OA21105A

OA21105A - New macrocyclic LRRK2 kinase inhibitors.

Info

Publication number: OA21105A
Application number: OA1202200455
Authority: OA
Inventors: Arnaud Le Tiran; Petra Marcella BLOM; Christopher Gaétan HOUSSEMAN; Alain Daugan; Audrey DUMOULIN; Maxime LAUGEOIS; Alexis Denis; Nicolas Faucher; Luliana Botez; Kenneth Christensen; Yann Lamotte
Original assignee: Les Laboratoires Servier; Oncodesign Precision Medicine (OPM)
Priority date: 2020-05-06
Filing date: 2021-05-05
Publication date: 2023-11-13

Abstract

Compounds of formula (I): wherein R, XI, X2, X3, Zl, Z2, Z3, A and Ra are as defined in the description Medicaments.

Description

NEW MACROCYCLIC LRRK2 KINASE INHIBITORS

Field of the invention

The present invention relates to novel macrocyclic compounds and compositions containing said compounds acting as kinase inhibitors, în particular as inhibitors of LRRK2 (Leucine-Rich Repeat Kinase 2). Moreover, the present invention provides processes for the préparation of the disclosed compounds, pharmaceutical compositions containing them, as well as methods of using them, for instance as a medicine or diagnostic agent, în particular for the treatment and/or diagnosis of diseases impacted or moduiated by LRRK2 kinase activity such as neurological disorders including Parkinson’s disease and Alzheimer’s disease, but also cardîac diseases or inilammatory 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. Parkinson’s disease affects approximately 1% of the population above 65 years and is characterized by the four classical core motor complications: resting tremor, bradykinesia, postural instability and muscular rigidity. Patients with Parkinson’s disease are also impacted by a host of non-motor symptoms such as constipation, hyposmia, orthostatic hypotension, sleep disturbances including REM sleep behavior disorder, dementia, vîsual disturbances, dépréssion, anxiety, hallucinations and mood swings.

Standard of care in Parkinson’s disease is symptomatîc relief of motor complications using dopamine replacement therapy such as the dopamine precursor L-dopa, dopamine agonists or compounds that impact the half-life of dopamine such as MAO-B inhibitors. As of today, there is no approved therapy to prevent, cure or delay the progression of Parkinson’s disease.

The pathological hallinarks of Parkinson’s disease are the loss of dopaminergic neurons in the substantia nigra pars compacta as well as postmortem evidence of protein inclusions, also known as Lewy bodies and Lewy neurites. In postmortem tissue from Parkinson’s disease patients Lewy bodies and neurites are seen throughout the central nervous System and in peripheral tissues as well. A major component of the inclusions is the aggregated and misfolded α-synuclein protein phosphorylated at a serine at amino acid position 129 (Nature 388, 839840, 1997; Nat Cell Biol 4, 160—64, 2002). Lewy bodies and neurites also contain proteins implicated in other neurodegenerative diseases such as the hyperphosphorylated tau protein which is a pathological hallmark of tauopathies such as Alzheimer’s disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) (Biochem Soc Trans 26(3), 463-71, 1998; Am J Hum Genet 64(2), 414-21, 1999; J Neuropathol Exp Neurol 62(4), 389-97, 2003). The pathological process in Parkinson’s dîsease is not restrîcted tothe loss of dopaminergic neurons in the basal ganglîa system. Distinct neuronal populations in other brain régions such as the neocortex, sleep nuclei or the raphe nucléus as well as peripheral organs and tissues such as the heart and the gastro-intestinal system are also impacted by degenerative processes in Parkinson’s disease patients.

Leucine-rich repeat kinase 2 (LRRK2) is a 2527 amino acid protein with a molecular weight of 286 kDa that is encoded by the LRRK2 gene. It consists of the following functional and structural proteins domains: armadillo (ARM), ankyrin (ANK), leucine rich repeat (LRR), Ras of complex domain (Roc), c-terminal of Roc (COR), map kinase (MAPK) and tryptophanaspartate repeat domain (WD40). LRRK2 exists primarily as a dimeric protein either associated with membrane structures or cytoplasmîc localized. The armadillo, ankyrin, LRR and WD40 protein-protein interaction domains enabies LRRK2 to interact with a host of different protein partners to impact its own as well as its partner proteins subcellular localization. The central enzymatic core of the LRRK2 protein containing the Roc-COR and the MAPK domain hâve distinct GTPase and ATPase enzymatic activities enabling LRRK2 to phosphorylate and control the function of intracellular substrates. LRRK2 impacts, via its enzymatic activity and substrate interactions, various subcellular processes and biological mechanisms important for trafficking of intracellular vesicular structures and organelles such as lysosomes, endosomes, autophagosomes, the Golgi and mitochondria. Structural work as well as modelling highlights how naturally occurrîng missense variation in functional and structural domains of LRRK2 impacts enzymatic activity (bioRxiv 2020.01.06.895367). In the inactive (open) LRRK2 conformation there are major interactions between the enzymatic GTPase (Roc-COR) and ATPase (MAPK) domains. In addition, the ultimate C-terminaî proceeding the WD40 domain binds along the entire kinase (MAPK) domain. In the active (closed) LRRK2 conformation the LRR domain positions the autophosphorylation site Serl292 in proximity to the kinase active site. Phosphorylation of LRRK2 at a cluster of serines immediately preceding the LRR domain enabies the LRR domain of LRRK2 to bind to 14-3-3 proteins. Among those phosphorylation sites are serines (Ser) at the following amino acid positions: Ser910, Ser935, Ser955 and Ser973. Pathogenic LRRK2 mutations originating in the GTPase domain has diminished phosphorylation at these sites and therefore reduced 14-3-3 bindîng leading to încreased microtubule network recruitment. Ail ATP-compétitive LRRK2 inhibitors induce déphosphorylation at the Ser9i0, Ser935, Ser955 and Ser973 sites making these sites useful as surrogate target engagement markers (Biochem J 430(3), 405-13, 2010; J Neurochem 120(1),

37-45, 2012). The bona fide LRRK2 substrates consists of a subset of small Rab GTPases including RablO and Rab29. The Golgi-resident protein Rab29 also known as Rab7Ll is a Parkinson’s disease susceptibility gene located at the PARKI6 locus (Nat Genet 41(12), 130812, 2009).

Rare protein-encoding 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 rendering the p.G2019S variant more active than the wild type LRRK2 protein (Lancet 365(9457), 412-5, 2005). This results in ïncreased autophosphorylation at the serine at amino acid position 1292 (Sci Transi Med, 4(164), 164ral61, 2012). The estïmated worldwide prevalence of the p.G2019S mutation in patients with PD is 1-2%; whereas , in Ashkenazi Jewish and North African Arab-Berber populations the p.G2019S prevalence in PD patients is up to 30% and 40%, respectively (Lancet Neurol 7, 583-90, 2008; N Engl J Med 354(4), 4245, 2006; Lancet Neurol 7, 591-4, 2008). The clinical manifestation of Parkinson’s disease in patients carrying the p.G2019S mutation is indistinguishable from patients with the sporadic form of Parkinson’s disease (Ann Neurol 57(5), 762-5, 2005). Besides p.G2019S seven additional rare LRRK2 exonic variants having non-synonymous amino acid substitutions in the central enzymatic core (p.N1437H; p.R1441C/G/H; p.YI699C; p.S1761R; p.I2020T) 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.G2019S the clinical représentations are indistinguishable from idiopathic PD (Neurology 70, 1456-60, 2008). LRRK2 missense variants exhibit ïncreased Ser 1292 phosphorylation, ïncreased trans-Golgi recruitment by Rab29 and ïncreased phosphorylation of RablO at amino acïd position 73 (Rabl0-Thr73) that can be reversed by LRRK2 inhibition (Sci Transi Med 4(164), 164raI61, 2012; EMBO J 37(1), 1-18, 2018; Proc Natl Acad Sci USA 111, 2626-31, 2014). Common protein-coding variants in the LRRK2 gene are also associated with risk of Parkinson’s disease. Variants such as p.A419V, p.M1646T, p.R1628P and p.G2385R increase the risk of Parkinson’s disease and hâve ïncreased kinase activity (bioRxiv 447946, 2018) (Proc Natl Acad Sci USA 116(5), 1579-1584, 2019) whereas the p.N551K variant is associated with reduced risk of Parkinson’s disease (Lancet Neurol 10(10), 898-908, 2011) and hâve reduced kinase activity (bioRxiv 447946, 2018). Evidence that LRRK2 also plays a rôle in sporadic Parkinson’s disease cornes from both genetic studies as well as postmortem analyses of PD brains. A single nucléotide polymorphism (SNP) at the LRRK2 genetic locus is genome-wide associated with risk of Parkinson’s disease (Nat Genet 46(9), 989-93, 2014). This particular SNP variant is associated with increased LRRK2 expression (Sci Transi Med 9 (421), 2017) which is in agreement with the increased LRRK2 kinase activity observed in surviving dopamine neurons from postmortem brains of sporadic PD patients (Sci Transi Med 10 (451), 2018).

Thus, inhîbîtors of LRR.K2 kinase activity can be used as thérapies for both sporadic PD patients as well as for PD patients with LRRK2 mutations or Rab29/Rab7Ll polymorphisms.

Parkinson’s disease risk loci containing several genes encoding proteins involved in endosomal-lysosomal processes such as GBA, SCARB2, GALC, VPS35, LAMP1, VPS13C, VPS35, TMEM175, ATP6V0A1 and CTSB hâve been identified by Genome Wide Association Study (GWAS) and linkage studies. LRRK2 also plays a key rôle in the endosomal-lysosomal System and in the processes linked to endosomal function such as autophagy and mitophagy. LRRK2 interacts with the vacuolar H+-ATPase a subunit to regulate lysosomal pH and endosomal-lysosomal dysfunction induced by rotenone, a toxin known to be associated with increased risk of Parkinson’s disease, can be alleviated by LRRK2 inhibition (Newobiol Dis 134, 104626, 2020). Dîsease-causing LRRK2 mutations induce lysosomal stress by enlarging lysosomes (Hum Mol Genet 24(21), 6013-28, 2015). Lîkewise, an aspartate to asparagine missense mutation in the retromer complex protein VPS35 at amino acid position 620 (VPS35D620N) causes late onset autosomal dominant familial Parkinson’s disease. In the disease State the VPS35-D620N missense mutation disrupts trafficking of cathepsin D, the protease responsible for dégradation of α-synuclein (Traffic 15(2), 230-44, 2014) and activâtes LRRK2 which leads to increased autophosphorylation atthe LRRK2-Serl292 site and increased RablOThr73 phosphorylation (Biochem J 475(11), 1861-1883, 2018). In the lysosomes LRRK2 interacts with GBA that is causally linked with the lysosomal storage disorder Gaucher’s disease and a risk gene for Parkinson’s disease. LRRK2 missense mutations reduce GBA activity that can be counteracted by LRRK2 inhibition (Nat Commun 10(1), 5570, 2019). Reversely, GBA disease-relevant déficits 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 în the mitochondrial kinase PINK1 and the E3 ligase PARKIN both cause autosomal récessive early onset Parkinson’s disease that is associated with mitochondrial dysfunction (Science 304(5674), 1158-60, 2004; Nature 392(6676), 605-8, 1998). LRRK2dependent phoshorylation ofRab8a on threonine at amino acid position 72 is modulated by PIN Kl phosphorylation of serine on amino acid position 111 on Rab8a (Biochem J. Mar 30,

2020, doi: 10.1042/BCJ20190664). Besides this LRRK2 activity impairs mitophagy that under normal conditions is 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 inhibitors of LRRK2 (Hum Mol Genet. 26(22), 4340-4351, 2017). This suggests that LRRK2 inhibitors are useful for treating lysosomal storage disorders such as Gaucher’s disease, Krabbe’s disease, Niemann-Pick’s disease and Fabry’s disease, disorders with mitochondrial déficits including early onset Parkinson’s disease associated with PINK1 and PARKIN missense mutations as well as Parkinson’s disease in patients with poiymorphisms in genes encoding proteins involved in the endosomal-lysosomal system such as GBA, GALC, VPS35, VPSI3C, ATP6V0A1, LAMP1, SCARB2, TMEM175 and CTSB.

Postmortem analysis of brains from Parkinson’s disease patient carrying LRRK2 mutations show presence of α-synuclein pathology (JAMA Neurol. 72(1), 100-5, 2015). In preclinical Parkinson’s disease (PD) models, p.G2019S aggravâtes PD-related pathology that can be reversed by LRRK2 inhibition. LRRK2 has been identified in Lewy bodies in nigral and brain stem régions (Neuropathol Appl Neurobiol 34(3), 272-83, 2008) and has also been shown to phosphorylate α-synuclein on Serl29 (Biochem Biophys Res Commun 387(1), 149-52, 2009). LRRK2 exonic variation is associated with risk of multiple system atrophy (Neurology 83(24), 2256-61, 2014) and LRRK2 missense mutations hâve also been reported in patients with multiple system atrophy (J Parkinsons Dis;8(l), 93-100, 2018). Single nucléotide poiymorphisms in the MAPT (tau) locus is associated with increased risk of Parkinson’s disease and multiple system atrophy (Hum Genet 124(6), 593-605, 2009; Parkinsonism Relat Disord 30, 40-5, 2016). Tau pathology is also a prominent feature seen in Parkinson’s disease patients with LRRK.2 missense mutations (ActaNeuropathol Commun 7(1), 183, 2019). Overexpression of pathogenic LRRK2 in animal models increase tau pathology (Neurobiol Dis 40(3), 503-17, 2010). LRRK2 missense mutations hâve been reported in patients suffering from tauopathies such as progressive supranuclear palsy and corticobasal degeneration (Mov Disord. 32(1), 115123, 2017). Common variation at the LRRK2 locus îs associated with survival in the primary tauopathy progressive supranuclear palsy (bioRxiv 2020.02.04.932335) and GWAS studies hâve identified risk for frontotemporal dementia at the LRRK2 locus (PLoS Med 15(1), e!002487, 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 broadly expressed but particular enriched in brain tissue as well as m peripheral organs more specifically kidney, lung, intestine and spleen. Besidesthîs 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 after pro-inflammatory stïmuli or pathogens thereby increasing LRRK2 kinase activity. In human peripheral blood mononuclear cells, the LRRK2 substrates RablO and Rabl2 are phosphorylated after stimulation with reagents mimicking viral infections (Sci Rep 7(1), 10300, 2017). Consistent with LRRK2 biology playing a rôle in response to înflammatory stimuli LRRK2 missense mutations are associated with risk of the Înflammatory bowel disorder Crohn’s disease and GWAS studies has identified single nucléotide polymorphisme in the LRRK2 locus associated with genome wide significant 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 increased risk of Crohn’s disease (PLoS Genet 14(5), e!007329, 2018). LRRK2 exonic variants such as p.N208lD and p.M2397T increase the risk of Crohn’s disease and as observed for Parkinson’s disease the protective haplotype variant p.N551 K/p.R1348H lowers the risk of Crohn’s disease. In cell-based studies the p.N2081D variant has increased kinase activity which leads to augmented RablO phosphorylation (bioRxiv 447946, 2018; Sci Transi Med 10(423), 2018). The biological link between Parkinson’s disease and autoimmune disorders are further supported by studies finding that commun genetic pathways which also includes LRRK2 are shared between Parkinson’s disease and autoimmune disorders such as rheumatoid arthritîs, 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 Transi Med 17(1), 37, 2019) and leprosy (N Engl J Med 361(27), 2609-18, 2009; PLoS One 8(8), e73I03, 2013; PLoSNegl Trop Dis 10(2), e0004412, 2016).

Thus, LRRK2 inhibitors can be used for treatment of Crohn’s disease and other autoimmune disorder such as but not restricted to rheumatoid arthritîs, ulcerative colitis, lupus and leprosy. LRRK2 play s a rôle in tumor growth in rénal and thyroid cancers by impacting MET signaling, and lowering of LRRK2 expression induces growth arrest (Proc Natl Acad Sci USA 108(4), 1439-44, 2011). LRRK2-PD patients hâve increased risks of leukemia as well as skin and colon cancers (Mov Disord34(9), 1392-8, 2019). Carriers of p.G2019S also hâve an overall increased risk of non-skin cancer;in particular breast cancer and hormone-related cancers in females (JAMA Neurol 72(1), 58-65, 2015). Studies hâve shown that LRRK2 silencing promûtes T-cell growth inhibition and facilitâtes apoptosis and cell cycle arrest (Int J Oncol 55(1), 21-34, 2019).

LRRK2 is also differentially expressed in lung adeno- and lung squamous cell carcinomas as well as ποη-small-cell lung cancer (J Cell Physiol 234(7), 10918-25, 2019; J Cell Physiol 234(12). 22742-52. 2019).

Thus, LRRK2 inhibitors hâve anti-carcinogenîc effects and can be used for treatment of skin cancer and non-skin cancers such as rénal cancer, colon cancer, adeno- and squamous lung cancers, non-small-cell lung cancer, hormone-related cancer, thyroid cancer, leukemia and breast cancer.

Description of prior art

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 compounds disclosed in WO2020/006267, non-macrocyclic or polycyclic structures such as compounds disclosed in WO2019/222173, WO2019/112269, WO2019/074809, WO2018/217946, WO2018/163066, WO20I8/155916, WO2018/137618, WO2018/06931, WO 2015/026683, and also macrocyclic derivatives such as compounds disclosed in WO2019/012093, WO2016/042089 and US 2015/290198. Notwithstanding the huge amounts of structures elaborated over the last years, there is a continuing need to design new scaffolds having a better potcncy and selectivity to meet the unmet medical needs.

Detailed description ofthe invention

The present invention will be described below. In the foilowing passages, different aspects of the invention are defined in more details. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

In a first aspect the present invention provides a compound of Formula (I)

wherein:

♦ R represents a hydrogen atom, a halogen atom or an alkyl group, ♦ Zl, Z2, Z3, independently each represents a carbon or a nitrogen atom, it being 5 understood that the 6-membered cycle containing Zl, Z2 and Z3 can hâve 0, 1 or 2 nitrogen atoms, ♦ -XI- is absent or represents -O-, -S-, or -N(R’a)-, wherein R’a represents a hydrogen atom or an alkyl group, ♦ -X2- represents an alkanediyl group optionally substituted with one or more 10 substituents, identical or different, selected from halogen atoms, polyhalogenoalkyl group, alkoxy group, hydroxy group, amino group, alkylamino group, dialkylamino group and cyano group, it being understood that the carbon atom in the alpha position of -N(Ra), and the carbon atom in alpha position of -Xl- when -Xl - represents -O-, -S-, or -N(R’a)-, cannot be 15 substituted with an oxygen or a nitrogen heteroatom, ♦ -X3- represents an alkanediyl group optionally substituted with one or more substituents, identical or different, selected from halogen atoms, polyhalogenoalkyl 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 în alpha position of -O-, and the carbon atom in alpha position of Al when Al represents a nitrogen atom, cannot be substituted with an oxygen or a nitrogen heteroatom, ♦ Ra represents a hydrogen atom or an alkyl group, it being understood that when Ra represents an alkyl group, one carbon atom of Ra can be linked to a carbon atom of -X2-, or to a carbon atom of -X3- to form a cyclic moiety containing 5 or 6 ring-members, ♦ A represents an aromatic or partially hydrogenated cyclic group of the fonnula (a):

*

A1—A2 / a\

AS _χΛ3 (a)

A4 / wherein ν' Al, A4 each independently represents a carbon atom or a nitrogen atom, / A2, A3, A5 each independently represents a carbon atom, an oxygen atom, a sulfur atom or a nitrogen atom, it being understood that Al, A2, A3, A4 and A5 cannot simultaneously represent a heteroatom,

- or an aromatic or partially hydrogenated cyclic group of the formula (b):

*

wherein A’I, 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 linked to X3, the aromatic or partially hydrogenated cyclic group A such defined being optionally substituted with one or more substituents, identîcal or different, selected from halogen atoms, alkyl group, alkoxy group, hydroxy group, oxo group, alkoxyalkyl group, alkoxyalkoxy group, polyhalogenoalkyl group, polyhalogenoalkoxy group, heterocycloalkyl group, heterocycloalkylalkyl group, (alkoxyalkyl)(alkyl)amino group, amino group, alkylamino group, dîalkylamino group, cycloalkyl group, (heterocycloalkyl)(alkyl)amino group, dialkylaminoalkyl group, heterocycloalkylalkoxy group, cyano group and cyanoalkyl group, wherein the heterocycloalkyl and cycloalkyl group such defined can be optionally substituted by one or more substituents chosen from alkyl group, halogen atoms, polyhalogenoalkyl group, poiyhalogenoalkoxy group, alkoxy group, alkoxyalkyl group, hydroxy group, cyano group and oxo group, their enantiomers, diastereoisomers, tautomers, racemic, hydrates, solvatés, 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 are to be construed in accordance with the following définitions, unless a context dictâtes otherwise:

The term alkyl by itself or as part of another substituent refers to fully saturated monovalent hydrocarbon radical, including corresponding deuterated derivatives. Alkyl groups of this invention comprise from l to 6 carbon atoms. Alkyl groups may be linear or branched, may include spirantc 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, hexyl and its isomers.

The term “alkanediyl” means a fully saturated divalent hydrocarbon radical having two single bonds for attachment to two other groups, and can be represented as “-(alkyl)- ” group wherein alkyl is as defined above. Alkanediyl groups of this invention comprise from 1 to 6 carbon atoms, may be linear or branched, may include spiranic structure, and may be substituted as indicated herein. Non-limiting examples of alkanediyl groups includes: -CH2-, -CH2-CH2-, -CD2-, -CD2-CD2-, -CH(CH₃)-, -CH(CH2-CH₃)-, -CH(i-Pr)-, -C(CH₃)(CH₃)-, h₂c—ch₂ h₂c—ch₂ h₂c—ch₂

V -CH₂^-

-CH₂-C(CH₃)(CH₃)-, -CH₂-CH2-C(CH₃)(CH₃)-, ’ ^{2 CH}^ ’ ²

-CH₂-CH(i-Pr)-, -CH(i-Pr)-CH₂-, -CH₂-CH(i-Bu)-, -CH(i-Bu)-CH₂-, -CH(CH₃)-CH₂-,

-CH₂-CH(CH₃)-, -CH₂-CH₂-CH₂-, -CD₂-CD2-CD₂-, -CH(CH₃)-CH₂-CH2-,

-CH2-CH₂-CH(CHi)-, -CH₂-CH(CH₃)-CH2-, -CH(CH₃)-CH2-CH(CH₃)-,

-CH2-CH2-CH(CH2-CHî)-, -CH(CH₂-CH₃)-CH2-CH2-, -CH(CH₂-CH₃)-CH2-CH(CH₃)-, ll

-CH(CHî)-CH2-CH(CH2-CH₃)-, it being possible for those groups, when indicated, to be further substituted. For example, an alkanedtyl group substituted by an alkoxy group will include, but will not be limited to, -CH(OCFh)-, -CH(OCH₃)-CH(CH3)-,

-CH₂-CH₂-CH(OCHj)-, -CH(OCH3)-CH₂-CH₂-, -CH2-CH₂-CI-I(CH2-OCH₃)-,

- CH(CH2-OCHj)-CH2-CH2-, -CH(O-CH2-CH₃)-CFl2-, -CH2-CH(O-CH2-CH₃)-. As nonlimited other example, an alkanediyl group substituted by a cycloalkyl group will include

- CH₂-CH(Cy-Pr)-, -CH(Cy-Pr)-CH₂-, wherein Cy-Pr means cyclopropyl. An alkanediyl group substituted by one or more halogen atoms includes for example, but will not be limited to -CHF-, -CHF-CH2-, -CF2-, -CF2-CH2-, -CH2-CF2-. An alkanediyl group substituted by a heterocycloalkyl group will include for example but will not be limited to

- CH₂-CH(tetrahydropyranyl)-, -CH(tetrahydropyranyl)-CH₂-, -CH₂-CH(oxolanyl)-, -CH(oxolanyl)-CH₂-.

The term “cycloalkyl” by itself or as part of another substituent is a monovalent, saturated, or unsaturated hydrocarbon group having one or two cyclic structures. Cycloalkyl includes ail saturated, partially saturated or aromatic hydrocarbon groups having one or two cyclic structures. Cycloalkyl groups comprise 3 or more carbon atoms and generally, according to this invention comprise from 3 to IO carbon atoms.

Examples of cycloalkyl groups having one cyclic structure include but are not limited to phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyL

When a bi-cyclic ring structure is envisaged, the two rings can be:

- fused, meaning they share a common bond; exemplary cycloalkyl bi-cyclic fused Systems include but is not limited to naphthalenyl, bîcyclo[l .1.0]butanyl, octahydropentalenyl, decahydronaphthalenyl, octahydro-lff-indenyl;

- linked via a bond between the two cyclic structures; exemplary cycloalkyl bi-cyclic linked Systems include but is not limited to bi-phenyl, bi-cyclopropanyl, bi-cyclopentenyl, bicyclohexanyl, cyclopropylcyclohexanyl, cyclopropylcyclopentanyl;

- 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 cycloalkyl bi-cyclic bridged Systems include but is not limited to bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl;

- or represent a spiro bi-cyclic ring system wherein the two rings are connected through a single atom; exemplary cycloalkyl spiro bi-cyclic Systems include but is not limited to spiro[2.2]pentanyl, spiro[2.4]heptanyl, spiro[4.4]nonanyl, spîro[5.5]undecanyl.

The “cycloalkyl group” such defined can be optionally substituted by l to 3 substituents chosen from alkyl group, halogen atoms, polyhalogenoalkyl group, polyhalogenoalkoxy group, alkoxy group, alkoxyalkyl group, hydroxy group, cyano group and oxo group. When the cycloalkyl group is substituted by 2 or 3 substituents, substituents can be beared by the same atom or different atoms, provided the valency of each atom is respected.

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

The term “alkoxyalkyl” refers to an “(alkyl)-O-(alkyl)-” group wherein “alkyl” is as defined above. Non-limiting examples include CH3-O-CH2-, CH3-O-CH2-CH2-.

The term “alkoxyalkoxy” refers to an “(alkyl)-O-(alkyl)-O-” group wherein “alkyl” is as defined above. Non-limiting examples include CHî-O-CI-b-O-, CH3-O-CH2-CH2-O-.

The term “alkylamîno” refers to an “-NH-(alkyl)” group wherein “alkyl” is as defined above. Non-limiting examples include -NH-CH3, -NH-CH2-CH₃₎ -NH-CH(CH3)(CH₃).

The term “di alkylamîno” refers to an “-N(alkyl)(alkyl)” group wherein “alkyl” is as defined above. Non-limiting examples include -NfCHah, -N(CH3)(CH2-CH3).

The term “polyhalogenoalkyl” refers to an alkyl group as defined above wherein one or more hydrogen atom, carried by the same or different carbon atoms, is replaced by one or more halogen atoms. Non-limiting examples includes fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl.

The term “polyhalogenoalkoxy” refers to a “(polyhalogenoalkyl)-O-” group wherein “polyhalogenoalkyl” is as defined above. Non-limiting examples includes fl uorom ethoxy, difl uorom ethoxy, trifluoromethoxy, 2-chloroethoxy.

The term “heterocycloalkyl” means a monovalent mono- or bi-cyclic aromatic or non-aromatic carbocyclic group containing from 3 to 10 ringmembers and containing from 1 to 3 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom. The heterocycloalkyl group can be linked by a carbon or a nitrogen atom when possible. The heterocycloalkyl group such defined can be a monocyclic ring system or a bi-cyclic ring system. Heterocycloalkyl monocyclic ring system include but is not limited to pyridinyl, piperazinyl, piperidinyl, tetrahydropyridinyl, tetrahydropyranyl, pyrrolidinyl, dihydropyrrolyl, oxolanyl, dîhydrofuranyl, morpholinyl, pyrazolyl, azetidinyl, oxetanyl. When a bi-cyclic ring System is envisaged, the two rings can be:

- fused, meaning they share a common bond; exemplary heterocycloalkyl bi-cyclic fused Systems include but is not limited to indolyl, indolinyl, benzopyranyl, benzofuranyl, naphthyridinyl, quinolinyl, pyridopyrazinyl, pyridopyridazinyl, pyridopyrimidinyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydrobenzofuranyl, benzopyranyl, d i hy drobenzopy rany I ;

- linked via a bond between the two cyclic structures; exemplary heterocycloalkyl bi-cyclic linked Systems include but is not limited to phenylpyridinyl, bipyridînyl, oxetanylpyridinyl, oxetany Ipiperidinyl oxetanyltetrahydropyridinyl, pyrrolidinylpiperidinyl, morpholinopiperidinyl, pyrrolidînyltetrahydro pyridinyl, pyrrolidinylpyrîdinyl, oxetanylpiperazinyl, pyrrolidinylpîperazinyl;

- 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 bi-cyclic bridged Systems include but is not limited to azabicyclo[2.2.1]heptanyl, oxaazabîcyclo[2.2.1]heptanyl; - or represent a spiro bi-cyclic ring system wherein the two rings are connected through a single atom; exemplary heterocycloalkyl spiro bi-cyclic Systems include but is not limited to oxaspirooctane, azaspirooctane, diazaspirooctane, oxaazaspirooctane, oxaspirononane, azaspirononane, diazaspirononane, oxaazaspirononane.

The ‘‘heterocycloalkyl group” such defined can be optionally substituted by I to 3 substituents chosen from alkyl group, halogen atoms, polyhalogenoalkyl group, polyhalogenoalkoxy group, alkoxy group, alkoxyalkyl group, hydroxy group, cyano group and oxo group. When the heterocycloalkyl group is substituted by 2 or 3 substituents, substituents can be beared by the same atom or different atoms, provided the valency of each atom is respected.

The term “heterocycloalkylalkyl” refers to a “(heterocycloalkyl)-(alkyl)-” group wherein the heterocycloalkyl and the alkyl moieties are as defined above. Non-limiting examples include morpholinylmethyl, pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl.

The term “halogen atoms” means a fluorine, chlorine, bromine or iodine atom.

Among the pharmaceutically acceptable acids there may be mentioned, without implyîng any 5 limitation, hydroehloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citrîc acid, ascorbic acid, oxalic acid, methanesulphonic acîd, camphoric acid etc.

Among the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.

Spécifie embodiments of compounds of formula (1) of the invention are described below. 15 Characteristics of those spécifie embodiments can be taken alone or combined to generate new spécifie embodiments.

In a spécifie embodiment, the invention more preferably refers to compounds of formula (I) wherein R represents a hydrogen atom.

In another embodiment, R represents advantageously a halogen atom, and most preferably a fluorine or a chlorine atom.

When R is an alkyl group, it is preferably a methyl group.

R is preferably linked to Z2 when Z2 represents a carbon atom.

In another spécifie preferred embodiment of the invention, Zl, Z2 and Z3 represent simultaneously a carbon atom.

In an advantageous alternative embodiment, one of ZI, Z2 and Z3 is a nitrogen atom while the two others represent a carbon atom. More particularly when one of Zl, Z2 and Z3 represents a nitrogen atom, it is preferentially Zl or Z2.

Another spécifie embodiment of the invention relates to compounds of formula (I) wherein

-XI- represents -O- or -NH-. More preferably, -XI- represents -O-,

In another spécifie embodiment of the invention, -X2- represents an alkanediyl group linear or branched having 2, 3, 4 or 5 carbon atoms, and more preferably 3, 4 or 5 carbon atoms. -X2- is preferably not substituted. When -X2- îs substituted, fluor or methoxy group is preferred. Advantageously -X2- represents <CH₂)₂-, -(CH₂)₃-, -CH(CH₃)-(CH₂)2-, -(CH₂)₂-CH(CH₃)-,

H₂C—ch₂ —CH₂^

- CH₂-CH(CH₃)-CH₂-, ^CH2 , -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-CF₃-CH2- or -CH2-CHF-CH2-.

The preferred value for Ra in compounds of formula (I) is hydrogen atom.

In another spécifie embodiment of the invention, -X3- represents an alkanediyl group linear or branched having 1,2, 3, 4 or 5 carbon atoms, and more preferably 1 or 2 carbon atoms. -X3- is preferably not substituted. Advantageously -X3- represents -CH2-, -CH(CH₃)-, -(CH₂)₂-, -(CH₂)₃-, -CH(CH₂-CH₃)-, -CH(CH₃)-CH₂-, -CH₂-CH(CH₃)-, -CH2-CI-I(i-Pr)-, -CH(i-Pr)-CH₂, -CH₂-CH(Cy-Pr)-, -CH(Cy-Pr)-CH₂-. Even more preferably, -X3- represents -(CH₂)2-, -CH₂-or -CH(CH₃)-.

Another spécifie embodiment of the present invention is represented by compounds of formula (I) for which A represents a group of formula (b):

*

---ΑΊ

AA A A2 (b) \---A'3

Preferred values for (A’ 1, A’2, A’3, A’4) are:

four carbon atoms, or three carbon atoms and one nitrogen atom, more preferably the nitrogen atom being in A’4,

- or two carbon atoms and two nitrogen atoms.

A’3 îs advantageously a carbon atom.

As a particular embodiment of the invention, A represents the following preferred scaffolds, being represented herein without any substitution:

Most preferred embodiment for A of formula (b) is phenyl or pyridinyl group. An advantageous alternative for A is pyrazinyl group.

An advantageous alternative for A is represented by a group of formula (a):

(a)

Most preferred scaffold of formula (a) contains one, two, or three heteroatoms, one of them being a nitrogen atom. Représentative preferred scaffolds of formula (a) are as follows, being represented herein without any substitution:

Most preferred embodiment for A of formula (a) is triazolyl or pyrazolyl group.

Preferentially the group A of the compounds of formula (!) is not substituted.

When the group A of the compounds of formula (I) îs substituted, the substitution can occur on any carbon or nitrogen atom of the A scaffblds having at least one free valence. Most preferred substitutions include halogen atoms, cyano group, cyanoalkyl group, oxo group, alkoxy group, 5 alkyl group, cycloalkyl group and heterocycloalkyl group. Particularly, preferred substitutions include fluor, bromine, or chlorine atoms, methyl, ethyl, cyclopropyl, methoxy, isopropyloxy, cyano, cyanomethyl and oxo groups.

Most preferred heterocycloalkyl group include pyrrolidînyl group, piperazinyl group, morpholinyl group, azetîdînyl group, piperidinyl, tetrahydropyridinyl, tetrahydrofuranyl, 10 dihydrofuranyl, oxetanyl, pyrazolîdinyi.

Most preferred substitutions of the group A are fluorine or bromine atom, methoxy group, methyl group, ethyl group, pyrrolidînyl group unsubstituted or substituted, piperazinyl group unsubstituted or substituted.

Another spécifie embodiment of the invention is represented by compounds of formula (I-a):

wherein XI, X2, X3, Ra and A are as defined for formula (I).

In another preferred embodiment the invention concerns compounds of formula (I-b):

wherein X2, X3, Ra and A are as defined for formula (I). Most preferred compounds of formula (I-b) are those for which -X2- represents -(CH2)3-, -CH(CHî)-(CH2)2-, -CH2-CHF-CH2-, -CH2-CF2-CH2- or -(CH₂)2-CH(CHî)-. Another most preferred compounds of formula (I-b ) are those for which -Xj- represents -CH2- or -(CHXCH3)-.

Another spécifie embodiment of the invention concerns compounds of formula (I) for which the -X1-X2-N(Ra)-C(O)O-X3- chain represents preferentially -O-(CH₂)3-NH-C(O)O-CH2-, -O-CH(CH3)-(CH₂)₃-NH-C(O)O-CH2-, -O-CH2-CHF-CH2-NHC(O)O-CH₂-,

-O-CH2-CF₂-CH₂-NHC(O)O-CH2-, -O-CH(CHî)-(CH₂)2-NHC(O)O-(CH₂)2- or

-O-CH(CH3)-(CH₂)2-NH-C(O)O-CH(CH3)-.

Preferentially, compounds of the invention are compounds of formula (I-c) or (I-c’):

wherein X1, X2, X3, Ra, A’ 1, A’2 and A’4 are as defined for formula (I).

Another spécifie embodiment is related to compounds of formula (1-d) or (I-d’):

wherein X2, X3, Ra, ΑΊ, A’2 and A’4 are as defined for formula (I). Most preferred compounds of formula (I-d) or (I-d’) are those for which -X2- represents -(CHhh-, -CH(CH₃)-(CH2)2-, -CH2-CHF-CH2-, -CH2-CF2-CH2- or -(CH₂)2-CH(CH₃)-. Another most preferred compounds of formula (I-d) or (I-d’) are those for which -X3- represents -CH2- or -(CH₂)2-,

Another preferred compounds of the invention are compounds of formula (I-e):

wherein XI, X2, X3, Ra, Al, A2 and A5 are as defined for formula (I).

Another preferred compounds of the invention are compounds of formula (1-f):

wherein X2, X3, Ra, Al, A2 and A5 are as defined for formula (1). Most preferred compounds of formula (I-f) are those for which -X2- represents -(CH2)3-, -CH(CH3)-(CH2)2-, -CH2-CHF-CH2-, -CH2-CF2-CH2- or -(CH2)₂-CH(CH3)-. Another most preferred compounds 5 of formula (I-f) are those for which -X3- represents -CH2- or -(CFbfr-.

In another spécifie embodiment, preferred compounds of the invention are:

- 8,14-di oxa-4,10,19,20-tetraazatetracyclo[ 13.5.2.1²·⁶.0¹⁸’² ^10053-1(20),2,4,6(23),15,17, 21-heptaen-9-one;

- 10-methyl-8,l4-dioxa-4,l 0,19,20-tetraazatetracyclo[ 13.5.2.1²’⁶.0^18,2 ^10033-1(20),2,4,

6(23), 15,17,21 -heptaen-9-one;

- 4-ί1υοΓθ-8,]4-όΐοχ3-10,19,20-trÎazatetracyclo[13.5.2.I²’⁶.0¹⁸’^2l]tricosa-l(20),2,4,6(23), 1 5,17,21-heptaen-9-one;

- 8,14-dioxa-10,19,20,23-tetra3zatetracycio[13.5.2.1²’⁶.0¹⁸’^2,]tricosa-l(20),2,4,6(23),

15,17,21 -heptaen-9-one;

- 8,14-dioxa-l0,19,20-triazatetracyclo[13.5.2.1²Z0^,s-^2,]tricosa-l(20),2,4,6(23),15^^^^ heptaen-9-one;

- 10-(propan-2-y 1)-8,14-dîoxa-4,10,19,20-tetraazatetracyclo[ 13.5.2.1²⁶.0'^8,21 ]tricosa- (20),2,4,6(23), 15,17,2 l-heptaen-9-one;

- 8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.i²-⁶.0ⁱ⁸’²¹]tricosa-l(20),2,4,6(23)_f

15,17,21 -heptaen-9-one;

- 4-methoxy-8,14-dioxa-10,19,20-trîazatetracyclo[13.5.2.1²’⁶.0^!8’²¹]tricosa-l(20),2,4, 6(23), 15,17,21 -heptaen-9-one;

- 4-bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0¹⁸’^2,]tricosa-l(20),2,4,6(23),

15,17,21 -heptaen-9-one;

- 5-fluoro-8,14-dioxa-I0,19,20-triazatetracyclo) 13.5.2.1²'⁶.0^18,2 “Jtrîcosa-1(20),2,4,6(23),

15,17,21 -heptaen-9-one;

- 5-methyl-8,I4-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^l8,2l]tricosa-l(20),2,4,6(23),

15,17,21 -heptaen-9-one;

- 4-(pyrrol idin-1-y l)-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2. l²’⁶.0’^8,21 Jtrîcosa-1(20), 2,4,6(23),15,17,21 -heptaen-9-one;

- 4-[4-(propan-2-yI)piperazin-l-yl]*8,14-dioxa-l0,19,20-triazatetracyclo[13.5.2.I²’⁶.0¹⁸¹²'] tricosa-1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 4-{2-oxa-6-azaspiro[3.4Joctan-6-yl}-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.1^2,6.0^18,21 Jtrîcosa-1(20),2,4,6(23),15,17,21-heptaen-9-one;

- 4-[4-(oxetan-3-yl)piperazîn-l-yI]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1^2,6.0^,8’^2,J tricosa-1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 4-(morpholin-4-yl)-8,l4-dioxa-10,l9,20-triazatetracyclo[13.5.2.[^2,6.0^,8’²¹]tricosa-l(20), 2,4,6(23), 15,17,21 -heptaen-9-one;

- 4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8,14-dioxa-10,1 9,20-triazatetracyclo [13.5.2.1²’⁶.0^,S’^2,]tricosa-I(20),2,4,6(23)J5,I7,21-heptaen-9-one;

- 4-methy 1-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1^2,6.0’^8,21 Jtrîcosa-1(20),2,4,6(23), 15,17,21 -heptaen-9~one;

- 5-methoxy-8,l4-dioxa-i0,19,20-triazatetracyclo[13.5.2.1²’⁶.0^l8,2l]tricosa-l(20),2,4, 6(23),15, 17,21-heptaen-9-one;

- 4-(4,4-d î fl uoropiperid in-1-y l)-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.1²’⁶.0 tricosa-1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 4-(3,3-difluoropyrrolidin-l -y l)-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1²’⁶.0^,8’^2,J tricosa-1 (20),2,4,6(23),15,17,21 -heptaen-9-one;

- 7-methyl-8,14-dioxa-10,19,20-trîazatetracyclo[l 3.5.2.1²’⁶.0^ts’^2l]tricosa-1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 4-[4-(2-methoxyethyl)piperidin-1 -yl]-8,14-dioxa-10,19,20-triazatetracyclo

[ 13.5.2.1^.0^18,2'jtrîcosa-1(20),2,4,6(23),15,17,21-heptaen-9-one;

- 9,14-dioxa-11,19,20-triazatetracyclo[l3.5.2. !²Λθ^18,21 Jtrîcosa-1(20),2,4,6(23), 15,17,21heptaen-10-one;

- 4-[(3R.)-3-hydroxypyiTolidin-l -y 1J-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.1²^0^l8'^2l]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one;

- 4-[(2-methoxyethyl)(methyi)amino]-8,14-dioxa-i 0,19,20-triazatetracyclo [13.5.2.1²'⁶.0¹⁸²¹]tricosa-1 (20),2,4,6(23),15,17,2 l-heptaen-9-one;

- 4-chloro-8,l 4-dioxa-10,19,20-triazatetracyclo[l3.5.2.l²’⁶.0^I8,21]tricosa-1(20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 4~fluoro-5-methyl-8,14“dioxa-10,19,20-triazatetracycio(13.5.2.1²’⁶.0ⁱ⁸’²¹]tricosa-l(20),2,

4,6(23),15,17,21-heptaen-9-one;

- 4,5-difluoro-8,l4-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0¹⁸’^2l]tricosa-l(20),2,4, 6(23), 15,17,21-heptaen-9-one;

- 5-bromo-8,14-dioxa-I0,19,20-trîazatetracyclo[ 13.5.2. l²’⁶.0^18,2']tricosa-1(20),2,4,6(23), 10 15,17,21 -heptaen-9-one;

- 4-(4-methylpiperazin-I-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-(3-inethoxyazetîdin-1 -yl)-8,14-dioxa-10,19,20-triazatetracyclo[l 3.5.2.1²’⁶.0^18,21] tricosa15 1 (20),2, 4,6(23),15,17,21 -heptaen-9-one;

- l-{9-oxo-8,14-dîoxa-10,19,20-trïazatetracyclo[l 3.5.2.1²’⁶.0^,8’^2,]tricosa-1 (20),2,4,6(23),

15,17,2 l-heptaen-4-yl}piperidine-4-carbonitrile;

- 4-[4-(pyrrolidin-1 -yl)piperidin-1 -yI]-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.1²’⁶.0^l8’²¹]trîcosa-l(20),2,4,6(23),15,17,21-heptaen-9-one;

- 4-(azetidin-l -y 1)-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1^2,6.0^18,21]tricosa-1(20),2,

4,6(23), 15,17,21 -heptaen-9-one;

- 4-(piperidin-I-yl)-8,l4-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^1S’²¹]tricosa-l(20),2, 4,6(23), 15,17,21 -heptaen-9-one;

- 4-(2,5-dihydrofuran-3-yl)-8,14-dioxa-! 0,19,20-triazatetracyclo[ 13.5.2.1²’⁶.0¹⁸’²¹]tricosa- t (20),2,4,6(23), 15,17,21 -heptaen-9-one;

4-[4-(morpholin-4-yl)piperidin-l -yl]-8,14-dioxa-10,19,20-triazatetracyclo [ 13.5.2.1^2,6.0¹⁸’²¹]tricosa-1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 4-(l -methyl-1,2,3,6-tetrahydropyridin-4-yl)-8,l 4-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;

- 4-[(2S,5 S)-2,5-dimethylmorpholin-4-yl]-8,l 4-dioxa-10,19,20-triazatetracyclo

[13.5.2.1^.0¹⁸²¹] tricosa-l(20),2,4,6(23),15,l7,21-heptaen-9-one;

- 4-[(morpholin-4-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0¹⁸-^2l]tricosa1(20),2,4,6(23),15,17,21-heptaen-9-one;

4-[(pyrrolidin-1 -y l)methyl]-8,14-dioxa-10,19,20-triazatetracyclo [ 13.5.2.1²’⁶.0’^{8 ,21}]tricosaI (20),2,4,6(23), 15,17,21 -heptaen-9-one;

4-[(pynOlidtn-l-yI)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[I3.5.2.1²ⁱ⁶.0^,8-^2l]tricosal (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 4-[(4-methylpiperazin-l -yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo

[l3.5.2.1²-⁶.0^l8-^2l]tricosa-I(20)₎2,4,6(23),15,17,21-heptaen-9-one;

- 5-(morpholin-4-y 1)-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.l^2,6.0^I8’^2,]tricosa- (20),2,4,6(23), 15,17,21-heptaen-9-one;

- 4-[4-(2-methoxyethyl)pîperazin-l -yl]-8,14-dioxa-10,19,20-triazatetracyclo

[13.5.2. l^2,6.0¹⁸’²¹]trîcosa-l(20),2,4,6(23),] 5,17,21-heptaen-9-one;

- 4-(diethylamino)-8,l4-dioxa-10,19,20-triazatetracyclo[ 13.5.2.l²’⁶.0^,8’^2l]tricosa-1(20),2, 4,6(23), 15,17,21 -heptaen-9-one;

- 4-cyclopropyi-8,l4-dioxa-10,19,20-triazatetracydo[13.5.2.1²’⁶.0¹⁸’²¹]tricosa-l(20),2, 4,6(23), 15,17,21 -heptaen-9-one;

- 5-(4-methylpiperazin-l-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^18,21]tricosa1 (20),2,4,6(23),15,17,21-heptaen-9-one;

- 13-methy 1-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1^.0^18,21 ]tricosa-1(20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 8,14-dioxa-4,5,l 0,19,20-pentaazatetracyclo[ 13.5.2. LLO^18,21 ]tricosa-1(20),2(23),3,

15(22),16,18(21 )-hexaen-9-one;

- 4-[methyl(oxetan-3-yl)amino]-8,l 4-dioxa-10,19,20-triazatetracyclo[l 3.5.2. l^2,6.0¹⁸²¹] tricosa-1 (20),2,4,6(23),15,17,21 -heptaen-9-one;

- 4-[(dimethylamino)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2. l²’⁶.0¹⁸’^2,]t_ricosa25 1 ¢20),2,4,6(23), 15,17,21-heptaen-9-one;

- 4,10-dîmethy 1-8,14-dîoxa-10,19,20-triazatetracyclo [ 13.5.2.1²’⁶.0^18,21 ]tricosa-1(20), 2,4,

6(23),15,17,21 -heptaen-9-one;

- 4-(propan-2-yloxy)-8,14-dioxa-10,19,20-triazatetracyclo[]3.5.2.1²’⁶.0¹⁸²¹]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 4-f1uoro-7-methy 1-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1²’⁶.0^18,21]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 4-[l-(oxetan-3-yl)-l,2,3,6-tetrahydropyrîdin-4-yl]-8,14-dioxa-l 0,19,20-triazatetracyclo

[13.5.2. ]^2,6.0^18,2I]tricosa-1(20),2,4,6(23),15,17,2 L-heptaen-9-one;

- 4-(3-methylpiperidin-l-yl)-8,i4-dioxa-l0,l9,20-triazatetracyclo[l3.5.2.l²’⁶.0^l8’^2l]tricosa1(20),2,4,6(23), 15,17,2I-heptaen-9-one;

- 4-[(3S)-3-hydroxypyrrolîdin-l-yl]-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2. l²'⁶.0^,S'^2,]tricosa-i(20),2,4,6(23),15,17,21-heptaen-9-one;

- 4-fluoro-8,14-dioxa-10,19,20-triazapentacyclo[13.5.2.1²ⁱ⁶.l⁷’^,0.0¹⁸’²¹]tetracosa’l(20),

2(24),3,5,15(22), 16,18(2 l)-heptaen-9-one;

- 4-(oxolan-3-yl)-8,14-dioxa-l 0,19,20-triazatetracycio[l3.5.2.1²⁶.0^18,2'jtrîcosa-l(20), 2,4,6(23), 15,17,21 -heptaen-9-one;

- (13S)-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[l 3.5.2. l^2,6.0¹⁸'^2l]tricosa-1(20),

2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- (13R.)-13-methyl·8,14-dioxa-l0,19,20-triazatetracyclo[l3.5.2.l²’⁶.0^l8’^2I]tricosa-l(20), 2(23),3,5,15(22),] 6,18(21 )-heptaen-9-one;

- 4-(l-methyl-lH-pyrazol-3-y[)-8,14-dioxa-10,I9,20-triazatetracyclo[ 13.5.2.1^{2 6}.0^18,21] tricosa-l(20),2(23),3,5,15(22),l6,18(21)-heptaen-9-one;

- (7S)-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^l8'^2l]tricosa-l(20), 2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- 4-[2-(morpholîn-4-yl)ethoxy]-8,l4-dioxa-l0,l9,20-triazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹] tricosa-1(20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one;

- 4-(2-methoxyethyl)-8,14-dîoxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0'⁸’²¹]tricosa-l(20),

2(23), 3,5,15(22), 16,18(21 )-heptaen-9-one;

- (7R.)-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^IS’²¹]tricosa-l(20), 2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- 5-cyclopropy 1-8,14-dîoxa-10,19,20-triazatetracyclo[ 13.5.2.1²⁶.0^18,2 'jtricosa-

1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 4-(2-methoxyethoxy)-8,14-dioxa-10,l9,20-triazatetracyclo[13.5.2.1²’⁶.0^l8’^2l]tricosa- (20),2,4,6(23), 1 5,17,21 -heptaen-9-one;

- 4-fluoro-13-methyl-8,14-dioxa-]0,l9,20-triazatetracyclo[13.5.2.1²’⁶.0^,S’^2,]tricosa-l(20), 30 2,4,6(23), 15,17,21- heptaen-9-one;

- 1 l-methyl-8,14-dioxa-10,19,20-trîazatetracyclo[l 3.5.2.1^2,6.0^18t21]tricosa-1(20),2,4,6(23), 15,1 7,21 -heptaen-9-one;

- 4-(3-oxomorpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1^2,6.0^18,21 ]tricosa- (20), 2(23),3,5,15(22),16,18(2 l)-heptaen-9-one;

- 4-(2-oxopyrrolidin-l-yl)-8, l4-dioxa-l0,I9,20-triazatetracyclo[l 3.5.2. l²’⁶.0^18,2’jtrîcosa1 (20).2(23), 3,5,15(22), [ 6,18(21 )-heptaen-9-one;

- 5-(2-oxopyrrolidin-l-y l)-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2. PAO^18,2'jtricosa1(20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one;

- 4-(2-methylpyrrolîdin-l-yl)-8,14-dioxa-i0,19,20-triazatetracyclo[13.5.2.]²’⁶.0¹⁸’^2l]tricosa1(20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one;

- 2-{9-oxo-8,I4-dioxa-l 0,19,20-trîazatetracyclo[l 3.5.2. l²ⁱ.0^{! 8,21} ]tricosa-1(20),2(23), 3,5,15(22), 16,18(21 )-heptaen-4-y!}acetonitrile;

- (II R)-I I-methy 1-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1²A0’^8,2l]tricosa-1(20),

2(23),3,5,15(22),16,18(21 )-heptaen-9-one;

( 11 S)-l 1-methy 1-8,14-dioxa-10,19,204riazatetracyclo[ 13.5.2. I^X6.0^l821]tricosa-1(20), 2(23),3,5,15(22),16,18(21 )-heptaen-9-one;

- 4-ethynyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.l²’⁶.0ⁱ⁸’²¹]tricosa-l(20),2(23),3,5, 15(22), 16,18(21 )-heptaen-9-one;

- 4-(piperazin-l-yl)-8,14-dioxa-l 0,19,20-triazatetracyclo[l 3.5.2.1²’⁶.0^,8’^2l]tricosa-1(20), 2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- 4-( 1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2. l²-⁶.0¹⁸’²¹]tricosa-1(20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- ] l-(methoxymethyl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.l²’⁶.0^,8’^2,]tricosa1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- 8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1²’⁵.0¹⁸’²¹]tricosa-l(20),2(23),3, 15(22), 16,18(21 )-hexaen-9-one;

- 11 -methy 1-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[l 3.5.2.1^2,5.0^18,21 ]tricosa-1(20),

2(23),3,15(22),16,18(21 )-hexaen-9-one;

- 12-methyl-8,14-dioxa-10,19,20-triazatetracyclo[l 3.5.2.1^2,6.0^18,21 ]tricosa-1(20),2(23), 3,5, 15(22),16,18(21 )-heptaen-9-one;

- 1 l-ethyl-8,14-dioxa-10,19,20-triazatetracyclo[l 3.5.2.1²’⁶.O^l8>²¹]tricosa-1(20),2(23),3,5, 15(22), 16,18(2 l)-heptaen-9-one;

- 4-fluoro-5,7-dimethy 1-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1 ^.0^18,21 ]tricosa1 (20),2(23), 3,5,15(22), 16,18(21 )-heptaen-9-one;

- 4-fluoro-5-methoxy-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0¹⁸ⁱ²¹] tricosa-1(20),2(23),3,5,15(22), 16,18(21)-heptaen-9-one;

- 5-fluoro-4,7-dimethyI-8,l4-dioxa-l0,l9,20-triazatetracyclo[l3.5.2.l²’⁶.0’⁸ⁱ²']tricosa1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- 8,14-dioxa-10,19,20-triazapentacyclo[13.5.2.1²’⁶.l^7jlo.0^,8’^2!]tetracosa-l(20),2(24),3,5, 5 15(22), 16,18(21 )-heptaen-9-one;

- 13-methyl-8,14-dioxa-l 0,19,20,23-tetraazatetracyclo[ 13.5,2.1²’⁶,0^18,21]tricosa-1(20), 2(23),3,5,15(22),16,18(21 )-heptaen-9-one;

- 12-methy 1- 8,14-d ioxa-4,5,10,19,20-pentaazatetracyc lo [ 13.5.2.1^2,5,0¹⁸·²¹ ]tricosa-1 (20), 2(23),3,15(22), 16,18(2 l)-hexaen-9-one;

- 7-me thy 1-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[l 3.5.2. l²⁵.0^,S21] tricosa-1 (20),

2(23),3,15(22), 16,18(21)-hexaen-9-one;

- 5-fltioro-4-methoxy-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[l 3.5.2.1²⁶.0¹⁸’²¹] tricosa-1 (20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one;

- (7R, 13R)-7,13-dimethy 1-8,14-dioxa-l 0,19,20-triazatetracyclo[ 13.5.2.1^2,6.0¹⁸’²¹]tricosa-

1 (20),2(23),3,5,15(22), 16,18(2 l)-heptaen-9-one;

- (13R)-13-methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[ 13.5.2. i²’⁵.0¹⁸²¹]tricosa1 (20),2(23),3,15,17,21 -hexaen-9-one;

- 8,15-dioxa-4,10,20,21 -tetraazapentacyclof 14.5.2.1²’⁶.1 ^l033 j)i9,22]p_entacosa_| (21 ),2(25), 3,5,16(23), 17,19(22)-heptaen-9-one;

- 8,14-d ioxa-5,10,19,20-tetraazatetracyclo[ 13.5.2. l²’⁵.0'^8,2'] tricosa-1 (20),2(23),3,15(22),

16,18(2 l)-hexaen-9-one;

- (13S)-4-fluoro-13-methyl-8,14-dioxa-IO,i 9,20-triazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹]tricosa1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- (13R)-4-fluoro-13-methy 1-8,14-dioxa-l 0,19,20-triazatetracyclo[ 13.5.2.1^.0^18,21]tricosa1 (20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one;

- (13R)-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1²’⁶.0^!8’²¹]trîcosaI (20),2(23), 3,5, ! 5(22),16,18(21 )-heptaen-9-one;

- 6-cyclopropyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2. l²’⁵.0^IS’²¹]tricosa-l (20),

2(23),3,15(22), 16,18(21 )-hexaen-9-one;

- 7-ethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.l²’⁶.0¹⁸’²¹]tricosa-l(20),2,4,6(23), 15,17,21 -heptaen-9-one;

- (13R)-13-ethyl-8,l 4-d ioxa-5,10,19,20,23-pentaazatetracyclo[l 3.5.2. l²’⁶.0^l8’^2,]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- (7R J 3 R)-4-t4uoro-7 J 3-dimethy 1-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2. l^2,6.0^18,2'| tricosa-1(20),2,4,6(23),15,17,21 -heptaen-9-one;

- 7-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹]tricosa-l(20),2,4, 6(23), 15,17,21 -heptaen-9-one;

- (7R)-4-fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1^2,6.0^18,2,]tricosaI (20),2,4,6(23),15,17,21-heptaen-9-one;

- (7S)-4-fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^I8’^2,]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 6-methyi-8,14-dioxa-4,5,I0,19,20-pentaazatetracyc[o[]3.5.2.l²’⁵.0¹⁸’^2l]tricosa-I(20),

2(23),3,15,17,21 -hexaen-9-one;

- 7-methyl-8,14-dioxa-l 0,19,20,23-tetraazatetracyclo[ 13.5.2.1^2,6.0^18,21 ]tricosa-1(20),2,4, 6(23), 15,17,2 l-heptaen-9-one;

- 6-(propan-2-yl)-8,14-dioxa-4,5,l0,l9,20-pentaazatetracyclo[l3.5.2.l²’⁵.0^,8’^2,]tricosa15 1(20),2(23),3,15(22), 16,18(21 )-hexaen-9-one;

- (13R)-7,13-dimethy 1-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[ 13.5.2.1^2,5.0^18,21 ]tricosa1 (20),2(23),3,15(22), 16,18(2 l)-hexaen-9-one;

- ( 13R)-13-methy 1-8,14-dioxa-l 0,19,20,23-tetraazatetracyclo[ 13.5.2.1²’⁶.0’^8,21 ]tricosa- (20),2,4,6(23),15,17,21 -heptaen-9-one;

- (7R)-7-ethyl·8,14-dioxa-10,i9,20-triazatetracyclo[13.5.2.1^2,6.0¹⁸'²¹]tricosa-l(20),2,4,

6(23),15, 17,21-heptaen-9-one;

- (7S)-7-ethy 1-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2. l^2,6.0¹⁸·²^tricosa-1(20),2,4, 6(23), 15,17,21 -heptaen-9-one;

- ( 13R)-13-methy 1-8,14-dîoxa-5,l 0,19,20-tetraazatetracyclo[ 13.5.2.1²’⁶.0^18,2,]tricosa-

1(20),2,4,6(23), [ 5,17,21 -heptaen-9-one;

- 6-(oxan-4-y 1)-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[ 13.5.2.1²’⁵.0^,8’^2l]tricosa- (20),2(23),3,15,17,21 -hexaen-9-one;

- 4-ethy 1-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[ 13.5.2.1^.0^18,2 'jtricosa-1(20), 2(23), 15,17,21 -pentaen-9-one;

- (13R)-23-fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1^2,6.0^182l]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 9,14-dioxa-4,5,l 1,19,20-pentaazatetracyclo[l 3.5.2. P^.O^18,21 ]tricosa-1(20),2(23), 3,15,17,21 -hexaen-10-one;

- 4-ethy 1-8,14-dioxa-5,i0,19,20,23-pentaazatetracyc!o[ 13.5.2.1²’⁵.0^18,21 ]tricosa-1(20), 2(23),3,15, i 7,21-hexaen-9-one;

- 3,9,15-trioxa-4,11,20,2 l-tetraazatetracycio[ 14.5.2.1^2,5.0^!9,22]tetracosa-1 (21),2(24), 4,16,18,22-hexaen-10-one;

- (13R)-16-fluoro-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[l 3.5.2. l^2,6.0^18,21] tricosa- i (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- (13R)-4-chloro-13-methy 1-8,14-dioxa-10,19,20,23-tetraazatetracyclo[ 13.5.2.1^2,6.0^18,21 ] tricosa-1 (20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one;

- 8,14-dioxa-2,4,10,19,20-pentaazatetracyclo[ 13.5.2.1^2,5.0¹⁸’²¹]tricosa-1(20),3,5(23),

15 (22), 16,18(21 )-hexaen-9-one;

- ( 13R)-4-methoxy-13-methyl-8,14-dioxa-10,19,20,23-tetraazatetracycio

[ 13.5.2.1^2,6.0^18,2 ']tricosa-1(20),2,4,6(23),15,17,21 -heptaen-9-one;

- (13R)-13-methyl-9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1^2,6.0¹⁸’²¹]tricosa1(20),2,4,6(23),15,17,21-heptaene-5-carbonîtrile;

- ( 13R)-13-methyl-4-(pynOlidin-1 -yl)-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo

[13.5.2.1²’⁶.0^18,2 ']tricosa-1(20),2,4,6(23), 15,17,21 -heptaen-9-one;

- (7S,13R)-7,13-dimethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1²’⁶.0^,s’²¹] tricosa-1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- (7R, 13R)-7,13-dimethy 1-8,14-dioxa-5,l 0,19,20,23-pentaazatetracyclo[ 13.5.2.1^2,6.0^18,21 ] tricosa-1(20),2,4,6(23), 15,17,2 l-heptaen-9-one;

- ( 13R)-16-fluoro-I3-methy 1-8,14-dioxa-10,19,20-triazatetracyclo[l 3.5.2.1^2,6.0^18,21 ]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- (13R)-13-methyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[ 13.5.2.1^2,6.0^18,21 Jtricosa25 1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 8,14-dioxa-4-thia-10,19,20,23-tetraazatetracyclo[13.5.2.1^2,5.0¹⁸’^2l]trÎcosa-l(20),2,5(23),

15,17,21 -hexaen-9-one;

- 8,14-dioxa-3-thia-10,19,20,23-tetraazatetracyclo[13.5.2.I^2,5.0^18,2l]tricosa-l(20),2(23),

4,15,17,21 -hexaen-9-one;

- (7R,13R)-7,13-dimethy 1-8,14-dioxa-10,19,20,23-tetraazatetracy clo[ 13.5.2. l^2,6.0'^8,2 *] tricosa-1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- ( 13R)-4-[(3R)-3-methoxypyrrolidin-1 -yl]-13-methyl-8,14-dioxa-5,l 0,19,20,23pentaazatetracyclo[ 13.5.2.1^2,6.0^18,21]tricosa-1 (20),2,4,6(23),15,17,21-heptaen-9-one;

- (13R)-16-chloro-13-methy 1-8,14-dioxa-l0,19,20-triazatetracyclo[ 13.5.2.1²'⁶.0^18,21]tricosa1 (20),2, 4,6(23), 15,17,21 -heptaen-9-one;

- ( 13R)-13,16-dimethyl-8,l 4-dioxa-l 0,19,20-trîazatetracyclo[ 13.5.2.1²’⁶.0¹⁸’²ⁱ]tricosa1 (20),2,4, 6(23), 15,17,2 l-heptaen-9-one;

- ( l3R)-13-methy 1-8,14-dioxa-3,l 0,19,20,23-pentaazatetracyclo[ 13.5.2.1²·⁶.0'^8,21 ]tricosal (20),2,4, 6(23), 15,17,2 l-heplaen-9-one;

- 8-oxa-10,14,19,20-tetraazatetracyclo[13.5.2.I²’⁶.0¹⁸’²¹]tricosa-l(20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one hydrochloride;

- 8-oxa-10,19,20-triazatetracyclo[I3.5.2.1^2,6.0¹⁸’²ⁱ]tricosa-l(20),2(23),3,5,15(22),16,18(21)heptaen-9-one;

- (13R)-5-methoxy-13-methyl-8,14-dioxa-4,I0,19,20-tetraazatetracyclo[13.5.2.l ²=⁶.0^18,21] tricosa-1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- (13R)-13-methyl-8,14-dioxa-4J0,19,20-tetraazatetracyclo[13.5.2.1²’⁶.0¹⁸’^2,]tricosa-l(20),2, 15 6(23), 15,17,21 -hexaene-5,9-dione;

- 4-methy I-8,14-dioxa-3,4,10,19,20-pentaazatetracyclo[ 13.5.2. l²'\0^18,21 ] tricosa-1(20),2, 5(23), 15(22), 16,18(21 )-hexaen-9-one;

- (13R)-16-fluoro-l 3-methy 1-8,14-dioxa-l 0,19,20,23-tetraazatetracyclo[l 3.5.2. l^2,6.0¹⁸’²¹] tricosa-1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 7,13-dioxa-4-thia-9,l 8,19,22-tetraazatetracyclo[12.5.2. l^2,5.0^l7’²°]docosa-1(19),2,5(22),

14(21 ), 15, l7(20)-hexaen-8-one;

- ( 13R)-4,13-dimethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[l 3.5.2.1²’⁶.0^!8,21]tricosaI (20),2(23),3,5,15(22),16,18(2l)-heptaen-9-one;

- 8,14-dioxa-23-thia-4,10,19,20-tetraazatetracyclo[13.5.2.1²’⁵.0^!8’²¹]tricosa-l(20),2,4,l5(22), 25 16,18(21 )-hexaen-9-one;

- (7S,13R)-7,13-dimethyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1²L0^ tricosa-1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- (13R)-13-methyl-9-oxo-8,14-dioxa-5,10,l9,20-tetraazatetracyclo[13.5.2.1²’⁵.0^l8’²¹]tricosa30 1(20), 2(23),3,15(22), 16,18(2l)-hexaene-4-carbonitrile;

- 12,12-dîfluoro-8,l 4-dioxa-l 0,19,20-trîazatetracyclo[ 13.5.2. l^2,6.0^18,2 ^tricosa-l (20),2(23), 3,5,15(22), 16,18(21 )-heptaen-9-one;

- (13R)-17-fluoro-l 3-methy 1-8,14-dioxa-l 0,19,20-triazatetracyclo[ 13.5.2.1²’⁶.0¹⁸’²¹]tricosa1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- (7S,l3R)-7J3-dimethyl-8,l4-dioxa-4,l0,l9,20,23-pentaazatetracyclo[l3.5.2.l²’⁶.0¹⁸·²¹] trîcosa-1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- (7R, 13R)-7,13-dimethyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1^2j6.0¹⁸’²¹] tricosa-1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- (13S)-13-methyl-8,14-dioxa-4,l 0,19,20,23-pentaazatetracyclo[l 3.5.2. l^2,6.0^18,21 ] tricosaI (20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one;

- ( 13R)-13-methyl-8,l 4-dioxa-10,19,20,22-tetraazatetracyclo[ 13.5.2. l^2,6.0^18,2 ^tricosa-1(20), 2(23),3,5,15,17,21 -heptaen-9-one;

- (l2R)-4,12-dimethyl-7,13-dioxa-4,9J8,!9,22-pentaazatetracydo[12.5.2.I²'⁵.0^I7’²⁰]docosa-

1 (i 9),2,5(22), 14(21 ),15,17(20)-hexaen-8-one;

- (l3R)-13-methyl-8,14-dioxa-4,5,l0,19,20,23-hexaazatetracyclo[13.5.2.1²’⁵.0¹⁸’^2,]tricosa1 (20),2(23),3,15, ï 7,21 -hexaen-9-one;

- ( 13 R)-13-methy 1 -8,14-d îoxa-23 -thia-4,10,19,20-tetraazatetracyc lo [ 13.5.2.1^2,5.0^18,21 ] trico sa1 (20),2,4,15,17,21 -hexaen-9-one;

- ( 13R)-4,13-dimethyl-8,14-dioxa-4,l 0,19,20,23-pentaazatetracyclo[l 3.5.2.1²’⁵,0¹⁸’²¹]tricosaI (20),2,5(23),15(22),16,18(21 )-hexaen-9-one;

- ( 13R)-13-methy 1-8,14-dioxa-i0,1 ô.^^O-tetraazatetracycloldSÂAPÂO’^Jtricosa-lQO), 2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- 14-methyl-8-oxa-10,14,19,20-tetraazatetracyclo[13.5.2.i²’^e.0^t8’²¹]tricosa-l(20),2(23),3,5,

15,17,2 l-heptaen-9-one;

- (13R)-13-methyl-8,I4-dioxa-4,10,19,20,22-pentaazatetracyclo[ 13.5.2.1²·⁶.0^18,21 ]tricosa1 (20),2(23),3,5,15,17,2 l-heptaen-9-one;

- (l3R)-13-methyl-8,14-dioxa-10,I7,19,20-tetraazatetracyclo[]3.5.2.1²’⁶.0^l82l]tricosa-l(20), 25 2(23),3,5,15(22), 16, i 8(21 )-heptaen-9-one;

- 8, l4-dioxa-4,5,10,19,20,23-hexaazatetracyclo[l 3.5.2.1^.0^18,2 ^tricosa-1(20),2(23),3, 15 (22), 16,18(21 )-hexaen-9-one;

- 12,12-dîfluoro-8,14-dioxa-4,5,l 0,19,20,23-hexaazatetracyclo[ 13.5.2.1^2,5.0^18,21]tricosa1 (20),2(23),3,15(22), 16,18(21 )-hexaen-9-one);

- ( 12R)-12-fluoro-8,14-dioxa-10,19,20-trîazatetracyclo[ 13.5.2.1²·⁶.0^18,2 'Jtricosa-KTO), 2(23),

3,5,15(22), 16,18(21 )-heptaen-9-one;

- ( 12S)-12-tluoro-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2 J ^2,6.0¹⁸'^2,]tricosa-1(20),2(23),

3,5,15(22),16,18(2 l)-heptaen-9-one;

- 12,l 2-difluoro-8,l 4-dioxa-4,10,19,20,23-pentaazatetracy cio [ 13.5.2.1^2j6.0^18,21]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[13.5.2.1²'⁶.0¹⁸’²¹]tricosa' 5 1 (20),2(23),3,5,15,17,21 -heptaen-9-one;

- (12R)-12-fluoro-8,14-dioxa-4,]0,19,20,23-pentaazatetracyclo[13.5.2.1²’^È.0ⁱ⁸’^2l]tricosa1(20),2(23),3,5,15,17,21-heptaen-9-one;

- ( 12S)-12-fluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[ 13.5.2.1²’⁵.0'^8,21 Jtricosa1 (20),2(23),3,15,17,21 -hexaen-9-one;

- (12R)-12-fluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[] 3.5.2. l²’⁵.0¹⁸’²¹]tricosa1 (20),2(23),3,15,17,21 -hexaen-9-one;

- 8\l4'-dioxa-10\l9\20'-triazaspiro[cyclopropane-l,]3'-tetracyclo[13.5.2. l²'⁶.0¹⁸²¹] tricosane]-1 -(20-),2-(23-),3-,5-,15’(22'),16’, 18’(21 ’)-heptaen-9’-one.

The invention relates also to a global process for the préparation of compounds of formula (I), which process is characterized that there is used as starting material the compound of formula (1-1):

(M) wherein R, XI, Z1, Z2 and Z3 are as defined for formula (I), on which is condensed first a compound PG1-LG1, then a compound PG2-LG2, or first a compound PG2-LG2 then a compound PG1-LG1 wherein PG1 is a protecting group or, when

-XI- 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 (1-2):

wherein R, X1, Z1, Z2, Z3, PG 1 and PG2 are as defined hereinbefore, compound of formula (1-2) on which:

- is condensed a leaving group LG3 to yield the compound of formula (1-3):

wherein R, Xl, Zl, Z2, Z3, PG1, PG2 and LG3 are as defined hereinbefore, compound of formula (1-3):

• on which is condensed, after deprotection ofXl, a compound LG4-X2-NPG3 wherein

LG4 is a leaving group, PG3 is a protecting group and X2 is as defined for formula (I) 10 to yield the compound of formula (1-4):

wherein R, Xl, X2, ZJ, Z2, Z3, PG2, PG3 and LG3 are as defined hereinbefore, compound of formula (1-4) on which is condensed a compound of formula (1-5):

HO-X3 \

wherein A and X3 are as defined in formula (I), or an organom étal lie derîvative of compound of formula (1-5) such as a boronate, to yield the compound of formula (1-6):

(1-6) wherein R, Xl, X2, X3, A, Zl, Z2, Z3, PG2 and PG3 are as defined hereinbefore, compound of formula (1-6) which is subjected to a deprotection of -X2-NPG3, then to a cyclization to give the compound of formula (1-7):

wherein R, Xl, X2, X3, A, Zl, Z2, Z3 and PG2 are as defined hereinbefore, compound of formula (1-7) which is optionally alkylated on the carbamate function, and/or optionally substituted on the A ring, then submitted to the deprotection of -N(PG2)- to give the compound of formula (I), • or compound of formula (1-3) on which is condensed a compound of formula (1-8):

wherein Ra. X2, X3, and A are as defined hereinbefore and LG4 is a leaving group, or an organom étal lie derîvative of compound of fonnula (1-8) such as a boronate, to yield the compound of formula (1-9):

wherein R, Ra, Xl, X2, X3, A, Zl, Z2, Z3, PGI, PG2 and LG4 are as defined hereinbefore, compound of formula (1-9) which is subjected, after deprotection ofXl, to acyclization to yield the compound of formula (1-7) as defined above, which, after deprotection of -N(PG2)-, and/or optional substitution on the A ring, gives the compound of formula (I), · or compound of fonnula (1-3) on which is condensed, after deprotection of Xl, a compound LG5-X2-NRaCOOBn 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

wherein R, Ra, Xl, X2, Zl, Z2, Z3, PG2 and LG3 are as defined hereinbefore,

compound of formula (I-10) on which is condensed a compound of formula (1-5):

HO

wherein X3 and A are as defined hereinbefore, or an organo métal lie derîvative of compound of formula (1-5) such as a boronate, to yield the compound of formula (I-l 1):

wherein R, Ra, Xl, X2, X3, Zl, Z2, Z3, A and PG2 are as defined hereinbefore, compound of formula (1-11) which is subjected to a cyclization to yield the compound of formula (1-7) as defined above, which, after deprotection of -N(PG2)-, and/or optional substitution on the A ring, gives the compound of fonnula (I), or compound of formula (1-2) on which is condensed, after deprotection of Xl, a compound of formula (1-12):

wherein A, X3 and X2 are as defined hereinbefore and LG6 and LG7 are leaving groups, to ] 5 yield a compound of formula (I-13) :

wherein R, Xl, X2, X3, A, Zl, Z2, Z3, PG2 and LG6 are as defined hereinbefore, compound of formula (l-l3) that is cyclized to yîeld the compound of formula (1-7) which is optionally alkylated on the carbamate function, then submitted to the deprotection of -N(PG2), 5 and/or optionally substituted on the A ring, to give the compound of formula (I), or compound of formula (1-2) which is transformed in a boronic derîvative of formula (1-14):

wherein R, XI, Zl, Z2, Z3, PG1 and PG2 are as defined hereinbefore, and R’ represents a hydrogen atom or an alkyl group, it being understood that the two R’ alkyl group can be linked to form a cyclic structure, • compound of formula (1-14) on which is condensed a compound of formula (1-15):

wherein A is as defined herein before, X4 is a carboxylic acid or an ester or a carbonyl dérivative of X3, and LG8 is a leaving group, to yield the compound of formula (1-16):

wherein R, Xl, ZI, Z2, Z3, X4, PG1 and PG2 are as defined hereinbefore, compound of formula (1-16) on which îs condensed, after deprotection ofXl a compound LG5X2-NRaCOOBn as defined hereinbefore to yield the compound of formula (1-17):

wherein R, Ra, Xl, X2, ZI, Z2, Z3, X4 and PG2 are as defined hereinbefore, which is submitted to a réduction to yield the compound of formula (1-11) that is converted to compound of formula (I) as described hereinabove, • or compound of formula (1-14) on which is condensed a compound of formula (1-18):

(1-18) wherein A, X2, X3 and Ra are as defined herein before, and LG9 is a leaving group, to yield the compound of formula (1-19):

wherein R, Ra, A, Xl, X2, X3, Zl, Z2, Z3, PG1 and PG2 are as defined hereinbefore, compound of formula (1-19) on which is introduced a leaving group to yield the compound of fonnula (1-9) as defined above, that is converted to compound of formula (I) as described above.

or compound of formula (1-2) on which is condensed, after deprotection of X1, a compound LG5-X2-NRaCOOBn as defined hereinbefore to yield a compound of formula (I20):

(1-20) wherein R, Ra, XI, X2, Zl, Z2, Z3 and PG2 are as defined hereinbefore, compound of formula (1-20) which îs transformed in a boronic dérivative of formula (1-21 ):

NRaCOOBn

wherein R, Ra, XI, X2, Zl, Z2, Z3, PG2 and R’ are as defined hereinbefore, • compound of formula (1-21) on which is condensed a compound of formula (1-22):

wherein X3 and A are as defined hereinbefore, and LG10 is a leaving group, to yieid the compound of formula (1-11) that is converted to compound of formula (I) as described 10 hereinabove, • or compound of formula (1-21) on which is condensed a compound of formula (1-15) as defined hereinbefore to yieid the compound of formula (1-17) that is converted to compound of formula (I) as described hereinabove, the compound of fonnula (I), may then be purified according to a conventionai séparation technique, and is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventionai séparation technique, ît being understood that at any moment considered appropriate during the course of the process described above, some groups of the starting reagents or of the synthesis intermediates can be protected, subsequently deprotected and functionalized, as required by the synthesis,

The compounds of formulae (1-5), (1-8), (1-12), (1-15), (1-18) and (1-22) are either commercially available or can be obtained by the person skilled in the art using conventionai Chemical reactions described in the literature.

Pharmacological studies of the compounds of the invention of formula (I) exhibit inhibitory activity against LRRK2 kinase, including LRRK2 mutant kinase, such as mutant 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 derîvative thereof). An exemplary kinase assay îs described in the Pharmacological Study.

Compounds of formula (I) of the invention or pharmaceutically acceptable salts thereof are inhibitors of LRRK2 kinase activity and are thus believed to be of potential use in the treatment of or prévention 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.

Particularly compounds of the invention are useful in the treatment of neurological diseases including but not limited to Parkinson’s disease (including sporadic Parkinson’s disease patients as well as patients with LRRK2 mutations such as p.G2019S or Rab29/Rab7Ll polymorphisms), Alzheimer’s disease, amyotrophie latéral sclerosis (ALS), dementia (including Lewy body dementia and vascular dementia, HIV-induced dementia), diabetic neuropathy, âge related memory disfunction, mild cognitive impairment, argyrophilic grain disease, Pick’s disease, epîlepsy, tauopathies such as progressive supranuclear palsy and corticobasal degeneration, other synucleinopathies such as multiple system atrophy, frontotemporal dementia, înherîted frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), withdrawal symptoms/reiapse associated with drug addiction, LDopa induced dyskinesia, ischémie stroke, traumatic brain injury, spinal cord injury and multiple sclerosis.

Other diseases potentially treatable by inhibition of LRRK2 activity are endosomal-lysosomal diseases including but not limited to Niemann-Pick Type A, B or C disease, Gaucher’s disease, Krabbe’s disease, Fabry’s disease and disorders with mitochondrial déficits; inflammatory diseases including but not limited to vasculîtis, pulmonary diseases such as chronic obstructive pulmonary disease, idiopathîc pulmonary fibrosîs, inflammatory myopathies, ankylosing spondylitis; autoimmune diseases including but not limited to Crohn’s disease, inflammatory bowel disease, rheumatoîd arthrîtis, ulcerative colitis, lupus, autoimmune hemolytic anémia, pure red cell aplasia, idiopathîc thrombocytopénie purpura, type I diabètes mellitus, obesity, Evans syndrome, bullous skin disorders, Sjogren’s syndrome, Devic’s disease and leprosy. Compounds of the invention hâve also anti carcînogenîc effects and are potentially useful in the treatment of cancers including but not limited to thyroid cancer, rénal cancer (including papillary rénal), breast cancer, hormone-reiated cancer, adeno-and squamous lung cancer, nonsmall-cell lung cancer, colon cancer, prostate cancers, skin cancers, leukemias (including acute myelogenous leukemia) and lymphomas.

Compounds of the invention are also potentially useful in the treatment of cardiovascular diseases including but not limited to stroke.

Other diseases potentially treatable by compounds of the invention are bacterial infections such as but not limited to leprosy and tuberculosis; viral infections such as but not limited to coronavirus such as SARS-CoV, MERS-CoV and SARS-CoV-2, HIV, West Nile virus and chikungunya virus.

Another aspect of the invention is related 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 interesting for use in the treatment or prévention 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 a spécifie embodiment, parmaceutical compositions of the invention are useful for the treatment or prévention of Parkinson’s disease (including sporadic Parkinson’s disease patients as well as patients with LRRK2 mutations or Rab29/Rab7Ll polymorphisms), Alzheimer’s disease, amyotrophie latéral sclerosis (ALS), dementia (including Lewy body dementia and vascular dementia, HlV-înduced dementia), diabetîc neuropathy, âge related memory disfunction, mild cognitive împairment, argyrophihc grain disease, Pick s disease, epilepsy, tauopathies such as progressive supranuclear palsy and corticobasal degeneration, other synucleinopathies such as multiple system atrophy, frontotemporal dementia, inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), withdrawal symptoms/ relapse associated with drug addiction, L-Dopa induced dyskinesia, ischémie stroke, traumatic brain injury, spinal cord injury, multiple sclerosis, Niemann-Pick Type A, B or C disease, Gaucher’s disease, Krabbe’s disease, Fabry’s disease, disorders with mitochondrial déficits, Crohn’s disease, inflammatory bowel disease, rheumatoid arthritis, ulcerative colîtis, lupus, autoimmune hemolytic anémia, pure red cell aplasia, idiopathic thrombocytopénie purpura, type I diabètes mellitus, obesity, Evans syndrome, bullous skin disorders, Sjogren’s syndrome, Devic’s disease, leprosy, thyroid cancer, rénal cancer (includîng papillary rénal), breast cancer, hormone-related cancer, adeno-and squamous lung cancer, non-small-cell lung cancer, colon cancer, prostate cancers, skin cancers, leukemias (includîng acute myelogenous leukemia), lymphomas, stroke, leprosy, tuberculosis, and SARS-CoV, MERS-CoV, SARSCoV-2, HIV, WestNile virus and chikungunya virus infections.

Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitabie for oral, parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocular or respîratory administration, especially tablets or dragées, sublingual tablets, sachets, paquets, capsules, glossettes, lozenges, suppositories, creams, ointments, dennal gels, and drinkable or injectable ampoules.

The pharmaceutical compositions according to the invention comprise one or more excipients or carriers selected from diluents, lubricants, binders, dis intégration agents, stabilisers, preservatives, absorbents, colorants, sweeteners, flavourings etc.

By way of non-limiting example there may be mentioned:

♦ as diluents: lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycérol, ♦ as lubricants: silica, talc, stearic acid and its magnésium and calcium salts, polyethylene glycol, ♦ as binders: magnésium aluminium silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone, ♦ as disintegrants: agar, al g i nie acid and its sodium sait, effervescent mixtures.

The dosage varies according to the sex, âge and weight of the patient, the administration route, the nature of the therapeutic indication, or of any associated treatments, and ranges from Û.Ol 5 mg to l g per 24 hours in one or more administrations.

The foîlowing Préparations and Examples illustrate the invention but do not limit it in any way.

The compounds ofthis invention can be prepared by any of several standard synthetic processes 10 commonly used by those skilled in the art of organic chemistry. The compounds are generally prepared from starting materials which are either commercially available or prepared by standard means obvious to those skilled in the art.

GENERAL SCHEMES

As indicated herein before, the present invention provides compounds according to formula (I):

wherein R, ZI, Z2, Z3, Xl, X2, X3, Ra and A are as defined for fonnula (I).

Wîth reference to the general reaction schemes suitable for preparing said compounds, these compounds can be represented by formula (I), for which the general reaction schemes can be found herein below. In the general schemes below, R, Zl, Z2, Z3, Xl, X2, X3, Ra and A will hâve the same meaning as defined for formula (l).

The fused pyrazolo bicyclic structure containing Zl, Z2, Z3 and R will be referred to as fused 25 pyrazolo structure in the followings.

In the general schemes below, Lgi and Lg₂ each independently represent suitable leaving groups. Pgi and Pg₃ each independently represent a suitable protecting group that can be used to protect X1 and/or X2. Pg₂ represents a protective group suitable to protect the NH of the fused pyrazolo structure.

Rb in the schemes below can be either H, alkyl or a cyclic alkyl.

For those compounds for which a transcarbamylation reaction is used, the CbzX2Lg2 moiety can be made either by reaction from the corresponding bromo alkyl amine through reaction with Cbz chloride or by reaction between the hydroxyalkylamine through reaction with Cbz chloride followed by mesylation or tosylation.

In ail of the general schemes below, before deprotection of the NH of the fused pyrazolo structure, the carbamate can be optionally substituted by an alkylation reaction to give a compound of formula (XlIIa) after which the NH of the fused pyrazolo structure can be deprotected to resuit in the final compound of formula (I).

Alternatively, in ail of the general schemes below, before deprotection of the NH of the fused pyrazolo structure, an optional cross-couplîng reaction such as a Buchwald, Suzuki, Sonogashira reaction or alternatively an O-alkylation or nucleophilic aromatic substitution can be carried out on the (hetero-) aromatic ring which contains a leaving group such as a halide, to fonn a compound of formula (XlIIa). After the cross-couplîng reaction such as a Buchwald, Suzuki, Sonogashira reaction or alternatively an O-alkylation or nucleophilic aromatic substitution, the NH of the fused pyrazolo structure can be deprotected to resuit in the final compound of fonnula (I).

The compounds of formula (I) can be prepared as shown in general Scheme A below wherein the compound of formula (II) is converted to a protected compound of formula (III). This compound of formula (III) can be converted to a compound of formula (IV) containing a leaving group on the fused pyrazolo structure 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 an intermediate of formula (VIII) containing a leaving group resulting in a compound of formula (IX). The compound of formula (VIII) can be prepared from a compound of formula (VII) through a nucleophilic substitution. The compound of formula (IX) can be coupled via organometallic cross-couplîng such as Suzuki or Ullmann coupling with a (hetero-)aryl of fonnula (X) or (Xa) to form a compound of formula (XI). The compound of formula (XI) can then be selectively deprotected to a compound of formula (XII) before being cyciized to form a compound of formula (XIII). Final

deprotection of the nitrogen of the fused pyrazolo structure, either or not after alkylation of the carbamate moiety and/or substitution of the A ring, results in the compound of formula (I). Scheme A

(il) (m) (iv) (V)

HO-X3

(VI) (VIII) (IX) (Xa) (XI)

(XII) (XIII) (XHla) (I)

In the above reaction Scheme A, the reaction between a compound of formula (VI) and a compound of formula (VIII) can be accomplished in a solvent such as A/JV-dimethylformamide or acetonitrile and a base such as césium carbonate or potassium carbonate.

In the above reaction between compound of formula (IX) and compound of formula (X), the 10 leaving groups Lgi is advantageously a halogen atom such as chlorine, bromine or iodine. Such a halogen displacement reaction can be effected under cross-coupling conditions such as Suzuki conditions using palladium catalysts such as for example tetrakis(triphenylphosphine) palladium(O) combined or not with 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl (Xphos) in the presence of potassium phosphate tribasic in a solvent mixture such as for 15 example 1,4-dioxane/water at an elevated température such as for example 90^QC either under microwave conditions or not.

Alternatively, the halogen displacement reaction can be effected 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 température such as for example 70°G.

Suitable compounds of formula (X) or formula (Xa) may be either commercially acquired or obtained through various sélective protection and deprotection steps known to the person skilled in the art. For the synthesis of compounds of formula (Xa) a borylation step might be required.

The deprotection of Pg3 results in a compound of formula (XII).

The cyclisation of the compound of fonnula (ΧΠ) to give compound of formula (XIII) can be performed by a method known by the person skilled in the art as a carbamylation reaction, for example by treatment with 1,1 '-carbonyldiimidazole and ATV-diisopropylethy lamine or sodium hydride in a solvent such as ATV-dimethylacetamide at for example 90°C. Final deprotection of the NH of the fused pyrazolo structure under acidic conditions, either or not after alkylation of the carbamate and/or substitution of the A ring yields the final compound of formula (I).

Altematively, 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 to a protected compound of formula (III). The NH of the fused pyrazolo structure can be protected to a compound of fonnula (XIV). This compound of formula (XIV) can be converted to a boronic acid (or boronate ester) of formula (XV). The compound of formula (XV) can be coupled via organometallic cross-coupling reaction such as Suzuki coupling with a (hetero-)aryl of formula (XVI) to form a compound of formula (XVII). The compound of formula (XVII) can be alkylated with an intermedîate of fonnula (XIX) containing a carbamate such as a benzyl carbamate resulting in a compound of formula (XX). The compound of formula (XIX) can commercially be acquired or being prepared from a compound of fonnula (XVIII) through a reaction with CbzCI or through the introduction of a leaving group Lg2 on the compound of formula (XVIIIa). The X4 moiety of compound (XX) can be transformed into X3-0H usually by a réduction of a carboxylic acid or a carboxylic ester or a (cyclo)alkyl-carbonyl or a heterocycloalkyl-carbonyl. The compound of fonnula (XXI) can then be cyclized by a transcarbamylation reaction to fonn a compound offormula (XIII). Final deprotection ofthe nitrogen of the fused pyrazolo structure, either or not after alkylation of the carbamate and/or substitution of the A ring results in the compound of formula (I).

Scheme B

Tran Scarba myîation CycHzation

(Xl»)

(Xllla)

Deprotection

In the above reaction Scheme B, fused pyrazolo structure borylation of a compound of formula (XV) lo the compound of formula (XVI) can be accomplished using an iridium catalyst and bis(pinacolato)diboron in a solvent such as TBME.

In the above reaction between compound of formula (XV) and compound of formula (XVI), the leaving groups Lgi îs advantageously a halogen atom such as chlorine, bromine or iodine.

Such a halogen displacement reaction can be affected under cross-coupling conditions such as Suzuki conditions using palladium catalysts such as for example tetrakis(triphenylphosphine) palladium(O) combined or not with 2-dÎcyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl (Xphos) in the presence of potassium phosphate tribasic in a solvent mixture such as for example 1,4-dioxane/water at an elevated température such as for example 110°C either under microwave conditions or not.

In the above reaction scheme, the alkylation between a compound of formula (XVII) with a compound of formula (XIX) can be accomplished in a solvent such as V-V-dimethyIformamide or acetonitrile and a base such as césium carbonate or potassium carbonate at an elevated température such as 120^?C. Suitable compounds of formula (XIX) may be either commercially acquired or obtained through reaction with CbzCl and sodium hydroxide of a compound of formula (XVIII) in water as a solvent, Alternatively, the compound of formula (XIX) can be made by introduction of Lg2 on the compound of the formula (XVIIIa).

X4 in the compound of formula (XX) can be a (cyclo)alkyl-carbonyl, heterocycloalkylcarbonyl or carboxylîc dérivative (carboxylîc acid or ester) which can be reduced into the corresponding alcohol making use of sodium borohydride or lithium aluminium hydride in a solvent such as THF at an elevated température such as !20°C.

The transcarbamylation ofthe compound of formula (XXI) to the macrocycle offormula (XIII) can be done using potassium carbonate or césium carbonate or potassium hydroxyde in a solvent such as acetonitrile at a température ranging from RT to retluxing solvent, or using sodium hydride in a dry solvent such as toluene at a température ranging from 0°C to refluxing solvent, either under microwave conditions or not.

Final deprotection ofthe nitrogen ofthe fused pyrazolo structure under acidic conditions, either or not after alkylation of the carbamate and/or substitution of the A ring 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 to a protected compound of formula (III). This compound of formula (III) can be converted to a compound of formula (IV) containing a leaving group on the fused pyrazolo structure and then 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 an intermediate of formula (XIX) containing a leaving group resulting in a compound of formula (XXII). The compound of formula (XIX) can commercially be acquired or being prepared from a compound of formula (XVIII) through a reaction with CbzCl or through the introduction of a leaving group Lg2 on the compound of formula (XVIIIa). The compound of formula (XXII) can be coupled via 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 of the fused pyrazolo structure, either or not after alkylation of the carbamate and/or substitution of the A ring results in the compound of formula (D21105

Scheme C

Pg1

(V) (IV]

In the above reaction Scheme C, the alkylation between a compound of formula (VI) with a compound of formula (XIX) can be accomplîshed in a solvent such as W/V-dimethyIformamide or acetonitrile and a base such as césium carbonate or potassium carbonate at an elevated température such as I2O^ÛC.

Suitable compounds of formula (XIX) may be either commercially acquired or obtained 10 through reaction with CbzCl and sodium hydroxide of a compound of formula (XVIII) in water as a solvent. Alternatively, the compound of formula (XIX) can be made by introduction of Lg2 on the compound of the formula (XVIIIa).

In the above reaction between compound of formula (XXII) and compound of formula (X), the leaving groups Lgi is advantageously a halogen atom such as chlorine, bromine or îodine. Such 15 a halogen displacement reaction can be effected under organometallîc coupling conditions such as Suzuki conditions using palladium catalysts such as for example tetrakis (triphenylphosphine)palladium(O) combined or not with 2-dicyclohexylphosphino-2’,4’,6’triîsopropylbiphenyl (Xphos) in the presence of potassium phosphate tribasic in a solvent mixture such as for example l ,4-dioxane/water at an elevated température such as for example 20 110°C either under mîcrowave conditions or not.

Suitable compounds of formula (X) may be either commercially acquired or obtained through various sélective protection and deprotection steps known to the person skilled m the art. A borylation step might be required to obtain 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 césium carbonate or potassium hydroxyde in a solvent such as acetonitrîle at a température ranging from RT to refluxing solvent, or using sodium hydride în a dry solvent such as toluene at a température ranging from 0°C to refluxing solvent, either under microwave conditions or not.

Final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, either or not after alkylation of the carbamate and/or substitution of the A ring yields the final compound of formula (I).

Altematively, the compounds of fonnula (I) can be prepared as shown in general Scheme D below wherein the fused pyrazolo structure of formula (II) is converted to a protected compound of formula (III) and then into a nitrogen protected compound of fonnula (XIV). The compound of formula (XIV) can be converted into a selectîvely protected fused pyrazolo structure of formula (XXIII) which is then alkylated with a compound of intermedîate (XIX) containing a Cbz group to resuit in a compound of formula (XXIV). Compound of formula (XIX) can be prepared from a compound of formula (XVIII) through a reaction with CbzCI or through the introduction of a leaving group Lg2 on the compound of formula (XVIlia). 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 fonnula (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 of the fused pyrazolo structure, either or not after alkylation of the carbamate and/or substitution of the A ring results in the compound of formula (I).

Scheme D

In the above reaction Scheme D, the reaction between a compound of formula (XXIII) and a compound of formula (XIX) can be accomplished in a solvent such as V,7V-dimethyl formant i de or acetonitrile and a base such as césium carbonate or potassium carbonate.

Suitable compounds of formula (XIX) may be either commercially acquired or obtaîned through reaction with CbzCI and sodium hydroxide of a compound of formula (XVIII) in water as a solvent. Altematively, the compound of formula (XIX) can be made by introduction of Lg2 on the compound of the formula (XVIIIa).

In the above réaction scheme, fused pyrazolo structure borylation of a compound of formula (XXIV) to the compound of formula (XXV) can be accomplished using an iridium catalyst and bis(pinacolato)diboron in a solvent such as TBME.

In the above reaction between compound of formula (XXV) and compound of fonnula (XXVI), the leaving groups Lgi is advantageously a halogen atom such as chlorine, bromine or iodine. Such a halogen displacement reaction can be effected under organometallic cross coupling conditions such as Suzuki conditions using palladium catalysts such as for example tetrakis (trîphenylphosphine)palladium(O) combined or not with 2-dicyclohexylphosphino-2’,4’,6’triisopropylbiphenyl (Xphos) in the presence of potassium phosphate tribasic in a solvent mixture such as for example 1,4-dioxane/water at an elevated température such as for example 90°C either under microwave conditions or not.

Suitable compounds of formula (XXVI) may be either commercially acquired or obtained through various reactions including sélective 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 césium carbonate or potassium hydroxyde in a solvent such as acetonitrile at a temperature ranging from RT to refluxing solvent, or using sodium hydride in a dry solvent such toluene at a temperature ranging from 0°C to refluxing solvent, either under microwave conditions or not.

Final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, either or not after alkylation of the carbamate and/or substitution of the A ring yields the final compound of formula (l).

Alternatively, the compounds of formula (I) can be prepared as shown in general Scheme E below wherein the fused pyrazolo structure of formula (II) is converted to a protected compound of formula (III). This compound of formula (III) can be converted to a compound of formula (IV) containing a leaving group on the fused pyrazolo structure and then 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 coupled în a crosscoupling reaction such as a Suzuki coupling with a (hetero-)aryl of formula (XXVII) to form a compound of formula (XXVIII). The X4 moiety in the compound of formula (XXVII) contains a carbonyl precursor such as (cycloialkyl-carbonyl, heterocycloalkyl-carbonyl, carboxylic acid or ester which can be reduced into a compound of formula (XXIX). The compound of formula (XXIX) is then alkylated with an intermediate of formula (XIX) containing a leaving group resulting în a compound of formula (XXI). The compound of formula (XIX) can commercially be acquired or being prepared from a compound of formula (XVIII) through a reaction with CbzCl or through the introduction of a leaving group Lg2 on the compound of formula (XVIIla). 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 fused pyrazolo structure, either or not after alkylation of the carbamate and/or substitution of the A ring results in the compound of formula (I).

(V)

(VI)

(XXVII)

Réduction

In the above Scheme E, reaction between compounds of formula (VI), the leaving groups Lgi is advantageously a halogen atom such as chlorine, bromine or îodine. Such a halogen 5 displacement reaction can be affected 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-dicyclohexylphosphino-2’,4’_}6’-triisopropylbiphenyl (Xphos) in the presence of potassium phosphate tribasic in a solvent mixture such as for example 1,4-dioxane/water at an elevated température such as for example 110°C either under microwave conditions or not.

Suitable compounds of formula (XXVII) contain a precursor moiety of the alcohol such as an ester or a carboxylic acid. Compounds of formula (XXVII) may be either commercially acquired or obtained through varions reactions including sélective protection and deprotection steps known to the person skilied in the art. For the compounds of formula (XXVII) a borylation 15 step might be required.

Réduction ofthe X4 carbonyl in the compound of formula (XXVIII) results in a compound of formula (XXIX).

In the above reaction scheme, the alkylation between a compound of formula (XXIX) with a compound of formula (XIX) can be accomplished in a solvent such as ΛζΝ-dimethylformamide 20 or acetonitrile and a base such as césium carbonate or potassium carbonate at an elevated température such as 120°C.

Suitable compounds of formula (XIX) may be either commercially acquired or obtained through reaction with CbzCI and sodium hydroxide of a compound of formula (XVIII) in water as a solvent. Altematively, the compound of formula (XIX) can be made by introduction of Lg2 on the compound of the fonnula (XVIIIa).

The transcarbamylation ofthe compound of formula (XXI) to the macrocycle of formula (XIII) can be done using potassium carbonate or césium carbonate or potassium hydroxyde in a solvent such as acetonitrîle at a température ranging from RT to refluxing solvent, or using sodium hydride in a dry solvent such as toluene at a température ranging from 0°C to refluxing solvent, either under microwave conditions or not.

Final deprotection of the nitrogen ofthe fused pyrazolo structure under acidic conditions, either or not after alkylation of the carbamate and/or substitution of the A ring yields the final compound of formula (I).

Altematively, the compounds of formula (I) can be prepared as shown in general Scheme F below wherein the fused pyrazolo structure of formula (II) is converted to a protected compound of fonnula (III). This compound of formula (III) can be converted to a compound of fonnula (IV) containing a leaving group on the fused pyrazolo structure and then into a nitrogen protected compound of formula (V). The compound of fonnula (V) can be converted into a selectîvely protected fused pyrazolo structure of formula (VI) which is then alkylated with an intermedîate of formula (XIX) containing a leaving group resulting in a compound of fonnula (ΧΧΠ). The compound of fonnula (XIX) can commercially be acquired or being prepared from a compound of formula (XVIII) through a reaction with CbzCI or through the introduction of a leaving group Lg2 on the compound of formula (XVIIIa). The compound of formula (XXII) can be coupled via organometallic cross coupling reaction such as 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 (cyclo)alkyl-carbonyl, heterocycloalkyl-carbonyl, carboxylic acid or ester which can be reduced into 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 pyrazolo structure, either or not after alkylation of the carbamate and/or substitution of the A ring results in the compound of formula (I).

De protection

(XXI)

In the above reaction Scheme F, the alkylation between a compound of formula (VI) with a compound of formula (XIX) can be accomplished in a solvent such as VA-dimethyiformamide 5 or acetonitrile and a base such as césium carbonate or potassium carbonate at an elevated température such as 120°C.

Suitabie compounds of formula (XIX) may be either commercially acquired or obtained through reaction with CbzCl and sodium hydroxide of a compound of formula (XVIII) in water as a solvent. Alternatively, the compound of formula (XIX) can be made by introduction of Lg2 on the compound of the formula (XVIIIa).

In the above reaction between compound of formula (XXII) and compound of formula (XXVII), the leaving groups Lgi is advantageously a halogen atom such as chlorine, bromine or iodine. Such a halogen displacement reaction can be affected under cross-coupling conditions such as Suzuki conditions using palladium catalysts such as for example 15 tetrakis(triphenylphosphine)palladium(0) combined or not with 2-dicyclohexylphosphino2’,4’,6’-triisopropylbiphenyl (Xphos) in the presence of potassium phosphate tribasic in a solvent mixture such as for example 1,4-dioxane/water at an elevated température such as for example 110°C either under microwave conditions or not.

Suitabie compounds of formula (XXVII) may be either commercially acquired or obtained 20 through various reactions includîng sélective protection and deprotection steps known to the person skilled in the art. For the compounds of formula (XXVII) a borylation step might be required.

Réduction of the X4 carbonyl in the compound of formula (XX) results in a compound of formula (XXI).

Transcarbamylation ofthe compound of formula (XXI) to the macrocycle offormula (XIII) can be achieved using sodium hydride in dry toluene at an elevated température such as ranging from !30°C or 150°C. Alternatively, the transcarbamylation can be done using potassium carbonate or KOH in a solvent such as acetonîtrile at an elevated température such as 14O°C. Final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, either or not after alkylation of the carbamate and/or substitution of the A ring yields the final compound of formula (I).

Alternatively, the compounds of formula (I) can be prepared as shown in general Scheme G below wherein the fused pyrazolo structure of formula (U) is converted to 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 a compound of intermediate (XIX) containing a Cbz group to resuit in a compound of fonnula (XXIV). Compound of formula (XIX) can be prepared from a compound of formula (XVIII) through a reaction with CbzCl or through the introduction of a leaving group Lg2 on the compound of fonnula (XVIIIa). The compound of formula (XXIV) can be boronated to a compound of fonnula (XXV). The boronated compounds of formula (XXV) can be reacted in a cross-coupling such as a Suzuki coupling with a (hetero)aryl of formula (XVI) to form a compound of fonnula (XX). The X4 moîety in the compound of formula (XX) contains a carbonyl precursor such as (cyclo)alkyl-carbonyl, heterocycloalkylcarbonyl, carboxylic acid or ester which can be reduced into a compound of fonnula (XXI).. The compound of formula (XXI) can then be cyciized by a transcarbamylation reaction to form a compound of formula (XIII). Final deprotection of the nitrogen of the fused pyrazolo structure, either or not after alkylation of the carbamate and/or substitution of the A ring results in the compound of formula (I).

Scheme G

In the above reaction Scheme G, the reaction between a compound of formula (XXIII) and a compound of formula (XIX) can be accomplished in a solvent such as VW-dimethylfonnamide 5 or acetonitrile and a base such as césium carbonate or potassium carbonate.

Suitable compounds of formula (XIX) may be either commercially acquired or obtained through reaction with CbzCl and sodium hydroxide of a compound of formula (XVIII) in water as a solvent. Alternatively, the compound of formula (XIX) can be made by introduction ofLg2 on the compound of the formula (XVIIIa).

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

In the above reaction between compound of formula (XXV) and compound of formula (XVI), the leaving groups Lgi îs advantageously a halogen atom such as chlorine, bromine or iodine.

Such a halogen displacement reaction can be affected under cross-coupling conditions such as Suzuki conditions using palladium catalysts such as for example tetrakis(triphenylphosphine) palladium(O) combined or not with 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl (Xphos) in the presence of potassium phosphate tribasic in a solvent mixture such as for example 1,4-dioxane/water at an eievated température such as for example 90°C either under microwave conditions or not.

Suitable compounds of formula (XVI) may be either commercially acquired or obtained through various reactions including sélective protection and deprotection steps known to the person skilled in the art.

The carbonyl moiety of X4 in the compound of formula (XX) can be reduced into the corresponding alcohol making use of, for instance, sodium borohydride or lithium aluminium hydride in a solvent such as THF at an elevated température 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 césium carbonate or potassium hydroxyde in a solvent such as acetonitrile at a température ranging from RT to refluxtng solvent, or using sodium hydride in a dry solvent such toluene at a température ranging from 0°C to refluxing solvent, either under microwave conditions or not.

Alternatively, the compounds of formula (I) can be prepared as shown in general Scheme H below wherein the fused pyrazolo structure of formula (II) is converted to 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 a compound of intermediate (XXX) containing a (hetero-)aromatic group to resuit in a compound of formula (XXXI). Compound of formula (XXX) can be prepared using different reaction steps known to the person skilled in the art and is în detail described for the exemplified compounds. The compound of formula (XXXI) can be macrocyclized through a CH-activation reaction. Final deprotection of the nitrogen of the fused pyrazolo structure, either or not after alkylation of the carbamate and/or substitution of the A ring results in the compound of formula (I).

In the above reaction Scheme H, the alkylation between a compound of formula (XXIII) with a compound of formula (XXX) can be accomplished in a solvent such as N,N5 dimethylfonnamide or acetonitrile and a base such as césium carbonate or potassium carbonate at an elevated température such as 80°C.

Suitable compounds of formula (XXX) may be either commercially acquired or obtained through synthesis routes avaîlable in the literature. In the above reaction between compound of formula (XXX) and compound of formula (XXIII), the leaving groups Lg₂ is advantageously a 10 mesylate group.

CH activation of 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 température such as 140°C. The leaving group Lgi is advantageously a halogen atom such as chlorine, bromine or iodine. Final deprotection of the 15 nitrogen of the fused pyrazolo structure under acidic conditions, either or not after alkylation ofthe carbamate and/or substitution ofthe A ring yields the final compound of formula (I).

Alternatively, the compounds of formula (I), a particular case of compounds of formula (I) wherein Xl is NR’a can be prepared as shown in general Scheme I below wherein the fused 20 pyrazolo structure of formula (XXXII) in which X5 is for instance a nitro group is converted to 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 pyrazolo structure of formula (VI) which is then alkylated with a compound of formula (VIII) containing a protecting group Pg3. After alkylation, deprotection of X2 results 25 in a compound of formula (XXXVI) which is then coupled in a cross-coupling reaction such as

a Suzuki reaction with a compound of formula (X). The resulting compound of formula (XII) can be macrocyclized affording a compound of formula (XIII), Final deprotection of the nitrogen of the fused pyrazolo structure, either or not after alkylation of the carbamate and/or substitution of the A ring results in the compound of formula (I).

Scheme I

H

(Vf} (VIH)

Alkylation

(1X)

X2 deprotection

(XXXVI) (X)

In the above reaction Scheme I, X5 is a nitro group and XI is in this scheme particularly NR’a. Halogénation of the fused pyrazolo structure can be achieved using for example iodine and potassium hydroxide in a solvent such as AW-dimethyIformamide at an elevated température 10 such as 60°C,

Réduction of the nitro group can be obtained usîng iron in the presence of ammonia chloride in a mixture of solvents such as EtOH, THF and water at an elevated température such as 80°C to yield a compound of formula (VI),

The alkylation between a compound of formula (VI) with a compound of formula (VIII) can be 15 accomplîshed in a solvent such as A', A-diméthylformamide or acetonitrile and a base such as césium carbonate or potassium carbonate at an elevated température such as 80 or 90°C. The compound of formula (VIII) contains a protecting group Pg3, which can be a phthalimide group. 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 température such as 60°C.

Organometallîc cross coupling such as Suzuki coupling of the compound of formula (XXXVI) with a compound of formula (X) can be done usmg palladium catalysts such as for example tetrakis(triphenylphosphine)palladium(0) combined or not with 2-dicyciohexylphosphino2’,4’,6’-triisopropylbiphenyl (Xphos) in the presence of potassium phosphate tribasic în a solvent mixture such as for example 1,4-dioxane/water at an elevated température such as for example 12O°C either under microwave conditions or not.

The cyclisation of the compound of formula (XII) to give compound of formula (XIII) can be performed by a method known by the person skilled in the art as a carbamylation reaction, for example by treatment with LF-carbonyldiimidazole and NJV-diisopropylethylamine in a solvent such asW-dimethylacetamide at for example 90°C. Final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, either or not after alkylation of the carbamate and/or substitution of the A ring yields the final compound of formula (I).

Alternatively, the compounds of formula (I) can be prepared as shown in general Scheme J below wherein the fused pyrazolo structure of formula (II) is converted to a protected compound of formula (III). This compound of formula (III) can be converted to a compound of formula (IV) containing a leavîng group on 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 then X1 is protected to form a compound of formula (XXXVII). The compound of formula (XXXVII) can be coupled via organometallîc cross coupling such as Suzuki coupling with a (hetero-)aryl of formula (XXXVIII) to form a compound of formula (XXXIX). Alkylation ofthe (hetero-)aromatic ring gives rise to a compound of formula (XL). Deprotection of Xl followed by alkylation with a compound of formula (XIX) results in a compound of formula (XL1I). The compound of formula (XIX) can commercially be acquired or being prepared from a compound of formula (XVIII) through a reaction with CbzCI or through the introduction of a leaving group Lg2 on the compound of formula (XVIIIa). Deprotection of X3 leads to a compound of formula (XXI). The compound of formula (XXI) can then be cyclized by a transcarbamylation réaction to form a compound of formula (XIII). Final deprotection of the nitrogen of the fused pyrazolo structure, either or not after alkylation of the carbamate and/or substitution of the A ring results in the compound of formula (I).

Scheme J

In the above reaction Scheme J, the protection of Xl of compound of formula (VI) can be accomplished with benzyl chloride in a solvent such as V-Y-dimethylformarnide or acetonitrîle 5 and a base such as césium carbonate or potassium carbonate at room température or at an elevated température.

In the above reaction between compound of formula (XXXVII) and compound of formula (XXXVI11), the leaving groups Lgi is advantageously a halogen atom such as chlorine, bromîne or iodine. Such a halogen displacement reaction can be effected via organometallic cross 10 coupling conditions such as Suzuki conditions using palladium catalysts such as for example tetrakis(trîphenylphosphine)palladium(0) combined or not with 2-dicyclohexylphosphîno2’,4’,6’-triisopropylbiphenyl (Xphos) in the presence of potassium phosphate tribasic in a solvent mixture such as for example 1,4-dîoxane/water at an elevated température such as for example 110°C either under microwave conditions or not.

5 Suitable compounds of formula (XXXVIII) may be either commercially acquired or obtained through various reactions including sélective protection and deprotection steps known to the person skilled in the art. For the compounds of formula (XXXVIII) a borylation step might be required.

In the above reaction scheme, the alkylation of compound of formula (XXXIX) can be accomplished using (2-bromoethoxy)(tert-butyl)dimethylsilane in a solvent such as Ν,Νdimethylformamide and a base such as sodium hydride at 0°C or at room température.

Deprotection of Xl in the compound of formula (XL) can be accomplished using hydrogen gas in the presence of Pd/C in a solvent such as EtOH at room température.

The alkylation between a compound of formula (XLI) with a compound of formula (XIX) can be accomplished in a solvent such as ΛζΧ-dtmethylformamide or acetonitrile and a base such as césium carbonate or potassium carbonate at an elevated température such as !20°C.

Suitable compounds of fonnula (XIX) may be either commercially acquired or obtaîned through reaction with CbzCl and sodium hydroxide of a compound of fonnula (XVIII) în water as a solvent. Altematively, the compound of fonnula (XIX) can be made by introduction of Lg2 on the compound of the formula (XVIIIa).

Deprotection of X3-OPg4 in the compound of formula (XLII) can be done using TBAF in a solvent such as THF at room température.

The transcarbamylation of the compound of formula (XXI) to the macrocycle of formula (XIII) can be done using potassium carbonate or césium carbonate or potassium hydroxyde in a solvent such as acetonitrile at a température ranging from RT to refluxing solvent, or using sodium hydride in a dry solvent such toluene at a température ranging from 0°C to refluxing solvent, either under microwave conditions or not.

Altematively, the compounds of formula (I) can be prepared as shown in general Scheme K below wherein the fused pyrazolo structure of formula (II) is converted to a protected compound of formula (111). The NH of the fused pyrazolo structure can be protected to a compound of fonnula (XIV). This compound of formula (XIV) can be converted to a boronic acid (or boronate ester) of formula (XV). The compound of formula (XV) can be coupled via organom étal lie cross coupling such as Suzuki coupling with a (hetero-)aryl of formula (XLIII) or of formula (XXVI) to form a· compound of formula (XLIV) or a compound of formula (XLIVa). Deprotection of Xl results in a compound of fonnula (XLV) or a compound of formula (XLVa). The compound of formula (XLV) or the compound of formula (XLVa) can be alkylated with an intermediate of formula (XIX) containing a carbamate resulting in a compound of fonnula (XLVI) or in a compound of formula (XXI). Deprotection of X3-OPg4 in the compound of fonnula (XLVI) results in 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 pyrazolo structure, either or not after alkylation of the carbamate and/or substitution of the A ring results in the compound of formula (I).

Scheme K

In the above reaction Scheme K, fused pyrazolo structure borylation of a compound of formula (XIV) to a compound of formula (XV) can be accomplished using an iridium catalyst and bis(pînacolato)diboron in a solvent such as TBME.

In the above reaction between compound of fonnula (XV) and compound of formula (XLIII) or compound of formula (XXVI), the leaving groups Lgi is advantageously a halogen atom such as chlorine, bromine or iodine. Such a halogen displacement reaction can be affected under cross-coupling conditions such as Suzuki conditions using palladium catalysts such as for example tetrakis(triphenylphosphÎne)palladium(0) combined with 2-dicyclohexylphosphino2’,4’,6’-triisopropylbiphenyl (Xphos) in the presence of potassium phosphate tribasic in a solvent mixture such as for example 1,4-dioxane/water at an elevated température such as for example 90°C either under microwave conditions or not.

Deprotection of XI 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 température.

