of formula (XXI) can then be cyclized by a transcarbamylation reaction to form a compound of formula (XIII).The final deprotection of the nitrogen of the fused pyrazolo structure, either after or not the alkylation of the carbamate and / or substitution of ring A, gives rise to the compound of formula (I). ML / a / ZUZZ / U 1 ÓOO I Scheme F Protection l . |. XI '..Halogenation Protection' - 1' - .·, 1.. / Cesprotection l MA / a / ZUZZ / UI ÓOO I Reduction CBZ connector Introduction of Lg2 ú^uilation Stockpiling; crossed 'transbarriilation :xj< Optional 'carbamate alkylation and / or A-ring substitution' Vulnerability In the above reaction Scheme F, alkylation between a compound of formula (VI) with a compound of formula (XIX) can be achieved in a solvent such as Λ / , / V-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 120°C. Suitable compounds of formula (XIX) may be commercially available or obtained by reaction with CbzCl and sodium hydroxide of a compound of formula (XVIII) in water as solvent. Alternatively, the compound of formula (XIX) may be prepared by introducing Lg2 into the compound of formula (XVIIIa). In the above reaction between the compound of formula (XXII) and the compound of formula (XXVII), the leaving group Il is advantageously a halogen atom such as chlorine, bromine, or iodine. This halogen displacement reaction can be carried out under cross-coupling conditions such as Suzuki conditions using palladium catalysts such as, for example, tetrakis(triphenylphosphine)palladium(O) combined or not with 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (Xphos) in the presence of tribasic potassium phosphate in a solvent mixture such as, for example, 1,4-dioxane / water at an elevated temperature such as, for example, 110°C, either under microwave conditions or not. Suitable compounds of formula (XXVII) may be commercially available or obtained through various reactions, including selective protection and deprotection steps known to those skilled in the art. A borylation step may be required for compounds of formula (XXVII). The reduction of carbonyl X4 in the compound of formula (XX) gives rise to a compound of formula (XXI). Transcarbamylation of the compound of formula (XXI) to the macrocycle of formula (XIII) can be achieved using sodium hydride in dry toluene at an elevated temperature, such as 130°C or 150°C. Alternatively, transcarbamylation can be carried out using potassium carbonate or KOH in a solvent such as acetonitrile at an elevated temperature, such as 140°C. Final deprotection of the nitrogen from the fused pyrazolone structure under acidic conditions, either after or without alkylation of the carbamate and / or substitution of ring A, yields the final compound of formula (I). Alternatively, compounds of formula (I) can be prepared as shown in General Scheme G below, wherein the fused pyrazolo structure of formula (II) is converted into a protected compound of formula (III) and then into a nitrogen-protected compound of formula (XIV). The compound of formula (XIV) can be converted into a selectively protected fused pyrazolo structure of formula (XXIII), which is then alkylated with an intermediate compound (XIX) containing a Cbz group to give a compound of formula (XXIV). The compound of formula (XIX) can be prepared from a compound of formula (XVIII) via a reaction with CbzCl or via the introduction of an Lg2 leaving group into the compound of formula (XVIHa). The compound of formula (XXIV) can be boronated to a compound of formula (XXV).Boronated compounds of formula (XXV) can be reacted in a cross coupling, such as a Suzuki coupling, with a (hetera-)aryl of formula (XVI) to form a compound of formula (XX). The X4 moiety in the compound of formula (XX) contains a carbonyl precursor, such as a (cyclo)alkylcarbonyl, heterocycloalkylcarbonyl, carboxylic acid, or ester, which can be reduced to a compound of formula (XXI). The compound of formula (XXI) can then be cyclized by a transcarbamylation reaction to form a compound of formula (XIII). Final deprotection of the nitrogen from the fused pyrazolone structure, either after or after alkylation of the carbamate and / or substitution of ring A, gives rise to the compound of formula (I). ML / a / ZUZZ / U 1 ÓOO I Scheme G Protection l XI ' . .* FjH I, ,, deprotection I Protection -γ'(-NX1r5>111 hh “--o: X.' . X. 13 Connector Introduction, from Lg2 Alkylation Coupling. ·. crossed Reduction xx :: xx transcarbarrulación''·., Cicla cion Optional carbamate alkylation and / or A-ring substitution Cesprotection x In the above reaction Scheme G, the reaction between a compound of formula (XXIII) and a compound of formula (XIX) can be achieved in a solvent such as Λ / , / V-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate. Suitable compounds of formula (XIX) may be commercially available or obtained by reaction with CbzCl and sodium hydroxide of a compound of formula (XVIII) in water as solvent. Alternatively, the compound of formula (XIX) may be prepared by introducing Lg2 into the compound of formula (XVIIIa). In the above reaction scheme, the borylation of the fused pyrazolo structure of a compound of formula (XXIV) to a compound of formula (XXV) can be achieved using an iridium and bis(pinacolato)diboron catalyst in a solvent such as TBME. In the above reaction between the compound of formula (XXV) and the compound of formula (XVI), the leaving group Lgi is advantageously a halogen atom such as chlorine, bromine, or iodine. This halogen displacement reaction can be carried out under cross-coupling conditions such as Suzuki conditions using palladium catalysts such as, for example, tetraquis(triphenylphosphine)palladium(O) combined or not with 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (Xphos) in the presence of tribasic potassium phosphate in a solvent mixture such as, for example, 1,4-dioxane / water at an elevated temperature such as, for example, 90°C, either under microwave conditions or not. Suitable compounds of formula (XVI) may either be commercially available or obtained through various reactions including selective protection and deprotection steps known to the person skilled in the art. The carbonyl group of X4 in the compound 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 an elevated temperature such as 120°C. The transcarbamylation of the compound of formula (XXI) to the macrocycle of formula (XIII) can be done using potassium carbonate or cesium carbonate or potassium hydroxide in a solvent such as acetonitrile at a temperature ranging from RT to solvent reflux, or using sodium hydride in a dry solvent such as toluene at a temperature ranging from 0°C to solvent reflux, either under microwave conditions or not. The final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, either after or not the alkylation of the carbamate and / or substitution of ring A, yields the final compound of formula (I). Alternatively, the compounds of formula (I) can be prepared as shown in General Scheme H below, wherein the fused pyrazolone structure of formula (II) is converted to a protected compound of formula (III) and then to a nitrogen-protected compound of formula (XIV). The compound of formula (XIV) can be converted to a selectively protected fused pyrazolone structure of formula (XXIII), which is then alkylated with an intermediate compound (XXX) containing a (hetero-)aromatic group to give a compound of formula (XXXI). The compound of formula (XXX) can be prepared using various known reaction steps. MA / a / ZUZZ / UI ÓOO I for the person skilled in the art and are described in detail for the exemplified compounds. The compound of formula (XXXI) can be macrocyclized via a CH activation reaction. The final deprotection of the nitrogen of the fused pyrazolone structure, either after or without alkylation of the carbamate and / or substitution of ring A, gives rise to the compound of formula (I). MA / a / ZUZZ / UI ÓOO I Scheme H Protection X1 M * •-N H M1 Protection xi descrotization X1 -you Page 2 1X1V) IXXJ1QjXXX} Ñ ​​h X? CH Activation L-alkylation, Γ-Macrocyclization” / zr * RVg2 x; ía 7' 'i h2 / A '--I* R >g2 Optional letter fitting and ring replacement AX'Zl / . \1 71 η' \ Cesprotection ·-...· - TO / i XXXI) IXIIII IXIII to In the above reaction Scheme H, alkylation between a compound of formula (XXIII) with a compound of formula (XXX) can be achieved in a solvent such as Λ / , / V-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 80°C. Suitable compounds of formula (XXX) can be either commercially available or obtained via synthetic routes described in the literature. In the above reaction between the compound of formula (XXX) and the compound of formula (XXIII), the leaving group Lg2 is advantageously a mesylate group. Activation of CH from the compound of formula (XXXI) to the macrocycle of formula (XIII) can be achieved using CataCXium, palladium acetate, and potassium acetate in dry toluene under microwave conditions at an elevated temperature such as 140°C. The leaving group Lgi is advantageously a halogen atom such as chlorine, bromine, or iodine. Final deprotection of the nitrogen from the fused pyrazolone structure under acidic conditions, either after or without alkylation of the carbamate and / or substitution of ring A, yields the final compound of formula (I). Alternatively, compounds of formula (I), a particular case of compounds of formula (I) where X1 is NR'a, can be prepared as shown in General Scheme I below, wherein the fused pyrazolone structure of formula (XXXII) in which X5 is, for example, a nitro group is converted into a protected compound of formula (XXXIII) and then into a nitrogen-protected compound of formula (XXXIV). The compound of formula (XXXIV) can be converted into a selectively protected fused pyrazolone structure of formula (VI), which is then alkylated with a compound of formula (VIII) containing a Pg3 protecting group. After alkylation, deprotection of X2 gives rise to 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 macrocyclize to yield a compound of formula (XIII). Final deprotection of the nitrogen of the fused pyrazolone structure, either after or before alkylation of the carbamate and / or substitution of ring A, gives rise to the compound of formula (I). Scheme I MA / a / ZUZZ / UI ÓOO I Reduction II IVh X? LgK NPai IVIII Rental X7 IIIXI In the reaction Scheme I above, X5 is a nitro group and X1 is, in this particular scheme, NR'a. Halogenation of the fused pyrazolone structure can be achieved using, for example, iodine and potassium hydroxide in a solvent such as Λ / , / V-dimethylformamide at an elevated temperature such as 60°C. The reduction of the nitro group can be obtained using iron in the presence of ammonium chloride in a mixture of solvents such as EtOH, THF and water at an elevated temperature such as 80°C to yield a compound of formula (VI). Alkylation between a compound of formula (VI) with a compound of formula (VIII) can be achieved in a solvent such as dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 80 or 90°C. The compound of formula (VIII) contains a protecting group Pg3, which may be a phthalimide group. The deprotection of X2-NPg3 in a compound 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. Organometallic cross-coupling such as Suzuki coupling of the compound of formula (XXXVI) with a compound of formula (X) can be done using palladium catalysts such as, for example, tetraquis(triphenylphosphine)palladium(0) combined or not with 2-dicyclohexylphosphine-2',4',6'triisopropylbiphenyl (Xphos) in the presence of tribasic potassium phosphate in a solvent mixture such as, for example, 1,4-dioxane / water at an elevated temperature such as, for example, 120°C either under microwave conditions or not. The delamination of the compound of formula (XII) to provide the compound of formula (XIII) can be carried out by a method known to the skilled worker as a carbamylation reaction, for example, by treatment with 1,1'-carbonyldiimidazole and / V,A / -diisopropylethylamine in a solvent such as A / ,A / -dimethylacetamide at, for example, 90°C. The final deprotection of the nitrogen of the fused pyrazolone structure under acidic conditions, either after or without alkylation of the carbamate and / or substitution of ring A, yields the final compound of formula (I). Alternatively, compounds of formula (I) can be prepared as shown in General Scheme J below, wherein the fused pyrazolo structure of formula (II) is converted into a protected compound of formula (III). This compound of formula (III) can be converted into a compound of formula (IV) containing a leaving group in the fused pyrazolo structure and then into a nitrogen-protected compound of formula (V). The compound of formula (V) can be converted into a selectively protected fused pyrazolo structure of formula (VI) in which X1 is then protected to form a compound of formula (XXXVII). The compound of formula (XXXVII) can be coupled via organometallic cross-coupling such as Suzuki coupling with a (hetero-)aryl of formula (XXXVIII) to form a compound of formula (XXXIX).Alkylation of the (hetero-)aromatic ring gives a compound of formula (XL). Deprotection of X1 followed by alkylation with a compound of formula (XIX) gives a compound of formula (XLII). The compound of formula (XIX) can be commercially available or prepared from a compound of formula (XVIII) by reaction with CbzCl or by introduction of a leaving group Lg2 into the compound of formula (XVIHa). Deprotection of X3 gives a compound of formula (XXI). The compound of formula (XXI) can then be cyclized by a transcarbamylation reaction to form a compound of formula (XIII). Final deprotection of the nitrogen of the fused pyrazolone structure, either after or after alkylation of the carbamate and / or substitution of ring A, gives the compound of formula (I). ML / a / ZUZZ / U 1 ÓOO I Scheme J Protection Xi Halogenation re Protection Lack of protection XI MA / a / ZUZZ / UI ÓOO I :V1! :iir IIV! r0: IV! Reprotection -T1·· xi J1 Cross L coupling l-Ul alkylation; χχχνιη ixxxviir ixxxix: IXLI Lack of protection xi Η NΊQ· “w· ” ¡XVIH] ¡XVIIIa: or Connector | IntroductionCfcztI of Lg2 Alkylation IXDC Vulnerability X3 ransearbanulation A Cycling Optional > 'carbamate alkylation' \and / or ring substitution A z;.·HDesprotection Y Xllla ixxr ixiir In the above reaction Scheme J, protection of X1 from the compound of formula (VI) can be achieved with benzyl chloride in a solvent such as / V, / V-dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at room temperature or at an elevated temperature. In the above reaction between the compound of formula (XXXVII) and the compound of formula (XXXVIII), the leaving group Il is advantageously a halogen atom such as chlorine, bromine, or iodine. This halogen displacement reaction can be carried out under organometallic cross-coupling conditions such as Suzuki conditions using palladium catalysts such as, for example, tetraquis(triphenylphosphine)palladium(O) combined or not with 2-dichohexylphosphine-2',4',6'-trisopropylphenyl (Xphos) in the presence of tribasic potassium phosphate in a solvent mixture such as, for example, 1,4-dioxane / water at an elevated temperature such as, for example, 110°C, either under microwave conditions or not. Suitable compounds of formula (XXXVIII) may be commercially available or obtained through various reactions, including selective protection and deprotection steps known to those skilled in the art. A borylation step may be required for compounds of formula (XXXVIII). In the above reaction scheme, the alkylation of the compound of formula (XXXIX) can be achieved using (2-bromoethoxy)(tert-butyl)dimethylsilane in a solvent such as Λ / , / V-dimethylformamide and a base such as sodium hydride at 0°C or room temperature. The deprotection of X1 in the compound of formula (XL) can be achieved using hydrogen gas in the presence of Pd / C in a solvent such as EtOH at room temperature. Alkylation between a compound of formula (XLI) with a compound of formula (XIX) can be achieved in a solvent such as dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 120°C. Suitable compounds of formula (XIX) may be commercially available or obtained by reaction with CbzCl and sodium hydroxide of a compound of formula (XVIII) in water as solvent. Alternatively, the compound of formula (XIX) may be prepared by introducing Lg2 into the compound of formula (XVIIIa). The deprotection of X3-OPg4 in the compound of formula (XLII) can be done using TBAF in a solvent such as THF at room temperature. The transcarbamylation of the compound of formula (XXI) to the macrocycle of formula (XIII) can be done using potassium carbonate or cesium carbonate or potassium hydroxide in a solvent such as acetonitrile at a temperature ranging from RT to solvent reflux, or using sodium hydride in a dry solvent such as toluene at a temperature ranging from 0°C to solvent reflux, either under microwave conditions or not. The final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, either after or not the alkylation of the carbamate and / or substitution of ring A, yields the final compound of formula (I). Alternatively, compounds of formula (I) can be prepared as shown in General Scheme K below, wherein the fused pyrazolone structure of formula (II) is converted into a protected compound of formula (III). The NH group of the fused pyrazolone structure can be protected to a compound of formula (XIV). This compound of formula (XIV) can be converted into a boronic acid (or boronate ester) of formula (XV). The compound of formula (XV) can be coupled via organometallic cross-coupling, such as Suzuki coupling, with a (hetero-)aryl group of formula (XLIII) or formula (XXVI) to form a compound of formula (XLIV) or a compound of formula (XLIVa). Deprotection of X1 results in a compound of formula (XLV) or a compound of formula (XLVa).The compound of formula (XLV) or the 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 the compound of formula (XLVI) gives the compound of formula (XXI). The compound of formula (XXI) can then be cyclized by a transcarbamylation reaction to form a compound of formula (XIII). Final deprotection of the nitrogen of the fused pyrazolone structure, either after or after alkylation of the carbamate and / or substitution of ring A, gives the compound of formula (I). ML / a / ZUZZ / U 1 ÓOO I Scheme K . . Coupling I Protection ι Protection k . ·. ... Bonlación .. crossed i XX — '. X?· ' X-A ' a Ψ MA / a / ZUZZ / UI ÓOO I / ' / Deprotection ' - / ' O-:'T' / Γ -: - CBZ Connectors | Introduction of Lg2 Alkylation Deprotection . / ' T / h Optional “transcartamylation\ alkylation carbamate T-cycling, and / or A-ring replacement Vulnerability XX In the above reaction Scheme K, the borylation of the fused pyrazolo structure of a compound of formula (XIV) to a compound of formula (XV) can be achieved using an iridium and bis(pinacolato)diboron catalyst in a solvent such as TBME. In the above reaction between the compound of formula (XV) and the compound of formula (XLIII) or the compound of formula (XXVI), the leaving group Il is advantageously a halogen atom such as chlorine, bromine, or iodine. This halogen displacement reaction can be carried out under cross-coupling conditions such as Suzuki conditions using palladium catalysts such as, for example, tetrakis(triphenylphosphine)palladium(O) combined with 2-dicyclohexylphosphine-2',4',6'-triisopropylphenyl(Xphos) in the presence of tribasic potassium phosphate in a solvent mixture such as, for example, 1,4-dioxane / water at an elevated temperature such as, for example, 90°C, either under microwave or non-microwave conditions. The deprotection of X1 in the compound of formula (XLIV) or in the compound of formula (XLIVa) can be achieved using a reagent such as TBAF in a solvent such as THF at room temperature. In the reaction scheme above, alkylation between a compound of formula (XLV) or a compound of formula (XLVa) with a compound of formula (XIX) can be achieved in a solvent such as dimethylformamide or acetonitrile and a base such as cesium carbonate or potassium carbonate at an elevated temperature such as 50°C. Suitable compounds of formula (XIX) can be either purchased commercially or obtained by reaction with CbzCl and sodium hydroxide from a compound of formula (XVIII) in water as solvent. Alternatively, the compound of formula (XIX) can be prepared by introducing Lg2 into the compound of formula (XVIIla). The deprotection of X3-OPg4 in the compound of formula (XLVI) can be achieved using conditions such as potassium carbonate in a solvent such as MeOH at room temperature. The transcarbamylation of the compound of formula (XXI) to the macrocycle of formula (XIII) can be done using potassium carbonate or cesium carbonate or potassium hydroxide in a solvent such as acetonitrile at a temperature ranging from RT to solvent reflux, or using sodium hydride in a dry solvent such as toluene at a temperature ranging from 0°C to solvent reflux, either under microwave conditions or not. The final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, either after or not the alkylation of the carbamate and / or substitution of ring A, yields the final compound of formula (I). Alternatively, compounds of formula (I) can be prepared as shown in General Scheme L below, wherein the fused pyrazolone structure of formula (II) is converted into a protected compound of formula (III). The NH group of the fused pyrazolone structure can be protected into a compound of formula (XIV). This compound of formula (XIV) can be converted into a boronic acid (or boronate ester) of formula (XV). The compound of formula (XV) can be coupled in a cross-coupling reaction, such as a Suzuki coupling, with a (hetera-)aryl group of formula (XLVIII) to form a compound of formula (XLIX). The introduction of a leaving group at X2 gives a compound of formula (L). Deprotection of X1 gives a compound of formula (Ll). The compound of formula (Ll) can then be cyclized by nucleophilic substitution to form a compound of formula (XIII).The final deprotection of the nitrogen of the fused pyrazolo structure, either after or not the alkylation of the carbamate and / or substitution of ring A, gives rise to the compound of formula (I). Scheme L MA / a / ZUZZ / UI ÓOO I :xlvii:ixxvr v'1Ί ' । I In—'nh· * Protection I । . . _ ys. - xi - Protection --τ··' >Γ--τ·, Bonlación 'γ -r ; . ,<; - i YO·. f - * y / py - V 1 / ” ' 'S :ii: ;iu: ¡xiv; ixv: :xlviir Cross coupling Introduction of the outgoing group 'Lack of protection'; X1 Nucleophilic substitution ;xux; :li: penis Optional: carbamate alkylation and / or A-ring substitution Xilla deprotection; In the above reaction Scheme L, the borylation of the fused pyrazolo structure a compound of formula (XIV) to a compound of formula (XV) can be achieved using an iridium and bis(pinacolato)diboron catalyst in a solvent such as TBME. In the above reaction between the compound of formula (XV) and the compound of formula (XLVIII), the leaving group Il is advantageously a halogen atom such as chlorine, bromine, or iodine. This halogen displacement reaction can be carried out under organometallic cross-coupling conditions such as Suzuki conditions using palladium catalysts such as, for example, tetraquls(triphenylphosphine)palladium(O) combined or not with 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (Xphos) in the presence of tribasic potassium phosphate in a solvent mixture such as, for example, 1,4-dioxane / water at an elevated temperature such as, for example, 90°C, either under microwave conditions or not. The compound of formula (XLVIII) can be prepared from a reaction of an alcohol of formula (XXVI), a chloroformate such as nitrophenyl chloroformate and an amine of formula (XLVII). The introduction of a leaving group on X2 such as a mesylate in the compound 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 and gives rise to a compound of formula (L). The deprotection of X1 to the compound of formula (Ll) can be achieved using a reagent such as TBAF in a solvent such as THF at room temperature. The macrocyclization of the compound of formula (Ll) by nucleophilic substitution can be done using cesium carbonate in a solvent such as / V, / V-dimethylformamide at an elevated temperature such as 80°C and gives a compound of formula (XIII). The final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, either after or not the alkylation of the carbamate and / or substitution of ring A, yields the final compound of formula (I). Alternatively, the compounds of formula (I) can be prepared as shown in the general Scheme M below, wherein the fused pyrazolo structure of formula (II) is converted into a protected compound of formula (III). This compound of formula (III) can be converted into a compound of formula (IV) containing a leaving group in the fused pyrazolo structure and then into a nitrogen-protected compound of formula (V). The compound of formula (V) can be converted into a selectively protected fused pyrazolo structure of formula (VI) which is then alkylated with a leaving-group intermediate of formula (XIX) to give a compound of formula (XXII).The compound of formula (XIX) can be commercially available or prepared from a compound of formula (XVIII) by reaction with CbzCl or by introduction of a leaving group Lg2 into the compound of formula (XVIIIa). The compound of formula (XXII) can be coupled in a copper-mediated coupling with a protected alkyne (LlI) to form a compound of formula (LUI). Deprotection of the alkyne leads to a compound of formula (LIV). From the alkyne, the (hetero-)aromatic ring can be formed, giving a compound of formula (XLII). Deprotection of X3-OPg4 leads to a compound of formula (XXI). The compound of formula (XXI) can then be cyclized by a transcarbamylation reaction to form a compound of formula (XIII). The final deprotection of the nitrogen of the fused pyrazolone structure, either after or before alkylation of the MA / a / ZUZZ / UI ÓOO I carbamate and / or substitution of ring A gives rise to the compound of formula (I). Scheme M Protection X1 N ----* h HX1, .-71. - Halogenation Protection h ----* NH xiZ1,lplUnprotection ; · '.i Version Py2 :v: MA / a / ZUZZ / UI ÓOO I x: H '1 ;xvnn Cb connector: , jM Lp?Cp alkylation? •jdzhh-·' or iXVIllal o Introduction of Lg2 Coupling :vii ; xjx; Ixxic :ur Py4U XI Ai .z' 7 Unprotected λ I? K Pq; Formation of heteroaromat N Why? follow lUVt HC '1 iiH ( ) 7~. What ..... / -rancarbamylation A / I11Cycle n *V Optional jn alkylation carbamate Xi í. . T T·1Y'0 ring substitution A ,4.