In the above reaction scheme, the alkylation between a compound of formula (XLV) or a compound of formula (XLVa) with a compound of formula (XIX) can be accomplîshed in a solvent such as N,?/-dimethy Iformamide or acetonitrile and a base such as césium carbonate or potassium carbonate at an elevated température such as 50°C. Suitable compounds of fonnula (XIX) may be eîther commercially acquîred or obtained through reaction with CbzCl and sodium hydroxide of a compound of formula (XVIII) in water as a solvent. Alternatively, the compound of fonnula (XIX) can be made by introduction of Lg2 on the compound of the formula (XVIIla).

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 température.

The transcarbamylation of the compound of formula (XXI) to the macrocycle of formula (XIII) can be done using potassium carbonate or césium carbonate or potassium hydroxyde in a solvent such as acetonitrile at a température ranging from RT to refluxing solvent, or using sodium hydrîde in a dry solvent such toluene at a température ranging from 0°C to refluxing solvent, either under microwave conditions or not.

Final deprotection ofthe nitrogen ofthe fused pyrazolo structure under acidic conditions, either or not after alkylation of the carbamate and/or substitution of the A ring yields the final compound of formula (l).

Alternatively, the compounds of formula (!) can be prepared as shown in general Scheme L below wherein the fused pyrazolo structure of formula (II) îs converted to a protected compound of formula (III). The NH of the fused pyrazolo structure can be protected to a compound of formula (XIV). This compound of formula (XIV) can be converted to a boronic acid (or boronate ester) of fonnula (XV). The compound of formula (XV) can be coupled in a cross coupling reaction such as a Suzuki coupling with a (hetero-)aryl of formula (XLVIII) to form a compound of formula (XLIX). Introduction of a leaving group on X2 results in a compound of formula (L). Deprotection of XI results in a compound of formula (Ll). The compound of fonnula (Ll) can then be cyciized by a nucleophilic substitution to form a compound of fonnula (XIII). Final deprotection of the nitrogen of the fused pyrazolo structure, either or not after alkylation of the carbamate and/or substitution of the A ring results in the compound of formula (D21105

ίη the above reaction Scheme L, fused pyrazolo structure borylation a compound of formula (XIV) to a compound of formula (XV) can be accomplished using an iridium catalyst and 5 bis(pinacolato)diboron in a solvent such as TBME.

In the above reaction between compound of formula (XV) and compound of formula (XLVIH), the leaving groups Lgi is advantageously a halogen atom such as chlorine, bromine or iodine. Such a halogen displacement reaction can be effected via organométal lie cross coupling conditions such as Suzuki conditions using palladium catalysis such as for example 10 tetrakis(triphenylphosphine)palladium(0) combined or not with 2-dicyclohexylphosphîno2’,4’,6’-trnsopropylbiphenyl (Xphos) in the presence of potassium phosphate tribasic in a solvent mixture such as for example 1,4-dioxane/water at an elevated température such as for example 90°C either under microwave conditions or not.

The compound of formula (XLVIII) can be made from a reaction of an alcohol of formula 15 (XXVI), a chloroformate such as nitro-phenyl chloroformate and an amine of formula (XLVII).

Introduction of a leaving group on X2 such as a mesylate on the compound of formula (XLIX) can be achieved using mesy! chloride in the presence of a base such as trimethylamine in a solvent such as DCM at room température and results in a compound of formula (L).

Deprotection of XI to the compound of formula (Ll) can be achieved using a reagent such as

TBAF in a solvent such as THF at room température.

The macrocyclization ofthe compound of formula (Ll) by nucleophilic substitution can be done on using césium carbonate in a solvent such as VAMÎmethylformamide at an elevated température such as 80°C and results in a compound of fonnula (XIII).

Alternatively, the compounds of formula (l) can be prepared as shown in general Scheme M below wherein the fused pyrazolo structure of formula (II) îs converted to a protected compound of formula (III). This compound of formula (III) can be converted to a compound of fonnula (IV) containing a leavîng group on the fused pyrazolo structure and then into a nitrogen protected compound of formula (V). The compound of fonnula (V) can be converted into a selectively protected fused pyrazolo structure of formula (VI) which is then alkylated with an intermediate of fonnula (XIX) containing a teaving group resulting in a compound of formula (XXII). The compound of formula (XIX) can commercially be acquired or being prepared from a compound of formula (XV11I) through a reaction with CbzCl or through the introduction of a leavîng group Lg2 on the compound of fonnula (XVIIIa). The compound of formula (XXII) can be coupled in a copper mediated coupling with a protected alkyne (LU) 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 resulting in a compound of formula (XLII). Deprotection of X3OPg4 results in a compound of formula (XXI). The compound of formula (XXI) can then be cyclized by a transcarbamylation reaction to fonn a compound of formula (XIII). Final deprotection of the nitrogen of the fused pyrazolo structure, either or not after alkylation of the carbamate and/or substitution of the A ring results in the compound of formula (I).

In the above Scheme M, A is a 5-membered aromatic cyclic group as define in formula (a) with A4 is a carbon atom and A5 represent a carbon atom optionally substituted.

In the above reaction scheme, the alkylation between a compound of formula (VI) with a compound of formula (XIX) can be accomplished in a solvent such as ALV-di methyl form ami de or acetonitrile and a base such as césium carbonate or potassium carbonate at an eievated température such as 120°C.

Suitable compounds of formula (XIX) may be either commercially acquired or obtained 10 through reaction with CbzCl and sodium hydroxide ofa compound of formula (XVIII) in water as a solvent. Alternatively, the compound of formula (XIX) can be made by introduction of Lg2 on the compound ofthe formula (XVIIIa).

In the above reaction between compound of formula (XXII) and compound of formula (LU), the leaving groups Lgi is advantageously a halogen atom such as chlorine, bromine or iodine.

Such a halogen displacement reaction can be effected under conditions using palladium catalysts such as for example tetrakîs(triphenylphosphine)palladium(0) combined or not with

Cul in the presence of triethylamine in a solvent such as for example THF at an elevated temperature such as for example 80°C.

Alkyne deprotection can be achieved using TBAF în a solvent such as THF at room temperature giving a compound of formula (LIV).

Heteroaromatic ring formation to a compound of formula (XLII) can be effected through reaction with a reagent such as tert-buty l-(3-nitropropoxy)-diphenyl-si lane in the presence of PhNCO and trimethylamine in a solvent such as THF at an elevated temperature such as 80°C. Deprotection of X3-OPg4 in compound (XLII) can be done using TBAF in a solvent such as THF at room temperature giving a compound of formula (XXI).

Alternatively, the compounds of formula (I) can be prepared as shown în general Scheme N below wherein the fused pyrazolo structure of formula (Π) is converted to a protected compound of formula (III). This compound of formula (III) can be converted to a compound of formula (IV) containing a leaving group on the fused pyrazolo structure and then 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 (Villa) to form a compound of formula (LV). Deprotection of X2-N(Ra)Pg3 results in a compound of formula (LVI). The compound of formula (LVI) can be coupled to the (hetero-)aromatic compound of formula (LVII) through a reaction with CDL The compound of formula (LVllI) can then be cyclized by a CH activation reaction to form a compound of formula (XIII). Final deprotection of the nitrogen of the fused pyrazolo structure, either or not after alkylation of the carbamate and/or substitution of the A ring results in the compound of formula (I).

Scheme N

In the above reaction Scheme N, the alkylation between a compound of formula (VI) with a compound of formula (Villa) can be accomplîshed in a solvent such as.N,N-dimethylformamide or acetonitrîle and a base such as césium carbonate or potassium carbonate at room température or at an elevated température. Suitable compounds of formula (Villa) may be either commercially acquired or obtained through various sélective protection and deprotection steps known to the person skilled in the art.

Deprotection of the compound of formula (LV) can be affected using palladium over carbon on charcoal and hydrogen gas at room température in a solvent such as MeOH.

Coupling of the (hetero-)aromatic part on formula (LVI) can be achieved at room température using 1,1 '-carbonyldiimidazole and a base such as césium carbonate in a solvent such as N,Ndi methy lacetam ide

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 température such as ] 50°C.

Alternatively, the compounds of formula (I) can be prepared as shown in general Scheme O below wherein the fused pyrazolo structure of formula (II) is converted to a protected compound

7]

of formula (III). The NH of the fused pyrazolo structure can be protected to a compound of formula (XIV). This compound of formula (XIV) can be converted to 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 of formula (XLIII) or of formula (XXVI) to form a compound of formula (XLIV) or a compound of fonnula (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). Altematively the compound of formula (XLIVa) can be first deprotected to a compound of fonnula (XLIVb) before the one-pot alkylation and cyclisation. Final deprotection of the nitrogen of the fused pyrazolo structure, either or not after alkylation of the carbamate and/or substitution of the A ring results in the compound of formula (I).

Scheme O

or j Deprotecikin

HO— X3

(XLJVb)

(Xllla) (I)

In the above reaction Scheme O, fused pyrazolo structure borylation of a compound of formula 15 (XIV) to a compound of formula (XV) can be accomplished using an iridium catalyst and bis(pinacolato)diboron in a solvent such as TBME.

In the above reaction between compound of formula (XV) and compound of formula (XLIII) or compound of formula (XXVI), the leaving groups Lgi is advantageously a halogen atom such as chlorine, bromine or iodine. Such a halogen displacement reaction can be affected under cross-coupling conditions such as Suzuki conditions using palladium catalysts such as for example tetrakis(triphenylphosphine)palladium(0) combined with 2-dicycIohexylphosphino2’,4’,6’-triisopropylbiphenyl (Xphos) in the presence of potassium phosphate tribasic in a 5 solvent mixture such as for example 1,4-dioxane/water at an elevated température such as for example 90°C either under microwave conditions or not,

The possibly deprotection of Xl can be done using TBAF in a solvent such as THF at a température such as room température.

The possibly one-pot alkylation with a compound of formula (XIX) and transcarbamylation to 10 the macrocycle of formula (XIII) can be done using césium carbonate in a solvent such as acetonitrile at a température ranging from RT to 80°C.

Alternatively, the compounds of formula (I) can be prepared as shown in general Scheme P below wherein the fused pyrazolo structure of formula (II) is converted to a protected compound of formula (III). The NH of the fused pyrazolo structure can be protected to a compound of formula (XIV). This compound of formula (XIV) can be converted to a boronic acid (or 20 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 of formula (XXVI) to form a compound of formula (XLIVa), which can then be alkyiated with a compound of formula (XLVI) and cyclized by a carbamylation reaction to form a compound of formula (XLVIII). Final deprotection of the nitrogen of the fused pyrazolo structure, either or not after 25 alkylation of the carbamate and/or substitution of the A ring results in the compound of formula (I).

(XLVIIQ

Optional substttion carbamate, A ring substitution Daprotec^on

In the above reaction Scheme P, fused pyrazolo structure borylation of a compound of formula (XIV) to a compound of formula (XV) can be accomplîshed using an iridium catalyst and 5 bis(pînacolato)diboron in a solvent such as TBME.

In the above reaction between compound of formula (XV) and compound of formula (XXVI), the leaving groups Lgi is advantageously a halogen atom such as chlorine, bromine or iodine. Such a halogen displacement reaction can be affected under cross-coupling conditions such as Suzuki conditions using palladium catalysts such as for example 10 tetrakis(triphenylphosphine)palladium(0) combined wîth 2-dicyclohexylphosphino-2’,4’,6’triisopropylbiphenyl (Xphos) in the presence of potassium phosphate tribasic in a solvent mixture such as for example 1.4-dioxane/water at an elevated température such as for example 90°C either under microwave conditions or not.

The alkylation of the compound of formula (XLV) with a compound of formula (XLVI) can be ] 5 done using césium carbonate in a solvent such as acetonitrile at a température ranging from RT to 80°C.

Carbamylation of the compound of formula (XLVIII) can be achieved using a reagent such as CDI, COCh, CO₂ or CO.

Final deprotection of the nitrogen of the fused pyrazolo structure under acidic conditions, either 20 or not after alkylation of the carbamate and/or substitution of the A ring yields the final compound of formula (I).

EXAMPLES

IUPAC names of compounds ofthe invention were generated usîng the following software:

Product version: MarvînSketch 18.3.0

Build Date: 2018-0I-26

Internai Build id: I8.3.0-7913

Operating System: amd64 Windows 10.10.0

Character encodîng: windows-1252

Java: Jeroen Frîjters Java 1.8.0

Memory: 43,8M total, 10,0M free

Environment: Application .NET Version: v2.0.50727

IKVM Version : 8.10.1.2

JChem .NET API Assembly Version : 18.3.07913

JChem .NET API File Version : 18.3.0.7913

Marvin .NET Version : 18.3.0.137

Process type : x64 http://www.chemaxon.com 20

In case of a discrepancy between the drawn Chemical structures and the corresponding Chemical names, the drawn Chemical structures will be considered as true structures.

To préparé the compounds described in the examples, the following experimental protocols 25 were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were stirred magnetically at room température. When organic solutions were “dried”, they were generally dried over a drying agent such as sodium sulfate or magnésium sulfate. When mixtures, solutions and extracts were “concentrated”, they were typically concentrated on a rotary evaporator under reduced pressure. 30

Ail intermediates and final exemplified compounds were analyzed by high-performance liquid chromatography (HPLC) following one of the described methods below.

LCMS method A

Analyses were carried out on a Thermo Scientific Accucore Cl 8 (50 mm long x 2.1 mm LD., 2.6 pm) at 35 °C, with a flow rate of l .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% 5 Acetonitrile in 1.30 minutes; the resulting composition was held for 0.5 min; then the final mobile phase composition; from 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. MS acquisition range and UV detector were set to 100-1000 m/z and 190-400 nm respectiveîy.

LCMS method B

Analyses were carried out on a Phenomenex Kinetex 00B-4475-AN CI 8 column (50 mm long x 2.1 mm LD.; 1.7 pm particîes) 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 + 15 0.1% Formic acid) / 90% Acetonitrile in 1.50 minutes; the resulting composition was held for

0.40 min; then the final mobile phase composition; from 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 Agilent autosampler injector or 5 pL with Gerstel MPS injector. MS acquisition range and DAD detector were set to 100-800 m/z and 190-400 nm respectiveîy. 20

LCMS method C

Analyses were carried out on an YMC pack ODS-AQ Cl8 column (50 mm long x 4.6 mm LD..; 3 pm 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 acîd)/95% 25 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 ranges were set to 190-400 nm for the UV-PDA detector and 100-1400 m/z for the TOF-LCMS detector. Total run time: 6.2 minutes.

LCMS method D

Analyses were carried out on a Phenomenex Kinetex C18 column (50 mm long x 2.1 mm LD..; 2.6 pm particle size) at 35 °C, with a flow rate of 0.7 mL/min. A gradient elution was performed from 95% (Water + 50mM Ammonium Acetate)/5% Acetonitrile to 5% (Water + 50mM Ammonium Acetate )/95% Acetonitrile in 4.8 min; the resulting composition was held for 1.0 min; from 5% (Water + 50mM Ammonium Acetate )/95% Acetonitrîle to 95% (Water + 50mM Ammonium Acetate)/5% Acetonitrîle in 0.2 min. The standard injection volume was 2 pL. Acquisition ranges were set to 190-400 nm for the UV-PDA detector and 100-1400 m/z for the MS detector. Total run time: 6.2 minutes.

LCMS method E

Analyses were carried out on an YMC pack ODS-AQ C18 column (50 mm long x 4.6 mm LD..;

pm particle size) at 35 °C, with a flow rate of 2.6 mL/mîn. A gradient elution was performed from 95% (Water + 0. ] % Formic acid)/5% Acetonitrîle to 5% (Water + 0.1 % Formic acid)/95%

Acetonitrîle in 4.8 min; the resulting composition was held for 1.0 min; from 5% (Water + 0.1% formic acid)/95% Acetonitrîle to 95% (Water + 0.1% formic acîd)/5% Acetonitrîle in 0.2 min. The standard injection volume was 2 pL. Acquisition ranges were set to 190-400 nm for the (JV-PDA detector and 100-1400 m/z for the MS detector.

LCMS method F

Analytical HPLC was conducted on a X-Select CSH Cl8 XP column (2.5 pm 30 x 4.6 mm id) eluting with 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrîle (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/minute at 40°C. The mass spectra (MS) were recorded on a Waters ZQ mass spectrometer (scan 200-900 uma) using electrospray positive ionisation [ES+ to give [M+H]⁺ molecular ions] or electrospray négative ionisation [ES- to give [M-H]' molecular ions] modes with a 20 V cône voltage.

LCMS method G

Analytical HPLC was conducted on a X-Select CSH C18 XP column (2.5 pm 30 x 4.6 mm id) eluting with (NH₄)2CO₃ aq. 2g/L in water (solvent A) and acetonitrîle (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/minute at 40°C. The mass spectra (MS) were recorded on a Waters ZQ mass spectrometer (scan 200-900 uma) using electrospray positive ionisation [ES+ to give [M+H]⁺ molecular ions] or electrospray négative ionisation [ES- to give [M-H]' molecular ions] modes with a 20 V cône voltage.

LCMS method H

Analytical HPLC was conducted on a X-Select CSH C 1 8 XP column (2.5 gm 30 x 4.6 mm id) eluting with 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrîle (solvent B), using the following elution gradient 0-4 minutes: 0% to 50% B at a flow rate of 1.8 5 mL/minute at 40°C. The mass spectra (MS) were recorded on a Waters ZQ mass spectrometer (scan 200-900 uma) using electrospray positive ionisation [ES+ to give [M+H]⁺ molecular ions] or electrospray négative ionisation [ES- to give [M-H] molecular ions] modes with a 20 V cône voltage.

LCMS method I

Analytical HPLC was conducted on aX-Select CSH C18 XP column (2.5 gm 30 x 4.6 mm id) 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 minutes: 40% to 100% B, 4-5min: 100%B at a flow rate of 1.8 mL/minute at 40°C. The mass spectra (MS) were recorded on a Waters ZQ mass 15 spectrometer (scan 200-900 uma) using electrospray positive ionisation [ES+ to give [M+H]⁺ molecular ions] or electrospray négative ionisation [ES- to give [M-H]' molecular ions] modes with a 20 V cône voltage.

LCMS method J

Analytical HPLC was conducted on a X-Select CSH Cl 8 XP column (2.5 gm 30 x 4.6 mm id) eluting with 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrîle (solvent B), using the following elution gradient 0-6 minutes: 5%to 100% B, 6-7min: 100%B at a flow rate of 1.8 mL/minute at 40°C. The mass spectra (MS) were recorded on a Waters ZQ mass spectrometer (scan 200-900 uma) using electrospray positive ionisation [ES+ to give [M+H]⁺ molecular ions] or electrospray négative ionisation [ES- to give [M-H]^- molecular ions] modes with a 20 V cône voltage.

Chiral analytical SFC was conducted on a Whelk 01 (R,R) column (1.8gm 100 x 4.6 mmid) eluting with CO2/methanol (70/30)at a flow rate of 2.5mL/minute at 35°C.

Ail final exemplified compounds were analysed by proton NMR.

'H NMR spectra were recorded in either CDCh, ί/6-DMSO or CDjOD on a Bruker Avance

400MHz or were recorded on a'Bruker Ultrashield AV300 MHz spectrometer, with a Bruker

5mm BBI 1H/D-BB Z-GRD probe, usîng a BACS-60 sample changer, and registered with Bruker Topspin 2.1 software. Chemical shifts are reported in parts per million (ppm) relative to the residual protiated solvent (7.26 ppm for CDCh, 2.50 ppm for J6-DMSO and 3.31 ppm for CD3OD). For 'H NMR spectra, multiplicities, coupling constants in hertz and numbers of 5 protons are indicated parenthetically. Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet, br s = broad singlet.

Alternatively, the 'H-NMR measurements were performed on Bruker Avance III 500 MHz spectrometer, using DMSO-d6 (hexadeutero-dimethylsulfoxide) or CDCh (deuterochloroform) 10 as solvent. Ή-NMR data is în the form of delta values, given in part per million (ppm), using the residual peak of the solvent (2.50 ppm for DMSO-d6 and 7.26 ppm for CDCh) as internai standard. Splitting patterns are designated as: s (singlet), 2s (2xsinglet), d (doublet), 2d (2xdoublet), t (triplet), 2t (2xtriplet), q (quartet), 2q (2xquartet), quint (quintet), sept (septet), m (multiplet), 2m (2xmultiplet), brs (broad singlet), brd (broad doublet), brt (broad triplet), brq 15 (broad quartet), brm (broad multiplet), vbrs (very broad singlet), dd (doublet of doublets), td (triplet of doublets), dt (doublet of triplets), dq (doublet of quartet), ddd (doublet of doublet of doublets), dm (doublet of multiplets), tm (triplet of multiplets), qm (quartet of multiplets).

Abbreviations:

The following abbreviations are employed herein:

Ph - phenyl

Ac = acetate

Bn = benzyl t-Bu = tert-butyl 25 n-Bu = linear butyl Me = methyl Et = ethyl Pr = propyl iPr = isopropyl 30 Bu = butyl

TMS = trimethylsilyl

TBS = tert-butyldimethylsîlyl

TFA = trifluoroacetic acid i-PrjNEt or DIPEA = VA-diisopropylethylamine

TEA = triethylamine

DMAP = 4-dimethylaininopyridine

Pd/C = palladium on carbon

KOH = potassium hydroxide

NaOH = sodium hydroxide

LiOH = lithium hydroxide

Ar = argon

N2 = nitrogen

H2 = hydrogen

LAH = lithium Aluminium Hydride

Boc = tert-butoxycarbonyl

Cbz = carboxybenzyl

LDA = lithium diisopropylamide

NBS =A-bromosuccinimide

NIS =N-iodosuccinîmide

ACN = acetonitrile

PTSA = p-toluenesulfonic acid

THF = tetrahydrofuran

DCM = dichloromethane

DMF = XN-dimethylform amide

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(l-adamantyl)-n-butylphosphine

XPhos = 2-Dicyclohexylphosphino-2^r,4',6'-triisopropylbiphenyl dppf = 1,1-Bis(diphenylphosphino)ferrocene wt% = weight % e.e. = enantiomeric excess min = mînute(s) h or hr = hour(s)

L = liter(s) mL = mil Ii hter(s) gL = microliter(s) g = gram(s) mg = milligram(s) mol = moles mmol = millimole(s) RT = room température ta = rétention time sat = saturated aq. = aqueous TLC = thin layer chromatography HPLC = high performance liquid chromatography LC/MS = high performance liquid chromatography/mass spectrometry MS or Mass Spec = mass spectrometry NMR = nuclear magnetic résonance ppm = parts per million

Example 1: 8,14-dioxa-4,10,Î9,20-tetraazatetracyclo(13.5.2.1²⁶.0¹⁸’²¹]tricosa-l(20),2,4,

6(23),15,17,21-heptaen-9-one

Example I is prepared according to the synthesis route described in general Scheme A.

Préparation of intermediate 1 : 5-((tert-butyldimethylsilyl)oxy)-lH-indazole

lH-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

SI

added and the mixture was stirred at RT for 16 hours. A saturated NaHCOr solution was added and the reaction mixture was extracted with DCM (2x). The combined organic layers were dried over MgSÛ4, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel using Hept/EtOAc (100:0 to 70:30). The desired fractions were combined and concentrated under reduced pressure yielding 5-((tertbutyldimethylsilyl)oxy)-lH-indazole 1 as a salmon solid.

LCMS method A: [M+H]⁺ = 249.0, t_R = 0.997 min

Préparation of intermediate 2 : 5-((tert-butyldimethylsilyl)oxy) -3-iodo-IH-indazole i c, J \ 2^Si ii V T Ir

H

5-((tert-butyldimethylsilyl)oxy)-3-iodo-lH-indazole 1 (20 g, 80.515 mmol) was dissolved in 240 mL of DCM, N-iodosuccinimide (19.021 g, 84.54] mmol) was added and the mixture was stirred at RT for 16 hours. The reaction mixture was diluted with DCM and a saturated NaHCOa solution was added. The two layers were 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 affording the crude product which was purified by flash chromatography on silica gel 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-((tertbutyldimethylsilyl)oxy)-3-iodo-lH-ïndazole 2 as a light brown solid.

LCMS method A: [M+H]⁺ = 374.9, t_R = L156 min

Préparation of intermediate 3 : 5-((tert-butyidimethylsilyl)oxy)-3-iodo-l-(tetrahydro-2Hpyran-2-yl)-lH-indazole

I w ô

To a solution of 5-((tert-butyldimethylsilyl)oxy)-3-iodo-lH-indazole 2 (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 atRT for 16 hours. The mixture was diluted with DCM and a saturated NaHC0₃ solution was added. The two layers were separated and the water layer was extracted with DCM (2x). The combined organic layers were dried over MgSO4, fîltered and the solvent was removed under reduced pressure. The concentrated was purified by flash chromatography (silica; Heptane/EtOAc 100:0 to 95:5). The desired fractions were combined and the solvent was removed under reduced pressure affording 5-((tert-butyldimethylsilyl)oxy)-3-iodo-l(tetrahydro-2H-pyran-2-yl)-lH-indazole 3 as a light orange oil.

LCMS method A: [M+H]⁺ = 458.9, îr = 1.377 min

Préparation of intermediate 4 ; 3-iodo-l-(tetrahydro-pyran-2-yl)-lH-indazol-5-oi

5-((t_ert-butyldimethylsilyl)oxy)-3-iodo-l-(tetrahydiO-2H-pyrar)-2-yl)-lH-indazole 3 (10.000 g, 21.814 mmol) was dissolved in 62 mL ofTHF. TBAF [IM] in THF (32.8 mL, 32.800 mmol) was added at 0 °C. The reaction was stirred at RT for 16 h. A saturated NaHCO₃ solution was added and the two layers were separated. The water layer was extracted with DCM (2x). The combined organic layers were dried over MgSÛ4, fîltered 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-lodo-l-(tetrahydro-pyran-2-yl)-lH-indazol5-ol 4 as a creamy solid.

LCMS method B: [M+H]⁺ = 345.0, tR = 0.767 min

Préparation of intermediate 5 : 3-(dibenzylamino)propan-l-oi

To a solution of 3-aminopropan-l-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 fîltered 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 giving the crude product which was purified by flash chromatography on silicagel using Hept/EtOAc (100:0 to 80:20) as eluents. The desired fractions were combined and the solvent was removed under reduced pressure yielding 35 (dibenzylamino)propan-l -ol 5 as a yellowish oil.

LCMS method B: no m/z detected, îr = 0.248 min

Préparation of intermedîate 6: 3-(dibenzylamîno)propyl methane sulfonate

3-(dibenzylamino)propan-l-ol 5 (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 methane sulfonyl chloride (1.970 mL, 25.454 mmol) was added. The mixture was stirred at RT for 16 hours. DCM and a saturated solution of NaHCO₃ were added. The two layers were separated and the mixture was extracted with DCM (x2). The combined organic layers were dried over

MgSO₄, filtered and the solvent under reduced pressure yielding 3'(dibenzylamino)propyl methane sulfonate 6 as a yellow oil which was used in the next step without purification.

LCMS method B: no m/z detected, îr = 0.380 min

Préparation of intermedîate 7: N,N-dibenzyl-3-((3-iodo-l-(tetrahydro-2U-pyran-2-yl)-lH20 indazol-5-yl)oxy)propan-l-amine

3-(dibenzylamino)propyl methane sulfonate 6 (crude, 6.298 g, 18.888 mmol) dissolved in 10 mL of À/JV-dimethyIformamide and was added to a stirred mixture of 3-îodo-l-(tetrahydro21105 pyran-2-yl)-lH-indazol-5-oI 4 (5.000 g, 14.529 mmol) and césium carbonate (7.101 g, 21.794 mmol) in 40 mL of ALV-dimethylfonnamide. The reaction was stirred at RT for 30 minutes and then heated at 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 MgSOi, filtered and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel, using Hept/EtOAc, (100:0 to 80:20). The fractions containing the desired compound were combined and the solvent is removed under reduced pressure to yield N,N-dibenzyl-3-((3-iodo-l-(tetrahydro-2H-pyran-2-yl)-lHindazol-5-yl)oxy)propan-l-amine 7 as a yellowish oil.

LCMS method B: [M+H]⁺ = 582.2, t_R = 0.890 min

Préparation of intermediate 8: (5-(hydroxymethyl)pyridin-3-yl)boronic acid

HO^BOH (5-bromopyridin-3-yl)methanol (3.000 g, 15.956 mmol), bis(pînacolato)diboron (4.862 g, 19.147 mmol) and potassium acetate (4.698g, 47.868 mmol) were dissolved in 50 mL of 1,4dioxane. After degassing with N2 for 5 minutes, Pd(dppf)Ch DCM (1.303 g, 1.596 mmol) was added and the reaction mixture was stirred at 1 !0°C for 4 hours. The mixture was diluted with EtOAc and filtered over a pad of celite. The solvent was evaporated under reduced pressure, yielding (5-(hydroxymethyl)pyridin-3-yl)boronic acid 8 as a dark brown solid. The crude was used in the next step without purification.

LCMS method B: [M+H]’ = 154.1, t_R - 0.107 min

Préparation of intermediate 9: {5-[5-(3-dibenzylamino-propoxy)-l-(tetrahydro-pyran-2-yi)1 H-indazol-3-yl]-pyridin-3-yl}-meth anoi

Tetrakis(triphenylphosphine)palladium(0) (1.411 g, 1.221 mmol) and XPhos (0.291 g, 0.611 mmol) were added to a mixture of N,N-dîbenzyl-3-((3-iodo-l-(tetrahydro-2H-pyran-2-yl)-l Hindazol-5-yl)oxy)propan-l-amine 7 (7.100 g, 12.210 mmol), (5-(hydroxymethyl)pyridin-35 yl)boronîc acid 8 (crude, 8.84 g, 15.873 mmol) and potassium phosphate tribasic (7.77 g, 36.63 mmol) in 122.00 mL of l,4-dioxane/H2O (3:1). The mixture was degassed with Ns for 5 min and stirred at 90°C for 16 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 10 crude was purified by flash chromatography on silica gel, using DCM:MeOH (100:0 to 98:2).

The desired fractions were combined and the solvent was removed under reduced pressure to obtain {5-[5-(3-dibenzylamîno-propoxy)-l-(tetrahydro-pyran-2-yl)-lH-indazol-3-yl]-pyridin3-yl}-methanol 9 as a yellow oil.

LCMS method B: [M+H]^h = 563.3, t_R = 0.749 min

Préparation of intermediate 10: {5-[5-(3-amino-propoxy)-l-(tetrahydro-pyran-2-yl)-lHindazol-3-yl]-pyridin-3-yl}-methanol

{5-[5-(3-Dibenzylamîno-propoxy)-l-(tetrahydro-pyran-2-yl)-lH-indazol-3-yl]-pyridin-3-yl}20 methanol 9 (6.000 g, 10.662 mmol) was dissolved in 106 mL of EtOAc, degassed with N2.

Pd/C 10% w/w (6.000 g) was added and the reaction mixture was stirred under H2 atmosphère with a balloon at RT for 66 hours. The reaction mixture was fïltered over a pad of celite and washed with a mixture of DCM:MeOH:DMA (9:1:1). lhe fîltrate was concentrated under reduced pressure to afford 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-amino-propoxy)-l (tetrahydro-pyran-2-yI)-lH-indazol-3-yl]-pyridin-3-yl}-methanol 10 as a cream solid.

LCMS method B: [M+H]⁺ = 383.3, t_R = 0.316 min

Préparation of intermediate 11: 19-(oxan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclof 13.5.2. l²’⁶.0^ls,2l]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

CDI (0.103 g, 0.633 mmol) was added to a solution of (5-(5-(3-amînopropoxy)-l-(tetrahydro2H-pyran-2-yl)-l H-indazol-3-yl)pyridin-3-yl)methanol 10 (0.220 g, 0.575 mmol) in 133 mL of DMA. The mixture was stirred at RT 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, fïltered 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 was removed under reduced pressure to afford 19-(oxan-2-yi)-8,14-dioxa-4,10,I9,20-tetraazatetracyclo[13.5.2.1²’⁶.0^1S’^2l]tricosa-](20),2,4, 6(23), 15,17,21 -heptaen-9-one 11 as a colorless foam.

LCMS method B: [M+Hf = 409.1, t_R = 0.753 min

Préparation of Example 1: 8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1²’⁶.0^,su'] tricosa-1 (20),2,4, 6(23),15,17,2 l-heptaen-9-one

A mixture of 19-(oxan-2-y l)-8,14-dioxa-4,10,19,20-tetraazatetracy c lo[ 13.5.2.1^2,6.0¹⁸’²¹ jtrîcosa1(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 RT for 2 hours. The mixture was cooled to 0°C, diluted with DCM and 5 quenched carefully with a saturated solution of NaHCOs. 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 chromatography on silica gel (DCM :MeOH, 100:0 to 94:6). The desired fractions were combined and the solvent was removed under reduced pressure yielding 8,14-dioxa-4,10,l9,2010 tetraazatetracyclo[ 13.5.2.1²Αθ’^8,21 ]tricosa-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, t_R = 2.020 min

LCMS method D: [M+H]⁺ = 325.1, t_R = 3.945 min

Ή NMR (300 MHz, DMSO) Ô 13.32 (s, IH), 9.03 (s, IH), 8.53 (s, 1 H), 8.15 (s, IH), 7.99 (t, J 15 - 5.9 Hz, IH), 7.54 (d, J - 9.0 Hz, IH), 7.21 (s, IH), 7.01 (d, J - 8.9 Hz, IH), 5.28 (brs, 2H),

4.29 (t, J = 8.3 Hz, 2H), 3.17 (d, J = 4.6 Hz, 2H), 1.97 (brs, 2I-I) ppm.

Example 2: 10-methyl-8,14-dioxa-4,10,19,20-tetraazatetracy cio [13.5.2. PAO¹⁸²'Itricosa20 l(20),2,4,6(23),15,17,21-heptaen-9-one

Example 2 is prepared according to the synthesis route described in general Scheme A.

Préparation of intermedîate 12 : 10-methyl-19-(oxan-2-yl)-8, 14-dioxa-4,10,19,20-tetraazatetracyclof13.5.2. i²’⁶,o^1s'²ⁱ]tricosa-l (20),2,4,6(23),15,17,21-heptaen-9-one

To a solution of intermedîate 11 (0.05 g, 0.12 mmol) in 5 mL of dry 7V,jV-dimethylformamide, under nitrogen atmosphère, at 0°C, sodium hydride 60% in minerai 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 RT for 15 minutes. The mixture was cooled to 0°C, diluted with EtOAc and quenched carefully 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 was removed under reduced pressure. The product was purified by flash chromatography on silica gel (DCM:MeOH 100:0 to 97.5:2.5). The desired fractions were combined and the solvent was removed under reduced pressure affording 10-methyl-19-(oxan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracy cio [13.5.2.1²⁶.

0¹⁸'^2l]tricosa-l(20),2,4,6(23 )J5J7,21-heptaen-9-one 12 as a yellow oil.

LCMS method B: [M+H]⁺ = 423.1, t_R = 0.897 min

Préparation of Example 2: 10-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.

l^2È.0i^s*²¹]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

A mixture of 10-methy l-19-(oxan-2-yl)-8,!4-dioxa-4,l 0,19,20-tetraazatetracyclo[ 13.5.2.

12,6 ₀ ^|e.2i]tricosa-l(20),2,4,6(23),15,l7,21-heptaen-9-one 12 (0.042 g, 0.099 mmol) in HCl in

1,4-dioxane [4N] (5.0 mL) was stirred at RT for 2h. The mixture was cooled at 0°C, diluted with DCM and quenched carefully 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 MgSCh, filtered and the solvent was removed under reduced pressure. The product was purified by flash chromatography on silica gel (DCM:MeOH, 100:0 to 94:6). The desired 5 fractions were combined and the solvent was removed under reduced pressure to afford 10methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1²’⁶.0^18J1]tricosa-l(20),2,4,6(23), 15,17.21-heptaen-9-one example 2 as a white solid.

LCMS method E: [M+H]⁺ = 339.1, îr = 2.298 min

LCMS method D: [M+H]⁺ = 339.1, t_R = 3.425 min 'HNMR(300 MHz, 100°C, r/6-DMSO) δ 13.00 (s, 1 H), 9.03 (s, 1H),8.55 (s, IH), 8.28 (s, IH), 7.52 (d, J = 9.0 Hz, IH), 7.20 (s, IH), 7.02 (dd, J = 9.0, 2.3 Hz, IH), 5.40 (brs, J = 17.6 Hz, 2H), 4.32 (t, J = 8.4 Hz, 2H), 3.68 - 3.21 (m, 2H), 3.03 (s, 3H), 2.33 - 2.04 (m, 2H) ppm.

Example 3: 4-lluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹]trîcosa-l(20),

2,4,6(23),15,17,21-heptaen-9-one

Example 3 is prepared according to the synthesis route described in general Scheme A.

Préparation of intermediate 13: 2-(3-(3-iodo-l-tetrahydropyran-2-yl-indazol-5-yl)oxy propyi]isoindoline-l,3-dione

A suspension of 3-îodo-I-tetrahydropyran-2-yl-indazol-5-ol 4 (4 g, 11.63 mmol), césium carbonate (7.560 g, 23.26 mmol) and V-(3-bromopropyl)phthahmide (4.679 g, 17.45 mmol) m ALV-dimethyIformamide (48 mL) was heated at 60°C for 16h. The reaction mixture was concentrated under reduced pressure. The resulting white solid was triturated with ethyl acetate and recovered. The recovered filtrate was washed with water. The aqueous layer was extracted with ethyl acetate (3 x). The combined organic layer was washed with water then brine, dried over sodium sulfate, filtered and evaporated under vacuum to give a cream solid. Both white and cream solids were gathered to give 2-[3-(3-iodo-l-tetrahydropyran-2-yl-indazol-5y l)oxypropy IJ isoindoline-1,3-dione 13 as a cream solid.

LCMS method F: [M+H]⁺ = 532, ta = 3.12 min

Préparation of intermediate 14: 3-(3-iodo-l-tetrahydropyran-2-yl-indazol-5-yl)oxypropan-lamine

A mixture of 2-[3-(3-iodo-l-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]isoindoline-l,3dione 13 (6.176 g, 11.63 mmol) and hydrazine monohydrate (2.04 mL, 58.15 mmol) in EtOH (40 mL) was heated to 50°C for 16 h. The reaction mixture was evaporated under reduced pressure and EtOH was added to the white solid. The solid was filtrated, washed with EtOH (3 x) and the filtrate was evaporated under reduced pressure to give 3-(3-iodo-l-tetrahydropyran2-yl-indazol-5-yl)oxypropan-l-amine 14 as a pale brown oil.

LCMS method F: [M+H]⁺ = 402, tR = 1.65 min

Préparation of intermediate 15: [3-f5-(3-aminopropoxy)-l-tetrahydropyran-2-yl-indazol-3yi]-5-fluoro-phenyl/methanol

To a degassed solution of 3-(3-iodo-l-tetrahydropyran-2-yl-indazol-5-y[)oxypropan-l-amÎne 14 (200 mg, 0.500 mmol), 3-fluoro-5-(hydroxymethyI)phenylboronic acid (127 mg, 0.750 mmol), tripotassium phosphate (318 mg, 1.500 mmol) and xPhos (24 mg, 0.050 mmol) in 1,45 dioxane (3.2 mL) and water (1.4 mL) was added tetrakîs(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol). The reaction mixture was irradiated under μ-waves (Biotage initiator+), absorption level: high at I20°C for Ih. The reaction mixture was filtered through a celite bed then 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 10 sulfate and concentrated under reduced pressure to give [3-[5-(3-aminopropoxy)-ltetrahydropyran-2-yl-indazol-3-yl]-5-fluoro-phenyl]methanol 15 as a pale yellow oil.

LCMS method F: [M+H]⁺ = 400, t_R = 1.76 min

Préparation of intermediate 16: 4-fluoro-19-(oxan-2-yl)-8_t14-dioxa~î0,19,20-triazatetra 15 cyclo[l3.5.2.1²⁶.0^ls,2}}tricosa-l(20),2(23),3,5,15(22),16,l8(21)-heptaen-9-one

To a solution of [3-[5-(3-aminopropoxy)-l-tetrahydropyran-2-yl-indazol-3-yl]-5-fluorophenyl]methanol 15 (199 mg, 0.499 mmol) in DMA (150 mL) was added 1,1carbonyldiimidazole (89 mg, 0.549 mmol). The reaction mixture was stirred at RT for 2 hours 20 then heated to 90°C for 48 hours. The reaction was concentrated under vacuum then ethyl acetate and a saturated aqueous solution of NaHCCh 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 was removed under reduced pressure. The crude product was purified by column chromatography eluting with cyclohexane/EtOAc/EtOH (3-1 );

100/0 to 70/30 to give 4-fluoro-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo [ 13.5.2.1^.0^18,2’jtricosa-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, t_R = 2.84 min

Préparation of Example 3: 4-fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹] trîeosa-l(20), 2,4,6(23),15,17,21-heptaen-9-one

To a solution of 4-fluoro-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2. 12=6.0^l8’²¹]tricosa-1(20),2(23),3,5,15(22), 16,18(2l)-heptaen-9-one 16 (92 mg, 0.217 mmol) in 1,4-dioxane (2.6 mL) was added 4M HCl in 1,4-dioxane (0.54 mL, 2.17 mmol) and the reaction was stirred at RT for 1 h30. 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 give 4-fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^,8’²¹]tricosa-l(20),2,4,6(23),15, 17,21-heptaen-9-one example 3 as a white solid.

LCMS method F: [M+H]⁺ = 342, t_R = 2.16 min

LCMS method G: [M+H]⁺ = 342, t_R = 2.24 min ‘H NMR (400 MHz, r/6-DMSO) δ 13.06 (IH, s), 7.74 (2H, m), 7.62 - 7.58 (1 H, m), 7.52 - 7.49 (IH, m), 7.35 (IH, m), 7.14 - 7.11 (IH, m), 7.00 (IH, 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-l0,19,20,23-tetraazatetracyclofl3.5,2.1²’⁶.0^l8’²¹]tricosa-l(20),2,4, 6(23),15,17,21-heptaen-9-one

H Q

N-...

H

Example 4 is prepared according to the synthesis route described in general Scheme B.

Préparation of intermediate 17: tert-butyl-dimethyl-(l~tetrahydropyran-2-ylindazol-5-yI)oxysilane

To a solution of tert-butyl-(l H-indazol-5-yloxyEdîmethyl-silane 1 (15.95 g, 64.28 mmol) in DCM (200 mL) and THF (100 mL) was added at RT methane sulfonic acid (0.834 mL, 12.86 mmol) and DHP (17.59 mL, 192.84 mmol). The resulting reaction mixture was stirred at RT ovemight. The residue was diluted with saturated sodium bicarbonate solution and extracted 10 with EtOAc twice. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash-column chromatography (120 g silica Biotage) chromatography (cyclohexane - ethyl acetate, 1:0 to 90/10) . The desired fractions were combined and the solvent was removed under reduced pressure to give terΐ-butyl-dimethyl·(l-tetrahydropyran-2-ylindazol-5-yl)oxy-silane 17 as 15 white crystals.

LCMS method F: [M+H]⁺ = 333.2, îr = 3.53 min

Préparation of intermediate 18: [5-[tert-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-ylin dazol-3-ylfboronic acid and 5-[(tert-butyldimethylsilyl)oxy]-l-(oxan-2-yl)-3-(tetramethyl20 1,3_f2-dioxaborolan-2-yi)-l H-indazole

In a sealed tube was added tert-butyl-dimethyl-(l-tetrahydropyran’2-ylindazol-5-yl)oxy-silane 17 (3 g; 9.03 mmol), TBME(15 mL), 4,4,5_J5-tetramethyl-2-(4₎4,5,5-tetramethyl-l,3,2dioxaborolan-2-y!)-l,3,2-dioxaborolane(2.3 g; 9.03 mmol), 4,4'-di-tert-butyl-2,2’25 bipyridine( 145 mg; 0.54mmol) and (I,5-cyclooctadiene)(methoxy)iridium(I) dimer (119 mg;

0.18 mmol). The réaction was degassed with Argon during 10 min then it was put 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 give a mixture of[5-[tert-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-ylindazol-3-yl] boron ic acid and 5-[(tert-butyldimethylsilyl)oxy]-l-(oxan-2-yl)-3-(tetramethyll,3,2-dîoxaborolan-2-yl)-lH-indazole 18 as a brown oil. The product was used in next step without further purification.

LCMS method F: [M+H]⁺ = 459, t_R = 3.80 min

LCMS method G: [M+H]⁺ = 377.2, t_R = 3.15 min

Préparation of intermediate 19: 2-(5-hydroxy~I-teirahydropyran-2-yl-indazol-3-yl)pyridine4-carhoxylate

To a solution of [5-[tert-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3-yl]boronic acid and 5-[(tert-buty ldi methy lsilyl)oxy]-l -(oxan-2-yl)-3-(tetramethyl-l,3,2-dioxaborolan-2yl)-lH-indazole 18 (1.5 g, 3.99 mmol) in jV,jV-dimethylformamide (5 mL) were added at RT methyl 6-bromopyridine-2-carboxylate (1.030 g, 4.78 mmol), césium carbonate (3.8 g, 11.96 mmol) and PdCbdppf.DCM (163 mg, 0.2 mmol). 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 with ethyl acetate twice. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash-col umn chromatography (30 g silica BIOTAGE) chromatography (cyclohexane - ethyl acetate, 100/0 to 50/50) affording methyl 2-(5-hydroxy-l-tetrahydropyran-2-yl-indazol-3-yl)pyridine-4carboxylate 19 as a yellow powder.

LCMS method F; [M+H]⁺ = 354.1, t_R = 2.59 min

Préparation of intermediate 20: benzyl N-(3-bromopropyl)carbamate

Γ HN^

Br

To a solution of 3-bromopropy lamine hydrochloride (6 g, 27 mmol) in aqueous NaOH 10 % (40 mL) at 0°C were added slowly CbzCl (4.3 mL, 30 mmol) and NaOH 10 % (40 mL). After 5 12 h, the reaction mixture was diluted with DCM. The aqueous layer was extracted two times with DCM (100 mL). The combined organic layers were washed with brine, dried over magnésium sulfate, filtered and concentrated under reduced pressure. This residue was purified by flash chromatography on silica gel (Macherey Nagel, 80 g) with gradient elution: cyclohexane/EtOAc 0-20 % to give benzyl N-(3-bromopropyl)carbamate 20 as a transparent 10 oil.

LCMS method F: [M+H]⁺ = 274, t_R = 2.41 min

Préparation of intermediate 21: methyl 6-[5-(3-{[(benzyloxy) carbonyl]amino}propoxy)-l(oxan-2-yl)-lH-indazol-3-yl]pyridine-2-carboxylate

To a solution of methyl 6-[5-hydroxy-1-(oxan-2-yl)-lH-indazol-3-yl]pyridine-2-carboxylate 19 (1 g, 2.82 mmol) in AW-dimethylformamide (100 mL), césium carbonate (1.83 g, 5.6 mmol) and benzyl N-(3-bromopropyl)carbamate 20 (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 20 (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 over sodium sulfate, filtered off and evaporated under reduced pressure to afford brown/orange oil.

This residue was purified by flash chromatography on silica gel (Macherey Nagel, 120 g) with gradient elution : cyclohexane/EtOAc 0-70 % to give methyl 6-[5-(3-{[(benzyloxy)carbonyl] amino}propoxy)-l-(oxan-2-yl)-lH-indazol-3-yl]pyridine-2-carboxylate 21 as a white solid. LCMS method F: [M+H]⁺ = 545.2, t_R = 3.21 min

Préparation of intermediate 22: benzyl N-[3-({3-[6-(hydroxymethyl)pyridin-2-yl]-l-(oxan-2yl)-lH-indazol-5-yl}oxy)propyllcarbamate

To methyl 6-[5-(3-{[(benzyloxy)carbonyl]amino}propoxy)-l-(oxan-2-yl)-lH-indazol-310 yl]pyridine-2-carboxylate 21 (1.2 g, 2.2 mmol) in THF (50 mL) was added a l M solution of lithium aluminium tetrahydride (4.4 mL, 4.2 mmol) 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 in a 10% solution of Rochelle’s sait (100 mL) and EtOAc (100 mL). The mixture was stirred at RT for 2 hours. After séparation, the aqueous layer was extracted with EtOAc (2x50 mL). The combined 15 organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to brown/orange oil. This residue was purified by flash chromatography on silica gel (Macherey Nagel, 120 g) with gradient elution : cyclohexane/EtOAc 0-100 % to give benzyl N-[3-({3-[6-(hydroxymethyl)pyridin-2-yl]-l-(oxan-2-yl)-iH-indazol-5-yI}oxy)propyl] carbamate 22 as a yellow oil.

LCMS method F: [M+H]⁺ = 517.3, t_R = 2.76 min

Préparation of intermediate 23: 19-(oxan-2-yl)-8,14-dioxa-10,19,20,23-tetraazatetracyclo [13.5.2.1²’⁶.0¹⁸·²¹]tricosa-l (20),2,4,6(23),15,17,21-heptaen-9-one

A solution of benzyl N-[3-({3-[6-(hydroxymethyl)pyridin-2-yl]-l-(oxan-2-yl)-l H-indazol-5yl}oxy)propyl]carbamate 22 (0.4 g; 0.775 mmol) in 100 mL oftoluene was added over 30 min to a solution a solution of sodium hydride (60% suspension in paraffin oil) (310 mg, 7.75 mmol) in 100 mL of toluene at room température. The reaction mixture was stirred at RT for 5 min and then one hour at !30°C. The reaction is allowed to cool down and then I0 mL of EtOH is added carefully. 100 mL of water in added. After séparation, 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 give an orange oil. A purification by column chromatography (DCM/MeOH 0-10 %) afforded pure !9-(oxan-2-yl)8,14-dîoxa-10,19,20,23-tetraazatetracyclo[l 3.5.2.1²’⁶.0^18,21 ]tricosa-1(20),2,4,6(23),15,17,21heptaen-9-one 23 as a whitish solid.

LCMS method F: [M+H]⁺ = 409.2, t_R = 2.53 min

Préparation of Example 4: 8,14-d ioxa-10,19,20,23-tetraaza tetra cycle [13.5.2.1^.0¹⁸²’] tricosa-l(20),2,4, 6(23),15,17,21-heptaen-9-one

To a solution of 19-(oxan-2-yl)-8,14-dioxa-l 0,19,20,23-tetraazatetracyclo [13.5.2.1²’⁶.0^182l]tricosa-l(20),2,4,6(23),l5,17,2l-heptaen-9-one 23 (0.2 g; 0.489 mmol) in DCM (20 mL) was added Trifluoroacetic acid (0.38 mL, 4.89 mmol) at room température. The mixture was stirred at 50 °C for 24 hours. The reaction is allowed to cool down. 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 and a 25 wt% aqueous solution of ammonia (1.5 mL) were added. After séparation, the aqueous layer was extracted with DCM (2x20 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give an orange oiL A purification by column chromatography (DCM/MeOH 0-5 %) afforded pure 8,14-dioxa-!0,l 9,20,23-tetraazatetracyclo [l3.5.2.]²’⁶.0^l8’²ⁱ]tricosa-l(20),2,4,6(23),l5,17,2l-heptaen-9-one example 4 as a whitish solid. LCMS method F: [M+Hf - 325.2, ta = 1.93 min

LCMS method G: [M+H]⁺ = 325.2, t_R = 1.94 min

Ή NMR (400 MHz, ί/6-DMSO) δ 13.2 (1 H, m), 8.08 (IH, d, J = 9.7 Hz), 7.90 (IH, d, J = 3.5 Hz), 7.83 (IH, t, J = 8.3 Hz), 7.75 (IH, t, J = 5.9 Hz), 7.47 (lH,d, J = 8.3 Hz), 7.26(1 H, d, J = 8.3 Hz), 6.97 ( IH, dd, J = 2.5, 9.1 Hz), 5.31 (2H, m),4.31 (2H, dd, J = 7.7, 8.6 Hz), 3.11 -3.09 (2H, m), 1.97-2.03 (2H, m) ppm.

Example 5: 8,14-dioxa-10,19,20-triazatetracyclo[13.5.2,l²’⁶.0^{18 2,}]tricosa-l(20),2,4,6(23), 15,17,21 -hep taen-9-one

Example 5 is prepared according to the synthesis route described in general Scheme A.

Préparation of intermediate 24: [3-[5-(3-aminopropoxy)-l-tetrahydropyran-2-yl-indazol-3yl/ph enyl]méthanol

To a degassed solution of 3-(3-iodo-l-tetrahydropyran-2-yl-indazol-5-yl)oxypropan-l-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) was added tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.050

mmol). The reaction mixture was heated under microwave conditions (Biotage initiator+) at 12O°C for Ih. The reaction mixture was fïltered through celite bed then the celite was washed with ethyl acetate. The fîltrate 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 5 under reduced pressure to give [3-[5-(3-aminopropoxy)-l-tetrahydropyran-2-yl-indazol-3yl]phenyl]methanol 24 as a pale yellow oil.

LCMS method F: [M+H]⁺ = 382, t_R = 1.64 min

Préparation of intermediate 25: 19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo

I13.5.2.1^2,6.0^is,2}]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

To a solution of [3-[5-(3-aminopropoxy)-l-tetrahydropyran-2-yl-indazol-3-yl]phenyl] methanol 24 (380 mg, 0.998 mmol) in DMA (300 mL) was added l,l'-Carbonyldiimidazole (178 mg, 1.100 mmol). The reaction mixture was stirred at RT for 2h then 90°C for 64h. The 15 reaction was concentrated under vacuum then ethyl acetate and a saturated aqueous solution of

NaHCO3 were added. The mixture was extracted with ethyl acetate (2 x). The combined organic layers were washed with water then brine, dried over sodium sulfate, fïltered and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with cyclohexane/ethyl acetate-EtOH (3-1) : 100/0 to 70/30 to give a 20 white solid. The solid was recrystallized with acetonitrile to give l9-(oxan-2-yl)-8,14-dîoxa10,19,20-triazatetracyclo [13.5.2. l^2,6.0^18,2']tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one 25 as a white solid.

LCMS method F: [M+H]⁺ = 408, t_R = 2.76 min

Préparation of Example 5: 8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹]tricosa1(20),2,4,6(23), 15,17,2 l-heptaen-9-one ιοο

To a solution of 19-(oxan-2-yl)-8,14-dioxa-10,l9,20-triazatetracyclo[l3.5.2.1²Αθ^18,21 ]tricosa1(20),2,4,6(23), 15,17,21-heptaen-9-one 25 (81 mg, 0.199 mmol) in dioxane (2.4 mL) was added 4M HCl in dioxane (0.75 mL, 2.985 mmol) and the reaction was heated to 50°C for 24h.

The reaction mixture was cooled down to RT and the solid was filtered then rinsed with diisopropyl ether (3 x) to give 8,14-dioxa-l 0,19,20-trîazatetracyclo[l3.5.2.l²'⁶.0^18,21]tricosa1 (20),2,4,6(23), 15,17,2l-heptaen-9-one example 5 as a white solid.

LCMS method F: [M+H]⁺ = 324, t_R = 2.02 min

LCMS method G: [M+H]⁺ = 324, t_R = 2.10 min

Ή NMR (400 MHz, ί/6-DMSO) δ 7.93 - 7.87 (2H, m), 7.69 - 7.66 (IH, m), 7.50 - 7.44 (2H, m), 7.36 (IH, d, J = 2.3 Hz), 7.28 - 7.25 (IH, m), 6.98 (IH, 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-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1²’⁶.0¹⁸²¹J tricosa-l(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 made using analog conditions as for example 2. 2-Iodopropane is used for the alkylation step of the carbamate to yield 10-(propan-2-yl)-8,l4-dioxa-4,10,19,20tetraazatetracyclofl 3.5.2.1^2,6.01^8,21 ]tricosa-l (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, tR = 3.832 min

ΙΟΙ 'HNMR (300 MHz, !00°C, J6-DMS0) δ 12.96 (s, IH), 9.0J (s, 1H),8.54(s, 1H), 8.39 (t, J = 2.1 Hz, IH), 7.50 (d, J = 9.0 Hz, IH), 7.23 (s, IH), 6.99 (dd, J = 9.0, 2.3 Hz, IH), 5.36 (brs, 2H), 4.28 (t, J = 8.6 Hz, 2H), 4.20 - 4.04 (m, 1H), 3.32 (brt, J = 7.3 Hz, 2H), 2.19 (brs, 2H),

1.18 (s, 3H), 1.15 (s, 3H) ppm.

Example 7: 8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1^î’⁶.0¹⁸’^2l]tricosa-l (20),2,4,

6(23),15,17,21-heptaen-9-one

LO Example 7 is prepared according to the synthesis route described in general Scheme B.

Example 7 is made using analog conditions as for example 4. Methyl 4-bromopyridine-2carboxylate is used for the Suzuki reaction to give 8,14-dioxa-5,10,19,20~ tetraazatetracyclo[13.5.2.I²’⁶.0^l8’²']tricosa-l(20),2,4,6(23),15,l7,21-heptaen-9-one example 7. 15 LCMS method F: [M+H]⁺ = 325.1, t_R = 1.58 min

LCMS method G: [M+H]⁺= 325.2, t_R = 1.83 min ‘H NMR (400 MHz, rf6-DMSO) δ 13.28 (IH, s), 8.59 - 8.57 (IH, m), 7.86 (2H, m), 7.83 (IH, dd, J = 2.1, 5.5 Hz), 7.55 (IH, d, J = 9.0 Hz), 7.44(1 H, d, J = 2.1 Hz), 7.03(1 H, dd, J = 2.1, 9.0 Hz), 5.32 - 5.31 (2H, m), 4.37 (2H, dd, J = 8.3, 8.6 Hz), 3.19 - 3.18 (2H, m), 2.10 - 2.05 (2H, 20 m) ppm.

Example 8: 4-methoxy-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

102

Example 8 is prepared according to the synthesis route described in general Scheme C.

Préparation of intermediate 26: benzyl N-[3-(3-iodo-l-tetrahydropyran-2-yl-indazol-5-yl) oxypropyljcarbamate

A suspension of 3-iodo-l-tetrahydropyran-2-yl-indazol-5-ol 4 (17.012 g. 49.453 mmol), césium carbonate (32.144 g, 98.906 mmol) and benzyl N-(3-bromopropyl)carbamate 20 (10.6 mL, 54.398 mmol) in A/A-dimethylformamide (250 mL) was heated at 60°C for 20 h. The reaction mixture was fîltered and rinsed with acetonitrile. The filtrate crystallized and it was fîltered to give a white solid which was rinsed with water (3x). The filtrate was recovered and evaporated under reduced pressure to give a pink solid. It was solubîlized with DCM and water was added. It was extracted with DCM (2x) then the combined organic layers were dried over 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-l-tetrahydropyran-2-yl-îndazol-5yl)oxypropyl]carbamate 26 as a white solid.

LCMS method F: [M+H]⁺ = 536.0, tR = 3.11 min

Préparation of intermediate 27: benzyl N-[3-[3-[3-(hydroxymethyl)-5-methoxy-phenyl]-ltetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate

103

To a degassed solution ofbenzyl N-[3-(3-iodo-l-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl] carbamate 26 (600 mg, 1.12 mmol), [3-Methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2yl)phenyl]methanol (444 mg, 1.68 mmol), tripotassium phosphate (713 mg, 3.36 mmol) and xPhos (53 mg, 0.112 mmol) în 1,4-dioxane (7 mL) and water (4.8 mL) was added tetrakis(triphenylphosphîne)palladÎum(0) (65 mg, 0.056 mmol). The reaction mixture was irradiated under μ-waves (Biotage initiator+), absorption level: high at 120°C for i h. The reaction mixture was filtered through celite bed then 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. The crude was purified by column chromatography eluting with DCM / Ethyl acetate, 100/0 to 70/30 to give benzyl N-[3-[3-[3-(hydroxymethyl)-5-methoxy-phenyl]-ltetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate 27 as a coîorless oil.

LCMS method F: [M+H]⁺ = 546, îr = 2.89 min

Préparation of intermediate 28: 4-meth oxy-19-(oxan -2-yl)-8,14-dioxa-l 0,19,20-triazatetra cyclo[13.5.2. FA O'^s·²¹ ]trieosa-l (20),2,4,6(23),15,17,21-heptaen-9-one

To a suspension of potassium carbonate (80 mg, 0.582 mmol) in acetonitrîle (12 mL) was dropwise added a solution of benzyl N-[3-[3-[3-(hydroxymethyl)-5-methoxy-phenyl]-1 tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate 27 (53 mg, 0.097 mmol) în

104 acetonitrile (7 mL) at RT. The reaction mixture was heated under micro wave conditions at

I40°C for 6 h. The reaction mixture was filtered and directly purified by column chromatography elutïng with DCM / Ethyl acetate, 100/0 to 80/20 to 4-methoxy-l9-(oxan-2yl)-8,14-dioxa-10,19,20-triazatetracyclo[l 3.5.2.1²’⁶.0^{18,2 l}]tricosa-1(20),2,4,6(23), 15,17,21heptaen-9-one 28 as a colorless oil.

LCMS method F: [M+H]⁺ = 438, t_R = 2.76 min

Préparation of Example 8: 4-methoxy-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.1²<0¹⁸'²qtricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

To a solution of 4-methoxy-l 9-(oxan-2-yl)-8,l 4-dioxa-l 0,19,20-triazatetracyclo [13.5.2.l²’⁶.0¹⁸’²¹]tricosa-l(20),2,4,6(23), 15,17,21-heptaen-9-one 28 (23 mg, 0.053 mmol) in DCM (4 mL) was added trifluoro acetic acid (80 pL, 1.06 mmol) at RT. The reaction mixture was irradiated under μ-waves (Biotage inîtîator+), absorption level: high at 80°C for 1 h30.

The crude reaction mixture was purified by flash-column chromatography eluting with DCM / Ethyl acetate : 100/0 to 80/20, to give 4-methoxy-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.1^2,6.0¹⁸’²¹]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one example 8 as a white solid. LCMS method F: [M+H]⁺ = 354, t_R = 2.07 min

LCMS method G: [M+H]* = 354, t_R = 2.09 min

Ή NMR (400 MHz, t/6-DMSO) δ 12.89(1 H, s), 7.67 (IH, m), 7.52 - 7.47 (2H, m), 7.42 - 7.34 (2H,m), 6.99-6.96(1 H, m), 6.88 (IH, 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-triazatetracycio[ 13.5.2.FAO'^8,2*]tricosa-1(20),

2,4,6(23),15,17,21-heptaen-9-one

105

Example 9 can be prepared according to the synthesis route described in general Scheme A, C and D.

Préparation of intermediate 29: l-tetrahydropyran-2-ylindazol-5-ol

To a solution of tert-buty l-dimethyl-(l-tetrahydropyran-2-ylindazol-5-yl)oxy-sîlane 17 (12.58 g, 37.8 mmol) in tetrahydrofuran (100 mL) was added by portions tetra-n-butylammonium fluoride 1.0 M in THF (47.58 mL, 47.58 mmol) at RT. The reaction mixture was stirred at RT 10 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 (2x150 mL). The combined organic layers were washed with brine (150 mL), dried over magnésium sulfate anhydrous and concentrated under reduced pressure. Purification on silica column (RS SiOH 80 g) using cyclohexane/ ethyl acetate as eluent from 90/10 to 80/20 gave l-tetrahydropyran-2-ylindazol-5-ol 29 as a colorless 15 oil.

LCMS method F: [M+H]⁺ = 219, ta = 1.81 min

Préparation of intermediate 30: benzyl N-[3-(l-tetrahydropyran-2-ylindazol-5-yl)oxypropyl] carbamate

106

HN

To a solution of l-tetrahydropyran-2-ylîndazol-5-ol 29 (7.06 g, 32.3 mmol) in N,Ndimethyl formant ide (l 10 mL) was added césium carbonate (21.0 g, 64.6 mmol) and benzyl N(3-bromopropyi)carbamate 20 (10.14 g, 37.3 mmol) at RT. The mixture was stirred at 80 °C 5 ovemight. The reaction mixture was concentrated under reduced pressure. Water ( 100 mL) and ethyl acetate (200 mL) were added to the residue. After séparation, the aqueous layer was extracted with ethyl acetate (2x 50 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure to dryness.

Purification on silica column (RS SiOH 200 g) using Cyclohexane/ Ethyl acetate from 80/20 to 60/40 as eluent gave benzyl N-[3-(l-tetrahydropyran-2-ylindazol-5-yl)oxypropyl]carbamate 30 as a beige solid.

LCMS method F: [M+H]⁺ = 410.2, t_R = 2.77 min (current 20V)

Préparation of intermediate 31: benzyl N-[3-[l-tetrahydropyran-2-yl-3-(4,4_f5,5-tetramethyll,3,2-dioxaborolan-2-yl)indazol-5-yl]oxypropyl]carbamate

To a solution of benzyl N-[3-(l-tetrahydropyran-2-ylindazol-5-yl)oxypropyl]carbamate 30 (11.42 g, 27.9 mmol) in TBME/THF (500/100 mL) was added 4,4,5,5-tetrameίhyl·2-(4,4,5,521105

107 tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (7.79 g, 30.69 mmol) and 4,4'-ditert-butyl-2,2'-bipyndine (450 mg, 1.67 mmol). The reaction mixture was degassed by bubbhng nitrogen for 15 min and (l,5-cyclooctadiene)(methoxy)iridium(I) dimer (370 mg, 0.56 mmol) was added. The reaction mixture was stirred at 80°C overnight under atmosphère of nitrogen. 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 give benzyl N-[3-[l-tetrahydropyran-2-y 1-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)indazol-5-yl]oxypropyl]carbamate 31 as a brown oil. The product was used in next step without further purification.

LCMS method F: [M+H]⁺ = 536.2, t_R = 3.18 min (current 20V)

Préparation of intermediate 32: (3-bromo-5-iodo-ph enyl)methanol

I

To a solution of 3-bromo-5-iodo-benzoic acid (10.0 g, 30.6 mmol) in THF (450 mL) was slowly added solid sodium borohydride (3.47 g, 91.8 mmol) at 0°C. After the end of the gas release (i.e. 5 min), boron trifluoride diethyl etherate (11.3 mL, 91.8 mmol) was dropwise added at 0°C. The reaction mixture was allowed to warm to RT and stirred at RT overnight. The reaction mixture was cooled to 0 °C and an aqueous I M solution of sodium hydroxide (100 mL) was slowly added. The reaction mixture was filtered off under celite pad and eluted with ethyl acetate. The solution was washed with water (100 mL) and with brine (100 mL). The organic layer was dried with sodium sulfate anhydrous, filtered off and the dried under reduced pressure to afford clean (3-bromo-5-iodo-phenyl)methanol 32 as a beige solid.

LCMS method F: [M+H]⁺ = not detected, t_R = 2.54 min (current 20V)

Préparation of intermediate 33: benzyl N-[3-[3-f3-bromo-5-(hydroxymethyl)phenyl]-ltetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate

108

To a solution of benzyl N-[3-[l-tetrahydropyran-2-y 1-3-(4,4,5,5-tetramethy 1-1,3,2dioxaborolan-2-yl)indazol-5-yl]oxypropyl]carbamate 32 (1.870 g, 3.50 mmol) in N,Ndimethyiformamide (15 mL) was added at RT (3-bromo-5-iodo-phenyl)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 PdChdppf (0.128 g, 0.18 mmol) was added. The resulting mixture was stirred at 110°C under micro wave 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 with ethyl acetate twice. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash-column chromatography (40 g RS SiOH) chromatography (cyclohexane - ethyl acetate, 100/ 0 to 50/ 50) gave benzyl N-[3-[3-[3-bromo-5-(hydroxymethyl)phenyl]-l-tetrahydropyran-2-yl-indazol5-yl]oxypropyl] carbamate 33 as an orange oil.

LCMS method F: [M+H]⁺ = 596.1, t_R = 3.07 min (current 20V)

Préparation of intertnediate 34: 4-bromo-19-(oxan-2-yl)-8,14-dioxa-l 0,19,20-triazatetra eyclo[I3.5.2. l²^0’^s’^2IJtricosa-l(20),2_f4,6(23),15,17,21-heptaen-9-one

To a solution of benzyl N-[3-[3-[3-bromo-5-(hydroxymethyl)phenyl]-l-tetrahydropyran-2-ylindazo 1-5-yl]oxypropyl]carbamate 33 (288 mg, 0.48 mmol) in dry toluene (300 mL) was added

109 sodium hydride 60% in oil (480 mg, 12 mmol) at RT. The reaction mixture was stirred at !30°C for lh. The reaction was then stirred at RT ovemight and sodium hydride 60 % in ou (192 mg, 4.8 mmol) was added. The reaction mixture was stirred at 130°C for 3h. More sodium hydride 60 % in oîl (192 mg, 4.8 mmol) was added and the reaction mixture was stirred at 140 °C for ovemight. More sodium hydride 60 % in oil (I92 mg, 4.8 mmol) was added and the reaction mixture was stirred at 140 °C for 5 h. Again sodium hydride 60 % in oil (192 mg, 4.8 mmol) was added and the reaction mixture was stirred at 140 °C for 1 h till completion of the reaction. The reaction mixture was allowed to RT and cooled in an ice bath. EtOH (50 mL) was slowly added. The reaction mixture was diluted with ethyl acetate (200 mL) and water was added (200 mL). After séparation, the aqueous layer was extracted with ethyl acetate (x3 50 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered and dried under reduced pressure to afford an orange oil.

Purification on silica column (RS SiOH 80 g) using cyclohexane/ ethyl acetate from 100/ 0 to 0/ 100 as and DCM/MeOH 90/ 10 as eluent gave 60 mg of the intended product. The impure fractions were pooled and the solvent was removed under reduced pressure. The residue was purified on silica column (RS SiOH 40 g) using clyclohexane/ ethyl acetate from 100/ 0 to 50/ 50 as eluent gave 4-bromo-19-(oxan-2-yl)-8,l 4-dioxa-10,19,20-triazatetracyclo [13.5.2. l²’⁶.0'^82t]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one 34 as a white solid.

LCMS method F: [M+H]⁺ = 487.7, t_R = 3.05 min

Préparation of Example 9: 4-bromo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1^2,6.0^18,ïl] tricosa-l(20), 2,4,6(23),15,17,2 l-heptaen-9-one

To a solution of 4-bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.1²A0^iVl]tricosa-](20),2,4,6(23), 15,17,21-heptaen-9-one 34 (30 mg, 0.062 mmol) in DCM (3 mL) was added trifluoroacetic acid (95 pL, 1.24 mmol). The reaction mixture was stirred at 80 °C under micro wave irradiation for 2h. The reaction mixture was diluted with DCM (20 mL). Water (50 mL) and ammonium hydroxide 25 % weight aqueous solution (3 mL) were added. After séparation, the aqueous layer was extracted with DCM (x3 10 mL). The combined

110 organic layers were washed with saturated sodium carbonate aqueous solution (30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate, fîltered and dried under reduced pressure to afford a beige solid. DCM was added to the solid. The precipitate was fîltered and the filtrate was purified on préparative TLC using cyclohexane/ ethyl acetate; 50/ 50 as eluent. The resulting product was purified a second time on préparative TLC using cyclohexane/ ethyl acetate ; 50/ 50 as eluent to give 4-bromo-8,14-dioxa-10,19,20triazatetracyclo [13.5.2.1²Gj¹⁸²¹]tricosa-l (2Û),2,4,6(23),15,17,21-hepÎaen-9-one example 9 as a beige solid.

LCMS method F: [M+Hf = 403, t_R = 2.40 min

LCMS method G: [M+H]⁺ = 403, t_R = 2.38 min

Ή NMR (400 MHz, r/6-DMSO) δ 13.07 (IH, s), 8.02 (IH, s), 7.87 (IH, s), 7.74 (IH, s), 7.51 (2H, q, J = 2.8 Hz), 7.32 (IH, d, J = 2.7 Hz), 7.00 (IH, 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-trîazatetracycIo[13.5.2.I²’⁶.0^,8’^2l]tricosa-1 (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.

Préparation of intermediate 35: 2-fluoro-5-[5-hydroxy-l-(oxan-2-yl)-lH-indazol-3-yl] benzoic acid

lll

To solution of 3-îodo-l-(oxan-2-yl)-lH-indazol-5-ol 4 (l g, 2.90 mmol), 2-fluoro-5(tetramethyl-l,3,2-dioxaborolan-2-yl)benzoic acid (0.925 g, 2.52 mmol) in dioxane/water; 70/30 (12 mL) was added tripotassium phosphate (1.84 g, 8.7 mmol). The mixture was degassed by bubbling nitrogen for 15 minutes. Xphos (O.l38 g, 0.29 mmol) and palladium5 tetrakis(tripheny[phosphine) (O.l67 g, O.l45 mmol) were added. The mixture was heated at 12O°C for 2 hours under microwaves irradiations (BIOTAGE). The reaction mixture was filtered over celite pad and eluted with ethyl acetate. The solution was washed with water (50 mL) and with brine (50 mL). The organic layer was dried with sodium sulfate and the solvent was removed under reduced pressure to afford a brown oil. Purification on silica column on 10 Biotage using cyclohexane/ethyl acetate from 100/0 to 20/80 as eluent gave 2-fluoro-5-[5hydroxy-l-(oxan-2-yl)-lH-indazol-3-yl]benzoic acid 35 as a white powder.

LCMS method F: [M+H]⁺ = 357.1, t_R = 2.34 min

Préparation of intermediate 36: 3-[4-fluoro-3-(hydroxymethyl)phenyl]-l-(oxan-2-yl)-lH15 indazol-5-ol

To a solution 2-fluoro-5-[5-hydroxy-l-(oxan-2-yl)-lH-indazol-3-yl]benzoic acid 35 (0.2 g, 0.56 mmol) in THF (25 mL) was added solid sodium borohydride (0.062 g, l .68 mmol) at RT. After the end of the gas release (i.e. 5 min), the reaction mixture was cooled to 0 °C and neat boron trifluoride diethyl etherate (O.l63 mL, 1.68 mmol) was added dropwise over l h. The reaction mixture was allowed to warm to RT and stirred at 65 °C for 2 h. The reaction mixture was cooled to 0 °C and an aqueous l M solution of sodium hydroxide (50 mL) was added. The mixture was stirred at RT for 2 h. The reaction mixture was filtered over celite and eluted with ethyl acetate. The solution was washed with water (50 mL) and with brine (50 mL). The organic layer was dried with sodium sulfate and the solvent was removed under reduced pressure to afford a brown oil. Purification (Biotage) on silica column using cyclohexane/ethyl acetate from 100/00 to 50/50 as eluent 3-[4-fluoro-3-(hydroxymethyl)phenyl]-l -(oxan-2-yl)-lH-indazol-5ol 36 as a white powder.

112

LCMS method F: [M+H] = 343.1, t_R = 2.27 min

Préparation of intermediate 37: benzyl N-[3-({3-[4-fluoro-3-(hydroxymethyl)phenyl]-l(oxan-2-yl)-lH-indazoi-5-yl}oxy)propyl]carbamate

To a solution 3-[4-fluoro-3-(hydroxymethyl)phenyl]-l-(oxan-2-yl)-lH-indazol-5-ol 36 (0.18 g, 0.52 mmol) in MW-dimethylformamide (10 mL), césium carbonate (0.338 g, 1.04 mmol) and tert-butyl 3-[(methanesulfonyloxy)methyl]pyrrolidine-l-carboxylate 20 (0.169 gr, 0.624 mmol) was added. The reaction was stirred at 80°C for 16 hours. The mixture was concentrated 10 under reduced pressure. Water (50 mL) was added and the resulting mixture was extracted with EtOAc (4 x 100 mL). Combined organic layers were washed with saturated brine (2 x 50 mL). The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to afford brown/orange oil. The residue was purified by flash chromatography on silica gel (Macherey Nagel, 12 g) with gradient elutîon : cyclohexane/EtOAc 0-70 % to give benzyl 15 N-[3-({3-[4-fluoro-3-(hydroxymethyl)phenyl]-l-(oxan-2-yl)-lH-indazol-5-yl}oxy)propyl] carbamate 37 as a white solid.

LCMS method F: [M+H]⁺ = 534.2, t_R = 2.90 min

Préparation of intermediate 38: 5-fluoro-l 9-(oxan-2-yl)-8,l4-dioxa-10,19,20-triazatetra

0 cyclo[13.5.2.I²’⁶.0^}*^2t]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

113

A solution of benzyl N-[3-({3-[4-fluoro-3-(hydroxymethyl)phenyl]-l-(oxan-2-yl)-lH-indazoî5-yl}oxy)propyl]carbamate 37 (0.153 g; 0.28 mmol) în 50 mL of toluene was added to a solution of sodium hydride (60% suspension in paraffin oîl) (114 mg, 24 mmol) in 50 mL of toluene at room température. The reaction mixture was stirred at RT for 5 min and then one 5 hourat 130°C. The reaction is allowed to cool down and then 10 mL of EtOH is added carefully.

100 mL of water în added. After séparation, the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with a saturated brine, dried over sodium sulfate and the solvent was removed under reduced pressure to give an orange oil. A purification by column chromatography (DCM/MeOH 0-10 %) afforded pure 5-fluoro-1910 (oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[l 3.5.2. l^2,6.0^18,21]tricosa-1(20),2,4,6(23), 15,

17,21 -heptaen-9-one 38 as a whitish solid.

LCMS method F: [M+H]⁺ = 426.2, t_R = 2.78 min

Préparation of Example 10: 5-fluoro-8,14-dioxa-10,19,20-triazatetracyclo

[13.5.2J²A0⁽ⁱ⁽’²'îtricosa-l(20), 2,4,6(23),15,17,21-heptaen-9-one

To a solution of 5-fl uoro-19-(oxan-2-y 1)-8,14-dioxa-10,19,20-trîazatetracy cio

[]3.5.2.1²’⁶.0ⁱ⁸’^2,]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one 38 (35 mg, 0.082 mmol) in DCM (5 mL) was added trifluoroacetic acid (63 pL, 0.82 mmol). The reaction mixture was 20 stirred at RT for 6 h and at 30 °C ovemight. More trifluoroacetic acid (32 pL ,0.41 mmol) was added and the reaction mixture was stirred at 50 °C for 5h. 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 ammonium hydroxide 25 % weight aqueous solution (3 mL) were added. 25 After séparation, the aqueous layer was extracted with DCM (3x 20 mL). The combined organic layers were washed with saturated sodium carbonate solution (100 mL) and brine (100 mL), dried over sodium sulfate anhydrous and the solvent was removed under reduced pressure to afford a beige solid.

114

Trituration of the residue one time in acetonitrile, five times in DCM and two times in EtOH gave 5-fl uoro-8,14-dioxa-l 0,19,20-triazatetracyclo[l 3.5.2.1^2,6.0^18,21]tricosa-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, t_R = 2.18 min

LCMS method G: [M+H]⁺ = 342.1, t_R = 2.36 min

Ή NMR (400 MHz, c/6-DMSO) Ô 12.95 (IH, s), 7.93 (2H, m), 7.81 (IH, s), 7.89 (IH, d, J = 9.0 Hz), 7.33 (2H, m), 6.99 (IH, 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[13.5.2.1^2,6.0¹⁸’²¹]tricosa1(20),2, 4,6(23),15,17,21-heptaen-9-one

Example I I is prepared according to the synthesis route described in general Scheme F.

Préparation of intermediate 39: methyl 5-f5-f3-(benzyloxycarbonylamino)propoxyJ-ltetrahydropyran-2-yl-indazol-3-yl/-2-methyl-benzoate

A solution of benzyl N-[3-(3-iodo-l -tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]carbamate 20 26 (1.2 g, 2.2 mmol postulated), (3-methoxycarbonyl-4-methyl-phenyl)boronic acid (467 mg,

2.42 mmol), potassium phosphate tribasîc (1.4 g, 6.6 mmol) and trîethyiamine (1.4 mL, 9.9 mmol) in THF/H2O (6.5/3.2 mL) was degassed for 15 minutes. Pd(dppf)C12.DCM (179 mg,

115

0.22 mmol) was added and the reaction mixture was stirred under nitrogen atmosphère at 100 °C for 17 hours. The reaction mixture was filtered over celite and washed with EtOAc. The filtrate was diluted with water (l00 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 (Macherey Nagel, 40 g) chromatography with eluent cyclohexane/EtOAc (l 00/0 to 80/20). The desired fractions were collected and the solvent was removed under reduced pressure to give methyl 5[5-[3-(benzyloxycarbonylamino)propoxy]-l-tetrahydropyran-2-yl-indazol-3-yl]-2-methylbenzoate 39 (l .04 g, 1.87 mmol) as a white solid.

LCMS method F: [M+H] = 558, t_R = 3.33 min

Préparation of intermediate 40: benzyl N-[3-[3-[3-(hydroxymethyl)-4-methyl-phenyi]-ltetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carhamate

To a solution of methyl 5-[5-[3-(benzyloxycarbonylamino)propoxy]-l-tetrahydropyran-2-ylindazol-3-yl]-2-methyl-benzoate 39 (l g, l .8 mmol) in THF (6 mL) under N?, LAH l M 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 quenched with water (l mL), NaOH I0 % (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 pad of silica with cyclohexane/EtOAc (60/40) as eluent to give benzyl N-[3-[3-[3-(hydroxymethyl)-4-methyl-phenyl]-l-tetrahydropyran-2-ylindazol-5-y l]oxypropyl] carbamate 40 as a white oil.

LCMS method F: [M+H]⁺ = 530, t_R = 2.90 min

116

Préparation of intermediate 41: 5-methyl-l 9-(oxan-2~yl)-8,14-dioxa-10,19,20-triazatetra cyclo[13.5.2.1^2,6.0‘^s’^2I}tricosa-l (20),2,4,6(23),15,17,21-heptaen-9-one

To a solution of benzyl N-[3-[3-[3-(hydroxymethyl)-4-methyl-phenyl]-l-tetrahydropyran-2-ylindazol-5-yl]oxypropyl]carbamate 40 (120 mg, 0.23 mmol) in acetonitrîle (40 mL), potassium carbonate (190 mg, 1.38 mmol) was added. The mixture was divided in two vials then heated in microwaves at 140 °C for 4 hours and 30 minutes. The two vials was heated again in microwaves at 140 °C for 4 hours. The mixture was filtered to removed potassium carbonate and the solvent was evaporated under reduced pressure to give 5~methyl-19-(oxan-2-yl)-8,14dioxa-l 0,19,20-trîazatetracyclo[ 13.5.2.1^2,6.0¹⁸-²¹ ]tricosa-1(20),2,4,6(23), 15,17,21-heptaen-9one 41 as a white powder. The crude was used in the next step without further purification. LCMS method F: (M+H]⁺ = 422, t_R = 2.87 min

Préparation of Example 11: 5-methyl-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.l²’^e.0^is’^2l]tricosa-l(20),2, 4,6(23),15,17,2l-heptaen-9-one

To a solution of 5-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.1²’⁶.0^l8s21]tricosa-l(20),2,4,6(23),l5,17,21-heptaen-9-one 41 (84 mg, 0.2 mmol) in DCM (15 mL) was added trifluoro acetic acid (306 gL, 4 mmol). The mixture was heated in microwaves at 80 °C for 1 hour. The solvent was removed under reduced pressure to afford an oily residue, which was dissolved in DCM (20 mL). A precipitate was formed and filtered. The solid was dissolved in DCM/MeOH (15 mL), then NaHCO₃ saturated was added (15 mL). After séparation, the aqueous layer was extracted with DCM (3x10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the

117 solvent was removed under reduced pressure to give 5-methyl-8,14-dioxa-10,l 9,20triazatetracyclo[13.5.2.1^2,6.0^18,2^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, t_R = 2.32 min

LCMS method G: [M+H]⁺ = 338, t_R = 2.35 min ^lH NMR (400 MHz, t/6-DMSO) δ 12.86 - 12.79 (IH, m), 7.84 (1 H, m), 7.82 (IH, m), 7.74 (1 H, s), 7.46 (I H, d, J = 8.9 Hz), 7.42 (1 H, m), 7.28 (IH, dd, J = 0.6, 8.3 Hz), 6.98 (I H, dd, J = 2.4, 9.0 Hz), 5.28 (2H, s), 4.34 (2H, dd, J = 8.2, 8.5 Hz), 3.2 (2H, m), 2.32 (3H, s), 2.04 - 1.99 (2H, m) ppm.

Example 12: 4-(pyrrolidin-l-yl)-8,14-dioxa-10,l 9,20-triazatetracyclo [13.5.2.1²’⁶,0^18,21] tricosa-1 (20),2,4,6(23),15,17,2l-heptaen-9-one

Example 12 is prepared according to the synthesis route described in general Scheme C.

Pyrrolidine îs used for the Buchwald reaction with the bromide intermediate 34.

Préparation of intermediate 42: 19-(oxan-2-yl)-4-(pyrrolidin-l-yl)-8,14-dîoxa-l0,19,20triazatetracyclo! 13.5.2.1²’⁶.0^!8,2!]tricosa-l (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 Jtrîcosa-1 (20),2,4,6(23), 15(22),16,] 8(21 )-heptaen-14one 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) was added Pd^dbaj (4 mg, 0.004

118 mmol) at RT. The réaction 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 during 20 min at 60°C. After being cooled to RT, the reaction mixture was diluted with water and extracted with ethyl acetate twice. 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 (5g SiO₂) chromatography (cyclohexane/Ethyl acetate, l :0 to 50/50) affording 19-(oxan-2-y l)-4-(pyrrolidin-l-yl)-8,14-dioxa-l 0,19,20triazatetracyclo [ 13.5.2.1²’⁶.0¹⁸’²¹]trîcosa-l (20),2,4,6(23), 15,17,21 -heptaen-9-one 42 as a white powder.

LCMS method F: [M+Hf = 477.2, t_R = 3.00 min

Préparation of Example 12: 4-(pyrrolidin-l-yl)-8,14-dioxa-10,19,20-triazatetracyclo 113.5.2.1 ^.0'^s’²¹] tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

To a mixture of 19-(oxan-2-yl)-4-(pyrrolidin-l-yl)-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.I²A0^,8-²¹]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-on^ 42 (60mg; 0.126mmol) in DCM (2.5mL) was added TFA (48μ1; 0.630mmol). The reaction mixture was stirred under microwaves irradiation at 80°C during 30 min. The solvent was removed under reduced pressure, the mixture was dissolved in EtOAc and washed with IN 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 give 4-(pyrrolidin-1 -y l)-8,14-dioxa-10,19,20triazatetracyclo [13.5.2.1^2,6.0¹⁸²¹ ]tricosa-l (20),2,4,6(23), 15,17,21 -heptaen-9-one example 12 as a yellow powder.

LCMS method F: [M+H]⁺ = 393.1, t_R = 2.39 min (current 20V)

LCMS method O: [M+H]⁺ = 393.1, t_R = 2.47 min (pHl 0 current 20V)

Ή NMR (400 MHz, r/6-DMSO) δ 7.61 (IH, m), 7.47 - 7.44 (IH, m), 7.36 (IH, d, J = 2.7 Hz), 7.20(1 H, s), 7.04(1 H, t, J = 1.9 Hz), 6.95 (IH, dd, J = 2.4, 9.0 Hz), 6.50(1 H, s), 5.22 - 5.20

119 (2H, m), 4.30 (2H, d, J = 16.9 Hz),3.32 (4H, m), 3.17 - 3.15 (2H, m), 2.03 - L99 (6H, m), 1.07 (IH, d. J = 6.1 Hz) ppm.

Example 13: 4-[4-(propan-2-yl)piperazin-l-yl]-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.1²\0^l8’^2I]tricosa-l (20),2,4,6(23),15,17,21-heptaen-9-one

Example 13 is prepared according to the synthesis route described in general Scheme C and procedures analogous to those used to obtain example 12. l-(propan-2-yl)piperazine is used 10 for the Buchwald reaction with the bromide intermediate 34 to give 4-[4-(propan-2yl)piperazin-l-yl]-8,l 4-dioxa-10,19,20-triazatetracyclo[l 3.5.2. l²‘⁶.0^,8’^2l]tricosa1(20),2,4,6(23),15,17,21 -heptaen-9-one example 13.

LCMS method F: [M+H]⁺= 450.2, t_R = 1.54 min

LCMS method G: [M+H]⁺ = 450.2, t_R = 2.26 min

Ή NMR (400 MHz, t/6-DMSO, 80°C) δ 12.80 (IH, s), 7.68 - 7.57 (IH, m), 7.46 (IH, d, J = 9.3 Hz), 7.37 - 7.34 (3H, m), 6.96 (IH, dd, J = 2.4, 8.8 Hz), 6.87 (1 H, s), 5.23 (2H, s), 4.28 (2H, s), 3.25 - 3.22 (4H, m), 3.17 (2H, s), 2.76 - 2.67 ( 1 H, m), 2.66 - 2.61 (4H, m), 2.02 (2H, s), 1.05 (6FI, d, J = 6.5 Hz) ppm.

Example 14: 4-{2-oxa-6-azaspiro[3.41octan-6-yl}-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2. l²’⁶.0^1H’ⁿ]tricosa-l(20),2,4,6(23),l 5,17,21-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

120 for the Buchwald reaction with the bromide intermediate 34 to give 4-{2-oxa-6azaspiro[3.4]octan-6~yl}-8,l4-dioxa40,l9,20-triazatetracyclo[l3.5.2.1²’⁶.0^l8’^2l]tricosa1(20),2,4,6(23), 15,17,21 -heptaen-9-one example 14, LCMS method F: [M+H]'¹' = 435, îr = 2.16 min

LCMS method G: [M+Hf = 435, t_R = 2.20 min

Ή NMR (400 MHz, J6-DMSO, 80°C) δ 12.77 (IH, s), 7.61 (IH, m), 7.46 (1 H, d, J = 9.2 Hz), 7.36 (IH, m), 7.22 (IH, m), 7.04 (IH, m), 6.96 (IH, m), 6.51 (IH, 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.

Example 15: 4-[4-(oxetan-3-yl)piperazin-l-yl)-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 15 is prepared according to the synthesis route described in general Scheme C and and procedures analogous to those used to obtain example 12. 1 -(oxetan-3-yl)piperazine is used for the Buchwald reaction with the bromide intermediate 34 to give 4-[4-(oxetan-3yl)piperazin-l-yl]-8,14-dioxa-10,19,20-trîazatetracyclo[13.5.2.1²’⁶.0¹⁸’^2,]tricosa-l(20),2,4,

6(23), i 5,17,21-heptaen-9-one example 15.

LCMS method F : [M+H]⁺ = 464.2, t_R = 1.47 min

LCMS method G: [M+H]⁺ = 464.2, t_R = 2.00 min

Ή NMR (400 MHz, r/6-DMSO, 80°C) ô 12.81 (IH, s), 7.64 (IH, s), 7.48 - 7.45 (IH, d, J = 9.0

Hz), 7.39 - 7.34 (3H, m), 6.96 (IH, dd, J =2.2, 8.8 Hz), 6.89 (IH, 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 (IH, q, J =

6.2 Hz), 3.30 - 3.26 (4H, m), 3.17 - 3.11 (2H, m), 2.10 - 1.99 (2H, m) ppm. 4 protons were located under the DMSO peak and are not reported here.

I2l

Example 16: 4-(morpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.PA0^18,21] tricosa-1 (20),2,4,6(23),15,17,2 l-heptaen-9-one

Example 16 is prepared according to the synthesis route described in general Scheme C and 5 procedures analogous to those used to obtain example 12. Morpholine îs used for the Buchwald reaction with the bromide intermediate 34 to give 4-(moipholin-4-yl)-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.1²A0^,8’^2,]tricosa-l(20),2,4,6(23),I5,17,21-heptaen-9-one example 16.

LCMS method F: [M+H]⁺ = 409.2, t_R = 2.13 min

LCMS method G: [M+H]⁺= 409.2, t_R = 2.15 min ‘H NMR (400 MHz, r/6-DMSO, 80°C) δ 12.82 (IH, s), 7.63 (IH, m), 7.48 - 7.45 (IH, d, J = 9.0 Hz ), 7.40 (2H, m), 7.34 (IH, m), 6.97 (1 H, dd, J = 2.3, 8.9 Hz), 6.89 (IH, s), 5.23 (2H, s), 4.33 - 4.28 (2H, t, J = 8.32), 3.82 - 3.76 (4H, t, J = 4.8 Hz), 3.23 - 3.20 (4H, t, J = 4.9 Hz), 3.17 (2H, s), 2.02 (2H, s) ppm.

Example 17: 4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8,14-dioxa-10,19,20-triazatetra cyclo[ 13.5.2. PAO¹⁸’²¹] tricosa-l(20),2,4,6(23),l 5,17,2 l-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-dimethylmoipholine is used for the Buchwald reaction with the bromide intermediate 34 to give 4-[(2R,6S)-2,6dimethylmorphol in-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1²Αθ’^8,2']tricosa-1(20),

2,4,6(23), 15,17,21 -heptaen-9-one example 17.

LCMS method F: [M+H]⁺ = 437.1, t_R = 2.30 min

122

LCMS method G: [Μ+ΗΓ = 437.2, t_R = 2.36 min

Ή NMR (400 MHz, aô-DMSO, 80°C) δ 12.81 (IH, s), 7.63 (IH, s), 7.48-7.45 (IH, 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, I2.l Hz), 3.17 (2H,s), 2.41 - 2.35 (2H, m), 2.06 - 2.05 (2H, m), l.2l (6H, d, J = 6.3 Hz) ppm.

Example 18: 4-methyI-8,14-dioxa-10,19,20-triazatetra cy cio [13.5.2. l^2,6.0^18,21 ]tricosa1(20),2,4,6(23),15,17,21 -heptaen-9-one

Example 18 îs prepared according to the synthesis 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 give 4-methyl8,14-dioxa- 10,19,20-triazatetracyclo[ 13.5.2. P’^.O^18,2 'jtricosa-1(20),2,4,6(23), 15,17,21 heptaen-9-one example 18.

LCMS method F: [M+H]⁺ = 338, t_R = 2.25 min

LCMS method G: [M+H]⁺ = 338, t_R = 2.30 min

Ή NMR (400 MHz, rf6-DMSO) δ 7.73 - 7.65 (3H, m), 7.49 - 7.45 (IH, m), 7.34 ( I H, d, J = 2.1 Hz), 7.10-7.07 (IH, m), 6.97 (1H, dd, J = 2.2, 9.0 Hz), 5.26 - 5.25 (2H, m), 4.34 - 4.28 (2H, m), 3.17 (2H, m), 2.41 (3H, s), 2.04 - 2.01 (2H, m) ppm. The indazole NH proton was not visible in this solvent.

Example 19: 5-methoxy-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1^2,6.0^I8’²¹]trÎcûsa1(20),2,4,6(23),15,17,2 l-heptaen-9-one

123

Example 19 is prepared according to the synthesis route described in 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 intermedîate 26 to give 5-methoxy5 8,14-dioxa-10,19,20-triazatetracyclof 13.5.2.1²Αθ^18,21 ]tricosa-1(20),2,4,6(23), 15,17,21heptaen-9-one example 19.

LCMS method F: [M+H]⁺ = 354, t_R = 2.19 min

LCMS method G: [M+H]⁺ = 354, t_R = 2.17 min ’H NMR (400 MHz, J6-DMSO) δ 12.75 (IH, s), 7.91 (IH, dd, J = 2.2, 8.6 Hz), 7.83 (I H, m), 10 7.72(1 H, m), 7.45 (IH, d, J = 8.9 Hz), 7.37(1 H, d, J = 2.2 Hz), 7.15 (IH, d, J = 8.5 Hz), 6.97 (IH, 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-l-yl)-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2. PAO^18,2 ‘Itricosa-1(20),2,4,6(23),15,17,2 l-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 20 the Buchwald réaction with the bromide intermedîate 34 to give 4-(4,4-difluoropiperidin-l-yl)8,14-dioxa-l 0,19,20-trîazatetracyclo[l 3.5.2.1²Αθ^18,21 ]tricosa-1(20),2,4,6(23),15,17,21heptaen-9-one example 20.

LCMS method F: [M+H]⁺ = 443.1, t_R = 2.46 min

LCMS method G: [M+H]⁺ = 443.1, t_R = 2.49 min

124

Ή NMR (400 MHz, rf6-DMSO, 80°C) δ 12.83 (IH, s), 7.64 (1 H, s), 7.49 - 7.43 (2H, m), 7.39 (IH, s), 7.36 - 7.33 (IH, 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.

Example 21: 4-(3,3-difluoropyrrolidin-l-y 1)-8,14-dioxa-l 0,19,20-triazatetracyclo

[13.5.2.1²⁶.0^{18 21} ] tricosa-1 (20),2,4,6(23),15,17,2 l-heptaen-9-one

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 Bucbwald reaction with the bromide intermediate 34 to give 4-(3,3-difluoropyrrolidin-ly 1)-8,14-dioxa-l 0,19,20-triazatetracyclo[ 13.5.2. l²’⁶.0^I8’²¹]tricosa-1(20),2,4,6(23),15,17,21 heptaen-9-one example 21.

LCMS method F: [M+H]⁺ = 429.1, t_R = 2.46 min

LCMS method G: [M+HJ* = 429.1, t_R = 2.48 min

Ή NMR (400 MHz, r/6-DMSO, 80°C) Ô 12.82 (IH, s), 7.63 (IH, s,), 7.47 (1 H, d, J = 8.9 Hz), 7.36 - 7.31 (2H, m), 7.10 - 7.08 (JH, m), 6.96 (IH, dd, J = 2.4, 9.0 Hz), 6.59 - 6.58 (IH, 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 EIz), 3.16 (2H, s), 2.63 - 2.53 (2H, m) 2.02 (2H, m) ppm.

Example 22: 7-methy 1-8,14-dioxa-l0,19,20-triazatetracyclo[13.5.2.1²’⁶.0^,8’²i]tricosa-l (20),

2,4,6(23),15,17,21-heptaen-9-one

125

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-(l-Hydroxyethyl)phenyl)boronic acid is used for the Suzuki coupling to give 7-methyl-8,l4-dioxa-l0,l9,20triazatetracyclo[l3.5.2.I²’⁶.0^l8i2l]tricosa-l(20),2,4,6(23),l5,17,2ï-heptaen-9-one example 22.

LCMS method F: [M+H]⁺ = 338, t_R = 2.22 min

LCMS method G: [M+H]⁺ = 338, t_R = 2.25 min

Ή NMR (400 MHz, r/6-DMSO) S 13.12 (IH, s), 7.95 - 7.92 (1 H, m), 7.86 - 7.83 (2H, m), 7.50 - 7.46 (2H, m), 7.35 (IH, m), 7.31 - 7.29 (IH, m), 7.00 - 6.97 (IH, m), 5.95 - 5.90 (IH, m), 4.37-4.25 (2H, m), 3.56 - 3.49 (IH, m), 2.77 - 2.68 (IH, m), 2.24-2.15 (IH, m), 1.77- 1.69 10 (1 H, m), 1.59 (3H, d, J = 6.7 Hz) ppm.

Example 23: 4-[4-(2-methoxyethyl)piperidin-l-yl]-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.1²\0¹⁸’²¹]tricosa-l (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)piperidine is used for the Buchwald reaction with the bromide intermediate 34 to give 4-[4-(2methoxyethyl)piperidîn-l-yl]-8,14-dioxa-10,19,20-triazatetracyc!o[13.5.2.1²’⁶.0^l821]tricosa20 1 (20),2,4,6(23), 15,17,21-heptaen-9-one example 23.

LCMS method F: [M+H]⁺ = 465.2, t_R = 1.81 min

LCMS method G: [M+H]⁺ = 465.2, t_R = 2.53 min 'HNMR (400 MHz, r/6-DMSO, 80 ^aC) δ 12.79 (IH, br. s), 7.63 - 7.59 (IH, m), 7.46 (IH, d, J = 9.2 Hz), 7.37 (IH, d, J = 2.0 Hz), 7.34 (IH, d, ./=2.0 Hz), 7.32 (IH, s), 6.96 (IH, dd, J= 2.3, 25 8.9 Hz), 6.86 (IH, s), 5.22 - 5.19 (2H, m), 4.33 - 4.28 (2H, m), 3.77 - 3.73 (2H, m), 3.43 (2H, t, J= 8.0 Hz), 3.21 - 3.16 (2H, m), 3.09 - 3.06 (3H, br. s), 2.78 (2H, dt, J= 4.0, 11.2 Hz), 2.05 -2.01 (2H, m), 1.82- 1.77 (2H, m), 1.58 - 1.49 (3H, m), 1.38 - 1.27 (2H, m) ppm.

126

Example 24: 9,14-dioxa-l 1,19,20-triazatetracy cio [13.5.2. l^2,6.0^18,21 J tricosa-1 (2 0),2,4,

6(23),15,17,21-heptaen-10-one

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-l,3,2dioxaborolan-2-yl)phenyl]ethan-l-ol is used for the Suzuki coupling to give 9,14-dioxa1 l,l9,20-triazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹]tricosa-l(20),2,4,6(23),15,17,21-heptaen-10-one example 24.

LCMS method F: [M+HJ⁺ = 324.1, t_R = 2.14 min

LCMS method G: [M+H]⁺ = 324.1, t_R = 2.19 min ‘H NMR. (400 MHz, r/6-DMSO) δ 13.05 - 13.03 (IH, m), 7.99 (IH, t, J = 5.9 Hz), 7.82 (1 H, s), 7.68 (IH, d, J = 7.6 Hz), 7.58 (IH, d, J= 1.9 Hz), 7.46 - 7.41 (2H, m), 7.28 - 7.25 (IH, m), 7.04 (IH, dd, J = 2.2, 9.0 Hz), 4.33 - 4.21 (4H, m), 3.40 - 3.3 (2H, m), 3.01 (2H, t, J = 5.0 Hz) ppm.

Example 25: 4-[(3R)-3-hydroxypyrrolidin-l-yl]-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2. l^2,6.0^18,21] tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

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)-Pyrrolidin-3-ol is used for the Buchwald reaction with the bromide intermediate 34 to give 4-[(3R)-3-hydroxypyrrolidin-lyl]-8,14-dioxa-10,19.20-triazatetracyclo[ 13.5.2.1²’⁶.0’^8,21 ]tricosa-1(20),2,4,6(23), 15,17,21 heptaen-9-one example 25.

LCMS method F: [M+H]⁺ = 409.1, t_R = 1.96 min

127

LCMS method G: [Μ+ΗΓ = 409.2, t_R = 2.04 min

Ή NMR (400 MHz, rf6-DMSO) δ 7.65- 7.56 (IH, m), 7.48 - 7.45 (IH, m), 7.36 (IH, d, J = 2.5 Hz), 7.l9(lH, s), 7.01 (IH, s), 6.93 (lH, dd, J = 2.3, 9.1 Hz), 6.46(1 H, s), 5.22 (2H, s), 4.48 4.43 ( 1 H, 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 (IH, m), 2.07 -1.97 (2H, m), 1.97 -1.92 (IH, m) ppm. The indazole NH proton was not visible în this solvent.

Example 26: 4-[(2- methoxy ethyl)(m ethyl)am in o]-8,14-dioxa-1 0,19,20-triazatetracyclo [13.5.2.1^2,6.0^18,21Jtricosa-l (20),2,4,6(23),15,17,2 l-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 the bromide intermediate 34 to give 4-[(2methoxyethy l)(methyl)amîno]-8,14-dioxa-10,19,20-triazatetracyclo[l 3.5.2.1²’⁶.0¹⁸²¹ Jtrîcosal(20),2,4,6(23),15,17,21-heptaen-9-one example 26.

LCMS method F: [M+H]⁺ = 411.2, t_R = 2.07 min

LCMS method G: [M+H]⁺ = 411.2, t_R = 2.32 min

Ή NMR (400 MHz, ί/6-DMSO) δ 12.74(1 H, s), 7.48 - 7.45 (lH,m),7.36 (lH,d, J = 2.3 Hz), 7.23 - 7.19 (2H, m), 6.96 (IH, dd, J = 2.4, 9.0 Hz), 6.67 (IH, dd, J = 1.3, 2.5 Hz), 5.22 (1 H, t, J = 9.7 Hz), 4.30 (2H, d, J = 16.7 Hz), 3.31 -3.31 (3H, m),3.11 -3.04 (8H,s),3.0l (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]tricosa-l(20),

2,4,6(23),15,17,21-heptaen-9-one

128

Example 27 is prepared according to the synthesis route described in general Scheme F and procedures analogous to those used to obtain example 11. (3-Chloro-5-methoxycarbonylphenyl)boronic acid îs used for the Suzuki coupling with intermediate 26 to give 4-chloro-8,145 dioxa-10,19,20-triazatetracyclo[l 3.5.2.1²’⁶.0¹⁸² ^6^0^-1(20),2,4,6(23),15,17,21-heptaen~9one example 27.

LCMS method F: [M+H]* = 358.0, t_R = 2.38 min

LCMS method G: [M+H]⁺ = 358.1, t_R = 2.52 min

Ή NMR (400 MHz, (76-DMSO, 80 °C) δ 13.08 (IH, s), 7.85 (2H, d, J= 15.0 Hz), 7.77-7.75 10 (lH,m), 7.50 (1H,d, J= 8.0 Hz), 7.36(1 H, s), 7.32 (lH, d, J = 2.4 Hz), 7.00 (1 H, dd, J = 2.3,

8.9 Hz), 5.29 - 5.25 (2H, m), 4.35 - 4.30 (2H, m), 3.23 - 3.12 (2H, m), 2.06 - 2.00 (2H, m) ppm.

Example 28: 4-fluoro-5-methy 1-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1²’⁶.0^18,2(] tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Example 28 is prepared according to the synthesis route described in general Scheme G.

Préparation of intermediate 43: methyl 5-[5-(3-{[(benzyloxy)carbonyl]amino}propoxy)-l20 (oxan-2-yl)-lH-indazol-3-yl]-3-f!uoro-2-methylbenzoate

129

To a solution of benzyl N-(3-{[l-(oxan-2-yl)-3-(tetramethyl-l,3,2-dîoxaborolan-2-yl)-IHindazol-5-yl]oxy}propyl)carbamate 31 (0.6 g, 1.12 mmol) in ATV-dimethylformamide (15 mL) was added at RT (methyl 5-bromo-3-fluoro-2-methyl benzoate (0.332 g, 1.35 mmol), CS2CO3 (1.096 g, 3.36 mmol) and PdCh(dppf) DCM (0.041 g, 0.06 mmol). The resulting mixture was degassed by bubbling nitrogen for 10 minutes and stirred at 110°C under microwave irradiation for 50 min. The solvent was removed under reduced pressure and the oil was dissolved in EtOAc and water. The two layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash-column chromatography (25 g silica BIOTAGE) chromatography (cyclohexane - ethyl acetate, 100/0 to 50/50) affording methyl 5-[5-(3-{[(benzyloxy)carbonyl]amino}propoxy)-l-(oxan-2-yl)-lHindazol-3-yl]-3-fluoro-2-methylbenzoate 43 as a yellow powder.

LCMS method F: [M+H]⁺ = 576.2, t_R = 3.48 min

Préparation of intermediate 44: benzyl N-[3-({3-[3-fiuoro-5-(hydroxymethyl)-4-methyl phenyl}-l-(oxan-2-yl)-I H-indazol-5-yl)oxy)propyl}carbamate

130

To a methyl 5-[5-(3-{[(benzyloxy)carbonyl]amino}propoxy)-l-(oxan-2-yl)-lH-indazol-3-yl]3-fIuoro-2-methylbenzoate 43 (0.225 g, 0.39 mmol) în THF (50 mL) was added a IM solution of Lithium aluminium tetrahydride (0.78 mL, 0.78 mmol) at 0°C. The mixture was stirred at 0 °C for l hour. To the reaction mixture, EtOAc ( 10 mL) was added at 0°C and poured in a 10% 5 solution of Rochelle’s sait (I00 mL) and EtOAc (100 mL). The mixture was stirred at RT for 2 hours. After séparation, the aqueous layer was extracted with EtOAc (2x50 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 chromatography on silica gel (Macherey Nagel, 25 g) with gradient elution: 10 cyclohexane/EtOAc 0-100 % to give benzyl N-[3-({3-[3-fluoro-5-(hydroxymethyl)-4methylphenyl]-l-(oxan-2-yl)-HLindazoL5-yl}oxy)propyl]carbamate 44 as a yellow oil.

LCMS method F: [M+H |⁺ = 548.2, t_R = 3.10 min

Préparation of intermedîate 45: 4-fluoro-5-methyl-l 9-(oxan-2-yl)-8,14-dioxa-l 0,19,2015 triazatetracyclof13.5.2.1 flo¹⁸·²¹]tricosa-l(20),2, 4,6(23), 15,17,21-heptaen-9-one

To a solution of benzyl-N-[3-({3-[3-fluoro-5-(hydroxymethyl)-4-methylphenyl]-l-(oxan-2yl)-lH-indazol-5-yl}oxy)propyl]carbamate 44 (0.125 g, 0.23 mmol) in anhydrous acetonitrîle (33 mL) was added at RT césium carbonate (0.447 g, 1.37 mmol). The resulting reaction 20 mixture was stirred at 90°C for lh30. The reaction mixture was filtered, the solvent was removed under reduced pressure and the residue was purified by flash-column (15g silica Macherey Nagel) chromatography (DCM - ethyl acetate, 1:0 to 8:2) affording 4-fluoro-5methyl-19-(oxan-2-yl)-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 45 as a white foam.

LCMS method F: [M+H]⁺ = 440.2, t_R = 3.03 min

Preparation of Exampie 28: 4-fluoro-5-methy 1-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.1²'⁶.0^lîU1]iricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

131

To a solution of 4-fluoro-5-methyl-19-(oxan-2-y 1)-8,14-dioxa-10,19,20-triazatetracycio [ 13.5.2.1^.0^18,2'Jtricosa-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 at RT TFA (0.143 mL, 1.92 mmol). The resulting reaction mixture 5 was stirred under microwave irradiation at 80°C for 1 h30. 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 (5g silica Macherey Nagel) chromatography (DCM - ethyl acetate, ] :0 to 4:6) 10 to give a solid, which was trîturated in acetonitrile and fîltered affording 4-fluoro-5-methyl8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1^2,6.0^l8’²¹]tricosa-1(20),2,4,6(23), 15,17,21 heptaen-9-one example 28 as a white solid.

LCMS method F: [M+H]⁺ = 356.2, îr = 2.36 min

LCMS method G: [M+H]⁺ = 356.2, t_R = 2.39 min

Ή NMR (400 MHz, rf6-DMSO) δ 7.80 (IH, s), 7.67 (IH, s), 7.63 (IH, d, J = 11.2 Hz), 7.48 (IH, dd, J = 0.6, 9.1 Hz), 7.40 (IH, d, J = 2.4 Hz), 6.96 (IH, dd, J = 2.3, 8.9 Hz), 5.29 (2H, s), 4.35 (2H, t, J = 8.1 Hz), 3.24 - 3.17 (2H, m), 2.22 (3H, d, J = 1.7 Hz), 2.06 - 2.05 (2H, m) ppm. The indazole NH proton was not visible in this solvent.

Example 29: 4,5-difluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^l8’²¹]tricosal(20),2,4,6(23),15,17,21-heptaen-9-one

Example 29 is prepared according to the synthesis 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

132 tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate is used for the Suzuki coupling with intermediate to give 4,5-difluoro-8,14-dioxa- 10,19,20-triazatetracyclo[ 13,5.2.l²’⁶.0'^8,21 Jtrîcosa-1 (20),2, 4,6(23), 15,17,21 -heptaen-9-one example 29.

LCMS method F: [M+H]⁺ = 360, t_R = 2.47 min

LCMS method G: [M+HJ⁺ = 360, t_R = 2.52 min ^lH NMR (400 MHz, J6-DMSO, 80 °C) δ 13.06 (IH, s), 7.84 - 7.78 (2H, m), 7.71 - 7.69 (IH, m), 7.51 (IH, d, J = 9.1 Hz), 7.31 (IH, d, J = 2.1 Hz), 7.01 (IH, 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.

Example 30: 5-bromo-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.1²ⁱ⁶.0^18,21Jtrïcosal(20),2,4,6(23),15,17,21-heptaen-9-one

Example 30 is prepared according to the synthesis route described in general Scheme C and procedures analogous to those used to obtain example 8.

Préparation of intermediate 46: [3-bromo-5-(hydroxymethyl)pheny!]boronic acid

Br

HO

ho-A OH

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-bromo-benzoic acid (500 mg, 2.05 mmol) in THF (30 mL) at 0 °C. The reaction mixture was allowed to reach room temperature and stirred for 16 hours. MeOH (25 mL) was added at 0°C to quench the reaction until no gas was produced. The solvent was evaporated, and the residue was partitioned between ethyl acetate (50 mL) and water (50 mL). After séparation, 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 sodium

133 magnésium sulfate, filtered and concentrated under reduced pressure to give [3-bromo-5(hydroxymethyl)phenyl]boromc acid 46 as a white solid.

LCMS method F: no m/z detected, t_R = l .58 min

Préparation of intermediate 47: benzyl N-[3-[3-[4-bromo-3-(hydroxymethyl)phenyl]-ltetrahydropyran-2-yl-indazol-5-yl]oxypropylj carbamate

To a solution of benzyl-N-[3-(3-iodo-l-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl] carbamate 26 (692 mg, 1.29 mmol), [4-bromo-3-(hydroxymethyl)phenyl]boronic acid 46 (357 mg, l .55 mmol) and a IM solution of Na₂CO3 (3.9 mL, 3,87 mmol) in DME (l 3 mL) was added palladium-tetrakis(trîphenylphosphine) (75 mg, 0.065 mmol, 5 mol %). The reaction mixture was stirred at 80 °C for 16 hours. After being cooled to room température, the réaction mixture was diluted with water (20 mL), extracted twice with ethyl acetate (2x50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a yellow solid. The crude was purified by flash chromatography (CyH/EtOAc 0 to 100% EtOAc) with a 24 g Redisep to afford benzyl N-[3[3-[4-bromo-3-(hydroxymethyl)phenyl]-l-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl] carbamate 47 as a white solid.

LCMS method F: [M+H]⁺ = 594, t_R = 3.12 min

Préparation of intermediate 48: 5-bromo-19-(oxan-2-yl)-8,l 4-dioxa-10,19,20-triaza tetracyclo[13.5.2.1^2,6.0^ls,2ijtricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one

134

A suspension of benzyl N-[3-[3-[4-bromo-5-(hydroxymethyl)phenyl]-l-tetrahydropyran-2-ylindazol-5-yl]oxy propyl] carbamate 47 (590 mg, 0.99 mmol) and césium carbonate (l .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 obtained solid was triturated with acetonitrile to give 5-bromo-l 9-(oxan-2-yl)-8,14-dioxa-l 0,19,20-triazatetracyclo

[ 13.5.2. PAo'^ftricosa-1(20),2,4,6(23),! 5,17,21 -heptaen-9-one 48 as a white solid.

LCMS method F: [M+H]⁺ = 486/488, t_R = 3.25 min

Préparation of Example 30: 5-bromo-8,14-dioxa-10,19,20-triazatetracyclo

[13.5.2.l^2,6.0^I8,2]] tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

To a solution of 5-bromo-l 9-(oxan-2-y 1)-8,14-dioxa-l 0,19,20-triazatetracyclo

[13.5.2.1²’⁶.0¹⁸’²¹]tricosa-l(20),2,4,6(23),l 5,17,21 -heptaen-9-one 48 (50 mg, 0.10 mmol) in 15 DCM (3 mL) was added trifluoroacetic acid (157 gL, 2.05 mmol). The reaction mixture was stirred at RT for 4 h. The reaction mixture was diluted with DCM (20 mL). Water (20 mL) and ammonium hydroxide 25 % weight aqueous solution (3 mL) were added. A white precipitate was presented in organic layer, and not soluble in DCM. The solid was filtered and dried under reduced pressure to afford 5-bromo-8,14-dioxa-l0,19,20-triazatetracyclo[13.5.2.1²ⁱ⁶.0¹⁸’²¹] 20 tricosa-1 (20),2,4,6(23),15,17,2l-heptaen-9-one example 30 as a white solid.

LCMS method F: [M+H]⁺ = 403, t_R = 2.58 min

LCMS method G: [M+H]⁺ = 403, t_R = 2.48 min

135

'HNMR (400 MHz, rf6-DMSO) δ I3.05 (IH, s), 7.91 - 7.87 (3H, m), 7.73 - 7.69 (l H, m), 7.52 - 7.49 (IH, m), 7.37 (IH, d, J = 1.7 Hz), 7.01 (IH, dd, J = 2.3, 8.9 Hz), 5.27 (2H, s), 4.37 - 4.33 (2H, m), 3.19 (2H, m), 2.02 - 1.99 (2H, m) ppm.

Example 31: 4-(4-methylpiperazin-l-yl)-8,14-dioxa-10,19,20-triazatetracyclo

[13.5.2.1²A0¹⁸²¹ltricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Example 31 is prepared according to the synthesis route described in general Scheme C and 10 procedures analogous to those used to obtain example 12. 1-Methylpiperazine is used for the

Buchwald reaction with the bromide intermediate 34 to give 4-(4-methylpiperazin-l-yl)-8,14dioxa-10,19,20-triazatetracyclo[ 13.5.2.1^2,6.0^18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9one example 31.

LCMS method F: [M+H]⁺ = 422, t_R = 1.44 min

LCMS method G: [M+H]⁺ = 422, t_R = 2.02 min

Ή NMR (400 MHz, J6-DMSO) δ 12.80 (IH, s), 7.62 (IH, m), 7.46 (IH, d, J = 9.2 Hz), 7.38 (IH, m), 7.35 (2H, m), 6.98-6.95 (IH, m), 6.88 (IH, 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-l-yl)-8,14-dioxa-10,19,20-triazatetracyclo

[13.5.2. l^2,6.0^18,2‘jtricosa-l (20),2,4,6(23),15,17,2 l-heptaen-9-one

Example 32 îs prepared according to the synthesis route described in general Scheme C and procedures analogous to those used to obtain example 12. 3-methoxyazetidine hydrochloride

136 is used for the Buchwald reaction with the bromide intermediate 34 to give 4-(3methoxyazetidin-l-yl)-8,l4-dioxa-I0,l9,20-triazatetracyclo[l3.5.2.l²A0^l8’^2l]tricosa-1(20),2, 4,6(23), 15,17,2 l-heptaen-9-one example 32.

LCMS method F: [M+H]⁺ = 409.2, t_R = 2.15 min

LCMS method G: [M+H]⁺ = 409.1, t_R = 2.13 min

Ή NMR (400 MHz, ί/6-DMSO, 80 °C) δ 12.85 (IH, br s), 7.61 (IH, br s), 7.48 - 7.45 (1 H, m), 7.36 - 7.34 (IH, m), 7.27 (IH, s), 6.95 (IH, dd, J = 2.4, 9.2 Hz), 6.90 (1 H, t, J = 2.0 Hz), 6.37 (lH,dd,J= 1.5,2.1 Hz), 5.20 (2H, s), 4.40 - 4.27 (3H, m), 4.15 - 4.11 (2H, m), 3.69 (2H, dd, J = 4.3, 8.6 Hz), 3.30 (3H, s), 3.22 - 3.12 (2H, m), 2.09 - 1.96 (2H, m) ppm.

Example 33: l-{9-oxo-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.1^2,6.0^18,21 Jtricosal(20),2,4,6(23),15,17,21-heptaen-4-yl}piperidine-4-carbonitrile

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 the bromide intermediate 34 to give l-{9-oxo-8,14-dioxa-10,19,20triazatetracyclof 13.5.2.1²’⁶.0^,8’²¹]tricosa-1 (20),2,4,6(23) J 5,17,21-heptaen-4-yl}piperidine-4carbonîtrile example 33.

LCMS method F: [M+H]⁺ = 432, t_R = 2.15 min

LCMS method G: [M+H]⁺ = 432, t_R = 2.2] min

Ή NMR (400 MHz, r/6-DMSO) δ 12.82 (1 H, s), 7.63 (1 H, m), 7.48 - 7.46 ( 1 H, m), 7.40 - 7.35 (3H, m), 7.98 - 7.95 (IH, m), 7.90 (IH, 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 (IH, d, J = 5.9 Hz) ppm.

Example 34: 4-[4-(py rrolid in-l-yl)piperidin-l-yl]-8,l 4-d ioxa-10,19,20-triazatetracyclo [13.5.2.1²’⁶.(l¹⁸’²¹]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

137

Example 34 is prepared according to the synthesis route described in general Scheme C and procedures analogous to those used to obtain example 12. 4-Pyrrolidin-l -ylpiperidine is used for the Buchwald reaction with the bromide intermediate 34 to give 4-[4-(pyrrolidin-lyl)piperidin-l-yl]-8,14-dioxa-l 0,19,20-triazatetracyclo[l 3.5.2.1²’⁶.0¹⁸’^2,]tricosa-1 (20),2,4, 6(23), 15,17,21-heptaen-9-one example 34.

LCMS method F: [M+H]⁺ = 476, t_R = 1.59 min

LCMS method G: [M+H]⁺ = 476, t_R = 1.51 min

Ή NMR (400 MHz, DMSO) δ 12.85 (IH, m), 7.47 (IH, d, J = 8.7 Hz), 7.37 (3H, t, J = 13.0 Hz), 6.98 - 6.92 (2H, m), 5.28 (2H, m), 4.30 (2H, s), 3.85 (2H, m), 3.42 (IH, 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-l-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0¹⁸'^2,l tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

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 the bromide intermediate 34 to give 4-(azetidin-l-yl)-8,14-dioxa-10,19,20triazatetracyclo[l 3.5.2.l²’⁶.0¹⁸’^2,]tricosa-1(20),2,4,6(23), 15,17,21-heptaen-9-one example 35. LCMS method F: [M+H]⁺ = 379, tR = 2.08 min , LCMS method G: [M+H]⁺ = 379, tR = 2.23 min

138

Ή NMR (400 MHz, <76-DMSO) δ 12.78 (1 H, m), 7.59 (IH, m), 7.48 - 7.44 ( LH, m), 7.35 (IH,

s), 7.25 (IH, s), 6.98 - 6.94 (IH, m), 6.88 - 6.87 (IH, m), 6.34 (IH, 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-l-yl)-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2,l^2,6.0^18,21 ] tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Example 36 is prepared according to the synthesis route described in general Scheme A. Piperidine îs used for the Buchwald reaction with the bromide intermediate 34 to give 4(piperidin-l-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^l8’^2l]tricosa-l(20),2,4,6(23), 15,17,21-heptaen-9-one example 36.

LCMS method F: [M+H]⁺ = 407.2, t_R = 1.65 min

LCMS method G: [M+H]⁺ = 407.2, t_R = 2.48 min

Ή NMR (400 MHz, rf6-DMSO, 80 °C) δ 12.79 (IH, s), 7.64 - 7.62 (IH, m), 7.48 - 7.44 (IH, d, J = 8.4 Hz), 7.38 - 7.32 (3H, m), 6.96 (IH, dd, J = 2.3, 9.1 Hz), 6.87 - 6.86 (IH, m), 5.22 (2H, s), 4.30 (2H, dd, J = 7.6, 10.0 Hz), 3.27 - 3.21 (4H, m), 3.20 - 3.11 (2H, m), 2.06 - 1.97 (2H, m), 1.71 -1.64 (4H, m), 1.63 - 1.58 (2H, m) ppm.

Example 37;

4-(2,5-dihydrofuran-3-yl)-8,l 4-dioxa-l 0,19,20-triazatetracyclo [13.5.2.l²’⁶.0^l8’^2l]tricosa-l(20),2,4,6(23),l5,l7,2l-heptaen-9-one

Example 37 is prepared according to the synthesis route described in general Scheme A. 2-(2,5Dihydrofuran-3-yl)-4,4,5,5-tetramethyl-I,3,2-dioxaborolane is used for the Suzuki reaction

139 with the bromide intermediate 34 to give 4-(2,5-dihydrofuran-3-yl)-8,l 4-dioxa-10,19,20trîazatetracyclo[ 13.5.2.1 .0 jtricosa-1(20),2,4,6(23),15,17,21 -heptaen-9-one example 37.

LCMS method F: [M+H]⁺ = 392.2, t_R = 2.19 min

LCMS method G: [M+H]⁺ = 392.2, t_R = 2.19 min

Ή NMR (400 MHz, (76-DMSO, 80 °C) δ 12.94 (IH, s), 7.85 (2H, d, J = 6.3 Hz), 7.69 (IH, s), 7.50(1 H, d, J =9.6 Hz), 7.37(1 H, s), 7.33 (1 H, d, J= 2.0 Hz), 6.99 (IH, dd, J = 2.3, 8.9 Hz), 6.55 - 6.52 (IH, 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-l-yl]-8,14-dîoxa-10,19,20-triazatetracyclo

[13.5.2.1²’⁶.0¹⁸’²¹]tricosa-l(20),2,4,6(23),l 5,17,2 l-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-Piperîdyl)morpholine is used for the Buchwald reaction with the bromide intermediate 34 to give 4-[4-(morpholin-4yl)piperidin-l-yl]-8,l 4-dioxa-10,19,20-triazatetracyclo[l 3.5.2.1²’⁶.0^18,21]tricosa-l (20),2,4, 6(23),15,17,21 -heptaen-9-one example 38.

LCMS method F: [M+H]⁺ = 492.2, t_R = 1.48 min

LCMS method G: [M+H]⁺ = 492.2, t_R = 2.07 min

Ή NMR (400 MHz, 476-DMSO) δ 12.79 (JH, s), 7.61 (IH, s), 7.47 (IH, d, J = 5.8 Hz),7.397.29 (3H, m), 6.97 (IH, dd, J = 2.2, 9.1 Hz), 6.89 (IH, 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 (IH, m), 2.09-1.88 (4H, m), 1.63- 1.5 (2H, m) ppm.

Example 39: 4-(l-methyl-l,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetra cyclo|13.5.2.1^î’⁶.0¹⁸’²¹]tricosa-l(20),2,4,6(23),15,17,21 -heptaen-9-one

140

Example 39 is prepared according to the synthesis route described in general Scheme A. Imethy 1-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaboroIan-2-yl)-3,6-dihydro-2H-pyridine is used for the Suzuki reaction with the bromîde intermediate 34 to give 4-(l-methyl-l,2,3,6tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracy clo[ 13,5,2.1 ^z,6.0^18,21 ]tricosa-l (20),2, 4,6(23), 15,17,2 l-heptaen-9-one example 39.

LCMS method F: [M+H]⁺ = 419.2, t_R = 1.49 min

LCMS method G: [M+H]⁺ = 419.2, t_R = 2.16 min

Ή NMR (400 MHz, ί/6-DMSO, 80 °C) δ 12.95 (IH, s), 7.97 (IH, s), 7.87 (IH, s), 7.71 - 7.69 (IH, m), 7.50 (IH, d, J =8.0 Hz), 7.40(1 H, s), 7.34(1 H, d, J = 1.5 Hz), 7.00 (I H, dd, J = 2.3, 8.9 Hz), 6.28 - 6.25 (IH, m), 5.35 - 5.32 (2H, m), 4.32 (2H, dd, 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-dimethylmorphoIin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.1²’⁶.0^I82I]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Example 40 is prepared according to the synthesis route described in general Scheme C and procedures analogous to those used to obtain example 12. (lS,4S)-2-Oxa-5-azabicyclo[2.2.1] heptane hydrochloride is used for the Buchwald reaction with the bromide intermediate 34 to give 4-[(2S,5S)-2,5-dimethylmorpholin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2. 1^2,6.0^1Sî21]tricosa-l (20),2,4,6(23), 15,17,2 l-heptaen-9-one example 40.

LCMS method F: [M+H]⁺ = 421.1, t_R = 2.06 min

141

LCMS method G: [M+H]⁺ = 421.2, t_R = 2.06 min ‘H NMR (400 MHz, </6-DMSO) δ 12.78 (IH, s), 7.62 (IH, m), 7.46 (IH, d, J = 9.1 Hz), 7.36 (IH, s), 7.23 (IH, s), 7.06 (IH, s), 6.97-6.95 (lH,m), 6.58 (IH, s), 5.21 (2H, m), 4.63 (2H, d, J = 17.5 Hz), 4.32 -4.28 (2H, m), 3.82 (IH, m), 3.76 (IH, m), 3.58 -3.56 (IH, m), 3.16 (2H,

m), 3.10(1 H, m), 2.03 (2H, m), 1.98- 1.95 (1H, m), 1.90- 1.88 (IH, m) ppm.

Example 41:

4-[(morphoIin-4-yl)methyI]-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.1²ⁱ⁶.0^,S2,]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Example 41 îs prepared according to the synthesis route described in general Scheme C.

Préparation of intermediate 49: 4-f(morpholin-4-yl)methyl]-l 9-(oxan-2-yl)-8,14dioxa-10,19,20-triazatetracyclo[13.5.2.I^2,6. 0^IX21 ]tricosa-l (20),2,4.6(23),15,17,21-heptaen-915 one

In a sealed tube, to a solution of 4-bromo-l9-(oxan-2-yl)-8,l 4-dioxa-10,19,20 triazatetracyclo[13.5.2.12,6.0l8,21]tricosa-l(20),2(23),3,5,15(22),16,l8(21)-heptaen-9-one example 12 (100 mg, 0.21 mmol) ïn THF/H2O 9/1 (4 mL) was added potassium I20 trifluoroboratomethylmorpholine (87 mg, 0.42 mmol) and césium carbonate (205 mg, 0.63 mmol) at RT. The reaction mixture was degassed for 15 min by bubbling nitrogen gas through the solution, then palladium acetate (2 mg, 0.01 mmol) and Xphos (10 mg, 0.02 mmol) were

142

added and the reaction mixture was stirred at 100°C for 18 hours. The reaction mixture was allowed to cool to RT 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 (2x20 mL), washed with brine, dried over sodium sulfate and the solvent was removed under reduced pressure to afford a yellow oil. The oil was triturated with acetonitrile and diethyl ether to afford 4-[(morpholin-4-yl)methyl]- l9-(oxan-2-yl)-8,14dioxa- 10,19,20-trîazatetracyclo[l 3.5.2. l~^,6.0^18,2 ’ Jtrîcosa-1(20),2,4,6(23), 15,17,2 l-heptaen-9one 49 as a beige powder.

LCMS method F: [M+H]⁺ = 507, t_R = 1.74 min

Préparation of example 41: 4-[(morpholin-4-yl)m ethyl]-8,14-dioxa-10,19,20triazatetracyclo [13.5.2· 1²AO^18,21 J tricosa-1(20),2,4,6(23),15,17,2 l-heptaen-9-one

To a solution of 4-[(morpholin-4-yl)methyl]-19-(oxan-2-yl)-8,14-dioxa-10,19,20tnazatetracyclo[13.5.2.1²’⁶.0^,8’^2l]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one 49 (60 mg, 0.13 mmol) in DCM (2 mL) was stirred at RT for 6 hours. The reaction mixture was evaporated under reduced pressure to give a brown oil. dDCM (20 mL) and a saturated solution of bicarbonate (10 mL) was added to the residue, after séparation, the organic layer was extracted with DCM (2x10 mL), washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give an yellow oil. Some acetonitrile and diethyl ether was added to the oil, the precipitate formed was filtered to afford 4-[(morpholin-4-yl)methyl]-8,14-dioxa-10,19,20triazatetracyclo[ 13.5.2. l²A0¹⁸’²¹ Jtrîcosa-1(20),2,4,6(23), 15,17,21 -heptaen-9-one example 41 as a beige solid.

LCMS method F: [M+H]⁺ = 423, t_R = 1.42 min

LCMS method G: [M+H]⁺ = 423, t_R = 2.03 min

Ή NMR (400 MHz, DMSO) δ 12.89 (IH, s), 7.81 (2H, d, J = 11.8 Hz), 7.66 (IH, s), 7.50 7.47(1 H, m), 7.35 (IH, d, J= 1.9 Hz), 7.22 (IH, s), 6.98 (1 H, dd, J = 2.4, 9.0 Hz), 5.29-5.26

143 (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.

Example 42: 4-[(pyrrolidin-l-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo

[13.5.2.1²<0¹⁸’^2,]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

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[(pyrrolidin-l10 yl)methyl]borate was used for the Suzuki coupling with the bromide intermediate 34 to give 4[(pyrrolidin-1 -y l)methyl]-8,l 4-dioxa-l 0,19,20-triazatetracyclo [ 13.5.2.1 ²⁶.0^l8’^2l]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one example 42.

LCMS method F: [M+H]⁺ = 407, t_R = 1.44 min

LCMS method G: [M+H]⁺ = 407, t_R = 2.12 min

Ή NMR (400 MHz, r/6-DMSO) δ 12.88 (IH, s), 7.84 (IH, s), 7.79 (IH, s), 7.66 (IH, m), 7.48 (IH, d, J = 8.8 Hz), 7.35 (III, d, J = 1.7 Hz), 7.22 (IH, s), 6.98 (IH, 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-[(py r roi id ΐ η-1-y l)methyl]-8,14-dioxa-l 0,19,20-triazatetracyclo [13.5.2.1²<0^,8’^2,]tricosa-l (20),2,4,6(23),15,17,21-heptaen-9-one

144

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-lyl)methyl] borate was used for the Suzuki coupling with the bromide intermedîate 34 to give 4[(pyrrolidin-l-y l)methyl]-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1^2,6.0’^8,2']tricosa1(20),2,4,6(23), 15,17,2 l-heptaen-9-one example 43.

LCMS method F: [M+H]⁺ = 421, t_R = 1.49 min

LCMS method G: [M+Hf = 421, t_R = 2.33 min

Ή NMR (400 MHz, rf6-DMSO, 80°C) δ 12.86 (IH, s), 7.86 (2H, m), 7.59 (IH, m), 7.48 (IH, d, J = 8.4 Hz), 7.37 (IH, d, J = 2.1 Hz), 7.25 (IH, m), 6.99 (IH, dd, J = 2.3, 8.9 Hz), 5.30 (2H, s), 4.32 (2H, m), 3.19 (2H, m), 2.05 (2H, m), 1.62 (4H, m), 1.48 (2H, m) ppm. Some protons are not visible due to different conformations. Structure confirmed by COSY.

Example 44: 4-[(4-m ethy I piperazin-1-y l)methyl]-8,14-dioxa-10,19,20-triazatetracyclo

[13.5.2.1^2,fi.0^18,if]tricosa-1 (20),2,4,6(23), 15,17,21-heptaen-9-one

Example 44 is prepared according to the synthesis route described in general Scheme C and procedures analogous to those used to obtain example 4L Potassium trîfluoro[(4methylpiperazin-l-yl)methyl]borate was used for the Suzuki coupling with the bromide intermedîate 34 to give 4-[(4-methylpiperazin-l-y[)methyl]-8,14-dioxa-10,19,20triazatetracyclo[ 13.5.2.l²Aû^18,2’]tricosa-1(20),2,4,6(23),15,17,2 l-heptaen-9-one example 44. LCMS method F: [M+H]⁺ = 436, t_R = 1.36 min (current 20V)

LCMS method G: [M+H]⁺ = 436, t_R = 1.95 min (pHIO current 20V)

Ή NMR (400 MHz, t/6-DMSO, 80 °C) δ 12.89 (IH, s), 7.81 (IH, s), 7.79 (IH, s), 7.66 (IH, m), 7.48 (IH, d, J= 8.8 Hz), 7.35 (IH, m), 7.20 (IH, m), 6.98 (IH, dd, J = 2.3, 9.1 Hz), 5.28

145

(2H, s), 4.3 ! (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-triazatetracyclo[13.5.2.1²A0¹⁸’²¹] tricosa-l(20),2,4,6(23),15,17,2 l-heptaen-9-one

Example 45 is prepared according to the synthesis route described in general Scheme C.

Morpholine was used for the Buchwald coupling with the bromide intermediate 48 to give 510 (morpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²'⁶.0¹⁸’²¹]tricosa-l(20),2,4,

6(23),15,17,21-heptaen-9-one example 45.

LCMS method F: [M+H]⁺ = 409, t_R = 2.17 min

LCMS method G: [M+H]⁺ = 409, t_R = 2.16 min ^lH NMR (400 MHz, rf6-DMSO) δ 12.80 ( 1 H, s), 7.89 - 7.86 (2H, m), 7.68 (IH, s), 7.49 - 7.45 15 (IH, m), 7.35 (1 H, d, J = 1.3 Hz), 7.29 - 7.25 (IH, m), 6.97 (IH, dd, J = 2.3, 8.9 Hz), 5.37 (2H, s), 4.3 l (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-methoxyethyl)piperazin-l-yl]-8,14-dioxa-10,19,20-triazatetracyclo

[13.5.2. l²A0^,8’²¹]tricosa-l(20),2,4,6(23),l 5,17,21-heptaen-9-one

Example 46 is prepared according to the synthesis route described in general Scheme A. l-(2methoxyethyl)piperazine is used for the Buchwald reaction with the bromide intermediate 34

146 to g i ve 4-14-(2-methoxyethy I )p iperazi n-1 -y I] - 8,14-dioxa-10,19,2 O-triazatetracyc I ο [ 13.5.2.

]^2,.O ^8,2 ]trîcosa-1(20),2,4,6(23), 15,17,21-heptaen-9-one example 46.

LCMS method F: [M+H]⁺ = 466.2, t_R = 1.48 min

LCMS method G: [M+H]⁺ = 466.2, t_R = 2.06 min

Ή NMR (400 MHz, ί/6-DMSO, 80 °C) δ 12.83 (IH, s), 7,64(1 H, s), 7,49 - 7.46 (1 H, m), 7.40 (2H, s), 7.34 (IH, s), 6.99 - 6.91 (2H, m), 5.24 (2H, s), 4.33 - 4.27 (2H, m), 3.67 - 3.63 (2H, m), 3.17-3.08 (15H, m), 2.10- 1.99 (2H, m) ppm.

Example 47: 4-(diethylamino)-8,14-dioxa-i 0,19,20-triazatetracyclo [13.5.2.17^.0^18,21] tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Example 47 is prepared according to the synthesis route described in general Scheme A. Diethylamine is used for the Buchwald reaction with the bromide intermediate 34 to give 4(diethylamino)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1^2,6.0¹⁸’^2l]tricosa-l(20),2,4, 6(23),15,17,21-heptaen-9-one example 47.

LCMS method F: [M+H]⁺ - 395.2, t_R = 1.57 min

LCMS method G: [M+H]⁺ = 395.2, t_R = 2.48 min

Ή NMR (400 MHz, ύ/6-DMSO, 80 °C) δ 12.73 (1 H, br s), 7.59 (IH, br s), 7.46 (I H, d, J = 9.3 Hz), 7.36 (IH, d, J = 2.1 Hz), 7.18 - 7.16 (2H,m), 6.95 (IH, dd, J =2.4, 8.8 Hz), 6.63 (IH, s), 5.21 - 5.20 (2H, m), 4.32 - 4.27 (2H, m), 3.42 (4H, q, J = 7.0 Hz), 3.21 - 3.10 (2H, m), 2.08 1.96 (2H, m), 1.17 (6H, t, J = 6.9 Hz) ppm.

Example 48 : 4-cyclopropyl-8,14-dioxa-10,19,20-triazatetracycIû[13.5.2.1²’⁶.0¹⁸²¹]tricosa1(20),2,4,6(23),15,17,21- heptaen-9-on e

147

Example 48 is prepared according to the synthesis route described în general Scheme C. Potassium trifkioro[cyclopropyl]borate was used for the Suzuki coupling with the bromide intermediate 34 to give 4-cyclopropyl-8,14-dioxa-l 0,19,20-triazatetracyclo[ 13.5.2.1²·⁶. 0^,8’²¹]tricosa-l(20),2,4,6(23),l 5,17,21 -heptaen-9-one example 48.

LCMS method F: [M+H]⁺ = 364, t_R = 2.40 min

LCMS method G: [M+H]⁺ = 364, t_R = 2.39 min

Ή NMR (400 MHz, t/6-DMSO, 80 °C) δ 12.87 (IH, s), 7.68 (IH, s), 7.64 (IH, m), 7.60 (IH, s), 7.47 (IH, d, J = 9.1 Hz), 7.33 (IH, d, J = 2.1 Hz), 6.99 (IH, s), 6.97 (IH, 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-l-yl)-8,14-dioxa-10,19,20-triazatetracyclo

[13.5.2,l^ï’⁶,0¹⁸’²¹]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Example 49 is prepared according to the synthesis route described in general Scheme C. 4Methylpiperazine was used for the Buchwald coupling with the bromide intermediate 48 to give 5-(4-methy lpiperazin-1-y l)-8,14-dioxa-10,19,20-trîazatetracyclo[ 13.5.2.1^2,6.0’^8,21 Jtricosa1(20),2,4,6(23),15,17,21-heptaen-9-one example 49.

LCMS method F: [M+H]^4- = 422, t_R = 1.44 min

LCMS method G: [M+H]⁺ = 422, t_R = 2.13 min

148

Ή NMR (400 MHz. CD₃OD) δ 8.01 - 7.99 (IH, m), 7.92 (IH, dd, J = 2.1, 8.4 Hz), 7.79 (IH, t,

J = 6.1 Hz), 7.49 - 7.34 (4H, m), 7.04 (IH, dd, J = 2.3, 9.1 Hz), 5.51 - 5.47 (2H, m), 4.36 (2H, m), 3.74 - 3.63 (2H, m), 3.42 (4H, m), 3.21 (4H, m), 3.03 (3H, s), 2.12 (2H, m) ppm.

Example 50: 13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1^2,fi.0^18,21 Jtricosal(20),2,4,6(23),15,17,21-hepiaen-9-one

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 pf 13-methyl-19-(oxan-2-yl)-8,!4-dÎoxa-10,19,20-triazatetracyclo [ 13.5.2. l^w.0^182l]tricosa-1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one (330 mg, 0.78 mmol) in dichloromethane (12 mL) was added trifluoroacetic acid (l.l9mL, 15.65 mmol) at RT. The solution was then irradiated under micro-waves (Bîotage initîator+) for 2h. The reaction mixture was concentrated under vacuo and the residue was dissolved in EtOAc. The organic phase was washed with a saturated aqueous solution of sodium hydrogen carbonate, with brine, dired over Na2SÛ4, filtered and evaporated under reduced pressure. The solid obtained was triturated in diisopropyl ether and dried to give the expected compound 13-methyl-8,14-dioxa10,19,20-triazatetracyclo[13.5.2.1²L0^l8,2l]tricosa-l(20),2,4,6(23),15,17,2I-heptaen-9-one example 50 as a pale yellow solid.

LCMS method F: [M+H]⁺ = 338, t_R = 2.25 min

LCMS method G: [M+H]⁺ = 338, t_R = 2.24 min ’H NMR (400 MHz, t/6-DMSO) δ 13.12 (IH, s), 7.93 - 7.84 (3H, m), 7.47 (2H, dd, J = 8.5, 15.8 Hz), 7.27 (2H, d, J = 7.0 Hz), 6.97 (IH, dd, J = 2.1, 8.9 Hz), 5.75 (IH, d, J = 12.1 Hz), 4.81 (IH, d, J = 12.5 Hz), 4.57 (IH, dd, J = 6.0, 9.2 Hz), 3.59 - 3.54 (IH, m), 2.93 - 2.86 ( 1 H, m), 2.47-2.33 (1 H, m), 1.41-1.38 (4H, m) ppm.

Example 51:

149

8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1²’⁵,0^lil,ïl]tricosa1(20),2(23),3,15(22),16,18(21)-hexaen-9-one

Example 51 is prepared according to the synthesis route described in general Scheme C.

Préparation of intermediate 50: benzyl N-f3-({3-[l-(2-hydroxyetbyl)-lH-pyrazol-4-yl]-l(oxan-2-yl)-lH~indazol-5-yl}oxy) propyl]carbamate

To a solution of benzyl-N-(3-{[3-iodo-l-(oxan-2-yl) -1 H-indazol-5-yl]oxy}propyl)carbamate 10 26 (0.535 g, 1.0 mmol) in dioxane (3 mL) and water (1 mL) was added at RT l-(2hydroxyethyl)-lH-pyrazole-4-boronic acid pînacol ester (0.286 g, 1.2 mmol), K.3PO4 (0.637 g, 3.0 mmol), XPhos (0.048 g, 0.1 mmol) and Pd(PPhj)4 (0.058 g, 0.05 mmol). The resulting réaction mixture was stirred under micro wave irradiation at I20°C for Ih. The residue was diluted with saturated sodium chloride solution and extracted with ethyl acetate twice. The 15 combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash-column (25g silica Macherey Nagel) chromatography (cyclohexane - ethyl acetate 3 / EtOH 1, 1:0 to 1:1) affording benzyl N-[3-({3-[l -(2-hydroxyethyl)-] H-pyrazol-4-yl]-l-(oxan-2-yl)-lH-indazol-5-yl}oxy) propyl]carbamate 50 as a yellow oil.

LCMS method F: [M+H]⁺ = 520.2, t_R = 2.56 min

Préparation of intermediate 51:

150

To a solution of benzyl N-[3-({3-[l-(2-hydroxyethyl)-IH-pyrazol-4-yl]-l-(oxan-2-yl)-lHindazol-5-yl}oxy)propyl]carbamate 50 (0.380 g, 0.73 mmol) in anhydrous acetonitrîle (146 mL) was added at RT césium carbonate (1.430 g, 4.39 mmol). The resulting reaction mixture 5 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 (15g silica Macherey Nagel) chromatography (cyclohexane - ethyl acetate 3 / EtOH 1, 1:0 to 3:7) affording 19-(oxan-2-yl)8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[l 3.5.2.1²⁵.0^ιε’² 'Jtricosa-1(20),2(23),3,15(22), 16,18(21 )-hexaen-9-one 51 as a white solid.

LCMS method F: [M+H]⁺ = 412.2, t_R = 2.20 min

Préparation of Example 51: 8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1²’⁵.0¹⁸’²¹] tricosa-1 (20),2(23), 3,15(22),16,18(2 l)-hexaen-9-one

To a solution of 19-(oxan-2-yl)-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo

[13.5.2.l²’⁵.0^l821]tricosa-l(20),2(23),3,l5(22),16,I8(21)-hexaen-9-one 51 (0.155 g, 0.38 mmol) in DCM (3 mL) was added at RT TFA (0.561 mL, 7.53 mmol). The resulting reaction mixture was stirred under micro wave irradiation at 80°C for lh30. The reaction mixture was concentrated under reduced pressure, diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flashcolumn (15g silica Macherey Nagel) chromatography (cyclohexane - ethyl acetate 3 / EtOH 1, 9:1 to 0:1) to give a solid (70 mg), which was triturated in diîsopropyl ether and filtered

151 affording 8,l4-di0xa-4,5,lOJ9,2O-pentaazatetracyclo[l3.5.2.l²ÂO^l82i]tricosa-l(2O),2(23), 3,15(22),16,18(2 l)-hexaen-9~one example 51 as a white solid.

LCMS method F: [M+H]⁺ = 328.1, t_R = 1.68 min

LCMS method G: [M+H]⁺= 328.1, t_R = 1.68 min ‘H NMR (400 MHz, rfô-DMSO) δ 12.82 (IH, s), 8.09 (1 FI, s), 7.86 (IH, t, J = 6.1 Hz), 7.77 (1 H, d, J = 0.6 Hz), 7.44 - 7.41 ( 1 H, m), 7.07 (IH, d, J = 2.3 Hz), 6.94 (IH, 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-10,19,20-triazatetracyclo

[13.5.2.1 ^.O'^'jtricosa-l (20),2,4,6(23),15,17,2 l-heptaen-9-one

Example 52 is prepared according to the synthesis route described in general Scheme C. Nmethyloxetan-3-amine îs used for the Buchwald reaction with the bromide intermediate 34 to 15 give 4-[methyl(oxetan-3-y])amino]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.û¹⁸’²¹] tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one example 52.

LCMS method F: [M+Hf = 409, t_R = 2.04 min

LCMS method G: [M+H]⁺ = 409, t_R = 2.06 min

Ή NMR (400 MHz, d6-DMSO) δ 12.81 ( 1 H, s), 7.62 (1 H, s), 7.46 (1 H, d), 7.34 (2H, s), 7.13 20 (IH, s), 6.98-6.95 (1H, m), 6.64 (IH, s), 5.22 (2H, m), 4.84 -4.81 (2H, m), 4.77 - 4.74 (IH, m), 4.65-4.64 (2H, m), 4.32-4.28 (2H, m), 3.16 (2H, m), 2.96 (3H, s), 2.03 (2H, m) ppm.

Example 53: 4-[(dimethylamino)methyl]-8,14-dioxa-10,19,20-triazatetracyclo

[13.5.2.1²⁶.0^I8’^2,]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-oue

152

Example 53 is prepared according to the synthesis route described in general Scheme C. Potassium (dimethylamino)methyltrifluoroborate was used for the Suzuki coupling with the bromide intermediate 34 to give 4-[(dimethylamino)methyl]-8,l 4-dioxa-l 0,19,205 triazatetracyclo[ 13.5.2.1²’⁶.0'^8,2'jtricosa-1(20),2,4,6(23), 15,17,21-heptaen-9-one example 53.

LCMS method F: [M+H]⁺ = 381, t_R = 1.39 min

LCMS method G: [M+H]⁺ = 381, t_R = 2.03 min

Ή NMR (400 MHz, rf6-DMSO) δ 12.93 (IH, s), 7.87 (2H, m), 7.70 - 7.66 (IH, m), 7.51 - 7.47 (IH, m), 7.36 (lH,d, J = 2.1 Hz), 7.25 (iH, s), 6.99 (IH, dd, J = 2.3, 9.1 Hz), 5.30 - 5.26 (2H, 10 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-dimethy 1-8,14-dioxa-l0,19,20-triazatetracyclo[13.5.2.GÊO^18,21 ]tricosa1 (20),2,4,6(23),15,17,2 l-heptaen-9-one

Example 54 is prepared according to the synthesis route described in general Scheme F.

Préparation of intermediate 52: 4,10-dimethyi-l 9-(oxan-2-yl)-8,14-dioxa-l 0,19,20triazatetracyclof13.5.2.1²·⁶.0^l8'²¹/tricosa-l (20),2,4,6(23), 15,17,21-heptaen-9-one

153

To a mixture of 4-methyl-l 9-(oxan-2-y 1)-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.l²’⁶.0^is,2i]tricosa-l(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 added NaH 60% in oil dispersion (8 mg, 0.328 mmol) and Mel (20 pL, 0.328 mmol). The reaction mixture was stirred ovemight at RT. More NaH 60% in oïl dispersion (8 mg, 0.328 mmol) and Mel (20 pL, 0.328 mmol) were added. The reaction mixture was stirred ovemight at RT. The solvent was removed under reduced pressure, EtOAc and water were added. The layers were separated, the aqueous one was extracted with ethyl acetate. The organic layers were combined and the solvent was removed under reduced pressure to give 4,10-dimethyl-l 9-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2. l^2,6.0^18,2,]tricosa-1(20),2,4,6(23), 15,17,21-heptaen-9-one 52 as a coiorless oil.

LCMS method F: [M+H]⁺ = 436.2, t_R = 3.15 min

Préparation of Example 54: 4,10-dîmethyl-8,14-dioxa-10,19,20-triazatetracyclo

[13.5.2.1²’⁶,0¹⁸’²¹]trîcosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

To a mixture of 4,10-dimethyl-I9-(oxan-2-yl)-8,l 4-dioxa-10,19,20-triazatetracyclo [13.5.2.1²A0^l8,21]tncosa-l(20),2,4,6(23),15J7,21-heptaen-9-one 52 (150 mg; 0.345 mmol) in DCM (2.5 mL) was added TFA (132 pl, 1.723 mmol). The reaction mixture was stirred under microwave conditions at 80°C during 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 the oil was purified by chromatography using a 10 g SiO₂ column eluted with DCM ! MeOH 100/0 to

I54

95/5. The desired fractions were combined but the product is not enough pure it was re-purified by chromatography using a 10 g SiO₂ column eluted with cyclohexane/Ethyl acetate 70/30 to 50/50. The desired fractions were combined, and the solvent was removed under reduced pressure then the oil was triturated with pentane. The solid was filtered and boîled în hot water, 5 it was filtered and dried under high vacuum to give 4, l0-dimethyl-8,14-dioxa-10,19,20triazatetracyclo [13.5.2.1^2,6.0^18,2'itricosa-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, t_R = 2.49 min

The 'H NMR analysis showed the presence of rotamers.

^lH NMR (400 MHz, d6-DMSO) δ 13.11 - 13.05 (IH, m), 7.68 (2H, d, J = 13.7 Hz), 7.51 -7.47 (IH, m), 7.20 - 7.12 (2H, m), 6.99 (IH, dd, J = 2.2, 9.0 Hz), 5.82 (0.75H, d, J = 13.3 Hz), 5.15 (0.25H, s), 4.78 (O.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 15 2.39 (4H, m), 2.27 - 2.16 (0.25H,m), 1.77 - 1.70 (0.75H, m) ppm.

Example 55: 4-(p ropan-2-yloxy)-8,14-dioxa-l 0,19,20-triazatetra cy cio [13.5.2. PAO¹⁸²¹] tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Préparation of intermediate 53: methyl 3-[5-[3-(benzyloxycarbonylamino)propoxy]-itetrahydropyran-2-yl-indazol-3-yl]-5-hydroxy-benzoate

155

To a degassed solution of benzyl N-[3-(3-iodo-l-tetrahydropyran-2-yl-indazol-5yl)oxypropyl]carbamate 26 (2.876 g, 5.372 mmol), methyl 3-hydroxy-5-(4,4,5,5-tetramethyll,3,2-dîoxaborolan-2-yl)benzoate (2.988 g, 10.473 mmol), XPhos (256 mg, 0.537 mmol) and 5 Κ₃ΡΟ4(3.421 g, I6.l I6 mmol) in dioxane (40.0 mL) and water (I0.0 mL) was added Pd(PPh₃)4 (3 H mg, 0.269 mmol). The resulting cloudy brown solution was degassed with nitrogen gas for 5 minutes and separated în three batches, sealed and heated to l20°C under microwave irradiation for l 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 10 mL) and the combined organic extracts were washed with a saturated aqueous NaCl solution (1 x 50 mL), dried over anhydrous Na₂SÜ4, filtered and concentrated under reduced pressure. The resulting crude material (brown oil, 4.1 g) was purified by column chromatography (220 g Macherey Nagel SiO₂, 100 mL/min, CyH/EtOAc 100:0 to 60:40) to afford methyl 3-[5-[3(benzy loxycarbony lam ino)propoxy] -1-tetrahy dropy ran-2-y I - indazo 1-3-y 1]-5-hydroxy15 benzoate 53 as a brown oil.

LCMS method F: [M+H]⁺ = 560.1, t_R = 2.97 min

Préparation of intermedîate 54: methyl 3-[5-[3-(benzyloxycarbonylannno)propoxyf-ltetrahydropyran-2-yl-indazol-3-yi]-5-isopropoxy-benzoate

156

To a solution of methyl 3-[5-[3-(benzyloxycarbonylamino)propoxy]-l-tetrahydropyran-2-ylindazol-3-yl]-5-bydroxy-benzoate 53 (2.800 g, 5.004 mmol) and K2CO3 (1.729 g, 12.510 mmol) in A.X-dimethylformamide (25.0 mL) was added 2-bromopropane (940 pL, 1.231 mg, 5 10.008 mmol). The resulting cîoudy brown solution was heated to 70°C for 2 h. The réaction was quenched with water (20 mL), EtOAc (50 mL) was added and phases were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic extracts were washed with saturated aqueous NaCi solution (1 x 20 mL), dried over anhydrous Na2SÛ4, filtered and the solvent was removed under reduced pressure. The resulting crude material (brown solid, 3.5 g) was purified by column chromatography (120 g Macherey Nagel S1O2, CyH/EtOAc 100;0 to 70;30) to afford methyl 3-[5-[3-(benzyloxycarbonylamino)propoxy]-ltetrahydropyran-2-yl-indazoL3-y 1]-5-isopropoxy-benzoate 54 as a brown solid.

LCMS method F: [M+H]⁺ = 602.3, t_R = 3.48 min

Préparation of intermediate 55: benzyl N~[3-[3-[3-(hydroxymethyl)-5-isopropoxy-phenyl]-ltetrahydropyran-2-yl-indazoi-5-yl]oxypropyi]carbamate

To a solution of methyl 3-[5-[3-(benzyloxycarbonylamino)propoxy]-l-tetrahydropyran-2-ylindazo!-3-yl]-5-isopropoxy-benzoate 54 (3.000 g, 4.986 mmol) in THF (50.0 mL) at 0°C was

157 added dropwise L1AIH4 (1.0 M in THF, 9.97 mL, 9.972 mmol). The resulting brown solution was stirred at 0°C for 15 minutes, then at room température for l h. The reaction was carefully quenched with saturated aqueous Rochelle’s sait (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 NaCi solution (1 x 50 mL), dried over anhydrous NaiSOi, filtered and concentrated under reduced pressure to afford crude benzy1 N-[3- [3 - [3 -(hydroxy m ethy 1)- 5 -isopropoxy-phenyl ] -1 -tetrahy dropy ran-2-y 1-indazo 1-5 yl]oxypropyl]carbamate 55 as a brown oil which was used in the next step without further purification.

LCMS method F: [M+H]⁺ = 574.2, t_R = 3.06 min

Préparation of intermediate 56: 19-(oxan-2-yl)-4-(propan-2-yloxy) -8,14-dioxa-l 0,19,20triazatetracyclof13.5.2.1^2,6.0^ls,2i]tricosa-l (20),2,4,6(23),15,17,21-heptaen-9-one

To a solution of benzyl N-[3-[3-[3-(hydroxymethyî)-5-isopropoxy-phenyl]-I-tetrahydropyran2-yl-indazol-5-yl]oxypropyl]carbamate 55 (100 mg, 0.174 mmol) in MeCN (18.0 mL) was added CS2CO3 (341 mg, 1.046 mmol). The resulting cioudy yellow mixture was heated under reflux for 5 h. The mixture was cooled to room température, filtered and concentrated under reduced pressure. The resulting crude materiai (yellow oil, 100 mg) was purified by column chromatography (4 g Macherey Nagel SiO2,15 mL/min, CIUClz/MeOH 100:0 to 98:2) to afford 19-(oxan-2-y l)-4-(propan-2-y loxy)-8,14-dioxa-l 0,19,20-triazatetracyclo[ 13.5.2.1^2,6.0^18,3'] tricosa-l(20),2,4,6(23),15J7,21-heptaen-9-one 56 as a transparent oil.

LCMS method F: [M+H]⁺ = 466.2, t_R = 3.03 min

Préparation of Example 55: 4-(propan-2-yloxy )-8,14-dioxa-l 0,19,20-triazatetracyclo

[13.5.2.1²’⁶.0^l8’²¹]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

158

To a solution of 19-(oxan-2-yl)-4-(propan-2-yloxy)-8,l4-dtoxa-10,l 9,20-triazatetracyclo [ 13.5.2. l²A0¹⁸’² ^tricosa-1 (20),2,4,6(23),15,17,2 l-heptaen-9-one 56 (54 mg, 0.116 mmol) in CH2CI2 (5.0 mL) was added TFA (300 pL, 447 mg, 3.920 mmol). The vial containing the resulting clear yellow solution was sealed and heated to 50°C under microwave irradiation for 3 h. Saturated aqueous NaIICO₃ (1 mL) was added and phases were separated. The aqueous layer was extracted with CI-I2CI2 (3x5 mL) and the combined organic extracts were washed with water (1x5 mL), dried over anhydrous Na₂SO4, fïltered and concentrated under reduced pressure. The resulting crude material (pale yellow oil, 49 mg) was triturated with ίΡηΟ to afford 4-(propan-2-yloxy)-8,I4-dioxa-10,l9,20-triazatetracyclo[13.5.2.1²’⁶.0^l82,]tricosa1(20),2,4,6(23),15,17,21-heptaen-9-one example 55 as a white amorphous solid.

LCMSmethodF: [M+H] ⁺ = 382.1, t_R = 2.41 min

LCMS method G: [M+H]⁺ = 382.2, t_R = 2.40 min

Ή NMR (400 MHz, c/6-DMSO, 80°C) δ 7.66 (brs, IH), 7.49 - 7.46 (m, 2H), 7.39 - 7.34 (m, 2H), 6.98 (dd, 2.4, 9.0 Hz, IH), 6.85 (brs, IH), 5.24 (brs, IH), 4.72 - 4.63 (sept, J= 5.9 Hz, IH), 4.33 -4.29 (m, 2H), 3.19 - 3.15 (m, 2H), 2.04 - 2.02 (m, 2H), 1.35 - 1.33 (m, 6H) ppm. Two labile protons were not visible in this solvent.

Example 56: 4-fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1^.0¹⁸²¹] tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Example 56 is prepared according to the synthesis route described in general Scheme A.

Préparation of intermediate 57: l-(3-bromo-5-fluoro-phenyl)ethanol

159

To a cooled solution of 3-bromo-5-fluorobenzaldéhyde (1.5 g, 7.389 mmol) în dry tetrahydrofuran (19 mL) was added dropwise méthylmagnésium bromide solution 3M in diethyl ether (4.93 mL, 14.778 mmol) at 0°C. The reaction mixture was stirred at 0°C for 20 min then RT for 16 h. The reaction mixture was quenched with a saturated aqueous solution of NH4CI then extracted with ethyl acetate (2 x). The combined organic layers were washed with water then brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash-column chromatography eluting with Cyclohexane/Ethyl acetateEtOH (3-1): 100 / 0 to 80 / 20, to give l-(3-bromo-5-fluoro-phenyl)ethanol 57 as a colorless oil.

LCMS method F: [M+H]⁺ = mass not detected, Ir = 2.32 min

Préparation of intermedîate 58: l-[3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dîoxaborolan-2yl)ph enyl]eth anol

To a degassed solution in a sealed tube of l-(3-bromo-5-fluoro-phenyl)ethanol 57 (LI96 g, 5.461 mmol), bis(pinacolato)dîboron (2.080 g, 8.192 mmol) and potassium acetate (2.144 g, 21.844 mmol) in dioxane (17 mL) was added PdCh(dppf) CH2CI2 (0.446 g, 0.546 mmol). The reaction mixture was heated at 90°C for 24h. The reaction mixture was filtered over celite on Whatman paper and rinsed with ethyl acetate. The réaction mixture was diluted with water and extracted with ethyl acetate (3 x). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1[3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dîoxaborolan-2-yl)phenyl]ethanol 58 as a black oil. LCMS method F: no m/z detected, tR = 2.65 min.

160

Préparation of intermediate 59: benzyl N-[3-[3-[3-fluoro-5-(l-hydroxyethyl)phenyl]-ltetrahydropyran-2-yi-indazol-5-yl]oxypropyl]earbamate

To a degassed solution of benzyl N-[3-(3-iodo-l-tetrahydropyran-2-yl-indazol·5yl)oxypropyi]carbamate 26 (1.462 g, 2.734 mmol), I -[3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)phenyl]ethanol 58 (1.453 g, 5.466 mmol), tripotassium phosphate (I.742 g, 8.202 mmol) and xPhos (0.130 g, 0.274 mmol) in dioxane (14.6 mL) and water (8.8 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.158 g, 0.137 mmol). The reaction mixture was irradiated under microwaves (Biotage initîator+) at l20°C for Ih. The réaction mixture was fîltered 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 eluting with DCM / ethyl acetate, 100/0 to 80/20 to give benzyl N-[3-[3-[3-fluoro-5-(i-hydroxyethyl)phenyl]-l-tetrahydropyran-2-ylindazol-5-y!]oxypropyl]carbamate 59 as a cream solid.

Yield: 780 mg of intermediate 59 (50%)

LCMS method F: [M-FH]⁺ = 548, t_R = 3.07 min

Préparation of intermediate 60: l-[3-[5-(3-aminopropoxy)-l-tetrahydropyran-2-yl-indazol3-yl]-5~fluoro-phenyl]ethanoi and 4-fluoro-7-methyl-l9-(oxan-2~yl)-8,14-dioxa-10,19,20triazatetracyclo[]3.5.2.1²’⁶.0^}S,2!]tricosa-l(20),2(23),3,5,15(22),16,18(2l)-heptaen-9-one

161

A suspension of benzyl N-[3-[3-[3-fluoro-5-(l-hydroxyethyl)phenyl]-l-tetrahydropyran-2-ylindazol-5-yl]oxypropyl]carbamate 59 (0.780 g, 1.426 mmoi) and césium carbonate (2.781 g, 8.556 mmol) in acetonitrile (300 mL) was heated to 90°C for 16h. LCMS analysis showed formation of the desired product but starting material remained and the formation of l-[3-[5(3-aminopropoxy)-l-tetrahydropyran-2-yl-îndazol-3-yl]-5-fluoro-phenyl]ethanol was observed. The reaction mixture was heated to 90°C for 16h. The reaction mixture was cooled to RT then filtered and concentrated under reduced pressure to give a mix of l-[3-[5-(3aminopropoxy)-l-tetrahydropyran-2-yl-indazol-3-yl]-5-fluoro-phenyl]ethanol (66 %) and 4fluoro-7-methyl-l 9-(oxan-2-y 1)-8,14-dioxa-10,19,20-trîazatetracyclo[ 13.5.2.1^2,6.0^18,21 ]tricosa1(20),2(23),3,5,15(22), 16,18(2 l)-heptaen-9-one (26 %) (0.667 g, 1.426 mmol (postuiated)) as an orange oil. The crude product was not purified, it was engaged in the next step without further purification.

Préparation of intermediate 61: 4-fluoro-7-methyl-l 9-(oxan-2-yl) -8,14-dioxa-10,19,20triazatetracyclo[13.5.2. l²^, 0^>82i]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

To a solution of l-[3-[5-(3-aminopropoxy)-l-tetrahydropyran-2-yl-indazol-3-yl]-5-fluorophenyl]ethanol and 4-fluoro-7-methyl-l 9-(oxan-2-yl)-8,l 4-dioxa-10,19,20-triazatetracyclo [13.5.2.l²’⁶.0^18,21]tricosa-l(20),2(23),3,5,15(22),16,18(2l)-heptaen-9-one 60 (0.567 g, 1.373 mmol) in DMA (350 mL) was added l,T-carbonyldiimidazole (0.245 g, 1.510 mmol). The reaction mixture was stirred at RT for 2h then 90°C for 22h. The reaction mixture was

162 concentrated under reduced pressure and ethyl acetate and a saturated aqueous solution of NaHCOj were added. The mixture was extracted with ethyl acetate (2 x). 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 elutïng with Cyclohexane / Ethyl acetate - EtOH (3-I) : 100/0 to 70/30 to give a cream solid. The solid was trîturated from diisopropyl ether to give 4-fluoro-7-methyl-19-(oxan-2-yl)-8,14-dioxa-10, i 9,20triazatetracyclo [13.5.2.1^.0^18,21 ] tricosa-1 (20),2,4,6(23),15,17,2 l-heptaen-9-one 61 as a white solid.

Yield: 100 mg of intermediate 61 (14%)

LCMS method F: [M+H]⁺ = 440, t_R = 2.96 min

Préparation of example 56: 4-fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2. l²’⁶.0^182,]tricosa-l(20),2,4,6(23),l 5,17,2 l-heptaen-9-one

To a solution of 4-fluoro-7-methyl-19-(oxan-2-yl)-8J 4-dioxa-10,19,20-trîazatetracyclo [13.5.2.1²’⁶.0^,8’²¹]tricosa-](20),2,4,6(23),l5,17,21-heptaen-9-one 61 (100 mg, 0.228 mmol) in DCM (16 mL) was added trifluoro acetic acid (350 pL, 4.560 mmol) at RT. The reaction mixture was irradiated under micro wave conditions (Biotage înîtiator). The solid was trîturated from diisopropyl ether to give 4-fluoro-7-methyl-8,I4-dioxa-10,19,20-triazatetracyclo [13.5.2.l²’⁶.0^l8’²¹]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one example 56 as a cream solid. LCMS method F: [M+H]⁺ = 356, tR = 2.33 min LCMS method G: [M+H]⁺ = 356, tR = 2.32 min

Ή NMR (400 MHz, ί/6-DMSO) δ 13.26(1 H, s), 8.01 -7.98 (1 H, m), 7.69 (1 H, s), 7.59 - 7.56 (IH, m), 7.53 - 7.50 (IH, m), 7.33 (IH, m), 7.22 - 7.18 (IH, m), 7.02 - 6.99 (1 H, m), 5.91 5.86 (IH, m), 4.35-4.28 (2H, m), 3.56 - 3.49 (IH, m), 2.79 - 2.72 (IH, m), 2.21 - 2.16 (1 H, m), 1.77-1.71 (lH,m), 1.61 - 1.58 (3H,d) ppm.

163

Example 57: 4-[l-(oxetan-3-y 1)-1,2,3,6-tetrahydropyr id in-4-yl]-8,14-d ioxa-10,19,20triazatetracyclo [13.5.2. l^2,6.0^18,21 ]tricosa-l(20),2,4,6(23),15,17,2 l-heptaen-9-one

Example 57 îs prepared according to the synthesis route described în general Scheme C.

Préparation of intermediate 62: l-(oxetan-3-y 1)-4-(4,4,5,5-tetramethy 1-1,3,2-dioxaborolan-2yl)-3,6-dihydro-2H-pyridîne

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

Préparation of intermediate 63: 19-(oxan-2-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-8,14dioxa-10,19,20-triazatetracyclo[13.5.2.FAO¹**·²¹ ltricosu-1(20),2, 4,6(23),15,17,2I-heptaen-9one

164

To a solution of 4-bromo-19-(oxan-2-yl)-8,l 4-dioxa-10,19,20-triazatetracyclo

[ 13.5.2.1 ^.O'^'jtrîcosa-1(20),2(23),3,5,15(22), 16,18(2l)-heptaen-9-one intermediate 34 (260 mg, 0.53 mmol) in dioxane/water (15/1.5 mL), 1 -(oxetan-3-yI)-4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine 62 (300 mg, 1.06 mmol postulated) and K3PO4 (337 mg, 1.59 mmol) were added. The mixture was degassed during 10 minutes, then Pd(dppf)Ch· DCM (17 mg, 0.021 mmol) was added. The mixture was heated at 90 °C for 20 hours. Monitoring by LCMS analysis showed formation of the expected product without oxetane. The reaction mixture was cooled to room temperature, then more l-(oxetan-3-yl)-4(4,4,5,5-tetramethyl-I,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (200 mg, 0.71 mmol postulated) and K3PO4 (168 mg, 0.79 mmol) were added. The mixture was degassed during 10 minutes and more Pd(dppf)Ch. DCM (8 mg, 0.0098 mmol) was added. The mixture was heated at 90 °C for 1 days. The reaction mixture was filtered over celite, diluted with EtOAc (50 mL) and water (50 mL). After séparation, 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 was purified by column (Macherey Nagel, 25 g) chromatography with DCM/(MeOH/NH3) (100/0 to 90/10). The desired fractions were collected, combined and evaporated to give 19-(oxan-2-yl)-4-(l,2,3,6tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1^2,6.0¹⁸’²'jtrîcosa-1 (20),2, 4,6(23),15,17,2 l-heptaen-9-one 63 as an orange solid.

LCMS method F: [M+H]⁺ = 489, t_R = 1.81 min

Préparation of intermediate 64:19-(oxan-2-yl)-4-[l-(oxetan-3-yl)-l ,2,3,6-tetrahydropyridin4-yl]-8,14~dioxa-l0,19,20-triazatetracyclo [13.5.2.1^2,6.0^!S,2l]tricosa-l(20),2,4,6(23),15,17,21heptaen-9-one

To a solution of 19-(oxan-2-yl)-4-(l,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20triazatetracyclo [13.5.2.1²Αθ^18,2'Jtrîcosa-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

165 was cooled to 0 °C then sodium tris(acetoxy)borohydride (248 mg, 1.18 mmol) was added. The réaction mixture was stirred at room température for 18 hours. The reaction mixture was quenched with Na₂CO₃ IM 7 mL, pH = 8), then the mixture was diluted with EtOAc (50 mL). After séparation, the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined 5 organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by column (Macherey Nagel, 15 g) flash chromatography with DCM/MeoH (100/0 to 97/3) as eluent, to give l9-(oxan-2-yl)4-[l-(oxetan-3-y 1)-1,2,3,6-tetrahydropy ridin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.1²’⁶.0’⁸'^2l]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one 64 as a white crystals.

LCMS method F: [M+H]⁺ = 545, t_R = 1.84 min

Préparation of example 57: 4-[l-(oxetan-3-yl)-l,2,3,6-tetrahydropyridin-4-yl]-8,14-dioxa10,19,20-triazatetracyclo [ 13.5.2.1 ^ï,6.0^18,21]tricosa-l(20),2,4,6(23),l 5,17,2 l-heptaen-9-one

To a solution of ]9-(oxan-2-yl)-4-[l-(oxetan-3-yl)-l,2,3,6-tetrahydropyridin-4-yl]-8,14-dioxa10,19,20-triazatetracyclo [13.5.2. l²A0^I8’^2,]tricosa-1(20),2,4,6(23), 15,17,2 l-heptaen-9-one 64 (82 mg, 0.15 mmol) in DCM (4 mL) was added trifluoro acetic acid (107 pL, 1.4 mmol). The mixture was stirred at room température for 24 hours. The reaction mixture was then heated at 40°C for 4 hours. More trifluoro acetic acid (26 pL, 0.35 mmol) was added and the reaction mixture was heated at 40 °C for 3 hours and at room température ovemight. The reaction mixture was diluted with DCM (25 mL) and a saturated NaHCO₃ solution (25 mL). After séparation, the aqueous layer was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude was triturated in acetonitrile, filtered and the solid was washed several times with acetonitrile to give 4-[l-(oxetan-3-yl)-l,2,3,6tetrahydropyridin-4-yl]-8,14-dioxa-10,19,20-triazatetracyclo[l3.5.2.1²’⁶.0^l8’^2l]tricosa1 (20),2,4,6(23), 15,17,21-heptaen-9-one example 57 as a cream powder.

LCMS method F: [M+H]⁺ = 461, t_R = 1.49 min

LCMS method G; [M+H]⁺ = 461, t_R = 2.19 min

166

’H NMR (400 MHz, J6-DMSO, 80 °C) δ 12.89 (IH, m), 7.90 (IH, s), 7.80 (1 H, s), 7.67 (IH, m), 7.48 (IH, d, J = 9.5 Hz), 7.35 (2H, m), 6.98 (IH, dd, J = 1.5, 8.9 Hz), 6.23 (IH, 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 (IH, 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-methylpiperidiii-l-yl)-8,14-dioxa-10,19,20-triazatetracyclo

[13.5.2.1^2,6.0^t8’²’]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Example 58 is prepared according to the synthesis route described in general Scheme C. 3Methylpiperidine is used for the Buchwald reaction with the bromide intermedîate 34 to give 4-(3-methylpiperidin-I-y 1)-8,14-dioxa-10,19,20-trîazatetracyclo[ 13.5.2.1^.0^18,2'jtricosal(20),2,4,6(23),15,17,21-heptaen-9-one example 58.

LCMS method F: [M+H]⁺ = 421.2, t_R = 1.88 min

LCMS method G: [M+H]⁺ = 421.2, t_R = 2.66 min

Ή NMR (400 MHz, (76-DMSO) δ 7.69 - 7.56 (IH , m), 7.48 - 7.45 (IH, m), 7.38 - 7.31 (3H, m), 6.95 (IH, dd, J = 2.4, 9.0 Hz), 6.87 - 6.86 (IH, 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 (IH, m), 2.07 - 1.98 (2H, m) 1.83 1.74 (3H, m), 1.7 - 1.55 (IH, m), 1.19 - 1.05 (IH, m) ppm. The indazole NH proton was not 20 visible in this solvent.

Example 59: 4-[(3S)-3-hydroxypyrrolidin-l-yl]-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2. l²’⁶.0^l8>^2,]tricosa-l (20),2,4,6(23),15,17,2 l-heptaen-9-one

167

Example 59 is prepared according to the synthesis route described in general Scheme C. (3S)pyrrolidin-3-ol is used for the Buchwald reaction with the bromide intermediate 34 to give 4[(3S)-3-hydroxypyrrolidin-I-y[]-8,l4-dioxa-10,19,20triazatetracyclo[13.5.2.1²⁶.0^,8’²¹]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one example 59. LCMS method F: [M+H]⁺ = 409.2, t_R = 1.98 min

LCMS method G: [M+H]⁺ = 409.2, t_R = 1.96 min

Ή NMR (400 MHz, t/6-DMSO) δ 12.84 (lH, m), 7.61 - 7.60 (IH, m), 7.48 - 7.45 (IH, m), 7.36 (1 H, d, J = 2.1 Hz), 7.21 -6.93 (3H, m), 6.47 (1 H, s), 5.25 - 5.21 (2H, m), 4.88 - 4.66 (IH, m) 4.48 -4.45 (IH, m), 4.32 -4.27 (2H, m), 3.53 - 3.32 (3H, m), 3.20 - 3.16 (3H, m), 2.16 2.07 (] H, m), 2.02 - 1.94 (3H, m) ppm.

Example 60:

4-fluoro-8,14-dioxa-10,19,20-triazapentacyclo[13.5.2.1²’⁶.l⁷’¹⁰.0¹⁸²¹] tetra cosa-1 (20),2(24),3,5,15(22),16,18(21)-h eptaen-9-one

Example 60 is prepared according to the synthesis route described below.

Préparation of intermediate 65: l-(3-bromo-5-fluorophenyl)~2-nitroethan-l-ol

OH o₂n

Br

To a stirred solution of 3-bromo-5-fluorobenzaldéhyde (2 g, 10 mmol) in THF (20 mL) was added dropwise at 0°C, nitromethane (0.536 mL, 10 mmol) and then dropwise sodium hydroxide solution IN (10 mL, 10 mmol). The solution was stirred at 0°C for 15 min. The solution was quenched with a solution of acetic acid (12 mL). To the resulting mixture was added water (25 mL). The water layer was extracted with EtOAc (4 x 50 mL). The combined organic layers were washed with saturated brine (2x50 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to afford

168 brown/orange oil, This residue was purified by flash chromatography on silica gel (Macherey

Nagel, Ï20 g) with gradient elution : cyclohexane/EtOAc 0-30 % to give l-(3-bromo-5fluorophenyl)-2-nitroethan-l-ol 65 as a white solid.

LCMS method F: [M-H] = 262.2, t_R = 2.28 min

Préparation of intermediate 66: 2-amino-l-(3-bromo-5-fluorophenyl)ethan-l-ol

OH h₂n.^^

Br

To a solution of l-(3-bromo-5-fluorophenyl)-2-nitroethan-l-ol 65 (6.2 g, 15.2 mmol) in EtOH ( 100 mL) was added Raney®-Nickel (2 g) and 0.5 mL of acetic acid. Dihydrogen was bubbled in the mixture for 5 min. The reaction mixture was stirred for 16 h under dihydrogen atmosphère. The reaction mixture was filtered over celite and the solvent of the filtrate was removed under reduced pressure to give 2-amîno-l'(3-bromo-5-fluorophenyl)ethan-l-ol 66 which is directly used in the next step without purification.

LCMS method F: [M+H]⁺= 236, t_R = 1.12 min

Préparation of intermediate 67: 5-(3-bromo-5-fluorophenyl)-l,3-oxazolidin-2-one

To a solution of 2-amino-l-(3-bromo-5-fluorophenyl)ethan-l-ol 66 (1.75 g , 1.75 mmol) in THF (100 mL) were added l,l'-carbonyldiimidazole (1.34 g, 8.25 mmol) and imidazole (0.561 g, 8.25 mmol). The reaction mixture was stirred at RT for 16h. To the reaction mixture was added a saturated aqueous solution of NH4CI (100 mL). 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 (31) : 100/0 to 70/30 to give a white solid as 5-(3-bromo-5-fluorophenyl)-l,3-oxazolidin-2-one 67.

LCMS method F: [M+H]⁺ = 262.0, t_R = 2.07 min

169

Préparation of intermediate 68: 5-(3-bromo-5~fliiorophenyl)~3-{3-[(tert-butyldimethylsilyl) oxy/propyI/-l,3-oxazolidin-2-one

To a stirred solution of 5-(3-bromo-5-fluorophenyl)-l,3-oxazoIidin-2-one 67 (1.6 g, 6.1 mmol) in THF (10 mL) was added sodium hydride (0.366 g, 9.1 mmol) at 0°C. The solution was stirred at 0°C for 10 mïn. Then a solution of (3-bromopropoxy)(tert-butyl)dimethylsilane (1.5 g, 6.1 mmol) in THF ( 10 mL) was added to the mixture. The mixture was stirred at room température for 16 h. The solution îs quenched with a solution of saturated chloride ammonium (25 mL). The resulting mixture was extracted with EtOAc (4 x 100 mL). Combined organic layers were washed wîth saturated brine (2 x 50 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to afford a brown/orange oil. This residue was purified by flash chromatography on silica gel (Macherey Nagel, 24 g) with gradient elution : cyclohexane/EtOAc 0-50 %to give 5-(3-bromo-5-fluorophenyl)-3-{3-[(tertbutyldimethylsilyl)oxy]propyl}-l,3-oxazolidin-2-one 68 as a yellow oil.

LCMS method F: [M+H]⁺ = 434.0, ta = 3.42 min

Préparation of intermediate 69: 5-(3-bromo-5-fluorophenyl)-3-(3-hydroxypropyl)-l,3oxazolidin-2-one

To a solution of 5-(3-bromo-5-fiuorophenyl)-3-{3-[(tert-butyldimethylsilyl)oxy]propyl}-l,3oxazolidin-2-one 68 (0.8 g, 1.85 mmol postulated) in tetrahydrofuran (50 mL) was added portion wîse tetra-n-butylammonium fluoride LO M in THF (1.85 mL, 1.85 mmol) at RT. The reaction mixture was stirred at RT 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 (2x100 mL). The combined organic layers were washed with brine (100 mL), dried over magnésium sulfate

170 and concentrated under reduces pressure. The residue was purified by flash-column chromatography (24 g silica BiOTAGE) chromatography (cyclohexane - ethyl acetate, 100/0 to 50/50) affording 5-(3-bromo-5-fluorophenyl)-3-(3-hydroxypropyl)-l ,3-oxazolidtn-2-one 69 a beige powder.

LCMS method F: [M+H]⁺ = 320.0, t_R = 2.02 min

Préparation of intermediate 70: 3-{5-(3-bromo-5-fluorophenyl)-2-oxo-l,3-oxazoHdin-3yljpropyl methane sulfonate

To a solution of 5-(3-bromo-5-fluorophenyl)-3-(3-hydroxypropyl)-l,3-oxazolidin-2-one 69 (0.5 g, 1.57 mmol) and diisopropylethylamine (0.545 mL, 3.14 mmol) in dichoromethane (50 mL) at 0 °C, was added dropwise methanesulfonyl chloride (0.145 mL,l.88 mmol). The reaction mixture was stirred at room température for 4 hours. The reaction mixture was washed with a saturated solution of ammonium chloride, with a saturated solution of sodium bicarbonate and brine, fïltered and the solvent was removed under reduced pressure to give 3[5-(3-bromo-5-fluorophenyl)-2-oxo-l ,3-oxazolidin-3-yl]propyl methane sulfonate 70 as a colorless oil.

LCMS method F: [M+H]⁺ = 397.9, t_R = 2.36 min

Préparation of intermediate 71: 5-(3-bromo-5-fluorophenyl)-3-(3-{[l-(oxan-2-yl)-IHindazol~5-yl]oxy]propyl)-l,3-oxazoHdin-2-one

171

To a solution of 3-[5-(3-bromo-5-fluorophenyl)-2-oxo-l,3-oxazolidin-3-yl]propyl methane sulfonate 70 (0.618 g, 1.57 mmol) in A/TV-dimethylformamide (100 mL), césium carbonate (1.02 g, 3.14 mmol) and l-(oxan-2-yl)-IH-indazol-5-ol 29 (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 (2x50 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a brown/orange oil. This residue was purified by flash chromatography on silica gel (Macherey Nagel. 120 g) with gradient elution : cyclohexane/EtOAc 0-70 % to give 5-(3-bromo-5fluorophenyl)-3-(3-{[l-(oxan-2-yl)-lH-indazol-5-yl]oxy (propyl)-l,3-oxazolidin-2-one 71 as a white solid.

LCMS method F: [M+H]⁺ = 520.0, t_R = 2.91 min

Préparation of intermedîate 72: 4-fluoro-19-(oxan-2-yl)-8,14-dioxa-l 0,19,20-triazapen ta cyelofl3.5.2.I²-\l⁷fl0^lg'²^etracosa-l (20),2(24), 3,5,15(22),16,18(21)-heptaen-9-one

To a solution of 5-(3-bromo-5-fluorophenyl)-3-(3-{[l-(oxan-2-yl)-lH-indazol-5-yl]oxy} propyl)-] ,3-oxazolidin-2-one 71 (50 mg, 0.0963 mmol) in 15 mL of toluene was added reagent potassium acetate (113 mg, 1.156 mmol) 2 eq) at room température. The mixture was degassed by bubbling nitrogen for 15 minutes. Palladium acetate (25 mg, 0.115 mmol, 0.2 eq) and cataxium (41 mg, 0.115 mmol, 0.2 eq) were added. The mixture was heated at 140°C for 2 hours under microwaves 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 (2x20 mL). The combined organic layers were washed with a brine, dried over sodium sulfate and concentrated under reduced pressure to an orange oil. A purification by column chromatography on a Biotage (cyclohexane /ethyl acetate 0-100%) afforded pure 4-fluoro-19

172 (oxan-2-y 1)-8,14-dioxa-l 0,19,20-triazapentacyclo[ 13.5.2.1²·⁶.Ι⁷’¹⁰.0'^8,21 ltetracosa-1 (20),2(24),

3,5,15(22),16,18(21)-heptaen-9-one 72 as a whitish solid.

LCMS method F: [M+H]⁺ = 438.1, t_R = 2.77 min

Préparation of example 60: 4-fluoro-8,14-dioxa-10,19,20-triazapentacyclo

[ 13.5.2.1^2,6. l^7,10.0^18,2‘itetracosa-1(20),2(24),3,5,15(22),16,18(21)-heptaen-9-one

To a solution of 4-fl uoro-19-(oxan-2-y 1)-8,14-dioxa-l 0,19,20-triazapentacyc lof 13.5.2.1²>⁶. 1⁷ io q¹ 87']_tetracosa-1(20),2(24),3,5,15(22), 16,18(2l)-heptaen-9-one 72 (0.113g; 0.258 mmol) in DCM (20 mL) was added trifluoroacetic acid (0.2 mL, 2.58 mmol) at room température. The mixture was stirred at room température for 24 h. The reaction is allowed to cool down to room température and toluene (50 mL) was added. The reaction mixture was concentrated under reduced pressure to give an orange oiL Water (25 mL), DCM (25 mL) and a 25 wt% aqueous solution of ammonia ( 1.5 mL) were added. After séparation, the aqueous layer was extracted with DCM (2x20 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to an orange oil. A purification by column chromatography on a Biotage (DCM/MeOH 0-5 %) afforded pure 4-fluoro-8,14-dioxa10,19,20-triazapentacyclo[13.5.2.1²’⁶.l⁷’^,0.0¹⁸’^2l]tetracosa-l(20),2(24),3,5, 15(22),16,18(21 )heptaen-9-one exampie 60 as a whitish solid.

LCMS method F: [M+H]⁺ = 354.1, t_R = 2.22 min

LCMS method G: [M+H]⁺ = 354.2, t_R = 2.22 min

Ή NMR (400 MHz, <76-DMSO) δ 13.26 - 13.24 (IH, m), 8.22 (IH, s), 7.59 (IH, ddd, J = 1.5, 2.5, 9.9 Hz), 7.52 (JH,d, J = 8.9 Hz), 7.49 (IH, d, J = 2.1 Hz), 7.36 (IH, td, J = 1.8,9.4 Hz), 7.02 ( 1 H, dd, J = 2.3, 9.3 Hz), 5.69 ( I H, dd, J = 2.8, 9.0 Hz), 4.47 - 4.38 (1 H, m), 4.22 ( 1 H, q, J = 3.9 Hz), 4.17(1 H, t, J = 6.0 Hz), 4.02 - 3.96 (IH, m), 3.57 - 3.46 (IH, m), 3.08 (IH, ddj = 4.6, 14.4 Hz), 2.36 -2.25 (IH, m), 1.98 - 1.88(1 H, m) ppm.

173

Example 61: 4-(oxolan-3-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’^e.0¹⁸’²¹]tricosal(20),2,4,6(23),15,17,21-heptaen-9-one

Example 61 is prepared according to the synthesis route described in general Scheme A.

Préparation of intermediate 73: 4-(2,5-dihydrofuran-3-yl)-19-(oxan-2-yl)-8,14-dioxa10,19,20-triazatetracyclo[13.5.2.I²⁶.0^ls,2}]tricosa-l (20),2,4,6(23), 15,17,21-heptaen-9-one

To a degassed solution of 4-bromo-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo [13.5.24^0^1100088-1(20),2(23),3,5,15(22),16,18(21)^^ 34 (125 mg, 0.25 mmol), 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (100 mg, 0.50 mmol), potassium phosphate tribasic (160 mg, 0.765 mmol) în dioxane / water (9/1, 5.0 nrL) was added [1,1 -bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (18.5 mg, 0.025 mmol, 10 mol%) under argon at room temperature. The reaction mixture was stirred for 5 hours at 90 °C. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3x15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium magnésium sulfate, filtered and the solvent was removed under reduced pressure to afford 4-(2,5-dihydrofuran-3-yl)-l 9-(oxan-2-yl)-8,l 4-dioxa-10,19,20triazatetracyclo [13.5.2.1^2,6.0^{18 2}'jtrîcosa-1(20),2,4,6(23), 15,17,21-heptaen-9-one 73 as an orange foam. The crude product was used in the next step without any further purification.

LCMS method F: [M+H]^T = 476.1, t_R = 2.74 min

174

Préparation of intermediate 74: 19-(oxan-2-yl)-4-(oxolan -3-yl)-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.1²’⁶.0‘^f2! !tricosa-! (20),2,4,6(23),15,17,21-heptaen-9-one

To a stirred solution of 4-(2,5~dihydrofuran-3-yl)-19-(oxan-2-yl)-8,14-dioxa-10,19,20triazatetracyclo[ 13.5.2.l^2,6.0^l8’²¹]tricosa-1(20),2.4,6(23), 15,17,2l-heptaen-9-one 73 (59 mg, 0.125 mmol) in 1.75 mL MeOH and 0.2 mL acetic acid was added 10 % palladium on charcoal (1.5 mg, 0.0013 mmol, 10 mol %) and the mixture was stirred for 20 minutes at room température under an atmosphère of hydrogen. The mixture was then filtered, washing with DCM, and the solvent of the filtrate was removed under reduced pressure to afford 19-(oxan2-y l)-4-(oxolan-3-yl)-8,l 4-dioxa-10,19,20-triazatetracyclo[l 3.5.2. l^2,6.0^18,21 ]tricosal(20),2,4,6(23),15,17,21-heptaen-9-one 74 as a colorless oil.

LCMS method F: [M+H]⁺ = 478.1, t_R = 2.71 min

Préparation of Example 61: 4-(oxolan-3-y 1)-8,14-dioxa-l 0,19,20-triazatetracyclo

[13.5.2.l^2,6.0^18,21] tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

To a solution of 19-(oxan-2-y l)-4-(oxolan-3-y 1)-8,14-dioxa-10,19,20-triazatetracyclo

[13.5.2.1^2,6.0^18,2']tricosa-1(20),2,4,6(23), 15,17,21-heptaen-9-one 74 (0.019 g, 0.039 mmol) in DCM (3 mL) was added trifluoro acetic acid (0.06 mL, 0.78 mmol). The mixture was heated under microwave conditions at 80 °C for l h. The solvent was removed under reduced pressure. The crude residue was purified on préparative TLC (DCM/MeOH/NHs : 90/9/1) to afford 4(oxolan-3-yl)-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1^2,6.0^18,21 ]tricosa-l (20),2,4,6(23), 15,17,21-heptaen-9-one example 61 as a white solid.

LCMS method F: [M+HJ⁺ = 394.1, t_R = 2.13 min

175

LCMS method G: [M+HT = 394.2, t_R = 2.13 min

Ή NMR (400 MHz, rf6-DMSO, 80 °C) δ 12.88 (IH, br. s), 7.77 (2H, m), 7.65 (1 H, br. s), 7.50 - 7.47 (1 H, m), 7.35 - 7.33 (1 H, m), 7.19 (1 H, s), 6.99 - 6.96 (1 H, dd, J= 2.0, 8.8 Hz), 5.28 (2H, s), 4.34 - 4.28 (2H, m), 4.12 - 4.07 (IH, m), 4.03 - 3.97 (IH, m), 3.88 - 3.82 (1 H, m), 3.67 (IH, t, J= 5.2 Hz), 3.53 - 3.44 (1 H, m), 3.22 - 3.11 (2H, m), 2.43 - 2.33 (IH, m), 2.06 - 1.96 (3H, m) ppm.

Example 62: (13S)-13-methyl-8,14-(lioxa-10,19,20“triazatetracyclo[13.5.2.1²ⁱ⁶.0¹⁸’²¹] tricosa-l(20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one

Example 62 îs prepared according to the synthesis route described in general Scheme C and by chiral HPLC séparation of example 50. The chiral séparation is done on a Chiralpak IA column 20x250mm 5 pm, eluent [C7/EtOH]+0.1%DEA [90/10] run time 40min, 19 mL/min RT to give (13S)-13-methyl-8,l 4-dioxa-10,19,20-triazatetracyclo[l 3.5.2.1²’⁶.0¹⁸’^2l]tricosa-1 (20),2(23), 3,5,15(22),16,18(21 )-heptaen-9-one example 62.

LCMS method F: [M+H]⁺ = 338.1, t_R = 2.24 min

LCMS method G: [M+H]⁺ = 338.1, t_R = 2.25 min

Ή NMR (400 MHz, r/6-DMSO) δ 13.11 (IH, s), 7.93 - 7.84 (3H, m), 7.47 (2H, dd, J = 8.4, 15.7 Hz), 7.29 - 7.25 (2H, m), 6.97 (IH, dd, J = 2.2, 9.0 Hz), 5.77 - 5.71 (IH, m), 4.83 - 4.79 (IH, m), 4.59 - 4.53 (IH, m), 3.58 (IH, m), 2.94 - 2.85 (IH, m), 1.41 - 1.38 (4H, m), 1.25 1.14 (1 H, m) ppm.

Chiral HPLC e.e. 98.2%

Example 63: (13R)-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0¹⁸'²¹] tricosa-l(20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one

176

Example 63 is prepared according to the synthesis route described in general Scheme C and by chiral HPLC séparation of example 50. The chiral séparation is done on a Chiralpak IA column 20x250mm 5 μιη, eluent [C7/EtOH]+0.1%DEA [90/10] run time 40min, 19 mL/min RT to give ( 13R)-13-methyl-8,14-dioxa-10,19,20-triazatetracyelo[ 13.5.2, l²’⁶.0^18,21]tricosa-1(20),2(23), 3,5,15(22),16,18(21)-heptaen-9-one example 63.

LCMS method F: [M+H]⁺ = 338.2, t_R = 2.25 min

LCMS method G: [M+H]⁺ = 338.2, t_R = 2.23 min ‘H NMR (400 MHz, rf6-DMSO) δ 13.11 (IH, s), 7.93 - 7.84 (3H, m), 7.47 (2H, dd, J = 8.6, 15.1 Hz), 7.29 - 7.25 (2H, m), 6.97 (IH, dd, J = 2.2, 9.0 Hz), 5.77 - 5.74 (IH, m), 4.83 - 4.79 (I H, m), 4.59 - 4.53 (1 H, m), 3.59 - 3.54 (1 H, m), 2.96 - 2.86 (1 H, m), 1.42-1.38 (4H, m), 1.25 -1.14 (IH, m) ppm.

Chiral HPLC e.e. 98.8%

Example 64: 4-(l-methyl-lH-pyrazol-3-yl)-8,14-dioxa-10,19,20-trîazatetracyclo

[13.5.2. l²’⁶.0^f8’^2,]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

Example 64 îs prepared according to the synthesis route described în general Scheme C. 1Methyl-lH-pyrazole-3-boronic acid pinacol ester was used for the Suzuki coupling with the bromide intermediate 34 to give 4-(l-methyl-lH-pyrazol-3-yl)-8,14-dioxa-l0,19,20triazatetracyclofl 3.5.2. !^2,6.0¹⁸’^2,]tricosa-1(20),2(23),3,5,15(22), 16,18(21)-heptaen-9-one example 64.

LCMS method F: [M+H]⁺ = 404, t_R = 2.12 min

LCMS method G: [M+H]⁺ = 404, t_R = 2.12 min

177 ’H NMR (400 MHz, <76-DMSO) δ 12.93 (1 H, s), 8.30 (1 H, s), 7.82 (1 H, s), 7.73 - 7.68 (3H, m),

7.51 - 7.49(1 H, d), 7.38 (IH, m), 7.01 -6.98(1 H, dd), 6.71 (IH, d, J = 2.3 Hz), 5.34 (2H, m), 4.35-4.31 (2H, m), 3.93 (3H, s), 3.19 (2H, m), 2.05 (2H, m) ppm.

Example 65: (7S)-7-methyl-8,14-dioxa-10,I9,20-triazatetracyclo[13.5.2.1²’⁶.0^18,21]tricosa1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

Example 65 is prepared according to the synthesis route described in general Scheme C. (IS)1 -[3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl]ethanol is used for the Suzuki coupling with intermediate 26 to give (7S)-7-methyl-8,14-dioxa-10,19,20trîazatetracyclof 13.5.2.1²’⁶.0¹⁸'²¹ ]tricosa-1(20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one example 65.

LCMS method F: [M+H]⁺ = 338, t_R = 2.19 min

LCMS method G: [M+H]⁺ = 338, t_R = 2.19 min

Ή NMR (400 MHz, c76-DMSO) δ 13.12 (IH, s), 7.94 (IH, m), 7.86 - 7.84 (2H, m), 7.50 - 7.46 (2H, m), 7.35 - 7.29 (2H, m), 7.00 - 6.98 (IH, dd), 5.95 - 5.90 (IH, q), 4.38 - 4.23 (2H, m), 3.56 - 3.49 (IH, m), 2.78 - 2.70 (IH, m), 2.25-2.15 (IH, m), 1.77- 1.69(IH, m), 1.59 (3H, d) PP™·

Example 66: 4-[2-(morpholin-4-yl)ethoxy]-8,14-dioxa-10,19,20-triazatetracyclo

[13.5.2. l^2,6.0^{182 f}]tricosa-l (20),2(23),3,5,15(22),16,18(2 l)-heptaen-9-one

Example 66 is prepared according to the synthesis route described în general Scheme F.

178

Préparation of intermediate 75: methyl 3-[5-[3-(benzyloxyeaibonylamino)propoxy]-ltetrahydropyran-2-yl-indazol-3-yl]-5-(2-morpholinoethoxy)benzoate

To a solution of methyl 3-[5~[3-(benzyloxycarbonylamino)propoxy]-l-tetrahydropyran-2-yL indazol-3-yl]-5-hydroxy-benzoate 53 (400 mg, 0.715 mmol), 2-morpholinoethanol (13I pL, I4l mg, l .073 mmol) and PPh₃ (281 mg, l .073 mmol) in THF (5.0 mL) was added dropwise a solution of DMEAD (251 mg, l .073 mmol) in THF (2.5 mL). The resulting clear yellow solution was stirred at room température for 16 h. The solvents were evaporated under reduced pressure and the residue was partitioned between EtOAc (20 mL) and water (20 mL). The aqueous phase was extracted with EtOAc (3 x 20 mL) and the combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na₂SO4, filtered and concentrated under reduced pressure. The resulting crude material (yellow oil, 700 mg) was purified by column chromatography (40 g Macherey Nagel SiO₂, 30 mL/min, CyH/EtOAc 100:0 to 80:20 then CHzCh/MeOH 95:5) to afford methyl 3-[5-[3-(benzyloxycarbonylamino)propoxy]-Itetrahydropyran-2-yl-indazol-3-yl]-5-(2-morpholinoethoxy)benzoate 75 as a paie yellow oil. LCMS method F: [M+H]⁺ = 673.3, t_R = 2.24 min

Préparation of intermediate 76: benzyl N-[3-[3-[3-(hydroxymethyl)-5-(2-morpholinoethoxy) phenyl]-l-tetrahydropyran-2-yl-indazoi-5-yl]oxypropyl]carbamate

179

To a solution of methyl 3-[5-[3-(benzyloxycarbonylamino)propoxy]-l-tetrahydropyran-2-ylindazol-3-yl]-5-(2-morpholinoethoxy)benzoate 75 (451 mg, 0.670 mmol) in THF (6.5 mL) at 0°C was added dropwise L1AIH4 (LO M solution in THF, 1.34 mL, 1.340 mmol). The resulting cloudy white solution was stirred at 0°C for 1 h. The reaction was quenched with saturated aqueous Rochelle’s sait (5 mL), EtOAc (20 mL) was added and the two layers were separated. The aqueous layer was extracted with EtOAc (3x10 mL) and the combined organic layers were washed with brine (1x5 mL), dried over anhydrous Na₂SO4, filtered and the solvent was removed under reduced pressure to afford crude benzyl N-[3-[3-[3-(hydroxymethyl)-5-(210 morpholinoethoxy)phenyI]-l-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate 76 as a transparent oil which was used in the next step without further purification.

LCMS method F: [M+H]⁺ = 645.3, t_R = 2.07 min

Préparation of intermedîate 77: 4-[2-(morphoHn-4-yl)ethoxy]-I9-(oxan-2-yl)-8,14-dioxa15 10,19,20-triazatetracyclofl3.5.2.1²·⁶.0^!8,2,]tricosa-l (20),2(23),3,5,15(22),16,18(21)-heptaen9-one

ISO

To a solution of benzyl N-[3-[3-[3-(hydroxymethyl)-5-(2-morpholinoethoxy)phenyn-ltetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate 76 (200 mg, 0.310 mmol) in degassed MeCN (30.0 mL) was added CS2CO3 (606 mg, I.860 mmol). The resulting cloudy yellow solution was heated under reflux for 5 h. The mixture was cooled to room température, filtered and the solvent was removed under reduced pressure to afford crude 4-[2-(morpholin-4yl)ethoxy]-]9-(oxan-2-yl)-8,l4-dioxa-l0,l9,20-triazatetracyclo[l3.5.2. l²'⁶.0^l8’²ⁱ]tricosa1(20),2(23),3,5,15(22),16, l8(21)-heptaen-9-one 77 as abrown solid which was used in the next step without further purification.

LCMS method F: [M+H]⁺ = 537.2, t_R = 1.82 min

Préparation of Example 66: 4-[2-(morpholin-4-yl)ethoxy]-8,14-dîoxa-10,19,20triazatetracyclo[13.5.2.1²’⁶.0^iS’^2l]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

To a solution of crude 4-[2-(morpholin-4-yî)ethoxy]-19-(oxan-2-yl)-8,14dioxa-l0,19,20-triazatetracyclo[13.5.2.1²'⁶.0ⁱ⁸’²¹]tricosa-l(20),2(23),3,5,15(22), 16,18(21)heptaen-9-one 77 (189 mg, 0.310 mmol postulated) în CH2CI2 (6.0 mL) was added TFA (475 pL, 707 mg, 6.200 mmol). The resulting clear yellow solution was stirred at room température for 6 h. Saturated aqueous NalICOj (5 mL) was added and the two layers were separated. The aqueous layer was extracted with CH2CI2 (3x5 mL) and the combined organic layers were washed with water (1x5 mL), dried over anhydrous Na2SO₄, filtered and concentrated under reduced pressure. The residue was purified by préparative reverse-phase chromatography (Column XSELECT PHENYL-HEXYL 19* 100mm 5pm, [(NH₄)₂CO₃ aq. 2 g/L / ACN] 35%B to 55%B in 7 min, 19 mL/min RT) to afford 4-[2-(morpholin-4-yl)ethoxy]-8,14-dioxaI0,19,20-triazatetracyclo[ 13.5.2. l²'⁶.0^,8-^2,]tricosa-l(20),2(23),3,5,15(22),16,18(2 i)-heptaen-9one example 66 as a pale orange solid.

LCMS method F; [M+H]⁺ = 453.3, t_R = 1.79 min

LCMS method G: [M+H]⁺ = 453.3, t_R = 2.80 min

181

Ή NMR (400 MHz, ί/6-DMSO, 80°C) δ 12.90 (brs, IH), 7.67 (brs, IH), 7.51 (brs, IH), 7.48 (d, J = 8.6 Hz, IH), 7.42 - 7.40 (m, IH), 7.36 - 7.34 (m, IH), 6.98 (dd, J = 8.6, 2.0 Hz, IH), 6.90 - 6.88 (m, IH), 5.25 (brs, IH), 4.34 - 4.31 (m, 2H), 4.20 (t, J = 5.7 Hz, 2H), 3.63 - 3.59 (m, 4H), 3.17 (brs, 2H), 2.77 (t, J= 5.7 Hz, 2H), 2.55 - 2.52 (m, 4H), 2.03 (brs, 2H) ppm.

Example 67: 4-(2-methoxyethyl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^1S21] trîcosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

Example 67 is prepared according to the synthesis route described in general Scheme A. Potassium (2-methoxyetbyl) trifluoroborate is used for the Suzuki coupling with intermediate 26 to give 4-(2-methoxy eth y 1)-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1²’⁶,0^18,21 Jtricosa1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one example 67.

LCMS method F: [M+H]⁺ = 382.2, t_R = 2.17 min

LCMS method G: [M+H]⁺ = 382.2, t_R = 2.18 min 'H NMR analysis indîcated the presence of two rotamers.

Ή NMR (400 MHz, c76-DMSO, 80 °C) δ 12.87 (IH, br. s), 7.82 (0.4H, d, J= 1.6 Hz, rot. 2), 7.74 (1.6H, d, ./=4.9 Hz, rot. 1),7.67 -7.63 (IH, m), 7.50 - 7.46 (IH, m), 7.34 (IH, d, J= 1.9 Hz), 7.22 (0.2H, s, rot. 2), 7.14 (0.8H, s, rot. 1), 6.99 - 6.96 (IH, m), 5.31 - 5.26 (2H, m), 4.34 - 4.28 (2H, m), 3.65 (2H, t, J = 6.80 Hz), 3.30 (3H, s), 3.20 - 3.11 (2H, m), 2.91 (2H, t, ./= 6.7 Hz), 2.07-1.99 (3H, m) ppm.

Example 68: (7R)-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^ls’²¹]tricosa1(20),2(23),3,5,15(22),16,18(2 l)-heptaen-9-one

182

Example 68 îs prepared according to the synthesis route described in general Scheme C. (IR)I -[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanol is used for the Suzuki coupling with intermediate 26 to give (7R)-7-methyl-8,l4-dioxa-l0,l9,20-triazatetracyclo 5 113.5.2.l²’⁶.0^l8’²¹]tricosa-l(20),2(23),3,5,15(22),] 6,18(21)-heptaen-9-one example 68.

LCMS method F: [M+H]⁺ = 338.2, t_R = 2.18 min

LCMS method G: [M+H]⁺ = 338.2, t_R = 2.19 min

Ή NMR (400 MHz, (76-DMSO) δ 13.13 - 13.11 (IH, m), 7.94 (1 H, dd, J = 4.7, 7.4 Hz), 7.877.83 (2H, m), 7.51 - 7.46 (2H, m), 7.36 - 7.29 (2H, m), 6.99 (1 H, dd, J = 2.3, 9.1 Hz), 5.93 ( 1 H, 10 q, J = 6.8 Hz), 4.38 - 4.23 (2H, m), 3.56 - 3.49 (IH, m), 2.78 - 2.70 (IH, m), 2.25 - 2.15 (IH, m), 1.78- 1.69 (lH,m), 1.61 - 1.58 (3H, m) ppm.

Example 69: 5-cyclopropyl-8,14-dioxa-10,19,20-triazatetracydo[13.5.2.1²’⁶.0^I8’²¹]tricosa15 1(20),2,4,6(23),15,17,21-heptaen-9-one

Example 69 is prepared according to the synthesis route described in general Scheme C. Potassium cyclopropyl(trifluoro)borate was used for the Suzuki coupling with the bromide intermediate 48 to give 5-cyclopropyl-8,14-dioxa-10,19,20-trîazatetracyclo[13.5.2.1^2,6.0¹⁸’²¹] 20 trîcosa-1(20),2,4,6(23),15,17,21-heptaen-9-one example 69.

LCMS method F: [M+H]⁺ = 364, t_R = 2.40 min

LCMS method G: [M+H]⁺ = 364, t_R = 2.40 min

183

Ή NMR (400 MHz, </6-DMSO) δ 7.86 - 7.83 (2H, m), 7.74 (IH, s), 7.50 - 7.37 (3H, m), 7.16

- 7.13 (IH, m), 6.99 - 6.96 (IH, m), 5.48 (2H, s), 4.37 - 4.32 (2H, m), 3.20 (2H, s), 2.00 (IH, m), 1.92 (IH, m), 1.16 (IH, m), 1.02-0.97 (2H, m), 0.73 - 0.68 (2H, m) ppm.

Example 70: 4-(2-m ethoxyethoxy )-8,14-d ioxa-10,19,20-triazatetracy cio [13.5.2.1² AO^18,21 J tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Example 70 is prepared according to the synthesis route described in general Scheme F and procedures analogous to those used to obtain example 66 to give 4-(2-methoxyethoxyF8,14dioxa-10,19,20-triazatetracyclo[ 13.5.2.1²A0^18,21 ]trîcosa-1(20),2,4,6(23),15,17,21-heptaen-9one example 70.

LCMS method F: [M+H]⁺ = 398.2, t_R = 2.89 min

LCMS method G: [M+H]⁺ = 398.2, t_R = 2.13 min

Ή NMR (400 MHz, ί/6-DMSO, 80°C) δ 12.89 (brs, IH), 7.67 (brs, IH), 7.52 (s, IH), 7.48 (d, ./=8.9 Hz, IH), 7.42-7.41 (m, IH), 7.36(d,J = 1.9 Hz, I H), 6.98 (dd, J= 8.9, 1.9 Hz, IH), 6.89 (s, IH), 5.25 (brs, 2H), 4.34 - 4.29 (m, 2H), 4.21 (t, J =4.5 Hz, 2H), 3.72 (t, J = 4.5 Hz, 2H), 3.37 (s, 3H), 3.22 - 3.12 (m, 2H), 2.08 - 1.98 (m, 2H) ppm.

Example 71: 4-fluoro-13-methyL8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0¹⁸²¹] tricosa-l(20),2,4,6(23),15,17,2 l-heptaen-9-one

184

Example 71 is prepared according to the synthesis route described in general Scheme C to give 4-fluoiO-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[I3.5.2.1²’⁶.0^l8'^2l]tricosa-l(20),2,4, 6(23),15,17,21-heptaen-9-one example 71.

LCMS method F: [M+H]⁺ - 356.1, t_R = 2.37 min

LCMS method G; [M+H]⁺ = 356.2, t_R = 2.33 min

Ή NMR (400 MHz, r/6-DMSO) δ 13.26 (IH, m), 8.01 - 7.96 (IH, m), 7.68 (1 H, s), 7.61 - 7.50 (2H, m), 7.27 (IH, d, J = 1.9 Hz), 7.17 (IH, ddd, J = 1.4, 2.4, 9.5 Hz), 6.99 (IH, dd, J = 2.2, 9.0 Hz), 5.71 (IH, d, J = 13.7 Hz), 4.89 - 4.83 (IH, m), 4.62 - 4.54 (IH, m), 3.61-3.50 (IH, m), 2.94-2.86 (IH, m), 2.43 -2.36(1H, m), 1.42-1.39 (4H, m) ppm.

Example 72: ll-methyl-8,14-dÎoxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹]tricosa1 (20),2,4,6(23),15,17,2 l-heptaen-9-one

Example 72 is prepared according to the synthesis route described in general Scheme C to give l l-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^l8’^2l]tricosa-l(20),2,4,6(23),15, 17,21 -heptaen-9-one example 72.

LCMS method F: [M+H]⁺ = 338, t_R = 2.26 min

LCMS method G: [M+H]⁺ = 338, t_R = 2.25 min

Ή NMR (400 MHz, fr6-DMSO) δ 12.92- 12.85 (IH, m), 7.95 ( 1 H, s), 7.86 (JH, d, J = 7.4 Hz), 7.56(1 H, s), 7.50 - 7.43 (2H, m), 7.35 (IH, d, J = 2.1 Hz), 7.28 - 7.26 (1 H, m), 6.99 (IH, dd. J = 2.3, 8.9 Hz), 5.68 (IH, s), 4.94 - 4.89 (IH, m), 4.41 - 4.34 (2H, m), 3.88-3.81 (lH,m), 2.19 (IH, s), 1.97- 1.95 (IH, m), 1.25 - 1.22 (3H, m) ppm.

Example 73: 4-(3-oxomorpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.

p.L0^,8zl]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

Example 73 is prepared according to the synthesis route described in general Scheme C and analogues procedures hâve been used as to obtain example 12. Morpholin-3-one is used for the Buchwald reaction with the bromide intermediate 34 to give 4-(3-oxomorphoIin-4-yl)-8,145 dioxa-10,19,20-trîazatetracyclo[ 13.5.2. l²⁶.0^18,2 ^10053-1(20),2(23),3,5,15(22), 16,18(21)heptaen-9-one example 73.

LCMS method F: [M+H]⁺ = 423, t_R = 1.88 min

LCMS method G: [M+H]’ = 423, t_R = 1.87 min

Ή NMR (400 MHz, J6-DMSO) δ 12.99 (IH, s), 7.87 (IH, s), 7.80 (IH, s), 7.72 (IH, s), 7.48 10 (IH, s), 7.34 (2H, d, J = 10.8 Hz), 6.99 (1 H, dd, J = 2.1, 8.9 Hz), 5.31 (2H, s), 4.35 - 4.30 (2H, m), 4.24 (2H, s), 4.03 (2H, t, J = 5.1 Hz), 3.82 (2H, t, J = 5.0 Hz), 3.18 (2H, s), 2.06 (2H, s) ppm.

Example 74: 4-(2-oxopy r rolid in-1-y 1)-8,14-dioxa-l 0,19,20-triazatetracyclo [13.5.2.

₁^^.Qi®'^i]_trÎc_OSa-1^20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

Example 74 îs prepared according to the synthesis route described in general Scheme C and procedures analogous to those used to obtain example 12. Pyrrolidin-2-one is used for the 20 Buchwald reaction with the bromide intermediate 34 to give 4-(2-oxopyrrolidin-1-y 1)-8,14dioxa-10,19,20-triazatetracyclo[ 13.5.2.1^2,6.0^18,21 Itricosa-1(20), 2(23),3,5,15(22), 16,18(21 )heptaen-9-one example 74.

LCMS method F: [M+H]⁺ = 407, t_R = 2.02 min

LCMS method G: [M+H]⁺ = 407, t_R = 2.01 min

186

Ή NMR (400 MHz, d6-DMSO) δ 12.93 (IH, s), 8.14 (1 H, s), 7.69 (2H, s), 7.59 (JH, s), 7.48 (IH, d, J = 9.54 Hz), 7.35 (IH, s), 6.98 (IH, dd, J = 2.4, 9.0 Hz), 5.28 (2H, s), 4.32 (2H, m), 3.93 (2H, m), 3.17 (2H, m), 3.53 (2H, m), 3.13 (2H, m), 2.03 (2H, m) ppm.

Example 75: 5-(2-oxopyrrolidin-l -y 1)-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.

l²A0^,8’^2l]tricosa-l (20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

Example 75 is prepared according to the synthesis route described in general Scheme C and procedures analogous to those used to obtain example 12. Pyrrolidin-2-one is used for the Buchwald reaction with the bromide intermediate 48 to give 5-(2-oxopyriOlidin-l-yl)-8,14dioxa-10,19,20-triazatetracyclo[ 13.5.2. l²’⁶.0^,8’²¹]tricosa-1(20),2(23),3,5,15(22),16,18(21 )heptaen-9-one example 75.

LCMS method F: [M+H]⁺ = 407, t_R = 1.92 min

LCMS method G: [M+H]⁺ = 407, t_R = 1.92 min

Ή NMR (400 MHz, rf6-DMSO) δ 12.95 (IH, s), 7.97 - 7.93 (2H, m), 7.71 (IH, s), 7.48 (JH, s), 7.40 - 7.37 (2H, m), 6.99 (IH, dd, J = 2.2, 8.8 Hz), 5.1 i (2H, s), 4.36 - 4.31 (2H, m), 3.81 (2H, t. J = 6.9 Hz), 3.17 (2H, s), 3.06 (2H, m hidden), 2.23 - 2.18 (2H, m), 2.03 (2FI, m) ppm.

Example 76: 4-(2-methylpyrrolidin-l-yl)-8,14-dioxa-10,19,20-triazatetracyclo

[13.5.2.1²A0¹⁸’²¹]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

187

Example 76 is prepared according to the synthesis route described in general Scheme C and procedures analogous to those used to obtain example 12. 2-Methylpyrrolidine is used for the Buchwald reaction with the bromide intermediate 34 to give 4-(2-methylpyrrolidin-l-yl)-8,14dioxa-10,19,20-triazatetracyclo[ 13.5.2.1^.0^{18,2 l}]tricosa-1(20),2(23),3,5,15(22), 16,18(21)5 heptaen-9-one example 76.

LCMS method F: [M+H]⁺ = 407, t_R = 2.27 min

LCMS method G: [M+H]⁺ = 407, t_R = 2.56 min ^lH NMR (400 MHz, rf6-DMSO) δ 12.75 (IH, m), 7.61 - 7.58 (IH, m), 7.47 - 7.44 (1 H, m), 7.36 (IH, d. J = 2.3 Hz), 7.18(1 H, s), 7.05 (IH, s), 6.95 (IH, dd, J = 2.4, 9.0 Hz), 6.50 (IH, s), 5.24 10 - 5.21 (2H, m), 4.32 - 4.27 (2H, m), 3.98 - 3.95 (IH, m), 3.48 - 3.43 (1 H, m), 3.19 (2H, m), 2.12

- 1.97 (6H, m), 1.73 - 1.70 (IH, m), 1.19 (3H, d, J = 6.1 Hz) ppm.

Example 77: 2-{9-oxo-8,l 4-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^18,21 Jtricosa15 1(20),2(23),3,5,15(22),16,18(2 l)-heptaen-4-yl}acetonitrîle

Example 77 is prepared according to the synthesis route described în general Scheme C.

Préparation of intermediate 78: 2-[19-(oxan-2-yl)-9-oxo-8,14-dioxa-10_rI9,20-triazatetra cycio[13.5.2.I²·⁶.0^iS21]tricosa-l(2ty,2(23),3,5,15(22),16,18(21)-heptaen-4-yl}ace^^

188

To a solution of 4-bromo-l 9-(oxan-2-y 1)-8,14-dioxa-10,19,20-triazatetracyclo

[13.5.2.]²’⁶.0¹⁸’²']tricosa-l(20),2,4,6(23),15,17,2I-heptaen-9-one 34 (100 mg, 0.21 mmol) in DMSO (2 mL) was added isoxazol-3-yl boron ic acid (49 mg, 0.25 mmol) and a 1 M solution of potassium fluoride (0.63 mL, 0.63 mmol) at RT. The réaction mixture was degassed for 15 min by bubbling nitrogen gas, then [1 ,r-Bis(diphenylphosphino)ferrocene]dichtoropalladium(n) (15 mg, 0.02 mmol) was added the reaction mixture was stirred at 130°C for 18 hours. The reaction mixture was filtered over celite, washed with ethyl acetate and concentrated under reduced pressure. EtOAc (30 mL) and water ( 10 mL) were added, the mixture was filtered over celite. The two layers were separated, the organic layer was extracted with EtOAc (2x20 mL), washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a black oil. The residue was purified by flash chromatography (CyH/AE 5/5) to afford 2-[19-(oxan-2-yl)-9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²'⁶.0¹⁸’²¹]tricosa1(20),2(23),3,5,15(22),16,18(2 l)-heptaen-4-yl]acetonitrile 78 as a white solid.

LCMS method F: [M+Hf = 447, t_R = 2.64 min

Préparation of Example 77: 2-{9-oxo-8,14-dioxa-10,19,20-triazatetracyclo

I13.5.2.1^2<i.0^t8’^2l]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-4-yl}acetonitrile

To a solution of 2-[ 19-(oxan-2-yl)-9-oxo-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.1^2,6.0’^8,2 ^tricosa-1(20),2(23), 3,5,15(22), 16,18(2 l)-heptaen-4-yl]acetonitrile 78 (38 mg, 0.085 mmol) in DCM (2 mL) was added TFA (130 μL, ! .70 mmol) and the reaction mixture was stirred at RT for 12 hours. To the réaction mixture was added a saturated solution sodium bicarbonate (10 mL) and DCM (10 mL). The two layers were separated, the organic layer was extracted twice with DCM (10 mL), washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow oil. The residue was put in diethyl ether and water, the precipitate was filtered to afford 2-{9-oxo-8,14-dioxa-10,19.20triazatetracyclo [13.5.2. l²A0^18,2 ']tricosa-l (20),2(23),3,5,15(22), 16,18(21 )-heptaen-4yljacetonitrile example 77 as a white solid.

LCMS method F: [M+H]⁺ = 363, t_R = 2.08 min

189

LCMS method G: [Μ+ΗΓ = 363, t_R = 2.08 min

Ή NMR (400 MHz, J6-DMSO) δ 12.97 (IH, s), 7.90 - 7.85 (2H, m), 7.73 - 7.69 (IH, m), 7.52 - 7.48 (IH, m), 7.35 (IH, d, J = 1.9 Hz), 7.25 (IH, s), 6.99 (IH, dd, J = 2.3, 8.9 Hz), 5.30 (2H, s), 4.32 (2H, dd, J = 7.6, 8.7 Hz), 4.10 (2H, s), 3.17 (2H, s), 2.02 (2H, s) ppm.

Example 78: (11R) or (HS)-ll-methyl-8,14-dioxa-10,19,20-triazatetracyelo (13.5.2. lW0^,8-²¹]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one o

Example 78 is prepared according to the synthesis route described in general Scheme C and by chiral HPLC séparation of the two enantiomers of example 72. The chiral séparation is done on aChiralpak IA column 20x250mm 5 pm, eluent [C7/EtOH]+û. 1%DEA [90/10] runtime 40 min, 19 mL/min RT to give (1 IR) or (11 S)-l l-methyl-8,14-dioxa-l0,19,20-triazatetracyclo [ 13.5.2.l²’⁶.0¹⁸’^2l]tricosa-1(20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one example 78.

LCMS method F: [M+H]⁺ = 338, t_R = 2.27 min

LCMS method G: [M+H]⁺ = 338, t_R = 2.27 min

Ή NMR (400 MHz, c/6-DMSO) δ 12.90 (IH, s), 7.94 (IH, s), 7.84 (IH, d, J = 7.8 Hz), 7.57 (IH, s), 7.50 - 7.43 (2H, m), 7.36 (IH, s), 7.28 - 7.26 (IH, m), 6.99 (IH, dd, J = 2.3, 8.9 Hz), 5.67 (IH, m), 4.90 (IH, m), 4.39 - 4.34 (2H, m), 3.82 (1 H, s), 2.20 (IH, m), 1.93 (III, m), 1.25 - 1.22 (3H, m) ppm.

Chiral HPLC e.e. 98.2%

The compound is a pure enantiomer, but the absolute stereochemistry of the chiral center is unknown.

Example 79: (HR) or (11S)-I l-methyl-8,14-dioxa-10,19,20-triazatetracyclo (13.5.2.1²A0^,8ilItricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

190

Example 79 is prepared according to the synthesis route described in general Scheme C and by chiral HPLC séparation of the two enantiomers. The chiral séparation is done on a Chiralpak IA column 20x250mm 5 gm, eluent [C7/EtOH]+0.l%DEA [90/10] run time 40 min, 19 5 mL/min RT to give (HR) or (l l S)-l l-methyl-8,l4-dioxa-10,l9,20-triazatetracyclo [ 13.5.2.1^{2 6}.0^{1 s}’²¹ ]tricosa- ï (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one example 79.

LCMS method F: [M+H]⁺ = 338, t_R = 2.27 min

LCMS method G: [M+H]⁺ = 338, t_R = 2.26 min

ΉNMR (400 MHz, DMSO) δ 12.89 (IH, s), 7.94 (IH, s), 7.87 - 7.84 (IH, m),7.55 (IH, m), 10 7.47 (2H, m), 7.35 (IH, m), 7.28 - 7.26 (lH,m), 7.01 -6.97 (IH, m), 5.66 (IH, m), 4.90 (IH,

m),4.41 -4.34 (2H, m),3.87-3.81 (IH, m), 2.22 (IH, m), 1.93 (IH, m), 1.25 - 1.22 (3H, m) ppm.

Chiral HPLC e.e. 98.5%

The compound îs a pure enantiomer, but the absolute stereochemistry of the chiral center is 15 un known.

Example 80: 4-ethynyI-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^18:!1]tricosa1(20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one

Example 80 is prepared according to the synthesis route described in general Scheme C.

191

Préparation of intermediate 79: 19-(oxan-2-yl)-4-[2-(triethylsiiyl)ethynyl]-8,l4-dioxa10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^}S’^2}]tricosa-l (20),2(23),3,5,15(22),16,18(21)-heptaen9-one

To a solution of intermediate 34 (100 mg, 0.21 mmol) in THF( 2 mL) in a sealed tube were added triethyl(ethynyl)silane (44.1 mg, 0.31 mmol) and triethylamine (63.63 mg, 0.63 mmol). The réaction mixture was degassed for 15 min by bubbling nitrogen gas and Pd(PPh₃)4 (12 mg, 0.01 mmol) and copper iodide (0.4 mg, 0.0021 mmol) were added. The reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a yellow oil. To the residue were added EtOAc (20 mL) and water (10 mL), after séparation of the two layers, the organic layer was extracted twice with EtOAc (10 mL), washed with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give an off-white solid. Diethyl ether was added to the residue, the beige precipitate was filtered, washed with water, to afford 19-(oxan-2-yl)-4-[2-(triethylsîlyl)ethynyl]-8,14-dioxa10,19,20-triazatetracyclo[ 13.5.2.1^2,6.0¹⁸’^2,]tricosa-1(20),2(23),3,5,15(22), 16,18(21 )-heptaen-9one 79 as a beige solid.

LCMS method F: [M+H]⁺ = 546, t_R = 3.88 min

Préparation of intermediate 80: 4-ethynyl-19-(oxan-2-yl) -8,14-dioxa-l 0,19,20triazatetracyclo[13.5.2.1²’⁶.0^}S2!]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

192

To a solution of 19-(oxan-2-yl)-4-[2-(triethylsilyl)ethynyl]-8,14-dioxa-10,19,20-triazatetra cyclofl 3.5.2. l²’⁶.0^l8’^2l]tricosa-1(20),2(23),3,5,15(22), 16,18(2l)-heptaen-9-one 79 (97 mg, 0.21 mmol) in MeOH (2 mL) was added potassium carbonate (87 mg, 0.63 mmol). The resulting reaction mixture was stirred at 60°C for 3h. The reaction mixture was filtered and washed with water to afford 4-ethynyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.l²A 0^l8,21]tricosa-i(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one 80 as awhite solid.

LCMS method F: [M+H]⁺ = 432, t_R = 2.93 min (current 20V)

Préparation of Example 80: 4-ethyny[-8,14-dioxa-10,19,20-triazatetracyclo 10 [13.5.2.l^2,6.0^1!i’²¹]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

To a solution of 4-ethynyl-19-(oxan-2-yl)-8,l 4-dioxa-l 0,19,20-triazatetracyclo [ 13.5.2. 1²·⁶.0'8.2ijtricosa-1(20),2(23),3,5,15(22), 16,18(2 l)-heptaen-9-one 80 (45 mg, 0.10 mmol) in DCM (2 mL) was added TFA (147 pL, 2.00 mmol) and stirred at RT for 12 hours. To the 15 reaction mixture was added a saturated solution sodium bicarbonate (10 mL) and DCM (10 mL). The two layers were separated and the water layer was extracted twice with DCM (10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow oil. The residue was purified by flash chromatography (CyH/AE 5/5) to afford 4-ethynyl-8,l 4-dioxa-10,19,20-triazatetracyclo 20 [13.5.2.1^2,6.0^1872l]tricosa-1(20),2(23),3,5,15(22), 16,18(21)-heptaen-9-one example 80 as a whîte solid.

LCMS method F: [M+H]⁺ = 348, t_R = 2.30 min

LCMS method G: [M+H]⁺ = 348, ta = 2.30 min

Ή NMR (400 MHz, ί/6-DMSO) δ 13.02 (I H, s), 7.93 (2H, d, J = 16.3 Hz), 7.74 - 7.72 (IH, m), 25 7.52 - 7.48 (LH, m), 7.39 (IH, s), 7.32 (LH, d, J = 1.9 Hz), 7.00 (IH, dd, J = 2.3, 9.1 Hz), 5.29

- 5.27 (2H, m), 4.35 - 4.29 (2H, m), 4.08 - 4.07 (1 H, m), 3.18 (2H, s), 2.02 (2H, s) ppm.

193

Example 81: 4-(piperazm-l-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^,ftn] tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

Example 81 is prepared according to the synthesis route described in general Scheme A. Tert5 butyl piperazine-1 -carboxylate is used for the Buchwald reaction with the bromide intermediate 34 to give 4-(piperazin4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2J²É0^Ivl]tricosa1(20),2(23),3,5,15(22), 16,18(2 l)-heptaen-9-one example 81.

LCMS method F: [M+H]⁺ = 408.2, t_R = 1.45 min

LCMS method G: [M+H]⁺ = 408.2, t_R = 1.85 min

Ή NMR (400 MHz, d6-DMSO, 80 °C) δ 12.82 (IH, s), 7.62 (IH, s), 7.47 (IH, d, J= 9.3 Hz), 7.39 - 7.33 (3H, m), 6.96 (IH, dd, ./=2.3, 8.9 Hz), 6.88 - 6.86 (IH, m), 5.23 - 5.22 (2H, m), 4.33 -4.27 (2H, m), 3.21-3.16 (7H, m), 2.96-2.92 (4H, m), 2.06 - 1.99 (2H, m) ppm.

Example 82: 4-(1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo

[13.5.2.1²’⁶.0^l8’^2,ltricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

Example 82 is prepared according to the synthesis route described in general Scheme A. Tertbutyl 4-(4,4,5,5-tetramethy l-l, 3,2-dioxaborolan-2-yl)-3,6-dihydiO-2H-pyridine-l-carboxylate 20 is used for the Suzuki coupling with the bromide intermediate 34 to give 4-(1,2,3,6tetrahydropyridin-4-yl)-8,14-dioxa-l 0,19,20-triazatetracyclo[ 13.5.2.1²-⁶.0¹⁸’²'jtricosa1 (20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one example 82.