* - - XJ / λ > . ; xí -1·'' ... Cesprotection * ixxc X.IILa In Scheme M above, A is a 5-membered aromatic cyclic group as defined in formula (a) with A4 being a carbon atom and A5 representing an optionally substituted carbon atom. In the above reaction scheme, alkylation between a compound of formula (VI) with a compound of formula (XIX) can be achieved in a solvent such as A / ,A / -dimethylformamide or acetanitri and a base such as cesta carbonate or potassium carbonate at an elevated temperature such as 120°C. Suitable compounds of formula (XIX) may be commercially available or obtained by reaction with CbzCl and sodium hydroxide of a compound of formula (XVIII) in water as solvent. Alternatively, the compound of formula (XIX) may be prepared by introducing Lg2 into the compound of formula (XVIIIa). In the above reaction between the compound of formula (XXII) and the compound of formula (LLI), the leaving group L1 is advantageously a halogen atom such as chlorine, bromine, or iodine. This halogen displacement reaction can be carried out under conditions using palladium catalysts such as, for example, tetrakis(triphenylphosphine)palladium(O), combined or not with Cu, in the presence of triethylamine in a solvent such as, for example, THF at an elevated temperature such as, for example, 80°C. The deprotection of the alkyne can be achieved using TBAF in a solvent such as THF at room temperature, providing a compound of the formula (LIV). The formation of the heteroaromatic ring to a compound of formula (XLII) can be effected through reaction with a reagent such as tert-butyl-(3-nitropropoxy)-diphenylsilane in the presence of PhNCO and trimethylamine in a solvent such as THF at an elevated temperature such as 80°C. The deprotection of X3-OPg4 in compound (XLII) can be done using TBAF in a solvent such as THF at room temperature, providing a compound of formula (XXI). The transcarbamylation of the compound of formula (XXI) to the macrocycle of formula (XIII) can be done using potassium carbonate or cesium carbonate or potassium hydroxide in a solvent such as acetonitrile at a temperature ranging from RT to solvent reflux, or using sodium hydride in a dry solvent such as toluene at a temperature ranging from 0°C to solvent reflux, either under microwave conditions or not. The final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, either after or not the alkylation of the carbamate and / or substitution of ring A, yields the final compound of formula (I). Alternatively, compounds of formula (I) can be prepared as shown in General Scheme N below, wherein the fused pyrazolo structure of formula (II) is converted into a protected compound of formula (III). This compound of formula (III) can be converted into a compound of formula (IV) containing a leaving group in the fused pyrazolo structure and then into a nitrogen-protected compound of formula (V). The compound of formula (V) can be converted into a selectively protected fused pyrazolo structure of formula (VI). The compound of formula (VI) is alkylated with a compound of formula (V1) to form a compound of formula (LV). Deprotection of X2-N(Ra)Pg3 gives a compound of formula (LVI).The compound of formula (LVI) can be coupled to the (hetero-)aromatic compound of formula (LVII) via a reaction with CDL. The compound of formula (LVIII) can then be cyclized by a CH activation reaction to form a compound of formula (XIII). Final deprotection of the nitrogen of the fused pyrazolone structure, either after or after alkylation of the carbamate and / or substitution of ring A, gives rise to the compound of formula (I). ML / a / ZUZZ / U 1 ÓOO I Scheme N Z1 a Zi People Protection X1 b ---» -NH mn -N Pul Halogenation X2 Z1 N •N IIVI Protection Ra hH X2 Xi zi y ' Lack of protection .?r \ *v TO - * P2 (VI Ί ' / « · - R Pp2 Alkylation I Elimination *' of Lg 1 Z1 iVlllal . Unprotected And X2 n' * 22 / >1 -M for: <vn ILV) ilvH Rj X2 Lg3 Ra h tjR X2 Activation of CH Macro cycling n _ Zi ” ·, Cartamylation A . — ► ILV1II -N >Π2 / Ζ3 R •N Pg2 Optional A-ring replacement Deprotection Z' / 23 ¡: R óoo i ILV1III (Xlltal In the reaction Scheme N above, alkylation between a compound of formula (VI) and a compound of formula (Villa) can be achieved in a solvent such as dimethylformamidate or acetonitrile and a base such as cesium carbonate or potassium carbonate at room temperature or elevated temperature. Suitable compounds of formula (Villa) can be either commercially available or obtained through various selective protection and deprotection steps known to the person skilled in the art. The deprotection of the compound of formula (LV) can be effected using palladium on carbon in carbon and hydrogen gas at room temperature in a solvent such as MeOH. The coupling of the (hetero-)aromatic part in the (LVI) formula can be achieved at room temperature using 1,1-carbonyldiimidazole and a base such as cesium carbonate in a solvent such as N,Nd-methylacetamide. Ring closure through CH activation of the compound of formula (LVIII) to the macrocycle of formula (XIII) can be achieved using cataCXium, palladium acetate and potassium acetate in dry toluene under microwave conditions at an elevated temperature such as 150°C. The final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, either after or not the alkylation of the carbamate and / or substitution of ring A, yields the final compound of formula (I). Alternatively, compounds of formula (I) can be prepared as shown in the General Scheme O below, wherein the fused pyrazolone structure of formula (II) is converted into a protected compound of formula (III). The NH group of the fused pyrazolone structure can be protected to a compound of formula (XIV). This compound of formula (XIV) can be converted into a boronic acid (or boronate ester) of formula (XV). The compound of formula (XV) can be coupled by an organometallic cross-coupling, such as a Suzuki coupling, with a (hetero-)aryl group of formula (XLIII) or formula (XXVI) 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) before alkylation and cyclization in a container. Final deprotection of the nitrogen from the fused pyrazolone structure, either after or before alkylation of the carbamate and / or substitution of ring A, results in the compound of formula (I). ML / a / ZUZZ / U 1 ÓOO I Scheme O Protection Protection Bortiació ι·ιχ: B_JPL30-»C Cross coupling Connector Cbz introduction of Lg2 Alkylation and transcarbamylation cyclization in a vessel Optional carbamate alkylation and / or A-ring substitution Lack of protection / Vulnerability In the above reaction Scheme O, the borylation of the fused pyrazolone structure of a compound of formula (XIV) to a compound of formula (XV) can be achieved using an iridium and bis(pinacolato)diboron catalyst in a solvent such as TBME. 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 Il is advantageously a halogen atom such as chlorine, bromine, or iodine. This halogen displacement reaction can be carried out under cross-coupling conditions such as Suzuki conditions using palladium catalysts such as, for example, tetraquis(triphenylphosphine)palladium(O) combined with 2-dichohexylphosphine-2',4',6'-trisopropylbiphenyl (Xphos) in the presence of tribasic potassium phosphate in a solvent mixture such as, for example, 1,4-dioxane / water at an elevated temperature such as, for example, 90°C, either under microwave or non-microwave conditions. The possible deprotection of X1 can be done using TBAF in a solvent such as THF at a K c NN temperature such as room temperature. Possible alkylation in a container with a compound of formula (XIX) and transcarbamylation to the macrocycle of formula (XIII) can be done using cesium carbonate in a solvent such as acetonitrile at a temperature ranging from RT to 80°C. The final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, either after or not the alkylation of the carbamate and / or substitution of ring A, yields the final compound of formula (I). Alternatively, the compounds of formula (I) can be prepared as shown in the general Scheme P below, where the fused pyrazolone structure of formula (II) is converted into a protected compound of formula (III). The NH group of the fused pyrazolone structure can be protected to a compound of formula (XIV). This compound of formula (XIV) can be converted into a boronic acid (or boronate ester) of formula (XV). The compound of formula (XV) can be coupled by an organometallic cross-coupling, such as a Suzuki coupling, with a (hetero-)aryl group of formula (XXVI) to form a compound of formula (XLIVa), which can then be alkylated with a compound of formula (XLVI) and cyclized by a carbamylation reaction to form a compound of formula (XLVIII).The final deprotection of the nitrogen of the fused pyrazolo structure, either after or not the alkylation of the carbamate and / or substitution of ring A, gives rise to the compound of formula (I). Scheme P Protection Protection Borilation Cross coupling Vulnerability Alkylation Carbamylation; _ Optional í' . J carbamate substitution. >-substitution ring A i.. Cesprotection In the above reaction Scheme P, the borylation of the fused pyrazolo structure of a compound of formula (XIV) to a compound of formula (XV) can be achieved using an iridium and bis(pinacolato)diboron catalyst in a solvent such as TBME. In the above reaction between a compound of formula (XV) and a compound of formula (XXVI), the leaving group Il is advantageously a halogen atom such as chlorine, bromine, or iodine. This halogen displacement reaction can be carried out under cross-coupling conditions such as Suzuki conditions using palladium catalysts such as, for example, tetrakis(triphenylphosphine)palladium(O) combined with 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (Xphos) in the presence of tribasic potassium phosphate in a solvent mixture such as, for example, 1,4-dioxane / water at an elevated temperature such as, for example, 90°C, either under microwave or non-microwave conditions. The alkylation of the compound of formula (XLV) with a compound of formula (XLVI) can be done using cesium carbonate in a solvent such as acetonitrile at a temperature ranging from RT to 80°C. Carbamylation of the compound of formula (XLVIII) can be achieved using a reagent such as CDI, COCL, CO2 or CO. The final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, either after or not the alkylation of the carbamate and / or substitution of ring A, yields the final compound of formula (I). EXAMPLES The IUPAC names of the compounds of the invention were generated using the following software: Product version: MarvinSketch 18.3.0 Date of construction: 26-01-2018 Internal Construction ID: 18.3.0-7913 Operating System: amd64 Windows 10.10.0 Character encoding: windows-1252 Java: Jeroen Frijters Java 1.8.0 Memory: 43.8M total, 10.0M free Environment: .NET Application 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 In case of a discrepancy between the drawn chemical structures and the corresponding chemical names, the drawn chemical structures shall be considered the true structures. To prepare the compounds described in the examples, the following experimental protocols were followed unless otherwise stated. Unless otherwise stated, reaction mixtures were magnetically stirred at room temperature. When organic solutions were "dried," they were generally dried over a drying agent such as sodium sulfate or magnesium sulfate. When mixtures, solutions, and extracts were MA / a / ZUZZ / UI ÓOO I “concentrated”, they were typically concentrated in a rotary evaporator under reduced pressure. All the exemplified intermediates and final compounds were analyzed by high-performance liquid chromatography (HPLC) following one of the methods described below. LCMS method A The analyses were performed in a Thermo Scientific Accucore C18 (50 mm long x 2.1 mm ID, 2.6 pm) at 35°C, with a flow rate of 1.50 mL / min. A 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 minutes; the resulting composition was held for 0.5 minutes; then the final mobile phase composition was 5% (Water + 0.1% Formic Acid) / 95% Acetonitrile to 90% (Water + 0.1% Formic Acid) / 10% Acetonitrile in 0.10 minutes. The injection volume was 1 pL. The MS acquisition variation and the UV detector were set to 100-1,000 m / zy 190-400 nm, respectively. LCMS method B The analyses were performed on a Phenomenex Kinetex 00B-4475-AN C18 column (50 mm long x 2.1 mm ID; 1.7 pm particles) at 60°C, with a flow rate of 1.5 mL / min. A 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 minutes; the resulting composition was held for 0.40 minutes; 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 minutes. The injection volume was 2 pL with an Agilent autosampler injector or 5 pL with a Gerstel MPS injector. The MS acquisition frequency and DAD detector were set to 100–800 m / s and 190–400 nm, respectively. LCMS method C The analyses were performed on a YMC pack ODS-AQ C18 column (50 mm long x 4.6 mm DL; 3 µm particle size) at 35°C, with a flow rate of 2.6 mL / min. A 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; then 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 pL. The acquisition frequencies were set to 190–400 nm for the UVPDA detector and 100–1400 m / z for the TOF-LCMS detector. Total operating time: 6.2 minutes. LCMS method D The analyses were performed on a Phenomenex Kinetex C18 column (50 mm long x 2.1 mm ID; particle size 2.6 µm) at 35°C, with a flow rate of 0.7 mL / min. A 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; then 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 pL. The acquisition variations were adjusted to 190-400 nm for the UV-PDA detector and 100-1400 m / z for the MS detector. Total operating time: 6.2 minutes. LCMS method E The analyses were performed on a YMC pack ODS-AQ C18 column (50 mm long x 4.6 mm DL; particle size 3 µm) at 35°C, with a flow rate of 2.6 mL / min. An elution was performed MA / a / ZUZZ / UI ÓOO I in a gradient 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; 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 pL. Acquisition variations were set to 190-400 nm for the UVPDA detector and 100-1400 m / z for the MS detector. LCMS method F Analytical HPLC was performed on an X-Select CSH C18 XP column (2.5 pm 30 x 4.6 mm d) eluting with 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B), using the following elution gradient: 0-3 minutes: 5% to 100% B, 3-4 minutes to 100% B, at a flow rate of 1.8 mL / min at 40°C. Mass spectra (MS) were recorded on a Waters ZQ mass spectrometer (200-900 scan array) using either positive electrospray ionization [ES+] to provide [M+H]+ molecular ions or negative electrospray ionization [ES-] to provide [MH] molecular ions with a cone voltage of 20 V. LCMS method G Analytical HPLC was performed on an X-Select CSH C18 XP column (2.5 pm 30 x 4.6 mm di) eluting with 2 g / L (NH₄CO₃) aq in water (solvent A) and acetonitrile (solvent B), using the following elution gradient: 0-3 minutes: 5% to 100% B, 3-4 minutes 100% B, at a flow rate of 1.8 mL / min at 40°C. Mass spectra (MS) were recorded on a Waters ZQ mass spectrometer (200-900 scan array) using positive ionization by electrospray [ES+] to provide [M+H]+ molecular ions or negative ionization by electrospray [ES-] to provide [MH]- molecular ions with a cone voltage of 20 V. LCMS method H Analytical HPLC was performed on an X-Select CSH C18 XP column (2.5 pm 30 x 4.6 mm d) eluting with 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B), using the following elution gradient 0-4 mins: 0% to 50% B at a flow rate of 1.8 mL / min at 40°C. Mass spectra (MS) were recorded on a Waters ZQ mass spectrometer (scan 200900 urn) using positive electrospray ionization [ES+] to provide [M+H]+ molecular ions or negative electrospray ionization [ES-] to provide [MH] molecular ions with a cone voltage of 20 V. LCMS method I Analytical HPLC was performed on an X-Select CSH C18 XP column (2.5 pm 30 x 4.6 mm d) eluting with 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B), using the following elution gradient: 0-4 min: 40% to 100% B, 4-5 min: 100% B at a flow rate of 1.8 mL / min at 40°C. Mass spectra (MS) were recorded on a Waters ZQ mass spectrometer (200-900 scan array) using positive electrospray ionization [ES+] to provide [M+H]+ molecular ions or negative electrospray ionization [ES-] to provide [MH] molecular ions with a cone voltage of 20 V. ML / a / ZUZZ / U 1 ÓOO I LCMS method J Analytical HPLC was performed on an X-Select CSH C18 XP column (2.5 pm 30 x 4.6 mm d) eluting with 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B), using the following elution gradient: 0-6 min: 5% to 100% B, 6-7 min: 100% B at a flow rate of 1.8 mL / min at 40°C. Mass spectra (MS) were recorded on a Waters ZQ mass spectrometer (200-900 scan array) using positive electrospray ionization [ES+] to provide [M+H]+ molecular ions or negative electrospray ionization [ES-] to provide [MH] molecular ions with a cone voltage of 20 V. Chiral analytical SFC was performed on a Whelk O1 (R,R) column (1.8 pm 100 x 4.6 mm di) eluting with CO2 / methanol (70 / 30) at a flow rate of 2.5 mL / minute at 35°C. All the final compounds exemplified were analyzed by proton NMR. The 1H NMR spectra were recorded either in CDCh, O6-DMSO, or CD3OD on a Bruker Avance 400 MHz spectrometer or on a Bruker Ultrashield AV300 MHz spectrometer, using a Bruker 5 mm BBI 1H / D-BB Z-GRD probe with a BACS-60 sample changer, and were recorded 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 CDCh, 2.50 ppm for O6-DMSO, and 3.31 ppm for CD3OD). For the 1H NMR spectra, multiplicities, coupling constants in hertz, and proton numbers are indicated in parentheses. The abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet, br s = wide singlet. Alternatively, 1H-NMR measurements were performed on a Bruker Avance III 500 MHz spectrometer, using DMSO-d6 (hexadeutero-dimethyl sulfoxide) or CDCh (deuterochloroform) as the solvent. 1H-NMR data are presented as delta values, in parts per million (ppm), using the residual peak of the solvent (2.50 ppm for DMSO-d6 and 7.26 ppm for CDCh) as the internal standard. The split patterns are designated as: s (single), 2s (2xsingle), d (doublet), 2d (2xdoublet), t (triple), 2t (2xtriple), q (quad), 2q (2xquad), quint (quint), sept (septet), m (multiplet), 2m (2xmultiplet), brs (wide singlet), brd (wide doublet), brt (wide triplet), brq (wide quad), brm (wide multiplet), vbrs (very wide singlet), dd (doublet of doublets), td (triple of doublets), dt (doublet of triplets), dq (doublet of quad), ddd (doublet of doublets), dm (doublet of multiplets), tm (triple of multiplets), qm (quad of multiples). Abbreviations: The following abbreviations are used in this report: Ph = phenyl Ac = acetate Bn = benzyl t-Bu = tert-butyl n-Bu = linear butyl Me = methyl Et = ethyl Pr = propyl MA / a / ZUZZ / UI ÓOO I ¡Pr = isopropyl Bu = butyl TMS = trimethylsilyl TBS = tert-butyldimethylsilyl TFA = trifluoroacetic acid i-Pr2NEt or DIPEA = A / . / V-diisopropylethylamine TEA = triethylamine DMAP = 4-dimethylaminopyridine Pd / C = palladium 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 = AZ-iodosuccinimide ACN = acetonitrile PTSA = p-toluenesulfonic acid THF = tetrahydrofuran DCM = dichloromethane DMF = / V, / V-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-Dicyclohex¡lfosphino-2',4',6'-triisoprop¡lbiphenyl dppf = 1 .T-Bis(diphenylphosphine)ferrocene wt % = % by weight ee = enantiomeric excess min = minute(s) ΜΛ / a / ZUZZ / U 1 ÓOO I ho hr = hour(s) L = liter(s) mL = milliliter(s) pL = microliter(s) g = gram(s) mg = milligram(s) mol = moles mmol = millimol(s) RT = ambient temperature tR = retention time sat = saturated ac. = acuous TLC = thin layer chromatography HPLC = high-performance liquid chromatography LC / MS = high-performance liquid chromatography / mass spectrometry MS or Spec Mas = mass spectrometry NMR = nuclear magnetic resonance ppm = parts per million Example 1: 8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.12'6.018'21]tricose óoo i 1(20),2,4,6(23),15,17,21-heptaen-9-one Example 1 is prepared according to the synthesis route described in General Scheme A. Preparation of the intermediate 1:5-((tert-butyldimethylsilyl)oxy)-1H-indazoleXO. % / N H 1 H-indazol-5-ol (19 g, 141.643 mmol) was dissolved in 425 mL of DCM, 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 hours. A saturated solution of NaHCO3 was added, and the reaction mixture was extracted with DCM (2x). The combined organic layers were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by flash silica gel chromatography using Hept / EtOAc (100:0 to 70:30). The desired fractions were combined and concentrated under reduced pressure yielding 5-((tert-butyldimethylsilyl)oxy)-1 H-indazole 1 as a salmon solid. LCMS method A: [M+H]+= 249.0, ir = 0.997 min Preparation of intermediate 2:5-((tert-butyldimethylsilyl)oxy)-3-vodo-1 H-indazole MA / a / ZUZZ / UI ÓOO I i H 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1H-indazole (20 g, 80.515 mmol) was dissolved in 240 mL of DCM, N-iodosuccinimide (19.021 g, 84.541 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM, and a saturated solution of NaHCOa was added. The two layers separated, and the water layer was extracted with DCM (2x). The combined organic layers were dried over MgSO4, filtered, and the solvent was removed under reduced pressure, yielding the crude product, which was purified by flash silica gel chromatography using Hept / EtOAc (100:0 to 80:20) as eluents. The desired fractions were combined and the solvent was removed under reduced pressure yielding 5-((tert-butyldimethylsilyl)oxy)3-iodo-1 H-indazole 2 as a light brown solid. LCMS method A: [M+H]+= 374.9, tR= 1.156 min Preparation of the intermediate 3:5-((tert-butyldimethylsilyl)oxi)-3-vodo-1-(tetrahydro-2H-oiran-2-yl)-1Hindazole To a solution of 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1H-indazole (27.960 g, 74.699 mmol) in 224 mL of DCM, 4-methylbenzenesulfonic acid monohydrate (1.421 g, 7.470 mmol) and 3,4-dihydro-2H-pyran (20.490 mL, 224.097 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with DCM, and a saturated solution of NaHCl was added. The two layers separated, and the water layer was extracted with DCM (2x). The combined organic layers were dried over MgSO₄, filtered, and the solvent 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, yielding 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole as a light orange oil. LCMS method A: [M+H]+= 458.9, ir = 1.377 min Preparation of the intermediate 4:3-iodo-1-(tetrahydropyran-2-yl)-1H-andazol-5-ol ML / a / ZUZZ / U 1 ÓOO I 5-((tert-butyldimethylsilyl)oxy)-3-iodo-1-(tetrahydro-2H-pyran-2-1l)-1H-indazole 3 (10,000 g, 21,814 mmol) was dissolved in 62 mL of THF. TBAF [1 M] was added to THF (32.8 mL, 32,800 mmol) at 0°C. The reaction was stirred at room temperature for 16 h. A saturated solution of NaHCO3 was added, and the two layers separated. The water layer was extracted with DCM (2x). The combined organic layers were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The crude was purified by flash chromatography (silica; Heptane / EtOAc 100:0 to 60:40). The fractions containing the desired product were combined and the solvent was evaporated under reduced pressure to yield 3-iodo-1-(tetrahydropyran-2-yl)-1H-indazol-5-ol 4 as a creamy solid. LCMS method B: [M+H]+= 345.0, tR = 0.767 min Preparation of the intermediate 5:3-(d¡benc¡lam¡no)prooan-1-ol To a solution of 3-aminopropan-1-ol (5 g, 66.569 mmol) in 200 mL of EtOH, 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 at 70°C under reflux for 4 hours. 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 MgSO4, filtered, and concentrated under reduced pressure, yielding the crude product, which was purified by flash silica gel chromatography using Hept / EtOAc (100:0 to 80:20) as eluents. The desired fractions were combined and the solvent was removed under reduced pressure yielding 3-(dibenzylamino)propan-1ol 5 as a yellowish oil. LCMS method B: no m / z detected, tR = 0.248 min Preparation of intermediate 6: 3-(dibenzylamino)propyl methanesulfonate 3-(Dibenzylamino)propan-1-ol (5.000 g, 19.580 mmol) was dissolved in 60 mL of DCM, 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 hours. DCM and a saturated NaHCO3 solution were added. The two layers separated, and the mixture was extracted with DCM (x2). The combined organic layers were dried over MgSCM, filtered, and the solvent was removed under reduced pressure, yielding 3-(dibenzylamino)propyl methanesulfonate as a yellow oil, which was used in the next step without further purification. LCMS method B: no m / z detected, tR = 0.380 min Preparation of intermediate 7: NN-dibenzyl-3-((3-vodo-1-(tetrahydro-2H-oiran-2-yl)-1H-indazol-5yl)oxy)propan-1-amine MA / a / ZUZZ / UI ÓOO I 3-(dibenzylamino)propyl methanesulfonate 6 (crude, 6.298 g, 18.888 mmol) was dissolved in 10 mL of A / ,A / -dimethylformamide and added to a stirred mixture of 3-iodo-1-(tetrahydropyran-2-yl)-1H-indazol-5-ol 4 (5.000 g, 14.529 mmol) and cesium carbonate (7.101 g, 21.794 mmol) in 40 mL of N,N-dimethylformamide. The reaction was stirred at room temperature for 30 minutes and then heated to 85°C for 2 hours. The mixture was diluted with EtOAc and water was added. The two layers were separated, and the water layer was extracted with DCM (x2). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was purified by flash silica gel chromatography using Hept / EtOAc (100:0 to 80:20). The 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 as a yellowish oil. LCMS method B: [M+H]+= 582.2, tR= 0.890 min Preparation of intermediate 8: (5-(hydroxymethyl)pyridin-3-1)boronic acid (5-Bromopyridin-3-yl)methanol (3.000 g, 15.956 mmol), bis(pinacolate)diboron (4.862 g, 19.147 mmol), and potassium acetate (4.698 g, 47.868 mmol) were dissolved in 50 mL of 1,4-dioxane. After degassing with N2 for 5 minutes, Pd(dppf)Cl2 DCM (1.303 g, 1.596 mmol) was added, and the reaction mixture was stirred at 110°C for 4 hours. The mixture was diluted with EtOAc and filtered over a Celite pad. The solvent was evaporated under reduced pressure, yielding (5-(hydroxymethyl)pyridin-3-yl)boronic acid as a dark brown solid. The crude oil was used in the next stage without purification. LCMS method B: [M+H]+= 154.1, tR= 0.107 min Preparation of intermediate 9: {5-[5-(3-dibenzylamino-propoxy)-1-(tetrahydro-pyran-2-yl)-1Hindazol-3-yl]-pyridín-3-yl}-methanol ML / a / ZUZZ / U 1 ÓOO I Tetraquis(triphenylphosphine)palladium(0) (1.411 g, 1.221 mmols) and XPhos (0.291 g, 0.611 mmols) were added to a mixture of N,N-dibenzyl-3-((3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)oxy)propan-1amine 7 (7.100 g, 12.210 mmols), (5-(hydroxymethyl)pyridin-3-yl)boronic acid 8 (crude, 8.84 g, 15.873 mmols) and tribasic potassium phosphate (7.77 g, 36.63 mmols) in 122.00 mL of 1,4-dioxane / H2O (3:1). The mixture was degassed with N2 for 5 min and stirred at 90°C for 16 h. It was then diluted with EtOAc and water was added. The two layers were separated, and the water layer was extracted with DCM (x2). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was purified by flash silica gel chromatography using DCM:MeOH (100:0 to 98:2).The desired fractions were combined and the solvent was removed under reduced pressure to obtain {5-[5-(3-dibenzylamino-propoxy)-1(tetrahydro-prayan-2-11)-1H-andazol-3-11]-pindin-3-11}-methanol 9 as a yellow oil. LCMS method B: [M+H]+= 563.3, ir = 0.749 min Preparation of intermediate 10: l5-f5-í3-amino-propoxy)-1-(tetrahydro-pyran-2-yl)-1H-indazol-3-yl1pyridin-3-yl}-methanol {5-[5-(3-dibenzylaminopropoxy)-1-(tetrahydropyran-2-11)-1H-indazol-3-11]-pyridin-3-11}-methanol (6.000 g, 10.662 mmol) was dissolved in 106 mL of EtOAc and degassed with N2. 10% w / w Pd / C (6.000 g) was added, and the reaction mixture was stirred under an H2 atmosphere in a round-bottom flask at RT for 66 hours. The reaction mixture was filtered over a Celite pad and washed with a mixture of DCM:MeOH:DMA (9:1:1). The filtrate was concentrated under reduced pressure to yield the crude product, which was purified by flash chromatography (silica gel, DCM / MeOH / MeOH (NH3) (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-aminopropoxy)-1-(tetrahydropyran-2-yl)-1-hindazol-3-yl]-pyridin-3-yl}-methanol 10 as a cream solid. LCMS method B: [M+H]+= 383.3, ir = 0.316 min Preparation of the intermediate 11:19-(oxan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.126.018'21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one óoo i CDI (0.103 g, 0.633 mmol) was added to a solution of (5-(5-(3-aminopropoxy)-1-(tetrahydro-2Hpyran-2-yl)-1H-indazol-3-yl)pyridin-3-yl)methanol (0.220 g, 0.575 mmol) in 133 mL of DMA. The mixture was stirred at room temperature for 2 hours and at 90°C for 72 hours. The reaction was diluted with EtOAc, cooled to 0°C, and a saturated solution of NaHCO3 was added. The two layers were separated, and the water layer was extracted with EtOAc (x2). The combined organic layers were dried over MgSO4, 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 yield 19-(oxan2-11)-8,14-dioxa-4,10,19,20-tetraazatetrachloro[13,5,2,12,6,018,21]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, ir = 0.753 min Example Preparation 1: 8,14-dioxa-4,10,19,20-tetraazatetraciclo[13.5.2.12'6.018'21]tricosa1 (20),2,4, 6(23),15,17,21 -heptaen-9-one Una mezcla de 19-(oxan-2-il)-8,14-dioxa-4,10,19,20-tetraazatetraciclo[13.5.2.12'6.018'21]tricosa74 1(20),2,4,6(23),15,17,21-heptaen-9-one 11 (0.135 g, 0.331 mmol) in HCl in 1,4-dioxane [4N] (33 mL) was stirred at room temperature for 2 hours. The mixture was cooled to 0°C, diluted with DCM, and carefully inactivated with a saturated solution of NaHCO3. The two layers were separated, and the water layer was extracted with DCM (x2). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The product was purified by flash silica gel chromatography (DCM:MeOH, 100:0 to 94:6). The desired fractions were combined and the solvent was removed under reduced pressure yielding 8,14-dioxa4,10,19,20-tetraazatetracyclo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one example 1 as a white solid. LCMS method C: [M+H]+= 325.05, tR = 2.020 min LCMS method D: [M+H]+= 325.1, tR= 3.945 min Ή NMR (300 MHz, DMSO) δ 13.32 (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 = 1.1H), H (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. Example 2:10-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaene-9-one ινΐΛ / a / zuzz / ui ooo i Example 2 is prepared according to the synthesis route described in General Scheme A. Preparation of the intermediate 12:10-methyl-19-(oxan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.12S.018'21]tricose-1(20),2,4,6(23),15,1,21-heptaene-en To a solution of intermediate 11 (0.05 g, 0.12 mmol) in 5 mL of dry A / ,A / -dimethylformamide, under a nitrogen atmosphere at 0°C, 60% sodium hydride in mineral oil (0.007 g, 0.15 mmol) was added. 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 inactivated with water. The two layers were separated, and the water layer was extracted with EtOAc (x2). The combined organic layers were washed with brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure. The product was purified by flash silica gel chromatography (DCM:MeOH 100:0 to 97.5:2.5). The desired fractions were combined and the solvent removed under reduced pressure yielding 10-methyl-19-(oxan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.12·6.01821]trichose-1(20),2,4,6(23),15,17,21-heptaen-9-one 12 as a yellow oil. LCMS method B: [M+H]+= 423.1, tR= 0.897 min Preparation of Example 2:10-methyl-8,14-dioxa-4,10,19,20tetraazatetracyclo[13.5.2.12'6.018'21]trichose-1(20),2,4,6(23),15,17,21-heptaen-9-one ινΐΛ / a / zuzz / ui ooo i A mixture of 10-methyl-19-(oxan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13,5,2,12,6,018,21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one (0.042 g, 0.099 mmol) in HCl in 1,4-dioxane [4N] (5.0 mL) was stirred at room temperature for 2 h. The mixture was cooled to 0°C, diluted with DCM, and carefully inactivated with a saturated solution of NaHCO3. The two layers were separated, and the water layer was extracted with DCM (x2). The combined organic layers were dried over MgSCl, filtered, and the solvent removed under reduced pressure. The product was purified by flash silica gel chromatography (DCM:MeOH, 100:0 to 94:6). The desired fractions were combined and the solvent removed under reduced pressure to yield 10-methyl-8,14dioxa-4,10,19,20-tetraazatetracyclo[13,5,2,12,6,018,21]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, tR= 2.298 min LCMS method D: [M+H]+= 339.1, tR= 3.425 min1H NMR (300 MHz, 100°C, Ó6-DMSO) δ 13.00 (s, 1H), 9.03 (s, 1H), 8.55 (s, 8. 1H2), J = 9.0 Hz, 1H), 7.20 (s, 1H), 7.02 (dd, J = 9.0, 2.3 Hz, 1H), 5.40 (brs, J = 17.6 Hz, 2H), 4.32 (t, J = 8.4 Hz, 0.6 2H-3), 7.2 (s, 3H), 2.33–2.04 (m, 2H) ppm. Example 3: 4-fluoro-8,14-dioxa-10,19,20-triazatetracycle[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaene-9-one Example 3 is prepared according to the synthesis route described in general Scheme A. Preparation of the intermediate 13:2-f3-(3-vodo-1-tetrahydrooiran-2-yl-ndazol-5yl)oxypropyl]isoindoline-1,3-dione MA / a / ZUZZ / UI ÓOO I A suspension of 3-iodo-1-tetrahydropyran-2-yl-indazol-5-ol (4 g, 11.63 mmol), cesium carbonate (7.560 g, 23.26 mmol), and A / -(3-bromopropyl)phthalamide (4.679 g, 17.45 mmol) in ΔV,ΔV-dimethylformamide (48 mL) was heated at 60°C for 16 h. The reaction mixture was concentrated under reduced pressure. The resulting white solid was ground with ethyl acetate and recovered. The recovered filtrate was washed with water. The aqueous layer was extracted with ethyl acetate (3x). The combined organic layer was washed with water, then brine, dried over sodium sulfate, filtered, and evaporated under vacuum to give a cream solid. The two solids, white and cream, were combined to provide 2-[3-(3-iodo-1-tetrahydropyran-2-1-andazol-5-yl)oxypropyl]isondoline-1,3-dione 13 as a cream solid. LCMS method F: [M+H]+= 532, tR= 3.12 min Preparation of intermediate 14:3-(3-iodo-1-tetrahydropan-2-H-andazol-5-1)oxypropan-1-amine H2N A mixture of 2-[3-(3-iodo-1-tetrahydropyran-2-11-indazol-5-11)oxypropan-1,3-amine]isondolin-1,3-dione (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, washed with EtOH (3x), and the filtrate was evaporated under reduced pressure to give 3-(3-iodo-1-tetrahydropyran-2-11-indazol-5-11)oxypropan-1-amine as a pale brown oil. LCMS method F: [M+H]+= 402, tR= 1.65 min Preparation of intermediate 15: [3-5-(3-aminoDroDoxy)-1-tetrahydroDiran-2-yl-indazol-3-yl]-5-fluorophenyl]methanol ML / a / ZUZZ / U 1 ÓOO I Tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) was added to a degassed solution of 3-(3-iodo-1-tetrahydropyran-2-1-indazol-5-1)oxypropan-1-amine (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). The reaction mixture was irradiated under μwaves (Biotage initiator+), absorption level: high at 120°C for 1 h. The reaction mixture was filtered through a bed of Celite, after which the Celite was 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-ylindazol-3-yl]-5-fluorophenyl]methanol as a pale yellow oil. LCMS method F: [M+H]+= 400, tR = 1.76 min Preparation of the intermediate 16:4-fluoro-19-(oxan-2-yl)-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.1ze.018'21]tricosa-1(20),2(23),3,5,15(22), 16,18(21)-heptaen-9-one To a solution of [3-[5-(3-aminopropoxy)-1-tetrahydropyran-2-1-indazol-3-1]-5-fluorophenyl]methanol (199 mg, 0.499 mmol) in DMA (150 mL) was added 1,T-carbonylimidazole (89 mg, 0.549 mmol). The reaction mixture was stirred at room temperature for 2 hours, then heated to 90°C for 48 hours. The reaction was concentrated under vacuum, then ethyl acetate and a saturated aqueous solution of NaHCO3 were added. The mixture was extracted with ethyl acetate (2x). The combined organic layers were washed with water, then brine, dried over sodium sulfate, filtered, and the solvent removed under reduced pressure. The crude product was purified by column chromatography by eluting with cyclohexane / EtOAc / EtOH (3-1): 100 / 0 to 70 / 30 to provide 4-fluoro-19-(oxan-2-yl)-8,14-dioxa-10,19,20 triazatetracyclo[13.5.2.12 6.018'21]tricose-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, tR= 2.84 min Preparation of Example 3:4-fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20), 2,4,6(23),15,17,21-heptaen-9-one ML / a / ZUZZ / U 1 OOP I To a solution of 4-fluoro-19-(oxan-2-1l)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one 16 (92 mg, 0.217 mmol) in 1,4-dioxane (2.6 mL) 4M HCl in 1,4-dioxane (0.54 mL, 2.17 mmol) was added and the reaction was stirred at RT for 1h30. The reaction mixture was heated to 50°C for 60 hours. The solvent was removed under reduced pressure and the cream solid was recrystallized with acetonitrile to provide 4-fluoro-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one example 3 as a white solid. LCMS method F: [M+H]+= 342, tR= 2.16 min LCMS method G: [M+H]+= 342, tR= 2.24 min Ή NMR (400 MHz, Ó6-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. Example 4: 8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one Example 4 is prepared according to the synthesis route described in General Scheme B. Preparation of intermediate 17: tert-butyl-dimethyl-(1-tetrahydropyran-2-lindazol-5-yl)oxysilane MA / a / ZUZZ / UI ÓOO I To a solution of tert-butyl-(1H-indazol-5-yloxy)-dimethylsilane 1 (15.95 g, 64.28 mmol) in DCM (200 mL) and THF (100 mL), methanesulfonic acid (0.834 mL, 12.86 mmol) and DHP (17.59 mL, 192.84 mmol) were added 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 Biotage silica) (cyclohexane-ethyl acetate, 1:0 at 90 / 10). The desired fractions were combined and the solvent was removed under reduced pressure to provide tert-butyl-dimethyl-(1-tetrahydropyran-2-ylindazol-5-yl)oxysilane 17 as white crystals. LCMS method F: [M+H]+= 333.2, tR = 3.53 min 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-H)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole In a sealed tube, tert-butyl-dimethyl-(1-tetrahydropyran-2-ylindazol-5-yl)oxysilane 17 (3 g; 9.03 mmol), TBME (15 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-1)-1,3,2-dioxaborolane (2.3 g; 9.03 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (145 mg; 0.54 mmol), and (1,5cyclooctadiene)(methoxy)iridium(1) dimer (119 mg; 0.18 mmol) were added. The reaction was degassed with argon for 10 min, then allowed to react overnight at 80°C. The solvent was removed under reduced pressure, then the oil was dissolved with 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 provide 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 as a brown oil.The product was used in the next stage without further purification. LCMS method F: [M+H]+= 459, tR = 3.80 min LCMS method G: [M+H]+= 377.2, tR= 3.15 min Preparation of intermediate 19:2-(5-hydroxy-1-tetrahydropyran-2-1-andazol-3-yl)pyridine-4-carboxylate MA / a / ZUZZ / UI ÓOO I To a solution of [5-[tert-butyl(dimethyl)silyl]oxy-1-tetrahydropyran-2-1-indazol-3-1]boronic acid and 5-[(tert-butyldimethylsilyl)oxy]-1-(oxan-2-1)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-indazole 18 (1.5 g, 3.99 mmols) in A / ,A / -dimethylformamide (5 mL) RT 6-bromopyridine-2-carboxylate methyl (1.030 g, 4.78 mmols), cesium carbonate (3.8 g, 11.96 mmols) and PdCbdppf.DCM (163 mg, 0.2 mmols). 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 BIOTAGE silica) (cyclohexane-ethyl acetate, 100 / 0 to 50 / 50) yielding methyl 2-(5-hydroxy-1-tetrahydropyran-2-1-indazol-3-yl)pyridine-4-carboxylate 19 as a yellow powder. LCMS method F: [M+H]+= 354.1, tR= 2.59 min Preparation of intermediate 20: benzyl N-(3-bromopropyl)carbamate L xx ,o ~ r HN Br 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. This residue was purified by flash silica gel chromatography (Macherey Nagel, 80 g) with gradient elution: 0–20% cyclohexane / EtOAc to give benzyl N-(3-bromopropyl)carbamate as a clear oil. LCMS method F: [M+H]+= 274, tR= 2.41 min Preparation of intermediate 21:6-[5-(3-{[(benzyloxy)carbonylaminopropoxy)-1-(oxan-2-yl)-1-Hindazol-3-yl]pyridine-2-carboxylate methyl MA / a / ZUZZ / UI ÓOO I To a solution of methyl 6-[5-hydroxy-1-(oxan-2-yl)-1H-indazol-3-yl]pyridine-2-carboxylate (1 g, 2.82 mmol) in N-dimethylformamide (100 mL), cesium carbonate (1.83 g, 5.6 mmol) and benzyl N-(3-bromopropyl)carbamate (0.765 g, 2.82 mmol) were added. The reaction was stirred at 120°C for 16 hours. The mixture was concentrated under reduced pressure. Water (200 mL) was added, and the resulting mixture was extracted with EtOAc (4 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL). The organic layer was dried on sodium sulfate, filtered, and evaporated under reduced pressure to yield a brown / orange oil. This residue was purified by flash silica gel chromatography (Macherey Nagel, 120 g) with gradient elution: cyclohexane / EtOAc 0-70% to provide methyl 6-[5-(3-[(benzyloxy)carbonyl]aminopropoxy)-(oxan-2-yl)-1H-indazol-3-yl]pyridine-2-carboxylate 21 as a white solid. LCMS method F: [M+H]+= 545.2, tR= 3.21 min Preparation of intermediate 22: N43-(f346-(hydroxymethyl)pyridin-2-11-1-(oxan-2-yl)-1H-indazol-5-yl)oxy)propyl]benzylcarbamate To methyl 6-[5-(3-{[(benzyloxy)carbonyl]amino}propoxy)-1-(oxan-2-1I)-1H-indazol-3-yl]pyridine-2-carboxylate (1.2 g, 2.2 mmol) in THF (50 mL), a 1 M solution of lithium aluminum tetrahydride (4.4 mL, 4.2 mmol) was added at 0°C. The mixture was stirred at 0°C for 1 hour. To the reaction mixture, the following was added: EtOAc (10 mL) at 0°C was poured into a 10% solution of Rochelle salt (100 mL) and EtOAc (100 mL). The mixture was stirred at room temperature for 2 hours. After separation, the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to a brown / orange oil. This residue was purified by flash silica gel chromatography (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 as a yellow oil. LCMS method F: [M+H]+= 517.3, tR= 2.76 min Preparation of intermediate 23:19-(oxan-2-yl)-8,14-dioxa-10,19,20,23tetraazatetracyclo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one ΐνΐΛ / a / ZUZZ / UI ΟΡΟΊ A solution of benzyl N-[3-({3-[6-(hydroxymethyl)pyridine-2-yl]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamate (0.4 g; 0.775 mmol) in 100 mL of toluene was added for 30 min to a solution of sodium hydride (60% suspension in paraffin oil) (310 mg, 7.75 mmol) in 100 mL of toluene at room temperature. The reaction mixture was stirred at room temperature for 5 min and then for one hour at 130°C. The reaction was allowed to cool, and then 10 mL of EtOH were carefully added. 100 mL of water were then added. After separation, the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to provide an orange oil. Purification by column chromatography (DCM / MeOH 0-10%) yielded 19-(oxan-2-yl)-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.126.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one 23 pure as a whitish solid. LCMS method F: [M+H]+= 409.2, tR= 2.53 min. Preparation of Example 4: 8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2,4, 6(23),15,17,21 -heptaen-9-one To a solution of 19-(oxan-2-yl)-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13,5,2,126,018,21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one 23 (0.2 g; 0.489 mmol) in DCM (20 mL) trifluoroacetic acid (0.38 mL, 4.89 mmol) was added at room temperature. The mixture was stirred at 50°C for 24 hours. The reaction was allowed to cool. 50 mL of toluene were added to the solution and the reaction mixture was concentrated under reduced pressure to give an orange oil. 25 mL of water and 25 mL of DCM were added, along with 1.5 mL of a 25 wt% aqueous ammonia solution. After separation, the aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to yield an orange oil. Purification by column chromatography (DCM / MeOH 0-5%) yielded 8,14-dioxa-10,19,20,23-tetraazatetracyclo[13,5,2,12,6.018'21]tr¡cosa-1(20),2,4,6(23),15,17,21-heptaene-9-one example 4 pure as a bleaching solid. LCMS method F: [M+H]+= 325.2, tR= 1.93 min LCMS method G: [M+H]+= 325.2, tR= 1.94 min Ή NMR (400 MHz, Ó6-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 = 8.7 Hz), 7.5 J (1H, t, J = 8.7 Hz), 7.5 J, t 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, 3.9 Hz), 3.9 Hz (3.1 Hz). m), 1.97-2.03 (2H, m) ppm. Example 5: 8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.0182^tricose-1(20),2,4,6(23),15,17,21heptaene-9-one MA / a / ZUZZ / UI ÓOO I Example 5 is prepared according to the synthesis route described in General Scheme A. Preparation of Intermediate 24: í3-í5-(3-aminoDroDoxi)-1-tetrahydropyran-2-yl-indazol-3yl]phenyl]methanol Tetraquis(triphenylphosphine)palladium(0) (58 mg, 0.050 mmol) was added to a degassed solution of 3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropan-1-amine (400 mg, 0.998 mmol), 3-(Hydroxymethyl)phenylboronic acid (227 mg, 1.497 mmol), tripotassium phosphate (636 mg, 2.994 mmol), and xPhos (48 mg, 0.100 mmol) in dioxane (6.4 mL) and water (2.8 mL). The reaction mixture was heated under microwave conditions (Biotage initiator+) at 120°C for 1 h. The reaction mixture was filtered through a bed of Celite, after which 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 as a pale yellow oil. LCMS method F: [M+H]+= 382, ​​tR= 1.64 min Preparation of the intermediate 25:19-(oxan-2-yl)-8,14-dioxa-10,19,20triazatetracyclo[ 13.5.2.12'6.018'21]trichose-1(20),2,4,6(23), 15,17,21-heptaen-9-one ΐνΐΛ / a / ZUZZ / UI ΟΡΟΊ To a solution of [3-[5-(3-aminopropoxy)-1-tetrahydropyran-2-yl-indazol-3-yl]phenyl]methanol (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, then at 90°C for 64 h. The reaction was concentrated under vacuum, then ethyl acetate and a saturated aqueous solution of NaHCO3 were added. The mixture was extracted with ethyl acetate (2x). 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 by eluting with cyclohexane / ethyl acetate-EtOH (3-1): 100 / 0 to 70 / 30 to give a white solid. The solid was recrystallized with acetonitrile to give 19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one 25 as a white solid. LCMS method F: [M+H]+= 408, tR= 2.76 min Preparation of Example 5: 8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2,4,6(23), 15,17,21 -heptaen-9-one To a solution of 19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricosa1(20),2,4,6(23),15,17,21-heptaen-9-one 25 (81 mg, 0.199 mmols) in dioxane (2.4 mL) 4M HCl in dioxane (0.75 mL, 2.985 mmols) was added and the reaction was heated to 50°C for 24h. The reaction mixture was cooled to RT and the solid was filtered, then washed with diisopropyl ether (3 x) to provide 8,14-dioxa10,19,20-triazatetracyclo[13.5.2.12'6.018'21]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, tR= 2.02 min LCMS method G: [M+H]+= 324, tR= 2.10 min Ή NMR (400 MHz, Ó6-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. Example 6: 10-(propan-2-¡l)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one Example 6 is prepared according to the synthesis route described in General Scheme A. Example 6 is prepared using conditions analogous to, for example, 2. 2-Iodopropane is used for the carbamate alkylation step to yield 10-(propan-2-yl)-8,14-dioxa-4,10,19,20tetraazatetracyclo[13,5,2,12,6,018,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one example 6. LCMS method E: [M+H]+= 367.2, tR= 2.829 min LCMS method D: [M+H]+= 367.2, ír = 3.832 min1H NMR (300 MHz, 100°C, Ó6-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 = 7.3Hz, 2H), 2.19 (brs, 2H), 1.18 (s, 3H), 1.15 (s, 3H) ppm. Example 7: 8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one Example 7 is prepared according to the synthesis route described in General Scheme B. Example 7 is prepared using conditions analogous to, for example, 4. Methyl 4-bromopyridine-2-carboxylate is used for the Suzuki reaction to provide 8,14-dioxa-5,10,19,20tetraazatetrachloro[13,5,2,12,6,018,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one example 7. LCMS method F: [M+H]+= 325.1, tR= 1.58 min LCMS method G: [M+H]+= 325.2, tR= 1.83 min Ή NMR (400 MHz, Ó6-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), 7.4 d.4 (1 Hz), 7.0, H 9.4 (1 Hz). (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 m), 3.19-3.18 (2.1, 2H), m ppm. Example 8: 4-methoxy-8,14-dioxa-10,19,20-triazatetracycle[13.5.2.12'6.018,21]tricose1(20),2,4,6(23),15,17,21-heptaene-9-one MA / a / ZUZZ / UI ÓOO I Example 8 is prepared according to the synthesis route described in general Scheme C. Preparation of intermediate 26: N-[3-(3-iodo-1 -tetrahydrop¡ran-2-¡l-indazol-5yl)oxypropyl]benzyl carbamate A suspension of 3-iodo-1-tetrahydropyran-2-1-indazol-5-ol (17.012 g, 49.453 mmol), cesium carbonate (32.144 g, 98.906 mmol), and benzyl N-(3-bromopropyl)carbamate (10.6 mL, 54.398 mmol) in A / ,A / -dimethylformamide (250 mL) was heated at 60°C for 20 h. The reaction mixture was filtered and washed with acetonitrile. The filtrate crystallized and was filtered to give a white solid, which was washed with water (3x). The filtrate was recovered and evaporated under reduced pressure to give a pink solid. It was solubilized with DCM, and water was added. The mixture was extracted with DCM (2x), then the combined organic layers were dried on anhydrous sodium sulfate and concentrated under reduced pressure to give a pale 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, ir = 3.11 min Preparation of intermediate 27: N-[3-[3-[3-(hydroxymethyl)-5-methoxyphenyl]-1-tetrahydropyran-2-ylindazol-5-yl]oxypropyl]carbamate benzyl Tetraquis(triphenylphosphine)palladium(0) (65 mg, 0.056 mmols) was added to a degassed solution of N-[3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl] benzyl carbamate 26 (600 mg, 1.12 mmols), [3-Methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (444 mg, 1.68 mmols), tripotassium phosphate (713 mg, 3.36 mmols) and xPhos (53 mg, 0.112 mmols) in 1,4-dioxane (7 mL) and water (4.8 mL). The reaction mixture was irradiated under μ-waves (Biotage Initiator+), high absorption level, at 120°C for 1 h. 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.The crude was purified by column chromatography by eluting with DCM / Ethyl Acetate, 100 / 0 to 70 / 30 to provide benzyl N-[3-[3-[3(hydroxymethyl)-5-methoxyphenyl]-1-tetrahydrophenylram-2-1-andazol-5-1]oxypropyl]carbamate 27 as a colorless oil. LCMS method F: [M+H]+= 546, ir = 2.89 min Preparation of intermediate 28:4-methoxy-19-(oxan-2-yl)-8,14-dioxa-10,19,20triazatetracyclo[ 13.5.2.12B.01821]tricose-1(20),2,4,6(23), 15,17,21-heptaen-9-one > your 88N c A suspension of potassium carbonate (80 mg, 0.582 mmol) in acetonitrile (12 mL) was added dropwise to a solution of N-[3-[3-[3-(hydroxymethyl)-5-methoxyphenyl]-1-tetrahydropyran-2-yl-andazol-5-S C* [1]oxypropyl]benzyl carbamate 27 (53 mg, 0.097 mmol) in acetonitrile (7 mL) at RT. The reaction mixture was heated under microwave conditions at 140°C for 6 h. The reaction mixture was filtered and purified directly by column chromatography by eluting with DCM / Ethyl Acetate, 100 / 0 to 80 / 20 to 4-methoxy-19(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetrachloro[13,5,2,12,6,018,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 28 as a colorless oil. LCMS method F: [M+H]+= 438, tR= 2.76 min Preparation of Example 8: 4-methoxy-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12>6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one To a solution of 4-methoxy-19-(oxan-2-yl)-8,14-dioxa-10,19,20triazatetracyclo[13,5,2,12,6,018,21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one 28 (23 mg, 0.053 mmol) in DCM (4 mL) trifluoroacetic acid (80 pL, 1.06 mmol) was added at RT. The reaction mixture was irradiated under μ-waves (Biotage initiator+), absorption level: high at 80°C for 1h30. The crude reaction mixture was purified by flash column chromatography by eluting with DCM / Ethyl Acetate: 100 / 0 to 80 / 20, to provide 4-methoxy-8,14-dioxa-10,19,20triazatetracyclo[13,5,2,12,6,018,21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one example 8 as a white solid. LCMS method F: [M+H]+= 354, tR= 2.07 min LCMS method G: [M+H]+= 354, tR= 2.09 min Ή NMR (400 MHz, Ó6-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. Example 9: 4-bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one Example 9 can be prepared according to the synthesis route described in the General Scheme A, C and D. Preparation of the intermediate 29:1-tetrahydropyran-2-ylindazol-5-ol HO To a solution of tert-butyl-dimethyl-(1-tetrahydropyran-2-ylindazol-5-yl)oxysilane (12.58 g, 37.8 mmol) in tetrahydrofuran (100 mL), 1.0 M tetra-n-butylammonium fluoride in THF (47.58 mL, 47.58 mmol) was added in parts 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 x 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 as eluent from 90 / 10 to 80 / 20 yielded 1-tetrahydropyran-2-ylindazol-5-ol 29 as a colorless oil. LCMS method F: [M+H]+= 219, tR= 1.81 min Preparation of intermediate 30: Benzene N-[3-(1-tetrahydropyran-2-ylindazol-5-yl)oxypropyl]carbamate To a solution of 1-tetrahydropyran-2-ylindazol-5-ol (7.06 g, 32.3 mmol) in N,N-dimethylformamide (110 mL), cesium carbonate (21.0 g, 64.6 mmol) and benzyl N-(3-bromopropyl)carbamate (10.14 g, 37.3 mmol) were added 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 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness. Purification on a silica column (RS SiOH 200 g) using 80 / 20 to 60 / 40 cyclohexane / ethyl acetate as eluent yielded N-[3-(1-tetrahydropyran-2-ylindazol-5-yl)oxypropyl]benzyl carbamate 30 as a beige solid. LCMS method F: [M+H]+= 410.2, ír = 2.77 min (current 20V) Preparation of intermediate 31: N-[3-[1-tetrahydroDÍran-2-yl-3-(4.4.5.5-tetramethyl-1.3.2dioxaborolan-2-yl)indazol-5-yl]oxypropyl]benzyl carbamate ΜΛ / a / ZUZZ / U 1 ÓOO I To a solution of benzyl N-[3-(1-tetrahydropyran-2-líndazol-5-¡l)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-1,3,2dioxaborolan-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 it for 15 min, and (1,5-cyclooctadiene)(methoxy)iridium(l) dimer (370 mg, 0.56 mmol) was added. The reaction mixture was stirred at 80°C overnight under a nitrogen atmosphere. The solvent was removed under reduced pressure, and the oil was then dissolved with 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 yield benzyl N-[3-[1-tetrahydropyran-2-l-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-l)indazol-5-l]oxypropyl]carbamate as a brown oil.The product was used in the next stage without further purification. LCMS method F: [M+H]+= 536.2, tR= 3.18 min (current 20V) Preparation of intermediate 32: (3-bromo-5-vodo-phenyl)methanol MA / a / ZUZZ / UI ÓOO I To a solution of 3-bromo-5-iodobenzoic acid (10.0 g, 30.6 mmol) in THF (450 mL), solid sodium borohydride (3.47 g, 91.8 mmol) was slowly added at 0°C. After the end of gas release (i.e., 5 min), boron trifluoride diethyl etherate (11.3 mL, 91.8 mmol) was added dropwise at 0°C. The reaction mixture was heated to RT and stirred at RT overnight. The reaction mixture was cooled to 0°C, and 100 mL of 1 M aqueous sodium hydroxide solution was slowly added. The reaction mixture was filtered over 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 with anhydrous sodium sulfate, filtered and dried under reduced pressure to yield clean (3-bromo-5-iodo-phenyl)methanol 32 as a beige solid. LCMS method F: [M+H]+= not detected, ir = 2.54 min (current 20V) Preparation of intermediate 33: N-[3-f3-f3-bromo-5-(hydroxymethyl)phenyl-1-tetrahydropyran-2-lindazol-5-yl]oxypropyl]carbamate benzyl A solution of benzyl N-[3-[1-tetrahydropyran-2-1-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-1)indazol-5-yl]oxypropyl]carbamate 32 (1.870 g, 3.50 mmol) in A / ,A / -dimethylformamide (15 mL) was added to RT (3-bromo-5-iodophenyl)methanol 31 (1.314 g, 4.20 mmol) and CS2CO3 (3.421 g, 10.50 mmol). The reaction mixture was degassed by bubbling nitrogen for 15 min and PdCldppf (0.128 g, 0.18 mmol) was added. The resulting mixture was stirred at 110°C under microwave irradiation for 50 min. The reaction mixture was filtered over 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) yielded benzyl N-[3-[3-[3-bromo-5-(hydroxymethyl)phenyl]-1-tetrahydropyran-2-yl-indazol-5-1]oxypropyl]carbamate 33 as an orange oil. LCMS method F: [M+H]+= 596.1, ír = 3.07 min (current 20V) Preparation of intermediate 34:4-bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20triazatetracyclo[ 13.5.2.12S.018>21]tricose-1(20),2,4,6(23), 15,17,21-heptaen-9-one MA / a / ZUZZ / UI ÓOO I To a solution of benzyl N-[3-[3-[3-bromo-5-(hydroxymethyl)phenyl]-1-tetrahydropyran-2-1-indazol-5-1]oxypropyl]carbamate 