LCMS method F: [M+H]⁺ = 405.2, t_R = 1.49 min

LCMS method G: [M+H]⁺ = 405.2, t_R = 1.95 min

194

Ή NMR. (400 MHz, t/6-DMSO, 80 °C) δ 12.95 (IH, s), 7.89 (IH, s), 7.79 (IH, s), 7.70 - 7.65 (IH, m), 7.50 - 7.47 (IH, m), 7.35 - 7.32 (2H, m), 6.98 (IH, dd, J = 2.4, 9.2 Hz), 6.29 - 6.25 (IH. m), 5.37 - 5.30 (2H, m), 4.34 - 4.28 (2H, m), 3.50 - 3.44 (2H, m), 3.14 - 3.00 (5H, m), 2.48 - 2.41 (2H, m), 2.06 - 2.03 (2H, m) ppm.

Example 83: 1 l-(methoxymethyl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²A0'⁸’²¹] tricosa-1 (20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

Example 83 is prepared according to the synthesis route described in general Scheme C.

Préparation of intermediate 81: 3-benzylamino-4-methoxy-but-2-enoic acid methyl ester

A solution of methyl-4-methoxyacetoacetate (5.00 g, 34.24 mmol), benzylamine (3.73 mL, 34.24 mmol) and acetic acid (0.097 mL, 1.71 mmol) in toluene (24 mL) was heated at 60°C for 6 hours. The mixture was concentrated under reduced pressure to give 3-benzylamino-4methoxy-but-2-enoic acid methyl ester 81 as an orange oil. The crude was used in the next step without purification.

Préparation of intermediate 82: methyl 3-(benzylamino)-4-methoxy-butanoate

195

To a solution of 3-benzylamino-4-methoxy-but-2-enoic acid methyl ester 81 (8.66 g, 34.24 mmol postulated) in DCE (80 mL) were added at 0°C, acetic acid (9.77 mL, 171 mmol) and sodium tris(acetoxy)borohydride (21.67 g, 102.72 mmol). The reaction mixture was allowed to warm up to room température, then stirred at room température for 17 hours. The mixture was diluted with DCM (30 mL), quenched with a saturated solution of NaHCO₃ (40 mL). Water (50 mL) was added and the aqueous layer was extracted with DCM (2 x 70 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, fîltered and concentrated under reduced pressure. The crude was purified by column (Macherey Nagel, 330 g) chromatography with cyclohexane/EtOAc (100/0 to 0/100) as eluent. DCM/MeOH (90/10) was used to elute the product. The desired fractions were combined and evaporated under reduced pressure to give methyl 3-(benzylamino)-4-methoxy-butanoate 82 as a brown oiL

LCMS method F: [M+H]⁺ = 238, t_R = 0.94 min

Préparation of intermediate 83: 3-(benzyiamino)-4-methoxy-butan-l-ol iii

To a solution of methyl 3-(benzyiamino)-4-methoxy-butanoate 82 (3.97 g, 16.8 mmol) in THF (70 mL) under N₂, LAH 1 M in THF (20.2 mL, 20.2 mmol) was added at 0°C. The réaction was stirred at 0°C for 18 hours. The mixture was quenched with water (1.8 mL), NaOH 10 % (i .8 mL) and water (1.8 mL). The mixture was fîltered with EtOAc as eluent. The filtrate was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). Combined organic layers were washed with brine (100 mL), dried with anhydrous sodium sulfate, fîltered and evaporated under reduced pressure to give 3-(benzylamino)-4-methoxy-butan-l-ol 83 as a brown oil. The crude was used in the next step without further purification.

LCMS method H: [M+H]⁺ = 210, t_R = 0.48 min

Préparation of intermediate 84: 3-amino-4-meth oxy-butan-l-ol; 2,2,2-trifluoroacetic acid

196

To a solution of 3-(benzylamino)-4-methoxy-butan-I-ol 83 (2.44 g, 11.7 mmol) in MeOH (200 mL), TFA (2.42 mL, 31.59 mmol) was added. The resulting mixture was degassed under N₂during 15 min. Pd(OH)₂ (819 mg, 5.85 mmol) was added and the reaction mixture was heated at 50 °C under H₂ for 19 hours. The mixture was fïltered over celite and the solvent was removed under reduced pressure to give 3-amino-4-methoxy-butan-l-oï;2,2,2-trifluoroacetic acid 84 as a yellow oil. The crude was used in the next step without further purification.

Préparation of intermediate 85: benzyl N-f3-hydroxy-l-(meth oxymethyl)propyl]carbamate

To a solution of 3-amino-4-methoxy-butan-!-ol;2,2,2-trifluoroacetic acid 84 (3.32 g, 13 mmol postulated) in THF (18 mL)/water (18 mL), was added at room température NaHCOs (3.28 g, 39 mmol). The reaction was stirred at room température during 15 minutes, then at 0 °C was slowly added CbzCl (1.85 mL, 13 mmol). The resulting mixture was stirred at room température ovemight. The mixture was diluted with water (50 mL) and EtOAc (50 mL). After séparation, the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, fïltered and concentrated under reduced pressure. The crude was purified by column (Macherey Nagel, 120 g) chromatography with cyclohexane/EtOAc (100/0 to 0/100), then DCM/MeOH (90/10) as eluent. The desired fractions were collected, combined and the solvent was removed under reduced pressure to give benzyl N-[3-hydroxy-l-(methoxymethyl)propyl]carbamate 85 as a colorless oiL

LCMS method F: [M+H]⁺ = 254, îr = 1.86 min

Préparation of intermediate 86: [3-(benzyloxycarbonylamino)-4-methoxy-butyl] methane sulfonate

197 ο

O^NH _o

II

O

To a solution of benzyl N-[3-hydroxy-1-(methoxy methyl)propyl] carbamate 85 (1,94 g, 7.67 mmol) and diisopropylethy lamine (2.66 mL, 15.34 mmol) in dichoromethane (70 mL) at 0 °C, was added dropwise methanesulfonyl chloride (0.71 mL, 9.20 mmol). The reaction mixture was stirred at room température for 2 hours. The mixture was diluted with water ( 100 mL) and DCM (100 mL). The water layer was extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine ( 150 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure to afford [3-(benzyloxycarbonylamino)-4-methoxy-butyl] methane sulfonate 86 as an orange viscous oil. The crude was used in the next step without further purification.

LCMS method F : [M+H] = 332, îr = 2.18 min

Préparation of intermediate 87: benzyl N-[3-(3-iodo-l-tetrahydropyran-2-yl-indazol-5yl)oxy-l-(methoxymethyl)propyl]carbamate

To a solution of 3-iodo-l-tetrahydropyran-2-yl-indazoî-5-ol 86 (2.33 g, 6.77 mmol) în N,Ndimethylformamide (60 mL) were added césium carbonate (6.21 g, 19.1 mmol) and [3(benzyloxycarbonylamino)-4-methoxy-butyl] methane sulfonate (2.53 g, 7.64 mmol). The resulting mixture was heated at 60 °C overnight. The mixture was filtered and concentrated under reduced pressure. The residue was diluted with water (100 mL) and EtOAc (100 mL). After séparation, the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed wîth brine (150 mL), dried over anhydrous sodium sulfate, filtered

198 and evaporated under reduced pressure to afford a red oil. The crude was purified by column (Macherey Nagel, 120 g) flash chromatography with cyclohexane/EtOAc fl00/0 to 80/20) as eluent. The desired fractions were collected, combined and the solvent was removed under reduced pressure to afford benzyl N-[3-(3-iodo-l-tetrahydropyran-2-yl-indazol-5-yl)oxy-l(methoxymethyl)propyl] carbamate 87 as a white oil.

LCMS method F : [M+H] ^F = 580, îr = 3.13 min

Préparation of intermediate 88: benzyl N-[3f3-[3-(hydroxymethyi)phenyl]-ltetrahydropyran-2-yl-indazol-5-yl]oxy-l-(meth oxymethytypropyl] carbamate

To a degassed solution of benzyl N-[3-(3-îodo-l-tetrahydropyran-2-yl-indazol-5-yl)oxy-l(methoxy methyl) propyl] carbamate 87 (2.81 g, 4.85 mmol), [3-(hydroxymethyl)phenyl]boronic acid (LH g, 7.28 mmol) and a IM solution ofNaiCCfi (14.55 mL, 14.55 mmol) in DME (50 mL) was added palladium-tetrakis(triphenylphosphine) (277 mg, 0.24 mmol, 5 mol %). The reaction mixture was stirred at 80 °C for 2 days. More [3-(hydroxymethyi)phenyl]boronic acid (72 mg, 0.48 mmol), IM solution of NazCCh (L45 mL, 1.45 mmol) and palladiumtetrakis(trîphenylphosphine) (56 mg, 0.049 mmol, 1 mol %) were added and the reaction mixture was stirred at 80 °C for 4 hours. After being cooled to room température, the reaction mixture was filtered over celite and the filtrate was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by column (Macherey Nagel, 120 g) flash chromatography with cyclohexane/EtOAc (100/0 to 60/40) as eluent. The desired fractions were collected, combined and the solvent was removed under reduced pressure to afford benzyl N-[3-[3-[3(hydroxymethyl)phenyl]-l-tetrahydropyran-2-yl-indazol-5-yl]oxy-l-(methoxymethyl)propyl] carbamate 88 as a yellow viscous oil.

LCMS method F: [M+H]⁺ = 560, t_R = 2.90 min

199

Préparation of intermediate 89: 11 -(methoxymethyl)-l9-(oxan-2-yl)-8,14-dioxa-l 0,19,20triazatetracyelo[13.5.2. l²*. O¹⁸’²¹jtrieosa-1(20),2(23),3,5,15(22), 16,18(21)-heptaen-9-one

A suspension of benzyl N-[3-[3-[3-(hydroxymethyl)phenyî]-l-tetrahydropyran-2-yl-indazol-5y I] oxy-1-(methoxy methy l)propyl] carbamate 88 (1.5 g, 2.68 mmol) and césium carbonate (5.23 g, 16.08 mmol) in acetonitrile (600 mL) was heated to 90°C for 6 hours. The reaction mixture was filtered at 90°C, cooled to room température and concentrated under reduced pressure. The crude was purified by column (Macherey Nagel, 80 g) chromatography with cyclohexane/EtOAc (100/0 to 60/40) as eluent. The desired fractions were collected, combined and the solvent was removed under reduced pressure to give 1 1-(methoxymethyl)-l9-(oxan-2y 1)-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.l²Ù0^,S'²¹]tricosa-l(20),2(23),3,5,15(22),16, 18(21)-heptaen-9-one 89 (757 mg, 1.67 mmol) as a white powder.

LCMS method F: [M+H]⁺ = 452, t_R = 2.87 min

Préparation of Example 83: 11-(m ethoxy methyl)-8,14-dioxa-l 0,19,20-triazatetracyclo [ 13.5.2. l²A0¹⁸’²¹|trieosa-l (20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

To a solution of 11-(methoxymethyl)-l 9-(oxan-2-yl)-8,14-dioxa-10,19,20triazatetracyclo[l 3.5.2.1³Αθ'^8,21 ]tricosa-1(20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one 89 (100 mg, 0.22 mmol) in DCM (15 mL) was added trifluoro acetic acid (0.34 mL, 4.4 mmol). The mixture was heated under micro wave conditions at 80 °C for 1 hour. The solvent was removed under reduced pressure to afford an oily residue, which was dissolved in DCM (20 mL) and a saturated solution of NaHCOj (20 mL) was added. After séparation, the aqueous

200 layer was extracted with DCM (3x10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude was triturated in acetonitrile but the resulting solid was not clean. The crude was solubilized in DCM and combined with the filtrate. The solvent was removed under reduced pressure. The crude was purified by column (Macherey Nagel, 15 g) flash chromatography with cyclohexane/EtOAc (100/0 to 60/40) as eluent. The desired fractions was collected, combined and the solvent was removed under reduced pressure under reduced pressure to give 1 l-(methoxymethy 1)-8,] 4-dioxa-10,19,20-triazate tracy cio [13.5.2.1²’⁶.0¹⁸²¹ ] tricosa-I (20),2(23),3,5,15(22),16,18(2 l)-heptaen-9-one example 83 as a pale yellow powder. LCMS method F: [M+H]⁺ = 368, t_R = 2.21 min

LCMS method G: [M+H]⁺ = 368, t_R = 2.20 min

Ή NMR (400 MHz, <76-DMSO, 80 °C) δ 12.9 (IH, m), 7.94 (IH, s), 7.86 (IH, m), 7.58 (IH, m), 7.47 (2H, m), 7.37 (1 H, d, J = 2.1 Hz), 7.27 ( 1 H, m), 6.99 (IH, dd, J = 2.3, 8.9 Hz), 5.61 (LH, m), 4.96 (IH, m), 4.33 (2H, m), 3.81 (lH,m), 3.51 (IH, m), 3.43 (1 H, dd, J =6.6, 10.0 Hz), 3.32 (3H, s), 2.15 (IH, m), 2.0 (IH, m) ppm.

Example 84: 8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1²’⁵.0^,8’²¹]tricosa

1(20),2(23),3,15(22),16,18(21)-hexaen-9-one

Example 84 îs prepared according to the synthesis route described in general Scheme K.

Préparation of intermediate 90: 2-(3-bromopyrazol-l-yl)eth anol

HO

201

To a solution of 3-bromopyrazole (1 g, 6.807 mmol) in VV-dimethylformamide (60 mL) was added potassium tert-butoxide solution (IM in THF) (10.2 mL, 10.211 mmol) at RT. The reaction mixture was stirred at RT for 10min then 1,3,2-Dioxathiolane 2,2-dioxide (1.267 g, 10.211 mmol) was added. The reaction mixture was stirred at RT for 4h30. Concentrated hydrochloric acid (6 mL) was added to the reaction mixture and it was stirred at RT for 16h. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. A saturated solution of NaHCO? was added and it was extracted with ethyl acetate (3 x). 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 flash column chromatography eluting with Cyclohexane / Ethyl acetate — EtOH (3-1), 100/0 to 60/40 to give 2-(3-bromopyrazol-1-yl)ethanol 90 as a coloriess oil.

LCMS method F: [M+H]⁺ = 193, t_R = 1.25 min

Préparation of intermediate 91: 2-[3-[5-[tert-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2yi-indazol-3-ylJpyrazol-l -yl]eth anol

HO

H

To a degassed solution of [5-[tert-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3yi]boronîc acid (563 mg, 1.496 mmol), 2-(3-bromopyrazol-l-yl)ethanol (300 mg, 1.571 mmol), tripotassîum phosphate (953 mg, 4.488 mmol), xPhos (71.5 mg, 0.150 mmol) in dioxane (4.52 mL) and water (1.51 mL) was added tetrakis(triphenylphosphine)palladium(0) (86.7 mg, 0.075 mmol). The reaction mixture was irradiated under micro wave conditions (Biotage initîator+) at 100°C for Ih.The reaction mixture was filtered over celite and washed with ethyl acetate. The Filtrate was 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 product was purified by column chromatography eluting with Cyclohexane / Ethyl acetate — EtOH (3-1), 100/0 to 70/30 to give 2-[3-[5-[tertbutyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3-yl]pyrazol-l-yl]ethanol 91 as an orange oil.

LCMS method F: [M+H]⁺ = 443, t_R = 3.25 min

202

Préparation of intermediate 92: 3-[l-(2-hydroxyethyl)pyrazol-3-yl]-l-tetrahydropyran-2-ylindazol-5-ol

HO

To a solution of 2-[3-[5-[tert-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3yl]pyrazol-l-yl]ethanol 91 (406 mg, 0.919 mmol) in THF (2 mL) was added a solution of tetrabutylammonium fluoride 1M in THF (1 mL, 1.012 mmol). The reaction mixture was stirred at room température for 16h. Ice water was added and the reaction mixture was stirred for 20 min. The aqueous phase was extracted with EtOAc (3x) and the combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude product was purified by flash column chromatography eluting with Cyclohexane / Ethyl acetate - EtOH (3-1), 100/0 to 60/40 to give 3-[l-(2-hydroxyethyl)pyrazol-3-yl]-ltetrahydropyran-2-yl-indazol-5-ol 92 as a yellow oil.

LCMS method F: [M+H]⁺ = 329, t_R = 1.92 min

Préparation of intermediate 93: benzyl N-[3-[3-fl-(2-hydroxyethyl)pyrazol-3-yl]-ltetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate

A suspension of 3-[I-(2-hydroxyethyl)pyrazol-3-yl]-l-tetrahydropyran-2-yl-indazol-5-ol 92 (150 mg, 0.457 mmol), césium carbonate (297 mg, 0.914 mmol) and benzyl N-(321105

203 bromopropyl)carbamate (98 pL, 0.503 mmol) in dry acetonitrile (4 mL) was stirred at RT for

h. More benzyl N-(3-bromopropyl)carbamate (25 pL, 0.091 mmol, 0.2 eq) in dry acetonitrile (1 mL) was added and the reaction mixture was stirred at RT for 32h. The reaction mixture was fîltered and rinsed with ethyl acetate. Water was added and it was extracted with ethyl acetate (3 x). The combined organic layers were washed with water and brine, dried over sodium sulfate, fîltered and concentrated under reduced pressure. The crude product was purified by flash column chromatography elutïng with Cyclohexane / Ethyl acetate — EtOH (3-1 ), 100/0 to 60/40, to give benzyl N-[3-[3-[l-(2-hydroxyethyl)pyrazol-3-yl]-l-tetrahydropyran-2-ylindazo 1-5-yIJoxypropyl]carbamate 93 as a white solid.

LCMS method F: [M+H]⁺ = 520, t_R = 2.64 min

Préparation of intermediate 94: 19-(oxan-2-yl)-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo [13.5.2.1²’^s. 0^!S’^2l]tricosa-l(20),2(23),3,15(22),16,18(21)-hexaen-9-one

A solution of benzyl N-[3-[3-[l-(2-hydroxyethyl)pyrazol-3-yl]-l-tetrahydropyran-2-ylindazo 1-5-yl]oxypropyl]carbamate 93 (187 mg, 0.360 mmol, leq) and césium carbonate (702 mg, 2.160 mmol, 6 eq) in acetonitrile (54 mL) was stirred at 85°C for 16 h. The reaction mixture was cooled to RT, fîltered, rinsed with ethyl acetate and evaporated under reduced pressure. The crude product was purified by column chromatography elutîng with DCM / Ethyl acetate : 100/0 to 60/40 to give the expected product 19-(oxan-2-yl)-8J4-dioxa-5,10,19,20,23pentaazatetracyclo[13.5.2.l²’⁵.0¹⁸’²¹]tricosa-l(20),2(23),3,15(22),16,18(2l)-hexaen-9-one 94 as a white solid.

LCMS method F: [M+H]⁺ = 412, t_R = 2.28 min

Préparation of Example 84: 8,14-dïoxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.PAO¹⁸’²¹] tricosa-1 (20),2(23),3,15(22),16,18(2 l)-hexaen-9-one

204

To a solution of 19-(oxan-2-yl)-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1²T0¹⁸^ tricosa-1 (20),2(23),3,15(22), 16,18(2 l)-hexaen-9-one 94 (51 mg, 0.124 mmol, 1 eq) in DCM (5 mL) was added trifluoroacetic acid (190 gL, 2.480 mmol, 20 eq) at RT. The solution was heated under micro wave conditions at 80°C for 2 h. The reaction mixture was concentrated under reduced pressure and the brown residue was dissolved in ethyl acetate. A saturated aqueous solution of sodium hydrogen carbonate was added and it was extracted with ethyl acetate (3 x). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography eluting with Cyclohexane / Ethyl acetate - EtOH (3-1), 100/0 to 50/50. The desired fractions were collected and the solvent was removed under reduced pressure. The compound was triturated with diisopropyl ether to give 8,14-dioxa5,10,19,20,23-pentaazatetracyclo[ 13.5.2. PAO^18,2'jtricosa-l (20),2(23),3,15(22),16,18(21)hexaen-9-one example 84 as a white solid.

LCMS method F: [M+H]⁺ = 328, t_R = 1.69 min

LCMS method G: [M+H]⁺ = 328, t_R = 1.66 min

Ή NMR (400 MHz, r/6-DMSO) δ 12.83 (IH, s), 7.82 (lH,d), 7.65 (IH, m), 7.61 - 7.58 (IH, m), 7.40 (IH, d), 6.95 - 6.92 ( 1 H, dd), 6.63 (IH, d), 4.52 -4.50 (2H, m), 4.42 - 4.40 (2H, m), 4.28 - 4.24 (2H, m), 3.11 - 3.07 (2H, m), 1.90- 1.84 (2H, m) ppm.

Example

85: ll-niethyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1²’^s.0¹⁸’²¹] tricosa-1(20).2(23),3,15(22),16,18(2 l)-hexaen-9-one

205

Example 85 is prepared according to the synthesis route described in general Scheme C to give

11-methy 1-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1²Λ0^Ι8·²'(tricosa-1(20),2(23), 3,15(22),l6,18(21)-hexaen-9-one example 85.

LCMS method F: [M+H]⁺ = 342, ta = 1.83 min

LCMS method G: [M+H]⁺ = 342, tR = 1.83 min

Ή NMR (400 MHz, r/6-DMSO) δ 12.82 - 12.79 (IH, m), 8.10 (IH, s), 7.76 - 7.71 (2H, m), 7.44.7.39 (1H, m), 7.08 (IH, d, J = 0.9 Hz), 6.94 (IH, dd, J = 1.7, 8.9 Hz), 4.68 - 4.62 (IH, m), 4.55 - 4.41 (3H, m), 4.35 - 4.26 (IH, m), 4.08 - 4.03 (IH, m), 3.82 - 3.76 (IH, m), 1.98 (1ΙΊ, s), 1.80 (IH, s), 1.14- 1.04 (3H, m) ppm.

Example 86: 12-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^l8’^2l]tncosal(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

Example 86 is prepared according to the synthesis route described în general Scheme E to give 12-methyl-8,14-dioxa-]0,19,20-triazatetracyclo[13.5.2.1²’⁶.0^,8’²ⁱ]tricosa-l(20),2(23)_s3,5, 15(22),16,18(21 )-heptaen-9-one example 86.

LCMS method F: [M+Hf = 338.2, t_R = 3.12 min

LCMS method G: [M+H]⁺ = 338.2, t_R = 3.09 min

Ή NMR (400 MHz, <76-DMSO) δ 13.13 (brs, IH), 8.04 - 7.99 (m, IH), 7.88 - 7.83 (m, 2H), 7,52 - 7.44 (m, 2H), 7.31 - 7.27 (m, 2H), 7.02 (dd, J = 2.5, 9.0 Hz, IH), 5.78 (d, J = 14.3 Hz, 1 H), 4.80 (d, J = 14.3 Hz, 1 H), 4.53 (d, J = 12.0 Hz, 1 H), 3.75 (t, J = 12.0 Hz, 1 H), 3.32 - 3.30 (m, 1 H), 0.96 (d, J = 6.5 Hz, 3H) ppm. Two protons were located under the DMSO peak and are not reported here.

l(20),2(23),3,5,15(22),16,18(21)-lieptaen-9-one

Example 87: 11-ethy 1-8,14-d ioxa-10,19,20-triazatetracy cio [13.5.2. l²’⁶.0^18,2 ’jtricosa21105

206

Example 87 is prepared according to the synthesis route described in general Scheme E to give 1 l-ethyl-8,14-dîoxa-l 0,19,20-trîazatetracyclo[l 3.5.2.1^2,6.0¹⁸’²¹]tricosa-1 (20),2(23),3,5, 15(22),16,18(21)-heptaen-9-one example 87.

LCMS method F: [M+H]⁺ = 352, t_R = 2.44 min

LCMS method G: [M+H]⁺ = 352, t_R = 2.38 min

Ή NMR (400 MHz, </6-DMSO, 80 °C) δ 12.87 (IH, m), 7.95 (IH, m), 7.86 (IH, m), 7.46 (3H, m), 7.37 (IH, d, J = 2.1 Hz), 7.27 (IH, dd, J = 0.7, 7.5 Hz), 6.98 (JH, dd, J = 2.3, 8.9 Hz), 5.67 (IH, m), 4.91 (IH, m), 4.35 (2H, m), 3.55 (IH, m), 2.21 (IH, m), 1.96 ( 1 H, m), 1.57 (2H, m), 0.95 (3H, t, J = 7.5 Hz) ppm.

Example 88: 4-fluoro-5,7-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹] tricosa-1 (20),2(23),3,5,15(22),16,18(2 l)-heptaen-9-one

Example 88 is prepared according to the synthesis route described in general Scheme A.

Préparation of intermediate 95: (5-bromo-3-fluoro-2-methyl-phenyl)meth anol

HO—_x 7 L j

Br

To a mixture of methyl 5-bromo-3-f1uoro-2-methyl-benzoate (3.00 g, 12.14 mmol) in THF (35 mL) at 0 °C, was added a solution of DIBAL-H (30.4 mL, 30.36 mmol, 1 0 M solution in THF).

The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was

207 diluted with ethyl acetate and cold I N HCl was added. The organic layer was washed with l

N HCl and brine, dried over MgSÛ4, filtered and the solvent was removed under reduced pressure to afford (5-bromo-3-fluoro-2-methyl-phenyl)methanol 95 as a white solid. The crude product was used in the next step without any further purification.

LCMS method F: [M-H20+H]⁺ = 201.0, t_R = 2.35 min

Préparation of intermediate 96: 5-bromo-3-fluoro-2-methyl~benzaldehyde

H

Br

To a solution of (5-bromo-3-fluoro-2-methyLphenyl)methanol 95 (2.66 g, 12.14 mmol) in DCM (160 mL) was added portion wise manganèse dioxide (10.56 g, 121.4 mmol). After stirring for 18 h at room température, the suspension was filtered through a sinter funnel. The filtrate was dried over anhydrous magnésium sulfate, filtered and the solvent was removed under reduced pressure to give 5-bromo-3-fluoro-2-methyl-benzaldehyde 96 as a slightly yellow. The crude product was used in the next step without any further purification.

LCMS method F: no m/z detected, ta - 2.67 min (current 20V)

Préparation of intermediate 97: l-(5-bromo-3-fluoro-2-methyl-phenyl)ethanol

To a cooled solution of 5-bromo-3-f1uoro-2-methyl-benzaldehyde 96 (2.43 g, 11.20 mmol) in dry tetrahydrofuran (30 mL) was added dropwise at 0 °C a 3M méthylmagnésium bromide solution în diethyI ether (7.5 mL, 22.40 mmol). The reaction mixture was stirred at 0 °C for 20 min and allowed to reach room température for 16 hours. The reaction mixture was quenched with a saturated aqueous solution of NH₄CI then extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with water the brine, dried over magnésium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash-column chromatography eluting with Cyclohexane / Ethyl acetate - EtOH (3-1): 100 / 0 to 80 / 20, to give l-(5-bromo-3-fluoro-2-methyl-pheny!)ethanol 97 as a colorless oil.

208

LCMS method F: [M-H2O+HJ+ = 217.0, t_R = 2.50 min

Préparation of intermediate 98: l-[3-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)phenyl]eth an ol

To a degassed solution in a sealed tube of l-(5-bromo-3-fluoro-2-methyl-phenyl)ethanol 97 (2.49 g, 10.66 mmol), bis(pînacolato)diboron (4.06 g, 15.99 mmol) and potassium acetate (4.18 g, 42.64 mmol) in dioxane (30 mL) was added [l,l '-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with DCM (0.874 g, l .07 mmol). The reaction mixture was stirred under argon atmosphère at 100 °C for 16 hours. The reaction mixture was filtered over celite on Whatman paper and rinsed with ethyl acetate. The reaction mixture was diluted with water and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water then brine, dried over anhydrous magnésium sulfate and concentrated under reduced pressure to afford l-[3-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2yl)phenyl]ethanol 98 as a dark brown oil. The crude product was used in the next step without any purification.

LCMS method F: [M-H2O+H]+ = 263.2, t_R = 2.77 min

Préparation of intermediate 99: benzyl N-[3-[3-[3-fluoro-5-(l-hydroxyethyI)-4-methylphenylf-l-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate

209

A solution of benzyl N-[3-(3-iodo-l-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]carbamate 26 (700 mg, 1.31 mmol), L[3-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2yî)phenyl]ethanol 98 (403 mg, 1.44 mmol), potassium phosphate tribasîc (833 mg, 3.93 mmol), Xphos (62 mg, 0.13 mmol) and palladium-tetrakis(triphenylphosphine) (75 mg, 0.065 mmol, 5 5 mol %) in a mixture of dioxane (22 mL) and water (5 mL) was heated at 110 °C for 2 days. The solution was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over magnésium sulfate, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (DCM/MeOH : 100/0 to 95/5) to give benzyl N-[3-[3-[3-fluoro-5-(l-hydroxyethyl)-4-methyl-phenyI]-Ltetrahydropyran-210 yl-indazol-5-yl]oxypropyl]carbamate 99 as a slightly yellow oil.

LCMS method F: [M+H]⁺ = 562.3, t_R = 3.15 min

Préparation of intermedîate 100: 4-fluoro-5,7-dimethyl-l 9-(oxan-2-yl)-8,14-dioxa-l 0,19,20triazatetracyclof 13.5.2. l^2,6.0^ls’²¹]trîcosa-l (20),2(23),3,5,15(22),16,18(21)-heptaen-9-one and l-[5~[5-(3-aminopropoxy)-l-tetrahydropyran-2-yl-indazol-3-yl]-3-fluoro-2-methyl-phenyl]

To a solution of benzyl N-[3-[3-[3-fluoro-5-(l-hydroxyethyl)-4-methyl-phenyl]-ltetrahydropyran-2-yî-indazol-5-yl]oxypropyl]carbamate 99 (594 mg, 1.06 mmol) in anhydrous acetonitrîle (200 mL) at room température was added césium carbonate (861 mg, 2.65 mmol).

The resulting reaction mixture was stirred at 90 °C for 17h30. LCMS showed the formation the expected macrocycle (40 % by LCMS) and a side-product arising from the carbamate hydrolysis (42 % by LCMS). The reaction mixture was filtered and concentrated under reduced pressure to afford a mixture of 4-fluoro-5,7-dimethyl-19-(oxan-2-yl)-8,14-dioxa-!0,19,20triazatetracyclo[13.5.2.1²’⁶.0^l8’^2,]tricosa-I(20),2(23),3,5,15(22),16,18(21)’heptaen-9-one and ]-[5-[5-(3-aminopropoxy)-l-tetrahydropyran-2-yl-îndazol-3-yl]-3-fluoro-2-methyl-phenyl] éthanol 100 as a yellow solid. The crude mixture was used in the next step (CDI, DMA, 90 °C) without any purification.

LCMS method F: expected macrocycle [M+H]⁺ = 454.2, t_R = 3.01 min

210

LCMS method F: hydrolyzed product [M+H]⁺ - 428,2. t_R - 1.94 min

Préparation of intermediate 101: 4-fluoro-5,7-dimethyl-l9-(oxan-2-yl)-8,l4-dioxa-l0,19,20triazatetracy clof 13. 5.2. l²’⁶.0^ÎS2I]tricosa-l (20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

To a solution of 4-fluoro-5,7-dimethyl-19-(oxan-2-yl)-8,14-dioxa-10,l9,20-trîazatetracyclo [!3.5.2.1²’⁶.0^187l]tricosa-l(20),2(23),3,5,l5(22), l6,18(21)-heptaen-9-one and l-[5-[5-(3aminopropoxy)-l-tetrahydropyran-2-yl-indazol-3-yl]-3-fluoro-2-methyl-phenyl]ethanol 100 (0.452 g, 1.06 mmol) in dîmethylacetamide (350 mL) was added I ,l'-carbonyldiimidazole (0.188 g, 1.16 mmol). The reaction mixture was stirred at room température for 16 hours. The mixture was diluted in water and extracted three times with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water, then brine, dried over anhydrous magnésium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: DCM/MeOH from 100/0 to 95/5) to afford 4-fluoro5,7-dimethy l-19-(oxan-2~yl)-8,14-dioxa-l 0,19,20-triazatetracyclo[ 13.5.2. l²’⁶.0^,8’²¹]tricosa1(20),2(23),3,5,15(22), 16,18(2 l)-heptaen-9-one 101 as a coîorless oil.

LCMS method F: [M+H]⁺ = 454.1, t_R = 2.99 min (current 20V)

Préparation of Example 88: 4-fluoro-5,7-dimethy 1-8,14-dioxa-l 0,19,20-triazatetracy cio [13.5.2.1²A0¹⁸’²¹]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

To a solution of 4-fluoro-5,7-dimethyl-19-(oxan-2-yl)-8,14-dioxa-l 0,19,20-triazatetracycio

[ 13.5.2.l²’⁶.0^18,2l]tricosa-1(20),2(23),3,5,15(22), 16,18(2l)-heptaen-9-one 101 (0.080 g, 0,176 mmol) in DCM (15 mL) was added triflLioroacetic acid (0.27 mL, 3.52 mmol). The mixture was

2ll heated under microwave conditions at 80 °C for Ihl5. The solvent was removed under reduced pressure to give a mixture of a yellow solid in an oily residue. The solid residue appeared to be the expected product, which was not soluble enough for column chromatography purification. In order to remove impurities from this solid, the crude mixture was suspended in MeOH (3 mL) and refluxed for 3 hours. The suspension was filtered and the filter cake was rinsed with MeOH. This filter cake was suspended again in MeOH (3 mL) and refluxed for 3 hours. After filtration, the residual solid was suspended in water (3 mL) and reflux for 2 hours. After Filtration ofthe resulting suspension, the solid was collected and dried under reduced pressure at 60°C to afford 4-fluoro-5,7-dimethyl-8,l4-dioxa-l 0,l 9,20-triazatetracyclo[l3.5.2.l^2,6.0¹⁸’²¹] tricosa-l(20),2(23),3,5,15(22),16,18(2i)-heptaen-9-one example 88 as a white solid.

LCMS method F: [M+H]* = 370.2, t_R = 2.38 min

LCMS method G: [M+H]* = 370.2, t_R = 2.35 min ‘H NMR (400 MHz, rf6-DMSO, 80 °C) δ 12.89 (IH, br. s), 7.70 - 7.67 (2H, m), 7.49 - 7.42 (2H, m), 7.36(1 H, s), 7.00 - 6.97 (1 H, m), 5.81 - 5.68 (1H, m), 4.35 -4.25 (2H, m), 3.52 (IH, br. s), 2.77 (1 H, br. s), 2.27 (3H, d, J= 1.9 Hz), 2.12 (IH, br. s), 1.75 (IH, br. s), 1.50 (3H, d, J = 7.2 Hz) ppm.

Example 89: 4-fluoro-5-methoxy-7-methy 1-8,14-dioxa-l 0,19,20-triazatetracyclo

[13.5.2.1^0^^^088-1(20),2(23),3,5,15(22),16,18(21)-1^13611-9-01^

Example 89 is prepared according to the synthesis route described in general Scheme A and according to the procedures described to obtain example 88 to give 4-fluoro-5-methoxy-7methy 1-8,14-dioxa-10,19,20-triazatetracyclo[] 3.5.2.1²’⁶,0^18,2'Jtricosa-l (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one example 89.

LCMS method F: [M+H]⁺ = 386.2, t_R = 2.40 min

LCMS method G: [M+H]* = 386.2, t_R = 2.37 min

212 'HNMR (400 MHz,ί/6-DMSO, 80 °C) δ 12.95 (IH, br. s), 7.74 (IH, s), 7.64 (IH, s), 7.55 (IH, d, J= 13.1 Hz), 7.49 - 7.46 (IH, m), 7.34 (IH, s), 7.01 - 6.97 (IH, m), 5.80 (IH, s), 4.38 - 4.27 (2H, m), 4.00 - 3.99 (3H, m), 3.53 (IH, br. s), 2.78 (IH, br. s), 2.15 (IH, br. s), 1.76 (IH, br. s), 1.54 (3H, d, J= 6.6 Hz) ppm.

Example 90: 5-fluoro-4,7-dimethyl-8,14-dioxa-10,19,20-triazatetracycloll3.5.2.1²>«.O^1W1] tricosa-1 (20),2(23),3,5,15(22),16,18(2 l)-heptaen-9-one

Example 90 îs prepared according to the synthesis route described în general Scheme A and according to the procedures described to obtain example 88 to give 5-fluoro-4,7-dimethyl-8,14dioxa-10,19,20-triazatetracyclo[l 3.5.2. l^2,6.0¹⁸²¹ ]tricosa-1(20),2(23),3,5,15(22), 16,18(21)heptaen-9-one example 90.

LCMS method F: [M+H]⁺ = 370.2, t_R = 2.44 min

LCMS method G: [M+Hf = 370.2, t_R = 2.43 min

Ή NMR (400 MHz, ί/6-DMSO, 80 °C) δ 12.83 (IH, s), 7.73 - 7.69 (3H, m), 7.48 - 7.44 (IH, m), 7.37 - 7.35 (IH, m), 6.98 (IH, dd, J= 2.3, 8.9 Hz), 5.88 - 5.82 (IH, m), 4.38 - 4.25 (2H, m), 3.56(1 H, br. s), 2.81 -2.76(lH,m), 2.36 - 2.33 (3H, m), 2.19 -2.14 (IH, m), 1.80- 1.73 ( 1 H, m), 1.58 (3H, d, J= 6.8 Hz) ppm.

Example 91: 8,14-dioxa-10,19,20-triazapentacyclo[13.5.2.1²’⁶.l⁷’^lfl.0¹⁸'²¹]tetracosa l(20),2(24),3,5,15(22),16,18(21)-heptaen-9-one

213

Example 91 is prepared according to the synthesis route described below.

Préparation of intermediate 102: \-(3-bromophenyl)-2-nitro-ethanol

OH

O₂N

In a round bottom flask, to a stirred solution of 3-bromo-benzaldehyde (1.850 g, 10.00 mmol) in THF (50.0 ml) was added dropwise at 0°C, nitromethane (535 pL, 10.00 mmol) and then sodium hydroxide solution IN (10.00 ml, 10.00 mmol). The mixture was stirred during 1 h. LC/MS analysis indîcated 70% formation of required product and 50% starting material. The orange mixture was stirred during 3h at room temperature. The solution was carrefuly quenched with a solution of acetic acid (10 ml) and water (20 ml). Phases were separated and the aqueous layer was extracted with AcOEt (3 x 35 ml). Combined organic layer were washed with brine (30 ml), and dried over MgSO4, filtered and concentrated under reduce pressure to afford a crude material (1.720 g). The crude was purified by chromatography column by solid deposit (Macherey Nagel, 4 g, Cyclohexane/AcOEt :90/10 to 70/30). Solvent was evaporated to afford l-(3-bromophenyl)-2-nitro-ethanol 102 as a yellow pale oil.

LCMS method F: [M-H]' = 246.1, t_R = 2.24 min

Préparation of intermediate 103: 2-amino-l-(3-bromophenyl)ethanol

OH

H₂N

The reaction was divided in 2 batches of 730 mg (2.97 mmol) of l-(3-bromophenyl)-2-nitroethanol 102. To a solution of l-(3-bromophenyl)-2-nitro-ethanol (0.730 g, 2.97 mmol) in EtOH/water (2:1 v:v) were added iron powder (0.829 g, 29.67 mmol) and ammonium chloride (4.758 g, 177.90 mmol). The resulting brown mixture was stirred during 16 h at room temperature. The solution was filtered to remove iron. Solvent was concentrated and to the residue was added water and EtOAc (50 ml) and phases were separated and extracted with EtOAc (3 x 50 ml). Organic phases were gathered and washed with brine, dried wîth MgSOi, filtered and concentrated under reduc pressure to afford 2-ammo-l-(3-bromophenyl)ethanol 103 as a pale yellow oil which was used in the next step without further purification.

214

LCMS method H: [Μ+ΗΓ = 216.0, t_R = 1.02 min

Préparation ofintermediate 104: 5-(3-bromophenyl)oxazohdin-2-one

To a solution of 2-amino-l-(3-bromophenyl)ethanol 103 (0.710 g, 3.29 mmol) in THF (33.0 mL) was added l,l'-Carbonyldiimidazole (0.587 g, 3.62 mmol) and imidazole (0.246 g, 3.62 mmol). The reaction mixture was stirred at RT for 16h. To the reaction mixture was added saturated aqueous solution of NH4CI (30 ml). The mixture was extracted with ethyl acetate (3 x 30 m!). The combined organic layer was washed with water then 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: 100/0 to 70/30 to give 5-(3-bromophenyl)oxazolidin-2-one 104.

Préparation of intermediate 105: 5-(3-bromophenyl)-3-[3-[tert-butyi (dimethytysilylj oxypropyljoxazûlidin-2-one

To a solution of 5-(3-bromophenyl)oxazolidin-2-one 104 (0.580 g, 2.40 mmol) in dry THF (25.0 ml) at 0°C was added sodium hydride (0.115 g, 4.80 mmol). The reaction was stirred 30 min at 0°C, then tetrabutylammonium iodide (0.044 g, 0.120 mmol) and 3-bromopropoxy-tertbutyl-dimethyl-silane (0.669 g, 612 pL, 2.64 mmol) were added. The resulting yellow mixture was stirred at 60°C during 2 days. It was quenched with a saturated solution of NaHCO₃ (25 ml) and extracted with EtOAc (3 x 50 ml). Organic phase was washed with brine (25 ml), then dried with MgSÛ4 , filtered and concentrated under reduce pressure to afford crude (1.200 g) which was purified by chromatography column by solid deposit (Macherey Nagel 24g, Cyclohexane/AcOEt 90/10 to 70/30). Solvent was evaporated to afford 5-(3-bromophenyl)-3[3-[tert-butyl(dimethyl)silyl]oxypropyl]oxazolidin-2-one 105 as a paie yellow oil.

215

LCMS method F: [M+H]⁺ = 416.1, t_R - 3.41 min

Préparation of intermediate 106: 5-(3-bromophenyl)-3-(3-hydroxypropyI)oxazolidm-2-one

O Ko ho' i^

Br

To a solution of 5-(3-bromophenyl)-3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]oxazolidin-2one 105 (0.650 g, 1.57 mmol) in dry THF (31.0 ml) at room température was added tetra-nbutylammonium fluoride (1.57 ml, 1.57 mmol, 1.0 M in THF). The reaction was stirred at room température during 16 h. The mixture was poured into ice water (20 ml) and stirred for 15 min. The aqueous phase was extracted with ethyl acetate (3 x 25 ml). The combined organic layers were washe with brine (25 ml), dried over MgSO₄, filtered and concentrated under reduce pressure to afford 5-(3-bromophenyl)-3-(3-hydroxypropyl)oxazolidin-2-one 106 as pale yellow oil.

LCMS method F: [M+H]⁺ = 302.0, t_R = 2.00 min

Préparation of intermediate 10 7: 3-[5-(3-bromophenyl)-2-oxo-oxazoUdin-3-yl]propyl methanesulfonate

To a solution of 5-(3-bromophenyl)-3-(3-hydroxypropyl)oxazolidin-2-one 106 (0.420 g, 1.40 mmol) and diîsopropylethylamine (0.487 mL, 2.80 mmol) in DCM (15.0 mL) at 0 °C, was added dropwise methanesulfonyl chloride (0.130 mL, 1.68 mmol). The reaction mixture was stirred at room température for 3 h. LC/MS analysis indicated the reaction was completed. The organic phase was washed with a saturated solution of ammonium chloride, with a saturated solution of sodium bicarbonate and brine, dried with MgSO₄, filtered and evaporated under reduced pressure to afford 3-[5-(3-bromophenyl)-2-oxo-oxazolidin-3-yl]propyl

216 methanesulfonate 107 as a pale yellow oil, which was used in the next step without further purification.

LCMS method F; [M+H]⁺ = 380.1, t_R = 2.28 min

Préparation of intermediate 108: 5-(3-bromophenyl) -3-[3-(l-tetrahydropyran-2-yiindazol-5yl)oxypropyl]oxazolidin-2-one

To a solution of 3-[5-(3-bromophenyl)-2-oxo-oxazolidin-3-yl]propyl methanesulfonate 107 (0.912 g, 1.40 mmol) în DMF (28.0 mL), césium carbonate (0.913 g, 2.80 mmol) and 1tetrahydropyran-2-ylindazol-5-ol (0.305 g, 1.40 mmol) were added. The reaction was stirred at 60°C during 1 h30. The mixture was concentrated under reduced pressure. Water (50 mL) was added and the resulting mixture was extracted with AcOEt (4 x 30 mL). Combined organic layers were washed with saturated brine (30 mL). The organic layer was dried over sodium sulfate, filtered off and evaporated under reduced pressure to afford brown oil. This resîude was purified by flash chromatography on silica gel (Macherey Nagel, 24 g, with gradient elution: Cyclohexane/AcOEt: 100/0 to 70/30) to give 5-(3-bromophenyl)-3-[3-(l-tetrahydropyran-2ylindazol-5-yl)oxypropyl]oxazolidin-2-one 108 as a yellow oil.

LCMS method F: [M+H]+ = 502.0, t_R = 2.45 min

Préparation of intermediate 109: 19-(oxan-2-y 1)-8,14-dioxa-l 0,19,20-triazapentacyclo [13.5.2.1^2<6.l^7!(>.0^}S'^2}]tetracosa-l(20),2(24),3,5,15(22),16,18(21)-heptaen-9-one

217

To a solution of 5-(3-bromophenyl)-3-[3-(l-tetrahydropyran-2-ylindazol-5yl)oxypropyl]oxazolidin-2-one 108 (0.300 g, 0.600 mmol) in 10.0 ml of toluene was added reagent potassium acetate (0.118 g, i.200 mmol) at room température. The mixture was degassed by bubbling nitrogen for 15 minutes. Palladium acetate (0.027 g, 0.120 mmol) and cataCXium A (0.043 g, 0.120 mmol) were then added. The mixture was heated at 120°C for Ih under microwaves irradiations (B1OTAGE), then 1 h30 at J30°C and 45 min at 140°C. The reaction mixture was fîltered over celite and 20 ml of water were added to the filtrate. The aqueous layer was extracted with ethyl acetate (2 x 20 ml). The combined organic layer was washed with a saturated brine, dried over MgSÛ4 and evaporated in vacuo to give crude (0.280 g), which was purified by column chromatography (Macherey Nagel, 12g, DCM/MeOI-I ammoniac : 100/0 to 95/5). Solvents were evaporated to afford 19-(oxan-2-yl)-8,14-dioxa10,]9,20-triazapentacyclo[13.5.2.1²’⁶.l^7jo.0^l8’^2l]tetracosa-l(20),2(24),3,5,15(22),16,18(2l )heptaen-9-one 109 as a yellow powder.

LCMS method F: [M+H]⁺ = 420.2, t_R = 2.57 min

Préparation of Example 91: 8,14-dioxa-10,19,20-triazapentacyclo[13.5.2.1²’⁶.l⁷’^1<1.0¹⁸’^2,l tetracosa-l(20),2(24),3,5,15(22),16,18(21)-heptaen-9-one

In a vial, 19-(oxan-2-y 1)-8,14-dioxa-10,19,20-triazapentacyclo[ 13.5.2.1²A1⁷’¹⁰.0^18,21 ]tetracosa 1 (20),2(24),3,5,15(22),16,18(21 )-heptaen~9-one 109 (0.195 g, 0.465 mmol) was dissolved in

218

CHiCh (9.0 mL) and TFA (0.1 M in CH2CI2, 80 pL) was added. The resulting clear yellow solution was stirred at room temperature for 3 days. The reaction was quenched with saturated aqueous NaHCOj (10 mL) and EtOAc (10 mL) was added. The aqueous phase was extracted with EtOAc (3x15 mL) and the combined organic extracts were washed with saturated aqueous NaHCOs (15 mL) and saturated aqueous NaCi (15 mL), dried over anhydrous MgSO^ filtered and concentrated under reduced pressure to afford crude (0.195 g) which purified by préparative reverse-phase chromatography (Column XSELECT PHENYL-HEXYL 19* 100mm 5pm [(NH4)2CO3 aq 2g/LACN] 30%B to 40%B in 7min 19mL/min R.T.). Solvent was removed and an other purification was done (0.015 g crude) by chromatography column (Macherey Nagel 4g, DCM/MeOH: 100/0 to 96/4) to give 8,14-dioxa-10,19,20triazapentacyclo[ 13.5.2.11⁷>io ₀'8,2' ]_tetracosa-1(20),2(24), 3,5,15(22), 16,18(21 )-heptaen-9one example 91.

LCMS method F: [M+H]⁺ = 336.2, t_R = 1.97 min

LCMS method G: [M+H]⁺ = 336.2, t_R = 1.96 min

Ή NMR (400 MHz, rf6-DMSO) δ 12.86 (IH, s), 8.39 (IH, t, J = 1.7 Hz), 7.92 - 7.86 (IH, m), 7.58 - 7.41 (4H, m), 7.01 - 6.97 (IH, m), 5.69 - 5.69 (2H, m), 4.46 - 4.37 (IH, m), 4.30 - 4.23 (IH, m), 4.12 - 3.99 (2H, m), 3.61 - 3.40 (I H, m), 2.35 - 2.24 (IH, m), 2.04 - 1.92 (IH, m) ppm.

Example 92: 13-m ethy 1-8,14-d ioxa-10,19,20,23-tetraazatetra cycle [13.5.2. PAO^18,21] tricosa-1(20),2(23),3,5,15(22),16,18(2l)-heptaen-9-one

Example 92 is prepared according to the synthesis route described in general Scheme B to give 13-methy 1-8,14-dioxa-10,19,20,23-tetraazatetracyclo[ 13.5.2. PAO^18,2 'Jtrîcosa-1(20),2(23), 3,5, 15(22), 16,18(21 )-heptaen-9-one example 92.

LCMS method F: [M+H]⁺ = 339.2, t_R = 2.09 min

LCMS method G: [M+H]⁺ = 339.2, t_R = 2.07 min

Ή NMR (400 MHz, ί/6-DMSO) δ 13.22 (IH, s), 8.09 - 8.06 (1 H, m), 7.90 - 7.81 (2H, m), 7.74 - 7.70 (IH, m), 7.48 - 7.44 (IH, m), 7.26 - 7.23 (IH, m), 6.95 (IH, dd, J=2.5, 8.9 Hz), 5.58 (I H,

219

s), 5.08 - 5.04 (IH, m), 4.62 (tH, s), 3.45 (IH, m), 2.92 (lH, s), 2.29 - 2.25 (IH, m), 1.38 - 1.35 (4H, m) ppm.

Example 93: 12-methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1²’⁵.0¹⁸’²¹] tricosa-1(20),2(23),3,15(22),16,18(2 l)-hexaen-9-one

Example 93 is prepared according to the synthesis route described in general Scheme C to give ] 2-methyl~8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[ 13.5.2.1^2,5.0¹⁸’²¹]tricosa-1(20),2(23),3, 10 15(22), 16,18(21 )-hexaen-9-one example 93.

LCMS method F: [M+H]⁺ = 342.1, t_R = 2.45 min

LCMS method G: [M+H]⁺ = 342.2, t_R = 2.40 min

Ή NMR (400 MHz, J6-DMSO) δ 12.80 (brs, IH), 8.08 (s, IH), 7.95-7.91 (m, IH), 7.77 (s, l H), 7.42 (d, J= 9.6 Hz, 1H),7.O7 (d,J=2.5Hz, 1 H), 6.99 - 6.96 (m, 1 H), 4.67 - 4.43 (m,4H), 15 4.07 (ddt, J= 2.4, 5.6, 6.1 Hz, IH), 3.70 (dd, J = 10.1, 12.7 Hz, 1 H), 3.36 - 3.26 (m, 1 H), 2.58

-2.53 (m, IH), 2.22-2.10 (m, 1 H), 0.93 (d, J= 6.6 Hz, 3H) ppm.

Example 94: 7-methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1²’⁵.0¹⁸’²¹] tricosa-l(20),2(23),3,15(22),16,18(21)-hexaen-9-one

Préparation of intermediate 110: 1-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazol25 l-yi]propan-2-ol

Example 94 îs prepared according to the synthesis route described in general Scheme C.

220

In a microwave vial, NaH (60% in minerai oil, 480 mg, 12.000 mmol) was suspended in N,Ndimethylformamîde (10.0 mL) and a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)-lH-pyrazole (776 mg, 4.000 mmol) ΐη Λ( Λ-dimethylfonnamide (10.0 mL) was added. The resulting cloudy white solution was stirred at room température for 15 minutes and racpropylene oxide (839 pL, 697 mg, 12.000 mmol) was added. The vial containing the resulting cloudy yellow solution was sealed and heated to 80°C for 2 h. The solvents were evaporated under reduced pressure and the residue was dissolved in CHzCh (50 mL), fïltered through a silica pad and concentrated under reduced pressure to afford crude 1 -[4-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)pyrazol-l-yl]propan-2-ol 110 as a brown solid which was used in the next step without further purification.

LCMS method F: [M+H]⁺ = 253.2, t_R = 1.93 min

Préparation of intermediate 111: benzyl N-[3-[3-[l-(2-hydroxypropyl)pyrazol-4-yl]-ltetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate

In a microwave vial, benzyl N-[3-(3-îodo-l-tetrahydropyran-2-yl-indazol-5yl)oxypropyl]carbamate 26 (803 mg, 1.500 mmol), 1 -[4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyrazol-l-yl]propan-2-ol 110 (567 mg, 2.250 mmol), XPhos (72 mg,

0.150 mmol) and K3PO4 (955 mg, 4.500 mmol) were suspended in dioxane (6.0 mL) and

221 water (1.5 mL) and the mixture was degassed with N₂ for 15 minutes. Pd(PPh₃)4 (87 mg,

0.075 mmol) was added and the resulting cloudy yellow solution was sealed and heated to 120°C under microwave conditions for 2 h. The mixture was cooled to room température and poured in EtOAc (25 mL) and water (25 mL) and the two layers were separated. The aqueous layer was extracted with EtOAc (3 x 25 mL) and the combined organic layers were washed with saturated aqueous NaCi (1 x 25 mL), dried over anhydrous Na₂SO4, filtered and concentrated under reduced pressure. The resulting crude materiai (yellow oil, 900 mg) was purified by column chromatography (40 g Macherey Nagel S1O2, CFLCh/MeOH 100:0 to 95:5) to afford benzyl N-[3-[3-[l-(2-hydroxypropyl)pyrazol-4-yl]-l-tetrahydropyran-2-ylindazo 1-5-y l]oxypropyl] carbamate 111 as a yellow solid.

LCMS method F: [M+H]⁺ = 534.3, t_R = 2.66 min

Préparation of intermediate 112: 7-methyl-l 9-(oxan-2-yl)-8,14-dioxa-4,5,10,19,20pentaazatetracyclo[13.5.2.I²⁵.0^!S2!]tricosa-l (20),2(23),3,15(22),16,18(21)-h exaen-9-one

To a solution of benzyl N-[3-[3-[l-(2-hydroxypropyl)pyrazol-4-yl]-l-tetrahydropyran-2-ylîndazol-5-yl]oxypropyl]carbamate 111 (180 mg, 0.334 mmol) in MeCN (18.0 mL) was added CsiCOa (659 mg, 2.024 mmol). The resulting cloudy white solution was heated to reflux for 6 h. LC/MS analysis indicated that the reaction was complété. The mixture was cooled to room température, filtered and concentrated under reduced pressure. The resulting crude materiai (pale yellow oil, 180 mg) was purified by column chromatography (4 g Macherey Nagel S1O2, 15 mL/min, CyH/EtOAc 100:0 to 0:100) to afford 7-methyl-19-(oxan-2-yl)-8,14-dioxa4,5,10,19,20-pentaazatetracyclo[l 3.5.2. l²-⁵.0^l8,21]trîcosa-l (20),2(23),3,15(22),16,18(21)hexaen-9-one 112 as a white solid.

LCMS method F: [M+H]⁺ = 426.2, t_R = 2.31 min

222

Préparation of Example 94: 7-methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo

[13.5.2. PAO^{18 21} Jtricosa-1 (20),2(23),3,15(22),16,18(21 )-hexaen-9-one

To a solution of 7-methyl-19-(oxan-2-yl)-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo 5 [13.5.2.l²A0^,S’²¹]tricosa-l(20),2(23),3,15(22), 16,18(2i)-hexaen-9-one 112 (43 mg, 0.101 mmol) in CH2CI2 (2.5 mL) was added TFA (0.39 mL, 0.576 mg, 5.050 mmol). The resulting transparent solution was stirred at room température for 6 h. The solvent was removed under reduced pressure and the residue was triturated with MeCN and dried (50°C, 5 mbar) for 3 h to afford 7-methyl·8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[l 3.5.2. PAO^18,2'Jtricosa10 1(20),2(23),3,15(22), 16,18(2 l)-hexaen-9-one example 94 as a white solid.

LCMS method F: [M+H]⁺ = 342.2, t_R = 2.42 min

LCMS method G; [M+H]⁺ = 342.2, t_R = 2.39 min

Ή NMR (400 MHz, ri6-DMSO) δ 12.81 (s, IH), 8.14 (s, IH), 7.86 - 7.82 (m, IH), 7.77 (s, IH), 7.42 (d, J= 9.0 Hz, IH), 7.08 (d, J = 2.5 Hz, 1 H), 6.94 (dd, J = 2.7, 9.1 Hz, IH), 4.96 - 4.89 15 (m, IH), 4.49 (dd, J=2.3, 14.9 Hz, IH), 4.42 (dd, J = 3.6, 12.2 Hz, IH), 4.30 (dd, J= 10.2,

14.5 Hz, IH), 4.24-4.16 (m, lH), 3.53 - 3.47 (m, 1 H), 2.78 - 2.71 (m, IH), 1.97- 1.88 (m, 1 H), 1.78 - 1.68 (m, IH), 1.31 (d, J =6.3 Hz, 3H) ppm.

Example 95: 5-fluoro-4-methoxy-7-methy 1-8,14-dioxa-l 0,19,20-triazatetracyclo

[13.5.2.PA0¹⁸’²¹]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

Example 95 is prepared according to the synthesis route described in general Scheme A and according to the procedures described to obtain example 88 to give 5-fluoro-4-methoxy-721105

223

methyl-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1^2,6.0'⁸’² ']tricosa-1 (20),2(23),3,5,15(22), I6,l 8(2l)-heptaen-9-one example 95.

LCMS method F: [M+H]⁺ = 386.2, ta = 2.4I min

LCMS method G: [M+H]⁺ = 386.2, t_R = 2.40 min

Ή NMR (400 MHz, t/6-DMSO) δ 13.14 (IH, br. s), 8.07 (1H, dd, J = 4.2, 7.8 Hz), 7.52 - 7.47 (2H, m), 7.43 - 7.40 (IH, m), 7.33 (IH, d, J =2.1 Hz), 6.99 (III, dd, J=2.2, 9.0 Hz), 5.84 5.77 (lH,m), 4.37-4.27 (2H, m), 3.93 (3H, s), 3.55 - 3.48 (IH, m), 2.77 -2.67 (IH, m), 2.15 -2.07(lH, m), 1.78- 1.69 (lH,m), 1.56 - 1.53 (3H, d, J=6A Hz) ppm.

Example 96: (7R,13R)-7,13-d im ethy 1-8,14-dioxa-10,19,20-triazatetracy cio (13.5.2. PAO¹*·²¹ J tricosa-1(20),2(23),3,5,15(22), 16,18(21)-heptaen-9-one

Example 96 is prepared according to the synthesis route described in general Scheme C and by 15 chiral HPLC purification. The chiral purification is done on a Chiralpak IA column 250x4.6mm gm, eluent [heptane/EtOH]+0.1%DEA [80/0], 1 mL/min RT to give (7R,l3R)-7,13-dimethyl8,14-dioxa-10,l9,20-triazatetracyclo[13.5.2.1²’⁶.0^,8:i]tricosa-l(20),2(23),3,5,15(22), 16,18(2l)-heptaen-9-one example 96.

LCMS method F: [M+H]⁺ = 352.2, t_R = 2.47 min

LCMS method G: [M+H]⁺ = 352.2, t_R = 2.44 min

Ή NMR (400 MHz, ί/6-DMSO) δ 12.81 - 12.77 (IH, m), 7.92 (IH, s), 7.76 (IH, d, J = 7.6 Hz), 7.53 - 7.36 (3H, m), 7.31 -7.27 (2H, m), 6.96 (1 H, dd, J = 2.3, 8.9 Hz), 5.92 (IH, s), 4.64 (IH, s), 3.26 - 3.22 (1 H, m), 3.15- 3.05 (1 H, m), 2.1-1.86 ( 1 H, m), 1.62 (4H, s), 1.41 - 1.37 (3H, m) ppm.

Chiral HPLC e.e. 100%

Example 97: (13R)-13-methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo

[13.5.2.1²’⁵.0¹⁸'^2f]tricosa-l(20),2(23),3,15,17,21-hexaen-9-one

224

Example 97 is prepared according to the synthesis route described in general Scheme C and by chiral HPLC purification. The chiral purification is done on a Chiralpak IB N-5 column 20x250mm 5 pm, eluent [heptane/EtOH]+0. !%DEA [85/l 5] run time 20 min, 19 mL/min RT to give (l3R)-l3-methyl-8,l4-dioxa-4,5,l0,19,20-pentaazatetracyclo[I3.5.2.l²’⁵.0^l8’^2l]tricosa1(20),2(23),3,15,17,2 l-hexaen-9-one example 97.

LCMS method F: [M+H]⁺ = 342.3, t_R = 1.91 min

LCMS method G: [M+H]⁺ = 342.2, t_R = 1.92 min

Ή NMR (400 MHz, rf6-DMSO) δ 12.80 (IH, s), 8.08 (IH, s), 7.77 - 7.76 (2H, m), 7.43 - 7.39 (IH, m), 7.07 (IH, d, J = 1.9 Hz), 6.92 (IH, dd, J = 2.2, 9.0 Hz), 4.68 - 4.42 (4H, m), 4.11 4.05 (IH, m), 3.58 - 3.46 (IH, mm), 2.94 - 2.86 (IH, m), 2.16 - 2.08 (IH, m), 1.39 - 1.36 (4H, m) ppm.

Chiral HPLC e.e. >99%

Example 98: 8,t5-dîoxa-4,10,20,21-tetraazapentacyclo[14.5.2.1²’⁶.l¹⁰’^i;ï.0¹⁹’^:ï]pentacosal(21),2(25),3,5,16(23),17,19(22)-heptaen-9-one

Example 98 is prepared according to the synthesis route described in general Scheme N.

Préparation of intermediate 113: benzyl 3-(hydroxymethyl)pyrroiidine-l-carboxylate

225

To a solution of 3-bromopropylamine hydrobromide (2.0 g, 19.8 mmol) in aq.NaOII 10 % (60 mL) at 0 °C was slowly added benzyl chlorformate (3.1 mL, 2L8 mmol) and the mixture was stirred at RT for l hour. The reaction mixture was diluted with DCM (100 mL). The aqueous layer was extracted two times with DCM (50mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow oil. The residue was purified by flash chromatography (CyH/AE 0 to 100% EtOAc) to afford benzyl 3-(hydroxymethyl)pyrrolidine-l-carboxylate 113 as an yellow oil. LCMS method F: [M+H]⁺ = 236, t_R = 1.97 min

Préparation of intermediate 114: benzyl 3-(methylsulfonyloxymethyl)pyrrolidine-lcarboxylate

To a solution of benzyl 3-(hydroxymethyl)pyrrolidine-l-carboxylate 113 (2.90 g, 12.3 mmol) and diisopropylethylamine (4.28 mL, 24.6 mmol) in dichoromethane (20 mL) at 0 °C, was added dropwise methanesulfonyl chloride (1.13 mL, 14.8 mmol). The reaction mixture was stirred at room température for 4 hours. The organic layer was washed with a saturated solution of ammonium chloride (50 mL), with a saturated solution of sodium bicarbonate (50 mL) and brine, filtered and the solvent was removed under reduced pressure to give benzyl 3(methylsulfonyloxymethyl)pyrrolidine-l-carboxylate 114 as a yellow oil. The crude product was used in the next step without further purification.

LCMS method F: [M+H]⁺ = 314, t_R = 2.29 min

Préparation of intermediate 115: benzyl 3-(methylsulfonyloxymethyl)pyrrolidine-lcarboxylate

226

To a solution of 3-iodo-l-tetrahydropyran-2-yl-indazol-5-ol 4 (4.33 g, 12.6 mmol) in N,Ndimethylfonnamide (100 mL) was added césium carbonate (l0.27 g, 3I.5 mmol). The resulting green solution was stirred at room température for 10 minutes, tert-butyl 35 (methylsulfonyloxymethyl)azetidine-l-carboxylate 114 (3.94 g, 12.6 mmol) was added and the mixture was stirred at 60 °C for 12 h. The mixture was cooled to room température and concentrated under reduced pressure. The residue was diluted with water (50 mL) and ethyl acetate (100 mL). After séparation, the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous magnésium 10 sulfate, filtered and evaporated under reduced pressure to afford a yellow oil. The oily residue was purified by flash chromatography (CyH/EtOAc 7/3) to afford benzyl 3(methylsulfonyloxymethyl)pyrrolidine-l-carboxylate 115 as a colorless oil.

LCMS method F: [M+H]⁺ = 562, t_R = 3.32 min

Préparation of intermediate 116: 5-(pyrrolidin-3-ylniethoxy)~l-tetrahydropyran-2-ylindazole

To a solution of benzyl 3-[(3-îodo-1 -tetrahydropyran-2-yl-indazol-5-yl)oxymethyl |pyrrolidine1-carboxylate 115 (4.00 g, 7.13 mmol) in MeOH (200 mL) were added triethylamine (2.4 mL) and 10 % Pd/C (75 mg). The reaction vessel was pressurized to 50 psi (approx. 3-4 bar) for 24

227

hours in a parr shaker. The mixture was fîltered over celite. The filtrate was concentrated under reduced pressure to give 5-(pyrrolidin-3-ylmethoxy)-l-tetrahydropyran-2-yl-indazole 116 as a slightly yellow foam. The crude product was used in the next step without any further purification.

LCMS method F: [M+H]⁺ = 302.2, t_R = 1.43 min

Préparation of intermediate 117: (5-bromo-3-pyridyl)methyI 3-[(l-tetrahydropyran-2ylindazol-5-yl)oxymethyl]pyrrolidine-l-carboxylate

To a solution of 5-(pyrrolidin-3-ylmethoxy)-I-tetrahydropyran-2-yl-indazole 116 (0.890 g, 2.95 mmol) in dimethylacetamide (200 mL) was added 1,1 '-carbonyldiimidazole (0.526 g, 3.25 mmol). The réaction mixture was stirred at room température for 2 hours. The reaction mixture was then added dropwise to a solution of (5-bromo-3-pyridyl)methanol (0.830 g, 4.42 mmol) and césium carbonate (4.79 g, 14.75 mmol) in DMA (50 mL) at 90 °C and the mixture was stirred at 90°C for 16 hours. The reaction mixture was allowed to cool down to room température and fîltered. The filtrate was diluted with water and extracted three times with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water, brine, dried over anhydrous magnésium sulfate, fîltered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: Cyclohexane/EtOAc from

95/5 to 50/50) to afford (5-bromo-3-pyridyl)methyl 3-[(l-tetrahydropyran-2-ylîndazol-5yl)oxymethyl]pyrrolidine-l-carboxylate 117 as a coiorless oil.

LCMS method F: [M+H]⁺ = 517.1, t_R = 2.81 min

Préparation of intermediate 118: 20-(oxan-2-yl)-8,15-dioxa-4,10,20,21-tetraazapentaeyclo

[14.5.2. F⁶. 1™’ ⁱ³.0^19,22]pentacosa-l (21),2(25),3,5,16(23),17,19(22)-heptaen-9-one

228

To a solution of (5-bromo-3-pyridyl)methyl 3-((1-te trahydropyran-2-ylindazol-5yl)oxymethyl]pyiTolidïne-l-carboxyiate 117 (0.530 g, 1.03 mmol) în toluene (60 mL) was added potassium acetate (0.202 g, 2.06 mmol) at room température. The mixture was degassed by bubbling nitrogen for 15 minutes, then, palladium acetate (0.047 g, 0.21 mmol,) and tricyclohexylphosphine (0.059 g, 0.21 mmol) were added. The mixture was heated under microwave conditions at 150 °C for i hour and 30 minutes. The reaction mixture was filtered over celite, concentrated under reduced pressure, diluted with DCM, extracted with water, dried over anhydrous magnésium sulfate, filtered and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (DCM/MeOH ; from 10/0 to 9/1) to afford 20-(oxan-2-yl)-8,15-dioxa-4,10,20,21 -tetraazapentacyclo[14.5.2.1²AI ⁱ⁰’¹³.O^l9’²²]pentacosa1(21),2(25),3,5,16(23),17,19(22)-heptaen-9-one 118 as a colorless oil.

LCMS method F: [M+H]⁺ = 435.3, t_R = 2.48 min

Préparation of Example 98: 8,15-dioxa-4,10,20,21-tetraazapentacyclo (14.5.2. l^2,6.l¹⁰’^I3.0^19,22]pentacosa-l (21),2(25),3,5,16(23),17,19(22)-heptaen-9-one

To a solution of 20-(o xan-2-y 1)-8,15-dioxa-4,10,20,21-tetraazapentacy cio

[14.5.2.1²A1^10,13.0’⁹-²²]pentacosa-l (21 ),2(25),3,5,16(23), 17,19(22)-heptaen-9-one 118 (0.043 g, 0.10 mmol) in DCM (8 mL) was added trifluoroacetic acid (0.15 mL, 2.00 mmol). The mixture was heated under microwave conditions at 80 °C for I hour. More trifluoroacetic acid (0.3 mL, 4.00 mmol) was added. The mixture was heated under microwave conditions at 90 °C

229 for 2 more hours. The solvent was evaporated under reduced pressure to give a yellow oily residue. The residue was recrystallized in DCM, filtered and dried under reduced pressure to affo rd 8,15 -dioxa-4,10,20,21 -tetraazapentacyc lo [ 14.5.2.1^2,6.1^{1 13}.0^19,22]pentacosa-1 (21 ),2 (2 5), 3,5,16(23), 17,19(22)-heptaen-9-one example 98 as a slightly brown beige solid.

LCMS method F: [M+H]⁺ = 351.2, t_R = 1.75 min

LCMS method G: [M+H]⁺ = 351.2, t_R = 1.96 min

The NMR showed a mixture of rotamers, reported as rot.l and rot.2 in the NMR description below.

Ή NMR (400 MHz, t76-DMSO) δ 13.33 (0.7H, rot.l, br. s), 13.30 (0.3H, rot.2, br. s), 8.95 10 (0.7H, rot.l, s), 8.89 (0.3H, rot.2, s), 8.60 (0.3H, rot.2, s), 8.56 (0.7H, rot.l, s), 8.29 (0.7H, rot. 1, s), 8.26 (0.3H, rot.2, s), 7.52 (0.7H, rot. 1, d, J = 9.4 Hz), 7.51 (0.3H, rot.2, d. J = 9.4 Hz), 7.23 - 7.05 (2H, rot.l + rot.2, m), 5.75 (0.7H, rot.l, d, J = 13.6 Hz), 5.67 (0.3H, rot.2, d, J = 14.0 Hz), 5.04 (0.7H, rot.l, d, J = 13.6 Hz), 5.02 (0.3H, rot.2, d, J = 13.6 Hz), 4.27 -4.20 (IH, rot.l + rot.2,m), 4.15-4.01 (IH, rot.l + rot.2, m), 3.89 (IH, rot.l + rot.2, t, J = !2.4Hz),3.72 15 -3.61 (IH,rot.l + rot.2, m), 3.57 - 3.47 (2H, rot.l + rot.2, m), 2.80 - 2.70 (IH, rot.l + rot.2,

m), 2.16- 1.98 (1 H, rot.l + rot.2, m), 1.74- 1.64 (IH, rot.l + rot.2, m) ppm.

Example 99: 8,14-dioxa-5,10,19,20-tetraazatetracyclo[l 3.5.2. l^2,5.0^18,21]trîcosa20 1(20),2(23),3,15(22),16,18(2 l)-hexaen-9-one

Example 99 is prepared according to the synthesis route described in general Scheme J.

Préparation of intermediate 119: 5-(benzyloxy)-3-iodo-l-(oxan-2-yl)-lH-indazole

230

To a solution of 3-iodo-]-(oxan-2-yl)-lH-indazol-5-ol (3.442 g, 10.0 mmol) in acetonitrile (100 mL) were added at RT césium carbonate (4.235 g, 13.0 mmol) and benzyl bromide (1.308 mL,

11.0 mmol). The resulting reaction mixture was stirred at RT ovemight. The réaction mixture was concentrated under reduced pressure. The residue was diluted with water and brine 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 triturated în acetonitrile and fïltered affording 5-(benzyloxy)-3-iodo-l -(oxan-2-yl)-l H-indazole 119 as a white solid.

LCMS method F: [M+Hf = 435.1, t_R = 3.33 min

Préparation of intermediate 120: S-(benzyloxy)-l-(oxan-2-yl)-3-(lH-pyrrol-3-yl)-lHindazole

To a solution of 5-(benzyloxy)-3-iodo-]-(oxan-2-yl)-IH-indazole 119 (1.000 g, 2.3 mmol) in 15 dioxane (6.9 mL) and water (2.3 mL) was added at RT 3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-lH-pyrrole (0.534 g, 2.76 mmol), K₃PO₄ (1.466 g, 6.91 mmol), XPhos (0.1 10 g, 0.23 mmol) and Pd(PPh₃)₄ (0.133 g, 0.12 mmol). The resulting reaction mixture was stirred under microwave conditions at 120°C for Ih. The residue was diluted with brine and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous 20 sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column (25g silica Macherey Nagel) chromatography (cyclohexane - ethyl acetate, 1:0 to 6:4) affording 5-(benzyloxy)-l-(oxan-2-y 1)-3-(lH-pyrrol-3-yl)-l H-indazole 120 as a yellow oil. LCMS method F: [M+Hf = 374.2, t_R = 2.95 min

H-pyrrol-3-yl) -l-(oxan-2-yl)-1 H-indazole

Préparation of intermediate 121: 5-(benzyloxy)-3-(l-{2-[(tert-butyldimethylsilyl)oxy]ethyl}~

231

To a solution of 5-(benzyloxy)-1-(oxan-2-y 1)-3-( lH-pyrrol-3-yI)-lH-indazole 120 (0.740 g, 1.98 mmol) in XjV-dimethyl formant ide (8 mL) at 0°C was added portion wise NaH (0.119 g, 2.97 mmol). After 20 min (2-bromoethoxy)(tert-butyl)dimethylsiiane (0.850 mL, 3.96 mmol) 5 in MN-dimethylformamide (2 mL) w^ras added dropwise at 0°C. The resulting reaction mixture was stirred at 0°C for 10 min and at RT for 2h. The reaction mixture was quenched by addition of MeOH and it was concentrated under reduced pressure. The residue was diluted with brine 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 flash10 column (25g silica Macherey Nagel) chromatography (cyclohexane - ethyl acetate, 1:0 to 9:1) afford i ng 5 -(benzy loxy )-3-( 1 - {2 -[(tert-buty Id imethy I s i ly l)oxy ]ethy I} -1H -py rro 1 -3 - y 1 ) -1 (oxan-2-yl)-lH-indazole 121 as a yellow oil.

LCMS method F: [M+H]⁺ = 532.4, t_R = 3.80 min

Préparation of intermediate 122: 3-(l-{2-[(tert-butyIdimethylsilyl)oxy]ethyl}-lH-pyrrol-3yl)-l-(oxan-2-yl)-IH-indazol-5~oi

232

To a solution of 5-(benzyloxy)-3-(l-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-lH-pyrrol-3-yl)-l(oxan-2-yl)-lH-indazole 121 (0.900 g, 1.69 mmol) in EtOH (15 mL) was added at RT palladium 10% on carbon (90 mg). The reaction mixture was stirred under hydrogen atmosphère at RT overnight. The reaction mixture was filtered and the filtrate was concentrated 5 under reduced pressure. The residue was purified by flash-column (25g silica Macherey Nagel) chromatography (cyclohexane - ethyl acetate, 1:0 to 8:2) affording 3-(l-{2-[(tertbutyldîmethylsilyl)oxy]ethyl}-l H-pyrrol-3-yl)-l-(oxan-2-yl)-l H-indazol-5-ol 122 as a colorless oil.

LCMS method F: [M+Hf = 442.2, tu = 3.27 min

Préparation of intermediate 123: benzyl N-(3-{[3-(l-{2-[(tert-butyldimethylsilyl)oxy]ethyl}1 H-pyrrol-3-yl)-l-(oxan-2-yl)-l H-indazol~5-yl]oxy}propyl)carbamate

To a solution of 3-(l-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-lH-pyrrol-3-yl)-l-(oxan-2-yl)15 lH-indazol-5-ol 122 (0.310 g, 0.70 mmol) în acetonitrile (5 mL) were added at RT césium carbonate (0.297 g, 0.91 mmol) and benzyl N-(3-bromopropyl)carbamate (0.150 mL, 0.77 mmol). The resulting reaction mixture was stirred at RT overnight. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and brine and extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous 20 sodium sulfate and concentrated under reduced pressure affording benzyl N-(3-{[3-( 1 -{2-[(tertbutyldimethylsilyl)oxy]ethyl}-lH-pyrrol-3-yl)-l-(oxan-2-yl)-l H-indazol-5-yl]oxy} propyl) carbamate 123 as a yellow oil. The product was used in the next step without further purification.

LCMS method F: [M+H]⁺ = 633.3, t_R = 3.64 min

233

Préparation of intermediate 124: benzyl N-[3-({3-[l~(2-hydroxyethyl)-lH-pyrrol-3-yl]-l(oxan-2-yl)-lH-indazol-5~yl}oxy)propyqcarbamate

To a solution of benzyl N-(3-{[3-(l-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-lH-pyriOl-3-yl)-I(oxan-2-yl)-lH-indazol-5-yl]oxy}propyl)carbamate 123 (0.444 g, 0.70 mmol) in THF (5 mL) was added at RT tetrabutylammonium fluoride IM in THF (1.4 mL, 1.40 mmol). The resulting reaction mixture was stirred at RT for 2h. The reaction mixture was diluted with brine and extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flashcol umn (15g silica Macherey Nagel) chromatography (cyclohexane - ethyl acetate 3 / EtOH 1, 1:0 to 7:3) affording benzyl N-[3-({3-[l-(2-hydroxyethyl)-lH-pyrrol-3-yl]-l-(oxan-2-yl)-lHindazo 1-5-yi}oxy)propyl]carbamate 124 as a colorless oil.

LCMS method F: [M+H]⁺ = 519.2, t_R = 2.72 min

Préparation of intermediate 125: 19-(oxan-2-yl)-8,14-dioxa-5,10,19,20-tetraazatetracyclo [13.5.2.1^{2 5}.0^,s’²⁾[tricosa-l (20),2(23),3,15(22), 16,18(21)-h exaen-9-one

To a solution of benzyl N-[3-({3-[l-(2-hydroxyethyl)-lH-pyrrol-3-yl]-l-(oxan-2-yl)-lHindazol·5-yl}oxy)propyl]carbamate 124 (0.230 g, 0.44 mmol) in anhydrous acetonitrile (88 mL) was added at RT césium carbonate (0.867 g, 2.66 mmol). The resulting reaction mixture was stirred at 90°C for 48h. The reaction mixture was filtered and the filtrate was concentrated

234 under reduced pressure. The residue was purified by flash-column (15g silica Macherey Nagel) chromatography (cyclohexane - ethyl acetate 3 / EtOH 1, 1:0 to 8:2) affording 19-(oxan-2-yl)8,14-4^3-5,10,19,20-161183781611-305^10(13.5.2.1^.0¹⁸² ^11-10033-1(20),2(23),3,15(22), 16,18(21 )-hexaen-9-one 125 as a coloriess oîl.

LCMS method F: [M+H]⁺ = 411.2, t_R = 2.42 min

Préparation of Example 99: 8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1²’⁵.0¹⁸’²¹) tricosa-l(20),2(23),3,15(22),16,18(2 l)-hexaen-9-one

To a solution of l9-(oxan-2-yl)-8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1²’⁵.0¹⁸’²¹] tricosa-1 (20),2(23),3,15(22),16,1 8(21 )-hexaen-9-one 125 (0.100 g, 0.24 mmol) in DCM (3 mL) was added at RT TFA (0.363 mL, 4.87 mmol). The resulting reaction mixture was stirred under microwave conditions at 80°C for 20 min. The réaction mixture was concentrated under reduced pressure, diluted with a saturated sodium bicarbonate solution and extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash-column (15g silica Macherey Nagel) chromatography (cyclohexane - ethyl acetate 3 / EtOH 1, 1:0 to 7:3) to give the product with some impurities. The product was purified twice by flash-column (2*4g silica Macherey Nagel) chromatography (DCM - MeOH, 1:0 to 98:2) to give a solid (10 mg), which was trîturated in diisopropyl ether and filtered affording 8,14-dioxa-5,10,19,20tetraazatetracyclo [ 13.5.2. l²’⁵.0'^8,2']tricosa-l (20),2(23),3,15(22),16,18(21 )-hexaen-9-one example 99 as a cream solid.

LCMS method F; [M+H]⁺ = 327.2, t_R = 1.82 min

LCMS method G: [M+H]⁺ = 327.3, t_R = i .90 min ^UH NMR (400 MHz, ί/6-DMSO) δ 12.56 (1 H, s); 7.90 - 7.86 (IH, m), 7.39 - 7.36 (IH, m), 7.26 - 7.24 (IH, m), 7.15 (IH, d, J = 1.9 Hz), 6.92 - 6.87 (2H, m), 6.39 (IH, dd, J = 1.7, 2.5 Hz), 4.35 - 4.23 (6H, m), 3.18-3.11 (2H, m), 1.92- 1.83 (2H, m) ppm.

235

Example 100: (13R) or (13S)-4-fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo

I13.5.2.1²’⁶.0¹⁸’³¹]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

Example 100 is prepared according to the synthesis route described in general Scheme C and 5 by chiral S FC séparation of example 71 togive (13R) or (13S)-4-fluoro-l 3-methy 1-8,14-dioxa10,19,20-triazatetracyclo[13.5.2.1^2,6.0^i8,21]tricosa-l(20),2(23),3,5,15(22),16,18(21 )-heptaen-9one example 100.

LCMS method F: [M+H]⁺ = 356.2, t_R = 2.46 min

LCMS method G: [M+H]⁺ = 356.2, t_R = 2.46 min

Ή NMR (400 MHz, ri6-DMSO) δ 13.26 (IH, s), 7.99 (IH, dd, J = 5.0, 7.3 Hz), 7.67 (IH, s), 7.61 - 7.50 (2H, m), 7.26 (IH,d, J = 1.7 Hz), 7.17 (1 H, d, J=9.5 Hz), 6.98 (IH, dd, J = 2.3, 8.9 Hz), 5.73 (IH, s), 4.89-4.83 (lH,m), 4.61 -4.54(1 H, m),3.61 - 3.58 (IH, m), 2.95 -2.87 (IH, m), 2.40-2.33 (IH, m), 1.42- 1.39 (4H, m) ppm.

Chiral HPLCe.e.>98%

Example 101: (13R) or (13S)-4-fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo

[13.5.2.1²'⁶.0^,8’²¹Jtricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

Example 101 is prepared according to the synthesis route described in general Scheme C and by chiral SFC séparation of example 71 to give (13R) or(13S)-4-fluoro-13-methyl-8,14-dioxa10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^18,21]tricosa-l(20),2(23),3,5,15(22),16,18(2l)-heptaen-9one example 101.

236

LCMS method F: [M+H]⁺ = 356.2, t_R = 2.47 min

LCMS method G: [M+H]⁺ = 356.2, t_R = 2.46 min

Ή NMR (400 MHz, rf6-DMSO) δ 13.28 - 13.26 (IH, m), 7.99 (IH, dd, J = 5.2, 6.7 Hz), 7.67 (IH, s), 7.61 - 7.50 (2H, m), 7.26 (1 H, d, J = 1.9 Hz), 7.19 - 7.15 (IH, m), 6.98 (IH, dd, J = 2.3, 5 8.9 Hz), 5.74 - 5.70 (IH, m), 4.89-4.79 (IH, m), 4.61 - 4.53 (IH, m), 3.59 (IH, s), 2.95 - 2.86 (IH, m), 2.40-2.33 (IH, m), 1.42 - 1.39 (4H, m)ppm.

Chiral HPLC e.e. >98%

The compound is a pure enantiomer, but the absolute stereochemistry of the chiral center is unknown

Example 102: (13R)-13-methy 1-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1²’⁶.0^{f 8,21} ] tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

Example 102 is prepared according to the synthesis route described in general Scheme C and by chiral HPLC purification. The chiral purification is done on a Chiralpak IB N-5 column 250x4.6mm 5 pm, eluent [C7/EtOH]+0.1%DEA [80/20], 1 mL/min RT to give (13R)-13methy 1-8,14-dioxa-4,10,19,20-tetraazatetracyclo[ 13.5.2.1²·⁶.0¹⁸’² ^tricosa-l (20),2(23),3,5, 15(22), 16,18(2 l)-heptaen-9-one example 102.

LCMS method F: (M+H]⁺ = 339, t_R = 1.80 min

LCMS method G: [M+H]⁺ = 339, t_R = 2.05 min ’H NMR (400 MHz, r/6-DMSO) δ 13.32 (IH, s), 9.04 (IH, d), 8.53 (IH, d), 8.15 (1 H, m), 8.02 - 7.99 (IH, m), 7.54 (IH, d), 7.19 (IH, m), 7.01 -6.98 (IH, dd, J = 2.2, 9.0 Hz), 5.77 - 5.74 (IH, m), 4.95 - 4.92 (IH, m), 4.59 - 4.52 (IH, m), 3.60 - 3.53 (IH, m), 2.95 - 2.87 (IH, m), 2.45 25 -2.38 (IH, m), 1.41 (3H, d), 1.38- 1.34 (1 H, m) ppm.

Chiral HPLC e.e. >99%

237

Example Î03: 6-cyclopropyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1²’⁵.0¹⁸’^2,] tricosa-l(20),2(23),3,15(22),16,18(21)-hexaen-9-one

Example 103 is prepared according to the synthesis route described in general Scheme B.

Préparation of intermediate 126: ethyl 2-(4-bromopyrazol-l -yl)-2-cyclopropyl-acetate

To a solution of 4-bromo-lH-pyrazole (588 mg, 4 mmol) în N,A-dimethyIformamide (2 mL) were added ethyl 2-bromo-2-cyclopropyl-acetate (1 g, 4.8 mmol), and potassium carbonate 10 ( 1.1 1 g, 8 mmol). The mixture was stirred for 4 hours at 80 °C. The reaction was quenched with water (15 mL) and the resulting solution was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl 2-(4-bromopyrazol-l-yl)-2-cyclopropylacetate 126 as a yellow liquid. The crude was used in the next step without any purification.

LCMS method F: [M+H]⁺ = 274, t_R = 2.53 min

Préparation of intermediate 127: ethyl 2-(4-(5-(tert-butyl(dimethyl)silyl]oxy-ltetrahydropyran-2-yl-indazol-3-yllpyrazol-l-yl]-2-cyclopropyl-acetate

238

To a solution of [5-[tert-buty l(dî methy 1 )si ly l]oxy-1-tetrahydropy ran-2-yl-indazo 1-3-y 1] boronic acid 18 (1.63 g, 4.35 mmol), ethyl 2-(4-bromopyrazol-l-yl)-2-cyclopropyl-acetate 126 (700 mg, 2.56 mmol), tripotassium phosphate (1.63 g, 7.68 mmol) in dioxane (7.7 mL) and water (2.6 mL) were added XPhos (122 mg, 0.25 mmol) and tetrakis(triphenylphosphine)palladium(0) (147 mg, 0.13 mmol). The reaction mixture was heated at 100°C under microwave conditions for 1 hour and 30 minutes. The reaction mixture was filtered over celite and the celite was washed with EtOAc. The fïltrate was then diluted with water and extracted with EtOAc (3 x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column (Macherey Nagel, 40 g) chromatography with cyclohexane/EtOAc (100/0 to 80/20) as eluent. The desired fractions were combined and evaporated under reduced pressure to give ethyl 2-[4-[5-[tert-butyl(dimethyl)silyl]oxy-ltetrahydropyran-2-yl-indazol-3-yl]pyrazol-l -yl]-2-cycîopropyl-acetate 127 as a yellow oil.

LCMS method F: [M+H]⁺ = 525, t_R = 3.76 min

Préparation of intermediate 128: ethyl 2-cyclopropyl-2-[4-(5-hydroxy-l-tetrahydropyran -2yl-mdazol-3-yl)pyrazol-l-yl}acetate

239

To a solution of ethyl 2-[4-[5-[tert-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3yl]pyrazol-l-yl]-2-cyclopropyl-acetate 127 (238 mg, 0.45 mmol) in THF (1.8 mL) was added dropwise at room température tetrabutylammonium fluoride IM in THF (0.5 mL, 0.5 mmol). The resulting reaction mixture was stirred at room température ovemight. The reaction mixture 5 was poured into ice water and stirred for 20 min. The aqueous phase was extracted twice with

EtOAc and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give ethyl 2-cyclopropy 1-2-[4-( 5-hydroxy l-tetrahydropyran-2-yl-indazol-3-yl)pyrazol-l-yl]acetate 128 as an orange solid.

LCMS method F: [M+Hf = 411, t_R = 2.53 min

Préparation of intermediate 129: ethyl 2-[4-[5-[3-(benzyloxycarbonylamino)propoxy]-ltetrahydropyran-2-yl-indazol-3-ylfpyrazol-l-yl]-2-cyclopropyl-acetate

To a solution of ethyl 2-cyclopropyl-2-[4-(5-hydroxy-l-tetrahydropyran-2-yl-indazol-315 yl)pyrazol-l-yl]acetate 128 (232 mg, 0.57 mmol,) in acetonitrile (6 mL), were added césium carbonate (370 mg, 1.14 mmol) and benzyl N-(3-bromopropyl)carbamate (169 mg, 0.62 mmol). The mixture was stirred at room température ovemight. The réaction mixture was fïltered and rinsed with EtOAc. Water was added and the water layer was extracted with EtOAc (3 x). The combined organic layers were washed with brine, dried over sodium sulfate, fïltered and 20 concentrated under reduced pressure to afford ethyl 2-[4-[5-[3-(benzyloxycarbonyl amino)propoxy]-l -tetrahydropyran-2-yl-îndazol-3-yl]pyrazol-l-yl]-2-cyclopropyl-acetate 129 as a brown oil.

LCMS method F: [M+Hf = 602, t_R = 3.18 min

4-yl]-l-tetrahydropyran-2-yl-indazol-5-ylJoxypropyl]carbamate

Préparation of intermediate 130: benzyl N-[3-[3-[l-(l-cyclopropyl-2-hydroxy-ethyl)pyrazol21105

240

A solution of ethyl 2-[4-[5-[3-(benzyloxycarbonylamino)propoxy]-l-tetrahydropyran-2-ylindazol-3-yl]pyrazol-l-yl]-2-cyclopropyl-acetate 129 (324 mg, 0.54 mmol) in THF (2.3 mL) was degassed with N₂ during 10 minutes, LAH 1 M in THF (0.65 mL, 0.65 mmol) was added 5 at 0°C and the reaction was stirred at 0°C for 2 hours and 30 minutes. The mixture was quenched with water (0.2 mL), 10% NaOH (0.2 mL) and water (0.2 mL). The mixture was filtered with EtOAc as eluent. The filtrate was diluted with water and extracted with EtOAc (3 x). The combined organic layers were washed with brine, dried with anhydrous sodium sulfate and the solvent was removed under reduced pressure to afford benzyl N-[3-[3-[l-(l-cyclopropyl-210 hydroxy-ethyl)pyrazol-4-yl]-1 -tetrahydropyran-2-y!-indazol-5-yl]oxypropyl]carbamate 130 as a coîorless oil.

LCMS method F: [M+H]⁺ = 560, îr = 2.76 min

Préparation of intermediate 131: 6-cyclopropyl-l 9-(oxan-2-yi)-8,14-dioxa-4,5,10,19,2015 pentaazatetracyclo[13.5.2A²f0^1s’^2t]tricosa-l(20),2(23),3,15(22),16,18(21)-hexaen-9-on^

A suspension of benzyl N-[3-[3-[l-(1-cyclopropyl^-hydiOxy-ethyljpyrazoM-ylJ-ltetrahydropyranU-yl-indazol-ï-yljoxypropyllcarbamate 130 (112 mg, 0.2 mmol) and césium carbonate (390 mg, 1.2 mmol) in acetonitrîle (44 mL) was heated to 80°C for 5 hours. The reaction mixture was filtered ai 80°C, cooled to room température and concentrated under

241 reduced pressure. The crude was purified by column (Macherey Nagel, 15 g) chromatography with DCM/MeOH (100/0 to 97/3) as eluent. The desired fractions were combined and the solvent was removed under reduced pressure to give 6-cyclopropyl-19-(oxan-2-yl)-8,14-dioxa4,5,10,19,20-pentaazatetracyclo[13.5.2. PAO^18,2’ ]tricosa-1(20),2(23),3,15(22), 16,18(21)hexaen-9-one 131 as a colorless solid.

LCMS method F: (M+H]⁺ = 452, t_R = 2.47 min

Préparation of Example 103: 6-cyclopropyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo |13.5.2.1²A0^l8’²¹]tricosa-l(20),2(23),3,15(22), 16,18(2 l)-hexaen-9-one

To a solution of 6-cyclopropyl-19-(oxan-2-yl)-8,14-dioxa-4,5,10,19,20pentaazatetracyclo[ 13.5.2.1²Αθ’^8,2 'jtricosa-1(20),2(23), 3,15(22), 16,18(21 )-hexaen-9-one 131 (46 mg, 0.1 mmol) in DCM (1 1 mL) was added trifluoro acetic acid (0.16 mL, 2.03 mmol). The mixture was heated at 80°C under microwave conditions for 1 hour. The reaction mixture was diluted with DCM (25 mL) and a saturated sodium bicarbonate solution (25 mL). After séparation, the aqueous layer was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by column (Macherey Nagel, 15 g) chromatography with DCM/EtOAc (100/0 to 25/75) as eluent. The desired fractions were combined and the solvent was removed under reduced pressure to afford 6-cyclopropyl-8,14dioxa-4,5,10,19,20-pentaazatetracyclo[l 3.5.2. l²A0^,8,2l]tricosa-1(20),2(23),3,15(22), 16,18(21 )-hexaen-9-one example 103 as a white solid.

LCMS method F: [M+H]⁺ = 368, t_R = 2.02 min

LCMS method G: [M+H]⁺ = 368, t_R = 2.03 min

Ή NMR (400 MHz, ri6-DMSO) δ 12.80 (IH, s), 8.17 (IH, s), 7.82 (IH, dd, J = 4.6, 7.3 Hz), 7.75 (IH, s), 7.42 (IH, d, J = 9 Hz), 7.09 (IH, d, J = 2.3 Hz), 6.94 (IH, dd, J = 2.3, 8.9 Hz), 4.55 (1H, dd, J = 2.5, 11.6 Hz), 4.40 (1 H, m), 4.23 (2H, m), 3.90 (IH, m), 2.89 ( 1 H, m), 1.85

242

(2H, m), 1.58 (IH, m), 0.67 (iH, m), 0.55 (2H, m), 0.44 (1 H, m) ppm. One proton was located under the residual water peak and was not reported here.

Example 104: 7-ethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1^2,6.0¹⁸'²¹]tricosa1(20),2,4,6(23),15,17,2 l-heptaen-9-one

Example 104 is prepared according to the synthesis route described in general Scheme G.

Préparation of intermediate 132: 1-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl] propan-l-one

To a mixture of l-(3-bromophenyl)propan-l -one (2 g, 9.4 mmol) in dioxane (30 mL) was added 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l ,3,2-dioxaborolane (2.63 g, 10.3 mmol), Pdîdbaj (431 mg, 0.471 mmol), KOAc (1.48 g, 15 mmol) and tricyclohexylphosphine (264 mg, 0.94 mmol). The reaction mixture was stirred at 100°C for 2 h. The solvent was removed under reduced pressure,then it was dissolved în EtOAc and washed with water (x3). The organic layer was filtered on a Guanidine(SPE) pad. Then the solvant was removed under reduced pressure to give 1 -[3-(4,4,5,5-tetramethy 1-1,3,2-dioxaborolan-2-yl)phenyi]propan-l20 one 132 as a yellow oil.

LCMS method F: [M+H]⁺= 261, t_R = 2.99 min

Préparation of example 104: 7-ethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²A0¹⁸’²¹] tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

243

To a solution of 7-ethyl-I9-(oxan-2-y 1)-8,14-dioxa-l0,19,20-triazatetracyclo [13.5.2. l^2,6.0^1S’²¹] tricosa-1 (20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one 124 (220 mg, 0.51 mmol) in DCM (10 mL) was added trifluoroacetic acid (775 pL, 10.11 mmol). Stirred at 50°C during 2h. The 5 reaction mixture was diluted with EtOAc (30 mL) and water (20 mL) After séparation, the aqueous layer was extracted with EtOAc (3x10 mL). The combined organic layers were washed with saturated sodium carbonate aqueous solution (30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate anhydrous, filtered off and concentrated to dryness. The oil was triturated in DCM and the solid was filtered and dried under reduced pressure to 10 give 7-ethy 1-8,14-dioxa-l 0,19,20-triazatetracyclo[ 13.5.2.1^2,6.0^18,2'ftricosa-l^O),2,4,6(23), 15, 17,21-heptaen-9-one 104 as a white powder.

LCMS method F: [M+H]* = 352.2, t_R = 2.41 min (current 20V)

LCMS method G: [M+H]⁺ = 352.2, t_R = 2.38 min (pHIO current 20V)

Ή NMR (400 MHz, c/6-DMSO) δ 7.96 (IH, dd, J = 4.7, 7.6 Hz), 7.85 - 7.80 (2H, m), 7.50 15 7.45 (2H, m), 7.37 - 7.28 (2H, m), 6.99 (IH, dd, J = 2.3, 8.9 Hz), 5.68 (IH, dd, J = 3.6, 8.5

Hz),4.41 - 4.2] (2H, m), 3.56 - 3.49 (IH, m), 2.78 - 2.67 (IH, m), 2.23 - 2.15 (IH, m), 2.10 2.01 (IH, m), 1.89- 1.69 (2H,m), 1.00 (3H, t, J = 7.3 Hz) ppm.

Example 105:

(13R)-13-methyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo

[13.5.2.1²’⁶.0^ls’²']tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Example 105 is prepared according to the synthesis route described in general Scheme B.

244

To a solution of (l3R)-l3-methyl-l9-(oxan-2-yl)-8,l4-dioxa-5,l0,l9,20,23pentaazatetracycio[l3.5.2.l²’⁶.0^IS’^2,]tricosa-l(20),2,4,6(23)_!15,17,2I-heptaen-9-one (100 mg,

0.24 mmol) in DCM (2 mL) was added trifluoroacetic acid (362 pL, 4.73 mmol). The mixture was heated under microwaves irradiation at 80 °C for 45 min. The reaction mixture was diluted with DCM (25 mL) and saturated NaHCO₃ (25 mL). A yellow precipitate was appeared and filtered to afford, after dried under vacuum at 60 °C for 12 hours (13R)-13-methyl-8,14-dioxa5,l0,19,20,23-pentaazatetracyclo[l3.5.2.1²’⁶.0^,8’^2,]tricosa-l(20),2,4,6(23),15,17,2l-heptaen-9one example 105 as a yellow solid.

LCMS method F: [M+H]⁺ = 340, t_R = 2.00 min

LCMS method G: [M+H]⁺ = 340, t_R = 2.02 min

Ή NMR (400 MHz, ί/6-DMSO) δ 13.68 - 13.67 (IH, m), 8,77 - 8.74 (IH, m), 8.05 (IH, d, J = 5.3 Hz), 7.92 - 7.87 (2H, m), 7.55 - 7.52 (IH, m), 7.00 (IH, dd, J = 2.3, 9.1 Hz), 5.61 - 5.55 (IH, m), 5.03 - 4.97 (1 H, m), 4.61 (1 H, t, J = 6.8 Hz), 3.50 (IH, m), 2.94 - 2.86 (IH, m), 2.38 2.31 (lH,m), 1.42 - 1.38 (4H, m) ppm.

Example 106: (7R,13R)-4-fluoro-7,13-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo

I13.5.2.1²⁰.0¹⁸’²¹]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Exampîe 106 is prepared according to the synthesis route described in general Scheme C.

Préparation of intermediate 133: (lR)-l-[3-fluoro-5-(4,4,5,5-tetramethyl-l ,3,2dioxaborolan-2-yl)phenyl]ethan-l-ol

245

To a degassed solution of (lR)-l-(3-bromo-5-fluorophenyl)ethan-I-ol (0.500 g, 2.28 mmol) in dioxane (3 mL) was added at RT bis(pinacolato)diboron (0.695 g, 2.74 mmol), KOAc (0.672 g, 6.85 mmol) and PdCh(dppf) DCM (0.093 g, 0.I l mmol). The resulting reaction mixture was stirred under microwave irradiation at l00°C for 2 h. The residue was fîltered on celite, diluted with water and extracted with ethyl acetate twice. The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo affording (IR)-l-[3-fluoro-5-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]ethan-l -ol 133 as a black oil, used without further purification in the next step.

LCMS method F: [M-H₂O+H]⁺ = 249.1, t_R = 2.68 min

Préparation of Example 106: (7R,13R)-4-fluoro-7,13-dîmethyl-8,14-dîoxa-10,19,20triazatetracyclo[13.5.2.1²’^fi.0¹⁸'²¹]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

To a solution of (7R,13R)-4-fluoro-7,B-dimethyl-l9-(oxan-2-yl)-8,14-dioxa-10,19,2015 triazatetracyclof 13.5.2.1^.0^18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one (0.530 g, 1.17 mmol) in DCM (10 mL) was added at RT TFA (1.740 mL, 23.37 mmol). The resulting reaction mixture was stirred under micro wave irradiation at 80°C for 1 h. The reaction mixture was concentrated in vacuo, diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate twice. The combined organic layer was dried over anhydrous sodium sulfate and 20 concentrated in vacuo. The residue was purified by flash-column (15g silica Macherey Nagel) chromatography (cyclohexane - ethyl acetate 3 / EtOH I, 1:0 to 6:4) to give a solid (0.380 g), which was triturated in acetonitrile and fîltered affording (7R,13R)-4-fluoro-7,13-dimethyl8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1²’⁶.0'^{8,2 l}]tricosa-1(20),2,4,6(23), 15,17,21 heptaen-9-one example 106 as a white solid.

LCMS method F: [M+H]⁺ = 370.1, [M-H]- = 368.3, tR = 2.51 min LCMS method G: [M+H]⁺ = 370.2, [M-H]- = 368.4, tR = 2.58 min Ή NMR (400 MHz, ί/6-DMSO, 80°C) δ 13.22- 13.20(1 H, m), 7.78 (1 H, dd, J = 4.6, 8.0 Hz), 7.65 (IH, d, J = 0.8 Hz), 7.52 - 7.44 (2H, m), 7.23 - 7.19 (2H, m), 7.00 - 6.96 (LH, m), 5.88

246 (EH, q, J = 6.6 Hz), 4.65 - 4.57 (iH, m), 3.24 - 3.17 (1 H, m), 3.10 - 3.04 (IH, m), 1.83 (IH, dd,

J = 8.4, 13.1 Hz), 1.72- 1.64 (EH, m), 1.62 (3H, d, J = 6.6 Hz), 1.38 - 1.35 (3H, m) ppm.

⁵ Example 107: 7-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹]tricosa-

1(20),2,4,6(23),15,17,2 l-heptaen-9-one

Example 107 is prepared according to the synthesis route described in general Scheme H.

To a solution of 7-methyl-19-(oxan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetracyclo [ 13.5.2.1²'⁶.0^{I8 2,}Jtricosa-l (20),2,4,6(23), 15,17,21-heptaen-9-one (32 mg, 0.076 mmol, 1 eq) in DCM ( 1.8 mL) was added trifluoroacetic acid (233 pL, 3.040 mmol, 40 eq) at RT. The solution was heated under microwave conditions at 80°C for 2 h 40 min. The reaction mixture (brown solution) was evaporated under vacuo, the brown residue was dissolved in EtOAc then a saturated aqueous solution of sodium hydrogen carbonate was added. After séparation, the aqueous layer was extracted with ethyl acetate (2 x). The combined organic layer was washed with water then brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to give an orange oil. The crude product was purified by column chromatography eluting with Cyclohexane / Ethyl acetate - EtOH (3-1), 100/0 to 60/40 to give the expected product. Et was triturated from diisopropyl ether and dîrectly transferred into the brown vial (without filtration due to the low mass), dried under vacuo to give 7-methy 1-8,14-dioxa-4,10,19,20tetraazatetracyclo[ 13.5.2. l²’⁶.0'^8,21 Jtrîcosa-1 (20),2,4,6(23),15,17,21 -heptaen-9-one example

107 as a white solid.

LCMS method F: [M+H]⁺ = 339, t_R = 1.69 min

LCMS method G: [M+H]⁺ = 339, t_R = i .98 min

Ή NMR (400 MHz, rf6-DMSO) δ 13.33 (IH, s), 9.03 (IH, d), 8.57(1 H, d), 8.15 (lH,m),8.04 -8.01 (IH, m), 7.55 - 7.53 (IH, d), 7.28 (IH, m), 7.03-7.01 (IH, dd), 5.98 - 5.93 (IH, q), 4.37 - 4.27 (2H, m), 3.55 - 3.48 (1 H, m), 2.80 - 2.71 (IH, m), 2.23-2.14 (1 H, m), 1.78- 1.70 (IH, m), 1.65 (3H, d) ppm.

247

Example 108: (7R)- or (7S)-4-fluoro-7-methy 1-8,14-dioxa-1 0,19,20-triazatetracyclo

[ 13.5.2. PAO^18,21 ] tricosa-1 (20),2,4,6(23),15,17,21-heptaen-9-one

Example 108 is prepared according to the synthesis route described in general Scheme A and by chiral SFC séparation to give (7R)- or (7S)-4-fluoro-7-methyl-8,14-dioxa-10,19,20triazatetracyclo[ 13,5.2. PAO^18,21 ]tricosa-1(20),2,4,6(23),15,17,21 -heptaen-9-one example 108. LCMS method F: [M+H]+ = 356, t_R = 2.39 min

LCMS method G: [M+H]⁺ = 356, t_R = 2.42 min 'HNMR (400 MHz, d/6-DMSO) δ 13.28 (IH, s), 8.01 -7.97(1 H, m), 7.69 (1 H, s), 7.59 - 7.56 (IH, m), 7.53 - 7.50 (IH, m), 7,33 (IH, d), 7.21 -7.18 (IH, m), 7.02-6.99 (IH, dd), 5.91 5,86 (1 H, q), 4.37 - 4.26 (2H, m), 3.55 - 3.49 (IH, m), 2.78 - 2.71 (IH, m), 2.23 - 2.14 (IH. m), 1.78 - 1.70 ( 1 H, m), 1.59 (3H, d) ppm.

Chiral HPLC : ee > 97.5 %

Example 109: (7R)- or (7S)-4-fluoro-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo

[13.5.2.PA0¹⁸²¹]tricosa-l(20),2,4,6(23),15,17,2ï-heptaen-9-one

248

Example 109 is prepared according to the synthesis route described in générai Scheme A and by chiral SFC séparation to give (7R)- or (7S)-4-fluoro-7-methyl-8,14-dioxa-î 0,19,20triazatetracyclo! 13.5.2.1⁸·²']tricosa-1(20),2,4,6(23), 15,17,21-heptaen-9-one example 109. LCMS method F: [M+H]* = 356, t_R = 2.39 min

LCMS method G: [M+H]* = 356, t_R = 2.41 min

Ή NMR (400 MHz, ί/6-DMSO) Ô 13.27 (! El, s), 8.01-7.98 (IH, m), 7.69 (IH, s), 7.59 - 7.56 (IH, m), 7.53-7.51 (IH, m), 7.33 (IH, d), 7.21 - 7.18 (IH, m), 7.01 -6.99 (IH, dd), 5.91 5.86 (1 H, q), 4.37 - 4.24 (2H, m), 3.56 - 3.49 (IH, m), 2.78 - 2.71 (IH, m), 2.23 - 2.14 (IH, m), 1.78 - 1.70 ( 1 H, m), 1.59 (3H, d) ppm.

Chiral HPLC : ee > 98.0 %

Example 110: 6-m ethy 1-8,14-dioxa-4,5,10,19,20-pentaazatetracy cio [13.5.2.1^.0^{18,2 l}] tricosa-1(20),2(23),3,15,17,21-hexaen-9-on e

Example 110 îs prepared according to the synthesis route described in general Scheme B.

Préparation of intermediate 134: ethyl 2-(4-bromopyrazol-l-yl)propanoate

O f < /-O N-N ' V Br

A suspension of 4-bromo-l H-pyrazoîe (2.00 g, 13.60 mmol), ethyl 2-bromopropanoate (2.1 mL, 16.32 mmol), and potassium carbonate (3.78 g, 27.20 mmol) in A.A-dirnethylformamide (8.0 mL) was stirred for 3 h at 80 °C. The reaction was quenched by water (30 mL), and the resulting solution was extracted twice with ethyl acetate (50 mL x 2). The combined organic

249 layers were dried over anhydrous magnésium sulfate, filtered, and concentrated under reduced pressure to give ethyl 2-(4-bromopyrazol-l-yl)propanoate 134 as a yellow oil.

Yield: 4.58 g of intermediate 134 (quantitative)

LCMS method F: [M+H]⁺ = 249, t_R = 2.29 min

Préparation of Example 110: 6-methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracycIo

[13.5.2.1²’⁵.0¹⁸’²¹]tricosa-l(20),2(23),3,15,17,21-hexaen-9-one

To a solution of 6-methyl-l9-(oxan-2-yl)-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo 10 [13.5.2.1²’⁵.0^1S’²¹]tricosa-l(20),2(23),3,15,17,21-hexaen-9-one (68 mg, 0.16 mmol) in DCM (2 mL) was added trifluoro acetic acid (245 pL, 3.20 mmol). The mixture was heated in micro waves at 80 °C for 30 min. The reaction mixture was diluted wîth DCM (25 mL) and NaHCO₃ saturated (25 mL). After séparation, aqueous layer was extracted with DCM (3 x 20 mL). The combined organic layer was washed with brine (25 mL), dried over anhydrous sodium 15 sulfate, filtered and evaporated under reduced pressure. The crude was purified by flash chromatography (DCM/MeOH 95/5) to afford 6-methyl-8,14-dioxa-4,5,10,19,20pentaazatetracyclo[13.5.2.1²’⁵.0¹⁸ⁱ²ⁱ]tricosa-l(20),2(23),3,l5,17,21-hexaen-9-one example 110 as an off-white solid.

LCMS method F: [M+H]⁺ = 342, t_R = 1.86 min

LCMS method G: [M+H]⁺ = 342, t_R = 1.89 min

H NMR (400 MHz, t/6-DMSO) δ 12.80 - 12.79 (IH, m), 8.07 (IH, s), 7.83 - 7.76 (2H, m), 7.43 - 7.40 (IH, m), 7.06 (IH, d, J = 2.1 Hz), 6.94 (IH, dd, J = 2.3, 8.9 Hz), 4.82 - 4.75 (IH, m), 4,44 - 4.15 (4H, m), 3.23 (I H, t, J = 7.1 Hz), 3.03 - 2.98 (IH, m), 1.91 - 1.82 (2H, m), 1.59 (3H,d, J = 7.0 Hz) ppm.

tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Example 111: 7-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹]

250

Example 111 is prepared according to the synthesis route described in general Scheme H using SEM as indazole protecting group.

Préparation of intermediate 135: \.-(6-bromo~2-pyridyl)ethanol

OH

Br

To a cooled solution of 6-bromopyridine-2-carbaldehyde (2.0 g, 10.81 mmol) in dry tetrahydrofuran (28 mL) was dropwise added méthylmagnésium bromide solution 3 M in diethyl ether (7.2 mL, 2 i .62 mmol) at û °C. The reaction mixture was stirred at 0 °C for 20 min 10 then allowed to reach room température for 16 hours. TLC analysis showed total consumption of starting materiai. The reaction mixture was quenched with a saturated aqueous solution of NHjCl then extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with water the brine, dried over magnésium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash-column chromatography eluting with Cyclohexane / Ethyl 15 acetate-EtOH (3-1): 100 /0 to 80/20, togive l-(6-bromo-2-pyridyl)ethanol 135 as acolorless oil.

LCMS method F: [M+H]⁺ = 202.0, t_R = 1.65 min

Préparation of Example 111: 7-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo 20 [13.5.2.1²’⁶.0^ls’²¹]tricosa-l(20),2,4,6(23),15,17_f21-heptaen-9-one

251

To a solution of 7-methy 1-20-{[2-(trimethylsilyl)ethoxy]methyl )-8,14-dioxa-10,19,20,23tetraazatetracyclo[l 3.5.2.1^.0^18,2’jtricosa-l^ 1),2(23),3,5,15(22), 16,18-heptaen-9-one (0.037 g, 0.079 mmol) in dichloroethane (2.0 mL) was added an aqueous solution of HCl (6 N, 0.15 mL, 0.95 mmol). The mixture was heated at 70 °C for 16 hours. The mixture was concentrated under reduced pressure and 1,4-dioxane (2.0 mL) and NH4OH solution (0.4 mL) were added. The mixture was heated at 75 °C for 3 hours, concentrated under reduced pressure and the residue was suspended in MeOH (0.4 mL) and filtered. The crude product was purified with two successive préparative TLC on silica gel (first using (DCM/MeOH : 95/5) as an eluent, then using Cyclohexane / EtOAc—EtOH : 4 / 6 (3-1)) to afford 7-methyl-8,14-dioxa10,19,20,23-tetraazatetracyclo) 13.5.2.1²’⁶.0^18,2 ']tricosa-1(20),2,4,6(23), 15,17,21 -heptaen-9one example 111 as a white solid.

LCMS method F: [M+H]⁺ = 339.2, t_R = 2.02 min

LCMS method G: [M+H]⁺ = 339.3, t_R = 2.07 min

Ή NMR (400 MHz, J6-DMSO) δ 13.27 (1 H, s), 8.04 (IH, d, J= 8.4 Hz), 7.88 - 7.84 (2H, m), 7.71 (IH, dd, J = 4.5, 7.7 Hz), 7.47 (IH, d, J= 8.0 Hz), 7.33 (IH, d, J = 7.2 Hz), 6.97 (IH, dd, J= 2.8, 9.6 Hz), 5.93 (IH, q, J= 6.8 Hz), 4.37 - 4.24 (2H, m), 3.52 - 3.40 (IH, rn), 2.78 - 2.67 (IH, m), 2.22-2.12(1 H, m), 1.64- 1.61 (4H, m) ppm.

Example 112: 6-(propan-2-yl)-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo fl3.5.2.1²’⁵.0^,8’²¹]tricosa-l(20),2(23),3,15(22),16,18(21)-hexaen-9-one

252

Example 112 is prepared according to the synthesis route described in general Scheme B.

Préparation of intermediate 136: ethyl 2-(4~hromopyrazol-l-yl)-3-methyl-butanoate —

N N ' V

Br

A suspension of 4-Bromo-lH-pyrazole (2.00 g, 13.60 mmol), ethyl 2-bromo-3-methylbutanoate (2.5 mL, 16.32 mmol), and potassium carbonate (3.78 g, 27.20 mmol) in N_tNdimethylformamide (4.0 mL) was stirred for 3 h at 80 °C. The reaction was quenched by water (30 mL), and the resulting solution was extracted twice with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous magnésium sulfate, filtered, and concentrated under reduced pressure to give ethyl 2-(4-bromopyrazol-1 -yl)-3-methyl-butanoate 136 as a colorless oil.

LCMS method F: [M+H]⁺ = 277.1, îr = 2.72 min

Préparation of Example 112: 6-(propan-2-yl)-8,14-dioxa-4,5,10,19,20-pentaaza tetra cyclo[ 13.5.2.l²A0^18,21]tricosa-l (20),2(23),3,15(22),16,18(2 l)-hexaen-9-one

To a solution of 19-(oxan-2-yl)-6-(propan-2-yl)-8,14-dioxa-4,5,10,I9,20-pentaazatetracyclo [13.5.2. PAO^18,21 Jtrîcosa-1(20),2(23),3,15(22),! 6,18(21)-hexaen-9-one (0.409 g, 0.90 mmol) in DCM (22 mL) was added trifluoroacetic acid ( l .37 mL, 18.0 mmol). The reaction mixture was dîrectly heated to 50 °C for 3 hours. LCMS analysis showed formation of the expected product and total consumption of starting material. The reaction mixture (brown solution) was evaporated under reduced pressure. The brown residue was dissolved in EtOAc then a saturated aqueous solution of sodium hydrogen carbonate was added. After séparation, the aqueous layer - was extracted with ethyl acetate (2 x). The combined organic layer was washed with water then

253 brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to give an orange oil. The crude product was purified by column chromatography eluting with Cyclohexane / Ethyl acetate - EtOH (3-1), 100/0 to 70/30. The pure fractions were combined and evaporated under reduced pressure. After évaporation of residual solvent, the product 5 turned out to be less soluble in DCM than before, allowing for recrystallization trials in this solvent. In order to do so, the solid (approx. 160 mg) was stirred in DCM (5 mL) for several minutes, while heating the suspension up to 40 °C. After cooling down to room température, the solid was isolated by filtration, then recovered and further dried under high vaccum at 60°C to afford 6-(propan-2-yl)-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.I ^.0^18,21 ] trie osa10 1(20),2(23),3,15(22),16,18(21 )-hexaen-9-one example 112 as a white solid.

LCMS method F: [M+H]⁺ = 370.3, t_R = 2.05 min

LCMS method G: [M+H]⁺ = 370.3, t_R = 2.12 min

Ή NMR (400 MHz, ί/6-DMSO) δ 12.80 (IH, s), 8.17 (IH, s), 7.76 - 7.75 (2H, m), 7.43 - 7.40 (IH, m), 7.09 (IH, d, J = 1.9 Hz), 6.94 (IH, dd, J = 2.3, 8.9 Hz), 4.53 (IH, dd, J = 1.6, 11.2 15 Hz), 4.43 (IH, dt, J = 4.4, 12 Hz), 4.29 -4.19 (3H, m), 3.44 - 3.35 (1 H, m), 3.30 ( 1 H, s), 2.88

-2.81 (IH, m), 1.97- 1.85 (IH, m), 1.80 - 1.75 (IH, m), 1.10 (3H, d, J= 6.6 Hz), 0.78 (3H, d, J= 6.6 Hz) ppm.

Example 113: (13R)-7,13-dimethyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo

[13.5.2.1²’^s.0¹⁸’^2Iltricosa-l(20),2(23),3,15(22),16,18(21)-hexaen-9-one

Example 113 is prepared according to the synthesis route described in general Scheme C.

5 Préparation of intermediate 13 7: 1-(4-(4_f4_f5_>5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazoll-ylJpropan-2-ol

254

HO N-N

B O' O

-nln a scelled round bottom flask, NaH (60% in minerai oil, 0.990 g, 41.24 mmol) was suspended in ΆζΝ-dimethylformamide (100.0 mL) and a solution of 4-(4,4,5,5-tetramethyl-l ,3,2dioxaborolan-2-yl)-lH-pyrazole (4.00 g, 20.62 mmol) was added. The reaction was stirred at room température for 15 minutes, then rac-propylene oxide (4.33 mL, 2.40 g, 41.24 mmol) was added. The round bottom flask containing the resulting cloudy brown solution was sealed and heated to 50°C for 4 h. LC/MS analysis indicated that the reaction was completed. Solvents were evaporated under reduced pressure to afford crude I-[4-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)pyrazol-l-yl]propan-2-ol 137 as a brown solid which was used in the next step without further purification.

LCMS method F: [M+H]⁺ = 253.2, t_R = 1.92 min

Préparation of Example 113: (13R)-7,13-dimethyl-8,14-dioxa-4,5,10,19,20-pentaazatetra cyclo[ 13.5.2.l^2,5.0¹⁸’²¹Jtrieosa-l(20),2(23), 3,15(22),16,18(21)-hexaen-9-one

To a solution of (13R)-7,13-dimethyl-19-(oxan-2-yl)-8,l4-dioxa-4,5,10,19,20-pentaazatetra cyclo[13.5.2.1²’⁵.0^iui]tricosa-l(20),2(23),3,15(22),16,18(21)-hexaen-9-one (0.090 g, 0.183 mmol) in DCM (3.0 mL) was added trifluoroacetic acid (140 pL, 1.83 mmol). The reaction mixture was stirred at room température during 4 h. LCMS analysis showed formation of the expected product. A saturated solution of NaHCO₃ (10 mL) was added and phases were separated. The aqueous phase was extracted with DCM (3x10 mL), and organic phase was washed with brine (10 mL), dried with MgSCL, filtered and concentrated under reduce pressure. The crude (120 mg) was purified by chromatography column (Macherey Nagel, 4g,

255

DCM/MeOH : 100/0 to 90/10). Solvents was evaporated to afïbrd (13R)-7,13-ditnethyl-8,14dioxa-4,5,10,19,20-pentaazatetracyclo[l 3.5.2. PAO^18,21 ]tricosa-1(20),2(23),

3,15(22),16,18(2 l)-hexaen-9-one example 113 as a white powder.

LCMS method F: [M+H]⁴' = 356.3, t_R = 1.96 and 2.02 min, diastereomers

LCMS method G: [M+H]⁺ = 356.3, t_R = 2.03 and 2.08 min, diastereomers

Ή NMR (400 MHz, ί/6-DMSO) (mixture of both diastereomers) δ 12.79 (s, IH), 8.13 - 8.12 (2H, m), 7.84 (dd, J = 3.3, 8.8 Hz, IH), 7.74 (dd, J = 0.7, 16.4 Hz, 2H), 7.61 - 7.56 (IH, m),

7.43 -7.39 (2H, m), 7.08 (d, J = 2.5 Hz, 1 H), 7.00 (d, J = 2.1 Hz, 1 H), 6.94 - 6.90 (2H, m), 5.12

- 5.04 (IH, m), 4.91 - 4.86 (IH, m), 4.72 - 4.64 (IH, m), 4.50 - 4.43 (2H, m), 4.38 - 4.25 (2H, m), 3.61 -3.51 (2H, m), 3.25 - 3.18 (I H, m), 2.86 (IH, t, J = 11.0 Hz), 2.08 (2H, t, J = 12.1 Hz), ] .86(1 H, s), 1.62 - 1.52 (1 H, m), 1.39 - 1.35 (9H, m), 1.32 - 1.28 (3H, m) ppm .

Example 114: (13R)-13-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo

[ 13.5.2. PA0¹⁸’²¹]tricosa-l (20),2,4,6(23),15,17,21-heptaen-9-one

Example 114 is prepared according to the synthesis route described in general Scheme K.

In 2 pwaves tubes were put a solution of (13R)-l3-methyl-19-(oxan-2-yl)-8,14-dioxa10,19,20,23-tetraazatetracyclo[l 3.5.2. l^2,6.0¹⁸²'jtricosa-1(20),2,4,6(23),15,17,21-heptaen-9one (300 mg, 0.71 mmol) in DCM (10 mL). To this solution was added trifluoroacetic acid (4.3 mL, 56.84 mmol). The reaction mixture was stirred at 80 °C under microwaves irradiations for I h. The solvant was removed under reduced pressure, the oil was dissolved in EtOAc and washed with a saturated solution of NaHCO₃. The phase were separated and the organic one was dried with Na₂SO4. The solvant was removed under reduced pressure. The crude was purified by chromatography using a 10 g SiO₂ column eluted with cyclohexane/Ethyl acetate 70/30 to 50/50. The good fractions were combined and the solvant was removed under reduced pressure. The oil was triturated in DCM and the solid formed was filtered and dried under reduced pressure to give (13R)-13-methyl-8,14-dioxa-l 0,19,20,23-tetraazatetracyclo

256

[l3.5.2.l²’⁶.0^l8’^2l]tricosa-l(20),2,4,6(23),l5,17,2l-heptaen-9-one example 114 as a light yellow powder.

LCMS method F: [M+H]⁺ = 339.3, t_R = 2.17 min

LCMS method G: [M+H]⁺ = 339.3, t_R = 2.16 min

Ή NMR. (400 MHz, rf6-DMS0) δ 13.24 - 13.21 (IH, m), 8.10-8.06 (IH, m), 7.90-7.80 (2H, m), 7.75 - 7.71 (IH, m), 7.48 - 7.45 (IH, m), 7.26 - 7.23 (IH, m), 6.96 (IH, dd, J = 2.3, 8.9 Hz), 5.59 (IH, d, J = 14.0 Hz), 5.06 (IH, d, J = 14.6 Hz), 4.66 -4.59 (IH, m), 3.5 - 3.42 (IH, m), 2.97 - 2.89 (IH, m), 2.29 - 2.22 (IH, m), 1.39 - 1.35 (4H, m) ppm.

Example 115: (7R)- or (7S)-7-ethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹l tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Example 115 is prepared according to the synthesis route described in general Scheme G and 15 by chiral HPLC séparation of example 104 using Chiralpak IB N-5 20x250mm 5 pm [C7/EtOH]+0.l%DEA [80/20] run 20 min, 19 mL/mîn RT to give (7R)- or (7S)-7-ethy 1-8,14dioxa-10,19,20-triazatetracyclo[l 3.5.2.1²’⁶.0^18,21 ]tricosa-1(20),2,4,6(23), 15,17,21-heptaen-9one example 115.

LCMS method F: [M+H]⁺ = 352.3, t_R = 2.42 min

LCMS method G: [M+H]⁺ = 352.3, t_R = 2.41 min

Ή NMR (400 MHz, r/6-DMSO) δ 7.96 (IH, dd, J = 5.0, 7.7 Hz), 7.85 - 7.80 (2H, m), 7.52 7.45 (2H, m), 7.37 - 7.27 (2H, m), 6.98 (IH, dd, J = 2.3, 8.9 Hz), 5.68 (IH, dd, J = 3.5, 8.8 Hz), 4.38 - 4.24 (2H, m), 3.58 - 3.466 (IH, m), 2.78 - 2.67 (1 H, m), 2.22 - 2.16 (IH, m), 2.10 - 2.02 ( 1 H, m), 1.87- 1.72 (2H, m), 1.08 - 0.98 (3H, m) ppm. The indazole NH proton was not visible 25 in this solvent.

Chiral HPLC: ee 100%

257

Example 116: (7R)- or (7S)-7-ethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^ls'²¹] tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Example 116 is prepared according to the synthesis route described in general Scheme G and by chiral HPLC séparation of example 104 using Chiralpak IB N-5 20x250mm 5 pm [C7/EtOH]+0.1%DEA [80/20] run 20min, 19 mL/min RT to give (7R)- or (7S)-7-ethyl-8,I4dioxa-10,19,20-triazatetracyclo[ 13.5.2.1^.0¹⁸^'jtricosa-1(20),2,4,6(23), 15,17,21-heptaen-9one example 116.

LCMS method F: [M+Hf = 352.2, ta = 2.42 min

LCMS method G: [M+Hf = 352.3, t_R = 2.41 min

Ή NMR (400 MHz, r/6-DMSO) δ 13.12 (IH, s), 7.96 (IH, dd, J = 4.7, 7.8 Hz), 7.85 - 7.80 (2H, m), 7.51 - 7.45 (2H, tn), 7.37 - 7.28 (2H, m), 6.99 (IH, dd, J = 2.1, 8.9 Hz), 5.68 (IH, dd, J = 3.6, 8.7 Hz), 4.39 - 4.24 (2H, m), 3.56 - 3.50 (IH, m), 2.78 - 2.67 (IH, m), 2.22 - 2.16 (1 H. m), 2.10-2.01 (IH, m), 1.87 - 1.72 (2H, m), 1.00 (3H, t, J = 7.2 Hz) ppm.

Chiral HPLC: ee 100%

The compound îs a pure enantiomer, but the absolute stereochemistry of the chiral center is unknown.

Example 117: (13R)-13-methyl-8,14-dioxa-5,10,19,20-tetraazatetracyclo |13.5.2.1²C0^IS2l| tricosa-1 (20),2,4,6(23),15,17,21-heptaen-9-one

Example 117 is prepared according to the synthesis route described in general Scheme K.

258

In a round bottom flask was added (l3R)-l 3-methyl-l9-(oxan-2-yl)-8,l4-dioxa5,10,19,20-tetraazatetracyclo[l 3.5.2.1^.0^18,21 ]tricosa-l (20),2,4,6(23), 15,17,2 l-heptaen-9-one (0.280 g, 0.663 mmol) in DCM (10.0 mL) and trifluoroacetic acid (2.02 mL, 26.52 mmol). The reaction mixture was stirred at 80 °C under microwaves irradiations during 2 h. LC/MS analysis indîcated the réaction was completed. The reaction was quenched with a saturated solution of NaHCOr (10 mL). Phases were separated and the aqueous phase was extracted with DCM (3 x 10 mL). Organic phase was washed with a saturated solution of NaCi (10 mL), dried with MgSOr, filtered and concentrated under reduce pressure to afford crude (0.250 g) which was purified by chromatography column (Macherey Nagel 4g, DCM/MeOH : 100/0 to 90/10). Solvents was removed and the powder was tritiirated with DCM, to afford (13R)-13-methyl8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1²'⁶.0^l8’^2,]tricosa-t(20),2,4,6(23),15,17,21heptaen-9-one example 117 as a yellow powder.

LCMS method F: [M+Hf = 339.2, t_R = 1.83 min

LCMS method G: [M+Hfi = 339.2, t_R = 2.07 min

Ή NMR (400 MHz, J6-DMSO) ô 13.57- 13.48 (IH, s), 8.59 (IH, d, J = 5.3 Hz), 8.14 (IH, s), 7.86 - 7.81 (2H, m), 7.58 - 7.55 (IH. m), 7.37 (IH, d, J = 1.9 Hz), 7.02 (IH, dd, J = 2.2, 9.0 Hz), 5.72 - 5.56 (IH, m), 4.99-4.85 (IH, m), 4.62 (IH, dd, J = 6.1, 11.2 Hz), 3.00-2.88 (IH, m), 2.70 - 2.66 (I H, m), 2.35 -2.32 (1H , m), 1.43 (3H, d, J = 5.9 Hz), 1.06 (IH, t, J = 7.0 Hz) ppm.

Example 118: 6-(oxan-4-yl)-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1²’^s.0^ls'²¹] tricosa-l(20),2(23),3,15,17,21-hexaen-9-one

Préparation of intermediate 138: ethyl 2-tetrahydropyran-4-ylideneacetate

Example 118 is prepared according to the synthesis route described in general Scheme B.

259

Sodium hydride (60 % dispersion in minerai oil, 0.88 g, 22.0 mmol) was suspended in THF (120 mL) and cooled to 0-5 °C in an ice bath. A solution of trîethy 1 phosphonoacetate (4.4 mL, 22.0 mmol) in THF (120 mL) was added dropwise. The mixture was stirred at room température for 30 min and a solution of tetrahydro-4H-pyran-4-one (1.9 mL, 20.0 mmol) în THF (120 mL) was added dropwise. The resulting mixture was stirred for additional 6 hours at room température, cooled to 0-5 °C and water (500 mL) was added. The mixture was extracted with diethylether (3 x 250 mL), the combined organic layers were dried over anhydrous magnésium sulfate, fdtered and concentrated under reduced pressure to afford ethyl 2-tetrahydropyran-4ylideneacetate 138 as a coloriess oil.

LCMS method F: [M+H]⁺ = 171. i, t_R = 2.08 min

Préparation of intermediate 139: ethyl 2-tetrahydropyran-4-ylacetate

O

To a solution of ethyl 2-tetrahydropyran-4-yiideneacetate 138 (3.40 g, 20.0 mmol) în MeOH (130 mL) under argon atmosphère, was added 10 % Pd/C (0.40 g, 0.40 mmol). The mixture was hydrogenated under a hydrogen atmosphère for 4 hours. The suspension was filtered through a pad of Celite, rinsed with MeOH (100 mL) and the filtrate was evaporated under reduced pressure to give ethyl 2-tetrahydropyran-4-ylacetate 139 as a coloriess oil. The crude product was used in the next step without any purification.

Préparation of intermediate 140: ethyl 2-bromo-2-tetrahydropyran-4-yl-acetate

260

To a solution of lithium diisopropylamîde (1.8 M in THF/heptane/ethylbenzene, 10.6 mL, I9.l mmol) in 30 mL of THF at - 78 °C was added trîmethylsilyl chloride (4.2 mL, 33.1 mmol) dropwise. Ethyl 2-tetrahydropyran-4-ylacetate 139 (3.000 g, 17.4 mmol) in 15 mL of THF was then added to the mixture dropwise very slowly. The mixture was stirred at -78°C for 2 hours then A-bromosuccinimide (3.258 g, 18.3 mmol) in 30 mL of THF was added dropwise very slowly. The reaction mixture was allowed to warm slowly to room température and was stirred for 16 hours. TLC showed complété reaction. The mixture was concentrated under reduced pressure and the residue was dissolved in 120 mL of ethyl acetate, washed 1 x 30 mL of water. The aqueous layer was extracted 3x30 mL of ethyl acetate. The combined organic layers were dried over anhydrous magnésium sulfate, fîltered and concentrated under reduced pressure to give a brown oily residue. The crude was purified by column chromatography on silica gel (Cyclohexane : EtOAc from 100 : 0 to 80 : 20) to provide ethyl 2-bromo-2-tetrahydropyran-4yl-acetate 140 as a yellow oil.

LCMS method F: t_R = 2.36 min, no m/z detected

Préparation of intermediate 141: ethyl 2-(4-bromopyrazol-l-yl)-2-tetrahydropyran-4-ylacetate /^O ο N-N ⁷ φ

Br

A suspension of 4-bromo-lH-pyrazole (1.50 g, 10.20 mmol), ethyl 2-bromo-2-tetrahydropyran4-yl-acetate 140 (3.07 g, 12.24 mmol), and potassium carbonate (2.83 g, 20.40 mmol) in N,NdimethyIformamide (3.0 mL) was stirred for 3 h at 80°C. The reaction was quenched by water (30 mL), and the resulting solution was extracted twice with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous magnésium sulfate, fîltered, and concentrated under reduced pressure to give ethyl 2-(4-bromopyrazol-l -yl)-2-tetrahydropyran4-yl-acetate 141 as a slightly yellow oil.

LCMS method F: [M+H]⁺ = 317.0, t_R = 2.38 min

Préparation of Example 118: 6-(oxan-4-yl)-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo

[13.5.2. l²A0^18I1]tricosa-l (20),2(23),3,15,17,21-hexaen-9-one

261

To a solution of 19-(oxan-2-yl)-6-(oxan-4-yl)-8,14-dioxa-4,5,10,19,20pentaazatetracyc lo[ 13.5.2. l^2,5.0'^8,21]tricosa-1(20),2(2 3), 3,15,17,21-hexaen-9-one (0.115 g, 0.23 mmol) in DCM (6.0 mL) was added trifluoroacetic acid (0.35 mL, 4.60 mmol). The 5 reaction mixture was directly heated to 50 °C for 3 hours. The reaction mixture (brown solution) was evaporated under reduced pressure. The brown residue was dissolved in EtOAc then a saturated aqueous solution of sodium hydrogen carbonate was added. After séparation, the aqueous layer w'as extracted with ethyl acetate (2 x). The combined organic layer was washed with water then brine, dried over sodium sulfate, filtered and evaporated under reduced pressure 10 to give an orange oil. The crude product was purified by préparative TLC plate on silica eluting with Cyclohexane / Ethyl acetate — EtOFI (3-1), 100/0 to 70/30 to afford 6-(oxan-4-yl)-8,14dioxa-4,5,10,19,20-pentaazatetracyclo[ 13.5.2.1^2,5.0^18,21 ]tricosa-1(20),2(23), 3,15,17,21 hexaen-9-one example 118 as a white solid.

LCMS method F: [M+H]* = 412.3, t_R = 1.92 min

LCMS method G: [M+H]* = 412.3, t_R = 1.92 min

Ή NMR (400 MHz, r/6-DMSO) δ 12.80 (IH, s), 8.22 (IH, s), 7.83 (IH, dd, 7=3.6, 8.0 Hz), 7.77 ( 1 H, s), 7.42 ( 1 H, d, J = 9.2 Hz), 7.10(1 H, d, .7 = 1.9 Hz), 6.94 (1 H, dd, J = 2.3, 8.9 Hz), 4.57 (IH, dd,7= 1.8, 12.1 Hz), 4.45 (IH, dt, J = 2.8, 12.0 Hz), 4.38 (IH, dq, J= 2.0, 10.4 Hz), 4.26 - 4.15 (2H, m), 3.95 (IH, dd, J= 2.8, 11.1 Hz), 3.84 - 3.80 (IH, m), 3.48 - 3.39 (IH, m), 20 3.32 - 3.28 (IH, m), 3.22 (JH, dt, 7 = 2.4, 11.2 Hz), 2.82 (IH, dt, J= 2.8, 11.2 Hz), 2.47 - 2.36 (IH, m), 1.95 - 1.88 (I H, m), 1.81-1.75 (2H, m), 1.48 (IH, dq,7=4.8, 12.8 Hz), 1.26 (IH, dq, 7=4.8, 12.8 Hz), 1.07(lH, d,7= 12.8 Hz) ppm.

Example 119: 4-ethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclofl3.5.2.1^2,5.0^18,21] tricosa-l(20),2(23),15,17,21-pentaen-9-one

262

Example 119 is prepared according to the synthesis route described in general Scheme B.

Préparation of intermediate 142: 5-ethylpyrazolidin-3-one

H H N-N oÂX

To a solution of hydrazine hydrate 50-60 % (1,00 mL, 15,94 mmol) in isopropanol (13 mL), was added a solution of methyl pent-2-enoate (2.000 g, 17,54 mmol) in isopropanol (10 mL) at room température. The reaction mixture was stirred at 80 °C for 16 hours. The mixture was evaporated under reduced pressure. Taken in DCM and again evaporated under reduced pressure twice to remove isopropanol affording the crude 5-ethylpyrazolidin-3-one 142 as a pale yellow oil. The crude was used in the next step without further purification.

Yield: 1.940 g of intermediate 142 (quantitative)

Préparation of intermediate 143: ethyl 2-(5-ethyl-3-oxo-pyrazoHdin-l-yl)acetate

O

O P H > N-N / \ /

To a solution of 5-ethylpyrazolidin-3-one 142 (1.817 g, 15.94 mmol) and ethyl glyoxylate 50% wt in toluene (3.576 g, 17.53 mmol) in DCM (35 mL) was added at 0 °C sodium trîacetoxyborohydride (13.45 g, 63.76 mmol). Gas évolution was observed. The reaction mixture was warmed up to room température and stirred for 48 hours. The reaction was quenched by slow' addition of an aqueous NaHCOs solution (50 mL). Gas évolution was observed. The resulting mixture was diluted with DCM (50 mL), follow'ed by an aqueous NaOH 1 M solution until pH - 8/9. After séparation, the aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layer was dried over anhydrous magnésium sulfate, filtered and

263

evaporated under reduced pressure to afford ethyl 2-(5-ethyl-3-oxo-pyrazolidin-l-yl)acetate

143 as a brown oil. The crude product was used in the next step without further purification.

Préparation of intermediate 144: ethyl 2-(5-bromo-3-ethyl-3,4-dihydropyrazol-2-yl)acetate

To a mixture of ethyl 2-(5-ethyl-3-oxo-pyrazolidin-l-yl)acetate 143 (1.443 g, 7.21 mmol) and tetraethylammonium bromide (0.453 g, 2.16 mmol) in DCM (3.5 mL) at 20-25 °C was added dropwise triethylamine (0.90 mL, 6.49 mmol) over 2-3 minutes, maintainîng the internai température below 35 °C. The resulting reaction mixture was then cooled to 0-5 °C. A solution 10 of phosphorus(V) oxybromide (2.680 g, 9.37 mmol) in DCM (3.7 mL) was added dropwise over 5-10 minutes, maintainîng the internai température below 20 °C. The reaction mixture was warmed to 30 °C and stirred for 5 hours at this température. After 5 hours, the reaction mixture was slowly poured into a separate reactor containing a solution ofNaOH (L298 g, 32.44 mmol) in water (26 mL) at 0-5 °C. This slow addition was performed using an addition funnel, 15 maintainîng the internai température below 20 °C. The addition funnel was rinsed with DCM (1.1 mL). The resulting bîphasic mixture was warmed to 20-25 °C, stirred for 3 hours, and the aqueous layer checked by pH. The layers were separated. The organic layer was sequentially washed with a 0.1 M aqueous solution of sodium dihydrogenophosphate (NaH₂PO4(aq), 10 mL) and water (10 mL), then concentrated under reduced pressure. The crude oily residue was 20 purified by column chromatography on silica gel (Cyclochexane / EtOAc : from 10/0 to 9/1) to afford ethyl 2-(5-bromo-3-ethyl-3,4-dihydropyrazol-2-yl)acetate 144 as a yellow oiL LCMS method F: [M+H]⁺ = 265.1, t_R = 2.42 min

Préparation of Example 119: 4-ethy 1-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo 25 [13.5.2. l²A0^t8’²¹]tricosa-l(20),2(23), 15,17,21-pentaen-9-one

264

To a solution of 4-ethyi-l9-(oxan-2-yl)-8,!4-dioxa-5,l0,l9,20,23-pentaazatetracyclo [13.5.2.1²TO¹⁸² “Jtricosa-l (20),2(23), 15,17,2 l-pentaen-9-one (0.052 g, 0.12 mmol) in DCM (3.0 mL) was added trifluoroacetic acîd (0.18 mL, 2.40 mmol). The reaction mixture was directly heated to 50 °C for 3 hours. LCMS analysis showed formation of the expected product 5 and total consumption of starting material. The reaction mixture (brown solution) was evaporated under reduced pressure. The brown residue was dissolved in EtOAc then a saturated aqueous solution of sodium hydrogen carbonate was added. After séparation, the aqueous layer was extracted with ethyl acetate (2 x). The combined organic layer was washed with water then brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to give an 10 orange oil. The crude product was purified over préparative TLC plate on silica eluting with

Cyclohexane / Ethyl acetate - EtOHormate (3-1), 100/0 to 70/30. The pure fractions were combined and evaporated under reduced pressure to afford 4-ethyl-8,14-dioxa-5,10,19,20,23pentaazatetracyclof 13.5.2.l²’⁵.0^,8’^2,]tricosa-1(20),2(23), 15,! 7,2]-pentaen-9-one example 119 as a sliglhty yellow solid.

LCMS method F: [M+H]⁺ = 358.2, t_R = 2.01 min

LCMS method G: [M+H]⁺ = 358.3, t_R = 2.13 min

Ή NMR (400 MHz, ί/6-DMSO, 80 °C) δ 12.70 (IH, br. s), 7.61 (lH,d, J= 1.9 Hz), 7.39 (IH, d, J=8.8 Hz), 7.1 I (1 H, br. s), 6.94 (IH, dd, J = 2.8, 8.8 Hz), 4,45 -4,17 (4H, m), 3.31 -3.07 (5H, m), 2.71 -2.59(1H, m), 1.92 - 1.80 (3H, m), 1.64 - 1.52 (IH, m), 1.32- 1.27 (IH, m), 0.98 20 (3H, t, 7.6 Hz) ppm.

Example 120: (13 R)-23-fluoro-13-methy 1-8,14-dioxa-10,19,20-triazatetracyclo

[13.5.2.1²’⁶.0^18,ïl|tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Example 120 is prepared according to the synthesis route described in general Scheme C.

In a gwave tube was put a solution of ( 13R)-23-fluoro-l3-methy 1-19-(oxan-2-y 1)-8,14dioxa-10,19,20-triazatetracyclo[ 13.5.2.1²’⁶.0^182l]tricosa-1 (20),2,4,6(23), 15,17,21 -heptaen-9one (165 mg, 0.391 mmoi) in DCM (10 mL). To this solution was added trifluoroacetic acid

265 (1.2 mL, 15.6 mmol). The reaction mixture was stirred at 80 °C under mîcrowaves irradiations for 1 h. The solvent was removed under reduced pressure, the oil was dissolved in EtOAc and washed with a saturated solution of NaHCO₃. The phase were separated and the organic one was dried with NazSO4. The solvant was removed under reduced pressure. The crude was 5 triturated in DCM, the solid formed was fîltered washed with water and dried to give (I3R)-23fluoro-13-methy 1-8,14-dioxa-l 0,19,20-triazatetracyclo[ 13.5.2. l^2,6.0^18,21 ]tricosa-1(20),2, 4,6(23), 15,17,2 l-heptaen-9-one example 120 as an off white powder.

LCMS method F: [M+H]⁺ = 356.2, t_R = 2.25 min

LCMS method G: [M+H]⁺ = 356.2, t_R = 2.25 min

Ή NMR (400 MHz, r/6-DMSO) δ 13.42- 13.11 (IH, s), 7.76 - 7.68 (2H, m), 7.56- 7.45 (2H, m), 7.30 (IH, t, J = 7.6 Hz), 6.96 - 6.90 (2H, m), 6.07 - 6.02 (IH, m), 4.65 (IH, d, J = 12.5 Hz), 4.58 -4.54( 1 H, m), 3.66 - 3.58 (IH, m), 2.81 -2.68 (IH, m), 2.23 -2.16(lH,m), 1.35 - 1.31 (4H, m) ppm.

Example 121: 9,14-dioxa-4,5,ll,19,20-pentaazatetracyclo[13.5.2.1²’⁵.0⁸’^îl]tricosa

1(20),2(23),3,15,17,21-hexaen-10-one

Example 121 is prepared according to the synthesis route described in general Scheme A.

Préparation of intermediate 145: 3-(4-(4,4,5,5-tetramethy 1-1,3,2-dioxaborolan-2-yl)-lHpyrazo!-l-yl]propan-l~ol

266

To a solution of 4-bromo-l-(3-hydroxypropyl)-lH-pyrazole (0.410 g, 2.0 mmol) in dioxane (4 mL) was added at RT bis(pinacolato)diboron (0.609 g, 2.4 mmol), KOAc (0.589 g, 6.0 mmol) and PdCl₂(dppf) DCM (0.082 g, 0.1 mmol). The resulting réaction mixture was stirred under microwave irradiation at 100°C for 2 h. The residue was diluted with water and extracted with ethyl acetate twice. The combined organic layer was dried over anhydrous sodium sulfate affording 3-[4-(4,4,5,5-tetramethyl-I,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl]propan-l-ol 145 as a brown oil, which was used in the next step without further purification.

Yield: 0.504 g of intermediate 145 (quantitative)

LCMS method F: [M+H]⁺ = 253.2, t_R = 1.91 min

Préparation of Example 121: 9,14-dioxa-4,5,ll,19,20-pentaazatetracyclo [13.5.2.1²’^s.0¹⁸’²¹]tricosa-l(20),2(23),3,15,17,21-hexaen-10-one

To a solution of 19-(oxan-2-yl)-9,14-dioxa-4,5,l l,19,20-pentaazatetracyclo[13.5.2.1²’⁵.0¹⁸’²¹] 15 tricosa-1(20),2(23),3,15,17,21 -hexaen-10-one (0.015 g, 0.04 mmol) in DCM (1 mL) was added at RT TFA (0.054 mL, 0.73 mmoi). The resulting reaction mixture was stirred under microwave irradiation at 80°C for Ih. The reaction mixture was concentrated in vacuo, diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate twice. The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue 20 was purified by flash-column (4 g silica Macherey Nagel) chromatography (cyclohexane-ethyl acetate 3 / EtOH 1, 1:0 to 6:4) affording 9,14-dioxa-4,5,l 1,19,20-pentaazatetracyclo [13.5.2.1²’⁵.O^l8;2^tricosa-1(20),2(23),3,15,17,21-hexaen-10-one example 121 as a white solid. LCMS method F: [M+H]⁺ = 328.2, [M-H]' = 326.3, t_R = 1.67

LCMS method G: [M+H]⁺ = 328.2, [M-H]' = 326.4, t_R = 1.75

Ή NMR (400 MHz, c/6-DMSO) δ 12.79 (IH, s), 8.31 (IH, s), 7.94 (lH,t, J = 5.5 Hz), 7.80 (1 H, s), 7.42 - 7.36 (2H, m), 7.00 (1 H, dd, J = 2.3, 8.9 Hz), 4.38 (2H, t, J = 6.0 Hz), 4.29 - 4.25 (2H, m), 3.60 (2H, t, J = 5.6 Hz), 3.41 - 3.35 (2H, m) 2.14 - 2.08 (2H, m) ppm.

267

Example 122: 4-ethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1²*^s.0¹⁸’²¹ tricosa-l(20),2(23),3,15,17,21-hexaen-9-one

Example 122 is prepared according to the synthesis route described in general Scheme B.

Préparation of intermediate 146: ethyl 2-[3-[5-[tert-butyl(dimethyl)silyl]oxy-ltetrahydropyran-2-yl-indazoi-3-yl]-5-ethyl-pyrazol-l-yl]acetate

Ethyl 2-[5-[5-[tert-butyl(dimethyl)silyl]oxy-I-tetrahydropyran-2-yl-indazol-3-yl]-3-ethyl-3,410 dihydropyrazol-2-yl] acetate (0.470 g, 0.91 mmol) was diluted in toluene (3.2 mL) and manganese(IV) dioxide (1.193 g, 13.72 mmol) and stirred at 100-105 °C for 24 hours. The reaction mixture was cooled down to room température, filtered over a celite pad, rinsed with ethyl acetate, then evaporated under reduced pressure. The crude residue was purified by column chromatography (DCM / EtOAc from 1 : 0 to 7:3) to afford ethyl 2-[3-[5-[tert15 butyl(dimethyl)si!yl]oxy-l-tetrahydropyran-2-yl-indazol-3-yl]-5-ethyl-pyrazol-l-yl]acetate 146 as yellow solid.

LCMS method F: [M+Hf = 513.4, ta = 3.77 min

Préparation of Example 122: 4-ethyl-8,14-dioxa-5,10_}19,20,23-pentaazatetracyclo

[13.5.2.1²’⁵.0¹⁸’^2I]tricosa-l(20),2(23),3,15,17,21-hexaen-9-one

268

To a solution of 4-ethyl-19-(oxan-2-yl)-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo [13.5.2.1²’⁵.0'⁸’²¹]tricosa-l(20),2(23),3,15,17,21-hexaen-9-one (0.024 g, 0.054 mmol) in DCM ( l .5 mL) was added trifluoroacetic acid (83 pL, 1.09 mmol). The réaction mixture was directly 5 heated to 50 °C (sandbathpreviously heated to 50 °C) for 6 hours. The reaction mixture (brown solution) was evaporated under reduced pressure. The brown residue was dissolved in EtOAc then a saturated aqueous solution of sodium hydrogen carbonate was added. After séparation, the aqueous layer was extracted with ethyl acetate (2 x). The combined organic layer was washed with water then brine, dried over sodium sulfate, fîltered and evaporated under reduced 10 pressure. The crude product was purified by préparative TLC plate using DCM/MeOH 9/1 as an eluant to give 4-ethy 1-8,14-dioxa-5,l0,19,20,23-pentaazatetracycio[13.5.2.1²·⁵.0^18,21 ]tricosa1 (20),2(23),3,15,17,21 -hexaen-9-one example 122 as an orange solid.

LCMS method F: [M+H]⁺ = 356.3, t_R = 1.99 min

LCMS method G: [M+H]⁺ = 356.3, t_R = 2.03 min

Ή NMR (400 MHz, ri6-DMSO) S 12.80 (III, s), 7.64 - 7.58 (2H, m), 7.38 (IH, d, J= 9.2 Hz), 6.92 (IH, dd, J= 9.2,3.2 Hz), 6.44 (IH, s), 4.41 (4H, s), 4.27 - 4.22 (2H, m), 3.11-3.06 (2H, m), 2.70 (2H, q, J =12 Hz), 1.92 - 1.82 (2H, m), 1.27 (3H, t, J =12 Hz) ppm.

Example 123: 3,9,15-trîoxa-4,ll,20,21-tetraazatetracyclo[14,5.2.1²’⁵.0^1!’’²²]tetracosal(21),2(24),4,16,18,22-hexaen-10-one

Example 123 îs prepared according to the synthesis route described in general Scheme M.

269

Préparation of intermedîate 147: benzyl N-[3-[l-tetrahydropyran-2-yl-3-(2triethylsilylethynyl)indazol-5-yl]oxypropyl]carbamate

To a degassed solution of benzyl N-[3-(3-îodo-l-tetrahydropyran-2-yl-indazol-5yl)oxy propyl]carbamate (2.500 g, 4.67 mmol) in THF (15.0 mL), tri ethy lamine (0.754 mL, 5.65 mmol), Cul (0.071 g, 0.374 mmol) and Tetrakis(triphenylphosphine) palladium (0.058 g, 0.050 mmol) was added. Triethylsilylacetylene (1.088 mL, 6.07 mmol) was slowly added and the reaction was heated to 80°C for 4 h. The reaction mixture was diluted with water (30 mL) and 10 EtOAc (30 mL) and extracted with EtOAc (3 x 30 mL). The organic layer was combined, washed with saturated brine (30 mL), dried with MgSO4, filtered and concentrated under reduced pressure. The crude material (3.0 g) was purified by column (Macherey Nagel, 40 g, CyH/EtOAc : 90/10 to 70/30). Solvents were evaporated to afford benzyl N-[3-[ltetrahydropyran-2-y 1-3-(2-triethylsilylethynyl)indazol-5-yl]oxypropyl]carbamate 147 as an 15 orange oil.

LCMS method F: [M+H]⁺ = 548.4, t_R = 3.81 min

Préparation of Intermedîate 148: benzyl N-[3-(3-ethynyl-l-tetrahydropyran-2-yI-indazol-5yl)oxypropyl]carbamate

270

To a solution of benzyl N-[3-[l-tetrahydropyran-2-y 1-3-(2-triethylsilylethynyl)indazol-5yl]oxypropyl]carbamate 147 (2.375 g, 4.36 mmol) in THF (100.0 mL) was added dropwise at room temperature tetrabutylammonium fluoride 1 M in THF (4.77 mL, 4.77 mmol). The resulting mixture was stirred at room temperature during 16 h. Water (35 mL) and EtOAc (35 mL) were added and phases were separated. The aqueous layer was extracted with EtOAc (3 x 25 mL) and the organic phase was washed with brine (35 mL) and dried with MgSÜ4, filtered and concentrated. The crude (2.0 g) was purified by chromatography column (Macherey Nagei, 24 g, CyH/EtOAc : 90/10 to 70/30). Solvents were evaporated to afford benzyl N-[3-(3-ethynyl1 -tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]carbamate 148 as a yellow oil.

LCMS method F: [Μ+Hf = 434.3, t_R = 3.05 min

Préparation of intermediate 149: tert-butyl-(4-n itrobutoxy)~dipbenyl-silane

In a round bottom flask, to a solution of 4-nitrobutan-l-ol (1.00 g, 8.39 mmol) and imidazole (0.686 g, 10.07 mmol) in DCM (85.0 mL) was added slowly tert-butyl(chloro)diphenylsilane (2.18 mL, 8.39 mmol). The mixture was stirred at room temperature during 3 h. Water was added (35 mL) and phases were separated. The aqueous layer was extracted with DCM (3 x 30 mL), then the organic layer was washed with a saturated solution of NaCi (25 mL), dried with MgSÛ4, filtered and concentrated under reduced pressure to afford crude tert-butyl-(421105

271

nitrobutoxy)-diphenyl-silane 149 as a colorless oil which was used in the next step without further purification.

LCMS method F: [M+H]⁺ = 358.3, t_R = 3.67 min

Préparation of intermediate 150: benzyl N-[3-[3-f3-[2-[tert-butyl(diphenyl) silyl]oxyethyl]isoxazol-5-yl]-l-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate

In a round bottom flask, to a solution of tert-butyl-(4-nitrobutoxy)-diphenyl-silane 149 (3.030 g, 8.39 mmol) and benzyl N-[3-(3-ethynyl-l-tetrahydropyran-2-yl-indazol-510 yl)oxypropy!]carbamate 141 (1.000 g, 2.31 mmol) in toluene (25.0 mL), were added phenyl isocyanate (0.276 mL, 2.54 mmol) and triethylamine (0.353 mL, 2.54 mmol). The reaction was stirred during 2 days at 60°C. The precipitate (urea) was fïltered and solvent was removed to give crude (4 g) which was purified by chromatography column by solid deposit (Macherey Nagel 40 g, Cyclo/EtOAc : 100/0 to 70/30). Solvents were evaporated to afford benzyl N-[3] 5 [3-[3-[2-[tert-butyl(diphenyl)silyl]oxyethyl]isoxazol-5-yl]-l-tetrahydropyran-2-yl-indazol-5yl]oxypropyl]carbamate 150 as a yellow solid.

LCMS method I: [M+H]⁺ = 773.5, t_R = 3.71 min

Préparation of intermediate 151: benzyl N-l3-[3-[3-(3-hydroxypropyl)isoxazol-5-yl]-l20 tetrahydropyran-2-yl-indazol-5-ytfoxypropyl]carbamate

272

In a round bottom flask, to a solution of benzyl N-[3-[3-[3-[3-[tert-butyl(diphenyl) silyl]oxypropyl]isoxazol-5-yl]-1 -tetrahydropyran-2-y]-indazol-5-yl]oxypropyl]carbamate 150 (2.00 g, 2.31 mmol) in THF (25.0 mL), was added TBAF (1.0 M in THF), 2.77 mL, 2.77 mmol).

The reaction was stirred during 2 h at room température. Water (20 mL) and EtOAc (20 mL) were added. Phases were separated and the aqueous phase was extracted with EtOAc (3 x 25 mL). Then, the organic phase was washed with a saturated solution of NaCl (20 mL), dried with MgSO4, filtered and concentrated under reduced pressure to give crude (1.8 g) which was purified by chromatography column (RediSep 25 g, CyH/EtOAc : 100/0 to 70/30, then

DCM/MeOH : 100/0 to 90/10). Solvents was evaporated to afford benzyl N-[3-[3-[3-(3hydroxypropyl)isoxazol-5-yl]-l-tetrahydropyran-2-yl-indazol·5-yl]oxyproρyl]carbamate 151 as an orange oil.

LCMS method F: [M+Hf = 535.3, t_R = 2.85 min

Préparation of intermediate 152: 20-(oxan-2-yl)-3,9,15-trioxa-4,11,20,2 l-tetraaz,atetraeyelo (14.5.2.1²’⁵.0^,922]tetracosa-l(21),2(24), 4,16,18,22-hexaen-10-one

273

The reaction was divided in 2 batches. In a round bottom flask, benzyl N-[3-[3-[3-(3hydroxypropyl)isoxazol-5-yl]-l-tetrahydropyran-2-yl-indazol-5-yl]oxypropyl]carbamate 151 (0.430 g, 0.805 mmol) in dry MeCN (300.0 mL) was added césium carbonate (1.572 g, 4.825 5 mmol). The reaction was stirred during 48 h at 85°C. The mixture was filtered and the filtrate was concentrated under reduce pressure to afford crude (2 x 400 mg) which were combined and purified by chromatography column by solid deposit (Macherey Nagel 4 g, DCM/MeOH : 100/0 to 95/5). Good fractions were gathered and solvent was removed, to afford 20-(oxan-2y 1)-3,9,15-trioxa-4,l 1,20,2 l-tetraazatetracyclo[ 14.5.2.1^2î5.0^,9’²²]tetracosa-1 (21),2(24),

4,16,18,22-hexaen-10-one 152 as a white powder.

LCMS method F; [M+H]⁺ = 427.2, ta = 2.51 min

Préparation of Example 123: 3,9,15-trioxa-4,11,20,21- tetraazatetraeyclo[14.5.2.1^2,s.0^19,22] tetracosa-l(21 ),2(24),4,16,18,22-hexaen-10-one

At 0°C, in a round bottom flask, to a solution of 20-(oxan-2-yl)-3,9, l5-trioxa-4,11,20,21tetraazatetracyclo[l 4.5.2.1²’⁵.0^,9'²²]tetracosa-1 (21 ),2(24),4,16(23), 17,19(22)-hexaen-10-one

152 (0.200 g, 0.470 mmol) in DCM (50.0 mL), was added trifluoroacetic acid (1.08 mL, 14.10 mmol). The reaction was stirred at room température during 18h. A saturated solution of

274

NaHCOj(50 mL) was added and phases were separated. The aqueous phase was extracted with

DCM (3 x 25 mL), dried with MgSÛ4, filtered and concentrated to afford crude (90 mg) which was purified by préparative reverse-phase chromatography (Column Waters XSELECT C18

19* 100mm, 5 pm (NHî^COs aq. 2 g/L MeCN 19 mL /min, RT 25% B to 55% B in 7 min).

Solvents were removed to afford 3,9,15-trioxa-4,l 1,20,21- tetraazatetracyclo[14.5.2.1²’⁵.0¹⁹²²] tetracosa-1(21),2(24),4,16,18,22-hexaen-10-one example 123 as a white powder.

LCMS method F: [M+H]⁺ = 343.3, t_R = 2.01 min

LCMS method G: [M+H]⁺ = 343.2, t_R = 1.99 min

Ή NMR (400 MHz, ί/6-DMSO) δ 13.59 (IH, s), 7.78 (lH,t, J = 6.0 Hz), 7.59 - 7.56 (IH. m), 10 7.16 (I H, d, J = 2.3 Hz), 7.04 (IH, dd, J = 2.4, 9.0 Hz), 6.86 (IH, s), 4.39 - 4.33 (2H, m), 3.85 (2H, t, J = 5.6 Hz), 3.08 (2H, dd, J = 6.2, 10.0 Hz), 2.93 (2H, t, J = 6.5 Hz), 2.02 - 1.96 (2H, m), 1.86 - 1.75 (2H, m) ppm.

Example 124: (13R)-16-fluoro-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo

[13.5.2.1²’⁶.0¹⁸’²¹]tricosa-l (20),2,4,6(23),15,17,2 l-heptaen-9-one

Example 124 is prepared according to the synthesis route described in general Scheme C.

Préparation of intermediate 153: benzyl N-[(3R)-3-[(6-fluoro-3-iodo-lH-indazol-5yi)oxy]butyl]carbamate

275

To a solution of benzyl 7V-[(3R.)-3-[(6-fluoro-lH-indazol-5-yl)oxy]butyl]carbamate (1.96 g,

5.49 mmol) in acetone ( 14 mL) was added portionwise M-lodosuccinimide (l .35 g, 6.04 mmol) at 0°C and the reaction mixture was then stirred at room température ovemight. The reaction mixture was evaporated to dryness and the residue was dissolved in EtOAc (50 mL). The organic phase was washed with a l M solution of sodium thiosulfate, with brine, dried over anhydrous sodium sulfate, fîltered and evaporated under reduced pressure to give a coiorless oil. The residue was purified by flash chromatography (CyH/EtOAc 5/5) to afford benzyl N[(3R)-3-[(6-fluoro-3-iodo-1 H-indazol-5-yl)oxy]butyl]carbamate 153.

LCMS method F: [M-hH]⁺ = 484, îr = 2.82 min

Préparation of intermediate 154: benzyl N~[(3R)-3-[(6-fluoro-3-iodo-lH-indazol-5yl)oxy]butyl]carbamate

To a mixture of benzyl benzyl jV-[(3R)-3-[(6-fluoro-3-iodo-l H-indazol-5yl)oxy]butyl]carbamate and benzyl A^|r-[(3R)-3-([6-fluoro-3-iodo-l-(oxan-2-yl)-lH-indazol-5yl]oxy}butyl]carbamate (900 mg, 1.59 mmol supposed) in DCM (20 mL) was added trifluoroacetic acid (0.6 mL, 7.95 mmol) and the solution was stirred at room température for 4 hours. The residue was diluted with saturated sodium bicarbonate solution (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layer was washed with brine, dried over NasSCri, fîltered and evaporated under reduced pressure. The residue was fîltered on a silice pad eluting with cyclohexane/EtOAc : 100/0 to 50/50 to afford the expected compound benzyl A^r-[(3R)-3-[(6-fluoro-3-iodo-lH-indazol-5-yl)oxy]butyl]carbamate 154 as a coiorless oiL

LCMS method F: [M+H]⁺ = 568, t_R = 3.25 min

276

Préparation of Example 124: (13R)-16-fluoro-13-methyl-8,14-dioxa-4,10,19,20tetraazatetracyclo[13.5.2.1^{2 6}.0¹⁸’²¹]tncosa-l(20),2,4, 6(23),15,17,2l-heptaen-9-one

To a solution of (l3R)-l6-fluoro-13-methyl-l9-(oxan-2-yl)-8,l4-dioxa-4,l 0,19,205 tetraazatetracyclof 13.5.2. ]²=⁶ O^18,2,]tricosa-1(20),2,4,6(23), 15,17,21-heptaen-9-one (126 mg, 0.29 mmol,) in DCM (3 mL) was added trifluoroacetic acid (438 pL, 5.73 mmol). The mixture was heated under microwave irradiation at 80 °C for 30 min. The reaction mixture was diluted with DCM (25 mL) and NaHCO? saturated (25 mL). A precipitate was formed between the layers after 2 hours at RT. This precipitate was filtered and washed with diethyl ether twice and 10 dried under vaccum at 60 °C for 12 hours to afford (13R)-16-fluoro-13-methyl-8,14-dioxa4_f10,19,20-tetraazatetracyclo[13.5.2.1²’⁶.0^,8’^2l]trîcosa-l(20),2,4, 6(23), 15,17,21-heptaen-9-one example 124 as a white solid.

LCMS method F: [M+H]⁺ = 357, t_R = 1.94 min

LCMS method G: [M+HJ* = 357, t_R = 1.93 min ’H NMR(400 MHz, </6-DMSO)Ô 13.43 (1 H, s), 9.04 (1 H, d, 1=1.1 Hz), 8.57 (1 H, s), 8.15 (IH, s), 8.03 - 8.00 (IH, m), 7.53 (IH, d, J=10.8 Hz), 7.32 - 7.28 (IH, m), 5.77 - 5.73 (IH, m), 4.98 - 4.94 (IH, m), 4.64 - 4.58 (1 H, m), 3.51 (IH, m), 2.93 (IH, dd, 1=13.3, 16.9 Hz), 2.41 - 2.39 (IH, m), 1.44 (4H, m) ppm.

Example 125: (13R)-4-chloro-13-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo [13.5.2.1²ⁱⁱ.0^l8’^:!l]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

277

Example 125 is prepared according to the synthesis route described in general Scheme K.

In a round bottom flask, was added (l3R)-4-chloro-l3-methyl-19-(oxan-2-yl)-8,!4-dioxa10,19,20,23-tetraazatetracyclo[l 3.5.2.1^2,6.0^18,21 ]tricosa-1(20),2(23),3,5,15 (22),16,18(21)heptaen-9-one (0.650 g, 1.42 mmol) in DCM (14.5 mL) and trifluoroacetic acîd (3.26 mL, 42.60 mmol). The reaction mixture was stirred at 80°C during 2 h. LC/MS analysis indicated the reaction was completed. The reaction was quenched with a saturated solution of NaHCO₃ (15 mL). Phases were separated and the aqueous phase was extracted with DCM (3x10 mL). Organic phase was washed with a saturated solution of NaCl (15 mL), dried with MgSO4, filtered and concentrated under reduce pressure to afford crude (0.600 g) which was purified by chromatography column (Macherey Nagel 12 g, DCM/MeOH : 100/0 to 95/5). Solvents were removed and the powder was triturated with DCM, to afford (I3R)-4-chloro-13-methyl8,14-dioxa-l 0,19,20,23-tetraazatetracycio[ 13.5.2.1^2,6.0¹⁸’² 'Jtricosa-1(20),2(23),3,5,15(22), 16,18(2 l)-heptaen-9-one example 125 as a white powder.

LCMS method F: [M+H]⁺ = 373.2, t_R = 2.32 min

LCMS method G: |M+H]⁺= 373.2, t_R = 2.31 min

Ή NMR (400 MHz, rf6-DMSO) δ 13.41 (IH, s), 8.08 (lH,d, J = 1.9 Hz), 7.84 - 7.76 (2H, m), 7.50 - 7.42 (2H, m), 6.97 (IH, dd, J = 2.4, 9.0 Hz), 5.62 - 5.57 (IH, m), 5.09 - 5.04 (IH, m), 4.60 (IH, t, J = 10.2 Hz), 3.50 - 3.44 (IH, m), 2.92 (1 H, t, J = 14.8 Hz), 2.27 - 2.23 (IH, m), 1.39 - 1.36 (4H, m) ppm.

Example 126: 8,14-dioxa-2,4,10,19,20-pentaazatetracyclo[13.5.2.1ⁱ’⁵.0^l821]tricosa l(20),3,5(23),15(22),16,18(21)-hexaen-9-one

To a solution of 19-(oxan-2-y 1)-8,14-dioxa-2,4,10,19,20-pentaazatetracyclo [l3.5.2.1²Â0¹⁸-^2l]tricosa-l(20),3,5(23),15(22),16,18(21)-hexaen-9-one (99 mg, 0.24 mmol) in

Example 126 is prepared according to the synthesis route described in general Scheme A.

278 dioxane (3.8 mL) was added HCl 4 M in dioxane (1.2 mL, 4.82 mmol). The mixture was heated under microwave irradiations at 100 °C for I hour and 30 minutes. HCl 4 M in dioxane (0.5 mL, 2 mmol) was added and the reaction was heated under micro wave irradiations for 1 hour and 20 minutes. In the reaction mixture a precipitate was formed so it was filtrated and the solid was triturated in acetonitrile.So the solid was dissolved with DCM/MeOH and diluted with NaHCO₃ saturated. After séparation, aqueous layer was extracted with DCM (3 x). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 8,14-dioxa-2,4,10,19,20- pentaazatetracyclo[ L3.5.2.1^2,5.0^,8’²¹]tricosa-1(20),3,5(23), 15(22),] 6,18(2I)-hexaen-9-one example 126 as a white powder.

LCMS method F: [M+H]⁺ = 328, t_R = 1.15 min

LCMS method G: [M+H]⁺ = 328, t_R = 1.62 min

Ή NMR (400 MHz, r/6-DMSO) δ 13.05 (1 H, m), 8.02 (IH, d, J= 1.3 Hz), 7.69 (1 H, t, J = 6.1 Hz), 7.50 (IH, m), 7.30 (IH, m), 7.04 (2H, dd, J = 2.3, 9.1 Hz), 6.95 (IH, m), 4.38 (2H. m), 15 4.25 (2H, m), 3.08 (2H, m), 2.95 (2H, t, J = 5.3 Hz), 1.85 ( 1 H, m) ppm.

Example 127: (13R)-4-methoxy-13-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo

[13.5.2.1²’⁶.0^l8’²¹]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Example 127 is prepared according to the synthesis route described in general Scheme K.

In a microwaves tube was put a solution of (13R)-4-methoxy-13-methyl-19-(oxan-2-yl)-8,14dioxa-10,19,20,23-tetraazatetracyclo[ 13.5.2.1²’⁶.O'^8,21 ]tricosa-1(20),2,4,6(23), 15,17,21 - heptaen-9-one (60 mg, 0.133 mmol) in DCM (2.5 mL). To this solution was added trifluoroacetic acid (0.813 mL, 10.6 mmol). The reaction mixture was stirred at 80 °C under microwave conditions for 1 h.

The solvant was removed under reduced pressure, the oil was dissolved in EtOAc and washed with a sol. sat. of NaHCO₃. The phase were separated and the organic one was dried with

279

Na₂SO4- The solvant was removed under reduced pressure. The crude was purified by chromatography using a 10 g SiO₂ column eluted with cyclohexane/Ethyl acetate 70/30 to

50/50. The good fractions were combined and the solvant was removed under reduced pressure.

The oil was trîturated in DCM and the solid formed was filtered and dried under reduced pressure to give (l 3R)-4-methoxy-l3-methyl-8,l4-dioxa-lO, 19,20,23-tetraazatetracyclo [13.5.2.1²’⁶.0¹⁸’^2l]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one example 127 as a white fluffy powder.

LCMS method F: [M+H]⁺ = 369.3, t_R = 2.05 min

LCMS method G: [M+H]⁴ = 369.3, t_R = 2.06 min

Ή NMR (400 MHz, J6-DMSO) δ 13.22 - 13.20 (IH, m), 7.88 (IH, d, J = 1.9 Hz), 7.72 (IH, dd, J = 5.4, 6.9 Hz), 7.60 (IH, d, J=2.5 Hz), 7.47 - 7.44 (1 H, m), 6.96 - 6.88 (2H, m), 5.55 (1 H, d, J = 14.6 Hz), 5.01 - 4.96 (IH, m), 4.61 (IH, dd, J = 2.9, 3.9 Hz), 3.91 (3H, s), 3.48 - 3.42 (IH. m), 2.96-2.88 (1 H,m), 2.34 - 2.22 (IH, m), 1.38 - 1.35 (4H, m) ppm.

Example 128: (13R)-13-methyl-9-oxo-8,14-dioxa-l 0,19,20-triazatetracyclo [ 13.5.2.PA

0¹⁸’²¹]tricosa-l(20),2,4,6(23),15,17,21-lieptaene-5-carbonitrile

Example 128 is prepared according to the synthesis route described in general Scheme B.

Préparation of intermedîate 155: ethyl 5-bromo-2-cyano-benzoate

To a solution of 5-bromo-2-cyano-benzoîc acid (2.500 g, 11.06 mmol) in ACN (50 mL) were added césium carbonate (7.207 g, 22.12 mmol) and ethyl iodide (1.33 mL, 16.59 mmol). The

280 mixture was stirred at 90°C for 30 min. Ethyl iodide (1.33 mL, 16.59 mmol) was added and the reaction was heated at 80°C. After 2 h, ethyl iodide (1.33 mL, 16.59 mmol) was added and the reaction was heated at 80°C for 3 additional hours. The solvent was evaporated under reduced pressure. The residue was diluted with water and EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 20 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Chromabond Macherey Nagel 80 g) using Cyclohexane/(EtOAc/EtOH 3:1) 100:0 to 80:20 as eluent. The expected fractions were combined and evaporated under reduced pressure to give ethyl 5-bromo-2-cyano-benzoate 155 as a white solid.

LCMS method F: t_R = 2.53 min, no m/z detected

Préparation of Example 128 : (13R)-13-methyl-9-oxo-8,14-dioxa-10,19,20-trîazatetra cyclo[13.5.2.1²’⁶.0¹⁸²¹]tricosa-l(20),2,4,6(23),15,17,21-heptaene-5-carbonitrile

To a suspension of (13R)-13-methyl-19-(oxan-2-yl)-9-oxo-8,14-dioxa10,19,20-triazatetracyclo[ 13.5.2.1²’⁶.0¹⁸’²¹]tricosa-1(20),2,4,6(23), 15,17,21-heptaene-5carbonitrile (102 mg, 0.23 mmol) in DCM (3 mL) was added TFA (0.03 mL, 0.35 mmol). The reaction mixture was stirred at room température for 30 min. TFA (0.03 mL, 0.35 mmol) was added and the reaction was stirred for 2 more hours. More TFA (0.03 mL, 0.35 mmol) was added for 3 additional hours. A saturated solution of NaHCO₃ was added and the layers were separated. The aqueous layer was extracted with DCM (3x15 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by préparative HPLC: Column Waters Phenyl-Hexyl Cl8 19*100 mm, 5 pm / A: (NH^COj aq. 2 g/L / B: ACN / 19 mL/min, RT / 40% B to 90% B in 7 min. The solvent was evaporated under reduced pressure to give (13R)-13-methyl-9-oxo8,14-dioxa-10,19,20-triazatetracyclo [ 13.5.2.1²Αθ'^8,21 ]tricosa-1(20),2,4,6(23), 15,17,21 heptaene-5-carbonitrile example 128 as a white solid.

281

LCMS method F; [Μ+ΗΓ = 363.3, t_R = 2.28 min

LCMS method G: [M+H] = 363,3, t_R = 2.26 min

Ή NMR (400 MHz, J6-DMSO) δ 13,49 (IH, s), 8.19 - 8.15 (IH, m), 8.11 - 8.07 (IH, m), 7.97 - 7.93 (2H, m), 7,58 - 7.54 (IH, m), 7.29 (IH, s), 7.04 - 6.99 (IH, m), 5.76 - 5.71 (IH, m), 5.16 - 5.10 (1 H, m), 4.61 - 4.57 (IH, m), 3.58 - 3.55 (IH, m), 2.99 - 2.90 (IH, m), 2.39 - 2.33 (IH, m), 1.44 - 1.40 (4H, m) ppm.

Example 129: (13Κ)-13-[ηείΙ^Ι-4-(ργιτοΙί(1ΐιι-1-γΙ)-8,14-άΐοχΗ-5,10,19,20,23-ρεηί33Ζ3 tetracyclo[13.5.2.1²’⁶.0¹⁸’²¹]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Example 129 is prepared according to the synthesis route described below.

Préparation of intermediate 156: 4-chloro-2-(chloromethyl)-6-pyrrolidin-l-yl-pyrimidine

Cl

To a solution of 4,6-dichIoro-2-(chloromethyl)pyrimidine (0.050 g, 0.253 mmol) in N,Ndimethylfonnamide (3.0 mL) at 0°C was added triethylamine (0.048 mL, 0.304 mmol), and the reaction was stirred during 20 minutes. Then, pyrrolidîne (0.021 mL, 0.253 mmol) was added and the mixture was stirred during 2 h. Solvent was evaporated. Water (10 mL) and EtOAc (10 mL) were added. The aqueous phase was extracted with EtOAc (3x10 mL), then organic phase was washed with a saturated solution of NaCl (10 mL), dried with MgSO₄, fïltered and concentrated. The crude (60 mg) was purified by chromatography column (Macherey Nagel 4g, CyH/EtOAc: 100/0 to 80/20). Solvents were removed to afford 4-chloro-2-(chloromethyl)-6pyrrolidin-l-yl-pyrimidïne 156 as a white powder.

LCMS method F: [M+H]⁺ = 232.2, t_R = 2.53 min

282

Préparation of intermediate 157: (4-ehloro-6-pyrrolidin-l-yl-pyrimidin-2-yl)methyl acetate

Cl

To a solution of 4-chloro-2-(chloromethyl)-6-pyrrolidin-l-yl-pyrimidine 156 (0.041 g, 0.177 mmol) in XN-di methy iformamide (3.0 mL) at 0°C was added sodium iodide (0.030 g, 0.195 5 mmol), and potassium acetate (0.035 g, 0.354 mmol) was added and the mixture was stirred during 3 days at room temperature. Solvent was evaporated. Water (10 mL) and EtOAc (10 mL) were added. The aqueous phase was extracted with EtOAc (3x10 mL), then organic phase was washed with a saturated solution of NaCi (10 mL), dried with MgSO4, filtered and concentrated to afford (4-chloro-6-pyrrolîdin-l-yl-pyrimidin-2-yl)methyl acetate 157 as a white 10 powder which was used in the next step without further purification.

LCMS method F: [M+H]⁺ = 256.1, t_R = 2.28 min

Préparation of intermediate 158: benzyl N-[(3R)-3-f3-[2-(hydroxymethyl)-6-pyrrolidin-l-ylpyrimidin-4-yl]-l-tetrahydropyran-2-yl-indazol-5-yl]oxybutyl]carbamate

To a suspension of [4-[5-[(IR)-3-(benzyloxycarbonylamino)-l-methyl-propoxy]-ltetrahydropyran-2-yl-indazol-3-yl]-6-pyrrolidin-l-yl-pyrimidin-2-yl]methyl acetate 157 (0.650 g, 1.011 mmol) in MeOH (20.0 mL) was added potassium carbonate (0.168 g, 1.214 mmol). The reaction was stirred at room temperature during 2 h. The reaction was stopped and filtered 20 and evaporated. The crude (1.0 g) was purified by chromatography column (RediSep, 12 g, DCM/MeOH: 100/0 to 95/5). Solvents was evaporated to afford benzyl N-[(3R)-3-[3-[2(hydroxymethyl)-6-pyrrolidin-l-yl-pyrimidin-4-yl]-l-tetrahydropyran-2-yl-indazol-5yl]oxybutyl]carbamate 158 as a yellow solid, which was used in the next step without further purification.

LCMS method F: [M+H]⁺ = 601.4, t_R = 2.33 min

283

Préparation of Example 129: (13R)-13-methyl-4-(pyrrolîdin-l-yI)-8,14-dioxa-5,10,19,

20,23-pentaazatetracyclo[13.5.2.1^2,6.0^l8,2l]tricosa-l(20),2,4,6(23),15,17,2 l-heptaen-9-one

In a round bottom flask, was added (13R)-13-methyl-19-(oxan-2-yl)-4-(pyrrolidin-Lyl)8,l4-dioxa-5,I0,19,20,23-pentaazatetracyclo[13.5.2.1²’⁶.0¹⁸ⁱ²¹]tricosa-l(20),2,4,6(23),15, 17,21-heptaen-9-one (0.210 g, 0.426 mmol) in DCM (25.0 mL) and trifluoroacetic acid (1.00 mL, 12.79 mmol). The reaction mixture was stirred at 50 °C during 6 h. A saturated solution of NaHCOj (30 mL) was added and phases were separated. The aqueous phase was washed with DCM (3 x 25 mL), and organic phase was washed with a saturated solution of NaCl (30 mL), dried with MgSO4, filtered and concentrated under reduce pressure to crude which was triturated with MeOH then dried (speedvac), to afford (13R)-13-methyl-4-(pyrrolidin-l-yl)8,14-dioxa-5,l0,19,20,23-pentaazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹]tricosa-l(20),2,4,6(23),15, 17,21-heptaen-9-one example 129 as a white powder.

LCMS method F: [M+H]⁺ = 409.4, tR = 2.03 min

LCMS method G: [M+H]⁺ = 409.4, îr = 2.20 min

Ή NMR (400 MHz, (76-DMSO) δ 13.35 (IH, s), 7.93 (IH, d, J = 2.1 Hz), 7.78 (IH, dd, J = 4.4, 7.6 Hz), 7.48 - 7.45 (IH, m), 7.05 (IH, s), 6.95 (IH, dd, J = 2.5, 8.9 Hz), 5.43 - 5.31 (IH, m), 4.80 - 4.53 (2H, m), 3.60 - 3.52 (6H, m), 2.96 - 2.80 (IH, m), 2.34 (1 H, dd, J = 1.9, 3.6 Hz), 1.99 (4H, s), 1.37 (3H, d, J = 6.1 Hz) ppm.

Example 130: (7R,13R)- or (7S,13R)-7,13-dimethyl-8,14-dioxa-5,10,19,20,23-penta azatetracyclop 3.5.2. l²’⁶.0^,8’^2,]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

284

Example 130 is prepared according to the synthesis route described below.

Préparation of intermediate 159: 4-chioro-2-iodopyrimidine

To a mixture of 4-chloropyrimidin-2-amine (50 g, 386.0 mmol), isopentyl nitrite (155.9 mL, I 157.9 mmol) and diiodomethane (139.9 mL, 1736.8 mmol) in 501 mL of THF, was added copper(I) iodide (73.5 g, 386.0 mmol) at room température. The mixture was stirred at 85°C for 6 hours. The mixture was filtered over a pad of celite and concentrated under vacuo. The 10 mixture was diluted with EtOAc and washed with a 10% solution of sodium bisulfite (x2). The orgranic layers were dried over MgSÛ4, filtered and concentrated udner reduced pressure. The product was purified by flash chromatography on silica gel, using as eluents heptane/ethyl acetate (100:0 to 80:20) to afford 4*chloro-2-iodopyrimidine 159 as a white solid.

LCMS method B: [M+H]⁺ = 240.9, t_R = 0.485 min

Préparation of intermediate 160: 1 -(4-chloropyrimidin-2-yl)ethan-l-ol

4-chloro-2-iodopyrimidine 159 (6.000 g, 24.955 mmol) was dissolved in 125 mL of dry THF under nitrogen atmosphère. The reaction was cooled at -78°C and méthylmagnésium chloride 20 (3 M in THF) (16.630 mL, 49.910 mmol) was added dropwise and the mixture was stirred at 78°C for 1 hour. Acetaldehyde (4.185 mL, 74.865 mmol) was added to the mixture and the reaction was warmed at 0°C over 2.5 hours. The reaction was diluted with EtOAc and a sat. solution ofNHiCl was added. The organic layerwas separated, dried over MgSO4, filtered and

285

concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel, using as eluents heptane/ethyl acetate (100:0 to 65:35) to afford 1-(4-chloropyrimidin-2yl)ethan-l-ol 160 as a yellow oil.

LCMS method E; [M+H]⁺ = 159.0, t_R = 1.297 min

Préparation of Example 130: (7R,13R)- or (7S,13R)-7,13-dimethyl-8,14-dioxa-5,10,19, 20,23-pentaazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Example 130 is prepared via chiral HPLC séparation of the two diastereoisomers. The chiral 10 séparation was done on a Column Waters XSELECT Cl 8 19*100 mm, 5 gm, 35% to 40%

MeCN in (NHijsCOî aq. 2 g/L, 19 mL/min, RT.

To a solution of (13R)-7,13-dimethyl-19-(oxan-2-yl)-8,14-dioxa-5,10,19,20,23-pentaazatetra cyclo[l 3.5.2.1²ⁱ⁶.0^,8’²¹]tricosa-1(20),2,4,6(23), 15,17,21 -heptaen-9-one (710 mg, 1.62 mmol) in

MeOH (27.8 mL) and water (4.6 mL) was added p-toluenesulfonic acid monohydrate (1.54 g, 8.12 mmol) and the reaction mixture was stirred at 80°C for 24 h. Then, to the reaction mixture was added p-toluenesulfonic acid monohydrate (308 mg, 1.62 mmol) and stirred for 2h at 80°C. The reaction mixture was evaporated under vacuo and the residue was dissolved in EtOAc (50 mL) then a saturated aqueous solution of sodium hydrogen carbonate (50 mL) was added. After séparation, the aqueous layer was extracted with ethyl acetate (2x). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to give the (7R,13R)- or (7S,13R)-7,13-dimethyl-8,14-dioxa-5,10,19,20,23pentaazatetracyclo[ 13.5.2.1²’⁶.0^,8,21]tricosa-1(20),2,4, 6(23), 15,17,21 -heptaen-9-one example 130 as a white solid.

LCMS method F: [M+H]⁺ = 354, t_R = 1.92 min

LCMS method G: [M+H]⁺ = 354, t_R = 1.92 min

Ή NMR (400 MHz, ί/6-DMSO) δ 13.63 (IH, m), 8.78 (IH, d, J = 5.3 Hz), 8.03 (IH, dd, J =

0.7, 5.2 Hz), 7.89 - 7.86 (2H, m), 7.55 - 7.52 (IH, m), 7.00 (IH, dd, J = 2.5, 8.9 Hz), 5.77 (IH,

286

q, J = 6.8 Hz), 4.63 - 4.57 (IH, m), 3.58 - 3.50 (IH, m), 2.89 - 2.80 (IH, m), 2.38 - 2.29 (IH, m), 1.67 (3H, d, J = 7.0 Hz), l .40 - l.37(4H, m) ppm.

Example 131: (7R,13R)- or (7S,13R)-7,13-dimethyl-8,14-dioxa-5,10,19,20,23-penta azatetracyclo[13.5.2.1²A0¹⁸’^2,]tricosa-l (20),2,4,6(23),15,17,2 l-heptaen-9-one

Example 13 1 is prepared according to the synthesis route described in general Scheme K and chiral HPLC séparation of the two diastereoisomers. The chiral séparation was done on a 10 Column Waters XSELECT C18 19*100 mm, 5 pm, 35% to 40% MeCN in (NHOîCOî aq. 2 g/L, 19 mL/min, RT.

The fractions for the second batch was evaporated in vacuo to afford (7R,13R)~ or (7S,13R)7,13-dimethyl-8,14-dioxa-5,]0,19,20,23-pentaazatetracyclo[13.5.2,l²A0^,8’^2,]trîcosa1(20),2,4,6(23),15,17,21-heptaen-9-one with a 90% of purity (contained 5 % of the other 15 diastereoisomer). So the powder was put in acetonitrile for a recrystallization, the solid obtained was fîltered to afford the pure (7R,13R)- or (7S,13R)-7,13-dimethyl-8,14-dioxa-5,L0,19,20,23pentaazatetracyclo[13.5.2.1²’⁶.0^l8’²¹]tricosa-l(20),2,4,6(23),15,ï7,21-heptaen-9-one example 131 as a white powder.

LCMS method F: [M+H]⁺ = 354, t_R = 2.03 min

LCMS method G: [M+H]⁺ = 354, t_R = 2.02 min

Ή NMR (400 MHz, r/6-DMSO) δ 13.62(1 H, s), 8.81 - 8.78 (IH, m), 8.02 -7.98 (2H, m), 7.60 -7.49 (2H, m), 7.04-6.97(1 H, m), 6.10(1 H, q, J = 6.7 Hz), 4.93 - 4.85 (IH, m), 3.25 (IH. m), 3.05 -2.97 (1 H, m), 1.85 - 1.77 (1 H, m), 1.71-1.51 (4H, m), 1.41 - 1.38 (3H, m) ppm.

Example

132: ( 13R)-16-fl u oro-13-methy 1-8,14-dioxa-1 0,19,20-triazatetracyclo

[13.5.2.1²A0¹⁸’²¹]tricosa-l (20),2,4,6(23),15,17,21 -heptaen-9-one

287

Example 132 is prepared according to the synthesis route described in general Scheme C.

To a solution of (13R)-16-fluoro-l 3-methy 1-19-(oxan-2-yl)-8,14-dioxa-l 0,19,205 triazatetracyclo[l3.5.2.1²’⁶.0^18,21]trîcosa-l(20),2,4,6(23),l5,17,21-heptaen-9-one (284 mg, 0.65 mmol) in MeOH (1 i mL) and water (2 mL) was added p-toluenesulfonic acid monohydrate (615 mg, 3.23 mmol) and the reaction mixture was stirred at 80°C for 12 h. The reaction mixture was evaporated under vacuo and the residue was dissolved in EtOAc (50 mL) then a saturated aqueous solution of sodium hydrogen carbonate (50 mL) was added. After séparation, the 10 aqueous layer was extracted with ethyl acetate (2x). The combined organic layer was washed brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to give an oil. The residue was put in acetonitrile, a solid appeared and was filtered to afford (13R)-16-fluoro13-methy 1-8,14-dioxa-l 0,19,20-triazatetracyclo[ 13.5.2. l^2,6.0¹⁸’²¹]tricosa-1(20),2,4,6(23), 15,1 7,21 -heptaen-9-one example 132 as a white solid.

LCMS method F: [M+H]⁺ = 356, t_R = 2.30 min

LCMS method G: [M+H]⁺ = 356, t_R = 2.38 min

Ή NMR (400 MHz, t/6-DMSO) δ 13.23 - 13.20 (1 H, m), 7.93 (IH, dd, J = 4.9, 7.0 Hz), 7.867.80 (2H, m), 7.50 - 7.45 (2H, m), 7.39 - 7.36 (IH, m), 7.31 - 7.28 (IH, m), 5.75 (IH, d, J = 12.9 Hz), 4.82 (IH, d, J = 12.0 Hz), 4.66 - 4.59 (IH, m), 3.59 - 3.54 (IH, m), 2.95 -2.87(1H, 20 m), 2.40 - 2.33 (IH, m), 1.45 - 1.42 (4H, m) ppm.

Example

133: (13R)-13-methyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo

[13.5.2.1²'\0^,8’^2lJtricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

288

Example 133 is prepared according to the synthesis route described in general Scheme K.

To a solution of (13R)-13-methyl-l 9-(oxan-2-yl)-8,14-dioxa-4,10,19,20,23-pentaazatetra 5 cyclo[13.5.2.1²'⁶.0¹⁸’^2l]tricosa-l(20),2,4,6(23),15,17,21-heptaen’9One (413 mg, 0.98 mmol) in

MeOH (16.8 mL) and water (2.8 mL) was added p-toluenesulfonic acid monohydrate (931 mg, 4.88 mmol) and the réaction mixture was stirred at 65°C ovemight. The reaction mixture was diluted with DCM and with a saturated aqueous solution of sodium hydrogen carbonate. After séparation, the aqueous layer was extracted with DCM (3x). The combined organic layer was 10 washed brine, dried over sodium sulfate, filtered and evaporated under reduced pressur to give an yellow oil. This oil was triturated in ACN and a cream precipitate was observed. The mixture was filtered and washed with ACN (2 x) the cream solid was dried for 1 night to give (13R)13-methyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹]tricosa1(20),2,4,6(23), 15,17,2 Lheptaen-9-one example 133 as a cream solid.

LCMS method F: [M+H]⁺ = 340, t_R = 1.92 min

LCMS method G; [M+H]⁺ = 340, t_R = 1.98 min

Ή NMR (400 MHz, rf6-DMSO) δ 13.51 (IH, m), 9.27 (IH, s), 8.52 (1 H, s), 7.83 (2H, m), 7.52 (IH, d, J = 8.9 Hz), 6.99 (IH, dd, J = 2.3, 8.9 Hz), 5.69(1 H, d, J = 15.0 Hz), 5.16 (IH, d, J =

14.8 Hz), 4.60 (IH, m), 3.49(1 H, m),2.9l (]H, t, J = l L4 Hz), 2.32 (IH, t, J = 11.8 Hz), 1.43 (IH, m), 1.38 (3H, d, J = 5.9 Hz) ppm.

Example 134: 8,14-dioxa-4-thia-10,19,20,23-tetraazatetracyclo[13.5.2.1²’⁵.0^{18 21}]trieosal(20),2,5(23),15,17,21-hexaen-9-one

289

Example 134 is prepared according to the synthesis route described in general Scheme L.

Préparation of intermediate 161: 2-(4-bromoth iazol-2-yi)ethyi N-(3-hydroxypropyi) 5 carbamate

O

Br

To a solution of 4-nitropheny] chloroformate (0.426 g, 2.11 mmol) and pyridine (0.311 mL, 3.84 mmol) in DCM (10 mL) was added dropwise at RT 2-(4-bromothiazol-2-yl)ethanol (0.400 g, 1.92 mmol) in DCM (5 mL). After 1 h at RT, a mixture of 3-aminopropan-l-ol (0.159 g, 2.1 1 mmol) and DIPEA (0.668 mL, 3.84 mmol) în DCM (5 mL) was added. The resulting reaction mixture was stirred at RT ovemight. The residue was diluted with 0.5 N NaOH solution and extracted with DCM twice. The combined organic layer was washed once again with 0.5 N NaOH solution and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash-column (25 g silica Macherey Nagel) chromatography (DCM - ethyl acetate 1:0 to 3:7) affordîng 2-(4-bromothiazol-2-yl)ethyl N-(3-hydroxypropyl)carbamate 161 as a coloriess oil.

LCMS method F: [M+Hf = 309, t_R = 1.65 min

Préparation of intermediate 162: 2-(4-(5-[tert-butyl(dunethyl)silyl]oxy-l-tetrahydropyran-22 0 yl-indazol-3-yi]th iazol-2-yl]ethyl N-(3-hydroxypropyl)carbamate

290

To a solution of tert-butyl-dÎmethyl-[]-tetrahydropyran-2-yl-3-(4,4,5,5-tetrarnethyl-l,3,2dioxaborolan-2-yl)indazol-5-yl]oxy-silane (0.700 g, 1.53 mmol) in dioxane (15 mL) and water (1.5 mL) were added at RT 2-(4-bromothiazol-2-yl)ethyl N-(3-hydroxypropyl)carbamate 161 (0.472 g, l .53 mmol), K3PO4 (0.972 g, 4.58 mmol), XPhos (0.073 g, 0.15 mmol) and Pd(PPh₃)4 (0.088 g, 0.08 mmol). The resulting reaction mixture was stirred under microwave irradition at 90°C for l h. The residue was diluted with saturated sodium chloride solution and extracted with ethyl acetate twice. The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash-column (25 g silica Macherey

Nagel) chromatography (cyclohexane - ethyl acetate, l :0 to 0:l) affording 2-[4-[5-[tertbuty l(dimethyl)silyl]oxy-Î-tetrahydropyran-2-yl-indazol-3-yl]thiazol-2-yl]ethyl N-(3-hydroxy propyl)carbamate 162 as a coloriess oil.

LCMS method F: [M+H]⁺ = 561.3, t_R = 3.29 min

Préparation of intermediate 163: 3-[2-[4-[5-ftert-butyl(dimethyl)silyl]oxy-ltetrahydropyran-2-yl-indazol-3-yl]thiazol-2-yl]ethoxycarbonylamino]propyi methanesulfonate

291

To a solution of 2-[4-[5-[tert-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3y l]th iazol-2-y IJethy I N-(3-hydroxypropyl)carbamate 162 (0.540 g, 0.96 mmol) and triethylamine (0.268 mL, 1.93 mmol) in DCM (18 mL) was added at 0°C methanesulfonyl 5 chloride (0.097 mL, 1.25 mmol) in DCM (2 mL). The reaction mixture was stirred at RT for

2h. The residue was diluted with saturated sodium chloride solution and extracted with DCM twice. The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo affording 3-[2-[4-[5-[tert-butyl(dimethyl)silyl}oxy-l-tetrahydropyran-2-yl-îndazoL3yl]thiazol-2-yl]ethoxycarbonylamino]propyl methanesulfonate 163 as a yellow oil, which was 10 used in the next step without further purification.

LCMS method F: [M-t-H]⁺ = 639.3, t_R = 3.41 min

Préparation of intermediate 164: 3-[2-[4-(5-hydroxy-l-tetrahydropyran-2-yl-indazo!-3yl)thiazol-2-yl]ethoxycarbonylamino]propyi methanesulfonate

292

To a solution of 3-[2-[4-[5-[tert-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3yl]thiazol-2-yl]ethoxycarbonylamino]propyl methanesulfonate 163 (0.615 g, 0.96 mmol) in THF (10 mL) was added at -10°C tetrabutylammonium fluoride 1 M in THF (1.06 mL, 1.06 5 mmol). The resulting reaction mixture was stirred at -10°C for 5 min. The reaction mixture was diluted with saturated ammonium chloride solution and extracted with ethyl acetate twice. The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo affording 3-[2-[4-(5-hydroxy-l-tetrahydropyran-2-yLindazol-3-yl)thiazol-2-yl]ethoxy carbonylamino]propyl methanesulfonate 164 as a yellow oil, which was used in the next step 10 without further purification.

LCMS method F: [M+H]⁺ = 525.1, t_R = 2.34 min

Préparation of intermediate 165: 19-(oxan-2-yI) -8,14-dioxa-4-th ia-10,19,20,23tetraazatetracyclo[13.5.2.I²·⁵.0^18,21/tricosa-1(20),2,5(23),15(22),16,18(21)-hexaen-9-one

To a suspension of césium carbonate (0.941 g, 2.89 mmol) in anhydrous NNdimethylformamide (192 mL) at 80°C was added dropwise (during 2 h) 3-[2-[4-(5-hydroxy-121105

293 tetrahydropyran-2-y 1-indazo I -3 -y l)th i azo 1-2-y I ] ethoxycarbonylam inojpropy ! methanesu Ifo nate

164 (0.505 g, 0.96 mmol) in VW-dimethylformamide (192 mL). After addition the resulting reaction mixture was stirred at 80°C for 2h. The reaction mixture was filtered and concentrated in vacuo, diluted with saturated sodium chloride solution and extracted with ethyl acetate twice. The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash-column (25 g silica Macherey Nagel) chromatography (DCM - ethyl acetate, 1:0 to 7:3) affording 19-(oxan-2-yl)-8,14-dioxa-4-thia-10,19,20,23tetraazatetracyclofi 3.5.2. 1²⁵.0¹⁸²¹ ]tricosa-1 (20),2,5(23), 15(22), 16,18(21 )-hexaen-9-one 165 as a white solid.

LCMS method F: [M+H]⁺ = 429.4, t_R = 2.45 min

Préparation of Example 134: 8,14-dioxa-4-thia-10,19,20,23-tetraazatetracycIo [ 13.5.2.1^2S.0¹⁸’²¹]tricosa-l (20),2,5(23),15,17,2 l-hexaen-9-one

To a suspension of 19-(oxan-2-yl)-8,14-dioxa-4-thia-10,19,20,23-tetraazatetracyclo

[13.5.2.1²^0¹⁸’²¹]tricosa-l(20),2,5(23), 15(22), 16,18(21)-hexaen-9-one 165 (0.150 g, 0.35 mmol) in MeOH (17.5 mL) and water (2.5 mL) was added p-toluenesulfonic acid monohydrate (0.333 g, 1.75 mmol) and the reaction mixture was stirred at 80°C for 4 h. The reaction mixture was concentrated under vacuo and the residue was neutralized by addition of saturated aqueous solution of sodium hydrogen carbonate. The residue was diluted with EtOAc. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layer was washed with sodium hydrogen carbonate, brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The solid was recrystallized in acetonitrile to give 8,14dioxa-4-îhia-10,19,20,23-tetraazatetracyclo[ 13.5.2.1^.0¹⁸’²¹]tricosa-1(20),2,5(23), 15,17,21 hexaen-9-one example 134 as a white solid.

LCMS method F: [M+H]⁺ = 345.2, t_R = 1.79 min

LCMS method G: [M+H]⁺ = 345.2, tR = 1.78 min, [M-H]^-= 343.1, tR = 1.78 min

294

Ή NMR (400 MHz, rf6-DMSO) δ 13.05 - 13.03 (IH, ni), 7.83 (IH, s), 7.59 - 7.51 (2H, m),

7.46 - 7.43 (IH, m), 6.95 (IH, dd, J = 2.4, 9.0 Hz), 4.42 (2H, t, J = 5.2 Hz), 4.27 - 4.22 (2H, m), 3.48 (2H, dd, J = 4.6, 5.8 Hz), 3.10-3.05 (2H, m), 1.82 (2H, d, J = 8.2 Hz) ppm.

Example 135: 8,14-dioxa-3-thia-10,19,20,23-tetraazatetracyclo[13.5.2.1²’^s,0¹⁸’²¹]tricosa1(20),2(23),4,15,17,21-hexaen-9-one

Example 135 is prepared according to the synthesis route described în general Scheme L.

Préparation of intermediate 166: 2-(2-bromothiazol-4-yl)ethyl N-(3-hydroxypropyl) carbamate

Br

To a solution of 4-nitrophenyl chloroformate (0.533 g, 2.64 mmol) and pyridine (0.388 mL, 4.81 mmol) in DCM (10 mL) was added dropwise at RT 2-(2-bromothiazol-4-yl)ethanol (0.500 g, 2.40 mmol) in DCM (5 mL). After I h atRT, a mixture of 3-aminopropan-l-ol (0.198 g, 2.64 mmol) and DIPEA (0.835 mL, 4.81 mmol) in DCM (5 mL) was added. The resulting reaction mixture was stirred at RT overnight. The residue was diluted with 0.5 N NaOH solution and extracted wîth DCM twice. The combined organic layer was washed once again with 0.5 N NaOH solution and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash-column (25 g silica Macherey Nagel) chromatography (DCM - ethyl acetate 1:0 to 2:8) affording 2-(2-bromothiazol-4-yl)ethyl N-(3-hydroxypropyl)carbamate 166 as a colorless oil·

LCMS method F: [M+H]⁺ = 309, t_R = 1.60 min

295

Préparation of Example 135: 8,14-(lioxa-3-thia-10,19,20,23-tetraazatetracyclo

[13.5.2.1²\0^IS2i]tricosa-l(20),2(23).4.15.17,21-hexaen-9-one

To a solution of 19-(oxan-2-yl)-8,14-dioxa-3-thia-10,19,20,23tetraazatetracyclo[l 3.5.2.1²’⁵.0¹⁸’²¹]tricosa-1 (20),2(23),4,15,17,21 -hexaen-9-one (0.360 g, 0.84 mmol) in MeOH (150 mL) and water (5 mL) was added p-toluenesulfonic acid monohydrate (0.799 g, 4.20 mmol) and the reaction mixture was stirred at 80°C for 4 days. The reaction mixture was concentrated under vacuo and the residue was neutralized by addition of saturated aqueous solution of sodium hydrogen carbonate. The residue was diluted with EtOAc. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layer was washed with sodium hydrogen carbonate, brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The solid was triturated in acetonitrile to give 8,14-dioxa-3-thia-l 0,19,20,23-tetraazatetracyclo[] 3.5.2.1^2,5.0^,8'^2,]tricosa-l (20),2(23),4,15,

17,21 -hexaen-9-one example 135 as a white solid.

LCMS method F: [M+H]⁺ = 345.2 t_R = 1.87 min

LCMS method G: [M+H]⁺ = 345.2, t_R = 1.85 min, [M-H]'= 343.1, t_R = 1.85 min 'HNMR (400 MHz, r/6-DMSO) δ 13.35 (IH, s), 7.69 - 7.67 (IH, m), 7.56 - 7.49 (2H, m), 7.35 (IH, s), 7.01 (IH, dd, J = 2.4, 9.0 Hz), 4.38 - 4.26 (4H, m), 3.18 - 3.05 (4H, m), 1.84 (2H, ddd, 20 J = 0.8, 8.9, 17.4 Hz) ppm.

Example 136: (7R,13R)-7,13-dimethyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo

[13.5.2.1²A0’⁸’^2l]tricosa-l(20),2,4,6(23),15,17,21-heptaeii-9-one

296

Example 136 is prepared according to the synthesis route described in general Scheme K.

Préparation of intermediate 167: [(lR)-l-(6~bromo-2-pyridyl)ethyQ acetate

Br

To a stirred solution of i-(6-bromo-2-pyridyl)ethanol (1 g, 4.94 mmol, I eq) in anhydrous diisopropyl ether (120 mL) at 0°C, was added vinyl acetate (2 mL, 21 mmol, 42 eq), 4A molecular sieves (1 g), and Lipase îmmobilized from Candida Antarctica (200 mg) and the reaction mixture was stirred at room température for 48 hours. The catalyst and molecular sîeves were filtered off and the solvent was concentrated under reduced pressure. The oily residue was purified by column chromatography eluting with cyclohexane/EtOAc : 90/10 to 80/20 to give [(1 R)-l-(6-bromo-2-pyridyl)ethyl] acetate 167 as colorless oil.

LCMS method F: [M+H]⁺ = 246, t_R = 2.28 min

Préparation of intermediate 168: (1R)-1~(6-bromo-2-pyridyl)ethanol

OH

Br

To a solution of [(1 R)-l-(6-bromo-2-pyridyI)ethyl] acetate 167 (563 mg, 2.3 mmol, 1 eq) in a mixture of MeOH/water: 1/1 (20 mL) was added potassium carbonate (317 mg, 2.3 mmol, 1 eq) and the solution was stirred at room température for 3 hours. MeOH was then evaporated and the aqueous phase was extracted with EtOAc (3x). The combined organic extract was

297 washed with brine, dried over Na₂SO4, filtered and evaporated uner reduced pressure to give the expected compound (lR)-l-(6-bromo-2-pyridyl)ethanol 168 as a coloriess oil.

LCMS method F: [M+H]⁺=202, t_R = 1.69 min

Préparation of Example 136: (7R,13R)-7,13-dimethyl-8,14-dioxa-10,19,20,23tetraazatetracyclo[13.5.2.1²’⁶.0^I8,2,]tricosa-l(20),2,4, 6(23),15,17,21 -heptaen-9-one

To a suspension of (7R,13R)-7,13-dimethyl-19-(oxan-2-yl)-8,I4-dioxa10,19,20,23-tetraazatetracyclo[ 13.5.2.1^2,6.0¹⁸’²¹]tricosa-1(20),2,4,6(23), 15,17,21-heptaen-9one (80 mg, 0.18 mmol, i eq) in MeOH/water (14 mL / 2 mL) was added para-toluenesulfonic acid monohydrate (174 mg, 0.91 mmol, 5 eq) and the reaction mixture was heated at 65°C for 24 hours. MeOH was removed partially under reduced pressure and a saturated solution of NaHCOa was added. The aqueous phase was extracted with EtOAc (2x) and the organic extract was washed with brine, dried overNa₂SO4, filtered and evaporated under reduced pressure. The solid residue was triturated in diîsopropyl ether, filtered and dried to give (7R,L3R)-7,13di methy 1-8,14-dioxa-10,19,20,23-tetraazatetracy c lo [ 13.5.2.1^2<5.0^{182 l}]tricosa-1(2 0),2,4, 6(23),15,17,21-heptaen-9-one example 136 as a white solid.

LCMS method F: [M+H]⁺ = 353.2, t_R = 2.28 min

LCMS method G: [M+H]⁺ = 353.3, t_R = 2.15 min

Ή NMR (400 MHz, rf6-DMSO, 80°C) δ 12.93 - 12.90(1 H, m), 8.1 1 - 8.05 (2H, m), 7.85 (IH, t, J = 7.7 Hz), 7.46 - 7.42 (IH, m), 7.34 - 7.29 (1 H, m), 7.22-7.08 ( 1 H, m), 6.97 - 6.94 (IH. m), 6.2-5.9 (IH, m), 5.05-4.8 (IH, m), 3.4-3.2 (IH, m), 3-2.95 (IH, m), 1.94-1.73 (IH, m), 1.721.51 (4H, m), 1.40 (3H, d, J = 6.1 Hz) ppm.

Example 137: (13R)-4-[(3R)-3-methoxypyrrolidin-l-yl]-13-methyl-8,14-dioxa-5,10,19,20,

23-pentaazatetracyclo(13.5.2.1²’⁶.0¹⁸’²¹]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Example 137 is prepared according to the synthesis route described in general Scheme K.

Préparation of intermediate 169: (4,6-dichloropyrimidin-2-yl)methyl acetate

O

Cl

To a solution of 4,6-dichloro-2-(chloromethyl)pyrimidine (0.830 g, 4.23 mmol) in N,Ndimethylfonnamide (50.0 mL) at 0°C was added potassium iodide (0.774 g, 4.66 mmol), and potassium acetate (0.457 g, 4.66 mmol) was added and the mixture was stirred during 12 hours at room température. Solvent was evaporated. Water (25 mL) and EtOAc (25 mL) were added.

Phases were separated and aqueous phase was extracted with EtOAc (3 x 25 mL), then organic phase was washed with a saturated solution of NaCl (25 mL), dried with Na2SO4, fïltered and concentrated to afford (4,6-dichloropyrimidin-2-yl)methyl acetate 169 as a white powder.

LCMS method F: [M+H]⁺ = 221, t_R = 2.07 min

Préparation ofintermediate 170: [4-[5-[tert-butyl(dimethyl)stlyl]oxy-l-tetrahydropyran-2-ylindazol-3-ylJ-6-chloro-pyrimidin-2-yl]methyl acetate

299

To a solution of tert-butyl-dîmethyl-[l-tetrahydropyran-2-yl-3-(4,4,5,5-tetramethy 1-1,3,2dioxaborolan-2-y[)indazol-5-yl]oxy-silane (2.5 g, 5.45 mmol) in dioxane (10 mL) and water (1 mL) was added at RT (4,6-dichloropyrîmidin-2-yl)methyl acetate 169 (999 mg, 4.54 mmol), Potassium phosphate tribasic (2.89 g, 13.62 mmol). The reaction mixture was degassed by bubbling nitrogen for 15 min, then XPhos (65 mg, 0.14 mmol) and Pd(PPh3)₄ (53 mg, 0.045 mmol) were added. The reaction mixture was stirred at 80°C for 45 min under microwave radiations. The reaction mixture was evaporated in vacuo to give a brown oil. To the reaction mixture was added EtOAc (100 mL) and water (50 mL). After séparation, the aqueous layer was extracted with EtOAc (2x50 mL), then the organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by flash chromatography (CyH/EtOAc 100 to 8/2 CyH/EtOAc) to afford [4-[5-[tertbutyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3-yl]-6-chloro-pyrimidin-2yl]methyl acetate 170 as an yellow oil.

LCMS method F: [M+H]⁺ = 517, t_R = 3.91 min

Préparation of intermediate 171: [4-chloro-6-(5-hydroxy-l-tetrahydropyran-2-yl-indazol-3yl)pyrimidin-2-yl]methyl acetate

To a solution of [4-[5-[tert-butyl(dîmethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3-yl]-6chloro-pyrimidin-2-yl]methyl acetate 170 (2.34 g, 4.53 mmol) in THF (40 mL) was added dropwise at RT tetrabutylammonium fluoride 1 M in THF (1.3 mL, 4.98 mmol). The resulting reaction mixture was stirred at RT ovemight. The reaction mixture was poured into ice water and stirred for 20 min. The aqueous phase was extracted with ethyl acetate (100 mL) twice and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a brown oil. The residue was purified by flash

300 chromatography CyH/EtOAc 5/5 to afford [4-chloro-6-(5-hydroxy-l -tetrahydropyran-2-ylindazol-3-yl)pynmidin-2-yI]methyl acetate 171 as a white solid.

LCMS method F: [M+H]⁺ = 403, t_R = 2.82 min

Préparation of intermediate 172: benzyl )4-)5-)(lR)-3-(benzyloxycarhonylamino)-l-methylpropoxy]-l-tetrahydropyran-2-yl-indazol-3-yl]-6-chloro-pyrimidin-2-yl]methyl acetate

To a mixture of [4-chloro-6-(5-hydroxy-1 -tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-2yl]methyl acetate 171 (945 mg, 2.35 mmol) and césium carbonate (1.53 g, 4.7 mmol) in acetonitrile (20 mL) and ΛζΛ'-dimethylformamide (5 mL) was added [(lS)-3(benzyioxycarbonylamino)-l -methy i-propyl] methanesulfonate (778 mg, 2.59 mmol postulated) and the suspension was heated for 8 hours at RT. The reaction mixture was filtered to removed césium carbonate and the salts were washed with acetonitrile. The filtrate was evaporated in vacuo to give an yellow oil. The oily residue was put in EtOAc (50 mL) and water (30 mL), the aqueous layer was extracted with EtOAc (2x50 mL), washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo to give an oil. The residue was purified by flash chromatography (CyH/AE 5/5) to afford benzyl [4-[5-[(lR)-3(benzyloxycarbonylamino)-l -methyl-propoxy]-! -tetrahydropyran-2-yl-indazol-3-yl]-6chloro-pyrimidin-2-yl]methyl acetate 172 as an off-white solid.

LCMS method I: [M+H]⁺ = 608, t_R = 2.86 min

Préparation of intermediate 173: [4-[5-[(lR)-3-(benzyloxycarbonylamino)-l-methylpropoxyj-l-tetrahydropyran-2-yl-indazol-3-yl]-6-[(3R)-3-methoxypyrrolidin-l-yl]pyrimidin2-yl]methyl acetate

301

To a mixture of [4-[ 5 - [( i R)-3-(benzyloxycarbonylamino)-l -methy 1-propoxy]-1 tetrahydropyran-2-yl-indazol-3-yl]-6-chloro-pyrimidin-2-yl]methyl acetate 172 (103 mg, 0.17 mmol) and potassium carbonate (94 mg, 0.37 mmol) in XA-dimethylfomramide (1.5 mL) was 5 added (3R)-3-methoxypyrrolidine hydrochloride (51 mg, 0.37 mmol) and the suspension was stirred for 8 hours at RT. The reaction mixture was evaporated in vacuo to give an yellow oîl. Then to the residue was added EtOAc (20 mL) and water (10 mL). After séparation of the layers, the aqueous layer was extracted with EtOAc (10 mL) twice, then the organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated în vacuo to afford the 10 crude [4-[5-[(l R)-3-(benzyloxycarbonylamino)-1-methy 1-propoxy]-I-tetrahydropyran-2-ylindazol-3-yl]-6-[(3R)-3-methoxypyrrolidin-l-yl]pyrimidin-2-yl]methyl acetate 173 as an yellow oil.

LCMS method F: [M+H]⁺ = 673, t_R = 2.89 min

Préparation of intermediate 174: benzyl N-[(3R)-3-[3-[2-(hydroxymethyl)-6-pyrrolidin-l-ylpyrimidin-4-yl]-l-tetrahydropyran-2-yi-indazoi-5-yl]oxybutyl]carbamate

302

To a suspension of [4-[5-[(lR)-3-(benzyloxycarbonylamino)-l-methyl-propoxy]-ltetrahydropyran-2-yl-indazol-3-yl]-6-[(3R)-3-methoxypyrrolidin-l-yl]pyrimidin-2-yl]methyl acetate 173 (0.155 g, 0.23 mmol) in MeOH (2.0 mL) was added potassium carbonate (0.038 g, 5 0.28 mmol). The reaction was stirred at room température during 2 h. The reaction was stopped and filtered and evaporated. The crude was purified by chromatography column (RediSep, 4 g, CyH/EtOAc : 0% to 100% EtOAc) to afford benzyl N-[(3R)-3-[3-[2-(hydroxymethyi)-6pyrrolidin-l-yl-pyrimidin-4-yl]-l-tetrahydropyran-2-yl-indazol-5-yl]oxybutyl]carbamate 174 as a light yellow oil.

LCMS method F: [M+Hf = 631, ta = 2.23 min

Préparation of intermediate 175: (13R)-4-[(3R)-3-methoxypyrrolidin-l-yl]-13-methyl~l9(oxan-2-y!)-8,14-dioxa-5,l0,19,20,23-pentaazatetracyclo[13.5.2.1²'⁶.0^!S’²¹]tricosa1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

To a solution of benzyl N-[(3R)-3-[3-[2-(hydroxymethyl)-6-[(3R)-3-methoxypyrrolidin-lyl]pyrimidin-4-yl]-l-tetrahydropyran-2-yl-indazoi-5-yl]oxybutyl]carbamate 174 (121 mg, 0.19

303 mmol) in dry acetonitrile (10 mL) was added at RT finely powdered potassium hydroxide (54 mg, 0.96 mmol) in one portion. The réaction mixture was stirred at RT for 12 h. The reaction mixture was fîltered then rinsed with ethyl acetate and evaporated under reduced pressure to gïve (13R)-4-[(3R)-3-methoxypyrrolidin-l-yl]-l 3-methy M9-(oxan-2-yl)-8,14-dioxa5,10,19,20,23-pentaazatetracyclo[13.5.2.i²’⁶.0¹⁸’^2l]tricosa-l(20),2(23),3,5,15(22),16,l 8(21 )heptaen-9-one 175 as a light yellow oil.

LCMS method F: [M+H]⁺ = 523, t_R = 2.68 min

Préparation of Example 137 : (13R)-4-[(3R)-3-methoxypyrrolidin-l-yl]-13-methyl-8,14dioxa-5,10,19,20,23-pentaazatetracyclo| 13.5.2. l²’⁶.0^18,21]tricosa-l(20),2,4,6(23),15,17,21heptaen-9-one

To a solution of ( 13R)-4-[(3R)-3-methoxypyrrolidin-l -yl]-13-methyl19-(oxan-2-yl)-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1²’⁶.0^,8’^2î]tricosa1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one 175 (53 mg, 0.10 mmol) in MeOHÆLO (2/0.3 mL) was added p-toluenesulfonic acid monohydrate (95 mg, 0.5 mmol). The mixture was heated at 80 °C for 5 hours. Then to the reaction mixture was added p-toluenesulfonic acid monohydrate (50 mg, 0.26 mmol) and stirred at 80 °C for 5 hours. The reaction mixture was evaporated in vacuo and a saturated solution of sodium bicarbonate (10 mL) and DCM (10 mL) was added. Then, the aqueous layer was extracted with DCM (2x10 mL), then the organic layer was washed with brine, dried over sodium sulfate, fîltered and evaporated in vacuo to give a solid. The solid was purified by flash chromatography (CyH to 100% EtOAc) to afford (13R)4-[(3R)-3-methoxypyrrolîdîn-1 -yl]-l 3-methyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo [13.5.2.1²A0¹⁸’^2l]tricosa-l(20),2,4,6(23),15,l7,21-heptaen-9-one example 137 as a white powder.

LCMS method F: [M+H]⁺ = 439, t_R = 2.06 min

LCMS method G: [M+H]⁺ = 439, t_R = 2.23 min

304

Ή NMR (400 MHz, (76-DMSO) δ 13.36 (l H, s), 7.93 (l H, d, J = l .9 Hz), 7.79 ( l H, dd, J = 4.9, 7.4 Hz), 7.49 - 7.46 (IH, m), 7.06 (IH, s), 6.95 (IH, dd, J = 2.4, 9.0 Hz), 5.41 - 5.36 (l H, m), 4.74 (IH, d, J = 15.6 Hz), 4.62 -4.56 (IH, m), 4.14-4.07 (IH, m), 3.57 (4H, m), 3.50 - 3.43 (3H, m), 2.87 (IH, t, J = 14.4 Hz), 2.35 - 2.28 (IH, m), 2.09 - 2.09 (3H, m), 1.39- 1.36(4H,m) 5 ppm.

Example 138: (13R)-16-chloro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo

[13.5.2.1^2É.0¹⁸’²¹]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Example 138 is prepared according to the synthesis route described în general Scheme K.

To a solution of (13R)-16-chloro-I3-methyl-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetra cyclo[I3.5.2.]^2,6.0¹⁸’²¹]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one (376 mg, 0.83 mmol) in 15 MeOH (49 mL) and water (6 mL) was added p-toluenesulfonic acid monohydrate (785 mg, 4.13 mmol) and the reaction mixture was heated to 65°C for 3 hours and 30 minutes. The reaction mixture was concentrated under vacuo and the crude was neutralized by slow addition of a saturated aqueous sodium hydrogen carbonate solution. It was diluted with EtOAc and after séparation, the aqueous layer was extracted with EtOAc (3 x). The combined organic layer was 20 washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure.

The crude was triturated from ACN then filtrated and washed two times with ACN to give ( 13R)-16-chloro-l 3-methy 1-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1²’⁶.0'^8,2 ^tricosa1 (20),2,4,6(23),15,17,21-heptaen-9-one example 138 as a white powder.

LCMS method F: [M+H]¹ = 372, t_R = 2.42 min

LCMS method G: [M+H]⁺ = 372, t_R = 2.40 min

Ή NMR (400 MHz, (76-DMSO) δ 13.24 (IH, m), 7.94 (IH, m), 7.85 (IH, m), 7.80 (IH, m), 7.74 (IH, s), 7.48 (IH, t, J = 7.7 Hz), 7.37 (IH, s), 7.29 (IH, m), 5.74 (IH, m), 4.8 (IH, m),

4.63 (IH, m), 3.56 (IH, m), 2.92 (IH, m), 2.37 (IH, m), 1.48 (IH, m), 1.44 (3H, d, J = 6 Hz) ppm.

305

Example 139: (13R)-13,16-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²⁰.0¹⁸’²¹] tricosa-l(20),2,4,6(23),I5,17,21-heptaen-9-one

Example 139 is prepared according to the synthesis route described in general Scheme K.

To a solution of (13R)-13,16-dimethyl-19-(oxan-2-ylF8,14-dioxa-l0,19,20-triazatetracyclo [13.5.2.l^2,6.0^l8i2I]tricosa-1(20),2,4,6(23), 15,17,21-heptaen-9-one (537 mg, 1.23 mmol) in MeOH (72 mL) and water (9 mL) was added p-toluenesulfonîc acid monohydrate (1.17 g, 6.17 mmol) and the reaction mixture was heated to 65°C for 3 hours and 30 minutes. The reaction mixture was concentrated under vacuo and the crude was neutral ized by slow addition of a saturated aqueous sodium hydrogen carbonate solution. It was diluted with EtOAc and after séparation, the aqueous layer was extracted with EtOAc (3 x). The combined organic layer was washed with brine, dried over sodium sulfate, fïltered and evaporated under reduced pressure. The crude was triturated from ACN then filtrated and washed two times with ACN to give (13R)-13,l6-dimethyl-8,14-dioxa-I0,19,20-triazatetracyclo[13.5.2.1²’⁶.0’⁸’^2l]tricosa1(20),2,4,6(23),15,17,2Lheptaen-9-one example 139 as a white powder.

LCMS method F: [M+H]⁺ = 352, t_R = 2.39 min

LCMS method G: [M+H]⁺ = 352, t_R = 2.38 min

Ή NMR (400 MHz, rf6-DMSO) δ = 12.97 (IH, s), 7.94 ( LH, m), 7.86(1 H, m), 7.84 (IH, m), 7.45 (IH, t, J = 7.8 Hz), 7.37 (IH, s), 7.26 (IH, m), 7.24 (IH, m), 5.74 (IH, m), 4.82 (IH, m), 4.58 (IH, m), 3.57 (IH, m), 2.9 (IH, m), 2.41 (IH, m), 2.27 (3H, d, J = 0.8 Hz), 1.42(3H, d, J = 5.9 Hz), 1.39 (IH, m) ppm

[13.5.2.1²'⁶.0¹⁸’²'] tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one

Example 140: (13R)-13-methyl-8,14-dioxa-3,10,19,20,23-pentaazatetracyclo

306

Example 140 is prepared according to the synthesis route described in general Scheme B.

To a solution of (13R)-13-methyl-l 9-(oxan-2-yl)-8,14-dioxa-3,10,19,20,235 pentaazatetracyclo[13.5.2. l²’⁶.0¹⁸’²ⁱJtricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one (77 mg, 0.18 mmol) in MeOH (10.6 mL) and water (1.3 mL) was added p-toluenesulfonic acid monohydrate (173 mg, 0.91 mmol) and the reaction mixture was heated to 65°C for 3 hours and 30 minutes. The mixture was heated at 65 °C for 1 day. The reaction mixture was concentrated under vacuo and the crude was neutralîzed by slow addition of a saturated aqueous 10 sodium hydrogen carbonate solution. It was diluted with EtOAc and after séparation, the aqueous layer was extracted with EtOAc (3 x). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude was triturated from ACN then fîltrated and washed two times with ACN to give (13R)-13-methyl8,I4-dioxa-3,10,19,20,23-pentaazatetracyclo[13.5.2.1²’⁶.0^l8’^2l]tricosa-l(20),2,4,6(23), 15 15,17,21 -heptaen-9-one example 140 as a pale yellow solid.

LCMS method F: [M+H]⁺ = 340, tR = 1.73 min

LCMS method G: [M+H]⁺ = 340, t_R = 1.74 min

Ή NMR (400 MHz, rfô-DMSO) δ 13.51 (IH, m), 8.81 (IH, d, J = 5 Hz), 7.84 (2H, m), 7.5 (IH, m), 7.33 (IH, m), 6.97 (IH, dd, J = 1.6, 8.4 Hz), 5.59 (1 H, m), 5.07 (1 H, m), 4.62 (1 H, m), 3.48 20 (IH, m), 2.91 (IH,m),2.3 (IH,m), 1.41 (lH,m), 1.38 (3H, d, J = 5.5 Hz) ppm.

Préparation of intermediate 176: benzyl N-f(3S)-3-hydroxybutyl]carbamate Ο _Ξ

H

To a solution of (2S)-4-aminobutan-2-ol (10 g, 112.36 mmol) in a mixture of THF (143 mL) and water (143 mL) was added sodium hydrogenocarbonate (10.38 g, 123.59 mmol). The suspension was cooled to 0°C and benzyl chloroformate (17.64 mL, 123.59 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hours. The solution

307 was diluted with water and extracted with EtOAc (3x). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The oily residue was purified by column chromatography eluting with dichloromethane / ethyl acetate: 100/0 to 80/20 to give benzyl jV-[(3S)-3-hydroxybutyl]carbamate intermediate 176 as a colorless oil.

LCMS method F: [M+H]* = 224, t_R = 1.94 min

Préparation of intermediate 177: [(lS)-3-(benzyloxycarbonylamino)-l-methyl-propyl] methanesulfonate

To a cooled solution (0°C) of benzyl N-[(3S)-3-hydroxybutyl]carbamate intermediate 176 (17.06 g, 76.52 mmol) and triethylamine (21.3 mL, 153.04 mmol) in dichloromethane (300 mL) was added dropwise methanesulfonyl chloride (7.7 mL, 99.47 mmol) and the reaction mixture was stirred at room température for 19 hours. The reaction mixture was quenched with an aqueous solution of IN HCl and extracted with dichloromethane (lx). The organic layer was washed with a saturated aqueous solution of NaHCO3 then water and brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to give [(lS)-3(benzyloxycarbonylamino)-l-methyl-propyl] methanesulfonate intermediate 177 as a yellow oil.

LCMS method F: [M+H]* = 302, tR = 2.26 min

Préparation of intermediate 178: benzyl N-f(3R)-3-(3-iodo-I-tetrahydropyran-2-yl-indazol5-yl)oxybutylJcarbamate

308

To a solution of 3-iodo-l-tetrahydropyran-2-yl-indazol-5-ol 4 (5.I52 g, 14.97 mmol) and césium carbonate (14.633 g, 44.91 mmol) in DMF (50 mL) was dropwise added a solution of [(lS)-3-(benzyloxycarbonylamino)-I-methyl-propyl] methanesulfonate 177 (5.406 g, 17.96 mmol) in DMF (26 mL) and the reaction mixture was stirred at RT for the week-end. The reaction mixture was filtered then concentrated under reduced pressure. The crude product was diluted with ethyl acetate and a saturated solution of NaHCO3 was added then it was extracted with ethyl acetate (2 x). The organic layer was washed with water then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography eluting with Cyclohexane / Ethyl acetate - Ethanol (3-1), 100/0 to 70/30, to give benzyl ?/-[(3R)-3-(3-iodo-l-tetrahydropyran-2-yl-indazo!-5yl)oxybutyl]carbamate 178 as a yellow oil.

LCMS method F: [M+H]⁺ = 550.1, t_R = 3.20 min

Préparation of intermediate 179: benzyl N-(3-hydroxybutyl)carbamate

To a solution of 4-aminobutan-2-ol (1.78 g, 20 mmol) in a mixture of THF (30 mL) and water (30 mL) was added sodium hydrogenocarbonate (1.84 g, 22 mmol). The suspension was cooled at 0°C and benzyl chloroformate (3.15 mL, 22 mmol) was added portionwise and the reaction mixture was stirred at room température ovemight. The solution was diluted with water and extracted with EtOAc (3x). The combined organic extract was washed with brine, dried over NasSOq, filtered and evaporated under reduce pressure. The oily residue was purified by

309 chromatography eluting with cyclohexane/EtOAc: 70/30 to 50/50 to give the expected compound benzyl 7v-(3-hydroxybutyl)carbamate intermediate 179 as a colorless oil.