33 (288 mg, 0.48 mmol) in dry toluene (300 mL), 60% sodium hydride in oil (480 mg, 12 mmol) was added at room temperature. The reaction mixture was stirred at 130°C for 1 h. The reaction was then stirred at room temperature overnight, and 60% sodium hydride in oil (192 mg, 4.8 mmol) was added. The reaction mixture was stirred at 130°C for 3 h. More 60% sodium hydride in oil (192 mg, 4.8 mmol) was added, and the reaction mixture was stirred at 140°C overnight. More 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 h until the reaction was complete. The reaction mixture was left at 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 (200 mL) was added. After separation, the aqueous layer was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered, and dried under reduced pressure to yield an orange oil. Purification on a silica column (RS SiOH 80 g) using cyclohexane / ethyl acetate from 100 / 0 to 0 / 100 and DCM / MeOH 90 / 10 as eluent yielded 60 mg of the intended product. The impure fractions were combined and the solvent removed under reduced pressure. The residue was purified on a silica column (RS SiOH 40 g) using cyclohexane / ethyl acetate from 100 / 0 to 50 / 50 as eluent, yielding 4bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12<3.01821]tricose-1(20),2,4,6(23),15,17,21heptaen-9-one 34 as a white solid. LCMS method F: [M+H]+= 487.7, tR = 3.05 min Preparation of Example 9:4-bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1 (20), 2,4,6(23),15,17,21 -heptaen-9-one solution ινΐΛ / a / zuzz / ui ooo i 4-bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20triazatetracyclo[13,5,2,12,6,018,21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one (30 mg, 0.062 mmol) in DCM (3 mL) was mixed with trifluoroacetic acid (95 pL, 1.24 mmol). The reaction mixture was stirred at 80°C under microwave irradiation for 2 h. The reaction mixture was diluted with DCM (20 mL). Water (50 mL) and a 25 wt% aqueous ammonium hydroxide solution (3 mL) were added. After separation, the aqueous layer was extracted with DCM (x3 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 dried under reduced pressure to yield 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 the eluent.The resulting product was purified a second time in preparative TLC using cyclohexane / ethyl acetate; 50 / 50 as eluent to provide 4-bromo-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.126.018'21]tricose-1 (20),2,4,6(23),15,17, 21-heptaen-9-one example 9 as a beige solid. LCMS method F: [M+H]+= 403, tR= 2.40 min LCMS method G: [M+H]+= 403, tR= 2.38 min Ή 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. Example 10: 5-fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricosa1(20),2,4,6(23),15,17,21-heptaen-9-one Example 10 is prepared according to the synthesis route described in General Scheme E. Preparation of intermediate 35: 2-fluoro-5-[5-hydroxy-1-(oxan-2-yl)-1H-indazol-3-yl]benzoic acid MA / a / zuzz / ui oo i To a solution of 3-iodo-1-(oxan-2-yl)-1H-indazol-5-ol (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) tripotassium phosphate (1.84 g, 8.7 mmol) was added. The mixture was degassed by bubbling nitrogen through it 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 for 2 hours under microwave irradiation (BIOTAGE). The reaction mixture was filtered over 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 with sodium sulfate, and the solvent was removed under reduced pressure to yield a brown oil.Purification on a silica column in Biotage using cyclohexane / ethyl acetate from 100 / 0 to 20 / 80 as eluent yielded 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, tR= 2.34 min Preparation of intermediate 36:3-[4-fluoro-3-(hydroxymethyl)phenyl-1-(oxan-2-yl)-1H-indazol-5-ol] To a solution of 2-fluoro-5-[5-hydroxy-1-(oxan-2-yl)-1H-andazol-3-yl]benzoic acid (0.2 g, 0.56 mmol) in THF (25 mL), solid sodium borohydride (0.062 g, 1.68 mmol) was added at room temperature. After the end of gas release (i.e., 5 min), the reaction mixture was cooled to 0°C, and solvent-free boron trifluoride diethyl etherate (0.163 mL, 1.68 mmol) was added dropwise for 1 h. The reaction mixture was then heated 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 over Celite and eluted with ethyl acetate. The solution was washed with water (50 mL) and brine (50 mL). The organic layer was dried with sodium sulfate, and the solvent was removed under reduced pressure to yield a brown oil.Purification (Biotage) on a silica column using cyclohexane / ethyl acetate from 100 / 00 to 50 / 50 as eluent yielded 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, tR= 2.27 min Preparation of Intermediate 37: Benzyl N-[3-((3-f4-fluoro-3-(hydroxymethyl)phenyl-1-(oxan-2-yl)-1H-ndazol-5yl}oxy)propyl]carbamate WlAia / ZVZZIVl óoo i To a solution of 3-[4-fluoro-3-(hydroxymethyl)phenyl]-1-(oxan-2-yl)-1H-andazol-5-ol (0.18 g, 0.52 mmol) in A / ,A / -dimethylformamide (10 mL), cesium carbonate (0.338 g, 1.04 mmol) and tert-butyl 3-[(methanesulfonyloxy)methyl]pyrrolidine-1-carboxylate (0.169 g, 0.624 mmol) were added. The reaction was stirred at 80°C for 16 hours. The mixture was concentrated under reduced pressure. Water (50 mL) was added, and the resulting mixture was extracted with EtOAc (4 x 100 mL). The combined organic layers were washed with saturated brine (2 x 50 mL). The organic layer was dried on sodium sulfate and the solvent was removed under reduced pressure to yield a brown / orange oil. The residue was purified by flash silica gel chromatography (Macherey Nagel, 12 g) with gradient elution: cyclohexane / EtOAc 0-70% to provide benzyl N-[3-({3[4-fluoro-3-(hydroxymethyl)phenyl]-1-(oxan-2-yl)-1H-andazol-5-yl}ox)propyl]carbamate 37 as a white solid. LCMS method F: [M+H]+= 534.2, tR= 2.90 min Preparation of the intermediate 38:5-fluoro-19-(oxan-2-yl)-8,14-dioxa-10,19,20triazatetraciclo[13.5.2.126.01821]tricosa-1(20),2,4,6(23), 15,17,21-heptaen-9-one A solution of benzyl N-[3-({3-[4-fluoro-3-(hydroxymethyl)phenyl]-1-(oxan-2-yl)-1H-andazol-5-yl}oxy)propyl]carbamate 37 (0.153 g; 0.28 mmol) in 50 mL of toluene was added to a solution of sodium hydride (60% suspension in paraffin oil) (114 mg, 24 mmol) in 50 mL of toluene at room temperature. The reaction mixture was stirred at room temperature for 5 min and then for one hour at 130°C. The reaction was allowed to cool, and then 10 mL of EtOH were carefully added. 100 mL of water were then added. After separation, the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to provide an orange oil. Purification by column chromatography (DCM / MeOH 0-10%) yielded 5-fluoro-19-(oxan-2-yl)-8,14-dioxa-10,19,20triazatetrachloro[13.5.2.12'6.018'21]tr¡cosa-1(20),2,4,6(23),15,17,21-heptaen-9-one pure 38 as a whitish solid. LCMS method F: [M+H]+= 426.2, tR= 2.78 min Preparation of Example 10: 5-fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1 (20), 2,4,6(23),15,17,21 -heptaen-9-one IVIA / a / ZUZZ / UI OOP I To a solution of 5-fluoro-19-(oxan-2-1l)-8,14-dioxa-10,19,20-triazatetrachloro[13,5,2,12,6,018,21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one 38 (35 mg, 0.082 mmol) in DCM (5 mL) trifluoroacetic acid (63 pL, 0.82 mmol) was added. The reaction mixture was stirred at room temperature for 6 h at 30°C overnight. More trifluoroacetic acid (32 pL, 0.41 mmol) was added and the reaction mixture was stirred at 50°C for 5 h. Again, more trifluoroacetic acid (32 pL, 0.41 mmol) was added, and the reaction mixture was stirred at 50°C for another 2 h. The reaction mixture was evaporated to dryness and co-evaporated with toluene. DCM (40 mL), water (125 mL), and a 25 wt% aqueous ammonium hydroxide solution (3 mL) were added. After separation, the aqueous layer was extracted with DCM (3 x 20 mL).The combined organic layers were washed with a saturated solution of sodium carbonate (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to yield a beige solid. Grinding the residue once in acetonitrile, five times in DCM and twice in EtOH yielded 5-fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12 6.018-21]tricose-1 (20),2,4,6(23),15,17,21 heptaen-9-one example 10 as a white powder. LCMS method F: [M+H]+= 342.1, tR= 2.18 min LCMS method G: [M+H]+= 342.1, tR= 2.36 min Ή NMR (400 MHz, Ó6-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. Example 11: 5-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricosa1(20),2,4,6(23),15,17,21-heptaen-9-one MA / a / ZUZZ / UI ÓOO I Example 11 is prepared according to the synthesis route described in General Scheme F. Preparation of the intermediate 39:5-f5-f3-(benzyloxycarbonylamino)propoxyl-1-tetrahydropyran-2-Hindazol-3-yl]-2-methylbenzoate A solution of benzyl N-[3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]carbamate (1.2 g, 2.2 mmol postulated), (3-methoxycarbonyl-4-methylphenyl)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 / H₂O (6.5 / 3.2 mL) was degassed for 15 minutes. Pd(dppf)Cl₂·DCM (179 mg, 0.22 mmol) was added, and the reaction mixture was stirred under a nitrogen atmosphere at 100°C for 17 hours. The reaction mixture was filtered over Celite and washed with EtOAc. The filtrate was diluted with water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (Macherey Nagel, 40 g) using cyclohexane / EtOAc eluent (100 / 0 to 80 / 20).The desired fractions were collected and the solvent was removed under reduced pressure to provide 5-[5-[3(benzyloxycarbonylamino)propoxy]-1-tetrahydrodropran-2-1l-indazol-3-1l]-2-methyl-methylbenzoate 39 (1.04 g, 1.87 mmol) as a white solid. LCMS method F: [M+H]+= 558, ir = 3.33 min Preparation of intermediate 40: N-f3-f3-f3-(hydroxymethyl)-4-methylphenyl]-1-tetrahydroDiran-2-ylindazol-5-yl]oxypropyl]benzylcarbamate MA / a / ZUZZ / UI ÓOO I To a solution of methyl 5-[5-[3-(benzyloxycarbonylamino)propoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-methylbenzoate (1 g, 1.8 mmol) in THF (6 mL) under N2, 1 M LAH in THF (2.2 mL, 2.2 mmol) was added at 0°C. The reaction was stirred at 0°C for 2 hours and 30 minutes. The mixture was inactivated with water (1 mL), 10% NaOH (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 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude was purified by silica pad with cyclohexane / EtOAc (60 / 40) as eluent to yield benzyl N-[3-[3[3-(hydroxymethyl)-4-methylphenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate 40 as a white oil. LCMS method F: [M+H]+= 530, tR = 2.90 min Preparation of intermediate 41:5-metll-19-(oxan-2-ll)-8,14-dloxa-10,19,20triazatetracyclo[ 13.5.2.12e.018'21]tricose-1(20),2,4,6(23), 15,17,21-heptaen-9-one To a solution of benzyl N-[3-[3-[3-(hydroxymethyl)-4-methylphenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate 40 (120 mg, 0.23 mmol) in acetonitrile (40 mL), potassium carbonate (190 mg, 1.38 mmol) was added. The mixture was divided into two vials, then microwaved at 140°C for 4 hours and 30 minutes. The two vials were then microwaved again at 140°C for 4 hours. The mixture was filtered to remove potassium carbonate and the solvent was evaporated under reduced pressure to yield 5-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.126.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one 41 as a white powder. The crude was used in the next stage without further purification. LCMS method F: [M+H]+= 422, tR= 2.87 min Preparation of Example 11: 5-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one MA / a / ZUZZ / UI ÓOO I To a solution of 5-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-thiazatetracyclo[13,5,2,12,6,0,18,21]thcosa(20),24,6(23),15,17,21-heptaen-9-one 41 (84 mg, 0.2 mmol) in DCM (15 mL) trifluoroacetic acid (306 µL, 4 mmol) was added. The mixture was microwaved at 80°C for 1 hour. The solvent was removed under reduced pressure to yield 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), then saturated NaHCO3 (15 mL) was added. After separation, the aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure to provide 5-methyl-8,14-dioxa-10,19,20triazatetrachloro[13,5,2,12,6,018,21]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, tR= 2.32 min LCMS method G: [M+H]+= 338, tR= 2.35 min Ή NMR (400 MHz, Ó6-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 ppm. Example 12: 4-(pyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one Example 12 is prepared according to the synthesis route described in the General Scheme C. Pyrrolidine is used for the Buchwald reaction with the bromide intermediate 34. 100 Preparation of intermediate 42:19-(oxan-2-yl)-4-(pyrrolidin-1-yl)-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.126.01821]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one To a degassed solution of 4-bromo-10-methyl-19-(oxan-2-yl)-7-oxa-10,13,19,20tetraazatetracyclo[13.5.2.12,6,018,21]tricose-1 (20),2,4,6(23), 15(22), 16,18(21 )-heptaen-14-one Example 9 (100 mg, 0.206 mmol), pyrrolidine (19 pl, 0.227 mmol), tBuONa (40 mg, 0.412 mmol) and SPhos (3 mg, 0.008 mmol) in dioxane (2.5 mL) Pdzdbaa (4 mg, 0.004 mmol) was added at RT. The reaction mixture was stirred under microwave irradiation for 45 min at 60°C. More pyrrolidine (2 pl; 0.021 mmol) was added, and the reaction was stirred under microwave irradiation for 20 min at 60°C. After cooling to room temperature, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was purified by flash column chromatography (5 g of SiO2) (cyclohexane / ethyl acetate, 1:0 to 50 / 50) yielding 19-(oxan-2-yl)-4-(pyrrolidine-1-yl)-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one 42 as a white powder. LCMS method F: [M+H]+= 477.2, ir = 3.00 min Preparation of Example 12: 4-(pyrrolidin-1 -i 1)-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]tricose-1 (20),2,4,6(23),15,17,21 -heptaen-9-one To a mixture of 19-(oxan-2-yl)-4-(pyrrolidine-1-yl)-8,14-dioxa-10,19,20triazatetrachloro[13,5,2,12,6,018,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 42 (60 mg; 0.126 mmol) in DCM (2.5 mL) TFA (48 μL; 0.630 mmol) was added. The reaction mixture was stirred under microwave irradiation at 80°C for 30 min. The solvent was removed under reduced pressure, the mixture was dissolved in EtOAc and washed with 1N NaOH (pH=7), then with water. The organic layer was concentrated under reduced pressure and the product was purified by chromatography using a 4 g SiO2 column eluted with DCM / MeOH 100 / 0 to 90 / 10. The desired fractions were combined to provide 4-(pyrrolidine-1-1)-8,14-dioxa-10,19,20-triazatetracyclo[13,5,2,12,6,018,21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one (Example 12) 101 like a yellow powder. LCMS method F: [M+H]+= 393.1, ír = 2.39 min (current 20V) LCMS method G: [M+H]+= 393.1, tR = 2.47 min (pH10 current 20V) Ή NMR (400 MHz, OH6-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. Example 13: 4-[4-(propan-2-yl)plperazin-1-yl]-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018 21]trichose-1 (20),2,4,6(23),15,17,21-heptaen-9-one MA / a / ZUZZ / UI OOP I Example 13 is prepared according to the synthesis route described in General Scheme C and procedures analogous to those used to obtain Example 12. 1-(Propan-2-yl)piperazine is used for the Buchwald reaction with the bromide intermediate 34 to provide 4-[4-(propan-2-yl)piperazin-1-yl]-8,14dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]trichose-1 (20),2,4,6(23), 15,17,21-heptaen-9-one example 13 . LCMS method F: [M+H]+= 450.2, tR= 1.54 min LCMS method G: [M+H]+= 450.2, ir = 2.26 min Ή NMR (400 MHz, Ó6-DMSO, 80°C) 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. Example 14: 4-{2-oxa-6-azaspiro[3.4]octan-6-yl}-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.126.018'21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 14 is prepared according to the synthesis route described in General Scheme C and procedures analogous to those used to obtain Example 12. 2-oxa-6-azaspiro[3.4]octane is used for the Buchwald reaction with bromide intermediate 34 to provide 4-{2-oxa-6-azaspiro[3.4]octan-6-yl}8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.126.01821]tricose-1 (20),2,4,6(23), 15,17,21 -heptaen-9-one Example 14. LCMS método F: [M+H]+= 435, tR= 2.16 min 102 LCMS método G: [M+H]+= 435, tR= 2.20 min Ή RMN (400 MHz, Ó6-DMSO, 80°C) 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. Ejemplo 15: 4-[4-(oxetan-3-il)piperazin-1 -il]-8,14-dioxa-10,19,20tr¡azatetraciclo[13.5.2.12’6.018’21]tricosa-1 (20),2,4,6(23),15,17,21 -heptaen-9-ona iviA / a / zuzz / ui ooo i Example 15 is prepared according to the synthesis route described in General Scheme C and procedures analogous to those used to obtain Example 12. 1-(oxetan-3-yl)piperazine is used for the Buchwald reaction with bromide intermediate 34 to provide 4-[4-(oxetan-3-yl)piperazin-1-yl]-8,14dioxa-10,19,20-trazatetracyclo[13,5,2,12,6,018,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 15. LCMS method F: [M+H]+= 464.2, tR= 1.47 min LCMS method G: [M+H]+= 464.2, tR= 2.00 min Ή NMR (400 MHz, Ó6-DMSO, 80°C) δ 12.81 (1H, s), 7.64 (1H, s), 7.48-7.45 (1H, d, J = 9.0 Hz), 7.397.34 (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), 2.101.99 (2H, m) ppm. 4 protons were located below the DMSO peak and are not reported here. Example 16: 4-(morpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one Example 16 is prepared according to the synthesis route described in General Scheme C and procedures analogous to those used to obtain Example 12. Morpholine is used for the Buchwald reaction with bromide intermediate 34 to provide 4-(morpholin-4-yl)-8,14-dioxa-10,19,20triazatetracyclo[13,5,2,12,6,018,21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 16. LCMS method F: [M+H]+= 409.2, tR= 2.13 min LCMS method G: [M+H]+= 409.2, tR= 2.15 min Ή NMR (400 MHz, c / 6-DMSO, 80°C)or 12.82 (1H, s), 7.63 (1H, m), 7.48-7.45 (1H, d, J = 9.0 Hz), 7.40 103 (2Η, 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), 3.823.76 (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. Example 17: 4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 17 is prepared according to the synthesis route described in General Scheme C and procedures analogous to those used to obtain Example 12. cis-2,6-dimethylmorpholine is used for the Buchwald reaction with bromide intermediate 34 to provide 4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8,14dioxa-10,19,20-trazatetracyclo[13.5.2.126.018'21]tricosa-1(20), 2,4,6(23), 15,17,21-heptaen-9-one Example 17. LCMS method F: [M+H]+= 437.1, tR= 2.30 min LCMS method G: [M+H]+= 437.2, tR= 2.36 min Ή NMR (400 MHz, c / 6-DMSO, 80°C) 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. Example 18: 4-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018Z1]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one Example 18 is prepared according to the synthetic route described in General Scheme F and procedures analogous to those used to obtain Example 11. (3-Methoxycarbonyl-5-methylphenyl)boronic acid is used for the Suzuki coupling with intermediate 26 to provide 4-methyl-8,14-dioxa-10,19,20triazatetracyclo[13,5,2,12,6,018,21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 18. LCMS method F: [M+H]+= 338, tR= 2.25 min LCMS method G: [M+H]+= 338, tR= 2.30 min Ή NMR (400 MHz, Ó6-DMSO) δ 7.73-7.65 (3H, m), 7.49-7.45 (1H, m), 7.34 (1H, d, J = 2.1 Hz), 7.107.07 (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 NH proton of indazole was not visible in this solvent. 104 Example 19: 5-methoxy-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one IVIA / a / ZUZZ / U1 ÓOO I Example 19 is prepared according to the synthetic route described in the general scheme F and procedures analogous to those used to obtain Example 11. (4-methoxy-3-methoxycarbonylphenyl)boronic acid is used for the Suzuki coupling with intermediate 26 to provide 5-methoxy-8,14-dioxa-10,19,20triazatetracyclo[13,5,2,12,018,21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 19. LCMS method F: [M+H]+= 354, tR= 2.19 min LCMS method G: [M+H]+= 354, tR= 2.17 min Ή NMR (400 MHz, c / 6-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. Example 20: 4-(4,4-difluoropiperidin-1-yl)-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 20 is prepared according to the synthesis route described in General Scheme C and procedures analogous to those used to obtain Example 12. 4,4-Difluoropiperidine is used for the Buchwald reaction with bromide intermediate 34 to provide 4-(4,4-difluoropiperidine-1-1)-8,14-dioxa-10,19,20-triazatetracyclo[13,5,2,12,6,018,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 20. LCMS method F: [M+H]+= 443.1, tR= 2.46 min LCMS method G: [M+H]+= 443.1, tR= 2.49 min Ή NMR (400 MHz, Ó6-DMSO, 80°C) 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. 105 Example 21: 4-(3,3-difluoropyrrolidin-1-yl)-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one H MA / a / ZUZZ / UI ÓOO I Example 21 is prepared according to the synthesis route described in General Scheme C and procedures analogous to those used to obtain Example 12. 3,3-Difluoropyrrolidine is used for the Buchwald reaction with bromide intermediate 34 to provide 4-(3,3-difluoropyrrolidine-1-yl)-8,14-dioxa10,19,20-triazatetrachloro[13,5,2,12,6,018,21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 21. LCMS method F: [M+H]+= 429.1, tR= 2.46 min LCMS method G: [M+H]+= 429.1, tR= 2.48 min Ή NMR (400 MHz, d6-DMSO, 80°C) 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. Example 22: 7-methyl-8,14-dioxa-10,19,20-triazatetrachloro[13,5,2,12,6,018,21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one Example 22 is prepared according to the synthesis route described in General Scheme C and procedures analogous to those used to obtain Example 8. (3-(1-hydroxyethyl)phenyl)boronic acid is used for the Suzuki coupling to provide 7-methyl-8,14-dioxa-10,19,20tnazatetracyclo[13,5,2,12,6,018,21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 22. LCMS method F: [M+H]+= 338, tR= 2.22 min LCMS method G: [M+H]+= 338, tR= 2.25 min Ή NMR (400 MHz, c / 6-DMSO) δ 13.12 (1H, s), 7.95-7.92 (1H, m), 7.86I-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. 106 Example 23: 4-[4-(2-methoxy¡ethyl)piperidin-1-yl]-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 23 is prepared according to the synthesis route described in General Scheme C and procedures analogous to those used to obtain Example 12. 4-(2-methoxyethyl)piperidin-1-11 is used for the Buchwald reaction with bromide intermediate 34 to provide 4-[4-(2-methoxyethyl)piperidin-1-11]-8,14dioxa-10,19,20-triazatetracyclo[13,5,2,12,6,018,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 23. LCMS method F: [M+H]+= 465.2, tR= 1.81 min LCMS método G: [M+H]+= 465.2, tR= 2.53 min Ή RMN (400 MHz, Ó6-DMSO, 80°C) 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), 5.225.19 (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. Ejemplo 24: 9,14-dioxa-11,19,20-triazatetraciclo[13.5.2.12’6.018’21]tricosa-1(20),2,4,6(23),15,17,21heptaen-10-ona Example 24 is prepared according to the synthesis route described in General Scheme C and procedures analogous 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 for Suzuki coupling to provide 9,14-dioxa-11,19,20triazatetracyclo[13.5.2.12 6.018'21]tricose-1 (20),2,4,6(23),15, 17,21-heptaen-10-one Example 24. LCMS method F: [M+H]+= 324.1, tR= 2.14 min LCMS method G: [M+H]+= 324.1, tR= 2.19 min Ή 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), 107 4.33-4.21 (4Η, m), 3.40-3.3 (2H, m), 3.01 (2H, t, J = 5.0 Hz) ppm. Example 25: 4-[(3R)-3-hydroxypyrrolidine-1-yl]-8,14-dioxa-10,19,20triazatetracyclo[13,5,2,12,6,018,21]tricose-1 (20),2,4,6(23),15,17,21 -heptaen-9-one ML / a / ZUZZ / U 1 ÓOO I Example 25 is prepared according to the synthesis route described in General Scheme C and procedures analogous to those used to obtain Example 12. (3R)-pyrrolidine-3-ol is used for the Buchwald reaction with bromide intermediate 34 to provide 4-[(3R)-3-hydroxypyrrolidine-1-yl]-8,14-dioxa10,19,20-triazatetracyclo[13,5,2,12,6,018,21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 25. LCMS method F: [M+H]+= 409.1, tR= 1.96 min LCMS method G: [M+H]+= 409.2, tR= 2.04 min Ή NMR (400 MHz, Ó6-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 NH₄⁺ proton of indazole was not visible in this solvent. Example 26: 4-[(2-methoxyethyl)(methyl)amino]-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]tricose-1 (20),2,4,6(23),15,17,21 -heptaen-9-one Example 26 is prepared according to the synthesis route described in General Scheme C and procedures analogous to those used to obtain Example 12. 2-Methoxy-N-methyl-ethanamine is used for the Buchwald reaction with bromide intermediate 34 to provide 4-[(2-Methoxyethyl)(methyl)amino]-8,14dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 26. LCMS method F: [M+H]+= 411.2, tR= 2.07 min LCMS method G: [M+H]+= 411.2, tR= 2.32 min Ή NMR (400 MHz, Ó6-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 Ηζ), 3.31-3.31 (3Η, m), 3.11-3.04 (8Η, s), 3.01 (3H, s), 2.01-2.02 (2H, m) ppm. Example 27: 4-chloro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018,21]trlcosa1(20),2,4,6(23),15,17,21-heptaen-9-one ινΐΛ / a / zuzz / ui οροί Example 27 is prepared according to the synthetic route described in General Scheme F and procedures analogous to those used to obtain Example 11. (3-chloro-5-methoxycarbonylphenyl)boronic acid is used for the Suzuki coupling with intermediate 26 to provide 4-chloro-8,14-dioxa-10,19,20triazatetracyclo[13,5,2,126,018,21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 27. LCMS method F: [M+H]+= 358.0, ir = 2.38 min LCMS method G: [M+H]+= 358.1, ir = 2.52 min Ή NMR (400 MHz, d6-DMSO, 80°C) 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), 7.3.3 s, (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), 2.06-2.0 (pm, 2H, m). Example 28: 4-ΑυοΓθ-5-πιβΑΙ-8,14-άϊοχ3-10,19,2(Μπ3Ζ3ί6ΐΓ3άοΙο[13.5.2 .12'6.018'21]1ποο531(20),2,4,6(23),15,17,21-heptaen-9-ona Example 28 is prepared according to the synthesis route described in General Scheme G. 109 Preparation of the intermediate 43:5-í5-(3-phi(benzyloxy)carbonyl]amino}propoxy)-1-(oxan-2-yl)-1Hindazol-3-yl]-3-fluoro-2-methlbenzoate methyl MA / a / ZUZZ / UI ÓOO I To a solution of N-(3-{[1-(oxan-2-yl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl]oxy}propyl)benzylcarbamate 31 (0.6 g, 1.12 mmol) in A / ,A / -dimethylformamide (15 mL) 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. The resulting mixture was degassed by bubbling nitrogen for 10 minutes and stirred at 110°C under microwave irradiation for 50 minutes. 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 BIOTAGE silica) (cyclohexane-ethyl acetate, 100 / 0 to 50 / 50) yielding methyl 5-[5-(3{[(benzyloxy)carbonyl]amino}propoxy)-1-(oxan-2-11)-1H-andazol-3-11]-3-fluoro-2-methylbenzoate 43 as a yellow powder. LCMS method F: [M+H]+= 576.2, tR= 3.48 min Preparation of intermediate 44: N-13-({3-13-fluoro-5-(hydroxymethyl)-4-methylphenyl]-1-(oxan-2-yl)-1Hindazol-5-H}oxy)propyl]carbamate benzyl 110 To methyl 5-[5-(3-{[(benzyloxy)carbonyl]amino}propoxy)-1-(oxan-2-yl)-1H-indazol-3-yl]-3-fluoro-2-methylbenzoate (0.225 g, 0.39 mmol) in THF (50 mL) a 1M solution of lithium aluminum tetrahydride (0.78 mL, 0.78 mmol) was added at 0°C. The mixture was stirred at 0°C for 1 hour. To the reaction mixture, EtOAc (10 mL) was added at 0°C and poured into a 10% solution of Rochelle salt (100 mL) and EtOAc (100 mL). The mixture was stirred at room temperature for 2 hours. After separation, the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to a brown / orange oil.This residue was purified by flash silica gel chromatography (Macherey Nagel, 25 g) with gradient elution: cyclohexane / EtOAc 0-100% to provide benzyl N-[3-({3-[3-fluoro-5-(hydroxymethyl )-4-methylphenyl]-1 -(oxan-2-yl)-1 H-indazol-5¡l}oxy)propyl]carbamate 44 as a yellow oil. LCMS method F: [M+H]+= 548.2, tR= 3.10 min Preparation of intermediate 45:4-fluoro-5-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20triazatetracyclo[ 13.5.2.12'6.018'21]tricose-1(20),2,4,6(23), 15,17,21-heptaen-9-one ΐνΐΛ / a / ZUZZ / UI ΟΡΟΊ A solution of benzyl N-[3-({3-[3-fluoro-5-(hydroxymethyl)-4-methylphenyl]-1-(oxan-2-11)-1H-indazol-5-yl}oxy)propyl]carbamate (0.125 g, 0.23 mmol) in anhydrous acetonitrile (33 mL) was added to 1 / 4 cesium carbonate (0.447 g, 1.37 mmol). The resulting reaction mixture was stirred at 90°C for 1 h 30. The reaction mixture was filtered, the solvent was removed under reduced pressure, and the residue was purified by flash column chromatography (15g Macherey Nagel silica) (DCM-ethyl acetate, 1:0 to 8:2) yielding 4fluoro-5-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one 45 as a white foam. LCMS method F: [M+H]+= 440.2, tR= 3.03 min Preparation of Example 28: 4-fluoro-5-methyl-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]tricose-1 (20),2,4,6(23),15,17,21 -heptaen-9-one 111 A solution of 4-fluoro-5-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one 45 (0.066 g, 0.15 mmol) in DCM (3 mL) was added to RT TFA (0.143 mL, 1.92 mmol). The resulting reaction mixture was stirred under microwave irradiation at 80°C for 1 h 30. 