LCMS method F: [M+H]⁺ = 224.1, t_R = 1.92 min

Préparation of intermediate 180: [3-(benzyIoxycarbonylamino)-l-methyl-propylJmethane sulfonate

To a cooled (0°C) solution of benzyl N-(3-hydroxybutyl)carbamate 179 (1.67 g, 7.5 mmoi) and EtjN (1.56 mL, 11.25 mmol) in dichoromethane (30 mL) was added dropwise methanesulfonyl chloride (638 pL, 8.25 mmol) and the reaction mixture was stirred at room température ovemight. The organic phase was washed with a IN HCl solution, with a saturated solution of NaHCOs, with brine, dried over Na₂SO4, filtered and evaporated under reduced pressure to gve the expected compound [3-(benzyloxycarbonylamino)-l-methy l-propyl] methanesulfonate 180 as a colorless oil. The crude compound was used in the next step without further purification. LCMS method F: [M+H]⁺ = 302, t_R = 2.24 min

Préparation of intermediate 181: N-[3-(3-iodo-l-tetrahydropyran-2-yl-indazoI-5yl)oxybutyl]carbamate

To a solution of 3-iodo-l -tetrahydropyran-2-yl-indazol-5-ol 4 (2 g, 6.08 mmol) and césium carbonate (5.94 g, 18.25 mmoi) in DMF (20 mL) was added dropwise a solution of [3(benzyloxycarbonylamino)-l-methy l-propyl] methanesulfonate 180 (2.2 g, 7.3 mmol) in DMF (10 mL) and the reaction mixture was stirred at 60°C ovemight. The reaction mixture was cooled to room température and water was added. The aqueous phase was extracted with EtOAc

310 (3x) and the organic phase was washed with brine, dried over NaaSO4, filtered and evaporated under reduced pressure. The residue was purified by chromatography eluting with cyclohexane/EtOAc: 70/30 to give the expected compound jV-[3-(3-iodo-l-tetrahydropyran-2y 1-indazo 1-5-y l)oxybutyl] carbamate 180 as a colorless oil.

LCMS method F: [M+H]⁺ = 550.1, t_R = 3.20 min

Intermediates 179 to 181 are used as intermediates in the synthesis of Examples 50, 71, 92. Examples 62,63, 96, 97,100,101,102,105,106,113,114,117,120,125,127,128,129,130, 131, 133, 136, 137, and 140 can be obtained by chiral HPLC séparation of the corresponding racemates, or through a chiral synthesis using intermediates 176 to 178.

Example 141: 8-oxa-10,14,19,20-tetraazatetracyclo[13.5.2.1^2,6.0^18,2I]tricosa-l (20),2(23), 3,5,15(22),16,18(21)-heptaen-9-one

H

Example 141 is prepared according to the synthesis route described in general Scheme 1.

To a solution of 19-(oxan-2-yl)-8-oxa-10,14,19.20-tetraazatetracyclo[13.5.2.1²’⁶.0¹⁸'^2l]tricosa1(20),2(23),3,5,15 (22), 16,18(2 l)-heptaen-9-one (37mg, 0.09mmol) in dioxane (7.5ml) was added HCI 4N dioxane (360μ1, 1.8mmol). The reaction mixture was stirred ovemight at 60°C. Three drops of HCl 37% were added and the reaction mixture was stirred Ih at 60°C. The solvent was removed under reduced pressure and the mixture was purified by chromatography using a 4g SiO2 column eluted with DCM/MeOH 100/0 to 90/10. The desired fractions were combined and the solvent was removed under reduced pressure to give 8-oxa-10,14,19,20tetraazatetracyclo[l 3.5.2. l²’⁶.û’^8,21 ]tricosa-1(20),2(23 ),3,5,15(22),16,18(21 )-heptaen-9one.hydrochloride example 141 as a cream powder.

LCMS method F: [M+H]⁺ = 323.2, t_R= 1.70 min

LCMS method G: [M+H]⁺ = 323.2, t_R = 1.72 min ’H NMR (400 MHz, rf6-DMSO) δ 7.92 (IH, s), 7.85 (214, d, >1.5 Hz), 7.53 - 7.45 (2H, m), 7.35 - 7.31 (2H, m), 6.54 (IH, q, >2.9 Hz), 5.3 (IH, m), 4.61 (2H, d, >6.1 Hz), 3.68 (2H, t, >5.5 Hz), 3.27 (2H, m), 2.03 - 1.97 (2H, m), 1.04 (IH,d, >6.1 Hz) ppm.

Example 142: 8-oxa-l 0,19,20-triazatetracyclo [13.5.2.1²’⁶.0¹⁸²'Itricosa-1(20),2(23),3,5,

3ll

15(22),16,18(21)-heptaen-9-one

Example 142 is prepared according to the synthesis route described below.

Préparation of intermediate 182: diisopropylammonium;4-spiro[7,9-dioxa-8silan uidabicyclo[4,3.0]nona-l(6)_f2,4-triene-8,8 7,9-dioxa-8-silanuidabicyclo[4.3. Ofnonal,3,5-trieneJ-8-ylbutanenitrile

To an oven-dried, 100 mL round bottom flask equipped with a stir bar, reflux condenser, and gas inlet adapter was added catechol (5.67 g, 51.58 mmol) followed by THF (62 mL) and iPrzNH (4.44 mL, 31.74 mmol). The mixture was placed under an argon atmosphère and was allowed to stir at room température for 5 minutes. The solution became pale red. 4Trimethoxysilylbutanenitrile (5.00 g, 26.45 mmol) was added. The solution was heated to reflux in an oil bath and allowed to stir at this température for 18 hours. The solvent was removed under reduced pressure. The resulting powder was collected via filtration through a medium porosity fritted funnel. The powder was washed with EtzO (-100 mL) and pentane (-150 mL). The solid was collected and dried further under reduced pressure to give dnsopropylammonium;4-spiro[7,9-dioxa-8-silanuidabicyclo[4.3.0]nona-l(6),2,4-triene-8,8'7,9-dioxa-8-silanuidabicyclo[4,3.0]nona-l,3,5-triene]-8-ylbutanenitrile 182 as a slightly pink powder.

LCMS method F; [M+H]⁺ = not detected, t_R = 1.01 min

312

Préparation of intermediate 183: 4-(lH-indazol-5-yl) butanemtrile

To a 500 mL round bottom flask equipped with a Teflon-coated magnetic stir bar was added 4,4’-di-tert-butyl-2,2’-bipyrîdine (134 mg, 0.5 mmol), and nickel(II) chloride ethylene glycol dimethyl ether complex (109 mg, 0.5 mmol). The vial was capped and purged with nitrogen, then 30 mL THF was introduced. The resulting suspension was heated briefly with a heat gun until the nickel and ligand were fully solubilized, yielding a pale green solution. The solution was cooled in an ice bath, resulting in the immédiate précipitation of an evergreen solid. Solvents were then evaporated under reduced pressure to give a fine coating ofthe ligated nickel complex.

Once dry, 5-iodo-l H-indazole (2.440 g, 10.0 mmol, 1.0 equiv), diisopropylammonium;4spiro[7,9-dioxa-8-silanuidabicyclo[4.3.0]nona-l(6),2,4-triene-8,8'-7,9-dioxa-8-silanuida bicyclo[4.3.0]nona-1,3,5-triene]-8-ylbutanenitrile 182 (8.280 g, 20.0 mmol), and tris(2,2'bipyridine)ruthenium(II) hexafluorophosphaie (172 mg, 0.2 mmol) were added in succession. The vial was then capped and purged four times. Under inert atmosphère, DMF (100 mL) was introduced. The vial containing ail the reagents was further sealed with parafihn and stirred approximately 10 cm away from a PR160L LED PhotoReaction Lighting setup (2 LED with different wavelengths: 390 nm and 456 nm) and was stirred for 24 hours. A fan was blown across the reaction setup to suppress the heat generated by the latter (the reaction températures were estimated to be -30 °C). The reaction mixture was allowed to stir for 24 more hours. The crude reaction mixture was poured in a separatory tunnel and diluted with H₂O ( 120 mL). The resulting suspension was extracted with Et2O (3 x 180 mL), and the combined organic extracts were washed with a saturated solution of Na₂CO₃ (2 ^x 120 mL) then H₂O (120 mL), dried over anhydrous magnésium sulfate, filtered and concentrated under reduced pressure. The combined residue was purified by column chromatography on silica gel, eluting with EtOAc and hexanes (from 99/1 to 40/60) to obtain 4-(lH-indazol-5-yl)butanenÎtrile 183 as a white solid.

LCMS method F: [M+H]⁺ = 186.3, t_R = 1.75 mtn

313

Préparation of intermediate 184: 4-(l -tetrahydropyran-2-yUndazol-5-yl)butaneniirile

To a solution of 4-(lH-indazol-5-yl)butanenitrile 183 (1.256 g, 6.79 mmol) in DCM (25 mL), 3,4-dihydro-2H-pyran (1.140 g, 1.24mL, 13.58 mmol) and/i-toluenesulfonic acid monohydrate (0.644 g, 3.39 mmol) were added and the reaction was stirred at room température for 24 hours. The residue was dissolved in ethyl acetate (150 mL), quenched wîth a I M aqueous NaHCOs solution (5 mL), washed with water (25 mL), brine (25 mL), dried over anhydrous magnésium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flashchromatography using cyclohexane/ethyl acetate (from 99/1 to 70/30) to give 4-(ltetrahydropyran-2-ylindazol-5-yi)butanenîtrile 184 as a colorless oil.

LCMS method F: [M+H]⁺ = not detected, t_R = 2.36 min

Préparation of intermediate 185: 4-(l-tetrahydropyran-2-ylindazol-5-yi)butan-l-amine

Lithium aluminium hydride 1.0 M solution in THF (14.3 mL, 14.30 mmol) was added dropwise to a solution of 4-(l-tetrahydropyran-2-ylîndazol-5-yl)butanenitrile 184 (1.540 g, 5.72 mmol) in THF (20 mL) at 0 °C and stirred at room température for 24 hours. The mixture was quenched with a saturated aqueous solution of Rochelle sait (100 mL) and the resulting mixture was stirred overnight to break up the aluminium émulsions. The resulting biphasic medium was extracted with dîchloromethane (2x150 mL). Combined organic layers were washed with brine (100 mL), dried over anhydrous magnésium sulfate, filtered and concentrated under reduced pressure to afford 4-(l-tetrahydropyran-2-ylindazol-5-yl)butan-l-amine 185 as a colorless oil. LCMS method F: [M+H]⁺ = not detected, t_R = 1.37 min

314

Préparation of intermediate 186: (3-bromophenyl)methyl N-[4-(l-tetrahydropyran-2ylindazol-5-yl)butyl]carbamate

To a solution of 4-(l-tetrahydropyran-2-ylindazol-5-yl)butan-l-amine 185 (1.076 g, 3.94 mmol) in acetonitrile (120 mL) was added 1 ,Γ-carbonyldiimidazole (0.701 g, 4.33 mmol). The réaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then added dropwise to a solution of (3-bromophenyl)methanol (2.36 mL, 19.70 mmol) and césium carbonate (12.805 g, 39.40 mmol) în acetonitrile (60 mL) at 90°C. The resulting mixture was 10 stirred at the 90°C for 5 hours. The reaction mixture was allowed to cool down to room temperature and filtered over a celite pad. The fdtrate was evaporated under reduced pressure to afford a yellow oiL This residue was partitioned between ethyl acetate (150 mL) and water ( 100 mL). The organic layer was extracted twice with ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine, dried over anhydrous magnésium sulfate, filtered and 15 concentrated under reduced pressure. The resulting oil was purified by column chromatography on silica gel, using DCM/MeOH (from 1/0 to 9/1) as an eluant, the desired fractions were combined and the solvent was removed under reduced pressure to afford (3bromophenyl)methyl A-[4-(l-tetrahydropyran-2-ylindazol-5-yl)butyl]carbamate 186 as a colorless oil.

LCMS method F: [M+H] ' = 488.1, t_R = 3.13 min

Préparation of intermediate 187: 19-(oxan-2-yl) -8-oxa-l 0,19,20-triazatetracyclo fl3.5.2.1²’⁶.0^,8’^2l]tricosa-l(20)_t2(23),3,5,15(22),16,18(21)-heptaen-9-one

315

To a solution of (3-bromophenyl)methyl 7V-[4-(l-tetrahydropyran-2-y 1 indazol-5-yl)butyl] carbamate 186 (340 mg, 0.70 mmol) in dry dioxane (68 mL), was added potassium acetate (137 mg, 1.40 mmol). An argon balloon with a long needle was placed in the reaction mixture, 5 bubbling for 15 minutes. Tricyclohexylphosphine (39 mg, 0.14 mmol) and palladium acetate (15 mg, 0.07 mmol) were added and the reaction mixture was placed in a sand bath, pre-heated at 200 °C, and stirred at this température for 16 hours. The réaction mixture was diluted with water. The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine, dried over anhydrous magnésium sulfate, filtered and evaporated 10 under reduced pressure. The crude product was purified by column chromatography on silica gel (DCM/MeOH/EtOAc : from 100/0/0 to 95/2.5/2.5) to afford the first fraction of the expected macrocycle (0.015 g) and another fraction which was a mixture of expected macrocycle and dehalogenated side-product benzyl A-[4-(l-tetrahydropyran-2-ylindazol-5-yl)butyl]carbamate (0.119 g). This second fraction was purified again by préparative TLC, using 15 (DCM/MeOH/EtOAc = 95/2.5/2.5) as an eluant. Pure macrocycle was recovered from the TLC plate and combined with the first fraction from column chromatography to afford 19-(oxan-2yl)-8-oxa-l 0,19,20-triazatetracyclo[l 3.5.2.1²’⁶.0^l8’^2l]tricosa-1(20),2(23),3,5,15(22),16,18(21 )heptaen-9-one 187 as a white solid.

LCMS method F: [M+H]⁺ = 406.2, t_R = 2.92 min

Préparation of Example 142: 8-oxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^l82l]tricosa1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

316

To a solution of l9-(oxan-2-yl)-8-oxa-l0,l9,20-triazatetracyclo[l3.5.2.l²’⁶.0^l8’^2l]tricosaI (20),2(23),3,5,15(22),16,18(2 l)-heptaen-9-one 187 (30 mg, 0.074 mmol) in methanol (4.0 mL) and water (0.4 mL) was added p-toluenesulfonic acid monohydrate (70 mg, 0.36 mmol) and the reaction mixture was heated to 65 °C for 4 hours. The reaction mixture was concentrated 5 under reduced pressure and the crude was neutralized by slow addition of a saturated aqueous sodium hydrogen carbonate solution. The resulting suspension was diluted with ethyl acetate. After séparation, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous magnésium sulfate, fîltered and evaporated under reduced pressure. The crude was purified by préparative TLC on silica gel, 10 eluting with DCM/MeOH 95/5, to give the expected product. DCM (5 mL) was added to give a white suspension. The precipitate was fîltered off and rineed with CH2CI2 (2 x 3 mL). The solid was recovered. Remaing solvents were removed under reduced pressure at 40°C to obtain 8-0 xa-10,19,20-triazatetracyclo[ 13.5.2.1^2,6.0^18,21 ]tricosa-1(20),2(23), 3,5,15(22), 16,18(21)heptaen-9-one example 142 as a white solid.

LCMS method F: [M+H]⁺ = 322.3, t_R = 2.25 min

LCMS method G: [M+Hf = 322.3, t_R = 2.25 min

Ή NMR (400 MHz, ri6-DMSO, 80 °C) δ 12.87 (IH, br. s), 7.92 (IH, s), 7.87 (IH, d, J = 8.0 Hz), 7.76 (IH. s), 7.54 (IH, br. s), 7.51 - 7.42 (2H, m), 7.27 (1 H, d, J = 8.0 Hz), 7.20 (1 H, dd, J = 1.6, 8.8 Hz), 5.28 (2H, s), 3.22 - 3.19 (2H, m), 2.92 - 2.88 (2H, m), 1.95 - 1.90 (2H, m), 20 1.72- 1.63 (2H,m) ppm.

Example 143: (13R)-5-methoxy-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo

[13.5.2.1²’⁶.0^ls’^2,|tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

Préparation of intermediate 184: 5-bromo-2-methoxy-pyridine-3-carbaldehyde

Example 143 is prepared according to the synthesis route described in general Scheme O.

317

ΙΟ

Ο

Br

Το a solution of 3,5-dibromo-2-methoxy-pyridîne (1.62 g, 6.11 mmol) in dry diethyl ether (24 mL) at -78°C was added dropwise a solution of tt-BuLi in hexane (4,16 M titrated) (L47 mL, 6.11 mmol). The reaction mixture was stirred at -78°C for 15 min then jV,A-dimethylfonnamide (0.95 mL, 12.22 mmol) was added dropwise and the reaction mixture was stirred at -50°C for 30 min. The reaction mixture was quenched dropwise with a saturated aqueous ammonium chloride solution at -78°C, warmed to room température and stirred for 30 min. Diethyl ether was added to the solution. After séparation, the aqueous layer was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford a yellow solid which was recrystallized in hexane to afford 5-bromo-2-methoxy-pyridine-3-carbaldehyde intermediate 184 as a yellow powder. ^lH NMR (400 MHz, CDCl?) δ 10.32 (IH, s), 8.44 (IH, d, J=2.7 Hz), 8.22 (IH, d, J=2.7Hz), 4.09 (3H, m) ppm.

Préparation of intermediate 185: (5-bromo-2-methoxy-3-pyridyl)methanol ''O

Br

To a solution of 5-bromo-2-methoxy-pyridine-3-carbaldehyde intermediate 184 (997 mg, 4.64 mmol) in methanol (21 mL) at 0°C was added sodium borohydride (176 mg, 4.64 mmol) in one portion. The reaction mixture was stirred at room température for 2 h. The reaction mixture was 20 evaporated under reduced pressure. The residue was diluted with dichloromethane and a sodium bicarbonate saturated solution. After séparation, the aqueous layer was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 50/50 as eluent to afford (525 bromo-2-methoxy-3-pyridyl)methanol intermediate 185 as yellow crystals.

LCMS method F: [M+H]* = 218-220, t_R = 1.81 min

318

Préparation of intermediate 186: l5-l5-itert-hutvl(dimethvl)silvlloxv-l-tetrahydropvran-2-vlmdazol-3-ytf-2-methoxy-3-pyridyljmethanol

To a solution of zert-butyl-dimethyl-[J-tetrahydropyran-2-yl-3-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)indazol-5-yl]oxy-silane (1.24 g, 2.71 mmol) in 1,4-dîoxane (20 mL) and water (2 mL) at room température was added (5-bromo-2-methoxy-3-pyridyl)methanol intermediate 185 (588 mg, 2.71 mmol), potassium phosphate tribasic (1.72 g, 8.13 mmol). The reaction mixture was degassed by bubbling argon for 15 min, then XPhos (388 mg, 0.8 mmol) and tetrakis(triphenylphosphine)-palladium(0) (312 mg, 0.27 mmol) were added. The reaction mixture was stirred at 80°C for 12 h. The reaction mixture was evaporated under reduced pressure. The residue was diluted with ethyl acetate and. After séparation, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 0/100 to afford [5-[5-[terA butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3-yl]-2-methoxy-3-pyrîdyl]methanol intermediate 186 as a light yellow oil.

LCMS method F: [M+H]^é = 470.4, t_R = 3.52 min

Préparation of intermediate 187: (13R)-5-methoxy-13-methyl-19-(oxan-2-yl) -8,14dioxa -4,19,l9,20-te{r(iaz.iite}facyclo[13.5.2.1²’⁶.0^IS2i]tricosa -1(20),2,4,6(23),15,17,21 heptaen-9-one

319

To a solution of [5-[5-[fë>butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3-yl]-2methoxy-3-pyridyl]methanol intermediate 186 (824 mg, 1.76 mmol) in anhydrous acetonitrile (190 mL) was added césium carbonate (2.86 g, 8.8 mmol) and [(1 S)-3-(benzyloxycarbonyl amino)-!-methyi-propyl] methanesulfonate (582 mg, 1.93 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at 80°C for 24 h. The reaction mixture was fïltered and the fîltrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 50/50 as eluent to afford (13R)-5-methoxy13-methyl-19-(oxan-2-y 1)-8,14-dîoxa-4,10,19,20-tetraazatetracyclo [13.5.2.1²’⁶,0^18,21]tricosa1(20),2,4,6(23), 15,17,2 l-heptaen-9-one intermediate 187 as a colorless oil.

LCMS method F: [M+Hf = 453.4, t_R = 2.82 min

Préparation of example 143: (13R)-5-methoxy-13-methyl-8,14-dioxa-4,10,19,20tetraazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹]trîcosa-l(20),2,4,6(23),15,17,21-heptaen-9-one

To a solution of (13R)-5-methoxy-I3-methyl-19-(oxan-2-yl)-8,14-dioxa-4,10,l9,20-tetraaza tetracyclo[!3.5.2.1²’⁶.0¹⁸'^2l]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one intermediate 187 (170 mg, 0.38 mmol) în methanol (7 mL) and water (1.2 mL) was added/Moluenesulfonic acid monohydrate (357 mg, 1.88 mmol). The reaction mixture was heated at 80 °C for 18 h. The solvent was evaporated under reduced pressure. The residue was dissolved in dîchloromethane and a saturated aqueous solution of bicarbonate. After séparation, the aqueous layer was extracted with dîchloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, fïltered and evaporated under reduced pressure. The residue was triturated in diethyl ether, fïltered and dried to afford (13R)-5-methoxy-l 3-methyl-8,l4-dioxa4,10,19,20-tetraazatetracyclo[l 3.5.2.1²’⁶.0^,8’^2,]tricosa-l (20), 2,4,6(23), 15,17,21 -heptaen-9-one example 143 as a white solid.

LCMS method F: [M+Hf = 369.3, t_R = 2.15 min

LCMS method G: [M+Hf = 369.3, > = 2.13 min

Ή NMR (400 MHz, fr6-DMSO) δ 13.13 (1 H, s), 8.67 (IH, d, >1.7 Hz), 8.11 - 8.07 (2H, m),

7.52 - 7.48 (IH, m), 7.24 (IH, d, J=0.8 Hz), 6.98 (IH, dd, >2.1, 9.1 Hz), 5.45 - 5.42 (JH, m),

320

4.95-4.91 (IH, m), 4.60 - 4.54 (1 H, m), 3.98 (3H, s), 3.53 (IH, s), 2.97 - 2.88 (IH, m), 2.33 (IH, s), 1.41 (4H, d, >5.9 Hz) ppm.

Example 144: (13R)-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1²’⁶,0¹⁸’²¹] tricosa-1(20),2,6(23),15,17,2 l-hexaene-5,9-dione

Example 144 is prepared by déméthylation and concomitant deprotection of intermediate 187.

A mixture of (13 R)-5-methoxy-13-methy 1-19-(oxan-2-yl)-8,14-dioxa-4,10,19,20-tetraazatetra10 cyclo[13.5.2.l²’⁶.0^l8’^2,]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one intermediate 187 (150 mg, 0.33 mmol), sodium iodide (99 mg, 0.66 mmol), chlorotrimethylsilane (83 pL, 0.66 mmol) and acetonitrile (3 mL) was heated at 70°C for 4 h. The solvent was evaporated under reduced pressure. Ethyl acetate and a saturated aqueous solution of bicarbonate were added. After séparation, the aqueous layer was extracted with ethyl acetate. The organic layer was washed 15 with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/méthanol 90/10 as eluent to afford (13R)-13-methy 1-8,14-dioxa-4,10,19,20tetraazatetracyclo[ 13.5.2.1²’⁶.0^l8’²¹]tricosa-1 (20),2,6(23), 15,17,21 -hexaene-5,9-dione example 144 as a light yellow solid.

LCMS method F: [M+H]⁺ = 355.3, t_R = 1.70 min

LCMS method G: [M+H]⁺ = 355.3, t_R = 1.69 min

Ή NMR (400 MHz, r/6-DMSO) 613.00 (1 H, s), 12.03 (IH, s), 8.01 (IH, t, >6.2 Hz), 7.90 (1 H, s), 7.81 (1 H, s), 7.48 - 7.44 (1 H, m), 7.16 (I H, s), 6.96 (I H, dd, >1.9, 9.1 Hz), 5.25 (1 H, m), 4.80 (IH, m), 4.57 - 4.51 (IH, m), 3.53 (IH, m), 2.91 (IH, s), 2.31 (IH, m), 1.39 (4H, d, >6.1 25 Hz) ppm.

Example 145: 4-methyl-8,14-dioxa-3,4,10,19,20-pentaazatetracyclo[13.5.2,I²'⁵.0¹⁸’²¹] tricosa-1(20),2,5(23),15(22),16,18(21)-hexaen-9-one

32I

Example 145 is prepared according to the synthesis route described in general Scheme L.

Préparation of intermediate 188: (2-(5-bromo-2-methyl-pyrazol-3-yl) ethyl N-(3-hydroxy propyl) carbamate

To a solution of 4-nitrophenyl chloroformate (432 mg, 2.15 mmol) and pyridine (0.315 mL, 3.90 mmol) in dichloromethane (10 mL) at room température was added dropwise 2-(5-bromo2-methyl-pyrazol-3-yl)ethanol (400 mg, 1.95 mmol) in dichloromethane (5 mL). The reaction 10 mixture was stirred at room température for 1 h. A mixture of 3-aminopropan-l-ol (161 mg, 2.15 mmol) and DIPEA (0.678 mL, 3.90 mmol) in dichloromethane (5 mL) was added. The reaction mixture was stirred at room température for 16 h. The residue was diluted with 0.5N aqueous sodium hydroxide solution and extracted with dichloromethane. The combined organic layers were washed once again with 0.5N aqueous sodium hydroxide solution and dried over 15 anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/ethyl acetate 100/0 to 0/100 as eluent to afford 2-(5-bromo-2-methyl-pyrazol-3-yl)ethyl N-(3-hydroxypropyl)carbamate intermediate 188 as a colorless oil.

LCMS method F: [M+H]⁺ = 306-308, t_R = 2.25 min

Préparation of intermediate 189: 2-[5-[5-[tert-butyl(dimethyl)silyl]oxy-l-tetrahydro-pyran2-yl-indazol-3-yl]-2-methyl-pyrazol-3-yl]ethyl-N-(3-hydroxypropyl)carbamate

322

To a solution of terAbutyl-dimethyl-[l -tetrahydropyran-2-yl-3-(4,4,5,5-tetramethyl-l ,3,2dioxaborolan-2-yl)indazol-5-yl]oxy-silane (600 mg, 1.31 mmol) in 1,4-dioxane (13 mL) and water (1.3 mL) at room température was added 2-(5-bromo-2-methyl-pyrazol-3-yl)ethyl N-(35 hydroxypropyl)carbamate intermediate 188 (441 mg, 1.44 mmol), potassium phosphate tribasic (833 mg, 3.93 mmol), XPhos (62 mg, 0.13 mmol) and tetrakis(triphenylphosphine)palladium(0) (76 mg, 0.07 mmol). The reaction mixture was stirred under microwave conditiond at 90°C for 1 h. The residue was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and 10 concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 0/100 as eluent to afford 2-[5-[5[ter/-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3-yl]-2-methyl-pyrazol-3yl]ethyl N-(3-hydroxypropyl)carbamate intermediate 189 as a colorless oil.

LCMS method F: [M+H]⁺ = 558.4, t_R = 3.17 min

Préparation of intermediate 190: 3-l2-[5-[5-[tert-butyl(dimethyl)silyI]oxy-l-tetrahydropyran-2-yl-indazol-3-yl]-2-methyl-pyrazol-3-yl]ethoxycarbonylaminoJpropyl meth anesulfonate

323

To a solution of 2-[5-[5-[tert-butyl(dimethyl)silyl]oxy-l -tetrahydropyran-2-yl-indazol-3-yl]-2methyl-pyrazol-3-yl]ethyl N-(3-hydroxypropyl)carbamate intermediate 189 (470 mg, 0.84 mmol) and triethylamine (0.235 mL, 1.69 mmol) in dichloromethane (6 mL) was added at 0°C methanesulfonyl chloride (0.085 mL, 1.10 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room température for 16 h. The residue was diluted with saturated sodium chloride solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 3-[2-[5-[5[tert-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3-yl]-2-methyl-pyrazol-3-yl] ethoxycarbonylamino]propyl methanesulfonate intermediate 190 as a yellow oil which was used in the next step without further purification.

LCMS method F: [M+H]⁺ = 636.4, t_R = 3.32 min

Préparation of intermediate 191: 4-methyl-19-(oxan-2-yl) -8,14-dioxa-3,4,10,19,2015 pentaazatetracyclo[13.5.2.1²'⁵.0^li2Ijtricosa-l(20),2,5(23),15(22),16,18(21) -hexaen -9-one

To a suspension of césium carbonate (0.824 g, 2.53 mmol) in anhydrous N,Ndimethylfonnamide (168 mL) at 80°C was added dropwise 3-[2-[5-[5-[tert21105

324 butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3-yl]-2-methyl-pyrazol-3-yl]ethoxy carbonylammo]propyl methanesulfonate intermediate 190 (0.536 g, 0.84 mmol) in N,Ndimethylformamide (168 mL). The reaction mixture was stirred at 80°C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure then diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/ethyl acetate, 100/0 to 50/50 as eluent to afford 4-methyl-19-(oxan-2-yl)-8,l4-dioxa-3,4,10,19,20pentaazatetracyclo[l 3.5.2. l²<0^18,21 ]tricosa-l (20),2,5(23), 15(22), 16,18(2 l)-hexaen-9-one intermediate 191 as a white solid.

LCMS method F: [M+H]⁺ = 426.4, ta = 2.10 min

Préparation of example 145: 4-methyl-8,14-dioxa-3,4,10,19,20-pentaazatetracyclo [13.5.2.1²'⁵.0¹⁸’²¹]tricosa-l (20),2,5(23),15(22),16,18(2 l)-hexaen-9-one

To a solution of 4-methyl-19-(oxan-2-yl)-8,14-dioxa-3,4,10,19,20-pentaazatetracyclo [13.5.2.1²’^S.0¹⁸’^2l]tricosa-l(20),2,5(23),15(22),16,18(2l)-hexaen-9-one intermediate 191 (55 mg, 0.13 mmol) in méthanol (3.5 mL) and water (0.5 mL) was added p-toluenesulfonic acid monohydrate (123 mg, 0.65 mmol). The reaction mixture was stirred at 65°C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was neutralized by slow addition of saturated aqueous sodium bicarbonate solution. The residue was diluted with ethyl acetate. After séparation, the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol 100/0 to 96/4 as eluent. The solid was crystallized in acetonitrile to give 4-methyl-8,14-dioxa-3,4,l0,19,20-pentaazatetracyclo [13.5.2.1^z’90^l8’²¹]tricosa-l(20),2,5 (23),15(22),16,18(2I)-hexaen-9-one example 145 as a white solid.

LCMS method F: [M+H]^h = 342.3, t_R = 1.63 min

325

LCMS method G: [M+H]⁺ = 342.3, t_R = 1.63 min ‘H NMR (400 MHz. J6-DMSO) δ 12.91 (IH, s), 7.74 (IH, t, J=6.0 Hz), 7.45 - 7.41 (IH, m),

7.11 (IH, d, J=1.9 Hz), 6.93 (IH, dd, J=2.2, 8.8 Hz), 6.38 (1H, s), 4.47 - 4.44 (2H, m), 4.27 4.21 (2H, m), 3.84 - 3.82 (3H, m),3.10-3.02 (4H, m), 1.91 - 1.84 (2H, m) ppm.

Example 146: (13R)-16-fluoro-13-methyl-8,14-dioxa-10,19,2Û,23-tetraazatetracyclo

[13.5.2.l²<0^,8’^2lltricosa-l(20),2,4,6(23),l5,l7,2l-heptaen-9-one

Example 146 is prepared according to the synthesis route described in general Scheme O.

Préparation of intermediate 192: tert-buty l-f6-fluoro-l-tetrahydropyran-2-y 1-3-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)indazol-5-yl]oxy-dimethyl-silane

A mixture of tert-buty l-dimethyl-(l-tetrahydropyran-2-ylindazol-5-yl)oxy-silane (500 mg, 1.43 mmol), TBME (dried on 3A molecular sieves) (6 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5tetramethyl-],3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (711 mg, 1.43 mmol), 4,4’-di-tertbutyl-2,2'-bipyridîne(23 mg, 0.09 mmol) and (1,5-cyclooctadiene) (methoxy)iridium(I) dimer (19 mg, 0.03 mmol) was purged wîth argon and stirred at 80°C for 16 h. The solvent was 20 evaporated under reduced pressure and the residue was dissolved with ethyl acetate and water.

After séparation, the aqueous phase was extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford tert-butyl-[6-fluoro-l-tetrahydropyran-2-yl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)

326 indazol-5-ylloxy-dimethyl-silane intermediate 192 as a brown oil which was used in next step without further purification.

LCMS method F: [M+H]⁺ = 477.2, tR = 3.87 min (major pic observed as boronic acid [M+H]⁺= 395.2, tR = 3.18 min)

Préparation of intermediate 193: [6-(5-(tert-butyl(dimethyl)silyl]oxy-6-fluoro-l-tetrahydro pyran-2-yl-indazol-3-yl]-2-pyridyl]methanol

To a solution of tert-butyl-[6-fluoro-l -tetrahydropyran-2-yl-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)indazol-5-yl]oxy-dimethyl-silane intermediate 192 (1.00 g, 2.10 mmol) in 1,4-dioxane (10 mL) and water (1 m!) at room température was added (6-bromo-2pyridyl)methanol (302 mg, 1.62 mmol) and potassium phosphate trîbasic (1.03 g, 4.86 mmol). The reaction mixture was degassed with argon for 15 min, then XPhos (76 mg, 0.16 mmol) and tetrakis(trîphenylphosphine)palladium(0) (56 mg, 0.05 mmol) were added. The reaction mixture was stirred at 80°C for 45 min under microwave radiations. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and water. After séparation, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 50/50 as eluent to afford [6-[5-[ta7-butyl(dimethyl)siiyl]oxy-6-fluoro-l-tetrahydropyran-2-ylindazol-3-yl]-2-pyridyl]methanol intermediate 193 as a colorless oil.

LCMS method F: [M+Hp = 458.2, t_R = 3.55 min

Préparation of intermediate 194: (13 R) -16 -fluoro -13 -methyl-19 -(oxan -2 -yl) -8,14 -dioxa 10,19,20,23-tetraazatetracyclo[ 13.5.2.I²·⁶. O¹*²¹ jtricosa -l (20),2,4,6(23),15,17,21 -hepuien -9 one

327

To a solution of [6-[5-[iert-butyl(dimethyl)silyl]oxy-6-fluoro-l-tetrahydropyran-2-yl-indazol3-yl]-2-pyrîdyl]methanol intermediate 193 (400 mg, 0.87 mmol) in anhydrous acetonitrile (90 mL) was added césium carbonate (2.83 g, 8.7 mmol) and a solution of [(1 S)-3-(benzyloxy 5 carbonylamino)-l-methyi-propyl] methanesulfonate (290 mg, 0.96 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at 80°C for 24 h. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was trîturated in diethyl ether, filtered and dried to afford (13R)-16-fluoro-l3-methyl-19-(oxan-2-yl)-8,14-dioxa-l0,19,20,23tetraazatetracyclo[ 13.5.2.1^2,6.0¹⁸’^2î]tricosa-l (20),2,4,6(23), 15,17,21 -heptaen-9-one intermediate 194 as an off-white powder.

LCMS method F: [M+H]⁺ = 441.2, t_R = 2.78 min

Préparation of example 146: (13R)-16-fluoro-13-methy 1-8,14-dioxa-10,19,20,23-tetraaza tetracvclo[l3.5.2.l²’⁶.0^l8’^2l]tricosa-1 (20),2,4,6(23),15,17,21-heptaen-9-one

To a solution of afford (13R)-16-fluoro-l 3-methyl-l 9-(oxan-2-yl)-8,l 4-dioxa-10,19,20,23tetraazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹]tricosa-l(20),2,4,6(23),15,l7,21-heptaen-9-one intermediate 194 (160 mg, 0.36 mmol) in methanol (4 mL) and water (0.7 mL) was added ptoluenesulfonic acid monohydrate (345 mg, 1.82 mmol). The reaction mixture was heated at 80 °C for 18 h. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and saturated aqueous solution of sodium bicarbonate (20 mL). After séparation, the aqueous layer was extracted with dichloromethane (10 mL). The organic layer

328 was washed with brine, dried over anhydrous sodium sulfate, fîltered and evaporated under reduced pressure. The residue was triturated with diethyl ether, fîltered and dried to afford (l3R)-16-fluoro-l 3-methy 1-8,14-dioxa-10,19,20,23-tetraazatetracyclo[l 3.5.2. PAO¹⁸’²¹] tricosa-1 (20),2,4,6(23),15,17,21-heptaen-9-one example 146 as a white powder.

LCMS method F: [M+H]⁺ = 357.1, t_R = 2.10 min

LCMS method G: [M+H]⁺ = 357.2, t_R = 2.09 min ‘H NMR (400 MHz, t/6-DMSO) δ 13.31 (1 H, s), 8.06 (2H, dd, >8.2, 15.9 Hz), 7.84 (IH, t, >7.9 Hz), 7.74 (IH, dd, >4.8, 6.7 Hz), 7.44 (1 H, d, >10.8 Hz), 7.29 - 7.26 (IH, m), 5.58 (IH, s), 5.10 - 5.06 (IH, m), 4.64 (IH, s), 3.52 - 3.50 (IH, m), 2.96 (1 H, s), 2.23 - 2.20 (IH, m), 1.51 (IH, s), 1.40 (3H, d, >6.1 Hz) ppm.

Example 147: 7,13-dioxa-4-tliia-9,18,19,22-tetraazatetracyclo[12.5.2.1²A0^,7’²⁰]docosa (19),2,5(22),14(21),15,17(20)-hexaen-8-one

Example 147 is prepared according to the synthesis route described in general Scheme L.

Préparation of intermediate 195: (4-bromothiazol-2-yl)methyl-N-(3-hydroxypropyl) carbamate

To a solution of 4-nitrophenyl chloroformate (572 mg, 2.84 mmol) and pyridine (0.416 mL, 5.15 mmol) in dichloromethane (10 mL) was added dropwise at room température (4bromothîazol-2-yl)methanol (500 mg, 2.58 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at room température for I h. A mixture of 3-aminopropan-l-ol (213 mg, 2.84 mmol) and DIPEA (0.896 mL, 5.15 mmol) in dichloromethane (2 mL) was added. The reaction mixture was stirred at room température for 2 h. The residue was diluted with 0.5N

329 aqueous sodium hydroxide solution and extracted with dichloromethane. The combined organic layer was washed once again with 0.5N aqueous sodium hydroxide solution and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/ethyl acetate 100/0 to 40/60 as 5 eluent to afford (4-bromothiazol-2-yl)methyl N-(3-hydroxypropyl)carbamate intermediate 195 as a colorless oil which crystallized.

LCMS method F: [M+Hf = 295-297, t_R = 1.51 min

Préparation of intermediate 196: 2-(4-(5-(tert-hutyl(dimethyl)silyl]oxy-l-tetrahydro pyran-210 yl-indazol-3-yl]thiazol-2-yl]ethyl-N-(3-hydroxypropyl) carbamate

To a solution of tert-butyl-dimethyl-[ 1-tetrahydropyran-2-y 1-3-(4,4,5,5-tetramethy 1-1,3,2dioxaborolan-2-yl)indazol-5-yl]oxy-silane (1.091 g, 2.38 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL) at room température was added (4-bromothîazol-2-yl)methyl N-(315 hydroxypropyl)carbamate intermediate 195 (585 mg, 1.98 mmol), potassium phosphate tribasic (1.263 g, 5.95 mmol), XPhos (95 mg, 0.20 mmol) and tetrakis(tripheny] phosphine)palladium(O) (115 mg, 0.10 mmol). The reaction mixture was stirred under microwave irradiations at 90°C for 1.5 h. The residue was diluted with saturated sodium chloride solution and extracted with ethyl acetate. The combined organic layer was dried over 20 anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography cyclohexane/ethyl acetate 100/0 to 0/100 as eluent to afford 2-[4-[5-[tert-butyl(dimethyl) silyl]oxy-1 -tetrahydropyran-2-yl-indazol-3-yl]thiazol-2yl]ethvl-N-(3-hydroxypropyl) carbamate intermediate 196 as a colorless oil.

LCMS method F: [M+H]⁺ = 547.4, t_R = 3.27 min

330

Préparation of intermediate 197: 3-[[4-[5-[tert-butyl(dimethyl)silyl]oxy-l-tetrahydro pyran2-yl-indazol-3-yl]thiazol-2-yl]methoxycarbonylamino]propylmethanesulfonate

To a solution of [4-[5-[fer/-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-35 yl]thiazol-2-yl]methyl N-(3-hydroxypropyl)carbamate intermediate 196 (500 mg, 0.91 mmol) and triethylamine (0.255 mL, 1.83 mmol) in dichloromethane (6 mL) at 0°C was added methanesulfonyl chloride (0.092 mL, 1.19 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room température for 16 h. The residue was diluted with saturated aqueous sodium chloride solution and extracted with dichloromethane. The combined organic 10 layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 3-[[4-[5-[tert-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3-yl]thiazol-2yljmethoxycarbonylamîno]propyl methanesulfonate intennediate 197 as a yellow oil which was used in the next step without further purification.

LCMS method F: [M+H]⁺ = 625.4, t_R = 3.41 min

Préparation of intermediate 198:18-(oxan -2 -yl) -7,13 -dioxa -4 -thia-9,18,19,22 -tetraaza tetracyclo[12.5.2.1^2ïS.0¹⁷²⁰]docosa-l(19),2,5(22),14(21),15,17(20)-hexaen-8-one

33]

To a suspension of césium carbonate (532 mg, 1,63 mmol) in anhydrous N,NdimethyIformamide (135 mL) at 85°C was added dropwise 3-[[4-[5-[tert-butyl(dimethyl) siiyl]oxy-l-tetrahydropyran-2-yLindazol-3-yl]thiazol-2-yl]methoxycarbonylamino]propyl methanesulfonate intermediate 197 (340 mg, 0.54 mmol) in jVW-dimethylformamide (135 mL).

The reaction mixture was stirred at 85°C for 30 min. The solvent was evaporated under reduced pressure, diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/ethyl acetate, 100/0 to 80/20 as eluent to afford 18-(oxan-2-yl)-7,13-dioxa-410 thia-9,18,19,22-tetraazatetracyclo[12.5.2. l²’'\0^17,20]docosa-l (19),2,5(22),14(21),15,17(20)hexaen-8-one intermediate 198 as a colorless oil which crystallized.

LCMS method F: [M+H]⁺ = 415.1, t_R = 3.47 min

Préparation of example 147: 7,13-dioxa-4-thia-9,18,19,22-tetraazatetracyclo 15 ll2.5.2.1²’^s.0^172<1]docosa-l(19),2,5(22),14(21),15,17(20)-hexaen-8-one

To a solution of 18-(oxan-2-yl)-7,l 3-dioxa-4-thia-9,l 8,19,22-tetraazatetracyclo [12.5.2. pA0^l7,20]doc_Osa-1(19),2,5(22),14(21),15,17(20)-hexaen-8-one intermediate 198 (67 mg, 0.16 mmol) in methanol (3.5 mL) and water (0.5 mL) was addedp-toluenesulfonic acid monohydrate 20 (154 mg, 0.81 mmol). The reaction mixture was stirred at 65°C for 2 h. The solvent was evaporated under reduced pressure and the residue was neutralized by slow addition of saturated aqueous sodium bicarbonate solution. The residue was diluted with ethyl acetate. After séparation, the aqueous phase was extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced 25 pressure. The residue was triturated în acetonitrile, filtered and dried to afford 7,l3-dioxa~4thia-9,18,19,22-tetraazatetracyclo[ 12.5.2. l^2,5.Oⁱ⁷’²⁰]docosa-1 ( 19),2,5(22), 14(21 ), 15,17(20)hexaen-8-one example 147 as a white solid.

LCMS method F: [M+H]⁺ = 331.2, t_R = 1.75 min

LCMS method G: [M+H]⁺ = 331.2, t_R = 1.75 min

332 ‘H NMR (400 MHz, ί/6-DMSO) δ 13.04 (1 H, s), 8.00 - 7.94 (3H, m), 7.44 - 7.41 (1 H, m), 6.95 (IH, dd, J=2.6, 9.0 Hz), 5.52 (2H, t, J=17.5 Hz), 4.32 - 4.26 (2H, m), 3.12 (2H, s), 2.08 - 1.99 (2H, m) ppm.

Example 148: (13R)-4,13-dimethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo [13.5.2.

l²’⁶.0¹⁸’²¹]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

Example 148 is prepared according to the synthesis route described in general Scheme O.

Préparation of intermediate 199: [(lS)-3-(benzyloxycarbonyiamino)-l-methyl-propy/] methane sulfonate

To a cooled solution (0°C) of benzyl N-[(3S)-3-hydroxybutyl]carbamate (17.06 g, 76.52 mmol) and triethylamine (21.3 mL, 153.04 mmol) in dichloromethane (300 mL) was added dropwise methanesulfonyl chloride (7.7 mL, 99.47 mmol) and the reaction mixture was stirred at room température for 19 hours. The reaction mixture was quenched with an aqueous solution of IN HCl and extracted with dichloromethane (Ix). The organic layer was washed wîth a saturated aqueous solution of NaHCO3 then water and brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to give [( 1 S)-3-(benzyloxycarbonylamino)-1 -methylpropyl] methanesulfonate intermediate 199 as a yellow oil.

LCMS method F: [M+H]⁺ = 302, tR = 2.26 min indazol-3-yll-6-methyl-pyrimidin-2-ylJmethyl acetate

Préparation of intermediate 200: !4-l5-[tert-butyl(dimeth vl)silyl]oxy-l-tetrahydropyran -2-yl21105

333

To a solution of /ert-butyl-dimethyl-[l-tetrahydropyran-2-yl-3-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)îndazol-5-yl]oxy-silane (1.37 g, 3 mmol) in 1,4-dioxane (10 mL) and water (1 mL) at room température was added (4-chloro-6-methyl-pyrimidin-2-yl)methyl acetate (499 5 mg, 2.5 mmol), potassium phosphate trîbasîc (1.59 g, 7.5 mmol). The reaction mixture was purged with nitrogen for 15 min then XPhos (36 mg, 0.075 mmol) and tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) were added. The reaction mixture was stirred at 80°C for 45 min under microwave irradiations. The reaction mixture was filtered over Celite pad and the filtrate was diluted with ethyl acetate and water. After 10 séparation, the aqueous layer was extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 80/20 as eluent to afford [4-[5-[to7butyl(dÎmethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3-yl]-6-methyl-pynrmdin-2-yl] 15 methyl acetate intermediate 200 as an orange oil.

LCMS method F: [M+H]⁺ = 497.3, t_R = 3.68 min

Préparation of intermediate 201: 3-[2-(hydroxymethyl)-6-methyl-pyrùnidln-4-ylJ-l-

To a solution of (4-[5-[/er/-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3-yl]-6methyl-pyrimîdin-2-yl]methyl acetate intermediate 200(1.33 g, 2.5 mmol) in méthanol (12 mL)

334 and water (12 mL) at room température was added potassium carbonate (690 mg, 5 mmol). The reaction mixture was stirred at 50°C for 24 h. Methanol was evaporated under reduced pressure. The resulting precipitate was filtrated, washed with water and dried to afford 3-[2(hydroxymethyl)-6-methyl-pyrimidin-4-yl]-l-tetrahydropyran-2-yl-indazol-5-ol intermediate 5 201 as a cream powder.

LCMS method F: [M+H]⁺= 341.2, t_R = 1.99 min

Préparation of intermediate 202: (13R) -4,13-dimethyl-19-(oxan-2-yl) -8,14-dioxa-5,10,19, 20,23 -pentaazatetracyclo[13.5.2.1²’⁶.0^ls·²¹/trîeosa-1(20),2(23),3,5,15(22), 16,18(21) -heptaen 10 9-one

To a mixture of 3-[2-(hydroxymethyl)-6-methyl-pyrimidin-4-yl]-l-tetrahydropyran-2-ylindazol-5-ol intermediate 201 (361 mg, 1.06 mmol) in A/N-dimethylformamide (8 mL) at room température was added césium carbonate (689 mg, 2.12 mmol). The reaction mixture was 15 stirred for 20 min and [(lS)-3-(benzyloxycarbonylamino)-l-methy 1-propyl] methanesulfonate intermediate 199 (383 mg, 1.27 mmol) in A(V-dimethylformamide (2 mL) was added. The reaction mixture was stirred at room température for 16 h. Additional |(lS)-3(benzyloxycarbonylamino)-l-methyl-propyl] methanesulfonate intermediate 199 (64 mg, 0.21 mmol) in Λζ/V-dimethyIformamide ( I mL) was added. The reaction mixture was stirred at room 20 température for 2 h then diluted with DMF (106 mL) and césium carbonate (L03 g, 3.18 mmol) was added. The reaction mixture was heated at 50°C for 16 h. Additional césium carbonate (344 mg, 1.06 mmol) was added and the reaction mixture was heated at 50 °C for 3 h. The reaction mixture was concentrated under reduced pressure then diluted with ethyl acetate and water. After séparation, the aqueous layer was extracted with ethyl acetate. The combined 25 organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 50/50 as eluent to atford (13R)-4,1321105

335 dimethyM9-(oxan-2-yl)-8J4’dioxa-5J0J9,20,23-pentaazatetracyclo[]3.5.2.1²⁶.0¹⁸’²¹ tricosa-1 (20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one intermediate 202 as a white solid.

LCMS method F: [M+H]⁺ = 438.3, t_R = 2.57 min

Préparation of example 148.· (13R)-4,13-dimethyl-8,14-dioxa-5,10,19,20,23-pentaazatetra cyclo[ 13.5.2.1^2,6.0^18,21]trîcosa-l (20),2(23),3,5,15(22),16,18(2 l)-heptaen-9-one

To a solution of (13R)-4,13-dîmethyl-i 9-(oxan-2-y 1)-8,14-dioxa-5,l 0,19,20,23-pentaaza tetracyclo[ 13.5.2. l²’⁶.0^18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one intermediate 202 (407 mg, 0.93 mmol) in methanol (16 mL) and water (2.6 mL) was added ptoluenesulfonic acid monohydrate (884 mg, 4.66 mmol). The reaction mixture was stirred at 65°C for 16 h. Additional /Moluenesulfonic acid monohydrate (176 mg, 0.93 mmol) was added and the reaction mixture was heated at 65 °C for 24 h. The reaction mixture was evaporated under reduced pressure then diluted with dichloromethane and saturated aqueous solution of sodium bicarbonate. After séparation, the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was triturated in acetonitrîle, filtrated, washed with acetonitrîle and dried to afford (l3R)-4,I3-dimethyl-8,14-dioxa-5,10,19,20,23pentaazatetracyclo[13.5.2.1²Z0'^ul]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one example 148 as a white powder.

LCMS method F: [M+H]⁺ = 354.3, t_R = 1.89 min

LCMS method G: [M+H]⁺ = 354.3, t_R = 1.91 min

Ή NMR (400 MHz, ί/6-DMSO) δ 13.64 (IH, m), 7.94 (IH, s), 7.91 (1H, d, J= 2.3 Hz), 7.86 (IH, m), 7.51 (1 H, d, J= 8.9 Hz), 6.99 (1 H, dd, J=2.4, 9.0 Hz), 5.54 (IH, m), 4.95 (1 H, m), 4.61 (IH, m), 3.52 (IH, m), 2.89 (IH, m), 2.50 (3H, s), 2.34(1 H, m), 1.39 (3H, d, J=6.l Hz), 1.34 (IH, m) ppm.

336

Example 149: 8,14-dioxa-23-thia-4,10,19,20-tetraazatetraeyelo[13.5.2.1²’⁵.0¹⁸²¹]tricosal(20),2,4,15(22),16,18(21)-hexaen-9-one

Example 149 is prepared according to the synthesis route described în general Scheme L.

Préparation of intermediate 203: 2-(5-bromothiazol-2-yl)ethyi N-(3-hydroxypropyl) carbamate

To a solution of 4-nitrophenyl chlorofonnate (266 mg, 1.32 mmol) and pyridine (0.194 mL, 10 2.40 mmol) in dichloromethane (5 mL) at room température was added dropwise 2-(5bromothiazol-2-yl)ethanol (250 mg, 1.20 mmol) în dichloromethane (3 mL). The reaction mixture was stirred at room température for l h then a mixture of 3-aminopropan-l-ol (99 mg, 1.32 mmol) and DIPEA (0.418 mL, 2.40 mmol) in dichloromethane (2 mL) were added. The reaction mixture was stirred at room température for 2 h. The residue was diluted with 0.5 N 15 aqueous sodium hydroxide solution and extracted with dichloromethane. The combined organic layers were washed once again with 0.5 N aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/ethyl acetate 100/00 to 30/70 as eluent to afford 2-(5-bromothiazol-2-yl)ethyl N-(3-hydroxypropyl)carbamate intermediate 203 20 as a yellow oil.

LCMS method F: [M+H]⁺ = 309-31 1, t_R = 1.71 min

Préparation of intermediate 204: 2-[5-[5-[tert-butyl(dimethyl)silyl]oxy-l-tetrahydro pyran-2yl-indazoi-3-yl]thiazol-2-yl]ethyl N-(3~hydroxypropyl)carbamate

337

To a solution of terr-butyI-dimethyl-[l-tetrahydropyran-2-y 1-3-(4,4,5,5-tetramethy 1-1,3,2dioxaborolan-2-yl)îndazol-5-yI]oxy-silane (409 mg, 0.89 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) at room température was added 2-(5-bromothiazol-2-yl)ethyl N-(35 hydroxypropyl)carbamate intermediate 203 (230 mg, 0.74 mmol), potassium phosphate tribasic (474 mg, 2.23 mmol), XPhos (35 mg, 0.07 mmol) and tetrakis(triphenylphosphine)palladium(0) (43 mg, 0.04 mmol). The reaction mixture was stirred under microwave irradiations at 90°C for 1.5 h. The reaction mixture was diluted with saturated sodium chloride solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and 10 concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 0/100 as eluent to afford 2-[5-[5[tert-butyl(dîmethyl)silyl]oxy-l -tetrahydropyran-2-yl-indazol-3-yl]thiazol-2-yl]ethyl N-(3hydroxypropyl)carbamate intermediate 204-as a colorless oil.

LCMS method F: [M+H]⁺ = 561.3, t_R = 3.23 min

Préparation of intermediate 205: 3-[2-[5-[5-[tert-butyl(dimethyl)silylJoxy-l-tetrahydro pyran-2-yl-indazol-3-yl]th iazol-2-ytfeth oxycarbonylaminojpropyl methanesulfonate

338

To a solution of 2-[5-[5-[to7-butyl(dimethyi)silyl]oxy-l-tetrahydropyran-2-yl-îndazol-3yl]thiazol-2-yl]ethyl N-(3-hydroxypropyl)carbamate intermediate 204 (345m g, 0.62 mmol) and triethylamine (0.172 mL, 1.23 mmol) in dichloromethane (5 mL) at 0°C was added 5 methanesulfonyl chloride (0.062 mL, 0.80 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at room température for 2 h. The reaction mixture was diluted with saturated aqueous sodium chloride solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 3-[2-[5-[5-[tert-butyl(dimethyl)sîlyl]oxy-1-tetrahydropyran-2-yLindazo 1-3-yl]thiazo 1-210 yl]ethoxycarbonylamîno]propylmethanesulfonate intermediate 205 as a yellow oil which was used in the next step without further purification.

LCMS method F: [M+H]⁺ = 639.3, t_R = 3.37 min

Préparation of intermediate 206:19-(oxan -2 -yl) -8,14-dioxa -23 -thia-4,10,19,20 4etraaza tetracyclo[13.5.2.1²ⁱ.0^182l]tricosa-l(20),2,4,15(22),16,18(21)-hexaen-9-one

To a suspension of césium carbonate (601 mg, 1.85 mmol) in anhydrous N,Ndimethylformamide (155 mL) at 85°C was added dropwise 3-[2-[5-[5-[teit~

339 butyl(dimethyl)sîlyl]oxy-l -tetrahydropyran-2-yl-indazol-3-yI]thiazol-2-yl]ethoxycarbonyl ami no] propyl méthanes ul fbnate intermediate 205 (393 mg, 0.62 mmol) in N,Ndimethylformamide (155 mL). The reaction mixture was stirred at 85°C for 2 h. The solvent was evaporated under reduced pressure, diluted with saturated sodium chloride solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/(ethyl acetate/ethanol 3/1) 100/0 to 60/40 as eluent to afford 19-(oxan-2-yl)-8,l4-dioxa-23-thia-4,10,19,20-tetraazatetracyclo[13.5.2.I²’⁵.0¹⁸’²¹] tricosa-1 (20),2,4,15(22), 16,18(21 )-hexaen-9-one intermediate 206 as a white solid.

LCMS method F: [M+H]⁺ = 429.4, t_R = 2.27 min

Préparation of Example 149.· 8,14-dioxa-23-thia-4,10,19,20-tetraazatetracyclo [13.5.2. l²’⁵.0¹⁸’² '] tricosa-1 (20).2,4,15(22),16,18(2 l)-hexaen-9-one

To a solution of l9-(oxan-2-yl)-8,14-dioxa-23-thîa-4,10,19,20-tetraazatetracyclo [13.5.2. 1 0¹⁸ⁱ²¹]tricosa-1(20),2,4,15(22), 16,18(21)-hexaen-9-one intermediate 206 (19 mg, 0.04 mmol) in methanol (14 mL) and water (2 mL) was added p-toluenesulfonic acid monohydrate (42 mg, 0.22 mmol) and the reaction mixture was stirred at 70°C for 24 h. The solvent was evaporated under reduced pressure and the residue was quenched by slow addition of saturated aqueous sodium hydrogen carbonate solution. The residue was diluted with ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, fïltered and evaporated under reduced pressure. The residue was triturated in acetonitrile, fïltered and dried to afford 8.14-dioxa-23-thia-4,10,19,20-tetraazatetracyclo[l3.5.2.1²’⁵.0¹⁸²'jtricosa-1(20),2,4, 15(22),16, 18(21)-hexaen-9-one example 149 as a white solid.

LCMS method F: [M+Hf = 345.3, t_R = 1.70 min

LCMS method G: [M+Hf = 345.3, t_R = 1.71 min

340

Ή NMR (400 MHz, ί/6-DMSO) δ 13.23 - 13.23 (I H, m), 8.00 - 8.00 (2H, m), 7.51 -7.48(1 H,

m), 7.42 (IH, d, >2.3 Hz), 7.00 (IH, dd, .1=2.3, 8.9 Hz), 4.41 (2H, t, >5.2 Hz), 4.34 - 4.29 (2H, m), 3.41 -3.35 (2H, m), 3.14 - 3.11 (2H, m), 1.91 - 1.84 (2H, m) ppm.

Example 150: (7S,13R)-7,13-dimethyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.

p^.0’⁸²>]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

Example 150 is prepared according to the synthesis route described in general Scheme K.

Préparation of intermediate 207: l-(6-bromo-2-pyridyl)ethanol

To a solution of l-(6-bromo-2-pyridyl)ethanone (6.0 g, 30.0 mmol) in dry methanol (80 mL) at 0 °C was added solution sodium borohydride (2.30 mL, 89.9 mmoi) in small portions. The reaction mixture was warmed up to room temperature and was stirred for 16 h. The reaction mixture was quenched with water then carefully by the addition of IM aqueous hydrochloric acid solution. The reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnésium, filtered and evaporated to afford l-(6bromo-2-pyridyl)ethanol intermediate 207 as a colorless oil.

Ή NMR (500 MHz, rf6-DMSO) δ 7.74 (t, 1 H), 7.53 (d, 1 H), 7.49 (d, I H), 5.5 (d), 4.67 (m. 1 H), 1.34 (d, 3 H) ppm.

Préparation of intermediate 208: l-/6-[5-{[tert-butyl(dimethyl)silyl]oxy}-l-(oxan-2-yl) -lilindazol-3-yl]pyridin-2-yl}ethan-l-ol

341

5-{[ter/-butyl(dimethyl)silyl]oxy}-l -(oxan-2-yl)-3-(4,4,5,5-tetramethyί-l,3,2-dioxaboroίan-2yl)-l//“indazole (2.4 g, 5.2 mmol), l-(6-bromO'2-pyridyl)ethanol intermediate 207 (l.O g, 4.9 mmol) and potassium phosphate monohydrate (2.3 g, 9.9 mmol) in a mixture of ],4-dioxane 5 (50 mL) and water (5 mL) was purged with nitrogen then palladium triphenylphosphane (290 mg, 0.25 mmol) was added. The reaction mixture was heated at 100°C for l h. After cooling to room température, the reaction mixture was diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnésium sulfate, filtered and concentrated under reduced pressure. The residue 10 was purified by silica gel column chromatography using hepthane/ethyl acetate 20/80 to 30/70 to afford l - {6-[5-{[/ert-butyl(dimethyl)silyl]oxy}-l-(oxan-2-yl)-l/7-indazol-3-yl]pyridin-2yl} ethan-l-ol intermediate 208 as a coloriess oil.

Ή NMR (500 MHz, r/6-DMSO) δ δ (m, 2 H), 8.11 (d, 1 H), 7.97 (d, 1 H), 7.87 (t, 1 H), 7.67 (d, 1 H), 7.48 (d, 1 H), 7.04 (dd, 1 H), 5.88 (d, 1 H), 5.48 (d, 1 H), 4.85 (m, 1 H), 3.91/3.76 15 (d+m, 2 H), 2.47/2.02 (m+m, 2 H), 2.07/1.77 (m+m, 2 H), 1.5 (d, 3 H), 0.99 (s, 9 H), 0.23 (s, 6

H) ppm.

Préparation of intermediate 209: benzyl [(3R)-3-({3-[6-(I-hydroxyethyl)pyridm-2-yl]-l(oxan-2-yl)-lH-indazol-5-yljoxy)butyl]carbamate

342

To a solution of l-{6-[5-{[ter/-butyl(dimethyl)silyl]oxy}-l-(oxan-2-yl)-l/f-indazol-3yi]pyrîdin-2-yl}ethan-l-ol intermediate 208 (1.84 g, 4.06 mmol) in acetonitrile (81.1 mL) was added [(lS)-3-(benzyloxycarbonylamino)-l-methyl-propyl] methanesulfonate intermediate 199 (1.47 g, 4.87 mmol) in acetonitrile (18.4 mL) and césium carbonate (3.970 g, 12.2 mmol) at 5 RT. The réaction mixture heated to 50°C and stirred for 22 h. The reaction mixture was filtered and the solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. After séparation, the aqueous phase washed wîth ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous magnésium sulfate. The solvent was evaporated under reduced pressure and heptane/ethyl acetate (80/20) was 10 added to the crude product. The precipitate was filtered off to afford benzyl [(3R)-3-({3-[6-(lhydroxyethyl)pyridin-2-yl]-l-(oxan-2-yl)-l H-indazol-5-yl)oxy)butyl] carbamate intermediate 209 as an off-white solid.

Ή NMR (500 MHz, t/6-DMSO) δ 8.12 (d, I H), 7.96 (d, 1 H), 7.88 (t, 1 H), 7.68 (d, I H), 7.49 (d, 1 H), 7.1 (dd, 1 H), 5.89 (d, 1 H), 5.46 (d, 1 H), 4.99/4.98 (s/s, 2 H), 4.88 (m, 1 H), 4.49 (m, 15 1 H), 3.91/3.76 (d+m, 2 H), 3.18 (m, 2 H), 1.87/1.79 (m+m, 2 H), 1.53 (d, 3 H), 1.32/1.31 (d/d,

H) ppm.

Préparation of intermediate 210: (7S,13R)-7,13 -dimethyi -19-(oxan -2 -yl) -8,14 -dioxa 10,19,20,23detraazatetracyclo[13.5.2. l²’⁶.0^iS'²¹jtricosa -1(20),2(23),3,5,15(22),16,18(21) 20 h eptaen -9 -on e

To benzyl [(3R)-3-({3-[6-(l-hydroxyethyl)pyridin-2-yl]-l-(oxan-2-yl)-l H-indazol-5-yl}oxy) butyljcarbamate intermediate 209 (500 mg, 0.918 mmol) in acetonitrile (45 mL) was added potassium hydroxide (258 mg, 4.59 mmol). The reaction mixture was stirred at room 25 température for 3 h. The reaction mixture was filtered then ethyl acetate and water were added to the filtrate. After séparation, the organic phase was washed with brine, dried over anhydrous magnésium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using heptane/ethyl acetate 90/10 to 70/30 as eluent. The

343 two diastereomers were separated. First eluted (7R,13R)-7,13-dimethyl-19-(oxan-2-yl)-8,14dioxa-10,19_s20₅23-tetraazatetracyclo[13.5.2.1²’⁶.0^l8>2,]tricosa-1(20),2(23),3,5,15(22), 16,18(2 l)-heptaen-9-one as a white solid. Second eluted the (7S,13R)-7,13-dimethyM9(oxan-2-yl)-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.l^2,6.0¹⁸’²¹]tricosa-l(20),2(23), 5 3,5,15(22),16,18(2 l)-heptaen-9-one intermediate 210 as a white solid.

Ή NMR (500 MHz, ί/6-DMSO) δ (m, 6 H), 8.02 (d, 1 H), 7.87 (t, 1 H), 7.81/7.8 (d/d, 1 H), 7.76/7.74 (t/t, 1 H), 7.66 (d, 1 H), 7.35 (d, 1 H), 7.02 (dd, 1 H), 5.88 (m, 1 H), 5.87 (m, 1 H), 4.55 (m, 1 H), 3.9/3.76 (m+m, 2 H), 3.54/2.82 (m+m, 2 H), 2.27/1.36 (m+m, 2 H), 1.61 (d, 3 H), 1.35 (d, 3 H) ppm.

Préparation of Example 150: (7S,13R)-7,13-dimethyl-8,14-dioxa-10,19,20,23-tetraaza tetracyclo[13.5.2.1²’⁶.0^I8’²¹ltncosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

(7S, 13R)-7,13-dimethy 1-19-(oxan-2-y 1)-8,14-dioxa-10,19,20,23-tetraazatetracyclo [13.5.2.

l^2>6.0^18,21 Jtricosa-1(20),2(23),3,5,15(22), 16,18(2 l)-heptaen-9-one intermediate 210 (200 mg,

0.46 mmol) and p-toluenesulfonic acid monohydrate (0.407 mL, 2.291 mmol) were added to methanol (33 mL) and water (4.5 mL). The reaction mixture was stirred at 65'C for 16 h. Methanol was removed partially by évaporation under reduced pressure and saturated aqueous sodium bicarbonate solution was added. The aqueous phase was washed with ethyl acetate. the organic phase was washed with brine, dried over anhydrous magnésium sulfate, fîltered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using heptane/ethyl acetate 70/30 to 40/60 to afford (7S,13R)-7,13-dimethyl8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.P^,6.0¹⁸’²¹]tricosa-l(20),2(23),3,5,15(22),16, 18(21)-heptaen-9-one example 150 as a white solid.

‘H NMR (500 MHz, J6-DMSO) δ 13.21 (s, 1 H), 8.03 (d, 1 H), 7.84 (t, I H), 7.8 (d, 1 H), 7.74 (dd, I H), 7.45 (d, 1 H), 7.31 (d, 1 H), 6.95 (dd, 1 H), 5.87 (q, 1 H), 4.54 (m, I H), 3.54/2.82 (m+m, 2 H), 2.28/1.35 (m+m, 2 H), 1.61 (d, 3 H), 1.34 (d, 3 H) ppm.

LCMS method F: [M+Hf = 353.3, t_R = 2.04 min

LCMS method G; [M+Hf = 353.2, t_R = 2.10 min

344

Example 151: (13R)-13-methyl-9-oxo-8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.

I²⁵.0¹⁸’²i]_tric_Osa-l(20),2(23),3,15(22),16,18(21)-hexaene-4-carbonitrile

Example 151 is prepared according to the synthesis route described in general Scheme O.

Préparation of intermediate 211: 4~[5-[tert-butyHdimethyl)silyl]oxy-l-tetrahydropyran-2-ylindazol-3-yl]-l-(2~hydroxyethyl)pyrrole-2-carbonitriïe

To a solution of re/-Lbutyl-dimethyl-[l-tetrahydiOpyran-2-y 1-3-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)indazol-5-yl]oxy-silane (936 mg, 2.045 mmol), 4-bromo-l-(2hydroxyethyl)pyrrole-2-carbonîtrile (350 mg, 1.635 mmol) and potassium phosphate tribasîc (1.04 g, 4.905 mmol) in 1,4-dioxane (3.5 mL) and water (250 pL) were added tetrakis(triphenylphosphine)palladium(0) (94 mg, 0.0817 mmol) and 2dicyclohexy]phosphino-2',4',6'-triisopropylbiphenyl (78 mg, 0.163 mmol). The reaction mixture was heated at 100 °C for Ih. The reaction mixture was filtered through a Celite pad and washed with ethyl acetate. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnésium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 50/50 as eluent to afford 421105

345

[5-[/er/-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3-yl]-l-(2-hydroxyethyl) pyrrole-2-carbonitrile intermediate 211 as a yellow oil.

LCMS method F: [M+H]* = 467.3, t_R = 3.37 min

Préparation of intermediate 212: (13R)-13-methyl-19-(oxan-2-yl) -9-oxo-8,14-dioxa5,10,19,20-tetraazatetracyclo[13.5.2.1^2,5.0^!S'²¹ /tricosa -1(20),2(23),3,15(22),16,18(21)hexaen e -4 -carbonitrile

To a suspension of 4-[5-[terZ-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3-yl]-l (2-hydroxyethy!)pyrrole-2-carbonitrile intermediate 211 (230 mg, 0.493 mmol) and césium carbonate (480 mg, 1,48mmol) in acetonitrile (60 mL) wad added [(1 S)-3(benzyloxycarbonylamino)-I-methyl-propyl] methanesulfonate (193 mg, 0.642 mmol). The reaction mixture was heated at 50°C 4 h. Additional césium carbonate (481 mg, 1.48 mmol) and acetonitrile (200 mL) were added. The reaction mixture was stirred at 80°C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved between water and ethyl acetate. After séparation, the aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 70/30 as eluent to afford (13R)-13~methyl-19-(oxan-2-yl)9-oxo-8,14-dioxa-5,10,19,20-tetraazatetracyclo[ 13.5.2.1^.0^18,2 ']tricosa-1(20),2(23),3,15(22), 16,18(21 )-hexaene-4-carbonitrile intermediate 212 as a white powder.

LCMS method F: [M+H]* = 366.3, t_R = 2.10 min

Préparation of Example 151 : (13R)-13-methyl-9-oxo-8,14-dioxa-5,10,19,20-tetraaza tetra cyclo[13.S.2.1²’⁵.0¹⁸’²¹]tricosa-l(20),2(23),3,15(22),16,18(21)-hexaene-4-carbonitrile

346

H

To a solution of (13R)-13-methyl-19-(oxan-2-yl)-9-oxo-8,14-dioxa-5,10,19,20-tetraazatetra cyclo[ 13.5.2 J ²’⁵.0¹⁸4i]trîcosa-1(20),2(23),3,15(22),16,18(2 l)-hexaene-4-carbonîtrile intermediate 212 (100 mg, 0.22 mmol) in methanol (10 mL) and water (1.5 mL) was added p5 toluenesulfonic acid monohydrate (212 mg, LH mmol). The reaction mixture was stirred at 65°C for 2 h. The solvent was evaporated under reduced pressure. The residue was neutralized by slow addition of saturated aqueous sodium hydrogen carbonate solution and was diluted with ethyl acetate. After séparation, the aqueous phase was extracted with ethyl acetate. The combined organic layer was washed with a saturated aqueous sodium bicarbonate solution, 10 water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 50/50 as eluent. The oily product was crystallized in dichloromethane to afford (13R)-13-methyl-9-oxo-8,14-dioxa-5,10,19,20-tetraazatetracyclo [13.5.2.l²4.0^,8^']tricosa-l(20),2(23),3,15(22),16,18(21)-hexaene-4-carbonitrile example 151 15 as a yellow powder.

LCMS method F: [M+H]⁺ = no mass observed, t_R = 2.03 min

LCMS method G: [M+H]⁺ = 366.2, t_R = 1.96 min ‘H NMR (400 MHz, c/6-DMSO) Ô 12.85 (IH, s), 7.84 (IH, dd, J=4.3, 7.7 Hz), 7.54 (IH, d, J=1.7 Hz), 7.44 - 7.40 (IH, m), 7.28 - 7.27 (1 H, m), 7.09 (IH, d, J=2.3 Hz), 6.93 (IH, dd, J=2.1, 20 8.9 Hz), 4.68 -4.59 (2H, m), 4.46 - 4.37 (2H, m), 4.18 - 4.12 (IH, m), 3.49 - 3.48 (1 H, m), 2.96

-2.88(1 H, m), 2.13 (lH,t, J= 14.0 Hz), 1.38 - 1.35 (4H, m) ppm.

Example 152: 12,12-difluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹] tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

347

Example 152 is prepared according to the synthesis route described in general Scheme C.

Préparation of intermediate 213: benzyl N-(2,2-difluoro-3-hydroxy-propyl)carbamate

To a solution of 3-amino-2,2-difluoropropan-l-ol (3 g, 27.005 mmol) in a mixture of 40.5 mL of THF and 40.5 mL of water was added sodium hydrogenocarbonate (4.991 g, 59.411 mmol). The suspension was cooled to 0°C and benzyl chloroformate (8.376 mL, 59.411 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. The product 10 was diluted with EtOAc, an aqueous saturated solution of NaHCO3 was added and the mixture was extracted with EtOAc (x4). The combined organic layers were dried over MgSO4, filtered and the solvents evaporated under reduced pressure. The product was purified by flash chromatography on silica gel, using as eluents heptane/EtOAc (from 100:0 to 75:25). The desired fractions were combined and concentrated under vacuum to afford benzyl (2,2-difluoro15 3-hydroxypropyl)carbamate intermediate 213 as a white solid.

LCMS method B: [M+H]⁺ = 246.0, t_R = 0.526 min

Préparation of intermediate 214: benzyl N-[2,2-difluoro-3-(3-iodo-l-tetrahydropyran-2-yiindazol-5-yl)oxy-propyl]carbamate

A solution of benzyl (2,2-difluoro-3-hydroxypropyl)carbamate intermediate 213 (2 g, 8.156 mmol) in dry THF (49 mL, 6 mL/mmol) were added 3-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH21105

348 indazol-5-ol (3.368 g, 9.787 mmol) and triphenylphosphine (3.209 g, 12.234 mmol) and the mixture was stirred for 5 minutes. DIAD (2.409 mL, 12.234 mmol) was added dropwise and the reaction mixture was stirred at 90°C for 1.5 h. The mixture was contrated under under reduced pressure and the crude product was purified by flash chromatography on silica gel, using as eluents heptane/EtOAc (from 100:0 to 80:20) to afford a mixture of 3-iodo-l(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-ol and benzyl (2,2-difluoro-3-((3-iodo-l(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-yl)oxy)propyl)carbamate. The mixture was purified by flash chromatography on silica gel, using as eluents DCM/EtOAc (from 100:0 to 98:2) to afford benzyl (2,2-difluoro-3-((3-iodo-l-(tetrahydro-2H-pyran-2-yl)-l H-îndazol-5-yl)oxy) propyl)carbamate intermediate 214 as a white solid.

LCMS method E: [M+H]⁺ = 572.0, t_R = 4.275 min

Préparation of intermediate 215: N-[2,2-difluoro-3-[3-f3-(hydroxymethyl)phenyl]-ltetrahydro pyran-2-yl-indazol-5-yl/oxy-propylJcarbamate

To a solution of benzyl 2V-[2,2-dif1uoro-3-(3-iodo-l-tetrahydropyran-2-yl-indazol-5-yl)oxypropyl]carbamate intermediate 214 (250 mg, 0.44 mmol), [3-(hydroxymethyl)phenyl]boronic acid (79 mg, 0.52 mmol) and potassium phosphate tribasic (280 mg, 1.32 mmol) in 1,4-dioxane (3.2 mL) and water (L6 mL), were added tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (21 mg, 0.044 mmol). The reaction mixture was heated at 100 °C for 2 h. The reaction mixture was filtered through a Celite pad and washed with ethyl acetate. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous magnésium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 99/1 to 40/60 as a eluent to afford benzyl À^r-[2,2-dif1uoro-3-[3-[3-(hydroxymethy])phenyl]-l -tetrahydropyran-2-yLindazol-5-yl] oxy-propyl]carbamate intermediate 215 as a colorless oil.

LCMS method F: [M-t-H]⁺ = 552.3, t_R = 2.90 min

349

Préparation of intermediate 216: 12,12 -difluoro -19-(oxan -2 -yl) -8,14 -dioxa -10,19,20 -triaza tetracyclo[13.5.2.1^2,6.0^13,21Jtricosa -1(20),2(23),3,5,15(22),16,18(21) -heptaen -9-one

To a solution of benzyl A42,2-dif]uoro-3-[3-[3-(hydroxymethyl)pheny[]-l-tetrahydropyran-2yl-indazol-5-yl]oxy-propyl]carbamate intermediate 215 (243 mg, 0.44 mmol) in dry acetonitrîle (28 mL) at room température was added potassium hydroxide (0.123 g, 2.20 mmol) in one portion. The reaction mixture was stirred at room température for 8 h. The reaction mixture was filtered then washed with ethyl acetate and the fîltrate was evaporated under reduced pressure.

The residue was purified by silica gel column chromatography using cyclohexane/(ethyl acetate/ethanol (3-1)) 100/0 to 80/20 as eluent to afford 12,12-difiuoro-19-(oxan-2-yl)-8,14dioxa-10,19,20-trîazatetracyclo[ 13.5.2.1^.0^18,2'jtricosa-1(20),2(23),3,5,15(22),1 6,18(21)heptaen-9-one intermediate 216 as a white solid.

LCMS method F: [M+Hf = 444.3, t_R = 2.78 min

Préparation of Example 152 : 12,12-difluoro-8,14-dioxa-10,19,20-triazatetracyclo

[13.5.2.1²’⁶.0^18,21]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

To a solution of 12,12-difluoro-19-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.

1²A0^18,2'jtricosa-1(20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one intermediate 216 (65 mg,

0.15 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (230 pL, 3.0 mmol). The reaction mixture was heated at 50°C for 2 h. The réaction mixture was evaporated under reduced

350 pressure and the residue was dissolved in ethyl acetate and saturated aqueous sodium bicarbonate solution. After séparation, the aqueous layer was extracted with ethyl acetate. The organic layers were washed with water then brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column 5 chromatography using dichloromethane/ethanol 100/0 to 95/5 as eluent. The resulting product was triturated in dichloromethane, filtered and dried to afford I2,12-difluoro-8,14-dioxa10,19,20-triazatetracyclo[ 13.5.2.1²-⁶.0^,8,21]tricosa-1(20),2(23),3,5,15(22), 16,18(21 )-heptaen-9one example 152 as a white solid.

LCMS method F: [M+H]⁺ = 360.3, t_R = 2.09 min

LCMS method G: [M+H]⁺ = 360.2, t_R = 2.10 min

Ή NMR (400 MHz, d6-DMSO, 80°C) δ 12.93 (IH, s), 8.00 - 7.99 (IH, m), 7.90 - 7.88 (2H, m), 7.51 - 7.45 (3H, m), 7.31 - 7.28 (1 H, m), 7.13 - 7.07 (IH, m), 5.39 - 5.31 (2H, m), 4.71 (2H, t J = 16.9 Hz), 3.71 - 3.52 (2H, m) ppm.

Example 153: (13R)-17-fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.

l^2,6.0^18,21} tricosa-1 (20),2(23),3,5,15(22),16,18(21)-lieptaen-9-one

O

Example 153 is prepared according to the synthesis route described in general Scheme C.

Préparation of intermediate 217: tert-buty’l-[(7-fluoro-lH-indazol-5-yl)oxy]-dimethyl-silane

To a stirred solution of 7-f1uoro-lH-indazol-5-ol (4.858g, 31.933mmol) in DCM (1 OOmL) was added imidazole (2.609g, 38.32mmol) followed by tert-butyldimethylchlorosilane (5.295g,

35.126mmol). The reaction mixture was stirred at room température for 16h. The mixture was

351 filtered over a pad of celite and was washed with dichloromethane. The filtrate was concentrated under vacuum to afford tert-butyl-[(7-fluoro-lH-indazol-5-yl)oxy]-dimethylsilane intermediate 217. The product was used in the next step without further purification. LCMS method B: [M+H]⁺ = 267.0, tR = 1.153 min

Préparation of intermediate 218: tert-butyl-[(7-finoro-3-todo-1 H-indazol-5-yl)oxy]dimethyl-silan e

-iodopyrrolidine-2,5-dîone (7.601g, 33.785mmole) in DMF (30mL) was added to a solution of tert-butyl-[(7-fluoro-lH-îndazol-5-yl)oxy]-dimethyl-silane intermediate 217 (6 g, 22.523 mmol) in DMF (15 mL). The reaction mixture was stirred at room temperature for Ih. A solution of 10% sodium thiosulfate (300ml) was added at 0°C and the mixture was extracted with EtOAC (4x200ml). The combined organic layers were dried over MgSO4, filtered and the solvent was removed under reduced pressure. The product was purified by column chromatography on silica gel using as eluent heptane/EtOAc (90:10) to afford tert-buty 1-[(7fluoro-3-iodo-lH-indazol-5-yl)oxy]-dimethyl-silane intermediate 218 as a stîcky transparent gum.

LCMS method B: [M+H]⁺= 392.9, t_R= 1.316 min

Préparation of intermediate 219: tert-butyi-(7-fluoro-3-iodo-l-tetrahydropyran-2-ylindazol-5-yl)oxy-dimethyl-silane

To a solution of tert-butyl-[(7-fluoro-3-iodo-l H-indazol-5-yl)oxy]-dimethyl-silane intermediate 218 (5.340 g, 13.612 mmol) in 54 ml of DCM were added 4methylbenzenesulfonic acid monohydrate (0.518 g, 2.722 mmol) and 3,4-dihydro-2H-pyran (3.734 ml, 40.836 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM and washed with a saturated aqueous NaHCO3

352 solution (3x500ml) and brine (500ml). The organic phase was dried over MgSO4, fïltered and evaporated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using a gradient of n-heptane/EtOAc (100:0 to 90:10) as eluents. The desired fractions were combined and the solvent was removed under reduced pressure to afford tert-buty l-(7-fluoro-3-iodo-l-tetrahydropyran-2-yl-indazol-5-y l)oxy-dimethyl-silane intermediate 219 as a colourless oil.

LCMS method B: [M-84+Hf = 392.9, t_R = 1.577 min

Préparation of intermediate 220: 7-fluoro-3-iodo~l-tetrahydropyran-2-yl-indazol-5-ol

Tert-butyl-(7-f1uoro-3-Îodo-l-tetrahydropyran-2-yl-îndazol-5-yl)oxy-dimethyl-silane intermediate 219 (5.390 g, 11.314 mmol) was dissolved in 35 ml of THF. The mixture was cooled to 0°C and TBAF 1 M in THF (14.708 ml, 14.708 mmol) was added. The reaction mixture was stirred at RT for 2h. The reaction mixture was cooled to 0°C, diluted with EtOAc 15 and the mixture was washed with a saturated aqueous solution ofNaHCO3 (x3). The organic layer was dried over MgSO4, filtered and the solvent was removed under reduced pressure to obtain a solid that was triturated with DCM to obain 7-fluoro-3-iodo-l-tetrahydropyran-2-ylindazol-5-ol intermediate 220 as a white solid.

LCMS method C: [M+H]⁺ = 363.0, t_R = 4.563 min 20

Préparation of intermediate 221: Benzyl N-[(3R) -3-(7-fluoro-3-iodo-l-tetrahydropyran-2-ylindazol-5-yl) oxybutyljcarbamate

To a solution of 7-fluoro-3-iodo-l-tetrahydropyran-2-yl-indazol-5-ol intermediate 220 (700 mg, 1.93 mmol) in VW-dimethylformamide (8 mL) at room température was added césium carbonate (942 mg, 2.90 mmol). The reaction mixture was stirred at room température for 30 min and a solution of [(lS)-3-(benzyloxycarbonylamino)-l-methyl-propyl] methanesulfonate (638 mg, 2.12 mmol) in V.V-dimethylformamide (2 mL) was added dropwise. The reaction mixture was stirred at room température for 5 h. The reaction mixture was filtered, washed with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 80/20 as eluent to afford benzyl N-[(3R)-3-(7-fluoro-3-iodo-l-tetrahydropyran-2-yl-indazol-5-yl)oxybutyl]carbamate intermediate 221 as a colorless oil.

LCMS method F: [M+H]⁺ = 568.2, t_R = 3.30 min

Préparation of intermediate 222: Benzyl N-[(3R)-3-[7-fluoro-3-[3-(hydroxymethyl) phenyljl-tetrahydropyran-2-yl-indazol-5-yl]oxybutyl]carbamate

To a solution of benzyl N-[(3R)-3-(7-fluoro-3-iodo-l-tetrahydropyran-2-yl-indazol-5yl)oxybutyl]carbamate intermediate 221 (755 mg, 1.33 mmol), [3-(hydroxymethyl) phenyl] boronîc acid (241 mg, 1.60 mmol) and potassium phosphate tribasic (848 mg, 4.00 mmol) in 1,4-dioxane (12 mL) and water (2 mL), were added tetrakîs(trÎphenylphosphine)palladium(0) (76 mg, 0.066 mmol) and 2-dicyclohexylphosphîno-2^r,4',6'-triisopropylbiphenyl (62 mg, 0.13 mmol). The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered through a Celite pad and washed with ethyl acetate. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous magnésium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate using 99/1 to 40/60 as eluent to afford benzyl N-[(3R)-3-[7-fluoro-3-[3-(hydroxymethyl)phenyl]-ltetrahydropyran-2-yl-indazol-5-yl]oxybutyl]carbamate intermediate 222 as a yellow solid. LCMS method F: [M+H]⁴' = 548.4, t_R = 3.09 min

354

Préparation of intermediate 223: (13R) -I7-fluoro -13 -methyl-19-(oxan -2 -yl) -8,14 -atoxa 10,I9,204riazatetracyclo[13.5.2.1^2,6.0^,S21 Jtricosa -1(20),2(23),3,5,15(22),16,18(21) -heptaen 9-one

A solution of benzyl JV-[(3Æ)-3-[7-fluoro-3-[3-(hydroxymethyl)phenyl]-l-tetrahydropyran-2y l-îndazol-5-y l]oxybutyl] carbamate intermediate 222 (550 mg, l.OO mmol) and césium carbonate (l .95 g, 6.00 mmol) in dry acetonitrile (150 mL) was stirred at 85 °C for 16 h. The reaction mixture was filtered, washed with ethyl acetate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/(ethyl acetate/ethanol 3/l) 100/0 to 80/20 as eluent to afford (l3R)-l7-fluoro-l3-methyl-l9-(oxan-2yl)-8,l4-dioxa-10,19,20-triazatetracyclo[13.5.2.1²'⁶.0^li;!’^2l]tricosa-!(20),2(23),3,5,l 5(22), 16,18(2 l)-heptaen-9-one intermediate 223 as a white solid.

LCMS method F: [M+H] ^h = 440.3, t_R = 3.08 min

Préparation of Example 153: (13R)-17-fluoro-13-methyl-8,14-dioxa-10,19,20-triazatetra cyclo[13.5.2.1^î’⁶.0^ls’²¹]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

To a solution of (l3R)-l7-fluoro-l3-methyl-19-(oxan-2-yl)-8,l4-dioxa-l0,l9,20triazatetracyclo [13.5.2. l^2,6.0'^8,2'jtricosa-l (20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one intermediate 223 (346 mg, 0.79 mmol) in dichloromethane (19 mL) was added trifluoroacetic

355 acid (l.20 mL, 15.8 mmol). The réaction mixture was heated at 50 °C for 16 h. The reaction mixture was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and saturated aqueous solution of sodium bicarbonate was added. After séparation, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, 5 brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure.

The residue was purified by silica gel column chromatography using dichloromethane/methanol 100/0 to 95/5 as eluent. The resulting product was triturated in dichloromethane, filtered and dried to afford (13R)-17-fluoro-13-methyl-8,14-dioxa-10,19,20triazatetracyclo [ 13.5.2.1^2,6.0^18,2'jtrîcosa-1 (20),2(23),3,5,15(22),16,18(21 )-heptacn-9-one example 153 as a white solid.

LCMS method F: [M+H]⁺ = 356.2, t_R = 2.41 min

LCMS method G: [M+H]⁺ = 356.2, t_R = 2.33 min ‘H NMR (400 MHz, d6-DMSO) δ 13.70 ( 1 H, s), 7.93 - 7.81 (3H, m), 7.51 - 7.46 (IH, m), 7.33

- 7.29 (IH, m), 7.08 (IH, s), 6.88 (IH, dd, 1.3, 12.1 Hz), 5.77 - 5.73 (IH, m), 4.84 - 4.80 15 (IH, m), 4.62 - 4.54 (IH, m), 3.58 - 3.53 (IH, m), 2.93 - 2.85 (IH, m), 2.44 - 2.37 (IH, m), 1.41

- 1.38 (4H, m) ppm.

Example 154: (7S,13R)-7,13-dimethyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo

[ 13.5.2.lⁱ’⁶.0^18,21] tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

Example 154 is prepared according to the synthesis route described below.

Préparation of intermediate 224: l-(6-chloropyrazin-2-yl)ethanol

0°C was added sodium borohydride (725 mg, 19.2 mmol) in small portions. The réaction

To a solution of 1-(6~chloropyrazin-2-yl)ethanone (1.00 g, 6.39 mmol) in methanol (15 mL) at

356 mixture was stirred at 0°C For 3 h. Water was added to reaction mixture then IM aqueous hydrochloric acid solution. The reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnésium sulfate, filtered and evaporated under reduced pressure to afford I-(6-chloropyrazin-2-yl)ethanol intermediate 224 as a 5 coîorless oil.

^lH NMR (500 MHz, d6-DMSO) δ 8.74 (s, I H), 8.69 (s, 1 H), 5.73 (d. 1 H), 4.79 (m, l H), 1.4 (d, 3 H) ppm.

Préparation of intermediate 225: l-[6-[5-ftert-butyl(dimethyl)sifyUoxy-l-tetrahydropyran-210 yl-indazol-3-ylfpyrazin-2-yl]ethanol

-(6-chloropyrazin-2-yl)ethanol intermediate 224 (970 mg, 6.12 mmol) in 1,4-dioxane (60 mL) was warmed to 60° C and ail the insoluble solid was filtered ont. To the fîltrate water (6 ml·), /i?rr-butyl-dimethyl-[l-tetrahydropyran-2-yl-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan15 2-yl) indazol-5-y!]oxy-silane (3.08 g, 6.73 mmol), potassium carbonate (1.69 g, 12.2 mmol) and fïnally palladium, triphenylphosphane (212 mg, 0.183 mmol) were added. The reaction mixture was purged with nitrogen for 10 min, then it was refluxed under nitrogen for 40 min. The reaction mixture was cooled to room température, diluted with ethyl acetate, washed with water, then the aqueous layer was extracted with ethyl acetate. The combined organic layer was 20 washed with brine, dried over anhydrous magnésium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using hcptane/ethyi acetate 80/20 to 50/50 as eluent to afford 1-[6-[5-[m7-butyl(dimethyl)silyl]oxy ]-Îetrahydropyran-2-yl-indazol-3-yl]pyrazin-2-yl]ethanol intermediate 225 as a brown oil.

Ή NMR (500 MHz, d6-DMSO) δ 9.19 (s, 1 H), 8.7 (s, 1 H), 7.98 (d, 1 H). 7.74 (d, 1 H), 7.09 25 (dd, 1 H), 5.94(dd, 1 H), 5.7 (d, 1 H), 4.94 (qn, 1 H), 3.93/3.78 (dt+td, 2 H), 2.48/2.05 (m+dd, 2 H), 2.09/1.79 (m+m, 2 H), 1.62 (qn, 2 H), 1.55 (d, 3 H). 0.99 (s, 9 H), 0.24/0.23 (s/s, 6 H) ppm.

357

Préparation o f intermediate 226:3-(6-(1-hydroxyethyl)pyrazin-2-yl(-l-tetrahydropyran-2-ylindazol-5-olate(tetrabutylammoniumsalt)

3b a solution of l-[6-[5-[te/7-Butyl(dimethyl)silyl]oxy-l-tetrahydiOpyran-2-yl-indazol-35 y llpyrazin-2-yl] éthanol intermediate 225 (2.61 g, 5.74 mmol) in tetrahydrofuran (15 mi.) at room température was added IM tetrabutyl ammonium fluoride solution in THF (6.3 ML, 6.32 mmol) dropwise. The reaction mixture was stirred for I h. The réaction mixture was stirred at 0°C for 10 mîn and the solid was filtered out then washed with THF (10 mL) and with diethyl ether to afford 3-|6-( l-hydroxyethyl)pyrazin-2-yl]-l-tetrahydropyran’2-yi-indazol-5-olate 10 tetrabutyl ammonium intermediate 226 as an off-white solid. The base acid ratio is ca. 1:2.

Ή NMR. (500 MHz, d6-DMSO) δ 9.1 (s, 1 H), 8.59 (s, 1 H), 7.52 (brs., 1 H), 7.39 (d, 1 H). 6.9 (dd. 1 II), 5.78 (dd, 1 H), 4.9 (q, 1 H), 3.91/3.73 (brd+td, 2 H), 2.53-1.53 (m, 6 H), 1.51 (d, 3 H) ppm.

Préparation of intermediate 227: Benzyl N~((3R)~3-(3-(6-(l-hydroxyetbyl)pyrazin-2-yl]~ltetrahydropyran-2-yl-indazol-5-yl]oxybutyl( carbamate

To a suspension of 3-|6-( I-hydiOxyethyl)pyrazjn-2-yl]-l-tetrahydropyran-2-yl-indazol-5-olate tetrabutylammonium intermediate 226 (2.24 g, 3.96 mmol) in NjV-dimethy Iformamide (20 mL) at 45°C was added césium carbonate (5.21 g, 16.0 mmol). The reaction mixture was stirred for

358 min. then a solution of [( 1 S)-3-(benzyloxycarbonylami no)-1-methyl-propyl] methane sulfonate (1.51 g, 5.00 mmol) in Λ^ΛΜΪ methy Iformamide (5 mL) was added. The reaction mixture was stirred at 45°C for 3 h. The warm solution was fïltered and the fîltrate was diluted with ethyl acetate then washed with brine. The organic phase was dried over anhydrous sodium sulfate, fïltered and evaporated under reduced pressure. The solid was suspended în diethyl ether then fïltered and dried to afford benzyl N-[(3R)-3-[3-[6-(l-hydroxyethyl)pyrazin-2-yl]-ltetrahydropyran-2-yl-indazol-5-yl]oxybutyl]carbamate as a mixture of diastereomers intermediate 227 as a beige solid.

‘H NMR (500 MHz, d6-DMSO) δ 9.19 (s, 1 H), 8.7 (s, 1 H), 7.98 (d. 1 H), 7.74 (d, 1 H), 7.417.19 (m. 6 H), 7.15 (dd. 1 H), 5.94 (dd, l H), 5.68 (d. 1 H), 4.98 (s, 2 H), 4.97 (m. 1 H), 4.51 (m, IH), 3.92/3.78 (brd+m, 2 H), 3.18 (m. 2 H), 2.48/2.04 (m+m, 2 H), 2.08/1.78 (m+m, 2 H), 1.87/1.79 (m+m, 2 H), 1.62 (m, 2 H), 1.57 (d, 3 H), 1.31 (d, 3 H) ppm.

Préparation of intermediate 228: (7S, 13R) -7,13 -dimethyl-19 -foxan -2 -yl) -8,14-dioxa 4,10,19,20,23 -pentaazatetracyclo[ 13.5.2.1²’⁶.0¹⁸²¹ jlricosa -1(20),2(23),3,5,15(22),16,18(21) heptaen-9-one

To a solution of’benzyl N-[(3R)-3-[3-[6-(l-hydroxyethyl)pyrazin-2-yl]-l-tetrahydropyran-2yi-indazol-5-yl]oxybuty!]carbamate intermediate 227(1.80 g, 3.30 mmol) in dry N,N-di methyl formamide (50 mL) was added potassium hydroxide (555 mg, 9.90 mmol) at 30°C in one portion. The reaction mixture was stirred at 30°C for 60 min. The solid was fil te red out and washed with ethyl acetate. The fîltrate was diluted with ethyl acetate, washed with brine, dried over anhydrous magnésium sulfate, fïltered and evaporated under reduced pressure. The residue was purified and separated as diastereomers by silica gel column chromatography using heptane/ethyi acetate 50/50 to 0/100 as eluent to afford (7S,13R)-7,13-dimethyl-19-(oxan-2yi)-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[l3.5.2.1²’⁶.0^l8'^2,]tricosa-l(20),2(23),3,5, 15(22), 16,18(21 )-heptaen-9-one intermediate 228 as a white solid.

359

Ή NMR (500 MHz, d6-DMSO) δ 9.23 (d, 1 H), 8.66 (d, I H), 7.87/7.85 (t/t, I H), 7.78/7.77 (d/d, l H), 7.72/7.71 (d/d, ! H), 7.05 (dd, l H), 5.94 (q, 1 H), 5.93 (dd, 1 H), 4.56 (m, 1 H),

3.91/3.77 (dq+td, 2 H), 3.53/2.83 (m+m, 2 H), 2.48/2.05 (m+m, 2 H), 2.3/1.33 (td+td, 2 H),

2.09/1.8 (m+m, 2 H), 1.68 (d. 3 H). 1.62 (m, 2 H), i .37 (d, 3 H) ppm.

Préparation of Example 154: (7S,13R)-7,13-dimethyl-8,14-dioxa-4,10,19,20,23-pentaaza tetracyclo[13.5.2.1²’⁶.0¹⁸’^2I]trîcosa-l (20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

To a suspension of (7S,13R)-7,13-dimethy 1-19-(oxan-2-y 1)-8,14-dioxa-4,l 0,19,20,23-pentaaza 10 tetracyclofl 3.5.2.1^2,6.0^18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one intermediate 228 (460 mg, 1.1 mmol) in a mixture of methanol (77 mL) and water (1 1 mL) was added p-tokienesulfonic acid monohydrate (0.93 mL, 5.3 mmol). The reaction mixture was stirred at 65°C for 16 h. The reaction mixture was cooled to room température and saturated aqueous sodium bicarbonate solution was added. Methanol was evaporated under reduced 15 pressure. The reaction mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous magnésium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/ethyl acetate 90/10 to 0/100 as eluent to afford (7S,13R)-7,t3-dimethyl-8,14dioxa-4,10,19,20,23-pentaazatetracyclo[ 13.5.2.1^.0^18,2 ^10083-1(20),2(23),3,5,15(22),

16,1 8(21 )-heptaen-9-one example 154 as a white solid.

LCMS method F: [M+H]⁺ = 354.2, t_R = 2.03 min

LCMS method G: [M+H]⁺ = 354.3, t_R = 1.89 min

Ή NMR (500 MHz, d6-DMSO) δ 13.48 (s, I H), 9.24 (s, 1 H), 8.62 (s, 1 H), 7.85 (dd, 1 H), .77 (d, 1 H), 7.51 (d. 1 H), 6.99 (dd, IH), 5.94 (q, 1 H), 4.56 (m, I H), 3.53/2.83 (dq+td, 2 H),

2.32/1.33 (t+td, 2 H), 1.68 (d. 3 H), 1.37 (d, 3 H) ppm.

Example 155: (7R,13R)-7,13-dimethyl-8,14-dioxa-4,10,19,20,23-pentaazatetracy cio [13.5.

2.12-6.0^,²¹]tricosa-l(20),2(23),3,5,15(22),16,18(21)-lieptaen-9-one

360

Example 155 is prepared according to the synthesis route described in general Scheme K.

Préparation of intermediate 229: (7R,13R)-7,13-dimethyl-19-(oxan-2-yl) -8,14-dioxa5 4,10,19,20,23-pentaazatetracyclo[13.5.2.1²·⁶.0^IS2![tricosa-1(20),2(23),3,5,15(22),16,18(21) heptaen-9-one

To a solution of benzyl N-[(3R)-3-[3-[6-(l-hydroxyethyl)pyrazin-2-yl]-l-tetrahydropyran-210 yl-indazol-5-yl]oxybutylJcarbamate intermediate 227 (1.80 g, 3.30 mmol) in dry N,N-dimethyl formamide (50 mL) was added potassium hydroxide (555 mg. 9.90 mmol) at 30°C in one portion. The réaction mixture was stirred at 30°C for 60 min. The solid was filtered out and washed with ethyl acetate. The filtrate was diluted with ethyl acetate, washed with brine, dried over anhydrous magnésium sulfate, filtered and evaporated under reduced pressure. The residue 15 was purified and separated as dîastereomers by silica gel column chromatography using heptane/ethyl acetate 50/50 to 0/100 as eluent to afford (7R,13R)-7,13-dimethyL19-(oxan-2yl)-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[!3.5.2.1²’⁶.0¹⁸’²¹]tricosa-l(20),2(23),3,5, 15(22),! 6,18(21 )-heptaen-9-one intermediate 229 as a white solid.

Ή NMR (500 MHz, d6-DMSO) δ 9.28/9.1 (s/s, 1 H). 8.65 (s, 1 H), 8.13/7.91 (d/d, 1 H), 20 7.72/7.69 (d/d. 1 H), 7.56/7.1 8 (ΐ/t, 1 H), 7.06/7.04 (dd/dd, 1 H), 6.14/5.78 (q/q, 1 H), 5.93 (dd,

H). 4.89 (m, 1 H), 3.93/3.78 (dq+td, 2 H), 3.24/2.98 (dq+dt, 2 II), 2.46/2.03 (td+dq, 2 H), 2.07/1.78 (m+m. 2 H), 1.75/1.6 (m+m, 2 H), 1.75 (d, 3 H), 1.61 (m, 2 H), 1.5/1.4 (d/d, 3 II) ppm.

361

Préparation of Example 155: (7R,13R)-7,13-dimethyl-8,14-dioxa-4,10,19,20,23-pentaaza tetracyclo[13.5.2.1²A0¹⁸’²¹]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

To a suspension of (7R,l3R)-7,13-dimethyl-19-(oxan-2-yl)-8,14-dioxa-4,10,19,20,23pentaazatetracyclo[ 13.5.2. l^2,6,0^18,2']tricosa-1(20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one intermediate 229 (86 mg, 0.20 mmol) in a mixture of methanol (14 mL) and water (2.0 mL) was added p-tokienesulfonîc acid monohydrate (190 mg, 0.98 mmol) and the reaction mixture was stirred at 65°C for 48 h. The reaction mixture was cooled to room température and saturated aqueous sodium bicarbonate solution and water were added. Methanol was evaporated meanwhîle solid was precipitated. The solid was filtered and dried under reduced pressure. The residue was purified by silica gel column chromatography to afford (7R.13R)-7,13-dimethyl8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[l 3.5.2.1²’⁶.0^l8’^2l]tricosa-1(20),2(23),3,5,15(22), 16,1 8(21)-heptaen-9-one example 155 as a white solid.

LCMS method F: [M+H]⁺ = 354.2, t_R = 2.14 min

LCMS method G: [M+H]⁺ = 354.3, t_R = 2.03 min

Ή NMR (500 MHz, d6-DMSO) δ 13.47(s, I H), 9.29/9.1 1 (s/s, 1 H), 8.61 (s. 1 H), 8.15/7.9 (d/d. 1 H), 7.55/7.17 (dd/dd, 1 H), 7.52/7.48 (d/d, I H), 7/6.98 (dd/dd. 1 H), 6.13/5.78 (q'q, 1 H), 4.89/4.34 (m/m, 1 H), 3.69/3.24/2.98/2.98 (dq+dq/dq+dq, 2 H), 2.76/1.77/1.59/1.42 (dd+td/dd+td, 2 H), 1.75/1.51 (d/d, 3 H), 1.38/1.37 (d/d, 3 H) ppm.

Example 156: (13S)-13-methyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.

P<0^,8’²¹]tricosa-1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one

362

Example 156 is prepared according to the synthesis route described in general Scheme K.

Préparation of intermediate 230: f6-l5-[tert-butyl(dimeth yl)silyl/oxy-l-tetrahydropyran-2-yl5 in dazol-3-yi]pyrazin-2-yl]methanol

To a solution of (6-chloropyrazin-2-yl)methanol (200 mg, 1.66 mmol) in 1,4-dioxane (10.8 mL) and water (1.2 mL) was added at room température feri-butyl-dimethyl-[l-tetrahydropyran-2y[-3_(4_j4_j5_j5-tetramethyl-l,3,2-dioxaborolan-2-yl)indazol-5-yl]oxy-silane (760 mg, 1.66 10 mmol) and potassium carbonate (380 mg, 2.76 mmol). The reaction mixture was purged with nitrogen and tetrakis(triphenylphosphine)palladium(0) (161 mg, 0.14 mmol) was added. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was filtered through a Celite pad and washed with ethyl acetate. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous magnésium 1 5 sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 99/1 to 70/30 as eluent to afford [6[5-[tert-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3-y[]pyrazin-2-yl]methanol intermediate 230 as a yellow solid.

LCMS method F: [M+H]⁺ = 441.3, t_R = 3.36 min

Préparation of intermediate 231:3-[6-(hydroxymethyl)pyrazin-2-yl]-l-tetrahydropyran-2-ylindazoi-5-ol

363

To a solution of [6-[5-[tori-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3-yl] pyrazin-2-y 1]methanol intermediate 230 (594 g, 1.35 mmol) in THF (10 mL) was added dropwise at room temperature 1.0 M tetrabutylammonium fluoride solution in THF (1.48 mL, 5 1.48 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into ice water and stirred for 20 min. The aqueous layer was extracted with ethyl acetate then combined organic layers were washed with brine, dried over anhydrous magnésium sulfate, filtered and concentrated under reduced pressure to give 3-[6(hydroxy methy l)pyrazin-2-y 1]-l-tetrahydropyran-2-yl-indazol-5-ol intermediate 231 as a ] 0 yellow solid which was used in the next step without further purification.

LCMS method F: [M+H]⁺ = 327.3, t_R = 2.01 min

Préparation of intermediate 232 ; benzyl N-[(3S)-3-[3-[6-(hydroxymethyl)pyrazin-2-yl]-ltetrahydropyran-2-yl-indazol-5-yi]oxybutyl]carbaniate

[(1 Æ)-3-(benzyloxycarbonylamino)-1 -methy 1-pro pyl]methanesulfonate was prepared according to the same synthesis procedures as intermediate 199 starting from (2R)-4aminobutan-2-ol.

To a mixture of 3-[6-(hydroxymethyl)pyrazin-2-yl]-l-tetrahydropyran-2-yl-indazol-5-ol intermediate 231 (0.414 g, 1.27 mmol) in A^-dimethylfonnamide (12 mL) was added césium carbonate (825 mg, 2.54 mmol). The reaction mixture was stirred for 20 min. Then, [(17?)-3(benzyloxycarbonylamino)-l-methyl-propyl] methanesulfonate (421 mg, 1.40 mmol) was

364 added, The reaction mixture was stirred at room température for 16 h. Additional [(Hî)-3(benzyloxycarbonylamino)-l-methyl-propyl] methanesulfonate was added (57 mg, O.l 9 mmol) and the reaction mixture was stirred at room température for 2 h. The reaction mixture was concentrated under reduced pressure then diluted with water and extracted with ethyl acetate, 5 The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/méthanol 100/0 to 95/5 as eluent to afford benzyl N[(3S)-3-[3-[6-(hydroxymethyl)pyrazin-2-yl]-l-tetrahydropyran-2-yl-indazol-5-yl]oxybutyl] carbamate intermediate 232 as a yellow solid.

LCMS method F: [M+H] ^h = 532.3, ta - 2.79 min

Préparation of intermediate 233: (Z3S) -13 -methyl-19 -(oxan -2 -yl) -8,14 -dioxa -4,10,19,20,23 pentaazatetracyclo[l 3.5.2. l²⁶.0^ls’²¹ ]tricosa-l (20),2(23),3,5,15(22),16,18(2l)-heptiien -9-one

To a solution of benzyl A/-[(3Sj-3-[3-[6-(hydroxymethyl)pyrazin-2-yl]-l-tetrahydropyran-2-ylindazol·5-yl]oxybutyl] carbamate intermediate 232 (562 mg, 1.06 mmol) in dry acetonitrile (53 mL) at room température was added potassium hydroxide (297 mg, 5.30 mmol) în one portion.

The reaction mixture was stirred at room température for 4 h. The reaction mixture was filtered and rinsed with acetonitrile and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol 100/0 to 95/5 as eluent to afford (13S)-13-methyl-I9-(oxan-2-y 1)-8,14-dioxa-4,10,19,20,23pentaazatetra cyclo[ 13.5.2. iW^'jtricosa-l (20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one intermediate 233 as a yellow foam.

LCMS method F: [M+H]⁺ = 424.3, t_R = 2.54 min

Préparation of Example 156.- (13S)-13-methyl-8,14-dioxa-4,10,19,20,23-pentaazatetra cyclo[13.5.2.1^2<i.0^IS’^2I]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

365

To a solution of(13S)-13-methy 1-19-(oxan-2-y 1)-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo [ 13.5.2. l^2,6.0^18,21 ]tricosa-1(20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one intermediate 233 (183 mg, 0.43 mmol) în methanol (7.4 mL) and water (1.2 mL) was added p-toluenesulfonic 5 acid monohydrate (409 mg, 2.15 mmol) and the reaction mixture was stirred at 65 °C for 16 h.

The reaction mixture was diluted with dichloromethane and saturated aqueous solution of sodium bicarbonate. After séparation, the aqueous layer was extracted with dichloromethane. The combined organic layers were washed brine, dried over anhydrous magnésium sulfate, filtered and evaporated under reduced pressure. The residue was crystallized în 10 dichloromethane, filtered, and dried to afford (13S)-13-methyl-8,14-dioxa-4,10,19,20,23pentaazatetra cyclo[ 13.5.2. l^2,6.0^l8,21]tricosa-1(20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one example 156 as a cream powder.

LCMS method F: [M+H]⁺ = 340.2, t_R = 1.86 min

LCMS method G: [M+H]⁺ = 340.3, ta = 1.81 min

Ή NMR (400 MHz, d6-DMSO) δ 13.49- 13.48 (1 H, m), 9.27 (1 H, s), 8.52 (IH, s), 7.86 - 7.81 (2H, m), 7.51 (lH,d, 7=8.8 Hz), 6.99 (IH, dd, 7=2.4, 9.0 Hz), 5.69 (IH, d, J= 15.6 Hz), 5.18 - 5.14 (IH, m), 4.62 - 4.58 (IH, m), 3.52 - 3.46 (IH, m), 2.95 - 2.87 (IH, m), 2.35 - 2.28 (IH, m), 1.40 - 1.37 (4H, m) ppm.

Example 157: (13R)-13-methyl-8,14-dioxa-10,19,20,22-tetraazatetracyclo[13.5.2.

^,6018,21 j_tricosa. i (20),2(23),3,5,15,17,2 l-heptaen-9-one

Example 157 is prepared according to the synthesis route described in general Scheme C.

366

Préparation of intermediate 234: 5-meth oxy-lH-pyrazolo[4,3~b]pyridine

H

To a solution of 6-methoxy-2-methyl-pyndin-3-amine (4.0 g, 28.95 mmol) in acetic acid (40 5 mL) at 0°C was added dropwise a solution of sodium nitrate (2.99 g, 43.42 mmol) în water (8 mL). The reaction mixture was stirred at room température for 1 h. A saturated aqueous sodium bicarbonate solution was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnésium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel column 10 chromatography using cyclohexane/ethyl acetate 100/0 to 80/20 as eluent to afford 5-methoxy1 H-pyrazolo[4,3-b]pyridine intermediate 234 as a brown solid.

LCMS method F: [M+H]⁺ = 150.2, t_R = 1.33 min

Préparation of intermediate 235: 3-iodo-5-methoxy-lH-pyrazolo[4,3-b]pyridine i

To a solution of 5-methoxy-lH-pyrazolo[4,3-b]pyridine intermediate 234 (1.88 g, 12.6 mmol) in acetonitrîle (20 mL) was added jV-iodosuccînimide (3.40 g, 15.12 mmol). The reaction mixture was heated under microwave irradiations at 120°C for 20 min. The reaction mixture was diluted with a saturated solution of sodium thiosulfate and ethyl acetate was added. After 20 séparation, the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnésium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 70/30 as eluent to afford 3-iodo-5-methoxy-lHpyrazolo[4,3-b]pyridine intermediate 235 as an orange solid.

LCMS method F: [M+H]⁺ = 276.0, t_R = 2.08 min

Préparation of intermediate 236: 3-iodo-5-methoxy-l-tetrahydropyran-2-yl-pyrazolo[4,3bfpyridine

367

To a solution of 3-iodo-5-methoxy-lH-pyrazolo[4,3-b]pyridine intermediate 235 (700 mg, 2.54 mmol) in dichloromethane (4.6 mL) was added 4-methylbenzenesulfonic acid monohydrate (242 mg, 1.27 mmol) and 3,4-dihydro-2H-pyran (0.46 mL, 5.08 mmol). The reaction mixture 5 was stirred at room température for 2 h. The reaction mixture was diluted with dichloromethane and a saturated aqueous sodium bicarbonate solution was added. After séparation, the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous magnésium sulfate, filtered and the solvent was evaporated under reduced pressure to afford 3-iodo-5-methoxy-l-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine intermediate 236 10 as an orange oil.

LCMS method F: [M+H]⁺ = 360.1, t_R = 2.82 min

Préparation of intermediate 237: 3-iodo-l-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-ol

To a solution of 3-iodo-5-methoxy-l-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine intermediate 236 (912 mg, 2.54 mmol) in acetonitrile (5 mL) was added sodium iodide (1.14 g, 7.62 mmol) and trimethylchlorosilane (0.97 mL, 7.62 mmol). The reaction mixture was stirred at 80°C for 1.5 h. The reaction mixture was diluted with water and ethyl acetate. After séparation, the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnésium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/(ethyl acetate/ethanol (3:1)) 100/0 to 30/70 as eluent. The resulting product was trîturated in acetonitrile, filtered and dried to afford 3-iodo-l-tetrahydropyran-2-yl. pyrazolo[4,3-b]pyridîn-5-ol intermediate 237 as a pale yellow solid.

LCMS method F: [M+H]⁺ = 346.1, îr= 1.74 min

368

Préparation of intermediate 238: benzyl N-[(3R)-3-(3-iodo-l-tetrahydropyran -2-yl-pyrazolo

[4,3-b]pyridin-5-yl)oxybutyljcarbamate

To a solution of 3-iodo-l-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-ol intermediate 237 (140 mg, 0.41 mmol) in acetonitrile (3.5 mL) was added césium carbonate (240 mg, 0.81 mmol) and [(lS)-3-(benzyloxycarbonylamino)-l-methyl-propyl]methanesulfonate intermediate 199 (159 mg, 0.53 mmol). The reaction mixture was stirred at 75°C for 1 h. The reaction mixture was cooled to room température and diluted with ethyl acetate. After séparation, the aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over anhydrous magnésium sulfate, filtered and concentrated under reduced pressure to afford benzyl N-[(3R)-3-(3-iodo-l -tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-yl)oxybutyl] carbamate intermediate 238 (as a beige solid.

LCMS method F: [M+H]⁺ = 551.2, t_R = 3.17 min

Préparation of intermediate 239: Benzyl N-[(3R)-3-[3-[3-(hydroxymethyl)phenyl]-ltetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-yl]oxybutyl]carbamate

To a suspension of benzyl N-((3R)-3-(3-iodo-l -tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin5-yl)oxybutyl]carbamate intermediate 238 (210 mg, 0.38 mmol) in 1,4-dioxane (2.2 mL) and water (0.11 mL) was added [3-(hydroxymethyl)phenyl]boronic acîd (69 mg, 0.46 mmol) and potassium phosphate tribasic (242 mg, 1.14 mmol). The reaction mixture was degassed with argon for 10 min and tetrak.is(triphenylphosphine)palladium(0) (22 mg, 0.02 mmol) and Xphos ( 18 mg, 0.04 mmol) were added. The mixture was stirred at 105°C for 7 h. The reaction mixture

369 was cooled to room température and diluted with water and ethyl acetate. After séparation, the aqueous layer was extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 60/40 as eluent to afford benzyl N-[(3R)-3-[3-[3-(hydroxymethyl)phenyl]-ltetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-yl]oxybutyl] carbamate intermediate 239 as a colorless oil.

LCMS method F: [M+H]⁺ = 531.4, t_R = 3.00 min

Préparation of intermediate 240: (13R) -13 -methyl -19-(oxan-2-yl) -8,14-dioxa-10,19, 20,22tetraazatetracyclo[13.5.2.1²A0^lli-^2l]tricosa-l(20),2(23),3,5,15,17,21-heptaen-9-one

To a solution of benzyl N-[(3R)-3-[3-[3-(hydiOxymethyl)phenyl]-l-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridin-5-yl]oxybutyl]carbamate intermediate 239 (156 mg, 0.29 mmol) in dry acetonitrîle (40 mL) was added césium carbonate (574 mg, 1.76 mmol). The resulting mixture was stirred at 90°C for 2 h. The suspension was filtered and the salts were washed with acetonitrîle. The filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol 100/0 to 95/5 as eluent to affo rd ( 13 R)-13 -m ethy 1 -19-(oxan-2 -y l)-8,14-d ioxa-10,19,20,22-tetraazatetracy cio

L13.5.2. l^2,6.0'^8,2 'Jtricosa-1(20),2(23),3,5,15,17,21-heptaen-9-one intermediate 240 as a colorless oil.

LCMS method F: [M+H]⁺ = 423.4, t_R = 2.88 min

Préparation of Example 157: (13R)-13-methyl-8,14-dioxa-l 0,19,20,22-tetraazatetracyclo [13.5.2.1²’⁶.0^182l]tricosa-l(20),2(23),3,5,15,17,21-lieptaeii-9-one

370

To a solution of (13R)-13-methyl-19-(oxan-2-y 1)-8,14-dioxa-10,19,20,22-tetraazatetracyclo [ 13.5.2. PAO^18,2^tricosa-1(20),2(23),3,5,15,17,21-heptaen-9-one intermediate 240 (124 mg, 0.29 mmol) in methanol (5.5 mL) and water (0.8 mL) was added p-toluenesulfonic acid (280 5 mg, 1.47 mmol). The reaction mixture was stirred at 65°C for 2 h. The reaction mixture was cooled to room temperature and the reaction was carefully quenched with a saturated aqueous sodium bicarbonate solution then ethyl acetate was added. After séparation, the aqueous layer was extracted with ethyl acetate and the organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was 10 purified by silica gel column chromatography using dichloromethane/methanol 100/0 to 96/4 as eluent to afford ( 13R)-13-methy 1-8,14-dioxa- 10,19,20,22-tetraazatetracyclo[ 13.5.2. [²A0^l82l]tricosa-l (20),2(23),3,5,15,17,2l-heptaen-9-one example 157 as a white solid.

LCMS method F: [M+H]’ = 339.3, t_R = 2.17 min

LCMS method G: [M+H]⁺ = 339.3, t_R = 2.15 min

Ή NMR (400 MHz, d6-DMSO) δ 13.25 (1 H, brs), 8.58 (IH, s), 8.04 - 7.93 (2H, m), 7.71 (IH, t, >6.3 Hz), 7.42 (IH, t, >7.7 Hz), 7.22 - 7.18 (IH, m), 6.81 (IH, d, >9.1 Hz), 5.61 - 5.53 (IH, m), 5.51 - 5.44 (IH, m), 5.10 - 5.03 (IH, m), 3.43 - 3.36 (IH, m), 3.02 - 2.94 (IH, m), 2.45 -2.36(1 H, m), 1.39 (3H, d, >6.2 Hz), 1.38 - 1.34 (IH, m) ppm.

Example 158: (12R)-4,12-dimethyl-7,13-dioxa-4,9,18,19,22-pentaazatetracyclo(12.5.2.

lrt\0^,7^jdocosa-l(19),2,5(22),14(21),15,17(20)-hexaen-8-one

Example 158 is prepared according to the synthesis route described în general Scheme K.

371

Préparation of intermediate 241: (4-bromo-l-methyl-imidazol-2-yl)methanol

OH

Br

To a suspension of methyl 4-bromo-l-methyl-imidazole-2-carboxylate (3.0 g. 13.76 mmol) in methanol (30 mL) at 0°C was added portion wise sodium borohydride (1.14 g, 30.27 mmol). The reaction mixture was stirred at 0°C for 2 h. Additional sodium borohydride (1.14 g, 30.27 mmol) was added and the reaction mixture was stirred at room température for 3 h. The reaction mixture was quenched by addition of water and methanol then evaporated under reduced pressure. The aqueous phase was extracted with ethyl acetate. The organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford (4-bromo-l-methyl-imidazol-2-yl)methanol intermediate 241 as a white solid.

LCMS method H: [M+H]⁺ = 191-193, t_R = 0.93 min

Préparation of intermediate 242: [4-[5-[tert-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-ylindazol-3-yl]-l-methyl-imidazol-2-yllmethanol

To a solution of teri-butyl-diniethyl-[l-tetrahydropyran-2-yl-3-(4_s4,5,5-tetraniethyl-l,3,2dioxaborolan-2-yl)indazol-5-yl]oxy-silane (753 mg, 1.64 mmol), (4-bromo-l-methyl-imidazol2-yl)methanol intermediate 241 (250 mg, 1.31 mmol) and potassium phosphate tribasic (833 mg, 3.93 mmol) in 1,4-dioxane (3 mL) and water (150 pL) were added tetrakis (triphenylphosphine) palladium(O) (76 mg, 0.065 mmol) and 2-dÎcyclohexylphosphino-2',4',6^rtriisopropylbiphenyl (62 mg, 0.131 mmol). The reaction mixture was heated at 100 °C for 1 h. The solvent was evaporated under reduced pressure and the residue was portioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, fïltered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate

372

100/0 to 50/50 then dichloromethane/methanol 90/10 to afford [4-[5-|7eributyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3-yl]-l-methy l-imidazol-2yl]methanol intermediate 242 as a yellow oil.

LCMS method F: [M+H]⁺ = 443.3, t_R = 2.33 min

Préparation of intermediate 243: benzyl N-[(3R)-3-[3-[2~(hydroxymethyl)-l-methylimidazol-4-yl}-l-tetrahydropyran-2-yl-indazol-5-yl]oxybutyl]carbamate

To a suspension of [4-[5-[terLbutyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3-yl]10 l-methyl-imidazol-2-yl]methanol intermediate 242 (100 mg, 0.226 mmol) and césium carbonate (220 mg, 0.678mmol) in acetonitrile (30 mL) wad added [( 1 S)-3(benzyloxycarbonylamino)-l-methy 1-propyl] methanesulfonate (88 mg, 0.294 mmol). The reaction mixture was stirred at 50°C for 16 h. Additional césium carbonate (220 mg, 0.678mmol) was added and the mixture was stirred at 60°C for 16 h. The solvent was i 5 evaporated under reduced pressure. The residue was portioned between water and ethyl acetate.

After séparation, the aqueous layer was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 70/30 as eluent to afford benzyl N-[(3R)-3-[3-[220 (hydroxymethyl)-l -methy l-imidazol-4-yl]-l-tetrahydropyran-2-yl-indazoI-5yl]oxybutyl]carbamate intermediate 243 as a yellow oil.

LCMS method F: [M+H]⁺ = 534.4, t_R = 2.08 min

Préparation of intermediate 244; (12R)-4,12-dimethyl-18-(oxan-2-yl)-7,13-dioxa-4,9,18,19,

22-pentaazatetracyclo[12.5.2.1^2,s.O^i7,20]docosa-l(19),2,5(22),14(21),15,17(20) -hexaen-8-one

373

To a solution of benzyl N-[(3R)-3-[3-[2-(hydroxymethyl)-1-methy l-imidazol-4-yl]-ltetrahydropyran-2-yl-indazol-5-yl]oxybutyl]carbamate intermediate 243 (200 mg, 0.375 mmol) in acetonitrîle (20 mL) was added potassium hydroxyde (105 mg, L87 mmol). The reaction 5 mixture was stirred at room température for 16 h. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol 100/0 to 90/10 as eluent to (12R)-4,l2-dimethyl-18-(oxan-2-yl)10 7,13-dioxa-4,9,18,19,22-pentaazatetracyclo[12.5.2.l²’⁵.O^l7,20]docosa-l(19),2,5(22), 14(21),15,

17(20)-hexaen-8-one intermediate 244 as a yellow oil.

LCMS method F: [M+H]⁺ = 426.3, îr = 2.16 min

Préparation of Example 158 : (12R)-4,12-dimethyl-7,13-dioxa-4,9,18,19,22-pentaazatetra cyclo[12.5.2.1ⁱ’⁵.0^17ïil]docosa-l(19),2,5(22),14(21),15,17(20)-hexaen-8-one

To a solution of (12R)-4,12-dimethyl-18-(oxan-2-yl)-7,13-dioxa-4,9,l 8,19.22-pentaaza tetracyclo[12.5.2.1²’³.0¹⁷’²⁽⁾]docosa-l (19),2,5(22),14(21),15,17(20)-hexaen-8-one intermediate 244 (56 mg, 0.13 mmol) in methanol (5 mL) and water (0.5 mL) was added p-toluenesulfonic 20 acid monohydrate (125 mg, 0.66 mmol). The réaction mixture was stirred at 65°C for 2 h. The solvent was evaporated under reduced pressure and the residue was neutralized by slow addition of saturated aqueous sodium bicarbonate solution. The residue was diluted with ethyl acetate. After séparation, the aqueous layer was extracted with ethyl acetate. The organic layer was

374 washed with saturated aqueous sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulfate, fdtered and evaporated under reduced pressure. The residue was purified by préparative TLC using dichloromethane/méthanol 100/0 to 95/5 as eluent to afford (12R)-4,12-dimethyl-7,13-dioxa-4,9,l 8,19,22-pentaazatetracyclo[ 12.5.2.1²AO^,7’²⁰]docosa5 1(19),2,5(22),14(21 ), 15, ! 7(20)-hexaen-8-one example 158 as a cream powder.

LCMS method F: [M+H]⁺ = 342.3, t_R = 1.67 min

LCMS method G: [M+H]⁺ = 342.3, t_R = 1.73 min

ΊΙ NMR (400 MHz, d6-DMSO) δ 12.6 - 12.4 (IH; m), 8.32 (IH, d, J=2.3 Hz), 7.88 - 7.85 (IH, m), 7.42 (IH, s), 7.32 - 7.29 (IH, m), 6.85 (IH, dd, J=2.5, 8.9 Hz), 5.48 (IH, d, J=14.8 10 Hz), 5.01 -4.96 (IH, m), 4.62 -4.52 (lH,m), 3.63 - 3.62 (3H, m), 2.91 - 2.78 (IH, m), 2.45 2.38 (1 H, m), 1.39 (3H, d, J=5.9 Hz), 1.27 - 1.24 (2H, m) ppm.

Example 159: (13R)-13-methyl·8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.

1² A0^18,21 ] tricosa-1(20),2(23) ,3,15,17,21 - hexaen-9-one

Example 159 îs prepared according to the synthesis route described in general Scheme O.

Préparation of intermediate 245: 4,5-dibromo-2-(2-tetrahydropyran-2-yloxyethyl) triazole

Br

To a solution of 4,5-dibromo-2FI-triazole (3.40 g, 15.0 mmol) in N,jV-dimethylformamide (100 mL) cooled at -10 °C was added potassium carbonate (4.14 g, 30.0 mmol). The reaction mixture was stirred at room température for 15 min. 2-(2-bromoethoxy)tetrahydropyran (3.44 g, 16.50 mmol) in ^N-dimethylformamide (10 mL) was added dropwise and the reaction mixture was stirred at room température for 16 h. The reaction mixture was quenched by addition of water then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnésium sulfate, filtered and the solvent was removed under reduced

375 pressure. The residue was purified by silica gel column chromatography using heptane/ethyl acetate 90/10 to 80/20 as eluent to afford 4,5-dibromo-2-(2-tetrahydropyran-2yloxyethyl)triazo!e intermediate 245 as a colorless liquid.

LCMS method F: [M+H]⁺ = 356.1, t_R = 2.69 min

Préparation of intermediate 246: 4-bromo-2-(2-tetrahydropyran-2-yloxyethyl)triazole

Br

To a solution of 4,5-dîbromo-2-(2-tetrahydropyran-2-yloxyethyl) triazole intermediate 245 (1.90 g, 5.35 mmol) in THF (50 mL) cooled at -20 °C was added dropwise a 2M of isopropylmagnesium chloride solution in THF (3.20 mL, 6.42 mmol). The reaction mixture was stirred at room température for 16 h then diluted with a saturated ammonium chloride solution. After séparation, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnésium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using heptane/ethyl acetate 100/0 to 90/10 as eluent to afford 4-bromo-2-(2tetrahydropyran-2-yloxyethyl)triazole intermediate 246 as a colorless liquid.

LCMS method F; [M+H]⁺ = 276-278, t_R = 2.34 min

Préparation of intermediate 247: 2-(4-bromotriazol-2-yi)ethanol

Br

To a solution of 4-bromo-2-(2-tetrahydropyran-2-yloxyethyl)triazole intermediate 246 (2.45 g, 8.88 mmol) in THF (70 mL) cooled at 0 °C was added 4M hydrogen chloride solution in 1,4dioxane (6.66 mL, 26.61 mmol). The reaction mixture was stirred at room température for 24 h. The reaction mixture was diluted with a saturated aqueous sodium bicarbonate solution. After séparation, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnésium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel flash chromatography using heptane/ethyl acetate 70/30 as eluent to afford 2-(4-biOmotriazol-2-yl)ethanol intermediate 247 as a colorless liquid.

376

LCMS method F: [M+H]⁺ = 192-l 94, t_R = l .20 min

Préparation of intermediate 248: 2-[4-[5-[tert~butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2yl-indazol-3-yl]triazol-2-yl]ethanol

To a solution of 2-(4-bromotriazol-2-yl)ethanol intermediate 247 (420 mg, 2.18 mmol) in l ,4dioxane (70 mL) and water (7 mL) was added tert-butyl-dimethyl-[l-tetrahydropyran-2-yl-3(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indazol-5-yl]oxy-silane (1.20 g, 2.62 mmol) and potassium phosphate tribasic (1.39 g, 6.56 mmol). The solution was purged with argon and tetrakis(triphenylphosphine)palladîum(0) (126 mg, O.ll mmol) was added. The reaction mixture was stirred at 90 °C for 16 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and ethyl acetate. After séparation, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnésium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel flash chromatography using heptane/ethyl acetate 80/20 as eluent to afford 2-[4-[5-[tert-butyl(dimethyl)silyl]oxy-l -tetrahydropyran-2-yl-indazol-3-yl]triazol-2-yl] éthanol intermediate 248 as a pale brown oil.

LCMS method F: [M+H]⁺ = 444.3, t_R = 3.28 min

Préparation of intermediate 249: (13R)-13-methyl-19-(oxan-2-yl)-8,14-dîoxa-4,5,10,19,20, 23-hexaazatetracyclo[13.5.2.l²’⁵.0^,8’²¹]tricosa-l(20),2(23),3,15,17,21-hexaen-9-one

377

To a suspension of 2-[4-[5-[tert-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3yl]triazol-2-yl]éthanol intermediate 248 (480 mg, 1.08 mmol) and césium carbonate (1.05 g, 3.24 mmol) in acetonitrile (25 mL) was added a solution of [(lS)-3-(benzyloxycarbonylamino)5 1 -methyl-propyl] methanesulfonate (391 mg, 1.29 mmol) in acetonitrile (5 mL). The resulting mixture was stirred at 50°C for 16 h. Additional acetonitrile (25 mL) and césium carbonate (1.05 g, 3.24 mmol) were added. The reaction mixture was stirred at 70°C for 3 h. The reaction mixture was filtered to remove salts and washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using heptane/ethyl acetate 70/30 to 60/40 as eluent to afford (l3R)-l3*methyl-l9-(oxan-2-yl)-8,14dioxa-4,5,10,19,20,23~hexaazatetracyclo[ 13.5.2.1 ^.O’^'jtricosa-1(20),2(23),3,15,17,21hexaen-9-one intermediate 249 as a white solid.

LCMS method F: [M+H]⁺ = 427.3, t_R = 2.50 min

Préparation of Example 159: (13R)-13-methyl-8,14-dioxa-4,5,10,19,20,23-hexaaza tetra cyclo[13.5.2.1²’⁵.0^ls’²¹]tricosa-l(20),2(23),3,15,17,21-hexaen-9-one

To a solution of (13R)-13-methyl- 19-(oxan-2-yl)-8,14-dioxa-4,5,10,19,20,23-hexaazatetra cyclo[l 3.5.2.1^2,5.0’⁸'^2l]tricosa-1 (20),2(23),3,15,17,21 -hexaen-9-one intermediate 249 (100 mg, 20 0.23 mmol) in methanol (14 mL) ) and water (2 mL) was added p-toluenesulfonic acid monohydrate (222 mg, 1.17 mmol). The reaction mixture was stirred at 65°C for 16 h. The solvent was partially removed under reduced pressure and a saturated aqueous sodium bicarbonate solution was added. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnésium sulfate.

378 filtered and the solvent was evaporated under reduced pressure, The residue was purified by silica gel column chromatography using dichloromethane/methanol 100/0 to 95/5 as eluent.

The resulting product was recrystallized in acetonitrile, filtered and dried to afford (13R)-13methyl-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[ 13.5.2.1²’⁵.0¹⁸ⁱ²¹]tricosa1 (20),2(23),3,15,17,21 -hexaen-9-one example 159 as a white solid.

LCMS method F: [M+H]⁺ = 343.3, t_R = 1.89 min

LCMS method G: [M+H]⁺ = 343.3, t_R = 1.90 min

Ή NMR (400 MHz, d6-DMSO) S 13.12 (IH, s), 8.12 (1 H, s), 7.64 (IH, t, J=6.0 Hz), 7.53 7.44 (2H, m), 6.96 (IH, dd, J=2.0, 9.0 Hz), 4.90 - 4.84 (IH, m), 4.78 - 4.72 (2H, m), 4.62 - 4.56 ( 1 H. m), 4.34 - 4.27 (IH, m), 3.42 - 3.29 (IH, m), 2.96 - 2.89 (IH, m), 2.13 - 2.06 (IH, m), 1.38 - 1.34 (4H, m) ppm.

Example 160: (13R)-13-methyl-8,14-dioxa-23-thia-4,10,19,20-tetraazatetracyclo[13.5.2. l²’\0¹⁸’²¹]tricosa-l(20),2,4,15,17,21-hexaen-9-one

Example 160 is prepared according to the synthesis route described in general Scheme L.

Préparation of intermediate 250: 2-(5-bromothiazol-2-yl)ethanoi

To a solution of ethyl 2-(5-bromothîazol-2-yl)acetate (1.50 g, 6.00 mmol) in THF (20 mL) cooled at 0 °C was added a solution of sodium borohydrîde (340 mg, 9.00 mmol) în éthanol (4 mL). The reaction mixture was stirred at room température for 48 h. The reaction mixture was quenched by addition of water at 0 °C and the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnésium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using heptane/ethyl acetate 100/0 to 50/50 as eluent to afford 2-(5-bromothiazol-2-yl)ethanol intermediate 250 as a yellow oil.

379

LCMS method F: [M+H]⁺ = 208-210, t_R = 1.46 min

Préparation of intermediate 251: 2-(5-bromothiazol-2-yl)ethyl N-f(3S)-3-hydroxybutylJ carbamate

To a solution of 4-nitrophenyl chloroformate (480 mg, 2.38 mmol) and pyrîdine (0.35 mL, 4.32 mmol) in dichloromethane (5 mL) was added dropwise a solution of 2-(5-bromothîazol2-yl)ethanol intermediate 250 (450 mg, 2.16 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at room température for 1 h. Then a solution of (2S)-4-aminobutan-2-oI 10 (210 mg, 2.38 mmol) and DIPEA (0.75 mL, 4.32 mmol) in dichloromethane (3 mL) was added.

The reaction mixture was stirred at room température for 16 h. The reaction mixture was diluted with an 0.5 M aqueous sodium hydroxide solution and extracted with dichloromethane. The combined organic layers were washed again with a 0.5 M aqueous sodium hydroxide solution, dried over anhydrous magnésium sulfate, filtered and evaporated under reduced pressure. The 15 residue was purified by silica gel column chromatography using dichloromethane/ethyl acetate 100/0 to 20/80 as eluent to afford 2-(5-bromothiazol-2-yl)ethyl N-[(3S)-3hydroxybutyl] carbamate intermediate 251 as a yellow oil.

LCMS method F: [M+H]⁺= 325.1, t_R = 1.75 min

0 Préparation of intermediate 252: 2-[5-[5-[tert-butyl(dimethyl)silyl/oxy-l-tetrahydropyran-2yl-indazol-3-yl/thiazol-2-ylJethyl N-[(3S)-3-hydroxybutyl/carbamate

Q

To a solution of 2-(5-bromothiazol-2-yl)ethyl N-[(3S)-3-hydroxybutylJcarbamate intermediate

251 (350 mg, 1.08 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added Zert-butyl25 dîmethyl-[l-tetrahydropyran-2-yî-3-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)indazol-521105

380 yl]oxy-silane (600 mg, l .30 mmol) and potassium phosphate tribasic (690 mg, 3.25 mmol). The solution was purged with nitrogen then XPhos (52 mg, O.ll mmol) and tetrakis(triphenylphosphine) palladîum(O) (63 mg, 0.05 mmol) were added. The reaction mixture was stirred under microwave irradiations at 90 °C for 1.5 h. The reaction was diluted with brine and extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnésium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography using heptane/ethyl acetate ] 00/0 to 30/70 as eluent to afford 2-[5-[5-[tert-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2yl-mdazoi-3-yl]thiazol-2-yl]ethyl N-[(3S)-3-hydroxybutyI]carbamate intermediate 252 as a 10 colorless oil.

LCMS method F: [M+H]⁺ = 575.4, t_R = 3.32 min

Préparation of intermediate 253: [(lS)-3-[2-[5-[5-[tert-butyl(dimethyl)silyl]oxy-l-tetrahydro pyran-2-yl-indazol-3-yl]thiazol-2-yllethoxycarbonylammo]-l-methyl-propyl]methane sulfonate

To a solution of 2-[5-[5-[tert-butyl(dimethyl)silyl]oxy-1 -tetrahydropyran-2-yl-indazol-3yl]thiazol-2-yl]ethyl N-[(3S)-3-hydroxybutyl]carbamate intermediate 252 (530 mg, 0.92 mmol) and triethy lamine (0.26 mL, 1.84 mmol) in dichlromethane (8 mL) cooled at 0 °C was 20 added methanesulfonyl chloride (0.09 mL, l .20 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room température for 16 h. The reaction mixture was diluted with brine and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnésium sulfate, filtered and the solvent was removed under reduced pressure to afford [(l S)-3-[2-[5-[5-[tert-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-225 yl-Îndazol-3-yl]thiazo[-2-yl]ethoxycarbonylamîno]-l-methyl-propyl]methanesulfonate intermediate 253 as a yellow oil.

381

LCMS method F: [M+H]⁺ = 653.5, t_R = 3.45 min

Préparation of intermediate 254: (13R) -13 -methyl -19-(oxan -2 -yl) -8,14 -dioxa -23 -thia4,10,19,20 -tetraazatetracyclo[13.5.2.l²⁵.0¹²²¹ Itricosu -1(20),2,4,15,17,21 -hexaen -9 -one

To a solution of [(lS)-3-[2-[5-l5-[tert-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-ylindazol-3-yl]thiazol-2-yl]ethoxycarbonylamino]-l -methy l-propyl]methanesulfonate intermediate 253 (500 mg, 0.77 mmol) in dry Ν,Ν-dimethylformamide (195 mL) at 80°C was added dropwise over 2 h a solution of césium carbonate (750 mg, 2.30 mmol) in dry N,N10 dimethylformamide (190 mL). The reaction mixture was stirred at 80°C for 1 h. The solvent was evaporated under reduced pressure and the residue was diluted with brine and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnésium sulfate, fîltered and the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography using 15 dichloromethane/ethyl acetate 100/0 to 20/80 as eluent to afford (13R)-13-methyl-I9-(oxan-2yl)-8,14-dioxa-23-thia-4,10,19,20-tetraazatetracyclo[l3.5.2.1²’⁵.0^ls’²¹]tricosa-l(20),2,4,15, 17,21-hexaen-9-one intermediate 254 as a coiorless oil.

LCMS method F: [M+H]⁺ = 443.4, t_R = 2.43 min

Préparation of Example 160: (13R)-13-methyT8,14-dioxa-23-thia-4,10,19,20-tetraaza tetracyclo[13.5.2.1²A0^,8’²¹]tricosa-l(20),2,4,15,I7,21-hexaen-9-one

382

Το a solution of (l3R)-l3-methyl·l9-(oxan-2-yI)-8,l4-dioxa-23-thia-4,l0J9,20-tetraazatetra cyclo[l3.5.2.l²’⁵.0^l8’²¹]tricosa-l(20),2,4,l5,l7,2l-hexaen-9-one intermediate 254 (44 mg, 0.10 mmol) în methanol (7 mL) and water (l mL) was added 77-toluenesulfonic acid monohydrate (95 mg, 0.50 mmol). The reaction mixture was stirred at 70°C for 24 h. The solvent was partially 5 removed under reduced pressure and a saturated aqueous sodium bicarbonate solution was added. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnésium sulfate, fïltered and the solvent was removed under reduced pressure. The residue was triturated in diisopropylether, fïltered and dried to afford ( l BR)-13-methyl-8,l 4-dioxa-23-thia-4,l 0,19,20-tetraazatetracyclo

I0 [l3.5.2.1²'⁵.0¹⁸’²¹]tricosa-l(20),2,4,15,17,21’hexaen-9-oneexample 160 as a light yellow solid.

LCMS method F: [M+H]⁺ = 359.3, t_R = 1.87 min

LCMS method G: [M+H]⁺ = 359.3, t_R = 1.87 min

Ή NMR (400 MHz, d6-DMSO) δ 13.22 (IH, s), 7.99 (IH, s), 7.92 (IH, dd, >4.4, 8.2 Hz), 7.50 - 7.47 (IH, m), 7.39 (IH, d, >2.5 Hz), 6.97 (1 H, dd, >2.4, 9.0 Hz), 4.71 - 4.61 (2H, m), 15 4.14.4.Ο8 (IH, m), 3.61 - 3.53 (IH, m), 3.41 -3.34 (2H, m), 2.93 - 2.86 (IH, m), 2.08 - 2.08 (IH, m), 1.41 - 1.38 (4H, m) ppm.

Example 161: (13R)-4,13-dimethyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.

Example 161 is prepared according to the synthesis route described in general Scheme L.

Préparation of intermediate 255: tert-butyl-[2-(lH-imidazol-2-yl)ethoxy!l-dimethyl-silane

383

To a solution of 2-(lH-imidazol-2-yl)ethanol (1.2 g, 10.7 mmol) in MN-dimethylformamide (11.5 mL) at room temperature was added imidazole (1.09 g, 16.05 mmol) and tertbutyldimethylsilyl chloride (1.61 g, 10.7 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured in water (150 mL) and extracted with 5 ethyl acetate. The combined organic layers were washed with 10 % lithium chloride aqueous solution, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield /eri-butyl-[2-(l H-imidazol-2-yl)ethoxy]-dimethyl-silane intermediate 255 as a yellow oil which was used in the next step without further purification.

LCMS method F: [M+H]⁺ = 227.3, t_R = 1.64 min

Préparation of intermediates 256A and 256B: tert-butyl-[2-(4,5-dibromo-lH-imidazol-2yl)ethoxy]-dimethyl-silane and 2-(4-bromo-lH-imidazol-2-yl)ethoxy-tert-butyi-dimethylsiiane

Intermediate 256A Intermediate 256B

To a suspension of rerf-butyl-[2-(l H-imidazol-2-yl)ethoxy]-dimethyl-silane intermediate 255 (2.379 g, 10.52 mmol) in THF (350 mL) at room temperature was added A-bromosuccinimide (1.955 g, 11.05 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over 20 anhydrous magnésium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 95/5 as eluent, to afford two different products: ieri-butyl-[2-(4,5-dibromo-lH-imidazol-2-yl)ethoxy]-dimethyl-silane intermediate 256A as a colorless oil; LCMS method F: [M+H]⁺ = 383.1-385.1-387.0, t_R = 3.00 min, and 2-(4-biOmo-lH-imidazol-2-yl)eÎhoxy-ten-butyl-dimethy!-silane intermediate 256B as a colorless oil; LCMS method F : [M+l1]⁺ = 305.1 -307.1, t_R = 2.34 min

Préparation of intermediate 257: tert-butyl-[2-(4,5-dibromo-I-methyl-imidazo!-2-yi)ethoxy]dimethyl-silan e

384

To a suspension of teri-buty 1-(2-(4,5-dibromo-1 H-imidazol-2-yl)ethoxy]-dimethyl-si lane intermediate 256A (600 mg, 1.56 mmol) în A/AMimethylformamide (2.5 mL) at room température was added potassium carbonate (473 mg, 3.43 mmol) followed by iodomethane 5 (0. i 1 mL, 1.87 mmol). The reaction mixture was stirred at room température for 16 h. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried over anhydrous magnésium sulfate, filtered and concentrated under reduced pressure to afford ZerA butyl-[2-(4,5-dibromo-l-methyl-imidazol-2-yl)ethoxy]-dimethyl-silane intermediate 257 as a yellow solid which was used without further purification.

LCMS method F: [M+H]⁺ = 397.0-399.1-401.0, t_R = 3.24 min

Préparation of intermediate 258: 2-(4-bromo-l-methyl-imidazol-2-yl)ethoxy-tert-butyldimethyl silane

To a degassed solution of terAbutyl-[2-(4,5-dibromo-l-methyl-imidazol-2-yl)ethoxy]dimethyl-silane intermediate 257 (614 mg, 1.54 mmol) in dry THF (24 mL) at -78 °C, was added 2.5 M «-BuLi solution in THF (0.6 mL, 1.54 mmol). The reaction mixture was stirred at -78 °C for 30 min. The reaction mixture was quenched by addition of water and warmed to room température. The aqueous layer was extracted with ethyl acetate. The combined organic 20 layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 2-(4-bromo-1 -methyl-imidazol-2-yl)ethoxy-tert-butyldimethyl-silane intermediate 258 as a yellow oil.

LCMS method F: [M+H]⁺= 319.2-321.2, t_R = 2.70 min

5 Préparation of intermediate 259: 2-(4-bromo-l-methyl-imidazol-2-yl)ethanol

385

HO

To a solution of 2-(4-bromo-l-methyl-imidazol-2-yl)ethoxy-tert-butyl-dimethyl-silane intermediate 258 (300 mg, 0.94 mmol) in THF (4 mL) at room température was added dropwise a solution of tetrabutylammonium fluoride l M in THF (1.03 mL, 1.03 mmol). The reaction 5 mixture was stirred at room température for 6 h. The reaction mixture was poured into ice water and stirred for 20 min. The aqueous phase was extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous magnésium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/m éthanol 100/0 to 95/5 as eluent to afford 2-(4-bromo-l-methyl-îmîdazol-210 yl)ethanol intermediate 259 as a white solid.

Ή NMR (400 MHz, CDCB) δ 6.78 (1 H, s), 4.02 (2H, t, J= 5.6 Hz), 3.89 (1 H, br. s), 3.57 (3H, s), 2.83 (2H, t, J= 5.8 Hz) ppm.

Préparation of intermediate 260: 2-(4-bromo-l-methyl-imidazol-2-yl)ethyl-N-[(3S)-315 hydroxy hutyljcarbamate

To a solution of 4-nitrophenyl chloroformate (137m g, 0.68 mmol) and pyridine (O.lOmL, 1.24 mmol) in dichloromethane (2.5 mL) at room température was added dropwise 2-(4-bromo-lmethyl-imidazol-2-yl)ethanol intermediate 259 (128 mg, 0.62 mmol) in dichloromethane (1.5 mL). The reaction mixture was stirred at room température for 1 h. A mixture of (2S)-4aminobutan-2-ol (60 mg, 0.68 mmol) and DIPEA (0.21 mL, 1.24 mmol) in dichloromethane (1 mL) was added. The reaction mixture was stirred at room température for 2 h. The reaction mixture was diluted with 0.5 N aqueous sodium hydroxide solution and extracted with dichloromethane. The combined organic layers were washed with 0.5 N aqueous sodium hydroxide solution and dried over anhydrous magnésium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using

386 dichloromethane/ ethyl acetate 100/0 to 30/70 as eluent to afford 2-(4-bromo-l-methy Iimidazol-2-yl)ethyI N-[(3S)-3-hydroxybutyl]carbamate intermediate 260 as a colorless oil.

LCMS method F: [M+H]⁺ = 320.1-322.I, t_R = l. 17 min

Préparation of intermediate 261: 2-f4-f5-ftert-butyl(dimeth yl)silyHoxy-l-tetrahydropyran-2yl-indazol-3-yl]-l-methyl-imidazol-2-yl]ethyl-N-[(3S)-3-hydroxybutyl] carbamate

To a degassed solution of 2-(4-bromo-l-methyl-imidazol-2-yl)ethyl-N-[(3S)-3hydroxybutyl] carbamate intermediate 260 (102 mg, 0.32 mmoi), /erZ-butyl-dimethyl-[l10 tetrahydropyran-2-yl-3-(4,4,5,5-tetramethyl-I,3,2-dioxaborolan-2-yl)indazol-5-yl]oxy-silane (175 mg, 0.38 mmol) and potassium phosphate tribasic (204 mg, 0.96 mmol) in 1,4-dioxane (2.7 mL) and water (0.1 mL), were added tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyi (15 mg, 0.032 mmol). The reaction mixture was heated at 125 °C for I h. The reaction mixture was filtered through a

Celite pad and washed with ethyl acetate. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous magnésium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol 100/0 to 98/2 as eluent to afford 2[4-[5-[tert-butyl(dîmethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3-yl]-l-methy 1-imidazol20 2-yl]ethy 1 N-[(3S)-3-hydroxybutyl]carbamate intermediate 261 as a yellow oil.

LCMS method F: [M+H]⁺ = 572.4, t_R = 2.28 min

Préparation of intermediate 262: [(1 S)-3-l2-[4f5-[tert-butyl(dimethyl)silyl]oxy-l-tetrahydro pyran-2-yl-indazol-3-yl]-l-methyl-imidazol-2-yl]ethoxycarbonylamino]~l-methyl-propyU methanesulfonate

387

To a solution of2-[4-[5-[terHbutyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3-yi]-lmethyl-imidazol-2-yl]ethyl N-[(3S)-3-hydroxybutyl]carbamate intermediate 261 (112 mg, 0.20 mmol) and triethylamine (56 pL, 0.40 mmol) in dichloromethane (2.2 mL) at 0 °C was added 5 dropwise methanesulfonyl chloride (20 pL, 0.26 mmol). The reaction mixture was stirred at room température for 2 h. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organics were washed with brine, dried over anhydrous magnésium sulfate, filtered and concentrated under reduced pressure to afford [(]S)-3-[2-[4-[5[tert-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol-3-yl]-l-methy l-imîdazol-2-yl] 10 ethoxycarbonylamino]-l-methyl-propyl] methanesulfonate intermediate 262 as a coloriess oil.

LCMS method F: [M+H]⁺ = 650.4, t_R = 2.53 min

Préparation of intermediate 263: (13 R) -4,13 -dimethyi-19-(oxan -2-yl) -8,14 -dioxa -4,10,19,

20,23-pentaazatetracyclo[13.5.2.1²ⁱ\ 0^,s,2} [tricosa-1(20),2,5(23),15(22),16,18(21) -hexaen -915 one

To a suspension of césium carbonate (112 mg, 0.34 mmol) in anhydrous N,Ndimethylformamîde (6 mL) at 60 °C was added dropwise [(lS)-3-[2-[4-[5-[tertbutyl(dimethyl)sîlyl]oxy-I-tetrahydropyran-2-yl-indazol-3-yl]-l-methy l-imidazol-2-yl]ethoxy carbonylaminoj-1 -methyl-propyl]methanesulfonate intermediate 262 (75 mg, 0.1 1 mmol) in

388

A+V-di methyl form ami de (3 mL). The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was allowed to cool down to room température, then filtered over a Celite pad, washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/(ethyl acetate/ethanol (3/1)) 100/0 to 60/40 as eluent to afford (]3R)-4,13-dimethyl-19-(oxan-2-yl)-8,14-dioxa4,10,19,20,23-pentaazatetracyclo[13.5.2.1²'⁵.0^18,2 ^100033-1(20),2,5(23),15(22),16,18(21)hexaen-9-one intermediate 263 as a yellow oiL

LCMS method F: [M+H]⁺ = 440.3, t_R = 1.71 min

Préparation of Example 161: (13R)-4,13-dimethyl-8,14-dioxa-4,10,19,20,23-pentaazatetra cyclo[13.5.2.1^2,5.0^182I]tricosa-l(20),2,5(23),15(22),16,18(21)-hexaen-9-one

To a solution of (13R)-4,13-dimethyl-19-(oxan-2-yl)-8,14-dioxa-4,10,19,20,23-pentaazatetra cyclo[ 13.5.2.1^2,5.0^l8’^2l]tricosa-1(20),2,5(23), 15(22), 16,18(2l)-hexaen-9-one intermediate 263 (38 mg, 0.086 mmol) in methanol (6 mL) and water (0.8 mL) was added p-toluenesulfonic acid monohydrate (82 mg, 0.43 mmol). The reaction mixture was stirred at 65°C for 22 h. The réaction mixture was diluted with dichloromethane and saturated aqueous sodium bicarbonate solution. After séparation, the aqueous layer was extracted with ethyl Acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by préparative TLC on silica gel using dichloromethane/methanol 90/10 as eluent to afford (13R)-4,13-dimethyl-8,14-dioxa4,10,19,20,23-pentaazatetracyclo[ 13.5.2.1²·⁵.0^18,21 ]tricosa-l (20),2,5(23),15(22),16,18(21)hexaen-9-one example 161 as a white solid.

LCMS method F: [M+H]⁺ = 356.3, t_R = 1.27 min

LCMS method G: [M+H]⁺ = 356.3, t_R = 1.76 min ‘H NMR (400 MHz, CDCh) δ 7.89-7.85 (IH, m), 7.34 (IH, s), 7.24 (IH, d, J = 9.6 Hz), 6.96 ( 1 H, dd, J= 2.4, 9.6 Hz), 5.58 (III, br. s), 4.77 - 4.67 (2H, m), 4.60-4.55 (IH, m), 3.67-3.62

389 (4H, m), 3.45-3.32 (2H, m), 3.04-2.94 (2H, m), 2.18-2.09 (IH, m), 1.64-1.50 (IH, m), l .46l .39 (3H, m) ppm.

Example 162: (13R)-13-methyl-8,14-dioxa-10,I6,19,20-tetraazatetracyclo[13.5.2.

1^.0^ls’^2I]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

Example 162 is prepared according to the synthesis route described in detail below.

Préparation of intermediate 264: 2-[(3Rj-.fr/4-meihy/-5-nitro-2-pyridyl) oxyjbutylj isoindoline-1,3-dione

A pressure vial containing a mixture of césium carbonate (26.41 g, 83.56 mmol), Pd₂(dba)a (1.64 g, 1.791 mmol), rac-BINAP (2.23 g, 3.581 mmol), (R)-2-(3-hydroxybutyl)isoindoline15 1,3-dione (18.32 g, 83.56 mmol) and 2-chloro-4-methyl-5-nîtropyridine (10.3 g, 59.686 mmol) were suspended in toluene (78 mL) under nitrogen atmosphère. The reaction mixture was stirred at 110°C for 16 h. The reaction mixture was diluted with ethyl acetate and filtered over a pad of celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using heptane/ethl acetate 100/0 to 90/10 as eluent to 20 afford 2-[(3R)-3-[(4-methyl-5-nitro-2-pyridyl)oxy]butyl] isoindoline-1,3-dione intermediate 264 as a white solid.

LCMS method B: [M+H]⁺ = 356.0, t_R = 1.020 min

390

Préparation of intermediate 265: 2-[(3R)-3-[(5-amino-4-methyl-2-pyridyl)oxyJb utyl] isoindohne-l,3-dione

To a solution of 2-[(3R)-3-[(4-methyl-5-nitro-2-pyridyl)oxy]butyl]isoindoline-l ,3-dione intermediate 264 ( 14.6 g, 41.086 mmol) in ethyl acetate (240 mL) under nitrogen atmosphère wxas added palladium 10%wt on carbon (2.9 g). The reaction mixture was stirred under hydrogen atmosphère at RT for 20 h. The suspension was filtered over a pad of celite and washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography using heptane/ethyl acetate 100/0 to 40/60 as eluent to afford 2-[(3R)-3-[(5-amino-4-methyl-2-pyridyl)oxy]butyl]isoindoline-L3-dione intermediate 265 as a orange foam.

LCMS method E: [M+H]⁺ = 3526.1, t_R = 2.092 min

Préparation of intermediate 266: N-[6-[(iR)-3-(l,3-dioxoisoindolin-2-yl)-l-methyipropoxy]-4-methyl-3-pyrldyl]acetamide

To solution of 2-[(3R)-3-[(5-amino-4-methyl-2-pyridyl)oxy]butyl] isoindoline- 1,3-dione intermediate 265 (5.0 g, 15.36 mmol) and triethylamine (4.26 mL, 30.37 mmol) in dichloromethane (75 mL) at 0°C was added acetic anhydride (2.18 mL, 23.05 mmol). The reaction mixture was stirred at 0°C for 5 min then warmed to room température and stirred for ! h. The reaction mixture was filtered and rinsed with dichloromethane. The fïltrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using cyelohexane/ethyl acetate 100/0 to 50/50 as eluent to afford N-[6-[( 1 R)21105

391

3-( l,3-dioxoisoindolin-2-y 1)-1-methy l-propoxy]-4-methyl-3-pyridyl]acetamide intermediate

266 as a white solid.

LCMS method F: [M+Hf = 368,2, t_R = 2.13 min

Préparation of intermediate 267: 2-[(3R)-3-(l-acetylpyrazolo[3,4-c]pyridin-5-yl)oxybutyl] isoindoline-l,3-dione ⁰ jjT> 7^°

A solution of N-[6-f(lR)-3-(i,3-dioxoisoindolin-2-yl)-l-methyl-propoxy]-4-methyi-3pyridyl]acetamîde intermediate 266 (5.0 g, 13.60 mmol), acetic anhydride (5.79 mL, 61.24 mmol) and potassium acetate (2.39 g, 20.41 mmol) în toluene (70 mL) was stirred at 80°C. Isoamyl nitrite (7.33 mL, 54.437 mmol) was added and the resulting mixture was stirred at 80°C for 16 h. The réaction mixture was cooled to room température and fïltered. The fîltrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 2/1 as eluent to afford 2-[(3R)-3-(lacetylpyrazolo[3,4-c]pyridin-5-yl)oxybutyl]isoindoline-l ,3-dîone intermediate 267 as a yellow solid.

LCMS method F: [M+H]⁺ = 379.3, t_R = 2.63 min

Préparation of intermediate 268: [(3R)-3-(lH-pyrazolo[3,4-c]pyridin-5-yloxy)hutyl] isoindoline-1,3-dione

To a solution of 2-[(3R)-3-(l -acetylpyrazolo[3,4-c]pyridin-5-yl)oxybutyl]isoindoline-1,3dione intermediate 267 (2.75 g, 7.28 mmol) in methanol (36 mL) was added 7N ammonia

392 solution in methanol (5.20 mL, 36.42 mmol). The reaction mixture was stirred at room température for 2 h. Solvents were concentrated under reduced pressure and the residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 50/50 as eluent to afford 2-[(3R)-3-(lH-pyrazolot3,4-c]pyridin-5-yloxy)butyl] isoindot ine-l,3-dione intermediate 268 as a pale orange solid.

LCMS method F: [M+Hf = 337.3, t_R = 2.09 min

Préparation of intermediate 269: 2-[(3R)-3-[(3-iodo-lH-pyrazolo[3,4-c]pyridin-5yl)oxy]butyl]isoindoline-l,3-dione

To a solution of 2-[(3R)-3-(lH-pyrazolo[3,4-c]pyridin-5-yloxy)butyl]isoindoline-l,3-dione intermediate 268 (673 mg, 2 mmol) in DMF (20 mL) was added N-iodo-succinimide (675 mg, 3 mmol). The reaction mixture was stirred at room température for 16 h. The reaction mixture was partîtioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 50/50 as eluent to afford 2-[(3R)-3-[(3-iodo-lHpyrazolo[3,4-c]pyridin-5-yl)oxy]butyl]isoindoline-l ,3-dione intermediate 269 as a yellow solid.

LCMS method F: [M+H]⁺ = 463.2, t_R = 2.54 min

Préparation of intermediate 270: 2-[(3R)-3-(3-iodo-I-tetrahydropyran-2-yl-pyrazolo[3,4cJpyridin-5-yl)oxybutylJ isoindoline-l,3-dione

To a solution of 2-[(3R)-3-[(3-iodo-1 H-pyrazolo[3,4-c]pyridin-5-yl)oxy]butyl]isoindoline-l,3dione intermediate 269 (897 mg, 1.94 mmol) and DHP (0.53 mL, 5.82 mmol) in dichloromethane (15 mL) and THF (5 mL) was added methanesulfonic acid (25 pL, 0.38 5 mmol). The reaction mixture was stirred at room température for 3 h. Saturated aqueous sodium bicarbonate solution was added. After séparation, the aqueous layer was extracted with dichloromethane and the combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 10 cyclohexane/ethyl acetate 100/0 to 35/65 as eluent to afford 2-[(3R)-3-(3-iodo-ltetrahydropyran-2-yl-pyrazolo[3,4-c]pyridin-5-yl)oxybutyl]isoindoline-l,3-dione intermediate 270 as a yellow solid.

LCMS method F: [M+H]⁺ = 547.2, t_R = 3.17 min

Préparation of intermediate 2 71: (3R)-3-(3-iodo-l-tetrahydropyran-2-yl-pyrazolo[3,4e]pyridin-5-yl)oxybutan-l-amine

To a solution of 2-[(3R)-3-(3-îodo-l-tetrahydropyran-2-yl-pyrazolo[3,4-c]pyridin-5yl)oxybutyl] tsoîndoline-1,3-dione intermediate 270 (800 mg, 1.464 mmol) in éthanol (15.0 20 mL) at 0°C was added hydrazine monohydrate (0.22 mL, 4.392 mmol). The reaction mixture was stirred at 0°C for 5 minutes and at room température for 16 h. THF (60 mL) was added and the mixture was stirred for 5 minutes, filtered and the solvent was removed under reduced

394 pressure. The residue was diluted with THF (15 mL), fîltered and the filtrate was concentrated under reduced pressure to afford crude (3R)-3-(3-îodo-l-tetrahydropyran-2-yl-pyrazolo[3,4c]pyridin-5-yl)oxybutan- !-amine intermediate 271 as an orange solid. The product was used in the next step without further purification.

LCMS method F: [M+H]⁺ = 417.2, t_R = 1.63 min

Préparation of intermediate 272: benzyl N-[(3R)-3-(3-iodo-l-tetrahydropyran-2-yl-pyrazolo [3,4-c]pyridin-5-yl)oxybutyll carbamate

To a solution of (3R)-3-(3-iodo-l -tetrahydropyran-2-yl-pyrazolo[3,4-c]pyrîdîn-5-yl)oxybutanI-amine intermediate 271 (650 mg, 1.464 mmol) in dichloromethane (15 mL) at 0°C were successîvely added triethylamine (0.24 mL, 1.75 mmol) and benzyl chlorofonnate (0.23 mL, 1.610 mmol). The reaction mixture was stirred at 0°C for 5 min then warmed to room température and stirred for 16 h. The reaction mixture was diluted with water. After séparation, the aqueous layer was extracted with dichloromethane and the combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, fîltered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100:0 to 50:50 as eluent to afford benzyl N[(3R)-3-(3-iodo-l -tetrahydropyran-2-yl-pyrazolo[3,4-c]pyridin-5-yl)oxybutyl]carbamate intermediate 272 as a transparent oil.

LCMS method F: [M+H]⁴ = 551.1, t_R = 3.17 min

Préparation of intermediate 273: benzyl N-[(3R)-3-[3-[3-(hydroxymethyl)phenyl]-l-tetra hydropyran-2-yi-pyrazolo[3,4-c]pyridin-5-yl]oxybutyl]carbamate

395

To a with argon degassed solution of benzyl N-[(3R)-3-(3-îodo-l-tetrahydropyran-2-ylpyrazolo[3,4-c]pyridîn-5-yl)oxybutyl]carbamate intermediate 272 (320 mg, 0.581 mmol), 3(hydroxy methyl)phenylboronic acid (106 mg, 0.698 mmol), potassium phosphate tribasic (370 5 mg, 1.744 mmol) and XPhos (28 mg, 0.058 mmol) in 1,4-dîoxane (5.5 mL) and water (0.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.029 mmol). The reaction mixture was heated at 100°C for 1 h. The reaction mixture was cooled and diluted with ethyl acetate and water. After séparation, the aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with saturated aqueous sodium chloride solution, dried 10 over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using cyclohexane/ethyl acetate 100/0 to 1/1 as eluent to afford benzyl N-[(3R)-3-[3-[3-(hydroxymethyl)phenyl]-l-tetrahydropyran-2-yl-pyrazolo [3,4-c]pyridin-5-yl]oxybutyl]carbamate intermediate 273 as a pale yellow oil.

LCMS method F: [M+H]⁺ = 531.3, t_R = 2.90 min

Préparation of intermediate 274: (13R)-13-methyl-19-(oxan-2-yl)-8,14-dioxa-10,16,19,20tetraazatetracyclo[I3.5.2.I²⁶,0^18,21 (tricosa-1(20),2(23),3,5,15(22),16,18(21 )-heptaen -9-one

To a solution of of benzyl N-[(3R)-3-[3-[3-(hydroxymethyl)phenyl]-i-tetrahydropyran-2-yl20 pyrazolo[3,4-c]pyridin-5-yl]oxybutyl]carbamate intermediate 273 (180 mg, 0.339 mmol) in acetonitrile (170 mL) was added potassium hydroxide (95 mg, 1.69 mmol). The reaction mixture was heated at 50°C for 16 h. The réaction mixture was cooled to room temperature,

396 filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 50/50 as eluent to afford (13R)-13methyl-19-(oxan-2-yl)-8,14-dioxa-10,16,19,20-tetraazatetracyclo[13.5.2.1²’⁶.0^,8’^2,]tricosa1(20),2(23),3,5,15(22), 16,18(21)-heptaen-9-one intermediate 274 as a yellow solid.

LCMS method F: [M+H]⁺ = 423.4, t_R = 2.49 min

Préparation of Example 162: (13R)-13-methyl-8,14-dioxa-10,16,19,20-tetraazatetracyclo [13.5.2.1^2<i.0^,8’²¹]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

To a solution of (13R)-13-methyl-19-(oxan-2-y 1)-8,14-dioxa-10,16,19,20-tetraazatetracyclo [13.5.2. l^2,6.0^l8,21]tricosa-l(20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one intermediate 274 (84 mg, 0.199 mmol) in methanol (1.8 mL) and water (0.2 mL) was added p-toluenesulfonic acid monohydrate ( 189 mg, 0.994 mmol). The réaction mixture was stirred at 65°C for 80 h. Solvents were evaporated under reduced pressure and the residue was partîtioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with saturated aqueous sodium bicarbonate solution then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The reaction mixture was triturated with dîisopropyl ether, filtered and dried to afford (13R)-13-methyl-8,14-dioxa-10,l6,19,20-tetraazatetracyclo [13.5.2. l²’⁶.0^l8’^2I]tricosa-l(20),2(23),3,5,15(22), 16,18(21)-heptaen-9-one example 162 as a white solid.

LCMS method F: [M+H]⁺ = 339.3, t_R = 2.45 min

LCMS method G; [M+H]^4- = 339.3, t_R = 2.48 min

Ή NMR (400 MHz, 76-DMSO) δ 13.64 (s, IH), 8.76 (s, IH), 7.97 (dd, 7 = 4.8, 6.8 Hz, IH), 7.88 (d, 7=7.6 Hz, IH), 7.84 (s, IH), 7.49 (t, 7=7.2 Hz, IH), 7.31 (d, 7=8.4 Hz, IH), 7.10 (s, IH), 5.76 (d, 7= 12.8 Hz, IH), 4.84 (d,7= 15.2 Hz, IH), 4.62 - 4.54 (m, IH), 3.61 - 3.58 (m, IH), 2.91 (t,7= 14.0 Hz, IH), 2.36 (t, 7= 12.4 Hz, IH), 1.48 - 1.46 (m, IH), 1.44 (d,7 = 5.6 Hz, 3H) ppm.

397

Example 163: 14-metIiyl-8-oxa-10,14,19,20-tetraazatetracyclo[ 13.5.2.1²’⁶.0¹⁸'²¹]trieosal(20),2(23),3,5,15,17,21-heptaen-9-one

Example 163 is prepared according to the synthesis route described in detail below.

Préparation of intermediate 275: N-(3-iodo-l-tetrahydropyran-2-yl-îndazol-5-yl)-2-nitrobenzenesulfonamide

To a mixture of 3-iodo-l-(oxan-2-yl)-lH-indazol-5-amine (2.0 g, 5,83 mmol) in acetonitrile ( 100 mL) was added pyridine (943 pL, 11.66mmol) and 2-nitrobenzenesulfonyl chloride ( 1.29 g, 5.83mmol). The reaction mixture was stirred at room température for 16 h. The solvent was removed under reduced pressure and the residue was portioned between ethyl acetate and water. After séparation, the aqueous phase was extracted with ethyl acetate. The organic phases were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 70/30 as eluent to afford N-(3-iodo-l-tetrahydropyran-2-yl-indazol-5-yl)-2-nitrobenzenesulfonamide intermediate 275 as a pink solid.

LCMS method F: [M+H]⁺ = 529.1, t_R = 2.83 min

Préparation of intermediate 276: Benzyl N-(3-l(3-iodo-I-tetrahydropyran-2-yl-indazol-5-yl)(2-nitrophenyl)suifonyl-amino]propyl]carbamate

398

To a mixture of N-(3-iodo-l-tetrahydropyran-2-yl-indazol-5-yl)-2-nitro-benzenesulfonamide intermediate 275 (800 mg, 1.51 mmol) in acetonitrîle (200 mL) was added potassium carbonate (229 mg, 1.66 mmol) and benzyl N-(3-bromopropyl)carbamate (410 mg, 1.51 mmol). The 5 réaction mixture was stirred at 90°C for 16 h. Additional potassium carbonate (229 mg, 1.66 mmol) and benzyl N-(3-bromopropyl)carbamate (410 mg, 1.51 mmol) were added. The reaction mixture was stirred at 90°C for 16 h. The solvent was removed under reduced pressure and the reaction mixture was dissolved with ethyl acetate and water. After séparation, the aqueous layer was extracted with ethyl acetate. The organic layers were dried over anhydrous 10 sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 50/50 as eluent to afford benzyl N-[3-[(3-iodo-l-tetrahydropyran-2-yl-indazol-5-yl)-(2-nitrophenyl)sulfonylamino]propyl]carbamate intermediate 276 as a yellow oil.

LCMS method F; [M+H]⁺ = 720.2, t_R = 3.09 min

Préparation of intermediate 277: benzyl N-[3-[(3-iodo-l-tetrahydropyran-2-yl-indazol-5yl)amino]propyl]carbamate

399

To a suspension of benzyl N-[3-[(3-iodo-l-tetrahydropyran-2-yl-indazol-5-yl)-(2nitrophenyl)sulfonyl-amino]propyl]carbamate intermediate 276 (810 mg, 1.15 mmol) and césium carbonate (749 mg, 2.30 mmol) in N, W-di methyl form ami de (40 mL) was added 4methylbenzenethiol (171 mg, 1.38 mmol). The reaction mixture was stirred at room température for ! 6 h. The solvent was evaporated under reduced pressure. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 50/50 as eluent to afford benzyl N-[3-[(3-iodo-l-tetrahydropyran-2-yl-indazol-5yl)amino]propyl]carbamate intermediate 277 as a white solid.

LCMS method F: [M+H]⁺ = 535.1, t_R = 2.75 min

Préparation of intermediate 278: benzyl N-[3-[(3-iodo-l-tetrahydropyran-2-yl-indazol-5-yi)methyl-amino]propyl]carbamate

To a solution of benzyl N-[3-[(3-iodo-l-tetrahydropyran-2-yl-indazol-5-yl)amino]propyl] carbamate intermediate 277 (360 mg, 0.673 mmol) in acetonitrile (54 mL) was added formaldéhyde (37% solution) (18 mL) and sodium triacetoxyborohydride (570 mg, 2.69 mmol). The reaction mixture was stirred at room température for 16 h. The solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 50/50 to afford benzyl N-[3-[(3-iodo-l-tetrahydropyran-2y 1-indazol-5-yI)-methyl-amino]propyl] carbamate intermediate 278 as a brown oil.

LCMS method F: [M+H]⁺ = 549.2, t_R = 2.73 min

400

Préparation of intermediate 279: benzyl N-[3-[[3-[3-(hydroxymethyl)phenylJ-I-tetrahydro pyran-2-yl-indazol-5-ylf-methyl-amino]propyl]carbamate

To a suspension of benzyl N-[3-[(3-iodo-l-tetrahydropyran-2-yl-indazol-5-yl)-methylamino]propyl]carbamate intermediate 278 (150 mg, 0.273 mmol) in 1,4-dioxane (2.2 mL) and water (0.11 mL) was added [3-(hydroxymethyl)phenyl]boronic acid (50 mg, 0.327 mmol) and potassium phosphate tribasîc (173mg, 0.819mmol). The reaction was purged with argon for 10 min and tetrakis(triphenylphosphine)palladium{0) (15 mg, 0.0136 mmol) and XPhos (13 mg, 0.0273 mmol) were added. The resulting mixture was stirred at 100°C for 16 h. The reaction mixture was cooled to room température and evaporated under reduced pressure. The residue was diluted with ethyl acetate and water. After séparation, the aqueous layer was extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified on silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 40/60 as eluent to afford benzyl N[3-[[3-[3-(hydroxymethyl)phenyl]-l-tetrahydropyran-2-yLindazol-5-yl]-methyl-amino] propyl]carbamate intermediate 279 as a yellow oil.

LCMS method F: [Μ+Η]^ψ = 529.4, t_R = 2.23 min

Préparation of intermediate 280:14-methyl-19-(oxan-2-yl) -8-oxa-10,14,19,20 Aetraaza tetracycloll3.5.2.f-’⁶.0ⁱ⁸’²¹jtricosa-l(20),2(23),3,3,lS,17,21-heptaen-9-one

401

To a solution of benzyl N-[3-[[3-[3-(hydroxymethyJ)phenyl]-l-tetrahydropyran-2-yl-indazol5-y 1]-methy 1-amino] propyl] carbamate intermediate 279 (110 mg, 0.208 mmol) in dry acetonitrile (30 mL) was added césium carbonate (406 mg, 1.24 mmol). The reaction mixture was stirred at 90°C for 16 h. The suspension was filtered and washed with acetonitrile. The 5 filtrate was evaporated under reduced pressure. The residue was purified on silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 50/50 as eluent to afford 14-methyl19-(oxan-2-yl)-8Oxa-10,14,19,20-tetraazatetracyclo[13.5.2.1²’⁶.0^,8’^2l]trÎcosa1(20),2(23),3,5,15,17,2l-heptaen-9-one intermediate 280 as a yellow solid.

LCMS method F : [M+H]* = 421.3, t_R = 2.59 min

Préparation of Example 163: 14-methyl-8-oxa-10,14,19,20-tetraazatetracyclo[13.5.2.

j 2,6 ₀18,21 ] _tricosa. ^20),2(23),3,5,15,17,21-heptaen-9-one

To a solution of 14-methyl-19-(oxan-2-yl)-8-oxa-10,14,19,20-tetraazatetracyclo [13.5.2.

l²'⁶.0¹⁸’^2!]tricosa-l(20),2(23),3,5,15,17,21-heptaen-9-one intermediate 280 (40 mg, 0.095 mmol) in methanol (L8 mL) and water (0.26 mL) was added /Moluenesulfonic acid monohydrate (90 mg, 0.475 mmol). The reaction mixture was stirred ai 65°C for 16 h. The reaction mixture was cooled to room température and quenched with a saturated aqueous sodium bicarbonate solution. Ethyl acetate was added. After séparation, the aqueous layer was extracted with ethyl acetate and the organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified on silica gel column chromatography using dichloromethane/methanol 100/0 to 95/5 as eluent to afford 14-methyl-8-oxa-10,14J9,20-ietraazatetracyclo[13.5.2.]²’⁶.0^18,21]tricosal(20),2(23),3,5,l5,17,2l-heptaen-9-one example 163 as ayellow solid.

LCMS method F: [M+H]⁺ = 337.1, t_R = 1.70 min

LCMS method G: [M+H]⁺ = 337.3, t_R = 2.12 min

HNMR (400 MHz, CDCh) δ 9.97 (IH, bs), 8.03 (IH, s), 7.98 - 7.94 (IH, m), 7.48 - 7.36 (2H, m), 7.23 - 7.20 (2H, m), 7.01 (1 H, dd, J=2.3, 9.1 Hz), 5.45 - 5.26 (3H, m), 3.49-3.27 (4H. m), 3.06 - 3.05 (3H, s), 2.05 - 1.97 (2H, m) ppm.

402

Example 164: (13R)“13-methyl·8,14-dioxa-4,10,19,20,22-peπtaazatetracyclo[13.5.2.

]2,6 _O18,2i]t_rj_COsa-l(20),2(23),3,5,15,17,21-heptaen-9-one

Example 164 îs prepared according to the synthesis route described in detail below.

Préparation of intermediate 281: 5-chloro-3-iodo-lH-pyrazolo[4,3-b]pyridine f

To a solution of 5-chloro-lH-pyrazolo[4,3-b]pyridine (LO g, 6.51 mmol) in acetonitrile (10 mL) was added Λ-iodosuccinimide (1.75 g, 7.81 mmol). The reaction mixture was heated under microwave irradiations at 100°C for 25 min. The solvent was partially evaporated under reduced pressure and the residue was diluted with water and ethyl acetate. After séparation, the organic layer was washed with a saturated sodium thiosulfate solution. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified on silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 60/40 as eluent to afford 5chloro-3-iodo-l H-pyrazolo[4,3-b]pyridine intermediate 281 as a yellow solid.

LCMS method F: [M+H]⁺ = 279.9, t_R = 2.00 min

Préparation of intermediate 282: 5-chloro-3-iodo-l-tetrahydropyran-2-yl-pyrazolo[4,3-b] pyridme

403

To a solution of 5-chloro-3-iodo-lH-pyrazolo[4,3-b]pyridine intermediate 281 (7.00 g, 25.05 mmol) in dichloromethane (45 mL) were added /Moluenesulfonic acîd monohydrate (2.38 g, 12.53 mmol) and then 3,4-dihydro-2H-pyran (4.1 1 mL, 45.09 mmol). The reaction mixture was stirred at room température for 1 h. The reaction mixture was diluted with a saturated aqueous sodium bicarbonate solution and more dichloromethane was added. After séparation, the aqueous layer was extracted with dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified on silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 75/25 as eluent to afford 5-chloro-3-iodo-l-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine intermediate 282 as a pale yellow solid.

LCMS method F: [M+H]* = 364.0, tR = 2.75 min

Préparation of intermediate 283: 3-iodo-5-meth oxy-l-tetrahydropyran-2-yi-pyrazolo[4,3b/pyridine

To a solution of 5-chloro-3-iodo-l-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine intermediate 282 (4.10 g, 11.28 mmol) in dry A^A-dimethylformamide (160 mL) was added sodium hydride (60 % dispersion in minerai oil) (2.25 g, 56.38 mmol) and methanol (2.28 mL, 56.38 mmol). The réaction mixture was stirred at 50°C for 2 h. The reaction mixture was cooled to room température and carefully quenched with water. The solvent was partially evaporated reduced pressure and water and ethyl acetate were added. After séparation, the aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified on silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 85/15 as eluent to afford 3iodo-5-methoxy-l-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridine intermediate 283 as a pale yellow oil.

LCMS method F: [M+Hl* = 360.0, t_R = 2.82 min

Préparation of intermediate 284: 3-iodo-I-tetrahydropyran-2-yl-pyrazolo{4,3-b/pyridin-S-ol

404

To a solution of 3-iodo-5-methoxy-l-tetrahydropyran-2-yi-pyrazolo[4,3-b]pyridine intennediate 283 (1.73 g, 4.84 mmol) în acetonitrile (18 mL) and 1,2~dichloroethane (18 mL) were added sodium iodide (2.17 g, 14.52 mmol) and then trimethylchlorosilane (1.22 mL, 5 9.67 mmol). The reaction mixture was stirred at 40°C for 4 h. The reaction mixture was diluted with a saturated aqueous sodium thiosulfate solution and ethyl acetate. After séparation, the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, fïltered and evaporated under reduced pressure. The residue was purified on silica gel column chromatography using 10 cyclohexane/(ethyl acetate/ethanol (3/1)) 100/0 to 30/70 as eluent. The resulting solid was triturated in acetonitrile, fïltered and dried to afford 3-iodo-l-tetrahydropyran-2-ylpyrazolo[4,3-b]pyridin-5-ol intermediate 284 as a white solid.

LCMS method F: [M+H]⁺ = 346.0, t_R = 1.85 min

Préparation of intermediate 285: benzyl N-[(3R)-3-(3-iodo-l -tetrahydropyran-2-yl-pyrazolo

[4,3-b]pyridin-5-yl)oxybutyl]carbamate

To a solution of [(lS)-3-(benzyloxycarbonylamino)-l-methyl·propyl]methanesulfonate intermediate 199 (783 mg, 2.6 mmol) in dry acetonitrile (20 mL) was added césium carbonate (1.3 g, 4.0 mmol) and 3-iodo-l-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-ol intermediate

284 (702 mg, 2.0 mmol). The reaction mixture was stirred at reflux for 16 h. The reaction

405 mixture was evaporated under reduced pressure and partitîoned with water and ethyl acetate.

After séparation, the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, fîltered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 40/60 as eluent to afford benzyl N-[(3R)-3-(3-iodo-ltetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-yl)oxybutyl]carbamate intermediate 285 as a white solid.

LCMS method F: [M+H]⁺ = 551.2, t_R = 3.17 min

Préparation of intermediate 286: Benzyl N-[(3R)-3-[3-[5-(hydroxymetkyl)-3-pyrîdyl]-lte1rahydropyran-2-yl-pyrazolo[4,3-b/pyridin-5-yl]oxybutyl[carbamate

To a suspension of benzyl N-[(3R)-3-(3-iodo-l-tetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin5-yl) oxy butyl] carbamate intermediate 285 (420 mg, 0.76 mmol) in 1,4-dioxane (4.0 mL) and water (0.2 mL) was added (5-(4,4,5,5-tetramcthy 1-1,3,2-dioxaboiOlan-2-yl)pyridin-3yl)methanol (214 mg, 0.91 mmol) and potassium phosphate tribasic (484 mg, 2.28 mmol). The reaction was purged with argon for 10 min then Xphos (36 mg, 0.08 mmol) and tetrakis(triphenylphosphine)palladium(0) (44 mg, 0.04 mmol) were added. The reaction mixture was stirred at reflux for 4 h. The reaction mixture was cooled to room température and diluted with water and ethyl acetate. After séparation, the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, fîltered and evaporated under reduced pressure. The residue was purified on silica gel column chromatography using cyclohexane/(ethyl acetate/ethanol (3/1)) 90/10 to 50/50 as eluent to afford benzyl N-[(3R)-3-[3-[5-(hydroxymethyl)-3-pyridyl]-ltetrahydropyran-2-yl-pyrazolo[4,3-b]pyridin-5-yl]oxybutyl]carbamate intermediate 286 as a white foain.

406

LCMS method F: ΙΜ+ΗΓ = 532.3, t_R = 2.23 min

Préparation of intermediate 287: (13R) -13 -methyl-19 -(oxan -2 -yl) -8,14-dioxa-4,10,19,20,22 pentaazatetracycloll 3.5.2.1O¹⁸·²¹ ]tricosa-i(20),2(23),3,5,15,17,21 -heptaen -9 -one

To a solution of benzyl N-[(3R)-3-[3-[5-(hydroxymethyl)-3-pyridyl]-l-tetrahydropyran-2-ylpyrazolo [4,3-b]pyndin-5-yl]oxybutyl]carbamate intermediate 286 (250 mg, 0.47 mmol) in dry acetonitrile (80 mL) was added césium carbonate (919 mg, 2.82 mmol). The reaction mixture was stirred at 90°C for 2 h. The suspension was filtered and the salts were washed with acetonitrile. The filtrate was evaporated under reduced pressure. The residue was purified on silica gel column chromatography using di ch loromethane/m éthanol 100/0 to 95/5 as eluent to afford (13R)- 13-methy 1-19-(oxan-2-y 1)-8,14-dioxa-4,l 0,19,20,22-pentaazatetracyclo[l 3.5.2. I^2,6.01⁸^jtrîcosa-1(20),2(23),3,5,15,17,21 -heptaen-9-one intermediate 287 as a colorless oil. LCMS method F: [M+Hj⁺ = 424.3, t_R = 2.17 min

Préparation of Example 164: ( 13R)-13-methy 1-8,14-dioxa-4,l0,19,20,22-pen taaza tetra cyclo [13.5.2.1 ^.0^18,2 *] tricosa-1 (20),2(23),3,5,15,17,21-heptaen-9-one

To a solution of (13R)-13-methyl-19-(oxan-2-yl)-8,14-dioxa-4,l 0,19,20,22pentaazatetracyclo[ 13.5.2.1²’⁶.0'^8,21 jtrîcosa-1 (20),2(23),3,5,15,17,21 -heptaen-9-one intermediate 287 (200 mg, 0.47 mmol) in methanol (11 mL) and water (1.6 mL) was added ptoluenesulfonic acid monohydrate (446 mg, 2.35 mmol). The reaction mixture was stirred at 65°C for 2 h then cooled to room temperature and carefuliy quenched with a saturated aqueous sodium bicarbonate solution. Ethyl acetate was added. After séparation, the aqueous layer was

407 extracted with ethyl acetate and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified on silica gel column chromatography using cyclohexane/(ethyl acetate-ethanol (3l)) 80/20 to 20/80 as eluent, The resulting solid was trîturated in diethyl ether, filtered then dissolved in dichloromethane/methanol and evaporated under reduced pressure to afford (13R)13-methy 1-8,14-dioxa-4,l 0,19,20,22-pentaazatetracyclo[ 13.5.2.1²·⁶.0¹⁸’² ^00058-1(20),2(23), 3,5,15,17,21 -heptaen-9-one example 164 as a white solid.

LCMS method F: [M+H]⁺ = 340.3, t_R = 1.63 min

LCMS method G: [M+H]⁺ = 340.3, t_R = 1.97 min

Ή NMR (400 MHz, J6-DMSO) δ 13.45 (1 H, s), 9.19 - 9.18 (IH, m), 8.88 (IH, s), 8.46 - 8.44 (IH, m), 8.02 - 7.98 (1 H, m), 7.87 - 7.82 (IH, m), 6.86 - 6.83 (IH, m), 5.57 - 5.46 (2H, m), 5.12 - 5.08 (IH, m), 3.46-3.40 (IH, m), 3.00 - 2.92(11-1, m), 2.45 (IH, d, J=14.3 Hz), 1.41-1.38 (4H, m) ppm.

Example 165: (13R)-13-methyl-8,14-dioxa-10,17,19,20-tetraazatetracyclo[13.5.2.

p, s .οι⁸-²'jtricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

Example 165 is prepared according to the synthesis route described in detail below.

Préparation of intermediate 288: 5-bromo-l-tetrahydropyran-2-yl-pyrazolo[3,4-b]pyridine

To a solution of 5-bromo-IH-pyrazolo[3,4-b]pyridine (3.96 g, 20.0 mmol) and 3,4dihydropyran (5.49 mL, 60.0 mmol) in dîchloromethane (45 mL) and THF (15 mL) was added methanesulfonic acid (0.26 mL, 4.0 mmol). The reaction mixture was stirred at room température for 3 h. Saturated aqueous sodium bicarbonate solution was added. After

408 séparation, the aqueous layer was extracted with dichloromethane and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 70/30 as eluent to afford 5-bromo-l-tetrahydropyran-2-ylpyrazolo[3,4-b]pyridine intermediate 288 as a pale yellow oil.

LCMS method F: [M+H]⁺ = 282.0-284.0, t_R = 2.45 min

Préparation of intermediate 289: l-tetrahydropyran-2-yl-5-(4,4,5_>5-tetramethyl-l,3,2dioxaborolan-2-yl)pyrazolo[3,4-b]pyridine

To an argon degassed mixture of 5-bromo~l-tetrahydropyran-2-yl-pyrazolo[3,4-b]pyridine intermediate 288 (1.25 g, 4.43 mmol), bis(pinacolato)diboron (2.81 g, 11.07 mmol), potassium acetate (1.30 g, 13.29 mmol) in DMF (20 mL) was added [l,lBis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (91 mg, 0.11 I mmol). The reaction mixture heated to 100°C for 2 h. The solvent was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford l-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2yl)pyrazolo [3,4-b]pyridine intermediate 289 as a brown oil which was used in the next step without further purification.

LCMS method F: [M+H]⁺ = 330.3, t_R = 2.73 min

Préparation of intermediate 290: l~tetrahydropyran-2-ylpyrazolo(3,4-b]pyridin-5-ol

409

To a solution of l-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) pyrazolo [3,4-b]pyridine intermediate 289 (6.0 g, 17.72 mmol) in THF (45 mL) and 1 N aqueous sodium hydroxide solution (45 mL) was added hydrogen peroxide (30%wt aqueous solution, 2.0 mL, 53.166 mmol). The reaction mixture was stirred at room température for 2 h. The 5 reaction mixture was quenched with saturated aqueous sodium thiosulfate solution and diluted with ethyl acetate. After séparation, the aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford l-tetrahydropyran-2-ylpyrazolo[3,4b]pyridin-5-ol intermediate 290 as a brown oil.

LCMS method F: [M+H]⁺ = 220.3, t_R = 1.58 min

Préparation of intermediate 291: tert-buty l-dimethyl-(lH-pyrazolo[3,4-b]pyridin-5-yloxy) silane

To a solution of l-tetrahydropyran-2-ylpyrazolo[3,4-b]pyridin-5-ol intermediate 290 (2.37 g, 17.59 mmol) and imidazole (1.43 g, 21.11 mmol) in DMF (18 mL) at 0°C was added tert-buty IdimethyIsilyI chloride (2.91 g, 19.35 mmol). The reaction mixture was stirred at 0°C for 5 min then warmed to room température and stirred for 16 h. Solvents were evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl-dimethyl-(l H-pyrazolo[3,4-b]pyridin-5-yloxy)silane intermediate 291 as a brown oil which was used in the next step without further purification.

LCMS method F: [M+H]⁺ = 334.2, t_R = 3.29 min

Préparation of intermediate 292: lH-pyrazolo[3,4-b]pyridin-5-oi

410

To a solution of /e?7-butyl-dimethyl-(l-tetrahydropyran-2-ylpyrazolo[3,4-b]pyridin-5-yl)oxysilane intermediate 291 (4.69 g, 14.50 mmol) in methanol (60 mL) and water (12 mL) was added toluenesulfonic acid monohydrate (5.52 g, 29.01 mmol). The solution was stirred at room température for 2 h. Solvents were evaporated and the residue was partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate, collected and evaporated under reduced pressure. The residue was purified by reverse-phase column chromatography using acetonitrile/water 10/90 to 50/50 as eluent. The requisite fraction were concentrated under reduced pressure and triturated with düsopropyl ether to afford 1 H-pyrazolo[3,4-b]pyridin-5-ol intermediate 292 as a beige solid.

LCMS method F: [M+Hf = 136.1, > = 1.36 min

Préparation of intermediate 293: tert-buty l-dimethyl-(lH-pyrazolo[3,4-b]pyridin-5-yloxy) silane

To a solution of crude lH-pyrazolo[3,4-b]pyridin-5-ol intermediate 292 (500 mg, 3.70 mmol) în DMF (16 mL) were successively added imidazole (504 mg, 7.40 mmol) and >rr-butyldimethyIsilyI chloride (669 mg, 4.44 mmol). The reaction mixture was stirred at room température for 16 h. Saturated aqueous ammonium chloride and ethyl acetate were added. After séparation, the aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, fïltered and concentrated under reduced pressure to afford /er/-butyl-dimethyl-(l H-pyrazolo[3,4-b]pyridin-5yloxy)silane intermediate 293 as a yellow oil which was used in the next step without further purification.

LCMS method F: [M+Hf = 250.3, t_R = 2.73 min

Préparation of intermediate 294: tert-butyl-f(3-iodo-lH-pyrazolo[3,4-b]pyridin-5-yl)oxy]dimethyl-silane

To a solution of fm-butyLdimethyl-(lH-pyrazolo[3,4-b]pyridin-5-yloxy)silane intermediate

293 (3.00 g, 12.03 mmol) in DMF (60 mL) was added ïV-Iodosuccinimide (3.24 g, 14.43 mmol).

411

The reaction mixture was stirred at room température for 16 h. Additional jV-Iodosuccinimide (1,12 g, 5.0 mmol) was added and the reaction mixture was stirred for 5 h. Solvents were concentrated under reduced pressure and the residue was partîtioned between ethyl acetate and saturated aqueous sodium thiosulfate solution. The aqueous layer was extracted with ethyl 5 acetate and the combined organic extracts were washed with saturated aqueous sodium bicarbonate solution then with brine, dried over anhydrous anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert-buty 1-[(3-iodo-1 H-pyrazolo[3,4b]pyridin-5-yl)oxy]-dimethyl-silane intermediate 294 as a yellow solid which was used in the next step without further purification.

LCMS method F: [M+H]⁺ = 376.2, t_R = 3.20 min

Préparation of intermediate 295: tert-butyl-(3-iodo-l -tetrahydropyran-2-yl-pyrazolo[3,4-b] pyridin-5-yl)oxy-dimethyi-silan e

To a solution of /ert-butyl-[(3-iodo-IH-pyrazolo[3,4-b]pyridin-5-yl)oxy]-dimethyl-silane intermediate 294 (1.16 g, 3.10 mmol) and DHP (0.85 mL, 9.303 mmol) in dichloromethane (12 mL) and THF (4 mL) was added methanesulfonic acid (40 pL, 0.62 mmol). The reaction mixture was stirred at room température for 16 h. Saturated aqueous sodium bicarbonate solution was added. After séparation, the aqueous layer was extracted with dichloromethane and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 70/30 as eluent to afford tertbutyl-(3-iodo-l-tetrahydropyran-2-yl-pyrazolo[3,4-b]pyridin-5-yl)oxy-dimethyl-sîlane intermediate 295 as a pale yellow oil.

LCMS method F: [M+H]⁺ = 460.1, t_R = 3.67 min

Préparation of intermediate 296: 3-iodo-l-tetrahydropyran-2-yl-pyrazoio[3,4-b]pyridin-5-ol

412

To a 0°C solution of rm-bu1y1-(3-iodo-l-tetrahydropyran-2-yt-pyrazolo[3,4-b]pyridiri-5yl)oxy-dîmethyl-silane intermediate 295 (630 mg, 1.371 mmol) in THF (15 mL) was added IM TBAF solution in THF (1.64 mL, 1.64 mmol) dropwise over 5 min. The reaction mixture was stirred at 0°C for 5 min then warmed to room température and stirred for 16 h. Solvents were evaporated under reduced pressure and the residue was partîtioned between ethyl acetate and saturated aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 3-iodo-l10 tetrahydropyran-2-yl-pyrazolo[3,4-b]pyridin-5-ol intermediate 296 as a yellow solid which was used in the next step without further purification.

LCMS method F: [M+H]⁺= 346.1, ta = 2.17 min

Préparation of intermediate 297: benzyl N-[(3R)-3-(3-iodo-l-tetrahydropyran-2-yl-pyrazolo

[3,4-h]pyrÎdin-5-yl)oxybutylJcarbamate

To a solution of 3-iodo-l-tetrahydropyran-2-yl-pyrazolo[3,4-b]pyridin-5-ol intermediate 296 (270 mg, 0.781 mmol) in DMF (4 mL) was added césium carbonate (382 mg, 1.17 mmol). The reaction mixture was stirred at room température for 30 min, then a solution of [(lS)-320 (benzyloxycarbonylaminol-l-methyl-propyl] methanesulfonate intermediate 199 (259 mg, 0.859 mmol) in DMF (4 mL) was added dropwise over 2 min. The réaction mixture was stirred at room température for 72 h. The reaction mixture was filtered. Ethyl acetate and water were added. After séparation, the aqueous layer was extracted with ethyl acetate and the combined

4I3 organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford benzyl N-[(3R)-3-(3-iodo-l-tetrahydropyran-2yI-pyrazolo[3,4-b]pyridîn-5-yl)oxybutyIjcarbamate intermediate 297 as a yellow oil which was used in the next step without further purification.

LCMS method F: [M+H]⁺ = 551.2, t_R = 3.06 min

Préparation of intermediate 298: benzyl N-[(3R)-3-[3-[3-(hydroxymethyl)phenytf-l-tetra hydropyran-2-yl-pyrazolo[3,4-b]pyridin-5-yl]oxybutytfcarbamate

To an argon degassed solution of benzyl N-[(3R)-3-(3-iodo-i-tetrahydropyran-2-ylpyrazolo[3,4-b]pyridin-5-yl)oxybutyl]carbamate intermediate 297 (260 mg, 0.472 mmol), [3(hydroxy methyl)phenyl]boronic acid (79 mg, 0.52 mmol), potassium phosphate tribasic (301 mg, l.4l mmol) and XPhos (22 mg, 0.047 mmol) in dioxane (4.75 mL) and water (0.25 mL) was added tetrakis(triphenylphosphine)-palladium(0) (28 mg, 0.024 mmol). The reaction mixture was stirred at 90°C for Ih. The reaction mixture was cooled to room température and ethyl acetate and water were added. After séparation, the aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 60/40 as eluent to afford benzyl N-[(3R)-3-[3-[3-(hydroxymethyl)phenyl]-I-tetrahydropyran-2-yl-pyrazolo[3,4b]pyridin-5-yl]oxybutyl] carbamate intermediate 298 as a pale yellow solid.

LCMS method F: [M+H]⁺ = 531.4, t_R = 2.82 min

Préparation of intermediate 299: (13R)-13-methyl-19-(oxan-2-yl)-8,14-dioxa-l0,17,19,20tetraazatetracyclo[13.5.2. l^2b.0‘⁸·²' Itricosa -1(20),2(23),3,5,15(22),16,18(21)-h eptaen -9-one

To a solution of benzyl N-[(3R)-3-[3-[3-(hydroxymethyl)phenyl]-l-tetrahydropyran-2-ylpyrazolo[3,4-b]pyrîdin-5-yl]oxybutyl]carbamate intermediate 298 (300 mg, 0.565 mmol) in acetonitrîle (300 mL) was added potassium hydroxide (159 mg, 2.82 mmol). The reaction 5 mixture was stirred at room température for 2 h. The reaction mixture was filtered and solvents were concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. after séparation, the aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column 10 chromatography using dichloromethane/methanol 100/0 to 95/5 as eluent to afford (13R)-13methyl-19-(oxan-2-y l)-8,14-dioxa-l 0,17,19,20-tetraazatetracyclo[ 13.5.2.1²’⁶.0^18,2‘Jtrîcosa1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one intermediate 299 as a pale yellow foam.

LCMS method F: [M+H]⁺ = 423.2, t_R = 2.73 min

Préparation of Example 165: (13R)-13-methyl-8,14-dioxa-l0,17,19,20-tetraazatetracyclo [13.5.2.1²<0¹⁸²¹ ]tricosa-1(20),2(23),3,5,15(22),16,18(21)-hep taen-9-one

To a solution of (13R)-l3-methyl-19-(oxan-2-yl)-8,14-dioxa-10,17,19,20-tetraazatetracycio [13.5.2.1²’⁶.0¹⁸⁼² ^tricosa-1 (20),2(23),3,5,15(22),16,18(21)-heptaen-9-one intermediate 299 (160 mg, 0.378 mmol) in methanol (3 mL) and water (1 mL) was added p-toluenesulfonic acid monohydrate (360 mg, 1.89 mmol). The reaction mixture at 50°C for 16 h. Solvents were concentrated under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. After séparation, the aqueous layer was

415 extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol 100/0 to 90/10 as eluent. The requisite fractions were concentrated under reduced pressure and triturated 5 in pentane/diethyl ether (10/1) solution to afford ( 13R)-13-methy 1-8,14-dioxa-10,17,19,20tetraazatetracyclo[l 3.5.2.1²A 0^l8’^2l]tricosa-l(20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one example 165 as a white solid.

LCMS method F: [M+H]⁺ = 339.3, t_R = 2.76 min

LCMS method G: [M+H]⁺ = 339.3, t_R = 2.75 min

Ή NMR(400 MHz, J6-DMSO) δ 13.73 (s, IH), 8.27 (d, J = 2.9 Hz, IH), 7.97 (dd, J= 4.9, 7.2 Hz, 1H), 7.87 (d, 7.9 Hz, IH), 7.81 (s, IH), 7.69 (d, J = 2.7 Hz, IH), 7.50 (t, J = 7.7 Hz,

IH), 7.31 (d, J=8.0Hz, IH), 5.79 - 5.74 (m, IH), 4.83 (d,J= 13.5 Hz, IH), 4.58 (dd, J = 5.9, 10.5 Hz, IH), 3.60 -3.56 (m, 1 H), 2.91 (t, J = 13.6 Hz, I H), 2.33 (t, J = 12.7 Hz, IH), 1.45 (d, J=6.2 Hz, 3 H), 1.42- 1.39 (m, IH) ppm.

Example 166: 8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.1²’⁵.0^18I1]tricosa1(20),2(23),3,15(22),16,18(21)-hexaen-9-one

Example 166 is prepared according to the synthesis route described în general scheme K.

Préparation of intermediate 300: benzyl N-[3-f3-[2-(2-hydroxyethyl)triazol-4-yl]-ltetrahydropyran-2-yl-îndazol-5-yl]oxypropyl]carbamate

416

To a stirred mixture of 2-[4-[5-[tert-butyl(dimethyl)silyl]oxy-l-tetrahydropyran-2-yl-indazol3-yl]triazol-2-yl]ethanol intermediate 248 (443 mg, 1 mmol), and césium carbonate (977 mg, 3.24 mmol) in acetonitrile (20 mL) was added a solution of benzyl N-(35 bromopropyl)carbamate (272 mg, 1.1 mmol) in acetonitrile (2 mL). The reaction mixture was stirred at 50°C for 16 hours. The salts were removed by filtration, rînced with acetonitrile and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 50/50 to 20/80 as eluent to afford benzyl N-[3-[3-[2-(2-hydroxyethyl)triazol-4-yl]-l-tetrahydropyran-2-yLindazol-5-yl]oxy 10 propyl]carbamate intermediate 300 as a white solid.

LCMS method F: [M+H]⁺ = 521.3, t_R = 2.64 min

Préparation of intermediate 301: 19-(oxan -2-yl) -8,14-dioxa -4,5,10,19,20,23 -hexaazatetra cydo[13.5.2.1²’⁵.0^l821Jtricosa-l(20),2(23),3,15(22),16,18(21)-hexaen-9-one

To a solution of benzyl N-[3-[3-[2-(2-hydroxyethyl)triazol-4-yl]-l-tetrahydropyran-2-ylindazoi-5-yl]oxypropyl]carbamate intermediate 300 (230 mg, 0.44 mmol, leq) in acetonitrile (50 mL) was added césium carbonate (860 mg, 2.65 mmol). The suspension was stirred at reflux for 48 h. The suspension was filtered and the salts were rînced with acetonitrile. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 50/50 to 30/70 to afford l9-(oxan-2-yl)-8,1421105

417 d i oxa-4,5,10,19,20,23-hexaazatetracy c Ιο Γ13.5.2. l²’⁵.0'^8,2 ^100053-1(20),2(23),3,15(22),16,

18(21)-hexaen-9-one intermediate 301 as a white solid.

LCMS method F: [M+H]^T = 413.2, t_R = 2.33 min

Préparation of Example 166: 8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2. 1²A0i⁸’^2l]_tric_Osa-l (20),2(23),3,15(22),16,18(2 l)-hexaen-9-one

To a suspension of 19-(oxan-2-yl)-8,14-dîoxa-4,5,l 0,19,20,23-hexaazatetracyclo [13.5.2.l²’⁵.0^l8’^2l]tricosa-l(20),2(23),3,15(22),16,18(21)-hexaen-9-one intermediate 301 (50 mg, 0.12 mmol) in methanol (7 mL) and water (1 mL) was added para-toluenesulfonic acid monohydrate (115 mg, 0.6 mmol). The reaction mixture was heated ai 65°C for 6 h. Methanol was partially removed under reduced pressure and a saturated aqueous NaHCOs was added until pH basic. The aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/méthanol 100/0 to 95/5 as eluent. The solid was trîturated with diethyl ether, filtered and dried to give 8,14-dioxa-4,5,10,19,20,234iexaazatetracyclo[13.5.2.1²’^:>.0¹⁸'²¹] tricosa-1 (20),2(23),3,15(22), 16,18(21 )-hexaen-9-one example 166 as a white solid.

LCMS method F: [M+H]⁺ = 329.2, t_R = 1.72 min

LCMS method G: [M+H]⁺ = 329.2, t_R = 1.75 min

Ή NMR (400 MHz, r/6-DMSO) δ 13.15 (IH, s), 8.13 (IH, s), 7.69 (IH, t, J=6.I Hz), 7.53 7.45 (2H, m), 6.98 (IH, dd, J=2.3, 8.9 Hz), 4.84 - 4.79 (2H, m), 4.53 (2H, dd, J=2.9, 5.2 Hz), 4.31 - 4.24 (2H, m), 3.09 - 3.06 (2H, m), L9I - 1.85 (2H, m) ppm.

Example 167: 12,12-dîiluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.

1^.0i84i]tricosa-l(20),2(23),3,15(22),16,18(21)-hexaen-9-one

418

Example 167 is prepared according to the synthesis route described în general scheme K.

Préparation of intermediate 302: [3-(benzyloxycarbonylamino)-2,2-difluoro-propyl} trifluoromethanesulfonate

To a solution of benzyl N-(2.2-difluoro-3-hydroxy-propyl)carbamate intermediate 213 (2.63 g, 10.725 mmol) and triethylamine (2.97 mL, 21.45 mmol) in dichloromethane (100 mL) at 0°C under argon atmosphère was added dropwise over a period of 5 min Tf?O (2.65 mL, 16.088 10 mmol). The reaction mixture was stirred at 0°C for 5 min and at room température for 16 h. A saturated aqueous NaHCOi solution was added and layers were separated. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure to afford crude [3-(benzyloxycarbonylamino)-2,2-difluoro-propyl] trifluoromethane 15 sulfonate intermediate 302 as a brown oil. The product was used in the next step without further purification.

'HNMR (400 MHz, d6 DMSO) δ 7.38 - 7.32 (m, 5H), 5.14 - 5.06 (m, 3H), 3.64 (dt, J= 6.5, 14.5 Hz, 2H), 3.14 - 3.07 (m, IH). [7 labile proton was not visible In this solvent}

Préparation of intermediate 303: benzyl N-[2_f2-diftuoro-3-[3-[2-(2-hydroxyethyl)triazol-4yl]-I-tetrahydropyran-2-yl-indazol-5-yl]oxy-propyl]carbamate

419

To a mixture of 3-[2-(2-hydroxyethyl)triazol-4-yl]-l -tetrahydropyran-2-yl-indazol-5-ol (210 mg, 0.638 mmol) and [[3-(benzyloxycarbonylamino)-2,2-dif1uoro-propyl] trifluoromethane sulfonate intermediate 302 (361 mg, 0.957 mmol ) in dry acetonitrile (20 mL) under argon 5 atmosphère was added césium carbonate (249 mg, 0.766 mmol) . The reaction mixture was stirred at 70°C for 16 h. Additional [[3-(benzyloxycarbonylamino)-2,2-difluoropropyl]trifluoro methanesulfonate intermediate 302 (361 mg, 0.957 mmol ) was added. The reaction mixture was stirred 4 h at 70°C. Additional [[3-(benzyloxycarbonylamino)-2,2dîfluoro-propyl] trifluoro methanesulfonate itermediate 302 (361 mg, 0.957 mmol ) was added.

The reaction mixture was stirred ovemight at 70°C. The solvent was removed under reduced pressure, ethyl acetate and water were added, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatographychromatography using cyclohexane/ethyl acetate 100/0 to 15 50/50 to afford benzyl N-(2,2-difluoro-3-(3-[2-(2-hydroxyethyl)triazol-4-yl]-l-tetrahydro pyran-2-yl-indazol-5-yl]oxy-propyl]carbamate intermediate 303 as a yellow oil.

LCMS method F : [M+H]⁺ = 557.4, t_R = 2.66 min

Préparation of intermediate 304:12,12-difluoro -19 -(oxan -2-y 1)-8,14 -dioxa -4,5,10,19,20,2320 h exaazatetracycio[13.5.2, l^2S.0^1S2i]tricosa -1(20),2(23),3,15(22),16,18(21) -hexaen -9 -one

420

A stirred solution of benzyl N-[2,2-difluoro-3-[3-[2-(2-hydroxyethyl)triazol-4-yl]-l-tetrahydro pyran-2-yl-indazol-5-yl]oxy-propyl]carbamate intermediate 303 (240 mg, 0.43 E mmol) and césium carbonate (844 mg, 2.59 mmol) in acetonitrile (42 mL) was heated at reflux température for 24 h. The reaction mixture was filtered and the salts were rinced with acetonitrile. The filtrate was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 70/30/ to 50/50 as eluent to afford 12,l2-difluoro-l9-(oxan-2-yl)-8,l4-dioxa-4,5,10,19,20,23-exaazatetracyclo[13.5.2.1²’⁵.0^1S’²¹] tricosa-1 (20), 2(23),3,15(22),16,18(21 )-hexaen-9-one interlediate 304 as a cream solid.

LCMS method F: [M+H] = 449.1, t_R = 2.45 min

Préparation of Example 167; 12,12-difluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetra cyclo[13.5.2.1²’⁵.0^,8’ⁿ]tricosa-l(20),2(23),3,15(22),16,18(21)-hexaen-9-one

To a suspension of 12,12-difluoro-19-(oxan-2-y 1)-8,14-dioxa-4,5,10,19,20,23-hexaazatetra 15 cyclof 13.5.2.1^2,5.0^18,2^tricosa-1(20),2(23),3,15(22), 16,18(21 )-hexaen-9-one intermediate 304 (85 mg, 0.19 mmol în methanol (12 mL) and water (1.7 mL) was added para-toluenesulfonîc acid monohydrate (180 mg, 0.948 mmol). The reaction mixture was heated at 65°C for 16 h. Methanol was partially removed under reduced pressure and a saturated aqueous NaHCOj solution of was added until pH basic. The aqueous phase was extracted with EtOAc and the 20 organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was triturated in dichloromethane and filtered. The solid obtained was recrystallized from acetonitrile to give 12,12-difluoro-8,14-dioxa4,5,10,19,20,23-hexaazatetracyclo[l 3.5.2. l^2,s.0’⁸’^2!]tricosa-1(20),2(23),3,15(22),16,18(21)hexaen-9-one example 167 as a white solid.

LCMS method F: [M+H]⁺ = 365.1, t_R = 1.89 min

LCMS method G: [M+H]* = 365.2, t_R = 1.87 min ¹H NMR (400 MHz. J6-DMSO) δ 13.37 (1 H, s), 8.16 - 8.15 (2H, m), 7.62(1 H, s), 7.51 -7.46 (IH, m), 7.13 - 7.08 (IH, m), 4.84 (2H, t, J=4.4 Hz), 4.68 - 4.59 (4H, m), 3.59 - 3.52 (2H, m).

421

Example 168: (12R)-12-fluoro-8,14-dioxa-10,19,20-triazatetracycloll3.5.2.1^:’⁶.0^ls’^zl] tricosa-1(20),2(23),3,5,15(22),16,18(21)-hcptaen-9-one

Example 168 is prepared according to the synthesis route described in general scheme E.

Préparation of intermediate 305: methyl (2S)-2-(dibenzylamino)-3-hydroxy-propanoate

To a solution of L-serine methyl ester hydrochloride (2 g, 12.9 mmol) in acetontrile (30 mL) was added at room température potassium carbonate (3.56 g, 25.8 mmol) and benzyl bromide (3.1 mL, 25.8 mmol). The reaction mixture was stirred at room température for 3.5 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 80/20 as eluent to afford methy! (2S)-2-(dibenzylamino)-3-hydroxy-propanoate intermediate 305 as a coloriess oil.

LCMS method F: [M+H]⁺ = 300.2, ta = 2.64 min

Préparation of intermediate 306: methyl (2R)-3-(dibenzylamino)-2-fluoro-propanoate

To a solution of DAST (1 mL, 7.91 mmol) in dry THF (15 mL) was slowly added, at room température a solution of methyl (2S)-2-(dibenzylamino)-3-hydroxy-propanoate intermediate

422

305 (2.15 g, 7.I9 mmol) in dry THF (15 mL). The reaction mixture was stirred at room température for 30 min. Ice water and ethyl acetate were added. The organic layer was washed 5% aqueous NaHCO₃ solution then brine, dried over anhydrous sodium sulfate, fïltered and concentrated to afford methyl (2R)-3-(dîbenzylamino)'2-fluoro-propanoate intermediate 306 as a yellow viscous oil. The product was used in the next step without further purification.

LCMS method F: [M+H]⁺ = 302.3, t_R = 2.81 min

Préparation of intermediate 307: (2R)-3-(dibenzylamino)-2-fluoro-propan-l-oi

To a degassed solution of lithium borohydride (302 mg, 7.97 mmol) in dry THF (10 mL) ai 10 °C was added dropwise a solution of methyl (2R)-3-(dibenzylamino)-2-f1uoro-propanoate intermediate 306 (2 g, 6.64 mmol) in dry THF (10 mL). The mixture was allowed to warm to room température and stirred ovemight. The reaction mixture was cooled to 0°C and quenched with a saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium suflate, fïltered and concentrated under reduced pressure. The crude product was dissolved în 2 M hydrochlorîc acid (9 mL, until pH = 2) and the aqueous layer was washed with diethyl ether. The aqueous layer was basitïed to approximately pH = 10 with a saturated aqueous solution of NaHCOj and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, fïltered and evaporated. The crude was dissolved in éthanol and fïltered, then the fîltrate was concentrated to afford (2R)-3-(dibenzylamino)-2-fluoro-propanl-ol intermediate 307 as a white viscous oil.

LCMS method F: [M+Hf = 274.3, ta = 1.32 min

Préparation of intermediate 308: (2R)-3-amino-2-fluoro-propan-I-ol

HO-7

To a solution of (2R)-3-(dibenzylamino)-2-fluoro-propan-l-ol itermediate 307 (1.55 g, 5.68 mmol) in éthanol (20 mL) was added at room température palladium hydroxide 10 wt. % loadîng (155 mg). The reaction mixture was stirred under hydrogen atmosphère at room

423 température for 2 days. The reaction mixture was fîltered and the filtrate was concentrated under reduced pressure to give (2R)-3-amino-2-fluoro-propan-l-ol intermediate 308 as a yellow liquid. The product was used in the next step without further purification.

Ή NMR (400 MHz, CDCb) δ 4.62 - 4.5 (IH, m), 3.9 (IH, m), 3.84 (IH, m), 3.1 (IH, m), 3.04 5 (IH, m), 2.0 (3H, br).

Préparation of intermediate 309: benzyl N-[(2R)-2-fluoro-3-hydroxy-propyl/carbamate

To a solution of (2R)-3-amino-2-fluoro-propan-l-ol itermediate 308 (541 mg, 5.68 mmol) in a 10 mixture of THF (9 mL) and water (9 mL) was added sodium hydrogenocarbonate (525 mg, 6.25 mmol). The suspension was cooled to 0 °C and benzyl chlorofonnate (0.89 mL, 6.25 mmol) was added dropwise and the reaction mixture was stirred at room température ovemight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, fîltered and 15 evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using cyclohexane/EtOAc 100/0 to 60/40 as eluent to afford benzyl N-[(2R)2-fluoro-3-hydroxy-propyl]carbamate intermediate 309 as a white solid.

LCMS method F: [M+Na]⁺ = 250.1, t_R = 1.79 min

Préparation of intermediate 310: [(2R)-3-(henzyloxycarbonylamino)-2-fluoro-propyl] methanesulfonate

To a solution of benzyl N-[(2R)-2-fluoro-3-hydroxy-propyl]carbamate intermediate 309 (726 mg, 3.2 mmol) in dîcholoromethane (13 mL) was added triethylamine (0.89 mL, 6.4 mmol). At 25 0°C was added methanesulfonyl chloride (0.32 mL, 4.16 mmol). The reaction mixture was stirred at room température for 1.5 h. The reaction mixture was quenched by addition of ammonium chloride solution and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous NaHCOj solution and brine, dried over anhydrous sodium sulfate, fîltered and concentrated under reduced pressure to give [(2R)-321105

424

(benzyloxycarbonylamino)-2-fluoro-propyl] methanesulfonate intermediate 310 as an orange oil. The product was used in the next step without further purification.

LCMS method F: [M+H]⁺ = 306.1, t_R = 2.15 min

Préparation of intermediate 311: benzyl N-[(2R)-2-fluoro-3-/3-[3-(hydroxymethyl)phenyl]l-tetrahydropyran-2-yl-indazol-5-yl]oxy-propyl/carbamate

To a mixture of 3-[3-(hydroxy methy l)phenyl]-l-tetrahydropyran-2-yl-indazol-5-ol (518 mg, 1.60 mmol) in DMF (18 mL) was added césium carbonate (1.04 g, 3.20 mmol). The reaction 10 mixture was stirred for 20 min. [(2R.)-3-(benzyloxycarbonylamino)-2-fluoro-propyl] methane sulfonate intermediate 310 (1.032 g, 3.2 mmol) in DMF (6 mL) was added. The reaction mixture was stirred at room température for 4 days. The reaction mixture was filtered and rînced with ethyl acetate. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered 15 and concentrated. The crude was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 60/40 as eluent to afford benzyl N-[(2R)-2-fluoro-3-[3-[3(hydroxymethyl)phenyl]-l-tetrahydropyran-2-yl-indazol-5-yl]oxy-propyl]carbamate intermediate 311 as a white oil which crystallized at room température.

LCMS method F : [M+H]⁺ = 534.2, t_R = 2.83 min

Préparation of intermediate 312: (12R) -12-fluoro-19-(oxan-2-yl)-8,14-dioxa-10,19,20triazatetracyclo[ 13.5.2, l^2,6.O^18,21/tricosa -1 (20),2(23),3,5,15(22),16,18(21) -heptaen -9-one

425

To a solution of benzyl N-[(2R)-2-fluoro-3-[3-[3-(hydroxymethyl)phenyl]-l-tetrahydropyran2-yl-indazol-5-yl]oxy-propyl]carbamate intermediate 311 (167 mg, 0.31 mmol) in dry acetonitrîle (16 mL) was added at room température ftnely powdered potassium hydroxide (87 5 mg, 1.55 mmol) in one portion. The reaction mixture was stirred at room température ovemight.

The reaction mixture was filtered, rinced with acetonitrîle and evaporated under reduced pressure. The residue was purified by silica gel coumn chromatography using cyclohexane/ethyl acetate 100/0 to 70/30 as eluent to afford (12R)-12-fluoro-19-(oxan-2-yl)8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2. l²A0¹⁸’² ']tricosa-1(20),2(23),3,5,15(22), 10 16,18(2 l)-heptaen-9-one intermediate 312 as a white solid.

LCMS method F: [M+H]' = 426.4, t_R = 2.76 min

Préparation of Example 168; (12R)-12-fluoro-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2. l²A0¹⁸’²¹]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

To a solution of (12R)-I2-fluoro-l9-(oxan-2-y 1)-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.1²’⁶.0¹⁸’^2l]tricosa-l(20),2(23),3,5,15(22),16,l 8(21 )-heptaen-9-one intermediate 312 (] 16 mg, 0.27 mmol) in methanol (4.6 mL) and water (0.8 mL) was added p-toluenesulfonic acid monohydrate (259 mg, 1.36 mmol). The reaction mixture was stirred at 65°C ovemight. 20 The reaction mixture was diluted with dichloromethane and a saturated aqueous NaHCOi solution. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using

426 cyclohexane/ethyl acetate 100/0 to 60/40 as eluent. The cream solid was triturated with diethyl ether, filtered and dried to afford (12R)-I2-fluoro-8,l4-dioxa-l0,l9,20triazatetracyclo [13.5.2.1^2,6/)^18,21 ] tricosa-1(20),2( 23),3,5 J 5(22), 16,18(2 l)-heptaen-9-one example 168 as a white powder.

LCMS method F: [M+H]⁺ = 342.2, t_R = 2.08 min

LCMS method G: [M+H]⁺ = 342.3, t_R = 2.07 min

Ή NMR (400 MHz, t/6-DMSO) δ 13.21 (IH, s), 8.05 (IH, t, >5.7 Hz), 7.86 (IH, d, J=7.9 Hz), 7.77 (IH, s), 7.56 (IH, d, >8.5 Hz), 7.49 (IH, t, >7.5 Hz), 7.31 (IH, m), 7.15 (IH, m), 7.08 (1 H, dd, >9.2, 2.2 Hz), 5.80 (IH, m), 5.16 (IH, m), 4.85 (IH, m), 4.61 (IH, m), 4.35 (IH, m, 10 3.61 (IH, m), 3.11 (IH, m) ppm.

Example 169: (12S)-12-fluoro-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0’⁸’²¹] tricosa-1(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

Example 169 is prepared according to the synthesis route described in general scheme E and according to the same methods described for example 168.

Préparation of intermediate 313: (12S) -12 -fluoro -19 -(oxan -2 -yl) -8,14 -dioxa-10,19,2020 triazatetracyclo[13.5.2.1²'⁶.0^l8'^2ljtricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

To a solution of benzyl N-[(2S)-2-fluoro-3-[3-[3-(hydroxymethyl)phenyl]-1-tetrahydropyran2-yl-indazol-5-yl]oxy-propyl]carbamate (0.265 g, 0.50 mmol) in dry acetonitrile (32 mL) was

427 added at room température finely powdered potassium hydroxide (140 mg, 2.50 mmol) in one portion. The reaction mixture was stirred at room température for 16 h. The reaction mixture was filtered and rinced with acetonitrile. The filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate

90/10 to 50/50 as eluent to afford (l2S)-l2-fluoro-l9-(oxan-2-yl)-8,l4-dîoxa-l0,l9,20triazatetracyclo[l 3.5.2. l²’⁶.0^I8’^2,]tricosa-l(20),2(23),3,5,15(22), 16,18(21)-heptaen-9-one intermediate 313 as a white solid.

LCMS method F: [M+H]⁺ = 426.2, t_R = 2.78 min

Préparation of Example 169: (12S)-12-fluoro-8,l4-dioxa-10,19,20-triazatetracyclo[13.5.2.

lï,6.0iMi]_tri_cosa.i(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

To a solution of (12S)-12-fluoro-l9-(oxan-2-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2. l²^0^l821]tricosa-l(20),2(23),3,5,l5(22),16,18(21)-heptaen-9-one intermediate 313 (115 mg, 15 0.27 mmol) in methanol (4.6 mL) and water (0.8 mL) was added p-toluenesulfonic acid monohydrate (259 mg, 1.36 mmol). The reaction mixture was stirred at 65 °C ovemight. The reaction mixture was diluted with dichloromethane and a saturated aqueous NaHCOi solution. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure.

The residue was purified by silica gel coumn chromatography using cyclohexane/ethyl acetate 100/0 to 60/40 as eluent. The white solid was triturated with diethyl ether, filtered and dried to afford ( 12S)-12-fluoro-8J 4-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1²A 0^18,21 ]tricosa-1 (20),

2(23),3,5,15(22), 16,18(21 )-heptaen-9-one example 169 as a white powder.

LCMS method F: [M+H]⁺ = 342.2, t_R = 2.08 min

LCMS method G: [M+H]⁺ = 342.2, t_R = 2.07 min

Ή NMR (400 MHz, ί/6-DMSO) Ô 13.21 (IH, s), 8.05 (IH, t, J = 5.7 Hz), 7.86 (IH, d, J = 7.9 Hz), 7.77 (IH, s), 7.55 (lH,d, J = 8.5 Hz), 7.49 J = 7.5 Hz), 7.31 (lH,m), 7.15 (IH, m), 7.08 (IH, dd, .1 = 9.2, 2.2 Hz), 5.80 (IH, m), 5.16 (IH, m), 4.85 (IH, m), 4.61 (IH, m), 4.35 (lH,m),3.61 (lH,m),3.11 (lH,m) ppm.

428

Example 170: 12,12-Difluoro-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo [13.5.2.

I²’⁶ .0¹⁸’²¹]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

Example 170 is prepared according to the synthesis route described in general Scheme K.

Préparation of intermediate 314: benzyl N-[2,2-difluoro-3-[3-[6-(hydroxytnethyl)pyrazin-2yl]-l-tetrahydropyran-2-yl-indazol-5-yl]oxy-propyl]carbamate

To a mixture of 3-[6-(hydroxymethyl)pyrazin-2-yl]-l-tetrahydropyran-2-yl-indazol-5-ol (125 mg, 0.38 mmol) and [3-(benzyloxycarbonylamino)-2,2-difluoro-propyl]trifluoromethane sulfonate (158 mg, 0.42 mmol) in acetonitrile (4 mL) was added potassium carbonate (1 57 mg, 1.14 mmol). The reaction mixture was stirred at 75 ^ÛC for 2 h. The reaction mixture was fïltered and rinsed with ethyl acetate. The fîltrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 99/1 to 50/50 as eluent to afford benzyl N-[2,2-difluoro-3-[3-[6-(hydroxymethyi)pyrazin-2-yl]-Itetrahydropyran-2-yl-indazol-5-yl]oxy-propyl]carbamate 314 as a yellow solid. LCMS method F: [M+Hf = 554.2, tR = 2.75 min

429

Préparation of intermediate 315: 12,12-difluoro-19~(oxan-2-yl)-8,14-dioxa-4,10,19,20,23pentaazatetracyclo[13.5.2.I²·⁶.0^!S,2!jtricosa-1(20),2(23),3,5,15(22),16,18(2l)-heptaen-9-one

To a stirred solution of benzyl N-[2,2-difluoro-3-[3-[6-(hydroxymethyl)pyrazin-2-yl]-l-tetra hydropyran-2-yl-indazol-5-yljoxy-propyl]carbamate 314 (57 mg, 0.11 mmol) in acetonitrile ( 12 mL) was added césium carbonate (208 mg, 0.64 mmol) and the réaction mixture was stirred at reflux for 24 h. The reaction mixture was filtered and rinsed with acetonitrile. The filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 70/30 to 50/50 as eluent to afford 12,12difluoro-19-(oxan-2-yl)-8,14-dioxa-4,I0,19,20,23-pentaazatetracyclo[13.5.2.1²’⁶.0^l8’²¹]tricosa1(20),2(23),3,5,15(22), 16,18(2 l)-heptaen-9-one 315 as a white solid.

LCMS method F: [M+H]⁺ = 446,1, t_R = 2.50 min

Préparation of example 170: 12,12-difluoro-8,14-dîoxa-4,10,19,20,23-pentaazatetracyclo [13.5.2.l^2,6.0¹⁸’²¹]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one

To a solution of 12,12-difluoro-l9-(oxan-2-yl)-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo [13.5.2.l²’⁶.0^I8’^2,]tricosa-](20),2(23),3,5,15(22),16,18(21)-heptaen-9-one 315 (13 mg, 0,029 mmol) în méthanol (0.55 mL) and water (85 pL) was added p-toluenesulfonîc acid monohydrate (28 mg, 0.145 mmol). The reaction mixture was stirred at 65°C overnight. Additional ^-toluenesulfonic acid monohydrate (28 mg, 0.145 mmol), méthanol (0.55 mL) and water (85 pL) were added and the reaction mixture was stirred at 65°C for 24 h. The reaction

430 mixture was diluted with dichloromethane and saturated aqueous NaHCO₃ solution. After séparation, the aqueous layer was extracted with dichloromethane. The combined organic layer was washed brine, dried over anhydrous sodium sulfate, fîltered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using 5 cyclohexane/ethyl acetate I00/0 to 60/40 as eluent. The resulting solid was triturated with dichloromethane, fîltered and dried to afford 12, l2-difluoro-8,i 4-dioxa-4,10,19,20,23pentaazatetracyclo [ 13.5.2.1²Αθ¹⁸’²¹] tricosa-1(20),2(23),3,5,15(22), 16,18(2 l)-heptaen-9-one example 170 as a white powder.

LCMS method F: [M+H]⁺ = 362.2, t_R = 1.88 min

LCMS method G: [M+H]⁺ = 362.2, t_R = l .85 min ‘H NMR (400 MHz, DMSO) : 13.57 (1 H, s), 9.29(1 H, s), 8.57 (iH, s), 8.19 (1 H, t, >6.6 Hz), 8.00 (IH, d, >1.1 Hz), 7.55 (IH, d, >8.9 Hz), 7.14 (IH, dd, >2.6, 9.0 Hz), 4.73 (2H, m), 3.61 (2H, m), 3.51 (2H, s) ppm.

Example 171 : (12S)-12-Fluoro-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo [13.5.2.

PAO^18,21 ] tricosa-1 (20),2 (23),3,5,15,17,21 -heptaen -9-one

Example 171 is prepared according to the synthesis route described in general Scheme K.