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 chromatography (5g Macherey Nagel silica) (Ethyl DCMacetate, 1:0 to 4:6) to provide a solid, which was ground in acetonitrile and filtered yielding 4fluoro-5-methyl-8,14-dioxa-10,19,20-triazatetrachloro[13.5.2.12B.01821]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9one example 28 as a white solid. LCMS method F: [M+H]+= 356.2, tR= 2.36 min LCMS method G: [M+H]+= 356.2, tR= 2.39 min Ή NMR (400 MHz, c / 6-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 = 2.4 Hz), 7.40 (1H, d). 6.96 (1H, dd, J = 2.3, 8.9 Hz), 5.29 (2H, s), 4.35 (2H, t, J = 8.1 Hz), 3.243.17 (2H, m), 2.22 (3H, d, J = 1.7 Hz), The NH proton of indazole was not visible in this solvent. Example 29: 4,5-difluoro-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaene-9-one ινΐΛ / a / zuzz / ui ooo i Example 29 is prepared according to the synthetic route described in General Scheme F and procedures analogous to those used to obtain Example 11. Methyl 2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate is used for the Suzuki coupling with intermediate 26 to provide 4,5-difluoro-8,14-dioxa-10,19,20-triazatetracyclo[13,5,2,12,6,018,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9one Example 29. LCMS method F: [M+H]+= 360, tR= 2.47 min LCMS method G: [M+H]+= 360, tR= 2.52 min Ή NMR (400 MHz, Ó6-DMSO, 80°C) 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. 112 Example 30: 5-bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricosa1(20),2,4,6(23),15,17,21-heptaen-9-one wiA / aizvzzivi óoo i Example 30 is prepared according to the synthesis route described in General Scheme C and procedures analogous to those used to obtain Example 8. Preparation of intermediate 46: 3-bromo-5-(hydroxymethyl)phenylboronic acid 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 reach room temperature and was stirred for 16 hours. MeOH (25 mL) was added at 0°C to inactivate the reaction until no more gas was produced. 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 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide [3-bromo-5-(hydroxymethyl)phenyl]boronic acid 46 as a white solid. LCMS method F: no m / z detected, tR= 1.58 min Preparation of intermediate 47: N-[3-[3-[4-bromo-3-(hydroxymethyl)phenyl]-1-tetrahydropyran-2-ylindazol-5-yl]oxypropyl] benzyl carbamate 113 To a solution of N-[3-(3-iodo-1-tetrahydropyran-2-1-indazol-5-yl)oxypropyl]benzyl carbamate 26 (692 mg, 1.29 mmol), [4-bromo-3-(hydroxymethyl)phenyl]boronic acid 46 (357 mg, 1.55 mmol), and a 1M solution of Na2CO3 (3.9 mL, 3.87 mmol) in DME (13 mL), palladium-tetrakis(triphenylphosphine) (75 mg, 0.065 mmol, 5 mol%) was added. The reaction mixture was stirred at 80°C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted twice with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a yellow solid. The crude was purified by flash chromatography (CyH / EtOAc 0 to 100% EtOAc) with a 24 g Redisep to yield benzyl N-[3-[3-[4-bromo3-(hydroxymethyl)phenyl]-1-tetrahydrophenamine-2-1-andazol-5-1]oxypropyl]carbamate 47 as a white solid. LCMS method F: [M+H]+= 594, tR= 3.12 min Preparation of intermediate 48:5-bromo- 19-(oxan-2-yl)-8,14-dioxa-10,19,20triazatetracyclo[ 13.5.2.12'6.018'21]tricose-1(20),2,4,6(23), 15,17,21-heptaen-9-one óoo i A suspension of benzyl N-[3-[3-[4-bromo-5-(hydroxymethyl)phenyl]-1-tetrahydropyran-2-1-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 RT, then filtered and concentrated under reduced pressure. The resulting solid was ground with acetonitrile to provide 5bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.01821]tricose-1 (20),2,4,6(23), 15,17,21 heptaen-9-one 48 as a white solid. LCMS method F: [M+H]+= 486 / 488, tR= 3.25 min Preparation of Example 30: 5-bromo-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.01821]tricose-1 (20),2,4,6(23),15,17,21 -heptaen-9-one solution 5-bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20 triazatetracyclo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one 48 (50 mg, 0.10 mmol) in 114 Trifluoroacetic acid (157 pL, 2.05 mmol) was added to DCM (3 mL). 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 solution (3 mL) were added. A white precipitate formed in the organic layer, insoluble in DCM. The solid was filtered and dried under reduced pressure to yield 5-bromo-8,14-dioxa-10,19,20-triazatetracyclo[13,5,2,12,6,018,21]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, tR= 2.58 min LCMS method G: [M+H]+= 403, tR= 2.48 min Ή NMR (400 MHz, OH6-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), 2,021.99(2H,m) ppm. Example 31: 4-(4-methylpiperazin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one ινΐΛ / a / zuzz / ui ooo i Example 31 is prepared according to the synthesis route described in general Scheme C and procedures analogous to those used to obtain Example 12. 1-Methylpiperazine is used for the Buchwald reaction with the bromide intermediate 34 to provide 4-(4-methylpiperazin-1-yl)-8,14-doxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]trichose-1(20),2,4,6(23),15,17,21-heptaen-9-one example 31 . LCMS method F: [M+H]+= 422, tR= 1.44 min LCMS method G: [M+H]+= 422, tR= 2.02 min Ή NMR (400 MHz, Ó6-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. Example 32: 4-(3-methoxyazetidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one Example 32 is prepared according to the synthetic route described in General Scheme C and procedures analogous to those used to obtain Example 12. 3-Methoxyazetidine hydrochloride is used for the Buchwald reaction with bromide intermediate 34 to provide 4-(3-Methoxyazetidin-1-yl)-8,14dioxa-10,19,20-trazatetrachloro[13,5,2,12,6,018,21]tricosa-1(20), 2,4,6(23), 15,17,21-heptaen-9-one (Example 32). LCMS method F: [M+H]+= 409.2, tR= 2.15 min LCMS method G: [M+H]+= 409.1, tR= 2.13 min Ή NMR (400 MHz, Ó6-DMSO, 80°C) 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, 8.6Hz), 3.30 (3H, s), 3.22-3.12 (2H, m), 2.09-1.96 (2H, m) ppm. Example 33: 1-{9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-4-yl}piperidine-4-carbonitrile ινΐΛ / a / zuzz / ui ooo i Example 33 is prepared according to the synthesis route described in General Scheme C and procedures analogous to those used to obtain Example 12. Piperidine-4-carbonitrile is used for the Buchwald reaction with bromide intermediate 34 to provide 1-{9-oxo-8,14-dioxa-10,19,20triazatetracyclo[13,5,2,12,6,018,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-4-yl}piperidine-4-carbonitrile Example 33. LCMS method F: [M+H]+= 432, tR= 2.15 min LCMS method G: [M+H]+= 432, tR= 2.21 min Ή NMR (400 MHz, Ó6-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. Example 34: 4-[4-(pyrrolidin-1-yl)piperidin-1-yl]-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one 116 Example 34 is prepared according to the synthetic route described in General Scheme C and procedures analogous to those used to obtain Example 12. 4-Pyrrolidin-1-ylpiperidine is used for the Buchwald reaction with bromide intermediate 34 to provide 4-[4-(pyrrolidine-1-yl)piperidine-1-yl]-8,14dioxa-10,19,20-trazatetracyclo[13,5,2,12,6,018,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 34. LCMS method F: [M+H]+= 476, tR= 1.59 min LCMS method G: [M+H]+= 476, ir = 1.51 min Ή 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), 6,986.92 (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 were located under the DMSO peak and are not reported here. Example 35: 4-(azetidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one ινΐΛ / a / zuzz / ui ooo i Example 35 is prepared according to the synthesis route described in General Scheme C and procedures analogous to those used to obtain Example 12. Azetidine is used for the Buchwald reaction with bromide intermediate 34 to provide 4-(azetidin-1-1)-8,14-dioxa-10,19,20triazatetracyclo[13,5,2,12,6,018,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 35. LCMS method F: [M+H]+= 379, ir = 2.08 min LCMS method G: [M+H]+= 379, ir = 2.23 min Ή NMR (400 MHz, Ó6-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. Example 36: 4-(piperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one Example 36 is prepared according to the synthesis route described in the general scheme A. Piperidine is used for the Buchwald reaction with the bromide intermediate 34 to provide 4-(piperidin-1-yl)-8,14dioxa-10,19,20-trazatetrachloro[13,5,2,12,6,018,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one example 36. LCMS method F: [M+H]+= 407.2, tR= 1.65 min LCMS method G: [M+H]+= 407.2, tR= 2.48 min Ή NMR (400 MHz, Ó6-DMSO, 80°C) 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, d, 1H, d), 7.38-7.32 (6H, d, d 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, 6-m), 1.71 -1.64 (4H, m), 1.63-1.58 (2H, m) ppm. Example 37: 4-(2,5-dihydrofuran-3-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12>6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaene-9-one MA / a / ZUZZ / UI OOP I Example 37 is prepared according to the synthetic route described in General Scheme A. 2-(2,5dih¡drofuran-3-¡l)-4.4,5,5-tetramethyl-1,3,2-dioxaborolane is used for Suzuki reaction with bromide intermediate 34 to provide 4-(2,5-dih¡drofuran-3-yl)-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.126.018'21]tricose1(20),2,4,6(23),15,17,21-heptaene-9-37 are examples. LCMS method F: [M+H]+= 392.2, tR= 2.19 min LCMS method G: [M+H]+= 392.2, tR= 2.19 min Ή NMR (400 MHz, Ó6-DMSO, 80°C) 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. Example 38: 4-[4-(morpholin-4-yl)piperidin-1-yl]-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 38 is prepared according to the synthesis route described in General Scheme C and procedures analogous to those used to obtain Example 12. 4-(4-piperidin-1-1)morpholine is used for the Buchwald reaction with bromide intermediate 34 to provide 4-[4-(morpholin-4-1)piperidin-1-1]-8,14dioxa-10,19,20-triazatetracyclo[13,5,2,12,6,018,21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 38. LCMS method F: [M+H]+= 492.2, tR= 1.48 min LCMS método G: [M+H]+= 492.2, tR= 2.07 min Ή RMN (400 MHz, Ó6-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), 1.631.5 (2H, m) ppm. Ejemplo 39: 4-(1-metil-1,2,3,6-tetrahidropiridin-4-il)-8,14-dioxa-10,19,20triazatetraciclo[13.5.2.12'6.018'21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-ona ΜΛ / a / ZUZZ / U 1 ÓOO I Example 39 is prepared according to the synthetic route described in General Diagram A. Use 1-methyl4-(4,4,5,5-tetramethyl-1,3,2-d¡oxaborolan-2-yl)-3.6-d¡hidro-2H-p¡r¡d¡na for Suzuki's reaction with it intermediate bromide 34 para proportionionar 4-(1-methyl-1,2,3,6-tetrahidropyridin-4-yl)-8,14-dioxa-10,19,20triazatetraciclo[13.5.2.12'6.018'21]tr¡cosa-1(20),2,4,6(23),15,17,21-heptaen-9-ona example 39. LCMS method F: [M+H]+= 419.2, tR= 1.49 min LCMS method G: [M+H]+= 419.2, tR= 2.16 min Ή NMR (400 MHz, Ó6-DMSO, 80°C) 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. Example 40: 4-[(2S,5S)-2.5-dimethylmorpholin-4-yl]-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.01821]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one 119 Example 40 is prepared according to the synthetic route described in General Scheme C and procedures analogous to those used to obtain Example 12. (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride is used for the Buchwald reaction with bromide intermediate 34 to provide 4[(2S,5S)-2,5-dimethylmorphol-4-yl]-8,14-dioxa-10,19,20-trazatetracyclo[13.5.2.12'6.018'21]tricosa1(20),2,4,6(23),15,17,21-heptaen-9-one Example 40. LCMS method F: [M+H]+= 421.1, tR= 2.06 min LCMS method G: [M+H]+= 421.2, tR= 2.06 min Ή NMR (400 MHz, Ó6-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. Example 41: 4-[(morfolin-4-yl)metil]-8,14-dioxa-10,19,20-triazatetraciclo[13.5.2.12'6.018'21]tricosa1(20),2,4,6(23),15,17,21-heptaen-9-ona óoo i Example 41 is prepared according to the synthetic route described in the general example C. Preparation of intermediate 49:4-[(morpholn-4-ll)methyl]-19-(oxan-2-ll)-8,14-dioxa-10,19,20triazatetraciclo[ 13.5.2.12e.018'21]tricosa-1(20),2,4,6(23), 15,17,21-heptaen-9-ona HOO N / N [i Π 7'n In a sealed tube, potassium methylmorpholine 1-trifluoroborate (87 mg, 0.42 mmol) and cesium carbonate (205 mg, 0.63 mmol) were added to a solution of 4-bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20 triazatetracyclo[13.5.2.12,6.018,21]tricose-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one (100 mg, 0.21 mmol) in THF / H2O 9 / 1 (4 mL) at room temperature. The reaction mixture was degassed for 15 minutes. The solution was bubbling nitrogen gas through it for 120 min, 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 over Celite. The filtrate was extracted with EtOAc (2 x 20 mL), washed with brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to yield a yellow oil. The oil was crushed with acetonitrile and diethyl ether to yield 4-[(morpholin-4-yl)methyl]-19-(oxan-2-yl)-8,14dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 49 as a beige powder. LCMS method F: [M+H]+= 507, tR= 1.74 min Preparation of Example 41: 4-[(morpholin-4-yl)methyl]-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]trichose-1 (20),2,4,6(23),15,17,21 -heptaen-9-one iviA / a / zuzz / ui óoo i H A solution of 4-[(morpholin-4-yl)methyl]-19-(oxan-2-yl)-8,14-dioxa-10,19,20triazatetrachloro[13,5,2,12,6,018,21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one 49 (60 mg, 0.13 mmol) in DCM (2 mL) 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 a saturated bicarbonate solution (10 mL) were added to the residue. After separation, the organic layer was extracted with DCM (2 x 10 mL), washed with brine, dried over sodium sulfate, and evaporated under reduced pressure to give a yellow oil. Some acetonitrile and diethyl ether were added to the oil, the precipitate formed was filtered to yield 4-[(morpholin-4yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13,5,2,12,6,018,21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one example 41 as a beige solid. LCMS method F: [M+H]+= 423, tR= 1.42 min LCMS method G: [M+H]+= 423, tR= 2.03 min Ή 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. 121 Example 42: 4-[(pyrrolidin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one iviA / a / zuzz / ui óoo i Example 42 is prepared according to the synthesis route described in General Scheme C and procedures analogous to those used to obtain Example 41. Potassium trifluoro[(pyrrolidine-1-yl)methyl]borate was used for the Suzuki coupling with bromide intermediate 34 to provide 4-[(pyrrolidine-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetrachloro[13,5,2,12,6,018,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 42. LCMS method F: [M+H]+= 407, tR= 1.44 min LCMS method G: [M+H]+= 407, tR= 2.12 min Ή NMR (400 MHz, c / 6-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. Example 43: 4-[(pyrrolidin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one Example 43 is prepared according to the synthesis route described in General Scheme C and procedures analogous to those used to obtain Example 41. Potassium trifluoro[(piperidin-1-yl)methyl]borate was used for the Suzuki coupling with bromide intermediate 34 to provide 4-[(pyrrolidin-1-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13,5,2,12,6,018,21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 43. LCMS method F: [M+H]+= 421, tR= 1.49 min LCMS method G: [M+H]+= 421, tR= 2.33 min Ή NMR (400 MHz, c / 6-DMSO, 80°C) δ 12.86 (1H, s), 7.86 (2H, m), 7.59 (1H, m), 7.48 (1H, d, J = 8.4 122 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 protones are not visible due to different shapes. Structure confirmed by COSY. Example 44: 4-[(4-methylpiperazin-1-yl)methyl]-8,14-dioxa-10,19,20triazatetraciclo[13.5.2.12'6.018'21]tricosa-1 (20),2,4,6(23),15,17,21 -heptaen-9-ona MA / a / ZUZZ / UI ÓOO I Example 44 is prepared according to the synthetic route described in General Scheme C and procedures analogous to those used to obtain Example 41. Potassium trifluoro[(4-methylpiperazin-1-yl)methyl]borate was used for the Suzuki coupling with bromide intermediate 34 to provide 4-[(4-methylpiperazin-1-1-yl)methyl]-8,14-dioxa-10,19,20-trazatetrachloro[13,5,2,12,6,018,21]tricosa-1(20),2,4,6(23),15,17,21heptaen-9-one Example 44. LCMS method F: [M+H]+= 436, ír = 1.36 min (current 20V) LCMS method G: [M+H]+= 436, tR = 1.95 min (pH10 current 20V) Ή NMR (400 MHz, c / 6-DMSO, 80°C) 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. Example 45: 5-(morpholin-4-yl)-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one Example 45 is prepared according to the synthetic route outlined in General Scheme C. Morpholine was used for Buchwald coupling with bromide intermediate 48 to provide 5-(morpholin-4-yl)8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose-1 (20),2,4, 6(23),15,17,21 -heptaene-9-one Example 45. 123 LCMS method F: [M+H]+= 409, tR = 2.17 min LCMS method G: [M+H]+= 409, ir = 2.16 min Ή NMR (400 MHz, Ó6-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. Example 46: 4-[4-(2-methoxiet¡l)p¡peraz¡n-1-¡l]-8,14-dioxa-10,19,20triazatetraciclo[13.5.2.12'6.018'21]tricosa-1 (20),2,4,6(23),15,17,21 -heptaen-9-ona / MA / a / ZUZZ / UI ÓOO I Example 46 is prepared according to the synthetic route described in the general diagram A. Use 1-(2methoxyethylpiperazine for the Buchwald reaction with intermediate bromide 34 to proportion 4-[4-(2metox¡et¡l)p¡peraz¡n-1-¡l]-8,14-d¡oxa-10,19,20-tr¡azatetraciclo[13.5.2.12'6.018'21]tr¡cosa-1(20),2,4,6(23),15,17,21heptaen-9-ona example 46. LCMS method F: [M+H]+= 466.2, ír = 1.48 min LCMS method G: [M+H]+= 466.2, ír = 2.06 min Ή NMR (400 MHz, Ó6-DMSO, 80°C) 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), 2.101.99(2H, m) ppm. Example 47: 4-(diethylamino)-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one Example 47 is prepared according to the synthetic route described in General Scheme A. Diethylamine is used for the Buchwald reaction with bromide intermediate 34 for provide4-(diethylamino)-8,14dioxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa-1(20),2,4,6(23),15,17,21-heptane-9-4 examples. LCMS method F: [M+H]+= 395.2, tR= 1.57 min LCMS method G: [M+H]+= 395.2, tR= 2.48 min Ή NMR (400 MHz, c / 6-DMSO, 80°C) δ 12.73 (1H, br s), 7.59 (1H, br s), 7.46 (1H, d, J = 9.3 Hz), 7.36 124 (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), 4.32-4.2 (2H, J, 4.4), q = 4.2 Hz. 7.0 Hz), 3.21-3.10 (2H, m), 2.08-1.96 (2H, m), 1.17 (6H, t, J = 6.9 Hz) ppm. Example 48: 4-cyclopropyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one MA / a / zuzz / ui ooo i Example 48 is prepared according to the synthesis route described in General Scheme C. Potassium trifluoro[cyclopropyl]borate was used for the Suzuki coupling with bromide intermediate 34 to provide 4-cyclopropyl-8,14-dioxa-10,19,20-triazatetrachloro[13,5,2,12,6,018,21]tricosa-1(20),2,4,6(23),15,17,21heptaen-9-one Example 48. LCMS method F: [M+H]+= 364, ir = 2.40 min LCMS method G: [M+H]+= 364, tR= 2.39 min Ή NMR (400 MHz, c / 6-DMSO, 80°C) 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. Example 49: 5-(4-methylpiperazin-1-yl)-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one Example 49 is prepared according to the synthetic route outlined in General Scheme C. 4methylpiperazine was used for Buchwald coupling with bromide intermediate 48 to provide 5-(4met¡lp¡peraz¡n-1-¡l)-8,14-d¡oxa-10,19,20-triazatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa-1(20),2,4,6(23),15,1,14-99-p. LCMS method F: [M+H]+= 422, tR= 1.44 min LCMS method G: [M+H]+= 422, tR= 2.13 min 125 Ή 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, mHz, d, 7.4 d). 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 Example 50:13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one ινΐΛ / a / zuzz / u 10001 Example 50 is prepared according to the synthesis route described in General Scheme C and procedures analogous to those used to obtain Example 8. To a solution of 13-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20triazatetracyclo[13,5,2,12,6,0,18,21]tricose-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one (330 mg, 0.78 mmol) in dichloromethane (12 mL) trifluoroacetic acid (1.19 mL, 15.65 mmol) at room temperature. The solution was then irradiated under microwaves (Biotage initiator+) for 2 h. The reaction mixture was concentrated under vacuum and the residue was dissolved in EtOAc. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate, with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting solid was ground in diisopropyl ether and dried to yield the expected compound 13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13,5,2,12,6,018,21]tricose-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, tR= 2.25 min LCMS method G: [M+H]+= 338, tR= 2.24 min Ή 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 = 7.9 Hz), 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), 2.2. 2.47–2.33 (1H, m), 1.41–1.38 (4H, m) ppm. Example 51: 8,14-dioxa-4,5,10,19,20-pentaazatetracycle[13.5.2.12'5.018'21]tricose1(20),2(23),3,15(22),16,18(21 )-hexaene-9-one Example 51 is prepared according to the synthesis route described in general Scheme C. 126 Preparation of intermediate 50: N-I3-U3-n-(2-hydroxyethyl)-1H-Dirazol-4-ill-1-(oxan-2-yl)-1H-indazol5-yl}oxy)propyl]benzyl carbamate MA / a / ZUZZ / UI ÓOO I To a solution of N-(3-{[3-iodo-1-(oxan-2-1)-1H-indazol-5-1]oxy}propyl)benzylcarbamate 26 (0.535 g, 1.0 mmol) in dioxane (3 mL) and water (1 mL) RT pinacol ester of 1-(2-hydroxyethyl)-1H-pyrazol-4-boronic acid (0.286 g, 1.2 mmol), K3PO4 (0.637 g, 3.0 mmol), XPhos (0.048 g, 0.1 mmol) and Pd(PPhs)4 (0.058 g, 0.05 mmol). The resulting reaction mixture was stirred under microwave irradiation at 120°C 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 chromatography (25 g Macherey Nagel silica) (cyclohexane-ethyl acetate 3 / EtOH 1, 1:0 to 1:1) yielding N-[3-({3-[1-(2-Hydroxyethyl)-1H-pyrazol-4-1]-1-(oxan-2-yl)-1H-indazol-5-yl}oxy)propyl]carbamate 50 as a yellow oil. LCMS method F: [M+H]+= 520.2, tR= 2.56 min Preparation for Intermission 51: 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 (0.380 g, 0.73 mmol) in anhydrous acetonitrile (146 mL) was added to 1.430 g of cesium carbonate (1.430 g, 4.39 mmol). 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 chromatography (15 g Macherey-Nagel silica) (cyclohexane-ethyl acetate 3 / EtOH, 1:0 to 127 3:7) yielding 19-(oxan-2-yl)-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.125.01821]tricose1(20),2(23),3,15(22),16, 18(21)-hexaen-9-one 51 as a white solid. LCMS method F: [M+H]+= 412.2, tR= 2.20 min Preparation of Example 51: 8,14-dioxa-4,5,10,19,20-pentaazetetracyclo[13.5.2.12'5.018'21]tricose1 (20),2(23), 3,15(22),16,18(21 )-hexaen-9-one ινΐΛ / a / zuzz / ui ooo i A solution of 19-(oxan-2-11)-8,14-dioxa-4,5,10,19,20-pentazatetracyclo[13,5,2,12,5,0,18,21]tricose1(20),2(23),3,15(22),16,18(21)-hexaen-9-one (0.155 g, 0.38 mmol) in DCM (3 mL) was added to RT TFA (0.561 mL, 7.53 mmol). The resulting reaction mixture was stirred under microwave irradiation at 80°C for 1 h 30. 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 chromatography (15 g Macherey Nagel silica) (cyclohexane-ethyl acetate 3 / EtOH 1, 9:1 to 0:1) to provide a solid (70 mg), which was ground in diisopropyl ether and filtered yielding 8,14-dioxa4,5,10,19,20-pentaazatetracyclo[13.5.2.12-5.01821]tricose-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, tR= 1.68 min LCMS method G: [M+H]+= 328.1, tR= 1.68 min Ή NMR (400 MHz, c / 6-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, d, J = 2.3 Hz), 6.94 (1H, dd, J = 2.3, 8.9 Hz), 4.53-4.49 (2H, m), 4.38-4.28 (4H, m), 3.14-3.09 (2H, m), 1.86 (2H, q, J = 8.7 Hz) ppm. Example 52: 4-[methyl(oxetan-3-yl)amino]-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 52 is prepared according to the synthetic route described in General Scheme C. N-methyloxetan-3-amine is used for the Buchwald reaction with bromide intermediate 34 to provide 4[methyl(oxetan-3-yl)amino]-8,14-dioxa-10,19,20-trazatetracyclo[13,5,2,12,6,018,21]tricosa-1(20),2,4,6(23),15,17,21 128 heptaen-9-one example 52. LCMS method F: [M+H]+= 409, ir = 2.04 min LCMS method G: [M+H]+= 409, ir = 2.06 min Ή 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), 4.324.28 (2H, m), 3.16 (2H, m), 2.96 (3H, s), 2.03 (2H, m) ppm. Example 53: 4-[(dimethylamino)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one ινΐΛ / a / zuzz / ui ooo i Example 53 is prepared according to the synthesis route described in General Scheme C. Potassium dimethylaminomethyltrifluoroborate was used for the Suzuki coupling with bromide intermediate 34 to provide 4-[(dimethylamino)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13,5,2,12,6,018,21]tricosa1(20),2,4,6(23),15,17,21-heptaen-9-one example 53. LCMS method F: [M+H]+= 381, tR = 1.39 min LCMS method G: [M+H]+= 381, ir = 2.03 min Ή NMR (400 MHz, Ó6-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. Example 54: 4,10-dimethyl·8,14-dioxa-10,19,20-triazatetraciclo[13.5.2.12'6.01821]tricosa1(20),2,4,6(23),15,17,21-heptaen-9-ona Example 54 is prepared according to the synthetic route described in the General Esquema F. 129 Preparation of intermediate 52:4,10-dimethyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20tríazatetraciclo[13.5.2.126.01821]tricosa-1(20),2,4,6(23), 15,17,21-heptaen-9-ona A mixture of 4-methyl-19-(oxan-2-11)-8,14-dioxa-10,19,20-tnazetetracyclo[13,5,2,12,6,0,18,21]tricose1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one example 18 (115 mg, 0.273 mmol) in THF (2.5 mL) at 0°C was mixed with a dispersion of 60% NaH in oil (8 mg, 0.328 mmol) and Mel (20 mL, 0.328 mmol). The reaction mixture was stirred overnight at RT. Further dispersion of 60% NaH in oil (8 mg, 0.328 mmol) and Mel (20 pL, 0.328 mmol) was added. The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure. EtOAc and water were added. The layers separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, and the solvent was removed under reduced pressure to provide 4,10-dimethyl-19-(oxan-2-11)-8,14-dioxa-10,19,20-trazatetrachloro[13,5,2,12,6,018,21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one 52 as a colorless oil. LCMS method F: [M+H]+= 436.2, tR= 3.15 min Preparation of Example 54: 4,10-dimethyl-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]tricose-1 (20),2,4,6(23),15,17,21 -heptaen-9-one To a mixture of 4,10-dimethyl-19-(oxan-2-11)-8,14-dioxa-10,19,20triazatetracyclo[13,5,2,12,6,018,21]cosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 52 (150 mg; 0.345 mmol) in DCM (2.5 mL) TFA (132 ml, 1.723 mmol) was added. The reaction mixture was stirred under microwave conditions at 80°C for 60 min. The solvent was removed under reduced pressure, the mixture was dissolved in EtOAc and washed with a saturated solution of 1 N NaHCO3 (pH=7), then with water. The organic layer was concentrated under reduced pressure, and the oil was purified by chromatography using a 10 g S1O2 column eluted with DCM / MeOH 100 / 0 to 95 / 5. The desired fractions were combined, but the product is not what was expected. 130 sufficiently pure and was further purified by chromatography using a 10 g column of SO2 eluted with 70 / 30 to 50 / 50 cyclohexane / ethyl acetate. The desired fractions were combined, and the solvent was removed under reduced pressure, after which the oil was crushed with pentane. The solid was filtered and boiled in hot water, filtered, and dried under high vacuum to give 4,10-dimethyl-8,14-dioxa-10,19,20triazatetracyclo[13,5,2,12,6,018,21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one example 54 as a white powder. LCMS method F: [M+H]+= 352.2, tR= 2.49 min LCMS method G: [M+H]+= 352.2, tR= 2.49 min The 1H NMR analysis showed the presence of rotamers. Ή RMN (400 MHz, Ó6-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. Ejemplo 55: 4-(propan-2-ilox¡)-8,14-dioxa-10,19,20-triazatetraciclo[13.5.2.12'6.018'21]tricosa1(20),2,4,6(23),15,17,21-heptaen-9-ona MA / a / ZUZZ / UI ÓOO I The game is 54 hours before starting the recording routine in the general Esquema F. Intermediate preparation 53:3-[5-í3-tbenciloxycarbonilamino)DroDoxil-1-tetrahidroDran-2-ilindazol-3-il]-5-hidroxi-benzoato metilo To a degassed solution of benzyl N-[3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-1)oxypropyl]carbamate (2.876 g, 5.372 mmol), methyl 3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-1)benzoate (2.988 g, 10.473 mmol), XPhos (256 mg, 0.537 mmol), and K3PO4 (3.421 g, 16.116 mmol) in dioxane (40.0 mL) and water (10.0 mL), Pd(PPh3)4 (311 mg, 0.269 mmol) was added. The cloudy brown solution The resulting 131 was degassed with nitrogen gas for 5 minutes and separated into three batches, sealed, and heated to 120°C under microwave irradiation for 1 h each. 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 x 100 mL), and the combined organic extracts were washed with a saturated aqueous solution of NaCl (1 x 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 of SiO2Macherey Nagel, 100 mL / min, CyH / EtOAc 100:0 to 60:40) to yield methyl 3-[5-[3-(benzyloxycarbonylamino)propoxy]-1-tetrahydroxydropran-2-lindazol-3-yl]-5-hydroxybenzoate 53 as a brown oil. LCMS method F: [M+H]+= 560.1, tR= 2.97 min Preparation of intermediate 54:3-[5-[3-(benzyloxycarbonylamino)DroDoxil-1-tetrahydrodropram-2-lindazol-3-yl]-5-isopropoxy-methylbenzoate To a solution of methyl 3-[5-[3-(benzyloxycarbonylamino)propoxy]-1-tetrahydrodropran-2-yl-indazol-3-yl]-5-hydroxybenzoate (2.800 g, 5.004 mmol) and K2CO3 (1.729 g, 12.510 mmol) in N,N-dimethylformamide (25.0 mL) 2-bromopropane (940 µL, 1.231 mg, 10.008 mmol) was added. The resulting cloudy brown solution was heated to 70°C for 2 h. The reaction was quelled with water (20 mL), EtOAc (50 mL) was added, and the phases were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic extracts were washed with a saturated aqueous solution of NaCl (1 x 20 mL), dried over anhydrous Na2SO4, filtered, and the solvent removed under reduced pressure. The resulting crude material (brown solid, 3.5 g) was purified by column chromatography (120 g of Macherey Nagel SiO2, CyH / EtOAc 100;0 to 70;30) to yield methyl 3-[5-[3-(benzyloxycarbonylamino)propoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-5-isopropoxybenzoate as a brown solid. LCMS method F: [M+H]+= 602.3, tR= 3.48 min 132 Preparation of Intermediate 55: N-[3-f3-f3-(h¡drox¡methyl)-5-isopropoxy¡-phenyl-1-tetrahydropyran-2-ilindazol-5-yl]oxypropyl]benzyl carbamate iviA / a / zuzz / u 1 0001 To a solution of methyl 3-[5-[3-(benzyloxycarbonylamino)propoxy]-1-tetrahydropyran-2-yl-indazol-3-1]-5-isopropoxybenzoate (3.000 g, 4.986 mmol) in THF (50.0 mL) at 0°C, 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 minutes, then at room temperature for 1 h. The reaction was carefully quelled with saturated aqueous Rochelle salt (20 mL), EtOAc (50 mL) was added, and the phases were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic extracts were washed with a saturated aqueous solution of NaCl (1 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield crude benzyl N-[3-[3-[3-(hydroxymethyl)-5-isopropoxyphenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate 55 as a brown oil which was used in the next stage without further purification. LCMS method F: [M+H]+= 574.2, tR= 3.06 min Preparation of intermediate 56:19-(oxan-2-yl)-4-(propan-2-yloxy)-8,14-dioxa-10,19,20triazatetracyclo[ 13.5.2.12'6.018'21]tricose-1(20),2,4,6(23), 15,17,21-heptaen-9-one To a solution of benzyl N-[3-[3-[3-(hydroxymethyl)-5-isopropoxyphenyl]-1-tetrahydroxyl-2-yl-andazol-5-yl]oxypropyl]carbamate 55 (100 mg, 0.174 mmol) in MeCN (18.0 mL) CS2CO3 (341 mg, 1.046 mmol) was added. 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 (oil 133 yellow, 100 mg) was purified by column chromatography (4 g of S1O2 Macherey Nagel, 15 mL / min, CH2Cl2 / MeOH 100:0 to 98:2) to yield 19-(oxan-2-yl)-4-(propan-2-yloxy)-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one 56 as a clear oil. LCMS method F: [M+H]+= 466.2, tR= 3.03 min Preparation of Example 55: 4-(propan-2-yloxy)-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]trichose-1 (20),2,4,6(23),15,17,21 -heptaen-9-one ινΐΛ / a / zuzz / u To a solution of 19-(oxan-2-yl)-4-(propan-2-yloxy)-8,14-dioxa-10,19,20triazatetracyclo[13,5,2,12,6,018,21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one 56 (54 mg, 0.116 mmol) in CH2Cl2 (5.0 mL) TFA (300 pL, 447 mg, 3.920 mmol) was added. The vial containing the resulting light yellow solution was sealed and heated to 50°C under microwave irradiation for 3 h. Saturated aqueous NaHCO3 (1 mL) was added and the phases separated. The aqueous layer was extracted with CH2CI2 (3 x 5 mL) and the combined organic extracts were washed with water (1 x 5 mL), dried over anhydrous Na2S4, filtered, and concentrated under reduced pressure. The resulting crude material (pale yellow oil, 49 mg) was ground with Pr2O to yield 4-(propan-2-yloxy)-8,14-dioxa-10,19,20-triazatetracyclo[13,5,2,12,6,0,18,21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one example 55 as an amorphous white solid. LCMS method F: [M+H]+= 382.1, tR= 2.41 min LCMS method G: [M+H]+= 382.2, tR= 2.40 min1H NMR (400 MHz, Ó6-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), 3.193.15 (m, 2H), 2.04-2.02 (m, 2H), 1.35-1.33 (m, 6H) ppm. Two labile protons were not visible in this solvent. Example 56: 4-fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one 134 Example 56 is prepared according to the synthesis route described in General Scheme A. Preparation of intermediate 57:1 -(3-bromo-5-fluorophenyl)ethanol HO O Br To a cooled solution of 3-bromo-5-fluorobenzaldehyde (1.5 g, 7.389 mmol) in dry tetrahydrofuran (19 mL), a 3M methylmagnesium bromide solution in diethyl ether (4.93 mL, 14.778 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 20 min, then at room temperature for 16 h. The reaction mixture was inactivated with a saturated aqueous solution of NH4Cl, 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 by eluting with Cyclohexane / Ethyl Acetate-EtOH (3-1): 100 / 0 to 80 / 20, to provide 1-(3-bromo-5-fluorophenyl)ethanol 57 as a colorless oil. LCMS method F: [M+H]+= undetected mass, tR = 2.32 min Preparation of intermediate 58:1-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanol MA / a / ZUZZ / UI ÓOO I To a degassed solution in a sealed tube of 1-(3-bromo-5-fluorophenyl)ethanol (1.196 g, 5.461 mmol), bis(pinacolate)diboron (2.080 g, 8.192 mmol), and potassium acetate (2.144 g, 21.844 mmol) in dioxane (17 mL), PdChfdppfjCFhCl₂ (0.446 g, 0.546 mmol) was added. The reaction mixture was heated at 90°C for 24 h. The reaction mixture was filtered over Celite on Whatman filter paper and washed 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 provide 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: no m / z detected, tR= 2.65 min. 135 Preparation of intermediate 59: N-I3-[3-[3-fluoro-5-(1-hydroxyethyl)phenin-1-tetrahydroDiran-2-ylindazol-5-yl]oxypropyl]benzylcarbamate To a degassed solution of N-[3-(3-iodo-1-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]benzylcarbamate 26 (1.462 g, 2.734 mmols), 1-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanol 58 (1.453 g, 5.466 mmols), tripotassium phosphate (1.742 g, 8.202 mmols) and xPhos (0.130 g, 0.274 mmols) in dioxane (14.6 mL) and water (8.8 mL) tetraquis(triphenylphosphine)palladium(0) (0.158 g, 0.137 mmols) was added. The reaction mixture was irradiated using a microwave oven (Biotage initiator+) at 120°C for 1 h. The reaction mixture was filtered over 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. The crude was purified by column chromatography by eluting with DCM / ethyl acetate, 100 / 0 to 80 / 20 to provide benzyl N-[3-[3-[3-fluoro-5-(1-hydroxyethyl)phenyl]-1-tetrahydropyran-2-1-andazol-5-1]oxypropyl]carbamate 59 as a cream solid. Yield: 780 mg of intermediate 59 (50%) LCMS method F: [M+H]+= 548, ir = 3.07 min Preparation of the intermediate 60:1 -[3-[5-(3-aminopropoxy)-1 -tetrahydropyran-2-yl-indazol-3-yl]-5fluoro-phenyl]ethanol and 4-fluoro-7-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.126.01821]tricose-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one 136 A suspension of benzyl N-[3-[3-[3-fluoro-5-(1-hydroxyethyl)phenyl]-1-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate (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. LC-MS analysis showed the formation of the desired product, but some starting material remained, and the formation of 1-[3-[5-(3-aminopropoxy)1-tetrahydropyran-2-yl-indazol-3-yl]-5-fluorophenyl]ethanol was observed. The reaction mixture was heated to 90°C for 16 h. The reaction mixture was cooled to RT, then filtered and concentrated under reduced pressure to provide a mixture of 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[13,5,2,12,6,0,18,21]tricose1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one (26%) (0.667 g, 1.426 mmol (postulated)) as an orange oil.The raw product was not purified; it was applied to the next stage without further purification. Preparation of intermediate 61:4-fluoro-7-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20triazatetracyclo[ 13.5.2.12'6.018'21]tricose-1(20),2,4,6(23), 15,17,21-heptaen-9-one IVIA / a / ZUZZ / UI ÓOO I To a solution of 1-[3-[5-(3-aminopropoxy)-1-tetrahydropyran-2-yl-indazol-3-yl]-5-fluoro-phenyl]ethanol and 4fluoro-7-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13,5,2,12,6,0,18,21]tricose1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one 60 (0.567 g, 1.373 mmol) in DMA (350 mL) 1,1-carbonyldiimidazole (0.245 g, 1.510 mmol) was added. The reaction mixture was stirred at RT for 2 h, then at 90°C for 22 h. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and a saturated aqueous solution of 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. The crude product was purified by column chromatography by eluting with cyclohexane / ethyl acetate-EtOH (3-1): 100 / 0 to 70 / 30 to give a cream solid. The solid was ground from diisopropyl ether to give 4-fluoro-7-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(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, ir = 2.96 min 137 Preparation of example 56:4-fluoro-7-methyl-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]tricose-1 (20),2,4,6(23),15,17,21 -heptaen-9-one iviA / a / zuzz / ui ooo i To a solution of 4-fluoro-7-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20triazatetrachloro[13,5,2,12,6,018,21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 61 (100 mg, 0.228 mmol) in DCM (16 mL) trifluoroacetic acid (350 pL, 4.560 mmol) was added at RT. The reaction mixture was irradiated under microwave conditions (Biotage initiator). The solid was ground from diisopropyl ether to provide 4fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12S.018'21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9one example 56 as a cream solid. LCMS method F: [M+H]+= 356, ir = 2.33 min LCMS method G: [M+H]+= 356, tR = 2.32 min Ή NMR (400 MHz, Ó6-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. Example 57: 4-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one Example 57 is prepared according to the synthesis route described in General Scheme C. Preparation of intermediate 62:1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3.6dihydro-2H-pyridine 138 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), triethylamine (245 µL, 1.77 mmol) and 3-bromooxethane (750 mg, 5.5 mmol) were added. The resulting mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated under reduced pressure to yield 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)3,6-dihydro-2H-pyridine (500 mg, 1.77 mmol) as an orange oil. The compound was used without further purification in the next step. Preparation of intermediate 63:19-(oxan-2-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa10,19,20-triazatetracyclo[13.5.2.126.0,82,]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one To a solution of 4-bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]tricose-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one intermediate 34 (260 mg, 0.53 mmol) in dioxane / water (15 / 1.5 mL), 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-3.6-dihydro-2H-pyridine 62 (300 mg, postulated 1.06 mmol) and K3PO4 (337) were added. mg, 1.59 mmol). The mixture was degassed for 10 minutes, then Pd(dppf)Cl2 was added. DCM (17 mg, 0.021 mmol). The mixture was heated at 90°C for 20 hours. Monitoring by LCMS analysis showed the formation of the expected product without oxethane. The reaction mixture was cooled to room temperature, then more 1-(oxetan-3-1)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-1)-3,6-dihydro-2H-pyridine (200 mg, 0.71 mmol) and K3PO4 (168 mg, 0.79 mmol) were added. The mixture was degassed for 10 minutes and more Pd(dppf)Cl2 was added. DCM (8 mg, 0.0098 mmol).The mixture was heated at 90°C for 1 day. The reaction mixture was filtered over Celite, diluted with EtOAc (50 mL) and water (50 mL). After separation, the aqueous layer was extracted with EtOAc (2 x 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 chromatography (Macherey-Nagel, 25 g) with DCM / (MeOH / NH3) (100 / 0 to 90 / 10). The desired fractions were collected, combined, and evaporated to provide 19-(oxan-2-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one 63 as an orange solid. LCMS method F: [M+H]+= 489, ir = 1.81 min 139 Preparation of Intermediate 64:19-(oxan-2-yl)-4-[1 -(oxetan-3-yl)- 1,2,3,6-tetrahydropyridine-4-H]-8,14dioxa-10,19,20-triazatetracidium[13.5.2.12'6.01821]tricose-1(20),2,4,6(23), 15,17,21-heptane-9-one MA / a / ZUZZ / UI OOP I To a solution of 19-(oxan-2-yl)-4-(1,2,3,6-tetrahydropyridine-4-yl)-8,14-dioxa-10,19,20tnanazatetracyclo[13,5,2,12,6,018,21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one 63 (289 mg, 0.59 mmol) in dry THF (15 mL), oxetan-3-one (212 mg, 2.95 mmol) was added. The mixture was cooled to 0°C, then sodium tris(acetoxy)borohydride (248 mg, 1.18 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was inactivated with 1M Na₂CO₃ (~7 mL, pH = 8), then diluted with EtOAc (50 mL). After separation, the aqueous layer was extracted with EtOAc (3 x 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 was purified by flash column chromatography (Macherey Nagel, 15 g) with DCM / MeOH (100 / 0 to 97 / 3) as eluent, to provide 19-(oxan-2-yl)-4-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-8,14-dioxa-10,19,20triazatetrachloro[13,5,2,12,6,018,21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one 64 as white crystals. LCMS method F: [M+H]+= 545, tR= 1.84 min Preparation of example 57:4-[1 -(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6,018,21]tricose-1 (20),2,4,6(23),15,17,21 -heptaen-9-one To a solution of 19-(oxan-2-yl)-4-[1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridine-4-yl]-8,14-dioxa-10,19,20triazatetracyclo[13,5,2,12,6,018,21]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one 64 (82 mg, 0.15 mmol) in DCM (4 mL) trifluoroacetic acid (107 pL, 1.4 mmol) was added. The mixture was stirred at room temperature for 24 hours. The reaction mixture was then heated to 40°C for 4 hours. More trifluoroacetic acid (26 pL, 0.35 mmol) was added, and the reaction mixture was heated to 40°C for 3 hours and then left at room temperature overnight. The reaction mixture was diluted with DCM (25 mL) and a saturated NaHCO3 solution (25 mL). After separation, the aqueous layer was extracted with DCM (3 x 20 mL). 140 combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. The crude was ground in acetonitrile, filtered, and the solid was washed several times with acetonitrile to provide 4-[1-(oxetan-3-1)-1,2,3,6-tetrahydropyridine-4-1]-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 example 57 as a creamy powder. LCMS method F: [M+H]+= 461, tR= 1.49 min LCMS method G: [M+H]+= 461, tR= 2.19 min Ή NMR (400 MHz, Ó6-DMSO, 80°C) 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 = 1.5, 8.9 Hz), 6.23 (1H, m), 5.29 (2H, m), 4.61 (2H, t, J = 6.5 Hz), 4.55 (2H, t, J = 5.9 Hz), 4.31 (2H, t, J = 9.3 Hz), 3.65 (1H, t, 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. Example 58: 4-(3-methylpiperidin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one iviA / a / zuzz / ui óoo i Example 58 is prepared according to the synthesis route described in General Scheme C. 3-methylpiperidine is used for the Buchwald reaction with bromide intermediate 34 to provide 4-(3-methylpiperidin-1-1)-8,14-dioxa-10,19,20-trazatetracyclo[13,5,2,12,6,018,21]tricose-1(20),2,4,6(23),15,17,21heptaen-9-one example 58. LCMS method F: [M+H]+= 421.2, tR= 1.88 min LCMS method G: [M+H]+= 421.2, tR= 2.66 min Ή NMR (400 MHz, Ó6-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, m), 5.24-5.20 (2H, m), 4.30 (2H, dd, J = 8.0, 9.1 Hz), 3.22-3.1 (2H, m), 3.07 (6H, s), 2.79-2.68 (1H, m), 2.07-1.98 (2H, m) 1.83-1.74 (3H, m), 1.7-1.55 (1H, m), 1.19-1.05 (1H, m) ppm. The NH₄⁺ proton of indazole was not visible in this solvent. Example 59: 4-[(3S)-3-hydroxypyrrolidine-1-yl]-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]tricose-1 (20),2,4,6(23),15,17,21 -heptaen-9-one 141 Example 59 is prepared according to the synthesis route described in the General Scheme C. (3S)pyrrolididin-3-ol is used for the Buchwald reaction with bromide intermediate 34 to provide 4-[(3S)-3-hydroxypyrrolididin-1-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13,5,2,12,6,018,21]tricose-1(20),2,4,6(23),15,17,21 heptaen-9-one example 59. LCMS method F: [M+H]+= 409.2, tR= 1.98 min LCMS method G: [M+H]+= 409.2, tR= 1.96 min Ή NMR (400 MHz, Ó6-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. Example 60: 4-fluoro-8,14-dioxa-10,19,20-triazapentacyclo[13.5.2.12'6.17'10.018,21]tetracose1(20),2(24),3,5,15(22),16,18(21 )-heptaen-9-one MA / a / ZUZZ / UI ÓOO I Example 60 is prepared according to the synthesis route described below. Preparation of intermediate 65:1-(3-bromo-5-fluorophenyl)-2-nitroethan-1-ol OH Br To a stirred solution of 3-bromo-5-fluorobenzaldehyde (2 g, 10 mmol) in THF (20 mL), nitromethane (0.536 mL, 10 mmol) was added dropwise at 0°C, followed by dropwise addition of 1N sodium hydroxide solution (10 mL, 10 mmol). The solution was stirred at 0°C for 15 min. It was then inactivated with acetic acid solution (12 mL). Water (25 mL) was added to the resulting mixture. The aqueous layer was extracted with EtOAc (4 x 50 mL). The combined organic layers were washed with saturated brine (2 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure to yield a brown / orange oil. This residue was purified by flash silica gel chromatography (Macherey Nagel, 120 g) with gradient elution: cyclohexane / EtOAc 0-30% to provide 1-(3-bromo-5-fluorophenyl)-2-nitroethan-1-ol 65 as a white solid. LCMS method F: [MH]' = 262.2, tR= 2.28 min 142 Preparation of intermediate 66:2-amino-1-(3-bromo-5-fluorophenyl)ethan-1-ol OH Br óoo 1 To a solution of 1-(3-bromo-5-fluorophenyl)-2-nitroethan-1-ol 65 (6.2 g, 15.2 mmol) in EtOH (100 mL) Raney® Nickel (2 g) and 0.5 mL of acetic acid were added. Dihydrogen was bubbled through the mixture for 5 min. The reaction mixture was stirred for 16 h under a dihydrogen atmosphere. The reaction mixture was filtered over Celite, and the solvent from the filtrate was removed under reduced pressure to provide 2-amino-1-(3-bromo-5-fluorophenyl)ethan-1-ol 66, which was used directly in the next step without further purification. LCMS method F: [M+H]+= 236, tR= 1.12 min Preparation of intermediate 67:5-(3-bromo-5-fluorophenyl)-1,3-oxazolidin-2-one Br To a solution of 2-amino-1-(3-bromo-5-fluorophenyl)ethan-1-ol (1.75 g, 1.75 mmol) in THF (100 mL) were added 1,T-carbonylimidazole (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. A saturated aqueous solution of NH4Cl (100 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (2 x 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 column chromatography on a Biotage eluting with cyclohexane / ethyl acetate (3-1): 100 / 0 to 70 / 30 to provide a white solid as 5-(3-bromo-5-fluorophenyl)-1,3-oxazolidin-2-one 67. LCMS method F: [M+H]+= 262.0, tR= 2.07 min Preparation of intermediate 68:5-f3-bromo-5-fluorophenyl)-3-{3-{tert-butyldimethylsII) oxy]propyl}1,3-oxazolidin-2-one Br 143To a stirred solution of 5-(3-bromo-5-fluorophenyl)-1,3-oxazolidin-2-one (1.6 g, 6.1 mmol) in THF (10 mL) sodium hydride (0.366 g, 9.1 mmol) was added at 0°C. The solution was stirred at 0°C for 10 min. Then, a solution of (3-bromopropoxy)(tert-butyl)dimethylsylane (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 inactivated with a saturated ammonium chloride solution (25 mL). The resulting mixture was extracted with EtOAc (4 x 100 mL). The combined organic layers were washed with saturated brine (2 x 50 mL). The organic layer was dried on sodium sulfate, filtered, and the solvent was removed under reduced pressure to yield a brown / orange oil. This residue was purified by flash silica gel chromatography (Macherey Nagel, 24 g) with gradient elution: 0-50% cyclohexane / EtOAc to provide 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, tR= 3.42 min Preparation of intermediate 69:5-(3-bromo-5-fluorophenyl)-3-(3-hydroxypropyl)-1,3-oxazolidin-2-one Br WlAia / ZVZZIVl ÓOO I To a solution of 5-(3-bromo-5-fluorophenyl)-3-{3-[(tert-butylmethylsilyl)oxy]propyl}-1,3-oxazolidin-2-one (0.8 g, 1.85 mmol postulated) in tetrahydrofuran (50 mL), 1.0 M tetra-nbutylammonium fluoride in THF (1.85 mL, 1.85 mmol) was added in parts 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 x 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 BIOTAGE silica) (cyclohexane-ethyl acetate, 100 / 0 to 50 / 50) yielding 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, tR= 2.02 min Preparation of intermediate 70: 3-[5-(3-bromo-5-fluorophenyl)-2-oxo-1,3-oxazolidin-3-yl]propyl methanesulfonate Br 144 To a solution of 5-(3-bromo-5-fluorophenyl)-3-(3-hydroxypropyl)-1,3-oxazolidin-2-one (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 hours. The reaction mixture was washed with a saturated solution of ammonium chloride, with a saturated solution of sodium bicarbonate and brine, filtered and the solvent was removed under reduced pressure to provide 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, tR= 2.36 min Preparation of the intermediate 71:5-(3-bromo-5-fluorophenyl]-3-(3-([1-(oxan-2-yl)-1H-indazol-5U]oxy}propU)-1.3-oxazoUdin-2-one MA / a / ZUZZ / UI ÓOO I To a solution of 3-[5-(3-bromo-5-fluorophenyl)-2-oxo-1,3-oxazolidin-3-yl]propyl methanesulfonate (0.618 g, 1.57 mmol) in A / ,A / -dimethylformamide (100 mL), cesium carbonate (1.02 g, 3.14 mmol) and 1-(oxan-2-yl)-1H-indazol-5-ol (0.343 g, 1.57 mmol) were added. The reaction was stirred at 80°C for 16 hours. The mixture was concentrated under reduced pressure. Water (200 mL) was added, and the resulting mixture was extracted with EtOAc (4 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL). The organic layers were dried on sodium sulfate, filtered, and concentrated under reduced pressure to yield a brown / orange oil. This residue was purified by flash silica gel chromatography (Macherey Nagel, 120 g) with gradient elution: cyclohexane / EtOAc 0-70% to provide 5-(3-bromo-5-fluorophenyl)3-(3-{[1-(oxan-2-yl)-1H-andazol-5-yl]oxi}propyl)-1,3-oxazolidin-2-one 71 as a white solid. LCMS method F: [M+H]+= 520.0, tR= 2.91 min 145 Preparation of intermediate 72:4-fluoro-19-(oxan-2-yl)-8,14-dioxa-10,19,20triazapentacyclo[13.5.2.12'6.17W.018'21]tetracose-1(20),2(24),3,5,15(22),16,18(21)-heptaen-9-one Potassium acetate reagent (113 mg, 1.156 mmol, 2 eq) was added to a solution of 5-(3-bromo-5-fluorophenyl)-3-(3-{[1-(oxan-2-11)-1H-indazol-5-11]oxy}propyl)-1,3-oxazolidin-2-one (50 mg, 0.0963 mmol) in 15 mL of toluene at room temperature. The mixture was degassed by bubbling nitrogen through it for 15 minutes. Palladium acetate (25 mg, 0.115 mmol, 0.2 eq) and CataCxium (41 mg, 0.115 mmol, 0.2 eq) were added. The mixture was heated to 140°C for 2 hours under microwave conditions. The reaction mixture was filtered over Celite and 20 mL of water was added to the filtrate. The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to an orange oil. Purification by column chromatography on a Biotage (cyclohexane / ethyl acetate 0–100%) yielded 4-fluoro-19-(oxan-2-yl)8,14-dioxa-10,19,20-triazapentacyclo[13.5.2.126.17W.01821]tetracose-1 (20),2(24),3,5,15(22), 16,18(21 )-heptaen9-one pure 72 as a whitish solid. LCMS method F: [M+H]+= 438.1, tR= 2.77 min Preparation of example 60: 4-fluoro-8,14-dioxa-10,19,20triazapentacyclo[13.5.2.12'6.17'1°.018'21]tetracose-1(20),2(24),3,5,15(22),16,18(21 )-heptaen-9-one Trifluoroacetic acid (0.2 mL, 2.58 mmol) was added to a solution of 4-fluoro-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazapentacyclo[13,5,2,12,6,17,1,0,18,21]tetracose-1(20),2(24),3,5,15(22),16,18(21)-heptaen-9-one (0.113 g; 0.258 mmol) in DCM (20 mL) at room temperature. The mixture was The mixture was stirred at room temperature for 24 h. The reaction was allowed to cool to room temperature, and toluene (50 mL) was added. The reaction mixture was concentrated under reduced pressure to yield an orange oil. Water (25 mL), DCM (25 mL), and a 25 wt% aqueous ammonia solution (1.5 mL) were added. After separation, the aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to an orange oil. Purification by column chromatography in a Biotage (DCM / MeOH 0-5%) yielded pure 4-fluoro-8,14-dioxa-10,19,20-triazapentacyclo[13.5.2.12'6.17'1°.018'21]tetracose1(20),2(24),3,5,15(22),16,18(21)-heptaen-9-one example 60 as a whitish solid. LCMS method F: [M+H]+= 354.1, tR= 2.22 min LCMS method G: [M+H]+= 354.2, tR= 2.22 min Ή NMR (400 MHz, Ó6-DMSO) δ 13.26–13.24 (1H, m), 8.22 (1H, s), 7.59 (1H, ddd, J = 1.5, 2.5, 9.9 Hz), 7.52 (1.H 7. d4, J = 2.1 Hz), 7.36 (1H, td, J = 1.8, 9.4 Hz), 7.02 (1H, dd, J = 2.3, 9.3 Hz), 5.69 (1H, dd, J = 2.8, 9.0 Hz), 4.47, H2, q =1 (1 =1 Hz), 4.17 (1H, t, J = 6.0 Hz), 4.023.96 (1H, m), 3.57-346 (1H, m), 3.08 (1H, dd, J = 4.6, 14.4 Hz), 2.36-2.1, m (1.8) 1.8 (1-m), Example 61: 4-(oxolan-3-yl)-8,14-dioxa-10,19,20-triazatetracycle[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaene-9-one ΜΛ / a / ZUZZ / U 1 ÓOO I Example 61 is prepared according to the synthesis route described in general Scheme A. Preparation of the intermediate 73:4-(2,5-dihydrofuran-3-yl)-19-(oxan-2-yl)-8,14-dioxa-10,19,20triazatetracycle[ 13.5.2.12'6.018'21]trico...