Préparation of intermediate 316: (12S) -12-fluoro-l 9-(oxan-2-y 1)-8,14-dioxa-4,l0,19,20,23pentauzatetracyclo [13.5.2A²E0^iS2I]tricosa-l(20),2(23),3,5,15,17,21-heptaen-9-one

431

To a mixture of 3-[6-(hydroxymethyl)pyrazin-2-yl]-l-tetrahydropyran-2-yl-indazol'5-ol (195 mg, 0.597 mmol) and benzyl [(2S)-3-(benzyloxycarbonylamino)-2-fluoro-propyl]methane suifonate (260 mg, 0.66 mmol) in acetonitrîle (10 mL) was added potassium carbonate (247 5 mg, 1.79 mmol). The reaction mixture was stirred at 75°C for 2 h then ovemight. Additional césium carbonate (583 mg, 1.79 mmol) was added and the reaction was stirred at reflux for 3 h. Solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column 10 chromatography using dichloromethane/methanol 100/0 to 95/5 as eluent to afford (12S)-12fluoro-19-(oxan-2-yl)-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[l3.5.2.1²'⁶.0¹⁸’²¹]tricosa1(20),2(23),3,5,15,17,2 l-heptaen-9-one 316 as a white solid.

LCMS method J : [M+H]⁺ = 428.4, t_R = 3.58 min

Préparation of example 171: (12S)-12-fluoro-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo

[13.5.2. l^2,6.0^18,21 ]tricosa-l (20),2(23),3,5,15,17,2 l-heptaen-9-one

To a solution of afford (l2S)-]2-fluoro-l9-(oxan-2-yl)~8,l4-dioxa-4,10,l9,20,23-pentaazatetra cyclo[ 13.5.2.l²’⁶.0^,82,]tricosa-1(20),2(23),3,5,15,17,21-heptaen-9-one 316 (30 mg, 0.07 mmol) în methanol (3 mL) and water (1 mL) was added p-toluenesulibnic acid monohydrate (67 mg,

0.35 mmol) and the reaction mixture was stirred at 75°C ovemight. Additional p21105

432 toluenesulfonic acid monohydrate (67 mg, 0.35 mmol) was added and the reaction mixture was stirred at 75°C for 6 h then at 60°C 72 h. The reaction mixture was diluted with ethyl acetate and saturated aqueousNaHCOî solution. After séparation, the aqueous layer was extracted with ethyl acetate, The combined organic layers were washed with brine, dried over anhydrous 5 sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by

NHz silica gel column chromatography using dichloromethane/methanol 100/0 to 95/5 as eluent. The resulting solid was successively triturated with hot methanol then hot water, filtered and dried to afford (12S)-12-fluoro-8,l4-dioxa-4,10,19,20,23-pentaazatetracyclo

[I3.5.2.1²’⁶.0¹⁸’²¹]tricosa-l(20), 2(23),3,5,l5,17,21-heptaen-9-one example 171 as a cream 10 powder.

LCMS method F: [M+H]⁺ = 344.2, t_R = 1.87 min

LCMS method G: [M+H]⁺= 344.2, t_R = 1.88 min

Ή NMR (400 MHz, DMSO) 13.59 (1H, s), 9.30-9.29 (IH, m), 8.56 - 8.54 (1 H, m), 8.04-8.00 (IH, m), 7.73-7.71 (IH, m), 7.61-7.58 (IH, m), 7.11 (IH, dd, J=2.4, 9.0 Hz), 5.78-4.92 (3H, 15 m), 4.74-4.58 (IH, m), 4.41-4.28 (IH, m), 3.56-3.47 (IH, m), 3.14 (IH, s) ppm.

Example 172 : (12R)-12-Fluoro-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo 113.5.2.

12,6 _₀i8^i]tricosa-l (20),2(23),3,5,15,17,2 l-heptaen-9-one

Example 172 îs prepared according to the synthesis route described in general Scheme K.

Préparation of intermediate 317: benzyl N-[(2R)-2-fluoro-3-({3-[6-(hydroxymethyl)pyrazin2-yl[-l-(oxan-2-yl)-lH-indazoi-5-yl}oxy)propyl}carbamate

433

To a solution of 3-[6-(hydroxymethyl)pyrazin-2-yl]-l-tetrahydropyran-2-yl-indazol-5-οl (400 mg, 1.23 mmol) and [(2R)-3-(benzyloxycarbony!amino)-2-fluoro-propyl]methanesulfonate (460 mg, 1.36 mmol) in acetonitrile (20 mL) was added césium carbonate (1.2 g, 3.69 mmol). 5 The réaction mixture was stirred at reflux for 4 h. Solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol 100/0 to 95/5 as eluent to afford (l2R)-l2-fluoro-l9-(oxan-2-yl)-8J4-dioxa-4,10,19,20,2310 pentaazatetracyclo[13.5.2.1²’⁶.0¹⁸=²¹]tricosa-l(20),2(23),3,5,15,17,2l-heptaen-9-one 317 as a light yellow solid.

LCMS method F: [M+H]⁺ = 428.4.2, t_R = 2.48 mîn

Préparation of example 172: (12R)-12-fluoro-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo

[13.5.2.1²A0¹⁸*²ⁱ]tricosa-l(20),2(23),3,5,15,17,21-heptaen-9-one

To a solution of (12R)-12-fluoro-l9-(oxan-2-y 1)-8,14-dioxa-4,l 0,19,20,23-pentaazatetracyclo [13.5.2.1²A0^,8’^2l]tricosa-l (20),2(23),3,5,15,17,21-heptaen-9-one 317 (291 mg, 0.681 mmol) in methanol (25 mL) and water (8 mL) was added p-toluenesulfonic acid monohydrate (647 mg, 20 3.4 mmol). The reaction mixture was stirred at 60 °C for 72 h. Additional p-toluenesulfonic acid monohydrate (647 mg, 3.4 mmol) was added and the mixture was stirred at 75°C for 2 h.

434

The solvents were evaporated under reduced pressure and the residue was diluted with ethyl acetate and saturated aqueous NaHCOj solution. After séparation, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was 5 purified by NH₂ silica gel column chromatography using dichloromethane/methanol 100/0 to 95/5 as eluent. The resulting solid was triturated with hot water, filtered an dried to afford (12R)-12-fluoro-8,14-dioxa-4,l0,19,20,23-pentaazatetracyclo[13.5.2.1²’⁶.0^,s'^2l]tricosa-l(20), 2(23),3,5,15,17,2 l-heptaen-9-one example 172 as a cream solid.

LCMS method F: [M+H]⁺ = 344.3, t_R = 1.80 min

LCMS method G: [M+H]⁺ = 344.2, t_R = 1.80 min

Ή NMR (400 MHz, DMSO) 13.59 (IH, s), 9.30 (IH, s), 8.56-8.54 (IH, m), 8.02 (IH, t, J=5.0 Hz), 7.73-7.71 (IH, m), 7.62-7.58 (IH, m), 7.11 (IH, dd, J=2.4, 9.0 Hz), 5.78-4.92 (3H, m), 4.73-4.58 (IH, m), 4.40-4.28 (IH, m), 3.52-3.48 (IH, m), 3.14 (IH, s) ppm.

Example 173 : (12S)-12-fluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.

12,5 0^,s.2^,j_tricosa-l(20),2(23),3,15,17,21-hexaen-9-one

Example 173 is prepared according to the synthesis route described in general Scheme O.

Préparation of intermediate 318: (12S)-12-fluoro-l9-(oxan-2-yl)-8,l4-dioxa-4,5,10,19,20, 23-hexaazatetracyclo[13,5.2. 0^lS21 ]tricosa-l (20),2(23),3,15,17,21-hexaen-9-one

435

To a mixture of 3-[2-(2-hydroxyethyl)triazol-4-yl]-l-tetrahydropyran-2-yl-indazol-5-ol (250 mg, 0.759 mmol) and [(2S)-3-(benzyloxycarbonylamino)-2-fluoro-propyl] methanesulfonate (348 mg, l. 14 mmol) în acetonitrile (50 mL) was added césium carbonate (743 mg, 2.28 mmol).

The reaction mixture was stirred at reflux for 6 h. The solvents were evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, fïltered and evaporated under reduced pressure. The resulting solid was trîturated with methanol, fïltered and dried to afford (!2S)-12-fluoro-l9(oxan-2-yl)-8,l4-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.1²’⁵.0^,8’²¹]tricosa-l(20),

2(23),3,15,17,21 -hexaen-9-one 318 as a white solid.

LCMS method F: [M+H]⁺ = 431.4, t_R = 2.46 min

Préparation of example 173: (12S)-12-fluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetra cyclo[13.5.2.1²’⁵.0¹⁸’²¹]tricosa-l(20),2(23),3,15,17,21-hexaen-9-one

To a solution of(12S^12-f^uoro-19-(oxan-2-yΓ^8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo [13.5.2.l³<0¹⁸’²¹]tricosa-l(20),2(23),3,15,17,21-hexaen-9-one 318 (130 mg, 0.302 mmol) in methanol (12 mL) and water (4 mL) was added p-toluenesulfonic acid monohydrate (287 mg, 1.51 mmol). The reaction mixture was stirred at 75 °C for 8 h. Methanol was evaporated under 20 reduced pressure. The resulting solid was trîturated with saturated aqueous NaHCOs solution

436 and filtered then washed with water and dried to afford (12S)-12-fluoro-8,14-dioxa4,5,10,19,20,23-hexaazatetracyclo[ 13.5.2,1^.0^18,21 ]trïcosa-1(20),2(23),3,15,17,2 l-hexaen-9one example 173 as a white solid.

LCMS method F: [M+H]⁺ = 347.3, t_R = 1.82 min

LCMS method G: [M+H]⁺ = 347.3, t_R = 1.75 min ^lH NMR (400 MHz, DMSO) 13.24 (IH, s), 8.16 (IH, s), 7.88-7.84 (IH, m), 7.55-7.51 (IH, m), 7.39 (IH, d, J=2.1 Hz), 7.08 (IH, dd, J=2.4, 9.0 Hz), 4.94-4.43 (6H, m), 4.35-4.24 (IH, m), 3.47-3.42 (IH, m), 3.20-3.11 (1 H, m) ppm.

Example 174 ; ( 12R)-12-fluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[ 13.5.2.

12,5 θ i Mi ] tricosa-1(20),2(23),3,15,17,21 -hexaen-9-one

Example 174 is prepared according to the synthesis route described in general Scheme O.

Préparation of intermediate 319: (12R)-12-fluoro-l 9-(oxan-2-yi)-8,14-dioxa-4,5,l 0,19,20, 23-hexaazatetracyclo[13.5.2. ffo¹⁸·²¹ [tricosa-1(20),2(23),3,15,17,21-hexaen-9-one

To a solution of 3-[2-(2-hydroxyethyl)triazol-4-yl]-l-tetrahydropyran-2-yl-indazol-5-ol (345 mg, 1.05 mmol) and [(2R)-3-(benzyloxycarbonylamino)-2-fluoro-propyl]methanesulfonate (530 mg, 0.482 mmol) in acetonitrile (70 mL) was added césium carbonate (1.03 g, 3.15 mmol).

437

The reaction mixture was stirred at reflux for 8 h. Solvent was removed under reduced pressure. The residue was trîturated with methanol, filtered, rinsed with methanol and dried to afford (l2R)-l2-fluoiO-I94oxan-2-yl)-8,I4-dioxa-4,5,l0,l9,20,23-hexaazatetracyclo[l3.5.2. |2,5_oisgi j_tri_Co_Sa_j (20),2(23),3,15,17,21-hexaen-9-one 319 as a white solid.

LCMS method F: [M+H]* = 431.4, t_R = 2.44 min

Préparation of example 174: (12R)-12-fluoro-S,14-dioxa-4,5,10,19,20,23-hexaazatetra cyclo[13.5.2.1²’^s.0^{18 21}]tricosa-l(20),2(23),3,15,17,21-hexaen-9-one

Toasolutionof(12R)-12-fluoro-19-(oxan-2-yl)-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo [13.5.2.1²’⁵.0^l8’^2,]tricosa-l(20),2(23),3,15,17,21-hexaen-9-one 319 (230 mg, 0.534 mmol) in methanol (24 mL) and water (8 mL) was added p-toluenesulfonic acid monohydrate (508 mg, 2.67 mmol). The reaction mixture was stirred at 65 °C overnight. The solvents were evaporated under reduced pressure. The resulting solid was trîturated with saturated aqueous NaHCOs solution. After tiltration the solid was washed with water and dried to afford (12R)-12-fluoro8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.1²’⁵.0^,8’²¹]tricosa-l(20),2(23),3,l 5,17, 21-hexaen-9-one example 174 as a cream solid.

LCMS method F: [M+H]⁺ = 347.2, t_R = 1.82 min

LCMS method G: [M+H]* = 347.3, t_R = 1.75 min ‘H NMR(400 MHz, DMSO) 13.24 (IH, s), 8.16 (IH, s), 7.89-7.83 (IH, m), 7.57-7.46 (1 H, m), 7.40-7.37 (IH, m), 7.15-7.05 (IH, m), 4.93-4.85 (IH, m), 4.81-4.57 (4H, m), 4.49-4.43 (IH, m), 4.36-4.23 (IH, m), 3.50-3.41 (IH, m), 3.21-3.12 (1 H, m) ppm.

Example 175: 8',14’-Dioxa-10',19',20'-triazaspiro[cycIopropane-l,13’-tetracyclo [13.5,2.

124.0¹⁸’²¹]tricosanel-r(20’),2'(23'),3^,,5’,15'(22’),16'48’(2r)-heptaen-9' one

438

Example 175 is prepared according to the synthesis route described in detail below.

Préparation of intermediate 320: (3-iodo-l-tetrahydropyran-2-yl-indazol-5-yl)3-(dibenzyi aminojpropanoate

To a solution of the 3-(dibenzylamino)propanoic acid hydrochloride (864 mg, 2.83 mmol) in DMF (10 mL) was added M-ethyl-W-diisopropylamine (1.47 mL, 8.50 mmol). The reaction mixture was cooled to 0 °C then X-(3-dimethylaminopropyl)-jV'-ethylcarbodiimide 10 hydrochloride (1.088 g, 5.67 mmol), 1-hydroxybenzotriazole (867 mg, 5.67 mmol) and and the 3-iodo-l-tetrahydropyran-2-yl-indazol-5-ol (1.46 g, 4.25 mmol) were added. The reaction mixture was stirred at RT ovemight. The mixture was poured onto water then extracted with ethyl acetate. The organic layer was successîvely washed with a saturated aqueous NalICOî solution, water, saturated aqueous ammonium chloride solution then brine, dried over 15 anhydrous magnésium sulfate, fîltered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 99/1 to 80/20 as eluent to provide (3-iodo-l-tetrahydropyran-2-yl-indazol-5-yl)-3-(dibenzylamino) propanoate 320 as a coiorless oil.

LCMS method F: [M+H]⁴ = 596.1, t_R = 2.73 min 20

Préparation of intermediate 321: N,N-dibenzyl-3-(3-iodo-l-tetrahydropyran-2-yl-indazol-5yi)oxy-but-3-en-l-amine

To a solution of (3-iodo-l-tetrahydropyran-2-yl-indazol-5-yl)-3-(dibenzylamino)propanoate 320 (1.541 g, 2.59 mmol) in dry THF (15 mL) at 0°C was added dropwise Tebbe reagent (0.5 M solution in toluene) (6.22 mL, 3.11 mmol). The reaction mixture was allowed to reach RT 5 and stirred overnight. The reaction mixture was poured into ice/water then IM aqueous sodium hydroxide solution was added. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnésium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethy! acetate 99/1 to 80/20 as eluent to afford N,N10 dibenzyl-3-(3-iodo-l-tetrahydropyran-2-yl-indazol-5-yl)oxy-but-3-en-l -amine 321 as a colorless oil.

LCMS method F: [M+H]⁺ = 594.1, t_R = 2.65 min

Préparation of intermediate 322: N,N-dibenzvl-3-[3-l3-f[tert-butyl(dimethyl)silyi]oxymethyl( 15 ph enyl]-l-tetrahydropyran-2-yl-indazol-5-yi]oxy-but-3-en-l-amine

To a degassed solution ofA,A-dibenzyl-3-(3-iodo-l-tetrahydropyran-2-yl-indazol-5-yl)oxybut-3-en-l-amine 321 (642 mg, 1.08 mmol), tert-buty l-dimethyl-[[3-(4,4,5,5-tetramethy 1-1,3,2dioxaborolan-2-yl)phenyl]methoxy]silane (487 mg, L40 mmol) and potassium phosphate tribasic (686 mg, 3.24 mmol) in dioxane (5.35 mL) and water (1.50 mL) was added

440 tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.05 mmoi) and 2-dicyclohexylphosphîno2',4',6'-triisopropylbiphenyl (52 mg, O.i l mmol). The reaction mixture was stirred at 1OO°C for l h. The reaction mixture was diluted with water and extracted with ethyi acetate. The organic layer was washed with water, brine, dried over anhydrous magnésium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 85/I5 as eluent to afford AQV-di benzyl-3-[3-[3-[[terr-butyl(dimethyl)silyl]oxymethyl]phenyl]-l-tetrahydropyran-2-yl-indazol5-yl]oxy-but-3-en-l-amine 322 as a slightly yellow oil.

LCMS method J: [M+H]* = 688.6, t_R = 5.42 min

Préparation of intermediate 323: N,N-dibenzyl-2-[l-[3-[3-[[tert-butyl(dimethyl)silyl]oxy methyl]phenyl]-l-tetrahydropyran-2-yl-indazol-5-yl]oxycyclopropyl]ethanamine

Dry DCE (20 mL) was degassed in a sealed tube then diethylzinc (] M in heptane) (2.43 mL, 15 2.43 mmol) and diiodomethane (210 pL, 2.43 mmol) were added at RT. The solution was stirred at RT for 5 min. A solution of A^r,A-dibenzyl-3-[3-[3-[[tert-butyl(dîmethyl)silyl]oxymethyl] phenyl]-l-tetrahydropyran-2-yl-indazoL5-yl]oxy-but-3-en-l-amine 322 (745 mg, l.06 mmol) in dry DCE (20 mL) was added dropwise and the resulting mixture was stirred at RT for 16.5 h. In a separate flask, under argon, dry' DCE (20 mL) was degassed then diethylzinc IM in 20 heptane (2.43 mL, 2.43 mmol) and diiodomethane (210 pL, 2.43 mmol) were added at RT for min. The resulting suspension was added to the initial reaction mixture and allowed to stirred at RT ovemight. The reaction mixture was quenched by pouring onto an aqueous solution of ammonium chloride then extracted with dichloromethane. The combined organic layers were washed with water, dried over anhydrous magnésium sulfate, filtered and concentrated under 25 reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 85/15 as eluent to afford N,N-dibenzyl-2-[l-[3-[3-[[tert21105

441 butyl(dimethyl)silyl]oxymethyl]phenyl]-l-tetrahydropyran-2-yl-indazol-5-yl]oxycyclopropyl] ethanamine 323 as a colorless oil.

LCMS method F: [M+H]⁺ = 702.4, t_R = 3.14 min

Préparation of intermediate 324: 2-[l-[3-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]phenyl]-ltetrahydropyran-2-yl-indazol-S-ylloxycyclopropyl]ethanamine

To a solution of Æ^-di benzyl-2-[1 -[3-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]phenyl]-ltetrahydropyran-2-yl-indazol-5-yl]oxycyc!opropyl]ethanamine 323 (210 mg, 0.30 mmol) in methanol (3 mL) and dichloromethane (3 mL) at RT was added palladium hydroxide on carbon 10 wt. % loading (5 mg). The reaction mixture was stirred under hydrogen atmosphère at RT for 2 h. The reaction mixture was filtered, rinsed with ethyl acetate and evaporated under reduced pressure to afford 2-[l-[3-[3-[[fert-butyl(dimethyl)silyI]oxymethyl]phenyl]-l-tetra hydropyran-2-y]-indazol-5-yl]oxycyclopropyl]ethanamine 324 as a white foam which was used in the next step without any further purification.

LCMS method F: [M+H]⁺ = 522.5, t_R = 2.68 min

Préparation of intermediate 325: benzyl 2-[l-[3-[3-[[tert-butyl(dimethyl)silyl]oxymethyl] phenyl]-l-tetrahydropyran-2-yl-indazol-5-yl]oxycyclopropyl}ethyl]carbamate

442

To a solution of 2-[l-[3-[3-[[/e^butyl(dimethyl)silyl]oxymethyl]phenyl]-l-tetrahydropyran2-yl-îndazol-5-yl]oxycyclopropyl]ethanamine 324 (156 mg, 0.30 mmol) in THF (2 mL) and water (1.5 mL) was added sodium hydrogenocarbonate (28 mg, 0.33 mmol). The suspension 5 was cooled to 0 °C and benzyl chlorofonnate (50 pL, 0.33 mmol) was added dropwise. The reaction mixture was stirred at RT for 2 h. The solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, fîltered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate 100/0 to 85/15 as eluent to 10 afford benzyl A^T-[2-[l-[3-[3-[[/er/-butyl(dimethyi)silyl]oxymethyl]phenyl]-l-tetrahydropyran2-y I-indazol-5-y l]oxycyclopropyl]ethyl] carbamate 325 as a coiorless oil.

LCMS method F: [M+H] = 656.3, t_R = 3.89 min

Préparation of intermediate 326: benzyl N-[2-[l-[3-[3-(hydroxymethyi)phenyfi-l-tetrahydro pyran-2-yl-indazol-5-yl]oxycyelopropyl]ethyl]carbamate

To a solution of benzyl A^r-[2-[l-[3-[3-[[te-r-butyl(dimethyl)silyl]oxymethyl]phenylJ-l-tetra hydropyran-2-yl-indazol-5-yl]oxycyclopropyl]ethyl]carbamate 325 (90 mg, 0.14 mmol) in

THF (1.5 mL) at RT was added dropwise tetrabutylammonium fluoride (1.0 M in THF) (0.15

443 mL, 0.15 mmol). The reaction mixture was stirred at RT ovemight. The reaction mixture was poured into ice water and stirred for 20 min. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over anhydrous magnésium sulfate, filtered and concentrated under reduced pressure to afford benzyl V-[2-[l-[3-[3(hydroxymethyl)phenyl]-l-tetrahydropyran-2-yl-indazol-5-yl]oxycyclopropyl]ethyl] carbamate 326 as a coloriess oil which was used in the next step without further purification. LCMS method J: [M+H]⁺ = 542.4, t_R = 4.57 min

Préparation of intermediate 327: 19’-(oxan-2-yl)-8(Id’-dioxa-lO',19',20'-triazaspirofcyclo propane-1,13 ’-tetracyclof 13,5,2.1^2,6.0^,g2I}tricosane]-l '(20),2'(23),3',5^r,15'(22’),16’, 18 '(21 ’)-heptaen-9 '-one

To a solution of benzyl N-[2-[l-[3-[3-(hydroxymethyl)phenyl]-l-tetrahydropyran-2-yl· indazo 1-5-y l]oxy cyclopropyl] ethyl] carbamate 326 (65 mg, 0.12 mmol) in dry acetonitrile (10 mL) was added at RT potassium hydroxide (33 mg, 0.60 mmol) in one portion. The reaction mixture was stirred at RT for 16 h. The reaction mixture was filtered then rinsed with ethyl acetate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/ethyl acetate 100/0 to 80/20 as eluent to afford 19'(oxan-2-yl)-8',14'-dîoxa-l 0',19',20'-triazaspiro[cyclopropane-l,13'-tetracyclo[l 3.5.2.1^2,6.0¹⁸'] tricosane]-r(20'),2'(23'),3',5', l5^,(22'),l6',18'(2l^,)-heptaen-9'-one 327 as a white solid.

LCMS method J: [M+H]⁺ = 434.4, t_R = 4.43 min

Préparation of example 175: 8',14'-dioxa-10’,19',20'-triazaspirolcyclopropane-l,13’-tetra cyclo[13.5.2.1^z’⁶.0^18îl]tricosanel-l'(20'),2’(23’),3',5',15'(22'),16',18'(21')-heptaen-9’-one

444

To a solution of 19'-(oxan-2-yl)-834'-dioxa-i039',20'-triazaspiro[cyclopropane-I ,l 3'-tetra cyclo[l 3.5.24^0^1^003306)-1^20^(23^,53 5^),1638^21-)-^ 327 (41 mg, 0.095 mmol) in methanol (2 mL) and water (0.3 mL) was addedp-toluenesulfonic acid 5 monohydrate (90 mg, 0.47 mmol). The reaction mixture was stirred at 65°C ovemight. The reaction mixture was diluted with dichloromethane and saturated aqueous NaHCCh solution. After séparation, the aqueous layer was extracted wîth dichloromethane. The combined organic layers were washed brine, dried over anhydrous magnésium sulfate, filtered and evaporated under reduced pressure. The residue was purified by préparative TLC using dichloromethane/ 10 methanol 95/5 as eluent to afford 834’-dioxa-103 9',20'-triazaspiro[cyclopropane-1,13'-tetra cyclo[ 13.5.2.1²’⁶.0^,s’²¹]tricosane]-1^20^(239,3-,53 5'(22'),16',18'(2 T)-heptaen-9'-one example 175 as a white solid.

LCMS method F: [M+H]⁺ = 350.1, t_R = 2.30 min

LCMS method G: [M+H]⁺ = 350.2, t_R = 2.18 min

Ή NMR (400 MHz, DMSO-d6, 80 °C); 12.85 (IH, s), 7.95 (I H, s), 7.86 (IH, d, J = 7.6 Hz), 7.51 (IH, d, J = 2.0 Hz), 7.49-7.40 (3H, m), 7.30-7.27 (IH, m), 6.90 (IH, dd, J= 2.3, 9.1 Hz), 5.27 (2H, s), 3.01-2.95 (2H, m), 2.58-2.52 (2H, m), 1.13-1.11 (2H, m), 0.79-0.75 (2H, m) ppm.

Table 1 provides the example number, the IUPAC name and the general scheme according to 20 which the compounds hâve been made.

Table 1

Example number	IUPAC Name	General scheme
Example 1	8,14-dioxa-4,10,19,20tetraazatetracyclo[l 3.5.2. ULO'^’ltricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme A

445

Example 2	10-methyl-8,14-dioxa-4,10,19,20tetraazatetracyclo[l 3.5.2. l^2,6.0^18,21 ]tricosa1(20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme A
Example 3	4-fluoro-8,l 4-dioxa-10,19,20triazatetracy cio [13.5.2.1²’⁶.0’^8,21 ]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme A
Example 4	8,14-dioxa-10,19,20,23tetraazatetracyclofl 3.5.2. l^2,6.0^l8,2l]tricosa1 (20),2,4,6(23), 15,17,21-heptaen-9-one	Scheme B
Example 5	8,14-dioxa-10,i9,20triazatetracyclof 13.5.2.^^.0^18,21 ]tricosa1(20),2,4,6(23),15,17,21 -heptaen-9-one	Scheme A
Example 6	10-(propan-2-yl)-8,14-dioxa-4,10,19,20tetraazatetracyclofl 3.5.2. l^2,6.0^,8,2l]tricosa- 1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme A
Example 7	8,14-dioxa-5,10,19,20tetraazatetracyclo[l 3.5.2. l^2,6.0’^8,21 ]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme B
Example 8	4-methoxy-8,14-dioxa-10,19,20trîazatetracyclo[13.5.2.1²^0^l8,2l]tricosal(20),2,4,6(23),15,17,21-heptaen-9-one	Scheme C
Example 9	4-bromo-8,14-dioxa-10,19,20triazatetracyclo[l3.5.2.1²’⁶.0^,8’^2l]tricosal(20),2,4,6(23),15,17,21-heptaen-9-one	Scheme D
Example 10	5-fluoro-8,14-dioxa-10,19,20triazatetracy cio [ 13.5.2.1²’⁶.0^,s,2,]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme E
Example 1 l	5-methyl-8,14-dioxa-10,l9,20triazatetracyclo[l3.5.2.1^2,6.0'^8>2,]tncosal(20),2,4,6(23),15,17,21-heptaen-9-one	Scheme F
Example 12	4-(pyrrolidin-l-yl)-8,14-dioxa-l 0,19,20triazatetracy cio [ ï 3.5.2.1^{2 6}.0^{1 s}’²¹ ] tri c o s a1 (20),2,4,6(23),] 5,17,21-heptaen-9-one	Scheme C

446

Example 13	4-[4-(propan-2-yl)piperazin-l-yl]-8,14-dioxa- 10,19,20-triazatetracyclo[ 13.5.2. l^2,6.0^18,2'{tricosa- 1 (20),2,4,6(23), 15,17,21-heptaen-9-one	Scheme C
Example 14	4-{2-o xa-6-azaspiro[3.4]octan-6-y 1)-8,14-dioxa- 10,19,20-triazatetracyclo[ 13.5.2. l²’⁶.0¹⁸’^2,]tricosa] (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C
Example 15	4-[4-(oxetan-3-yl)piperazin-l-yI]-8,14-dioxa- 10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^,8,21]tricosa- 1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C
Example 16	4-(morpholin-4-y 1)-8,14-dioxa-l 0,19,20triazatetracyclofl 3.5.2.1²·⁶.0^18,21 ]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C
Example 17	4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-8,14dîoxa-10,19,20-triazatetracyclo[ 13.5.2. l^2,6.0^t8,21] tricosa-1 (20),2,4,6(23),15,17,21 -heptaen-9-one	Scheme C
Example 18	4-methyl-8,l 4-dioxa-l 0,19,20triazatetracyclo[l 3.5.2.1²-⁶.0^18,21 ] tri cosa1 (20),2,4,6(23), 15,17,2 l-heptaen-9-one	Scheme F
Example 19	5-methoxy-8,14-dioxa-10,19,20triazatetracyclo[l 3.5.2. l^2,6.0^18,2l]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme F
Example 20	4-(4,4-difluoropiperidin-1 -yl)-8,l 4-dioxa- 10,19,20-triazatetracyclo[l 3.5.2. l²’⁶.0^l8’²¹]tricosa- 1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C
Example 21	4-(3,3-difluoropyrrolîdin-l-yl)-8,14-dioxa- 10,19,20-triazatetracyclo[ 13.5.2. l²’⁶.0¹⁸’²¹]tricosa- 1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C
Example 22	7-methyl-8,l 4-dioxa-10,19,20triazatetracyclo[l 3.5.2.1²’⁶.0^,8,21]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C
Example 23	4-[4-(2-methoxyethyl)piperidin-l -yl]-8,14-dioxa10,19,20-triazatetracyclo[ 13.5.2.1^2,6.0^18,2 'jtricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C

447

Example 24	9, ] 4-dioxa-H, 19,20triazatetracyclo [13.5.2. l²’⁶.0¹⁸’²¹]tricosa1(20),2,4,6(23), 15,17,21 -heptaen-10-one	Scheme C
Example 25	4-[(3R)-3-hydroxypyrrolidin-l-yl]-8,14*dioxa- 10,19,20-triazatetracyclo[l 3.5.2.1^2j6.0^18,2']tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C
Example 26	4-[(2-methoxyethyl)(rnethyl)amino]-8,14-dioxa- 10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^,8’²¹]tricosa- 1 (20),2,4,6(23),15,17,21-heptaen-9-one	Scheme C
Example 27	4-chloro-8,14-dioxa-10,19,20triazatetracyclo [ I 3.5.2.1^8,2'jtrîcosa1(20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme F
Example 28	4-fluoro-5-methyl-8,14-dioxa-10,19,20triazatetracyclofl 3.5.2. l²’⁶.0^18,21]trïcosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme G
Example 29	4,5-difluoro-8,14-dioxa-10,19,20triazatetracyclo [13. 5.2.1 ^2,6.0 ^18,21 ]tricosa1 (20),2,4,6(23),15,17,21 -heptaen-9-one	Scheme F
Example 30	5-bromo-8,14-dioxa-10,19,20triazatetracyclo [13.5.2.1^2,6.0^18,21 ]tricosa1(20),2,4,6(23),15,17,21-heptaen-9-one	Scheme C
Example 31	4-(4-methylpiperazin-1 -y l)-8,14-dioxa-10,19,20triazatetracyclo [ 13.5.2.1^2,6.0^18,21 ] tr i cosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C
Example 32	4-(3-methoxyazetidin- i-yl)-8,14-dîoxa-10,]9,20triazatetracyclo[13.5.2.1²’⁶.0^,8’²¹]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C
Example 33	1 - [ 9-oxo-8,14-dioxa- i 0,19,20-trîazatetra cyclo[l 3.5.2.1²’⁶.0¹⁸’²¹]trîcosa-1 (20),2,4,6(23), 15,17,21 -heptaen-4-yl}piperidine-4-carbonitrile	Scheme C
Example 34	4-[4-(pyrrolidin-]-yl)piperîdin-]-yl]-8,14-dioxa- 10,19,20-trîazatetracyclo[l 3.5.2. l^2,90^18,2!]tricosa- 1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C

448

Example 35	4-(azetidin-1 -yl)-8,14-dîoxa-l 0,19,20triazatetracyclo[ 13.5.2.1^2,6.0^18,21 ]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C
Example 36	4-(piperid in-1 -y 1)-8,14-dioxa-10,19,20triazatetracyclo [l3.5.2.1²’⁶.0^l8,2i ]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme A
Example 37	4-(2,5-dihydrofuran-3-yl)-8,l 4-dioxa-10,19,20triazatetracyclo[ 13.5.2.1^.0^18,21 ]tricosal (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme A
Example 38	4-[4-(morpholin-4-yl)piperidin-l-yl]-8,14-dioxa- 10,19,20-triazatetracyclo[13.5.2.1^2,6.0^18,21]tricosa- 1(20),2,4,6(23),15,17,2 ! -heptaen-9-one	Scheme C
Example 39	4-(l-methyl-l,2,3,6-tetrahydropyridin-4-yl)-8,14dioxa-10,19,20-triazaletracyclo[13.5.2.1²’⁶.0^18,2!] tricosa-1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme A
Example 40	4-[(2S,5S)-2,5-dimethylmorpholin-4-yl]-8,14dioxa-10,19,20-triazatetracyclo [13.5.2.1^2,6.0^18,21 ] tricosa-1(20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C
Example 41	4-[(morpholin-4-yl)methyl]-8,14-dioxa-10,19,20triazatetracyclo[l 3.5.2. i²’⁶.0¹⁸’²¹]trîcosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C
Example 42	4-[(pyrrolidin-l -yl)methyl]-8,l 4-dioxa-10,19,20triazatetracyclo [13.5.2.1^2,6.0^18,21]tricosa1 (20),2,4,6(23),15,17,21 -heptaen-9-one	Scheme C
Example 43	4-[(py rro lid i η-1-y l)methy 1]-8,14-dioxa-10,19,20triazatetracyclo [13.5.2.1²’⁶.0^18,21 ]tricosa1(20),2,4,6(23), 15,17,2 l-heptaen-9-one	Scheme C
Example 44	4-[(4-methylpiperazin-l-yl)methyl]-8,14-dioxa- 10,19,20-triazatetracyclo[13.5.2.1^2>6.0¹⁸’²¹]tricosa- 1 (20),2,4,6(23),15,17,21 -heptaen-9-one	Scheme C
Example 45	5-(morpholin-4-yl)-8,14-dioxa-10,19,20triazatetracyclo [ 13.5.2.1²A 0¹¹ ]tri cosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C

449

Example 46	4-[4-(2-methoxyethyl)piperazin-l-yl]-8,l4-dioxa10,19,20-triazatetracyclo[13.5.2.1²’⁶.0¹⁸’^2l]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme A
Example 47	4-(diethylamino)-8,14-dioxa-l 0,19,20triazatetracyclo [ 13.5.2.1^2,6.0'^8,21 Jtricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme A
Example 48	4-cyclopropyl-8,14-dîoxa-l 0,19,20trîazatetracy c 1 o[13.5.2.]²’⁶.0¹⁸’²']tricosal(20),2,4,6(23),15,17,21-heptaen-9-one	Scheme C
Example 49	5-(4-methylpiperazin-l -yl)-8,l 4-dioxa-10,19,20trîazatetracyclo[l 3.5.2. l²’⁶.0^l8,2lJtricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C
Example 50	13-methyl-8,14-dioxa-10,19,20triazatetracycloj 13.5.2. l^2,6.0'⁸=²'Jtricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C
Example 51	8,14-dioxa-4,5,10,19,20pentaazatetracyclo[ 13.5.2. l²’⁵.0¹⁸’²']tricosa1 (20),2(23),3,15(22), 16,18(21 )-hexaen-9-one	Scheme C
Example 52	4-[methyl(oxetan-3-yl)ammoJ-8,14-dioxa- 10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^,8’^2l]tricosa- 1(20),2,4,6(23),15,17,21 -heptaen-9-one	Scheme C
Example 53	4~[(dimethylamino)methyl]-8,l 4-dioxa-10,19,20triazatetracyclo [13.5.2.1²⁶.0^18,21 Jtricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C
Example 54	4,10-dîmethyl-8,14-dioxa-10,19,20trîazatetracycîofl 3.5.2.1^2,6.0^18,2']tricosa1 (20),2,4,6(23),15,17,21 -heptaen-9-one	Scheme F
Example 55	4-(propan-2-yloxy)-8,14-dioxa-10,19,20triazatetracycio[13.5.2.1²’⁶.0'⁸’²']tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme F
Example 56	4-f1uoro-7-methyl-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.1^2,6.0^l8’²¹Jtricosa1(20),2,4,6(23),15,17,21-heptaen-9-one	Scheme A

450

Example 57	4-[ l-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]8,14-dioxa-10,19,20- triazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹]trîcosa1(20),2,4,6(23),15,17,21 -heptaen-9-one	Scheme C
Example 58	4-(3-methylpiperidin-l -yl)-8,14-dioxa-10,19,20triazatetracyclo[l 3.5.2. l^2,6.0'^8,21 ]tricosa1 (20),2,4,6(23),15,17,21 -heptaen-9-one	Scheme C
Example 59	4-[(3S)-3-hydroxypyrrolidin-l-yl]-8,14-dioxa- 10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^l8’^2l]tricosa- 1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C
Example 60	4-fluoro-8_t14-dîoxa-10,19,20triazapentacyclo[l 3.5.2.1^2>6. l^7JI).0¹⁸’²¹]tetracosa1 (20),2(24),3,5,15(22), 16,18(21 )-heptaen-9-one	Synthesis described in details
Example 61	4-(oxolan-3-yl)-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.1²’⁶.0^,s’^2,]tricosal(20),2,4,6(23),15,17,21-heptaen-9-one	Scheme A
Example 62	(13S)-13-methyl-8,14-dioxa-10,19,20triazatetracyclo[13.5.2. l²’⁶.0¹⁸’²¹]tricosa1 (20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one	Scheme C
Example 63	(13R)-13-methyl-8,14-dioxa-l 0,19,20- triazatetracyclo[13.5.2.1^2,6.0^,8’^2,]tricosa1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Scheme C
Example 64	4-( 1 -methyl-1 H-pyrazol-3-yl)-8,14-dioxa- ] 0,19,20-triazatetracy cio [ 13.5.2.1^2,6.0^18,21 ] tricosa1 (20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one	Scheme C
Example 65	(7S)-7-methyl-8,l 4-dioxa-10,19,20triazatetracyc lo [ 13.5.2.1^2,6.0^18,21 ]tricosa- 1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Scheme C
Example 66	4-[2-(morpholin-4-yl)ethoxy]-8,14-dioxa- 10,19,20-triazatetracyclo[13.5.2.]^2,6.0^,8,2l]tricosa1(20), 2(23),3,5,15(22), 16,18(2 l)-heptaen-9-one	Scheme F

451

Example 67	4-(2-methoxyethyl)-8,14-dioxa-10,19,20triazatetracyclo [ l 3.5.2.I²’⁶.0^{18,2 !} ]tricosa- 1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Scheme A
Example 68	(7R)-7-methy 1-8,14-dioxa-10,19,20triazatetracyclo [ 13.5.2.1^.0^18,2 ^tricosa] (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Scheme C
Example 69	5-cyclopropy 1-8,14-dioxa-10,19,20triazatetracyclo [ 13.5.2. 1^2,6.0^18,21]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C
Example 70	4-(2-methoxy ethoxy)-8,14-dioxa-10,19,20triazatetracyclo[ 13.5.2.1^.0^18,21 ]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme F
Example 71	4-fluoro-l 3-methy 1-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.1^2,6.0^18,21]tricosa1 (20),2,4,6(23),15,17,2 l-heptaen-9-one	Scheme C
Example 72	11-methy 1-8,14-dioxa-l 0,19,20triazatetracy cio [13.5.2.1²⁶.0^18,21 ]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C
Example 73	4-(3-oxomorpholin-4-yl)-8,14-dioxa-10,19,20triazatetracyclofl 3.5.2.1^2,6.0^18,21 ]tricosa- 1 (20),2(23),3,5, L 5 (22), 16,18(21 )-heptaen-9-one	Scheme C
Example 74	4-(2-oxopyrrolidin-l-yl)-8,14-dioxa-10,19,20triazatetracyclofl 3.5.2.1^2,6.0^18,21 ]tricosa- 1(20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Scheme C
Example 75	5-(2-oxopyrrolidin-1 -yl)-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.1^2,6.0¹⁸²¹]tricosa- 1(20),2(23),3,5,15(22), 16,18(2 l)-heptaen-9-one	Scheme C
Example 76	4-(2-methy lpyrrolidin-1 -yl)-8,14-dioxa-l 0,19,20triazatetracyclo[ 13.5.2.1^2,6.0^18,21 Jtricosa- 1 (20),2(23),3,5,15 (22), 16,1 8(21 )-heptaen-9-one	Scheme C
Example 77	2- {9-oxo-8,14-dioxa-10,19,20-triazatetracyclo [I3.5.2.l^2,6.0¹⁸’²¹]tricosa-l(20),2(23),3,5,l5(22), 16,18(21 )-heptaen-4-yl] acetonitrile	Scheme C

452

Example 78	( 11 R) or ( 11 S)-11 -methyl-8,14-dioxa-10,19,20triazatetracyclo [ 13.5.2.1² A 0¹⁸·²¹ ]tricosa- 1 (20),2(23),3,5,15(22), 16, i 8(21 )-heptaen-9-one	Scheme C
Example 79	( 11 R) or (11 S)-l 1 -methyl-8,14-dioxa-10,19,20triazatetracyclo [ 13.5.2.1² AO^18,21 Jtricosa- 1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Scheme C
Example 80	4-ethynyl-8,14-dioxa-10,19,20triazatetracyclo[ 13.5.2.Ι²Αθ’^8,21 Jtricosal (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Scheme C
Example 81	4-(piperazin-1 -yl)-8,14-dioxa-10,19,20triazatetracyclof 13.5.2.1²A0^18i2I]tricosa- 1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Scheme A
Example 82	4-(l ,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa10,19,20-triazatetracycio[ 13.5.2.1²A0^l8,21]tricosa1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Scheme A
Example 83	1 l-(methoxymethyl)-8,14-dioxa-10,19,20triazatetracyclo[l 3.5.2.1²Αθ'^8,21 ]tricosa- 1 (20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one	Scheme C
Example 84	8J4-dioxa-5,10,19,20,23pentaazatetracyclo[ 13.5.2.1²A0¹⁸’²’]tricosa1(20),2(23),3,15(22), 16,18(2 l)-hexaen-9-one	Scheme K
Example 85	1 i -methyl-8,14-dioxa-4,5,10, ! 9,20pentaazatetracyclo[ 13.5.2.1²A0’⁸²'jtrîcosa1 (20),2(23),3,15(22),16,1 8(21 )-hexaen-9-one	Scheme C
Example 86	l2-methyl-8, ]4-dioxa-10,19,20triazatetracyclof i 3.5.2. PAO^18,21 ]tricosa1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Scheme E
Example 87	1 l-ethyl-8,14-dîoxa-10,19,20triazatetracyclo [ 13.5.2.1² A0^18,21 ]tricosa1 (20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one	Scheme E
Example 88	4-fluoro-5,7-dimethyl-8,14-dioxa-10,19,20triazatetracyclo [ 13.5.2.1² A0^{! 8,21} ]tricosa- 1 (20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one	Scheme A

453

Example 89	4-fluoro-5-methoxy-7-methyl-8,!4-dioxa- I0,19,20-triazatetracyclo[13.5.2.1²’⁶.0^,8’^2,]tricosa1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Scheme A
Example 90	5-fluoro-4,7-dimethyl-8,14-dioxa-10,19,20triazatetracyclo[ 13.5.2. l^2,6.0’^8,21 Jtricosa1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Scheme A
Example 91	8,14-dioxa-10,19,20triazapentacyclo[13.5.2.1^2,6.] ⁷’¹⁰.0¹⁸’²¹]tetracosa1 (20),2(24),3,5,15(22),16,18(21 )-heptaen-9-one	Synthesis described in details
Example 92	13-methyl-8,l 4-dioxa-l 0,19,20,23tetraazatetracyclo[13.5.2.1^2,6.0¹⁸’^2l]tricosa- 1 (20),2(23),3,5,15 (22), 16,18(21 )-heptaen-9-one	Scheme B
Example 93	12-methy 1-8,14-dioxa-4,5,10,19,20pentaazatetracyc lo[ 13.5.2.1^2,5.0^18,21 ]tricosa1 (20),2(23),3,15(22), 16,18(2 l)-hexaen-9-one	Scheme C
Example 94	7-methyl-8,14-dioxa-4,5,10,19,20pentaazatetracyclo[ 13.5.2. ]²+.o^18,21]tricosa1 (20),2(23),3,15(22),16,18(21 )-hexaen-9-one	Scheme C
Example 95	5-fluoro-4-methoxy-7-methyl-8,I4-dioxa- 10,I9,20-triazatetracyclo[13.5.2.1²’⁶.0^l82l]tricosa- 1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Scheme A
Example 96	(7R, 13R)-7,13-di methy 1-8,1 4-dioxa-10,19,20triazatetracyclo[l 3.5.2. l^2,0.0^,8’²¹]tricosa- 1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Scheme C
Example 97	( 13R)-13-methy 1-8,14-dioxa-4,5,10,19,20pentaazatetracyclo[l 3.5.2.1²·⁵.0^18,21 ]tricosa1 (20),2(23),3,15 J 7,21 -hexaen-9-one	Scheme C
Example 98	8,15-dioxa-4,l 0,20.21 -tetraazapentacyclo [14.5.2.l²’⁶.l¹⁰’¹³.0^,9,22]pentacosa- 1(21),2(25),3,5,16(23),17,19(22)-heptaen-9-one	Scheme N
Example 99	8,14~dioxa-5,10,19,20tetraazatetracyclo[13.5.2.1^2,5.0^,8’^2,]tricosa1(20),2(23),3,15(22), 16,18(21 )-hexaen-9-one	Scheme J

454

Example 100	(I3R) or (13S)-4-fluoro-l3-methyl-8,l4-dioxa- !0,19,20-triazatetracyclo[13.5.2.1^2,6.0^,8,2l]tricosa1(20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one	Scheme C
Example 101	(13R) or (13S)-4-fluoro-l3-methyl-8,l4-dioxa- 10,19,20-triazatetracyclo[l3.5.2.1^2,6.0^l8,21]tricosa1 (20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one	Scheme C
Example 102	(13R)-l3-methyl-8,14-dioxa-4,l 0,19,20- tetraazatetracyclo[ 13.5.2 J ^2,6.0^18,21 ]tricosa- 1 (20),2(23),3,5,15(22), 16,18(21)-heptaen-9-one	Scheme C
Example 103	6-cyclopropyl-8,14-dioxa-4,5,10,19,20pentaazatetracyclofl 3.5.2. ]^2,5.0^18,2'jtricosa1 (20),2(23),3,15(22), 16,18(21 )-hexaen-9-one	Scheme B
Example 104	7-ethy 1-8,14-dioxa-10,19,20triazatetracyclo[l 3.5.2. l^2,6.0^,8,2']tricosa1 (20),2,4,6(23),15,17,21 -heptaen-9-one	Scheme G
Example 105	(l3R)-l3-methyl-8,14-dioxa-5,l0,l9,20,23pentaazatetracyclo[l 3.5.2. l^2,6.0'^8,21 ]trîcosa1(20),2,4,6(23), 15,17,21-heptaen-9-one	Scheme B
Example 106	(7R, 13R)-4-fluoro-7,13-dimethyl-8,14-dioxa- 10,19,20-triazatetracyclo[13.5.2.1^2,6.0'⁸’²¹]tricosa1(20),2,4,6(23),15,17,21-heptaen-9-one	Scheme C
Example 107	7-methy 1-8,14-dioxa-4,l 0,19,20tetraazatetracyclo[l 3.5.2. l^2,6.0^18,2l]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme H
Example 108	(7R)- or (7S)-4-fiuoro-7-methyl-8,14-dioxa- 10,19,20-triazatetracyclo[ 13.5.2.1²⁶.0^18,21 ]tricosa- 1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme A
Example 109	(7R.)- or (7S)-4-fluoro-7-methy 1-8,14-dioxa- 10,19,20-triazatetracyclo[ 13.5.2.1^2,6.0^18,21 Jtricosa- 1 (20),2,4,6(23),15,17,21 -heptaen-9-one	Scheme A
Example 110	6-methyl-8,14-dioxa-4,5,10,19,20pentaazatetracyclofl 3.5.2.1²⁵.0'^8,21 jtricosa1 (20),2(23),3,15,17,21 -hexaen-9-one	Scheme B

455

Example 111	7-methyl-8,14-dioxa-10,19,20,23tetraazatetracyclo[l 3.5.2. 1^2j6.0^,8j21 ]trîcosa1 (20),2,4,6(23), i 5,17,21 -heptaen-9-one	Scheme H
Example 112	6-(propan-2-yl)-8,14-dioxa-4,5,10,19,20pentaazatetracyclo( 13.5.2.1^2,5.0’^8,21 ]tricosa1(20),2(23), 3,15(22), 16,18(2 l)-hexaen-9-one	Scheme B
Example 113	(13R)-7J3-dimethyl-8,I4-dioxa-4,5,10,19,20pentaazatetracyclo(l 3.5.2. l²’⁵.0'^8,21 ]tricosa1(20),2(23),3,15(22), 16,18(2 l)-hexaen-9-one	Scheme C
Example 114	(13R)-13-methyl-8,14-dioxa-10,19,20,23tetraazatetracyclo[ 13.5.2. l²’⁶.0^l8’^2l]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme K
Example 115	(7R)- or (7S)-7-ethyl-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.1²’⁶.0^,8’^2,]tricosa1 (20),2,4,6(23),15,17,21-heptaen-9-one	Scheme G
Example 116	(7R)- or (7S)-7-ethyl-8,14-dioxa-10,19,20triazatetracyclo[13.5.2.1²’⁶.0^,8’^2,]tricosal(20),2,4,6(23),15,17,21-heptaen-9-one	Scheme G
Example 117	( 13R)-13-methyl-8,14-dioxa-5,10,19,20tetraazatetracyclo[ 13.5.2.l²⁶.0¹⁸²¹]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme K
Example 118	6-(oxan-4-y 1)-8,14-dioxa-4,5,10,19,20pentaazatetracyclo[ 13.5.2.1²’⁵.0^l8,21]tricosai (20),2(23),3,15,17,21 -hexaen-9-one	Scheme B
Example 119	4-ethyi-8,14-dioxa-5,10,19,20,23pentaazatetracyclo[l 3.5.2.1^2,5.0^l8-²¹]tricosa1 (20),2(23), 15,17,21 -pentaen-9-one	Scheme B
Example 120	( l3R)-23-fluoro- 13-methyl-8,14-dioxa-10,19,20triazatetracyclo [ 13.5.2.1^2,6.0^18,21 ]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C
Example 121	9,14-dioxa-4,5,11,19,20pentaazatetracyclo[ 13.5.2.1²’⁵.0^18,21]tricosa1 (20),2(23),3,15,17,21 -hexaen-10-one	Scheme A

456

Example 122	4-ethyl-8,14-dioxa-5,10,19,20,23pentaazatetracyclo[13.5.2.I^2,5.0^l8,2l]tricosa1 (20),2(23),3,15,17,21 -hexaen-9-one	Scheme B
Example 123	3,9,15-trioxa-4,l 1,20,21tetraazatetracyclo[14.5.2.1²’⁵.0^l9,22]tetracosa1 (21 ),2(24),4,16,18,22-hexaen-10-one	Scheme M
Example 124	(13R)~ 16-fluoro-13-methy 1-8,14-dîoxa4,10,19,20-tetraazatetracyc 1 o[ 13.5.2.1^2,6.0^18,21 ] tricosa-1 (20),2,4,6(23),15,17,21 -heptaen-9-one	Scheme C
Example 125	(13R)-4-chloro-l 3-methy 1-8,14-dioxa-l 0,19,20, 23-tetraazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹] tricosa1(20),2(23),3,5,15(22), 16,18(2 l)-heptaen-9-one	Scheme K
Example 126	8,14-dioxa-2,4,10,19,20pentaazatetracyc lo [ 13.5.2.1^2,5.0^18,21 ]trîcosa1 (20),3,5(23),15(22), 16,18(21 )-hexaen-9-one	Scheme A
Example 127	(13R)-4-methoxy-l 3-methy 1-8,14-dioxa-10,19,20, 23-tetraazatetracyclo[l 3.5.2.1²-⁶.0^18,21 Jtricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme K
Example 128	(13R)-13-methyl-9-oxo-8,l 4-dioxa-10,19,20triazatetracyclo[13.5.2.1²A0’^8>2,]tricosal(20),2,4,6(23),15,17,21-heptaene-5-carbonitrile	Scheme B
Example 129	(13R)-13-methy l-4-(pyrrolidin-l-y l)-8,14-dioxa- 5,10,19,20,23-pentaazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹] tricosa-1 (20),2,4,6(23),15,17,21 -heptaen-9-one	Synthesis described in details
Example 130	(7R, 13R)- or (7S, 13R)-7,13-dimethyl-8,14-dioxa- 5,10,19,20,23-pentaazatetracyclo[13.5.2.1^2,6.0¹⁸²¹] tricosa-1 (20),2,4,6(23),15,17,21-heptaen-9-one	Synthesis described in details
Example 131	(7R,13R)- or (7S, 13R)-7,I3-dimethyl-8,14-dioxa- 5,10,19,20,23-pentaazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹] tricosa-1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme K
Example 132	(13R)-16-fluoro-l 3-methy 1-8,14-dioxa-10,19,20triazatetracyclo[l 3.5.2. l^2,6.0^18,21 Jtricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme C

457

Example 133	(l 3R)-13-methy 1-8,14-dioxa-4,l 0,19,20,23pentaazatetracyclo[l 3.5.2. l²’⁶.0^18,21]trîcosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme K
Example 134	8,14-dioxa-4-thia-10,19,20,23tetraazatetracyc lo [ 13.5.2.1^2,5.0^18,21 ]tricosa1 (20),2,5(23), 15,17,21 -hexaen-9-one	Scheme L
Example 135	8,14-dioxa-3-thîa-10,19,20,23tetraazatetracy c lo [ 13.5.2.1^2,5.0^18,21 ]tricosa1 (20),2(23),4,15,17,21 -hexaen-9-one	Scheme L
Example 136	(7R,13R)-7,13-dimethy 1-8,14-dioxa-10,19,20,23tetraazatetracyclo[ 13.5.2. l^2,6.0¹⁸⁼²¹ ] tri cosa1 (20),2,4,6(23),15,17,21 -heptaen-9-one	Scheme K
Example 137	(l3R)-4-[(3R)-3-methoxypyrrolidin-l-yl]-13methyl-8,14-dioxa-5,l 0,19,20,23pentaazatetracyc lo[ 13.5.2.1²⁼⁶.0^l8,2l]tricosal(20),2,4,6(23),15,17,21-heptaen-9-one	Scheme K
Example 138	(13R)-16-chloro-l 3-methy 1-8,14-dioxa-l 0,19,20triazatetracyclo [ 13.5.2.1^2,6.0¹⁸ ’²¹ ] tr i co sa ] (20),2,4,6(23),15,17,21 -heptaen-9-one	Scheme K
Example 139	( 13R)-13,16-dimethyl-8,14-dioxa-l 0,19,20triazatetracyclof 13.5.2. l^2,6.0^18,21 ]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme K
Example 140	( 13R)-13-methy 1-8,14-dioxa-3,l 0,19,20,23pentaazatetracyclo[ 13.5.2.1^2,6.0^18,21 ]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one	Scheme B
Example 141	8-oxa-10,14,19,20-tetraazatetracyclo [ 13.5.2.1^2,6.0^18,21]tricosa- 1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Scheme I
Example 142	8-oxa-10,19,20-triazatetracyclo [I3.5.2.l^2,6.0^l8,21]tricosa- 1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Synthesis described în details

458

Example 143	(13 R)-5-methoxy-13-methy 1-8,14-dioxa4,10,19,20-tetraazatetracyclo [13.5.2.1² AO^18,21 ] trîcosa-1(20),2,4,6(23), 15, i 7,21 -heptaen-9-one	Scheme O
Example 144	( 13 R)-13-methy 1-8,14-dioxa-4,10,19,20tetraazatetracyclo[13.5.2.1²’⁶.0^18,2,]tricosal(20),2,6(23),15,17,21-hexaene-5,9-dione	Demethyla tion of example 143
Example 145	4-methyl-8,14-dioxa-3,4,10,19,20pentaazatetracyclo[13.5.2.1^2,5.0^I8’²¹]tricosa1(20),2,5(23),15(22),16,18(21 )-hexaen-9-one	Scheme L
Example 146	(13 R)-16-fluoro-l 3-methyl-8,14-dioxa- 10,19,20,2 3-tetraazatetracy cio [ 13.5.2.1² AO^18,21 ] trîcosa-1 (20),2,4,6(23),15,17,21 -heptaen-9-one	Scheme O
Example 147	7,13-dioxa-4-thia-9,18,19,22tetraazatetracyclo[12.5.2.1²A0^17,2°]docosa1(19),2,5(22),14(21),15,17(20)-hexaen-8-one	Scheme L
Example 148	(l3R)-4,13-dimethyl-8,l4-dioxa-5,l 0,19,20,23pentaazatetracyclo[l 3.5.2.Ι²Αθ’ ^8,21]tricosa1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Scheme O
Example 149	8,14-dioxa-23-thia-4,10,19,20tetraazatetracyclofl 3.5.2.1²A0^18,2,]tricosa1 (20),2,4, i 5(22), 16,18(21 )-hexaen-9-one	Scheme L
Example 150	(7S,13R)-7,13-dimethyl-8,14-dioxa-]0,19,20,23tetraazatetracyclo[13.5.2.1²A0^,8-^2l]tricosa1(20),2(23),3,5,15(22), 16,18(21)-heptaen-9-one	Scheme K
Example 151	(13R)-13-methy l-9-oxo-8,14-dioxa-5,10,19,20tetraazatetracyclo[l 3.5.2. l²A0^18,21]tricosa-1(20), 2(23),3,15(22), 16,18(21 )-hexaene-4-carbonitrile	Scheme O
Example 152	12,12-difluoro-8,14-dioxa-10,19,20triazatetracy cio [ 13.5.2.1² A 0^18,21 ] trîco sal (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Scheme C

459

Example 153	( 13R)-17-fluoro-l 3-methy 1-8,14-dioxa-10,19,20triazatetracyclo [13.5.2.1^.0^18,21 ]tricosa- 1 (20),2(23),3,5,15(22),16,18(2 l)-heptaen-9-one	Scheme C
Example 154	(7S,13R)-7,l3-dimethyl-8,14-dioxa-4,10,19, 20,23-pentaazatetracyclo[l 3.5.2. PAO¹⁸²’] tricosa1 (20),2(23),3,5,15(22), 16,18(21 )-îieptaen-9-one	Synthesis described in details
Example I55	(7R, 13R)-7,13-dimethy 1-8,14-dioxa-4,10,19,20, 23-pentaazatetracyclo[13.5.2.1²Αθ¹⁸²¹] trîcosa1 (20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one	Scheme K
Example 156	(13S)-13-methy 1-8,14-dioxa-4,10,19,20,23pentaazatetracyclo[13.5.2.1^2,6.0^18,21 ]tricosa- 1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Scheme K
Example I57	( 13R)-13-methy 1-8,14-dioxa-10,19,20,22tetraazatetracyclo[ 13.5.2.1²’⁶.0^18,21 ]tricosa1 (20),2(23),3,5,15,17,21 -heptaen-9-one	Scheme C
Example 158	( 12R)-4,12-dimethy 1-7,13-dioxa-4,9,18,19,22pentaazatetracyclo[ 12.5.2.I^2,5.O^17,20]docosa1 ( 19),2,5(22), 14(21 ), 15,17(20)-hexaen-8-one	Scheme K
Example 159	(13R)-13-methyl-8,14-dioxa-4,5,10,19,20,23· hexaazatetracyclo[13.5.2.1²’⁵.0^18,21 ]tricosa1 (20),2(23),3,15,17,21 -hexaen-9-one	Scheme 0
Example 160	( ] 3 R)-13-methyl-8,14-dioxa-23-thia-4,l 0,19,20tetraazatetracyclo[13.5.2.1^2,5.0^I821]tricosa1(20),2,4,15,17,21 -hexaen-9-one	Scheme L
Example I6l	(13R)-4,13-dimethy 1-8,14-dioxa-4,l 0,19,20,23pentaazatetracyclo[l 3.5.2.1²Αθ^18,21 ]tricosa1 (20),2,5(23), 15(22),16,18(21 )-hexaen-9-one	Scheme L
Example 162	(13R)-13-methyl-8,l4-dioxa-10,16,19,20- tetraazatetracyclo[l 3.5.2. l^2,6.0^l82l]tricosa1(20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Synthesis described in details

460

Example 163	14-methyl-8-oxa-10,14,19,20- tetraazatetracyclo[l 3.5.2. I^.O’^^tricosa1 (20),2(23),3,5,15,17,21 -heptaen-9-one	Synthesis described in details
Example 164	( 13R)-13-methyl-8,14-dioxa-4,10,19,20,22pentaazatetracyclo[13.5.2. l^2,6.0’^8,21 ]tricosa1(20),2(23),3,5,15,17,21 -heptaen-9-one	Synthesis described in details
Example 165	(13R)-13-methyl-8,14-dioxa-10,17,19,20- tetraazatetracyclof 13.5.2. l²’⁶.0¹⁸’²¹]tricosa1(20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Synthesis described in details
Example 166	8, !4-dioxa-4,5,10,19,20,23-hexaazatetracyclo [13.5.2.1²'⁵.0^l8,21]tricosa-l(20),2(23),3,15(22), 16,18(21 )-hexaen-9-one	Scheme K
Example 167	12,12-difluoro-8,14-dioxa-4,5,10,19,20,23hexaazatetracyclofl 3.5.2. l^2,5.0^i8>21]tricosa- 1 (20),2(23),3,15(22), 16,18(21 )-hexaen-9-one	Scheme K
Example 168	( 12R)-12-fluoro-8,l 4-dioxa-10,19,20triazatetracyclo[l 3.5.2.1^2,6.0^ls,2l]tricosa1 (20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one	Scheme E
Example 169	(12S)-12-fluoro-8,l 4-dioxa-10,19,20triazatetracyclo[l 3.5.2. l²’⁶.0’^8,2,]tricosal (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Scheme E
Example 170	12,12-difluoro-8,14-dioxa-4,10,19,20,23pentaazatetracyclo [ 13.5.2.1²’⁶.0^l8-^2,]tricosa1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one	Scheme K
Example 171	( 12S)-12-fluoro-8,14-dioxa-4,10,19,20,23pentaazatetracyclo [13.5.2.1²’⁶.0^I8’²¹]tricosa1 (20),2(23),3,5,15,17,21 -heptaen-9-one	Scheme K
Example 172	(12R)-12-fluoro-8,14-dioxa-4,l 0,19,20,23pentaazatetracyclo [ 13.5.2.1^2,6.0 ’^8,21 ]tricosa1(20),2(23),3,5,15,17,21 -heptaen-9-one	Scheme K
Example'173	(12S)-l2-fluoro-8,l 4-dioxa-4,5,l 0,19,20,23hexaazatetracy clo[ 13.5.2.1^2,3.0^18,21 ]tricosa1 (20),2(23),3,15,17,21 -hexaen-9-one	Scheme O

461

Example 174	(12R)-l2-fluoro-8,l4-dioxa-4,5,10,19,20,23- hexaazatetracyclo[13.5.2.l²’⁵.0^l82l]tricosa1(20),2(23),3,15,17,2 l-hexaen-9-one	Scheme 0
Example 175	8', 14'-dioxa-l O'JQ'^O'-triazaspirofcyclopropanel,I3'-tetracyclo[13.5.2.1²’⁶.0^,8’^2l]tricosane]-r(20'), 2'(23'),3',5', 15’(22‘), 16',18'(2 l’)-heptaen-9'-one	Synthesis described in details

462

PHARMACOLOGICAL STUDY

EXAMPLE A: LRRK2 Kinase Activity Assay

Protocol

LRRK2 Kinase reactions were carried out in 384-well white polystyrène plates in a final volume of 6 μΙ using ADP-Glo™ Kinase Assay kit (Promega Corp.). Compound and substrates (LRRKtide peptide and ATP) in assay buffer were first dispensed in wells. Kinase reaction was then started by the addition of human recombinant LRRK2 protein. After l h-incubation at 37°C, the enzymatic reaction was stopped by the addition of 6 μΐ of ADP-Glo Reagent-1 and an additional 40-minutes incubation at 23°C (residual ATP déplétion). A final 30-minutes incubation after !2gL reagent-2 addition (ADP to ATP conversion and luciferin/luciferase reaction) was performed before luminescent signal acquisition (EnVision™ multimode plate reader - PerkînElmer, Inc.). Data from 10 individual concentrations of tested compounds (N=2) were fitted (XLfit™ - ID Business Solutions Ltd) to deliver IC50S (compound concentration leading to 50% inhibition of reference enzymatic activity).

Compounds

The compounds are dissolved to 5 mM in DMSO. When needed, solutions are sonicated in a bath sonicator.

Table 2 provides the IC50 values of the compounds according to the invention, obtained using the above-mentioned kinase assay. Activities are represented as +++, ++ and +, having the following meanings:

+++ means IC50 < 10 nM ++ means 10 nM < IC50 < 100 nM + means 100 nM < IC50 < l μΜ.

463

Table 2

Example number	ICso LRRK2 wt ADP-Glo	Example number	IC₅₀ LRRK2 wt ADP-Glo
Example 1	+-H-	Example 89	+
Example 2	++	Example 90	+++
Example 3	+++	Example 91	+++
Example 4	+++	Example 92	l i i
Example 5	+++	Example 93	+++
Example 6	++	Example 94	+++
Example 7	+++	Example 95	+++
Example 8	+++	Example 96	+++
Example 9	+-H-	Example 97	-H—h
Example 10	+4—H	Example 98	+++
Example 11	+++	Example 99	-H—h
Example 12	+-H-	Example 100	+++
Example 13	+++	Example 101	+++
Example 14	-H-+	Example 102	+++
Example 15	+++	Example 103	“H—h
Example 16	+++	Example 104	++
Example 17	+++	Example 105	+++
Example 18	+++	Example 106	+++
Example 19	+++	Example 107	+++
Example 20	+++	Example 108	++
Example 21	+++	Example 109	+++
Example 22	+++	Example 110	+++
Example 23	+++	Example 1 11	++
Example 24	-H-	Example 112	++
Example 25	+++	Example 1 13	+-r+
Example 26	+++	Example 114	+++
Example 27	+++	Example 115	4-
Example 28	+++	Example 116	+++
Example 29	+++	Example 117	-H-+

464

Example 30	+++	Example 118	+
Example 31	+++	Example 119	++
Example 32	+++	Example I20	-t-
Example 33	+++	Example I2l	+
Example 34	+++	Example 122	+++
Example 35	+++	Example 123	+++
Example 36	4-++	Example 124	+++
Example 37	I I \|	Example 125	+++
Example 38	4-4-4-	Example 126	+-H
Example 39	+++	Example 127	+++
Example 40	+++	Example 128	4—1—r
Example 4I	+++	Example 129	+++
Example 42	4+4-	Example 130	++
Example 43	++	Example I3l	+++
Example 44	++4-	Example I32	+++
Example 45	+++	Example 133	4-++
Example 46	+++	Example 134	-H-+
Example 47	+4-4-	Example 135	+++
Example 48	+++	Example I36	+++
Example 49	++	Example 137	+++
Example 50	+++	Example 138	+++
Example 51	+++	Example 139	+++
Example 52	+++	Example I40	++
Example 53	++	Example I4l	+
Example 54	+++	Example 142	+++
Example 55	+++	Example 143	-1 \| \|
Example 56	+++	Example 144	+++
Example 57	+++	Example 145	_L
Example 58	+++	Example 146	+++
Example 59	+++	Example 147	4—1—H
Example 60	+++	Example 148	+++
Example 6!	+++	Example 149	+++
Example 62	4	Example 150	++

465

Example 63	+++	Example 151	+++
Example 64	+++	Example 152	+++
Example 65	++	Example 153	+++
Example 66	+++	Example 154	4'+
Example 67	+++	Example 155	+++
Example 68	+++	Example 156	+++
Example 69	+++	Example 157
Example 70	+++	Example 158	++
Example 71	+++	Example 159	+++
Example 72	+++	Example 160	+++
Example 73	+++	Example 161	+4-
Example 74	+++	Example 162	4—1—H
Example 75	+++	Example 163	+++
Example 76	+++	Example 164	+++
Example 77	+++	Example 165	+4—h
Example 78	+++	Example 166	4-4-4-
Example 79	+++	Example 167	4-++
Example 80	+++	Example 168	++4
Example 81	+++	Example 169	+4—H
Example 82	+++	Example 170	+++
Example 83	+++	Example 171	-H-4-
Example 84	++	Example 172	H—h+
Example 85	+4-	Example 173	+++
Example 86	+++	Example 174	+++
Example 87	+++	Example 175	-J-++
Example 88	4-+

466

EXAMPLE B: Pharmaceutical composition: Tablets

1000 tablets containing a dose of 5 mg of a compound selected from Examples l to 175.... 5 g

Wheat starch..........................................................................................................................20g

Maize starch..........................................................................................................................20g

Lactose..................................................................................................................................30g

Magnésium stéarate.................................................................................................................2g

Silica........................................................................................................................................Ig

Hydroxypropylcellulose..........................................................................................................2g

Claims

1. Compound of formula (I):

wherein:

♦ R represents a hydrogen atom, a halogen atom or an alkyl group, ♦ ZI, Z2, Z3, independently each represents a carbon or a nitrogen atom, it being understood that the 6-membered cycle containing Zl, Z2 and Z3 can hâve 0, 1 or 2 nitrogen atoms, ♦ -Xl- is absent or represents -O-, -S-, or -N(R’a)-, wherein R’a represents a hydrogen atom or an alkyl group, ♦ -X2- represents an alkanediyl group optionally substituted with one or more substituents, identical or different, selected from halogen atoms,polyhalogenoalkyl group, alkoxy group, hydroxy group, amino group, alkylamîno group, dialkylamino group and cyano group, it being understood that the carbon atom in the alpha position of -N(Ra), and the carbon atom in alpha position of -Xl- when -Xl- represents -O-, -S-, or -N(R’a)-, cannot be substituted withan oxygen or a nitrogen heteroatom, ♦ -X3- represents an alkanediyl group optionally substituted with one or more substituents, identical or different, selected from halogen atoms, polyhalogenoalkyl group, alkoxy group, hydroxy group, amino group, alkylamîno group, dialkylamino group, cyano group, cycloalkyl group and heterocycloalkyl group, it being understood that the carbon atom in alpha position of -O-, and the carbon atom in alpha position of Al when Al represents a nitrogen atom, cannot be substituted

468 with an oxygen or a nitrogen heteroatom, ♦ Ra represents a hydrogen atom or an alkyl group, it being understood that when Ra represents an alkyl group, one carbon atom of Ra can be linked to a carbon atom of -X2-, or to a carbon atom of -X3- to form a cyclic moiety containing 5 or 6 ring-members, ♦ A represents

- an aromatic or partially hydrogenated cyclic group of the formula (a):

*

A1 — A2 / a\

A5 _χΑ3 (a) ^A4 /

wherein

V Al, A4 each independently represents a carbon atom or a nitrogen atom,

C PCI, A3, A5 each independently represents a carbon atom, an oxygen atom, a sulfur atom or a nitrogen atom, it being understood that Al, A2, A3, A4 and A5 cannot simultaneously represent a heteroatom,

- or an aromaticor partially hydrogenated cyclic group of the formula (b):

(b) wherein ΑΊ, 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 linked to X3, the aromatic or partially hydrogenated cyclic group A such definedbeing optionally substituted with one or more substituents, identical or different, selected from halogen atoms, alkyl group, alkoxy group, hydroxy group, oxo group, alkoxyalkyl group, alkoxyalkoxy group,polyhalogeno alkyl group, polyhalogenoalkoxy group, heterocycloalkyl group, heterocyclo alkyl alkyl group, (alkoxyalkyl )(alkyl)amîno group, amino group, alkylamino group, dialkylamino group, cycloalkyl group,

469 (heterocycloalkyl )( alkyl )ami no group, di alkyl aminoalkyl group, heterocycloalkylalkoxy group, cyano group and cyanoalkyl group, wherein the heterocycloalkyl and cycloalkyl group such defined can be optionally substituted by one or more substituents chosen from alkyl group, halogen atoms, polyhalogenoalkyl group,polyhalogenoalkoxy group, alkoxy group, alkoxyalkyl group, hydroxy group, cyano group and oxo group, their enantiomers, dîastereoisomers, tautomers, racemic, hydrates, solvatés, N-oxide, isotopes, deuterated derivatives and addition salts thereof with a pharmaceutically acceptable acid or base.

2. Compound according to claim l, wherein R represents a hydrogen atom.

3. Compound according to claim 1, wherein R represents a halogen atom.

4. Compound according to any of claimsl to 3, wherein Zl, Z2 and Z3 represent simultaneously a carbon atom.

5. Compound according to any of claim 1 to 3, wherein one of Zl or Z2 represents a nitrogen atom and Z3 represents a carbon atom.

6. Compound according to any of claims 1 to 5, wherein -Xl - represents -O-.

7. Compound according to any of claims 1 to 6, wherein -X2- represents an alkanediyl group linear or branched having 2, 3,4 or 5 carbon atoms.

8. Compound according to claim 7, wherein -X2- represents -(CHi^-, -CH(CH₃)-(CH2)2, -CH2-CHF-CH2-, -CH2-CF2-CH2-, or -(CH₂)2-CH(CHj)-.

9. Compound according to any of claimsl to 8, wherein Ra is a hydrogen atom.

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

470

11. Compound according to claim 10, wherein -X3- represents -(CH₂)₂-, -CH₂- or

-CH(CH₃)-.

12. Compound according to any of claims 1 to 11, whereinA represents a group of formula (b):

(b) wherein A’1,A’2,A’3,A’4 and * are as defined in claim 1.

13. Compound according to claim 12, wherein A represents

such defined A groups being not substituted or optionally substituted.

14. Compound according to claim 12 wherein A represents a phenyl group.

15. Compound according to claim 12 wherein A represents a pyridinyl group.

16. Compound according to claim 12 wherein A represents a pyrazinyl group.

17. Compound according to any of claims 1 to 11, wherein A represents a group of formula (a):

471

(a) wherein Al, A2, A3, A4, A5 and * are as defined in claim l.

18. Compound according to claim 17, wherein A represents

such defined A groups being not substituted or optionally substituted.

19. Compound according to claim 17 wherein A represents a triazolyl group.

10

20. Compound according to claim 17 wherein A represents a pyrazolyl group.

21. Compound according to any of claims 12 to 20, wherein A is not substituted.

22. Compound according to any of daims 12 to 20, wherein A is substituted with one or 15 more groups chosen from halogen atoms, cyano group, cyanoalkyl group, oxo group, alkoxy group, alkyl group, cycloalkyl group and heterocycloalkyl group.

23. Compound according to claim 1, which is compound of formula (I-a):

472

wherein Xl, X2, X3, Ra and A are as defined in claim l.

24. Compound according to claim 23, which is compound of formula (I-b):

wherein X2, X3, Ra and A are as defined in claim l.

25. Compound according to claim 23, which is compound of formula (l-c)or (I-c’):

wherein Xl, X2, X3, Ra, A’ l, A’2and A’4 are as defined in claim l.

473

26. Compound according to claim 23 or 25, which is compound of formula (l-d)or (I-d’):

wherein X2, X3, Ra,A’l,A’2and A’4 are as defined for fonnula (I).

5

27. Compound according to claim 23, which is compound of formula (I-e):

wherein XI, X2, X3, Ra, Al, A2 and A5 are as defined for fonnula (I).

28. Compound according to claim 23 or 27, which îs compound of fonnula ( l-f):

474

wherein X2, X3, Ra, Al, A2 and A5 are as defined for formula (I).

29. Compound according to claim 23, 25 or 27, wherein the -Xl-X2-N(Ra)-C(O)O-X3chain 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. Compounds according to claim l which are:

- 8,l4-dioxa-4,l0,l9,20-tetraazatetracyclo[l3.5.2.l³’⁶.0^l8'^2,]tricosa-l(20),2,4,6(23),l5 ,17,21 -heptaen-9-one;

- 10-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[ 13.5.2. l^2,6.0^18,21 Jtrîcosa-1(20),2 ,4, 6(23), 15,17,21 -heptaen-9-one;

- 4-fl uoro-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2. l^2,6.0¹⁸²¹ Jtrîcosa-1(20),2,4,6(2 3), 15,17,21-heptaen-9-one;

- 8,14-dioxa-I0,19,20,23-tetraazatetracyclo[13.5.2.1³’⁶.0¹⁸’^3lJtricosa-l(20),2,4,6(23),

15,17,21 -heptaen-9-one;

- 8,14-dioxa-l0,19,20-triazatetracyclo[I3.5.2.1²^0^ls'^2lJtricosa-l(20),2,4,6(23),l 5,17, 21 -heptaen-9-one;

- 10-(propan-2-yl)-8,14-dioxa-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;

- 8,14-dioxa-5,l0,19,20-tetraazatetracyclo[13.5.2.1²’⁶.0^l8’^2l]tricosa-l(20),2,4,6(23),

15,17,21 -heptaen-9-one;

475

- 4-methoxy-8,14-dioxa-l0,l9,20-triazatetracyclo[l3.5.2.l²⁶.0^l8’^2l]tricosa-i(20),2,4, 6(23 ), 15,17,21 -heptaen-9-one;

- 4-bromo-8,14-dioxa-10,19G0-tnazatetracycIo[ 13.5.2.+.0¹⁸²']tricosa-1(20),2,4,6( 23), 15,17,2 l-heptaen-9-one;

- 5-fluoro-8,I4-dioxa-10,l9,20-triazatetracyclo[13.5.2.1²'⁶.0¹⁸'^2I]tricosa-l(20),2,4,6(2 3), 15,17,21-heptaen-9-one;

- 5-methyl-8,l 4-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1^2,6.0^I8’^2l]tricosa-1(20), 2,4,6( 23), 15,17,21-heptaen-9-one;

- 4-(pyrrolidm-l-yl)-8,l 4-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1²'⁶.0^l821]tricosa-1( 20), 2,4,6(23), 15,17,21 -heptaen-9-one;

- 4-[4-(propan-2-yl)piperaziii-i-yl]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0 ^{1 8,21} ]tricosa-1 (20),2,4,6(23 ), 15, i 7,21 -heptaen-9-one;

- 4- {2-oxa-6-azaspiro[3.4]octan-6-yl }-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.1+0^IS+tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one;

- 4-[4-(oxetan-3-yl )pî perazin-1 -yl]-8,14-dioxa-l 0,19,20-triazatetracyclo[ 13.5.2.1²'⁶.0 ^!8+tricosa-l (20),2,4,6(23),15,17,2 l-heptaen-9-o^

- 4-(morpholin-4-yl)-8,l 4-dioxa-10,19,20-triazatetracycïo[ 13.5.2.1²'⁶.0¹⁸’^2l]tricosa-1( 20), 2,4,6(23), 15,17,21 -heptaen-9-one;

- 4-[(2R, 6S)-2,6-dimethylmorpholin-4-yl]-8,l 4-dioxa-l 0,19,20-triazatetracyclo [13.5.2.1²’+^l8+tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one;

- 4-methyl-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2. l+o^{18,2 l}]tricosa-1(20), 2,4,6( 23), 15,17,21 -heptaen-9-one;

- 5-methoxy-8,14-dioxa-10,l9,20-triazatetracycIo[13.5.2.l²’⁶.0^l8’^2l]tricosa-l(20),2,4, 6(23),15, 17,21-heptaen-9-one;

- 4-(4,4-difluoropiperidin- l-yl)-8,14-dioxa-10,l 9,20triazatetracyclo [ 13.5.2.1^{2 6}.0^{1 s}'²¹ ]tricosa-1(20) ,2,4,6(23),15,17,21 -heptaen-9-one;

- 4-(3,3-difluoropyrrolidin-I-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²°⁶.O^IS’^{2 1} ]tricosa-l (20),2,4,6(23), 15,17,2 l-heptaen-9-one;

- 7-inethyl-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2. l^2,6.0¹⁸’^2,]tricosa-1(20),2,4,6( 23),15,17,21 -heptaen-9-one;

- 4-[4-(2-methoxyethyl)piperidin-l -yl]-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2. i+0^18,21 ]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one;

476

- 9,14-dioxa-l 1,19,20-triazatetracyclo[l 3.5.2. l²'^ 0^l8’^2l]tricosa-l(20),2,4,6(23),15,1 7, 21 -heptaen-10-one;

- 4-[(3R)-3-hydroxypyrrolidin-l-yl]-8,14-dioxa-l 0,19,20-triazatetracyclo [13.5.2. l^2,6.0¹⁸'^2l]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one;

- 4-[(2-methoxyethyl)(methyl)amino]-8,l 4-dioxa-10,19,20-triazatetracyclo [13.5.2.1²’⁶.0^l8'^2l]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one;

- 4-chloro-8,14-dioxa-10,I9,20“triazatetracyclo[i 3.5.2.1²’⁶.0^{18,2 !}]tricosa-1(20),2,4,6(2 3), 15,17,21-heptaen-9-one;

- 4-fluoro-5-methyl-8,]4-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^,8’^2l]tricosa-l(2 0),2, 4,6(23),15,17,2 l-heptaen-9-one;

- 4,5-difluoro-8,14-dioxa-l0,19,20-triazatetracyclo[ 13.5.2. l²'⁶.0^18,21 ]tricosa-1(20),2,4 , 6(23), 15,17,21 -heptaen-9-one;

- 5-bromo-8,14-dioxa-10,19,20-triazatetracyclo [ 13.5.2.1^2,6.0^I8’^2,]tricosa-1 (20),2,4,6( 23),15,17,21 -heptaen-9-one;

- 4-(4-methylpiperazin-l-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹] tricosa-1 (20),2,4,6(23), 15,17,2 l-heptaen-9-one;

- 4-(3-methoxyazetidin-l-yl)-8,l 4-dioxa-10,19,20-triazatetracyclof 13.5.2.1²⁶.0¹⁸'²¹] tricosa-1 (20),2, 4,6(23), 15,17,21 -heptaen-9-one;

- l-[9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[I3.5.2.1²’⁶.0^l8’^2l]tricosa-l(20),2,4,6( 23 ), 15,17,21 -heptaen-4-yl} piperidme-4-carbonitrile;

- 4-[4-(pyrrolidîn-1 -yl)piperidtn-1 -yl j-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.1²’⁶.0¹⁸'²¹ Jtricosa-1(20),2,4,6(23), 15,17,21-heptaen-9-one;

- 4-(azetîdin-1-yl )-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1^.0^{18,2 l}]tricosa-1(20 ),2, 4,6(23),15,17,21-heptaen-9-one;

- 4-( piperidin-1-yl)-8,14-dioxa-l 0,19,20-triazatetracyclo[ 13.5.2.1²'⁶.θ'^8,2'jtricosa-1(2 0),2,4,6(23), 15,17,21 -heptaen-9-one;

- 4-(2,5-dihydrofuran-3-yl)-8,14-dioxa- 10,19,20-triazatetracyclof 13.5.2.1²⁶.0^{1 s 21} ]tric osa-1 (20),2,4,6(23),15,17,21 -heptaen-9-one;

- 4-[4-(morpholin-4-yl)piperidin-l-yl]-8,14-dioxa-l 0,19,20-triazatetracyclo [13.5.2. l²'⁶.0¹⁸’²¹]tricosa-l(20),2,4,6(23), 15,17,21-heptaen-9-one;

- 4-( 1 -methyl-1,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.l²⁶.0^s8·²¹] tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one;

477

- 4-[(2S,5S)-2,5-dimethylmorpholin-4-y]]-8,14-dioxa-10,19,20-triazatetracyclo [I 3.5.2.1²⁶.0^,s’²¹] tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one;

- 4-[(morpholin-4-yl)metliyl]-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1^2,6.0^18,21 ] tricosa-1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 4-[(pyrrolidin-1 -yl)methy 1 ]-8,14-dioxa-10,19,2 0- triazatetracyclo [ 13.5.2.1^.0^18,21] tricosa-1 (20),2,4,6(23),15,17,21 -heptaen-9-one;

4-[(pyrrolidin-l-yl)methyl]-8,14-dioxa-l 0,19,20-triazatetracyclo[ 13.5.2. l²’⁶.0’^8,2'] tricosa-1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 4-[(4-methylpiperazin-l-yl)methyl]-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.1²'⁶.0^l8'²¹]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one;

- 5-(morpholin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²'^û.0^,8'^2l]tricosa-l( 20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 4-[4-(2-methoxyethyl)piperazin-l-yl]-8,14-dioxa-10,19,20-triazatetracyclo [ 13.5.2.1²'⁶.0^l8~^,]tricosa-1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 4-( diethyl amino)-8,14-dioxa-10,19,20-triazatetracyc lof 13.5.2.1²’⁶.0^18,2 *] tricosa-1(20 ),2, 4,6(23), 15,17,21 -heptaen-9-one;

- 4-cyclopropyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^{18 21} ]tricosa-1(20),2 , 4,6(23), 15,17,2 l-heptaen-9-one;

- 5-(4-methylpiperazin-l-y 1)-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2. Ι^2Λ.0^18,21] tricosa-1(20),2,4,6(23),15,17,21 -heptaen-9-one;

- 13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^l8'^2l]tricosa-l(20),2,4,6 (23), 15,17,21-heptaen-9-one;

- 8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1²’⁵.0^l8,2l]tricosa-l(20),2(23),3, 15(22), 16,18(2 l)-hexaen-9-one;

- 4-[methyl(oxetan-3-yl)amino]-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²‘⁶.0^,8'²‘]tricosa-1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 4-[(dimethylamino)methyI]-S, 14-dioxa-10,19,20-triazatetracyclo [ 13.5.2.1^{2 6} o^1H ’²¹ ] tricosa-1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 4,10-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2. l²'⁶.0^18,2 ’jtricosa-l^O), 2 ,4, 6(23), 15,17,21 -heptaen-9-one;

- 4-(propan-2-yloxy)-8,14-dioxa-10,19,20-Îriazatetracyçlo[13.5.2.1²’⁶.0^l821]tricosa-l( 20),2,4,6(23), 15,17,21 -heptaen-9-one;

478

- 4-fluoro-7-i-nethyl-8,Î4-dioxa-]0,l9,20-triazatetracyclo[l3.5.2.l²’⁶.0^ls'^2l]tricosa-l(2 0),2,4,6(23), 15,17,21 -heptaen-9-one;

- 4-[1 -(oxetan-3-yi)-1,2,3,6-tetrahydropyridîn-4-yï]-8,1 4-dioxa-l 0,19,20-triazatetrac ycio[l 3.5.2.1^2,6.0^{! 8,2}’jtricosa-1(20),2,4,6(23), 15,17,21-heptaen-9-one;

5 - 4-(3-methylpiperidiïi-l-yl)-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;

- 4-[(3S)-3-hydroxypyrrolidin-1 -yl]-8,14-dioxa-10,19,20-triazatetracyclo [13.5.2.1²’⁶.0¹⁸’²¹ Jtricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one;

- 4-fluoro-8,14-dioxa-l0,19,20-triazapentacyclo[13.5.2.1²’⁶.l⁷’¹⁰.0¹⁸’^2l]tetracosa-l(20)

10 , 2(24),3,5,15(22), 16,18(21 )-heptaen-9-one;

- 4-(oxolan-3-yl)-8,14-dioxa-10,t9,20-triazatetracyclo[13.5.2.1²<0^l8’²¹]tricosa-l(20), 2,4,6(23), 15,17,21 -heptaen-9-one;

- (13S)-

15 13-methyl-8,l 4-dioxa-l 0,19,20-triazatetracyclo[ 13.5.2. l²’⁶.0¹⁸’²¹]tricosa-1(20),

2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- (13R)-

13-methyl-8,14-dioxa-l 0,19,20-triazatetracyclo[ 13.5.2. l²’⁶.0^18,21]tricosa-1(20), 2(23),3,5,15(22),16,18(21 )-heptaen-9-one;

20 - 4-(l-methyl-1 H-pyrazol-3-yl)-8,14-dioxa-l 0,19,20-triazatetracyclo[ 13.5.2.1^2,6.0^18,2’ ] tri cosa-l(20),2(23 ),3,5,15(22),16,18(21)-heptaen-9-one;

- (7S)-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²'⁶.0^l8'^2l]tricosa-l(20), 2(23),3,5,15(22),16,18(21 )-heptaen-9-one;

- 4-[2-(morpholin-4-yl)ethoxy]-8,i4-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0ⁱ⁸'²¹

25 ]tricosa-1(20),2(23),3,5,15(22), 16,18(2 l)-heptaen-9-one;

- 4-(2-methoxyethyl)-8,l 4-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1^2,6.θ’^8,21 ]tricosa-l( 20), 2(23), 3,5,15(22), 16,18(21)-heptaen-9-one;

- (7R)-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²'⁶.0^I8’²¹]tricosa-l(20), 2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

30 - 5-cyclopropyl-8,l 4-dioxa-10,19,20-tri azatetracyclo[ 13.5.2.1^2,6.θ'^8,2']tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 4-(2-methoxyethoxy)-8,l 4-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;

479

- 4-fluoro-l 3-methyl-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1²⁶.0^18,2 'jtricosa-1 ( 20), 2,4,6(23),15,17,21- heptaen-9-one;

- 11 -methyl-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1²’⁶.0¹⁸’²¹ Jtricosa-1 (20),2,4,6 (23), 15,17,21-heptaen-9-one;

- 4-(3-oxomorpholin-4-yi)-8,14-dioxa-10,19,20-triazatetracycIo[13.5.2.I²'⁶.0¹⁸'²'] tricosa-1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- 4-(2-oxopyrrolidin-l-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²'⁶.0^,8’²'j tricosa-1 (20),2(23),3,5,15(22), i 6,18(21 )-heptaen-9-one;

- 5-(2-oxopyrrolidin-l-yl)-8,14-dioxa-l0,19,20-triazatetracyclo[13.5.2.1²’⁶.0^I8'²'jtrico sa-1(20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- 4-(2-methylpyrroIidin-Î-yl)-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1^2:6.0^,8'²'j tricosa-1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- 2-{9-oxo-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²'⁶.0^I8'²¹]tricosa-l(20),2(23), 3,5,15(22), 16,18(21 )-heptaen-4-yl} acetonitrile;

- (1I R)-11-methyl-8,14-dioxa-l 0,19,20-triazatetracyclo[ 13.5.2.1²’⁶.0¹⁸'²¹ Jtricosa-1(20 ), 2(23),3,5,15(22),16,18(21 )-heptaen-9-one;

( 11 S)-l l-methyl-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1²’⁶.θ'^8,21 ]tricosa-1(20 ), 2(23),3,5,15(22),16,18(21 )-heptaen-9-one;

- 4-ethynyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0^l8'^2l]tricosa-l(20),2(23), 3,5,15(22), 16,18(21 )-heptaen-9-one;

- 4-(piperazin-1-yl)-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1²’⁶.0¹⁸’²¹ Jtricosa-1(2 0), 2(23 ),3,5,15(22),16,18(21 )-heptaen-9-one;

- 4-(l ,2,3,6-tetrahydropyridin-4-yl)-8,14-dioxa-10,19,20-triazatetracyclo

[ 13.5.2.1^2,6.θ'^8,21 Jtricosa-1(20),2(23 ),3,5,15(22), 16,18(21 )-heptaen-9-one;

- 11 -(methoxymethyl )-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2.1²’⁶.0^I8,2']tricosa-

1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- 8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1²’⁵.0'⁸'²'jtricosa-l(20),2(23),3, 15(22), 16,18(2 l)-hexaen-9-one;

- 11 -methyl-8,14-dioxa-4,5,10,19,2 0-pentaazatetracyclo[l 3.5.2. l²'⁵.0^18,2 'jtricosa-1(2 0), 2(23 ),3,15(22), 16,18(21 )-hexacn-9-one;

- 12-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0'⁸’²']tricosa-l(20),2(23 ),3,5, 15(22), 16,18(21 )-heptaen-9-one;

480

- I l-cthyl-8,l4-dioxa-10J9,20-triazatetracyclo[l3.5.2.l²’⁶.0^l8'²ⁱ]tricosa-l(20),2(23),3 ,5, 15(22), ] 6,18(21 )-heptaen-9-one;

- 4-fluoro-5,7-dimethyl-8,l4-dioxa-l0,I9,20-triazatetracyclo[l3.5.2.l²'⁶.0^l8’^2l]tricosa -l (20),2(23), 3,5,15(22), 16,l 8(21 )-heptaen-9-one;

- 4- fl uoro-5-methoxy-7-methyl -8,14-dioxa-10,19,2 O-triazatetracycl ο [13.5.2.1^2,6.0^18,21]tricosa-l (20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one;

- 5-fluoro-4,7-dimethyl-8,14-dioxa-10,19,20triazatetracyclo[ 13.5.2. l²<0^l8'^2l]tricosa-l(20),2(23),3,5,15(22), 16,18(2 l)-heptaen-9 -one;

- 8,14-dioxa-10,19,20-triazapentacyclo[13.5.2.1²^ l⁷'^w0^lvl]tetracosa-l(20),2(24),3, 5, 1 5(22), 16,18(21 )-heptaen-9-one;

- 13-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1²’⁶.0^IS’²¹]tricosa-l(20), 2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- 12-methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracycio[13.5.2.1²'⁵.0^l8'²¹]tricosa-l(2 0), 2(23),3,15(22),16,18(21 )-hexaen-9-one;

- 7-methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2. l²’⁵.0^l8’^2l]tri_COsa-l(20) , 2(23),3,15(22),16,18(21 )-hexaen-9-one;

- 5-fluoro-4-inethoxy-7-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0¹⁸’²¹]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

- (7R,13R)-7,13-dimethyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²'⁶.0^l8'²¹]trico sa-1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- (13R)-13-methyl-8,14-dioxa-4,5,10,19,20- pentaazatetracyclof 13.5.2.1^.0¹⁸'²¹] tricosa-1 (20),2(23),3,15,17,21-hexaen-9-one;

- 8,15-dioxa-4,10,20,21-tetraazapentacyclo[14.5.2.1²'⁶.l ^l°'^l3.0^l9'²²]pentac_OSa-1(21),2( 25), 3,5,16(23),17,19(22)-heptaen-9-one;

- 8,14-dioxa-5,10,19,20-tetraazatetracyclo[13.5.2.1^2,5.0¹⁸'^2I]tricosa-

1 (20),2(23),3,15(22),16,18(21 )-hexaen-9-one;

- (13S)-4-fluoro-13-methyI-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²'⁶.0ⁱ⁸'^2l]tric osa-1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- ( 13R)-4- fluoro-13 -meth yl-8,14-dioxa-10,19,20-triazatetracyclo[l 3.5.2. l^2,6.0^18,2tri cosa-1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

481

- (13R)-l3-methyl-8,l4-dioxa-4, ΙΟ, I9,20-tetraazatetracyclo[l 3.5.2. l^2,6.0^l8’^2l]tric_OSal (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- 6-cyclopropyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo) 13.5.2.1^2,5.θ'^8,2'jtricosaI (20), 2(23),3,15(22), 16,18(2 i )-hexaen-9-one;

5 - 7-ethyI-8,14-dioxa-10,19,20-triazatetracyclo)13.5.2.1²’⁶.0^l8’^2l]tricosa-I(20),2,4,6(23 ),15,17,21 -heptaen-9-one;

- (13R)-

13-ethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[ 13.5.2.1^2,6.0¹⁸'^2l]tricosa-1 (20 ),2,4,6(23), 15,17,2 l-heptaen-9-one;

10 - (7R,13R)-4-fluoro-

7,13-dimethyl-8,14-dioxa-l 0,19,20-triazatetracyclo) 13.5.2. l^2,6.0^18,21 Jtricosa-1(20),2 ,4,6(23), 15,17,21 -lieptaen-9-one;

- 7-methyI-8,14-dioxa-4,10,Î9,20-tetraazatetracyclo[13.5.2.1^2,6.0^i8,2,]iricosa-l(20),2, 4, 6(23 ),15,17,21 -heptaen-9-one;

15 - (7R)-4-fluoro7-methyl-8,14-dioxa-l 0,19,20-triazatetracyclo) 13.5.2. l^2,6.0¹⁸’²¹]tricosa-1(20),2,4,6( 23), 15,17,21 -heptaen-9-one;

- (7S)-4-fluoro-

7-methyl-8,14-dioxa-10,19,20-triazatetracyclo) 13.5.2.1²’⁶.θ’^8,21 ]tricosa-1(20), 2,4,6(

20 23), 15,17,21 -heptaen-9-one;

- 6-methyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo) 13.5.2. l^2,5.0^18,2i Jtricosa-1(20) , 2(23),3,15,17,21 -hexaen-9-one;

- 7-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[13.5.2.1²⁶.0^18,2'jtricosa-1(20),2 25 ,4, 6(23), 15,17,21 -heptaen-9-one;

- 6-(propan-2-yl)-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo) 13.5.2.1²^.0^,8’^2l]tricosa -1 (20),2(23),3,15(22),16,18(21 )-hexaen-9-one;

- (13R)-7,13-dimethyl-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo) 13.5.2.1^2,5.O¹⁸’²¹] tricosa-1 (20),2(23),3,15(22),16,18(2 i )-hexaen-9-one;

30 - ( 13R)-13-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo[ 13.5.2. l²‘⁶.0¹⁸²'jtricosa

-1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- (7R)-

7-ethyl-8,14-dioxa-10,19,20-Îriazatetracyclo[13.5.2.1²'⁶.0^l8'^2l]tricosa-l(20),2,4, 6(23),15, 17,21-heptaen-9-one;

482

- (7S)-

7-ethyl-8,l4-dioxa-10,19,20-triazatetracyclo[l 3.5.2. l^2,6.0^18,21 ]tricosa-1(20),2,4, 6(23), 15,17,21 -heptaen-9-one;

- (13R)-13-methyl-8,14-dioxa-5,I0,19,20-tetraazatetracyclo[13.5.2.1²'⁶.0^,s'²¹]tricosa1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 6-(oxan-4-yl)-8,14-dioxa-4,5,10,19,20-pentaazatetracyclo[13.5.2.1²’⁵.0^ls'^2l]tricosa-l (20),2(23),3,15,17,21 -hexaen-9-one;

- 4-ethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1²’⁵.0¹⁸’^2l]tricosa-l(20), 2(23), 15,17,21-pentaen-9-one;

- (13R)-23-tluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1^2,6.0¹⁸'²¹] tricosa-1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 9,14-di oxa-4,5,l l, 19,20-pentaazatetracyclo[ 13.5.2.1²^^18,21 ]tricosa-1(20),2(23), 3,15,1 7,21-hexaen-10-one;

- 4-ethyi-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[13.5.2.1²’⁵.0^î8’^2l]tricosa-l(20), 2(23),3,15,17,2 l-hexaen-9-one;

- 3,9,15- trioxa-4,l l,20,21-tetraazatetracyclo[14.5.2.1²’⁵.0^l9’²²]tetracosa-l(21),2(24), 4,16,18,22-hexaen-10-one;

- (13R)-16-fluoro-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[13.5.2.1²‘⁶.0^{18, 2} ']tricosa-l (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- (13R)-4-chloro-13-methyï-8,14-dioxa-10,19,20,23-tetraazatetracyclo[I3.5.2.1^2t6.0¹⁸' ² ^tricosa-1(20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one;

- 8,14-dioxa-2,4,10,19,20-pentaazatetracyclo[13.5.2.1²'⁵.0¹⁸’²']tricosa-l(20),3,5(23), 15(22), 16,18(21)-hexaen-9-one;

- ( 13R)-4-methoxy-l 3-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo [13.5.2. l^2,6.0^l82l]tricosa-1(20),2,4,6(23),15,17,21-heptaen-9-one;

- (13R)-13-methyl-9-oxo-8,l 4-dioxa-10,19,20-triazatetracyclo[13.5.2.1^2,6.θ'^8,21 ]tricos a-1(20),2,4,6(23),15,17,21-heptaene-5-carbonitrile;

- (13R)-13-methyl-4-(pyrrolidin-l-yi)-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo [13.5.2.1²’⁶.0^l8’^2,]tricosa-l(20),2,4,6(23),15,17,21-heptaen-9-one;

- (7S,13R)-7,13-dimethyl-8,14-dioxa-5,10,19,20,23-penÎaazatetracyclo[13.5.2.1²’⁶.0¹ ^{8 ,2} ’]Îricosa-1(20),2,4,6(23),15,17,21 -heptaen-9-one;

483

- (7R,13R)-7,13-dimethyl-8,14-dioxa-5,10,19,20,23-pentaazatetracyclo[l 3.5.2.1²'⁶.0^{1 821} ]tricosa-l (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- ( 13R)-16-fluoro- 13-methyl-8,14-dioxa-10,19,2Ü-triazatetracyclo[ 13.5.2. l²⁶.0¹⁸'²¹] tricosa-1 (20),2,4,6(23),15,17,21 -heptaen-9-one;

- (13R)-13-inethyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1²'⁶.0^I8’^2l]tric osa-1 (20),2,4,6(23), 15,17,21 -heptaen-9-one;

- 8,14-dioxa-4-thîa-IÜ,19,20,23-tctraazatetracyclo[ 13.5.2. l^2,5.Oⁱ⁸'²¹]tricosa-1(20),2,5( 23),15,17,21 -hexaen-9-one;

- 8,14-dioxa-3-thia-I0,19,20,23-tetraazatetracyclo[13.5.2.1²'⁵.0¹⁸'²¹]tricosa-l(20),2(2 3),4,15,17,21 -hexaen-9-one;

- (7R, 13R)-7,13-dimethyl-8_} 14-dioxa-10,19,20,23-tetraazatetracyclo[ 13.5.2.1²’⁶.O¹⁸²¹]tricosa-1 (20),2,4,6(23),15,17,21 -heptaen-9-one;

- (13R)-4-[(3R)-3-methoxypyrrolidin-I-yl]-13-methyl-8J4-dioxa-5,10,19,20,23pentaazatetracyclo[13.5.2.1²'⁶.0¹⁸²¹]tricosa-l(20),2,4,6(23),15,17,21 -heptaen-9-one;

- (13R)-16-chloro-13-methyl-8,14-dioxa-10,I9,20-triazatetracyclo[ 13.5.2.1^2,6^^{18 2I}] tricosa-1(20),2, 4,6(23),15,17,21 -heptaen-9-one;

- (13R)-13,16-dimethyl-S, 14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²'⁶.0^!8,2I]tricosa

- 1 (20),2,4, 6(23), i 5,17,21 -hcptaen-9-one;

- ( 13R)-13-methyl-8,14-dioxa-3,l 0,19,20,23-pentaazatetracyclo[l 3.5.2. l^2,6.0^18,21 ] tricosa-1(20),2,4,6(23),15,17,21 -heptaen-9-one;

- 8-oxa-10,14,19,20-tetraazatetracyclo[13.5.2.1^2,6.0¹⁸'²']tricosa-l(20),2(23),3,5,15(22 ),16,18(21 )-heptaen-9-one hydrochloride;

- 8-oxa-10,19,20-triazatetracyclo[ 13.5.2. l²’⁶.0'^{82 !}]tricosa-1(20),2(23 ),3,5,15(22), 16,

18(21 )-heptaen-9-one;

- (13R)-5-mcthoxy-13-methyl-8,14-dioxa-4,10_sI9,20-tetraazatetracyclo

[ 13.5.2. l²'⁶.0^18,2l]tricosa-1(20),2,4,6(23),15,17,21 -heptaen-9-one;

- (13R)-13-methyl-8,14-dioxa-4,10,19,20-tetraazatetracyclo[l 3.5.2. 1²'⁶.θ’⁸²¹ ]tricosa1 (20),2, 6(23),15,17,21 -hexaene-5,9-dione;

- 4-methyl-8,14-dioxa-3,4,10,19,20-pentaazatetracyclo[13.5.2.1²’⁵.0¹⁸’^2l]tricosa-l(20) ,2, 5(23), 15(22), 16,18(21 )-hexaen-9-one;

- ( 13R)-16-tluoro-13-methyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo [13.5.2. l^2,6.0^l8,21]tricosa-1(20),2,4,6(23), 15,17,21-heptaen-9-one;

484

- 7,13-di oxa-4-thia-9,l 8,19,22-îetraazatetracyclo[l 2.5.2.1^.0^^000(^-1( 19),2,5(2 2), 14(21 ), 15,17(20)-hexaen-8-one;

- (ΐ3R)-4,13-dimethyl-8,14-dioxa-5,10,ï9,20,23-pentaazatetracyclo[13.5.2.1²’⁶.0^,8'^2l] trîcosa-1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- 8,14-dioxa-23-thia-4,10,19,20-tetraazatetracyclo[13.5.2.1²'⁵.0^!8'^2l]tricosa-l(20),2,4, 1 5(22), 16,18(21 )-hexaen-9-one;

- (7S,13R)-7,13-dimethyl-8,14-dioxa-10,19,20,23-tetraazatetracyclo [13.5.2. l²’⁶.O^l8'^2l]tricosa-1(20),2(23), 3,5,15(22), 16,18(21 )-heptaen-9-one;

- (13R)-13-methyl-9-oxo-8,14-dioxa-5,l 0,19,20-tetraazatetracyclo[ 13.5.2.1^2-5.0¹⁸'²¹] trîcosa-1(20), 2(23),3,15(22), 16,18(21 )-hexaene-4-carbonitrile;

- 12,12-difluoro-8,14-dioxa-l0J9,20-triazatetracycio[13.5.2.1²’⁶.0^IÎi’^2l]tricosa-l(20), 2(23), 3,5,15(22), 16,18(21 )-heptaen-9-one;

- (13R)-17-iluoro-13-methyl-8,14-dioxa-10,19,20-triazatetracyclo[13.5.2.1²’⁶.0¹⁸'²¹] trîcosa-1 (20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one;

- (7S, 13R)-7,13-dimcthyl-8,14-dioxa-4,l 0,19,20,23-pentaazatetracyclo [13.5.2.1^2-6.0¹⁸’^2l]tricosa-1(20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one;

- (7R, 13R)-7,13-dîmethyl-8,l 4-dioxa-4,10,19,20,23-pentaazatetracyclo [13.5.2.1²<0¹⁸'^2,]tricosa-l(20),2(23),3,5,15(22),16,18(21)-heptaen-9-one;

- ( 13 S )-13 -methyl-8,14-di oxa-4,10,19,20,23- pentaazatetracyclo [ 13.5.2. i ^2,6.0^18,21 ] tri c osa-1(20),2(23 ),3,5,15(22), 16,18(21 )-heptaen-9-one;

- (l3R)-13-methyl-8,14-dioxa-l0,19,20,22-tetraazatetracycIo[13.5.2.1²’⁶.0^l8-21]tricosa -1(20), 2(23),3,5,15,17,21-heptaen-9-one ;

- (12R)-4,12-dimethyl-7,13-dioxa-4,9,18,19,22-pentaazatetracyclo[I2.5.2.1²’⁵.0¹⁷’²°]d ocosa-1 (19),2,5(22),14(21 ), 15,17(20)-hexaen-8-one;

- (13R)-13-methyl-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[l 3.5.2. l^2,5.O^!8’^2l]tri cosa-1(20),2(23),3,15,17,21 -hexaen-9-one;

- (13R)-13-methyl-8,14-dioxa-23-thîa-4,10,19,20-tetraazatetracyclo[ 13.5.2.1²Αθ^18,21 ] trîcosa-1(20),2,4,15,17,21 -hexaen-9-one ;

- (l3R)-4,13-dimethyl-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[Î3.5.2.1^2,s.0’⁸’²¹] trîcosa-1 (20),2,5(23),15(22), 16, i 8(21 )-hexaen-9-one;

485

- (13 R)-13-methy]-8,14-dioxa-10,16,19,20-tetraazatetracyclo[l 3.5.2. l^2,6.0^18,21 Jtrîcosa -I (20),2(23),3,5,15(22),16,18(21 )-heptaen-9-one;

- 14-methyl-8-oxa-10,14J9,20-tetraazatetracyclo[I3.5.2.1²⁶.0¹⁸’²¹]tricosa-l(20),2(23 ),3,5, 15,17,21-heptaen-9-one;

- (13R)-13-methyl-8,14-dioxa-4,l 0,19,20,22-pentaazatetracyclo[ 13.5.2. l²’⁶.0¹⁸²¹ ]tric osa-1 (20),2(23),3,5,15, ] 7,21 -heptaen-9-one;

- (13R)-13-methyl-8,14-dioxa-10,17,19,20-tetraazatetracyclo [13.5.2.1^2,6.0¹⁸'²¹ Jtrîcosa

- 1 (20),2(23),3,5,15(22), ] 6,18(21 )-heptaen-9-one;

- 8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2.1²’⁵.0^,8'^2lJtricosa-l(20),2(23), 3, 15(22), 16,18(21 )-hexaen-9-one;

- 12,12-difluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[13.5.2. l^2,5.0^,8'^2l]trico sa-1 (20),2(23),3,15(22),16,18(21 )-hexaen-9-one;

- ( 12R)-12-fluoro-8,14-dioxa-10,19,20-triazatetracyclo[l 3.5.2.1²’⁶.0¹⁸’²¹ Jtrîcosa-1(20) ,2(23), 3,5,15(22),16,18(21 )-heptaen-9-one;

- ( 12S)-12-fl uoro-8,14-dioxa-10,19,20-triazatetracyclo[ 13.5.2. l^2,6.0¹⁸:²¹ Jtrîcosa-1(20) ,2(23), 3,5,15(22), 16,18(21 )-heptaen-9-one;

- I2,12-difluoro-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[13.5.2.1²'^&.0^t82l]tricos a-1 (20),2(23),3,5,15(22), 16,18(21 )-heptaen-9-one;

- (12S)-12-fluoro-8,14-dioxa-4,10,19,20,23-pentaazatetracyclo[ 13.5.2.1^2,6.0'^8,21 ]trico sa-1 (20),2(23),3,5,15,17,2 l-heptaen-9-one;

- ( 12 R) -12- fluoro- 8,14-dioxa-4,10,19,20,23 -pentaazatetracyclo [ 13.5.2.1^2,6.0^18,21J tri co sa-1 (20),2(23),3,5,15,17,21 -heptaen-9-one;

- (12S)-12-fluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[l 3.5.2.1²’⁵.0^18,21 ]tric osa- ] (20),2(23),3,15,17,21 -hexaen-9-one;

- ( 12R)-12-fluoro-8,14-dioxa-4,5,10,19,20,23-hexaazatetracyclo[l 3.5.2. l^2,5.0^18,21 ]tric osa-1 (20),2(23),3,15,17,21 -hexaen-9-one;

- S'Jd'-dioxa-lOUÇ'^O'-triazaspiroCcyclopropane-IJS'-tetracyclofB.S^.l+o¹⁸’²¹] tricosane]-l Χ20'),2Χ23'),3',5’,15'(22'}, 16’, 18'(21 ’)-heptaen-9’-one.

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

486

32. 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.

33. Pharmaceutical composition for use according to claim 33 wherein the neurological disease is selected from Parkinson’s disease, Alzheimer s disease, amyotrophie latéral sclerosis (ALS), démenti a,diabetic neuropathy, âge related memory disfunctîon, mild cognitive impairment, argyrophilic grain disease, Pick’s disease,epilepsy, tauopathies includingprogressîve supranuciear palsy and corticobasal degeneration, other synucleinopathiesincluding multiple system atrophy, frontotemporal dementia, inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), withdrawal symptoms/relapse associated with drug addiction, L-Dopa induced dyskinesia, ischémie stroke, traumatic brain injury, spinal cord injury and multiple sclerosis.

34. Phannaceutîcal composition for use according to claim 34 for use in the treatment of Parkinson’s disease or Alzheimer’s disease.

35. Pharmaceutical composition for use according to claim 33 wherein the endosomallysosomal disorder is selected from Niemann-Pick TypeA, B or C disease, Gaucher’s disease, Krabbe’s disease, Fabry’s disease and disorders with mitochondrial déficits.

36. Pharmaceutical composition for use according to claim 33 wherein the inflammatory disease is selected from vasculitis, pulmonary diseases including chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, inflammatory myopathies, ankylosing spondylitis.

37. Pharmaceutica] composition for use according to claim 33 wherein autoimmune disease is selected from Crohn’s disease, inflammatory bowel disease, rheumatoid arthritis, ulcerative colitis, lupus, autoimmune hemolytic anémia, pure red cell aplasia, idiopathic thrombocytopénie purpura,type I diabètes mellitus, obesity, Evans syndrome, bullous skin disorders, Sjogren’s syndrome, Devic’s disease and leprosy.

487

38. Phannaceutical composition for use according to claim 33 wherein cancer is selected from thyroid cancer, rénal cancer, breast cancer, honnone-related cancer, adeno-and squamous lung cancer, non-small-cell lung cancer, colon cancer, prostate cancers, skin cancers, leukemias and lymphomas.

39. Phannaceutical composition for use according to claim 33 wherein cardiovascular disease is stroke.

40. Pharmaceutical composition for use according to claim 33 wherein bacterial or viral infections are selected from leprosy, tuberculosis, SARS-CoV, MERS-CoV and SARS-CoV-2, HIV, West Nile virus and chikungunya virus.

41. Compound of formula (I) according to any one of claims 1 to 30, or an addition sait thereof with a pharmaceutically acceptable acid or base, for use m the treatment of Parkinson’s disease, Alzheimer’s disease, amyotrophie latéral sclerosis (ALS), dementia,diabetic neuropathy, âge related memory dîsfunction, mild cognitive impairment, argyrophilic grain disease, Pick’s disease,epilepsy, tauopathies including progressive supranuclear palsy and corticobasal degeneration, other synucleinopathies, frontotemporal dementia, inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-I7), withdrawal symptoms/ relapse associated with drug addiction, L-Dopa induced dyskinesia, ischémie stroke, traumatic brain injury, spinal cord injury, multiple sclerosis, Niemann-Pick TypeA, B or C disease, Gaucher’s disease, Krabbe’s disease, Fabry’s disease, disorders with mitochondrial déficits, Crohn’s disease, înflammatory bowel disease, rheumatoid arthritîs, ulcerative colitis, lupus, autoimmune hemolytic anémia, pure red cell aplasia, idiopathic thrombocytopénie purpura,type I diabètes mellitus, obesity, Evans syndrome, bullous skin disorders, Sjogren’s syndrome, Devic’s disease, leprosy, thyroid cancer, rénal cancer (including papillary rénal), breast cancer, hormone-related cancer, adeno-and squamous lung cancer, non-small-cell lung cancer, colon cancer, prostate cancers, skin cancers, leukemias (including acute myelogenous leukemia), lymphomas, stroke, leprosy, tuberculosis, and SARS-CoV, MERS-CoV, SARS-CoV-2, HIV, West Nile virus and chikungunya virus infections.