Claims

1. A compound of formula (I): characterized in that: ♦ R represents a hydrogen atom, a halogen atom, or an alkyl group, ♦ Z1, Z2, Z3 each independently represent a carbon or nitrogen atom, it being understood that the 6-membered ring containing Z1, Z2, and Z3 may have 0, 1, or 2 nitrogen atoms, ♦ -X1- is absent or represents -O-, -S-, or -N(R'a)-, wherein R'a represents a hydrogen atom or an alkyl group, ♦ -X2- represents an alkanedyl group optionally substituted with one or more identical or different substituents selected from halogen atoms, polyhalogenalkyl groups, alkoxy groups, hydroxy groups, amino groups, alkylamino groups, dialkylamino groups, and cyano groups, it being understood that the carbon atom in the alpha position of -N(Ra), and the carbon atom in the position alpha 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 halogen atoms, polyhalogenalkyl group, alkoxy group, hydroxy group, amino group, alkylamino group, dialkylamino group, cyano group, cycloalkyl group and heterocycloalkyl group, it being understood that the carbon atom in the alpha position of -O-, and the carbon atom in the alpha 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, it being understood that when Ra represents an alkyl group, a carbon atom of Ra can be bonded to a carbon atom of -X2-, or to a carbon atom of -X3- to form a cyclic residue containing 5 or 6 ring members, 401 ♦ A represents an aromatic or partially hydrogenated cyclic group of the formula (a): * A1—A2 / a\ A5 χΑ3 (a) XA4 / where X Α1,A4 each independently represents a carbon atom or a nitrogen atom, X A2, A3, A5 each independently represents a carbon atom, an oxygen atom, a sulfur atom or a nitrogen atom, it being understood that A1, A2, A3, A4 and A5 cannot simultaneously represent a heteroatom or an aromatic or partially hydrogenated cyclic group of the formula (b): MA / a / ZUZZ / UI ÓOO IAAA A'2 (b) \---A'3 where A1, A'2, A'3, A'4 each independently represents a carbon atom or a nitrogen atom, it being understood that * means that the bond is attached to X3, the aromatic or partially hydrogenated cyclic group A thus defined being optionally substituted with one or more identical or different substituents selected from halogen atoms, alkyl group, alkoxy group, hydroxy group, oxo group, alkoxyalkyl group, group alkoxy, polyhalogen alkyl group, polyhalogen alkoxy group, heterocycloalkyl group,heterocycloalkylalkyl group, (alkoxyalkyl)(alkyl)amino group, amino group, alkylamino group, dialkylamino group, cycloalkyl group, (heterocycloalkyl)(alkyl)amino group, dialkylaminoalkyl group, heterocycloalkylalkoxy group, cyano group, and cyanoalkyl group, wherein the heterocycloalkyl and cycloalkyl groups thus defined may be optionally substituted with one or more substituents selected from alkyl groups, halogen atoms, polyhalogenalkyl groups, polyhalogenalkoxy groups, alkoxy groups, alkoxy groups, alkoxyalkyl groups, hydroxy groups, cyano groups, and oxo groups, their enantiomers, diastereomers, tautomers, racemics, hydrates, solvates, N-oxides, isotopes, deuterated derivatives, and addition salts thereof with a pharmaceutically acceptable acid or base.

2. The compound according to claim 1, further characterized in that R represents a hydrogen atom. 402 3. The compound according to claim 1, further characterized in that R represents a halogen atom.

4. The compound according to any of claims 1 to 3, further characterized in that Z1, Z2 and Z3 simultaneously represent a carbon atom.

5. The compound according to any one of claims 1 to 3, further characterized in that one of Z1 or Z2 represents a nitrogen atom and Z3 represents a carbon atom.

6. The compound according to any of claims 1 to 5, further characterized in that -X1- represents -O-.

7. The compound according to any of claims 1 to 6, further characterized in that -X2- represents a linear or branched alkanedyl group having 2, 3, 4 or 5 carbon atoms.

8. The compound according to claim 7, further characterized in that -X2 represents -(CH2)3-, -CH(CH3)-(CH2)2-, -CH2-CHF-CH2-, -CH2-CF2-CH2-, or -(CH2)2-CH(CH3)-.

9. The compound according to any of claims 1 to 8, further characterized in that Ra is a hydrogen atom.

10. The compound according to any of claims 1 to 9, further characterized in that -X3- represents a linear or branched alkanedyl group having 1, 2, 3, 4 or 5 carbon atoms.

11. The compound according to claim 10, further characterized in that -X3 represents -(CH2)2-, -CH2- or -CH(CH3)-.

12. The compound according to any of claims 1 to 11, further characterized in that A represents a group of formula (b): MA / a / ZUZZ / UI ÓOO I A4 A A'2 (b) \---A'3 wherein AΊ, A'2, A'3, A'4 and * are as defined in claim 1.

13. The compound according to claim 12, further characterized in that A represents 403, said defined A groups not being substituted or optionally substituted.

14. The compound according to claim 12, further characterized in that A represents a phenyl group.

15. The compound according to claim 12, further characterized in that A represents a pyridinyl group.

16. The compound according to claim 12, further characterized in that A represents a pyrazinyl group.

17. The compound according to claims 1 to 11, further characterized in that A represents a group of formula (a): MA / a / ZUZZ / UI ÓOO I wherein A1, A2, A3, A4, A5 and * are as defined in claim 1.

18. The compound according to claim 17, further characterized in that A represents said defined A groups not being substituted or optionally substituted.

19. The compound according to claim 17, further characterized in that A represents a triazolyl group.

20. The compound according to claim 17, further characterized in that A represents a pyrazolyl group.

21. The compound according to claims 12 to 20, further characterized in that A is not substituted.

22. The compound according to claims 12 to 20, further characterized in that A is substituted with one or more groups selected from halogen atoms, cyano group, cyanoalkyl group, oxo group, alkoxy group, alkyl group, cycloalkyl group, and heterocycloalkyl group.

23. The compound according to claim 1, which is a compound of the formula (a): iviA / a / zuzz / ui ooo i further characterized in that X1, X2, X3, Ra and A are as defined in claim 1.

24. The compound according to claim 23, which is a compound of formula (lb): (1-b) further characterized in that X2, X3, Ra and A are as defined in claim 1.

25. The compound according to claim 23, which is a compound of the formula (lc) or (l-o): 405 Characterized further in that X1, X2, X3, Ra, AΊ, A'2 and A'4 are as defined in claim 1.

26. The compound according to claim 23 or 25, which is a compound of the formula (ld)o(l-d'): ML / a / ZUZZ / U 1 ÓOO I Characterized further in that X2, X3, Ra, AΊ, A'2 and A'4 are as defined for formula (I).

27. The compound according to claim 23, which is a compound of formula (I): further characterized in that X1, X2, X3, Ra, A1, A2 and A5 are as defined for formula (I). 406 28. The compound according to claim 23 or 27, which is a compound of formula (lf): ινΐΛ / a / zuzz / ui ooo i further characterized in that X2, X3, Ra, A1, A2 and A5 are as defined for formula (I).

29. The compound according to claim 23, 25 or 27, further characterized in that the chain -X1-X2-N(Ra)-C(O)O-X3- represents -O-(CH2)3-NHC(O)O-CH2-, -O-CH(CH3)-(CH2)2-NHC(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)-.

30. The compound conforming to claim 1, further characterized because it is: 8,14-dioxa-4,10,19,20-tetraazatetraciclo[13.5.2.126.018'21]tricosa-1 (20),2,4,6(23), 15,17,21heptaen-9-one; 10-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.12'6.018'21]trlcosa1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.01821]tricosa-1 (20),2,4,6(23), 15,17,21 heptaen-9-one; 8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.126.01821]tricosa-1 (20),2,4,6(23), 15,17,21 heptaen-9-one; 8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.01821]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[13.5.2.12'6.018'21]tricosa1(20),2,4,6(23),15,17,21-heptaen-9-one; 8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.12'6.018'21]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-methoxy-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.126.018'21]tricose-1(20),2,4,6(23),15,17,21heptaene-9-one; 4-bromo-8,14-d¡oxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.018'21]tr¡cosa-1(20),2,4,6(23),15,17,21heptaene-9-one; 407 5-fluoro-8,14-dioxa-10J9,20-triazatetrac¡chlo[13.5.2.126O1821]tricose-1(20),2,4,6(23),15,17,21heptaen-9-one; 5-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose-1 (20),2,4,6(23), 15,17,21heptaene-9-one; 4-(p¡rrol¡d¡n-1-¡l)-8,14-dioxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[4-(propan-2-¡l)p¡peraz¡n-1-¡l]-8,14-d¡oxa-10,19,20-tr¡azatetrac¡c lo[13.5.2.12'6.018'21]tricosa1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-{2-oxa-6-azaesp¡ro[3.4]octane-6-yl}-8,14-d¡oxa-10,19,20-tr¡azatetrac¡clo[13.5.2.12'6.018'21]tr¡cosa1 (20) ,2,2,2,15(1,15) -heptane-9-one; 4-[4-(oxetan-3-yl)piperaz¡n-1-¡l]-8,14-d¡oxa-10,19,20-triazetetracyclo[13.5.2.12'6.01821]tricose1(20),2,4,6(23),15,17,2-19-hepta; 4-(morphol¡n-4-¡l)-8,14-dioxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaene-9-one; 4-[(2R,6S)-2.6-dimethylmorpholin-4-yl]-8,14-d¡oxa-10,19,20-triazatetracyclo[13.5.2.12i6.018'21]tricose1 (20) ,2,4,6(23), 15,17, 219-hepone; 4-methyl-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tr¡cosa-1 (20),2,4,6(23), 15,17,21heptaene-9-one; 5-methoxy-8,14-d¡oxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.126.018'21]tr¡cosa-1(20),2,4,6(23),15,17,21heptaen-9-one; 4-(4,4-difluoiOp¡perid¡n-1-¡l)-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,2-heptaene; 4-(3,3-d¡fluoropyrrol¡d¡n-1-¡l)-8,14-d¡oxa-10,19,20-triazatetrac¡chlo[13.5.2.12l3.018'21]tncosa1(20),2,4,6(23),15,2-19-hepta; 7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.01821]tricose-1 (20),2,4,6(23), 15,17,21heptaene-9-one; 4-[4-(2-methox¡et¡l)piper¡d¡n-1-¡l]-8,14-d¡oxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(2,5,2,19-17-hepta; 9,14-dioxa-11,19,20-triazatetracyclo[13.5.2.12'6.01821]tricose-1 (20),2,4,6(23), 15,17,21 -heptaene-10one; 4-[(3R)-3-hydroxyp¡rrolidin-1-yl]-8,14-d¡oxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,17-heptaene; 4-[(2-methoxyethyl )(methyl )amino]-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptane-9-one; 4-chloro-8,14-dioxa-10,19,20-triazatetrac¡chlo[13.5.2.12'6.01821]tricose-1(20),2,4,6(23),15,17,21heptaen-9-one; 4-fluoiO-5-methyl-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one; 4,5-difluoro-8,14-d¡oxa-10,19,20-triazatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa-1(20),2,4,6(23),15,17,21 ιν / ΐΛ / Λ / Λ / 080 ooo i heptane-9-one; 5-bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12-6.018'21]tricose-1 (20),2,4,6(23), 15,17,21heptaene-9-one; 4-(4-met¡lp¡peraz¡n-1-yl)-8,14-dioxa-10,19,20-triazatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(3-methox¡azet¡d¡n-1-¡l)-8,14-d¡oxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),17,2-9-hepta; 1 -{9-oxo-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose-1 (20),2,4,6(23), 15,17,21heptaene-4-¡l}piperna¡d¡4-tricarbon; 4-[4-(p¡rrol¡n-1-¡l)p¡per¡d¡n-1-¡l]-8,14-d¡oxa-10,19,20-tr¡azatetrac iclo[13.5.2.12'6.018'21]tricosa1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(azet¡d¡n-1-¡l)-8,14-dioxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(piperidin-1-yl)-8,14-dioxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaene-9-one; 4-(2,5-dihydrofuran-3-¡l)-8,14-d¡oxa-10,19,20-triazatetracyclo[13.5.2.126.018'21]tricose1 (20) ,2,4,6(23), 15,17,21 -heptaen-9-one; 4-[4-(morphol¡n-4-yl)p¡peridin-1-¡l]-8,14-dioxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-(1 -methyl-1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.12'6.018'21]tricose-1 (20),2,4,6(23),15,17,2-heptaone; 4-[(2S,5S)-2.5-dimethylmorpholin-4-yl]-8,14-d¡oxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1 (20) ,2,4,6(23), 15,17,219-hepone; 4-[(morphol¡n-4-¡l)met¡l]-8,14-d¡oxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,1-9-hepta; 4-[(p¡rrol¡n-1-¡l)met¡l]-8,14-d¡oxa-10,19,20-tr¡azatetracyclo[13.5.2.126.018'21]tr¡cosa1(20),2,4,6(23,2,17-17-hep; 4-[(pyrrOlidin-1-yl)met¡l]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-[(4-met¡lp¡peraz¡n-1-yl)met¡l]-8,14-dioxa-10,19,20-tr¡azatetetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23,2,19-17-hepta; 5-(morphol¡n-4-¡l)-8,14-dioxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaene-9-one; 4-[4-(2-methoxyet¡l)p¡peraz¡n-1-yl]-8,14-dioxa-10,19,20-triazatetrac¡chlo[13.5.2.12'6.018'21]tricosa1(20),2,4,6(23),15,21,1-9-hep; 4-(d¡et¡lam¡no)-8,14-d¡oxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,21-heptane-one; 4-cycloprop¡l-8,14-d¡oxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.018'21]tr¡cosa-1(20),2,4,6(23),15,17,21heptane-9-one; ΜΛ / a / ZUZZ / U 1 ÓOO I 409 5-(4-methylpiperazin-1-yl)-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one; 13-met¡l-8,14-d¡oxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa-1(20),2,4,6(23),15,17,21heptane-9-one; 8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.12'5.018'21]tricose1 (20),2(23),3,15(22), 16,18(21 )-hexaen-9-one; 4-[met¡l(oxetane-3-l)am¡no]-8,14-dioxa-10,19,20-triazatetrac¡chlo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaene-9-one; 4-[(d¡met¡lam¡no)methyl]-8,14-d¡oxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.018'21]tr¡cosa1 (20) ,2,4,6(23), 15,17, 21 --hepta; 4,10-d¡met¡l-8,14-d¡oxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21heptaen-9-one; 4-(propan-2-¡loxi)-8,14-d¡oxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1 (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-10,19,20triazatetracyclo[13.5.2.12'6.018'21]tricose-1 (20),2,4,6(23,5,19-17-hepta; 4-(3-met¡lp¡per¡din-1-¡l)-8,14-d¡oxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.018'21]tricosa1(20),2,4,6(23),15,1,1,1-9-hep; 4-[(3C)-3-hydroxypyrrolidin-1 -yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.126.01821]tricose1(20),2,4,6(23),15,17,21-heptaene-9-one; 4-fluoro-8,14-dioxa-10,19,20-triazapentac¡chlo[13.5.2.12'6.17'10.018'21]tetracosa1(20),2(24),3,5,15(22),16,18(21 )-heptaen-9; 4-(oxolan-3-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one; (13S)-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-heptane-9-one; (13R)-13-methyl-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1(20),2(23),3,5,15(22), 16,18(21 )-heptane-9-one; 4-(1-meth¡l-1H-pyrazol-3-yl)-8,14-d¡oxa-10,19,20-triazatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa1 (20),2(23),3,5,15(22,18),(21) )-heptane-9-one; (7S)-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-heptane-9-one; 4-[2-(morpholin-4-¡l)ethoxy]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one; 4-(2-methoxyethyl)-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.126.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-heptane-9-one; (7R)-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricoseΜΛ / a / ZUZZ / U 1 ÓOO I 410 1 (20),2(23),3,5,15(2,218),(16) )-heptane-9-one; 5-cycloprop¡l-8,14-d¡oxa-10,19,20-triazatetrac¡chlo[13.5.2.12i6.018'21]tr¡cosa-1(20),2,4,6(23),15,17,21heptaene-9-one; 4-(2-methox¡ethox¡)-8,14-d¡oxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,21-heptaen-9-one; 4-fluoro-13-met¡l-8,14-d¡oxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one; 11-methyl-8,14-d¡oxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21heptaen-9-one; 4-(3-oxomorpholin-4-¡l)-8,14-d¡oxa-10,19,20-triazatetrac¡chlo[13.5.2.12'6.018'21]tricose1(20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one; 4-(2-oxop¡rrol¡d¡n-1-yl)-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tr¡cosa1 (20),2(23),3,5,15(22), 16-hep-one; 5-(2-oxopyrrolidin-1-¡l)-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12S.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-taen-9-hepone; 4-(2-methylpyrrolidin-1-yl)-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.126.01821]tr¡cosa1(20),2(23),3,5,15(22), 16,18(21 )-hepone; 2-{9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.126.018'21]tr¡cosa1(20),2(23),3,5,15(22), 16,18(21 )-heptaen-4-yl alcohol; (11 R)-11-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-heptane-9-one; (11S)-11-met¡l-8,14-d¡oxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.01821]tr¡cosa1(20),2(23),3,5,15(22),16,18(21 )-hepone; 4-ethynyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one; 4-(piperazin-1-yl)-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12 6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one; 4-(1,2,3,6-tetrah¡dropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetrac¡chlo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16(21)-hepone; 11-(methoxy¡methyl)-8,14-d¡oxa-10,19,20-triazatetrac¡chlo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-taen-9-hepone; 8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.12'5.018'21]tricose1 (20),2(23),3,15(22), 16,18(21 )-hexaen-9-one; 11 -methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.12'5.018'21]tricose1 (20),2(23),3,15(22), 16,18(21 )-hexaen-9-one; 12-meth¡l-8,14-dioxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa1(20),2(23),3,5,15(22), 16,18(21 )-heptane-9-one; 11-ethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one; ΜΛ / a / ZUZZ / U 1 ÓOO I 411 4-fluoro-5.7-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricosa1 (20),2(23,5),16,2(2), )-heptane-9-one; 4-fluoro-5-methoxy¡-7-met¡l-8,14-d¡oxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.018'21]tr¡cosa1(20),2(23),3,5,15(22), 16,18-(21-9); 5-fluoro-4,7-dimeth¡l-8,14-d¡oxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21)-hep-9; 8,14-d¡oxa-10,19,20-triazapentac¡chlo[13.5.2.12'6.1710.018'21]tetracosa1 (20),2(24),3,5,15(22), 16,18(21 )-heptaen-9-one; 13-methyl-8,14-d¡oxa-10,19,20,23-tetraazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2(23),3,5,15(22), 16,18(21 )-heptane-9one; 12-methyl-8,14-dioxa-4,5,10,19,20-pentaazetetracyclo[13.5.2.125Oi8'2i]tr¡COSa1 (20),2(23),3,15(22), 16,18(21 )-hexaen-9-one; 7-methyl-8,14-dioxa-4,5,10,19,20-pentaazetetracyclo[13.5.2.12'5.018'21]tricosa1 (20),2(23),3,15(22), 16,18(21 )-hexaen-9-one; 5-fluoro-4-methox¡-7-methyl-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tricose1(20),2(23),3,5,15(22),16,18(21 )-heptane-9-one; (7R,13R)-7,13-dimethyl-8,14-d¡oxa-10,19,20-tnazatetrac¡chlo[13.5.2.^^ 1 (20),2(23),3,5,15(22), 16,18(21 )-heptane-9-one; (13R)-13-methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.12'5.018'21]tricose1 (20),2(23),3,15,17,21 -hexaen-9-one; 8,15-dioxa-4,10,20,21-tetraazapentacyclo[14.5.2.12'6.110'13.019'22]pentacos1 (21 ),2(25),3,5,16(23), 17,19(22)-heptane-9-one; 8,14-dioxa-5,10,19,20-tetrazatetracyclo[13.5.2.12'5.018'21]tricose-1 (20),2(23),3,15(22),16,18(21 )hexaene-9; (13S)-4-fluoro-13-met¡l-8,14-d¡oxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tr¡cosa1 (20),2(23),3,5,15(22), 16,18(21)-hep; (13R)-4-fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.01821]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one; (13R)-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2(23),3,5,15(22), 16,18(21 )-heptane-9one; 6-cycloprop¡l-8,14-d¡oxa-4,5,10,19,20-pentaazatetrac¡chlo[13.5.2.12'5.018'21]tricose1 (20),2(23),3,15(22), 16,18(21 )-hexaene-9; 7-ethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose-1 (20),2,4,6(23), 15,17,21heptaene-9-one; (13R)-13-ethyl-8,14-dioxa-5,10,19,20,23-pentaazetetracyclo[13.5.2.12B.018'21]tricose1 (20) ,2,4,6(23), 15,17,21 -heptane-9-one; (7R,13R)-4-fluoro-7,13-d¡met¡l-8,14-d¡oxa-10,19,20-tr¡azatetracyclo[13.5.2.12'6.01821]tr¡cosa1(20),2,4,6(23),15,17-1-9-hep; 7-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.12'6.018'21]tr¡cosa-1(20),2,4,6(23),15,17,21 iviA / a / zuzz / ui óoo i 41-hepta-92; (7R)-4-fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1 (20) ,2,4,6(23), 15,17,21 -heptaen-9-one; (7S)-4-fluoro-7-met¡l-8,14-d¡oxa-10,19,20-tnazatetracyclo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,17,21-heptaene-9-one; 6-met¡l-8,14-dioxa-4,5,10,19,20-pentaazatetrac¡chlo[13.5.2.12'5.018'21]tr¡cosa1 (20),2(23),3,15,17,21 -hexaen-9-one; 7-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaene-9-one; 6-(propan-2-¡l)-8,14-d¡oxa-4,5,10,19,20-pentaazatetrac¡chlo[13.5.2.12'5.018'21]tricose1 (20),2(23),3,15(22), 16,18)-hexaenone; (13R)-7,13-dimet¡l-8,14-d¡oxa-4,5,10,19,20-pentaazatetrac¡chlo[13.5.2.12'5.018'21]tr¡cosa1 (20),2(23),3,15(22), 26-hexane(19); (13R)-13-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaene-9-one; (7R)-7-et¡l-8,14-dioxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.018'21]tricose-1(20),2,4,6(23),15,17,21heptaene-9-one; (7S)-7-et¡l-8,14-d¡oxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.01821]tricosa-1(20),2,4,6(23),15,17,21heptaene-9-ona; (13 R)-13-methyl-8,14-dioxa-5,10,19,20-tetraazatetracycle[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaene-9-one; 6-(oxan-4-¡l)-8,14-d¡oxa-4,5,10,19,20-pentaazatetracycle[13.5.2.12í>.018'21]tricose1 (20),2(23),3,15,17,21 -hexaene-9-one; 4-ethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracycle[13.5.2.12'5.018'21]tricose-^^ pentaen-9-one; (13R)-23-fluoro-13-met¡l-8,14-d¡oxa-10,19,20-tr¡azatetrac¡clo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,ona;17,9-9-8 9,14-dioxa-4,5,11,19,20-pentaazatetracycle[13.5.2.12'5.01821]tricose-1 (20),2(23),3, 15,17,21hexaene-10-one; 4-ethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracycle[13.5.2.125.01821 Jtricose-1 (20),2(23),3,15,17,21hexaene-9-one; 3,9,15-tr¡oxa-4,11,20,21-tetraazatetracycle[14.5.2.12'5.01922]tetracose-1(21),2(24),4,16,18,22hexaene-10-one; (13R)-16-fluoro-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracycle[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaene-9-one; (13R)-4-chloiO-13-methyl-8,14-dioxa-10,19,20,23-tetraazetetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa1(20),2(23),3,5,15(22),16,18(9)-taen; 8,14-dioxa-2,4,10,19,20-pentaazatetrac¡chlo[13.5.2.12'5.018'21]tr¡cosa1 (20),3,5(23), 15(22), 16,18(21 )-hexaen-9-one; ινΐΛ / a / zuzz / ui ooo i 413 (13R)-4-methoxy-13-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.12'6.01821]tricose1(20),2,4,6(23),15,17,21-heptane-9-one; (13R)-13-methyl-9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaene-5-carbonitrile; (13R)-13-methyl-4-(pyrrolidin-1-¡l)-8,14-dioxa-5,10,19,20,23pentaazetetracyclo[13.5.2.12'6.018'21]tr¡cosa-1(20),2,4,6(23),15,2-9-hepta; (7S, 13R)-7,13-dimethyl-8,14-dioxa-5,10,19,20,23-pentaazetetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptane-9-one; (7R,13R)-7,13-dimethyl-8,14-d¡oxa-5,10,19,20,23-pentaazatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa1 (20) ,2,4,6(23), 15,17,21 -heptaen-9-one; (13R)-16-fluoroO-13-met¡l-8,14-d¡oxa-10,19,20-tr¡azatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa1(20),2,4,6(23),15,1,17-hepta; (13 R)-13-methyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptane-9-one; 8,14-dioxa-4-thia-10,19,20,23-tetraazatetrac¡chlo[13.5.2.12i5.018'21]tricose-1(20),2,5(23),15,17,21hexaen-9-one; 8,14-d¡oxa-3-thia-10,19,20,23-tetraazatetracyclo[13.5.2.12'5.018'21]tr¡cosa-1(20),2(23),4,15,17,21hexaen-9-one; (7R,13R)-7,13-d¡methyl-8,14-dioxa-10,19,20,23-tetraazatetrac¡chlo[13.5.2.12'6.01821]tr¡cosa1(20),2,4,6(23),15,17,21-hepone-9; (13R)-4-[(3R)-3-methoxypyrrolidin-1-yl]-13-methyl-8,14-dioxa-5,10,19,20,23pentaa zatetracyclo[13.5.2.12'6.01821]tricose-1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-16-chloro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13,16-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13-methyl-8,14-dioxa-3,10,19,20,23-pentaazetetracyclo[13.5.2.126.018'21]tr¡cosa1(20),2,4,6(23),15,17,21-heptaen-9-one; 8-oxa-10,14,19,20-tetraazatetracyclo[13.5.2.12'6.018'21]tr¡cose1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one hydrochloride; 8-oxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose-1(20),2(23),3,5,15(22), 16,18(21 )-heptaen9-one; (13R)-5-methoxy-13-methyl-8,14-doxa-4,10,19,20-tetraazatetracyclo[13.5.2.12'6.018'21]trichose1(20),2,4,6(23),15,17,21-heptaen-9-one; (13R)-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.126.018'21]tricose1(20),2,6(23), 15,17,21-hexaen-5.9-dione; 4-methyl-8,14-dioxa-3,4,10,19,20-pentaazatetracyclo[13.5.2.12′5.018′21]tricose1(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[13.5.2.12'6.01821]tricosaινΐΛ / a / zuzz / ui ooo i 414 1 (20),2,4,6(23),15,17,21 -heptaen-9-one; 7,13-dioxa-4-tia-9,18,19,22-tetraazatetracyclo[12.5.2.12'5.0172°]docosa1 (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[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22), 16,18(21 )-hepone; 8,14-dioxa-23-thia-4,10,19,20-tetraazatetrac¡chlo[13.5.2.12'5.018'21]tr¡cosa-1(20),2A hexaen-9-one; (7C,13R)-7,13-d¡methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22),16,18(2)-hep; (13R)-13-methyl-9-oxo-8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.12'5.018'21]tricose1 (20),2(23),3,15(22), 16,18(21 )-hexaentrile-4; 12,12-difluoro-8,14-dioxa-10,19,20-triazetetracyclo[13.5.2.12'6.018'21]tr¡cosa1 (20),2(23),3,5,15(22),16,18(21 )-heptane-9-one; (13R)-17-fluoiO-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricose1 (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[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22),16,18(21)-hep-one; (7R,13R)-7,13-d¡methyl-8,14-d¡oxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22),16,2-91-hepone; (13S)-13-methyl-8,14-dioxa-4,10,19,20,23-pentaazetetracyclo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22),16,18(21 )-heptanone-9-9; (13R)-13-methyl-8,14-dioxa-10,19,20,22-tetraazatetracyclo[13.5.2.126.018'21]tricose1(20),2(23),3,5,15,17,21-heptaene-9-one; (12R)-4,12-dimethyl-7,13-d¡oxa-4,9,18,19,22-pentaazatetrac¡clo[12.5.2.12'5.01720]docosa1 (19),2,5(22), 14(21), 15,17)-hexa-8-one; (13R)-13-methyl-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.12'5.018'21]tricose1(20),2(23),3,15,17,21-hexaen-9-one; (13R)-13-methyl-8,14-dioxa-23-thia-4,10,19,20-tetraazatetracyclo[13.5.2.12'5.018'21]tricosa1(20),2,4,15,17,21-hexaen-9-one; (13R)-4,13-dimethyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.12'5.018'21]tricose1 (20),2,5(23),15(22), 16,18(21 )-hexaene; (13R)-13-met¡l-8,14-dioxa-10,16,19,20-tetraazatetrac¡clo[13.5.2.12'6.018'21]tricose1 (20),2(23),3,5,15(22),16,18(21 )-taen-9-hepone; 14-methyl-8-oxa-10,14,19,20-tetraazatetracyclo[13.5.2.12'6.018'21]tr¡cosa-1(20),2(23),3,5,15,17,21heptaen-9-one; (13R)-13-methyl-8,14-dioxa-4,10,19,20,22-pentaazatetracyclo[13.5.2.12'6.018'21]tricose1(20),2(23),3,5,15,17,21-heptane-9-one; (13R)-13-met¡l-8,14-dioxa-10,17,19,20-tetraazatetrac¡chlo[13.5.2.12'6.018'21]tr¡cosa1 (20),2(23),3,5,15(22),16,18(21)-hep-9-taen; ινΐΛ / a / zuzz / ui ooo i 415 8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.12 5.01821]trÍcosa1 (20),2(23),3,15(22,18),(19)-hexane; 12,12-difluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.12'5.018'21]tricosa1 (20),2(23),3,15(22), 16,18(21 )-hexaen-9-one); (12R)-12-fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricosa1 (20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one; (12S)-12-fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.12'6.018'21]tricosa1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one; 12,12-difluoro-8,14-d¡oxa-4,10,19,20,23-pentaazatetrac¡clo[13.5.2.12'6.018'21]tr¡cosa1(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[13.5.2.126.018'2i]triCOSa1 (20),2(23),3,5,15,17,21-heptaen-9-one; (12R)-12-fluoro-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.12'6.018'21]tricosa1 (20),2(23),3,5,15,17,21 -heptaen-9-one; (12S)-12-fluoiO-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.12'5.018'21]tricosa1 (20),2(23),3,15,17,21 -hexaen-9-one; (12R)-12-fluoiO-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.12'5.018'21]tr¡cosa1 (20),2(23),3,15,17,21 -hexaen-9-one; 8',14'-dioxa-10,,19',20'-triazasp¡ro[c¡cloprOpane-1.13'-tetracyclo[13.5.2.12'6.018'21]tr¡cosan]1 '(20'),2'(23'),3',5', 15'(22'), 16',18'(21 ')-heptaen-9'-one.

31. A pharmaceutical composition characterized in that it comprises a compound of formula (I) according to any 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. The pharmaceutical composition according to claim 31 for use as an inhibitor of LRRK2 kinase activity.

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

34. The pharmaceutical composition according to claim 33, further characterized in that 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 granulosa disease, 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 chromosome 17-linked parkinsonism (FTDP-17), withdrawal / relapse symptoms associated with drug addiction, L-dopa-induced dyskinesia, ischemic stroke, traumatic brain injury, spinal cord injury, and multiple sclerosis. MA / a / ZUZZ / UI ÓOO I 416 35. The pharmaceutical composition according to claim 34 for use in the treatment of Parkinson's disease or Alzheimer's disease.

36. The pharmaceutical composition according to claim 33, further characterized in that the endosomal-lysosomal disorder is selected from Niemann-Pick disease Type A, B or C, Gaucher disease, Krabbe disease, Fabry disease and disorders with mitochondrial deficiencies.

37. The pharmaceutical composition according to claim 33, further characterized in that the inflammatory disease is selected from vasculitis, pulmonary diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, inflammatory myopathies, ankylosing spondylitis.

38. The pharmaceutical composition according to claim 33, further characterized in that 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 mellitus, obesity, Evans syndrome, bullous skin disorders, Sjogren's syndrome, Devicy's disease, leprosy.

39. The pharmaceutical composition according to claim 33, further characterized in that the cancer is selected from thyroid cancer, kidney cancer, breast cancer, hormone-related cancer, adeno-squamous lung cancer, non-small cell lung cancer, colon cancer, prostate cancers, skin cancers, leukemias, and lymphomas.

40. The pharmaceutical composition according to claim 33, further characterized in that the cardiovascular disease is stroke.

41. The pharmaceutical composition according to claim 33, further characterized in that the bacterial or viral infections are selected from leprosy, tuberculosis, SARS-CoV, MERS-CoV and SARS-CoV-2, HIV, West Nile virus and chikungunya virus.

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